FULL PAPER
DOI: 10.1002/chem.201101630
An Efficient, Overall [4+1] Cycloadditon of 1,3-Dienes and Nitrene
Precursors
Qiong Wu,[b] Jian Hu,[a] Xinfeng Ren,[a] and Jianrong (Steve) Zhou*[a]
Abstract: Intermolecular cycloaddi-
tions of conjugated dienes and nitrene
precursors usually produce aziridines.
A generally useful method was lacking
to directly provide the [4+1] cycload-
ducts, 3-pyrrolines. We have realized
this transformation by using an
uniquely active catalyst, copper(II)
1,1,1,5,5,5-hexafluoroacetylacetonate
ble to a wide array of dienes with good
yields. When 1,4-disubsituted dienes
are used as substrates, good-to-excel-
lent cis or trans selectivity can be ob-
tained. Interestingly, the cis or trans
preference depends on the nature of
the substituents, rather than diene ge-
ometry. Mechanistic studies reveal that
the [4+1] cycloaddition proceeds
through diene aziridination and subse-
quent ring expansion. Among common
copper catalysts, only [CuACTHNUTRGNEG(NU hfacac)2] can
Keywords: aziridination · copper ·
cycloaddition · nitrenes · ring ex-
pansion
efficiently catalyze both steps, which
explains the unique efficiency of the
catalyst.
([CuACHTUNGTRENNUNG(hfacac)2]). The method is applica-
Introduction
Substituted pyrrolidines are frequently present in many nat-
ural products and therapeutic agents. Due to their important
biological activities, a wide variety of methods have been
developed to prepare these compounds, often with defined
stereochemistry.[1] We are particularly interested in intermo-
lecular cycloadditions for the construction of azacycles due
to material convergence and catalytic control of the stereo-
chemical outcome. Typical examples are [3+2] cycloaddi-
tions of olefins/alkynes with azomethine ylides[2]/aziridines[3]
and [3+2] cycloadditions of imines with allenes,[4] trimethy-
lenemethanes,[5] or cyclopropanes.[6] However, these reac-
tions usually require activation of the reactants (alkenes, al-
kynes, allenes, and cyclopropanes) with electron-withdraw-
ing groups.
Scheme 1. Intermolecular [4+1] cycloaddition of conjugated dienes and
nitrene equivalents to access 3-pyrrolines.
olefin groups of which can be readily transformed into other
functionalities. For example, olefine dihydroxylation can
lead to stereoselective synthesis of 3,4-dihydroxypyrroli-
dines,[7] which are core structures in many bioactive com-
pounds.[8]
Formal intramolecular [4+1] cycloadditions have been ex-
tensively studied by Hudlicky[9] and Pearson[10] via thermoly-
sis of 1,3-dienyl azides, which proceeds via triazoline inter-
mediates.[11] However, these reactions are often accompa-
nied by side reactions and low yields of the [4+1] cycload-
ducts. Furthermore, 2- and 3-pyrroline isomers are pro-
duced, dependent on the substitution of the dienes.
Intermolecular cycloadditions of stabilized nitrenes with
1,3-dienes usually lead to aziridines[12] and a generally useful
method to directly produce [4+1] cycloadducts was lack-
ing.[13] Thus, a separate step is needed to convert preformed
vinylazirdines[14] into pyrrolines.[15] Herein, we report an effi-
cient, intermolecular overall [4+1] cycloaddition of
1,3-dienes and nitrene precursors.
We envision intermolecular [4+1] cycloaddition of conju-
gated dienes and nitrene equivalents as an alternative gener-
al approach to access pyrrolidines (Scheme 1). Besides the
attributes of convergence and catalytic control of the stereo-
chemistry, the [4+1] cycloaddition produces 3-pyrrolines, the
[a] Dr. J. Hu, Dr. X. Ren, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
637371 (Singapore)
Fax : (+65)67911961
[b] Q. Wu
Results and Discussion
Department of Medicinal Natural Products
West China School of Pharmacy
Sichuan University
For the model reaction (Table1), we selected an ester-con-
taining 1,3-butadiene and a common nitrene precursor,
(N-p-tosylimino)phenyliodinane (PhI=Ts).[16] After exten-
sive research, we found that copper(II) 1,1,1,5,5,5-hexa-
Chengdu, 610041 (P. R. China)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2011, 17, 11553 – 11558
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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