Chlorotrimethylsilane-promoted synthesis of 1,2-dihydro-1-arylnaphtho [1,2-e] [1,3]oxazine-3-ones

Article abstract of DOI:10.3184/030823409X12615635710356

Chlorotrimethylsilane (TMSCl) is effective as a catalyst for the preparation of 1,2-dihydro-1-arylnaphtho[1,2-e] [1,3]oxazine-3- ones using a one-pot condensation of 2-naphthol, aromatic aldehydes and urea in DMF as solvent. The reaction times, temperatur

Full text of DOI:10.3184/030823409X12615635710356

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 19
JANUARY, 19–21
Chlorotrimethylsilane-promoted synthesis of 1,2-dihydro-1-arylnaphtho
[1,2-e] [1,3]oxazine-3-ones
Chenggang Jiang, Xin Geng, Zonglei Zhang, Hangxian Xu and Cunde Wang*
College of Chemistry and ChemicalTechnology,Yangzhou University, Yangzhou 225002, P. R. China
Chlorotrimethylsilane (TMSCl) is effective as a catalyst for the preparation of 1,2-dihydro-1-arylnaphtho[1,2-e]
[1,3]oxazine-3- ones using a one-pot condensation of 2-naphthol, aromatic aldehydes and urea in DMF as solvent.
The reaction times, temperature, and catalyst amounts were varied.
Keywords: 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-ones, Betti base, 2-naphthol, aromatic aldehydes, chlorotrimethyl-
silane
1-(α-Aminobenzyl)-2-naphthols, known as Betti bases, and
their derivatives are attractive for use in asymmetric syntheses.
These compounds have been employed as precursors in the
preparation of chiral ligands for asymmetric catalysis. They
are suitable for such purposes owing to their ease of synthesis,
the ready availability of the precursors, and their potential
for enantiomeric separation.1–4 Important new applications as
synthons have been found in asymmetric syntheses.5–8 These
compounds have also has been used as chiral auxiliaries in the
total syntheses of natural alkaloidal products such as (2S,6R)-
dihydropinidine and (2S,6R)-isosolenopsins.9 In recent years,
these oxazinone derivatives of 1-(α-aminobenzyl)-2-naphthols
have attracted interest. A number of oxazinone derivatives are
biologically active.10–12 In general ,substituted Betti bases were
prepared utilising the classical synthesis involving the three-
component condensation of 2-naphthol, benzaldehyde and
ammonia in alcoholic solution at room temperature. Sub-
sequently, condensation reactions of substituted Betti bases
with phosgene or carbonyl diimidazole gave naphthalene-
condensed 1,3-oxazin-3-ones.13,14 Recently there have been
some reports of the preparation of 1-aminoalkyl-2-naphthols
by the three-component reaction between 2-naphthol, aromatic
aldehydes and amides or urea using different catalysts.15–21
With the growing realization that some oxazinone derivatives
of 1-(α-aminobenzyl)-2-naphthols display significant biologi-
cal activities, the development of novel synthetic methods has
attracted attention. All these methods required either expensive
toxic or hazardous reagents or solvents. Therefore, easy-to-
handle and highly efficient methods in which the reagents used
are nontoxic, inexpensive and safe are still targets. Previous
studies have shown that chlorotrimethylsilane (TMSCl) is
a mild and efficient promoter for various organic transfor-
mations.22–25 It has also been reported as a mild useful and
inexpensive Lewis acid catalyst for one-pot multicomponent
preparations of heterocyclic compounds.26–30 In our previous
work,31–33 TMSCl was employed to carry out several unusual
cyclo-condensations including one-pot synthesis of substituted
quinolines and pyrroles. We selected TMSCl as the catalyst,
for the preparation of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]
oxazine-3-ones The results obtained are now reported.
Table 1 The effect of varous catalysts and solvents on the
reactiona
Entry
Catalyst
Solvent
Yields /%b
1
2
3
4
5
6
7
8
9
AcOH
PTSA
DMF
62c
65d
67
48
40
68
66
26
43
DMF
BF3Et2O
ZnCl
DMF
DMF
ZnO 2
DMF
TMSCl
TMSCl
TMSCl
TMSCl
DMF
DMSO
THF
dioxane
aBenzaldehyde (1 mmol), urea (1.1 mmol), β-naphthol (1 mmol),
catalyst (0.05 mmol), solvent (10 mL); reflux for THF and
dioxane, 140 °C for DMSO and DMF; 12 h.
bIsolated yields.
c Without solvent 45% in yield.16
d Without solvent 58% in yield.16
At the outset, various catalysts and solvents were screened. To
our delight, we observed the formation of the desired product
4a (Table 2) when the reaction was carried out using benzalde-
hyde (1 mmol), urea (1.1 mmol), β-naphthol (1 mmol), DMF
(10 mL) in the presence of various catalysts (0.05 mmol) under
reflux for 12 h. A comparison of the method using TMSCl as
a catalyst (Table 1, entry 6, 68% in yield), with other selected
catalysts such as acetic acid and PTSA and other Lewis
acid (BF3 ·Et2O, ZnCl2) or ZnO (Table 1, entry 1, 62% in yield;
entry 2, 65% in yield; entry 3, 67% in yield; entry 4, 48% in
yield; entry 5, 40% in yield, respectively) demonstrated that
the method using TMSCl as a catalyst was superior to several
of the other protocols.
We then investigated the preparation of 1,2-dihydro-1-
arylnaphtho[1,2-e][1,3]oxazine-3-ones by multi-components
cyclocondensation of 2-naphthol, urea and aromatic aldehydes
via a tandem reaction in the presence of TMSCl. In order to
optimise the reaction conditions, solvent, time, and the amount
of TMSCl were varied. Firstly the solvent used in the prepara-
tion of 1-phenyl-1,2-dihydronaphtho[1,2-e][1,3]oxazin-3-one
(4a) from benzaldehyde (1 mmol), 2-naphthol (1 mmol) and
urea (1.1 mmol) in the presence of TMSCl (0.05 mmol) was
varied. Among the solvents tested (Table 1, entries 6–9), DMF
and DMSO gave the best result. The result showed that DMF,
DMSO gave the product 4a in 68%, 66% yield, respectively.
In the second set of experiments, the model reaction with
benzaldehyde, 2-naphthol and urea in DMF was carried out
at various temperatures. After some experimentation, it was
found that the model reaction using a reaction temperature of
135–140 °C produced the product 4a in excellent yield. Fur-
thermore, the reaction time and the catalyst concentration
could be reduced to 12 h and 10%, respectively. Thus, with
these results in hand, we synthesised nine naphthoxazin-
3-ones (Table 2, 4a–i) in yields varying from 49 to 83% by
the cyclo-condensation reaction of 1.0 mmol 2-naphthol
Results and discussion
Although these oxazine-3-ones were prepared under micro-
wave or thermal solvent-free conditions in the previous report,16
the limitations of these methods it was very difficult to sythe-
sise these oxazine-3-ones on a large scale. In order to facilitate
their industrial production, we selected a convenient and
efficient procedure for the preparation of oxazine-3-ones in
the liquid phase. The reaction was initially studied with 2-
naphthol, urea and benzaldehyde, in various solvents (Table 1).
* Correspondent. E-mail: cundeyz@hotmail.com

20 JOURNAL OF CHEMICAL RESEARCH 2010
Table 2 One-pot synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e]
[1,3]oxazine-3-ones via tandem reaction promoted by TMSCl
0.10 mol), urea (6.6 g, 0.11 mol), β-naphthol (14.4 g,
0.10 mol) and TMSCl (0.50 g, 5.0 mmol) in DMF (120 mL) at
140 °C for 12 h; benzaldehyde (21.2 g, 0.20 mol), urea (13.2 g,
0.22 mol), β-naphthol (28.8 g, 0.10 mol) and TMSCl (1.0 g,
10.0 mmol) in DMF (200 mL) at 140 °C for 12 h; the yield
of product 4a was 68, 66 and 66%, respectively. The results
showed that approximately the same yields were obtained.
Many studies of using aldehydes for a range of condensa-
tions in the presence of chlorotrimethylsilane as promoting
reagents have been recently reported. According to these
results, the mechanism can be explained tentatively as in
Scheme 2 for the conversion of intermediate acylimine from
the aldehyde with urea, and the subsequent addition of the
β-naphthol to the acylimine, followed by cyclisation in the
presence of TMSCl affords the corresponding products and
ammonia.
In summary, a novel, efficient and one-pot synthesis has
been described for the preparation of naphthoxazine-3-ones in
three-component cyclo-condensation reactions of 2-naphthol,
aromatic aldehydes and urea. This involves the use of inexpen-
sive and relatively nontoxic reagent TMSCl as a catalyst.
The novelty and synthetic utility of this methodology was
demonstrated in the efficient synthesis of naphthoxazinone
derivatives.
Entry
Aldehydes(R)(2)
Oxazine-3-ones (4)a/%
a
b
c
d
e
f
g
h
i
H
68
49
68
73
59
83
56
76
78
m-NO
m-CH 2O
m-CF33
p-CF3
3,4-(OCH2O)
o-NO
p-NO22
p-(CH3)2N
aIsolated yields.
and 1.0 mmol of the appropriate aromatic aldehyde (2a–i) in
7.5 mL DMF with 1.1 mmol urea in the presence of 0.1 mmol
TMSCl at 135–140 °C for 12 h (Scheme 1).
The structural and chemical data for the products (Table 2,
4a–i) are given in the experimental section. The IR spectra of
the products showed C=O stretching band at about 1740 cm−1.
1H NMR spectra, C1–H and N–H protons of the oxazin-3-one
ring were observed near 6.0 and 6.20 ppm. The protons belong-
ing to the aromatic ring and substitutent groups were observed
with the expected chemical shift values. The structures of
the products were confirmed by IR, 1H NMR, MS spectra and
by comparison with authentic samples prepared according to
literature methods.
Based on the above results, some larger scale reactions were
carried out using the following amounts of the starting materi-
als: benzaldehyde (5.3 g, 0.05 mol), urea (3.3 g, 0.055 mol),
β-naphthol (7.2 g, 0.05 mol) and TMSCl (0.25 g, 2.5 mmol)
in DMF (80 mL) at 140 °C for 12 h; benzaldehyde (10.6 g,
Experimental
General procedures
IR spectra were measured with a model 408 IR spectrometer; Elemen-
tal analytical data were obtained by using a model 240 elementary
instrument; 1H NMR spectra were recorded on a JNM-90Q Spectrom-
eter by using TMS as an internal standard (CDCl3 as solvent). Melting
points are uncorrected; the MS spectra were obtained on a ZAB-HS
mass spectrometer with 70 eV.
Scheme 1 One-pot reaction of 2-naphthol, aromatic aldehydes and urea
promoted by TMSCl.
Scheme 2 Plausible reaction mechanism.

JOURNAL OF CHEMICAL RESEARCH 2010 21
One-pot synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-
3-ones from 2-naphthol, urea and aromatic aldehydes via tandem
reaction promoted by TMSCl; general procedure
Calcd for C19H13NO4: C, 71.47; H, 4.10; N, 4.39. Found: C, 71.32;
H, 4.00; N, 4.32%.
1-(4-(Dimethylamino)phenyl)-1,2-dihydronaphtho[1,2-e][1,3]
oxazin-3-one (4i): M.p. 223–225 °C (EtOAc-CH2Cl2); IR (KBr, cm−1)
To a mixture of 2-naphthol (288 mg, 2.0 mmol), aromatic aldehydes
(2.0 mmol) and urea (132 mg, 2.2 mmol) in dry DMF (10 mL) was
added TMSCl (10 mg, 0.1 mmol) at room temperature. The resulting
mixture was stirred at 135–140 °C for 12 h. After the mixture was
cooled to room temperature, 10% Na2CO3 (10 mL) was added to the
reaction mixture and the resultant mixture was extracted with CH2Cl2
(2 × 15 mL), the combined organic phase was washed with water and
brine, dried over Na2SO4. The solvent was removed and the residues
were purified by column chromatography (silica gel, EtOAc/PE, 3/1)
to give a product (Table 2, 4a–i).
1
3149, 1736, 1610, 1518, 1224; H NMR (CDCl3, 600 MHz, ppm) δ
2.92 (s, 2XCH 6H), 5.88 (s, 1H), 6.01 (d, J = 2.4 Hz, 1H), 6.74 (s,
2H), 7.16 (d, J 3=; 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 3.6
Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.84 7.16 (d, J = 9.0 Hz, 2H);
MS m/z 318 (M+, 10). Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70;
N, 8.80. Found: C, 75.40; H, 5.48; N, 8.62%.
We are grateful to the Natural Science Foundation of Jiangsu
Education Ministry of China for financial support. (Grant
07KJB150135).
1-Phenyl-1,2-dihydronaphtho[1,2-e][1,3]oxazin-3-one16 (4a): M.p.
219–220 °C (EtOAc/Hexanes) (lit. [6b] 218–220 °C (EtOAc/
Hexanes); IR (KBr, cm−1) 3263, 1744, 1663, 1533, 1438, 1359, 1268;
1H NMR (CDCl3, 600 MHz, ppm) δ 5.80 (s, 1H), 6.20 (d, J = 2.1 Hz,
1H), 7.23–7.90 (m, 11H); MS m/z 275 (M+, 8). Anal. Calcd for
C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.28; H, 4.90; N,
5.06%.
Received 13 October 2009; accepted 10 December 2009
Paper 090825 doi: 10.3184/030823409X12615635710356
Published online: 20 January 2010
1-(3-Nitrophenyl)-1,2-dihydronaphtho[1,2-e][1,3]oxazin-3-one
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1-(3-Trifluoromethylphenyl)-1,2-dihydronaphtho[1,2-e][1,3]
oxazin-3-one (4d): M.p. 229–232 °C (EtOAc/CH2Cl2); IR (KBr, cm−1)
1
3252, 2923, 2853, 1752, 1669, 1323, 1223, 1172, 1116; H NMR
(CDCl3, 600 MHz, ppm) δ 6.10 (s, 1H), 6.14 (s, 1H), 6.61 (s, 1H), 7.34
(d, J = 8.4 Hz, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 7.79 (d, J = 7.8 Hz,
1H), 7.80 (m, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H),
8.08 (m, 1H); MS m/z 343 (M+, 52). Anal. Calcd for C19H12F3NO2:
C, 66.47; H, 3.52; N, 4.08. Found: C, 66.22; H, 3.80; N, 4.14%.
1-(4-Trifluoromethylphenyl)-1,2-dihydronaphtho[1,2-e][1,3]
oxazin-3-one (4e): M.p. 218–220 °C (EtOAc); IR (KBr, cm−1) 3238,
1
3152, 1756, 1626, 1590, 1516, 1325, 1223; H NMR (CDCl3, 600
MHz, ppm) δ 6.14 (s, 1H), 7.20 (s, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.35
(m, 1H), 7.39 (m, 1H), 7.43–7.47 (m, 2H), 7.49 (m, 1H), 7.55 (d,
J = 8.4 Hz, 2H), 7.84–7.86 (m, 1H), 7.89 (d, J = 9.0 Hz, 1H); MS m/z
343 (M+, 40). Anal. Calcd for C19H12F3NO2: C, 66.47; H, 3.52; N,
4.08. Found: C, 66.10; H, 3.56; N, 4.04%.
1-(2-Nitrophenyl)-1,2-dihydronaphtho[1,2-e][1,3]oxazin-3-one
(4f): M.p. 211–214 °C (EtOAc-CH2Cl2); IR (KBr, cm−1) 3242, 3146,
1
1748, 1627, 1486, 1397, 1225; H NMR (CDCl3, 600 MHz, ppm) δ
6.50 (s, 1H), 6.53 (s, 1H), 6.85 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.2 Hz,
1H), 7.30–7.41 (m, 5H), 7.81 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.2 Hz,
1H), 8.09 (d, J = 7.2 Hz, 1H); MS m/z 320 (M+, 16). Anal. Calcd for
C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found: C, 67.42; H, 3.68;
N, 8.52%.
1-(Benzo[d][1,3]dioxol-5-yl)-1,2-dihydronaphtho[1,2-e][1,3]
oxazin-3-one (4g): M.p. 212–214 °C (EtOAc-CH2Cl2); IR (KBr, cm−1)
1
3267, 1724, 1634, 1586, 1523, 1381, 1224; H NMR (CDCl3, 600
MHz, ppm) δ 5.83 (d, J = 20.8 Hz, 2H), 5.93 (s, 1H), 5.96 (s, 1H),
6.58 (s, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.76 (m, 1H), 7.26 (m, 1H),
7.36 (m, 2H), 7.50 (m, 1H), 7.55 (m, 2H); MS m/z 319 (M+, 20). Anal.