Correction: Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

[This corrects the article DOI: 10.3762/bjoc.12.47.].


Introduction
The benzoin reaction (or condensation) is named after the product it furnishes via a catalytic assembly of two molecules of aromatic aldehydes. One molecule of the aldehyde functions as an acyl anion and the other as a carbonyl electrophile to afford α-hydroxy ketones (benzoins). It is a 100% atom-economic process wherein a new stereocentre is produced. The reaction is sometimes referred to as acyloin condensation to encompass reactions of aliphatic aldehydes. The assembly of two molecules of the same aldehyde is known as homo-benzoin reaction and that of two different aldehydes is known as crossed benzoin reaction. Mechanistically the reaction involves polarity reversal (umpolung) of one aldehyde to generate an acyl anion equivalent and this event is mediated by the catalyst. Alkali metal cyanides and N-heterocyclic carbenes (NHCs) are the two main classes of catalysts that are known to mediate benzoin reactions. This review focuses on the recent advancements made in the area of NHC-catalysed benzoin reactions.
Historically, the first benzoin reaction was reported by Wöhler and Liebig in 1832. They discovered that the cyanide anion can catalyze the union of two molecules of aromatic aldehydes to afford α-hydroxy ketones [1]. More than a century later, a thia-Scheme 1: Breslow's proposal on the mechanism of the benzoin condensation. zolium salt-catalysed benzoin reaction was reported by Ukai [2]. This may be regarded as an early example of organocatalysis using an azolium salt. Breslow postulated in 1958 a mechanistic rationale for the thiazolium salt-catalysed benzoin reaction [3]. He depicted the catalytically active species as a thiazolium zwitterion (the resonance structure of an NHC) and proposed that the reaction proceeds via an enaminol intermediate. The latter is now popularly known as 'Breslow intermediate'. This seminal discovery by Breslow paved the way for further developments in the area of carbene catalysis. Almost three decades later Bertrand and co-workers proved the existence of carbenes as catalytically active species in the benzoin reaction, with the synthesis of a stable phosphinocarbene [4]. Arduengo and co-workers isolated and characterised a stable NHC in 1991 [5]. These two reports on the isolation of NHCs implied that they are more stable and robust than previously considered. Subsequent years witnessed a renewal of interest in NHCs and a flurry of reports, mainly focusing on their catalytic activity, appeared in the literature [6,7].
The original mechanistic proposal by Breslow for the thiazolium salt-catalysed benzoin reaction can be delineated as follows (Scheme 1) [3]. Lapworth had suggested how the cyanide anion functions first as a nucleophile and then as a leaving group in cyanide-catalysed benzoin reactions [8]. Analogously, Breslow invoked the generation of a nucleophilic thiazolylidene species 1 via deprotonation of the thiazolium salt by base. The ylide 1 may also be represented as its resonance structure 1' (carbene). Nucleophilic addition of 1 to aromatic aldehyde generates the tetrahedral intermediate 2. The latter then undergoes a proton shift to furnish an enaminol derivative 3. The aldehyde carbonyl carbon has now transformed into a nucleophilic entity by virtue of conjugation to the nitrogen and sulfur lone pairs. This acyl anion equivalent 3 is known as the "Breslow intermediate". Its reaction with another molecule of aldehyde leads to the formation of an alkoxide intermediate 4.
Proton transfer and subsequent release of thiazolylidene 1 affords the final product, the α-hydroxy ketone 5. Breslow demonstrated that imidazolium-derived ylides also catalysed benzoin reactions. In most of the cases, the NHC-catalysed formation of benzoin from aldehydes is reversible in nature.
In the following sections, detailed discussions on various types of benzoin reactions catalysed by NHCs are presented. In general, thiazolium salt-derived NHCs have found widespread application as catalysts for benzoin reactions, whereas triazolium-derived NHCs have emerged as popular catalysts for enantioselective benzoin transformations.

Homo-benzoin reactions
The homo-benzoin condensation constitutes an overall catalytic dimerization of an aldehyde wherein the acyl anion derived from one molecule adds to another molecule of the aldehyde. (It may be noted that the term 'homo' implies the reaction between two molecules of the same aldehyde. It should not be misconstrued as a 'homologous' benzoin reaction). Benzoin reactions are reversible in basic medium and homo-benzoin products are often isolated as byproducts in other NHC-mediated reactions of aldehydes. The absence of chemoselectivity issues makes homo-benzoin reactions less challenging when compared to the cross-benzoin variant. NHC-mediated aerial oxidation of aldehydes to the corresponding carboxylic acids could compete with homo-benzoin reactions, but can be limited by careful exclusion of oxygen from the reaction mixture. A few recent reports of homo-benzoin reactions are discussed in the following passages.
Stetter's report in 1976 of thiazolium salt-catalysed benzoin reactions may be regarded as the first report of an NHC-catalysed benzoin reaction on a synthetically useful scale [9]. Much later, in 2005, Xu and Xia used N-alkyl-substituted imidazolium carbene 6 to efficiently promote benzoin reactions. Although a high catalyst loading (50 mol %) was required, the reactions could be run at mild conditions. It was observed that Scheme 4: Homobenzoin condensation catalysed by bis(benzimidazolium) salt 8. neutral and electron rich aromatic aldehydes afford good yields of benzoin products whereas electron deficient aromatic aldehydes and aliphatic aldehydes reacted sluggishly (Scheme 2) [10]. Scheme 2: Imidazolium carbene-catalysed homo-benzoin condensation.
The easily accessible NHC precatalyst 7 endowed with long aliphatic side chains was used by Iwamoto and co-workers for promoting benzoin reactions in aqueous medium. The improved reactivity was attributed to the formation of micelles from the hydrophobic alkyl chains of the catalyst in aqueous medium. The reaction proceeded well with various aromatic and heteroaromatic aldehydes (Scheme 3) [11]. Subsequently, the same group disclosed the application of bis(benzimidazolium) precursor 8 as a more efficient catalyst for the benzoin condensation in aqueous medium. Here, the NHC precatalyst incorporated a long aliphatic bridge between the two imidazolium entities. The aggregation of these units creates a hydrophobic environment in which the two aromatic aldehydes are subjected to catalysis (Scheme 4) [12].

Asymmetric homo-benzoin reactions
Much of the progress in the area of NHC-catalysed asymmetric benzoin reactions has been covered in two excellent reviews [6,7]. Some additional recent examples are discussed below.
A selected list of chiral NHC catalysts that have been explored for mediating asymmetric benzoin reactions is presented in Scheme 5. The bis-triazolium catalyst 9 developed by You promoted asymmetric benzoin reactions in 95% ee [13]. Enders developed the pyroglutamic acid-derived triazolium salt 10 which mediated benzoin reactions in similar enantioselectivities [14].
The pentafluorophenyltriazolium catalyst 15 featured in the most efficient asymmetric benzoin reaction reported so far. Inoue and co-workers found that it promotes homocoupling of benzaldehyde at a low loading (4 mol %) to afford benzoin in 90% yield and >99% ee (Scheme 6) [19].

Cross-benzoin reactions
A cross-benzoin reaction unites two different aldehydes wherein one of them functions as the acyl anion equivalent. A total of four products are possible; a pair of homo-benzoin and cross-benzoin adducts each. A substrate-driven selectivity may be observed when one of the aldehydes is significantly less reactive due to electronic or steric reasons. The latter effect may be amplified by employing bulky NHCs. In general, NHCmediated selective cross-benzoin reactions of electronically and sterically similar aldehydes remain as a highly challenging transformation.
In 1985, Inoue and co-workers reported the NHC-catalysed selective cross-benzoin reactions of aromatic and aliphatic aldehydes with formaldehyde leading to the formation of α-hydroxy ketones. Although an excellent selectivity was observed for the cross-benzoin product, the yields were low (Scheme 7) [20]. Later Kuhl and Glorius employed an NHC generated from the thiazolium salt 17 to synthesise α-hydroxyketones 18 in good yields. This highly selective cross-benzoin reaction has a very broad substrate scope (Scheme 8) [21].
Yang and co-workers developed an intermolecular cross coupling of aromatic aldehydes with acetaldehyde. The reaction showed an interesting divergence in reactivity controlled by the catalysts, viz., the thiazolium salt 19 and triazolium salt 20. The thiazolium-derived carbene preferentially mediated the formation of the Breslow intermediate from the aromatic aldehyde followed by coupling with acetaldehyde. In contrast, the triazolium-derived carbene prefered to activate acetaldehyde to generate the corresponding acyl anion equivalent followed by coupling with aromatic aldehydes (Scheme 9) [22]. It may be mentioned that Connon, Zeitler and co-workers have also reported the use of thiazolium and triazolium precatalysts for selective cross-benzoin reactions [23].
Glorius introduced a number of thiazolium NHC precatalysts endowed with sterically bulky aryl groups on the nitrogen with varying backbone substitution. These NHCs exhibited high levels of reactivity and selectivity in intermolecular crossbenzoin reactions to afford a library of unsymmetrically substituted benzoins [24]. The presence of an ortho-substituent on the electrophilic aromatic aldehyde (which presumably hinders the direct addition of NHC to these aldehydes) was necessary for the high levels of selectivity (Scheme 10).
The NHC-catalysed chemoselective intermolecular crossbenzoin condensation reaction of aromatic and aliphatic alde-hydes was reported by Yang and co-workers. The chemoselectivity was achieved by using a large excess of the aliphatic aldehyde (molar ratio of 1:15) [25]. Thus, directing groups on the aromatic aldehydes were not a prerequisite for high levels of selectivity in contrast to the earlier example. Consecutive catalytic reactions were utilized in order to reuse the excess of aliphatic aldehydes employed for achieving selectivity. Interestingly, the reaction could be repeated up to five times without affecting the yield of product and chemoselectivity (Scheme 11).
Morpholinone and piperidinone-derived triazolium precatalysts can catalyze highly chemoselectively the cross-benzoin reaction of aliphatic and aromatic aldehydes [26]. Smooth and selective benzoin reactions were observed with a wide variety of linear and branched aliphatic aldehydes as well as aromatic aldehydes (Scheme 12). Notably, the aliphatic aldehydes functioned as acyl anion equivalents leading to the formation of alkyl ketone (benzoin) products.

Asymmetric cross-benzoin reactions
The development of enantioselective cross-benzoin reactions is an arduous task as both chemoselectivity and stereoselectivity must be controlled by a single catalyst. Unsurprisingly, most of the NHC-catalysed, enantioselective cross-benzoin reactions employ a combination of two distinct carbonyl components to minimize chemoselectivity issues. A selected group of asymmetric cross-benzoin reactions are described in the following section.
An NHC-catalysed union of aryl aldehydes and aryl trifluoromethyl ketones was developed in the laboratory of Enders. This direct intermolecular cross-benzoin reaction proceeded with high yields and chemoselectivity [27]. The reaction furnished excellent yields of α-hydroxy-α-trifluoromethyl ketones 25 possessing a quaternary stereocentre. The homo-benzoin condensation between two aldehydes is reversible under the reaction conditions. This eventually leads to the selective formation of the observed cross-benzoin product. Later, it was found that trifluoromethyl ketimines 26 also function as electrophiles under similar reaction conditions [28]. Although initial attempts of asymmetric transformations were not successful, enantiose-lective cross-benzoin reactions of heteroaromatic aldehydes (acyl donors) and aryl trifluoromethyl ketones were later developed using the chiral catalyst 27 (Scheme 13) [29]. The electron-deficient triazolium-derived NHC 23 mediated efficient and chemoselective cross-benzoin reactions of aldehydes and α-ketoesters to produce acyloin products endowed with a quaternary stereocentre [30]. Remarkably, the competing hydroacylation reaction was not observed under these reaction conditions. A variety of aliphatic and aromatic aldehydes functioned as acyl donors, whereas several α-ketoesters could be employed as the electrophilic coupling partner to afford the desired products in moderate to good yields (Scheme 14). Interestingly, preliminary experiments to develop an enantioselective version of this reaction using a chiral NHC returned promising levels of enantioselectivity (76% ee). Subsequently, Gravel and co-workers reported a high yielding chemoselective and enantioselective intermolecular crossbenzoin reaction of aliphatic aldehydes and α-ketoesters. Notably, the reaction affords enantiomerically enriched tertiary alcohols. Excellent levels of enantioselection were obtained by using an electron-deficient valine-derived triazolium salt precatalyst 28 (Scheme 15) [31]. Moreover, diastereoselective reduction of the cross-benzoin products with NaBH 4 afforded valuable syn-diol products.
Goodman and Johnson disclosed a dynamic kinetic resolution of β-halo-α-ketoesters via NHC-catalysed asymmetric cross-benzoin reaction. Here, the cross-benzoin reaction of aromatic aldehydes with β-stereogenic-α-keto esters afforded fully substituted β-halo-α-glycolic acid derivatives in high diastereoselectivity and enantioselectivity [32]. The NHC generated from the amino indanol-derived chiral triazolium salt 29 provided the best results (Scheme 16). A variety of aromatic aldehydes and a series of β-halo α-ketoesters partake in the reaction to furnish the chiral glycolic acid derivatives.
The enantioselective benzoin reaction between a variety of aldehydes and alkynones is catalysed by the NHC generated from chiral aminoindanol-triazolium salt 29. The reactions afforded substituted propargylic alcohols in high yields and enantioselectivity (Scheme 17). It is noteworthy that the catalytically generated Breslow intermediates undergo selective 1,2-addition with ynones and the competing Stetter-type reactivity was not observed [33].

Aza-benzoin reactions
In aza-benzoin reactions, the acyl anions generated from aldehydes react with an aza electrophile. Imines possessing an elec-Scheme 18: Aza-benzoin reaction of aldehydes and acylimines. tron-withdrawing N-substituent constitute the most commonly used aza electrophile and the reaction affords an α-aminocarbonyl compound as the product. The NHC-mediated addition of aldehyde-derived acyl anions to nitroso compounds leading to the formation of hydroxamic acid derivatives are also discussed in this section for convenience.
Acylimines function as electrophiles in NHC-catalysed azabenzoin reaction with aldehydes. The reactive acylimine is generated in situ by the action of base on the sulfonylamide derivative 30 [34]. Meanwhile, the Breslow intermediate is produced from the aldehyde by the thiazolium 31-derived NHC. The union of these two reactive intermediates furnished α-amidoketones 32 in excellent yields (Scheme 18).
A diastereoselective [4 + 1] annulation of phthalaldehyde with imines leading to the formation of cis-2-amino3-hydroxyindanones is catalysed by NHC 31. The imine electrophile is generated in situ from α-sulfonyl-N-Boc amine 33 (Scheme 19). Initial cross-aza-benzoin reaction of one of the aldehyde functionalities with the imine is followed by an intramolecular aldol reaction to furnish the indanone framework [35].
The thiazolium precatalyst 31 can also efficiently mediate cross-aza-benzoin reactions of aromatic and heteroaromatic aldehydes with unactivated aromatic imines 34 (Scheme 20) [36]. A control reaction of the corresponding benzoin (instead of the aldehyde) and imine 34 also afforded the α-amino ketone product 35 in 71% yield. This indicates that the reaction involves reversible formation of aldehyde-homobenzoin adducts.
Enantioselective cross aza-benzoin reaction of aliphatic aldehydes with N-Boc-protected imines are promoted efficiently by NHC generated from the chiral triazolium salt 36. The aldehydes function as the acyl donor and the imines behave as the receptors (Scheme 21). Addition of NHC to the highly electrophilic N-Boc imines leads to the formation of corresponding aza-Breslow intermediates; however, it is reversible under the reaction conditions. Importantly, the chirally pure α-amino ketones formed in this reaction are valuable building blocks in organic synthesis [37].
The NHC generated from the bicyclic pentafluoro triazolium salt promoted the chemoselective cross aza-benzoin reaction of In 2005, Miller and co-workers used the chiral thiazolium salt 38 to catalyse an enantioselective cross-aza-benzoin reaction. Racemisation of the products under the reaction conditions caused erosion of enantioselectivity. This problem was successfully addressed by using a hindered base, pentamethyl piperidine, which was inert towards the products (Scheme 24) [40].
In 2013, Ye disclosed a remarkable NHC-catalysed enantioselective aza-benzoin reaction of enals and activated ketimines leading to the formation of functionalised α-aminoketones 39 in high enantioselectivity [41]. Notably, the homoenolate or enolate reactivity of the NHC-enal adduct was not observed in this case. The presence of a tertiary alcohol functionality and the steric bulk of the NHC-precatalyst 40 were essential for the selective formation of the aza-benzoin adduct. A variety of trifluoromethylated α-aminoketones could be synthesised in enantiomerically pure form using this method (Scheme 25).
Isatin derived ketimines 41 were employed as electrophiles in the NHC-catalysed chemo-and stereoselective cross-azabenzoin reaction with enals by Chi. The reaction afforded chiral quaternary aminooxindole derivatives. The NHC-enal adduct prefers to react via the acyl anion pathway and the competing homoenolate/enolate reactivity was not observed. The sterically non-congested, electron-deficient NHC-catalyst 42 presumably does not hinder bond formation at the catalyst-bound acyl carbon (Scheme 26) [42].
The aza-benzoin reaction of aldehydes and phosphinoylimines catalysed by the bis(amino)cyclopropenylidene (BAC) carbene 43 was reported recently. The reaction showed excellent selectivity for the aza-benzoin products over the homo-benzoin adducts. A wide variety of aldehydes react with phosphinoylimines (generated from their sulfinic acid adducts 44) to afford N-phosphinoyl amnioketones (Scheme 27) [43]. The attempted enantioselective version of this reaction using a chiral BAC catalyst was, however, unsuccessful.
As mentioned earlier, nitrosoarenes have been used as the electrophilic component in a few reactions of NHC-bound aldehydes. The addition of acyl anions occur at the nitrogen atom of the nitroso compound. A NHC-catalysed cascade reaction of o-vinylarylaldehydes with nitrosoarenes afforded function-alised 2,3-benzoxazin-4-ones 45 [44]. The initial intermolecular aza-benzoin reaction is followed by an intramolecular oxa-Michael reaction to form the observed product (Scheme 28).
Enders reported a cascade reaction which is initiated by an NHC-catalysed aza-benzoin condensation between various aldehydes and nitrosobenzenes to generate the hydroxamic acids 47. This is followed by a redox esterification of the latter (47) with enals. The overall process constitutes a one-pot synthesis of hydroxamic esters 48 [45]. Notably, both steps can be performed using the single NHC catalyst 22 under same reac-Scheme 29: One-pot synthesis of hydroxamic esters via aza-benzoin reaction.

Scheme 30: Cookson and Lane's report of intramolecular benzoin condensation.
Scheme 31: Intramolecular cross-benzoin condensation between aldehyde and ketone moieties. tion conditions (Scheme 29). This two-step, one-pot synthesis of formahydroxamic esters constitutes a valuable addition to a thin list of NHC-mediated three-component reactions.

Intramolecular benzoin reactions
One of the earliest reports of an intramolecular benzoin condensation appeared in 1976. Cookson and Lane found that the treatment of anhydrous glutaraldehyde with thiazolium salt 49 and triethylamine resulted in the formation of 2-hydroxycyclopentanone. The latter underwent oxidation to afford 2-hydroxycyclopent-2-en-1-one 50 upon treatment with Cu(OAc) 2 (Scheme 30) [46]. Hexanedial furnished the corresponding α-hydroxycyclohexanone under identical reaction conditions. An intramolecular cross-benzoin condensation between aldehyde and ketone moieties was developed by Suzuki in 2003. The isoxazole-fused cyclohexanone 51 endowed with an aryl aldehyde underwent a smooth cross-benzoin cyclisation in the presence of the thiazolium catalyst 19 and DBU. Although the presence of an isoxazole moiety is not a prerequisite for the success of this annulation, its rigid nature presumably renders the reaction highly stereoselective [47]. This simple and mild method allowed the construction of orthogonally protected polycyclic quinones from readily available starting materials. Later in 2006, they developed the enantioselective version of this reaction using an aminoindanol-derived triazolium salt 52 (Scheme 31) [48]. Another intramolecular crossed aldehyde-ketone benzoin reaction of simple dicarbonyl systems was developed by Enders (Scheme 32). This method employs commercially available thiazolium salt 19 as precatalyst and affords five-and six-membered cyclic acyloins in good yields [49]. The enantioselective NHC-catalysed crossed aldehyde-ketone benzoin reaction for the synthesis of five-and six-membered cyclic acyloins was also developed by Enders. NHC generated from the tetracyclic triazolium salt 53 gave the best results [50]. It is noteworthy that the absolute stereochemistry of the α-carbonyl quaternary center of benzo-fused carbocycles and chromanones is installed with excellent control (Scheme 33).
A combination of D-camphor-derived triazolium precatalyst 54 and DBU promoted enantioselective intramolecular crossbenzoin reaction of 55 to afford chromanone 56 in excellent yield and enantioselectivity (Scheme 34). The NHC-precatalyst is conveniently prepared from camphor in 5 steps [51].
The synthesis of bicyclic tertiary alcohols possessing two quaternary stereocentres at the bridgehead positions was Scheme 36: Synthesis of bicyclic tertiary alcohols by intramolecular benzoin reaction.
achieved via an asymmetric intramolecular crossed benzoin reaction. A relatively high loading (30 mol %) of the NHC precatalyst 59 was necessary for efficient reactions (Scheme 36) [53].
A multicatalytic Michael-benzoin cascade process for the asymmetric synthesis of functionalised cyclopentanones was disclosed in 2009 by Rovis. The chiral secondary amine 60 catalyzes the initial asymmetric Michael addition of an 1,3-diketone and an enal to afford a δ-ketoaldehyde 61. Subsequently, a cross-benzoin reaction of the latter promoted by the NHC precatalyst 22, installs the cyclopentenone system (Scheme 37). It may be noted that the absolute stereochemistry of the process is controlled by the prolinol catalyst 60 and the NHC precatalyst 22 is achiral. Control experiments revealed that the Michael addition is reversible but the NHC catalyst rapidly shuttles the intermediate δ-keto aldehyde 61 to the final product preventing the erosion of enantioselectivity [54]. This cascade reaction constitutes a fine example of symbiotic dual-catalysis wherein both catalysts perform better together in a one-pot reaction than they do independently over two steps.
A conceptually similar enamine-NHC dual-catalytic Michael-benzoin cascade was also developed by Rovis. The reaction proceeds via the generation of an enamine from the enolizable aldehyde 62 in presence of the prolinol catalyst 60 and its subsequent addition to the Michael acceptor 63. This is followed by NHC-mediated intramolecular cross-benzoin condensation to afford the cyclopentanone 64. Clear evidence for the co-operative relationship between the catalysts was obtained from control experiments. Chiral triazolium catalyst 65 preferentially converts only one of the diastereomeric Michael adducts into the benzoin product. The prolinol catalyst 60, on the other hand, mediates the epimerisation of the less reactive diastereomer. This synergy leads to the enrichment of the diastereomeric ratio of the final product 64 (Scheme 38) [55].
Enders developed a closely related iminium-cross-benzoin cascade process involving enals and β-oxo sulfones to generate enantioenriched cyclopentanone derivatives with three contiguous stereocentres. A dual secondary amine/NHC catalytic system comprising of the prolinol 60 and NHC precatalyst 22 was found to give the best results (Scheme 39) [56]. The influence of these catalysts on the diastereoselectivity of the reaction was also studied using NMR techniques.
An NHC-catalysed intramolecular benzoin condensation of carbohydrate-derived dialdehydes has been applied for the construction of carbocyclic sugars. Diastereoselective benzoin reactions of manno-and galacto-configured dialdehydes 66 were promoted by the triazolium carbene precatalyst 22 to produce single inosose stereoisomers 67 in high yields (Scheme 40) [57]. Stereospecific reduction and deprotection of the inosose derivatives furnished alloand epi-inositol in good yields.
The camphor-derived triazolium precatalyst 54 promoted enantioselective intramolecular benzoin reactions of N-tethered ketoaldehydes effectively. The substrates for the cyclisation are easily accessible and dihydroquinolinone systems possessing a quaternary stereocentre are produced in high yields and enantioselectivities (Scheme 41) [58].
Further investigations in Cheng's group revealed an intriguing divergent catalytic dimerisation of 2-formylcinnamates 72.  A one-pot multicatalytic reaction for the asymmetric synthesis of complex tetracyclic tetrahydrocarbazole derivatives from readily available precursors was described by Melchiorre. A Diels-Alder reaction of indole-2,3-quinodimethane 76 (generated from 77 and the prolinol catalyst 78 ) with the enone 79 affords a tetrahydrocarbazole derivative 80. The NHC precatalyst 22 then promotes an intramolecular cross-benzoin conden-sation of the keto-aldehyde to furnish the tetracyclic product 81 (Scheme 45). The yields are moderate; however excellent diastereo-and enantioselectivities were observed for the onepot reaction [62].
In a similar fashion, an asymmetric multicatalytic cascade reaction involving the dienal 82 and unsaturated cyclic sulfonylimine 83 afforded spiro-fused cycloadducts 84 in good yield and enantioselectivity [63]. Initially, the trienamine 85 is generated by the action of prolinol catalyst 86 on the dienal 82. The former (85) then undergoes a Diels-Alder reaction with the sulfonylimine 83 to generate the keto-aldehyde 87. Finally, the NHC precatalyst 22 mediates a cross-benzoin reaction of the latter to furnish the spirocyclic product 84 (Scheme 46).
Scheme 46: NHC-chiral secondary amine co-catalysis for the synthesis of complex spirocyclic scaffolds.

Conclusion
The first report of a benzoin reaction by Wöhler and Liebig appeared merely four years after the former disclosed the paradigm-changing urea synthesis. However, detailed investigations of this reaction remained elusive due to a variety of reasons, the toxicity of cyanide catalysts being one of them. Breslow's discovery in 1958 of the thiazolylidene-catalysed benzoin condensation via polarity reversal of aldehydes formed the conceptual basis for the later development of NHCorganocatalysis. The rekindling of interest in NHC-catalysed benzoin reactions coincided with the emergence of N-heterocyclic carbenes in the late twentieth century as non-toxic, readily available and versatile catalysts for a variety of organic transformations. Since then, a number of reports on a variety of benzoin reactions have appeared in the literature. They include homo, crossed, intramolecular and various asymmetric benzoin reactions leading to products that are difficult to access by other means. Aza-benzoin reactions, intramolecular benzoin condensations, use of aldehyde surrogates and use of non-carbonyl electrophiles (nitroso compounds) are some of the developments that revamped the synthetically unattractive, monotonous image of benzoin condensations. The driving force behind this remarkable evolution of benzoin reaction is NHC-catalysis. Benzoin chemistry is well-set to benefit, in the near future, from new developments in the rapidly growing realm of NHC-catalysis.