Reaction of 4-iminothiazolidin-2-one with acetylacetone

Article abstract of DOI:10.1134/S1070428012020170

By the reaction of acetylacetone and arylazoacetylacetones with 4-iminothiazolidin-2-one thiazolo[4,5-b]pyridines were obtained in good yields. Optimum reaction conditions were chosen and some properties of compounds obtained were studied. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012020170

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 2, pp. 268−272. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © T.I. Chaban, B.S. Zimenkovskii, I.D. Komaritsa, I.G. Chaban, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 2,
pp. 277−280.
Reaction of 4-Iminothiazolidin-2-one with Acetylacetone
T. I. Chaban, B. S. Zimenkovskii, I. D. Komaritsa, and I. G. Chaban
Danylo Halytsky Lviv National Medical University, L’vov,79010 Ukraine
e-mail: chabantaras@ukr.net
Received February 11, 2011
Abstract—By the reaction of acetylacetone and arylazoacetylacetones with 4-iminothiazolidin-2-one
thiazolo[4,5-b]pyridines were obtained in good yields. Optimum reaction conditions were chosen and some
properties of compounds obtained were studied.
DOI: 10.1134/S1070428012020170
Five-membered heterocycles fused to the pyridine ring
attract constant attention since many compounds of this
class possess the biologic action. Thiazolo[4,5-b]pyridines
are among the least accessible and in turn poorly under-
stood representatives of this class of organic substances.
The information on their biological activity is also
insufficient. In particular, among this type compounds
substances were found possessing fungicidal action [1],
antagonists of Н3-histamine receptors [2], antagonists
of metabotropic glutamate receptors 5 (mGluR5) [3] of
high inhibitor activity with respect to the receptors of
the epidermal growth factor [4] and a number of other
enzymes [5, 6].
We report here on a convenient method of preparation
of 3H-thiazolo[4,5-b]pyridin-2-one derivatives. We used
4-iminothiazolidin-2-one (I) as the initial compound[16]
that was reacted with acetylacetone (II). We optimized
the conditions of this reaction that made it possible to
obtain 5,7-dimethyl-3H-thiazolo[4,5-b]-pyridin-2-one
(IV) in good yield. The best results were observed at
keeping the reagents mixture in methanol in the presence
of sodium methylate over 5 days. Similar procedure was
described earlier in patent [17], but due to the low yield
the method had no preparative value.
We also studied the behavior in this reaction of
acetylacetone arylazo derivatives IIIа–IIIg (Scheme 1).
Under the chosen conditions the corresponding 6-arylazo-
5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-ones Vа–Vg
formed in good yields. These substances were orange or
red crystalline powders well soluble in DMF and DMSO,
sparingly soluble in water and the other organic solvents.
Two fundamentally different approaches exist with
respect to the synthesis of the thiazolo[4,5-b]pyridine
system. The first one is based on the fusion of the thiazole
ring to the pyridine. Here 2-aminopyridines [7], thio-
ureas[8–10], or thiocarbamates [11] are used as initial
compounds. The second procedure of the pyridine ring
fusion is underlain by a three-component condensation
of derivatives of 4-aminothiazoles and 4-aminosele-
nazoles with aromatic or aliphatic aldehydes and the
Meldrum’s acid [12]. At the use in the reaction with
2,4-diaminothiazoles of ethyl acetoacetate and acetyl-
acetone 2-amino-5,7-dimethylthiazolo[4,5-b]pyridines
and 2-amino-7-methyl-4Н-thiazolo[4,5-b]pyridin-5-ones
were obtained respectively [13]. Examples are also known
of the synthesis of 1,3-thiazolo[4,5-b]pyridine derivatives
with the use of solid-phase carriers [14] and with the ap-
plication of dominoreactions [15].
The structure of compounds obtained was proved
by NMR spectra. For instance, the proton signals of
the methyl groups of the pyridine ring are observed at
2.42–2.46 and 2.49–2.87 ppm respectively, and of NH
groups, in a relatively wide range of 9.78–14.29 ppm.
Some properties of compounds obtained were inves-
tigated. The proton in the position 3 retained the acid
properties, and the reaction with potassium hydroxide
afforded the corresponding salts VIа, VIb. The obtained
salts exhibited nucleophilic properties and under mild
conditions reacted with electrophilic reagents to give
N-alkylated products (Scheme 2).
268

REACTION OF 4-IMINOTHIAZOLIDIN-2-ONE WITH ACETYLACETONE
269
Scheme 1.
H3C
CH3
H
N
O
O
H3C
N
II
O
S
HN
CH3
IV
NH
H3C
O
H
N
O
S
I
O
RC6H4
N
H
N
H3C
N
CH3
IIIа_IIIg
O
N
S
RC6H4
N
CH3
Vа_Vg
O
S NH
O
S
O
S NH
O
S
N
(g).
(f),
III, V, R = H (a), 2-CH3 (b), 4-CH3 (c), NO2 (d), COOH (e),
N
N
Et
Scheme 2.
K
N
ClCH2R'
VII
H3C
N
H3C
R
N
R'
N
S
KOH
IV, Va
O
S
R
O
CH3
VIIIа_VIIIf
CH3
VIа, VIb
H
N
H3C
H2N
N
Zn
Va
O
S
CH3
IX
VI, R = H (а), C6H5N=N (b); VIII, R = H, R' = 4-NO2C6H4 (а), 4-CH3C6H4NHC(O) (b), 2-C2H5C6H4NHC(O) (c),
2-ClC6H4NHC(O) (d); R = C6H5N=N, R' = 4-CH3C6H4NHC(O) (e), 4-C2H5C6H4NHC(O) (f).
In reaction with reducers compound Vа was readily
converted into 6-amino-5,7-dimethyl-3H-thiazolo[4,5-b]
pyridin-2-one (IX). Optimum yield of compound IX was
obtained in the process carried out in the mixture acetic
acid–pyridine using zinc powder as reducer.
reagents. The possibilities of their synthetic application
were demonstrated.
EXPERIMENTAL
1H NMR spectra of compounds in DMSO-d6 solution
were registered on a spectrometer Varian Mercury VX-
400 (400 MHz), internal reference TMS.
Thus a convenient method was developed for the
preparation of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-
2-one derivatives in high yields from available initial
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CHABAN et al.
270
5,7-Dimethyl-3H-thiazolo[4,5-b]pyridin-2-one
pyridin-6-ylazo)benzoic acid (Ve). Yield 74%, mp
350°С (decomp.) (2-propanol). H NMR spectrum, δ,
1
(IV). In 125 ml of anhydrous methanol 2.5 g (109 mmol)
of sodium was dissolved, and to the solution obtained at
20°С was added 6.8 g (50 mmol) of 4-iminothiazolidin-
2-one (I) and 8 ml of acetylacetone. The mixture was left
standing for 5 days with the intermittent stirring, then it
was acidified with acetic acid to рН ~5, five-fold diluted
with water, the precipitate was filtered off, washed with
water, and dried. Yield 6.7 g (74%), mp 277°С (ethanol).
White crystalline powder, well soluble in DMF, DMSO,
solutions of alkali and mineral acids, sparingly soluble in
ppm: 2.45 s (3H, CH3), 2.49 s (3H, CH3), 7.65 d (2H,
C6H4, J 8.6 Hz), 7.98 d (2H, C6H4, J 8.6 Hz), 13.68 s
(1H, NH), 14.08 s (1H, COOH). Found, %: C 54.99;
H 3.60; N 17.86. C15H12N4O3S. Calculated, %: C 54.87;
H 3.68; N 17.06.
4-(5,7-Dimethyl-2-oxo-2,3-dihydrothiazolo[4,5-b]-
pyridin-6-ylazo)-N-thiazol-2-ylbenzenesulfonamide
(Vf). Yield 76%, mp 264–265°С (decomp.) (benzene).
1H NMR spectrum, δ, ppm: 2.45 s (3H, CH3), 2.65 s
(3H, CH3), 6.88 d (1H, thiazole, J 4.0 Hz), 6.89 d (1H,
thiazole, J 4.0 Hz), 7.97–8.02 m (4H, C6H4), 12.85 s (1H,
NH). Found, %: C 45.93; H 3.23; N 18.92. C17H14N6O3S3.
Calculated, %: C 45.73; H 3.16; N 18.82.
1
the other organic solvents. H NMR spectrum, δ, ppm:
2.27 s (3H, CH3), 2.40 s (3H, CH3), 6.91 s (1H, Py),
12.44 s (1H, NH). Found, %: C 53.31; H 4.47; N 15.54.
C8H8N2OS. Calculated, %: C 53.02; H 4.49; N 15.44.
5,7-Dimethyl-6-arylazo-3H-thiazolo[4,5-b]pyridin-2-
ones Va–Vg were obtained similarly from compound I
and appropriate α-arylazoacetylacetones IIIa–IIIg [18].
4-(5,7-Dimethyl-2-oxo-2,3-dihydrothiazolo[4,5-b]-
pyridin-6-ylazo)-N-[1,3,4]thiadiazol-2-ylbenzenesul-
fonamide (Vg). Yield 85%, mp 280–281°С (decomp.)
1
(toluene). H NMR spectrum, δ, ppm: 1.24 t (3H, CH3,
5,7-Dimethyl-6-phenylazo-3H-thiazolo[4,5-b]-
pyridin-2-one (Va). Yield 86%, mp 258–259°С (toluene).
1H NMR spectrum, δ, ppm: 2.42 s (3H, CH3), 2.61 s (3H,
CH3), 7.60 m (3H, C6H5), 7.80 d (2H, C6H5, J 8.0 Hz),
12.78 s (1H, NH) Found, %: C 58.81; H 4.32; N 19.79.
C14H12N4OS. Calculated, %: C 59.14; H 4.25; N 19.70.
J 7.5 Hz), 2.66 s (3H, CH3), 2.87 q (2H, CH2, J 7.5 Hz),
8.00 s (4H, C6H4), 12.86 s (1H, NH), 14.10 s (1H, NH).
Found, %: C 43.10; H 2.25; N 21.99. C16H13N7O3S3.
Calculated, %: C 42.94; H 2.93; N 21.91.
5,7-Dimethyl-3H-thiazolo[4,5-b]-pyridin-2-one po-
tassium salt (VIа). To 20 ml of water and 0.56 g (10 mmol)
of potassium hydroxide was added 1.8 g (10 mmol) of
compound IV, and the mixture was heated to complete
dissolution. The solution obtained was evaporated to dry-
ness. The residue was dried at 100°С. Yield quantitative,
mp >300°С (water). Lightly colored crystalline powder
soluble in water and alcohols, sparingly soluble in organic
solvents. 1H NMR spectrum, δ, ppm: 2.30 s (3H, CH3),
2.44 s (3H, CH3), 6.44 s (1H, Py). Found, %: C 44.22;
H 3.53; N 12.80. C8H7KN2OS. Calculated, %: C 44.03;
H 3.23; N 12.84.
5,7-Dimethyl-6-o-tolylazo-3H-thiazolo[4,5-b]-
pyridin-2-one (Vb). Yield 85%, mp 259–260°С
(decomp.) (toluene). 1H NMR spectrum, δ, ppm:
2.47 s (3H, CH3), 2.65 s (3H, CH3), 2.67 s (3H, CH3),
7.33–7.37 m (1H, C6H4), 7.46 d (2H, C6H4, J 3.9 Hz),
7.59 d (1H, C6H4, J 8.0 Hz), 12.75 (1H, NH). Found, %:
C 60.30; H 4.63; N 18.75. C15H14N4OS. Calculated, %:
C 60.38; H 4.73; N 18.78.
5,7-Dimethyl-6-p-tolylazo-3H-thiazolo[4,5-b]-pyri-
dine-2-one (Vc). Yield 75%, mp 252°С (decomp.) (tolu-
1
ene). H NMR spectrum, δ, ppm: 2.42 s (3H, CH3С6Н4),
5,7-Dimethyl-6-phenylazo-3H-thiazolo[4,5-b]pyri-
din-2-one potassium salt (VIb) was obtained similarly.
Yield quantitative, mp >300°С (water). Red crystalline
powder soluble in water and alcohols, sparingly soluble
2.42 s (3H, CH3), 2.60 s (3H, CH3), 7.41 d (2H, C6H4,
J 7.6 Hz), 7.78 d (2H, C6H4, J 7.6 Hz), 12.74 s (1H,
NH). Found, %: C 60.30; H 4.63; N 18.75. C15H14N4OS.
Calculated, %: C 60.38; H 4.73; N 18.78.
1
in organic solvents. H NMR spectrum, δ, ppm: 2.48 s
5,7-Dimethyl-6-(4-nitrophenylazo)-3H-thiazolo-
[4,5-b]pyridine-2-one (Vd). Yield 81%, mp 194°С.
(toluene). H NMR spectrum, δ, ppm: 2.46 s (3H, CH3),
2.49 s (3H, CH3), 7.74 d (2H, C6H4, J 9.1 Hz), 8.28 d (2H,
C6H4, J 9.1 Hz), 13.30 s (1H, NH). Found, %: C 51.18;
H 3.47; N 21.00. C14H11N4O3S. Calculated, %: C 51.06;
H 3.37; N 21.26.
(3H, CH3), 2.64 s (3H, CH3), 7.43 d (1H, C6H5, J 6.8 Hz),
7.53 t (2H, C6H5, J 7.6 Hz), 7.75 d (2H, C6H5, J 7.6 Hz).
Found, %: C 52.34; H 3.32; N 17.41. C14H11KN4OS.
Calculated, %: C 52.15; H 3.44; N 17.38.
1
General alkylation procedure. To a solution obtained
by heating 9 mmol of potassium salt VIa or VIb in 12 ml
of DMF was added 9 mmol of an appropriate alkylating
agent. The mixture was boiled for 20 min, a bulky white
4-(5,7-Dimethyl-2-oxo-2,3-dihydrothiazolo[4,5-b]-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 2 2012

REACTION OF 4-IMINOTHIAZOLIDIN-2-ONE WITH ACETYLACETONE
271
2-(5,7-Dimethyl-2-oxo-6-phenylazothiazolo[4,5-
b]-pyridin-3-yl)-N-(4-ethylphenyl)acetamide (VІІІf).
Yield 79%, mp 200–201°С (DMF–ethanol, 1 : 1).
1H NMR spectrum, δ, ppm: 1.17 t (3H, CH2CH3,
J 7.3 Hz), 2.51 s (3H, CH3), 2.64 s (3H, CH3), 3.29 q
(2H, CH2СН3), 4.85 s (2H, CH2), 7.16 d (2H, С6H4C2H5,
J 7.8 Hz), 7.48 d (2H, С6H4C2H5, J 7.8 Hz), 7.62 m (3H,
Ar), 7.89 d (2H, Ar, J 6.8 Hz), 10.38 s (1H, NH). Found,
%: C 64.84; H 5.02; N 15.78. C24H23N5O2S. Calculated,
%: C 64.70; H 5.20; N 15.72.
precipitate separated. The hot mixture was filtered, the
precipitate was washed on the filter with hot DMF. To
the filtrate cooled to ~50°С was added at stirring 100 ml
of water, and the mixture was cooled to 12–15°С. The
separated precipitate was filtered off, washed with water,
and dried.
5,7-Dimethyl-3-(4-nitrobenzyl)-3H-thiazolo-[4,5-b]
pyridin-2-one (VIIІа). Yield 72%, mp 180°С (DMF).
1H NMR spectrum, δ, ppm: 2.33 s (3H, CH3), 2.44 s
(3H, CH3), 5.29 s (2H, СH2), 7.04 s (1H, Py) 7.56 d (2H,
C6H4, J 10.5 Hz), 8.20 d (2H, C6H4, J 10.5 Hz). Found,
%: C 57.25; H 4.05; N 13.40. C15H13N3O3S. Calculated,
%: C 57.13; H 4.16; N 13.33.
6-Amino-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-
2-one (IX). To a solution of 20 ml of pyridine and 15 ml
of acetic acid was added 1.42 g (5 mmol) of compound
Vа. The mixture was heated to boiling, compound Va
completely dissolved. To the solution obtained was added
at heating in several portions within 1 h 2.3 g (35 mmol)
of activated zinc powder, the solution decolorized, it
was filtered, the filtrate cooled to room temperature was
diluted with 50 ml of water and left standing for 4 h.
The separated precipitate was filtered off, washed with
water, and dried. Yield 0.6 g (62%), mp 280°С (decomp.)
(acetic acid). White crystalline powder, well soluble in
DMF, DMSO, solutions of alkali and mineral acids, in-
soluble in water. 1H NMR spectrum, δ, ppm: 2.11 s (3H,
CH3), 2.83 s (3H, CH3), 4.67 s (2H, NH2), 11.89 s (1H,
NH). Found, %: C 49.25; H 4.73; N 21.57. C8H9N3OS.
Calculated, %: C 49.21; H 4.65; N 21.52.
2-(5,7-Dimethyl-2-oxothiazolo[4,5-b]pyridin-3-
yl)-N-p-tolylacetamide (VIІІb). Yield 90%, mp 202°С
1
(DMF–ethanol, 1 : 1). H NMR spectrum, δ, ppm: 2.26 s
(3H, CH3), 2.34 s (3H, CH3), 2.43 s (3H, CH3), 4.78 s
(2H, CH2), 7.02 s (1H, Py), 7.12 d (2H, C6H4, J 8.1 Hz),
7.45 d (2H, C6H4, J 8.1 Hz), 10.30 s (1H, NH). Found,
%: C 62.20; H 5.33; N 12.53. C17H17N3O2S. Calculated,
%: C 62.37; H 5.23; N 12.83.
2-(5,7-Dimethyl-2-oxothiazolo[4,5-b]pyridin-3-yl)-
N-(2-ethylphenyl)acetamide (VIIІc). Yield 86%, mp
1
190–191°С (DMF–ethanol, 1 : 1). H NMR spectrum, δ,
ppm: 1.15 t (3H, CH3CH2, J 7.3 Hz), 2.34 s (3H, CH3),
2.45 s (3H, CH3), 2.63 q (2H, CH2СН3, J 7.3 Hz), 4.81 s
(2H, CH2), 7.17 s (1H, Py), 7.25–7.30 m (4H, C6H4),
10.78 s (1H, NH). Found, %: C 63.24; H 5.72; N 12.50.
C18H19N3O2S. Calculated, %: C 63.32; H 5.61; N 12.31.
REFERENCES
2-(5,7-Dimethyl-2-oxothiazolo[4,5-b]pyridin-3-yl)-
N-(2-chlorоphenyl)acetamide (VIIІd). Yield 74%, mp
174°С (DMF–ethanol, 1 : 1). H NMR spectrum, δ, ppm:
1. Marzoog, S. and Al-Thebeiti, Farmaco, 2000, vol. 55,
p. 109.
1
2. Walczynski, K., Zuiderveld, O., and Timmerman, H., Eur.
J. Med. Chem., 2005, vol. 40, p. 15.
2.34 s (3H, CH3), 2.45 s (3H, CH3), 4.88 s (2H, CH2),
4
3
7.02 s (1H, Py), 7.21 d.t (1H, C6H4, J 1.2, J 8.0 Hz),
7.33 d.t (1H, C6H4, 4J 1.2, 3J 8.0 Hz), 7.52 d.d (1H, C6H4,
4J 1.2, 3J 7.8 Hz), 7.70 d.d (1H, C6H4, 3J 1.2, J 7.8 Hz),
10.08 s (1H, NH). Found, %: C 55.18; H 4.17; N 12.08.
C16H14ClN3O2S. Calculated, %: C 55.25; H 4.06; N 12.08.
3. Kulkarni, S.S. and Newman, A.H., Bioorg. Med. Chem.
Lett., 2007, vol. 17, p. 2987.
4. Lin, R., Johnson, S.G., Connolly, P.J., Wetter, S.K.,
Binnun, E., Hughes, T.V., Murray, W.V., Pandey, N.B.,
Moreno-Mazza, S.J.,Adams, M., Fuentes-Pesquera,A.R.,
and Middleton, S.A., Bioorg. Med. Chem. Lett., 2009,
vol. 19, p. 2333.
2-(5,7-Dimethyl-2-oxo-6-phenylazothiazolo[4,5-b]-
pyridin-3-yl)-N-p-tolylacetamide (VІІІe). Yield 74%,
5. Komoriya, S., Kobayashi, S., Osanai, K., Yoshino, T.,
Nagata, T., Haginoya, N., Nakamoto, Y., Mochizuki, A.,
Nagahara, T., Suzuki, M., Shimada, T., Watanabe, K.,
Isobe, Y., and Furugoori, T., Bioorg. Med. Chem., 2006,
vol. 14, p. 1309.
1
mp 250°С (DMF–ethanol, 1 : 1). H NMR spectrum, δ,
ppm: 2.26 s (3H, С6H4CH3), 2.37 s (3H, CH3), 2.64 s (3H,
CH3), 4.86 s (2H, CH2) 7.13 d (2H, С6H4CH3, J 7.6 Hz),
7.46 d (2H, С6H4CH3, J 7.6 Hz), 7.62 m (3H, С6Н5),
7.90 d (2H, С6Н5, J 7.20 Hz), 10.38 s (1H, NH). Found,
%: C 64.22; H 4.92; N 16.43. C23H21N5O2S. Calculated,
%: C 64.02; H 4.91; N 16.23.
6. Singh, B., Bacon, E.R., Lesher, G.Y., Robinson, S., Pen-
nock, P.O., Bode, D.C., Pagani, E.D., Bentley, R.G., Con-
nell, M.J., Hamel, L.T., and Silver, P.J., J. Med. Chem.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 2 2012

CHABAN et al.
13. Flaig, R. and Hartmann, H., Monatsh. Chem., 1997,
272
1995, vol. 38, p. 2546.
vol. 128, p. 1051.
7. Couture, A., Grandclaudon, P., and Huguerre, E., J. Het-
erocycl. Chem., 1987, vol. 24, p. 1765.
14. Lee, T., Lee, D., Lee, I.Y., and Gong, Y.-D., J. Comb. Chem.,
2010, vol. 12, p. 95.
8. Sarkis, G.Y. and Faisal, E.D., J. Heterocycl. Chem., 1985,
vol. 22, p. 725.
15. Shestopalov, A.M., Rodinovskaya, L.A., and Shesto-
palov, A.A., Tetrahedron, 2010, vol. 66, p. 8945.
9. Jain, S., Nagda, D. and Talesara, G., Phosph., Sulfur, Sili-
con, Relat. Elem., 2006, vol. 181, p. 1665.
16. Komaritsa, I.D., Khim. Geterotsikl. Soedin., 1968, vol. 3,
p. 436.
10. Okafor, C.O., J. Med. Chem., 1967, vol. 10, p. 126.
17. Sekachev, P.G. , USSR Inventor’s Certificate 323404, 1972;
SSSR Byull. Izobr., 1972, no. 1.
11. Gamal,A., El-Hit. Monatsh. Chem., 2003, vol. 134, p. 837.
12. Dudinov, A.A., Lichitskii, B.V., Antonov, I.A., Ko-
mogortsev, A.N., Belyakov, P.A., and Krayushkin, M.M.,
Izv. Akad. Nauk, Ser. Khim., 2008, vol. 8, p. 1707.
18. Ried, W. and Muhle, G., Lieb. Ann., 1962, vol. 656,
p. 119.
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