Ternary condensation of Biginelli thiones, chloroacetic acid, and aldehydes as an effective approach towards thiazolo[3,2-a] pyrimidines and 5-arylidenethiazolidine-2,4-diones

Article abstract of DOI:10.1002/jhet.323

(Chemical Equation Presented) At the process of ethyl 6-methyl-4-aryl-2- thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates condensation with aryl aldehydes and chloroacetic acid the unexpected formation of 5- arylidenethiazolidine-2,4-diones was determined in high yields as the reaction time was increased to 20 h. The latter represent the products of destructive hydrolyzes of ethyl 2-benzylidene-7-methyl-3-oxo-5-aryl-2,3-dihydro-5H-[1,3] thiazolo[3,2-a]pyrimidine-6-carboxylates which have been proved by independent synthesis.

Full text of DOI:10.1002/jhet.323

368
Ternary Condensation of Biginelli Thiones, Chloroacetic Acid,
and Aldehydes as an Effective Approach towards Thiazolo[3,2-a]
pyrimidines and 5-Arylidenethiazolidine-2,4-diones
Vol 47
Iryna O. Lebedyeva,a* Mykhaylo V. Povstyanoy,a Aleksey B. Ryabitskii,b
and Vyacheslav M. Povstyanoya
aKherson National Technical University, Berislavskoe Highway 24, Kherson 73000, Ukraine
bSpoluka Chemical Company, 5 Murmanska str., Kiev 02660, Ukraine
*E-mail: ira_lebedeva2001@mail.ru
Received September 20, 2009
DOI 10.1002/jhet.323
Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com).
At the process of ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates conden-
sation with aryl aldehydes and chloroacetic acid the unexpected formation of 5-arylidenethiazolidine-
2,4-diones was determined in high yields as the reaction time was increased to 20 h. The latter represent
the products of destructive hydrolyzes of ethyl 2-benzylidene-7-methyl-3-oxo-5-aryl-2,3-dihydro-5H-
[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylates which have been proved by independent synthesis.
J. Heterocyclic Chem., 47, 368 (2010).
INTRODUCTION
hydes and surplus of anhydrous sodium acetate using
glacial acetic acid as solvent has been employed. The
formation of corresponding thiazolo[3,2-a]pyrimidine
derivatives 4a–i (D, Scheme 1) results in three consecu-
tive stages which include alkylation leading to the com-
pound 2a (A, Scheme1) formation [2(c)], intramolecular
heterocyclisation 3a (B, Scheme 1) [9(c,h)], and conden-
sation (C, Scheme 1) [9(a)] of primary DHPMs 1a–c.
Thus, a newly formed heterocyclic system 3a, readily
reacts with carbonyl compounds giving rise to substi-
tuted arylidene derivarives 4a–i. The reaction time
depends on the carbonyl reagent and lasts for 1–3 h. It
is obvious that at the condensation of this type 7H iso-
mer may be formed together with the 5H one (4a–i).
Unambiguous formation of 4a–i type ending products
has been previously established with the extensive X-ray
study [9(c)].
Multicomponent reactions (MCRs) have been widely
used in organic and medicinal chemistry over the last
years for producing a number of libraries for bioscreening
[1]. A three-component condensation of aromatic alde-
hydes with ureas (thioureas) and b-ketoesters known as
Biginelli reaction [2] takes an important place among
MCRs. The reaction allows forming a dihydropyrimidine
cycle where the nature of the subsistent in the basic struc-
ture can be widely modified. Dihydropyimidines
(DHPMs) found their use as antimicrobial [3], antiviral
[4], antiinflammatory [5], anticarcenogenic preparations
[6], and calcium channel modulators [7]. The principle of
Biginelli condensation is employed to construct complex
heterocyclic scaffolds analogous to those isolated from
Batzelladines A-B which have been found to be potent
HIVgp-120-CD4 inhibitors [8]. To broaden the study on
the range of biological activity of 2-thioxo-DHPM deriva-
tives the library of substituted ethyl 5-aryl-3-oxo-7-
methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-car-
boxylates (4a–i) have been synthesized [9].
RESULTS AND DISCUSSION
Quite unexpectedly, as the reaction time (D, Scheme
1) was increased to 18–20 h, the final products,
extracted from the reaction mixture, were identified as
5-arylidene-2,4-thiazolidinediones (5a–g, Scheme 2)
[10]. Thus, thiazolo[3,2-a]pyrimidines 4a–i represent
A standard method of a multicomponent one-step
condensation of substituted pyrimidine-2-thiones 1a [9],
1b [9], 1c [2(b,f)], haloacetic acids, aryl(heteryl)alde-
C
V
2010 HeteroCorporation

March 2010 Ternary Condensation of Biginelli Thiones, Chloroacetic acid and Aldehydes as an
Effective Approach towards Thiazolo[3,2-a]pyrimidines and 5-Arylidenethiazolidine-2,4-diones
369
Scheme 1
intermediate products for the synthesis of 5-arylidene-
2,4-thiazolidinediones (5a–g).
from the reaction somewhat speeds up the destruction
process and in 8 h of reaction time the ratio of 4a to 5a
was 38 to 42%.
To determine the conditions when the destruction pro-
cess takes place, a series of technical mixtures extracted
from the mother liquor on different stages of the reac-
tion time has been studied. A sample, taken in 30 min
of reaction mixture reflux revealed the presence of the
primary compound 1a 27% and the intermediate product
4a 72%. The destruction product 5a was not determined
on this reaction stage. Specimen, extracted in 3 h of
reflux, revealed the presence of thiazolo[3,2-a]pyrimi-
dine 4a at the amount of 88% and 11% of 5-arylidene-
thiazolidine-2,4-dione (5a). Sample, taken in 18 h of
reaction mixture reflux contained both 5a 76 and 4a
20%, respectively. It should be noted that refluxing 4a
as a starting compound under the condensation condi-
tions (glacial acetic acid, anhydrous sodium acetate, cor-
responding aromatic aldehyde), for 20 h did not reveal
the presence of 5-arylidene thiazolidine-2,4-dione (5a).
As water was added to the analogous reaction mixture
to 4e, the ratio of target products was 5e 24, to 4e 30%.
5-Arylidenethiazolidine-2,4-dione (5a) was formed in
55% yield when alkylated dihydropyrimidine-2-thione
(2a) was used as a primary compound and cyclization
took place under standard reaction duration and condi-
tions. As analogous reaction conditions were followed
excluding presence of water for 3a as a primary com-
pound the destruction process was not determined and
reaction mixture contained 95% of thiazolo[3,2-a]pyrim-
idine 4a. The exclusion of anhydrous sodium acetate
Thus, it may be concluded that the destruction process
takes place due to slow hydrolyses of 4a–i with water
emitted during the condensation course. Therefore, the
presence of anhydrous sodium acetate is obviously not
enough to exclude the influence of water on the reaction
course. As acetic anhydride surplus is added to the reac-
tion mixture the process of destructive hydrolyses had
not been determined either on the 3rd or on the 18th h
of the reaction duration and the presence of formed thia-
zolo[3,2-a]pyrimidines (4a) was 97% and 98%
respectively.
As terephthalic aldehyde was employed in ethyl thia-
zolo[3,2-a]pyrimidine-6-carboxylates synthesis, bis-thia-
zolo[3,2-a]pyrimidine of 6a type (Scheme 3) has been
obtained as a target product. It should be mentioned that
possible destruction product (7a, Scheme 3) was not
determined even under rigid reaction conditions such as
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

370
I. O. Lebedyeva, M. V. Povstyanoy, A. B. Ryabitskii, and V. M. Povstyanoy
Vol 47
Scheme 3
synthesis of 6a in a sealed tube at 180ꢀC for 12 h due
to 6a possessing low ability to dissolve in organic
solvents.
Because of the nN-pC¼O conjugation both the N(1)-C(1)
1.369(2) A and the N(1)-C(2) 1.365(2) A bonds are sig-
nificantly shortened in comparison with the standard
˚
˚
2
2
˚
The structure of compounds 5a–g has been deter-
mined by NMR (1H, 13C), IR, elemental, LC/MS analy-
value for the N(sp )-C(sp ) single bonds of 1.43–1.45 A
[11,12]. In the solid state the molecules of 5a are joined
in the centrosymmetric dimers by the N(1)-H. . .O(2)
1
ses. H NMR spectra of compounds 5a–g are character-
ꢀ
˚
ized with the presence of the representative singlet at
6.0–6.1 ppm corresponding to the one of pyrimidine
cycle at C4, and also with the singlet at 7.6–7.9 ppm
relevant to the proton of methine group of the multiple
bond C¼¼CH-Ar. For 6a corresponding signals are deter-
mined at 6.52 and 8.31 ppm at CF3COOD.
(N. . .O 2.834(2), O. . .H 1.96(2) A, NHO 169(23) inter-
molecular hydrogen bonds.
CONCLUSIONS
The formation of 5-arylidene-2,4-thiazolidinediones
has been determined during the synthesis of substituted
ethyl 5-aryl-3-oxo-7-methyl-2,3-dihydro-5H-thiazolo[3,
2-a]pyrimidine-6-carboxylates library. Therefore, it is
strongly suggested to reconsider the traditional reaction
conditions and to take special care on the exclusion of
water influence on the reaction process (e.g. acetic anhy-
dride should be employed at the reaction rather than
waterfree sodium acetate). Otherwise, as the reaction
time expanded for the period of 18 h and more, allow-
ing the emitted water to hydrolyze the desired thia-
zolo[3,2-a]pyrimidines the formation of 5-arylidene-2,4-
thiazolidinediones reaches up to 76%.
13C NMR spectroscopy was also applied to determine
the structure of 5a revealing eight signals. APT experi-
ment determined the presence of four quaternary carbon
atoms including two carbonyle and four protonated terti-
ary carbon atoms: d ¼ 167.65 (q), 167.09 (q), 132.85
(q), 131.61 (t), 130.20 (t), 129.83 (t), 129.10 (t), 123.36
(q) ppm. IR spectra of 5a–g (KBr platelets) revealed
˜
broadened picks due to the intermolecular bonds of NH
and C¼O groups. The structure of 5a has been unam-
biguously determined by the single crystal X-ray diffrac-
tion. The perspective view of the molecule 5a and
selected geometrical parameters are given in Figure 1.
The molecule 5a is almost planar (deviations of non-
hydrogen atoms from the least-square plane do not
˚
exceed 0.069 A). The N(1) atom has trigonal-planar
EXPERIMENTAL
bond configuration (sum of the bond angles 360.0ꢀ).
All chemicals were obtained from commercial sources and
used without further purification. Melting points (mp) were
measured on an electrothermal capillary melting point appara-
tus and are uncorrected. IR spectra were recorded with a UR-
20 spectrophotometer (KBr platelets). The NMR measurements
were carried out on a Varian GEMINI 2000 spectrometer with
1H and 13C frequencies of 400.07 and 100.61 MHz, respec-
1
tively at 293 K. H NMR spectra were recorded with spectral
width 8000 Hz and numbers of points 32,000; 13C NMR spec-
tra were recorded with spectral width 30,000 Hz and numbers
of points 128,000. DMSO-d6 and CF3COOD were used as sol-
vents and TMS as internal standard. HPLC-MS was carried
out on a system consisting of an Agilent 1100 Series high-
pressure liquid chromatograph equipped with a diode matrix
and Agilent LC/MSD SL mass-selective detector. HPLC-MS
parameters: column: Zorbax SB-C18, 1.8 lm, 4.6 ꢁ 30 mm2;
solvents: Me-CN-H2O (95:5), 0.1% TFA; eluent flow: 3 mL
Figure 1. Perspective view and labeling ꢀscheme for the molecule 5a.
˚
Selected bond lengths (A) and angles ( ): S(1)-C(1) 1.786(2), S(1)-
C(3) 1.756(2), N(1)-C(1) 1.369(2), N(1)-C(2) 1.365(2), C(2)-C(3)
1.484(2), C(3)-C(4) 1.331(2); C(1)S(1)C(3) 91.68(8), C(1)N(1)C(2)
117.9(1).
s
215, 254, 265 nm; ionization method: chemical ionization
ꢂ1; injected sample volume: 1 lL; UV detector: k ¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010 Ternary Condensation of Biginelli Thiones, Chloroacetic acid and Aldehydes as an
Effective Approach towards Thiazolo[3,2-a]pyrimidines and 5-Arylidenethiazolidine-2,4-diones
371
under atmospheric pressure (APCI); ionization mode; simulta-
neous scanning of positive and negative ions in m/z range
100–650. Microanalyses were performed in the Microanalytical
Laboratory of the Institute of Organic Chemistry, National
Academy of Sciences of Ukraine. Crystallographic data of 5a
including atomic coordinates, bond lengths and thermal param-
eters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC). These data can be obtained free of
charge via www.ccdc.cam.uk/conts/retrieving.html (or from
CCDC, 12 Union Road, Camridge CB2 1EZ, UK, fax: þ44
1223 336 033, or deposit@ccdc.cam.ac.uk). Any request to the
CCDC for data should quote the full literature citation and
CCDC reference number 734605.
C6H4NO2], 7.96 [d, 3J(H,H) ¼ 7.6 Hz, 1 H, H4 C6H4NO2],
7.90 [s, 1 H, O2NC6H4CH], 7.78 [m. 1 H, H5 C6H4NO2], 7.32
[m, 5 H, C6H5], 6.08 [s, 1 H, C6H5CH], 4.08 [m, 2 H,
3
CH2CH3], 2.42 [s, 3 H, CH3], 1.16 [t, J(H,H) ¼ 6.8 Hz, 3 H,
CH2CH3]; ms: m/z 450 (Mþ). Anal. Calcd. for C23H19N3O5S:
C: 61.46; H, 4.26; N, 9,35. Found: C, 60.24; H, 4.19; N, 9.42.
Ethyl 5-phenyl-(2-furfuryl)-7-methyl-3-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyrimidine-6-carboxylate (4g). Grey solid in
40% yield, mp 149–150ꢀC (i-PrOH); IR (KBr): m 1600
(C¼¼N), 1690 (C¼¼O) 2960 (CH) cmꢂ1
.
1H NMR (400 MHz,
DMSO-d6): d ¼ 8.06 [deg. s, 1 H, 5-H fur], 7.61 [s, 1 H,
furCH], 7.33 [m, 5 H, C6H5], 7.09 [deg. s, 1 H, 3-H fur], 6.74
[deg. s, 1 H, 4-H fur], 6.05 [s, 1 H, C6H5CH], 4.06 [m, 2 H,
3
General procedures.
4-Phenyl-5-carbethoxy-6-methyl-
CH2CH3], 2.39 [s, 3 H, CH3], 1.13 [t, J(H,H) ¼ 7.2 Hz, 3 H,
pyrimidine-2-mercaptoacetic acid (2a). A solution of 1a 2.76
g (0.01 mole) and bromoacetic acid 1.5 g (0.011 mole) was
refluxed in 15 mL acetic acid for 30 min. Then the mixture
was taken to dryness in vacuo. The remained residue was neu-
tralized with sodium carbonate solution to pH 5, filtered,
washed with 100 mL of hot water. Recrystallized from EtOH.
Compound 2a was obtained as yellow solid in 68% yield. Mp
and spectral data has appeared to be identical to those reported
in literature [2(c)].
CH2CH3]; m/z 395 (Mþ). Anal. Calcd. for C21H18N2O3S: C,
63.95; H, 4.60; N, 7.10. Found: C, 62.69; H, 4.53; N, 7.18.
General procedure for the synthesis of substituted 5-ary-
lidene-2,4-thiazolidinedione (5 a–g). A mixture of 1a–c (0.01
mole), anhydrous sodium acetate 1.0 g (0.015 mole), chloro-
acetic acid 1.0 g (0.011 mole), and the appropriate aldehyde
(0.01 mole) was refluxed for 18 h in 10 mL of glacial AcOH.
Sodium acetate was separated by decantation. The reaction
mixture was left for 24 h at ambient temperature, and the pre-
cipitate (5a–g) was filtered off and purified by recrystallization
from 2-PrOH/DMF.
Ethyl
5-phenyl-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo
[3,2-a]pyrimidine-6-carboxylate (3a). Compound 2a 1.82 g,
(0.005 mole) was dissolved in 5 mL acetic anhydride and
refluxed for 15 min, and then allowed to cool. The precipitate
formed was filtered off and recrystallized from i-PrOH. Com-
pound 3a was obtained as yellow solid in 80% yield. Mp and
spectral data has appeared to be identical to those reported in
literature [2(c),10(a,b)].
General procedure for the synthesis of ethyl 5-aryl-
methylene-3-oxo-7-methyl-2,3-dihydro-5H-thazolo[3,2-a]py-
rimidine-6-carboxylates (4a–i). A mixture of 1a–c (0.01
mole), anhydrous sodium acetate 1.0 g, (0.015 mole), chloro-
acetic acid 1.0 g, (0.011 mole), and the appropriate aldehyde
(0.01 mole) was refluxed for 3 h in 10 mL of glacial AcOH.
After cooling, the mixture was poured onto crushed ice. The
precipitate formed 4a–i was filtered off and recryatllized from
i-PrOH.
Compounds (Yield) 5a [10(a,g,h,i)] (76%), 5b [10(b,e)]
(54%), 5c [10(a,g)] (12%), 5d [10(b,d,g)] (49%), 5e [10(g)]
(24%), 5f [10(b,c)] (53%), 5g [10(b,f)] (23%) have been
described in the literature.
4,40-Bis(5-phenyl-6-carbethoxy-7-methyl-3-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidinyl-2-ylmethylene)benzene (6a). A
mixture of 1a 2.76 g (0.01 mole), anhydrous sodium acetate
1.0 g (0.015 mole), chloroacetic acid 1.0 g (0.011 mole), ter-
ephthalic aldehyde 0.67 g (0,005 mole) at 10 mL glacial
AcOH was thoroughly sealed in a tube and allowed to stand at
180ꢀC for 12 h. The precipitate formed was filtered off,
washed with 100 mL of hot water, and purified with recrystal-
lization from DMF.
Red solid, yield 76%, mp: <300ꢀC (DMF); IR (KBr): m
1560 (C¼¼N), 1715 (C¼¼O) 2990 (CH) cmꢂ1
.
1H NMR (400
Compounds (Yield) 4a [9(c)] (20%), 4b [9(c)] (34%), 4c
[9(c,g)] (80%), 4e [9(f)] (30%), 4h [9(e)] (88%), 4i [9(c)]
(37%) have been described in the literature.
MHz, CF3COOD): d ¼ 8.31 [s, 2 H, C6H4(CH)2], 7.81 [s, 4
H, C6H4], 7.47 [m, 10 H, 2 ꢁ C6H5], 6.52 [s, 2 H, 2 ꢁ
C6H5CH], 4.34 [m, 4 H, 2 ꢁ CH2CH3], 2.75 [s, 6 H, 2 ꢁ
NCCH3], 1.32 [t, 6 H, 2 ꢁ CH2CH3]. Anal. Calcd. for
C40H34N4O6S2: C, 65.74; H, 4.69; N, 7.67. Found: C, 64.45;
H, 4.61; N, 7.81.
Ethyl
5-phenyl-2-(4-hydroxyphenylmethylene)-7-methyl-
3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(4d). Yellow solid, yield 43%, mp 192ꢀC (i-PrOH); IR (KBr):
1
m 1545 (C¼¼N), 1695 (C¼¼O), 2990 (CH) 3430 (OH) cmꢂ1. H
X-ray structure determination of 5a.
Crystal
NMR (400 MHz, DMSO-d6): d ¼ 10.22 [s, 1 H, OH], 7.66 [s,
1H, HOC6H4CH], 7.39 [d, 3J(H,H) ¼ 8.8 Hz, 2 H, H2 H6
data. C10H7NO2S, M ¼ 205.2, monoclinic, a ¼ 9.5115(6), b
ꢀ
˚
11.6786(7), c ¼ 8.2306(6) A, b ¼ 96.146(4) , V ¼ 909.0(1)
3
3
A , Z ¼ 4, d ¼ 1.50 g cmꢂ1, space group P21/c (N 14), l ¼
˚
C6H4OH], 7.30 [m, 5 H, C6H5], 6.87 [d, J(H,H) ¼ 8.8 Hz, 2
H, H3 H5 C6H4OH], 6.03 [s, 1 H, C6H5CH], 4.05 [m, 2 H,
3.24 cmꢂ1, F(000) ¼ 424, crystal size ca. 0.12 ꢁ 0.44 ꢁ 0.45
mm3. All crystallographic measurements were performed at
293ꢀC on a Bruker Apex II CCD diffractometer. The intensity
data were collected within the range 2.8 < y < 26.3ꢀ (ꢂ11 <
h < 11, ꢂ14 < k < 14, ꢂ10 < l < 8) using graphite mono-
3
CH2CH3], 2.40 [s, 3 H, NCCH3], 1.16 [t, J(H,H) ¼ 8.0 Hz, 3
H, CH2CH3]; ms: m/z 419 (Mꢂ). Anal. Calcd. for
C23H20N2O4S: C, 65.70; H, 4.79; N, 6.66. Found: C, 64.39; H,
4.70; N, 6.73.
˚
Ethyl 5-phenyl-2-(3-nitrophenylmethylene)-7-methyl-3-oxo-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (4f). Yellow
solid in 37% yield, mp 173ꢀC (i-PrOH); IR (KBr): m 1330,
1540 (NO2), 1610 (C¼¼N), 1690, 1730 (C¼¼O) 2980 (CH)
chromated Mo-Ka radiation (k ¼ 0.71073 A). Intensities of
6416 reflections (1846 unique, Rint ¼ 0.003) were measured.
Data were corrected for Lorentz and polarisation effects and
an absorption correction using the Sadabs procedure was
applied [13]. The structure was solved by direct methods and
refined by full-matrix least-squares technique in the anisotropic
1
cmꢂ1. H NMR (400 MHz, DMSO-d6): d ¼ 8.39 [deg. s, 1 H,
H2 C6H4NO2], 8.25 [d, 3J(H,H)
¼
8.0 Hz, 1 H, H6
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I. O. Lebedyeva, M. V. Povstyanoy, A. B. Ryabitskii, and V. M. Povstyanoy
Vol 47
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In the refinement 1313 reflections with I > 3r(I) were used.
All hydrogen atoms were located in the different Fourier maps
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obs./variabl. 8.5). Chebushev weighting scheme [15] with pa-
rameters 1.59, 1.50, 1.79, 0.55, and 0.47 was used.
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Acknowledgments. This work was supported by Fundamental
Researchers State Fund (F25.3/023).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet