Reactions of cyclopropyl aryl ketones with sulfonamides mediated by Zr(OTf)4: Cascade preparation of 5-aryl-3,4-dihydro-2H-pyrrole

Article abstract of DOI:10.1055/s-2004-829062

We found that the Lewis acid Zr(OTf)₄ can effectively promote the ring-opening reaction of cyclopropyl aryl ketones with sulfonamides. By controlling the reaction conditions, we could obtain the ring-opened products 3 and the cyclized products 5 in moderate to good yields. This process provides a novel and efficient route for the synthesis of 5-aryl-3,4-dihydro-2H-pyrrole in the presence of a Lewis acid.

Full text of DOI:10.1055/s-2004-829062

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1622
LETTER
Reactions of Cyclopropyl Aryl Ketones with Sulfonamides Mediated by
Zr(OTf)4: Cascade Preparation of 5-Aryl-3,4-dihydro-2H-pyrrole
R
eactions of Cyclopro
i
A
ry
n
l
K
etones
w
ith Sul
S
fonamide
s
and
h
Z
r(O
T
f)4 i,* Yong-Hua Yang, Bo Xu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: mshi@pub.sioc.ac.cn
Received 29 March 2004
Interestingly, we found that if this reaction was carried out
for a long time (about 2 d), the cyclized products 5 (5-aryl-
3,4-dihydro-2H-pyrrole) were formed in good yields. The
results are summarized in Table 2 (Table 2, entries 1 and
Abstract: We found that the Lewis acid Zr(OTf)4 can effectively
promote the ring-opening reaction of cyclopropyl aryl ketones with
sulfonamides. By controlling the reaction conditions, we could ob-
tain the ring-opened products 3 and the cyclized products 5 in mod-
erate to good yields. This process provides a novel and efficient 3–7).5 In this cyclization reaction, Zr(OTf)4 (50 mol%) is
route for the synthesis of 5-aryl-3,4-dihydro-2H-pyrrole in the pres-
ence of a Lewis acid.
also an effective Lewis acid mediator. Using Lewis acid
BF3·OEt2 (50 mol%) as a promoter, the corresponding cy-
Key words: cyclopropyl aryl ketones, Lewis acid, Zr(OTf)4, ring-
opening reaction, sulfonamides, cyclization, 5-aryl-3,4-dihydro-
2H-pyrrole
clized product 5a was obtained in somewhat lower yield
(52%, Table 2, entry 2). Their structures were determined
by 1H and 13C NMR spectroscopic data and microanalysis.
For sulfonamide 2b similar results were obtained, al-
though this reaction was slower than that of 2a
(Scheme 1). The corresponding ring-opened product 6
was obtained in 30% yield along with the cyclized product
5a in 26% yield after 10 hours at 60 °C in DCE in the pres-
ence of Zr(OTf)4 (100 mol%). When this reaction was car-
ried out for 24 hours in the presence of 50 mol% of
Zr(OTf)4, the cyclized product 5a was formed in 63%
yield as the sole product (Scheme 1).
In recent years, ring-opening reactions of cyclopropyl ke-
tones for the preparation of enolates have attracted much
attention from synthetic organic chemists, and these reac-
tions have been investigated extensively.1,2 However, the
ring-opening reactions of monoactivated cyclopropane
derivatives are generally sluggish due to their low reactiv-
ities towards nucleophiles. Several examples have been so
far reported under severe reaction conditions, for exam-
ple, assisted by stronger nucleophiles such as I– and stron-
ger Lewis acids such as TiCl4,2a or assisted by the b-effect
of silicon atom of trimethylsilyl group.2b Thus, it is neces-
sary to develop a method for the ring-opening reaction of
simple monoactivated cyclopropane derivatives under
mild conditions. Herein, we present a Lewis acid-mediat-
ed ring-opening reaction of arylcarbonyl activated cyclo-
propanes (monoactivated cyclopropane) with sulfon-
amides under mild conditions.
Table 1 Reaction of Various Cyclopropyl Aryl Ketone (0.5 mmol)
with NH2Ts (2a, 1.0 mmol) Mediated by Zr(OTf)4 (100 mol%)
Entry
R
Time (h) Yield (%)a
3
4
The ring-opening reaction of cyclopropyl phenyl ketone
(1a, 0.5 mmol) with NH2Ts (2a, 1.0 mmol) proceeded
smoothly in 1,2-dichloroethane (DCE) in the presence of
Lewis acid Zr(OTf)4 (100 mol%)3 to give product 3a in
85% yield along with trace amount of product 4a for 1.5
hours at 60 °C (Table 1, entry 1).4 Under these reaction
conditions, we examined an array of cyclopropyl aryl
ketones with 2a. The results are summarized in Table 1.
In all cases the corresponding ring-opened products 3
were obtained in moderate to good yields (Table 1, entries
2–6). For cyclopropyl methyl ketone (1g), no reaction
occurred (Table 1, entry 7).
1
2
3
4
5
6
7
C6H5 (1a)
1.5
1.5
2
3a, 85
3b, 68
3c, 65
3d, 41
3e, 36b
3f, 62b
NR
4a, trace
p-FC6H4 (1b)
0
0
0
0
0
p-MeC6H4 (1c)
3,5-(Me)2C6H3 (1d)
p-MeOC6H4 (1e)
2-thiophenyl (1f)
methyl (1g)
2
2
3
10
a Isolated yields.
b Determined by 1H NMR spectroscopy.
SYNLETT 2004, No. 9, pp 1622–1624
2
2.
0
7.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829062; Art ID: U08904ST
© Georg Thieme Verlag Stuttgart · New York

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LETTER
Reactions of Cyclopropyl Aryl Ketones with Sulfonamides and Zr(OTf)4
1623
Table 2 Reaction of Various Cyclopropyl Aryl Ketone (0.5 mmol)
with NH2Ts (1.0 mmol) Mediated by Zr(OTf)4 (50 mol%) for a Long
Reaction Time
Based on the above results, a plausible reaction mecha-
nism for the formation of 3 and 5 is shown in Scheme 3.
The sulfonamide attacks the Lewis acid activated cyclo-
propyl aryl ketone 1 to give the ring-opened zwitterionic
intermediate A. The ring-opened product 3 was then
formed from intermediate A. In the presence of Lewis ac-
id, the further intramolecular attack of the nitrogen atom
in NHSO2R to the carbonyl group of 3 produces the zwit-
terionic intermediate B. The intramolecular elimination
gives another intermediate C and regenerates the Lewis
acid. Usual work-up furnishes the cyclized product 5
(Scheme 3).
Entry
Ar
Time (h)
48
Yield (%)a 5
5a, 80
1
2b
3
4
5
6
7
C6H5 (1a)
C6H5 (1a)
72
5a, 73
p-FC6H4 (1b)
p-MeC6H4 (1c)
3,5-(Me)2C6H3 (1d)
p-MeOC6H4 (1e)
2-thiophenyl (1f)
36
5b, 74
5c, 77
In conclusion, we have found that Lewis acid Zr(OTf)4
can effectively promote the ring-opening reaction of cy-
clopropyl aryl ketones with sulfonamides to give the prod-
ucts 3 and cyclized products 5 in moderate to good yields
during different reaction time. This process provides a
novel and efficient route for the synthesis of 5-aryl-3,4-di-
hydro-2H-pyrrole in the presence of Lewis acid. Efforts
are in progress to elucidate the mechanistic details of this
reaction and to determine its scope and limitations.
48
48
5d, 82
5e, 47
48
48
5f, 82
a Isolated yields.
b Mediated by BF3·OEt2 (0.5 equiv).
Scheme 1
Scheme 3 A plausible reaction mechanism for the reaction of cyclo-
propyl aryl ketone with sulfonamide catalyzed by Lewis acid
In the presence of Zr(OTf)4, we confirmed that 3a could
be transformed to cyclized product 5a in DCE at 60 °C in
86% yield after 36 hours (Scheme 2). The cyclized prod-
uct 5 was therefore indeed derived from the ring-opened
product 3 in the presence of Zr(OTf)4. On the other hand,
we found that p-toluenesulfonyl (Ts) protected benzyl-
amine 7 remained intact under the same conditions for 2
days. In addition, in the presence of acetophenone, no re-
action occurred (Scheme 2). These results suggested that
sulfonyl groups (Ts and Ms groups) were removed during
the ring-closing process.
Acknowledgment
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Chinese Academy of Sciences (KGCX2-210-
01), Shanghai Municipal Committee of Science and Technology,
and the National Natural Science Foundation of China for financial
support (203900502, 20025206 and 20272069).
References
(1) For reviews on the use of cyclopropanes in organic
synthesis, see: (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.;
Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89,
165. (b) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
(c) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
Rev. 2003, 103, 1213. (d) Ichiyanagi, T.; Kuniyama, S.;
Shimizu, M.; Fujisawa, T. Chem. Lett. 1997, 1149.
(e) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 5248.
(f) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 9159.
(2) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.;
Oshima, K. Tetrahedron 2001, 57, 987. (b) Yadav, V. K.;
Balamurugan, R. Org. Lett. 2003, 5, 4281; and references
cited therein.
Scheme 2
Synlett 2004, No. 9, 1622–1624 © Thieme Stuttgart · New York

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1624
M. Shi et al.
LETTER
(3) In the presence of catalytic amount of Zr(OTf)4, a prolonged
reaction time was required. During a prolonged reaction
time, this reaction accompanied the cyclized product 5. In
order to accelerate the reaction rate and let the reaction
complete within a short time to give the ring-opened
compound 3 as a major product, Zr(OTf)4 (100 mol%) was
employed.
(4) A variety of Lewis acids and solvent have been tested in this
reaction (unpublished results from our laboratory). As a
result of these investigations, we found that Zr(OTf)4 is the
best Lewis acid for this reaction.
(5) For other examples of the synthesis of 5-aryl-3,4-dihydro-
2H-pyrrole, see: (a) Stevens, R. V.; Ellis, M. C.; Wentland,
M. P. J. Am. Chem. Soc. 1968, 90, 5576; and references cited
therein. (b) Stevens, R. V.; Wentland, M. P. J. Am. Chem.
Soc. 1968, 90, 5580. (c) Keely, S. L. Jr.; Tahk, F. C. J. Am.
Chem. Soc. 1968, 90, 5584.
Synlett 2004, No. 9, 1622–1624 © Thieme Stuttgart · New York