Highly selective catalyst-directed pathways to dihydropyrroles from vinyldiazoacetates and imines

Article abstract of DOI:10.1021/ja029745q

Copper-catalyzed reactions of vinyldiazoacetates with imines occur via a pathway in which the activated imine undergoes electrophilic addition to the vinyldiazo compound, whereas reactions catalyzed by rhodium(II) proceed through a metal carbene to an int

Full text of DOI:10.1021/ja029745q

Published on Web 03/29/2003
Highly Selective Catalyst-Directed Pathways to Dihydropyrroles from
Vinyldiazoacetates and Imines
Michael P. Doyle,* Ming Yan, Wenhao Hu, and Luisa S. Gronenberg
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721-0041
Received December 13, 2002; E-mail: mdoyle@u.arizona.edu
Scheme 1
Copper and dirhodium(II) catalysts have been remarkably
effective for metal carbene reactions of diazo compounds. Their
basic success is derived from their activities as Lewis acids for
electrophilic addition to the diazo compound and in the stabilization
of the metal carbene formed upon dinitrogen dissociation.1 Recently,
versatile catalytic approaches to ylide generation and reactions
leading to heterocyclic compounds from aryl- and vinyldiazoacetates
have been reported.2-4 Epoxides, aziridines, and, in selected
examples, dihydropyrrolidines and dihydroazepines are among the
compounds whose highly stereoselective syntheses have been
demonstrated in Rh2(OAc)4-catalyzed reactions (Scheme 1).
In the course of investigating catalytic ylide-derived reactions
of vinyldiazo compounds with imines, we surveyed a broad
selection of catalysts that were suitable for ylide generation,
including copper(I) hexafluorophosphate and triflate, and copper-
(II) triflate. Whereas Rh2(OAc)4 and reactive chiral carboxylates
and carboxamidates of dirhodium(II) gave the anticipated dihy-
dropyrrole 3 from the reaction between styryldiazoacetate 1a and
imine 2a (R ) trans-PhCHdCH) with high stereocontrol (100:0
c:t), use of copper catalysts, including those like CuPF6 and CuOTf
that normally operate through the same mechanistic pathway as
rhodium(II) catalysts,1 produced the isomeric dihydropyrrole 4
Table 1. Catalyst-Dependent Product Distributions from Reactions
between 1 and 2b (R ) Ph)a
competitively (eq 1), and Cu(OTf)2 was optimum for this trans-
formation (3:4 ) 0:100, 74% yield). The structures of these
compounds were confirmed by 2-D and nOe NMR experiments.
Formation of 3 occurred in competition with dihydroazepine
production (32:68 3:dihydroazepine), and only its cis-stereoisomer
was obtained; 4 was produced in a 70:30 t:c ratio.
catalyst
1
isolated yield, %
3 (t:c)
4 (t:c)
b
Rh2(OAc)4
a
b
c
d
f
66d
42
51
14e
64
67
76
100 (<98:2)
100 (90:10)
100 (93:7)
100
100 (65:35)
0
0
0
0
0
0
c
Cu(OTf)2
a
f
100 (91:9)
100 (93:7)
0
a Reactions performed in refluxing CH2Cl2 by adding 1 to an equal molar
amount of 2b over 1 h. b 1.0 mol %. c 5.0 mol %. d 1.2 equiv of 1a was
used in this case. e Yield of 5.
Other Lewis acids were employed in efforts to develop the
generality of the process,6 but only Sn(OTf)2 showed comparable
product yield (but t:c ) 84:16).
Accordingly, 3 is formed from a ylide originating with a metal
carbene intermediate,3 whereas 4 is formed by a process in which
the metal catalyst, acting as a Lewis acid, activates the imine for
electrophilic addition to the diazo compound (Scheme 2). In
previous investigations of copper-catalyzed aziridination reactions
of ethyl diazoacetate, copper carbene species were the proposed
intermediates.6,7 However, activation of imines for electrophilic
addition by copper salts has recently been utilized in cycloaddition
reactions.8,9 In the present case, addition is proposed to occur
directly into the diazo carbon to generate an intermediate that is
aligned for SN2′ displacement of dinitrogen. Only 3 is formed with
Rh2(OAc)4 catalysis, and only 4 is obtained from reactions catalyzed
by Cu(OTf)2.
This contrasting, highly stereoselective, behavior is also evident
in reactions of a diverse set (Table 1) of vinyldiazoacetates (1) with
imine 2b (R ) Ph) and led us to understand the alternative copper-
(II)-catalyzed pathway to 4 (and 9) as being due to a Lewis acid-
catalyzed process that is reminiscent of that used by W. Wulff for
the efficient construction of aziridines with ethyl diazoacetate.5
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J. AM. CHEM. SOC. 2003, 125, 4692-4693
10.1021/ja029745q CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
no crossover in these transformations; Rh2(OAc)4 catalyzed the
formation of 8, and use of Cu(OTf)2 led only to 9. Stereoselectivity
was high in both transformations, but in the rhodium(II)-catalyzed
reactions only the trans isomer (8) was isolated. A substituent effect
on stereoselectivity was evident in the formation of 9.
Table 2. Imine Substituent Effect on Product Yield and
Selectivities in Reactions with Methyl Styryldiazoacetatea
% yield 8 from
Rh2(OAc)4-catal.b
% yield 9 from
Cu(OTf)2-catal.c
Ar in imine (7)
p-NO2C6H4
p-ClC6H4
C6H5
p-MeC6H4
p-MeOC6H4
12
47
66
56
62
40 (98:2)
66 (96:4)
67 (91:9)
63 (88:12)
74 (83:17)
Lewis acid catalysis of imine addition reactions is a recent
development,5,10-12 and in most instances the activation mechanism
is not known. The present study implicates imine coordination as
an integral step in the addition process with accompanying
stereocontrol. Efforts are underway to develop asymmetric catalytic
analogues of these transformations.
a Reactions performed as in Table 1 with equimolar amounts of 1a and
7. b Only trans-8 was obtained; a minor product having two units of the
vinylcarbene and one of the imine was also obtained. c Trans:cis ratio in
parentheses.
Acknowledgment. Support for this research from the National
Science Foundation and the National Institutes of Health (GM
46503) is gratefully acknowledged.
The dihydropyrrole product formed from 1d with Rh2(OAc)4
catalysis was unstable and converted to the corresponding pyrrole
(5) with loss of HCl. The product from 1a with Cu(OTf)2 was
converted in 96% yield to pyrrole 6 by oxidation with DDQ, thus
demonstrating the accessibility of this methodology to both dihy-
dropyrroles and pyrroles. The p-nitrophenyl group is a suitable
protective group that can be conveniently removed (reduction of
NO2/CAN oxidation).2
Supporting Information Available: Experimental procedures and
product analyses (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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recovered under the same conditions used with 1a-d,f. However,
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