Novel thiazolone derivatives of N-aryl-β-alanines

Full text of DOI:10.1007/s10593-011-0874-1

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
NOVEL THIAZOLONE DERIVATIVES
OF N-ARYL--ALANINES
M. Stasevych1, V. Lubenets1, R. Musyanovych1, V. Novikov1*,
V. Mickevicius2, Z. I. Beresnevicius2, and K. Rutkauskas2
Keywords: N-aryl-N-thiocarbamoyl--alanines, 4-thiazolones, cyclocondensation.
Thanks to the efforts of many scientific groups in the last decade, the spectrum of pharmacological
activity of 4-thiazolones has been significantly broadened. Amongst these are compounds with hypoglycemic,
anticancer, anti-inflammatory, antimicrobial, antioxidant, antiviral, and antitubercular activity [1]. This has
served as the basis for the synthesis and study of the named heterocycles modified by novel pharmacophoric
groups with the aim of their practical use in pharmacy, medicine, agriculture, etc. One of the classical routes
most often and efficiently used for the preparation of a thiazolidone ring is a [2+3] cyclocondensation reaction
[2]. The reaction of the N-aryl-N-thiocarbamoyl--alanines 1a-e [3] with monochloroacetic acid or maleic
anhydride was carried out in acetic acid in the presence of sodium acetate to give the novel 4-thiazolone
derivatives of N-aryl--alanines 2a-f.
R
ClCH2CO2H or
R
O
O
O
N
O
N
AcONa, AcOH
H2N
N
O
O
S
OH
S
OH
R1
1a–e
2a–f
1, 2 a, f R = H; b R = Me; c R = OMe; d R = NO2; e R = PhNH;
2ae R1 = H; f R1 = CH2CO2H
1H and 13C NMR spectra were recorded on a Bruker MSL-400 instrument (400 and 100 MHz
respectively) at 25ºC for solutions in DMSO-d6 and with TMS as internal standard.
_______
*To whom correspondence should be addressed, e-mail: vnovikov@polynet.lviv.ua.
1Lviv Polytechnic National University, 12 St. Bandery St., Lviv 79013, Ukraine.
2Kaunas University of Technology, 73 K. Donelaičio St., Kaunas LT-44029, Lithuania; e-mail:
Vytautas.Mickevicius@ktu.lt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1272-1274, August, 2011.
Original article submitted April 21, 2011.
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0009-3122/11/4708-1050©2011 Springer Science+Business Media, Inc.

N-(4-Oxo-4,5-dihydro-1,3-thiazol-2-yl)-N-(4-R-phenyl)--alanines (2) (General Method). A mixture
of the corresponding N-aryl-N-thiocarbamoyl--alanine 1 [3] (0.02 mol) and monochloroacetic acid or maleic
anhydride (0.02 mol) in acetic acid (50 ml) in the presence of sodium acetate (0.02 mol) was heated at 85-90ºC
for 3 h. The precipitate formed after cooling the reaction mixture was filtered off to give the novel 4-thiazolone
derivatives of N-aryl--alanines 2 which were recrystallized from a 4:1 mixture of AcOH and EtOH.
N-(4-Oxo-4,5-dihydro-1,3-thiazol-2-yl)-N-phenyl--alanine (2a). Yield 68%; mp 198-199ºC.
1H NMR spectrum, , ppm (J, Hz): 2.72 (2H, t, J = 7.1, CH2C(O)); 3.60 (2H, s, CH2 thiazole); 4.03 (2H, t,
J = 7.1, CH2N); 7.04-7.06 (3H, m, H Ar); 7.69-7.72 (2H, m, H Ar); 10.90 (1H, s, CO2H). 13C NMR spectrum, ,
ppm: 188.2 (4-C=O); 173.9 (CO2H); 156.5 (C-2 thiazole); 143.3 (C-1 Ar); 129.9 (C-3,5 Ar); 124.3 (C-4 Ar);
123.7 (C-2,6 Ar); 41.5 (NCH2); 40.6 (SCH2); 30.3 (CH2CO2H). Found, %: C 54.61; H 4.51; N 10.71; S 12.19.
C12H12N2O3S. Calculated, %: C 54.53; H 4.58; N 10.60; S 12.13.
N-(4-Methylphenyl)-N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)--alanine (2b). Yield 75%; mp
1
195-196ºC. H NMR spectrum, , ppm (J, Hz): 2.27 (3H, s, CH3); 2.72 (2H, t, J =7.1, CH2C(O)); 3.61 (2H, s,
CH2 thiazole); 4.04 (2H, t, J = 7.1, CH2N); 7.20 (2H, d, J = 9.0, H Ar); 7.44 (2H, d, J = 9.0, H Ar); 10.92 (1H,
s, CO2H). 13C NMR spectrum, , ppm: 179.7 (4-C=O); 173.7 (CO2H); 156.1 (C-2 thiazole); 139.5 (C-1 Ar);
135.2 (CCH3); 130.6 (C-3,5 Ar); 123.1 (C-2,6 Ar); 41.8 (NCH2); 36.1 (SCH2); 30.2 (CH2CO2H); 20.8 (CCH3).
Found, %: C 56.15; H 5.15; N 9.99; S 11.46. C13H14N2O3S. Calculated, %: C 56.10; H 5.07; N 10.06, S 11.52.
N-(4-Methoxyphenyl)-N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)--alanine (2c). Yield 79%; mp
1
189-191ºC. H NMR spectrum, , ppm (J, Hz): 2.71 (2H, t, J =7.1, CH2C(O)); 3.62 (2H, s, CH2 thiazole); 3.72
(3H, s, CH3); 4.05 (2H, t, J = 7.1, CH2N); 6.71 (2H, d, J = 9.2, H Ar); 7.02 (2H, d, J = 9.2, H Ar); 10.95 (1H, s,
CO2H). 13C NMR spectrum, , ppm: 179.9 (4-C=O); 173.9 (CO2H); 155.7 (C-2 thiazole); 155.4 (C-4 Ar); 135.6
(C-1 Ar); 126.7 (C-2,6 H Ar); 115.2 (C-3,5 Ar); 55.6 (CH3); 41.5 (NCH2); 36.2 (SCH2); 30.3 (CH2CO2H).
Found, %: C 53.15; H 4.74; N 9.60; S 10.92. C13H14N2O4S. Calculated, %: C 53.05; H 4.79; N 9.52, S 10.89.
N-(4-Nitrophenyl)-N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)--alanine (2d). Yield 74%; mp 206-207ºC.
1H NMR spectrum, , ppm (J, Hz): 2.73 (2H, t, J =7.1, CH2C(O)); 3.63 (2H, s, CH2 thiazole); 4.02 (2H, t,
J = 7.1, CH2N); 7.27 (2H, d, J = 8.9, H Ar); 8.47 (2H, d, J = 8.9, H Ar); 10.91 (1H, s, CO2H). 13C NMR
spectrum, , ppm: 179.8 (4-C=O); 173.7 (CO2H); 155.2 (C-2 thiazole); 146.7 (C-1 Ar); 142.4 (C-4 Ar); 125.1
(C-3,5 Ar); 123.8 (C-2,6 Ar); 41.2 (NCH2); 36.0 (SCH2); 30.1 (CH2CO2H). Found, %: C 46.35; H 3.67;
N 13.50; S 10.45. C12H11N3O5S. Calculated, %: C 46.60; H 3.58; N 13.59; S 10.37.
N-(4-Oxo-4,5-dihydro-1,3-thiazol-2-yl)-N-(4-(phenylamino)phenyl--alanine (2e). Yield 70%; mp
1
205-206ºC. H NMR spectrum, , ppm (J, Hz): 2.73 (2H, t, J =7.1, CH2C(O)); 3.61 (2H, s, CH2 thiazole); 4.04
(2H, t, J = 7.1, CH2N); 6.84-7.44 (9H, m, H Ar); 8.06 (1H, s, NH); 10.64 (1H, s, CO2H). 13C NMR spectrum, ,
ppm: 179.7 (4-C=O); 173.6 (CO2H); 153.7 (C-2 thiazole); 146.6 (C-1' Ar); 136.8 (C-1 Ar); 136.7 (C-4 Ar);
128.8 (C-3',5' Ar); 123.4 (C-3,5 Ar); 123.3 (C-2,6 Ar); 116.9 (C-4' Ar); 113.6 (C-2',6' Ar); 41.1 (NCH2); 36.2
(SCH2); 30.0 (CH2CO2H). Found, %: C 60.79; H 4.87; N 11.91; S 9.06. C18H17N3O3S. Calculated, %: C 60.83;
H 4.82; N 11.82; S 9.02.
N-[5-(Carboxymethyl)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-phenyl--alanine (3). Yield 70%; mp
223-225ºC. 1H NMR spectrum, , ppm (J, Hz): 2.71 (2H, t, J =7.1, CH2C(O)); 4.02 (2H, t, J = 7.1, CH2N); 3.13
2
3
2
3
(1H, dd, J = 17.2, J = 8.0) and 3.33 (2H, dd, J = 17.2, J = 6.5, CH2); 4.53 (1H, m, CH thiazole); 7.06-7.18
(3H, m, H Ar); 7.69-7.72 (2H, m, H Ar); 10.96 (1H, s, CO2H); 11.98 (1H, s, CO2H). 13C NMR spectrum, ,
ppm: 177.6 (4-C=O); 173.9 (CO2H); 173.0 (CO2H); 156.9 (C-2 thiazole); 141.5 (C-1 Ar); 131.0 (C-3,5 Ar);
126.4 (C-2,6 Ar); 125.7 (C-4 Ar); 44.3 (CHS); 42.7 (CHCH2); 41.5 (NCH2); 30.1 (CH2CO2H). Found, %:
C 52.15; H 4.45; N 8.62; S 10.01. C14H14N2O5S. Calculated, %: C 52.17; H 4.38; N 8.69; S 9.95.
The work was carried out with the support of the Ministry of Education and Science of Ukraine and of
Lithuania (Ukraine-Lithuania agreement M/43-2009 and Lithuania-Ukraine agreement TMP3-1/2009).
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