Oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawesson's reagent

Article abstract of DOI:10.1016/j.tetlet.2018.02.014

2,2′-Dimers with a central double bond were prepared by the oxidation of 5,6-disubstituted 7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawesson's reagent at room temperature. The role of DMSO as an oxidizing reagent was confirmed by NMR spectroscopy. The E-configuration of the central C[dbnd]C bond for the two diastereomers of compound 8m was proven by single crystal X-ray data. The dimeric thiazolopyrimidines were orange or red colored and absorption bands at 283–330 and 459–476 nm were observed in the UV spectra.

Full text of DOI:10.1016/j.tetlet.2018.02.014

Accepted Manuscript
Oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawes-
son’s reagent
Eugenia A. Lashmanova, Anastasiya I. Kirdyashkina, Pavel A. Slepukhin,
Andrey K. Shiryaev
PII:
S0040-4039(18)30181-3
https://doi.org/10.1016/j.tetlet.2018.02.014
TETL 49699
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 November 2017
31 January 2018
6 February 2018
Please cite this article as: Lashmanova, E.A., Kirdyashkina, A.I., Slepukhin, P.A., Shiryaev, A.K., Oxidation of
thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawesson’s reagent, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.02.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
Oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-
ones with DMSO and Lawesson’s reagent
Eugenia A. Lashmanova, Anastasiya I. Kirdyashkina, Pavel A. Slepukhin, Andrey K. Shiryaev
Samara State Technical University, 244 Molodogvardeyskaya St., 443100 Samara, Russia

1
Tetrahedron Letters
journal homepage: www.els evier.com
Oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawesson’s
reagent
Eugenia A. Lashmanovaa, Anastasiya I. Kirdyashkinaa, Pavel A. Slepukhinb, Andrey K. Shiryaeva,*
a Samara State Technical University, 244 Molodogvardeyskaya St., 443100 Samara, Russia
b I. Ya. Postovsky Institute of Organic Synthesis, 20/22, Academicheskaya/S. Kovalevskoi St., 620990 Ekaterinburg, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2,2’-Dimers with a central double bond were prepared by the oxidation of 5,6-disubstituted
7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-3(2H)-ones with DMSO and Lawesson’s
reagent at room temperature. The role of DMSO as an oxidizing reagent was confirmed by
NMR spectroscopy. The E-configuration of the central C=C bond for the two
diastereomers of compound 8m was proven by single crystal X-ray data. The dimeric
thiazolopyrimidines were orange or red colored and absorption bands at 283-330 and 459-
476 nm were observed in the UV spectra.
Available online
Keywords:
Thiazolopyrimidine
Dimethyl sulfoxide
Lawesson’s reagent
Oxidation
2009 Elsevier Ltd. All rights reserved
.
Dimerization
1. Introduction
Thiazolo[3,2-a]pyrimidines are readily available structures,
and their derivatives show antimicrobial, antiparkinsonian,
antiviral, anticancer, anti-inflammatory, antioxidant and other
2d
activities (Fig. 1).1, Thiazolo[3,2-a]pyrimidin-3(2H)-ones are
typically synthesized2 by the reaction of 2-halogenocarboxylic
acids
or
their
derivatives
with
2-thioxo-1,2,3,4-
tetrahydropyrimidines prepared by one of the variants3 of the
Biginelli reaction. Thiazolo[3,2-a]pyrimidin-3(2H)-ones possess
an active methylene group at C-2, and this feature has been used
for the preparation of 2-benzylidene4 (1, 2, Fig. 1), 2-hydrazono,5
and 2-oxyimino6 derivatives.
Until now, oxidation of the thiazolo[3,2-a]pyrimidin-3(2H)-
one scaffold has not been reported, despite it being a simplified
analogue of thioindigo. First synthesized by Friedländer in 1906,7
novel derivatives have recently been used as sensitizers in solar
cells,8 for imaging and data storage9 (Fig. 2), and as molecular
switches.10 The spectral and stability properties of thioindigo
have been studied by experimental and theoretical methods,11 and
the H-shaped chromophore identified (Fig. 2).
Figure 1. Selected derivatives of thiazolo[3,2-a]pyrimidin-
3(2H)-ones showing antiparkinsonian (1), anti-inflammatory (2)
and antiviral (3) activities.
The hemithioindigo scaffold, whose structure is similar to
thiazolo[3,2-a]pyrimidine 2-benzylidene derivatives 1, 2 (Fig. 1),
has been used for the preparation of photoswitchable
molecules.10d
The synthesis of thioindigo derivatives and analogs12 includes
oxidation of the active methylene group with K3[Fe(CN)6], air,
selenium dioxide, or various condensation reactions. Recently
a Ley-oxidation13 with TPAP-NMO was employed for the
dimerization of 3-R-4-oxotetrahydrothiophene-3-carboxylic acid,
and this reagent gave slightly lower yields in comparison with
K3[Fe(CN)6].14
__________
∗ Corresponding author. Tel.: +7-846-332-2122; fax: +7-846-
332-2122; e-mail: andrey_shiryaev@yahoo.com

2
Tetrahedron
Table 1. Synthesis of dimeric thiazolo[3,2-a]pyrimidine 8a
Entrya
7a : DMSO : LR
Solvent
Time (h)
Yield 8a
(%)b
12
18
37
35
41
35
40
1
2
3
4
5
6
7
8
1 : 1 : 1
1 : 2 : 1
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DMSO
CH2Cl2
10
10
10
10
10
20
10
10
10
5
1 : 5 : 1.5
1 : 5 : 1.5
1 : 7 : 1.5
1 : 7 : 1.5
1 : 7 : 1.2
1 : 7 : 1.5
1 : 70 : 1.5
1 : 7 : 1.5
Figure 2. H-Chromophore and thioindigo derivatives applicable
for solar cells (4, 5) and imaging or data storage (6).
23
20
29
9
10
Herein, we report the synthesis of dimeric thioindigo-like
molecules by the oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-
ones.
a Reagents and conditions: 7a (1 mmol), solvent (5 mL). b Isolated yield.
Table 2. Synthesis of dimeric thiazolo[3,2-a]pyrimidinesa
2. Results and Discussion
The oxidation of thiazolo[3,2-a]pyrimidin-3(2H)-one 7a with
K3[Fe(CN)6] in the presence of piperidine14 gave the dimeric
product 8a and 2-thioxo-1,2,3,4-tetrahydropyrimidine 9a in low
yields (Scheme 1). To avoid hydrolysis of the thiazolidine ring in
water/ethanol, the oxidation reaction was examined with DMSO.
Thiazolopyrimidine 7a was stable in hot DMSO and did not react
with well-known DMSO reagents15 such as DMSO-P2O5, DMSO-
acetic anhydride, DMSO-DCC, and DMSO-BF3•OEt2. Fortunately,
the addition of P4S10 gave product 8a in low yield (14%). The
reaction with excess DMSO and the more soluble Lawesson’s
reagent (LR) in CH2Cl2 at room temperature, afforded 8a in 40%
yield. Changing the solvent, temperature and excess of reagent
did not improve the yield (Table 1), probably, due to possible
cleavage of the dihydropyrimidine16 or thiazolidine17 rings in the
thiazolopyrimidine scaffold.
Produc
t
8a
8b
8c
R
Ar
Time
(h)
10
10
16
10
16
14
14
16
16
20
16
16
16
24
Yield 8b
(%)
40
48
32
48
38
46
46
34
48
36
36
50
36
30
OEt
OEt
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
Ph
Ph
4-MeOC6H4
2-MeOC6H4
3,4-(MeO)2C6H3
4-(HO)-3-(MeO)C6H3
2-ClC6H4
Ph
4-MeOC6H4
2-MeOC6H4
3,4-(MeO)2C6H3
4-ClC6H4
2-ClC6H4
Ph
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
Adc
Ph
a
Reagents and conditions: 7 (1 mmol), LR (1.2 mmol), DMSO (7 mmol),
CH2Cl2 (5 mL). b Isolated yield. c 1-Adamantyl.
No reaction of the thiazolopyrimidine-3(2H)-ones 7a-n was
observed with either LR or DMSO separately. Typically, LR
transforms carbonyl compounds to thiocarbonyl ones,19 but
thionation products were not detected in this reaction. Also,
heating a mixture of thiazolopyrimidine 7a and LR in toluene did
not give thiocarbonyl derivatives, whereas thiazolidine-4-ones
were transformed to the corresponding thiones under similar
conditions.20 A dimeric product was isolated from the reaction of
3-(prop-2-en-1-yl)-2-thioxo-1,3-thiazolidin-4-one with LR in
toluene at reflux, however, the dimer was fully thionated.21 It is
known that LR reacts with DMSO at elevated temperatures to
yield dimethyl sulfide and dimethyl disulfide.22 The reaction of
LR with DMSO did not proceed in CH2Cl2 at rt without
thiazolopyrimidine 7. The reaction only started when all three
components were mixed together; the solution became light red
immediately, and the color became dark red after several hours.
Scheme 1. Oxidation of thiazolopyrimidine with K3[Fe(CN)6].
Reagents and conditions: 7a (0.8 mmol), K3[Fe(CN)6] (3.2
mmol), piperidine (3.2 mmol), EtOH (3 mL), H2O (2 mL), 0.5 h
at 60oC then 0.5 h at 25oC.
Using the optimal conditions (Entry 7), a number of
thiazolopyrimidine thioindigo analogs 8a-n were synthesized
(Table 2). In all cases, thionation products or
tetrahydropyrimidine-2-thiones were not isolated or detected by
TLC. Recently, the oxidation of active methylene compounds
with DMSO in the presence of a base has been developed.18
However, the authors noted this procedure was not applicable to
methylene groups neighboring a heteroatom as is the case in the
thiazolo[3,2-a]pyrimidine-3(2H)-one (7a) structure.

3
Running the reaction of thiazolopyrimidine 7a in an NMR
tube with DMSO-d6 as a reagent and CDCl3 as a solvent, was
then investigated. After preparing the reaction mixture, the
doublet of one thiazole methylene proton was shifted to the low
field (from 3.78 to 3.93 ppm), the singlet of the benzyl proton at
C-5 was shifted to the high field (from 6.03 to 5.82 ppm), and a
signal of the neighboring carbonyl carbon was slightly shifted to
the high field (see ESI). These data confirm the formation of a
complex due to the reaction of LR and DMSO with the
thiazolopyrimidine. After 10 h the dimethyl sulfide septet signal
at 17.1 ppm was observed in the 13C NMR spectrum, which
proves that DMSO is the oxidizing agent in the examined
reaction. The proposed mechanism of the dimeric structures
formation, probably, includes nucleophilic substitution at the
sulfur atom23 as a key step (Scheme 2).
the racemic RR/SS form and the other is formed by the RS
meso-form (Fig. 3 and 4). Both isomers are crystallized as
solvates with DMF and have an E-configuration of the central
double bond. The bis-heterocyclic moieties of both molecules are
planar in the limits 0.2 Å for RR/SS-8m (maximum deviation
from the plane for the Csp3-atoms) and 0.13 Å for RS-8m
(maximum deviation from the plane for S-atoms).
Figure 4. ORTEP drawing of bis-thiazolopyrimidine RS-8m (50%
probability level). Selected bond lengths (Å) and angles (o): C7-C7
(central C=C bond) 1.343, C2-C3-C14-O2 129.57.
Compounds 8a-n are orange to red colored, and their UV
spectra showed two absorption bands at 283-330 and 459-476
nm. TD-DFT calculations11b of the exited states using the PBE0
hybrid functional and the 6-311G+(2d,p) basis set gave an
accurate prediction of the λmax in the visible spectra for thioindigo
derivatives. The calculations confirmed the larger λmax values for
the trans-isomers (519-591 nm) in comparison with the cis-
isomers (467-515 nm). Diapason of λmax for the trans-
thiazolopyrimidine dimers 8a-n matches the corresponding
diapason for thioindigo cis-isomers (Fig. 3, 4). The pyrimidine
ring in 8a-n is not aromatic which causes the shift of the
absorbtion band to shorter wavelengths.
The starting thiazolopyrimidines 7a-n were prepared2 by
heating the corresponding 2-thioxo-1,2,3,4-tetrahydropyrimidine3
(1 mmol) with ethyl chloroacetate (9.3 mmol) at 110-115 ºC for
0.5-5 h (see ESI and Table 3).
Scheme 2. Proposed mechanism of thiazolopyrimidine oxidation
with DMSO-LR (substituents at the pyrimidine ring are omitted for
clarity).
Table 3. Synthesis of thiazolo[3,2-a]pyrimidines
Time
(h)
Yield 7
(%)a
67
65
82
62
54
61
52
42
51
47
55
40
74
18
Compound
R
Ar
7a
7b
7c
7d
7e
7f
OEt
OEt
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
Ph
Ph
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5
4-MeOC6H4
2-MeOC6H4
3,4-(MeO)2C6H3
4-(HO)-3-(MeO)C6H3
2-ClC6H4
Ph
4-MeOC6H4
2-MeOC6H4
3,4-(MeO)2C6H3
4-ClC6H4
2-ClC6H4
Ph
Figure 3. ORTEP drawing of bis-thiazolopyrimidine RR/SS-8m
(50% probability level, RR-enantiomer is shown). Selected bond
lengths (Å) and angles (o): C1-C20 (central C=C bond) 1.318, C5-
C6-C14-O3 131.38.
7g
7h
7i
Presumably, dimers 8a-n are formed as mixtures of
diastereomers, but in the NMR spectra only one set of signals
was found for each compound. To confirm the dimeric structure,
compound 8m was crystallized from DMF for single crystal X-
ray analysis. Fortunately, two types of crystals were found in the
course of crystal selection for analysis. Single crystal X-ray
analysis of two selected crystals showed that one is formed by
7j
7k
7l
7m
8n
Adb
Ph
a Isolated yield. b 1-Adamantyl.

4
Tetrahedron
3. Conclusion
9. Cherepy NJ, Sanner RD. Optical Materials. 2006;28:1350-1354.
10. (a) Boice G, Patrick BO, McDonald R, Bohne C, Hicks R. J Org
Chem. 2014; 79:9196-9205;
(b) Kurata H, Kim S, Matsumoto K, Kawase T, Oda M. Chem
Lett. 2007;36:386-387;
(c) Schadendorf T, Hoppmann C, Rück-Braun K. Tetrahedron
Lett. 2007;48:9044-9047;
In summary, a new method was developed for the oxidative
dimerization of thiazolo[3,2-a]pyrimidin-3(2H)-ones using
DMSO and Lawesson’s reagent at rt. The dimers were prepared
as a mixture of diastereomers with an E-configuration of the
central double bond, and can possibly be used for the
development of pigments, sensitizers in solar cells and molecular
switches.
(d) Schulz M, Christoffers J. Tetrahedron. 2013;69:802-809.
11. (a) Jacquemin D, Preat J, Wathelet V, Perpéte EA. J Mol
Structure: THEORCHEM. 2005;731:67-72;
(b) Jacquemin D, Preat J, Wathelet V, Fontaine M, Perpéte EA. J
Am Chem Soc. 2006;128:2072-2083.
12. (a) Hartough, H. D.; Meisel, S. L. In Compounds with condensed
thiophene ring. Chapter III. Thioindigo and Related Dyes;
Interscience: London, 1954; pp 175-224;
Acknowledgments
This work was financially supported by the Russian Ministry of
Education and Science as a basic part of a research project
(4.6764.2017/BP).
(b) Zollinger, H. In Color chemistry: Synthesis Properties and
Applications of Organic Dyes and Pigments; Helvetica Chimica
Acta: Zürich, 2003; pp 259-268.
13. Ley SV, Norman J, Griffith WP, Marsden SP. Synthesis.
1994;1994:639-666.
References and notes
14. Schulz M, Christoffers J. Tetrahedron. 2013;69:802-809.
15. (a) Mancuso AJ, Swern D. Synthesis. 1981;1981:165-185;
(b) Tidwell, T. T. Synthesis 1990;1990:857-870;
(c) Rafique J, Saba S, Rosario AR, Braga AL. Chem Eur J. 2016;
22:11854-11862;
(d) Azeredo JB, Godoi M, Martins GM, Silveira CC, Braga AL.
J Org Chem. 2014;79:4125-4130.
16. Li X, Yi P, Yu X. Chin J Chem. 2010;28:97-101.
17. Lebedyeva IO, Povstyanoy MV, Ryabitskii AB, Povstyanoy VM.
J Heterocycl Chem. 2010;47:368-372.
18. Chebolu R, Bahuguna A, Sharma R, Mishra V K, Ravikumar
PC. Chem Commun. 2015;51:15438-15441.
19. (a) Ozturk T, Ertas E, Mert O. Chem Rev. 2007;107:5210-5278;
(b) Jesberger M, Davies TP, Barner L. Synthesis. 2003;2003:
1929-1958;
(c) Przychodzen W. Eur J Org Chem. 2005;2005:2002-2014;
(d) Cava MP, Levinson MI. Tetrahedron. 1985;41:5061-5087.
20. (a) Erol S, Dogan I. Tetrahedron. 2013;69:1337-1344;
(b) Isikgor FH, Erol S, Dogan I. Tetrahedron Asymm. 2014;25:
449-456;
1. (a) Keshari AK, Singh AK, Saha S. Mini-Reviews Med Chem.
2017;17:1488-1499;
(b) Kashyap SJ, Sharma PK, Garg VK, Dudhe R, Kumar NJ. Adv
Sci Res. 2011;2:18-24.
2. (a) Kappe CO, Roschger P. J Heterocycl Chem. 1989;26:55-64;
(b) Zhi H, Chen L, Zhang L, Liu S, Wan DCC, Lin H, Hu C.
Arkivoc. 2008; XIII:266-277;
(c) Kulakov IV, Nurkenov OA, Turdybekov DM, Issabaeva
GM, Mahmutova AS, Turdybekov KM. Chem Heterocycl Copmd.
2009;45:856-859;
(d) Dhiman P, Malik N, Verma PK, Khatkar A. Res Chem
Intermed. 2015;41:8699–8711;
(e) Zhao D, Chen C, Liu H, Zheng L, Tong Y, Qu D, Han S. Eur J
Med Chem. 2014;87:500 – 507;
(f) Salem MAI, Marzouk MI, Salem MS, Alshibani GA. J
Heterocycl Chem. 2016;53:545 – 557.
(g) Shiryaev AK, Baranovskaya NS, EreminMS. Chem Heterocycl
Copmd. 2013;48:1550-1554.
(h) Lashmanova EA, Rybakov VB, Shiryaev AK. Synthesis.
2016;48:3965-3970.
(i) Sherif MS, Mohamed MY, Khaled MM, Abdel-Samei
MAF. Tetrahedron. 1993;49:9561-9572.
(j) Pathak A, Narayanaswamy VK, Joshi A, Rao GK, Devi K.
Ind. J. Heterocycl Chem. 2010;19:273-276.
(k) Mobinikhaledi A, Zendehdel M, Nasab MH, Fard MAB.
Heterocycl Comm. 2009;15:451-458.
3. (a) Suresh, Sandhu JS. Arkivoc. 2012;i:66-133;
(b) Alvim HGO, Lima TB, de Oliveira AL, de Oliveira HCB,
Silva FM, Gozzo FC, Souza RY, da Silva WA, Neto BAD. J Org
Chem. 2014;79:3383-3397.
4. Patel V, Patel V. Der Pharm. Sinica. 2013; 4(5):72-78.
5. Moty SGA, Hussein MA, Aziz SAA, Abou-Salim MA. Saudi
Pharm. J. DOI: 10.1016/j.jsps.2013.12.016.
6. Lashmanova EA, Shiryaev AK. Chem Heterocycl Copmd.
2015;51:377-380.
7. Friedländer P. Ber Dtsch Chem Ges. 1906;39:1060-1066.
8. (a) Hosseinnezhad M, Moradian S, Gharanjig K. Prog. Color,
Colorants, Coatings. 2017;10:XX-XXX;
http://www.pccc.icrc.ac.ir/files/cu113se1up4046.pdf;
(b) Hosseinnezhad M. Materials Technology: Adv Perform
Materials. 2016;31:348-351;
(c) Cinar SA, Ercan S, Gunal SE, Dogan I, Aviyente V. Org
Biomol Chem. 2014;12:8079-8086.
21. Abdel-Malek HA. Phosphorus Sulfur Silicon. 2012;187:506-514.
22. Rasmussen JB, Jørgensen KA, Lawesson S-O. Bull Soc Chim
Belg. 1978;87:307-308.
23. Tillett JD. Chem Rev. 1976;76:747-772.
24. Sheldrick GM. Acta Cryst. 2008;A64:112-122.
25. Sheldrick GM. Acta Cryst. 2015;C71:3-8.
26. (a) Khatri CK, Potadar SM, Chaturbhuj GU. Tetrahedron Lett.
2017;58:1778-1780;
(b) Damgaard M, Al-Khawaja A, Nittegaard-Nielsen M, Petersen
RF, Wellendorph P, Frølund B. Eur J Med Chem. 2017;138:300-
312;
(c) Mohammadian N, Akhlaghinia B. Res Chem Intermed. 2017;
43:3325–3347.
27. Salehi P, Dabiri M, Zolfigol MA, Baghbanzadeh M.
Heterocycles. 2005;65:1177-1181.
Supplementary Material
Click here to remove instruction text...
(c) Hosseinnezhad M, Moradian S, Gharanjig K. Dyes Pigments.
2015;123:147-153.

5
Highlights
•
The oxidation of the thiazolo[3,2-
a]pyrimidin-3(2H)-ones was studied for the
first time.
•
•
•
DMSO with Lawesson’s reagent was
employed as an oxidant for the first time.
The reaction proceeds at room temperature
selectively at C2 position.
Novel thioindigo-like compounds were
obtained.