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Published in final edited form as: Chem. 2019 Mar 7;5(4):929–939. doi: 10.1016/j.chempr.2019.02.005

Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catalysis

Renhe Li 1,3, Feipeng Liu 1,2,3,+, Guangbin Dong 1,4,*,+
PMCID: PMC6879102  NIHMSID: NIHMS1521633  PMID: 31773067

SUMMARY

Palladium/norbornene (Pd/NBE) cooperative catalysis, also known as the Catellani reaction, has become an increasingly useful method for site-selective arene functionalization; however, certain constraints still exist due to its intrinsic mechanistic pathway. Herein we report a redox-neutral ortho functionalization of aryl boroxines via Pd/NBE catalysis. An electrophile, such as carboxylic acid anhydrides or O-benzoyl hydroxylamines, is coupled at the boroxine ortho position, and a proton as the second electrophile is introduced at the ipso position. This reaction does not require extra oxidants or reductants, and avoids stoichiometric bases or acids, thereby tolerating a wide range of functional groups. In particular, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated, which could be used to control reaction sequences. Finally, a deuterium labelling study supports the ipso-protonation pathway. This unique mechanistic feature could inspire the development of a new class of Pd/NBE-catalyzed transformations.

eTOC blurb

A redox-neutral ortho functionalization of aryl boroxines via palladium/norbornene cooperative catalysis is developed. Ortho amination and acylation are achieved by using carboxylic acid anhydrides and O-benzoyl hydroxylamines as an electrophile, respectively, while protonation occurs at the ipso position. This transformation avoids using either extra oxidants and reductants or stoichiometric bases and acids. In addition, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated for pathway divergence.

Graphical Abstract

graphic file with name nihms-1521633-f0001.jpg

INTRODUCTION

Site-selectivity control still represents an ongoing quest in organic synthesis.1–2 Especially, site-selective functionalization of arenes has been playing a key role in preparing aromatic moieties ubiquitously found in drugs and agrichemicals. Recently, the palladium/norbornene (Pd/NBE) cooperative catalysis, pioneered by Catellani3 and Lautens4, has emerged as a useful set of tools to access poly-substituted arenes. In a typical Catellani reaction, a nucleophile and an electrophile are coupled at the ipso and ortho positions, respectively, through selective reactions with the aryl-NBE palladacycle (ANP) intermediate (Scheme 1A).3–33 In particular, when the nucleophile is a hydride equivalent, a reductive ortho functionalization is realized. While efficient, the Catellani reaction contains a non-productive process, which is the removal of the generated HX with stoichiometric bases. In addition, the reaction needs to be terminated by a nucleophile or reductant in order to reform the Pd(0) catalyst. Moreover, the compatibility between the nucleophile and the electrophile is an inevitable concern, and typically, only masked or weak nucleophiles are suitable. Very recently, Zhang34 and Zhou35 concurrently reported a novel arylboronic acid-based Catellani reaction also through coupling an electrophile/nucleophile pair, but stoichiometric bases and oxidants were still required (Scheme 1B).

Scheme 1.

Scheme 1.

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Palladium/Norbornene Cooperative Catalysis

Stimulated by these intrinsic constraints in the Catellani reaction, we felt it could be attractive to develop a redox-neutral arene ortho functionalization, in which an aryl nucleophile (e.g. aryl boron compounds) could be coupled with two electrophiles without the need for stoichiometric bases or oxidants (Scheme 1C). Mechanistically, after the ortho functionalization with ANP followed by NBE extrusion, the resulting aryl-Pd(II) species could then react with another electrophile (instead of a nucleophile or reductant) to regenerate the Pd(II) catalyst. Seminal work by Lautens has shown that such a aryl-Pd(II) species could attack an adjacent carbonyl group, but this has been limited to an intramolecular transformation.15 Clearly, many challenges can be envisioned with this redox-neutral strategy, including the difficulty of controlling site-selectivity and the choice of suitable electrophiles. Thus, at this preliminary stage, we have been focused on a simplified system with one electrophile being a proton source (Scheme 1D).31–33 In this reaction, the acid generated during the ANP formation could be re-coupled at the ipso position, which leads to a net proton swap. Herein, we describe our initial development of Pd/NBE-catalyzed redox-neutral acylation and amination using aryl boroxines as substrates, which directly introduces a functional group at the arene ortho position without extra stoichiometric oxidants or reductants.

RESULTS AND DISCUSSION

The challenges for developing such a redox-neutral transformation are two-fold. First, given that the aryl-Pd(II) intermediate formed after the NBE extrusion is typically less nucleophilic, protonation of such a species could be difficult.36 Second, transmetalation of aryl boronates is generally promoted by basic conditions, while the final protonation step requires the presence of an acid. Hence, the compatibility of these two steps could be another concern. We hypothesized that the key for the success of this reaction would be to discover a catalyst system that can promote both transmetalation and protonation. The use of arsine-type ligands caught our attention because first, AsPh3 is known to promote fast transmetalation in Stille reactions;37 and second, AsPh3 was also found to be the most efficient ligand in our previous meta C−H arylation reaction,32 which requires facile de-protonation and re-protonation at the arene ortho position.

To test this hypothesis, ortho acylation was studied as the model reaction; 2-tolylboroxine (1a) and benzoic anhydride (2a) were employed as the initial model substrates. After careful evaluation of various reaction parameters (Tables S1–S4), the Pd(TFA)2/AsPh3 combination indeed provided the desired ortho acylation product 3aa in 65% yield (Figure 1, entry 1). No direct ipso substitution between the aryl boroxine and benzoic anhydride was observed in this case. A number of control experiments were subsequently carried out. First, the Pd salt, NBE and AsPh3 were all essential to this reaction (entries 2–4). Other Pd(II) precatalysts or phosphine-based ligands were less efficient (entries 5–7). It is noteworthy that, while the majority of the prior Pd/NBE-catalyzed reactions use a high loading or excess NBE,5–10 only 20 mol% NBE was sufficient in this reaction. A catalytic amount of benzoquinone could improve the reaction yield (entry 8), which likely serves as a Pd(0) scavenger or a π-ligand38–40 to prevent catalyst decomposition. A catalytic amount of CuI and K2CO3 also enhanced the yield, though their roles were not critical (entries 9 and 10).41 One hypothesis is that a catalytic amount of carbonate base may facilitate the transmetalation of boroxines or promote the concerted metalation deprotonation step to form the ANP. The reaction was sensitive to water, and adding molecular sieves significantly increased the yield (entries 11 and 12). Use of aryl boroxines instead of boronic acids was beneficial, though the commercial “boronic acid” that contains ~28% ArB(OH)2 and ~72% boroxine (Figures S1–S3) still afforded the desired product in 52% yield (entry 13). In contrast, the corresponding pinacol-derived substrate was not reactive, likely due to its difficulty in the transmetalation step (entry 14).42

Figure 1. Control Experiments for ortho Acylation with 2-Tolylboroxine[a].

Figure 1.

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[a] The reaction was run with 0.2 mmol 1a (monomer of the boroxine) and 0.4 mmol 2a in 4 mL toluene for 14h. [b] Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard. [c] Toluene after freeze-pump-thaw treatment was used. [d] Purchased from Combi-Blocks, containing 28% free 2-toylboronic acid determined by 1H NMR analysis.

The scope of the reaction with respect to the acyl part was examined first (Figure 2; Figures S4–S47). Anhydrides with electron-donating and -withdrawing groups all afforded the desired ortho acylation products in moderate to good yields. Generally, the more electron-deficient aromatic anhydrides (e.g. 3ab and 3ae) gave slightly higher yields than the electron-richer ones, probably owing to their enhanced reactivity towards the ANP intermediate. One important feature is that a number of functional groups, including aryl fluoride (3ab-3ad), chloride (3ae and 3af), bromide (3ag), iodide (3ah, vide infra, Schemes 3 and 4), trifluoromethyl (3ai), ester (3aj) and anisole moieties (3am-3ao), were tolerated. Ortho-substituted aromatic anhydrides (3ak and 3ao) were competent substrates. It is noteworthy that pinacol boronates were compatible (3ap), which could serve as a handle for further functionalization. In addition, ferrocene- (3aq) and thiophene-derived ketone products (3ar) could be isolated in moderate yields. Encouragingly, aliphatic carboxylic acid anhydrides also proved to be suitable coupling partners (3as and 3at).

Figure 2. Substrates Scope with Respect to Anhydrides[a].

Figure 2.

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[a] The reaction was run with 0.3 mmol 1a and 0.6 mmol 2a in 4 mL toluene for 14h.

Scheme 3.

Scheme 3.

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Tolerance of Aryl Iodide and Bromide Moieties.

Scheme 4.

Scheme 4.

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Controlling the Reaction Sequence Enabled by Orthogonal Chemoselectivity

Next, the scope of the aryl boroxines was explored. Notably, a lower palladium loading (7.5 mol%) was applied in these reactions (Figure 3; Figures S48–S101). Substitutions at C2, C3, C4 and C5 positions of aryl boroxines could all be tolerated. For the para-substituted aryl boroxines, aryl fluoride (3hb), chloride (3lb), ester (3ib), amide (3jb), Weinreb amide (3kb), phenyl (3gb) and alkyl groups (3fb) were compatible. In addition, aryl boroxines that contain an electron-donating or -withdrawing substituent smoothly provided the ortho acylation products in moderate to good yields. While the trend of the electronic effect with the aryl boroxine substrates was not obvious, those bearing a strong electron-withdrawing group at the C3 position (3pb and 3qb) typically gave lower yields. Moreover, a naphthalene-derived substrate (3sb) also provided the desired ketone product.

Figure 3. Substrates Scope with Respect to Aryl Boroxines[a].

Figure 3.

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[a] The reaction was run with 0.3 mmol 1b-s and 0.6 mmol 2b in 4 mL toluene for 14h. [b] 10 mol% of Pd(TFA)2 and 30 mol% of AsPh3 was used.

To gain some mechanistic insight into this reaction, deuterium labelling studies were performed (Scheme 2; Figures S102 and S103). When the fully deuterated substrate 1s-d reacted with anhydride 2b, the desired product (3sb-d) was isolated with 60% deuterium incorporated at the ipso position (Scheme 2, Eq. 1). The erosion of deuterium incorporation was possibly due to the H-D exchange with adventitious water in the reaction system. To examine the possibility of the H-D exchange, a reverse control experiment was conducted. Using regular 2-toylboroxine 1a as the substrate, the standard reaction was run in the presence of 2.0 equiv of D2O (Scheme 2, Eq. 2). Although the reaction still contained a significant amount of molecular sieves, 38% deuterium was nevertheless observed as the ipso position of the product. These results are consistent with an ipso-protonation pathway proposed in Scheme 1D.

Scheme 2.

Scheme 2.

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Deuterium Labelling Studies

One potential merit of aryl boroxine-mediated reactions is the compatibility of aryl iodide moieties,35 which are otherwise highly reactive under the typical Pd/NBE catalysis conditions (Scheme 3A).5–10 First, in the presence of aryl iodide 4a, ortho acylation of 2-tolylboroxine 1a still proceeded selectively with a full recovery of unreacted aryl iodide 4a. Encouragingly, a more complex aryl iodide (4b) derived from strychnine remained intact under the reaction conditions, while the ortho acylation with boroxine 1a provided the desired product (3ab) in 55% yield.43 In addition, substrates bearing halogens and boroxines on the same aromatic ring were tested (Scheme 3B; Figures S128–S140). Gratifyingly, both the aryl bromide (1t) and iodide (1u) groups survived under the standard ortho acylation conditions; such compatibility allows for convenient sequential functionalization of the arene substrates.

Encouraged by the unique chemoselectivity in the aryl boroxine-mediated reactions, orthogonal reactivity between aryl iodide (I) and boroxine (B) moieties was next explored, which, if successful, would provide a convenient way to control the reaction sequence without significant alteration of the substrates (Scheme 4; Figures S116–S127). Diaryl compound 5 containing both “I” and “B” groups was employed as the model substrate. First, as expected, the “B first, then I” sequence worked smoothly, which first gave an ortho acylation on the boroxine site and then an ortho amination on the iodide site. On the other hand, the “I first, then B” sequence was also successful: the Pd(0)-catalyzed reductive ortho amination of the aryl iodide tolerated the pinacol boronate moiety; the resulting intermediate after hydrolysis then participated in the Pd(II)-catalyzed ortho acylation uneventfully. Thus, without the need to prepare different substrates, the order of the reaction sequence between the boroxine and iodide sites could be controlled by different catalytic systems.

Besides the ortho acylation, preliminary success has also been obtained for achieving the ortho amination under the redox-neutral conditions (Figure 4; Figures S104 and S115). O-benzoyl hydroxylamines were found to be suitable electrophiles. Under modified reaction conditions, the desired ortho amination products could be obtained in moderate to good yields without the need of reductants.17 Phosphite ligands, e.g. P(OPh)3, proved to work better than arsine ligands, while other types of ligands were less efficient (Tables S5–S7). To the best of our knowledge, phosphite ligands have not been used in the Pd/NBE catalysis previously. A piperazine-derived electrophile also afforded the desired amination product (4ab) in 58% yield. Efforts on further enhancing the efficiency and scope of this ortho amination reaction through detailed mechanistic studies are ongoing.

Figure 4. Substrates Scope of the ortho Amination Reaction[a].

Figure 4.

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[a] Reaction conditions: 1 (0.5 mmol), 2 (0.2 mmol), Pd(OPiv)2 (20 mol%), P(OPh)3 (40 mol%), NBE (50 mol%), BQ (15 mol%), Cs2CO3 (50 mol%), CsI (50 mol%), toluene (4 mL), 100 °C, 12 h. [b] When 10 mol% Pd was used instead, 55% isolated yield was observed.

In summary, a redox-neutral Catellani-type transformation is developed using aryl boroxines as substrates. The reaction is enabled by a arsine or phosphite ligand and a palladium(II) catalyst, showing broad functional group compatibility. Compared to the classical reductive Catellani-type reactions, this approach does not require stoichiometric bases or reductants; in addition, it can tolerate various aryl halide moieties. While the efficiency of these methods remains to be further improved, the unique mechanistic pathway discovered here could have important implications on developing a new class of Pd/NBE-catalyzed reactions.

Supplementary Material

1

Highlights.

  • First Redox-Neutral Direct Ortho Functionalization of Aryl Boroxines

  • Proton as the Second Electrophile Coupled at the Ipso Position

  • Avoiding Stoichiometric Bases in the Pd/NBE Catalysis

  • Orthogonal Chemoselectivity Between Aryl Iodide and Boroxine Moieties

The Bigger Picture.

Poly-substituted aromatics are ubiquitously found in drugs and agrochemicals. To realize streamlined synthesis, it is highly attractive if functional groups can be site-selectively introduced at unactivated positions with common arene starting materials. Here, a method is developed to directly introduce acyl and amino groups at unactivated ortho positions of readily available aryl boron compounds. Compared to the known ortho functionalization approaches, this method does not require stoichiometric bases, external oxidants or reductants. Consequently, the reaction is chemoselective: a wide range of functional groups can be tolerated, including highly reactive aryl iodides. The primary innovation lies in the use of a proton to terminate the ipso aryl intermediate and regenerate the active palladium catalyst. This unique mode of reactivity in the palladium/norbornene catalysis should open the door for developing new redox-neural methods for site-selective arene functionalization.

ACKNOWLEDGEMENTS

Financial supports from the University of Chicago and NIGMS (1R01GM124414-01A1) are acknowledged. F.L. is supported by a CSC fellowship. We thank Dr. Zhe Dong for preliminary investigation. Mr. Jianchun Wang is thanked for checking the experiments.

Footnotes

DECLARATION OF INTERESTS

The authors declare no competing interests.

SUPPLEMENTAL INFORMATION

Supplemental Information includes Supplemental Experimental Procedures, 140 figures, and 7 tables and can be found with this article online.

EXPERIMENTAL PROCDURES

Full experimental procedures are provided in the Supplemental Information.

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Supplementary Materials

1
NIHMS1521633-supplement-1.pdf (4.3MB, pdf)

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