Carbenoid homologation

Carbocupration of chiral alkynylsulfoxides 47 in a regio- and stereospecific manner produces alkenyl organocopper 48, which is subsequently reacted with bis(iodomethyl) zinc in the presence of aldehydes or imines. The zinc carbenoid homologation step leads to 49, the conformation of which is controlled by intramolecular chelation 49 reacts with the aldehyde or imine before it can undergo a -elimination (cf. equation 20). The final product 63 is generally obtained with high diastereoselectivity and in good overall yield (Table 8). 

For a discussion of organozinc carbenoid homologation reactions, see Marek, I. Tetrahedron 2002,58, 9463. 

Varghese, J. P., Knochel, P. and Marek, I. 2000. New aUene synthesis via carbocupration-zinc carbenoid homologation and AY-efimination sequence. Org. Lett. 2 2849-2852. 

Scheme 10.129 Diastereoselective formation of aldol surrogates by sequential carbocupra-tion of chiral ynamides/zinc carbenoid homologation/aldol-type addition [110].

The homologation of selenoesters 379 with diazomethane in the presence of Cu or Cul to give a-selenoketones is thought not to involve a carbenoid pathway and an Se-ylide intermediate but rather a tetrahedral species resulting from nucleophilic attack of CH2N2 at the carbonyl carbon atom. The role of the catalyst is seen in facilitating nucleophilic attack at C=0 by complexation at the selenium atom. 

The reaction of olefins with dihalogenomethanes to form homologs with one additional carbon atom has been included in the list (no. 37) of reactions in Table I because CH2X2 should form a carbenoid methylene-nickel bond able to give a metallacycle with the olefin, followed by hydrogen transfer. 

The use of copper as a catalyst in carbenoid transfer has its roots in the Amdt-Eistert reaction, Eq. 1 (3). Although the original 1935 paper describes the Wolff rearrangement of a-diazo ketones to homologous carboxylic acids using silver, the authors mention that copper may be substituted in this reaction. In 1952, Yates (4) demonstrated that copper bronze induces insertion of diazo compounds into the X-H bond of alcohols, amines, and phenols without rearrangement, Eq. 2. Yates proposal of a distinct metal carbenoid intermediate formed the basis of the currently accepted mechanistic construct for the cyclopropanation reaction using diazo compounds. 

Here an alkynyl sulfoxide 55 is first carbocuprated with an organocopper reagent 56 to provide a vinylcopper intermediate 57, which is then zinc homologated with the primary zinc sp3-carbenoid 58 to yield the allylzinc intermediate 59. This, in a spontaneous syw-/)-climination, gives the corresponding allene 60. This protocol could also be adopted to the preparation of chiral allenes. 

Finally, the addition of the carbanion of 1-chloroalkyl p-tolyl sulfoxides 154 to carbonyl compounds gave the adducts 155, which were treated with alkyllithium such as f-C4H9Li to afford the one-carbon homologated carbonyls compounds 158, from their lithium enolate forms 157, having an alkyl group at the a-position, via the carbenoid /S-alkoxides 156 (equation 53) °. 

SCHEME 13. Conversion of aldehydes into alkynes under homologation. Application of hydride shifts in vinylidene carbenoids... 

In 1990, Hahn and Tompkins reported an interesting multi-carbon homologation of alkyl halides by the reaction of magnesium carbenoid with a Grignard reagent (Scheme 2) . 

SCHEME 29. Homologation of zinc enolate using a zinc carbenoid... 

The first practical approach applying this strategy consisted of a carbocupration of an alkynyl sulfoxide 47 followed by methylene homologation of 48 with a zinc carbenoid and /3-elimination (equation 20)25. Yields of 1,1-disubstituted allenes 50 are good to high as outlined in Table 4. 

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