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. 2017 Oct 9;56(42):13088-13093.
doi: 10.1002/anie.201707906. Epub 2017 Sep 14.

Electrochemically Enabled, Nickel-Catalyzed Amination

Chao Li  1 , Yu Kawamata  1 , Hugh Nakamura  1 , Julien C Vantourout  1 , Zhiqing Liu  2 , Qinglong Hou  2 , Denghui Bao  2 , Jeremy T Starr  3 , Jinshan Chen  3 , Ming Yan  1 , Phil S Baran  1
Affiliations

Electrochemically Enabled, Nickel-Catalyzed Amination

Chao Li et al. Angew Chem Int Ed Engl. .

Abstract

Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides).

Keywords: amination; arylation; cross-coupling; electrochemistry; nickel.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A) Background and historical context of nickel-based aryl amination methods. B) Invention and optimization of nickel-catalyzed amination. DABCO =1,4-diazobicyclo[2.2.2]octane, DMA =N,N′-dimethylacetamide, RVC =reticulated vitreous carbon, di-tBubpy =4,4′-di-tert-butyl-2,2′-bipyridine.
Scheme 1
Scheme 1
Scope of the electrochemically enabled nickel-catalyzed amination of aryl bromides. [a] Reaction conditions: aryl bromide (1.0 equiv), amine (3.0 equiv), NiBr2·glyme (10 mol%), di-tBubpy (10 mol%), DMA (0.1 M), LiBr (4 equiv), RVC anode, Ni cathode, constant current (I = 4 mA for 0.2 mmol scale), RT. [b] Based on results reported in Ref. [9 a]. [c] Based on specified references for each substrate (Ref. [18]). [d] I =8 mA for 0.2 mmol scale. [e] Using NiBr2·glyme (5 mol%), di-tBubpy (5 mol%) [f] I = 2 mA for 0.2 mmol scale. Boc = tert-butoxycarbonyl.
Scheme 2
Scheme 2
Applications and extensions of the electrochemically enabled amination reaction to achieve drug modifications (A), decagram scale C–N coupling (B), amination of aryl chlorides/triflates/iodides (C), and cross-coupling using alcohol and amide as nucleophiles (D). [a] Reaction conditions: aryl bromide (3.0–5.0 equiv), amine (1.0 equiv), NiBr2·glyme (10 mol%), di-tBubpy (10 mol%), DBU (2.0 equiv), DMA (0.08 M), LiBr (4.8 equiv), RVC anode, Ni cathode, constant current (I =4 mA for 0.167 mmol scale), RT (see the Supporting Information for experimental details). [b] Experimental procedures adapted from the standard conditions with modifications indicated. For details, see the Supporting Information. [c] Comparisons based on specified references for each substrate (Ref. [18] and [8d]). DBU =1,8-diaza-bicyclo[5.4.0]undec-7-ene.
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References

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    1. Analysis based on representative publications in J Med Chem Brown DG, Boström J. J Med Chem. 2016;59:4443.

    1. For a review on the Ullmann coupling, see: Sambiagio C, Marsden SP, Blacker AJ, McGowan PC. Chem Soc Rev. 2014;43:3525.

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    1. For a review on nickel-catalyzed amination of aryl halides, see: Mar%n M, Rama RJ, Nicasio MC. Chem Rec. 2016;16:1819.

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