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.


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 stepeconomic 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).  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 transitionmetal-catalyzed arylative and alkylative cyclizations of alkyneand 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.
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.

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] 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 sp 2 -hybridized, rather than sp 3hybridized 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] 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] 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 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-furyland 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.

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,βunsaturated ketones to give diverse products such as 1naphthylamines, quinolines, pyrroles, isoquinolines, pyridines, thiophenopyridines, β-carbolines, and indenes (Scheme 3B).
In 2016, Liu and co-workers reported the seminal report of nickel-catalyzed anti-arylmetallative cyclizations of alkyne-teth-ered 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 · 2H 2 O (10 mol %), P(4-F 3 CC 6 H 4 ) 3 (10 mol %), and Cs 2 CO 3 (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 regioselectiv-ities 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(2,6diisopropylphenyl)-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 nickelcatalyzed anti-arylmetallative cyclization of alkyne-tethered nitriles follows the general catalytic cycle shown in Scheme 2A with nickel in the + 1 oxidation state.
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 Table 1. Synthesis of 1-naphthylamines by anti-arylmetallative cyclization onto nitriles.
[a] Using Ni(acac) 2 · 2H 2 O (5 mol %), P(4-F 3 CC 6 H 4 ) 3 (5 mol %) and Cs 2 CO 3 (0.1 equiv.).  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)]. (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 · 4H 2 O 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.
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 5lipoxygenase 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 POCl 3 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.
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 %), PPh 3 (10 mol %), and Cs 2 CO 3 (0.2 equiv.) in 1,4dioxane 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 Table 3. Synthesis of pyrroles by anti-arylmetallative cyclizations onto Ntosylamides. 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] Further examples of the scope of this process are shown in Equations (9)- (17). Arylative cyclization with substituted phenyl-boronic 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)].

Enantioselective Arylative Cyclization of Alkyne-Tethered Electrophiles Involving Reversible Alkenylnickel E/Z Isomerization
Enantioselective variants of arylative cyclizations of alkynetethered electrophiles involving reversible alkenylnickel E/Z isomerization have been achieved using chiral phosphineoxazoline 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.
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 1,3diketone, with a (hetero)arylboronic acid (2.0 equiv.), Ni-(OAc) 2 · 4H 2 O (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-1,3dione led to the tricyclic product 42 g in 70 % yield and 42 % ee.
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 % H 2 SO 4 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.
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 3thienylboronic 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).
[a] The product contained trace quantities of inseparable, unidentified impurities, and the ratio of 49 : 50 could not be determined. 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)]. (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 Zstereochemistry 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 Ealkene have been described in other reactions [Eq. (16), Table 12, Eq. (27), Scheme 9A, Eq. (29), and Table 14]. [64,70,71] (20) 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.

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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 allcarbon 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 H 2 O (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 ), 3furylboronic 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 sevenmembered 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 2pyridyl-substituted alkyne was also attempted but none of the product 60 d was observed. The reaction of a methylalkynecontaining 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.
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. 13 C kinetic isotopic effect (KIE) experiments of a substrate at natural abundance revealed a significant 13 C KIE for Table 9. Enantioselective anti-arylmetallative desymmetrizing cyclizations onto malononitriles.

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Review doi.org/10.1002/chem.202104230 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, 31 P NMR studies suggested that water aids the transmetalation step.
To prepare a carbocyclic product 67, the reaction of alkynetethered 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 · 4H 2 O (5 mol %) in TFE at 100°C for 16-18 h. Regarding the electrondeficient alkene, the reaction tolerates α,β-unsaturated ketones with a range of substituents at the ketone, including methyl   , 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) 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 CÀ 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.
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 %), PPh 3 (10 mol %), and Cs 2 CO 3 (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 electronwithdrawing (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 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 · 4H 2 O (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 welltolerated (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 13. Syn-arylmetallative cyclizations onto aldehydes.

Chemistry-A European Journal
Review doi.org/10.1002/chem.202104230 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.

Chemistry-A European Journal
Review doi.org/10.1002/chem.202104230 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), PhBF 3 K, 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 · 4H 2 O [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.
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 · 4H 2 O, 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
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)]. (40)
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 sug-gested 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.
The nickel-catalyzed arylative and alkenylative 1,2-allylation of allene-tethered ketones to give enantioenriched tertiaryalcohol-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  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. (41) 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.

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.
[a] Isolated with an unknown impurity; the yield of 124 h was determined by 1 H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
(3 : 2) at room temperature for 24 h. Using 2-acetylphenylboronic acid, the scope of the reaction regarding the electronwithdrawing 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). Noncarbonyl 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.

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 2formylarylboronic 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,βunsaturated 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, Table 25. Nickel-catalyzed annulations between activated allenes and 2acetyphenylboronic acid; generation of contiguous quaternary centers. 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.