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

Article abstract of DOI:10.1007/s11172-008-0230-5

7-Aryl- and 7-alkyl-6,7-dihydro-4H-thiazolo[4,5-b]pyridin-5-ones were obtained by three-component condensation of 5-unsubstituted 2-amino-4- iminothiazolidine hydrochlorides with aromatic or aliphatic aldehydes and Meldrum's acid.

Full text of DOI:10.1007/s11172-008-0230-5

Russian Chemical Bulletin, International Edition, Vol. 57, No. 8, pp. 1740—1743, August, 2008
1740
Threeꢀcomponent condensation of 2,4ꢀdiaminothiazoles
with aldehydes and Meldrum´s acid. The synthesis of 7ꢀarylꢀ
and 7ꢀalkylꢀ6,7ꢀdihydroꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones
A. A. Dudinov, B. V. Lichitsky, I. A. Antonov, A. N. Komogortsev, P. A. Belyakov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mkray@ioc.ac.ru
7ꢀArylꢀ and 7ꢀalkylꢀ6,7ꢀdihydroꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones were obtained by threeꢀ
component condensation of 5ꢀunsubstituted 2ꢀaminoꢀ4ꢀiminothiazolidine hydrochlorides with
aromatic or aliphatic aldehydes and Meldrum´s acid.
Key words: 2ꢀaminoꢀ4ꢀiminothiazolidinium chlorides, threeꢀcomponent condensation,
Meldrum´s acid, 7ꢀarylꢀ and 7ꢀalkylꢀ6,7ꢀdihydroꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones.
We have proposed a convenient route to 4,7ꢀdihydroꢀ
5Hꢀthieno[2,3ꢀb]pyridinꢀ6ꢀones through unstable 2ꢀaminoꢀ
thiophenes.1 Here we applied this approach to the syntheꢀ
sis of earlier unknown 7ꢀarylꢀ and 7ꢀalkylꢀ6,7ꢀdihydroꢀ
4Hꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones 1 (Scheme 1). Threeꢀ
component condensation involves reactions of labile
2,4ꢀdiaminothiazoles generated from stable 2ꢀaminoꢀ
4ꢀiminothiazolidinium chlorides 2 with aromatic (or
aliphatic) aldehydes 3 and Meldrum´s acid (4). 2,4ꢀDiaminoꢀ
thiazoles are known to be ambident nucleophiles: they
react with appropriate substrates at both the amino N
atom in position 4 and the C(5) atom of the thiazole ring
to form a new ring annulated with the thiazole fragment.
The resulting novel heterocyclic system can be
regarded as modified 2,4ꢀdiaminothiazole, whose known
derivatives exhibit a high specific biological activity in
inhibition of cyclineꢀdependent kinases.2—5 The sole
relevant example described in the literature includes the
annulation of 2ꢀaminoꢀ4ꢀiminothiazolidinium chloride
with ethyl acetoacetate or pentaneꢀ2,5ꢀdione, giving the
corresponding 2ꢀaminoꢀ5,7ꢀdimethylthiazolo[4,5ꢀb]pyriꢀ
dines and 2ꢀaminoꢀ7ꢀmethylꢀ4Hꢀthiazolo[4,5ꢀb]pyridinꢀ
5ꢀones.6
We used stable 5ꢀunsubstituted 2ꢀaminoꢀ4ꢀiminothiaꢀ
zolidinium chlorides 2. The synthesis of such salts is
described for either a primary or tertiary amino group
(amino, 1ꢀpiperidyl, 4ꢀmorpholino, etc.) as a substituent
in position 2.6 In this case, 5ꢀunsubstituted 2,4ꢀdiaminoꢀ
thiazoles are difficult to use as the starting reagents
because of their instability.7 Moreover, when dissolved,
they are in equilibrium with their tautomer 2ꢀaminoꢀ
4ꢀiminothiazolidine; the imino form is dominant,8,9 which
makes them prone to hydrolysis.
Scheme 1
O
O
+
–
Cl H2N
O
O
N
+
+
R″CHO
R´
S
3
2a—c
4
H
N
N
O
N
O
R´
S
AcONa
EtOH
R″
1a—n
Comꢀ
pound
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
R´
R″
NH
NH
NH
NH
NH
NH
NH
NH
Me CHCH
2
3ꢀPyridyl
3,4ꢀ(MeO) C H
2,5ꢀ(MeO) C H
2ꢀThienyl
4ꢀPhCH2OꢀC H
CH(CH )
2 5
4ꢀClꢀC H
4ꢀClꢀC H
4ꢀClꢀC H
6
2ꢀMeOꢀC H
2,4ꢀ(MeO) C H
2 6
2,4ꢀ(MeO) C H
2,5ꢀClꢀC H
2
2
2
2
2
2
2
2
2
2
6
3
3
2 6
6
4
6
4
4
4
N(CH )
2 5
6
N(CH ) O
2 4
N(CH )
2 5
6 4
N(CH ) O
2 4
3
3
N(CH )
2 5
2
6
N(CH ) O
2 4
6
3
The condensation was carried out in boiling ethanol
in the presence of a small excess of AcONa and a catalytic
amount of Nꢀmethylmorpholine (see Scheme 1, Table 1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1707—1710, August, 2008.
1066ꢀ5285/08/5708ꢀ1740 © 2008 Springer Science+Business Media, Inc.

Threeꢀcomponent condensation of 2,4ꢀdiaminothiazoles Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Table 1. Yields, melting points, and elemental analysis data for compounds 1a—n
1741
Compound
M.p./°C
Yield (%)
Found
Calculated
Molecular
formula
(%)
С
H
N
S
Cl
—
1a
1b
1c
1d
1e
1f
228—230
292 (decomp.)
224—227
231—232
260 (decomp.)
325
44
56
48
46
53
55
67
47
57
62
49
54
51
65
53.04
53.31
53.43
53.64
54.79
55.07
54.80
55.07
47.47
53.64
64.65
64.94
57.55
55.07
51.32
51.52
58.92
58.70
55.06
54.93
62.76
55.07
57.73
57.58
60.83
61.10
49.77
50.01
6.64
6.71
4.62
4.09
4.89
4.95
4.89
4.95
3.57
4.09
4.82
4.88
6.89
4.95
3.53
3.60
5.24
5.22
4.64
4.61
6.13
4.95
5.67
5.64
6.18
6.21
3.89
3.93
18.52
18.65
22.34
22.75
13.91
13.76
13.86
13.76
16.51
22.75
12.14
11.96
16.34
13.76
14.81
15.02
11.87
12.08
11.90
12.01
12.07
13.76
11.38
11.19
11.37
11.25
11.12
10.93
14.38
14.23
13.27
13.02
10.32
10.50
10.34
10.50
25.79
13.02
9.18
C10H15N3OS
C11H10N4OS
—
—
—
—
—
—
C14H15N3O3S
C14H15N3O3S
C10H9N3OS2
C19H17N3O2S
C12H17N3OS
9.12
1g
1h
1i
271—273
285
12.48
10.50
11.66
11.46
9.15
9.22
9.22
9.17
9.45
10.50
8.50
8.54
8.73
8.59
12.45
12.67
10.37
10.19
10.08
10.13
—
C12H10ClN3OS
C17H18ClN3OS
C16H16ClN3O2S
C18H21N3O2S
C18H21N3O4S
C19H23N3O3S
C16H15Cl2N3O2S
199—201
178—180
134—136
124—126
183—185
244—246
1j
1k
1l
—
—
1m
1n
8.40
8.34
18.32
18.45
Scheme 2
Apparently, the first step involves the formation of
free 2,4ꢀdiaminothiazoles 5 under the action of sodium
acetate (with a release of an equimolar amount of AcOH)
and the formation of arylmethylidene derivatives of
Meldrum´s acid (6) (catalyzed by Nꢀmethylmorpholine
or its acetate). This is followed by conjugated addition of
2,4ꢀdiaminothiazole to compound 6 and cyclization with
a release of CO2 and acetone (Scheme 2).
O
O
Ar
O
Me
H2N
+
O
N
Me
6
R´
S
Compounds 1 are crystalline solids. Their structures
were proved by elemental analysis, NMR spectroscopy,
and mass spectrometry. The mass spectra of compounds 1
contain characteristic molecular ion peaks. The structure
of compound 1h was confirmed by 2D C—H correlation
experiments. The signals for the protonꢀbearing C atoms
in the 13C NMR spectra and for the corresponding
protons in the 1H NMR spectra were assigned from HSQC
data.10 The signals for the quaternary C atoms were
assigned from HMBC data.11 The observed correlations
allowed identification of all the protons and all the C
atoms (except for the fragment C—NH2 because the corꢀ
responding signal shows no cross peaks).
5
NH2
NH
O
O
Me
Me
Me
Me
O
O
N
N
O
O
S
S
R´
R´
Ar
Ar
O
O
H
N
O
N
R´
S
Ar
2

1742
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
Dudinov et al.
Table 2. 1H NMR spectra (DMSOꢀd6, δ, J/Hz) of compounds 1a—n
Comꢀ
pound
Ar
H—C—H
( dd, 1 H)
H—C—H
CH
R
NH
(br.s, 1 H)
1a
1b
1c
1d
0.85 (m, 6 Н, СН3);
1.25 (m, 2 H, CH2);
1.65 (m, 1 H, CH)
2.2 (dd,
J = 7, 16)
2.6 (dd, 1 H,
J = 7, 16)
2.9
6.95
(s, 2 H, NH2)
(m, 1 H, CH)
10.05
10.30
7.35 (m, 1 H, Py);
7.55 (m, 1 H, Py);
8.45 (m, 2 H, Py)
2.5 (dd,
J = 7, 16)
2.95 (dd, 1 H,
J = 7, 16)
4.25 (dd, 1 H,
7.05
(s, 2 H, NH2)
J = 7)
3.70 (s, 6 Н, ОСН3);
6.65 (m, 1 Н, H(Ar));
6.85 (m, 2 Н, H(Ar))
2.55 (dd,
J = 8, 16)
2.8 (dd, 1 H,
J = 8, 16)
4.1 (dd, 1 H,
7.0
10.20
10.20
J = 8)
(s, 2 H, NH2)
3.65 (s, 3 Н, ОСН3);
3.80 (s, 3 Н, ОСН3);
6.45 (m, 1 Н, H(Ar));
6.80 (m, 1 Н, H(Ar));
6.95 (m, 1 Н, H(Ar))
2.55 (dd,
J = 6, 16)
2.95 (dd, 1 H,
J = 8, 16)
4.35 (dd, 1 H,
7.05
(s, 2 H, NH2)
J = 6.8)
1e
1f
6.85 (m, 1 H, H(Het));
6.95 (m, 1 H, H(Het));
7.35 (m, 1 H, H(Het))
2.6 (dd,
J = 7, 16)
3.0 (dd, 1 H,
J = 7, 16)
4.45 (dd, 1 H,
7.05
(s, 2H, NH2)
10.25
10.20
J = 7)
5.05 (s, 2 Н, ОСН2);
6.95 (m, 4 Н, H(Ar));
7.40 (m, 5 Н, H(Ar))
2.45 (dd,
J = 7, 15)
2.85 (dd, 1 H,
J = 7, 15)
4.13 (dd, 1 H,
7.0
J = 7)
(s, 2H, NH2)
1g
1h*
1i
0.80—1.80
(m, 11 Н, C6H11)
2.35 (m, CH)
2.65
(m, 2 H, CH2)
2.65
(m, 2 H, CH2)
6.95
(s, 2 H, NH2)
10.00
10.25
7.15 (d, 2 H, Н(Ar), J = 8);
7.35 (d, 2 H, H(Ar), J = 8)
2.5 (dd,
J = 7, 16)
2.9 (dd, 1 H,
J = 7, 16)
4.3 (dd, 1 H,
7.05
(s, 2 H, NH2)
J = 7)
7.2 (d, 2 H, H(Ar), J = 6);
7.35 (d, 2 H, H(Ar), J = 6)
2.55 (dd,
J = 7, 16)
2.9 (dd, 1 H,
J= 7, 16)
4.3 (dd, 1 H, 1.55 (s, 6 H, CH2);
10.45
J = 7)
3.3 (s, 4 H, NCH2)
1j
7.15 (d, 2 H, H(Ar), J = 6);
7.3 (d, 2 H, H(Ar), J = 6)
2.55 (dd,
J = 7, 17)
2.9 (dd, 1H,
J = 7, 17)
4.3
(t, J = 7)
3.25 (m, 4 H, NCH2); 10.40
3.65 (m, 4 H, OCH2)
1k
3.85 (s, 3 H, OMe);
6.95 (m, 3 H, Н(Ar));
7.25 (m, 1 H, H(Ar))
2.55 (dd,
J = 4, 16)
2.95 (dd, 1 H,
J = 8, 16)
4.45 (dd, 1 H,
1.55
(s, 6 H, CH2)
10.30
J = 4.8)
1l
6.45 (m, 1 H, H(5)(Ar));
6.55 (m, 1 H, H(3)(Ar));
6.8 (m, 1 H, H(6)(Ar))
2.5 (dd,
J = 5, 17)
2.9 (dd, 1 H,
J = 7, 17)
4.35 (dd,
3.25 (m, 4 H, NCH2); 10.25
1 H, J = 5, 7) 3.65 (m, 4 H, OCH2)
1m
1n
6.4 (m, 1 H, H(5)(Ar));
6.55 (m, 1 H, H(3)(Ar));
6.8 (m, 1 H, H(6)(Ar))
2.5 (m, CH)
2.9 (m, 1 H, CH)
4.35 1.55 (s, 6 H, CH2);
10.20
10.45
(m, 1 H, CH) 3.3 (s, 4 H, NCH2)
5.2 (dd, 1 H, 3.2 (m, 4 H, NCH2);
7.3 (m, 1 H, C6H3);
7.45 (m, 2 H, H(Ar))
2.75 (dd,
J = 7, 17)
3.0 (dd, 1 H,
J = 10, 17)
J = 7, 10)
3.65
(m, 4 H, CH2OCH2)
* The 13C NMR spectrum of compound 1h: 35.51 (C(7)), 93.45 (C(7a)), 128.58, 128.62 (C(2´), C(3´), C(5´), C(6´)), 131.35 (C(4)),
142.75 (C(1´)), 143.61 (C(4a)), 167.64 (C(2)), 168.64 (C(5)).
Thus, threeꢀcomponent condensation of 2ꢀaminoꢀ
4ꢀiminothiazolidine hydrochlorides with aromatic or
aliphatic aldehydes and Meldrum´s acid provides a conꢀ
venient route to substituted dihydrothiazolo[4,5ꢀb]pyriꢀ
dinones.
Experimental
1H and 13C NMR spectra were recorded on Bruker
Avance II 300 and Bruker DRXꢀ500 instruments in DMSOꢀd6.
Mass spectra were recorded on a FINNIGAN MAT INCOS 50

Threeꢀcomponent condensation of 2,4ꢀdiaminothiazoles Russ.Chem.Bull., Int.Ed., Vol. 57, No. 8, August, 2008
1743
instrument (direct inlet probe, EI, 70 eV). Melting points were
measured on a Boetius hot stage and are given uncorrected.
The course of the reactions was monitored and the purity of the
products was checked by TLC on Silica gel 60 F254 plates
(Merck) with ethyl acetate—hexane as an eluent.
2. K. J. Moriarty, H. Koblish, D. L. Johnson, R. A. Galemmo, Jr.,
Top. Med. Chem., 2007, 1, 207.
3. R. K. Vats, V. Kumar, A. Kothari, A. Mital, U. Ramachandran,
Cur. Sci., 2005, 88, 2, 441.
4. CA Pat. 2 455 753.
Compounds 2a—c were prepared as described earlier.12
5. US Pat. 7 211 576.
Synthesis of 6,7ꢀdihydroꢀ4ꢀthiazolo[4,5ꢀb]pyridinꢀ5ꢀones
(1a—n). Ethanol (6—10 mL) was added to a mixture of 2ꢀaminoꢀ
4ꢀiminothiazolidine hydrochloride 2 (3 mmol), Meldrum´s acid
(0.5 g, 3.2 mmol), AcONa (0.25 g, 3 mmol), an appropriate
aldehyde (3 mmol), and Nꢀmethylmorpholine (3 drops). The
reaction mixture was refluxed for 4 h. The precipitate that formed
was filtered off, washed with ethanol (2×5 mL), water (5 mL),
and again ethanol (5 mL), and dried to a constant weight.
6. R. Flaig, H. Hartmann, Monatsh. Chem., 1997, 128, 1051.
7. W. Davies, J. A. Maclaren, L. R. Wilkinson, J. Chem. Soc.,
1950, 3491.
8. O. Ceder, B. Beijer, Tetrahedron, 1975, 31, 963.
9. S. Angelova, V. Enchev, N. Markova, P. Denkova, K. Kostova,
J. Mol. Struct., 2004, 711, 1—3, 201.
10. A. Bax, S. Subramanian, J. Magn. Reson., 1986, 67, 565.
11. A. Bax, M. F. Summers, J. Am. Chem. Soc., 1986, 108, 2093.
12. R. Flaig, H. Hartmann, Heterocycles, 1997, 45, 875.
References
1. B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M.
Krayushkin, Izv. Akad. Nauk, Ser. Khim., 2008, No. 10 [Russ.
Chem. Bull., Int. Ed., 2008, 57, 10].
Received February 5, 2008;
in revised form March 19, 2008