An efficient one-pot synthesis of pyrimido[2,1-b][1,3]thiazine derivatives by reaction of activated acetylenes, thiouracils, and isocyanides

Article abstract of DOI:10.1016/j.tetlet.2011.09.008

The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by thiouracils to yield a ketenimine intermediate, which cyclized and then rearranged to afford pyrimido[2,1-b][1,3]thiazines

Full text of DOI:10.1016/j.tetlet.2011.09.008

Tetrahedron Letters 52 (2011) 6018–6020
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Tetrahedron Letters
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An efficient one-pot synthesis of pyrimido[2,1-b][1,3]thiazine derivatives
by reaction of activated acetylenes, thiouracils, and isocyanides
Robabeh Baharfar a, , Seyed Meysam Baghbanian a, Seyed Mohammad Vahdat b
⇑
a Department of Chemistry, University of Mazandaran, PO Box 47415, Babolsar, Iran
b Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, PO Box 678, Amol, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedi-
carboxylates, was trapped by thiouracils to yield a ketenimine intermediate, which cyclized and then
rearranged to afford pyrimido[2,1-b][1,3]thiazines in good yields.
Received 24 May 2011
Revised 3 August 2011
Accepted 2 September 2011
Available online 7 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimido[2,1-b][1,3]thiazines
Isocyanides
Activated acetylenes
Multicomponent reaction
Multi-component reactions (MCRs) play an important role in
combinatorial chemistry because of their ability to synthesize
small drug-like molecules with several degrees of structural diver-
sity. This reaction allows compounds to be synthesized in a few
steps and usually in a one-pot operation. The synthesis of novel
fused heterocyclic rings is an important task for heterocyclic chem-
ists. Heterocyclic systems linked to pyrimidine derivatives are of
interest because they constitute an important class of natural
and non-natural products, many of which exhibit useful biological
activity.1–3
and antipyretic properties of pyrimido[2,1-b][1,3]thiazine deriva-
tives.8 Several methods have previously been reported for the prep-
aration of 1,3-thiazines.9–12 Despite their biological activity, few
syntheses of pyrimido[2,1-b][1,3]thiazines have been reported.9–
16
The diverse pharmacological and biological activities of pyrimi-
do[2,1-b][1,3]thiazine derivatives have encouraged us to develop
a concise synthetic route to these heterocyclic compounds.
The reaction of isocyanide nucleophiles with activated acetylenic
compounds such as dialkyl acetylenedicarboxylates leads to acti-
vated zwitterions. These types of zwitterions can be trapped by a
variety of electrophiles such as activated carbonyl compounds17 or
reagents containing NH, OH, CH, and SH acidic groups.18–21
In continuation of our studies on the development of new
routes in heterocyclic synthesis,22–28 after some preliminary
1,3-Thiazines are very useful as sedative, anticancer, and antimi-
crobial agents and as central nervous system depressants, and have
been reported to exhibit a variety of other biological activities.4–7
Furthermore, Bózsing et al. have reported the anti-inflammatory
O
N
O
N
O
R2
R2
CO2R3
C
R2
R1
N
N
NH
1,4-dioxane
R4
N C
R1
S
R1
S
r.t.
C
N
H
1
S
R4
R4
CO2R3
R3O2C
N
H
R3O2C
N
H
3
2
R3O2C
R3O2C
4
5
Scheme 1. One-pot synthesis of pyrimido[2,1-b][1,3]thiazine derivatives from thiouracils.
⇑
Corresponding author. Fax: +98 112 534 2350.
E-mail address: baharfar@umz.ac.ir (R. Baharfar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.008

R. Baharfar et al. / Tetrahedron Letters 52 (2011) 6018–6020
6019
Table 1
experimentation, it was found that the reaction of a mixture of
the thiouracil derivative 1 as an NH-acid source, dialkyl acety-
lenedicarboxylate 2, and alkyl or aryl isocyanide 3 in 1,4-dioxane
over 12 h gave a mixture of pyrimido[2,1-b][1,3]thiazine deriva-
tives 4 and 5. These were separated by flash chromatography
(Scheme 1). The optimized results are summarized in Table 1.
The 1H and 13C NMR spectra of the crude products clearly
indicated the formation of 4,8-dihydropyrimido[2,1-b][1,3]thia-
Synthesis of pyrimido[2,1-b][1,3]thiazine derivatives 4a–h and 5a,d,e,g,i
Product
R1
R2
R3
R4
Yield 4 (%)
Yield 5 (%)
4a/5a
4b
4c
4d/5d
4e/5e
4f
4g/5g
4h
H
H
H
Me
Me
Ph
H
Me
Me
H
H
H
H
H
H
H
Me
Me
Me
Et
t-Bu
t-Bu
t-Bu
Cyclohexyl
t-Bu
t-Bu
Cyclohexyl
t-Bu
65
85
80
70
65
86
75
80
68
20
—
—
15
22
—
15
—
t-Bu
Me
Me
Me
Me
Me
Et
zine-3,4-dicarboxylate
4
and 2,8-dihydropyrimido[2,1-b][1,3]
thiazine-3,4-dicarboxylates 5. The structures of the pyrimido
[2,1-b][1,3]thiazines were established by IR, 1H and 13C NMR spec-
troscopy, mass spectrometry, and elemental analysis. The structure
of 4b was confirmed by single-crystal X-ray analysis (Fig. 1).29 The
mass spectrum of 4a displayed the molecular ion (M+) peak at m/z
352, which was consistent with the product structure. The 1H NMR
spectrum of 4a in CDCl3 exhibited four sharp signals due to the
tert-butyl (d = 1.50), two methoxy, (d = 3.78 and 3.80) and methine
(d = 7.16) protons. Two doublets were observed at d = 6.21 and 7.33
(3JHH = 8.0 Hz) for the adjacent alkene protons, along with a broad
singlet at d = 9.57 for the NH group. The 1H NMR of compound 5a
was similar to that of 4a, except for the CH group which exhibited a
singlet at d = 5.77. The proton decoupled 13C NMR spectrum of 5a
showed 14 distinct resonances in agreement with the proposed
structure.
4i/5i
Cyclohexyl
20
A plausible mechanism for this reaction is proposed in Scheme
2. On the basis of the well-established chemistry of isocyanides,11
it is reasonable to assume that the functionalized pyrimido
[2,1-b][1,3]thiazines 4 and 5 could result from initial addition of
the isocyanide to the acetylenic ester and subsequent protonation
of 1:1 adduct 6 by thiouracil 1, followed by attack of the anion of
the NH-acid 7 on the positively charged ion 8 to form ketenimine
9. Finally, intermediate ketenimine 9 cyclizes to form the fused
heterocyclic system 4. The products 5 are presumably produced
by isomerization of compound 4 under the reaction conditions.
In conclusion, we have described a novel, efficient, and simple
method for the preparation of pyrimido[2,1-b][1,3]thiazines of
potential synthetic and pharmaceutical interest. In addition, the
present procedure affords advantages of good yields and a simple
Figure 1. X-ray crystal structure (ORTEP) of 4b.
CO2R3
C
CO2R3
R4
N C
R4
N C
C
R3O2C
6
CO2R3
O
N
O
O
R2
R2
R1
R2
N
CO2R3
R4
NH
NH
S
N
6 + 1
R1
S
C
R1
N
H
N
7
S
R4
R4
CO2R3
8
N
R3O2C
N
H
C
R3O2C
R3O2C
CO2R3
4
O
N
N
R2
R1
S
R4
R3O2C
R3O2C
N
H
5
Scheme 2. Possible mechanistic pathways for the synthesis of the pyrimido[2,1-b][1,3]thiazine derivatives.

6020
R. Baharfar et al. / Tetrahedron Letters 52 (2011) 6018–6020
work-up. Further investigation of the present method will be re-
quired to establish its utility and scope.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.008.
General procedure
References and notes
To a magnetically stirred solution of thiouracil (2 mmol) and
dialkyl acetylenedicarboxylate (2 mmol) in anhydrous 1,4-dioxane
(5 mL) was added dropwise a solution of the isocyanide (2 mmol)
in 1,4-dioxane (2 mL) over a period of 10 min. The mixture was
stirred for 12 h at room temperature. After completion of the reac-
tion as indicated by TLC, the solvent was removed and the residue
purified by silica gel column chromatography (hexane-EtOAc, 3:1)
to afford products 4a–h and 5a,d,e,g,i. If necessary, the isolated
product was further purified by recrystallization from dichloro-
methane-ether.
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[2,1-b][1,3]thiazine-3,4-dicarboxylate (4a, C15H19N3O5S)
White powder; yield 65%, mp 189–191 °C. IR (KBr) (m
max /cmÀ1):
3193 (NH), 1744, and 1696 (C@O). 1H NMR (400.13 MHz, CDCl3):
d = 1.50 (9 H, s, t-Bu), 3.74, and 3.81 (6 H, 2 s, 2 OCH3), 6.43 (1 H,
3
3
d, JHH = 8.0 Hz, CH), 7.16 (1 H, s, CHN), 7.82 (1 H, d, JHH = 8.0 Hz,
CH), 9.58 (1 H, s, NH). 13C NMR (100.6 MHz, CDCl3): d = 30.5
(CMe3), 51.6, and 52.6 (2 OCH3), 53.4 (CMe3), 54.4 (CHN), 86.8
(C@C–S), 113.2, 152.7 (2 CH), 155.4, 156.4 (2 C), 163.0, 166.9,
and 168.5 (3 C@O). MS, m/z (%): 352 [M+]. Anal. Calcd for
C15H19N3O5S: C, 50.98; H, 5.42; N, 11.89. Found: C, 50.8; H, 5.3;
N, 11.8.
Dimethyl 2-(tert-butylamino)-8-oxo-2,8-dihydropyrimido
[2,1-b][1,3]thiazine-3,4-dicarboxylate (5a, C15H19N3O5S)
21. Baharfar, R.; Baghbanian, S. M.; Hossein-nia, R. Lett. Org. Chem. 2007, 4, 567–
570.
22. Baharfar, R.; Baghbanian S. M. J. Heterocycl. Chem. 2011, in press.
23. Baharfar, R.; Vahdat, S. M.; Baghbanian, S. M. Acta Crystallogr., Sect. E. 2008, E64,
01203.
24. Baharfar, R.; Hossein-nia, R.; Baghbanian, S. M. Lett. Org. Chem. 2008, 5, 128–
132.
25. Baharfar, R.; Asghari, S.; Hamedaninejad, A.; Abbasi, A.; Ostadzadeh, A.;
Bijanzadeh, H. R. Lett. Org. Chem. 2007, 4, 429–432.
26. Baharfar, R.; Vahdat, S. M.; Ahmadian, M. Monatsh. Chem. 2010, 141, 213–218.
27. Baharfar, R.; Vahdat, S. M.; Hakimabadi, F. G. Monatsh. Chem. 2009, 140, 489–
493.
28. Baharfar, R.; Poorahmad, N. Phosphorus Sufur Silicon Relat. Elem. 2011, in press.
29. Crystallographic data for compound 4b have been deposited with the Cambridge
Crystallographic Data Centre, CCDC 815098, Copies of the data can be obtained,
free of charge, on application to The Director, Union Road, Cambridge CB2 1EZ,
UK. Fax: 44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
White powder; yield 20%, mp 151 °C. IR (KBr) (mmax /cmÀ1):
3207 (NH), 1746, and 1648 (C@O). 1H NMR (400.13 MHz, CDCl3):
d = 1.50 (9 H, s, t-Bu), 3.78, and 3.80 (6 H, 2 s, 2 OCH3), 5.77 (1 H,
br s, CHS), 6.21 (1 H, d, 3JHH = 8.0 Hz, CH), 7.33 (1 H, d, 3JHH = 8.0 Hz,
CH), 9.57 (1 H, s, NH). 13C NMR (100.6 MHz, CDCl3): d = 30.4
(CMe3), 51.7, and 53.8 (2 OCH3), 54.8 (CMe3), 50.2 (CHS), 85.8
(C@C–N), 111.7, and 142.8 (2 CH), 156.1 and 156.4 (2 C), 166.0,
167.8, and 168.0 (3 C@O). MS, m/z (%): 352 [M+]. Anal. Calcd for
C15H19N3O5S: C, 50.98; H, 5.42; N, 11.89. Found: C, 50.8; H, 5.5;
N, 11.8.
Acknowledgements
This research was supported by the Research Council of the
University of Mazandaran, Iran.