Acid-catalyzed cyclization of vinylsilanes bearing an amino group. Stereoselective synthesis of pyrrolidines

Article abstract of DOI:10.1021/ol991341o

(FORMULA PRESENTED) In the presence of an acid catalyst, vinylsilanes 1 bearing an amino group protected by an electron-withdrawing group were smoothly cyclized to 2-(silylmethyl)pyrrolidines 2. This cyclization was utilized for the stereoselective synthe

Full text of DOI:10.1021/ol991341o

ORGANIC
LETTERS
2000
Vol. 2, No. 3
385-388
Acid-Catalyzed Cyclization of
Vinylsilanes Bearing an Amino Group.
Stereoselective Synthesis of
Pyrrolidines1
Katsukiyo Miura, Takeshi Hondo, Takahiro Nakagawa, Tatsuyuki Takahashi, and
Akira Hosomi*
Department of Chemistry and Graduate School of Chemistry, UniVersity of Tsukuba,
Tsukuba, Ibaraki 305-8571, Japan
hosomi@staff.chem.tsukuba.ac.jp
Received December 13, 1999
ABSTRACT
In the presence of an acid catalyst, vinylsilanes 1 bearing an amino group protected by an electron-withdrawing group were smoothly cyclized
to 2-(silylmethyl)pyrrolidines 2. This cyclization was utilized for the stereoselective synthesis of 2,n-disubstituted pyrrolidines (n ) 3−5). The
cyclized products could be converted to the corresponding alcohols by oxidative cleavage of the carbon−silicon bond with TBAF and H O .
2
2
In recent years, the silicon-directed reactions via intramo-
lecular nucleophilic addition to a â-silylcarbenium ion
intermediate, particularly [3 +2 ] cycloadditions of allylsi-
lanes to electron-deficient unsaturated bonds, have been
proven to provide an efficient and reliable method for the
stereoselective synthesis of carbocycles and heterocycles
containing an oxygen or nitrogen atom.2-5 In this context,
we have reported that vinylsilanes bearing a hydroxy group
undergo acid-catalyzed cyclization to give tetrahydrofurans
with high levels of diastereoselectivity, and the cyclization
proceeds through a stepwise mechanism including protona-
tion of the R-carbon and intramolecular addition of the
oxygen nucleophile to the formed â-silylcarbenium ion
intermediate (Scheme 1).6,7 Thus, our attention was next
(1) Studies on Organosilicon Chemistry. 151.
(2) Reviews: (a) Kno¨lker, H.-J. J. Prakt. Chem. 1997, 339, 304. (b)
Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293. (c) Panek, J. S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 1, p 579.
Scheme 1
(3) Recent reports on [3 + 2] cycloadditions of allylsilanes: (a) Roberson,
C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434. (b) Kno¨lker, H.-J.;
Jones, P. G.; Wanzl, G. Synlett 1998, 613. (c) Akiyama, T.; Hoshi, E.;
Fujiyoshi, S. J. Chem. Soc., Perkin Trans. 1 1998, 2121. (d) Akiyama, T.;
Yamanaka, M. Tetrahedron Lett. 1998, 39, 7885. (e) Groaning, M. D.;
Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998, 63, 5517.
(4) Other reactions via â-silylcarbenium ions generated from allylsi-
lanes: (a) Sugimura, H. Tetrahedron Lett. 1990, 31, 5909. (b) Kiyooka,
S.; Shiomi, Y.; Kira, H.; Kaneko, Y.; Tanimori, S. J. Org. Chem. 1994,
59, 1958. (c) Akiyama, T.; Nakano, M.; Kanatani, J.; Ozaki, S. Chem. Lett.
1997, 385. (d) Brocherieux-Lanoy, S.; Dhimane, H.; Poupon, J.-C.; Vanucci,
C.; Lhommet, G.; J. Chem. Soc., Perkin Trans. 1 1997, 2163. (e) Monti,
H.; Rizzotto, D.; Le´andri, G. Tetrahedron 1998, 54, 6725. (f) Akiyama,
T.; Ishida, Y. Synlett 1998, 1150; 1999, 160. (g) Akiyama, T.; Ishida, Y.;
Kagoshima, H. Tetrahedron Lett. 1999, 40, 4219.(h) Sugita, Y.; Kimura,
Y.; Yokoe, I. Tetrahedron Lett. 1999, 40, 5877. (i) Angle, S. R.; El-Said,
N. A. J. Am. Chem. Soc. 1999, 121, 10211.
focused on the application of this cyclization to the construc-
tion of cyclic amines.1
Cyclization of alkenyl amines is one of the most straight-
forward routes to cyclic amines.8 Although several methods
(5) Reactions using vinylsilanes: (a) Brook, M. A.; Sebastian, T.;
Jueschke, R.; Dallaire, C. J. Org. Chem. 1991, 56, 2273. (b) Brook, M. A.;
Henry, C.; Jueschke, R.; Modi, P. Synlett 1993, 97. (c) Yamazaki, S.;
Tanaka, M.; Yamabe, S. J. Org. Chem. 1996, 61, 4046.
10.1021/ol991341o CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/07/2000

have been developed to realize this strategy, acid-catalyzed
systems are rarely utilized for the cyclization.4g Herein, we
report that the cyclization of vinylsilanes bearing an amino
group protected by an electron-withdrawing group is ef-
fectively promoted by an acid catalyst, and it serves for the
stereoselective synthesis of 2,n-disubstituted (n ) 3-5)
pyrrolidines.9
1g was also efficiently converted to the corresponding
pyrrolidine 2g (entry 11), which could be easily unprotected
by the action of 3 M HCl in MeOH (Scheme 2). Interestingly,
Scheme 2
Initially, vinylsilane 1a (P, R ) Bn) bearing a benzylamino
group was used as a substrate. The TiCl4-catalyzed reaction,
however, gave no cyclized product. This seemed to be due
to the low acidity of the proton on the nitrogen, which would
prevent protonation of the carbon R to the silyl group (vide
infra). Therefore, the amino group was protected by an
electron-withdrawing group for promotion of the acid-
catalyzed cyclization. As expected, treatment of N-acetyl-
protected substrate 1b with a catalytic amount of TiCl4 or
TsOH gave the corresponding cyclized product, pyrrolidine
2b, although the yield was rather low (entries 1 and 2 in
Table 1). Sulfonyl groups were effective in accelerating the
the cyclization of 1g was only slightly induced by TsOH
(entry 12). The reactivity of vinylsilanes was affected by
the substituent on the silicon as well as nitrogen. The change
of the benzyl to a phenyl group diminished the cyclization
rate (entries 13 and 14). This observation is consistent with
our previous results in the cyclization to tetrahydrofurans.10
While the present method was applicable to the synthesis
of piperidines 5 (Table 2), the cyclization efficiency de-
Table 1. Acid-Catalyzed Cyclization of Vinylsilanes 1a
Table 2. Acid-Catalyzed Cyclization of Vinylsilanes 4a
vinylsilane
yield (%)
entry
P
R
condnsa
time (h)
2
3
vinylsilane
R
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ac
Bn
Bn
Bn
Bn
Bn
Bn
Ph
1b
1b
1c
1c
1d
1d
1e
1e
1f
A
B
Ab
B
A
B
A
B
A
B
A
B
A
B
24
24
34
48
3.3
3.3
1.2
1.2
44
11
24
25
11
6.5
26c
14c
33
78
93
96
90
86
64d
0
entry
condnsa
time (h)
5
6
0
55
<1
5
CF3CO
Ts
1
2
3
4
Bn
4a
Ab
B
Ab
24
24
3.5
22
54
75
78
76
45
25
21
15
4a
4b
4b
CHMePh
<4
B
Ms
a,b See footnotes a and b in Table 1.
Tf
1f
92
Boc
Ts
1g
1g
1h
1h
89e
<1d
80
creased because of competitive desilylation to 6. For inhibi-
tion of the desilylation, a more bulky substituent, a 1-phen-
ylethyl group, was introduced on the silicon atom instead of
the benzyl group (entries 3 and 4).11 The change of
substituent suppressed the desilylation and somewhat im-
proved the yield of 5 in the TiCl4-catalyzed system.
0
9
5
92
a All reactions were performed with a vinylsilane (0.50 mmol) in CHCl3
(2.5 mL). Condition A: TiCl4 (5 mol %) at room temperature. Condition
B: TsOH‚H2O (5 mol %) at 60 °C. b 10 mol % of TiCl4. c Estimated by
1H NMR analysis of the crude product including 1b and 2b. d More than
95% of 1g and 20% of 1f were recovered. e A mixture of 2d (89%) and 1d
(7%) was obtained after purification by column chromatography.
We next investigated the diastereoselectivity of the present
cyclization using racemic vinylsilanes 7a-c with a phenyl
group on the methylene tether (Scheme 3). The TiCl4 (5 mol
%)-catalyzed reaction of 7a at room temperature gave 2,5-
disubstituted pyrrolidine 8a in a moderate yield with low
cis-selectivity. This result stands in sharp contrast to our
previous finding that the acid-catalyzed addition of a hydroxy
cyclization, and a tosyl group provided the best result among
the examined protective groups (entries 5 and 6). In the
presence of the TiCl4 catalyst, N-Boc-protected vinylsilane
(6) (a) Miura, K.; Okajima, S.; Hondo, T.; Hosomi, A. Tetrahedron Lett.
1995, 36, 1483. (b) Miura, K.; Hondo, T.; Okajima, S.; Hosomi, A.
Tetrahedron Lett. 1996, 37, 487. (c) Miura, K.; Hondo, T.; Saito, H.; Ito,
H.; Hosomi, A. J. Org. Chem. 1997, 62, 8292.
(7) Related work: Adiwidjaja, G.; Flo¨rke, H.; Kirschning, A.; Schau-
mann, E. Liebigs Ann. 1995, 501.
(9) We used only (Z)-vinylsilanes as substrates in the present work
because (E)-isomers exhibit lower reactivity and stereoselectivity than (Z)-
isomers in the cyclization shown in Scheme 1. See ref 6.
(10) Miura, K.; Hondo, T.; Hosomi, A. Manuscript submitted.
(11) Kno¨lker, H.-J.; Foitzik, N.; Goesmann, H.; Graf, R. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1081.
(8) Jahn, U.; Aussieker, S. Org. Lett. 1999, 1, 849 and references therein.
386
Org. Lett., Vol. 2, No. 3, 2000

group to vinylsilanes is valuable for the synthesis of trans-
2,5-disubstituted tetrahydrofurans (Scheme 1).6b In this case,
unreacted 7a was recovered in 29% yield. An increased
amount of TiCl4 effected complete conversion of 7a but did
not improve the yield of 8a because of a considerable
formation of 9a. However, it led to higher cis-selectivity of
8a. TsOH was more effective in the cyclization of 7a, which
exhibited no stereoselectivity. The cyclization of 7b pro-
ceeded much faster than that of 7a, forming 8b in a high
yield with high cis-selectivity. Lowering the reaction tem-
perature further improved the selectivity. The allylic phenyl
group of 7c completely controlled the diastereoselectivity,
and only trans-8c was obtained independently of the reaction
conditions.
Scheme 4
Scheme 3
forms a â-silylcarbenium ion intermediate, and (3) nucleo-
philic attack of the nitrogen to the positively charged carbon
from the opposite site to the silyl group gives a cyclic amine
and regenerates the acid catalyst. This mechanism indicates
that the proton transfer in step 2 and the nucleophilic attack
in step 3 take place on the same side of the initial π-face,
and the diastereoselectivity in the cyclization of 7 is
determined in step 2.6b Therefore, the high stereoselectivity
with 7b and 7c is attributable to diastereoface-selective
protonation via chairlike conformations B and C bearing a
phenyl group at the pseudoequatorial position. On the other
hand, a similar conformation A arising from 7a would be
destabilized by the steric repulsion between the phenyl and
protective groups, which reduces the energy difference
between A and another conformation (A′). This consideration
provides a reasonable explanation for the low selectivity in
the TsOH-catalyzed cyclization of 7a.
Scheme 5
The increased cis-selectivity in the cyclization of 7a using
20 mol % of TiCl4 is attributable to fast desilylation of trans-
8a. Indeed, treatment of a ca. 1:1 diastereomeric mixture of
8a with 20 mol % of TiCl4 gave a cis-rich mixture of 8a
and desilylated product 9a (Scheme 4). The use of 50 mol
% of TiCl4 completely desilylated trans-8a to 9a, and only
cis-8a was recovered in 49% yield. The trans-selective
desilylation resulted probably because the cis-isomer is
thermodynamically more stable than the trans-isomer, which
has an unfavorable steric interaction between the tosyl and
silylmethyl groups or the phenyl and tosyl groups.
From our previous results,6b the present cyclization of 1
is considered to proceed via a mechanism comprising the
following steps (Scheme 5): (1) an acid adds to the protected
amino group of 1 on the nitrogen atom and/or the oxygen
atom of the protective group,12 (2) intramolecular proton
transfer from the nitrogen to the carbon R to the silyl group
To enhance the synthetic utility of the present cyclization,
we attempted oxidative cleavage of the silicon-carbon bond
of the cyclized products. As shown in Scheme 6, benzyldi-
methylsilyl and dimethyl(1-phenylethyl)silyl groups could
beconverted to hydroxy groups in high yield with stereo-
chemical retention by the Tamao method.13
(12) For simplification, attachment of an acid to the oxygen atom or
both the nitrogen and oxygen atoms is not depicted in Scheme 5. In these
cases also, the reaction mechanism and the stereochemical outcome can be
explained as in the text.
In conclusion, we have developed a new method for the
stereoselective construction of cyclic amines utilizing the
Org. Lett., Vol. 2, No. 3, 2000
387

Acknowledgment. This work is supported by Grants-in-
Aid for Scientific Research on Priority Areas from the
Ministry of Education, Japan. We thank Dow Corning Toray
Silicone Co. Ltd. and Shin-Etsu Chemical Co. Ltd. for a gift
of organosilicon reagents. T.H. thanks the Japan Society for
the Promotion of Science for Young Scientists for a research
fellowship.
Scheme 6
Supporting Information Available: Experimental pro-
cedure, stereochemical assignment, and spectral data for the
substrates and the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL991341O
reactivity of vinylsilanes. The scope and limitations of the
present cyclization are now under investigation, and the
results will be presented in due course.
(13) (a) Tamao, K.; Ishida, N. J. Organomet. Chem. 1984, 269, C 37.
(b) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.; Andersson,
P. G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487.
388
Org. Lett., Vol. 2, No. 3, 2000