A Review on Generation and Reactivity of the N-Heterocyclic Carbene-Bound Alkynyl Acyl Azolium Intermediates

N-heterocyclic carbene (NHC) has been widely used as an organocatalyst for both umpolung and non-umpolung chemistry. Previous works mainly focus on species including Breslow intermediate, azolium enolate intermediate, homoenolate intermediate, alkenyl acyl azolium intermediate, etc. Notably, the NHC-bound alkynyl acyl azolium has emerged as an effective intermediate to access functionalized cyclic molecular skeleton until very recently. In this review, we summarized the generation and reactivity of the NHC-bound alkynyl acyl azolium intermediates, which covers the efforts and advances in the synthesis of achiral and axially chiral cyclic scaffolds via the NHC-bound alkynyl acyl azolium intermediates. In particular, the mechanism related to this intermediate is discussed in detail.

Over recent decades, acyl azolium has represented a central reactive species for reaction designs in the modern era of NHC-based catalysis. Overall, acyl azolium intermediates can be categorized into the following types: alkyl acyl azoliums [17], alkenyl acyl azoliums [18][19][20], dienyl acyl azoliums [21][22][23], and alkynyl acyl azoliums [20] (Scheme 1A). Among them, NHC-based alkynyl acyl azolium intermediates, initially identified independently by Chi [24], Du [25], and Wang [26] between 2017 and 2018, were less commonly studied. Although only a few reaction models involving the species have been developed, alkynyl acyl azolium intermediates have been recognized as a new NHC-bound specie for the discovery of new reactions. Until now, three procedures have been disclosed to produce alkynyl acyl azoliums intermediates according to their precursors (i) via the addition of NHCs to ynals and subsequent oxidation of the Breslow intermediates (Scheme 1B, I); (ii) via the reaction of NHCs with activated alkynoic acid esters (Scheme 1B, II); (iii) via the reaction of NHCs with in situ activated alkynoic acids (Scheme 1B, III).
However, despite recent developments gradually enabling the diverse transformation of these species, the area is in the early stages of its development. The main challenge to exploring the reactivity of alkynyl acyl azoliums intermediates is attributed to the difficulty to control the chemo-and regioselectivities, which would result in undesired byproducts. For instance, the NHC-bound alkynyl acyl anion intermediates Int. I, allene intermediates Int. II, and alkenyl acyl azoliums intermediates Int. III might also be formed during the generation of alkynyl acyl azoliums intermediates (Scheme 1C). Furthermore, the control of the regioselectivity of the [3 + n] annulations between binucleophile and alkynyl acyl azolium intermediates is another challenge to explore in this reaction (Scheme 1C, IV,V).
Herein, we summarized the efforts and advances in the NHC-catalyzed [3 + n] annulation reactions involving alkynyl acyl azoliums intermediates with focus on their generation and reactivity as well as the mechanism of the reactions. We present these achievements in generally chronological order and some seminal efforts or closely related works Scheme 1. N-heterocyclic carbene (NHC)-bound acyl azoliums (A), generation and reactivity of the alkynyl acyl azoliums (B), and the main challenges to explore the concerning reactivity of alkynyl acyl azoliums (C).
However, despite recent developments gradually enabling the diverse transformation of these species, the area is in the early stages of its development. The main challenge to exploring the reactivity of alkynyl acyl azoliums intermediates is attributed to the difficulty to control the chemo-and regioselectivities, which would result in undesired byproducts. For instance, the NHC-bound alkynyl acyl anion intermediates Int. I, allene intermediates Int. II, and alkenyl acyl azoliums intermediates Int. III might also be formed during the generation of alkynyl acyl azoliums intermediates (Scheme 1C). Furthermore, the control of the regioselectivity of the [3 + n] annulations between binucleophile and alkynyl acyl azolium intermediates is another challenge to explore in this reaction (Scheme 1C, IV,V).
Herein, we summarized the efforts and advances in the NHC-catalyzed [3 + n] annulation reactions involving alkynyl acyl azoliums intermediates with focus on their generation and reactivity as well as the mechanism of the reactions. We present these achievements in generally chronological order and some seminal efforts or closely related works are mentioned as well. All the NHCs described in this article are summarized in Scheme 2.

Scheme 2.
Overview of NHC structures discussed in this review.

Discussion
In 2018, Wang described the generation of alkynyl acyl azolium intermediates through the addition of NHC catalyst to ynals and subsequent oxidation of the Breslow intermediates (Scheme 3) [26]. The reaction of alkynyl acyl azoliums with binucleophile cyclic 1,3-diones 1 affords the axially chiral α-pyrone-aryls 3, along with byproducts 4, 5 and 6 which are derived from the annulation of α,β-unsaturated acyl azoliums intermediate Int. III, regioselective annulation between alkynyl acyl azoliums intermediate and oxygen nucleophile of cyclic 1,3-diones 1, as well as Knoevenagel reaction of 3 with 1, respectively. are mentioned as well. All the NHCs described in this article are summarized in Scheme 2.

Scheme 2.
Overview of NHC structures discussed in this review.

Discussion
In 2018, Wang described the generation of alkynyl acyl azolium intermediates through the addition of NHC catalyst to ynals and subsequent oxidation of the Breslow intermediates (Scheme 3) [26]. The reaction of alkynyl acyl azoliums with binucleophile cyclic 1,3-diones 1 affords the axially chiral α-pyrone-aryls 3, along with byproducts 4, 5 and 6 which are derived from the annulation of α,β-unsaturated acyl azoliums intermediate Int. III, regioselective annulation between alkynyl acyl azoliums intermediate and oxygen nucleophile of cyclic 1,3-diones 1, as well as Knoevenagel reaction of 3 with 1, respectively. The release of NHC catalyst finally delivers the targeted product 3. Importantly, the addition of Lewis acid was essential to modulate the regioselectivity. The chelation of the oxygen atom with magnesium ion promoted carbon nucleophilic addition of 1,3-dione to alkynyl acyl azoliums intermediate 7 and the formation of byproduct was inhibited. In addition, the attempt of oxidative dehydrogenation of 4 under their standard reaction conditions did not deliver product 3, which suggested that the direct annulation of cyclic 1,3-dione with unsaturated acyl azolium intermediate pathway was excluded (Scheme 4). The release of NHC catalyst finally delivers the targeted product 3. Importantly, the addition of Lewis acid was essential to modulate the regioselectivity. The chelation of the oxygen atom with magnesium ion promoted carbon nucleophilic addition of 1,3-dione to alkynyl acyl azoliums intermediate 7 and the formation of byproduct was inhibited. In addition, the attempt of oxidative dehydrogenation of 4 under their standard reaction conditions did not deliver product 3, which suggested that the direct annulation of cyclic 1,3-dione with unsaturated acyl azolium intermediate pathway was excluded (Scheme 4). In 2020, Qi and co-workers developed a similar NHC-catalyzed [3 + 3] annulation of alkynyl acyl azoliums intermediate by replacing the binucleophile of pyrrol-4-one 13 [27]. In this reaction, the simple ynal 12a underwent [3 + 3] annulation smoothly and afforded the non-axially chiral pyrones in good yield. By optimizing a particular class of chiral indanol-derived NHCs and other conditions, the formation of axially chiral pyrones was also proven to be feasible by using 3-(2-methoxynaphthalen-1-yl)propiolaldehyde (12b) in the presence of chiral NHC catalyst A2 (Scheme 5). In 2020, Qi and co-workers developed a similar NHC-catalyzed [3 + 3] annulation of alkynyl acyl azoliums intermediate by replacing the binucleophile of pyrrol-4-one 13 [27]. In this reaction, the simple ynal 12a underwent [3 + 3] annulation smoothly and afforded the non-axially chiral pyrones in good yield. By optimizing a particular class of chiral indanol-derived NHCs and other conditions, the formation of axially chiral pyrones was also proven to be feasible by using 3-(2-methoxynaphthalen-1-yl)propiolaldehyde (12b) in the presence of chiral NHC catalyst A2 (Scheme 5).
Chi, Jin and co-workers also disclosed a [3 + 3] annulation of NHC-bound alkynyl acyl azoliums with N-Ts imine 16 [24]. In this case, the alkynyl acyl azolium intermediate was generated by the reaction of NHC catalyst with activated alkynoic acid ester. The alkynyl acyl azolium intermediates have great potential for reaction discovery due to the highly reactive carbon-carbon triple bond. In this work, they explored the reactivity of alkynyl acyl azoliums with binucleophile N-Ts imine 16 in order to access a variety of functionalized pyridines 17 (Scheme 6). Chi, Jin and co-workers also disclosed a [3 + 3] annulation of NHC-bound alkynyl acyl azoliums with N-Ts imine 16 [24]. In this case, the alkynyl acyl azolium intermediate was generated by the reaction of NHC catalyst with activated alkynoic acid ester. The alkynyl acyl azolium intermediates have great potential for reaction discovery due to the highly reactive carbon-carbon triple bond. In this work, they explored the reactivity of alkynyl acyl azoliums with binucleophile N-Ts imine 16 in order to access a variety of functionalized pyridines 17 (Scheme 6). Subsequent lactamization occurs to release the NHC catalyst and delivers the N-Ts δ-lactams 18. Finally, isomerization of N-Ts δ-lactam 18 at a slightly elevated temperature produces the pyridines 17. This work pioneered the use of activated alkynoic acid ester as the precursor to generate the alkynyl acyl azolium intermediate.

Scheme 5. NHC-catalyzed [3 + 3] atroposelective annulation of ynal and pyrrol-4-one.
In 2020, Qi and co-workers explored even further the reactivity of alkynyl acyl azolium intermediate for the [3 + 3] annulation reaction (Scheme 7) [28]. In this work, the N-Tsprotected 2-aminoacrylate 24 serves as a nucleophile for conjugated addition and affords a range of pyridines 25 in moderate yields. Besides [3 + 3] annulation reactions, Du and co-workers also developed an NHCcatalyzed [3 + 2] annulation of alkynyl acyl azolium intermediate in 2017 [25]. In this process, activated esters 15 were used to generate the alkynyl acyl azolium intermediates, which reacted with β-diacyl 32 to afford the desired Z-2-vinylfuran-3(2H)-one 33 with various substituents in moderate to excellent yields. The reaction was compatible with both electron-withdrawing and electron-donating groups with regard to esters. However, undesired six-membered ring byproduct 39 was also observed with low to moderate yields in some cases (Scheme 8). Besides [3 + 3] annulation reactions, Du and co-workers also developed an NHCcatalyzed [3 + 2] annulation of alkynyl acyl azolium intermediate in 2017 [25]. In this process, activated esters 15 were used to generate the alkynyl acyl azolium intermediates, which reacted with β-diacyl 32 to afford the desired Z-2-vinylfuran-3(2H)-one 33 with various substituents in moderate to excellent yields. The reaction was compatible with both electron-withdrawing and electron-donating groups with regard to esters. However, undesired six-membered ring byproduct 39 was also observed with low to moderate yields in some cases (Scheme 8). Therefore, attack of the α-carbon by oxygen anion is more favorable for yielding five-membered products in the intramolecular addition process. Due to the less-steric hindrance between alkenyl hydrogen and carbonyl, Z-isomers are able to be obtained with high stereoselectivity (Scheme 8).
To further investigate the reactivity of NHC-bound alkynyl acyl azoliums intermediates, Wang and co-workers extended binucleophile to amidines 40 [29]. In this case, they explored another NHC catalyzed [3 + 3] annulation of alkynyl acyl azoliums to construct multiply substituted pyrimidin-4-ones (Scheme 9). The reaction was compatible with both electron-withdrawing and electron-donating groups on ynals and amidines. Furthermore, the desired products were obtained in good yields even with the bulkier amidines, which enabled this reaction to be applied for further diversification. Therefore, attack of the α-carbon by oxygen anion is more favorable for yielding five-membered products in the intramolecular addition process. Due to the less-steric hindrance between alkenyl hydrogen and carbonyl, Z-isomers are able to be obtained with high stereoselectivity (Scheme 8).
Mechanistically, the reaction is initiated by the addition of NHC catalyst to activated alkynoic acid esters 15 followed by the elimination of 4-nitrophenolate to afford alkynyl acyl azolium intermediate 56.  [3 + 3] annulation product 54 with the release of the NHC free carbene. Although the nucleophilic addition of resonant isomer enolate 59′ of 59 to alkynyl acyl azolium intermediate 56 could produce byproduct 55, its formation could be completely inhibited by optimizing the base and solvent. When the reaction carried out at 90 °C or tetrahydrofuran was used as the solvent, byproduct 55 was obtained in 30-45% yields. Reducing the heat from 90 °C to room temperature and replacing tetrahydrofuran with other solvent (toluene, acetonitrile, or dichloromethane) could essentially completely inhibit the Scheme 11. [3 + 3] annulation of alkynyl acyl azolium intermediates and 3-oxo indolin-2-ide or 3-imino benzofuran-2-ide.
Mechanistically, the reaction is initiated by the addition of NHC catalyst to activated alkynoic acid esters 66 followed by the elimination of 4-nitrophenolate to afford alkynyl acyl azolium intermediate 69. in the reaction. According to DFT calculations, the main reason for the lower energy of TS1 R than TS1 S is that the noncovalent interactions (LP . . . π, C-H . . . N, π . . . π, etc.) of the former are stronger than the latter.
The above works referred to the construction of achiral compounds or molecules with the C-C axis through NHC-bound alkynyl acyl azolium intermediates. However, investigation of the C-hetero chiral axis remained underexplored. In 2021, Jin, Chi, and co-workers realized NHC-catalyzed asymmetric synthesis of C-N axial chiral thiazine 73 via the [3 + 3] annulation of alkynyl acyl azolium intermediate and thioureas 72 (Scheme 13) [42]. In this approach, in the presence of NHC-free carbene A10 and Scandium trifluoromethanesulfonate additive, a variety of bulky aryl substituted thioureas 72 annulated with ynals 23 afforded thiazine 73 with moderate to good yields and high to excellent enantioselectivities. carbonate and followed by Michael addition to intermediate 69 forms allenolate azolium intermediate 70. Subsequent proton transfer produces alkenyl acyl azolium intermediate 71 which undergoes lactamization to yield the corresponding formal [3 + 3] annulation δlactams 68 with release of the NHC catalyst. Further thermal treatment of δ-lactams 68 affords the aromatized product 67. DFT calculation indicates that in the process of nucleophilic attack to intermediate 69, the energy of transition state TS1 R is 1.8 kcal/mol lower than that of transition state TS1 S, so R configuration isomer plays a dominant role in the reaction. According to DFT calculations, the main reason for the lower energy of TS1 R than TS1 S is that the noncovalent interactions (LP…π, C-H…N, π…π, etc.) of the former are stronger than the latter.
The above works referred to the construction of achiral compounds or molecules with the C-C axis through NHC-bound alkynyl acyl azolium intermediates. However, investigation of the C-hetero chiral axis remained underexplored. In 2021, Jin, Chi, and co-workers realized NHC-catalyzed asymmetric synthesis of C-N axial chiral thiazine 73 via the [3 + 3] annulation of alkynyl acyl azolium intermediate and thioureas 72 (Scheme 13) [42]. In this approach, in the presence of NHC-free carbene A10 and Scandium trifluoromethanesulfonate additive, a variety of bulky aryl substituted thioureas 72 annulated with ynals 23 afforded thiazine 73 with moderate to good yields and high to excellent enantioselectivities.  [3 + 3] annulation product 73a with the release of the NHC catalyst. It is worth noting that although Scandium promotes the reaction, it has no effect on ee value.
In 2021, as a continuous work on NHC-catalyzed atroposelective [3 + n] annulation to access chiral C-N axis heterocyclic compounds, Chi and co-workers disclosed the atroposelective [3 + 2] annulation between ynals 23 and 4-arylurazole 79 using a desymmetrization strategy (Scheme 14) [43]. A wide range of ynals 23 and symmetric urazole 79 with bulky 4-aryl bearing diverse substituents were well tolerated and underwent the desymmetric atroposelective [3 + 2] annulation to afford pyrazolo[1,2-a]triazoles 80 containing a C-N axis in good to excellent yield with high enantiomeric excess. The mechanism is similar to that reported previously, in which atroposelective nucleophilic addition of the deprotonated 79 to the alkynyl acyl azolium intermediate 75 occurs to yield formal [3 +2] annular product.
der the action of chiral NHC, intermediate 78 undergoes 6-exo-trig cyclization to yield the corresponding formal [3 + 3] annulation product 73a with the release of the NHC catalyst. It is worth noting that although Scandium promotes the reaction, it has no effect on ee value.

Conclusions
Since its discovery, NHC-based alkynyl acyl azolium intermediates have made significant progress in the past five years. Three methods to access the NHC-based alkynyl acyl azolium intermediates have been discussed, (1) via the oxidation of ynals, (2) via the activation of alkynoic acid ethers, and (3) via the in situ activation of alkynoic acids. These intermediates exhibit bielectrophilicity and react with binucleophiles via conjugated addition followed by 1,2-addition to yield structurally and functionally diverse cyclic molecules such as pyridines, lactones, and lactams containing a ring-fused structure, as well as multiple heteroatoms. Particularly, with the participation of alkynyl acyl azolium intermediates, the construction of C-N chiral axes and C-C chiral axes was achieved. Scheme 14. NHC-catalyzed atroposelective [3 + 2] annulation of ynals and urazoles.

Conclusions
Since its discovery, NHC-based alkynyl acyl azolium intermediates have made significant progress in the past five years. Three methods to access the NHC-based alkynyl acyl azolium intermediates have been discussed, (1) via the oxidation of ynals, (2) via the activation of alkynoic acid ethers, and (3) via the in situ activation of alkynoic acids. These intermediates exhibit bielectrophilicity and react with binucleophiles via conjugated addition followed by 1,2-addition to yield structurally and functionally diverse cyclic molecules such as pyridines, lactones, and lactams containing a ring-fused structure, as well as multiple heteroatoms. Particularly, with the participation of alkynyl acyl azolium intermediates, the construction of C-N chiral axes and C-C chiral axes was achieved.
However, due to the formation of several other reactive species during the generation of alkynyl acyl azolium intermediates and the difficulty of controlling the regioselectivity of the nucleophilic addition, these reactions lead to the formation of several byproducts. Unfortunately, only a few reports concerning this topic have been produced. On the other hand, only four relatively successful cases for the synthesis of chiral compounds have been developed. In the future, more efforts will be required to explore new reactions for the synthesis of axially chiral molecules and to further investigate the mechanism by which NHC-based alkynyl acyl azolium intermediates participate.