Three-component condensation of 2,4-diaminothiazoles with aldehydes and Meldrum's acid: synthesis of 7-aryl(alkyl)-substituted 6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-ones

Article abstract of DOI:10.1016/j.mencom.2009.03.011

The new method of the synthesis of 6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-ones, based on decarboxylation of corresponding 2,4-diamino-5-thiazolecarboxylic acids has been elaborated; unstable derivatives of 2,4-diaminothiazole, generated in situ as a resu

Full text of DOI:10.1016/j.mencom.2009.03.011

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 87–88
Three-component condensation of 2,4-diaminothiazoles with
aldehydes and Meldrum’s acid: synthesis of 7-aryl(alkyl)-substituted
6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-ones
Arkady A. Dudinov, Boris V. Lichitsky, Andrey N. Komogortsev and Mikhail M. Krayushkin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mkray@ioc.ac.ru
DOI: 10.1016/j.mencom.2009.03.011
The new method of the synthesis of 6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-ones, based on decarboxylation of corresponding
2,4-diamino-5-thiazolecarboxylic acids has been elaborated; unstable derivatives of 2,4-diaminothiazole, generated in situ as a
result of decarboxylation, react with aldehydes and Meldrum’s acid forming target compounds.
It is known that derivatives of modified 2,4-diaminothiazole show
specific biological activity as inhibitors of CDK.1,2
R'
COOH
NH2
R'
We have shown earlier that the hydrochlorides of 2,4-diamino-
thiazoles unsubstituted at the 5-position of the heterocyclic ring
can enter three-component condensation with various aldehydes
2 and Meldrum’s acid 3 to form substituted 6,7-dihydro-4H-
thiazolo[4,5-b]pyridin-5-ones 43 (Scheme 1). This method is
simple and allows one to obtain, in particular, the new condensed
structures from unstable 2,4-diaminothiazoles, generated in situ
from hydrochlorides of 2-amino-4-iminothiazolidines 1. It should
be emphasized that the synthesis of starting salts was described
only for substances bearing primary or tertiary amino groups in
the 2-position of thiazole rings.
R''
R''
NH2
S
S
5
6
O
O
Ar
+ ArCHO
R'
O
O
R''
S
N
H
O
7
Scheme 2
O
Cl
H2N
entered into three-component condensation in ethanol as the
solvent. Addition of acetic acid to a reaction mixture leads to
O
O
N
+ ArCHO +
+ AcONa
R
S
†
1H NMR spectra were recorded on Bruker AM-300 (300 MHz) and
O
Bruker WM-250 (250 MHz) instruments in [2H6]DMSO. Melting points
were measured on a Boetius hot stage and not corrected. Mass spectra
were determined on Finnigan MAT Incos 50 (direct injection, electron
impact, 70 eV). The reaction mixtures were analyzed and the purity of
the products was checked using TLC on Merck Silica gel 60 F254 plates
using an AcOEt–hexane mixture (3:1) for elution.
1
2
3
H
N
O
O
N
N
R
EtOH
S
Ar
,
General procedure for the synthesis of 6,7-dihydro-4H-thiazolo[4,5-b]-
pyridin-5-ones 4a–j. Mixture of ester 8a,b (2 mmol) and 0.16 g of
NaOH (4 mmol) in 5 ml of ethanol and 5 ml of water was refluxed for 2 h
and then evaporated to dryness. To obtained residue 0.32 g (2.2 mmol)
of Meldrum’s acid, 2.1 mmol of a corresponding aldehyde and 0.36 g
(6 mmol) of acetic acid and 4 ml of ethanol were added. This mixture
was refluxed for 2 h, evaporated; the residue was crystallized from
ethanol, filtered off, rinsed with ethanol and water and dried.
4
R = NH2
,
N
N
O
Scheme 1
We have suggested that in result of the decarboxylation of
corresponding 2,4-diamino-5-thiazolecarboxylic acids bearing
secondary amino groups in the 2-position, the unstable 2,4-di-
aminothiazoles can be obtained in situ. In the case of 2-amino-
thiophene derivatives, we have shown the possibility of decar-
boxylation of 2-amino-3-thiophenecarboxylic acids 5 and sub-
sequent condensation of 2-aminothiophenes 6, generated in situ,
with aromatic aldehydes and Meldrum’s acid, leading to 7-dihydro-
5H-thieno[2,3-b]pyridin-6-ones 75 (Scheme 2).
2-Ethylamino-7-(4-methoxyphenyl)-6,7-dihydro-4H-thiazolo[4,5-b]-
1
pyridin-5-one 4a: yield 81%, mp 198–200 °C. H NMR ([2H6]DMSO)
d: 1.12 (t, 3H, Me, J 7 Hz), 2.54 (dd, 1H, HCH, J 7 and 17 Hz), 2.87
(dd, 1H, HCH, J 7 and 17 Hz), 3.16 (m, 2H, CH2), 3.72 (s, 3H, OMe),
4.16 (dd, 1H, CH, J 7 and 7 Hz), 6.87 (d, 2H, HAr, J 8 Hz), 7.11 (d, 2H,
HAr, J 8 Hz), 7.63 (t, 1H, NH, J 4 Hz), 10.21 (s, 1H, NH). Found (%): C,
59.23; H, 5.71; N, 13.77; S, 10.46. Calc. for C15H17N3O2S (303.39) (%):
C, 59.39; H, 5.65; N, 13.85; S, 10.57.
7-(3,4-Dimethoxyphenyl)-2-ethylamino-6,7-dihydro-4H-thiazolo[4,5-b]-
pyridin-5-one 4b: yield 56%, mp 139–140 °C. 1H NMR ([2H6]DMSO)
d: 1.12 (t, 3H, Me, J 7 Hz), 2.61 (dd, 1H, HCH, J 7 and 17 Hz), 2.82 (dd,
1H, HCH, J 7 and 17 Hz), 3.16 (m, 2H, CH2), 3.72 (s, 6H, 2OMe), 4.15
(dd, 1H, CH, J 7 and 7 Hz), 6.69 (m, 1H, HAr), 6.89 (m, 2H, HAr), 7.63
(t, 1H, NH, J 4 Hz), 10.21 (s, 1H, NH). Found (%): C, 57.77; H, 5.68;
N, 12.69; S, 9.50. Calc. for C16H19N3O3S (333.41) (%): C, 57.64; H,
5.74; N, 12.60; S, 9.62.
Here, we applied this approach to the synthesis of dihydro-
thiazolopyridinones 4a–j (Scheme 3).†
We have elaborated the general effective method for the
synthesis of compounds 4, based on decarboxylation of readily
available 2,4-diamino-5-thiazolecarboxylic acids, which were
obtained by alkaline hydrolysis of corresponding esters 8.‡
Isolated sodium salt 9, Meldrum’s acid and aromatic aldehyde
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 87–88
formation of a free acid and its decarboxylation to the corre-
NH2
CO2Me
NH2
CO2Na
sponding unstable 2,4-diaminothiazole 10. Formation of 4 takes
place through a conjugated addition of 2,4-diaminothiazole 10
to arylmethylene derivatives 11 (formed directly in the reaction
N
N
NaOH
R
R
EtOH/H2O
N
N
S
S
H
H
8a,b
9a,b
2-Ethylamino-7-(4-hydroxy-3-methoxyphenyl)-6,7-dihydro-4H-thiazolo-
[4,5-b]pyridin-5-one 4c: yield 40%, mp 214–216 °C. 1H NMR ([2H6]DMSO)
d: 1.12 (t, 3H, Me, J 7 Hz), 2.55 (dd, 1H, HCH, J 7 and 17 Hz), 2.81 (dd,
1H, HCH, J 7 and 17 Hz), 3.16 (m, 2H, CH2), 3.72 (s, 6H, 2OMe), 4.09
(dd, 1H, CH, J 7 and 7 Hz), 6.55 (m, 1H, HAr), 6.70 (m, 1H, HAr), 6.80
(m, 1H, HAr), 7.63 (t, 1H, NH, J 4 Hz), 8.90 (br. s, 1H, OH), 10.20 (s,
1H, NH). Found (%): C, 56.56; H, 5.45; N, 13.27; S, 10.18. Calc. for
C15H17N3O3S (319.39) (%): C, 56.41; H, 5.37; N, 13.16; S, 10.04.
2-Ethylamino-7-thiophen-3-yl-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-
O
O
O
H
N
+ ArCHO
O
O
N
R
N
S
EtOH/AcOH
H
Ar
8, 9: a R = Et
b R = Ph
4a R = Et, Ar = 4-MeOC6H4
4b R = Et, Ar = 3,4-(MeO)2C6H3
4c R = Et, Ar = 3-MeO-4-HOC6H3
4d R = Et, Ar = thiophen-3-yl
4e R = Et, Ar = 4-ClC6H4
4f R = Ar = Ph
4g R = Ph, Ar = pyridin-3-yl
4h R = Ph, Ar = 2,4-(MeO)2C6H3
4i R = Ph, Ar = 4-ClC6H4
4j R = Ph, Ar = Bui
1
5-one 4d: yield 42%, mp 205–206 °C. H NMR ([2H6]DMSO) d: 1.12
(t, 3H, Me, J 7 Hz), 2.65 (dd, 1H, HCH, J 7 and 17 Hz), 2.87 (dd, 1H,
HCH, J 7 and 17 Hz), 3.16 (m, 2H, CH2), 4.29 (dd, 1H, CH, J 7 and
7 Hz), 7.00 (m, 1H, HThi), 7.18 (s, 1H, HThi), 7.49 (m, 1H, HThi), 7.63 (t,
1H, NH, J 4 Hz), 10.22 (s, 1H, NH). Found (%): C, 51.73; H, 4.75; N,
15.15; S, 23.09. Calc. for C12H13N3O3S2 (279.38) (%): C, 51.59; H, 4.69;
N, 15.04; S, 22.95.
Scheme 3
7-(4-Chlorophenyl)-2-ethylamino-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-
5-one 4e: yield 65%, mp 228–229 °C. 1H NMR ([2H6]DMSO) d: 1.12 (t,
3H, Me, J 7 Hz), 2.55 (dd, 1H, HCH, J 7 and 17 Hz), 2.93 (dd, 1H, HCH,
J 7 and 17 Hz), 3.16 (m, 2H, CH2), 4.23 (dd, 1H, CH, J 7 and 7 Hz),
7.21 (d, 2H, HAr, J 8 Hz), 7.39 (d, 2H, HAr, J 8 Hz), 7.63 (t, 1H, NH,
J 4 Hz), 10.30 (s, 1H, NH). Found (%): C, 54.76; H, 4.51; N, 13.77; S,
10.56; Cl, 11.64. Calc. for C14H14ClN3OS (307.80) (%): C, 54.63; H, 4.58;
N, 13.65; S, 10.42; Cl, 11.52.
mixture) followed by imino–enamine tautomerisation and subse-
quent intermolecular cyclization attended with loss of acetone
and carbon dioxide (Scheme 4).
Compounds 4a–j are stable crystalline solids, their structures
were confirmed by elemental analysis, NMR spectroscopy and
mass spectrometry. 1H NMR spectra exhibit characteristic signals
of protons of the dihydropyridinone system3,5 in the field of
3.02–4.40 ppm for methine fragment and in the field of 2.30–
2.70 ppm for nonequivalent protons of methylene.3,5 In mass
spectra of compounds 4, peaks of corresponding molecular ions
are found.
7-Phenyl-2-phenylamino-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-one
4f: yield 67%, mp 260–261 °C. 1H NMR ([2H6]DMSO) d: 2.65 (dd, 1H,
HCH, J 7 and 17 Hz), 2.99 (dd, 1H, HCH, J 7 and 17 Hz), 4.31 (dd, 1H, CH,
J 7 and 7 Hz), 6.90–7.60 (m, 10H, HAr), 10.20 (s, 1H, NH), 10.49 (s, 1H,
NHAr). Found (%): C, 67.41; H, 4.76; N, 13.19; S, 10.12. Calc. for
C18H15N3OS (321.40) (%): C, 67.27; H, 4.70; N, 13.07; S, 9.98.
2-Phenylamino-7-pyridin-3-yl-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-
O
Ar
1
5-one 4g: yield 56%, mp 249–250 °C. H NMR ([2H6]DMSO) d: 2.70
NH2
N
(dd, 1H, HCH, J 7 and 17 Hz), 3.01 (dd, 1H, HCH, J 7 and 17 Hz), 4.40 (dd,
1H, CH, J 7 and 7 Hz), 6.95 (m, 1H, HAr), 7.29 (m, 2H, HAr), 7.35 (m,
1H, HPy), 7.59 (m, 2H, HAr), 7.62 (m, 1H, HPy), 8.49 (s, 2H, HPy), 10.24
(s, 1H, NH), 10.52 (s, 1H, NHAr). Found (%): C, 63.49; H, 4.43; N, 17.24;
S, 10.10. Calc. for C17H14N4OS (322.39) (%): C, 63.34; H, 4.38; N,
17.38; S, 9.95.
O
R
+
N
H
S
O
O
11
10
7-(2,4-Dimethoxyphenyl)-2-phenylamino-6,7-dihydro-4H-thiazolo[4,5-b]-
NH
NH2
O
O
O
O
1
pyridin-5-one 4h: yield 57%, mp 254–255 °C. H NMR ([2H6]DMSO)
N
N
R
R
d: 2.53 (dd, 1H, HCH, J 7 and 17 Hz), 2.99 (dd, 1H, HCH, J 7 and 17 Hz),
3.61 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.40 (dd, 1H, CH, J 7 and 7 Hz),
6.41–7.65 (m, 8H, HAr), 10.19 (s, 1H, NH), 10.40 (s, 1H, NHAr). Found
(%): C, 63.11; H, 4.95; N, 11.13; S, 8.53. Calc. for C20H19N3O3S
(381.46) (%): C, 62.98; H, 5.02; N, 11.02; S, 8.41.
7-(4-Chlorophenyl)-2-phenylamino-6,7-dihydro-4H-thiazolo[4,5-b]-
pyridin-5-one 4i: yield 68%, mp 279–280 °C. 1H NMR ([2H6]DMSO) d:
2.61 (dd, 1H, HCH, J 7 and 17 Hz), 3.00 (dd, 1H, HCH, J 7 and 17 Hz),
4.35 (dd, 1H, CH, J 7 and 7 Hz), 6.95 (m, 1H, HAr), 7.29 (m, 4H, HAr),
7.40 (d, 2H, HAr, J 8 Hz), 7.58 (d, 2H, HAr, J 8 Hz), 10.25 (s, 1H, NH),
10.51 (s, 1H, NHAr). Found (%): C, 60.90; H, 4.06; N, 11.92; S, 9.14;
Cl, 10.08. Calc. for C18H14ClN3OS (355.85) (%): C, 60.76; H, 3.97; N,
11.81; S, 9.01; Cl, 9.96.
N
N
O
O
S
S
H
H
Ar
Ar
O
O
O
H
N
N
R
N
S
H
Ar
4
Scheme 4
References
7-Isobutyl-2-phenylamino-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-one
4j: yield 45%, mp 236–237 °C. 1H NMR ([2H6]DMSO) d: 0.89 (m, 6H,
2Me), 1.35 (m, 2H, CH2), 2.30 (dd, 1H, HCH, J 7 and 17 Hz), 2.69 (m, 1H,
CH), 2.70 (dd, 1H, HCH, J 7 and 17 Hz), 3.02 (dd, 1H, CH, J 7 and 7 Hz),
6.94 (m, 1H, HAr), 7.30 (m, 2H, HAr), 7.58 (m, 2H, HAr), 10.25 (s, 1H, NH),
10.30 (s, 1H, NHAr). Found (%): C, 70.13; H, 6.21; N, 11.20; S, 8.62.
Calc. for C22H23N3OS (301.41) (%): C, 70.00; H, 6.14; N, 11.13; S, 8.49.
1 K. J. Moriarty, H. Koblish, D. L. Johnson and R. A. Galemmo Jr., Top.
Med. Chem., 2007, 1, 207.
2 R. K. Vats, V. Kumar, A. Kothari, A. Mital and U. Ramachandran, Curr.
Sci., 2005, 88, 441.
3 A. A. Dudinov, B. V. Lichitsky, I. A. Antonov, A. N. Komogortsev, P. A.
Belyakov and M. M. Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2008,
1707 (in Russian).
Ester 8b was obtained by the described method.6
‡
4 R. Flaig and H. Hartmann, Heterocycles, 1997, 45, 875.
5 B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov and M. M. Krayushkin,
Izv. Akad. Nauk, Ser. Khim., 2008, 2135 (in Russian).
6 K. Gewald, P. Blauschmidt and R. Mayer, J. Prakt. Chem., 1967, 35, 97.
Methyl 4-amino-2-ethylaminothiazole-5-carboxylate 8a was obtained
analogously to ester 8b. Yield 69%, mp 149–150 °C. 1H NMR ([2H6]DMSO)
d: 1.16 (t, 3H, Me), 3.21 (m, 2H, CH2), 3.60 (s, 3H, OMe), 7.75 (s, 2H,
NH2), 8.29 (s, 1H, NH). Found (%): C, 41.61; H, 5.60; N, 20.75; S,
16.04. Calc. for C7H11N3O2S (201.25) (%): C, 41.78; H, 5.51; N, 20.88;
S, 15.93.
Received: 10th October 2008; Com. 08/3226
– 88 –