Chromium-catalyzed para-selective formation of quaternary carbon centers by alkylation of benzamide derivatives

Pei Liu,Xuefeng Cong,Changpeng Chen,Jinghua Tang,Xiaoming Zeng

doi:10.1038/s41467-018-07069-1

Pei Liu, Xuefeng Cong + Show 3 more

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https://doi.org/10.1038/s41467-018-07069-1

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Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry. We report here the chromium-catalyzed, para-selective formation of arylated quaternary carbon centers by alkylative reactions of benzamide derivatives with tertiary alkylmagnesium bromides at room temperature. The reaction, which was enabled by a low-cost chromium(III) salt combined with trimethylsilyl bromide, introduces a sterically bulky tertiary alkyl scaffold on the para-position of benzamide derivatives in a highly selective fashion without either isomerization of the tertiary alkyl group or formation of ortho-alkylated byproducts. Forming low-valent Cr species in situ by reaction of CrCl3 with t-BuMgBr accompanied by evolution of hydrogen can be considered, which serves as reactive species to promote the reaction. The para-alkylation likely occurs via a radical-type nucleophilic substitution of imino-coordination benzimidate intermediate.

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Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry
We report that the para-selective formation of arylated quaternary carbon centers was enabled by using low-cost chromium(III) salt combined with trimethylsilyl bromide to achieve alkylative reaction of benzamides with tertiary alkylmagnesium bromides at room temperature (Fig. 1c)
We initially probed the reactivity of chromium in promoting the alkylation of N-methylbenzamide (1) with t-butylmagnesium bromide (Table 1)

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Introduction

Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry. The reaction, which was enabled by a lowcost chromium(III) salt combined with trimethylsilyl bromide, introduces a sterically bulky tertiary alkyl scaffold on the para-position of benzamide derivatives in a highly selective fashion without either isomerization of the tertiary alkyl group or formation of ortho-alkylated byproducts. We report that the para-selective formation of arylated quaternary carbon centers was enabled by using low-cost chromium(III) salt combined with trimethylsilyl bromide to achieve alkylative reaction of benzamides with tertiary alkylmagnesium bromides at room temperature (Fig. 1c). This reaction proceeded with high selectivity, with only the para-carbons of benzamides being alkylated without isomerization of bulky tertiary alkyl groups

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