A highly efficient catalyst-free cycloisomerization approach to indolizinones

Article abstract of DOI:10.1055/s-2008-1078022

A highly efficient catalyst-free synthetic route to indolizinones was established from readily available tertiary propargylic alcohols via a facile thermally induced cycloisomerization. In addition, this transformation was found to be further expedited by

Full text of DOI:10.1055/s-2008-1078022

2334
LETTER
A Highly Efficient Catalyst-Free Cycloisomerization Approach to
Indolizinones
C
atalyst-
k
Free Cyclois
y
omerization
o
A
pproachto
nIndolizinones Kim,* Jihyun Choi, Sunkyung Lee, Ge Hyeong Lee
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 13 May 2008
Dedicated to Professor Moon Woo Chun on the occasion of his retirement
communicate the highly efficient metal-free approach to
indolizinones.
Abstract: A highly efficient catalyst-free synthetic route to indoli-
zinones was established from readily available tertiary propargylic
alcohols via a facile thermally induced cycloisomerization. In addi-
tion, this transformation was found to be further expedited by mi-
crowave irradiation.
To test the viability of the above idea, we used 1a for op-
timization study. At the outset, we simply warmed the so-
lution of 1a in methanol to reflux for 24 hours. To our
delight, this resulted in the desired indolizinone 10a in
75% isolated yield (Scheme 3).7 No other side products
were detected except for the remaining starting material.
In order to improve the conversion rate, a higher-boiling
solvent such as ethanol was employed instead of metha-
nol, furnishing 10a in almost quantitative yield after 24-
hour reflux.8 A brief survey of other solvents (propanol,
acetonitrile, toluene, DMF, etc.) indicated that ethanol
was the solvent of choice for this transformation.9
Key words: indolizinones, catalyst-free, cyclization, 1,2-migra-
tion, microwave
As part of our continuing interest in the fused azacycles,1
we recently communicated the highly efficient syntheses
of 2-iodoindolizinones 3 and indolizinones 6 based on a
iodocyclization–1,2-shift sequence (Scheme 1).1e In this
work, cesium carbonate in methanol was successfully em-
ployed for an effective 1,2-migration of the R1 group.
Thus, exposure of indolizinium salts 2 or 5 to cesium car-
bonate in refluxing methanol provided 3 or 6, respective-
ly, in excellent yields.
To further increase the rate of cycloisomerization, we then
decided to exploit microwave since microwave has been
successfully implemented to expedite a number of reac-
tions as compared with conventional heating conditions.10
Gratifyingly, we were able to find that exposure of 1a to
microwave (150 °C) for 30 minutes cleanly led to 10a in
a quantitative yield.
Mechanistically, zwitterions 7a and 7b generated under
basic conditions are believed to facilitate 1,2-shift,2 there-
by providing 2-iodoindolizinones 3 and indolizinones 6 as
shown in Scheme 2. Since 5-endo-dig-type ring closure is
known to be a facile process,3 we reasoned that the zwit-
terionic species such as 84,5 as a consequence of successful
cyclization of 1 would capture the hydrogen to generate
the isomeric zwitterion 9, which in turn would be rear-
ranged to indolizinone 10 (the lower box in Scheme 2).
Motivated by this hypothesis, we decided to explore this
catalyst-free route to indolizinones.6 Herein we wish to
With these optimized conditions in hand, the reaction
scope was examined with various substrates. As outlined
in Table 1, various indolizinones were rapidly synthe-
sized in excellent yields.11,12 Although all the products can
be delivered under conventional heating conditions,13 use
of microwave irradiation proved to be essential for rapid
and complete conversion. Interestingly, when a solution
of 1f in ethanol was heated to reflux in the presence of ce-
R1
N+
O
R1
N
OH
R1 OH
5-endo-dig
iodocyclization
1,2-shift
I
I
N
R2
R2
R2
I–
1
2
3
R1
O
R1
N
OH
R1 OH
5-endo-trig
iodocyclization
dehydroiodination–
1,2-shift
R2
R3
I
R2
N+
R2
N
R3
R3
I–
4
5
6
Scheme 1
SYNLETT 2008, No. 15, pp 2334–2338
1
5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078022; Art ID: U05108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst-Free Cycloisomerization Approach to Indolizinones
2335
base
base
R1
N+
R1
O
O–
R1
N
O
H
I
I
I
+N
R2
R2
R2
O
I–
2
3
7a
R1
R1
O–
O
H
R1
I
R2
R2
N+
+ N
R2
N
R3
R3
R3
H
I–
5
base
7b
R1
6
R1
O
O–
R1
N
O
H
R1 OH
–
+ N
N
R2
+
N
R2
R2
R2
8
1
10
9
Scheme 2
ture (entry 10). Thiophene- or morpholine-containing in-
dolizinone 10c or 10k was easily accessed as well (entries
3 and 11).
O
Ph
N
Ph OH
conditions
N
t-Bu
In conclusion, we have described here a very convenient
metal-free synthesis of indolizinones from readily avail-
able tertiary propargylic alcohols via a thermally promot-
ed cycloisomerization. Moreover, it was demonstrated
that this process coupled with microwave irradiation tech-
nology proceeded with remarkable efficiency, allowing
for ready access to excellent yields of various indolizi-
nones. Compared with the previous metal-catalyzed ap-
proaches to indolizinones, our protocol is much easier to
perform and provides higher yields of indolizinones while
avoiding any toxic and/or expensive catalysts. Current ef-
forts are directed to incorporate the indolizinone skeleton
as a key pharmacophore in the context of our medicinal
program and will be reported in due course.
t-Bu
10a
1a
Scheme 3 Reagents and conditions: MeOH, reflux for 24 h: 75%,
EtOH, reflux for 24 h: 95%, EtOH, microwave (150 °C) for 30 min:
100%.
O–
O
O
Me
N
Me
N
Me
N
H+
EtO
EtO
EtOH
10f
11
Equation 1
Acknowledgment
sium carbonate, 11 was also obtained as a mixture of dia-
stereomers along with the expected 10f, probably arising
from Michael addition of ethanol to 10f (Equation 1). In
the absence of the base, however, 10f was the only isol-
able product (entry 6).
We thank the Center for Biological Modulators and the Korea Re-
search Institute of Chemical Technology for generous financial sup-
port. We also thank Dr. Jung-Nyoung Heo for helpful discussions.
References and Notes
It should be mentioned that longer time (30 min vs. 20
min) was needed for complete conversion under micro-
wave heating conditions when R2 was a tert-butyl group,
presumably resulting from the steric bulkiness prohibiting
the nucleophilic attack on alkyne moiety by pyridinyl ni-
trogen (entries 1 and 7). Propargylic alcohol 1j (R1 =
pyridyl and R2 = t-Bu), however, underwent relatively fast
cycloisomerization under microwave conditions since full
conversion was observed within 20 minutes, giving rise to
indolizinone 10j bearing a pyridyl group at the ring junc-
(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) Choi, J.; Lee, G. H.; Kim, I. Synlett 2008, 1243.
(2) For recent synthetic approaches involving 1,2-shift, see:
(a) Kirsch, S. F.; Binder, J. T.; Liébert, C.; Menz, H. Angew.
Chem. Int. Ed. 2006, 45, 5878. (b) Crone, B.; Kirsch, S. F.
Chem. Eur. J. 2008, 14, 3514; and references therein.
(3) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734
Synlett 2008, No. 15, 2334–2338 © Thieme Stuttgart · New York

2336
I. Kim et al.
LETTER
Table 1 Synthesis of Various Indolizinones
.
O
R1
R1 OH
EtOH, reflux, 24–36 h or
EtOH, MW (150 °C), 20–30 min
N
N
R2
R2
1
10
Entry
1
1
10
Yield (%)a
O
Ph
N
Ph OH
1a
1b
10a
10b
100b (95)
100 (92)
N
t-Bu
Ph
t-Bu
O
Me
N
Me OH
2
3
N
Ph
O
Me
N
Me OH
N
1c
10c
100 (91)
S
S
O
Me
N
Me OH
N
4
1d
10d
100 (89)
OMe
OMe
O
Et
N
Et OH
5
6
1e
1f
10e
10f
100 (94)
100 (96)
N
Ph
Ph
O
Me
N
Me OH
N
O
Me
N
Me OH
7
8
1g
1h
10g
10h
100b (85)
100 (91)
N
t-Bu
t-Bu
O
Me
N
Me OH
N
n-Bu
n-Bu
O
Me
N
Me OH
N
9
1i
10i
100 (91)
Synlett 2008, No. 15, 2334–2338 © Thieme Stuttgart · New York

LETTER
Catalyst-Free Cycloisomerization Approach to Indolizinones
2337
Table 1 Synthesis of Various Indolizinones (continued)
O
R1
R1 OH
EtOH, reflux, 24–36 h or
EtOH, MW (150 °C), 20–30 min
N
N
R2
R2
1
10
Entry
10
1
10
Yield (%)a
O
py
N
py OH
1j
1k
1l
10j
10k
10l
100 (93)
100 (95)
100 (92)
N
t-Bu
t-Bu
O
Ph
N
Ph OH
N
O
11
12
N
N
O
O
Ph
N
Ph OH
N
OPMB
OPMB
a Isolated yields under microwave heating conditions (150 °C for 20 min) unless otherwise noted. Yields under conventional heating conditions
(refluxing EtOH for 24–36 h) are in parentheses.
b Microwave irradiation for 30 min.
(4) For recent examples on the chemistry of zwitterions (1,4-
dipoles) generated from the reaction of pyridines or
quinolines with dimethyl acetylenedicarboxylate (DMAD),
see: Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron 2008,
64, 3567; and references therein.
(5) No examples on the generation of zwitterions such as 8 from
intramolecular cyclization have been disclosed in the
literature.
(6) Indolizinone skeleton was known to be accessed by the
similar type of cyclization–1,2-shift sequence using either
PtCl2 or CuI: (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.
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
(e) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
653.
(11) In most cases, the desired indolizinones were the only
isolable product so that the evaporation of the reaction
solvent was enough for the characterization of compounds.
(12) 10b: 1H NMR (300 MHz, CDCl3): d = 7.52 (s, 5 H), 6.53 (d,
J = 7.2 Hz, 1 H), 5.89–5.97 (m, 2 H), 5.36–5.40 (m, 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, 123.3,
122.1, 109.0, 99.0, 68.8, 25.2. HRMS (EI): m/z [M+] calcd
for C15H13NO: 223.0997; found: 223.0995. 10c: 1H NMR
(300 MHz, CDCl3): d = 7.68–7.70 (m, 1 H), 7.47–7.50 (m, 1
H), 7.27–7.30 (m, 1 H), 6.67 (d, J = 6.9 Hz, 1 H), 5.90–5.98
(m, 2 H), 5.46 (m, 1 H), 5.20 (s, 1 H), 1.42 (s, 3 H). 13C NMR
(75 MHz, CDCl3): d = 202.9, 166.6, 130.6, 128.0, 127.4,
127.3, 124.4, 123.3, 122.0, 109.4, 98.3, 68.7, 24.9. HRMS
(EI): m/z [M+] calcd for C13H11NOS: 229.0561; found:
229.0566. 10d: 1H NMR (300 MHz, CDCl3): d = 7.96 (s, 1
H), 7.83 (t, J = 9.3 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.22–
7.27 (m, 1 H), 7.19 (s, 1 H), 6.64 (d, J = 7.5 Hz, 1 H), 5.90–
5.99 (m, 2 H), 5.39 (t, J = 5.9 Hz, 1 H), 5.27 (s, 1 H), 3.96 (s,
3 H), 1.49 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 203.1,
173.0, 159.4, 136.0, 130.3, 128.4, 128.3, 127.8, 125.4,
124.8, 124.1, 123.6, 122.0, 120.4, 108.9, 106.0, 99.0, 68.9,
55.7, 25.2. HRMS (EI): m/z [M+] calcd for C20H17NO2:
303.1259; found: 303.1255. 10e: 1H NMR (300 MHz,
CDCl3): d = 7.49 (s, 5 H), 6.50 (d, J = 7.2 Hz, 1 H), 5.84–
5.93 (m, 2 H), 5.27–5.32 (m, 1 H), 5.18 (s, 1 H), 1.85 (q, J =
7.5 Hz, 2 H), 0.89 (t, J = 7.2 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 202.7, 174.5, 131.2, 129.8, 129.3, 128.1, 124.1,
123.8, 122.3, 109.2, 100.8, 72.2, 32.8, 7.1. HRMS (EI): m/z
[M+] calcd for C16H15NO: 237.1154; found: 237.1155. 10f:
1H NMR (300 MHz, CDCl3): d = 6.54 (d, J = 7.2 Hz, 1 H),
6.14–6.22 (m, 1 H), 5.87–5.88 (m, 2 H), 5.32–5.42 (m, 1 H),
(7) Spectral data of 10a: 1H NMR (300 MHz, CDCl3): d = 7.18–
7.37 (m, 5 H), 6.84 (d, J = 7.2 Hz, 1 H), 6.39 (d, J = 9.0 Hz,
1 H), 6.03 (dd, J = 5.3, 9.2 Hz, 1 H), 5.39–5.43 (m, 1 H), 4.98
(s, 1 H), 1.46 (s, 9 H). 13C NMR (75 MHz, CDCl3): d =
201.0, 184.5, 140.1, 128.6, 127.9, 125.5, 124.8, 124.6,
123.3, 110.0, 97.1, 72.2, 34.4, 29.0. HRMS (EI): m/z [M+]
calcd for C18H19NO: 265.1467; found: 265.1469.
(8) Heating a solution of 1a in ethanol in the presence of cesium
carbonate was also carried out but did not shorten the
reaction time.
(9) Alcoholic solvents seemed crucial for effective conversion.
Propanol also gave similar efficiency as ethanol. Reaction
under refluxing toluene gave very low conversion whereas
no reaction took place in DMF or acetonitrile.
(10) For books and reviews on microwave in organic synthesis,
see: (a) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225. (b) Loupy, A. Microwaves in
Organic Synthesis; Wiley-VCH: Weinheim, 2002.
(c) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(d) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Synlett 2008, No. 15, 2334–2338 © Thieme Stuttgart · New York

2338
I. Kim et al.
LETTER
4.96 (s, 1 H), 2.00–2.40 (m, 4 H), 1.68–1.78 (m, 4 H), 1.34
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 203.4, 174.4,
133.5, 128.6, 124.0, 123.7, 121.9, 108.3, 96.8, 68.2, 27.6,
25.5, 25.0, 22.3, 21.7. HRMS (EI): m/z [M+] calcd for
C15H17NO: 227.1310; found: 227.1315. 10g: 1H NMR (300
MHz, CDCl3): d = 6.68 (d, J = 7.2 Hz, 1 H), 5.86–5.96 (m, 2
H), 5.41–5.46 (m, 1 H), 4.98 (s, 1 H), 1.36 (s, 9 H), 1.29 (s,
3 H). 13C NMR (75 MHz, CDCl3): d = 203.4, 182.2, 125.4,
124.3, 122.0, 108.9, 96.5, 68.7, 34.0, 28.8, 24.2. HRMS (EI):
m/z [M+] calcd for C13H17NO: 203.1310; found: 203.1312.
10h: 1H NMR (300 MHz, CDCl3): d = 6.44 (d, J = 6.9 Hz, 1
H), 5.90 (d, J = 3.3 Hz, 2 H), 5.43–5.48 (m, 1 H), 4.93 (s, 1
H), 2.48 (t, J = 7.7 Hz, 2 H), 1.64 (quint, J = 7.5 Hz, 2 H),
1.38–1.50 (m, 2 H), 1.30 (s, 3 H), 0.97 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 203.3, 175.4, 124.6, 122.0,
121.8, 109.1, 97.0, 68.0, 28.9, 27.1, 24.5, 22.7, 13.9. HRMS
(EI): m/z [M+] calcd for C13H17NO: 203.1310; found:
203.1313. 10i: 1H NMR (300 MHz, CDCl3): d = 6.48 (dd,
J = 0.6, 7.2 Hz, 1 H), 5.89 (d, J = 3.3 Hz, 2 H), 5.42–5.47 (m,
1 H), 4.94 (s, 1 H), 2.86–2.96 (m, 1 H), 1.95–2.16 (m, 2 H),
1.63–1.79 (m, 6 H), 1.30 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 203.5, 179.7, 124.6, 122.2, 122.1, 109.0, 94.6,
68.1, 37.3, 31.8, 31.5, 25.8, 25.6, 24.5. HRMS (EI): m/z [M+]
calcd for C14H17NO: 215.1310; found: 215.1309. 10j: 1H
NMR (300 MHz, CDCl3): d = 8.55 (d, J = 4.8 Hz, 1 H), 7.60
(dt, J = 1.8, 7.8 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.13 (ddd,
J = 1.2, 4.8, 7.5 Hz, 1 H), 6.85 (d, J = 7.2 Hz, 1 H), 6.49 (d,
J = 6.3 Hz, 1 H), 6.09 (dd, J = 5.6, 9.2 Hz, 1 H), 5.39 (dd,
J = 6.3, 7.2 Hz, 1 H), 5.00 (s, 1 H), 1.47 (s, 9 H). 13C NMR
(75 MHz, CDCl3): d = 199.4, 185.1, 158.6, 149.7, 136.7,
125.8, 124.2, 123.5, 122.7, 120.0, 109.3, 97.2, 73.7, 34.3,
29.0. HRMS (EI): m/z [M+] calcd for C17H18N2O: 266.1419;
found: 266.1423. 10k: 1H NMR (300 MHz, CDCl3): d =
7.37–7.40 (m, 2 H), 7.23–7.33 (m, 3 H), 6.94 (d, J = 7.2 Hz,
1 H), 6.31 (d, J = 9.0 Hz, 1 H), 6.00 (dd, J = 5.4, 9.0 Hz, 1
H), 5.42 (t, J = 6.3 Hz, 1 H), 5.05 (s, 1 H), 3.79 (t, J = 4.5 Hz,
4 H), 3.58 (d, J = 14.4 Hz, 1 H), 3.42 (d, J = 14.4 Hz, 1 H),
2.53–2.67 (m, 4 H). 13C NMR (75 MHz, CDCl3): d = 201.3,
172.5, 140.5, 128.8, 128.1, 124.5, 124.3, 123.6, 123.1,
109.8, 99.8, 72.1, 67.1, 55.1, 54.2. HRMS (EI): m/z [M+]
calcd for C19H20N2O2: 308.1525; found: 308.1523. 10l: 1H
NMR (300 MHz, CDCl3): d = 7.41–7.42 (m, 2 H), 7.22–7.39
(m, 5 H), 6.89–6.93 (m, 2 H), 6.69 (d, J = 7.2 Hz, 1 H), 6.31
(dd, J = 0.9, 9.3 Hz, 1 H), 5.96–6.01 (m, 1 H), 5.39 (t, J = 7.2
Hz, 1 H), 5.08 (s, 1 H), 4.46–4.64 (m, 4 H), 3.78 (s, 3 H). 13
NMR (75 MHz, CDCl3): d = 201.4, 172.4, 160.0, 140.2,
130.0, 129.0, 128.8, 128.1, 124.7, 124.0, 123.4, 123.2,
C
114.3, 110.1, 98.5, 73.1, 72.0, 63.5, 55.6. HRMS (EI): m/z
[M+] calcd for C23H21NO3: 359.1521; found: 359.1523.
(13) The slightly lower product yields under conventional
heating conditions as compared to those under microwave
conditions are ascribed to the small amount of remaining
starting material under the former conditions.
graphic
gra
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