Synthesis of New 2-Substituted 5-Hydroxypyrano[2,3-d][1,3]oxazine-4,7-diones

Article abstract of DOI:10.1134/S1070363220040325

Abstract: The reaction of carboxylic acid amides with malonyl chloride in acetonitrile or tetrahydrofuran without heating leads to the formation of previously unknown 2-substituted 5-hydroxypyrano[2,3-d][1,3]oxazines. The structure of the obtained compoun

Full text of DOI:10.1134/S1070363220040325

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 757–759. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 4, pp. 650–653.
LETTERS
TO THE EDITOR
Synthesis of New 2-Substituted
5-Hydroxypyrano[2,3-d][1,3]oxazine-4,7-diones
V. O. Komissarova,*, N. M. Chernova, G. L. Starovab, T. L. Semakovaa, G. V. Ksenofontovaa,
V. E. Zakhsa, and I. P. Yakovleva
a St. Petersburg State University of Chemistry and Pharmacy, St. Petersburg, 197376 Russia
b St. Petersburg State University, St. Petersburg, 198504 Russia
*e-mail: vladimir.olegovich51@gmail.com
Received February 5, 2020; revised February 7, 2020; accepted February 8, 2020
Abstract—The reaction of carboxylic acid amides with malonyl chloride in acetonitrile or tetrahydrofuran without
heating leads to the formation of previously unknown 2-substituted 5-hydroxypyrano[2,3-d][1,3]oxazines. The
structure of the obtained compounds was established by high resolution mass spectrometry, NMR spectroscopy,
and X-ray analysis.
Keywords: pyrano[2,3-d][1,3]oxazine, malonyl chloride, X-ray analysis
DOI: 10.1134/S1070363220040325
Oxo derivatives of 1,3-oxazines are important reagents
for organic synthesis. Molecules of 1,3-oxazin-4-ones
possess three electrophilic centers, and their reactions
with nucleophiles lead to the formation of various acyclic
and heterocyclic compounds, in particular malonamic
acid derivatives exhibiting hypotensive activity [1] and
1,2,4-triazoles with antiviral activity [2]. On the other
hand, related fused structures, pyranooxazines, have been
poorly studied.
unknown heterocyclic system, pyrano[2,3-d][1,3]-
oxazines 4a–4h [4] (Scheme 1).
Thus, we have found that carboxylic acid amides
2a–2h react with 2 equiv of malonyl chloride in
acetonitrile or tetrahydrofuran at room temperature
to afford 2-substituted 5-hydroxypyrano[2,3-d][1,3]-
oxazine-4,7-diones [5]. The presence of five electrophilic
centers in their molecules makes them valuable substrates
for reactions with various nucleophiles and potential
precursors to new privileged heterocyclic structures.
Ziegler and Meindl [3] previously reported the reaction
of carboxylic acid amides 2a and 2b with malonyl
chloride (1), which led to the formation of 2-substituted
4-hydroxypyrano[3,4-e][1,3]oxazine-5,7diones 3a and 3b
(Scheme 1). The reactions were carried out under fairly
harsh conditions, on heating without a solvent.
In continuation of studies in this field, amides 2a–2h
were reacted with malonyl chloride 1 at a molar ratio
of 1 : 2 in acetonitrile or tetrahydrofuran 20–25°C. The
isolated products were characterized by high-resolution
mass spectrometry and NMR. According to the HRMS
data, compounds 4a and 4b had the same elemental
compositions as pyranooxazines 3a and 3b described in
[3]. However, the X-ray analysis of a single crystal of
p-bromophenyl derivative 4e (Fig. 1) showed that the
isolated compounds are representatives of previously
Fig. 1. Structure of the molecule of 2-(4-bromophenyl)-5-
hydroxypyrano[2,3-d][1,3]oxazine-4,7-dione (4e) in crystal
according to the X-ray diffraction data.
757

758
KOMISSAROV et al.
Scheme 1.
O
O
O
O
O
Cl
Cl
O
50ꢀ70o
C
N
O
2
+
R
without solvent
NH2
2a 2h
R
OH
3a, 3b
ꢀ
1
O
O
20ꢀ25oC
MeCN or THF
N
OH
R
O
O
4a 4h
ꢀ
R = Ph (ɚ), 4-MeC6H4 (b), 4-MeOC6H4 (c), 4-NO2C6H4 (d), 4-BrC6H4 (e), 3-MeOC6H4 (f),
PhCH=CH (g), furan-2-yl (h).
5-Hydroxy-2-phenylpyrano[2,3-d][1,3]oxazine-4,7-
spectrum, δC, ppm: 49.66, 89.27, 93.73, 115.39, 129.83,
131.81, 154.38, 159.93, 163.49, 165.63, 167.68, 168.77.
Mass spectrum: m/z 286.0341 [M – H]–; calculated for
C14H8NO6: 286.0357.
dione (4a). A solution of 9.4 g (20 mmol) of malonyl
chloride in 25 mL of anhydrous tetrahydrofuran was
slowly added dropwise to a cold suspension of 4 g
(10 mmol) of amide 2a in 25 mL of anhydrous
tetrahydrofuran. Amide 2a dissolved during the addition
process. The mixture was stirred for 18 h at room
temperature, and the precipitate was filtered off, washed
with tetrahydrofuran, and dried. Yield 5.7 g (67%), mp
5-Hydroxy-2-(4-nitrophenyl)pyrano[2,3-d][1,3]-
oxazine-4,7-dione (4d). Yield 4.15 g (57%), mp 214–
216°C. 1H NMR spectrum, δ, ppm: 5.57 s (1H, 6-H), 8.15 d
(2H, Harom, J = 8.8 Hz), 8.42 d (2H, Harom, J = 8.8 Hz),
13.30 s (1H, OH). 13C NMR spectrum, δC, ppm: 83.07,
89.83, 124.65, 129.56, 139.35, 150.30, 159.59, 159.99,
163.97, 168.72, 170.97. Mass spectrum: m/z 301.0114
[M – H]–; calculated for C13H6N2O7: 301.0102.
1
218–220°C. H NMR spectrum, δ, ppm: 5.50 s (1H,
6-H), 7.52 m (2H, Ph), 7.79 m (1H, Ph), 8.20 m (2H, Ph),
12.77 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 88.53,
93.38, 127.32, 128.07, 131.59, 135.01, 154.43, 154.68,
165.87, 167.59, 168.46. Mass spectrum: m/z 256.0248
[M – H]–; calculated for C13H6NO5: 256.0251.
2-(4-Bromophenyl)-5-hydroxypyrano[2,3-d][1,3]-
oxazine-4,7-dione (4e). Yield 4.15 g (62%), mp 220–
222°C. 1H NMR spectrum, δ, ppm: 5.52 s (1H, 6-H), 7.86
d (2H, Harom, J = 8.5 Hz), 8.10 d (2H, Harom, J = 8.5 Hz),
12.89 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 89.77,
93.92, 128.28, 129.53, 131.13, 133.04, 154.13, 159.78,
165.04, 167.36, 168.74. Mass spectrum: m/z 333.9357
[M – H]–; calculated for C13H6NO5Br: 333.9357.
Compounds 4b–4h were synthesized in a similar way.
5-Hydroxy-2-(4-methylphenyl)pyrano[2,3-d]-
[1,3]oxazine-4,7-dione (4b). Yield 5.79 g (72%), mp
210–212°C. 1H NMR spectrum, δ, ppm: 2.44 s (3H, Me),
5.47 s (1H, 6-H), 7.46 d (2H, Harom, J = 8.3 Hz), 8.09 d
(2H, Harom, J = 8.3 Hz), 12.65 br.s (1H, OH). 13C NMR
spectrum, δC, ppm: 21.53, 88.66, 93.32, 129.46, 130.08,
130.51, 143.77, 154.39, 154.64, 165.92, 167.72, 168.59.
Mass spectrum: m/z 270.0401 [M – H]–; calculated for
C14H8NO5: 270.0408.
5-Hydroxy-2-(3-methoxyphenyl)pyrano[2,3-d][1,3]-
oxazine-4,7-dione (4f). Yield 5.33 g (70%), mp 224–
1
226°C. H NMR spectrum, δ, ppm: 3.87 s (3H, MeO),
5.50 s (1H, 6-H), 7.35 m (1H), 7.56 pseudo-t (1H, J =
7.8 Hz), 7.62 m (1H), 7.78 m (1H, Harom), 12.77 br.s
(1H, OH). 13C NMR spectrum, δC, ppm: 55.98, 89.87,
93.69, 113.36, 121.62, 121.82, 130.29, 131.10, 154.19,
159.75, 160.07, 165.54, 167.40, 168.52. Mass spectrum:
m/z 286.0361 [M – H]–; calculated for C14H8NO6:
286.0357.
5-Hydroxy-2-(4-methoxyphenyl)pyrano[2,3-d]-
[1,3]oxazine-4,7-dione (4c). Yield 5.94 g (78%), mp
1
221–223°C. H NMR spectrum, δ, ppm: 3.81 s (3H,
MeO), 5.53 s (1H), 6.97 d (2H, Harom, J = 8.8 Hz), 7.85 d
(2H, Harom, J = 8.8 Hz), 12.84 br.s (1H, OH). 13C NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020

SYNTHESIS OF NEW 2-SUBSTITUTED
759
1158.59(5) Å3; Z = 4; μ(MoKα) = 3.568 mm–1; dcalc
=
1.927 g/cm3. Total of 11710 reflection intensities were
measured in the range 6.624° ≤ 2θ ≤ 55°), including 2661
independent reflections (Rint= 0.0400, Rσ = 0.0317) which
were used in all calculations; final divergence factors:
R1 = 0.0275 [reflections with I > 2σ(I)], wR2 = 0.0658
(all independent reflections). The X-ray diffraction data
were deposited to the Cambridge Crystallographic Data
Centre (CCDC entry no. 1941265).
5-Hydroxy-2-(2-phenylethenyl)pyrano[2,3-d][1,3]-
oxazine-4,7-dione (4g). Yield 5.04 g (65%), mp 110–
1
112°C. H NMR spectrum, δ, ppm: 5.60 s (1H, 6-H),
7.05 d (1H, CH=CH, J = 16.1 Hz), 7.47 m (3H, Harom),
7.88 m (2H, Harom), 7.99 d (1H, CH=CH, J = 16.1 Hz),
12.86 br.s (1H, OH). 13C NMR spectrum, δC, ppm: 89.59,
93.33, 118.47, 128.65, 129.59, 132.02, 134.33, 146.88,
154.33, 159.89, 166.21, 167.43, 168.68. Mass spectrum:
m/z 282.0409 [M – H]–; calculated for C15H8NO5:
282.0408.
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
REFERENCES
2-(Furan-2-yl)-5-hydroxypyrano[2,3-d][1,3]-
oxazine-4,7-dione (4h). Yield 6.77 g (76%), mp 178–
180°C. 1H NMR spectrum, δ, ppm: 5.45 s (1H), 6.91 d
(1H, HFu, J = 3.8 Hz), 7.75 d (1H, HFu, J = 3.8 Hz), 8.25 s
(1H, HFu), 12.73 br.s (1H, OH). 13C NMR spectrum,
δC, ppm: 89.40, 93.14, 114.55, 122.19, 143.76, 151.01,
153.71, 157.47, 159.74, 167.50, 168.61. Mass spectrum:
m/z 246.0037 [M – H]–; calculated for C11H4NO6:
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020