A new synthesis of 1,3-thiazines and their transformation into 1-substituted-6-alkyluracils by extrusion of carbonyl sulfide

Article abstract of DOI:10.1016/S0040-4039(03)01262-0

A simple synthesis of 5-acyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-diones from malonic acid, potassium thiocyanate and acid anhydrides is described. A new, general, regioselective method for the synthesis of 1-substituted-6-alkyluracils by the reaction of these thiazines with primary alkyl and arylamines is reported.

Full text of DOI:10.1016/S0040-4039(03)01262-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5279–5280
A new synthesis of 1,3-thiazines and their transformation into
1-substituted-6-alkyluracils by extrusion of carbonyl sulfide
Valera N. Yuskovets* and Boris A. Ivin
Department of Organic Chemistry, Saint-Petersburg State Chemical & Pharmaceutical Academy, Saint-Petersburg,
Professor Popov St. 14, 197376, Russia
Received 8 October 2002; revised 28 April 2003; accepted 16 May 2003
Abstract—A simple synthesis of 5-acyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-diones from malonic acid, potassium thio-
cyanate and acid anhydrides is described. A new, general, regioselective method for the synthesis of 1-substituted-6-alkyluracils by
the reaction of these thiazines with primary alkyl and arylamines is reported. © 2003 Elsevier Science Ltd. All rights reserved.
The purpose of the work described in this letter was to
investigate the approaches to the synthesis of 1,3-thiazi-
nes. In our study of synthetic routes to 1,3-thiazines,1
we decided to use thiocyanate as a building block for
the construction of the 1,3-thiazine ring. When malonic
acid, KSCN and acetic anhydride were allowed to react
in acetic acid at room temperature for 24 h, 5-acetyl-4-
hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione2 1a, mp
198–200°C (benzene) was formed in 46% yield. (Scheme
1). Using propionic anhydride and propionic acid we
were able to obtain 4-hydroxy-5-propionyl-3,6-dihydro-
2H-1,3-thiazine-2,6-dione 1b, mp 139–140°C (benzene/
hexane), in 30% yield, while with butyric anhydride and
butyric acid, 5-butyryl-4-hydroxy-3,6-dihydro-2H-1,3-
thiazine-2,6-dione 1c, mp 128–129°C (acetone/water)
was obtained in 20% yield.
We next investigated the reaction of thiazine 1a with
different primary amines. Thus heating 1a in dioxane or
ethanol gave the corresponding Schiff bases 2a–b.3 We
also carried out the reaction with a large excess of
amine, without solvent and under reflux. In the case of
aniline, evolution of carbonyl sulfide was observed and
1-phenyl-6-methyluracil 3a was isolated, mp 284–
285°C, (lit.4 280°C), in 75% yield. However, benzy-
lamine afforded a mixture of 1-benzyl-6-methyluracil 3b
mp 231–232°C (lit.5 230–231°C) and 1,3-dibenzylurea,
mp 170–171°C (lit.6 170–171°C), under the same condi-
tions. The mixture was readily separated by treatment
with aqueous NaOH, filtration and reprecipitation of
the uracil by HCl. Formation of 1,3-substituted ureas
from amines and carbonyl sulfide is well known.7 When
thiazine 1a and 1,2-phenylenediamine were refluxed in
Scheme 1.
Keywords: 1,3-thiazine; 6-methyluracil; thiocyanate; malonic acid; carbonyl sulfide; 1,3-disubstituted urea.
* Corresponding author. Tel.: +7-(812)-234-1172; fax: +7-(812)-434-3070; e-mail: oxazin@yahoo.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01262-0

5280
V. N. Yusko6ets, B. A. I6in / Tetrahedron Letters 44 (2003) 5279–5280
DMF for 30 min, 1-(2-aminophenyl)-6-methyluracil8 3d
was formed, mp 275–276°C, in 67% yield. Thiazine 1a
with monoethanolamine gave 1-(2-hydroxyethyl)-6-
methyluracil9 3c, mp 234–235°C (55%). While thiazine
1b and aniline gave 1-phenyl-6-ethyluracil,10 3e mp
274–275°C (73%). Uracils 3a–e may also be prepared
from the corresponding Schiff bases by refluxing in
DMF for 1–3 h.
(DMSO-d6, 125 MHz) l 180.6, 173.4, 168.4, 163.0, 135.7,
129.5, 128.3, 125.9, 97.6, 20.7; MS (70 eV): m/e 262 (M+,
100%), 234 (15), 201 (23), 163 (27), 158 (65), 130 (69), 118
(42), 77 (100), 67 (38), 51 (54), 39 (42).
5-(1-Benzyliminoethyl-4-hydroxy-3,6-dihydro-2H-1,3-thia-
1
zine-2,6-dione, 2b. Mp 187–188°C. H NMR (CDCl3, 500
MHz) l 12.93 (br s, 1H), 8.62 (s, 1H), 7.26–7.41 (m, 5H),
1
4.67 (d, 2H, J=5 Hz), 2.64 (s, 3H); H NMR (DMSO-d6,
500 MHz) l 12.88 (br s, 1H), 11.40 (s, 1H), 7.32–7.40 (m,
5H), 4.69 (d, 2H, J=5 Hz), 2.58 (s, 3H); 13C NMR
(DMSO-d6, 125 MHz) l 180.1, 174.1, 167.7, 163.1, 135.8,
128.9, 127.9, 127.5, 96.9, 47.3, 18.8; MS (70 eV): m/e 276
(M+, 45%), 187 (25), 144 (35), 91 (100), 65 (27), 39 (15).
4. Singh, H.; Singh, P.; Aggarwal, P.; Kumar, S. J. Chem.
Soc., Perkin Trans. 1 1993, 731–735.
In conclusion, we have reported a new method for the
synthesis of 1,3-thiazines from simple starting sub-
stances and have developed a new, general, regioselec-
tive method for the synthesis of 1-substituted-6-
alkyluracils from 1,3-thiazines by a hitherto unknown
extrusion reaction of carbonyl sulfide.
5. Kato, T.; Chiba, T.; Shimuzu, T.; Takahashi, H. Chem.
Pharm. Bull. 1981, 29, 862–866.
6. Shiina, I.; Suenaga, Y.; Nakano, M.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 2000, 73, 2811–2818.
References
7. Findeisen, K.; Goerdeler, J., In Methoden der Organis-
chen Chemie (Houben-Weyl), E4: Kohlensaure derivate;
Hagemann, H., Ed.; Georg Thieme Verlag: Stuttgart,
1983, pp. 725–914.
1. For reviews on 1,3-thiazine chemistry, see: (a) Mironova,
G. A.; Kuklin, V. N.; Kirillova, Ye. N.; Ivin, B. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 1986, 22, 1–13; (b)
Quiniou, H.; Guilloton, O. Adv. Heterocycl. Chem. 1990,
50, 85–156; (c) Ryabukhin, Yu. I.; Korzhavina, O. B.;
Suzdalev, K. F. Adv. Heterocycl. Chem. 1996, 66, 131–
191.
2. Ziegler, E.; Steiner, E. Monatsh. Chem. 1964, 95, 495–
500. The authors described the synthesis of compound 1a
starting from xantogenamid, malonic acid and PCl3.
They reported an mp of 184°C for this product. We have
repeated this reaction and obtained the product with mp
198–200°C, which has exactly the same spectral charac-
teristics as 1a obtained by our method: 1H NMR (CDCl3,
500 MHz) l 17.67 (s, 1H), 8.43 (br s, 1H), 2.69 (s, 3H);
13C NMR (DMSO-d6, 125 MHz) l 198.4, 180.3, 173.4,
163.2, 101.2, 26.8; MS (70 eV): m/e 187 (M+, 28%), 127
(28), 99 (30), 84 (22), 69 (25), 43 (100).
1
8. 3d: H NMR (DMSO-d6, 500 MHz) l 11.11 (s, 1H), 7.09
(t, 1H, J=8 Hz), 6.94 (d, 1H, J=8 Hz), 6.75 (d, 1H, J=7
Hz), 6.57 (t, 1H, J=8 Hz), 5.60 (s, 1H), 5.32 (s, 2H), 1.76
(s, 3H); 13C NMR (DMSO-d6, 125 MHz) l 163.2, 154.1,
151.1, 145.5, 129.5, 129.4, 120.9, 115.9, 115.5, 101.2, 19.2.
MS (70 eV): m/e 217 (M+, 100%), 200 (12), 159 (52), 133
(88), 92 (16), 65 (32), 50 (12), 39 (24).
1
9. 3c: H NMR (DMSO-d6, 500 MHz) l 10.99 (br s, 1H),
5.44 (s, 1H), 4.94 (br s, 1H), 3.77 (t, 2H, J=5 Hz), 3.56
(t, 2H, J=5 Hz), 2.26 (s, 3H); 13C NMR (DMSO-d6) l
162.5, 155.0, 151.5, 100.6, 58.4, 45.8, 19.8; MS (70 eV):
m/e 170 (M+, 20%), 127 (30), 126 (43), 96 (100), 55 (33),
39 (25).
10. 3e: 1H NMR (DMSO-d6, 500 MHz) l 11.34 (s, 1H),
7.36–7.52 (m, 5H), 5.56 (s, 1H), 2.01 (q, 2H, J=7 Hz),
0.93 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6, 125 MHz) l
162.9, 158.4, 151.4, 136.3, 129.24, 129.19, 128.81, 98.7,
25.66, 10.96.
3. Selected spectroscopic data: 4-Hydroxy-5-(1-phenylimino-
ethyl)-3,6-dihydro-2H-1,3-thiazine-2,6-dione, 2a. Mp 244–
1
245°C. H NMR (DMSO-d6, 500 MHz) l 14.14 (s, 1H),
11.87 (s, 1H), 7.38–7.54 (m, 5H), 2.47 (s, 3H); 13C NMR