Reaction of 2-alkoxy-4,5-diphenyl-1,3-oxazin-6-one with different alcohols and elucidation of the products

Article abstract of DOI:10.1002/jhet.741

Reaction of 2-methoxy-4,5-diphenyl-1,3-oxazin-6-one 1a with methanol was studied, and the product of the reaction was determined by spectroscopic data and X-ray analysis. In addition, a series of (Z)-alkyl 3-(alkoxycarbonylamino)- 2,3-diphenylacrylate 4 was synthesized and characterized. Copyright

Full text of DOI:10.1002/jhet.741

358
Reaction of 2-Alkoxy-4,5-diphenyl-1,3-oxazin-6-one with
Different Alcohols and Elucidation of the Products
Vol 49
Amir Assadieskandar,a Mohsen Amini,a Matti Haukka,b and Abbas Shafieec*
aDepartment of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development
Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran
bDepartment of Chemistry, Faculty of Science and Forestry, University of Eastern Finland,
Joensuu 80101, Finland
cDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran 14176, Iran
*E-mail: ashafiee@ams.ac.ir
Received June 30, 2010
DOI 10.1002/jhet.741
Published online 31 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of 2-methoxy-4,5-diphenyl-1,3-oxazin-6-one 1a with methanol was studied, and the product
of the reaction was determined by spectroscopic data and X-ray analysis. In addition, a series of (Z)-
alkyl 3-(alkoxycarbonylamino)-2,3-diphenylacrylate 4 was synthesized and characterized.
J. Heterocyclic Chem., 49, 358 (2012).
INTRODUCTION
RESULTS
Diarylheterocycle scaffold and other central ring phar-
macophore templates have been extensively studied as
cyclooxygenase (COX) inhibitors. In pursuit of our
research on design and synthesis of COX inhibitors [1–
3], we focused on the synthesis of diarylheterocycles
with central six-membered lactone (2-pyrone, 1,3-oxa-
zin-6-one, and 2,3-dihydro-6H-1,3-oxazin-6-one), which
is expected to inhibit the COX enzyme. The synthesis
of 2-pyrone and 1,3-oxazin-6-one derivatives were
reported previously [4–6]. In addition, 2,2-dialkoxy-4,5-
By refluxing compound 1a in methanol, a product
was obtained in good yield. The mass spectra, elemental
analysis, and 1H NMR data were similar to that one
reported for compound 2a [5]. In 13C NMR spectra, two
deshielded signals were observed at 153.32 and 169.83
ppm that could be assigned to carbon 2 and carbonyl
group, respectively. For evaluating the structure of the
product, HMBC data were obtained. It was expected
that in compound 2a, correlation between two methoxy
groups and carbon 2 was observed. However, a correla-
tion between two methoxy groups at 3.64 and 3.73 ppm
was observed with the carbonyl carbons at 153.32 and
169.83, respectively (Fig. 1).
disubstituted-2,3-dihydro-6H-1,3-oxazin-6-ones
were
suggested as product by refluxing compound 1 in metha-
nol by Sasaki et al. [5]. This structure was assigned by
using infrared and NMR data (Scheme 1).
Furthermore, two carbonyl peaks were found at 1751
and 1669 cmꢀ1 in infrared spectra. These observations
suggested the probability of the cleavage of the ring.
For further confirmation of the structure 4a, carbamate
acid 3a was prepared by route b. A method for cleavage
In contrast, our findings have suggested that reaction
of 2-alkoxy-4,5-diphenyl-1,3-oxazin-6-one 1 with meth-
anol under reflux condition resulted to carbamate ester 4
involving cleavage of the oxazinone ring as illustrated
in Scheme 2. Furthermore, new derivatives of (Z)-alkyl
3-(alkoxycarbonylamino)-2,3-diphenylacrylate were pre-
pared via reaction of some alcohols (or thioethanol)
with 1b. Based on some previous reports, carbamate
ester were expected to have some biological activities
such as inhibition of platelet aggregation [7], inhibition
of LPS-stimulated production of TNF-a [8], and inhibi-
tion of RNA polymerase [9].
Scheme 1. Reaction proposed by Sasaki.
C
V
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Reaction of 2-Alkoxy-4,5-diphenyl-1,3-oxazin-6-one with Different Alcohols and
Elucidation of the Products
359
Scheme 2. Reaction of compound 1a with methanol.
of some oxazinone derivatives was reported previously
[10]. Hydrolysis of compound 1a with dilute sodium hy-
droxide solution at room temperature (r.t.) followed by
HCl gave acid 3a that subsequently was converted to
carbamate ester 4a by diazomethane. Compound 4a,
which was prepared from route b, showed the same
spectroscopic data with the one prepared from route a
(Scheme 2). However, with considering of closure the
ring via an internal rearrangement (formation of 2a from
4a), it was necessary to establish the structure of com-
pound 4a with X-ray diffraction analysis. Figure 2
shows the crystal structure of compound 4a [11].
Figure 2. Crystal structure of compound 4a.
3.73 and 4.06 ppm, respectively. On the other hand, in
compound 4c OCH3 and OCH2CH3 groups were
observed at 3.64 and 4.21 ppm respectively. As a result,
for each alkoxy group, two different shield and deshield
signals were observed that are related to the carbamate
and ester moiety, respectively.
Reaction of compound 1b with sodium alkoxide for 1
h in related alcohols gave only one product. The struc-
ture of all compounds was confirmed by NMR data.
Furthermore, similar reaction with sodium ethanethiolate
for 1 h in THF gave only one product that was assigned
as compound 4h (Scheme 4, Table 1). In 13C NMR
spectra of 4h, two deshielded signals were observed at
152.90 and 195.36 ppm that could be assigned to car-
bonyl in carbamate and thioester groups, respectively.
For evaluating the structure of compound 4h, HMBC
data were acquired. There was a correlation between
two CH2 groups at 4.06 and 2.87 ppm with the carbons
at 152.90 and 195.36, respectively (Scheme 4).
According to Sasaki et al., reaction of compound 1b
with methanol under reflux condition gave only one
product, which was assigned as 2b. Our experiment
showed that under similar condition, a mixture of three
compounds were obtained in 12.4, 6.8, and 72.1% yields
that were assigned as 4a, 4b, and 4c, respectively. Here
again, for further confirmation of the structure 4b, car-
bamate acid 3b was prepared by route b. Alkaline hy-
drolysis of compound 1b followed by HCl gave com-
pound 3b that subsequently was converted to carbamate
1
ester 4b by diazomethane (Scheme 3). In H NMR of
4a and 4d, two different signals (3.65 and 3.73 ppm) for
the two OCH3 groups and two different signals (4.06
and 4.22 ppm) for the two OCH2CH3 groups were
observed, respectively. Furthermore, in compound 4b
that was synthesized by direct methylation of carboxylic
group, OCH3 and OCH2CH3 groups were observed at
DISCUSSION
Mechanism for ring-opening of 1,3-oxazin-6-
one. According to Beccalli and Marchesini report about
chemical reactivity of the 2-(dialkylamino)-1,3-oxazin-
6-ones [10], a thermal equilibrium between ketene inter-
mediate a and b in the cleavage of compound 1b could
be postulated (Scheme 5).
It could be assumed that under reflux condition, com-
pound 4c was formed from nucleophilic attack of meth-
anol to the intermediate b. On the other hand, by using
sodium alkoxide in related alcohol at r.t., the major
products were 4a and 4d–4g. Finally, compound 4h was
Figure 1. Correlation in HMBC experiment.
Journal of Heterocyclic Chemistry
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360
A. Assadieskandar, M. Amini, M. Haukka, and A. Shafiee
Vol 49
Scheme 3. Reaction of compound 1b with methanol.
CH3), 6.9–7.2 (m, 10H, phenyl), 10.86 (bs, 1H, NH), 12.79
(bs, 1H, COOH); 13C NMR (125 MHz, DMSO-d6): d 52.61,
115.14, 126.58, 127.67, 128.32, 129.59, 131.87, 135.66,
136.95, 149.43, 153.24, 170.96. Anal. Calcd. for C17H15NO4:
C, 68.68; H, 5.09; N, 4.71. Found: C, 68.31; H, 5.19; N, 4.61.
prepared from nucleophilic reaction of sodium ethane-
thiolate with 1b at r.t.
Mechanistic
formation
of
1,3-oxazin-6-
one. Classically, two mechanistic speculations were
postulated for the preparation of compound 1a via reac-
tion of N-acylpyridinium imines with diphenylcyclopro-
penone in benzene (Scheme 6) [4,5].
(Z)-3-(Ethoxycarbonylamino)-2,3-diphenylacrylic
acid
(3b). Yield: 72%; mp 155–158ꢁC; IR (KBr, cmꢀ1): m 1751,
1
1642 (C¼¼O); H NMR (DMSO-d6): d 1.11 (t, J ¼ 7 Hz, 3H,
CH3), 3.96 (q, J ¼ 7 Hz, 2H, CH2), 6.9–7.2 (m, 10H, phenyl),
10.84 (bs, 1H, NH), 12.79 (bs, 1H, COOH); 13C NMR
(DMSO-d6): d 14.67, 61.29, 114.72, 126.55, 127.64, 128.25,
129.53, 131.91, 135.75, 137.00, 149.79, 152.72, 170.94. Anal.
Calcd. for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.32; H, 5.61; N, 4.46.
Pathway b passes from ketene intermediate via an
intramolecular cyclization process. Sasaki et al. studied
the appearance of ketene intermediate by quenching the
reaction. They reported that formation of 4a (via path b)
by using methanol instead of benzene was not success-
ful. Their conclusion was based on this fact that they
erroneously attributed structure 4a as 2a. Therefore, the
presence of ketene intermediate could be considered in
1,3-oxazin-6-one formation. Similar study was carried
out using N-aminopyridinum iodide instead of N-acyl-
pyridinium imines in which the presence of ketene inter-
mediate in this reaction was also suggested [12].
General procedure for esterification of
3
with
diazomethane. A THF solution of acid 3 (0.34 mmol) was
esterified with a solution of diazomethane in diethyl ether to
give the corresponding ester 4. Compounds 4a and 4b were
prepared in 86 and 81% yield, respectively.
Scheme 4. Reaction of compound 1b with sodium alkoxide and so-
dium ethanethiolate.
EXPERIMENTAL
1H NMR spectra were recorded on a 500 MHz Bruker spec-
trometer using CDCl3 or DMSO-d6 as solvent.13C NMR spec-
tra were recorded on a 125 MHz Bruker spectrometer using
CDCl3 or DMSO-d6 as solvent. Chemical shifts (d) are
reported in ppm relative to tetramethylsilane as internal stand-
ard. Infrared spectra were acquired on a Nicolet Magna 550-
FT spectrometer. IR spectra of solids were recorded in KBr,
and the absorption band was given in wave numbers m in
cmꢀ1. Elemental microanalyses were within 60.4% of the the-
oretical values for C, H, and N.
Table 1
Synthesis of compounds 4a and 4d–h.
Products
R1
R2
Yielda (%)
mp (ꢁC)
General procedure for alkaline hydrolysis of
oxazinones. 1,3-Oxazin-6-one 1 (0.4 mmol) was dissolved in
dioxane (5 mL), and sodium hydroxide solution (3 mL of
2.7% w/v) was added. The reaction mixture was stirred at r.t.
for 12 h. The solution was evaporated under reduced pressure
at 40ꢁC. Water (5 mL) was added and, cooling in an ice bath,
the solution was acidified with 16% HC1 (1 mL). The precipi-
tate was filtered, dried, and crystallized from methanol.
4a
4d
4e
4f
4g
4h
OMe
OEt
OnPr
OiPr
OnBu
SEt
OMe
OEt
OnPr
OiPr
OnBu
OEt
76
68
52
56
42
72b
166–169
84–86
50–52
98–100
46–48
110–112
a All products were purified by preparative thin layer chromatography
on silica gel using ethyl acetate-petroleum ether (1:10) as mobile
phase and crystallized from methanol.
(Z)-3-(Methoxycarbonylamino)-2,3-diphenylacrylic
acid
(3a). Yield: 76%; mp 182–185ꢁC; IR (KBr, cmꢀ1): m 1752,
1
b Compound 4h was crystallized from diethyl ether-n-hexane.
1646 (C¼¼O); H NMR (500 MHz, DMSO-d6): d 3.54 (s, 3H,
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Reaction of 2-Alkoxy-4,5-diphenyl-1,3-oxazin-6-one with Different Alcohols and
Elucidation of the Products
361
Scheme 5. Rearrangement for the ethoxy group in 1,3-oxazin-6-one ring.
Reaction of compound 1b with methanol. A solution of
the oxazin-6-one 1b (0.4 mmol) in methanol (30 mL) was
heated under reflux for 24 h. The mixture was then concen-
trated under reduced pressure, and the residue was purified by
preparative thin layer chromatography on silica gel using ethyl
acetate–petroleum ether (1:10) as mobile phase. The product
was crystallized from methanol.
(Z)-Methyl 3-(methoxycarbonylamino)-2,3-diphenylacrylate
(4a). Yield: 12.4%; mp 166–169ꢁC; IR (KBr, cmꢀ1): m 1751,
1669 (C¼¼O); 1H NMR (500 MHz, CDCl3): d 3.65 (s, 3H,
CH3), 3.73 (s, 3H, CH3), 6.9–7.3 (m, 10H, phenyl), 11.12 (bs,
1H, NH); 13C NMR (125 MHz, CDCl3): d 52.09, 52.59,
111.26, 126.46, 127.35, 128.17, 128.85, 131.90, 134.65,
135.33, 152.79, 153.32, 169.83. Anal. Calcd. for C18H17NO4:
C, 69.44; H, 5.50; N, 4.50. Found: C, 69.31; H, 5.32; N, 4.61.
(Z)-Methyl 3-(ethoxycarbonylamino)-2,3-diphenylacrylate
(4b). Yield: 6.8%; mp 135–138ꢁC; IR (KBr, cmꢀ1): m 1752, 1663
(C¼¼O); 1H NMR (CDCl3): d 1.21 (t, J ¼ 7 Hz, 3H, CH3), 3.73 (s,
3H, CH3), 4.06 (q, J ¼ 7 Hz, 2H, CH2), 6.9–7.3 (m, 10H, phenyl),
11.05 (bs, 1H, NH); 13C NMR (CDCl3): d 14.27, 52.05, 61.56,
111.00, 126.41, 127.32, 128.10, 128.83, 131.93, 134.79, 135.40,
152.83, 152.96, 169.85. Anal. Calcd. for C19H19NO4: C, 70.14; H,
5.89; N, 4.31. Found: C, 70.32; H, 5.96; N, 4.48.
General procedure for the reaction of 1b with sodium
alkoxide. Sodium (20 mg) was added in related alcohol (50
mL) and mixed. Compound 1b was added, and the reaction
was allowed to stir for 1 h at r.t. The mixture was then con-
centrated under reduced pressure, and the residue was purified
by preparative thin layer chromatography on silica gel using
ethyl acetate–petroleum ether (1:10) as mobile phase. The
product was crystallized from methanol.
(Z)-Ethyl
3-(ethoxycarbonylamino)-2,3-diphenylacrylate
(4d). Yield: 68%; mp 84–86ꢁC; IR (KBr, cmꢀ1): m 1756, 1663
1
(C¼¼O); H NMR (CDCl3): d 1.21 (m, 6H, CH3), 4.06 (q, J ¼ 7
Hz, 2H, CH2), 4.21 (q, J ¼ 7 Hz, 2H, CH2), 6.9–7.3 (m, 10H, phe-
nyl), 11.05 (bs, 1H, NH); 13C NMR (CDCl3): d 14.15, 14.27, 60.82,
61.51, 111.53, 126.24, 127.28, 128.03, 128.89, 131.96, 134.95,
135.52, 152.51, 152.88, 169.38. Anal. Calcd. for C20H21NO4: C,
70.78; H, 6.24; N, 4.13. Found: C, 70.82; H, 6.11; N, 4.34.
(Z)-Propyl 2,3-diphenyl-3-(propoxycarbonylamino)acrylate
(4e). Yield: 52%; mp 50–52ꢁC; IR (KBr, cmꢀ1): m 1752, 1658
(C¼¼O); 1H NMR (CDCl3): d 0.84 (t, J ¼ 7 Hz, 3H, CH3),
0.92 (t, J ¼ 7 Hz, 3H, CH3), 1.5–1.7 (m, 4H, CH2), 3.98 (t, J
¼ 7 Hz, 2H, CH2), 4.12 (t, J ¼ 7 Hz, 2H, CH2), 6.9–7.2 (m,
10H, phenyl), 11.1 (bs, 1H, NH). Anal. Calcd. for C22H25NO4:
C, 71.91; H, 6.86; N, 3.81. Found: C, 71.78; H, 6.56; N, 3.94.
(Z)-Isopropyl 3-(isopropoxycarbonylamino)-2,3-diphenyla-
crylate (4f). Yield: 56%; mp 98–100ꢁC; IR (KBr, cmꢀ1): m
1753, 1650 (C¼¼O); 1H NMR (CDCl3): d 1.18 (d, J ¼ 7 Hz,
6H, CH3), 1.2 (d, J ¼ 7 Hz, 6H, CH3), 4.81 (septet, J ¼ 7 Hz,
1H, CH), 5.10 (septet, J ¼ 7 Hz, 1H, CH), 6.9–7.2 (m, 10H,
phenyl), 11.0 (bs, 1H, NH). Anal. Calcd. for C22H25NO4: C,
71.91; H, 6.86; N, 3.81. Found: C, 72.19; H, 6.53; N, 3.68.
(Z)-Ethyl 3-(methoxycarbonylamino)-2,3-diphenylacrylate
(4c). Yield: 72.1%; mp 136–139ꢁC; IR (KBr, cmꢀ1): m 1751,
1664 (C¼¼O); 1H NMR (CDCl3): d 1.21 (t, J ¼ 7 Hz, 3H,
CH3), 3.64 (s, 3H, CH3), 4.21 (q, J ¼ 7 Hz, 2H, CH2), 6.9–7.3
(m, 10H, phenyl), 11.11 (bs, 1H, NH); 13C NMR (CDCl3): d
14.14, 52.55, 60.88, 111.79, 126.28, 127.33, 128.11, 128.88,
131.92, 134.77, 135.42, 152.34, 153.37, 169.37. Anal. Calcd.
for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.28;
H, 5.78; N, 4.46.
(Z)-Butyl
3-(butoxycarbonylamino)-2,3-diphenylacrylate
(4g). Yield: 42%; mp 46–48ꢁC; IR (KBr, cmꢀ1): m 1754, 1662
Scheme 6. Mechanistic formation of 1,3-oxazin-6-one ring.
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A. Assadieskandar, M. Amini, M. Haukka, and A. Shafiee
Vol 49
(C¼¼O); 1H NMR (CDCl3): d 0.88 (t, J ¼ 6.7 Hz, 3H, CH3),
0.92 (t, J ¼ 6.7 Hz, 3H, CH3), 1.27 (sextet, J ¼ 6.7 Hz, 2H,
CH2), 1.35 (sextet, J ¼ 6.7 Hz, 2H, CH2), 1.5–1.6 (m, 4H,
CH2), 4.02 (t, J ¼ 6.7 Hz, 2H, CH2), 4.17 (t, J ¼ 6.7 Hz, 2H,
CH2), 6.9–7.2 (m, 10H, phenyl), 11.09 (bs, 1H, NH). Anal.
Calcd. for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found: C,
72.65; H, 7.51; N, 3.75.
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1
m 1755, 1610 (C¼¼O); H NMR (CDCl3): d 1.22 (t, J ¼ 7 Hz,
3H, CH3), 1.25 (t, J ¼ 7 Hz, 3H, CH3), 2.87 (q, J ¼ 7 Hz,
2H, CH2), 4.06 (q, J ¼ 7 Hz, 2H, CH2), 6.9–7.3 (m, 10H, phe-
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Acknowledgment. This project was supported by grants from
Research Council of Tehran University of Medical Sciences and
INSF (Iran National Science Foundation).The authors thank Antti
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet