Synthesis and reactivity of 4-hydroxy-5-methyl-2-(2-oxo-2H-chromen-3-yl)-6H-1,3-oxazin-6-ones

Article abstract of DOI:10.1134/S1070363216060128

4-Hydroxy-6H-1,3-oxazin-6-ones with a coumarin fragment in position 2 of the oxazine ring were synthesized. Their hydrolysis, alcoholysis, and hydrazinolysis afforded a number of new coumarin derivatives containing malonamic acid and 1,2,4-triazole residu

Full text of DOI:10.1134/S1070363216060128

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 6, pp. 1292–1299. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © N.M. Chernov, P.V. Filippova, I.P. Yakovlev, V.E. Zakhs, A.V. Belyakov, 2016, published in Zhurnal Obshchei Khimii, 2016,
Vol. 86, No. 6, pp. 962–969.
Synthesis and Reactivity of 4-Hydroxy-5-methyl-2-(2-oxo-
2H-chromen-3-yl)-6H-1,3-oxazin-6-ones
N. M. Chernova, P. V. Filippovaa, I. P. Yakovleva, V. E. Zakhsa, and A. V. Belyakovb
a St. Petersburg State Chemical Pharmaceutical Academy,
ul. Professora Popova 14/A, St. Petersburg, 197376 Russia
e-mail: nikita.chernov@pharminnotech.com
b St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
Received February 18, 2016
Abstract—4-Hydroxy-6H-1,3-oxazin-6-ones with a coumarin fragment in position 2 of the oxazine ring were
synthesized. Their hydrolysis, alcoholysis, and hydrazinolysis afforded a number of new coumarin derivatives
containing malonamic acid and 1,2,4-triazole residues. The low stability of the title compounds toward oxygen-
centered nucleophiles was interpreted by quantum chemical calculations.
Keywords: 4-Hydroxy-6H-1,3-oxazin-6-one, coumarin, malonamic acid, 1,2,4-triazole, quantum chemical
calculations
DOI: 10.1134/S1070363216060128
Coumarin derivatives constitute an abundant group
of natural and synthetic compounds, many of which
exhibit important pharmacological activities. In parti-
cular, a number of indirect anticoagulants (e.g.,
warfarin) are 4-hydroxycoumarin derivatives. Nowa-
days, extensive search for biologically active sub-
stances is performed among coumarin derivatives
containing an amide or hydrazide moiety, as well as
nitrogen heterocycle residues, in the 3-position [1–4].
Such compounds were found to possess antitubercular
[1], antitumor [2, 3], and many other kinds of
biological activity [4].
According to published data, the Knoevenagel con-
densation of salicylaldehydes 1a–1c with cyano-
acetamide (2) is carried out in a two-phase system
water–methylene chloride (9 : 1) in the presence of a
phase-transfer catalyst. The subsequent acidification of
the reaction mixture leads to closure of pyran ring with
formation of coumarin-3-carboxamides 3a–3c in 84–
90% yield. Instead of cetyl(trimethyl)ammonium
bromide [8] or Katamin AB [9], as phase-transfer
catalyst we used more accessible benzyl(triethyl)-
ammonium chloride (BTEAC). In this case, the yields
of the target products did not decrease, and the
experimental procedure was not complicated. Addition
of methylene chloride to the reaction mixture made it
possible to accomplish the reaction with solid 5-bromo-
and 5-methylsalicylaldehydes 1a and 1c. The melting
On the other hand, 4-hydroxy-6H-1,3-oxazin-6-
ones are known to react with nucleophiles to give
various acyclic (malonamic acid derivatives [5]) and
heterocyclic systems (azoles [6], azines [7]). Herein,
we report the synthesis of 1,3-oxazines containing a
coumarin fragment and their reactions with nucleo-
philes with the goal of obtaining new biologically
active compounds.
1
point and H NMR spectrum of 3b coincided with
published data for 2-oxo-2H-chromene-3-carbox-
1
amide [9]. Apart from aromatic proton signals, the H
NMR spectrum of 3b characteristically showed two
broadened singlets due to protons of the NH2 group (δ
7.91 and 8.08 ppm) and 4-H signal at δ 8.86 ppm. The
structure of 3a–3c was also confirmed by 13C NMR
spectra and elemental analyses (Tables 1, 2).
A convenient procedure for the synthesis of 4-
hydroxy-6H-1,3-oxazin-6-ones is based on the well
studied reaction of the corresponding carboxylic acid
amides with malonyl chlorides [5, 7]. The required
coumarin-3-carboxamides 3a–3c were prepared by a
modified known procedure [8, 9] (Scheme 1).
Amides 3a–3c were reacted with methylmalonyl
chloride (4) in aprotic solvents such as carbon
1292

SYNTHESIS AND REACTIVITY OF 4-HYDROXY-5-METHYL-...
1293
Scheme 1.
O
O
(1) TEBAC, NaHCO3
R1
R1
CONH2
H2O−CH2Cl2
O
NH2
+
(2) 1 M HCl
OH
CN
O
3а−3c
2
1а−1c
R1 = Br (a), H (b), Me (c).
tetrachloride, benzene, 1,2-dichloroethane, and aceto-
nitrile at the boiling point. Acetonitrile turned out to be
the best solvent; it ensured reaction completion in 2–
3 h, and the yield of 1,3-oxazines 5a–5c was 76–84%
(Scheme 2). 1,2-Dichloroethane was less efficient: the
reactions were complete in 4–6 h, and the yields were
slightly lower (70–78%). Insofar as initial amides 3a–
3c are poorly soluble in carbon tetrachloride and
benzene, the reaction time in these solvents increased
to 8–10 h, and the yield of 5a–5c decreased to 20–
24%, which may be due to polymerization of methyl-
malonyl chloride on prolonged heating.
1
The H NMR spectra of 5a–5c contained signals
from aromatic protons of the coumarin fragment (δ
7.43–8.86 ppm), a singlet at δ 1.82–1.83 ppm from the
Table 1. Yields, melting points, and elemental analyses of compounds 3 and 5–10
Found, %
Calculated, %
H
Comp.
no.
Yield,
%
mp,
°С
R1
R2
R3
Formula
C
H
N
C
N
3а
3b
3c
Br
H
–
–
–
–
86
90
84
84
76
79
95
97
95
87
91
94
69
81
72
85
89
81
83
294–296
263–264
218–220
251–252
197–200
205–207
209–210
191–193
194–195
173–174
144–145
153–153
288–290
270–271
212–214
210–211
172–174
153–155
158–159
44.03
63.31
64.77
47.93
61.85
63.01
45.46
57.92
59.33
48.44
60.46
61.43
41.98
46.07
58.68
59.93
54.40
66.04
66.97
1.89
3.51
4.12
2.20
3.29
3.65
2.61
3.64
4.12
3.51
4.52
4.79
2.35
5.17 C10H6BrNO3
7.04 C10H7NO3
6.76 C11H9NO3
3.89 C14H8BrNO5
5.00 C14H9NO5
4.72 C14H11NO5
3.77 C14H10BrNO6
4.80 C14H11NO6
4.49 C15H13NO6
3.47 C16H14BrNO6
4.35 C16H15NO6
4.07 C17H17NO6
44.81
63.49
65.02
48.03
62.00
63.16
45.68
58.14
59.41
48.51
60.57
61.63
2.26
3.73
4.46
2.30
3.34
3.89
2.74
3.83
4.32
3.56
4.77
5.17
2.53
5.23
7.40
6.89
4.00
5.16
4.91
3.80
4.84
4.62
3.54
4.41
4.23
7.04
Me
Br
H
–
–
5а
–
–
5b
5c
–
–
Me
Br
H
–
–
6а
H
H
H
Et
Et
Et
–
–
6b
6c
–
Me
Br
H
–
7а
–
7b
7c
–
Me
Br
Br
H
–
8а
H
H
H
H
Ph
Ph
Ph
6.91 C14H10Br2N2O2 42.24
9а
–
2.53 11.21 C14H10BrN3O4
3.82 14.42 C14H11N3O4
4.17 13.86 C15H13N3O4
46.18
58.95
60.20
54.56
66.48
67.19
2.77 11.54
3.89 14.73
4.38 14.04
9b
9c
–
Me
Br
H
–
10а
10b
10c
–
2.98
9.33 C20H14BrN3O4
3.21
9.54
–
4.12 11.39 C20H15N3O4
4.36 10.97 C21H17N3O4
4.18 11.63
4.56 11.19
Me
–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1294
CHERNOV et al.
Table 2. 1H and 13C NMR spectra (DMSO-d6) of compounds 3 and 5–10
Comp.
no.
1H NMR spectrum, δ, ppm (J, Hz)
13C NMR spectrum, δC, ppm
3a
3b
3c
7.44 d (1H, 8-H, J = 8.8), 7.86 d.d (1H, 7-H, J = 2.4, 8.8), 7.97 br. s 117.0, 118.8, 120.8, 120.9, 132.5, 136.7,
(1H, NH), 8.04 br.s (1H, NH), 8.20 d (1H, 5-H, J = 2.4), 8.81 s (1H, 146.9, 153.5, 160.3, 162.7
4-H)
7.43 t (1H, 6-H, J = 7.8), 7.48 d (1H, 8-H, J = 7.8), 7.74 t (1H, 7-H, 116.6, 118.9, 119.7, 125.5, 130.7, 134.5,
J = 7.8), 7.91 br.s (1H, NH), 7.96 d (1H, 5-H, J = 7.8), 8.08 br.s 148.3, 154.5, 160.8, 163.0
(1H, NH), 8.86 s (1H, 4-H)
2.36 s (3H, CH3), 7.34 d (1H, 8-H, J = 8.5), 7.52 d.d (1H, 7-H, J = 20.7, 116.3, 118.6, 119.4, 130.1, 134.9,
1.3, 8.5), 7.68 d (1H, 5-H, J = 1.3), 7.90 br.s (1H, NH), 8.08 br.s 135.5, 148.2, 152.6, 160.9, 163.0
(1H, NH), 8.74 s (1H, 4-H)
5a
5b
5c
1.83 s (3H, CH3), 7.45 d (1H, 8-H, J = 8.8), 7.90 d (1H, 7-H, J = 8.6, 91.6, 117.0, 118.9, 119.0, 120.3, 132.6,
8.8), 8.25 s (1H, 5-H), 8.74 s (1H, 4-H), 12.66 br.s (1H, OH)
1.82 s (3H, CH3), 7.46 m (2H, 6-H, 8-H), 7.76 t (1H, 7-H, J = 8.0), 8.5, 91.2, 116.6, 117.8, 118.4, 118.6, 125.5,
7.97 d (1H, 5-H, J = 8.0), 8.78 s (1H, S4N), 12.65 br. s (1H, OH)
130.8, 135.1, 148.2, 154.5, 156.1, 158.4, 165.6
1.83 s (3H, CH3), 7.37 d (1H, 8-H, J = 8.5), 7.59 d (1H, 7-H, J = 8.4, 20.9, 90.5, 116.4, 118.7, 119.3, 130.4,
137.2, 146.8, 153.8, 155.6, 158.0, 162.0, 165.5
8.5), 7.75 s (1H, 5-H), 8.69 s (1H, 4-H), 12.65 br.s (1H, OH)
134.7, 135.6, 148.3, 152.5, 160.5, 162.2,
163.0, 165.6
6a
6b
1.29 d (3H, J = 7.0, CH3), 3.97 q (1H, J = 7.0, CH), 7.51 d (1H, J = 13.6, 48.0, 117.3, 119.1, 120.5, 122.1, 132.6,
8.8, 8-H), 7.93 d.d (1H, 7-H, J = 2.4, 8.8), 8.23 d (1H, 5-H, J = 2.4), 137.2, 146.3, 153.5, 159.4, 162.3, 171.1, 171.7
8.71 s (1H, 4-H), 11.30 s (1H, NH), 12.81 br.s (1H, COOH)
1.31 d (3H, CH3, J = 7.2), 4.01 q (1H, CH, J = 7.2), 7.48 t (1H, 6-H, 13.6, 48.1, 116.8, 118.6, 120.1, 125.9, 130.9,
J = 7.5), 7.54 d (1H, 8-H, J = 8.3), 7.80 t (1H, 7-H, J = 8.3), 7.98 d 135.3, 148.5, 154.4, 160.2, 162.1, 171.2,
(1H, 5-H, J = 8.3), 8.83 s (1H, 4-H), 11.29 s (1H, NH), 12.73 br.s 171.8.
(1H, COOH)
6c
7a
7b
1.31 d (3H, CH3, J = 7.3), 4.03 q (1H, CH, J = 7.3), 7.40 d (1H, 8- 13.6, 20.6, 48.2, 116.5, 118.4, 119.7, 130.3,
H, J = 8.4), 7.58 d (1H, 7-H, J = 8.4), 7.71 s (1H, 5-H), 8.74 s (1H, 135.3, 136.2, 148.7, 152.7, 160.3, 162.0,
4-H), 11.28 s (1H, NH), 12.71 br.s (1H, COOH)
171.1, 171.8.
1.19 t (3H, CH3CH2, J = 7.0), 1.32 d (3H, CH3, J = 7.3), 4.06 m 13.5, 14.4, 48.0, 61.3, 117.3, 119.1, 120.5,
(3H, CH3CH2, CH), 7.50 d (1H, 8-H, J = 8.8), 7.91 d (1H, 7-H, J = 121.9, 132.7, 137.2, 146.6, 153.5, 159.4,
8.8), 8.22 s (1H, 5-H), 8.71 s (1H, 4-H), 11.33 s (1H, NH)
162.3, 170.2, 170.7
1.14 t (3H, CH3CH2, J = 7.0), 1.29 d (3H, CH3, J = 7.2), 3.99 q (1H, 13.6, 14.4, 48.1, 61.5, 116.7, 118.7, 120.2,
CH, J = 7.2), 4.10 q (2H, CH3CH2, J = 7.0), 7.49 t (1H, 6-H, J = 125.8, 130.8, 135.2, 148.5, 154.4, 160.1,
7.5), 7.55 d (1H, 8-H, J = 8.3), 7.78 t (1H, 7-H, J = 7.8), 7.98 d (1H, 162.2, 171.1, 172.8
5-H, J = 7.8), 8.74 s (1H, 4-H), 11.22 s (1H, NH)
7c
1.19 t (3H, CH3CH2, J = 7.0), 1.30 d (3H, CH3, J = 7.3), 4.00 q (1H, 13.6, 14.4, 20.8, 48.2, 61.4, 116.6, 119.2,
CH, J = 7.3), 4.11 q (2H, CH3CH2, J = 7.0), 7.42 d (1H, 8-H, J = 120.8, 120.9, 132.4, 137.6, 146.3, 152.3,
8.4), 7.59 d (1H, 7-H, J = 8.4), 7.70 s (1H, 5-H), 8.72 s (1H, 4-H), 159.7, 162.2, 170.8, 172.6
11.32 s (1H, NH)
8a
9a
6.97 d (1H, 3-H, J = 8.8), 7.53 d. d (1H, 4-H, J = 2.0, 8.0), 7.90 d 111.0, 119.4, 121.1, 132.0, 135.9, 158.2,
(1H, 6-H, J = 2.0), 8.93 s (1H, CH=N), 11.18 br. s (1H, OH)
161.1
1.49 d (3H, CH3, J = 7.3), 3.92 q (1H, CH, J = 7.3), 7.45 d (1H, 8- 16.4, 39.3, 117.0, 117.1, 118.8, 121.1, 131.9,
H, J = 8.8), 7.82 d.d (1H, 7-H, J = 2.3, 8.8), 8.22 d (1H, 5-H, J = 135.6, 141.1, 151.1, 152.7, 158.1, 161.5,
2.3), 8.76 s (1H, 4-H), 12.24 br. s (1H, NH), 13.87 br.s (1H, COOH) 173.8
9b
9c
1.48 d (3H, CH3, J = 7.1), 3.90 q (1H, CH, J = 7.1), 7.43 t (1H, 6-H, 16.4, 39.3, 115.8, 116.6, 119.2, 125.4, 130.1,
J = 7.4), 7.50 d (1H, 8-H, J = 8.2), 7.70 t (1H, 7-H, J = 7.8), 7.99 d 133.4, 142.5, 150.4, 153.7, 158.6, 161.9,
(1H, 5-H, J = 7.8), 8.81 s (1H, 2-H), 12.85 br.s (2H, NH, COOH)
173.9
1.48 d (3H, CH3, J = 7.3), 3.91 q (1H, CH, J = 7.3), 7.39 d (1H, 8- 16.4, 20.8, 39.4, 115.7, 116.4, 118.9, 129.6,
H, J = 8.3), 7.51 d.d (1H, 7-H, J = 1.5, 8.3), 7.75 d (1H, 5-H, J = 134.4, 134.7, 142.5, 150.0, 151.9, 158.8,
1.5), 8.72 s (1H, 4-H), 12.33 br.s (1H, NH), 13.90 br.s (1H, COOH) 162.0, 173.8
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

SYNTHESIS AND REACTIVITY OF 4-HYDROXY-5-METHYL-...
1295
Table 2. (Contd.)
Comp.
no.
1H NMR spectrum, δ, ppm (J, Hz)
13C NMR spectrum, δC, ppm
10a
10b
10c
1.54 d (3H, CH3, J = 7.3), 4.07 q (1H, CH, J = 7.3), 7.42 d (1H, 8- 16.2, 37.5, 116.7, 118.7, 119.3, 121.1, 126.0,
H, J = 8.9), 7.62 m (5H, Ph), 7.80 d. d (1H, 7-H, J = 2.4, 8.9), 8.23 130.0, 130.1, 131.7, 135.3, 137.2, 141.7,
d (1H, 5-H, J = 2.4), 8.73 s (1H, 4-H), 12.96 br.s (1H, COOH)
153.00, 155.9, 156.5, 156.8, 172.3
1.55 d (3H, CH3, J = 7.3), 4.07 q (1H, CH, J = 7.3), 7.40 t (1H, 6-H, 16.2, 37.3, 116.4, 119.1, 119.2, 125.2, 126.1,
J = 7.5), 7.45 d (1H, 8-H, J = 8.3), 7.63 m (6H, Ph, 7-H), 7.96 d 130.0, 130.1, 130.3, 133.2, 137.0, 143.0,
(1H, 5-H, J = 7.5), 8.75 s (1H, 4-H), 12.81 br.s (1H, COOH)
153.5, 155.8, 156.3, 156.8, 172.4
1.54 d (3H, CH3, J = 7.3), 4.06 q (1H, CH, J = 7.3), 7.36 d (1H, 8- 16.2, 20.8, 37.4, 116.2, 118.7, 119.1, 125.9,
H, J = 8.2), 7.50 d.d (1H, 7-H, J = 1.5, 8.2), 7.63 m (5H, Ph), 7.73 d 129.3, 130.0, 130.2, 134.1, 134.5, 137.1,
(1H, 5-H, J = 1.5), 8.68 s (1H, 4-H), 12.78 br.s (1H, COOH)
142.9, 153.3, 155.6, 156.4, 156.6, 172.2
5-methyl group, and a broadened singlet of the
hydroxy proton at δ 12.65–12.66 ppm. In the 13C NMR
spectra of these compounds, the 5-CH3 and C5 carbon
nuclei resonated at δC 8.4–8.6 and 90.5–91.6 ppm,
respectively, and signals of C2, C4, and C6 of the
oxazine ring were located in the downfield region (δC
156.1–165.6 ppm). The structure of 5a–5c was also
confirmed by elemental analyses (Tables 1, 2) and by
the high-resolution mass spectrum of 5b.
6c. Complete hydrolysis of 5a–5c with quantitative
formation of 6a–6c was also observed on exposure to
atmospheric moisture for 10–12 days. Further studies
showed that oxazines 5a–5c equally readily (at room
temperature) reacted with another O-nucleophile,
ethanol, to form malonamic acid esters 7a–7c which
were isolated in 87–94% yield (Scheme 3).
It should be noted that such hydrolytic stability is
not typical of 2-aryl- and 2-styryl-substituted 4-
hydroxy-5-methyl-6H-1,3-oxazin-6-ones [6]. The
latter do react with O-nucleophiles to give products of
oxazine ring cleavage at the C6–O bond [5, 6], the
corresponding malonamic acids or their esters
analogous to 6 and 7. However, these reactions occur
under more severe conditions, on heating in aqueous
While determining the structure of we have noticed
their anomalously low hydrolytic stability. Compounds
5a–5c underwent partial or complete hydrolysis via
cleavage of the C6–O bond during recording their
NMR spectra in DMSO containing traces of water. The
hydrolysis products were N-acylmalonamic acids 6a–
Scheme 2.
O
N
O
CH3
OH
Cl
O
O
CH CN, Δ
3
3а−3c
+
CH3
R1
Cl
O
O
4
5а−5c
Scheme 3.
O
O
O
O
R2OH
R1
OR2
5а−5c
N
H
CH3
O
6а−6c, 7а−7c
R2 = H (6а−6c), Et (7а−7c).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1296
CHERNOV et al.
Scheme 4.
R3
N
N
CH3
OH
AcOH
R1
N
O
O
O
3
R NHNH
2
9а−9c, 10а−10c
5а−5c
HO
MeOH
Br
N
N
1
Br
R = Br
3
R = H
OH
8а
R3 = H (9), Ph (10).
acetonitrile or in alcohols at the boiling point for 1–
2 h.
5c: the corresponding carbon nuclei resonated in the
13C NMR spectra at δC 13.4–16.2 (CH3) and 37.5–
48.2 ppm (CH). Malonamic acid derivatives 6 and 7
showed a singlet at δ 11.22–11.33 ppm in the 1H NMR
spectra due to the NH proton, and triazoles 9 and 10
showed a broadened singlet at δ 12.85–13.87 ppm due
to hydroxy proton of the COOH group). Signals in the
region δC 155.9–158.8 ppm were assigned to carbon
atoms of the triazole ring.
As shown previously [5, 6], reactions of 4-hydroxy-
6H-1,3-oxazin-6-ones react with binucleophiles, such
as hydrazines and guanidine, in methanol involve
opening of the oxazine ring via cleavage of the C2–O
bond usually with subsequent recyclization to azole or
azine heterocyclic system. Analogous reaction of 5a
with hydrazine in methanol resulted in decomposition
of the pyran ring with formation of aldehyde azine 8a
as the major product (yield 69%; Scheme 4).
Compound 8a was identified by comparing its melting
point and 1H NMR data with those reported in [10] for
5-bromosalicylaldehyde azine. According to published
data [10, 11], such behavior is typical of 3-acetyl-
coumarin and coumarin-3-carboxylic acid derivatives.
Oxazines 5a–5c can also be regarded as analogs of the
latter. When the reactions of 5a–5c with hydrazine and
phenylhydrazine were carried out in glacial acetic acid,
the nucleophilic attack was directed mainly at C2 of the
oxazine ring, and the final products were coumarin-
containing 1,2,4-triazole derivatives 9a–9c and 10a–
10c (yield 72–89%; Scheme 4).
Our results led us to conclude that the presence of a
coumarin fragment in the 2-position strongly affects
the chemical behavior of the 1,3-oxazine system. Pre-
sumably, the 2-substituent affects geometric param-
eters of the oxazine ring in 5a–5c, which largely
determine their reactivity toward O-nucleophiles. In
order to evaluate the effect of the 2-substituent we
performed B3LYP/6-31+G(d,p) quantum chemical
calculations (GAUSSIAN 09 A.02 [12]) of the
geometric parameters and free energies of tautomeric
forms of 2-coumarinyloxazine (A and A*) and 2-
phenyloxazine (B and B*). While optimizing the
geometric parameters, stationary points on the
potential energy surfaces were identified as energy
minima by the absence of imaginary vibration
frequencies in the corresponding Hessian matrices.
The structure of 6a–6c, 7a–7c, 9a–9c, and 10a–10c
1
was confirmed by elemental analyses and H and 13C
NMR spectra (Tables 1, 2). Compound 9b was also
We previously showed [13] by both theoretical and
experimental methods that 4-hydroxy-1,3-oxazin-6-
ones exist preferentially as 4-hydroxy-6-oxo tautomers
(A and B) among four theoretically possible ones. One
of the minor tautomers which could exist in
equilibrium with the major form is dipolar ion A* or
characterized by the high-resolution mass spectrum. In
1
the H NMR spectra of 6, 7, 9, and 10 we observed
two signals belonging to a CH3CH fragment (a doublet
at δ 1.29–1.54 ppm and a quartet at δ 3.90–4.07 ppm)
instead of 5-CH3 singlet typical of initial oxazines 5a–
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SYNTHESIS AND REACTIVITY OF 4-HYDROXY-5-METHYL-...
1297
Scheme 4.
O
O
CH3
CH3
O−
O
O
O
O
ΔG = 7.97 kJ/mol
+
N
OH
N
H
O
O
O
А*
А
O
O
CH3
OH
CH3
O−
O
ΔG = 34.06 kJ/mol
+
N
N
H
B
B*
B*. On the basis of the calculated Gibbs energies we
estimated the compositions of tautomeric mixtures A/A*
and B/B* (χ, %) by the equation ΔG = –R T ln K
(Table 3). It is seen that the transformation of tautomer
A of 5b into structure A* should be relatively facile
and that analogous transformation of 2-phenyloxazine
is hindered. The equilibrium concentration of A* is
3.85%, whereas zwitterionic tautomer B* of 2-
phenyloxazine is almost absent in the equilibrium
mixture. This difference in the tautomeric composi-
tions may be related to the effect of the oxo group in
the coumarin fragment of 5b, which stabilizes structure
A* due to formation of hydrogen bond C=O···H–N
(d = 1.962 Å). The formation of this hydrogen bond
was confirmed by topological analysis of electron
density distribution in tautomer A* by the atoms-in-
molecules method [14] (AIMAll [15]) (see figure). A
critical point of the (3, –1) type was found for tautomer
A*, which corresponded to N–H···O hydrogen
bonding. The bond energy was determined from the
potential energy density at the critical point according
to the procedure described in [16], EHB = 28.4 kJ/mol.
tion of A into A* is accompanied by appreciable
elongation of C6–O in 5b (from 1.433 to 1.618 Å);
simultaneously, the C6–O bond order decreases.
Analogous pattern was observed for tautomers B and
B* of 2-phenyloxazine. Thus, dissociation of the C6–O
bond in dipolar tautomers A* and B* is much easier
than in major 4-hydroxy-6-oxo tautomers A and B, and
the low stability of 5a–5c toward hydrolysis and
alcoholysis is determined by the presence of dipolar
tautomer A* which readily undergoes ring opening
because of low strength of the C6–O bond.
In summary, we have synthesized for the first time
4-hydroxy-6H-1,3-oxazin-6-one derivatives containing
a coumarin fragment in the 2-position of the oxazine
ring. These compounds react with with nucleophiles to
give previously unknown coumarin derivatives posses-
sing malonamic acid and 1,2,4-triazole fragments.
Taking into account published data [1–4], the syn-
thesized compounds attract interest as potential
biologically active substances with antitumor, anti-
tubercular, and other valuable therapeutic properties.
Assuming that reactions of 1,3-oxazines 5a–5c with
O-nucleophiles are favored by anomalously high
concentration of dipolar structure A*, we compared the
reactivities of tautomers A and A*. As we already
noted, the hydrolysis and alcoholysis of 1,3-oxazines
involves cleavage of the C6–O bond. Its strength was
quantitatively assessed by its length and order in
structures A/A* and B/B* (Table 3). The bond orders
were calculated according to Wiberg using the NBO
(natural bond orbital) module implemented in
Gaussian 09. The results showed that the transforma-
Table 3. Characterisitc of tautomers A/A* and B/B*
Oxazin 5b 2-Phenyloxazine
Parameter
A
A*
7.973
B
B*
Gibbs energy ΔG, kJ/
34.059
99.9999 0.0001
mol
Equilibrium concentration 96.15 3.85
χ, %
Bond length C6–O, Å
1.433 1.618 1.435 1.613
0.840 0.579 0.838 0.587
Bond order C6–O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1298
CHERNOV et al.
Topological analysis of tautomer A*.
According to quantum chemical calculations, high
reactivity of coumarin-containing 1,3-oxazines toward
O-nucleophiles is related to their partial existence as
reactive zwitterionic tautomers.
Coumarin-3-carboxamides 3b and 3c were
synthesized in a similar way.
4-Hydroxy-5-methyl-2-(2-oxo-2H-chromen-3-yl)-
6H-1,3-oxazin-6-one (5b). A mixture of 1.5 g (8 mmol)
of amide 3b and 1.8 g (12 mmol) of methylmalonyl
chloride (4) in 20 mL of anhydrous acetonitrile was
refluxed for 2–3 h (until the initial amide disappeared
according to the TLC data). The mixture was cooled,
and the yellow precipitate was filtered off, washed
with acetonitrile, and dried in a vacuum desiccator
over phosphoric anhydride. Yield 1.7 g (76%). Mass
spectrum (HRMS ESI): m/z 294.0377 [M + Na]+;
calculated for C14H9NNaO5: 294.0374.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded from
solutions in DMSO-d6 on a Bruker Avance III
spectrometer (400 and 100 MHz, respectively), using
the residual proton and carbon signals of the solvent as
reference. The elemental analyses were obtained on a
LECO CHNS-932 analyzer. The mass spectra were
recorded on a Bruker micrOTOF instrument (electro-
spray ionization, positive ion detection). The purity of
the isolated compounds was checked, and the progress
of reactions was monitored, by thin-layer chromato-
graphy on Silica gel 60 F254 plates (Merck) using
ethyl acetate as eluent; spots were visualized under UV
light. The solvents were purified and dried by standard
methods. The yields, melting points, and analytical
data of compound 5–10 are given in Table 1, and their
spectral parameters are presented in Table 2.
Oxazines 5a and 5c were synthesized in a similar way.
3-[(6-Bromo-2-oxo-2H-chromen-3-ylcarbonyl)-
amino]-2-methyl-3-oxopropanoic acid (6a). Oxazine
5a, 1.4 g (4 mmol), was kept on exposure to air for 10–
12 days (TLC). Yield 1.4 g (95%).
N-Acylmalonamic acids 6b and 6c were syn-
thesized in a similar way.
Ethyl 3-[(6-bromo-2-oxo-2H-chromen-3-ylcar-
bonyl)amino]-2-methyl-3-oxopropanoate (7a).
A
6-Bromo-2-oxo-2H-chromene-3-carboxamide (3a).
A mixture of 20 g (10 mmol) of 5-bromosalicyl-
aldehyde (1a), 12.6 g (15 mmol) of cyanoacetamide
(2), 2.3 g (1 mmol) of benzyl(triethyl)ammonium
chloride, 5 g of sodium hydrogen carbonate, 450 mL of
water, and 50 mL of methylene chloride was stirred for
3 h at 18–20°C. The mixture was acidified with 1 M
aqueous HCl to pH 2–3 and heated for 2 h at 60–65°C.
The mixture was then cooled, and the white solid was
filtered off, washed with water, and dried at 50°C.
Yield 23.0 g (86%).
suspension of 1.4 g (4 mmol) of oxazine 5a in 10 mL
of ethanol was stirred for 3–4 h. When the reaction
was complete, the precipitate was filtered off and dried
in air. Yield 1.4 g (87%).
Esters 7b and 7c were synthesized in a similar way.
5-Bromosalicylaldehyde azine (8a). A mixture of
1.4 g (4 mmol) of oxazine 5a and 200 μL (200 mg,
4 mmol) of hydrazine hydrate in 10 mL of methanol
was stirred for 12 h until the initial oxazine
disappeared (TLC). The precipitate was filtered off,
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SYNTHESIS AND REACTIVITY OF 4-HYDROXY-5-METHYL-...
1299
8. Brufola, G., Fringuelli, F., Piermatti, O., and Pizzo, F.,
Heterocycles, 1996, vol. 43, no. 6, p. 1257. DOI:
10.3987/COM-96-7447.
washed with methanol, and dried in air. Yield 0.55 g
(69%), mp 288–290°C [10].
2-[3-(2-Oxo-2H-chromen-3-yl)-1H-1,2,4-triazol-
5-yl]propanoic acid (9b). A mixture of 1.1 g (4 mmol)
of oxazine 5b and 200 μL (200 mg, 4 mmol) of
hydrazine hydrate in 10 mL of glacial acetic acid was
stirred for 2–3 days (TLC). The white solid was
filtered off, washed with acetic acid, and dried under
reduced pressure. Yield 0.9 g (72%). Mass spectrum
(HRMS ESI): m/z 308.0640 [M + Na]+; calculated for
C14H11N3NaO4: 308.0642.
9. Avetisyan, A.A., Aleksanyan, I.L., and Alvandzhyan, A.G.,
Chem. Heterocycl. Compd., 1996, vol. 32, no. 7, p. 773.
10. Yaragatti, N.B., Kulkarni, M.V., Kumar, G.N.A., and
Gururow, T.N., Lett. Org. Chem., 2012, vol. 9, p. 594.
DOI: 10.2174/157017812802850294.
11. Soliman, F.S.G., Labouta, I.M., and Stadlbauer, W.,
Arch. Pharm. Chemi, Sci. Ed., 1985, vol. 13, p. 49.
12. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V.,
Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M.,
Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J.,
Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M.,
Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T.,
Montgomery, J.A., Jr., Peralta, J.E., Ogliaro, F.,
Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N.,
Staroverov, V.N., Kobayashi, R., Normand, J.,
Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S.,
Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M.,
Knox, J.E., Cross, J.B., Bakken, V., Adamo, C.,
Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O.,
Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W.,
Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A.,
Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D.,
Farkas, Ö., Foresman, J.B., Ortiz, J.V., Cioslowski, J.,
and Fox, D.J. Gaussian 09, Revision A.02, Wallingford
CT: Gaussian, 2009.
Triazoles 9a, 9c and 10a–10c were synthesized in a
similar way. In the synthesis of 1-phenyl-1,2,4-
triazoles 10a–10c phenylhydrazine was used instead of
hydrazine hydrate.
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