The Versatile and Strategic O-Carbamate Directed Metalation Group in the Synthesis of Aromatic Molecules: An Update

Abstract

The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry, especially in the form Ar-OCONEt₂. Since the last comprehensive review of metalation chemistry involving ArOAms (published more than 30 years ago), the field has expanded significantly. For example, it now encompasses new substrates, solvent systems, and metalating agents, while conditions have been developed enabling metalation of ArOAm to be conducted in a green and sustainable manner. The ArOAm group has also proven to be effective in the anionic ortho-Fries (AoF) rearrangement, Directed remote metalation (DreM), iterative DoM sequences, and DoM-halogen dance (HalD) synthetic strategies and has been transformed into a diverse range of functionalities and coupled with various groups through a range of cross-coupling (CC) strategies. Of ultimate value, the ArOAm group has demonstrated utility in the synthesis of a diverse range of bioactive and polycyclic aromatic compounds for various applications.

1. Introduction

1.1. The Aryl O-Carbamate (ArOAm): Significance of the Functional Group

1.1.1. History of the Carbamate Group

The O-carbamate group, −OCONR₂ (R = H or alkyl group), a salt or ester derived from carbamic acid, received its christening in 1845 with Wohler’s formulation of ethyl carbamate, a product of the reaction between urea with ethanol.¹ While the carbamate is now a common functional group,² its natural origins arose with the discovery of physostigmine (1), isolated from the calabar bean (Physostigma venenosum) of the Ivory Coast (Figure 1).³ Physostigmine holds a compelling folklore as a truth serum⁴ and more recently was found to show reversible acetyl cholinesterase (AChE) inhibition with an application toward treating glaucoma.⁵ Undoubtedly because of its AChE inhibitor activity and proteolytic stability, the carbamate group has been incorporated into a number of pesticide products and entered medicinal chemistry programs.⁶ The main action of these carbamate derivatives serves to inhibit the AChE enzyme by overstimulation of the nervous system.⁵

Figure 1.

O-carbamate functional group in pesticides and drugs 1–8.

1.1.2. Carbamates in Agriculture and Medicine

The first commercial carbamate product, Carbaryl (2), was introduced in 1956 and became the largest selling insecticide worldwide compared to all other carbamates combined (Figure 1).⁷ Unfortunately, the viewpoint of carbamate pesticides such as Carbaryl (2), Isoprocarb (3), and Carbofuran (4) received infamy as a result of the Bhopal pesticide plant tragedy in 1983.⁸

Presently, the bioactive significance of carbamates in drug design is evident in medications such as Rivastigmine (5),⁶ Irinotecan (6),⁶ Ritonavir (7),⁶ and Danoprevir (8). Danoprevir was found to be preferable as a treatment for COVID-19⁹ compared with Lopinavir/Ritonavir.¹⁰ These few examples are representative of a vast library of compounds. We refer the readers to two recent comprehensive reviews of pharmaceutical compounds containing organic carbamates.^6,11

Traditionally, ArOAms have been prepared from the reaction of alcohols with toxic phosgene (or its derivatives), followed by treatment of the resulting phenyl carbonochloridates with amines.¹² In more recent times, CO₂ as a “nontoxic, renewable, and easily available C1 reagent”¹³ has been studied as a replacement for phosgene in this synthetic process.¹⁴⁻¹⁶ Building on growing interest in the synthesis of ArOAm, this review focuses on the utilization of OAm as a directed metalation group (DMG) in DoM and other metalation chemistry.

1.2. The Advent of the ArOAm in Directed ortho Metalation (DoM) Chemistry

In 1983, as part of early studies of the DoM reaction, the Snieckus’ group serendipitously discovered the ArOAm to serve as a directed metalation group (DMG).¹⁷ As DoM became more popular for the construction of polysubstituted aromatic molecules, a hierarchy of relative “DMG power” was established for O-based DMGs (see section 2, Table 1). Accordingly, the ArOAm DMG, especially as OCONEt₂, demonstrated the greatest relative DMG power according to inter- and intramolecular competition studies.¹⁸ In these experiments, two DMG substrates and two DMGs on the same substrate, respectively, competed for 1 equiv of base, followed by quenching with a deuterium source (typically MeOD). Although the discovery of the ArOAm anionic ortho-Fries (AoF) rearrangement¹⁷ and the directed remote metalation (DreM) reaction¹⁹ fuelled interest in this functional group, this was initially somewhat dampened by the resistance of the ArOAm system to hydrolysis, a problem subsequently overcome via base-catalyzed hydrolysis (to phenols)¹⁷ and various cross-coupling (CC) strategies²⁰ (see section 8).

Table 1. Hierarchy of Some O-Based DMGs in DoM^a.

^aAdapted with permission from ref (85). Copyright 2018 John Wiley and Sons.

1.3. Aims of This Review

In this review, we aim to update the literature related to DoM and AoF chemistry of the aryl O-carbamate (ArOAm) system since our previous comprehensive review in 1990²¹ and fragmentary appraisals thereafter.^22,23 For a deeper discussion of AoF, we recommend Korb’s 2019 review.²⁴

Following a general overview of the DoM reaction, the function and applications of the O-carbamate DMGs will be discussed with the inclusion of work from other research laboratories and highlights of preceding reviews.^22,23 The contextual value of the OAm DMG will be refreshed alongside a comparison with other oxygen-based DMGs (e.g., OMe, OMOM). Furthermore, recent applications from our work and those of other research groups will be provided.

2. Directed ortho Metalation (DoM) Chemistry

2.1. Background: DoM History

In 1939–1940, the DoM reaction of anisole was independently discovered by Gilman²⁵ and Wittig.²⁶ Then, in the 1940–60 period, the breadth of DMG reactions was studied and expanded by the work of Puterbaugh (N-methylbenzamide),²⁷ Shirley (indoles and phenoxathiine oxides),^28,29 Wittig (substituted anisoles),^26,30,31 Morton (cumene),³² and Gilman (aryl sulfides, naphthalenes, dibenzothiophene, and fluorene),³³⁻³⁵ further accelerating the field of synthetic organolithium chemistry. Additional development of the DoM reaction thereafter was strongly motivated by the contributions of Beak, Christensen, Meyers, and Parham,^22,36 among others.

The DoM process is well documented.²¹ A general regioselective DoM process (Scheme 1) involves treatment of a DMG bearing substrate 9 with a strong base, typically an alkyl lithium (represented as RLi) or lithium amide base (LiNR₂)_n at cryogenic temperatures (−78 °C). Coordination of the base as an aggregate to the heteroatom-containing DMG occurs and deprotonation leads to ortho-lithiated species 10. Upon treatment with an electrophilic reagent, this species in turn yields a 1,2-disubstituted product 11.

Scheme 1. General DoM Reaction.

2.2. The DoM Reaction: Mechanism

The mechanism of DoM is not entirely understood and is controversial due to several considerable shortcomings in its mechanistic picture. The first main point of dispute involves the formation^37,38 (or not^19,39) of intermediate complexes as a step preceding the accepted rate-determining deprotonation.^40,41 Further mechanistic concerns involve the determination of the actual existing structure of such complexes,⁴² the described mechanism of activation of the abstracted ortho H atoms,⁴³⁻⁴⁷ and the ambiguous role displayed by TMEDA in comparison with other common donor additives/solvents (e.g., ethers).⁴⁸⁻⁵⁰ As a result, two conflicting perspectives of the mechanism of DoM mechanism have been proposed: the complex-induced proximity effect (CIPE)⁵¹ and the kinetically enhanced metalation (KEM).⁵²

The viewpoint of CIPE in deprotonation reactions follows the mechanisms which underlie carbanion chemistry. CIPE encompasses the idea that a momentarily bound species can promote a chemical reaction. Generally, the phenomenon of CIPE involves carbanion development by organolithium bases where the formation of a prelithiation complex gathers reactive groups into the same vicinity for a focused deprotonation reaction (Scheme 2a).⁵¹

Scheme 2. (a) General CIPE Concept (Adapted with Permission from ref (53), Copyright 2016 John Wiley and Sons); (b) Schleyer’s KEM Mechanism for ortho-Lithiation of Anisole with n-BuLi (Adapted from ref (52), Copyright 1989 American Chemical Society)^{17,18,26,31,37,85−119}.

The CIPE concept is qualitatively outlined for a DoM reaction as follows. Treatment of 9 with an organolithium reagent affords the complex 12. Consequent directed lithiation of 12 through the transition state 13 leads to 10, which, when treated with an electrophile, gives the disubstituted product 11. CIPE has been considered in cases involved with deprotonative mono- and dilithiations, heteroatom–lithium exchanges, displacements, and additions.^{42,47,54−56} CIPE may also be suggested to govern the regioselectivity of DoM reactions by modifying the balance of inductive and association effects.^51,57

Solid-state and solution studies provide circumstantial support for complexation preceding the deprotonation reaction. Stable organolithium compounds are well-established as highly aggregated and associated with ligands.⁵⁸⁻⁶² The stabilization can be accredited based on a favorable binding energy between the positive charge of the lithium atom and the negative charge of the carbanion or the electron pair of a Lewis base in intermolecular and/or intramolecular interactions. Supportive data for the complexation of lithium–electron pair in ground states has been provided by X-ray crystallographic structures.⁶³ Furthermore, HF and DFT ab initio calculations by Saá⁶⁴ provide theoretical evidence for the requirement of precomplexation, either associative or dissociative, and thus offer additional inferred support for CIPE mechanism of ortho-lithiation.

The early Li NMR studies based on HOESY and MNDO calculations by Bauer and Schleyer⁵² offer contrasting mechanistic evidence for the formation of structure 10, represented by 18 in Scheme 2b. The results revealed that the ortho-lithiation of anisole encompassed an unreactive complex between “free” anisole and n-BuLi, exhibiting Li–H interaction, detected by HOESY. In a toluene solution at −64 °C, anisole and n-BuLi exist as a tetrameric aggregate 14. The addition of 1 equiv of TMEDA produces the 1:1 n-BuLi-TMEDA dimer 15 and “free” anisole (no HOESY anisole–Li interactions), which does not undergo ortho-lithiation. It appears that this n-BuLi·anisole complex 15 is seemingly uninvolved in the reaction. Exchange of one of the two coordination sites on species 15 (via 16) by coordination of anisole leads to species 17 with oxygen agostic Li–H interactions. Irreversible deprotonation in turn gives ortho-lithiated species 18 (representative of 10) and 1:1 n-BuLi-TMEDA species 19, which can both undergo reaggregation. Therefore, in addition to CIPE, the kinetic (Li bears more than one available coordinating site) and thermodynamic (coordination of a heteroatom ortho to Li) aspects seem noteworthy mechanistic considerations of the DoM process for the OMe DMG.

2.2.1. CIPE vs Schleyer’s KEM

Both CIPE and Schleyer’s KEM mechanisms agree that proton transfer is the rate-determining step. The major difference between the two reaction pathways centers on whether a complex forms prior to proton transfer. In the case of CIPE, studies of intramolecular versus intermolecular isotope effects rule out a one-step process;⁶⁵ i.e., CIPE postulates a complex as an intermediate along the reaction pathway whereas KEM does not.⁵¹ Furthermore, KEM necessitates proton transfer as the only step between the reactant and the lithiated product. Qualitatively, experimental observations^42,51,66,67 based on geometrical consideration of a coordinated DMG-base species proximate to the reactive site are suggestive of the significance of the CIPE supposition. Furthermore, kinetic analyses on the ortho-lithiation of anisole⁶⁸ and ArOAms⁶⁹ provide evidence for mixed dimers⁷⁰⁻⁷² or triple ions^49,73,74 as plausible intermediates for the exhibited first-order kinetics of the reactions. The rate studies^69,75 of the LDA-mediated ortho-lithiation of carbamate 20(Scheme 3) offer no evidence for carbamate–LDA complexation; the resulting divergent rate behaviors for the ortho-lithiation of 20 seem to arise from mixed aggregates and autocatalysis instead.⁷⁶⁻⁸¹ Increasing evidence suggests that autocatalysis may be widespread in LDA/THF-mediated reactions at −78 °C.⁷⁵ Thus, the examination of LDA-mediated ortho-lithiation would provide further insights into how aggregation and solvation may influence organolithium reactivity. In the proposed mechanistic model for the LDA-mediated metalation of carbamate 20, autocatalysis results from the transformation of interceding LDA–ArLi mixed dimer 22 into 23 (Scheme 3, steps I and II).

Scheme 3. Collum’s Mechanism for the DoM Reaction of ArOAms.

Adapted from ref (75). Copyright 2008 American Chemical Society.

Metalation of another incoming arene 20 occurs via 24 (step III) and condensation of free species 24 with LDA dimer 21 (step IV) is rate limiting. Although no kinetic evidence is observed for precomplexation by Collum, there are implications of CIPE being important to ortho-lithiation in several mechanisms involving either Li–O or (C=C)–Li (π) interactions.⁶⁸

At least two profoundly distinctive ortho-lithiation mechanisms are exhibited by the experiments of Pansegran et al. (involves the formation of a benzyne intermediate)⁸² and Maggi et al. (DMG- and solvent-dependent mechanism),⁸³ just to complicate the discussion further.

2.3. The DoM Reaction: Synthetic Aspects

2.3.1. DMG Hierarchy and Methodology

An effective DMG simultaneously involves the contrasting properties of being an appropriate coordinating-ortho-deprotonating group and a poor electrophilic target for nucleophilic alkyl lithium, enabling successful coordination-deprotonation. Steric hindrance and charge deactivation (or both) are also considered when crafting a favorable metalation director.²¹ Thus, more effective DMGs consist of stronger Lewis bases, such as the OCONR₂ group, while weaker DMGs tend to also be weaker Lewis bases, e.g., the 2-methoxyethoxymethyl ether (OMEM) group.

For a complete list of carbon- and heteroatom-DMGs, we refer the reader to works by Snieckus.^18,21,22,84 For the focus of this review, a summary list of the most reliable and widely used oxygen-based DMGs, ordered according to their ortho-directing ability (for the most powerful five DMGs, at least), is depicted in Table 1.

From the established but qualitative hierarchy of DMGs,^18,21,22,84 we focus on a repertoire of valuable oxygen based DMGs (Table 1). The leading hierarchical position of the O-carbamate DMG strongly classifies it as a worthy choice for the regioselective construction of substituted aromatics by DoM chemistry, especially for substrates with Lewis acid stability requirements (Table 1).⁸⁵ Of the ranked positions 2, 3, and 4, the mildly acid sensitive O-DMGs, OMOM (2-methoxymethyl ether), have experienced the most utility.^18,120−124 Conversely, due to reactivity and convenience,^125,126 it is unclear why OMEM (2-methoxyethoxymethyl ether) and OTHP (tetrahydropyranyl ether) have not been more widely tested as DMGs. It is interesting to note that the addition of 0.5 mol % LiCl as a catalyst slows down the lithiation of O-carbamates compared to other DMGs, especially halides.¹²⁷

We also introduce the additional consideration of ortho-, meta-, and para-related di-DMG frameworks (Figure 2).¹⁸

Figure 2.

DoM hierarchy of all theoretically possible di-DMG-substituted aromatics. For 27, the 1st and 2nd point of attack are indicated (1st versus 2nd). Adapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

A combination of two DMGs, systems 25 and 26, are unremarkable in that metalation is predicted to be followed in hierarchical fashion (as denoted by the arrows), while meta-DMG system 27 possesses the advantageous attribute of synergistic metalation between the two DMGs.

In a comprehensive methodological investigation of the DoM reaction for O-phenyl N,N-diethylcarbamate 28a under the formerly established standard conditions,¹⁷ a diversity of electrophiles was employed to afford products 28b–n in good-to-excellent yields⁸⁵ (Table 2). Among the alkylation and allylation products (28b and 28h), ortho-sulfur (28l), and -halo (28m and 28n) substituted compounds were also cleanly obtained. Products 28h and 28i are exceptions, possibly because of single electron transfer (SET) reactions and the presence of acidic C–H bonds in the electrophiles, respectively. These results demonstrate that aryl N,N-diethyl-O-carbamate is an outstanding DMG for the regioselective assembly of ortho-substituted phenol derivatives.

Table 2. DoM Synthesis of ortho-Substituted O-Aryl N,N-Diethylcarbamates^a.

E+	product	E	yield (%)
MeI	28b	Me	80
DMF	28c	CHO	73c
CO2	28d	CO2H	73
ClCONEt2	28e	CONEt2	86
Me3SiCl (TMSCl)	28f	SiMe3	79
MeOD	28g	D	95c
3-bromoprop-1-ene	28h	–CH2C=CH2	75
Ac2O	28i	COMe	22
PhCHO	28j	CH(OH)Ph	90
Ph2CO	28k	C(OH)Ph2	22
(MeS)2	28l	SMe	79
BrCH2CH2Br	28m	Br	86
I2	28n	I	78

^aAdapted with permission from ref (85). Copyright 2018 John Wiley and Sons.

^b42% of this product was isolated as salicylaldehyde.

^c96% d-incorporation.

The summarized results of a competitive metalation study¹⁸ featuring four DMG-bearing derivatives at either the o-, m-, or p- position (DMG = Cl, OMe, OMOM, and CONEt₂, 28o–u) adjacent to the OCONEt₂ DMG are shown in Table 3. When in a 1,3-association with a stronger DMG (see Figure 2), the chloro group may contribute to regioselective 2-deprotonation to give 29a (entry 1) even though it is a poor DMG on its own. Noteworthy is the fact that the 4-OMOM derivative 28s gives the major product 29e (70%; entry 5), a result which confirms the greater DMG power of OCONEt₂ over OMOM. In considering the overall selected results in Table 3, the strength of the O-carbamate group as an ortho director is evident when compared to the chloro, methoxy, tertiary amide, and methoxymethoxy groups. Coupled with the results of O-based DMGs (Table 1), the O-carbamate is the principal choice for the preparation of polysubstituted phenol-based products.

Table 3. Selective DoM Reactions for DMG-Substituted ArOAms 28^a.

entry	compd	DMG	E+	product	DMG	E	yield (%)
1	28o	3-Cl	PhCHO	29a	3-Cl	2-PhCH(OH)	81
2	28p	2-OMe	ClCONEt	29b	6-OMe	2-CONEt2	90
3	28q	3-OMe	I2	29c	3-OMe/5-OMe	2-I/2-I	75 (92:8)
4	28r	3-OMOM	ClCONEt2	29d	3-OMOM	2-CONEt2	24
5	28s	4-OMOM	ClCONEt2	29e	4-OMOM	2-CONEt2	70
6	28t	3-CONEt2	ClCONEt2	29f	3-CONEt2	2-CONEt2	7
7	28u	4-CONEt2	ClCONEt2	29g	4-CONEt2	2-/3-CONEt2	69 (3:2)

^aAdapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

2.3.2. Comparison of ArOAm with Aryl O-Thiocarbamates

Like the ArOAm functionality, the corresponding aryl O-thiocarbamate (ArOCSNR₂) group also acts as an ortho-directing metalation group.¹²⁸ However, the directing ability of −OCSNEt₂ is far weaker than that of −OCONEt₂.¹²⁹ Indeed, the O-thiocarbamate group is weaker than OMe (the fifth most powerful DMG, see Table 1) according to intramolecular competition experiments in which p-methoxythiocarbamate 30 preferentially metalated ortho to the methoxy group over the O-thiocarbamate (mole ratio of 31a:31b ∼ 2:5) (Scheme 4).¹³⁰

Scheme 4. Regioselective Metalation of p-Methoxythiocarbamate 30, Resulting in the Formation of 31a and 31b in a Stoichiometric Ratio of Approx 2:5.

Adapted with permission from ref (130). Copyright 1997 Taylor & Francis.

In comparison, p-methoxycarbamate solely metalates ortho to the carbamate group.¹⁷ Nevertheless, aryl O-thiocarbamates are useful for the preparation of ortho-substituted thiophenols from phenols 32 (Scheme 5).¹³¹ This can be carried out by first forming the O-thiocarbamate from the corresponding phenol¹³² before performing DoM on the aryl O-thiocarbamates 33 to form the ortho-substituted aryl O-thiocarbamates 34. This can be converted to S-phenyl diethylcarbamothioates 35 via a Newman–Kwart rearrangement (NKR)¹³¹ followed by acid/base hydrolysis to the corresponding thiophenols 36 (Scheme 5).^133,134

Scheme 5. Conversion of Phenols 32 into ortho-Substituted Thiophenols 36 via the NKR (34→35).

Adapted with permission from ref (131). Copyright 1992 Thieme.

The sequence is useful and circumvents the oxidative complications that arise when attempting to obtain 36 directly via electrophilic substitution.¹³⁵

Similar chemistry was used by Kunz et al. in the preparation of benzothiadiazole-based plant activators.¹³⁶ In this case, once the aryl O-thiocarbamate was converted to the aryl S-thiocarbamate (by NKR), the S-thiocarbamate functionality served as a useful protecting and leaving group in the final cyclization step to form the benzothiadiazole.

As a caution, Mondragón et al.¹³⁷ reported that attempts to convert ortho-halogeno-aryl O-thiocarbamates to the corresponding aryl S-thiocarbamates via NKR were thwarted by competition with nucleophilic attack of the thiocarbamoyl S atom at the ortho-position. This difficulty was overcome by replacement of the halide with a carbonyl group.

Apart from the NKR, postsynthetic modifications of the aryl O- and S-thiocarbamate directing groups might include the AoF²⁴ and O-neophyl¹³⁸ rearrangements, as well as in S-thiocarbamate-Grignard cross-couplings, although more rigorous conditions are required compared with the corresponding O-carbamate coupling reactions.¹³⁵

We only located one report involving the aryl S-thiocarbamate group (ArSCONR₂) in reaction with an organolithium base.¹³⁹ In this case, treatment of S-(o-tolyl) diethylcarbamothioate (37) with LDA at −30 °C followed by quenching with various aromatic aldehydes provided 3-substituted E- and Z- derivatives of 3-benzylidenebenzo[b]thiophen-2(3H)-ones (Scheme 6). The results in the scheme show that the Z- diastereomers (Z-38a–d) were obtained as major products in reasonable to good yields with the E- diastereomers in smaller amounts (E-38a–d). Mechanistically, this is due to the initial abstraction of a proton from the ortho-methyl group by LDA to give an anion which undergoes cyclization followed by condensation with the aromatic aldehyde, forming isomers E-38 and Z-38 upon acidic workup.

Scheme 6. Synthesis of E- and Z-3-Benzylidenebenzo[b]thiophen-2(3H)-ones (E-38a–d and Z-38a–d) by Treatment of 37 with LDA Followed by Various Aromatic Aldehydes.

Adapted with permission from ref (139). Copyright 2004 The Japan Institute of Heterocyclic Chemistry.

In conclusion, we point out that phenols can be converted to selenophenols in the same way that phenols can be converted to thiophenols via NKR.¹⁴⁰ However, the ortho metalation of aryl Se-carbamates is yet to be explored. In general, aryl S-carbamates and Se-carbamates have not been explored more fully, probably due to their toxicity to transition metals.^141,142 Aryl dithiocarbamates have not yet been explored in the context of DoM; this could also be a worthy pursuit given their biological relevance.¹⁴³

2.3.3. DoM Reactions of ArOAm on Solid Support

Organic synthesis involving reactants or reagents on solid support is a rapidly growing field as it offers multiple advantages including, for example, using excess reactants/reagents to drive reactions to completion, combined with their easy recovery and reuse in subsequent reactions.^144,145 The first report of a solid-supported DoM reaction involving ArOAms was in 2005.¹⁴⁶ In this work, ArOAm 39 on PS-DVB resin (immobilized using a trityl linker, “TrO”) was metalated and exposed to a range of electrophiles followed by removal of the support to give substituted benzyl alcohols (40) in high purity at low temperatures and short metalation times (Scheme 7).

Scheme 7. DoM Reaction of ArOAms on PS-DVB Resin Using a Trityl Linker.

Adapted from ref (146). Copyright 2005 American Chemical Society.

Some reaction conditions had to be modified for the reaction of ArOAms on solid support. Normally, 1.2 equiv of s-BuLi base and TMEDA additive are used for the solution phase DoM reaction of the same substrate, whereas 5.0 equiv of base was required for the solid phase reaction while exclusion of TMEDA additive increased the yield/purity of the product 40 almost quantitatively. Furthermore, increasing the amount of THF in the reaction (THF/hexane ratio of 10:1) gave 99% yield for MeI electrophile.

2.3.4. Alternative Metalation Reagents with the OAm Group

Traditionally, organolithiums are used to realize DoM, and these are typically alkyl lithium compounds or bulky lithium amides. However, these reagents are highly reactive and tend to attack electrophilic DMGs or sensitive functional groups, causing undesired side reactions.¹⁴⁷ Subsequent research to establish alternative, less harsh metalation reagents has been fruitful, with the discovery of metalation reagents in the form of single metals (Na),¹⁴⁸ sodium and metal amides,^53,149−151 sodium isopropyl(trimethylsilyl)amide,¹⁵² NaTMP (TMP = 2,2′,6,6′-tetramethylpiperidine) with tridentate donor PMDTA (N,N,N′,N″,N″-pentamethyldiethylenetriamine),¹⁵³ mixed metals,^154,155 metalates (magnesiates, zincates, and aluminates),^156−159 (2,2,6,6-tetramethylpiperidino)magnesium chloride (TMPMgCl),¹⁶⁰ mixed aggregates,^161,162 “superbases,”⁵³ and “Turbo bases”.^163,164 There are only a few examples which have been demonstrated for ArOAms, shown in Table 4.

Table 4. Alternative Metalation Agents to Organolithium Reagents^{147,165−168}.

Ma et al.¹⁶⁵ demonstrated the possibility of performing AoF rearrangements using sodium diisopropylamide, NaDA, to obtain dialkyl-2-hydroxybenzamides in moderate to good yields (an example is shown in entry 1). A sodium-mediated TMP-zincation demonstrated by Balloch et al.¹⁴⁷ resulted in ortho-metalation via a sodium TMP-zincate [(TMEDA)Na(μ-TMP)(μ-t-Bu)Zn(t-Bu)] (43), generated in situ, followed by electrophilic quench with a I₂ solution (THF) to generate 28n in 75% yield (entry 2). The yield is similar to that for the same product obtained using s-BuLi (Table 2, synthesis of 28n).

Clear opportunities exist to understand other metalating reagents capable of metalation/functionalization of the ArOAms, e.g., sodium dispersion in sand or micronized (reduced to a fine powder).

3. ArOAm and Remote Metalation Chemistry

As demonstrated by Bellan and Knochel,^169,170 sterically hindered ArOAm can direct metalation (regioselectively) at the para position of aromatic molecules. For example, ArOAm with two bulky triethylsilyl groups at both ortho positions (47) can be regiospecifically lithiated in the para position with n-BuLi/PMDTA (PMDTA = N,N,N′,N″,N″-pentamethyldiethylenetriamine, a reactivity enhancing tridentate ligand¹⁷¹) (Scheme 8).

Scheme 8. An Example of Direct Regioselective Remote Metalation of an Aromatic Molecule with Bulky TES Groups in the ortho Position.

Synthesis of 49 adapted with permission from ref (169). Copyright 2019 John Wiley and Sons. Synthesis of 50 adapted with permission from ref (170). Copyright 2019 Thieme.

Martínez-Martínez et al.¹⁷² demonstrated that steric hindrance is not necessarily required: in this case, the use of a disodium-monomagnesium alkyl-amide could extend the regioselectivity of the metalation to more distant arene sites (ortho-meta′/meta-meta′, depending on the nature of the directing group). When the DG is OAm, ortho-meta magnesiated complex 51 forms (Scheme 9), which can be trapped with an electrophile, demonstrated using I₂, to form trisubstituted 52.

Scheme 9. An Example of Remote Metalation to More Distant Arene Sites with OAm as DG.

Adapted with permission from ref (172). Copyright 2014 American Association for the Advancement of Science.

4. ArOAm and the Anionic ortho-Fries (AoF) Rearrangement

In the absence of an electrophile, when ArOAm 28a forms an intermediate lithiated species under standard conditions of s-BuLi/TMEDA, this intermediate undergoes an AoF rearrangement upon slow warming to room temperature to produce the salicylamide derivative 53a (Scheme 10).¹⁸ Similarly, methyl-substituted salicylamide derivatives 53b–d (R, in relation to −OH) are formed from 28b,w,x. Thus, tertiary O-carbamates are unstable at temperatures higher than −78 °C with respect to the 1,3-O→C carbamoyl rearrangement²⁴ whose rate is primarily dependent upon the extent of substitution, especially ortho to the developing anion or to the OCONR₂ group as well as the substituents on the N atom.⁶⁹

Scheme 10. AoF Rearrangement to Salicylamide Derivatives (53).

Adapted with permission from ref (85). Copyright 2018 John Wiley and Sons.

This rearrangement, more widely known for the transformation of aromatic esters to ortho- and para-acyl phenols with Lewis acids, is named after its discoverer, Karl Fries, who published the first examples of this process in 1908.¹⁷³ ArOAms have yet to be transformed into ortho- and para-acyl phenols in this manner. An example of where this transformation may have been anticipated but was not observed can be found in work by Silberstein et al., in which the coupling of an ortho-substituted ArOAm 54 with an alkyl Grignard reagent 55 in the presence of a Lewis acid (FeCl₂) provided the alkylated product 56 in 72% yield with no evidence for formation of the ortho-acyl phenol side-product 57 (Scheme 11).¹⁷⁴ The anticipated Lewis-acid mediated Fries rearrangement product 57 was not observed.

Scheme 11. Iron-Catalyzed Coupling of O-Carbamate 54 with Cyclohexylmagnesium Chloride (55) to Furnish 56.

Adapted from ref (174). Copyright 2012 American Chemical Society.

The anionic version of this transformation, the AoF, was only discovered decades later in 1981 by Melvin,¹¹⁷ with the first examples reported by Snieckus’ group in 1983.¹⁷ In the AoF rearrangement, the O-carbamate can be conceptualized as acting as a “carrier” of the amide group into the ortho position and the creation of this new DMG may then facilitate further DoM chemistry.

A slight adjustment of the base employed changes the reaction outcome. For example, when treated with LDA instead of s-BuLi, 2-tolyl O-carbamate 28b undergoes lateral metalation to give a phenylacetamide 58, which can be hydrolyzed to a benzo[b]furan-2(3H)-one (59) in reasonable yield (Scheme 12).¹⁸

Scheme 12. AoF Rearrangement Results in the Transformation of the o-Methylated Carbamate 28b to Benzofuranone (59).

Adapted with permission from ref (85). Copyright 2018 John Wiley and Sons.

In a parallel study, the 1- and 2-naphthyl O-carbamates 60 and 62 were also subjected to standard AoF rearrangement conditions to give amides 61 and a mixture of amides 63 and 64 (Scheme 13). Alternative DMGs have also been applied to this reaction scheme in other work.¹⁸

Scheme 13. AoF Rearrangement of Naphthalenes 60 (a) and 62 (b) to Naphthamide Derivatives 61, 63, and 64.

Adapted with permission from ref (85). Copyright 2018 John Wiley and Sons.

4.1. The Scope of the AoF Rearrangement

The synthetic playground of aromatics is enlarged by considering substrates with two different DMGs in competition experiments (Table 5).¹⁸ Using standard AoF conditions, the 2-chloro and 2-methoxy ArOAms 28y and 28p afford the contiguously 1,2,3-trisubstituted salicylamides 65a and 65b, respectively (entries 1 and 2). By contrast, the 3-OMOM 28r and 3-OCONEt₂28z furnish the in-between AoF rearrangement products 65c (68% yield; entry 3) and 65d (86% yield; entry 4), respectively. Lastly, the amide ArOAm 28t was subjected to the AoF rearrangement to afford 65e (Table 5, entry 5) in relatively low yield. These results further emphasize the strength of the O-carbamate DMG as an ortho director in the AoF rearrangement and, not without synthetic consequence, furnish trisubstituted aromatics.

Table 5. Competitive AoF Rearrangement of DMG-Substituted ArOAms 28^a.

entry	compd	DMG2	product	DMG2 (product)	yield (%)
1	28y	2-Cl	65a	3-Cl	72
2	28p	2-OMe	65b	3-OMe	68
3	28r	3-OMOM	65c	6-OMOM	68
4	28z	3-OCONEt2	65d	6-OCONEt2	86
5	28t	3-CONEt2	65e	6-CONEt2	16

^aAdapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

It is noteworthy that the AoF of ArOAms can be suppressed using a zincate base (generated by the reaction of HTMP with n-BuLi and Et₂Zn in THF at −78 °C under inert conditions), which reacts preferably with the aromatic component to give stable intermediates able to resist rearrangement.¹⁶⁸

The AoF rearrangement also provides various opportunities for one-pot conversions of the ArOAm group to other functionalities. For example, the salicylamide 66 can be transformed into a o-hydroxyacetophenone derivative 67(175) or a 2′-hydroxychalcone 68(176) using the conditions shown in Scheme 14.

Scheme 14. AoF Rearrangement of an ArOAm Forming Salicylamide 66 Followed by the Formation of Either a o-Hydroxyacetophenone Derivative 67 (Adapted with Permission from ref (175), Copyright 2014 John Wiley and Sons) or 2′-Hydroxychalcone 68 (Adapted from ref (176), Copyright 2018 American Chemical Society), Both via an Anionic Si → C Alkyl Rearrangement and Claisen–Schmidt Condensation.

These transformations were shown to be useful in the formation of various medicinal compounds, namely the PI3K inhibitor LY294002 (72, Scheme 15a)¹⁷⁵ used in cancer therapy, and the chalcone Lonchocarpin (75), a natural product with numerous pharmacological properties (Scheme 15b).¹⁷⁶

Scheme 15. Synthesis of (a) the PI3K Inhibitor LY294002 (72) and (b) Lonchocarpin (75) by Application of the Extended AoF Rearrangement.

(a) Adapted with permission from ref (175). Copyright 2014 John Wiley and Sons. (b) Adapted from ref (176). Copyright 2018 American Chemical Society.

Compound 72 was obtained in 4 steps with a 68% total yield, commencing with the preparation of diethylcarbamate 28aa from o-phenylphenol (69) and diethylcarbamoyl chloride (Scheme 15a). Carbamate 28aa was then subjected to an AoF rearrangement–methylation procedure to afford 70 which was coupled with 4-morpholinecarbonyl chloride to form salicylacetamide 71. Subsequent cyclodehydration of 71 using trifluoromethanesulfonic anhydride provided LY294002 (72).¹⁷⁵ Similarly, 2,2-dimethyl-2H-chromen-5-ol (73), prepared from 3-hydroxycyclohex-2-en-1-one and senecialdehyde,^177−179 was transformed into carbamate 74, which was then subjected to standard AoF reaction conditions to furnish the natural product Lonchocarpin (75) in 62% yield.¹⁷⁶

5. OAm in Iterative (Walk-around-the-Ring) DoM

5.1. The Iterative DoM Strategy Conceptualized

The application of sequential multiple DoM reactions uncovers a plethora of opportunities. In general, successive metalation-electrophile quench with two electrophiles (same or different) can lead to a 1,2,3-substituted aromatic compound 76 (Scheme 16). Moreover, the use of a protecting group (PG) as in 77 allows another route to a contiguously trisubstituted derivative (step a).¹⁸ If DMG¹ is reasonably strong, a further DoM reaction (step b) may allow for a third DMG (DMG³) introduction (to form 78).¹⁸ Thus, the adaption to the walk-around-the-ring tactic for the conversion of an ArOAm to a tetrasubstituted aryl may be envisioned. Given two DMGs, the ortho, meta, and para relations may be considered. For the meta-DMG¹–DMG² isomer (27),¹⁸ the cooperative DMG effects influence the introduction of E¹ (step a). If DMG¹ > DMG² in metalation power, DMG³ may be introduced (step b). Additional metalation may also occur if the introduced DMG³ > DMG² in power which then permits the introduction of DMG⁴ (step c) followed by E² (step d) to form 79.

Scheme 16. Conceptual Framework of Walk-around-the-Ring Iterative DoM Strategies to Various Generic Compounds 76, 78, and 79.

Adapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

5.2. The OAm DMG Iterative DoM in Practice

Two cases of the ArOAm DMG in iterative metalation experiments are presented herein (Scheme 17).¹⁸ In evidence of potential synthetic utility, O-phenyl N,N-diethylcarbamate 28a was employed in sequential metalation, silylation, metalation, and carbamoylation with equivalent amounts of base and electrophile at −78 °C. The 1,2,3-substituted product 80 was obtained in reasonable 54% yield. Standard reaction of 80 with ClCONEt₂ afforded the 1,2,3,4-substituted aromatic molecule 81 in good 75% yield.

Scheme 17. Two Tested Iterative DoM Cases Using ArOAm DMGs.

Adapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

In the second tested case, 2-methoxy O-carbamate 28p was subjected to two metalation–electrophile quench sequences in one pot with quenching reagents ClCONEt₂ and MeI to give a contiguously tetrasubstituted product 82 in an acceptable 66% yield.

5.3. Comparative Analysis of Different Approaches to Synthesis of Substituted Aromatic Compounds

A compiled collection of 1,2,3-substituted (entries 1–4) and 1,2,3,4-substituted aromatic systems (entries 5 and 6) is shown in Table 6 to provide a general summary of O-carbamate DoM methodologies in comparison to alternative synthetic procedures.

Table 6. Competitive Methods (DoM-Based vs Alternative) for the Synthesis of Substituted Phenols. Approximate Value of Chemical Shown in USD (Average Calculated from the Price Supplied by Three Universal Vendors)^{18,114,156,178−192}.

The relatively inexpensive 2,6-dimethylphenol 83 (Table 6, entry 1) is produced in industrial chemistry from ortho-cresol (84) using high-pressure and high-temperature in two steps and 36% yield,¹⁸ whereas, with the opportunity for scale-up and consideration of cost, the same starting material, same number of steps, and 50% yield is attainable by ortho-lithiation of 28b to 2,6-dimethylphenyl diethylcarbamate (85).¹⁸

Lehnert et al. prepared 83 in 57% in one-step using a Simmons–Smith reagent prepared in situ from diethylzinc and diiodomethane (entry 1).¹⁸⁰83 can also be prepared in a 3-step process involving DoM of 28b, with OAm as DMG. The low cost of 83 makes neither route particularly appealing. By contrast, the comparatively expensive differentially halogenated phenol 86 (entry 2) has been prepared by DoM chemistry from 2-chlorophenol (87) in an overall acceptable yield (56%).^18,11486 has also been prepared in far lower yields starting from 87, e.g., 4% yield, using N-iodosuccinimide and p-toluenesulfonic acid (para-substituted iodophenol is produced in 82% yield)¹⁸¹ or 7% yield via oxyiodination (para-substituted iodophenol is produced in 93% yield).¹⁸² A more attractive route commences with 2-iodophenol 91, providing 86 in 75% yield via traditional electrophilic aromatic substitution using sulfuryl chloride.¹⁸³

For the synthesis of 3-methoxy-2-methylphenol (92) (entry 3) starting from 3-methoxyphenol (93), the target molecule is accessible either using the carbamate 28q (three steps: synthesis of ArOAm from 93 (96%),¹⁸⁴ followed by DoM and installation of the methyl group (68%),¹⁸ and, finally, hydrolysis of OAm to OH (88%),¹⁸⁵ giving a 57% overall yield) or relatively more expensive 1,3-dimethoxy-2-methylbenzene, 95 (one step, 82%),¹⁸⁶ or cheaper 2-methylresorcinol, 96 (one step, 43%¹⁸⁷ or 53% yield¹⁸⁸).

For contiguously tetrasubstituted systems, the methods begin with resorcinol (98), hydroquinone (101), and catechol (105) via O-dicarbamates 28z, 28ab, and 28ac, respectively, using DoM to provide the respective isophthalic (entry 4), and terephthalic (entries 5 and 6) target molecules (97, 102, and 106, respectively) in a reasonable number of steps with modest yields via reduction and hydrolysis reactions.

While alternative syntheses have been reported (e.g., selective carboxylation of 98 to 97,¹⁸⁹ hydrolysis of ester groups in 104 to form 102(190) and selective carboxylation of 105 to form 106(192)) and developed for large-scale commercial production,^191−195 these routes typically involve high temperatures, dangerous materials, and corrosive reagents in variable yields. Therefore, the comparative examination of synthetic reactions in Table 6 competitively positions O-carbamate DoM methodology against other procedures for the manipulation of contiguously functionalized substituted aromatic derivatives. The provided approximations may guide informative decisions in synthetic efforts toward preparing alternative poly substituted aromatic targets.

5.4. Combined DoM-Halogen Dance (HalD) Synthetic Strategies

The HalD reaction involves the intraring migration of a halogen substituent and is essentially a 1,2-rearrangement reaction based on a combination of halogen/lithium exchange and deprotonative lithiation.^196,197 Miller et al.¹⁹⁸ have demonstrated one-pot sequential DoM and HalD of ArOAm 28o forming either the tetrasubstituted 108 via HalD followed by electrophile quench or substituted phenol 109 via an ortho-Fries rearrangement (in the absence of an electrophile) (Scheme 18). Compound 110 was initially prepared by DoM of substrate 28o with I₂ as electrophile in 88% yield (Sanz et al.¹⁹⁹).

Scheme 18. HalD-AoF of ArOAm 28o via Initial Transformation to 110 via DoM (Adapted from ref (199), Copyright 2007 American Chemical Society), Which Can Be Transformed to 108 and 109 (Adapted with Permission from ref (198), Copyright 2010 John Wiley and Sons).

Feberero et al.²⁰⁰ applied this chemistry in the preparation of alkynyl-5-chloro-2-iodophenyl carbamates 112 from dihalogeno-ArOAm 113 via an anionic intermediate (Scheme 19). Such materials are useful in forming o,o′-dialkynyl carbamates (exemplified by 115a–c) by Sonogashira coupling with select terminal alkynes.

Scheme 19. (a) Synthesis of Alkynyl-5-chloro-2-iodophenyl Carbamates 112, and (b) Their Application in Cross-Coupling (CC) Reactions with Terminal Alkynes.

Adapted from ref (200). Copyright 2022 MDPI.

Similarly, Miller et al.¹⁹⁸ demonstrated the HalD with three iodo-pyridyl O-carbamates 119–121 (prepared by DoM from the corresponding isomeric O-carbamate substrates 116–118) to form the trisubstituted pyridyl O-carbamates 122–124 with a variety of electrophiles (Table 7).

Table 7. Selected Products of DoM-HalD on Isomeric Pyridine O-Carbamates (122–124) and Secondary HalD (125c, 126d, and 127d)^a.

^aAdapted with permission from ref (198). Copyright 2010 John Wiley and Sons.

Subsequent HalD reactions of select products with LDA (2.2 equiv for 122c and 123d) and LiTMP (for 124d) resulted in additional substitution on the aromatic ring, forming compounds 125–127, further demonstrating the synthetic potential of the DoM-HalD (and secondary HalD) sequence.

6. ArOAm and Silyl Groups

The synthesis of ortho-silylated aromatic and heteroaromatic compounds can be facilitated by the O-carbamate group, quenching with chlorotrimethylsilane (TMSCl) as electrophile. However, silylated O-aryl carbamates themselves have significant utility. Three main approaches lend value to these materials, and each is discussed in detail in the following subsections.

6.1. Ipso-Substitution of Silyl Groups

Ipso-substitutions (substitutions of attachments other than H on the aromatic ring) of silyl groups can occur via nucleophilic or electrophilic aromatic substitution mechanisms. When the silyl group is positioned ortho to a DMG such as the O-carbamate group, ipso-substitutions can be of significant preparative importance, e.g., for the regioselective synthesis of conventionally inaccessible disubstituted arenes. The ipso-desilylation of silylated ArOAms can be halogeno-,^114,201 boro-,²⁰² and nitroso-induced,²⁰³ introducing a highly expedient approach to halogenoarenes, nitrosoarenes, nitroarenes, and arylboronopinacolates (Figure 3).

Figure 3.

Schematic to show ipso-substitution of silylated ArOAms with various electrophiles.

For example, the treatment of DoM-derived silylated aromatics 28ad and 128 under standard electrophilic halogenation conditions cleanly affords ipso-desilylated products 28m,n,y and 129, respectively, in good to excellent yields (Scheme 20).²⁰⁴ Similarly, DoM-derived silylated naphthalene substrates 130 and 132 afford halogeno ipso-desilylated products (Table 8).^205,206

Scheme 20. Ipso-Desilylation Products of Compounds 28ad and 128.

Adapted from ref (204). Copyright 2005 American Chemical Society.

Table 8. Halo-ipso-Desilylation Reactions of Naphthalene Substrates 130 and 132^a.

entry	compd, R	E+ (equiv)	product, R	yield (%)
1	130, R1 = H; R2 = TMS	pyHBr3 (2.0)	131, R3 = H; R4 = Br	87
2	130, R1 = TMS; R2 = TMS	pyHBr3 (1.0)	131, R3 = Br; R4 = TMS	84
3	130, R1 = TMS; R2 = TMS	ICl (1.0)	131, R3 = I; R4 = TMS	81
4	130, R1 = I; R2 = TMS	Br2 (1.1)	131, R3 = I; R4 = Br	96
5	130, R1 = Br; R2 = TMS	ICl (2.5)	131, R3 = Br; R4 = I	96
6	132	Br2 (2.0)	133	87

^aAdapted from ref (205). Copyright 2014 American Chemical Society.

Thus, treatment of naphthyl O-carbamate from entry 1 with pyridinium tribromide (pyHBr₃) cleanly afforded the corresponding 3-bromo derivative in 87% yield.²⁰⁵ With only 1 equiv of pyHBr₃, the 1,3-disilylated carbamate from entry 2 gave the corresponding derivative, also in high yield via regioselective 1-bromo ipso-desilylation. The authors attribute this to the extended conjugation and greater stabilization afforded by the β-arenium intermediate compared with when the bromonium ion attacks at C3. The same regioselectivity was observed upon iodination of the same substrate to form the 1-iodo derivative (entry 3) in 81% yield. When naphthyl O-carbamate 131 from entry 3 (i.e., 130, R¹ = I, R² = TMS) was exposed to bromination by Br₂ in CH₂Cl₂ at 80 °C in a microwave (the use of pyHBr₃ was unsuccessful), the reaction provided the 3-bromo-1-iodo derivative in quantitative yield (entry 4). Conversely, the carbamate in entry 5 actively reacted with excess ICl at −20 °C to provide the inverted isomer of the product found in entry 4 in a high yield. Treatment of the bis(O-carbamate) 132 with Br₂ caused bromodesilylation, providing 133 in 87% yield (entry 6).

Following halogeno-induced ipso-desilylation, the new halogeno-aromatic compound can be treated under a plethora of cross-coupling conditions, e.g., with boronic acids, to obtain a versatile range of biaryl compounds. Similarly, but more advantageous, combining the ipso-borodesilylation procedure (Figure 3, E⁺ = BX₂⁺) with Suzuki–Miyaura cross-coupling (CC) chemistry constitutes an in situ protocol to unsymmetrical biaryls and heterobiaryls and m-terphenyls.^202,204 For example, sequential ipso-borodesilylation of 28ad to 28ae followed by treatment with aryl halides under Pd-catalyzed conditions provides biaryl compounds 28aa,af,ag (Scheme 21a).

Scheme 21. In Situipso-Borodesilylation and Suzuki CC of ortho-O-Carbamate-Substituted Arylsilanes, Commencing with (a) Monosilylated ArOAm 28ad (Adapted with Permission from ref (202), Copyright 1987 Elsevier), and (b) bisilylated ArOAm 134 (Adapted from ref (204), Copyright 2005 American Chemical Society).

In the case of bisilyl 134, reaction with 1.2 equiv of BX₂⁺ and subsequent excess of pinacol leads to the formation of 135, which can form either 136a or 136b when reacted with bromobenzene under Suzuki coupling conditions (136b forms when 2 equiv of bromobenzene are used) (Scheme 21b).²⁰⁴

Zhao and Snieckus²⁰⁴ described the nitroso-induced desilylation of the ortho-silylated O-carbamate 28ad to the ipso-nitroso product 28ah in a good (72%) yield with sodium nitrite and trifluoroacetic anhydride (Scheme 22).

Scheme 22. ipso-Nitrosodesilylation of 28ad to Nitroso 28ah, Which Can Either Be Oxidized to 28ai or Reduced to 28aj. Under Mild Nitration Conditions, 28ad Instead Forms a Mixture of 137a, 137b, and 28ai.

Adapted from ref (204). Copyright 2005 American Chemical Society.

Compound 28ah was then either oxidized to nitrobenzene 28ai or reduced to aniline 28aj under standard conditions in good yields. Interestingly, exposing 28ad instead to mild nitration conditions (ammonium nitrate) led to the formation of the corresponding para-, ortho-, and ipso-nitro-substituted products, 137a, 137b, and 28ai, respectively, in a ratio of 7.5:1.5:1, via a mix of non-ipso-electrophilic substitution and nitro-induced ipso-desilylation.

The silyl group can also be used in CC, opening the final products of the above chemistry to further manipulation, although we only found one example of this: in the formation of ortho-aryl silanes.²⁰⁷ This is an area ripe for further exploration.

6.2. Silyl-Mediated Non-ipso-Substitutions

In the presence of electron-donating groups (EDGs) along the aromatic component, the steric effect of the silyl groups instead promotes non-ipso-electrophilic substitution (particularly with E⁺ = NO₂⁺), as shown in Figure 4 (compare with Figure 3).

Figure 4.

Schematic to show non-ipso-substitution with various electrophiles as directed by silylated ArOAms.

For example, the nitration of methoxy substituted 28p and 138 leads to corresponding non-ipso isomers 139 and 140 (Scheme 23a).²⁰⁴

Scheme 23. (a) Nitration of O-Aryl Carbamates 28p and 138b–c to Form a Mixture of Isomers 139 and 140; (b) Synthesis of 2-Methoxy-3-nitrophenol (141) via Removal of TMS From 139b to Form 139a, Followed by Hydrolysis of the O-Carbamate Group.

Adapted from ref (204). Copyright 2005 American Chemical Society.

Compared with the unsubstituted 28p, TMS- and TIPS-substituted O-carbamates 138b and 138c favor electrophilic nitration at C3 to a greater extent, as dictated by a silicon steric effect, forming 139b and 139c, respectively.²⁰⁴ To demonstrate further utility of this chemistry, the silyl group of 139b can then be removed (by F^–) to form 139a and the O-carbamate functionality hydrolyzed to −OH to form 2-methoxy-3-nitrophenol (141, CAS no. 20734-71-8, costs USD188/0.1 g) (Scheme 23b), otherwise only accessible via a fastidious, lengthy (5 step) and low yielding protocol.²⁰⁸

6.3. Silyl Groups as Blocking Groups

Silyl groups can also be used as blocking groups that prevent metalation of an ArOAm ortho-site during the DoM method. Ortho-silyl and -siloxane substituted ArOAms can be utilized for the regiospecific synthesis of specific ortho-substituted carbamates.^18,209 For example, Miah et al.¹⁸ demonstrated the sequential metalation, silylation, and carbamoylation (with equivalent amounts of base and electrophile and the reaction temperature maintained at −78 °C) of O-phenyl N,N-diethylcarbamate (28a), through 28ad, to obtain the trisubstituted 142 in reasonable yield (Scheme 24).

Scheme 24. Utilization of the Silyl Group (TMS) as a Blocking Group as the OAm Group Directs the Lithiation Followed by E⁺ (Et₂NCOCl) Quench ortho to the OAm Group to Form 142 and ortho to the Am Group to Form 143.

Adapted with permission from ref (18). Copyright 2018 John Wiley and Sons.

If 142 is isolated, purified, and subjected to standard conditions for deprotonation before being treated with ClCONEt₂, the contiguously tetrasubstituted aromatic molecule 143 is formed in 75% yield. Treatment with F^– (e.g., as CsF or TBAF) enables the facile removal of the TMS group due to the formation of the strong Si–F bond compared with the C–Si bond.

Because the O-carbamate functionality can be hydrolyzed to OH, silylated O-carbamates are also useful for the regiospecific synthesis of ortho-substituted phenols. For example, 145a and 145b, can be prepared by the initial formation of carbamates 28ad and 144 from 28a and 28ak, respectively, prior to base-catalyzed carbamate removal as shown in Scheme 25.¹⁷

Scheme 25. Synthesis of ortho-TMS Phenols 145a and 145b via Base-Catalyzed Hydrolysis of ArOAms 28ad and 144, Respectively.

Adapted from ref (17). Copyright 1983 American Chemical Society.

Reductive cleavage by the Schwartz reagent is another recently reported methodology for conversion of ArOAms to phenols.¹⁸⁴ The manipulation of the ArOAm functionality forms the focus of section 7 (reductive cleavage and other methodologies will be discussed in more detail in section 7).

Silyl groups also play a significant role in the Ir-catalyzed borylation of ArOAms in which 1,3-disubstituted systems generally lead to meta-borylation with high regioselectivity and efficiency.²¹⁰ For example, in Ir-catalyzed borylation of selected 1,2,3-trisubstituted silylated ArOAms 134, 138b, 146, and 148, all derived by efficient DoM chemistry, borylated products 147a–c, and 149 could be obtained in synthetically useful yields (Scheme 26).

Scheme 26. Ir-Catalyzed Borylation of 1,2,3-Trisubstituted Silylated ArOAms 134, 138b, 146, and 148.

Adapted with permission from ref (210). Copyright 2010 John Wiley and Sons.

Silyl groups as ortho-blocking groups during DoM is also especially useful for promoting ortho-substitution in π-electron deficient heteroaromatics such as pyridine via DoM chemistry where such substrates with low-lying LUMO molecular orbitals typically undergo nucleophilic attack by RLi reagents.²¹¹ For example, the deprotonation of O-3-pyridyl carbamate (117) can be achieved by adapting the blocking tactic: when 117 was subjected to 2.2 equiv of LDA followed by treatment with excess TMSCl, the 2,4-disilylated derivative (150) was obtained in quantitative yield (Scheme 27). Treatment of 150 with a suitable electrophile (e.g., benzoyl chloride) resulted in mono ipso-carbodesilylation to form 151.

Scheme 27. Synthesis of 2,4-Disilylated Derivative 150 Followed by a Mono ipso-Carbodesilylation to Form 151.

Adapted from ref (211). Copyright 1993 The Japan Institute of Heterocyclic Chemistry.

If 4-(trimethylsilyl)-3-pyridinyl carbamate (152) is treated with 1.2 equiv of LiTMP followed by a suitable electrophile, a variety of 2-substituted pyridine derivatives (including 153a–f and 154a–f) can be formed (Table 9), taking advantage of the C4 protection by a silicon group.²¹¹ The silyl group can then be removed through the addition of F^– (due to the formation of the strong Si–F bond resulting in desilylation)²¹² to form 154.

Table 9. Synthesis of Pyridine Derivatives (153 and 154) Using LiTMP as Base and TMS as PG^c.

entry	methoda	E+	product	E	yield (%)
1	A	CD3OD	153a	D	87b
2	A	PhCHO	153b	CH(OH)Ph	82
3	A	PhCOCl	153c	COPh	41
4	B	CCl3CCl3	153d	Cl	64
5	B	(PhS)2	153e	SPh	79
6	B	Et3SiCl	153f	SiEt3	89

^aMethod A: 1.5 equiv of LiTMP. Method B: 1.2 equiv of LiTMP.

^b58% D-incorporation (by mass spectrometry).

^cAdapted with permission from ref (211). Copyright 1993 The Japan Institute of Heterocyclic Chemistry.

This tactic can also be used to facilitate 4- and 6-substitution of π-excessive heterocycles such as indoles.²¹³ For example, N,N-diethylindole 5-O-carbamate can be silicon protected as 155 and further protected as 156; when 156 is subjected to metalation and quenched with electrophiles, the 6-substituted products 157 are provided (Scheme 28). When quenched with iodine, 157a is formed in 63% yield, as is 157b (quench with iodomethane). Under standard conditions¹⁷ followed by acylation, 158 is afforded via the AoF rearrangement. Both products (157 and 158) are amenable to further metalation chemistry.

Scheme 28. Silylation of 155 to Form 156, Which Is Treated under Standard Metalation Conditions Followed by Quenching with I₂ or Mel to Give 157.

Adapted from ref (213). Copyright 1995 American Chemical Society. When 156 undergoes AoF followed by acylation, 158 is afforded in 85% yield.

Another interesting application involving the AoF rearrangement was reported by Groom et al. for silylated naphthalene compounds.²⁰⁵ As shown in Scheme 29, when silylated compound 159 (prepared by DoM of substrate 62, followed by quench with TESCl) is allowed to warm to room temperature instead of electrophile quench, 160 forms via a “sequential C3-deprotonation–silylation, C1-deprotonation–AoF rearrangement”.²⁰⁵ When the same reaction of 62 was carried out with TMSCl instead of TESCl, the analogous product 163 forms in 28% yield along with the desired product 164 (31%) and compound 162 (26%), the result of “CIPE-induced α-silyl methyl deprotonation–carbamoyl migration”. The greater acidity of the α-methyl of the TMS groups combined with a possible steric effect may be the reason for the observed difference in reactivity between intermediates 159 and 161.

Scheme 29. Results of AoF Rearrangements When Silyl Blocking Group Is Either TES (Route A) or TMS (Route B).

Adapted from ref (205). Copyright 2014 American Chemical Society.

7. OAm Manipulation

The O-carbamate functionality is synthetically valuable due to its relative stability and capability as a directing group as well as its ability to be converted into other functional groups. This differs from the cross-coupling of ArOAms which is covered in section 8. We discuss 10 useful transformations in this section, commencing with the most widely investigated conversion: reductive cleavage of the O-carbamate group (section 7.1). Other transformations include AoF-product manipulation (section 7.2), decarboxylation of ArOAms to form aromatic amines (section 7.3), conversion of N,O-diaryl carbamates into ureas (section 7.4), ArOAms to ArOCONRCHO (section 7.5) and triflates (section 7.6), borylation of ArOAms (section 7.7), and sulfonamidation (section 7.8), amidation (section 7.9) and cyanation (section 7.10) of ArOAms.

7.1. Cleavage of ArOAm

7.1.1. Reductive Cleavage to Phenols

The reductive cleavage of ArOAms by the Schwartz reagent (Cp₂Zr(H)Cl) in the synthesis of polysubstituted phenols (method F)¹⁸⁴ employs relatively mild conditions compared with methods A–E (Table 10).

Table 10. Methods for Cleavage of ArOAms to Phenols.

method	reagents	ref
A	NaOH (large excess), EtOH, reflux (5–8 h)	Sanz et al. 2005;214 Zou et al. 2009215
B	DBU, Et2NH, MeCN, rt	Yoshida et al. 2014;216 Medina et al. 2014217
C	LiAlH4, THF, refluxa,b LiAlH4, Et2O, refluxc,d	aSchön et al. 2012;218bSibi et al. 198317 cYamazaki et al. 2010;219dZhang et al. 2019220
D	cat. Rh/i-PrOH, toluene, K3PO4, 180 °C, 4 h	Yasui et al. 2017221
E	TFA (0 °C), 6 min (rt)	Metallinos et al. 1999116
F	Cp2Zr(H)Cl (Schwartz reagent), THF, rt, 2–12 h	Morin et al. 2013;184 Zhao et al. 2014222

Method F was based on the reduction procedure initially implemented by Spletstoser et al. in the reduction of amides to aldehydes.²²³ Under conditions using commercially acquired Schwartz reagent (3 equiv), an assortment of ArOAms afforded the corresponding phenols in moderate to excellent yields (Table 11).¹⁸⁵

Table 11. Schwartz Reagent Mediated Reduction of Select ArOAms Using the Georg Procedure^d.

^aYields of isolated products.

^b5 equiv.

^c6 equiv of Schwartz reagent required for full conversion.

^dAdapted from ref (185). Copyright 2013 American Chemical Society.

Moreover, Zhao et al. developed economically valuable in situ generation of Schwartz conditions for the ArOCONR₂ → ArOH transformation (see Table 12).^222,224 The demonstrated in situ reduction method is highly effective, accomplished in several hours (TLC analysis), to provide good yields of isolated phenol products. When compared with the direct Schwartz reagent reduction, the in situ method is an equally efficient and less expensive practical approach for the reductive cleavage of aromatic O-carbamates to phenols.

Table 12. Reduction of Selected ArOAms to Phenols Using in Situ Generated Schwartz Reagent^c.

^aYields of isolated products.

^bYields in parentheses refer to direct Schwartz reduction; see Table 11.

^cAdapted from ref (222). Copyright 2014 American Chemical Society.

Both direct (Spletstoser et al.²²³) and the greatly more economical in situO-carbamate reduction methods comprise practical procedures for the synthesis of a variety of phenols, especially costly and less available ones, such as 3,5-disubstituted phenols.²²⁵ Future valuable synthetic opportunities may be anticipated with combined DoM–Schwartz reduction and DoM–Suzuki CC–Schwartz reduction practices for the assembly of challenging-to-obtain multisubstituted phenols of type 165 or 166 (Figure 5).

Figure 5.

Synthetic potential of combined ArOAm DoM–Schwartz reduction chemistry.

A useful variation of O-carbamate DoM chemistry encompasses the in situ protection of secondary carbamates 167 (against the known fragmentation to phenols and isocyanates) by TMSOTf/TMEDA as the N-silylated species 168, which, upon sequential treatment with s-BuLi and electrophile (E⁺) to the ortho-conditions, accomplishes, through 169, provision of the phenols 170 (Table 13).^201,226

Table 13. In Situ TMS Protection and DoM of 167 Followed by Electrophile Quench (to Form 168), Deprotection of the N-Silyl Group (to 169), and Hydrolytic Cleavage of the Aryl-O,N-Isopropylcarbamate Functionality to Form Phenols 170.

^aCbH = CONHi-Pr.

Of particular interest was the use of this chemistry in the preparation of 3,3-disubstituted 2,2-dihydroxy-1,1-binaphthyls, frequently used as chiral ligands in enantioselective catalysis.²²⁷ In this case, the N,N-bis(trimethylsilyl)diurethane was reacted with s-BuLi/TMEDA before being quenched with excess TMSCl to form 169e in 96% yield (entry 5). Subsequent carbamate cleavage using aqueous NaOH gave the bis-silylated BINOL derivative 170e [the I-enantiomer] in 99% yield.²²⁶

This chemistry was also useful when combined with the meta-arylation of ArOAms, enabling an easily accessible route to meta-aryl phenols (Scheme 30).²²⁸ Electron-donating and electron-withdrawing substrates were all well tolerated, generating the desired products (171a,b,e–j) in good yields. An ortho-arylated product (para to the OMe group), 171c, was obtained in 19% yield as a side-product in the reaction to form 171b. The authors attributed this to the strong influence exerted by the ArOAm group over the OMe group in directing the incoming aryl moiety. Compound 171d was produced by exclusive meta-arylation of naturally occurring estrone.

Scheme 30. Scope of meta-Arylation of ArOAms.

Adapted from ref (228). Copyright 2021 American Chemical Society.

7.1.2. Reductive Removal of OAm

ArOAms can also be reductively cleaved such that the O-carbamate group is removed completely. Sengupta et al.²²⁹ demonstrated this in 1992 for the first time by reductively cleaving 172 to 173, using a Ni(0) catalyst and i-PrMgX as reducing agent (Scheme 31a). This was subsequently extended to the synthesis of phenanthrenes from biaryl amides (exemplified by 174a–c), in which application of the turbo-Grignard reagent (i-PrMgCl·LiCl) in the Ni-catalyzed Corriu–Kumada reaction enabled efficient reductive decarbamoylation to form compounds 177a–c (Scheme 31b).²³⁰

Scheme 31. (a) Reductive Cleavage of 172 to 173 upon Treatment with i-PrMgCl/Ni(acac) (Adapted from ref (229), Copyright 1992 American Chemical Society) and (b) Transformation of Biaryls 174 through 175 and 176 to Phenanthrenes 177 (Adapted from ref (230), Copyright 2015 American Chemical Society).

Later, Mesganaw and co-workers found that reductive cleavage at 178 occurred efficiently using catalytic amounts of NiCl₂(PCy₃)₂ together with 1,1,3,3-tetramethyldisiloxane (TMDSO) and K₃PO₄ in toluene at 115 °C, affording arenes 179 (both fused and nonfused aromatics) in reasonable yields (Table 14).²³¹ For example, entry 2 shows a convenient approach to the preparation of borylated indoles (179b), while entry 3 demonstrates that fused aromatics were excellent substrates, as 178c gave rise to product 179c via a double-decarbamoylation in 82% yield.

Table 14. Select Examples of ArOAms 178 Undergoing Ni-Catalyzed Cine Substitution to 179^b.

^a62% yield over 2 steps (DoM-borylation followed by cine substitution).

^bAdapted from ref (231). Copyright 2012 American Chemical Society.

Yasui et al.²²¹ demonstrated an alternative route which employs a rhodium catalyst along with i-PrOH as a milder reductant than either i-PrMgX or hydrosilane (which react with functional groups such as ketones, pyridyls, and unsaturated bonds). This reductive cleavage method extends the utility of the ArOAm group to the synthesis of multiply functionalized arenes, as exemplified by the synthesis of compound 182 via a combined DoM-reductive cleavage sequence (Scheme 32). However, from a green chemistry perspective, this new approach still operates under relatively harsh conditions (temperature) and utilizes a nonrecycled precious metal catalyst.

Scheme 32. A Synthetic Application of the Reductive Cleavage.

Adapted with permission from ref (221). Copyright 2017 Thieme.

7.2. AoF Rearrangement-Product Manipulation

The use of the AoF rearrangement (section 4) provides various opportunities for one-pot conversions of the ArOAm group to other functional groups, including o-hydroxyacetophenones (67) and 2′-hydroxychalcones (68) via derivatives of N,N-diethyl-2-hydroxybenzamides, 66 (Scheme 14). The reader is referred to section 4.1 for more details.

In addition, the AoF rearrangement products 183, upon mild lithium aluminum hydride (LAH) reduction, affords 2-(aminomethyl)phenols 184a–j in yields ranging from 65% to 81% (Table 15).²³² This provides an alternative facile route to the classical formaldehyde-amine reaction with phenols to prepare these Mannich bases,^233−235 which, as incipient ortho-quinodimethide species, have seen considerable use for Diels–Alder cycloaddition chemistry.^236−238

Table 15. Reduction of the AoF Rearrangement Products to Mannich Bases^a.

^aAdapted with permission from ref (232). Copyright 2009 Thieme.

7.3. Decarboxylation of ArOAm to Form Aromatic Amines

Nishizawa and co-workers²³⁹ demonstrated that ArOAms 185 can be decarboxylated to form aryl amines 186 using a nickel catalyst and a bisphosphine ligand immobilized on a polystyrene support, producing CO₂ gas as a byproduct (Scheme 33). The ligand is key to the success of this reaction, as it generates a catalytic species that is significantly more active than nonsupported variants by enabling more control over the metal complexation by the bisphosphine unit (suppressing any undesired comproportionation, which is initiated when two metal centers collide). This procedure tolerates a range of functionalities (including ketones) as it proceeds in the absence of free amines but has only been demonstrated for the formation of tertiary amines.

Scheme 33. Nickel-Catalyzed Decarboxylation of ArOAms 185 to Amines 186.

Adapted from ref (239). Copyright 2019 American Chemical Society.

To prepare primary and secondary amines from ArOAms, the protocol involves nickel-catalyzed amination of ArOAms with ammonia and primary amines, respectively.^240−242 More details concerning this latter chemistry are included in section 8.5.

7.4. Conversion of N,O-Diaryl Carbamates into Ureas

Yamasaki et al.²⁴³ developed a method to transform N,O-diaryl carbamates directly and spontaneously into N,N′-diarylureas (Table 16). The Et₃N catalyzes the reaction by abstraction of the carbamate proton, forming the aniline derivative, which can then react with more of substrate 187 to form diarylurea 188.

Table 16. Select Examples of N,O-Diaryl Carbamates 187 Converted into Ureas 188 Based on the Method Developed by Yamasaki et al.^243a.

entry	187	R1	R2	yield (%)
1	a	4-nitrophenyl	C6H5	87
2	b	4-methoxyphenyl	C6H5	75
3	c	benzyl	C6H5	0
4	d	C6H5	4-nitrophenyl	91
5	e	C6H5	4-methoxyphenyl	80

^aReproduced with permission from ref (243). Copyright 2018 Pharmaceutical Society of Japan.

7.5. Conversion of ArOAm to ArOCONRCHO

Lian et al.²⁴⁴ established a simple and economical CuCl₂-photoredox system for the oxidative functionalization of a wide range of nonreactive amine derivatives, including carbamate 44 (Scheme 34). This method utilizes molecular oxygen for the oxidation of the terminal C–H bond and an inexpensive catalyst system under exceptionally mild conditions, complementing current methods that require stoichiometric toxic and expensive reagents.

Scheme 34. Simple and Economical Photoredox Oxidative Functionalization of Terminal C–H Bond in O-Carbamate 45.

Adapted with permission from ref (244). Copyright 2022 Royal Society of Chemistry.

7.6. Conversion of ArOAm to Triflates

One approach to convert ArOAms to aryl triflates involves initial cleavage of the O-carbamate to the phenol followed by deprotonation of the phenol to form a phenoxide, which then reacts with trifluoromethanesulfonic anhydride or some other analogue of Comin’s reagent.^216,245 This process can also be performed in one pot.^217,246 Some examples from the literature for various substrates (substituted arene 190,^217,247 benzo[b]thiophene 191,²⁴⁶ pyridine 192,²⁴⁸ and thiophene 193(249)) are shown in Scheme 35a–d, respectively.

Scheme 35. Selected Examples of One-Pot Transformation of ArOAm Group to Aryl Triflate as Demonstrated in (a) Substituted Arenes 190 (Adapted with Permission from ref (247), Copyright 2018 American Association for the Advancement of Science); (b) benzo[b]thiophenes 191 (Adapted with Permission from ref (246), Copyright 2018 Royal Society of Chemistry); (c) Pyridines 192 (Adapted with Permission from ref (248), Copyright 2013 Springer Nature)²⁴⁸ and (d) Thiophenes 193 (Adapted from ref (249), Copyright 2021 American Chemical Society); Structures of Selected Arynes That Can Be Formed Thereafter Are Also Shown (198–200).

Overall, the process occurs via the initial deprotonation of the carbamate NH by a base (e.g., n-BuLi), leading to the loss of isopropyl isocyanate, which reacts irreversibly with the diethyl amine to form a urea, leaving a phenoxide (rather than ArOH). After warming, addition of the triflating agent (e.g., PhNTf₂) gives the ArOTf. This transformation is limited to secondary ArOAms. To triflate tertiary ArOAms, it is necessary to cleave the ArOAm to form a ArOH before applying a triflating agent.^245,250,251

The synthetic significance of introducing triflates ortho to TMS lies in the preparation of arynes. A typical procedure involves OAm-directed regioselective C-silylation via ortho-lithiation, removal of the directing OAm group, triflylation, and fluoride-mediated activation. It enabled the preparation of a benzyne,^{216,217,245,247} thienobenzyne,^246,249 indolyne,²⁵¹ pyridine,²⁴⁸ and chromene-type aryne²⁵⁰ precursors, for example. The structures of selected arynes (198–200) are shown in Scheme 35.

7.7. Borylation of ArOAm

Aryl, alkenyl, and heteroArOAms could be converted into boronic acid esters by nickel-catalyzed borylation.^252,253 This was realized using two sets of catalytic systems (with either NaOt-Bu or K₃PO₄ as complementary base), covering a broad substrate scope, such as is represented by the preparation of neopentyl glycol boronic esters (Bneo) 201 (Table 17).

Table 17. Borylation of Naphthyl, Aryl, and HeteroArOAms Using Two Sets of Systems (Bneo = Neopentyl Glycol Boronic Esters)^c.

^aCondition A: [Ni(PCy₃)₂Cl₂] (5 mol %), PCy₃ (20 mol %), NaOt-Bu (1 equiv), 110 °C, 24 h.

^bCondition B: [Ni(PCy₃)₂Cl₂] (5 mol %), K₃PO₄ (1 equiv), PhMe:DME (1:1), 100 °C, 48 h.²⁵²

^cAdapted with permission from ref (252). Copyright 2011 John Wiley and Sons.

Whereas NaOt-Bu gave better yields for naphthyl carbamates, K₃PO₄ was preferred for the borylation of phenyl and heteroaryl carbamates, due to effects of steric hindrance (compare the yields of neopentylglycolborylation reactions to give 201a,b,g,h). Oxygen-containing groups such as MeO (201c) were compatible despite having been shown to be very reactive in previously reported CC transformations.²⁵⁴ The borylation was extended to alkenyl carbamates to afford 201i, with both bases enabling similar yields. Steric hindrance as well as electronic properties influenced the efficacy of reactions carried out with different derivatives of 2-naphthol, e.g., borylation of naphthalen-2-yl dimethylcarbamate enabled the borylated product 201a in 81% yield versus 76% for naphthalen-2-yl diethylcarbamate and 41% for naphthalen-2-yl acetate.

Using an iron(II) triflate [Fe(OTf)₂] catalyst to activate the C–O bond, Geng et al.²⁵⁵ borylated more than 55 alkenyl and aryl carbamates (and five biomolecules containing the ArOAm functionality). The resulting borylated products could be formed in reasonable yields with good functional group tolerance (e.g., Cl, F, CF₃, Tips, 2-pyridyloxy, and benzyl ether). Select examples (202a–p) are shown in Figure 6. These boronic esters can then undergo Suzuki–Miyaura CC reactions with suitable aryl halides.

Figure 6.

Selected examples of products of the borylation of alkenyl and ArOAms catalyzed by Fe(OTf)₂ to demonstrate the scope of the chemistry developed by Geng et al.²⁵⁵ Adapted from ref (255). Copyright 2020 American Chemical Society.

Wang et al.²⁵⁶ developed a photocatalytic strategy for the ipso-borylation of substituted arenes with a very broad range of inert C–X bonds, including C–O bonds of phenol derivatives, such as carbamate 44, by using thiolate as a catalyst in a radical borylation reaction, thereby expanding the scope of available aryl radical precursors. Despite the high reducing power, this reaction leads to borylated products in moderate yield (Scheme 36).

Scheme 36. Photoinduced Thiolate-Catalytic Strategy for the ipso-Borylation of a Strong C–O Bond in Carbamate 44.

Adapted with permission from ref (256). Copyright 2021 Springer Nature.

7.8. Sulfonamidation of ArOAm

McGuire et al.²⁵⁷ demonstrated that naphthyl O-carbamate 60 could be coupled with aryl sulfonamide 204 to form N-(naphthalen-1-yl)benzenesulfonamide (205) in 95% yield (by GC) using the air-stable precatalyst (PhPAd-DalPhos)NiCl(o-Tol) (CAS 2290490-29-6) (Scheme 37).

Scheme 37. Ni-Catalyzed N-Arylation of a Primary Sulfonamide with Naphthyl O-Carbamate.

Adapted with permission from ref (257). Copyright 2020 John Wiley and Sons.

Given the potential applications of benzenesulfonamides as carbonic anhydrase inhibitors,^258−260 it would be beneficial to expand the substrate scope, e.g., by evaluating substituted naphthyl O-carbamates and ArOAms as substrates.

7.9. Amidation of ArOAm

There is also one isolated example of the amidation of phenyl O-carbamate 44 (Scheme 38). This was performed by Kathiravan et al.²⁶¹ as part of a screening process involving the copper catalyzed amidation of aryl halides and other functionalized arenes.

Scheme 38. Amidation of Phenyl O-Carbamate 44 to Form N-Phenyl-N-Hexanamide (207) in 10% Yield.

Adapted with permission from ref (261). Copyright 2015 Royal Society of Chemistry.

7.10. Cyanation of ArOAm

Takise et al.²⁶² developed an environmentally friendly and easy-to-use method for arylnitrile synthesis using carbamates (exemplified by 208) and metal-free cyanating agents, aminoacetonitriles (Scheme 39a).

Scheme 39. Selected Substrate Scope for Cyanation of (a) (hetero)ArOAms 208 to Form (Hetero)arylnitriles 210 and (b) Enols 211 to Give Alkenyl Nitriles 212.

Adapted from ref (262). Copyright 2016 American Chemical Society.

The reaction was catalyzed by Ni/dcype (1,2-bis(dicyclohexylphosphino)ethane) catalyst. Of the various aminoacetonitriles investigated, the morpholinoacetonitrile (209) gave the best yields of the products 210. The method was also applicable to the synthesis of heteroaryl (HetOAm) 210e and alkenyl nitriles 212 from the corresponding HetOAm 208e and enol derivatives 211, respectively (Scheme 39b).

8. Cross-Coupling (CC) Reactions Involving ArOAm

8.1. Introduction

The synthesis of new carbon–carbon (C–C), carbon–nitrogen (C–N), carbon–hydrogen (C–H) and carbon–silicon (C–Si) bonds usually occurs through transition metal-catalyzed CC reactions, with aryl halides generally playing the role of the electrophilic coupling partner.^263−268 However, because of their costly synthesis and the halide waste produced, cheaper and greener alternatives have been explored such as phenols and phenolic derivatives, sometimes referred to as pseudohalides in this context.^269−272 Thus, along with other DMGs,¹³⁵ ArOAms have recently found utility as a C(sp²)–O electrophilic coupling partner^{271,273−277} due to their relative stability²⁷⁰ and their use as a directing group in metalation (section 2) and C–H activation chemistry (section 10). Indeed, combining DoM with CC for ArOAms is an effective strategy for synthesis of polyaromatic compounds. There are several CC strategies which complement the DoM reaction for ArOAms: arylation, alkylation, and alkynylation. In this section, we will discuss each coupling strategy according to the type of metal-catalyzed CC, which we have based on the coupling reagents, following a broad definition of CC set out by Reimann et al.²⁶⁷

8.2. Suzuki–Miyaura CC Reactions

8.2.1. DoM Installation of Boronic Acid, Followed by Suzuki–Miyaura CC Reactions

The Nobel prize discovery of the Suzuki–Miyaura reaction^278−280 provided opportunities for DoM-CC combined chemistry. Sharp and Snieckus were among the first to confirm this potential via efficient CC of aryl boronic acids derived by DoM with aryl, heteroaryl, and benzyl bromides to yield unsymmetrical biaryls,²⁸¹ subsequently applied to the first steps of the large-scale synthesis of losartan (sold under the brand name Cozaar).²⁸² The now-appreciated DoM strategy has witnessed numerous applications and extensions, including extensive application in the synthesis of bioactive molecules (section 9).

As a demonstration of the expectant value of the DoM-CC strategy, conversion of 28a into ortho-boronic acid 28al by direct DoM, quenching with trimethyl borate,²⁸³ or via the corresponding TMS reagent followed by ipso-borodesilylation,²⁰² followed by the CC procedure under standard conditions (Ar¹Br as limiting reagent/3 mmol % of Pd(PPh₃)₄/2 M Na₂CO₃(aq)/toluene/reflux/6–12 h) gives biaryl 213 (Scheme 40). Repetition of the sequence through 214 affords triaryl 215. The incorporation of DMGs into Ar¹ and/or Ar² of 215 clearly suggests further iterative processes.

Scheme 40. ortho-Boronation to Form 28al Followed by Suzuki–Miyaura CC for the Synthesis of Triaryl Compound 215.

Adapted from ref (113). Copyright 2011 American Chemical Society.

ArOAms can couple with aryl boronic acids via Suzuki–Miyaura–CC chemistry catalyzed by either nickel, rhodium, or iron catalysts. Each of these metal catalysts is discussed in more detail below.

8.2.2. Nickel-Catalyzed CC Reactions of ArOAm

Consideration of bond dissociation energies suggested the expectation of using ArOAms directly in Suzuki–Miyaura CC.¹¹³ After considerable exploration, conditions of NiCl₂(PCy₃)₂ catalysis under defined ratio of starting (ArBO)₃ (aryl boroxine):ArB(OH)₂ = 10:1 (4 equiv) resulted in a general synthesis of biaryls in good to excellent yields,¹¹³ as shown by the examples provided in Table 18.

Table 18. CC of Heteroaryl- and ArOAms with Select Aryl Boronates to Form Substituted Biaryl Compounds 216^b.

^a[Ar–B(OR)₂], ratio of (ArBO)₃:ArB(OH)₂ = 10:1.

^bAdapted from ref (113). Copyright 2011 American Chemical Society.

The discussed methodology is amenable to substrates bearing electron-donating and electron-withdrawing groups (entries 1–4), in addition to those that occupy ortho-substituents (entry 5) and heterocyclic structures (entries 6–7). In the case of electron-withdrawing groups, unlike the meta-F derivative 28am (entry 3), which gave a high yield (69%), the p-cyano derivative 28an (entry 4) gave an anomalous result (low yield of 216d) because of CC at the cyano group, resulting in a mixture of products. Thus, the ability of other functional groups to participate in CC needs to be taken into consideration when designing DoM-CC procedures.

The first CC of ArOAms with aryl boronic acids was simultaneously published in 2009 by Quasdorf et al.²⁸⁴ and Antoft-Finch et al.²⁰ Both groups employed the same stable commercially available and air/moisture stable catalyst [NiCl₂(PCy₃)₂] and similar conditions (base, heating) except that Antoft-Finch et al. also used an air-stable ligand, tricyclohexylphosphine tetrafluoroborate (PCy₃HBF₄) for the CC and included several reactions with heteroArOAm substrates (Scheme 41). Quasdorf et al.²⁸⁴ also used aryl boronic acid ArB(OH)₂ which reversibly forms aryl boroxine (ArBO)₃ at elevated temperatures (Scheme 41a), while Antoft-Finch et al. employed a 10:1 mixture of (ArBO)₃ and ArB(OH)₂, commonly referred to as ArB(OR)₂ (Scheme 41b).²⁰

Scheme 41. Ni-Catalyzed CC of ArOAms as Reported by (a) Quasdorf et al.²⁸⁴ and (b) Antoft-Finch et al.²⁰ Separately but Simultaneously in 2009.

(a) Adapted from ref (284). Copyright 2011 American Chemical Society. (b) Adapted from ref (20). Copyright American Chemical Society.

A few years later, in a collaborative effort, the two groups joined together and extended this work¹¹³ to improve the yields for some of the compounds already appearing in their separate 2009 work and to demonstrate CC of new ortho-substituted ArOAms. This included the synthesis of polysubstituted aromatic compounds (PAHs) as exemplified by the synthesis of 5-phenyl-2H-chromene 221 (Scheme 42), a heterocyclic scaffold of interest for bioactive compounds²⁸⁵ and natural products.²⁸⁶ The synthesis of 221 commences from bis(carbamate) precursor 219: sequential treatment with t-BuLi, 3-methylbut-2-enal, and AcOH in one-pot enables the conversion of compound 219 into 2H-chromene carbamate 220. Suzuki–Miyaura CC of 220 with PhB(OR)₂ provided biaryl 221 in 56% yield. More examples of the use of DoM-CC sequence to form bioactive compounds and PAHs can be found in section 9.

Scheme 42. Synthesis of 5-Phenyl-2H-chromene 221 Beginning from Bis(carbamate) Precursor 219 ([PhB(OR)₂], Ratio of (PhBO)₃:PhB(OH)₂ = 10:1.

Adapted from ref (113). Copyright 2011 American Chemical Society.

Shortly after the initial 2009 reports, Xu et al.²⁵³ developed the Suzuki–Miyaura reaction of ArOAms with a mixture of aryl boroxine (ArBO)₃ and 0.88 equiv of H₂O, using [NiCl₂(PCy₃)₂] as a precatalyst (selected substrates shown in Scheme 43). Using aryl boroxines results in an improvement in the coupling efficiency for electron rich ArOAms. These are typically challenging substrates for this type of chemistry due to deactivation of the ArOAms by the electron-donating substituents.

Scheme 43. Suzuki–Miyaura CC of ArOAms with Aryl Boroxines Using [NiCl₂(PCy₃)₂] as a Precatalyst.

Adapted from ref (253). Copyright 2010 American Chemical Society.

Thus, coupled products (e.g., 216a,i) were produced, albeit in slightly lower yields than for naphthyl and phenyl carbamates with electron-withdrawing groups (e.g., in forming 216j,k). The use of aryl boroxines also offered lower catalyst loading (1 mol %) for alkenyl O-carbamates and easy scale-up.

Baghbanzadeh et al.²⁸⁷ demonstrated that microwave (MW) heating enabled a shorter reaction time and reduced amount of phosphine ligand for both fused and nonfused aromatics (Table 19). Remarkably, the yields of challenging substrates (those with electron-donating groups) were significantly higher when prepared using MW heating compared with conventional heating (e.g., entry 2).

Table 19. ArOAms in Microwave-Assisted Suzuki–Miyaura CC Reactions^c.

^aNiCl₂(PCy₃)₂ (5 mol %), ArB(OH)₂ (2.5 equiv), K₃PO₄ (4.5 equiv), toluene (0.3 M), 110 °C, 24 h.²⁸⁴

^b[Ni(Triaz^Nme2-I-Pr)Cl] (2 mol %), ArB(OH)₂ (1.5 equiv), K₃PO₄ (2 equiv), toluene (0.025 M), 135 °C, 16 h.²⁸⁸

^cAdapted from ref (287). Copyright 2011 American Chemical Society.

Shortly after this, Leowanawat et al.²⁸⁹ explored CC of ArOAms in Ni-catalyzed CC with phenyl neopentylglycolboronates containing electron-rich and electron deficient substituents in the para-position (Scheme 44). Generally, low yields were reported for the coupling products (216l–p). In some cases, 0% yield was recorded, although this could be improved using sulfamate and sulfonate directing groups to give 216p.

Scheme 44. CC of ArOAms with para-Substituted Aryl Neopentylglycolboronates.

Adapted from ref (284). Copyright 2012 American Chemical Society. ^a 4.5 equiv of CsF, ^b 3 equiv of K₃PO₄, ^c toluene, and ^d THF.

Malineni et al.²⁹⁰ went further to develop an air stable and yet reactive Ni(II) precatalyst (more reactive than currently employed Ni(II)phosphine complexes and π-Ni(0) precatalysts) for the CC of naphthyl O-carbamate (62) with aryl neopentylglycolboronates 222 containing para-electron-rich and electron deficient substituents in quantitative yields (Scheme 45).

Scheme 45. CC of Naphthyl OAm with Aryl Neopentylglycolboronates Catalyzed by Ni^IICl(1-naphthyl)(PCy₃)₂/PCy₃.

Adapted with permission from ref (290). Copyright 2016 Thieme.

Ohtsuki et al.²⁹¹ were the first to demonstrate Ni/NHC-catalyzed CC of ArOAms with arylboron reagents (Table 20), with the optimal catalyst/ligand combination consisting of bis(cyclooctadiene) nickel(0) [Ni(COD)₂] and NHC ligands bearing 2-adamantyl groups (generated the most active nickel species among the ligands examined).

Table 20. Nickel/NHC-Catalyzed CC of ArOAm 28a with p-Tolylboronic Esters 223^a.

entry	boron reagent (223)	ligand	yield of 216q (%)
1	a	L5	70
2	a	PCy3	trace
3	b	L5	39 (61)b
4	b	PCy3	trace
5	c	L5	81
6	c	PCy3	75

^aAdapted from ref (291). Copyright 2016 American Chemical Society.

^b160 °C.

An advantage of using an NHC over the PCy₃ ligand in the nickel-catalyzed Suzuki–Miyaura reaction is the anhydrous nature of the reaction, and therefore its tolerance of aryl boronic esters (essentially boronic acid PGs), enabling reliable understanding of reaction stoichiometry (aryl boronic esters have known molecular masses), and facilitating reactions when the analogous boronic acids are unstable,²⁹² or for boron compounds prepared by C–H borylation (typically boronic esters).²⁹³

In another study involving a variation of the nickel catalyst, Mastalir et al.²⁸⁸ focused on 4-methoxyphenyl diethylcarbamate (28ak), demonstrating that it could be coupled with phenylboronic acid using an air-stable triazine-based Ni(II) PNP pincer complex using K₃PO₄ as base. The yield for this reaction was 84%, higher than what was achieved using alternative conditions (67%,;²⁸⁷ 41%,²⁸⁴) (Table 19, entry 2). Hence, it is unfortunate that no other ArOAms were tested in their study.

Yet another variation of the nickel catalyst was reported by Purohit et al.:²⁹⁴ nickel–palladium heterobimetallic nanoparticles (NPs) were developed for activation of C–O bonds in ortho-heteroaryl-tethered aryl carbonates for Suzuki–Miyaura cross-coupling with aryl boronic acids. However, these NP catalysts (generated in situ from NiCl₂·6H₂O and PdCl₂) were also found to catalyze the coupling of an aryl O-carbamate (224) with boronic acid 225 to form 226 in a modest 50% yield (Scheme 46).

Scheme 46. Ni–Pd Binary NP-Catalyzed Suzuki–Miyaura Cross-Coupling of ortho-Heteroaryl-Tethered Aryl O-Carbamate 224 with Boronic Acid 225 to Form Cross-Coupled Product 226.

Adapted from ref (294). Copyright 2017 American Chemical Society.

As already mentioned, the O-carbamate functionality is inert to certain catalysts, e.g., Pd(PPh₃)₄. This allows ArOAm to assume an orthogonal CC partner role when linked with the Ni coupling strategy.^20,295,296 For example, the synthesis of 229 (Scheme 47) involves the Suzuki–Miyaura CC of 227 and 2-iodobenzofuran 228;²⁹⁵229 can then be coupled with phenylboronic acid (230) using a Ni catalyst to form compound 231 in 52% yield.

Scheme 47. Synthetic DoM-CC Interconnections of ArOAms 227 and 229: (a) Pd-Catalyzed Coupling of 227 and 228 to Form 229; (b) 229 Is Coupled with Phenylboronic Acid (230) Using a Ni-Catalyst to Form 231.

Adapted from ref (295). Copyright 2009 American Chemical Society.

The inertness of O-carbamate functionality toward Pd-catalysts is also evident in the work of Cívicos et al.,^297,298 who attempted to use an oxime palladacycle 233 as a catalyst for the CC of naphthalen-2-yl dimethylcarbamate 232 and phenylboronic acid 230 (Scheme 48). A disappointing <5% yield for the desired 2-phenylnaphthalene (216n) was reported.

Scheme 48. An Attempt to Use Oxime Palladacycle 233 for the Suzuki–Miyaura Arylation of Naphthalen-2-yl Dimethylcarbamate 232.

Adapted with permission ref (297). Copyright 2012 John Wiley and Sons. TBAB = tetra-n-butylammonium bromide.

Inaloo et al.²⁹⁹ developed recoverable and reusable magnetic catalysts to create a more sustainable approach to C–C bond formation. The catalysts consisted of nickel(II) nanoparticles immobilized on EDTA-modified iron catalysts for oxide coated with silica (Fe₃O₄@SiO₂) nanospheres and were explored as recyclable ligand-free Suzuki–Miyaura coupling of ArOAms with phenylboronic acids. The nanoparticle catalysts were used to catalyze CC reactions between various ArOAms and phenylboronic acid substrates. As shown by a few selected examples in Scheme 49 (conditions A), the process enabled CC in good to excellent yields of product 216. The yield of the reaction decreased negligibly over six cycles (catalyst recovered and regenerated before each fresh run), indicating the recyclability of these NPs.

Scheme 49. Suzuki–Miyaura CC of ArOAms Catalyzed by Ni(II) (Condition A) or Ni(0) (Condition B) Nanoparticles Immobilized on EDTA-Modified Fe₃O₄@SiO₂.

Adapted from ref (299). Copyright 2020 American Chemical Society.

The same authors modified their procedure to incorporate Ni(0) catalysts, i.e., nickel(0) nanoparticles immobilized on EDTA-modified Fe₃O₄@SiO₂ nanospheres [Fe₃O₄@SiO₂–EDTA–Ni(0)] as these were believed to lead to higher yields of coupled products compared with Ni(II).³⁰⁰Scheme 49 (conditions B) shows some examples of CC reactions performed with these recyclable catalysts. A close analysis of these results (and the other published results) reveals that there is not a significant difference between using Ni(II) versus Ni(0).

In a similar study intended to make the Suzuki–Miyaura process more sustainable, Ramgren et al.³⁰¹ successfully performed Ni-catalyzed CC of ArOAms with aryl boronic acids in green solvents (2-methyltetrahydrofuran; tert-amyl alcohol). Five substrates including fused and nonfused ArOAms as well as a carbazole and quinoline O-carbamate were coupled with phenylboronic acid, providing coupled products in good to excellent yields (63–100%).

Molander and Beaumard³⁰² developed a general method for the Ni-catalyzed C–O activation of various phenol derivatives (including that of 1-naphthyl O-carbamate) with potassium (hetero)aryltrifluoroborates. When evaluated alongside other phenol derivatives in a reaction with potassium furan-3-yltrifluoroborate (234), 1-naphthyl O-carbamate 60 afforded the product 216v less efficiently in a 55% yield (Scheme 50), whereas the O-mesylate, tosylate, sulfamate, and pivaloyl provided the corresponding products in quantitative, 85%, 85%, and 68% yields, respectively.

Scheme 50. Reaction of 1-Naphthyl O-Carbamate (60) with Potassium Furan-3-yltrifluoroborate 234.

Adapted from ref (302). Copyright 2010 American Chemical Society.

There is also one isolated example of the Ni-catalyzed reaction of 1-naphthyl O-carbamate 60 with ethyl acetate as a feedstock solvent, reported by MacMillan et al.³⁰³ (Scheme 51).

Scheme 51. Reaction of 1-Naphthyl O-carbamate 60 with Ethyl Acetate to Form 235.

Adapted with permission from ref (303). Copyright 2022 John Wiley and Sons.

8.2.3. Rhodium-Catalyzed CC Reactions of ArOAm

The research groups of Tobisu and Chatani (Osaka University)³⁰⁴ collaboratively developed rhodium-catalyzed CC of phenyl (Scheme 52a) and naphthyl O-carbamates (Scheme 52b) with organoboron reagents using an NHC ligand to form coupled products 216.

Scheme 52. Examples of Products Prepared via Suzuki–Miyaura Reaction of (a) Phenyl O-Carbamates and (b) Naphthyl O-Carbamates with Boronic Esters (Ester Group = Neopentylglycolate), Using a Rhodium Catalyst.

Adapted with permission from ref (304). Copyright 2015 Elsevier.

This reaction involves the rhodium-mediated activation of the relatively inert C(aryl)–O bond of the aryl carbamates. Similar to the work carried out by Mastalir et al.,²⁸⁸ the use of an NHC ligand bearing a 2-adamantyl group was essential to the success of the reaction.

8.2.4. Iron-Catalyzed CC Reactions of ArOAm

An example of Fe-catalyzed CC reaction of aryl and heteroArOAms with alkyl bromides via inert C–O bond activation was reported by Chen et al.³⁰⁵ (Scheme 53). This reaction proceeds under mild conditions with good functional compatibility and yields the alkylated arenes and pyridines 236 with good efficiency. This protocol enables the late functionalization of bioactive compounds, the direct alkylation of phenols and the simple synthesis of multisubstituted arenes.

Scheme 53. Selected Examples of Iron-Catalyzed CC Reaction of Aryl and HeteroArOAms with Alkyl Bromides into Alkylated Arenes and Pyridines 236^d.

L1 (0.1 equiv), FeCl₂ (0.1 equiv).

L2 (0.1 equiv), FeBr₂ (0.1 equiv).

L1 (0.1 equiv), FeBr₂ (0.1 equiv).

This figure has been published in CCS Chemistry in 2023, ref (305).

Another example of Fe-catalyzed coupling reaction is a simple silylation of aryl and alkenyl O-carbamates to 237 by activation of the C–O bond (Scheme 54), developed by Zhang et al.³⁰⁶ The reaction is highly efficient with a broad substrate range and high yield and could be used for late silylation of bioactive compounds, offering potential applications in drug discovery and development.

Scheme 54. Examples of Iron-Catalyzed Silylation of Aryl and Alkenyl O-Carbamates into Silylated Products 237.

Adapted from ref (306). Copyright 2020 American Chemical Society.

8.3. Kumada–Corriu CC Reactions

8.3.1. Nickel-Catalyzed Kumada–Corriu CC Reactions

To test the possibility of the equally respected Kumada–Corriu CC reaction, Sengupta et al.²²⁹ applied Ni(0)-catalysis, demonstrated the first general application of ArOAms in CC with Grignard reagents to give substituted biaryls 216 (Scheme 55a). This discovery established a distinctive ortho-functionalization through combined DoM-nucleophilic ipso-substitution (28a), introducing a concept of 1,2-dipole equivalency 238 (Scheme 55b), different to what is observed for aryl O-triflates.²²⁹

Scheme 55. (a) General Ni(0)-Catalyzed CC Reactions of ArOAms with Grignard Reagents (to Form Biaryl 216); (b) in the Combined DoM-Nucleophilic ipso-Substitution, the ArOAm Substrate Can Be Viewed as an Aromatic 1,2-Dipole Equivalent (238).

Adapted from ref (229). Copyright 1992 American Chemical Society.

In contrast to methyl-, TMSCH₂-, and aryl-Grignards, affording the corresponding products 216 (R′ = Me, TMSCH₂, and Ar, respectively), n-BuMgCl, and i-PrMgCl, caused reductive removal of the O-carbamate group (introduced in section 7.1.2.). The authors demonstrated the utility of the concept shown in Scheme 55b by consecutive DoM introduction of carbamoyl and silyl electrophiles on to 60 to form 239 (Scheme 56), which, upon treatment with i-PrMgCl/Ni(acac)₂, afforded 240, a compound offering further DoM chemistry options.

Scheme 56. DoM-Mediated Consecutive Introduction of Carbamoyl and Silyl Electrophiles to Naphthyl O-Carbamate 60, Leading to 239, Which, upon Treatment with i-PrMgCl/Ni(acac)₂, Gives 240.

Adapted from ref (229). Copyright 1992 American Chemical Society.

Similar to the work done by Sengupta et al. (Scheme 55), Murugesan et al.³⁰⁷ achieved nickel-mediated CC of naphthyl and heteroArOAms with silylmagnesium reagents under ambient conditions for a wide range of ArOAms (Scheme 57). For instance, 1-naphthyl diethylcarbamate gave the silanes 241a–c in 82–93% isolated yield depending on the bulkiness of the silylmagnesium reagent. It was interesting to note the compatibility of certain functional groups with this chemistry, notably fluoride (241d), Bpin (241e), TMS (241f), ethers (241g), and morpholine (241h). Three heterocycles were also shown to tolerate these reaction conditions namely pyrazole (not shown), pyridine (241i,j) and quinoline (241k).

Scheme 57. Examples Showing Scope of Aryl and Naphthyl O-Carbamate Substrates Undergoing Silylation.

Adapted with permission from ref (307). Copyright 2019 Elsevier.

There is also one report of methyltrimethylsilylation of naphthalene-2,7-diyl bis(diethylcarbamate) 242 (Scheme 58).³⁰⁸ This was carried out using [(trimethylsilyl)methyl]magnesium chloride in the presence of Ni(acac)₂ to form 243, which was subsequently transformed into the unsymmetrical dibromide 244, found to undergo cyclo-oligocondensation to form tetrameric [2.2.2.2]naphthalenophane 245, potentially useful as a chiral host molecule (through modification of the bromine atoms by larger groups, suppressing ring inversion) or as a precursor to curved aromatic compounds via intramolecular C–C coupling reactions. Interestingly, there are no reports of CC between nonfused ArOAms and silylmagnesium reagents in the literature. The poor reactivity of ArOAms (and nonfused aryl compounds in general) can be attributed to a dearomatization process (based on possible coordination from arene π-bond to metal via η²-fashion) that occurs during the oxidative addition step. This is not observed in fused π-systems due to the inherent stabilization they provide.^{254,309−312}

Scheme 58. Synthesis of [2.2.2.2](2,7)-1-Bromonaphthalenophane 245 Commencing with Naphthalene-2,7-diyl Bis(diethylcarbamate) 242.

Adapted with permission from ref (308). Copyright 2019 John Wiley and Sons.

Other examples showcasing nickel-catalyzed Kumada–Corriu CC reactions with aryl O-carbamates are shown in Table 21. Coupling of m-oxygen (entry 1) and o-oxygen (entry 2) EDGs with Grignard reagents (RMgX) occurs in reasonable yields, while comparison of triflate with O-carbamate shows reduced yield for the more highly hindered carbamates (entries 3a and 3b). The scope of this chemistry is illustrated by the functionalization of steroids (entry 4), although it has also been demonstrated with phenethylamines, naphthyls, phenanthryls, binaphthyls, pyridines (entry 5), quinolines, and uracils.²²⁹

Table 21. Ni(0)-Catalyzed CC of Aryl and HeteroArOAms with Grignard Reagents (RMgX)^b.

^aVariable yield presumably due to possible Grignard-induced decarbamoylation.

^bAdapted from ref (229). Copyright 1992 American Chemical Society.

Kinsman and Snieckus³¹³ applied this chemistry to the preparation of indole quaternary salts (248), useful for the synthesis of 4,5-fused indoles (250 or 251) via trapping with a variety of dienophiles such as methyl acrylate (to form 250) or dimethyl acetylene dicarboxylate (to form benz[e]indole, 251) (Scheme 59). Synthesis of 250 or 251 was achieved by the initial preparation of the precursor 246 by DoM of indole O-carbamate 155 (electrophile = Et₂NCOCl), followed by nickel-catalyzed Grignard-O-carbamate CC to form benzyl silane 247. Compound 247 was then converted to the quaternary salt 248 via DIBAL reduction followed by treatment with MeI. Compound 248 could then undergo cycloaddition with several dienophiles (in a large excess) in the presence of CsF or TBAF at ambient temperature to form the desired cycloadducts (250 or 251) in good to excellent yields (69–95%), except for cycloadduct 252 (trapping with N-phenylmaleimide and diisopropyl azodicarboxylate), formed in 40% yield.³¹³

Scheme 59. Synthesis of 4,5-Fused Indoles (250 and 251) and New Ring System 252 by Combined DoM/Nickel-Catalyzed CC Followed by Cycloaddition with Various Dienophiles.

Reaction conditions: (a) (i) s-BuLi, TMEDA, THF, −78 °C; (ii) Et₂NCOCl; (b) TMSCH₂MgCI, Ni(acac)₂, THF, 50 °C, 4 h; (c) (i) DIBAL, THF, 0 °C to rt, (ii) Rochelle salt; (d) MeI, MeCN, rt, 12 h; (e) (Boc)₂O, CsF, MeCN, rt, 12 h. ^a Adapted with permission from ref (313). Copyright 1999 Elsevier.

The product heteroaryl/naphthyl silanes shown in Schemes 55–58 and Table 21 have further utility because the silane groups can now be replaced by halogens,³⁰⁷ protodesilylated,^314,315 borylated,³¹⁶ carboxylated,³¹⁷ or used as a site for further CC.^318−322

In a separate study published by Yoshikai et al.³²³ involving similar chemistry to that shown in Scheme 58, when p-cresol derivatives were coupled with phenylmagnesium bromide, a considerable amount of the homocoupling product (253) was formed (Table 22, entry 1). In the presence of hydroxyphosphine ligands (PO ligands), however, the desired product (216) formed in 95% yield (entry 2). This could be replicated with a diversity of ArOAm substrates (entries 3–6).

Table 22. Ni-Catalyzed CC Reaction of ArOAms with Phenylmagnesium Bromide^a.

				yield (%)
entry	R	Ni catalystb	reaction time (h)	216	253
1	4-Me	Ni(acac)2 (5 mol %)	2.5	64	27
2	4-Me	Ni(acac)2/PO (3 mol %)	1	95	4
3	4-OMe	Ni(acac)2/PO (3 mol %)	1	90
4	2-OMe	Ni(acac)2/PO (3 mol %)	18	87
5	3-NH2	Ni(acac)2/PO (3 mol %)	1	96
6	estrone	Ni(acac)2/PO (5 mol %)	6	89 (254)

^aAdapted from ref (323). Copyright 2009 American Chemical Society.

^bPO = hydroxyphosphine ligands.

The PO ligands accelerate the Ni(0)-catalyzed CC reactions of ArOAms (and other unreactive electrophiles) with Grignard reagents via a nickel phosphine/magnesium alkoxide bimetallic species that activates the C–O bond in the aryl-O-carbamate functionality.

Only one example of a CC reaction involving an ArOAm (in this case, naphthyl O-carbamate) with an aryl halide has been reported in the literature.³²⁴ In this case, the authors reported Ni-catalyzed CC of various naphthol-based electrophiles with aryl bromides in the presence of magnesium in the synthesis of 2-(p-tolyl) naphthalene 216as (Scheme 60), i.e., a nickel-catalyzed Kumada–Corriu CC. Under the given conditions, naphthol (255a) was unsuitable as a substrate unless protected as an isopropyl ether (255b), pivalate ester (255c), or O-carbamate (255d). No further reactions were carried out using the naphthyl O-carbamate (255d). To the best of our knowledge, CC between aryl bromides and nonfused ArOAms has not yet been reported but would be a suitably valuable chemo-transformation.

Scheme 60. Yields of Select Examples (Product 216as) from the CC of Naphthol (255a) and Protected Naphthol (255b–d) with 1-Bromo-4-methylbenzene (It-Bu = 1,3-di-tert-butylimidazol-2-ylidene).

Adapted from ref (324). Copyright 2016 American Chemical Society.

8.3.2. Iron-Catalyzed Kumada–Corriu Alkylations and Arylations of ArOAm

Li et al.³²⁵ demonstrated Fe(II)-catalyzed CC of naphthalen-2-yl dimethylcarbamate (256) with n-hexylMgCl to form 2-hexylnaphthalene (258a) in 80% yield (compared with naphthalen-2-yl pivalate (257), which only formed 2-hexylnaphthalene in 40% yield) (Scheme 61a). This chemistry was further explored with more substrates (ArOAms and alkyl-based Grignard reagents) by Silberstein et al.,¹⁷⁴ obtaining a range of compounds (56, 258b–i) in good to excellent yields (Scheme 61b).

Scheme 61. (a) Fe(II)-Catalyzed CC of Naphthalen-2-yl Dimethylcarbamate (256) with n-HexylMgCl (Adapted from ref (325), Copyright 2009 American Chemical Society); (b) Expansion of the Scope of Substrates for the Fe(II)-Catalyzed CC (Adapted from ref (174), Copyright 2008 American Chemical Society).

Wang et al.³²⁶ reported a Fe/Ti-cocatalyst system that efficiently catalyzed the biaryl couplings between ArOAms and aryl Grignard reagents (Scheme 62). The catalyst system FeCl₃/SIPr (SIPr = 1,3-bis(2,6-diisopropylphenyl)imidazolinium) with Ti(OEt)₄/PhOMgBr transformed O-carbamate 259 and phenylmagnesium bromide 260 into the desired product 216a in 78% yield. Various sensitive functional groups, including ester (216ad), nitrile (216ae,af,ag,ah,ai) and amide (216af,ah,aj) groups, were well tolerated on both the electrophilic (ArOAm) and nucleophilic (Ar’MgX) partners, with no notable addition of the Grignard reagents to these groups detected. CC to sterically hindered biaryls were also achieved smoothly (216n,ac,ae,af,aj).

Scheme 62. Selected Example of the Iron-Catalyzed CC of Aryl Dimethylcarbamates 259 with PhMgBr (260) to Give 216 and the Substrate Scope.

Adapted from ref (326). Copyright 2019 American Chemical Society.

Compared to aryl iodides (261a), ArOAm were less reactive and allowed selective coupling of iodide over OCONMe₂ (entry 1, Table 23). On the other hand, the reactivity of the chloride 261c was only slightly higher than that of the carbamate, resulting in a significant decrease in selectivity (entry 3).

Table 23. Reactivity Comparison of Selected Electrophiles in Kumada–Corriu Arylations Using an Fe/Ti Cocatalyst System^a.

entry	ArOAm	X	yield (%) of product 216ak	yield (%) of product 216al
1	261a	I	78	11
2	261b	Br	63	25
3	261c	Cl	56	31

^aAdapted from ref (326). Copyright 2019 American Chemical Society.

The Kumada–Tamao–Corriu coupling reaction has also been catalyzed using a rhodium–aluminum bimetallic complex.³²⁷ However, prior screening showed that the O-carbamate was not as good a leaving group as chloride, fluoride, or the mercapto group.

8.4. DoM-Negishi CC Reactions

Not surprisingly, the O-carbamate moiety is stable toward Pd-catalyzed Negishi CC reactions, thus providing the opportunity for chemoselective arene manipulations such as has been shown by Griffen et al.²¹³ in the preparation of 4-(pyridinyl)indole 264 (Scheme 63). The coupling partner 262 was prepared by initial s-BuLi mediated DoM of 155, quenching with ZnBr₂.

Scheme 63. Preparation of 4-(Pyridinyl)indole 264.

Adapted from ref (213). Copyright 1995 American Chemical Society.

Kalinin et al.³²⁸ exploited the inertness of the ArOAm group to Negishi CC conditions further by using this to prepare arylalkyl ketones (265), which could then be transformed regiospecifically into substituted 4-hydroxycoumarins (267) via a carbamoyl Baker–Venkataraman rearrangement involving intermediate 266 (Scheme 64).

Scheme 64. Scheme Showing the Synthesis of 4-Hydroxycoumarins 267 Commencing with ArOAms and Proceeding via a Carbamoyl Baker–Venkataraman Rearrangement.

Adapted with permission from ref (328). Copyright 1998 Taylor & Francis.

This methodology was also used in the preparation of 2-(3-thienyl)-O-aryl carbamates, e.g., 269, where the organozinc compound 268 was prepared by initial organolithium mediated DoM of 28ak, quenched with ZnCl₂ (Scheme 65a).²⁹⁵ The Negishi CC reactions to the furyl analogue 271, in which the coupling partners were used with reversed functionality, starting from 28p via the corresponding iodide 270, was found to be more efficient (Scheme 65b).

Scheme 65. Synthesis of Representative: (a) 2-(3-Thienyl)-O-aryl Carbamate 269 and (b) Furyl Analogue 271 via Negishi CC.

Adapted with permission from ref (295). Copyright 2009 American Chemical Society.

8.5. Amine CC Reactions of ArOAm

Shimasaki et al.³²⁹ were the first to report the amination of an ArOAm: the nickel-catalyzed coupling of phenyl diethylcarbamate with morpholine to form 4-phenylmorpholine (Table 24, entry 1). Mesganaw et al.³³⁰ were the first to demonstrate this chemistry on a large scope of ArOAms and secondary amine (cyclic/acyclic) and aniline substrates using the same nickel catalyst [Ni(COD)₂], NHC ligand (SIPr·HCl, 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride), and base (NaOt-Bu) (Table 24, entries 2–8).^329,330

Table 24. Amination of Aryl and Heterocyclic O-Carbamates^a,^b.

^aReaction conditions: [Ni(COD)₂], NHC ligand (SIPr·HCl), base (NaOt-Bu), toluene, 80 °C, 3 h.

^bEntry 1: adapted with permission from ref (329). Copyright 2010 John Wiley and Sons. Entries 2–8 (Mesganaw et al.) adapted from ref (330). Copyright 2011 American Chemical Society.

For example, the reaction was successful with both electron-rich and electron poor ArOAms (entries 2, 3, and 6), heterocycles (entries 4 and 8), and sterically hindered carbamates (entry 5) and anilines (entry 7). A few years later, the research groups of Schranck²⁴⁰ and Stradiotto^241,242 extended this scope to include ammonia and primary amines, both research groups using specially designed nickel(II) precatalysts. Schranck and co-workers²⁴⁰ realized the amination of naphthyl O-carbamates with ammonia and greener and cheaper ammonium salts (Table 25, entries 1–3), while Stradiotto’s group^241,242 performed amination of aryl and naphthyl O-carbamates with ammonia and primary alkylamines (Table 25, entries 4–8).

Table 25. Nickel-Catalyzed Amination of ArOAms^a,^d.

^aConditions A (Schrank et al.²⁴⁰): Nickel precatalyst (CAS no. 2049086-35-1), L, NH₃/(NH₄)₂SO₄/RNH₃Cl, NaOt-Bu, o-xylene, 110 °C, 16 h. Conditions B (MacQueen et al.²⁴¹): Nickel precatalyst (CAS no. 1998756-52-7), L, NH₃/RNH₂, NaOt-Bu, 1,4-dioxane, 80 °C, 16 h. Conditions C (Bodé et al.²⁴²): Nickel precatalyst (CAS no. 1594113-09-3/2688050-42-0), L, NaOt-Bu, 1,4-dioxane, 65 °C, 18 h.

^bL = CyPF-Cy.

^cL = CyPBn-Cy.

^dEntries 1–3: Schrank et al., adapted with permission from ref (240). Copyright 2017 John Wiley and Sons. Entries 4–8: Stradiotto and coworkers, Adapted with permission from ref (241). Copyright 2017 Thieme.

Similarly, Hie et al.³³¹ developed an approach to the amination of ArOAms that makes use of an air-stable Ni(II) precatalyst. In combination with a mild reducing agent (e.g., phenylboronic acid pinacol ester), this catalyst provides aminated products (select examples, 272a–h) in reasonable to excellent yields (Scheme 66). As can be seen, the scope of the method is broad with respect to both coupling partners and includes heterocyclic substrates.

Scheme 66. Amination of ArOAms Using Various Amines.

Adapted from ref (331). Copyright 2009 American Chemical Society.

Similar to their work mentioned previously (section 8.2.2), Inaloo et al.^332,333 developed recoverable and reusable magnetic Ni(0) catalysts in an effort to create a circular, more sustainable approach to C–N bond formation. Two different catalysts were prepared: nickel(0) and nickel(II) nanoparticles (NPs) immobilized on EDTA-modified Fe₃O₄@SiO₂ nanospheres [Fe₃O₄@SiO₂-EDTA Ni(0)]. Both catalysts were used to direct amination of (hetero)ArOAms without the need for an external ligand and reducing agent with a range of (hetero)arylamines and primary and secondary alkylamines (Table 26). For example, heterocyclic amines such as imidazole (entries 1, 6–8), indazole (entries 2 and 9), and indole (entry 10) gave the desired coupling product with various ArOAms in good yields. N-Arylation of nucleobases occurred in good yield (e.g., guanine, entry 3); it was interesting to note that arylation occurred exclusively over other potential coupling positions (amine groups). Aliphatic amines were successfully coupled as well, e.g., phenylmethanamine (entry 4) and dibutylamine (entry 5). Both catalysts were recovered and reused in six subsequent runs for the coupling of phenyl diethylcarbamate with pyrrole (the “model reaction”) with a reduction in yield of 3–4% by the end of the 6 runs. Thus, despite the initial synthesis and characterization, these magnetic NPs seem to be a worthwhile investment.

Table 26. Nickel-Catalyzed Amination of ArOAms Using Fe₃O₄@SiO₂-EDTA-Ni(0) and -Ni(II) NPs^c.

^aConditions A: Fe₃O₄@SiO₂-EDTA-Ni(0) NPs, Ni catalyst (1 mol % Ni), NaOt-Bu (2 mmol), ethylene glycol (EG), 100 °C, 12 h.

^bConditions B: Fe₃O₄@SiO₂-EDTA-Ni(II) NPs, Ni catalyst (1 mol % Ni), NaOt-Bu, EG, 100 °C, 12 h.

^cConditions A: adapted with permission from ref (332). Copyright 2020 Royal Society of Chemistry. Conditions B: adapted with permission from ref (333). Copyright 2020 Elsevier.

Nathel et al.³³⁴ developed an amination procedure which could be performed in the green solvent 2-methyl-THF. Although the process was geared toward the amination of aryl chlorides and sulfamates, one example of the coupling of 2-naphthyl OAm with morpholine was demonstrated, forming the coupled product 273 in 76% yield (Scheme 67a).

Scheme 67. Scope of the Buchwald–Hartwig Amination Reaction with Naphthyl and (Hetero)aromatic OAms: (a) with NaOt-Bu (Adapted from ref (334), Copyright 2014 American Chemical Society); (b) under Exogeneous Base-Free Conditions (Adapted with Permission from ref (335), Copyright 2022 Springer Nature).

(a) Ni(cod)₂ (10 mol %), dcypt, 3,4-bis(dicyclohexylphosphaneyl)thiophene (20 mol %), NIE (2.0 equiv), amine (1.0 equiv), PhMe (0.2 M), 160 °C, 24 h.

Ni(cod)₂ (10 mol %), dcypt (20 mol %), NIE (1.5 equiv), amine (1.0 equiv), PhMe (0.2 M), 160 °C, 24 h.

Ni(cod)₂ (5 mol %), dcypt (10 mol %), amine (1.0 equiv), PhMe (0.2 M), 150 °C, 24 h.

Similarly, Toupalas and Morandi³³⁵ demonstrated new Buchwald–Hartwig amination conditions involving aryl and naphthyl O-carbamates without the use of an exogeneous inorganic base, problematic for the formation of heterogeneous reaction mixtures and are incompatible with certain substrates such as 6-bromoisoquinoline-1-carbonitrile³³⁶ and primary and secondary β-fluorinated alkyl amines.³³⁷ The major change was the use of the O-carbamates as “non-innocent electrophiles (NIE)”, as they contained a masked base (−N(I-Pr)₂) that is released during the oxidative addition step. Substrates included diisopropyl aryl and naphthyl O-carbamates and a diverse set of primary as well as secondary aryl/alkyl amines to form naphthyl and aryl amines 274 and 275, respectively (select examples shown in Scheme 67b). Aryl amines allowed for near-quantitative coupling (e.g., 274b), while base-sensitive primary and secondary β-fluorinated alkyl amines provided reasonable yields of the corresponding products (e.g., 274d). Electron-deficient ArOAm substrates afforded products in quantitative yield (e.g., 275a), whereas electron-rich ones required slight adjustments to the reaction conditions to provide yields >15% (e.g., 275b,c, and 275e). The methodology was compatible with a range of FGs (e.g., phenothiazines, enabling synthesis of 274e) and heteroaromatic ArOAms and amines (e.g., enabling the formation of 274a and 275d).

8.6. Arylations of ArOAm

8.6.1. Ni/Cu-Catalyzed Coupling of Polyfluoroarenes with ArOAm

Wang et al.³³⁸ reported the CC of ArOAms with polyfluoroarenes using a cooperative Cu/Ni catalytic system (the Ni catalyst activates the C–O bond, while the Cu cocatalyst activates the C–H bond). Such fluorinated compounds are potentially useful due to their unique physicochemical and biological properties.³³⁹ Using Ni(COD)₂ as catalyst, CuF·3PPh₃·2EtOH as cocatalyst, and 1,2-bis(dicyclohexylphosphino)ethane (dcype) as ligand, various nonfused and fused ArOAms were reacted with a range of polyfluoroarenes (276), with examples shown in Scheme 68.

Scheme 68. CC of Polyfluoroarenes with ArOAms by Cooperative Ni/Cu Catalysis.

Adapted from ref (338). Copyright 2016 American Chemical Society.

The methyl-substituted naphthyl O-carbamate provided a higher yield than the nonsubstituted analogue (277a versus 277b) due to better solubility. The low yield of 277c can be attributed to desilylation of the TMS group by the presence of fluoride anion. Also, as expected, an electron-deficient carbamate substrate (277e) enabled a higher yield than an electron-rich one (277d). Good yields were obtained for substrate quinolinyl N,N-dimethylcarbamate (277f), whereas the benzoylphenyl O-carbamate substrate required double the catalyst and ligand loading and yet 277g was only obtained in 51% yield. The electronic character of the polyfluoroarene substrate can influence the yield (277h–j).

8.6.2. Nickel-Catalyzed Arylation of ArOAm

Ogawa et al.³⁴⁰ developed CC chemistry between aromatic aluminum reagents 278 and ArOAms in the presence of a Ni catalyst [NiCl₂(PCy₃)₂], as shown by selected substrates (Scheme 69). It was found that (1) the reactivity of the ArOAms was lower than their naphthyl counterparts (216am), although heating afforded biaryl products in high yields (216a,u,am); (2) the reaction conditions were tolerated by a variety of functional groups including methoxy (216a), trifluoromethyl (216u), ester (216an), amide (216ao), as well as various heterocycles, e.g., thiophene (216t) and pyridine (216s,ap,aq,ar); (3) electron-rich aromatic aluminums showed higher reactivity compared with their electron-deficient analogues (compare 216ap with 216ar); and (4) steric factors could be overcome with heating to achieve decent yields (216am and 216aq).

Scheme 69. CC between Aluminum Reagents and ArOAms in the Presence of a Ni catalyst.

Adapted from ref (340). Copyright 2017 American Chemical Society.

It was further observed that alkenyl- and alkynyl-aluminum reagents could also be utilized for this CC, providing the corresponding products in reasonable yields (also see section 8.7).

Muto et al.³⁴¹ demonstrated the first Ni-catalyzed C–H arylation and alkenylation of imidazoles (and other 1,3-azoles) 279–280 with ArOAms to form benzimidazoles/imidazoles/triazoles (281a–h) and thiazoles/oxazoles (282a–c) (Scheme 70). The arylations/alkenylations with ArOAms was accomplished using an Ni(OTf)₂/diphosphine/K₃PO₄/t-amylOH system. The choice of diphosphine ligand determined the efficiency with which the arylation or alkenylation occurred. 1,2-Bis(dicyclohexylphosphino)ethane (dcype) facilitated the C–H arylations, while 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) promoted C–H alkenylations. Notably, the success of the couplings was dependent on the use of a tertiary alcohol solvent, enabling the use of an air-stable Ni (II) salt (acts as the catalyst precursor).

Scheme 70. Substrate Scope of C–H Arylations and Alkenylations of (a) Imidazoles (279, Except for c, Which Is a Triazole) and (b) other 1,3-Azoles (280) with ArOAms.

^a Adapted with permission from ref (341). Copyright 2015 Royal Society of Chemistry. ^b dcypt as ligand was used. ^c Ni(OTf)₂ (10 mol %) and dcypt (12 mol %) were used. (dcype = 1,2-bis(dicyclohexylphosphino)ethane, dcypt = 3,4-Bis(dicyclohexylphosphino)thiophene).

Steinberg et al.³⁴² showed that it is also possible to cross couple ArOAms with benzoxazoles 283 and oxazoles 284 (Scheme 71). Under the optimal conditions, ArOAms performed similarly to the corresponding pivalates and mesylates.

Scheme 71. Substrate Scope of C–H Arylations of (a) Benzoxazoles 283 and (b) Oxazoles 284 with ArOAms into 285 and 286, Respectively (dcypt = 3,4-Bis(dicyclohexylphosphino)thiophene).

Adapted with permission from ref (342). Copyright 2017 Elsevier.

8.6.3. Cobalt-Catalyzed Arylation of ArOAm

Song and Ackermann³⁴³ used inexpensive cobalt catalysts to perform arylations of (hetero)arenes with ArOAms over a wide scope of substrates, including phenylpyridines and pyrimidines 287 and indoles 290, with select examples shown in parts a and b of Scheme 72.

Scheme 72. Cobalt-Catalyzed Direct Arylation of Heteroarenes: (a) Phenylpyridines/Phenylpyrimidines and (b) 1-(Pyridin-2-yl)-1H-indoles, with ArOAms to Form Coupled Products 288, 289, and 291.

Adapted with permission from ref (343). Copyright 2012 John Wiley and Sons. DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.

Arenes with electron-donating and electron-withdrawing substituents enabled synthesis of the desired products 288, 289, and 291 in overall high yields. The synthesis of 288a proceeded in a 74% yield at room temperature, while the synthesis of phenylbenzo[h]quinolines 289 using cobalt catalysts gave yields equivalent to or higher than when using them when prepared with rhodium^344−346 or ruthenium^347,348 catalysts. Different pyridyl-directing groups as well as a less electron-donating 2-pyrimidyl substituent ensured selectivity at the C2 position (288b–e). Similarly, mono-N-substituted indoles were also selectively arylated at the C2 position, enabling the synthesis of sterically encumbered 291f.³²⁴

8.6.4. Rhodium-Catalyzed Arylation of Aryl Oxazoles

The research groups of Tobisu and Chatani³⁴⁹ developed chemistry enabling the arylation of aryl oxazoles using ArOAms as arylating agents (Scheme 73).

Scheme 73. Arylation of a Series of Aryl Oxazoles 292 with Various ArOAms 293 Using in Situ Generated Rhodium Bis(NHC) Catalyst.

Adapted with permission from ref (349). Copyright 2017 John Wiley and Sons.

Key to the procedure was the in situ generation of a rhodium bis(NHC) catalyst, needed for activation of the inert C(sp²)–O bond of the ArOAms. A range of substrates could be coupled together, from aryl carbamates with a range of functional groups, including ketones (294ab), nitriles (294ad), fluorides (294ac and 294ae), amides (294ak), and heteroaromatic carbamates (294al and 294am), to arenes where arylation occurs exclusively at the less hindered C–H bond (294ca and 294da), while a sterically congested C–H bond can be arylated if it is the only reactive site (294ea). This arylation is also applicable to fused arenes (294ia) and heteroarenes (294ja and 294ka). The 4-methyl-4,5-dihydrooxazol-2-yl (Ox) group used as the directing group is easily converted to the carboxylic acid derivative, which allows further synthetic elaboration of the C–H/C–O coupling products. Because the carbamate group is completely stable under standard palladium-catalyzed CC conditions, further sequential functionalization of the C–X and C–O bonds is possible.

8.7. Alkynylation of ArOAm

The cooperative Cu/Ni catalytic system developed by Wang et al.³³⁸ (section 8.6.1) also proved to be effective for CC of terminal alkynes 297 with naphthyl O-carbamates, although only two substrates (295 and 296) were examined and under harsh reaction conditions (Scheme 74a). The organoaluminum reagent 298 developed by Ogawa et al.³⁴⁰ enabled the preparation of one phenyl alkyne 299c in good yield using slightly milder conditions (Scheme 74b).

Scheme 74. Extension of the (a) Cooperative Ni/Cu Catalytic System to the CC of Naphthyl O-Carbamates with Alkynes (Adapted from ref (338), Copyright 2016 American Chemical Society) and (b) Use of Organoaluminum Reagents to Prepare Phenyl-Based Alkynes (Adapted from ref (340), Copyright 2017 American Chemical Society).

Similarly, Yasui et al.³⁵⁰ reported the alkynylation of 15 diverse substrates, e.g., containing esters (299d), ketones (299e), and amides (299f), typically incompatible with organometallic alkynylating reagents (Scheme 75).²⁹² Naphthyl and heteroaromatic O-carbamates (e.g., quinoline) also provided the corresponding alkynylated products (299g,h).

Scheme 75. Examples of Aryl-O-carbamates Able to Participate in Rhodium-Catalyzed Alkynylation with Propargyl Alcohols.

Adapted from ref (350). Copyright 2018 American Chemical Society.

8.8. Alkylation of ArOAm

Chen et al.³⁵¹ demonstrated cross-electrophile coupling of (hetero)ArOAms with alkyl bromides, catalyzed by an iron/B₂pin₂ catalytic system to form alkylated (hetero)aryl compounds 300 (Scheme 76).

Scheme 76. Example of Products Formed during the Alkylation of (Hetero)aryl-O-carbamates with Alkyl Bromides.

Adapted with permission from ref (351). Copyright 2023 Chinese Chemical Society.

This reaction was found to proceed under mild conditions, enabling good functional group tolerability, as exemplified by the ester 300a. Alkylated pyridines 300c and 300d were produced by the meta- and para-alkylations of pyridine O-carbamates, respectively. Late-stage functionalization was demonstrated for five bioactive compounds, e.g., 300e (alkylation of estradiol with a cyclopentyl group). As was seen in the preceding example (Scheme 76), the type of reaction depended on the ligand used. Three different ligands were explored: TMEDA, (1R,2R)-N¹,N¹,N²-trimethyl-1,2-diphenylethane-1,2-diamine (L1) and (2,2,6,6-tetramethylheptane-3,5-dione) (L2). TMEDA was effective for over half of the transformations, while L1 (containing an unprotected primary amine group) was effective mainly for biphenyl O-carbamates (e.g., synthesis of 300b) and pyridines with the O-carbamate at the meta position (e.g., to form 300c), while L2 was only effective for facilitating transformations involving pyridines with the O-carbamate group at the para-position, e.g., to form compound 300d.

A striking feature of the O-carbamate group is that it can also act as a leaving group; this was demonstrated by Leith et al.³⁵² in the Ni(0)-catalyzed Grignard methylation of naphthyl O-carbamate (242), providing 2,7-dimethylnaphthalene 301 in the quest to prepare corannulene-based materials (Scheme 77a) (regrettably no yield for this reaction was provided). This aspect was first discovered by Sengupta and Snieckus,³⁵³ albeit with a vinylic substrate 302 (via 303) to form 304 (Scheme 77b). A similar reaction was carried out by Li et al.³⁵⁴ on an alkenyl O-carbamate (305) using a CrCl₂ catalyst with cyclohexylmagnesium chloride (c-Hex-MgCl) as alkylating agent (Scheme 77c). It would be interesting to see if this chemistry could be extrapolated to ArOAms and perhaps with other alkyl magnesium bromides, e.g., EtMgBr.

Scheme 77. (a) Ni(0)-Catalyzed Kumada–Corriu CC of 242 with MeMgBr to Form 2,7-Dimethylnaphthalene 301 (Adapted with Permission from ref (352), Copyright 2021 Royal Society of Chemistry); (b) an Example of a Vinylic DoM Reaction Followed by a Kumada–Corriu CC Reaction with Methylmagnesiumbromide (MeMgBr) to Form Prop-1-en-derivative 304 (Adapted from ref (353), Copyright 1990 American Chemical Society); (c) Cr(II)-Catalyzed Grignard CC Reaction of 305 with c-Hex-MgCl to Form 306 (Adapted from ref (354), Copyright 2019 American Chemical Society).

8.9. CC Reactions with Aryl Silane Reagents

Shi et al.³¹¹ extended nickel-catalyzed Stille CC of C–O electrophiles (aryl sulfamates, tosylates, and mesylates, to nickel-catalyzed CC of ArOAms with arylsilanes (307) to yield biaryl compounds (select examples shown in Scheme 78). This new coupling reaction demonstrates good functional group tolerance, e.g., toward amines (216au), esters (216av), nitriles (216aw), quinolines (216ay), thiophenes (216aaa), and TMS (216aab), includes nonfused ArOAms (216at) and fused aromatics (216ax), and is not affected negatively by steric hindrance on the ArOAm (216au) or arylsilane (216aab).

Scheme 78. Examples Showing Scope of Aryl and Naphthyl O-Carbamate Substrates Coupling with Arylsilanes.

Adapted with -ermission from ref (311). Copyright 2016 John Wiley and Sons.

The key to the success of these reactions was the use of CuF₂ to facilitate the transmetalation step of silicon reagents (to form more reactive organocopper reagents, as 309), shown in Scheme 79, and which has been observed in other similar scenarios.^355−357

Scheme 79. Proposed Mechanism of the Stille CC between ArOAms and Aryl Silanes, Showing the Roles Played by Ni(COD)₂ and the CuF₂.

Adapted with permission ref (311). Copyright 2016 John Wiley and Sons.

9. OAm in the Synthesis of Bioactive Molecules, Natural Products, and Polyaromatic Hydrocarbons (PAHs)

The methodology and utility of the OAm group presented in the prior sections has culminated in the synthesis of valuable end products in the form of bioactive molecules, natural products, and PAHs over the past decades. This section provides a summary of some of the compounds and compound architectures that have been prepared from substrates containing the OAm group. For more details and to compare the utility of OAm with other DMGs, we refer the reader to other in-depth publications.^{135,358−360}

We have classified the various reactions into four main pathways, namely: (1) regioselective aromatic functionalization with DoM and/or AoF rearrangement, (2) DoM followed by annulation/cyclization, (3) combined DoM-CC reactions, and (4) direct C–H/C–O bond arylation (see overview in Figure 7 below).

Figure 7.

Summary of different ways in which ArOAm has been utilized in the synthesis of complex molecules and PAHs.

9.1. Regioselective Aromatic Functionalization with DoM and/or AoF Rearrangement

Focken et al.³⁶¹ developed two routes for the lateral functionalization of monosubstituted [2.2]paracyclophanes. After protecting the ortho site of an O-([2.2]paracyclophanyl) diisopropylcarbamate 311, a remote Fries rearrangement led to the substitution of the benzylic position and gave syn-4-hydroxy-N,N-diisopropyl-5-triethylsilyl-2-[2.2]paracyclophanecarboxamide (313) in excellent yield and with a syn/anti diastereoselectivity of more than 99:1 (Scheme 80a). An alternative route involved direct functionalization of the lateral position of N-tert-butyl-4-[2.2]paracyclophanecarboxamide (316) by directed metalation. The reaction is highly stereoselective, and only syn isomer 317 is formed in high yields (Scheme 80b).

Scheme 80. Two Routes for the Lateral Functionalization of Monosubstituted [2.2]Paracyclophanes 311: (a) Protection of the ortho Site of 311, AoF Rearrangement, and Deprotection Gives 314 in Excellent Yield; (b) DoM Reaction of 316 Gives Only the syn-Isomer 317 in High Yield.

Adapted with permission from ref (361). Copyright 2001 John Wiley and Sons.

Nguyen et al.³⁶² synthesized the tetracyclic A/B/C/D ring core of the antitumor agent camptothecin (327) using a combined DoM/transition metal-catalyzed CC approach in seven steps and 11% overall yield (Scheme 81). The design is based on the initial coupling of 321, prepared by AoF rearrangement of quinoline 2-O-carbamate 319, with organozinc species (formed from 322 and ZnBr₂) to give 323, leading to the formation of the C-ring by simple functional group manipulation and cyclization (326). The simplicity of the steps, the ready availability of starting materials for both A/B- and D-ring fragments by DoM chemistry, and the potential for further modifications of the D-ring allow further synthetic studies of camptothecin.

Scheme 81. Synthesis of the Tetracyclic A/B/C/D Ring Core of the Antitumor Agent Camptothecin (327) Using a Combined DoM/Transition Metal-Catalyzed CC Approach as Key Steps in the Synthesis.

Adapted from ref (362). Copyright 2004 American Chemical Society.

Cai et al.³⁶³ used a combined DoM/Suzuki–Miyaura CC/DreM approach that provides short, efficient, and regioselective synthesis of alkylphenanthrenes 332 in four to seven steps and 21–36% overall yield (Scheme 82). This general strategy provides the phenanthrene class of PAHs as single isomers in preparative amounts and high purity that can be used as analytical standards.

Scheme 82. Regiospecific Synthesis of Alkylphenanthrenes 332 Using a Combined DoM/Suzuki–Miyaura CC/DreM Protocol.

Adapted with permission from ref (363). Copyright 2004 Canadian Science Publishing.

Kancherla et al.⁸⁷ demonstrate the utility and performance of the DoM strategy for the synthesis and derivatization of other larger PAH scaffolds such as chrysene 333 (Scheme 83). The starting O-carbamates 333 were prepared from the corresponding chrysenols available by oxidative photochemical cyclization or DreM tactics. Chrysen-1-yl and chrysen-3-yl ring site selectivity of DoM and AoF rearrangement protocols with s-BuLi/TMEDA followed by electrophilic quenching using a selection of electrophiles was observed and led to new chrysenyl derivatives 334–337. 5-Chrysenyl N,N-diethyl-O-carbamate underwent an immediate AoF rearrangement to chrysenyl o-hydroxycarboxamide 337 even at −100 °C.

Scheme 83. Derivatization of Chrysene, 333, One of the Larger PAH Scaffolds Using the DoM Strategy.

Adapted from ref (87). Copyright 2018 American Chemical Society.

The synthesis of sulfur analogues of the biologically active linear naphthopyrone semivioxanthin (338) is an example of the usefulness of the DoM method introduced by Pradhan and De.³⁶⁴ Analogue (342) of semivioxanthin, in which ring A of the natural product was replaced by thiophene, was synthesized in high overall yield (68–72%) from 339, using an AoF and transmetalation protocol (Scheme 84a). Both demethylation and desilylation occurred during cyclization to give an air-stable compound 342. In another example of semivioxanthin analogues, ring B of the natural product was replaced by thiophene (345) (Scheme 84b). The starting material (343) was subjected to a DoM and acid-induced cyclization protocol accompanied by demethylation of the methoxy groups. The air sensitive phenolic compounds were immediately O-methylated in high yield to give the air-stable compound 345.

Scheme 84. Examples of the Usefulness of the DoM Method in the Synthesis of Sulfur Analogues of Biologically Active Semivioxanthines (338).

Adapted from ref (364). Copyright 2005 The Japan Institute of Heterocyclic Chemistry.

The same authors also reported another class of fused heterocycles in which a [1,4]oxathiin ring is fused to an aromatic nucleus (346, 347). This synthesis is another example of the versatility of the DoM method. The introduction of a methylsulfanyl group in the ortho-position to the O-carbamate function (349) is followed by lateral metalation of the introduced functionality and anionic rearrangement in situ (350). Acid-induced cyclization of the rearranged product completes the annulation process (351). Tricyclic compounds can be prepared with [1,4]oxathiin rings fused angularly (346) or linearly (347) to a benzo[b]tiophene core (Scheme 85).

Scheme 85. Synthesis of Fused Heterocycles with a [1,4]Oxathiin Ring (346, 347) Using DoM, DreM-Rearrangement, and Cyclization.

Adapted from ref (364). Copyright 2005 The Japan Institute of Heterocyclic Chemistry.

Ma et al.³⁶⁵ presented bridging chiral p-tert-butylcalix[4]arenes (p-t-Bu-BCC’s) with various N-substituted carbamoyl bridge-substituents (N,N-dimethylcarbamoyl, 354a; N,N-diethylcarbamoyl, 354b; morpholinocarbonyl, 354c) by AoF rearrangement from mono-O-carbamates of 1,3-dipropyl-p-tert-butylcalix[4]arene 353 in 65–75% yield (Scheme 86). In addition, p-t-Bu-BCC with two N,N-dimethylcarbamoyl bridging substituents 356a was also prepared by this method from mono-O-carbamate of p-t-Bu-BCC 355a with one N,N-dimethylcarbamoyl bridging substituent in 71% yield. The racemic p-t-Bu-BCC with a morpholinocarbonyl bridging substituent 357c was also optically resolved into a pair of diastereomers 357c-1 and 357c-2 in 90% overall yield (357c-1, 48%; 357c-2, 42%).

Scheme 86. Chiral p-tert-Butylcalix[4]arenes (p-t-Bu-BCCs), 354a–c, with Various N-Substituted Carbamoyl Bridge Substituents, and p-t-Bu-BCC with Two N,N-Dimethylcarbamoyl Bridge Substituents 356a, Prepared by AoF Rearrangement, and Optical Resolution of 357c into a Pair of Diastereomers 357c-1 and 357c-2.

Adapted with permission from ref (365). Copyright 2020 John Wiley and Sons.

The Reinhoudt group applied the DoM concept for the introduction of upper rim functional groups via a 4-fold homologous AoF rearrangement in the doubly bridged tetra-O-carbamate 360 to prepare resorc[4]arene 361 in 68% yield (Scheme 87).³⁶⁶ Carbamate 360 was prepared by selective carbamoylation of methylresorc[4]arene 358, followed by bridging of the remaining OH groups in tetra-O-carbamate 359. Resorc[4]arene 361 could be further converted to 362, an interesting building block for supramolecular chemistry.

Scheme 87. First Example of a Four-fold Homologous AoF Rearrangement of 360 to the Double Bridged Tetrakis(carboxamidomethyl)resorc[4]aren 361, a Potentially Interesting Precursor for Supramolecular Chemistry (via 362).

Adapted with permission from ref (366) Copyright 2001 Canadian Science Publishing.

Carroll et al.³⁶⁷ developed a method for the synthesis of epibatidine analogues with fused 3,4-pyridine ring (363 and 364), a nicotinic acetylcholine receptor, starting from readily available pyridin-3-yl-diethylcarbamate (117) (Scheme 88). DoM of 117, followed by silylation to 365, cleavage of the carbamate group and addition of trifluoromethanesulfonic anhydride leads to 367, which reacts in a crucial step with tert-butyl-1H-pyrrole-1-carboxylate (368) to form 369. Catalytic hydrogenation of 369 gave 370. Treatment of 369 and 370 with hydrogen chloride in methanol gave the desired epibatidine analogues 363 and 364 in an overall yield of 6–10% each.

Scheme 88. Synthesis of a Nicotinic Acetylcholine Receptor Epibatidine Analogues with Fused 3,4-Pyridine Ring (363 and 364).

Adapted from ref (367). Copyright 2007 American Chemical Society.

Hao et al.³⁶⁸ presented another interesting ortho-lithiation of phenyl O-carbamates starting from phenols (371) treated with DMF (to form 372) and hydrolyzed with HCl in the final step to demonstrate a general route for the regioselective preparation of various ortho-hydroxybenzaldehydes 373 in moderate to excellent yields (Scheme 89). The chiral binaphthol carbaldehyde 373a is an example of a useful building block.

Scheme 89. An Efficient Route to the Preparation of Useful ortho-Hydroxybenzaldehydes 373 via ortho-Lithiation of O-Carbamates, Exemplified by Chiral Binaphthol 373a.

Adapted with permission from ref (368). Copyright 2008 CAOD (China/Asia on Demand).

An efficient ruthenium(II)-catalyzed C–H hydroxylation of ArOAms was developed for the facile synthesis of catechol (374) and pyrogallol derivatives (375) from readily accessible phenols (Scheme 90).³⁶⁹ This method has excellent regio- and chemoselectivity, good functional group tolerance and high yield, and offers a new route for the construction of some biologically important molecules. For example, l-DOPA can be easily obtained from the catechol derivative 374p, which is synthesized from protected l-tyrosine. In addition, catechols can be further converted into synthetically sophisticated, valuable pyrogallol derivatives (375a,b).

Scheme 90. A New Approach for the Synthesis of Catechol (374) and Pyrogallol (375) Derivatives by Ru-Catalyzed C–H Hydroxylation.

^aAdapted with permission from ref (369). Copyright 2014 John Wiley and Sons. ^b PhI(OAc)₂ (1.5 equiv) as oxidant instead of K₂S₂O₈.

Finally, Feberero et al.³⁷⁰ found that the regioselective DoM of O-(3-halophenyl)-N,N-diethylcarbamates 376 can be extended to a wide range of related carbamates with an additional halogen substituent (Scheme 91). The cooperative effect of the halide in meta-position to the carbamate group influences the reaction outcome. The organolithium intermediate can either be trapped with iodine at low temperature to give a variety of trihalophenol derivatives 377 in high yield (70–88%), or AoF rearrangement of the organolithium intermediate at room temperature leads to a broad family of new dihalosalicylamides 378 in high yield (76–91%).

Scheme 91. A Regioselective DoM of meta-Halogenated Carbamates 376 to Obtain Either Trihalophenol Derivatives 377 or Further AoF Rearranged Dihalosalicylamides 378.

Adapted with permission from ref (370). Copyright 2016 John Wiley and Sons.

9.2. DoM Followed by Annulation/Cyclization

The earliest preparation of PAH compounds using ArOAm was reported by Sibi et al. in 1984³⁷¹ and in 1985.³⁷² The work focused on the synthesis of isocoumarins (383), precursors for the toxic fungal metabolites ochratoxin B (384a) and ochratoxin A (384b), respectively (Scheme 92).

Scheme 92. Synthetic Scheme to Ochratoxin A and B (384) via Isocoumarins (383) Which Can Be Prepared from ArOAm (28a, 28ap) Using a Mix of DoM and AoF Chemistry (First Two Steps).

Adapted from ref (371). Copyright 1984 American Chemical Society. Adapted from ref (372). Copyright 1985 American Chemical Society.

The first steps were dependent on the ArOAm group for installation of the amide group followed by AoF to afford 380, which could be methylated to 381. Subsequent synthesis of isocoumarins 383a and 383b involved DoM/transmetalation chemistry followed by allylation and hydrolysis. The final step, as described by Bouisseau et al.,³⁷³ involves the coupling of 383 with l-phenylalanine-tert-butyl ester using oxalyl chloride followed by deprotection of the acid using TFA.

Two years later, a metalation/AoF/Suzuki coupling/lactonization was reported by Cheng and Snieckus in 1987³⁷⁴ for the synthesis of chromenopyridinone 391 (Scheme 93). The synthetic protocol commenced with synthesis of m-terphenyl 386 via Pd-catalyzed coupling of 385 and 28m, exploiting the inertness of OAm to Pd catalysis. Compound 386 was then metalated and allowed to warm to room temperature before the crude product was hydrolyzed with aq HCl and methylated with diazomethane (CH₂N₂) to afford amide 387. Using the amide functionality as a DMG, 387 was transformed into aryl boronic acid 388, which, when coupled with 389, provided the pyridotetraphenyl 390.

Scheme 93. Synthesis of Chromenopyridinone 391 via a Metalation/AoF/Suzuki Coupling/Lactonization.

Adapted with permission from ref (374). Copyright 1987 Elsevier.

Compound 390 was then converted to the chromenopyridinone 391 via a lactonization process. This scheme shows the old-fashioned approach for the cyclization of phenol to amide. In this case, the O-carbamate is basically just a protected phenol (spectator) and is hydrolyzed under rather harsh conditions. The diethylamide on the ring is probably also forced to lactonize under these conditions by the initial hydrolysis.

Similar compounds (393, 394, 396, 398, and 399) have been prepared by Snieckus et al.³⁷⁵ using DreM/AoF rearrangement/lactonization sequence (examples shown in Scheme 94a–c).

Scheme 94. (a) DreM/AoF/Lactonization of 392 to Form Isomeric Chromenopyridinones 393 and 394; (b) Regiospecific DreM Facilitated by meta-Substituted Pyridine to Form 396; (c) Synthesis of Isomeric Benzochromenopyridinones 398 and 399 by DreM/AoF/Lactonization of Naphthalenylpyridine 397.

Adapted from ref (375). Copyright 2012 The Japan Institute of Heterocyclic Chemistry.

In comparison, an alternative synthetic approach to the same class of compounds (401) was developed by Li’s research group, involving the rhodium(II)-catalyzed aryl C–H carboxylation of 2-pyridylphenols (400) with CO₂ (Scheme 95).^376,377

Scheme 95. Rhodium-Catalyzed Carboxylation of Aryl and Alkenyl C–H Bonds with CO₂.

Adapted with permission from ref (376). Copyright 2018 John Wiley and Sons.

Advantages of this approach include the use of CO₂,³⁷⁸ compatibility with challenging electron-deficient pyridine heterocycles, and avoidance of the formation of isomeric compounds.

James and Snieckus extended DreM/AoF rearrangement/lactonization sequence to the synthesis of heteroaryl-fused benzopyranones²⁹⁵Scheme 96a) and the aglycones of the gilvocarcins (V, M, and E), 402, and arnottin I (403)³⁷⁹ (Scheme 96b).

Scheme 96. DreM/CC Sequence Used (a) in the Synthesis of Heteroaryl-Fused Benzopyranones (Adapted from ref (295), Copyright 2009 American Chemical Society) and (b) in the Synthesis of the Aglycones of the Gilvocarcins (V, M, and E), 402, and Arnottin I, 403 (Adapted from ref (379), Copyright 2009 American Chemical Society); (c) The DoM/CC/DreM Sequence Used in the Synthesis of Dibenzo[b,d]pyranones, 404, and the Fluorenone Dengibsin, 405 (Adapted from ref (19), Copyright 2009 American Chemical Society).

A recently (2017) developed method for preparing the same compounds uses an N-heterocyclic carbene (NHC)-catalyzed reaction between enals and furanones,³⁸⁰ which is a greener, metal-free option.^381,382

Snieckus’ research group applied a DoM/Suzuki CC/remote AoF rearrangement/cyclization to produce dibenzo[b,d]pyranones (e.g., 404), and dengibsin (405), a naturally occurring fluorenone (from orchids)^19,383 (Scheme 96c). The synthesis of dengibsin was achieved in 15 steps (some steps omitted for clarity in Scheme 96c) by DreM. Since the publication of this synthesis in 1992, several synthesis protocols have been published for both dibenzo[b,d]pyranones and fluorenones. For example, dibenzo[b,d]pyranones have been prepared via a multicomponent (substituted salicylaldehyde, dimethyl glutaconate, cyclopentanone, base, solvent) domino reaction,³⁸⁴ a [3 + 3] cyclization of a 1,3-bis(silyl enol ether) with a 3-silyloxy-2-en-1-one,³⁸⁵ a [3 + 3] cyclization–Suzuki CC method,³⁸⁶ Pd-catalyzed cyclization of an enediyne,³⁸⁷ Rh(III)-catalyzed coupling of aryl ketone O-acetyl oximes and quinones,³⁸⁸ an “inverse electron demand Diels–Alder reaction,”³⁸⁹ and a one-pot Sonogashira coupling-benzannulation of aryl 3-bromopropenoates.³⁹⁰

Similarly, the synthesis of fluorenones has been reported using different approaches, nicely summarized by Jourjine et al.³⁹¹ A gram-scale total synthesis of dengibsin was reported by Jones and Ciske in 1996.³⁹²

Kamila et al.³⁹³ reported the synthesis of several analogues of (±)-semivioxanthin, a naturally occurring linear naphthopyrone with a stereogenic center at C-3 (406) (Scheme 97a), using an aryl-O-carbamate-mediated DoM to prepare functionalized naphthalene substrates (408 and 409) prior to annealing the pyrone (Scheme 97b). Critical to the success of the reaction sequence was the introduction of an allyl group ortho- to the amide function in 408 (using allyl bromide) and the cyclization of the resulting compound (409) to give the final product 410. The harsh reaction conditions required for cyclization (heating under reflux with 6 N HCl for 36 h) resulted in hydrolysis of the O-carbamate. The somewhat labile phenolic compound formed was immediately O-methylated to afford the (±)-semivioxanthin analogues (410).

Scheme 97. (a) A Naturally Occurring Linear Naphthopyrone (±)-Semivioxanthin (406); (b) The AoF/DoM Sequence Followed by Annelation Used for the Synthesis of (±)-Semivioxanthin Analogues 410; (c) An Example of the AoF/DoM/Lactonization Sequence Used for the Synthesis of 412.

Adapted with permission from ref (393). Copyright 2003 Elsevier.

Sanz et al.²¹⁴ used ArOAm to prepare selected 2,3-dihalophenols, which could then be used to form 4-functionalized benzo[b]furans. The synthesis commenced with the halogen substituted ArOAm compounds 28o, 28am, and 28aq. After O-carbamate-mediated DoM (electrophilic quenching with I₂) and subsequent hydrolysis of the O-carbamate group, 28o, 28am, and 28aq gave the halophenols 414a–c, which are otherwise only available from specialized suppliers at exorbitant prices (e.g., 2-fluoro-3-iodophenol (CAS no. 863870-85-3) costs USD$ 750/1 g from Matrix Scientific, May 2024) (Scheme 98a).

Scheme 98. (a) The Synthesis of 2,3-Dihalophenols, 414, Using DoM Protocol and Further Preparation of 4-Halobenzo[b]furans, 415; (b) An Example of Further Transformation of 4-Halobenzo[b]furans.

Adapted from ref (214). Copyright 2005 American Chemical Society.

Subsequent reaction of the 2-iodo-3-halophenol derivatives 414 with two different terminal alkynes (phenylacetylene and 1-hexyne) via a tandem Sonogashira coupling/5-endo-dig cyclization (catalyzed by [Pd(OAc)₂(PPh₃)₂]/CuI) gave the expected 4-halobenzo[b]furans 415 in moderate (60%) to good (79%) yields (Scheme 98a). Substituted 4-halobenzo[b]furans could then be modified by other transformations, e.g., lithiation (quenching with benzophenone to form 416a) or Suzuki coupling with phenylboronic acid under Pd catalysis (416b) (Scheme 98b). This work was later improved to extend the scope of regioselective lithiation of the O-dihalophenyl-N,N-diethylcarbamates to exclude the use of transition metals (Pd and Cu) and the need for an ortho-iodine (consumed in the Sonogashira coupling process) in the cyclization step.²⁰⁰ The O-carbamate (417) was still crucial, this time to access O-o-alkynylaryl N,N-diethylcarbamates (418) (by using arylsulfonylacetylenes as alkynylation reagents for the lithiated compound), which allowed the synthesis of halobenzo[b]furans by basic hydrolysis–cyclization of 419, bypassing the Sonogashira step (Scheme 99a). Finally, the authors further developed this process into a one-pot procedure with microwave heating, as shown by the synthesis of halobenzo[b]furan 422 (Scheme 99b).

Scheme 99. (a) Synthesis of Halobenzo[b]furans, 420, Using an Improved DoM/Hydrolysis/Cyclization Sequence; (b) An Example of One-Pot Synthesis of the Halobenzo[b]furan, 422.

Adapted from ref (200). Copyright 2022 MDPI.

Oliveira et al.³⁹⁴ used O-carbamate to form a tetracyclic benzopsoralen analogue (425), which was also tested for antitumor activity (Scheme 100). In this case, 9H-carbazol-2-yl diethylcarbamate (423) was converted to the aldehyde 424 by metalation, followed by treatment with DMF. Compound 424 was then cyclized with diethyl malonate to form 425 in 20% yield. Unfortunately, even at high concentrations (150 μm), the congener 425 proved to be ineffective as a growth inhibitor compared to 9H-xanthen-9-ones such as 426 (due to the difference in geometry, i.e., angular versus linear and functional groups present).

Scheme 100. Synthesis of a Tetracyclic Benzopsoralen Analogue, 425, with a 9H-Carbazole Framework, Commencing with O-Carbamate 423.

Adapted with permission from ref (394). Copyright 2007 John Wiley and Sons.

Mohri et al.³⁹⁵ developed a five-step synthesis of benzo[b]fluorenone (431) based on the use of O-carbamate as DMG for DoM installation of the “blocker” TMS (to form 428), followed by facilitation of a crucial O→C ring-to-ring carbamoyl transfer (with excess LDA) to provide 429a in 62% yield (Scheme 101).

Scheme 101. Synthesis of Benzo[b]fluorenone, 431, via a Five-Step Method.

Adapted from ref (395). Copyright 1997 American Chemical Society.

Phenol 429a was methylated to give biarylamide 429b, which was subjected to a second remote metalation/cyclization to give fluorenone 430 (78% yield). Finally, 430 was treated with TFA to give benzofluorenone 431 in quantitative yield. Compared to other routes to this material, the combined sequence of DoM and CC has the advantage of providing direct access to important and diverse intermediates of the antibiotic kinamycin.

Kalinin et al.³⁹⁶ discovered a new LDA-induced O→C-carbamoyl migration that provides easy access to phenylacetamides 433 and thus substituted benzo- and naphthofuranones 434 (Scheme 102a), extending the utility of DoM. Introduction of the methylsulfanyl function in ortho- position to the O-carbamate functionality and deprotonation of the side chain with s-BuLi at −78 °C afforded the rearranged products, N,N-diethyl-2-hydroxyarylthioacetamides 436 (Scheme 102b). Their heating with glacial acetic acid under reflux led to the condensed oxathiin-2-ones 437 in excellent yields.³⁹⁷

Scheme 102. (a) Synthesis of Benzofuranones, 434, Using LDA-Induced O→C-Carbamoyl Migration/Cyclization Sequence; (b) An Introduction of the Methyl Sulfanyl Function in the AoF–Cyclization Sequence Gives Condensed Oxathiin-2-ones 437.

Adapted with permission from ref (397). Copyright 2003 Thieme.

Beaulieu and Snieckus³⁹⁸ extended their work on heteroatom-bridged biaryl metalation by LDA-mediated reactions of 2-carboxamido- and 2-O-carbamoyl diaryl sulfones 439, leading to thioxanthen-9-one 10,10-dioxides, 440 and 442, respectively (Scheme 103). These formal anionic equivalents of the Friedel–Crafts reaction and the sequential remote Fries rearrangement and Friedel–Crafts reaction (via 441) allow the construction of fused heterocycles from heteroatom-bridged biaryl systems that replace or effectively compete with the classical routes.

Scheme 103. Synthesis of Thioxanthen-9-one 10,10-Dioxides, 440 and 442 via LDA-Mediated Reactions of 2-Carboxamido- and 2-O-Carbamoyl Diaryl Sulfones 439 Using Friedel–Crafts and Sequential Remote Fries Rearrangement and Friedel–Crafts Reaction.

Adapted from ref (398). Copyright 1994 American Chemical Society.

Macklin et al.³⁹⁹ developed a short synthesis of the alkaloid schumanniophytine (449) starting with the metalation of symmetric O-carbamate 443 and, after boronation, yields the intermediate 444 in excellent yield (Scheme 104). Further Suzuki–Miyaura CC with commercial 4-bromopyridine hydrochloride led to azabiaryl 445, followed by a regioselective second DoM reaction and silylation with TESCl to give highly hindered derivative 446. With silicon protection present, remote AoF rearrangement led to a smooth carbamoyl translocation to the pyridine ring to give arylnicotinamide 447 after direct benzoylation. Regioselective demethylation with BCl₃ gave the lactone 448 in high overall yield after acidic protodesilylation, debenzylation, and reacylation. Release of the free phenol from 448 with sodium bicarbonate, followed by adaptation of the versatile Eaton’s reagent and efficient demethylation under BCl₃ conditions, gave schumanniophytine (449).

Scheme 104. Synthesis of the Alkaloid Schumanniophytine (449) Starting from a Simple Building Block (443) and Involving DoM, Suzuki–Miyaura CC, and an ortho-Silicon Induced O-Carbamate-AoF Rearrangement.

Adapted with permission from ref (399). Copyright John Wiley and Sons.

Based on initial model studies of schumanniophytine synthesis, Macklin et al.²³ developed a new general and regioselective synthetic method for polysubstituted chromone 3- and 8-carboxamides, by anionic carbamoyl translocation reactions (Scheme 105). The reactions involve sequential intramolecular AoF rearrangement and Michael addition, which mechanistic studies indicate proceed via an intriguing coumulenolate intermediate 451 and open pathways to chromones that exhibit both unusual and elusive C8 substitutions and common and biologically significant 3-substitution patterns. When the cumulenolate 451 is heated to room temperature to promote carbamoyl transfer, a deep-red solution appears, indicating the formation of the lithium dienolate 453. The color quickly disappears upon treatment with AcOH to give 454 in high yield. This result indicates a reaction pathway involving buta-2,3-dienamide, 452, followed by intramolecular Michael addition of the resulting phenolate and subsequent protonation to give the chromone product 454. The need for additional base amounts for effective conversion of 450 to 455 suggests that this reaction may also involve the cumulenolate 451, which undergoes an AoF rearrangement followed by protonation and Michael addition.

Scheme 105. Regioselective Synthesis of Polysubstituted Chromone 3- and 8-Carboxamides by Anionic Carbamoyl Translocation Reactions with Sequential DoM, Intramolecular AoF, and Michael Addition via the Cumulenolate Intermediate 451.

Additional amounts of base (LTMP) efficiently convert 450 to 455 via an AoF and Michael addition sequence. Adapted with permission from ref (23). Copyright 2008 John Wiley and Sons.

Stefinovic at al.⁴⁰⁰ prepared multisized benzannulated oxygen heterocycles by a combination of DoM and ring-closing metathesis (RCM) (Scheme 106). This first report of such RCM procedure for various ring sizes, demonstrating the synthetic link between RCM and regiospecific DoM strategy, finds its effective expression in the first total synthesis of the calmodulin inhibitor radulanin A (456) and helianane (457). In the synthesis of 456, the readily prepared 458 was subjected to a DoM/transmetalation/C-allylation sequence to give 459, and further O-allylation (460) and RCM reaction gave benzoxepine 461. Reduction with LAH completed the synthesis of radulanin A (456) in 11 steps and 14% overall yield. Helianane (457), a racemic natural product, was synthesized in a very similar reaction sequence in nine steps with an overall yield of 9%.

Scheme 106. Synthesis of Benzene-Fused Oxygen Heterocycles with Multisized Rings by Combining DoM and Olefin Ring Closing Metathesis to Afford the First Synthesis of Radulanin A (456) and (±)-Helianane (457).

Adapted from ref (400). Copyright 1998 American Chemical Society.

Zhao et al.⁴⁰¹ developed a Rh-catalyzed annulation of aryl thiocarbamates (462) with alkynes (463) via DoM C–H bond activation and a desulfurization to construct 3,4-disubstituted coumarins (464) in moderate yields (46–81%) (Scheme 107).

Scheme 107. Synthesis of 3,4-Disubstituted Coumarins (464) by Combining DoM and Rh-Catalyzed Annulation of Aryl Thiocarbamates (462) with Alkynes (463).

Adapted from ref (401). Copyright 2015 American Chemical Society.

9.3. Combined DoM-CC Reactions

Kalinin et al.³²⁸ reported a general synthesis of substituted 4-hydroxycoumarins 467 in 43–82% overall yield by carbamoyl–Baker–Venkataraman rearrangement. Intermediate ortho-acylated ArOAms 465 were prepared from ArOAms 28 via a DoM/Negishi CC protocol (59–91% yield), and the overall sequence provides a regiospecific anionic Friedel–Crafts complement for the assembly of 2-hydroxyarylacetamides 466 (78–99% yield) and final coumarins 467 in high yield (79–95%) (Scheme 108).

Scheme 108. General Synthesis of Substituted 4-Hydroxycoumarins 467 Using a DoM/Negishi CC Protocol and a Carbamoyl–Baker–Venkataraman Rearrangement As the Key Step.

Adapted with permission from ref (328). Copyright 1998 Elsevier.

The same research group²¹³ demonstrated the regiospecific construction of 4-, 5-, and 6-substituted indoles and tryptophols, 469, by adapting DoM and transition metal-catalyzed CC reactions to N,N-diethylindole-5-O-carbamate, 468 (Scheme 109a). Selective 4- and 6-substitutions can be achieved via TMS protection and AoF tactics (470–472) with moderate yields (50–99%). In addition, they have adapted the above organozinc and Grignard transition metal catalyzed CC reactions to develop powerful new protocols for C–C bond formation (473a,b, 474) with excellent yields (≈ 90%) (Scheme 109b). The authors also demonstrated the preliminary chemistry of tryptophol metalation (469, X = OH), anticipating a broader perspective.

Scheme 109. (a) General Strategies for the Regiospecific Construction of 4-, 5-, and 6-Substituted Indoles and Tryptophols 469 Using DoM and Transition Metal-Catalyzed CC Reactions on N,N-Diethylindole-5-O-carbamate, 468; (b) Examples of Selective Regiospecific Construction of Indoles 471–474.

Adapted with permission from ref (213). Copyright 2022 John Wiley and Sons.

Kinsman and Snieckus³¹³ reported the first preparation of indolo-4,5-quinodimethane 475 as an intermediate over the ortho-quinodimethane precursor 248 by O-carbamate-DoM/Kumada–Corriu CC tactics and its conversion with various dienophiles to new ring systems, such as benz[e]indole 476 (Scheme 110a), in modest and excellent yields (40–95%). The preparation of the ortho-quinodimethane precursor 248 began with a highly regioselective metalation-carboxamidation of O-carbamate 155 to give 477 in 80% yield, leading to benzylsilane 478 (59%) after Grignard transition metal-catalyzed CC. DIBAL reduction followed by treatment with MeI gave the quaternary salt 248 in excellent yield (89%), which was treated with CsF and (Boc)₂O to give the N-Boc derivative 249 in a convenient and mild one-pot procedure (Scheme 110b).

Scheme 110. (a) Preparation of the Indolo-4,5-quinodimethane Intermediate (475) from 248 and Its Conversion with Various Dienophiles to New Ring Systems, Such as Benz[e]indole, 476; (b) Preparation of 248–249 by O-Carbamate-DoM/CC Tactics.

Adapted with permission from ref (313). Copyright 1999 Elsevier.

Jo̷rgensen et al.²³⁰ reported a general, efficient, and regioselective synthesis of a series of hydroxylated 1-methylphenanthrenes 485 by a combined DoM/Suzuki–Miyaura CC/DreM sequence (Scheme 111). Additional diversity of this method was achieved by a regioselective DoM reaction instead of a DreM reaction, which gave higher substituted phenanthrols. Boronic acid benzamides and halobenzamides, 480, were prepared by DoM reactions using standard procedures. CC of boronic acid benzamides with bromoarenes or vice versa proceeded in high yield under two different conditions to give both monomethyl and dimethyl biaryls, 481, in moderate to excellent yields (40% to near quantitative). Further conversion of biarylamides, 481, to phenanthrols, 482, was carried out in good yield (68–89%) under standard LDA conditions using the DreM method for the final reductive cleavage of O-arylcarbamates, 483, to the oxygenated 1-methylphenanthrenes, 484, the initial observation from the Ni-catalyzed Kumada–Corriu CC reaction was applied, namely, that Grignard reagents reductively cleave aryl halides and O-carbamates. With this step, efficient regioselective synthesis of the series of 4-OMe 1-methylphenanthrenes 484 was carried out in high yields (75–97%). Finally, BBr₃ deprotection of the methoxy derivatives afforded the corresponding phenols 485 in good to excellent yields (57–94%).

Scheme 111. Synthesis of a Series of Hydroxylated 1-Methylphenanthrenes 485 by a Combined DoM/Suzuki–Miyaura CC/DreM Sequence.

Adapted from ref (230). Copyright 2015 American Chemical Society.

Groom et al.²⁰⁵ developed a regioselective synthesis of 2,3-di- and 1,2,3-trisubstituted naphthalenes via DoM strategies of N,N-diethyl-O-naphthyl-2-carbamate, 62 (Scheme 112). Sequential LiTMP metalation–electrophilic quenching and s-BuLi/TMEDA (or t-BuLi)-electrophilic quenching of naphthyl-2-carbamate 62 provides a general route to contiguously substituted naphthalenes 486 with full regioselectivity and good yields. Further derivatization via ipso-halodesilylation and Suzuki–Miyaura CC leads to various phenyl-substituted halonaphthalenes (90–94% yield). Additional treatment with an excess of LDA in THF (to promote AoF rearrangement) followed by heating in acetic acid afforded the benzonaphthopyranones 487 in moderate yield.

Scheme 112. Regioselective Synthesis of 2,3-Di- and 1,2,3-Trisubstituted Naphthalenes 486 Using DoM strategies of carbamate 62; Further Derivatization via Suzuki–Miyaura CC/AoF/Cyclization Sequence Leads to Benzonaphthopyranones 487.

Adapted from ref (205). Copyright 2014 American Chemical Society.

Wang et al.⁴⁰² prepared gymnopusin (499) in a total synthesis using a combined DoM, Suzuki–Miyaura CC, and DreM strategy to demonstrate the correct structure of 499 by regioselective assembly of the 9-phenanthrole core (Scheme 113). The natural gymnopusin was prepared from commercially available starting materials in 12 steps and with an overall yield of 18%. The value of this work lies in providing conditions for highly hindered Suzuki–Miyaura couplings, facilitating DreM-induced carbamoyl transfer (AoF) to produce hindered biaryls that are difficult or impossible to achieve by direct couplings, and in the advantages of DoM chemistry.

Scheme 113. Total Synthesis of Gymnopusin, 499, in 12 Steps.

Adapted with permission from ref (402). Copyright 2012 John Wiley and Sons.

Bavikar et al.⁴⁰³ reported an enantioselective total synthesis of (−)-panduratin D (500), a novel secondary metabolite against human pancreatic PANC-1 cancer cells, from commercial 3-methoxyphenol (501) in nine steps with an overall yield of 5.4% (Scheme 114). Key steps include Sonogashira coupling, AoF rearrangement, and DoM to form the furanochalcone unit (506) and tandem Si–C alkyl rearrangement/Claisen–Schmidt condensation to form the chalcone structure (507). The asymmetric Diels–Alder cycloaddition of chalcone 507 and ocimene (508) promoted by a chiral boron complex provides the final chiral cyclohexene core of (−)-panduratin D (500).

Scheme 114. Enantioselective Total Synthesis of (−)-Panduratin D (500) via the Chalcone Key Structure (507) in Nine Steps.

Adapted with permission from ref (403). Copyright 1996 Royal Society of Chemistry.

Benniston et al.⁴⁰⁴ synthesized a series of viologens using a successful alternative strategy via DoM of pyridin-3-yl diethylcarbamate (117) to generate 4-iodo- and 4-boronato-pyridin-3-yl carbamates 509 and 510. They used a standard Suzuki coupling to combine them and isolate the monoprotected derivative 511 (Scheme 115). The last carbamoyl group was easily removed from 511 with NaOH to give 512 in 75% yield. Tethering reactions of 512 were carried out by deprotonation of the hydroxy groups and subsequent slow addition of ditosyloxyalkane/ether. The isolated yields of 513a–e were modest (9–33%). The simple methylation of 513a–e with iodomethane, followed by anion exchange and recrystallization, finally gave the desired viologen analogues 514a–e as crystalline solids in 54–84% yield.

Scheme 115. Synthesis of Viologens 514a–e Using DoM/Suzuki CC Sequence as an Efficient Protocol to Prepare 4,4′-Bipyridine Derivatives (511 and 512) before the Final Tethering Reactions.

Adapted with permission from ref (404). Copyright 2007 John Wiley and Sons.

9.4. Direct C–H/C–O Bond Arylation, Benzylation, and Alkynylation

Song and Ackermann³⁴³ reported the use of a highly efficient cobalt catalyst for the direct C–H bond arylation of arenes with readily accessible aryl O-carbamates via a challenging C–H/C–O bond cleavage. Both electron-rich and electron-poor functionalized aryl O-carbamates were converted with remarkably high catalytic efficiency, even at room temperature (Scheme 116a). Moreover, both arenes with electron-donating substituents and arenes with electron-withdrawing substituents gave the desired products 516 in high yield. A variety of different pyridyl-directing groups could also be employed to achieve site selectivity. An intramolecular competition experiment gave the biaryl product 516a in excellent yield (90%) by functionalization of the kinetically more acidic C–H bond. Aryl-O-carbamates functionalized with sterically hindered substituents in the ortho position gave sterically crowded product 516b in high yield (72%), demonstrating the suitability of aryl-O-carbamates for strategies combining DoM and C–H bond functionalization. In addition, mono-N-substituted indoles 517 were selectively arylated at the C2 position, allowing the synthesis of sterically loaded heterobiaryls 518 (Scheme 116b). This capability could be useful in future applications involving asymmetric C–H bond arylation. The reader is referred to section 8.6.3. for more details.

Scheme 116. (a) Cobalt-Catalyzed C–H/C–O Arylation of Arenes 515 with Aryl O-Carbamates; (b) Cobalt-Catalyzed Direct Arylation of Heteroarenes 517 with Aryl O-Carbamates.

Adapted with permission from ref (343). Copyright 2012 John Wiley and Sons.

Zou et al.²¹⁵ prepared an electron-rich, axially chiral TunePhos-type biaryl ligand, 522 (Scheme 117), which was used in a Rh-catalyzed asymmetric hydrogenation. The initial 3-bromophenyl carbamate, 28aq, was subjected to DoM lithiation, followed by oxidative coupling with FeCl₃ to form the biaryl bacbone 519 in 56% yield. The carbamate groups were then removed under basic conditions to form the dibromo substituted biphenol, 520, which was then subjected to Mitsunobu reaction in the presence of a chiral 2,4-diol. Two diastereomers with opposite axial chiralities were obtained, from which the desired diastereomer 521 was obtained by column chromatographic purification in 22% yield. Finally, 521 was treated with n-BuLi at low temperature to perform Li–Br exchange. Subsequent quenching with Cy₂PCl afforded the ligand 522 in moderate yield.

Scheme 117. Synthesis of an Electron-Rich, Axially Chiral, TunePhos-Type Biaryl Ligand 521 Using Regioselective DoM Lithiation and Oxidative Coupling in the Crucial Reaction Step.

Adapted with permission from ref (215). Copyright 2009 Elsevier.

Another example is an efficient and modular synthesis of an axially chiral bidentate biaryl ligand of the C3*-TunePhos type (529a) (Scheme 118) developed by Deng et al.⁴⁰⁵ The synthesis started with the protection of commercially available 3-bromophenol (523), giving carbamate 524 in excellent yield, which was subjected to DoM lithiation and then quenched with I₂, giving the aryl iodide 525 in good yield. Saponification of compound 525 afforded phenol 526, which was converted to the coupling precursor 527 in high yield by reaction with (2S,4S)-pentane-2,4-diol. The key oxidative coupling reaction with CuCl₂ and TMEDA/LiCl led to the intermediate 528 in high yield, which could be prepared on a gram scale. The dibromide 528 was treated with n-BuLi at low temperature and quenched with Ph₂PCl to give the ligand 529a in 27% overall yield.

Scheme 118. Synthesis of an Axially Chiral Bidentate Biaryl C3*-TunePhos Ligand 529a, Using Regioselective DoM Lithiation, Quenching with I₂, Deprotection, Mitsunobu Reaction with (2S,4S)-Pentane-2,4-diol, and Oxidative Coupling in the Crucial Reaction Step.

Adapted with permission from ref (405). Copyright 2017 Thieme.

Blakemore et al.⁴⁰⁶ directly prepared 7,7′-bis(((diethylamino)-carbonyl)oxy)-6,6′-diiodo-8,8′-biquinolyl (531) in 54% yield with regioselective DoM of 530, followed by the addition of anhydrous ferric chloride (Scheme 119). An efficient tandem HalD-dimerization process is an alternative for the synthesis of highly substituted biaryl molecules.

Scheme 119. Direct Synthesis of Highly Substituted Biquinolyl 531 by an Efficient Tandem HalD-Dimerization Process.

Adapted from ref (406). Copyright 2004 American Chemical Society.

Ruano et al.⁴⁰⁷ demonstrated a simple and efficient regioselective alkynylation, which made use of DoM quenching with electrophile source p-tolylsulfonyl acetylene (532), first with phenyl O-carbamate, to form 533 in a quantitative yield, followed by an estradiol derivative 534 to form 535 in high yield (Scheme 120).

Scheme 120. Regioselective Alkynylation of (a) Phenyl O-Carbamate, to Form 533, and (b) Estradiol Derivative (534).

Adapted with permission from ref (407). Copyright 2012 John Wiley and Sons.

10. OAm as Directing Group in ortho-Functionalization via C–H Activation Couplings

10.1. Introduction to C–H Activation

Selective C–H activation at a specific and tactical site among the occupancy of numerous C–H bonds of an aromatic compound is a powerful technique of C–H functionalization. The most effective of methodologies thus far utilized for accomplishing site selectivity has been via the application of Lewis-basic directing groups in proximal C–H bond functionalization.^408−421 Similar to the utility of a DMG in DoM chemistry, these directing groups function to lead the transition metal to specific C–H bonds through applying distance and geometry as factors to differentiate between proximal and distal C–H bonds. However, installation and removal of directing groups has some drawbacks, as it can be costly and labor intensive. Therefore, to improve the effectiveness of this method, attachment of the DMG to the substrates by a transient covalent bond has been considered for rendering the directing group catalytic.⁴²² In this way, the O-carbamate (OCONR₂) DMG has been developed for Pd, Rh, Ru, Ir, and Co catalysts in a wide range of C–H activation transformations (Figure 8).

Figure 8.

Scope of transition metal-catalyzed O-carbamate-directed C–H activation followed by coupling reaction to afford ortho-functionalized ArOAm products.

Due to the abundance of C–H bonds in organic molecules, endless opportunities reside in the structural alteration of compounds via C–H activation. However, attaining site selectivity in C–H functionalization can be extremely difficult to achieve. Therefore, a key concern involves identifying parameters which may help in guiding the catalysts to the desired C–H bond. One potentially valuable tactic involves the development of catalytic systems that can characterize C–H bonds based on their distal and geometric association with respect to an existing functional group. Thus, to advance this method, it is necessary to develop practical DMGs that are (1) easy to install and remove, (2) have a lower mass, and (3) coordinate weakly to metal catalysts so that external ligands can coordinate and exert a greater effect on the metal catalysts, thereby controlling reactivity, stereoselectivity, and site selectivity.

In general, pyridines, oxazolines, and imines are broadly used as DMGs in directed C–H activation with transition-metal catalysts to achieve reactivity through a chelating effect in the employment of coordinating heteroatoms. Throughout the literature, these DMGs have been widely successful at promoting transition-metal-catalyzed C–H cleavage, in part because the cyclometalated intermediates are thermodynamically stable and simple to separate. Yet, due to the thermodynamic stability of the metalacycle complexes (536) (Figure 8) created in association with strongly coordinating DMGs, the functionalization stage can be problematic at times when a lack of reactivity is present. Disadvantages of strongly coordinating DMGs also arise when (1) two equivalents of a strongly coordinating substrate could bind simultaneously to a metal, thus preventing a ligand from binding, and (2) a metal complex coordinated to an electron-donating ligand, and the substrate may not hold suitable electronic properties required for the C–H bond cleavage. As a result, an alternative methodology has been established in which weakly coordinating DMGs or existing functional groups are applied to drive the metalation of C–H bonds. In this way, thermodynamically less stable metalacycle complexes can form, which in turn can be more easily functionalized than strongly coordinated complexes, greatly expanding the knowledge of C–H activation transformations. The extensive progress made by the ArOAm DMG is a remarkable example of this strategy.

10.2. OAm as a Directing Group for C–H Activation

It is fundamental to investigate a variety of different catalysts or strategies that can selectively activate C–H bonds at numerous sites for the late-stage modification of sophisticated intermediates or end products. The effectiveness of the simple and weakly coordinating ArOAm directing group is demonstrated by its compatibility with a comprehensive variety of substrates, transformations, metal catalysts (Pd, Rh, Ru, Ir, and Co), and mild conditions (room temperature).

As in the case of other directing groups, the most studied transformation with ArOAm is Pd-catalyzed ligand-directed C–H activation followed by C–C coupling to give ortho-arylated, alkenylated, or carbonylated products. With rhodium and ruthenium catalysis, alkenylation predominates, while iridium proved to be superior for borylation reactions. Transition metal-catalyzed ligand-directed C–H functionalization has also been utilized for C–N, C–O, and C–halogen bond formation (Table 27).

Table 27. Representative Examples of Transition-Metal-Catalyzed Ligand-Directed C–H Functionalization at ArOAm^a.

^a(a) An attempt has been made to show representative examples from the substrate scope described in each reference to allow comparison between methods. (b) Isolated yield of pure product.

10.2.1. Palladium

The first palladium-catalyzed ortho-arylation using the carbamate group as the directing group for ortho-C–H bond activation was developed by Bedford et al.²⁹⁶ in 2009 (Table 27, entry 1a). Relatively low monoselectivity and yields were subsequently improved by using diaryliodonium salts as coupling partners⁴²³ (entry 1b). In this case, in the absence of Ag salts under solvent-free conditions, CC and in situ carbamate deprotection were observed to afford monoarylated free phenol products with excellent selectivity. Under modified reaction conditions, Xiao et al.⁴²⁴ found that the acid additives were important for the outcome of the reaction, either by supporting the C–H deprotonation step or by stabilizing the active Pd intermediates (entry 1c). The authors succeeded in the preparation and NMR characterization of O-phenylcarbamate palladacycle 537, a plausible reaction intermediate likely formed by acyloxy-directed Pd(II) insertion into the C–H bond ortho to the carbamate (Figure 9a), and they proposed a mechanism operating via a Pd(II)/Pd(IV) species. More recently, Zhao et al.⁴²⁵ used this methodology for a regioselective arylation of 7-hydroxyflavone derivatives at the C6 position (Table 27, entry 1d).

Figure 9.

(a) O-Phenylcarbamate palladacycle intermediate 537 prepared and NMR characterized by Xiao et al.⁴²⁴ Adapted from ref (424). Copyright 2010 American Chemical Society. (b) Proposed intermediates 538 and 539 in meta-arylation of O- β-naphthyl carbamates by Zhang et al.⁴²⁸ Adapted with permission from ref (428). Copyright 2014 Royal Society of Chemistry. (c) A bimetallic Pd species 540 prepared, and X-ray characterized by Zhao et al. Adapted from ref (429). Copyright 2010 American Chemical Society. (d) Intermediates 541 and 542 in Pd-catalyzed oxidative Ar–H/Ar–H CC between ArOAm and p-cresol as coupling partners, as proposed by Truchan et al. Adapted with permission from ref (431). Copyright 2019 Thieme.

In addition to aryl iodides and diaryliodonium salts, a Pd-catalyzed ortho-directed arylation of O-phenylcarbamates was carried out by Ma et al.⁴²⁶ using pinacol aryl boronates (entry 1e). Sharma et al.⁴²⁷ developed ortho-acylation by using α-oxocarboxylic acids as coupling partners to provide benzophenone products in moderate to good yields (entry 1f). Recently, this method was used to prepare a series of 6-acyl 7-O-carbamate coumarins that exhibited anti-inflammatory activity against RAW 264.7 macrophage cell line.⁴⁵⁴ Selective meta-arylation of O-β-naphthyl carbamates with a series of phenylboronic acids as coupling partners was investigated out by Zhang et al.⁴²⁸ (entry 1g). The O-carbamate group proved to have a unique effect, allowing ortho-carbometalation to generate the Wheland intermediate 538, which, during the reaction pathway, passes into the products after transmetalation to 539 and nucleophilic attack of the aryl group in the meta-position (Figure 9b). It is noteworthy that the C–H bond ortho to the carbamate group is preserved throughout the reaction. Similar observations in Pd-mediated arylation of O-β-naphthyl carbamates were made by Ma et al.⁴²⁶ The mechanistic considerations of ligand-directed transition-metal C–H activation have been reviewed comprehensively elsewhere.^408−421

A complementary Pd-catalyzed oxidative Ar–H/Ar–H CC reaction of O-phenylcarbamates used excess amounts of simple arenes (e.g., benzene, o-dichlorobenzene) as coupling partners avoiding the need for aryl iodide, hypervalent iodine, or boronate reagents, was proposed by Zhao et al.⁴²⁹ in 2010 (entry 1h). The authors proposed a distinct Pd(0/II) catalytic cycle with a plausible dimeric bimetallic Pd intermediate 540 (Figure 9c), in which strongly acidic additive TFA plays an important role in the reaction. Complexes like these were prepared and studied by John et al.⁴³⁴

Five years later, Zhang et al.⁴³⁰ developed a unique Pd(II)-catalyzed chelate-assisted oxidative Ar–H/Ar–H CC reaction between two different coupling partners with weakly coordinating directing groups to afford a broad range of 2,2′-difunctional biaryls (entry 1i). Screening through a large variety of the reaction conditions, the authors reported that the choice of hexafluoroisopropanol (HFIP) as reaction solvent and sodium periodate/potassium persulfate as the oxidizing agents were crucial factors in this reaction. No products were observed in other common solvents such as (e.g., DMSO, DMF, ethanol), and the authors suggested that HFIP could serve not only as a solvent system but also as an effective ligand for palladium to promote this reaction. Symmetric biaryls, a result of homodehydrogenative CC, were obtained in good yields when only one coupling partner, e.g., ArOAm, was present in the reaction mixture.⁴³⁰

Phenols were subsequently described by Truchan et al.⁴³¹ to generate 2,2′-dihydroxy- and 2,4′-dihydroxybiphenyls with relatively low regioselectivity in both coupling partners, phenols, and carbamates (entry 1j). In the proposed Pd(II)/Pd(0) mechanism with p-cresol as coupling partner, the aromatic ring was activated by initial coordination through the oxygen atom to the palladacyclic intermediate (similar to Figure 9a), giving rise to 541, which then rearranged to the regioisomeric complex 542, as shown in Figure 9d. In the case of para-unsubstituted phenol, two isomeric products were formed.

In the Pd-catalyzed oxidative C–H olefination of arenes, known as the Fujiwara–Moritani reaction, Santiago et al.⁴³² observed some regioselectivity in the functionalization of the pesticide carbofuran with ethyl acrylate to give a 60:30:10 mixture of α:β:γ regioisomeric products, attributed to the ortho-directing properties of the O-carbamate group (entry 1k). In addition to the ortho-directed C–C bond forming reactions, ArOAm compounds were also found to be suitable substrates in the Pd-catalyzed formation of C–O (entry 1l)³⁶⁹ and C–halogen bonds [entries 1m–1p)].^{423,433−435} There is a strong desire to use more sustainable approaches for the synthesis of halogenated aromatic compounds.⁴⁵⁵ Under the same reaction conditions as in entry 1b, the use of the Cu(oAc)₂/CuCl₂ system instead of aryl iodide led to monochlorination (entry 1m).⁴²³ Under milder reaction conditions, ortho-halogenated products were obtained in good to excellent yields upon reaction with the corresponding N-halosuccinimide (entries 1n and 1o)^433,434 Sun et al.⁴³⁵ developed an approach to access ortho-iodinated phenols through Pd(II) catalyzed C–H activation using cyclic hypervalent iodine(III) reagents (Togni’s reagent and related), which serve not only as an oxidant but also as a iodine source in sp² C–H iodination (entry 1p). The developed Pd-catalyzed ortho C–H activation has seen many practical applications in synthetic organic chemistry,^255,456 including the modification of estrone and estriol derivatives.^457,458

10.2.2. Rhodium

In contrast to palladium catalysis, directed ortho C–H olefination predominates in rhodium-catalysis. The first Rh(III)-catalyzed directed oxidative olefination of phenol carbamate was reported by Gong et al.⁴³⁶ (entry 2a) and Feng et al.⁴³⁷ (entry 2b). Treatment of a wide variety of phenol and 2-naphthol carbamates with acrylates and styrenes using [Cp*RhCl₂]₂ as catalyst, AgSbF₆ as halide scavenger, and Cu(OAc)₂ as oxidant, gave the desired olefins in moderate to excellent yields and high regioselectivity.^436,437 This protocol was subsequently used to obtain a range of advanced phenol and naphthol derivatives.^459−462 An ortho-directed Rh-catalyzed alkyne hydroarylation reaction was carried out using internal alkynes as coupling partners to afford substituted alkenes with high regio- and stereoselectivity (entry 2c).⁴³⁸ Under slightly modified reaction conditions (by using Cu(OAc)₂), the reaction led to polycyclic aromatic compounds (entry 2d).⁴³⁹ Recently, Tanaka et al.⁴⁴⁰ succeeded in the oxidative ortho-olefination of phenyl carbamates with both acrylates and styrenes under mild conditions using Rh(III) complex bearing an unsubstituted cyclopentadienyl (Cp) supporting ligand in place of the commonly used pentamethylcylopentadienyl (Cp*) ligand, with a broad substrate scope (entry 2e). Ortho-unsubstituted substrates generally returned a mixture of mono- and disubstituted products. The reaction mechanism was scrutinized experimentally and theoretically, suggesting that the less sterically hindered CpRh(III) complex can stabilize the transition states of the reaction pathway more than the Cp*Rh(III) complex.

The first example of a dual Rh-catalyzed chelate-assisted oxidative Ar–H/Ar–H CC reaction between two different coupling partners (one being an O-carbamate) having strongly and weakly coordinating directing groups was reported by Zhang et al.²²⁰ in 2019 (entry 2f).

Carbamates were successfully used in the Rh-catalyzed directed ortho-C–H bond bromination of arenes. Unlike the palladium catalyzed reactions (entries 1m–1p), the Cp*Rh(III) complex (Figure 10a) developed by Schröder et al.⁴⁴¹ avoided the use of Bro̷nsted acid additives (entry 2g). However, this reaction required an elevated temperature and a stoichiometric amount of Cu(oAc)₂. In turn, a modified cyclopentadienyl-rhodium(III) complex based on a pentasubstituted fulvene Cp^A5Rh(III) (Figure 10b) developed by Tanaka et al.⁴⁴² was able to catalyze the ortho-bromination of O-phenyl carbamates with NBS at room temperature with only a catalytic 20 mol % amount of Cu(oAc)₂ (entry 2h; compare with entry 2g). Unlike the Cp* ligand, the presence of the acidic secondary amide moiety on the Cp^A5 ligand accelerated bromination through the hydrogen bonding between the acidic NH group of the Cp^A5 ligand and the carbonyl group of NBS, as suggested in the transition state shown in Figure 10c.

Figure 10.

Structures of (a) [RhCp*Cl₂]₂, (b) [RhCp^A5Cl₂]₂, and (c) suggested transition state in the mechanism of [RhCp^A5Cl₂]₂-catalyzed ortho-bromination of ArOAm with NBS, indicating peculiar hydrogen bonding between the acidic NH group of the Cp^A5 ligand and the carbonyl group of NBS as proposed by Tanaka et al.⁴⁴² Adapted with permission from ref (442). Copyright 2020 John Wiley and Sons.

On the other hand, compared with oxime ether and other nitrogen-containing functional groups, carbamate acted as a pure directing group in Rh-catalyzed borylation with the supported triptycene-type bridgehead triarylphosphine (silica-TRIP)–Rh system, as shown by Kawamorita et al.⁴⁶³ Borylation ortho- to the carbamate into 545 was detected only in low (9%) NMR yield (Scheme 121).

Scheme 121. Competitive ortho-Borylation of Compound 543 Bearing Carbamate and Oxime Ether Directing Groups with (Silica-TRIP)–Rh System Prepared in Situ from Silica-SMAP and [Rh(OH)(COD)]₂.

Adapted from ref (463). Copyright 2011 American Chemical Society.

10.2.3. Ruthenium

Under the same reaction conditions used for Cp*Rh(III) catalysis, the groups of Ackermann (entry 3a),⁴⁴³ Wang (entry 3b),⁴³⁸ and Jeganmohan (entry 3c)⁴⁴⁴ reported the Ru(II)/p-cymene complex-catalyzed oxidative ortho-C–H alkenylation of ArOAm. The catalytic system was proved to be remarkably active and highly regioselective, even feasible in an aerobic manner with ambient air as the terminal oxidant. The protocol was suitable for acrylates, styrenes, and internal alkynes (entry 3d)⁴⁴⁵ as coupling partners.

Ruthenium catalysts enabled efficient ortho-directed oxygenations of ArOAms under remarkably mild reaction conditions. [RuCl₂(p-cymene)]₂, as the catalyst of choice, combined with PhI(TFA)₂ and DCE as the best oxidant and solvent, respectively, enabled ortho-oxygenations at only 50 °C in moderate to good yields (entry 3e).⁴⁴⁶ Yang et al.³⁶⁹ investigated a range of oxidants including Selectfluor, PhI(OAc)₂, (NH₄)₂S₂O₈, Na₂S₂O₈, and K₂S₂O₈, with the latter proving to be the most effective in the trifluoroacetic acid/trifluoroacetic anhydride (TFA/TFAA) solvent system (entry 3f). The practicality of this new method was tested successfully on a gram-scale synthesis. Furthermore, this reaction found application in the key step of the synthesis of 2-methoxyestradiol.⁴⁶⁴

10.2.4. Iridium

The propensity of iridium(III) to activate ortho-C–H bonds in ArOAm, forming Ir-cyclometallates and undergoing an efficient redox-active catalytic cycle that enables a directed oxidative C–H/C–H CC reaction between two (hetero)arenes, was first reported in 2018 by Tan et al. (entry 4a).⁴⁴⁷ A comparative reactivity study of iridium catalysis with rhodium catalysis for this transformation performed by the authors showed that IrCp*(III) performed better than RhCp*(III). Under otherwise identical conditions, no reaction was observed when [RhCp*Cl₂]₂ was used for the coupling reaction shown in entry 4a.⁴⁴⁷

There has been significant development in the field of ortho-directed iridium-catalyzed C–H borylations of aromatic substrates.^414,419 Iridium-catalyzed borylation using silicon-constrained monodentate trialkylphosphine (SMAP) ligands, pioneered by the group of Sawamura²¹⁹ showed a broad scope and excellent selectivity for ortho-directed borylations (entry 4b). To stabilize the Ir catalyst, the groups of Smith⁴⁴⁸ (entry 4c) and Li⁴⁴⁹ (entry 4d) developed N,Si- and B,N-bidentate ligands, respectively. Recently, Chattopadhyay’s group⁴⁵⁰ discovered a new class of C–H borylation catalysts with anionic Ir–C(thienyl) ligands instead of the neutral ligands from entries 4c and 4d. These catalysts were air stable and showed remarkable efficiency and selectivity in site-selective C(sp²)–H and C(sp³)–H borylation of various classes of aromatic, heteroaromatic, and aliphatic substrates (entry 4e). The iridium-catalyzed O-carbamate-directed ortho-C–H amidation of arenes with sulfonyl azides and dioxazolones as amidating reagent was reported by Chang’s research group (entries 4f and 4g).^451,452

10.2.5. Cobalt

Cobalt has also been used in the ortho-directed C–H functionalization of ArOAm but with only one example in the literature. In 2020, Bera et al.⁴⁵³ developed a selective carbamate-directed C–H alkylation under stable, high-valent, cost-effective cobalt(III) catalysis (entry 5a). The use of pivalic acid was crucial to suppress the formation of unsaturated cinnamic acid derivatives. Under the same reaction conditions, but in the absence of pivalic acid and with thiocarbamate as a directing group, the authors reported the coupling of aryldioxazolones to give products of selective C–H amidation (entry 5b).

10.3. Conclusion and Outlook

Transition metal-catalyzed directed C–H functionalization is a complementary tool to the well-established directed ortho-metalation (DoM) methods. Better selectivity and tolerance to functional groups, which can be achieved by selecting the appropriate metal in combination with other (ancillary) ligands that can further finetune the reactivity, can be considered as the main advantage of the former over DoM. Also, the transformations with transition metals are often insensitive to moisture or air and do not require flammable reagents or cryogenic reaction conditions in contrast to reactions involving alkyl lithiums.

Among the selective intermolecular ortho C–H activation approaches, the ortho-C–H activation predominates. Reaching the distal positions of arene systems is very challenging, with ArOAm as the directing group, and there seems to be only one successful example of this (Table 27, entry 1g).

Despite their success, many transition metal-catalyzed directed C–H functionalization reactions using ArOAm as substrates remain unexplored, including C–H alkynylation, alkylation, alkoxylation, chalcogenation, trifluoromethylation, and deuteration,⁴⁶⁵ as well as C–H activation of distal bonds, already demonstrated with N-carbamates,⁴⁶⁶ to name a few. There are no reports of carboxylation with CO₂,⁴⁶⁷ or carbonylation with CO or less toxic supplements, such as azodicarboxylates, for ArOAm.

Other avenues open for future exploration include more sustainable approaches to site-selective C–H activation such as those that utilize photoredox, electrochemistry, mechanochemistry, and flow processes.^420,468 This may be enabled by the fact that the O-carbamate group is also tolerated by a variety of nonstandard reactive species and reaction conditions, including the radical cations proposed in the thianthrenation of phenyl dimethylcarbamate 45 with 546 to arylsulfonium salt 547 in 84% yield,⁴⁶⁹ as well as photoinduced arylation CC under strong UV light conditions giving 548 in 56% yield,⁴⁷⁰ as shown in Scheme 122.

Scheme 122. An Example of the Compatibility of the OAm Group for Thianthrenation under Radical Conditions (45→547) and Strong UV Light (547→548).

Adapted from ref (469). Copyright 2019 Springer Nature.

Adapted from ref (470). Copyright 2021 American Chemical Society.

11. ArOAm in DoM and AoF under Greener and More Sustainable Conditions

To conform with trends in industry and academia,^471−476 research has gone into the development of organometallic chemistry which uses fewer polluting reagents, less harsh conditions, and promotes the use of more sustainable and circular chemistry.^477−483 Thus, far, regarding the DoM and AoF of aryl O-carbamates, this work has mainly focused on conducting the reactions under aerobic conditions using greener solvents. Ghinato et al.⁴⁸⁴ were the first to report efficient protocols for enabling DoM using and AoF of ArOAms with hindered lithium amide metalating agents, using cyclopentyl methyl ether (CPME) as sustainable reaction solvent⁴⁸⁵ under aerobic conditions. For example, when O-phenyl N,N-diisopropylcarbamate was treated with s-BuLi in CPME at 0 °C followed by quench (after 5 s) with various electrophilic reagents, ortho-functionalized adducts were obtained in good to excellent yields select examples are shown in Scheme 123a). AoF could be accomplished using LiTMP in CPME under air (Scheme 123b) for a variety of substrates (select examples shown): electron deficient (a–d), electron rich with competing DGs (e–g), polycyclic (h–j), substrates bearing a range of functional groups, e.g., double bonds (k), and pharmaceutical compounds, e.g., (S)-rivastigmine (l) in reasonable to very good yields. The choice of N-alky groups on the O-carbamate influenced the yield [Scheme 123(b), compare c/d and h/i], likely due to steric effects.

Scheme 123. (a) Electrophilic ortho-Functionalization of O-Phenyl N,N-Diisopropylcarbamate under Aerobic Conditions ; (b) LiTMP-Promoted AoF Rearrangement of O-Aryl Carbamates in CPME under Aerobic Conditions. Reported Yields Refer to Isolated Products.

Adapted with permission from ref (484). Copyright 2022 John wiley and Sons.

The authors then investigated ortho- versus homo-Fries rearrangements in ortho-tolyl O-carbamates to gain more insight into the regioselectivity of the metalation/migration sequence under aerobic conditions. In this case, a series of ortho-tolyl N,N-diisopropylcarbamates (549) decorated with different substituents, e.g., EDG (a), EWG (b), aryl (c), and halogenated (d), on the aromatic ring were subjected to one of two optimized metalation conditions: s-BuLi in CPME at room temperature and under air versus LiTMP in a heterogeneous mixture of CPME and deep eutectic solvents (DES) (in this case, a choline chloride (ChCl) and glycerol (Gly) mix) at room temperature and under air, to obtain either corresponding 1,2,3-contiguously substituted salicylamides (550b–d) or homologous α-arylacetamide derivatives 551a–d with high regioselectivity (Scheme 124).

Scheme 124. Regioselective ortho- vs homo-Fries Rearrangement of 549a–d.

Adapted with permission from ref (484). Copyright 2022 John Wiley and Sons.

Metalation of 549 with s-BuLi in CPME (at room temperature and under air) favors the ortho-Fries rearrangement, likely driven by the relative stability of the corresponding phenoxide (described in detail by Miah et al.⁸⁵), whereas using LiTMP in a CPME/DES mixture promotes the lateral lithiation/homo-Fries rearrangement reaction instead. This demonstrates the utility of eco-friendly solvents in causing AoF versus lateral rearrangements.

Flow chemistry is another approach that has been recognized to promote green and sustainable chemistry^486,487 and, in recent times, has been extended to include metalation chemistry. For example, Kim et al.⁴⁸⁸ developed a microfluidic technique that outpaces the very rapid AoF rearrangement to chemoselectively functionalize iodophenyl carbamates at the ortho position, forming rearranged product 552 (Scheme 125). Central to the technique is a chip microreactor, which can shorten a reaction time in the submillisecond range, even at cryogenic temperatures.

Scheme 125. Chemoselective Functionalization of Iodophenyl Carbamates at the ortho Position (Unrearranged Products) Controlled by a Microfluidic Chip Microreactor That Outperforms Very Fast AoF Rearrangement (Rearranged Products).

Adapted with permission from ref (488). Copyright 2016 The American Association for the Advancement of Science.

Later, the same group reported improved control of the AoF reaction in a 3D-printed stainless steel microreactor with a circular fluidic channel of a few tenths of a micrometer in cross-section.⁴⁸⁹ They investigated the mixing efficiency of different channel configurations with different designs. The simple T-shaped channel structure showed superior synthetic yield of the unrearranged product at residence times of less than milliseconds, raising the prospect of upgrading microreactor technology for high-throughput production. Yoshida’s latest advances in this field encompass performing [1,4], [1,5], and [1,6] anionic Fries-type rearrangements using flow chemistry.⁴⁹⁰

12. Conclusions and Implications for Future Research

This review covers the main chemistry of the ArOAm group since Victor Snieckus’ seminal 1990 review.²¹ We focused on advances made with the DoM and DreM, AoF rearrangements, and C–H functionalization of aromatic compounds containing the O-carbamate group, including how accompanying silyl groups have been exploited as protecting groups as well as mediating both ipso- and non-ipso-substitutions. It was necessary to elaborate on possible manipulations and CC reactions of the O-carbamate group to highlight the utility of the ArOAm. We also included a comprehensive section highlighting practical applications of the ArOAm in the synthesis of various valuable bioactive compounds (section 9). Our work consolidates the many discoveries and developments made in the field over the past 30 years while exposing gaps in the literature and encouraging fresh research in these (and other) directions. Some ideas for research to address gaps in the literature are discussed as follows.

12.1. Metalation of ArOAm Using Alternative Metalating Agents

First, the development of alternative metalating reagents to what have already been tried (see section 2.3.4) is necessary for enabling less harsh conditions and to use alternative Group 1 and 2 metals, given the recent surge in demand for Li (in Li ion batteries).⁴⁹¹ We point readers to a comprehensive 2022 review⁴⁹² covering the latest “ate” complexes which might be explored. New metalating agents developed by the research group of Knochel^493,494 (the creator of “TurboGrignards”) are also worth delving into.

12.2. Boron-Mediated Functionalization of ArOAms

We anticipate that ArOAms could form BBr₂ or BF₂ complexes in a similar fashion to what has already been described for phenylacetamides by Iqbal et al.⁴⁹⁵ and N-aryl amides by Shinde et al.⁴⁹⁶ These complexes could be utilized for further functionalization, e.g., halogenation. The BX₂ group could also be tested as a coupling group with aryl halides via Suzuki coupling as has been demonstrated with potassium aryltrifluoroborates.^497,498

12.3. CC of ArOAm

Although much has been achieved with developing chemistry enabling CC of the ArOAm group (see section 8), there are still some areas worth further study. These include the following:

• (1)CC with aryl bromides: there are no examples of CC of fused O-carbamates with aryl bromides in the literature (only naphthyl O-carbamates) (see Scheme 60). This is an opportunity, and the prevalence of (hetero)aryl bromides implies that any methodology developed in this area would be of great value to various fields.
• (2)CC of ArOAm with compounds containing boron-containing functional groups other than boronic esters such as BX2 (X = Br, F)^412,499 would provide access to a diverse range of products.
• (3)There is scope for investigating the CC of ArOAms with other FGs such as nitriles, organozincs, and organostannanes, as has been demonstrated with other phenol-derived electrophiles.^500−502
• (4)The lack of examples of CC between nonfused ArOAms and silylmagnesium reagents (during which the ArOAms are converted to aryl silanes, i.e., the process is silylation via C–O cleavage) hints at the difficulty of this procedure (outlined in section 8.9. above). Any solution to overcome this challenge would pay dividends.
• (5)There is only one report of CC of alkyl-aluminum reagents with ArOAms (section 8.7). Thus, any advancement with this chemistry would provide opportunities for diversification of products using a relatively well-tolerated (and high yielding) procedure.
• (6)Examples of CC incorporating green/sustainable chemistry have been investigated. In the future, more can be done to advance this area, especially with the current public motivation to convert from linear to circular chemistry.⁵⁰³ Related to this, the use of electrocatalysis, organocatalysis, photocatalysis (and combinations of these), as well as mechanochemistry, for the transformations of ArOAms, are worth future investigation. Thus, far, electrocatalysis has only been demonstrated for alkyne annulations via C–H/Het–H activation of aryl O-carbamates,⁴⁶⁸ while photocatalysis has been applied to facilitate the cycloamination of of prenyl O-carbamates and ureas.⁵⁰⁴ Reynes et al.⁵⁰⁵ reported mechanochemical nickel-catalyzed Suzuki–Miyaura coupling of aryl sulfamates.
• (7)Although there are examples of CC of alkenyl O-carbamates (sections 8.2.2. and 8.2.4), progress made with CC of linear, cyclic, and annulated aliphatic and benzylic O-carbamates could unlock new, valuable new avenues of exploration.

12.4. Functionalization of 1,8-Naphthalenediyl Bis(diethylcarbamate)s

Apart from the previously mentioned 2,7-naphthalenediyl bis(diethylcarbamate) compounds (Table 8, Scheme 13), there is only one example in the literature of the functionalization of analogous 1,8-naphthalenediyl bis(diethylcarbamate) compounds using DoM.²⁰⁶ In this case, the metalated compounds were converted to 1,8-naphthalenediol derivatives which could be complexed with transition metals to form functional materials (e.g., capable of catalysis). The as-yet unexplored 2,7-arylation of 1,8-naphthalenediyl bis(diethylcarbamate)s followed by DreM or AoF of the 1,8-naphthalenediyl bis(diethylcarbamate) compounds could provide access to a new set of interesting materials. This has been carried out for the amide analogues.⁵⁰⁶

12.5. Broadening the Scope of Metalation Chemistry to Include Other Heteroaromatic O-Carbamates

Throughout this review, we have focused on the utilization of the OAm FG as a DMG in metalation chemistry in aryl and naphthyl substrates. Examples of heteroaryl compounds have appeared such as pyridyl and thiophene O-carbamates (e.g., see Scheme 35). However, there are several heteroaromatic O-carbamates which have not been functionalized using DoM chemistry. These include the following: furans, oxazoles, thiazoles, oxadiazoles, benzodioxoles, pyrazines, pyridazines, pyrimidines, and quinolines. The functionalization could involve metalation directed by an O-carbamate positioned on the N itself (restricted to heterocycles with an N–H, e.g., indole, imidazole). These heteroaromatic compounds are useful in many applications ranging from medicine and pharmaceutics^507−509 to agriculture,⁵¹⁰ catalysis,^511,512 and new functional materials (e.g., in organic electronics);⁵¹³ thus, further functionalization of these would be of interest.

12.6. Broadening the Scope of Metalation Chemistry to Include Alkenyl and Alkyl O-Carbamates

Another area of interest involves the extension of the metalation chemistry of ArOAms to alkenyl and alkyl O-carbamates, e.g., (hetero)benzylic compounds.^514,515 Since this has not yet been reported, it is implicit that these systems are too unreactive. Nevertheless, the ready access to linear, cyclic, and annulated (e.g., adamantyl) aliphatic O-carbamates^516−518 beckons a foray into this potentially rich field.

12.7. Further Exploration of Aryl Se- and S-Carbamates

Finally, as mentioned in Section 2.3.2, the metalation chemistry of aryl Se-carbamates, aryl S-carbamates, and aryl dithiocarbamates has hardly been explored. There is much research interest in developing new synthetic routes to dithiocarbamates (due to the importance of organosulfur compounds in biological compounds),⁵¹⁹ but little investigation has taken place regarding the functionalization of these materials.

12.8. Comparison of ArOAm with Recently Reported Directing Groups

The introduction of DMGs such as triflones (trifluoromethyl sulfones),⁵²⁰ sulfonyl fluorides and fluorosulfates,⁵²¹ aziridino groups,⁵²² tetraethylphosphorodiamidate,⁵²³ phosphoric acids and N-triflylphosphoramides,⁵²⁴ sulfoximines,^525,526 α-lithiobenzyloxy,¹⁰¹ THP-protected hydroxy group (OTHP),¹²⁶ and small-ring heterocycles⁵²⁷ invites exploration into how these compare with (or how they might be used in tandem with) ArOAm for the synthesis of complex molecules.

In addition, there are still numerous functional groups yet to be discovered as directing groups for (hetero)aryl ortho-metalation, e.g., the O-protecting methoxyethoxymethyl ether (MEM), pivaloyl, and aryl glyoxal groups. These might be valuable given their facile transformational capabilities and wider utility.

12.9. ArOAm-Mediated Synthesis of Isotopically Labeled Compounds

The rising interest in isotopically labeled compounds (especially deuterated/tritiated pharmaceuticals) as therapeutic agents,^528,529 bioanalytical standards^530,531 as functional materials in organic electronic applications^532−535 and in mechanistic studies^536,537 has encouraged researchers to find new synthetic methodologies to these materials.^538,539 However, there are scant examples where isotopologues have deliberately been prepared via ortho metalation chemistry.^540,541 The utility of the ArOAm both as DMG (as described in this review) and within bioactive compounds containing ArOAm^6,11,509 or compounds containing functionalities accessible from ArOAm, such as phenols,^542−544 suggests that the ArOAm could be exploited more widely in this area, especially now that milder and greener/more sustainable reactions conditions are being developed (Section 11).

12.10. Final Word

Despite the progress made with developing the functionality of the ArOAm group, there are still numerous avenues worth exploration. These are especially significant given increased interest in converting readily available CO₂ into organic carbamates^{13,15,16,545−547} and the functionalization of aromatic phenolic monomers obtained via the depolymerization of biomass-derived lignin.^548,549 Furthermore, compounds containing the ArOAm functional group continue to be developed for a range of applications such as for potential Alzheimer’s disease treatments.^{509,550−552}

Glossary

Abbreviations

Acac

acetylacetone

AChE

acetyl cholinesterase

Am

amide

t-am

tert-amyl

AoF

anionic ortho-Fries

aq

aqueous

ArOAm

aryl O-carbamate

B₂pin₂

bis(catecholato)diboron

Bn

benzyl

Boc

tert-butyloxycarbonyl

Bpin

catecholatodiboron

bpy

2,2′-bipyridine

BTPP

tert-butylimino-tri(pyrrolidino)phosphorane

n-BuLi

n-butyllithium

s-BuLi

sec-butyllithium

t-BuLi

tert-butyllithium

CC

cross coupling

CIPE

complex-induced proximity effect

COD

1,5-cyclooctadiene

Cp*

pentamethylcyclopentadienyl

CPME

cyclopentyl methyl ether

Cy

cyclohexyl

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

DCE

1,2-dichloroethane

DCM

dichloromethane

dcype

1,2-bis(dicyclohexylphosphino)ethane

dcypt

3,4-bis(dicyclohexylphosphino)thiophene

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DES

deep eutectic solvent

DFT

density functional theory

DG

directing group

DIAD

diisopropyl azodicarboxylate

DIBAL

diisobutylaluminum hydride

DME

dimethyl ether

DMG

directed metalation group

DMPU

1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone

DoM

directed ortho metalation

DreM

directed remote metalation

dtbpy

4,4′-di-tert-butyl-2,2′-bipyridine

E⁺

electrophile

EDG

electron donating group

EDTA

ethylenediaminetetraacetic acid

equiv

equivalent

EWG

electron withdrawing group

HalD

halogen dance

HF

Hartree–Fock

HFIP

hexafluoroisopropanol

HOESY

Heteronuclear Overhauser Effect Spectroscopy

HTMP

(2,2,6,6-Tetramethylpiperidine)

It-Bu

1,3-di-tert-butylimidazol-2-ylidene

KEM

kinetically enhanced metalation

LAH

lithium aluminum hydride

LDA

lithium diisopropylamide

LiTMP

lithium 2,2′,6,6′-tetramethylpiperidide

MNDO

modified neglect of diatomic overlap

MTBE

methyl tert-butyl ether

MW

microwave

NaDA

sodium diisopropylamide

NBS

N-bromosuccinimide

NCS

N-chlorosuccinimide

neo

neopentyl

NIS

N-iodosuccinimide

NKR

Newman–Kwart rearrangement

NMR

nuclear magnetic resonance

OAm

O-carbamate

OMEM

2-methoxyethoxymethyl ether

OMOM

2-methoxymethyl ether

OTHP

tetrahydropyranyl ether

Piv

pivalic acid

PMDTA

N,N,N′,N″,N″-pentamethyldiethylenetriamine

Py

pyridine

Pym

2-pyrimidyl

SET

single electron transfer

SIPr

1,3-bis(2,6-diisopropylphenyl)imidazolinium

SMAP

silicon constrained monodentate trialkylphosphine

TBAB

tetra-n-butylammonium bromide

TBAF

tetra-n-butylammonium fluoride

TBS

tert-butyldimethylsilyl

TES

triethylsilyl

Tf

trifluoromethanesulfonate, triflate

TFA

trifluoroacetic acid

TFAA

trifluoroacetic anhydride

THF

tetrahydrofuran

TIPS

triisopropylsilyl

TMAF

tetramethylammonium fluoride

TMDSO

1,1,3,3-tetramethyldisiloxane

TMEDA

tetramethylethylenediamine

TMP

2,2′,6,6′-tetramethylpiperidine

TMS

trimethylsilyl

TRIP

triptycene

Ts

tosyl

Biographies

Ross D. Jansen-van Vuuren is a Senior Research Fellow at the University of Ljubljana and a member of the EUTOPIA Young Leaders Academy. He received his B.Sc. (Hons) in Chemistry from Rhodes University in 2004 and his Ph.D. in Chemistry at the University of Queensland (UQ) with Prof. Paul Burn in 2012. This was followed by three postdocs: Prof. Paul Burn (2012–2015), Prof. Philip Jessop, Queen’s University, Canada (2017–2019), and Prof. Victor Snieckus (also at Queen’s) (2020–2021). Ross was then awarded a EUTOPIA Science and Innovation Fellowship (2021–2023) and funding from ARIS (2023–2026), to conduct independent research into developing greener and more sustainable approaches (including the use of flow chemistry) to the synthesis of deuterated organic compounds. He is also a member of the EUTOPIA Young Leaders Academy.

Susana Liu is currently a Doctor of Pharmacy (PharmD) candidate at the University of Waterloo’s School of Pharmacy. She is presently completing her final patient care rotations within the region of Niagara with the hopes of continuing health promotion via evidence-based medicine in her future pharmacy practice as a licensed pharmacist. Prior to studying at the University of Waterloo, Susana earned her Bachelor of Science (Honours) in Chemistry from Queen’s University, Kingston, in 2020.

M. A. Jalil Miah obtained his M. Sc. Degrees in Chemistry from Rajshahi University, Bangladesh (1974), and Lakehead University, Ontario, Canada (1981), respectively. For his Ph.D. degree in Chemistry under the supervision of Professor Victor A. Snieckus, University of Waterloo, Ontario, Canada (1985), he carried out research involving developing DoM methodologies for the synthesis of polysubstituted aromatic and heteroaromatic compounds of biological and medicinal interest. He has several postdoctoral experiences: (1) University of Ottawa, October 1985–November 1986, with Professor Robert R. Fraser, (2) University of Florida, Gainesville, Florida, USA, August 1995–September 1996, with Professor Tomas Hudlicky, and (3) as a Research Professor at Chungbuk National University, South Korea, May 2004–November 2005 with Professor K. Han. Finally, he has worked as a visiting Researcher/Professor at Queen’s University, Ontario, Canada (2013—2018), with Professor Victor A. Snieckus. Professor M. A. Jalil Miah has been a faculty member in the Department of Chemistry at Rajshahi University, Bangladesh, from January 1976–June 2017.

Janez Cerkovnik is Professor of Chemistry at the University of Ljubljana, Faculty of Chemistry and Chemical Technology. He received his Ph.D. in Chemistry from the University of Ljubljana with Emeritus Prof. Božo Plesničar in 1993. As a postdoctoral fellow, he was a research associate with Prof. Gary H. Posner at Johns Hopkins University (Baltimore, USA). His main research interests include investigating the mechanisms of reactions of oxidation. Recently, he has also devoted himself to the development of chemical tools for predicting reactivity in various chemical systems.

Janez Košmrlj is a Professor of Organic Chemistry at the University of Ljubljana. He received his Ph.D. from the University of Ljubljana with Emeritus Professor Slovenko Polanc and was a postdoctoral fellow with Professor Guy L. F. Lemière at the University of Antwerp and Dr. Leland O. Weigel at Eli Lilly and Company in Indianapolis. His research focuses on the development of methods for organic synthesis and the investigation of reaction mechanisms. Professor Košmrlj is the recipient of The Zois Certificate of Recognition (2018), the highest national recognition conferred to researchers in the Republic of Slovenia for their achievements and lasting contribution to scientific, research, and development activities.

Victor Snieckus (August 1, 1937–December 18, 2020) was a synthetic organic chemist, most well-known for his research on Directed ortho-Metalation (DoM) chemistry. Vic was awarded his B.Sc. in Chemistry from the University of Alberta in 1959, his Master’s degree from the University of California (Berkeley) in 1961, and his Ph.D. from the University of Oregon in 1965 with Prof. Virgil Boekelheide. In 1966, he worked as a postdoctoral scholar at the National Research Council of Canada (NSERC) before joining the faculty of the University of Waterloo as an assistant professor, becoming an associate professor in 1971 and a full professor in 1979. He relocated to Queen’s University in 1998, where he assumed the Bader Chair of Chemistry. He retired and became professor emeritus in 2009, continuing to work on various projects until October 2020.

Author Contributions

CRediT: Ross David Jansen-van Vuuren funding acquisition, project administration, software, supervision, writing-original draft, writing-review & editing; Susana Liu writing-original draft; M. A. Jalil Miah writing-review & editing; Janez Cerkovnik writing-original draft, writing-review & editing; Janez Košmrlj funding acquisition, writing-original draft, writing-review & editing; Victor A. Snieckus conceptualization, funding acquisition, supervision, writing-original draft, writing-review & editing.

The authors declare no competing financial interest.

Dedication

^∥ V.S. passed away in December 2020.