Diversity-oriented construction of highly substituted indolizinones

Article abstract of DOI:10.1021/cc100015k

Rapid generation of a small library of highly functionalized indolizonones was realized by exploiting three palladium-catalyzed cross-coupling reactions of 2-iodoindolizinones which in turn were readily accessed via sequential iodine-mediated cyclization/1,2-shift reactions of propargylic alcohols.

Full text of DOI:10.1021/cc100015k

J. Comb. Chem. 2010, 12, 379–382
379
Diversity-Oriented Construction of Highly Substituted Indolizinones
Kyungsun Kim and Ikyon Kim*
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology,
Daejeon 305-600, Republic of Korea
ReceiVed January 26, 2010
Rapid generation of a small library of highly functionalized indolizonones was realized by exploiting three
palladium-catalyzed cross-coupling reactions of 2-iodoindolizinones which in turn were readily accessed
via sequential iodine-mediated cyclization/1,2-shift reactions of propargylic alcohols.
(Scheme 2).5 Nucleophilic addition of the appropriate
terminal acetylide to 2-acylpyridine 1 provided tertiary
propargylic alcohol 2 which was converted to the corre-
sponding 2-iodoindolizinone 3 via a sequential iodocycliza-
tion/1,2-shift. By using this protocol, the requisite 2-iodo-
indolizinones in which two diversity points are occupied by
different groups were rapidly synthesized in excellent overall
yields.
Introduction
In the context of drug discovery, halogenated heterocyclic
compounds serve as a useful platform for increasing mo-
lecular diversity.1 This is particularly true as enormous
progress has been made in the modern transition-metal
catalyzed cross-coupling technology, which enables a number
of functional groups to be installed at the halogen site.2 In
this regard, the reactions incorporating halogens into the
molecular framework of interest in a regioselective manner
have been increasingly gaining attention. Among these,
halocyclization3,4 is highly valuable because of its ability to
introduce halide(s) as a functional handle for further synthetic
elaboration as well as to form new ring(s) under relatively
mild reaction conditions.
Having secured diverse 2-iodoindolizinones in hand, we
next focused our attention on introduction of new functional
groups at the third diversity point. To this end, we planned
to employ three Pd-catalyzed cross-coupling reactions,
namely, Heck,9 Sonogashira,10 and Suzuki-Miyaura reac-
tions11 (Scheme 3).
As shown in Figure 2, methyl acrylate was used as a
coupling partner for the Heck reaction. For the Sonogashira
and Suzuki-Miyaura reactions, small sets of terminal
acetylenes and boronic acids were chosen as reacting
partners. Heck coupling was conducted under the Jeffery’s
ligandless conditions.12 Two reaction conditions (methods
C and D) were employed for Suzuki-Miyaura coupling
reactions.
We recently established the novel approach to 2-iodoin-
dolizinones 3 based on 5-endo-dig iodocyclization and
subsequent 1,2-migration strategy (Scheme 1).5 Thus, a wide
range of 2-iodoindolizinones were easily prepared in excel-
lent yields under very mild conditions. As indolizines
constitute an important class of heterocycles with diverse
biological activities, many efforts have been devoted to
search for new drugs bearing an indolizine moiety.6 For
example, indolizine oxalylamide A was reported to exhibit
antifungal activity whereas indolizine acetic acid B was
known to be a ligand of the CRTH2 receptor useful for the
treatment of inflammatory respiratory diseases (Figure 1).7
Thus, a number of synthetic methods toward this skeleton
have been developed.8
Indolizinones, however, have not been evaluated as a
pharmacophore to our knowledge. As part of our medicinal
research program, we decided to construct a focused mo-
lecular library based on an indolizinone core. Particularly,
we envisioned that at least three positions are available in
this scaffold for diversification (Scheme 1). Herein we report
an expedient route to highly substituted indolizinones using
Pd-catalyzed cross-coupling reactions of 2-iodoindolizinones.
As outlined in Table 1, three palladium-catalyzed cross-
couplings of 3 enabled us to synthesize a wide range of
highly functionalized indolizinones 4 in good to excellent
yields, displaying good functional group tolerance. Both
Heck and Sonogashira reactions proceeded well to give the
desired products in good yields for all 2-iodoindolizinones
tested except for the thiophene-containing one 3{7}. Although
modest yields were obtained in some cases (for example,
entries 9, 12, 18, 47, 49, 50, and 59), Suzuki-Miyaura
Scheme 1. Our Strategy for the Synthesis of Poly-Substituted
Indolizinones
Results and Discussion
We began this study with the preparation of 2-iodoin-
dolizinones 3 by following the procedure reported by us
* To whom correspondence should be addressed. E-mail: ikyon@krict.re.kr.
Phone: +82 42 860 7177. Fax: +82 42 860 7160.
10.1021/cc100015k  2010 American Chemical Society
Published on Web 03/31/2010

380 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Kim and Kim
Figure 1. Selected molecular structures bearing an indolizine core.
Scheme 2. Preparation of 2-Iodoindolizinones
a Overall yield from 1.
coupling of 3 generally provided the corresponding products
in good to excellent yields. Preliminary biological screening
of these compounds in several cancer cell lines indicated
that some are capable of killing cancer cells selectively
although the mode of action is not clear at this point.
In summary, diversity-oriented construction of poly substi-
tuted indolizinones was accomplished from three simple build-
ing blocks in a highly efficient manner. Nucleophilic addition
of lithium acetylides to 2-acylpyridines provided propargylic
alcohols which underwent smooth iodocyclization/1,2-shift to
afford 2-iodoindolizinones in excellent overall yields. Finally,
Pd-catalyzed cross-coupling reactions with alkenes, alkynes, and
boronic acids delivered a variety of highly substituted indoliz-
inones. Biological evaluation of these compounds is currently
ongoing and will be reported soon.
was added n-BuLi (1.1 equiv, 1.6 M solution in hexanes) at
-78 °C. After 5 min, a solution of ketone 1 (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 2. To a solution of propargylic alcohol 2 (1.0 equiv) in
CH2Cl2 was added iodine (1.5 equiv) at room temperature. After
being stirred at room temperature (rt) for 5 h, the reaction
mixture was quenched by the addition of excess aqueous
NaHSO3 solution. The solid (indolizinium salt) was filtered,
washed with dichloromethane, and dried. A mixture of indoliz-
inium salt (1.0 equiv) and Cs2CO3 (1.5 equiv) in MeOH was
heated to reflux for 1 h. After being cooled to rt, the reaction
mixture was concentrated in vacuo. The residue was diluted
Experimental Section
General Procedure for the Synthesis of 3. To a stirred
solution of terminal alkyne (1.2 equiv) in tetrahydrofuran (THF)

Construction of Highly Substituted Indolizinones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 381
Table 1. Synthesis of Poly-Substituted Indolizinones
Scheme 3. Pd-Catalyzed Cross-Coupling Reactions of 3a
entry
3
5
method
product (4)
yield (%)a
1
2
3
4
5
6
7
8
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{2}
3{2}
3{2}
3{2}
3{2}
3{2}
3{2}
3{2}
3{2}
3{3}
3{3}
3{3}
3{3}
3{3}
3{4}
3{4}
3{4}
3{4}
3{4}
3{4}
3{4}
3{5}
3{5}
3{5}
3{5}
3{5}
3{5}
3{5}
3{5}
3{5}
3{6}
3{6}
3{6}
3{7}
3{7}
3{7}
3{7}
3{7}
3{7}
3{7}
3{8}
3{8}
3{9}
3{9}
3{9}
3{9}
5{1}
5{2}
5{3}
5{4}
5{5}
5{6}
5{7}
5{8}
A
B
B
B
C
C
C
C
C
C
C
C
C
C
A
B
C
D
C
D
D
D
D
B
C
C
C
C
A
B
B
D
D
D
D
A
B
D
C
C
C
D
D
D
A
B
D
A
B
D
D
D
D
D
A
B
A
B
D
D
4{1}
4{2}
4{3}
4{4}
4{5}
4{6}
4{7}
4{8}
84
99
88
90
91
83
88
63
35
93
95
30
56
76
58
77
66
33
85
77
65
68
45
70
67
82
71
69
93
73
92
55
61
55
68
76
93
66
83
78
56
52
88
48
50
63
35
45
38
36
75
46
89
49
53
48
56
71
33
89
9
5{9}
4{9}
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5{10}
5{11}
5{12}
5{13}
5{14}
5{1}
5{2}
5{5}
5{6}
5{7}
4{10}
4{11}
4{12}
4{13}
4{14}
4{15}
4{16}
4{17}
4{18}
4{19}
4{20}
4{21}
4{22}
4{23}
4{24}
4{25}
4{26}
4{27}
4{28}
4{29}
4{30}
4{31}
4{32}
4{33}
4{34}
4{35}
4{36}
4{37}
4{38}
4{39}
4{40}
4{41}
4{42}
4{43}
4{44}
4{45}
4{46}
4{47}
4{48}
4{49}
4{50}
4{51}
4{52}
4{53}
4{54}
4{55}
4{56}
4{57}
4{58}
4{59}
4{60}
a Method A: Pd(OAc)2 (0.1 equiv), methyl acrylate (4.1 equiv),
n-Bu4NCl (1 equiv), NaHCO3 (2 equiv), DMF, 100 °C; Method B: terminal
alkyne (2 equiv), PdCl2(PPh3)2 (0.1 equiv), CuI (0.1 equiv), Et3N (3 equiv),
DMF, rt; Method C: boronic acid (1.5 equiv), 10% Pd/C (0.1 equiv),
Na2CO3 (3 equiv), DME/H2O (1:1), 100 °C; Method D: boronic acid (1.5
equiv), Pd(Ph3P)4 (0.1 equiv), K2CO3 (2 equiv), toluene/EtOH/H2O
(4:2:1), 100 °C.
5{8}
5{10}
5{11}
5{16}
5{2}
5{6}
5{7}
5{12}
5{15}
5{1}
5{2}
5{4}
5{6}
5{10}
5{11}
5{17}
5{1}
5{3}
5{6}
5{7}
5{10}
5{11}
5{16}
5{17}
5{15}
5{1}
5{4}
5{12}
5{1}
5{2}
5{6}
5{10}
5{11}
5{17}
5{9}
5{1}
5{2}
5{1}
5{2}
5{8}
5{11}
Figure 2. Coupling partners for Pd-catalyzed reactions.
with ethyl acetate and washed with H2O. The water layer was
extracted with ethyl acetate one more time. The combined
organic layers were dried over MgSO4, filtered, and evaporated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate/dichlo-
romethane ) 7:1:2) to give 2-iodoindolizinone 3.
General Procedure for the Heck Reaction of 3 with
Methyl Acrylate (Method A). A mixture of 2-iodoindoliz-
inone 3 (1 equiv), methyl acrylate (4.1 equiv), sodium bicarbon-
ate (2 equiv), tetra-n-butylammonium chloride (1 equiv),
palladium(II) acetate (0.1 equiv) in N,N-dimethylformamide
(DMF) was heated at 100 °C for 18 h. After being cooled to rt,
the reaction mixture was diluted with ethyl acetate and water.
The organic layer was washed with water two times, and the
aqueous layer was extracted with ethyl acetate one more time.
a Isolated yield (%).
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/
dichloromethane )10:1:2) to give 4.
General Procedure for the Sonogashira Coupling with
3 with Terminal Alkyne (Method B). A mixture of
2-iodoindolizinone 3 (1 equiv), terminal alkyne (2 equiv),
copper(I) iodide (0.1 equiv), triethylamine (3 equiv), bis-
(triphenylphosphine)palladium(II) dichloride (0.1 equiv) in
DMF was stirred at rt for 18 h. The reaction mixture was

382 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Kim and Kim
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diluted with ethyl acetate and water. The organic layer was
washed with water two times, and the aqueous layer
was extracted with ethyl acetate 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/
dichloromethane ) 15:1:2) to give 4.
General Procedure for the Suzuki-Miyaura Coupling
of 3 with Boronic Acid (Method C). A mixture of
2-iodoindolizinone 3 (1 equiv), boronic acid (1.5 equiv), 10%
Pd/C (0.1 equiv), Na2CO3 (3 equiv) in 1,2-dimethoxyethane:
H2O (1:1) was heated at 100 °C for 5 h. After being cooled
to rt, the reaction mixture was concentrated in vacuo. The
residue was diluted with ethyl acetate and washed with water.
The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography (hexane/ethyl acetate/
dichloromethane) to give 4.
General Procedure for the Suzuki-Miyaura Coupling
of 3 with Boronic Acid (Method D). A mixture of
2-iodoindolizinone 3 (1 equiv), boronic acid (1.5 equiv),
Pd(Ph3P)4 (0.1 equiv), K2CO3 (2 equiv) in toluene/EtOH/
H2O (4:2:1) was heated at 100 °C for 5 h. After being cooled
to rt, the reaction mixture was concentrated in vacuo. The
residue was diluted with ethyl acetate and washed with water.
The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography (hexane/ethyl acetate/
dichloromethane) to give 4.
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Acknowledgment. This work was financially supported
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Supporting Information Available. General synthetic
1
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CC100015K