Disubstituted ketenes

In an alternative mode of catalyst action, a disubstituted ketene 66 initially suffers a nucleophilic attack of 64, leading to zwitterionic enolate 71 (Fig. 38). 

Making use of the same reaction principle, disubstituted ketenes 66 have been reacted with aldehydes 80 to form p-lactones 81 [100], with diazo-compounds 82 to form 1,2-diazetidin-3-ones 83 [101] and with nitroso-compounds 84 to form 1,2-oxazetidin-3-ones 85 as precursors of a-hydroxy carboxylic acids (Fig. 42) [102],... 

Wilson JE, Fu GC (2004) Asymmetric synthesis of highly substituted P-lactones by nucleophile-catalyzed [2 -t 2] cycloadditions of disubstituted ketenes with aldehydes. Angew Chem Int Ed 43 6358-6360... 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

Ketene dimerization is the principal synthetic route to 4-methylene-2-oxetanones. This reaction proceeds very satisfactorily for ketene and methylketene, but disubstituted ketenes dimerize only to cyclobutane-1,3-diones. The cycloaddition reaction of r-butylcyanoketene to ketene and to methylketene gives a-cyanoalkylidene-/3-lactones in about 40% yield in addition to the cyclobutane-1,3-dione dimer of f-butylcyanoketene. A mechanism has been proposed for the formation of both types of dimers from a common zwitterionic intermediate (equation 111), with the relative amount of each product determined by the configurational equilibrium of the intermediate (80JOC4483, 75JOC3417). 

Planar-chiral derivatives of 4-(pyrrolidino)pyridine (PPY) have been reported as efficient catalysts for enantioselective Staudinger reactions [75]. These chiral derivatives catalyzed the reactions between a range of symmetrical and unsymmet-rical disubstituted ketenes and a wide imine array leading to (3-lactams with good stereoselections and yields. 

Figure 4 shows the main geometric features of the transition structures associated with the [n4c] and [n6d] steps in the reaction between ketene and prop-2-en-l-imine. Experimental and computational studies [42, 43] showed that the periselectivity of this reaction is very sensitive to substituent effects. Thus, in general disubstituted ketenes and/or imines possessing bulky substituents at the (3-position favor the formation of [2+2] cycloadducts because of severe steric... 

Disubstituted ketene acetals 263 have been prepared in a similar way (Scheme 80) <2001TL3183>. 

The cumulated double bonds of ketenes, isocyanates, and carbon suboxide are also very reactive. Disubstituted ketenes yield enolate ions (equation 38), which may be protonated to ketones or used in situ. The very high reactivity... 

Deoxygenation of a-diketones can be effected by triethyl phosphite to furnish acetylenes and triethyl phosphate (equation 103). Either one equivalent of the a-diketone is treated with 2 equivalents of trielhyl phosphite at 215 °C to furnish diaryl- or alkylarylacetylenes in 24-60% yields, or the 1 1 adducts 33 of the a-diketones and (EtO)3P are treated with excess reagent at 215 °C to afford the above acetylenes in 54-81% yields . The reaction apparently involves a disubstituted ketene, since diphenylketene gives with (EtO)3P a 1 1 adduct which on pyrolysis furnishes diphenylacetylcne in 40% yield (equation 103) . Several diacetylenes of types 34 and 35 have been prepared in this manner . ... 

Mono-and disubstituted ketenes react with N-imidoyl phosphoranimines (19) to give pyrimidinone (20) and quinazoline (21) derivatives ... 

An unprecedented cyclopropanation reaction was observed during the reaction of ketene alkylsilyl acetals (191) with bromoform-diethylzinc. When monosubstituted acetals were used, cyclopropanecarboxylic esters (195) were formed by a novel C-H insertion. When disubstituted ketene acetals were used, byproducts such as a,)5-ethylenic esters (197) were also formed presumably via 196 (equation 49). This reaction provides a convenient method for the preparation of the bicyclo[3.1.0] hexane system and can be advantageously compared to the copper-catalysed intramolecular cyclization of unsaturated a-diazoketones . 

Reaction of silyl ketene acetals with aryldiazonium salts produces a-keto ester hydrazones196197 by rearrangement of the initially formed azo compounds (Eq. 121). The latter are obtained with disubstituted ketene acetals.197... 

Mixtures of cyclobutanones are formed from unsymmetrical disubstituted ketenes. The extent of stereoselectivity depends on the size difference of the substituents. The larger substituent on the ketene ends up in the more hindered position in the major product9,12a. Z-Alkenes are also more reactive than A-alkcnes in these cycloadditions as a consequence of the transition state10 2. 

We have met ketenes (1) already as intermediates in the Arndt-Eistert procedure (Chapter 31) for chain elongation. They are highly electrophilic at the curious sp carbon atom ( in 1). Nucleophiles give acyl derivatives (3) via enolate (2). Ketenes are unstable and eannot be stored. In the absence of nucleophiles they dimerise ketene itself gives ester (4) (which is available commercially) and disubstituted ketenes give cyclobutadiones (5). Mono-substituted ketenes may give either type of product. 

The situation is more involved with unsymmetrically disubstituted ketenes, like alkyl-halogenoketenes . 

Enantiomerically pure boron-based Lewis acids have also been used successfully in catalytic aldol reactions. Corey s catalyst (7.10a) provides good enantioselectivity with ketone-derived silyl enol ethers, including compound (7.11). Other oxazaborolidine complexes (7.13) derived from a,a-disubstituted a-amino acids give particularly high enantioselectivity, especially with the disubstituted ketene... 

Cydopentadiene gives adducts with unsymmetrical disubstituted ketenes in which the larger ketene substituent occupies an endo position. Offer an explanation for this stereochemistry. 

ExceUent yields, diastereo- and enantioselectivities are achieved in the synthesis of 3,4-dihydro-2J/-pyran-2-ones through asymmetric cycloaddition reactions of disubstituted ketenes with p,y-unsaturated a-keto esters carried out in the presence of a chiral Lewis acid (Scheme 44) (140L134). 

In 2008, Ye and coworkers reported that chiral NHCs prepared from l-pyroglutamic acid were efficient catalysts for the enantioselective Staudinger reaction of ketenes with imines. The corresponding c/s-p-lactams 158 were obtained in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee) (Scheme 20.66). In the same year. Smith and coworkers independently reported the NHC-catalysed [2 + 2] cycloaddition of disubstituted ketenes and N-tosylimines. ... 

The [4 + 2] cycloaddition reactions of ketenes are efficient approaches to six-membered heterocycles. In 2008, Ye and coworkers reported a NHC-catalysed [4 + 2] cycloaddition reaction of disubstituted ketenes with enones to give the corresponding -lactones 183 in good yield and with good diastereoselectivity and high enantioselectivity. The frans-isomers were... 

Rate constants for reactions of a group of ketenes with n-BuNH2 differ over a range of 5 X 10, consistent with the steric and electronic characteristics of the ketenes (Table 4.7). Thus monosubstituted ketenes with conjugating substituents are more reactive, while disubstituted ketenes are less reactive, as are monosubstituted ketenes with non-conjugating substituents. 

The use of iV-trialkylsilylimines can be advantageous, since the protecting A -substituent can easily be cleaved from the f amino acid esters produced. The reaction of mono- or disubstituted ketene silyl acetals with A -trimethylsilyl-benzylideneamine in the presence of 10 mol% of 1 gives the corresponding P-amino acid esters in good yield (eq 3) (5). p-Lactams have also been synthesized in moderate yield by in situ treatment of the intermediate with MeMgBr(eq 3) (J). 

Ketene-0,0-, N,N-, N,0-, N,S- and 5,5-acetals react readily with alkyl, aryl and especially arenesulfonyl isocyanates to give 1 1 adducts. The structure of the adducts depends on the degree of substitution on the jS-carbon atom. The /3-disubstituted ketene acetals give [2+2] cycloadducts In the reaction of phenyl isocyanate with ketene diethylacetal, a six-membered ring 2 1 cycloadduct is obtained and mixtures of the [2+2] and the [2+2+2] are obtained from substituted keten 0,0-acetals Heterocyclic e-caprolactim ethers 92, which are in equilibrium with ketene OW-acetals, react with aryl isocyanates at room temperature to give [2+2] cycloadducts 93 and at 150 °C to produce [2+2+2] cycloadducts 94. ... 

Ketenes 2 are generally synthesized by dehydrochlorination of carboxylic acid chlorides 1, which is best conducted using ahydrogen chloride scavenger, such as triethylamine. Mono substituted ketenes (RCH=C=0) are less stable than disubstituted ketenes (R2C=0=0). 

Disubstituted ketenes usually form the symmetric dimers. However, Staudinger and Klever also obtained a small amount of the j8-lactone dimers. This dimer is the only reaction product if the dimerization of dimethylketene is conducted in the presence of aluminum chloride as the catalyst Diphenylketene produces the -lactone dimer on addition of a catalytic amount of sodium methoxide . 

The symmetrical trimers of disubstituted ketenes are obtained by heating the corresponding dimers with a catalytic amount of base. For example, heating of the symmetrical dimer of dimethylketene 77 with sodium methoxide at 100 °C affords a 97 % yield of the trimer 78 . In a similar manner, 78 is obtained from the unsymmetrical dimethylketene dimer 79 in high yield. The symmetrical trimer of diphenylketene was similarly obtained... 

Likewise, chiral Af-heterocyclic carbenes are efficient catalysts for the enantioselective [2+2] cycloaddition reaction of disubstituted ketenes with oxoaldehydes, and yields of up to 99 % are achieved with enantioselectivities of up to 99 %... 

Even disubstituted ketenes undergo the cycloaddition reaction with aldehydes in the presence of planar chiral catalysts at —78 °C in THE to give the [2+2] cycloadducts 226 in high yields and good stereoselectivity . ... 

The ketenimine 42 is generated in situ in an aza-Wittig reaction of an iminophosphorane with a disubstituted ketene. 

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