Carbomagnesiation

With the advent of enantioselective zirconocene-catalyzed alkene carbomagnesiation,27 27a 27c 28 28a chirally modified zirconocenes soon were applied to asymmetric reductive diene carbocyclization.2 a c As demonstrated by the reductive cyclization of 5a,29 highly enantioselective cyclization is enabled through the use Brintzinger s chiral, mszz-zirconocene.30 30a (For the preparation and resolution of chiral tf .szz-zirconocene 6, see Refs 30,30a.) However, moderate diastereoselectivities and yields are generally observed (Scheme 5). 

Titanocene dichloride also catalyzes a regioselective carbomagnesiation of alkenes 187 (equation 115) and dienes 188 (equation 116). The reaction proceeds at 0°C in THF in the presence of Cp2TiCl2, an organic halide and n-BuMgCl which leads to the catalytic species, affording benzyl, allyl or a-silyl alkylmagnesium halides, which are trapped with electrophiles (equation 117) . ... 

II. CARBOMAGNESIATION REACTIONS OF ALKYNES A. Intramolecular Addition to Simple Alkynes... 

Similar experiments using substrates having a methyl group a to magnesium 7 furnishes a mixture of stereoisomers 8 and 9 (Scheme 6)". Whether the mixture of cis and tram isomers is formed in the carbomagnesiation step, or by isomerization of a single isomer after addition, has not been discussed. Kinetic experiments indicate that fi/2 of cyclization using bromide is ca 15 hours at 100 °C. 

The development of a catalytic system leading to an intermolecular carbomagnesiation of simple aikynes has been a challenge. In 1972, Duboudin and Jousseaume reported the Ni-catalyzed carbomagnesiation of aikynes (Scheme Although this may be one... 

Normant and coworkers demonstrated that the intermolecular carbomagnesiation across acetylene (HC=CH) could be catalyzed by a copper salt . The treatment of w-heptylmag-nesium bromide with acetylene in the presence of a catalytic amount of CuBr (5 mol%) in EtgO at —20 °C followed by the reaction with C2H5CHO and quenching with H2O results in the formation of allylic alcohol 12 in 31% yield (Scheme 9) . The carbomagnesiation takes place in a yw-addition manner. 

Since this report on the copper catalysis in carbomagnesiation across acetylene, a variety of Cu-catalyzed carbomagnesiation reactions of afkynes have been reported. However, the applicable aUcynes are somewhat limited to electronically biased (activated) or heteroatom-containing aUcynes, which will be discussed later. 

Chromium salts can catalyze the carbomagnesiation reactions of 1,6-enynes with cy-clization (Scheme 12) . This reaction is probably initiated by carbometalation of the alkyne unit. The resultant organomagnesium species 16 undergoes further functionalization upon treatment with various electrophiles (Scheme 12) . ... 

A carbomagnesiation of aikynyisiianes is an attractive method generating synthetically versatile silyl-substituted alkenylmagnesium species. Snider and coworkers reported the... 

Marek and coworkers have developed the regio- and stereocontrolled carbomagnesiation of alkynyl amine derivatives. For example, PhMgBr adds across the triple bond of ynamide 30 in the presence of a catalytic amount of CuBr Me2S (10 mol%). The following... 

When the phenyl-substituted alkynyl sulfone 42 is used as a substrate for the Cu-catalyzed carbomagnesiation, interesting nucleophile-dependent stereoselectivity is observed. While the use of allyl Grignard reagent results in a syn addition, the use of aryl Grignard reagent results in an awh -carbomagnesiation (Scheme 25). ... 

The carbomagnesiation reaction proceeds with a range of organomagnesium compounds (Scheme 30) °. Not only aryl, alkenyl and aUcynyl groups, but also alkyl groups were found to add across a triple bond. The enhanced reactivity of cyano-substituted alkynes is worthwhile, and this may be due to accelerated alkyl transfer from 53 with activation of the cyano group by MgX2 (Scheme 29). 

Chelation is essential for this carbomagnesiation. A control experiment, in which the THP-protected cyanoalkyne 55 is exposed to n-BuMgCl, leads to 90% recovery of unchanged alkyne (Scheme 31). In addition, homopropargyUc alcohol 56 does not undergo carbomagnesiation . 

When enyne alcohol 57 is subjected to awf/-carbomagnesiation using vinyhnagnesium chloride, the resultant triene 58 undergoes further electrocyclization (Scheme 32). ... 

As electrophiles for post-functionalization of awfi-carbomagnesiation, aryl and alkenyl halides can also be used when Pd catalyst is employed. By merging such Pd-catalyzed arylation, tamoxifen can be synthesized in a stereoselective manner (Scheme 36) . ... 

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