Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with O-nucleophiles

Article abstract of DOI:10.1134/S1070363210100269

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with oxygen-centered nucleophiles were studied. 2-Alkoxy-4-hydroxy-6H-1,3- oxazin-6-ones reacted with water and alcohols to give the corresponding alkyl 3-amino-3-oxopropanoates as

Full text of DOI:10.1134/S1070363210100269

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 10, pp. 2043–2047. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © B.Yu. Lalaev, I.P. Yakovlev, N.N. Kuz’mich, G.V. Ksenofontova, V.E. Zakhs, 2010, published in Zhurnal Obshchei Khimii, 2010,
Vol. 80, No. 10, pp. 1734–1738.
Reactions of 2-Alkylsulfanyl- and 2-Alkoxy-4-hydroxy-
6H-1,3-oxazin-6-ones with O-Nucleophiles
B. Yu. Lalaev, I. P. Yakovlev, N. N. Kuz’mich, G. V. Ksenofontova, and V. E. Zakhs
St. Petersburg State Chemical and Pharmaceutical Academy, ul. Professora Popova 14, St. Petersburg, 197376 Russia
e-mail: lalaevb80@mail.ru
Received March 11, 2010
Abstract—Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with oxygen-centered
nucleophiles were studied. 2-Alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones reacted with water and alcohols to give
the corresponding alkyl 3-amino-3-oxopropanoates as a result of opening of the oxazine ring at the C6–O bond,
whereas their 2-alkylsulfanyl analogs turned out to be stable toward O-nucleophiles. The different reactivities
of the title compounds were interpreted in terms of quantum-chemical calculations of their electronic structure.
DOI: 10.1134/S1070363210100269
2-Alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-
oxazin-6-ones were synthesized by us for the first time
by reactions of the corresponding alkyl carbamates and
S-alkyl thiocarbamates Ia–Ic with malonyl chlorides
IIa–IIe [1, 2] (Scheme 1).
The oxazine ring in molecules IIIa–IIIi possesses
three evident electron-deficient centers, C2, C4, and C6,
which could be responsible for their reactions with
nucleophilic reagents [3–5]. Taking the above stated
into account, we examined reactions of oxazines IIIa–
IIIi with oxygen-centered nucleophiles, such as water,
methanol, and ethanol. The reactions of 2-alkoxy-4-
hydroxy-6H-1,3-oxazin-6-ones IIIa–IIIf with water
and alcohols involved cleavage of the oxazine ring at
the C6–O bond with formation of malonamic acid
esters IVa–IVg as shown in Scheme 2.
Scheme 1.
OH
O
R2
O
R2
O
N
Cl
+
R1X
NH2
Ia_Ic
R1X
O
O
Cl
IIa_IIe
IIIa_IIIi
Scheme 3 illustrates a probable reaction me-
chanism. Oxazines IIIa–IIIg reacted with aqueous
dioxane (100°C) or boiling alcohol to give, respect-
tively, the corresponding N-alkoxycarbonylmalonamic
acid A or its ester B as a result of cleavage of the C6–O
bond. The subsequent attack on acid A with water
I, X = O: R1 = Me (a), Et (b); X = S, R1 = Me (I); II, R2 =
Me (a), Et (b), Bu (c), cyclo-C6H11 (d), PhCH2 (e); III, X =
O: R1 = R2 = Me (a), R1 = Me, R2 = Et (b); R1 = Et, R2 = Me
(c), Et (d), Bu (e), cyclo-C6H11 (f), PhCH2 (g); X = S: R1 =
R2 = Me (h), R1 = Me, R2 = Ph (i).
Scheme 2.
O
O
O
R3 = H
OH
O
H2N
H2N
OR1
R2
R2
R3OH
N
IVa_IVg
O
R1
OH
IIIa_IIIg
R3 = Me, Et
OR3
R2
IVa_IVg
III, R1 = MeO: R2 = Me (a), Et (b), R1 = EtO, R2 = Me (c), Et (d), Bu (e), cyclo-C6H11 (f), PhCH2 (g); IV, R1 (R3) = Me, R2 =
Me (a), Et (b), R1 (R3) = Et, R2 = Me (c), Et (d), Bu (e), cyclo-C6H11 (f), PhCH2 (g).
2043

2044
LALAEV et al.
molecule generates unstable alkyl hydrogen carbonate
C which undergoes decarboxylation with liberation of
alcohol, and the latter reacts with malonamic acid E to
produce ester IVa–IVg. In the reactions of oxazines III
with alcohols, excess alcohol reacts with ester B
yielding more stable dialkyl carbonate D and malon-
amic acid ester IVa–IVg. Thus the reactions of 2-al-
koxy-4-hydroxy-6H-1,3-oxazin-6-ones IIIa–IIIg with
water and alcohols afforded only malonamic acid
esters IVa–IVg. 2-Alkylsulfanyl-substituted oxazines
IIIh and IIIi failed to react with water or alcohols
under analogous conditions.
Scheme 3.
OH
O
O
O
R2
O
O
O
O
R3OH, Δ
H2O, 100°C
N
R1O
N
OH
6
R1O
N
OR3
a
C
b
R1O
O
H
R2
H
R2
IIIа–IIIg
B
A
O
O
R1O
H2O
R3OH
1
–
R O
OH
C
OR3
D
–CO2
O
O
O
O
–R1OH
H2N
OH
H2N
OR3(R1)
R2
R2
IVа–IVg
E
In order to rationalize different reactivities of 2-
alkoxy- IIIa–IIIg and 2-sulfanyloxazines IIIh and IIIi
toward O-nucleophiles, we performed quantum-
chemical calculations (Gaussian 03) of electronic
structure of their molecules. The electron density in
molecules IIIa–IIIf is distributed in such a way that
the C2, C4, and C6 atoms are clearly electrophilic;
therefore, they can be involved in reactions with
various nucleophiles. The geometric parameters of 4-
hydroxy-2-methoxy-5-methyl-6H-1,3-oxazin-6-one
(IIIa) and 4-hydroxy-5-methyl-2-methylsulfanyl-6H-
1,3-oxazin-6-one (IIIh) were optimized at the DFT/
B3LYP level of theory using 6-31+G** basis set [6–9].
In addition, the effective charges on atoms in the
heteroring were calculated in terms of the NPA (natural
population analysis) method at the MP2/6-31+G**
level (Table 1), and topology of electron density dis-
tribution was simulated in terms of the AIM theory
Table 1. NPA charges (q) and bond ellipticities (εb) at the bond critical points of oxazines IIIa and IIIh
OH
OH
4
4
CH3
O
CH3
O
3N
3N
5
5
2
2
6
6
H3CO
O
H3CS
O
1
1
IIIa
IIIh
q
εb
Atom
O1
Bond
IIIa
IIIh
IIIa
IIIз
–0.617
–0.517
O1–C2
0.114
0.085
C2
N3
1.117
0.400
C2–N3
N3–C4
0.312
0.113
0.216
0.058
–0.766
–0.586
C4
C5
C6
0.694
–0.368
0.948
0.528
–0.248
0.743
C4–C5
C5–C6
C6–O1
0.383
0.210
0.027
0.490
0.230
0.215
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REACTIONS OF 2-ALKYLSULFANYL-
2045
Table 2. Yields, melting points, Rf values, and elemental analyses of compounds IVa–IVg
Found, %
Calculated, %
Comp.
no.
Yield, %
mp, °C
Rfa
Formula
C
H
N
C
H
N
11.5
102–104
90–92
75 (a), 70 (b)
79 (a), 82 (b)
77 (a), 71 (b)
70 (a), 80 (b)
70 (a), 73 (b)
75 (a), 75 (b)
82 (a), 77 (b)
0.52
0.54
0.47
0.53
0.46
0.55
0.47
49.4
55.7
59.5
59.5
58.7
46.2
53.5
6.5
8.2
7.1
7.0
6.7
4.7
7.7
11.3
9.5
C10H16N2O5
C14H24N2O5
C16H23N3O4
C16H23N3O4
C17H23N3O5
C12H14N4O6
C10H18N2O4
49.2
56.0
59.8
59.8
58.4
46. 5
53.3
6.6
8.0
7.2
7.2
6.6
4.6
7.9
IVа
IVb
IVc
IVd
IVe
IVf
IVg
9.3
13.1
13.1
12.0
18.1
12.2
160–162
148–150
130–132
135–137
45–48
13.2
12.9
12.2
17.9
12.4
a
Eluent ethyl acetate.
Table 3. 1H NMR, UV, and IR spectra of compounds IVa–IVg
R1
H2N
OR2
2
O
O
1H NMR spectrum (DMSO-d6), δ, ppm
IR spectrum, ν, cm–1
UV
spectrum,
λmax, nm
Comp.
no.
R1
R2
NH2 (d)
C2H (q)
3.34
N–H
3400
C=O
1.18 d (3H)
3.64 s (3H)
7.04–7.50
207
208
210
208
208
1770, 1650
IVa
IVb
IVc
IVd
IVe
0.85 t (3H), 1.35 m (2H)
1.18 d (3H)
3.63 s (3H)
7.01–7.49
7.04–7.51
7.07–7.50
7.06–7.51
3.35
3.20
3.15
3.20
3400
3380
3400
3390
1770, 1640
1780, 1640
1770, 1650
1780, 1650
1.22 t (3H), 4.05 q (2H)
1.20 t (3N), 4.07 q (2H)
0.83 t (3H), 1.32 m (2H)
0.85 t (3H), 1.27 m (4H), 1.67 1.16 t (3H), 4.07 q (2H)
t (2H)
1.19–1.67 m (11H)
1.19 t (3H), 4.09 q (2N)
7.05–7.50
7.07–7.52
3.36
3.58
209
3400
3380
1780, 1645
1780, 1650
IVf
3.02 m (2H), 7.18–7.27 m
(5H)
1.17 t (3H), 4.06 q (2H)
209, 255
IVg
(atoms in molecules) using AIMAll 09.02.01 program,
taking into account that bond ellipticity εb (Table 1) at
the bond critical point (BCP) quantitatively charac-
terizes its π-order or multiplicity [6, 9].
oxazines IIIa and IIIh showed that the ellipticity of
the C6–O1 bond in the latter is higher by an order of
magnitude than that in the former (0.215 and 0.027,
respectively). This means that the C6–O1 bond in 2-me-
thylsulfanyloxazine IIIh is stronger than the cor-
responding bond in 2-metoxyoxazine IIIa due to its
higher π-order. Obviously, this factor responsible for
the stability of oxazine IIIa toward such nucleophiles
as water and alcohols even at elevated temperature.
Analysis of the BCPs in oxazine molecules IIIa
and IIIh showed that the ellipticity of the C6–O1 bond
in molecule IIIa is lower by an order of magnitude
than the ellipticities of the other bonds in the oxazine
ring (0.027 and 0.113–0.383, respectively; Table 1).
Moreover, the C6 atom possesses the second largest
positive charge (0.948). These two factors, i.e., low
ellipticity of the C6–O1 bond and large positive charge
on C6, are likely to determined the direction of nucleo-
philic attack at the C6 atom in 2-methoxyoxazine IIIa.
Comparison of the electronic structure parameters of
The yields, melting points, TLC data, and elemental
analyses of compounds IVa–IVg are given in Table 2.
1
Their structure was confirmed by H and 13C NMR,
UV, and IR spectroscopy and mass spectrometry
(Tables 3, 4). Compounds IVa–IVg displayed in the 1H
NMR spectra (DMSO-d6, Table 3) a doublet signal at δ
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 10 2010

2046
LALAEV et al.
Table 4. 13C NMR and mass spectra of compounds IVa–IVg
13C NMR spectrum (DMSO-d6), δC, ppm
Comp.
no.
Mass spectrum,
m/z ([M]+)
R2
R1 (R3)
C2
C(O)NH2
170.97
C(O)OR2
171.06
51.65 (MeO)
13.81 (Me)
13.88 (Me)
45.58
45.70
131
145
145
159
187
213
221
IVa
IVb
IVc
IVd
IVe
IVf
IVg
13.97, 60.23 (EtO)
170.58
171.16
51.60 MeO)
12.65, 21.50 (Et)
45.65
53.23
51.62
51.80
53.29
170.40
169.87
169.96
169.45
169.20
171.10
169.94
170.45
170.60
169.36
13.92, 60.10 (EtO)
13.94, 60.13 (EtO)
13.85, 60.45 (EtO)
13.87, 60.32 (EtO)
12.82, 21.80 (Et)
13.71, 21.80, 28.16, 28.90 (Bu)
25.37–29.41 (cyclo-C6H11)
34.18 (CH2), 126.14, 128.06,
128.66, 138.70 (Ph)
7.01–7.51 ppm due to protons in the amide NH2 group,
the signal at δ 3.15–3.58 ppm was assigned to proton
on C2, and signals from protons in the alkyl groups (R1
or R3 and R2) were observed. In the 13C NMR spectra
of IVa–IVg in DMSO-d6 (Table 4), the C2 nucleus
resonated at δC 45–48 ppm, and signals at δC 169.20–
170.97 and 169.36–171.16 ppm corresponded to
carbon atoms in the amide and ester carbonyl groups,
respectively. In addition, signals from carbon atoms in
the alkyl substituents were present.
path length of 1 cm. The IR spectra were recorded in
KBr on an FSM-1201 spectrometer with Fourier
transform. The mass spectra (electron impact, 70 eV)
were obtained on an MKh-1321 mass spectrometer
with direct sample admission into the ion source; ion
source temperature 200°C. The elemental composi-
tions were determined at the Microanalysis Laboratory,
St. Petersburg Chemical and Pharmaceutical Academy.
Alkyl 3-amino-3-oxopropanoates IVa–IVg (general
procedure). a. A mixture of 0.01 mol of oxazine IIIa–
IIIg and 10 ml of 50% aqueous dioxane was heated for
5 h under reflux. The mixture was concentrated under
reduced pressure, and the precipitate was filtered off,
washed with water, and dried.
The IR spectra of IVa–IVg in KBr (Table 3) con-
tained an absorption band at 1780–1760 cm–1 due to
stretching vibrations of the ester carbonyl group, and
the band at 1650–1640 cm–1 appeared due to amide
carbonyl group. Stretching vibrations of the N–H
bonds gave rise to absorption at 3400–3380 cm–1. The
electronic spectra of IVa–IVg, recorded from solutions
in 96% ethanol (Table 3), were characterized by an
absorption maximum at λ 207–210 nm, and the spec-
trum of IVg contained an additional maximum at
λ 255 nm. Compounds IVa–IVg displayed in the mass
spectra molecular ion peaks with m/z values of 131,
145, 145, 159, 187, 213, and 221, respectively (Table 4).
b. A mixture of 0.01 mol of oxazine IIIa–IIIg and
10 ml of methanol or ethanol was heated for 5 h under
reflux. The mixture was concentrated under reduced
pressure, and the precipitate was filtered off, washed
with water, and dried. As a rule, no additional purifica-
tion of compounds IVa–IVg was necessary.
ACKNOWLEDGMENTS
The authors thank I.S. Podkorytov, L.F. Strelkova,
and A.D. Misharev for recording the IR, NMR, and
mass spectra.
EXPERIMENTAL
The H and 13C NMR spectra of solutions of IVa–
1
IVg in DMSO-d6 were recorded on a Bruker AM-500
spectrometer. The electronic absorption spectra were
measured from solutions in 96% ethanol on an SF-
2000 spectrophotometer using quartz cells with a cell
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