A highly regioselective tandem 1,3-dipolar cycloaddition of cyclopropene 1,1-diesters and nitrile oxides: synthesis of highly functionalized isoxazoles

Article abstract of DOI:10.1016/j.tet.2009.09.034

A highly regioselective tandem 1,3-dipolar cycloaddition of cyclopropene 1,1-diesters with nitrile oxides was described. This reaction supplied a new method for synthesis of polyfunctionalized isoxazole derivatives in moderate to excellent yields under mi

Full text of DOI:10.1016/j.tet.2009.09.034

Tetrahedron 65 (2009) 9146–9151
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A highly regioselective tandem 1,3-dipolar cycloaddition of cyclopropene
1,1-diesters and nitrile oxides: synthesis of highly functionalized isoxazoles
*
Shaojin Chen, Jun Ren, Zhongwen Wang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2009
Received in revised form 3 September 2009
Accepted 8 September 2009
Available online 12 September 2009
A highly regioselective tandem 1,3-dipolar cycloaddition of cyclopropene 1,1-diesters with nitrile oxides
was described. This reaction supplied a new method for synthesis of polyfunctionalized isoxazole
derivatives in moderate to excellent yields under mild conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropene
Nitrile oxide
Cycloaddition
Isoxazole
Tandem reaction
1. Introduction
situ from hydroximoyl chlorides), which was quite different from
that of unactivated cyclopropenes reported by Bolesov et al. (Scheme
Developing new cycloaddition reactions1 and tandem2 reactions
of multi-functionalized synthons is one of the most attractive themes
in organic synthesis. Cyclopropenes, the readily accessible and the
smallest unsaturated carbocycles are an important class of synthons
for organic synthesis.3 One of the most important reaction types of
cyclopropenes is the highly strained carbon-carbon double bond-
involved cycloadditions, including 1,3-dipolar cycloaddition (1,3-DC)
reactions3g (e.g., with diazos,4 carbonyl ylides,5 azides,6 nitrile ox-
ides,7 nitrile imines,8 and other 1,3-dipoles9), Diels–Alder cyclo-
additions,10 hetero Diels–Alder cycloadditions,11 Pauson–Khand
reactions,12 [2þ2] cycloadditions13 and [2þ1]14 cycloadditions.15
Several cycloaddition-based tandem ring-opening reactions of
cyclopropenes have also been investigated.16 We noticed that most of
the cyclopropenes applied in the above-mentioned examples are
unactivated or being activated by one electron-withdrawing group
(EWG) at the sp3-carbon of the cyclopropene ring. Our attention has
been drawn to cyclopropenes activated by two geminal EWGs at the sp3-
carbon of the cyclopropene ring, which easily underwent ring-opening
reactions.17 We wondered that the di-activated cyclopropenes
might supply novel cycloaddition-based chemical transformations
for organic synthesis. In our research, we found a novel tandem 1,3-
DC of a cyclopropene 1,1-diester with a nitrile oxide (generated in
1).7 In our result, a post-tandem ring-opening of cyclopropane ring
was involved and an isoxazole heterocycle was obtained. This pro-
vided a new method for synthesis of isoxazole derivatives,18 which
are embedded in a number of pharmaceutically important com-
pounds.19 Herein, we wish to report this tandem reaction. It should
be noted that the regioselectivity for the formation of the poly-
substituted isoxazoles was excellent.
R1 R2
R1=Me, Ph
R1
R2
1
R2=Me, Ph, CN, et al.
(Bolesov et al.)
Ar
O
N
R3
2
3
+
R1, R2=COOMe,
COOEt
R2
R1 R2
R1
R3
Ar
N O
R3
Ar
Ar
O
N
O
N
(This work)
Scheme 1. Cycloaddition reactions of nitrile oxides with cyclopropenes.
2. Results and discussion
Initially, we examined the reaction of cyclopropene 1a and
4-chloro-N-hydroxybenzimidoyl chloride 2a in the presence of
various bases. While imidazole and potassium tert-butoxide were
proved to be good bases (Table 1, entries 3–4 and 7–9), Et3N, DMAP,
K2CO3 and DBU led to relatively lower yields (Table 1, entries 1, 2, 5
* Corresponding author.
E-mail address: wzwrj@nankai.edu.cn (Z. Wang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.034

S. Chen et al. / Tetrahedron 65 (2009) 9146–9151
9147
Table 1
Table 2
Optimization of conditions for the cycloaddition of cyclopropene 1,1-diester 1a with
Reactions of various cyclopropenes 1 and nitrile oxide precursorsa
hydroximoyl chloride 2a in the present of bases.a
CO2R3
R2
R4
CO2R3
R4
R2
R1
CO2R3
R2
R1
Cl
R4
O
Imid.
Cl
OH
O
N
MeO2C CO2Me
+
N
MeO2C CO2Me
+
+
R1
N
DCM, rt.
Cl
Base
rt.
OH
O N
3
Ph
1
2
4
O N
3aa
Cl
Cyclopropenes
1a
2a
MeO2C CO2Me
R
EtO2C CO2Et
Ph CO2Me
Entry
1a:2a (equiv)
Base (equiv)
Solvent
DCM
Time (h)
Yieldc (%)
1b
2
3
4
5
6
7
8
1:2.8
1:2.1
1:2
1:1.4
1:1.4
1:1.4
1:1.4
1:2
1:2.1
1:2.7
1:2.5
1:2.4
1:2.1
1:2.5
Et3N (2)
87
20
72
43
39
115
90
72
29
71
64
48d
84
88
64
64
82
83
77
44
80
77
70
80
Ph
Ph
1f
1d
DMAP (1.5)
Imid. (2.5)
Imid. (1.5)
K2CO3 (1)
DBU (1.5)
KOBut (1.5)
KOBut (2)
KOBut (2.2)
Imd. (4)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
DCE
Et2O
CHCl3
Toluene
1a
1b
1c
1e R=4-ClC6H4
R=Ph
R=n-Bu
1g
R=4-MeOC6H4
R=H
Entry
Substrates
R4
Time (h)
Yieldc (%)
3
4
9b
10
11
12
13
14
1
2
3
1a/2a
1a/2b
1a/2c
1a/2d
1a/2e
1a/2f
1a/2g
1a/2h
1a/2i
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-ClC6H4
i-Pr
4-FC6H4
Ph
4-BrC6H4
4-NO2C6H4
1-Naphthyl
Styryl
43
43
96
68
61
55
92
45
72
67
65
182
42
34
39
72
37
42
34
36
d
3aa (88)
3ab (99)
3ac (75)
3ad (46)
3ae (23)
3af (84)
3ag (99)
3ah (71)
3ai (62)
3aj (67)
3ak (74)
3al (32)
3am(54)
3an (78)
3ao (66)
3bb (63)
3cb (45)
3db (37)
3eb (90)
3fb (61)
N.R.d
d
d
d
Imid. (3)
Imid. (2.2)
Imid. (2)
111
86
67
4
4ad (40)
d
5b
6
d
Imid. (3)
86
7
8
9
d
a
Conditions: cyclopropene (0.3 mmol), hydroximoyl chloride (0.42 mmol), base
(0.3 mmol) in solvent (5 mL) at room temperature under N2. More 2a and base were
added until the reaction was completed (monitored by TLC).
d
d
10
11
12b
13
14
15
16
17
18
19
20
21
1a/2j
1a/2k
1a/2l
4aj (30)
d
b
2a and base were added in one portion, respectively.
Isolated yields.
43% of 1a was recovered.
c
n-Pr
d
d
1a/2m
1a/2n
1a/2o
1b/2b
1c/2b
1d/2b
1e/2b
1f/2b
1g/2b
2-BrC6H4
3-ClC6H4
2-Furyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4am(41)
d
d
d
d
d
d
d
and 6). When 2a and imidazole were added in portions to a solution
of cyclopropene 1a in dichloromethane (DCM), the best result was
obtained and 3aa was formed in 88% yield. Lower yields were ob-
served in other common solvents (Table 1, entries 10–14).
We next evaluated the scope of the reaction by submitting
various imidoyl chlorides 2 to the optimized conditions. In general,
good results were obtained with meta- and para-substituted phenyl
groups. In contrast, besides the expected product 3, imidoyl chlo-
rides 2 with ortho-substituted phenyl afforded another product 4
(Table 2, entries 4,10 and 13). Imidoyl chlorides 2 bearing styryl and
2-furyl groups were also competent reactants (Table 2, entries 11
and 15). While aromatic substituents worked well under the
standard conditions, i-Pr and n-Pr substituted reactants 2 (Table 2,
entries 5 and 12) failed to achieve satisfying yields.
We next studied the reactions of various cyclopropene 1,1-di-
esters (1b–1e and 1g) with 2b. While electron-poor phenyl
substituted cyclopropene 1,1-diester 1e performed superbly (Table
2, entry 19), no reaction happened between the p-MeO substituent
1g and 2b (Table 2, entry 21). Reactions of n-butyl-substituted
cyclopropene 1b and unsubstituted cyclopropene 1c with imidoyl
chloride 2b underwent smoothly to afford the corresponding
products 3bb (Table 2, entry 16) and 3cb (Table 2, entry 17), re-
spectively. When cyclopropene bearing only one ester group (1f)
was employed, the tandem reaction also successfully underwent
(Table 2, entry 20). A dramatical drop in yield was observed in the
reaction of diethyl ester 1d and imidoyl chloride 2b, which might
be due to the steric effect of the ethyl ester.
a
Reaction conditions: 1:2¼1:1.4 (equiv), 1.5 equiv of Imid., DCM, rt, N2. If nec-
essary, more 2 and Imid. were added in portions to complete the reaction.
b
Et3N and toluene were used.
Isolated yields.
No reaction.
c
d
besides the hydrogen migration process (path a), a competing
pathway may happen due to the steric hindrance from the ortho-
substituent and give 10 and 11 via a C–C and N–O bonds cleavage
process (path b), in which the possible mechanism for the reaction
of cyclopropenes and nitrones reported by Molchanov can be
invoked.16e Finally, 10 is trapped by nitrile oxides 7 to give the cor-
responding 1,3-DC products 4. Intermediates 10 and 11 were suc-
cessfully isolated when 2 equiv of 1a and 1 equiv of nitrile oxide
(from 2j) were employed in the reaction.21
3. Conclusions
In conclusion, we have reported a highly regioselective tandem
reaction that involves a 1,3-dipolar cycloaddition of cyclopropene
1,1-diesters with nitrile oxides. This provides an efficient method
for the synthesis of 3,4,5-trisubstituted isoxazole derivatives. The
novel chemistry of the doubly activated cyclopropenes may be
extended to other 1,n-dipoles. Applications of this tandem reaction,
as well as reactions of cyclopropene 1,1-diesters and other 1,n-di-
poles are under investigation.
Regioselectivity for these reactions was high, and no other
regio-isomers of products 3 or 4 were observed. The structures of
3aa and 4aj were characterized by NMR analysis and further con-
firmed by single-crystal X-ray analysis (Fig. 1).20
A plausible mechanism for the formation of isoxazoles 3 and
isoxazolines 4 is illustrated in Scheme 2. Highly regioselective 1,3-
DC of nitrile oxides 7 and cyclopropene 1,1-diester 1a afford in-
termediates 8, which undergo a push-pull ring-opening process to
give intermediates 9. When R is a hydrogen atom, intermediates 9
can be directly converted to products 3 via an intramolecular hy-
drogen migration process (path a). When R is not a hydrogen atom,
4. Experimental section
4.1. General method
All solvents were purchased from commercial sources and were
purified according to standard procedures. Reactions were run

9148
S. Chen et al. / Tetrahedron 65 (2009) 9146–9151
were prepared according to previously reported procedures.22
Benzohydroximinoyl chlorides23 2o,24 2e25 and 2l25 were prepared
according to literature methods.
4.2. General procedure for the cycloadditions of
cyclopropenes 1 and hydroximoyl chlorides 2
Under a positive pressure of nitrogen, to a stirred solution of
cyclopropenes 1 (0.3 mmol, 1 equiv) in CH2Cl2 (9 mL) were added
hydroximoyl chlorides 2 (0.45 mmol, 1.4 equiv) and imidazole
(0.3 mmol, 1 equiv), followed by stirring at room temperature.
The reaction mixture was monitored by TLC. After 12 h, imidazole
(0.15 mmol, 0.5 equiv) was added. If necessary, more hydroximoyl
chlorides 2 (0.3 mmol) and imidazole (0.3 mmol) were added in
portions. After the completion of the reaction, the solution was
concentrated under reduced pressure to afford the crude products
3 (and 4), which were purified by silica gel column chromatography
using petroleum ether and EtOAc (DCM or ether) as eluents.
4.2.1. 2-[3-(4-Chloro-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
dimethyl ester (3aa). White solid, mp: 83–85 ꢀC. Yield: 88%. 1H
NMR (400 M, CDCl3):
7.50–7.48 (m, 3H), 7.44 (d, J¼8.4 Hz, 2H), 4.77 (s, 1H), 3.54 (s, 6H).
13C NMR (75 M, CDCl3):
169.1, 167.5, 162.7, 136.1, 130.7, 130.4,
d
7.67–7.65 (m, 2H), 7.60 (d, J¼8.4 Hz, 2H),
d
128.9, 128.8, 128.0, 127.3, 127.1, 107.0, 52.9, 47.9.HRMS (ESI) calcd
for C20H16ClNO5 (MþNa)þ: 408.0609, found 408.0604. IR (KBr):
n
3455, 3074, 3008, 2953, 2844, 1758, 1740, 1601, 1491, 1429, 1336,
1287, 1226, 1159, 1132, 1093, 1016, 977, 947, 842, 757 cmꢁ1
.
4.2.2. 2-[3-(4-Methoxy-phenyl)-5-phenyl-isoxazol-4-yl]-malonic
acid dimethyl ester (3ab). White solid, mp: 115–117 ꢀC. Yield: 99%.
1H NMR (400 M, CDCl3):
d
7.69–7.67 (m, 2H), 7.56 (d, J¼8.4 Hz, 2H),
7.49–7.48 (m, 3H), 6.99 (d, J¼8.4 Hz, 2H), 4.76 (s, 1H), 3.83 (s, 3H),
3.54 (s, 6H). 13C NMR (75 M, CDCl3):
168.7, 167.6, 163.4, 160.9, 130.5,
d
Figure 1. X-ray structure of compounds 3aa and 4aj.
130.3, 128.8, 128.0, 127.4, 120.9, 114.1, 107.1, 55.3, 52.8, 48.1. HRMS
(ESI) calcd for C21H19NO6 (MþNa)þ: 404.1105, found 404.1099. IR
MeO2C
Ph
CO2Me
H
R
Cl
O
N
(KBr): n 3471, 3077, 3006, 2950, 2842, 1744, 1614, 1596, 1493, 1449,
R
OH
MeO2C CO2Me
N
1327, 1287, 1232, 1197, 1164, 1114, 1029, 999, 979, 839, 763 cmꢁ1
.
NH
N
+
O
Ph
N
2
1a
7
4.2.3. 2-(5-Phenyl-3-p-tolyl-isoxazol-4-yl)-malonic acid dimethyl
R
ester (3ac). White solid, mp: 105–107 ꢀC. Yield: 75%. 1H NMR
O
(400 M, CDCl3):
d 7.71–7.68 (m, 2H), 7.51–7.48 (m, 5H), 7.28 (d,
O
O
H
OMe
J¼8.0 Hz, 2H), 4.76 (s, 1H), 3.53 (s, 6H), 2.40 (s, 3H). 13C NMR (75 M,
MeO2C
Ph
MeO2C
Ph
MeO2C
Ph
OMe
OMe
R
H
R
CDCl3):
d 168.8, 167.6, 163.7, 139.8, 130.5, 129.4, 128.8, 128.0, 127.4,
H
R
O
125.7, 107.1, 52.8, 48.0, 21.4. HRMS (ESI) calcd for C21H19NO5
O
O
N
(MþNa)þ: 388.1155, found 388.1154. IR (KBr):
n
3458, 3070, 3005,
N
N
8
9
9
2952, 2847, 1757, 1740, 1615, 1496, 1447, 1336, 1274, 1225, 1193, 1160,
1050, 1018, 978, 946, 837, 777 cmꢁ1
.
path a
(R=H)
path b
R
MeO2C
MeO2C
MeO2C
Ph
CO2Me
H
O
N
4.2.4. 2-[3-(2-Chloro-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
R
NC
dimethyl ester (3ad). Yellow oil. Yield: 46%. 1H NMR (400 M, CDCl3):
CO2Me
O
7
O
O
+
N
d
7.77–7.76 (m, 2H), 7.51–7.49 (m, 5H), 7.42 (t, J¼7.6 Hz, 1H), 7.36 (t,
Ph
CO2Me
Ph
J¼7.2 Hz, 1H), 4.61 (s, 1H), 3.52 (s, 6H). 13C NMR (75 M, CDCl3):
10
11
3
4
d
168.8, 167.2, 161.8, 134.1, 132.1, 131.3, 130.6, 129.7, 128.8, 128.0,
Scheme 2. Proposed mechanism for the tandem reaction of cyclopropene 1,1-diester
1a and nitrile oxides.
127.6, 127.2, 126.8, 107.9, 52.9, 47.6. HRMS (ESI) calcd for
C20H16ClNO5 (MþNa)þ: 408.0609, found 408.0601. IR (KBr):
n 3474,
under an atmosphere of nitrogen, and visualization was accom-
plished with UV light (254 nm). Purification of products was carried
out by flash chromatography using silica gel (200–300 mesh). All
NMR spectra were recorded with a Varian or Bruker spectrometer
3063, 3005, 2953, 2849, 1739, 1622, 1598, 1494, 1435, 1412, 1289,
1239, 1196, 1159, 1076, 1033, 951, 929, 837, 757 cmꢁ1
.
4.2.5. 4-Benzoyl-3-(2-chloro-phenyl)-4H-isoxazole-5,5-dicarboxylic
at 300 MHz or 400 MHz (1H NMR) and 75 MHz or 100 MHz (13
C
acid dimethyl ester (4ad). Yellowish oil. Yield: 40%. 1H NMR (400 M,
NMR) in CDCl3. Proton nuclear magnetic resonance spectra (1H
NMR) are reported in ppm using solvent as an internal standard
(CDCl3 at 7.26 ppm). High-resolution mass spectra were recorded
on an FTMS spectrometer. IR spectra were recorded on a MAGNA-
560 spectrometer made by Nicolet Company. Cyclopropenes 1a–1g
CDCl3):
J¼7.4 Hz, 1H), 7.43 (t, J¼7.6 Hz, 2H), 7.27–7.25 (m, 3H), 6.89 (s, 1H),
3.93 (s, 3H), 3.52 (s, 3H). 13C NMR (100 M, CDCl3):
193.1, 166.8,
165.4, 155.9, 135.7, 134.4, 132.5, 132.2, 131.6, 130.0, 128.9, 128.8,
127.2, 126.7, 92.3, 62.0, 54.4, 53.3. HRMS (ESI) calcd for C20H16ClNO6
d
7.98 (d, J¼7.6 Hz, 2H), 7.62 (d, J¼7.4 Hz, 1H), 7.57 (t,
d

S. Chen et al. / Tetrahedron 65 (2009) 9146–9151
9149
(MþNa)þ: 424.0558, found 424.0555. IR (KBr):
n
3479, 3066, 3008,
1H NMR (400 M, CDCl3):
d
8.72 (d, J¼8.4 Hz, 1H), 7.91 (d, J¼8.0 Hz,
2956, 2848, 1750, 1683, 1596, 1476, 1449, 1336, 1287, 1217, 1185,
2H), 7.81 (d, J¼8.4 Hz, 2H), 7.63 (t, J¼7.6 Hz, 1H), 7.53 (q, J¼7.6 Hz,
1127, 1080, 1040, 934, 906, 857, 761 cmꢁ1
.
2H), 7.41–7.37 (m, 3H), 7.29 (d, J¼8.0 Hz, 1H), 6.71 (s, 1H), 3.97 (s,
3H), 3.59 (s, 3H). 13C NMR (100 M, CDCl3):
d 193.4, 167.3, 165.6,
4.2.6. 2-(3-Isopropyl-5-phenyl-isoxazol-4-yl)-malonic acid dimethyl
ester (3ae). Yellow oil. Yield: 23%. 1H NMR (400 M, CDCl3):
7.66–
7.63 (m, 2H), 7.49–7.48 (m, 3H), 4.78 (s, 1H), 3.72 (s, 6H), 3.07–3.00
156.4, 135.9, 134.3, 133.8, 131.3, 130.9, 128.9, 128.8, 128.4, 127.8,
127.7, 126.6, 126.1, 124.6, 124.4, 91.3, 63.0, 54.4, 53.4. HRMS (ESI)
calcd for C24H19NO6 (MþNa)þ: 440.1105, found 440.1099. IR (KBr):
d
(m, 1H), 1.36 (d, J¼6.8 Hz, 6H). 13C NMR (100 M, CDCl3):
d
168.8,
n 3435, 3335, 3042, 2959, 2852, 1773, 1750, 1674, 1594, 1449, 1330,
167.7, 130.3, 128.9, 128.1, 127.4, 106.1, 53.1, 47.3, 26.3, 22.1. HRMS
1290, 1226, 1188, 1137, 1078, 1059, 933, 908, 862, 770 cmꢁ1
.
(ESI) calcd for C17H19NO5 (MþNa)þ: 340.1155, found 340.1148. IR
(KBr):
n
3472, 3063, 2972, 2935, 2873, 1743, 1627, 1597, 1465, 1448,
4.2.13. 2-(5-Phenyl-3-styryl-isoxazol-4-yl)-malonic acid dimethyl
1312, 1288, 1256, 1196, 1152, 1089, 1029, 959, 929, 880, 760 cmꢁ1
.
ester (3ak). Yellowish solid, mp: 118–120 ꢀC. Yield: 74%. 1H NMR
(400 M, CDCl3):
J¼7.2 Hz, 2H), 7.33 (d, J¼7.2 Hz, 1H), 7.04 (d, J¼16.4 Hz, 1H), 4.90 (s,
1H), 3.75 (s, 6H). 13C NMR (75 M, CDCl3):
168.5, 167.6, 160.5, 136.2,
d 7.69–7.68 (m, 2H), 7.56–7.52 (m, 6H), 7.39 (t,
4.2.7. 2-[3-(4-Fluoro-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
dimethyl ester (3af). White solid, mp: 101–103 ꢀC. Yield: 84%. 1H
d
NMR (400 M, CDCl3):
d
7.67–7.63 (m, 4H), 7.51 (br, 3H), 7.16 (t,
135.7, 130.6, 129.1, 128.8, 128.7, 128.0, 127.2, 127.1, 114.4, 106.6, 53.2,
J¼8.8 Hz, 2H), 4.77 (s, 1H), 3.55 (s, 6H). 13C NMR (100 M, CDCl3):
47.5. HRMS (ESI) calcd for C22H19NO5 (MþNa)þ: 400.1155, found
d
169.0, 167.5, 165.0, 162.9, 162.5, 131.1, 131.0, 130.7, 128.9, 127.9,
400.1151. IR (KBr): n 3456, 3074, 3033, 2956, 2843, 1763, 1736, 1620,
127.1, 124.8, 124.7, 115.8, 115.6, 107.0, 52.9, 47.9. HRMS (ESI) calcd
1498, 1423, 1341, 1242, 1219, 1146, 1115, 1076, 1023, 967, 920, 867,
for C20H16FNO5 (MþNa)þ: 392.0905, found 392.0899. IR (KBr):
761 cmꢁ1
.
n
3453, 3064, 3011, 2955, 2840, 1750, 1735, 1606, 1525, 1430, 1327,
1289, 1237, 1193, 1159, 1139, 1014, 973, 949, 844, 756 cmꢁ1
.
4.2.14. 2-(5-Phenyl-3-propyl-isoxazol-4-yl)-malonic acid dimethyl
ester (3al). Yellow oil. Yield: 32%. 1H NMR (400 M, CDCl3):
7.65–
d
4.2.8. 2-(3,5-Diphenyl-isoxazol-4-yl)-malonic acid dimethyl ester
7.63 (m, 2H), 7.50–7.48 (m, 3H), 4.78 (s, 1H), 3.73 (s, 6H), 2.67 (t,
(3ag). White solid, mp: 94–95 ꢀC. Yield: 99%. 1H NMR (400 M,
J¼7.8 Hz, 2H), 1.81 (q, J¼7.6 Hz, 2H), 1.04 (t, J¼7.4 Hz, 3H). 13C NMR
CDCl3):
d
7.69 (t, J¼3.6 Hz, 2H), 7.62 (t, J¼2.8 Hz, 2H), 7.50–7.46 (m,
(100 M, CDCl3): d 167.9, 167.6, 163.6, 130.3, 129.0, 128.0, 127.4, 106.8,
6H), 4.77 (s,1H), 3.53 (s, 6H). 13C NMR (100 M, CDCl3):
d
168.9,167.6,
53.0, 47.3, 27.6, 20.7, 14.1. HRMS (ESI) calcd for C17H19NO5 (MþNa)þ:
163.7, 130.6, 129.8, 129.0, 128.9, 128.6, 128.0, 127.3, 107.1, 52.9, 48.0.
340.1155, found 340.1155. IR (KBr): n 3336, 3064, 2958, 2935, 2874,
HRMS (ESI) calcd for C20H17NO5 (MþNa)þ: 374.0999, found
1742, 1629, 1598, 1502, 1449, 1380, 1290, 1252, 1196, 1155, 1120,
374.1002. IR (KBr):
n
3456, 3056, 2967, 2952, 2851, 1753, 1625, 1574,
1030, 961, 930, 837, 757 cmꢁ1
.
1499, 1441, 1328, 1292, 1234, 1202, 1159, 1131, 1019, 977, 946, 834,
750 cmꢁ1
.
4.2.15. 2-[3-(2-Bromo-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
dimethyl ester (3am). Yellowish oil. Yield: 54%. 1H NMR (400 M,
4.2.9. 2-[3-(4-Bromo-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
CDCl3):
4H), 7.42 (t, J¼7.4 Hz, 1H), 7.35 (t, J¼7.8 Hz, 1H), 4.60 (s, 1H), 3.53 (s,
6H). 13C NMR (100 M, CDCl3):
168.8,167.2, 163.1, 132.9, 132.1, 131.4,
d
7.78–7.77 (m, 2H), 7.70 (d, J¼8.0 Hz, 1H), 7.50–7.47 (m,
dimethyl ester (3ah). White solid, mp: 118–120 ꢀC. Yield: 71%. 1H
NMR (400 M, CDCl3):
7.53 (d, J¼8.4 Hz, 2H), 7.51–7.50 (m, 3H), 4.76 (s, 1H), 3.55 (s, 6H).
13C NMR (100 M, CDCl3):
169.2, 167.5, 162.8, 131.9, 130.7, 130.6,
d
7.67–7.66 (m, 2H), 7.61 (d, J¼8.0 Hz, 2H),
d
130.6, 129.7, 129.3, 128.8, 128.0, 127.3, 127.2, 123.7, 107.6, 52.9, 47.7.
d
HRMS (ESI) calcd for C20H16BrNO5 (MþNa)þ: 452.0104, found
129.0, 128.0, 127.7, 127.0, 124.4, 107.0, 53.0, 47.9. HRMS (ESI) calcd
452.0101. IR (KBr): n 3473, 3063, 3005, 2953, 2846, 1743, 1698, 1622,
for C20H16BrNO5 (MþNa)þ: 452.0104, found 452.0100. IR (KBr):
1493, 1447, 1326, 1279, 1237, 1196, 1160, 1072, 1028, 983, 951, 837,
n
3471, 3074, 3010, 2952, 2842, 1744, 1620, 1595, 1492, 1448, 1325,
781 cmꢁ1
.
1281, 1229, 1197, 1163, 1105, 1025, 983, 948, 839, 780 cmꢁ1
.
4.2.16. 4-Benzoyl-3-(2-bromo-phenyl)-4H-isoxazole-5,5-di-
4.2.10. 2-[3-(4-Nitro-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
carboxylic acid dimethyl ester (4am). Yellow oil. Yield: 41%. 1H NMR
dimethyl ester (3ai). Yellow solid, mp: 96–100 ꢀC. Yield: 62%. 1H
(400 M, CDCl3):
d
7.97 (dd, J¼8.4 Hz, 1.0 Hz, 2H), 7.57 (tt, J¼7.4 Hz,
NMR (400 M, CDCl3):
2H), 7.67–7.65 (m, 2H), 7.53 (br, 3H), 4.81 (s, 1H), 3.58 (s, 6H). 13C
NMR (100 M, CDCl3): 169.6, 167.3, 161.9, 148.6, 135.3, 130.9, 130.1,
d
8.32 (d, J¼8.4 Hz, 2H), 7.89 (d, J¼8.4 Hz,
1.2 Hz, 1H), 7.53 (dd, J¼8.4 Hz, 1.6 Hz, 1H), 7.48 (dd, J¼8.0 Hz, 1.2 Hz,
1H), 7.43 (t, J¼7.8 Hz, 2H), 7.29 (dt, J¼8.0 Hz, 1.2 Hz, 1H), 7.21 (dt,
J¼8.0 Hz, 1.7 Hz, 1H), 6.93 (s, 1H), 3.95 (s, 3H), 3.56 (s, 3H). 13C NMR
d
129.0, 127.9, 126.6, 123.5, 106.9, 53.0, 47.7. HRMS (ESI) calcd for
(100 M, CDCl3): d 193.1, 166.9, 165.4, 156.8, 135.7, 134.4, 133.0, 132.7,
C20H16N2O7 (MþNa)þ: 397.1030, found 397.1025. IR (KBr):
n
3456,
131.7, 128.9, 128.8, 128.7, 127.8, 121.7, 92.2, 62.1, 54.4, 53.4. HRMS (ESI)
3069, 2956, 2922, 2851, 1757, 1738, 1605, 1526, 1432, 1348, 1290,
calcd for C20H16BrNO6 (MþNa)þ: 468.0053, found 468.0049. IR
1273, 1195, 1160, 1132, 1011, 974, 949, 854, 747 cmꢁ1
.
(KBr): n 3346, 3065, 3008, 2956, 2849, 1778, 1683, 1596, 1472, 1449,
1335, 1286, 1217, 1185, 1162, 1059, 1039, 934, 904, 857, 761 cmꢁ1
.
4.2.11. 2-(3-Naphthalen-1-yl-5-phenyl-isoxazol-4-yl)-malonic acid
dimethyl ester (3aj). Yellow oil. Yield: 67%. 1H NMR (400 M,
4.2.17. 2-[3-(3-Chloro-phenyl)-5-phenyl-isoxazol-4-yl]-malonic acid
CDCl3):
3H), 7.65 (d, J¼6.8 Hz, 1H), 7.58 (d, J¼8.0 Hz, 1H), 7.55–7.50 (m,
5H), 4.53 (s, 1H), 3.33 (s, 6H). 13C NMR (100 M, CDCl3):
168.7,
d
7.99 (d, J¼8.0 Hz, 1H), 7.92 (d, J¼7.6 Hz, 1H), 7.83–7.78 (m,
dimethyl ester (3an). White solid, mp: 108–110 ꢀC. Yield: 78%. 1H
NMR (400 M, CDCl3):
7.51 (m, 4H), 7.48–7.40 (m, 2H), 4.76 (s, 1H), 3.58 (s, 6H). 13C NMR
(75 M, CDCl3): 169.2, 167.4, 162.5, 134.5, 130.7, 130.5, 129.9, 129.1,
d 7.70–7.68 (m, 2H), 7.64–7.63 (m, 1H), 7.56–
d
167.4, 162.8, 133.5, 132.1,130.6, 130.3, 128.8, 128.5, 128.3, 128.0,
127.4,126.8, 126.3, 125.5, 125.4, 125.1, 108.7, 52.6, 47.8. HRMS (ESI)
calcd for C24H19NO5 (MþNa)þ: 424.1155, found 424.1161. IR (KBr):
d
128.9, 128.0, 127.2, 127.1, 107.0, 52.9, 47.9. HRMS (ESI) calcd for
C20H16ClNO5 (MþNa)þ: 408.0609, found 408.0608. IR (KBr):
n 3456,
n
3468, 3058, 3006, 2953, 2845, 1739, 1622, 1594, 1514, 1435, 1324,
3080, 3061, 2962, 2853, 1752, 1735, 1617, 1500, 1418, 1331, 1299,
1289, 1240, 1196, 1159, 1058, 1025, 979, 942, 805, 733 cmꢁ1
.
1278, 1199, 1166, 1083, 1018, 953, 934, 834, 802 cmꢁ1
.
4.2.12. 4-Benzoyl-3-naphthalen-1-yl-4H-isoxazole-5,5-dicarboxylic
acid dimethyl ester (4aj). Yellow solid, mp: 137–141 ꢀC. Yield: 30%.
4.2.18. 2-(3-Furan-2-yl-5-phenyl-isoxazol-4-yl)-malonic acid dimethyl
ester (3ao). White solid, mp: 85–87 ꢀC. Yield: 66%. 1H NMR (400 M,

9150
S. Chen et al. / Tetrahedron 65 (2009) 9146–9151
CDCl3):
d
7.68–7.67 (m, 2H), 7.56 (s, 1H), 7.51–7.49 (m, 3H), 7.01 (d,
Supplementary data
J¼2.8 Hz,1H), 6.54 (t, J¼1.6 Hz,1H), 5.06 (s,1H), 3.60 (s, 6H). 13C NMR
(100 M, CDCl3):
d
169.2, 167.4, 154.6, 144.0, 143.8, 130.7, 128.8, 128.2,
Supplementary data associated with this article can be found in
the online version, at: doi:10.1016/j.tet.2009.09.034.
126.9, 111.7, 111.2, 106.2, 52.9, 47.8. HRMS (ESI) calcd for C18H15NO6
(MþNa)þ: 364.0792, found 364.0791. IR (KBr):
n 3153, 3061, 3004,
2954, 2847, 1740, 1630,1595,1508,1436,1323,1294,1240, 1197, 1158,
References and notes
1058, 1014, 981, 932, 835, 779 cmꢁ1
.
1. Selected reviews on some typical cycloadditions, see: (a) Cycloaddition Re-
actions in Organic Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH:
Weinheim, 2001; (b) Synthetic Applications of 1,3-Dipolar Cycloaddition Chem-
istry Toward Heterocycles and Natural Products: The Chemistry of Heterocyclic
Compounds; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: New York, NY,
2002; Vol. 59; (c) The Diels–Alder Reaction: Selected Practical Methods; Fringuelli,
F., Taticchi, A., Eds.; John Wiley & Sons: Chichester, UK, 2002.
2. For reviews, see: (a) Tieze, L. F. Chem. Rev. 1996, 96, 115; (b) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195; (c) Bunce, R. A. Tetrahedron
1995, 51, 13103; (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134; (e) Pellissier, H. Tetrahedron 2006, 62, 1619; (f) Pellissier,
H. Tetrahedron 2006, 62, 2143; (g) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed.
Engl. 1993, 32, 131.
3. For reviews, see: (a) Baird, M. S. Top. Curr. Chem. 1988, 144, 137; (b) Nakamura,
M.; Isabe, H.; Nakamura, E. Chem. Rev. 2003, 103, 1295; (c) Fox, J. M.; Yan, N.
Curr. Org. Chem. 2005, 9, 719; (d) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis
2006, 1221; (e) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117;
(f) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364; (g)
Deem, M. L. Synthesis 1982, 701; (h) Binger, P.; Buch, H. M. Top. Curr. Chem. 1987,
135, 77; (i) Wege, D. Eur. J. Org. Chem. 2001, 849.
4. (a) Al Dulayymi, A. R.; Baird, M. S. Tetrahedron 1998, 54, 12897; (b) Wiberg, K. B.;
Bartley, W. J. J. Am. Chem. Soc. 1960, 82, 6375; (c) Baird, M. S.; Hussain, H. H.
Tetrahedron 1987, 43, 215.
4.2.19. 2-[5-Butyl-3-(4-methoxy-phenyl)-isoxazol-4-yl]-malonic acid
dimethyl ester (3bb). Yellow oil. Yield: 63%. 1H NMR (400 M, CDCl3):
d
7.49 (d, J¼8.0 Hz, 2H), 6.98 (d, J¼8.4 Hz, 2H), 4.60 (s, 1H), 3.82 (s,
3H), 3.70 (s, 6H), 2.80 (t, J¼7.4 Hz, 2H), 1.71 (t, J¼7.2 Hz, 2H), 1.40 (q,
J¼7.2 Hz, 2H), 0.93 (t, J¼7.2 Hz, 3H). 13C NMR (100 M, CDCl3):
d
172.8, 167.8, 162.4, 160.7, 130.1, 120.8, 114.3, 105.7, 55.3, 53.0, 46.8,
29.1, 26.4, 22.5, 13.8. HRMS (ESI) calcd for C19H23NO6 (MþNa)þ:
384.1418, found 384.1412. IR (KBr):
n 3470, 3003, 2957, 2873, 1742,
1614, 1530, 1460, 1435, 1326, 1296, 1253, 1179, 1155, 1121, 1031, 936,
907, 838, 797 cmꢁ1
.
4.2.20. 2-[3-(4-Methoxy-phenyl)-isoxazol-4-yl]-malonic acid dimethyl
ester (3cb). Yellow oil. Yield: 45%. 1H NMR (400 M, CDCl3):
8.73 (s,
1H), 7.51 (d, J¼8.4 Hz, 2H), 7.00 (d, J¼8.8 Hz, 2H), 4.62 (s, 1H), 3.84 (s,
3H), 3.75 (s, 6H). 13C NMR (100 M, CDCl3):
167.6, 161.1, 160.9, 159.1,
d
d
130.0, 120.1, 114.5, 110.5, 55.4, 53.4, 46.8. HRMS (ESI) calcd for
C15H15NO6 (MþNa)þ: 328.0792, found 328.0793. IR (KBr):
n 3458,
5. (a) DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 1101; (b)
Diev, V. V.; Molchanov, A. P. J. Org. Chem. 2006, 71, 4066; (c) Molchanov, A. P.;
Diev, V. V.; Kopf, J.; Kostikov, R. R. Russ. J. Org. Chem. 2004, 40, 431.
6. (a) Aue, D. H.; Lorens, R. B.; Helwig, G. S. J. Org. Chem.1979, 44,1202; (b) Aue, D. H.;
Helwig, G. S. Tetrahedron Lett. 1974, 15, 721.
7. (a) Bolesov, I. G.; Ignatchenko, A. V.; Bovin, N. V.; Prudchenko, I. A.; Surmina, L. S.;
Plemenkov, V. V.; Petrovskii, P. V.; Romanov, I. V.; Mel’nik, I. I. Zh. Org. Khim. 1990,
26, 102; (b) Baird, M. S.; Huber, F. A. M.; Clegg, W. Tetrahedron 2001, 57, 9849.
8. Visser, J. P.; Smael, P. Tetrahedron Lett. 1973, 16, 1139.
3123, 3024, 2959, 2844,1762,1735,1613,1531,1460,1331,1308,1286,
1205, 1162, 1123, 1015, 998, 934, 839, 810 cmꢁ1
.
4.2.21. 2-[3-(4-Methoxy-phenyl)-5-phenyl-isoxazol-4-yl]-malonic
acid diethyl ester (3db). White solid, mp: 102–105 ꢀC. Yield: 37%. 1H
NMR (400 M, CDCl3):
d
7.75–7.72 (m, 2H), 7.60 (d, J¼8.4 Hz, 2H),
7.50–7.48 (m, 3H), 6.99 (d, J¼8.8 Hz, 2H), 4.73 (s, 1H), 4.00 (t,
9. (a) Matsumoto, K.; Uchida, T. J. Chem. Soc., Perkin Trans. 1 1981, 73; (b) Ohsawa,
A.; Wada, I.; Igeta, H.; Akimoto, T.; Tsuji, A. Y. Iitaka Tetrahedron Lett. 1978, 19,
4121.
J¼7.2 Hz, 4H), 3.86 (s, 3H), 1.12 (t, J¼7.0 Hz, 6H). 13C NMR (75 M,
CDCl3):
d 168.7, 167.3, 163.5, 160.8, 130.4, 130.3, 129.0, 128.0, 127.6,
10. (a) Payne, A. D.; Skelton, B. W.; Wege, D.; White, A. H. Eur. J. Org. Chem. 2007,
1184; (b) Billups, W. E.; Lee, C.-A.; Arney, B. E., Jr.; Whitmire, K. H. J. Am. Chem.
Soc. 1991, 113, 7980; (c) Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.;
Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916; (d) Salomon, R. G.; Salomon, M. F.;
Heyne, T. R. J. Org. Chem.1975, 40, 756; (e) Yan, N.; Liu, X.; Pallerla, M. K.; Fox, J. M.
J. Org. Chem. 2008, 73, 4283; (f) Lee, G.-A.; Chen, K. C. Org. Lett. 2008, 10, 1843.
11. (a) Sauer, J.; Bauerlein, P.; Ebenbeck, W.; Gousetis, C.; Sichert, H.; Troll, T.; Utz, F.;
Wallfahrer, U. Eur. J. Org. Chem. 2001, 2629; (b) Sauer, J.; Bauerlein, P.; Ebenbeck,
W.; Dyllick-Brenzinger, R.; Gousetis, C.; Sichert, H.; Troll, T.; Wallfahrer, U. Eur. J.
Org. Chem. 2001, 2639; (c) Al Dulayymi, J. R.; Baird, M. S.; Hussain, H. H.;
Alhourani, B. J.; Alhabashna, Al-M. Y.; Coles, S. J.; Hursthouse, M. B. Tetra-
hedron Lett. 2000, 41, 4205.
12. (a) Pallerla, M. K.; Yap, G. P. A.; Fox, J. M. J. Org. Chem. 2008, 73, 6137; (b)
Marchueta, I.; Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2001,
3, 3193; (c) Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, 3593; (d) Pallerla, M. K.;
Fox, J. M. Org. Lett. 2007, 9, 5625.
13. (a) Grimme, Wolfram.; Koser, H. G. J. Am. Chem. Soc. 1981, 103, 5919; (b) Padwa,
A.; Kennedy, G. D. J. Org. Chem. 1984, 49, 4344.
121.0, 114.1, 107.0, 62.2, 55.3, 48.5, 13.8. HRMS (ESI) calcd for
C23H23NO6 (MþNa)þ: 432.1418, found 432.1415. IR (KBr):
n 3452,
3167, 3077, 2933, 2841, 1749, 1731, 1610, 1572, 1462, 1330, 1296,
1254, 1178, 1135, 1113, 1023, 963, 944, 841, 833 cmꢁ1
.
4.2.22. 2-[5-(4-Chloro-phenyl)-3-(4-methoxy-phenyl)-isoxazol-4-yl]-
malonic acid dimethyl ester (3eb). Yellow oil. Yield: 90%. 1H NMR
(400 M, CDCl3):
(d, J¼8.4 Hz, 2H), 6.98 (d, J¼8.8 Hz, 2H), 4.73 (s, 1H), 3.82 (s, 3H), 3.56
(s, 6H). 13C NMR (100 M, CDCl3):
167.6, 167.5, 163.6, 160.9, 136.7,
d
7.66 (d, J¼8.4 Hz, 2H), 7.53 (d, J¼8.4 Hz, 2H), 7.46
d
130.3, 129.3, 129.1, 125.9, 120.5, 114.2, 107.3, 55.3, 53.0, 47.9. HRMS
(ESI) calcd for C21H18ClNO6 (MþNa)þ: 438.0715, found 438.0709. IR
(KBr):
n 3086, 3005, 2954, 2840, 2255, 1740, 1613, 1576, 1494, 1458,
1328, 1296, 1253, 1196, 1178, 1094, 1049, 984, 948, 837, 770 cmꢁ1
.
14. (a) Dowd, P.; Schappert, R.; Garner, P.; Go, C. L. J. Org. Chem. 1985, 50, 44; (b)
Guenther, M.; Bernd, W. Synthesis 1985, 871.
4.2.23. [3-(4-Methoxy-phenyl)-5-phenyl-isoxazol-4-yl]-phenyl-ace-
15. Examples for cycloadditions of cyclopropenone & ketal: (a) For review see Ref.
3b; (b) Hemming, K.; Redhouse, A. D.; Smalley, R. K.; Thompson, J. R.; Kennewell,
P. D.; Westwood, R. Tetrahedron Lett. 1992, 33, 2231; (c) Hemming, K.; O’Gorman,
P. A.; Page, M. I. Tetrahedron Lett. 2006, 47, 425; (d) O’Gorman, P. A.; Chen, T.;
Cross, H. E.; Naeem, S.; Pitard, A.; Qamar, M. I.; Hemming, K. Tetrahedron Lett.
2008, 49, 6316; (e) Cunha, S.; Damasceno, F.; Ferrari, J. Tetrahedron Lett. 2007, 48,
5795; (f) Sato, S.; Isobe, H.; Tanaka, T.; Ushijima, T.; Nakamura, E. Tetrahedron
2005, 61, 11449; (g) Delgado, A.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2002, 4,
3091; (h) Boger, D. L.; Brothertonlb, C. E. J. Org. Chem.1985, 50, 3425; (i) Boger, D. L.;
Brothertonlb, C. E. J. Am. Chem. Soc.1986,108, 6695; (j) Potts, K. T.; Elliot, A. J.; Sorm,
M. J. Org. Chem. 1972, 37, 3838; (k) Tokuyama, H.; Isaka, H.; Nakamura, E. J. Am.
Chem. Soc. 1992, 114, 5523; (l) Breslow, R.; Eicher, T.; Krebs, A.; Peterson, R. A.;
Posner, J. J. Am. Chem. Soc. 1965, 87, 1320.
tic acid methyl ester (3fb). Yellow oil. Yield: 61%. 1H NMR (400 M,
CDCl3):
7.32 (s, 2H), 7.26 (s, 3H), 6.96 (d, J¼8.4 Hz, 2H), 4.49 (s, 1H), 3.87 (s,
3H), 3.46 (s, 3H). 13C NMR (100 M, CDCl3):
170.7,161.5,158.5, 131.3,
d
7.73 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼4.4 Hz, 2H), 7.43 (s, 3H),
d
131.2, 130.4, 129.7, 129.5, 128.8, 128.6, 128.2, 121.7, 114.3, 55.4, 53.0,
42.9. HRMS (ESI) calcd for C25H21NO4 (MþNa)þ: 422.1363, found
422.1361. IR (KBr): n 3409, 3052, 2999, 2953, 2837, 1715, 1607, 1515,
1497, 1447, 1302, 1248, 1175, 1116, 1055, 1036, 1025, 971, 922, 863,
782 cmꢁ1
.
16. (a) Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1997, 62, 1642; (b) Lawlb, D. C. F.;
Tobey, S. W. J. Am. Chem. Soc. 1968, 90, 2376; (c) Orugunty, R. S.; Wright, D. L.;
Battiste, M. A.; Helmich, R. J.; Abboud, K. J. Org. Chem. 2004, 69, 406; (d) Orugunty,
R. S.; Ghiviriga, I.; Abboud, K. A.; Battiste, M. A.; Wright, D. L. J. Org. Chem. 2004, 69,
570; (e) Diev, V. V.; Molchanov, A. P. J. Org. Chem. 2008, 73, 2396; (f) Orugunty, R. S.;
Wright, D. L.; Battiste, M. A.; Abboud, K. A. Org. Lett. 2002, 4, 1997; (g) Tan, Y.;
Hartmann, T.; Huch, V.; Durr, H.; Valat, P.; Wintgens, V.; Kossanyi, J. J. Org. Chem.
2001, 66, 1130; (h) Padwa, A.; Kumagai, T.; Tohidi, M. J. Org. Chem. 1983, 48,
1834.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20572045) and the Ministry of Education of China
(RFDF20070055022) for financial support.

S. Chen et al. / Tetrahedron 65 (2009) 9146–9151
9151
17. (a) Ma, S.; Zhang, J.; Lu, L.; Jin, X.; Cai, Y.; Hou, H. Chem. Commun. 2005, 909; (b)
Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954; (c) Wang, Y.; Lam,
H. W. J. Org. Chem. 2009, 74, 1353; (d) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam,
H. W. Angew. Chem., Int. Ed. 2008, 47, 7350; (e) Fordyce, E. A. F.; Wang, Y.; Lueb-
bersb, T.; Lam, H. W. Chem. Commun. 2008, 1124; Related examples for
cyclopropene 1,1-ketoesters; (f) Ma, S.; Zhang, J. J. Am. Chem. Soc. 2003, 125, 12386;
(g) Sato, H.; Hiroi, K. Tetrahedron Lett. 2006, 47, 5793.
18. (a) Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2005, 9, 925; (b) Grecian, S.; Fokin,
V. V. Angew. Chem., Int. Ed. 2008, 47, 8285; (c) Hansen, T. V.; Wu, P.; Fokin, V. V.
J. Org. Chem. 2005, 70, 7761.
19. (a) Sperry, J.; Wright, D. B. Curr. Opin. Drug Discov. Devel. 2005, 8, 723; Selected
examples for their biological activities; (b) Pallett, K. E.; Cramp, S. M.; Little, J. P.;
Veerasekaran, P.; Crudace, A. J.; Slater, A. E. Pest Manag. Sci. 2001, 57, 133; (c)
Simoni, D.; Rondanin, R.; Baruchello, R.; Rizzi, M.; Grisolia, G.; Eleopra, M.;
Grimaudo, S.; Cristina, A. D.; Pipitone, M. R.; Bongiorno, M. R.; Aric, M.; Invidiata,
F. P.; Tolomeo, M. J. Med. Chem. 2008, 51, 4796; (d) Patrick, D. A.; Bakunov, S. A.;
Bakunova, S. M.; Kumar, E. V. K. S.; Lombardy, R. J.; Jones, S. K.; Bridges, A. S.;
Zhirnov, O.; Hall, J. E.; Wenzler, T.; Brun, R.; Tidwell, R. R. J. Med. Chem. 2007, 50,
2468.
20. CCDC-727368 (3aa) and CCDC-727369 (4aj) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data.request/cif.
21. Isolation of intermediates 10 and 11: Under nitrogen atmosphere, to a stirred
solution of cyclopropene 1a (1.5 mmol, 2 equiv) in CH2Cl2 (20 mL) were added
hydroximoyl chloride 2j (0.75 mmol, 1 equiv) and imidazole (0.75 mmol,
1 equiv), followed by stirring at room temperature for 13 h. The solution was
concentrated under reduced pressure. 1-Naphthonitrile (11, 58%) and ben-
zoylmethylenemalonate (10, 7%) were isolated by silica gel column chroma-
tography using petroleum ether, DCM and ether as eluents.
22. (a) Liao, L.-a.; Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M. Tetrahedron 2004, 60,
1803; (b) Chuprakov, S.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127,
3714; (c) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125,
7198.
23. Liu, K.-C.; Becky, R. S.; Robert, K. H. J. Org. Chem. 1980, 45, 3916.
24. Ghabrial, S. S.; Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand., B, Org. Chem.
Biochem. 1987, 41, 426.
25. Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984, 40, 2985.