A novel approach to 3-acylated indolizine structures via iodine-mediated hydrative cyclization

Article abstract of DOI:10.1016/j.tetlet.2007.10.101

We have discovered a new route to 3-acylated indolizine structures via iodine-mediated hydrative cyclization. Reaction mechanism is proposed for this novel transformation, which involves a 5-exo-dig iodocyclization, deprotonation, incorporation of another

Full text of DOI:10.1016/j.tetlet.2007.10.101

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Tetrahedron Letters 48 (2007) 8976–8981
A novel approach to 3-acylated indolizine structures via
iodine-mediated hydrative cyclization
Ikyon Kim,* Sun Gi Kim, Ji Young Kim and Ge Hyeong Lee
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 21 September 2007; revised 12 October 2007; accepted 19 October 2007
Available online 24 October 2007
Abstract—We have discovered a new route to 3-acylated indolizine structures via iodine-mediated hydrative cyclization. Reaction
mechanism is proposed for this novel transformation, which involves a 5-exo-dig iodocyclization, deprotonation, incorporation of
another iodo group, deprotonation, and subsequent replacement of the diiodo group by H2O. Various 3-acylated indolizine deriv-
atives were obtained using this mild procedure in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
In the course of our research program on the facile
synthesis of heterocycles using mild and environment-
friendly conditions,1 we recently reported on the conve-
nient synthesis of indolizines based upon 5-endo-dig and
5-endo-trig iodocyclizations,1b,c,2 respectively (Scheme
1). These two complementary methods allowed us to
synthesize a wide range of highly substituted indolizines
under very mild conditions. Particularly, a pyridinyl
nitrogen was employed as an internal nucleophile in
these iodocyclizations for the first time.
Driven by these successful results as well as our interest
in the indolizine nucleus3,4 for medicinal purpose,5 we
decided to investigate 5-exo-dig iodocyclization6 of
alkynes v. Herein we wish to describe a new method
for the synthesis of 3-acylated indolizines facilitated by
iodine.
As shown in Scheme 2, we anticipated smooth cycliz-
ation of alkyne v to proceed in a 5-exo fashion to
provide vinyl iodide vi which was envisioned to be useful
for the synthesis of partially reduced indolizines.
To test this idea, cyclization precursors were first pre-
pared by the reaction of ethyl pyridineacetate and
appropriate propargylic bromides (Scheme 3). Thus,
the treatment of 1 with LHMDS followed by the addi-
tion of propargylic bromides afforded 2 in good yields.7
OAc
OAc
8
5
1
I2
rt
7
6
I
2
N
N
N
R2
N
R1
4
R1
3
To our surprise, when 2a was initially exposed to
1.5 equiv of iodine in CH2Cl2 at rt, about 10% yield of
3a was isolated (Table 1, entry 1). This compound was
R2
i
ii
OAc
OAc
1
unambiguously identified by H NMR, 13C NMR, IR,
R2
R3
I2, rt;
Et3N
and mass spectra. The expected vinyl iodide was not iso-
lated from the mixture. The reaction seemed to proceed
R2
N
R1
R1
R3
iii
iv
CO2Et
CO2Et
Scheme 1.
I2
N
N
Keywords: Indolizine; Iodine; 5-exo-dig Iodocyclization; Hydrative
cyclization.
I
R
v
vi
R
*
Corresponding author. Tel.: +82 42 860 7177; fax: +82 42 860
7160; e-mail: ikyon@krict.re.kr
Scheme 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.101

I. Kim et al. / Tetrahedron Letters 48 (2007) 8976–8981
8977
carbonyl functionality at C3 position of indolizine core
was presumed to come from external H2O source, we
expected that the addition of H2O to the reaction med-
ium would facilitate the reaction. Pleasingly, when we
employed CH3CN–H2O (=10:1) as the solvent, yield
of 3a increased to 83% (entry 6).8 Use of MeOH–H2O
(=10:1) led to inferior result (entry 7).
CO2Et
R2
LHMDS, THF
-78 oC
CO2Et
N
Br
N
R1
R1
1
2
R2
Scheme 3.
Table 1.
The formation of unexpected product 3a can be ratio-
nalized by the sequence described in Scheme 4. Thus,
initial 5-exo-dig type iodocyclization would generate
vinyl iodide A. Deprotonation would lead to B. Attack
of another iodine by the enamine unit in B would then
produce a geminal diiodide C which loses proton to
furnish 3-formylindolizine 3a via substitution of the
diiodo group of D by H2O. Two equivalent of iodine
is needed to complete the reaction, which is in agreement
with our experimental result. Overall, iodine was used
for hydrative cyclization9 and oxidation to gain aroma-
ticity. Notably, only one example has been found in the
literature, where iodine is used as a promoter in hydra-
tive cyclizations.10,11
CO2Et
CO2Et
I2, rt
conditions
N
N
O
3a
2a
Entry Equiv of iodine Solvent
Time Yield
(h)
(%)
1
2
3
4
5
6
7
1.5
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
5
5
2
2
5
4
4
10
22
14
16
25
83
60
1.5a
1.5b
2.5
2.5
2.5
To demonstrate the reaction scope, other cyclization
substrates were exposed to the above conditions (Table
2). Gratifyingly, various 3-acylated indolizine deriva-
tives12,13 were successfully synthesized under these mild
conditions. 4-Methoxyphenyl group attached to an al-
kyne unit inhibited the desired transformation (entry
5). However, 3-methoxyphenyl or 4-tolyl group did
not affect the yield. Indolizine bearing a thiophene-2-
carbonyl moiety at C3 position was obtained albeit in
modest yield (entry 10). Substitution (R2) at C2 position
of alkynes 2 rather gave the low yield of products (en-
tries 11 and 12).
CH3CN–H2O (=10:1)
MeOH–H2O (=10:1)
a NBS was used instead of I2.
b NIS was used instead of I2.
cleanly by the judgement of TLC monitoring but the iso-
lated yield of 3a was in the range of 10–20%. The crude
1H NMR indicated a complex mixture of products
including 3a which was actually formed upon I2
treatment.
For comparison, when 4,14 6, and 8 were subjected to
the identical conditions, respectively, pyridinium salts
5, 7, and 9 were isolated as major products (Scheme
5).15 It is not clear at this point what determines the
reaction pathway, but relatively acidic proton next to
Increasing the amount of iodine did improve the yield
albeit still low (entry 2). Interestingly, NBS or NIS also
provided 3a in 14% and 16% yields, respectively (entries
3 and 4). Acetonitrile gave a little better result than
dichloromethane (entry 5). Since the newly generated
CO2Et
CO2Et
I2, rt
N
N
H2O
I
H
I
O
B
H
H2O
2a
3a
H
CO2Et
CO2Et
N
N
I
I
H
H
I
CO2Et
CO2Et
A
D
H
N
N
B
I
I
H
H
I
B
C
I
I
Scheme 4.

8978
I. Kim et al. / Tetrahedron Letters 48 (2007) 8976–8981
Table 2.
CO2Et
R2
CO2Et
R2
I2, rt
N
N
R1
O
R1
3
2
Entry
Substrate 2
Product 3
Isolated yield (%)
CO2Et
CO2Et
1
2a
3a
83
N
N
N
N
O
CO2Et
CO2Et
2
2b
3b
60
Me
O
Me
CO2Et
CO2Et
N
N
3
2c
2d
2e
2f
3c
3d
3e
3f
55
O
CO2Et
CO2Et
CO2Et
CO2Et
N
4
5
6
70
25
63
N
N
N
O
O
O
CO2Et
N
OMe
OMe
CO2Et
N
OMe
MeO

I. Kim et al. / Tetrahedron Letters 48 (2007) 8976–8981
8979
Table 2 (continued)
Entry
Substrate 2
CO2Et
Product 3
Isolated yield (%)
CO2Et
7
2g
3g
52
N
N
N
N
O
Me
Me
CO2Et
CO2Et
8
2h
3h
62
N
O
F
F
CO2Et
CO2Et
9
2i
3i
77
N
O
Cl
Cl
CO2Et
CO2Et
N
10
2j
3j
40
N
S
O
S
CO2Et
CO2Et
Me
Me
N
11
2k
3k
27
N
O
CO2Et
Et
CO2Et
Et
N
12
2l
3l
35
N
O
CO2Et
Et
CO2Et
Et
N
N
13
2m
3m
22
O
BnO
OBn

8980
I. Kim et al. / Tetrahedron Letters 48 (2007) 8976–8981
Grundon, M. F. Nat. Prod. Rep. 1989, 6, 523; (d) Flitsch,
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OH
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I2, rt
82%
N
N
I
I
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5
4
OAc
OAc
I2, rt
85%
N
N
I
I
H
6
7
Me
Me
N
ˇ
ˇ
´
´
´
ˇ´
´
´ˇ
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N
I2, rt
63%
N
N
I
I
H
9
8
Scheme 5.
5. For selected examples on indolizine-based drug develop-
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Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.;
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the carboethoxy group of 3 seemed to be relevant to the
above hydrative cyclization.
In conclusion, we have discovered a novel route to 3-
acylated indolizines based upon a facile 5-exo-dig iodo-
cyclization of alkynes 2 where a pyridinyl nitrogen was
again engaged as an internal nucleophile. A series of
reaction cascades after the cyclization allowed this
hydrative cyclization to be feasible. Given the mildness
and eco-friendliness of this procedure, it should be valu-
able for the synthesis of other structurally related com-
pounds as well. Further studies are ongoing along this
line and will be reported in due course.
Acknowledgments
We thank the Center for Biological Modulators and
Korea Research Institute of Chemical Technology for
generous financial support.
6. For recent examples on 5-exo-dig iodocyclizations, see: (a)
GowriSankar, S.; Lee, M. J.; Lee, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2004, 25, 1963; (b) Wu, Z.; Minhas, G.
S.; Wen, D.; Jiang, H.; Chen, K.; Zimniak, P.; Zheng, J. J.
Med. Chem. 2004, 47, 3282; (c) Hessian, K. O.; Flynn, B.
L. Org. Lett. 2003, 5, 4377; (d) Ren, X. F.; Turos, E.
Tetrahedron Lett. 1993, 34, 1575.
Supplementary data
1
Characterization data and copies of H and 13C NMR
spectra for compounds 2–9. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.10.101.
7. General procedure for the synthesis of alkynes 2: To a
stirred solution of ethyl pyridineacetate (1.5 mmol,
1 equiv) in THF was added LHMDS (1.0 M solution in
THF, 1.1 equiv) at ꢀ78 °C. After 15 min, a solution of the
appropriate propargylic bromides (1.1 equiv) in THF was
slowly added to this reaction mixture at ꢀ78 °C. After
being stirred for 16 h while slowly warming up to rt, the
reaction mixture was quenched with saturated aqueous
NH4Cl at 0 °C. The organic layer was washed with brine
and the aqueous layer was extracted with ethyl acetate one
more time. The combined organic layers were dried over
MgSO4, filtered, and evaporated in vacuo. The resulting
residue was purified by flash column chromatography
(hexanes–ethyl acetate = 10:1) to afford alkynes 2.
References and notes
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, in press. doi:10.1016/
j.tet.2007.10.037.
2. For recent reviews on iodocyclizations, see: (a) Togo, H.;
Iida, S. Synlett 2006, 2159; (b) Martins da Silva, F.; Jones,
J., Jr.; de Mattos, M. C. S. Curr. Org. Synth. 2005, 2, 393.
3. For general reviews, see: (a) Shipman, M. Sci. Synth. 2001,
745; (b) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579; (c)
1
2-Pyridin-2-yl-pent-4-ynoic acid ethyl ester (2a): H NMR

I. Kim et al. / Tetrahedron Letters 48 (2007) 8976–8981
8981
(300 MHz, CDCl3) d 8.59 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H),
7.67 (dt, J = 7.8, 2.1 Hz, 1H), 7.33 (dd, J = 7.8, 0.9 Hz,
1H), 7.21 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 4.24–4.13 (m,
2H), 4.01 (t, J = 7.5 Hz, 1H), 3.03 (ddd, J = 16.8, 7.2,
2.7 Hz, 1H), 2.86 (ddd, J = 16.8, 8.1, 2.7 Hz, 1H), 1.94 (t,
J = 2.6 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 171.6, 157.2, 149.8, 136.9, 123.4,
122.7, 81.6, 70.2, 61.4, 52.9, 21.5, 14.3; IR (thin film) 3294,
2983, 1732, 1586, 1470, 1227 cmꢀ1; HRMS (EI) calcd for
[C12H13NO2]+: m/z 203.0949; found, 203.0947.
M.; Lee, C. B. J. Am. Chem. Soc. 2005, 127, 12184; (e)
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127,
4763.
10. Iodine-promoted hydrative cyclization was exploited by
Flynn and co-workers in their approach to variously
substituted benzothiophenes but with a little different
mechanism. See Ref. 6c.
11. For the use of hypervalent iodine reagents such as PIFA in
hydrative cyclizations, see: Tellitu, I.; Serna, S.; Herrero,
M. T.; Moreno, I.; Dominguez, E.; SanMartin, R. J. Org.
Chem. 2007, 72, 1526, and references cited therein.
12. Structurally relevant indolizine oxalylamides (for example,
STA-5312) are known to exhibit microtubule inhibitory
effect Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L.
Org. Process Res. Dev. 2007, 11, 246.
8. General procedure for the hydrative cyclization of alkynes 2
to 3-acylated indolizines 3: To a stirred solution of alkyne 2
(0.2 mmol, 1 equiv) in CH3CN–H2O (=10:1) was added
iodine (2.5 equiv) at room temperature. After 1 h, more
iodine (0.5 equiv) was added if necessary by the judgement
of tlc monitoring. After being stirred for another 1 h, the
reaction mixture was concentrated under reduced pres-
sure. The residue was diluted with dichloromethane, and
washed with Na2S2O3 and NaHCO3. The aqueous layer
was extracted with dichloromethane one more time. The
combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The resulting residue was
purified by flash column chromatography (hexanes–ethyl
acetate–dichloromethane = 15:1:2) to give the 3-acylated
indolizine 3. 3-Formyl-indolizine-1-carboxylic acid ethyl
ester (3a): 1H NMR (300 MHz, CDCl3) d 9.76 (s, 1H), 9.72
(d, J = 6.9 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H),
7.47 (ddd, J = 8.1, 6.9. 1.1 Hz, 1H), 7.08 (dt, J = 6.9,
1.2 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 178.7, 163.9, 140.3,
129.7, 129.1, 128.5, 124.0, 119.8, 115.8, 107.6, 60.4, 14.7;
S
N
HN
O
Me
O
N
CN
STA-5312
.
13. Przewloka, T.; Chen, S.; Xia, Z.; Li, H.; Zhang, S.;
Chimmanamada, D.; Kostik, E.; James, D.; Koya, K.;
Sun, L. Tetrahedron Lett. 2007, 48, 5739.
14. 4 was prepared by following the procedure of Lee. See:
Lee, P. H.; Kim, H.; Lee, K. Adv. Synth. Catal. 2005, 347,
1219.
IR (thin film) 3005, 1702, 1657, 1524, 1371, 1221 cmꢀ1
;
HRMS (EI) calcd for [C12H11NO3]+: m/z 217.0739; found,
217.0742.
15. In case of 4, small amount of 50 was also isolated.
O
9. Transition-metal catalyzed hydrative cyclization is well
known. For recent examples, see: (a) Chang, H.-K.; Datta,
S.; Das, A.; Odedra, A.; Liu, R.-S. Angew. Chem., Int. Ed.
2007, 46, 4744; (b) Trost, B. M.; Huang, X. Chem.-Asian J.
2006, 1, 469; (c) Matsuda, T.; Kadowaki, S.; Murakami,
M. Helv. Chim. Acta 2006, 89, 1672; (d) Chen, Y.; Ho, D.
N
I
H
5'