Four-Component Reaction for the Synthesis of Indolizines by Copper-Catalyzed Aerobic Oxidative Dehydrogenative Aromatization

Article abstract of DOI:10.1002/ejoc.201601272

A one-pot, four-component reaction was developed for the synthesis of indolizines from pyridines, α-halide carbonyl compounds, primary amines, and maleic anhydride. The key step in this reaction involved the copper-catalyzed aerobic oxidative aromatization of a tetrahydrogen–indolizine intermediate. Oxygen gas was employed as a clean oxidant to facilitate the catalytic process. Notably, this transformation used readily available starting materials, exhibited broad substrate scope, was easy to handle, and required mild reaction conditions.

Full text of DOI:10.1002/ejoc.201601272

A Journal of
Accepted Article
Title: Four-Component Reaction for the Synthesis of Indolizines via a Copper-
Catalyzed Aerobic Oxidative Dehydrogenative Aromatization
Authors: Juanfang Xu; Huayou Hu; Yun Liu; Xiang Wang; Yuhe Kan; Chao Wang
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601272
Link to VoR: https://doi.org/10.1002/ejoc.201601272
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601272
Supporting Information
Table of Contents
General Methods and materials
S1
S1
S1
General procedures for synthesizing indolizines
Optimization of reaction conditions
Procedures for isotope experiments and control experiments
Characteristic data of new compounds
Copies of Compounds’ NMR spectra
ORTEP of 7a
S2
S4
S5
S35
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European Journal of Organic Chemistry
10.1002/ejoc.201601272
General Methods and materials:
Unless otherwise noted, all commercial reagents and solvents were obtained from the
commercial provider and used without further purification. 1H NMR and 13C NMR
spectra were recorded on Bruker 400 MHz spectrometers. Chemical shifts were
reported relative to internal tetramethylsilane or CDCl3 for 1H NMR and CDCl3 for
13C NMR. Flash column chromatography was performed on 300-400 mesh silica gels.
Analytical thin layer chromatography was performed with pre-coated glass baked
plates (250μ) and visualized by fluorescence. HRMS were recorded on Bruker
micrOTOF-Q spectrometer. IR spectra were recorded by Nicolet iS50 FT-IR
spectrometer.
General procedures for synthesizing indolizines Characteristic data of new
compounds:
Amine (0.20 mmol, 1.0 equiv.) and maleic anhydride (0.30 mmol, 1.5 equiv.) and
0.20 mL of ethyl acetate were added to a reaction vial and the mixture was heated at
60 oC for 4 h. Then pyridine (0.40 mmol, 2.0 equiv.) and α-halide carbonyl compound
were added to the mixture and heated at 60 oC for another 5 h. Then cuprous bromide
(0.06 mmol, 30%), potassium carbonate (0.50 mmol, 2.5 equiv.) and 1.8 mL of
DMSO (dimethylsulfoxide) were added to the vial. Then the mixture was heated at 80
oC under oxygen atmosphere (balloon). The reaction was monitored by TLC. After
the reaction was completed, the mixture was poured into water and extracted by ethyl
acetate (10 mL ×3). The organic layers were combined, washed with brine, dried with
anhydrous sodium sulfate and filtered. The organic solvent was removed under
vacuum and the residue was purified by flash chromatography (silica gel, eluted by
petroleum ether/ ethyl acetate).
Optimization of reaction conditions
Table 1. Optimization of reaction conditions.
entry
Catalyst a
Cu(OAc)2
CuI
Base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
yield of 7a (%) b
1
2
3
4
5
6
7
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
83
69
59
78
61
68
73
CuCl
CuBr2
CuCl2
CuSO4
Cu(AcAc)2
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European Journal of Organic Chemistry
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8
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
-
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
DMF
DMSO
DMSO
DMSO
DMA
87
91
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
91
91
91
1,4-dioxane
MeCN
toluene
NMP
66
50
32
40
water
trace
83
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
KHCO3
NaHCO3
Na2CO3
NEt3
80
74
69
71
pyridine
K2CO3
NaOAc
-
21
96
68 d
10
NaOAc
NaOAc
K2CO3
NaOAc
NaOAc
K2CO3
69 e
38
CuBr
CuBr
CuBr
CuBr
100 f
64 g
61 h
86 i
a Reaction conditions: 5a (0.40 mmol, 2.0 equiv.), 6a (0.20 mmol, 1.0 equiv.), base (0.80 mmol, 4.0 equiv.) with
catalyst (30%), in solvent (2.0 mL) under O2 (balloon) heated at 80 °C for 8 h. b Isolated yield. c See SI. d 20%
CuBr was used. e 1.0 mL DMSO was used. f 0.50 mmol K2CO3 was used. g Under air. h 0.30 mmol of 5a was used.
i Four-component reaction conditions: maleic anhydride (0.30 mmol, 1.5 equiv.) and aniline (0.20 mmol, 1.0
equiv.) were heated in 0.20 mL ethyl acetate at 60 oC for 4 h, then pyridine (0.40 mmol, 2.0 equiv.) and ethyl
2-bromoacetate (0.40 mmol, 2.0 equiv.) were added and heated at 60 oC for another 5 h, then copper bromide (0.06
mmol, 0.30 equiv.), K2CO3 (0.50 mmol, 2.5 equiv.) and 1.8 mL DMSO were added, the mixture was heated at 80
oC for 12 h under oxygen atmosphere (balloon).
Procedures for isotope experiments and control experiments:
Procedure for prepared D5-5ab:
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European Journal of Organic Chemistry
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D5-pyridine (10 mmol) and 2-bromo-1-phenylethan-1-one (10 mmol) and 10 mL ethyl acetate was
heated at 60 oC for 4 h in a round bottom flask. Then the mixture was cooled to room temperature
and filtered. The solid was washed with cold ethyl acetate and dried to give D5-5ab in 81% yield
(2.29 g).
Procedure for prepared D7-5ab and D2-5ab:
D5-5ab or 5ab (2.0 mmol) and 1.0 mL MeOD was added to a sealed flask and heated
at 60 oC for 4 h, then the solvent was removed under vacuum. The ratios of deuterium
were monitored by 1H NMR. The procedures were repeated to confirm the ratios of
deuterium were more than 95%.
Procedure for prepared 6a:
Aniline (10 mmol) and maleic anhydride (10 mmol) and ethyl acetate 10 mL was
heated at 60 oC for 4 h. Then the mixture was cooled to room temperature and filtered.
The solid was washed with cold ethyl acetate and dried to give 6a in 90% yield (1.74
g).
Procedures for isotope experiments:
D7-5ab, D7-5ab, D2-5ab and 5ab (0.40 mmol) were added to different vials, then 6a
(0.20 mmol), CuBr (0.06 mmol), K2CO3 (0.50 mmol) and 2.0 mL DMSO were added
to vials. Then all vials were heated and stirred at 80 oC under O2 (balloon) for 15 min.
Then all reaction mixture were poured into water and extracted by ethyl acetate (10
mL *3). The organic layers were combined, washed with brine, dried with anhydrous
sodium sulfate and filtered. The organic solvent was removed under vacuum and the
residue was purified by flash chromatography (silica gel, eluted by petroleum ether/
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European Journal of Organic Chemistry
10.1002/ejoc.201601272
ethyl acetate). The relative reaction speed was calculated based on the yields of D4-9a
or 9a.
Characteristic data of new compounds
Ethyl 1-(phenylcarbamoyl)indolizine-3-carboxylate (7a): 53.0 mg (52 %, PE/ EA = 3/1); yellow
solid; m. p. 141.7-143.9 oC; 1H NMR (CDCl3, 400 MHz): 9.55 (d, J = 7.1 Hz, 1H), 8.61 (d, J = 9.0
Hz, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.39 – 7.32
(m, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 6.8 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.1
Hz, 3H); 13C NMR (CDCl3, 100 MHz): 162.4, 161.0, 139.0, 138.3, 129.0, 127.5, 125.3, 124.0,
120.1, 120.1, 119.7, 114.6, 114.1, 108.2, 60.4, 14.5; IR (KBr): 3302, 3117, 2984, 1689, 1635, 1594,
1560, 1522, 1481, 1442, 1372, 1347, 1305; HRMS (ESI): m/z calcd for C18H16N2O3: 331.1059
[M+Na]+; found: 331.1055.
Ethyl 1-((4-methoxyphenyl)carbamoyl)indolizine-3-carboxylate (7b): 54.4 mg (80 %, PE/ EA =
o
1
5/1); yellow solid; m. p. 152.8-153.9 C; H NMR (CDCl3, 400 MHz): 9.45 (d, J = 7.1 Hz, 1H),
8.51 (d, J = 8.9 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.54 (d, J = 7.1 Hz, 2H), 7.29 – 7.21 (m, 1H),
6.95 (t, J = 6.9 Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 4.38 (q, J = 7.3 Hz, 2H), 3.80 (d, J = 1.6 Hz, 3H),
1.40 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 162.4, 161.0, 156.3, 138.9, 131.3, 127.5,
125.1, 122.1, 120.2, 119.7, 114.6, 114.2, 114.0, 108.2, 60.3, 55.5, 14.5; IR (KBr): 3276, 3123,
2972, 2928, 2835, 1687, 1631, 1597, 1537, 1511, 1481, 1425, 1373, 1349, 1302; HRMS (ESI):
m/z calcd for C19H18N2O4: 361.1164 [M+Na]+; found: 361.1160.
Ethyl 1-((4-nitrophenyl)carbamoyl)indolizine-3-carboxylate (7c): 32.9 mg (45 %, PE/ EA = 4/1);
o
1
yellow solid; m. p. 217.4-218.8 C; H NMR (DMSO-D6, 400 MHz): 10.43 (s, 1H), 9.42 (d, J =
7.0 Hz, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J = 9.2 Hz, 2H), 8.05 (d, J = 9.2 Hz,
2H), 7.46 (t, J = 7.8 Hz 1H), 7.19 (t, J = 6.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz,
3H); 13C NMR (DMSO-D6, 100 MHz): 162.9, 160.8, 146.4, 142.3, 139.3, 127.9, 126.8, 125.2,
122.0, 120.0, 119.7, 115.8, 114.1, 107.7, 60.6, 14.9; IR (KBr): 3735, 3725, 3649, 3420, 1673,
1541, 1527, 1497, 1426, 1375, 1331, 1301; HRMS (ESI): m/z calcd for C18H15N3O5: 376.0909
[M+Na]+; found: 376.0909.
Ethyl 1-(o-tolylcarbamoyl)indolizine-3-carboxylate (7d): 38.0 mg (59 %, PE/ EA = 5/1); yellow
solid; m. p. 140.9-141.8 oC; 1H NMR (CDCl3, 400 MHz): 9.50 (d, J = 7.0 Hz, 1H), 8.54 (d, J = 8.9
Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.62 (s, 1H), 7.33 – 7.21 (m, 3H), 7.11 (t, J = 7.4
Hz, 1H), 6.99 (t, J = 6.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H);
13C NMR (CDCl3, 100 MHz): 162.5, 161.0, 139.0, 135.9, 130.5, 129.5, 127.6, 126.8, 125.3, 125.0,
123.5, 120.2, 119.6, 114.7, 114.1, 108.1, 60.4, 18.0, 14.6; IR (KBr): 3299, 2979, 1694, 1654, 1637,
1523, 1487, 1444, 1376, 1302; HRMS (ESI): m/z calcd for C19H18N2O3: 345.1215 [M+Na]+;
found: 345.1219.
Ethyl 1-(m-tolylcarbamoyl)indolizine-3-carboxylate (7e): 28.9 mg (45 %, PE/ EA = 5/1); yellow
solid; m. p. 159.1-160.0 oC; 1H NMR (CDCl3, 400 MHz): 9.46 (d, J = 7.1 Hz, 1H), 8.53 (d, J = 9.0
Hz, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.31 – 7.21 (m, 2H),
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European Journal of Organic Chemistry
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6.93 – 6.99 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): 162.4, 161.0, 139.0, 138.9, 138.2, 128.8, 127.5, 125.3, 124.8, 120.7, 120.1,
119.7, 117.1, 114.7, 114.0, 108.2, 60.4, 21.6, 14.6; IR (KBr): 3300, 3109, 3048, 2980, 1692, 1632,
1540, 1525, 1486, 1443, 1374, 13051; HRMS (ESI): m/z calcd for C19H18N2O3: 345.1215
[M+Na]+; found: 345.1212.
Ethyl 1-(p-tolylcarbamoyl)indolizine-3-carboxylate (7f): 55.5 mg (80 %, PE/ EA = 3/1); yellow
solid; m. p. 170.2-172.4 oC; 1H NMR (CDCl3, 400 MHz): 9.45 (d, J = 7.0 Hz, 1H), 8.51 (d, J = 8.9
Hz, 1H), 7.78 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.29 – 7.22 (m, 1H), 7.15 (d, J = 8.0
Hz, 2H), 6.95 (t, J = 6.8 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).;
13C NMR (CDCl3, 100 MHz): 162.4, 161.0, 138.9, 135.7, 133.6, 129.5, 127.5, 125.2, 120.2, 120.1,
119.6, 114.6, 114.0, 108.3, 60.3, 20.9, 14.5; IR (KBr): 3282, 3112, 2984, 2919, 1689, 1636, 1517,
1483, 1422, 1373, 1302; HRMS (ESI): m/z calcd for C19H18N2O3: 345.1215 [M+Na]+; found:
345.1210.
Ethyl 1-((4-methoxybenzyl)carbamoyl)indolizine-3-carboxylate (7g): 45.9 mg (65 %, PE/ EA =
o
1
5/1); yellow solid; m. p. 152.8-154.2 C; H NMR (CDCl3, 400 MHz): 9.44 (d, J = 7.0 Hz, 1H),
8.53 (d, J = 8.9 Hz, 1H), 7.68 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.9 Hz, 1H), 6.93 (t, J
= 6.8 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.34 (s, 1H), 4.58 (d, J = 5.3 Hz, 2H), 4.34 (q, J = 7.1 Hz,
2H), 3.79 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 164.1, 161.0, 159.0,
138.7, 130.8, 129.2, 127.4, 124.8, 120.2, 119.7, 114.4, 114.1, 113.9, 108.0, 60.2, 55.3, 42.9, 14.5;
IR (KBr): 3268, 3115, 2982, 2932, 2837, 1686, 1624, 1548, 1513, 1485, 1375, 1348; HRMS (ESI):
m/z calcd for C20H20N2O4: 375.1321 [M+Na]+; found: 375.1318.
Ethyl 1-(benzylcarbamoyl)indolizine-3-carboxylate (7h): 46.4 mg (72 %, PE/ EA = 7/1); yellow
solid; m. p. 159.9.3-161.9 oC; 1H NMR (CDCl3, 400 MHz): 9.45 (d, J = 7.0 Hz, 1H), 8.54 (d, J =
9.0 Hz, 1H), 7.70 (s, 1H), 7.40 – 7.32 (m, 4H), 7.31 – 7.22 (m, 2H), 6.94 (t, J = 6.9 Hz, 1H), 6.37
(s, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): 164.1, 161.0, 138.7, 138.7, 128.7, 127.9, 127.5, 127.4, 125.0, 120.2, 119.6,
114.5, 113.9, 107.8, 60.3, 43.5, 14.5; IR (KBr):3263, 3034, 2983, 2926, 1686, 1616, 1542, 1478,
1376, 1349; HRMS (ESI): m/z calcd for C19H18N2O3: 345.1215 [M+Na]+; found: 345.1216.
Ethyl 1-(butylcarbamoyl)indolizine-3-carboxylate (7i): 31.7 mg (55 %, PE/ EA = 7/1); yellow
solid; m. p. 121.9-123.7 oC; 1H NMR (CDCl3, 400 MHz): 9.45 (d, J = 7.0 Hz, 1H), 8.51 (d, J = 9.0
Hz, 1H), 7.67 (s, 1H), 7.27 – 7.20 (m, 1H), 6.94 (t, J = 7.0 Hz, 1H), 6.02 - 5.94 (m, 1H), 4.39 (qd, J =
7.1, 1.6 Hz, 2H), 3.47 (q, J = 6.8 Hz, 2H), 1.68 – 1.55 (m, 2H), 1.49 – 1.38 (m, 5H), 0.97 (t, J = 7.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 164.3, 161.0, 138.6, 127.4, 124.7, 120.2, 119.4, 114.3, 113.8,
108.3, 60.2, 39.2, 32.1, 20.2, 14.5, 13.8; IR (KBr): 3275, 2961, 2930, 2862, 1690, 1624, 1549,
1519, 1479, 1374; HRMS (ESI): m/z calcd for C16H20N2O3: 311.1366 [M+Na]+; found: 311.1369.
Ethyl 1-(phenethylcarbamoyl)indolizine-3-carboxylate (7j): 44.9 mg (67 %, PE/ EA = 5/1); yellow
solid; m. p. 130.5-131.7 oC; 1H NMR (CDCl3, 400 MHz): 9.44 (d, J = 7.0 Hz, 1H), 8.48 (d, J = 8.9
Hz, 1H), 7.60 (s, 1H), 7.36 – 7.29 (m, 2H), 7.25 (d, J = 7.5 Hz, 4H), 6.93 (t, J = 6.9 Hz, 1H), 6.14
(s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.72 (q, J = 6.7 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 1.38 (t, J = 7.1
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European Journal of Organic Chemistry
10.1002/ejoc.201601272
Hz, 3H); 13C NMR (CDCl3, 100 MHz): 164.3, 161.0, 139.2, 138.5, 128.9, 128.6, 127.4, 126.5,
124.8, 120.1, 119.6, 114.3, 113.9, 108.2, 60.2, 40.7, 36.1, 14.5; IR (KBr): 3276, 3025, 2976, 2957,
2926, 2854, 1689, 1618, 1550, 1523, 1481, 1373; HRMS (ESI): m/z calcd for C20H20N2O3:
359.1372 [M+Na]+; found: 359.1369.
Ethyl 1-(tert-butylcarbamoyl)indolizine-3-carboxylate (7k): 12.0 mg (21 %, PE/ EA = 5/1);
yellow solid; m. p. 208.0-210.1 oC; 1H NMR (CDCl3, 400 MHz): 9.44 (d, J = 7.1 Hz, 1H), 8.50 (d,
J = 9.0 Hz, 1H), 7.60 (s, 1H), 7.26 – 7.18 (m, 1H), 6.93 (t, J = 6.5 Hz, 1H), 5.81 (s, 1H), 4.40 (q, J
= 7.1 Hz, 2H), 1.51 (s, 9H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 164.0, 161.1,
138.5, 127.3, 124.6, 120.2, 119.5, 114.3, 113.5, 109.3, 60.2, 51.4, 29.2, 14.6; IR (KBr): 3300,
3120, 2976, 2934, 1687, 1620, 1546, 1519, 1483, 1455, 1444, 1373; HRMS (ESI): m/z calcd for
C16H20N2O3: 311.1372 [M+Na]+; found: 311.1371.
Ethyl 1-(phenylcarbamoyl)pyrrolo[2,1-a]isoquinoline-3-carboxylate (8b): 64.4 mg (90 %, PE/ EA
1
= 7/1); yellow solid; m. p. 218.3-220.4 oC; H NMR (CDCl3, 400 MHz): 9.32 (d, J = 7.4 Hz, 1H),
9.12 – 9.04 (m, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.71 – 7.67 (m, 3H), 7.61 – 7.52 (m, 2H), 7.42 (t, J
= 7.3 Hz, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 1.44 (t,
J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 164.5, 161.0, 138.4, 133.5, 129.1, 129.0, 128.4,
127.9, 126.8, 126.2, 124.5, 124.4 123.9, 120.9, 120.1, 115.5, 114.6, 114.0, 60.5, 14.5.; IR (KBr):
3294, 3129, 3059, 2979, 2927, 2854, 1694, 1645, 1596, 1541, 1521, 1467, 1455, 1439, 1379, 1341;
HRMS (ESI): m/z calcd for C22H18N2O3: 381.1215 [M+Na]+; found: 381.1214.
Ethyl 7-methyl-1-(phenylcarbamoyl)indolizine-3-carboxylate (8c): 33.5 mg (52 %, PE/ EA = 5/1);
yellow solid; m. p. 193.1-194.6 oC; 1H NMR (CDCl3, 400 MHz): 9.28 (d, J = 7.2 Hz, 1H), 8.25 (s,
1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.10 (t, J = 7.4
Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H);
13C NMR (CDCl3, 100 MHz): 162.7, 161.0, 139.4, 138.4, 136.7, 129.0, 126.8, 123.8, 120.0, 119.9,
118.7, 117.1, 113.5, 106.9, 60.2, 21.3, 14.5; IR (KBr): 3332, 3117, 3058, 2979, 1694, 1641, 1596,
1537, 1499, 1487, 1441, 1372, 1352, 1313; HRMS (ESI): m/z calcd for C19H18N2O3: 345.1215
[M+Na]+; found: 345.1212.
Ethyl 8-chloro-1-(phenylcarbamoyl)indolizine-3-carboxylate (8e): 20.7 mg (30 %, PE/ EA = 5/1);
o
1
yellow solid; m. p. 88.8-91.2 C; H NMR (CDCl3, 400 MHz): 9.35 (d, J = 7.0 Hz, 1H), 8.18 (s,
1H), 7.77 – 7.66 (m, 3H), 7.39 (t, J = 7.7 Hz, 2H), 7.17 (m, 2H), 6.78 (t, J = 7.2 Hz, 1H), 4.38 (q,
J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 162.9, 160.8, 138.3, 131.8,
129.1, 125.9, 124.6, 124.3, 124.3, 122.8, 119.8, 114.6, 113.2, 113.0, 60.6, 14.4; IR (KBr): 3423,
3267, 3134, 2985, 1695, 1686, 1652, 1597, 1535, 1500, 1473, 1443, 1377, 1315; HRMS (ESI):
m/z calcd for C18H15ClN2O3: 365.0669 [M+Na]+; found: 365.0669.
Ethyl 6-chloro-1-(phenylcarbamoyl)indolizine-3-carboxylate (8e’): 11.6 mg (17 %, PE/ EA = 5/1);
yellow solid; m. p. 156.6-158.2 oC; 1H NMR (CDCl3, 400 MHz): 9.56 (s, 1H), 8.49 (d, J = 9.5 Hz,
1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.26 – 7.22 (m,
1H), 7.13 (t, J = 7.4 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz): 161.9, 160.7, 138.0, 137.0, 129.1, 126.4, 125.5, 124.2, 123.3, 120.5, 120.1, 119.4,
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114.5, 109.0, 60.7, 14.5; IR (KBr): 3289, 3127, 2983, 1694, 1640, 1597, 1537, 1499, 1482, 1443,
1375, 1315; HRMS (ESI): m/z calcd for C18H15ClN2O3: C18H15ClN2O3: 365.0668 [M+Na]+; found:
365.0669.
Ethyl 8-phenyl-1-(phenylcarbamoyl)indolizine-3-carboxylate (8f): 45.3 mg (59 %, PE/ EA = 5/1);
yellow solid; m. p. 185.1-186.3 oC; 1H NMR (CDCl3, 400 MHz): 9.67 (s, 1H), 8.49 (d, J = 9.4 Hz,
1H), 8.09 (d, J = 7.0 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.47
(m, 3H), 7.39 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz): 162.5, 161.0, 138.3, 137.8, 136.9, 129.1, 129.0, 128.7, 128.1, 127.0,
125.4, 124.9, 124.0, 120.1, 120.1, 119.8, 114.2, 108.2, 60.5, 14.5; IR (KBr): 3302, 3124, 3058,
2982, 1690, 1640, 1596, 1544, 1522, 1499, 1483, 1443, 1376, 1311; HRMS (ESI): m/z calcd for
C24H20N2O3: 407.1372 [M+Na]+; found: 407.1370.
Ethyl 6-phenyl-1-(phenylcarbamoyl)indolizine-3-carboxylate (8f’): 30.7 mg (40 %, PE/ EA = 5/1);
yellow solid; m. p. 196.0-198.0 oC; 1H NMR (CDCl3, 400 MHz): 9.60 (d, J = 7.0 Hz, 1H), 7.96 (s,
1H), 7.51 (d, J = 7.4 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.15 (m, 4H), 7.08 (d, J = 7.8 Hz, 2H), 7.04
– 6.96 (m, 2H), 6.76 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz): 162.5, 161.2, 138.3, 137.8, 133.2, 132.8, 129.0, 128.5, 128.4, 127.9, 126.7, 125.8,
124.4, 123.8, 119.2, 114.5, 113.7, 112.8, 60.3, 14.5; IR (KBr): 3351, 3123, 3057, 2981, 1685, 1655,
1599, 1538, 1499, 1467, 1445, 1431, 1378, 1313; HRMS (ESI): m/z calcd for C24H20N2O3:
407.1372 [M+Na]+; found: 407.1374.
3-(4-Methoxybenzoyl)-N-phenylindolizine-1-carboxamide (9c): 53.6 mg (72 %, PE/ EA = 3/1);
yellow solid; m. p. 106.2-108.4 oC; 1H NMR (CDCl3, 400 MHz): 9.77 (d, J = 7.0 Hz, 1H), 8.46 (d,
J = 8.9 Hz, 1H), 8.22 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.5 Hz, 3H), 7.36 – 7.26 (m,
3H), 7.08 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 3.81 (s, 3H); 13
C
NMR (CDCl3, 100 MHz): 184.2, 162.6, 162.4, 139.6, 138.3, 132.2, 131.1, 129.0, 128.6 127.1,
124.2, 124.0, 122.0, 120.3, 119.8, 115.3, 113.6, 109.2, 55.4; IR (KBr): 3315, 3126, 2933, 2838,
1603, 1526, 1498, 1480, 1441, 1346, 1312; HRMS (ESI): m/z calcd for C23H18N2O3: 393.1215
[M+Na]+; found: 393.1218.
3-(4-Nitrobenzoyl)-N-phenylindolizine-1-carboxamide (9d): 23.7 mg (31 %, PE/ EA = 3/1);
yellow solid; m. p. 229.6-231.7 oC; 1H NMR (DMSO-D6, 400 MHz): 9.96 – 9.88 (m, 2H), 8.62 (d,
J = 8.9 Hz, 1H), 8.43 (d, J = 8.5 Hz, 2H), 8.25 (s, 1H), 8.09 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 7.9
Hz, 2H), 7.66 (t, J = 7.9 Hz, 1H), 7.39 – 7.30 (m, 3H), 7.07 (t, J = 7.3 Hz, 1H); 13C NMR
(DMSO-D6, 100 MHz): 182.8, 162.2, 149.4, 145.7, 140.4, 139.5, 130.6, 129.02, 128.98, 126.7,
124.1, 123.8, 121.4, 120.8, 120.2, 116.8, 110.3; IR (KBr): 3393, 2925, 1652, 1616, 1596, 1527,
1497, 1479, 1442, 1342, 1311, 1227, 1207, 1078; HRMS (ESI): m/z calcd for C22H15N3O4:
408.0960 [M+Na]+; found: 408.0957.
3-(4-Chlorobenzoyl)-N-phenylindolizine-1-carboxamide (9e): 62.5 mg (84 %, PE/ EA = 5/1);
yellow solid; m. p. 89.3-91.3 oC; 1H NMR (CDCl3, 400 MHz): 9.84 (d, J = 7.0 Hz, 1H), 8.50 (d, J
= 9.0 Hz, 1H), 8.28 (s, 1H), 7.70 – 7.63 (m, 3H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 – 7.37 (m, 1H),
7.36 – 7.27 (m, 4H), 7.08 (q, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz): 183.7, 162.3, 140.0,
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138.1, 138.0, 137.7, 130.2, 129.0, 128.8, 128.6, 127.8, 124.7, 124.2, 121.6, 120.4, 119.9, 115.8,
109.7; IR (KBr): 3347, 3125, 1596, 1527, 1498, 1480, 1442, 1345, 1313; HRMS (ESI): m/z calcd
for C22H15ClN2O2: 397.0720 [M+Na]+; found: 398.0718.
3-(4-Bromobenzoyl)-N-phenylindolizine-1-carboxamide (9f): 62.5 mg (75 %, PE/ EA = 5/1);
yellow solid; m. p. 80.2-81.7 oC; 1H NMR (CDCl3, 400 MHz): 9.85 (d, J = 7.0 Hz, 1H), 8.51 (d, J
= 8.9 Hz, 1H), 8.24 (s, 1H), 7.65 (s, 1H), 7.60 (t, J = 8.1 Hz, 4H), 7.51 (d, J = 8.0 Hz, 2H), 7.41 (t,
J = 7.9 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.09 (q, J = 7.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
183.8, 162.3, 140.0, 138.5, 138.0, 131.6, 130.4, 129.0, 128.078, 127.9, 126.2, 124.7, 124.2, 121.6,
120.4, 120.0, 115.9, 109.7; IR (KBr): 3423, 3126, 1596, 1528, 1497, 1478, 1442, 1345, 1313,;
HRMS (ESI): m/z calcd for C22H15BrN2O2: 441.0215 [M+Na]+; found: 441.0218.
3-(4-Nitrophenyl)-N-phenylindolizine-1-carboxamide (9g): 41.6 mg (58 %, PE/ EA = 5/1); yellow
o
1
solid; m. p. 232.2-233.6 C; H NMR (DMSO-D6, 400 MHz): 9.79 (s, 1H), 8.69 (d, J = 6.7 Hz,
1H), 8.45 (d, J = 9.0 Hz, 1H), 8.40 (d, J = 8.6 Hz, 2H), 8.02 – 7.94 (m, 3H), 7.80 (d, J = 8.1 Hz,
2H), 7.34 (t, J = 7.1 Hz, 2H), 7.25 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 6.9 Hz, 1H), 6.98 (t, J = 6.7 Hz,
1H); 13C NMR (DMSO-D6, 100 MHz): 162.9, 146.3, 140.1, 138.0, 137.3, 129.0, 128.4, 125.0,
124.6, 123.7, 123.5, 123.3, 120.5, 120.4, 116.6, 114.4, 108.8; IR (KBr): 3277, 3112, 2924, 1623,
1593, 1541, 1512, 1498, 1442, 1343, 1319, 1308; HRMS (ESI): m/z calcd for C21H15N3O3:
380.1011 [M+Na]+; found: 380.1008.
tert-Butyl 1-(phenylcarbamoyl)indolizine-3-carboxylate (9h): 63.2 mg (94 %, PE/ EA = 5/1);
yellow solid; m. p. 174.7-175.7 oC; 1H NMR (CDCl3, 400 MHz): 9.46 (d, J = 6.5 Hz, 1H), 8.50 (d,
J = 9.5 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 5.8 Hz, 2H), 7.23
(t, J = 7.8 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 6.93 (t, J = 6.7 Hz, 1H), 1.64 (s, 9H); 13C NMR
(CDCl3, 100 MHz): 162.6, 160.6, 138.7, 138.3, 129.0, 127.6, 125.0, 123.9, 120.2, 120.0, 119.6,
115.4, 114.4, 107.8, 81.4, 28.6; IR (KBr): 3293, 3135, 3058, 2975, 2930, 1682, 1644, 1596, 1540,
1524, 1487, 1442, 1368, 1304; HRMS (ESI): m/z calcd for C20H20N2O3: 359.1372 [M+Na]+;
found: 359.1371.
3-Cyano-N-phenylindolizine-1-carboxamide (9i):19.0 mg (36 %, PE/ EA = 5/1); yellow solid; m.
p. 194.9-196.8 oC; 1H NMR (CDCl3, 400 MHz): 8.54 (d, J = 9.1 Hz, 1H), 8.34 (d, J = 6.8 Hz, 1H),
7.76 (s, 1H), 7.69 – 7.61 (m, 3H), 7.38 (t, J = 7.8 Hz, 2H), 7.35 – 7.30 (m, 1H), 7.15 (t, J = 7.4 Hz,
1H), 7.06 (t, J = 6.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz): 161.4, 137.8, 137.8, 129.1, 125.7,
125.5, 124.4, 121.0, 120.6, 120.3, 115.3, 112.7, 108.9, 96.1; IR (KBr): 3402, 3123, 2210, 1655,
1632, 1596, 1541, 1524, 1500, 1486, 1442, 1365, 1314; HRMS (ESI): m/z calcd for C16H11N3O:
284.0800 [M+H]+; found: 284.0896.
1
3-Benzoyl-N-phenylindolizine-5,6,7,8-d4-1-carboxamide (D4-9a): H NMR (CDCl3, 400 MHz):
7.84 (s, 1H), 7.76 (d, J = 7.0 Hz, 2H), 7.61 – 7.55 (m, 3H), 7.51 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.3
Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.09 (t, J = 6.3 Hz, 1H).
Copies of New Compounds’ NMR spectra
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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