Enolates from ketenes

The formation of enolates from ketenes generates tetrasubstituted enolates regio- and stereo-selecdve-ly.s8-ei Deprotonation of the corresponding ketones gives mixtures of enolates. Ketenes are produced... 

Scheme 14.22 Catalytic generation and reactions of NHC-enolates from ketenes (HMDS = hexamethyldisilazide TBDMS = t-butyldimethylsilyl).

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Monobactams have been investigated as p-lactamase inhibitors <98CHE1308, 98CHE1319>. The ketene-imine route to P-lactams was used to obtain 1,3,4-trisubstituted derivatives with high trans selectivity. The enolate from 4-hydroxy-y-lactone reacted with the imine (Ar CH NAr ) to give 59, vdiich cyclized in the presence of lithium chloride at low temperature to yield 60. The compounds were assayed for cholesterol absorption inhibition and 61 (R = = OH, R = F) was found to be a potent inhibitor of 3-hydroxy-3-... 

Michael reactions of silyl enolates or ketene silyl acetals with a, -unsaturated carbonyl compounds are among the most important carbon-carbon bond-forming processes in organic synthesis. Sc(OTf)3 was found to be effective [4], and the reactions proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, under extremely mild conditions, to give the corresponding 1,5-dicarbonyl compounds in high yields after acid work-up (Eq. 2). Silyl enolates derived from ketones, thioesters, and esters were applicable, and no 1,2-addition products were obtained. The products could, furthermore, be isolated as synthetically valuable silyl enol ethers (I) when acid-free work-up was performed. The catalyst could be recovered almost quantitatively and could be re-used. 

C-aryl glycosides, 528 C-glycosides, 528 C-glycoside synthesis, 505 fronj enol ethers, 505 by free-radical methods, 507 from ketene acetals, 505 from malonate anion, 505 from 2-pyridylthio glycosides, 385... 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

A catalytic enantio.se/ective protonation with remarkable high efficiency is observed employing enolate 12-Li (prepared from ketene 8 and butyllithium) together with 0.5 equivalents of 9-H and 0.5 equivalents of several achiral acids190. 

Reaction of lithium enolates from primary alkyl esters with chloro-trimethylsilane occurs under mild conditions and affords the water-sensitive ketene-acetals RCH=C(OR )(OSiMe3). f-Butyl esters yield comparable amounts of the O and C-silylated derivatives [5],... 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

The same class of [2 - - 2] cycloaddition reactions between ketenes and aldehydes has been the subject of subsequent studies, which have enlarged its scope to different substrates. Thus, key contributions by Lectka and coworkers have demonstrated the applicability of zwitterionic enolates from... 

Catalytic and highly enantioselective fluorination of acyl chlorides was reported by Lectka et al. where O-benzoyl quinidine (O-Bz-QD), is combined with a transition metal-based cocatalyst, (l,3-dppp)NiCl2 or trans-(PPh3)2PdCl2, to generate chiral ketene enolates from acyl chlorides, which are fluorinated with NFSI to produce ot-fluorinated carboxylic acid derivatives. These derivatives are then in situ reacted with different nucleophiles such as methanol, water or variety of amines affording a-fluoro esters, acids... 

A key aspect of the stereochemistry of the rearrangement results from the stereochemistry of the silyl ketene acetal. The silyl ketene acetals are designated as Z- when the higher priority substituent at Cl is cis to the OSiRj group and E-when it is trans (Scheme 4.4). For simplicity, the geometries of the corresponding enolates and ketene acetals other than silyl will designated as Z-(0)-M- or -(0)-M-, where M = metal, etc. 

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