Synthesis of 9,10-substituted 3,4,10,10a-tetrahydro-2H,9H-1-oxa-4a,9- diazaphenanthrenes by reductive cyclization method

Article abstract of DOI:10.14233/ajchem.2014.15859

Commercially available o-phenylenediamine (1) was treated with methyl α-bromo-α-aryl acetate to obtain 3-aryl-3,4-dihydro-1Hquinoxalin- 2-one (2). The latter was reacted with benzyl bromide to obtain 4-benzyl-3-aryl-3,4-dihydro-1H-quinoxalin-2-one (3). Tr

Full text of DOI:10.14233/ajchem.2014.15859

Asian Journal of Chemistry; Vol. 26, No. 11 (2014), 3161-3165
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15859
Synthesis of 9,10-Substituted 3,4,10,10a-Tetrahydro-2H,9H-1-oxa-4a,9-diazaphenanthrenes
by Reductive Cyclization Method
1,*
1
1
1
2
V. RAJACHANDRASEKHAR , C. HARIPRASAD , V. VENUGOPALA RAO , S. VENKATAIAH and P.K. DUBEY
1Ci Venti Chem (India) Private Limited, Plot No 72/A, Part 2 Phase-1, IDA Jeedimetla, Hyderabad-500 055, India
2Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
*Corresponding author: E-mail: shekar.valamoni@gmail.com
Received: 4 June 2013;
Accepted: 10 September 2013;
Published online: 25 May 2014;
AJC-15205
Commercially available o-phenylenediamine (1) was treated with methyl α-bromo-α-aryl acetate to obtain 3-aryl-3,4-dihydro-1H-
quinoxalin-2-one (2). The latter was reacted with benzyl bromide to obtain 4-benzyl-3-aryl-3,4-dihydro-1H-quinoxalin-2-one (3). Treatment
of 3 with ethyl 3-bromopropionate resulted in the formation of 3-(4-benzyl-3-aryl-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)propionic acid
ethyl ester (4), which on reaction with LiAlH4 gave 9-benzyl-10-phenyl-3,4,10,10a-tetrahydro-2H,9H-1-oxa-4a,9-diazaphenanthrene (5)
via a reductive cyclization. In another sequence of reactions, 2 was treated with benzyl chloroformate to obtain 3-oxo-2-aryl-3,4-dihydro-
2H-quinoxalin-1-carboxylic acid benzyl esters (6). The latter on treatment with ethyl 3-bromopropionate gave 4-(2-ethoxycarbonylethyl)-
3-oxo-2-phenyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid benzyl esters (7). Then 7 was reductively cyclized with LiAlH4 to obtain
10-phenyl-3,4,10,10a-tetrahydro-2H-1-oxa-4a,9-diazaphenanthrene-9-carboxylic acid benzyl esters (8). In an yet another sequence of
reactions, 2 was treated with catalytic amount of p-toluene sulphonic acid in toluene under refluxing conditions to obtain 3-phenyl-1H-
quinoxaline-2-one (9). The latter, on treatment with ethyl 3-bromopropionate gave 3-[3-phenyl-2-oxo-2H-quinoxalin-1-yl]propionic
acid ethyl esters (10), followed by reductive cyclization with LiAlH4 to afford 10-phenyl-3,4-dihydro-2H,10aH-1-oxa-4a,9-
diazaphenanthrene (11). All the new products obtained in the above three sequences of reactions have been adequately characterized by
spectral data.
Keywords: Synthesis, Substituted diazaphenanthrenes, Reductive cyclization.
point apparatus. 1H NMR spectra were recorded using a Bruker
300 MHz spectrometer (300 MHz) with TMS as internal
INTRODUCTION
The presence of two functionally active amino groups in
o-phenylenediamine increases the possibility of various
standard in DMSO-d6 or CDCl3. Mass spectra were recorded
on a agilent 6120 single qudrapole LC-MS instrument giving
as M+.Values either on (M + H)+ or (M – H)+ modes. IR spectra
interactions leading to a number of products like benzofused
2-quinoxalinones. Their use in different therapeutic areas have
been listed as antidepressant1, anticancer2, antidiabetic3, anti-
(KBr Pellets). Analytical TLC was conducted on E-Merck
were obtained on a Perkin-Elmer 1720 FT-IR spectrometer
inflammatory4,5, antimicrobial6,7 and antiviral8,9 activities. Of
60F254 aluminum-packed silicagel plates (0.2 mm).
particular interest are the styryl, N-alkyl10, arylhydrazino-
Developed plates were visualized under UV light or iodine
carbonyl9-12, oxadiazolyl12-15, and thioalkyl16,17 quinoxalines
chamber.
which are reported to possess antibacterial10,13-16, antifungal11,12,15,17
and antiviral9 activity, etc. Keeping in view the biological
activities of various quinoxalines derivatives, it was considered
General procedure for the preparation of 2:A mixture
of 1 (10 g, 0.092 mol), K2CO3 (25.5 g, 0.185 mol) DMF (40
mL) and α-bromo-α-aryl acetate (Ar = Ph or 4-F-phenyl)
worthwhile to prepare fused derivatives of quinoxalines as
(0.097 mol) was stirred at 60 °C for 0.5 h. At the end of this
potentially biologically active compounds.
period, the reaction mixture was poured into ice-cold water
(100 mL). The separated solid was filtered, washed with water
EXPERIMENTAL
(50 mL) and dried to obtain 2.
2a: yield = 15 g (72.8 %); m.p. = 202-205 °C; 1H NMR
All experiments were conducted under nitrogen atmos-
phere unless stated otherwise. All solvents and reagents were
of reagent grade and used without further purification. All
melting points were determined on Pullman MP-96 melting
(CDCl3, 300 MHz) δ 4.28 (br s, 1H), 6.59 (s, 1H), 6.75-6.76
(d, 3H), 6.93 (m, 1H), 7.32-7.44 (m, 5H), 8.15 (br s, 1H); LC-
MS (ESI) (M + H)+ m/z 225.

3162 Rajachandrasekhar et al.
Asian J. Chem.
2b: Yield = 17.3 g (77 %); m.p. = 185-187 °C; 1H NMR
(CDCl3, 300 MHz) δ 4.91 (s, 1H), 5.08 (s, 1H), 6.71-6.80 (d,
J = 4.2 Hz, 3H), 7.03-7.05 (t, J = 8.1 Hz, 1H), 7.36-7.39 (m,
4H), 10.34 (s, 1H); LC-MS (ESI) (M + H)+ m/z 243.
General procedure for the preparation of 3: A mixture
of 2 (0.022 mol), benzyl bromide (4.38 g, 0.025 mol), Na2CO3
(4.73 g, 0.044 mol) and ethanol-water (9:1, 30 mL/3 mL) was
stirred at reflux temperature for 5 h, at the end of this period,
ethanol was rotary evaporated and the residue diluted with
water (30 mL). The separated solid was filtered, washed with
water and dried to obtain 3.
1H), 3.21 (t, J = 9.6 Hz, 1H), 3.94 (t, J = 9.3 Hz, 1H ), 4.19-
4.20 (m, 2H), 5.22 (d, J = 7.5 Hz, 1H), 5.34 (d, J = 10.8 Hz,
1H), 5.72 (s, 1H), 5.92 (s, 1H), 6.85-6.90 (m, 5H), 7.18 (d, J =
10.8 Hz,1H), 7.25-7.33 (m, 7H); LC-MS (ESI) (M + H)+ m/z:
375.
General procedure for the preparation of 6:A mixture
of 2 (21.4 mmol), benzyl chloroformate (7.3 g, 42.9 mmol),
NaHCO3 (3.6 g, 42.8 mmol) and DMF (25 mL) was stirred at
60 °C for 5 h. Then the reaction mixture was poured into ice-
cold water (150 mL). The separated solid was filtered, washed
with water (50 mL) and dried to obtain 6.
3a:Yield = 6 g (86 %); m.p. = 154-158 °C; IR (KBr, νmax
,
6a: Yield = 6.2 g (81 %); m.p. = 154-158 °C; IR (KBr,
νmax, cm–1) 3074, 2918, 1686, 1504,1383, 1229, 754, 534; 1H
NMR (CDCl3, 300 MHz) δ 5.27 (d, J = 12.0 Hz, 1H), 5.34 (d,
J = 12.0 Hz, 1H), 6.29 (br s, 1H), 6.85 (t, J = 6.1 Hz, 1H), 7.06
(m, 2H), 7.23-7.52 (m, 11H), 8.99 (br s, 1H); LC-MS (ESI)
(M + H)+ m/z: 359.
cm-1) 3064, 1681, 1507, 1381, 739, 693; H NMR (CDCl3,
300 MHz) δ 4.12 (d, J = 11.2 Hz, 1H), 4.71(d, J = 11.2 Hz,
1H), 4.99 (s, 1H), 6.72-6.82 (m, 3H), 6.99 (m, 1H), 7.16-7.43
(m, 10H), 8.65 (br s, 1H); LC-MS (ESI) (M + H)+ m/z 315.
1
1
3b: Yield = 6.1 g (88 %); m.p. =174-177 °C; H NMR
1
(CDCl3, 300 MHz) δ 4.03-4.08 (d, J = 15 Hz, 1H), 4.65-4.70
(d, J = 15 Hz, 1H), 4.94 (s, 1H), 6.74-6.82 (m, 3H), 6.91 (m,
1H), 7.11-7.16 (m, 2H), 7.26-7.36 (m, 5H), 8.45 (s, 1H); LC-
MS (ESI) (M + H)+ m/z 333.
6b: Yield = 6.0 g (80 %); m.p. = 171-173 °C; H NMR
(CDCl3, 300 MHz) δ 5.25-5.29 (d, J = 11.1 Hz, 1H), 5.32-
5.36 (d, J = 12.0 Hz, 1H), 6.29 (br s, 1H), 6.89-7.07 (m, 5H),
7.24-7.36 (m, 9H), 9.36 (br s, 1H); LC-MS (ESI) (M + H)+
m/z: 377.
General procedure for the preparation of 4:A mixture
of 3 (0.0127 mol), K2CO3 (3.5 g, 0.025 mol), DMF (20 mL)
and 3-bromopropionate (2.76 g, 0.015 moL) was stirred at
80 °C for 12 h. At the end of this period, the reaction mixture
was diluted with water and ethyl acetate (40/30 mL) .The
separated organic layer was washed with water (20 mL), dried
over Na2SO4 and evaporated to obtain crude 4. This was purified
by column chromatography (6 % EtOAc/hexane) giving pure
compound 4.
General procedure for the preparation of 7: Same as
above general procedure for 4.
7a:Yield = 4.3 g (67 %); m.p. = 52-54 °C; IR (KBr, νmax
,
cm-1) 1730, 1678; 1H NMR (CDCl3,300 MHz) δ 1.20 (t, J =
6.7 Hz, 3H), 2.60-2.81 (m, 2H), 4.12 (q, J = 6.7 Hz, 2H), 4.32
(m, 2H), 5.29 (m, 2H), 6.37 (s, 1H), 7.03-7.37 (m, 14H); LC-
MS (ESI) (M + H)+ m/z 459.
7b: Yield = 4.1 g (70 %); thick syrup; IR (KBr, νmax, cm-1)
1
3443, 1715, 1681, 1507, 1393, 1270, 1026, 754; H NMR
4a: Yield = 4 g (76 %); m.p. = 65-66 °C; IR (KBr, νmax
,
1
cm-1) 3443, 1730, 1680, 1454, 697; H NMR (CDCl3, 300
MHz) δ 1.21 (t, J = 6.6 Hz, 3H), 2.65 (m, 2H), 4.12 (m, 3H),
4.30 (2H), 4.67 (d, J = 12.3 Hz, 1H), 5.02 (s, 1H), 6.75-7.12
(m, 5H), 7.23-7.42 (m, 9H); LC-MS (ESI) (M + H)+ m/z 414.
(CDCl3, 300 MHz) δ 1.24 (t, J = 7.2 Hz, 3H), 2.83 (t, J = 6.7
Hz,2H), 4.17 (q, J = 7.2 Hz, 2H), 4.63 (t, J = 6.7 Hz, 2H), 5.26
(m, 2H), 6.33 (s, 1H), 7.15-7.19 (m, 2H), 7.36-7.44 (m, 2H),
7.56-7.61 (m, 1H), 7.93-7.96 (m, 1H), 8.38-8.42 (m, 2H); LC-
MS (ESI) (M + H)+ m/z: 477.
1
4b: Yield = 3.8 g (73 %); m.p. =72-74 °C; H NMR
(CDCl3, 300 MHz) δ 1.21 (t, J = 6.6 Hz, 3H), 2.83 (t, J = 8.7
Hz, 2H), 4.06-4.21 (m, 3H), 4.60-4.67 (m, 3H), 4.96 (s, 1H),
6.91-7.44 (m, 9H), 7.56-7.61 (m, 1H), 7.93-7.96 (d, J = 8.1
Hz, 1H), 8.38-8.43 (m, 1H); LC-MS (ESI) (M + H)+ m/z: 433.
General procedure for the preparation of 5: To a solution
of 4 (0.0024 mol) in THF (10 mL) was added LiAlH4 (0.11 g,
0.0029 mol) in 5 min at 10 °C and the mixture stirred at room
temperature for 1 h. At the end of this period, the reaction
mixture was quenched with saturated Na2SO4 solution (1 mL)
at 5 °C and diluted with ethyl acetate (20 mL). The separated
cake was filtered and washed with EtOAc (10 mL).The filtrate
was dried over Na2SO4 and then evaporated to obtain a crude
product which was purified by column chromatography (4 %
EtOAc/hexane) affording pure 5.
General procedure for the preparation of 8: Same as
above general procedure for 5.
1
8a: Yield = 0.56 g (64 %); m.p. = 82-85 °C; H NMR
(CDCl3, 300 MHz) δ 1.38-1.40 (m, 1H), 2.13-2.19 (m, 1H),
3.31 (t, J = 12.6 Hz, 1H), 3.92 (t, J = 9.3 Hz, 1H), 4.15-4.28
(dd, J = 8.4, 12 Hz, 2H), 4.96 (br s, 1H), 5.44 (d, J = 10.8 Hz,
1H), 5.64 (m, 1H), 5.75 (br s, 1H), 6.82-6.89 (m, 2H), 7.19-
7.10 (m, 1H), 7.23-7.320 (m, 11H); LC-MS (ESI) (M + H)+
m/z 401.
8b:Yield = 0.6 g (69 %); m.p. = 89-93 °C; IR (KBr, νmax
,
cm-1) 3442,1693,754; 1H NMR (CDCl3, 300 MHz) δ 1.43 (d,
J = 11.7 Hz, 1H), 1.99-2.13 (m, 1H), 3.21 (t, J = 9.6 Hz, 1H),
3.94 (t, J = 9.3 Hz, 1H), 4.19-4.20 (m, 2H), 4.92 (s, 1H), 5.21
(d, J = 7.5 Hz, 1H), 5.34 (d, J = 10.8 Hz, 1H), 5.72 (s, 1H),
6.85-6.90 (m, 5H), 7.18-7.19 (d, J = 10.8 Hz, 1H), 7.25-7.33
(m, 7H); LC-MS (ESI) (M + H)+ m/z 419.
5a: Yield = 0.65 g (64 %); m.p. = 138-143 °C; IR (KBr,
νmax, cm-1) 2949, 1592, 1511, 727; 1H NMR (CDCl3, 300 MHz)
δ 1.22 (d, J = 6.3 Hz, 1H), 2.20 (m, 1H), 3.20 (m, 1H), 3.90-
(m, 1H), 4.30 (m, 3H), 4.59 (s, 1.6 H), 4.60 (s, 0.4 H), 4.78 (s,
0.8H), 4.82 (s, 0.2H), 6.50 (d, J = 7.5 Hz, 1H), 6.66 (m, 2H),
6.82 (d, J = 7.5 Hz, 1H), 7.12-7.35 (m,10H); LC-MS (ESI)
(M + H)+ m/z 357.
General procedure for the preparation of 9: To a stirred
solution of 2 (7.9 mmol) in toluene (20 mL) was added catalytic
amount of PTSA (27 mg) at room temperature. Then, the
reaction mixture was stirred at reflux temperature for 5-24 h.
On completion of the reaction (as shown by disappearance of
2 on TLC), the mixture was cooled to room temperature. The
resulting solid was filtered, washed with hexane to obtain 9.
1
5b: Yield = 0.6 g (69 %); m.p. = 153-157 °C; H NMR
(CDCl3, 300 MHz) δ 1.43 (d, J = 11.7 Hz, 1H), 1.99-2.13 (m,

Vol. 26, No. 11 (2014)
Synthesis of 9,10-Substituted 3,4,10,10a-Tetrahydro-2H,9H-1-oxa-4a,9-diazaphenanthrenes 3163
9a: yield = 1.74 g (89 %); m.p. = 225-228 °C; 1H NMR
(CDCl3, 300 MHz) δ 7.29-7.36 (m, 2H), 7.81-7.84 (d, J = 7.8
Hz, 1H), 8.27-8.30 (d, J = 6.3 Hz, 1H), 12.63 (br s, 1H); LC-
MS (ESI) (M + H)+ m/z: 223.
7.12 (m, 5H), 7.23-7.42 (m, 9H). Its LC-MS showed the
molecular ion (M + H)+ peak at m/z 415 corresponding to a
molecular mass of 414. Finally, 4a was treated with lithium
aluminium hydride in tetrahydrofuran (THF) to yield a product
which has been characterized as 9-benzyl-10-phenyl-
3,4,10,10a-tetrahydro-2H,9H-1-oxa-4a,9-diazaphenanthrene
(5a). Its IR (KBr) spectrum did not show any diagnostic peaks
due to -NH- and -CO- group Its 1H NMR (CDCl3, 300 MHz)
δ 1.22 (d, J = 6.3 Hz, 1H), 2.20 (m, 1H), 3.20 (m, 1H), 3.90
(m, 1H), 4.30 (m, 3H), 4.59 (s, 1.6H), 4.60 (s, 0.4H), 4.78 (s,
0.8H), 4.82 (s, 0.2H), 6.50 (d, J = 7.5 Hz, 1H), 6.66 (m, 2H),
6.82 (d, J = 7.5 Hz, 1H), 7.12-7.35 (m,10H); Its LC-MS showed
the molecular ion ((M + H)+ peak at m/z 357 corresponding to
a molecular mass of 356. (Scheme -I). The above reactions
were found to be general and were carried out through the
sequence 2b → 3b → 4b → 5b (Scheme-I).
9b:Yield = 1.8 g (91 %); m.p. = > 230 °C; IR (KBr, νmax
,
cm-1) 2838, 1665, 1590, 1222, 1162, 847; 1H NMR (CDCl3,
300 MHz) δ 7.31-7.35 (m, 4H), 7.53-7.54 (t, J = 6.5 Hz, 2H),
7.83-7.84 (d, J = 7.5 Hz,1H), 8.40-8.43 (d, J = 7.5 Hz, 2H),
12.59 (br s, 1H); LC-MS (ESI) (M + H)+ m/z: 241.
General procedure for the preparation of 10: Same as
above general procedure 4.
10a: Yield = 1.43 g (66 %); m.p. = 61-64 °C; IR (KBr,
νmax, cm-1) 1678; 1H NMR (CDCl3, 300 MHz) δ 1.25 (t, J = 6.9
Hz, 3H), 2.83 (t, J = 7.8 Hz, 2H), 4.17 (q, J = 6.9 Hz, 2H),
4.63 (t, J = 7.8 Hz, 2H), 7.35-7.61 (m, 6H), 7.95-7.98 (dd, J =
8.1 Hz, 1H), 8.30-8.33 (m, 2H); LC-MS (ESI) (M + H)+ m/z
323.
In another sequence of reactions, 2a was treated with
benzyl chloroformate in the presence of sodium bicarbonate
in DMF at room temperature, to obtain the 3-oxo-2-phenyl-
3,4-dihydro-2H- quinoxalin-1-carboxylic acid benzyl ester
(6a), which was treated with ethyl 3-bromopropionate in the
presence of K2CO3 in DMF at 80 °C for 12 h, to yield a product
which has been characterized as 4-(2-ethoxycarbonylethyl)-
3-oxo-2-phenyl-3,4-dihydro-2H-quinoxaline-1-carboxylic
acid benzyl ester (7a). Its IR (KBr) spectrum showed diagnostic
peaks at 1730 cm-1 (due to ester carbonyl stretching) and at
10b: Yield = 1.5 g (70.5 %); m.p.= 69-71 °C; IR (KBr,
νmax, cm-1) 2989, 1725, 1644, 1049, 848, 543, 1H NMR (CDCl3,
300 MHz) δ 1.25 (t, J = 6.9 Hz, 3H), 2.82 (t, J = 6.3 Hz, 2H),
4.17 (t, J = 6.9 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 7.17 (t, J =
6.6 Hz, 2H), 7.44 (m, 2H), 7.60 (t, J = 6.7 Hz, 1H), 7.96 (d, J
= 7.7 Hz, 1H), 8.39 (m, 2H); LC-MS (ESI) (M + H)+ m/z: 341.
General procedure for the preparation of 11: Same as
above general procedure 5.
11a:Yield = 0.56 g (62 %); Low melting solid; 1H NMR
(CDCl3, 300 MHz) δ 1.56-1.58 (m, 1H), 2.23-2.30 (m, 1H),
3.49 (t, J = 12.0 Hz, 1H), 4.13 (d, J = 7.5 Hz, 2H), 4.30 (d, J =
12.9 Hz, 1H), 5.87 (s, 1H), 6.92-7.01 (m, 2H), 7.30 (d, J = 1.2
Hz, 1H), 7.44-7.48 (m, 3H), 7.57 (dd, J = 7.5 Hz, 1H), 8.03
(dd, J = 9.6 Hz, 2H); LC-MS (ESI) (M + H)+ m/z 265.
11b: Yield = 0.5 g (60 %); m.p. = 141-143 °C; IR (KBr,
1
1678 cm-1 (due to amide carbonyl stretching). H NMR
(CDCl3,300 MHz) δ 1.20 (t, J = 6.7 Hz, 3H), 2.60-2.81 (m,
2H), 4.12 (q, J = 6.7 Hz, 2H), 4.32 (m, 2H), 5.29 (m, 2H),
6.37 (s, 1H), 7.03-7.37 (m, 14H); Its LC-MS showed the
molecular ion (M + H)+ peak at m/z 459 corresponding to a
molecular mass of 458. Then 7a was treated with lithium
aluminium-hydride in tetrahydrofuran to yield a crude product
that was purified by column chromatography giving a pure
product which has been characterized as 10-phenyl-3,4,10,10a-
tetrahydro-2H-1-oxa-4a,9-diazaphenanthrene-9- carboxylic
acid benzyl ester (8a) on the basis of its spectral data. Thus,
its IR (KBr) spectrum did not show any diagnostic peaks due
to -NH- and -CO- groups. Its 1H NMR (CDCl3, 300 MHz) δ
1.38-1.40 (m, 1H), 2.13-2.19 (m, 1H), 3.31 (t, J = 12.6 Hz,
1H), 3.92 (t, J = 9.3 Hz, 1H), 4.15-4.28 (dd, J = 8.4, 12 Hz,
2H), 4.96 (br s, 1H), 5.44 (d, J = 10.8 Hz, 1H), 5.64 (m, 1H),
5.75 (br s, 1H), 6.82-6.89 (m, 2H), 7.19-7.10 (m, 1H), 7.23-
7.320 (m, 11H); Its LC-MS showed the molecular ion (M +
H)+ peak at m/z 401 corresponding to a molecular mass of 400
(Scheme-I). The above reaction was found to be general and
was carried out through the sequence 2b → 6b → 7b → 8b
(Scheme-I).
1
νmax, cm-1) 2844, 1611, 1491, 1221, 745; H NMR (CDCl3,
300 MHz) δ 1.50 (d, J = 8.7 Hz, 1H), 2.39 (m, 1H), 3.50 (t, J
= 8.7 Hz, 1H), 4.12 (d, J = 5.1 Hz, 2H), 4.29 (d, J = 9.3 Hz,
1H), 5.83 (s, 1H), 6.94 (t, J = 4.5 Hz, 1H), 6.99 (d, J = 11.4
Hz, 1H), 7.13 (t, J = 5.1 Hz, 1H), 7.25-7.26 (m, 2H), 7.56 (d,
J = 4.5 Hz, 1H), 8.02 (m, 2H); LC-MS (ESI) (M + H)+ m/z
283.
RESULTS AND DISCUSSION
Commercially available o-phenylenediamine (1) was
treated with methyl α-bromo-phenyl acetate in the presence
of K2CO3 in DMF to obtain the 3-phenyl-3,4-dihydro-1H-
quinoxalin-2-one18 (2a) (Scheme-I). The latter, on treatment
with benzyl bromide in the presence of sodium carbonate in
aqueous ethanol (9:1) under reflux for 4-5 h, gave the 4-benzyl-
3-phenyl-3,4-dihydro-1H-quinoxaline-2-one19 (3a). Then 3a
was treated with ethyl 3-bromopropionate in the presence of
K2CO3 in DMF at 80 °C for 10 h, to yield a crude product which
on purification by column chromatography afforded the pure
product 3a, which has been characterized as 3-(4-benzyl-3-
phenyl-2-oxo-3, 4 dihydro 2H-quinoxalin-1-yl propionic acid
ethyl ester (4a). Its IR (KBr) spectrum showed diagnostic peaks
at 1749 cm-1 (due to ester carbonyl stretching) and at 1678
cm-1 (due to amide carbonyl stretching). It's 1H NMR (CDCl3,
300 MHz) δ 1.21 (t, J = 6.6 Hz, 3H), 2.65 (m, 2H), 4.12 (m,
3H), 4.30 (2H), 4.67 (d, J = 12.3 Hz, 1H), 5.02 (s, 1H), 6.75-
In an yet another sequence of reactions, 2a was treated
with catalytic amount of p-toluene sulphonic acid in toluene
under reflux for 5 h, resulted 3-phenyl-1H-quinoxaline-2-one
(9a). The latter on treatment with ethyl 3-bromopropionate in
the presence of K2CO3 in DMF at 80 °C for 8 h, gave a crude
product which was purified by column chromatography to
obtain a product that has been characterized as 3-[(3- phenyl)-
2-oxo-2H-quinoxalin-1-yl]-propionic acid ethyl ester (10a).
Its IR (KBr) spectrum peaks showed diagnostic peaks at 1678
cm-1 (due to amide carbonyl stretching). Its 1H NMR (CDCl3,
300 MHz) δ 1.25 (t, J = 6.9 Hz, 3H), 2.83 (t, J = 7.8 Hz, 2H),

3164 Rajachandrasekhar et al.
Asian J. Chem.
NH2
NH2
1
Ar
Br
K2CO3
COOMe
DMF, 50 oC,1h
H
N
Ar
2(a-b)
O3
x
C
2
N
H
O
a
N
,
e
d
u
l
i
f
m
e
r
,
o
r
r
Benzylchloroformate
NaHCO3, DMF, rt, 3 h
b
e
t
l
y
a
z
w
,
l
n
e
5
h
-
o
2
4
6
B
n
-
h
a
5
h
t
E
O
O
N
N
Ar
O
N
Ar
Ar
O
N
H
O
N
H
N
H
6(a-b)
3(a-b)
9(a-b)
Br
O
Br
O
O
Br
O
K2CO3 DMF, 80°C
O
O
K2CO3 DMF, 80°C
K2CO3 DMF, 80°C
8-10h
8-10h
8-10h
O
O
N
N
Ar
O
N
N
N
Ar
Ar
N
O
O
10(a-b)
4(a-b)
7(a-b)
O
O
O
O
O
O
LAH
THF, rt, 1 h
LAH
THF, rt, 1 h
LAH
THF, rt, 1 h
O
O
N
Ar
11(a-b)
N
N
Ar
Ar
8(a-b)
5(a-b)
N
O
N
O
N
O
Ar = Phenyl,4-F-Phenyl
Ar = Phenyl,4-F-Phenyl
Ar = Phenyl,4-F-Phenyl
Scheme-I

Vol. 26, No. 11 (2014)
Synthesis of 9,10-Substituted 3,4,10,10a-Tetrahydro-2H,9H-1-oxa-4a,9-diazaphenanthrenes 3165
4. S.B. Kadin, Ger. Offen., 2,186 (1974); Chem. Abstr., 81, 37574 (1974).
4.17 (q, J = 6.9 Hz, 2H), 4.63 (t, J = 7.8 Hz, 2H), 7.35-7.61
(m, 6H), 7.95-7.98 (dd, J = 8.1 Hz, 1H), 8.30-8.33 (m, 2H);
Its LC-MS showed the molecular ion (M + H)+ peak at m/z
323 corresponding to a molecular mass of 322. Compound 10a
on treatment with lithium aluminium hydride in tetrahydro-
furan gave a crude product that on purification by column
chromatography afford a product which has been characterized
as 10-phenyl-3,4-dihydro-2H,10aH-1-oxa-4a,9-diazaphenan-
threne (11a). Its IR (KBr) spectrum did not show any diagnostic
peaks due to -NH and -CO groups. 1H NMR (CDCl3, 300 MHz)
δ 1.56-1.58 (m, 1H), 2.23-2.30 (m, 1H), 3.49 (t, J = 12.0 Hz,
1H), 4.13 (d, J = 7.5 Hz, 2H), 4.30 (d, J = 12.9 Hz, 1H), 5.87
(s, 1H), 6.92-7.01 (m, 2H), 7.30 (d, J = 1.2 Hz, 1H), 7.44-7.48
(m, 3H), 7.57 (dd, J = 7.5 Hz, 1H), 8.03 (dd, J = 9.6 Hz, 2H);
Its LC-MS showed the molecular ion (M + H)+ peak at m/z
265 corresponding to a molecular mass of 264 (Scheme-I).
The above reactions were found to be general and were carried
out through the sequence 2b → 9b → 10b → 11b (Scheme-I).
5. C.V. Reddy Sastry, K.S. Rao, V.S.H. Krishnan, K. Rastogi, M.L. Jain
and G.K.A.S.S. Narayan, Indian J. Chem., 29B, 396 (1990).
6. I.M.A. Awad, Indian J. Chem., 30B, 89 (1991).
7. Y. Kurasawa and H.S. Kim, J. Heterocycl. Chem., 35, 1101 (1998).
8. Z. Zhu, S. Saluja, J.C. Drach and L.B. Townsend, J. Chin. Chem. Soc,
45, 465 (1998).
9. G. Campiani, F. Aiello, M. Fabbrini, E. Morelli, A. Ramunno, S.
Armaroli, V. Nacci, A. Garofalo, G. Greco, E. Novellino, G. Maga, S.
Spadari, A. Bergamini, L. Ventura, B. Bongiovanni, M. Capozzi, F.
Bolacchi, S. Marini, M. Coletta, G. Guiso and S. Caccia, J. Med. Chem.,
44, 305 (2001).
10. M.M. Ali, M.M.F. Ismail, M.S.A. El-Gaby, M.A. Zahran and Y.A.
Ammar, Molecules, 5, 864 (2000).
11. Y. Kurasawa, M. Muramatsu, K. Yamazaki, S. Tajima, Y. Okamoto and
A. Takada, J. Heterocycl. Chem., 23, 1379 (1986).
12. Y. Kurasawa, M. Muramatsu, K. Yamazaki, S. Tajima, Y. Okamoto and
A. Takada, J. Heterocycl. Chem., 23, 1391 (1986).
13. Y. Kurasawa, M. Muramatsu, K.Yamazaki,Y. Okamoto and A. Takada,
J. Heterocycl. Chem., 23, 1387 (1986).
14. M.Z.A. Badr, S.A. Mahgoub, F.F. Abdel-Latif, A.M. Fahmy and O.S.
Moustafa, J. Indian Chem. Soc., 67, 216 (1990).
15. H.M. Refaat, A.A. Moneer and O.M. Khalil, Arch. Pharm. Res., 27,
1093 (2004).
ACKNOWLEDGEMENTS
16. J.P. Dirlam, J.E. Presslitz and B.J. Williams, J. Med. Chem., 26, 1122
(1983).
This work was supported by Civentichem (India) Private
Limited. The authors thank Dr. BhaskarVenepalli and Dr. Vasu
Cittineni, for their support. Thanks are also due to authorities
of J.N.T.University Hyderabad for encouragement.
17. M.M. Badran, K.A.M. Abouzid and M.H.M. Hussein, Arch. Pharm.
Res., 26, 107 (2003).
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(2006).
19. (a)V. Laurinavicius, B. Kurtinaitiene, V. Liauksminas, B. Puodziunaite,
R. Janciene, L. Kosychova and R. Meskys, Monatsh. Chem., 130, 1269
(1999); (b) R.F. Smith, W.J. Rebel and T.N. Beach, J. Org. Chem., 24,
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