A novel and efficient approach to highly substituted indolizines via 5-endo-trig iodocyclization

Article abstract of DOI:10.1016/j.tet.2007.10.037

A new approach to indolizines has been developed using a 5-endo-trig iodocyclization of allylic esters followed by isomerization and dehydroiodination facilitated by triethylamine at rt. This mild procedure enabled us to synthesize a number of highly subs

Full text of DOI:10.1016/j.tet.2007.10.037

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 12954–12960
A novel and efficient approach to highly substituted
indolizines via 5-endo-trig iodocyclization
*
Ikyon Kim, Hye Kyoung Won, Jihyun Choi and Ge Hyeong Lee
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 3 September 2007; revised 8 October 2007; accepted 9 October 2007
Available online 12 October 2007
Abstract—A new approach to indolizines has been developed using a 5-endo-trig iodocyclization of allylic esters followed by isomerization
and dehydroiodination facilitated by triethylamine at rt. This mild procedure enabled us to synthesize a number of highly substituted indo-
lizines in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of this program, we decided to investigate 5-endo-trig iodo-
cyclization7 of allylic esters to construct the same carbon
framework (Scheme 1). Here we wish to report a convenient
approach to indolizine structure featuring a 5-endo-trig
iodocyclization followed by isomerization and dehydroiodi-
nation promoted by base.
Pyrrolo[1,2-a]pyridine, known as indolizine, is an important
structural motif frequently found in nature and has been
utilized as a key scaffold in the pharmaceutical industry
due to the broad spectrum of biological activities associated
with this privileged structure.1 Thus, indolizine-based scaf-
folds have been actively investigated as antiviral, anti-
inflammatory, anticancer, and cardiovascular agents.2
Besides, indolizine-bearing polycyclic compounds have
drawn much attention owing to their possible usage as
dyes and chemosensors.3 Not surprisingly, many synthetic
approaches to this skeleton have been disclosed in the liter-
ature.4 In the context of our research program on the facile
synthesis of heterocycles using mild and environment-
friendly conditions,5 we recently communicated on the con-
venient synthesis of highly substituted indolizines based
upon a facile 5-endo-dig iodocyclization.5a,6 As an extension
2. Results and discussion
At the outset, we envisioned that indolizine 4 having two
different groups (R2 and R3) at C2 and C3 centers could
be obtained if the cyclization precursor, allylic ester 3, con-
tains two functional groups at C2 and C3 sites. In a related
5-endo-dig iodocyclization of propargylic acetate 1, further
functional group at C2 position of indolizine has to be
installed by manipulation of an iodo group of 2.
Our approach commenced with the preparation of allylic
acetate 3. Thus, reaction of 2-pyridinyl lithium with a,b-
unsaturated aldehyde afforded allylic alcohol, which was
converted to the corresponding allylic acetate 3 in good yield
(Scheme 2).
OAc
OAc
8
5
1
7
6
I2
rt
2
I
R2
N
N
4
N
N
R1
R1
3
R2
1
2
OAc
1) n-BuLi, THF 2) Ac2O, Et3N,
Br
R2
R3
OAc
OAc
-78 °C;
cat. DMAP
R2
R3
N
O
R2
R1
N
R2
(this work)
R1
N
R1
R1
R3
R3
5
3
3
4
Scheme 2. Preparation of the cyclization substrates 3.
Scheme 1. Two novel approaches to indolizines.
When 3a was initially exposed to iodine (2 equiv) in CH2Cl2
at rt, 6 was formed as a mixture of diastereomers (in about
2.8:1 ratio)8 almost quantitatively. This result is different
from that of 5-endo-dig iodocyclization of propargylic
Keywords: Indolizine; Iodine; 5-endo-trig Iodocyclization; Environmentally
benign.
* Corresponding author. Tel.: +82 42 860 7177; fax: +82 42 860 7160;
e-mail: ikyon@krict.re.kr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.037

I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
12955
Table 1. (continued)
acetate 1 where indolizine structure was directly con-
structed. To induce both isomerization and elimination of
HI, 6 was then treated with base. Pleasingly, this provided
indolizine 4a in 77% yield (Scheme 3).
Entry
Substrate 3
Product 4
Isolated
yield (%)
OAc
Me
OAc
Me
4
5
3d
3e
4d
—
OAc
OAc
OAc
N
N
I
Et3N
I2, rt
OAc
OAc
OAc
N
I-
N
OAc
N
4e 84
4f 74
4g 60
N
N
N
N
3a
6
4a
N
Scheme 3. One-pot procedure from allylic acetate to indolizine.
OAc
6
7
3f
Notably, exposure of 3a to iodine and triethylamine or
NaHCO3 at the same time gave rather low conversion.
This result is surprising because base such as Et3N or
NaHCO3 is commonly employed with iodine in most iodo-
cyclizations. Two equivalents of iodine are needed to com-
plete the reaction. Among the solvents screened, CH3CN
gave the best result. Thus, the following reaction condition
was used. Allylic ester 3 was treated with iodine (2 equiv)
in CH3CN at rt for 3 h. After the disappearance of the start-
ing material was checked by TLC, triethylamine (2 equiv)
was added at rt. After being stirred at rt for another 3 h,
the reaction mixture was concentrated in vacuo. The result-
ing residue was diluted with ethyl acetate and washed with
NaHSO3 and NaHCO3, successively. The water layer was
extracted with ethyl acetate one more time. The organic
layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (hexanes/ethyl acetate/dichloro-
methane¼10:1:2) to give 4.
N
OAc
Me
3g
Me
N
Et
Et
OAc
OAc
Me
Me
8
3h
4h 89
N
OAc
OAc
N
9
3i
3j
4i 55
N
OAc
OAc
OAc
OAc
OAc
OMe
NO2
N
10
4j 56
N
OMe
NO2
As shown in Table 1, other allylic esters 3 were subjected to
the optimized conditions mentioned above to evaluate the re-
action scope. Indeed, various indolizine derivatives were
successfully synthesized in good yields. It should be men-
tioned that allylic acetate 3d was exposed to the optimized
N
11
12
13
14
3k
3l
4k 45
4l 83
4m 74
4n 84
N
Table 1. Synthesis of various indolizine derivatives
OAc
R3
OAc
R2
R3
OAc
I2, rt;
Et3N
R2
N
N
R1
N
R1
N
O
3
4
O
Entry
Substrate 3
Product 4
Isolated
yield (%)
OAc
OAc
OAc
N
OAc
N
3m
3n
N
1
3a
4a 77
N
Me
OAc
Me
Me OAc
N
Me
OAc
OAc
N
2
3
3b
3c
4b 65
N
N
Me
Me
OAc
OAc
Me
OAc
OAc
Me
Me
N
Me
4c 60
15
3o
4o 73
Me
N
N
N
Me
Me
Me
(continued)

12956
I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
conditions (entry 4), but cyclization did not occur. Only the
starting material was recovered.9 In contrast, substitution at
C2 position of allylic acetate 3 does not affect the yield
(entries 2 and 3). Substitution at C3 of allylic acetate except
hydrogen seemed crucial for the successful cyclization un-
der our conditions. When R2 and R3 of allylic ester are phen-
yl and benzyl, respectively, a modest yield of 4i was obtained
(entry 9). Allylic acetates possessing electron-donating
(2-methoxyphenyl) and electron-withdrawing (2-nitro-
phenyl) groups were also submitted to examine the role of
these in iodocyclizations. Contrary to our expectation, yields
in both cases were lower than that of 4a although 3j gave
a better yield of product than 3k (entries 10 and 11). Fu-
ran-containing indolizine 4l was obtained in excellent yield
(entry 12). When (S)-(ꢀ)-perillaldehyde was used as an a,b-
unsaturated aldehyde partner, chiral indolizine derivative
4m was prepared in good yield (entry 13). When 3-methyl-
and 5-methylpyridinyllithium were coupled with a-methyl-
trans-cinnamaldehyde, respectively, the corresponding
indolizines 4n and 4o were synthesized in high yields (en-
tries 14 and 15). Overall, this simple process enabled us to
construct indolizine nucleus in good to excellent yields
while demonstrating a wide functional group tolerance.
was accomplished with Silicycle silica gel 60 (230–
400 mesh). Proton nuclear magnetic resonance spectra
were recorded in deuterated solvents on a Varian systems-
300 (300 MHz) instrument. Chemical shifts are reported in
parts per million (ppm, d) relative to tetramethylsilane
(TMS, d 0.00). Carbon nuclear magnetic resonance spectra
were recorded in deuterated solvents on a Varian systems-
300 (75 MHz) instrument. Infrared spectra were measured
on a Mattson Polaris FT-IR spectrometer, and signals are
recorded in wavenumbers. High resolution mass spectra
(HRMS) using electron ionization (EI) were measured on
a Micromass mass spectrometer.
4.2. General procedure for allylic acetate 3
To a stirred solution of 2-bromopyridine (1.5 equiv) in THF
was slowly added n-BuLi (1.6 M solution in hexanes,
1.4 equiv) at ꢀ78 ꢁC. After 20 min, a solution of a,b-unsat-
urated aldehyde (8 mmol) in THF was slowly added to this
mixture at ꢀ78 ꢁC. After being stirred for 30 min, the reac-
tion mixture was quenched with satd NH4Cl at ꢀ78 ꢁC. The
reaction mixture was diluted with ethyl acetate, washed with
H2O and brine, successively. The water layer was extracted
with ethyl acetate one more time. The combined organic
layers were dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chroma-
tography (hexanes/ethyl acetate/dichloromethane¼10:1:2 to
5:1:2 to 1:1:1) to afford allylic alcohol, which was dissolved
in CH2Cl2. To this solution were added triethylamine
(1.5 equiv), DMAP (0.01 equiv), and acetic anhydride
(1.1 equiv) at 0 ꢁC. After being stirred at rt for 2 h, the
mixture was washed with aqueous citric acid and NaHCO3,
successively. The water layer was extracted with CH2Cl2 one
more time. The organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromato-
graphy (hexanes/ethyl acetate/dichloromethane¼10:1:2) to
give allylic acetate 3.
3. Conclusions
In conclusion, we have demonstrated a new approach to
highly substituted indolizines 4 under very mild conditions
where a facile and efficient 5-endo-trig iodocyclization of
allylic acetate 3, and subsequent isomerization and aromati-
zation (by the loss of HI) were accomplished. In this one-pot
reaction sequence, a pyridinyl nitrogen was again involved
as an internal nucleophile of iodocyclization.10 While simi-
lar 5-endo-dig iodocyclization provides an iodo group at C2
of indolizine ring structure, which is a functional handle for
subsequent elaboration, this 5-endo-trig process allows
direct introduction of functional groups at C2 position possi-
ble, depending on the substitution pattern of the cyclization
precursor. Given the simplicity and environment-friendli-
ness of this operation, it should be useful for the synthesis
of other fused azacycles as well.
1
4.2.1. (E)-3-Phenyl-1-(pyridin-2-yl)allyl acetate (3a). H
NMR (300 MHz, CDCl3) d 8.61 (ddd, J¼4.8, 1.7, 0.9 Hz,
1H), 7.67 (dt, J¼7.7, 1.8 Hz, 1H), 7.42–7.37 (m, 3H),
7.31–7.17 (m, 4H), 6.78–6.71 (m, 1H), 6.51–6.45 (m, 2H);
13C NMR (75 MHz, CDCl3) d 170.2, 158.6, 149.8, 137.2,
136.3, 133.7, 128.8, 128.4, 127.0, 126.5, 123.2, 121.6,
77.43, 21.5; IR (thin film) 3053, 3025, 2932, 1736, 1585,
1226 cmꢀ1; HRMS (EI) calcd for [C16H15NO2]+: m/z
253.1103, found: 253.1105.
4. Experimental
4.1. General
The solvents used in the reactions were dried prior to use:
tetrahydrofuran was distilled from sodium benzophenone
ketyl; dichloromethane was distilled from calcium hydride.
All other reagents were used as received without purifica-
tion. All moisture-sensitive reactions were performed in
flame-dried and/or oven-dried glassware under a positive
pressure of nitrogen unless otherwise noted. ‘Concentrated’
refers to the removal of volatile solvents via distillation
using a Buchi rotary evaporator. ‘Dried’ refers to pouring
onto, or passing through anhydrous sodium sulfate or mag-
nesium sulfate followed by filtration. Thin layer chromato-
graphy was carried out with E. Merck (Darmstadt) TLC
plates precoated with silica gel 60 F254. Visualization was
accomplished using a UV lamp, iodine vapors, and/or a
p-anisaldehyde (PAA) stain. Flash column chromatography
4.2.2. (E)-1-(Pyridin-2-yl)but-2-enyl acetate (3b). 1H
NMR (300 MHz, CDCl3) d 8.60 (ddd, J¼4.8, 1.6, 0.8 Hz,
1H), 7.69 (dt, J¼7.7, 1.8 Hz, 1H), 7.18 (d, J¼7.9 Hz, 1H),
7.20 (dd, J¼7.5, 4.9 Hz, 1H), 6.24 (d, J¼7.1 Hz, 1H),
5.86–5.76 (m, 2H), 2.14 (s, 3H), 1.73 (d, J¼5.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 170.0, 158.9, 149.5, 137.0,
130.9, 128.6, 122.9, 121.3, 77.2, 21.3, 18.0; IR (thin film)
3011, 2932, 1737, 1588, 1371, 1232 cmꢀ1; HRMS (EI)
calcd for [C11H13NO2]+: m/z 191.0946, found: 191.0943.
4.2.3. (E)-2-Methyl-1-(pyridin-2-yl)but-2-enyl acetate
(3c). H NMR (300 MHz, CDCl3) d 8.52 (ddd, J¼4.9, 1.7,
1
0.9 Hz, 1H), 7.60 (dt, J¼7.7, 1.8 Hz, 1H), 7.26 (d,
J¼7.9 Hz, 1H), 7.11 (dd, J¼7.5, 4.9 Hz, 1H), 6.16 (s, 1H),

I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
12957
5.64 (q, J¼6.8 Hz, 1H), 2.08 (s, 3H), 1.57 (d, J¼6.8 Hz, 3H),
1.48 (s, 3H); 13C NMR (75 MHz, CDCl3) d 169.5, 158.4,
148.9, 136.6, 133.0, 122.5, 122.4, 120.8, 80.9, 20.9, 12.1;
IR (thin film) 2982, 2923, 1739, 1587, 1234 cmꢀ1; HRMS
(EI) calcd for [C12H15NO2]+: m/z 205.1103, found:
205.1104.
J¼4.5 Hz, 1H), 7.56 (t, J¼7.8 Hz, 1H), 7.28–7.12 (m,
12H), 6.58 (s, 1H), 6.11 (t, J¼7.5 Hz, 1H), 3.27 (d,
J¼7.5 Hz, 2H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 170.1, 157.9, 149.5, 139.8, 137.3, 136.6, 130.5, 129.6,
128.7, 128.3, 127.5, 126.2, 122.9, 121.9, 80.2, 35.0, 21.5;
IR (thin film) 3024, 2923, 1741, 1464, 1229 cmꢀ1; HRMS
(EI) calcd for [C23H21NO2]+: m/z 343.1572, found:
343.1568.
4.2.4. 2-Methyl-1-(pyridin-2-yl)allyl acetate (3d). 1H NMR
(300 MHz, CDCl3) d 8.27 (ddd, J¼4.1, 1.5, 0.8 Hz, 1H), 7.53
(dt, J¼7.7, 1.7 Hz, 1H), 7.22 (d, J¼7.9 Hz, 1H), 7.05 (dd,
J¼7.5, 4.9 Hz, 1H), 6.10 (s, 1H), 5.00 (s, 1H), 4.87 (s, 1H),
2.00 (s, 3H), 1.54 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 158.2, 149.6, 142.4, 136.9, 123.0, 121.5, 114.3, 79.6,
21.4, 18.9; IR (thin film) 2960, 2900, 1741, 1580,
1220 cmꢀ1; HRMS (EI) calcd for [C11H13NO2]+: m/z
191.0946, found: 191.0942.
4.2.10. (E)-3-(2-Methoxyphenyl)-1-(pyridin-2-yl)allyl
acetate (3j). 1H NMR (300 MHz, CDCl3) d 8.63 (dd,
J¼4.8, 0.9 Hz, 1H), 7.70 (dt, J¼9.0, 1.8 Hz, 1H), 7.43 (dt,
J¼7.2, 1.5 Hz, 2H), 7.27–7.20 (m, 2H), 7.09 (d, J¼
15.3 Hz, 1H), 6.88 (q, J¼8.7 Hz, 2H), 6.56–6.44 (m, 2H),
3.86 (s, 3H), 2.18 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 170.3, 158.8, 157.3, 149.8, 137.1, 129.5, 128.9, 127.5,
126.8, 125.2, 123.1, 121.7, 120.8, 111.1, 78.0, 55.6, 21.6;
IR (thin film) 2936, 1738, 1591, 1490, 1243 cmꢀ1; HRMS
(EI) calcd for [C17H17NO3]+: m/z 283.1208, found:
283.1205.
4.2.5. (E)-1-(Pyridin-2-yl)hex-2-enyl acetate (3e). 1H NMR
(300 MHz, CDCl3) d 8.59 (ddd, J¼4.9, 1.8, 0.9 Hz, 1H), 7.67
(dt, J¼7.7, 1.8 Hz, 1H), 7.35 (d, J¼7.9 Hz, 1H), 7.19 (dd,
J¼7.5, 4.9 Hz, 1H), 6.25 (d, J¼6.9 Hz, 2H), 5.87–5.74 (m,
2H), 2.13 (s, 3H), 2.12–2.01 (m, 2H), 1.44–1.37 (m, 2H),
0.87 (t, J¼7.35 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 170.2, 159.1, 149.7, 136.9, 135.9, 127.3, 122.9, 121.4,
77.5, 34.5, 22.1, 21.5, 13.8; IR (thin film) 2959, 2930,
4.2.11. (E)-3-(2-Nitrophenyl)-1-(pyridin-2-yl)allyl ace-
1
tate (3k). H NMR (300 MHz, CDCl3) d 8.63 (dd, J¼8.1,
1.2 Hz, 1H), 7.93 (dd, J¼8.4, 1.1 Hz, 1H), 7.74 (dt, J¼7.7,
1.8 Hz, 1H), 7.63–7.52 (m, 2H), 7.46–7.37 (m, 2H), 7.27–
7.15 (m, 2H), 6.55–6.47 (m, 2H), 2.21 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 170.1, 157.9, 149.8, 137.3, 133.4,
132.2, 131.8, 129.0, 128.8, 128.1, 124.8, 123.4, 121.8,
76.4, 21.4; IR (thin film) 2922, 2851, 1740, 1525,
1229 cmꢀ1; HRMS (EI) calcd for [C16H14N2O4]+: m/z
298.0954, found: 298.0951.
1738, 1370, 1231 cmꢀ1
[C13H17NO2]+: m/z 219.1259, found: 219.1261.
;
HRMS (EI) calcd for
1
4.2.6. Cyclohexenyl(pyridin-2-yl)methyl acetate (3f). H
NMR (300 MHz, CDCl3) d 8.50 (ddd, J¼4.8, 1.6, 0.8 Hz,
1H), 7.58 (dt, J¼7.7, 1.7 Hz, 1H), 7.25 (d, J¼7.9 Hz, 1H),
7.19 (dd, J¼7.5, 4.9 Hz, 1H), 6.12 (s, 1H), 5.73 (s, 1H),
2.07 (s, 3H), 1.98 (s, 2H), 1.96 (d, J¼3.8 Hz, 2H), 1.52–
1.41 (m, 4H); 13C NMR (75 MHz, CDCl3) d 169.5, 158.4,
148.9, 136.6, 133.0, 122.5, 122.4, 120.8, 80.9, 20.9, 12.1;
4.2.12. (E)-3-(Furan-2-yl)-1-(pyridin-2-yl)allyl acetate
1
(3l). H NMR (300 MHz, CDCl3) d 8.62 (ddd, J¼4.7, 1.5,
0.9 Hz, 1H), 7.70 (dt, J¼7.7, 1.7 Hz, 1H), 7.38 (d,
J¼7.8 Hz, 1H), 7.33 (s, 1H), 7.22 (dd, J¼7.5, 4.9 Hz, 1H),
6.57–6.28 (m, 5H), 2.17 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 170.2, 158.4, 151.9, 149.9, 142.6, 137.1, 124.8,
123.2, 121.8, 121.5, 111.6, 109.6, 77.2, 21.5; IR (thin film)
3020, 2920, 1738, 1643, 1100 cmꢀ1; HRMS (EI) calcd for
[C14H13NO3]+: m/z 243.0895, found: 243.0894.
IR (thin film) 3055, 2924, 1737, 1583, 1434, 1299 cmꢀ1
;
HRMS (EI) calcd for [C14H17NO2]+: m/z 231.1259, found:
231.1262.
4.2.7. (E)-2-Methyl-1-(pyridin-2-yl)pent-2-enyl acetate
1
(3g). H NMR (300 MHz, CDCl3) d 8.44 (ddd, J¼4.9, 1.7,
0.8 Hz, 1H), 7.35 (dt, J¼7.7, 1.7 Hz, 1H), 7.05 (d,
J¼7.9 Hz, 1H), 6.85 (dd, J¼7.4, 5.0 Hz, 1H), 5.95 (s, 1H),
5.34 (t, J¼7.0 Hz, 1H), 1.83 (s, 3H), 1.80–1.73 (m, 2H),
1.27 (s, 3H), 0.66 (t, J¼7.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 169.5, 158.4, 148.9, 136.6, 131.9, 122.5, 122.4,
80.9, 20.9, 20.8, 13.7, 12.3; IR (thin film) 2964, 2932,
1741, 1586, 1370, 1233 cmꢀ1; HRMS (EI) calcd for
[C13H17NO2]+: m/z 219.1259, found: 219.1255.
4.2.13. (4-(Prop-1-en-2-yl)cyclohex-1-enyl)(pyridin-2-
yl)methyl acetate (3m). 1H NMR (300 MHz, CDCl3)
d 8.59 (ddd, J¼4.9, 1.7, 0.9 Hz, 1H), 7.68 (dt, J¼7.1,
1.8 Hz, 1H), 7.34 (d, J¼7.9 Hz, 1H), 7.20 (dd, J¼7.4,
4.9 Hz, 1H), 6.20 (d, J¼3.9 Hz, 1H), 5.85 (dd, J¼10.1,
8.9 Hz, 1H), 4.68 (s, 1H), 4.67 (s, 1H), 2.16 (s, 3H), 2.09–
2.08 (m, 5H), 2.04 (s, 3H), 2.00–1.69 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 170.3, 170.2, 158.5, 149.8, 149.8,
149.5, 149.4, 136.8, 135.2, 135.1, 126.9, 126.3, 122.8,
122.8, 121.4, 121.2, 108.9, 108.9, 79.9, 40.9, 40.9, 30.8,
30.7, 27.5, 25.3, 25.2, 21.4, 21.4, 20.9; IR (thin film) 2924,
2853, 1741, 1586, 1370, 1232 cmꢀ1; HRMS (EI) calcd for
[C17H21NO2]+: m/z 271.1572, found: 271.1569.
4.2.8. (E)-2-Methyl-3-phenyl-1-(pyridin-2-yl)allyl ace-
tate (3h). 1H NMR (300 MHz, CDCl3) d 8.60 (ddd, J¼4.1,
1.4, 0.8 Hz, 1H), 7.69 (dt, J¼7.7, 1.7 Hz, 1H), 7.42 (d,
J¼7.9 Hz, 1H), 7.31–7.20 (m, 4H), 7.20–7.18 (m, 2H),
6.73 (s, 1H), 6.40 (s, 3H), 2.05 (s, 3H), 1.83 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 170.1, 158.3, 149.6, 137.2,
136.9, 135.2, 129.4, 128.3, 127.1, 122.9, 121.5, 81.3, 21.5,
14.6; IR (thin film) 3056, 2928, 1739, 1586, 1367,
1229 cmꢀ1; HRMS (EI) calcd for [C17H17NO2]+: m/z
267.1259, found: 267.1261.
4.2.14. (E)-2-Methyl-1-(3-methylpyridin-2-yl)-3-phenyl-
allyl acetate (3n). H NMR (300 MHz, CDCl3) d 8.51 (d,
1
J¼3.9 Hz, 1H), 8.47 (dd, J¼7.8, 0.9 Hz, 1H), 7.34–7.21
(m, 5H), 7.16–7.12 (m, 1H), 6.54 (s, 1H), 6.48 (s, 1H),
2.45 (s, 3H), 2.20 (s, 3H), 1.89 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 170.7, 147.1, 138.8, 137.2, 134.5,
131.8, 129.3, 129.2, 129.1, 128.3, 127.0, 123.0, 78.0, 21.4.
4.2.9.
(E)-2,4-Diphenyl-1-(pyridin-2-yl)but-2-enyl
acetate (3i). 1H NMR (300 MHz, CDCl3) d 8.60 (d,

12958
I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
18.8, 15.0; IR (thin film) 3050, 2930, 1734, 1233, 1016,
791 cmꢀ1; HRMS (EI) calcd for [C18H19NO2]+: m/z
281.1416, found: 281.1420.
(t, J¼7.0 Hz, 1H), 2.72 (t, J¼7.5 Hz, 2H), 2.31 (s, 3H),
1.79–1.71 (m, 2H), 1.02 (t, J¼7.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 169.9, 126.1, 121.7, 121.5, 121.2,
116.3, 115.1, 110.3, 104.8, 28.2, 21.1, 20.7, 14.3; IR (thin
film) 2961, 1748, 1413, 1214, 1080 cmꢀ1; HRMS (EI) calcd
for [C13H15NO2]+: m/z 217.1103, found: 217.1105.
4.2.15. (E)-2-Methyl-1-(5-methylpyridin-2-yl)-3-phenyl-
allyl acetate (3o). H NMR (300 MHz, CDCl3) d 8.44 (s,
1
1H), 7.50 (dd, J¼8.1, 1.7 Hz, 1H), 7.34–7.27 (m, 5H),
7.24–7.18 (m, 1H), 6.69 (s, 1H), 6.35 (s, 1H), 2.33 (s, 3H),
2.20 (s, 3H), 1.83 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 170.8, 155.4, 150.0, 137.4, 137.3, 135.4, 132.5, 129.3,
128.8, 128.3, 127.0, 121.1, 81.2, 21.5, 77.7, 18.4, 14.7; IR
4.3.5. 1,2,3,4-Tetrahydropyrido[1,2-a]indol-10-yl acetate
1
(4f). H NMR (300 MHz, CDCl3) d 7.49 (d, J¼7.1 Hz,
1H), 7.13 (d, J¼9.1 Hz, 1H), 6.54 (dt, J¼6.4, 0.9 Hz, 1H),
6.39 (dt, J¼7.0, 1.3 Hz, 1H), 2.69 (t, J¼6.1 Hz, 2H), 2.59
(t, J¼6.1 Hz, 2H), 2.34 (s, 3H), 1.97–1.92 (m, 2H), 1.91–
1.79 (m, 2H); 13C NMR (75 MHz, CDCl3) d 170.1, 123.7,
121.4, 120.7, 117.4, 116.3, 115.3, 115.2, 109.5, 23.3, 22.9,
21.3, 21.2, 20.8; IR (thin film) 2930, 2848, 1762, 1367,
1210 cmꢀ1; HRMS (EI) calcd for [C14H15NO2]+: m/z
229.1103, found: 229.1100.
(thin film) 2919, 2851, 1738, 1367, 1228, 1023 cmꢀ1
;
HRMS (EI) calcd for [C18H19NO2]+: m/z 281.1416, found:
281.1413.
4.3. General procedure for iodocyclization
To a stirred solution of allylic acetate 3 (0.5 mmol) in
CH3CN (3 mL) was added iodine (2 equiv) at rt. The reac-
tion mixture was stirred at rt for 3 h. After the disappearance
of the starting material was checked by TLC, triethylamine
(2 equiv) was added at rt. After being stirred at rt for another
3 h, the reaction mixture was concentrated in vacuo. The
resulting residue was diluted with ethyl acetate and washed
with NaHSO3 and NaHCO3, successively. The water layer
was extracted with ethyl acetate one more time. The organic
layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (hexanes/ethyl acetate/dichloro-
methane¼10:1:2) to give indolizine 4.
4.3.6. 3-Ethyl-2-methylindolizin-1-yl acetate (4g). 1H
NMR (300 MHz, CDCl3) d 7.62 (d, J¼7.1 Hz, 1H), 7.11
(d, J¼9.0 Hz, 1H), 6.53 (t, J¼6.5 Hz, 1H), 6.41 (dt, J¼7.1,
1.1 Hz, 1H), 2.88–2.80 (m, 2H), 2.35 (s, 3H), 2.11 (s, 3H),
1.18 (t, J¼7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 170.2, 121.3, 121.0, 120.5, 115.4, 114.9, 113.2, 109.7,
20.8, 17.4, 12.4, 8.4; IR (thin film) 2920, 1768, 1368,
1210, 1146 cmꢀ1; HRMS (EI) calcd for [C13H15NO2]+: m/z
217.1103, found: 217.1107.
4.3.7. 2-Methyl-3-phenylindolizin-1-yl acetate (4h). 1H
NMR (300 MHz, CDCl3) d 7.96 (d, J¼7.1 Hz, 1H), 7.54–
7.40 (m, 4H), 7.39–7.36 (m, 1H), 7.20 (d, J¼8.4 Hz, 1H),
6.63 (t, J¼6.8 Hz, 1H), 6.34 (t, J¼6.5 Hz, 1H), 2.42 (s,
3H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.0,
131.3, 130.2, 129.2, 127.8, 126.2, 122.5, 121.8, 120.1,
116.9, 115.5, 115.3, 110.2, 20.9, 9.2; IR (thin film) 3058,
2950, 1769, 1349, 1205, 1150 cmꢀ1; HRMS (EI) calcd for
[C17H15NO2]+: m/z 265.1103, found: 265.1104.
4.3.1. 3-Phenylindolizin-1-yl acetate (4a). 1H NMR
(300 MHz, CDCl3) d 8.16 (d, J¼7.3 Hz, 1H), 7.55 (d,
J¼7.0 Hz, 2H), 7.46 (t, J¼7.4 Hz, 2H), 7.28–7.02 (m, 2H),
6.82 (s, 1H), 6.64 (t, J¼6.4 Hz, 1H), 6.43 (t, J¼7.4 Hz,
1H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) d 169.6,
132.1, 129.2, 129.1, 128.4, 127.5, 123.3, 122.3, 121.9,
116.7, 116.5, 111.1, 106.8, 21.2; IR (thin film) 3683, 1764,
1514, 1211, 736 cmꢀ1
;
HRMS (EI) calcd for
4.3.8. 3-Benzyl-2-phenylindolizin-1-yl acetate (4i). 1H
NMR (300 MHz, CDCl3) d 7.43 (d, J¼7.1 Hz, 2H), 7.38
(d, J¼4.1 Hz, 2H), 7.32–7.09 (m, 6H), 7.06 (d, J¼7.4 Hz,
2H), 6.64 (t, J¼6.5 Hz, 1H), 6.37 (t, J¼6.8 Hz, 1H), 4.30
(s, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.4,
161.0, 138.1, 133.2, 129.8, 129.1, 128.8, 128.0, 127.2,
126.8, 122.8, 122.1, 121.6, 116.7, 116.2, 116.1, 110.8,
30.6, 20.9; IR (thin film) 3123, 2926, 1740, 1266,
1097 cmꢀ1; HRMS (EI) calcd for [C23H19NO2]+: m/z
341.1416, found: 341.1418.
[C16H13NO2]+: m/z 251.0946, found: 251.0945.
4.3.2. 3-Methylindolizin-1-yl acetate (4b). 1H NMR
(300 MHz, CDCl3) d 7.55 (d, J¼7.1 Hz, 1H), 7.22 (d,
J¼7.8 Hz, 1H), 6.57 (t, J¼6.4 Hz, 1H), 6.51 (s, 1H), 6.46
(t, J¼6.9 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 169.9, 125.9, 121.6, 121.2, 116.8,
116.1, 115.0, 110.4, 105.9, 21.1, 11.7; IR (thin film) 2910,
1748, 1556, 1350, 1214 cmꢀ1; HRMS (EI) calcd for
[C11H11NO2]+: m/z 189.0790, found: 189.0787.
4.3.9. 3-(2-Methoxyphenyl)indolizin-1-yl acetate (4j). 1H
NMR (300 MHz, CDCl3) d 7.53 (d, J¼7.2 Hz, 1H), 7.42–
7.29 (m, 2H), 7.27 (t, J¼9.0 Hz, 1H), 7.00 (q, J¼8.0 Hz,
2H), 6.81 (s, 1H), 6.63 (dt, J¼6.5, 0.6 Hz, 1H), 6.39 (dt,
J¼7.4, 2.9 Hz, 1H), 3.78 (s, 3H), 2.34 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 169.6, 157.5, 132.4, 129.7, 127.1,
123.8, 122.9, 121.1, 120.8, 119.1, 116.4, 116.0, 111.3,
110.1, 107.4; IR (thin film) 3100, 2915, 1762, 1475,
1244 cmꢀ1; HRMS (EI) calcd for [C17H15NO3]+: m/z
281.1052, found: 281.1050.
1
4.3.3. 2,3-Dimethylindolizin-1-yl acetate (4c). H NMR
(300 MHz, CDCl3) d 7.52 (d, J¼7.1 Hz, 1H), 7.12 (d,
J¼9.0 Hz, 1H), 6.54 (t, J¼7.1 Hz, 1H), 6.42 (t, J¼7.1 Hz,
1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.11 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 170.3, 125.1, 121.3, 121.0, 115.2,
116.1, 115.0, 114.6, 113.9, 109.8, 20.8, 9.5, 8.6; IR
(thin film) 2909, 1761, 1454, 1368, 1211 cmꢀ1; HRMS
(EI) calcd for [C12H13NO2]+: m/z 203.0946, found:
203.0943.
4.3.4. 3-Propylindolizin-1-yl acetate (4e). 1H NMR
(300 MHz, CDCl3) d 7.58 (d, J¼7.1 Hz, 1H), 7.20 (d,
J¼9.0 Hz, 1H), 6.54 (t, J¼6.4 Hz, 1H), 6.53 (s, 1H), 6.42
4.3.10. 3-(2-Nitrophenyl)indolizin-1-yl acetate (4k). 1H
NMR (300 MHz, CDCl3) d 8.09 (dd, J¼8.1, 1.2 Hz, 1H),
7.69 (dt, J¼7.8, 0.6 Hz, 1H), 7.63–7.53 (m, 2H), 7.46 (d,

I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
12959
J¼7.2 Hz, 1H), 7.34 (d, J¼9.1 Hz, 1H), 6.86 (s, 1H), 6.71
(dt, J¼7.8, 2.2 Hz, 1H), 6.46 (dt, J¼6.8, 1.1 Hz, 1H), 2.36
(s, 3H); 13C NMR (75 MHz, CDCl3) d 169.3, 149.1, 133.8,
133.3, 129.2, 127.5, 126.3, 125.1, 123.9, 121.8, 117.5,
116.6, 116.2, 111.7, 107.9, 21.2; IR (thin film) 3116, 2930,
1743, 1635, 1547, 1117 cmꢀ1; HRMS (EI) calcd for
[C16H12N2O4]+: m/z 296.0797, found: 296.0795.
associated with this article can be found in the online
version, at doi:10.1016/j.tet.2007.10.037.
References and notes
1. For general reviews, see: (a) Shipman, M. Sci. Synth. 2001, 10,
745; (b) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579; (c)
Grundon, M. F. Nat. Prod. Rep. 1989, 6, 523; (d) Flitsch, W.
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 443;
(e) Uchida, T.; Matsumoto, K. Synthesis 1976, 4, 209.
4.3.11. 3-(Furan-2-yl)indolizin-1-yl acetate (4l). 1H NMR
(300 MHz, CDCl3) d 8.39 (d, J¼7.2 Hz, 1H), 7.49 (t,
J¼0.9 Hz, 1H), 7.29 (d, J¼9.0 Hz, 1H), 7.00 (s, 1H), 6.69
(dd, J¼9.0, 6.5 Hz, 1H), 6.67–6.49 (m, 3H), 2.36 (s, 3H);
13C NMR (75 MHz, CDCl3) d 169.4, 147.3, 141.3, 127.5,
123.6, 117.1, 116.3, 113.4, 111.8, 111.6, 106.1, 105.7,
105.6, 21.1; IR (thin film) 3005, 2950, 1748, 1385,
1213 cmꢀ1; HRMS (EI) calcd for [C14H11NO3]+: m/z
241.0739, found: 241.0736.
2. (a) Gundersen, L.-L.; Charnock, C.; Negussie, A. H.; Rise, F.;
Teklu, S. Eur. J. Pharm. Sci. 2007, 30, 26; (b) Hynd, G.; Ray, N.
C.; Finch, H.; Montana, J. G.; Cramp, M. C.; Harrison, T. K.;
Arienzo, R.; Blaney, P.; Griffon, Y.; Middlemiss, D. WO
2007031747 A1, 2007; (c) Millet, R.; Domarkas, J.; Rigo, B.;
Goossens, L.; Goossens, J.-F.; Houssin, R.; Henichart, J.-P.
Bioorg. Med. Chem. 2002, 10, 2905; (d) Sonnet, P.;
Dallemagne, P.; Guillon, J.; Enguehard, C.; Stiebing, S.;
Tanguy, J.; Bureau, R.; Rault, S.; Auvray, P.; Moslemi, S.;
Sourdaine, P.; Seralini, G.-E. Bioorg. Med. Chem. 2000, 8,
945; (e) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.;
Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.;
Ueno, M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.;
Ohtani, M. J. Med. Chem. 1996, 39, 3636; (f) Gubin, J.; de
Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux,
J.; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain,
P. J. Med. Chem. 1993, 36, 1425; (g) Jaffrezou, J. P.; Levade,
T.; Thurneyssen, O.; Chiron, M.; Bordier, C.; Attal, M.;
Chatelain, P.; Laurent, G. Cancer Res. 1992, 52, 1352; (h)
Cingolani, G. M.; Claudi, F.; Massi, M.; Venturi, F. Eur. J.
Med. Chem. 1990, 25, 709.
3. (a) Surpateanu, G. G.; Becuwe, M.; Lungu, N. C.; Dron, P. I.;
Fourmentin, S.; Landy, D.; Surpateanu, G. J. Photochem.
Photobiol., A 2007, 185, 312; (b) Delattre, F.; Woisel, P.;
Surpateanu, G.; Cazier, F.; Blach, P. Tetrahedron 2005, 61,
3939; (c) Retaru, A. V.; Druta, L. D.; Deser, T.; Mueller, T. J.
Helv. Chim. Acta 2005, 88, 1798; (d) Sonnenschein, H.;
Henrich, G.; Resch-Genger, V.; Schulz, B. Dyes Pigments 2000,
46, 23; (e) Saeva, F. D.; Luss, H. R. J. Org. Chem. 1988, 53, 1804.
4. For recent examples, see: (a) Schwier, T.; Sromek, A. W.; Yap,
D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 9868; (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V.
Org. Lett. 2007, 9, 3433; (c) Chuprakov, S.; Hwang, F. W.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757; (d) El
Kaim, L.; Gizolme, M.; Grimaud, L. Synlett 2007, 227; (e)
Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R.
Org. Lett. 2007, 9, 1169; (f) Liu, Y.; Hu, H.-Y.; Liu, Q.-J.;
Hu, H.-W.; Xu, J.-H. Tetrahedron 2007, 63, 2024; (g)
4.3.12. (S)-3-(Prop-1-en-2-yl)-1,2,3,4-tetrahydropyr-
ido[1,2-a]indol-10-yl acetate (4m). H NMR (300 MHz,
1
CDCl3) d 7.51 (d, J¼7.1 Hz, 1H), 7.15 (d, J¼9.1 Hz, 1H),
6.56 (t, J¼6.5 Hz, 1H), 6.41 (dt, J¼7.1, 1.1 Hz, 1H), 4.84
(s, 2H), 2.85 (d, J¼10.3 Hz, 1H), 2.75–2.57 (m, 3H), 2.35
(s, 3H), 2.01 (d, J¼11.0 Hz, 1H), 1.84 (s, 3H), 1.79–1.70
(m, 2H); 13C NMR (75 MHz, CDCl3) d 170.0, 149.3,
123.6, 121.8, 120.7, 117.1, 115.9, 115.4, 115.3, 109.9,
109.6, 42.1, 28.5, 26.8, 21.3, 21.0, 20.8; IR (thin film)
2918, 2846, 1768, 1368, 1210 cmꢀ1; HRMS (EI) calcd for
[C17H19NO2]+: m/z 269.1416, found: 269.1418; [a]2D8
ꢀ44.97 (c 0.12, CHCl3).
4.3.13. 2,8-Dimethyl-3-phenylindolizin-1-yl acetate (4n).
1H NMR (300 MHz, CDCl3) d 7.78 (d, J¼6.9, 1H), 7.51–
7.44 (m, 4H), 7.39–7.33 (m, 1H), 6.28 (dt, J¼6.6, 0.9 Hz,
1H), 6.23 (t, J¼6.9 Hz, 1H), 2.43 (s, 3H), 2.37 (s, 3H),
2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.8, 131.4,
130.3, 129.1, 127.7, 127.1, 126.6, 122.4, 120.2, 120.0,
117.1, 115.3, 110.0, 20.9, 18.3, 8.9; IR (thin film) 2921,
2850, 1758, 1518, 1374, 1208 cmꢀ1; HRMS (EI) calcd for
[C18H17NO2]+: m/z 279.1259, found: 279.1262.
4.3.14. 2,6-Dimethyl-3-phenylindolizin-1-yl acetate (4o).
1H NMR (300 MHz, CDCl3) d 7.71 (s, 1H), 7.51–7.43 (m,
4H), 7.38–7.34 (m, 1H), 7.07 (d, J¼9.0 Hz, 1H), 6.47 (d,
J¼9.0 Hz, 1H), 2.38 (s, 3H), 2.11 (s, 6 H); 13C NMR
(75 MHz, CDCl3) d 170.1, 131.5, 130.2, 129.1, 127.6,
126.1, 121.5, 120.2, 119.6, 119.4, 119.1, 115.0, 114.6,
20.9, 18.7, 9.1; IR (thin film) 3015, 2950, 1755, 1522,
1436, 1393 cmꢀ1; HRMS (EI) calcd for [C18H17NO2]+:
m/z 279.1259, found: 279.1260.
ˇ
ꢁ
ꢀ
ꢀ
ꢁꢀ
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ꢀˇ
Marchalın, S.; Zuziova, J.; Kadlecıkova, K.; Safar, P.; Baran,
ꢀꢁ
€
P.; Dalla, V.; Daıch, A. Tetrahedron Lett. 2007, 48, 697; (h)
Acknowledgements
Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
12050; (i) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005, 7,
4305; (j) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074; (k) Padwa, A.; Austin, D. J.;
Precedo, L.; Zhi, L. J. Org. Chem. 1993, 58, 1144.
We thank the Center for Biological Modulators and Korea
Research Institute of Chemical Technology for generous
financial support.
5. (a) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett.
2007, 48, 6863; (b) Kim, I.; Lee, G. H.; No, Z. S. Bull. Korean
Chem. Soc. 2007, 28, 685.
Supplementary data
6. 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.
1H and 13C NMR spectra for compounds 3 and 4 are
included as supplementary material. Supplementary data

12960
I. Kim et al. / Tetrahedron 63 (2007) 12954–12960
7. For selected examples on 5-endo-trig iodocyclizations, see: (a)
Amjad, M.; Knight, D. W. Tetrahedron Lett. 2006, 47, 2825; (b)
Donohue, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem.
2005, 70, 7297; (c) Knight, D. W.; Shaw, D. E.; Staples,
E. R. Eur. J. Org. Chem. 2004, 1973; (d) Knight, D. W.;
Staples, E. R. Tetrahedron Lett. 2002, 43, 6771; (e) Bedford,
S. B.; Bell, K. E.; Bennett, F.; Hayes, C. J.; Knight, D. W.;
Shaw, D. E. J. Chem. Soc., Perkin Trans 1 1999, 2143; (f)
Barks, J. M.; Knight, D. W.; Seaman, C. J.; Weingarten,
G. G. Tetrahedron Lett. 1994, 35, 7259; (g) Kang, S. H.; Lee,
S. B. Tetrahedron Lett. 1993, 34, 7579; (h) Kang, S. H.; Lee,
S. B. Tetrahedron Lett. 1993, 34, 1955.
8. The relative stereochemistry of these diastereomers was not
determined.
9. Similarly, exposure of propargylic acetate a to iodine failed to
deliver the indolizine b, only yielding a complex mixture.
Unpublished results.
OAc
OAc
I2
X
N
N
a
b
10. A pyridine group was first used as an internal nucleophilic
partner in iodocyclizations by us. See Ref. 5a.