Synthesis of symmetrical and asymmetrical phenethyl thiourea compounds as nonnucleoside inhibitors of HIV-1 reverse transcriptase

Article abstract of DOI:10.1081/SCC-200066677

Synthesis of symmetrical and asymmetrical phenethyl thioureas was accomplished in two steps with an overall yield of 75-80%. Condensation of a substituted phenethyl amine with thiocarbonyldiimidazole, followed by treatment with one more equivalent of the phenethylamine in DMF, yielded the desired symmetrical phenethyl thiourea compound as a crystalline solid. In the case of asymmetrical thiourea derivatives, different amines were selected and condensed using a similar procedure. A series of 45 thioureas was synthesized. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200066677

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Synthesis of Symmetrical
and Asymmetrical Phenethyl
Thiourea Compounds as
Nonnucleoside Inhibitors of
HIV‐1 Reverse Transcriptase
T. K. Venkatachalam a b & F. M. Uckun b c
a Department of Chemistry , Parker Hughes
Institute , Roseville, Minnesota, USA
b Drug Discovery Program, Parker Hughes Cancer
Center , Roseville, Minnesota, USA
c Departments of Virology and Immunology , Parker
Hughes Institute , Roseville, Minnesota, USA
Published online: 16 Aug 2006.
To cite this article: T. K. Venkatachalam & F. M. Uckun (2005) Synthesis of
Symmetrical and Asymmetrical Phenethyl Thiourea Compounds as Nonnucleoside
Inhibitors of HIV‐1 Reverse Transcriptase, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:15, 2039-2056,
DOI: 10.1081/SCC-200066677
To link to this article: http://dx.doi.org/10.1081/SCC-200066677
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Synthetic Communicationsw, 35: 2039–2056, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200066677
Synthesis of Symmetrical and Asymmetrical
Phenethyl Thiourea Compounds as
Nonnucleoside Inhibitors of HIV-1
Reverse Transcriptase
T. K. Venkatachalam
Department of Chemistry, Parker Hughes Institute, Roseville,
Minnesota, USA and Drug Discovery Program, Parker Hughes Cancer
Center, Roseville, Minnesota, USA
F. M. Uckun
Drug Discovery Program, Parker Hughes Cancer Center, Roseville,
Minnesota, USA and Departments of Virology and Immunology,
Parker Hughes Institute, Roseville, Minnesota, USA
Abstract: Synthesis of symmetrical and asymmetrical phenethyl thioureas was accom-
plished in two steps with an overall yield of 75–80%. Condensation of a substituted
phenethyl amine with thiocarbonyldiimidazole, followed by treatment with one more
equivalent of the phenethylamine in DMF, yielded the desired symmetrical
phenethyl thiourea compound as a crystalline solid. In the case of asymmetrical
thiourea derivatives, different amines were selected and condensed using a similar
procedure. A series of 45 thioureas was synthesized.
Keywords: Thiourea, NNRTI, HIV
INTRODUCTION
Several thiourea compounds have been observed to inhibit HIV reverse tran-
scriptase (RT).[1–16] In a systematic search for nonnucleoside inhibitors of
Received in the USA March 28, 2005
Address correspondence to Fatih M. Uckun, Parker Hughes Cancer Center, 2699
Patton Road, St. Paul, MN 55113, USA. Tel.: 651-796-5450; Fax: 651-796-5493;
E-mail: fatih_uckun@ih.org
2039

2040
T. K. Venkatachalam and F. M. Uckun
HIV RT, we prepared 45 substituted phenethyl thiourea derivatives with
various substitutions on the phenyl ring.
MATERIALS AND METHODS
All chemicals were purchased from Aldrich (Milwaukee, WI) and were used
without further purification. Unless otherwise noted, each reaction vessel was
secured with a rubber septa, and the reaction was performed under a nitrogen
atmosphere. NMR spectra were obtained on a 300-MHz Varian Mercury 300
instrument at ambient temperature in CDCl3. Chemical shifts are reported as
d values in parts per million downfield from tetramethylsilane (TMS,
d ¼ 0.0 ppm) as an internal standard in the case of CDCl3, and
d ¼ 77.0 ppm for 13C NMR spectra. 19F NMR spectra were obtained using
either of these solvents and a capillary containing 0.1% trifluoroacetic acid
in water, which served as the internal standard (d ¼ 0.0 ppm). Splitting
patterns are designated as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; and br, broad peak. FT-IR spectra were recorded on a Nicolet
´ ´
Protege 460 spectrometer as KBr pellets. Mass spectra were performed on a
Scheme 1. Synthesis of substituted phenethyl thioureas: i) ACN, thiodicarbonyldi-
imidazole, 08C for 1–2 h, rt for 20 h, and ii) anhydrous DMF, R2CH2CH2NH2,
1008C, 20 h.

Phenethyl Thiourea Compounds
2041
Hewlett Packard MALDI-TOF spectrometer (Model G2025 MALDI-TOF).
Melting points were determined using a Melt John’s apparatus and are uncor-
rected. HPLC was done using a Hewlett Packard 1100-series instrument that
consisted of a automatic sampler, a electronic degasser, a thermostatic control
unit, and a diode array detector in conjunction with Chemstation software. The
column used was an analytical Lichrospher RP–18 column (5 mm,
4.6 ꢀ 250 mm) (Hewlett Packard), and the eluent was methanol. The flow
rate was maintained at 1.0 mL/min and the detection wavelength was set at
275 nm. The column was maintained at room temperature throughout the
analysis. Column chromatography was performed using silica gel (60 mesh)
obtained from the Baker Company. The solvents used for elution was ethyl
acetate and hexane.
RESULTS AND DISCUSSION
The thiourea compounds were prepared by condensing appropriately phenyl-
substituted phenylethyl amines and thiocarbonyldiimidazole in acetonitrile
medium at 08C (ice bath) for 15 h to yield the corresponding phenethyl-
substituted thicarbonylimidazole as an intermediate. Treatment of the inter-
mediate with one more equivalent of the substituted phenylethyl amine in
dimethylformamide at 1008C for 20 h over an oil bath furnished
the required symmetrical thiourea derivatives (Table 1) (Scheme 1).
Condensation of the thiocarbonylimidazole intermediate with other amines
furnished the asymmetrical thiourea compounds. (Table 2). Use of the thio-
carbonyldiimidazole methodology is simple and is an advantageous
alternative to isothiocyante method used in the past.[17,18] Isothiocyantes are
more difficult to handle because of their reactive nature as compared with
their comparative thiocarbonyldiimidazole precursors.
GENERAL SYNTHETIC PROCEDURE
The following is a synthetic procedure for 1 and is a representative synthetic
procedure for the compounds described in this article. Thiodicarbonyldimida-
zole (1.78 g, 1 mmol) was dissolved in anhydrous acetonitrile (75 mL) in a
250-ml, round-bottomed flask with an addition funnel and a magnetic stir
bar. The contents were stirred for 30 min. The flask was cooled with an
external ice bath, and the addition funnel was charged with phenethyl
amine (1.21 g, 1.0 mmol). The amine was added dropwise with stirring.
After completion of addition, the mixture was allowed to stir at room tempera-
ture for 15 h, which was followed by removal of the solvent by rotary evapo-
ration under vacuum, yielding the thiocarbonylimidzole intermediate. This
was directly used for the next step without further purification.

2042
T. K. Venkatachalam and F. M. Uckun
Table 1. Structures of PETT derivatives
Compound
R1
R2
1
2
H
H
4-Bromo
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
2-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
3-Chloro
4-Chloro
4-Chloro
4-Chloro
4-Chloro
4-Chloro
4-Chloro
4-Chloro
4-Chloro
2-Fluoro
2-Fluoro
2-Fluoro
2-Fluoro
2-Fluoro
2-Fluoro
2-Fluoro
2-Fluoro
3
2-Chloro
3-Chloro
4
5
4-Chloro
2-Fluoro
6
7
4-Hydroxy
2-Methoxy
3-Methoxy
2,5-Dimethoxy
3,4-Dimethoxy
4-Methyl
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
4-Bromo
3-Chloro
2-Fluoro
4-Hydroxy
2-Methoxy
3-Methoxy
2,5-Dimethoxy
3,4-Dimethoxy
4-Methyl
4-Bromo
2-Fluoro
4-Hydroxy
2-Methoxy
3-Methoxy
2,5-Dimethoxy
3,4-Dimethoxy
4-Methyl
4-Bromo
2-Fluoro
4-Hydroxy
2-Methoxy
3-Methoxy
2,5-Dimethoxy
3,4-Dimethoxy
4-Methyl
The crude thicarbonylimidazole intermediate was dissolved in anhydrous
dimethylformamide (50 mL) in a 250-mL, round-bottomed flask with a
condenser and a magnetic stir bar. Using a dry syringe, one equivalent of phe-
nethylamine (1.22 g, 1 mmol) was added and the mixture heated over an oil

Phenethyl Thiourea Compounds
Table 2. Structures of PETT derivatives
2043
Compound
R1
R2
38
39
40
41
42
43
44
45
2-Chloro
2-Chloro
3-Chloro
3-Chloro
4-Chloro
4-Chloro
2-Fluoro
2-Fluoro
1-Cyclohexene
3-Indole
1-Cyclohexene
3-Indole
1-Cyclohexene
3-Indole
1-Cyclohexene
3-Indole
bath at 1008C for 20 h. The solution was allowed cool to room temperature and
then poured into crushed ice. The solution was stirred for 45 min, during which
a precipitate was formed. The precipitate was filtered and washed with
3 ꢀ 200 ml of water and dried under vacuum. The product was further
purified by column chromatography using ethyl acetate/hexanes as eluent.
Further purification of the product was achieved by crystallization in
ethanol to furnish 1 as a crystalline solid in 65% yield. A similar procedure
was followed for all the other thioureas described in Tables 1 and 2.
PHYSICAL DATA FOR SYNTHESIZED COMPOUNDS 1–45
N-[2-(Phenethyl)]-N0-[2-(Phenethyl)]thiourea (1). Yield: 65%; mp 82–
858C; UV (CHCl3) lmax: 218, 254 nm; IR (KBr) n 3275, 3205, 3051, 2928,
2862, 1562, 1494, 1450, 1379, 1346, 1311, 1284, 1136, 1001, 908, 752,
1
704 cm21; H NMR (CDCl3) d 7.36–7.10 (m, 10H), 5.83 (bs, 2H), 3.64 (bs,
4H), 2.88–2.83 (t, 4H); 13C NMR (CDCl3) d 181.2, 138.2, 128.8, 128.7,
126.7, 45.3, 35.0; MS: Found 285 (Mþ1), calcd.: 284; HPLC: Rt: 2.5 min,
single peak with purity 100%; Anal. calcd. for C17H20N2S: C, 71.79; H,
7.09; N, 9.85. Found: C, 71.95; H, 7.17; N, 9.78.
N-[2-(2-Chlorophenethyl)]-N0-[2-(4-Bromophenethyl)]-thiourea (2). Yield:
97%; mp 88–898C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3401, 3255,
3060, 3022, 2931, 2863, 1550, 1488, 1475, 1442, 1384, 1346, 1280, 1186,
1120, 1072, 1053, 1010, 808, 752, 676, 528 cm21 1H NMR (CDCl3)
;
d 7.43–7.05 (m, 8H), 6.00 (s, 1H), 5.87 (s, 1H), 3.64 (q, 4H), 3.01–2.97
(t, 2H), 2.86–2.81 (t, 2H); 13C NMR (CDCl3) d 181.6, 137.2, 135.7, 133.8,
131.7, 131.0, 130.4, 129.6, 128.3, 127.2, 120.5, 45.2, 43.7, 31.5, 32.9;
MALDI-TOF found: 398.9; (Mþ1), calcd.: 397.8. HPLC: Rt: 2.5 min, single

2044
T. K. Venkatachalam and F. M. Uckun
peak with purity 100%; Anal. calcd. for C17H18N2SBrCl: C, 51.33; H, 4.56; N,
7.04. Found: C, 51.42; H, 4.46; N, 6.96.
N-[2-(2-Chlorophenethyl)]-N0-[2-(2-Chlorophenethyl)]-thiourea (3). Yield:
62%; mp 112–1138C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3407, 3270,
3056, 3041, 2931, 2865, 1550, 1475, 1442, 1384, 1346, 1301, 1280, 1188,
1053, 999, 941, 750, 675, 594 cm21 1H NMR (CDCl3) d 7.35–7.13
;
(m, 8H), 6.21 (s, 2H), 3.65 (q, 4H), 3.02–2.97 (t, 4H); 13C NMR (CDCl3)
d 181.4, 135.7, 133.7, 130.9, 129.4, 128.1, 127.0, 43.6, 32.8; MALDI-TOF
found: 354.0 (Mþ1), calcd.: 353.3; HPLC: Rt: 2.5 min, single peak with
purity 100%; Anal. calcd. for C17H18N2SCl2: C, 57.79; H, 5.13; N, 7.93.
Found: C, 57.80; H, 5.05; N, 7.83.
N-[2-(2-Chlorophenethyl)]-N0-[2-(3-Chlorophenethyl)]-thiourea (4). Yield:
94%; mp 71–728C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3405, 3251,
3062, 3020, 2933, 2865, 1687, 1598, 1560, 1442, 1384, 1346, 1297, 1203,
1080, 1053, 999, 908, 823, 783, 754, 684, 555, 441 cm21 1H NMR
;
(CDCl3) d 7.33–7.05 (m, 8H), 6.29 (s, 1H), 6.20 (s, 1H), 3.63 (q, 4H),
2.99–2.95 (t, 2H), 2.86–2.81 (t, 2H); 13C NMR (CDCl3) d 181.3, 140.2,
135.6, 134.1, 133.6, 130.8, 129.8, 129.4, 128.6, 128.1, 127.0, 126.8, 126.6,
445.1, 43.5, 34.7, 32.8; MALDI-TOF found: 354.3 (Mþ1), calcd.:
353.3; HPLC: Rt: 2.5 min, single peak with purity 100%; Anal. calcd.
for C17H18N2SCl2: C, 57.79; H, 5.13; N, 7.93. Found: C, 57.38; H, 5.23;
N, 7.91.
N-[2-(2-Chlorophenethyl)]-N0-[2-(4-Chlorophenethyl)]-thiourea (5). Yield:
77%; mp 85–868C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3403, 3253,
3062, 2933, 2865, 1664, 1552, 1492, 1442, 1346, 1299, 1188, 1091, 1053,
1016, 943, 811, 754, 376, 509 cm21 1H NMR (CDCl3) d 7.37–7.09
;
(m, 8H), 5.98 (s, 1H), 5.86 (s, 1H), 3.63 (q, 4H), 3.02–2.97 (t, 2H), 2.88–
2.83 (t, 2H); 13C NMR (CDCl3) d 181.7, 136.7, 135.7, 133.8, 132.5, 131.0,
130.0, 129.6, 128.8, 128.3, 127.2, 45.3, 43.7, 34.5, 32.9; MALDI-TOF
found: 353.8 (Mþ1), calcd.: 353.3; HPLC: Rt: 2.5 min, single peak with
purity 100%; Anal. calcd. for C17H18N2SCl2: C, 57.79; H, 5.13; N, 7.93.
Found: C, 57.64; H, 5.08; N, 8.13.
N-[2-(2-Chlorophenethyl)]-N0-[2-(2-Fluorophenethyl)]-thiourea (6). Yield:
63%; mp 74–758C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3407, 3253,
3064, 2935, 2867, 1552, 1492, 1456, 1348, 1284, 1230, 1188, 1120, 1053,
1
1000, 910, 754, 675, 663 cm21; H NMR (CDCl3) d 7.34–6.98 (m, 8H),
6.21 (s, 2H), 3.64 (q, 4H), 3.01–2.96 (t, 2H), 2.93–2.88 (t, 2H); 13C NMR
(CDCl3) d 181.4, 161.5, 159.63, 135.7, 133.7, 130.94, 130.86, 129.4, 128.4,
128.3, 128.0, 127.0, 125.1, 124.9, 124.21, 124.17, 115.3, 115.0, 44.1, 43.6,
32.8, 28.6; 19F NMR (CDCl3) d 242.74, 242.72; MALDI-TOF found:
337.4 (Mþ1), calcd.: 336.9; HPLC: Rt: 2.3 min, single peak with purity

Phenethyl Thiourea Compounds
2045
100%; Anal. calcd. for C17H18N2SCl F: C, 60.62; H, 5.39; N, 8.32. Found:
C, 60.74; H, 5.38; N, 8.38.
N-[2-(2-Chlorophenethyl)]-N0-[2-(4-Hydroxyphenethyl)]-thiourea (7). Yield:
93%; mp 111–1128C; UV (CHCl3) lmax: 255, 284 nm; IR (KBr) n 3396, 3070,
3016, 2939, 2865, 1612, 1556, 1513, 1475, 1442, 1346, 1218, 1172, 1107,
1
1053, 948, 827, 754, 667, 559, 459 cm21; H NMR (CDCl3) d 7.34–6.76
(m, 8H), 5.98 (s, 1H), 5.87 (s, 2H), 3.59 (s, 4H), 2.99–2.95 (t, 2H), 2.79–
2.74 (t, 2H); 13C NMR (CDCl3) d 181.2, 154.6, 135.8, 133.8, 131.0, 129.7,
129.6, 128.3, 127.2, 115.7, 45.5, 43.9, 34.1, 32.9; MALDI-TOF found:
336.9 (M þ 2), calcd.: 334.9; HPLC: Rt: 2.1 min, single peak with purity
100%; Anal. calcd. for C17H19N2SOCl: C, 60.98; H, 5.72; N, 8.37. Found:
C, 60.68; H, 5.83; N, 8.41.
N-[2-(2-Chlorophenethyl)]-N0-[2-(2-Methoxyphenethyl)]-thiourea (8). Yield:
66%; mp 73–748C; UV (CHCl3) lmax: 256, 264 nm; IR (KBr) n 3355, 3251,
3062, 3006, 2937, 2834, 1600, 1552, 1492, 1475, 1438, 1346, 1290, 1243,
1124, 1053, 1031, 752, 675, 462 cm21 1H NMR (CDCl3) d 7.34–6.81
;
(m, 8H), 6.56 (s, 1H), 6.29 (s, 1H), 3.73 (s, 3H), 3.49 (q, 4H), 3.16–3.01
(t, 2H), 2.86–2.82 (t, 2H); 13C NMR (CDCl3) d 181.0, 156.9, 136.0, 133.6,
131.0, 130.3, 129.3, 127.9, 126.9, 120.8, 110.2, 55.16, 44.0, 32.8, 29.7;
MALDI-TOF found: 349.9 (Mþ1), calcd.: 348.9; HPLC: Rt: 2.4 min, single
peak with purity 100%; Anal. calcd. for C18H21N2SOCl: C, 61.97; H, 6.07;
N, 8.03. Found: C, 61.17; H, 5.98; N, 7.78.
N-[2-(2-Chlorophenethyl)]-N0-[2-(3-Methoxyphenethyl)]-thiourea (9). Yield:
56%; mp 64–658C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3251, 3058, 3010,
2935, 2865, 2833, 1594, 1550, 1488, 1475, 1438, 1384, 1346, 1259, 1189,
1
1153, 1053, 1002, 871, 777, 754, 696, 570, 451 cm21; H NMR (CDCl3)
d 7.33–6.73 (m, 8H), 6.17 (s, 2H), 3.75 (s, 3H), 3.62 (q, 4H), 2.97–2.93
(t, 2H), 2.84–2.80 (t, 2H); 13C NMR (CDCl3) d 181.3, 159.5, 139.7, 135.7,
133.6, 130.8, 129.5, 129.3, 128.0, 126.9, 120.8, 114.2, 111.8, 55.0, 45.2,
43.6, 35.0, 32.7; MALDI-TOF found: 349.6 (Mþ1), calcd.: 348.9; HPLC:
Rt: 2.4 min, single peak with purity 100%; Anal. calcd. for C18H21N2SOCl:
C, 61.97; H, 6.07; N, 8.03. Found: C, 61.62; H, 6.01; N, 7.92.
N-[2-(2-Chlorophenethyl)]-N0-[2-(2,5-Dimethoxyphenethyl)]-thiourea (10).
Yield: 31%; mp 55–568C; UV (CHCl3) lmax: 254, 295 nm; IR (KBr) n
3349, 3257, 3064, 2998, 2937, 2833, 1552, 1500, 1465, 1442, 1346, 1282,
1224, 1180, 1128, 1051, 867, 802, 754, 709, 675, 455 cm21 1H NMR
;
(CDCl3) d 7.37–6.70 (m, 7H), 6.37 (s, 1H), 6.04 (s, 1H), 3.75 (s, 3H), 3.71
(s, 3H), 3.47 (q, 4H), 3.08–3.03 (t, 2H), 2.85–2.80 (t, 2H); 13C NMR
(CDCl3) d 181.3, 153.7, 151.2, 133.8, 131.2, 129.5, 128.2, 127.1, 116.8,
112.2, 111.4, 55.9, 55.7, 32.9, 30.1; MALDI-TOF found: 379.8 (Mþ1),
calcd.: 378.9; HPLC: Rt: 24 min, single peak with purity 100%; Anal. calcd.

2046
T. K. Venkatachalam and F. M. Uckun
for C19H23N2SO2Cl: C, 60.23; H, 6.12; N, 7.39. Found: C, 60.09; H, 6.16;
N, 7.22.
N-[2-(2-Chlorophenethyl)]-N0-[2-(3,4-Dimethoxyphenethyl)]-thiourea (11).
Yield: 68%; mp 139–1408C; UV (CHCl3) lmax: 253, 283 nm; IR (KBr) n
3345, 3064, 3014, 2935, 2869, 2834, 1606, 1553, 1515, 1473, 1442, 1419,
1
1346, 1261, 1236, 1191, 1141, 1053, 1027, 808, 754, 665 cm21; H NMR
(CDCl3) d 7.33–6.70 (m, 7H), 6.12 (s, 2H), 3.80 (s, 6H), 3.66 (q, 4H),
3.00–2.95 (t, 2H), 2.84–2.79 (t, 2H); 13C NMR (CDCl3) d 181.5, 148.7,
154.4, 135.8, 133.7, 130.8, 129.4, 128.0, 126.9, 120.7, 111.6, 111.2,
55.7, 45.4, 43.7, 34.6, 32.8; MALDI-TOF found: 380.2 (Mþ1), calcd.:
378.9; HPLC: Rt: 2.2 min, single peak with purity 100%; Anal. calcd.
for C19H23N2SO2Cl: C, 60.23; H, 6.12; N, 7.39. Found: C, 58.55; H, 6.09;
N, 7.30.
N-[2-(2-Chlorophenethyl)]-N0-[2-(4-Methylphenethyl)]-thiourea (12). Yield:
90%; mp 107–1088C; UV (CHCl3) lmax: 256 nm; IR (KBr) n 3403, 3264,
3058, 3018, 2927, 2863, 1552, 1515, 1475, 1442, 1382, 1346, 1282, 1184,
1120, 1053, 810, 754, 698, 487 cm21 1H NMR (CDCl3) d 7.35–7.04
;
(m, 8H), 6.01 (s, 2H), 3.60 (q, 4H), 2.98–2.93 (t, 2H), 2.83–2.79 (t, 2H),
2.30 (s, 3H); 13C NMR (CDCl3) d 181.4, 136.1, 135.8, 135.0, 133.7, 130.9,
129.4, 129.3, 128.4, 128.1, 127.0, 45.4, 43.6, 34.6, 32.8, 20.9; MALDI-TOF
found: 334.0 (Mþ1), calcd.: 332.9; HPLC: Rt: 2.4 min, single peak with
purity 100%; Anal. calcd. for C18H21N2SCl: C, 64.95; H, 6.36; N, 8.42.
Found: C, 64.72; H, 6.25; N, 8.33.
N-[2-(3-Chlorophenethyl)]-N0-[2-(4-Bromophenethyl)]-thiourea (13). Yield:
90%; mp 79–808C; UV (CHCl3) lmax: 253 nm; IR (KBr) n 3399, 3247,
3060, 2931, 2863, 1596, 1548, 1488, 1432, 1384, 1346, 1292, 1243, 1203,
1
1072, 1010, 885, 810, 781, 684, 486 cm21; H NMR (CDCl3) d 7.40–7.01
(m, 8H), 6.14 (s, 2H), 3.60 (q, 4H), 2.83–2.76 (m, 4H); 13C NMR (CDCl3)
d 181.4, 140.2, 137.1, 134.2, 131.6, 130.3, 129.8, 128.6, 126.8, 126.7, 120.3,
45.0, 34.6, 34.4; MALDI-TOF found: 398.5 (Mþ1), calcd.: 397.8; HPLC:
Rt: 2.5 min, single peak with purity 100%; Anal. calcd. for C17H18N2SBrCl:
C, 51.33; H, 4.56; N, 7.04. Found: C, 51.56; H, 4.48; N, 6.99.
N-[2-(3-Chlorophenethyl)]-N0-[2-(3-Chlorophenethyl)]-thiourea (14). Yield:
74%; mp 75–768C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3407, 3257,
3062, 2865, 1683, 1598, 1548, 1475, 1430, 1384, 1346, 1294, 1080, 1008,
1
908, 868, 823, 783, 732, 684, 557, 441 cm21; H NMR (CDCl3) d 7.25–
7.03 (m, 8H), 6.16 (s, 1H), 6.13 (s, 1H), 3.60 (q, 4H), 2.85–2.80 (t, 4H);
13C NMR (CDCl3) d 181.5, 140.2, 134.2, 129.9, 128.6, 126.8, 126.7, 45.0,
34.6; MALDI-TOF found: 353.1, calcd.: 353.3; HPLC: Rt: 2.4 min, single
peak with purity 100%; Anal. calcd. for C17H18N2SCl2: C, 57.79; H, 5.13;
N, 7.93. Found: C, 57.37; H, 5.02; N, 7.77.

Phenethyl Thiourea Compounds
2047
N-[2-(3-Chlorophenethyl)]-N0-[2-(2-Fluorophenethyl)]-thiourea (15). Yield:
75%; mp 70–718C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3409, 3257,
3062, 2933, 2865, 1664, 1556, 1492, 1348, 1290, 1230, 1189, 1103, 1080,
999, 869, 827, 756, 684, 553 cm21; 1H NMR (CDCl3) d 7.27–6.99 (m, 8H),
6.09 (s, 1H), 6.02 (s, 1H), 3.64–3.63 (q, 4H), 2.92–2.83 (m, 4H); 13C NMR
(CDCl3) d 181.6, 162.6, 159.4, 140.3, 134.3, 131.04, 130.98, 129.9, 128.7,
128.6, 128.5, 126.9, 126.8, 124.9, 124.3, 115.4, 115.2, 45.1, 44.1, 34.7,
28.6; 19F NMR (CDCl3) d 242.81, 242.76; MALDI-TOF found: 337.5
(Mþ1), calcd.: 336.9; HPLC: Rt: 2.4 min, single peak with purity 100%;
Anal. calcd. for C17H18N2SClF: C, 60.62; H, 5.39; N, 8.32. Found: C,
60.66; H, 5.37; N, 8.51.
N-[2-(3-Chlorophenethyl)]-N0-[2-(4-Hydroxyphenethyl)]-thiourea (16).
Yield: 60%; mp 101–1028C; UV (CHCl3) lmax: 254, 277, and 286 nm; IR
(KBr) n 3266, 3064, 3016, 2933, 2863, 1612, 1596, 1556, 1513, 1475,
1438, 1346, 1220, 1172, 1103, 1080, 999, 827, 784, 752, 684, 644, 592,
1
545, 503, 439 cm21; H NMR (CDCl3) d 7.27–6.74 (m, 8H), 6.16 (s, 1H),
5.91 (s, 1H), 5.79 (s, 1H), 3.60–3.51 (q, 4H), 2.82–2.72 (m, 4H); 13C NMR
(CDCl3) d 181.2, 154.6, 140.3, 134.3, 130.0, 129.7, 128.8, 126.9, 115.8,
45.4, 34.7, 34.0; MALDI-TOF found: 335.7 (Mþ1), calcd.: 334.9; HPLC:
Rt: 2.1 min, single peak with purity 100%; Anal. calcd. for C17H19N2SOCl:
C, 60.98; H, 5.72; N, 8.37. Found: C, 60.74; H, 5.75; N, 8.41.
N-[2-(3-Chlorophenethyl)]-N0-[2-(2-Methoxyphenethyl)]-thiourea (17).
Yield: 30%, (gel); UV (CHCl3) lmax: 256 nm; IR (KBr) n 3355, 3253,
3062, 3006, 2937, 2834, 1726, 1598, 1552, 1494, 1465, 1438, 1382, 1346,
1
1290, 1243, 1122, 1080, 1029, 869, 754, 684, 665, 543 cm21; H NMR
(CDCl3) d 7.28–6.83 (m, 7H), 6.49 (s, 1H), 6.17 (s, 2H), 3.74 (s, 3H),
3.69–3.46 (q, 4H), 2.90–2.82 (m, 4H); 13C NMR (CDCl3) d 181.1,
160.0, 140.5, 139.7, 134.1, 130.4, 129.7, 128.7, 128.0, 126.9, 126.6,
120.8, 110.3, 55.3, 45.4, 34.8, 29.7; MALDI-TOF found: 349.4 (Mþ1),
calcd.: 348.9; HPLC: Rt: 2.3 min, single peak with purity 100%; Anal.
calcd. for C18H21N2SOCl: C, 61.97; H, 6.07; N, 8.03. Found: C, 61.52;
H, 6.14; N, 7.92.
N-[2-(3-Chlorophenethyl)]-N0-[2-(3-Methoxyphenethyl)]-thiourea (18).
Yield: 77%; mp 48–498C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3257,
3060, 2937, 2834, 1598, 1548, 1488, 1436, 1346, 1259, 1153, 1080, 1043,
1
910, 871, 783, 732, 696, 648, 555, 460 cm21; H NMR (CDCl3) d 7.23–
6.72 (m, 8H), 6.13 (s, 2H), 3.75 (s, 3H), 3.60 (q, 4H), 2.83–2.77 (m, 4H);
13C NMR (CDCl3) d 181.3, 159.6, 140.2, 139.7, 134.1, 129.8, 129.6, 128.6,
126.8, 126.6, 120.8, 114.3, 111.8, 55.0, 45.1, 35.0, 34.6; MALDI-TOF
found: 349.7 (Mþ1), calcd.: 348.9; HPLC: Rt: 2.3 min, single peak with
purity 100%; Anal. calcd. for C18H21N2SOCl: C, 61.97; H, 6.07; N, 8.03.
Found: C, 61.72; H, 6.01; N, 7.93.

2048
T. K. Venkatachalam and F. M. Uckun
N-[2-(3-Chlorophenethyl)]-N0-[2-(2,5-Dimethoxyphenethyl)]-thiourea (19).
Yield: 40%; (gel); UV (CHCl3) lmax: 253 and 294 nm; IR (KBr) n 3345,
3251, 3060, 2998, 2937, 2833, 1596, 1552, 1500, 1465, 1430, 1346, 1282,
1
1224, 1047, 869, 800, 756, 692, 553 cm21; H NMR (CDCl3) d 7.28–6.70
(m, 7H), 6.49 (s, 1H), 6.12 (s, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.46 (q, 4H),
2.91–2.80 (m, 4H); 13C NMR (CDCl3) d 181.2, 153.6, 151.2, 140.5, 134.2,
129.8, 128.7, 126.9, 126.7, 116.7, 112.1, 111.4, 55.9, 55.6, 45.4, 34.8, 29.9;
MALDI-TOF found: 380.3 (Mþ1), calcd.: 378.9; HPLC: Rt: 2.3 min, single
peak with purity 100%; Anal. calcd. for C19H23N2SO2Cl: C, 60.23; H, 6.12;
N, 7.39. Found: C, 60.04; H, 6.06; N, 7.42.
N-[2-(3-Chlorophenethyl)]-N0-[2-(3,4-Dimethoxyphenethyl)]-thiourea (20).
Yield: 61%; mp 97–988C; UV (CHCl3) lmax: 252 and 283 nm; IR (KBr) n
3344, 3278, 2998, 2935, 2867, 2834, 1596, 1546, 1515, 1465, 1344, 1261,
1234, 1141, 1026, 910, 869, 784, 730, 684, 646, 441 cm21 1H NMR
;
(CDCl3) d 7.28–6.70 (m, 7H), 6.01 (s, 2H), 3.80 (s, 3H), 3.79 9 (s, 3H), 3.65
(q, 4H), 2.85–2.78 (m, 4H); 13C NMR (CDCl3) d 181.7, 148.8, 147.5, 140.4,
134.2, 130.7, 129.8, 128.8, 128.6, 126.8, 126.7, 120.5, 111.6, 111.2, 55.7,
46.6, 45.3, 45.1, 40.2, 34.9, 34.7, 34.6; MALDI-TOF found: 379.9 (Mþ1),
calcd.: 378.9; HPLC: Rt: 2.4 min, purity 98.1%; Anal. calcd. for
C19H23N2SO2Cl: C, 60.23; H, 6.12; N, 7.39. Found: C, 59.10; H, 6.22; N, 7.75.
N-[2-(3-Chlorophenethyl)]-N0-[2-(4-Methylphenethyl)]-thiourea (21).
Yield: 92%; mp 74–758C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3403,
3251, 3054, 3020, 2925, 2861, 1598, 1550, 1515, 1475, 1430, 1384, 1346,
1
1292, 1203, 1095, 1022, 869, 810, 783, 684, 489 cm21; H NMR (CDCl3)
d 7.26–7.04 (m, 8H), 6.00 (s, 2H), 3.59 (q, 4H), 2.82–2.78 (t, 4H) 2.31
(s, 3H); 13C NMR (CDCl3) d 181.4, 140.3, 136.2, 134.9, 134.2, 129.8,
129.3, 128.7, 128.4, 126.8, 126.7, 45.3, 45.1, 34.7, 34.6, 21.0; MALDI-TOF
found: 333.8 (Mþ1), calcd.: 332.9; HPLC: Rt: 2.5 min, single peak with
purity 100%; Anal. calcd. for C18H21ClN2S: C, 64.95; H, 6.36; N, 8.42.
Found: C, 64.51; H, 6.17; N, 8.17.
N-[2-(4-Chlorophenethyl)]-N0-[2-(4-Bromophenethyl)]-thiourea (22).
Yield: 62%; mp 131–1328C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3264,
3062, 2937, 2856, 1645, 1548, 1488, 1405, 1348, 1124, 1107, 1012, 811,
1
759, 694, 665, 509 cm21; H NMR (CDCl3) d 7.44–7.03 (m, 8H), 5.75
(s, 2H), 3.60 (q, 4H), 2.85–2.79 (m, 4H); 13C NMR (CDCl3) d 181.8,
137.1, 136.6, 132.5, 131.8, 130.4, 130.0, 128.8, 45.2, 34.5, 34.4; MALDI-
TOF found: 399.1 (Mþ1), calcd.: 397.8; HPLC: Rt: 2.5 min, single peak
with purity 100%; Anal. calcd. for C17H18BrClN2S: C, 51.33; H, 4.56;
N, 7.04. Found: C, 51.23; H, 4.53; N, 7.03.
N-[2-(4-Chlorophenethyl)]-N0-[2-(2-Fluorophenethyl)]-thiourea
Yield: 87%; mp 81–828C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3411,
(23).

Phenethyl Thiourea Compounds
2049
3276, 3064, 2933, 2865, 1704, 1662, 1552, 1492, 1456, 1348, 1290, 1228,
1188, 1091, 1016, 939, 811, 757, 661, 532 cm21 1H NMR (CDCl3)
;
d 7.28–7.00 (m, 8H), 5.98 (s, 1H), 5.89 (s, 1H), 3.63 (q, 4H), 2.92–2.82
(m, 4H); 13C NMR (CDCl3) d 181.7, 162.7, 136.7, 132.4, 131.1, 131.0,
130.0, 128.7, 128.6, 128.5, 124.4, 115.5, 115.2, 45.2, 44.1, 34.4, 28.7; 19F
NMR (CDCl3) d 242.86, 242.82, 242.77; MALDI-TOF found: 337.2,
calcd.: 336.9; HPLC: Rt: 2.4 min, single peak with purity 100%; Anal.
calcd. for C17H18FClN2S: C, 60.62; H, 5.39; N, 8.32. Found: C, 60.47; H,
5.38; N, 8.20.
N-[2-(4-Chlorophenethyl)]-N0-[2-(4-Hydroxyphenethyl)]-thiourea (24).
Yield: 29%; mp 154–1558C; UV (CHCl3) lmax: 255 and 273 nm; IR (KBr)
n 3355, 2935, 2865, 1691, 1612, 1554, 1513, 1442, 1346, 1255, 1091, 1014,
1
819, 651, 511 cm21; H NMR (CDCl3) d 8.39–8.37 (m, 1H), 7.33–6.76
(m, 8H), 6.57 (s, 2H), 3.69 (q, 4H), 2.86-2.75 (m, 4H); 13C NMR (CDCl3)
d 182.2, 155.4, 137.5, 131.8, 130.1, 129.5, 128.3, 115.4, 43.4, 45.0, 40.1,
34.5, 34.2; MALDI-TOF found: 335.5 (Mþ1), calcd.: 334.9; HPLC: Rt:
2.1 min, single peak with purity 100%; Anal. calcd. for C17H19ClN2SO: C,
60.98; H, 5.72; N, 8.37. Found: C, 60.01; H, 5.79; N, 8.18.
N-[2-(4-Chlorophenethyl)]-N0-[2-(2-Methoxyphenethyl)]-thiourea (25).
Yield: 75%; mp 99–1008C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3357,
3261, 3064, 3012, 2939, 2836, 1600, 1552, 1492, 1346, 1290, 1243, 1091,
1016, 892, 811, 754, 665, 532 cm21 1H NMR (CDCl3) d 7.37–6.83
;
(m, 8H), 6.42 (s, 1H), 6.06 (s, 1H), 3.74 (s, 3H), 3.66–3.45 (q, 4H), 2.91–
2.80 (m, 4H); 13C NMR (CDCl3) d 181.1, 157.0, 136.9, 132.2, 130.5, 130.0,
128.6, 128.1, 120.9, 110.4, 55.3, 45.5, 34.5, 29.8; MALDI-TOF found:
349.1, calcd.: 348.9; HPLC: Rt: 2.3 min, single peak with purity 100%;
Anal. calcd. for C18H21N2SOCl: C, 61.97; H, 6.07; N, 8.03. Found:
C, 61.73; H, 5.95; N, 7.98.
N-[2-(4-Chlorophenethyl)]-N0-[2-(3-Methoxyphenethyl)]-thiourea (26).
Yield: 78%; mp 53–548C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3264,
3060, 2937, 2865, 2934, 1583, 1552, 1490, 1346, 1259, 1153, 1091, 1014,
1
811, 781, 696, 489 cm21; H NMR (CDCl3) d 7.27–6.73 (m, 8H), 5.91
(s, 2H), 3.78 (s, 3H), 3.61 (q, 4H), 2.85–2.78 (m, 4H); 13C NMR (CDCl3)
d 181.6, 159.7, 139.8, 136.7, 132.4, 130.0, 129.7, 128.7, 120.9, 114.4,
111.9, 55.2, 45.2, 35.1, 34.4; MALDI-TOF found: 349.6 (Mþ1), calcd.:
348.9; HPLC: Rt: 2.4 min, single peak with purity 100%; Anal. calcd.
for C18H21N2SOCl: C, 61.97; H, 6.07; N, 8.03. Found: C, 61.09; H, 6.03;
N, 8.44.
N-[2-(4-Chlorophenethyl)]-N0-[2-(2,5-Dimethoxyphenethyl)]-thiourea (27).
Yield: 62%; mp 86–878C; UV (CHCl3) lmax: 256 and 293 nm; IR (KBr) n
3353, 3261, 3064, 3014, 2948, 2934, 1552, 1500, 1346, 1282, 1222, 1047,

2050
T. K. Venkatachalam and F. M. Uckun
1016, 810, 756, 667, 532 cm21; 1H NMR (CDCl3) d 7.28–6.70 (m, 7H), 6.34
(s, 1H), 5.95 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.46 (q, 4H), 2.89–2.80
(m, 4H); 13C NMR (CDCl3) d 181.3, 153.7, 151.2, 136.9, 132.4, 130.1,
128.7, 116.8, 112.2, 111.5, 56.0, 55.7, 45.7, 34.6, 30.0; MALDI-TOF found:
379.5 (Mþ1), calcd.: 378.9; HPLC: Rt: 2.4 min, single peak with purity
100%. Anal. calcd. for C19H23N2SO2Cl: C, 60.23; H, 6.12; N, 7.39. Found:
C, 60.82; H, 6.01; N, 7.34.
N-[2-(4-Chlorophenethyl)]-N0-[2-(3,4-Dimethoxyphenethyl)]-thiourea (28).
Yield: 53%; mp 96–978C; UV (CHCl3) lmax: 253 and 278 nm; IR (KBr) n
3345, 3062, 3018, 2867, 2836, 1592, 1548, 1515, 1465, 1348, 1261, 1141,
1
1027, 810, 757, 665, 541 cm21; H NMR (CDCl3) d 7.28–6.67 (m, 7H),
5.89 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.64 (q, 4H), 2.84–2.78 (m, 4H);
13C NMR (CDCl3) d 181.7, 14839, 147.6, 136.7, 132.4, 130.7, 129.9, 128.7,
120.5, 111.6, 111.2, 55.8, 45.3, 34.6, 34.4; MALDI-TOF found: 379.5
(Mþ1), calcd.: 378.9; HPLC: Rt: 2.3 min, single peak with purity 100%;
Anal. calcd. for C19H23N2SO2Cl: C, 60.23; H, 6.12; N, 7.39. Found:
C, 60.14; H, 6.25; N, 7.48.
N-[2-(4-Chlorophenethyl)]-N0-[2-(4-Methylphenethyl)]-thiourea
(29).
Yield: 55%; mp 129–1308C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3450,
3266, 3062, 2927, 2875, 1645, 1567, 1492, 1446, 1353, 1259, 1108, 1016,
1
813, 767, 663, 572, 487 cm21; H NMR (CDCl3) d 7.289–7.04 (m, 8H),
5.76 (s, 1H), 5.65 (s, 1H), 3.60 (q, 4H), 2.84–2.79 (t, 4H) 2.32 (s, 3H);
13C NMR (CDCl3) d 181.6, 136.7, 136.4, 134.9, 132.5, 130.0, 129.5, 128.8,
128.5, 45.3, 34.6, 34.4, 21.0; MALDI-TOF found: 334.2 (Mþ1), calcd.:
332.9; HPLC: Rt: 2.5 min, single peak with purity 100%; Anal. calcd.
for C18H21ClN2S: C, 64.95; H, 6.36; N, 8.42. Found: C, 63.81; H, 6.25;
N, 8.50.
N-[2-(2-Fluorophenethyl)]-N0-[2-(4-Bromophenethyl)]-thiourea (30).
Yield: 70%; mp 91–928C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3407,
3264, 3062, 2933, 2865, 1695, 1618, 1550, 1490, 1456, 1348, 1292, 1228,
1
1186, 1105, 1072, 1010, 939, 810, 757, 649, 505 cm21; H NMR (CDCl3)
d 7.45–7.00 (m, 8H), 5.84 (s, 1H), 5.75 (s, 1H), 3.64–3.62 (q, 4H), 2.93–
2.82 (m, 4H); 13C NMR (CDCl3) d 181.7, 137.2, 131.8, 131.1, 13.4, 128.7,
128.6, 125.1, 124.4, 120.6, 115.5, 115.3, 45.2, 44.2, 34.5, 28.7; 19F NMR
(CDCl3) d 242.88, 242.85, 242.79; MALDI-TOF found: 382.8 (Mþ1),
calcd.: 381.3; HPLC: Rt: 2.4 min, single peak with purity 100%; Anal.
calcd. for C17H18BrFN2S: C, 53.55; H, 4.76; N, 7.35. Found: C, 53.93; H,
4.74; N, 7.35.
N-[2-(2-Fluorophenethyl)]-N0-[2-(2-Fluorophenethyl)]-thiourea
(31).
Yield: 73%; mp 87–888C; UV (CHCl3) lmax: 255 nm; IR (KBr) n 3413,
3257, 3064, 2934, 2867, 1618, 1552, 1492, 1456, 1386, 1348, 1288, 1228,

Phenethyl Thiourea Compounds
2051
1
1191, 1120, 1037, 1000, 939, 850, 827, 754, 665, 559, 462 cm21; H NMR
(CDCl3) d 7.25–6.99 (m, 8H), 6.09 (s, 2H), 3.64 (q, 4H), 2.93–2.89
(t, 4H); 13C NMR (CDCl3) d 181.6, 162.6, 159.4, 131.04, 130.98, 128.5,
128.4, 125.2, 125.0, 124.3, 115.4, 115.1, 44.1, 28.6; 19F NMR (CDCl3)
d
242.87, 242.81, 242.78; MALDI-TOF found: 321.2 (Mþ1),
calcd.: 320.4; HPLC: Rt: 2.5 min, single peak with purity 100%; Anal. calcd.
for C17H18 F2N2S: C, 63.73; H, 5.66; N, 8.74. Found: C, 63.67; H, 5.61; N, 8.86.
N-[2-(2-Fluorophenethyl)]-N0-[2-(4-Hydroxyphenethyl)]-thiourea (32).
Yield: 84%; mp 134–1358C; UV (CHCl3) lmax: 255 and 273 nm; IR (KBr)
n 3315, 3066, 2935, 2867, 1693, 1554, 1513, 1456, 1348, 1228, 1105, 1035,
1
1002, 960, 829, 759, 661, 559, 478 cm21; H NMR (CDCl3) d 7.26–6.74
(m, 8H), 5.98 (s, 1H), 5.86 (s, 2H), 3.59 (q, 4H), 2.90–2.74 (m, 4H);
13C NMR (CDCl3) d 181.2, 162.7, 159.4, 154.6, 131.1, 129.7, 128.7, 128.5,
124.9, 124.4, 115.7, 115.5, 115.2, 114.7, 45.4, 44.3, 34.0, 28.7; 19F NMR
(CDCl3) d 242.80, 242.75; MALDI-TOF found: 319.3 (Mþ1), calcd.:
318.4; HPLC: Rt: 2.0 min, single peak with purity 100%; Anal. calcd.
for C17H19 FN2SO: C, 64.13; H, 6.01; N, 8.80. Found: C, 62.92; H, 6.01;
N, 8.70.
N-[2-(2-Fluorophenethyl)]-N0-[2-(2-Methoxyphenethyl)]-thiourea (33).
Yield: 68%; mp 78–798C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3357,
3264, 3064, 3004, 2937, 2836, 1708, 1552, 1230, 1116, 1031, 939, 850,
1
754, 665, 530 cm21; H NMR (CDCl3) d 7.34–6.84 (m, 8H), 6.34 (s, 1H),
6.03 (s, 1H), 3.77 (s, 3H), 3.70–3.47 (q, 4H), 2.93–2.83 (m, 4H); 13C NMR
(CDCl3) d 181.2, 157.1, 131.2, 130.5, 128.5, 128.4, 128.2, 124.3, 121.0,
115.4, 115.1, 110.4, 55.3, 44.4, 29.8, 28.8; 19F NMR (CDCl3) d 242.89;
MALDI-TOF found: 333.2 (Mþ1), calcd.: 332.4; HPLC: Rt: 2.3 min, single
peak with purity 100%; Anal. calcd. for C18H21N2SOF: C, 65.03; H, 6.37;
N, 8.43. Found: C, 64.84; H, 6.22; N, 8.39.
N-[2-(2-Fluorophenethyl)]-N0-[2-(3-Methoxyphenethyl)]-thiourea (34).
Yield: 97%; mp 59–608C; UV (CHCl3) lmax: 255 and 273 nm; IR (KBr) n
3257, 3060, 2937, 2834, 1585, 1552, 1490, 1259, 1153, 1041, 910, 757,
1
696, 665, 570, 462 cm21; H NMR (CDCl3) d 7.19–6.66 (m, 8H), 5.92
(s, 2H), 3.69 (s, 3H), 3.54 (q, 4H), 2.82–2.73 (m, 4H); 13C NMR (CDCl3)
d 181.5, 162.6, 159.7, 159.4, 139.8, 131.02, 130.96, 129.6, 128.5, 128.4,
125.1, 124.9, 124.2, 120.9, 115.4, 115.1, 114.3, 111.9, 55.1, 45.2, 44.1,
35.1, 28.6; 19F NMR (CDCl3) d 242.84, 242.81, 242.78; MALDI-TOF
found: 332.4, calcd.: 332.4; HPLC: Rt: 2.3 min, single peak with purity
100%; Anal. calcd. for C18H21N2SOF: C, 65.03; H, 6.37; N, 8.43. Found:
C, 64.74; H, 6.26; N, 8.22.
N-[2-(2-Fluorophenethyl)]-N0-[2-(2,5-Dimethoxyphenethyl)]-thiourea (35).
Yield: 73%; mp 71–728C; UV (CHCl3) lmax: 256 and 292 nm; IR (KBr) n

2052
T. K. Venkatachalam and F. M. Uckun
3345, 3257, 3064, 2998, 2937, 2833, 1556, 1494, 1456, 1224, 1047, 910, 804,
757, 732, 646, 553, 464 cm21; 1H NMR (CDCl3) d 7.28–6.71 (m, 7H), 6.51
(s, 1H), 6.21 (s, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.49–3.47 (q, 4H), 2.97–
2.93 (t, 2H), 2.84–2.79 (t, 2H); 13C NMR (CDCl3) d 181.1, 162.6, 159.4,
153.6, 151.1, 131.1, 128.4, 128.3, 124.2, 116.6, 115.3, 115.0, 112.0, 111.3,
55.8, 55.6, 44.4, 29.9, 28.7; 19F NMR (CDCl3) d -42.91; MALDI-TOF
found: 364.1 (M þ 2), calcd.: 362.5; HPLC: Rt: 2.3 min, single peak with
purity 100%; Anal. calcd. for C19H23N2SO2 F: C, 62.96; H, 6.40; N, 7.73.
Found: C, 62.72; H, 6.37; N, 7.63.
N-[2-(2-Fluorophenethyl)]-N0-[2-(3,4-Dimethoxyphenethyl)]-thiourea (36).
Yield: 77%; mp 105–1068C; UV (CHCl3) lmax: 255 and 273 nm; IR (KBr)
n 3257, 3060, 2937, 2865, 2834, 1585, 1552, 1490, 1456, 1259, 1163, 1041,
850, 757, 696, 555, 462 cm21; 1H NMR (CDCl3) d 7.27–6.74 (m, 7H), 5.91
(s, 2H), 3.78 (s, 6H), 3.63 (q, 4H), 2.90–2.82 (m, 4H); 13C NMR (CDCl3)
d 181.6, 162.6, 159.8, 159.4, 139.8, 131.1, 131.0, 129.7, 128.6, 128.4,
125.2, 125.0, 124.3, 120.9, 115.4, 115.2, 114.4, 112.0, 55.1, 45.2, 44.2,
35.1, 28.6; 19F NMR (CDCl3) d 242.85, 242.81, 242.79; MALDI-TOF
found: 363.3 (Mþ1), calcd.: 362.5; HPLC: Rt: 2.2 min, single peak with
purity 100%; Anal. calcd. for C19H23N2SO2 F: C, 62.96; H, 6.40; N, 7.73.
Found: C, 62.70; H, 6.42; N, 7.82.
N-[2-(2-Fluorophenethyl)]-N0-[2-(4-Methylphenethyl)]-thiourea
(37).
Yield: 70%; mp 76–778C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3272,
3222, 3050, 2933, 2856, 1695, 1548, 1492, 1456, 1351, 1261, 1228, 1197,
1
1110, 1027, 939, 811, 757, 707, 665, 561, 497 cm21; H NMR (CDCl3)
d 7.26–6.99 (m, 8H), 5.88 (s, 2H), 3.60 (q, 4H), 2.90–2.80 (m, 4H), 2.31
(s, 3H); 13C NMR (CDCl3) d 181.5, 162.6, 159.4, 136.2, 135.0, 131.1,
131.0, 129.4, 128.5, 125.2, 125.0, 124.3, 115.4, 115.2, 45.4, 44.2, 34.6,
28.6, 21.0; 19F NMR (CDCl3) d 242.85, 242.82, 242.76; MALDI-TOF
found: 317.4 (Mþ1), calcd.: 316.4; HPLC: Rt: 2.4 min, single peak with
purity 100%; Anal. calcd. for C18H21 FN2S: C, 68.32; H, 6.69; N, 8.85.
Found: C, 68.13; H, 6.60; N, 8.87.
N-[2-(2-Chlorophenethyl)]-N0-[2-(1-Cyclohexenyl)ethyl]-thiourea
(38).
Yield: 45%; mp 62–638C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3396,
3249, 3060, 2927, 2856, 2833, 1510, 1475, 1384, 1344, 1284, 1243, 1188,
;
1153, 1053, 1002, 918, 771, 752, 675, 486 cm21 1H NMR (CDCl3)
d 7.29–7.08 (m, 4H), 6.14 (s, 1H), 5.95 (s, 1H), 3.63 (m, 2H), 3.35
(m, 2H), 2.99–2.95 (t, 2H), 2.13–2.09 (t, 2H), 1.90–1.42 (m, 8H); 13C
NMR (CDCl3) d 181.2, 135.9, 133.9, 133.7, 130.9, 129.4, 128.0, 126.9,
124.0, 60.3, 43.7, 41.7, 36.7, 32.8, 27.7, 25.1, 22.6, 22.1, 20.9, 14.0;
MALDI-TOF found: 324.0 (Mþ1), calcd.: 322.9; HPLC: Rt: 2.5 min, purity
99.9%; Anal. calcd. for C17H23ClN2S: C, 63.24; H, 7.18; N, 8.68. Found: C,
62.65; H, 7.15; N, 8.68.

Phenethyl Thiourea Compounds
2053
N-[2-(2-Chlorophenethyl)]-N0-[2-(3-Indole)ethyl]-thiourea
(39). Yield:
38% (gel); UV (CHCl3) lmax: 249, 255, 261, 281, 291 nm; IR (KBr) n
3471, 3399, 3361, 3278, 3060, 3016, 2941, 2873, 1726, 1548, 1475, 1442,
1375, 1342, 1249, 1216, 1095, 1053, 1010, 931, 752, 667, 609, 582, 462,
;
424 cm21 1H NMR (CDCl3) d 8.33 (s, 1H), 7.44–6.81 (m, 8H), 5.94
(s, 2H), 3.55–3.44 (q, 4H), 2.86–2.73 (m, 4H); 13C NMR (CDCl3) d 181.2,
171.2, 136.1, 135.8, 133.7, 130.8, 129.3, 128.0, 126.9, 122.3, 122.0, 119.3,
118.3, 111.8, 111.3, 60.3, 44.3, 43.7, 32.7, 24.7; MALDI-TOF found: 359.2
(Mþ1), calcd.: 357.9; HPLC purity 98.0%; Anal. calcd. for C19H20ClN3S:
C, 63.76; H, 5.63; N, 11.74. Found: C, 62.65; H, 6.08; N, 10.24.
N-[2-(3-Chlorophenethyl)]-N0-[2-(1-Cyclohexenyl)ethyl]-thiourea
(40).
Yield: 81%; mp 70–718C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3421,
3266, 3020, 2937, 2860, 2836, 1598, 1542, 1492, 1436, 1342, 1215, 1080,
1
1010, 921, 756, 669, 441 cm21; H NMR (CDCl3) d 7.28–7.09 (m, 5H),
5.92 (s, 2H), 3.72 (m, 2H), 3.36 (m, 2H), 2.93–2.88 (t, 2H), 2.21–2.16
(t, 2H), 2.00–1.53 (m, 8H); 13C NMR (CDCl3) d 181.2, 140.4, 1134.3,
133.9, 129.9, 128.7, 126.9, 126.8, 124.3, 45.2, 41.5, 36.7, 34.8, 27.7, 25.1,
22.6, 22.2; MALDI-TOF found: 323.5 (Mþ1), calcd.: 322.9; HPLC: Rt:
2.6 min, purity 99.8%; Anal. calcd. for C17H23ClN2S: C, 63.24; H, 7.18; N,
8.68. Found: C, 62.78; H, 7.15; N, 8.64.
N-[2-(3-Chlorophenethyl)]-N0-[2-(3-Indole)ethyl]-thiourea
(41). Yield:
51%; mp 127–1288C; UV (CHCl3) lmax: 246, 254, 283, and 291 nm; IR
(KBr) n 3405, 3357, 3259, 3054, 2925, 2852, 1596, 1548, 1496, 1456,
1390, 1342, 1292, 1228, 1093, 1080, 1010, 867, 786, 746, 684, 482 cm21
;
1H NMR (CDCl3) d 8.16 (s, 1H), 7.56–6.95 (m, 8H), 5.85 (s, 1H), 5.61
(s, 1H), 3.62–3.47 (q, 4H), 2.99–2.95 (t, 2H), 2.68–2.63 (t, 2H); 13C NMR
(CDCl3) d 181.4, 140.3, 136.3, 134.2, 129.9, 128.7, 126.9, 126.8, 122.5,
122.4, 119.6, 118.4, 111.4, 45.2, 34.6, 24.8; MALDI-TOF found: 358.7
(Mþ1), calcd.: 357.9; HPLC: Rt: 2.2 min, single peak with purity 100%;
Anal. calcd. for C19H20ClN3S: C, 63.76; H, 5.63; N, 11.74. Found: C,
63.76; H, 5.63; N, 11.78.
N-[2-(4-Chlorophenethyl)]-N0-[2-(1-Cyclohexenyl)ethyl]-thiourea
(42).
Yield: 62%; mp 137–1388C; UV (CHCl3) lmax: 254 nm; IR (KBr) n 3266,
3060, 2935, 2856, 2836, 1668, 1537, 1438, 1348, 1270, 1130, 1095, 1014,
918, 811, 767, 707, 551, 514 cm21; 1H NMR (CDCl3) d 7.30–7.13 (m, 5H),
5.77 (s, 2H), 3.70 (m, 2H), 3.34 (m, 2H), 2.92–2.88 (t, 2H), 2.20–2.16
(t, 2H), 1.99–1.51 (m 8H); 13C NMR (CDCl3) d 181.3, 157.9, 136.7, 132.5,
130.0, 128.8, 124.4, 45.4, 41.5, 36.7, 34.5, 27.7, 25.2, 22.7, 22.2; MALDI-
TOF found: 323.6 (Mþ1), calcd.: 322.9; HPLC: Rt: 2.5 min, purity 97.7%;
Anal. calcd. for C17H23ClN2S: C, 63.24; H, 7.18; N, 8.68. Found: C, 63.33;
H, 7.18; N, 8.60.

2054
T. K. Venkatachalam and F. M. Uckun
(43). Yield:
N-[2-(4-Chlorophenethyl)]-N0-[2-(3-Indole)ethyl]-thiourea
30%; mp 152–1538C; UV (CHCl3) lmax: 254 and 291 nm; IR (KBr) n
3396, 3058, 2933, 1619, 1548, 1490, 1456, 1340, 1290, 1228, 1091, 1014,
1
810, 744, 503 cm21; H NMR (CDCl3) d 8.17 (s, 1H), 7.57–6.98 (m, 9H),
5.84 (s, 1H), 5.59 (s, 1H), 3.63 (m, 2H), 3.49 (m, 2H), 3.01–2.96 (t, 2H),
2.69–2.64 (t, 2H); 13C NMR (CDCl3) d 181.5, 136.7, 136.3, 132.4, 130.0,
128.7, 126.9, 122.7, 119.7, 118.4, 112.1, 111.4, 45.2, 44.3, 34.3, 24.8;
MALDI-TOF found: 359.7 (M þ 2), calcd.: 357.9; HPLC: Rt: 2.2 min,
purity 97.8%; Anal. calcd. for C19H20ClN3S: C, 63.76; H, 5.63; N, 11.74.
Found: C, 62.83; H, 5.33; N, 11.67.
N-[2-(2-Fluorophenethyl)]-N0-[2-(1-Cyclohexenyl)ethyl]-thiourea
(44).
Yield: 40%, mp 53–548C; UV (CHCl3) lmax: 253 nm; IR (KBr) n 3415,
3251, 3062, 2929, 2858, 2834, 1618, 1552, 1492, 1456, 1382, 1348, 1261,
1
1230, 1195, 1103, 1037, 1014, 910, 800, 757, 732, 646, 553, 472 cm21; H
NMR (CDCl3) d 7.17–6.91 (m, 5H), 6.12 (s, 1H), 5.95 (s, 1H), 3.60
(m, 2H), 3.33 (m, 2H), 2.89–2.85 (t, 2H), 2.13–2.09 (t, 2H), 1.90–1.42
(m, 8H); 13C NMR (CDCl3) d 181.1, 162.5, 159.3, 133.8, 131.0, 130.9,
128.4, 128.3, 125.2, 125.0, 124.1, 115.3, 115.0, 44.1, 41.7, 36.7, 28.6, 27.6,
25.0, 22.6, 22.1; 19F NMR (CDCl3) d 242.89, 242.87, 242.84, 242.81;
MALDI-TOF found: 307.7 (Mþ1), calcd.: 306.4; HPLC: Rt: 2.5 min, purity
95.6%; Anal. calcd. for C17H23 FN2S: C, 66.63; H, 7.56; N, 9.14. Found: C,
65.61; H, 7.56; N, 8.72.
N-[2-(2-Fluorophenethyl)]-N0-[2-(3-Indole)ethyl]-thiourea
(45). Yield:
86%; mp 113–1148C; UV (CHCl3) lmax: 256, 284, and 291 nm; IR (KBr) n
3403, 3353, 3280, 3056, 2935, 2865, 1695, 1618, 1550, 1492, 1456, 1342,
1
1228, 1188, 1103, 1010, 939, 825, 746, 649, 584, 478, 426 cm21; H NMR
(CDCl3) d 8.14 (s, 1H), 7.57–6.96 (m, 9H), 5.84 (s, 1H), 5.70 (s, 1H),
3.65–3.52 (q, 4H), 3.01–2.97 (t, 2H), 2.80–2.75 (t, 2H); 13C NMR
(CDCl3) d 181.4, 162.6, 159.4, 136.3, 131.1, 131.0, 128.5, 128.4, 126.9,
124.3, 122.3, 119.6, 118.4, 115.4, 115.2, 112.1, 111.4, 44.3, 28.5, 24.8; 19F
NMR (CDCl3) d 242.81, 242.76; MALDI-TOF found: 342.2 (Mþ1),
calcd.: 341.5; HPLC: Rt: 2.2 min, single peak with purity 100%; Anal.
calcd. for C19H20 FN3S: C, 66.84;H, 5.90; N, 12.31. Found: C, 66.00;
H, 5.85; N, 12.15
CONCLUSIONS
Substituted phenylethyl thioureas were synthesized as Nonnucleoside Reverse
Transcriptase Inhibitor (NNRTI) candidates. Synthesis of these derivatives
was accomplished in two steps utilizing thiocarbonyldiimidazole instead of
isothiocyanates with typical yields of approximately 70%.

Phenethyl Thiourea Compounds
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2055
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