Azolium enol intermediate

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). 

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]. 

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 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). 

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. 

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)... 

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]. 

A mechanistic rationale for this process, which is common for many NHC-catalyzed formal [2+2] cycloadditions, is shown in Figure 3.11. Initial attack of NHC 167 on the ketene a-carbon, anti to the aryl unit [18], gives rise to the (Z)-azolium enolate 168 that attacks the isocyanate 165 giving the zwitterionic intermediate 169. Collapse of this species generates thioxo-p-lactam 166 with concurrent catalyst regeneration (Figure 3.11). 

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). 

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. 

Building on the formal redox esterification of ynals discovered by Zeitler [104], the group of Bode showed that the unsaturated acyl azolium intermediate could be trapped by enols to yield dihydropyranones 128 enantioselectively (Scheme 18.24) [11a]. Mechanistically, the enol 127 could perform a 1,4-addition on the acyl azolium followed by a lactonization. Instead, the authors postulate a 1,2-addition/ Coates-Claisen rearrangement pathway that is supported by kinetic and computational studies [105]. Another notable finding was a strong counterion dependence on the reaction rate in the absence of added base. The data presented is consistent with the chloride ion in 74 effectively playing the role of base to deprotonate the triazoUum cation. 

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