Palladium-catalyzed construction of poly-substituted indolizinones

Article abstract of DOI:10.1016/j.tet.2012.04.091

We have developed a highly efficient one-pot approach to poly-substituted indolizinones from tertiary propargylic alcohols by using a palladium-catalyzed domino reaction. This reaction is proposed to proceed via successive aminopalladation, reductive elim

Full text of DOI:10.1016/j.tet.2012.04.091

Tetrahedron 68 (2012) 5464e5480
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed construction of poly-substituted indolizinones
*
Hanyang Cho, 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 3 April 2012
Received in revised form 20 April 2012
Accepted 23 April 2012
Available online 2 May 2012
We have developed a highly efficient one-pot approach to poly-substituted indolizinones from tertiary
propargylic alcohols by using a palladium-catalyzed domino reaction. This reaction is proposed to
proceed via successive aminopalladation, reductive elimination, and 1,2-shift. While our previous effort
to the same skeleton via 2-iodoindolizinones selected
a,b-unsaturated esters, terminal acetylenes, or
boronic acids as coupling partners, this strategy introduces new functional groups at the C2 position of
indolizinone core with (hetero)aryl halides or diallyl carbonate, expanding the substrate scope for
decoration at the C2 site. Furthermore, a new preparation route to tertiary propargylic alcohols for this
study is described to rapidly diversify the molecular framework.
Keywords:
Indolizinones
Palladium
Domino process
Aminopalladation
Reductive elimination
1,2-Migration
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
In connection with our latter report, we hope to construct the
same framework in a one-pot fashion by using the power of orga-
Synthetic maneuvers with unsaturated double or triple bonds
represent one of the main areas in organic chemistry owing to our
capability to activate these bondsdin particular, unactivated
onesdwith the aid of either catalytic or stoichiometric amounts of
reagents. A number of electrophilic reagents including halogens
and transition metals have increasingly played a pivotal role in
activating unsaturated chemical bonds, enabling us to make new
chemical bonds with either internal or external reacting partners.1
In this vein we have investigated the facile construction of
nitrogen-fused bicycles such as indolizines2,3 and indolizinones4,5
by employing electrophilic cyclization of alkenes or alkynes bear-
ing a pyridine unit (Scheme 1). Thus, 2-iodoindolizines 2 and 2,3-
disubstituted indolizines 4 were synthesized by 5-endo-dig iodo-
cyclization and 5-endo-trig iodocyclization/dehydroiodination, re-
spectively (Eqs. 1 and 2).6,7 More recently, a similar strategy was
applied to the synthesis of indolizinones by using subsequent 1,2-
shift after ring closing event, resulting in excellent yields of
2-iodoindolizinones 6 and 2,3-disubstituted indolizinones 9 under
mild conditions (Eqs. 3 and 4).8 The utility of 2-iodoindolizinones 6
was further demonstrated by rapid construction of a diversity-
oriented indolizinone library 7 via installation of various new
functional groups at the C2 position of the core skeleton under
palladium catalysis.9
nopalladium species to activate unsaturated bonds, thereby facili-
tating smooth ring closure. Indeed, this idea was successfully
realized to allow direct access to poly-substituted indolizinones
(7 from 5), which was recently communicated (Scheme 2).10,11 Here
we wish to describe the full details of this work based on Pd-
catalyzed domino process12 including a new preparation method
of tertiary propargylic alcohols, starting materials of this study.
2. Results and discussion
Palladium-catalyzed activation of alkenes or alkynes has served
as a highly useful means for triggering a number of subsequent
synthetic operations such as cyclization.13 For instance, (hetero)aryl
palladium intermediates formed in situ from oxidative addition of
(hetero)aryl halides to Pd(0) indeed facilitate diverse modes of
cyclization by intramolecularly tethered nucleophilic components
through coordination to unsaturated bonds, giving rise to many
useful carbo- or heterocycles very often with concomitant forma-
tion of multiple bonds.14 Guided by this concept, we surmised that
arylpalladium species would activate alkyne moiety of 5, inducing
smooth 5-endo-dig cyclization by the neighboring pyridine group
as shown in Scheme 3. The resulting indolizinium salt 10 would
undergo reductive elimination to give 11.15 Finally, 1,2-migration16
of R1 group would occur to furnish the desired indolizinone 7.
To explore the feasibility of this strategy, we began our
investigations with propargylic alcohol 12 and 1-iodo-4-
nitrobenzene as substrates. To our delight, the desired product 13
* 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.
doi:10.1016/j.tet.2012.04.091

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5465
OAc
OAc
5-endo-dig
iodocyclization
R1
(1)
I
R1
N
N
N
R2
R2
1
2
OAc
5-endo-trig
OAc
iodocyclization;
R2
R3
R2
R1
(2)
(3)
R1
N
dehydroiodination
R3
O
3
4
R1
O
R1
Pd-cataly zed
cross-coupling
5-endo-dig
R1 OH
iodocyclization;
R3
I
N
N
R2
1,2-shift
N
R2
R2
5
6
7
one pot approach
O
R1
R1 OH
5-endo-trig
R2
R3
iodocyclization;
R2
(4)
N
dehydroiodination
/ 1,2-shift
N
R3
8
9
Scheme 1. Our approaches to highly substituted indolizines and indolizinones.
acids for installing new functional groups at the C2 site, this pro-
tocol used (hetero)aryl halides as coupling partner, expanding the
substrate scope to decorate the C2 position of indolizinone.
To examine the reaction scope, we first reacted 12 with a variety
of aryl iodides under optimized conditions (Table 2). Excellent yields
of the desired products were obtained with aryl iodides containing
electron-withdrawing groups (entries 1e6). Thus, phenyl group
bearing 4-cyano-, 4-chloro-, 3-nitro-, 4-acetyl-, 4-ethoxycarbonyl-,
O
R1
cat. Pd(0), base
R3X
R1 OH
R3
N
N
R2
R2
5
7
Scheme 2. Pd-catalyzed one-pot approach to poly-substituted indolizinones.
R3X
Pd (0)
R3X
O
R1
Pd (0)
base
R1 OH
3
R PdX
R3
N
N
R2
R2
7
5
base
R1
R1
OH
R3
OH
PdR3
N
N
X
X
R2
R2
10
11
Scheme 3. Plausible mechanism.
was isolated in 69% yield from the reaction of 12 and 1-iodo-4-
nitrobenzene (1.5 equiv) in acetonitrile in the presence of 10 mol
% Pd(PPh3)4 and triethylamine (2.5 equiv) at 90 ꢀC after 13 h
(Table 1, entry 1). Switching the organic base to inorganic ones such
as Na2CO3 and Cs2CO3 gave inferior results (entries 2 and 3).
However, we were pleased to find that use of K2CO3 as base pro-
vided an excellent yield of 13 (entry 4). Catalyst loading can be
reduced to 5 mol % without compromising the yield while de-
creased yield of 13 was obtained with 1 mol % of Pd(0) (entries 5
and 6). When the reaction was carried out in THF instead of ace-
tonitrile, similar efficiency was observed (entry 7). Using dioxane or
DMF as solvent, however, produced lower yield (entries 8 and 9).
Other Pd(0) sources were tested to furnish the similar yield (entries
10 and 11). It is worth mentioning that compared with our previous
approach toward the same skeleton via 2-iodoindolizinones, which
or 3-trifluoromethyl moiety was successfully introduced at the C2
site of indolizinone. Furthermore, heterocycles such as thiophene
and 2-chloropyridine were incorporated without any event by using
the corresponding heteroaryl iodides (entries 11 and 12). On the
other hand, the reactions with aryl iodides having electron-donating
groups such as methoxyphenyl or tolyl gave the corresponding
products in modest yields presumably due to the slower oxidative
addition step (entries 7e10).
To demonstrate the generality of this process, several other
tertiary propargylic alcohols containing different substituents at R1
and R2 sites (26e37) were then prepared and subjected to the
identical reaction conditions with various (hetero)aryl iodides. As
outlined in Table 3, to our delight, a diverse array of densely-
functionalized indolizinones was readily constructed in good to
excellent yields. Again, electronic nature of aryl iodides seemed to
play a key role in determining isolated yield; electron-poor aryl
utilized
a,b-unsaturated esters, terminal acetylenes, or boronic

5466
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
Table 2 (continued)
Table 1
Reaction optimization
Entry
RI
Product
Yielda
O
Me
N
Me OH
N
O
Me
N
I
NO2
NO2
CO2Et
a
conditions
5
18
19
20
21
22
23
24
78
I
CO2Et
12
13
O
Yieldf
CF3
Me
N
Entry
Pd(0)
Base
Solvent
CF3
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Dioxane
DMF
CH3CN
CH3CN
69
50
56
96
99
80
98
85
52
91
90
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
6
92
47
55
53
45
77
I
b
c
O
OMe
Me
MeO
I
9
10
11
Pd2(dba)3þPh3Pd
N
7
Pd(OAc)2þPh3Pe
aA mixture of 12 (0.13 mmol), 1-iodo-4-nitrobenzene (1.5 equiv), Pd(0) (10 mol %),
and base (2.5 equiv) in solvent (1 mL) was heated at 90 ꢀC for 13 h unless otherwise
stated.
O
OMe
b
Me
Pd(PPh3)4 of 5 mol %was used.
Pd(PPh3)4 of 1 mol % was used.
Pd2(dba)3 of 5 mol % and 10 mol % PPh3 were used.
Pd(OAc)2 of 5 mol %and 10 mol % PPh3 were used.
c
OMe
d
N
8
e
I
f
Isolated yield (%).
O
Me
N
Table 2
OMe
Synthesis of indolizinones from the reaction of 12 with various (hetero)aryl iodides
9
I
OMe
Me
O
Pd(PPh3)4 (5 mol %)
K2CO3 (2.5 equiv)
RI (1.5 equiv)
Me
N
Me OH
N
R
O
CH3CN
90 °C
Me
N
Me
10
11
I
12
14-25
Entry
RI
Product
Yielda
100
O
Me
O
Me
N
S
CN
Cl
S
N
1
14
I
CN
Cl
I
O
Me
O
Cl
Me
N
Cl
N
2
15
86
I
N
N
12
25
95
I
O
NO2
Me
a
Isolated yield (%).
NO2
N
3
4
16
17
82
95
I
iodides furnished better yields of the products than electron-rich
aryl iodides. Notably, because of the difference in reactivity under
these conditions, reactions of 26 and 27 with 2-bromo-5-
iodopyridine only afforded 2-bromopyridine-containing indolizi-
nones, 39 and 44, providing a functional handle for further coupling
reactions (entries 2 and 7). Not only alkyl but also aryl groups in-
cluding pyridine and 4-methoxyphenyl moiety smoothly move
their position from propargylic sites to the ring junction of
indolizinones.
O
Me
O
O
N
I

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5467
Table 3
Synthesis of indolizinones from the reaction of diverse propargylic alcohols with various (hetero)aryl iodides
Pd(PPh3)4 (5 mol %)
K2CO3 (2.5 equiv)
O
R1
R1 OH
R3I (1.5 equiv)
R3
N
CH3CN
90 °C
N
R2
R2
26-37
38-81
Entry
Starting material
R3I
Product
Yielda
O
Me
Me OH
N
NO2
N
1
26
38
90
I
NO2
Me
Me
O
Me
N
Br
N
N
2
26
39
77
I
Br
Me
O
CF3
Me
CF3
N
3
26
40
89
I
Me
O
Me
N
Me OH
NO2
4
27
41
95
I
NO2
N
S
S
S
O
S
Me
Me
Me
5
27
42
63
I
N
Me
Me
O
Me
N
N
N
6
27
43
72
I
N
N
S
O
Me
N
Br
N
N
7
27
44
78
I
Br
(continued on next page)
S

5468
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
Table 3 (continued )
Entry
Starting material
Ph OH
R3I
Product
Yielda
98
O
Ph
N
NO2
8
9
28
28
45
46
I
NO2
N
O
NO 2
Ph
NO2
89
N
I
O
Ph
N
O
O
10
11
12
13
28
29
29
29
47
48
49
50
100
100
77
I
O
Me
N
Me OH
N
NO2
I
NO2
n-Bu
n-Bu
O
Me
N
N
I
N
n-Bu
O
Me
N
CO2Et
71
I
CO2Et
n-B u
O
Ph
Ph OH
N
NO 2
N
14
30
51
81
I
NO2
O
Ph
N
N
N
15
16
30
30
52
53
96
85
I
O
Ph
S
S
N
I

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5469
Table 3 (continued )
Entry
Starting material
R3I
Product
Yielda
O
Ph
N
Ph OH
N
NO2
17
18
19
31
31
31
54
55
56
99
100
78
I
NO2
N
N
O
NO2
Ph
N
NO2
I
N
O
Ph
N
S
S
I
N
N
N
O
OH
20
32
57
99
NO2
I
NO2
N
N
N
O
O
O
21
32
58
100
I
N
N
O
22
23
24
32
32
32
59
60
61
86
99
89
Cl
I
Cl
N
N
O
CO 2Me
I
CO2Me
N
N
O
CO 2Me
CO2Me
N
I
(continued on next page)

5470
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
Table 3 (continued )
Entry
Starting material
R3I
Product
Yielda
N
O
S
S
25
26
27
32
32
32
62
63
64
90
I
N
N
O
94
I
N
N
O
64
OMe
I
OMe
N
OMe
MeO
O
O
OH
O
28
33
65
91
I
N
N
OMe
O
29
30
31
33
33
33
66
67
68
99
91
60
I
CN
CN
N
OMe
O
N
N
I
N
N
N
OMe
O
I
OMe
OMe
N

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5471
Table 3 (continued )
Entry
Starting material
R3I
Product
Yielda
OMe
O
OMe
OMe
32
33
69
61
I
N
N
OH
N
N
O
33
34
35
36
34
34
34
34
70
71
72
73
93
97
91
68
I
I
CN
O
CN
O
N
N
n-Bu
n-Bu
O
N
n-Bu
N
O
I
Cl
Cl
N
n-Bu
N
O
S
S
I
N
n
-Bu
OMe
MeO
O
OH
37
35
74
81
I
CO2Me
CO2Me
N
N
OMe
MeO
O
OH
38
36
75
64
I
N
N
S
S
OMe
O
O
O
39
36
76
99
I
N
(continued on next page)
S

5472
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
Table 3 (continued )
Entry
Starting material
R3I
Product
Yielda
OMe
O
40
41
42
36
36
36
77
78
79
99
I
CN
CN
N
S
OMe
O
83
I
Cl
Cl
N
S
OMe
O
CO 2Me
CO2Me
100
I
N
S
O
Me
N
Me OH
Me
O
Me
O
43
44
37
37
80
81
63
86
I
N
O
Me
Me
CO2Me
N
I
CO2Me
a
Isolated yield (%).
It turned out that aryl bromides are also suitable reaction
partners of this cascade process with similar efficiency.17 Thus,
exposure of several aryl bromides to these reaction conditions
delivered the corresponding indolizinones in good to excellent
yields except 4-bromoanisole as shown in Table 4. Even 4-
bromobenzaldehyde participated well in this reaction to afford
indolizinone with 4-formylphenyl moiety at the C2 position in 68%
yield (entry 5).
catalytic system was switched to Pd(OAc)2 (5 mol %) and xantphos
(5 mol %) under identical conditions rather gave inferior result
(entry 2). Employing allyl acetate (10 equiv) as an allyl source
produced a complex mixture (entry 3). After extensive experi-
mentation, we found that the desired C2-allylated product 85 was
obtained by utilizing diallyl carbonate (10 equiv) in the presence of
Pd(PPh3)4 (5 mol %) and K2CO3 (2.5 equiv) albeit in modest yield
(entry 4). Under these conditions, O-allylated product 86 was ini-
tially formed as well but seemed to disappear after 18 h. In-
terestingly, O-allylated product was produced in high yield (84%) by
use of Pd(OAc)2 (5 mol %) and xantphos (5 mol %) instead of
Pd(PPh3)4 (5 mol %) in the absence of K2CO3 (entry 5). Based on the
previous reports where O- or N-allylated o-alkynylbenzenes de-
livered C-allylated products such as C2-allylated benzofurans or
We also investigated the possibility of installing an allyl group at
the C2 position of indolizinone by using
p-allylpalladium com-
plexes as alkyne activator (Table 5).18 Our efforts began with the
reaction of 12 with allyl bromide (10 equiv) in the presence of
Pd(PPh3)4 (5 mol %) and K2CO3 (2.5 equiv) in THF at 80 ꢀC, only
leading to O-allylated product 86 in 58% yield (entry 1). When the

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5473
Table 4
Table 5
Synthesis of indolizinones from the reaction of 12 with various (hetero)aryl
Reaction optimization for the synthesis of C2-allylated indolizinone
bromides
Pd(0)
base
O
O
Pd(PPh3)4 (5 mol %)
K2CO3 (2.5 equiv)
RBr (1.5 equiv)
Me
N
Me
N
Me
N
O
Me OH
X
Me OH
N
R
+
temperature
Ph
Ph
N
a
CH3CN
90 °C
Ph
conditions
12
85
86
12
13, 15, 22,
82, 83, 84
Entry Pd(0)
Base
X
Temp Product Yielde
(ꢀC)
1
2
3
4
5
6
7
Pd(PPh3)4
K2CO3 Br
80
80
80
86
86
d
58
Entry
RI
Product
Yielda
Pd(OAc)2þxantphosb K2CO3 Br
36
c
Pd(OAc)2þxantphos K2CO3 OAc
O
Me
Pd(PPh3)4
K2CO3 OCO2CH2CH]CH2 80
85
86
86
86
35
84d
35
22
Pd(OAc)2þxantphos
d
OCO2CH2CH]CH2 80
OCO2CH2CH]CH2 120
NO2
N
Pd(OAc)2þxantphos
d
1
13
95
Br
NO2
Pd(OAc)2þxantphos K2CO3 OCO2CH2CH]CH2 80
aA mixture of 12 (0.22 mmol), allylating reagent (10 equiv), Pd(0) (5 mol %), and
base (2.5 equiv) in THF (2 mL) was heated at 80 ꢀC for 18 h unless otherwise stated.
b
Xantphos¼4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
O
c
Me
Complex mixture.
d
Reaction time¼1.5 h.
Cl
e
Isolated yield (%).
N
2
3
4
15
84
28
68
Br
Cl
O
Pd(PPh3)4 (5 mol %)
K2CO3 (2.5 equiv)
Me
Me
N
O
O
N
Me
THF, 80 °C
Ph
Ph
OMe
86
85
N
22
Br
OMe
Scheme 4. Cycloisomerization attempts from 86 to 85.
Table 6 further demonstrated that we were able to obtain
O-allylated propargylic ethers or C2-allylated indolizinones
depending on the reaction conditions.
O
Me
N
82
Br
Table 6
Synthesis of O-allylated propargylic alcohols or C2-allylated indolizinones
R1
O
R1
O
conditions
Ba
R1 OH
A
or
+
N
O
R2
N
R2
Me
N
R2
88, 90, 92
CHO
31, 32, 36
87, 89, 91
N
5
83
68
Br
CHO
Entry
Starting material
Conditions
Product
Yieldb
1
2
3
4
5
6
31
31
32
32
36
36
A
B
A
B
A
B
87
88
89
90
91
92
90
28
73
68
80
43
O
O
Me
S
S
N
6
84
86
aConditions A: a mixture of propargylic alcohol (0.22 mmol), diallyl carbonate
(10 equiv), Pd(OAc)2 (5 mol %), xantphos (5 mol %) in THF (2 mL) was heated at 80 ꢀ
Br
C
for 3 h. Conditions B: a mixture of propargylic alcohol (0.22 mmol), diallyl carbonate
(10 equiv), Pd(PPh3)4 (5 mol %), and K2CO3 (2.5 equiv) in THF (2 mL) was heated at
80 ꢀC for 18 h.
a
Isolated yield (%).
b
Isolated yield (%).
indoles under Pd catalysis,18b,c,d,g we expected that increased re-
action temperature or prolonged heating of 86 might lead to the
same type of cycloisomerization. However, only decreased yield of
O-allylated product was observed, presumably, as a result of de-
composition (entries 6 and 7).
In order to confirm that an allyl migration from O to C2 position
of indolizinone does not occur in this system, we also subjected the
pure 86 to Pd(PPh3)4 (5 mol %) and K2CO3 (2.5 equiv) in THF at 80 ꢀC
for 24 h, resulting in no formation of C2-allylated product. Starting
material of 66% was recovered along with partial decomposition
(Scheme 4).
In the meantime, we sought to obtain the starting material, ter-
tiary propargylic alcohols with more diverse R2 group via a distinct
route from conventional method through nucleophilic addition of
appropriate terminal acetylides to pyridyl ketones 93 (Scheme 5,
route A).19 Although many terminal alkynes necessary for route A
are commerciallyavailable or can be easily prepared, for example, by
CoreyeFuchs protocol20 or OhiraeBestmann method,21 we decided
to assemble the same tertiary alcohols by way of Sonogashira
cross-coupling22 of terminal alkynes 94 with (hetero)aryl halides
(route B), thereby extending the structural diversity more easily.

5474
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
Sonogashira
R1 OH
R1 OH
O
Li
R2
coupling with R2X
R1
N
R2
N
route A
route B
N
93
5
94
Scheme 5. Two routes to propargylic alcohols.
Our initial attempts in this line with 95 and 1-iodo-4-
nitrobenzene (1.3 equiv) in the presence of Pd(PPh3)2Cl2 (10 mol
%), CuI (10 mol %), and Et3N (5 equiv) in CH3CN resulted in fast
consumption of the starting material at room temperature. After
column chromatographic purification, however, poor isolated yield
(less than 10%) of the desired product was observed despite the
relatively clean TLC pattern.23 After some experimentation, we
found that the desired transformation could be performed in rea-
sonable yields with triethylamine as solvent. Thus, exposure of 95
to 1-iodo-4-nitrobenzene (1.3 equiv), Pd(PPh3)2Cl2 (10 mol %), CuI
(10 mol %), and Et3N at room temperature led to 97 in 74% yield
(Table 7, entry 2). Gentle heating was required to expedite the re-
action in some cases. Under these conditions, reactions of 95 or 96
with several aryl iodides allowed direct access to several new
propargylic alcohols such as 100 and 103, which are difficult to
obtain by other means although more optimization of this route
needs to be done (entries 5 and 8).
3. Conclusions
In summary, we have described here that the power of orga-
nopalladium species to trigger intramolecular cyclization via al-
kyne activation was implemented to allow for facile construction of
poly-substituted indolizinones from readily available tertiary
propargylic alcohols in a domino fashion where aminopalladation
and reductive elimination were successfully combined with 1,2-
rearrangement for the first time. Some features of this highly effi-
cient protocol include mild reaction conditions, ease of operation,
high chemical yields, and a wide variety of functional-group tol-
erance. In addition, we introduced a new approach to tertiary
propargylic alcohols containing a pyridine moiety, starting mate-
rials used for this study by employing Sonogashira coupling re-
action. The chemistry described here should be useful for the rapid
generation of a library of indolizinone derivatives for biological
evaluation.24
Table 7
4. Experimental section
Preparation of tertiary propargylic alcohols via Sonogashira reaction
Pd(PPh3)2Cl2 (10 mol %)
CuI (10 mol %)
4.1. General procedure for the synthesis of tertiary
propargylic alcohols
R1 OH
R1 OH
R2I (1.3 equiv)
To a stirred solution of terminal alkyne (1.2 equiv) in THF was
added n-BuLi (1.1 equiv, 1.6 M solution in hexanes) at ꢁ78 ꢀC. After
5 min, a solution of pyridinyl ketone 93 (1.0 equiv) in THF was
slowly added to this mixture at ꢁ78 ꢀC. After 15 min at ꢁ78 ꢀC, the
reaction mixture was quenched with saturated NH4Cl. The reaction
mixture was diluted with ethyl acetate and washed with aqueous
NH4Cl. The organic layer was dried over MgSO4 and concentrated in
vacuo to give a crude mixture, which was purified by silica gel
column chromatography (hexane/ethyl acetate/dichloromethane)
to afford the propargylic alcohol.
Et3N
temperature
N
R2
N
(R1 = Me)
(R1 = Ph)
12, 31, 97-104
95
96
Entry Starting material
R2I
Temp (ꢀC) Product Yielda
1
2
3
4
5
95
95
95
95
95
55
rt
12
97
98
99
100
33
74
66
43
56
I
I
I
I
NO2
CN
4.1.1. 4-Phenyl-2-(pyridin-2-yl)but-3-yn-2-ol (12). Pale yellow
solid, mp: 102.9e103.4 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.54 (d,
rt
J¼4.5 Hz, 1H), 7.77 (td, J¼1.5, 8.0 Hz, 1H), 7.69 (d, J¼8.0 Hz, 1H),
7.49e7.44 (m, 2H), 7.31e7.24 (m, 4H), 5.62 (s, 1H), 1.87 (s, 3H); 13C
45
30
NMR (125 MHz, CDCl3) d 162.1,147.5,137.6,131.9,128.5,128.3,122.9,
Cl
O
122.8, 120.2, 92.4, 83.9, 69.1, 32.4; IR (ATR) 3238, 3056, 2989, 1587,
1435 cmꢁ1; HRMS (FAB) calcd for C15H14NO 224.1075 ([MþH]þ),
found 224.1066.
I
4.1.2. 2-(Pyridin-2-yl)-4-p-tolylbut-3-yn-2-ol (26). Pale yellow
6
7
8
9
96
96
96
96
45
45
45
45
101
102
103
104
22
23
54
37
I
solid, mp: 80.3e81.1 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.54 (d,
J¼4.5 Hz, 1H), 7.76 (td, J¼1.5, 8.0 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.33
(d, J¼8.0 Hz, 2H), 7.26 (dd, J¼1.0, 7.0 Hz, 1H), 7.09 (d, J¼7.5 Hz, 2H),
5.58 (s, 1H), 2.33 (s, 3H), 1.86 (s, 3H); 13C NMR (125 MHz, CDCl3)
I
Cl
d
162.2, 147.5, 138.6, 137.5, 131.8, 129.1, 120.3, 119.7, 91.6, 84.0, 76.9,
I
CO2Me
69.1, 32.5, 21.6; IR (ATR) 3093, 3030, 3000, 2977, 1591, 1509, 1468,
1431 cmꢁ1; HRMS (FAB) calcd for C16H16NO 238.1232 ([MþH]þ),
found 238.1234.
I
CN
N
4.1.3. 2-(Pyridin-2-yl)-4-(thiophen-3-yl)but-3-yn-2-ol
(27). Pale
8.54
brown solid, mp: 102.7e103.7 ꢀC; 1H NMR (500 MHz, CDCl3)
d
10
96
45
31
36
I
(d, J¼4.5 Hz, 1H), 7.77 (td, J¼1.0, 8.0 Hz, 1H), 7.67 (d, J¼8.0 Hz, 1H),
7.44 (dd, J¼1.0, 3.0 Hz, 1H), 7.27 (dd, J¼5.0, 7.0 Hz, 1H), 7.23 (dd,
J¼3.0, 5.0 Hz, 1H), 7.10 (d, J¼5.0 Hz, 1H), 5.61 (s, 1H), 1.86 (s, 3H); 13C
a
Isolated yield (%).

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5475
NMR (125 MHz, CDCl3)
d
162.1,147.5,137.6,131.9,128.5,128.3,122.9,
6.58 (s, 1H), 2.32 (t, J¼7.5 Hz, 2H), 1.59e1.50 (m, 2H), 1.45e1.35 (m,
122.8, 120.2, 92.4, 83.9, 69.1, 32.4; IR (ATR) 3167, 3097, 2989, 2933,
1587, 1360 cmꢁ1; HRMS (FAB) calcd for C13H12NOS 230.0640
([MþH]þ), found 230.0644.
2H), 0.89 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 161.7, 148.1,
137.1, 122.8, 121.4, 86.9, 82.3, 74.0, 30.8, 22.2, 18.9, 13.7; IR (ATR)
3417, 3044, 2955, 2869, 1584, 1461, 1427 cmꢁ1; HRMS (FAB) calcd
for C17H19N2O 267.1497 ([MþH]þ), found 267.1495.
4.1.4. 4,4-Dimethyl-1-phenyl-1-(pyridin-2-yl)pent-2-yn-1-ol
(28). White solid, mp: 116.0e116.9 ꢀC; 1H NMR (500 MHz, CDCl3)
4.1.11. 3-Cyclohexenyl-1-(4-methoxyphenyl)-1-(pyridin-2-yl)prop-2-
d
8.49 (d, J¼5.0 Hz, 1H), 7.67e7.59 (m, 3H), 7.43 (d, J¼8.0 Hz, 1H),
7.33e7.28 (m, 2H), 7.25e7.21 (m,1H), 7.19 (dd, J¼5.0, 7.5 Hz,1H), 6.46
(s, 1H), 1.30 (s, 9H); 13C NMR (125 MHz, CDCl3)
162.1, 146.9, 145.1,
yn-1-ol (35). Brown gum; 1H NMR (500 MHz, CDCl3)
d 8.50 (d,
J¼5.0 Hz, 1H), 7.64 (td, J¼2.0, 8.0 Hz, 1H), 7.54 (d, J¼8.5 Hz, 2H), 7.39
(d, J¼8.0 Hz, 1H), 7.20 (dd, J¼5.0, 7.5 Hz, 1H), 6.84 (d, J¼9.0 Hz, 2H),
6.42 (br s, 1H), 6.21e6.15 (m, 1H), 3.78 (s, 3H), 2.22e2.14 (m, 2H),
2.13e2.05 (m, 2H), 1.68e1.53 (m, 4H); 13C NMR (125 MHz, CDCl3)
d
137.5, 128.3, 127.7, 126.4, 122.7, 121.7, 95.7, 80.8, 73.2, 31.0, 27.8; IR
(ATR) 3193, 3059, 2966, 2862, 2240, 1587, 1446 cmꢁ1; HRMS (FAB)
calcd for C18H20NO 266.1545 ([MþH]þ), found 266.1552.
d
162.0, 159.3, 146.9, 137.5, 137.0, 135.8, 127.9, 122.7, 121.8, 120.3,
113.7, 88.6, 88.5, 73.3, 55.4, 29.2, 25.8, 22.4, 21.6; IR (ATR) 3316,
3056, 2929, 2858, 1587, 1505, 1431 cmꢁ1; HRMS (FAB) calcd for
C21H22NO2 320.1651 ([MþH]þ), found 320.1645.
4.1.5. 2-(Pyridin-2-yl)oct-3-yn-2-ol (29). Pink liquid; 1H NMR
(500 MHz, CDCl3)
d
8.51 (d, J¼5.0 Hz, 1H), 7.74 (dt, J¼1.5, 7.5 Hz,1H),
7.61 (d, J¼8.0 Hz, 1H), 7.22 (dd, J¼5.0, 7.5 Hz, 1H), 5.39 (s, 1H), 2.23
(t, J¼7.0 Hz, 2H), 1.75 (s, 3H), 1.54e1.46 (m, 2H), 1.44e1.34 (m, 2H),
4.1.12. 1-(4-Methoxyphenyl)-1-(pyridin-2-yl)-3-(thiophen-3-yl)
0.90 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
162.7, 147.4,
prop-2-yn-1-ol (36). Pale brown solid, mp: 109.5e111.0 ꢀC; 1H NMR
137.3, 122.7, 120.1, 84.7, 83.4, 68.8, 32.8, 30.8, 22.1, 18.6, 13.7; IR
(ATR) 3380, 2929, 2862, 2247, 1591, 1431, 1379 cmꢁ1; HRMS (FAB)
calcd for C13H18NO 204.1388 ([MþH]þ), found 204.1386.
(500 MHz, CDCl3)
d
8.54 (d, J¼5.0 Hz, 1H), 7.67 (td, J¼1.0, 8.0 Hz,
1H), 7.59 (d, J¼9.0 Hz, 2H), 7.50 (d, J¼3.0 Hz, 1H), 7.44 (d, J¼8.0 Hz,
1H), 7.28e7.21 (m, 2H), 7.16 (d, J¼5.0 Hz, 1H), 6.87 (d, J¼8.5 Hz, 2H),
6.54 (s, 1H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 161.5, 159.4,
4.1.6. 3-Cyclohexenyl-1-phenyl-1-(pyridin-2-yl)prop-2-yn-1-ol
147.0, 137.6, 136.5, 130.1, 129.4, 1247.9, 125.4, 122.9, 121.9, 121.7,
113.8, 90.9, 81.8, 73.4, 55.4; IR (ATR) 3287, 3085, 2992, 2962, 2929,
2221, 1569, 1505, 1248 cmꢁ1; HRMS (FAB) calcd for C19H16NO2S
322.0902 ([MþH]þ), found 322.0904.
(30). Pale brown solid, mp: 85.5e87.7 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.51 (d, J¼5.0 Hz, 1H), 7.67e7.61 (m, 3H), 7.42 (d, J¼8.0 Hz, 1H),
7.34e7.29 (m, 2H), 7.27e7.23 (m,1H), 7.22e7.18 (m,1H), 6.49 (s,1H),
6.22e6.17 (m, 1H), 2.23e2.15 (m, 2H), 2.13e2.06 (m, 2H), 1.68e1.54
(m, 4H); 13C NMR (125 MHz, CDCl3)
d
161.7, 147.0, 144.7, 137.5, 135.9,
4.1.13. 2-(4-Methylpyridin-2-yl)-4-phenylbut-3-yn-2-ol (37). Pale
128.3,127.9,126.6,122.8,121.8,120.3, 88.6, 88.4, 73.7, 29.2, 25.8, 22.4,
21.6; IR (ATR) 3372, 3059, 2918, 2210, 1591, 1427, 1353 cmꢁ1; HRMS
(FAB) calcd for C20H20NO 290.1545 ([MþH]þ), found 290.1553.
brown solid, mp: 91.8e94.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.39 (d,
J¼5.0 Hz, 1H), 7.47 (s, 1H), 7.46e7.42 (m, 2H), 7.32e7.27 (m, 3H),
7.09 (d, J¼5.0 Hz, 1H), 5.68 (s, 1H), 2.42 (s, 3H), 1.86 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 161.9, 149.0, 147.2, 132.0, 128.5, 128.3, 124.1,
4.1.7. 1-Phenyl-1-(pyridin-2-yl)-3-(pyridin-3-yl)prop-2-yn-1-ol
122.9, 120.9, 92.6, 83.7, 68.9, 32.4, 21.4; IR (ATR) 3097, 2992, 2929,
(31). Pale yellow solid, mp: 101.2e102.9 ꢀC; 1H NMR (500 MHz,
2784, 1669 cmꢁ1
; HRMS (FAB) calcd for C16H16NO 238.1232
CDCl3)
d
8.73 (d, J¼1.5 Hz,1H), 8.56 (d, J¼5.0 Hz,1H), 8.53 (dd, J¼1.5,
([MþH]þ), found 238.1247.
5.0 Hz, 1H), 7.78 (dt, J¼1.5, 8.0 Hz, 1H), 7.73e7.63 (m, 3H), 7.48 (d,
J¼8.0 Hz, 1H), 7.33e7.28 (m, 2H), 7.28e7.22 (m, 1H), 7.28e7.23 (m,
4.1.14. 2-(Pyridin-2-yl)but-3-yn-2-ol (95). Ethynylmagnesium bro-
mide solution (0.5 M inTHF) was used for the synthesis of 95 and 96.
2H), 6.72 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 160.8, 152.6, 149.1,
147.2, 143.8, 138.9, 137.8, 128.6, 128.2, 126.5, 123.2, 123.1, 121.8,
119.8, 94.7, 83.2, 73.8; IR (ATR) 3123, 3085, 3048, 2787, 1584, 1565,
1409 cmꢁ1; HRMS (FAB) calcd for C19H15N2O 287.1184 ([MþH]þ),
found 287.1191.
Pale pink solid, mp: 88.9e89.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.53
(d, J¼4.5 Hz, 1H), 7.77 (td, J¼1.5, 8.0 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H),
7.27 (dd, J¼6.0, 6.5 Hz, 1H), 5.49 (s, 1H), 2.55 (s, 1H), 1.80 (s, 3H); 13C
NMR (125 MHz, CDCl3)
d 161.5, 147.6, 137.6, 123.0, 120.2, 87.2, 72.0,
68.5, 32 0; IR (ATR) 3223, 3089, 2985, 2754, 2109, 1617, 1431 cmꢁ1
;
4.1.8. 3-Phenyl-1,1-di(pyridin-2-yl)prop-2-yn-1-ol (32). Dark or-
HRMS (FAB) calcd for C9H10NO 148.0762 ([MþH]þ), found 148.0765.
ange solid, mp: 89.9e91.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.54 (d,
J¼4.0 Hz, 2H), 7.94 (d, J¼8.0 Hz, 2H), 7.74e7.67 (m, 2H), 7.54e7.45
4.1.15. 1-Phenyl-1-(pyridin-2-yl)prop-2-yn-1-ol (96). Pale yellow
(m, 2H), 7.32e7.24 (m, 3H), 7.23e7.16 (m, 2H), 6.81 (s, 1H); 13C NMR
solid, mp: 66.0e66.7 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.53 (d,
(125 MHz, CDCl3)
d
161.0, 148.1, 137.2, 132.0, 128.6, 128.2, 123.0,
J¼5.5 Hz, 1H), 7.69e7.62 (m, 3H), 7.41 (d, J¼8.5 Hz, 1H), 7.36e7.31
122.6, 121.5, 91.2, 85.6, 74.3; IR (ATR) 3346, 3078, 2921, 2225, 1569,
1427 cmꢁ1; HRMS (FAB) calcd for C19H15N2O 287.1184 ([MþH]þ),
found 287.1180.
(m, 2H), 7.28e7.26 (m, 1H), 7.23 (dd, J¼5.0, 7,5 Hz, 1H), 6.50 (s, 1H),
2.80 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 160.8, 147.1, 143.6, 137.7,
128.5., 128.2, 126.4,123.1,121.7, 85.8, 74.9, 73.2; IR (ATR) 3305, 3261,
3052, 3022, 1591, 1427, 1364 cmꢁ1; HRMS (FAB) calcd for C14H12NO
210.0919 ([MþH]þ), found 210.0921.
4.1.9. 1-(4-Methoxyphenyl)-3-phenyl-1-(pyridin-2-yl)prop-2-yn-1-
ol (33). Brown oil; 1H NMR (500 MHz, CDCl3)
d
8.84 (d, J¼4.5 Hz,
1H), 7.69 (t, J¼7.5 Hz, 1H), 7.61 (d, J¼7.5 Hz, 2H), 7.54e7.48 (m, 2H),
7.46 (d, J¼8.0 Hz, 1H), 7.37e7.27 (m, 3H), 7.25 (d, J¼6.5 Hz, 1H), 6.87
(d, J¼8.5 Hz, 2H), 6.55 (s, 1H), 3.79 (s, 3H); 13C NMR (125 MHz,
4.2. General procedure for the synthesis of poly-substituted
indolizinones
CDCl3)
d
161.6, 158.5, 147.0, 137.7, 136.6, 132.0, 128.7, 128.4, 127.9,
A mixture of tertiary propargylic alcohol 5 (0.13 mmol), (hetero)
aryl halide (1.5 equiv), Pd(PPh3)4 (5 mol %), and K2CO3 (2.5 equiv) in
CH3CN (1 mL) was heated at 90 ꢀC for 13 h. The reaction mixture was
concentrated underreducedpressure togive thecrude residue, which
was diluted with ethyl acetate and washed with water. The organic
layer was dried over MgSO4 and concentrated in vacuo to give a crude
mixture, which was purified by silica gel column chromatography
(hexane/ethyl acetate/dichloromethane) to afford the indolizinone 7.
122.9, 122.7, 121.9, 113.8, 91.3, 86,6, 73.4, 55.4; IR (ATR) 3320, 3052,
2929, 2836, 2221, 1587, 1505, 1245 cmꢁ1; HRMS (FAB) calcd for
C21H18NO2 316.1338 ([MþH]þ), found 316.1330.
4.1.10. 1,1-Di(pyridin-2-yl)hept-2-yn-1-ol (34). Brown solid, mp:
60.9e62.8 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.51 (d, J¼4.5 Hz, 2H),
7.91 (d, J¼8.0 Hz, 2H), 7.69 (t, J¼8.0 Hz, 2H), 7.18 (t, J¼6.0 Hz, 2H),

5476
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
For spectral data of 13e25 and 38e56, see the Supplementary
data of Ref. 10. For spectral data of 82, see the Supplementary data
of Ref. 9.
J¼4.5 Hz, 1H), 6.51 (d, J¼9.0 Hz, 1H), 6.38 (d, J¼7.0 Hz, 1H), 6.14 (dd,
J¼5.5, 9.5 Hz, 1H), 5.34e5.27 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 195.9, 168.2, 158.5, 149.5, 137.0, 132.5, 130.9, 129.5, 129.01, 128.97,
126.4, 124.4, 124.3, 124.0, 123.1, 122.9, 121.9, 120.5, 108.8, 106.4,
72.7; IR (ATR) 3048, 2921, 2851, 1669, 1423 cmꢁ1; HRMS (FAB) calcd
for C23H17N2OS 369.1062 ([MþH]þ), found 369.1064.
4.2.1. 2-(4-Nitrophenyl)-3-phenyl-8a-(pyridin-2-yl)indolizin-
1(8aH)-one (57). Orange solid, mp: 163.0e163.8 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
8.56 (d, J¼5.0 Hz, 1H), 7.95 (d, J¼9.0 Hz, 2H),
7.68 (td, J¼2.0, 8.0 Hz, 1H), 7.65e7.40 (m, 6H), 7.32 (d, J¼9.5 Hz, 2H),
7.19 (dd, J¼5.0, 7.5 Hz, 1H), 6.62e6-53 (m, 2H), 6.18 (dd, J¼5.5,
9.0 Hz, 1H), 5.39 (dd, J¼5.5, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
4.2.7. 2,3-Diphenyl-8a-(pyridin-2-yl)indolizin-1(8aH)-one (63). Red
gum; 1H NMR (500 MHz, CDCl3)
d
8.58 (d, J¼4.5 Hz, 1H), 7.66 (dt,
J¼2.0, 8.0 Hz, 1H), 7.57 (d, J¼8.0 Hz, 1H), 7.56e7.45 (m, 5H), 7.17 (dd,
J¼5.0, 7.5 Hz, 1H), 7.15e7.09 (m, 4H), 7.08e7.02 (m, 1H), 6.57 (d,
J¼7.5 Hz,1H), 6.51 (d, J¼9.0 Hz,1H), 6.14 (dd, J¼5.5, 9.0 Hz,1H), 5.30
d
196.5, 171.9, 158.1, 149.4, 145.1, 138.9, 137.1, 131.3, 129.7, 128.7,
128.6, 128.3, 124.3, 124.2, 123.2, 123.1, 122.2, 120.7, 109.9, 108.5,
73.5; IR (ATR) 3044, 2918, 1673, 1535, 1323 cmꢁ1; HRMS (FAB) calcd
for C25H18N3O3 408.1348 ([MþH]þ), found 408.1359.
(dd, J¼5.5, 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 197.4, 170.3,
158.9, 149.5, 136.9, 130.9, 130.7, 129.6, 129.3, 129.2, 128.8, 127.9,
126.0, 124.7, 124.1, 122.9, 122.0, 120.4, 110.8, 108.3, 73.0; IR (ATR)
3048, 2921, 2851, 1669, 1535, 1423, 1364, 1323 cmꢁ1; HRMS (FAB)
calcd for C25H19N2O 363.1497 ([MþH]þ), found 363.1512.
4.2.2. 2-(4-Acetylphenyl)-3-phenyl-8a-(pyridin-2-yl)indolizin-
1(8aH)-one (58). Red gum; 1H NMR (500 MHz, CDCl3)
d 8.57 (d,
J¼5.0 Hz, 1H), 7.70 (d, J¼8.0 Hz, 2H), 7.66 (dd, J¼1.5, 7.5 Hz, 1H), 7.57
(d, J¼8.0 Hz, 2H), 7.54 (br s, 4H), 7.25 (d, J¼8.5 Hz, 2H), 7.18 (dd, J¼5.0,
7.0 Hz, 1H), 6.58 (d, J¼7.5 Hz, 1H), 6.54 (d, J¼9.0 Hz, 1H), 6.16 (dd,
J¼5.5, 9.0 Hz,1H), 5.39e5.32 (m,1H), 2.49 (s, 3H); 13C NMR (125 MHz,
4.2.8. 2-(4-Methoxyphenyl)-3-phenyl-8a-(pyridin-2-yl)indolizin-
1(8aH)-one (64). Orange solid, mp: 127.3e132.4 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
8.58 (d, J¼5.0 Hz, 1H), 7.65 (td, J¼2.0, 8.0 Hz,
CDCl3)
d
197.8,196.9,171.3,158.4,149.4,137.0,136.6,134.2,131.0,129.5,
1H), 7.56 (d, J¼8.0 Hz, 1H), 7.55e7.45 (m, 5H), 7.16 (dd, J¼5.0, 7.5 Hz,
1H), 7.06 (d, J¼9.0 Hz, 2H), 6.67 (d, J¼9.0 Hz, 2H), 6.55 (d, J¼7.5 Hz,
1H), 6.49 (d, J¼9.5 Hz, 1H), 6.14 (dd, J¼5.5, 9.0 Hz, 1H), 5.32e5.24
128.93, 128.90, 128.2, 128.0, 124.4, 124.1, 123.0, 122.1, 120.5, 109.5,
109.2, 73.3, 26.5; IR (ATR) 3048, 2918, 2851, 1669, 1263 cmꢁ1; HRMS
(FAB) calcd for C27H21N2O2 405.1603 ([MþH]þ), found 405.1594.
(m,1H), 3.70 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 197.7,169.5, 159.0,
158.0, 149.5, 136.9, 130.6, 129.9, 129.5, 129.3, 129.2, 124.7, 124.1,
123.1, 122.8, 121.8, 120.3, 113.5, 110.6, 108.0, 72.8, 55.3; IR (ATR)
3044, 3003, 2929, 2832, 1669, 1539, 1509, 1423, 1364, 1323,
1245 cmꢁ1; HRMS (FAB) calcd for C26H21N2O2 393.1603 ([MþH]þ),
found 393.1583.
4.2.3. 2-(4-Chlorophenyl)-3-phenyl-8a-(pyridin-2-yl)indolizin-
1(8aH)-one (59). Orange solid, mp: 152.3e154.1 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
8.57 (d, J¼5.0 Hz, 1H), 7.66 (td, J¼2.0, 8.0 Hz,
1H), 7.56 (d, J¼8.0 Hz,1H), 7,52 (br s, 5H), 7,17 (dd, J¼5.0, 7.5 Hz,1H),
7.07 (s, 4H), 6.56 (d, J¼7.5 Hz, 1H), 6.51 (d, J¼9.0 Hz, 1H), 6.14 (dd,
J¼5.5, 9.0 Hz, 1H), 5.35e5.28 (m, 1H); 13C NMR (125 MHz, CDCl3)
4.2.9. 2-(4-Acetylphenyl)-8a-(4-methoxyphenyl)-3-phenylindolizin-
d
197.1, 170.4, 158.7, 149.4, 137.0, 131.6, 130.8, 129.8, 129.5, 129.4,
1(8aH)-one (65). Orange gum; 1H NMR (500 MHz, CDCl3)
d 7.71 (d,
129.0, 128.1, 124.5, 124.2, 122.9, 121.9, 120.5, 109.6, 108.7, 73.1; IR
(ATR) 3052, 2921, 2851, 1673, 1535, 1327 cmꢁ1; HRMS (FAB) calcd
for C25H18ClN2O 397.1108 ([MþH]þ), found 397.1099.
J¼8.5 Hz, 2H), 7.58e7.50 (m, 3H), 7.49 (d, J¼9.0 Hz, 2H), 7.47e7.41
(m, 2H), 7.24 (d, J¼8.5 Hz, 2H), 6.90 (d, J¼9.0 Hz, 2H), 6.51 (d,
J¼7.5 Hz,1H), 6.41 (d, J¼9.5 Hz,1H), 6.08 (dd, J¼7.0, 9.5 Hz,1H), 5.40
(dd, J¼5.5, 7.5 Hz, 1H), 3.77 (s, 3H), 2.50 (s, 3H); 13C NMR (125 MHz,
4.2.4. Methyl 4-(1-oxo-3-phenyl-8a-(pyridin-2-yl)-1,8a-dihydroindo-
CDCl3) d 198.7, 197.8, 170.5, 159.9, 136.4, 134.4, 132.3, 131.1, 129.6,
lizin-2-yl)benzoate (60). Orange solid, mp: 141.8e145.7 ꢀC; 1H NMR
128.9, 128.8, 128.3, 128.0, 125.7, 123.9, 123.4, 123.0, 114.3, 110.2,
(500 MHz, CDCl3)
d
8.57 (d, J¼5.0 Hz,1H), 7.77 (d, J¼9.0 Hz, 2H), 7.67
109.5, 71.1, 55.4, 26.6; IR (ATR) 3052, 2925, 1669, 1416, 1245 cmꢁ1
;
(td, J¼1.5, 7.5 Hz, 1H), 7.57 (d, J¼8.0 Hz, 1H), 7.53 (br s, 5H), 7.22 (d,
J¼8.5 Hz, 2H), 7.18 (dd, J¼4.5, 7.0 Hz, 1H), 6.58 (d, J¼7.5 Hz, 1H), 6.53
(d, J¼9.0 Hz, 1H), 6.16 (dd, J¼9.0, 5.5 Hz, 1H), 6.34 (dd, J¼5.5, 7.0 Hz,
HRMS (FAB) calcd for C29H24NO3 434.1756 ([MþH]þ), found
434.1748.
1H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
197.0, 171.2, 167.2,
4.2.10. 4-(8a-(4-Methoxyphenyl)-1-oxo-3-phenyl-1,8a-dihy-
158.6, 149.5, 137.0, 136.3, 131.0, 129.5, 129.2, 129.02, 128.99, 128.2,
127.1,124.5,124.2,123.0,122.2,120.6,109.7,109.1, 73.3, 52.0; IR (ATR)
3048, 2996, 2944, 1714, 1673, 1602, 1539, 1416, 1271 cmꢁ1; HRMS
(FAB) calcd for C27H21N2O3 421.1552 ([MþH]þ), found 421.1532.
droindolizin-2-yl)benzonitrile (66). Orange gum; 1H NMR
(500 MHz, CDCl3)
d 7.61e7.51 (m, 3H), 7.50e7.39 (m, 4H), 7.37 (d,
J¼8.5 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H), 6.90 (d, J¼9.0 Hz, 2H), 6.50 (d,
J¼7.5 Hz, 1H), 6.46 (d, J¼9.0 Hz, 1H), 6.08 (dd, J¼5.5, 9.5 Hz, 1H),
5.45e5.37 (m, 1H), 3.76 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 198.4,
4.2.5. Methyl 3-(1-oxo-3-phenyl-8a-(pyridin-2-yl)-1,8a-dihydroin-
170.8, 159.6, 136.4,132.1, 131.6, 131.3, 129.7,128.6, 125.7,123.7, 123.5,
123.0, 119.3, 114.3, 110.6, 108.8, 108.6, 71.2, 55.4; IR (ATR) 3048,
2951, 2929, 2221, 1677, 1535,1248, 1178 cmꢁ1; HRMS (FAB) calcd for
C28H21N2O2 417.1603 ([MþH]þ), found 417.1613.
dolizin-2-yl)benzoate (61). Red gum; 1H NMR (500 MHz, CDCl3)
d
8.58 (d, J¼4.0 Hz, 1H), 7.80 (t, J¼1.5 Hz, 1H), 7,73 (dt, J¼1.5, 8.0 Hz,
1H), 7.67 (td, J¼2.0, 8.0 Hz,1H), 7.58 (d, J¼8.0 Hz,1H), 7.52 (br s, 5H),
7.36 (dt, J¼1.0, 8.0 Hz, 1H), 7.22e715 (m, 2H), 6.58 (d, J¼8.5 Hz, 1H),
6.53 (d, J¼9.5 Hz, 1H), 6.16 (dd, J¼5.5, 9.0 Hz, 1H), 5.37e5.29 (m,
4.2.11. 8a-(4-Methoxyphenyl)-3-phenyl-2-(pyrazin-2-yl)indolizin-
1H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
197.1, 170.8, 167.2,
1(8aH)-one (67). Red gum; 1H NMR (500 MHz, CDCl3)
d 8.85 (d,
158.7, 149.5, 137.0, 133.0, 131.4, 130.8, 129.9, 129.8, 129.4, 129.01,
128.99, 128.2, 127.1, 124.6, 124.2, 122.9, 122.0, 120.5, 109.8, 108.8,
J¼1.0 Hz, 1H), 8.22e8.17 (m, 2H), 7.57e7.41 (m, 7H), 6.90 (d.
J¼9.0 Hz, 2H), 6.51 (d, J¼7.0 Hz, 1H), 6.47 (d, J¼9.5 Hz, 1H), 6.11 (dd,
J¼5.5, 9.0 Hz, 1H), 5.47e5-42 (m, 1H), 3.78 (s, 3H); 13C NMR
73.1, 52.0; IR (ATR) 3048, 2948, 1718, 1673, 1535, 1423, 1241 cmꢁ1
;
HRMS (FAB) calcd for C27H21N2O3 421.1552 ([MþH]þ), found
(125 MHz, CDCl3) d 197.9,173.1,159.7,147.8,144.7,143.6, 141.2,131.8,
421.1567.
130.8, 129.1, 128.7, 125.9, 124.0, 123.8, 123.1, 114.4, 111.3, 107.7, 71.6,
55.5; IR (ATR) 3048, 2921, 2851, 1673, 1494, 1405, 1248 cmꢁ1; HRMS
(FAB) calcd for C25H20N3O2 394.1556 ([MþH]þ), found 394.1551.
4.2.6. 3-Phenyl-8a-(pyridin-2-yl)-2-(thiophen-2-yl)indolizin-
1(8aH)-one (62). Brown gum; 1H NMR (500 MHz, CDCl3)
d 8.56 (d,
J¼4.5 Hz, 1H), 7.66 (td, J¼6.5, 8.0 Hz, 1H), 7.60 (br s, 5H), 7.55 (d,
4.2.12. 2,8a-Bis(4-methoxyphenyl)-3-phenylindolizin-1(8aH)-one
J¼8.0 Hz, 1H), 7.16 (dd, J¼5.0, 7.0 Hz, 1H), 7.00e6.96 (m, 2H), 6.80 (t,
(68). Orange gum; 1H NMR (500 MHz, CDCl3)
d 7.55e7.48 (m, 5H),

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5477
7.48e7.43 (m, 2H), 7.07 (d, J¼9.0 Hz, 2H), 6.90 (d, J¼9.0 Hz, 2H), 6.70
(d, J¼9.0 Hz, 2H), 6.49 (d, J¼8.0 Hz, 1H), 6.36 (d, J¼9.5 Hz, 1H), 6.07
(dd, J¼5.5, 9.5 Hz, 1H), 5.33 (dd, J¼5.5, 7.0 Hz, 1H), 3.77 (s, 3H), 3.71
1H), 6.14 (dd, J¼5.5, 9.5 Hz, 1H), 5.48 (dd, J¼5.5, 7.0 Hz, 1H),
3.09e2.88 (m, 2H), 1.93e1.77 (m, 2H), 1.66e1.54 (m, 2H), 1.04 (t,
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 195.7, 171.9, 158.4, 149.3,
(s, 3H); 13C NMR (125 MHz, CDCl3)
d
199.6, 168.7, 159.5, 158.0, 133.0,
136.8, 132.7, 127.0, 124.3, 124.0, 123.3, 123.2, 123.1, 122.8, 120.4,
109.9, 105.0, 72.3, 29.6, 26.1, 23.1, 13.9; IR (ATR) 3048, 2955, 2925,
2869, 1669, 1539, 1423 cmꢁ1; HRMS (FAB) calcd for C21H21N2OS
349.1375 ([MþH]þ), found 349.1359.
130.6, 130.0, 129.5, 129.3, 129.0, 125.9, 124.3, 123.1, 123.0, 122.9,
114.2, 113.6, 110.6, 108.8, 70.6, 55.4, 55.3; IR (ATR) 3048, 2996, 2832,
1673, 1543, 1505, 1241 cmꢁ1; HRMS (FAB) calcd for C28H24NO3
422.1756 ([MþH]þ), found 422.1770.
4.2.18. Methyl 4-(3-cyclohexenyl-8a-(4-methoxyphenyl)-1-oxo-1,8a-
4.2.13. 2-(3-Methoxyphenyl)-8a-(4-methoxyphenyl)-3-
dihydroindolizin-2-yl)benzoate (74). Yellow solid, mp: 143.2e146.1 ꢀC;
phenylindolizin-1(8aH)-one (69). Orange gum; 1H NMR (500 MHz,
1H NMR (500 MHz, CDCl3)
d
7.94 (d, J¼8.5 Hz, 2H), 7.62 (d, J¼8.5 Hz,
CDCl3)
d
7.54e7.43 (m, 7H), 7.02 (t, J¼8.0 Hz, 1H), 6.89 (d, J¼9.0 Hz,
2H), 7.36 (d, J¼9.0 Hz, 2H), 6.85 (d, J¼9.0 Hz, 2H), 6.70 (d, J¼7.0 Hz,
1H), 6.35 (d, J¼9.0 Hz, 1H), 6.20 (br s, 1H), 6.06 (dd, J¼5.5, 9.5 Hz, 1H),
5.45 (dd, J¼5.5, 7.0 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.32e2.24 (m,
2H), 2.18e2.10 (m, 2H), 1.81e1.70 (m, 4H); 13C NMR (125 MHz, CDCl3)
2H), 6.72 (d, J¼8.0 Hz, 2H), 6.63 (d, J¼8.5 Hz, 1H), 6.48 (d, J¼7.0 Hz,
1H), 6.37 (d, J¼9.5 Hz, 1H), 6.07 (dd, J¼5.5, 9.0 Hz, 1H), 5.38e5.30
(m,1H), 3.78 (s, 3H), 3.58 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 199.3,
169.7, 159.5, 159.2, 132.8, 132.1, 130.7, 129.5, 129.4, 129.0, 128.9,
125.9, 124.2, 123.2, 123.1, 121.3, 114.3, 113.5, 112.8, 110.5, 109.4, 70.8,
d 198.7, 172.7, 167.3, 159.5, 136.9, 133.9, 132.4, 129.3, 128.5, 127.3, 127.2,
125.7, 123.7, 123.4, 123.1, 114.2, 109.9, 107.6, 70.6, 55.4, 52.1, 27.1, 25.4,
22.3, 21.5; IR (ATR) 3048, 2921, 2832, 1707, 1599, 1532, 1502, 1420,
1252 cmꢁ1; HRMS (FAB) calcd for C29H28NO4 454.2018 ([MþH]þ),
found 454.2020.
55.5, 55.1; IR (ATR) 3056, 2921, 2851, 1673, 1599, 1502, 1245 cmꢁ1
;
HRMS (FAB) calcd for C28H24NO3 422.1756 ([MþH]þ), found
422.1760.
4.2.14. 4-(3-Butyl-1-oxo-8a-(pyridin-2-yl)-1,8a-dihydroindolizin-2-
4.2.19. 8a-(4-Methoxyphenyl)-2-phenyl-3-(thiophen-3-yl)indolizin-
yl)benzonitrile (70). Yellow solid, mp: 120.5e124.9 ꢀC; 1H NMR
1(8aH)-one (75). Brown gum; 1H NMR (500 MHz, CDCl3)
d 7.53
(500 MHz, CDCl3)
d
8.49 (d, J¼5.0 Hz, 1H), 7.64 (dd, J¼1.5, 8.0 Hz,
(s, 1H), 7.50e7.43 (m, 3H), 7.23e7.07 (m, 6H), 6.88 (d, J¼8.5 Hz,
2H), 6.65 (d, J¼7.0 Hz, 1H), 6.34 (d, J¼9.5 Hz, 1H), 6.07 (dd, J¼5.5,
9.0 Hz, 1H), 5.42e5.33 (m, 1H), 3.77 (s, 3H); 13C NMR (125 MHz,
1H), 7.61 (d, J¼8.5 Hz, 2H), 7.47 (d, J¼8.5 Hz, 2H), 7.42 (d, J¼8.0 Hz,
1H), 7.15 (dd, J¼5.0, 7.5 Hz, 1H), 6.75 (d, J¼7.0 Hz, 1H), 6.50 (d,
J¼9.5 Hz, 1H), 6.17 (dd, J¼5.5, 9.0 Hz, 1H), 5.56e5.51 (m, 1H),
2.90e2.75 (m, 2H), 1.90e1.75 (m, 2H), 1.58e1.46 (m, 2H), 0.99 (t,
CDCl3)
d 199.1, 164.5, 159.5, 132.8, 130.9, 129.2, 128.9, 128.3,
128.0, 127.7, 127.4, 126.4, 125.9, 124.4, 123.13, 123.07, 114.2, 111.0,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
196.3, 173.9, 158.0,
109.3, 70.9, 55.4; IR (ATR) 3100, 2921, 1677, 1505, 1245 cmꢁ1
;
149.3, 137.0, 136.9, 132.0, 129.0, 124.0, 123.1, 123.0, 122.9, 120.5,
119.3, 110.4, 109.3, 108.8, 72.6, 29.9, 25.6, 22.9, 13.7; IR (ATR) 3044,
2951, 2925, 2862, 2217, 1666, 1524, 1423 cmꢁ1; HRMS (FAB) calcd
for C24H22N3O 368.1763 ([MþH]þ), found 368.1744.
HRMS (FAB) calcd for C25H20NO2S 398.1215 ([MþH]þ), found
398.1227.
4.2.20. 2-(4-Acetylphenyl)-8a-(4-methoxyphenyl)-3-(thiophen-3-yl)
indolizin-1(8aH)-one (76). Brown gum; 1H NMR (500 MHz, CDCl3)
4.2.15. 2-(4-Acetylphenyl)-3-butyl-8a-(pyridin-2-yl)indolizin-
d
7.75 (d, J¼8.0 Hz, 2H), 7.57e7.54 (m, 1H), 7.54e7.50 (m, 1H), 7.45
1(8aH)-one (71). Yellow solid, mp: 108.2e109.1 ꢀC; 1H NMR
(d, J¼8.5 Hz, 2H), 7.26 (d, J¼8.5 Hz, 2H), 7.14 (d, J¼5.0 Hz, 1H),
6.88 (d, J¼9.0 Hz, 2H), 6.65 (d, J¼7.5 Hz, 1H), 6.39 (d, J¼9.5 Hz,
1H), 6.08 (dd, J¼5.5, 9.0 Hz, 1H), 5.45e5.39 (m, 1H), 3.76 (s, 3H),
(500 MHz, CDCl3)
d
8.51 (d, J¼5.0 Hz, 1H), 7.93 (d, J¼8.5 Hz, 2H),
7.63 (dt, J¼2.0, 8.0 Hz, 1H), 7.46 (d, J¼8.5 Hz, 2H), 7.42 (d, J¼8.2 Hz,
1H), 7.14 (dd, J¼5.0, 7.5 Hz, 1H), 6.76 (d, J¼7.0 Hz, 1H), 6.51 (d,
J¼9.5 Hz, 1H), 6.16 (dd, J¼5.0, 9.0 Hz, 1H), 5.54e5.48 (m, 1H),
2.95e2.75 (m, 2H), 2.58 (s, 3H), 1.95e1.75 (m, 2H), 1.60e1.45 (m,
2.52 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 198.5, 197.8, 165.4,
159.6, 136.5, 134.6, 132.3, 128.8, 128.44, 128.38, 128.1, 128.0, 127.5,
125.8, 124.1, 123.5, 123.0, 114.3, 110.2, 109.7, 71.2, 55.4, 26.6; IR
2H), 0.98 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
197.8,
(ATR) 3085, 2921, 2854, 1669, 1595, 1546, 1505, 1427, 1245 cmꢁ1
;
196.6, 173.7, 158.3, 149.3, 137.0, 136.8, 134.8, 128.6, 128.4, 123.9,
123.2, 123.1, 122.8, 120.3, 110.0, 109.5, 72.5, 30.0, 26.6, 25.7, 22.9,
HRMS (FAB) calcd for C27H22NO3S 440.1320 ([MþH]þ), found
440.1313.
13.8; IR (ATR) 3044, 2955, 2925, 2862, 1669, 1423, 1267 cmꢁ1
;
HRMS (FAB) calcd for C25H25N2O2 385,1916 ([MþH]þ), found
4.2.21. 4-(8a-(4-Methoxyphenyl)-1-oxo-3-(thiophen-3-yl)-1,8a-di-
385.1906.
hydroindolizin-2-yl)benzonitrile (77). Brown gum; 1H NMR
(500 MHz, CDCl3)
d 7.58e7.53 (m, 2H), 7.45e7.39 (m, 4H), 7.26 (d,
4.2.16. 3-Butyl-2-(4-chlorophenyl)-8a-(pyridin-2-yl)indolizin-
J¼8.5 Hz, 2H), 7.13 (dd, J¼1.5, 4.0 Hz, 1H), 6.88 (d, J¼9.0 Hz, 2H),
6.64 (d, J¼7.5 Hz, 1H), 6.40 (d, J¼9.5 Hz, 1H), 6.09 (dd, J¼5.5, 9.0 Hz,
1H), 5.44 (dd, J¼5.5, 7.0 Hz, 1H), 3.76 (s, 3H); 13C NMR (125 MHz,
1(8aH)-one (72). Brown gum; 1H NMR (500 MHz, CDCl3)
d 8.51 (d,
J¼5.0 Hz, 1H), 7.62 (dt, J¼2.0, 8.0 Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H),
7.30 (d, J¼8.5 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H), 7.14 (dd, J¼4.5, 7.0 Hz,
1H), 6.72 (d, J¼7.0 Hz, 1H), 6.48 (d, J¼9.0 Hz, 1H), 6.1 (dd, J¼5.0,
8.0 Hz, 1H), 5.50e5.44 (m, 1H), 2.87e2.70 (m, 2H), 1.86e1.72 (m,
2H), 1.55e1.43 (m, 2H), 0.97 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3)
d 198.2, 165.7, 159.7, 136.4, 132.0, 131.7, 128.7, 128.5, 128.41,
128.37, 127.3, 125.8, 123.9, 123.6, 123.0, 119.3, 114.3, 110.7, 109.1,
108.9, 71.4, 55.4; IR (ATR) 3130, 2951, 2221, 1673, 1505, 1431, 1319,
1245 cmꢁ1; HRMS (FAB) calcd for C26H19N2O2S 423.1167 ([MþH]þ),
found 423.1176.
CDCl3)
d 196.8, 173.2, 158.5, 149.3, 136.8, 132.3, 130.3, 130.0, 128.6,
124.0, 123.3, 122.9, 122.8, 130.3, 109.6, 109.5, 72.4, 30.0, 25.6, 22.9,
13.8; IR (ATR) 3048, 2955, 2929, 2869, 1669, 1532, 1423 cmꢁ1
;
4.2.22. 2-(4-Chlorophenyl)-8a-(4-methoxyphenyl)-3-(thiophen-3-
HRMS (FAB) calcd for C23H22ClN2O 377.1421 ([MþH]þ), found
yl)indolizin-1(8aH)-one (78). Brown gum; 1H NMR (500 MHz,
377.1406.
CDCl3)
d
7.53 (dd, J¼1.5, 3.0 Hz, 1H), 7.50 (dd, J¼2.5, 5.0 Hz, 1H), 7.44
(d, J¼9.0 Hz, 2H), 7.15e7.10 (m, 3H), 7.10e7.05 (d, J¼8.5 Hz, 2H),
6.88 (d, J¼9.0 Hz, 2H), 6.63 (d, J¼7.0 Hz, 1H), 6.36 (d, J¼9.5 Hz, 1H),
6.07 (dd, J¼5.5, 9.5 Hz, 1H), 5.39 (dd, J¼5.5, 7.5 Hz, 1H), 3.77 (s, 3H);
4.2.17. 3-Butyl-8a-(pyridin-2-yl)-2-(thiophen-2-yl)indolizin-1(8aH)-
one (73). Brown gum; 1H NMR (500 MHz, CDCl3)
d 8.45 (d,
J¼5.0 Hz, 1H), 7.61 (dt, J¼2.0, 8.0 Hz, 1H), 7.46 (d, J¼8.0 Hz, 1H), 7.29
(d, J¼3.5 Hz, 1H), 7.19 (d, J¼5.0 Hz, 1H), 7.13 (dd, J¼5.0, 7.5 Hz, 1H),
7.02 (dd, J¼3.5, 5.0 Hz, 1H), 6.74 (d, J¼7.5 Hz, 1H), 6.49 (d, J¼8.0 Hz,
13C NMR (125 MHz, CDCl3)
d 198.8, 164.7, 159.6, 132.5, 132.0, 130.0,
129.4, 128.9, 128.3, 128.2, 127.8, 127.6, 125.9, 124.3, 123.3, 123.1,
114.3, 109.73, 109.69, 71.0, 55.4; IR (ATR) 3078, 2921, 2851, 1669,

5478
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
1505, 1245 cmꢁ1; HRMS (FAB) calcd for C25H19ClNO2S 432.0825
under reduced pressure and purified by silica gel column chro-
matography (hexane/ethyl acetate/dichloromethane) to give O-
allylated tertiary propargylic alcohol.
([MþH]þ), found 432.0837.
4.2.23. Methyl 3-(8a-(4-methoxyphenyl)-1-oxo-3-(thiophen-3-yl)-
1,8a-dihydroindolizin-2-yl)benzoate (79). Brown gum; 1H NMR
4.3.1. 2-(2-(Allyloxy)-4-phenylbut-3-yn-2-yl)pyridine (86). Yellow
(500 MHz, CDCl3)
d
7.81e7-76 (m, 2H), 7.55e7.53 (m, 1H), 7.50 (dd,
gum; 1H NMR (500 MHz, CDCl3)
d
8.67 (d, J¼4.5 Hz, 1H), 7.78 (d,
J¼3.0, 5.0 Hz, 1H), 7.46 (d, J¼9.0 Hz, 2H), 7.39 (d, J¼8.0 Hz, 1H),
7.28e7.21 (m, 1H), 7.12 (dd, J¼1.0, 5.0 Hz,1H), 6.88 (d, J¼9.0 Hz, 2H),
6.65 (d, J¼7.5 Hz, 1H), 6.38 (d, J¼9.0 Hz, 1H), 6.08 (dd, J¼5.5, 9.0 Hz,
1H), 5.44e5.36 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H); 13C NMR
J¼8.0 Hz, 1H), 7.72 (td, J¼1.5, 7.5 Hz, 1H), 7.55e7.48 (m, 2H),
7.36e7.30 (m, 3H), 7.23 (dd, J¼5.0, 7.0 Hz, 1H), 6.07e5.94 (m, 1H),
5.32 (d, J¼17.0 Hz, 1H), 5.16 (d, J¼10.5 Hz, 1H), 4.28 (dd, J¼5.5,
12.0 Hz, 1H), 3.93 (dd, J¼5.5, 12.0 Hz, 1H), 1.93 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
198.7, 167.1, 165.1, 159.5, 133.2, 132.5, 131.4,
(125 MHz, CDCl3) d 161.4, 149.4, 136.7, 135.1, 132.0, 128.5, 128.3,
130.0, 129.9, 128.8, 128.3, 128.1, 127.9, 127.5, 127.4, 125.9, 124.2,
123.3, 123.1, 114.3, 109.84, 109.76, 71.0, 55.4, 52.1; IR (ATR) 3108,
2921, 1714, 1673, 1505, 1420, 1245 cmꢁ1; HRMS (FAB) calcd for
C27H22NO4S 456.1270 ([MþH]þ), found 456.1266.
122.8, 122.7, 120.7, 116.7, 89.5, 87.2, 77.3, 66.6, 30.1; IR (ATR) 3056,
2985, 2929, 2858, 2228, 1584, 1431 cmꢁ1; HRMS (FAB) calcd for
C18H18NO 264.1388 ([MþH]þ), found 264.1380.
4.3.2. 2,50-(3-(Allyloxy)-3-phenylprop-1-yne-1,3-diyl)dipyridine
4.2.24. 2-(4-Acetylphenyl)-7,8a-dimethyl-3-phenylindolizin-1(8aH)-
(87). Brown solid, mp: 77.9e79.6 ꢀC; 1H NMR (500 MHz, CDCl3)
one (80). Dark yellow solid, mp: 102.8e105.5 ꢀC; 1H NMR
d
8.78 (s, 1H), 8.26 (dd, J¼1.5, 10.0 Hz, 2H), 7.87e7.80 (m, 2H),
(500 MHz, CDCl3)
d
7.73 (d, J¼8.5 Hz, 2H), 7.55e7.44 (m, 3H), 7.35
7.74e7.65 (m, 3H), 7.36 (t, J¼7.5 Hz, 2H), 7.29 (d, J¼7.5 Hz, 1H),
7.28e7.23 (m, 1H), 7.16 (dd, J¼5.0, 7.5 Hz, 1H), 6.15e6.00 (m, 1H),
5.40 (d, J¼12.5 Hz, 1H), 5.21 (d, J¼10.5 Hz, 1H), 4.28 (dd, J¼5.0,
14.0 Hz, 1H), 4.02 (dd, J¼5.0, 12.0 Hz, 1H); 13C NMR (125 MHz,
(d, J¼6.5 Hz, 2H), 7.24 (d, J¼8.5 Hz, 2H), 6.34 (d, J¼7.5 Hz, 1H), 5.74
(s, 1H), 5.27 (dd, J¼1.0, 7.5 Hz, 1H), 2.52 (s, 3H), 1.80 (s, 3H), 1.49 (s,
3H); 13C NMR (125 MHz, CDCl3)
d 200.8, 197.8, 168.6, 137.0, 134.2,
130.9, 130.8, 129.5, 129.1, 128.8, 128.3, 128.1, 122.3, 119.3, 113.3,
109.3, 68.4, 26.6, 25.7, 20.7; IR (ATR) 2918, 2851, 2240, 1666, 1595,
1539, 1341, 1263 cmꢁ1; HRMS (FAB) calcd for C24H22NO2 356.1651
([MþH]þ), found 356.1642.
CDCl3) d 161.8, 152.7, 149.4, 149.1, 141.7, 139.0, 136.9, 134.7, 128.5,
128.2, 127.1, 123.0, 122.7, 120.2, 119.8, 116.5, 91.9, 85.9, 82.0, 66.4; IR
(ATR) 3089, 2854, 1580, 1431 cmꢁ1
; HRMS (FAB) calcd for
C22H19N2O 327.1497 ([MþH]þ), found 327.1498.
4.2.25. Methyl 4-(7,8a-dimethyl-1-oxo-3-phenyl-1,8a-dihydroindo-
4.3.3. 2,20-(1-(Allyloxy)-3-phenylprop-2-yne-1,1-diyl)dipyridine
lizin-2-yl)benzoate (81). Orange gum; 1H NMR (500 MHz, CDCl3)
(89). Pale brown solid, mp: 95.5e98.2 ꢀC; 1H NMR (500 MHz,
d
7.80 (d, J¼8.5 Hz, 2H), 7.55e7.43 (m, 3H), 7.34 (d, J¼6.0 Hz, 2H),
CDCl3)
d
8.56 (d, J¼4.5 Hz, 2H), 8.01 (d, J¼8.0 Hz, 2H), 7.74 (td, J¼1.5,
7.21 (d, J¼8.5 Hz, 2H), 6.33 (d, J¼7.5 Hz, 1H), 5.74 (br s, 1H), 5.26 (dd,
7.5 Hz, 2H), 7.59e7.52 (m, 2H), 7.35e7.29 (m, 3H), 7.17 (dd, J¼5.0,
7.5 Hz, 2H), 6.12e6.00 (m, 1H), 5.37 (dd, J¼1.5, 17.0 Hz, 1H), 5.19 (dd,
J¼1.0, 10.0 Hz, 1H), 4.21 (d, J¼5.5 Hz, 2H); 13C NMR (125 MHz,
J¼1.5, 7.5 Hz, 1H), 3.85 (s, 3H), 1.80 (s, 3H), 1.49 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 200.9, 168.5, 167.3, 136.7, 130.9, 130.8, 129.4,
129.3, 129.1, 128.8, 128.2, 127.1, 122.3, 119.3, 113.2, 109.5, 68.4, 52.0,
25.7, 20.7; IR (ATR) 2921, 2851, 1714, 1673, 1602, 1580, 1431,
1271 mꢁ1; HRMS (FAB) calcd for C24H22NO3 372.1600 ([MþH]þ),
found 372.1612.
CDCl3) d 160.9, 149.4, 136.7, 134.8, 132.1, 128.7, 128.3, 122.7, 122.6,
121.6, 116.7, 89.3, 88.1, 82.7, 66.7; IR (ATR) 3089, 2959, 1580,
1427 cmꢁ1; HRMS (FAB) calcd for C22H19N2O 327.1497 ([MþH]þ),
found 327.1488.
4.2.26. 4-(8a-Methyl-1-oxo-3-phenyl-1,8a-dihydroindolizin-2-yl)
4.3.4. 2-(1-(Allyloxy)-1-(4-methoxyphenyl)-3-(thiophen-3-yl)prop-
benzaldehyde (83). Yellow solid, mp: 147.7e152.1 ꢀC; 1H NMR
2-ynyl)pyridine (91). Brown gum; 1H NMR (500 MHz, CDCl3)
d 8.56
(500 MHz, CDCl3)
d
9.88 (s,1H), 7.65 (d, J¼8.5 Hz, 2H), 7.58e7.45 (m,
(d, J¼4.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.69 (t, J¼7.5 Hz, 1H), 7.60
(d, J¼9.0 Hz, 2H), 7.53 (s, 1H), 7.28e7.24 (m, 1H), 7.19 (d, J¼5.0 Hz,
1H), 7.13 (dd, J¼5.0, 7.5 Hz,1H), 6.86 (d, J¼9.0 Hz, 2H), 6.10e5.98 (m,
1H), 5.37 (d, J¼17.5 Hz, 1H), 5.18 (d, J¼10.5 Hz, 1H), 4.27 (dd, J¼5.5,
12.5 Hz, 1H), 4.02 (dd, J¼5.5, 12.5 Hz, 1H), 3.78 (s, 3H); 13C NMR
3H), 7.36 (d, J¼5.5 Hz, 2H), 7.32 (d, J¼9.0 Hz, 2H), 6.38 (d, J¼8.0 Hz,
1H), 6.06 (d, J¼9.5 Hz, 1H), 5.99 (dd, J¼5.5, 9.0 Hz, 1H), 5.42 (dd,
J¼5.5, 7.0 Hz, 1H), 1.53 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 200.2,
192.0, 168.9, 138.4, 133.7, 131.0, 129.6, 129.5, 128.9, 128.72, 128.68,
124.4, 122.8, 122.4, 109.8, 108.8, 68.2, 25.7; IR (ATR) 3052, 2921,
2851, 1688,1666, 1595, 1539 cmꢁ1; HRMS (FAB) calcd for C22H18NO2
328.1338 ([MþH]þ), found 328.1327.
(125 MHz, CDCl3)
d 162.4, 159.4, 149.4, 136.8, 135.1, 134.2, 130.2,
129.5, 128.6, 125.3, 122.4, 121.7, 120.2, 116.3, 113.7, 88.1, 84.4, 81.7,
66.2, 55.6; IR (ATR) 3067, 2907, 2854, 2221, 1584, 1505, 1461, 1431,
1245 cmꢁ1; HRMS (FAB) calcd for C22H20NO2S 362.1215 ([MþH]þ),
found 362.1228.
4.2.27. 8a-Methyl-3-phenyl-2-(thiophen-3-yl)indolizin-1(8aH)-one
(84). Yellow gum; 1H NMR (500 MHz, CDCl3)
d 7.57e7.49 (m, 3H),
7.45e7.36 (m, 3H), 7.06 (dd, J¼3.0, 5.0 Hz, 1H), 6.67 (dd, J¼1.0,
5.0 Hz, 1H), 6.23 (d, J¼7.0 Hz, 1H), 6.00 (d, J¼9.0 Hz, 1H), 5.95 (dd,
J¼5.0, 9.0 Hz, 1H), 5.34 (dd, J¼5.0, 7.5 Hz, 1H), 1.49 (s, 3H); 13C
4.4. General procedure for the synthesis of C2-allylated
indolizinones
NMR (125 MHz, CDCl3)
d
200.8, 166.5, 131.0, 130.6, 129.7, 129.4,
A mixture of propargylic alcohol (0.22 mmol), diallyl carbonate
(10 equiv), Pd(PPh3)4 (5 mol %), and K2CO3 (2.5 equiv) in THF (2 mL)
was heated at 80 ꢀC for 18 h. The reaction mixture was concen-
trated under reduced pressure to give the crude residue, which was
diluted with ethyl acetate and washed with water. The organic layer
was dried over MgSO4 and concentrated in vacuo to give a crude
mixture, which was purified by silica gel column chromatography
(hexane/ethyl acetate/dichloromethane) to give the C2-allylated
indolizinone.
128.7, 126.7, 124.2, 123.8, 123.1, 122.5, 121.2, 108.6, 106.3, 67.4,
25.5; IR (ATR) 3160, 3115, 2921, 2851, 1666, 1543, 1420, 1315 cmꢁ1
;
HRMS (FAB) calcd for C19H16NOS 306.0953 ([MþH]þ), found
306.0971.
4.3. General procedure for the O-allylation of 12, 31, 32, and
36 with diallyl carbonate
A mixture of propargylic alcohol (0.22 mmol), diallyl carbonate
(10 equiv), Pd(OAc)2 (5 mol %), xantphos (5 mol %) in THF (2 mL)
was heated at 80 ꢀC for 3 h. The reaction mixture was concentrated
4.4.1. 2-Allyl-8a-methyl-3-phenylindolizin-1(8aH)-one (85). Brown
gum; 1H NMR (500 MHz, CDCl3)
d 7.54e7.46 (m, 3H), 7.44e7.36 (m,

H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
5479
2H), 6.25 (d, J¼7.0 Hz, 1H), 5.91e5.87 (m, 2H), 5.84e5.74 (m, 1H),
5.27 (ddd, J¼1.5, 5.0, 8.5 Hz, 1H), 4.92 (dd, J¼1.5, 10.0 Hz, 1H), 4.89
(dd, J¼2.0, 17.0 Hz, 1H), 2.83 (dd, J¼6.0, 14.5 Hz, 2H), 1.43 (s, 3H); 13C
1H), 7.80 (td, J¼1.5, 8.0 Hz, 1H), 7.64 (d, J¼7.5 Hz, 1H), 7.58 (d,
J¼7.5 Hz, 2H), 7.51 (d, J¼8.0 Hz, 2H), 7.31 (dd, J¼5.0, 6.5 Hz,1H), 5.72
(s, 1H), 1.88 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 161.3, 147.7, 137.8,
NMR (125 MHz, CDCl3)
d
202.8, 168.5, 136.2, 130.4, 129.1, 129.0,
132.4, 132.0, 127.7, 123.2, 120.1, 118.5, 111.9, 96.9, 82.1, 68.9, 31.9; IR
128.5, 123.6, 123.0, 122.4, 114.8, 108.0, 107.5, 66.9, 26.0, 25.2; IR
(ATR) 3063, 2854, 1673, 1241 cmꢁ1; HRMS (FAB) calcd for C18H18NO
264.1388 ([MþH]þ), found 264.1361.
(ATR) 3387, 3056, 2929, 2854, 2221, 1587, 1502, 1431, 1364 cmꢁ1
;
HRMS (FAB) calcd for C16H13N2O 249.1028 ([MþH]þ), found
249.1031.
4.4.2. 2-Allyl-8a-phenyl-3-(pyridin-3-yl)indolizin-1(8aH)-one
4.5.3. 4-(4-Chlorophenyl)-2-(pyridin-2-yl)but-3-yn-2-ol
(88). Red gum; 1H NMR (500 MHz, CDCl3)
d
8.80 (s, 2H), 7.85 (d,
(99). Brown solid, mp: 67.7e69.6 ꢀC; 1H NMR (500 MHz, CDCl3)
J¼8.0 Hz, 1H), 7.54e7.47 (m, 3H), 7.36 (t, J¼7.5 Hz, 2H), 7.32e7.27
(m, 1H), 6.36 (d, J¼7.5 Hz, 1H), 6.29 (d, J¼9.0 Hz, 1H), 5.79e5.66 (m,
1H), 5.33 (dd, J¼5.5, 7.0 Hz, 1H), 4.89 (d, J¼10.0 Hz, 1H), 4.81 (d,
J¼17.0 Hz, 1H), 2.88e2.75 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
8.55 (d, J¼5.0 Hz,1H), 7.78 (td, J¼2.0, 8.0 Hz,1H), 7.66 (d, J¼8.0 Hz,
1H), 7.36 (d, J¼7.5 Hz, 2H), 7.31e7.23 (m, 3H), 5.64 (s, 1H), 1.86 (s,
3H); 13C NMR (125 MHz, CDCl3)
161.8, 147.6, 137.6, 134.6, 133.2,
d
128.7, 123.0, 121.3, 130.2, 93.4, 82.7, 69.0, 32.2; IR (ATR) 3216, 2925,
2851, 1587, 1487, 1468 cmꢁ1; HRMS (FAB) calcd for C15H13ClNO
258.0686 ([MþH]þ), found 258.0682.
d
200.6, 166.7, 151.8, 149.8, 140.4, 136.2, 135.7, 128.9, 128.1, 125.3,
124.5, 124.1, 123.8, 123.2, 122.4, 115.4, 109.8, 109.2, 70.7, 25.6; IR
(ATR) 3056, 2918, 1681, 1599, 1543, 1409 cmꢁ1; HRMS (FAB) calcd
for C22H19N2O 327.1497 ([MþH]þ), found 327.1475.
4.5.4. 1-(4-(3-Hydroxy-3-(pyridin-2-yl)but-1-ynyl)phenyl)ethanone
(100). Brown gum; 1H NMR (500 MHz, CDCl3)
d
8.56 (d, J¼4.5 Hz,
4.4.3. 2-Allyl-3-phenyl-8a-(pyridin-2-yl)indolizin-1(8aH)-one
1H), 7.88 (d, J¼7.5 Hz, 2H), 7.80 (td, J¼1.5, 8.0 Hz, 1H), 7.67 (d,
J¼10.0 Hz, 1H), 7.52 (d, J¼7.5 Hz, 2H), 7.30 (dd, J¼5.0, 7.5 Hz, 1H),
5.70 (s, 1H), 2.59 (s, 3H), 1.89 (s, 3H); 13C NMR (125 MHz, CDCl3)
(90). Brown solid, mp: 102.6e106.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.58 (d, J¼4.5 Hz, 1H), 7.66 (t, J¼8.0 Hz, 1H), 7.62e7.46 (m, 6H),
7.17 (dd, J¼5.0, 7.0 Hz, 1H), 6.47 (d, J¼8.0 Hz, 1H), 6.38 (d, J¼9.5 Hz,
1H), 6.11 (dd, J¼5.5, 9.0 Hz, 1H), 5.81e5.69 (m, 1H), 5.24 (t,
J¼6.0 Hz, 1H), 4.88 (s, 1H), 4.86 (d, J¼6.0 Hz, 1H), 2.88e2.77 (m,
d 197.5, 161.6, 147.6, 137.7, 136.5, 132.0, 128.2, 127.7, 123.1, 120.2, 95.7,
83.0, 69.0, 32.1, 26.7; IR (ATR) 3365, 2921, 2851, 1677, 1599, 1356,
1260 cmꢁ1; HRMS (FAB) calcd for C17H16NO2 266.1181 ([MþH]þ),
found 266.1187.
2H); 13C NMR (125 MHz, CDCl3)
d 199.3, 171.1, 159.3, 149.5, 136.8,
136.0, 130.6, 129.1, 129.0, 128.7, 125.0, 124.1, 122.7, 121.2, 120.5,
115.0, 108.8, 107.5, 72.4, 26.1; IR (ATR) 3044, 2910, 1658,
1427 cmꢁ1; HRMS (FAB) calcd for C22H19N2O 327.1497 ([MþH]þ),
found 327.1476.
4.5.5. 1,3-Diphenyl-1-(pyridin-2-yl)prop-2-yn-1-ol (101). Orange
gum; 1H NMR (500 MHz, CDCl3)
d
8.55 (d, J¼4.5 Hz, 1H),
7.73e7.69 (m, 2H), 7.68 (dd, J¼1.5, 7.5 Hz, 1H), 7.53e7.47 (m, 3H),
7.38e7.27 (m, 6H), 7.26e7.23 (m, 1H), 6.62 (s, 1H); 13C NMR
4.4.4. 2-Allyl-8a-(4-methoxyphenyl)-3-(thiophen-3-yl)indolizin-
(125 MHz, CDCl3)
d161.3, 147.1, 144.3, 137.7, 132.0, 128.7, 128.5,
1(8aH)-one (92). Brown gum; 1H NMR (500 MHz, CDCl3)
d 7.69 (dd,
128.4, 128.1, 126.6, 123.0, 122.7, 121.9, 91.2, 86.7, 73.8; IR (ATR)
J¼1.0, 3.0 Hz, 1H), 7.54 (dd, J¼3.0, 5.0 Hz, 1H), 7.41 (d, J¼9.0 Hz, 2H),
7.32 (dd, J¼1.0, 5.0 Hz, 1H), 6.87 (d, J¼9.0 Hz, 2H), 6.58 (d, J¼7.0 Hz,
1H), 6.25 (d, J¼9.5 Hz, 1H), 6.02 (dd, J¼5.5, 9.0 Hz, 1H), 5.87e5.75
(m, 1H), 5.31 (dd, J¼5.5, 7.0 Hz, 1H), 4.94 (dd, J¼2.0, 10.0 Hz, 1H),
4.89 (dd, J¼1.5, 12.0 Hz, 1H), 3.78 (s, 3H), 2.94e2.80 (m, 2H); 13C
3298, 3056, 2921, 2851, 2225, 1681, 1587, 1446, 1431, 1379 cmꢁ1
;
HRMS (FAB) calcd for C20H16NO 286.1232 ([MþH]þ), found
286.1222.
4.5.6. 3-(4-Chlorophenyl)-1-phenyl-1-(pyridin-2-yl)prop-2-yn-1-ol
NMR (125 MHz, CDCl3)
d
201.0, 165.3, 159.3, 136.3, 132.9, 129.2,
(102). Orange solid, mp: 85.2e88.9 ꢀC; 1H NMR (500 MHz, CDCl3)
128.0, 127.3, 125.9, 124.8, 123.1, 122.3, 115.0, 114.1, 108.5, 108.4, 70.2,
55.4, 26.2; IR (ATR) 3074, 3000, 2929, 1669, 1576, 1505, 1420,
1245 cmꢁ1; HRMS (FAB) calcd for C22H20NO2S 362.1215 ([MþH]þ),
found 362.1227.
d
8.55 (d, J¼5.0 Hz, 1H), 7.72e7.65 (m, 3H), 7.46 (d, J¼8.0 Hz, 1H),
7.43 (d, J¼8.5 Hz, 2H), 7.38e7.33 (m, 2H), 7.31e7.23 (m, 4H), 6.63 (s,
1H); 13C NMR (125 MHz, CDCl3)
161.1, 147.1, 144.1, 137.7, 134.8,
133.2, 128.8, 128.5, 128.2, 126.5, 123.1, 121.9, 121.1, 92.1, 85.5, 73.7; IR
d
(ATR) 3272, 3082, 3056, 2921, 2225, 1591, 1487, 1431, 1394 cmꢁ1
;
4.5. General procedure for the Sonogashira coupling of 95 or
96 with aryl iodide
HRMS (FAB) calcd for C20H15ClNO 320.0842 ([MþH]þ), found
320.0840.
A mixture of 95 or 96 (0.14 mmol), aryl iodide (1.3 equiv), cop-
per(I) iodide (0.1 equiv), and bis(triphenylphosphine)palladium(II)
dichloride (0.1 equiv) in Et3N (2 mL) was stirred at temperature as
indicated in Table 7. After the reaction was complete, the reaction
mixture was concentrated under reduced pressure and purified by
silica gel column chromatography (hexane/ethyl acetate/dichloro-
methane) to give tertiary propargylic alcohols.
4.5.7. Methyl 4-(3-hydroxy-3-phenyl-3-(pyridin-2-yl)prop-1-ynyl)
benzoate (103). Pale brown solid, mp: 103.2e106.3 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
8.56 (d, J¼4.5 Hz, 1H), 7.99 (d, J¼8.5 Hz, 2H),
7.73e7.67 (m, 3H), 7.57 (d, J¼8.5 Hz, 2H), 7.47 (d, J¼8.0 Hz, 1H),
7.39e7.34 (m, 2H), 7.32e7.24 (m, 2H), 6.66 (s, 1H), 3.92 (s, 3H); 13C
NMR (125 MHz, CDCl3)
d 166.6, 160.9, 147.2, 143.9, 137.8, 131.9,
130.0, 129.6, 128.5, 128.2, 127.3, 126.5, 123.2, 121.9, 94.1, 85.8, 73.8,
52.4; IR (ATR) 3261, 2921, 2851, 1722, 1591, 1435, 1401, 1271 cmꢁ1
;
4.5.1. 4-(4-Nitrophenyl)-2-(pyridin-2-yl)but-3-yn-2-ol (97). Brown
HRMS (FAB) calcd for C22H18NO3 344.1287 ([MþH]þ), found
gum; 1H NMR (500 MHz, CDCl3)
d
8.57 (d, J¼4.5 Hz, 1H), 8.16 (d,
344.1279.
J¼8.0 Hz, 2H), 7.81 (td, J¼1.5, 7.5 Hz, 1H), 7.65 (d, J¼8.0 Hz, 1H), 7.58
(d, J¼9.0 Hz, 2H), 7.32 (dd, J¼5.0, 7.50 Hz, 1H), 5.76 (s, 1H), 1.90 (s,
4.5.8. 4-(3-Hydroxy-3-phenyl-3-(pyridin-2-yl)prop-1-ynyl)benzoni-
3H); 13C NMR (125 MHz, CDCl3)
d
161.1, 147.7, 147.3, 137.8, 132.7,
trile (104). Pale brown solid, mp: 108.0e111.9 ꢀC; 1H NMR
129.7, 123.6, 123.3, 120.1, 97.8, 81.9, 69.0, 31.9; IR (ATR) 3283, 3074,
2925, 2851, 2236, 1591, 1513, 1338 cmꢁ1; HRMS (FAB) calcd for
C15H13N2O3 269.0926 ([MþH]þ), found 269.0926.
(500 MHz, CDCl3)
d
8.57 (d, J¼5.0 Hz, 1H), 7.70 (td, J¼1.5, 7.5 Hz,
1H), 7.78e7.65 (m, 2H), 7.63e7.56 (m, 4H), 7.44 (d, J¼8.0 Hz, 1H),
7.39e7.34 (m, 2H), 7.33e7.29 (m, 1H), 7.28 (dd, J¼5.0, 7.5 Hz, 1H),
6.67 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 160.6, 147.2, 143.6, 137.8,
4.5.2. 4-(3-Hydroxy-3-(pyridin-2-yl)but-1-ynyl)benzonitrile
132.5, 132.1, 128.6, 128.6, 127.5, 126.5, 123.3, 121.8, 118.5, 112.2,
95.6, 84.8, 73.7; IR (ATR) 3272, 2921, 2851, 2225, 1587, 1431,
(98). Brown gum; 1H NMR (500 MHz, CDCl3)
d
8.56 (d, J¼5.0 Hz,

5480
H. Cho, I. Kim / Tetrahedron 68 (2012) 5464e5480
1394 cmꢁ1; HRMS (FAB) calcd for C21H15N2O 311.1184 ([MþH]þ),
8. Choi, J.; Lee, G. H.; Kim, I. Synlett 2008, 1243.
9. Kim, K.; Kim, I. J. Comb. Chem. 2010, 12, 379.
10. Kim, I.; Kim, K. Org. Lett. 2010, 12, 2500.
found 311.1182.
11. A similar approach to 2,3-disubstituted indolizines under Pd catalysis was
disclosed by Gevorgyan and co-workers Chernyak, D.; Skontos, C.; Gevorgyan,
V. Org. Lett. 2010, 12, 3242.
Acknowledgements
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We thank Yonsei University for financial support.
Supplementary data
Copies of 1H and 13C NMR spectra of 12, 26e37, 57e81, 83e92,
and 95e104. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2012.04.091.
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