JOURNAL OF CHEMICAL RESEARCH 2018 VOL.

42 JUNE, 291–293 RESEARCH PAPER 291

Three-component one-pot condensation of 2-hydroxy-1,4-naphthoquinone

with aromatic aldehydes and methyl carbamate: synthesis of
4-aryl-3,4-dihydronaphtho[3,4-e][1,3]oxazine-2,5,10-trione in aqueous media
Nooshin Ghaffari-Nia and Alireza Hassanabadi*
Department of Chemistry, Zahedan Branch, Islamic Azad University, Zahedan, Iran
A green and efficient method for oxazine ring formation is established using the reaction of 2-hydroxy-1,4-naphthoquinone and aromatic
aldehydes with methyl carbamate catalysed by p -toluenesulfonic acid in aqueous media to afford 4-aryl-3,4-dihydronaphtho[3,4- e][1,3]
oxazine-2,5,10-triones in excellent yields. The salient features of this protocol are short reaction times and high yields while avoiding any
hazardous organic solvent. Therefore, this procedure could be classified as green chemistry.

Keywords: 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes, methyl carbamate, p-toluenesulfonic acid, green chemistry

Oxazines constitute an important class of heterocycles
that have attracted considerable synthetic interest due to
their wide range of biological activities.1–5 The synthesis of
chromeno[3,4-e][1,3]oxazine is performed by condensation
of 4-hydroxycoumarins with azomethines and aldehydes.6,7
The reaction of 2-(3,4-dimethoxyphenyl)chromen-4-one with
chlorosulfonyl isocyanate proved to be inefficient due to the
formation of chromenooxathiazines as side products.8 Reaction
between cyclic β-diketones and 1-chloroalkyl isocyanates leads
to the formation of carbo-fused 1,3-oxazines.9
Recently, synthesis of oxazine derivatives has been
reported.10–13 Mosslemin et al.12 used a procedure in which
they synthesised a series of oxazine derivatives via the
TEBA (triethylbenzylammonium chloride)-catalysed cyclo-
condensation reaction of 6-quinolinol or 2-naphthol, aromatic
aldehydes and methyl carbamate in aqueous media. Vovk et
al.13 demonstrated that 1-chlorobenzyl isocyanates react with
4-hydroxy-6-methylpyran-2-one and with 4-hydroxycoumarin
to form 4-aryl-3,4-dihydro-2H,5H-pyrano(chromeno)[3,4-e]
[1,3]oxazine-2,5-diones, but there are many limitations, such as
long reaction times, hazardous organic solvents and reagents,
and low yields. Hence, in continuation of our previous work
on the synthesis of oxazine derivatives,14–16 we have used the
procedure of Mosslemin et al.12 to synthesise another class of
oxazine derivatives via a three-component condensation reaction
of 2-hydroxy-1,4-naphthoquinone and aromatic aldehydes with
methyl carbamate in the presence of p-toluenesulfonic acid
(p-TSA) in aqueous media. We have developed a mild, one-pot,
three component reaction that affords oxazine derivatives in
excellent yield.
Results and discussion
Reaction of 2-hydroxy-1,4-naphthoquinone 1 with aromatic
aldehydes 2 and methyl carbamate 3 in the presence of p-TSA
in aqueous media affords 4-aryl-3,4-dihydronaphtho[3,4-e]
[1,3]oxazine-2,5,10-trione 4 in excellent yields (Scheme 1).
The structures of compounds 4a–f were deduced from
elemental analyses and their IR, 1H NMR and 13C NMR
spectra. The mass spectra of compounds 4a–f are fairly similar
and display molecular ion peaks. For example, the mass
spectrum of compound 4a showing a molecular ion peak at
m/z 339 confirmed that compound 4a is a condensation product
of 2-hydroxy-1,4-naphthoquinone, 4-chlorobenzaldehyde
and methyl carbamate. The 1H NMR spectrum of compound
4a displayed a sharp singlet signal at δ 6.17 for the methine
proton, along with characteristic signals at 7.12 and 7.98 ppm
for the aromatic protons. A singlet was observed at δ 8.35 that
disappeared on addition of D2O, corresponding to the NH
proton. The 13C NMR spectrum of compound 4a showed 16
distinct signals consistent with the proposed structure. The IR
spectrum showed an absorption band at 3167 cm−1 for the NH
group. The carbonyl stretching vibrations were observed as
strong absorption bonds at 1643 and 1682 cm−1.
The mechanism of the reaction is probably similar to that
published by Mosslemin et al.12 (Scheme 2). The 2-hydroxy-
1,4-naphthoquinone 1 reacts with aromatic aldehyde 2 in the

Scheme 1

* Correspondent. E-mail: ar_hasanabadi@yahoo.com

292 JOURNAL OF CHEMICAL RESEARCH 2018
O O
OH O O
p-TSA
+
H Ar -H2O
1 O 2 5
O
OH
O
_ CH OH
N OMe 3
O H
6 Ar
Scheme 2
presence of p-TSA to give the Knoevenagel product 5. From
Michael-type nucleophilic attack of methyl carbamate 3 on
Knoevenagel product 5, intermediate 6 was obtained. The
intermediate 6 undergoes cyclisation with the elimination of
CH3OH to give the desired product 4.
In conclusion, we have developed a mild, excellent
yielding, fast reaction, employing a cheap catalyst, p-TSA,
in a one-pot synthesis for the preparation of 4-aryl-3,4-
dihydronaphtho[3,4-e][1,3]oxazine-2,5,10-triones in a three-
component cyclo-condensation reaction of 2-hydroxy-1,4-
naphthoquinone and aromatic aldehydes with methyl carbamate
in aqueous media. This method does not involve any hazardous
organic solvent. Therefore, this procedure could be classified as
green chemistry.
Experimental
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyser. Mass spectra were recorded on a Finnigan-MAT
8430 mass spectrometer operating at an ionisation potential of 70 eV.
IR spectra were recorded on a Shimadzu IR-470 spectrophotometer.
NMR spectra were obtained on a Bruker DRX 300 MHz spectrometer
(1H NMR at 300.1 Hz, 13C NMR at 75.46 Hz) in DMSO-d6 using TMS
as an internal standard. Chemical shifts (δ) are given in ppm and
coupling constants (J) are given in Hz. The chemicals used in this work
were purchased from Fluka (Buchs, Switzerland) and used without
further purification.
Synthesis of 4-aryl-3,4-dihydronaphtho[3,4-e][1,3]oxazine-2,5,10-
triones (4a–f); general procedure
A mixture of 2-hydroxy-1,4-naphthoquinone (1.0 mmol), aromatic
aldehyde (1.0 mmol), methyl carbamate (1.5 mmol) and p-TSA (0.1
mmol) was suspended in water (10 mL) and stirred at 80 °C for 3 h.
The reaction was monitored by TLC. After reaction completion, the
mixture was allowed to cool to room temperature. The solid was
collected by filtration and recrystallised from ethanol to afford the
pure product.
4- (4-Chlorophenyl) -3,4-dihydronaphtho[3,4-e][1,3]oxazine-
2,5,10-trione (4a): Yellow powder; m.p. 90–92 °C; IR (KBr) (νmax
cm−1): 3167 (NH), 1643 and 1682 (C=O); 1H NMR (300.1 Hz,
DMSO-d6): δ 6.17 (1H, s, CH), 7.12–7.98 (8H, m, 8 × ArH), 8.35 (1H, s,
NH); 13C NMR (75.46 Hz, DMSO-d 6): δ 39.1 (CH), 111.5, 125.8, 126.0,
126.4, 128.6, 131.0, 132.3, 133.6, 134.9, 138.4, 145.7, 160.0, 172.2, 181.7
and 185.1; MS m/z (%): 339 (10). Anal. calcd for C18H10ClNO4: C,
63.64; H, 2.97; N, 4.12; found: C, 63.77; H, 3.08; N, 4.25%.
4-(4-Nitrophenyl)-3,4-dihydronaphtho[3,4-e][1,3]oxazine-2,5,10-
trione (4b): Yellow powder; m.p. 66–68 °C; IR (KBr) (νmax cm−1): 3152
O
H2N 3 OMe
O Ar
4
(NH), 1643 and 1680 (C=O); 1H NMR (300.1 Hz, DMSO-d6): δ 6.05
(1H, s, CH), 7.07–7.99 (8H, m, 8 × ArH), 8.23 (1H, s, NH); 13C NMR
(75.46 Hz, DMSO-d6): δ 38.4 (CH), 111.2, 123.9, 125.5, 126.2, 126.5,
128.5, 131.1, 132.5, 133.7, 139.0, 144.7, 156.7, 170.1, 181.6 and 183.7;
MS m/z (%): 350 (8). Anal. calcd for C18H10N2O6: C, 61.72; H, 2.88; N,
8.00; found: C, 61.83; H, 3.00; N, 8.11%.
4-Phenyl-3,4-dihydronaphtho[3,4-e][1,3]oxazine-2,5,10-trione
(4c): Yellow powder; m.p. 113–115 °C, IR (KBr) (νmax cm−1): 3117
(NH), 1650 and 1671 (C=O); 1H NMR (300.1 Hz, DMSO-d6): δ 6.23
(1H, s, CH), 7.07–7.92 (9H, m, 9 × ArH), 8.16 (1H, s, NH); 13C NMR
(75.46 Hz, DMSO-d 6): δ 38.4 (CH), 111.1, 126.3, 126.5, 126.7, 127.3,
128.4, 128.9, 131.2, 132.6, 133.8, 139.1, 143.2, 171.2, 181.8 and 183.6;
MS m/z (%): 305 (4). Anal. calcd for C18H11NO4: C, 70.82; H, 3.63; N,
4.59; found: C, 70.95; H, 3.72; N, 4.76%.
4- (4-Bromophenyl) -3,4-dihydronaphtho[3,4-e][1,3]oxazine-
2,5,10-trione (4d): Yellow powder; m.p. 163–165 °C; IR (KBr)
(νmax cm−1): 3110 (NH), 1647 and 1674 (C=O); 1H NMR (300.1 Hz,
DMSO-d6): δ 6.18 (1H, s, CH), 7.40–8.00 (8H, m, 8 × ArH), 8.28
(1H, s, NH); 13C NMR (75.46 Hz, DMSO-d6): δ 37.9 (CH), 111.5,
125.7, 126.1, 126.5, 130.3, 131.0, 132.3, 133.6, 134.8, 135.1, 141.0,
160.0, 172.5, 181.7 and 185.0; MS m/z (%): 384 (5). Anal. calcd for
C18H10BrNO4: C, 56.27; H, 2.62; N, 3.65; found: C, 56.40; H, 2.73; N,
3.80%.
4- (2-Chlorophenyl) -3,4-dihydronaphtho[3,4-e][1,3]oxazine-
2,5,10-trione (4e): Yellow powder; m.p. 105–107 °C; IR (KBr)
(νmax cm−1): 3161 (NH), 1640 and 1676 (C=O); 1H NMR (300.1 Hz,
DMSO-d6): δ 6.11 (1H, s, CH), 7.13–7.92 (8H, m, 8 × ArH), 8.22 (1H,
s, NH); 13C NMR (75.46 Hz, DMSO-d6): δ 39.1 (CH), 111.3, 125.8,
125.9, 126.5, 127.9, 131.0, 131.2, 132.5, 133.1, 133.7, 134.8, 140.3, 142.1,
160.1, 172.3, 181.8 and 185.0; MS m/z (%): 339 (6). Anal. calcd for
C18H10ClNO4: C, 63.64; H, 2.97; N, 4.12; found: C, 63.79; H, 3.11; N,
4.21%.
4- (4-Methoxyphenyl) -3,4-dihydronaphtho[3,4-e][1,3]oxazine-
2,5,10-trione (4f): Yellow powder; m.p. 126–128 °C; IR (KBr) (νmax
cm−1): 3145 (NH), 1638 and 1672 (C=O); 1H NMR (250 MHz, CDCl3):
δ 3.71 (3H, s, OCH3), 6.19 (1H, s, CH), 6.78–8.00 (8H, m, 8 × ArH),
8.21 (1H, s, NH); 13C NMR (75.46 Hz, DMSO-d 6): δ 37.7 (CH), 55.5
(OCH3), 111.5, 122.8, 126.5, 128.0, 129.8, 131.0, 132.6, 133.1, 133.6,
135.1, 158.5, 160.0, 169.4, 181.7 and 185.3; MS m/z (%): 335 (9). Anal.
calcd. for C19H13NO5: C, 68.06; H, 3.91; N, 4.18; found: C, 68.15; H,
4.06; N, 4.30%.
Received 22 January 2018; accepted 11 May 2018
Paper 1805218
https://doi.org/10.3184/174751918X15287173761289
Published online: 19 June 2018

References
1 A. Krantz, W.R. Spencer, F.T. Tam, J.T. Liak, J.L. Copp, M.E. Thomas and
P.S. Rafferty, J. Med. Chem., 1990, 33, 464.
2 M. Gutschow, L. Kuerschner, U. Neumann, M. Pietsch, R. Loser, N. Koglin
and K. Eger, J. Med. Chem., 1999, 42, 5437.
3 W.P. Hsieh, R.F. Chang, H.C. Chang, W.P. Cheng, C.L. Chiang, L.F. Zeng,
K.H. Lin and C.Y. Wu, Bioorg. Med. Chem. Lett., 2004, 14, 4751.
4 M. Gutschow and U. Neumann, Bioorg. Med. Chem., 1997, 5, 1935.
5 D.A. Brown and C.J. Powers, Bioorg. Med. Chem., 1995, 3, 1091.
6 M. Nagesam, K.M. Rajuand and M.S. Raju, J. Indian Chem. Soc., 1992,
69, 592.
7 S.V. Dike and J.R. Merchant, Tetrahedron Lett., 1978, 19, 3607.
8 M. Tripathi and D.M. Dhar, Indian J. Chem. Sect. B, 1987, 26, 1082.
JOURNAL OF CHEMICAL RESEARCH 2018 293
9 M.V. Vovk, V.A. Sukach, N.G. Chubaruk, A.N. Chernega and A.V. Bol’but,
Zh. Org. Khim., 2007, 43, 264.
10 M.S. AL-Ajely, H.A. Busheer and A. Abdul Ghnni, National J. Chem.,
2007, 26, 348.
11 M.A. Khalilzadeh, I. Yavari, Z. Hossaini and H. Sadeghifar, Monatsh.
Chem., 2009, 140, 467.
12 M.H. Mosslemin, M.R. Nateghi and R. Mohebat, Monatsh. Chem., 2008,
139, 1247.
13 M.V. Vovk, V.A. Sukach and V.I. Dorokhov, Russ. J. Org. Chem., 2007,
43, 1186.
14 A. Khazaeian and A. Hassanabadi, J. Chem. Res., 2015, 39, 492.
15 S. Bougan and A. Hassanabadi, J. Chem. Res., 2017, 41, 136.
16 A. Abdollahi–Irandegan and A. Hassanabadi, J. Chem. Res., 2016, 40, 727.