Synthesis of N-(3,4,10,10a-Tetrahydro-2H-1,9-dioxa-4aazaphenanthrene- 6-yl)alkyl and Aryl Sulfonamides

Article abstract of DOI:10.14233/ajchem.2014.17017

Commercially available 2-amino-4-nitrophenol (1) was treated with chloroacetyl chloride to obtain 6-nitro-4H-benzo[1,4]oxazine-3,2- one (2). The latter was reacted with ethyl 3-bromopropionate to obtain 3-(6-nitro-3-oxo-2,3-dihydrobenzo[1,4]oxazine-4-yl)propionic acid ethyl ester (3), which on treatment with lithium aluminiumhydride gave 6-nitro-3,4,10,10a-tetrahydro-2H-1,9-dioxo-4aazaphenanthrene (4) by reductive cyclization. Compound, 4 was treated with H2/Pd-C containing di-tert-butyldicarbonate (Boc)2O in THF to obtain the (3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl)carbamic acid tert-butyl ester (5). The latter, on treatment with alkyl or arylsulfonyl chlorides in the presence of NaH gave N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl or aryl sulfonamide-N1-carbamic acid tert-butyl ester (6). N-Boc group of 6 was de-protected with Cs2CO3/imidazole in acetonitrile to give the title compounds N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl or aryl sulfonamides (7) as potential antibacterial agents. All the new products obtained in the above sequences of reactions have been adequately characterized by spectral data.

Full text of DOI:10.14233/ajchem.2014.17017

Asian Journal of Chemistry; Vol. 26, No. 16 (2014), 5263-5267
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17017
Synthesis of N-(3,4,10,10a-Tetrahydro-2H-1,9-dioxa-4a-
azaphenanthrene-6-yl)alkyl and Aryl Sulfonamides
1
,*
1
2
V. RAJACHANDRASEKHAR , B. GEORGE VINEEL , S. VENKATAIAHA and P.K. DUBEY
1
2
CiVentiChem (India) Private Limited, Plot No 72/A, Part 2 Phase-1, IDA Jeedimetla, Hyderabad-500 055, India
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500 085, India
*
Corresponding author: E-mail: shekar.valamoni@gmail.com
Received: 10 January 2014; Accepted: 24 April 2014;
Published online: 28 July 2014;
AJC-15674
Commercially available 2-amino-4-nitrophenol (1) was treated with chloroacetyl chloride to obtain 6-nitro-4H-benzo[1,4]oxazine-3,2-
one (2). The latter was reacted with ethyl 3-bromopropionate to obtain 3-(6-nitro-3-oxo-2,3-dihydrobenzo[1,4]oxazine-4-yl)propionic
acid ethyl ester (3), which on treatment with lithium aluminiumhydride gave 6-nitro-3,4,10,10a-tetrahydro-2H-1,9-dioxo-4a-
2 2
azaphenanthrene (4) by reductive cyclization. Compound, 4 was treated with H /Pd-C containing di-tert-butyldicarbonate (Boc) O in
THF to obtain the (3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl)carbamic acid tert-butyl ester (5). The latter, on treatment
with alkyl or arylsulfonyl chlorides in the presence of NaH gave N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl
1
or aryl sulfonamide-N -carbamic acid tert-butyl ester (6). N-Boc group of 6 was de-protected with Cs
2
CO
3
/imidazole in acetonitrile to
give the title compounds N-(3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-azaphenanthrene-6-yl) alkyl or aryl sulfonamides (7) as potential anti-
bacterial agents. All the new products obtained in the above sequences of reactions have been adequately characterized by spectral data.
Keywords: Synthesis, Substituted azaphenanthrenes, Reductive cyclization.
aluminium-packed silica gel plates (0.2 mm). Developed plates
were visualized under UV light or iodine chamber.
INTRODUCTION
1,4-Benzoxazin-3(4H)-one derivatives have shown various
biological activities, such as antiinflammatory , antiulcer ,
Preparation of compound 2: A mixture of 1 (100 g, 0.649
mol), diisopropylethylamine (165 g, 1.298 mol), chloroacetyl
chloride (73.3 g, 0.649 mol) and THF (700 mL) was stirred at
1
2
3
antiplatelet , antihypertensive , antifungal , antimicrobial ,
4
5
6
7
neuropeptide Y (NPY) Y5 receptor antagonist , serotonin
room temperature for 4 h. To this solution was added K
2 3
CO
8
reuptake inhibitors , prostacyclin receptor agonist , etc. Keeping
9
(134 g, 0.974 mol) with continued stirring at 60 °C for 2 h. At
in view the biological activities of various 1,4-benzoxazin-3-
(
the end of this period, the mixture was filtered and the filtrate
rotary evaporated. The crude residue obtained was diluted with
ice-cold water (2 L). The separated solid was filtered, washed
with water (500 mL) and dried to obtain compound 2. Yield:
4H)-one derivatives, it was considered worthwhile to prepare
fused derivatives of benzoxazines as potentially biologically
active compounds.
10
1
1
03 g (80 %); m.p. 236-239 °C (Lit . m.p. 235-237 °C), H
NMR (CDCl , 300 MHz): δ 4.75 (s, 2H -O-CH ), 7.06-7.08
(d, J = 5.1 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.19-7.94 (dd,
EXPERIMENTAL
3
2
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 Poloman MP-96 melting
J = 9 Hz, 1H, Ar-H), 8.01 (bs, 1H -NH-D O exchangeable).
2
+
LC-MS (ESI) (M + H) m/z 194.
Preparation of compound 3: A mixture of 2 (30 g, 0.154
mol), K CO (42.5 g, 0.308 mol), DMF (150 mL) and ethyl
1
point apparatus. H NMR spectra were recorded using a Bruker
2
3
300 MHz spectrometer with TMS as internal standard in
DMSO-d
3-bromo-propionate (30.7 g, 0.170 mol) was stirred at 80 °C
for 10 h.At the end of this period, the reaction mass was diluted
with water (700 mL). The separated solid was filtered, washed
with water (100 mL) and the wet cake crystallized from methanol
(150 mL) to obtain compound 3.Yield: 35 g (77 %); m.p. 92-
94 °C.
6
or CDCl . Mass spectra were recorded on anAgilent
3
+
120 single quodrupole LCMS instrument giving M . values
6
+
-
either on [M + H] or [M – H] modes. IR spectra were obtained
on a Perkin-Elmer 1720 FT-IR spectrometer as KBr Pellets.
Analytical TLC was conducted on E-Merck- 60 GF-254

5
264 Rajachandrasekhar et al.
Asian J. Chem.
Preparation of compound 4: A solution of compound 3
NMR (CDCl /TMS, 300 MHz); δ 1.25-1.26 (d, J = 6.3 Hz,
3
(
20 g, 0.0682 mol) in THF (150 mL) was cooled to 10 °C and
lithium aluminium-hydride (4.77 g , 0.136 mol) was added in
min and the mixture stirred at room temperature for 3 h. At
the end of this period, the mixture was quenched with saturated
Na SO solution (20 mL) at 5 °C and the precipitated cake
1H, one proton of 3-CH
1H, one proton of 3-CH ), 2.98 (s, 6H, -N(CH
(t, J = 6 Hz, 1H, one proton of -N-CH ), 3.87-3.96 (t, J = 6.5
Hz, 1H, one proton of -N-CH ), 3.99-4.02 (d, J = 9 Hz, 1H,
one proton of 10-CH ), 4.17 (m, 3H, one of the protons of
2-CH & 10a-CH), 4.66 (s, 1H, one proton of 10-CH), 6.53-
2
), 1.42 (s, 9H, tert-butyl), 2.02 (m,
2
3 2
)
), 3.96-3.3.98
5
2
2
2
4
2
was diluted with ethyl acetate (200 mL), filtered and washed
with EtOAc (100 mL) and the organic filtrate dried over anhy-
2
6.56 (d, J = 9 Hz, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 6.98-7.00 (d,
+
J = 6 Hz, 1H, Ar-H). LC-MS (ESI) (M + H) m/z 414.
drous Na SO
2
4
. Then, the solvent was removed under reduced
pressure on a rotary evaporator below 40 °C. The crude residue
was stirred in methyl tert-butylether (50 mL) for 10 min and
filtered to obtain pure compound 4 as insoluble solid. Yield:
Compound 6e: Yield: 0.43 g (74 %); m.p. 132-135 °C;
-1
IR (KBr, νmax, cm ): 1725 (carbamide stretching) and 1355
1
(sulfonamide stretching), 1145 (sulfonamide stretching); H-
1
1 g (69 %); m.p. 112-114 °C.
Preparation of compound 5: A mixture of compound 4
NMR (CDCl
1.45 (d, J = 6 Hz, 1H, one proton of 3-CH
proton of 3-CH ), 3.28-3.30 (t, J = 6 Hz, 1H, one proton of
-N-CH ), 3.87-3.98 (m, 2H, one of the protons of -N-CH
10-CH ), 4.20 (m, 3H, one of the protons of 2-CH & 10a-
3
/TMS, 300 MHz); δ 1.34 (s, 9H, tert-butyl),1.42-
2
), 2.10 (m, 1H, one
(
(
8 g, 0.033 mol), (BoC)
0.8 g) in THF-MeOH (80-20 mL), was applied hydrogen gas
2
O (7.38 g, 0.033 mol) and Pd/C 10 %
2
2
2
&
pressure through balloons for 4 h. At the end of this period,
the reaction mixture was filtered through celite pad and washed
with THF (20 mL). The filtrate was rotary evaporated to obtain
pure compound 5. Yield: 9 g (87 %); m.p. 121-123 °C.
Preparation of compound 6 (general procedure): A
mixture of compound 5 (1.63 mmol), NaH (77 mg, 3.2 mmol)
and DMF (2 mL) at 0 °C, was added alkyl or arylsulfonyl
chloride (1.79 mmol). The reaction mixture was stirred at room
temperature for 30-40 min. At the end of this period, the
reaction mixture was diluted with ice cold water (10 mL). The
separated solid was filtered, washed and dried to obtain
compound 6.
2
2
CH), 4.67 (s, 1H, one proton of 10-CH), 6.51-6.51 (d, J = 6
Hz, 1H, Ar-H), 6.78 (s, 1H, Ar-H), 6.81-6.83 (d, J = 6 Hz, 1H,
Ar-H), 7.52-7.64 (m, 3H, Ar-H), 7.98-8.00 (d, J = 6 Hz, 2H,
+
Ar-H). LC-MS (ESI) (M + H) m/z 447.
Compound 6f: Yield: 0.412 g (77 %); m.p. 142-145 °C;
-1
IR (KBr, νmax, cm ): 1729 (carbamide stretching) and 1360
1
(sulfonamide stretching), 1151 (sulfonamide stretching); H-
NMR (CDCl
(d, J = 6 Hz, 1H, one proton of 3-CH
proton of 3-CH ), 2.44 (s, 3H, -Ph-CH
Hz, 1H, one proton of -N-CH ), 3.80-3.92 (m, 2H, one of the
protons of -N-CH & 10-CH), 4.18-4.19 (m, 3H , one of the
protons of 2-CH & 10a-CH), 4.61 (s, 1H, one proton of 10-
3
/TMS, 300 MHz); δ 1.34 (s, 9H, tert-butyl), 1.45
), 2.16 (m, 1H, one
), 3.18-3.21 (t, J = 9
2
2
3
2
Compound 6a: Yield: 0.25 g (66 %); m.p. 105-107 °C.
Compound 6b: Yield: 0.55 g (84 %); m.p. 121-123 °C;
2
2
-1
IR (KBr, νmax, cm ): 1721 (carbamide stretching) and 1345
CH), 6.42-6.46 (d, J = 12 Hz, 1H, Ar-H), 6.73 (s, 1H, Ar-H),
6.76-6.79 (d, J = 9 Hz, 1H, Ar-H),7.30-7.32 (d, J = 6 Hz, 2H,
Ar-H), 7.84-7.86 (d, J = 6 Hz, 2H, Ar-H). LC-MS (ESI) (M +
1
(
sulfonamide stretching), 1142 (sulfonamide stretching); H
NMR (CDCl /TMS,300 MHz); δ 1.43 (s, 9H, tert-butyl), 1.52
-CH & one of the protons of 3-CH ), 1.98-2.02
m, 1H, one proton of 3-CH ), 3.195-3.197 (t, J = 8 Hz, 1H,
), 3.62-3.66 (m, 2H, -CH -CH ), 3.87-
.97 (t, 1H, J = 8 Hz, one proton of -N-CH ), 3.98-4.01 (d,
J = 9 Hz, 1H, one proton of 10-CH ), 4.17-4.28 (m, 3H, one
of the protons of 2-CH & 10a-CH), 4.65 (s, 1H, one proton
3
+
(m, 4H, -CH
2
3
2
H) m/z 461.
(
2
Compound 6g: Yield: 0.35 g (78 %); m.p. 152-154 °C;
-1
one proton of -N-CH
2
2
3
IR (KBr, νmax, cm ): 1717 (carbamide stretching) and 1351
1
(sulfonamide stretching), 1149 (sulfonamide stretching); H-
3
2
2
NMR (CDCl
1.38 (d, J = 6 Hz, 1H, one proton of 3-CH
proton of 3-CH ), 3.18-3.20 (t, J = 6 Hz, 1H, one proton of
-N-CH ), 3.88-3.90 (t, J = 6 Hz, 1H, one proton of N-CH ),
3.96-3.99 (d, J = 6 Hz, 1H, one proton of 10-CH), 4.18-4.19
(m, 3H, one of the protons of 2-CH & 10a-CH), 4.66 (s, 1H,
3
/TMS, 300 MHz); δ 1.29 (s, 9H, tert-butyl), 1.36-
2
2
), 2.16 (m, 1H, one
of 10-CH), 6.52-6.54 (d, J = 6 Hz, 1H, Ar-H), 6.71 (s, 1H,
2
Ar-H ), 6.79-6.82, (d, J = 6 Hz, 1H, Ar-H). LC-MS (ESI) (M
+
H) m/z 399.
2
2
+
Compound 6c: Yield: 0.46 g (69 %); m.p. 129-132 °C;
2
-1
IR (KBr, νmax, cm ): 1719 (carbamide stretching) and at 1352
one of the proton of 10-CH), 6.75-6.79 (d, J = 12 Hz, 1H, Ar-
H), 6.84-6.86 (m, 2H, Ar-H), 7.24-7.30 (m, 2H, Ar-H),7.62
(m, 1H, Ar-H), 8.19-8.20 (t, J = 3 Hz, 1H, Ar-H). LC-MS
1
(
sulfonamide stretching), 1147 (sulfonamide stretching); H-
NMR (CDCl /TMS, 300 MHz); δ 1.08-1.11 (t, J = 9 Hz, 3H,
SO -CH -CH -CH ), 1.39-1.39 (d, J = 9 Hz, 1H, one proton
of 3-CH ), 1.42 (s, 9H, tert-butyl), 1.90 (m, 2H, -CH -CH
CH ), 1.98-2.1 (m, 1H, one proton of 3-CH ), 3.18-3.20 (t,
J = 6.2 Hz, 1H, one proton of -N-CH ), 3.56-3.58 (m, 2H,
), 3.87-3.95 (t, J = 7.2 Hz , 1H, one proton of
), 3.98-4.01 (d, J = 9 Hz, 1H, one proton of 10-CH ),
.14-4.17 (m, 3H, one of the protons of 2-CH & 10a-CH),
.65 (s, 1H, one proton of 10-CH), 6.51-6.53 (d, J = 6 Hz, 1H,
3
+
2
2
2
3
(ESI) (M + H) m/z 465.
2
2
2
-
Compound 6h: Yield: 0.56 g (72 %); m.p. 151-154 °C;
-1
3
2
IR (KBr, νmax, cm ): 1726 (carbamide stretching) and 1349
1
(sulfonamide stretching) 1147 (sulfonamide stretching); H-
2
-CH
2
-CH
2
-CH
3
NMR (CDCl
1.44 (d, J = 6 Hz, 1H, one proton of 3-CH
proton of 3-CH ), 3.19-3.19 (t, J = 6 Hz, 1H, one proton of
-N-CH ), 3.92 (m, 5H, -N-CH , 10-CH & -O-CH ), 4.19-4.20
(m, 3H one of the protons of 2-CH & 10a-CH), 4.67 (s, 1H,
3
/TMS, 300 MHz); δ 1.32 (s, 9H, tert-butyl), 1.42-
-N-CH
2
2
2
), 2.12 (m, 1H, one
4
4
2
2
2
2
3
Ar-H), 6.78 (s, 1H, Ar-H), 6.79-6.80, (d, J = 3 Hz, 1H, Ar-H).
+
LC-MS (ESI) (M + H) m/z 413.
2
one proton of 10-CH), 6.48-6.49 (d, J = 12 Hz, 1H, Ar-H),
6.7(s 1H, Ar-H) 6.74-6.79 (t, J = 12 Hz, 1H Ar-H), 6.98-7.00
(d, J = 5.1Hz, 2H, Ar-H),7.91-7.93 (d, J = 5.1 Hz, 2H, Ar-H).
Compound 6d: Yield: 0.45 g (67 %); m.p. 154-156 °C;
-1
IR (KBr, νmax, cm ): 1720 (carbamide stretching) and 1347
(
1
sulfonamide stretching), 1151 (sulfonamide stretching); H-
+
LC-MS (ESI) (M + H) m/z 477.

Vol. 26, No. 16 (2014)
Synthesis of Substituted Azaphenanthrene-6-yl)alkyl and Aryl Sulfonamides 5265
Compound 6i: Yield: 1 g (86 %); m.p. 164-168 °C; IR
10-CH), 6.12 (br s, 1H, NH, D
2
O exchangeable proton), 6.49-
-1
(
KBr, νmax, cm ): 1730 (carbamide stretching) and 1355 (sulfo-
1
namide stretching), 1156 (sulfonamide stretching); H NMR
6.51 (dd, J & J = 1.5 & 2.7 Hz, 1H, Ar-H), 6.72 (s, 1H , Ar-
2
1
H), 6.74-6.79 (d, J = 6 Hz, 1H, Ar-H), 6.82 (s, 1H, Ar-H),
+
LC-MS (ESI) (M + H) m/z 314.
(
CDCl
d, J = 7.8 Hz, 1H, one proton of 3-CH
), 3.19-3.22 (t, J = 9 Hz, 1H, one proton of
3
/TMS, 300 MHz); δ 1.38 (s, 9H, tert-butyl), 1.44-1.47
(
2
), 2.15 (m,1H, one
Compound 7e: Yield: 0.23 g (85 %); m.p. 160-162 °C;
-1
proton of 3-CH
N-CH ), 3.90 (m, 2H, one of the protons of -N-CH
CH), 4.19-4.21 (m, 3H , one of the protons of 2-CH
2
IR (KBr, νmax, cm ): 3215 (sulfonamide N-H stretching), 1342
1
(sulfonamide stretching), 1150 (sulfonamide stretching); H-
-
2
2
, & 10-
& 10a-
2
NMR (CDCl
1H, one proton of 3-CH
3.15-3.19 (t, J = 11 Hz, 1H, one proton of -N-CH
2H, one of the protons of -N-CH & 10-CH), 4.15 (m, 3H,
one of the protons of 2-CH & 10a-CH), 4.63 (s,1H, one proton
of 10-CH), 6.21-6.21 (dd, J = 2.1 Hz, 1H, Ar-H), 6.40 (br s,
1H, NH, D O exchangeable proton), 6.62-6.63 (d, J = 5.1 Hz,
3
/TMS,3 00 MHz); δ 1.35-1.37 (d, J = 6.3 Hz,
), 1.92 (m, 1H, one proton of 3-CH ),
), 3.89 (m,
CH), 4.69 (s, 1H, one proton of 10-CH), 6.47-6.48 (d, J = 3
Hz, 1H, Ar-H), 6.74 (s,1H, Ar-H), 6.83-6.85 (d, J = 6 Hz, 1H,
Ar-H), 7.77-7.80 (t, J = 9 Hz, 1H, Ar-H), 8.32-8.34 (d, J = 6
2
2
2
2
Hz, 1H, Ar-H), 8.49-8.51 (d, J = 6 Hz, 1H, Ar-H). LC-MS
+
ESI) (M + H) m/z 492.
2
(
Preparation of 7 (general procedure): A mixture of
2
compound 6 (0.7 mmol), Cs
2
Co
3
(0.5 g, 1.51 mmol) and
1H, Ar-H), 6.68-6.69 (s, 1H, Ar-H), 7.41-7.53 (m, 3H, Ar-H),
+
7.71-7.72 (m, 2H, Ar-H). LC-MS (ESI) (M + H) m/z 347;
imidazole (0.1 g, 1.51 mmol) in acetonitrile (10 mL), was
stirred at reflux temperature for 6 h. At the end of this period,
the reaction mass was filtered and washed with acetonitrile (5
mL). The acetonitrile was rotary evaporated to obtain the title
compounds compound 7 as solids.
Purity (HPLC) = 99.88 %.
Compound 7f: Yield: 0.25 g (92 %); m.p. 138-140 °C;
-1
IR (KBr, νmax, cm ): 3244 (sulfonamide N-H stretching), 1348
1
(sulfonamide stretching), 1158 (sulfonamide stretching); H-
Compound 7a: Yield: 0.13 g (88 %); m.p. 77-82 °C.
Compound7b: Yield: 0.195 g (86 %); m.p. 145-147 °C;
NMR (CDCl
1H, one proton of 3-CH2), 1.8-1.9 (m, 1H, one proton of
3-CH ), 2.38 (s, 3H, -Ph-CH ), 3.15-3.19 (t, J = 11 Hz, 1H,
one proton of -N-CH ), 3.89 (m, 2H, one of the protons of -N-
CH & 10-CH), 4.12 (m, 3H, one of the protons of 2-CH
10a-CH), 4.62 (s, 1H, one proton of 10-CH), 6.19-6.20 (dd,
J = 2.5 Hz, 1H,Ar-H ), 6.35 (br s, 1H, NH, D O exchangeable
3
/TMS, 300 MHz); δ 1.36-1.38 (d, J = 6.3 Hz,
-1
IR (KBr, νmax, cm ): 3224 (sulfonamide N-H stretching), 1324
2
3
1
(
sulfonamide stretching), 1143 (sulfonamide stretching); H-
NMR (CDCl /TMS, 300 MHz); δ 1.35-1.36 (t, J = 3.5 Hz,
H, CH -CH ), 1.42-1.45 (d, J = 6.2 Hz, 1H, one proton of 3-
CH ), 1.97-2.05 (m, 1H, one proton of 3-CH ), 3.195-3.197
m, 2H, -CH -CH ), 3.17-3.20 (t, J = 5.1 Hz, 1H, one proton
of -N-CH ), 3.88-3.90 (t, J = 6 Hz, 1H, one proton of 10-
CH ), 3.96-4.00 (d, J = 9 Hz, 1H, one proton of 10-CH ),
.13-4.16 (m, 3H, one of the protons of 2-CH & 10a-CH),
.65 (s, 1H, one proton of 10-CH), 6.37 (br s, 1H, NH, D
2
3
2
2
&
3
2
3
2
2
2
(
2
3
proton), 6.60-6.61 (d, J = 4.8 Hz, 1H, Ar-H), 6.69 (s, 1H, Ar-
H), 7.19-7.20 (m, 2H, Ar-H), 7.57-7.58 (d, J = 4.7 Hz, 2H, Ar-
+
H). LC-MS (ESI) (M + H) m/z 361; Purity (HPLC) = 96.29 %.
2
2
2
4
4
2
Compound 7g: Yield: 0.35 g (78 %); m.p. 143-145 °C;
-1
2
O
IR (KBr, νmax, cm ) 3254 (sulfonamide N-H stretching), 1341
1
( sulfonamide stretching), 1152 ( sulfonamide stretching); H-
exchangeable proton ), 6.48-6.49 (dd, J = 1.2 Hz, 1H, Ar-H),
.75-6.77 (d, J = 2.1 Hz, 1H, Ar-H), 6.84 (s, 1H, Ar-H). LC-
6
MS (ESI) (M + H) m/z 299, Purity (HPLC) = 99.45 %.
Compound7c:Yield: 0.3 g (79 % ); m.p. 112-114 °C; IR
NMR (CDCl
one proton of 3-CH
3.13-3.16 (t, J = 6 Hz, 1H, one proton of-N-CH
2H, one of the protons of -N-CH & 10-CH), 4.13 (m, 3H,
one of the protons of 2-CH & 10a-CH), 4.62 (s, 1H, one
proton of 10-CH), 6.32-6.33 (dd, J = 3.0 Hz, 1H, Ar-H), 6.58
(br s, 1H, NH, D O exchangeable proton), 6.59-6.62 (d, J = 9
3
/TMS,300 MHz); δ 1.36-1.39 (d, J = 9 Hz, 1H,
), 1.82-1.91 (m, 1H, one proton of 3-CH ),
), 3.85 (m,
+
2
2
2
-1
(
KBr, νmax, cm ): 3242 (sulfonamide N-H stretching) 1340
1
sulfonamide stretching),1147 (sulfonamide stretching); H-
2
(
2
NMR (CDCl
CH -CH -CH
CH ) 1.83-1.85 (m, 2H, -CH
one proton of 3-CH ), 2.99-3.02 (t, J = 4.5 Hz, 1H, -CH
CH -CH ), 3.18-3.10 (t, J = 6 Hz, 1H, one proton of -N-CH
.88-3.91 (t, J = 9 Hz, 1H, one proton of N-CH ), 3.96-4.00
d, J = 12 Hz, 1H, one proton of 10-CH), 4.12-4.21 (m, 3H,
one of the protons of 2-CH & 10a-CH), 4.66 (s, 1H, one
proton of 10-CH), 6.28 (br s, 1H, NH, D O exchangeable
proton), 6.49-6.50 (dd, J & J = 1.2 Hz, 1H, Ar-H), 6.76-
.84, (d, J = 5.1 Hz, 1H , Ar-H), 6.84 (s, 1H, Ar-H). LC-MS
3
/TMS, 300 MHz); δ 1.01-1.04 (t, J = 4.5Hz, 3H,
), 1.40-1.42 (d, J = 9 Hz, 1H, one proton of 3-
-CH -CH ),1.98-2.20 (m, 1H,
-
2
2
3
2
2
2
2
3
Hz, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 7.16-7.19 (m, 2H, Ar-H),
7.58 (m, 1H, Ar-H), 7.74 (m, 1H, Ar-H). LC-MS (ESI) (M +
+
H) m/z 365; Purity (HPLC) = 96.90 %.
2
2
-
2
3
2
),
3
2
Compound 7h:Yield: 0.3 g (85 %); m.p. 123-125 °C; IR
-1
(
(KBr, νmax, cm ): 3256 (sulfonamide N-H stretching) 1372
1
(sulfonamide stretching), 1161 (sulfonamide stretching); H-
2
2
NMR (CDCl
1H, one proton of 3-CH
3.12-3.16 (t, J = 9 Hz, 1H, one proton of N-CH
5H, one of the protons of -N-CH , 10-CH & -O-CH
4.15 (m, 3H, one of the protons of 2-CH & 10a-CH), 4.62 (s,
1H, one proton of 10-CH ), 6.20-6.22 (dd, J = 3.50 Hz, 1H,
Ar-H), 6.34 (br s, 1H, NH, D O exchangeable proton), 6.14-
3
/TMS, 300 MHz); δ 1.38-1.44 (d, J = 6.2 Hz,
), 1.98 (m, 1H, one proton of 3-CH ),
), 3.89 (m,
), 4.13-
1
2
2
2
6
2
+
(
ESI) (M + H) m/z 313; Purity (HPLC) = 99.79 %.
2
3
Compound 7d: Yield: 0.06 g (80 % ); m.p. 123-125 °C;
2
-1
IR (KBr, νmax, cm ): 3220 (sulfonamide N-H stretching), 1350
1
(
sulfonamide stretching), 1152 (sulfonamide stretching); H-
NMR (CDCl /TMS, 300 MHz); δ 1.42-1.44 (d, J = 6 Hz, 1H,
one proton of 3-CH ), 1.98 (m, 1H, one proton of 3-CH ),
.84-2.85 (s, 6H, N(CH )2), 3.19-3.3.20 (t, J = 3.2 Hz, 1H,
one proton of -N-CH ), 3.89-4.00 (m, 2H, one of the protons
of -N-CH & 10-CH), 4.19-4.22 (m, 3H, one of the protons of
-CH &10a-CH), 4.35-4.38 (t, J = 2.1 Hz, 1H, one proton of
2
3
6.21 (d, 1H, J = 6.2 Hz, Ar-H) ,6.7 (s, 1H, Ar-H), 6.86-6.88 (t,
J = 5.1 Hz, 2H, Ar-H), 7.62-7.64 (d, J = 5.4 Hz, 2H, Ar-H).
LC-MS (ESI) (M + H) + m/z 377 Purity (HPLC) = 99.66 %.
Compound 7i:Yield: 0.6 g (76 %); m.p. 173-176 °C; IR
2
2
2
3
2
-1
2
(KBr, νmax, cm ): 3256 (sulfonamide N-H stretching) 1332
2
2
(sulfonamide stretching), 1167 (sulfonamide stretching), 1535

5
266 Rajachandrasekhar et al.
Asian J. Chem.
1
-1
stretching) and at 1713 cm (due to carbamide stretching);
(
Nitro group stretching), 1370 (Nitro group stretching); H-
NMR (CDCl /TMS,300 MHz); δ 1.44-1.47 (d, J = 7.8 Hz,
H, one proton of 3-CH ), 1.98 (m, 1H, one proton of 3-CH ),
.195-3.21 (t, J = 8.5 Hz, 1H, one proton of -N-CH ), 3.90
, & 10-CH ), 4.19-4.21
& 10a-CH), 4.62 (s, 1H,
1
3
Its H-NMR (CDCl
signals at δ1.37-1.40 (d, J = 9 Hz, 1H, one proton of 3-CH
1.50 (s, 9H, tert-butyl), 2.06-2.15 (m, 1H, one proton of 3-
CH ), 3.17-3.19 (t, J = 6 Hz, 1H, one proton of -N-CH ),
3.82-3.85 (t, J = 9 Hz, 1H, one proton of -N-CH -), 3.98-
4.02 (d, J = 12 Hz, 1H, one proton of 10-CH), 4.11-4.13 (m,
3H, one of the protons of 2-CH & 10a-CH), 4.63-4.64 (s,
3
/TMS, 300 MHz) spectrum showed
1
3
2
2
2
),
2
(
(
m, 2H, one of the protons of -N-CH
m, 3H, one of the protons of 2-CH
2
2
2
2
2
2
one proton of 10-CH), 6.26-6.29 (d, J = 9 Hz, 1H, Ar-H), 6.5
br s, 1H, NH, D O exchangeable proton), 6.61-6.69 (d, J = 6
(
2
2
Hz, 1H, Ar-H), 6.79 (s, 1H, Ar-H ),7.63-7.68 (t, J = 9 Hz, 1H,
Ar-H), 7.95-7.99 (d, J = 6 Hz, 1H Ar-H), 8.39-8.40 (d, J = 6
1H, one proton of 10-CH), 6.3 (s,1H, Ar-H), 6.47-6.48 (d,
J = 3 Hz, 1H, Ar-H), 6.71-6.73 (d, J = 6 Hz, 1H, Ar-H), 7.18
+
Hz, 1H, Ar-H), 8.61 (s, 1H, Ar-H). LC-MS (ESI) (M + H)
2
(br s, 1H, NH, D O exchangeable proton). Its LCMS showed
+
m/z 392, Purity (HPLC) = 98.54 %.
the molecular ion (M + 1) peak at m/z 307 corresponding to
a molecular mass of 306 when recorded in the Q + 1 ion
mode. Treatment of compound 5 with methanesulfonyl
chloride in the presence of NaH in DMF at 0 °C to room tempe-
rature for 40 min, gave a product which has been charac-
terized as N-(3,4,10,10a-terhydro-2H-1,9-dioxa-4a-aza-
RESULTS AND DISCUSSION
Commercially available 2-amino-4-nitrophenol (1) was
2 3
treated with chloroacetyl chloride in the presence of K CO in
10
1
THF at 50 °C for 5 h, to obtain the previously reported 6-
nitro-4H-benz[1,4]oxazin-3-one (2). Compound, 2 was treated
phenanthrene-6-yl)methane sulfonamide-N -carbamic acid
tert-butyl ester (6a), on the basis of its spectral data. Thus,
with ethyl 3-bromopropionate in the presence of K CO
2
3
in
its IR ( KBr pellet), spectrum showed diagnostic peaks at
-1
-
1717 cm (due to carbamide stretching) and at 1342 cm
1
DMF at 80 °C for 10 h, to obtain a product that has been
characterized as 3-(6-nitro-3-oxo-2,3-dihydrobenz[1,4]oxazin-
-
1
(due to sulfonamide stretching) 1167 cm (due to sulfon-
1
amide stretching); H-NMR (CDCl /TMS, 300 MHz) spectrum
4
data. Thus, its IR (KBr pellet) spectrum showed diagnostic
-yl)propionic acid ethyl ester (3), on the basis of its spectral
3
showed signals at δ 1.42 (s, 9H, tert-butyl ), 1.25-1.27 (d,
J = 6 Hz, 1H, one proton of 3-CH ), 1.96-2.00 (m, 1H, one
-1
peaks at 1717 cm (due to ester carbonyl stretching) and at
2
-1
-1
682 cm (due to amide carbonyl stretching), 1520 cm (due
1
to nitro group stretching), 1344 cm (due to nitro group
proton of 3-CH ), 3.19-3.19 (t, J = 6 Hz, 1H, one proton of
2
-
1
-N-CH ), 3.4 (s, 3H, -SO -CH ), 3.82-3.85 (t, J = 8.2 Hz,
2
2
3
1
stretching); Its H NMR (CDCl
at δ 1.23-1.26 (t, J = 9.1 Hz, 3H, CH
6 Hz, 2H -N-CH ), 4.12-4.16 (q, 2H, -CH
.4.29 (t, J = 6 Hz, 2H, -CH -CH -CO-), 4.71 (s, 2H,-O-
CH ), 7.06-7.08 (d, J = 5.1 Hz, 1H, Ar-H), 7.92-7.95 (m,
H, Ar-H). Its LCMS showed the molecular ion (M + 1)
3
, 300 MHz) showed signals
-CH ), 2.70-2.73 ( t, J
-CH ), 4.26-
1H, one proton of -N-CH -), 3.92-4.02 (d, J = 10 Hz, 1H,
2
2
3
one proton of 10-CH), 4.18-4.20 (m, 3H, one of the protons
of 2-CH & 10a-CH), 4.64 (s, 1H, one proton of 10-CH),
6.53-6.55 (d, J = 6 Hz, 1H, Ar-H), 6.71-6.73 (s, 1H, Ar-H),
=
2
2
3
2
4
2
2
2
6.79-6.81, (d, J = 6 Hz, 1H, Ar-H). Its LCMS showed the
+
molecular ion (M + 1) peak at m/z 385 corresponding to a
+
2
peak at m/z 295 corresponding to a molecular mass of 294
when recorded in the Q+1 ion mode. Reduction of compound
molecular mass of 384 when recorded in the Q + 1 ion mode.
6a was de-protected with Cs Co and imidazole in aceto-
2
3
3
with lithium aluminium-hydride in tetrahydrofuran afforded
nitrile at 70 °C to obtain a pure compound, which has been
characterized as N-(3,4,10,10a-terhydro-2H-1,9-dioxa-4a-
azaphenanthrene-6yl)methylsul-fonamide (7a) on the basis
of its spectral data. Thus, its IR (KBr pellet), spectrum
a product which has been characterized as 6-nitro-3,4,10,10a-
tetrahydro-2H-1,9-dioxo-4a-azaphenanthrene (4) on the basis
of its spectral data. Thus, its IR (KBr pellet) spectrum showed
-1
-1
diagnostic peaks at 1514 cm (due to Nitro group stretching),
showed a diagnostic peak at 3220 cm (due to sulfonamide
-1
N-H stretching vibration), 1325 cm (due to sulfonamide
-1
1
1
344 cm (due to Nitro group stretching); Its H-NMR (CDCl
TMS, 300 MHz) spectrum showed signals at δ 1.45-1.48 (d,
J = 9 Hz, 1H, one proton of 3-CH ), 2.01-2.03 (m, 1H, one
proton of 3-CH ), 3.26-3.26 (t, J = 8 Hz, 1H, one proton of
N-CH ), 3.91-3.94 (t, J = 9 Hz, 1H, one proton of -N-CH -),
.05-4.26 (d, J = 8.4 Hz, 1H, one proton of 10-CH ), 4.15-
.26 (m, 3H, one of the protons of 2-CH & 10-CH ), 4.69-
3
/
-
stretching), 1143 cm (due to sulfonamide stretching); Its
1
1
2
H-NMR (CDCl /TMS, 300 MHz) spectrum showed signals
3
2
at δ 1.40-1.43 (d, J = 9 Hz, 1H, one proton of 3-CH ), 1.95-
2
-
2
2
2.05 (m, 1H, one proton of 3-CH ), 2.94-3.00 (s, 3H, -SO -
2
2
4
4
4
1
2
3 2
CH ), 3.19-3.19 (t, J = 5.6 Hz, 1H, one proton of -N-CH ),
2
2
3.88-3.90 (t, J = 5.6 Hz, 1H, one proton of -N-CH ), 3.97-
2
.70 (s, 1H, one proton of 10-CH), 6.85-6.87 (d, J = 6.1 Hz,
H, Ar-H), 7.65-7.85 (dd, J =13, Hz, 1H, Ar-H), 7.72 (s, 1H,
4.00 (d, J = 9 Hz, 1H , one proton of 10-CH), 4.13-4.17
(m, 3H, one of the protons of 2-CH & 10a-CH), 4.66 (s,
2
+
Ar-H) and its LCMS showed the molecular ion (M + 1) peak
at m/z 237 corresponding to a molecular mass of 236 when
recorded in the Q + 1 ion mode. Compound 4 was treated
1H, one proton of 10-CH), 6.13 (br s,1H, NH, D O
2
exchangeable proton), 6.49-6.51 (dd, J = 3 Hz, 1H, Ar-H),
6.77-6.79 (d, J = 5.1 Hz, 1H, Ar-H), 6.83 (s, 1H, Ar-H).
+
Its LCMS showed the molecular ion (M + 1) peak at
with H
2
in the presence of Pd/C as catalyst containing
di-tert-butyl dicarbonate in THF-MeOH (8:2) at room tempe-
rature for 2 h, giving a pure product which has been charac-
terized as (3,4,10,10a-tetrahydro-2H-1,9-dioxa-4a-
azaphenanthrene-6-yl)carbamic acid tert-butyl ester (5) on
the basis of its spectral data. Its IR (KBr pellet), spectrum
m/z 285 corresponding to a molecular mass of 284. The
above reaction was found to be a general one and was
extended to prepare other derivatives of compound 7
through the sequence 6(b-i) → 7(b-i), respectively. All
the above reactions are shown in the summarized form
(Scheme-I).
-
1
showed diagnostic peaks at 3290 cm (due to amide N-H

Vol. 26, No. 16 (2014)
Synthesis of Substituted Azaphenanthrene-6-yl)alkyl and Aryl Sulfonamides 5267
6
1
O
N
8
5
5
1
2
LAH/THF/
RT,1h.
OH (i)Chloroacetyl chloride
O
2
Ethyl 3-bromo propionate
7
6
4
4
O N
2
O
O N
2
K CO / DMF,80 °c
2
NH2
/
DIPEA
3
3
1
O N
2
N 3 O
H
3
COOEt
) i i) K CO / 70 °c
2
3
2
O
S
R
9
O
N
8
5
Cl
O
10
O
7
(i) H /Pd-C
2
O
HN
O
(
ii)
Di BOC /THF/RT
O
O N
2
N10a
1
2
NaH/DMF/0°c-RT.
O
6
O
4
5
3
4
O
CS CO
2
3
O
O
HN
S
N
O
O
N
S
R
N
O
/Immidazole
ACN/70°c
O
O
O
-
R
7(a-i)
6
(a i)
R
a) Methyl b) ethyl, c) Propyl ,d) N-dimethyl,e) Phenyl, f) P-toluyl , g) 2-flouro phenyl , h) 4-
methoxyphenyl, i) 3-nitrophenyl.
Scheme-I
4
5
6
.
.
.
M. Kajino, Y. Shibouta, K. Nishikawa and K. Meguro, Chem. Pharm.
Bull. (Tokyo), 39, 2896 (1991).
ACKNOWLEDGEMENTS
R. Fringuelli, D. Pietrella, F. Schiaffella, A. Garraci, S. Perito, F. Bistoni
and A. Vecchiarelli, Bioorg. Med. Chem., 10, 1681 (2002).
S. Alper-Hayta, E. Aki-Sener, B. Tekiner-Gulbas, I. Yildiz, O. Temiz-
Arpaci, I. Yalcin and N. Altanlar, Eur. J. Med. Chem., 41, 1398 (2006).
This work was supported by Civentichem (India) Private
Limited. The authors thank Dr. Bhaskar Rao Venepalli and
Dr. Vasu Cittineni, for their support. The authors also thank
the authorities of Jawaharlal Nehru Technological University
Hyderabad for encouragement.
7. S. Deswal and N. Roy, Eur. J. Med. Chem., 41, 552 (2006).
8
.
D. Zhou, B.L. Harrison, U. Shah, H. Andree, G.A. Hornby, R. Scerni,
L.E. Schechter, D.L. Smith, K.M. Sullivan and R.E. Mewshaw, Bioorg.
Med. Chem. Lett., 16, 1338 (2006).
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