Nickel‐Catalyzed Arylative Cyclizations of Alkyne‐ and Allene‐Tethered Electrophiles using Arylboron Reagents

Abstract

The use of arylboron reagents in metal‐catalyzed domino addition–cyclization reactions is a well‐established strategy for the preparation of diverse, highly functionalized carbo‐ and heterocyclic products. Although rhodium‐ and palladium‐based catalysts have been commonly used for these reactions, more recent work has demonstrated nickel catalysis is also highly effective, in many cases offering unique reactivity and access to products that might otherwise not be readily available. This review gives an overview of nickel‐catalyzed arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described.

The use of arylboron reagents in metal‐catalyzed domino addition‐cyclization reactions is a well‐established strategy for the preparation of diverse carbo‐ and heterocyclic products. Recent studies have demonstrated nickel catalysis is highly effective in these reactions, in many cases offering unique reactivity and access to products that might otherwise not be readily available using other metal catalysts. This review gives an overview of nickel‐catalyzed arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents.

1. Introduction

Domino reactions are a versatile tool in synthetic chemistry by combining several bond formation steps into one process, allowing for the synthesis of complex molecules in a step‐economic manner.[ ¹ , ² , ³ , ⁴ , ⁵ ] Alkyne‐ and allene‐tethered electrophiles are excellent substrates for domino reactions because their multiple reactive sites provide many possibilities for reaction design. These substrates (1 and 5) have been used in a wide range of transition‐metal catalyzed arylative and alkylative cyclization reactions to prepare diverse carbo‐ and heterocycles (Scheme 1).[ ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ ] These processes typically occur by the reaction of a pronucleophilic reagent with the transition‐metal catalyst to generate an organometallic species 2. The alkyne or allene of the substrate then undergoes migratory insertion into this organometallic species to generate an alkenylmetal species 3 or allylmetal species 6, respectively, which can then cyclize onto the tethered electrophile. Overall, two new bonds are formed to give cyclic products, typically of general structure 4 or 7. It should be mentioned that mechanistically different transition‐metal‐catalyzed arylative and alkylative cyclizations of alkyne‐ and allene‐tethered electrophiles also exist, which proceed via oxidative cyclization to give metallacyclic intermediates,[ ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ ] and these reactions are not covered in this review.

Scheme 1.

Arylative and alkylative cyclizations of alkyne‐ and allene‐tethered electrophiles by a migratory insertion‐cyclization pathway.

Because of their generally good chemical stability, low toxicity, and widespread availability, arylboron compounds are commonly used as pronucleophiles in transition‐metal‐catalyzed domino carbometalation‐cyclization reactions of alkyne‐ ^[60] or allene‐tethered electrophiles. Arylative cyclization reactions of alkyne‐tethered electrophiles involving an arylboron species have been described using rhodium,[ ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ ] palladium,[ ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ ] and copper catalysis. ^[42] Similarly, palladium‐catalyzed arylative cyclization reactions of allene‐tethered electrophiles involving arylboron reagents have been described.[ ⁴³ , ⁴⁴ ] By varying the tether or the electrophile of the substrate, a variety of cyclic products can be obtained, and by employing non‐racemic chiral ligands, enantioselective reactions can be achieved. More recently, nickel catalysis has also been shown to be highly effective in these reactions.[ ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ ] As well as being less expensive and more readily available than the more commonly used rhodium or palladium catalysts, nickel catalysis can offer unique possibilities in reaction development not readily available to these other catalyst systems.[ ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ ]

This review will describe nickel‐catalyzed arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents, that proceed by the general mechanistic pathways shown in Scheme 1. It will highlight the breadth of carbo‐ and heterocyclic compounds that can be obtained and will discuss the scope and limitations of the reactions. The review begins with a consideration of mechanistic aspects of nickel‐catalyzed arylative cyclizations. This section is followed by discussion of various classes of reactions that differ according to whether alkyne‐ or allene‐tethered electrophiles are used, the mode of cyclization taking place, and whether the reactions are enantioselective or not. Related processes that do not utilize alkyne‐ or allene‐tethered electrophiles, but instead involve the annulation of 2‐formyl or 2‐acetylarylboronic acids with alkynes or allenes, are also described because they proceed by similar mechanisms.

Some elements of this review have been covered in other reviews on nickel‐catalyzed alkyne functionalization reactions. Liu and Kong recently reviewed nickel‐catalyzed difunctionalization of alkynes, ^[88] while Wilger and co‐workers focused on nickel‐catalyzed functionalization of alkynes that proceed with anti‐selectivity. ^[89] These reviews describe both inter‐ and intramolecular alkyne (di)functionalizations using a wide variety of reaction manifolds, whereas our review focuses specifically on arylative cyclizations using organoboron reagents and describes in detail the scope and limitations of these reactions.

2. Mechanistic Aspects of Nickel‐Catalyzed Arylative Cyclizations

This section will introduce mechanistic aspects relevant to nickel‐catalyzed arylative cyclizations. Scheme 2 depicts generalized catalytic cycles for the arylative cyclization of alkyne‐ or allene‐tethered electrophiles using arylboronic acids, which are by far the most commonly employed arylboron reagents in these reactions. Only a few examples using other arylboron reagents such as aryl pinacolboronates, aryl trifluoroborates, or arylboroxines have been reported.[ ⁶⁸ , ⁷³ ]

Scheme 2.

Generalized catalytic cycles for nickel‐catalyzed arylative cyclizations of alkyne‐ or allene‐tethered electrophiles using arylboronic acids.

In nickel‐catalyzed arylative cyclizations of alkyne‐tethered electrophiles, two modes of cyclization are generally possible, which differ in both their regio‐ and stereochemical outcomes. ^[90] The first of these is anti‐arylmetallative cyclization.[ ¹⁷ , ¹⁸ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ ] Here, the reactions are initiated by transmetalation of the arylboronic acid with the nickel complex 8 (formed by coordination of a ligand to a nickel(II) salt) to give arylnickel species 9 (Scheme 2A). Coordination of 9 to the alkyne of the substrate 1, followed by syn‐stereospecific migratory insertion of the alkyne places nickel distal to the electrophile. Direct cyclization of the resulting alkenylnickel species 10 onto the electrophile is not possible because of geometric constraints. However, 10 can undergo reversible E/Z isomerization to give the stereoisomeric alkenylnickel species 11, which can now cyclize onto the electrophile to give product 12 containing an endocyclic alkene. The mechanism for the E/Z isomerization step is currently not clear; however, this step has been discussed in some detail by Wilger and co‐workers in their review on nickel‐catalyzed anti‐selective alkyne functionalizations. ^[89] The E/Z isomerization of alkenylnickel species has also been observed in other types of reactions.[ ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ , ⁹⁶ ] Regarding the oxidation state of nickel in anti‐carbometallative cyclizations, different possibilities involving nickel in either the +1 or +2 oxidation states have been proposed.

The second common mode of nickel‐catalyzed arylative cyclization of alkyne‐tethered electrophiles is syn‐arylmetallative cyclization (Scheme 2B). The initial steps of the catalytic cycle are identical to those shown in Scheme 2A, to form an arylnickel species 9. This time, however, syn‐stereospecific migratory insertion of the alkyne of the substrate 1 into 9 occurs to place nickel proximal to the electrophile. Direct cyclization of the resulting alkenylnickel species 13 onto the electrophile then occurs to give cyclic products 14 containing an exocyclic alkene.

Because nickel‐catalyzed anti‐ and syn‐arylmetallative cyclizations require opposite regioselectivities in the alkyne migratory insertion step, the factors that influence this regioselectivity deserve some comment. It is known that alkynes containing an alkyl group on one side and an aryl or alkenyl substituent on the other generally undergo migratory insertion with organometallic species to form alkenylmetal species with the metal adjacent to the aryl or alkenyl group. Presumably, the alkenylmetal species is better stabilized by adjacent sp²‐hybridized, rather than sp³‐hybridized groups, because the higher s‐character leads to a stronger electron‐withdrawing effect. Therefore, it is not surprising that the majority of nickel‐catalyzed anti‐arylmetallative cyclizations of alkyne‐tethered electrophiles employ substrates 1 where R=(hetero)aryl or alkenyl (see Scheme 2A and the reaction scope in Sections 3 and 4) because this results in the selective formation of alkenylnickel species 10, where nickel is distal to the electrophile. Only a few examples of alkyne‐tethered electrophiles 1 where R=alkyl successfully resulting in anti‐arylmetallative cyclization have been reported,[ ⁶¹ , ⁷⁰ , ⁷³ ] but lower yields of products are generally observed [see Tables 1 and 12, and Equation (38)] and in many cases, no desired products were observed.[ ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ ]

Table 1.

Synthesis of 1‐naphthylamines by anti‐arylmetallative cyclization onto nitriles.

[a] Using Ni(acac)₂ ⋅ 2H₂O (5 mol %), P(4‐F₃CC₆H₄)₃ (5 mol %) and Cs₂CO₃ (0.1 equiv.).

Table 12.

Enantioselective anti‐arylmetallative cyclizations onto acyclic electron‐deficient alkenes.

[a] Using 2.0 equiv. of PhB(OH)₂ and 20 mol % each of Ni(OAc)₂ ⋅ 4H₂O and L2. [b] Using 2.0 equiv. of boronic acid and 10 mol % each of Ni(OAc)₂ ⋅ 4H₂O and L2.

In contrast, in nickel‐catalyzed syn‐arylmetallative cyclizations of alkyne‐tethered electrophiles, which require migratory insertion to place nickel proximal to the electrophile, substrates containing terminal or dialkyl‐substituted alkynes are typically employed (see the reaction scope in Section 5), though there are examples where an aryl‐alkyl alkyne is employed (Table 16). ^[73]

Table 16.

Synthesis of bridged tricyclo[5.2.1.0^1,5]decanes by enantioselective nickel‐catalyzed asymmetric domino cyclization of enynones.

In nickel‐catalyzed arylative cyclizations of allene‐tethered electrophiles, migratory insertion of the allene of the substrate 5 into the arylnickel species 9 invariably occurs to place the aryl group at the central carbon of the allene to give an allylnickel intermediate 15 (Scheme 2C). Allylnickel intermediate 15 can then cyclize onto the electrophile in a nucleophilic allylation to give product 16 containing a terminal alkene.

As well as arylboron reagents, other organoboron reagents have been employed in nickel‐catalyzed carbometallative cyclizations. Heteroarylboronic acids are well‐known to be more challenging than arylboronic acids in transition‐metal‐catalyzed reactions because of their higher propensity to undergo protodeboronation. However, certain heteroarylboronic acids that are less susceptible to protodeboronation (such as 3‐furyl‐ and 3‐thienylboronic acid), have been successfully employed.[ ⁶¹ , ⁶² , ⁶³ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ¹¹³ ] The use of alkenylboron reagents in these reactions have also been described [see Tables 7, and Equation (41)][ ⁶⁶ , ⁷⁰ , ⁷⁵ ] although low yields are often observed because of competitive protodeboronation. To our knowledge, no examples of nickel‐catalyzed alkylative cyclization using alkylboron reagents have been reported.

Table 7.

Enantioselective anti‐arylmetallative cyclizations onto Z‐allylic phosphates.

Yields are of isolated products 49, free from the minor isomers 50. [a] The product contained trace quantities of inseparable, unidentified impurities, and the ratio of 49 : 50 could not be determined.

3. Non‐Enantioselective anti‐Arylmetallative Cyclizations of Alkyne‐Tethered Electrophiles

As discussed in the previous section, nickel catalysis enables the development of anti‐arylmetallative cyclization of alkyne‐tethered electrophiles. A key step in these reactions is the reversible E/Z isomerization of the intermediate alkenylnickel species (Scheme 2A and 3A). This section describes non‐enantioselective arylative cyclizations of alkyne‐tethered electrophiles that produce either achiral products or racemic chiral products. These reactions encompass a wide range of electrophiles that includes nitriles, azides, N‐tosyl amides, ketones, and α,β‐unsaturated ketones to give diverse products such as 1‐naphthylamines, quinolines, pyrroles, isoquinolines, pyridines, thiophenopyridines, β‐carbolines, and indenes (Scheme 3B).

Scheme 3.

Overview of non‐enantioselective nickel‐catalyzed anti‐arylmetallative cyclizations of alkyne‐tethered electrophiles.

In 2016, Liu and co‐workers reported the seminal report of nickel‐catalyzed anti‐arylmetallative cyclizations of alkyne‐tethered electrophiles using arylboronic acids, which involves the cyclization of alkenylnickel intermediates onto nitriles (Table 1). ^[61] 2‐(Cyano)phenyl propargyl ethers were reacted with an arylboronic acid (2.0 equiv.), Ni(acac)₂ ⋅ 2H₂O (10 mol %), P(4‐F₃CC₆H₄)₃ (10 mol %), and Cs₂CO₃ (0.2 equiv.) in 1,4‐dioxane at 90 °C to give highly functionalized 1‐naphthylamines. As well as phenylboronic acid (18 a), the reaction tolerates electron‐withdrawing (18 b) and electron‐donating (18 c and 18 d) groups on the arylboronic acid. However, the use of alkylboronic acids such as n‐butylboronic acid did not give the desired products. Aryl groups on the alkyne are tolerated (18 a–18 e) as are heteroaryl groups such as 2‐thienyl (18 f) and 3‐benzothienyl (18 g). Furthermore, cyclohexenyl (18 h), n‐propyl (18 i), and cyclopropyl (18 j) substituents on the alkyne are compatible with the reaction; however, lower yields were obtained. The latter two cases are rare examples of alkyl substitution on the alkyne in nickel‐catalyzed anti‐arylmetallative cyclization. As discussed in section 2, a (hetero)aryl or alkenyl substituent on the alkyne is generally necessary to obtain high regioselectivities in the migratory insertion step and the low yields of 18 i and 18 j may be a consequence of lower regioselectivity.

Experiments were carried out to gain mechanistic insight into the reactions (Scheme 4). To gain insight into the oxidation state of the active nickel species, Ni(acac)₂ was reacted with 1,3‐bis(2,6‐diisopropylphenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ylidene (IPr), which was also found to be an effective ligand during optimization studies, in the presence of two equivalents each of KOt‐Bu and PhB(OH)₂ [Eq. (1)]. This experiment gave biphenyl (19) in 30 % yield and the three‐coordinate distorted T‐shaped Ni(I) complex 20 in 62 % yield, which was characterized by X‐ray crystallography. It was suggested that biphenyl (19) is formed by reductive elimination of a biarylnickel(II) species which would result in the release of a Ni(0) species. A comproportionation reaction between Ni(0) and Ni(II) could then provide the observed Ni(I) species 20. The stoichiometric reaction of Ni(COD)₂ and Ni(acac)₂ in the presence of IPr (2.0 equiv.) was carried out and provided Ni(I) species 20 in 55 % yield [Eq. (2)], which provides some support for this hypothesis. Ni(I) complex 20 was also found to catalyze the arylative cyclization reaction of 2‐(cyano)phenyl propargyl ether 17 a with PhB(OH)₂ to give the desired product 18 a in 53 % yield, suggesting that a Ni(I) species is catalytically competent [Eq. (3)]. The proposed mechanism for the nickel‐catalyzed anti‐arylmetallative cyclization of alkyne‐tethered nitriles follows the general catalytic cycle shown in Scheme 2A with nickel in the +1 oxidation state.

Scheme 4.

Mechanistic studies.

In 2018, Reddy and co‐workers reported the synthesis of 2,3‐diarylquinolines by the nickel‐catalyzed anti‐arylmetallative cyclization of azidophenyl propargyl alcohols 21 with arylboronic acids (1.2 equiv.) in the presence of Ni(acac)₂ (10 mol %), PPh₃ (10 mol %), and Cs₂CO₃ (0.2 equiv.) in 1,4‐dioxane at 90 °C. (Table 2). ^[62] The reaction tolerates a range of arylboronic acids including 4‐bromophenylboronic acid (23 b) as well as 1,3‐benzodioxole‐5‐boronic acid (23 c). The reaction works well with electron‐donating (23 d) or electron‐withdrawing (23 e) aryl groups on the alkyne. A gram‐scale reaction using phenylboronic acid gave 23 a in 86 % yield. The reaction of a substrate containing a cyclohexenyl‐substituted alkyne with phenylboronic acid gave 23 f in 71 % yield. A substrate with an alkyl azide did not afford any of the product 23 g.

Table 2.

Synthesis of quinolines by anti‐arylmetallative cyclizations onto azides.

The proposed mechanism follows the general catalytic cycle shown in Scheme 2A, with the intermediate alkenylnickel species cyclizing onto the azide (as in 22) to eject dinitrogen as a leaving group. The authors proposed that nickel adopts the +2 oxidation state throughout the catalytic cycle, in contrast to the proposal by Liu and co‐workers for their nickel‐catalyzed synthesis of 1‐naphthylamines (Table 1). ^[61]

The propargylic hydroxyl group in the substrates is important for the success of the reaction, as shown by the reaction of a substrate without this functionality, which led only to slow decomposition and none of the desired 2,3‐diarylquinoline being formed [Eq. 4].

In 2018, Lam and co‐workers described the synthesis of multisubstituted pyrroles by the nickel‐catalyzed arylative cyclization of N‐tosyl alkynamides with (hetero)arylboronic acids (2.0 equiv.) (Table 3). ^[63] The conditions employed were 5 mol % each of Ni(OAc)₂ ⋅ 4H₂O and racemic Ph‐PHOX (rac‐L1) in TFE at 80 °C. The process is tolerant of a range of substituents on the alkyne such as phenyl (26 a), 2‐fluorophenyl (26 b), 2‐thienyl (26 c), and an alkenyl group (26 d); however, a substrate with a methyl‐substituted alkyne led to a complex mixture of products. Excellent yields were obtained with various aryl (26 a–26 e) or alkyl substituents (26 f–26 h) on the N‐acyl group. Substituted phenylboronic acids are tolerated in the reaction (26 i) as well as heteroarylboronic acids such as 5‐indolyl (26 j), 3‐thienyl (26 k), and 3‐furylboronic acid (26 l). However, 4‐pyridinylboronic acid, methylboronic acid, and cyclopropylboronic acid did not provide the desired products. The proposed mechanism follows the generalized catalytic cycle shown in Scheme 2A, with cyclization of the intermediate alkenylnickel species onto the N‐acyl group giving nickel alkoxide 25 (Table 3, top). Protonation of 25, followed by elimination of water, gives the pyrrole products.

Table 3.

Synthesis of pyrroles by anti‐arylmetallative cyclizations onto N‐tosylamides.

The utility of this process was demonstrated in the synthesis of pyrroles 27 and 29 that have been used in the preparation of 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) derivatives 28 and 30 ^[97] (Scheme 5A) and bovine cyclooxygenase and 5‐lipoxygenase inhibitor 32 ^[98] (Scheme 5B). Removal of the tosyl group from pyrrole 26 a was achieved using KOH in MeOH:THF (1 : 1) at 70 °C to obtain pyrrole 27, a precursor to BODIPY derivative 28. In addition, the reaction of 26 a with POCl₃ in DMF at 100 °C led to formylation with concomitant tosyl deprotection to give pyrrole 29, a precursor to BODIPY derivative 30. A further application was described in the synthesis of pyrrole 31, a precursor to the bovine cyclooxygenase and 5‐lipoxygenase inhibitor 32, through tosyl deprotection of 26 f followed by N‐alkylation with n‐hexyl bromide.

Scheme 5.

Synthetic applications of pyrroles prepared by nickel‐catalyzed arylmetallative cyclizations.

In 2020, Reddy and co‐workers reported the nickel‐catalyzed arylative cyclization of substrates containing seemingly electronically and sterically unbiased diaryl alkynes to give various pyridine and indene derivatives [Scheme 6 and Equations (7)‐(17)]. ^[64] The reactions were conducted by heating the substrate with the (hetero)arylboronic acid (2.0 equiv.), Ni(acac)₂ (10 mol %), PPh₃ (10 mol %), and Cs₂CO₃ (0.2 equiv.) in 1,4‐dioxane under air at 90 °C. The arylative cyclization reaction of substrate 33, which contains an azide and a diarylalkyne, with phenylboronic acid led to the isoquinoline 34 in 85 % yield (Scheme 6). This result was initially surprising because with a diarylalkyne one might have expected some of the alternative product 36 to be formed, resulting from migratory insertion of the alkyne with the intermediate arylnickel species with the opposite regioselectivity to give 35. Indeed, nickel‐catalyzed hydroarylation of an diarylalkyne that lacks the azido group led to a mixture of regioisomers 37 and 38 [Eq. (5)], which suggests the presence of the electrophile is important in controlling regioselectivity.

Scheme 6.

Nickel‐catalyzed arylative cyclizations of ortho‐functionalized diarylalkynes.

A substrate containing an alkyl‐substituted aryl alkyne did not provide any of the desired isoquinoline [Eq. (6)]. However, substrates containing an aryl group and an alkenyl group on either side of the alkyne in one of two alternative connectivities successfully led to the desired products [Eq. (7) and (8)]. These results further highlight the importance of the electrophile in these arylative cyclizations of alkynes that have seemingly electronically unbiased alkynes. The authors suggest two possible mechanisms for these reactions. In the first possibility, favored by the authors, it was proposed that the regioselectivity of the migratory insertion of the alkyne with the arylnickel species is controlled by a polarizing effect of the tethered electrophile (as in 39) as opposed to any steric or electronic effect of the alkyne substituents, to give the alkenylnickel species 40 (Scheme 7). Following the generalized catalytic cycle in Scheme 2A, 40 can then undergo reversible E/Z isomerization and cyclization onto the azide to eventually give the isoquinoline. In this mechanism, the oxidation state of nickel was not specified. The second suggested mechanism involves an initial “anti‐Wacker“‐type addition.[ ³² , ⁹⁹ , ¹⁰⁰ ]

Scheme 7.

Proposed electrophile‐driven migratory insertion.

Further examples of the scope of this process are shown in Equations (9)‐(17). Arylative cyclization with substituted phenylboronic acids bearing methoxy [Eq. (9)] or fluoride groups [Eq. (10)] worked well. A substrate containing a secondary alkyl azide led to a trisubstituted isoquinoline in 65 % yield [Eq. (11)]. Thiophenopyridines [Eq. (12)] and β‐carbolines [Eq. (13)] were successfully prepared from thiophene‐ and indole‐containing substrates, respectively. The reaction also worked with substrates containing other electrophiles such as ketones [Eq. (14) and (15)] or conjugated enones [Eq. (16)], leading to the synthesis of racemic chiral indenes. Arylative cyclization onto a nitrile gave an indenone [Eq. (17)].

4. Enantioselective Arylative Cyclization of Alkyne‐Tethered Electrophiles Involving Reversible Alkenylnickel E/Z Isomerization

Enantioselective variants of arylative cyclizations of alkyne‐tethered electrophiles involving reversible alkenylnickel E/Z isomerization have been achieved using chiral phosphine–oxazoline ligands (Scheme 8A). A diverse range of functionalized carbo‐ and heterocyclic compounds containing tertiary or quaternary centers have been prepared using this strategy (Scheme 8B), often via desymmetrization reactions, and the range of electrophiles used include ketones, electron‐deficient alkenes, allylic phosphates, esters, and nitriles.

Scheme 8.

Overview of enantioselective nickel‐catalyzed anti‐arylmetallative cyclizations of alkyne‐tethered electrophiles.

In 2016, Lam and co‐workers reported the first example of enantioselective nickel‐catalyzed anti‐carbometallative cyclization of alkyne‐tethered electrophiles involving reversible alkenylnickel E/Z isomerization (Table 4). ^[65] Treatment of substrates 41, which contain an aryl alkyne tethered to a cyclic 1,3‐diketone, with a (hetero)arylboronic acid (2.0 equiv.), Ni(OAc)₂ ⋅ 4H₂O (10 mol %), and (R)‐Ph‐PHOX (L1, 10 mol %) in a 3 : 2 mixture of MeCN and 2‐MeTHF at 80 °C gave fused bicyclic products 42 with often high enantioselectivities. As well as phenylboronic acid (42 a), 4‐substituted (42 b) and 2‐substituted (42 c) phenylboronic acids are tolerated in the reaction; however, 2‐fluorophenylboronic acid led to a lower yield of the corresponding product 42 c but with a higher enantioselectivity. 3‐Thienylboronic acid is also effective (42 d) but a decrease in enantioselectivity was observed. The use of alkenylboronic acids instead of arylboronic acids did not lead to any desired products. The reaction is tolerant of a range of aryl groups on the alkyne, including those with methoxy (42 e) or chloro substituents (42 f). None of the desired products were obtained with substrates containing a terminal alkyne, methyl alkyne, or trimethylsilyl‐substituted alkyne, though in the latter two cases, some success was obtained using the achiral ligand 2‐[2‐(diphenylphosphino)ethyl]pyridine (pyphos) in place of L1 to give racemic products. Arylative cyclization onto an indan‐1,3‐dione led to the tricyclic product 42 g in 70 % yield and 42 % ee.

Table 4.

Enantioselective anti‐arylmetallative cyclizations onto five‐membered cyclic 1,3‐diketones.

Six‐membered cyclic 1,3‐diketones are also effective electrophiles in this process (Table 5). However, under the standard conditions, mixtures of the expected tertiary‐alcohol‐containing cyclization product and dehydration product (44) were obtained. Therefore, after cyclization was complete, 20 % H₂SO₄ in AcOH was added to drive the dehydration reaction to completion. Compared with the corresponding reactions of five‐membered cyclic 1,3‐diketones, the products 44 a–44 c were obtained in generally higher enantiomeric excesses.

Table 5.

Enantioselective anti‐arylmetallative cyclizations onto six‐membered cyclic 1,3‐diketones.

Changing the electrophile from cyclic 1,3‐diketones to cyclohexa‐2,5‐dienones in substrates 45 was also investigated and the products 46 were isolated together with small quantities of minor products 47, which resulted from migratory insertion of the alkyne into the intermediate arylnickel species with the opposite regioselectivity (Table 6). As well as phenylboronic acid (46 a), 4‐acetylphenylboronic acid (46 b), and 3‐thienylboronic acid (46 c) are tolerated. The substituent at the quaternary center of the substrates can be changed from a methyl (46 a–46 c and 46 f) to an ethyl group (46 d); however, a phenyl group led to a lower yield and enantioselectivity (46 e, 20 %, 69 % ee). A substrate containing a 4‐cyanophenyl group on the alkyne also gave good results (46 f).

Table 6.

Enantioselective anti‐arylmetallative cyclizations onto cyclohexa‐2,5‐dienones.

Regarding the proposed mechanism, the authors suggested a catalytic cycle analogous to the one shown in Scheme 2A with nickel in the +2 oxidation state throughout; however, they do not rule out alternative mechanisms involving Ni(I) species, for example as suggested by Liu and co‐workers. ^[61]

In 2020, Kong and co‐workers reported reactions similar to the arylative cyclizations onto cyclic 1,3‐diketones shown in Tables 4 and 5; however, this process is a reductive cyclization using aryl bromides instead of arylboronic acids, and manganese was used as a stoichiometric reductant [Eq. (18)]. ^[17] One enantioselective example using (S)‐Ph‐PHOX (ent‐L1) was reported, which gave 42 a in 65 % yield and 81 % ee [Eq. 18].

In 2017, the Lam group reported enantioselective nickel‐catalyzed intramolecular arylative allylic alkenylations, where the intermediate alkenylnickel species cyclizes onto a Z‐allylic phosphate to give chiral 1,4‐diene‐containing hetero‐ and carbocycles (Table 7). ^[66] These reactions used (S)‐t‐Bu‐NeoPHOX (L2) as the chiral ligand in TFE as the solvent, and excellent enantioselectivities were observed. Similar to cyclizations onto cyclohexa‐2,5‐dienones reported previously (Table 6), ^[65] small quantities of minor products 50 were observed in most of these reactions. Substrates containing aryl‐ (49 a, 49 b and 49 f–49 i), heteroaryl‐ (49 d and 49 e), or alkenyl‐substituted (49 c) alkynes are effective in the reaction; however, the alkenyl‐substituted alkyne gave a decreased yield and enantioselectivity (49 c, 45 %, 49 % ee). The use of a methyl‐substituted alkyne led to a complex mixture of products, which is similar to other reports of nickel‐catalyzed anti‐carbometallative cyclizations using dialkyl alkynes.[ ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ ] A disubstituted phenylboronic acid worked in the reaction (49 d), as did 2‐naphthylboronic acid (49 e). Interestingly, using an alkenylboronic acid was also successful; however, the product 49 f was obtained in a low yield (13 %) most likely due to extensive protodeboronation of the alkenylboronic acid. No reaction occurred when methylboronic acid was used. Variation of the tethering group showed that a 4‐nitrophenylsulfonamide is compatible (49 g). Substrates containing an all‐carbon tether also cyclized successfully to give carbocyclic products 49 h and 49 i. The proposed mechanism follows the general catalytic cycle shown in Scheme 2A with nickel in the +2 oxidation state throughout; however, an additional β‐phosphate elimination step of intermediate 51 is required to liberate the product 49 and regenerate the active Ni(II) species [Eq. 19].

The attempted arylative cyclization of a substrate containing an E‐allylic phosphate was not successful and gave only the alkyne hydroarylation product as a 2 : 1 mixture of geometric isomers [Eq. (20)]. This experiment demonstrates that the Z‐stereochemistry of the allylic phosphate is crucial for cyclization to occur, perhaps because the steric requirements of this particular reaction are better accommodated by a Z‐allylic phosphate. However, it should be noted that successful cyclization onto acyclic Michael acceptors containing an E‐alkene have been described in other reactions [Eq. (16), Table 12, Eq. (27), Scheme 9A, Eq. (29), and Table 14].[ ⁶⁴ , ⁷⁰ , ⁷¹ ]

Scheme 9.

Enantioselective anti‐arylmetallative cyclization onto an α,β‐unsaturated ester and mechanistic rationale.

Table 14.

Syn‐arylmetallative cyclizations onto enones.

In contrast to previous work, ^[65] a substrate containing a trimethylsilyl‐substituted alkyne is compatible with the enantioselective arylative cyclization [Eq. (21)]. (S)‐i‐Pr‐NeoPHOX (L3) gave better results than (S)‐t‐Bu‐NeoPHOX (L2), and gave the desired product in 70 % yield and 69 % ee.

A five‐membered product could also be obtained from a 1,5‐enyne in reasonable yield but with only 42 % ee using (R)‐PhPHOX (L1) in place of (S)‐t‐Bu‐NeoPHOX (L2) [Eq. 22].

In 2018, the Lam group reported the synthesis of chiral cyclopent‐2‐enones by the enantioselective nickel‐catalyzed desymmetrizing arylative cyclization of alkyne‐tethered malonate esters (Table 8). ^[67] Bis(2,2,2‐trifluoroethyl) malonates 52 were found to exhibit excellent reactivities in this reaction. Treatment of substrates 52 with a (hetero)arylboronic acid (2.0 equiv.) and 10 mol % each of Ni(OAc)₂ ⋅ 4H₂O and (R)‐Ph‐PHOX (L1) in TFE at 80 °C (Table 8) gave cyclopent‐2‐enones 53 in generally good yields and high enantioselectivities. The reaction is tolerant of substrates containing various groups (R²) at the 2‐position, such as 2‐thienyl (53 a–53 c), 4‐methoxyphenyl (53 d, 53 h, and 53 i), anilino (53 e), 3‐thienylmethoxy (53 f) and benzyloxy groups (53 g). As well as phenylboronic acid (53 a and 53 d–53 i), various other boronic acids can be used such as 3‐bromophenylboronic acid (53 b) and 3‐thienylboronic acid (53 c). Regarding the alkynyl substituents, phenyl (53 a–53 g), alkenyl (53 h), and 2‐thienyl (53 i) groups are tolerated.

Table 8.

Enantioselective anti‐arylmetallative desymmetrizing cyclizations onto malonate esters.

[a] Conducted at 100 °C. [b] Using 20 mol % each of Ni(OAc)₂ ⋅ 4H₂O and L1.

The reaction of substrates containing a methyl or benzyl substituent at the 2‐position led to moderate yields and poor enantioselectivities when using (R)‐PhPHOX (L1) as the ligand; however, switching to (S)‐t‐Bu‐NeoPHOX (L2) gave improved but still modest ee values [Eqs. (23) and (24), respectively].

The arylative cyclization of a substrate 54 containing an alkyne tethered to a phenyl ester was also described using (S)‐i‐ Pr‐NeoPHOX (L3) as a ligand, and this gave a 27 : 1 inseparable mixture of the desired product 55 and minor product 56 in 68 % yield [Eq. 25].

In 2020, Liu and co‐workers reported the enantioselective nickel‐catalyzed anti‐carbometallative desymmetrization of malononitriles to give cyclic enones with a nitrile‐containing all‐carbon quaternary center (Table 9). ^[68] The reactions were conducted by treatment of malononitriles that are tethered to (hetero)aryl alkynes with a (hetero)arylboronic acid (2.0 equiv.), (S)‐t‐Bu‐PHOX (L4, 12 mol %), Ni(OTf)₂ (10 mol %), and H₂O (4.0 equiv.) in toluene at 80 °C. Changing the substituent at the α‐position of the malononitrile from a benzyl group (60 a–60 d) to allyl (60 e), 3‐oxobutyl (60 f), methyl (60 g), or phenyl groups (60 h) was tolerated. Various boronic acids can be used in this reaction, including phenylboronic acid (60 a–60 c, 60 e–60 h ), 3‐furylboronic acid (60 i), and 4‐substituted phenylboronic acids with formyl (60 j) or vinyl (60 k) groups. 4‐Carboxyphenylboronic acid, 4‐aminocarbonylphenylboronic acid, 3‐pyridylboronic acid, unprotected 5‐indolylboronic acid, 2‐methoxycarbonylphenylboronic acid, and (E)‐phenylvinylboronic acid did not react successfully. Cyclopentenone 60 l and seven‐membered imine 61 were obtained by shortening or extending the carbon tether of the substrate, respectively. Interestingly, seven‐membered imines are stable enough to be isolated by column chromatography; however, they are readily hydrolyzed to the corresponding ketone by treatment with 3 M HCl at 0 °C. The arylative cyclization of a malononitrile containing a 2‐pyridyl‐substituted alkyne was also attempted but none of the product 60 d was observed. The reaction of a methylalkyne‐containing malononitrile gave a mixture of isomers 60 m and 62, likely because of poor regioselectivity in the migratory insertion of the alkyne into the arylnickel species as discussed in Section 2.

Table 9.

Enantioselective anti‐arylmetallative desymmetrizing cyclizations onto malononitriles.

The proposed mechanism is analogous to that shown in Scheme 2A where in this case cyclization of the alkenynickel intermediate occurs onto one of the nitrile groups (as in 58, Table 9). Following cyclization, protonation of 59 initially gives an imine that, with the exception of the reaction producing 61, undergoes hydrolysis to the ketone in situ. Competition experiments revealed that electron‐rich arylboronic acids react slightly faster than electron‐poor arylboronic acids. Also, electron‐rich aryl alkynes react significantly faster than electron‐poor aryl alkynes. ¹³C kinetic isotopic effect (KIE) experiments of a substrate at natural abundance revealed a significant ¹³C KIE for the nitrile carbon, suggesting that the addition to the nitrile (58 to 59) is likely the rate‐determining step (RDS); however, the transmetalation step cannot be ruled out as the RDS. Finally, ³¹P NMR studies suggested that water aids the transmetalation step.

Various phenylboron sources were investigated in the reaction with alkyne‐tethered malononitrile 57 a, and triphenylboroxine and potassium phenyltrifluoroborate performed comparably to phenylboronic acid with respect to both yield and enantioselectivity (Table 10). The use of phenylboronic acid pinacol ester did not provide the desired product, perhaps due to slow transmetalation under base‐free conditions.[ ¹⁰¹ , ¹⁰² ]

Table 10.

Investigation of various arylboron reagents.

As discussed previously (Tables 4 and 5), the use of cyclic 1,3‐diketones as electrophiles in enantioselective nickel‐catalyzed arylative cyclizations was reported by the Lam group. ^[65] However, until recently, less reactive acyclic ketones had not been investigated in enantioselective reactions, though Reddy and co‐workers did report two non‐enantioselective examples [Eqs. (14) and (15)]. ^[64] In 2021, the Lam group reported that substrates 63 containing an alkyne tethered to an acyclic ketone can indeed be employed in enantioselective cyclizations, when using a (hetero)arylboronic acid (2.0 equiv.), (S)‐t‐Bu‐PHOX (L4, 10 mol %), and Ni(OAc)₂ ⋅ 4H₂O (10 mol %) in TFE at 60 °C, to give products 64 (Table 11). ^[69] Similar to previous examples,[ ⁶⁵ , ⁶⁶ ] small quantities of minor arylative cyclization products 65 were formed resulting from the arylnickel species adding across the alkyne with the opposite regioselectivity. The reaction tolerates a range of substituents at the ketone including methyl (64 a, 64 e, and 64 g–64 j), ethyl (64 f), i‐propyl (64 b), 3‐(trifluoromethyl)phenyl, (64 c) and 3‐methoxy‐3‐oxopropyl groups (64 d). Various alkynyl substituents are tolerated including phenyl (64 a–64 d and 64 h–64 j), 4‐carbomethoxyphenyl (64 e), and vinyl (64 f), although the enantioselectivity was only 45 % ee in the latter case. Interestingly, a substrate containing a chloroalkyne was successful in providing product 64 g; however, the yield was only 12 % and the enantioselectivity was modest (71 % ee). A substrate containing a 4‐nitrophenylsulfonamide was used to investigate the scope of the boronic acid. 4‐(Trimethylsilyl)phenylboronic acid (64 h), 3‐hydroxyphenylboronic acid (64 i), and 3‐thienylboronic acid (64 j) worked well, and good yields and excellent enantioselectivities were observed.

Table 11.

Enantioselective anti‐arylmetallative cyclizations onto acyclic ketones.

Unless otherwise stated, yields are of isolated products 64, free from the minor isomers 65. [a] Conducted at 80 °C. [b] Product 64 f was obtained as an inseparable 12 : 1 mixture together with the minor product 65 f in 90 % combined yield.

To prepare a carbocyclic product 67, the reaction of alkyne‐tethered ketone 66 was conducted and the desired product was obtained in 25 % yield with 84 % ee [(Eq. (26)]. However, a second product 68 was obtained in 14 % yield and 85 % ee, which resulted from a desymmetrizing cyclization of the intermediate alkenylnickel species onto one of the ester groups. ^[67] Attempts at shortening and extending the tether to obtain five‐ or seven‐membered products were unsuccessful.

Nickel‐catalyzed arylative cyclizations onto electron‐deficient alkenes to give enantioenriched cyclopentenes were reported by the Lam group (Table 12). ^[70] Successful arylative cyclizations were achieved in high enantioselectivities when heating the substrates 69 with aryl‐ or alkenylboronic acids (1.2 equiv.), (S)‐t‐Bu‐NeoPHOX (L2, 5 mol %), and Ni(OAc)₂ ⋅ 4H₂O (5 mol %) in TFE at 100 °C for 16–18 h. Regarding the electron‐deficient alkene, the reaction tolerates α,β‐unsaturated ketones with a range of substituents at the ketone, including methyl (70 a, 70 f, and 70 g), chloromethyl (70 c), and various (hetero)aryl groups (70 d, 70 e, and 70 h). An α,β‐unsaturated aldehyde (70 b) and nitroalkenes (70 i–70 l) are also competent electrophiles. Variation of the substituent on the alkyne showed that as well as phenyl groups (70 a–70 e and 70 i–70 l), vinyl (70 f), and 2‐thienyl (70 g) groups are also tolerated; however, slight decreases in enantioselectivity were observed in the latter two cases. A substrate with a methyl‐substituted alkyne led to desired product 70 h in 92 % ee but only 31 % yield, with the low yield likely resulting from poor regioselectivity in migratory insertion of the alkyne into the phenylnickel species as disussed in Section 2. A range of arylboronic acids worked well in the reaction (product 70 i is one representative example). Various alkenylboronic acids also reacted to give the desired products 70 j–70 l in high enantioselectivities but in low yields (25–36 %). These results are in contrast with comparable nickel‐catalyzed arylative cyclizations where alkenylboronic acids did not work,[ ⁶⁵ , ⁶⁸ , ⁷¹ , ⁷³ ] though it should be noted that an alkenylboronic acid could be used in nickel‐catalyzed intramolecular allylic alkenylations, though also in a low (13 %) yield (product 49 f, Table 7). ^[66]

Interesting results were obtained with substrates containing α,β‐unsaturated t‐butyl ketones [Eq. (27) and (28)]. Arylative cyclization of a substrate with the enone in the E‐configuration led to the desired cyclopentene 70 m in 25 % yield and >99 % ee, along with hydroarylation product 71 in 30 % yield as a 0.7 : 1 inseparable mixture of E : Z isomers [(Eq. (27)]. Interestingly, however, the reaction of a stereoisomeric substrate with the enone in the Z‐configuration gave cyclopentene 70 m in 90 % yield and >99 % ee [(Eq. (28)]. The greater propensity of electron‐deficient Z‐alkenes to undergo nickel‐catalyzed arylative cyclization compared with their E‐configured counterparts was also observed in intramolecular allylic alkenylations reported previously [compare Table 7 and Eq. (20)]. ^[66] The absolute configuration of cyclopentene 70 m was the same when starting from either the Z‐ or E‐alkene, which is in contrast to some other enantioselective 1,4‐additions of carbon nucleophiles to electron‐deficient alkenes where E‐ and Z‐isomers of the substrates provide opposite enantiomers of the products.[ ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ ] However, examples of conjugate additions where E‐ and Z‐isomers give the same major enantiomers of the products have also been reported.[ ³⁰ , ¹⁰⁴ ]

The reaction of phenylboronic acid with a substrate containing an α,β‐unsaturated ester as the electron‐deficient alkene gave some unexpected products. (Scheme 9A). The desired cyclopentene 70 n was obtained in 14 % yield and >99 % ee, but the conjugated dienes 73 (23 % yield) and 74 (15 % yield), along with the reductive cyclization product 72 (which could not be isolated cleanly) were also formed. A mechanistic rationale for the formation of these products is depicted in Scheme 9B. Initially, addition of a phenylnickel species across the alkyne followed by E/Z isomerization gives alkenylnickel species 75. A stereospecific migratory insertion of the alkene into the alkenylnickel species leads to a C‐bound nickel enolate 76, which can undergo protodenickelation to give the cyclopentene 70 n. However, the low yield of 70 n (14 %) suggests that this step is slow compared with all the substrates described thus far, which would proceed via ketone enolate or nitronate intermediates. A possible reason for the slower protodenickelation of ester‐derived nickel enolates is that this step proceeds faster via the O‐bound, rather than the C‐bound enolate (or nitronate), and ester‐derived enolates would be expected to have a higher ratio of C‐ vs. O‐bound forms compared to ketone‐derived enolates and nitronates. A competing reaction can occur where the nickel enolate 76 can undergo rotation around the C−C bond to give 76′, followed by syn‐β‐hydride elimination to give diene 73 and a nickel hydride 77. This type of reactivity has been observed previously in nickel‐catalyzed additions of boronic acids to α,β‐unsaturated esters, amides, nitriles, and ketones giving either Mizoroki‐Heck products or 1,4‐addition products by fine‐tuning of the ligand. ^[108] The nickel hydride 77 can then undergo hydronickelation with the alkyne of the substrate followed by E/Z isomerization to give alkenylnickel species 78, which produces the reductive cyclization product 72 and conjugated diene 74 via a sequence of steps analogous to those discussed above. Similar to the examples discussed above [(Eq. (27)) and (28)], arylative cyclization onto an α,β‐unsaturated nitrile was much more successful when the alkene had the Z‐configuraton. Attempted arylative cyclization of a substrate with an E‐configured α,β‐unsaturated nitrile gave diene (E)‐79 in 18 % yield and a trace of diene 80 [(Eq. (29)]. However, the corresponding reaction of a substrate with a Z‐configured α,β‐unsaturated nitrile led to the desired cyclopentene 70 o in 60 % yield and 99 % ee along with diene (Z)‐79 in 25 % yield [(Eq. (30)]. The formation of the dienes 79 and 80 can be explained by mechanistic pathways similar to those shown in Scheme 9. Interestingly, the dienes (E)‐79 and (Z)‐79 obtained from the reaction of E‐ and Z‐configured substrates, respectively, are of opposite configuration, presumably because the migratory insertion of the α,β‐unsaturated nitrile into the intermediate alkenylnickel species, and the β‐hydride elimination steps, are both syn‐stereospecific.

5. Syn‐Arylmetallative Cyclizations of Alkyne‐Tethered Electrophiles

Rhodium‐,[ ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ ] palladium‐,[ ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ ] or copper‐catalyzed ^[42] arylative cyclizations of alkyne‐tethered electrophiles involving 1,2‐arylmetallation of the alkyne to place the metal proximal to the electrophile, followed by direct intramolecular trapping of the intermediate alkenylmetal species with the tethered electrophile (see Scheme 1A), have been reported extensively. However, the use of catalyst systems based upon other metals are of interest because this could allow access to new reactivity and different reaction outcomes, with a consequent increase in scope. Recently, nickel has been reported to be effective in such reactions (Scheme 10A). Nickel‐catalyzed arylative cyclizations onto ketones, α,β‐unsaturated ketones, or esters are described in this section, along with more complex domino sequences where cyclization onto an alkene is followed by a second cyclization onto a ketone. These reactions lead to the synthesis of various carbo‐ and heterocyclic products such as chromanes, tetrahydroquinolines, benzoxepines, benzofurans, tricyclo[5.2.1.0^1,5]decanes, and bicyclo[2.2.1]heptanes (Scheme 10B).

Scheme 10.

Overview of syn‐arylmetallative cyclizations of alkyne‐tethered electrophiles.

The first example of syn‐selective nickel‐catalyzed carbometalation of alkynes using arylboron reagents, followed by cyclization of the resultant alkenylnickel species onto a tethered electrophile, was reported by Reddy and co‐workers in 2018 (Table 13). ^[71] Treatment of substrates 80, which contain a terminal alkyne tethered to a ketone, with a (hetero)arylboronic acid (2.0 equiv.), Ni(acac)₂ (10 mol %), PPh₃ (10 mol %), and Cs₂CO₃ (0.2 equiv.) in 1,4‐dioxane at 90 °C gave various chromane and tetrahydroquinoline products. The proposed mechanism follows the generalized catalytic cycle shown in Scheme 2B. Disubstituted phenylboronic acids with electron‐withdrawing (81 a) or electron‐donating groups (81 b), as well as 3‐furylboronic acid (81 c) are effective in the reaction. However, alkenylboronic acids were found to be unsuitable. Substitution at the aryl moiety of the o‐propargyloxy benzaldehyde was also explored and bromo (81 d), nitro (81 e), and alkoxy (81 e and 81 f) groups are well‐tolerated. The scope of the arylboronic acid was investigated in reactions of 2‐propargylamino benzaldehydes. 1,3‐Benzodioxole‐5‐boronic acid (81 g), 3‐nitrophenylboronic acid, (81 h) and 4‐cyanophenylboronic acid (81 i) are all tolerated. The reaction of 2‐homopropargyloxy benzaldehyde 82 provided benzoxepine 83 in 68 % yield [(Eq. 31].

Table 13.

Syn‐arylmetallative cyclizations onto aldehydes.

The scope of this process was successfully increased by changing the electrophile from a ketone to an enone (Table 14). The reaction tolerates enones with phenyl (85 a) or methyl ketones (85 b and 85 c). A chloride within the benzene tethering moiety is also tolerated (85 c). Phenylboronic acid (85 a and 85 c) and 3‐furylboronic acids (85 b) were used successfully.

In 2019, Cho and co‐workers reported nickel‐catalyzed arylative cyclizations onto ester electrophiles to give multisubstituted benzofurans 88 (Table 15). ^[72] The reaction conditions involved heating alkyne‐tethered phenyl esters 86 with (hetero)arylboronic acids (1.5 equiv.), Ni(OAc)₂ ⋅ 4H₂O (1–5 mol %), and pyphos (L5, 1.2–6 mol %) in TFE at 80 °C. Investigation of the scope of the arylboronic acid revealed that substituents such as a trifluoromethyl group (88 b) or a free hydroxyl group (88 c) are tolerated. Benzothiophen‐2‐ylboronic acid was also successfully utilized (88 d). Exploration of the scope of the alkyne‐tethered phenyl ester showed that electron‐withdrawing groups on the benzene ring are well‐tolerated (88 e–88 g). Substrates with various primary or secondary alkyl substituents at the acyl group led to products 88 a–88 k in good yields; however, a substrate with a chloroalkyl group gave 88 l in a lower 33 % yield. The reaction of a benzoyl ester was also successful to give benzofuran 88 m. The proposed mechanism follows the generalized catalytic cycle shown in Scheme 2B; however, the cyclization step is followed by protonation of the intermediate nickel alkoxide and subsequent elimination of water from the resulting species 87 to give the product.

Table 15.

Syn‐arylmetallative cyclizations onto esters.

The alkynyl substituent can be changed from a methyl group to isopropyl [Eq. (32)], isobutyl [Eq. (33)], and benzyl [Eq. (34)] groups, though in the latter two cases, the products were isolated as mixtures of E/Z isomers at the trisubstituted alkene.

In 2020, Kong and co‐workers developed a process that incorporates nickel‐catalyzed difunctionalizations of alkynes into a more complex domino reaction, by using substrates containing three reactive sites in the form of an alkyne, an unactivated alkene, and a cyclic 1,3‐diketone (Table 16). ^[73] Heating enynones 89 in the presence of a (hetero)arylboronic acid (2.0 equiv.), Ni(OAc)₂ ⋅ 4H₂O (10 mol %), and (1R,1′R,2S,2′S)‐DuanPhos (L6) (12 mol %) in TFE at 100 °C gave complex bridged tricyclo[5.2.1.0^1,5]decanes 93 with three new carbon‐carbon bonds in high regio‐ and enantioselectivities. The first steps of the proposed mechanism are identical to those depicted in the generalized catalytic cycle in Scheme 2B; however, the alkenylnickel intermediate 90 cyclizes onto the unactivated alkene to give alkylnickel species 91, which then undergoes cyclization onto one of the ketones to give nickel alkoxide 92. Finally, protonation of 92 releases the product 93.

Various (hetero)arylboronic acids can be used, including phenylboronic acid (93 a), an amide‐substituted boronic acid (93 b), pyrimidine‐5‐boronic acid (93 c), and 4‐(methanesulfonyl)phenylboronic acid (93 e–93 j). A boronic acid derived from estrone also worked well to give the corresponding product 93 d in 80 % yield and >20 : 1 diastereomeric ratio. However, alkylboronic acids and alkenylboronic acids failed to give the desired products. The scope of the alkyne substituent was also investigated. In addition to methyl‐substituted alkynes (93 a–93 e, 93 i, and 93 j), alkynes containing allyl (93 g) or hydroxymethyl groups (93 h) are compatible with the reaction. Interestingly, a phenyl‐substituted alkyne also provided the desired product in a moderate yield (93 f, 61 %). Based upon other nickel‐catalyzed arylative cyclizations of substrates containing aryl‐substituted alkynes, and as discussed in Section 2, the phenyl‐substituted alkyne of this substrate might have been expected to undergo migratory insertion with the intermediate arylnickel species with the regioselectivity opposite to that required to form product 93 f. Therefore, the formation of 93 f in 61 % yield is notable. It appears likely that the ligand (1R,1′R,2S,2′S)‐DuanPhos (L6) plays an important role in controlling this regioselectivity. Terminal alkynes are not tolerated in the reaction and provided only complex mixtures of unidentified products. The scope of the alkene substituent was also explored and substrates containing methoxymethyl or ester groups performed well to give products 93 i and 93 j, respectively.

Other arylboron reagents such as PhB(pin), PhBF₃K, and (PhBO)₃ were also investigated to give 93 a, and all gave results similar to phenylboronic acid.

To gain insight into the oxidation state of the active nickel catalyst, mechanistic studies were carried out (Scheme 11). Reaction of enynone 89 a with a stoichiometric quantity of PhNiBr(dppe) led to product rac‐93 a in 28 % yield, suggesting that a Ni(II) species is involved in the catalytic cycle [Eq. (35)]. However, similar to the report by the Liu group on the synthesis of 1‐naphthylamines by nickel‐catalyzed arylative cyclizations [Eq. (1)], ^[61] a biaryl species was observed in the stoichiometric reaction of 4‐(methylsulfonyl)phenylboronic acid with Ni(OAc)₂ ⋅ 4H₂O [Eq. (36)], and as discussed previously, ^[61] this could indicate the formation of a Ni(I) species. Therefore, the reaction of enynone 89 a with Ni(I) species 20 was performed, which gave rac‐93 a in 15 % yield [Eq. (37)], suggesting that a catalytic cycle involving arylnickel(I) intermediates is also viable.

Scheme 11.

Mechanistic studies.

During optimization of the process to produce bridged tricyclo[5.2.1.0^1,5]decanes, Kong and co‐workers observed that the reaction of methyl‐substituted enynone 89 a with PhB(OH)₂, Ni(OAc)₂ ⋅ 4H₂O, and (S)‐Ph‐PHOX (ent‐L1) in MeCN led to only a trace amount of the desired product 93 a [Eq. (38)]. ^[73] Instead, product 94, resulting from anti‐arylmetallative cyclization as also described by the Lam group (Table 4), ^[65] was formed in 60 % yield. It appears the chiral ligand used; either (R,R,S,S)‐DuanPhos (L6) or (S)‐Ph‐PHOX (ent‐L1) has a significant impact on the reaction outcome. The formation of 94 rather than 93 a stems from migratory insertion of the alkyne into the arylnickel intermediate occurring with the opposite regioselectivity, and the fact that 94 is obtained in 60 % yield is interesting because alkyne‐tethered electrophiles containing two alkyl substituents are generally less effective substrates for nickel‐catalyzed anti‐arylmetallative cyclizations. Usually, the formation of complex mixtures or significantly reduced yields are observed in other studies using this type of substrate.[ ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ ]

Under the standard conditions, the reaction of substrate 95, which contains an acyclic 1,3‐diketone, gave highly functionalized bicyclo[2.2.1]heptane 96 in 51 % yield and 99 % ee [(Eq. (39)].

The arylative cyclization reaction of substrate 97, which contains an allene in place of an alkene, was also successful using dppe as an achiral ligand to give rac‐ 98 in a moderate 35 % yield [(Eq. 40].

6. Enantioselective Arylative Cyclizations of Allene‐Tethered Electrophiles

Intermolecular nickel‐catalyzed additions of arylboron reagents examples to allenes have been reported,[ ¹⁰⁹ , ¹¹⁰ , ¹¹¹ ] where the intermediate allylnickel species are either protonated ^[111] or engage in nucleophilic attack of an aldehyde.[ ¹⁰⁹ , ¹¹⁰ ] However, at the time of writing, only two reports of nickel‐catalyzed arylative cyclization of allene‐tethered electrophiles involving an arylboron reagent have been reported. In these studies, cyclohexa‐2,5‐dienones or ketones were used as electrophiles, leading to the synthesis of various carbo‐ and heterocyclic products such as hexahydroindol‐5‐ones, hexahydrobenzofuran‐5‐ones, pyrrolidine‐2‐ones, pyrrolidines, cyclopentanes, and piperidines in high diastereo‐ and enantioselectivities.

The first enantioselective nickel‐catalyzed arylative cyclizations of allene‐tethered electrophiles were reported by the Lam group in 2018 (Table 17). ^[74] Treatment of substrates containing an allene tethered to a cyclohexa‐2,5‐dienone with (hetero)arylboronic acids (2.0 equiv.), Ni(OAc)₂ ⋅ 4H₂O (10 mol %), and (R)‐Ph‐PHOX (L1) in a 3 : 2 mixture of MeCN/1,4‐dioxane at 80 °C gave hexahydroindol‐5‐ones and hexahydrobenzofuran‐5‐ones with three contiguous stereocenters in high diastereo‐ and enantioselectivities. The reactions are successful using both N‐sulfonyl‐tethered and O‐tethered substrates leading to 6,5‐bicycles 100. Methyl (100 e–100 j), ethyl (100 a and 100 b), or phenyl (100 c) groups at the quaternary center of substrate 99 are tolerated. The reaction of a substrate containing a longer tether was largely unsuccessful and provided only a trace of the 6,6‐bicycle 100 d. The reaction tolerates various substituted phenylboronic acids with substituents such as vinyl (100 e), acetoxy (100 h), and chloro (100 i) groups. A disubstituted phenylboronic acid (100 f), 2‐naphthylboronic acid (100 g), and 3‐furylboronic acid (100 j) were also successful in the reactions. The proposed mechanism for these reactions is analogous to that shown in Scheme 2C.

Table 17.

Enantioselective nickel‐catalyzed arylative intramolecular 1,4‐allylations of cyclohexa‐2,5‐dienones.

[a] Isolated together with cyclobutane side products as inseparable mixtures in ratios of between 17 : 1 and 20 : 1. Yields have been adjusted accordingly.

The use of certain substituted phenylboronic acids containing strongly electron‐withdrawing substituents led to the unexpected formation of 3,4‐disubstituted phenols 101 in addition to the desired products 100, with both products obtained in high enantioselectivities (Table 18). It was suggested that the formation of phenol 101 is the result of enolization of the ketone to give 102, which then undergoes ring‐opening of the furan ring to give 103 (Scheme 12). Presumably, this step is promoted by a Brønsted acid or a hydrogen bond donor. Finally, proton loss from 103 leads to phenol 101.

Table 18.

Reactions producing phenols.

Scheme 12.

Rationale for phenol formation.

The nickel‐catalyzed arylative and alkenylative 1,2‐allylation of allene‐tethered ketones to give enantioenriched tertiary‐alcohol‐containing pyrrolidin‐2‐ones was reported by Lam and co‐workers (Table 19). ^[75] Substrates containing a terminal allene tethered to an α‐ketoamide were studied first, and the optimized reaction conditions involved reacting the substrates with an arylboronic acid (1.5 equiv.), Ni(OAc)₂ ⋅ 4H₂O (5 mol %), and (S)‐t‐Bu‐PHOX (L4, 5 mol %) in TFE at 80 °C for 24 h. Products were formed in high yields and enantioselectivities from substrates 104 having phenyl (105 a), methyl (105 b), i‐propyl (105 c), or 2‐furyl (105 d) substitutents at the ketone. Changing the nitrogen substituent from a para‐methoxyphenyl to a benzyl group led to a slight decrease in the enantioselectivity; however, when switching the solvent to MeCN, the product 105 e was obtained in 99 % ee. Notably, the reaction was successful with a substrate lacking a protecting group on the nitrogen atom, which gave 105 f in 90 % yield and 99 % ee. Varying the arylboronic acid showed that para‐substituents such as acetoxy (105 g), chloro (105 h), and vinyl (105 i) are compatible with the reaction. A variety of 2‐substituted phenylboronic acids containing methyl (105 j), fluoro (105 k), or amino (105 l) groups are also tolerated; however, the latter example led to the product in a moderate yield and low ee. The proposed mechanism is analogous to the one shown in Scheme 2C.

Table 19.

Enantioselective nickel‐catalyzed arylative cyclizations of allene‐tethered ketones to give 3‐hydroxypyrrolidin‐2‐ones.

[a] Conducted in MeCN instead of TFE. [b] Conducted using the pinacol boronate instead of the boronic acid.

Interestingly, the reaction of allene‐tethered α‐ketoamide 104 a with potassium vinyltrifluoroborate in place of an arylboronic acid was successful in providing pyrrolidin‐2‐one 106 in 65 % yield and 93 % ee [(Eq. (41)].

By replacing the α‐ketoamide with a simple ketone and modifying the tethering group connecting the allene to the electrophile, this process can also be applied to the synthesis of tosyl‐, 4‐methoxyphenyl‐, and 4‐chlorophenyl‐protected pyrrolidines (108 a–108 c), a piperidine (108 e), a cyclopentane (108 d), and a cyclohexane (108 f) (Table 20). Compared with the synthesis of 3‐hydroxypyrrolidin‐2‐ones (Table 19), the yields and enantioselectivities were more variable and modest in a few cases.

Table 20.

Further exploration of scope of enantioselective nickel‐catalyzed arylative cyclizations of allene‐tethered ketones.

[a] Conducted in MeCN instead of TFE. [b] The reaction time was 48 h. [c] Conducted using 10 mol % each of Ni(OAc)₂ ⋅ 4H₂O and L4.

7. Related Annulation Reactions of 2‐Formyl‐ or 2‐Acylarylboronic Acids with Alkynes or Allenes

This section describes nickel‐catalyzed domino arylation‐cyclization reactions where the electrophile is not tethered to an alkyne or allene, but is instead attached to the 2‐position of the arylboronic acid. Although the connectivity of the reacting components is different, the inclusion of these related annulation reactions is relevant because they proceed via mechanistic steps very similar to those already discussed in the previous sections, involving the cyclization of an alkenyl‐ or allylnickel species onto an electrophile.

In their first report of enantioselective nickel‐catalyzed anti‐arylmetallative cyclizations of alkyne‐tethered electrophiles, ^[65] the Lam group also described one example of the annulation of 1‐phenyl‐1‐butyne with 2‐formylphenylboronic acid using Ni(OAc)₂ ⋅ 4H₂O (10 mol %) and (S,S)‐t‐Bu‐FOXAP (L7, 10 mol %) in MeCN/2‐MeTHF (3 : 2) at 80 °C for 20 h [(Eq. (42)]. This reaction provided an indenol in 81 % yield and 87 % ee. Gu, Chen, and Xu later developed an enantioselective palladium‐catalyzed version of this reaction. ^[112]

Recently, Kong and co‐workers incorporated the annulation reaction shown in Eq. (42) into more complex domino reactions where three new bonds are formed (Table 21). ^[113] This process achieves the diastereo‐ and enantioselective synthesis of spirocyclic products via nickel‐catalyzed cascade borrowing hydrogen cyclization. The reactions involve the annulation between 2‐formylphenylboronic acid and 1,6‐enynes 109 in the presence of Ni(OAc)₂ ⋅ 4H₂O (10 mol %) and (S,S)‐i‐Pr‐FOXAP (L8, 20 mol %) in NMP at 100 °C to give nickel alkoxide 110. β‐Hydride elimination of 110 gives indene 111 along with a nickel hydride species, which can then undergo migratory insertion into the alkene to give alkylnickel species 112. Cyclization by 1,4‐addition of the alkylnickel species to the enone provides the nickel enolate 113 that undergoes protonolysis to give the product 114 and regenerate the active nickel catalyst.

Table 21.

Enantioselective synthesis of spirocycles by nickel‐catalyzed cascade borrowing hydrogen cyclization; 1,6‐enyne scope.

The scope of the reaction with respect to the alkyne substituent was investigated. As well as a simple phenyl group (114 a), various substituted phenyl groups containing dimethylamino (114 d), trifluoromethyl (114 e), or pinacolboronate (114 f) groups at the 4‐position are tolerated. A substrate with a dibenzofuran group at the alkyne also reacted well to give 114 g. In the presence of a methyl alkyne the reaction proceeded to give 114 b in moderate yield (42 %) but with high enantioselectivity (90 % ee). The reaction of terminal alkyne led to a low yield and poor enantioselectivity (114 c, 31 % yield, 19 % ee). Interestingly, the reaction of a substrate 109 h with a benzyloxymethyl group on the alkyne gave alkene 115, via β‐alkoxide elimination, in 32 % yield and 98 % ee [Eq. (43)]. This reaction also gave indenol 116 in 30 % yield, where the second cyclization did not occur.

Next, the authors investigated the scope using more highly substituted 2‐formylarylboronic acids in the reaction with electron‐deficient 1,6‐enyne 117 a (Table 22). Methoxy (118 b) or chloro (118 c) substitutents on the 2‐formylphenylboronic acid are tolerated, but the use of 5‐[(tert‐butyldimethylsilyl)oxy]‐2‐formylphenylboronic acid led to the deprotected phenol 118 d. (2‐Formylthiophen‐3‐yl)boronic acid also successfully underwent the reaction; however, a low yield and decreased ee was observed (118 e, 42 %, 64 % ee). The reaction of 2‐vinylphenylboronic acid with 1,6‐enyne 117 a was unsuccessful in providing 119 [Eq. 44].

Table 22.

Enantioselective synthesis of spirocycles by nickel‐catalyzed cascade borrowing hydrogen cyclization; 2‐formylarylboronic acid scope.

Finally, the authors investigated the scope of the alkenyl substituent of the 1,6‐enyne 117 in the reaction with 2‐formylphenylboronic acid (Table 23). Substituents such as hydrogen (120 a), n‐hexyl (120 b), ester (120 c), and phenyl (120 d) are tolerated and provide moderate to good yields of the products in excellent enantiomeric excesses. Also, a 1,6‐enyne 121 with a trisubstituted alkene reacted successfully to give product 122 in 42 % yield and 97 % ee [Eq. 45].

Table 23.

Enantioselective synthesis of spirocycles by nickel‐catalyzed cascade borrowing hydrogen cyclization; scope of alkenyl substituent on the 1,6‐enyne.

Highly diastereoselective nickel‐catalyzed annulation reactions between activated allenes and 2‐formyl‐ or 2‐acetylarylbonic acids to give 3‐methyleneindan‐1‐ols 124 were reported by Lam and co‐workers (Table 24). ^[114] The optimized reaction conditions were Ni(OAc)₂ ⋅ 4H₂O (10 mol %) in MeCN/1,4‐dioxane (3 : 2) at room temperature for 24 h. Using 2‐acetylphenylboronic acid, the scope of the reaction regarding the electron‐withdrawing group on the allene was investigated and benzyl, ethyl, and phenyl esters (124 a–124 c) are tolerated as well as amide, thioester, and phenyl ketone groups (124 d–124 f). Non‐carbonyl substituents on the allene, such as phosphonate (124 g) or phenylsulfone (124 h) are also successful in providing the desired products; however, in the latter example a low yield was observed. 2‐Formylphenylboronic acid reacted successfully with allenes containing a benzyl ester (124 i) or diphenylamide (124 j). More highly functionalized 2‐formylphenylboronic acids containing chloride or [1,3]‐dioxol‐5‐yl groups also reacted successfully to give products 124 k and 124 l, respectively, in modest yields.

Table 24.

Nickel‐catalyzed annulations between activated allenes and 2‐acetyl‐ or 2‐formylarylboronic acids.

[a] Isolated with an unknown impurity; the yield of 124 h was determined by ¹H NMR analysis using 1,3,5‐trimethoxybenzene as an internal standard.

The reaction of 2‐acetylphenylboronic acid with more sterically demanding 1,1‐disubstituted allenes was also investigated (Table 25). Allenyl esters 125 with substituents such as α‐methyl or α‐cyanomethyl were successful in providing the desired products 126 a and 126 b in 51 % and 61 % yields, respectively. Also, spirocycle 126 c was obtained in 71 % yield from 3‐vinylidenedihydrofuran‐2(3H)‐one.

Table 25.

Nickel‐catalyzed annulations between activated allenes and 2‐acetyphenylboronic acid; generation of contiguous quaternary centers.

In addition, the reaction of a trisubstituted allene with 2‐acetylphenylboronic acid gave a product with a fully substituted exocyclic alkene in 31 % yield [Eq. 45].

An enantioselective variant of the annulation reaction was also conducted [(Eq. (46)]. Phosphine‐oxazoline ligand L9 was employed in the presence of Ni(O₂CCF₃)₂ ⋅ 4H₂O and 1,4‐dioxane to give the enantioenriched product 124 a in 76 % yield and 74 % ee.

8. Summary and Outlook

This Review has summarized the substantial growth in recent years in the application of nickel catalysis to promote arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents, and in related annulation reactions of 2‐formylarylboronic acids or 2‐acetylphenylboronic acid with alkynes or allenes. Although rhodium and palladium catalysis has featured heavily in these types of reactions in the past, the discovery that nickel opens up new modes of reactivity not readily available to other metals has resulted in an impressive range of new developments and allowing access to a broad range of carbo‐ and heterocyclic products.

For alkyne‐tethered electrophiles, by using electronically dissimilar substituents on the alkyne, the regioselectivity of the migratory insertion of the arylnickel species into the alkyne can be controlled, leading to the selective synthesis of diverse cyclic products containing either exocyclic or endocyclic alkenes. Furthemore, many of the reactions of alkyne‐tethered electrophiles are anti‐carbometallative cyclizations that rely upon the reversible E/Z isomerization of alkenylnickel intermediates, a mode of reactivity that had previously been underexplored. By using allene‐tethered electrophiles, carbo‐ and heterocycles containing an alkenyl group can be obtained. A wide range of electrophiles can be used in nickel‐catalyzed arylative cyclizations, such as cyclic and acyclic ketones, nitriles, allylic phosphates, azides, amides, malonic esters, esters, alkenes, malononitriles, cyclic and acyclic α,β‐unsaturated ketones, α,β‐unsaturated nitriles, and nitroalkenes. Products containing five‐, six‐, or seven‐membered rings have been prepared using this chemistry. Additionally, by using chirally modified catalysts, highly enantioselective reactions have been reported.

The integration of nickel‐catalyzed arylative cyclizations into more complex domino reaction sequences has also recently appeared. Although these processes present greater challenges with respect to chemoselectivity, recent work has demonstrated impressive progress to give complex products with high regio‐, diastereo‐, and enantioselectivities.

However, limitations in this area of nickel catalysis have been identified. In general, increasing the scope of the pronucleophile beyond arylboron reagents has met with limited success, with only a few examples of heteroarylboron or alkenylboron reagents being successfully used. The greater propensity of these reagents to undergo unproductive protodeboronation has been a major challenge, and future methods to overcome this difficulty will have a welcome benefit on increasing the reaction scope. Furthermore, attempted reactions using alkylboronic acids have thus far been unsuccessful, which may stem from difficulties in transmetallation. Possible solutions to successfully engage alkylboron reagents may lie in the generation of alkyl radicals and the formation of open‐shell Ni(I) or Ni(III) species, which may greatly expand the scope of accessible products.

A greater mechanistic understanding of the elementary steps in the nickel‐catalyzed arylative cyclizations (such as the reversible E/Z isomerization of alkenylnickel species), and what factors influence them, would be advantageous to guide the design of future reactions. Future mechanistic studies are expected to support the continued development of this exciting and rapidly growing area of nickel catalysis.

Conflict of interest

The authors declare no conflict of interest.

Biographical Information

Hon Wai Lam received an MChem degree from the University of Oxford in 1998 and a PhD in chemistry from the University of Nottingham in 2001. He conducted postdoctoral studies at Harvard University during 2002 and 2003, and returned to the UK to take up a lectureship at the University of Edinburgh in October 2003, where he was promoted to Reader. In October 2013, he moved to the University of Nottingham as a Professor of Chemistry. Hon's research interests are in the development of new catalytic reactions for organic synthesis, with a focus on transitional metal catalysis and asymmetric synthesis.

Biographical Information

Simone M. Gillbard is currently undertaking her PhD at the University of Nottingham (United Kingdom) under the supervision of Prof. Hon Wai Lam following the completion of her MSc degree in 2018 in the same group. Her research interests are organic synthesis using metal catalysis and she has recently been working on asymmetric nickel‐catalyzed cyclization reactions.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

S. M. Gillbard, H. W. Lam, Chem. Eur. J. 2022, 28, e202104230.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.