Ketenes from diazo ketones

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 bicyclic product 59 proved not to be derived from diazo ketone 58. It may arise from the reaction of diazenyl ketene intermediate 53 with diazomethane via the postulated 2-[2-methyl-2-(phenyldiazenyl)propyl] cyclopropanone intermediate 60 and its subsequent isomerization to the bicyclic product 59 (Scheme 14). The formation of the diazenyl ketene intermediate 53 has been made plausible by carrying out the reaction in the presence of an excess of isobutyl alcohol to afford isobutyl 3-methyl-3-[(E)-phenyldiazenyl]butanoate (61) in a competing addition. 

This work was extended to a one-pot multicomponent procedure involving two different ketenes derived from diazo ketones 145 and 149, respectively, and using 4-methoxyphenylazide (ArN3), and rhodium acetate, with in situ conversion of ketene 150 derived from diazo ketone 149 to the imine 147 by reaction with the arylazide, and then subsequent cycloaddition of 147 with ketene 146, also generated in situ, from diazo ketone 145, again forming the P-lactam 148 (Eqn (4.90)). ... 

More definitive evidence for the formation of an oxirene intermediate or transition state was presented recently by Cormier 80TL2021), in an extension of his earlier work on diazo ketones 77TL2231). This approach was based on the realization that, in principle, the oxirene (87) could be generated from the diazo ketones (88) or (89) via the oxocarbenes 90 or 91) or from the alkyne (92 Scheme 91). If the carbenes (90) (from 88) and (91) (from 89) equilibrate through the oxirene (87), and if (87) is also the initial product of epoxidation of (92), then essentially the same mixture of products (hexenones and ketene-derived products) should be formed on decomposition of the diazo ketones and on oxidation of the alkyne this was the case. 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

To select between these two alternative structures it was necessary to synthesize a labeled analog. Three hydrogen atoms of the methyl moiety of the ester group were substituted for deuterium. One of the principal pathways of fragmentation of [M N2]+ ions involves the loss of CH3 radical. Since all R substitutes in diazo ketones 4-1 were also methyls it was important to detect what group exactly is eliminated from the [M N2]+ ion. The spectrum of deuterated sample has confirmed that the methyl radical of the ester moiety leaves the parent ion. As a result the cyclic structure 4-2 was selected as the most probable. The ketene structure 4-3 is hardly able to trigger this process, while for heterocyclic ion 4-2 it is highly favorable (Scheme 5.22). 

With 0,-y-unsaturated a -diazo ketones, the resulting [2.1.0]-bicyclic systems (40) were quite unstable and underwent a [2 + 2] cycloreversion to generate ketenes (41), which were then trapped by nucleophiles (Scheme 7). The overall scheme has been named a vinylogous Wolff rearrangement and offers a novel entry to products usually derived from a Claisen rearrangement.102 A recent report describes its application for functionalized angular alkylation in fused ring systems.103 In contrast, the intramolecular re-... 

Fig. 9.1 Generating an oxo carbene (a ketocarbene ) from a labelled diazo ketone sometimes leads to a ketene in which the label is scrambled. This indicates that a species with the symmetry of oxirene is formed...

Fig. 14.29. Preparation of an a-diazoketone (compound E) from a ketone (A) and subsequent Wolff rearrangement of the a-diazoketone. Initially, A is transformed to give the enolate B of its a-formyl derivative. In a Regitz diazo group transfer reaction, this will then be converted into the a-diazoketone E. Ring contraction via Wolff rearrangement occurs and the 10-membered cyclic diazoketone C rearranges in aqueous media to give the nine-membered ring carboxylic acid E via the ketene D.

The Wolff rearrangement of a-diazocarbonyl compounds (8.58, R = H, alkyl, aryl, OR) has great synthetic importance because in most cases the ketenes formed react smoothly with water, alcohols, and amines (Scheme 8-34). An early application that still has considerable importance is the homologization of carboxylic acids (Arndt-Eistert reaction Arndt and Eistert, 1935). As shown in Scheme 8-34, the reaction starts from the chloride of the acid RCOOH, which leads to an a-diazo ketone with diazomethane (R = H), followed by the Wolff rearrangement and the hydrolysis of the ketene intermediate to give the homologous carboxylic acid (8.59, R =H). In alcohols and amines esters (8.60) and amides (8.61, R = H), respectively. 

Photolysis at 270 run of diazoacetone with ultrafast IR detection gives ketene generation in a concerted process, interpreted as showing a predominance of the syn-conformation of the diazo ketone (Scheme 7.48). Photolysis of azibenzil with UV-visible detection shows formation of the singlet benzoylcarbene in acetonitrile. The IR absorbance at 2100cm shows formation of the ketene by a concerted process arising from the syn[Pg.250]

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