Synthesis and characterization of new 3,4-dihydro-2H-benzoand naphtho-1,3-oxazine derivatives

Article abstract of DOI:10.14233/ajchem.2016.19666

New 1,3-benzoxazine and naphthoxazine monomers were synthesized using a modified step-wise technique in which formaldehyde was replaced with methylene bromide for ring-closure reaction in the last synthetic step. Salicylaldehyde and 2-hydroxy-1-naphthalde

Full text of DOI:10.14233/ajchem.2016.19666

Asian Journal of Chemistry; Vol. 28, No. 6 (2016), 1304-1306
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19666
Synthesis and Characterization of New 3,4-Dihydro-2H-benzo-
and Naphtho-1,3-oxazine Derivatives
*
A.U. GARIN GABBAS, M.B. AHMAD , N. ZAINUDDIN and N.A. IBRAHIM
Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
*Corresponding author: Tel: +60 1 22117882; E-mail: mansorahmad@upm.edu.my
Received: 12 October 2015;
Accepted: 16 January 2016;
Published online: 29 February 2016;
AJC-17796
New 1,3-benzoxazine and naphthoxazine monomers were synthesized using a modified step-wise technique in which formaldehyde was
replaced with methylene bromide for ring-closure reaction in the last synthetic step. Salicylaldehyde and 2-hydroxy-1-naphthaldehyde
were used as the aromatic aldehydes and 4-fluoroaniline, 4-butylaniline, hexamethylenediamine, p-phenylenediamine and 2-aminothiazole
were used as the primary amines. Condensation of the aromatic aldehydes and the aromatic primary amines in absolute ethanol gives
imine compounds which on reduction with sodium borohydride in methanol give 2-hydroxybenzylamines/2-hydroxynaphthylamines.
Ring-closure reaction between 2-hydroxybenzylamines/2-hydroxynaphthylamines and methylene bromide in absolute ethanol gives the
1,3-benzoxazines and naphthoxazines in good yields. The structures of the new 1,3-benzoxazine and naphthoxazine monomers were
confirmed by FT-IR, 1H NMR and 13C NMR spectral analysis, Mass spectroscopy (GC-MS) and elemental analysis. The mass spectrum
of the synthesized compounds showed molecular ion peaks centered at m/z 229, 218, 316, 317, 444 and 268 which are equivalent to the
molecular weights of the new synthesized compounds a, b, c, d, e and f, respectively. Results of elemental analysis also confirm the
calculated result to be in agreement with the experimental result.
Keywords: 1,3-Benzoxazines, 1,3-Naphthoxazines, Methylene bromide, Characterization, Modified step-wise process.
procedure is used in the synthesis of different benzoxazine
compounds.
INTRODUCTION
The synthesis of benzoxazine compounds dates back over
70 years [1-4] but their potential was only realized recently
[5].Among all benzoxazine compounds, 1,3-benzoxazine have
received greater attention as they are used in the production
of polymeric materials [6-8] and are also of significant interest
in pharmacological fields [9].
1,3-Benzoxazines as monomers are used in the synthesis of
a new type of phenolic resins called polybenzoxazines through
thermally activated ring-opening polymerization [10,11].
These polybenzoxazines possesses not only the properties of
traditional phenolic resins but other unique properties such as
low water absorption, high modulus, high strength, high glass
transition temperatures, high char yield and low volumetric
shrinkage upon curing [12-15]. Furthermore, 1,3-benzoxazines
are known for their wide range of biological activities and hence
used as fungicides, bactericide, anti-inflammatory, antidepre-
ssants and antitumor agents [16,17].
In this paper, formaldehyde which is a suspected human
carcinogen and a confirmed animal carcinogen [22] was replaced
with methylene bromide for the ring-closure reaction in the conven-
tional step-wise procedure. Methylene bromide can provide the
necessary methylene bridge needed between oxygen and nitrogen
necessary for ring-closure to take place leading to the formation
of 1,3-benzoxazine and naphthoxazine monomers.
EXPERIMENTAL
Salicylaldehyde (98 %), 2-hydroxy-1-naphthaldehyde
(97 %), 4-butylaniline (98 %), 2-aminothiazole (97 %), 4-
fluoroaniline (98 %), p-phenylenediamine (98 %) and sodium
borohydride (99.5 %) (Sigma Aldrich Chemical Company),
absolute ethanol (99.8 %), methanol (98 %) (HmbG
Chemicals). All chemicals were used as received without any
further purification.
Characterization: FT-IR spectra were recorded using
Perkin Elmer FTIR model 100 series spectrophotometer (KBr
Numerous approaches are used for the synthesis of 1,3-
benzoxazine compounds using different solvents [18-20].
Among the approaches is the step-wise procedure which has
recently gained considerable interest and more importantly
tolerates various functional groups [21]. For this reason, the
1
Pellet) in the region 4000-280 cm-1. H NMR and 13C NMR
spectral analysis was conducted on JEOL 500 MHz NMR
spectrometer using acetone-d6 as the NMR solvent. GC-MS

Vol. 28, No. 6 (2016)
Synthesis of New 3,4-Dihydro-2H-benzo- and Naphtho-1,3-oxazine Derivatives 1305
analysis was conducted using Shimadzu model QP 5050A
GC-MS analyzer. Elemental analysis was performed with a
VARIO EL III rapid Elemental analyzer. Melting points of
the synthesized compounds were determined using a Barnstead
electrothermal melting point instrument 9100 Model and are
uncorrected.
Synthesis of imine compounds 1(a-f): The imine com-
pound 1 (Fig. 1) were prepared as usual by refluxing necessary
molar proportion of the salicylaldehyde/2-hydroxy-1-naphthal-
dehyde and individual primary amines in absolute alcohol for
5 h under nitrogen atmosphere.
Synthesis of 2-hydroxybenzylamines/2-hydroxy-
naphthylamines 2(a-f): In all cases, 150 mmol of the imine
compounds were added into a conical flask containing 100 mL
of ethanol. To this solution was added 100 mmol of NaBH4 in
small portions at ambient temperature while stirring until the
reaction is complete. 150 mL of water was then added and the
product was extracted with ethyl acetate, washed with water, dried
overnight with anhydrous Na2SO4 and concentrated to dryness.
Synthesis of 1,3-benzoxazine and naphthoxazine
derivatives 3(a-f): In all cases, 100 mmol of the 2-hydroxy-
benzylamines/2-hydroxynaphthylamines and 200 mmol of
methylene bromide were added to 100 mL of absolute ethanol
and the mixture refluxed for 18-24 h under nitrogen atmos-
phere. The mixture was allowed to cool to room temperature
and the solvent removed by rotary evaporation. 100 mL of
water was then added and the compound extracted with ethyl
acetate, washed with water, dried overnight with anhydrous
Na2SO4 and concentrated to dryness.All solid compounds were
purified by recrystallization in 50:50 water:ethanol mixture
and liquid compounds by flash chromatography.
3-(4-Fluorophenyl)-3,4-dihydro-2H-1,3-benzoxazine
(a):Yield 62 %, light brown solid, m.p. 101-102 °C. IR (KBr,
ν
max, cm-1): 3038, 2890, 22820, 1866, 1591, 1498, 1375, 1215,
1153, 1032, 935, 823, 748, 662, 583, 520, 442; 1H NMR (500
MHz, Acetone-d6, ppm): δH 7.46-6.64 (Ar-H), 5.36 (O-CH2-N),
4.56 (C-F), 4.38 (Ar-CH2-N). 13C NMR (500 MHz, Acetone-d6,
ppm): δC 156.2 (C-O), 145.4 (C-O), 127.6 (CH), 127.2 (CH),
120.2 (CH), 120.0 (CH), 114.4 (CH), 114.2 (CH), 79.6 (O-CH2-
N), 50.14 (C-F), 44.8 (Ar-CH2-N). MS: m/z 229 (M+). Elemental
analysis: C14H12NOF (229.25). Calculated (%): C, 73.28; H, 5.23;
N, 6.11. Experimental (%): C, 73.14; H, 5.18; N, 6.08.
3-(1,3-Thiazol-2-yl)-3,4-dihydro-2H-1,3-benzoxazine
(b): Yield 64 %, viscous brown red liquid, b.p. 120-121 °C. IR
(KBr, νmax, cm-1): 3273, 2968, 2754, 1521, 1453, 1368, 1239,
1150, 1042, 962, 855, 749, 692, 612, 509, 433; 1H NMR (500
MHz, Acetone-d6, ppm): δH 7.32-6.68 (4H, Ar-H), 7.58 (CH,
thiazole), 6.52 (CH, thiazole), 5.46 (O-CH2-N), 4.42 (Ar-CH2-
N). 13C NMR (500 MHz, Acetone-d6, ppm): δC 158.00 (C,
thiazole), 146.20 (C, benzene), 129.20 (CH, thiazole), 128.6
(C, benzene), 122.00-115.20 (4H, Ar-H), 79.00 (O-CH2-N),
46.20 (Ar-CH2-N). MS: m/z 218 (M+). Elemental analysis:
C11H10N2OS (218.27). Calculated (%): C, 60.48; H, 4.58; N,
12.83. Experimental (%): C, 60.34; H, 4.40; N, 12.74.
CHO
R
R
R
NaBH4/
MeOH
N
N
H
Br
N
EtOH
EtOH
H2N
R
+
+
Reflux (5 h)
Br
Reflux (18-24 h)
OH
OH
OH
O
3(a-c)
1(a-c)
2(a-c)
S
H
N
N
S
N
H
3a: R =
F
3b: R =
3c: R =
S
R
N
R
R
NH
N
CHO
OH
OH
OH
O
Br
EtOH
NaBH4
MeOH
EtOH
H2N
R
+
+
Reflux (18-24 h)
Reflux (5 h)
Br
3(d-e)
1(d-e)
2(d-e)
N
(CH2)3
CH3
3d: R =
3e: R =
S
R
R
R
N
N
NH
CHO
OH
OH
OH
O
Br
EtOH
Reflux (18-24 h)
NaBH4
MeOH
EtOH
H2N
R
NH2
+
+
Reflux (5 h)
Br
3(f)
1(f)
2(f)
3f: R =
N
O
Fig. 1. Modified step-wise procedure for the synthesis of 3,4-dihydro-2H-1,3-benzoxazine and naphthoxazine derivatives (a-f)

1306 Garin Gabbas et al.
Asian J. Chem.
Benzyl 2H-1,3-benzoxazine-3(4H)-yldithiocarbamate
218, 316, 317, 444 and 268 which are equivalent to the mole-
cular weights of the synthesized compounds a, b, c, d, e and f,
respectively. However, it is important to note that the degra-
dation pattern of benzoxazine compounds has been poorly
understood to date.Also, one serious disadvantage of the step-
wise synthetic process is the excessive formation of oligomers
which ultimately reduces the yield and makes purification
difficult [23]. This disadvantage is evident from the mass
spectrum of some of the synthesized compounds.
(c): Yield 68 %, bright yellow, m.p. 54-55 °C. IR (KBr, νmax
,
cm-1): 3028, 2972, 2820, 1608, 1475, 1379, 1320, 1259, 1198,
1030, 970, 891, 699, 556, 456, 328; MS: m/z 316 (M+). Elemental
analysis: C16H16N2OS2 (316.44). Calculated (%): C, 60.68; H,
5.06; N, 8.85. Experimental (%): C, 60.54; H, 5.02; N, 8.75.
3-(4-Butylphenyl)-3,4-dihydro-2H-naphtho[2,1-e][1,3]-
oxazine (d): Yield 62 %, viscous dark red, b.p. 125-126 °C.
IR (KBr, νmax, cm-1): 3030, 2925, 2861, 1615, 1509, 1463,
1373, 1312, 1226, 1061, 940, 811, 743, 676, 495, 417, 318;
1H NMR (500 MHz, Acetone-d6, ppm): δH 8.62-6.99 (8H, Ar-
H), 5.46 (2H, O-CH2-N), 4.92 (2H, Ar-CH2-N), 2.55 (CH2
aliphatic), 1.62 (CH2 aliphatic), 1.34 (CH2 aliphatic), 0.94 (CH3
aliphatic). 13C NMR (500 MHz, Acetone-d6, ppm): δC 194.2
(C), 169.2 (C), 164.4 (C), 153.2 (C), 146.6 (C), 134.2 (C),
129.4 (CH), 129.2 (CH), 128.6 (CH), 122.6 (CH), 120.2 (CH),
119.4 (CH), 113.8 (CH), 79.6 (O-CH2-N), 49.2 (Ar-CH2-N),
34.6 (CH2 aliphatic), 34.2 (CH2 aliphatic), 22.8 (CH2 aliphatic),
14.2 (CH3 aliphatic). MS: m/z 317 (M+). Elemental analysis:
C22H23NO (317.42). Calculated (%): C, 83.17; H, 7.25; N, 4.41.
Experimental (%): C, 82.96; H, 7.11; N, 4.22.
Conclusion
New 3,4-dihydro-2H-benzo-and naphtho-1,3-oxazine
derivatives were successfully synthesized via a modified step-
wise procedure in which formaldehyde which is a suspected
human carcinogen was replaced with methylene bromide for
the ring-closure reaction in the last synthetic step.The synthesized
compounds were fully characterized and their structures
confirmed on the basis of their spectral analysis. Methylene
bromide provides the methylene bridge needed between oxygen
and nitrogen necessary for ring-closure to take place leading to
the formation of 1,3-benzoxazine and naphthoxazine monomers.
3,3′-(1,4-Phenylene)bis(3,4-dihydro-2H-1,3-naphtho-
xazine) (e): Yield 72 %, dark red solid, m.p. 211-212 °C. IR
(KBr, νmax, cm-1): 3457, 3012, 2946, 2886, 1601, 1509, 1377,
1220, 1059, 1000, 938, 809, 745, 680, 629, 556, 489, 422,
367; MS: m/z 444 (M+). Elemental analysis: C30H24N2O2
(444.52). Calculated (%): C, 80.98; H, 5.40; N, 6.30. Experi-
mental (%): C, 80.90; H, 5.32; N, 6.21.
3-(1,3-Thiazol-2-yl)-3,4-dihydro-2H-naphtho[2,1-
e][1,3]oxazine (f):Yield 65 %, viscous brown red liquid, b.p.
106-107 °C. IR (KBr, νmax, cm-1): 3242, 3061, 2968, 2882,
1612, 1513, 1455, 1366, 1232, 1045, 966, 865, 808, 742, 694,
612, 509, 420; 1H NMR (500 MHz,Acetone-d6, ppm): δH 8.18-
6.82 (8H, Ar-H), 7.22 (C-4, thiazole), 6.94 (C-5, thiazole),
5.62 (O-CH2-N), 5.16 (Ar-CH2-N). 13C NMR (500 MHz,Acetone-
d6, ppm): δC 170.0 (C-2, thiazole), 151.6 (C, naphthalene),
138.6 (C-4, thiazole), 128.6-118.0 (8H,Ar-H), 114.2 (C, naph-
thalene), 109.4 (C-5, thiazole). MS: m/z 268 (M+). Elemental
analysis: C15H12N2OS (268.33). Calculated (%): C, 67.08; H,
4.47; N, 10.43. Experimental (%): C, 66.92; H, 4.33; N, 10.31.
ACKNOWLEDGEMENTS
The authors thank Department of Chemistry, Faculty of
Science, Universiti Putra Malaysia for their assistance through-
out the work.
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All the synthesized compounds showed appropriate
characteristic signals to confirm their structures. To illustrate
with compound (a), the FT-IR spectrum showed characteristic
absorption bands due to trisubstituted benzene rings at 935
and 1498 cm-1 which are characteristic absorptions of benzoxa-
zines and naphthoxazines. In addition, other bands observed
are those of asymmetricAr-H stretching vibration at 3033 cm-1,
asymmetric stretching for C-O-C at 1215 cm-1 and aliphatic
CH2 stretching bands between 2971 and 2829 cm-1. In the 1H
NMR spectra, the characteristic proton resonance signals of
the oxazine ring O-CH2-N and Ar-CH2-N were observed at
5.36 and 4.56 ppm. In the 13C NMR spectra, the carbon chemical
shifts corresponding to O-CH2-N andAr-CH2-N were observed
at 79.6 and 44.8 ppm.
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The mass spectra of the synthesized compounds a, b, c,
d, e and f showed molecular ion peaks centered at m/z 229,