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N-Heterocyclic Carbene–Cu-Catalyzed Enantioselective Conjugate Additions with Alkenylboronic Esters as Nucleophiles Qinglei Chong, Zhenting Yue, Shuo-Qing Zhang, Chonglei Ji, Fengchang Cheng, Haiyan Zhang, Xin Hong, and Fanke Meng ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02132 • Publication Date (Web): 18 Jul 2017 Downloaded from http://pubs.acs.org on July 18, 2017
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ACS Catalysis
Carbene–Cu-Catalyzed
N-Heterocyclic Enantioselective
Conjugate
Additions
with
Alkenylboronic Esters as Nucleophiles Qinglei Chong†, Zhenting Yue†, Shuoqing Zhang‡, Chonglei Ji‡, Fengchang Cheng†, Haiyan Zhang†, Xin Hong‡* and Fanke Meng†* †
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
345 Lingling Road, Shanghai, 200032, China. ‡
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, China.
ABSTRACT:
Catalytic
enantioselective
conjugate
additions
with
easily
accessible
alkenylboronic acid pinacol esters as nucleophiles promoted by chiral copper complexes of Nheterocyclic carbenes are presented. These processes constitute an unprecedented instance of conjugate additions of a variety of functionalized alkenyl groups and afford desired products that are otherwise difficult-to-access in up to 98% yield and 99.5:0.5 enantiomeric ratio. The origins of ligand-controlled enantioselectivity are elucidated with density functional theory (DFT) calculations.
KEYWORDS: Conjugate addition, copper catalysis, alkenylboron, enantioselective catalysis, Nheterocyclic carbene
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Introduction Copper-catalyzed enantioselective conjugate additions of organometallic reagents to α,βunsaturated compounds stand for a powerful method for efficient and selective construction of C–C bonds.1 Reactions with highly reactive organometallic reagents such as Grignard reagents,1c-f,
1l, 2
organozinc reagents1b,
1g, 1h, 3
and organoaluminum,1c-i,
4
organozirconium
reagents1k, 5 have been well established. In contrast, the utility of more robust nucleophiles has been much less studied. Organoboronic acids and their derivatives are attractive due to their high functional group tolerance and diversity, low toxicity and ease of access and handling. There are only two reports regarding Cu-catalyzed enantioselective 1,4-conjugate additions with arylboronic acid derivatives by Hayashi (Scheme 1a)6 and Zhou (Scheme 1b)7. In addition, Sawamura disclosed the use of organoboranes as nucleophiles in Cu-catalyzed enantioselective conjugate additions (Scheme 1c).8
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ACS Catalysis
Scheme 1. Cu-Catalyzed Enantioselective Conjugate Additions with Organoboron Nucleophiles. Introduction of an alkenyl group into α,β-unsaturated compounds is desirable in organic synthesis. Although Rh-catalyzed enantioselective conjugate additions with organoboron compounds have been well studied,1j-k alkenylboron compounds still stands for a class of challenging nucleophiles. To the best of our knowledge, there is no protocol for highly efficient and enantioselective conjugate additions of alkenylboron nucleophiles promoted by Cu-based catalysts.9 Herein, we describe the first catalytic enantioselective 1,4-additions of alkenylboronic acid pinacol esters to enoates promoted by N-heterocyclic carbene (NHC)–Cu complexes. We envision that a suitable Cu(I) complex could promote transmetallation with alkenyl– B(pin)
to
generate
alkenyl–Cu
complex
I,
which
could
coordinate
with
diethyl
benzylidenemalonate 1a to form a π-complex II. Transfer of alkenyl group to the π-bond would deliver the Cu(I) complex III, which rapidly collapsed to Cu enolate IV. Exchange of IV with NaOt-Bu released addition product V and regenerated the catalyst. (Scheme 1d) The challenge for reactions with alkenylboron nucleophiles is their lower reactivity. In addition, the metal salts that are present in the reactions with more reactive Grignard reagents, organozinc reagents and organoaluminum reagents might work as Lewis acids to activate α,βunsaturated compounds and lead to more organized transition states, resulting in higher reactivity and better control of enantioselectivity.4g, 10 Such activation is significantly diminished in the case of alkenylboronic esters as nucleophiles due to their weaker Lewis acidity. Therefore, ligands that are strong σ-donor might be necessary to enhance the nucleophilicity of alkenylcopper intermediate.11
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Results and discussion In our initial investigation, reactions of commercially available alkenyl–B(pin) (pin = pinacolato) 2a with ethyl cinnamate in the presence of NHC–Cu or bisphosphine–Cu complexes resulted in
