New regioselective synthesis of 7H-imidazo[2,1-b][1,3]thiazine and 2H,6H-pyrimido[2,1-b][1,3]thiazine derivatives

Article abstract of DOI:10.1055/s-2002-20044

A series of the title compounds were prepared by the reaction of amidines 2 with α-bromoketones, acid chlorides or acrylic dienophiles. The four steps synthesis reaction from thiourea and full characterisation of 7H-imidazo[2,1-b][1,3]thiazines 4, 2H,6H-pyrimido[2,1-b][1,3]thiazin-6-ones 5, and 2H,6H-pyrimido[2,1-b][1,3]thiazines 6 are described.

Full text of DOI:10.1055/s-2002-20044

PAPER
403
New Regioselective Synthesis of 7H-Imidazo[2,1-b][1,3]thiazine and 2H,6H-
Pyrimido[2,1-b][1,3]thiazine Derivatives.
S
C
ynthesis of
7
H
-I
y
midazo[2,1-
r
b
]
[1,3]th
i
iazine
a
l
nd 2
H
l
,6
H
-Py
e
rimido[2,1-
b
][1,3
L
]thiazine Deriv
a
atives ndreau, David Deniaud,* Alain Reliquet, Jean Claude Meslin
Laboratoire de Synthèse Organique, UMR CNRS 6513, Faculté des Sciences et des Techniques 2, Rue de la Houssinière, BP 92208, 44322
Nantes Cedex 03, France
Fax +33(2)51125402; E-mail: david.deniaud@chimie.univ-nantes.fr
Received 2 January 2002
imidine derivatives involving amidines prepared from the
Abstract: A series of the title compounds were prepared by the re-
action of amidines 2 with -bromoketones, acid chlorides or acrylic
2
18
2
-amino- -thiazoline.
dienophiles. The four steps synthesis reaction from thiourea and full We now wish to report the synthesis and characterisation
characterisation of 7H-imidazo[2,1-b][1,3]thiazines 4, 2H,6H-py-
rimido[2,1-b][1,3]thiazin-6-ones 5, and 2H,6H-pyrimido[2,1-
b][1,3]thiazines 6 are described.
of 7H-imidazo[2,1-b][1,3]thiazines, 2H,6H-pyrimido-
[
2,1-b][1,3]thiazin-6-ones and 2H,6H-pyrimido[2,1-
b][1,3]thiazines, following a similar synthetic strategy.
Key words: bicyclic compounds, heterocycles, alkylations, acyla-
The key step consisted in the reaction of amidines 2 with
substituted bromomethyl compounds, acid chlorides, or
acrylic dienophiles leading to imidazothiazines, pyrimi-
dothiazinones, or pyrimidothiazines. Starting amidines 2
were obtained in three steps in about 90% overall yields.
Thus, 2-amino-4,6,6-trimethyl-6H-1,3-thiazine (1) was
tions, Diels–Alder reactions
Imidazo[2,1-b][1,3]thiazines represent a rare class of bi-
cyclic heterocyclic compounds with various interesting
pharmacological properties. Derivatives of this ring sys-
tem were recently found to possess antitumor activity, to
be of interest in the synthesis of modified nucleosides,
and were used as substitutes for benzodiazepines. Fur-
thermore, Bózsing et al. have reported anti-inflammatory
1
prepared by condensation of mesityl oxide and thiourea
2
9,20
(
Scheme 1).1
Subsequent treatment using N,N-dime-
3
thylamide dimethyl acetal (formamide or acetamide) af-
forded the desired heterocyclic diazadienes 2.
4
and antipyretic properties of pyrimido[2,1-b][1,3]thiazine Alkylation of compounds 2 with arylacyl bromides affect-
5
derivatives. Although many potent biological activities ed the intracyclic nitrogen atom providing probably the N-
have been published, few syntheses of imidazothiazines alkyl amidinium bromides 3 (Scheme 2). These unisolat-
and pyrimidothiazines have been proposed, most of them ed salts were deprotonated in situ by addition of Et N, to
3
6
–8
using imidazoline-2-thiones,
imidazolidine-2-thi- generate enolate, which reacted with the iminium group.
as starting materials Cyclisation occurred spontaneously followed by loss of
9
,10
11–13
ones, or 2-thioxopyrimidines
inducing the formation of two regioisomers in certain cas- dimethylamine to provide 7H-imidazo[2,1-b][1,3]thia-
es. Therefore, the purpose of this work was to investigate zines 4a–d in moderate yields due to the fragility of the
an alternative, convenient and versatile preparation of thiazinic ring in basic media (Table 1).
these heterocyclic ring systems.
Moreover, we found that 2H,6H-pyrimido[2,1-b][1,3]thi-
During the last years, we have focused our research on the azin-6-ones 5a–d can be prepared in good yields (Table 2)
development of efficient methodologies to build hetero- from compounds 2 and acid chlorides (Scheme 3). The
1
4–17
cyclic compounds.
cess to imidazo[2,1-b]thiazole and thiazolo[3,2-a]pyr- slight excess of reagent at room temperature, followed by
We recently described a novel ac- heterocyclisation occurred smoothly, by the action of a
H2N
S
R
N
S
O
S
i, ii
5%
iii
+
9
N
N
N
H N
2
NH2
2
a
R =H (95%)
R =CH3 (98%)
1
2b
Scheme 1 Reagents and conditions: (i) gaseous HCl, EtOH, r.t., 1 h; (ii) Et N, CH Cl , r.t., 4 h; (iii) (CH ) NCH(OCH ) , CH Cl , reflux, 5
3
2
2
3 2
3 2
2
2
h for 2a; (CH ) NCCH (OCH ) , CH Cl , reflux, 17 h for 2b.
3
2
3
3 2
2
2
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
437-210X,E;2002,0,03,0403,0408,ftx,en;Z12301SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
1
©

4
04
C. Landreau et al.
PAPER
R
N
S
Br
S
N
N
S
N
N
N
R
i
ii
N
2a, b
R
N
R'
R'
O
4a-d
Br
O
R'
3
O
Scheme 2 Reagents and conditions: (i) THF, 78 °C, 20 h; (ii) Et N, r.t., 24 h.
3
Table 1 Yields of 7H-Imidazo[2,1-b][1,3]thiazines 4
Table 2 Yields of 2H,6H-Pyrimido[2,1-b][1,3]thiazin-6-ones 5
Product
R
R
Yield(%)
Product
5a
R
R
Yield(%)
4
4
4
4
a
b
c
H
p-BrC H
44
29
28
30
H
COOCH3
COOCH3
74
95
80
59
92
94
6
4
H
p-ClC H
5b
CH3
H
6
4
H
p-CH C H
5c
COOC H
3
6
4
2
5
d
CH3
p-BrC H
5d
H
C H
5
6
4
6
5
5
e
f
H
H
CH3
H
addition of two equivalents of triethylamine. Also, the
4+2] cycloaddition reaction between amidines 2 and
[
ketene, formed by cracking of acetone, afforded 7-unsub-
stituted pyrimidothiazin-6-ones in good yields. In both
cases, the final step consisted of deamination of the sup-
posed intermediary cycloadduct gives the fused heterocy-
cles (Scheme 3, Table 2).
In order to verify the 2H,6H structure of these com-
pounds, a single crystal of 5b was used for X-ray structure
analysis. The ORTEP diagram of the molecule is shown
in Figure 1.
Similarly, the expected 2H,6H-pyrimido[2,1-b][1,3]thiaz-
ine derivatives 6 were obtained in an absolute regiocon-
trolled manner by reaction of amidines 2 with acrylic
Figure 1 ORTEP-plot of molecular structure of 5b in the crystal
the crystallographic numbering does not reflect the systematic num-
bering).
dienophiles in CHCl (for 6a, 6b) or using dienophiles as
3
(
1
solvent (for 6c–e) (Scheme 4, Table 3). The H NMR
2a, b
R
N
S
N
N
O
S
i
N
N
R
H
R'
5
a-d
ii
N
Cl
R'
R
N
O
S
O
-HNMe2
N
R'
2
a, b
N
N
S
N
N
O
S
iii
R
H
H
H R
C
N
O
5e,f R' = H
N
H
C
Scheme 3 Reagents and conditions: (i) CH Cl , r.t., 6 h; (ii) Et N, 0 °C to r.t., 16 h; (iii) CH Cl , r.t, 1 h.
2
2
3
2
2
Synthesis 2002, No. 3, 403–408 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 7H-Imidazo[2,1-b][1,3]thiazine and 2H,6H-Pyrimido[2,1-b][1,3]thiazine Derivatives
405
spectra of 6a–e showed a singlet due to the methylene N,N-Dimethyl-N -(4,6,6-trimethyl-6H-1,3-thiazin-2-yl)-form-
amidine (2a)
Yield: 95%; yellow oil; R = 0.4 (EtOAc).
group in position 6, and thus excluded the regioisomeric
f
6
-substituted structure. The [4+2] cycloaddition with ac-
–
1
IR (film): 1616, 1505, 1423, 1321, 1163, 1097, 998 cm .
1H NMR (CDCl3): = 1.27 [s, 6 H, C(CH ) ], 1.91 (d, 3 H, J = 1.2
rolein, methyl vinyl ketone or methyl acrylate was always
followed by dimethylamine elimination.
3
2
Hz, CH ), 3.02, 3.03 [2s, 6 H, N(CH ) ], 4.75 (q, 1 H, J = 1.2 Hz,
3
3 2
CH), 8.09 (s, 1 H, NCH).
R
N
S
1
3C NMR (CDCl3): = 23.7 (CH ), 30.4 [C(CH ) ], 35.3, 41.0
3 3 2
R'
i
2
a,b
+
[
(
(NCH ) ], 43.2 [C(CH ) ], 110.6 (CH), 143.6 (CCH ), 156.7
3 2 3 2 3
NCH), 161.1 (SCN).
N
R'
+
MS (EI): m/z (%) = 211 (M , 48), 196 (100), 178 (19), 115 (73), 98
6
a-e
(23), 83 (34).
Scheme 4 Reagents and conditions: (i) CHCl , 45 °C for 6a or r.t.
for 6b, 18 h; neat, 70 °C for 6c,6e, 4 h, or reflux for 6d, 4 d.
3
N,N-Dimethyl-N -(4,6,6-trimethyl-6H-1,3-thiazin-2-yl)-acet-
amidine (2b)
–
1
IR (KBr): 1585, 1525, 1419, 1399, 1158, 1134, 983 cm .
Table 3 Yields of 2H,6H-Pyrimido[2,1-b][1,3]thiazines 6
Yield: 98%; yellow crystals; mp 55 °C.
1H NMR (CDCl3): = 1.36 [s, 6 H, C(CH ) ], 1.95 (d, 3 H, J = 1.2
Product
R
R
Yield(%)
3
2
Hz, CH ), 2.13, 3.02 [s, 6 H, N(CH ) ], 4.74 (q, 1 H, J = 1.2 Hz,
CH).
3
3 2
6
6
6
6
6
a
b
c
H
CHO
74
75
49
47
50
1
3
C NMR (CDCl ): = 16.4 [NC(N)CH ], 23.8 (CH ), 30.9
CH3
H
CHO
3
3
3
[
C(CH ) ], 38.1 [(NCH ) ], 43.1 [C(CH ) ], 109.0 (CH), 143.0
3 2 3 2 3 2
COCH3
COOCH3
COCH3
(CCH ), 159.4 [NC(N)CH ], 161.6 (SCN).
3
3
+
MS (EI): m/z (%) = 225 (M , 37), 210 (47), 192 (18), 129 (100), 112
53), 97 (45).
d
e
H
(
CH3
7
H-Imidazo[2,1-b][1,3]thiazines 4; General Procedure
A solution of -bromoketone (2.2 mmol) (2,4 -dibromoacetophe-
In summary, we have shown that heterocyclic diazadienes none for 4a,d, 2-bromo-4 -chloroacetophenone for 4b, 2-bromo-4 -
2
are versatile precursors of 7H-imidazo[2,1-b][1,3]thia- methylacetophenone for 4c) and amidine 2 (2 mmol) in THF (10
mL) was refluxed for 20 h. After cooling to r.t., Et N (4.4 mmol)
zines 4a–d, 2H,6H-pyrimido[2,1-b][1,3]thiazin-6-ones
a–f and 2H,6H-pyrimido[2,1-b][1,3]thiazines 6a–e. Ad-
vantages of the present method are: easy availability of
starting materials, good yields in the [4+2] cycloaddition,
high regioselectivity, and experimental simplicity of pro-
3
was added. The reaction mixture was further stirred at r.t. for 24 h,
5
diluted with CH Cl (100 mL) and washed with H O (100 mL). The
2
2
2
aqueous phase was extracted with CH Cl (3 70 mL). The com-
2
2
bined organic layers were washed with H O (3 70 mL), dried
2
(
MgSO ), and concentrated under reduced pressure. The resulting
4
cedure. Further investigations towards sophisticated imi- residue was purified by chromatography using CH Cl to furnish
2
2
dazothiazine and pyrimidothiazine precursors are compounds 4, which were crystallized from hexane for 4a,c or pe-
troleum ether (bp 35 60 °C)for 4b,d.
currently underway.
(4-Bromophenyl)(5,7,7-trimethyl-7H-imidazo[2,1-b][1,3]-thia-
All reagents were purchased either from Acros Organics or Aldrich.
The C.N.R.S. Analysis Laboratory (Vernaison) performed the ele-
mental analyses. Column chromatography was conducted on silica
gel 60 (40–63 m), available from E. Merck. Thin layer chromatog-
raphy was performed on 0.5 mm 20 cm 20 cm E. Merck silica
gel plates (60 F-254). Melting points measured using a Reichert mi-
zin-3-yl)methanone (4a)
Yield: 44%; white crystals; mp 129 °C.
IR (KBr): 1627, 1582, 1502, 1403, 1353, 1333, 1249, 1163, 892,
–1
7
56 cm .
1
H NMR (CDCl3): = 1.52 [s, 6 H, C(CH ) ], 2.14 (d, 3 H, J = 1.2
3 2
1
3
1
Hz, CH ), 5.36 (q, 1 H, J = 1.2 Hz, CH), 7.44 (s, 1 H, NCH), 7.62–
croscope were uncorrected. The C and H NMR spectra were re-
corded at room temperature using a Brucker AC 200 at 50 and 200
MHz respectively. Chemical shifts ( ) are given in ppm downfield
from tetramethylsilane as internal standard. Mass spectra were re-
corded with a Hewlett Packard 5989 spectrometer. The IR spectra
were obtained using a Brucker Vector 22 spectrometer. All chemi-
cals were reagent grade and used without further purification. THF
was freshly distilled from Na/benzophenone ketyl, while CH Cl
3
7
.85 (m, 4 H, ArH).
13
C NMR (CDCl ): = 20.6 (CH ), 28.6 [C(CH ) ], 43.4 [C(CH ) ],
3
3
3
2
3 2
1
19.6 (CH), 128.2, 131.0, 133.7 (NCCO, 2 ArC), 130.9, 132.0 (4
ArCH), 136.5 (CCH ), 141.9 (NCH), 153.2 (SCN), 181.8 (CO).
3
+
MS (EI): m/z (%) = 364/362 (M , 25/23), 349/347 (11/11), 306/304
(
11/11), 185/183 (39/39), 179 (100).
2
2
was distilled over CaH . All reactions were carried in a N atm.
Anal. Calcd for C16 H BrN OS (363.3): C, 53.81; H, 7.74; N,
2
2
15
2
1
7.93. Found: C, 53.95; H, 7.61; N, 17.78.
Amidines 2; General Procedure
A solution of 2-amino-4,6,6-trimethyl-6H-1,3-thiazine
1
9,20
1 (10
(4-Chlorophenyl)(5,7,7-trimethyl-7H-imidazo[2,1-b][1,3]-thia-
zin-3-yl)methanone (4b)
Yield: 29%; white crystals; mp 141 °C.
mmol) and N,N-dimethylformamide dimethylacetal (11 mmol, for
a) or N,N-dimethylacetamide dimethylacetal (13 mmol, for 2b) in
CH Cl (10 mL) was refluxed for 5 h (for 2a) or for 16 h (for 2b).
2
2
2
1H NMR (CDCl3): = 1.53 [s, 6 H, C(CH ) ], 2.15 (d, 3 H, J = 1.2
3
2
Compounds 2 were obtained by evaporation of the solvent.
Hz, CH ), 5.37 (q, 1 H, J = 1.2 Hz, CH), 7.45 (s, 1 H, NCH), 7.47–
3
7
.94 (m, 4 H, ArH).
Synthesis 2002, No. 3, 403–408 ISSN 0039-7881 © Thieme Stuttgart · New York

4
06
C. Landreau et al.
PAPER
1
3C NMR (CDCl3): = 20.6 (CH ), 28.6 [C(CH ) ], 43.4 [C(CH ) ],
13
C NMR (CDCl ): = 19.7 (CH ), 28.5 [C(CH ) ], 42.5 [C(CH ) ],
3
3
2
3 2
3
3
3
2
3 2
1
2
19.5 (CH), 129.0, 130.8 (4 ArCH), 131.0, 133.7, 136.1 (NCCO,
52.2 (OCH ), 112.6 (CCO), 127.1 (CH), 136.3 (CCH ), 156.6
(NCH), 157.1, 164.2, 167.2 (SCN, 2 CO).
3
3
ArC), 139.6 (CCH ), 141.8 (NCH), 153.2 (SCN), 181.7 (CO).
3
+
+
MS (EI): m/z (%) = 320/318 (M , 13/33), 305/303 (6/16), 262/260
MS (EI): m/z (%) = 266 (M , 85), 251 (45), 234 (89), 223 (72), 219
(5/15), 179 (100), 141/139 (30/89), 113/111 (16/48).
(100), 206 (87), 178 (70).
IR (KBr): 1627, 1589, 1502, 1405, 1354, 1333, 1248, 1165, 1090,
Anal. Calcd for C12 H N O S (266.3): C, 54.12; H, 5.30; N, 10.52.
Found: C, 54.01; H, 5.38; N, 10.43.
14
2
3
–1
8
93, 759 cm .
Anal. calcd for C16 H ClN OS (318.8): C, 60.28; H, 4.74; N, 8.79.
Found: C, 60.34; H, 4.65; N, 8.87.
15
2
7
-Methoxycarbonyl-2,2,4,8-tetramethyl-2H,6H-pyrimido[2,1-
b][1,3]thiazin-6-one (5b)
Yield: 95%; white crystals; mp 130 °C.
(
4-Methylphenyl)(5,7,7-trimethyl-7H-imidazo[2,1-b][1,3]-thia-
–
1
zin-3-yl)methanone (4c)
IR (KBr): 1729, 1685, 1662, 1496, 1255, 1201, 1131, 1088 cm .
Yield: 28%; yellow crystals; mp 105 °C.
1H NMR (CDCl3): = 1.49 [s, 6 H, C(CH ) ], 2.23 (d, 3 H, J = 1.2
3
2
IR (KBr): 1633, 1602, 1508, 1408, 1357, 1336, 1249, 1161, 896,
Hz, CH ), 2.36 [s, 3 H, NC(CH )CCO], 3.90 (s, 3 H, OCH ), 5.59
(q, 1 H, J = 1.2 Hz, CH).
3
3
3
–1
7
53 cm .
1H NMR (CDCl3): = 1.53 [s, 6 H, C(CH ) ], 2.15 (d, 3 H, J = 1.2
13C NMR (CDCl3): = 19.7 (CH ), 22.5 [NC(CH )CCO], 28.6
3 2
3
3
Hz, CH ), 2.45 (s, 3 H, ArCH ), 5.35 (q, 1 H, J = 1.2 Hz, CH), 7.29–
[C(CH ) ], 42.2 [C(CH ) ], 52.4 (OCH ), 114.1 (CCO), 126.9 (CH),
3 2 3 2 3
3
3
7
.89 (m, 4 H, ArH), 7.44 (s, 1 H, NCH).
136.0 (CCH ), 157.5, 158.5, 162.1, 165.8 [NC(CH )CCO, SCN, 2
3
3
1
3
CO].
C NMR (CDCl ): = 20.6 (CH ), 21.8 (ArCH ), 28.7 [C(CH ) ],
3
3
3
3 2
+
4
1
1
3.3 [C(CH ) ], 119.4 (CH), 129.4, 129.7 (4 ArCH), 131.5, 133.8,
MS (EI): m/z (%) = 280 (M , 53), 248 (74), 237 (100), 233 (44), 220
3
2
35.2 (NCCO, 2 ArC), 141.3 (CCH ), 144.0 (NCH), 152.3 (SCN),
(64), 205 (32), 192 (35), 159 (29).
3
83.0 (CO).
Anal. Calcd for C13 H N O S (280.3): C, 55.70; H, 5.75; N, 9.99.
Found: C, 55.56; H, 5.65; N, 10.09.
16
2
3
+
MS (EI): m/z (%) = 298 (M , 23), 283 (11), 240 (9), 179 (57), 119
(100), 91 (97).
7
-Ethoxycarbonyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b][1,3]-
Anal. Calcd for C H N OS (298.4): C, 68.43; H, 6.08; N, 9.39.
Found: C, 68.55; H, 6.15; N, 9.48.
17
18
2
thiazin-6-one (5c)
Yield: 80%; white crystals; mp 72 °C.
–
1
(
4-Bromophenyl)(2,5,7,7-tetramethyl-7H-imidazo[2,1-b][1,3]-
IR (KBr): 1712, 1685, 1558, 1471, 1354, 1284, 1207, 1135 cm .
thiazin-3-yl)methanone (4d)
Yield: 30%; white crystals; mp 53 °C.
1
H NMR (CDCl ): = 1.37 (t, 3 H, J = 7.2 Hz, CH CH ), 1.50 [s, 6
3
2
3
H, C(CH ) ], 2.24 (d, 3 H, J = 1.2 Hz, CH ), 4.36 (q, 2 H, J = 7.2
Hz, OCH ), 5.61 (q, 1 H, J = 1.2 Hz, CH), 8.44 (d, 1 H, NCH).
3
2
3
–
1
IR (KBr): 1623, 1586, 1386, 1347, 1282, 1066, 936, 795 cm .
2
1H NMR (CDCl3): =1.54 [s, 6 H, C(CH ) ], 1.95 (d, 3 H, J = 1.2
13C NMR (CDCl3): = 14.3 (CH CH ), 19.7 (CH ), 28.5 [C(CH ) ],
3
2
2
3
3
3 2
Hz, CH ), 2.06 [s, 3 H, NC(CH )CN], 5.25 (q, 1 H, J = 1.2 Hz, CH),
42.4 [C(CH ) ], 61.1 (OCH ), 112.9 (CCO), 127.0 (CH), 136.4
3
3
3 2 2
7
.61–7.75 (m, 4 H, ArH).
(CCH ), 156.2 (NCH), 157.1, 163.5, 167.0 (SCN, 2 CO).
3
1
3C NMR (CDCl3): = 15.8 [NC(CH )CN], 20.7 (CH ), 28.7
+
MS (EI): m/z (%) = 280 (M , 41), 265 (39), 234 (64), 219 (100), 206
3
3
[
C(CH ) ], 43.1 [C(CH ) ], 118.7 (CH), 127.5, 128.3, 133.3, (NC-
(89), 178 (61).
3
2
3 2
CO, 2 ArC), 130.9, 132.2 (4 ArCH), 137.5 (CCH ), 147.7
3
Anal. Calcd for C13 H N O S (280.3): C, 55.70; H, 5.75; N, 9.99.
Found: C, 55.78; H, 5.70; N, 9.90.
16
2
3
(
NCH), 150.5 (SCN), 184.9 (CO).
+
MS (EI): m/z (%) = 378/376 (M , 34/32), 363/361 (22/23), 193
100), 185/183 (22/23).
(
7-Phenyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-
one (5d)
Yield: 59%; white crystals; mp 154 °C.
Anal. Calcd for C H BrN OS (377.3): C, 54.12; H, 4.54; N, 7.42.
1
7
17
2
Found: C, 54.21; H, 4.59; N, 7.49.
–
1
IR (KBr): 1685, 1659, 1487, 1361, 1315, 1211, 785, 697 cm .
2
H,6H-Pyrimido[2,1-b][1,3]thiazin-6-ones 5;
1H NMR (CDCl3): = 1.52 [s, 6 H, C(CH ) ], 2.26 (d, 3 H, J = 1.2
3
2
General Procedure Method A:
Hz, CH ), 5.64 (q, 1 H, J = 1.2 Hz, CH), 7.34–7.67 (m, 5 H, ArH),
3
A solution of amidine 2 (2 mmol) and acid chloride (2.4 mmol) (me-
thyl malonyl chloride for 5a,b, ethyl malonyl chloride for 5c or phe-
nylacetyl chloride for 5d) in CH Cl (10 mL) was stirred at r.t. for 6
h. After cooling to 0 °C, Et N (4.8 mmol) was added and stirring
was continued at r.t. for 16 h. After removal of the solvent, the res-
idue was chromatographed using as eluent CH Cl –EtOAc (9:1).
7
.88 (s, 1 H, NCH).
1
3
C NMR (CDCl ): = 19.8 (CH ), 28.6 [C(CH ) ], 42.0 [C(CH ) ],
3
3
3
2
3 2
2
2
1
1
23.8 (CCO), 127.5 (CH), 128.1, 128.4 (5 ArCH), 133.2 (ArC),
3
36.3 (CCH ), 148.6 (NCH), 159.9, 160.4 (SCN, CO).
3
+
2
2
MS (EI): m/z (%) = 284 (M , 100), 269 (31), 241 (35), 223 (12), 188
Compounds 5a,d were crystallized from Et O and 5b,c were crys-
tallized from petroleum ether.
2
(24), 160 (38).
Anal. Calcd for C16 H N OS (284.4): C, 67.58; H, 5.67; N, 9.85.
16
2
Found: C, 67.54; H, 5.64; N, 9.82.
7
[
-Methoxycarbonyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b]-
1,3]thiazin-6-one (5a)
Yield: 74%; white crystals; mp 139 °C.
Method B:
Ketene (CAUTION), produced by cracking of acetone, was bub-
bled into a solution of amidine 2 (4 mmol) in CH Cl (150 mL) until
–
1
IR (KBr): 1713, 1694, 1563, 1469, 1353, 1292, 1204, 1130 cm .
2
2
1H NMR (CDCl3): = 1.50 [s, 6 H, C(CH ) ], 2.24 (d, 3 H, J = 1.2
all starting material was consumed, (as monitored by TLC, approx-
imately 1 h). After evaporation of the solvent, the residue was dis-
3 2
Hz, CH ), 3.89 (s, 3 H, OCH ), 5.62 (q, 1 H, J = 1.2 Hz, CH), 8.47
3
3
solved in a small amount of CH Cl and subjected to flash
(d, 1 H, NCH).
2
2
Synthesis 2002, No. 3, 403–408 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 7H-Imidazo[2,1-b][1,3]thiazine and 2H,6H-Pyrimido[2,1-b][1,3]thiazine Derivatives
407
–
1
chromatography (CH Cl –EtOAc, 5:1 for 5e; CH Cl –EtOAc, 5:1
for 5f). Compound 5f was crystallized from hexane.
IR (film): 2964, 1635, 1480, 1351, 1207, 1138 cm .
1H NMR (CDCl3): = 1.45 [s, 6 H, C(CH ) ], 2.00 (d, 3 H, J = 1.2
2
2
2
2
3
2
Hz, CH ), 2.24 [s, 3 H, NC(CH )CCO], 4.34 (s, 2 H, CH ), 5.19 (q,
3
3
2
2
,2,4-Trimethyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (5e)
1
H, J = 1.2 Hz, CH), 9.81 (s, 1 H, CHO).
Yield: 92%; white oil; R = 0.4 (EtOAc).
f
1
3C NMR (CDCl3): = 18.3, 19.0 [CH , NC(CH )CCO], 29.9
–
1
3 3
IR (KBr): 2971, 1700, 1669, 1574, 1489, 1290, 1208, 820 cm .
1H NMR (CDCl3): = 1.49 [s, 6 H, C(CH ) ], 2.23 (d, 3 H, J = 1.2
[
C(CH ) ], 41.3, 41.6 [CH , C(CH ) ], 112.1 (CCO), 119.5 (CH),
3 2 2 3 2
135.3 (CCH ), 161.0, 163.3 [NC(CH )CCO, NCH], 186.8 (CHO).
3 2
3
3
Hz, CH ), 5.60 (q, 1 H, J = 1.2 Hz, CH), 6.19 (d, 1 H, J = 6.4 Hz,
CHCO), 7.67 (d, 1 H, J = 6.4 Hz, NCH).
+
3
MS (EI): m/z (%) = 236 (M , 100), 221 (24), 207 (11), 183 (12), 155
20), 141 (29).
(
1
3C NMR (CDCl3): = 19.8 (CH ), 28.6 [C(CH ) ], 41.8 [C(CH ) ],
3
3
2
3 2
Anal. Calcd for C12 H N OS (236.3): C, 60.94; H, 6.77; N, 11.85.
Found: C, 60.73; H, 6.59; N, 11.98.
16
2
1
1
12.1 (CHCO), 127.3 (CH), 136.0 (CCH ), 151.1 (NCH), 160.6,
62.1 (SCN, CO).
3
+
MS (EI): m/z (%) = 208 (M , 100), 193 (86), 175 (23), 165 (60), 150
7-Acetyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b][1,3]thiazine
(
26), 112 (62).
(6c)
Yield: 49%; yellow oil; R = 0.5 (EtOAc).
1H NMR (CDCl3): = 1.44 [s, 6 H, C(CH ) ], 1.99 (d, 3 H, J = 1.2
f
Anal. Calcd for C H N OS (208.3): C, 59.38; H, 5.40; N, 12.59.
Found: C, 59.21; H, 5.58; N, 12.32.
10
12
2
3
2
Hz, CH ), 2.28 (s, 3 H, COCH ), 4.39 (s, 2 H, CH ), 5.19 (q, 1 H,
3
3
2
2
(
,2,4,8-Tetramethyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one
5f)
Yield: 94%; white crystals; mp 79 °C.
J = 1.2 Hz, CH), 7.39 (s, 1 H, NCH).
13
C NMR (CDCl ): = 19.0 (CH ), 24.6 (COCH ), 29.9 [C(CH ) ],
3
3
3
3 2
4
1.6, 42.1 [CH , C(CH ) ], 116.0 (CCO), 119.7 (CH), 135.6
2 3 2
–
1
IR (KBr): 2973, 1686, 1667, 1582, 1487, 1357, 1200, 836 cm .
(CCH ), 147.1 (NCH), 163.9 (SCN), 195.0 (CO).
3
1H NMR (CDCl3): = 1.48 [s, 6 H, C(CH ) ], 2.22 (d, 3 H, J = 1.2
MS (EI): m/z (%) = 236 (M , 100), 221 (41), 193 (21), 134 (23).
+
3 2
Hz, CH ), 2.23 [s, 3 H, NC(CH )CCO], 5.58 (q, 1 H, J = 1.2 Hz,
CH), 6.04 (s, 1 H, CHCO).
IR (KBr): 1645, 1471, 1362, 1210, 1145, 618 cm–1.
3
3
Anal. Calcd for C12 H N OS (236.3): C, 60.94; H, 6.77; N, 11.85.
1
3C NMR (CDCl3): = 19.8 (CH ), 23.2 [NC(CH )CCO], 28.6
16
2
3
3
Found: C, 61.04; H, 6.61; N, 11.77.
[
C(CH ) ], 41.8 [C(CH ) ], 109.6 (CHCO), 126.8 (CH), 136.0
3 2 3 2
(
CCH ), 160.6, 160.8, 161.8 [NC(CH )CCO, SCN, CO].
3
3
7
-Methoxycarbonyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b]-
+
MS (EI): m/z (%) = 222 (M , 100), 207 (44), 189 (17), 179 (69), 161
33), 126 (43).
[1,3]thiazine (6d)
Yield: 47%; yellow oil; R = 0.3 (CH Cl ).
(
f
2
2
–
1
Anal. Calcd for C H N OS (222.3): C, 59.43; H, 6.32; N, 12.65.
IR (film): 1696, 1481, 1434, 1295, 1210, 1105, 618 cm .
11
14
2
Found: C, 59.54; H, 6.38; N, 12.54.
1H NMR (CDCl3): = 1.44 [s, 6 H, C(CH ) ], 1.99 (d, 3 H, J = 1.2
3
2
Hz, CH ), 3.75 (s, 3 H, OCH ), 4.38 (s, 2 H, CH ), 5.20 (q, 1 H,
J = 1.2 Hz, CH), 7.39 (s, 1 H, NCH).
3
3
2
2
H,6H-Pyrimido[2,1-b][1,3]thiazines 6; General Procedure
A mixture of amidine 2 (4 mmol) and dienophile [acrolein (20
mmol) in CHCl (10 mL) for 6a,b; methyl acrylate (5 mL) for 6d;
methyl vinyl ketone (5 mL) for 6c,e] was stirred for 18 h at 45 °C
1
3
C NMR (CDCl3): = 18.7 (CH ), 29.5 [C(CH ) ], 41.2, 42.4
3
3 2
3
[
CH , C(CH ) ], 51.2 (OCH ), 105.5 (CCO), 119.7 (CH), 135.1
2 3 2 3
(
CCH ), 145.2 (NCH), 162.4, 165.9 (SCN, CO).
(
6a), 24 h at 45 °C (6b), 4 h at 70 °C (6c,e) or 4 d at reflux (6d), then
3
evaporated under reduced pressure, and chromatographed (CH Cl –
EtOAc, 5:1 for 6a,c,e; 7:3 for 6b,d).
+
2
2
MS (EI): m/z (%) = 252 (M , 55), 237 (100), 193 (23), 177 (15).
Anal. Calcd for C12 H N O S (252.3): C, 57.07; H, 6.34; N, 11.09.
16
2
2
Found: C, 57.17; H, 6.14; N, 11.23.
7
(
-Formyl-2,2,4-trimethyl-2H,6H-pyrimido[2,1-b][1,3]thiazine
6a)
Yield: 74%; yellow oil; R = 0.4 (EtOAc).
7
-Acetyl-2,2,4,8-tetramethyl-2H,6H-pyrimido[2,1-b][1,3]-thia-
f
zine (6e)
–
1
IR (film): 2962, 1653, 1616, 1449, 1386, 1353, 1201 cm .
1
Yield: 50%; yellow oil; R = 0.6 (EtOAc: CH Cl 1:1).
f
2
2
H NMR (CDCl3): = 1.45 [s, 6 H, C(CH ) ], 2.01 (d, 3 H, J = 1.2
IR (film): 1661, 1622, 1489, 1360, 1331, 1256, 1217, 982 cm–1.
1H NMR (CDCl3): = 1.43 [s, 6 H, C(CH ) ], 1.98 (d, 3 H, J = 1.2
3 2
Hz, CH ), 4.43 (s, 2 H, CH ), 5.22 (q, 1 H, J = 1.2 Hz, CH), 7.21 (s,
1
3
2
3
2
H, NCH), 9.36 (s, 1 H, CHO).
Hz, CH ), 2.31, 2.39 [2s, 6 H, COCH , NC(CH )CCO], 4.34 (s, 2 H,
3
3
3
1
3
C NMR (CDCl ): = 18.9 (CH ), 29.8 [C(CH ) ], 41.6 [CH ,
3
3
3 2
2
CH ), 5.17 (q, 1 H, J = 1.2 Hz, CH).
2
C(CH ) ], 117.2 (CCO), 120.0 (CH), 135.3 (CCH ), 153.8 (NCH),
1
3
2
3
13
C NMR (CDCl ): = 18.6 (CH ), 23.1 (COCH ), 29.6 [C(CH ) ],
3
3
3
3 2
64.9 (SCN), 188.4 (CHO).
3
1
1
0.7 [NC(CH )CCO], 41.5, 42.9 [CH , C(CH ) ], 112.1 (CCO),
3 2 3 2
+
MS (EI): m/z (%) = 222 (M , 100), 207 (40), 193 (22), 162 (18), 141
19.2 (CH), 134.9 (CCH ), 155.3, 160.7 [SCN, NC(CH )CCO],
3
3
(
43).
95.0 (CO).
Anal. Calcd for C11 H N OS (222.3): C, 59.43; H, 6.32; N, 12.65.
Found: C, 59.46; H, 6.41; N, 12.38.
+
14
2
MS (EI): m/z (%) = 250 (M , 100), 235 (30), 207 (17), 169 (19).
Anal. calcd for C13 H N OS (250.4): C, 62.30; H, 7.19; N, 11.18.
18
2
Found: C, 62.49; H, 7.26; N, 11.43.
7
-Formyl-2,2,4,8-tetramethyl-2H,6H-pyrimido[2,1-b][1,3]-
thiazine (6b)
Yield: 75%; yellow oil; R = 0.6 (EtOAc).
f
Synthesis 2002, No. 3, 403–408 ISSN 0039-7881 © Thieme Stuttgart · New York

4
08
C. Landreau et al.
PAPER
(9) Hammouda, H. A.; Abd-Allah, S. O.; Zoorob, H. H. Acta
Chim. Acad. Sci. Hung. 1985, 119, 49.
10) Potts, K. T.; Ehlinger, R.; Kanemasa, S. J. Org. Chem. 1980,
Acknowledgement
The authors are indebted to the French Ministry of Education and
the CNRS for financial support.
(
(
(
(
(
(
(
(
(
(
(
45, 2474.
11) Ram, V. J.; Vanden Berghe, D. A.; Vlietinck, A. J. J.
Heterocycl. Chem. 1984, 21, 1307.
12) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26,
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Synthesis 2002, No. 3, 403–408 ISSN 0039-7881 © Thieme Stuttgart · New York