Regioselective cyclization of unsymmetrical dicyanoanilines to novel 2,3-bifunctionalised indole regioisomers and their use in the synthesis of 4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitriles

Article abstract of DOI:10.1016/j.tet.2005.02.046

Synthesis of novel-2,3-bifunctionalised indole regioisomers (2/3 and 6/7) from unsymmetrical dicyanoanilines 1 by regioselective cyclization in two independent ways. Regioisomers 6 are further utilized in synthesis of novel 4,5-dihydro[1,3]oxazino[5,4-b] indole-6-carbonitriles 9.

Full text of DOI:10.1016/j.tet.2005.02.046

Tetrahedron 61 (2005) 3999–4008
Regioselective cyclization of unsymmetrical dicyanoanilines to
novel 2,3-bifunctionalised indole regioisomers and their use in the
synthesis of 4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitriles*
D. Maitraie,a G. Venkat Reddy,a V. V. V. N. S. Rama Rao,a S. Ravikanth,a B. Narsaiah,a,
*
P. Shanthan Rao,a K. Ravikumarb and B. Sridharb
aFluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
bLaboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 28 October 2004; revised 2 February 2005; accepted 18 February 2005
Abstract—Synthesis of novel-2,3-bifunctionalised indole regioisomers (2/3 and 6/7) from unsymmetrical dicyanoanilines 1 by
regioselective cyclization in two independent ways. Regioisomers 6 are further utilized in synthesis of novel 4,5-dihydro[1,3]-
oxazino[5,4-b] indole-6-carbonitriles 9.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
multidrug resistance. In addition most important among
non-steroidal anti-inflammatory agent is indomethacin.8d
The hetero-ring fused benzene derivatives play a prominent
role in synthetic organic chemistry because of their wide
range applications in pharmaceutical field. More specifi-
cally pyrrole-fused benzene (indole) derivatives have been
considered as useful intermediates in drugs, pesticides1 and
also as potential pharmaceuticals.2a,b Among the tryptamine
derivatives, sumatriptan3a,b is a highly selective 5-hydroxy
tryptamine receptor-1 (5-HT1D) agonist and a new drug for
the treatment of migraine. The tropisetron3c is considered as
5-HT3-receptor selective antagonist for the treatment of
nausea and vomiting induced by cancer chemotherapy and
radiotherapy. Bopindolol4,5 is also a potent, long acting
b-adrenergic blocker used to treat hypertension and related
to the well-known Pindolol. Delaviridin6 and Ateviridine7
are in clinical trials, are reverse transcriptase inhibitors and
prevent the spread of HIV-1 in human lymphocytes.
A large number of methods for the construction of the indole
nucleus have been reported.9 However, synthesis of indole
and indole fused derivatives by novel approach is of current
interest due to their promising activity. In this paper, we
studied the regioselective cyclization of unsymmetrical 2,6-
dicyanoanilines10 in a way to obtain indole regioisomers in
two ways. The influence of substituents on formation of two
regioisomers in different proportion and identification of
each isomer has been established. The indole derivatives are
further used in the synthesis of novel 4,5-dihydro[1,3]-
oxazino [5,4-b]indole-6 carbonitriles.
2. Results and discussion
N-Heterocyclic indolyl glyoxylamides8a and indole quino-
ne8b as orally active anticancer agents. Some of the
derivatives and analogues8c are considered as selective
multidrug resistance associated protein inhibitors in
The 2,6-dicyano-3-trifluoromethyl-5-phenyl/methyl aniline
1 is considered to be an interesting trifunctional synthon
having two cyano groups ortho to amine function and
possibility for regioselective cyclisation to obtain indole
derivatives. Initially the anilines 1 were reacted with ethyl
bromoacetate in DMF under basic medium at 110–120 8C
and found that the reaction is highly sensitive to temperature
and polarity of solvent, as a result several polymeric
products are formed. In order to overcome the problem, the
similar reaction is carried in acetonitrile at 80–85 8C under
basic medium and obtained 2,3-bifunctionalised indole
* IICT communication No. 040207.
Keywords: 2,6-Dicyanoanilines; Ethyl bromoester; Substituted-iodoben-
zenes; 2,3-Bifunctionalised indole derivatives; Regioisomers; Sandmeyer
reaction; Thorpe–Ziegler reaction.
*
Corresponding author. Tel.: C91 40 27193185; fax: C91 40 27160757;
e-mail: narsaiah@iict.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.046

4000
D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
Scheme 1.
regioisomers (2,3) in different proportion. The reaction
details schematically drawn in Scheme 1.
Our earlier experience on alkylation of aniline 1 with ethyl
iodide in acetonitrile, potassium carbonate and potassium
iodide resulted N,N-diethylaniline irrespective of mole ratio
used. Based on the finding, the following mechanism is
formulated. Thus, the reaction is mainly dialkylation of
amine function irrespective of the mole ratio of ethyl
bromoacetate used and the resultant product is then cyclised
by abstraction of a proton from the active methylene by
base, followed by attack on one of the nitrile functions in
two ways to give two regioisomers in various proportions in
a single pot. This type of cyclisation is also called Thorpe–
Ziegler11 reaction. The role of the substituent on the
benzene ring during formation of two regioisomers was
studied and we found that the phenyl group promotes
formation of product 2 as major and product 3 as minor,
while methyl group reverses the formation of two isomers.
This is attributed to the steric hindrance of phenyl group
promotes attack of nucleophile in para position rather than
ortho position. Whereas a methyl group promotes attack of
the nucleophile in the ortho position. The regioisomers 2,3
being very close polarity, a column chromatography method
as cited in experimental section is devised to separate them.
Each isomer has been identified based on 1H NMR data with
reference to thesubstituentspresent on benzene ring. A repre-
sentative pair of isomers is chosen for discussion below.
Figure 1. X-ray crystal structure 2b. Displacement ellipsoids are drawn at
30% probability level and H atoms are shown as small spheres of arbitrary
radii.
A characteristic difference between two regioisomers 2b
and 3b is based on chemical shift of NH2 protons and proton
on C-5 carbon in H NMR. In isomer 2b the NH2 protons
1
appeared as a broad peak at d 4.75 whereas in isomer 3b at d
5.4 and proton on C-5 carbon at d 7.21 and at d 7.59,

D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
4001
respectively. Based on the facts, it is presumed that the
change in chemical shift of NH2 and proton on C-5 carbon
in both the isomers is mainly due to the influence of CF3 and
nitrile groups in benzene ring. The groups CF3 and CN para
to each other shifts absorption up field and ortho to each
other shifts absorption to down field due to electronic
effects. 13C NMR data further supports that the CF3 carbon
in 2b isomer appeared as quartet at d 126.54 and in 3b
isomer as quartet at d 123.34 with same coupling constant
272 Hz. However, a clear-cut difference of absorption of
C–CF3 is observed. In isomer 2b the C–CF3 appeared as
quartet at d 132.6 with coupling constant 31 Hz whereas in
isomer 3b the C–CF3 appeared as quartet at d 126.56 with
coupling constant 33 Hz. Thus, the structure of each
isomer is determined. It is further confirmed by single
crystal X-ray structures determined for both 2b and 3b
(Figs. 1 and 2).
Figure 2. X-ray crystal structure 3b. Displacement ellipsoids are drawn at
30% probability level and H atoms are shown as small spheres of arbitrary
radii.
A similar trend is observed in all the isomers. The products
resulted in these reactions have been tabulated in Table 1.
In order to synthesise a number of specified N-alkylated
indole derivatives and to develop a general methodology
for the synthesis of bifunctionalised indole regioisomers
an alternate approach is adopted starting from 2,6-
dicyanoanilines 1, as method discussed above is being
specific to N-acetoxyethyl derivatives due to dialkylation
followed by cyclization. Thus compounds 1 were
diazotised-using NaNO2/HCl followed by reaction with
potassium iodide through Sandmeyer reaction and obtained
Table 1. Reaction of 2,6-dicyanoanilines with ethyl bromo ester
Entry
Product
R
Ratio
(%)
Yield
(%)
1
2
3
4
2a
3a
2b
3b
CH3
CH3
Ph
20
80
85
15
14
56
72
13
Ph
Scheme 2.
2,6-dicyano iodo benzenes 4 in good yields. The iodo
benzenes 4 are further reacted with various alkyl amines at
room temperature to access to number of different
substituted anilines 5. The reaction details presented in
Scheme 2 and products are tabulated in Table 2.
Table 2. Preparation of substituted iodobenzenes and anilines
Entry
Product
R
R1
Yield
(%)
5
6
7
8
4a
4b
5a
5b
5c
5d
5e
5f
CH3
Ph
CH3
CH3
CH3
Ph
—
—
60
80
45
58
60
68
70
78
CH3
C2H5
CH2Ph
CH3
C2H5
CH2Ph
Each N-substituted aniline 5 on reaction with ethyl
bromoacetate in acetonitrile using base gave two regio-
isomers of indole derivatives 6 and 7 in definite proportions.
The initial reaction is an alkylation of anilines followed by
Thorpe–Ziegler cyclisation on nitrile (CN) function to result
9
10
11
12
Ph
Ph

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D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
Scheme 3.
The 3-amino-7-(aminocarbonyl)-6-substituted-4-(trifluoro-
methyl)-1H-indole-2-carboxylic acids 8 are reacted with
acetic anhydride at 110 8C to give 1,3-oxazines 9 in good
yields. Under the set of conditions, the amide also under-
goes dehydration and results in nitrile formation. The
number of products formed have been tabulated in Table 5
(Schemes 5 and 6).
Table 3. Reaction of substituted anilines with ethyl bromo acetate
Entry
Product
R
R1
Ratio
(%)
Yield
(%)
13
14
15
16
17
18
19
20
21
22
23
24
6a
7a
6b
7b
6c
7c
6d
7d
6e
7e
6f
CH3
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
CH3
CH3
23
77
20
80
17
83
90
10
89
11
93
07
12
38
10
42
10
50
63
7
71
9
81
6
C2H5
C2H5
CH2Ph
CH2Ph
CH3
3. Conclusion
CH3
C2H5
C2H5
CH2Ph
CH2Ph
Regioselective cyclization of 2,6-dicyanoanilines is estab-
lished based on substituents used as a result bifunctionalised
indole regioisomers are formed. Each regioisomer is
identified and further utilized to build tricyclic heterocycles.
7f
Ph
Scheme 4.
products 6 and 7. The preferential cyclisation to a specified
nitrile carbon is mainly depending on substituents present
on benzene ring and is similar as established in formation of
products 2 and 3. The reaction details presented in Scheme 3
and products have been tabulated in Table 3.
Thus, active functional groups in ortho position are fully
utilized in anilines to get indoles and further to 1,3-
oxazino[5,4-b] indoles.
Table 4. Hydrolysis of substituted-1H-indole-2-carboxylate
The indole derivatives 6 are further utilized in order to
synthesize indole-fused derivatives. Thus, the ethyl-1H-
indole-2-carboxylates 6 are subjected to alkaline hydrolysis
using 20% potassium hydroxide solution on reflux for 2 h.
The reaction mixture is cooled to room temperature and
diluted with cold water followed by neutralization with
glacial acetic acid resulted solid acid product 8. The product
is highly polar and insoluble in most of the organic solvents
and identified as 3-amino-7-(aminocarbonyl)-6-substituted-
4-trifluoromethyl-1H-indole-2-carboxylic acid 8 based on
spectral data. The yields are independent of substituents
used in benzene as well as in pyrrole ring. During the ester
hydrolysis, the nitrile is also hydrolyzed to amide. The
compounds are considered as active synthons for further
cyclization to obtain tricyclic derivatives (Scheme 4).
R0
Compound No.
R
Yield (%)
8a
8b
8c
8d
8e
8f
CH3
CH3
CH3
C6H5
C6H5
C6H5
CH3
78
72
68
85
81
77
CH2C6H5
C2H5
CH3
CH2C6H5
C2H5
Table 5. Cyclisation of 1H-indole-2-carboxylic acids to 1,3-oxazines
R0
Compound No.
R
Yield (%)
9a
9b
9c
9d
9e
9f
CH3
CH3
CH3
C6H5
C6H5
C6H5
CH3
82
80
78
82
76
78
CH2C6H5
C2H5
CH3
CH2C6H5
C2H5
The compounds prepared in the above reactions are
tabulated in Table 4.

D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
4003
Scheme 5.
Scheme 6.
4. Experimental
crude product mixture of two isomers. Each isomer is
separated in pure form by column chromatography using
silica gel 100–200 mesh size and n-hexane–EtOAc (100:3)
as eluent.
1H NMR spectra were recorded in CDCl3 on Bruker AV 300
and Unity 400 spectrometers, chemical shifts are reported in
ppm relative to 0 for TMS melting points were recorded on
VMP-AM melting point apparatus and are uncorrected.
Elemental analyses were carried out on Elemental Vario EL
(Germany) apparatus. IR spectra were recorded on FT-IR
Schimadzu Perkin–Elmer 1310 infrared spectrometer.
Electron Impact (EI) and Chemical ionization mass spectra
(CIMS) were recorded on VG 7070 H eV instrument at
70 eV. During usual workup, all organic extracts were dried
over Na2SO4 and evaporated. All reactions were monitored
by thin layer chromatography (TLC) on precoated silica gel
60 F254 (Merck); spots were visualized with UV light.
Merck silica gel (100–200 mesh) was used for
chromatography.
4.1.1. Ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-6-
methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate
(2a). 0.19 g, 20% red solid; mp 158 8C; [Found: C, 54.39; H,
4.58; N, 10.53. C18H18F3N3O4 requires C, 54.41; H, 4.56; N,
10.57%]; nmax (KBr) 3489, 3371 (NH2), 2980 (C–H), 2232
(CN), 1735 (CO), 1672 (CO), 1621, 1555, 1324 (C–F),
723 cmK1; dH (200 MHz, CDCl3) 1.32 (3H, t, JZ7.3 Hz,
CH3), 1.38 (3H, t, JZ7.3 Hz, CH3), 2.8 (3H, s, CH3–C (6)),
4.28 (2H, q, JZ7.0 Hz, OCH2), 4.38 (2H, q, JZ7.0 Hz,
OCH2), 5.23 (2H, br s, NH2), 5.58 (2H, s, N–CH2), 7.06
(1H, s, H–C (5)); m/z (LSIMS) 398 (MHC, 100%), 69
(75%).
4.1. N-1-(2I-ethoxy-2I-oxoethyl) 2,3-bifunctionalised-4 or
6-trifluoromethyl indole derivatives (2/3). General
procedure
4.1.2. Ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-4-
methyl-6-(trifluoromethyl)-1H-indole-2-carboxylate
(3a). 0.77 g, 80% yellow solid; mp 144 8C; [Found: C,
54.42; H, 4.59; N, 10.59. C18H18F3N3O4 requires C, 54.41;
H, 4.56; N, 10.57%]; nmax (KBr) 3492, 3380 (NH2), 2982
(C–H), 2241 (CN), 1742 (CO), 1669 (CO), 1619, 1534,
1331 cmK1; dH (200 MHz, CDCl3) 1.36 (3H, t, JZ7.3 Hz,
CH3), 1.42 (3H, t, JZ7.3 Hz, CH3), 2.7 (3H, s, CH3–C (4)),
4.29 (2H, q, JZ7.0 Hz, OCH2), 4.40 (2H, q, JZ7.0 Hz,
OCH2), 5.38 (2H, br s, NH2), 5.6 (2H, s, N–CH2), 7.31 (1H,
s, H–C (5)); m/z (LSIMS) 398 (MHC, 100%), 69 (75%).
The 2,6-dicyanoanilines 1 (3.48 mmol) were taken in
acetonitrile (5 mL) with potassium carbonate (6.96 mmol),
potassium iodide (5 mg) and ethyl bromoacetate
(6.96 mmol) was added. The reaction mixture was heated
to 80–85 8C under stirring in N2 atmosphere and continued
for 12 h. The progress of reaction was monitored by TLC
and after completion, the reaction mixture was cooled to
room temperature. The solvent (CH3CN) was evaporated
under reduced pressure. The residue was extracted with
EtOAc, organic layer was washed with water till the
washings were neutral to pH and dried over anhyd Na2SO4.
The EtOAc was removed by Rotary-evaporator to obtain
4.1.3. Ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-6-
phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate
(2b). 1.1 g, 85% red solid; mp 148 8C; [Found: C, 60.14; H,
4.38; N, 9.16. C23H20F3N3O4 requires C, 60.13; H, 4.39; N,

4004
D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
9.15%]; nmax (KBr) 3492, 3385 (NH2), 2983 (C–H), 2220
(CN), 1753 (CO), 1694 (CO), 1442, 1259 and 1134 cmK1
period of 30 min, while stirring. The reaction mixture was
further stirred at 0 8C for 30 min, warmed to room
temperature and the stirring was continued for another
2 h. The solvent was evaporated off and the residue was
poured into ice-cold H2O, the precipitated solid was filtered
off, washed with H2O, and dried. The resulted product is
sufficiently pure and is used for further reaction.
;
dH (200 MHz, CDCl3) 1.32 (3H, t, JZ6.9 Hz, CH3) 1.39
(3H, t, JZ6.9 Hz, CH3), 4.29 (2H, q, JZ7.0 Hz, OCH2),
4.35 (2H, q, JZ7.0 Hz, OCH2), 4.75 (2H, br s, NH2), 5.68
(2H, s, N–CH2), 7.21 (1H, s, H–C (5)), 7.5 (5H, m, phenyl);
dC (50 MHz, CDCl3) 14.0, 14.2, 47.3, 47.66, 50.17, 51.76,
60.74, 61.57, 61.76, 90.99, 111.8, 114.6, 117.9, 119.6, 126.5
(q, CF3, JZ272 Hz), 128.6, 128.8, 129.2, 132.6 (q, C–CF3,
JZ31 Hz), 137.07, 137.22, 137.87, 142.68, 142.93, 162.05,
168.9, 170.71; m/z (LSIMS) 460 (MHC, 35%).
4.3.1. 2-Iodo-4-methyl-6-(trifluoromethyl)isophthalo-
nitrile (4a). 1.4 g, 60% colourless solid; mp 68 8C;
[Found, C 35.70, H 1.21, N 8.37. C10H4F3IN2 requires C
35.71, H 1.20, N 8.34%]; nmax (KBr) 2366, 2238 (CN),
1592, 1150, 706 cmK1; dH (200 MHz, CDCl3) 2.75 (3H, s,
CH3), 7.65 (1H, s, H–C (4)); m/z (LSIMS) 336 (MC, 89%).
4.1.4. Ethyl 3-amino-7-cyano-1-(2-ethoxy-2-oxoethyl)-4-
phenyl-6-(trifluoromethyl)-1H-indole-2-carboxylate
(3b). 0.2 g, 15% yellow solid; mp 135 8C; [Found: C, 60.16;
H, 4.32; N, 9.19. Anal. Calcd for C23H20F3N3O4 requires C,
60.13; H, 4.39; N, 9.15%]; nmax (KBr) 3500, 3361 (NH2),
2986, 2221 (CN), 1758 (CO), 1678 (CO), 1613, 1437, 1199,
1122 cmK1; dH (200 MHz, CDCl3) 1.31 (3H, t, JZ6.9 Hz,
CH3) 1.42 (3H, t, JZ6.9 Hz, CH3), 4.27 (2H, q, JZ7.0 Hz,
OCH2), 4.41 (2H, q, JZ7.0 Hz, OCH2), 5.41 (2H, br s,
NH2), 5.68 (2H, s, N–CH2), 7.52 (5H, m, phenyl), 7.59 (1H,
s, H–C (5)); dC (50 MHz, CDCl3)14.1, 14.23, 47.59, 60.89,
61.75, 97.5, 112.06, 114.57, 116.42, 123.34 (q, CF3, JZ
272 Hz), 126.56 (q, C–CF3, JZ33 Hz), 129.15, 135.59,
137.61, 138.35, 146.39, 162.15, 168.91; m/z (LSIMS) 460
(MHC, 35%).
4.3.2. 3-Iodo-5-(trifluoromethyl)biphenyl-2,4-dicarbo-
nitrile (4b). 2.22 g, 80% colourless solid; mp 178 8C;
[Found: C, 45.29; H, 1.49; N, 7.06. C15H6F3IN2 requires C,
45.22; H, 1.51; N, 7.03%]; nmax (KBr) 2234 (CN), 1592,
1539 cmK1; dH (200 MHz, CDCl3) 7.58 (5H, s, aromatic),
7.8 (1H, s, H–C (4)); m/z (LSIMS) 398 (MC, 100%).
4.4. 2,6-Dicyano-3-trifluoromethyl-5-substituted-N-
substituted anilines (5). General procedure
The iodo compound 4 (2.5 mmol) was suspended in methyl/
ethyl/benzyl amine solution (22 mL). The mixture was
stirred at room temperature over a period of 6 h. The
reaction mixture was partitioned between EtOAc and water;
the organic layer was separated, washed with H2O till
washings are neutral to pH and dried over Na2SO4. The
solvent is removed under reduced pressure and the crude
product is purified by column chromatography using Silica
gel and hexane–EtOAc (1:50) as eluents.
4.2. X-ray crystallography
4.2.1. Compound 2b. The crystal belongs to the
monoclinic crystal system, space group is P21/c
˚
˚
(NO.14) with aZ11.3429(8) A, bZ15.9684(11) A, cZ
3
˚
˚
12.9811(9) A, bZ113.329(1), VZ2159.0(3) A , rcalc
Z
1.413 mg mK3, lZ0.71073 A, m(Mo Ka)Z0.115 mm
,
K1
˚
F000Z952, TZ273(2) K. Data collection yielded 15,353
reflection resulting in 3793 unique, averaged reflection,
3265 with IO2s(I), q range: 1.96–24.99. Full-matrix least-
squares refinement led to a final RZ0.0561, wRZ0.1331
and GOOFZ1.144. Intensity data were measured on Bruker
Smart Apex with CCD area detector. CCDC 262067
contains supplementary Crystallographic data for the
structure 2b.
4.4.1. 4-Methyl-2-(methylamino)-6-(trifluoromethyl)-
isophthalonitrile (5a). 0.27 g, 45% pale yellow solid; mp
115 8C; [Found: C, 55.21; H, 3.34; N, 17.53. C11H8F3N3
requires C, 55.23; H, 3.37; N, 17.57%]; nmax (KBr) 3331
(NH), 2975 (C–H), 2350, 2232 (CN), 1570, 1121 cmK1; dH
(200 MHz, CDCl3) 2.55 (3H, s, CH3), 3.45 (3H, d, JZ
5.1 Hz, N–CH3), 5.4 (1H, br s, NH), 6.9 (1H, s, H–C (4));
m/z (LSIMS) 239 (MC, 100%).
4.2.2. Compound 3b. The crystal belongs to the
monoclinic crystal system, space group is P21/c
4.4.2. 2-(Ethylamino)-4-methyl-6-(trifluoromethyl)-
isophthalonitrile (5b). 0.37 g, 58% pale yellow solid; mp
59 8C; [Found: C, 56.89; H, 3.93; N, 16.58. C12H10F3N3
requires C, 56.92; H, 3.98; N, 16.59%]; nmax (KBr) 3338
˚
˚
(NO.14) with aZ10.2408(6) A, bZ16.9379(10) A, cZ
3
˚
˚
12.7844(7) A, bZ90.425(1), VZ2217.5(2) A , rcalc
Z
,
1.376 mg mK3, lZ0.71073 A, m(Mo Ka)Z0.112 mm
K1
˚
(NH), 2985 (C–H), 2359, 2225 (CN), 1581, 1133 cmK1
;
F000Z952, TZ273(2) K. Data collection yielded 15,735
reflection resulting in 3901 unique, averaged reflection,
3147 with IO2s(I), q range: 1.99–25.00. Full-matrix least-
squares refinement led to a final RZ0.0602, wRZ0.1668
and GOOFZ1.036. Intensity data were measured on Bruker
Smart Apex with CCD area detector. CCDC 262068
contains supplementary Crystallographic data for the
structure 3b.
dH (200 MHz, CDCl3) 1.39 (3H, t, CH3, JZ7.1 Hz), 2.6
(3H, s, CH3), 3.9 (2H, qui, JZ6.7 Hz, N–CH2), 5.1 (1H, br
s, NH), 6.9 (1H, s, H–C (4)); m/z (LSIMS) 253 (MC, 77%),
238.
4.4.3. 2-(Benzylamino)-4-methyl-6-(trifluoromethyl)-
isophthalonitrile (5c). 0.47 g, 60% pale yellow solid; mp
100 8C; [Found: C, 64.74; H, 3.79; N, 13.34. C17H12F3N3
requires C, 64.76; H, 3.83; N, 13.32%]; nmax (KBr) 3329
(NH), 2990 (C–H), 2366, 2288 (CN), 1579, 1165 cmK1; dH
(200 MHz, CDCl3) 2.6 (3H, s, CH3), 4.95 (2H, d, JZ5.1 Hz,
CH2), 5.42 (1H, br s, NH), 6.97 (1H, s, H–C (4)), 7.4 (5H, s,
aromatic H); m/z (LSIMS) 315 (MC, 40%), 91 (100%).
4.3. Substituted iodobenzenes (4). General procedure
To a mixture of 2,6-dicyanoanilines 1 (6.96 mmol), NaNO2
(17.42 mmol) and KI (17.42 mmol) in MeCN (30 mL) at
0 8C was added cold concd HCl (7 mL) drop wise over a

D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
4005
4.4.4. 3-(Methylamino)-5-(trifluoromethyl)biphenyl-2,4-
dicarbonitrile (5d). 0.51 g, 68% pale yellow solid; mp
167 8C; [Found: C, 63.73; H, 3.31; N, 13.91. C16H10F3N3
requires C, 63.79; H, 3.35; N, 13.95%]; nmax (KBr) 3368
(NH), 2223 (CN), 1552, 1476, 1389, 1285 cmK1; dH
(200 MHz, CDCl3) 3.48 (3H, d, JZ5.8 Hz, CH3), 5.45
(1H, br s, NH), 7.05 (1H, s, H–C (4)), 7.50 (5H, s, aromatic
H); m/z (LSIMS) 301 (MC, 100).
(CO), 1617, 1472 cmK1; dH (200 MHz, CDCl3) 1.45 (3H, t,
JZ6.9 Hz, CH3), 2.7 (3H, s, CH3), 4.30 (3H, s, N–CH3),
4.45 (2H, q, JZ6.8 Hz, O–CH2), 5.33 (2H, br s, NH2) 7.26
(1H, s, H–C (5)); m/z (LSIMS) 326 (MHC, 42%) 325 (MC,
100%).
4.5.3. Ethyl 3-amino-7-cyano-1-ethyl-6-methyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylate (6b). 0.11 g,
20% red solid; mp 156 8C; [Found: C, 56.67; H, 4.71; N,
12.32. C16H16F3N3O2 requires C, 56.63; H, 4.75; N,
12.38%]; nmax (KBr) 3504, 3408 (NH2), 2990 (C–H),
2221 (CN), 1690 (CO), 1615, 1615, 1162, 1120 cmK1; dH
(200 MHz, CDCl3) 1.45 (6H, t, JZ7.3 Hz, 2CH3), 2.83 (3H,
s, CH3), 4.45 (2H, q, JZ7.0 Hz, N–CH2) 4.90 (2H, q, JZ
7.0 Hz, OCH2), 5.25 (2H, br s, NH2), 7.07 (1H, s, H–C(5));
m/z (LSIMS) 340 (MHC, 40%) 339 (MC, 100%).
4.4.5. 3-(Ethylamino)-5-(trifluoromethyl)biphenyl-2,4-
dicarbonitrile (5e). 0.55 g, 70% pale yellow solid; mp
163 8C; [Found: C, 64.72; H, 3.85; N, 13.38. C17H12F3N3
requires C, 64.76; H, 3.83; N, 13.32%]; nmax (KBr) 3375
(NH), 2977 (C–H), 2219 (CN), 1559, 1457, 1380 cmK1; dH
(200 MHz, CDCl3) 1.42 (3H, t, JZ6.9 Hz, CH3), 3.92 (2H,
qui, JZ6.7 Hz, CH2), 5.2 (1H, br s, NH), 7.05 (1H, s, H–C
(4)), 7.5 (5H, s, aromatic H); m/z (LSIMS) 315 (MC, 80%),
300.
4.5.4. Ethyl 3-amino-7-cyano-1-ethyl-4-methyl-6-(tri-
fluoromethyl)-1H-indole-2-carboxylate (7b). 0.45 g,
80% yellow solid; mp 135 8C; [Found: C, 56.69; H, 4.78;
N, 12.32. C16H16F3N3O2 requires C, 56.63; H, 4.75; N,
12.38%]; nmax (KBr) 3482, 3401 (NH2), 2987 (C–H), 2213
(CN), 1682 (CO), 1619 cmK1; dH (200 MHz, CDCl3) 1.45
(6H, t, JZ7.32 Hz, 2CH3), 2.72 (3H, s, CH3), 4.42 (2H, q,
JZ7.0 Hz, N–CH2), 4.91 (2H, q, JZ7.0 Hz, O–CH2), 5.35
(2H, br s, NH2), 7.27 (1H, s, H–C (5)); m/z (LSIMS) 340
(MHC, 40%), 339 (MC, 100%).
4.4.6. 3-(Benzylamino)-5-(trifluoromethyl)biphenyl-2,4-
dicarbonitrile (5f). 0.74 g, 78% pale yellow solid; mp
143 8C; [Found: C, 70.04; H, 3.76; N, 11.11. C22H14F3N3
requires C, 70.02; H, 3.74; N, 11.13%]; nmax (KBr) 3378
(NH), 2220 (CN), 1558, 1466, 1382, 1283 cmK1; dH
(200 MHz, CDCl3) 5.03 (2H, d, JZ5.8 Hz, CH2), 5.58
(1H, br s, NH), 7.18 (1H, s, H–C (4)), 7.4 (5H, s, aromatic
H), 7.55 (5H, s, aromatic H); m/z (LSIMS) 377 (MC,
100%), 91 (45%).
4.5.5. Ethyl 3-amino-1-benzyl-7-cyano-6-methyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylate (6c). 0.13 g, 17%
red solid; mp 125 8C; [Found: C, 62.81; H, 4.53; N, 10.49.
C21H18F3N3O2 requires C, 62.84; H, 4.52; N, 10.46%]; nmax
(KBr) 3490, 3372 (NH2), 2982 (C–H), 2223 (CN), 1677
(CO), 1610, 1524, 1262, 733 cmK1; dH (200 MHz, CDCl3)
1.26 (3H, t, JZ7.3 Hz, CH3), 2.87 (3H, s, CH3), 4.33 (2H, q,
JZ6.7 Hz, O–CH2), 5.32 (2H, br s, NH2), 6.17 (2H, s,
N–CH2), 6.9 (2H, m, aromatic H), 7.09 (1H, s, H–C (5)), 7.2
(3H, m, aromatic H); m/z (LSIMS) 402 (MHC, 52%), 401
(MC, 100%).
4.5. N-Alkyl-2-ethylcarboxy-3-amino-4/6-trifluoro-
methyl-6/4-substituted 7-cyano-indole derivatives (6 and
7). General procedure
The substituted aniline 5 (3.17 mmol) was dissolved in
MeCN (9 mL) and anhydrous potassium carbonate
(6.34 mmol) followed by ethyl bromoacetate (3.30 mmol)
with a catalytic amount of potassium iodide (10 mg) was
added to it. The resulting mixture was refluxed for 10–12 h
under N2 atmosphere. The reaction mixture is cooled to
room temperature, concentrated in vacuum to remove water
miscible acetonitrile. To the residue, ice-cold water was
added and extracted with ethyl acetate. The organic layer
was washed with brine, followed by water and dried over
anhyd Na2SO4. Concentrated and chromatographed using
Silica gel of 100–200 mesh and hexane–EtOAc, (100:3) as
eluents to afford the pure product.
4.5.6. Ethyl 3-amino-1-benzyl-7-cyano-4-methyl-6-(tri-
fluoromethyl)-1H-indole-2-carboxylate (7c). 0.63 g, 83%
yellow solid; mp 139 8C; [Found: C, 62.82; H, 4.55; N,
10.42. C21H18F3N3O2 requires C, 62.84; H, 4.52; N,
10.47%]; nmax (KBr) 3491, 3379 (NH2), 2990 (C–H),
2222 (CN), 1678 (CO), 1611, 1525, 1337, 733 cmK1; dH
(200 MHz, CDCl3) 1.28 (3H, t, JZ7.3 Hz, CH3), 2.69 (3H,
s, CH3), 4.35 (2H, q, JZ6.7 Hz, O–CH2), 5.49 (2H, br s,
NH2), 6.22 (2H, s, N–CH2), 6.92 (2H, m, aromatic H), 7.25
(1H, s, H–C (5)), 7.30 (3H, m, aromatic H); m/z (LSIMS)
402 (MHC, 55%), 401 (MC, 100%), 91 (67%).
4.5.1. Ethyl 3-amino-7-cyano-1,6-dimethyl-4-(trifluoro-
methyl)-1H-indole-2-carboxylate (6a). 0.12 g, 23% red
solid; mp 174 8C; [Found: C, 55.35; H, 4.39; N, 12.88.
C15H14F3N3O2 requires C, 55.38; H, 4.34; N, 12.92%]; nmax
(KBr) 3502, 3404 (NH2), 2984 (C–H), 2226 (CN), 1691
(CO), 1614, 1474 cmK1; dH (200 MHz, CDCl3) 1.45 (3H, t,
JZ6.9 Hz, CH3), 2.82 (3H, s, CH3), 4.30 (3H, s, N–CH3),
4.45 (2H, q, JZ6.8 Hz, OCH2), 5.2 (2H, br s, NH2), 7.05
(1H, s, H–C (5)); m/z (LSIMS) 326 (MHC, 42%) 325 (MC,
100%).
4.5.7. Ethyl 3-amino-7-cyano-1-methyl-6-phenyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylate (6d). 0.77 g, 90%
red solid; mp 147 8C; [Found: C, 62.06; H, 4.19; N, 10.81.
C20H16F3N3O2 requires C, 62.01; H, 4.16; N, 10.85%]; nmax
(KBr) 3519, 3380 (NH2), 2979 (C–H), 2218 (CN), 1665
(CO), 1605, 1513, 1443, 620 cmK1; dH (200 MHz, CDCl3)
1.42 (3H, t, JZ6.9 Hz, CH3), 4.35 (3H, s, N–CH3), 4.40
(2H, q, JZ6.9 Hz, O–CH2), 4.71 (2H, br s, NH2), 7.18 (1H,
s, H–C (5)), 7.45 (2H, m, aromatic H), 7.52 (3H, m,
aromatic H); m/z (LSIMS) 388 (MHC, 49%), 387 (MC,
100%).
4.5.2. Ethyl 3-amino-7-cyano-1,4-dimethyl-6-(trifluoro-
methyl)-1H-indole-2- carboxylate (7a). 0.4 g, 77% yellow
solid; mp 133 8C; [Found: C, 55.31; H, 4.31; N, 12.89.
C15H14F3N3O2 requires C, 55.38; H, 4.34; N, 12.92%]; nmax
(KBr) 3521, 3410 (NH2), 2892 (C–H), 2218 (CN), 1689

4006
D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
4.5.8. Ethyl 3-amino-7-cyano-1-methyl-4-phenyl-6-(tri-
fluoromethyl)-1H-indole-2-carboxylate (7d). 0.08 g, 10%
yellow solid; mp 217 8C; [Found: C, 62.05; H, 4.12; N,
10.81. C20H16F3N3O2 requires C, 62.01; H, 4.16; N,
10.85%]; nmax (KBr) 3520, 3381 (NH2), 2980 (C–H),
2219 (CN), 1667 (CO), 1607, 1514, 1445, 621 cmK1; dH
(200 MHz, CDCl3) 1.51 (3H, t, JZ6.9 Hz, CH3), 4.37 (3H,
s, N–CH3), 4.45 (2H, q, JZ6.9 Hz, O–CH2), 5.40 (2H, br s,
NH2), 7.42 (1H, s, H–C (5)), 7.55 (5H, m, aromatic H); m/z
(LSIMS) 388 (MHC, 45%), 387 (MC, 100%).
mixture was poured in crushed ice, then neutralised
with glacial acetic acid till it shows acidic to litmus
paper. Separated solid was filtered, washed with water and
dried.
4.6.1. 3-Amino-7-(aminocarbonyl)-1,6-dimethyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylic acid (8a). 0.5 g,
78% brown colored solid; mp 168 8C; [Found: C, 49.51;
H, 3.81; N, 13.29. C13H12F3N3O3 requires C, 49.53; H, 3.84;
N, 13.33%]; nmax (KBr) 3414, 2360, 1730, 1670, 1132 cmK1
;
dH (200 MHz, CDCl3) 2.75 (3H, s, CH3), 3.92 (3H, s, N–
CH3), 5.4 (2H, br s, NH2), 6.95 (1H, s, H–C(5)), 7.92 (1H,s,
NH, CONH2), 8.19 (1H, s, NH, CONH2); m/z (LSIMS) 315
(MC), 271.
4.5.9. Ethyl 3-amino-7-cyano-1-ethyl-6-phenyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylate (6e). 0.9 g, 89%
red solid; mp 120 8C; [Found: C, 62.88; H, 4.59; N, 10.41.
C21H18F3N3O2 requires C, 62.84; H, 4.52; N, 10.47%]; nmax
(KBr) 3382 (NH2), 2960 (C–H), 2221 (CN), 1688 (CO),
1603 cmK1; dH (200 MHz, CDCl3) 1.5 (6H, t, JZ6.9 Hz,
2CH3), 4.40 (2H, q, JZ7.0 Hz, N–CH2), 4.7 (2H, br s,
NH2), 4.98 (2H, q, JZ7.0 Hz, O–CH2), 7.19 (1H, s, H–C
(5)), 7.5 (5H, m, aromatic-H); m/z (LSIMS) 402 (MHC,
72%), 401 (MC, 100%).
4.6.2. 3-Amino-7-(aminocarbonyl)-1-benzyl-6-methyl-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8b).
0.56 g, 72% brown colored solid; mp 157 8C; [Found: C,
58.27; H, 4.11; N, 10.71. C19H16F3N3O3 requires C, 58.31;
H, 4.12; N, 10.74%]; nmax (KBr) 3444, 2360, 1660,
1117 cmK1; dH (200 MHz, CDCl3) 2.72 (3H, s, CH3),
5.35 (2H, br s, NH2), 6.78 (2H, s, N–CH2), 6.98 (1H, s,
H–C(5)), 7.08–7.15 (5H, m, phenyl), 7.82 (1H, s, NH,
CONH2), 8.12 (1H, s, NH, CONH2); m/z (LSIMS) 392
(MHC), 391, 347, 91.
4.5.10. Ethyl 3-amino-7-cyano-1-ethyl-4-phenyl-6-(tri-
fluoromethyl)-1H-indole-2-carboxylate (7e). 0.11 g, 11%
yellow solid; mp 196 8C; [Found: C, 62.88; H, 4.57; N,
10.43. C21H18F3N3O2 requires C, 62.84; H, 4.52; N,
10.47%]; nmax (KBr) 3496, 3366 (NH2), 2963 (C–H),
2223 (CN), 1667 (CO), 1122 cmK1; dH (200 MHz, CDCl3)
1.5 (6H, t, JZ6.9 Hz, 2CH3), 4.45 (2H, q, JZ7.0 Hz, N–
CH2), 5.0 (2H, q, JZ7.0 Hz, O–CH2), 5.42 (2H, br s, NH2),
7.4 (1H, s, H–C (5)), 7.57 (5H, m, aromatic-H); m/z
(LSIMS) 402 (MHC, 72%), 401 (MC, 100%).
4.6.3. 3-Amino-7-(aminocarbonyl)-1-ethyl-6-methyl-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8c).
0.45 g, 68% brown colored solid; mp 182 8C; [Found: C,
51.02; H, 4.23; N, 12.72. C14H14F3N3O3 requires C, 51.07;
H, 4.29; N, 12.76%]; nmax (KBr) 3425, 2372, 1725, 1692,
1135 cmK1; dH (200 MHz, CDCl3) 1.45 (3H, t, CH3), 2.62
(3H, s, CH3), 4.3 (2H, q, N–CH2), 5.20 (2H, br s, NH2), 7.0
(1H, s, H–C(5)), 7.65 (1H, s, NH, CONH2), 7.9 (1H, s, NH,
CONH2); m/z (LSIMS) 329 (MC), 285.
4.5.11. Ethyl 3-amino-1-benzyl-7-cyano-6-phenyl-4-(tri-
fluoromethyl)-1H-indole-2-carboxylate (6f). 1.19 g, 93%
red solid; mp 125 8C; [Found: C, 67.36; H, 4.39; N, 9.09.
C26H20F3N3O2 requires C, 67.38; H, 4.35; N, 9.07%]; nmax
(KBr) 3450, 3378 (NH2), 2923 (C–H), 2232 (CN), 1672
(CO), 1135 cmK1; dH (200 MHz, CDCl3) 1.28 (3H, t, JZ
7.1 Hz, CH3), 4.30 (2H, q, JZ7.0 Hz, OCH2), 4.83 (2H, br
s, NH2), 6.25 (2H, s, N–CH2), 6.97 (2H, m, aromatic H),
7.23 (1H, s, H–C (5)), 7.25 (3H, m, aromatic H), 7.50 (5H,
m, aromatic-H); m/z (LSIMS) 464 (MHC, 60%), 463 (MC,
100%), 91 (46%).
4.6.4. 3-Amino-7-(aminocarbonyl)-1-methyl-6-phenyl-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8d).
0.64 g, 85% brown colored solid; mp 178 8C; [Found: C,
57.27; H, 3.72; N, 11.11. C18H14F3N3O3 requires C, 57.30;
H, 3.74; N, 11.14%]; nmax (KBr) 3448, 2320, 1659, 1370,
1128 cmK1; dH (200 MHz, CDCl3) 4.2 (3H, s, CH3), 5.15
(2H, br s, NH2), 6.99 (1H, s, H–C(5)), 7.45 (2H, m, phenyl),
7.55 (3H, m, phenyl), 8.05 (1H, s, NH, CONH2) 8.32 (1H, s,
NH, CONH2); m/z (LSIMS) 377 (MC), 333.
4.5.12. Ethyl 3-amino-1-benzyl-7-cyano-4-phenyl-6-(tri-
fluoromethyl)-1H-indole-2-carboxylate (7f). 0.09 g, 7%
yellow solid; mp 159 8C; [Found: C, 67.32; H, 4.31; N, 9.11.
C26H20F3N3O2 requires C, 67.38; H, 4.35; N, 9.07%]; nmax
(KBr) 3451, 3378 (NH2), 2922 (C–H), 2234 (CN), 1673
(CO), and 1136 cmK1; dH (200 MHz, CDCl3) 1.30 (3H, t,
JZ7.1 Hz, CH3), 4.32 (2H, q, JZ7.0 Hz, O–CH2), 5.52
(2H, br s, NH2) 6.25 (2H, s, N–CH2), 6.93 (2H, m, aromatic
H), 7.25 (3H, m, aromatic H), 7.45 (1H, s, H–C (5)), 7.51
(5H, m, aromatic-H); m/z (LSIMS) 464 (MHC, 72%), 463
(MC, 100%) 91 (46%).
4.6.5. 3-Amino-7-(aminocarbonyl)-1-benzyl-6-phenyl-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8e).
0.73 g, 81% brown colored solid; mp 150 8C; [Found: C,
63.53; H, 3.97; N, 9.24. C24H18F3N3O3 requires C, 63.57; H,
4.00; N, 9.27%]; nmax (KBr) 3446, 2380, 1652, 1381,
1121 cmK1; dH (200 MHz, CDCl3) 5.43 (2H, br s, NH2),
5.73 (2H, s, N–CH2), 7.1 (1H, s, H–C(5)), 7.15 (2H, m,
phenyl), 7.32 (3H, m, phenyl), 7.5 (5H, m, phenyl), 7.61
(1H, s, NH, CONH2), 7.85 (1H, s, NH, CONH2); m/z
(LSIMS) 453 (MC), 409, 91.
4.6. Preparation of 3-amino-7-(aminocarbonyl)-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8a–f)
4.6.6. 3-Amino-7-(aminocarbonyl)-1-ethyl-6-phenyl-4-
(trifluoromethyl)-1H-indole-2-carboxylic acid (8f).
0.6 g, 77% brown colored solid; mp 135 8C; [Found: C,
58.27; H, 4.09; N, 10.71. C19H16F3N3O3 requires C, 58.31;
H, 4.12; N, 10.74%]; nmax (KBr) 3435, 3369, 2380, 1659,
1262 cmK1; dH (200 MHz, CDCl3) 1.23 (3H, t, CH3), 4.75
The ethyl 3-amino-4-trifluoromethyl substituted 1H-indole-
2-carboxylate (2 mmol) was suspended in 20% potassium
hydroxide solution (5 mL) and refluxed for 2 h. Reaction

D. Maitraie et al. / Tetrahedron 61 (2005) 3999–4008
4007
(2H, q, N–CH2), 5.46 (2H, br s, NH2), 7.01 (1H, s, H–C(5)),
7.41–7.49 (5H, m, phenyl), 7.52 (1H, s, NH, CONH2), 7.89
(1H, s, NH, CONH2); m/z (LSIMS) 391 (MC), 347.
4.7.6. 5-Ethyl-2-methyl-4-oxo-7-phenyl-9-(trifluoro-
methyl)-4,5-dihydro[1,3] oxazino[5,4-b]indole-6-carbo-
nitrile(9f). 0.3 g, 78% pale yellow colored solid; mp
205 8C; [Found: C, 63.43; H, 3.51; N, 10.54.
C21H14F3N3O2 requires C, 63.48; H, 3.55; N, 10.58%];
nmax (KBr) 2984, 2207, 1747, 1194 cmK1; dH (200 MHz,
CDCl3) 1.65 (3H, t, CH3), 2.35 (3H, s, CH3), 5.2 (2H, q,
CH2), 7.4 (1H, s, H–C(8)), 7.43–7.56 (5H, m, phenyl); m/z
(LSIMS) 397 (MC).
4.7. Preparation of 2-methyl-4-oxo-7-substituted-9-
(trifluoromethyl)-4,5-dihydro[1,3] oxazino[5,4-b]-6-
carbonitriles (9a–f)
The 3-amino-7-(aminocarbonyl)-4-(trifluoromethyl)-1H-
indole-2-carboxylic acids (1 mmol) were taken in acetic
anhydride (2 mL), heated to reflux for 2 h. The reaction
mixture was cooled to room temperature and poured into
crushed ice. The separated solid was extracted with
chloroform dried over sodium sulphate and concentrated.
The crude product is purified through column using Silica
gel and EtOAc–hexane (5:100) as eluents.
Acknowledgements
Authors are thankful to Dr. J. S. Yadav, Director, IICT
and Shri S. Narayan Reddy, Head Fluoroorganic
division for their constant encouragement. D. M., G. V. R,
V. V. V. N. S. S. R. and S. R. K. are also thankful to Council
of Scientific and Industrial Research (CSIR), New Delhi,
India for the financial support in the form of Senior
Research Fellowship (SRF) grant.
4.7.1. 2,5,7-Trimethyl-4-oxo-9-(trifluoromethyl)-4,5-
dihydro[1,3]oxazino[5,4-b] indole-6-carbonitrile (9a).
0.26 g, 82% pale yellow colored solid; mp 210 8C;
[Found: C, 56.02; H, 3.11; N, 13.03. C15H10F3N3O2 requires
C, 56.08; H, 3.14; N, 13.08%]; nmax (KBr) 2971, 2223,
1742, 1615, 1122 cmK1; dH (200 MHz, CDCl3) 2.5 (3H, s,
CH3), 2.93 (3H, s, CH3), 4.55 (3H, s, CH3), 7.32 (1H, s,
H–C(8)); m/z (LSIMS) 321 (MC).
References and notes
4.7.2. 5-Benzyl-2,7-dimethyl-4-oxo-9-(trifluoromethyl)-
4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitrile
(9b). 0.32 g, 80% pale yellow colored solid; mp 212 8C;
[Found: C, 63.43; H, 3.52; N, 10.54. C21H14F3N3O2 requires
C, 63.48; H, 3.55; N, 10.58%]; nmax (KBr) 2976, 2224,
1747, 1615, 1338, 1127 cmK1; dH (200 MHz, CDCl3) 2.58
(3H, s, CH3), 3.02 (3H, s, CH3), 6.35 (2H, s, CH2), 7.1 (2H,
m, phenyl), 7.25 (3H, m, phenyl), 7.41 (1H, s, H–C(8)); m/z
(LSIMS) 397 (MC).
1. Tarkaharu, K.; Kazuo, T.; Restu, H.; Usaji, T. Jpn. Kokai
Tokkyo Koho JP. 08, 319, 273, 1996. Chem. Abstr. 1997, 126,
1040001n.
2. (a) Sundberg, R. J. Indoles; Academic: London, 1996. (b)
Joshi, K. C.; Chand, P. Die Pharmazie. 1982, 37, 1. Sugden,
J. K.; Yoloye, T. O. Pharma. Acta Helv. 1978, 53, 65.
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Alan, P. W.; Bindi, S.; Denise, R.; Margaret, S. B.; Josephine,
A. S. J. Med. Chem. 1998, 41, 2667. (c) Strupczewski, J. D.;
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4.7.3. 5-Ethyl-2,7-dimethyl-4-oxo-9-(trifluoromethyl)-
4,5-dihydro[1,3]oxazino[5,4-b]indole-6-carbonitrile (9c).
0.26 g, 78% pale yellow colored solid; mp 198 8C; [Found:
C, 57.28; H, 3.59; N, 12.51. C16H12F3N3O2 requires C,
57.32; H, 3.61; N, 12.53%]; nmax (KBr) 2983, 2229, 1752,
1622, 1131 cmK1; dH (200 MHz, CDCl3) 1.68 (3H, t, CH3),
2.51 (3H, s, CH3), 2.91 (3H, s, CH3), 4.72 (2H, q, CH2), 7.35
(1H, s, H–C(8)); m/z (LSIMS) 335 (MC).
6. Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.;
May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso,
M.; Tan, C.; Voorman, R. L.; Reusser, F.; Althaus, I. W.;
Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.;
Aristoff, P. A. J. Med. Chem. 1994, 37, 999.
4.7.4. 2,5-Dimethyl-4-oxo-7-phenyl-9-(trifluoromethyl)-
4,5-dihydro[1,3]oxazino [5,4-b]indole-6-carbonitrile
(9d). 0.31 g, 82% pale yellow colored solid; mp 220 8C;
[Found: C, 62.63; H, 3.11; N, 10.92. C20H12F3N3O2 requires
C, 62.67; H, 3.16; N, 10.96%]; nmax (KBr) 2222, 1748,
1618, 1217, 1130 cmK1; dH (200 MHz, CDCl3) 2.62 (3H, s,
CH3), 4.7 (3H, s, CH3), 7.5–7.65 (5H, m, phenyl), 7.71 (1H,
s, H–C(8)); m/z (LSIMS) 383 (MC).
7. Romero, D. L. In Bristol, J. A., Ed.; Annual Reports Medicinal
Chemistry; Academic: New York, 1994; Vol. 29, p 123.
8. (a) Wen-Tai, L.; Der-Ren, H.; Ching-Ping, C.; Chien-Wei, S.;
Chen-Long, H.; Tung-Wei, S.; Chi-Hung, L.; Yee-Ling, C.;
Ying-Ying, C.; Yue-Kan, L.; Huan-Yi, T.; Chu-Chung, L.;
Jeng-Shin, S.; Hua-Chien, C.; Shu-Jen, C.; Se-Hui, W.;
Chiung-Tong, C. J. Med. Chem. 2003, 46, 1706. (b) Mattew,
A. N.; Elizabeth, S.; Steven, A. E.; Mohammed, J.; John, N.;
Naomi, R.; Stacey, D. L.; Kantilal, B. P.; Madeleine, F. D.;
Michael, R. L. S.; Peter, W.; Gerald, E. A.; Christopher, J. M.;
Ian, S. J. J. Med. Chem. 1998, 41, 2720. (c) Shoumin, W.; Nan,
C. W.; John, H.; Warren, M.; Irina, C.; Sukhjit, S.; Timothy,
C. H.; Stewart, B.; Adrian, F.; Francis, W.; Deanne, T.; Simon,
C.; Haylay, F.; Anthony, B.; Caroline, F.; Jan, B.; John, S.;
Paul, D.; Richard, F.; Prakash, M.; Peter, C. J. Med. Chem.
4.7.5. 5-Benzyl-2-methyl-4-oxo-7-phenyl-9-(trifluoro-
methyl)-4,5-dihydro[1,3] oxazino [5,4-b]indole-6-carbo-
nitrile (9e). 0.35 g, 76% pale yellow colored solid; mp
232 8C; [Found: C, 67.94; H, 3.48; N, 9.11. C26H16F3N3O2
requires C, 67.97; H, 3.51; N, 9.15%]; nmax (KBr) 2228,
1752, 1612, 1214, 1128 cmK1; dH (200 MHz, CDCl3) 2.38
(3H, s, CH3), 6.43 (2H, s, CH2), 7.15 (1H, s, H–C(8)), 7.22–
7.27 (5H, m, phenyl), 7.49 (3H, m, phenyl), 7.58 (2H, m,
phenyl); m/z (LSIMS) 459 (MC).

4008
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Gribble, G. W. J. Chem. Soc. Perkin. Trans. 1 2000, 1045.
10. Maitraie, D.; Venkat Reddy, G.; Rama Rao, V. V. V. N. S.;
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