Synthesis of novel fluorinated 11h-azaindolo[3,2-c]isoquinolines

Article abstract of DOI:10.1002/jhet.1511

A series of novel fluorinated 11H-azaindolo[3,2-c]isoquinolines (7) have been synthesized starting from 2(1H)pyridones (1) via azaindoles (5). Initially, compound 1 was treated with POCl₃/DMF, and the resulting compound 2 was reacted with benzy

Full text of DOI:10.1002/jhet.1511

Month 2013
Synthesis of Novel Fluorinated 11H-Azaindolo[3,2-c]isoquinolines
Krishnaiah Atmakur, * Narender Reddy Emmadi, and Sridhar Balasubramanian
a,
a
b
a
Organic Chemistry Division-II, Indian Institute of Chemical Technology Hyderabad, 500 007, India
Laboratory of X-Ray Crystallography, Indian Institute of Chemical Technology Hyderabad, 500 007, India
b
*
E-mail: krishnua@rediffmail.com
Received June 17, 2011
DOI 10.1002/jhet.1511
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel fluorinated 11H-azaindolo[3,2-c]isoquinolines (7) have been synthesized starting
from 2(1H)pyridones (1) via azaindoles (5). Initially, compound 1 was treated with POCl /DMF, and the
3
resulting compound 2 was reacted with benzylamine to obtain compounds 3 that were subjected to cycliza-
tion after protecting the secondary amine to get azaindoles (5). Further, compounds 5 were subjected to cy-
clization as per Pictet–Spengler reaction condition. However, it was not successful. Subsequently, the
azaindoles (5) were acetylated and then cyclized to give title compounds 7. These compounds are new
and well characterized by spectral data.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
substituted azaindoloisoquinolines (7) by a novel method.
In this instance, 3-amino-2,6-diphenyl-4-trifluoromethyl
azaindoles (5) have been prepared starting from 3-cyano-
Pyrrolo[2,3-b]pyridines also known as azaindoles have
received significant synthetic importance as they have
been used as various pharmaceutical [1–4] and antipsy-
chotic agents [5–9]. Tetracyclic ring systems similar to
indoloquinolines and indoloisoquinolines have received
considerable synthetic importance because of their inter-
esting biological properties such as anti-inflammatory, anti-
tumor, antibacterial, and fungicidalactivities [10–12].
Further, indoloisoquinolines constitute important struc-
tural moieties in natural products, and adoption of an addi-
tional nitrogen atom in the aromatic ring confers its own
unique properties to the systems. In addition, the presence
of fluorine at a specified position in a molecule alters the
reactivity apart from liphophilicity. The synthesis of iso-
quinolines and indoloisoquinolines has been extensively
reported in the literature [13]. However, no reports are
available on the synthesis of azaindoloisoquinolines as
availability of natural azaindoles is relatively scarce.
Hence, the synthesis of azaindoloisoquinolines especially
trifluoromethyl-substituted azaindoloisoquinolines is of
significant importance.
4
-trifluoromethyl-6-phenyl-2(1H) pyridones (1). Thus,
compound 1 was reacted with benzylamine to obtain 2-N-
benzylamino-3-cyano-4-trifluoromethyl-6-phenylpyridine (3)
to prepare 5.
Here, it is interesting to mention the important finding
that NMR of the crude product 2(1H) pyridone and ben-
zylamine reaction has shown the protons corresponding
to benzyl function, but mass spectrum confirmed the
molecular ion peak corresponding to benzylamine addi-
tion onto compound 1 instead of product 3. However,
when the crude product was passed through the column
of silica gel, the starting material 1 was recovered (on
the basis of NMR and mass data). To clear the ambigu-
ity, the crude product was recrystallized and the X-ray
crystallograph was recorded. Surprisingly, it was known
by X-ray crystallography data that the benzyl amine
functional and 2(1H) pyridone were in the form of a salt
(
Fig. 1).
It could be reasoned that the existence of salt form was at-
tributed to the starting material 1 to come back when passed
through column of silica gel that is of acidic nature. This was
further confirmed by adding few drops of HCl to the crude
product. Therefore, compound 3 was prepared by an alter-
nate method where compound 1 was treated with POCl3/
DMF, and the resulted 2-chloro-3-cyano-4-trifluoromethyl-
6-phenylpyridine (2) was then reacted with benzylamine to
give compound 3 (Schemes 1).
RESULTS AND DISCUSSION
In continuation of our work on the synthesis of
pyrazolopyridines [14] starting from 2(1H) pyridones (1),
their subsequent utilization in ring fusion reactions has
prompted us to synthesize 7-azaindoles and construct
isoquinoline ring system over them. Therefore, we are
reporting here a hitherto unreported trifluoromethyl-
Efforts to cyclize compound 3 onto nitrile group in the
presence of a base to obtain azaindoles (5) were
©
2013 HeteroCorporation

K. Atmakur, N. R. Emmadi, and S. Balasubramanian
Vol 000
Figure 1. (X-ray crystallograph. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Azaindoles and Azaindoloisoquinolines
Scheme 3
Scheme 4
in DMF (10mL), triethylamine (0.40 ml) was added followed by
unsuccessful. However, when the secondary amine was
protected with alkyl or benzyl functional (4) and subjected
to cyclization under basic condition, the desired com-
pounds (5) were obtained (Schemes 2.
Further, compound 5 was unsuccessfully subjected to
cyclization using, p-formaldehyde in the presence of
trifluoroaceticacid to obtain title compounds (7) as per
Pictet–Spengler reaction condition (Schemes 3.
ꢀ
POCl
3
(2.8 mL), and the reaction mass was heated to 90 C for
8
h while stirring. After completion of reaction, the mass was
brought to room temperature and transferred on to crushed ice.
The uniform aqueous mass was extracted with ethylacetate
(
3 Â 50 mL) for desired compound. After evaporation of organic
solvent under reduced pressure, the leftover residual mass was
purified by column chromatography (silica gel 60–120) with the
use of hexane and ethylacetate as eluent (90:10) to afford
1
compound 2.Yield 84%, mp 88–90 C. H NMR (CDCl3;
Hence, compounds 5 were first acetylated and the resulted
compounds 6 were then cyclized in the presence of P O in
3
7
1
00 MHz) d 8.12–8.08 (m, 2H, ArH), 8.0 (s, 1H, ArH), 7.57–
2
5
.50 (m, 3H, ArH) ppm. IR (KBr) 3087, 2922, 2234, 1595, 1376,
toluene to afford 11H-azaindolo, [3,2-c]isoquinolines (7) in
high yields (Schemes 4.
À1
+
314, 1262, 1144 cm . MS (ESI) m/z 283 (M + H) .
Preparation of 2-benzylamino-6-phenyl-4-triflouromethyl-
In conclusion, we have synthesized a number of new
fluorinated azaindoloisoquinoline molecules, and the
described methodologies are useful tools to synthesize a
number of new heterocyclic compounds of biological interest.
nicotinonitrile (3).
in DMF (20 mL), benzylamine (1.636 g, 15.31 mmol) was added
To a solution of 2 (3.60 g, 12.76 mmol)
followed by K
2
CO
3
(2.54 g, 25.53 mmol), and the reaction
ꢀ
mixture was heated to 80 C for 2 h while stirring. After
completion of reaction as indicated by TLC, the mass was
allowed to come to room temperature and transferred on to
crushed ice. The desired compound in aqueous mass was
extracted with ethylacetate (3 Â 50 mL), dried over anhydrous
sodium sulfate, and the solvent evaporated under reduced
pressure. The crude product was purified by column
chromatography (silica gel 60–120) with the use of hexane and
ethylacetate as eluent (90:10) to afford compound 3. Yield 94%,
EXPERIMENTAL
Melting points were determined in open glass capillaries on a
Fischer-Johns melting point apparatus (Canada) and were uncor-
1
rected. H NMR spectra were recorded on 300-MHz (Bruker,
Switzerland) and 500-MHz (Varian, USA) spectrometers
ꢀ
1
3 6
(CDCl /DMSO-d ) with TMS as internal standard. IR spectra were
mp 158–160 C. H NMR (CDCl ; 300 MHz) d 8.0 (s, 1H,
3
recorded on Nicolet Nexus 670 spectrometer (USA) IR instrument
on KBr pellets. Mass spectra were recorded on low resolution mass
spectra (ESI-MS), and HRMS were recorded on MicroMass Quat-
tro LC (Applied biosystems /MDS Sciex, USA) and QSTAR XL
ArH), 7.56–7.39 (m, 5H, ArH), 7.38–7.20 (m, 5H, ArH), 4.80
(s, 2H, Ph–CH –N) ppm.IR (KBr) 3363, 3062, 2927, 2214,
2
À1
+
1572, 1372, 1261, 1131, 1058 cm . MS (ESI) m/z 354 (M + H) .
General procedure for the preparation of 2-(benzyl-
substituted-amino)-6-phenyl-4-trifluoromethyl-nicotinonitrile
(4a–4c). To a solution of compound 3 (1.0 g, 2.82 mmol) in
acetone (10 mL), NaOH (0.224 g, 5.64 mmol) and methyl
iodide (0.26 ml) was added, and the reaction mixture was
heated to reflux while stirring. After completion of reaction
1
3
spectrometers(Manchester, UK), respectively. C NMR spectra
19
were recorded on 75-MHz and 125-MHz spectrometers. F NMR
spectra were recorded on 400-MHz spectrometer.
Preparation of 2-chlro-6-phenyl-4-trifluoromethyl-nicotino-
nitrile (2). To a solution of 2(1H) pyridone 1 (2.0 g, 7.5 mmol)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. Atmakur, N. R. Emmadi, and S. Balasubramanian
Vol 000
as indicated by TLC, the mass was cooled to room temperature
and transferred on to crushed ice, and the separated solid was
filtered and purified by column chromatography (silica gel
General procedure for the preparation of N-(1-substituted-
2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-
benzamide/acetamide (6a–6i). To a solution of compound 5a
(0.1 g, 0.244 mmol) in 1,4-dioxane(5 mL), acetyl chloride(0.026 mL,
1.5 eq) (in the case of benzoyl chloride and p-chlorobenzoyl
chloride (1.2 eq)) was slowly added at room temperature, and the
6
(
8
0–120) with the use of hexane and ethylacetate as eluent
90:10) to give compound 4a. The yields are in the range of
8–96%.
-(Benzyl-methyl-amino)-6-phenyl-4-trifluoromethyl nicoti-
ꢀ
2
reaction mass was heated to 90 C for 2 h while stirring. After
ꢀ
1
nonitrile (4a).
Yield 96%, mp 85–87 C; H NMR (CDCl
00 MHz) d 7.96–7.92(m, 2H, ArH), 7.45–7.41 (m, 4H, ArH),
.35–7.24 (m, 5H, ArH), 5.06 (s, 2H, Ph–CH –N), 3.38 (s, 3H,
3
;
completion of reaction as indicated by TLC, the 1,4-dioxane was
removed under reduced pressure, and ethylacetate was added to
the residue. The organic solution was washed with NaHCO3
solution and dried over the anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified by column
chromatography (silica gel 60–120) with the use of hexane and
ethylacetate as eluent (80:20) to give compound 6a. The yields
are in the range of 72–85%.
3
7
2
N–CH3) ppm. IR (KBr) 2924, 2205, 1558, 1414,
À1
+
1
(
372, 1257, 1130, 1006 cm . MS (ESI) m/z 368 (M + H) , 390
+
M + Na) .
-(Benzyl-ethyl-amino)-6-phenyl-4-trifluoromethyl nicotino-
2
ꢀ
1
nitrile (4b).
3
7
(
Yield 95%, mp 78–80 C; H NMR (CDCl3;
00 MHz) d 7.91–7.86 (m, 2H, ArH), 7.45–7.38 (m, 4H, ArH),
.34–7.22 (m, 5H, ArH), 5.04 (s, 2H, Ph–CH –N), 3.86
–CH ), 1.40 (t, J = 6.98 Hz, 3 H,
ppm. IR (KBr) 2925, 2854, 2207,1587,
N-(1-Methyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
ꢀ
1
2
pyridin-3-yl)-acetamide (6a).
Yield 85%, mp 221–223 C; H
q, J = 6.98Hz, 2H, N–CH
N–CH –CH
560,1495, 1371, 1259, 1140 cm
2
3
NMR (CDCl ; 300MHz) d 8.10 (d, J = 7.17 Hz, 2H, ArH), 7.84
3
2
3
)
(s, 1H, ArH), 7.56–7.36 (m, 8H, ArH), 6.54 (br s,1H, NH–CO),
À1
1
(
.
MS (ESI) m/z 382
3.89 (s, 3H, N–CH ) 2.12(s, 3H, COCH ) ppm. IR (KBr) 3360,
3
3
+
+
À1
M+ H) , 404 (M+ Na) .
-Di-benzylamino-6-phenyl-4-trifluoromethyl nicotinonitrile
4c). Yield 88%, mp 90–93 C; H NMR (CDCl
3059, 2925, 1602, 1461, 1372, 1260, 1123cm . MS (ESI) m/z
410 (M+ H) , 432 (M + Na) .
+
+
2
ꢀ
1
(
3
; 300 MHz)
N-(1-Methyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
ꢀ
1
d 7.94–7.89 (m, 2H, ArH), 7.47–7.39 (m, 4H, ArH), 7.35–7.22
pyridin-3-yl)-benzamide (6b). Yield 85%, mp 226–228 C; H
(
3
m, 10H, ArH), 5.01 (s, 4H, 2 Ph–CH –N) ppm. IR (KBr)
NMR (CDCl ; 300MHz) d 8.12 (d, J = 7.55 Hz, 2H, ArH), 7.86
(s, 1H, ArH), 7.78 (d, J = 6.79 Hz, 2H, ArH), 7.58 (d, J = 9.06 Hz,
2H, ArH), 7.52–7.39 (m, 9H, ArH), 7.23 (br s, 1H, NH–CO),
2
3
À1
030, 2925, 2217, 1583, 1553, 1443, 1373, 1257, 1133 cm
.
+
+
MS (ESI) m/z 444 (M + H) , 466 (M + Na) .
General procedure for the preparation of 1-substituted-2,6-
diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine
3.94 (s, 3H, N–CH ) ppm. IR (KBr) 3413, 2925, 1674, 1474,
3
À1
+
1366, 1260, 1129 cm . MS (ESI) m/z 472 (M + H) , 494
+
(
5a–5c).
2-(Benzyl-methyl-amino)-6-phenyl-4-trifluoromethyl-
(M+ Na) .
nicotinonitrile 4a (1 g, 2.72 mmol) was added to a mixture of
4-Chloro-N-(1-methyl-2,6-diphenyl-4-trifluoromethyl-1H-
NaH (5 eq) (60% w/w in mineral oil) in DMF (4 mL) at room
temperature and was stirred at 80 C for 1 h. After the reaction
pyrrolo[2,3-b]pyridin-3-yl)-benamide (6c).
Yield 72%, mp
ꢀ
ꢀ
1
220–223 C. H NMR (CDCl ; 300 MHz) d 8.10 (d, J = 7.55Hz,
3
was completed (monitored by TLC), the mass was cooled
to room temperature and transferred on to crushed ice. The
desired compound was extracted into ethylacetate (3 Â 20 mL);
the combined organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure. The
leftover residual mass was purified by column chromatography
2H, ArH), 7.83 (s, 1H, ArH), 7.729 (d, J = 8.31Hz, 2H, ArH),
7.56–7.36 (m, 10H, ArH), 7.24 (br s, 1H, NH–CO), 3.93
(s, 3H, N–CH )ppm. IR (KBr) 3217, 2922, 2851, 1649, 1528,
3
À1
+
1460, 1368, 1211, 1133 cm . MS (ESI) m/z 506 (M + H) , 528
+
(M + Na) .
N-(1-Ethyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
ꢀ
(
neutral alumina) with the use of hexane as eluent to obtain
pyridin-3-yl)-acetamide (6d).
Yield 85%, mp 220–222 C;
1
compound 5a as yellow color solid. The yields are in the range
of 76–77%.
H NMR (CDCl
7.84 (s, 1H, ArH), 7.55–7.39 (m, 8H, ArH), 6.50 (br s, 1H,
NH–CO), 4.39 (q, J = 7.17 Hz, 2H, N–CH –CH ), 2.06 (s, 3H,
COCH ), 1.32 (t, J = 7.17 Hz, 3H, N–CH –CH ) ppm. IR
3
; 300 MHz) d 8.09 (d, J = 8.498 Hz, 2H, ArH),
1
-Methyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
2
3
ꢀ
1
pyridin-3-ylamine (5a).
Yield 76%, mp100–101 C; H NMR
3
2
3
À1
(
CDCl ; 300 MHz) d 8.13 (d, J= 7.81 Hz, 2H, ArH), 7.74 (s, 1H,
(KBr) 3295, 2994, 2937, 1667, 1517, 1371, 1261, 1133 cm .
3
+
+
ArH), 7.54–7.48 (m, 4H, ArH), 7.46–7.34 (m, 4H, ArH), 3.82 (s,
MS (ESI) m/z 424 (M + H) , 446 (M + Na) .
N-(1-Ethyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
3
1
H, N–CH
532, 1371, 1124 cm . MS (ESI) m/z 368 (M + H) .
-Ethyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
3
), 3.40 (br s, 2H, NH) ppm. IR (KBr) 3268, 3059, 2924,
À1
+
ꢀ
1
pyridin-3-yl)–benzamide (6e). Yield 87%, mp 210–212 C; H
1
NMR (CDCl ; 300 MHz) d 8.10 (d, J = 7.36 Hz, 2H, ArH), 7.85
3
ꢀ
1
pyridin-3-ylamine (5b).
CDCl ; 300MHz) d 8.15 (d, J = 7.81 Hz, 2H, ArH), 7.75 (s,
H, ArH), 7.60–7.30 (m, 8H, ArH), 4.45–4.35 (q, J = 6.98 Hz, 2H,
N–CH –CH ), 3.35 (br s, 2H, NH), 1.25 (t, J = 6.98 Hz, 3H, N–
Yield 77%, mp 84–86 C; H NMR
(s, 1H, ArH), 7.75 (d, J = 6.79 Hz, 2H, ArH), 7.60–7.55 (m, 2H,
ArH), 7.51–7.37 (m, 9H, ArH), 7.18 (br s, 1H, NH–CO), 4.45
(
1
3
(q, J = 7.17 Hz, 2H, N–CH
2 3
–CH ), 1.43 (t, J = 7.17 Hz, 3H,
N–CH –CH ) ppm. IR (KBr) 3416, 3060, 2921, 2852, 1673,
2
3
2
3
À1
+
CH –CH ) ppm. IR (KBr) 3338, 2928, 1623, 1460, 1367, 1261,
1473, 1418, 1259, 1128 cm . MS (ESI) m/z 486 (M + H) ,
508 (M + Na) .
2
3
À1
+
+
1
115cm . MS (ESI) m/z 382 (M + H) .
1
-Benzyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
4-Chloro-N-(1-ethyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo
[2,3-b]pyridin-3-yl)-benzamide (6f). Yield 75%, mp 216–217 C;
H NMR (CDCl3; 300 MHz) d 9.79 (br s, 1H, NH–CO), 8.23 (d,
ꢀ
1
ꢀ
pyridin-3-ylamine (5c). Yield 77%, mp 98–100 C; H NMR
CDCl ; 300 MHz) d 8.10 (d, J = 7.36 Hz, 2H, ArH), 7.81 (s,
1
(
3
1
6
H, ArH), 7.52–7.31 (m, 9H, ArH), 7.18–7.11 (m, 2H, ArH),
J = 7.17 Hz, 2H, ArH), 7.98 (s, 1H, ArH), 7.86 (d, J= 8.49 Hz, 2H,
ArH), 7.62 (d, J= 6.42 Hz, 2H, ArH), 7.57–7.43 (m, 8H, ArH), 4.48
(q, J = 6.98Hz, 2H, N–CH –CH ), 1.33 (t, J = 6.98 Hz, 3H,
.93–6.88 (m, 2H, ArH), 5.51(s, 2H, Ph–CH –N) ppm. IR
2
À1
(
KBr) 3439, 3030, 2920, 1459, 1268, 1116 cm . MS (ESI)
2
3
+
+
m/z 444 (M + H) , 466 (M + Na) .
N–CH –CH ) ppm. IR (KBr) 3228, 2926, 2855, 1652, 1530,
2
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Azaindoles and Azaindoloisoquinolines
À1
+
À1
+
1
421, 1373, 1300, 1256 cm . MS (ESI) m/z 520 (M + H) , 542
1135 cm . MS (ESI) m/z 454 (M + H) , HRMS Calcd for
+
+
(
M + Na) .
8 18 3 3
C H F N (M + H) 454.1531. Found 454.1528.
2
N-(1-Benzyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
5
-(4-Chloro-phenyl)-11-methyl-9-phenyl-7-trifluoromethyl-11H-
ꢀ
1
pyridin-3-yl)-acetamide (6g).
Yield 73%, mp 138–140 C; H
6
2
,10,11-triaza-benzo[a]fluorine (7c).
Yield 83%, mp 276–
ꢀ
1
3
NMR(CDCl ; 500 MHz) d 8.06 (d, J = 6.83 Hz, 2H, ArH), 7.88
78 C; H NMR (CDCl3; 300 MHz) d 8.75 (d, J = 8.49 Hz, 1H,
(
s, 1H, ArH), 7.49–7.31 (m, 8H, ArH), 7.20–7.15 (m, 3H, ArH),
ArH), 8.35 (d, J = 8.49 Hz, 1H, ArH), 8.23 (d, J = 7.36 Hz, 2H,
7
2
2
6
.00–6.97 (m, 2H, ArH), 6.52 (br s, 1H, NH–CO), 5.55 (s,
H, Ph–CH –N), 2.07 (s, 3H, COCH ) ppm. IR (KBr) 3273,
925, 2853, 1661, 1515, 1441, 1367, 1263, 1127, 766,
ArH), 8.00 (s, 1H, ArH), 7.84–7.77 (m, 3H, ArH), 7.63–7.45
1
9
2
3
(
3 3
m, 6H, ArH), 4.68(s, 3H, N–CH ) ppm. F NMR(CDCl ;
1
3
4
1
1
1
1
00 MHz) d À62.92. C NMR (CDCl ; 75 MHZ) d 155.70,
3
À1
+
+
97 cm . MS (ESI) m/z 486 (M+ H) , 508 (M+ Na) .
41.99, 139.67, 136.23, 134.60, 131.99, 129.98, 129.60,
29.48, 128.96, 128.90, 128.44, 127.33, 127.24, 126.63,
21.97, 109.9 (q, JCF = 6.58 Hz), 29.70 ppm. IR (KBr) 2926,
N-(1-Benzyl-2,6-diphenyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]
ꢀ
1
pyridin-3-yl)-benzamide (6h). Yield 81%, mp 166–169 C; H
NMR (DMSO-d ; 300 MHz) d 9.07 (br s, 1H, NH–CO), 8.09 (d,
J = 7.17 Hz, 2H, ArH), 7.89 (s, 1H, ArH), 7.83 (d, J = 6.98 Hz,
À1
+
6
460, 1339, 1218, 1130 cm . MS (ESI) m/z 488 (M + H) ,
+
HRMS Calcd for C H ClF N (M + H) 488.1141. Found
2
8
17
3 3
2
H, ArH), 7.51–7.36 (m, 11H, ArH), 7.20–7.17 (m, 3H, ArH),
4
88.1143.
1-Ethyl-5-methyl-9-phenyl-7-trifluoromethyl-11H-6,10,11-
7
.04–6.99 (m, 2H, ArH), 5.65 (s, 2H, Ph–CH –N) ppm. IR
2
1
À1
(
KBr) 3097, 2956, 1748,1660, 1414, 1254cm . MS (ESI) m/z
ꢀ
1
triaza-benzo[a]fluorine (7d). Yield 78%, mp 202–205 C; H
+
+
5
48 (M + H) , 570 (M + Na) .
-Chloro-N-(1-benzyl-2,6-diphenyl-4-trifluoromethyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)-benzamide (6i). Yield 84%, mp
NMR (CDCl ; 300 MHz) d 8.52 (d, J = 8.31 Hz, 1H, ArH), 8.32
3
4
(
d, J = 8.31 Hz, 1H, ArH), 8.21 (d, J = 6.98 Hz, 2H, ArH), 8.00
(
s, 1H, ArH), 7.83 (t, J = 6.98 Hz, 1H, ArH), 7.67 (t,
ꢀ
1
1
2
7
78–179 C; H NMR (CDCl ; 300 MHz) 8.07 (d, J = 8.12 Hz,
3
J = 8.12 Hz, 1H, ArH), 7.54–7.41 (m, 3H, ArH), 5.21
H, ArH), 7.90 (s, 1H, ArH), 7.70 (d, J = 8.49 Hz, 2H, ArH),
.50–7.33 (m, 10H, ArH), 7.23–7.15 (m, 3H, ArH), 7.04–6.97
(
q, J = 7.17 Hz, 2H, N–CH –CH ), 3.11 (s, 3H, CH ), 1.67 (t,
2
3
3
19
J = 7.17 Hz, 3H, N–CH –CH ) ppm.
F
NMR (CDCl3;
2
3
(
m, 2H, ArH), 5.60 (s, 2H, Ph–CH
2
–N) ppm. IR (KBr) 3235,
13
À1
400 MHz) d À62.70. C NMR (CDCl
3 6
+ DMSO-d ; 100 MHz)
2
925, 1649, 1596, 1520, 1480, 1370, 1262, 1160, 1129 cm
.
+
+
d 152.40, 151.44, 149.51, 145.22, 141.66, 131.58, 129.29,
MS (ESI) m/z 582 (M + H) , 604 (M + Na) .
1
1
29.23, 129.12, 128.62, 128.58, 128.54, 128.08, 128.04,
26.54, 126.29, 125.88, 125.82, 123.41, 121.23, 108.65 (q,
General procedure for the preparation of 5,11-disubstituted-
9-phenyl-7-trifluoromethyl-11H-6,10,11-triaza-benzo[a]fluorine
J
1
CF = 4.50 Hz), 37.72, 23.45, 14.27 ppm. IR (KBr) 2924, 2854,
(
7a–7i). Compound 6a (0.1 g, 0.243 mmol) in toluene (15 mL)
À1
+
433, 1364, 1271, 1139 cm . MS (ESI) m/z 406 (M + H) ,
along with P O (0.5 g) was refluxed for 18 h. Then the
2
5
+
HRMS Calcd for C H F N (M + H) 406.1531. Found
2
4 18 3 3
reaction mixture was cooled to room temperature and poured
into ice cold water (30 mL).The solution was neutralized
with 2M NaOH and extracted with ethyl acetate (3 Â 30 mL).
The combined organic layer was dried over anhydrous
sodium sulfate, the solvent evaporated, and the leftover
residual mass purified by column chromatography (silica gel
4
06.1517.
1-Ethyl-5,9-diphenyl-7-trifluoromethyl-11H-6,10,11-triaza-
1
ꢀ
1
benzo[a]fluorine (7e). Yield 85%, mp 228–230 C; H NMR
CDCl ; 300 MHz) d 8.60 (d, J = 8.31 Hz, 1H, ArH), 8.44 (d,
(
3
J = 8.49 Hz, 1H, ArH), 8.23 (d, J = 8.31 Hz, 2H, ArH), 8.04 (s,
1
5
H, ArH), 7.86–7.80 (m, 3H, ArH), 7.64–7.42 (m, 7H, ArH),
.27 (q, J = 7.17 Hz, 2H, N–CH –CH ), 1.73 (t, J = 7.17 Hz, 3H,
6
(
7
0–120) with the use of hexane and ethyl acetate as eluent
90:10) to give compound 7a.The yields are in the range of
7–85%.
,11-Dimethyl-9-phenyl-7-trifluoromethyl-11H-6,10,11-triaza-
2
3
19
13
N–CH –CH ) ppm. F NMR(CDCl ; 400 MHz) d À62.79.
C
2
3
3
NMR (CDCl
138.76, 134.28, 131.97, 129.83, 129.46, 129.02, 128.93,
28.43, 127.23, 126.55, 125.72, 125.03, 121.95, 110.10 (q,
3
;75 MHz) d 153.97, 153.22, 151.07, 138.88,
5
ꢀ
1
benzo[a]fluorine (7a).
Yield 85%, mp 207–209 C; H NMR
1
(
(
(
CDCl ; 300MHz) d 8.69 (d, J = 8.49 Hz, 1H, ArH), 8.30
d, J = 8.31 Hz, 1H, ArH), 8.22 (d, J = 8.49 Hz, 2H, ArH), 8.00
s, 1H, ArH),7.79 (t, J = 7.36 Hz, 1H, ArH), 7.66 (t, J = 7.17 Hz,
3
JCF = 4.39 Hz), 38.71, 15.18 ppm. IR (KBr) 2928, 1727, 1594,
À1
1
462, 1433, 1366, 1342, 1225, 1134 cm . MS (ESI) m/z 468
+
+
1
3
H, ArH), 7.56–7.41 (m, 3H, ArH), 4.63 (s, 3H, N–CH ),
(M + H) . HRMS Calcd for C29
20 3 3
H F N (M + H) 468.1687.
3
1
9
.11 (s, 3H, CH
3
) ppm. F NMR (CDCl
; 75 MHz) d 152.38, 151.1, 138.88,
29.34, 129.39, 129.25, 128.49, 127.21, 127.10, 126.43,
3
; 400 MHz) d
Found 468.1667.
1
3
À62.64. C NMR (CDCl
3
5-(4-Chloro-phenyl)-11-ethyl-9-phenyl-7-trifluoromethyl-11H-
1
1
6,10,11-triaza-benzo[a]fluorine (7f).
Yield 78%, mp 220–
ꢀ
1
21.92, 109.65(q, JCF = 4.39 Hz) 31.47, 23.41 ppm. IR (KBr)
222 C; H NMR (CDCl
3
; 300 MHz) d 8.58 (d, J = 9.06 Hz, 1H,
À1
2
3
3
923, 2853, 1463, 1348, 1262, 1120, 1052 cm . MS (ESI) m/z
92 (M + H) . HRMS Calcd for
92.1374. Found 392.1374.
ArH), 8.38 (d, J = 8.31 Hz, 1H, ArH), 8.22 (d, J = 8.31 Hz, 2H,
ArH), 8.03 (s, 1H, ArH), 7.86–7.77 (m, 3H, ArH), 7.64–7.43
+
+
C
23
H
16
F
3
N
3
(M + H)
(m, 6H, ArH), 5.27 (q, J = 6.79 Hz, 2H, N–CH
–CH
F NMR(CDCl
NMR (CDCl ;75 MHz) d
), 1.71
2
3
19
1
1-Methyl-5,9-diphenyl-7-trifluoromethyl-11H-6,10,11-triaza-
(t, J = 6.79 Hz, 3H, N–CH
2
–CH
C
3
)
ppm.
3
;
ꢀ
1
13
benzo[a]fluorine (7b).
Yield 81%, mp 248–252 C; H NMR
400 MHz)
d
À62.91.
3
(
CDCl ; 300 MHz) d 8.72 (d, J = 8.31Hz, 1H, ArH), 8.40
153.97, 153.22, 151.07, 138.88, 138.76, 134.28, 131.97, 129.83,
129.46, 129.02, 128.93, 128.43, 127.23, 126.55, 125.72,
125.03,121.95,110.08 (q, JCF = 4.39 Hz), 38.69, 15.20 ppm. IR
3
(
d, J = 8.31 Hz,1H, ArH), 8.23 (d, J = 7.36Hz, 2H, ArH), 8.00
(
s, 1H, ArH), 7.86–7.75 (m, 3H, ArH), 7.61–7.42 (m, 7H, ArH),
19
À1
4
.66 (s, 3H, N–CH ) ppm. F NMR(CDCl ; 400 MHz) d À62.77.
(KBr) 2926, 1432, 1336, 1224, 1140cm . MS (ESI) m/z 502
3
3
1
3
+
+
3
C NMR (CDCl ; 75MHz) d 154.52, 153.74, 151.27, 140.13,
(M+ H) , 524 (M + Na) . HRMS Calcd for C29
H19ClF
3
N
3
+
138.76, 130.71, 129.40, 129.33, 129.25, 128.87, 128.53, 128.12,
(M+ H) 502.1297. Found 502.1281.
1
27.79, 127.18, 126.37, 125.91, 125.44, 121.77, 109.85
11-Benzyl-5-methyl-9-phenyl-7-trifluoromethyl-11H-6,10,11-
ꢀ
(q, JCF = 6.587 Hz), 29.67 ppm. IR (KBr) 2924, 2853, 1460,
triaza-benzo[a]fluorine (7g).
Yield 83%, mp 240–241 C;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. Atmakur, N. R. Emmadi, and S. Balasubramanian
Vol 000
1
H NMR (CDCl ; 300 MHz) d 8.28–8.24 (m, 2H, ArH), 8.17 (d,
calculated for all nonhydrogen atoms. The hydrogen atoms
attached to nitrogen atoms were located in a difference
density map and refined isotropically. All other H atoms were
positioned geometrically and treated as riding on their
parent C atoms, with C–H distances of 0.93–0.96 Å and with
3
J = 7.17 Hz, 2H, ArH), 8.06 (s, 1H, ArH), 7.60–7.57 (m, 2H,
ArH), 7.49–7.37 (m, 3H, ArH), 7.29–7.21 (m, 3H, ArH), 7.18–
7
2 3
.14 (m, 2H, ArH) 6.37 (s, 2H, Ph–CH –N), 3.12 (s, 3H, CH )
1
9
13
ppm.
F NMR(CDCl
3
; 400 MHz) d À62.32.
C NMR
(
CDCl ; 75 MHz) d 137.21, 131.94, 129.93, 129.43, 129.01,
Uiso(H) = 1.2U (C). The anisotropic displacement parameters
3
eq
1
1
2
28.84, 128.41, 127.48, 127.33, 126.71, 126.05, 124.44,
CF3 were restrained to be similar (SIMU instruction in
SHELXL97 [16]).
22.50, 110.55 (q, JCF = 4.39 Hz), 47.19, 29.69 ppm. IR (KBr)
À1
924, 2853, 1449, 1349, 1260, 1144, 1088, 1021, 802 cm
.
+
MS (ESI) m/z 468 (M + H) . HRMS Calcd for C H F N
29
20
3
3
+
(
M + H) 468.1687. Found 468.1680.
1-Benzyl-5,9-diphenyl-7-trifluoromethyl-11H-6,10,11-triaza-
1
Acknowledgments. The authors are thankful to the director of the
IICT Dr. J. S. Yadav and Head of the Department Dr.V. V.
Narayana Reddy for the encouragement. Narender Reddy is
thankful to the CSIR New Delhi for the JRF.
ꢀ
Yield 77%, mp 206–208 C; H NMR
1
benzo[a]fluorine (7h).
CDCl ; 300 MHz) d 8.38–8.31 (m, 2H, ArH), 8.18 (d, J=6.79Hz,
H, ArH), 8.08 (s, 1H, ArH), 7.83 (d, J = 7.55 Hz, 2H, ArH),
.62–7.38 (m, 9H, ArH), 7.32–7.18 (m, 4H, ArH), 6.41 (s, 2 H,
(
2
7
3
1
9
13
Ph–CH
2
–N) ppm. F NMR(CDCl
À75 MHz) d 154.91, 153.98, 151.67, 140.25,
38.47, 137.16, 130.58, 129.42, 129.31, 129.03, 128.89,
28.69, 128.11, 128.03, 127.36, 127.09, 126.28, 126.22,
25.90, 122.06, 122.01, 110.25 (q, J = 6.587 Hz), 47.01 ppm.
3
; 400 MHz) d À62.59.
C
NMR (CDCl
3
REFERENCES AND NOTES
1
1
1
[
1] Chi, S. M.; Choi, J.-K.; Yum, E. K.; Chi, D. Y. Tetrahedron
Lett 2000, 41, 919.
[2] Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.;
CF
À1
IR (KBr) (cm ) 2924, 2854, 1450, 1346, 1261, 1144. MS
+
Wadsworth, S. A.; Cavender, D. E.; Fahmy, B.; Olini, G. C.; Davis, J. E.;
Pellegrino-Gensey, J. L.; Schafer, P. H.; Siekierka, J. J.J Med Chem
(
(
ESI) m/z 530 (M + H) . HRMS Calcd for
M + H) 530.1844. Found 530.1858.
C
34
H
22
F
3
N
3
+
1998, 41, 4196.
1
1-Benzyl-5-(4-chloro-phenyl),9-diphenyl-7-trifluoromethyl-
[
[
3] Henry, J. R.; Dodd, J. H. Tetrahedron Lett 1998, 39, 8763.
4] Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.; Mawer, I. M.;
1
2
2
1H-6,10,11-triaza-benzo[a]fluorine (7i).
32–235 C; H NMR (CDCl
H, ArH), 8.18 (d, J= 7.81 Hz, 2H, ArH), 8.08 (s, 1H, ArH), 7.80
Yield 84%, mp
; 500 MHz) d 8.32 (t, J = 8.78 Hz,
ꢀ
1
3
Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S. B.; Marwood, R.;
Patel, S.; Patel, S.; Ragan, C. I.; Leeson, P. D. J Med Chem 1996,
39, 1941.
(
7
d, J = 7.81 Hz, 2H, ArH), 7.61 (t, J = 8.78 Hz, 1H, ArH),
.54–7.46 (m, 5H, ArH), 7.43–7.40 (m, 1H, ArH), 7.31–7.28
[5] Baker, R.; Kulagowski, J. J.; Curtis, N. R.; Leeson, P. D.;
Ridgill, M. P.; Smith, A. I. US Patent 5, 576,319 (1996)
[6] [6].Marot, C.; Chavatte, P.; Morin-Allory, L.; Viaud, M. C.;
Guillaumet, G.; Renard,P.; Lesieur, D.; Michel, A. J Med Chem 1998,
(
m, 2H, ArH), 7.24–7.19 (m, 3H, ArH), 6.40 (s, 2H, Ph–
1
9
13
CH
2
–N) ppm. F NMR(CDCl
3
; 400 MHz) d À62.85. C
3
NMR (CDCl ; 75MHz) d 154.25, 153.66, 151.70, 138.65,
41, 4453.
1
1
1
38.55, 137.12, 134.29, 131.93, 130.15, 129.58, 129.49, 129.09,
28.84, 128.67, 128.40, 128.13, 127.52, 127.23, 126.54, 125.99,
[7] Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.;
Nemeth, G. A.; Arvanitis, A.; Cheeseman, R. S.; Chorvat, R. J.; Ciganek, E.;
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Chem 1999, 42, 819.
25.74, 124.86, 122.30, 110.51 (q, JCF = 5.84 Hz), 42.2 ppm. IR
À1
(
KBr) 2923, 2852, 1447, 1343, 1227, 1136, 1055 cm . MS (ESI)
+
+
[8] Verbiscar, A. J. J Med Chem 1972, 15, 149.
m/z 564 (M+ H) . HRMS Calcd for C34
64.1463. Found 564.1457.
X-ray crystallographic analysis. X-ray data were collected
3 3
H21ClF N (M+ H)
[
9] Beattie, D. E.; Crossley, R.; Curran, A. C. W.; Hill, D. G.;
Lawrence, A. E. J Med Chem 1977, 20, 718.
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34, 507–517.
[12] Saundane, A. R.; Ranganath, S. H.; Prayagraj, G.; Rudresh, K.;
5
[
at room temperature with the use of a Bruker Smart Apex CCD
diffractometer with graphite monochromated MoKa radiation
1
[
(l = 0.71073 Å) by the o-scan method [15]. Preliminary lattice
parameters and orientation matrices were obtained from four
sets of frames. Unit cell dimensions were determined using
7
Satyanarayana, N. D. Orient. J. Chem. 1998, 14, 251.
ꢀ
[13] Ji Q., N. Kumar, M. Alamgir, D. StC. Black. Tetrahedron Lett
227 reflections in the range of 2.19 < θ < 23.19 .
2
009, 50, 5628–5630.
14] Krishnaiah, A.; Narsaiah, B. Journal of Fluorine Chemistry
001, 109, 183.
15] Bruker. SAINT (Version 6.28a) & SMART (Version 5.625).
Integration and scaling of intensity data were accomplished
[
using the program SAINT [15]. The structures were solved by
direct methods using SHELXS97 [16], and refinement was
carried out by full-matrix least-squares technique using
SHELXL97 [16]. Anisotropic displacement parameters were
2
[
Bruker AXS Inc., Madison: Wisconsin, USA, 2001.
[16] Sheldrick, G. M.. Acta Crystallogr 2008, A64: 112–122.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet