Application of primary halogenated hydrocarbons for the synthesis of 3-Aryl and 3-Alkyl indolizines

Article abstract of DOI:10.1039/c7ob00980a

Indolizine is an important heterocyclic compound with several interesting properties that make it suitable for numerous applications in many fields, such as biology, medicine and materials. However, the synthesis of 3-Alkyl indolizines from bulky primary halogenated alkanes has not yet been reported. Herein, a transition-metal-free synthetic route to 3-Aryl and 3-Alkyl indolizines from electron-deficient alkenes, pyridines and primary halogenated hydrocarbons has been reported for the first time using a tandem reaction. The key step of this method is the oxidative dehydrogenative aromatization of a tetrahydroindolizine intermediate with 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) as the oxidant. The advantages of this protocol are its use of easily available and low-cost starting materials, the transition-metal-free conditions and its ready scalability.

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE TYPE
Application of Primary Halogenated Hydrocarbons for the Synthesis of
3-Aryl and 3-Alkyl Indolizines
Yan Liu, a, b Huayou Hu, *a, b Junyu Zhou, c Wenhui Wang, b Youliang He b and Chao Wang *a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Indolizine is an important heterocyclic compound with several interesting properties that make it suitable
for numerous applications in many fields, such as biology, medicine and materials. However, the
synthesis of 3-alkyl indolizines from bulky primary halogenated alkanes has not yet been reported. Herein,
a transition-metal-free synthetic route to 3-aryl and 3-alkyl indolizines from electron-deficient alkenes,
10 pyridines and primary halogenated hydrocarbons is reported for the first time using a tandem reaction.
The key step of this method is the oxidative dehydrogenative aromatization of a tetrahydroindolizine
intermediate with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as the oxidant. The advantages of this
protocol are its use of easily available and cheap starting materials, the transition-metal-free conditions
and its ready scalability.
F
O
NH2
R1
O
N
15 Introduction
O
H
O
Cl
N
NH2
F
N
Indolizine is an important heterocycle that has long drawn the
attention of synthetic and theoretical chemists.1 The indolizidine
skeleton is found in many natural products, which, along with
numerous synthetic indolizine derivatives, show a variety of
20 biological activities and have thus been applied in many fields.2
Indolizine derivatives exhibit long wavelength absorption and
fluorescence in the visible region, and have therefore been used
as dyes and in optoelectronic materials.3 In particular, 3-aryl and
3-alkyl indolizines (Figure 1) exhibit important biological
25 activities and are used as phosphoinositide 3-kinase,4 human
OH
HO
F
N
N
N
N
N
S
OMe
N
treatment of
diseases
N
neurodegenerative
3-kinases inhibitor
phoshoinositide
inhibitors of sPLA2
SO2
Cl
PhO2S
O
O
N
Me
S
N
H
Cl
NC
Cl
N
N
N
O
O
OH
group
IIA
secreted
phospholipase
A2
(sPLA2),5
OH
OH
inhibitors of PDE4
phosphodiesterase IV (PDE4),6 sodium glucose cotransporter 2
(SGLT2),7 15-lipoxygenase8 and tumor necrosis factor (TNFα)
inhibitors;9 as orexin receptor10 and 5-hydroxytryptamine (5-HT3)
30 receptor11 antagonists; and for treatment of neurodegenerative
diseases,12 inflammatory diseases,13 and lung and ovarian
cancer,14 among other things. Furthermore, 3-alkyl indolizines
have also been used as hair dyes.15
treatment of inflammatory diseases
O
O
N
O
S
O
N
O2S
H
NC
N
N
Ph
O
N
Ph
15-lipoxygenase
N
OMe
inhibitors of
orexin
TNFa inhibitors
receptor
antagonists
35 Figure 1. 3-Aryl and 3-alkyl indolizines with various biological activities.
Owing to their multiple biological activities, the development of
new synthetic routes to indolizines has become a hot topic in
organic chemistry.16 1,3-Dipolar cycloaddition of pyridinium
40 ylides with electron-deficient alkynes or alkene derivatives is one
of the most efficient methods for the preparation of indolizines
because of the easy availability of the starting materials, broad
substrate scope, high atom efficiency and mild reaction
conditions.17 However, the synthesis of 3-aryl and 3-alkyl
45 indolizines through 1,3-dipolar cycloaddition has rarely been
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successful because of the low acidity of the corresponding
93%, whereas other bases were less efficient. This is likely to be
pyridinium salts.18 The reported reactions have several drawbacks, 30 due to the low acidity of pyridinium salt 3aa. Further
such as limited substrate scope or the need for not readily
available or expensive starting materials. Following our previous
work on indolizines,19 we report herein a transition-metal-free
synthetic route to 3-aryl and 3-alkyl indolizines using a 1,3-
investigation led us to establish the following optimized reaction
conditions: 0.40 mmol of 3aa and 0.20 mmol of 4a as the starting
materials, 0.80 mmol of TEMPO as the oxidant, 0.50 mmol of
LiOH as the base and 3.0 mL of DMSO as the solvent, at 100 °C
5
dipolar cycloaddition reaction with simple alkene and primary 35 for 12 h under air (Table 1, entry 12). Notably, the yield of 5aa
halogenated hydrocarbon starting materials (Scheme 1).
did not decrease when a one-pot procedure was applied (Table 1,
entry 15).21
Previous method:
Cl-
H
N
Table 1 Optimization of reaction conditions.
N
R1
N
SOCl2
N+
N
+
N
+
R
2CHO
Br
O
N
N
CH2Cl2
N
R1
R2
O
base
[O],
+
N+
Br-
solvent, temp.
R4
N
N
Cl-
R2
N
N
R3
+
base
R4
3aa
N+
N
R3
4a
Ph
or
N
5a
R3
R4
R1
entr
y
Oxidant,
Amount
(mmol)
K2Cr2O7
, 0.15
K2Cr2O7
, 0.15
Cu(OAc)
2, 0.60
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
Base, Amount
(mmol)
Solvent,
Amount
(mL)
Temp.
Yield
(%) a
R2
R4
R1
(oC), time
(h)
=
or
=
R
electron withdrawing
4
R2
aryl
group
alkyl,
1
2
3
4
5
6
N. A. b
DMF, 2.0
80, 12
0
0
works:
R2
Our
R1
previous
Cs2CO3, 0.80
Cs2CO3, 0.80
Cs2CO3, 0.80
Cs2CO3, 0.80
Cs2CO3, 0.80
DMF, 2.0
DMF, 2.0
DMF, 2.0
DMSO, 2.0
80, 12
80, 12
X2
R1
R3
N
+
N
X
base
R3
+
36
R4
X1
100, 12
100, 12
100, 12
66
R2
R4
77
R3
R4
R2
R1
Other
solvents, c
2.0
0 - 72
R3
N
+
base
X
N
+
R1
7
8
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
TEMPO,
0.80
N. A.
DMSO, 2.0
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
80, 12
0
0-64
68
R2
Cl,
Other bases, d
0.80
t-BuOLi, 0.80
DMSO, 2.0
DMSO, 2.0
DMSO, 2.0
DMSO, 2.0
DMSO, 3.0
DMSO, 3.0
DMSO, 3.0
DMSO, 3.0
=
or
=
+
or
=
R
electron withdrawing
4
X
Br, X1
X
X
Br
Cl
,
I,
group
2
work:
Present
9
R4
N
10
11
12
13 e
14
15 f
LiOH, 0.80
LiOH, 0.50
LiOH, 0.50
LiOH, 0.80
LiOH, 0.80
LiOH, 0.80
93
base
R1
TEMPO
R3
+
R3
R2
R4
N
R1
93
R2
=
or
=
or
=
alkyl R4 electron withdrawing
group
X
Br, R2
Cl
Aryl
98
10
Scheme 1. Various approaches to the synthesis of 3-aryl and 3-alkyl
66
indolizines by 1,3-dipolar cycloaddition.
18
Results and discussion
TEMPO,
0.80
100, 12
98
In a preliminary study, 1-benzylpyridinium bromide (3aa) and
15 N,N-dimethyl acrylamide (4a) were chosen as the starting
materials for optimization of the reaction conditions. Several
previously reported oxidants, including potassium dichromate19b
40 a Isolated yield. b Not added. c Other solvents included toluene,
tetrahydrofuran, acetonitrile, 1,4-dioxane, 1,2-dicholoroethane, ethyl
acetate, N,N-dimethyl acetamide, N-methyl pyrrolidone and
hexamethylphosphoric triamide. d Other bases included NEt3, K2CO3,
,
Na2CO3, KOH, NaOH, t-BuOK and t-BuONa. e Using 0.24 mmol of 3aa
45 as the starting material. f One-pot reaction starting with pyridine (1a, 0.40
mmol) and benzyl bromide (2a, 0.40 mmol) in 0.20 mL DMF. The
mixture was heated at 60 °C in a stoppered test tube for 4 h to form 3aa in
situ, and then 3aa was reacted with N,N-dimethyl acrylamide (4a, 0.20
mmol) in the presence of TEMPO (0.80 mmol) and LiOH (0.50 mmol) at
50 100 °C for 12 h with an additional 2.80 mL DMSO as solvent.
copper acetate19a and 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO)19f-g were tested within this system in N,N-
20 dimethylformamide (DMF) solvent. Desired product 5a was
isolated in 66% yield with TEMPO as the oxidant, but no product
was observed with potassium dichromate, and copper acetate
gave 5a only in low yield (36%). We then turned to optimizing
the reaction solvent. The results showed that aprotic solvents with
25 high polarity were suitable, and that dimethylsulfoxide (DMSO)
was the best solvent. We also found that the choice of base had a
great influence on the yield of the desired product. When lithium
hydroxide was used as the base, the yield of 5a was increased to
To study the substrate scope for the alkene starting material, a
series of alkenes bearing various electron-withdrawing groups
was reacted with 3aa under standard conditions in a one-pot
2
|
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O
N
fashion (Scheme 2). A series of acrylic acid derivatives smoothly
mmol
0.80
TEMPO
gave the corresponding indolizines, which included acrylates,
acrylonitrile, acrylamide and mono- and di-substituted
acrylamides (5b, 5c, 5f, 5g and 5i). Notably, reaction with (Z)-4-
(anilino)-4-oxobut-2-enoic acid gave 5i in only 45% yield, which
mmol
0.20 mL DMF
base
0.50
+
R1
R1
R2
0.40
X
N
N+
X-
R2
60 o 4 h
mmol
4a 0.20
N
,
C,
R1
2.8 mL DMSO
mmol
mmol
1
0.40
2
,
R2
,
100 o 12 h
5
3
in situ
,
C,
5
CONMe2
CONMe2
CONMe2
Ph
CONMe2
is much lower than the yield obtained with N-phenyl acrylamide
+
19a
N
N
N
(70%). These results did not agree with our previous results
,
N
Ph
Ph
Ph
Ph
and may indicate a different reaction mechanism. Other alkenes,
including unsaturated aldehydes and ketones, dimethyl maleate
10 and coumarin also gave the corresponding indolizines in
Ph
5k
Ph
c
b
=
5a 98%
5l/5l' 1/2, 63
,
%
(75%)
34%
,
CONMe2
CONMe2
CONMe2
Ph
MeO2C
moderate yields (5d, 5h and 5j).
N
N
N
EWG
Ph
5m 83%
Ph
Ph
mmol
mmol
0.80
0.50
TEMPO
Cs2CO3
5n 62%
,
5o 54% d
,
,
Br
0.2 mL DMF
R1
+
N+
Ph
mmol
4
0.20
,
N
N
CONMe2
60 o 2 h
C,
CONMe2
CONMe2
CONMe2
Br-
,
2.8 mL DMSO
100 o 20 h
Ph
C,
mmol
mmol
2a 0.40
,
1a 0.40
,
3aa in situ
5
N
N
N
N
O
n
CONMe2
CO2 -Bu
Et
CO2t
-Bu
CHO
Br
Ph
F
N
N
N
N
N
Ph
5a 84%
5p 75% e
NO
5s 54%
,
Ph
5c 80% b
,
5q 77%
,
5r 75%
,
OMe
Ph
5b 96% b
Ph
5d 76%
2
Ph
5e 59%
,
,
,
,
,
Scheme 3. Substrate scope of pyridines and halogenated hydrocarbons. a
One-pot reaction starting from pyridine (1, 0.40 mmol) and halogenated
hydrocarbon (2, 0.40 mmol) in 0.20 mL DMF. The mixture was heated at
45 60 °C in a stoppered test tube for 4 h to form 3 in situ, and then 3 was
reacted with N,N-dimethyl acrylamide (4a, 0.20 mmol) in the presence of
TEMPO (0.80 mmol) and LiOH (0.50 mmol) at 100 °C for 12 h with an
additional 2.80 mL DMSO. b Using benzyl chloride as the starting
material. c Ratio determined by 1H NMR spectroscopy. d Using Cs2CO3
50 as the base. e Using 1-(chloromethyl)-4-methoxybenzene as the starting
material.
CONH2
O
O
CN
H
N
CO2Me
CO2Me
O
Ph
N
N
N
N
N
Ph
5f 34%
Ph
5g 94%
Ph
5h 51% c
Ph
,
Ph
5j 61%
,
,
d
5i 70%
,
,
(45%)
Scheme 2. Substrate scope of alkenes. a One-pot reaction starting from
pyridine (1a, 0.40 mmol) and benzyl bromide (2a, 0.40 mmol) in 0.20 mL
15 DMF. The mixture was heated at 60 °C in a stoppered test tube for 2 h to
form 3aa in situ, and then 3aa was reacted with alkenes (4, 0.20 mmol) in
the presence of TEMPO (0.80 mmol) and Cs2CO3 (0.50 mmol) at 100 °C
for 20 h with an additional 2.80 mL DMSO. b Reaction of 0.20 mmol
pyridine, 0.20 mmol benzyl bromide, 0.60 mmol alkene, 0.25 mmol
20 Cs2CO3 at 120 °C. c Using dimethyl maleate as the starting material. d
Using (Z)-4-(anilino)-4-oxobut-2-enoic acid as the starting material.
We then tried simple primary halogenated hydrocarbons, such as
1-bromobutane, under the standard reaction conditions. To our
surprise, corresponding indolizine (7a) was isolated, albeit in
55 very low yield. To the best of our knowledge, this type of
substrate has not previously been used for 1,3-dipolar
cycloaddition reactions because of the very low acidity of the
corresponding pyridinium salts. Encouraged by this preliminary
result, we reoptimized the reaction conditions and examined the
60 substrate scope. The results are listed in Scheme 4. A series of
alkyl bromides gave the corresponding indolizines (7a–e) in good
yields. However, reaction with methyl 6-bromohexanoate (6f),
which contains an ester group, was less efficient, probably as a
result of hydrolysis by lithium hydroxide. Silane-protected
65 alcohol 6h gave deprotected indolizine 7h in moderate yield.
Pyridines with meta or para substituents smoothly yielded the
corresponding indolizines (7i–l); however, ortho-substituted
pyridines failed to yield the corresponding indolizines owing to
high steric hindrance. Meta-phenyl pyridine (1c) gave two
70 isomers (7j and 7j’) which were isolated and fully characterized.
To evaluate the substrate scope of the reaction, a series of
pyridines was reacted with various halogenated hydrocarbons to
form corresponding pyridinium salts 3 in situ, and 3 was then
25 reacted with 4a under standard conditions (Scheme 3). Pyridines
with ortho, meta or para substituents smoothly yielded the
corresponding indolizines (5k, 5l and 5m). However, the yield of
the ortho-substituted product (5b) was decreased owing to the
high steric hindrance. The meta-substituted pyridine gave two
1
30 isomers with a ratio of 5l/5l′ = 1: 2, as determined by H NMR
spectroscopy and the total yield of the two isomers was 63%. 5l
was isolated and fully characterized but 5l’ was only
1
characterized by H NMR with small amount of 5l. Reaction of
unsubstituted pyridine with 4-methoxybenzyl chloride gave 5p
35 and reaction with benzyl chloride gave 5a, both in 75% yield.
These results indicate that chlorinated and brominated
hydrocarbons give indolizines in good yields. When the product
contained an ester group (5o), it is largely hydrolyzed in the
presence of lithium hydroxide and better yields were achieved
40 with cesium carbonate as the base.
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EWG
Unless otherwise noted, all commercial reagents and solvents
30 were obtained from the commercial provider and used without
mmol
1.0
TEMPO
0.20 mL DMF
mmol
+
0.80
LiOH
R1
R1
R2
Br
N+
R2
R3
100 o 4 h
4
0.20
N
mmol
,
C,
N
Br-
further purification. 1H NMR and 13C NMR spectra were
recorded on Bruker 400 MHz spectrometers. Chemical shifts
were reported relative to internal tetramethylsilane (δ 0.00 ppm)
or CDCl3 (δ 7.26 ppm) for 1H NMR and CDCl3 (δ 77.0 ppm) for
35 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
40 Avatar 360 spectrometer.
R1
1.8 mL DMSO
mmol
mmol
1
0.60
6, 0.60
140 o 24 h
,
R2
7
3
in situ
,
C,
CN
CN
CN
CN
CN
CN
N
N
N
N
N
N
Ph
7c 69%
O
O
MeO2C
OMe
7b 54%
Ph
7d 80%
7a 83%
,
,
,
7f 26%
,
,
7e 82%
,
CN
CN
CN
Ph
CN
CN
N
N
N
+
N
N
Ph
Ph
Ph
OH
CN
7g 55%
OMe
7h 35% b
OMe
Ph
OMe
General procedure for the preparation of indolizines 5
,
7i 93%
,
,
+
7j
(26%) 7j' (22%)
O
N
CONMe2
CN
CN
Ph
Pyridine derivative (1, 0.40 mmol) and halogenated hydrocarbon
45 (2, 0.40 mmol) in 0.20 mL of DMF were heated at 60 oC in a test
tube with a stopper for 4 h to form 3 in situ. Then alkene (4, 0.20
mmol), TEMPO (0.80 mmol), base (0.50 mmol) and 2.80 mL of
DMSO were added to the tube. Then the mixture was heated at
PhOC
N
N
N
N
OMe
7m 61%
OMe
OMe
OMe
7k 41%
7l 97%
CO2t-Bu
,
,
7n 35%
o
100 C for another 12 h (the reaction course was monitored by
CHO
COPh
50 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 sulphate and filtered. The organic solvent was removed
under vacuum and the residue was purified by flash
55 chromatography (silica gel, eluted by petroleum ether/ ethyl
acetate).
Ph
N
N
N
OMe
7o 37%
OMe
7p 39%
OMe
83%
,
,
7q,
Scheme 4. Substrate scope for the synthesis of 3-alkyl indolizines. a One-
pot reaction starting from pyridine (1, 0.60 mmol) and alkyl bromide (6,
0.60 mmol) in 0.20 mL DMF. The mixture was heated at 100 °C in a
5 sealed tube for 4 h to form 3 in situ, and then 3 was reacted with alkenes
(4, 0.20 mmol) in the presence of TEMPO (1.0 mmol) and LiOH (0.80
mmol) at 140 °C for 24 h in a sealed tube with an additional 1.80 mL
DMSO. b From (3-bromopropoxy)(tert-butyl)dimethylsilane.
Preparation of indolizine 5a at gram scale
60 Pyridine (1a) 40 mmol and benzyl bromide (2a) 40 mmol and 5.0
mL DMF were mixed in a round botton flask at r.t.. The mixture
was stirred for 4h at 60 oC. Then alkene (4a, 20 mmol), TEMPO
(80 mmol), LiOH (50 mmol) and 70 mL of DMSO were added to
the flask. Then the mixture was heated at 100 oC for another 12 h
65 (the reaction course was monitored by TLC). After the reaction
was completed, the mixture was poured into water and extracted
by ethyl acetate (50 mL ×3). The organic layers were combined,
washed with brine twice, dried with anhydrous sodium sulphate
and filtered. The organic solvent was removed under vacuum and
70 the residue was purified by flash chromatography (silica gel,
eluted by petroleum ether/ ethyl acetate).
Furthermore, the reaction scale was easily increased to 20 mmol,
10 with only a slight decrease in the yield (Scheme 5).
O
N
mmol)
TEMPO
LiOH
(80
mmol)
DMF ml)
(5
Br
(50
mmol
4a 20
,
N+
Br-
+
60 o 4 h
C,
N
N
DMSO
100 o
C
(70 ml),
Ph
2.05 78%
mmol
mmol
40
In situ
40
g,
Scheme 5 The synthesizing of indolizine 5a by gram scale.
Conclusions
A one-pot transition-metal-free method for the synthesis of 3-aryl
15 and 3-alkyl indolizines was developed, and uses primary
halogenated hydrocarbons, pyridines and electron deficient
alkenes as starting materials. In this method, an organic oxidant
(TEMPO) was used, which renders this transformation
environmentally friendly and likely to attract the interest of
20 medicinal chemists. The substrate scope is broad; various
electron-deficient alkenes, pyridines and primary halogenated
hydrocarbons were successfully converted into the corresponding
indolizines. Importantly, 3-alkyl indolizines were synthesized
from primary halogenated alkanes using a simple procedure for
25 the first time.
N,N-Dimethyl-3-phenylindolizine-1-carboxamide (5a)19e
PE/EA = 1/1; brown oil; H NMR(CDCl3, 400 MHz): 8.23 (d, J
75 = 7.1 Hz, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.56 - 7.45 (m, 4H), 7.37
(t, J = 7.3 Hz, 1H), 6.97 (s, 1H), 6.91 (dd, J = 9.1, 6.5 Hz, 1H),
6.60 (t, J = 6.8 Hz, 1H), 3.20 (s, 6H).
1
tert-Butyl 3-phenylindolizine-1-carboxylate (5b)19e
80 PE/EA = 8/1; white solid; 1H NMR(CDCl3, 400 MHz): 8.25 (t, J
= 7.4 Hz, 2H), 7.54 – 7.44 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.09
– 6.96 (m, 1H), 6.67 – 6.59 (m, 1H), 1.68 (s, 9H).
Butyl 3-phenylindolizine-1-carboxylate (5c)19e
85 PE/ EA = 6/1; yellow oil; 1H NMR (CDCl3, 400 MHz): 8.29 (d, J
= 7.0 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.59 – 7.44 (m, 4H), 7.39
(t, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.07 (dd, J = 9.0, 6.5 Hz, 1H),
Experimental
General
4
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Organic & Biomolecular Chemistry
6.69 (t, J = 6.7 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 1.86 – 1.71 (m,
2H), 1.50 (p, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).
60
N,N-Dimethyl-3,5-diphenylindolizine-1-carboxamide (5k)
PE/EA = 1/1; brown oil; H NMR(CDCl3, 400 MHz): 8.19 (d, J
1
2,3-Diphenylindolizine-1-carbaldehyde (5d)
PE/EA = 4/1; yellow solid; m. p. 208-209 C; H NMR(CDCl3,
400 MHz): 9.91 (s, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.14 (d, J = 7.0 65 = 8.3, 6.1 Hz, 6H), 4.95 (s, 1H), 3.10 (s, 3H), 2.99 (s, 3H); 13C
= 7.3 Hz, 2H), 7.93 (dd, J = 7.9, 1.8 Hz, 2H), 7.68 (t, J = 7.8 Hz,
1H), 7.62 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.41 (td, J
o
1
5
Hz, 1H), 7.44 – 7.34 (m, 3H), 7.32 – 7.23 (m, 8H), 6.83 (t, J = 6.9
Hz, 1H); 13C NMR (CDCl3, 100 MHz): 186.0, 135.5, 132.5,
131.7, 131.2, 130.9, 129.6, 129.1, 128.5, 128.1, 127.3, 125.2,
NMR (CDCl3, 100 MHz): 191.3, 166.6, 156.5, 151.8, 138.1,
137.4, 134.6, 134.0, 129.2, 128.8, 128.8, 128.6, 126.8, 119.9,
119.3, 67.2, 66.2 , 36.7, 35.4; IR (NaCl) ν: 3060, 2929, 1695,
1659, 1599, 1580, 1537, 1514, 1493, 1449, 1400, 1372 cm-1;
10 124.3, 123.4, 120.4, 114.4, 112.0; IR (KBr) ν: 3057, 2838, 1654,
1640, 1622, 1547, 1527, 1493, 1474, 1440, 1399, 1382, 1327, 70 HRMS Calculated for [C23H20N2O+Na]+: 363.1468, Found:
1309 cm-1; HRMS Calculated for [C21H15NO+Na]+: 320.1046,
Found: 320.1031.
363.1467.
N,N-Dimethyl-3,8-diphenylindolizine-1-carboxamide (5l)
1
15 1-(3-Phenylindolizin-1-yl)propan-1-one (5e)
PE/EA = 6/1; yellow oil; 1H NMR (CDCl3, 400 MHz): 8.55 (d, J
= 9.1 Hz, 1H), 8.29 (d, J = 7.1 Hz, 1H), 7.61 – 7.38 (m, 5H), 7.25
– 7.08 (m, 2H), 6.76 (t, J = 6.8 Hz, 1H), 2.94 (q, J = 7.4 Hz, 2H),
1.27 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz): 196.4,
20 136.0, 131.1, 129.2, 128.6, 128.2, 126.3, 123.7, 123.2, 121.1,
115.8, 113.5, 112.9, 33.2, 9.1; IR (NaCl) ν: 2972, 2934, 1645,
1626, 1602, 1541, 1523, 1503, 1457, 1446, 1427, 1361, 1300 cm-
1; HRMS Calculated for [C17H15NO+Na]+: 272.1046, Found:
272.1043.
PE/EA = 2/1; yellow oil; H NMR(CDCl3, 400 MHz): 8.25 (d, J
75 = 7.1 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.54-7.48 (m, 4H), 7.45-
7.35 (m, 5H), 6.95 (s, 1H), 6.75 (d, J = 6.7 Hz, 1H), 6.63 (t, J =
6.9 Hz, 1H), 2.49 (s, 6H); 13C NMR (CDCl3, 100 MHz): 168.5,
138.5, 133.5, 131.8, 129.8, 129.1, 128.6, 128.4, 128.0, 127.9,
127.8, 126.1, 121.8, 120.3, 114.8, 111.2, 110.2, 38.9, 34.4; IR
80 (NaCl) ν: 3057, 2928, 1628, 1550, 1514, 1491, 1449, 1399, 1365,
1339, 1301 cm-1; HRMS Calculated for [C23H20N2O+Na]+:
363.1468, Found: 363.1450.
25
3-Phenylindolizine-1-carboxamide (5f)19e
N,N-Dimethyl-3,6-diphenylindolizine-1-carboxamide (5l’)
PE/EA = 6/1; yellow solid; 1H NMR (CDCl3, 400 MHz): 8.42 (d, 85 1H NMR(CDCl3, 400 MHz): 8.55 (s, 1H), 7.98 (d, J = 9.3 Hz,
J = 9.1 Hz, 1H), 8.27 (d, J = 7.1 Hz, 1H), 7.59 – 7.46 (m, 4H),
7.46 – 7.38 (m, 1H), 7.09 – 6.95 (m, 2H), 6.75 – 6.64 (m, 1H),
30 5.74 (br, 2H).
1H), 7.50 (d, J = 7.1 Hz, 2H), 7.46-7.40 (m, 4H), 7.37 – 7.31 (m,
3H), 7.27 (t, J = 7.2 Hz, 1H), 7.14 (dd, J = 9.3, 1.6 Hz, 1H), 6.93
(s, 1H), 3.15 (s, 6H). (With small amount of 5l).
3-Phenylindolizine-1-carbonitrile (5g)19e
90 N,N-Dimethyl-3,7-diphenylindolizine-1-carboxamide (5m)
PE/EA = 1/1; brown oil; H NMR(CDCl3, 400 MHz): δ 8.37 -
PE/EA = 6/1; white solid; 1H NMR(CDCl3, 400 MHz): 8.27 (d, J
= 7.1 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.56 – 7.38 (m, 5H), 7.13
35 – 6.96 (m, 2H), 6.74 (t, J = 6.9 Hz, 1H).
1
8.26 (m, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.3 Hz, 2H),
7.52 (t, J = 7.6 Hz, 2H), 7.47-7.34 (m, 4H), 7.02 (s, 1H), 6.96 (dd,
J = 7.4, 2.0 Hz, 1H), 3.25 (s, 6H); 13C NMR (CDCl3, 100 MHz):
95 167.7, 139.0, 135.7, 133.0, 131.5, 129.1, 128.8, 128.4, 127.8,
127.7, 126.5, 125.0, 122.8, 117.1, 115.2, 111.8, 108.1; IR (NaCl)
ν: 3058, 3027, 2927, 1659, 1601, 1541, 1514, 1462, 1445, 1409,
1399, 1370, 1339 cm-1; HRMS Calculated for [C23H20N2O+Na]+:
363.1468, Found: 363.1468.
Dimethyl 3-phenylindolizine-1,2-dicarboxylate (5h)19e
1
PE/ EA = 4/1; white solid; H NMR(CDCl3, 400 MHz): 8.23 (d,
J = 9.1 Hz, 1H), 8.05 (d, J = 7.1 Hz, 1H), 7.58 – 7.40 (m, 5H),
40 7.12 (dd, J = 9.2, 6.5 Hz, 1H), 6.72 (t, J = 6.9 Hz, 1H), 3.91 (s,
3H), 3.81 (s, 3H).
100
N,N-Dimethyl-3-phenylpyrrolo[2,1-a]isoquinoline-1-
carboxamide (5n)
N,3-Diphenylindolizine-1-carboxamide (5i)
o
1
PE/EA = 4/1; white solid; m. p. 156- 158 C; H NMR(CDCl3,
45 400 MHz): 8.48 (d, J = 9.1 Hz, 1H), 8.28 (d, J = 7.1 Hz, 1H),
7.76 – 7.61 (m, 3H), 7.58 – 7.48 (m, 4H), 7.42 (t, J = 7.1 Hz, 1H),
7.36 (t, J = 7.7 Hz, 2H), 7.14 – 7.01 (m, 3H), 6.72 (t, J = 6.8 Hz,
1H); 13C NMR (CDCl3, 100 MHz): 163.2, 138.6, 136.1, 131.1,
129.2, 129.0, 128.6, 128.2, 126.2, 123.7, 123.1, 122.1, 120.6,
50 120.0, 112.9, 112.1, 107.0; IR (KBr) ν: 3278, 3050, 2925, 2852,
PE/ EA = 1/1; brown oil; 1H NMR(CDCl3, 400 MHz): 8.12 (d, J
= 8.1 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.60 - 7.45 (m, 6H), 7.45
105 - 7.36 (m, 2H), 6.79 (t, J = 3.8 Hz, 2H), 3.30 (s, 3H), 3.07 (s, 3H);
13C NMR (CDCl3, 100 MHz): 169.6, 131.5, 129.0, 128.9, 128.4,
127.9, 127.9, 127.7, 126.8, 126.7, 126.3, 126.0, 123.1, 121.9,
112.2, 112.0, 112.0, 39.0, 35.2; IR (NaCl) ν: 3054, 2928, 1697,
1626, 1558, 1519, 1483, 1459, 1396, 1373, 1337 cm-1; HRMS
1651, 1628, 1594, 1542, 1529, 1512, 1498, 1438, 1410, 1313, 110 Calculated for [C21H18N2O+Na]+: 337.1311, Found: 337.1285.
1303 cm-1; HRMS Calculated for [C21H16N2O+Na]+: 335.1155,
Methyl
1-(dimethylcarbamoyl)-3-phenylindolizine-7-
Found: 335.1157.
carboxylate (5o)
PE/EA = 1/1; brown oil; 1H NMR(CDCl3, 400 MHz): 8.73 – 8.60
115 (m, 1H), 8.22 (d, J = 7.4 Hz, 1H), 7.57-7.50 (m, 4H), 7.43 (t, J =
7.1 Hz, 1H), 7.19 (dd, J = 7.4, 1.9 Hz, 1H), 7.06 (s, 1H), 3.92 (s,
3H), 3.22 (s, 6H).; 13C NMR (CDCl3, 100 MHz): 166.8, 166.0,
133.0, 130.8, 129.2, 128.4, 128.4, 127.3, 123.5, 121.9, 121.0,
116.0, 112.4, 111.1, 52.1, 36.4, 35.4; IR (NaCl) ν: 2950, 1714,
55 12-Phenyl-6H-chromeno[3,4-a]indolizin-6-one (5j)19e
PE/EA = 4/1; yellow solid; 1H NMR(CDCl3, 400 MHz): 8.39 (d,
J = 8.8 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.71 – 7.53 (m, 5H),
7.39 – 7.29 (m, 3H), 7.27 – 7.21 (m, 1H), 6.99 (t, J = 7.5 Hz, 1H),
6.89 (t, J = 6.8 Hz, 1H).
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1659, 1614, 1539, 1515, 1471, 1434, 1411, 1340, 1375, 1338,
1305 cm-1; HRMS Calculated for [C19H18N2O3+Na]+: 345.1210,
Found: 345.1185.
60
3-Propylindolizine-1-carbonitrile (7a)
o
1
PE/EA = 10/1; yellow solid; m. p. 75 - 76 C; H NMR(CDCl3,
400 MHz): δ 7.88 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H),
7.06 – 7.00 (m, 1H), 6.81 – 6.76 (m, 2H), 2.77 (t, J = 7.6 Hz, 2H),
5
3-(4-Methoxyphenyl)-N,N-dimethylindolizine-1-carboxamide
(5p)19e
65 1.83 - 1.74 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 137.8, 126.1, 123.1, 121.1, 118.0, 117.4, 114.1,
112.6, 80.5, 27.6, 20.2, 13.9; IR (NaCl) ν: 2960, 2880, 2201,
1634, 1525, 1512, 1489, 1469, 1455, 1409, 1379, 1338, 1329,
1313 m-1; HRMS Calculated for [C12H12N2+Na]+: 207.0893,
70 Found: 207.0889.
PE/ EA = 2/1; brown oil; 1H NMR(CDCl3, 400 MHz): 8.13 (d, J
= 7.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H),
7.01 (d, J = 8.7 Hz, 2H), 6.93 – 6.85 (m, 2H), 6.58 (t, J = 6.7 Hz,
10 1H), 3.86 (s, 3H), 3.19 (s, 6H).
N,N-Dimethyl-3-(4-nitrophenyl)indolizine-1-carboxamide
(5q)19f
PE/EA = 2/1; yellow solid; 1H NMR(CDCl3, 400 MHz): 8.32 (dd,
15 J = 7.8, 5.0 Hz, 3H), 7.95 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 8.4 Hz,
3-(2-Methoxyethyl)indolizine-1-carbonitrile(7b)
PE/EA = 3/1; yellow solid; m. P. 44-46 oC; 1H NMR(CDCl3, 400
MHz): δ 8.00 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.08 –
2H), 7.10 (s, 1H), 7.00 (dd, J = 9.1, 6.6 Hz, 1H), 6.73 (t, J = 6.9 75 7.00 (m, 1H), 6.84 (s, 1H), 6.77 (t, J = 6.9 Hz, 1H), 3.72 (t, J =
Hz, 1H), 3.20 (s, 6H).
6.4 Hz, 2H), 3.37 (s, 3H), 3.08 (t, J = 6.4 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): δ 138.0, 123.6, 123.6, 121.4, 117.9, 117.2,
114.9, 112.6, 80.8, 70.8, 58.9, 26.4; IR (NaCl) ν: 3114, 2925,
2893, 2208, 1713, 1636, 1513, 1457, 1411, 1380, 1322 cm-1;
3-(3-Fluorophenyl)-N,N-dimethylindolizine-1-carboxamide
20 (5r)
PE/EA = 1/1; brown oil; H NMR(CDCl3, 400 MHz): 8.23 (d, J 80 HRMS Calculated for [C12H12N2O+Na]+: 223.0842, Found:
1
= 7.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.43 (td, J = 7.9, 5.9 Hz,
1H), 7.31 (d, J = 7.7 Hz, 1H), 7.22 (dt, J = 9.9, 2.1 Hz, 1H), 7.05
(td, J = 8.5, 2.6 Hz, 1H), 6.98 (s, 1H), 6.92 (dd, J = 9.1, 6.5 Hz,
25 1H), 6.63 (t, J = 6.8 Hz, 1H), 3.19 (s, 6H); 13C NMR (CDCl3, 100
223.0842.
3-Benzylindolizine-1-carbonitrile (7c)
PE/EA = 8/1; yellow solid; m. p. 97-99 oC; 1H NMR(CDCl3, 400
MHz): δ 167.5, 163.1 (d, J = 247.0 Hz), 135.4, 133.6 (d, J = 8.3 85 MHz): δ 7.75 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.33 –
Hz), 130.7 (d, J = 8.6 Hz), 123.9 (d, J = 2.9 Hz), 123.7 (d, J = 2.6
Hz), 122.5, 120.6, 120.3, 115.1 (d, J = 22.0 Hz), 115.0, 114.5 (d,
J = 21.0 Hz), 112.4, 107.7; IR (NaCl) ν: 3069, 2929, 1609, 1541,
30 1511, 1478, 1451, 1410, 1367, 1339, 1305 cm-1; HRMS
Calculated for [C17H15FN2O+Na]+: 305.1061, Found: 305.1080.
7.24 (m, 3H), 7.14 (s, 2H), 7.05 – 7.00 (m, 1H), 6.81 (s, 1H), 6.70
(t, J = 7.0 Hz, 1H), 4.19 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ
138.3, 136.2, 128.9, 128.3, 127.1, 124.2, 123.4, 121.6, 118.0,
117.1, 116.3, 112.8, 80.8, 32.2; IR (NaCl) ν: 3062, 3029, 2918,
90 2208, 1636, 1602, 1543, 1511, 1495, 1454, 1434, 1411, 1374,
1316 cm-1; HRMS Calculated for [C16H12N2+Na]+: 255.0893,
Found: 255.0889.
3-(2-Bromophenyl)-N,N-dimethylindolizine-1-carboxamide
(5s)
1
35 PE/EA = 1/1; brown oil; H NMR(CDCl3, 400 MHz): 8.01 (d, J
3-Phenethylindolizine-1-carbonitrile (7d)
1
= 9.1 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 95 PE/EA = 8/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
7.41 (d, J = 4.6 Hz, 2H), 7.30 (dt, J = 8.8, 4.6 Hz, 1H), 7.01 –
6.89 (m, 2H), 6.62 (t, J = 6.8 Hz, 1H), 3.20 (s, 6H); 13C NMR
(CDCl3, 100 MHz): 167.6, 134.8, 133.3, 133.2, 132.4, 130.2,
40 127.7, 125.4, 123.4, 123.2, 120.5, 120.0, 115.6, 111.8, 106.7; IR
7.79 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.29 (t, J = 7.3
Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 2H), 7.03 -
6.99 (m, 1H), 6.78 (s, 1H), 6.74 (t, J = 6.9 Hz, 1H), 3.11 – 3.02
(m, 4H); 13C NMR (CDCl3, 100 MHz): δ 140.4, 137.9, 128.7,
(NaCl) ν: 3052, 2929, 1633, 1607, 1543, 1510, 1448, 1410, 1366, 100 128.3, 126.5, 125.4, 123.0, 121.3, 118.0, 117.3, 114.4, 112.7,
1339, 1308 cm-1; HRMS Calculated for [C17H15BrN2O+Na]+:
365.0260, Found: 365.0233.
80.7, 33.5, 27.5; IR (NaCl) ν: 3110, 3085, 3061, 3027, 2927,
2858, 2208, 1636, 1603, 1512, 1497, 1454, 1410, 1378, 1330,
1314 cm-1; HRMS Calculated for [C17H14N2+Na]+: 269.1049,
Found: 269.1044.
45 General procedure for the preparation of indolizines 7
105
Pyridine derivative (1, 0.60 mmol) and alkyl bromide (6, 0.60
mmol) in 0.20 mL of DMF were heated at 100 oC in a sealed tube
for 4 h to form 3 in situ. Then alkene (4, 0.20 mmol), TEMPO
50 (1.00 mmol), LiOH (0.80 mmol) and 1.80 mL of DMSO were
3-((1,3-Dioxolan-2-yl)methyl)indolizine-1-carbonitrile (7e)
PE/EA = 3/1; yellow solid; m. p. 79-81 oC; 1H NMR(CDCl3, 400
MHz): δ 8.14 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.05 (t,
J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.77 (t, J = 6.9 Hz, 1H), 5.15 (t, J =
o
110 4.2 Hz, 1H), 3.90-3.82 (m, 4H), 3.23 (d, J = 4.2 Hz, 2H); 13C
NMR (CDCl3, 100 MHz): δ 138.2, 124.2, 121.6, 121.6, 120.5,
117.7, 117.1, 116.8, 112.5, 103.1, 65.2, 31.0; IR (NaCl) ν: 3117,
2956, 2889, 2710, 2209, 1636, 1543, 1514, 1473, 1428, 1412,
1397, 1375, 1339, 1320 cm-1; HRMS Calculated for
115 [ C13H12N2O2+Na]+: 251.0791, Found: 251.0787.
added to the tube. Then the mixture was heated at 140 C for
another 24h under sealed (the reaction course 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
55 layers were combined, washed with brine, dried with anhydrous
sodium sulphate 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).
Methyl 5-(1-cyanoindolizin-3-yl)pentanoate (7f)
6
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1
PE/EA = 3/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
7.48 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.31 (d, J = 9.2
7.86 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.04 (dd, J = 60 Hz, 1H), 6.88 (s, 1H), 3.75 (t, J = 6.3 Hz, 2H), 3.38 (s, 3H), 3.14
9.0, 6.6 Hz, 1H), 6.81 (s, 1H), 6.78 (d, J = 7.4 Hz, 1H), 3.68 (s,
3H), 2.82 (t, J = 6.9 Hz, 2H), 2.40 (t, J = 6.9 Hz, 2H), 1.83 – 1.77
(m, 4H); 13C NMR (CDCl3, 100 MHz): δ 173.6, 137.9, 125.6,
123.0, 121.2, 118.1, 117.2, 114.2, 112.7, 80.7, 51.6, 33.6, 26.3,
(t, J = 6.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 137.4, 137.0,
129.2, 128.0, 127.1, 126.9, 124.2, 122.2, 121.1, 117.8, 117.2,
115.5, 80.9, 71.0, 59.0, 26.6; IR (NaCl) ν: 3507, 2924, 2208,
1637, 1601, 1554, 1532, 1510, 1494, 1450, 1428, 1386, 1333 cm-
5
25.3, 24.6; IR (NaCl) ν: 3114, 2949, 2866, 2208, 1733, 1698, 65 1; HRMS Calculated for [C18H16N2O+Na]+: 299.1155, Found:
1681, 1636, 1541, 1511, 1489, 1456, 1435, 1411, 1362, 1320 cm-
1; HRMS Calculated for [ C15H16N2O2+Na]+: 279.1104, Found:
299.1149.
10 279.1098.
3-(2-Methoxyethyl)-7-phenylindolizine-1-carbonitrile (7k)
PE/EA = 4/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
1
3-(2-Cyano-2,2-diphenylethyl)indolizine-1-carbonitrile (7g)
70 8.07 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H),
7.47 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 8.3
Hz, 1H), 6.85 (s, 1H), 3.73 (t, J = 6.3 Hz, 2H), 3.38 (s, 3H), 3.11
(t, J = 6.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 138.3, 138.2,
134.3, 129.1, 128.3, 126.6, 123.8, 123.6, 117.3, 115.5, 114.6,
o
1
PE/EA = 1/1; yellow solid; m. p. 158-160 C; H NMR(CDCl3,
400 MHz): δ 7.54 (d, J = 9.3 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H),
15 7.36 – 7.30 (m, 10H), 6.98 - 6.94 (m, 1H), 6.66 (s, 1H), 6.53 (t, J
= 6.8 Hz, 1H), 3.94 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ
139.1, 138.1, 129.1, 128.6, 127.1, 122.8, 121.9, 121.8, 119.1, 75 112.4, 81.4, 71.0, 58.9, 26.5; IR (NaCl) ν: 3060, 2924, 2207,
118.4, 117.8, 116.7, 112.6, 81.6, 51.8, 36.0; IR (NaCl) ν: 3062,
3032, 2932, 2249, 2211, ,1732, 1716, 1704, 1688, 1681, 1636,
20 1597, 1541, 1511, 1495, 1472, 1449, 1414, 1378, 1339, 1322 cm-
1; HRMS Calculated for [C24H17N3+Na]+: 370.1315, Found:
370.1311.
1682, 1641, 1601, 1541, 1516, 1495, 1464, 1409, 1361, 1343 cm-
1; HRMS Calculated for [C18H16N2O+Na]+: 299.1155, Found:
299.1153.
80 7-Benzoyl-3-(2-methoxyethyl)indolizine-1-carbonitrile (7l)
PE/EA = 3/1; yellow solid; m. p. 120 - 122 oC; 1H NMR(CDCl3,
400 MHz): δ 8.13 (d, J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.80 (d, J =
8.2 Hz, 2H), 7.64 (t, J = 7.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H),
7.36 (d, J = 7.3 Hz, 1H), 7.01 (s, 1H), 3.76 (t, J = 6.1 Hz, 2H),
3-(2-Hydroxyethyl)indolizine-1-carbonitrile (7h)
1
25 PE/EA = 1/2; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
8.07 (d, J = 7.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.11 - 7.07 (m,
1H), 6.92 (s, 1H), 6.84 (t, J = 6.8 Hz, 1H), 4.04 (t, J = 6.3 Hz, 85 3.38 (s, 3H), 3.16 (t, J = 6.1 Hz, 2H); 13C NMR (CDCl3, 100
2H), 3.15 (t, J = 6.3 Hz, 2H), 2.11 (br, 1H); 13C NMR (CDCl3,
100 MHz): δ 138.2, 123.5, 123.2, 121.6, 117.9, 117.1, 115.2,
30 112.7, 80.8, 60.7, 28.9; IR (NaCl) ν: 3420, 3114, 2927, 2208,
1636, 1512, 1472, 1434, 1411, 1378, 1319 cm-1; HRMS
Calculated for [C11H10N2O+Na]+: 209.0685, Found: 209.0681.
MHz): δ 194.1, 137.0, 135.5, 132.7, 129.6, 129.4, 128.7, 126.7,
123.7, 122.0, 117.4, 116.1, 112.1, 86.4, 70.8, 59.0, 26.6; IR
(NaCl) ν: 3060, 2925, 2892, 2214, 1651, 1630, 1597, 1577, 1520,
1489, 1465, 1446, 1409, 1363, 1343, 1311 m-1; HRMS
90 Calculated for [C19H16N2O2+Na]+: 327.1104, Found: 327.1103.
3-(2-Methoxyethyl)-6,8-dimethylindolizine-1-carbonitrile (7i)
35 PE/EA = 5/1; yellow solid; m. p. 108-110 C; H NMR(CDCl3,
400 MHz): δ 7.61 (s, 1H), 6.77 (s, 1H), 6.62 (s, 1H), 3.71 (t, J =
3-(2-Methoxyethyl)-N,N-dimethylindolizine-1-carboxamide
o
1
(7m)
1
PE/EA = 1/1; yellow oil; H NMR(CDCl3, 400 MHz): 7.94 –
6.6 Hz, 2H), 3.38 (s, 3H), 3.03 (t, J = 6.5 Hz, 2H), 2.66 (s, 3H), 95 7.82 (m, 2H), 6.89 (t, J = 7.8 Hz, 1H), 6.78 (s, 1H), 6.66 (t, J =
2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 136.0, 128.3, 124.9,
123.0, 122.4, 119.2, 115.5, 79.9, 70.4, 58.8, 26.5, 18.4, 18.3; IR
40 (NaCl) ν: 3079, 3047, 3016, 2974, 2945, 2918, 2879, 2212, 2755,
2201, 1732, 1640, 1564, 1537, 1510, 1482, 1436, 1425, 1398
6.9 Hz, 1H), 3.72 (t, J = 6.8 Hz, 2H), 3.38 (s, 3H), 3.17 (s, 6H),
3.11 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): 168.0,
134.3, 122.3, 121.1, 119.9, 119.3, 113.3, 111.6, 106.1, 70.9, 58.9,
42.7, 26.5; IR (NaCl) ν: 2926, 1723, 1633, 1604, 1544, 1511,
1378, 1349, 1339, 1302 cm-1; HRMS Calculated for 100 1455, 1411, 1385, 1302 cm-1; HRMS Calculated for
[C14H16N2O+Na]+: 251.1155, Found: 251.1153.
[C14H18N2O2+Na]+: 269.1260, Found: 269.1262.
45 3-(2-Methoxyethyl)-8-phenylindolizine-1-carbonitrile (7j)
PE/EA = 4/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
8.01 (d, J = 6.8 Hz, 1H), 7.49 (s, 5H), 6.92 (d, J = 6.3 Hz, 1H), 105 PE/ EA = 1/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
3-(2-Methoxyethyl)-N-methyl-N-phenylindolizine-1-
1
carboxamide (7n)
1
6.89 (s, 1H), 6.86 (t, J = 6.9 Hz, 1H), 3.76 (t, J = 6.4 Hz, 2H),
3.39 (s, 3H), 3.12 (t, J = 6.4 Hz, 2H); 13C NMR (CDCl3, 100
50 MHz): δ 172.1, 136.4, 135.6, 133.7, 129.4, 128.8, 128.2, 123.9,
122.5, 122.1, 117.0, 112.6, 81.8, 70.7, 58.9, 26.7; IR (NaCl) ν:
8.37 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.34 (t, J = 7.5
Hz, 2H), 7.28-7.22 (m, 3H), 6.98 – 6.92 (m, 1H), 6.67 (t, J = 6.8
Hz, 1H), 5.59 (s, 1H), 3.50 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 3.25
(s, 3H), 2.83 (t, J = 6.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
3055, 2925, 2210, 1732, 1716, 1681, 1661, 1647, 1540, 1497, 110 δ 146.2, 136.4, 129.2, 127.5, 126.4, 122.2, 120.8, 120.7, 120.2,
1447, 1398, 1386, 1326, 1303 cm-1; HRMS Calculated for
[C18H16N2O+Na]+: 299.1155, Found: 299.1153.
114.2, 111.9, 105.8, 70.6, 58.7 , 38.3, 26.2; IR (NaCl) ν: 2927,
1651, 1592, 1541, 1495, 1472, 1456, 1429, 1396, 1339, 1300 cm-
1; HRMS Calculated for [C19H20N2O2+Na]+: 331.1417, Found:
331.1413.
55
3-(2-Methoxyethyl)-6-phenylindolizine-1-carbonitrile (7j’)
1
PE/EA = 6/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ 115
8.19 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 7.4 Hz, 2H),
tert-Butyl 3-(2-methoxyethyl)indolizine-1-carboxylate (7o)
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Organic & Biomolecular Chemistry
DOI: 10.1039/C7OB00P98a0gAe 8 of 9
1
476; (c) J. Ewing, G. K. Hughes, E. Ritchie, W. C. Taylor, Nature
PE/EA = 6/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
8.14 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.03 (s, 1H),
7.02 – 6.97 (m, 1H), 6.71 (t, J = 6.6 Hz, 1H), 3.73 (t, J = 6.7 Hz,
2H), 3.37 (s, 3H), 3.08 (t, J = 6.7 Hz, 2H), 1.62 (s, 9H); 13C NMR
(CDCl3, 100 MHz): δ 164.7, 135.3, 123.0, 122.3, 121.0, 119.9,
114.6, 112.0, 104.7, 79.4, 70.9, 58.9, 28.7, 26.5; IR (NaCl) ν:
2975, 2928, 1683, 1636, 1547, 1510, 1479, 1454, 1422, 1390,
1366, 1311 cm-1; HRMS Calculated for [C16H21NO3+Na]+:
298.1414, Found: 298.1409.
60
65
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5
70
10
3-(2-Methoxyethyl)-2-phenylindolizine-1-carbaldehyde (7p)
1
PE/EA = 4/1; yellow sticky oil; H NMR(CDCl3, 400 MHz): δ
9.73 (s, 1H), 8.48 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 6.9 Hz, 1H),
7.47-7.41 (m, 5H), 7.28 – 7.23 (m, 1H), 6.93 (t, J = 6.5 Hz, 1H),
75
15 3.60 (t, J = 6.5 Hz, 2H), 3.29 (s, 3H), 3.12 (t, J = 6.5 Hz, 2H); 13
C
NMR (CDCl3, 100 MHz): δ 185.4, 135.5, 132.8, 132.1, 130.8,
128.3, 127.6, 124.5, 123.9, 121.6, 120.1, 114.1, 111.8, 71.7, 58.8,
24.8; IR (NaCl) ν: 3056, 2926, 2875, 2826, 2743, 1716, 1649,
1624, 1555, 1526, 1502, 1450, 1400, 1381, 1339, 1303 cm-1;
20 HRMS Calculated for [C18H17NO2+Na]+: 302.1151, Found:
302.1150.
80
3
85
(3-(2-Methoxyethyl)-2-(p-tolyl)indolizin-1-
yl)(phenyl)methanone (7q)
25 PE/EA = 3/1; yellow solid; m. p. 151 - 152 oC; 1H NMR(CDCl3,
400 MHz): δ 8.18 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H),
7.48 (d, J = 6.6 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.10 – 7.04 (m,
3H), 7.00 (d, J = 7.9 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 6.81 (t, J
= 6.8 Hz, 1H), 3.60 (t, J = 6.7 Hz, 2H), 3.30 (s, 3H), 3.12 (t, J =
30 6.7 Hz, 2H), 2.23 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 192.0,
140.7, 136.7, 136.0, 131.7, 130.7, 130.6, 130.4, 129.3, 128.3,
127.3, 123.6, 122.5, 121.3, 119.9, 112.9, 112.0, 71.7, 58.8, 25.1,
21.0; IR (NaCl) ν: 3023 2922, 2873, 1632, 1609, 1576, 1544,
1524, 1495, 1447, 1424, 1394, 1348, 1317 m-1; HRMS
35 Calculated for [C25H23NO2+Na]+: 392.1621, Found: 392.1618.
90
4
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This work was supported by grants from the NSFC (No.:
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Organic & Biomolecular Chemistry
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