Synthesis of new spiro isoxazoline-pyrrolizinone derivatives via 1,3-dipolar cycloaddition of nitrile oxide

Article abstract of DOI:10.1002/jhet.1610

The 1,3-dipolar cycloaddition of nitrile oxide to 2-arylmethylidene-2,3- dihydro-1H-pyrrolizin-1-ones afforded new 4-(aryl)-3-(2,6-dichlorophenyl)- 1′H,4H-spiro[isoxazole-5,2′-pyrrolizin]-1′-ones in moderate yields. The structures of all the products were

Full text of DOI:10.1002/jhet.1610

274
Synthesis of New Spiro Isoxazoline-Pyrrolizinone Derivatives via
Vol 51
1,3-Dipolar Cycloaddition of Nitrile Oxide
*
X. Li, R. Yi, B. Liu, A. Zheng, X. Yu, and P. Yi
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan Province College
Key Laboratory of QSAR/QSPR, School of Chemistry and Chemical Engineering, Hunan University of Science and
Technology, Xiangtan, Hunan 411201, China
*
E-mail: pgyi@hnust.edu.cn
Received May 26, 2011
DOI 10.1002/jhet.1610
Published online 22 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
Ar
Cl
Cl
Cl
Cl
Benzene
Reflux
N
N O
+
N
O
Ar
N
3a-3h
1a-1h
2
Ar: a, C6H5; b, 4-ClC6H4; c, 2-ClC6H4 d, 4-CH3OC6H4; e, 4-FC6H4;
f
g
h
, 4-CH3SC6H4; , 4-CH3C6H4; , 3,4,5-(OCH3)3C6H2;
The 1,3-dipolar cycloaddition of nitrile oxide to 2-arylmethylidene-2,3-dihydro-1H-pyrrolizin-1-ones
afforded new 4-(aryl)-3-(2,6-dichlorophenyl)-10H,4H-spiro[isoxazole-5,20-pyrrolizin]-10-ones in moderate
yields. The structures of all the products were characterized thoroughly by NMR, IR, MS, and elemental
analysis together with X-ray crystallographic analysis.
J. Heterocyclic Chem., 51, 274 (2014).
INTRODUCTION
range of d 6.52–7.31 for aromatic protons. The singlet at
d 5.89 is in accord with the proton of Ar–CH (H-4) in
isoxazoline ring.
Spiro isoxazoline compounds represent an important
class of naturally occurring substances characterized by
highly pronounced biological properties [1]. One of the
most widely used methods for the synthesis of these
compounds is via 1,3-dipolar cycloaddition reactions of
nitrile oxides to exocyclic double bonds [2].
The pyrrolizinones derivatives are known for their anti-
inflammatory and analgesic activities [3]; their pyrrolizidine
framework is a frequently encountered structural motif in
many alkaloids with important bioactivity [4].
The 13C NMR spectrum of the product 3a exhibited the
presence of CH2 carbon (C-1) at d 51.48 and carbonyl
carbon at d 183.61 (C-3). The signal at d 59.80 is assignable
to the carbon of Ar–CH (C-4) (based on HSQC). The signal
at d 155.66 is in agreement with the carbon of C-5 in
isoxazoline ring. The existence of signal at d 96.25 is
assignable for the spiro carbon of C-2.
In the 1H–13C HMBC map of 3a (Fig. 1), protons of H-1
correlate with a spiro carbon (C-2), carbonyl carbon (C-3),
and Ar–CH (C-4). Proton of Ar–CH (H-4) existed in
isoxazoline ring correlates with the spiro carbon (C-2),
C═N (C-5), and carbonyl carbon (C-3). Further, the struc-
ture of 3d was confirmed by X-ray diffraction, supporting
the structural assignments of all compounds made using
spectroscopic methods (Fig. 2) [6].
As part of our endeavor to synthesize novel heterocyclic
system [5], we herein report the synthesis of a series of new
spiro isoxazoline heterocycles containing pyrrolizinone
framework (Scheme 1).
RESULTS AND DISCUSSION
The 1,3-dipolar cycloaddition reaction of 2-arylmethylidene-
EXPERIMENTAL
2,3-dihydro-1H-pyrrolizin-1-ones 1 to the nitrile oxide
2
yields 4-(aryl)-3-(2,6-dichlorophenyl)- 10H,4H-spiro
Compounds 1 [7] and 2 [8] were prepared according to the
reported procedures. All NMR spectra were recorded on a Bruker
AV-II 500 MHz NMR spectrometer (Bruker, Switzerland), oper-
[isoxazole-5,20-pyrrolizin]-10-one 3.
The structures of all compounds 3a–3h were established
by different spectroscopic techniques (NMR, IR, and MS)
and elemental analysis. The IR spectrum of 3a displayed
nC═O at 1706.7 cmꢀ1. The 1H NMR spectrum of 3a
revealed two doublets at d 4.09 (J = 12.5 Hz) and 4.42
(J = 12.5 Hz) resulting from CH2 (H-1), which existed in
pyrrolizidine ring, several multiplets, and doublets in the
1
ating at 500 MHz for H and 125 MHz for 13C. TMS was used
as an internal reference for 1H and 13C chemical shifts, and CDCl3
was used as solvent. Elemental analysis was performed with an
Elementar analyzer (varioEL II; Hessen, Germany). MS was
conducted with
a Finnigan LCQ Advantage MAX mass
spectrometer (San Jose, Ca). IR spectra were recorded on a
Perkin-Elmer spectrometer (Spectrum One; Waltham, MA).
© 2013 HeteroCorporation

January 2014
Synthesis of Novel Spiro Isoxazoline-Pyrrolizinone Derivatives
275
via 1,3-Dipolar Cycloaddition of Nitrile Oxide
Scheme 1
O
O
Ar
Cl
Cl
Cl
Cl
Benzene
Reflux
N
N O
+
N
O
Ar
N
3a-3h
1a-1h
2
Ar: a, C6H5; b, 4-ClC6H4; c, 2-ClC6H4 d, 4-CH3OC6H4; e, 4-FC6H4;
f
g
h
, 4-CH3SC6H4; , 4-CH3C6H4; , 3,4,5-(OCH3)3C6H2;
6.89–6.90 (m, 1H), 6.93–6.94 (m, 1H), 7.17–7.20 (m, 3H),
7.25–7.26 (m, 3H), 7.29 (d, J= 4.0 Hz, 1H), 7.31 (d, J=4.0Hz,
1H); 13C NMR (CDCl3, 125 MHz) d: 51.48 (C1), 59.80
(C4), 96.25 (C2), 111.10, 118.04, 124.77, 127.04, 128.77, 128.82,
129.20, 129.27, 129.83, 131.23, 132.40, 135.55, 155.66 (C5),
183.61 (C3); IR (KBr) v: 1706.7 cmꢀ1; ESI MS m/z: 397 [M+ H]+.
Anal. Calcd. for C21H14Cl2N2O2: C 63.49, H 3.55, N 7.05; found C
63.30, H 3.61, N 7.18.
O
Cl
3
4
N
2
5
1
O
N
4-(4-Chlorophenyl)-3-(2,6-dichlorophenyl)-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3b). White solid, yield 58%;
Cl
Figure 1. Partial HMBC diagram of 3a.
mp
: d 4.09
179–180ꢁC; 1H NMR (CDCl3, 500 MHz):
(d, J = 12.5Hz, 1H, H1), 4.43 (d, J = 12.5 Hz, 1H, H1), 5.86
(s, 1H, H4), 6.53–6.55 (m, 1H), 6.89–6.90 (m, 1H), 6.96–6.97
(m, 1H), 7.14–7.16 (m, 2H), 7.20–7.26 (m, 3H), 7.31–7.32
(m, 2H); 13C NMR (CDCl3, 125 MHz) d: 51.33 (C1), 59.08
(C4), 96.11 (C2), 111.30, 118.19, 124.78, 126.79, 128.90, 129.47,
129.77, 130.62, 130.94, 131.38, 134.84, 135.55, 155.25 (C5),
183.19 (C3); IR (KBr) v: 1709.0cmꢀ1; ESI MS m/z: 431
[M+ H]+. Anal. Calcd. for C21H13Cl3N2O2: C 58.43, H 3.04, N
6.49; found C 58.58, H 3.15, N 6.29.
4-(2-Chlorophenyl)-3-(2,6-dichlorophenyl)-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3c). White solid, yield 60%; mp
: 199–200ꢁC; 1H NMR (CDCl3, 500 MHz): d 3.98 (d, J = 12.5Hz,
1H, H1), 4.36 (d, J = 12.5Hz, 1H, H1), 6.54–6.55 (m, 1H), 6.57
(s, 1H, H4), 6.90–6.91 (m, 1H), 6.94–6.95 (m, 1H), 7.19–7.25
(m, 3H), 7.30–7.33 (m, 3H), 7.42–7.44 (m, 1H); 13C NMR
(CDCl3, 125MHz) d: 51.34 (C1), 55.87 (C4), 95.66 (C2), 111.19,
117.95, 124.27, 126.63, 127.36, 129.01, 129.57, 130.05, 130.31,
130.41, 131.22, 134.76, 135.84, 154.52 (C5), 183.44 (C3); IR
(KBr) v: 1707.7 cmꢀ1; ESI MS m/z: 431 [M+ H]+. Anal. Calcd.
for C21H13Cl3N2O2: C 58.43, H 3.04, N 6.49; found C 58.56, H
3.20, N 6.32.
Figure 2. ORTEP diagram of 3d.
3-(2,6-Dichlorophenyl)-4-(4-methoxyphenyl)-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3d). White solid, yield 53%;
mp
: d 4.14
190–191ꢁC; 1H NMR (CDCl3, 500 MHz):
Melting points were measured with a Yanaco MP500 melting
point apparatus (Tokyo, Japan) and are uncorrected.
(d, J = 12.5Hz, 1H, H1), 4.39 (d, J = 12.5 Hz, 1H, H1), 5.83
(s, 1H, H4), 6.52–6.54 (m, 1H), 6.77–6.78 (m, 2H), 6.87–6.94
(m, 2H), 7.11 (d, J = 7.5 Hz, 2H), 7.17–7.20 (m, 1H), 7.28
(d, J = 7.5Hz, 2H); 13C NMR (CDCl3, 125 MHz) d: 51.41
(C1), 55.22 (ꢀOCH3), 59.26 (C4), 96.13 (C2), 111.00, 114.51,
117.96, 124.17, 124.64, 127.17, 128.80, 129.92, 130.48, 131.14,
General procedure for the synthesis of 4-(aryl)-3-(2,6-
dichlorophenyl)-10H,4H-spiro[isoxazole-5,20-pyrrolizin]-10-one
(3a–3h). A mixture of 1 (1 mmol) and 2 (2 mmol) in benzene
(15 mL) was refluxed overnight. The solvent was evaporated in
vacuum. The residue was purified by column chromatography
on silica gel with the use of petroleum ether and ethyl acetate
(5:1 v/v) as eluent to afford the corresponding 3a–3h.
135.57, 155.88 (C5), 183.87 (C3); IR (KBr) v: 1713.5 cmꢀ1
;
ESI MS m/z: 427 [M+ H]+. Anal. Calcd. for C22H16Cl2N2O3:
C 61.84, H 3.77, N 6.56; found C 61.98, H 3.85, N 6.40.
3-(2,6-Dichlorophenyl)-4-phenyl-10H,4H-spiro[isoxazole-5,20-
pyrrolizin]-10-one (3a). White solid, yield 64%; mp : 183–185ꢁC;
1H NMR (CDCl3, 500 MHz): d 4.09 (d, J= 12.5 Hz, 1H, H1), 4.42
(d, J= 12.5 Hz, 1H, H1), 5.89 (s, 1H, H4), 6.52–6.54 (m, 1H),
3-(2,6-Dichlorophenyl)-4-(4-fluorophenyl)-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3e). White solid, yield 55%;
mp : 198–200ꢁC; 1H NMR (CDCl3, 500MHz): d 4.12 (d, J= 12.5 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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X. Li, R. Yi, B. Liu, A. Zheng, X. Yu, and P. Yi
Vol 51
1H, H1), 4.45 (d, J =12.5 Hz, 1H, H1), 5.89 (s, 1H, H4), 6.56–6.57
(m, 1H), 6.92–6.93 (m, 1H), 6.97–7.00 (m, 3H), 7.19–7.23 (m, 2H),
7.24–7.26 (m, 1H), 7.33–7.35 (m, 2H); 13C NMR (CDCl3,
125 MHz) d: 51.33 (C1), 59.03 (C4), 96.07 (C2), 111.25, 116.20,
116.37, 118.12, 124.66, 126.90, 128.24, 128.26, 128.86, 129.84,
131.01, 131.08, 131.30, 135.57, 155.45 (C5), 183.36 (C3); IR
(KBr) v: 1702.4 cmꢀ1; ESI MS m/z: 415 [M +H]+. Anal. Calcd.
for C21H13Cl2FN2O2: C 60.74, H 3.16, N 6.75; found C 60.99, H
3.26, N 6.52.
Acknowledgment. This research was supported by the National
Natural Science Foundation of China (Nos. 20971041,
21172066), the Key Project of Chinese Ministry of Education
(No. 210146), the Scientific Research Fund of Hunan Provincial
Education Department (09K081), and the Open Project Program
of Key Laboratory of Theoretical Chemistry and Molecular
Simulation of Ministry of Education (Hunan University of
Science and Technology).
3-(2,6-Dichlorophenyl)-4-[4-(methylthio)phenyl]-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3f). White solid, yield 51%;
REFERENCES AND NOTES
1
mp : 175–177ꢁC; H NMR (CDCl3, 500 MHz): d 2.40 (s, 3H, –
SCH3), 4.11 (d, J = 12.5 Hz, 1H, H1), 4.40 (d, J = 12.5 Hz, 1H,
H1), 5.84 (s, 1H, H4), 6.52–6.53 (m, 1H), 6.88–6.89
(m, 1H), 6.94–6.95 (m, 1H), 7.10–7.11 (m, 4H), 7.18–7.22
(m, 1H), 7.29–7.31 (m, 2H); 13C NMR (CDCl3, 125 MHz) d:
15.10 (–SCH3), 51.42 (C1), 59.35 (C4), 96.18 (C2), 111.13,
118.05, 124.68, 126.40, 127.04, 128.66, 128.85, 129.65, 129.88,
131.22, 135.58, 155.57 (C5), 183.54 (C3); IR (KBr) v:
1715.8cmꢀ1; ESI MS m/z: 443 [M+ H]+. Anal. Calcd. for
C22H16Cl2N2O2S: C 59.60, H 3.64, N 6.32; found C 59.43,
H 3.58, N 6.51.
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[isoxazole-5,20-pyrrolizin]-10-one (3g). White solid, yield 50%; mp :
188–189ꢁC; 1H NMR (CDCl3, 500 MHz): d 2.25 (s, 3H, –CH3), 4.10
(d, J= 12.5 Hz, 1H, H1), 4.39 (d, J= 12.5 Hz, 1H, H1), 5.85 (s, 1H,
H4), 6.51–6.52 (m, 1H), 6.88–6.89 (m, 1H), 6.93–6.94 (m, 1H),
7.05–7.09 (m, 4H), 7.17–7.20 (m, 1H), 7.28–7.30 (m, 2H); 13C
NMR (CDCl3, 125MHz) d: 21.14 (–CH3), 51.49 (C1), 59.52 (C4),
96.22 (C2), 111.04, 117.97, 124.65, 127.18, 128.80, 129.15,
129.28, 129.87, 131.13, 135.59, 138.62, 155.83 (C5), 183.77 (C3);
IR (KBr) v: 1712.5 cmꢀ1; ESI MS m/z: 411 [M + H]+. Anal. Calcd.
for C22H16Cl2N2O2: C 64.25, H 3.92, N 6.81; found C 64.44, H
4.03, N 6.99.
3-(2,6-Dichlorophenyl)-4-(3,4,5-trimethoxyphenyl)-10H,4H-spiro
[isoxazole-5,20-pyrrolizin]-10-one (3h). White solid, yield 53%; mp :
1
221–223ꢁC; H NMR (CDCl3, 500 MHz): d 3.73 (s, 6H, –OCH3),
3.78 (s, 3H, –OCH3), 4.10 (d, J= 12.5 Hz, 1H, H1),
4.38 (d, J= 12.5 Hz, 1H, H1), 5.88 (s, 1H, H4), 6.34 (s, 2H,
–ArH), 6.54–6.55 (m, 1H), 6.90–6.91 (m, 1H), 6.98–6.99
(m, 1H), 7.25–7.28 (m, 1H), 7.34–7.36 (m, 2H); 13C NMR (CDCl3,
125 MHz) d: 51.55 (C1), 56.14 (–OCH3), 59.94 (C4), 60.76
(–OCH3), 96.29 (C2), 105.81, 111.16, 118.05, 124.83, 127.33,
127.87, 128.95, 129.93, 131.33, 135.54, 137.82, 155.23 (C5),
183.65 (C3); IR (KBr) v: 1701.3 cmꢀ1; ESI MS m/z: 487 [M+H]+.
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58.95, H 4.01, N 5.96.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet