1,1,3-Trisubstituted cyclobutanes containing thiazole and thiourea fragments

Article abstract of DOI:10.1007/s10593-006-0095-1

The synthesis of 1-aryl-3-(2-chloro-1-hydroxyethyl)-1-methylcyclobutanes, 1-aryl-3-(2-chloro-1-oxoethyl)-1-methylcyclobutanes, 2-amino-4-(3-aryl-3- methylcyclobutyl)thiazoles, and N-[4-(3-aryl-3-methylcyclobutyl)thiazole-2-yl]- N′-arylthioureas is reported. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0095-1

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
1,1,3-TRISUBSTITUTED CYCLOBUTANES
CONTAINING THIAZOLE AND THIOUREA FRAGMENTS
M. Koparir, A. Cansiz, and M. Ahmedzade
The synthesis of 1-aryl-3-(2-chloro-1-hydroxyethyl)-1-methylcyclobutanes, 1-aryl-3-(2-chloro-1-
oxoethyl)-1-methylcyclobutanes, 2-amino-4-(3-aryl-3-methylcyclobutyl)thiazoles, and N-[4-(3-aryl-3-
methylcyclobutyl)thiazole-2-yl]-N'-arylthioureas is reported.
Keywords: cyclobutanes, substituted thiazoles, substituted thioureas.
The formation of substituted cyclobutanes from the reaction of 1-chloro-2,3-epoxy-5-methyl-5-hexene
with aromatic hydrocarbons such as benzene, xylene, toluene, naphthalenes, and mesitylene has been reported
[1-3]. The aryl-substituted cyclobutanes obtained are chlorohydrin derivatives, too.
Thiazole and its derivatives have biological significance, e.g., it is a struc- tural fragment of the vitamin
B1 and of the coenzyme cocarboxylase molecules [4]. The penicillin molecule also contains a thiazolidine ring.
2-Aminothiazoles are known mainly as biologically active compounds with a broad range of activities and as
intermediates in the synthesis of antibiotics and dyes [5].
It is well known that 3-substituted cyclobutanecarboxylic acid derivatives exhibit anti-inflammatory and
antidepressant activities [6, 7] and liquid crystal properties [8]. Various thiazole derivatives show herbicidal [9],
anti-inflammatory [10, 11], antimicrobial [12], or antiparasitic activity [13]. 1,1,3-Tri- substituted cyclobutanes
containing thiazole and thiourea functions in their molecules seem to be suitable candidates for further chemical
modifications and might be of interest as pharmacologically active compounds and ligands useful in
coordination chemistry.
Thiouracil moieties play a vital role in many biological processes and are used as intermediates for the
synthesis of drugs [14, 15]. It is well known that derivatives of thiourea compounds exhibit anti-HIV activity
[16, 17].
The syntheses of target compounds 1-4 are shown in the Scheme. The first step is the reaction of 1-aryl-
3-(2-chloro-1-hydroxyethyl)-1-methylcyclobutanes 1a-c and Na2Cr2O7/H2SO4. In the second step
cyclocondensation of chloro ketones 2a-c obtained with thiourea in ethanol resulted in 2-amino-4-
cyclobutylthiazoles 3a-c. The latter undergo reaction with aryl isothiocyanates in dry C6H6 to give the
corresponding N-substituted thiourea derivatives 4a-o.
In the IR spectra of 3a-c, 4a-o the most characteristic absoptions are at 3285 and 3310 cm-1 (NH2), 3275
and 3200 cm-1 (sec-NH), 1460-1340 cm-1 (C=S), 1604 cm-1 (C=N), and 685 cm-1 (C–S–C). Since there are no
C–Cl and C=O bonds in the IR spectra, these peaks indicate the formation of the expected compounds 3a-c.
1H NMR spectra showed the methine proton at 3.65, which is characteristic of the cyclobutane ring. The NH
proton is at 5.99 as a broad singlet and the thiazole proton (1H) at 6.08 as a singlet. The aromatic protons
appeared as a multiplet at 7.10-7.35 ppm.
__________________________________________________________________________________________
Department of Chemistry, Firat Universty, Faculty of Science and Arts, 23119, Elazig, Turkey; e-mail:
mkoparin@hotmail.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 424-429, March,
2006. Original article submitted June 9, 2003.
0009-3122/06/4203-0377©2006 Springer Science+Business Media, Inc.
377

H
C
Me
Na2Cr2O7/H2SO4
Me
CH2Cl
C
O
CH2Cl
R
R
25–26 h at room temp.
OH
1a–c
2a–c
thiourea
EtOH
Me
S
R1–NCS
Me
N
N
N
R1
R
N
H
R
PhH
H
S
NH2
S
4a–o
3a–c
1a-c – 3a-c, 4a-e R = 5,6,7,8-tetrahydro-2-naphthyl; 4 f-j R = mesityl, k-o R = Ph;
4 a, f, k R1 = Ph, b, g, l R1 = 4-ClC6H4, c, h, m R1 = 4-NO2C6H4, d, i, n R1 = 4-MeC6H4,
e, j, o R1 = 4-MeOC6H4
EXPERIMENTAL
Tetralin, mesitylene, benzene, and aryl isothiocyanates (Merck) were dried over anhydrous MgSO4
before use. Diethyl ether, anyhydrous CaCl2, KOH (Aldrich), anhydrous AlCl3 (Riedel), Na2Cr2O7, and H2SO4
(Merck) were used as received. Melting points were determined in open capillary tubes on digital Gallenkamp
melting point apparatus and are uncorrected. The IR spectra (KBr pellets) were recorded with a Mattson 1000
13
FT-IR spectrophotometer. 1H NMR and C NMR in CDCl3 spectra were recorded on a FX 90 JEOL (90 MHz)
NMR and Varian Gemini 200 MHz (50 MHz for 13C), respectively. Elemental analyses were done on a
LECO-CHNS-938.
1-Aryl-3-(2-chloro-1-hydroxyethyl)-1-methylcyclobutanes 1 were prepared according to a method
given in the literature [1].
3-(2-Chloro-1-oxoethyl)1-1-methyl-1-(2-tetralyl)cyclobutane (2a). Na2Cr2O7 (0.29 mol), compound
1a (0.52 mol), and water (50 ml) were placed in 1000 ml, four-necked flask fitted with a condenser, a
thermometer, a stirrer, and an addition funnel containing 75 ml of H2SO4 (68%, v/v). The sulfuric acid solution
was added over about 7-8 h, with the temperature maintained at room temperature. The reaction content was
stirred at the same temperature for about 18 h more, and then solid particles were filtered off. The filtrate was
extracted several times with diethyl ether and dried over anhydrous CaCl2. After removal of diethyl ether, 2a
was distilled off at 186°C (1 mm Hg) and filtered through a column filled with silica gel [20:1 benzene–ethyl
acetate mixture; Rf (retention time) 0.48]. The yield of the ketone was about 75%. IR spectrum, ν, cm-1: 1730
(C=O), 736 (C–Cl; no OH absorption).
3-(2-Chloro-1-oxoethyl)-1-mesityl-1-methylcyclobutane (2b) was synthesized similarly, except that
the product was crystallized rather than distilled, mp 98°C, and the yield was about 75%. IR spectrum, ν, cm-1:
1728 (C=O), 738 (C–Cl; no O–H absorption).
Compound 2c was synthesized by the method described in the literature [1] and purified through
column chromatography prior to use. The yield was about 75%. IR spectrum, ν, cm-1: 1750 (C=O), 735 (C–Cl;
no O–H absorption).
2-Amino-4-[3-methyl-3-(2-tetralyl)cyclobutyl]thiazole (3a). To a solution of thiourea (0.76 g,
10 mmol) in absolute ethanol (50 ml) a solution of compound 2a (2.76 g, 10 mmol) in absolute ethanol (30 ml)
was added dropwise at 50-60°C with continuous stirring. By monitoring the IR frequency of the carbonyl group
of 2a the completion of the reaction was easily seen. The solution was then made alkaline with an aqueous
378

solution of NH3 (5%) to separate the pale white compound 3a. from the reaction mixture. The precipitate was
filtered off, washed with aqueous ammonia solution and water several times, dried in air, and recrystallized from
aqueous ethanol (1:3). Yield 74%. White solid; mp 222-223°C. IR spectrum, ν, cm-1: 3285-3310 (NH2), 1604
1
(C=N), 685 (C–S–C). H NMR spectrum (CDCl3), δ, ppm: 6.86-7.06 (3H, m, Ar–H); 5.95 (1H, s, =CH–S,
thiazole); 5.48 (2H, s, NH2); 3.52 (1H, quint, J = 8.80, CH, cyclobutane); 2.76-2.80 (4H, m, the alicyclic protons
of tetralin); 2.33-2.55 (4H, m, CH2, cyclobutane); 1.81-1.84 (4H, m, alicyclic protons of tetralin); 1.54 (3H, s,
CH3). 13C NMR spectrum, δ, ppm: 170.60 (C(1)), 157.85 (C(2)), 152.09 C(3)), 42.55 (C(4)), 40.18 C(5)), 32.66 C(6)),
31.50 C(7)), 31.05 (C(8)), 138.87 C(9)), 136.18 (C(10)), 131.04 (C(11)), 127.52 (C(12)), 124.30 (C(13)), 102.27 (C(14)),
25.35 (C(15)), 25.31 (C(16)). Found, %: C 72.10; H 7.41; N 8.93; S 10.68. C18H22N2S. Calculated, %: C 72.44;
H 7.43; N 9.39; S 10.74.
2-Amino-4-(3-mesityl-3-methylcyclobutyl)thiazole (3b) was synthesized like compound 3a except that
the product was crystallized from aqueous methanol (1:4). Yield 65%. White solid; mp 243-244°C. IR spectrum,
ν, cm-1: 3290-3313 (NH2), 1605 (C=N), 688 (C–S–C). 1H NMR spectrum, δ, ppm: 6.70 (2H, s,
Ar–H); 5.96 (1H, s, =CH, thiazole ring); 5.44 (2H, s, NH2); 3.50 (1H, quint, J = 9.00, CH, cyclobutane); 2.55
13
(4H, m, CH2, cyclobutane); 2.21 (3H, s, CH3, mesityl); 2.14 (6H, s, CH3, mesityl); 1.49 (3H, s, CH3). C NMR
spectrum, δ, ppm: 170.53 (C(1)), 157.86 (C(2)), 130.30 (C(3)), 127.41 (C(4)), 126.98 (C(5)), 126.96 (C(6)), 102.56
(C(7)), 42.43 (C(8)), 40.62 (C(9)), 32.73 (C(10)), 32.24 (C(11)), 26.45 (C(12)), 23.38 (C(13)). Found, %: C 71.13;
H 7.51; N 9.21; S 10.99. C17H22N2S. Calculated, %: C 71.28; H 7.74; N 9.78; S 11.19.
2-Amino-4-(3-methyl-3-phenylcyclobutyl)thiazole (3c) was synthesized like compound 3a except that
the product was crystallized from aqueous ethanol (1:4). Yield 70%. Light-yellow solid; mp 174-175°C.
1
IR spectrum, ν, cm-1: 3282-3309 (NH2), 1603 (C=N), 687 (C–S–C). H NMR spectrum, δ, ppm: 7.14-7.39 (5H,
m, Ar–H); 5.99 (1H, s, =CH, thiazole ring); 5.44 (2H, s, NH2); 3.51 (1H, quint, J = 7, CH, cyclobutane); 2.40
13
(4H, m, CH2, cyclobutane); 1.53 (3H, s, CH3). C NMR spectrum, δ, ppm: 170.53 (C(1)), 157.83 (C(2)), 130.30
(C(3)), 127.41 (C(4)), 126.97 (C(5)), 126.94 (C(6)), 102.51 (C(7)), 42.41 (C(8)), 40.59 (C(9)), 32.74 (C(10)), 32.51
(C(11)). Found, %: C 68.60, H 6.37; N 11.09; S 12.85. C14H16N2S (244). Calculated, %: C 68.82; H 6.60;
N 11.46; S 13.12.
Compounds 4. (General procedure). A mixture of (0.01 mol) of compounds 3a-c and isothiocyanate
(0.01 mol) in dry C6H6 was refluxed for 6 h; the solid material obtained on cooling was filtered off and
recrystallized from MeOH to give compound 4a-o.
N-{4-[3-Methyl-3-(2-tetralyl)cyclobutyl]thiazol-2-yl}-N'-phenylthiourea (4a). Yield 60%, mp 299°C.
1
IR spectrum, ν, cm-1: 3280, 3107, 3055, 2980, 1600, 1360, 1159, 655. H NMR spectrum, δ, ppm: 1.51 (3H, s,
CH3); 1.74-1.80 (4H, m, CH2, tetralin); 2.35-2.57 (4H, m, CH2, cyclobutane); 2.62-2.76 (4H m, CH2, tetralin);
3.55-3.74 (1H, m, >CH, cyclobutane); 6.40 (1H, s, =CH, thiazole ring); 6.83-7.43 (8H, m, aromatic protons);
10.00-10.60 (2H, br, NH). 13C NMR spectrum, δ, ppm: 179.30, 163.90, 151.50, 151.40, 138.88, 137.40, 136.09,
131.00, 127.03, 125.50, 123.81, 106.34, 79.60, 78.30, 78.10, 42.36, 40.85, 40.50, 32.10, 31.52, 31.01, 29.93,
22.27. Found, %: C 69.10; H 6.18; N 9.84; S 14.70. C25H27N3S2. Calculated, %: C 69.25; H 6.28; N 9.69; S
14.79.
N-{4-[3-Methyl-3-(2-tetralyl)cyclobutyl]thiazol-2-yl}-N'-(4-chlorophenyl)thiourea (4b). Yield 68%,
mp 219°C. IR spectrum, ν, cm-1: 3288, 3106, 3050, 2980, 1650, 1600, 1360, 1160, 730, 690. 1H NMR spectrum,
δ, ppm: 1.53 (3H s, CH3); 1.73-1.82 (4H, m, CH2, tetralin); 2.35-2.55 (4H, m, CH2, cyclobutane); 2.61-2.75 (4H,
m, CH2, tetralin); 3.56-3.73 (1H, m, >CH–, in cyclobutane ring); 6.41 (1H, s, =CH, thiazole); 6.79-7.46 (7H, m,
aromatic protons); 10.01-10.59 (2H, br, NH). 13C NMR spectrum, δ, ppm: 178.30, 164.90, 152.50, 151.50,
139.88, 137.40, 135.09, 131.00, 126.03, 125.56, 123.81, 106.34, 79.60, 79.30, 78.10, 42.36, 40.50, 39.85, 32.20,
31.52, 31.05, 29.83, 23.27. Found, %: C 63.97; H 5.68; N 8.89; S 13.68. C25H26ClN3S2. Calculated, %: C 64.15;
H 5.60; N 8.98; S 13.70.
N-{4-[3-Methyl-3-(2-tetralyl)cyclobutyl]thiazol-2-yl}-N'-(4-nitrophenyl)thiourea (4c). Yield 65%,
1
mp 239°C. IR spectrum, ν, cm-1: 3289, 3105, 3049, 2980, 1650, 1600, 1590, 1560, 1405, 1159, 690. H NMR
spectrum, δ, ppm: 1.59 (3H, s, CH3); 1.74-1.81 (4H, m, CH2, tetralin); 2.38-2.56 (4H, m, CH2, cyclobutane);
379

2.61-2.76 (4H, m, CH2, tetralin); 3.58-3.72 (1H, m, >CH, cyclobutane); 6.40 (1H, s, =CH, thiazole); 6.76-7.44
(7H, m, aromatic protons); 10.11-10.55 (2H, br, NH). 13C NMR spectrum, δ, ppm: 177.70, 162.90, 157.35,
151.05, 139.08, 137.48, 135.09, 131.00, 126.03, 125.56, 123.82, 106.44, 79.50, 79.30, 78.10, 42.38, 41.50,
39.85, 32.20, 31.52, 31.05, 29.83, 25.27. Found, %: C 62.44; H 5.38; N 11.70; S 13.38. C25H26N4O2S2.
Calculated, %: C 62.73; H 5.48; N 11.71; S 13.40.
N-{4-[3-Methyl-3-(2-tetralyl)cyclobutyl]thiazol-2-yl}-N'-(4-methylphenyl)thiourea (4d). Yield 75%;
1
mp 209°C: IR spectrum, ν, cm-1: 3260, 3105, 3049, 2981, 1654, 1590, 1305, 1157, 691. H NMR spectrum,
δ, ppm: 1.53 (3H, s, CH3); 1.74-1.81 (4H, m, CH2, tetralin); 2.35 (3H, s, Ar–CH3); 2.41-2.57 (4H, m, CH2,
cyclobutane); 2.62-2.76 (4H, m, CH2, tetralin); 3.55-3.74 (1H, m, >CH, cyclobutane); 6.40 (1H, s, =CH,
13
thiazole); 6.82-7.43 (7H, m, aromatic protons); 10.11-10.55 (2H, br, NH). C NMR spectrum, δ, ppm: 178.70,
162.92, 157.33, 150.15, 139.08, 137.47, 135.10, 131.10, 126.03, 125.56, 123.81, 106.34, 79.60, 79.30, 78.11,
42.36, 41.51, 39.83, 32.22, 31.52, 31.05, 29.81, 25.22, 22.94. Found, %: C 69.44; H 5.58; N 9.31; S 14.38.
C26H29N3S2. Calculated, %: C 69.76; H 5.53; N 9.39; S 13.32.
N-{4-[3-Methyl-3-(2-tetralyl)cyclobutyl]thiazol-2-yl}-N'-(4-methoxyphenyl)thiourea (4e). Yield 67%;
1
mp 287°C. IR spectrum, ν, cm-1: 3281, 3105, 3050, 2981, 1647, 1598, 1400, 1200, 690. H NMR spectrum,
δ, ppm: 1.49 (3H, s, CH3); 1.53-1.85 (4H, m, CH2, tetralin); 2.41-2.50 (4H, m, CH2, cyclobutane); 2.56-2.66 (4H,
m, CH2, tetralin); 3.61-3.69 (1H, m, >CH, cyclobutane); 3.82 (3H, s, OCH3); 6.40 (1H, s, =CH, thiazole);
13
6.79-7.86 (7H, m, aromatic protons); 10.11-10.55 (2H, br, NH). C NMR spectrum, δ, ppm: 178.44, 163.39,
160.35, 151.05, 139.08, 137.48, 135.09, 131.00, 126.03, 125.55, 123.84, 106.31, 79.60, 79.30, 78.10, 57.11,
42.36, 41.50, 39.85, 32.22, 31.52, 31.04, 30.83, 25.26. Found, %: C 67.08; H 6.18; N 8.99; S 13.78.
C26H29N3OS2. Calculated, %: C 67.35; H 6.22; N 9.01; S 13.81.
N-{4-[3-Mesityl-3-methylcyclobutyl]thiazol-2-yl}-N'-phenyl)thiourea (4f). Yield 69%; mp 297°C.
1
IR spectrum, ν, cm-1: 3278, 3107, 3056, 2983, 1600, 1363, 1151, 688. H NMR spectrum, δ, ppm: 1.53-1.62
(3H, s, CH3); 2.11-2.25 (9H, s, CH3, mesityl); 2.54-2.69 (4H, m, CH2, cyclobutane); 3.43-3.81 (1H, m, >CH,
cyclobutane); 6.59 (1H, s, =CH, thiazole); 7.42-8.22 (9H, m, 2NH– and aromatic protons). Found, %: C 68.14;
H 6.39; N 9.99; S 14.98. C24H27N3S2. Calculated, %: C 68.37; H 6.45; N 9.97; S 15.21.
N-{4-[3-Mesityl-3-methylcyclobutyl]thiazol-2-yl}-N'-(4-chlorophenyl)thiourea (4g). Yield 67%;
1
mp 291°C. IR spectrum, ν, cm-1: 3282, 3102, 3052, 2981, 1605, 1365, 1159, 735, 687. H NMR spectrum, δ,
ppm: 1.53-1.62 (3H, s, CH3); 2.13-2.29 (9H, s, CH3, mesityl); 2.58-2.78 (4H, m, CH2, cyclobutane); 3.48-3.57
(1H, m, >CH, cyclobutane); 6.42 (1H, s, =CH, thiazole); 6.73-8.12 (8H, m, 2NH– and aromatic protons).
13C NMR spectrum, δ, ppm: 182.91, 163.45, 160.73, 159.77, 146.05, 136.99, 133.46, 132.46, 132.11, 129.36,
128.75, 126.83, 116.81, 106.00, 46.04, 45.64, 42.91, 33.26, 26.70, 26.55, 23.31, 22.38. Found, %: C 62.98;
H 5.70; N 9.19; S 14.00. C24H26ClN3S2. Calculated, %: C 63.21; H 5.75; N 9.21; S 14.06.
N-{4-[3-Mesityl-3-methylcyclobutyl]thiazol-2-yl}-N'-(4-nitrophenyl)thiourea (4h). Yield 65%;
1
mp 300°C. IR spectrum, ν, cm-1: 3278, 3107, 3055, 2984, 1605, 1360, 1290, 1159, 691. H NMR spectrum,
δ, ppm: 1.53-1.61 (3H, s, CH3); 2.13-2.28 (9H, s, CH3, mesityl); 2.58-2.77 (4H, m, CH2, cyclobutane); 3.48-3.57
(1H, m, >CH, cyclobutane); 6.36-6.42 (1H, s, =CH, thiazole); 6.73-8.13 (8H, m, 2NH– and aromatic protons).
13C NMR spectrum, δ, ppm: 182.93, 163.43, 160.75, 159.77, 146.05, 136.99, 133.46, 132.46, 132.10, 129.35,
128.73, 126.83, 116.80, 106.02, 46.04, 45.64, 42.91, 33.26, 26.71, 26.55, 23.30, 22.38. Found, %: C 61.44;
H 5.60; N 11.99; S 13.70. C24H26N4O2S2. Calculated, %: C 61.78; H 5.62; N 12.01; S 13.74.
N-{4-[3-Mesityl-3-methylcyclobutyl]thiazol-2-yl}-N'-(4-methylphenyl)thiourea (4i). Yield 70%;
1
mp 280°C. IR spectrum, ν, cm-1: 3288, 3107, 3055, 2980, 1605, 1368, 1292, 1159, 692. H NMR spectrum,
δ, ppm: 1.53-1.62 (3H, s, CH3); 2.13-2.29 (9H, s, CH3, mesityl and 3H, Ar–CH3); 2.58-2.78 (4H m, CH2,
cyclobutane); 3.48-3.57 (1H, m, >CH, cyclobutane); 6.36-6.42 (1H, s, =CH, thiazole); 6.73-8.11 (8H, m, 2NH–
13
and aromatic protons). C NMR spectrum, δ, ppm: 182.91, 163.45, 160.73, 159.77, 146.05, 136.98, 133.48,
132.46, 132.11, 129.36, 128.75, 126.83, 116.81, 106.02, 46.04, 45.64, 42.91, 33.26, 26.70, 26.55, 23.29, 22.38.
Found, %: C 68.74; H 6.69; N 9.61; S 14.70. C25H29N3S2. Calculated, %: C 68.93; H 6.71; N 9.65; S 14.72.
380

N-{4-[3-Mesityl-3-methylcyclobutyl]thiazole-2-yl}-N'-(4-methoxyphenyl)thiourea (4j). Yield 71%;
1
mp 284°C. IR spectrum, ν, cm-1: 3280, 3101, 3055, 2978, 1605, 1367, 1159, 692. H NMR spectrum, δ, ppm:
1.53-162 (3H, s, CH3); 2.11-2.25 (9H, s, CH3, mesityl); 2.54-2.69 (4H, m, CH2, cyclobutane); 3.43-3.56 (1H, m,
>CH, cyclobutane); 3.75-3.81 (3H, s, OCH3); 6.39 (1H, s, =CH, thiazole); 6.72-7.98 (8H, m, 2NH– and aromatic
protons). 13C NMR spectrum, δ, ppm: 182.93, 163.48, 160.71, 159.75, 146.05, 136.97, 133.46, 132.44, 132.11,
129.36, 128.76, 126.82, 116.80, 106.01, 57.47, 46.04, 45.64, 42.91, 33.25, 26.72, 26.55, 23.31, 22.38. Found, %:
C 65.97; H 6.44; N 9.28; S 14.18. C25H29N3OS2. Calculated, %: C 66.48; H 6.47; N 9.30; S 14.20.
N-[4-(3-Methyl-3-phenylcyclobutyl)thiazol-2-yl]-N'-phenylthiourea (4k). Yield 63%; mp 274°C.
1
IR spectrum, ν, cm-1: 3285, 3100, 3052, 2978, 1605, 1340, 1150, 670. H NMR spectrum, δ, ppm: 1.56 (3H, s,
CH3); 2.46-2.68 (4H, m, CH2, cyclobutane); 3.60-3.73 (1H, m, >CH, cyclobutane); 6.42 (1H, s, =CH, thiazole);
7.12-7.55 (10H, m, aromatic protons); 10.06-10.46 (2H, br, 2NH). 13C NMR spectrum, δ, ppm: 178.22, 163.11,
157.09, 153.81, 140.79, 131.41, 130.30, 127.84, 126.49, 125.47, 106.56, 42.73, 40.93, 32.61, 32.03. Found, %:
C 66.40; H 5.60; N 11.00; S 16.88. C21H21N3S2. Calculated, %: C 66.46; H 5.58; N 11.07; S 16.90.
N-[4-(3-Methyl-3-phenylcyclobutyl)thiazol-2-yl]-N'-(4-chlorophenyl)thiourea (4l). Yield 75%;
1
mp 264°C. IR spectrum, ν, cm-1: 3280, 3107, 3055, 2980, 1600, 1360, 1158, 733, 691. H NMR spectrum,
δ, ppm: 1.59 (3H, s, CH3); 2.46-2.51 (4H, m, CH2, cyclobutane); 3.18-3.76 (1H, m, >CH, cyclobutane); 6.67
(1H, s, =CH, thiazole); 7.14-7.70 (9H, m, aromatic protons); 10.16-10.40 (2H, br, 2NH). 13C NMR spectrum,
δ, ppm: 178.21, 163.11, 157.09, 153.81, 140.79, 131.41, 130.32, 127.84, 126.49, 125.46, 106.56, 42.73, 40.92,
32.61, 32.03. Found, %: C 60.60; H 4.79; N 10.11; S 15.48. C21H20ClN3S2. Calculated, %: C 60.93; H 4.87;
N 10.15; S 15.49.
N-[4-(3-Methyl-3-phenylcyclobutyl)thiazol-2-yl]-N'-(4-nitrophenyl)thiourea (4m). Yield 71%;
1
mp 274°C. IR spectrum, ν, cm-1: 3269, 3101, 3048, 2970, 1600, 1354, 1290, 1158, 691. H NMR spectrum,
δ, ppm: 1.56 (3H, s, CH3); 2.46-2.68 (4H, m, CH2, cyclobutane); 3.60-3.73 (1H, m, >CH, cyclobutane); 6.42
(1H, s, =CH thiazole); 7.12-7.55 (9H, m, aromatic protons); 10.06-10.46 (2H, br, 2NH). 13C NMR spectrum,
δ, ppm: 178.22, 163.11, 157.09, 153.83, 140.77, 131.41, 130.32, 127.84, 126.49, 125.47, 106.56, 42.73, 40.93,
32.59, 32.03. Found, %: C 59.10; H 4.69; N 13.13; S 15.00. C21H20N4O2S2. Calculated, %: C 59.41; H 4.75;
N 13.20; S 15.11.
N-[4-(3-Methyl-3-phenylcyclobutyl)thiazol-2-yl]-N'-(4-methylphenyl)thiourea (4n). Yield 63%;
1
mp 263°C. IR spectrum, ν, cm-1: 3278, 3103, 3055, 2979, 1600, 1372, 1156, 691. H NMR spectrum, δ, ppm:
1.56 (3H, s, CH3); 2.31-2.35 (3H, s, Ar–CH3); 2.45-2.65 (4H, m, CH2, cyclobutane); 3.59-3.76 (1H, m, >CH,
cyclobutane); 6.41 (1H, s, =CH, thiazole); 7.11-7.40 (9H, m, aromatic protons); 10.40-10.61 (2H, br, 2NH).
13C NMR spectrum, δ, ppm: 178.28, 163.53, 157.16, 157.12, 153.81, 140.79, 131.41, 130.30, 127.84, 126.49,
125.47, 106.56, 42.73, 40.93, 32.59, 32.57, 32.03. Found, %: C 67.00; H 5.72; N 10.59; S 16.61. C22H23N3S2.
Calculated, %: C 67.14; H 5.89; N 10.68; S 16.29.
N-[4-(3-Methyl-3-phenylcyclobutyl)thiazol-2-yl]-N'-(4-methoxyphenyl)thiourea (4o). Yield 64%;
1
mp 273°C. IR spectrum, ν, cm-1: 3279, 3105, 3055, 2979, 1600, 1368, 1156, 691. H NMR spectrum, δ, ppm:
1.51 (3H, s, CH3); 2.45-2.55 (4H, m, CH2, cyclobutane); 3.31-3.79 (3H, m, OCH3 and 1H, >CH, cyclobutane);
6.37 (1H, s, =CH, thiazole); 6.81-7.47 (9H, m, aromatic protons); 12.72-13.01 (2H, br, 2NH). 13C NMR
spectrum, δ, ppm: 178.28, 163.53, 157.16, 157.12, 153.81, 140.79, 131.41, 130.30, 127.84, 126.49, 125.47,
106.56, 57.14, 42.73, 40.93, 32.59, 32.57, 32.03. Found, %: C 64.20; H 5.56; N 10.14; S 15.35. C22H23N3OS2.
Calculated, %: C 64.52; H 5.66; N 10.26; S 15.66.
We are indebted to the Firat Universty Research Foundation (FÜBAP) for financial support of this work
(Project number: 477)
381

REFERENCES
1.
M. A. Ahmedov, Z. G. Mustafayeva, I. M. Ahmedov, and R. R. Kostikov, Zh. Org. Khim., 27, 1434
(1991).
2.
3.
M. Coskun, K. Demirelli, and M. Ahmedzade, J. Macromol. Sci Pure Appl. Chem., 34, 429(1997).
A. Ince, M. A. Ahmedov, M. Coskun, A. Cansiz, and A. Mete, in: 10th National Congress of Chemistry;
University of Uludag Pres: Bursa, Turkey, 1994, p.300.
4.
M. Koparir, Doctoral Thesis, Firat University, Graduate School of Natural and Applied Sciences, Elazig,
2002.
5.
6.
H. Beyer, Organic Chemistry, Verlag Harry Deutsch, Frankfurt/Main und Zürich, 1963, pp. 609-610.
U. G. Ibatullin, T. F. Petrushina, L. Y. Leitis, I. Z. Minibaev, and B. O. Logvin, Khim. Geterotsikl.
Soedin., 715 (1993).
7.
E. Roger, C. J. Pierre, G. Pualette, J. P. Chepat, and G. Robert, Eur. J. Med. Chem., Chem. Ther., 12,
501 (1977).
8.
9.
10.
G. Gerard, Eur. J. Med. Chem., Chem. Ther., 14, 493 (1979).
E. V. Dehmion and S. S. Schmidt, Liebigs Ann. Chem., 411 (1990).
H. Foerster, W. Hofer, V. Mues, L. Eue, and R. R. Schmidt, Ger. Pat. 2822155 (1979); Chem. Abstr., 92,
146754 (1980).
11.
12.
S. N. Sawheny, S. K. Arora, and J. V. Sing, Indian J. Chem., 16B, 605 (1978); Chem. Abstr., 90, 22879
(1979).
K. Brown, D. P. Cater, J. F. Cavalla, D. Green, R. A. Newbery, and A. B. Wilson, J. Med. Chem., 14,
177 (1974).
13.
14.
15.
16.
17.
N. Suzuki, Y. Tanaka, and R. Dohmori, Chem. Pharm. Bull., 27, 1 (1979).
P. I. Slip, M. Closier, and M. Neville, J. Med. Chem., 17, 207 (1974).
S. A. Abdel-Rahman and A. M. Abdel-Halim, Coom. La. Far. Des. Sci., Ankara, Turkey, 31 (1995).
S. A. Abdel-Aziz, H. A. Allimony, and H. M. El-Shaaer, Phosphorus, Sulfur, Silicon, 113, 67 (1996).
T. K. Venkatachalam, E. A. Sudbeck, C. Mao, and M. F. Uckun, Bioorg. Med. Chem. Lett., 11, 523
(2001).
382