Angewandte
Chemie
DOI: 10.1002/anie.201210088
Radical Reactions
Umpolung of Hemiaminals: Titanocene-Catalyzed Dehydroxylative
Radical Coupling Reactions with Activated Alkenes**
Xiao Zheng,* Xi-Jie Dai, Hong-Qiu Yuan, Chen-Xi Ye, Jie Ma, and Pei-Qiang Huang
Bis(cyclopentadienyl)titanium(III)
chloride
(Nugentꢀs
reagent)[1] is an efficient single-electron reductant and has
been used as a versatile tool in organic synthesis,[2,3] owing to
the ease of handling, its functional-group compatibility, and
a broad array of reactions that can be effected under
relatively mild conditions. Today, [Cp2TiCl] is used as
a catalyst for several types of radical reactions by employing
a catalytic amount of [Cp2TiCl2] as a catalyst precursor and
a metal (such as Mn, Zn, Al, In, Mg, and Sm)[4] as a co-
reductant in the presence of TMSCl or protic acids. Among
the [Cp2TiCl]-catalyzed radical reactions, reductive epoxide
opening reaction,[5] first demonstrated by Nugent and Rajan-
Babu,[1] then by Gansꢁuer et al.,[5b,c] has been the subject of
intensive studies and found applications in natural product
synthesis.[6] In this reaction, a [Cp2TiCl]-initialized homolysis
Scheme 1. Dehydroxylative radical coupling reactions of hemiaminals
with activated alkenes. Cp=cyclopentadienyl, EWG=electron-with-
drawing group, TMS=trimethylsilyl.
ꢀ
of C O bonds is involved. As an extension of this feature,
Barrero and co-workers recently described a deoxygenation
of alcohols usually mediated by a stoichiometric amount of
[Cp2TiCl]. In addition, catalytic examples have also been
reported.[7] In view of these precedents, the [Cp2TiCl]-
catalyzed dehydroxylative coupling reactions of alcohols
and other hydroxy-containing compounds, such as sugars,
hemiacetals, and hemiaminals seemed possible.
It is known that umpolung of hemiaminals can provide
radical carbon intermediates in a position to amino groups
through dehydroxylation and one-electron reduction of the
corresponding carbenium ions.[8] We have recently developed
a SmI2-mediated dehydroxylative radical cross-coupling reac-
tion of hemiaminals with activated alkenes [Scheme 1,
Eq. (1)],[9] which was assumed to proceed through a SmI2-
based single-electron reduction of N-acyliminium ions. This
ꢀ
methodology provides a useful and efficient strategy for C C
bond formation at the carbon atoms in a position to amino
groups, and can be employed for the synthesis of alkaloids and
other pharmaceuticals.[10] Based on these considerations, it
would be particularly interesting and valuable to develop
transition-metal-catalyzed dehydroxylative radical coupling
reactions of hemiaminals under mild conditions, which have
not been reported so far. We envisioned that the singular
ꢀ
ability of [Cp2TiCl] to cleave a C O bond might help us to
achieve this goal.
Herein we report titanocene-catalyzed dehydroxylative
radical coupling reactions of hemiaminals with activated
alkenes [Scheme 1, Eq. (2)]. This novel reaction was per-
formed by using a [Cp2TiCl2](cat.)/Mg/TMSCl reduction
system[11] in the presence of tert-butanol. An application of
this radical methodology has been demonstrated by an
efficient synthesis of (ꢁ)-9,10-diepi-stemoamide.
[*] Assoc. Prof. Dr. X. Zheng, X.-J. Dai, H.-Q. Yuan, C.-X. Ye, J. Ma,
Prof. P.-Q. Huang
Department of Chemistry and Fujian Provincial Key Laboratory of
Chemical Biology, College of Chemistry and Chemical Engineering,
Xiamen University
Xiamen, Fujian 361005 (P.R. China)
E-mail: zxiao@xmu.edu.cn
We began our study with the treatment of hemiaminal 1[12]
and methyl acrylate (2.0 equiv) with [Cp2TiCl2] (0.025 equiv),
Mg powder (2.0 equiv), and TMSCl (2.0 equiv); the desired
cross-coupling product 2a was obtained in 54% yield
(Table 1, entry 1). The influence of other reaction factors,
including Lewis acids, protic additives, and metals, was
systematically investigated. TMSCl played a pivotal role in
this reaction. The use of tBuOH gave the fastest reactions and
highest yields (Table 1, entry 3 versus entry 2). After exten-
sive trials, the optimized coupling conditions were defined as
carrying out the reactions in THF with [Cp2TiCl2] as a catalyst
precursor (0.025 equiv) and magnesium turnings as a co-
reductant (5.0 equiv) in the presence of TMSCl (4.0 equiv)
and tBuOH (4.0 equiv). Using this catalytic system, the
Assoc. Prof. Dr. X. Zheng
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences (P.R. China)
[**] We are grateful to the National Basic Research Program (973
Program) of China (Grant No. 2010CB833200), the NSF of China
(21172183), the Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT), the Natural Science
Foundation of Fujian Province of China (No. 2010J01050), the
Fundamental Research Funds for the Central Universities (No.
CXB2011015), and NFFTBS (No. J1210014) for financial support.
We also thank Prof. Lin-Feng Xie and Dr. Ai-E Wang of XMU for kind
and helpful discussions on this paper.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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