Efficient synthesis of highly substituted indolizinones via iodocyclization and 1,2-shift

Article abstract of DOI:10.1055/s-2008-1072721

The 5-endo-dig iodocyclization of propargylic alcohols followed by a 1,2-shift provided rapid access to 2-iodoindolizinones, while the 5-endo-trig iodocyclization of allylic alcohols and subsequent dehydroiodination and 1,2-shift led to indolizinones. A number of highly substituted indolizinones were constructed under these mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072721

LETTER
1243
Efficient Synthesis of Highly Substituted Indolizinones via Iodocyclization and
1,2-Shift
Synthesis
i
of
H
igh
h
ly Substitut
y
unes n Choi, Ge Hyeong Lee, Ikyon Kim*
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
Fax +82(42)8607160; E-mail: ikyon@krict.re.kr
Received 31 January 2008
As an extension of these studies, we envisioned that the
Abstract: The 5-endo-dig iodocyclization of propargylic alcohols
followed by a 1,2-shift provided rapid access to 2-iodoindolizino-
nes, while the 5-endo-trig iodocyclization of allylic alcohols and
subsequent dehydroiodination and 1,2-shift led to indolizinones. A
structurally related 2-iodoindolizinone 7 would be con-
structed from 5 via iodocyclization and 1,2-migration. As
shown in Scheme 2, a facile 5-endo-dig iodocyclization of
number of highly substituted indolizinones were constructed under 5 would produce a indolizinium salt 6 which would under-
go 1,2-migration of R1 to lead to 2-iodoindolizinone 7.
these mild reaction conditions.
Likewise, similar iodocyclization of allylic alcohol 8 and
subsequent dehydroiodination and 1,2-shift would lead to
indolizinone 10. Recently, two research groups (Sarpong
and Liu) reported the synthesis of indolizinones utilizing
the similar strategy.2 One drawback of their approaches is
that C2-substituted indolizinones can not be accessed. In
contrast, our approach could potentially provide a solution
to this problem since an iodo group at the C2 position of
7 could be useful for further elaboration. Moreover, our
latter route to indolizinones 10 from allylic alcohols 8
could directly deliver C2,C3-substituted indolizinones de-
pending on the substitution pattern of the starting allylic
alcohols 8. Herein we wish to describe the two convenient
approaches to highly functionalized indolizinones relying
upon iodocyclization–1,2-shift.
Key words: indolizinones, iodine, cyclizations, rearrangements,
1,2-migration
As part of our research program on the facile synthesis of
heterocycles using mild and environment-friendly condi-
tions,1 we recently reported on the novel approach to 2-io-
doindolizines 2 and indolizines 4 based on 5-endo-dig
iodocyclization and 5-endo-trig iodocyclization, respec-
tively (Scheme 1).1b,c These two methods allow direct ac-
cess to a wide range of highly substituted indolizines
under very mild conditions.
OAc
OAc
I2
1
8
5
I
R2
7
6
N
r.t.
N
R1
To test the feasibility of this idea, we began our investiga-
tion with the preparation of the starting material. The req-
uisite propargylic alcohol 5 was easily prepared in high
yield from the reaction of ketone 11 and terminal acetyl-
ide 12 while the allylic alcohol 8 was obtained from the
nucleophilic addition of 2-pyridinyllithium to a,b-unsat-
urated ketone 13 in excellent yield (Scheme 3).
R1
2
R2
N
4
3
1
2
OAc
OAc
R2
R3
I2, r.t.
Et3N
R2
N
N
R1
R1
R3
3
4
Scheme 1 Our previous work on the synthesis of indolizines
R1
O
R1
N
OH
R1 OH
5-endo-dig
iodocyclization
1,2-shift
I
I
N
N
R2
R2
R2
I
5
6
7
R1
O
OH
R1
N
R1 OH
5-endo-trig
iodocyclization
dehydroiodination,
1,2-shift
R2
R3
I
R2
R2
N
N
R3
R3
I
8
9
10
Scheme 2 Two novel strategies to highly substituted indolizinones
SYNLETT 2008, No. 8, pp 1243–1249
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072721; Art ID: U00908ST
© Georg Thieme Verlag Stuttgart · New York

1244
J. Choi et al.
LETTER
R1 OH
O
equally well under these conditions to furnish 2-iodoin-
dolizinone 7l bearing a pyridyl group at the ring juncture
(entry 12).
M
R2
R1
12
R2
N
N
(M = Li or MgX)
As an attempt to make 2-iodoquinolizinones, 5m and 5n
were subjected to the iodocyclization conditions
(Scheme 5). In these cases, however, different products
(16 and 17) were obtained instead of the corresponding
quinolinium iodides. The plausible mechanism is postu-
lated in Scheme 5. Thus, initial loss of H2O7 would gener-
ate carbocation A. The resonance-stabilized structure A¢
would then be attacked by iodide to form iodoallene B. By
analogy to the report by Gevorgyan,8 intramolecular
Michael-type addition of iodo group in B to the neighbor-
ing olefin would lead to iodoirenium zwitterion C which
is subsequently cyclized to furnish a pyrrolo[1,2-a]quino-
line skeleton. The stabilization of the carbocation by the
additional phenyl group in 5m and 5n should be ascribed
to this different reactivity profile.9
11
5
R1 OH
1) n-BuLi, THF
–78 °C;
Br
R2
R3
N
N
O
R2
R1
8
13
R3
Scheme 3 Synthesis of the cyclization substrates 5 and 8
OAc
OAc
I
2 (1.5 equiv)
X
I
N
CH2Cl2, r.t.
N
Having established the highly efficient iodocyclization
and 1,2-shift strategy for constructing 2-iodoindolizino-
nes, we next directed our attention to the synthesis of in-
dolizinones 10 from allylic alcohols 8. By employing the
similar conditions as above, a number of indolizinones 10
were easily accessed from allylic alcohols 8 via 910
(Table 2).11 Since one equivalent of base is needed for the
dehydroiodination of 9, 2.5 equivalents of cesium carbon-
ate were used for the second step. Also, heating the reac-
tion mixture to reflux was found to be essential to
complete the migration within a reasonable reaction time.
Compared with the iodocyclization step of propargylic al-
cohol 5, yield of 9 is generally lower presumably as a re-
sult of less facile 5-endo-trig cyclization.12 As mentioned
in the introductory section, 2,3-disubstituted indolizino-
nes (10c and 10h) were directly prepared from 2,3-disub-
stituted allylic alcohols (8c and 8h), respectively (entries
3 and 8).
14
15
Equation 1
Initially, a stepwise approach was conducted. Thus, when
5a was exposed to 1.5 equivalents of iodine in dichlo-
romethane at room temperature, almost quantitative yield
of indolizinium salt 6a was obtained. In order to promote
the 1,2-migration of R1, the isolated indolizinium salt 6a
was then treated with 1.5 equivalents of cesium carbonate
in methanol3,4 at room temperature for six hours, thereby
resulting in a quantitative yield of 2-iodoindolizinone 7a.
This rearrangement was accelerated by elevating the reac-
tion temperature, which again provided the desired 7a in
an excellent yield within an hour (Scheme 4).5
With these optimized conditions in hand, the reaction
scope was examined with various substrates. As outlined
in Table 1, a wide range of 2-iodoindolizinones was syn-
thesized in excellent overall yields via indolizinium inter-
mediates under mild conditions. Notably, 5f underwent
iodocyclization to give the corresponding indolizinium
salt 6f which, upon exposure to cesium carbonate in meth-
anol, was transformed to 7f in 59% overall yield (entry 6).
Previously, we observed that similar substrate 14 did not
afford 15 only to give a complex mixture under the iden-
tical iodocyclization conditions (Equation 1).6
Since the first step (iodocyclization) can be carried out in
methanol, one-pot procedure was next attempted instead
of stepwise approaches (Scheme 6). Thus, cesium carbon-
ate was added to the reaction mixture after disappearance
of 5k or 8e that was confirmed by TLC. In order to facili-
tate the 1,2-shift, stirring the reaction mixture at room
temperature was enough in the case of 5k, whereas heat-
ing the reaction mixture under reflux was necessary in the
case of 8e. To our delight, this one-pot protocol provided
2-iodoindolizinone 7k and indolizinone 10e, respectively,
without compromising the yields.
Both alkyl groups and aryl groups were effectively mi-
grated. A pyridyl moiety as a migrating group shifted
O
Me
OH
Me
N
Me OH
Cs2CO3
MeOH
I2
I
I
N
CH2Cl2, r.t.
r.t. or reflux
N
Ph
Ph
Ph
I
6a
5a
7a
Scheme 4 Stepwise approach to 2-iodoindolizinone 7a
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Substituted Indolizinones
1245
R1 OH
R1
I
2 (2.0 equiv)
I
N
R2
N
CH2Cl2, r.t.
R2
5m: R1 = Ph, R2 = t-Bu
5n: R1 = Me, R2 = n-Bu
16: 85%
17: 83%
HI
R1
R1
R1
H2O
I
I
N
R2
N
N
R2
R2
A
B
C
R1
I
N
R2
A'
Scheme 5 Formation of pyrrolo[1,2-a]quinolines
Table 1 Synthesis of Various 2-Iodoindolizinones
R1
O
R1
OH
R1 OH
Cs2CO3
(1.5 equiv)
I
2 (1.5 equiv)
I
I
N
N
CH2Cl2, r.t.
MeOH
reflux
N
R2
R2
R2
I
6
5
7
Entry
1
5
6
Yield of 6
7
Yield of 7
(%)a
(%)a
O
Me
Me
N
OH
Me OH
N
5a
6a
6b
99
98
7a
7b
100
100
I
I
I
N
Ph
Ph
O
Ph
I
Me
N
OH
Me
N
Me OH
N
I
2
5b
I
Me
N
O
OH
Me
N
Me OH
N
3
4
5c
6c
80
94
7c
95
99
I
I
n-Bu
t-Bu
n-Bu
n-Bu
I
Me
N
O
OH
Me
N
Me OH
N
5d
I
6d
7d
I
t-Bu
t-Bu
I
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

1246
J. Choi et al.
LETTER
Table 1 Synthesis of Various 2-Iodoindolizinones (continued)
R1
O
R1
N
OH
R1 OH
Cs2CO3
(1.5 equiv)
I
2 (1.5 equiv)
I
I
N
CH2Cl2, r.t.
MeOH
reflux
N
R2
R2
R2
I
6
5
7
Entry
5
6
Yield of 6
7
Yield of 7
(%)a
(%)a
O
Me
N
Me
N
OH
Me OH
N
I
I
5
5e
6e
100
66
7e
7f
98
89
I
Me
N
OH
OH
Me OH
N
O
O
Me
N
6
7
5f
6f
I
I
I
Me
N
Me
N
I
I
Me OH
N
5g
6g
100
7g
100
I
OMe
OMe
OMe
Me OH
N
Me
N
O
O
OH
OH
Me
N
8
9
5h
5i
6h
6i
85
93
7h
7i
98
I
I
OBn
OBn
BnO
I
Me
N
Me
N
Me OH
N
I
I
100
I
S
S
S
O
Et
N
OH
Et
N
Et OH
I
I
10
5j
6j
100
7j
100
N
I
Ph
N
O
OH
Ph
N
Ph OH
N
11
12
5k
5l
6k
6l
100
100
7k
7l
100
99
I
I
I
t-Bu
t-Bu
t-Bu
OH
t-Bu
I
I
Py
N
O
Py
N
Py OH
I
N
t-Bu
t-Bu
a Isolated yield (%).
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Substituted Indolizinones
1247
Table 2 Syntheses of Various Indolizinones
R1
O
R1
N
OH
I
R1 OH
Cs2CO3
(2.5 equiv)
R2
R3
I
2 (2.0 equiv)
R2
R2
N
MeOH
reflux
CH2Cl2, r.t.
N
R3
R3
I
8
9
10
Entry
1
8
9
Yield of 9 10
Yield of 10
(%)a
(%)a
Me
N
O
OH
I
Me
N
Me OH
8a
9a
100
63
10a
10b
80
N
Ph
Ph
OH
I
Ph
O
I
Me
N
Me
N
Me OH
N
2
3
4
8b
8c
8d
9b
9c
9d
90
89
88
Me
Me
Me
O
I
I
Me
N
OH
I
Me
N
Me OH
N
59
65
10c
10d
Ph
N
O
OH
I
Ph
N
Ph OH
N
Ph
Ph
OH
I
Ph
O
I
I
Me
N
Me OH
Me
N
5
6
8e
8f
9e
9f
71
73
10e
10f
93
87
N
Et
N
O
OH
I
Et
N
Et OH
N
Me
Me
Me
O
I
I
Me
N
OH
I
Me
N
Me OH
7
8
8g
8h
9g
9h
77
90
10g
10h
91
93
N
O
O
O
Me
N
O
OH
I
Me
N
Me OH
N
Me
Ph
Me
Me
Ph
Ph
I
a Isolated yield (%).
Finally, we briefly investigated the viability of the forma- end, propargylic alcohol 5n13 was treated with iodine to
tion of indolizinone with concomitant ring contraction. As furnish indolizinium salt 6n uneventfully.14 By exposure
shown in Scheme 7, the final 2-iodoindolizinone product to cesium carbonate in methanol, bond reorganization
C would have a one-carbon-smaller ring if the R1 group is took place leading to the tricyclic 2-iodoindolizinone 7n
tethered to the pyridine moiety (for example, A). To this albeit in low yield.
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

1248
J. Choi et al.
LETTER
O
References and Notes
Ph
N
Ph OH
Cs2CO3
(2.0 equiv)
I
2 (1.5 equiv)
MeOH, r.t.
(1) (a) Kim, I.; Lee, G. H.; No, Z. S. Bull. Korean Chem. Soc.
2007, 28, 685. (b) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H.
Tetrahedron Lett. 2007, 48, 6863. (c) Kim, I.; Won, H. K.;
Choi, J.; Lee, G. H. Tetrahedron 2007, 63, 12954. (d) Kim,
I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron Lett. 2007,
48, 8976. (e) Kim, I.; Kim, S. G.; Choi, J.; Lee, G. H.
Tetrahedron 2008, 64, 664.
(2) (a) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R.
Org. Lett. 2007, 9, 1169. (b) Yan, B.; Zhou, Y.; Zhang, H.;
Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783.
I
100%
N
t-Bu
t-Bu
5k
7k
O
Me
Me OH
Cs2CO3
(3.0 equiv)
I
2 (2.0 equiv)
N
then reflux
60%
MeOH, r.t.
N
(3) We also observed the direct synthesis of indolizinones from
propargylic alcohols with Cs2CO3 (Scheme 8). These results
will be communicated elsewhere.
8e
10e
Scheme 6 One-pot approaches to 2-iodoindolizinones 7k and indo-
lizinone 10e
O
R1
R1 OH
Cs2CO3
ROH
In conclusion, we described highly efficient and conve-
nient approaches to 2-iodoindolizinones 7 and indolizino-
nes 10 from propargylic alcohols 5 and allylic alcohols 8
via indolizinium salts 6 and 9, respectively. We also dem-
onstrated this stepwise approach can be performed in a
one-pot manner. Particularly, our procedure should be
useful for the synthesis of highly substituted indolizinones
since an iodo group in 2-iodoindolizinones can be further
elaborated to a variety of other functional groups, for ex-
ample, via metal-catalyzed coupling reactions. Given the
importance of indolizinone core as a pharmacophore, the
routes delineated here should be valuable for the synthesis
of indolizinone-based pharmacologically important com-
pounds. In addition, ring saturation by diastereoselective
catalytic hydrogenation15 of these compounds would open
access to more diverse fused azacycles. Further studies
are ongoing along these lines and will be reported in due
course.
N
reflux
N
R2
R2
Scheme 8
(4) When Et3N was employed instead to initiate the 1,2-shift,
very long reaction times (more than 48 h) and elevated
temperatures were required.
(5) General Procedure: To a stirred solution of propargylic
alcohol 5a (0.84 mmol) in CH2Cl2 (3 mL) was added iodine
(1.5 equiv) at r.t. After being stirred at r.t. for 5 h, the
reaction mixture was quenched by the addition of excess aq
NaHSO3 solution. The solid (indolizinium salt 6a) was
filtered, washed with CH2Cl2, and dried.
1-Hydroxy-2-iodo-1-methyl-3-phenyl-1H-indolizinium
Iodide (6a)
1H NMR (300 MHz, DMSO-d6) d = 8.64–8.59 (m, 2 H), 8.49
(d, J = 7.2 Hz, 1 H), 7.97 (t, J = 7.2 Hz, 1 H), 7.70–7.65 (m,
5 H), 6.71 (s, 1 H), 1.63 (s, 3 H). 13C NMR (75 MHz, DMSO-
d6): d = 160.0, 145.6, 142.6, 136.6, 132.1, 131.3, 130.3,
128.3, 126.4, 124.0, 114.5, 82.6, 24.8. IR (KBr): 3496, 3214,
3080, 1622, 1481, 1360 cm–1. ESI-HRMS: m/z calcd for
C15H14INO [M + 1]+: 351.0036; found: 351.0041.
A mixture of indolizinium salt 6a (0.31 mmol) and Cs2CO3
(1.5 equiv) in MeOH (10 mL) was heated to reflux for 1 h.
After being cooled to r.t., the reaction mixture was
concentrated in vacuo. The residue was diluted with EtOAc
and washed with H2O. The water layer was extracted with
EtOAc one more time. The combined organic layers were
Acknowledgment
This work was financially supported by the Center for Biological
Modulators and Korea Research Institute of Chemical Technology.
n
n
n
O
OH
OH
R2
I
I
N
N
R2
N
R2
O
I
A
B
C
Cs2CO3
(1.5 equiv)
OH
OH
I
2 (1.5 equiv)
I
I
CH2Cl2, r.t.
100%
N
MeOH, reflux
39%
N
t-Bu
N
t-Bu
t-Bu
I
5n
6n
7n
Scheme 7 Formation of 2-iodoindolizinone with concomitant ring contraction
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

LETTER
dried over MgSO4, filtered, and evaporated under reduced
Synthesis of Highly Substituted Indolizinones
1249
(m, 5 H), 6.89, 6.87 (s, 1 H), 6.20, 6.17 (d, J = 10.8 Hz, 1 H),
4.77, 4.74 (d, J = 10.8 Hz, 1 H), 1.79, 1.66 (s, 1 H). 13C NMR
(75 MHz, DMSO-d6): d = 159.9, 157.5, 147.7, 140.7, 140.4,
132.4, 132.3, 131.3, 131.1, 130.4, 130.2, 130.0, 129.9,
128.3, 128.1, 123.7, 123.6, 78.9, 78.1, 76.8, 76.7, 37.7, 37.5,
28.3, 22.2. IR (KBr): 3100, 1678, 1536, 1486, 1392, 1251
cm–1. ESI-HRMS: m/z calcd for C15H16INO [M + 1]+:
353.0193; found: 353.0198.
pressure. The resulting residue was purified by silica gel
column chromatography (hexanes–EtOAc–CH2Cl2, 7:1:2)
to give 2-iodoindolizinone 7a.
2-Iodo-8a-methyl-3-phenylindolizin-1(8aH)-one (7a)
1H NMR (300 MHz, CDCl3): d = 7.57–7.55 (m, 3 H), 7.50–
7.46 (m, 2 H), 6.30 (d, J = 7.2 Hz, 1 H), 5.97–5.89 (m, 2 H),
5.33 (t, J = 6.3 Hz, 1 H), 1.48 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 199.0, 131.2, 129.2, 129.1, 129.0, 123.9, 123.1,
122.2, 109.3, 67.8, 63.5, 25.5. IR (KBr): 3092, 2978, 1674,
1522, 1420, 1295 cm–1. HRMS (EI): m/z calcd for
[C15H12INO]+: 348.9964; found: 348.9968.
8a-Methyl-3-phenylindolizin-1 (8aH)-one (10a)
1H NMR (300 MHz, CDCl3): d = 7.56–7.47 (m, 5 H), 6.53
(d, J = 7.3 Hz, 1 H), 5.98–5.88 (m, 2 H), 5.38 (ddd, J = 6.8,
4.7, 1.9 Hz, 1 H), 5.18 (s, 1 H), 1.45 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 203.2, 172.7, 131.2, 129.8, 129.2, 128.3.
124.0. 123.0, 122.1, 109.0, 99.0, 68.8, 25.2. IR (KBr): 3275,
2939, 1622, 1573, 1485, 1380, 1261, 1136 cm–1. HRMS
(EI): m/z calcd for [C15H13NO]+: 223.0997; found: 223.0993.
(12) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(13) For the synthesis of 5,6,7,8-tetrahydro-8-quinolinone, see:
(a) Thummel, R. P.; Lefoulon, F.; Cantu, D.; Mahadevan, R.
J. Org. Chem. 1984, 49, 2208. (b) Kelly, T. R.; Lebedev, R.
L. J. Org. Chem. 2002, 67, 2197.
(6) For other unsuccessful iodocyclization results with terminal
alkynes, see: (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.;
Larock, R. C. J. Org. Chem. 2007, 72, 1347. (b) Bew, S. P.;
El-Taeb, G. M. M.; Jones, S.; Knight, D. W.; Tan, W.-F.
Eur. J. Org. Chem. 2007, 5759.
(7) Reaction of I2 with a small amount of H2O contained in
CH2Cl2 is known to produce HI, which would be responsible
for generation of carbocation A.
(8) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2005, 127, 10500.
(14) Nonaqueous workup, i.e. filtration of the reaction mixture,
was used in this case to isolate the indolizinium salt 6n.
Addition of aq NaHSO3 solution to the reaction mixture
resulted in uncharacterizable product instead, indicating that
6n is, unlike others, unstable to an aqueous environment.
(15) For diastereoselective catalytic hydrogenation approaches to
indolizidines, see: (a) Shono, T.; Matsumura, Y.; Tsubata,
K.; Inoue, K.; Nishida, R. Chem. Lett. 1983, 21. (b) Jiang,
C.; Frontier, A. J. Org. Lett. 2007, 9, 4939; and references
therein. (c) Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F.
J. Org. Chem. 2008, 73, 1154; and references therein.
(9) The different nucleophilicity of the nitrogens in pyridine and
quinoline should be also important. We thank one of the
reviewers for this comment.
(10) The diastereomeric ratios of indolizinium salts 9 vary
depending on the cyclization substrates 8 although they were
inconsequential.
(11) 1-Hydroxy-2-iodo-1-methyl-3-phenyl-2,3-dihydro-1H-
indolzinium iodide (9a) Mixture of diastereomers (1.1:1).
1H NMR (300 MHz, DMSO-d6): d = 8.70–8.65 (d, J = 7.8
Hz, 1 H), 8.43, 8.34 (d, J = 8.1 Hz, 1 H), 8.27, 8.25 (d,
J = 6.0 Hz, 1 H), 7.99, 7.93 (d, J = 7.5 Hz, 1 H), 7.64–7.54
Synlett 2008, No. 8, 1243–1249 © Thieme Stuttgart · New York

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