Metal-free aminothiation of alkynes: Three-component tandem annulation toward indolizine thiones from 2-alkylpyridines, ynals, and elemental sulfur

Article abstract of DOI:10.1021/acs.joc.9b01802

A metal-free three-component annulation reaction for the synthesis of indolizine thiones via tandem C-C/C-N/C-S bond formation was developed. Various 2-alkylpyridines with aromatic ynals and elemental sulfur proceeded smoothly under catalyst-free conditions, and the desired products were obtained in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.9b01802

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Note
Metal-Free Aminothiation of Alkynes: Three-Component
Tandem Annulation toward Indolizine Thiones
from 2-Alkylpyridines, Ynals, and Elemental Sulfur
Zhengwang Chen, Pei Liang, Fan Xu, Zhen Deng, Lipeng Long, Guotian Luo, and Min Ye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01802 • Publication Date (Web): 23 Sep 2019
Downloaded from pubs.acs.org on September 23, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Metal-Free Aminothiation of Alkynes:
Three-Component Tandem Annulation toward
Indolizine Thiones from 2-Alkylpyridines, Ynals,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
and Elemental Sulfur
Zhengwang Chen,* Pei Liang, Fan Xu, Zhen Deng, Lipeng Long, Guotian Luo, Min Ye*
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal
University, Ganzhou 341000, P.R. China
E-mail: chenzwang@126.com; yemin811@gnnu.cn
R1
R1
S8
O
H
S8
I2 (10 mol%)
N
R1
DMF, 80 oC, 4 h
N
DMF, 80 oC, 1 h
N
R2
R2
R2
S
R1 = Ester or ketone group
R1 = Cyano or amide group
S
35 examples
15 examples
Metal-free
Elemental sulfur as S source
C-C and C-X bonds formation
One-pot multicomponent reaction
Good functional group tolerance
Abstract: A metal-free three-component annulation reaction for the synthesis of
indolizine thiones via tandem C-C/C-N/C-S bonds formation was developed. Various
2-alkylpyridines with aromatic ynals and elemental sulfur proceeded smoothly under
catalyst-free conditions, and the desired products were obtained in moderate to
excellent yields.
Indolizines are privileged structural motif occurring frequently in natural products,
synthetic pharmaceuticals, and materials chemistry.1 Many substituted indolizines
exhibit remarkable bioactivity, such as antibacterial, antifungal, antioxidant,
anticancer, and antitumor activity.2 As a result, much research has focused on access
to indolizine skeletons based on pyridine3 or pyrrole derivatives.4 Among these
approaches, transition metal catalysts, including copper,5 rhodium,6 palladium,7 gold,8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 39
1
2
3
4
5
6
7
8
9
platinum,9 cobalt,10 and iron,11 have been widely utilized for the synthesis of
indolizine derivatives through intramolecular or intermolecular annulation. However,
in view of environmental and economical viewpoints, the development of efficient
and complementary approaches to synthesize indolizine frameworks under metal-free
conditions is highly desirable.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Elemental sulfur is a nontoxic and inexpensive agent, which has been widely used
for the preparation of sulfur-containing molecules over the past decades.12
Multicomponent reaction (MCR) was a powerful tool to generate relatively complex
heterocyclic scaffolds in a straightforward and atom-economical manners by forming
multiple bonds in a single step procedure. Very recently, Cao group13 and our group14
have reported three-component tandem reactions for the formation of functionalized
indolizines from 2-pyridylacetates, ynals and coupling partners (Schemes 1a and 1b).
Herein we report three-component annulation for the construction of indolizine
thiones from 2-alkylpyridines, ynals, and elemental sulfur via a Knoevenagel
condensation and aminothiation tandem process under metal-free conditions by
forming the C-C, C-N and C-S bonds in one pot (Scheme 1c).
Scheme 1. Synthesis of Indolizines from 2-Alkylpyridines, Ynals and Coupling
Partners
ACS Paragon Plus Environment

Page 3 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
R1
Previous work
O
Acid-catalyzed
R3XH
R1
(a)
(b)
H
N
N
R2
R2
X = O or S
R3X
O
OR1
O
Catalyst-free
O
O2
H
N
O
N
OR1
R2
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
This work
O
Metal-free
S8
(c)
R1
H
N
S
N
R2
R2
After obtaining the optimal reaction conditions (details in the Supporting
Information), we subsequently investigated the substrate scope of this
three-component annulation reaction. As illustrated in Scheme 2, various ynals were
firstly explored, and indolizine thiones were achieved in moderate to good yields
(3b-s). In general, both the electron-donating and electron-withdrawing groups
substituted ynals worked well to furnish the desired products in 50%-86% yields. The
reactants with a methyl or methoxy at the ortho-position of benzene ring had very
little impact on the efficiency of this reaction (3c and 3i). The disubstituted substrates
proceeded well to furnish the products in 70% and 52% yields, respectively (3d and
3n). Ynals bearing both the weak and strong electron-poor groups reacted smoothly
(3j-s). Unluckily, aliphatic ynal did not afford the corresponding product in this
transformation (3t). We next examined the scope of substituted 2-alkylpyridines and
ynals in this tandem process. A series of pyridines with ester groups were compatible
with the standard conditions, resulting in the formation of the corresponding product
in good yields (3u-3ae). For example, the ester groups bearing primary, secondary
and tertiary alkyl groups reacted successfully and delivered the products in 68%-86%
yields (3v-y). To our delight, the substrates containing the unsaturated alkene or
alkyne groups participated well in the tandem reaction, providing the desired products
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 39
1
2
3
4
5
6
7
8
9
in good yields and showing good functional group tolerance (3z-3ae). It is worth
mentioning that 2-pyridyl acetone was suitable and formed 3af in 88% yield.
Furthermore, both the electron-rich and electron-deficient groups on the pyridine ring
could be applied to the indolizine thione scaffold (3ag and 3ah). Gratifyingly, the
reaction could be performed on large scale synthesis and achieved the product in good
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield (3a).
Scheme 2. Substrate Scope of 2-Alkylpyridines and Ynalsa
COR2
O
S8
R1
H
R1
R3
N
COR2
DMF, 80 oC, 1 h
N
S
R3
1
2
3
b
COOEt
COOEt
3a
3b
: R' = H, 75%
COOEt
: R' = 3-Me, 73%
N
N
S
O
N
3c: R' = 2-Me, 71%
R'
3d
: R' = 3,5-(Me)2, 70%
O
S
3g
S
t
3e
: R' = 4- Bu, 86%
: 61%
3f
: 80%
3h
3n
3o
: R' = 4-OMe, 68%
: R' = 3,5-(F)2, 52%
: R' = 3-CF3, 65%
COOEt
3i
3j
: R' = 2-OMe, 60%
3p
3q
: R' = 4-F, 54%
: R' = 4-Ac, 50%
: R' = CO2Me, 53%
: R' = CN, 54%
N
3k
: R' = 3-F, 81%
: R' = 4-Cl, 52%
S
3l
3m
3r
3s
3t
: 0%
: R' = 4-Br, 55%
: R' = NO2, 58%
O
O
O
O
S
COOMe
O
O
CF3
N
N
N
N
Ph
S
Ph
: 86%
Ph
Ph
S
S
3u
3v
: 84%
O
3x
: 79%
O
3w
: 81%
O
O
O
S
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
S
S
S
3y
3z
3aa
: 68%
: 80%
: 72%
O
3ab
: 63%
O
O
O
O
O
O
N
N
N
N
Ph
S
Ph
Ph
S
N
S
S
3af
: 88%
3ac
3ad
3ae
: 78%
: 73%
: 69%
COOMe
COOMe
COOMe
COOMe
N
N
N
Br
S
Ph
Ph
S
COOMe
S
S
3ag
3ah
3ai
: 61%
: 58%
: 54%
3aj
: 77%
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol) with S8 (12.8 mg, 0.05 mmol) in
DMF (1.0 mL) under argon at 80 oC for 1 h. b 2 mmol scale of the reaction.
Besides esters and ketone, the heterocycle bearing nitrile and amides were
ACS Paragon Plus Environment

Page 5 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
important to the biological activities. However, no corresponding products were
detected under the catalyst-free conditions when 2-pyridylacetonitriles or
2-pyridylacetamides replaced 2-pyridylacetates as the activating moieties. Fortunately,
the desired products were obtained in satisfactory yields when catalytic amounts of I2
was added.15 We subsequently concentrated on the generality of the multicomponent
reaction under the I2-catalyzed conditions (Scheme 3). A variety of substituents were
compatible with the conditions, such as methyl, tert-butyl, phenyl, methoxy, fluoro,
chloro, bromo, and trifluoromethyl groups (4b-j). Interestingly, the ynal with a
naphthalene moiety led to the product in excellent yield (4e). Notably, the heterocycle
ynal was also perfectly tolerated in the reaction, giving the thienyl produced 4k in
53% yield. As an alternative to nitrile, we found that both the aromatic and aliphatic
amides were also applicable to afford indolizine thiones in good yields (4l-o).
Scheme 3. I2-Catalyzed Aminothiation of 2-Alkylpyridines with Ynals and
Elemental Sulfura
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
S8
O
I2 (10 mol%)
R1
CN
CN
N
H
DMF, 80 oC, 4 h
N
R2
R2
S
4
1
2
CN
4f
: R' = 2-OMe, 71%
4a
4b
: R' = H, 85%
4g
: R' = 4-F, 56%
N
: R' = 3-Me, 62%
N
R'
4h
: R' = 4-Cl, 60%
: R' = 4-Br, 52%
: R' = 3-CF3, 71%
t
4c
4d
: R' = 4- Bu, 65%
S
4i
4j
: R' = Ph, 57%
S
4e
: 93%
Ph
O
NH
O
NH
4m
: R' = H, 61%
N
4n
: R' = 3-Me, 75%
N
R'
S
N
S
4o
: R' = 4-Cl, 82%
S
Ph
S
4k
4l
: 72%
: 53%
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), S8 (12.8 mg, 0.05 mmol) with I2
(10 mol%) in DMF (1.0 mL) under argon at 80 oC for 4 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 39
1
2
3
4
5
6
7
8
9
To gain insight into the reaction mechanism, some control experiments were
conducted and the results were summarized in Scheme 4. At first, the reaction of
2-pyridyl acetonitrile 1p and 2o under the catalyst-free conditions afforded 5a in 93%
yield (Scheme 4a).16 Next, the intermediate 5a was converted into the desired product
4j in 85% yield catalyzed by I2 (Scheme 4b). These results proved that the
three-component annulation underwent an enyne intermediate. Although an enyne
intermediate has been proposed for the formation of indolizines, it has not been
isolated in previous work.13-14 The reaction of 5b and elemental sulfur with or without
I2 could not yield 3a, which inferred that the direct thiation of the carbonyl group was
not involved in this process (Scheme 4c). In order to determine the catalytic role of I2,
some additives were added to the reaction system, and acids were advantageous for
the formation of 4a. The results indicated that this transformation may be an
acid-catalyzed process (Scheme 4d).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Control Experiments
O
CN
CF3
H
(a)
F3
C
CN
N
N
DMF, 80 oC, 1 h
5a
: 93%
1p
2o
CN
CF3
CN
CF3
I2 (10 mol%)
(b)
S8
N
N
DMF, 80 oC, 4 h
S
: 85%
5a
4j
COOEt
COOEt
with or without I2
DMF, 80 oC, 1 h
(c)
S8
N
N
Ph
O
S
, not detected
3a
5b
CN
S8
O
A (10 mol%)
H
(d)
N
CN
Ph
DMF, 80 oC, 4 h
Ph
N
S
4a
4a
(1) A = KI, , 0%
1p
2a
4a
(2) A = TFA, , 80%
4a
(3) A = HI, , 65%
Based on above results and previous reports, a plausible mechanism was proposed
in Scheme 5. Initially, an enyne intermediate A was formed through Knoevenagel
ACS Paragon Plus Environment

Page 7 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
condensation of 1a with 2a. Then the intermediate A underwent intramolecular
nucleophilic attack and activation of elemental sulfur to render intermediate B. Finally,
the indolizine thione product 3a was formed via the cleavage of disulfide bond
(Scheme 5a). On the other hand, 5a in cis configuration was isomerized into 5a’
through electrophilic addition and elimination process, which was subsequently
converted into the desired product 4j via aminothiation with elemental sulfur (Scheme
5b).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Possible Reaction Mechanism
CO2Et
CO2Et
CO2Et
N
(a)
1a
2a
S-
N
N
-
H2O
S
- Sn-1
S
Sn-3
S
Ph
Ph
Ph
Sn
A
B
3a
CN
H
CN
+
I2
H2O
N
N
CN
CF3
H+
HI
-
(b)
5a
4j
H
N
5a'
D
C
CF3
CF3
In conclusion, we have developed an efficient tandem annulation for the synthesis
of indolizine thiones from 2-alkylpyridines with ynals and elemental sulfur. The
advantages of the present method include metal-free process, user-friendly elemental
sulfur as the sulfur source, one-pot three-component reaction, tandem C-C/C-N/C-S
bonds formation, readily available starting materials, wide substrate scope, high
functional group tolerance, etc. The ability to incorporate ester, carbonyl, cyano and
amide groups into the products makes this reaction potentially valuable for further
synthetic transformation. Further investigations on the detailed mechanism are
currently underway in our laboratory.
EXPERIMENTAL SECTION
1
13
General Information: H and C{1H} NMR spectra were obtained on a 400 and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 39
1
2
3
4
5
6
7
8
9
100 MHz NMR spectrometer. The chemical shifts are referenced to signals at 7.26
and 77.0 ppm, respectively, and chloroform was used as the solvent with TMS as the
internal standard unless otherwise noted. Mass spectra were recorded on a GC-MS
spectrometer at an ionization voltage of 70 eV equipped with a DB-WAX capillary
column (internal diameter: 0.25 mm, length: 30 m). Elemental analyses were
performed with a Vario EL elemental analyzer. High resolution mass spectra (HRMS)
(TOF) were measured using an electrospray ionization (ESI) mass spectrometry.
Silica gel (300-400 mesh) was used for flash column chromatography, eluting (unless
otherwise stated) with ethyl acetate/petroleum ether (PE) (60-90 oC) mixture.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The 2-pyridylacetates 1a, 1b, 1o, 2-pyridylacetone 1m, 2-pyridylacetonitrile 1p,
and propargyl aldehydes 2a were commercially available from Sigma-Aldrich China.
Substituted 2-pyridylacetates 1c-1l and 1n, 2-pyridylacetamides 1q-1r, and aryl
substituted propargyl aldehydes 2b-2s have been prepared using the literature
procedure.17 The typical experimental procedures for the preparation of starting
materials and the characterization data for new compounds are given below.
General procedure for the preparation of 2-pyridylacetates (1c-1l and 1n). To
a suspended solution of 2-pyridylacetic acid hydrochloride (173 mg, 1.0 mmol) and
alcohol (1.5 mmol) in 5 mL dichloromethane was added triethylamine (0.27 mL, 2.0
mmol), 1,3-dicyclohexylcarbodiimide (DCC) (210 mg, 1.0 mmol) and a catalytic
o
amount of 4-(dimethylamino)pyridine (DMAP) (6.1 mg, 0.05 mmol) at 25 C. The
o
reaction mixture was stirred in a preheated oil bath at 45 C for 12 h, the reaction
mixture was filtered to remove 1,3-dicyclohexylurea. The filtrate was washed with
ACS Paragon Plus Environment

Page 9 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
water (3×5 mL), dried with MgSO4 and concentrated under reduced pressure, the
crude product was purified by column chromatography to give the pure sample.
pent-4-yn-2-yl 2-(pyridin-2-yl)acetate (1l). Yellow oil (187 mg, 92%); Rf = 0.51
(ethyl acetate/petroleum ether = 1:4); 1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J =
4.8 Hz, 1H), 7.53 (td, J = 7.7, 1.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.2,
5.2 Hz, 1H), 4.97 – 4.89 (m, 1H), 3.73 (s, 2H), 2.38 – 2.31 (m, 2H), 1.91 (t, J = 2.7
Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 169.6, 153.9,
149.0, 136.3, 123.5, 121.8, 79.2, 70.3, 68.9, 43.5, 25.1, 18.6. MS (EI) m/z: 203, 188,
170, 158, 144, 131, 120, 92, 65, 41. Anal. Calcd. for C12H13NO2 C, 70.92; H, 6.45; N,
6.89. Found: C, 70.71; H, 6.50; N, 6.83.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the preparation of 2-pyridylacetamides (1q-1r). To a
suspended solution of 2-pyridylacetic acid hydrochloride (173 mg, 1.0 mmol), amine
(1.0 mmol), 1-hydroxybenzotriazole (HOBt) (135 mg, 1.0 mmol), and
ethyldiisopropylamine (DIPEA) (259 mg, 2.0 mmol) in 5 mL dichloromethane was
added
slowly
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
o
(EDCl.HCl) (192 mg, 1.0 mmol) at 0 C. Then the reaction mixture was stirred
overnight at room temperature. After completion of the reaction, the mixture was
washed with water (3×5 mL), dried with Na2SO4 and concentrated under reduced
pressure, the crude product was purified by column chromatography to give the pure
sample.
General procedure for the preparation of aryl substituted propiolaldehydes
(2b-2s). For the synthesis of F: To a stirred of substituted iodobenzene (1 mmol) in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 39
1
2
3
4
5
6
7
8
9
triethylamine (5 mL) under argon were sequentially added Pd(PPh3)2Cl2 (14 mg, 2
mol%), and CuI (7.6 mg, 4 mol%) at room temperature. The mixture was allowed to
stirred for 10 min. Then propargyl alcohol (1.1 mmol) was added. The mixture was
allowed to stir overnight. After the reaction was finished, water (5 mL) was added and
the solution was extracted with ethyl acetate (3×5 mL), the combined extract was
dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by
column chromatography to give the aryl substituted propargyl alcohol F (The yields
were between 90% to 99%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For the synthesis of (2b-2s): MnO2 (652 mg, 7.5 mmol) was added to a solution of
aryl substituted propargyl alcohol F (0.5 mmol) in dichloromethane (5 mL) at room
temperature. The mixture was allowed to stir overnight. Then the solid was filtered,
and the solvent were removed under reduced pressure. The residue was purified by
column chromatography to give the pure aryl substituted propiolaldehydes.
General Procedure for the Preparation of indolizine thiones (3a-3aj). A
mixture of 2-pyridylacetate (0.2 mmol), ynal (0.2 mmol), and elemental sulfur (12.8
mg, 0.05 mmol) in DMF (1.0 mL) was stirred in a preheated oil bath at 80 °C for 1 h
in a sealed tube under argon atmosphere. After the reaction was finished, water (5
mL) was added and the solution was extracted with ethyl acetate (3×5 mL), and the
combined extract was dried with anhydrous MgSO4. Solvent was removed, and the
residue was separated by column chromatography to give the pure sample.
Large Scale Synthesis. An oven-dried 25 mL screw cap test tube was charged with
a magnetic stir bar, 1a (330 mg, 2 mmol), 2a (260 mg, 2 mmol), elemental sulfur (128
ACS Paragon Plus Environment

Page 11 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mg, 0.5 mmol), and DMF (6.0 mL). The tube was then evacuated and backfilled with
argon three times. Then, the tube was placed in a preheated oi bath at 80 °C for 1 h.
After cooling to room temperature, water (10 mL) was added and the solution was
extracted with ethyl acetate (3×10 mL), the combined extract was dried with
anhydrous MgSO4. Solvent was removed, and the residue was separated by column
chromatography (ethyl acetate/petroleum ether = 1:6) to give 3a (464 mg, 75%).
ethyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3a). Red solid (56 mg,
90%); mp 108−110 °C; Rf = 0.55 (ethyl acetate/petroleum ether = 1:6); 1H NMR (400
MHz, CDCl3): δ = 11.27 (d, J = 7.1 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H),
7.65 – 7.60 (m, 1H), 7.58 – 7.54 (m, 2H), 7.49 – 7.44 (m, 1H), 7.40 (t, J = 7.3 Hz, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.19 (t, J = 7.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). C{1H}
NMR (100 MHz, CDCl3): δ = 210.1, 163.7, 149.8, 141.7, 134.5, 130.3, 129.7, 129.0,
128.5, 127.9, 127.4, 119.7, 116.6, 107.5, 60.3, 14.4. MS (EI) m/z: 309, 280, 264, 236,
204, 121, 89, 77, 51. HRMS (ESI): calcd. for C18H16NO2S [M+H]+ 310.0896; found
310.0889.
ethyl 3-(3-methylphenylcarbonothioyl)indolizine-1-carboxylate (3b). Red solid
1
(47 mg, 73%); mp 112−114 °C; Rf = 0.52 (ethyl acetate/petroleum ether = 1:10); H
NMR (400 MHz, CDCl3): δ = 11.27 (d, J = 7.0 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.69
(s, 1H), 7.64 – 7.60 (m, 1H), 7.41 (s, 1H), 7.32 (d, J = 4.1 Hz, 1H), 7.28 (d, J = 4.6 Hz,
2H), 7.19 (t, J = 6.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.38 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 210.4, 163.7, 149.8, 141.7, 137.6, 134.5,
130.5, 130.2, 129.2, 129.0, 127.6, 127.4, 125.6, 119.6, 116.5, 107.4, 60.3, 21.3, 14.44.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 39
1
2
3
4
5
6
7
MS (EI) m/z: 323, 294, 250, 204, 135, 89, 78, 51. HRMS (ESI): calcd. for
C19H18NO2S [M+H]+ 324.1053; found 324.1052.
8
9
ethyl 3-(2-methylphenylcarbonothioyl)indolizine-1-carboxylate (3c). Red liquid
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(46 mg, 71%); Rf = 0.56 (ethyl acetate/petroleum ether = 1:8); H NMR (400 MHz,
CDCl3): δ = 11.50 (d, J = 7.0 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H), 7.68 (t, J = 7.9 Hz,
1H), 7.46 (s, 1H), 7.31 – 7.26 (m, 2H), 7.22 (dd, J = 6.3, 3.6 Hz, 3H), 4.35 (q, J = 7.1
Hz, 2H), 2.21 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ =
211.3, 163.6, 149.0, 141.6, 134.3, 132.8, 130.6, 130.3, 128.5, 127.9, 127.6, 127.0,
125.4, 119.7, 117.1, 108.0, 60.3, 19.3, 14.4. MS (EI) m/z: 323, 294, 250, 204, 135, 89,
78, 51. HRMS (ESI): calcd. for C19H18NO2S [M+H]+ 324.1053; found 324.1048.
ethyl 3-(3,5-dimethylphenylcarbonothioyl)indolizine-1-carboxylate (3d). Red
solid (47 mg, 70%); mp 101−103 °C; Rf = 0.58 (ethyl acetate/petroleum ether = 1:6);
1H NMR (400 MHz, CDCl3): δ = 11.26 (dt, J = 7.1, 1.0 Hz, 1H), 8.53 – 8.45 (m, 1H),
7.70 (s, 1H), 7.62 (ddd, J = 8.7, 6.9, 1.1 Hz, 1H), 7.21 – 7.16 (m, 3H), 7.11 (s, 1H),
4.37 (q, J = 7.1 Hz, 2H), 2.37 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H). C{1H} NMR (100
13
MHz, CDCl3): δ = 210.9, 163.8, 149.9, 141.7, 137.4, 134.6, 131.4, 130.1, 129.1,
127.5, 126.3, 119.6, 116.4, 107.4, 60.3, 21.2, 14.4. MS (EI) m/z: 337, 308, 292, 264,
232, 204, 149, 115, 89, 78, 51. HRMS (ESI): calcd. for C20H20NO2S [M+H]+
338.1209; found 338.1216.
ethyl 3-(4-(tert-butyl)phenylcarbonothioyl)indolizine-1-carboxylate (3e). Red
solid (63 mg, 86%); mp 71−73 °C; Rf = 0.66 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.25 (d, J = 7.1 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H),
ACS Paragon Plus Environment

Page 13 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.75 (s, 1H), 7.64 – 7.59 (m, 1H), 7.56 – 7.52 (m, 2H), 7.44 – 7.40 (m, 2H), 7.19 (td, J
= 7.0, 1.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.41 (d, J = 7.1 Hz, 3H), 1.37 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ = 210.2, 163.8, 153.4, 147.1, 141.6, 134.5, 130.0,
129.0, 128.6, 127.4, 124.9, 119.6, 116.3, 107.3, 60.3, 34.8, 31.1, 14.4. MS (EI) m/z:
365, 336, 320, 232, 204, 147, 124, 78, 44. HRMS (ESI): calcd. for C22H24NO2S
[M+H]+ 366.1522; found 366.1527.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 3-(naphthalene-1-carbonothioyl)indolizine-1-carboxylate (3f). Red solid
1
(57 mg, 80%); mp 115−117 °C; Rf = 0.52 (ethyl acetate/petroleum ether = 1:6); H
NMR (400 MHz, CDCl3): δ = 11.64 (d, J = 6.6 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.88
(t, J = 7.5 Hz, 3H), 7.73 – 7.68 (m, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.46 – 7.36 (m, 4H),
7.30 (td, J = 7.0, 1.2 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 1.31 (d, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 209.3, 163.5, 146.6, 141.7, 135.2, 133.5, 130.8,
130.3, 129.1, 128.3, 128.0, 127.7, 126.4, 125.9, 125.5, 124.9, 124.3, 119.8, 117.3,
108.2, 60.3, 14.3. MS (EI) m/z: 359, 330, 284, 254, 156, 142, 104, 78, 44. HRMS
(ESI): calcd. for C22H18NO2S [M+H]+ 360.1053; found 360.1055.
ethyl 3-(benzo[d][1,3]dioxole-5-carbonothioyl)indolizine-1-carboxylate (3g).
Red solid (43 mg, 61%); mp 133−135 °C; Rf = 0.35 (ethyl acetate/petroleum ether =
1:10); 1H NMR (400 MHz, CDCl3): δ = 11.08 (d, J = 7.1 Hz, 1H), 8.46 (d, J = 8.8 Hz,
1H), 7.71 (s, 1H), 7.63 – 7.56 (m, 1H), 7.22 (d, J = 1.2 Hz, 1H), 7.18 – 7.09 (m, 2H),
6.82 (d, J = 8.1 Hz, 1H), 6.05 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 208.6, 163.8, 149.8, 147.5, 144.1, 141.7,
134.5, 129.8, 128.5, 127.4, 123.9, 119.7, 116.2, 109.9, 107.4, 107.2, 101.6, 60.3, 14.4.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 39
1
2
3
4
5
6
7
MS (EI) m/z: 353, 324, 308, 280, 232, 204, 177, 139, 110, 89, 78, 51. HRMS (ESI):
calcd. for C19H16NO4S [M+H]+ 354.0795; found 354.0791.
8
9
ethyl 3-(4-methoxyphenylcarbonothioyl)indolizine-1-carboxylate (3h). Red
solid (46 mg, 68%); mp 118−120 °C; Rf = 0.48 (ethyl acetate/petroleum ether = 1:6);
1H NMR (400 MHz, CDCl3): δ = 11.11 (d, J = 7.1 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H),
7.71 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.62 – 7.57 (m, 1H), 7.19 – 7.14 (m, 1H), 6.94
(d, J = 8.8 Hz, 2H), 4.42 – 4.36 (m, 2H), 3.90 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 209.2, 163.9, 161.7, 142.6, 141.6, 134.4, 131.0, 129.6,
128.4, 127.3, 119.6, 116.0, 113.2, 107.0, 60.2, 55.4, 14.4. MS (EI) m/z: 339, 310, 267,
207, 133, 111, 89, 73, 44. HRMS (ESI): calcd. for C19H18NO3S [M+H]+ 340.1002;
found 340.1022.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 3-(2-methoxyphenylcarbonothioyl)indolizine-1-carboxylate (3i). Red solid
(41 mg, 60%); mp 145−147 °C; Rf = 0.28 (ethyl acetate/petroleum ether = 1:10); 1H
NMR (400 MHz, CDCl3): δ = 11.47 (d, J = 7.0 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.65
(t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.40 – 7.35 (m, 1H), 7.29 (dd, J = 7.5, 1.5 Hz, 1H),
7.25 – 7.20 (m, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 4.35 (q, J = 7.1
Hz, 2H), 3.73 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ =
207.8, 163.8, 154.2, 141.5, 138.6, 134.8, 130.2, 129.6, 129.0, 128.7, 127.6, 120.5,
119.7, 116.8, 111.5, 107.9, 60.3, 55.8, 14.4. MS (EI) m/z: 339, 306, 278, 260, 234,
204, 89, 78, 45. HRMS (ESI): calcd. for C19H18NO3S [M+H]+ 340.1002; found
340.1000.
ethyl 3-(4-fluorophenylcarbonothioyl)indolizine-1-carboxylate (3j). Red solid
ACS Paragon Plus Environment

Page 15 of 39
The Journal of Organic Chemistry
1
2
3
4
1
(35 mg, 54%); mp 129−131 °C; Rf = 0.46 (ethyl acetate/petroleum ether = 1:10); H
NMR (400 MHz, CDCl3): δ = 11.22 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.67
– 7.62 (m, 2H), 7.61 – 7.55 (m, 2H), 7.23 – 7.18 (m, 1H), 7.10 (t, J = 8.6 Hz, 2H),
4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 208.1, 163.8 (d, J = 250 Hz), 163.7, 145.9 (d, J = 3 Hz), 141.8, 134.5, 130.7 (d, J
= 8 Hz), 130.4, 128.7, 127.4, 119.7, 116.7, 114.9 (d, J = 21 Hz), 107.6, 60.4, 14.4. MS
(EI) m/z: 327, 298, 282, 254, 232, 204, 139, 107, 95, 78, 51. HRMS (ESI): calcd. for
C18H15FNO2S [M+H]+ 328.0802; found 328.0801.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 3-(3-fluorophenylcarbonothioyl)indolizine-1-carboxylate (3k). Red solid
1
(53 mg, 81%); mp 132−134 °C; Rf = 0.58 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.27 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.69
– 7.63 (m, 2H), 7.37 (td, J = 7.8, 5.7 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.22 (td, J = 7.0,
1.3 Hz, 1H), 7.19 – 7.13 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 207.3, 163.6, 162.1 (d, J = 245 Hz), 151.3 (d,
J = 7 Hz), 141.9, 134.4, 130.6, 129.3 (d, J = 8 Hz), 128.9, 127.4, 124.9 (d, J = 2 Hz),
119.8, 116.9, 116.4 (d, J = 21 Hz), 115.6 (d, J = 23 Hz), 107.9, 60.4, 14.4. MS (EI)
m/z: 327, 298, 282, 254, 232, 204, 139, 107, 89, 78, 43. HRMS (ESI): calcd. for
C18H15FNO2S [M+H]+ 328.0802; found 328.0805.
ethyl 3-(4-chlorophenylcarbonothioyl)indolizine-1-carboxylate (3l). Red solid
1
(35 mg, 52%); mp 135−137 °C; Rf = 0.60 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.25 (d, J = 7.1 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.69
– 7.64 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 7.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 39
1
2
3
4
5
6
7
8
9
13
6.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). C{1H} NMR (100
MHz, CDCl3): δ = 207.9, 163.6, 148.0, 141.9, 136.0, 134.5, 130.5, 129.9, 128.7,
128.2, 127.5, 119.8, 116.8, 107.8, 60.4, 14.4. MS (EI) m/z: 343, 314, 270, 235, 204,
155, 117, 89, 78, 43. HRMS (ESI): calcd. for C18H14ClNNaO2S [M+Na]+ 366.0326;
found 366.0331.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 3-(4-bromophenylcarbonothioyl)indolizine-1-carboxylate (3m). Red solid
1
(42 mg, 55%); mp 133−135 °C; Rf = 0.48 (ethyl acetate/petroleum ether = 1:10); H
NMR (400 MHz, CDCl3): δ = 11.27 (d, J = 7.1 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.70
– 7.66 (m, 2H), 7.58 – 7.54 (m, 2H), 7.48 – 7.45 (m, 2H), 7.24 (td, J = 7.0, 1.3 Hz,
1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz,
13
CDCl3): δ = 207.7, 163.6, 148.4, 141.9, 134.3, 131.1, 130.6, 130.0, 128.7, 127.4,
124.2, 119.8, 116.8, 107.8, 60.4, 14.4. MS (EI) m/z: 388, 360, 342, 314, 279, 234, 204,
132, 117, 95, 78, 51. HRMS (ESI): calcd. for C18H15BrNO2S [M+H]+ 388.0001; found
388.0009.
ethyl 3-(3,5-difluorophenylcarbonothioyl)indolizine-1-carboxylate (3n). Red
solid (36 mg, 52%); mp 150−152 °C; Rf = 0.48 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.27 (dt, J = 7.1, 1.0 Hz, 1H), 8.55 – 8.49 (m, 1H),
7.73 – 7.68 (m, 1H), 7.65 (s, 1H), 7.26 (t, J = 3.5 Hz, 1H), 7.09 – 7.04 (m, 2H), 6.91
(tt, J = 8.7, 2.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.39 (d, J = 7.1 Hz, 3H). C{1H}
13
NMR (100 MHz, CDCl3): δ = 204.9, 163.5, 162.1 (dd, J = 249, 12 Hz), 151.9 (t, J = 9
Hz), 142.1, 134.2, 131.1, 128.9, 127.5, 119.9, 117.2, 111.5 (d, J = 27 Hz), 108.4,
104.6 (t, J = 25 Hz), 60.5, 14.4. MS (EI) m/z: 345, 316, 300, 272, 232, 204, 157, 125,
ACS Paragon Plus Environment

Page 17 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
89, 78, 51. HRMS (ESI): calcd. for C18H14F2NO2S [M+H]+ 346.0708; found
346.0703.
7
8
9
ethyl 3-(3-(trifluoromethyl)phenylcarbonothioyl)indolizine-1-carboxylate (3o).
Red solid (49 mg, 65%); mp 154−156 °C; Rf = 0.54 (ethyl acetate/petroleum ether =
1:6); 1H NMR (400 MHz, CDCl3): δ = 11.30 (d, J = 7.0 Hz, 1H), 8.52 (d, J = 8.8 Hz,
1H), 7.82 (s, 1H), 7.70 (dd, J = 13.6, 7.0 Hz, 3H), 7.60 (s, 1H), 7.54 (t, J = 7.7 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H), 7.26 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). C{1H} NMR
(100 MHz, CDCl3): δ = 206.9, 163.5, 150.0, 142.0, 134.5, 131.3, 130.8, 130.5 (q, J =
33 Hz), 128.8, 128.4, 127.5, 126.0 (q, J = 4 Hz), 125.2 (q, J = 4 Hz), 123.8 (q, J = 271
Hz), 119.8, 117.1, 108.2, 60.4, 14.4. MS (EI) m/z: 377, 348, 332, 304, 232, 204, 189,
89, 78, 51. HRMS (ESI): calcd. for C19H15F3NO2S [M+H]+ 378.0770; found
378.0775.
ethyl 3-(4-acetylphenylcarbonothioyl)indolizine-1-carboxylate (3p). Red solid
1
(35 mg, 50%); mp 155−157 °C; Rf = 0.31 (ethyl acetate/petroleum ether = 1:6); H
NMR (400 MHz, CDCl3): δ = 11.33 (d, J = 7.0 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.00
(d, J = 8.2 Hz, 2H), 7.73 – 7.68 (m, 1H), 7.64 – 7.59 (m, 3H), 7.26 (s, 1H), 4.36 (q, J
= 7.1 Hz, 2H), 2.67 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 207.8, 197.6, 163.5, 153.5, 142.0, 137.4, 134.4, 130.8, 128.9, 128.4,
128.0, 127.5, 119.9, 117.1, 108.2, 60.5, 26.7, 14.4. MS (EI) m/z: 351, 322, 306, 279,
234, 204, 153, 117, 95, 78, 43. HRMS (ESI): calcd. for C20H18NO3S [M+H]+
352.1002; found 352.1006.
ethyl
3-(4-(methoxycarbonyl)phenylcarbonothioyl)indolizine-1-carboxylate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 39
1
2
3
4
5
6
7
8
9
(3q). Red solid (39 mg, 53%); mp 131−133 °C; Rf = 0.40 (ethyl acetate/petroleum
ether = 1:7); 1H NMR (400 MHz, CDCl3): δ = 11.32 (d, J = 7.0 Hz, 1H), 8.51 (d, J =
8.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.71 – 7.66 (m, 1H), 7.59 (d, J = 6.5 Hz, 3H),
7.25 (d, J = 3.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 207.8, 166.6, 163.5, 153.3, 141.9, 134.4,
130.8, 130.6, 129.2, 128.9, 128.2, 127.5, 119.8, 117.1, 108.1, 60.4, 52.3, 14.4. MS (EI)
m/z: 367, 338, 322, 294, 234, 204, 153, 117, 95, 63. HRMS (ESI): calcd. for
C20H18NO4S [M+H]+ 368.0951; found 368.0947.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl 3-(4-cyanophenylcarbonothioyl)indolizine-1-carboxylate (3r). Red solid
1
(36 mg, 54%); mp 162−164 °C; Rf = 0.26 (ethyl acetate/petroleum ether = 1:10); H
NMR (400 MHz, CDCl3): δ = 11.25 (d, J = 7.0 Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.69
– 7.63 (m, 3H), 7.56 – 7.52 (m, 2H), 7.50 (s, 1H), 7.22 (td, J = 7.1, 1.4 Hz, 1H), 4.31
13
(q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ =
205.7, 163.3, 153.0, 142.0, 134.2, 131.8, 131.2, 128.8, 128.7, 127.5, 119.9, 118.4,
117.4, 112.7, 108.5, 60.5, 14.4. MS (EI) m/z: 334, 305, 289, 261, 232, 204, 146, 114,
78, 51. HRMS (ESI): calcd. for C19H15N2O2S [M+H]+ 335.0849; found 335.0843.
ethyl 3-(4-nitrophenylcarbonothioyl)indolizine-1-carboxylate (3s). Red solid
1
(41 mg, 58%); mp 190−192 °C; Rf = 0.40 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.27 (d, J = 7.0 Hz, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.24
– 8.15 (m, 2H), 7.71 – 7.65 (m, 1H), 7.63 – 7.54 (m, 2H), 7.49 (s, 1H), 7.24 (td, J =
13
7.0, 1.4 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). C{1H} NMR
(100 MHz, CDCl3): δ = 205.1, 163.3, 154.6, 147.9, 142.1, 134.3, 131.3, 128.8, 128.7,
ACS Paragon Plus Environment

Page 19 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
127.5, 123.3, 120.0, 117.5, 108.7, 60.6, 14.4. HRMS (ESI): calcd. for C18H15N2O4S
[M+H]+ 355.0747; found 355.0752.
8
9
methyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3u). Red solid (49 mg,
84%); mp 128−130 °C; Rf = 0.50 (ethyl acetate/petroleum ether = 1:7); 1H NMR (400
MHz, CDCl3): δ = 11.28 (d, J = 7.1 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H),
7.67 – 7.62 (m, 1H), 7.58 – 7.55 (m, 2H), 7.46 (dt, J = 2.8, 2.1 Hz, 1H), 7.43 – 7.38
(m, 2H), 7.22 (td, J = 7.0, 1.4 Hz, 1H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 210.4, 164.1, 149.8, 141.8, 134.6, 130.3, 129.7, 129.0, 128.5, 127.9,
127.5, 119.6, 116.7, 107.1, 51.4. MS (EI) m/z: 295, 264, 235, 218, 131, 121, 89, 77,
51. HRMS (ESI): calcd. for C17H14NO2S [M+H]+ 296.0740; found 296.0729.
2,2,2-trifluoroethyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3v). Red
solid (62 mg, 86%); mp 126−128 °C; Rf = 0.47 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.22 – 11.18 (m, 1H), 8.45 – 8.39 (m, 1H), 7.73 (s,
1H), 7.69 – 7.64 (m, 1H), 7.58 (dd, J = 5.2, 3.2 Hz, 2H), 7.51 – 7.47 (m, 1H), 7.44 –
7.40 (m, 2H), 7.22 (td, J = 7.0, 1.4 Hz, 1H), 4.71 (q, J = 8.5 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 211.6, 161.7, 149.6, 141.6, 134.7, 130.7, 130.1, 129.0, 128.6,
128.0, 127.5, 123.1 (q, J = 276 Hz), 119.4, 116.8, 104.9, 59.9 (q, J = 36 Hz). MS (EI)
m/z: 363, 286, 235, 131, 121, 89, 77, 51. HRMS (ESI): calcd. for C18H13F3NO2S
[M+H]+ 364.0614; found 364.0611.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isopropyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3w). Red solid (52
mg, 81%); mp 100−102 °C; Rf = 0.38 (ethyl acetate/petroleum ether = 1:10); 1H NMR
(400 MHz, CDCl3): δ = 11.29 (d, J = 7.1 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.68 (s,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 39
1
2
3
4
5
6
7
8
9
1H), 7.66 – 7.61 (m, 1H), 7.60 – 7.56 (m, 2H), 7.49 – 7.45 (m, 1H), 7.43 – 7.39 (m,
2H), 7.20 (td, J = 7.0, 1.3 Hz, 1H), 5.27 (dt, J = 12.5, 6.3 Hz, 1H), 1.37 (d, J = 6.3 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ = 209.9, 163.3, 149.7, 141.7, 134.5, 130.2,
129.7, 129.0, 128.5, 127.9, 127.4, 119.7, 116.5, 108.0, 67.8, 22.0. MS (EI) m/z: 323,
280, 264, 236, 204, 132, 121, 89, 77, 43. HRMS (ESI): calcd. for C19H18NO2S
[M+H]+ 324.1053; found 324.1059.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cyclohexyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3x). Red solid (57
mg, 79%); mp 110−112 °C; Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR
(400 MHz, CDCl3): δ = 11.30 – 11.26 (m, 1H), 8.50 – 8.45 (m, 1H), 7.69 (s, 1H), 7.65
– 7.60 (m, 1H), 7.59 – 7.55 (m, 2H), 7.49 – 7.45 (m, 1H), 7.43 – 7.38 (m, 2H), 7.19
(td, J = 7.0, 1.4 Hz, 1H), 5.06 – 4.99 (m, 1H), 2.02 – 1.95 (m, 2H), 1.81 – 1.74 (m,
2H), 1.61 – 1.51 (m, 3H), 1.44 (dddd, J = 13.6, 10.6, 7.0, 3.3 Hz, 2H), 1.36 – 1.28 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 210.0, 163.2, 149.8, 141.6, 134.5, 130.2,
129.7, 129.1, 128.5, 127.8, 127.4, 119.7, 116.5, 108.1, 72.8, 31.8, 25.3, 23.8. HRMS
(ESI): calcd. for C22H22NO2S [M+H]+ 364.1366; found 364.1363.
tert-pentyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3y). Red liquid (48
1
mg, 68%); Rf = 0.63 (ethyl acetate/petroleum ether = 1:10); H NMR (400 MHz,
CDCl3): δ = 11.31 (d, J = 7.1 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.64 –
7.59 (m, 1H), 7.59 – 7.54 (m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.3 Hz, 2H),
7.19 (td, J = 7.0, 1.2 Hz, 1H), 1.93 (q, J = 7.5 Hz, 2H), 1.57 (s, 6H), 0.93 (t, J = 7.5
13
Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 209.6, 163.1, 149.7, 141.5, 134.4,
130.1, 129.7, 129.4, 128.5, 127.8, 127.4, 119.7, 116.4, 109.2, 83.6, 33.5, 25.8, 8.3.
ACS Paragon Plus Environment

Page 21 of 39
The Journal of Organic Chemistry
1
2
3
4
5
HRMS (ESI): calcd. for C21H22NO2S [M+H]+ 352.1366; found 352.1367.
6
7
allyl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3z). Red solid (51 mg,
8
9
1
80%); mp 102−104 °C; Rf = 0.51 (ethyl acetate/petroleum ether = 1:10); H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3): δ = 11.28 (d, J = 7.1 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.71 (s,
1H), 7.67 – 7.62 (m, 1H), 7.59 – 7.56 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.41 (t, J =
7.3 Hz, 2H), 7.24 – 7.19 (m, 1H), 6.10 – 5.97 (m, 1H), 5.37 (dd, J = 17.2, 1.3 Hz, 1H),
13
5.27 (dd, J = 10.4, 1.0 Hz, 1H), 4.82 (d, J = 5.7 Hz, 2H). C{1H} NMR (100 MHz,
CDCl3): δ = 210.3, 163.3, 149.7, 141.7, 134.5, 132.3, 130.3, 129.8, 129.0, 128.5,
127.9, 127.4, 119.6, 118.3, 116.6, 107.0, 64.9. MS (EI) m/z: 321, 280, 264, 236, 204,
121, 89, 77, 39. HRMS (ESI): calcd. for C19H16NO2S [M+H]+ 322.0896; found
322.0886.
hept-1-en-3-yl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3aa). Red
1
liquid (54 mg, 72%); Rf = 0.56 (ethyl acetate/petroleum ether = 1:12); H NMR (400
MHz, CDCl3): δ = 11.28 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H),
7.64 (t, J = 7.4 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.49 – 7.46 (m, 1H), 7.41 (dd, J = 7.9,
6.7 Hz, 2H), 7.20 (td, J = 7.0, 1.3 Hz, 1H), 5.89 (ddd, J = 17.1, 10.5, 6.4 Hz, 1H),
5.50 (dd, J = 13.3, 6.4 Hz, 1H), 5.33 – 5.27 (m, 1H), 5.20 (d, J = 10.5 Hz, 1H), 1.79 –
1.66 (m, 2H), 1.39 – 1.33 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 210.1, 163.1, 149.7, 141.7, 136.7, 134.6, 130.2, 129.8, 129.0, 128.6,
127.8, 127.4, 126.8, 119.7, 116.6, 107.6, 74.9, 33.9, 27.3, 22.3, 13.9. MS (EI) m/z:
377, 280, 264, 236, 204, 121, 89, 78, 41. HRMS (ESI): calcd. for C23H24NO2S
[M+H]+ 378.1522; found 378.1519.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 39
1
2
3
4
5
cyclohex-3-en-1-ylmethyl
3-(phenylcarbonothioyl)indolizine-1-carboxylate
6
7
8
9
(3ab). Red solid (47 mg, 63%); mp 92−94 °C; Rf = 0.63 (ethyl acetate/petroleum
ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 11.27 (d, J = 7.1 Hz, 1H), 8.46 (d, J =
8.8 Hz, 1H), 7.70 (s, 1H), 7.66 – 7.62 (m, 1H), 7.57 (dd, J = 5.2, 3.2 Hz, 2H), 7.49 –
7.45 (m, 1H), 7.41 (dd, J = 7.2, 5.8 Hz, 2H), 7.20 (td, J = 7.0, 1.4 Hz, 1H), 5.66 (dd, J
= 10.8, 2.7 Hz, 2H), 4.23 (d, J = 6.2 Hz, 2H), 2.20 – 2.07 (m, 4H), 1.89 – 1.80 (m,
2H), 1.42 – 1.33 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 210.2, 163.8, 149.7,
141.6, 134.6, 130.3, 129.8, 129.1, 128.6, 127.9, 127.4, 127.0, 125.4, 119.6, 116.6,
107.5, 68.6, 33.1, 28.3, 25.3, 24.3. MS (EI) m/z: 375, 280, 264, 236, 204, 121, 89, 79,
41. HRMS (ESI): calcd. for C23H22NO2S [M+H]+ 376.1366; found 376.1365.
prop-2-yn-1-yl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3ac). Red
solid (50 mg, 78%); mp 99−101 °C; Rf = 0.28 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.23 (d, J = 6.8 Hz, 1H), 8.49 (d, J = 8.6 Hz, 1H),
7.71 (s, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 7.3 Hz, 2H), 7.47 (d, J = 7.0 Hz,
1H), 7.41 (d, J = 7.3 Hz, 2H), 7.20 (t, J = 6.7 Hz, 1H), 4.90 (s, 2H), 2.51 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ = 210.7, 162.7, 149.6, 141.7, 134.6, 130.5, 129.8,
128.9, 128.5, 127.9, 127.4, 119.5, 116.7, 106.0, 77.8, 74.8, 51.6. MS (EI) m/z: 319,
280, 264, 236, 204, 191, 159, 131, 121, 89, 77, 39. HRMS (ESI): calcd. for
C19H13NNaO2S [M+Na]+ 342.0559; found 342.0567.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
but-3-yn-2-yl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3ad). Red solid
(48 mg, 73%); mp 131−133 °C; Rf = 0.38 (ethyl acetate/petroleum ether = 1:10); 1H
NMR (400 MHz, CDCl3): δ = 11.24 (d, J = 7.0 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.71
ACS Paragon Plus Environment

Page 23 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(s, 1H), 7.67 – 7.62 (m, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.42
(d, J = 7.5 Hz, 2H), 7.21 (t, J = 6.8 Hz, 1H), 5.73 – 5.66 (m, 1H), 2.50 (d, J = 1.8 Hz,
8
9
13
1H), 1.63 (d, J = 6.7 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 210.7, 162.5,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
149.7, 141.8, 134.6, 130.4, 129.8, 128.9, 128.5, 127.9, 127.5, 119.7, 116.6, 106.6,
82.3, 73.0, 59.9, 21.3. MS (EI) m/z: 333, 280, 264, 236, 204, 191, 132, 121, 89, 77, 51.
HRMS (ESI): calcd. for C20H16NO2S [M+H]+ 334.0896; found 334.0894.
pent-4-yn-2-yl 3-(phenylcarbonothioyl)indolizine-1-carboxylate (3ae). Red
solid (48 mg, 69%); mp 98−100 °C; Rf = 0.61 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.26 (d, J = 7.0 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H),
7.71 (s, 1H), 7.66 – 7.61 (m, 1H), 7.57 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H),
7.40 (t, J = 7.4 Hz, 2H), 7.20 (t, J = 6.9 Hz, 1H), 5.27 (dt, J = 12.2, 6.1 Hz, 1H), 2.60
(dd, J = 5.6, 2.4 Hz, 2H), 2.03 (t, J = 2.4 Hz, 1H), 1.47 (d, J = 6.3 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 210.2, 162.9, 149.7, 141.6, 134.6, 130.3, 129.8, 129.2,
128.5, 127.8, 127.4, 119.7, 116.5, 107.4, 79.7, 70.5, 68.5, 25.6, 19.2. MS (EI) m/z:
347, 280, 264, 236, 204, 131, 121, 89, 77, 39. HRMS (ESI): calcd. for C21H18NO2S
[M+H]+ 348.1053; found 348.1058.
1-(3-(phenylcarbonothioyl)indolizin-1-yl)ethan-1-one (3af). Red solid (49 mg,
1
88%); mp 98−100 °C; Rf = 0.42 (ethyl acetate/petroleum ether = 1:8); H NMR (400
MHz, CDCl3): δ = 11.23 (d, J = 7.0 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 7.67 (dd, J =
8.4, 7.4 Hz, 1H), 7.57 (dd, J = 6.4, 4.9 Hz, 3H), 7.47 (d, J = 7.4 Hz, 1H), 7.41 (t, J =
7.4 Hz, 2H), 7.23 (t, J = 7.0 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 210.0, 193.3, 149.7, 141.3, 134.3, 131.3, 129.8, 128.6, 128.5, 127.9, 127.3, 120.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 39
1
2
3
4
5
6
7
8
9
117.3, 115.3, 27.7. MS (EI) m/z: 279, 264, 235, 202, 191, 121, 89, 77, 43. Anal.
Calcd. for C17H13NOS C, 73.09; H, 4.69; N, 5.01. Found: C, 72.81; H, 4.78; N, 5.09.
methyl 6-methyl-3-(phenylcarbonothioyl)indolizine-1-carboxylate (3ag). Red
solid (36 mg, 58%); mp 118−120 °C; Rf = 0.57 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.20 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.62 (s, 1H),
7.55 (d, J = 7.1 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.40 (t, J =
7.3 Hz, 2H), 3.87 (s, 3H), 2.49 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 209.7,
164.2, 149.9, 140.4, 134.5, 133.1, 129.6, 128.8, 128.5, 127.9, 127.0, 125.7, 118.9,
107.1, 51.3, 18.7. MS (EI) m/z: 309, 294, 232, 138, 121, 89, 77, 51. HRMS (ESI):
calcd. for C18H16NO2S [M+H]+ 310.0896; found 310.0898.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methyl 6-bromo-3-(phenylcarbonothioyl)indolizine-1-carboxylate (3ah). Red
solid (40 mg, 54%); mp 148−150 °C; Rf = 0.61 (ethyl acetate/petroleum ether = 1:10);
1H NMR (400 MHz, CDCl3): δ = 11.46 (d, J = 0.9 Hz, 1H), 8.38 (d, J = 9.3 Hz, 1H),
7.69 (dd, J = 9.3, 1.7 Hz, 1H), 7.64 (s, 1H), 7.57 – 7.54 (m, 2H), 7.48 (dd, J = 7.9, 1.8
Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ =
211.8, 163.8, 149.6, 139.7, 134.0, 132.9, 130.1, 128.5, 128.4, 128.0, 127.1, 120.1,
111.7, 107.5, 51.5. MS (EI) m/z: 374, 342, 314, 294, 234, 190, 131, 121, 89, 77, 51.
HRMS (ESI): calcd. for C17H12BrNNaO2S [M+Na]+ 395.9664; found 395.9671.
methyl
6-methyl-3-(3-methylphenylcarbonothioyl)indolizine-1-carboxylate
(3ai). Red solid (39 mg, 61%); mp 140−142 °C; Rf = 0.42 (ethyl acetate/petroleum
ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 11.41 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H),
7.55 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J = 6.4 Hz, 1H), 7.24 – 7.17 (m, 3H),
ACS Paragon Plus Environment

Page 25 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3.84 (s, 3H), 2.51 (s, 3H), 2.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 210.6,
164.0, 149.1, 140.3, 134.2, 133.4, 132.8, 130.3, 128.3, 127.9, 127.6, 127.0, 125.9,
125.5, 119.0, 107.6, 51.3, 19.3, 18.7. MS (EI) m/z: 323, 290, 264, 231, 145, 115, 102,
65, 39. HRMS (ESI): calcd. for C19H18NO2S [M+H]+ 324.1053; found 324.1055.
methyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-(methoxycarbonyl)phenylcarbonothioyl)-6-methylindolizine-1-carboxylate
(3aj). Red solid (57 mg, 77%); mp 159−161 °C; Rf = 0.28 (ethyl acetate/petroleum
ether = 1:7); 1H NMR (400 MHz, CDCl3): δ = 11.20 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H),
8.06 (d, J = 8.3 Hz, 2H), 7.57 – 7.51 (m, 4H), 3.95 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 207.1, 166.5, 163.9, 153.4, 140.5, 134.2, 133.6,
130.5, 129.2, 128.7, 128.1, 127.6, 125.7, 118.9, 107.5, 52.2, 51.4, 18.7. MS (EI) m/z:
367, 280, 264, 236, 204, 131, 121, 89, 77, 41. HRMS (ESI): calcd. for C20H18NO4S
[M+H]+ 368.0951; found 368.0947.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 39
1
2
3
4
5
6
7
8
9
General procedure for the preparation of indolizine thiones (4a-4o). A mixture
of 2-pyridylacetonitrile or 2-pyridylacetamide (0.2 mmol), ynal (0.2 mmol), elemental
sulfur (12.8 mg, 0.05 mmol), and I2 (5 mg, 10 mol%) in DMF (1.0 mL) was stirred in
a preheated oil bath at 80 °C for 4 h in a sealed tube under argon atmosphere. After
the reaction was finished, water (5 mL) was added and the solution was extracted with
ethyl acetate (3×5 mL), and the combined extract was dried with anhydrous MgSO4.
Solvent was removed, and the residue was separated by column chromatography to
give the pure sample.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(phenylcarbonothioyl)indolizine-1-carbonitrile (4a). Red solid (45 mg, 85%);
mp 126−128 °C; Rf = 0.38 (ethyl acetate/petroleum ether = 1:7); 1H NMR (400 MHz,
CDCl3): δ = 11.16 (d, J = 7.1 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.69 – 7.65 (m, 1H),
7.57 – 7.54 (m, 2H), 7.52 (s, 1H), 7.49 (t, J = 4.8 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H),
7.27 (d, J = 5.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 211.7, 149.4, 142.6,
134.4, 130.3, 130.1, 129.2, 128.5, 128.1, 127.6, 117.8, 117.1, 114.5, 86.5. MS (EI)
m/z: 262, 229, 185, 141, 114, 95, 78, 51. HRMS (ESI): calcd. for C16H11N2S [M+H]+
263.0638; found 263.0635.
3-(3-methylphenylcarbonothioyl)indolizine-1-carbonitrile (4b). Red solid (34
mg, 62%); mp 127−129 °C; Rf = 0.52 (ethyl acetate/petroleum ether = 1:7); 1H NMR
(400 MHz, CDCl3): δ = 11.15 (dt, J = 7.1, 1.0 Hz, 1H), 7.89 (dt, J = 8.7, 1.2 Hz, 1H),
7.68 – 7.64 (m, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.34 – 7.29 (m, 3H), 7.24 (dd, J = 7.0,
1.3 Hz, 1H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 212.1, 149.4, 142.6,
137.9, 134.4, 131.2, 130.0, 129.2, 129.2, 127.9, 127.6, 125.7, 117.7, 117.0, 114.6,
ACS Paragon Plus Environment

Page 27 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
86.4, 21.3. MS (EI) m/z: 276, 243, 185, 137, 114, 91, 78, 51. HRMS (ESI): calcd. for
C17H13N2S [M+H]+ 277.0794; found 277.0794.
8
9
3-(4-(tert-butyl)phenylcarbonothioyl)indolizine-1-carbonitrile (4c). Red solid
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(41 mg, 65%); mp 64−66 °C; Rf = 0.43 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.11 (dt, J = 7.1, 1.0 Hz, 1H), 7.88 (dt, J = 8.7, 1.2 Hz,
1H), 7.66 – 7.61 (m, 1H), 7.56 (s, 1H), 7.54 – 7.51 (m, 2H), 7.44 – 7.41 (m, 2H), 7.23
(td, J = 7.0, 1.4 Hz, 1H), 1.37 (s, 9H). C{1H} NMR (100 MHz, CDCl3): δ = 211.6,
13
154.2, 146.7, 142.5, 134.3, 129.8, 129.0, 128.6, 127.5, 125.0, 117.7, 116.8, 114.6,
86.2, 34.9, 31.1. MS (EI) m/z: 318, 302, 287, 261, 229, 185, 161, 137, 115, 91, 78, 51,
41. HRMS (ESI): calcd. for C20H19N2S [M+H]+ 319.1263; found 319.1259.
3-([1,1'-biphenyl]-4-carbonothioyl)indolizine-1-carbonitrile (4d). Brown solid
1
(38 mg, 57%); mp 173−175 °C; Rf = 0.31 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.14 (d, J = 7.1 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.68
– 7.64 (m, 7H), 7.62 (s, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.26 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 210.9, 148.1, 143.5, 142.7, 140.0, 134.4,
130.0, 129.31, 129.0, 128.9, 127.9, 127.6, 127.1, 126.8, 117.8, 117.0, 114.6, 86.5.
HRMS (ESI): calcd. for C22H15N2S [M+H]+ 339.0950; found 339.0949.
3-(naphthalene-1-carbonothioyl)indolizine-1-carbonitrile (4e). Brown solid (58
mg, 93%); mp 173−175 °C; Rf = 0.43 (ethyl acetate/petroleum ether = 1:7); 1H NMR
(400 MHz, CDCl3): δ = 11.52 (d, J = 7.0 Hz, 1H), 7.95 – 7.91 (m, 2H), 7.91 – 7.87 (m,
1H), 7.82 (d, J = 8.5 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.57 – 7.53 (m, 1H), 7.53 – 7.48
(m, 1H), 7.47 (dd, J = 7.1, 1.2 Hz, 1H), 7.41 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.33 (td, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 39
1
2
3
4
5
6
7
8
9
= 7.0, 1.2 Hz, 1H), 7.23 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 211.0, 146.2,
142.3, 134.8, 133.3, 130.7, 130.0, 129.6, 128.7, 128.0, 127.6, 126.5, 126.0, 125.2,
124.8, 124.5, 117.8, 117.7, 114.1, 87.1. MS (EI) m/z: 312, 279, 185, 156, 142, 78, 51.
HRMS (ESI): calcd. for C20H13N2S [M+H]+ 313.0794; found 313.0791.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2-methoxyphenylcarbonothioyl)indolizine-1-carbonitrile (4f). Green solid
1
(41 mg, 71%); mp 171−173 °C; Rf = 0.26 (ethyl acetate/petroleum ether = 1:7); H
NMR (400 MHz, CDCl3): δ = 11.35 (d, J = 7.1 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.69
– 7.65 (m, 1H), 7.42 – 7.37 (m, 1H), 7.36 (s, 1H), 7.29 – 7.26 (m, 2H), 7.02 (td, J =
13
7.5, 0.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.73 (s, 3H). C{1H} NMR (100 MHz,
CDCl3): δ = 209.6, 154.0, 142.3, 138.1, 134.5, 130.2, 130.1, 129.2, 129.0, 127.7,
120.6, 117.7, 117.4, 114.6, 111.3, 86.8, 55.7. MS (EI) m/z: 292, 259, 231, 216, 185,
166, 138, 114, 78, 51. HRMS (ESI): calcd. for C17H13N2OS [M+H]+ 293.0743; found
293.0742.
3-(4-fluorophenylcarbonothioyl)indolizine-1-carbonitrile (4g). Brown solid (31
mg, 56%); mp 181−183 °C; Rf = 0.33 (ethyl acetate/petroleum ether = 1:7); 1H NMR
(400 MHz, CDCl3): δ = 11.09 (dt, J = 7.1, 1.0 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.70 –
7.65 (m, 1H), 7.60 – 7.56 (m, 2H), 7.50 (s, 1H), 7.28 – 7.24 (m, 1H), 7.13 – 7.08 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ = 209.6, 164.2 (d, J = 251 Hz), 145.5 (d, J
= 3 Hz), 142.7, 134.3, 130.7 (d, J = 8 Hz), 130.2, 128.8, 127.5, 117.8, 117.2, 115.1 (d,
J = 22 Hz), 114.4, 86.6. MS (EI) m/z: 279, 247, 185, 139, 114, 95, 78, 51. HRMS
(ESI): calcd. for C16H10FN2S [M+H]+ 281.0543; found 281.0540.
3-(4-chlorophenylcarbonothioyl)indolizine-1-carbonitrile (4h). Brown solid (36
ACS Paragon Plus Environment

Page 29 of 39
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mg, 60%); mp 201−203 °C; Rf = 0.32 (ethyl acetate/petroleum ether = 1:7); 1H NMR
(400 MHz, CDCl3): δ = 11.12 (d, J = 7.1 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.71 –
7.66 (m, 1H), 7.52 – 7.49 (m, 3H), 7.41 – 7.38 (m, 2H), 7.28 (dd, J = 7.0, 1.2 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ = 209.4, 147.5, 142.7, 136.7, 134.2, 130.3, 129.8,
128.9, 128.3, 127.5, 117.8, 117.3, 114.3, 86.8. MS (EI) m/z: 296, 259, 185, 155, 130,
108, 78, 51. HRMS (ESI): calcd. for C16H10ClN2S [M+H]+ 297.0248; found
297.0243.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-bromophenylcarbonothioyl)indolizine-1-carbonitrile (4i). Brown solid (35
mg, 52%); mp 202−204 °C; Rf = 0.34 (ethyl acetate/petroleum ether = 1:7); 1H NMR
(400 MHz, CDCl3): δ = 11.13 (d, J = 7.1 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.71 –
7.67 (m, 1H), 7.58 – 7.54 (m, 2H), 7.51 (s, 1H), 7.46 – 7.41 (m, 2H), 7.29 (dd, J = 7.0,
1.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 209.4, 148.0, 142.7, 134.2, 131.3,
130.4, 130.0, 128.9, 127.5, 125.0, 117.9, 117.4, 114.3, 86.8. MS (EI) m/z: 341, 309,
281, 259, 229, 216, 185, 141, 114, 88, 78, 51. HRMS (ESI): calcd. for C16H10BrN2S
[M+H]+ 340.9743; found 340.9737.
3-(3-(trifluoromethyl)phenylcarbonothioyl)indolizine-1-carbonitrile (4j). Red
solid (47 mg, 71%); mp 132−134 °C; Rf = 0.31 (ethyl acetate/petroleum ether = 1:7);
1H NMR (400 MHz, CDCl3): 11.17 (dt, J = 7.1, 0.9 Hz, 1H), 7.92 (dt, J = 8.7, 1.1 Hz,
1H), 7.80 (s, 1H), 7.75 – 7.68 (m, 3H), 7.55 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.31 (td,
J = 7.0, 1.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ =208.4, 149.5, 142.8, 134.2,
131.3, 130.8, 130.6 (q, J = 33 Hz), 129.0, 128.6, 127.5, 126.5 (q, J = 4 Hz), 125.0 (q,
ACS Paragon Plus Environment