NHC-Catalyzed Generation of Î±,Î²-Unsaturated Acylazoliums for the

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles Santigopal Mondal,† Santhivardhana Reddy Yetra,† Subrata Mukherjee,† and Akkattu T. Biju*,‡ †

Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India

Acc. Chem. Res. Downloaded from pubs.acs.org by TULANE UNIV on 01/17/19. For personal use only.

‡

CONSPECTUS: This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-unsaturated acylazoliums to form various five and sixmembered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/ pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,β-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldolβ-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,βunsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atomeconomic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N−H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,β-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs. “Breslow intermediates” (Figure 1).4 The two important transformations proceeding via the umpolung strategy are benzoin condensation5 and Stetter reaction.6 Moreover, NHCs are also employed in the conjugate umpolung of α,β-unsaturated aldehydes, and these reactions proceed via the generation of homoenolate equivalents.7 In addition, the reaction of NHC

1. INTRODUCTION Since the seminal, independent, isolation of free carbenes by the Bertrand1 and Arduengo2 groups, N-heterocyclic carbene (NHC)-based organocatalysis has emerged as an effective and sophisticated synthetic strategies for the rapid construction of medicinally and biologically important molecules from simple starting materials.3 In general, NHCs are useful for the umpolung of aldehydes. The addition of carbenes to aldehydes generate the nucleophilic enaminol intermediate known as the © XXXX American Chemical Society

Received: October 31, 2018

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DOI: 10.1021/acs.accounts.8b00550 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Figure 1. Four important modes of NHCs in organocatalysis.

with α-functionalized aldehydes such as α-chloroaldehydes, αepoxyaldehydes or ketenes could result in the generation of NHC-bound enolates.8 A wide variety of carbocycles, heterocycles and acyclic molecules can be accessed using the NHCumpolung concept, and the use of chiral NHCs in the process results in the synthesis of enantiomerically enriched compounds. In addition to the application of NHCs in umpolung strategies, carbenes are also useful as catalysts in non-umpolung transformations.9 An important mode of reactivity in this domain proceeds through the α,β-unsaturated acylazoliums. In many cases, α,β-unsaturated acylazolium intermediate acts as a bis-electrophile allowing the conjugate addition of various bisnucleophiles followed by 1,2-addition to form a wide variety of carbocycles and heterocycles. Important methods for the generation of α,β-unsaturated acylazoliums include (i) the reaction of α,β-unsaturated aldehydes with NHCs in the presence of stoichiometric oxidants, (ii) the reaction of ynals with NHCs in the absence of external oxidants, (iii) the reaction of 2-bromoenals and rarely 3-bromoenals with NHCs, (iv) the reaction of NHCs with α,β-unsaturated esters, thioester, or acyl fluorides and more recently, and (v) the reaction of NHCs with α,β-unsaturated acids and amides (Figure 2). The purpose of this Account is to summarize the recent developments in our

laboratory on the NHC-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactions with bis-nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. To put things in proper perspective, adequate description of related work carried out by others is also included in this Account. Analogous to the NHC-catalyzed umpolung of aldehydes, the chemistry of α,β-unsaturated acylazoliums also has a biological origin. α,β-Unsaturated acylazoliums were found to be the key intermediates in the biosynthesis of clavulanic acid (2). In 2007, Merski and Townsend successfully demonstrated that the conjugate addition of L-arginine to the α,β-unsaturated acylazolium 1 derived from thiamine diphosphate (ThDP, vitamin B1) is the key step in the biosynthesis of the potent βlactamase inhibitor clavulanic acid (2) (Scheme 1).10 The Scheme 1. Biosynthesis of Clavulanic Acid

strategies for the enantioselective construction of carbocycles and heterocycles proceeding via the NHC-catalyzed generation of α,β-unsaturated acylazolium intermediates, developed in our laboratory are presented in the following sections.

2. [3 + 3] ANNULATION OF α,β-UNSATURATED ACYLAZOLIUMS WITH 1,3-BISNUCLEOPHILES In 2009, Lupton and co-workers demonstrated that NHCs can catalyze the intramolecular cyclization reactions of α,βunsaturated enol esters 3 leading to the synthesis of dihydropyranones 4. The reaction proceeds via the intermediacy of the α,β-unsaturated acylazolium 5 (Scheme 2, eq 1).11 The

Figure 2. Methods for the generation of α,β-unsaturated acylazoliums. B


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Mechanistically, the reaction proceeds via the addition of NHC to the ynals generating the key α,β-unsaturated acylazolium intermediate. The 1,2-addition of kojic acid 12 to the intermediate acylazolium generates the hemiacetal 14, which undergoes a Claisen rearrangement to give the enol intermediate 15. Rapid proton transfer to the intermediate 16 followed by methanolysis afforded the observed product 13. In 2010, De Sarkar and Studer disclosed an elegant conjugate addition of soft carbon nucleophiles such as 1,3-dicarbonyl compounds 17 to catalytically generated α,β-unsaturated acylazoliums generated from enals 18 under NHC-catalysis in the presence of the bisquinone oxidant 20 (Scheme 4, eq 3).14

Scheme 2. Synthesis of Dihydropyranones from Enolesters/ α,β-unsaturated Acid Fluorides

Scheme 4. Synthesis of Dihydropyranones from Enals/Ynals

reaction is initiated by the 1,2-addition of NHC generated from the imidazolium salt A to the enol ester leading to the α,βunsaturated acylazolium 5 and the enolate 6. Michael addition of the enolate 6 to the azolium 5 generates the NHC-bound enolate 7, which undergoes a proton transfer to form the azolium 8. The intramolecular acylation then affords the dihydropyranone 4. A variety of enol esters with β,βdisubstitutions underwent smooth annulation reactions to afford the dihydropyranone products in good yields (up to 92%). Moreover, the Lupton group demonstrated that NHCs can catalyze the [3 + 3] annulation reaction of TMS enol ethers 9 with α,β-unsaturated acid fluorides 10 leading to the synthesis of dihydropyranones 11 in 37−76% yields (eq 2). After Zeitler successfully demonstrated that α,β-unsaturated acylazoliums can be reliably generated from ynals,12 coupling of ynals with enolic C-nucleophiles such as kojic acids 12 proceeding via the enantioselective Claisen rearrangement was disclosed by Bode and co-workers (Scheme 3).13 The expected dihydropyranone product was unstable under the reaction conditions. In the presence of methanol, the ring-opened product 13 was formed in good yields (78−98%) and excellent enantioselectivities (up to >99%). In addition to kojic acid, pyruvic esters and β-naphthol afforded the corresponding functionalized dihydropyranone under identical conditions.

The reaction afforded functionalized dihydropyranones 19 in good to excellent yields (51−92%) using NHC generated from the triazolium salt D. A wide variety of α,β-unsaturated aldehydes were well tolerated under the optimized reaction conditions and nucleophiles such as β-diketones and βketoesters underwent smooth annulation reaction to afford the desired products. In the same year, Xiao and co-workers disclosed an efficient and atom-economic NHC-catalyzed annulation reaction of ynals with 1,3-diketones or 1,3-keto esters for the synthesis of dihydropyranones (eq 4).15 In the presence of NHC generated from the imidazolium salt A and KOt-Bu, the desired dihydropyranones were obtained in moderate to good yields (41−74%). Subsequently, Xiao and co-workers developed the enantioselective version of this [3 + 3] annulation reaction using NHC generated from the chiral

Scheme 3. Annulation of Ynals with Kojic Acid via Claisen Rearrangement

C


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Accounts of Chemical Research triazolium salt ent-C under base-free conditions.16 In addition, an enantioselective version of the oxidative NHC-catalyzed dihydropyranone synthesis was developed by the You group.17 Furthermore, the generation of α,β-unsaturated acylazoliums from 2-bromoenals followed by their interception with 1,3dicarbonyl compounds was demonstrated by the Ye18 and Yao groups.19 Inspired by these studies, we envisioned a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. Treatment of 2bromoenal 21 with 1,3-dicarbonyl compound 22 in the presence of carbene generated from the chiral triazolium salt C using DABCO as the base and LiOAc as the additive furnished the dihydropyranones 23 in excellent yields (up to 96%) and enantioselectivities (up to 99%) (Table 1).20 For good reactivity

Table 2. Enantioselective Synthesis of Dihydropyridinones

Table 1. Enantioselective Synthesis of Dihydropyranones

indicated that the addition of acetyl acetone from below the plane containing the triazolium moiety (leading to the intermediate 28a) is energetically more favored than the approach from above the plane of the triazolium (leading to the intermediate 28b). This is because the addition of nucleophile from below the plane is stabilized by possible intramolecular hydrogen bonding between the carbonyl oxygen and enol hydrogen, which is absent when the nucleophile approaches from above the plane of the azolium moiety. Motivated by the success of this reaction, we have envisioned the interception of the chiral α,β-unsaturated acylazolium intermediates with various cyclic and acyclic bisnucleophiles. Employing enolizable aldehydes 30 as the coupling partner for 2-bromoenals 21 resulted in a chemoselective NHC-catalyzed enantioselective cross-coupling for the synthesis of 4,5disubstituted dihydropyranones 31 (Table 3).21 It is noteworthy that the enantioselective formation of dihydropyranones took place in favor of eight possible byproducts (two γ-butyrolactones, four benzoin products, and two Stetter products). The use of NHC generated from the chiral triazolium salt C using Na2CO3 as the base afforded the desired products in good yields (41−96%) and excellent enantioselectivities (87−99%) under mild reaction conditions and relatively low catalyst loading. Various electron-donating and -withdrawing substituents on βaryl ring of 2-bromoenals as well as aliphatic 2-bromoenals are well tolerated under the optimized reaction conditions. Additionally, a series of enolizable aldehydes also underwent smooth annulation reaction to form the desired product. Moreover, the heterocyclic C−H acids such as 4-hydroxy coumarins (32) were successfully employed as the 1,3bisnucleophilic component for the interception of α,βunsaturated acylazolium, generated from 2-bromoenals and NHCs, for the synthesis of biologically important coumarinfused dihydropyranones 33.22 The NHC generated from imidazolium salt A was efficient for this transformation, resulting in various oxygen heterocycles, and the target products 33 were obtained in 37−95% yield. The use of N-methyl quinolinones as

and selectivity, the combination of two bases was found to be important. A broad range of 2-bromoenals as well as 1,3dicarbonyl compounds were well tolerated under the optimized reaction condition. Notably, the reaction proceeds under mild conditions and relatively low catalyst loading (5 mol %). Employing primary vinylogous amides 24 as the bisnucleophile resulted in the enantioselective synthesis of dihydropyridinones 25 (Table 2).20 The protection of the vinylogous amide nitrogen was not required for this annulation and the amide-bond forming side reaction was not observed under the present conditions. Mechanistically, the reaction proceeds via the generation of free carbene from C followed by its addition to 2-bromoenal 21 and subsequent proton transfer. The resulting Breslow intermediate 26,4 then undergoes debromination to afford the key α,β-unsaturated acylazolium intermediate 27 (Scheme 5). Nucleophilic addition of 22 or 24 to intermediate 27 generates the NHC-bound enol intermediate 28, which undergoes proton transfer and a subsequent intramolecular acylation resulting in the formation of the dihydropyranones 23 or dihydropyridinones 25 via the azolium 29. To get insight into the mode of enantioinduction, DFT studies were carried out. These studies D


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Accounts of Chemical Research Scheme 5. Mechanism of Dihydropyaranone and Dihydropyridinone Formation from 2-Bromoenals

Table 3. Enantioselective Annulation of α-Bromo Enals with Enolizable Aldehydes

Table 4. Enantioselective Synthesis Functionalized Coumarins

and base-free conditions. Interestingly, in the absence of the NHC catalyst, simple Knoevenagel condensation of enals with 34 occurred. A wide variety of functional groups on the enal as well as on the pyrazolone moiety were well tolerated under the reaction conditions. Moreover, the β,β-disubstituted enal underwent smooth annulation reaction to afford the desired product. Considering the importance of functionalized pyrazoles in the pharmaceutical and agricultural industries, the NHC-catalyzed enantioselective routes to these compounds under metal-free conditions are attractive.

the bisnucleophile afforded quinolinone-fused dihydropyranones in high yields. The enantioselective version of this reaction using NHC generated from the chiral triazolium salt C furnished the coumarin-fused dihydropyranones in up to 86% ee (Table 4). Competition experiments revealed that the presence of electron-withdrawing groups on β-aryl ring of 21 enhances the reaction rate. Subsequently, the use of pyrazolones as bisnucleophiles in oxidative NHC-catalysis was investigated. The formal [3 + 3] annulation of pyrazolones 34 with α,β-unsaturated acylazoliums generated from enals 18 under oxidative conditions (using bisquinone 20) afforded the dihydropyranone-fused pyrazoles 35 in good yields (up to 82%) and ee values (up to 96%) (Table 5).23 The reaction proceeds under mild, operationally simple

3. [3 + 2] ANNULATION OF α,β-UNSATURATED ACYLAZOLIUMS WITH 1,2-BISNUCLEOPHILES In view of the interesting results obtained with the interception of α,β-unsaturated acylazoliums with 1,3-bisnucleophiles for the synthesis of six-membered heterocycles, we then focused our attention on 1,2-bisnucleophiles for the synthesis of fivemembered rings. Treatment of 3-hydroxy oxindoles 36 with catalytically generated α,β-unsaturated acylazoliums under E


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undesired ester formation and several functional groups were tolerated under the optimized reaction conditions. Our mechanistic investigation revealed the possibility of the formation of isatin from 36 in presence oxidant and a subsequent [3 + 2] annulation with the catalytically generated homoenolate intermediates from enal and NHCs (Scheme 6).25

Table 5. Enantioselective Synthesis of DihydropyranoneFused Pyrazoles

Scheme 6. Mechanism of the NHC-Catalyzed Spiro γButyrolactone Synthesis

oxidative conditions resulted in the enantioselective synthesis of spiro γ-butyrolactones 37 in good yields and enantioselectivity with moderate diastereoselectivities (Table 6).24 The conjugated addition of the C-nucleophile to α,β-unsaturated acylazolium followed by intramolecular acylation afforded the desired spirocyclic product in the presence of carbene generated from chiral triazolium salt C and DBU under oxidative conditions. The choice of base was crucial to avoid the

Considering the oxidation of dioxindoles to the corresponding isatins in air and in the absence of external oxidants, it is reasonable to assume the possibility of a [3 + 2] annulation of NHC-homoenolate generated from enals with the in situ generated isatins 38 (Scheme 6). A closely related NHCcatalyzed oxidative [3 + 2] annulation of dioxindoles with enals for the synthesis of spiro γ-butyrolactones 37 was uncovered by Ye and co-workers.26 Interestingly, the use of nitrobenzene as a single electron oxidant enables the generation of radical cation 39 (single electron oxidation of the homoenolate) and the enol radical 40 from dioxindole. The coupling of the two radicals is the key for the formation of 37 (Scheme 6). Similar strategies for the [3 + 2] annulation of α,β-unsaturated acylazolium leading to five-membered nitrogen heterocycles were developed by Lu and Du, Huang, Ye, and Chi groups.27

Table 6. NHC-Catalyzed Enantioselective Synthesis of Spiro γ-Butyrolactones

4. REACTION OF α,β-UNSATURATED ACYLAZOLIUMS WITH α-SUBSTITUTED 1,3-DICARBONYLS Next, we focused our attention on the use of α-substituted 1,3dicarbonyls as the coupling partner for α,β-unsaturated acylazoliums. The NHC-catalyzed reaction of α,β-unsaturated acylazoliums generated from 2-bromoenals with malonic ester 41 bearing a γ-aroyl group resulted in the enantioselective synthesis of functionalized cyclopentenes 42 (Table 7).28 This cascade reaction follows a Michael-intramolecular aldol-βlactonization-decarboxylation sequence to deliver the products in good yields and excellent ee values. The use of NHC generated from C in the presence of Na2CO3 in DME was found to be optimal for this reaction. A variety of substitution pattern on the β-aryl ring of 2-bromoenal as well as substitution on the γaroyl moiety were tolerated well under the optimized reaction conditions to afford the desired product in moderate to good yields (40−85% yield) and high enantioselectivities (up to >99%). Moreover, the reaction resulted in the diastereoselective and enantioselective synthesis of cyclopentane-fused β-lactones F


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Accounts of Chemical Research Table 7. NHC-Catalyzed Enantioselective Synthesis of Cyclopentenes

Scheme 8. Proposed Mechanism of the Reaction

when performed with malonate derivatives bearing an alkyl group at the γ-position. The interception of chiral α,β-unsaturated acylazolium with malonates 43 having alkyl group at the γ-position was disclosed independently by Studer and co-workers. The enantioselective synthesis of highly substituted β-lactones 44 were achieved through oxidative carbene catalysis using NHC generated from chiral triazolium salt C and oxidant 20 with LiCl as a cooperative Lewis acid (Scheme 7).29a Moreover, a closely related

cyclopentene 42. The driving force for the rapid decarboxylation of 44 (when R2 = aryl) might probably due to the enhanced stability of 42 via formation of the styrenic double bond. Recently, we have employed α-substituted cyclic βketoamides 47 as the coupling partner for α,β-unsaturated acylazoliums. The formal [3 + 3] annulation of 2-bromoenals 21 with 47 furnished diastereoselective and enantioselective route to spiro-glutarimide derivatives 48 (Table 8).30 Again, the carbene generated from C in the presence of Na2CO3 in CH3CN provided the product bearing two contiguous stereocenters including one all-carbon quaternary spirocenter. A broad range of β-aryl-α-bromoenals and cyclic β-ketoamides were well tolerated under the optimized reaction conditions and delivered the desired products in high yields (up to 95%), enantiose-

Scheme 7. Enantioselective Synthesis of Highly Substituted β-Lactones

Table 8. NHC-Catalyzed Enantioselective Synthesis of SpiroGlutarimides

interception of α,β-unsaturated acylazoliums with donor− acceptor cyclopropanes for the selective synthesis of cyclopentane-fused β-lactones was demonstrated by Lupton and coworkers.29b A tentative mechanism for this NHC-catalyzed cyclopentene/ highly substituted β-lactone synthesis is described in Scheme 8. The key chiral α,β-unsaturated acylazolium intermediate 27 was generated from 21 and NHC generated from C. Alternatively, 21 can also be formed from enal and C using the oxidant 20. Conjugate addition of enolate generated from 41/43 onto intermediate 27 resulted in the NHC-bound enolate intermediate 45 formation. The intermediate 45 can undergo a highly selective intramolecular aldol reaction leading to the formation of the cyclopentane intermediate 46. β-Lactonization of intermediate 46 followed by the release of free NHC afforded the cyclopentane-fused β-lactone 44. In the case of substrate 41, a rapid decarboxylation of 44 resulted in the formation of the G


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Accounts of Chemical Research lectivities (up to 96%) and diastereoselectivities (up to 17:1). Mechanistically, this [3 + 3] annulation proceeds via the Michael addition-proton transfer-intramolecular amidation sequence to deliver the product. Notably, the aliphatic 2bromoenal afforded the spirocyclic product in poor yield and selectivity. However, good yield and selectivity was observed while performing the reactions with β-alkyl enal under oxidative conditions.

Mechanistically, the reaction proceeds via the generation of chiral α,β-unsaturated acylazolium intermediate 27, generated by the nucleophilic attack of NHC generated from C onto the enal followed by the oxidation of the generated Breslow intermediate 26 using the oxidant 20 (Scheme 9). The Scheme 9. Proposed Mechanism for the Synthesis of Tricyclic δ-Lactones

5. MICHAEL−MICHAEL-LACTONIZATION CASCADE INVOLVING α,β-UNSATURATED ACYLAZOLIUMS NHCs are known to catalyze several cascade or domino reactions.31 Cascade reaction involving α,β-unsaturated acylazoliums are usually initiated by Michael addition and the final catalyst regeneration takes place via an acylation reaction. Highly efficient and enantioselective cascade reactions via α,βunsaturated acylazoliums initiated by Michael addition for the synthesis of functionalized δ-lactones was demonstrated by the groups of Hui,32 Studer,33 Ye,34 Chi,35 and Xu.36 We have recently employed dinitrotoluene derivatives 49 bearing two nitro groups to trap the catalytically generated α,β-unsaturated acylazolium under oxidative conditions in a cascade reaction following the Michael/Michael/lactonization sequence. In the presence of NHC generated from C using DABCO, the functionalization of benzylic C(sp3)-H bond of 49 resulted in the synthesis of tricyclic δ-lactone 50 as a single diastereomer with three-contiguous stereocenters. The generality of this mild, atom-economic and highly stereoselective cascade reaction was demonstrated by performing the reaction with a broad range of aromatic and heteroaromatic enals (Table 9).37 Moreover, the synthetic utility of this methodology was further extended by converting the tricyclic δ-lactones to synthetically useful compounds while preserving the enantiopurity.

conjugated addition of the anion generated from 49 from the bottom face of the azolium 27 under basic conditions could result in the NHC-bound enolate intermediate 51 formation, which could undergo a second intramolecular 1,4-addition to the vinyl ketone moiety to provide the enolate intermediate 52. Intramolecular acylation of 52 afforded the desired δ-lactone 50 concomitant with the NHC catalyst regeneration. Cascade reactions proceeding via α,β-unsaturated acylazoliums, initiated by aza-Michael addition enabled the enantioselective synthesis of nitrogen heterocycles as reported by the groups of Hui32 and Chi.38 We have recently used this concept for the N−H functionalization of indoles leading to the highly selective synthesis of pyrroloquinolines. While using indole derivative 53 (bearing a COCF3 group at the 3-position) as the nucleophilic component, the reaction proceeds via an azaMichael/Michael/lactonization sequence to afford the tetracyclic products 54 in good yields, diastereoselectivities, and enantioselectivities (Table 10).39 The carbene generated from the triazolium salt C using DABCO under oxidative conditions using 20 in DMSO was optimal for high reactivity and selectivity, and the reaction tolerates a broad range of functional groups. It is noteworthy that the reaction features a simultaneous improvement in reactivity/selectivity employing polar aprotic solvents.

Table 9. NHC-Catalyzed Cascade Reaction for the Enantioselective Synthesis of Tricyclic δ-Lactones

6. TANDEM DIENOLATE-ENOLATE ADDITION TO α,β-UNSATURATED ACYLAZOLIUMS Inspired by the addition of enolates from acyclic/cyclic 1,3dicarbonyls to α,β-unsaturated acylazoliums, we envisioned the H


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Accounts of Chemical Research Table 10. NHC-Catalyzed N−H Functionalization for the Synthesis of Pyrroloquinolines

Table 11. Enantioselective Synthesis of Pyrazolone-Fused Spirocyclohexadienones

Scheme 10. Proposed Mechanism for the Synthesis of Spirocyclohexadienones extension of this concept to dienolates. The addition of dienolates to α,β-unsaturated acylazoliums in a formal [3 + 3] pathway for the construction of all-carbon six-membered rings has been demonstrated by Lupton,40 Wang,41 and Ye groups.42 However, the simultaneous interception of α,β-unsaturated acylazoliums using dienolate/enolate generated from the single precursor was unknown. We have used α-arylidene pyrazolinones 55 as the precursor for the tandem generation of dienolate/enolate, which reacts with α,β-unsaturated acylazoliums under oxidative conditions in a [3 + 3] fashion for the synthesis of pyrazolone-fused spirocyclohexadieneones 56 (Table 11).43 This cascade reaction proceeds in a vinylogous Michael addition/spiroannulation/dehydrogenation sequence. In the presence of NHC generated from C using DBU, and excess oxidant 20, the products bearing an all-carbon quaternary stereocenter are formed in moderate to good yields and excellent ee values. Under the optimized reaction conditions, a variety of substituents on the β-aryl ring of enals and α-arylidene pyrazolinones were well tolerated. The mechanism of this formal [3 + 3] annulation reaction leading to spirocyclic frameworks is shown in Scheme 10. The reaction proceeds via the generation of chiral α,β-unsaturated acylazolium intermediate 27 from enals and C using 20 via the Breslow intermediate 26, and the dienolate 57 generated from the pyrazolinone 55. Reaction of these intermediates generated the NHC-bound enolate 58, which under basic conditions afforded the second dienolate intermediate 59. Intramolecular acylation of 59 resulted in the formation of 60, which underwent oxidation to provide the spirocyclohexadienone 56.

one of the important non-umpolung modes of NHC reactivity. As explained, these key intermediates can be generated from enals (under oxidative conditions), 2-bromoenals, ynals and various acid derivatives. We have demonstrated the interception of α,β-unsaturated acylazoliums with various cyclic and acyclic 1,3-bisnucleophiles for the enantioselective synthesis of

7. CONCLUSIONS This Account has summarized the rich and fascinating chemistry of NHC-catalyzed generation of α,β-unsaturated acylazoliums followed by their interception with various nucleophiles. This is I


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Accounts of Chemical Research dihydropyranones and dihydropyridinones in a formal [3 + 3] pathway. When a malonic ester derivative having a γ-benzoyl group was used as the coupling partner for α,β-unsaturated acylazoliums, functionalized cyclopentenes were obtained via a cascade process involving Michael-intramolecular aldol-βlactonization-decarboxylation sequence. Moreover, the enantioselective synthesis of spiro-glutarimides has been achieved by using cyclic β-ketoamides, and the reaction proceeds in a Michael addition-intramolecular amidation pathway. Additionally, the α,β-unsaturated acylazoliums have been employed for cascade processes for the enantioselective synthesis of tricyclic δ-lactones and pyrroloquinolines by using dinitrotoluene derivatives and suitably substituted N−H indoles respectively, and these reactions proceed via the (aza)-Michael/Michael/ lactonization sequence. Furthermore, the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones has been developed by using α-arylidene pyrazolinones as the bisnucleophile for the tandem generation of dienolate/enolate, this formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. Although tremendous development has occurred in this area, some aspects of the chemistry of these reactive intermediates are not well understood yet. For instance, the addition of oxygen/nitrogen nucleophiles in a 1,4-pathway is not well explored in this realm of NHC-catalysis. Further advances in this area will provide new reactions involving this key electrophilic intermediate. It is reasonable to believe that NHCcatalysis using α,β-unsaturated acylazoliums will continue to flourish and result in more developments in the years to come.

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University, Taipei and an Alexander von Humboldt fellow with Prof. Frank Glorius at the Westfälische Wilhelms-Universität Münster, Germany. In June 2011, he began his independent research career at the CSIR-NCL, Pune. Since June 2017, he has been an Associate Professor in the Department of Organic Chemistry, Indian Institute of Science, Bangalore. His research focuses on the development of transitionmetal-free reactions using NHC organocatalysis and aryne chemistry, and their applications in organic synthesis.

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ACKNOWLEDGMENTS We are grateful to the generous financial support provided by Board of Research in Nuclear Sciences (BRNS), Government of India (Grant No. 37(2)/14/49/2014-BRNS/), and the Indian Institute of Science, Bangalore (start-up grant for A.T.B.) for our work on NHC-catalysis. We thank Dr. Anup Bhunia, Dr. Atanu Patra, and Mr. Arghya Ghosh for experimental and intellectual contributions. Sa.M. and Su.M. thank UGC for the fellowship and S.R.Y. thanks CSIR-New Delhi for senior research fellowship.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Akkattu T. Biju: 0000-0002-0645-8261 Notes

The authors declare no competing financial interest. Biographies Santigopal Mondal was born in 1990 in South 24 Parganas, (WB), India. He completed his M.Sc. from IIT Delhi in 2013. He has recently completed his Ph.D. from the research group of Prof. A. T. Biju at the CSIR-NCL, Pune working on enantioselective NHC-catalyzed transformations. Presently, he is a postdoctoral fellow at the University of Pennsylvania with Professor Jeffrey D. Winkler. Santhivardhana Reddy Yetra was born in 1988 in Guntur, (AP), India. He completed his M.Sc. from Andhra University in 2010. In 2016, he completed his Ph.D. from the research group of Prof. A. T. Biju at the CSIR-NCL, Pune working on asymmetric catalysis using NHCs. Currently, he is a postdoctoral fellow with Professor Lutz Ackermann at the University of Göttingen, in Germany. Subrata Mukherjee was born in 1991 in Burdwan, (WB), India. He completed his B.Sc. (Hons) in Chemistry at Calcutta University in 2011, and his M.Sc. at the IIT-Madras in 2014. Currently, he is a Ph.D. student in the research group of Prof. A. T. Biju. His research focuses on asymmetric catalysis by using NHCs and related chemistry. Akkattu T. Biju received his Ph.D. under the guidance of Dr. Vijay Nair at the CSIR-NIIST, Trivandrum, India. Subsequently, he was a postdoctoral fellow with Prof. Tien-Yau Luh at the National Taiwan J


Article

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NHC-Catalyzed Generation of Î±,Î²-Unsaturated Acylazoliums for the

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