Synthesis of novel spiro[cyclopropane-indolizine] derivatives via magnesium-mediated conjugate addition of bromoform

Article abstract of DOI:10.3184/174751913X13814138618396

The reaction of 6,7-dihydroindolizin-8(5H)-one and an aromatic aldehyde yielded (E)-7-(arylmethylene)-6,7-dihydroindolizin-8(5H)-ones which underwent addition of bromoform in the presence of magnesium under N₂ to give a novel series of 3-aryl-2,2-dibromo-5′H-spiro[cyclopropane-1,7′- indolizin]-8′(6′H)-one derivatives. The structures of the products were established by ¹H NMR, ¹³C NMR, IR spectroscopy and mass spectra.

Full text of DOI:10.3184/174751913X13814138618396

JOURNAL OF CHEMICAL RESEARCH 2013
NOVEMBER, 681–683
RESEARCH PAPER 681
Synthesis of novel spiro[cyclopropane-indolizine] derivatives via
magnesium-mediated conjugate addition of bromoform
Bin Liu, Xiaofang Li*, Jie Zhang, Liyun Du and Rongjin Zeng
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, P.R. China
The reaction of 6,7-dihydroindolizin-8(5H)-one and an aromatic aldehyde yielded (E)-7-(arylmethylene)-6,7-dihydroindolizin-
8(5H)-ones which underwent addition of bromoform in the presence of magnesium under N to give a novel series of 3-aryl-
2,2-dibromo-5′H-spiro[cyclopropane-1,7′-indolizin]-8′(6′H)-one derivatives. The structures of 2the products were established by
1H NMR, 13C NMR, IR spectroscopy and mass spectra.
Keywords: cyclopropane, indolizine, spiroheterocyclic, magnesium-mediated conjugate addition, bromoform
The indolizine building block1–3 is found in biologically
Table 1 Synthesis of spiro[cyclopropane-indolizin] derivatives
active alkaloids such as (+)-monomorine4, indolizidine 209D5,
Entry
Ar
Product
Time/h
Yield/%
polygonatines6 and kinganone.7 Related natural products such as
rhazinilam possesses intriguing anti-mitotic properties8 whilst
the vincamine alkaloid also has interesting cardiovascular
properties9.
There are some interesting natural products which contain
the cyclopropane ring.10–12 Heterocyclic compounds containing
a cyclopropane ring and an indolizine unit could be a useful
framework with potential biological activity. We now report
the synthesis of a new series of 3-aryl-2,2-dibromo-5′H-
spiro[cyclopropane-1,7′-indolizin]-8′(6′H)-one 3a–j via the
addition of bromoform in the presence of Mg (Scheme 1) to (E)-
7-(arylmethylene)-6,7-dihydroindolizin-8(5H)-one 2a–j.
1
2
3
4
5
6
7
8
9
C6H5
4Cl-C6H4
4-FC6H4
4-CH3SC6H4
4-CH3C6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
2.0
3.0
3.0
1.5
1.5
1.5
1.0
1.0
1.0
82
56
58
68
72
78
84
86
92
4–CH3OC6H4
3,4-(OCH3)2C6H3
3,5-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
were isolated in good yield when the substituents on the phenyl
ring were single and multiple electron-donating groups (entries
4–9).
The structures of all compounds 3a–i were established by
different spectroscopic techniques (NMR, infrared spectrum
and mass spectrum). The IR spectrum of 3f revealed the
presence of a carbonyl stretching vibration bands at 1663 cm–1.
The 1H NMR spectrum of 3f revealed one doublet of triplets at
δ 2.06 (dt, J1 =17.0 Hz, J2 =2.5 Hz) and one doublet of doublet
of doublets at 2.75 (ddd, J1 =14.5 Hz, J2 =13.5 Hz, J3 =4.5 Hz)
corresponding to the protons of methylene (H2C-3′). Another
doublet of doublet of doublets at 4.21 (ddd, J1 =7.0 Hz,
J2 =4.5 Hz, J3 =2.0 Hz) and one triplet of doublets at 4.45 (td,
J1 =12.5 Hz, J2 =2.5 Hz) correspond to the protons of methylene
(H2C-4′). A singlet at δ 3.94 was assigned to the proton of CH
(HC-3) in cyclopropane ring. The other singlet at δ 3.81 was
assigned to the proton of the –OCH3 on the phenyl ring. There
was a doublet of doublet at δ 6.33 (dd, J1 =4.0 Hz, J2 =2.5 Hz)
which was assigned to the protons of HC-7′ on the indolizinone
ring. The doublet at δ 7.16 (d, J=4.5 Hz) and the triplet at 6.93
(t, J=2.0 Hz) were assigned to the protons of HC-6′ and HC-8′
on the indolizinone ring.
Results and discussion
The reaction of 6,7-dihydroindolizin-8(5H)-one
1 and
an aromatic aldehyde to yield (E)-7-(arylmethylene)-6,7-
dihydroindolizin-8(5H)-ones 2 in moderate yields was based
on literature methods.14 The conjugate addition reaction
of bromoform (20 equiv.) to (E)-7-(arylmethylene)-6,7-
dihydroindolizin-8(5H)-ones 2 (1 equiv.) obtained 3-aryl-
2,2-dibromo-5′H-spiro[cyclopropane-1,7′-indolizin]-8′(6′H)-
one 3 in the presence of Mg (10 equiv.) in dry THF at room
temperature under N2 in moderate yields (Table 1). The progress
of this reaction was monitored by TLC and the target products
were purified by flash column chromatography on silica gel.
As shown in Table 1, the effect of different substituent groups
containing electron-donating and electron-withdrawing
groups on the phenyl ring of the (E)-7-(arylmethylene)-
6,7-dihydroindolizin-8(5H)-ones were investigated in this
reaction (entries 2–9). In general, the conjugate addition and
cyclopropanation was completed in less than 3 h, and the
products were isolated in moderate to good yield (56–92%).
Substrates with an electron-withdrawing group located on
the phenyl ring reacted with bromoform to afford the desired
products in moderate yield (entries 2, 3). The target products
The 13C NMR spectrum of the product 3f exhibited the
presence of carbonyl carbon at δ 179.7 (C-1′). The signal at δ
30.2 and 43.3 were assigned to the carbons of CH2 (H2C-3′)
and CH2 (H2C-4′) respectively on the indolizinone ring (based
on the HSQC spectrum). The signal at δ 37.7 was assigned to
the carbons of CH (HC-3), of the cyclopropane ring (based on
the HSQC spectrum). The signals at δ 111.3, 115.9 and 126.8
represent the carbons of HC-7′, HC-6′ and HC-8′ respectively.
The signal at δ 40.6 was in accord with the spiro carbon of C-1.
O
Br
O
O
Br
H
ArCHO
CHBr3
,
Mg
N
N
N
THF, 0oC-RT
r
A
NaOH(aq)
Ar
a-
3 3i
a-
2i
2
1
Ar: a
b
c
d
, C6H5; , 4-ClC6H4; , 4-FC6H4; , 4-CH3SC6H4;
1
In the H–13C HMBC map of 3f (Fig. 1), protons of H2C-3′
e
f
g
, 4-CH3C6H4; , 4-CH3OC6H4; , 3,4-(OCH3)2C6H3;
h
i
, 3,5-(OCH3)C6H3; , 3,4,5-(OCH3)3C6H2;
and H2C-4′ on the indolizinone ring and HC-3 in cyclopropane
ring were correlated with the spiro carbon C-1 (40.6 ppm),
whilst the protons of HC-6′ correlated with the carbon of C-4′
(43.3 ppm). The proton of H2C-3′ correlated with the carbon
of C-3 (30.2 ppm). The correlation between H2C-3′ and HC-3
Scheme 1
* Correspondent. E-mail: lixiaofang@iccas.ac.cn
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682 JOURNAL OF CHEMICAL RESEARCH 2013
(E)-7-(4-(Methylthio)benzylidene)-6,7-dihydroindolizin-8(5H)-one
(2d): Pale yellow solid, yield 52%; m.p. 152–153°C; H NMR (CDCl3,
with C-1′ revealed the carbon atom of carbonyl carbon (C-1′) at
179.7 ppm. The stereochemistry of the products was determined
by a NOESY spectrum. There was no correlation between
protons of HC-3 and protons of H2C-3′ in the NOESY spectrum
of 3f, which showed that the proton of HC-3 and the proton of
H2C-3′ were on the different sides of the cyclopropane ring.
A possible mechanism of the reaction from 2 to 3 is that of a
dibromocarbene addition.
1
500 MHz): δ 2.51 (s, 3H, -SCH3), 3.23–3.25 (m, 2H), 4.11 (t, J=6.5 Hz,
2H), 6.30 (dd, J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.86 (t, J=2.0 Hz, 1H),
7.14 (dd, J1 =4.0 Hz, J2 =1.5 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.33 (d,
J=8.0 Hz, 2H), 7.81 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 15.3, 27.4,
44.2, 111.1, 115.5, 125.7, 126.0, 130.3, 131.4, 131.6, 132.1, 136.1, 140.0,
177.6; IR (KBr) v 1647 cm–1; HRMS (ESI) m/z 270.0937 [M+H]+, calcd
for C16H16NOS 270.0947.
Br
1
O
1'
(E)-7-(4-Methylbenzylidene)-6,7-dihydroindolizin-8(5H)-one
(2e): Pale yellow solid, yield 62%; m.p. 134–135°C; H NMR (CDCl3,
2
Br
1
'
8
500 MHz): δ 2.38 (s, 3H, –CH3), 3.24 (ddd, J1 =7.5 Hz, J2 =6.0 Hz,
J3 =1.5 Hz, 2H), 4.10 (t, J=6.5 Hz, 2H), 6.29 (dd, J1 =4.0 Hz, J2 =2.0 Hz,
1H), 6.85 (t, J=2.0 Hz, 1H), 7.13 (dd, J1 =4.0 Hz, J2 =1.5 Hz, 1H), 7.22 (d,
J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.84 (s, 1H); 13C NMR (CDCl3,
125 MHz) δ 21.4, 27.3, 44.3, 111.0, 115.4, 125.6, 129.3, 129.8, 131.44,
131.48, 132.8, 136.7, 138.9, 177.9; IR (KBr) v 1645 cm–1; HRMS (ESI) m/z
238.1223 [M+H]+, calcd for C16H16NO 238.1226.
3
7'
N
'
3
'
6
4'
O
Fig. 1 Partial HMBC diagram of 3f.
(E)-7-(4-Methoxybenzylidene)-6,7-dihydroindolizin-8(5H)-one
1
(2f): Pale yellow solid, yield 54%; m.p. 150–151°C; H NMR (CDCl3,
Experimental
Compound 1 was prepared according to the reported procedures.13
All NMR spectra were recorded on a Bruker AV-II 500 MHz NMR
spectrometer, operating at 500 MHz for H, and 125 MHz for 13C.
500 MHz): δ 3.25 (t, J=6.5 Hz, 2H), 3.84 (s, 3H, –OCH3), 4.10 (t,
J=6.5 Hz, 2H), 6.29 (dd, J1 =3.0 Hz, J2 =2.5 Hz, 1H), 6.85 (t, J=1.5 Hz,
1H), 6.93–6.95 (m, 2H), 7.11–7.12 (m, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.82
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 27.3, 44.2, 55.4, 110.9, 114.0, 115.3,
125.5, 128.1, 130.3, 131.5, 131.6, 136.5, 160.0, 177.9; IR (KBr) v 1656 cm–
1; HRMS (ESI) m/z 254.1181 [M+H]+, calcd for C16H16NO2 254.1176.
(E)-7-(3,4-Dimethoxybenzylidene)-6,7-dihydroindolizin-8(5H)-one
1
TMS was used as an internal reference for 1H and 13C chemical
shifts and CDCl3 was used as solvent. The MS were obtained with a
Finnigan LCQ Advantage MAX mass spectrometer. 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. Mg turnings were activated by
washing with 1% dilute HCl, water, and acetone followed by drying
in an oven overnight. The solvents were all distilled prior to use. THF
was distilled from Sodium. Other commercially available materials
were purchased from Aladdin-Reagent, and were used without further
purification.
1
(2g): Pale yellow solid, yield 64%; m.p. 130–131°C; H NMR (CDCl3,
500 MHz): δ 3.27 (t, J=6.0 Hz, 2H), 3.90 (s, 3H, –OCH3), 3.91 (s, 3H,
–OCH3), 4.11 (t, J=6.0 Hz, 2H), 6.29 (m, 1H), 6.85–6.86 (m, 1H), 6.91 (d,
J=8.0 Hz, 1H), 6.94 (d, J=1.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.11–7.12
(m, 1H), 7.81 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 27.4, 44.2, 55.97,
55.98, 110.9, 111.0, 113.2, 115.3, 123.0, 125.6, 128.4, 130.5, 131.5, 136.7,
148.9, 149.6, 177.7; IR (KBr) v 1650 cm–1; HRMS (ESI) m/z 284.1266
[M + H]+, calcd for C17H18NO3 284.1281.
Synthesis of (E)-7-(arylmethylene)-6,7-dihydroindolizin-8(5H)-ones;
general procedure
(E)-7-(3,5-Dimethoxybenzylidene)-6,7-dihydroindolizin-8(5H)-one
1
(2h): Pale yellow solid, yield 62%; m.p. 120–121°C; H NMR (CDCl3,
A mixture of 6,7-dihydroindolizin-8(5H)-one 1 (10 mmol) in ethanol
(10 mL) and sodium hydroxide (20 mmol) in water (10 mL) was treated
with the aromatic aldehyde (10 mmol) with stirring. The reaction
mixture was heated to at 45°C for 2 h (the reaction was followed by
TLC). After the reaction, the mixture was cooled to room temperature
and the crude product was isolated by filtration through a Buchner
funnel. The residue so obtained was washed with water and purified by
crystallisation using ethanol to give pure product 2.
(E)-7-Benzylidene-6,7-dihydroindolizin-8(5H)-one (2a): Pale yellow
solid, yield 55%; m.p. 114–115°C; 1H NMR (CDCl3, 500 MHz): δ 3.21–
3.23 (m, 2H), 4.08 (t, J=6.5 Hz, 2H), 6.29 (dd, J1 =3.5 Hz, J2 =2.5 Hz,
1H), 6.85 (d, J=1.5 Hz, 1H), 7.13 (dd, J1 =4.0 Hz, J2 =1.0 Hz, 1H), 7.32–
7.35 (m, 1H), 7.37–7.42 (m, 4H), 7.85 (s, 1H); 13C NMR (CDCl3, 125 MHz)
δ 27.3, 44.3, 111.1, 115.5, 125.8, 128.5, 128.6, 129.7, 131.4, 132.3, 135.6,
136.5, 177.7; IR (KBr) v 1656 cm–1; HRMS (ESI) m/z 224.1066 [M+H]+,
calcd for C15H14NO 224.1070.
500 MHz): δ 3.23–3.24 (m, 2H), 3.80 (s, 3H, –OCH3), 3.81 (s, 3H,
–OCH3), 4.09–4.10 (m, 2H), 6.29 (d, J1 =2.0 Hz, 1H), 6.46 (t, J=1.5 Hz,
1H), 6.51–6.52 (m, 2H), 6.86–6.87 (m, 1H), 7.13–7.14 (m, 1H), 7.77 (s,
1H); 13C NMR (CDCl3, 125 MHz) δ 27.5, 44.3, 55.4, 100.5, 107.7, 111.1,
115.5, 125.8, 131.4, 132.7, 136.5, 137.5, 160.8, 177.6; IR (KBr) v 1653 cm–1;
HRMS (ESI) m/z 284.1261 [M+H]+, calcd for C17H18NO3 284.1281.
(E)-7-(3,4,5-Trimethoxybenzylidene)-6,7-dihydroindolizin-8(5H)-one
1
(2i): Pale yellow solid, yield 61%; m.p. 155–156°C; H NMR (CDCl3,
500 MHz): δ 3.27 (t, J=6.5 Hz, 2H), 3.88 (s, 3H, –OCH3), 3.89 (s, 6H, –
OCH3), 4.13 (t, J=6.5 Hz, 2H), 6.30–6.31 (m, 1H), 6.63 (s, 2H), 6.87 (s,
1H), 7.13–7.14 (m, 1H), 7.79 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 27.4,
44.2, 56.3, 61.0, 107.2, 111.1, 115.5, 125.7, 131.1, 131.4, 131.6, 136.7, 153.2,
177.5; IR (KBr) v 1658 cm–1; HRMS (ESI) m/z 314.1375 [M+H]+, calcd
for C18H20NO4 314.1387.
(E)-7-(4-Chlorobenzylidene)-6,7-dihydroindolizin-8(5H)-one
(2b): Pale yellow solid, yield 60%; m.p. 185–186°C; H NMR (CDCl3,
Synthesis of 3-aryl-2,2-dibromo-5′H-spiro[cyclopropane-1,7′-indolizin]-
8′(6′H)-one; general procedure
1
500 MHz): δ 3.20–3.21 (m, 2H), 4.11 (t, J=6.0 Hz, 2H), 6.31 (dd,
J1 =4.0 Hz, J2 =2.0 Hz, 1H), 6.87 (s, 1H), 7.14–7.15 (m, 1H), 7.31–7.33 (m,
2H), 7.37–7.39 (m, 2H), 7.79 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 27.3,
44.2, 111.2, 115.7, 125.9, 128.8, 130.9, 131.3, 132.7, 134.1, 134.5, 135.2,
177.4; IR (KBr) v 1650 cm–1; HRMS (ESI) m/z 258.0671 [M+H]+, calcd
for C15H13ClNO 258.0680.
(E)-7-(Arylmethylene)-6,7-dihydroindolizin-8(5H)-ones 2 (1 mmol)
and magnesium (240 mg, 10 mmol) were weighed and added to dry
THF (20 mL) in a round-bottomed flask at 0 °C under N2. Bromoform
(4.9 g, 2 mL, 20 mmol) was added dropwise into the stirred mixture
over a period of 10 min. The reaction mixture was brought to room
temperature for 1–3 hours. The reaction was carried out until TLC
analysis showed that no reactant was left in the reaction mixture. The
reaction mixture was subsequently quenched with saturated aqueous
NH4Cl (10 mL). The water layer was separated and the organic layer
was dried (Na2SO4), and the solvent evaporated under vacuum to
give the crude product. The crude product was subjected to column
chromatography using petroleum/ethyl acetate (V:V =5:1) as eluent to
afford the corresponding compound 3.
(E)-7-(4-Fluorobenzylidene)-6,7-dihydroindolizin-8(5H)-one
1
(2c): Pale yellow solid, yield 58%; m.p. 145–146°C; H NMR (CDCl3,
500 MHz): δ 3.21 (t, J=5.0 Hz, 2H), 4.09 (dd, J1 =6.5 Hz, J2 =1.5 Hz, 2H),
6.30 (dd, J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.86–6.87 (m, 1H), 7.08–7.14 (m,
3H), 7.37 (t, J=6.5 Hz, 2H), 7.80 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ
27.2, 44.2, 111.1, 115.5, 115.7, 125.9, 131.3, 131.56, 131.63, 131.69, 131.72,
132.1, 135.4, 161.7, 163.6, 177.5; IR (KBr) v 1644 cm–1; HRMS (ESI) m/z
242.0689 [M+H]+, calcd for C15H13FNO 242.0697.
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JOURNAL OF CHEMICAL RESEARCH 2013 683
2,2-Dibromo-3-phenyl-5′H-spiro[cyclopropane-1,7′-indolizin]-
8′(6′H)-one (3a): White solid, yield 82%; m.p. 166–167°C; H NMR
2,2-Dibromo-3-(3,4-dimethoxyphenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3g): White solid, yield 84%; m.p. 177–178°C; 1H
NMR (CDCl3, 500 MHz): δ 2.09 (dt, J1 =14.5 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.75 (ddd, J1 =14.0 Hz, J2 =13.0 Hz, J3 =4.5 Hz, 1H, H2C-3′), 3.88(s, 3H,
–OCH3), 3.89(s, 3H, –OCH3), 3.96 (s, 1H, HC-3), 4.22 (ddd, J1 =6.5 Hz,
J2 =4.0 Hz, J3 =2.0 Hz, 1H, H2C-4′), 4.46 (td, J1 =12.5 Hz, J2 =3.0 Hz,
1H, H2C-4′), 6.34 (dd, J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.79–6.86(m, 3H),
6.93 (t, J=2.0 Hz, 1H), 7.16–7.17 (m, 1H); 13C NMR (CDCl3, 125 MHz)
δ 30.4, 36.2, 38.0, 43.3, 55.9, 56.0, 111.0, 111.4, 113.1, 116.0, 122.0, 125.2,
126.9, 129.8, 148.5, 148.9, 179.6; IR (KBr) v 1668 cm–1; HRMS (ESI) m/z
374.0391 [M–Br]+, calcd for C18H17BrNO3 374.0392.
1
(CDCl3, 500 MHz): δ 2.06 (dt, J1 =14.0 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.76 (ddd, J1 =14.5 Hz, J2 =13.5 Hz, J3 =4.5 Hz, 1H, H2C-3′), 4.01 (s, 1H,
HC-3), 4.21 (ddd, J1 =6.5 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H, H2C-4′), 4.44
(td, J1 =13.0 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.33 (dd, J1 =4.0 Hz, J2 =2.0 Hz,
1H), 6.94 (s, 1H), 7.17 (dd, J1 =4.0 Hz, J2 =1.0 Hz, 1H), 7.33–7.40 (m, 5H);
13C NMR (CDCl3, 125 MHz) δ 30.3, 35.8, 38.2, 40.6, 43.3, 111.4, 115.9,
126.9, 127.7, 128.6, 129.7, 129.9, 132.9, 179.5; IR (KBr) v 1652 cm–1;
HRMS (ESI) m/z 314.0169 [M–Br]+, calcd for C16H13BrNO 314.0181.
Anal. Calcd for C16H13Br2NO: C, 48.64; H, 3.32; N, 3.55. Found: C, 48.62;
H, 3.36; N, 3.49%.
2,2-Dibromo-3-(3,5-dimethoxyphenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3h): White solid, yield 86%; m.p. 174–175°C; 1H
NMR (CDCl3, 500 MHz): δ 2.12 (dt, J1 =14.5 Hz, J2 =3.0 Hz, 1H, H2C-3′),
2.75 (ddd, J1 =14.5 Hz, J2 =13.0 Hz, J3 =4.5 Hz, 1H, H2C-3′), 3.78(s, 6H,
–OCH3), 3.96 (s, 1H, HC-3), 4.22 (ddd, J1 =9.0 Hz, J2 =4.5 Hz, J3 =2.5 Hz,
1H, H2C-4′), 4.45 (td, J1 =13.0 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.33 (dd,
J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.41(s, 3H), 6.94 (t, J=2.0 Hz, 1H), 7.15 (dd,
J1 =4.0 Hz, J2 =1.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 30.4, 35.6,
38.4, 40.6, 43.3, 55.4, 99.7, 107.8, 111.4, 115.9, 127.0, 129.7, 134.9, 160.8,
179.5; IR (KBr) v 1646 cm–1; HRMS (ESI) m/z 374.0365 [M–Br]+, calcd
for C18H17BrNO3 374.0392.
2,2-Dibromo-3-(4-chlorophenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3b): White solid, yield 56%; m.p. 202–203°C; 1H
NMR (CDCl3, 500 MHz): δ 2.03 (dt, J1 =14.5 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.75 (ddd, J1 =14.0 Hz, J2 =13.0 Hz, J3 =4.5 Hz, 1H, H2C-3′), 3.96 (s, 1H,
HC-3), 4.22 (ddd, J1 =6.5 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H, H2C-4′), 4.46
(td, J1 =13.0 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.34 (dd, J1 =4.0 Hz, J2 =2.5 Hz,
1H), 6.95 (t, J=1.5 Hz, 1H), 7.17 (dd, J1 =4.0 Hz, J2 =1.5 Hz, 1H), 7.21–
7.22 (m, 2H), 7.33–7.34 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 30.2,
35.2, 37.5, 40.6,43.2, 111.5, 116.2, 127.0, 128.9, 129.6, 131.3, 131.4, 133.8,
179.2; IR (KBr) v 1661 cm–1; HRMS (ESI) m/z 347.9768 [M–Br]+, calcd
for C16H12BrClNO 347.9791. Anal. Calcd for C16H12Br2ClNO: C, 44.74; H,
2.82; N, 3.26. Found: C, 44.68; H, 2.75; N, 3.28%.
2,2-Dibromo-3-(3,4,5-trimethoxyphenyl)-5′H-spiro[cyclopropane-
1,7′-indolizin]-8′(6′H)-one (3i): White solid, yield 92%; m.p. 178–179°C;
1H NMR (CDCl3, 500 MHz): δ 2.09 (dt, J1 =12.0 Hz, J2 =2.5 Hz, 1H,
H2C-3′), 2.75 (ddd, J1 =14.5 Hz, J2 =13.0 Hz, J3 =4.5 Hz, 1H, H2C-3′),
3.78(s, 9H, –OCH3), 3.97 (s, 1H, HC-3), 4.26 (ddd, J1 =6.5 Hz, J2 =4.5 Hz,
J3 =2.0 Hz, 1H, H2C-4′), 4.48 (td, J1 =12.5 Hz, J2 =3.0 Hz, 1H, H2C-4′),
6.35 (dd, J1 =4.5 Hz, J2 =2.5 Hz, 1H), 6.48(s, 2H), 6.96 (t, J=2.0 Hz, 1H),
7.17 (dd, J1 =4.0 Hz, J2 =1.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 30.5,
35.7, 38.4, 40.7, 43.4, 56.2, 60.9, 106.8, 111.4, 116.0, 127.0, 128.2, 129.7,
137.5, 153.3, 179.5; IR (KBr) v 1650 cm–1; HRMS (ESI) m/z 404.0497
[M–Br]+, calcd for C19H19BrNO4 404.0497.
2,2-Dibromo-3-(4-fluorophenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3c): White solid, yield 58%; m.p. 155–157°C; 1H
NMR (CDCl3, 500 MHz): δ 2.04 (dt, J1 =14.0 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.75 (ddd, J1 =14.0 Hz, J2 =13.0 Hz, J3 =4.5 Hz, 1H, H2C-3′), 3.95 (s, 1H,
HC-3), 4.22 (ddd, J1 =6.5 Hz, J2 =4.5 Hz, J3 =2.0 Hz, 1H, H2C-4′), 4.44
(td, J1 =13.0 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.34 (dd, J1 =4.0 Hz, J2 =2.5 Hz,
1H), 6.95 (t, J=2.0 Hz, 1H), 7.05–7.08 (m, 2H), 7.16 (dd, J1 =4.0 Hz,
J2 =1.5 Hz, 1H), 7.17–7.24 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 30.2,
35.5, 37.5, 40.6, 43.2, 111.4, 115.6, 115.8, 116.1, 128.71, 128.73, 129.6,
131.5, 131.6, 161.2, 163.2, 179.3; IR (KBr) v 1651 cm–1; HRMS (ESI) m/z
332.0073 [M–Br]+, calcd for C16H12BrFNO 332.0086. Anal. Calcd for
C16H12Br2FNO: C, 46.52; H, 2.93; N, 3.39. Found: C, 46.54; H, 2.91; N,
3.46%.
This research was supported by the National Natural Science
Foundation of China (Nos. 21172065 and 21371054), the Key
Project of Chinese Ministry of Education (No. 210146), and the
Hunan Province University Innovation Platform Open Fund
(No. 11K024).
2,2-Dibromo-3-(4-(methylthio)phenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3d): White solid, yield 68%; m.p. 172–173°C; 1H
NMR (CDCl3, 500 MHz): δ 2.05 (dt, J1 =14.0 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.45(s, 3H, –SCH3), 2.74 (ddd, J1 =14.0 Hz, J2 =12.5 Hz, J3 =4.5 Hz, 1H,
H2C-3′), 3.95 (s, 1H, HC-3), 4.21 (ddd, J1 =7.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz,
1H, H2C-4′), 4.45 (td, J1 =12.5 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.33 (dd,
J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 7.15–7.19 (m, 5H);
13C NMR (CDCl3, 125 MHz) δ 15.6, 30.2, 35.8, 37.8, 40.6, 43.2, 111.4,
116.0, 126.3, 126.9, 129.5, 129.7, 130.3, 138.3, 179.5; IR (KBr) v 1651 cm–1;
HRMS (ESI) m/z 360.0057 [M–Br]+, calcd for C17H15BrNOS 360.0058.
2,2-Dibromo-3-p-tolyl-5′H-spiro[cyclopropane-1,7′-indolizin]-
Received 24 July 2013: accepted 23 August 2013
Paper 1302081 doi: 10.3184/174751913X13814138618396
Published online: 11 November 2013
1
References
8′(6′H)-one (3e): White solid, yield 72%; m.p. 183–184°C; H NMR
1
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(CDCl3, 500 MHz): δ 2.06 (dt, J1 =14.5 Hz, J2 =3.0 Hz, 1H, H2C-3′),
2.35(s, 3H, –CH3), 2.75 (ddd, J1 =14.5 Hz, J2 =13.0 Hz, J3 =5.0 Hz, 1H,
H2C-3′), 3.96 (s, 1H, HC-3), 4.20 (ddd, J1 =6.5 Hz, J2 =4.5 Hz, J3 =2.0 Hz,
1H, H2C-4′), 4.44 (td, J1 =12.5 Hz, J2 =3.0 Hz, 1H, H2C-4′), 6.33 (dd,
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126.8, 129.3, 129.8, 129.9, 137.5, 179.7; IR (KBr) v 1651 cm–1; HRMS
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2,2-Dibromo-3-(4-methoxyphenyl)-5′H-spiro[cyclopropane-1,7′-
indolizin]-8′(6′H)-one (3f): White solid, yield 78%; m.p. 174–176°C; 1H
NMR (CDCl3, 500 MHz): δ 2.06 (dt, J1 =17.0 Hz, J2 =2.5 Hz, 1H, H2C-3′),
2.75 (ddd, J1 =14.5 Hz, J2 =13.5 Hz, J3 =4.5 Hz, 1H, H2C-3′), 3.81(s, 3H,
–OCH3), 3.94 (s, 1H, HC-3), 4.21 (ddd, J1 =7.0 Hz, J2 =4.5 Hz, J3 =2.0 Hz,
1H, H2C-4′), 4.45 (td, J1 =12.5 Hz, J2 =2.5 Hz, 1H, H2C-4′), 6.33 (dd,
J1 =4.0 Hz, J2 =2.5 Hz, 1H), 6.88–6.91(m, 2H), 6.93 (t, J=2.0 Hz, 1H),
7.16 (d, J=4.5 Hz, 1H), 7.16–7.20 (m, 2H); 13C NMR (CDCl3, 125 MHz)
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131.0, 159.0, 179.7; IR (KBr) v 1663 cm–1; HRMS (ESI) m/z 344.0273 [M–
Br]+, calcd for C17H15BrNO2 344.0286. Anal. Calcd for C17H15Br2NO2: C,
48.03; H, 3.56; N, 3.29. Found: C, 47.81; H, 3.59; N, 3.37%.
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