Facile approach to diverse 3-acylated indolizines via a sequential Sonogashira coupling/iodocyclization process

Article abstract of DOI:10.1016/j.tet.2012.07.068

Successful implementation of a sequential Pd-catalyzed Sonogashira cross-coupling/iodine-promoted 5-exo-dig cyclization procedure with pyridines bearing a terminal alkyne moiety provided direct and straightforward access to a diverse array of 3-acylated i

Full text of DOI:10.1016/j.tet.2012.07.068

Tetrahedron 68 (2012) 8198e8206
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Facile approach to diverse 3-acylated indolizines via a sequential Sonogashira
coupling/iodocyclization process
*
Youngeun Jung, Ikyon Kim
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2012
Received in revised form 18 July 2012
Accepted 18 July 2012
Available online 31 July 2012
Successful implementation of a sequential Pd-catalyzed Sonogashira cross-coupling/iodine-promoted 5-
exo-dig cyclization procedure with pyridines bearing a terminal alkyne moiety provided direct and
straightforward access to a diverse array of 3-acylated indolizines under mild conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indolizines
Palladium
Sonogashira coupling
Iodine-mediated cyclization
1. Introduction
As part of our continuing interest on nitrogen-fused heterocy-
cles,7 herein we describe our effort in this context with particular
3-Acylated indolizine1 is a useful scaffold known for a wide
variety of biological activities including anticancer, anticonvulsant,
anti-inflammatory, and antimalarial activities as shown in Fig. 1.2
Despite its versatile use in drug discovery programs, however, not
many synthetic methods toward 3-acylindolizines are available.3
Most approaches to this skeleton rely on 1,3-dipolar cycloaddition
reactions of pyridinium ylides with electron-deficient alkenes or
alkynes.
Recently, we have reported a new synthetic method of 3-acylated
indolizines using iodine-mediated4 efficient hydrative cyclization.5
Although the starting materials 2 for this transformation were eas-
ily prepared by propargylation of ethyl pyridineacetate 1 with ap-
propriately functionalized propargylic bromides, we envisioned
that a more succinct route to diversely propargylated starting ma-
terials 5 be feasible via palladium-catalyzed Sonogashira cross-
coupling6 of 4 with (hetero)aryl halides, thereby expanding the
substrate scope more rapidly (Scheme 1). Due to a wide functional
group tolerance of Sonogashira cross-coupling reactions, further-
more, we anticipated more substrate diversity by installing some
aryl groups (Ar) containing functional groups, such as ketone or
ester, which are sensitive to basic conditions (i.e., from 1 to 2) under
mild conditions.
focus on rapid generation of 3-acylated indolizine library.
2. Results and discussion
We began our study with Sonogashira coupling of terminal
acetylene 4 with iodobenzene in the presence of (Ph3P)2PdCl2
(5 mol %), CuI (5 mol %), and Et3N (5 equiv)inTHFor CH3CNas solvent
at 45 ꢀC to afford 5a in 37 and 58% yield, respectively (Table 1, entries
1 and 2). Reactions in THF at room temperature rather improved the
yield whereas similar result was observed in CH3CN at ambient
temperature (entries 3 and 4). Copper-free Sonogashira cross-
coupling reactions did not produce the desired product with the
starting material 4 remained even after 24 h (entries 5 and 6). To our
delight, exposure of 4 and iodobenzene (1.3 equiv) to (Ph3P)2PdCl2
(5 mol %), CuI (5 mol %) in Et3N as solvent at 45 ꢀC delivered 5a in 78%
yield (entry 7).
Several aryl iodides were subjected to these optimized condi-
tions to provide the corresponding aryl-substituted alkynes
(Table 2). Two other terminal alkynes, 6 and 7, were coupled as well
with several aryl iodides under these identical conditions to pro-
duce the internal alkynes. Not only aryl iodides bearing electron
withdrawing group but also those with electron donating group
participated well in Sonogashira cross-coupling reactions giving
rise to the coupling products in good yields. Heterocycles, such as
thiophene or pyridine were incorporated under these conditions
without any event (entries 9, 10, and 17). As noted in the in-
troduction section, it should be worthwhile to mention that some
* Corresponding author. Tel.: þ82 32 749 4515; fax: þ82 32 749 4105; e-mail
address: ikyonkim@yonsei.ac.kr (I. Kim).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.068

Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
8199
Fig. 1. Some biologically active 3-acylated indolizines.
Scheme 1. Synthetic approaches to 3-acylated indolizines.
iodocyclization substrates having functional groups incompatible
with basic conditions, which could not be accessible by our pre-
vious approach, were readily prepared by this method (for exam-
ple, entries 2e5).
Table 1
Sonogashira coupling of 4 with iodobenzene
Having secured a wide variety of internal alkynes in hand, we
undertook iodine-mediated hydrative cyclization8 to furnish the
corresponding 3-acylated indolizines.9 Thus, a number of new 3-
acylated indolizines were rapidly synthesized under mild reaction
conditions (Table 3). In general, alkynes bearing electron-deficient
aryl groups as well as electron-rich aryl groups were converted to
their corresponding 3-aroylindolizines in good yields. Indolizines
with heterocycle substituents, such as thiophene and pyridine at
the R site were readily prepared although yield was modest in case
of thiophene-substituted alkyne 5j (entries 10, 11, and 18). It turned
out that position of substituent around the phenyl ring (R) could
play a crucial role in this transformation, affecting the chemical
yield. For instance, it was revealed that alkynes possessing 4-
methoxyphenyl and 3-methoxyphenyl groups exhibited different
chemical reactivities (entries 7 and 8). In contrast, similar results
were obtained with 5e and 5f (entries 5 and 6). Exposure of 2-
acetylphenyl-susbstituted alkyne 5o to these conditions gave
a low yield of the desired product presumably due to the in-
teraction of acetyl group with the neighboring activated alkyne8a,10
by the action of iodine whereas the reaction of 4-acetylphenyl-
substituted alkyne 5p delivered the desired product in good yield
(entries 15 and 16). As good yield of the product 8e was observed
Entry
Pd
Cu
Base
Solvent
Temp (ꢀC)
Yieldd
1
2
3
4
5
6
7
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(Ph3P)4
CuI
CuI
CuI
Et3N
Et3N
Et3N
Et3N
Piperidine
Piperidine
Et3N
THF
CH3CN
THF
45
45
25
25
25
45
45
37
58
52
CuI
CH3CN
57
b
e
THF
b
c
e
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
c
CuI
78
aA mixture of 4 (0.098 mmol), iodobenzene (1.3 equiv), Pd catalyst (5 mol %), Cu
catalyst (5 mol %), and base (5 equiv) in solvent (1 mL) was stirred at the temper-
ature indicated in the table for 13 h unless otherwise stated.
b
No Cu catalyst was used.
Base was used as solvent.
Isolated yield (%).
c
d
e
Starting material remained without formation of the desired product 5a after
24 h.

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Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
Table 2 (continued)
Table 2
Sonogashira cross-coupling of 4, 6, and 7 with various (hetero)aryl iodides
Entry
Starting material
RI
Product
Yielda
83
17
7
5r
18
19
7
7
5s
5t
77
88
Entry
1
Starting material
RI
Product
Yielda
87
20
7
7
5u
5v
74
67
4
5b
21
2
3
4
4
4
4
5c
5d
5e
34
93
48
a
Isolated yield (%).
with 5e, cyclization of 5s was expected to proceed well but, sur-
prisingly, poor result was observed (entries 5 and 19). Alkynes with
3-trifluoromethylphenyl and 3-chlorophenyl substituents, 5t and
5u, were transformed to their corresponding products in good
yields (entries 20 and 21).
5
6
7
4
4
4
5f
57
67
66
5g
5h
3. Conclusions
In conclusion, a new synthetic route to a variety of 3-acylated
indolizines was developed by employing
a sequential Pd-
catalyzed Sonogashira cross-coupling/iodine-mediated 5-exo-dig
cyclization procedure. Particularly, rapid and facile introduction of
more diverse (hetero)aroyl moieties including base-sensitive
functional groups at C3 position of an indolizine core was re-
alized by employing Sonogashira cross-coupling technique, which
was not possible by our previous approach. This was demonstrated
in several examples. Biological evaluation of these 3-acylated
indolizines is in progress and will be reported in due course.
8
9
4
4
5i
5j
64
70
10
4
5k
75
4. Experimental section
11
12
13
6
6
6
5l
57
63
73
4.1. General procedure for the Sonogashira coupling of 4, 6 or
7 with aryl iodide
5m
5n
A mixture of 4, 6, or 7 (0.98 mmol),11 aryl iodide (1.3 equiv),
bis(triphenylphosphine)palladium(II) dichloride (5 mol %), and
copper(I) iodide (5 mol %) in Et3N (4 mL) was stirred at 45 ꢀC. After
the reaction was complete, the reaction mixture was concentrated
under reduced pressure and purified by silica gel column chro-
matography (hexane/ethyl acetate/dichloromethane) to give the
internal alkyne 5.
14
15
6
6
5o
5p
63
87
4.1.1. Ethyl 5-phenyl-2-(pyridin-2-yl)pent-4-ynoate (5a). Yellow
gum; 1H NMR (500 MHz, CDCl3)
d
8.59 (dd, J¼1.0, 5.0 Hz, 1H), 7.67
(td, J¼2.0, 8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.30e7.28 (m, 2H),
7.25e7.23 (m, 3H), 7.20 (ddd, J¼1.0, 5.0, 7.5 Hz, 1H) 4.26e4.15 (m,
2H), 4.09 (t, J¼8.0 Hz, 1H), 3.20 (dd, J¼7.0, 17.0 Hz, 1H), 3.08 (dd,
J¼8.0, 17.0 Hz, 1H), 1.22 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
16
6
5q
63
d
171.7, 157.4, 149.7, 136.7, 131.6, 128.2, 127.9, 123.6, 123.3, 122.6,
87.2, 82.3, 61.3, 53.2, 22.5, 14.3; IR (ATR) 3055, 2980, 1731, 1589,

Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
8201
Table 3
Table 3 (continued )
Iodine-mediated cyclization of 5
Entry Starting material
Product
Yielda
8
5h
8h 63
Entry Starting material
Product
Yielda
9
5i
8i
52
1
2
3
4
5
5a
5b
5c
5d
5e
8a
70
10
5j
8j
40
8b 83
11
12
13
5k
8k 73
8c
58
5l
8l
78
8d 68
5m
8m 51
8e
73
14
5n
8n 55
6
5f
8f
65
15
5o
8o 13
7
5g
8g 25
(continued on next page)

8202
Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
Table 3 (continued )
7.41 (d, J¼9.0 Hz, 2H), 7.37 (d, J¼8.0 Hz, 1H), 7.24 (ddd, J¼1.0, 5.0,
Yielda
7.5 Hz, 1H), 4.26e4.16 (m, 2H), 4.11 (t, J¼7.5 Hz, 1H), 3.26 (dd, J¼7.5,
Entry Starting material
Product
17.0 Hz, 1H), 3.14 (dd, J¼8.0, 17.0 Hz, 1H), 1.23 (t, J¼7.0 Hz, 3H); 13
C
NMR (125 MHz, CDCl3)
d 171.3, 157.0, 149.8, 146.8, 136.8, 132.3,
130.6, 123.5, 123.2, 122.7, 93.4, 80.8, 61.5, 52.7, 22.5, 14.2; IR (ATR)
3075, 2925, 2853, 1733, 1592, 1512, 1435, 1339, 1209 cmꢁ1; HRMS
(FAB) calcd for C18H17N2O4 325.1188 ([MþH]þ), found 325.1198.
16
5p
8p 58
4.1.3. Ethyl 5-(4-cyanophenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5c). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.60 (d, J¼4.5 Hz,
1H), 7.69 (t, J¼7.5 Hz,1H), 7.53 (d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 3H),
7.23 (dd, J¼5.5, 7.0 Hz, 1H), 4.26e4.16 (m, 2H), 4.09 (t, J¼7.5 Hz, 1H),
3.24 (dd, J¼7.5, 17.0 Hz, 1H), 3.12 (dd, J¼8.0, 17.0 Hz, 1H), 1.22 (t,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 171.4, 157.1, 149.8, 136.8,
132.2,132.0,128.6,123.2,122.7,118.6,111.2, 92.4, 81.0, 61.5, 52.8, 22.5,
17
5q
8q 66
14.3; IR (ATR) 3052, 2980, 2928, 2226, 1731, 1589, 1435, 1161 cmꢁ1
;
HRMS(ESI) calcd forC19H17N2O2 305.1290 ([MþH]þ), found 305.1295.
4.1.4. Ethyl 5-(4-acetylphenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5d). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.60 (d, J¼5.0 Hz,
1H), 7.84 (d, J¼8.5 Hz, 2H), 7.69 (td, J¼1.5, 7.5 Hz,1H), 7.37 (d, J¼7.5 Hz,
1H), 7.36 (d, J¼8.5 Hz, 2H), 7.22 (ddd, J¼1.0, 5.0, 7.5 Hz,1H), 4.26e4.16
(m, 2H), 4.10 (t, J¼7.5 Hz, 1H), 3.24 (dd, J¼7.5, 17.0 Hz, 1H), 3.12 (dd,
J¼8.0, 17.0 Hz, 1H), 2.57 (s, 3H), 1.23 (t, J¼7.0 Hz, 3H); 13C NMR
18
5r
8r
66
(125 MHz, CDCl3) d 197.4, 171.5, 157.2, 149.8, 136.7, 136.0, 131.8, 128.6,
128.2,123.2,122.7, 91.0, 81.7, 61.4, 52.9, 26.7, 22.6,14.3; IR (ATR) 3053,
2980, 2931, 2223, 1732, 1680, 1600, 1435, 1260, 1162 cmꢁ1; HRMS
(FAB) calcd for C20H20NO3 322.1443 ([MþH]þ), found 322.1447.
19
5s
8s
35
4.1.5. Methyl 4-(5-ethoxy-5-oxo-4-(pyridin-2-yl)pent-1-yn-1-yl)ben-
zoate (5e). Pale yellow solid, mp: 72.2e73.3 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
8.60 (d, J¼5.0 Hz, 1H), 7.92 (d, J¼8.0 Hz, 2H), 7.69 (t, J¼8.0 Hz,
1H), 7.37 (d, J¼8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz, 2H), 7.23e7.21 (m, 1H),
4.26e4.16 (m, 2H), 4.10 (t, J¼7.5 Hz, 1H), 3.90 (s, 3H), 3.23 (dd, J¼7.0,
17.0 Hz, 1H), 3.11 (dd, J¼8.0, 17.0 Hz, 1H), 1.23 (t, J¼7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 171.5, 166.7, 157.2, 149.8, 136.7, 131.6, 129.5,
129.2, 128.4, 123.3,122.7, 90.7, 81.8, 61.4, 53.0, 52.3, 22.6, 14.3; IR (ATR)
20
5t
8t
53
3062, 2983, 2920, 2224, 1730, 1710, 1604, 1438, 1279, 1209, 1174 cmꢁ1
;
HRMS (ESI) calcd for C20H20NO4 338.1392 ([MþH]þ), found 338.1392.
4.1.6. Methyl
3-(5-ethoxy-5-oxo-4-(pyridin-2-yl)pent-1-yn-1-yl)
8.61 (d,
benzoate (5f). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
J¼4.0 Hz, 1H), 7.96 (s, 1H), 7.91 (d, J¼8.0 Hz, 1H), 7.69 (td, J¼2.0,
8.0 Hz, 1H), 7.46 (d, J¼8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.32 (t,
J¼7.5 Hz, 1H), 7.24e7.21 (m, 1H), 4.26e4.16 (m, 2H), 4.10 (t,
J¼7.5 Hz, 1H), 3.91 (s, 3H), 3.22 (dd, J¼7.5, 17.0 Hz, 1H), 3.09 (dd,
J¼8.0, 17.0 Hz, 1H), 1.23 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
21
5u
8u 58
d
171.6, 166.6, 157.3, 149.8, 136.8, 135.9, 132.8, 130.4, 128.9, 128.4,
124.1, 123.3, 122.7, 88.3, 81.7, 61.4, 53.1, 52.3, 22.5, 14.3; IR (ATR)
3066, 2982, 2952, 1720, 1589, 1472, 1292, 1227, 1163 cmꢁ1; HRMS
(ESI) calcd for C20H20NO4 338.1392 ([MþH]þ), found 338.1402.
4.1.7. Ethyl 5-(4-methoxyphenyl)-2-(pyridin-2-yl)pent-4-ynoate
22
5v
8v
38
(5g). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.58 (ddd, J¼1.0, 1.5,
5.0 Hz, 1H), 7.66 (td, J¼2.0, 8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.22 (d,
J¼9.0 Hz, 2H), 7.19 (ddd, J¼1.0, 5.0, 7.5 Hz, 1H), 6.77 (d, J¼9.0 Hz, 2H),
4.25e4.14 (m, 2H), 4.08 (t, J¼7.5 Hz, 1H), 3.76 (s, 3H), 3.19 (dd, J¼7.0,
17.0 Hz, 1H), 3.06 (dd, J¼8.0, 17.0 Hz, 1H), 1.21 (t, J¼6.5 Hz, 3H); 13C
a
Isolated yield (%).
NMR (125 MHz, CDCl3) d 171.7, 159.2, 157.4, 149.6, 136.6, 132.9, 123.2,
122.5,115.7,113.8, 85.5, 82.1, 61.2, 55.3, 53.2, 22.5,14.2; IR (ATR) 3051,
2979, 2837, 1731, 1606, 1436, 1170 cmꢁ1; HRMS (FAB) calcd for
C19H20NO3 310.1443 ([MþH]þ), found 310.1451.
1435, 1159 cmꢁ1; HRMS (FAB) calcd for C18H18NO2 280.1338
([MþH]þ), found 280.1330.
4.1.2. Ethyl 5-(4-nitrophenyl)-2-(pyridin-2-yl)pent-4-ynoate
4.1.8. Ethyl 5-(3-methoxyphenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5b). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.61 (ddd, J¼1.0,
(5h). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.59 (d, J¼4.5 Hz,
2.0, 5.0 Hz, 1H), 8.11 (d, J¼9.0 Hz, 2H), 7.70 (td, J¼1.5, 8.0 Hz, 1H),
1H), 7.67 (t, J¼8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.21e7.19 (m, 1H),

Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
8203
7.15 (t, J¼7.5 Hz, 1H), 6.89 (d, J¼7.5 Hz, 1H), 6.82e6.80 (m, 2H),
4.25e4.15 (m, 2H), 4.09 (t, J¼7.5 Hz,1H), 6.02 (s, 3H), 3.20 (dd, J¼7.0,
17.0 Hz, 1H), 3.07 (dd, J¼8.0, 17.0 Hz, 1H), 1.22 (t, J¼7.5 Hz, 3H); 13C
d
8.60 (d, J¼5.0 Hz, 1H), 7.69 (td, J¼2.0, 8.0 Hz,1H), 7.36 (d, J¼8.0 Hz,
1H), 7.24e7.19 (m, 5H), 4.10 (t, J¼7.5 Hz, 1H), 3.73 (s, 3H), 3.20 (dd,
J¼7.0, 17.0 Hz, 1H), 3.08 (dd, J¼7.0, 17.0 Hz, 1H); 13C NMR (125 MHz,
NMR (125 MHz, CDCl3)
d
171.6, 159.3, 157.4, 149.7, 136.6, 129.3,
CDCl3) d 172.0, 157.1, 149.8, 136.8, 133.9, 132.9, 128.6, 123.3, 122.7,
124.6, 124.2, 123.3, 122.6, 116.6, 114.3, 87.0, 82.3, 61.3, 55.3, 53.1,
122.0, 88.1, 81.3, 52.9, 52.6, 22.5; IR (ATR) 3052, 2947, 2230, 1732,
1588, 1432, 1164, 1084 cmꢁ1; HRMS (ESI) calcd for C17H15ClNO2
300.0791 ([MþH]þ), found 300.0791.
22.5, 14.3; IR (ATR) 3067, 2979, 2835, 1731, 1572, 1469, 1160 cmꢁ1
;
HRMS (FAB) calcd for C19H20NO3 310.1443 ([MþH]þ), found
310.1450.
4.1.15. Methyl 5-(2-acetylphenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5o). Brown gum; 1H NMR (500 MHz, CDCl3)
d
8.60 (d, J¼4.5 Hz,
4.1.9. Ethyl
5-(4-methylcyclohexa-1,5-dien-1-yl)-2-(pyridin-2-yl)
8.59
pent-4-ynoate (5i). Orange gum; 1H NMR (500 MHz, CDCl3)
d
1H), 7.69 (td, J¼2.0, 8.0 Hz, 1H), 7.63 (d, J¼7.5 Hz, 1H), 7.39e7.35 (m,
3H), 7.34e7.31 (m, 1H), 7.23 (dd, J¼5.0, 7.5 Hz, 1H), 4.14 (t, J¼7.5 Hz,
1H), 3.73 (s, 3H), 3.28 (dd, J¼7.0, 17.0 Hz, 1H), 3.18 (dd, J¼8.0,
(d, J¼4.5 Hz, 1H), 7.66 (td, J¼2.0, 8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H),
7.21e7.18 (m, 3H), 7.05 (d, J¼7.5 Hz, 2H), 4.25e4.15 (m, 2H), 4.08 (t,
J¼7.5 Hz, 1H), 3.19 (dd, J¼7.0, 17.0 Hz, 1H), 3.06 (dd, J¼8.0, 17.0 Hz,
1H), 2.30 (s, 3H), 1.22 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
17.0 Hz, 1H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 200.1, 172.0,
157.0, 149.9, 141.2, 136.9, 134.2, 131.2, 128.4, 128.0, 123.5, 122.8,
121.8, 93.4, 81.3, 52.7, 52.6, 30.1, 22.7; IR (ATR) 3061, 2953, 2856,
1735, 1681, 1590, 1434, 1163 cmꢁ1; HRMS (ESI) calcd for C19H18NO3
308.1287 ([MþH]þ), found 308.1289.
d
171.7, 157.5, 149.7, 137.9, 136.6, 131.5, 129.0, 123.3, 122.5, 120.5,
86.3, 82.4, 61.3, 53.2, 22.6, 21.5, 14.3; IR (ATR) 3049, 2980, 2921,
1732, 1589, 1435, 1159 cmꢁ1; HRMS (FAB) calcd for C19H20NO2
294.1494 ([MþH]þ), found 294.1484.
4.1.16. Methyl 5-(4-acetylphenyl)-2-(pyridin-2-yl)pent-4-ynoate
4.1.10. Ethyl 2-(pyridin-2-yl)-5-(thiophen-2-yl)pent-4-ynoate
(5p). White solid, mp: 71.9e73.0 ꢀC; 1H NMR (500 MHz, CDCl3)
(5j). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.59 (d, J¼4.0 Hz,
d
8.60 (d, J¼4.0 Hz, 1H), 7.84 (d, J¼7.0 Hz, 2H), 7.70 (td, J¼1.5, 7.5 Hz,
1H), 7.67 (td, J¼1.0, 7.5 Hz, 1H), 7.36 (d, J¼7.5 Hz, 1H), 7.20 (ddd,
J¼1.0, 5.0, 7.0 Hz, 1H), 7.15 (dd, J¼1.0, 5.0 Hz, 1H), 7.04 (d, J¼3.5 Hz,
1H), 6.89 (dd, J¼3.5, 5.0 Hz,1H), 4.25e4.15 (m, 2H), 4.08 (t, J¼7.5 Hz,
1H), 3.23 (dd, J¼7.5, 17.0 Hz, 1H), 3.09 (dd, J¼7.5, 17.0 Hz, 1H), 1.22 (t,
1H), 7.38e7.35 (m, 3H), 7.25e7.22 (m,1H), 4.12 (t, J¼8.0 Hz,1H), 3.74
(s, 3H), 3.25 (dd, J¼7.0,17.0 Hz,1H), 3.12 (dd, J¼8.0,17.0 Hz,1H), 2.57
(s, 3H); 13C NMR (125 MHz, CDCl3)
d 197.4, 171.9, 157.0, 149.8, 136.8,
136.0,131.7,128.5,128.2,123.3,122.7, 90.9, 81.8, 52.8, 52.6, 26.7, 22.5;
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
171.5, 157.2, 149.7, 136.7,
IR (ATR) 3070, 2998, 2927, 2223, 1734, 1678, 1588, 1436, 1172 cmꢁ1
;
131.4, 126.8, 126.3, 123.7, 123.3, 122.6, 91.2, 75.5, 61.4, 52.9, 22.8,
14.3; IR (ATR) 3076, 2980, 2933, 1730, 1588, 1434, 1160 cmꢁ1; HRMS
(FAB) calcd for C16H16NO2S 286.0902 ([MþH]þ), found 286.0905.
HRMS (ESI) calcd for C19H18NO3 308.1287 ([MþH]þ), found 308.1297.
4.1.17. Methyl 5-(2-cyanophenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5q). Brown gum; 1H NMR (500 MHz, CDCl3)
d
8.60 (d, J¼4.0 Hz,
1H), 7.70 (td, J¼2.0, 7.5 Hz, 1H), 7.58 (d, J¼7.5 Hz, 1H), 7.48 (td, J¼1.5,
8.0 Hz,1H), 7.45 (d, J¼7.5 Hz,1H), 7.40 (d, J¼7.5 Hz,1H), 7.34 (td, J¼1.0,
7.5 Hz, 1H), 7.22 (ddd, J¼1.0, 5.0, 8.0 Hz, 1H), 4.17 (dd, J¼7.0, 8.0 Hz,
1H), 3.75 (s, 3H), 3.33 (dd, J¼7.0, 17.0 Hz, 1H), 3.18 (dd, J¼8.0, 17.0 Hz,
4.1.11. Ethyl 2-(pyridin-2-yl)-5-(pyridin-3-yl)pent-4-ynoate
(5k). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.60 (d, J¼5.0 Hz,
1H), 8.51 (d, J¼1.0 Hz, 1H), 8.47 (dd, J¼1.5, 5.0 Hz, 1H), 7.69 (td,
J¼1.5, 8.0 Hz, 1H), 7.57 (dt, J¼2.0, 8.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H),
7.22 (ddd, J¼1.0, 5.0, 7.5 Hz, 1H), 7.18 (dd, J¼5.0, 8.0 Hz, 1H),
4.26e4.16 (m, 2H), 4.10 (t, J¼7.5 Hz, 1H), 3.23 (dd, J¼7.0, 17.0 Hz,
1H), 3.12 (dd, J¼8.0, 17.0 Hz, 1H), 1.23 (t, J¼7.0 Hz, 3H); 13C NMR
1H);13CNMR(125 MHz, CDCl3)
d171.8, 156.8, 149.8,137.0, 132.6,132.6,
132.5,132.3,128.0,127.4,123.8,122.7,117.7,115.2, 94.4, 78.7, 52.6, 52.5,
22.55; IR (ATR) 3067, 2952, 2229, 1735,1590,1434,1163 cmꢁ1; HRMS
(ESI) calcd for C18H15N2O2 291.1134 ([MþH]þ), found 291.1136.
(125 MHz, CDCl3)
d 171.5, 157.2, 152.5, 149.8, 148.3, 138.5, 136.7,
123.3, 123.0, 122.7, 120.7, 90.9, 79.1, 61.4, 52.9, 22.5, 14.3; IR (ATR)
3049, 2980, 2934, 2226, 1731, 1588, 1473, 1161 cmꢁ1; HRMS (FAB)
calcd for C17H17N2O2 281.1290 ([MþH]þ), found 281.1280.
4.1.18. 2-(Pyridin-2-yl)-5-(pyridin-3-yl)pent-4-ynenitrile
(5r). Yellow gum; 1H NMR (400 MHz, CDCl3)
d
8.64 (d, J¼2.8 Hz,
1H), 8.58 (s, 1H), 8.51 (d, J¼3.2 Hz, 1H), 7.78 (td, J¼1.2, 7.6 Hz, 1H),
7.66 (d, J¼8.0 Hz, 1H), 7.56 (d, J¼7.6 Hz, 1H), 7.32 (t, J¼7.5 Hz, 1H),
7.24 (t, J¼8.0 Hz, 1H), 4.29 (t, J¼6.4 Hz, 1H), 3.26 (dd, J¼6.4,
17.2 Hz, 1H), 3.19 (dd, J¼7.2, 16.8 Hz, 1H); 13C NMR (100 MHz,
4.1.12. Methyl 5-phenyl-2-(pyridin-2-yl)pent-4-ynoate (5l). Brown
solid, mp: 51.2e53.7 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.59 (d,
J¼4.5 Hz, 1H), 7.67 (t, J¼7.5 Hz, 1H), 7.37 (d, J¼8.0 Hz, 1H), 7.29e7.27
(m, 2H), 7.24e7.19 (m, 4H), 4.11 (t, J¼8.0 Hz, 1H), 3.73 (s, 3H), 3.21
(dd, J¼7.0, 17.0 Hz, 1H), 3.09 (dd, J¼8.5, 17.0 Hz, 1H); 13C NMR
CDCl3)
d 153.4, 152.5, 150.2, 148.8, 137.4, 123.6, 122.3, 120.0,
118.9, 87.7, 81.1, 39.3, 24.9; IR (ATR) 3051, 2922, 2246, 1588,
1435 cmꢁ1; HRMS (ESI) calcd for C15H12N3 234.1031 ([MþH]þ),
found 234.1021.
(125 MHz, CDCl3)
d 172.1, 157.3, 149.8, 136.7, 131.6, 128.2, 127.9,
123.5, 123.4, 122.6, 87.0, 82.4, 53.0, 52.5, 22.5; IR (ATR) 3033, 2954,
2113, 1736, 1589, 1434, 1172 cmꢁ1; HRMS (ESI) calcd for C17H16NO2
266.1181 ([MþH]þ), found 266.1181.
4.1.19. Methyl 4-(4-cyano-4-(pyridin-2-yl)but-1-yn-1-yl)benzoate
(5s). Yellow solid, mp: 88.4e89.9 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.65 (d, J¼4.0 Hz,1H), 7.95 (d, J¼8.4 Hz, 2H), 7.78 (td, J¼2.0, 8.0 Hz,
4.1.13. Methyl 5-(4-fluorophenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5m). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.61 (d, J¼4.0 Hz,
1H), 7.56 (d, J¼7.6 Hz, 1H), 7.42 (d, J¼8.4 Hz, 2H), 7.32 (ddd, J¼0.8,
4.8, 7.6 Hz, 1H), 4.29 (t, J¼6.4 Hz, 1H), 3.19 (s, 3H), 3.25 (dd, J¼6.0,
16.8 Hz, 1H), 3.18 (dd, J¼7.6, 16.8 Hz, 1H); 13C NMR (100 MHz,
1H), 7.69 (td, J¼2.0, 8.0 Hz, 1H), 7.36 (d, J¼8.0 Hz, 1H), 7.27e7.22 (m,
3H), 6.94 (t, J¼8.5 Hz, 2H), 4.10 (t, J¼8.0 Hz, 1H), 3.74 (s, 3H), 3.20
(dd, J¼7.0, 17.0 Hz, 1H), 3.07 (dd, J¼8.0, 17.0 Hz, 1H); 13C NMR
CDCl3)
d 166.6, 153.5, 150.2, 137.4, 131.8, 129.7, 129.5, 127.5, 123.6,
122.3, 119.0, 87.3, 83.7, 52.4, 39.4, 25.0; IR (ATR) 3064, 2952, 2237,
1705, 1590, 1436, 1280 cmꢁ1; HRMS (ESI) calcd for C18H15N2O2
291.1134 ([MþH]þ), found 291.1120.
(125 MHz, CDCl3)
d 172.1, 163.3, 161.3, 157.2, 149.8, 136.8, 133.5,
133.4, 123.4, 122.7, 119.6, 115.6, 115.4, 86.7, 81.3, 53.0, 52.6, 22.5; IR
(ATR) 3056, 2952, 1736, 1590, 1505, 1434, 1218, 1155 cmꢁ1; HRMS
(ESI) calcd for C17H15FNO2 284.1087 ([MþH]þ), found 284.1090.
4.1.20. 2-(Pyridin-2-yl)-5-(3-(trifluoromethyl)phenyl)pent-4-
ynenitrile (5t). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.64 (d,
4.1.14. Methyl 5-(4-chlorophenyl)-2-(pyridin-2-yl)pent-4-ynoate
(5n). Yellow solid, mp: 81.8e83.9 ꢀC; 1H NMR (500 MHz, CDCl3)
J¼4.5 Hz, 1H), 7.77 (t, J¼7.5 Hz, 1H), 7.60 (s, 1H), 7.56e7.53 (m, 3H),

8204
Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
7.41 (t, J¼8.0 Hz, 1H), 7.32e7.30 (m, 1H), 4.29 (t, J¼6.5 Hz, 1H), 3.24
(dd, J¼6.0, 17.0 Hz, 1H), 3.18 (dd, J¼7.0, 17.0 Hz, 1H); 13C NMR
6.5 Hz, 1H), 4.39 (q, J¼7.0 Hz, 2H), 1.41 (t, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3)
d 183.4, 163.9, 143.8, 140.5, 132.5, 129.49, 129.46,
(125 MHz, CDCl3)
d
153.5, 150.2, 137.4, 135.0, 131.4, 131.1, 130.8,
129.3, 128.6, 122.0, 119.9, 118.3, 116.0, 115.0, 107.3, 60.5, 14.7; IR
(ATR) 3120, 2974, 2229, 1680, 1614, 1513, 1484, 1212 cmꢁ1; HRMS
(ESI) calcd for C19H15N2O3 319.1083 ([MþH]þ), found 319.1075.
130.6, 128.9, 128.59, 128.56, 128.53, 128.5, 125.0, 124.99, 124.96,
124.9,124.8,123.8, 123.6, 122.7, 122.3, 119.0, 86.0, 82.9, 39.3, 24.8; IR
(ATR) 3055, 2921, 2246, 1589, 1434, 1238, 1165, 1121 cmꢁ1; HRMS
(ESI) calcd for C17H12F3N2 301.0953 ([MþH]þ), found 301.0947.
4.2.4. Ethyl 3-(4-acetylbenzoyl)indolizine-1-carboxylate
(8d). Yellow solid, mp: 138.1e140.9 ꢀC; 1H NMR (500 MHz, CDCl3)
4.1.21. 5-(3-Chlorophenyl)-2-(pyridin-2-yl)pent-4-ynenitrile
d
9.98 (d, J¼7.0 Hz, 1H), 8.41 (d, J¼9.0 Hz, 1H), 8.10 (d, J¼8.0 Hz, 2H),
(5u). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.63 (d, J¼5.0 Hz,
7.89 (d, J¼8.0 Hz, 2H), 7.77 (s, 1H), 7.49 (t, J¼7.5 Hz, 1H), 7.13 (t,
J¼7.0 Hz,1H), 4.38 (q, J¼7.0 Hz, 2H), 2.69 (s, 3H),1.40 (t, J¼7.0 Hz, 3H);
1H), 7.77 (td, J¼1.5, 7.5 Hz, 1H), 7.55 (d, J¼7.5 Hz, 1H), 7.34e7.19 (m,
5H), 4.27 (t, J¼7.0 Hz, 1H), 3.22 (dd, J¼6.0, 17.0 Hz, 1H), 3.16 (dd,
13C NMR (125 MHz, CDCl3)
d 197.6, 184.5, 163.9, 143.9, 140.2, 139.1,
J¼7.5, 17.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
153.5, 150.2, 137.4,
129.4, 129.22, 129.15, 128.4, 128.3, 122.3, 119.7, 115.7, 106.9, 60.3, 27.0,
14.6; IR (ATR) 3120, 2995, 1681, 1603, 1513, 1480, 1271 cmꢁ1; HRMS
(ESI) calcd for C20H18NO4 336.1236 ([MþH]þ), found 336.1231.
134.2, 131.7, 130.0, 129.6, 128.7, 124.5, 123.6, 122.3, 119.0, 85.5, 83.0,
39.4, 24.8; IR (ATR) 3060, 2919, 2246, 1590, 1472, 1151, 1094 cmꢁ1
;
HRMS (ESI) calcd for C16H12ClN2 267.0689 ([MþH]þ), found
267.0683.
4.2.5. Ethyl 3-(4-(methoxycarbonyl)benzoyl)indolizine-1-
carboxylate (8e). Brown solid, mp: 118.7e120.3 ꢀC; 1H NMR
4.1.22. 5-(2-Fluorophenyl)-2-(pyridin-2-yl)pent-4-ynenitrile
(500 MHz, CDCl3)
d
9.99 (d, J¼7.0 Hz, 1H), 8.42 (d, J¼9.0 Hz, 1H),
(5v). Yellow gum; 1H NMR (500 MHz, CDCl3)
d
8.63 (d, J¼4.0 Hz,
8.19 (d, J¼8.0 Hz, 2H), 7.86 (d, J¼8.0 Hz, 2H), 7.77 (s, 1H), 7.50 (t,
1H), 7.76 (td, J¼1.5, 7.5 Hz, 1H), 7.57 (d, J¼8.0 Hz, 1H), 7.36 (td, J¼1.5,
7.5 Hz, 1H), 7.31e7.25 (m, 2H), 7.07e7.01 (m, 2H), 4.28 (t, J¼6.5 Hz,
1H), 3.26 (dd, J¼6.5, 17.0 Hz, 1H), 3.20 (dd, J¼7.0, 17.0 Hz, 1H); 13C
J¼8.0 Hz, 1H), 7.14 (t, J¼7.0 Hz, 1H), 4.38 (q, J¼7.0 Hz, 2H), 3.98 (s,
3H), 1.33 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 184.6, 166.6,
164.0, 143.9, 140.3, 132.6, 129.8, 129.4, 129.3, 128.9, 128.3, 122.4,
119.7, 115.8, 106.9, 60.4, 52.6, 14.7; IR (ATR) 3000, 2926, 1721, 1700,
1603, 1436, 1274, 1217 cmꢁ1; HRMS (ESI) calcd for C20H18NO5
352.1185 ([MþH]þ), found 352.1184.
NMR (125 MHz, CDCl3)
d 164.0, 162.0, 153.5, 150.1, 137.3, 133.74,
133.73, 130.13, 130.06, 123.98, 123.95, 123.5, 122.5, 119.0, 115.6,
115.4, 111.4, 111.3, 89.43, 89.40, 77.8, 39.3, 25.1; IR (ATR) 3060, 2923,
2245, 1588, 1491, 1215, 1104 cmꢁ1; HRMS (ESI) calcd for C16H12FN2
251.0985 ([MþH]þ), found 251.0982.
4.2.6. Ethyl 3-(3-(methoxycarbonyl)benzoyl)indolizine-1-
carboxylate (8f). White solid, mp: 145.0e145.8 ꢀC; 1H NMR
4.2. General procedure for iodine-mediated cyclization
(500 MHz, CDCl3)
d
9.97 (d, J¼7.0 Hz, 1H), 8.46 (s, 1H), 8.41 (d,
J¼9.0 Hz, 1H), 8.25 (d, J¼7.5 Hz, 1H), 7.99 (d, J¼7.5 Hz, 1H), 7.77 (s,
1H), 7.61 (t, J¼7.5 Hz, 1H), 7.48 (ddd, J¼1.0, 7.0, 9.0 Hz, 1H), 7.12 (td,
J¼1.0, 7.0 Hz, 1H), 4.38 (q, J¼7.0 Hz, 2H), 3.96 (s, 3H), 1.40 (t,
To a stirred solution of alkyne 5 (0.14 mmol, 1 equiv) in CH3CN/
H2O (¼5:1) was added iodine (3 equiv) at room temperature. After
the reaction was complete, the reaction mixture was concentrated
under reduced pressure. The residue was diluted with dichloro-
methane, and washed with aqueous Na2S2O3 and aqueous NaHCO3.
The aqueous layer was extracted with dichloromethane one more
time. The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate/dichloro-
methane) to afford the 3-acylated indolizine 8.
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 184.5, 166.5, 164.0,
140.4, 140.2, 133.1, 132.4, 130.0, 129.4, 129.2, 128.7, 128.1, 122.4,
119.7, 115.6, 106.8, 60.3, 52.5, 14.7; IR (ATR) 3128, 2981, 1731, 1709,
1614, 1484, 1288, 1206 cmꢁ1; HRMS (ESI) calcd for C20H18NO5
352.1185 ([MþH]þ), found 352.1181.
4.2.7. Ethyl 3-(4-methoxybenzoyl)indolizine-1-carboxylate
(8g). Pale yellow solid, mp: 106.9e108.5 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
9.95 (d, J¼7.0 Hz, 1H), 8.39 (d, J¼9.0 Hz, 1H), 7.83 (s, 1H),
4.2.1. Ethyl 3-benzoylindolizine-1-carboxylate (8a). Pale brown
7.74 (d, J¼8.0 Hz, 2H), 7.44 (t, J¼7.5 Hz, 1H), 7.32 (d, J¼8.0 Hz, 2H),
solid, mp: 80.7e83.1 ꢀC; 1H NMR (500 MHz, CDCl3)
d 9.98 (d,
7.08 (t, J¼8.5 Hz, 1H), 4.38 (q, J¼7.0 Hz, 2H), 2.49 (s, 3H), 1.40 (t,
J¼7.0 Hz, 1H), 8.40 (d, J¼9.0 Hz, 1H), 7.86e7.78 (m, 3H), 7.62e7.55
(m, 1H), 7.55e7.49 (m, 2H), 7.46 (dd, J¼7.5, 8.5 Hz, 1H), 7.10 (td,
J¼1.0, 7.0 Hz, 1H), 4.38 (q, J¼7.0 Hz, 2H), 1.40 (t, J¼7.0 Hz, 3H); 13C
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 185.6, 164.3, 142.2,
139.9, 137.3, 129.3, 129.2, 128.9, 127.6, 122.8, 119.6, 115.3, 106.2, 60.2,
21.7, 14.7; IR (ATR) 3114, 2978, 1682, 1603, 1518, 1482, 1203 cmꢁ1
;
NMR (125 MHz, CDCl3)
d
185.7,164.2,140.1,131.6,129.4,129.2,129.1,
HRMS (ESI) calcd for C19H18NO4 324.1236 ([MþH]þ), found
128.5, 127.8,122.7,119.7,115.4,106.4, 60.3, 14.7; IR (ATR) 3061, 2979,
1689, 1632, 1611, 1477, 1209 cmꢁ1; HRMS (FAB) calcd for C18H16NO3
294.1130 ([MþH]þ), found 294.1135.
324.1231.
4.2.8. Ethyl 3-(3-methoxybenzoyl)indolizine-1-carboxylate
(8h). White solid, mp: 125.0e125.9 ꢀC; 1H NMR (500 MHz, CDCl3)
4.2.2. Ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate (8b). Yellow
d
9.97 (d, J¼7.0 Hz,1H), 8.40 (d, J¼9.0 Hz,1H), 7.85 (s, 1H), 7.50e7.36
solid, mp: 139.2e140.5 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.99 (d,
(m, 3H), 7.34 (s, 1H), 7.16e7.06 (m, 2H), 4.38 (q, J¼7.0 Hz, 2H), 3.88
J¼7.0 Hz, 1H), 8.44 (d, J¼9.0 Hz, 1H), 8.38 (d, J¼8.5 Hz, 2H), 7.96 (d,
J¼8.5 Hz, 2H), 7.74 (s, 1H), 7.54 (ddd, J¼1.0, 7.0, 9.0 Hz, 1H), 7.17 (td,
J¼1.0, 7.0 Hz, 1H), 4.39 (q, J¼7.0 Hz, 2H), 1.40 (t, J¼7.0 Hz, 3H); 13C
(s, 3H), 1.40 (s, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 185.4,
164.2, 159.7, 141.4, 140.1, 129.5, 129.4, 129.2, 127.8, 122.6, 121.7, 119.7,
117.8, 115.4, 113.8, 106.5, 60.2, 55.6, 14.7; IR (ATR) 3122, 2920, 1693,
1606, 1577, 1425, 1217 cmꢁ1; HRMS (ESI) calcd for C19H18NO4
324.1236 ([MþH]þ), found 324.1232.
NMR (125 MHz, CDCl3)
d 183.0, 163.8, 149.5, 145.5, 140.5, 129.9,
129.5, 129.3, 128.7, 123.8, 122.0, 119.8, 116.1, 107.4, 60.5, 14.7; IR
(ATR) 3111, 2977, 1705, 1616, 1598, 1478, 1202 cmꢁ1; HRMS (ESI)
calcd for C18H15N2O5 339.0981 ([MþH]þ), found 339.0974.
4.2.9. Ethyl 3-(4-methylbenzoyl)indolizine-1-carboxylate
(8i). Green solid, mp: 104.6e106.7 ꢀC; 1H NMR (500 MHz, CDCl3)
4.2.3. Ethyl 3-(4-cyanobenzoyl)indolizine-1-carboxylate (8c). Pale
d
9.95 (d, J¼7.0 Hz, 1H), 8.39 (d, J¼9.0 Hz, 1H), 7.83 (s, 1H), 7.74 (d,
yellow solid, mp: 135.7e136.4 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.98
J¼8.0 Hz, 2H), 7.44 (t, J¼7.5 Hz, 1H), 7.32 (d, J¼8.0 Hz, 2H), 7.08 (t,
J¼7.0 Hz, 1H), 4.38 (q, J¼7.0 Hz, 2H), 2.46 (s, 3H), 1.40 (t, J¼7.0 Hz,
(d, J¼7.0 Hz, 1H), 8.43 (d, J¼9.0 Hz, 1H), 7.90 (d, J¼8.5 Hz, 2H), 7.83
(d, J¼8.0 Hz, 2H), 7.74 (s, 1H), 7.52 (t, J¼8.0 Hz, 1H), 7.16 (td, J¼1.0,
3H); 13C NMR (125 MHz, CDCl3)
d 185.6, 164.3, 142.2, 139.9, 137.3,

Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
8205
129.3, 129.2, 128.9, 127.6, 122.8, 119.6,115.3,106.2, 60.2, 21.7,14.7; IR
(ATR) 3124, 2980, 1633, 1604, 1518, 1481, 1202 cmꢁ1; HRMS (ESI)
calcd for C19H18NO3 308.1287 ([MþH]þ), found308.1281.
J¼7.0 Hz, 1H), 3.90 (s, 3H), 2.69 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
197.6, 184.5, 164.3, 143.8, 140.3, 139.1, 129.4, 129.3, 129.2, 128.43,
128.36, 122.4, 119.6, 115.8, 106.5, 51.5, 27.0; IR (ATR) 3135, 2924,
1697, 1680, 1612, 1515, 1442, 1207 cmꢁ1; HRMS (ESI) calcd for
C19H16NO4 322.1079 ([MþH]þ), found 322.1071.
4.2.10. Ethyl 3-(thiophene-2-carbonyl)indolizine-1-carboxylate
(8j). Yellow solid, mp: 100.2e102.6 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.86 (d, J¼7.0 Hz, 1H), 8.41 (d, J¼9.0 Hz, 1H), 8.16 (s, 1H), 7.84 (dd,
4.2.17. Methyl 3-(2-cyanobenzoyl)indolizine-1-carboxylate
J¼1.0, 3.5 Hz,1H), 7.69 (d, J¼4.5 Hz,1H), 7.45(t, J¼8.0 Hz,1H), 7.22 (dd,
J¼3.5, 5.0 Hz,1H), 7.08 (t, J¼7.0 Hz,1H), 4.42 (q, J¼7.0 Hz, 2H), 1.44 (t,
(8q). Pale yellow solid, mp: 172.4e173.1 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
10.04 (d, J¼7.0 Hz, 1H), 8.41 (d, J¼9.0 Hz, 1H), 7.85 (d,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
176.6, 164.2, 144.4, 140.0,
J¼8.0 Hz, 1H), 7.75e7.72 (m, 2H), 7.67e7.63 (m, 1H), 7.63 (s, 1H),
132.21, 132.16, 129.2, 127.9, 127.7, 127.4, 122.3, 119.7, 115.3,106.5, 60.3,
14.7; IR (ATR) 3133, 2975, 1692, 1684, 1577, 1413, 1208 cmꢁ1; HRMS
(ESI) calcd for C16H14NO3S 300.0694 ([MþH]þ), found 300.0690.
7.54 (t, J¼8.0 Hz, 1H), 7.18 (t, J¼7.0 Hz, 1H), 3.89 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 181.9, 164.1, 143.3, 140.6, 134.1, 132.4, 130.8,
129.7,129.4,129.0,122.0,119.7,117.3,116.2,111.7,107.1, 51.5; IR (ATR)
3100, 2955, 2227, 1712, 1694, 1609, 1439, 1209 cmꢁ1; HRMS (ESI)
calcd for C18H13N2O3 305.0926 ([MþH]þ), found 305.0925.
4.2.11. Ethyl 3-nicotinoylindolizine-1-carboxylate (8k). Brown solid,
mp: 106.2e107.3 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.99 (d, J¼7.0 Hz,
1H), 9.05 (d, J¼1.5 Hz, 1H), 8.82 (dd, J¼1.5, 5.0 Hz, 1H), 8.44 (d,
J¼9.0 Hz, 1H), 8.12 (dt, J¼2.0, 8.0 Hz, 1H), 7.82 (s, 1H), 7.56e7.43 (m,
2H), 7.14 (td, J¼1.5, 7.0 Hz,1H), 4.39 (q, J¼7.0 Hz, 2H),1.40 (t, J¼7.0 Hz,
4.2.18. 3-Nicotinoylindolizine-1-carbonitrile (8r). White solid, mp:
223.6e225.1 ꢀC; 1H NMR (400 MHz, CDCl3)
d
9.97 (d, J¼7.2 Hz, 1H),
9.02 (s, 1H), 8.84 (d, J¼4.4 Hz, 1H), 8.10 (d, J¼8.0 Hz, 1H), 7.88 (d,
J¼8.8 Hz,1H), 7.64 (s,1H), 7.56 (t, J¼7.6 Hz,1H), 7.50 (dd, J¼5.2, 7.6 Hz,
3H); 13C NMR (125 MHz, CDCl3)
d 183.1, 163.9, 152.2, 149.9, 140.4,
136.4, 135.7, 129.4, 129.2, 128.4, 123.6, 122.3, 119.8, 115.9, 107.1, 60.4,
14.7; IR (ATR) 3155, 2983, 1695, 1610, 1514, 1477, 1211 cmꢁ1; HRMS
(ESI) calcd for C17H15N2O3 295.1083 ([MþH]þ), found 295.1076.
1H), 7.20 (t, J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 182.8, 152.7,
149.7, 141.6, 136.3, 135.0, 129.7, 129.5, 128.7, 123.6, 122.7, 117.8, 116.5,
114.9, 85.7; IR (ATR) 3085, 2914, 2217, 1614, 1587, 1476 cmꢁ1; HRMS
(ESI) calcd for C15H10N3O 248.0824 ([MþH]þ), found 248.0808.
4.2.12. Methyl 3-benzoylindolizine-1-carboxylate (8l). Brown solid,
mp: 152.5e153.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.98 (d, J¼7.0 Hz,
4.2.19. Methyl 4-(1-cyanoindolizine-3-carbonyl)benzoate (8s). Yellow
1H), 8.41 (d, J¼9.0 Hz, 1H), 7.82 (s, 1H), 7.81 (d, J¼7.0 Hz, 2H), 7.58 (t,
solid, mp: 238.5e240.2 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.98 (d,
J¼7.5 Hz, 1H), 7.52 (t, J¼7.5 Hz, 2H), 7.47 (t, J¼7.5 Hz, 1H), 7.11 (t,
J¼6.8 Hz, 1H), 8.20 (d, J¼7.6 Hz, 2H), 7.87e7.84 (m, 3H), 7.60 (s, 1H),
J¼7.0 Hz,1H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 185.8, 164.6,
7.54 (t, J¼7.6 Hz, 1H), 7.21 (t, J¼6.4 Hz, 1H), 3.99 (s, 3H); 13C NMR
140.0,131.6,129.4,129.2,129.1,128.5,127.9,122.7,119.6,115.5,106.0,
51.4; IR (ATR) 3033, 2924, 1691, 1619, 1516, 1451, 1199 cmꢁ1; HRMS
(ESI) calcd for C17H14NO3 280.0974 ([MþH]þ), found 280.0967.
(100 MHz, CDCl3) d 184.3, 166.4, 143.1, 141.6, 133.1, 129.9, 129.7, 129.6,
128.9, 128.5, 122.8, 117.7, 116.4, 115.0, 85.5, 52.7; IR (ATR) 3119, 2921,
2219, 1718, 1614, 1478 cmꢁ1; HRMS (ESI) calcd for C18H13N2O3
305.0926 ([MþH]þ), found 305.0921.
4.2.13. Methyl 3-(4-fluorobenzoyl)indolizine-1-carboxylate
(8m). Yellow solid, mp: 168.9e170.0 ꢀC; 1H NMR (500 MHz,
CDCl3)
4.2.20. 3-(3-(Trifluoromethyl)benzoyl)indolizine-1-carbonitrile
(8t). White solid, mp: 186.2e186.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.93 (d, J¼7.0 Hz,1H), 8.40 (d, J¼9.0 Hz,1H), 7.85 (dd, J¼5.0,
9.0 Hz, 2H), 7.79 (s, 1H), 7.47 (t, J¼8.0 Hz, 1H), 7.20 (t, J¼8.5 Hz, 2H),
d
9.96 (d, J¼7.0 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J¼7.5 Hz, 1H), 7.87 (d,
7.11 (t, J¼7.0 Hz, 1H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3)
J¼8.0 Hz, 2H), 7.68 (t, J¼8.0 Hz, 1H), 7.59 (s, 1H), 7.55 (t, J¼8.0 Hz,
d
184.2, 166.0, 164.5, 163.9, 140.1, 136.2, 136.1, 131.5, 131.4, 129.3,
1H), 7.21 (t, J¼7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 183.5, 141.6,
128.9, 128.0, 122.5, 119.6, 115.7, 115.57, 115.55, 106.1, 51.5; IR (ATR)
3062, 2951, 1689, 1606, 1510, 1455, 1342, 1199 cmꢁ1; HRMS (ESI)
calcd for C17H13FNO3 298.0879 ([MþH]þ), found 298.0876.
140.0, 132.1, 131.5, 131.3, 129.7, 129.4, 129.3, 128.57, 128.55, 125.9,
125.83, 125.80, 125.77, 122.6, 117.8, 116.4, 114.9, 85.6; IR (ATR) 3127,
2923, 2227, 1620, 1517, 1480, 1320, 1216, 1108 cmꢁ1; HRMS (ESI)
calcd for C17H10F3N2O 315.0745 ([MþH]þ), found 315.0735.
4.2.14. Methyl 3-(4-chlorobenzoyl)indolizine-1-carboxylate
(8n). White solid, mp: 155.7e156.2 ꢀC; 1H NMR (500 MHz, CDCl3)
4.2.21. 3-(3-Chlorobenzoyl)indolizine-1-carbonitrile
(8u). Pale
9.94
d
9.94 (d, J¼7.0 Hz, 1H), 8.41 (d, J¼9.0 Hz, 1H), 7.78 (d, J¼4.5 Hz, 2H),
brown solid, mp: 199.1e199.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.76 (s, 1H), 7.52e7.45 (m, 3H), 7.11 (t, J¼3.5 Hz,1H), 3.91 (s, 3H); 13C
(d, J¼7.0 Hz, 1H), 7.85 (d, J¼8.5 Hz, 1H), 7.77 (s, 1H), 7.66 (d,
J¼7.5 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J¼8.5 Hz, 1H), 7.55e7.51 (m, 1H),
7.47 (t, J¼8.0 Hz, 1H), 7.19 (t, J¼7.0 Hz, 1H); 13C NMR (125 MHz,
NMR (125 MHz, CDCl3)
d 184.2, 164.4, 140.2, 138.3, 138.0, 130.5,
129.3, 129.0, 128.8, 128.1, 122.4, 119.6, 115.7, 106.3, 51.5; IR (ATR)
3144, 2952, 1700, 1611, 1515, 1478, 1210, 1145, 1046 cmꢁ1; HRMS
(ESI) calcd for C17H13ClNO3 314.0584 ([MþH]þ), found 314.0579.
CDCl3)
d 183.5, 141.6, 140.9, 135.0, 132.1, 130.0, 129.7, 129.5, 129.0,
128.4, 127.1, 122.6, 117.8, 116.3, 115.0, 85.4; IR (ATR) 3135, 2925,
2226, 1615, 1564, 1478, 1219 cmꢁ1
; HRMS (ESI) calcd for
4.2.15. Methyl 3-(2-acetylbenzoyl)indolizine-1-carboxylate
C16H10ClN2O 281.0482 ([MþH]þ), found 281.0473.
(8o). Pale yellow solid, mp: 157.6e160.2 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
10.00 (d, J¼6.5 Hz,1H), 8.36 (d, J¼9.5 Hz,1H), 7.88 (d, J¼8.0 Hz,
4.2.22. 3-(2-Fluorobenzoyl)indolizine-1-carbonitrile (8v). White solid,
1
1H), 7.65e7.57 (m, 2H), 7.52 (d, J¼7.0 Hz,1H), 7.46 (t, J¼8.0 Hz,1H), 7.39
mp: 152.1e152.5 ꢀC; H NMR (500 MHz, CDCl3)
d
10.02 (d, J¼7.0 Hz,
(s, 1H), 7.12 (t, J¼6.5 Hz, 1H), 3.86 (s, 3H), 2.54 (s, 3H); 13C NMR
1H), 7.84 (d, J¼9.0 Hz, 1H), 7.57e7.52 (m, 3H), 7.51 (d, J¼2.0 Hz, 1H),
(125 MHz, CDCl3) d 199.2, 186.8, 164.5, 140.8, 139.9, 137.9, 132.0, 129.9,
7.29 (t, J¼7.5 Hz, 1H), 7.24e7.19 (m, 2H); 13C NMR (125 MHz, CDCl3)
129.50,129.46,128.8,127.93.127.90,123.3,119.6,115.6,106.0, 51.4, 28.2;
IR (ATR) 3123, 2923, 1697, 1678, 1614, 1522, 1443, 1215 cmꢁ1; HRMS
(ESI) calcd for C19H16NO4 322.1079 ([MþH]þ), found 322.1073.
d 181.2, 160.6, 158.6, 141.6, 132.9, 132.8, 130.2, 130.2, 129.8, 129.8, 128.4,
124.5, 124.5, 117.8, 116.2, 116.5, 116.4, 114.9, 85.7, 77.4, 77.2, 76.9; IR
(ATR) 3076, 2925, 2227, 1608, 1518, 1479, 1224, 1205 cmꢁ1; HRMS (ESI)
calcd for C16H10FN2O 265.0777 ([MþH]þ), found 265.0773.
4.2.16. Methyl 3-(4-acetylbenzoyl)indolizine-1-carboxylate
(8p). Yellow solid, mp: 181.1e182.0 ꢀC; 1H NMR (500 MHz, CDCl3)
Acknowledgements
d
9.98 (d, J¼7.0 Hz, 1H), 8.41 (d, J¼9.0 Hz, 1H), 8.09 (d, J¼8.0 Hz, 2H),
7.88 (d, J¼8.0 Hz, 2H), 7.77 (s, 1H), 7.50 (t, J¼8.0 Hz, 1H), 7.14 (t,
We thank Yonsei University for financial support.

8206
Y. Jung, I. Kim / Tetrahedron 68 (2012) 8198e8206
Zhang, Y. Org. Lett. 2011, 13, 1342; (d) Mao, Z.; Li, X.; Lin, X.; Lu, P.; Wang, Y.
Supplementary data
Tetrahedron 2012, 68, 85; (e) Liu, Y.; Sun, J.-W. J. Org. Chem. 2012, 77, 1191.
4. (a) Togo, H.; Iida, S. Synlett 2006, 2159; (b) Mphahlele, M. J. Molecules 2009, 14,
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vatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem.dEur. J. 2012, 18, 5460.
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Copies of 1H and 13C NMR spectra of 5 and 8. Supplementary
data related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2012.07.068.
References and notes
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