An efficient Biginelli one-pot synthesis of new naphthalene-condensed oxazine derivatives under microwave-assisted conditions

Article abstract of DOI:10.1007/s00706-011-0716-y

1-Aryl-N,N-dimethyl-1H-naphtho[1,2-e][1,3]- oxazine-3-amine derivatives were synthesized in moderate to high yields using a novel, facile, and one-pot condensation of N,N,N',N'-tetramethylguanidine, aromatic aldehydes, and β-naphthol under microwave-assisted conditions. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-011-0716-y

Monatsh Chem (2012) 143:1417–1420
DOI 10.1007/s00706-011-0716-y
ORIGINAL PAPER
An efficient Biginelli one-pot synthesis of new
naphthalene-condensed oxazine derivatives
under microwave-assisted conditions
•
Javad Azizian Khadijeh Yadollahzadeh
•
•
Akram Sadat Delbari Mohammad Mehdi Ghanbari
Received: 18 July 2011 / Accepted: 28 December 2011 / Published online: 7 February 2012
Ó Springer-Verlag 2012
Abstract 1-Aryl-N,N-dimethyl-1H-naphtho[1,2-e][1,3]-
oxazine-3-amine derivatives were synthesized in moder-
ate to high yields using a novel, facile, and one-pot
condensation of N,N,N0,N0-tetramethylguanidine, aromatic
aldehydes, and b-naphthol under microwave-assisted
conditions.
class of compounds has also been used as precursors in the
preparation of phosphinic ligands for asymmetric catalysis
[11]. There are some reports in the literature of the synthesis
of amidoalkylnaphthols or oxazine derivatives with b-naph-
thol, aldehydes, and urea or thiourea [12, 13]. Many of these
processes have several disadvantages such as the need for a
prolonged reaction time, formation of side products, and use
of volatile and toxic organic solvents, expensive reagents or
solvents, or toxic and hazardous reagents. Furthermore, for
the preparation of starting materials such as aminoalkyl-
Keywords Microwave-assisted ꢀ Naphthoxazine ꢀ
b-Naphthol ꢀ N,N,N0,N0-Tetramethylguanidine
naphthols requires
a multistep reaction using harsh
Introduction
conditions [14, 15]. Therefore, the discovery of new, simple,
green, and one-pot methods for the synthesis of naph-
thoxazine derivatives is of prime interest.
Aromatic-condensed oxazine derivatives are an important
class of heterocyclic compounds because many of them
exhibit biological activities [1, 2]. A thorough literature
survey revealed that the compounds containing a dihydro-
1,3-oxazine ring system exhibited a wide spectrum of phar-
macological activities, e.g., as antitumor [3–5], antibacterial
[6, 7], anti-HIV [8, 9], and antimalarial [10] agents. This
Multicomponent reactions (MCRs) constitute an espe-
cially attractive synthetic strategy because the products are
formed in a single step and diversity can be achieved simply
by varying the reacting components [16–18]. The rapid
microwave (MW)-assisted heat transfer allows reactions to
be carried out very much faster compared with conventional
heating methods and often resulting in increased product
yield. In order to decrease the reaction time, MW irradiation
under solvent-free conditions was used.
J. Azizian (&)
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Ponak, Tehran, Iran
e-mail: j-azizian@cc.sbu.ac.ir
In continuation of our previous work on the synthesis of
heterocyclic compounds and MCRs [19–27], we wish to
report a novel, efficient, one-pot, three-component method
for the preparation of 1-aryl-N,N-dimethyl-1H-naph-
tho[1,2-e][1,3]oxazine-3-amine derivatives under MW-
assisted conditions.
K. Yadollahzadeh
Department of Chemistry, Aliabad Katoul Branch,
Islamic Azad University, Aliabad Katoul, Iran
A. S. Delbari
Department of Chemistry, Islam Shahr Branch,
Islamic Azad University, Tehran, Iran
Results and discussion
M. M. Ghanbari
Young Researchers Club, Sarvestan Branch,
Islamic Azad University, Sarvestan, Iran
The reaction of N,N,N0,N0-tetramethylguanidine (TMG, 1)
with benzaldehyde (2a) and b-naphthol (3) in the presence
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J. Azizian et al.
Scheme 1
In conclusion, we have developed a simple and efficient
method for the synthesis of functionalized naphthoxazine
derivatives in three-component cyclocondensation reac-
tions. The one-pot nature of the present procedure makes it
an acceptable method for the preparation of target mole-
cules with variable functionalities. The advantages of the
present method include good functional group tolerance,
high yields of products, simple experimental procedure and
purification, no solvent, no prior activation, and short
reaction times. We hope that this approach may be of value
to others seeking novel synthetic fragments with unique
properties for medicinal chemistry.
Table 1 Catalyst effect on the reaction
Entry
Catalyst
Yield/%a
1
2
3
4
5
AcOH
PTSA
LiCl
NiCl2
–
85
58
38
–
35
Benzaldehyde (1 mmol), N,N,N0,N0-tetramethylguanidine (1.5 mmol),
b-naphthol (1 mmol), catalyst (0.3 mmol)
PTSA para-toluenesulfonic acid
a
Isolated yields
Experimental
of a catalytic amount of acetic acid for 6 min under MW-
assisted conditions afforded N,N-dimethyl-1-phenyl-1H-
naphtho[1,2-e][1,3]oxazine-3-amine (4a) in 85% yield
(Scheme 1).
Materials were purchased from Merck and Fluka companies.
Melting points were obtained using an Electrothermal-9100
1
apparatus. H and 13C NMR spectra were recorded with a
In order to find the best catalyst for the synthesis of the
naphthalene-condensed oxazine derivatives, the reaction of
TMG, benzaldehyde, and b-naphthol was carried out either
in the absence of catalyst or in the presence of various
protic or Lewis acids under similar conditions (Table 1).
As shown, the best yield was achieved when acetic acid
was used (entry 1).
Bruker DRX-300 Avance instrument using CDCl3 as solvent
and tetramethylsilane as internal standard at 300 and
75 MHz, respectively. EIMS (70 eV) mass spectra were
obtained with a Finnigan-MAT-8430 mass spectrometer.
Elemental analyses (C, H, N) were obtained with a Heraeus
CHN-O- Rapid analyzer. A microwave oven (Milestone
Microsynth, 2,450 Hz, 1,000 W, fiber optic thermal sensor)
was used for irradiation.
Encouraged by this success, we attempted the reaction
of TMG with a range of other aromatic aldehydes 2b–2h
and b-naphthol under similar conditions (using acetic acid),
furnishing the respective naphthoxazines 4b–4h in good
yields.
General procedure under MW-assisted conditions
A mixture of TMG (1, 1.5 mmol), aldehyde 2 (1 mmol),
b-naphthol 3 (1 mmol), and acetic acid (0.3 mmol) was
finely mixed together. The reaction mixture was placed in a
screw-capped vial and irradiated for 6 min at a power of
900 W. After cooling the residue was purified by column
chromatography (SiO2; hexane/EtOAc 3:1) to afford the
title compounds.
Although the mechanism of the reaction has not been
established experimentally, a possible explanation is pro-
posed in Scheme 2. According to these results, the reaction
can be mechanistically considered to proceed through the
intermediate 5 (formed in situ by reaction of the aldehyde
with TMG) [28–31]. The subsequent addition of b-naph-
thol to the intermediate 5 followed by cyclization affords
the corresponding products 4a–4h and dimethylamine.
Replacement of TMG with guanidine or N,N0-dimethylurea
gave no product. In addition, replacement of b-naphthol
with a-naphthol under both conditions produced no
product.
N,N-Dimethyl-1-phenyl-1H-naphtho[1,2-e][1,3]oxazine-3-
amine (4a, C20H18N2O)
1
Yield: 0.26 g (85%); white powder; m.p.: 141–143 °C; H
NMR (300 MHz, CDCl3): d = 3.06 (s, 6H, 2 CH3), 6.30 (s,
1H, CH), 7.16–7.46 (m, 8H, CH), 7.81 (d, JHH = 9 Hz,
3
123

An efficient Biginelli one-pot synthesis of new naphthalene-condensed oxazine derivatives
1419
Scheme 2
3
1H, CH), 7.85 (d, JHH = 9 Hz, 1H, CH), 7.93 (d,
3JHH = 9 Hz, 1H, CH) ppm; 13C NMR (75 MHz, CDCl3):
d = 37.6 (2 CH3), 56.2 (CH), 116.6 (CH), 116.9 (C), 123.6
(CH), 125.0 (CH), 127.3 (CH), 127.7 (2 CH), 128.5 (C),
128.8 (CH), 128.9 (2 CH), 129.3 (CH), 130.2 (C), 130.6
(CH), 131.4 (C), 147.4 (C), 151.4 (C=N) ppm; IR (KBr):
vꢀ = 1,662, 1,519, 1,449 cm-1; MS (EI, 70 eV): m/z
(%) = 302 (M?, 5), 225 (100), 140 (32), 127 (47).
(EI, 70 eV): m/z (%) = 332 (M?, 5), 301 (54), 225 (100),
140 (28), 127 (48).
1-(4-Chlorophenyl)-N,N-dimethyl-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4d, C20H17ClN2O)
1
Yield: 0.25 g (75%); white powder; m.p.: 154–157 °C; H
NMR (300 MHz, CDCl3): d = 3.12 (s, 6H, 2 CH3), 6.22 (s,
1H, CH), 6.83 (d, JHH = 9 Hz, 2H, CH), 7.23–727 (m,
3
3
3H, CH), 7.36–7.46 (m, 2H, CH), 7.79 (d, JHH = 9 Hz,
3
1H, CH), 7.82 (d, JHH = 9 Hz, 1H, CH), 7.93 (d,
N,N-Dimethyl-1-(3-methylphenyl)-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4b, C21H20N2O)
3JHH = 9 Hz, 1H, CH) ppm; 13C NMR (75 MHz, CDCl3):
d = 37.2 (2 CH3), 54.1 (CH), 117.2 (CH), 118.9 (C), 123.6
(CH), 125.0 (CH), 127.3 (2 CH), 129.7 (2 CH), 128.5 (C),
128.8 (CH), 128.9 (CH), 129.3 (CH), 130.2 (C), 130.6 (C),
131.4 (C), 147.4 (C), 151.4 (C=N) ppm; IR (KBr):
vꢀ = 1,660, 1,520, 1,448 cm-1; MS (EI, 70 eV): m/z
(%) = 336 (M?, 5), 301 (59), 225 (100), 140 (32), 127 (45).
1
Yield: 0.25 g (81%); white powder; m.p.: 131–133 °C; H
NMR (300 MHz, CDCl3): d = 2.84 (CH3), 3.00 (s, 6H, 2
CH3), 6.44 (s, 1H, CH), 6.55 (d, JHH = 6 Hz, 1H, CH),
3
3
7.01 (t, JHH = 8.4 Hz, 1H, CH), 7.37–7.44 (m, 5H, CH),
7.81 (d, 3JHH = 9 Hz, 1H, CH), 7.85 (d, 3JHH = 9 Hz, 1H,
CH), 7.93 (d, JHH = 9 Hz, 1H, CH) ppm; 13C NMR
3
(75 MHz, CDCl3): d = 24.6 (CH3), 36.9 (2 CH3), 54.2
(CH), 117.2 (CH), 118.9 (C), 120.7 (CH), 123.6 (CH),
124.6 (CH), 125.0 (CH), 127.3 (CH), 127.7 (CH), 128.5
(C), 128.8 (CH), 128.9 (CH), 129.3 (CH), 130.2 (C), 130.6
(C), 131.4 (C), 147.4 (C), 151.4 (C=N) ppm; IR (KBr):
vꢀ = 1,662, 1,519, 1,449 cm-1; MS (EI, 70 eV): m/z
(%) = 316 (M?, 5), 301 (67), 225 (100), 140 (21), 127 (34).
N,N-Dimethyl-1-(4-nitrophenyl)-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4e, C20H17N3O3)
1
Yield: 0.26 g (76%); white powder; m.p.: 171–173 °C; H
NMR (300 MHz, CDCl3): d = 3.12 (s, 6H, 2 CH3), 6.22 (s,
1H, CH), 7.23 (d, JHH = 6 Hz, 1H, CH), 7.36–7.40 (m,
3
3
2H, CH), 7.46 (d, JHH = 9 Hz, 2H, CH), 7.81 (d,
3
3JHH = 9 Hz, 1H, CH), 7.85 (d, JHH = 9 Hz, 1H, CH),
7.93 (d, 3JHH = 9 Hz, 1H, CH), 8.12 (d, 3JHH = 9 Hz, 2H,
CH) ppm; 13C NMR (75 MHz, CDCl3): d = 37.2 (2 CH3),
54.1 (CH), 117.2 (CH), 118.9 (C), 123.6 (CH), 125.0 (CH),
127.3 (2 CH), 129.7 (2 CH), 128.5 (C), 128.8 (CH), 128.9
(CH), 129.3 (CH), 130.2 (C), 130.6 (C), 141.4 (C), 147.4
(C), 154.4 (C=N) ppm; IR (KBr): vꢀ = 1,662, 1,518,
1,449 cm-1; MS (EI, 70 eV): m/z (%) = 347 (M?, 5),
301 (63), 225 (100), 140 (27), 127 (42).
1-(4-Methoxyphenyl)-N,N-dimethyl-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4c, C21H20N2O2)
1
Yield: 0.24 g (73%); white powder; m.p.: 162–166 °C; H
NMR (300 MHz, CDCl3): d = 3.00 (s, 6H, 2 CH3), 3.74 (s,
3H, CH3O), 6.21 (s, 1H, CH), 6.79 (d, JHH = 9 Hz, 2H,
3
CH), 7.23–727 (m, 3H, CH), 7.36–7.46 (m, 2H, CH), 7.80
(d, 3JHH = 9 Hz, 1H, CH), 7.84 (d, 3JHH = 9 Hz, 1H, CH),
3
7.92 (d, JHH = 9 Hz, 1H, CH) ppm; 13C NMR (75 MHz,
CDCl3): d = 37.2 (2 CH3), 51.6 (CH3O), 53.2 (CH), 115.2
(2 CH), 116.4 (CH), 117.2 (2 CH), 118.9 (C), 120.7 (CH),
123.6 (CH), 125.0 (CH), 127.3 (CH), 128.5 (C), 128.9
(CH), 130.2 (C), 130.6 (C), 144.4 (C), 147.4 (C), 151.4
(C=N) ppm; IR (KBr): vꢀ = 1,660, 1,520, 1,448 cm-1; MS
1-(2-Bromophenyl)-N,N-dimethyl-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4f, C20H17BrN2O)
1
Yield: 0.29 g (78%); white powder; m.p.: 145–147 °C; H
NMR (300 MHz, CDCl3): d = 3.12 (s, 6H, 2 CH3), 6.22 (s,
1H, CH), 7.23 (m, 1H, CH), 7.36–7.40 (m, 2H, CH), 7.46
123

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J. Azizian et al.
3
(d, JHH = 9 Hz, 2H, CH), 7.74–7.83 (m, 3H, CH), 8.12
(m, 2H, CH) ppm; 13C NMR (75 MHz, CDCl3): d = 37.2
(2 CH3), 54.1 (CH), 117.2 (CH), 118.9 (C), 123.6 (CH),
125.0 (CH), 127.3 (2 CH), 129.7 (2 CH), 128.5 (C), 128.8
(CH), 128.9 (CH), 129.3 (CH), 130.2 (C), 130.6 (C), 141.4
(C), 147.4 (C), 154.4 (C=N) ppm; IR (KBr): vꢀ = 1,660,
1,520, 1,448 cm-1; MS (EI, 70 eV): m/z (%) = 380 (M?,
5), 301 (51), 225 (100), 140 (25), 127 (65).
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N,N-Dimethyl-1-(2-thienyl)-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4g, C18H16N2OS)
1
Yield: 0.25 g (83%); white powder; m.p.: 131–133 °C; H
NMR (300 MHz, CDCl3): d = 3.12 (s, 6H, 2 CH3), 6.51 (s,
1H, CH), 6.70 (d, JHH = 4.3 Hz, 1H, CH), 6.81 (t,
3
3JHH = 4.5 Hz, 1H, CH), 7.15 (d, JHH = 6 Hz, 1H, CH),
3
3
7.23 (d, JHH = 6 Hz, 1H, CH), 7.44–7.55 (m, 2H, CH),
7.81 (d, 3JHH = 9 Hz, 1H, CH), 7.85 (d, 3JHH = 9 Hz, 1H,
CH), 7.93 (d, JHH = 9 Hz, 1H, CH) ppm; 13C NMR
3
(75 MHz, CDCl3): d = 37.2 (2 CH3), 50.2 (CH), 105.9
(CH), 110.4 (CH), 114.9 (C), 116.7 (CH), 123.2 (CH),
125.0 (CH), 127.3 (CH), 128.9 (CH), 129.4 (CH), 130.5
(C), 131.3 (C), 142.1 (CH), 147.6 (C), 152.2 (C), 157.1
(C=N) ppm; IR (KBr): vꢀ = 1,670, 1,448 cm-1; MS (EI,
70 eV): m/z (%) = 308 (M?, 5), 225 (100), 140 (45), 127
(42).
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1-(2-Furanyl)-N,N-dimethyl-1H-naphtho-
[1,2-e][1,3]oxazine-3-amine (4h, C18H16N2O2)
1
Yield: 0.23 g (79%); white powder; m.p.: 139–141 °C; H
NMR (300 MHz, CDCl3): d = 3.09 (s, 6H, 2 CH3), 6.08
(d, JHH = 5.4 Hz, 1H, CH), 6.23 (t, JHH = 6.2 Hz, 1H,
CH), 6.36 (s, 1H, CH), 7.21–727 (m, 2H, CH), 7.43–7.51
3
3
3
(m, 2H, CH), 7.79 (d, JHH = 9 Hz, 1H, CH), 7.80 (d,
3
3JHH = 9 Hz, 1H, CH), 7.92 (d, JHH = 9 Hz, 1H,
CH) ppm; 13C NMR (75 MHz, CDCl3): d = 37.2 (2
CH3), 50.2 (CH), 105.9 (CH), 110.4 (CH), 114.9 (C),
116.7 (CH), 123.2 (CH), 125.0 (CH), 127.3 (CH), 128.9
(CH), 129.4 (CH), 130.5 (C), 131.3 (C), 142.1 (CH), 147.6
(C), 152.2 (C), 157.1 (C=N) ppm; IR (KBr): vꢀ = 1,668,
1,450 cm-1; MS (EI, 70 eV): m/z (%) = 292 (M?, 5), 225
(100), 140 (23), 127 (45).
123