Synthesis of Two Types of Nitriles Both Bearing Quaternary Carbon Centers in One-Pot Manner

doi:10.6023/cjoc202107017

Abstract

α-Bromocarboxamides and electrophilic cyanide reagent were transformed into the corresponding α-cyanocarboxamides and ketene imine zinc intermediate in the presence of Zn reductant. Trapping of such Zn species with additional electrophiles resulted another type of nitriles, which realized the synthesis of two types of nitriles both bearing quaternary carbon centers in one-pot manner. This approach could be used to construct C—C, C—S, or C—F bond. Formal synthesis of several key pharmaceutical intermediates including loperamide, proadifen, verapamil, and gallopamil as well as α-fluoroibuprofen and α-fluoroflurbiprofen demonstrated the potential application of this methodology.

Key words: electrophilic cyanide reagent, nitrile, quaternary carbon center, pharmaceutical intermediate

Cite this article

Xinyi Ren, Guangzhu Wang, Xiaolei Ji, Kaiwu Dong. Synthesis of Two Types of Nitriles Both Bearing Quaternary Carbon Centers in One-Pot Manner[J]. Chinese Journal of Organic Chemistry, 2022, 42(2): 526-533.

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Fig. & Tab. 5

Scheme 1. Selected pharmaceuticals with a nitrile-bearing quaternary center and cyanation of organometallic reagents with electrophilic CN source

. Shceme 2 Synthesis of two types of nitriles both bearing quaternary carbon centers in one-pot manner

Electrophile (E-Y)	Nitrile	Electrophile (E-Y)	Nitrile

Table 1. Scope of various electrophilesa

Table 2. Scope of electrophilic cyanide reagents

Table 3. Cyanation with allyl bromidesa

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一锅法合成两种含有季碳中心的氰基化合物