A radical cyclization route to pyrrolidines based on conjugate addition to electron deficient phenylselenenylalkenes

Article abstract of DOI:10.1016/S0040-4039(00)00446-9

α-Phenylselenenyl-α,β-unsaturated esters, amides, ketones, nitriles and sulfones were prepared by zinc chloride promoted chloroselenation/dehydrochlorination of the corresponding α,β-unsaturated compounds. After Michael addition of allyl or propargylamine and triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane, pyrrolidine and dihydropyrrole derivatives, respectively, were obtained. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00446-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3701–3704
A radical cyclization route to pyrrolidines based on conjugate
addition to electron deficient phenylselenenylalkenes
Stefan Berlin and Lars Engman ∗
Uppsala University, Institute of Chemistry, Department of Organic Chemistry, Box 531, S-751 21 Uppsala, Sweden
Received 17 February 2000; accepted 13 March 2000
Abstract
α-Phenylselenenyl-α,β-unsaturated esters, amides, ketones, nitriles and sulfones were prepared by zinc chloride
promoted chloroselenation/dehydrochlorination of the corresponding α,β-unsaturated compounds. After Michael
addition of allyl or propargylamine and triethylborane initiated reductive radical cyclization in the presence of
tris(trimethylsilyl)silane, pyrrolidine and dihydropyrrole derivatives, respectively, were obtained. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: selenium and compounds; radicals and radical reactions; pyrrolidines; addition reactions.
Vinylic selenides can be easily prepared by a variety of methods.1 Their usefulness in synthesis stems
from the ability of the heteroatom to stabilize both negative2 and positive3 charges and from the inherent
weakness of the carbon–selenium bond. Thus, under the proper reaction conditions, vinylic selenides
undergo Michael addition with alkyllithiums whereas sterically hindered bases deprotonate them α to
selenium. Under acidic conditions, vinylic selenides are hydrolyzed to carbonyl compounds.4 Cross-
coupling with various organometallic reagents is catalyzed by transition metals.5 In addition, certain
vinylic selenides undergo vinylic substitution6 and cycloaddition and ene reactions.7
Piancatelli and co-workers recently reported the conjugate addition of nucleophiles (alkyllithiums8
and amines9) to α-phenylselenenyl-α,β-unsaturated esters. It occurred to us that a tandem conjugate
addition–radical cyclization as shown in eqn 1 could provide a useful entry to a variety of heterocyclic
compounds. Vinylic selenides 1 are most conveniently10 accessed by addition of phenylselenenyl chloride
to electron deficient olefins, followed by base-induced dehydrochlorination.11,12 However, in contrast to
∗
Corresponding author. Tel: 46 18 4713784; fax: 46 18 512524; e-mail: lars.engman@kemi.uu.se (L. Engman)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00446-9
tetl 16726

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simple alkenes, electron deficient ones react slowly and sometimes incompletely with phenylselenenyl
chloride.13,14 Some time ago, zinc chloride was shown to greatly promote addition of phenylselenenyl
chloride to α,β-unsaturated esters.14 We have found that the binary reagent PhSeCl–ZnCl2 adds essen-
tially instantaneously to a variety of electron deficient olefins (Table 1, eqn 2). After removal of zinc
residues, the crude addition product can be treated with triethylamine12 to obtain good overall yields of
a variety of electron deficient phenylselenenylalkenes 1. For some reason, triethylamine induced reversal
of the chloroselenation reaction with the adducts derived from crotonic acid, N,N-dimethylacrylamide
and ethyl cinnamate (Table 1, entries 5, 6 and 12).
Table 1
Preparation of phenylselenenylalkenes 1 from electron deficient olefins by PhSeCl–ZnCl2 addi-
tion/dehydrochlorination
Conjugate addition of allylamine to vinylic selenides 1 proceeded best in a neat solution of the amine
(Table 2, eqn 3). After 30 min at ambient temperature, 1H NMR analysis indicated complete consumption
of the starting material. In the case of β-substituted compounds, a diastereomeric mixture (ca 3:1) of
Michael adducts was obtained and used in the following cyclization reactions. Dimethyl phenylselen-
enylfumarate and dimethyl phenylselenenylmaleate afforded the same mixture of Michael addition
products when treated with allylamine. This shows that the configuration of the vinylic selenide is of little
significance in the preparation of the radical precursor. Reductive radical cyclization was conveniently
effected in toluene at ambient temperature with triethylborane initiation and tris(trimethylsilyl)silane
(TTMSS) serving as the hydrogen atom donor (Table 2, eqn 3). Since chromatographic purification
of the pyrrolidines formed was difficult, the crude reaction product was routinely treated with tosyl
chloride/triethylamine before isolation. As seen in Table 2, β-unsubstituted vinylic selenides 1 afforded
N-tosyl-3,4-disubstituted pyrrolidines 2 in fair to good yields as mixtures of cis- and trans-isomers. Here,
it should be noted that epimerization to the thermodynamically favoured trans-isomer is possible. Thus,
treatment of compound 2a (Table 2, entry 1) with sodium methoxide in refluxing methanol afforded
compound 2b. The unstable12 α-phenylselenenylacrolein failed to undergo a clean conjugate addition
with allylamine. Unfortunately, the two diastereomers formed in the conjugate addition of allylamine to
the β-substituted vinylic selenides could not be separated and cyclized separately. However, in view of the
radical stabilizing effect of the electron withdrawing substituent, the radical formed prior to cyclization

3703
is expected to be planar/rapidly inverting. Thus, the diastereoselectivity in the cyclization is probably
unrelated to the configuration of the radical precursor.
Table 2
Preparation of N-tosylpyrrolidines 2 from vinylic selenides 1 by tandem allylamine conjugate addi-
tion–radical cyclization
Michael additions of propargylamine to compounds 1 proceeded as readily as those employing
allylamine. However, product yields after radical cyclization/N-tosylation were not as good as those
obtained with allylamine adducts. Thus, the addition product of propargylamine and dimethyl α-
phenylselenenylfumarate (3) afforded only a 31% yield of N-tosyldihydropyrrole 4. The initially formed
exo-methylene pyrrole 5 was clearly the primary product of the reaction (47% yield as determined by 1H
NMR using an internal standard), but it isomerized during N-tosylation. Attempts to isolate compound
5 by chromatography or distillation also caused migration of the exocyclic double bond. The addition
product of propargylamine and α-phenylselenenylacrylonitrile similarly afforded the dihydropyrrole
derivative 6 in 36% yield.
Acknowledgements
Financial support from the Swedish Natural Science Research Council is gratefully acknowledged.

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