From thiourea to bicyclic structures: An original route to imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines

Article abstract of DOI:10.1021/jo034381l

We report an example of an efficient regioselective synthesis of biheterocyclic compounds using thiourea as starting material. In fact, N,N′-bis(dimethylaminomethylene)thiourea (1), easily prepared by double condensation of N,N-dimethylformamide dimethyl acetal with thiourea, can be reacted with haloketones or acrylic dienophiles to give thiazolic (2) and thiazinic (3) diazadienes, respectively, themselves undergoing cyclization reactions to yield imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines without any regioisomeric ambiguity. This straightforward route represents an original and unambiguously regioselective pathway to these valuable heterocycles.

Full text of DOI:10.1021/jo034381l

F r om Th iou r ea to Bicyclic Str u ctu r es: An Or igin a l Rou te to
Im id a zo[2,1-b]th ia zoles, 5H-Th ia zolo[3,2-a ]p yr im id in es,
7H-Im id a zo[2,1-b][1,3]th ia zin es, a n d
2H,6H-P yr im id o[2,1-b][1,3]th ia zin es†
Cyrille Landreau, David Deniaud,* and J ean Claude Meslin
Laboratoire de Synthe`se Organique, UMR CNRS 6513, Faculte´ des Sciences et des Techniques, 2, Rue de
la Houssinie`re, 44322 Nantes Cedex 03, France
david.deniaud@chimie.univ-nantes.fr
Received March 25, 2003
We report an example of an efficient regioselective synthesis of biheterocyclic compounds using
thiourea as starting material. In fact, N,N′-bis(dimethylaminomethylene)thiourea (1), easily
prepared by double condensation of N,N-dimethylformamide dimethyl acetal with thiourea, can
be reacted with haloketones or acrylic dienophiles to give thiazolic (2) and thiazinic (3) diazadienes,
respectively, themselves undergoing cyclization reactions to yield imidazo[2,1-b]thiazoles, 5H-
thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines
without any regioisomeric ambiguity. This straightforward route represents an original and
unambiguously regioselective pathway to these valuable heterocycles.
In tr od u ction
interest due to their antiinflammatory,2a,b psychophar-
macological,2c bactericidal,2d and antiviral activity as
inhibitors of HIV-1 reverse transcriptase.2e On the other
hand, imidazo[2,1-b][1,3]thiazines and pyrimido[2,1-b]-
[1,3]thiazines have prompted less interest, although some
of these compounds proved to be biologically active as
benzodiazepine substitutes3 and antiinflammatory agents,
respectively.4
In recent years, the synthesis of bicyclic compounds
possessing an alkylthioamidine central core has been the
focus of great interest. This is due, in part, to the broad
spectrum of biological properties of these compounds.1-4
Imidazo[2,1-b]thiazole derivatives are of considerable
interest because of their activities as antiarthritic,1a,b
immunomodulating,1c herbicidal,1d cardiotonic,1e antiar-
rhythmic1f and antitumor agents.1g,h One recent paper
has shown them to be effective against tuberculosis.1i
Thiazolo[3,2-a]pyrimidines are also of pharmacological
Numerous methods for the synthesis of these hetero-
cycles involve approaches based on either (i) alkylations
of cyclic thioureas by appropriate 1,2- or 1,3-dielectro-
philes5 or (ii) condensations of 2-aminothiazoles or thi-
azines with 1,2- or 1,3-difunctionalized units, such as R,â-
unsaturated esters or lactam acetals.6 Although frequently
used, both routes can give mixtures of regiosiomers.7
Known regioselective syntheses of these structures in-
volve the retrodiene decomposition of the corresponding
norbornene-fused derivatives8 or the condensation of
2-(cyanoimino)thiazolidine with acyl chlorides,9 2-ami-
nothiazoles with R-halogenoketones,10 isothiocyanato-2-
† Dedicated to the memory of Dr. Alain Reliquet.
(1) (a) Lantos, I.; Gombatz, K.; McGuire, M.; Pridgen, L.; Remich,
J .; Shilcrat, S. J . Org. Chem. 1988, 53, 4223. (b) Shilcrat, S. C.; Hill,
D. T.; Bender, P. E.; Griswold, D. E.; Baures, P. W.; Eggleston, D. S.;
Lantos, I.; Pridgen, L. N. J . Heterocycl. Chem. 1991, 28, 1181. (c)
Devlin, J . P.; Hargrave, K. D. Tetrahedron 1989, 45, 4327. (d) Andreani,
A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Andreani, F.; Gehret, J .-C.
Pharm. Acta Helv. 1996, 71, 247. (e) Andreani, A.; Rambaldi, M.; Leoni,
A.; Locatelli, A.; Bossa, R.; Chiericozzi, M.; Galatulas, I.; Salvatore,
G. Eur. J . Med. Chem. 1996, 31, 383. (f) Andreani, A.; Leoni, A.;
Rambaldi, M.; Locatelli, A.; Bossa, R.; Galatulas, I.; Chiericozzi, M.;
Bissoli, M. Eur. J . Med. Chem. 1997, 32, 151. (g) Andreani, A.; Leoni,
A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Recanatini, M.; Garaliene,
V. Bioorg. Med. Chem. 2000, 8, 2359. (h) Andreani, A.; Rambaldi, M.;
Leoni, A.; Locatelli, A.; Bossa, R.; Fraccari, A.; Galatulas, I.; Salvatore,
G. J . Med. Chem. 1996, 39, 2852. (i) Andreani, A.; Granaloia, M.; Leoni,
A.; Locatelli, A.; Morigi, R.; Rambaldi, M. Eur. J . Med. Chem. 2001,
36, 743.
(2) (a) Tozkoparan, B.; Ertan, M.; Krebs, B.; La¨ge, M.; Kelicen, P.;
Demirdamar, R. Arch. Pharm. Pharm. Med. Chem. 1998, 331, 201.
(b) Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Farmaco
1999, 54, 588. (c) Van Laar, M.; Volkerts, E.; Verbaten, M. Psychop-
harmacology 2001, 154, 189. (d) Parmar, J . M.; Parikh, A. R. Hetero-
cycl. Commun. 1998, 4, 463. (e) Danel, K.; Pedersen, E. B.; Nielsen, C.
J . Med. Chem. 1998, 41, 191.
(5) J arosinski, M. A.; Reddy, P. S.; Anderson, W. K. J . Med. Chem.
1993, 36, 3618.
(6) (a) Malesˇicˇ, M.; Krbavcˇicˇ, A.; Stanovnik, B. J . Heterocycl. Chem.
1997, 37, 813. (b) Bohrish, J .; Pa¨tzel, M.; Liebscher, J .; Maas, G.
Synthesis 1993, 5, 521. (c) Gewald, K.; Heinhold, G. Monatsh. Chem.
1976, 107, 1413.
(7) (a) Lantos, I.; Bender, P. E.; Razgaitis, K. A.; Sutton, B. M.;
DiMartino, M. J .; Griswold, D. E.; Walz, D. T. J . Med. Chem. 1984,
27, 72. (b) Kappe, C. O.; Roschger, P. J . Heterocycl. Chem. 1989, 26,
55. (c) Liu, Y.-S.; Huang, W.-Y. J . Chem. Soc., Perkin Trans 1 1997,
981.
(8) Fu¨lo¨p, F.; Huber, I.; Szabo´, AÄ .; Berna´th, G.; Soha´r, P. Tetrahe-
dron 1991, 47, 7673.
(9) (a) Iwata, C.; Watanabe, M.; Okamoto, S.; Fujimoto, M.; Sakae,
M.; Katsurada, M.; Imanishi, T. Synthesis 1988, 261. (b) Tanaka, T.;
Iwata, C. J . Synth. Org. Chem. J pn. 1998, 56, 182.
(10) Meakins, G. D.; Musk, S. R. R.; Robertson, C. A.; Woodhouse,
L. S. J . Chem. Soc., Perkin Trans. 1 1989, 643.
(3) (a) Kiec´-Kononowicz, K.; Karolak-Wojciechowska, J .; Mu¨ller C.
E.; Schumacher, B.; Pe¸kala, E.; Szyman´ska, E. Eur. J . Med. Chem.
2001, 36, 407. (b) Geis, U.; Kiec´-Kononowicz, K.; Mu¨ller, C. E. Sci.
Pharm. 1996, 64, 383.
(4) Bo´zsing, D.; Soha´r, P.; Gigler, G.; Kova´cs, G. Eur. J . Med. Chem.
1996, 31, 663.
10.1021/jo034381l CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003
4912
J . Org. Chem. 2003, 68, 4912-4917

From Thiourea to Bicyclic Structures
TABLE 1. Yield s of Com p ou n d s 2a -d a n d 3a ,b
SCHEME 1. P r ep a r a tion of Bicyclic Str u ctu r es
compd
R
yield (%)
2a
COOCH3
81
74
82
72
48
45
2b13j
2c
COC6H4Br-p
COC6H4Cl-p
COC6H4CH3-p
CHO
2d
3a
3b13j
COCH3
dimethylformamide dimethyl acetal and thiourea in
dichloromethane. It is worth noting that monoconden-
sation was favored when methanol was employed as the
solvent.13c
With gram quantities of precursor (1) in hand, initial
work focused on exploring its reactivity toward various
electrophiles. First, treatment of N,N′-bis(dimethylami-
nomethylene)thiourea (1) with R-bromoketones or methyl
bromoacetate gave nonisolated S-alkyl salts, which un-
derwent cyclization when treated with a base via con-
densation of the generated enolate with one of the
amidinium moieties. Spontaneous deamination of the
intermediary cycloadduct afforded N,N-dimethyl-N′-
(thiazol-2-yl)amidines (2) in high yields (Table 1, Scheme
2). This mirrors work described by Knoll and Liebscher;14
however, these authors did not make any attempts
toward further cyclizations.
We then decided to investigate the feasibility of a
reaction between N,N′-bis(dimethylaminomethylene)th-
iourea (1) and acrylic dienophiles. This reaction gave
N,N-dimethyl-N′-(6H-1,3-thiazin-2-yl)formamidines (3) in
only moderate yields after loss of dimethylamine (Table
1, Scheme 2). In accordance with the literature, we
assume that the reaction proceeds by a classical hetero-
Diels-Alder reaction rather than a conjugate addition/
alkylation.15 When acrolein was used as the dienophile,
partial degradation (20-30%) of the product amidine side
chain was observed during the workup procedure, leading
to the undesired 5-formyl-2-formylamino-6H-1,3-thiazine.
Whereas with methyl vinyl ketone the main problem was
double condensation resulting from second [4 + 2] cy-
cloaddition between this dienophile and the resulting
thiazine 3b, occurring before complete consumption of the
starting material. Consequently bicycle 9c was observed
as a major side product (15%). Compounds 3 were
unambiguously characterized by spectroscopy techniques.
The proof of the thiazine structure, so the total regiose-
lectivity, was given by the 1H NMR spectra where we
observed the loss of dimethylamino group and the pres-
ence of two singlets (3.68 and 7.52 for S-CH2 and N-CH,
respectively).
propenium salts with R-aminoketones11 or other specific
reactants.12 The methods mentioned above offer variable
versatility and convenience.
New routes to these structures would be of great
interest, and recently we published efficient synthetic
procedures involving heterocyclic diazadienes.13e,f We
showed that such amidines, prepared by condensation
of 2-aminothiazoline or 2-amino-4,6,6-trimethyl-6H-1,3-
thiazine with N,N-dimethylacetamide or formamide dim-
ethyl acetal, were useful building blocks for the regiose-
lective synthesis of these heterocycles. As part of our
continuing study on the reactivity of polyheteropoly-
enes,13 we now report that title compounds can be
conveniently prepared in three steps starting from thio-
urea. By this method, we recently described a novel acces
to thiazolopyrimidine and imidazo-1,3-thiazine deriva-
tives involving compound 1.13j Our method utilizes N,N′-
bis(dimethylaminomethylene)thiourea (1) as a common
intermediate, undergoing cyclization reactions to afford
either five- (2) or six-membered-ring (3) monocyclic
diazadienes, themselves being precursors to the bicyclic
structures (Scheme 1).
Resu lts a n d Discu ssion
Compound 1 was easily prepared in 95% yield by
double condensation of commercially available N,N-
(11) Liebscher, J .; Hassoun, A. Synthesis 1988, 10, 816.
(12) (a) Bossio, R.; Marcaccini, S.; Pepino, R.; Paoli, P. J . Heterocycl.
Chem. 1993, 30, 33. (b) Malesˇicˇ, M.; Krbavcˇicˇ, A.; Stanovnik, B. J .
Heterocycl. Chem. 1997, 34, 49. (c) Kutyrev, A.; Kappe, T. J . Heterocycl.
Chem. 1999, 36, 237.
We have previously demonstrated 4,5-dihydrothiazole
amidines to be useful heterodienes.13e It therefore seemed
reasonable to investigate the feasibility of cycloadducts
2 to act as heterodienes, their aromaticity being clearly
decreased by the presence of an electron-withdrawing
group in the 5-position. Moreover, the same consideration
(13) (a) Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J . C. Synthesis
2000, 5, 695. (b) Landreau, C.; Deniaud D.; Reliquet, A.; Reliquet, F.;
Meslin, J . C. Heterocycles 2000, 53, 2667. (c) Landreau, C.; Deniaud
D.; Reliquet, A.; Reliquet, F.; Meslin, J . C. J . Heterocycl. Chem. 2001,
38, 93. (d) Charrier, J .-D.; Landreau, C.; Deniaud D.; Reliquet, A.;
Reliquet, F.; Meslin, J . C. Tetrahedron 2001, 57, 4195. (e) Landreau,
C.; Deniaud, D.; Reliquet, A.; Meslin, J . C. Synthesis 2001, 13, 2015.
(f) Landreau, C.; Deniaud, D.; Reliquet, A.; Meslin, J . C. Synthesis
2002, 3, 403. (g) Landreau, C.; Deniaud, D.; Evain, M.; Reliquet, A.;
Meslin, J . C. J . Chem. Soc., Perkin Trans. 1 2002, 6, 741. (h) Landreau,
C.; Deniaud, D.; Reliquet, A.; Meslin, J . C. Phosphorus, Sulfur Silicone
2002, 177 (11), 2651. (i) Landreau, C.; Deniaud, D.; Reliquet, A.;
Meslin, J . C. Tetrahedron Lett. 2002, 43, 4099. (j) Landreau, C.;
Deniaud, D.; Reliquet, A.; Meslin, J . C. Eur. J . Org. Chem. 2003, 3,
421.
(14) (a) Knoll, A.; Liebscher, J . Synthesis 1984, 51. (b) Knoll, A.;
Liebscher, J .; Radeglia, R. J . Prakt. Chem. 1985, 327, 463.
(15) (a) Meslin, J . C.; Quiniou, H. Bull. Soc. Chim. Fr. 1979, 347.
(b) Marchand, A.; Pradere, J . P.; Guingant, A. Tetrahedron Lett. 1997,
38, 1033. (c) Saito, T.; Fujii, H.; Hayashibe, S.; Matsushita, T.; Kato,
H.; Kobayashi, K. J . Chem. Soc., Perkin Trans. 1 1996, 1897. (d)
Barluenga, J .; Toma´s, M.; Ballestero´s, A.; Lopez, L. A. J . Org. Chem.
1991, 56, 5680. (e) Barnish, I. T.; Fishwick, C. W. G.; Hill, D. R.
Tetrahedron Lett. 1991, 32, 405.
J . Org. Chem, Vol. 68, No. 12, 2003 4913

Landreau et al.
SCHEME 2. Syn th esis of 2 a n d 3a
a
Reagents and conditions: (a) CH2Cl2, rt, 15 min then TEA, rt, 20 h; (b) CH2Cl2, rt, 18 h.
TABLE 2. Yield s of Com p ou n d s 4a -e a n d 5a ,b
TABLE 3. Yield s of Com p ou n d s 6a -e a n d 7a -c
compd
R
R1
yield (%)
compd
R
R2
yield (%)
4a
4b
4c
4d
CO2CH3
COC6H4Cl-p
COC6H4Br-p
COC6H4CH3-p
COC6H4Cl-p
COC6H4CH3-p
COC6H4Br-p
COC6H4Br-p
68
74
73
87
82
41
49
6a
6b
6c
6d
6e
7a
7b
7c
COC6H4Cl-p
COC6H4Br-p
COC6H4Cl-p
COC6H4CH3-p
COC6H4Cl-p
COCH3
H
55
77
86
65
63
58
51
59
COC6H4Br-p
COC6H4Br-p
COC6H4CH3-p
COC6H4Cl-p
CHO
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
H
4e
5a
5b13j
COCH3
CHO
COCH3
CO2C2H5
CO2C2H5
SCHEME 3. Syn th esis of 4a -e a n d 5a ,ba
SCHEME 4. Syn th esis of 6a -e a n d 7a -ca
a
Reagents and conditions: THF, reflux, 6 or 20 h then TEA,
rt, 24 h.
a
Reagents and conditions: (a) R2 ) H, CH2Cl2, rt, 1 h; (b) R2 *
H, CH2Cl2, rt, 4 h, then TEA, 0 °C f rt, 16 h.
could be applied to compounds 3, which should react in
a similar way as the thiazine amidines previously studied
by our group.13f
Initially the reaction of amidines 2 and 3 with R-bro-
moketones was examined. As expected, the resulting
N-alkyl salts, whose isolations were not encouraged, were
converted in situ by addition of triethylamine, leading
after spontaneous deamination to the corresponding
imidazo[2,1-b]thiazoles (4) and 7H-imidazo[2,1-b][1,3]-
thiazines (5) (Table 2, Scheme 3).
TABLE 4. Yield s of Com p ou n d s 8a -c a n d 9a -c
compd
R
R2
yield (%)
8a 13j
8b
8c
COC6H4Br-p
COC6H4Cl-p
COC6H4CH3-p
CHO
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
CHO
47
53
46
48
53
52
9a
9b
9c13j
COCH3
Treatment of compounds 2 and 3 with a range of
ketenes led to a [4 + 2] cyclocondensation which gave
5H-thiazolo[3,2-a]pyrimidin-5-ones (6) and 2H,6H-py-
rimido[2,1-b][1,3]thiazin-6-ones (7), respectively, by loss
of dimethylamine (Table 3, Scheme 4). Our pathway
excludes any regioisomeric ambiguity: indeed, the 1H
NMR deshielding effect observed for the proton signal
in position 3 (for 6a -e) or 4 (for 7a -c) is unambiguously
attributed to the proximity of the carbonyl function of
pyrimidinic ring. Moreover, the final step that consisted
of deamination of the supposed intermediary cycloadduct
was not possible for the unlikely isomer.
tandem [4 + 2] cycloaddition/deamination process oc-
curred as expected, furnishing 5H-thiazolo[3,2-a]pyrim-
idines (8) and 2H,6H-pyrimido[2,1-b][1,3]thiazines (9)
respectively, albeit in moderate yields (Table 4, Scheme
5). It is worth noting that this synthetic sequence makes
it possible to obtain regioisomers 9a and 9b, both bearing
an acetoxy and a formyl group, in a regiocontrolled
manner. Similarly, the expected derivatives 8 and 9 were
1
obtained with an absolute regioselectivity. The H NMR
spectra of 8a -c and 9a -c showed a singlet due to the
methylene group in position 5 or 6, respectively, and thus
excluded the regioisomeric substituted structure.
In conclusion, we have demonstrated N,N′-bis(dim-
ethylaminomethylene)thiourea 1 to be a suitable building
Finally, to complete this study, we decided to investi-
gate the behavior of amidines 2 and 3 with acrylic
dienophiles (either as neat liquids or in chloroform). The
4914 J . Org. Chem., Vol. 68, No. 12, 2003

From Thiourea to Bicyclic Structures
SCHEME 5. Syn th esis of 8a -c a n d 9a -ca
Compounds 3a was isolated as a yellow oil by chromatography
(elution ethyl acetate/acetone 3/2) (yield 48%). Rf (acetone) )
0.2. IR: 2928, 1618, 1453, 1108 cm-1. 1H NMR (CDCl3) δ: 3.16
(s, 3H), 3.20 (s, 3H), 3.68 (s, 2H), 7.52 (s, 1H), 8.40 (s, 1H),
9.46 (s, 1H). 13C NMR (CDCl3) δ: 21.9, 35.7, 41.7, 114.5, 157.3,
158.3, 171.7, 190.1. MS m/z: 197 (52, M+), 168 (100), 115 (64).
Anal. Calcd for C8H11N3OS: C, 48.71; H, 5.62; N, 21.30.
Found: C, 48.63; H, 5.76; N, 21.18.
Im id a zo[2,1-b]th ia zoles (4). Compounds 4 were prepared
using the same procedure described above for the synthesis
of 2.
5-p-Ch lor oben zoyl-2-m eth oxyca r bon ylim id a zo[2,1-b]-
th ia zole (4a ). Colorless crystals (yield 68%). Mp: 180.5-181.5
°C. IR (KBr): 1726, 1264 cm-1 1H NMR (CDCl3) δ: 3.98 (s,
.
a
Reagents and conditions: neat or CHCl3, reflux, 6 h or 4 days.
3H), 7.50-7.88 (m, 4H), 7.97 (s, 1H), 9.12 (s, 1H). 13C NMR
(CDCl3) δ: 53.2, 124.5, 127.3, 129.2 (2), 130.1 (2), 136.0, 139.2,
145.0 (2), 156.5, 161.2, 181.7. MS m/z: 322/320 (39/100, M+),
209 (76), 141/139 (12/37), 113/111 (16/51). Anal. Calcd for
block for the synthesis of imidazo[2,1-b]thiazoles (4), 5H-
thiazolo[3,2-a] pyrimidines (6 and 8), 7H-imidazo[2,1-b]-
[1,3]thiazines (5) and 2H,6H-pyrimido[2,1-b] [1,3]thiaz-
ines (7 and 9). This straightforward route represents an
original and unambiguously regioselective pathway to
these valuable heterocycles.
C
14H9ClN2O3S: C, 52.43; H, 2.83; N, 8.73. Found: C, 52.61;
H, 3.02; N, 8.58.
2,5-Bis(p-br om oben zoyl)im idazo[2,1-b]th iazole (4b). Col-
orless crystals (yield 74%). Mp: 253-255 °C. IR (KBr): 2362,
1629, 1618, 1585, 1438, 1400 cm-1. 1H NMR (CDCl3) δ: 7.67-
7.83 (m, 8H), 8.01 (s, 1H), 8.95 (s, 1H). 13C NMR (CDCl3) δ:
127.5, 127.9, 129.3 (2), 130.1 (2), 130.4 (2), 130.7 (2), 134.3,
134.4, 134.9, 135.1, 144.2, 145.0, 156.4, 181.9, 182.6. MS m/z:
492/490/488 (52/92/46, M+), 335/333 (35/36), 185/183 (95/100),
157/155 (70/73). Anal. Calcd for C19H10Br2N2O2S: C, 46.56; H,
2.06; N, 5.72. Found: C, 46.77; H, 2.14; N, 5.59.
Exp er im en ta l Section
N,N-Dim eth yl-N′-(th ia zol-2-yl)a m id in es (2). The R-car-
bonylated bromide (5 mmol) (methyl bromoacetate for 2a ,
p-bromophenacyl bromide for 2b,13j p-chlorophenacyl bromide
for 2c, p-toluoylacyl bromide for 2d ) was added to a solution
of N,N′-bis(dimethylaminomethylene)thiourea 1 (5 mmol) in
dichloromethane (10 mL). After 15 min of stirring at room
temperature, the triethylamine (10 mmol) was added. The
reaction mixture was further stirred for 20 h, and then the
solvent was evaporated. The residue, diluted with dichlo-
romethane, was purifed by chromatography (elution dichlo-
romethane/ethyl acetate 1/9 for 2a , 4/1 for 2b, 3/2 for 2c, 3/1
for 2d ). Compounds 2 were recrystallized from ether.
2-p -Br om ob en zoyl-5-p -t olu oylim id a zo[2,1-b]t h ia zole
(4c). Colorless crystals (yield 73%). Mp: 193-196 °C. IR
(KBr): 1632, 1620, 1587, 1380 cm-1. 1H NMR (CDCl3) δ: 2.47
(s, 3H), 7.33-7.84 (m, 8H), 8.03 (s, 1H), 8.97 (s, 1H). 13C NMR
(CDCl3) δ: 21.6, 127.1, 128.1, 128.7 (2), 129.5 (2), 130.2 (2),
132.3 (2), 129.5, 134.2, 134.6, 135.1, 143.7, 145.0, 156.2, 182.8,
186.1. MS m/z: 426/424 (63/59, M+), 185/183 (47/48), 119 (66),
91 (100). Anal. Calcd for C20H13BrN2O2S: C, 56.48; H, 3.08;
N, 6.59. Found: C, 56.27; H, 3.22; N, 6.38.
N ′-(5-Me t h oxyca r b on ylt h ia zol-2-yl)-N ,N -d im e t h yl-
for m a m id in e (2a ). Yellow crystals (yield 81%). Mp: 104.5-
5-p -Ch lor ob en zoyl-2-p -t olu oylim id a zo[2,1-b]t h ia zole
(4d ). Colorless crystals (yield 87%). Mp: 184.5-185.5 °C. IR
105.5 °C. IR (KBr): 3087, 1703, 1621, 1401, 1318, 1249 cm-1
.
1
(KBr): 2358, 1652, 1645, 1373, 897 cm-1. H NMR (CDCl3) δ:
1H NMR (CDCl3) δ: 3.11 (s, 3H), 3.14 (s, 3H), 3.85 (s, 3H),
7.98 (s, 1H), 8.35 (s, 1H). 13C NMR (CDCl3) δ: 34.9, 40.9, 51.7,
120.9, 147.0, 156.0, 162.4, 179.7. MS m/z: 213 (52, M+), 153
(86), 42 (100). Anal. Calcd for C8H11N3O2S: C, 45.06; H, 5.20;
N, 19.70. Found: C, 44.87; H, 5.06; N, 19.53.
2.49 (s, 3H), 7.36-7.88 (m, 8H), 8.00 (s, 1H), 8.96 (s, 1H). 13C
NMR (CDCl3) δ: 21.6, 126.7, 127.5, 129.0 (2), 129.1 (2), 129.7
(2), 129.9 (2), 133.6, 135.1, 135.7, 139.1, 144.4, 145.2, 156.7,
181.6, 186.6. MS m/z: 382/380 (31/70, M+
), 269 (19), 119 (100),
91 (74). Anal. Calcd for C20H13ClN2O2S: C, 63.08; H, 3.44; N,
7.36. Found: C, 63.25; H, 3.29; N, 7.54.
N′-(5-p-Ch lor oben zoylth ia zol-2-yl)-N,N-d im eth ylfor m -
a m id in e (2c). Yellow crystals (yield 82%). Mp: 159-160 °C.
2-p -Ch lor ob en zoyl-5-p -t olu oylim id a zo[2,1-b]t h ia zole
(4e). Colorless crystals (yield 82%). Mp: 160.5-161.5 °C. IR
IR (KBr): 2918, 1632, 1608, 1448 cm-1 1H NMR (CDCl3) δ:
.
1
(KBr): 1636, 1620, 1380, 1302, 899 cm-1. H NMR (CDCl3) δ:
3.15 (s, 3H), 3.17 (s, 3H), 7.44-7.78 (m, 4H), 7.81 (s, 1H), 8.36
(s, 1H). 13C NMR (CDCl3) δ: 35.0, 40.9, 128.7 (2), 130.1 (2),
131.9, 136.6, 138.1, 149.0, 156.4, 181.1, 185.8. MS m/z: 295/
293 (40/100, M+), 154 (87). Anal. Calcd for C13H12ClN3OS: C,
53.15; H, 4.12; N, 14.30. Found: C, 53.01; H, 3.91; N, 14.15.
2.47 (s, 3H), 7.33-7.80 (m, 8H), 8.02 (s, 1H), 8.97 (s, 1H). 13C
NMR (CDCl3) δ: 21.5, 127.0, 128.1, 128.3 (2), 128.4 (2), 128.4
(2), 130.1 (2), 130.1, 134.1, 134.6, 139.8, 143.7, 145.0, 156.1,
182.7, 185.8. MS m/z: 382/380 (42/100, M+), 291/289 (9/22),
141/139 (16/52), 119 (45), 91 (59). Anal. Calcd for C20H13
ClN2O2S: C, 63.08; H, 3.44; N, 7.36. Found: C, 63.21; H, 3.63;
N, 7.60.
-
N ,N -Dim e t h yl-N ′-(5-p -t olu oylt h ia zol-2-yl)for m a m i-
d in e (2d ). Yellow crystals (yield 72%). Mp: 146-148 °C. IR
1
(KBr): 1610, 1442, 1371, 1283, 1100 cm-1. H NMR (CDCl3)
δ: 2.44 (s, 3H), 3.14 (s, 3H), 3.17 (s, 3H), 7.26-7.76 (m, 4H),
7.84 (s, 1H), 8.35 (s, 1H). 13C NMR (CDCl3) δ: 21.5, 35.2, 41.1,
128.9 (2), 129.1 (2), 132.5, 135.6, 142.6, 148.6, 156.4, 180.1,
187.0. MS m/z: 273 (100, M+), 154 (59), 119 (41). Anal. Calcd
for C14H15N3OS: C, 61.52; H, 5.53; N, 15.37. Found: C, 61.40;
H, 5.76; N, 15.51.
3-p -Br om ob e n zoyl-6-for m yl-7H -im id a zo[2,1-b][1,3]-
th ia zin e (5a ). The p-bromophenacyl bromide (1.1 mmol) was
added to a solution of amidine 3 (1 mmol) in tetrahydrofuran
(10 mL). The reaction mixture was refluxed for 6 h. After the
mixture was cooled to room temperature, triethylamine (2.2
mmol) was added. The mixture was further stirred for 24 h.
The solvent was then evaporated, and the residue, diluted with
dichloromethane, was purifed by chromatography (elution
dichloromethane/ethyl acetate 9/1). Compound 5 was recrys-
tallized from ether. Colorless crystals (yield 41%). Mp: 144-
N,N-Dim et h yl-N′-(5-for m yl-6H -1,3-t h ia zin -2-yl)for m -
a m id in e (3a ). The N,N′-bis(dimethylaminomethylene)thio-
urea 1 (4 mmol) was added to a solution of acroleine (20 mmol)
in dichloromethane (10 mL). The reaction mixture was stirred
for 18 h at room temperature, diluted with acetone (80 mL),
and filtered through a short pad of Celite. The solvent was
evaporated, and the residue was diluted with dichloromethane.
1
146 °C. IR (KBr): 1685, 1646, 1623, 1422, 1336, 894 cm-1. H
NMR (CDCl3) δ: 3.88 (d, 2H, J ) 0.9 Hz), 7.63 (s, 1H), 7.64-
7.76 (m, 4H), 8.50 (t, 1H, J ) 0.9 Hz), 9.65 (s, 1H). 13C NMR
J . Org. Chem, Vol. 68, No. 12, 2003 4915

Landreau et al.
(CDCl3) δ: 20.4, 120.6, 128.3, 129.8, 136.5, 130.4 (2), 132.3
(2), 141.3, 142.6, 150.4, 183.0, 188.3. MS m/z: 350/348 (35/33,
M+), 185/183 (99/100), 157/155 (56/58). Anal. Calcd for C14H9-
BrN2O2S: C, 48.15; H, 2.60; N, 8.02. Found: C, 48.23; H, 2.49;
N, 7.98.
2H ,6H -P yr im id o[2,1-b][1,3]t h ia zin -6-on es (7). Com-
pounds 7 were prepared using the same procedure described
above for the synthesis of 6.
3-Acetyl-2H,6H-p yr im id o[2,1-b][1,3]th ia zin -6-on e (7a ).
Colorless crystals (yield 58%). Mp: 159.5-160.5 °C. IR (KBr):
1696, 1673, 1409, 1401. 1H NMR (CDCl3) δ: 2.51 (s, 3H), 3.83
(d, 2H, J ) 0.9 Hz), 6.27 (d, 1H, J ) 6.6 Hz), 7.73 (d, 1H, J )
6.6 Hz), 8.43 (t, 1H, J ) 0.9 Hz). 13C NMR (CDCl3) δ: 21.4,
25.5, 111.2, 122.1, 132.1, 152.5, 158.3, 158.8, 194.5. MS m/z:
208 (100, M+), 165 (47), 112 (59). Anal. Calcd for C9H8N2O2S:
C, 51.91; H, 3.87; N, 13.45. Found: C, 51.84; H, 3.93; N, 13.60.
7-E t h oxyca r b on yl-3-for m yl-2H ,6H -p yr im id o[2,1-b]-
[1,3]th ia zin -6-on e (7b). Colorless crystals (yield 51%). Mp:
150.5-151.5 °C. IR (KBr): 1745, 1663, 1496. 1H NMR (CDCl3)
δ: 1.38 (t, 3H, J ) 7.2 Hz), 3.85 (d, 2H, J ) 0.9 Hz), 4.38 (q,
2H, J ) 7.2 Hz), 8.34 (t, 1H, J ) 0.9 Hz), 8.48 (s, 1H), 9.70 (s,
1H). 13C NMR (CDCl3) δ: 14.3, 21.0, 61.7, 113.2, 122.2, 138.0,
155.1, 162.8, 163.5, 157.6, 188.2. MS m/z: 266 (86, M+), 221
(99), 220 (100), 194 (98). Anal. Calcd for C11H10N2O4S: C,
49.62; H, 3.79; N, 10.52. Found: C, 49.68; H, 3.89; N, 10.77.
3-Acetyl-7-eth oxyca r bon yl-2H,6H-p yr im id o[2,1-b][1,3]-
th ia zin -6-on e (7c). Colorless crystals (yield 59%). Mp: 109-
5H -Th ia zolo[3,2-a ]p yr im id in -5-on es (6). Met h od A.
Ketene (CAUTION!) produced by cracking of acetone, was
bubbled into a solution of thiazolylamidine 2c (2 mmol) in
dichloromethane (100 mL) until complete consumption of the
starting material, as monitored by TLC (1 h). The solvent was
then evaporated, and the resulting residue was diluted with
dichloromethane and purifed by chromatography (elution ethyl
acetate/dichloromethane 5/1).
Meth od B. The acyl chloride (2.4 mmol) (methyl malonyl
chloride for 6b,c,d , ethyl malonyl chloride for 6e) was added
to a solution of amidine 2b-d (2 mmol) in dichloromethane
(10 mL). After 4 h of stirring at room temperature, the reaction
mixture was cooled to 0 °C and triethylamine (4.8 mmol) was
added. The mixture was stirred at room temperature for
further 16 h, and then the solvent was evaporated. The residue
was diluted with dichloromethane and purifed by chromatog-
raphy (elution dichloromethane/ethyl acetate 9/1). Compounds
6b-e were recrystallized from ether.
1
111 °C. IR (KBr): 1710, 1487 cm-1. H NMR (CDCl3) δ: 1.39
(t, 3H, J ) 7.2 Hz), 2.51 (s, 3H), 3.86 (d, 2H, J ) 0.9 Hz), 4.38
(q, 2H, J ) 7.2 Hz), 8.46 (t, 1H, J ) 0.9 Hz), 8.49 (s, 1H). 13C
NMR (CDCl3) δ: 14.3, 21.4, 25.6, 61.6, 112.7, 121.8, 131.9,
155.6, 163.0, 163.7, 157.5, 194.3. MS m/z: 280 (26, M+), 234
(100). Anal. Calcd for C12H12N2O4S: C, 51.42; H, 4.31; N, 9.99.
Found: C, 51.64; H, 4.48; N, 10.15.
2-p -Ch lor ob e n zoyl-5H -t h ia zolo[3,2-a ]p yr im id in -5-
on e (6a ). Yellow foam (yield 55%). IR (KBr): 1689, 1635, 1587,
1
1323, 1222, 1091, 817 cm-1. H NMR (CDCl3) δ: 6.36 (d, 1H,
J ) 6.6 Hz), 7.54-7.88 (m, 4H), 8.05 (d, 1H, J ) 6.6 Hz), 8.43
(s, 1H). 13C NMR (CDCl3) δ: 106.9, 127.5, 129.4, 129.7 (2),
130.5 (2), 134.0, 140.7, 154.3, 158.5, 163.3, 185.2. MS m/z: 292/
290 (36/97, M+), 141/139 (34/100), 113/111 (12/35). Anal. Calcd
for C13H7ClN2O2S: C, 53.71; H, 2.43; N, 9.64. Found: C, 53.51;
H, 2.49; N, 10.01.
5H-Th ia zolo[3,2-a ]p yr im id in es (8). A solution of amidine
2b-d (4 mmol) in methyl vinyl ketone (7 mL) was heated
under reflux for 4 days. The excess methyl vinyl ketone was
evaporated, and then the residue was diluted with dichlo-
romethane and purifed by chromatography (elution ethyl
2-p-Br om oben zoyl-6-m eth oxycar bon yl-5H-th iazolo[3,2-
a ]p yr im id in -5-on e (6b). Colorless crystals (yield 77%). Mp:
acetate). Compounds
8 were recrystallized from dichlo-
romethane (for 8a 13j) or dichloromethane/ether (for 8b,c).
5-Acetyl-2-p-ch lor oben zoyl-5H-th ia zolo[3,2-a ]p yr im i-
d in e (8b). Yellow crystals (yield 53%). Mp: 219-221 °C. IR
177-179 °C. IR (KBr): 1749, 1491, 1313 cm-1 1H NMR
.
(CDCl3) δ: 3.94 (s, 3H), 7.76-7.78 (m, 4H), 8.54 (s, 1H), 8.85
(s, 1H). 13C NMR (CDCl3) δ: 52.3, 108.5, 127.7, 129.6, 130.4
(2), 132.6 (2), 130.5, 133.9, 154.8, 159.3, 164.0, 166.7, 184.7.
MS m/z: 394/392 (67/68, M+), 363/361 (100/94), 185/183 (69/
69), 157/155 (52/53). Anal. Calcd for C15H9BrN2O4S: C, 45.82;
H, 2.31; N, 7.12. Found: C, 45.68; H, 2.46; N, 7.01.
(KBr): 1617, 1592, 1496, 1250 cm-1 1H NMR (CF3CO2D) δ:
.
2.56 (s, 3H), 5.28 (s, 2H), 7.59-7.90 (m, 4H), 7.76 (s, 1H), 8.09
(s, 1H). 13C NMR (CF3CO2D) δ: 25.1, 48.8, 115.3, 132.1 (2),
132.4 (2), 133.4, 134.6, 136.0, 138.6, 145.5, 165.7, 188.5, 201.6.
MS m/z: 320/318 (36/100, M+), 141/139 (16/48), 113/111 (12/
40). Anal. Calcd for C15H11ClN2O2S: C, 56.52; H, 3.48; N, 8.79.
Found: C, 56.37; H, 3.32; N, 8.63.
2-p -Ch lor ob en zoyl-6-m et h oxyca r b on yl-5H -t h ia zolo-
[3,2-a ]p yr im id in -5-on e (6c). Colorless crystals (yield 86%).
Mp: 179.5-180.5 °C. IR (KBr): 1747, 1492, 1371, 1312, 1191
cm-1. 1H NMR (CDCl3) δ: 3.94 (s, 3H), 7.55-7.89 (m, 4H), 8.53
(s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ: 52.4, 108.5, 127.8,
129.7 (2), 130.5 (2), 130.6, 133.6, 140.9, 154.9, 159.3, 164.1,
166.8, 184.6. MS m/z: 350/348 (29/66, M+), 319/317 (47/100),
251/249 (12/30). Anal. Calcd for C15H9ClN2O4S: C, 51.66; H,
2.60; N, 8.03. Found: C, 51.47; H, 2.49; N, 7.94.
5-Acetyl-2-p-tolu oyl-5H-th ia zolo[3,2-a ]p yr im id in e (8c).
Yellow crystals (yield 46%). Mp: 224-227 °C. IR (KBr): 1617,
1
1604, 1506, 1253. H NMR (CF3CO2D): 2.53 (s, 3H), 2.57 (s,
3H), 5.30 (s, 2H), 7.46-7.88 (m, 4H), 7.78 (s, 1H), 8.11 (s, 1H).
13C NMR (CF3CO2D): 22.7, 25.5, 49.1, 115.6, 131.8 (2), 132.7
(2), 133.8, 134.2, 136.4, 139.1, 151.2, 166.1, 189.7, 202.0. Anal.
Calcd for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39. Found: C,
64.57; H, 4.81; N, 9.49.
2H,6H-P yr im id o[2,1-b][1,3]th ia zin es (9). Thiazinylami-
dine 3 (1 mmol) was added to methyl vinyl ketone (5 mL) for
9a ,c or to a solution of acrolein (8 mmol) in chloroform (10
mL) for 9b. The reaction mixture was stirred for 6 h at 45 °C
(for 9a ), at 60 °C (for 9b), and for 4 h under reflux (for 9c13j).
The mixture was then diluted with acetone (60 mL) and
6-Met h oxyca r bon yl-2-p -t olu oyl-5H -t h ia zolo[3,2-a ]p y-
r im id in -5-on e (6d ). Colorless crystals (yield 65%). Mp: 158-
161 °C. IR (KBr): 1712, 1699, 1487, 1320, 1126 cm-1. 1H NMR
(CDCl3) δ: 2.49 (s, 3H), 3.94 (s, 3H), 7.36-7.84 (m, 4H), 8.55
(s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ: 21.8, 52.4, 108.4,
127.5, 129.3 (2), 130.0 (2), 131.2, 132.7, 145.5, 155.0, 159.3,
164.3, 167.0, 185.3. MS m/z: 328 (80, M+), 297 (100), 119 (85),
91 (81). Anal. Calcd for C16H12N2O4S: C, 58.53; H, 3.68; N,
8.53. Found: C, 58.42; H, 3.76; N, 8.77.
filtered through
a short pad of Celite. The solvent was
evaporated, the residue was diluted with dichloromethane, and
compounds 9 were isolated after chromatography (elution
dichloromethane/ethyl acetate 1/1 for 9a , ethyl acetate/acetone
19/1 for 9b, ethyl acetate for 9c). Compound 9a was isolated
as an oil; compounds 9b,c were recrystallized from ether.
7-Acetyl-3-for m yl-2H,6H-p yr im id o[2,1-b][1,3]th ia zin e
(9a ). Yellow oil (yield 48%). Rf (EtOAc) ) 0.4. IR (KBr): 2924,
1641, 1499, 1259, 1208, 1143. 1H NMR (CDCl3) δ: 2.32 (s, 3H),
3.68 (d, 2H, J ) 0.9 Hz), 4.53 (d, 2H, J ) 1.2 Hz), 6.79 (t, 1H,
J ) 0.9 Hz), 7.36 (t, 1H, J ) 1.2 Hz), 9.40 (s, 1H). 13C NMR
(CDCl3) δ: 21.0, 24.9, 48.7, 117.5, 118.8, 144.2, 148.2, 163.2,
187.0, 195.3. MS m/z: 222 (75, M+), 43 (100). Anal. Calcd for
2-p-Ch lor oben zoyl-6-eth oxyca r bon yl-5H-th ia zolo[3,2-
a ]p yr im id in -5-on e (6e). Yellow crystals (yield 63%). Mp:
135-137 °C. IR (KBr): 1745, 1477, 1131 cm-1 1H NMR
.
(CDCl3) δ: 1.40 (t, 3H, J ) 7.2 Hz), 4.40 (q, 2H, J ) 7.2 Hz),
7.55-7.88 (m, 4H), 8.54 (s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3)
δ: 14.3, 61.4, 108.9, 127.9, 129.7 (2), 130.5 (2), 130.5, 133.6,
140.9, 154.9, 159.1, 163.5, 166.7, 184.6. MS m/z: 364/362 (12/
28, M+), 292/290 (41/100), 141/139 (27/79), 113/111 (15/46).
Anal. Calcd for C16H11ClN2O4S: C, 52.97; H, 3.06; N, 7.72.
Found: C, 53.19; H, 3.25; N, 7.81.
4916 J . Org. Chem., Vol. 68, No. 12, 2003

From Thiourea to Bicyclic Structures
10H10N2O2S: C, 54.04; H, 4.53; N, 12.60. Found: C, 54.26;
C
Ack n ow led gm en t. We are grateful to the French
Ministry of Education and the CNRS for financial
support.
H, 4.61; N, 12.48.
7 -F o r m y l -3 -a c e t y l -2 H ,6 H -p y r i m i d o [2 ,1 -b ][1 ,3 ]-
th ia zin e (9b). Yellow crystals (yield 53%). Mp: 159.5-160.5
°C. IR (KBr): 1653, 1472, 1223 cm-1. 1H NMR (CDCl3) δ: 2.37
(s, 3H), 3.72 (d, 2H, J ) 0.9 Hz), 4.52 (d, 2H, J ) 1.2 Hz), 6.97
(t, 1H, J ) 0.9 Hz), 7.22 (t, 1H, J ) 1.2 Hz), 9.44 (s, 1H). 13C
NMR (CDCl3) δ: 21.9, 25.1, 48.1, 118.2, 119.0, 141.6, 151.6,
162.2, 188.8, 193.4. MS m/z: 222 (100, M+), 43 (69). Anal. Calcd
for C10H10N2O2S: C, 54.04; H, 4.53; N, 12.60. Found: C, 53.87;
H, 4.63; N, 12.52.
Su p p or tin g In for m a tion Ava ila ble: General procedures,
detailed experimental procedures for compounds 1, 4, and 7,
spectroscopic data for 1, 2b, 3b, 5b, 8a , and 9c, and copies of
1H and 13C NMR for all compounds (except 1H for 8b and 13C
for 4b). This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034381L
J . Org. Chem, Vol. 68, No. 12, 2003 4917