Azolium enolate

Azolium enolates such as 65 can be generated directly through addition of NHCs to symmetrical or unsymmetrical ketenes. For example, Smith and co-workers have shown that NHC promoted p-lactam formation from isobutylphenylketene 61 and AT-tosyl imines 63 proceeds with good yields and moderate levels of diastereoselec-tivity via enolate 65 (Scheme 12.12) [17]. 

Ye and co-workers have shown that NHC 67 can catalyse the aza-Morita-Bay-lis-Hillman reaction of enones 66 and N-tosyl imines 63, presumably via initial NHC conjugate addition to the enone to generate an azolium enolate 68 [18]. A related conjugate addition approach has been exploited by Fu and co-workers, with tautomerisation of the initial enolate 72 derived from NHC conjugate addition to 70 giving 73, with subsequent cyclisation resulting in the umpolung of Michael acceptors (Scheme 12.13) [19]. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

N-t-butyl derivatives (e.g., 58) can give satisfactory results but are prone to a number of side reactions, including that just mentioned.173-175 Diacyl-amides (63) may arise as by-products from the ketoketenimine via an imino-anhydride (as shown in Scheme 11) rather than from the enol ester.176 Tetrahydrobenzisoxazolium ions (59) and related compounds are promising as far as freedom from rearrangement and lack of promotion of racemiza-tion are concerned, but they do not appear to have been evaluated in actual peptide syntheses.171 Although beyond the scope of this review, benzisox-azolium salts have also been applied as reagents for peptide synthesis.177,178... 

The Scheidt group reported a highly diastereo- and enantioselective NHC-catalyzed reaction of a,p-unsaturated aldehydes with nitrones to afford y-amino esters. It is postulated that a rare six-membered heterocycle is generated as the initial product of the reaction, which gives the final y-amino ester product upon the addition of an alcohol. The mechanism for this reaction involves the addition of the homoenolate equivalent to the nitrone as the stereochemical-determining step, and catalyst turnover is promoted by an intramolecular acylation after the tautomerization of enol to acyl azolium (Scheme 7.60). 

This section will focus on the generation and utility of azolium enolates using NHC (N-heterocyclic carbene) catalysts. Azolium enolates are commonly accessed from enals, a-functionalized aldehydes, or aliphatic aldehydes in the presence of a stoichiometric oxidant. This section exclusively concentrates on strategies for the generation of azolium enolate intermediates from alternative, bench-stable starting materials (Scheme 7.66). 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

Most recently, the Wang group and the Sun group described simultaneously the first NHC-catalyzed oxidative asymmetric a-fluorination of simple aliphatic aldehydes. NFSI serves both as an oxidant and as an F source. Under the optimized conditions, the desired a-fluorinated esters were obtained in up to 92% yield and 98% ee, while no competitive difluorination or nonfluorination occurred. A postulated mechanism of this reaction process is depicted via an NHC-bound enolate intermediate which behaves as a nucleophile to interact with the second NFSI to eventually form the a-flu-oro ester product. Furthermore, acyl fluoride was employed as the starting material under the optimized conditions. Pleasingly, with NFSI (only 1.1 equiv.), the expected a-fluoro ester was obtained in 90% yield and 96% ee, which supported the formation of an NHC-bound acyl azolium intermediate (Scheme 7.94). 

The Bode group documented detailed research on the asymmetric NHC-catalyzed annulation reaction of ynals and stable enols (kojic acid) to afford enantioenriched dihydropyranone products in excellent yields. Mechanistically, the key a,p-unsaturated acyl azolium intermediate was accessible via an NHC-catalyzed redox neutral reaction of ynals. The annulation occurs via... 

The Bode group disclosed NHC-catalyzed highly enantioselective annulations of a,P,P -trisubstituted enals with cyclic sulfonylimines. Mechanistically, it is proposed that the combination of enal and free NHC leads to the formation of the Breslow intermediate, which is oxidized to form the key a,p-unsaturated acyl azolium. Tautomerization between the imine and the enamine occurs readily in the presence of base, and the enamine is intercepted by the key a,p-unsaturated acyl azolium to form a hemiaminal which further engages in a Stork-Hickmott-Stille-type annulation via a tight-ion-pair/aza-Claisen type transition state. Lactam formation follows the protonation of enolate and brings about catalyst turnover to complete the catalytic cycle (Scheme 7.113). 

The method involves a new way to generate enolate intermediates 148 by oxidation of the generated Breslow intermediate 146 to give aycl azolium 147, followed by deprotonation (Scheme 20.62). 

The catalytic cycle is initialed by the addition of NHC to the ketene to generate azolium enolate I, which, after oxidation with oxaziridine 179, furnishes intermediate II and imine 181. Reaction between intermediate II and newly formed imine 181 generates zwitterionic compound III that collapses to yield the final product 180 and regenerate the NHC catalyst C9 (Scheme 20.76). 

Finally, a method to generate enantioenriched a-fluoro carboxylic acids using N-heterocyclic carbene catalysts was reported by Rovis (Scheme 13.12) [28]. Starting from achiral a-fluoroenals, initial attack of the carbene to the aldehyde and subsequent tautomerization generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by water produced enantiopure a-fluoro carboxylic acids. Thus, in contrast to the other methods... 

An alternative method for the formation of enantioenriched a-chloroesters, using A-heterocyclic carbene catalysts, was reported by Reynolds and Rovis (Scheme 13.14) [34]. In a similar mechanism to that presented in Scheme 13.12, initial attack of the carbene to the aldehyde and loss of HCl generated a chiral enolate. Asymmetric protonation of this enolate followed by displacement of the azolium species by a phenol produced enantiopure a-chloroesters. In contrast to the approach to chiral a-chloroesters presented in Scheme 13.13, a variety of aryl esters can be incorporated into the product by using different aryl alcohols (ArOH). Additionally, a carbon-chlorine bond is not formed in this reaction. Rather the introduction of a stereocenter in the chlorinated products is achieved via asymmetric protonation. This method was elaborated to use water as the proton/alcohol source to produce chiral a-chloro carboxylic acids (i.e., as in Scheme 13.12) [28]. Moreover, the use of D2O generated chiral a-chloro-a-deutero carboxylic acids. 

Phenylmethylketene reacts with the N-heterocychc carbene 137 with preferential attack on the least hindered side of the ketene forming the isolable azolium enolate 139, with the structure proved by X-ray... 

The kinetics of the reactions of the azolium enolate 139 and other examples obtained similarly with other ketenes and oleates have been determined, and correlated with the electrophihcities of a group of benzhydrihum ions At2CH" by Eqn (4.86). The reactions in some cases gave biexponential kinetics with competing processes for O and C attack on the oleates, and separate rate constants for the two processes were determined, as well as nucleophihcity parameters N for attack at carbon or oxygen of the oleates. 

NHC-catalysed umpolung reactions of both simple and a, -unsaturated aldehydes have been studied by NMR spectroscopy and X-ray diffraction key intermediates characterized include diamino enols, diamino dienols, azolium enolates, and the first report of an azolimn enol (92). Interconversion of these species has been followed by NMR kinetics, with mechanistic characterization further supported by DPT calculations. 

A series of azolium enolates (99 Ar = phenyl, mesityl) have been synthesized and characterized. Their ambident reactivities have been measured by studying their reactions with benzhydryl cations, Ar2CH , in r/ -acetonitrile, using known electrophilicity parameters for the latter. NMR shows predominantly 0-attack initially, with a switch to C-product over 1-2 days, with second-order rate constants for the two processes calculable. The azolium enolate reactivities have been compared with those of the corresponding free carbenes, and deoxy-Breslow intermediates. 

These benzhydrilium carbocations were also used to develop a comprehensive scale of hydride donor strength. Both Si-H and C-H donors were evaluated by their second-order rate constants of hydride transfers to the carbocation electrophiles. The respective nucleophilicity parameter, N and %, were then determined. The benzhydryl cation series was also used to evaluate the nucleophilic reactivities of azolium enolates (1). ... 

An innovative stereoselective synthesis of A-acylhydrazones via an unprecedented A-heterocyclic carbene-catalysed addition of aldehydes to diazo compounds has been presented. Enals exclusively afforded A-acylhydrazones, in yields up to 91% (Scheme 13). The observed regioselectivity was traced back to the reaction of the viny-logous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge. 

In order to separate structural effects from the electronic differences of these two catalyst classes. Bode synthesized chiral imidazolium salt 57 (Scheme 14.28). This allowed direct comparison of imidazolium versus triazolium precatalysts across a number of different reaction manifolds including those involving the catalytic generation of homoenolate equivalents, ester enolate equivalents, and acyl anions. These studies conclusively demonstrated that imidazolium-derived catalysts are superior for homoenolate reactions with less reactive electrophiles, while the triazolium-derived pre-catalysts are preferred for all other reactions. Interestingly, from the currently published body of the work, it does not appear to be any effects from the counterion of the azolium pre-catalysts in the presence of bases. 

Dou as J, ChurchiU G, Smith AD. NHCs in asymmetric organocatalysis recent advances in azolium enolate generation and reactivity. Synthesis. 2012 44 2295-2309. 

In the absence of a suitable nucleophile, the homoenolate-derived acyl azolium intermediate can undergo deprotonation to generate a nucleophilic azolium enolate. Bode and coworkers showed such enolates to be competent dienophiles in hetero-Diels-Alder reactions with N-sulfonyl azadiene partners, providing dihy-dropyridinone products in very high diastereo- and enantioselectivity [106]. This work was quickly followed up by an analogous hetero-Diels-Alder reaction with oxodienes 130 (Scheme 18.25) [107]. In this case, the enolate intermediates (132)... 

The NHC-generated azolium enolate can also react in a Mannich [lid], Michael [108], or aldol fashion [86], such as in the desymmetrization of 1,3-diketones to access enantiomerically-enriched cyclopentenes following decarboxylation of the P-lactone product [109]. Scheldt and coworkers took advantage of this reaction in the total synthesis of bakkenolides 1, J, and S (Scheme 18.26) [110]. 

N-heterocyclic carbene catalysis has become one of the major categories in orga-nocatalysis. Azolium salts are ready deprotonated by weak bases to generate a carbene, which then adds to an aldehyde to form an acyl anion equivalent, generally called the Breslow intermediate. The reactive acyl anion attacks an electrophile to promote the various transformations such as benzoin, Stetter, and redox reactions [107]. Recently, an interesting approach for NHC-catalyzed generation of an enol/enolate intermediate was reported. Enantio-enriched (i-amino acid derivatives (217) are formed by the reaction between the a-aryloxyaldehyde 214 and N-tosyl-imines (215) in the presence of phenyalanine-derived azoUum salt 216 as a pre-catalyst and aryl phenoxide as a base (Scheme 28.28) [108]. 

The reaction is initiated by the addition of NHC 218 to an a-aryloxyaldehyde 214. A phenoxide anion is eliminated to generate an enol/enolate (220). Asymmetric Mannich-type reactions between 220 and 215 furnish acyl azolium 221, and the desired product 217 is assembled through an acyl transfer reaction (Scheme 28.29). 

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