Synthesis and biological activity of some 3-aryl-3,4-dihydro-2h-benz[e]-1, 3-oxazines/6-bromo-3-aryl-3,4-dihydro-2h-benz[e]-1,3-oxazines

Article abstract of DOI:10.14233/ajchem.2013.14091

N-(2-Hydroxy)-benzyl-arylamine (1) gives substantially pure 3-aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines/6-bromo-3-aryl-3,4-dihydro-2H-benz[e] -1,3-oxazines (2) on cyclization with formaldehyde in methanol within 0.5-1.0 h at 65-68 C in excellent yields. Th

Full text of DOI:10.14233/ajchem.2013.14091

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 5921-5924
http://dx.doi.org/10.14233/ajchem.2013.14091
Synthesis and Biological Activity of Some 3-Aryl-3,4-dihydro-2H-benz[e]-
1,3-oxazines/6-bromo-3-aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines
1
1
1,*
2
2
DAVENDER KUMAR SHUKLA , MANJU RANI , ARIF ALI KHAN , KAVITA TIWARI and RAJINDER K. GUPTA
1University School of Basic &Applied Sciences, Guru Gobind Singh Indraprastha University, Sector 16C, Dwarka, New Delhi-110 078, India
2University School of Biotechnology, Guru Gobind Singh Indraprastha University, Sector 16C, Dwarka, New Delhi-110 078, India
*Corresponding author: E-mail: khanaarif@hotmail.com
(Received: 9 June 2012;
Accepted: 18 April 2013)
AJC-13368
N-(2-Hydroxy)-benzyl-arylamine (1) gives substantially pure 3-aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines/6-bromo-3-aryl-3,4-dihydro-
2H-benz[e]-1,3-oxazines (2) on cyclization with formaldehyde in methanol within 0.5-1.0 h at 65-68 ºC in excellent yields. The compounds
thus prepared were screened for their antimicrobial studies against Gram-positive bacteria (Staphylococcus aureus, MTCC 96) and Gram-
negative bacteria (E. coli, MTCC 739). For estimating antifungal activity the organism used is Candida albicans. Minimum inhibitory
concentration of all the compounds was determined using the micro-broth dilution method.
Key Words: Arylamine, Formaldehyde, Benz-1,3-oxazine, Cyclization, Heterocyclic.
to pure isolated substances. NMR spectra were recorded on a
Bruker AV300 MHz spectrophotometer. The chemical shifts
are reported in ppm downfield of internal standard tetra-
methylsilane for 1H NMR and 13C NMR. Chemical shifts are
designated using the following abbreviations: s = singlet, d =
doublet, t = triplet, m = multiplet. Mass spectra were recorded
on a Shimadzu GCMS QP2010 plus instrument and fragments
having intensity more than 20 % has been given. Infrared spectrum
was recorded on Shimadzu FTIR-8700. Elemental analysis
was carried out using EURO EA 3000 elemental analyzer.
Melting points were recorded in open capillary method and
are uncorrected.
INTRODUCTION
Many important medicines, dyes, insecticides, etc., are
found in the series of heterocyclic compounds, called oxazines1
and thiazines2. They are found mainly in the polycyclic divisions
in which other rings, such as the benzene ring, are fused to the
oxazines or thiazine ring. A considerable number of reports
concerning 1,3-oxazine3-5 derivatives which have undergone
their greatest development in the last few years came in to the
notice. This is due to partially the fact that these compounds
show interesting pharmacological activity6-11 and wide range
of biological activity with uses as herbicides and agricultural
microbiocides, as well as bactericide, fungicide, antidepressive,
antiinflammatory and antitumor agents12-15. Moreover 1,3-oxazine
monomers were recently used to develop a new type of phenolic
resin namely polybenzoxazines, by the ring openining poly-
Synthesis of N-(2-hydroxy)-benzyl-arylamines (1): Schiff
bases were prepared by dissolving aldehyde (0.1 mol) in
methanol, was mixed with corresponding aryl amine (0.1 mol)
at room temperature. The mixture was stirred at 20-25 ºC for
0.5 h and poured in ice water. The separated product was
collected by filtration and recrystallized with methanol. The
recrystallized Schiff bases (0.1 mol) were dissolved in methanol,
sodium borohydride (0.25 mol) was added lot wise at 0-5 ºC
over a period of 1 h. The contents were further stirred for
2-3 h at 25-30 ºC. The solvent was removed under vacuum,
added water to precipitate the mass. Filter and wash with
water to get crude material. The crude product thus obtained
was recrystallized with methanol to get 1 as crystalline solid.
Synthesis of 3,4-dihydro-3-phenyl-2H-benz[e]-1,3-
oxazine (2a): N-(2-hydroxy)benzylamine (1a) (1.99 g, 0.01
mol) dissolved in methanol (20 mL) was taken in round bottom
merization on thermal curing16,17
.
EXPERIMENTAL
Salicyldehyde (spectrochem), sodium borohydride
(spectrochem), aniline (CDH), 4-methyl aniline (Thomas Baker),
4-chloro aniline (CDH), 4-bromo aniline (spectrochem), 2-amino-
pyridine (spectrochem), 3-aminopyridine (spectrochem), 5-
bromo-salicyldehyde (spectrochem) were used as received.
Solvents were purified by standard procedures.
All reactions and workup were conducted under air, except
when noted otherwise. TLC was performed on MERCK TLC
Silica gel 60 F254 plates and visualized by iodine. Yields refer

5922 Shukla et al.
Asian J. Chem.
flask. Formaldehyde (37 % solution in water) (1.62 mL, 0.02
mol) was added with constant stirring over a period of 0.5 h.
The reaction mixture was heated at 65-68 ºC for 0.5-1.0 h.
The progress of reaction was monitored by TLC (hexane:
EtOAc, 80:20). After completion of reaction, the solvent was
recovered under reduced pressure to get viscous material,
which was crystallized from methanol to give 2a as white
crystalline material. Yield 1.73 g (82.0 %), m.p. 51-52 ºC;
156.86, 145.87, 138.74, 131.39, 129.83, 124.05, 119.06,
117.81, 114.10, 108.74, 81.05, 49.44; GCMS m/z: 212.0, mass
fragments, 52.10 (21.96), 79.10 (100.00), 94.10 (74.67),
211.15 (22.52), 212.20 (35.21); Elemental analysis calculated
for C13H12N2O: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.52;
H, 5.62; N, 13.15.
Synthesis of 3,4-dihydro-3-pyridin-3-yl-2H-benz[e]-
1,3-oxazine (2f):White crystalline solid.Yield 63 %, m.p. 111-
112 ºC; FTIR (cm-1) 1045 (-C-O-C) sym., 1170 (-C-N-C); 1H
NMR (300 MHz, CDCl3): δ 3.401 (s, 2H, ArCH2N), 4.711 (s,
2H, OCH2N), 6.763-7.332 (m, 8H, ArH); depth (75 MHz,
CDCl3): δ 85.02, 51.23; 13C NMR (75 MHz, CDCl3): δ 155.56,
143.51, 139.60, 137.11, 128.88, 123.73, 122.89, 122.51, 119.75,
116.34, 85.03, 55.18, 51.27; GCMS m/z: 212.0, mass fragments,
78.10 (34.99), 105.10 (40.96), 106.10 (100.00), 212.15 (34.75);
elemental analysis calculated for C13H12N2O: C, 73.56; H, 5.70;
N, 13.20. Found: C, 73.46; H, 5.48; N, 13.12.
1
FTIR (cm-1) 1032 (-C-O-C) sym., 1151 (-C-N-C); H NMR
(300 MHz, CDCl3): δ 4.616 (s, 2H, ArCH2N), 5.346 (s, 2H,
OCH2N), 6.785-7.277 (m, 9H,ArH); Depth (75 MHz, CDCl3):
δ 79.51, 50.45; 13C NMR (75 MHz, CDCl3): δ 154.36, 148.37,
129.24, 127.83, 126.7, 121.40, 120.87, 120.78, 118.23, 116.92,
79.44, 50.38; GCMS m/z: 211.25, Mass fragments, 77.10
(32.62), 104.10 (45.97), 105.15 (100.00), 211.25 (31.74);
elemental analysis calculated for C14H13NO: C, 79.59; H, 6.20;
N, 6.63. Found: C, 79.41; H, 6.18; N, 6.58.
Synthesis of 3,4-dihydro-3-(4-methylphenyl)-2H-
benz[e]-1,3-oxazine (2b): White crystalline solid.Yield 85.0
%, m.p. 81-82 ºC; FTIR (cm-1) 1034 (-C-O-C) sym., 1149.5
(-C-N-C); 1H NMR (300 MHz, CDCl3): δ 2.249 (s, 3H,ArCH3),
4.582 (s, 2H, ArCH2N), 5.319 (s, 2H, OCH2N), 6.773-7.229
Synthesis of 6-bromo-3,4-dihydro-3-(4-methylphenyl) -
2H-benz[e]-1,3-oxazine (2g): White crystalline solid.Yield 86.5
%, m.p. 82-83 ºC; FTIR (cm-1) 1070.4 (-C-O-C) sym., 1159.1
(-C-N-C); 1H NMR (300 MHz, CDCl3): δ 2.248 (s, 3H,ArCH3),
4.521 (s, 2H, ArCH2N), 5.284 (s, 2H, OCH2N), 6.641-7.218
(m, 7H,ArH); depth (75 MHz, CDCl3): δ 80.31, 50.45; 13C NMR
(75 MHz, CDCl3): δ 153.39, 145.69, 131.46, 130.71, 129.81,
129.32, 122.75, 118.78, 118.64, 112.58, 80.15, 50.35, 20.52;
GCMS m/z: 303.0, mass fragments, 91.10 (36.84), 118.10
(24.13), 119.15 (100.00), 303.20 (8.38), 304.20 (2.69), 305.20
(8.01); elemental analysis calculated for C15H14NO2Br: C, 59.23;
H, 4.64; N, 4.60. Found: C, 59.19; H, 4.58; N, 4.56.
13
(m, 8H, ArH); depth (75 MHz, CDCl3): δ 80.02, 50.67; C
NMR (75 MHz, CDCl3): δ 154.35, 146.08, 131.02, 129.76,
127.79, 126.71, 120.89, 120.70, 118.61, 116.86, 79.95, 50.60,
20.49; GCMS m/z: 225.00, mass fragments, 91.05 (40.93),
118.10 (30.77), 119.10 (100.00), 225.00 (40.28); elemental
analysis calculated for C15H15NO: C, 79.97; H, 6.71; N, 6.22.
Found: C, 79.81; H, 6.62; N, 6.12.
Synthesis of 3,4-dihydro-3-(4-chlorophenyl)-2H-
benz[e]-1,3-oxazine (2c): White crystalline solid. Yield 83.0
%, m.p. 52-53 ºC; FTIR (cm-1) 1036 (-C-O-C) sym., 1155
Synthesis of 6-bromo-3,4-dihydro-3-(4-chlorophenyl)-
2H-benz[e]-1,3-oxazine (2h): White crystalline solid. Yield
82.5 %, m.p. 98-99 ºC; FTIR (cm-1) 1070.4 (-C-O-C) sym.,
1
1
(-C-N-C); H NMR (300 MHz, CDCl3): δ 4.580 (s, 2H,
1155.3 (-C-N-C); H NMR (300 MHz, CDCl3): δ 4.540 (s,
ArCH2N), 5.301 (s, 2H, OCH2N), 6.784-7.235 (m, 8H, ArH);
Depth (75 MHz, CDCl3): δ 79.37, 50.65; 13C NMR (75 MHz,
CDCl3): δ 154.16, 147.03, 129.15, 128.01, 126.70, 126.44,
120.95, 120.48, 119.56, 116.95, 79.32, 50.60; GCMS m/z: 245,
Mass fragments, 138.05 (40.25), 139.05 (100.00), 140.05
(21.00), 141.05 (34.43), 244.95 (40.00); elemental analysis
calculated for C14H12NOCl: C, 68.44; H, 4.92; N, 5.70. Found:
C, 68.39; H, 4.81; N, 5.58.
2H, ArCH2N), 5.280 (s, 2H, OCH2N), 6.662-7.245 (m, 7H,
ArH); depth (75 MHz, CDCl3): δ 79.62, 50.32; 13C NMR (75
MHz, CDCl3): δ 153.24, 146.70, 130.96, 129.34, 129.24,
126.94, 122.34, 119.85, 118.76, 112.90, 79.58, 50.37; GCMS
m/z: 322.97, mass fragments, 138.05 (33.38), 139.10 (100.00),
141.10 (30.88), 323.10 (7.41), 324.15 (3.03), 325.10 (9.53);
elemental analysis calculated for C14H11NOBrCl: C, 51.80; H,
3.42; N, 4.32. Found: C, 51.76; H, 3.32; N, 4.28.
Synthesis of 3,4-dihydro-3-(4-bromophenyl)-2H-
benz[e]-1,3-oxazine (2d): White crystalline solid. Yield
88.0 %, m.p. 83-84 ºC; FTIR (cm-1) 1036 (-C-O-C) sym., 1155
Synthesis of 6-bromo-3,4-dihydro-3-pyridin-3-yl-2H-
benz[e]-1,3-oxazine (2i); White crystalline solid. Yield 76.0
%, m.p. 81-82 ºC; FTIR (cm-1) 1058.8 (-C-O-C) sym., 1134.1
1
1
(-C-N-C); H NMR (300 MHz, CDCl3): δ 4.588 (s, 2H,
(-C-N-C); H NMR (300 MHz, CDCl3): δ 3.413 (s, 2H,
ArCH2N), 5.307 (s, 2H, OCH2N), 6.785-7.352 (m, 8H, ArH);
depth (75 MHz, CDCl3): δ 79.22, 50.59; 13C NMR (75 MHz,
CDCl3): δ 154.17, 147.50, 132.11, 128.04, 126.71, 120.98,
120.46, 119.97, 116.98, 113.85, 79.20, 50.56; GCMS m/z:
289.0, mass fragments, 51.10 (20.43), 77.10 (29.38), 78.05
(20.29), 183.00 (100.00), 289.15 (32.61), 291.20 (31.69);
elemental analysis calculated for C14H12NOBr: C, 57.95; H,
4.17; N, 4.83. Found: C, 57.94; H, 4.05; N, 4.78.
ArCH2N), 4.700 (s, 2H, OCH2N), 6.487-7.394 (m, 7H, ArH);
depth (75 MHz, CDCl3): δ 75.52, 45.92; 13C NMR (75 MHz,
CDCl3): δ 154.73, 143.20, 142.94, 141.05, 138.89, 131.40,
130.69, 129.38, 125.43, 123.72, 118.89, 84.99, 55.20; GCMS
m/z: 290.0, mass fragments, 78.10 (19.70), 105.05 (31.98),
106.10 (100.00), 290.10 (11.95), 291.10 (6.17), 292.15
(11.33); elemental analysis calculated for C13H11N2OBr: C,
53.63; H, 3.81; N, 9.62. Found: C, 53.56; H, 3.69; N, 9.59.
Biological activity-organisms: The organisms used as
reference for antibacterial activity consisted of one Gram-
positive bacteria (Staphylococcus aureus, MTCC 96) and
Gram-negative bacteria (E. coli, MTCC 739). For estimating
antifungal activity the organism used is Candida albicans.
Minimum inhibitory concentration of all the compounds was
Synthesis of 3,4-Dihydro-3-pyridin-2-yl-2H-benz[e]-
1,3-oxazine (2e): White crystalline solid. Yield 54.0 %, m.p.
88-89 ºC; FTIR (cm-1) 1065 (-C-O-C) sym., 1163 (-C-N-C);
1H NMR (300 MHz, CDCl3): δ 3.370 (s, 2H, ArCH2N), 4.718
(s, 2H, OCH2N), 6.704-8.180 (m, 8H, ArH); depth (75 MHz,
CDCl3): δ 81.11, 49.49; 13C NMR (75 MHz, CDCl3): δ 157.56,

Vol. 25, No. 11 (2013)
Synthesis and Biological Activity of Some 2H-benz[e]-1,3-oxazine Derivatives 5923
determined using the micro-broth dilution method for estima-
ting MIC using Mueller Hinton broth (MHB-Difco) as per the
guidelines prescribed by NCCLS. MIC was defined as the lowest
concentration of antibiotic at which no visible growth could
be detected in the micro-titre plate. The results obtained on
the basis of zone diameter were summarized in Table-1.
library of 3-aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines by a
simple, facile and efficient synthetic route. The starting mate-
rial, 2-hydroxybenzylamines can be conveniently synthesized
by reduction of imines generated by condensation of variously
substituted 2-hydroxy benzaldehyde and primary amines.
Synthesis of 3-Aryl-3,4-dihydro-2H-benz[e]-1,3-ox-
azines
R
TABLE-1
MIC (µg/mL) OF THE COMPOUNDS AGAINST
THE TEST ORGANISMS 2(a-i)
O
N
(E)
X
X
R-NH2
H
H
MeOH
OH
S. aureus
(µg/mL)
>32
>32
32
E. coli
(µg/mL)
>32
C. albicans
OH
25-30 °C
Compound
(µg/mL)
>32
32
NaBH4
0-5 °C
2a
2b
2c
2d
2e
2f
R
>32
HN
X
R
>32
16
X
HCHO
N
H
32
>32
16
MeOH
65-68 °C
O
OH
>32
>32
16
>32
>32
>32
16
2
1
>32
Scheme-I
>32
2g
2h
2i
For the present study, we had prepared the various imines29
by reacting variously substituted arylamines with variously
substituted salicyldehyde. These imines were subjected to
reduction by sodium borohydride in alcohol to give resultant
N-(2-hydroxy)benzyl-arylamines30 1 (Table-2). 3-Aryl-3,4-
dihydro-2H-benz[e]-1,3-oxazines/6-bromo-3-aryl-3,4-
dihydro-2H-benz[e]-1,3-oxazines (2) (Scheme-I), were prepared
by cyclization of N-(2-hydroxy)-benzyl-arylamines (1) with
formaldehyde in methanol in 0.5-1.0 h at 65-68 ºC (Table-3).
4
>32
8
>32
>32
32
RESULTS AND DISCUSSION
Synthesis of 3,4-dihydro-2H-1,3-benzoxazines include
Mannich condensation of phenol and primary amine with
formaldehyde18,19 condensation of o-hydroxybenzylamine with
an aldehyde20-22, rearrangement reactions of 2-(allyloxy)
benzylamine with H2/CO in the presence of rhodium catalyst23
and reaction of o-lithiated phenoldianions with N,N-
bis[(benzotriazol-1-yl)methyl]amines24.
TABLE-2
SYNTHESIS OF N-(2-HYDROXY)BENZYL-ARYLAMINES 1
Among these processes, broadly two approaches have
been used for the synthesis of 3-aryl-3,4-dihydro-2H-benz[e]-
1,3-oxazines. Burke and Stephens25 have reported a one pot
synthesis of 3-alkyl/aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines.
In this process alkyl/aryl amines were reacted with formaldehyde
in dioxane, followed by phenol. After completion of reaction,
reaction mixture was subjected to treatment with KOH, solvent
extraction, layer separation and usual workup. This process,
apart from lower yield and process complicacy, when applied
to some hindered and substituted amines like 2-amino and
3-aminopyridine, a number of compounds along with
unreacted phenol were observed. Later on Noda et al.26 has
reported the cyclization of N-(2-hydroxy)-benzyl-arylamines
with formaldehyde solution in 2-3 h. Although the process
was simple but results in lower yield and typical work up.
From all these synthetic methods, the condensation of
substituted 2-hydroxybenzylamine with formaldehyde seemed
the most reliable for the synthesis of variously substituted
3-aryl-3,4-dihydro-2H-benz[e]-1,3-oxazines. During the
present study, we have observed that the molar ratio of form-
aldehyde plays an important role. After performing several
manipulations, molar ratio of formaldehyde and reaction
conditions, we have observed that two moles of formaldehyde
compared to 1 produces lower amount of oligomeric by products.
To the best of our knowledge pyridine amine derived 1,3-
benzoxazines are not yet reported. Since reactivity of pyridine
derivative towards a variety of functional group as well as
towards microbial activity is well documented in the litera-
ture27,28. Keeping these things on priority, we are presenting a
Entry
R
X
Product m.p. (ºC) Yield (%)
1
2
3
4
5
6
7
8
9
-C6H5
-H
-H
-H
-H
-H
-H
-Br
-Br
-Br
108-110
118-120
120-121
125-126
105-106
188-189
120-121
90-91
82.0
85.0
83.0
88.0
54.0
63.0
86.5
82.5
76.0
1a
1b
1c
1d
1e
1f
-4-CH C H
4
3
6
-4-ClC6H4
-4-BrC6H
4
-2-Aminopyridyl
-3-Aminopyridyl
-4-CH C H
1g
1h
1i
3
6
4
-4-ClC6H4
-3-Aminopyridyl
168-170
TABLE-3
SYNTHESIS OF 3-ARYL-3,4-DIHYDRO-
2H-BENZ[E]-1,3-OXAZINE 2
m.p.
Yield
(%)
Entry Educt
R
X
Product
(ºC)
51-52
81-82
52-53
83-84
88-89
111-112
82-83
98-99
81-82
1
2
3
4
5
6
7
8
9
-C6H5
-H
-H
-H
-H
82.0
85.0
83.0
88.0
54.0
63.0
86.5
82.5
76.0
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
-4-CH3C6H4
-4-ClC6H4
-4-BrC6H4
-2-Aminopyridyl -H
-3-Aminopyridyl -H
-4-CH3C6H4
-4-ClC6H4
-Br
-Br
1g
1h
1i
2g
2h
2i
-3-Aminopyridyl -Br
In summary, a simple and economically viable synthetic
method is developed for the preparation of various potential
pharmaceutically useful benz-1,3-oxazines. This simple and
effective process will help to develop the compound of this
class in future.

5924 Shukla et al.
ACKNOWLEDGEMENTS
Asian J. Chem.
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for financial support.
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