Angewandte
Chemie
DOI: 10.1002/anie.201004073
Cycloaddition
Stereoselective Synthesis of a-Diazo Oxime Ethers and Their Appli-
cation in the Synthesis of Highly Substituted Pyrroles through a
[3+2] Cycloaddition**
Emmanuvel Lourdusamy, Lin Yao, and Cheol-Min Park*
a-Diazocarbonyl compounds have been extensively studied
for their synthetic applications over the last few decades.[1]
They are well recognized as the precursors for highly reactive
metal carbenoids, particularly with copper[2] and rhodium,[3]
medicinal agents,[11,12] and conducting polymers.[13] In addi-
tion, N-alkoxy pyrroles are used as insecticides for crop
protection.[14] These properties continue to stimulate interest
in the development of new synthetic methods for pyrroles. In
general, pyrroles are prepared by cycloaddition reactions[15]
([4+1] and [3+2]) or intramolecular cyclization reactions.[16]
In addition, ring contraction of N-heterocycles[17] and three-
component reactions[18] have also been employed for the
preparation of pyrroles. A few studies using a-diazocarbonyl
compounds in the synthesis of pyrroles have also been
reported.[19] Despite a number of synthetic methods available
for pyrroles, the need for the development of an efficient
method that provides highly substituted pyrroles still remains.
We envisaged that the reaction of a-oximino carbenoids with
alkenes would result in the formation of pyrroles through
electrophilic attack of a-oximino carbenoid [Eq. (3)].
which promote a number of unique transformations including
[5]
addition,[4] C H insertion, and ylide formation.[6] In con-
ꢀ
trast, their nitrogen analogues, that is, a-diazo imines, remain
unexplored largely because of their limited availability as they
undergo spontaneous cyclization to produce 1,2,3-triazoles.[7]
Recently, Fokin and co-workers reported the use of
N-sulfonyl 1,2,3-triazoles 1 as a precursor for a-imino
carbenoids 2 [Eq. (1)].[8] Murakami et al. also used this ring-
chain tautomerization of N-sulfonyl triazoles for the synthesis
of pyrroles by nickel-carbenoid-mediated alkyne insertion
albeit with low regioselectivity.[9] Herein, we wish to report
the use of a-diazo oxime ethers 3 as general precursors of a-
oximino carbenoids 4 and their application in the synthesis of
highly substituted pyrroles [Eq. (2)].
Our efforts to synthesize a-diazo oxime ethers began with
a judicious choice of a precursor. Since triazole formation is
triggered by a lone pair disposed cis to a diazo group, we
reasoned that it could be avoided if the geometry of an imine
is controlled such that the lone pair is disposed trans to the
diazo group. It was also anticipated that the reduced basicity
of oximes over imines would lead to an increased stability of
the corresponding diazo compounds. Thus, when a 1:1
mixture of the cis/trans oxime ether 5a was treated with
p-toluenesulfonyl azide as a diazo transfer agent, we were
delighted to observe that the diazo product 6a was formed in
51% yield as a single isomer along with triazole 7a (30%;
Scheme 1). The cis geometry of the diazo compounds was
unambiguously assigned from the single-crystal structure of
the analogue 6c (Figure 1).[20]
Encouraged by this result, we set out to improve the yield
by screening several diazo transfer agents and solvents
(Table 1). Whereas arylsulfonyl azides having electron-donat-
ing groups such as amido and methyl groups resulted in poor
yields (Table 1, entries 2 and 3), those with strong electron-
withdrawing groups gave improved results. Remarkably, the
use of 4-nitrobenzenesulfonyl azide provided the cis-diazo
product in 64% yield from a 1:1 mixture of the cis/trans oxime
ether 5a (Table 1, entry 5). We reason that a rapid equilib-
Pyrroles, one of the most valuable N-heterocyclic com-
pounds, constitute the core motif of natural products,[10]
[*] E. Lourdusamy, L. Yao, Prof. Dr. C.-M. Park
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
Fax: (+65)6513-2748
E-mail: cmpark@ntu.edu.sg
[**] We gratefully acknowledge Nanyang Technological University Start
Up Grant for the funding of this research. We thank Dr. Yongxin Li
for X-ray crystallographic analysis. We also thank Prof. Sunggak Kim
for careful reading of the manuscript.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 7963 –7967
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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