Chirality transfer in the ene-reactions of 3-{2-(2s)-[2-(substituted)vinyl]pyrrolidin-1-yl}-2-(substituted)acrolein derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01536-7

Ene-reactions of 3-{2-(2S)-[2-(substituted)vinyl]pyrrolidin-1-yl}-2-(substituted)acrolein derivatives 5, 8, 13, and 16 have been described. Carbonyl-ene reaction of 5 and 16 and imine-ene reaction of 8 proceeded in a highly selective manner to lead to azepine derivatives 6 and 17, and 9, respectively. The chirality of the starting acroleins was transferred almost perfectly to the azepine-ring through the ene reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01536-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8489–8493
Chirality transfer in the ene-reactions of 3-{2-(2S)-
[
2-(substituted)vinyl]pyrrolidin-1-yl}-2-(substituted)acrolein
derivatives
a,
a
a
a
Michihiko Noguchi, * Ryo Matsushita, Shinji Takamura, Takehiko Uchida,
b
c
a
Akikazu Kakehi, Motoo Shiro and Hidetoshi Yamamoto
a
Department of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
b
Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato,
Nagano 380-8553, Japan
c
Rigaku X-Ray Research Laboratory, Rigaku Corporation, Matsubara, Akishima, Tokyo 196-0003, Japan
Received 5 July 2000; revised 7 September 2000; accepted 8 September 2000
Abstract
Ene-reactions of 3-{2-(2S)-[2-(substituted)vinyl]pyrrolidin-1-yl}-2-(substituted)acrolein derivatives 5, 8,
3, and 16 have been described. Carbonyl-ene reaction of 5 and 16 and imine-ene reaction of 8 proceeded
1
in a highly selective manner to lead to azepine derivatives 6 and 17, and 9, respectively. The chirality of
the starting acroleins was transferred almost perfectly to the azepine-ring through the ene reactions.
©
2000 Elsevier Science Ltd. All rights reserved.
Keywords: ene reactions; cyclization; enantioselection; azepines.
Construction of new strategies for the stereoselective synthesis of azepines continues to attract
1
interest in heterocyclic chemistry, and various methods have been proposed toward this goal.
We have also reported that ene reactions of 3-[(E)-alk-2-enyl]amino-2-cyano- and 3-[(E)-alk-2-
enyl]amino-2-(methoxycarbonyl)-acroleins and their imines and vinyl substrates have been
revealed to be a powerful and effective tool for mono-cyclic 4,5-dihydro-1H-azepine deriva-
2
tives. Therein, we proposed that this azepine ring formation from acyclic systems constitutes of
two consecutive orbital-allowed reactions: the [1,6] sigmatropic shift of the allylic hydrogen (TS
1
) generating a conjugated azomethine ylide (Intermediate) and its [1,7] electrocyclic ring closure
(
TS 2). This means that the azepine ring formation is expected to proceed in a highly selective
manner. In continuation of our study, we examined the ene reaction of the titled acrolein
derivatives bearing a chiral center at the alkenylamino moiety and their imines and vinyl
compounds, so as to develop further utility of these ene reactions.
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01536-7

8490
At first, 3-{2-(2S)-[2-(E)-(ethoxycarbonyl)vinyl]pyrrolidin-1-yl}-2-cyanoacrolein 5a and {2-
2S)-[2-(E)-cyanovinyl]pyrrolidinyl} substrate 5b were prepared by the reaction of 3-butoxy-2-
cyanoacrolein 2 and pyrrolidine 4a and 4b in moderate to poor yields, respectively. These
acrolein derivatives 5a and 5b were obtained as ca. 4:1 inseparable mixtures of two geometric
isomers, and the mixtures were utilized for the ene reaction without further purification due to
their low instability (Scheme 1).
(
3
Scheme 1.
Heating 5a and 5b in refluxing toluene gave 7,9a-oxapyrrolo[1,2-a]azepines 6a and 6b in
moderate to good yields as single isomers, together with unidentified polymeric products. The
reaction of acrolein 5a and aniline (7a) in refluxing xylene in the presence of toluene-p-sulfonic
acid (PTSA) gave 7,9a-iminopyrrolo[1,2-a]azepine 9a, via the corresponding imine ene reaction
4
of 8a, and vinamidine 10a in 68 and 20% yield, respectively. Further reaction of 5a with chiral
primary amines 7b–d also gave iminopyrroloazepines 9b–d and vinamidines 10b–d in good total
yields (Table 1). Iminopyrroloazepines 9b–d obtained were revealed to be single isomers (d.e:
1
>
99%) from the H NMR spectra and/or HPLC of the crude reaction mixtures. This means that
the imine-ene reaction from acroleins 5a and 7b–d proceeds with perfect induction of the
chirality in acrolein 5a on the resulting three chiral centers of the iminopyrroloazepine nuclei of
9
b–d. To elucidate the efficiency of the chirality transfer of these ene reactions, we performed
similar carbonyl- and imine-ene reactions using a racemic substrate (rac)-5a from (rac)-3a as a
reference. High enantioselectivity of the reactions utilizing chiral substrates was attained by a
5
chiral HPLC method; the e.e. of carbonyl-ene product 6a was 98% from the starting -proline,
L
while that of imine-ene product 9a was 93%; therefore, the enantioselectivity of the ene reaction
process was more than 98 and 93%, respectively. In order to obtain a more precise understand-
Table 1
Reaction of chiral aldehyde 5a and primary amines 7
a
Run Amine Solvent
Additive
Time/h
Iminopyrroloazepine/yield (%);
selectivity
Vinamidine/yield
(%)
a
1
2
3
4
7a
7b
7c
7d
Xylene
Toluene MS (4 A
Xylene
Xylene
PTSA (cat.)
2.5
6
1
9a/68; e.e.: \93
9b/66; d.e.: \99
9c/63; d.e.: \99
9d/34; d.e.: \99
10a/20
10b/25
10c/21
10d/45
,
)
)
)
MS (4 A
MS (4 A
,
,
1
a
Based on isolated product.

8491
ing of the reaction pathway, we examined the absolute structure of 7,9a-iminopyrrolo[1,2-
a]azepines 9; the structure of 9b, obtained from acrolein 5a and (R)-1-phenylethylamine (7b),
6
was unambigiously established by X-ray single-crystal analysis. Therefore, the stereochemistry
of azepine derivative 11b, the precursor of 9b, was deduced to be (7S,8S) based on the absolute
R configuration derived from the 1-phenylethylamino moiety. The structure of the azomethine
ylide intermediate 12b was deduced by the conrotatory ring-opening of azepine 11b. The
formation of intermediate 12b was ascribed to the antarafacial [1,6]hydrogen shift of the chiral
imine 8b (Scheme 2).
Scheme 2.
Stimulated by these results, we further examined chiral transfer of the olefin-ene reaction of
7
the related system; condensation of acrolein 5a with dimethyl malonate gave conjugated diene
compound 13a. Thermal reaction of 13a in refluxing toluene proceeded in a highly stereoselec-
tive manner to afford pyrroloazepine derivative 14a (chemical yield: 86%; e.e.: 58% from 3a). As
regards the lowered e.e. of azepine 14a, it occurred to us that the condensation conditions from

8492
acrolein 5a and dimethyl malonate would cause a racemization of conjugated diene 13a. To
check this possibility, we examined the e.e. of the starting conjugated diene 13a. Unfortunately,
we have not succeeded in finding the optimal HPLC conditions to separate the two enantiomers
of (rac)-11a. Our next concern was focussed on the reaction of 3-{2-(2S)-[2-(E)-(ethoxy-
carbonyl)vinyl]pyrrolidin-1-yl}-2-(methoxycarbonyl)acrolein 16a and {2-(2S)-[2-(E)-cyanovinyl]-
pyrrolidinyl} substrate 16b; they were expected to have higher reactivity toward these ene
reactions than the 2-cyano derivatives 5 due to the restriction of configurational and/or
2
conformational flexibility of the substrates. The desired 16a and 16b were prepared from
8
2
-(methoxycarbonyl)malonaldehyde (15) in moderate yield, similarly to the method for
acroleins 5. Interestingly, acroleins 16 were not so stable and cyclized spontaneously at room
temperature to afford oxapyrroloazepines 17a and 17b in almost quantitative yields. The
efficiency of the chirality transfer in the carbonyl-ene reaction was almost perfect (e.e.: more
than 98%). Unfortunately, the preparation of imines from acrolein 14a failed due to its too-high
reactivity toward the carbonyl-ene reaction; the reactions of 14a with aniline and N-
(
triphenylphosphoranylidene)aniline under several conditions gave only oxapyrroloazepine 17a
and vinamidine 10a (Scheme 3).
Scheme 3.
In conclusion, an almost perfect chirality transfer has been accomplished in the carbonyl- and
imine-ene reactions of the titled systems leading to enantiopure functionalized pyrroloazepines
and related compounds. These findings should lead to a useful application of the ene reactions
to further chiral induction, and employment of the resulting products as asymmetric building
blocks.

8493
Acknowledgements
We thank Ube Industries Ltd. for a gift of 1,3,3-tributoxy-2-cyanopropene. The author
M.N.) is also grateful for the financial support by a Grant-in-Aid for Scientific Research No.
(
0
9650940 from the Ministry of Education, Science, Sports and Culture of Japan.
References
1. For a recent review on the preparation and properties of azepines: Proctor, G. R.; Redpath, J. In The Chemistry
of Heterocyclic Compounds; Taylor, E. C., Ed. Monocyclic azepines. Wiley-Interscience Publication: Chichester,
1996; Vol. 56.
2
. (a) Noguchi, M.; Yamada, H.; Takamura, S.; Uchida, T.; Hironaka, M.; Kakehi, A.; Yamamoto, H. Eur. J. Org.
Chem. 2000, 1489–1496. (b) Noguchi, M.; Yamada, H.; Takamura, S.; Okada, K.; Kakehi, A.; Yamamoto, H.
Tetrahedron 2000, 56, 1299–1307 and references cited therein.
3. Fuji, T.; Ohba, M.; Sakari, M.; Matsubara, S. Chem. Pharm. Bull. 1990, 38, 2702–2706 and references cited
therein.
4. Preparation and physical properties of vinamidine derivatives including 10a: Kamimura, A.; Sato, E.; Kanayama,
D.; Noguchi, M., unpublished data.
5
6
. In the cases of other ene reactions, e.e.s were determined based on N-Boc pyrrolidines 3a and 3b.
. Crystallographic data for the structure of 7,9a-iminopyrrolo[1,2-a]azepines 9b have been deposited with the
Cambridge Crystallographic Data Centre No. 146707.
7
8
. (a) Lehnert, W. Tetrahedron 1972, 28, 663–666. (b) Lehnert, W. Tetrahedron 1973, 29, 635–638.
. B u¨ chi, G.; Carlson, J. A.; Powell Jr., J. E.; Tietze, L.-F. J. Am. Chem. Soc. 1973, 95, 540–545.
.