Synthesis of novel spiro[oxirane-pyrrolizin] derivatives by epoxidation of α,β-unsaturated pyrrolizinone with cyclohexylidenebishydroperoxide

Article abstract of DOI:10.3184/174751915X14411919524595

A simple epoxidation of E-2-(arylmethylidene)-2,3-dihydro-1H-pyrrolizin-1-ones was accomplished using cyclohexylidenebishydroperoxide as the oxygen source. A number of 3-arylspiro[oxirane-2,2'-pyrrolizin]-1'(3'H)-ones were obtained in moderate to good yie

Full text of DOI:10.3184/174751915X14411919524595

558 RESEARCH PAPER
VOL. 39 OCTOBER, 558–560
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of novel spiro[oxirane-pyrrolizin] derivatives by epoxidation of α,β-
unsaturated pyrrolizinone with cyclohexylidenebishydroperoxide
Leilei Yang, Xiaofang Li*, Xiaolian Hu and Zhenqiang Tang
School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, P.R. China
A simple epoxidation of E-2-(arylmethylidene)-2,3-dihydro-1H-pyrrolizin-1-ones was accomplished using cyclohexylidenebishydroperoxide
as the oxygen source. A number of 3-arylspiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-ones were obtained in moderate to good yields.
Keywords: epoxidation, α,β-unsaturated carbonyl compounds, pyrrolizinone, cyclohexylidenebishydroperoxide, spiro[oxirane-pyrrolizin]
derivatives
Epoxidation of olefins has attracted considerable attention in
recent years due to the fact that epoxide products are significant
building blocks in organic synthesis.1-3 Numerous strategies
for epoxidation of olefins have been developed and various
oxidants have been successfully used for epoxidation, including
oxygen,4 dioxiranes,5 hypervalent iodine reagents,6 hydrogen
peroxide7-13 and hydroperoxide.14-17 Among these oxidants,
hydrogen peroxide is probably the most environmentally benign
with the remarkable advantage of producing water as the only
by-product. Unfortunately, hydrogen peroxide is usually used
together with a catalyst in epoxidation reactions because its
oxidant power is too low to oxidise some organic compounds.13
By contrast, hydroperoxides have similar structures and
stronger oxidant power. These are also useful oxidants for
the epoxidation of α,β-unsaturated carbonyl compounds in
excellent yields under simple and mild reaction conditions.15
Most recently, our group reported a simple method to
synthesise a series of α,β-unsaturated carbonyl compounds
containing the interesting building block pyrrolizinone.18
Pyrrolizinones are an important type of heterocycle compound
both in synthetic medicines and natural pharmacologically
relevant alkaloids.10,20 Past research has shown that pyrrolizinone
compounds have broad biological activities, including
psychostimulant,21 analgesic,22 antitubulin23 and antidiabetic24
effects and asneurokinin-1 (NK1) antagonists.25 In this context,
we have tried to introduce an oxirane ring structure into the
pyrrolizine compound to synthesise new pyrrolizine derivatives
for further preparations of products which may be useful.
We report here the synthesis of 3-arylspiro[oxirane-2,2’-
pyrrolizin]-1’(3’H)-ones by an epoxidation reaction between
E-2-(arylmethylidene)-2,3-dihydro-1H-pyrrolizin-1-ones (1a–i)
and cyclohexylidenebishydroperoxide (Scheme 1).
in the presence of aqueous KOH in dioxane to afford the desired
3-arylspiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-ones in moderate
to good yields (Table 1). The reaction progress was monitored
by TLC and the target products were purified by flash column
chromatography on silica gel with petroleum ether:ethyl acetate as
eluent. In order to understand the scope of this reaction, we studied
various E-2-(arylmethylidene)-2,3-dihydro-1H-pyrrolizin-1-ones
and the results are summarised in Table 1. It is clear that the yield
of compounds containing electron-withdrawing substituents in
the aryl group was higher than electron-donating groups. For
example, those containing E-2-(2,4-dichlorobenzylidene)-2,3-
dihydro-1H-pyrrolizin-1-one yielded the desired product (2e) in
the highest yield (88%, entry 5) while the epoxide of E-2-(3,4-
dimethoxybenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one
(2i)
formed the product in the lowest yield (47%, entry 9). A similar
trend has been shown in other epoxidations of α,β-unsaturated
carbonyl compounds with hydrogen peroxide.26
Structural elucidation of the 3-arylspiro[oxirane-2,2’-
pyrrolizin]-1’(3’H)-ones 2a–i was unambiguously accomplished
by various spectroscopic techniques (NMR, IR and HRMS).
The high resolution mass spectrum of 3-phenylspiro[oxirane-
2,2’-pyrrolizin]-1’(3’H)-one (2a) contained a peak at m/z
Table 1 Synthesis of spiro[oxirane-pyrrolizin] derivatives
Entry Ar
Product
2a
2b
2c
2d
2e
2f
2g
2h
Time/h
5.0
6.0
4.0
4.5
6.0
5.5
6.5
5.0
Yield/%
63
53
72
78
88
54
56
60
1
2
3
4
5
6
7
8
9
C6H5
4-FC6H4
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H4
4–CH3C6H4
4–CH3SC6H4
4–CH3OC6H4
3,4-(OCH3)2C6H3
Results and discussion
At ambient temperature, E-2-(arylmethylidene)-2,3-dihydro-1H-
pyrrolizin-1-ones reacted with cyclohexylidenebishydroperoxide
2i
8.0
47
O
O
H
OO
H
OO
O
dioxane
KOH, rt
+
Ar
N
N
Ar
1a-1i
2a-2i
Ar: a
f
b
c
;
d
e
, C H5 , 4-FC H4 , 4-ClC6H4; , 2-ClC6H4; , 2,4-Cl2C6H3;
;
6
6
g
h
i
;
, 4-CH C H4 , 4-CH SC H4 , 4-CH OC H4 , 3,4-(OCH ) C6H ;
;
;
3
6
3
6
3
6
3 2
3
Scheme 1
* Correspondent. E-mail: lixiaofang@iccas.ac.cn

JOURNAL OF CHEMICAL RESEARCH 2015 559
(E)-2-Benzylidene-2,3-dihydro-1H-pyrrolizin-1-one (1a): Pale
yellow solid; yield 58%; m.p. 132–133°C (lit.18 132–133°C).
O
O
1'
(E)-2-(4-Fluorobenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one
(1b): Pale yellow solid; yield 58%; m.p. 169–170°C; 1H NMR (CDCl3,
500 MHz): d 5.16 (d, J = 2.0 Hz, 2H), 6.55 (dd, J1 = 4.0 Hz, J2 = 2.0 Hz,
1H), 6.88 (dd, J1 = 4.0 Hz, J2 = 1.0 Hz, 1H), 7.12–7.13 (m, 1H), 7.15 (t,
J = 8.5 Hz, 2H), 7.44–7.47 (m, 2H), 7.15 (t, J = 2.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) : d 47.5, 108.9, 116.3, 116.4, 116.9, 122.2, 130.3,
130.7, 130.8, 132.0, 132.1, 134.36, 134.38, 134.42, 162.3, 164.3, 179.2;
IR (KBr) v 1696 cm-1; ESI-HRMS calcd for[C14H11FNO]+, [M + H]+:
m/z = 228.0819; found: 228.0812.
7'
3
2
6'
N
3'
5'
Fig. 1 Partial HMBC diagram of 2a.
226.0865 ([M +H]+), which indicated the existence of 2a
(calculated value 226.0863). The IR spectrum of 2a revealed the
presence of a carbonyl stretching vibration band at 1707 cm-1,
which was assigned to the carbonyl group of the pyrrolizinone
moiety. The 1H NMR spectrum of 2a revealed two doublets at δH
4.05 ppm (J = 13.0 Hz) and 4.31 ppm (J = 13.0 Hz), which were
assigned to the protons of methylene (H2C-3’) and one singlet at
δH 4.56, which was assigned to the proton of CH (HC-3) in the
oxirane ring (for numbering see Fig. 1). There was a singlet at
δH 6.57 ppm, which was assigned to the proton of HC-6’ in the
pyrrolizinone ring. The doublet at δH 6.82 ppm (d, J = 3.5 Hz)
and the singlet at δ 7.08 ppm were assigned to the proton of
HC-7’ and that of HHC-5’ respectively in the pyrrolizinone ring.
The 13C NMR spectrum of the product 2a exhibited the
presence of carbonyl carbon at δ 183.1 ppm (C-1’). The signal
at δC 44.8 ppm was assigned toCthe carbons of CH2 (H2C-3’),
which existed in the pyrrolizine ring [based on Heteronuclear
Singular Quantum Correlation (HSQC)]. The signal at δC 61.7
ppm was assigned to the carbons of CH (HC-3) present in the
oxirane ring (based on HSQC). The signals at δC 110.1, 117.2
and 125.0 ppm represented the carbons of HC-7’, HC-6’ and
HC-5’, respectively. The signal at δC 68.9 ppm was assigned to
the spiro carbons of C-2.
(E)-2-(4-Chlorobenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one (1c):
Pale yellow solid; yield 62%; m.p. 228–220°C (lit.18 218–220°C).
(E)-2-(2-Chlorobenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one
(1d): Pale yellow solid; yield 58%; m.p. 195–196°C (lit.18 195–196°C).
(E)-2-(2,4-Dichlorobenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one
(1e): Pale yellow solid; yield 48%; m.p. 201–202°C (lit.18 201–202°C).
(E)-2-(4-Methylbenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one (1f):
Pale yellow solid; yield 56%; m.p. 176–178°C (lit.18 177–178°C).
(E)-2-(4-(Methylthio)benzylidene)-2,3-dihydro-1H-pyrrolizin-1-
one (1g): Pale yellow solid; yield 41%; m.p. 193–194°C (lit.18 192–193).
(E)-2-(4-Methoxybenzylidene)-2,3-dihydro-1H-pyrrolizin-1-one
(1h): Pale yellow solid; yield 71%; m.p. 182–184°C (lit.18 182–184°C).
(E)-2-(3,4-Dimethoxybenzylidene)-2,3-dihydro-1H-pyrrolizin-
1
1-one (1i): Pale yellow solid; yield 82%; m.p. 208–209°C; H NMR
(CDCl3, 500 MHz): d 3.93 (s, 3H), 3.94 (s, 3H), 5.15 (d, J = 1.5 Hz,
2H), 6.54 (dd, J1 = 3.5 Hz, J2 = 2.0 Hz, 1H), 6.86 (dd, J1 = 4.5 Hz, J2
= 1.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 7.07
(dd, J1 = 4.5 Hz, J2 = 1.0 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.15 (s, 1H);
13C NMR (CDCl3, 125 MHz) : d 47.5, 55.97, 55.99, 108.5, 111.4, 113.2,
116.6, 122.0, 123.7, 127.4, 131.6, 132.6, 134.6, 149.2, 150.6, 179.5; IR
(KBr) v 1698 cm-1; ESI-HRMS calcd for[C16H16NO3]+, [M + H]+: m/z =
270.1125; found: 270.1131.
Synthesis of 3-arylspiro[oxirane-2, 2’-pyrrolizin]-1’(3’H)-ones (2a–i);
In the 1H–13C heteronuclear multiple bond correlation
(HMBC) map of 2a (Fig. 1), protons of H2C-3’ present in the
pyrrolizine ring and HC-3 in the oxirane ring correlated with the
spiro carbon C-2 (68.9 ppm), protons of H2C-3’ correlated with
the carbon C-3(61.7 ppm) and carbonyl carbon C-1’ (183.1 ppm).
Furthermore, the correlation between the proton of HC-3 and
carbonyl carbon C-1’ also supported the structural assignment.
general procedure
A solution containing the E-2-(arylmethylidene)-2,3-dihydro-1H-
pyrrolizin-1-one 1, cyclohexylidenebishydroperoxide (1 mmol)
and aqueous KOH (1.0 M, 1.0 mL) in 5 mL of dioxane was stirred at
room temperature. Completion of the reaction was evidenced by TLC
analysis (Rf = 0.4–0.5) using petroleum ether (60–80°C):ethyl acetate
(V:V = 5:1) as eluent. Then, the reaction mixture was diluted with ethyl
acetate (15 mL) and washed with water (4 mL). The organic layer was
dried over MgSO4 and then the solvent was evaporated under reduced
pressure. The crude product was subjected to column chromatography
using petroleum ether (60–80 oC):ethyl acetate (V:V = 5:1) as eluent to
afford the corresponding 2.
3-Phenylspiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-one (2a): White
solid; yield 63%; m.p. 152–153°C; 1H NMR (CDCl3, 500 MHz): d 4.05
(d, J = 13.0 Hz, 1H, H2C-3’), 4.31 (d, J = 13.0 Hz, 1H, H2C-3’), 4.56
(s, 1H, HC-3), 6.57 (s, 1H), 6.82 (d, J = 3.5 Hz, 1H), 7.08 (s, 1H), 7.29
(d, J = 7.0 Hz, 2H), 7.36–7.43 (m, 3H); 13C NMR (CDCl3, 125 MHz) :
d 44.8, 61.7, 68.9, 110.1, 117.2, 125.0, 126.0, 128.8, 128.9, 131.8, 133.9,
183.1; IR (KBr) v 1707 cm-1; ESI-HRMS calcd for[C14H12NO2]+, [M +
H]+: m/z = 226.0863; found: 226.0865.
3-(4-Fluorophenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-one
(2b): White solid; yield 53%; m.p. 165–166°C; 1H NMR (CDCl3, 500
MHz): d 4.03 (d, J = 12.5 Hz, 1H, H2C-3’), 4.30 (d, J = 12.5 Hz, 1H,
H2C-3’), 4.54 (s, 1H, HC-3), 6.58 (s, 1H), 6.89 (s, 1H), 7.09 (s, 1H), 7.20
(d, J = 8.5 Hz, 2H), 7.27–7.20 (m, 2H); 13C NMR (CDCl3, 125 MHz) : d
44.7, 61.0, 68.8, 110.1, 115.9, 116.1, 117.2, 125.0, 127.75, 127.82, 129.73,
129.76, 131.8, 162.0, 164.0, 182.7; IR (KBr) v 1703 cm-1; ESI-HRMS
calcd for[C14H11FNO2]+, [M + H]+: m/z = 244.0768; found: 244.0773.
3-(4-Chlorophenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-one
Experimental
All chemicals and solvents were of reagent-grade quality and used
without further purification. 2,3-Dihydro-1H-pyrrolizin-1-one18 and
cyclohexylidenebishydroperoxide26 were prepared according to the
reported procedures. NMR spectra were recorded on a Bruker AV-II 500
1
MHz NMR spectrometer, operating 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. HRMS were obtained on a
Thermo EXACTIVE spectrometer and the HRMS m/z values for 2c, 2d
and 2e refer to the ion containing only the 35Cl isotope. IR spectra were
recorded on a PE-2000 spectrometer in KBr pellets and are reported in
cm-1. Melting points were measured with a Yanaco MP500 melting point
apparatus and are uncorrected. The analytical TLCs were performed
with silica gel 60 F254 plates. Column chromatography was carried out
by using silica gel 60 (200–300 mesh ASTM).
Synthesis of (E)-2-arylmethylidene-2,3-dihydro-1H-pyrrolizin-1-ones
(1a–i); general procedure
The aromatic aldehyde (10 mmol) was added to a stirring mixture
of 2,3-dihydro-1H-pyrrolizin-1-one (10 mmol) in ethanol (10 mL)
and sodium hydroxide (20 mmol) in water (10 mL). The mixture
was stirred at 45°C and completion of the reaction was evidenced by
1
(2c): White solid; yield 72%; m.p. 173–174°C; H NMR (CDCl3, 500
o
TLC analysis (Rf = 0.3–0.4) using petroleum ether (60–80 C)-ethyl
MHz): d 4.03 (d, J = 13.0 Hz, 1H, H2C-3’), 4.30 (d, J = 13.0 Hz, 1H,
H2C-3’), 4.54 (s, 1H, HC-3), 6.58 (s, 1H), 6.89 (d, J = 3.5 Hz, 1H), 7.09
(s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H); 13C NMR
acetate (V:V = 5:1) as eluent. The reaction mixture was then cooled and
filtered and the product was recrystallised from ethanol to give 1a–i.

560 JOURNAL OF CHEMICAL RESEARCH 2015
(CDCl3, 125 MHz) : d 44.7, 61.0, 68.8, 110.2, 117.3, 125.0, 127.4, 129.1,
129.4, 131.2, 133.7, 132.5, 134.9, 182.5; IR (KBr) v 1714 cm-1; ESI-
HRMS calcd for[C14H11ClNO2]+, [M + H] +: m/z = 260.0473; found:
260.0477.
1-ones by cyclohexylidenebishydroperoxide under very mild
reaction conditions. This simple and efficient method gives
products that should now be able to be converted into useful
products.
3-(2-Chlorophenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-one
(2d): White solid; yield 78%; m.p. 153–154°C; 1H NMR (CDCl3, 500
MHz): d 3.93 (d, J = 13.0 Hz, 1H, H2C-3’), 4.15 (d, J = 13.0 Hz, 1H,
H2C-3’), 4.76 (s, 1H, HC-3), 6.59 (s, 1H), 6.92 (d, J = 4.0 Hz, 1H), 7.07
(s, 1H), 7.34 (s, 3H), 7.40 (t, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 125
MHz) : d 44.8, 59.6, 68.2, 110.2, 117.2, 124.9, 126.8, 127.2, 129.5,
130.0, 131.8, 132.4, 133.3, 182.4; IR (KBr) v 1711 cm-1; ESI-HRMS
calcd for[C14H11ClNO2]+, [M + H]+: m/z = 260.0473; found: 260.0465.
3-(2,4-Dichlorophenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-
This research was supported by the Scientific Research Fund
of the Hunan Provincial Education Department (14C0463,
13A026, 12C0116) and the Hunan Provincial Natural Science
Foundation of China (14JJ4045).
Received 28 June 2015; accepted 22 August 2015
Paper 1503448 doi: 10.3184/174751915X14411919524595
Published online: 2 October 2015
1
one (2e): White solid; yield 88%; m.p. 187–188°C; H NMR (CDCl3,
500 MHz): d 3.94 (d, J = 13.0 Hz, 1H, H2C-3’), 4.16 (d, J = 13.0 Hz,
1H, H2C-3’), 4.71 (s, 1H, HC-3), 6.06 (s, 1H), 6.92 (d, J = 4.0 Hz, 1H),
7.09 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.43
(s, 1H); 13C NMR (CDCl3, 125 MHz) : d 44.7, 59.1, 68.2, 110.4, 117.3,
125.1, 127.6, 127.7, 129.5, 131.1, 131.7, 133.9, 135.4 181.9; IR (KBr) v
1711 cm-1; ESI-HRMS calcd for[C14H10Cl2NO2]+, [M + H] +: m/z =
294.0083; found: 294.0086.
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500 MHz): d 2.50 (s, 3H, –SCH3), 4.05 (d, J = 13.0 Hz, 1H, H2C-3’),
4.29 (d, J = 13.0 Hz, 1H, H2C-3’), 4.51 (s, 1H, HC-3), 6.57 (s, 1H), 6.88
(d, J = 4.0 Hz, 1H), 7.07 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) : d 15.5, 44.8, 61.5, 68.9, 110.0,
117.1, 124.9, 126.4, 130.5, 131.8, 139.9, 182.9; IR (KBr) v 1712 cm-1;
ESI-HRMS calcd for[C15H14NO2S]+, [M + H]+: m/z = 272.0740; found:
272.0736.
3-(4-Methoxyphenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-one
1
(2h): White solid; yield 60%; m.p. 151–152°C; H NMR (CDCl3,
500 MHz): d 3.83 (s, 3H, –OCH3), 4.07 (d, J = 13.0 Hz, 1H, H2C-
3’), 4.30 (d, J = 13.0 Hz, 1H, H2C-3’), 4.51 (s, 1H, HC-3), 6.57 (s, 1H),
6.89 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 7.07 (s, 1H), 7.21
(d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) : d 44.8, 55.4, 61.7,
68.9, 109.9, 114.3, 117.0, 124.8, 125.8, 127.3, 131.9, 160.1, 183.2; IR
(KBr) v 1710 cm-1; ESI-HRMS calcd for[C15H14NO3]+, [M + H]+: m/z =
256.0968; found: 256.0976.
3-(3,4-Dimethoxyphenyl)spiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-
1
one (2i): White solid; yield 47%; m.p. 158–160°C; H NMR (CDCl3,
500 MHz): d 3.89 (s, 3H, –OCH3), 3.90 (s, 3H, –OCH3), 4.06 (d,
J = 13.0 Hz, 1H, H2C-3’), 4.29 (d, J = 13.0 Hz, 1H, H2C-3’), 4.52 (s,
1H, HC-3), 6.58 (s, 1H), 6.78 (s, 1H), 6.86–6.90 (m, 3H), 7.09 (s, 1H);
13C NMR (CDCl3, 125 MHz) : d 44.8, 56.0, 61.7, 68.9, 108.6, 110.0,
111.3, 117.1, 118.6, 124.9, 126.3, 131.9, 140.3, 149.5, 183.1; IR (KBr)
v 1707 cm-1; ESI-HRMS calcd for[C16H16NO4]+, [M + H]+: m/z =
286.1074; found: 286.1077.
25 G. J. Morriello, G. Chicchi, T. Johnson, S. G. Mills, J. DeMartino, M. Kurtz,
K. L. C. Tsao, S. Zheng, X. Tong, E. Carlson, K. Townson, A. Wheeldon,
S. Boyce, N. Collinson, N. Rupniak and R. J. DeVita, Bioorg. Med. Chem.
Lett., 2010, 20, 5925.
Conclusion
We have successful developed a method for the synthesis
of 3-arylspiro[oxirane-2,2’-pyrrolizin]-1’(3’H)-ones by the
epoxidation of E-2-(arylmethylidene)-2,3-dihydro-1H-pyrrolizin-
26 Y. Y. Chu, X. H. Liu, W. Li, X. L. Hu, L. L. Lin and X. F. Feng, Chem. Sci.,
2012, 3, 1996.
27 K. Zÿmitek, M. Zupan, S. Stavber and J. Iskra, Org. Lett., 2006, 8, 2491.