Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Article abstract of DOI:10.1016/j.tet.2009.03.076

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addit

Full text of DOI:10.1016/j.tet.2009.03.076

Tetrahedron 65 (2009) 4593–4603
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-
dipolar cycloadducts of nitrones with allenic esters/ketones and alternative
cycloaddition–palladium catalyzed cyclization pathway
Ashish Kapur a, Kamal Kumar a, Lakhwinder Singh a, Parminder Singh a, Munusamy Elango b,
,
Venkatesan Subramanian b, Vivek Gupta c, Priyanka Kanwal c, Mohan Paul S. Ishar a
*
a Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
b Chemical Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
c P. G. Department of Physics, University of Jammu, Jammu Tawi 180 006, Jammu & Kashmir, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a–c) and allenic
ketones (18a–d) furnish benzoindolizines (9a–k, 19a–d) in good yields. The formation of benzoindoli-
Received 24 February 2009
Received in revised form 25 March 2009
Accepted 25 March 2009
Available online 1 April 2009
zines is postulated to involve regioselective addition of 1,3-dipole to C2–C3
p bond of allenic esters/
ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza
Diels–Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dieno-
phile components in the proposed intermediate C have revealed that conformational constraints im-
posed by the alkyl groups (R¼Me, Et) favor intramolecular aza-Diels–Alder cycloaddition. An alternative
domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a–
c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been
developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Allenic esters
Benzoindolizines
Cycloaddition
Domino routes
Heck reaction
1. Introduction
cycloadducts of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenylnitrone
(7) with allenic esters (8, Scheme 2).5
Domino processes offer useful one-pot atom economic pro-
tocols for the synthesis of a variety of complex molecular
frameworks.1 1,3-Dipolar cycloadditions of nitrones with olefinic
and acetylenic dipolarophiles afford five-membered heterocycles
(isoxazolidine/isoxazoline),2 and have been extensively exploited
for the synthesis of a variety of natural products, and scaffolds
for biologically active molecules.3 Available reports on cycload-
dition of nitrones with variedly substituted allenes indicate that
isoxazolidines (3) derived from addition of nitrones (1) to allenes
(2) undergo rearrangement by N–O bond cleavage to yield 3-
pyrrolinones (4), and in the case of N-phenylnitrones the cleav-
age of N–O bond of isoxazolidines (3) leads to benzazepinones
(5); the latter undergo sequence of retro-Mannich reaction, hy-
drolysis, and cyclization leading to 2-substituted indoles (6,
Scheme 1).4
Indolizines form the main framework and constitute common
structural core in many naturally occurring alkaloids.6 Indolizines
based molecules are known for their use as synthetic dyes,7a,b
fluorescent materials,7c–e and also as key intermediates for the
synthesis of indolizine based molecules.7f–h Indolizines both syn-
thetic and natural have also been ascribed with a number of useful
biological activities8–12 such as antibacterial, antiviral, anti-in-
flammatory (10, 11),8a,b testosterone-3 -reductase inhibitors,8c 5-
a
HT4 receptor antagonists,8d CNS depressants,8e,f anti-HIV (12),9
anti-cancer10 (13) and have been used for treating cardiovascular
ailments.11 For instance, aminoalkyloxybenzenesulfonylindolizine
compounds such as fantofarone (14) and butoprozine (15) have
been used for the treatment of hypertension, arrhythmia, and an-
gina pectoris.11 Several oxygenated indolizines have been shown to
prevent, due to their strong anti-oxidative effects, the initiation of
oxidation processes that lead to DNA damage.12
Consequently, synthesis of indolizines has attracted considerable
attention and a number of synthetic methodologies have been de-
veloped for a variety of indolizines, making use of in particular,
transition metal catalyzed reactions.13 In view of the anticipated
pharmacological properties of indolizines with potential therapeutic
We had reported preliminary observations on the formation of
benzo[b]indolizines (9) by tandem reorganization of 1,3-dipolar
* Corresponding author. Tel.: þ91 183 2258802 09x3321; fax: þ91 183 2258820.
E-mail address: mpsishar@yahoo.com (M.P.S. Ishar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.076

4594
A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
R
N
R
N
R
N
R1
R2
H
Ph
R1
R2
H
R= Me
Ph
O
O
+
Ph
(1)
W
R1
W
W
O
R2
(2)
(3)
(4)
R1= R2= H, CH3, C2H5
W= CN, SO2Ph,
CO2Me
R= Ph
R2
O
R1
W
H
W
N
H
N
Ph
H
(5)
(6)
Scheme 1.
N
O
O
O
O
X
X
Ph
+
R
H
Dry PhH
Reflux
H
CHR
CO2Et
N
O
H
CO2Et
O
X = H
R = H. Me. Et.
A
(7)
(8)
R
CO2Et
N
a) R = H
b) R = Me
c) R = Et
X
O
H
O
(9a-c)
Scheme 2.
applications, it was decided to explore synthesis of variedly
substituted benzoindolizines, utilizing the reactions of nitrones with
allenic esters and allenic ketones. An alternative one-pot sequential
aza-Diels–Alder cycloaddition–Heck coupling route to benzoindoli-
zines has also been developed.
spectroscopically. Further elution lead to the isolation of nitrone
rearranged product (17).14,16 The results are summarized in Table 2.
In order to prevent the excessive rearrangement of nitrones (7)
to 17,14,16 the reactions with allenic esters were also performed at
room temperature but it takes longer time for completion of re-
action (3–5 days) with slight improvements in yield and conse-
quent decrease in the yields of nitrone rearranged products (17).
The reactions with allenic ketones could not be carried out under
refluxing conditions as they undergo excessive polymerization,
drastically reducing the yield of indolizines.
2. Result and discussion
Substituted nitrones (7) were synthesized from 6-substituted-3-
formyl chromones by reported method.14 Initially, the reactions of
nitrone (7) were carried out with allenic esters (8) by refluxing the
solution of addends (1:1.2 molar, respectively) in dry benzene. The
obtained substituted benzoindolizines (9a–h, 29–59%, Scheme 3)
were isolated by column chromatography over silica gel and char-
acterized on the basis of spectroscopic (1H NMR, 13C NMR, IR, mass)
and microanalytical data. The structure of 9f was confirmed by
X-ray crystallography (Fig.1).15 Varied amounts (25–40%) of nitrone
rearrangement product (17)14,16 were also isolated from the re-
actions. The results of the reactions between nitrones (7) and
allenic esters (8) are summarized in Table 1.
Further, the investigations were extended to reactions of nitrone
(7) with allenic ketones (18). The solutions of addends (7 and 18;
1:1.2 molar, respectively) were stirred in dry benzene at ambient
temperature till the completion of reaction (TLC) and obtained
benzoindolizines (19a–d, 28–42%, Scheme 4) were isolated by
column chromatography over silica gel and characterized
Mechanistically, the formation of the benzoindolizines can be
explained on the basis of the domino process as outlined in
Scheme 5. It is postulated that indolizines are derived from
initial regioselective addition of nitrones (7) to the activated C2–
C3
p bond of allenic esters (8)/allenic ketones (18), followed by
homolytic scission of N–O bond of the formed isoxazolidines (A)
and the recyclization of the diradical intermediate onto the or-
tho position of the N-phenyl ring leads to the formation of B. 1,3
H-shift in B results in tetrahydrobenzazepinone (B1) and the
latter undergoes retro-Mannich ring opening to yield the in-
termediate (C). Intramolecular aza-Diels–Alder reaction in C
followed by subsequent loss of water and opening of the chro-
mone ring results in the formation of benzoindolizines (9, 19).
The 2-substituted indoles were formed in some cases by the
hydrolysis of C]N in the intermediate C, followed by cyclization
(Scheme 5).

A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4595
NH2
HO
O
NH2
O
O
HO
O
A
O
O
N
R2
N
R2 = Et
R3 = O-Ph-C6H4, m-Cl-C6H4
R3
A= O, NH
(10)
(11)
Indoxam (10) and related analogues (11)
Inhibitors of mammalian phospholipase A2 ( Anti Inflammatory)
RO
O
N
O
R = H, X = H
Z
H3C
R = SO3Na, X = H
R = H, X = OMe
MeO
HO
MeO
Z
N
X
R
X
R= H, OMe.
X= CH3, H.
MeO
OMe
Z= CH2OCONHCH(CH3)2.
(12)
(13)
Alkaloid Lamellarins
Anti HIV-1
Anti-Leukaemic
O(CH2)n Amine
O2S
C2H5
N
R2
N
O(CH2)3NBu2
O
Fantofarone (14)
Butoprozine (15)
Calcium Channel Blockers
(Anti-anginal)
Some representative biologically active indolizines
It is observed that alkyl substitution on allenic moiety (8a/
8b) leads to improved yields of benzoindolizines with reduced
reaction times and further improvement of yields and short-
ening of reaction times occur as the size of alkyl substituent
increases from methyl to ethyl (8b/8c, Table 1). Thinking that
intramolecular aza-Diels–Alder cycloaddition in intermediate C
is a crucial step for the formation of benzoindolizines (9a–k),
Fukui functions (fþ, f0, fꢀ) for reacting atoms in the intermediate
C have been calculated and given in Table 4. Keeping the azadiene
part constant (X¼H), parameters such as energies of HOMO and
LUMO (in Hartrees), chemical hardness (
h
), chemical potential (
m),
and global electrophilicity (u, Table 5, all values in eV) for dien-
ophile part in intermediate C (R¼H, Me, Et) were also computed. All
the calculations were carried out at B3LYP/6-31G level.
*
DFT calculations were carried out at B3LYP/6-31G level for
*
R
H
OH
azadiene and dienophilic components in intermediate C. The
results of calculations are shown in Tables 3–5. The calculation
CO2Et
4
C
R = H, Me, Et
X = H
H
3
O
of activation energy for cycloaddition in
C leading to D
1
N
revealed (Table 3) that the activation energy decreases as R in
C changes from H, through CH3, to C2H5, which parallels the
enhanced yield of benzoindolizines (9b,c) with reduced re-
action times.
2
O
X
C
R
O
CO2Et
R
X
Ph
N
R
H
Benzene
(Reflux)
N
O
+
+
H
CO2Et
N
H
CH2CO2Et
O
X
O
H
X = H, Cl, F, Me
(8)
R = H, Me, Et.
(7)
O
(a) R= H
(b) R= Me
(c) R= Et
(16) traces
(9a-k)
+
O
(a) R = H, X = H (g) R = H, X = Cl
(b) R = Me, X = H (h) R = Me, X = Cl
(c) R = Et, X = H (i) R = Et, X = Cl
(d) R = H, X = Me (j) R = Me, X = F
(e) R = Me, X = Me (k) R = Et, X = F
(f) R = Et, X = Me
X
CHO
NHPh
O
X = Cl, F, Me
(17)
Scheme 3.

4596
A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
Table 2
Product yields and reaction times for reactions of nitrone (7) with allenic ketones
(18)
Sr. no.
R0
R00
Benzoindolizines
%Yield
(reaction time, days)
1
2
3
4
H
H
H
Ph
CH3
CH2Ph-p-OCH3
CH2Ph
19a
19b
19c
19d
34 (6)
28 (6)
39 (5)
42 (5)
CH3
As the proposed mechanism (Scheme 5) involves an intra-
molecular (4þ2) cycloaddition reaction, hence it was realized
that an alternative intermediate (H) can be easily approached
utilizing a convenient strategy involving tandem intramolecular
aza-Diels–Alder reaction of silyl-enol ether and azadienes, which
can be subsequently subjected to Heck coupling using palladium
acetate as
a catalyst to obtain substituted benzoindolizines
(Scheme 6).
Hence, it was decided to use the sequential one-pot cycloaddi-
tion of azadienes (22) with silyl-enol ether (23) followed by
intramolecular palladium(0)-catalyzed Heck coupling reaction to
synthesize benzoindolizines (9a,d,g). The variedly substituted
azadienes (22) were prepared by heating a solution of 3-for-
mylchromone (20, X¼H, Me, Cl) with o-iodoaniline (21, 1:1 molar,
respectively) in dry toluene. The ethyl 3-trimethylsiloxy-2-bute-
noate (23) was synthesized by the reported method.17 The in situ
generated azadienes (22, X¼H, Me, Cl) were subjected to cycload-
dition reaction with ethyl 3-trimethylsiloxy-2-butenoate (23,
1:1.2 mol equiv) followed by intramolecular Heck coupling reaction
using catalytic amount of Pd(OAc)2 (5–10 mol %) in the presence of
slight excess of triethylamine as a base, by heating their solution in
dry toluene at 90 ꢁC. After completion of reaction (TLC), the product
benzoindolizines (9a,d,g, 18–25%, Scheme 7) were purified through
column chromatography and their structures were established by
spectroscopic analysis. The relative yields and reaction times of
benzoindolizines (9a,d,g) are given in Table 6.
Mechanistically, the formation of the benzoindolizines (9a,d,g)
by palladium catalyzed domino transformations can be explained
on the basis of the pathway summarized in Scheme 8. The cascade
reactions begin with aza Diels–Alder reaction of 3-[(2-iodo-phe-
nylimino)-methyl]-chromen-4-one (22) with ethyl 3-trimethylsil-
oxy-2-butenoate (23, silyl-enol ether). The initially formed (4þ2)
cycloadduct leads to the formation of intermediate (H or H0) either
through direct thermal elimination of trimethyl silanol in the
presence of base or by its hydrolysis followed by the loss of H2O.
The intermediate H subsequently undergoes intramolecular Heck
coupling in the presence of palladium acetate and a base, followed
by the opening of chromone ring leading to the formation of ben-
zoindolizines (9a,d,g). Alternatively, the intermediate H0 could also
undergo opening of chromone ring prior to the intramolecular
Heck coupling (Scheme 8).
Figure 1. ORTEP view of 9f.
Table 1
Product yields and reaction times for reactions of nitrones (7) with allenic esters (8)
Sr. no.
R
X
Benzoindolizines
%Yield (reaction time, h)
1
2
3
4
5
6
7
8
H
Me
Et
H
Me
Et
H
Me
Et
Me
Et
H
H
H
Me
Me
Me
Cl
Cl
Cl
F
9a
9b
9c
9d
9e
9f
9g
9h
9i
35 (22)
55 (16)
60 (14)
32 (21)
49 (15)
59 (12)
29 (20)
45 (15)
50 (13)
40 (17)
45 (15)
9
10
11
9j
9k
F
The insignificant change in these parameters in the series (R¼H,
Me, Et) revealsthatthe observed changeinthereactivityispurelydue
toconformationalrestrictionsimposedbythealkylgroups. Thisfactis
corroborated by the decreasing distance between the reacting atoms
in intermediate C as well as in the putative transition states, in their
optimized geometries (Fig. 2). It is observed that there is reduction in
distance with increase in the size of the substituents in dienophile
component of intermediate
C
(R¼H/Me/Et), consequently,
resultingindecreaseofactivationenergy, whichcontributestohigher
yields of benzoindolizines on going from 9a to 9c and also from 9d to
9f (X¼Me), from 9g to 9i (X¼Cl), and from 9j to 9k (X¼F, Table 1).
R'
O
COR''
Ph
R'
H
N
H
Benzene
N
O
+
(17)
+
Ambient Temp.
COR''
O
O
H
(18)
(7)
O
R' = H, Ph
R'' = Me, CH2Ph-p-OMe, CH2Ph
(19a-d)
(a) R' = H, R'' = Me,
(b) R' = H, R'' = CH2Ph-p-OMe
(c) R' = H, R'' = CH2Ph
(d) R' = Ph, R'' = Me
Scheme 4.

A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4597
O
O
O
X
Ph
R1
H
R1
CHR1
COR2
H
Dry PhH
Reflux
COR2
N
N
N
O
O
O
+
X
O
H
O
H
H
COR2
(8/18)
(7)
O
X
(B)
(A)
R1
H
OH
R1
H
H
O
COR2
O
OH
R1
COR2
COR2
H
N
H
N
[4+2]
cycloaddition
O
N
O
O
H
O
O
(D)
(B1)
(C)
X
X
X
-H2O
R1
H2O
R1 OH
CHCOR2
R1
CH2COR2
COR2
H
N
-H2O
N
H
NH2
X
O
H
(16)
1 = H, Me, Et, R2 = OEt
O
R
(9,19)
(9) R1 = H, Me, Et, R2 = OEt
(19) R1 = H, Ph, R2 = Me, CH2Ph, CH2Ph-p-OMe.
Scheme 5.
3. Conclusions
Table 3
Calculated activation energies for cycloaddition in C leading to D at B3LYP/6-31G
*
level
A method for the synthesis of novel substituted benzoindolizines
(9a–k) by the reaction of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phe-
nylnitrones (7) with allenic esters (8) is elaborated. Further, the re-
actions of nitrone (7) have been extended to allenic ketones (18) to
obtain variedly substituted benzoindolizines (19a–d). The DFT cal-
culations of the parameters such as Fukui functions (fþ, f0, fꢀ), en-
X
R
Reaction time (h)
Activation energy (kJ/mol)
H
H
H
H
CH3
C2H5
22
16
14
103.6
99.2
96.0
ergies of HOMO and LUMO, chemical hardness (
h), chemical
potential ( ), and global electrophilicity ( ) for dienophile compo-
nent in the intermediate C and activation energies of transition
states for the intramolecular cycloaddition in intermediate C leading
m
u
Table 4
Fukui function values for the reacting atoms of intermediate C
Fukui functions
fþ
X
R
4C
3C
2N
1C
to D, in the proposed domino pathway at B3LYP/6-31G level have
*
H
H
H
H
CH3
C2H5
0.004
0.005
0.004
0.002
0.001
0.001
0.062
0.062
0.061
0.099
0.101
0.100
been carried out, which revealed that conformational restrictions in
C may be responsible for improved yields of indolizines along with
reduced reaction times, observed in the case of allenic esters bearing
alkyl substituents. It is observed that there is reduction in distance
with increase on the size of the substituents R in intermediate C,
consequently, resulting in decrease of activation energy.
An alternative route to benzoindolizines (9a,d,g) involving cy-
cloaddition of azadienes (22a–c) with silyl-enol ether (23) followed
by palladium(0)-catalyzed Heck coupling reaction is also de-
veloped. Both these approaches represent novel domino routes for
the synthesis of benzoindolizines.
f0
H
H
H
H
CH3
C2H5
0.002
0.002
0.002
0.012
0.012
0.009
0.063
0.062
0.064
0.066
0.066
0.066
fꢀ
H
H
H
H
CH3
C2H5
0.001
0.001
0.001
0.023
0.023
0.019
0.064
0.063
0.067
0.032
0.032
0.032
Table 5
Theoretical parameters calculated for dienophile part of intermediate C (X¼H)
Parameters
R
4. Experimental
H
CH3
C2H5
4.1. General information
eHOMO (Hartrees)
eLUMO (Hartrees)
Chemical hardness (
Chemical potential (
Electrophilicity (u, eV)
ꢀ0.21699
ꢀ0.06636
2.049
ꢀ0.21617
ꢀ0.06589
2.045
ꢀ0.21566
ꢀ0.06498
2.050
h
, eV)
, eV)
All melting points are uncorrected and measured in open
glass-capillaries on a Veego (make) MP-D digital melting point
apparatus. Bruker AC-200 FT (200 MHz) and JEOL AL-300FT
m
ꢀ3.855
ꢀ3.838
ꢀ3.818
3.626
3.601
3.556

4598
A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
Figure 2. Optimized geometries of C and transition states in C in going from C to D (X¼H) at B3LYP/6-31G
*
level (the distances are given in Å).
I
I
Heck
Coupling
OR1
CO2Et
N
CO2Et
CO2Et
N
N
O
O
X
O
H
O
O
Pd (0)
O
H
X
X
Retero-synthethic approach towards synthesis of benzoindolizines
Aza-Diels Alder
reaction
I
OHC
OR1
O
I
O
X
N
+
O
+
OEt
O
X
NH2
O
Scheme 6.

A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4599
O
O
NH2
O
O
X
CHO
+
Na
I
Et
O
+
ethy acetoacetate
X = H, Me, Cl.
(21)
Me3SiCl
toluene
(20)
toluene, heat
O
O
Me3SiO
X
O
+
N
Et
I
O
(23)
(22)
Pd(OAc)2, Toluene
Et3N, 90 °C
CO2Et
N
O
X
HO
(9)
Scheme 7.
(300 MHz) spectrometers were used to record 1H NMR and 13C
NMR (50 and 75 MHz) spectra. Chemical shifts ( ) are reported as
4.2. General procedure for the reaction of C-(4-oxo-
4H[1]benzopyran-3-yl)-N-phenylnitrones (7) with allenic
esters (8)
d
downfield displacements from TMS used as internal standard and
coupling constants (J) are reported in hertz. IR spectra were
recorded with Shimadzu FT-IR-8400S spectrophotometer on KBr
pellets. Mass spectra, EI and ESI methods, were recorded on Shi-
madzu GC–MS-QP-2000A and Bruker Daltonics Esquire 300 mass
spectrometers, respectively. Elemental Analyses were carried out
using Vario EL-III elemental analyzer and are reported in percent
atomic abundance.
Reagents were purchased from commercial suppliers and pu-
rified/distilled/crystallized before use. Hexane, petroleum ether,
and ethyl acetate used in column chromatography were distilled
before use; petroleum ether employed was the fraction boiling in
the range of 40–60 ꢁC. Benzene was dried over sodium-benzo-
phenone. C-(4-Oxo-4H[1] benzopyran-3-yl)-N-phenylnitrone and
its 6-substituted derivatives (7) were prepared according to the
reported procedure14 and allenic esters (8) were prepared by the
method of Lang and Hansen.18 Penta-3,4-diene-2-one and its de-
rivatives (18) were prepared by reported methods.19 All the calcu-
lations were performed using Gaussian 98 package.20 The
A
solution of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl-
nitrones (7, 200 mg) and allenic esters (8, 1.2 mol equiv) in 20 mL
dry benzene was refluxed under nitrogen atmosphere till the
completion of reaction (TLC). Benzene was removed under vacuum
and the benzoindolizines (9a–k) were purified by column chro-
matography (silica gel, 60–120 mesh, eluent hexane/EtOAc 9.5:0.5).
Further elution with increasing concentration of EtOAc in hexane
afforded the rearranged products (17) of nitrone (25–40%) and in
some cases indoles (16, <5%) were also obtained and detected by 1H
NMR of some column fractions.
4.3. General procedure for the reaction of azadienes (22) and
ethyl 3-trimethylsiloxy-2-butenoate (23)
A solution of 3-formylchromone (20, 200 mg) was refluxed with
o-iodoaniline (21, 1.0 mol equiv) in dry toluene using Dean Stark
water separator till the completion of reaction (TLC). To the
resulting solution of in situ generated azadiene (22) in dry toluene
at 90 ꢁC were added ethyl 3-trimethylsiloxy-2-butenoate (23,
1:1.4 mol), and triethylamine (0.25 ml, excess) and Pd(OAc)2 (5–
10 mol %). The heating of the mixture was continued at 90 ꢁC, till
the completion of reaction as observed by TLC and formed benzo-
indolizines (9a,d,g) were isolated through column chromatography
(silica gel 60–120 mesh, eluent hexane/EtOAc 9.5:0.5), further
elution afforded an intangible mass.
molecules have been optimized at B3LYP/6-31G level. All of them
*
were found to be minimum on the potential energy surface with
zero imaginary frequency. Global reactivity indexes were calculated
using the working equations available in the literature. Local re-
activity indices, Fukui functions, have been calculated using the
DMOL program implemented in Cerius2 package employing
Hershfeld populations scheme.
Table 6
All the benzoindolizines were obtained as red and orange red
crystalline compounds, recrystallized from CCl4/hexane (1:9).
Product yields and reaction times for the formation of benzoindolizines (9a,d,g)
S. no.
X
Benzoindolizines
% Yield
4.3.1. 1-Ethoxycarbonyl-3-(20-hydroxybenzoyl)-benzo[b]-
indolizine (9a)
Red needles (CCl4/hexane, 1:9); mp 114–115 ꢁC; yield (35%);
Rf¼0.54 (CHCl3/hexane, 9:1); IR (KBr): nmax 3060, 3015, 1715, 1624,
(reaction time, h)
1
2
3
H
CH3
Cl
9a
9d
9g
27 (15)
34 (12)
25 (17)

4600
A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
O
O
Me3SiO
O
X
+
Et
N
O
I
(23)
[4+2]
cycloaddition
X = H, Me, Cl
(22)
O
O
X
N
I
Base
-Me3SiOH
Base
-Me3SiOH
OSiMe3
CO2Et
O
O
O
O
X
X
X
-H2O
-H2O
N
N
N
I
I
I
O
O
OH
CO2Et
CO2Et
CO2Et
H'
H
-H2O
Pd(OAc)2, Et3N
Toluene
OH
X
O
O
X
N
N
H
I
O
EtO2C
CO2Et
CO2Et
Pd(OAc)2, Et3N
Toluene
N
O
X
X = H, Me, Cl
HO
(9a,d,g)
Scheme 8.
1600, 1483, 1458, 1422, 1352, 1333, 1304, 1288, 1265, 1213,
1198 cmꢀ1 1H NMR (200 MHz, CDCl3):
analysis calcd (%) for C23H19NO4 (373.13): C 73.98, H 5.13, N 3.75.
Found C 73.38, H 5.03, N 3.67.
;
d
¼1.41 (t, J¼7.11 Hz, 3H),
4.40 (q, J¼7.11 Hz, 2H), 6.88 (t, J¼7.53 Hz, 1H), 7.03 (d, J¼8.24 Hz,
1H), 7.25–7.51 (m, 4H), 7.63 (dd, J¼1.35 and 7.91 Hz, 1H), 7.76 and
7.80 (overlapping doublets, J¼7.62 and 8.02 Hz, 1H each), 8.11 (s,
4.3.3. 1-Ethoxycarbonyl-3-(20-hydroxybenzoyl)-10-ethyl-
benzo[b]indolizine (9c)
1H), 8.93 (s, 1H), 11.47 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼14.4,
Red needles (CCl4/hexane, 1:4); mp 68–69 ꢁC; yield (60%);
Rf¼0.73 (CHCl3/hexane, 9:1); IR (KBr): nmax 3052, 1726, 1632, 1607,
61.5, 97.9, 110.6, 117.5, 118.8, 119.1, 119.3, 120.1, 121.6, 121.9, 125.2,
128.0, 130.5, 131.3, 131.9, 132.4, 133.9, 136.2, 162.6, 164.6, 195.1; MS
(70 eV, EI): m/z: 360 (Mþþ1), 359 (Mþ); elemental analysis calcd
(%) for C22H17NO4 (359.12): C 73.53, H 4.77, N 3.90. Found: C 73.34,
H 4.68, N 3.80.
1529,1487, 1427, 1222, 1029 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
¼1.29 (t, J¼7.40 Hz, 3H), 1.46 (t, J¼7.11 Hz, 3H), 3.08 (q, J¼7.40 Hz,
2H), 4.46 (q, J¼7.11 Hz, 2H), 6.94 (t, J¼7.54 Hz, 1H), 7.09 (d,
J¼8.30 Hz, 1H), 7.37–7.52 (m, 4H), 7.63 (overlapping dd and s, 1H
each), 7.83 (d, J¼7.74 Hz, 1H), 8.92 (s, 1H), 11.50 (s, 1H); 13C NMR
4.3.2. 1-Ethoxycarbonyl-3-(20-hydroxybenzoyl)-10-methyl-
benzo[b]indolizine (9b)
(50 MHz, CDCl3):
d
¼14.5, 15.3, 18.1, 61.5, 110.0, 112.0, 116.3, 118.6,
118.7, 119.4, 119.5, 122.0, 123.1, 124.6, 125.4, 127.0, 130.2, 131.3, 131.5,
133.6, 135.7, 162.6, 165.8, 195.3; MS (70 eV, EI): m/z: 388 (Mþþ1),
387 (Mþ); elemental analysis calcd (%) for C24H21NO4 (387.15): C
74.40, H 5.46, N 3.62. Found C 74.23, H 5.37, N 3.54.
Red needles (CCl4/hexane, 1:9); mp 123–124 ꢁC; yield (55%);
Rf¼0.68 (CHCl3/hexane, 9:1); IR (KBr): nmax 3068, 1720, 1628, 1609,
1530, 1483, 1428, 1230, 1028 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
¼1.44 (t, J¼7.16 Hz, 3H), 2.55 (s, 3H), 4.45 (q, J¼7.16 Hz, 2H), 6.98 (t,
J¼7.60 Hz, 1H), 7.09 (d, J¼8.28 Hz, 1H), 7.37–7.52 (m, 4H), 7.68–7.86
4.3.4. 1-Ethoxycarbonyl-3-(20-hydroxy-50-methyl-benzoyl)-
benzo[b]indolizine (9d)
(m, 3H), 8.93 (s, 1H), 11.50 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
¼10.6, 14.4, 61.4, 105.1, 110.2, 116.4, 118.7, 118.9, 119.4, 119.6, 121.1,
Red needles (CCl4/hexane, 1:9); mp 160–162 ꢁC; yield (32%);
Rf¼0.58 (CHCl3/hexane, 9:1); IR (KBr): nmax 2924, 2854, 1713, 1628,
123.3, 124.7, 125.7, 128.3, 130.0, 131.5, 132.3, 135.8, 162.7, 165.8,
195.0; MS (70 eV, EI): m/z: 374 (Mþþ1), 373 (Mþ); elemental
1543, 1458, 1365, 1311, 1288, 1257, 1196 cmꢀ1 1H NMR (300 MHz,
;

A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4601
CDCl3):
d
¼1.49 (t, J¼7.2 Hz, 3H), 2.33 (s, 3H), 4.48 (q, J¼7.2 Hz, 2H),
4.3.9. 1-Ethoxycarbonyl-3-(20-hydroxy-50-chloro-benzoyl)-10-
7.01 (d, J¼8.4 Hz, 1H), 7.33–7.50 (m, 5H), 7.86 and 7.89 (overlapping
ethyl-benzo[b]indolizine (9i)
doublets, J¼9.3 and 8.7 Hz, 2H), 8.21 (s, 1H), 9.01 (s, 1H), 11.38 (s,
Red needles (CCl4/hexane, 1:9); mp 136–138 ꢁC; yield (50%);
1H); 13C NMR (50 MHz, CDCl3):
d
¼14.5, 20.6, 61.2, 97.9, 110.5, 117.5,
Rf¼0.65 (CHCl3/hexane, 9:1); IR (KBr): nmax 3063, 1720, 1620, 1527,
118.7, 119.0, 119.9, 121.7, 121.8, 125.1, 127.9, 128.1, 130.5, 131.3, 131.5,
132.4, 133.7, 137.0, 160.8, 164.3, 195.5; MS (ESI): m/z: 396.0
(MþNa)þ; elemental analysis calcd (%) for C23H19NO4 (373.13): C
73.98, H 5.13, N 3.75. Found C 73.67, H 5.08, N 3.69.
1458, 1419, 1311, 1265, 1234, 1188, 1142 cmꢀ1 1H NMR (300 MHz,
;
CDCl3):
d
¼1.29 (t, J¼7.35 Hz, 3H), 1.47 (t, J¼7.05 Hz, 3H), 3.07 (q,
J¼7.4 Hz, 2H), 4.46 (q, J¼7.1 Hz, 2H), 7.05 (d, J¼8.7 Hz, 1H), 7.24 (s,
1H), 7.30–7.50 (m, 2H), 7.70 (dd, J¼1.5 and 2.7 Hz, 2H), 7.84 (t,
J¼9.15 Hz, 2H), 8.92 (s, 1H), 11.37 (s, 1H); 13C NMR (75 MHz, CDCl3):
4.3.5. 1-Ethoxycarbonyl-3-(20-hydroxy-50-methyl-benzoyl)-10-
methyl-benzo[b]indolizine (9e)
d
¼14.4, 15.4, 18.2, 61.7, 110.4, 112.7, 115.9, 119.8, 120.2, 120.4, 122.5,
123.6, 123.7, 124.9, 125.1, 130.4, 130.6, 132.9, 133.9, 134.9, 135.6,
161.0, 165.7, 194.2; MS (ESI): m/z: 444.5 (MþNa)þ; elemental
analysis calcd (%) for C24H20ClNO4 (421.11): C 68.33, H 4.78, N 3.32.
Found C 68.16, H 4.71, N 3.23.
Red needles (CCl4/hexane, 1:9); mp 180–181 ꢁC; yield (49%);
Rf¼0.64 (CHCl3/hexane, 9:1); IR (KBr): nmax 3062, 1728, 1635, 1574,
1543, 1458, 1319, 1296, 1265, 1227 cmꢀ1 1H NMR (200 MHz,
;
CDCl3):
d
¼1.45 (t, J¼7.15 Hz, 3H), 2.35 (s, 3H), 2.58 (s, 3H), 4.50 (q,
J¼7.14 Hz, 2H), 7.05 (d, J¼8.44 Hz, 1H), 7.37–7.54 (m, 4H), 7.82–7.89
4.3.10. 1-Ethoxycarbonyl-3-(20-hydroxy-50-fluoro-benzoyl)-10-
methyl-benzo[b]indolizine (9j)
(m, 3H), 8.94 (s, 1H), 11.37 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
¼10.4, 14.2, 20.5, 61.6, 105.1, 110.2, 116.4, 118.4, 119.0, 119.5, 122.1,
Red needles (CCl4/hexane, 1:9); mp 122–124 ꢁC; yield (40%);
Rf¼0.73 (CHCl3/hexane, 9:1); IR (KBr): nmax 3064, 1710, 1598, 1478,
122.9, 124.6, 125.7, 127.7, 128.1, 129.8, 131.4, 132.0, 133.6, 136.9,
160.2, 165.9, 195.5; MS (ESI): m/z: 410.0 (MþNa)þ; elemental
analysis calcd (%) for C24H21NO4 (387.15): C 74.40, H 5.46, N 3.62.
Found C 74.28, H 5.41, N 3.56.
1466, 1420, 1266, 1227, 1188 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.46 (t, J¼7.2 Hz, 3H), 2.53 (s, 3H), 4.46 (q, J¼7.2 Hz, 2H), 7.06 (d,
J¼9.0 Hz, 1H), 7.23–7.30 (m, 1H), 7.33 (s, 1H), 7.39(sd, J¼7.15 Hz, 1H),
7.49 (t, J¼7.5 Hz, 1H), 7.73 (s, 1H), 7.79 and 7.84 (overlapping dou-
blets, J¼8.1 Hz each, 1H each), 8.90 (s, 1H), 11.20 (s, 1H); 13C NMR
4.3.6. 1-Ethoxycarbonyl-3-(20-hydroxy-50-methyl-benzoyl)-10-
ethyl-benzo[b]indolizine (9f)
(75 MHz, CDCl3):
d¼10.5, 14.3, 61.7, 105.7, 110.3, 115.9, 116.4, 116.7,
Orange red needles (CCl4/hexane, 1:9); mp 116–118 ꢁC; yield
(59%); Rf¼0.69 (CHCl3/hexane, 9:1); IR (KBr): nmax 3055, 1720, 1628,
118.9, 119.0, 119.6, 119.9, 120.1, 122.3, 123.1, 123.3, 123.4, 124.9, 125.1,
127.7, 130.1, 132.2, 133.8, 153.2, 156.4, 158.6, 160.3, 165.7, 194.4; MS
(ESI): m/z: 414.1 (MþNa)þ; elemental analysis calcd (%) for
C23H18FNO4 (391.12): C 70.58, H 4.64, N 3.58. Found C 70.46, H 4.57,
N 3.52.
1589, 1466, 1312, 1288, 1227 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
d
¼1.31 (t, J¼7.42 Hz, 3H), 1.46 (t, J¼7.13 Hz, 3H), 2.33 (s, 3H), 3.10 (q,
J¼7.42 Hz, 2H), 4.48 (q, J¼7.12 Hz, 2H), 7.03 (d, J¼8.44 Hz, 1H), 7.35–
7.56 (m, 4H), 7.78 (s, 1H), 7.87 (fused d, J¼8.24 Hz, 2H), 8.93 (s, 1H),
11.35 (s,1H); 13C NMR (75 MHz, CDCl3):
d
¼14.2,15.2,18.0, 20.5, 61.6,
4.3.11. 1-Ethoxycarbonyl-3-(20-hydroxy-50-fluoro-benzoyl)-10-
ethyl-benzo[b]indolizine (9k)
110.3, 111.9, 116.3, 118.3, 119.0, 119.5, 122.0, 123.0, 124.5, 125.5, 126.9,
128.0, 130.1, 131.1, 131.3, 133.6, 136.8, 160.2, 166.1, 195.4; MS (ESI):
m/z: 424.05 (MþNa)þ; elemental analysis calcd (%) for C25H23NO4
(401.16): C 74.79, H 5.77, N 3.49. Found C 74.48, H 5.64, N 3.43.
Red needles (CCl4/hexane, 1:9); mp 143–145 ꢁC; yield (45%);
Rf¼0.76 (CHCl3/hexane, 9:1); IR (KBr): nmax 3078, 1736, 1651, 1589,
1481, 1419, 1265, 1188, 1149 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.22 (t, J¼7.5 Hz, 3H), 1.39 (t, J¼7.05 Hz, 3H), 3.01 (q, J¼7.4 Hz,
4.3.7. 1-Ethoxycarbonyl-3-(20-hydroxy-50-chloro-benzoyl)-
benzo[b]indolizine (9g)
2H), 4.40 (q, J¼7.0 Hz, 2H), 7.01 (d, J¼9.0 Hz, 1H), 7.17–7.46 (m, 4H),
7.65 (s, 1H), 7.77 and 7.80 (overlapping doublets, J¼0.9, 7.2 Hz, 2H),
Red needles (CCl4/hexane, 1:9); mp 144–145 ꢁC; yield (29%);
Rf¼0.59 (CHCl3/hexane, 9:1); IR (KBr): nmax 3078, 2978, 1713,
8.86 (s, 1H), 11.13 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼14.2, 15.3,
18.1, 61.5, 110.4, 112.4, 115.9, 116.3, 116.6, 118.9, 119.6, 120.0, 122.3,
122.7, 123.3, 124.8, 125.0, 126.9, 130.2, 131.4, 140.5, 158.6, 168.9,
194.2; MS (ESI): m/z: 428.1 (MþNa)þ; elemental analysis calcd (%)
for C24H20FNO4 (405.14): C 71.10, H 4.97, N 3.45; Found C 70.86, H
4.91, N 3.37.
1620, 1458, 1311, 1257, 1219 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.49 (t, J¼7.05 Hz, 3H), 4.49 (q, J¼7.1 Hz, 2H), 7.08 (d, J¼8.7 Hz,
1H), 7.40–7.51 (m, 4H), 7.69 (d, J¼2.4 Hz, 1H), 7.86 and 7.91
(overlapping doublets, J¼7.5 and 8.4 Hz, 2H), 8.17 (s, 1H), 9.01 (s,
1H), 11.41 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
¼14.4, 61.4, 98.4,
110.6, 116.9, 119.9, 120.4, 120.9, 121.7, 122.1, 123.8, 125.3, 127.4,
130.6, 130.7, 131.4, 132.3, 134.0, 135.9, 161.1, 164.3, 194.6; MS (ESI):
m/z: 416.18 (MþNa)þ; elemental analysis calcd (%) for
C22H16ClNO4 (393.08): C 67.10, H 4.10, N 3.56. Found C 66.82, H
4.03, N 3.50.
4.3.12. 2-(Carboethoxymethyl)indole (16a)
Viscous oil; yield (5%); Rf¼0.64 (CHCl3/hexane, 9:1); IR (KBr):
nmax 1732,1532,1555,1537,1508,1488,1468,1458,1450,1432,1409,
1378, 1355, 1242 cmꢀ1
;
1H NMR (200 MHz, CDCl3):
d
¼1.28 (t,
J¼7.07 Hz, 3H), 3.82 (s, 2H), 4.20 (q, J¼7.07 Hz, 2H), 6.35 (s, 1H),
7.01–7.50 (m, 4H), 8.68 (s, 1H, NH); 13C NMR (50 MHz, CDCl3):
4.3.8. 1-Ethoxycarbonyl-3-(20-hydroxy-50-chloro-benzoyl)-10-
methyl-benzo[b]indolizine (9h)
Red needles (CCl4/hexane, 1:9); mp 144–146 ꢁC; yield (45%);
Rf¼0.63 (CHCl3/hexane, 9:1); IR (KBr): nmax 3055, 1728, 1635, 1574,
1512, 1465, 1311, 1288, 1227, 1188 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
¼14.1, 33.9, 61.3, 101.7, 110.7, 119.7, 120.0, 121.6, 126.4, 132.8, 135.8,
170.6; MS (70 eV, EI): m/z: 204 (Mþþ1), 203 (Mþ); elemental
analysis calcd (%) for C12H13NO2 (203.09): C 70.92, H 6.45, N, 6.89.
Found C 70.78, H 6.42, N 6.86.
d
¼1.47 (t, J¼7.05 Hz, 3H), 2.55 (s, 3H), 4.46 (q, J¼7.1 Hz, 2H), 7.06 (d,
4.3.13. 2-(Carboethoxymethyl)-3-methylindole (16b)
J¼9.0 Hz, 1H), 7.38–7.52 (m, 3H), 7.69 (d, J¼2.4 Hz, 1H), 7.75 (d,
J¼1.5 Hz, 1H), 7.81 and 7.86 (overlapping doublets, J¼7.8 Hz each,
Viscous oil; yield (w1%); Rf¼0. 71 (CHCl3/hexane, 9:1); IR (KBr):
nmax 1732,1532,1555,1537,1508,1488,1468,1458,1450,1432,1409,
2H), 8.93 (s, 1H), 11.37 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼10.6,
1378, 1355, 1242 cmꢀ1
;
1H NMR (200 MHz, CDCl3):
d
¼1.24 (t,
14.4, 61.6, 105.9, 110.3, 115.9, 119.7, 120.1, 120.4, 122.5, 123.3, 123.7,
124.9, 125.3, 127.7, 130.2, 130.6, 132.3, 133.9, 135.6, 161.0, 165.5,
194.2; MS (ESI): m/z: 429.97 (MþNa)þ; elemental analysis calcd (%)
for C23H18ClNO4 (407.09): C 67.73, H 4.45, N 3.43. Found C 67.52, H
4.41, N 3.41.
J¼7.10 Hz, 3H), 2.48 (s, 3H), 3.82 (s, 2H), 4.20 (q, J¼7.10 Hz, 2H),
7.09–7.46 (m, 3H), 7.49 (d, J¼7.30 Hz, 1H), 8.71 (s, 1H, NH); MS
(70 eV, EI): m/z: 218 (Mþþ1), 217 (Mþ); elemental analysis calcd (%)
for C13H15NO2 (217.11): C 71.87, H 6.96, N 6.45. Found C 71.59,
H 6.89, N 6.38.

4602
A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4.3.14. 2-(Carboethoxymethyl)-3-ethylindole (16c)
1483, 1431, 1342, 1226, 1034 cmꢀ1 1H NMR (200 MHz, CDCl3):
;
Viscous oil; yield (<1%); Rf¼0. 74 (CHCl3/hexane, 9:1); IR (KBr):
d
1.89 (s, 3H), 6.95 (t, J¼7.61 Hz, 1H), 7.14 (d, J¼8.20 Hz, 1H), 7.24–
nmax 1732,1572,1555,1537,1508,1488, 1468,1458,1450, 1432,1409,
7.62 (m, 8H), 7.72 and 7.68 (overlapping doublets, J¼7.97 and
1378, 1355, 1242 cmꢀ1
;
1H NMR (200 MHz, CDCl3):
d¼1.16 (t,
7.63 Hz, 2H), 7.90–7.97 (m, 2H), 9.01 (s, 1H), 11.57 (s, 1H); 13C NMR
J¼7.43 Hz, 3H), 1.25 (t, J¼7.12 Hz, 3H), 2.64 (q, J¼7.43 Hz, 2H), 3.66
(s, 2H), 4.16 (q, J¼7.12 Hz, 2H), 6.99–7.30 (m, 3H), 7.43 (d, J¼7.25 Hz,
1H), 8.71 (s, 1H, NH); MS (70 eV, EI): m/z: 232 (Mþþ1), 231 (Mþ);
elemental analysis calcd (%) for C14H17NO2 (231.13) C 72.70, H 7.41,
N 6.06. Found C 72.52, H 7.34, N 5.98.
(50 MHz, CDCl3): d 28.9, 107.1, 110.5, 116.3, 118.8, 119.9, 120.1, 122.6,
123.7, 125.3, 126.9, 127.2, 127.4, 127.5, 128.5, 129.4, 129.8, 130.4,
131.6, 132.2, 133.5, 135.9, 162.7, 195.5, 198.9; MS (EI): m/z: 405 (Mþ);
elemental analysis calcd (%) for C27H19NO3 (405.14): C 79.98, H 4.72,
N 3.45. Found C 79.84, H 4.65, N 3.39.
4.4. General procedure for the reaction of C-(4-oxo-
4H[1]benzopyran-3-yl)-N-phenylnitrone (7) with allenic
ketones (18)
Acknowledgements
Use of NMR facilities provided by the Department of Science and
Technology, Government of India, at Department of Chemistry,
Guru Nanak Dev University, Amritsar, is gratefully acknowledged.
A solution of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenylnitrone
(7, 200 mg) and allenic ketones (18, 1.5 mol equiv) in 20 mL dry
benzene was stirred at ambient temperature under nitrogen at-
mosphere till the completion of reaction (TLC). Benzene was re-
moved under vacuum and the benzoindolizines (19a–d) were
purified by column chromatography (silica gel, 60–120 mesh, elu-
ent hexane/ EtOAc 9.5:0.5). Further elution with increasing con-
centration of EtOAc in hexane afforded the rearranged product (17)
of nitrones (30–45%).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.076.
References and notes
4.4.1. 1-Acetyl-3-(20-hydroxybenzoyl)benzo[b]indolizine (19a)
Red needles (CCl4/hexane, 1:4); mp 144–145 ꢁC; yield (34%);
Rf¼0.63 (CHCl3/hexane, 9:1); IR (KBr): nmax 1684, 1632, 1611, 1601,
1530, 1487, 1431, 1226, 1034, 936 cmꢀ1; 1H NMR (200 MHz, CDCl3):
1. (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006; (b) Bunce, R. A. Tetrahedron 1995, 51, 13103; (c)
Tietze, L. F. Chem. Rev. 1996, 96, 115; (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131; (e) Tietze, L. F. Chem. Ind. 1995, 453; (f) Waldmann, H. In
Domino Reaction in Organic Synthesis; Waldmann, H., Ed.; VCH: Weinheim,
1995; pp 193–202; (g) Hall, N. Science 1994, 266, 32.
2. (a) Caruthers, W. R. Cycloadditions in Organic Synthesis; Pergamon: London, 1990,
Chapter 6, p 269; (b) Black, D. C. S.; Cozier, R. F.; Davis, V. C. Synthesis 1975, 205; (c)
Synthetic Applications of 1,3 Dipolar Cycloadditions Chemistry Towards Heterocycles
and Natural Products; Padwa, A., Taylor, E. C., Pearson, W. H., Eds.; Wiley Inter-
science: New York, NY, 2002; (d) Paquette, L. A. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapter 3; (e)
Frederickson, M. Tetrahedron 1997, 53, 403; (f) Gothelf, K. V.; Jorgenson, K. A. Chem.
Rev. 1998, 98, 863; (g) Padwa, A.; Schoffstall, A. M. In Advances in Cycloaddition;
Curran, D., Ed.; JAI: Greenwich, CT, 1990; p 2.
d
¼2.70 (s, 3H), 6.99 (t, J¼7.64 Hz, 1H), 7.14 (d, J¼8.34 Hz, 1H), 7.30–
7.54 (m, 4H), 7.72 (overlapping d and s, 1H each), 7.82 (d, J¼7.98 Hz,
1H), 8.12 (s,1H), 9.00 (s,1H),11.48 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
¼26.9, 99.4, 110.5, 116.9, 118.7, 118.9, 120.7, 121.8, 122.1, 125.2, 127.5,
128.4, 129.7, 130.2, 131.6, 133.2, 134.5, 136.2, 162.5, 195.7, 195.9; MS
(70 eV, EI): m/z: 329 (Mþ); elemental analysiscalcd (%)for C21H15NO3
(329.11): C 76.58, H 4.59, N 4.25; Found C 76.46, H 4.51, N 4.21.
3. (a) Simonsen, K. B.; Bayon, P.; Hazell, R. G.; Goethelf, K. V.; Jorgensen, K. A. J. Am.
Chem. Soc. 1999, 121, 3845; (b) Tamura, O.; Gotanda, K.; Yoshino, J.; Morita, Y.;
Terashima, R.; Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.; Ishibashi, H.;
Sakamota, M. J. Org. Chem. 2000, 65, 8544; (c) Aurich, H. G.; Geiger, M.; Gentes,
C.; Harms, K.; Koster, H. Tetrahedron 1998, 54, 3181; (d) Goethelf, K. V.; Hazell,
R. G.; Jorgenson, K. A. J. Org. Chem. 1998, 63, 5483; (e) Chiacchio, U.; Corsaro, A.;
Iannazzo, D.; Piperno, A.; Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 2002, 67, 4380; (f) Knobloch, K.; Eberbach, W. Org. Lett. 2000, 2, 1117; (g)
Long, A.; Baldwin, S. W. Tetrahedron Lett. 2001, 42, 5343; (h) Voinov, M. A.;
Grigor’ev, I. A. Tetrahedron Lett. 2002, 43, 2445; (i) Merino, P.; Anoro, S.; Franco,
S.; Merchan, F. L.; Tejero, T.; Tunon, V. J. Org. Chem. 2000, 65, 1590; (j) Dagoneau,
C.; Tomassini, A.; Denis, J.-N.; Vallee, Y. Synthesis 2001, 150; (k) Mernyak, E.;
Benedek, G.; Schneider, G.; Wolfling, J. Synlett 2005, 637; (l) Kanemasa, S.;
Ueno, N.; Shirahase, M. Tetrahedron Lett. 2002, 43, 657; (m) Singh, R.; Bhella, S.
S.; Sexana, A. K.; Shanmugavel, M.; Faruk, A.; Ishar, M. P. S. Tetrahedron 2007, 63,
2283; (n) Singh, G.; Ishar, M. P. S.; Gupta, V.; Singh, G.; Kalyan, M.; Bhella, S. S.
Tetrahedron 2007, 63, 4773; (o) Aouadi, K.; Vidal, S.; Msaddek, M.; Praly, J.-P.
Synlett 2006, 3299; (p) Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P. Syn-
thesis 2007, 3399; (q) Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P. Tetra-
hedron: Asymmetry 2008, 19, 1145.
4. (a) Padwa, A.; Bullock, W. H.; Kline, D. N.; Perumattam, J. J. Org. Chem. 1989, 54,
2862; (b) Padwa, A.; Kline, D. N.; Norman, B. H. J. Org. Chem. 1989, 54, 810.
5. Ishar, M. P. S.; Kumar, K. Tetrahedron Lett. 1999, 40, 175.
6. Two alkaloids containing an indolizine nucleus within a fused ring system have
been reported: Flitsch, W. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Ress, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 476.
7. (a) Weidner, C. H.; Wadsworth, D. H.; Bender, S. L.; Beltman, D. J. J. Org. Chem.
1989, 54, 3660; (b) Jaung, J. Y.; Jung, Y. S. Bull. Korean Chem. Soc. 2003, 24, 1565;
(c) Rotaru, A. V.; Druta, I. D.; Oeser, T.; Mu¨ller, T. J. J. Helv. Chim. Acta 2005, 88,
1798; (d) Saeva, F. D.; Luss, H. R. J. Org. Chem. 1988, 53, 1804; (e) Delattre, F.;
Woisel, P.; Surpateanu, G.; Cazier, F.; Blach, P. Tetrahedron 2005, 61, 3939; (f) Hu,
J.; Jiang, X.; He, T.; Zhou, J.; Hu, Y.; Hu, H. J. Chem. Soc., Perkin Trans. 1 2001, 1820;
(g) Sonnenschein, H.; Kreher, T.; Grundemann, E.; Kruger, R. P.; Kunath, A.;
Zabel, V. J. Org. Chem. 1996, 61, 710; (h) Kel’in, A. V.; Sromek, A. W.; Gevorgyan,
V. J. Am. Chem. Soc. 2001, 123, 2074.
8. (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Stirton, C. H.; Carter, D.; Hegarty, M. P.;
Bell, E. A. Phytochemistry 1988, 27, 1403; (b) Molyneux, R. J.; James, L. F. Science
1982, 216, 190; (c) Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H.
Eur. Pat. Appl. EP 519353, 1992; Chem. Abstr. 1993, 118, 212886y; (d) King, F. D.;
Gaster, L. M.; Joiner, G. F. PCT Int. Appl. WO 9308187, 1993; Chem. Abstr. 1993,
4.4.2. 1-p-Methoxybenzylcarbonyl-3-(20-hydroxybenzoyl)-
benzo[b]indolizine (19b)
Red needles (CCl4/hexane, 1:3); mp 178–179 ꢁC; yield (28%);
Rf¼0.57 (CHCl3/hexane, 9:1); IR (KBr): nmax 3099, 1677, 1632, 1602,
1528, 1486, 1222, 1158, 1027 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d¼3.80 (s, 3H), 4.32 (s, 2H), 6.90 (d, J¼8.80 Hz, 2H), 6.94 (t,
J¼7.08 Hz, 1H), 6.99 (d, J¼8.19 Hz, 1H), 7.15 (d, J¼8.59 Hz, 2H),
7.43–7.55 (m, 3H), 7.62 (dd, J¼8.70 & 1.48 Hz, 1H), 7.76 (over-
lapping d and s, 1H each), 7.88 (t, J¼7.67 Hz, 1H), 8.21 (d,
J¼1.04 Hz, 1H), 9.05 (s, 1H), 11.49 (s, 1H); MS (70 eV, EI): m/z: 436
(Mþþ1), 435 (Mþ), 369, 355, 112, 58; elemental analysis calcd (%)
for C28H21NO4 (435.15): C 77.23, H 4.86, N 3.22. Found C 77.16, H
4.81, N 3.17.
4.4.3. 1-Benzylcarbonyl-3-(20-hydroxybenzoyl)benzo[b]-
indolizine (19c)
Red needles (CCl4/hexane, 1:3); mp 161–162 ꢁC; yield (29%);
Rf¼0.62 (CHCl3/hexane, 9:1); IR (KBr): nmax 3068 (OH), 1675, 1628,
1602,1525,1482,1427,1218, 1162, 1030, 931 cmꢀ1; 1H NMR (300 MHz,
CDCl3):
d
4.38 (s, 2H), 6.98 (t, J¼7.86 Hz, 1H), 7.15 (d, J¼8.88 Hz, 1H),
7.28–7.58 (m, 8H), 7.60 (dd, J¼8.80 and 1.23 Hz, 1H), 7.73 (s, 1H), 7.88
(overlapping ds, Jw7.31 Hz, 2H), 8.21 (d, J¼1.28 Hz, 1H), 9.05 (s, 1H),
11.49 (s, 1H); MS (EI): m/z: 406 (Mþþ1), 405 (Mþ), 356, 355, 284, 283,
269, 241, 58; elemental analysis calcd (%) for C27H19NO3 (405.14): C
79.98, H 4.72, N 3.45. Found C 79.76, H 4.67, N 3.40.
4.4.4. 1-Acetyl-3-(20-hydroxybenzoyl)-10-phenyl-
benzo[b]indolizine (19d)
Red needles (CCl4/hexane, 1:3); mp 201–202 ꢁC; yield 42%;
Rf¼0.69 (CHCl3/hexane, 9:1); IR (KBr): nmax 1696, 1632, 1611, 1530,

A. Kapur et al. / Tetrahedron 65 (2009) 4593–4603
4603
119, 160281; (e) Harrell, W. B.; Doerge, R. F. J. Pharm. Sci. 1967, 56, 225; (f)
Harrell, W. B. J. Pharm. Sci. 1970, 59, 275.
M. H. J. Med. Chem. 2008, 51, 4708 and references cited therein; (c) Nasir, A. I.;
Gundersen, L. L.; Rise, F.; Antonsen, F.; Kristensen, T.; Langhelle, B.; Bast, A.;
Custers, L.; Haenen, G. R. M. M.; Wikstrom, H. Bioorg. Med. Chem. Lett. 1998, 8,
1829; (d) Østby, O. B.; Dalhus, B.; Gundersen, L. L.; Rise, F.; Bast, A.; Haenen, G.
R. M. M. Eur. J. Org. Chem. 2000, 3763.
9. (a) Ruprecht, R. M.; Mullaney, S.; Anderson, J.; Bronson, R. J. Acquir. Immune
Defic. Syndr. 1989, 2, 149; (b) Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; De
Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987,
330, 74; (c) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S.
K.; Ramsden, N. G.; Jacob, G. S.; Radamacher, T. W. Proc. Natl. Acad. Sci. U.S.A.
1989, 86; (d) Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.;
Bushman, F. D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901.
10. (a) Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Cancer Res. 1986, 46,
5215; (b) Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R. Cancer Res. 1988,
48, 1091; (c) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002,
102, 515; (d) Pearson, W. H.; Guo, L. Tetrahedron Lett. 2001, 42, 8267; (e) Asano,
N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645; (f) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. J. Med. Chem. 1988, 31,
2097; (g) Anderson, W. K.; De Ruiter, J.; Heider, A. R. J. Org. Chem. 1985, 50, 722;
(h) Gubin, J.; Descamps, M.; Chatelain, P.; Nisato, D. Eur. Pat. Appl. EP 235111,
1987; Chem. Abstr. 1988, 109, 6405b.
13. (a) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005, 7, 4305 and references cited
therein; (b) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9, 409; (c) Smith, C. R.;
Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169; (d) Chuprakov,
S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463; (e) Yan, B.; Liu, Y. Org. Lett. 2007, 9,
4323; (f) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett. 2003, 5, 435.
14. Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett. 1998, 39, 6547.
15. The crystal data of 9f had already been submitted to The Cambridge Crystal-
lographic Data Centre (CCDC No. 285370).
16. Singh, G.; Singh, R.; Girdhar, N. K.; Ishar, M. P. S. Tetrahedron 2002, 58, 2471.
17. West, R. J. Org. Chem. 1958, 23, 1552.
18. Lang, R. W.; Hansen, H. J. Helv. Chim. Acta 1980, 63, 438.
19. (a) Kumar, K.; Kaur, S.; Ishar, M. P. S. Synlett 1999, 1237; (b) Buono, G. Synthesis
1981, 872; (c) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
20. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Mo-
rokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.7; Gaussian, Inc.:
Pittsburgh, PA, 1998.
11. (a) Gubin, J.; Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux, J.; Ros-
seels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1993, 36,
1425; (b) Gupta, S. P.; Mathur, A. N.; Nagappa, A. N.; Kumar, D.; Kumaran, S. Eur.
J. Med. Chem. 2003, 38, 867; (c) Gubin, J.; Lucchetti, J.; Mahaux, J.; Nisato, D.;
Rosseels, G.; Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1992, 35, 981; (d)
Rosseels, G.; Peiren, M.; Inion, H.; Deray, E.; Prost, M.; Descamps, M.; Bauthier,
J.; Richard, J.; Tornay, C.; Colot, M.; Claviere, M. Eur. J. Med. Chem. 1982, 17, 581;
(e) Gundersen, L. L.; Malterud, K. E.; Negussie, A. H.; Rise, F.; Teklu, S.; Østby, O.
B. Bioorg. Med. Chem. 2003, 11, 5409 and references cited therein.
˜
12. (a) Rise, F.; WikstrOm, H.; Ugland, S.; Dijkstra, D.; Gundersen, L. L.; De Boer, P.;
Bast. A.; Haenen, G.; Antonsen, F.; Liao, Y.; Nasir, A. I. PCT Int. Appl. WO 9621,
662/1996; Chem. Abstr. 1996, 125, 195681; (b) Oslund, R. C.; Cermak, N.; Gelb,