Highly stereoselective synthesis of cyclopropyl heterocycles via cyclopropanation of olefin with arsonium salt

Article abstract of DOI:10.1002/jhet.5570450105

(Chemical Equation Presented) An efficient and highly stereoselective approach for the preparation of highly functionalized cyclopropyl heterocycles via the cyclopropanation of olefines with arsonium salts in the presence of KF 2H₂O has been developed.

Full text of DOI:10.1002/jhet.5570450105

Jan-Feb 2008
Highly Stereoselective Synthesis of Cyclopropyl Heterocycles via
85
Cyclopropanation of Olefin with Arsonium Salt
a
a, b
a
a
a
Zhongjiao Ren *, Weiguo Cao ,Weiqi Tong , Jie Chen and Changqing Wang
a. Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. China
b. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China
Received October 25, 2006
Ar
H
CN
_
+
KF
.
2H O
2
ArCH=C(CN)HetAr
+
Ph AsCH CORBr
3 2
H
DME r.t.
HetAr
COR
1
2
3
ArHet = 1,3,4-oxadiazole, benzothiazole
R = OCH , Ph, 2-furyl, 2-thiophenyl
79-90 %
3
An efficient and highly stereoselective approach for the preparation of highly functionalized cyclopropyl
.
heterocycles via the cyclopropanation of olefines with arsonium salts in the presence of KF 2H O has been
2
developed.
J. Heterocyclic Chem., 45, 85 (2008).
INTRODUCTION
and pharmaceutical activities. To our knowledge,
relatively little attention has been paid to the stereo-
selective synthesis of tetra-substituted cyclopropane, so it
is a significant subject. Here we report an approach for
highly stereoselective synthesis of functionalized cyclo-
Cyclopropyl heterocyclic compounds now occupy an
important place in bioorganic and pharmaceutical research
due to their biological properties [1], natural occurrence
[
2] and synthetic utility [3]. Moreover, the introduction of
propyl heterocycles from olefins and arsonium salts in the
cyclopropyl group into pharmaceuticals has proved to be
a very efficient strategy for the improvement and
enhancement of their biological activity [4]. These results
stimulated synthetic chemists to develop new and efficient
methods for synthesis of cyclopropyl heterocycles in
order to test their biological activity [5].
.
presence of KF 2H O. (Scheme 1)
2
Scheme 1
Ar
H
CN
_
+
2
KF 2H O
.
DME r.t.
ArCH=C(CN)HetAr + Ph AsCH CORBr
H
3
2
HetAr
In general, the most efficient methods for preparing the
cyclopropyl heterocycles are (1) halomethylmetal-
mediated cyclopropanation, (2) transition metal-catalyzed
decomposition of diazoalkanes and (3) Michael-initiated
ring closure [6]. Although these methods are efficient for
the synthesis of cyclopropyl heterocyclic compounds,
they are often not highly stereoselective, therefore, a
mixture of cis/trans isomers is generally obtained [7-9].
Thus a new efficient and stereoselective approach is still
strongly required.
COR
1
2
3
ArHet = 1,3,4-oxadiazole, benzothiazole
R = OCH , Ph, 2-furyl, 2-thiophenyl
3
The needed olefins incorporating the heterocyclic ring
system are easily prepared via Knoevenagel condensation
of aryl aldehydes with active methylene compounds
possessing heteroaryl and cyano groups. The common
way of generating arsonium ylide is the deprotonation of
In recent years, the concept of privileged structure,
repeatedly occurring in biologically active molecules, has
become important for the design and synthesis of drug
candidates. The 1,3,4-oxadiazole [10] and benzothiazole
arsonium salt with a suitable base [12]. We first test some
.
inorganic bases, such as K CO , NaHCO , KF 2H O [13].
2
3
3
2
[
11] have been employed as a core structural feature of
In model experiment, a mixture of olefin 1a (1 equiv),
arsonium salt 2a (1 equiv) and base (3 equiv) in
many drug candidates due to their wide range of
biological activity. And cyclopropanes, bearing the
appropriate functional groups, have been widely used for
biological and pharmaceutical studies.
dimethoxyethane (DME) was stirred at room temperature.
.
The results showed that KF 2H O as base provided the
2
best yield (Table 1 entry 2). Further, the screening for a
Based on the facts mentioned above, we hope to
construct the cyclopropanes possessing carbonyl, cyano,
aryl and heteroaryl groups in order to test their biological
suitable solvent was performed in the presence of
.
KF 2H O at room temperature. It was found that DME
2
was the best solvent for this reaction (Table 1 entry 5).

8
6
Z. Ren, W. Cao, W.Tong, ,J. Chen and C. Wang
Vol 45
Table 1
The results of the optimization of base and solvent
entry
Base
CO
KF2H
NaHCO
Solvent
Time
h)
24
24
24
Yield
(%)
69
88
78
entry
Base
Solvent
THF
Time
(h)
24
Yield
(%)
77
(
.
1
2
3
K
2
3
DME
DME
DME
4
5
KF2H
2
2
O
O
.
.
2
O
KF2H
CHCl
3
24
86
3
To determine the generality of this approach, a variety
A plausible mechanism for this process may involve
of olefins and arsonium salts were employed in the
reaction under the optimized condition. In all case, the
cyclopropanation reactions proceeded smoothly to afford
the desired cyclopropyl heterocyclic compounds with
high stereoselectivity in high to excellent yields. The
results are summarized in Table 2.
following key steps (Scheme 2).
(1) The arsonium ylide A is formed from arsonium salt
.
with KF 2H O used as base. (2) The arsonium ylide A
2
nucleophilically attacks the olefin B to provide two of
intermediates D or E. Apparently the E should be favored
over the D, due to the steric repulsion between bulky
COR and Ar groups in the conformation of D. (3) The
intramolecular ring closure via intermediate E takes place
to afford the cyclopropane F.
The structures of cyclopropyl heterocycles (3a-s) were
1
confirmed by H NMR, MS, IR, elemental analysis and
X-ray (3a and 3h).
Figure. 1 X-ray structure of compound 3a.
Figure 2. X-ray structure of compound 3h.
Scheme 2
_
.
KF 2H O
2
+
Ph AsCH CO CH Br
Ph As=CHCO CH
3 2 3
3
2
2
3
A
B
N
N
Ph
O
Ph As=CHCO CH
3
+
PhCH=C
3
2
CN
B
C
I
II
+
+
AsPh3
AsPh3
N
N
H
Ph
H
H
Ph
H
CO
2
CH
3
Ph
O
H CO C
H
CO
2
CH
3
3
2
CN
Ph
N
N
N
N
H
_
Ph
_
Ph
NC
NC
O
O
D
E
F

Jan-Feb 2008
Synthesis of Cyclopropyl Heterocycles via Cyclopropanation of Olefin with Arsonium Salt
87
According to the present mechanism, in the structure of
product F the COR and heteroaryl groups are situated on
the same side of the ring. It is obvious that the repulsion
interaction of these groups becomes serious and is
unfavorable for the construction of the structure of
cyclopropane F when R is a bulky heteroaryl (furan or
thiophene) or phenyl group. It is unclear whether this
steric hindrance results in a different configuration of
cyclopropane. The determination of their structures is
useful for understanding the reaction pathway. The
structure of product 3h was determined by X-ray analysis.
The result showed that the configuration of 3h (Fig. 2)
was the same as that of 3a (Fig. 1). It clearly
demonstrated that the stereoselectivity of the reactions
was general. In addition, it confirmed that the
intermediate E played crucial role for stereoselectively
controlling pathway.
In summary, we have developed an approach for the
synthesis of highly functionalized cyclopropyl hetero-
cycles from olefins and arsonium salts in the presence of
.
KF 2H O. Its advantages are mild reaction, high yield and
2
stereoselectivity.
Table 2
Synthesis of Heterosubstituted Cyclopropanes
a
entry
product
3a
3b
3c
3d
3e
Heterosubstituted
oxadiazole
oxadiazole
oxadiazole
oxadiazole
oxadiazole
oxadiazole
oxadiazole
oxadiazole
Ar
R
Time (h)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Yield %
1
2
3
4
5
6
7
8
9
C
6
H
5
OCH
OCH
OCH
OCH
OCH
Ph
Ph
2-furyl
2-thiophenyl
Ph
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
88
90
86
81
83
87
79
87
83
88
89
76
84
81
80
87
86
90
87
p-ClC
p-CH
p-NO
6
H
OC
4
3
6
H
4
2
C
6
H
4
o-ClC
6
H
4
3f
C
6
H
5
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
p-NO
2
C
6
H
4
C
C
6
H
H
5
oxadiazole
6
5
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
C
6
H
5
p-ClC
p-CH
p-CH
m-NO
o-ClC
m-ClC
6
H
4
3
OC
6
H
4
3
C
6
H
4
2
C
H
6
4
H
4
6
6
H
4
Ph
2-furyl
2-furyl
2-thiophenyl
C
6
H
5
24
24
24
p-ClC
p-ClC
6
H
H
4
4
3s
6
[a] Isolated yield
Table 3
Selected bond lengths and bond angels for compounds 3a and 3h
Compound 3a
Lengths
A)
Angels
(deg)
Compound 3h
Lengths
Angels
(deg)
(
(A)
1.480 (3)
1.519 (3)
1.535 (3)
1.486 (3)
1.552 (3)
1.452 (3)
1.467 (3)
C(1)-C(2)
C(1)-C(12)
C(1)-C(3)
C(2)-C(18)
C(2)-C(3)
C(3)-C(20)
C(3)-C(4)
1.488 (2)
1.495 (2)
1.5189 (18)
1.487 (2)
1.543 (2)
1.448 (2)
1.4775 (9)
C(1)-C(2)
C(1)-C(18)
C(1)-C(3)
C(2)-C(4)
C(2)-C(3)
C(3)-C(23)
C(3)-C(10)
C(2)-C(1)-C(12)
C(2)-C(1)-C(3)
C(12)-C(1)-C(3)
C(18)-C(2)-C(1)
C(18)-C(2)-C(3)
C(1)-C(2)-C(3)
C(20)-C(3)-C(4)
C(20)-C(3)-C(1)
C(4)-C(3)-C(1)
C(20)-C(3)-C(2)
C(4)-C(3)-C(2)
C(1)-C(3)-C(2)
122.79 (13)
61.73 (9)
121.22 (12)
119.61 (13)
116.78 (12)
60.12 (9)
112.79 (11)
120.16 (12)
119.65 (11)
115.36 (12)
120.37 (12)
58.15 (9)
C(2)-C(1)-C(18)
C(2)-C(1)-C(3)
C(18)-C(1)-C(3)
C(1)-C(2)-C(4)
C(1)-C(2)-C(3)
C(4)-C(2)-C(3)
C(23)-C(3)-C(10)
C(23)-C(3)-C(1)
C(10)-C(3)-C(1)
C(23)-C(3)-C(2)
C(10)-C(3)-C(2)
C(1)-C(3)-C(2)
117.34 (18)
61.95 (14)
122.14 (17)
125.28 (19)
60.76 (13)
121.73 (18)
111.35 (19)
117.98 (17)
123.48 (18)
115.03 (17)
121.81 (17)
57.28 (13)

8
8
Z. Ren, W. Cao, W.Tong, ,J. Chen and C. Wang
Vol 45
1
3
EXPERIMENTAL
General Experimental Conditions. All reagents and
solvents were obtained from commercial source and used
without purification. The 2-arylidenecyanomethyl-1,3,4-
oxadiazole was prepared according to the literature [14]. The 2-
arylidenecyanomethyl-benzothiazoles was prepared according to
the literature [15]. All melting points were uncorrected. Melting
points were determined on WRS-1 digital melting point
apparatus made by Shanghai physical instrument factory
C nmr (75 MHz, deuteriochloroform): ꢀ 21.1, 34.0, 35.6, 53.1,
5
1
(
5.2, 76.6, 77.0, 77.4, 114.4, 122.5, 123.0, 127.0, 129.1, 129.4,
32.2, 158.5, 160.1, 165.9, 166.4; ir (potassium bromide): 2246
CN), 1731 (CO), 1611, 1549 cm- ; ms (m/z) (%): 375 (4) (M ),
1
+
+
+
3
16 (36) [M-CO CH ] , 77 (77) [Ph-H] . Anal. calcd. for
2 3
C H N O : C, 67.19; H, 4.56; N, 11.19. Found: C, 67.25; H,
4
21 17
3
4
.31; N, 11.09.
Methyl (1R,2R,3S)-2-cyano-3-(4-nitrophenyl)-2-(5-
phenyl-1,3,4-oxadiazol-2-yl)cyclopropanecarboxylate
(3d). This compound was obtained as a white solid, mp 188-189
°C (CH
deuteriochloroform): ꢀ 3.34 (d, J=8.0 Hz, 1H), 3.76 (s, 3H), 4.16
(d, J= 8.0 Hz, 1H), 7.53-7.59 (m, 3H), 7.66 (d, J=8.8 Hz, 2H),
1
(
SPOIF), China. IR spectra were measured in KBr on a PE-580B
2
Cl
2
/petroleum ether; v:v=1:1); H nmr (300 MHz,
1
spectrometer. H NMR spectra were recorded on a Bruker AM-
00 or Bruker AV-500, using CDCl as solvent and TMS as
3
3
1
3
internal reference. Mass spectra were taken with a HP5989A
mass spectrometer at an ionizing voltage of 70 eV. Elemental
analyses were measured on the elementar vario EL III. X-Ray
crystal data were collected with Smart Apex CCD or Bruker
Smart Apex2 CCD.
General procedure for preparing heterosubstituted
cyclopropanes (3a-s). The general process for synthesis of
heterosubstituted cyclopropanes (3a-s) is as follows: a mixture
8.07-8.10 (m, 2H), 8.34 (d, J=8.8 Hz, 2H); C nmr (75 MHz,
deuteriochloroform): ꢀ 21.2, 34.0, 35.0, 53.5, 76.6, 77.0, 77.4,
113.7, 122.8, 124.3, 127.1, 129.1, 129.5, 132.5, 137.9, 148.3,
157.7, 165.7, 166.3; ir (potassium bromide): 2253 (CN), 1731
1
+
(CO), 1607, 1546 cm- ; ms (m/z) (%): 390 (3) (M ), 331 (22)
+
+
[M-CO
CH ] , 77 (77) [Ph-H] . Anal. calcd. for C20H N O : C,
2 3 14 4 5
61.54; H, 3.61; N, 14.35. Found: C, 61.43; H, 3.23; N, 14.29.
Methyl (1R,2R,3S)- 3-(2-chlorophenyl)-2-cyano-2-(5-
of olefin (1) (1 mmole), arsonium salt (2) (1 mmole) and
phenyl-1,3,4-oxadiazol-2-yl)cyclopropanecarboxylate
.
KF 2H O (0.284 g, 3 mmoles) was stirred at room temperature in
(3e). This compound was obtained as a white solid, mp 121-122
2
1
dimethoxyethane (DME) (5 ml). Completion of the reaction was
determined by TLC. The DME was removed under reduced
pressure and the residue was run on a silica gel chromatographic
column (petroleum ether-ethyl acetate, 8:1). Triphenylarsine can
be recovered and the desired products (3) obtained respectively.
Methyl (1R,2R,3S)-2-cyano-3-phenyl-2-(5-phenyl-1,3,
°C (CH
2
Cl
2
/petroleum ether; v:v=1:1); H nmr (300 MHz,
deuteriochloroform): ꢀ 3.29 (d, J=8.0 Hz, 1H), 3.76 (s, 3H), 4.12
(d, J=8.0 Hz, 1H), 7.35-7.42 (m, 3H), 7.51-7.59 (m, 4H), 8.08-
1
3
8.11 (m, 2H); C nmr (75 MHz, deuteriochloroform): ꢀ 20.8,
34.4, 53.2, 76.6, 77.0, 77.4, 114.0, 123.0, 126.9, 127.2, 129.0,
129.3, 130.0, 130.5, 132.2, 135.8, 158.2, 165.8, 166.0; ir
1
4
-oxadiazol-2-yl)cyclopropanecarboxylate (3a). This
(potassium bromide): 2248 (CN), 1738 (CO), 1608, 1549 cm- ;
+
+
compound was obtained as a white solid, mp 173-174 °C
ms (m/z) (%): 381 (2) (M +1), 380 (5) (M ), 321 (30) [M-
CO
1
+
+
(
CH Cl /petroleum ether; v:v=1:1);
H
nmr (300 MHz,
CH ] , 77 (99) [Ph-H] . Anal. calcd. for C20H14ClN O : C,
2 3 3 3
2
2
deuteriochloroform): ꢀ 3.27 (d, J=7.9 Hz, 1H), 3.71 (s, 3H), 4.07
63.25; H, 3.72; N, 11.06. Found: C, 63.25; H, 3.59; N, 11.00.
(
d, J=7.9 Hz, 1H), 7.43-7.50 (m, 5H), 7.64-7.67 (m, 3H), 8.08-
.11 (m, 2H); C nmr (75 MHz, deuteriochloroform): ꢀ 21.1,
4.0, 36.0, 53.2, 76.6, 77.0, 77.4, 114.2, 123.1, 127.1, 128.3,
(1R,2R,3S)-2-Benzoyl-3-phenyl-1-(5-phenyl-1,3,4-oxa-
diazol-2-yl)cyclopropanecarbonitrile (3f). This compound
1
3
8
3
1
was obtained as a white solid, mp >300 °C (decomp.)
1
29.1, 129.2, 130.7, 132.3, 158.4, 166.1, 166.4; ir (potassium
(CH Cl /petroleum ether; v:v=1:1);
H nmr (300 MHz,
2
2
1
bromide): 2245 (CN), 1731 (CO), 1608, 1549 cm- ; ms (m/z)
deuteriochloroform): ꢀ 4.11 (d, J=8.0 Hz, 1H), 4.28 (d, J= 8.0
+
+
+
(%): 345 (2) (M ), 286 (59) [M-CO CH ] , 77 (100) [Ph-H] .
Hz, 1H), 7.45-7.57 (m, 10 H), 7.64-7.66 (m, 1H), 7.97-8.05 (m,
2
3
1
3
Anal. calcd. for C H N O : C, 69.56; H, 4.38; N, 12.17. Found:
C, 69.56; H, 4.21; N, 11.91.
Methyl (1R,2R,3S)-3-(4-chlorophenyl)-2-cyano-2-(5-
phenyl-1,3,4-oxadiazol-2-yl)cyclopropanecarboxylate
4H); C nmr (75 MHz, deuteriochloroform): ꢀ 22.6, 36.2, 37.5,
76.6, 77.0, 77.4, 114.7, 123.0, 127.0, 128.2, 128.4, 128.9 129.0,
129.1, 131.2, 132.1, 134.5, 135.7, 158.6, 165.8, 190.2; ir
2
0
15
3
3
1
(potassium bromide): 2244 (CN), 1673 (CO), 1597, 1551 cm- ;
+
+
(3b). This compound was obtained as a white solid, mp 221-222
ms (m/z) (%): 286 (5) [M- COPh] , 105 (100) [COPh] , 77 (99)
1
+
°
C (CH Cl /petroleum ether; v:v=1:1); H nmr (300 MHz,
[Ph-H] . Anal. calcd. for C H N O : C, 76.71; H, 4.38; N,
2
2
25 17
3
2
deuteriochloroform): ꢀ 3.23 (d, J=8.0 Hz, 1H), 3.72 (s, 3H), 4.04
10.74. Found: C, 76.74; H, 4.28; N, 10.72.
(
2
d, J=8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz,
H), 7.54-7.60 (m, 3H), 8.07-8.12 (s, 2H); C nmr (75 MHz,
(1R,2R,3S)-2-Benzoyl-3-(4-nitrophenyl)-1-(5-phenyl-
1,3,4-oxadiazol-2-yl)cyclopropanecarbonitrile (3g). This
1
3
deuteriochloroform): ꢀ 21.1, 34.0, 35.3, 53.3, 76.6, 77.0, 77.4,
compound was obtained as a white solid, mp 174-175 °C
1
1
1
1
3
14.0, 123.0, 127.1, 129.1, 129.3, 129.4, 129.7, 132.4, 135.3,
58.2, 166.1; ir (potassium bromide): 2249 (CN), 1729 (CO),
(CH Cl /petroleum ether; v:v=1:1);
H nmr (300 MHz,
2
2
deuteriochloroform): ꢀ 4.17 (d, J=8.0 Hz, 1H), 4.38 (d, J=8.0
Hz, 1H), 7.47-7.59 (m, 5H), 7.66-7.75 (m, 3H), 7.96 (d, J= 8.8
1
+
+
605, 1548 cm- ; ms (m/z) (%): 381 (1) (M +1), 380 (5) (M ),
+
+
13
21 (35) [M-CO CH ] , 77 (75) [Ph-H] . Anal. calcd. for
Hz, 2H), 8.03-8.05 (m, 2H), 8.37 (d, J= 8.8 HZ, 2H); C nmr
2
3
C H ClN O : C, 63.25; H, 3.72; N, 11.06. Found: C, 63.46; H,
(75 MHz, deuteriochloroform): ꢀ 22.7, 35.1, 37.5, 76.6, 77.0,
77.4, 114.1, 122.8, 124.2, 127.0, 128.5, 129.1, 129.4, 129.5,
132.3, 134.8, 135.4, 138.5, 148.2, 157.9, 166.1, 189.3; ir
20
14
3
3
3
.57; N, 11.04.
Methyl (1R,2R,3S)-2-cyano-3-(4-methoxyphenyl)-2-(5-
1
phenyl-1,3,4-oxadiazol-2-yl)cyclopropanecarboxylate
3c). This compound was obtained as a white solid, mp 196-197
(potassium bromide): 2245 (CN), 1678 (CO), 1598, 1548 cm- ;
+
+
(
°
ms (m/z) (%): 436 (1) (M ), 331 (4) [M-COPh] , 105 (100)
1
+
+
C (CH Cl /petroleum ether; v:v=1:1); H nmr (300 MHz,
[COPh] , 77 (43) [Ph-H] . Anal. calcd. for C25H N O : C,
16 4 4
2
2
deuteriochloroform): ꢀ 3.23 (d, J=8.0 Hz, 1H), 3.71 (s, 3H),
68.80; H, 3.70; N, 12.84. Found: C, 68.89; H, 3.55; N, 12.73.
(1R,2R,3S)-2-(Furan-2-carbonyl)-3-phenyl-1-(5-phenyl-
1,3,4-oxadiazol-2-yl)cyclopropanecarbonitrile (3h). This
3
7
.84, (s, 3H), 4.02 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H),
.37 (d. J=8.8 Hz, 2H), 7.51-7.58 (m, 3H), 8.07-8.09 (m, 2H);

Jan-Feb 2008
Synthesis of Cyclopropyl Heterocycles via Cyclopropanation of Olefin with Arsonium Salt
89
compound was obtained as a white solid, mp 150-151 °C
114.6, 117.4, 121.7, 123.8, 124.5, 126.0, 126.7, 128.6, 129.1,
1
(
CH Cl /petroleum ether; v:v=1:1);
H
nmr (300 MHz,
129.7, 134.2, 135.5, 136.6, 152.7, 160.1, 160.5, 190.4; ir
2
2
1
deuteriochloroform): ꢀ 4.13 (d, J=8.0 Hz, 1H), 4.24 (d, J=8.0
(potassium bromide): 2244 (CN), 1680 (CO), 1611, 1515 cm- ;
+
+
Hz, 1H), 6.64-6.67 (m, 1H), 7.35-7.37 (m, 1H), 7.44-7.56 (m,
ms (m/z) (%): 410 (14) (M ), 305 (11) [M-COPh] , 105 (100)
13
+
+
8
H), 7.73-7.74 (m, 1H), 8.02-8.06 (m, 2H); C nmr (75 MHz,
[COPh] , 77 (77) [Ph-H] . Anal. calcd. for C H N O S: C,
25 18 2 2
deuteriochloroform): ꢀ 22.4, 36.0, 36.4, 76.6, 77.0, 77.4, 113.2,
73.15; H, 4.42; N, 6.82. Found: C, 73.11; H, 4.24; N, 6.77.
1
1
1
14.5, 119.2, 123.0, 126.9, 128.3, 128.9, 131.1, 132.0, 148.0,
51.9, 158.4, 165.8, 178.6; ir (potassium bromide): 2243 (CN),
(1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(4-
methylphenyl)cyclopropanecarbonitrile (3m). This
1
+
655 (CO), 1609, 1566 cm- ; ms (m/z) (%): 381 (1) (M ), 286
compound was obtained as a white solid, mp 150-151 °C
+
+
+
1
(27) [M-C H O ] , 95 (100) [C H O ] , 77 (15) [Ph-H] . Anal.
(CH Cl /petroleum ether; v:v=1:1);
H nmr (500 MHz,
5
3
2
5
3
2
2
2
calcd. for C H N O : C, 72.43; H, 3.96; N, 11.02. Found: C,
deuteriochloroform): ꢀ 2.38 (s, 3H), 4.07 (d, J=8.0 Hz, 1H), 4.39
(d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.35-7.39 (m, 1H),
7.42 (d, J=8.0 Hz, 2H), 7.46-7.58 (m, 3H), 7.56-7.59 (m, 1H),
7.70 (d, J=8,5 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.00-8.02 (m,
23
15
3
3
7
2.36; H, 3.69; N, 11.04.
(
1R,2R,3S)-2-Phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-
yl)-3-(thiophene-2-carbonyl)cyclopropanecarbonitrile (3i).
1
3
This compound was obtained as a white solid, mp 156-157 °C
2H); C nmr (125 MHz, deuteriochloroform): ꢀ 21.4, 30.7, 36.8,
40.4, 117.3, 121.7, 123.8, 126.o, 126.7, 129.1, 129.5, 135.5,
136.6, 138.8, 152.6, 160.5, 183.5, 190.4; ir (potassium bromide):
1
(
CH Cl /petroleum ether; v:v=1:1).
H nmr (300 MHz,
2
2
deuteriochloroform): ꢀ 3.99 (d, J=8.0 Hz, 1H), 4.27 (d, J=8.0
Hz, 1H), 7.23-7.26 (m, 2H), 7.47-7.56 (m, 7H), 7.78-7.80 (m,
1
2240 (CN), 1680 (CO), 1596, 1518 cm- ; ms (m/z) (%): 393 (M-
1
3
+
+
+
+
1
ꢀ
1
1
1
H), 8.01-8.04 (m, 3H); C nmr (75 MHz, deuteriochloroform):
22.5, 36.3, 37.9, 76.6, 77.0, 77.4, 114.6, 123.1, 127.1, 128.2,
28.7, 129.0, 129.1, 131.1, 132.1, 133.7, 136.1, 142.8, 158.5,
65.9, 182.5; ir (potassium bromide): 2248 (CN), 1650 (CO),
H) , 289 (29) [M-COPh] , 105 (100) [COPh] , 77 (59) [Ph-H] .
Anal. calcd. for C H N OS: C, 76.12; H, 4.60; N, 7.10. Found:
2
5
18
2
C, 76.17; H, 4.30; N, 6.96
(1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(3-
nitrophenyl)cyclopropanecarbonitrile (3n). This
1
+
608, 1546 cm- ; ms (m/z) (%): 397 (1) (M ), 286 (20) [M-
+
+
+
C H OS] , 111 (100) [C H OS] , 77 (14) [Ph-H] . Anal. calcd.
compound was obtained as a white solid, mp 184-185 °C
5
3
5
3
1
for C H N O S: C, 69.50; H, 3.81; N, 10.57. Found: C, 69.56;
(CH Cl /petroleum ether; v:v=1:1);
H nmr (500 MHz,
2
3
15
3
2
2
2
H, 3.43; N, 10.54.
deuteriochloroform): ꢀ 4.17 (d, J=8.0 Hz, 1H), 4.57 (d, J=8.0
Hz, 1H), 7.37-7.40 (m, 1H), 7.45-7.52 (m, 3H), 7.60-7.68 (m,
2H), 7.78 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.97 (d, J=8.0 Hz,
(1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-phenyl-
cyclopropanecarbonitrile (3j). This compound was obtained
1
3
as a white solid, mp 144-145 °C (CH Cl /petroleum ether;
1H), 8.02 (m, 2H), 8.27-8.29 (m, 1H), 8.37 (s, 1H); C nmr
(125 MHz, deuteriochloroform): ꢀ 30.5, 35.5, 40.2, 116.7,
121.8, 123.7, 124.0, 126.3, 126.9, 128.7, 129.2, 130.4, 134.6,
134.9, 135.0, 135.6, 136.1, 148.7, 152.5, 159.1, 189.3; ir
(potassium bromide): 2242 (CN), 1677 (CO), 1594, 1530
2
2
1
v:v=1:1); H nmr (500 MHz, deuteriochloroform): ꢀ 4.09 (d,
J=8.0 Hz, 1H), 4.42 (d, J= 8.0 Hz, 1H), 7.33-7.51 (m, 9H), 7.56-
7
7
3
1
1
1
.59 (m, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H),
13
.99-8.01 (m, 2H); C nmr (125 MHz, deuteriochloroform): ꢀ=
0.6, 36.9, 40.3, 117.2, 121.7, 123.9, 126.1, 126.7, 128.5, 128.6,
28.9, 129.1, 129.2, 132.6, 134.2, 135.6, 135.5, 152.6, 160.3,
90.3; ir (potassium bromide): 2243 (CN), 1680 (CO), 1596,
1
+
+
cm- ; ms (m/z) (%): 426 (2) (M+1) , 320 (18) [M-COPh] ,
+
+
105 (100) [COPh] , 77 (69) [Ph-H] . Anal. calcd. for
C H N O S: C, 67.75; H, 3.55; N, 9.88. Found: C, 67.66; H,
2
4
15
3
3
1
+
513 cm- ; ms (m/z) (%): 275 (28) [M-COPh] , 105 (100)
3.28; N, 9.76.
+
+
[COPh] , 77 (66) [Ph-H] . Anal. calcd. for C H N OS: C,
(1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(2-
chlorophenyl)cyclopropanecarbonitrile (3o). This
compound was obtained as a white solid, mp 145-146 °C
2
4
16
2
7
5.77; H, 4.24; N, 7.36. Found: C, 75.93; H, 4.04; N, 7.36.
(
1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(4-
1
chlorophenyl)cyclopropanecarbonitrile (3k). This
(CH Cl /petroleum ether; v:v=1:1); H nmr (500 MHz, deuterio-
2
2
compound was obtained as a white solid, mp 177-178 °C
chloroform): ꢀ 4.10 (d, J=8.0 Hz, 1H), 4.38 (d, J=8.0 Hz, 1H),
7.35-7.44 (m, 5H), 7.47-7.53 (m, 2H), 7.53-7.55 (m, 1H), 7.58-
7.61 (m, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H),
1
(
CH Cl /petroleum ether; v:v=1:1); H nmr (500 MHz, deuterio-
2
2
chloroform): ꢀ 4.02 (d, J=8.0 Hz, 1H), 4.38 (d, J=8.0 Hz, 1H),
.32-7.35 (m, 1H), 7.43-7.47 (m, 7H), 7.56-7.58 (m, 1H), 7.74
1
3
7
8.02-8.04 (m, 2H); C nmr (125 MHz, deuteriochloroform): ꢀ
30.4, 35.7, 40.4, 117.0, 121.7, 123.9, 126.1, 126.6, 127.4, 128.7,
129.1, 129.6, 130.2, 130.4, 131.3, 134.3, 135.5, 136.4, 136.5,
152.7, 160.2, 190.2; ir (potassium bromide): 2239 (CN), 1668
1
3
(d, J=8.0 Hz,1H), 7.92 (d, J=8.0 Hz, 1H), 7.96-7.98 (m, 2H);
C
nmr (125 MHz, deuteriochloroform): ꢀ 30.5, 36.0, 40.4, 117.0,
1
1
21.7, 123.9, 126.2, 126.8, 128.6, 129.2, 129.4, 129.9, 131.2,
1
+
34.4, 135.0, 135.5, 136.4, 152.6, 159.9, 189.9; ir (potassium
(CO), 1598, 1493 cm- ; ms (m/z) (%): 310 (5) [M-COPh] , 105
+ +
1
bromide): 2240 (CN), 1679 (CO), 1597, 1498 cm- ; ms (m/z)
(100) [COPh] , 77 (65) [Ph-H] . Anal. calcd. for C H ClN OS:
24 15 2
+
+
(%): 105 (100) [COPh] , 77 (62) [Ph-H] . Anal. calcd. for
C, 69.48; H, 3.64; N, 6.75. Found: C, 69.60; H, 3.54; N, 6.72.
(1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(3-
chlorophenyl)cyclopropanecarbonitrile (3p). This
C H ClN OS: C, 69.48; H, 3.64; N, 6.75. Found: C, 69.62; H,
24
15
2
3
.46; N, 6.59.
1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-benzoyl-3-(4-
(
compound was obtained as a white solid, mp 174-175 °C
1
methoxyphenyl)cyclopropanecarbonitrile (3l). This
(CH
2
Cl
2
/petroleum ether; v:v=1:1); H nmr (300 MHz, deuterio-
compound was obtained as a white solid, mp 165-166 °C
chloroform): ꢀ 4.07 (d, J=8.0 Hz, 1H), 4.43 (d, J=8.0 Hz, 1H),
7.35-7.40 (m, 4H), 7.43-7.50 (m, 4H), 7.59-7.62 (m, 1H), 7.78
(d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 8.00-8.02 (m, 2H);
1
(
CH Cl /petroleum ether; v:v=1:1); H nmr (500 MHz, deuterio-
2
2
chloroform): ꢀ 3.83 (s, 3H), 4.04 (d, J=8.0 Hz, 1H)), 4.37 (d,
J=8.0Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.34-7.37 (m, 1H), 7.43
1
3
C nmr (Hz, deuteriochloroform): ꢀ 30.5, 36.0, 40.2, 116.9,
(
d, J=8.5 Hz, 2H), 7.45-7.49 (m, 3H), 7.57-7.61 (m, 1H), 7.78
121.8, 123.9, 126.2, 126.7, 126.8, 128.6, 128.9, 129.1, 129.2,
130.5, 134.2, 134.7, 135.1, 135.6, 136.4, 152.6, 1259.8, 189.8; ir
(potassium bromide): 2239 (CN), 1669 (CO), 1598, 1570 cm- ;
1
3
(d, J=8.0Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.99-8.02 (m, 2H);
C
1
nmr (125 MHz, deuteriochloroform): ꢀ 30.7, 36.6, 40.1, 55.5,

9
0
Z. Ren, W. Cao, W.Tong, ,J. Chen and C. Wang
Vol 45
+
+
ms (m/z) (%): 415 (1) (M ), 310 (4) [M-COPh] , 105 (100)
[
6
Acknowledgements. Thanks are due to the National Natural
Science Foundation of China for financial support (No.
20472047).
+
+
COPh] , 77 (68) [Ph-H] . Anal. calcd. for C H ClN OS: C,
24 15 2
9.48; H, 3.64; N, 6.75. Found: C, 69.47; H, 3.34; N, 6.58.
1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-(furan-2-carbonyl)-
-phenylcyclopropanecarbonitrile (3q). This compound was
(
3
REFERENCE AND NOTES
obtained as a white solid, mp 154-155 °C (CH Cl /petroleum
2
2
1
ether; v:v=1:1); H nmr (500 MHz, deuteriochloroform): ꢀ 4.10
d, J=8.0 Hz, 1H), 4.38 (d, J=8.0 Hz, 1H), 6.59-6.60 (m, 1H),
.29-7.30 (m, 1H), 7.40-7.52 (m, 7H), 7.68 (s, 1H), 7.83 (d,
J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H); C nmr (125 MHz,
deuteriochloroform): ꢀ= 30.6, 31.1, 36.5, 39.2, 113.2, 117.0,
18.9, 121.8, 124.0, 126.2, 126.8, 128.6, 129.0, 129.3, 132.5,
35.8, 147.8, 152.7, 160.2, 178.7; ir (potassium bromide): 2245
CN), 1671 (CO), 1562, 1513 cm- ; ms (m/z) (%): 275 (7) [M-
[
*] Corresponding author, Fax: +86-21-6613-4856; E-mail:
renrui198229@hotmail.com
1] (a) Maag, H.; Nelson, J. T.; Steiner, J. L. R.; Prisbe, E. J. J.
(
7
[
1
3
Med. Chem. 1994, 37, 431. (b) Pevarello, P.; Brasca, M. G.; Orsini, P.;
Traquandi, G.; Longo, A.; Nesi, M.; Orzi, F.; Piutti, C.; Sansonna, P.;
Varasi, M.; Cameron, A.; Vulpetti, A.; Roletto, F.; Alzani, R.; Ciomei,
M.; Albanese, C.; Pastori, W.; Marsiglio, A.; Pesenti, E.; Fiorentini, F.;
Bischoff, J. R.; Mercurio, C. J. Med. Chem. 2005, 48, 2944.
1
1
(
1
+
+
+
[2] (a) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.;
Boyce, C. W.; Boger, D. L. Bioorg. Med. Chem. Lett. 1999, 9, 3087.
C H O ] , 95 (100) [C H O ] , 77 (8) [Ph-H] . Anal. calcd. for
5
3
2
5
3
2
C H N O S: C, 71.33; H, 3.81; N, 7.56. Found: C, 71.03; H,
22
14
2
2
(
b) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386.
3] (a) Swain, N. A.; Brown, R. C. D.; Bruton, G. J. Org. Chem.
004, 69, 122 . (b) Florio, S.; Perna, I. M.; Luisi, R.; Barluenga, J.;
3
.64; N, 7.50.
1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)-
-(furan-2-carbonyl)cyclopropanecarbonitrile (3r). This
[
(
2
2
Faꢀanas, F. J.; Rodríguez, F. J. Org. Chem. 2004, 69, 9204.
compound was obtained as a white solid, mp 179-180 °C
[4] (a) Ali, S. M.; Tedford, C.; Gregory, R.; Handley, M. K.;
Yates, S. L.; Hirth, W. W.; Phillips, J. G. J. Med. Chem. 1999, 42, 903.
1
(
CH Cl /petroleum ether; v:v=1:1);
H nmr (500 MHz,
2
2
(
2
b) Muray, E.; Rifé, J.; Branchadell, V.; Ortuꢀo, R. M. J. Org. Chem.
002, 67, 4520.
5] (a) Esposito, A.; Taddei, M. J. Org. Chem. 2000, 65, 9245.
b) Kazuta, Y.; Matsuda, A.; Shuto, S. J. Org. Chem. 2002, 67, 1669. (c)
deuteriochloroform): ꢀ 4.06 (d, J= 8.0 Hz, 1H), 4.36 (d, J=8.0
Hz, 1H), 6.60-6.61 (m, 1H), 7.28-7.31 (m, 1H), 7.40-7.50 (m,
[
6
1
1
1
2
H), 7.69 (s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 8.01 (d, J= 8.0 Hz,
(
13
H); C nmr (125 MHz, deuteriochloroform): ꢀ 30.5, 35.7, 39.2,
13.3, 119.0, 121.8, 124.0, 126.3, 126.8, 129.5, 130.0, 131.0,
35.0, 135.8, 147.9, 152.6, 159.7, 178.4; ir (potassium bromide):
Rocchetti, M. T.; Fino, V.; Capriati, V.; Florio, S.; Luisi, R. J. Org.
Chem. 2003, 68, 1394. (d) Miki, K.; Yokoi, T.; Nishino, F.; Kato, Y.;
Washitake, Y.; Ohe, K.; Uemura, S. J. Org. Chem, 2004, 69, 1557.
[6] Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977.
1
244 (CN), 1669 (CO), 1561, 1512 cm- ; ms (m/z) (%): 310 (6)
+
+
+
[M-C H O ] , 95 (70) [C H O ] , 77 (12) [Ph-H] . Anal. calcd.
5 3 2 5 3 2
[
7] de Frutos, M. P.; Fernández, M. D.; Fernández-Alvarez, E.;
Bernabé, M. Tetrahedron Lett. 1991, 32, 541.
8] Shimamoto, k.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J.
Org.Chem. 1991, 56, 4167.
9] Ma, D. ; Cao, Y. ; Yang, Y.; Cheng, D. Org. lett. 1999, 1, 285.
10] (a) Omar, F. A.; Mahfouz, N. M. Eur. J. Med. Chem. (italic)
for C H ClN O S: C, 65.27; H, 3.24; N, 6.92. Found: C, 65.40;
22
13
2
2
H, 2.93; N, 6.74.
1R,2R,3S)-1-(Benzo[d]thiazol-2-yl)-2-(4-chlorophenyl)-
-(thiophene-2-carbonyl)cyclopropanecarbonitrile (3s).
This compound was obtained as a white solid, mp >300 °C
[
(
3
[
[
1
(
decomp.) (CH Cl /petroleum ether; v:v=1:1); H nmr (500
2 2
1996, 31, 819. (b) Holla, B, S.; Gonsalves, R.; Shenoy, S. Eur. J. Med.
Chem. (italic) 2000, 35, 267.
MHz, deuteriochloroform): ꢀ 3.97 (d, J=8.0 Hz, 1H), 4.39 (d,
J=8.0 Hz 1H), 7.19 (dd, J=4.0, 4.5 Hz, 1H), 7.38-7.49 (m, 6H),
[11] (a) Hutchinson, I.; Jennings, S. A.; Vishnuvajjala, B. R.;
Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2002, 45, 744 . (b)
Barchéchath, S. D.; Tawatao, R. I.; Corr, M.; Carson, D. A.; Cottam, H.
B. J. Med. Chem. 2005, 48, 6409.
7
.71 (d, J= 4.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.94 (d, J=4.0
13
Hz, 1H), 7.99 (d, J=8.0 Hz, 1H); C nmr (125 MHz,
deuteriochloroform): ꢀ 30.4, 36.1, 40.6, 116.9, 121.8, 124.0,
[
12] He, H. S.; Chung, C. W. Y.; But, T. Y. S.; Toy, P. H.
Tetrahedron 2005, 61, 1385.
13] Ren, Z.; Cao, W.; Ding, W.; Wang, Y.; Wang, L. Synth.
1
1
26.2, 126.8, 128.9, 129.5, 130.0, 131.1, 133.6, 135.1, 135.6,
35.8, 143.5, 152.6, 159.8, 182.2; ir (potassium bromide): 2246
[
1
+
(CN), 1656 (CO), 1557, 1514 cm- ; ms (m/z) (%): 421 (1) (M )
Commun. 2004, 34, 3785.
+
+
+
3
10 (11) [M-C H OS] , 111 (100) [C H OS ] , 77 (15) [Ph-H] .
[14] Milcent, R. Ann, Chim, 1967, 2, 169.
[15] Salto, K.; Kambe, S.; Nakano, Y.; Sakural, A.; Micorikawa,
H. Synthesis 1983, 210.
5
3
5
3
Anal. calcd. for C H ClN OS : C, 62.78; H, 3.11; N, 6.66.
2
2
13
2
2
Found: C, 62.69; H, 2.83; N, 6.42.