Chemodivergent transformations of amides using gem-diborylalkanes as pro-nucleophiles

Wei Sun,Chao Liu,Xudong Wu,Chungu Xia,Yue Hu,Lu Wang

doi:10.1038/s41467-020-16948-5

Abstract

Amides are versatile synthetic building blocks and their selective transformations into highly valuable functionalities are much desirable in the chemical world. However, the diverse structure and generally high stability of amides make their selective transformations challenging. Here we disclose a chemodivergent transformation of primary, secondary and tertiary amides by using 1,1-diborylalkanes as pro-nucleophiles. In general, selective B-O elimination occurs for primary, secondary amides and tertiary lactams to generate enamine intermediate, while tertiary amides undergo B-N elimination to generate enolate intermediate. Various in situ electrophilic trapping of those intermediates allows the chemoselective synthesis of α-functionalized ketones, β-aminoketones, enamides, β-ketoamides, γ-aminoketones, and cyclic amines from primary, secondary, tertiary amides and lactams. The key for these transformations is the enolization effect after the addition of α-boryl carbanion to amides.

Highlights

Amides are versatile synthetic building blocks and their selective transformations into highly valuable functionalities are much desirable in the chemical world
A few transition metal catalyzed C–N activation of some activated amides have been achieved in cross-couplings (Fig. 1a)[5,6,7], the major transformation of amides was initiated by the addition of highly active organometallic reagents, such as organolithiums and Grignard reagents onto their carbonyl groups to generate a tetrahedral intermediate Int-I (Fig. 1b)
Evans and Szostak attempted to form a stable tetrahedral intermediates upon addition of organometallics by tuning the N-substituent groups[10,11,18]; Weinreb developped a variety of N-methoxy-N-methyl amides which formed stable fivemembered-ring metal chelated intermediate after the addition of organometallic reagents, in which acidic quenching provided a diverse synthesis of ketones (Weinreb ketone synthesis)[12,13,14]

Summary

Results and discussion

When D2O was used as the quenching reagent, the α-deuterated ketone D-K1 was obtained in 87% yield (Fig. 3, eq d) These results showed that an enolate species was generated in the case of tertiary amide. A variety of aromatic and aliphatic tertiary amides were well performed under the standard conditions for tertiary amides (K22–K27) Functional groups, such as p-Br and o-Me were all well compatible to release the corresponding ketones in good to excellent yields (K22 and K23). 1,1-Diborylalkanes bearing galactose functionality were well conducted with both secondary and tertiary amides to give their corresponding ketones in moderate to good yields (K47 and K48). Efficient synthesis of those motifs still remain challenging In this case, after the completion of the reaction between primary amides and 1,1-diborylalkanes, the addition of tertiary butanol followed by TFAA successfully captured enamines to afford various enamides (Fig. 5). Bpin Bpin (1) nBuLi (4.0 equiv), THF, 0 oC, 5 min 100 oC, 24 h (2) tBuOH, 100 oC, 0.5 h TFAA, 100 oC, 2 h

B B Base

C NHBn Ph

Methods