Multistep synthesis of pyrido[3′,2′:4,5]pyrrolo[3,2-d][1,3] oxazin-4(5H)-one from 2-aminonicotinonitriles

Article abstract of DOI:10.3987/COM-05-10334

Pyrido[3′,2′:4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)-ones (7) were synthesized starting from 2-aminonicotinonitriles (1) through multistep synthesis involving Sandmeyer reaction, amination, Thorpe-Ziegler reaction, hydrolysis and cyclisation.

Full text of DOI:10.3987/COM-05-10334

HETEROCYCLES, Vol. 65, No. 6, 2005
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HETEROCYCLES, Vol. 65, No. 6, 2005, pp. 1415 - 1423
Received, 13th January, 2005, Accepted, 24th March, 2005, Published online, 24th March, 2005
MULTISTEP SYNTHESIS OF PYRIDO[3’,2’:4,5]PYRROLO[3,2–
d][1,3]OXAZIN-4( 5H )-ONE FROM 2–AMINONICOTINONITRILES†
Sribhashyam R. Kanth, Dravidum Maitraie, Ghojala V. Reddy, Banda Narsaiah,*
and Pamulaparty S. Rao
Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad -500007, India
Abstract - Pyrido[3’,2’:4,5]pyrrolo[3,2–d][1,3]oxazin-4(5H)-ones (7) were
synthesized starting from 2-aminonicotinonitriles (1) through multistep
synthesis involving Sandmeyer reaction, amination, Thorpe-Ziegler reaction,
hydrolysis and cyclisation.
INTRODUCTION
The pyrrolo[2,3-b]pyridines are also known as 7-azaindoles and have similar chemical properties to that of
imidazoles which form the basic skeleton of alkaloids.1 The primary interest in azaindoles is mainly based
on their use as potential antimetabolites compared to naturally occurring indole derivatives.2 The 7-
azaindoles are also considered as anti-malarial agents due to their similarity in structure with quinoline
derivatives3 and some are multidrug resistance associated specific protein ( MRP1 ) inhibitors.4 Synthesis of
7-azaindoles and fusion of another ring over 7-azaindoles in order to see the influence of additional ring
over activity is of current interest. Our continued interest on fusion of oxazine ring over furo [2,3–b]
pyridines,5 indoles6 prompted us to synthesize a number of new 7-azaindoles and fusion of 1,3-oxazine ring
over it. Thus the 2-aminonicotinonitriles (1)7 is choosen as starting material and synthesized
pyrido[3’,2’:4,5]pyrrolo[3,2–d][1,3]oxazin-4-(5H)-ones (7) via Sandmeyer reaction, amination, Thorpe-
Ziegler reaction, hydrolysis followed by cyclisation. The interesting aspect of these studies is mainly to have
trifluoromethyl group at a specific position of each molecule and its influence in altering the reactivity apart
from increasing solubility in lipid system due to its high liphophilicity. The strategies adopted in each step of
the methodology is compatible with the predicted products except in one case where alkylation of amine
resulted in dialkylation product.
†IICT communication No. 041023
*Corresponding author. Fax:+91-40-27160387, 27160757
E-mail : narsaiah@iict.res.in
RESULTS AND DISCUSSION

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HETEROCYCLES, Vol. 65, No. 6, 2005
RESULTS AND DISCUSSION
The 2-amino-4- trifluoromethyl- 6-substituted nicotinonitriles (1) on reaction with ethyl iodide under basic
conditions resulted in exclusively N-diethyl product (2), irrespective of stoichiometric quantity used and
obtained in low yield (45%). In order to have monoalkylated products, number of procedures were examined
using ethyl iodide with potassium carbonate in DMF, sodium carbonate / Cu powder in acetone, sodium
hydride in DMF and so on. In all the cases dialkylated products were formed exclusively. Therefore an
alternate strategy is applied to obtain monoalkylated products. Thus 2-amino-4-trifluoromethyl-6-substituted
nicotinonitriles (1) was reacted with sodium nitrite and 33% HCl solution at 0 0C.
The resulting diazonium salt is treated with potassium iodide solution at room temperature and gave 2-iodo-
4-trifluoromethyl-6-substituted nicotinonitriles (3). In order to see the role of substituents of the phenyl ring
in formation of products (3), the phenyl is para substituents with electron releasing methyl group, electron
withdrawing chloro group were tested, however there was no effect of substituent on yield or rate of reaction.
The iodo compounds (3) were further reacted with alkyl / arylamine which gave the corresponding N-
monoalkylated/monoarylated nicotinonitriles (4) leaving the nitrile group intact. This is due to facile
nucleophilic substitution at 2-position in pyridine ring. The yield of products with alkyl amines are
comparatively higher than with aryl amines and it is attributed to steric factors.
The 2-N-substituted aminonicotinonitriles (4) have active functional groups ortho to each other and
considered as active synthons to facilitate fusion of five membered ring and to have novel 7-azaindoles of
promising activity. Thus 2-N-substituted aminonicotinonitriles (4) were further reacted with ethyl
0
bromoacetate in DMF using potassium carbonate as base at 110 C and formed 2,3- bifunctionalised 7-
azaindole derivatives (5). The reaction involves initial alkylation of substituted amine followed by
abstraction of methylene hydrogen to generate carbanion and cyclisation on to nitrile carbon to give the
corresponding azaindole derivatives (5) in single step. This type of cyclisation is also known as Thorpe –
Ziegler reaction. The compounds (5) have active functional groups ortho to each other and are further
utilized to build up oxazine ring. Compounds (5) are subjected to alkaline hydrolysis to afford the acids (6).
The presence of amino and carboxylic acid functional groups ortho to each other in compound (6) is
conveniently utilized for the formation of oxazine ring. Thus compounds (6) on reaction with acetic
anhydride/ trifluoroacetic anhydride gave the corresponding pyrido[3’,2’:4,5]pyrrolo[3,2–d][1,3]oxazin
(5H )-ones (7) in high yields. The reaction is initially N-acylation followed by cyclisation. The reactions are
drawn in Scheme 1and 2.

HETEROCYCLES, Vol. 65, No. 6, 2005
1417
CF3
CF3
CF3
CN
CN
I
CN
NaNO2
/ KI / HCl
R'NH2
CH3CN / 0 - 5 0
C
R
N
NH2
R
N
R
N
NH
R'
1
4
3
reflux
C2H5I / K2CO3 /
Acetone
2) R = C6H5
3a)
4a) R = C6H5, R' = CH3 4b) R = C6H5, R' = C2H5
R = C6H5
3c) R = p-CH3-C6H4
3b) R = p-Cl-C6H4
CF3
4c) R = C6H5, R' = CH2Ph
CN
N
4d) R = C6H5 , R' = C6H5
4e) R = p-Cl-C6H4 , R' = C6H5 4f) R = p-CH3-C6H4 ,
R' = C6H5
C2H5
R
N
Scheme- 1
C2H5
2
CF3
CF3
NH2
CF3
CN
CN
K2CO3 / DMF
COOEt
_
+
BrCH2COOC2H5
NaI / 110 0 C / 8 h
N
R
N
N
COOEt
R
N
R
N
NHR'
R'
5
R'
4
R''
O
CF3
CF3
N
NH2
(R"CO) 2O
30% KOH Solution
reflux
COOH
O
N
N
2 h
reflux
/
R
N
R
N
R'
R'
7
6
5a) R = C6H5 , R' = CH2C6H5
6a ) R = C6H5, R' = CH2C6H5
5 b) R = C6H5,
5c) R = p-Cl-C6H4 , R' = C6H5
5d) R = p-CH3-C6H4, R' = C6H5
6d ) R = p-CH3-C6H4 , R' = C6H5
R' = C6H5
6b) R = C6H5, R' = C6H5
6c) R = p-Cl-C6H4 , R' = C6H5
7b ) R = C6H5 , R' = CH2C6H5 , R'' = CF3 7c) R = C6H5, R' = C6H5 , R'' = CH3
7d ) R' = C6H5 , R' = C6H5 , R'' = CF3 7e) R = p-Cl-C6H4 , R' = C6H5 , R'' = CH3 7f ) R = p-Cl-C6H4 , R' = C6H5 , R'' = CF3
7a) R = C6H5, R' = CH2C6H5 , R'' = CH3
7h ) R = p-CH3-C6H4 , R' = C6H5 , R'' = CF3
7g ) R = p-CH3-C6H4 , R' = C6H5 , R'' = CH3
Scheme - 2
CONCLUSION
The sequence of reactions provided active synthons like N- substituted nicotinonitriles and 2,3-
bifunctionalised indole derivatives, which are useful for further building a variety of heterocycles of
biological interest.

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EXPERIMENTAL
Melting points were recorded on Casia-siamia (VMP - AM) melting point apparatus and are uncorrected. IR
1
spectra were recorded on a Perkin-Elmer FT-IR 240-C spectrophotometer using KBr optics. H NMR
spectra were recorded on Bruker AV 300 and Unity 400 spectrometer in CDCl3 using TMS as internal
standard. Electron impact (EI) and chemical ionization MS spectra were recorded on a VG 7070 H
instrument at 70 ev. All reactions were monitored by thin layer chromatography (TLC) on precoated
silicagel 60 F254 (mesh); Spots were visualized with UV light. Merck silicagel (60-120 and 100-200 mesh)
was used for chromatography. CHN analyses were recorded on a Vario EL analyser.
2-Diethylamino-4-trifluoromethyl-6-substituted nicotinonitrile (2)
To a solution of 1 ( 2.0 g, 7.6 mmol ) in acetone (25 mL), K2CO3 ( 2.09 g, 15.2 mmol ) and ethyl iodide
(1.2 g, 7.6 mmol ) were added and the resulting mixture was refluxed for 8 h. The reaction mixture was
cooled to rt and acetone was evaporated under vacuum. The residual solid was diluted with water, filtered,
washed and dried. The crude product was purified by column using 60-120 mesh silica gel and the desired
product was eluted using 15% chloroform in hexane.
0
1
Yield: 1.0 g (45%); mp 164 C, recrystallised from hexane+DCM; IR (KBr): 2220 ( CN ). H NMR(300
MHz, CDCl3): δ 1.4 (6H, t, J = 9.5 Hz , 2 CH3 ), 3.8 ( 4H, quartet, J = 9.5 Hz , 2 CH2 ), 7.35 ( 1H, s , Ar-
H ), 7.5 ( 3H, m, Ar-H ) , 8.0 ( 2H , m , Ar-H ). EI MS , m/z : 319 (M+,) , 290 (M+- C2H5 ). Anal. Calcd for
C17H16N3F3: C, 63.93 ; H, 5.04 ; N, 13.15. Found: C, 63.85; H, 5.15; N, 13.28.
2-Iodo-4-trifluoromethyl-6-substituted nicotinonitrile (3)
To a mixture of compounds (1) ( 4 g, 15 mmol ) , CH3CN ( 8 mL ) and conc. HCl ( 10 mL) at 00C , a cooled
solution of NaNO2 (2.0 g, 30 mmol ) in H2O ( 12 mL ) was added slowly while stirring such that the
0
temperature was maintained below 5 C . To the diazonium chloride solution thus formed a solution of KI
( 5.0 g, 30 mmol ) added slowly while stirring and the mixture was stirred for 3 h at rt. Acetonitirile was
evaporated under vacuum and the reaction mixture was diluted with ice cold water .The separated crude
product was collected and purified by column using 60-120 mesh silica gel. The desired product was eluted
with 20% CHCl3 in hexane.
2-Iodo-6-phenyl-4-trifluoromethylnicotinonitrile (3a)
Yield: 4.6 g ( 82%) ; mp 92 0C , recrystallised from hexane + EtOAc ; IR (KBr): 2248( CN).1H NMR(200
MHz, CDCl3): δ 7.5 – 7.6 (3H, m, Ar-H ), 8.0 - 8.15 (3H, m, Ar-H); LSIMS, m/z : 375 (M++ 1). Anal.
Calcd for C13H6N2F3I: C, 41.74; H, 1.62; N, 7.49. Found: C, 41.66; H, 1.58; N, 7.55.
2-Iodo-6-(4-chlorophenyl)-4-trifluoromethylnicotinonitrile (3b)
Yield: 4.58 g ( 85%); mp 144 0C, recrystallised from hexane + EtOAc ; IR (KBr): 2240 (CN).1H NMR(300
MHz, CDCl3): δ 7.5 (2H, d, J = 15 Hz, Ar-H ), 7.65(1H, s, Ar-H), 8.05 ( 2H, d, J = 15 Hz, Ar-H ) ; LSIMS,

HETEROCYCLES, Vol. 65, No. 6, 2005
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m/z : 409 (M++1). Anal. Calcd for C13H5N2ClF3I: C, 38.22; H, 1.23; N, 6.86. Found: C, 38.31; H, 1.18; N,
6.78.
2-Iodo-6-( 4-methylphenyl)-4-trifluoromethylnicotinonitrile (3c)
Yield: 3.92 g (70%); mp 152 0C, recrystallised from hex + DCM ; IR (KBr): 2245( CN ). 1H NMR(300
MHz, CDCl3): δ 2.3 ( 3H, s , CH3 ), 7.25 - 7.3 ( 2H, m , Ar-H ), 8.0 – 8.1 (3H, m , Ar-H) . LSIMS, m/z :
389 (M++ 1). Anal. Calcd for C14H8N2F3I: C, 43.32; H, 2.08; N, 7.22. Found: C, 43.25; H, 2.15; N, 7.18
2 - (N-Subtituted amino)-4-trifluoromethyl-6-substituted nicotinonitrile (4)
The iodo compound (3) ( 2 g , 5.3 mmol ) was taken in excess of alkyl/arylamine ( 15 mL ) and the
mixture was stirred for 4 h at rt ( in case of aniline the reaction was carried out at 110 0 C for 6 h ) . The
reaction mixture was diluted with cold water and the solid was collected by filtration, washed and dried (in
case of aniline the reaction mixture was cooled to rt, aniline was removed under vacuum and the solid
product was washed with hexane and dried. The resulted product was purified by column using 60-120
mesh silica gel. The desired product was eluted with 25% CHCl3 in hexane )
2-Methylamino-6-phenyl-4-trifluoromethylnicotinonitrile (4a)
Yield: 1.35 g ( 91%); mp 138 0C, recrystallised from hex + EtOAc ; IR (KBr): 3310 ( N-H ), 2228 ( CN ).
1H NMR(200 MHz, CDCl3): δ 3.2 (3H, J = 8.2Hz, d ) , 6.2 (1H, br s , NH ), 7.4 ( 1H, s, Ar-H ), 7.6 - 7.7
( 3H, m, Ar-H ) , 8.0 – 8.1 ( 2H , m , Ar-H ). EIMS, m/z : 277 (M+) , 262 (M+- CH3 ). Anal. Calcd for
C14H10N3F3: C, 60.86 ; H, 3.64 ; N, 15.20. Found: C, 60.75; H, 3.55; N, 15.38.
2-Ethylamino-6-phenyl-4-trifluoromethylnicotinonitrile (4b)
Yield: 1.32 g ( 87%); mp 159 0C, recrystallised from hex + DCM ; IR (KBr): 3315(N-H), 2225(CN). 1H
NMR(300 MHz, CDCl3): δ 1.4 (3H, t, J = 10.45 Hz, CH3 ), 3.8 ( 2H, quartet, J = 10.45 Hz, CH2 ), 5.6 (1H,
br t , NH ), 7.35 ( 1H, s , Ar-H ), 7.7 – 7.8 ( 3H, m, Ar-H ) , 8.0- 8.05 (2H , m , Ar-H). EIMS , m/z(%);
291 (M+) , 276 (M+-CH3 ). Anal. Calcd for C15H12N3F3: C, 61.98 ; H, 4.15 ; N, 14.42 Found: C, 61.82; H,
4.22; N, 14.55.
2-Benzylamino-6-phenyl-4-trifluoromethylnicotinonitrile (4c)
Yield: 1.55 g ( 82%); mp 168 0C, recrystallised from hex + EtOAc ; IR (KBr): 3322 ( N-H ), 2220 ( CN ).
1H NMR(300 MHz, CDCl3): δ 4.9 (2H, d, J = 12.5 Hz, N-CH2 ), 5.9 (1H, br t , NH ), 7.3 – 7.5 ( 9H, m ,
Ar-H ), 8.0 ( 2H, m, Ar-H ) . LSIMS, m/z : 354 (M+ + 1), 262 (M+- CH2Ph ). Anal. Calcd for C20H14N3F3:
C, 67.98 ; H, 3.99 ; N, 11.89. Found: C, 67.85; H, 3.85; N, 11.92.
2-Phenylamino-6-phenyl-4-trifluoromethylnicotinonitrile (4d)
0
1
Yield: 1.52 g (84%); mp 134 C recrystallised from CHCl3 ; IR (KBr): 3320 ( N-H ), 2225( CN ). H
NMR(300 MHz, CDCl3): δ 7.15 - 7.2 ( 1H, m , Ar-H ), 7.4 – 7.5 ( 6H, m, Ar-H ), 7.65 (2H , d, J = 18.5 Hz,
Ar-H), 8.0 – 8.05 ( 2H , m , Ar - H ) . LSIMS, m/z : 340 (M++ 1),. Anal. Calcd for C19H12N3F3: C, 67.26 ;
H, 3.56 ; N, 12.38. Found: C, 67.32; H, 3.66; N, 12.45.

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HETEROCYCLES, Vol. 65, No. 6, 2005
2-Phenylamino-6-(4-chlorophenyl)-4-trifluoromethylnicotinonitrile (4e)
0
1
Yield: 1.43 g (79%); mp 181 C, recrystallised from CHCl3 ; IR (KBr): 3319 ( N-H ), 2226 ( CN ). H
NMR(300 MHz, CDCl3): δ 7.2 ( 1H, s , Ar-H ), 7.4 – 7.5 ( 5H, m, Ar-H ), 7.6 ( 2H , d , J = 22.8 Hz, Ar-
H ) , 7.95 ( 2H , d , J = 22.8 Hz, Ar - H ) . LSIMS, m/z : 374 (M++ 1 ), 296 ( M+- Ph ). Anal. Calcd for
C19H11N3ClF3: C, 61.06 ; H, 2.97 ; N, 11.27. Found: C, 61.15; H, 2.86; N, 11.35.
2-Phenylamino-6-(4-methylphenyl)-4-trifluoromethylnicotinonitrile (4f)
0
1
Yield: 1.48 g (81%); mp 184 C, recrystallised from CHCl3 ; IR (KBr): 3317 ( N-H ), 2223 ( CN ). H
NMR(300 MHz, CDCl3): δ 2.4 ( 3H, s) , 7.15 ( 1H, s , Ar-H ), 7.3 – 7.5 ( 5H, m, Ar-H ), 7.65 ( 2H , d , J
= 18.8 Hz, Ar - H ) , 7.9 ( 2H , d , J = 18.8 Hz, Ar – H ) ; LSIMS, m/z : 354 (M++1 ) . Anal. Calcd for
C20H14N3F3: C, 67.98 ; H, 3.99 ; N, 11.89. Found: C, 67.85; H, 3.86; N, 11.75.
Ethyl 3-amino-1,6-disubstituted 4-trifluoromethyl-1H-pyrrolo[2,3- b]pyridine-2-carboxylate (5)
To a solution of compounds (4) (900 mg, 2.6 mmol) in DMF (5 mL), K2CO3 (730 mg, 5.3 mmol), ethyl
bromoacetate (850 mg, 5.3 mmol) and a pinch of NaI were added and the resulting mixture was heated to
120 0 C for 8 h while stirring under N2 atmosphere. The reaction mixture was cooled to rt and DMF was
removed under vacuo. The residual solid was diluted with water, filtered, washed with water until washings
were neutral to pH. The crude product was purified by column using 60 – 120 mesh silica gel. The desired
product was eluted with 15% CHCl 3 in hexane solvent mixture
Ethyl 3-amino-1-benzyl-6-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (5a)
Yield: 786 mg (70%); mp 1310 C, recrystallised from MeOH ; IR (KBr): 3490, 3370 ( NH2 ), 1735
1
( C=O ); H NMR(300 MHz, CDCl3): δ 1.2 (3H, t, J = 10.72 Hz, CH3 ), 4.3 (2H, quartet, J = 8.92 Hz,
CH2 ) , 5.35 ( 2H, br s, NH2 ), 5.95 ( s, 2H, CH2Ph ), 7.1- 7.3 ( m, 5H, Ar-H ), 7.4 – 7.5 ( 3H, m, Ar- H ),
7.75 ( 1H, s ,Ar-H ) , 8.05 - 8.1 ( 2H , m, Ar-H ) ; LSIMS, m/z ; 439 (M+). 348 ( M+- CH2Ph) ; Anal. Calcd
for C24H20N3O2F3: C, 65.45; H, 4.81; N, 9.54. Found: C, 65.56; H, 4.77; N, 9.62.
Ethyl 3-amino-1,6-diphenyl-4-trifluoromethyl- 1H-pyrrolo[2,3-b]pyridine-2-carboxylate ( 5b)
0
Yield: 852 mg (76%); mp 139 C, recrystallised from MeOH ; IR (KBr): 3465, 3390 ( NH2 ), 1730
( C=O ); 1H NMR(300 MHz, CDCl3): δ 1.1 (3H, t, J= 15 Hz, CH3 ), 4.1 (2H, quartet, J = 11.6 Hz , OCH2 ) ,
5.45 ( 2H, br s, NH2 ), 7.3- 7.5 ( 8H, m, Ar-H ), 7.75 ( 1H, s, Ar- H ), 7.9 - 8.0 ( 2H , m, Ar-H ) ;
LSIMS), m/z ; 425 (M+). Anal. Calcd for C23H18N3O2F3: C, 64.94; H, 4.26; N,9.88. Found: C, 64.82; H,
4.38; N, 6.78.
Ethyl 3-amino-6-(4-ch1orophenyl)-1-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-
carboxylate ( 5c)
0
Yield: 956 mg (86%); mp 144 C, recrystallised from MeOH ; IR (KBr): 3485, 3360 (NH2), 1733 (C=O)
1H NMR(300 MHz, CDCl3): δ 1.1 (3H, t, J= 7.5 Hz, CH3 ), 4.3 (2H, quartet, J= 7.5 Hz , OCH2 ) , 5.5 (2H,
br s, NH2), 7.3- 7.5 (7H, m, Ar-H), 7.7 (1H, s, Ar- H), 7.85 - 7.9 (2H, m , Ar-H) ; LSIMS, m/z : 459 (M+),
461(M+ + 2) Anal. Calcd for C23H17N3O2ClF3: C, 60.07; H, 3.73; N, 9.14. Found:C, 60.15; H, 3.61; N, 9.28.

HETEROCYCLES, Vol. 65, No. 6, 2005
1421
Ethyl 3-amino-6-(4-methylphenyl)-1-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-
carboxylate ( 5d)
Yield: 775 mg (70%); mp 135 0C, recrystallised from MeOH ; IR (KBr): 3475, 3345 ( NH2 ), 1730(C=O )
1H NMR (300 MHz, CDCl3): δ 1.1 (3H, t, J= 8.82 Hz, CH3 ), 2.4 ( 3H, s ) , 4.1 (2H, quartet, J= 5.88 Hz ,
OCH2 ) , 5.5 ( 2H, br s, NH2 ), 7.15 - 7.2 ( 2H, m, Ar-H ), 7.3 - 7.35 ( 3H, m, Ar- H ), 7.4 – 7.5 ( 2H, m ,
Ar-H ), 7.75 ( 1H , s , Ar- H ), 7.8 - 7.85 ( 2H, m , Ar – H ) ; LSIMS, m/z : 439 (M+), 362 ( M+- Ph ). Anal.
Calcd for C24H20N3O2F3 : C, 65.60; H, 4.59; N, 9.56. Found: C, 65.75; H, 4.66; N, 9.68.
3-Amino-1,6-disubstituted 4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ( 6 )
Compounds (5) ( 650 mg , 1.5 mmol ) was suspended in 30% KOH solution (10 mL ) and heated to reflux
while stirring for 6 h. The reaction mixture was cooled to rt diluted with cold water and neutralized with 5%
HCl solution. The separated solid was filtered, washed with water, dried and recrystallised in methanol.
3-Amino-1-benzyl-6-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2- carboxylic acid (6a)
Yield: 475 mg (76%); mp 255 0C, recrystallised from MeOH ; IR (KBr):3400 – 3600 ( O-H ), 1725 (C=O ).
1H NMR(200 MHz, DMSO- d6): δ 5.3 ( 2H, br s, NH2 ), 6.1 (2H, s, CH2Ph ), 7.2- 7.3 ( m, 4H, Ar-H ), 7.5
– 7.6 ( 4H, Ar- H ), 7.75 ( 1H, s, Ar-H ), 8.2 ( 2H , m, Ar-H ) ; LSIMS, m/z : 411 (M+), 393 ( M+ – H2O ),
367 ( M+- CO2) Anal. Calcd for C22H16N3O2F3 : C, 64.23; H, 3.92; N, 10.21. Found: C, 64.38; H, 3.88; N,
10.33.
3-Amino-1,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (6b)
0
Yield: 480 mg (78%) ; mp 268 C, recrystallised from EtOH ; IR (KBr): 3400 – 3550 ( O-H ), 1720
1
( C=O ) H NMR (200 MHz, DMSO- d6): δ 5.1 ( 2H, br s, NH2 ), 7.2 ( 2H, m, Ar-H ), 7.35 ( 3H, m, Ar-
H ), 7.4 – 7.5 ( 3H, m, Ar-H ), 7.75 ( 1H, s, Ar- H ), 7.85 ( 2H, m, Ar – H ); .LSIMS, m/z : 397(M+),
379(M+- H2O), 353 ( M+– CO2 ). Anal. Calcd for C21H14N3O2F3: C, 63.48; H, 3.55; N, 10.58. Found: C,
66.55; H, 3.67; N, 10.44.
3-Amino-6-(4-chlorophenyl)-1-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(6c)
Yield: 535 mg (86%); mp 272 0C, recrystallised from EtOH , IR (KBr): 3455 – 3600 ( O-H ), 1725 ( C=O ).
1H NMR(200 MHz, DMSO- d6): δ 5.5 ( 2H, br s, NH2 ) 7.3- 7.5 ( 7H, m, Ar-H ), 7.7 ( 1H, s, Ar- H ), 7.85
- 7.9 ( 2H, m , Ar-H ). LSIMS, m/z : 431 (M+), 413 (M+- H2O), 387 (M+- CO2) . Anal. Calcd for
C21H13N3O2ClF3 : C, 58.41; H, 3.03; N, 9.73. Found: C, 58.55; H, 3.15; N, 9.88.
3-Amino-6-(4-methylphenyl)-1-phenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
(6d)
0
Yield: 433 mg (70%) ; mp 248 C, recrystallised from MeOH ; IR (KBr): 3400 – 3580 ( O-H ) , 1720
( C=O ). 1H NMR(200 MHz, DMSO- d6): δ 2.45 ( 3H, s, CH3 ), 5.25 ( 2H, br s, NH2 ), 7.15 - 7.2 ( 2H, m,
Ar-H ), 7.25 - 7.35 ( 3H, m, Ar- H ), 7.4 – 7.5 ( 2H, m , Ar- H ), 7.75 ( 1H , s , Ar- H ), 7.80 - 7.85 ( 2H, m,

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HETEROCYCLES, Vol. 65, No. 6, 2005
Ar – H ); LSIMS, m/z : 411 (M+), 393(M+-H2O), 367 (M+-CO2). Anal. Calcd for C22H16N3O2F3 : C,
64.23; H, 3.92; N, 10.21. Found: C, 64.33; H, 3.85; N, 10.35.
2,5,7-Trisubstituted 9-trifluoromethylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)- one ( 7 )
Compounds (6) (420 mg , 1 mmol) was taken in acetic anhydride ( 5 mL, 48 mmol )/trifluoroacetic
0
anhydride ( 5 mL, 34 mmol ) and the mixture was heated to 110 C (400C in case of trifluoroacetic
anhydride) while stirring for 2 h. The reaction mixture was cooled to rt and poured on to crushed ice. The
separated solid was filtered, washed with water until neutral to pH (7) and dried. The crude product was
purified by column using 60-120 mesh silica gel and the desired product was eluted with 10% CHCl3 in
hexane.
2-Methyl-5-benzyl-7-phenyl-9-trifluoromethylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)-one(7a)
Yield: 350 mg (79%), mp 282 0C, recrystallised from MeOH ; IR (KBr): 1751 ( C=O). 1H NMR(300 MHz,
CDCl3): δ 2.55 (3H, s, CH3 ), 6.0 ( 2H , s , CH2Ph ), 7.15 - 7.25 ( 4H, m, Ar-H ), 7.5 – 7.6 ( 4H, m, Ar- H ),
8.0 ( 1H , s , Ar – H ), 8.2 ( 2H , m , Ar – H ) ; MS (LSIMS), m/z : 437 (M++1), 392 (M+ - CO2 ) , 421 (M+
– CH3 ) ; Anal Calcd for C24H16N3O2F3: C, 66.21; H, 3.70; N, 9.65. Found: C, 66.15; H, 3.88; N, 9.78.
2,9-Bis(trifluoromethyl)-5-benzyl-7-phenylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)- one (7b)
Yield: 445 mg (87%) , mp 224 0C, recrystallised from MeOH ; IR (KBr): 1750 ( C=O). 1H NMR(300 MHz,
CDCl3): δ 6.05 ( 2H , s , CH2Ph ), 7.2 – 7.3 ( 4H, m, Ar-H ), 7.5 – 7.6 ( 4H, m, Ar- H ), 8.1 ( 1H , s , Ar –
H ), 8.20 - 8.25 ( 2H , m , Ar – H ); LSIMS, m/z : 490 (M++1), 420 ( M+- CF3 ) , 445 ( M+ - CO2 ) . Anal.
Calcd for C24H13N3O2F6: C, 58.90; H, 2.60; N, 8.59. Found: C, 58.84; H, 2.77; N, 8.66.
2-Methyl-5,7-diphenyl-9-trifluoromethylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)- one ( 7c)
Yield: 356 mg (78%), mp 266 0C, recrystallised from MeOH ; IR (KBr): 1755 ( C=O). 1H NMR(300 MHz,
CDCl3): δ 2.6 ( 3H , s , CH3 ), 7.3 - 7.4 ( 4H, m, Ar-H ), 7.5 - 7.6 ( 4H, m, Ar- H ), 8.0 - 8.05 ( 3H , m ,
Ar – H ) ; LSIMS, m/z : 422 (M+ + 1), 406 (M+ – CH3 ) , 377 ( M+ - CO2) . Anal. Calcd for C23H14N3O2F3:
C, 65.56; H, 3.35; N, 9.97. Found: C, 65.44; H, 3.28; N, 9.88.
2,9-Bis(trifluoromethyl)-5,7-diphenylpyrido[3’,2’:4,5]pyrrolo[3,2- d][1,3]oxazin- 4(5H)- one (7d )
Yield: 422 mg (85%), mp 268 0C, recrystallised from MeOH ; IR (KBr): 1752 (C=O). 1H NMR(300 MHz,
CDCl3): δ 7.4 – 7.6 ( 6H, m, Ar-H ), 7.75 - 7.8 ( 2H, m, Ar- H ), 7.9 ( 1H , s , Ar- H ), 8.0 - 8.05 ( 2H , m ,
Ar – H ) LSIMS, m/z : 476 (M++1), 406 (M+ – CH3 ) , 377 (M+– CO2 ) . Anal. Calcd for C23H11N3O2F6: C,
58.12; H, 2.33; N, 8.84. Found: C, 58.22; H, 2.45; N, 8.95
2-Methyl-5-phenyl-7-(4-chlorophenyl)-9-trifluoromethylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-
4(5H)- one ( 7e )
Yield: 375 mg (82%), mp 274 0C, recrystallised from MeOH ; IR (KBr): 1784(C=O). 1H NMR(400 MHz,
CDCl3): δ 2.6 ( 3H , s , CH3 ), 7.45 ( 2H, m, Ar-H ), 7.5 - 7.6 ( 5H, m, Ar- H ), 7.9 - 8.0 ( 3H , m , Ar –
H ) . LSIMS, m/z ; 456 (M++1), 440(M+ – CH3 ) , 411 (M+ - CO2) . Anal. Calcd for C23H13N3O2ClF3 : C,
60.61; H, 2.87; N, 9.22. Found: C, 60.72; H, 2.95; N, 9.38.

HETEROCYCLES, Vol. 65, No. 6, 2005
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2,9-Bis(trifluoromethyl)7-(4-chlorophenyl)-5-phenylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)-
one ( 7f )
1
Yield: 462 mg (88%), mp 177 0C, recrystallised from MeOH ; IR (KBr): 1745 ( C=O). H NMR(400
MHz, CDCl3): δ 7.4 - 7.45 ( 3H, m, Ar-H ), 7.45 - 7.6 ( 4H, m, Ar-H), 7.9 - 8.0 ( 3H , m , Ar – H ) ; .
LSIMS), m/z : 510 (M++1), 440 (M+-CF3), 490 (M+-F) . Anal. Calcd for C23H10N3O2ClF6: C, 54.19; H,
1.98; N, 8.24. Found: C, 54.28; H, 1.85; N, 8.33
2-Methyl-7-(4-methylphenyl)-5-phenyl-9-trifluoromethylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-
4(5H)- one ( 7g)
Yield: 384 mg ( 82%), mp 257 0C, recrystallised from MeOH ; IR (KBr): 1751(C=O). 1H NMR(400 MHz,
CDCl3): δ 2.4 ( 3H , s , CH3 ), 2.6 ( 3H, s , CH3- C (2) ), 7.2 – 7.3 ( 2H, m, Ar-H ), 7.5 - 7.6 ( 6H, m, Ar-
H ), 7.95 - 8.0 ( 2H , m , Ar – H ); LSIMS, m/z : 436 (M++1), 420 (M+– CH3); 391(M+ – CO2). Anal Calcd
for C24H16N3O2F3 : C, 66.21; H, 3.70; N, 9.65. Found: C, 66.38; H, 3.85; N, 9.55.
2,9-Bis(trifluoromethyl)-7-(4-methylphenyl)-5-phenylpyrido[3',2':4,5]pyrrolo[3,2-d][1,3]oxazin-4(5H)-
one ( 7h )
Yield: 420 mg (83%), mp 265 0C, recrystallised from MeOH ; IR (KBr): 1735(C=O). 1H NMR(400 MHz,
CDCl3): δ 2.4 ( 3H , s , CH3 ), 7.3 – 7.4 ( 3H, m, Ar-H ), 7.55 - 7.6 ( 3H, m, Ar- H ), 7.8 - 8.0 ( 4H , m ,
Ar – H ) ; LSIMS, m/z : 490 (M++1), 470 (M+-F ), 420 ( M+– CF3 ). Anal Calcd for C24H13N3O2F6: C,
58.90; H, 2.68; N,8.59. Found: C, 58.85; H, 2.55; N, 8.65.
ACKNOWLEDGEMENTS
Authors are thankful to Dr. J.S. Yadav, Director, IICT, Hyderabad, Shri S. Narayan Reddy, Head,
Fluoroorganic division, IICT for their constant encouragement and SRK is grateful to CSIR, New
Delhi for grant of senior research fellowship.
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