α- and γ-Regiocontrol and Enantiospecificity in the Copper-Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents

The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3-methylpicolinate, and diethylphosphonate derivatives of Ph(CH2)(2)CH(OH)C equivalent to CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7-2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 degrees C for 1 h afforded the alpha-substitution product from the phosphate with >= 98 % r.s. and 99 % e.s. CuBr.Me2S gave similar selectivity. The reaction system was then applied to phosphates derived from (RCH)-C-1(OH)C equivalent to CR2 and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R-2=TMS, Ph, whereas iPr was borderline in terms of size as an R-1 substituent. The presence of a substituent at the o-position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)(2) in a 2:1 ratio in THF produced the gamma-substitution products (allenes) with high r.s. and e.s.

Automated summary

This study investigated the regioselectivity and enantiospecificity of substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts. The results showed that under certain reaction conditions, highly selective products could be obtained.