Ketenes from acid chlorides

Many examples of the usual route to /S-lactams via imines and acid chlorides, ketens, or keten equivalents have appeared.These include syntheses of 3-[bis(alkylthio)methylenamino]-2-azetidinones, ° of spiro-azetidinones and bis-azetidinones, and the use of l-methyl-2-halogenopyridinium salts to activate carboxylic acids towards coupling with imines. A non-hazardous alternative route to 3-amido-2-azetidinones, avoiding the use of azidoacetyl chloride, involves the reaction of Schiff bases with salts of [(a-methyl-/3-methoxycar-bonyl)vinylamino]acetic acid, e.g. (20), in the presence of ethyl chloroformate, as shown in Scheme 5. Formaldimines can be generated from their trimers by treatment with Lewis acids immediately prior to reaction with acid chlorides, so allowing the formation of the nocardicin nucleus which is unsubstituted at C-4. ... 

Thioketenes can be prepared in several ways, from carboxyHc acid chlorides by thionation with phosphoms pentasulfide [1314-80-3] 2 5 ketene dithioacetals by -elimination, from l,2,3-thiadia2oles with flash pyrolysis, and from alkynyl sulfides (thioacetylenes). The dimeri2ation of thioketenes to 2,4-bis(alkyHdene)-l,3-dithietane compounds occurs quickly. They can be cleaved back pyrolyticaHy (63). For a review see Reference 18. 

Such copolymers of oxygen have been prepared from styrene, a-methylstyrene, indene, ketenes, butadiene, isoprene, l,l-diphen5iethylene, methyl methacrjiate, methyl acrylate, acrylonitrile, and vinyl chloride (44,66,109). 1,3-Dienes, such as butadiene, yield randomly distributed 1,2- and 1,4-copolymers. Oxygen pressure and olefin stmcture are important factors in these reactions for example, other products, eg, carbonyl compounds, epoxides, etc, can form at low oxygen pressures. Polymers possessing dialkyl peroxide moieties in the polymer backbone have also been prepared by base-catalyzed condensations of di(hydroxy-/ f2 -alkyl) peroxides with dibasic acid chlorides or bis(chloroformates) (110). 

The first /3 -lactam was produced by addition of a ketene to an imine and there are now many examples of this type of approach. The ketenes are most frequently generated in situ from acid chlorides by dehydrohalogenation, but have also been produced from diazo ketones, by heating of alkoxyacetylenes and in the case of certain cyanoketenes by thermolysis of the cyclic precursors (162) and (163). 

The submitters have shown that these reactions proceed by dehydro-chlorination of the acid chloride to the ketene, which is then trapped by reaction with the phosphorane. The resulting betaine decomposes to the allenic ester via an oxaphosphetane. In contrast, the reaction of acid chlorides with 2 equivalents of phosphoranes involves initial acylation of the phosphorane followed by proton elimination from the phosphonium salt. ... 

The intermediacy of ketenes in some enamine acylation reactions using acid chlorides was described above (386,387). Direct addition of ketene to enamines was studied simultaneously by several groups (414-420). The initially formed aminocyclobutanone products could be isolated in some instances, depending on the substitution of the initial enamine. Opening to give either the acylated enamine or the alternative vinylogous amide was found to occur spontaneously or on heating, particularly in adducts derived from enamines with an olefinic proton. 

The reaction of ketenes (usually formed from treatment of acid chlorides with tertiary amines) with imines is a classic way to form /J-lactams [17,18]. Although widely used, it suffers limitations in scope and efficiency, since free ketenes are... 

Amides prepared from carboxylic acids and primary amines using azolides obtained from acid chloride/imidazolea) or ketene/imidazole systems.b)... 

This Asian species is a major agricultural pest. The pheromone has been proposed to consist of three male-specific compounds, only one of which, (Z)-exo-a-bergamotenal 150, has been reported in the literature [114]. The racemic compound was synthesized starting from farnesoic acid chloride 146 (Scheme 25) [114]. Thus, the vinyl ketene prepared from acid chloride 146 underwent 2+2 cycloaddition to give bicyclic ketone 147. The ketone function was removed by reaction with hydrazine followed by treatment of the resulting hy-... 

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) ... 

The beta lactam moiety is formed by the 2-1-2 cycloaddition of a ketene with an imine. Thus reaction of the acid chloride (37-7) with the benzylimine from 3-fiirylacrolein (38-2) in the presence of triethylamine goes directly to the azetidone (38-3),... 

Thomas Lectka of Johns Hopkins University has reported (J. Org. Chem. 68 5819,2003) that benzoylquinine (BQ) catalyzes the two-carbon homologation of a ketene, derived from the acid chloride, with chloroamide such 7, to give the (3-amino acid derivative 8 with control of both relative and absolute configuration. The authors suggest that the BQ is involved five times in the course of the transformation of 6 into 8. The two esters of the product are differentiated, so one can imagine, inter alia, reduction of... 

Enantioselective halogenation is a powerful transformation, directly installing an efficient leaving group. Thomas Leckta of Johns Hopkins University has shown (7. Am. Chem. Soc. 2004,126, 4245) that benzoylquinine 11 catalyzes the a-chlorination of ketenes derived from acid chlorides such as 10, to give 12 in high . 

The procedure described here offers a general route to a variety of unsymmetrically substituted y-pyrones from Meldrum s acid.2 Substitution at the 2-position depends on the acid chloride chosen, while substitution at the 5-position is derived from the vinyl ether. A variety of substituted y-pyrones have been synthesized by utilization of this method as illustrated in the Table. The intermediate pyrandione is believed to arise through the addition of the vinyl ether to an acyl ketene that results... 

The synthesis of chlorocyanoketene presented here has advantages over other routes such as dehydrohalogenation of the appropriate acid chloride.5 The most obvious advantage is that the ketene is generated slowly during thermolysis. Thus, its concentration is always low. In addition, since it is generated by pyrolytic means, the presence of tert-amines and/or metals is avoided. No other method for the synthesis of chlorocyanoketene has been reported. However, we have found that it can be prepared with difficulty from chlorocyanoacetyl chloride. 

Sordo et al. [144] explained the stereoselectivity on the basis of torquoelectronic effects. Low-temperature infrared spectroscopy was also used to identify the reactive intermediates [145]. Two mechanisms were proposed to explain the product distribution in the (3-lactam formation reaction. The ketene mechanism was observed in a low temperature infrared spectroscopy study [145], while the acylation of imine mechanism was believed to be involved in some [122]. Both mechanisms were supported by evidences. It had been hypothesized that cycloaddition of the imine occurs from the least hindered side of the ketene, and this process generates zwitterionic intermediates conrotatory cyclization of these intermediates then produce cis- and //Y/ .v-[S-lactanis. Acylation of the imine by the acid chloride to form /V-acyliminium chloride also produced zwitterionic intermediates (Scheme 10). 

The Lectka group also reported an exciting development in this organocatalytic synthesis of /I-lactams - application of the concept of column asymmetric catalysis [50, 51]. This concept is based, e.g., on two jacketed columns linked together (Scheme 5.32) [50]. The top column is packed with the polymer-supported dehy-drohalogenation agent BEMP, which produces the desired ketenes, in high purity, from acid chlorides. In addition to this in-situ-formed pure ketene, an imine is... 

Ketenes are normally prepared by the base-catalysed elimination of HC1 from an acid chloride 9 or by elimination of chlorine from a chloroalkyl acid chloride with zinc dust, often assisted by ultrasound. For reactions with nucleophiles, the solution would already contain the nucleophile before the ketene 6 was generated. 

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