Ph3P-mediated one-pot synthesis of functionalized 3,4-dihydro-2H-1,3-thiazines from N,N1-dialkylthioureas and activated acetylenes in water

Article abstract of DOI:10.1007/s00706-009-0247-y

A one-pot synthesis of alkyl 3,4-dihydro-4- oxo-2H-1,3-thiazine-6- carboxylates from dialkyl acetylen- edicarboxylates and N,N¹- dialkylthioureas in the presence of triphenylphosphine (20 mol%) is described. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-009-0247-y

Monatsh Chem (2010) 141:229–232
DOI 10.1007/s00706-009-0247-y
ORIGINAL PAPER
Ph3P-mediated one-pot synthesis of functionalized 3,4-dihydro-
2H-1,3-thiazines from N,N0-dialkylthioureas and activated
acetylenes in water
•
Issa Yavari Manijeh Nematpour
•
Zinatossadat Hossaini
Received: 27 April 2009 / Accepted: 23 December 2009 / Published online: 12 February 2010
Ó Springer-Verlag 2010
Abstract A one-pot synthesis of alkyl 3,4-dihydro-4-
oxo-2H-1,3-thiazine-6-carboxylates from dialkyl acetylen-
edicarboxylates and N,N0-dialkylthioureas in the presence
of triphenylphosphine (20 mol%) is described.
systems often give better results than in organic solvents and
the insolubility of the final products facilitates their isolation
[23, 24].
As part of our current studies on the development of new
routes in heterocyclic synthesis [25–27], we report a simple
and environmentally benign strategy for synthesis of
functionalized 3,4-dihydro-2H-1,3-thiazines. Thus, reac-
tion of dialkylthioureas 1 with activated acetylenic esters 2
in the presence of 20 mol% of triphenylphosphine (Ph3P)
in water as a solvent produced functionalized 2H-1,3-thi-
azines 3 in good yields (Scheme 1). Organophosphorus
compounds have been used in organic synthesis as useful
reagents, and as ligands in a number of transition metal
catalysts [28, 29]. However, there are few reactions in
which organophosphorus(III) species work as catalysts
[30–38].
Keywords 1,3-Thiazines ꢀ Dialkylthiourea ꢀ
Acetylenic ester ꢀ Triphenylphosphine
Introduction
1,3-Thiazines and their derivatives possess remarkable
biological activity, for example antibacterial, antitumor,
insecticidal, and fungicidal [1–5]. They are also known as
anti-radiation agents and used as radiation-sickness drugs
[6]. Furthermore, the antibiotic activity of cephalosporins
is because of the presence of the 1,3-thiazine nucleus [7].
Also, 1,3-thiazines are important synthetic intermediates in
organic synthesis [8]. Transformation of 1,3-thiazines into
6-alkyluracils and dihydropyrimidines has also been
reported [2, 9]. Owing to their chemical and biological
importance, syntheses of various 1,3-thiazine derivatives
have been reported [1, 2, 10–22].
The structures of compounds 3a–3f were assigned by
1
consideration of their IR, H NMR, and 13C NMR spec-
troscopic and mass spectrometric data. For example, the 1H
NMR spectrum of 3a contained three singlets for methyl
protons at d = 3.17, 3.19, and 3.75 ppm, together with a
characteristic signal for the methine proton at d =
6.77 ppm. In the 13C NMR spectrum of 3a, signals corre-
sponding to carbonyl and thionyl groups were observed at
d = 150.6, 164.6, and 166.2 ppm. The mass spectrum of
3a contained the molecular ion peak at m/z = 214.
Although the mechanistic details of the reaction are not
known, a plausible rationalization may be advanced to
explain the product formation. Presumably, the reaction
involves the initial formation of a 1:1 zwitterionic inter-
mediate 4 between the activated acetylenes 2 and Ph3P,
which undergoes reaction with 1 to produce the salt pair 5.
Combination of this salt pair will produce 6. This inter-
mediate is converted to product 3 via elimination of Ph3P
and cyclization (Scheme 2).
Water is an ideal solvent and reagent for biochemical
transformations. In the past, water was not used as solvent for
synthetic organic chemistry because of the poor solubility
and, in some cases, the instability of organic reagents in
aqueous solutions. Now, it has been recognized that chemi-
cal reactions in mixed aqueous solutions or two-phase
I. Yavari (&) ꢀ M. Nematpour ꢀ Z. Hossaini
Chemistry Department, Tarbiat Modares University,
Tehran, Iran
e-mail: yavarisa@modares.ac.ir
123

230
I. Yavari et al.
Scheme 1
R
N
CO2R'
CO2R'
S
R
O
PPh3 (20 mol%)
H2O, 50°C
N
S
R
R
+
N
N
H
H
CO2R'
R
R' Yield (%)
R
3
1
2
R'
a
b
c
d
e
f
Me Me
Me Et
87
85
90
83
92
89
a
b
c
Me
Et
Ph
a
b
Me
Et
Et
Et
Me
Et
Ph Me
Ph Et
Scheme 2
S
CO2R'
R'O2C
Ph3P
CO2R'
R
R'O2C
R
1
+
N
N
H
PPh3
2
+
Ph3P
4
5
R
R
R
S
N
N
N
R
R
_
R
Ph3P
N
S
N
S
N
_
H
R'OH
H
H
3
R'O2C
R'O2C
R'O2C
CO2R'
CO2R'
CO2R'
Ph3P
PPh3
6
7
8
When these reactions were performed in the absence of
Ph3P or in the presence of Et3N, the starting materials were
recovered unchanged.
IR-460 spectrometer. 1H and 13C NMR spectra were
measured on a Bruker Avance DRX-500 spectrometer at
500.1 and 125.8 MHz, respectively.
In conclusion, the reaction between N,N0-dialkylthiou-
reas and electron-deficient acetylenic esters in the presence
of Ph3P leads to functionalized 3,4-dihydro-2H-1,3-thia-
zines in good yields. This procedure has the advantage that
the reaction is performed under neutral conditions, and the
starting materials can be used without any preactivation or
modification.
General procedure for the preparation of 3
To a stirred mixture of 1 (2 mmol) and 2 (2 mmol) in
5 cm3 water was added 0.21 g Ph3P (20 mol%) at 50 °C.
After completion of the reaction (1–3 h) as indicated by
TLC (n-hexane–EtOAc 8:1), the resulting solid was iso-
lated by filtration and dried.
Methyl 3,4-dihydro-3-methyl-2-(methylimino)-4-oxo-2H-
1,3-thiazine-6-carboxylate (3a, C8H10N2O3S)
Experimental
Pale yellow powder, yield 0.37 g (87%); m.p.: 98–100 °C;
IR (KBr): ꢀm = 1,717, 1,695, 1,658, 1,621, 1,433, 1,331,
1,211 cm-1; EI-MS: m/z = 214 (M?, 25), 199 (45), 186
(62), 155 (70), 144 (75), 69 (100); 1H NMR (CDCl3):
d = 3.17 (3H, s, MeN), 3.19 (3H, s, MeN), 3.75 (3H, s,
MeO), 6.77 (1H, s, CH) ppm; 13C NMR (CDCl3): d = 28.9
(MeN), 30.7 (MeN), 52.3 (MeO), 115.1 (CH), 141.1 (C),
150.6 (C=O), 164.6 (C=O), 166.2 (C=S) ppm.
Chemicals were purchased from Fluka and used without
further purification. Melting points were measured on an
Electrothermal 9100 apparatus. Elemental analyses for C,
H, and N were performed using a Heraeus CHN-O-Rapid
analyzer, and the results agreed favorably with the calcu-
lated values. Mass spectra were recorded on a Finnigan
MAT 8430 spectrometer operating at an ionization poten-
tial of 70 eV. IR spectra were measured on a Shimadzu
123

Ph3P-mediated one-pot synthesis of functionalized 3,4-dihydro-2H-1,3-thiazines
231
Ethyl 3,4-dihydro-3-methyl-2-(methylimino)-4-oxo-2H-1,3-
thiazine-6-carboxylate (3b, C9H12N2O3S)
1,192 cm-1; EI-MS: m/z = 352 (M?, 15), 323 (68), 279
(52), 220 (68), 118 (100), 45 (88); 1H NMR (CDCl3):
d = 1.33 (3H, t, 3J = 7.2 Hz, Me), 4.30 (2H, q,
Pale yellow powder, yield 0.37 g (85%); m.p.: 112–
114 °C; IR (KBr): ꢀm = 1,714, 1,692, 1,657, 1,613, 1,423,
1,197 cm-1; EI-MS: m/z = 228 (M?, 15), 199 (68), 185
(76), 158 (68), 70 (100), 29 (65); 1H NMR (CDCl3):
3
3J = 7.2 Hz, CH2O), 6.94 (1H, d, J = 7.2 Hz, 2 CHo),
3
7.01 (1H, s, CH), 7.23 (2H, t, J = 7.2 Hz, 2 CHm), 7.34
(1H, t, 3J = 7.2 Hz, CHp) ppm; 13C NMR (CDCl3):
d = 14.2 (Me), 61.8 (CH2O), 120.6 (CH), 127.9 (C),
115.3 (2 CH), 117.1 (2 CH), 125.3 (CH), 147.4 (C=O),
164.7 (C=S), 166.0 (C=O) ppm.
3
d = 1.34 (3H, t, J = 7.2 Hz, Me), 3.28 (3H, s, MeN),
3
3.29 (3H, s, MeN), 4.30 (2H, q, J = 7.2 Hz, CH2O), 6.89
(1H, s, CH) ppm; 13C NMR (CDCl3): d = 14.2 (Me), 29.1
(MeN), 38.9 (MeN), 61.6 (CH2O), 115.8 (CH), 140.9 (C),
150.9 (C=O), 164.9 (C=O), 166.0 (C=S) ppm.
Methyl 3-ethyl-2-(ethylimino)-3,4-dihydro-4-oxo-2H-1,3-
thiazine-6-carboxylate (3c, C10H14N2O3S)
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White powder, yield 0.43 g (90%); m.p.: 125–127 °C; IR
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(KBr): m = 1,712, 1,643, 1,610, 1,434, 1,392, 1,317 cm
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3
q, J = 7.3 Hz, CH2N), 3.83 (3H, s, MeO), 3.86 (2H, q,
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3
45 (88); H NMR (CDCl3): d = 1.14 (3H, t, J = 7.2 Hz,
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ꢀ
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123

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I. Yavari et al.
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123