Facile synthesis of 6-aryl-5H-8-oxa-4b, 7-diaza-benzo[a]azulen-9-one derivatives, new tricyclic heterocycles

Article abstract of DOI:10.1002/jhet.5570450421

(Chemical Equation Presented) 8-Oxa-4b,7-diaza-benzo[a]azulene-9-one system, a new tricyclic heterocyclic framework is designed through a simple and convenient synthetic sequence. Its 6-aryl derivatives are synthesized starting from ethyl indole-2-carboxylate. Reaction of differently substituted phenacyl bromides with ethyl indole-2-carboxylate, treatment of the resultant N-substituted indole-2-carboxylates with hydroxylamine hydrochloride to provide corresponding oximes, subsequent ester hydrolysis followed by dehydrative cyclisation furnished the desired compounds 5 a-g.

Full text of DOI:10.1002/jhet.5570450421

Jul-Aug 2008
1083
Facile Synthesis of
6-Aryl-5H-8-oxa-4b, 7-diaza-benzo[a]azulen-9-one Derivatives,
New Tricyclic Heterocycles
Gade Srinivas Reddya, b, Cherukupally Praveena, Javvaji Rama Raoa, Kaga Mukkantib
and Padi Pratap Reddy*, a
aResearch & Development, Integrated Product Development, Dr. Reddy’s Laboratories Limited,
Survey No: 42, 45 and 46, Bachupally, Qutubullapur, RangaReddy District-500055,
Andhra Pradesh, India
bInstitute of Science and Technology, Jawaharlal Nehru Technological University,
Kukatpally, Hyderabad-500072, Andhra Pradesh, India.
E-mail: praveench@drreddys.com
Received August 17, 2007
O
O
N
N
COOC2H5
N
H
R
8-Oxa-4b,7-diaza-benzo[a]azulene-9-one system, a new tricyclic heterocyclic framework is designed
through a simple and convenient synthetic sequence. Its 6-aryl derivatives are synthesized starting from
ethyl indole-2-carboxylate. Reaction of differently substituted phenacyl bromides with ethyl indole-2-
carboxylate, treatment of the resultant N-substituted indole-2-carboxylates with hydroxylamine
hydrochloride to provide corresponding oximes, subsequent ester hydrolysis followed by dehydrative
cyclisation furnished the desired compounds 5 a-g.
J. Heterocyclic Chem., 45, 1083 (2008).
INTRODUCTION
Hydrolysis of ester function in 3a with aqueous NaOH
in ethanol smoothly yielded the N-substituted indole
carboxylic acid derivative 4a which readily underwent
acetic anhydride mediated cyclisation at room temperature
to provide 6-(p-methylphenyl)-5H-8-oxa-4b,7-diaza-
benzo[a]azulene-9-one (5a). 8-Oxa-4b,7-diaza-benzo[a]-
azulene-9-one is a new fused tricyclic heterocyclic system
hitherto unreported.
The substituted indole nucleus is found in several
natural products [1-3]. Being very important in medicinal
chemistry, its synthesis continues to attract significant
interest [4-8]. A variety of well-established classical
methods for the synthesis and functionalization of indoles
are known in the literature [9]. There are very few reports
on the reactions of indole-2-carboxylates substituted on
nitrogen with phenacyl groups [10].
To verify the generality of this synthetic sequence, we
have extended this synthetic sequence to six other
p-substituted phenacyl bromides and in all the corre-
sponding 6-aryl-5H-8-oxa-4b,7-diaza-benzo[a]-azulen-9-
one derivatives, 5b-g were obtained as final products
(Scheme). All the compounds, 2a-g, 3a-g, 4a-g and 5a-g
As part of our ongoing research work on N-substituted
indole-2-carboxylates, we became interested in the design
and synthesis of new fused tricyclic heterocyclic
compounds 5a-g. Ethyl indole-2-carboxylate (1), which
can be readily accessed from commercially available
indole-2-carboxylic acid, was chosen as the starting
material.
1
are fully characterized based on their IR, H- NMR and
Mass spectral data (Table-2).
EXPERIMENTAL
RESULTS AND DISCUSSION
The 1H and 13C NMR spectra were recorded in CDCl3 at 200 and
50 MHz, respectively, on a Varian Gemini 200 MHz FT NMR
spectrometer. The chemical shifts are reported in ꢀ ppm relative
to TMS. The FT-IR spectra were recorded in the solid state as
KBr dispersion using a Perkin–Elmer 1650 FTIR spectro-
photometer. The mass spectrum (70 eV) was recorded on a HP-
5989a LC–MS spectrometer and C, H, N analysis was done
Ethyl indole-2-carboxylate 1 was reacted with 4-methyl
phenacyl bromide in the presence of potassium carbonate
in refluxing acetone to give the N-phenacyl derivative 2a,
which on condensation with hydroxylamine hydrochloride
in ethanol in the presence of sodium acetate at reflux
temperature gave the corresponding oxime 3a.

1084
G. S. Reddy, Ch. Praveen, J. R. Rao, K. Mukkanti, P. P. Reddy
Vol 45
Scheme 1
COOC2H5
COOC2H5
O
(i)
N
(ii)
N
COOC2H5
N
OH
N
H
O
NH2OH . HCl
Br
3
1
2
R
R
R
(iii)
O
COOH
N
O
N
N
(iv)
N
OH
4
5
R
R
2,3,4,5
R
a
b
c
d
e
f
g
p-CH3
p-OCH3
p-H
p-SCH3
p-C2H5
p-Isobutyl
p-Cl
Reagents and conditions: (i) Acetone, K2CO3, reflux (ii) Ethanol, CH3COONa, reflux (iii) NaOH, ethanol, RT (iv) Acetic anhydride, RT.
Table-1
Physical and analytical data of 2a-g, 3a-g, 4a-g, 5a-g
MP
(oC)
Molecular
formula
Analyses % Calcd/Found
H
Compound
R
Yield (%)
78
C
N
2a
2b
2c
2d
2e
2f
p-CH3
p-OCH3
H
134-136
128-130
120-122
126-128
117-119
125-126
143-145
122-124
116-118
110-112
126-127
118-119
105-106
128-130
228-230
219-220
225-226
210-212
220-222
209-210
234-236
210-212
213-214
206-207
220-222
201-202
192-194
210-220
C20H19NO3
C20H19NO4
C19H17NO3
C20H19NO3S
C21H21NO3
C23H25NO3
74.75/74.61
71.20/71.12
74.25/74.10
67.97/67.83
75.20/75.11
76.01/75.89
66.77/66.62
71.41/71.32
68.17/68.00
70.79/70.86
65.20/65.15
71.98/71.92
72.99/72.87
63.96/63.87
70.12/70.14
66.66/66.57
69.38/69.24
63.51/63.44
70.79/70.67
71.98/71.87
62.11/62.00
74.47/74.38
70.58/70.47
73.90/73.88
67.06/66.93
74.98/74.86
75.88/75.79
65.71/65.59
5.96/5.87
5.68/5.57
5.58/5.49
5.42/5.36
6.31/6.24
6.93/6.82
4.72/4.65
5.99/5.88
5.72/5.64
5.63/5.54
5.47/5.35
6.33/6.24
6.92/6.84
4.80/4.74
5.23/5.11
4.97/4.86
4.79/4.87
4.74/4.66
5.63/5.55
6.33/6.24
3.99/3.87
4.86/4.77
4.61/4.54
4.38/4.31
4.38/4.29
5.30/5.21
6.06/5.97
3.57/3.48
4.36/4.24
4.15/4.14
4.56/4.47
3.96/3.87
4.18/4.15
3.85/3.76
4.10/3.94
8.33/8.25
7.95/7.86
8.69/8.58
7.60/7.52
7.99/7.88
7.40/7.33
7.85/7.76
9.09/8.97
8.64/8.56
9.52/9.45
8.23/8.15
8.69/8.61
7.99/7.88
8.52/8.45
9.65/9.56
9.15/9.04
10.14/10.12
8.69/8.58
9.20/9.11
8.43/8.36
9.02/8.95
74
75
79
p-SCH3
p-C2H5
p-Isobutyl
p-Cl
70
69
2g
3a
3b
3c
3d
3e
3f
66
79
C19H16ClNO3
C20H20N2O3
C20H20N2O4
C19H18N2O3
C20H20N2O3S
C21H22N2O3
C23H26N2O3
C19H17ClN2O3
C18H16N2O3
C18H16N2O4
C17H14N2O3
C18H16N2O3S
C19H18N2O3
C21H22N2O3
C17H13ClN2O3
C18H14N2O2
C18H14N2O3
C17H12N2O2
C18H14N2O2S
C19H16N2O2
C21H20N2O2
C17H11ClN2O2
p-CH3
p-OCH3
H
83
86
81
p-SCH3
p-C2H5
p-Isobutyl
p-Cl
86
80
75
3g
4a
4b
4c
4d
4e
4f
p-CH3
p-OCH3
H
89
86
83
81
p-SCH3
p-C2H5
p-Isobutyl
p-Cl
80
81
77
4g
5a
5b
5c
5d
5e
5f
p-CH3
p-OCH3
H
61
67
66
62
p-SCH3
p-C2H5
p-Isobutyl
p-Cl
69
62
57
5g

Jul-Aug 2008
Facile Synthesis of 6-Aryl-5H-8-oxa-4b, 7-diaza-benzo[a]azulen-9-one Derivatives
1085
Table-2
IR, Mass and 1H NMR spectral analysis for compounds 2a-g 3a-g, 4a-g, 5a-g
Compound
IR (KBr) (ꢀ/Cm-1)
Mass
(m/z)
322(M+1)
1H NMR (Solvent/ꢁ values in ppm)
2a
Aromatic(C=O)
1608
(DMSO-d6): 1.2 (t, 3H), 2.4 (s, 3H), 4.3 (q, 2H), 6.1(s, 2H), 7.14 (t, 1H), 7.34 (m, 4H),
7.36 (dd, 2H), 8.0 (d, 2H)
Ester (C=O)
1697
Aromatic (C=O)
1606
Ester (C=O)
1695
Aromatic (C=O)
1608
Ester (C=O)
1695
Aromatic (C=O)
1604
Ester (C=O)
1699
Aromatic(C=O)
1604
Ester (C=O)
1698
Aromatic(C=O)
1606
Ester (C=O)
1697
Aromatic (C=O)
1603
2b
2c
2d
2e
2f
338(M+1)
308(M+1)
354(M+1)
336(M+1)
364(M+1)
342(M+1)
(DMSO-d6): 1.3 (t, 3H), 3.8 (s, 3H), 4.2 (q, 2H), 5.9(s, 2H), 7.1 (t, 1H), 7.3 (m, 4H),
7.4 (dd, 2H), 8.1 (d, 2H)
(DMSO-d6): 1.25 (t, 3H), 4.3 (q, 2H), 6.0(s, 2H), 7.14 -8.0 (d, 2H)
(DMSO-d6): 1.2 (t, 3H), 3.1 (s, 3H), 4.3 (q, 2H), 5.8(s, 2H), 7.2 (t, 1H), 7.4 (m, 4H),
7.5 (dd, 2H), 8.0 (d, 2H)
(DMSO-d6): 1.3 (t, 3H), 1.2 (t, 3H), 2.4 (q, 2H), 4.4 (q,2H), 6.0 (s, 2H), 7.2 (t, 1H), 7.3
(m, 4H), 7.4 (dd, 2H), 8.1 (d, 2H)
(DMSO-d6): 1.1 (d, 6H), 1.4 (t, 3H), 2.3 (m, 1H), 2.6 (d, 2H), 4.3 (q, 2H), 6.2(s, 2H),
7.2 (t, 1H), 7.4 (m, 4H), 7.6 (dd, 2H), 8.1 (d, 2H)
2g
(DMSO-d6): 1.25 (t, 3H), 4.5 (q, 2H), 6.2(s, 2H), 7.2 -8.1 (m, 8H)
Ester (C=O)
1692
3a
3b
3c
3d
3e
3f
3244 (OH)
1700 (C=O)
1609 (C=N)
3238 (OH)
1704 (C=O)
1612 (C=N)
3230 (OH)
1710 (C=O)
1610 (C=N)
3240 (OH)
1708 (C=O)
1612 (C=N)
3238 (OH)
1704 (C=O)
1606 (C=N)
3233 (OH)
1704 (C=O)
1604 (C=N)
3236 (OH)
1704 (C=O)
1607 (C=N)
3526 (Acid OH)
3366(oxime-OH)
1675 (C=O)
1638 (C=N)
3520 (Acid OH)
3361 (oxime-OH)
1672 (C=O)
1634 (C=N)
3530 (Acid OH)
3350 (oxime-OH)
1669 (C=O)
1640 (C=N)
337(M+1)
353(M+1)
323(M+1)
379(M+1)
351(M+1)
389(M+1)
351 (M+1)
307(M-1)
(CDCl3): 1.2 (m, 3H), 2.2 (s, 3H), 4.7 (q, 2H), 5.65 (s, 1H), 6.0 (s, 2H), 6.9 (d, 1H),
7.0-7.8 (m, 8H)
(CDCl3): 1.3 (d, 3H), 3.6 (s, 3H), 4.4 (q, 2H), 5.5 (s, 1H), 6.9 (s, 2H), 7.0 (d, 1H), 7.3-
8.1 (m, 8H)
(CDCl3): 1.3 (m, 3H), 4.7 (q, 2H), 5.1 (s, 1H), 6.1 (s, 2H), 6.9 (d, 1H), 7.2-7.9 (m, 9H)
(CDCl3): 1.3 (d, 3H), 3.4 (s, 3H), 4.2 (q, 2H), 5.6 (s, 1H), 7.1 (s, 2H), 7.2 (d, 1H), 7.4-
8.2 (m, 8H)
(CDCl3): 1.2 (m, 3H), 1.3 (m, 3H), 2.5 (q, 2H), 4.4 (q, 2H), 5.1 (s, 1H), 6.0 (s, 2H), 7.0
(d, 2H), 7.2-7.8 (m, 8H)
(CDCl3): 1.0 (d, 6H), 2.2 (m, 1H), 2.5 (d, 2H), 4.2 (q, 2H), 4.9 (s, 1H), 6.1 (s, 2H), 7.1
(d, 2H), 7.2-7.9 (m, 8H)
3g
4a
(CDCl3): 1.25 (d, 3H), 4.2 (q, 2H), 5.0 (s, 1H), 6.1 (s, 2H), 7.0 (d, 2H), 7.0-7.8 (m, 8H)
(CDCl3+DMSO-d6): 2.2 (s, 3H), 5.7 (s, 1H), 6.1 (s, 2H), 6.8 (d, 1H), 6.9-7.6 (m, 8H)
4b
4c
323(M-1)
293(M-1)
(CDCl3+DMSO-d6): 3.7 (s, 3H), 5.2 (s, 1H), 6.0 (s, 2H), 7.0 (d, 1H), 7.2-7.9 (m, 8H)
(CDCl3+DMSO-d6): 4.8 (s, 1H), 5.9 (s, 2H), 6.7 (d, 1H), 6.9-7.7(m, 9H)

1086
G. S. Reddy, Ch. Praveen, J. R. Rao, K. Mukkanti, P. P. Reddy
Vol 45
Table 2 (continued)
Mass
(m/z)
IR (KBr) (ꢀ/Cm-1)
1H NMR (Solvent/ꢁ values in ppm)
Compound
4d
4e
4f
3521 (Acid OH)
3360 (oxime-OH)
1673 (C=O)
1632 (C=N)
3520 (Acid OH)
3361 (oxime-OH)
1672 (C=O)
1634 (C=N)
3529 (Acid OH)
3360 (oxime-OH)
1672(C=O)
349(M-1)
(CDCl3+DMSO-d6): 3.4 (s, 3H), 4.9 (s, 1H), 5.9 (s, 2H), 6.8 (d, 1H), 7.0-7.8 (m, 8H)
321(M-1)
359(M-1)
321 (M-1)
(CDCl3+DMSO-d6): 1.2 (t, 3H), 2.5 (q, 2H), 4.5 (s, 1H), 6.0 (s, 2H), 6.7 (d, 1H), 7.0-
7.9 (m, 8H)
(CDCl3+DMSO-d6): 1.1 (d, 6H), 2.2 (m, 1H), 2.45 (d, 2H) 4.6 (s, 1H), 5.9 (s, 2H), 6.7
(d, 1H), 7.0-7.9 (m, 8H)
1638(C=N)
4g
3519 (Acid OH)
3362(oxime-OH)
1671(C=O)
(CDCl3+DMSO-d6): 4.2 (s, 1H), 5.8 (s, 2H), 7.1 (d, 1H), 7.2-8.0 (m, 8H)
1634(C=N)
1716 (C=O)
1678(C=N)
5a
5b
5c
5d
5e
5f
289(M+1)
307(M+1)
275(M+1)
323(M+1)
305(M+1)
333(M+1)
311(M+1)
(CDCl3): 2.4 (s, 3H), 5.4 (s, 1H of N-CH2), 6.4 (s, 1H of N-CH2), 7.1-7.8 (m, 8H), 8.3
(d,1H)
(CDCl3): 3.8 (s, 3H), 5.45 (s, 1H of N-CH2), 6.6 (s, 1H of N-CH2), 6.9-7.7 (m, 8H),
8.3 (d, 1H)
(CDCl3): 5.5 (s, 1H of N-CH2), 6.35 (s, 1H of N-CH2), 7.2-7.9 (m, 8H), 8.3 (d, 1H)
1717 (C=O)
1675 (C=N)
1712 (C=O)
1672 (C=N)
1714 (C=O)
1677(C=N)
1713 (C=O)
1675 (C=N)
1716(C=O)
(CDCl3): 2.9 (s, 3H), 5.7 (s, 1H of N-CH2), 6.6 (s, 1H of N-CH2), 7.2-7.9 (m, 8H),
8.25 (d, 1H)
(CDCl3): 1.4 (t, 3H), 2.5 (q, 2H), 5.8 (s, 1H of N-CH2), 6.6 (s, 1H of N-CH2), 7.0-7.7
(m,8H), 8.35 (d,1H)
(CDCl3): 1.2 (d, 6H), 2.2 (m, 1H), 2.5 (d, 2H), 5.4 (s, 1H of N-CH2), 6.6 (s, 1H of N-
CH2), 7.2-7.9 (m, 8H), 8.3 (d, 1H)
1678(C=N)
1716(C=O)
5g
(CDCl3): 5.5 (s, 1H of N-CH2), 6.6 (s, 1H of N-CH2), 7.3-7.9 (m, 8H), 8.35 (d, 1H)
1676(C=N)
using Perkin-Elmer 2100. The melting points were determined
by using the capillary method on a POLMON (model MP-96)
melting point apparatus. The solvents and reagents were used
without any purification. The reactions were routinely monitored
by thin layer chromatography (TLC) on silica gel plates.
General procedure for the preparation of ethyl 1-(2-oxo-2-
aryl-ethyl)-1H-indole-2-carboxylates 2a-g. To a solution of
ethyl indole-2-carboxylate (1, 50 g, 0.264 mol) in acetone (350
mL) was added phenacyl bromide (0.264 mol), potassium
carbonate (0.528 mol) and catalytic amount of potassium
bromide and was refluxed for 4-5 hours. Acetone was stripped
off and the reaction mixture was then quenched in water and
filtered to get the crude product 2a-g which was recrystallised
from acetone to give the pure product.
General procedure for the preparation of 6-aryl-5H-8-oxa-
4b,7-diaza-benzo[a]azulen-9-one 5a-g. solution of
A
compound 4 (0.32 mol) in acetic anhydride (40 mL) was stirred
for 6 hours at ambient temperature. The reaction mixture was
quenched in ice water and extracted with methylene chloride.
The solvent was evaporated under reduced pressure and the
crude product 5 was isolated in methanol. The crude product
was recrystallised from acetone to get the pure compound 5a-g.
Conclusion. In conclusion we have described a simple and
efficient synthetic route for 8-oxa-4b,7-diaza-benzo[a]azulene-
9-one system, a new tricyclic heterocyclic framework and its 6-
aryl derivatives. Further investigations are under progress to
enlarge the scope of these heterocycles.
Acknowledgements: We thank the management of Dr.
Reddy’s Laboratories Ltd. for extending supporting to the work.
Co-operation from the project colleagues and analytical
department is highly appreciated.
General procedure for the preparation of ethyl 1-(2-
Hydroxyimino-2-aryl-ethyl)-1H-indole-2-carboxylates 3a-g.
A
mixture of ethyl 1-(2-oxo-2-aryl-ethyl)-1H-indole-2-car-
boxylate (2, 0.062 mol), hydroxylamine hydrochloride (0.187
mol) and sodium acetate (0.187 mol) was refluxed in ethanol for
30 min. The reaction mixture was quenched with ice water,
crude product 3a-g was filtered and recrystallised from ethanol.
General procedure for the preparation of 1-(2-
hydroxyimino-2-aryl-ethyl)-1H-indole-2-carboxylic acids 4a-
g. To a solution of ethyl 1-(2-hydroxyimino-2-aryl-ethyl)-1H-
indole-2-carboxylate 3 (0.074 mol) in 50 mL of ethanol was
added 300 mL of 1N sodium hydroxide solution and the mixture
was stirred at room temperature for 12 hours. After completion
of the reaction, the reaction mixture was acidified with acetic
acid to precipitate the compound 4. The crude compound was
filtered and washed with water to get the compound 4a-g.
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