Vol. 27, No. 9 (2015)
Synthesis of 1,9-Diazaphenoxazine Carboxamide Derivatives 3465
Synthesis of linear diazaphenoxazine carboxamides
(18a-e): These compounds were prepared using the procedure
developed byAnderson and co-workers21. 1,4-Bis(2-hydroxyl-
3,5-di-tert-butyl benzyl)piperazine (16) (0.016 g, 0.003 mmol)
and palladium acetate (0.002 g, 0.001 mmol) were placed in a
100 mL two necked flask. Nitrogen gas was introduced for 30
s, 2 mL of water was added and the mixture heated for 2 min
at 80 ºC. The catalyst pre-activation was monitored visually
using colour change from yellow to black. Then 3-chloro-1,9-
diazaphenoxazine (13) (0.208 g, 1.0 mmol), potassium
carbonate (0.193 g, 1.4 mmol) and substituted carboxamide
derivatives (17a-e) (1.2 mmol) in DMF (2 mL) were mixed
with toluene (2 mL) and evacuated with nitrogen gas for
another 30 s. The entire mixture was heated under reflux
with stirring for 2 h at 110 ºC in an oil bath under nitrogen
atmosphere. The crude product obtained was cooled at room
temperature, air dried and recrystallized from aqueous ethyl
acetate.
C17H11N5O4 (% calcd./found): C: 58.45/58.50, H: 3.17/3.15,
N: 20.05/20.01.
3-Benzamido-1,9-diazaphenoxazine (18d): 3-Benzamido-
1,9-diazaphenoxazine (18d) was obtained as a reddish-brown
solid, yield 0.242 g, (68.5 %), mp 129 ºC. UV-visible (ethanol)
λ
max: 307.50 nm (log ε 2.32). IR (KBr, νmax, cm–1): 3740 and
3365 (2 N-H stret), 3178 (ArC-H), 1646 (C=O), 1400 (C=N
stret), 1021 (C-O stret), 785 and 665 (substituted aromatic
ring). 1H NMR (400 MHz, DMSO): δ 8.5 (5H, m, Ar-H), 8.0
(1H, s, b, NH), 7.3 (3H, m, Ar-H), 7.1 (1H, s,Ar-H). 13C NMR
(400 MHz, DMSO): δ 160.01, 146.64, 146.07, 142.34, 140.92,
135.76, 132.44, 128.09, 126.99, 126.23, 125.87, 125.03,
122.93, 122.13, 121.90, 120.58, 119.89.Analysis of C17H12N4O2
(% calcd./found): C: 67.10/67.11, H: 3.97/4.01, N: 18.41/
18.35.
3-Acetamido-1,9-diazaphenoxazine (18e): 3-Acetamido-
1,9-diazaphenoxazine (18e) was obtained as a yellow solid,
yield 0.222 g, (79.6 %), mp 310 ºC. UV-visible (ethanol) λmax
:
3-Formamido-1,9-diazaphenoxazine (18a): 3-Formamido-
1,9-diazaphenoxazine (18a) was obtained as an ash solid, yield
0.168 g (78.7 %), mp 200 ºC. UV-visible (ethanol) λmax: 280.5
nm (log ε 2.36). IR (KBr, νmax, cm–1): 3855 and 3741(2 N-H
stret), 1685 (C=O stret), 1534 (C=N stret); 1HNMR (DMSO):
δ 8.12 (1H, s, Ar-H), 7.2 (3H, m, Ar-H), 5.2 (1H, s, b, NH),
3.5 (1H, s, C-H). 13C NMR (DMSO): δ 170.10, 147.20, 142.60,
138.50, 136.39, 130.68, 127.68, 127.10, 125.90, 124.76,
123.29. Analysis of C11H8N4O2 (% calcd./found): C: 57.89/
58.01, H: 3.53/3.48, N: 24.55/24.50.
218 (log ε 3.04), 225 (log ε 3.05), 232.5 (log ε 3.06), 283.5
(log ε 2.78) nm. IR (KBr, νmax, cm–1): 3736 and 3394 (2 N-H
stret), 1655 (C=O stret), 1452 (C=N stret), 1058 (C-O stret),
773 (substituted aromatic ring). 1H NMR (400 MHz, DMSO):
δ 8.2 (3H, m, Ar-H), 8.0 (1H, s, b, NH), 7.6 (1H, s, Ar-H), 2.5
(3H, s, CH3). 13C NMR (400 MHz, DMSO): δ 159.76, 145.23,
142.98, 136.45, 135.99, 135.10, 130.24, 128.81, 126.91,
123.12, 120.35, 50.23. Analysis of C12H10N4O2 (% calcd./
found): C: 59.50/59.60, H: 4.16/4.10, N: 23.13/23.10.
RESULTS AND DISCUSSION
3-Phthalamido-1,9-diazaphenoxazine (18b): 3-Phthal-
amido-1,9-diazaphenoxazine (18b) was obtained as an ash
solid, yield 0.209 g, (54.6 %), mp 247 ºC. UV-visible (ethanol)
The synthesis of 3-chloro-1,9-diazaphenoxazine (13) was
achieved by the reaction of 2-amino-3-hydroxypyridine (11)
with 2,3,5-trichloropyridine (12) in 1,4-dioxane in aqueous
medium at 80 ºC for 4 h (Scheme-II). The ligand 1,4-bis(2-
hydroxyl-3,5-di-tert-butylbenzyl)piperazine (16) was prepared
by the reaction of piperazine (14) and aqueous formaldehyde
solution in methanol under reflux for 2 h. The clear solution
obtained was then refluxed with 2,4-di-tert-butylphenol (15)
solution in methanol for 12 h to obtain the ligand as a white
crystalline solid according to literature (Scheme-III)20. The
water mediated catalyst pre-activation was monitored visually
using colour change from yellow to black. The linear diazaphe-
noxazine carboxamide derivatives (18a-e) were synthesized
by the reaction of 3-chloro-1,9-diazaphenoxazine (13) and
substituted carboxamides (17a-e) in the presence of activated
1,4-bis(2-hydroxyl-3,5-di-tert-butylbenzyl) piperazine (16),
palladium acetate and potassium carbonate under nitrogen in
an oil bath at 110 ºC for 2 h using 50:50 DMF and toluene as
solvent to obtain the carboxamide derivatives (Scheme-IV).
The linear diazaphenoxazine carboxamides were obtained in
excellent yield (Table-1).
λ
max: 282.5 nm (log ε 2.91). IR (KBr, νmax, cm–1): 3393 and
3297 (2 N- H stret), 3137(ArC- H), 1690 (C=O), 1449 (C=N
stret), 1008 (C-O stret), 845-722 (substituted aromatic ring).
1H NMR (400 MHz, DMSO): δ 5.25 (1H, s, 1H, NH), 7.0–6.6
(2H, m,Ar-H). 13C NMR (400 MHz, DMSO): δ 170.01, 169.90,
150.45, 149.60, 146.01, 145.67, 145.10, 146.01, 145.98,
145.24, 140.21, 130.00, 128.09, 126.10, 125.05, 124.90,
124.10 and 119.10. Analysis of C18H10N4O3 (% calcd./found):
C: 65.45/65.35, H: 3.05/3.10, N: 16.96/17.01.
3-(4-Nitrobenzamido)-1,9-diazaphenoxazine (18c): 3-
(4-Nitrobenzamido)-1,9-diazaphenoxazine (18c) was obtained
as an ash solid, yield 0.357 g, (87.8 %), mp 310 ºC. UV-visible
(ethanol) λmax: 280.5 nm (log ε 2.91). IR (KBr, νmax, cm–1):
3741and 3855 (2 N-H stret), 1664 (C=O), 1535 (C=N stret).
1H NMR (400 MHz, DMSO): δ 8.6 (1H, s, NH), 8.4 (1H, s,
Ar-H), 7.64 (4H, m, Ar-H), 7.46 (3H, m, Ar-H). 13C NMR
(400 MHz, DMSO): δ 168.23, 164.40, 150.05, 143.90, 143.45,
142.76, 142.03, 138.69, 138.10, 136.49, 135.89, 135.12,
134.32, 130.24, 126.45, 122.23 and 119.94. Analysis of
H
N
N
N
NH2
OH
N
Cl
Cl
N
KOH, 1,4-dioxane
reflux, 4 h, heat
+
O
13
Cl
Cl
11
12
Scheme-II: Synthesis of 3-chloro-1,9-diazaphenoxazine