Regiospecific synthesis of 5-halo-substituted thiophene pyridyl thiourea compounds as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Article abstract of DOI:10.1081/SCC-120039499

The regiospecific synthesis of 5-halothiophenethylamines and halo-substituted phenylethyl thioureas was accomplished with an overall yield of 45-60%. Condensation of t-boc protected 2-thiophenethylamine with N-halo succinamide in dimethylformamide furnished the desired halo-substituted thiophenethylamines. These thiophenethyl amines were further converted into biologically active thiourea compounds using thiocarbonyldiimidazole chemistry. Several of the halo-substituted thiophene pyridyl thiourea compounds inhibited HIV-1 reverse transcriptase (RT) at nanomolar concentrations.

Full text of DOI:10.1081/SCC-120039499

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2451–2461, 2004
Regiospecific Synthesis of
5-Halo-substituted Thiophene
Pyridyl Thiourea Compounds
as Non-nucleoside Inhibitors of
HIV-1 Reverse Transcriptase
T. K. Venkatachalam1,2 and F. M. Uckun2,3,4,
*
2
1Department of Chemistry, Department of Immunology and
3Department of Virology, Parker Hughes Institute,
Roseville, Minnesota, USA
4Drug Discovery Program, Parker Hughes Clinics,
Roseville, Minnesota, USA
ABSTRACT
The regiospecific synthesis of 5-halothiophenethylamines and halo-
substituted phenylethyl thioureas was accomplished with an overall
yield of 45–60%. Condensation of t-boc protected 2-thiophenethylamine
with N-halo succinamide in dimethylformamide furnished the desired
*
Correspondence: F. M. Uckun, M.D., Ph.D., Drug Discovery Program, Parker Hughes
Clinics, 2699 Patton Road, St. Paul, MN 55113, USA; Fax: 651-796-5493; E-mail:
fatih_uckun@ih.org.
2451
DOI: 10.1081/SCC-120039499
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Venkatachalam and Uckun
halo-substituted thiophenethylamines. These thiophenethyl amines were
further converted into biologically active thiourea compounds using thio-
carbonyldiimidazole chemistry. Several of the halo-substituted thiophene
pyridyl thiourea compounds inhibited HIV-1 reverse transcriptase (RT) at
nanomolar concentrations.
Key Words: Thiourea compounds; Non-nucleoside inhibitors; HIV-1;
Reverse transcriptase.
INTRODUCTION
We have previously reported[1,2] that certain thiophene-substituted
thiourea compounds exhibit potent non-nucleoside reverse transcriptase
inhibitory (NNRTI) activity. In the present study, we examined the effect
of halogen substitution on the thiophene ring on the NNRTI activity of
thiophene thiourea compounds. Since commercially available precursors
are not available, we developed a regioselective method for halogenating
the thiophene ring.
Synthesis of Halothiophenethylamines
Synthesis of halothiophenesubstituted thioureas was conducted following
the procedure shown in Sch. 1, Table 1. In brief, commercially available
2-thiophenethylamine was treated with di-tert-butyldicarbonate in chloroform
and the contents were refluxed for 6–8 hr. The reaction mixture was cooled
Scheme 1. Reagents: (a) (Boc)2O, CHCl3, reflux, 6 hr; (b) NXS, DMF, rt, over-
night; (c) 12 M HCl, EtOAc, overnight; (d) CH3CN/RT/48 hr; (e) K2CO3/DMF/
1108C/24 hr.

Synthesis of 5-Halo-substituted Thiophene Pyridyl Thiourea
2453
Table 1. Structures of synthesized compounds and their melting points.
Compound no.
X
Y
Z
Mp (8C)
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
5-Br
5-Br
5-Br
5-Br
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-I
Me
Cl
S
S
S
S
S
S
S
S
S
S
S
O
O
S
S
S
S
S
S
S
159–160
115–116
156–157
163–164
160–161
154–155
128–129
168–169
175–176
209–210
163–164
157–158
141–142
202–204
186–187
195–196
160–161
176–178
167–168
154–155
H
Br
Me
H
H
H
4-Me
6-OMe
Br
Br
5-I
5-I
H
Me
5-I
5-I
H
4,6-Dimethyl
5-I
5-I
6-Me
H
Br
5-I
5-I
Cl
and the solvent removed in vacuo to furnish the desired t-boc protected
thiophenethylamines. For the preparation of the halo-substituted thiophene
analogs, t-boc protected thiophenethylamines were dissolved in anhydrous
dimethylformamide and stirred at room temperature. N-Halosuccinamide
dissolved in dimethylformamide was added to this solution followed by
further stirring at room temperature. The flask was covered with aluminium
foil to protect the reaction mixture from light and the reaction was monitored
by TLC until complete.
The solution was then poured into ice water and the product was extracted
with methylene chloride. The aqueous layer was separated and the organic
layer was dried over anhydrous magnesium sulfate. Filtration and evaporation
of the solvent yielded the halo-substituted, t-boc-protected thiophenethyl-
amines. In the subsequent step, the above intermediates were taken up in

2454
Venkatachalam and Uckun
ethylacetate, and 2 equiv. of 12 N hydrochloric acid was added to this solution
drop-wise over 30–45 min with vigorous stirring. The reaction was allowed to
stir for 5–6 days at room temperature. The reaction mixture was then filtered
and the solid was rinsed with ethyl acetate, air dried for several hours, and then
dried in vacuo to yield the hydrochloride salt. Electrophilic substitution on
the thiophene ring generally occurs at the 2- and 5-positions since the allylic
cation intermediate can be stabilized by charge delocalization. Accordingly,
halogenation of thiophene compounds yields preferentially and regiospecifi-
cally 2-halo-substituted or 2,5-disubstituted thiophene compounds as major
products.[3–5] Thus the experimentally observed regioselective halogenation
of protected 2-ethylaminothiophene at the 5-position was expected.
Preparation of Thicarbonylimidazole Derivatives
of Pyridyl Amines
Synthesis of halopyridyl thiocarbonylimidazole was accomplished using
the following procedure: 5-halo-2-amino pyridine was dissolved in a round-
bottomed flask with anhydrous acetonitrile under nitrogen atmosphere. After
obtaining a clear solution, 1 equiv. of solid thiocarbonyldiimidazole was
added and the contents were stirred for 48–72 hr at room temperature until
a precipitate appeared in the flask. The content was filtered, the precipitate
washed with additional anhydrous acetonitrile, and the residue dried under
vacuum to furnish the thiocarbonylimidazole intermediate.
Synthesis for all Thioureas
Synthesis of thiourea compounds was accomplished using the halothio-
phenethylamine hydrochloride salt and halopyridyl thiocarbonylimidazole
derivative following the method[6–10] shown in Sch. 1. Anhydrous dimethyl-
formamide, 60 mL, was added to a RB flask containing both compounds
followed by addition of 30–40 mg anhydrous potassium carbonate. The
content was stirred, heated over an oil bath at 1108C for 30 hr, then cooled
to room temperature, and the solution was poured into ice water. The precipi-
tated product was filtered, washed with water, and dried. The product was then
redissolved in chloroform, transferred into a separatory funnel, and washed
thoroughly with brine and water. The organic layer was separated and
dried over anhydrous magnesium sulfate. Filtration and evaporation of the
solvent furnished the crude thioureas as colorless solids. The crude material
was then subjected to column chromatography (hexane/THF, 80 : 20) and
re-crystallized using ethanol to yield thioureas as shiny crystals.

Synthesis of 5-Halo-substituted Thiophene Pyridyl Thiourea
Physical Constants of Thioureas
2455
N-[2-(5-Bromothiophenethyl)]-N0-[2-(5-methylpyridyl)]thiourea (2001).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 159–1608C;
1H NMR (DMSO-d6) d 11.70 (t, 1H), 10.53 (s, 1H), 7.90 (s, 1H), 7.57 (d, 1H,
J ¼ 8.1 Hz), 7.06 (s, 1H), 7.03 (s, 1H), 6.79 (d, 1H, J ¼ 3.0 Hz), 3.82 (q, 2H),
3.10 (t, 2H), 2.18 (s, 3H); 13C NMR (DMSO-d6) d 179.4, 151.7, 144.6, 143.7,
139.7, 130.2, 126.8, 126.7, 112.2, 108.8, 45.9, 29.1, 17.5; IR n 3563, 3220,
3035, 2935, 1608, 1565, 1535, 1488, 1330, 1188 cm21; MALDI-TOF m/z
357.5 (C13H14BrN3S2 þ 2Hþ); HPLC Rt: 12.42 min. Single peak in HPLC purity
(AUC) 99.2%. Anal. Calcd. for C13H14BrN3S2: C, 43.82; H, 3.96; N, 11.79.
Found: C, 43.70; H, 3.91; N, 11.73.
N-[2-(5-Bromothiophenethyl)]-N0-[2-(5-chloropyridyl)]thiourea (2002).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 115–1168C;
1H NMR (DMSO-d6) d 11.29 (t, 1H), 10.77 (s, 1H), 8.11 (t, 1H), 7.85 (dd,
1H, J ¼ 3.0, 9.3 Hz), 7.17 (d, 2H, J ¼ 8.7Hz), 7.07 (d, 1H, J ¼ 3.6 Hz), 6.80
(d, 1H, J ¼ 3.0 Hz), 3.81 (q, 2H), 3.11 (t, 2H); 13C NMR (DMSO-d6) d 179.3,
152.0, 143.5, 138.9, 130.2, 126.7, 123.8, 114.1, 108.8, 46.0, 28.9; IR n 3490,
3212, 3039, 2923, 1592, 1554, 1531, 1473, 1226 cm21; MALDI-TOF m/z
378.3 (C12H11BrClN3S2 þ 2Hþ); HPLC Rt: 14.04 min. Single peak in HPLC
purity (AUC) 98.2%. Anal. Calcd. for C12H11BrClN3S2: C, 38.26; H, 2.94; N,
11.15. Found: C, 38.69; H, 2.90; N, 12.12.
N-[2-(5-Bromothiophenethyl)]-N0-[2-(pyridyl)]thiourea (2003). Column
chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 156–1578C; 1H NMR
(DMSO-d6) d 11.78 (s, 1H), 10.61 (s, 1H), 8.08 (d, 1H, J ¼ 3.0 Hz), 7.74
(t, 1H), 7.13 (d, 1H, J ¼ 8.4 Hz), 7.06 (t, 1H), 7.01 (t, 1H), 6.81 (d, 1H,
J ¼ 3.0 Hz), 3.83 (q, 2H), 3.12 (t, 2H); 13C NMR (DMSO-d6) d 179.6,
153.6, 145.3, 143.7, 138.9, 130.2, 126.7, 117.9, 112.6, 108.8, 45.9, 29.1; IR
n 3452, 3220, 3050, 2931, 1600, 1562, 1535, 1477, 1199, 775 cm21
;
MALDI-TOF m/z 343.8 (C12H12BrN3S2 þ 3Hþ); HPLC Rt: 9.29 min. Single
peak in HPLC purity (AUC) 99.1%. Anal. Calcd. for C12H12BrN3S2: C, 42.11;
H, 3.53; N, 12.28. Found: C, 42.11; H, 3.47; N, 12.12.
N-[2-(5-Bromothiophenethyl)]-N0-[2-(5-bromopyridyl)]thiourea (2004).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 163–1648C;
1H NMR (DMSO-d6) d 11.29 (t, 1H), 10.73 (s, 1H), 8.17 (d, 1H, J ¼ 2.4 Hz),
7.93 (dd, 1H, J ¼ 3.0, 9.0 Hz), 7.10 (d, 1H, J ¼ 9.0Hz), 7.04 (d, 1H,
J ¼ 3.9 Hz), 6.79 (d, 1H, J ¼ 3.6 Hz), 3.81 (q, 2H), 3.10 (t, 2H); 13C NMR
(DMSO-d6) d 179.4, 152.4, 145.9, 143.7, 141.6, 130.3, 126.9, 114.7, 112.2,
108.9, 46.2, 29.0; IR n 3506, 3212, 3037, 2925, 1591, 1552, 1529, 1473,
1227, 796cm21; MALDI-TOF m/z 423.3 (C12H11Br2N3S2 þ 2Hþ); HPLC Rt:
15.18min. Single peak in HPLC purity (AUC) 99.3%. Anal. Calcd. for
C12H11Br2N3S2: C, 34.22; H, 2.63; N, 9.98. Found: C, 34.33; H, 2.55; N, 10.03.

2456
Venkatachalam and Uckun
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(5-methylpyridyl)]thiourea (2005).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 160–1618C;
1H NMR (DMSO-d6) d 11.69 (t, 1H), 10.52 (s, 1H), 7.90 (s, 1H), 7.56 (dd, 1H,
J ¼ 2.1, 8.4 Hz), 7.04 (d, 1H, J ¼ 8.7 Hz), 6.96 (d, 1H, J ¼ 3.6 Hz), 6.81 (d, 1H,
J ¼ 3.9 Hz), 3.81 (q, 2H), 3.08 (t, 2H), 2.19 (s, 3H); 13C NMR (DMSO-d6) d
179.4, 151.7, 144.6, 141.0, 139.7, 126.8, 126.6, 125.8, 125.6, 112.2, 45.9,
29.1, 17.5; IR n 3423, 3220, 3037, 2939, 1610, 1565, 1537, 1490, 1332, 1203,
1189, 802 cm21; MALDI-TOF m/z 313.00 (C13H14ClN3S2 þ 2Hþ); HPLC Rt:
10.55 min. Single peak in HPLC purity (AUC) 99.3%. Anal. Calcd. for
C13H14ClN3S2: C, 50.07; H, 4.52; N, 13.47. Found: C, 50.17; H, 4.54; N, 13.48.
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(thiazolyl)]thiourea (2006). Column
1
chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 154–1558C; H NMR
(DMSO-d6) d 11.66 (s, 1H), 9.64 (s, 1H), 7.34 (d, 1H, J ¼ 3.6 Hz), 7.08 (d, 1H,
J ¼ 3.3 Hz), 6.94 (d, 1H, J ¼ 3.6 Hz), 6.78 (d, 1H, J ¼ 3.3 Hz), 3.75 (q, 2H),
3.05 (t, 2H); 13C NMR (DMSO-d6) d 178.4, 161.9, 140.7, 136.4, 126.6, 125.8,
125.6, 112.1, 45.5, 28.9; IR n 3453, 3172, 3016, 2968, 1556, 1510, 1249,
1176, 794 cm21; MALDI-TOF m/z 304.8 (C10H10ClN3S3 þ 2Hþ); HPLC Rt:
8.03 min. Single peak in HPLC purity (AUC) 100%. Anal. Calcd. for
C10H10ClN3S3: C, 39.53; H, 3.32; N, 13.83. Found: C, 39.47; H, 3.30; N, 13.89.
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(pyridyl)]thiourea (2007). Column
chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 128–1298C; 1H NMR
(DMSO-d6) d 11.78 (t, 1H), 10.61 (s, 1H), 8.08 (d, 1H, J ¼ 5.1 Hz), 7.73
(m, 1H), 7.12 (dd, 1H, J ¼ 0.9, 8.4 Hz), 7.00 (t, 1H), 6.95 (dd, 1H, J ¼ 0.9,
3.6 Hz), 6.82 (dd, 1H, J ¼ 0.9, 3.9 Hz), 3.82 (q, 2H), 3.09 (t, 2H); 13C NMR
(DMSO-d6) d 179.6, 153.7, 145.3, 140.9, 138.9, 126.6, 125.7, 117.9, 112.6,
45.9, 29.1; IR n 3444, 3218, 3052, 2944, 1604, 1560, 1535, 1479, 1330,
1203, 1188, 773 cm21
;
MALDI-TOF m/z 298.6 (C12H12ClN3S2 þ
2Hþ); HPLC Rt: 8.03 min. Single peak in HPLC purity (AUC) 100%. Anal.
Calcd. for C12H12ClN3S2: C, 48.40; H, 4.06; N, 14.11. Found: C, 48.41; H,
4.06; N, 14.13.
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(benzothiazolyl)]thiourea (2008).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 168–1698C;
1H NMR (DMSO-d6) d 11.97 (bs, 1H), 10.11 (bs, 1H), 7.88–7.86 (d, 1H,
J ¼ 6.0 Hz), 7.57–7.55 (d, 1H, J ¼ 6.0Hz), 7.41–7.36 (m, 1H), 7.27–7.22
(m, 1H), 6.96–6.94 (m, 1H), 6.84–6.83 (d, 1H, J ¼ 3.0 Hz), 3.82 (q, 2H),
3.12–3.07 (t, 2H); 13C NMR (DMSO-d6) d 179.2, 161.4, 141.2, 140.8, 129.6,
126.7, 126.4, 125.9, 125.7, 123.7, 121.9, 118.9, 45.7, 28.9; IR n 3170, 3027,
2943, 1572, 1529, 1456, 1402, 1348, 1313, 1259, 1207, 1169, 1059, 1014,
989, 937, 891, 792, 756, 715 cm21; UV l (MeOH), 203, 219, 247, 292 nm;
HPLC Rt: 14.45min. Single peak in HPLC purity (AUC) 94%. Anal. Calcd.
for C14H12ClN3S3: C, 47.51; H, 3.42; N, 11.87. Found: C, 47.43; H, 3.40;
N, 11.66.

Synthesis of 5-Halo-substituted Thiophene Pyridyl Thiourea
2457
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(4-methylbenzothiazolyl)]thiourea
(2009). Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp.
1
175–1768C; H NMR (DMSO-d6) d 11.95 (bs, 1H), 10.20 (bs, 1H), 7.70–
7.68 (d, 1H, J ¼ 6.0 Hz), 7.19–7.11 (m, 2H), 6.92–6.91 (d, 1H,
J ¼ 3.0 Hz), 6.80–6.78 (d, 1H, J ¼ 6.0 Hz), 3.85 (q, 2H), 3.09 (t, 2H), 2.41
(s, 3H); 13C NMR (DMSO-d6) d 178.2, 159.9, 147.9, 140.8, 129.7, 129.2,
126.8, 126.7, 125.8, 125.6, 123.8, 119.0, 45.5, 28.9, 17.8; IR 3176, 3026,
2929, 2844, 1574, 1525, 1504, 1448, 1342, 1313, 1273, 1244, 1207, 1163,
1108, 1062, 991, 871, 802, 767, 744, 694, 621 cm21; UV l (MeOH), 203,
219, 248 nm; HPLC Rt: 21.4 min. Single peak in HPLC purity (AUC)
97.9%. Anal. Calcd. for C15H14ClN3S3: C, 48.97; H, 3.84; N, 11.42. Found:
C, 48.88; H, 3.80; N, 11.36.
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(6-methoxybenzothiazolyl)]thiourea
(2010). Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp.
1
209–2108C; H NMR (DMSO-d6) d 11.79 (bs, 1H), 10.21 (bs, 1H), 7.49
(m, 2H), 7.00–6.95 (m, 2H); 6.85–6.84 (d, 1H, J ¼ 3.0 Hz), 3.83–3.81
(m, 2H), 3.77 (s, 3H), 3.09 (t, 2H); 13C NMR (DMSO-d6) d 178.2, 159.1,
156.2, 142.7, 140.8, 131.1, 126.7, 125.9, 125.7, 120.4, 114.6, 105.5, 55.8,
45.8, 28.9; IR n 3184, 3049, 2993, 2942, 2825, 1604, 1572, 1533, 1462,
1437, 1348, 1303, 1265, 1194, 1093, 1055, 1029, 975, 923, 860, 818, 794,
725, 681 cm21; UV l (MeOH), 208, 222, 251 nm; HPLC Rt: 14.1 min. Single
peak in HPLC purity (AUC) 89.0%. Anal. Calcd. for C15H14ClN3S3O: C,
46.93; H, 3.68; N, 10.94. Found: C, 47.12; H, 3.57; N, 10.78.
N-[2-(5-Chlorothiophenethyl)]-N0-[2-(5-bromopyridyl)]thiourea (2011).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 163–1648C;
1H NMR (DMSO-d6) d 11.27–11.26 (d, 1H, J ¼ 3.0Hz); 10.75–10.72 (d, 1H,
J ¼ 6.0 Hz), 8.17–8.14 (m, 1H), 7.95–7.90 (m, 1H), 7.11–7.05 (m, 1H), 6.94–
6.90 (m, 1H), 6.82–6.78 (m, 1H), 3.79 (q, 2H), 3.07 (t, 2H); 13C NMR (DMSO-
d6) d 179.4, 152.3, 145.8, 141.5, 140.9, 126.7, 125.9, 125.8, 114.6, 112.1, 46.1,
29.1; IR n 3228, 3152, 3084, 3025, 2927, 1595, 1560, 1533, 1473, 1340, 1307,
1228, 1174, 1089, 1064, 988, 864, 821, 792, 696cm21; UV l (MeOH), 206, 258,
275 nm; HPLC Rt: 14.1 min. Single peak in HPLC purity (AUC) 94.1%: Anal.
Calcd. for C12H11ClN3S2Br: C, 38.26; H, 2.94; N, 11.15. Found: C, 37.81; H,
2.77; N, 11.46.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(5-bromopyridyl)]urea
(2012).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 157–
1588C; 1H NMR (DMSO-d6) d 9.34 (s, 1H,); 8.20–8.19 (d, 1H,
J ¼ 3.0 Hz), 7.86–7.83 (dd, 1H, J ¼ 6.0, 3.0 Hz), 7.73 (t, 1H), 7.46–7.43
(d, 1H, J ¼ 9 Hz), 7.16–7.14 (d, 1H, J ¼ 6.0 Hz), 6.64–6.63 (d, 1H,
J ¼ 3.0 Hz), 3.36–3.32 (m, 2H), 2.98–2.93 (t, 2H); 13C NMR (DMSO-d6) d
154.4, 152.3, 147.9, 147.3, 140.6, 136.7, 127.8, 113.5, 110.9, 73.3, 40.7,
30.3; UV l (MeOH), 205, 248, 298 nm; HPLC Rt: 11.1 min. Single peak in

2458
Venkatachalam and Uckun
HPLC purity (AUC) 95.0%. Anal. Calcd. for C12H11N3SOBr: C, 31.88; H,
2.45; N, 9.29. Found: C, 32.11; H, 2.42; N, 9.41.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(thiazolyl)]urea (2013). Column
chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 141–1428C; 1H
NMR (DMSO-d6) d 10.41 (bs, 1H); 8.20–8.19 (d, 1H, J ¼ 3.0 Hz), 7.28–
7.26 (m, 1H), 7.16–7.14 (d, 1H, J ¼ 6.0 Hz), 6.99–6.97 (d, 1H,
J ¼ 6.0 Hz), 6.64–6.59 (m, 2H), 3.37–3.31 (m, 2H), 2.97–2.93 (t, 2H); 13C
NMR (DMSO-d6) d 159.9, 153.8, 147.7, 137.3, 136.6, 127.7, 111.9, 73.3,
40.8, 30.2; IR: 3332, 3172, 3043, 2939, 2918, 1670, 1593, 1529, 1441,
1323, 1294, 1257, 1167, 1136, 1037, 947, 785, 714, 684 cm21; UV l
(MeOH), 202, 208, 258 nm; HPLC Rt: 4.4 min. Single peak in HPLC purity
(AUC) 99.0%. Anal. Calcd. for C10H10ION3S2: C, 31.67; H, 2.66; N, 11.08.
Found: C, 31.77; H, 2.64; N, 11.17.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(4-methylbenzothiazolyl)]thiourea
(2014). Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp.
1
202–2048C; H NMR (DMSO-d6) d 11.92 (bs, 1H); 10.19 (bs, 1H), 7.70–
7.67 (d, 1H, J ¼ 9.0 Hz), 7.20–7.12 (m, 3H), 6.67–6.66 (d, 1H,
J ¼ 3.0 Hz), 3.86–3.84 (m, 2H), 3.16–3.12 (t, 2H), 2.40 (s, 3H); 13C NMR
(DMSO-d6) d 178.2, 159.9, 147.4, 136.7, 129.3, 127.9, 126.9, 123.8, 119.1,
73.6, 45.7, 28.8, 17.9; UV l (MeOH), 205, 209, 249 nm; HPLC Rt:
23.5 min. Single peak in HPLC purity (AUC) 98.4%. Anal. Calcd. for
C15H14IN3S3: C, 39.22; H, 3.07; N, 9.15. Found: C, 39.32; H, 3.06;
N, 9.05.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(benzothiazolyl)]thiourea (2015).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 186–1878C;
1H NMR (DMSO-d6) d 11.92 (bs, 1H), 10.14 (bs, 1H), 7.88–7.86 (d, 1H,
J ¼ 6.0 Hz), 7.56–7.54 (d, 1H, J ¼ 6.0 Hz), 7.40–7.36 (t, 1H), 7.27–7.22
(t, 1H), 7.18–7.16 (d, 1H, J ¼ 6.0 Hz), 6.72–6.71 (d, 1H, J ¼ 3.0 Hz), 3.84–
3.79 (m, 2H), 3.17–3.13 (t, 2H); 13C NMR (DMSO-d6) d 178.3, 161.1,
147.3, 136.7, 129.8, 127.9, 127.5, 126.3, 123.7, 121.0, 119.6, 73.6, 45.8,
28.7; IR: 3448, 3178, 3037, 1568, 1525, 1456, 1441, 1431, 1257, 1205, 1165,
795, 754 cm21; UV l (MeOH), 205, 218, 289, 303 nm; HPLC Rt: 16.0min:
Single peak in HPLC purity (AUC) 98.7%. Anal. Calcd. for C14H12IN3S3: C,
37.76; H, 2.72; N, 9.44. Found: C, 37.92; H, 2.64; N, 9.18.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(4,6-dimethylpyridyl)]thiourea (2016).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 195–1968C;
1H NMR (DMSO-d6) d 11.98 (bs, 1H); 10.45 (bs, 1H), 7.14–7.12 (m, 1H),
6.72 (bs, 1H), 6.69 (bs, 1H), 6.68–6.66 (m, 1H), 3.89–3.84 (m, 2H), 3.15–3.10
(t, 2H), 2.18 (s, 6H); 13C NMR (DMSO-d6) d 179.7, 154.0, 153.3, 149.9, 147.9,
136.7, 127.8, 118.3, 109.4, 73.5, 45.7, 29.1, 23.4, 20.9; IR: 3217, 3043, 2916,
2870, 2847, 1616, 1541, 1460, 1336, 1313, 1265, 1203, 1112, 1029, 937, 833,
796, 725, 683 cm21; UV l (MeOH), 204, 264, 295 nm; HPLC Rt: 15.7 min. Single

Synthesis of 5-Halo-substituted Thiophene Pyridyl Thiourea
2459
peak in HPLC purity (AUC) 90.0%. Anal. Calcd. for C14H16IN3S2: C, 40.29; H,
3.86; N, 10.07. Found: C, 40.52; H, 3.88; N, 10.02.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(6-methylpyridyl)]thiourea (2017).
Column chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 160–1618C;
1H NMR (DMSO-d6) d 11.90–11.89 (d, 1H, J ¼ 3.0 Hz), 10.52–10.51 (d, 1H,
J ¼ 3.0 Hz), 7.63–7.56 (m, 1H), 7.15–7.12 (t, 1H), 6.92–6.90 (m, 1H), 6.86–
6.82 (m, 1H), 6.68–6.65 (m, 1H); 3.90–3.86 (q, 2H), 3.13–3.12 (t, 2H), 2.23
(s, 3H); 13C NMR (DMSO-d6) d 179.6, 154.5, 153.2, 147.9, 139.2, 136.7,
127.8, 117.0, 109.4, 73.5, 45.7, 29.1, 23.6; IR: 3224, 3195, 3122, 3043, 2912,
2871, 1612, 1570, 1537, 1450, 1378, 1315, 1228, 1205, 1186, 1159, 1145,
1083, 1030, 947, 898, 787 cm21; UV l (MeOH), 206, 261, 298nm; HPLC Rt:
11.6 min. Single peak in HPLC purity (AUC) 98.0%. Anal. Calcd. for
C13H14IN3S2: C, 38.72; H, 3.50; N, 10.42. Found: C, 39.15; H, 3.43; N, 10.60.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(pyridyl)]thiourea (2018). Column
chromatography (hexane/THF, 80 : 20), Xst EtOH: mp. 176–1788C; 1H
NMR (DMSO-d6) d 11.77–11.74 (m, 1H), 10.59 (bs, 1H), 8.07–8.05
(m, 1H), 7.76–7.69 (m, 1H), 7.17–7.15 (d, 1H, J ¼ 6.0 Hz), 7.13–7.10
(d, 1H, J ¼ 9.0 Hz), 6.98–7.02 (m, 1H), 6.69–6.68 (d, 1H, J ¼ 3.0 Hz),
3.84–3.78 (q, 2H), 3.16–3.11 (t, 2H), 13C NMR (DMSO-d6) d 179.6,
153.7, 147.6, 145.4, 139.0, 136.6, 128.0, 117.9, 112.7, 73.5, 46.1, 28.9; IR:
3230, 3041, 2933, 2908, 2872, 1591, 1566, 1533, 1477, 1429, 1331, 1305,
1236, 1186, 1146, 1091, 948, 804, 775 cm21; UV l (MeOH), 205, 262,
293 nm; HPLC Rt: 8.8 min. Single peak in HPLC purity (AUC) 97.0%.
Anal. Calcd. for C12H12IN3S2: C, 37.03; H, 3.11; N, 10.79. Found: C,
37.38; H, 3.09; N, 10.81.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(5-bromopyridyl)]thiourea (2019).
Column chromatography (hexane/THF, 80: 20), Xst EtOH: mp. 167–1688C;
1H NMR (DMSO-d6) d 11.29–11.27 (d, 1H, J ¼ 60 Hz), 10.75–10.74
(d, 1H, J ¼ 3.0 Hz), 8.17–8.14 (m, 1H), 7.98–7.92 (m, 1H), 7.19–7.16
(m, 1H), 7.13–7.08 (m, 1H), 6.71–6.68 (m, 1H), 3.84–3.79 (q, 2H), 3.16–
3.10 (m, 2H); 13C NMR (DMSO-d6) d 179.9, 152.9, 148.1, 146.4, 142.0,
137.3, 128.6, 115.2, 112.6, 74.2, 46.7, 29.3; IR: 3346, 3203, 3107, 3070,
3035, 2964, 2873, 2729, 1682, 1583, 1550, 1477, 1433, 1363, 1296, 1261,
1230, 1142, 1043, 1006, 954, 933, 908, 829, 798, 740, 700 cm21; UV l
(MeOH), 205, 265, 268, 306 nm; HPLC Rt: 15.1 min. Single peak in HPLC
purity (AUC) 98.8%. Anal. Calcd. for C12H11BrIN3S2: C, 30.79; H, 2.37;
N, 8.98. Found: C, 30.91; H, 2.28; N, 8.95.
N-[2-(5-Iodothiophenethyl)]-N0-[2-(5-chloropyridyl)]thiourea (2020).
Column chromatography (hexane/THF, 80: 20), Xst EtOH: mp. 154–1558C;
1H NMR (DMSO-d6) d 11.29–11.26 (t, 1H), 10.75 (bs, 1H), 8.08–8.06
(d, 1H, J ¼ 6.0 Hz), 7.85–7.81 (dd, 1H, J ¼ 9.0, 9.0 Hz), 7.16–7.13
(m, 2H), 6.69–6.68 (d, 1H, J ¼ 3.0 Hz), 3.84–3.78 (q, 2H), 3.15–3.10

2460
Venkatachalam and Uckun
(t, 2H); 13C NMR (DMSO-d6) d 179.3, 152.0, 147.5, 143.5, 138.8, 136.7,
127.9, 123.8, 114.1, 73.6, 46.1, 28.8; IR: 3207, 3149, 3076, 3035, 2945,
1594, 1550, 1525, 1466, 1427, 1301, 1228, 1190, 1134, 1109, 1099, 954,
823, 808, 744, 709 cm21; UV l (MeOH), 205, 265, 307 nm; HPLC Rt:
13.7 min. Single peak in HPLC purity (AUC) 99.6%. Anal. Calcd. for
C12H11Cl IN3S2: C, 34.02; H, 2.62; N, 9.92. Found: C, 34.10; H, 2.57; N, 9.83.
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 nitro-
1
gen atmosphere. H-, 13C NMR spectra were obtained on a 300 MHz Varian
Mercury 300 instrument at ambient temperature in DMSO-d6. Chemical shifts
are reported as d values in parts per million downfield from tetramethylsilane
(d ¼ 0.00 ppm) as an internal standard or from the residual dimethylsulfoxide
1
signal (d ¼ 2.49 ppm for H NMR or d ¼ 39.7 ppm for 13C NMR). Splitting
patterns are designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet;
br, broad peak. FT-IR spectra were recorded on a Nicolet Protege 460 spec-
trometer (KBr pellets). Mass spectra were performed on a Hewlett Packard
MALDI-TOF spectrometer (Model G2025A LD-TOF). Melting points were
determined using a Melt John’s apparatus and are uncorrected. HPLCs were
done using a Hewlett Packard 1100 series instrument consisting 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 RP-18 Lichrospher column, 5u (4.6 ꢀ 150 mm) and eluent
was 35 : 65, H2O (0.1% ACOH) : CH3CN. 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 chro-
matography was performed using silica gel obtained from the Baker Com-
pany. The solvents used for elution varied depending on the compound and
included either one or a combination of the following: ethylacetate, methanol,
chloroform, hexane, methylene chloride, THF, and ether.
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Synthesis of 5-Halo-substituted Thiophene Pyridyl Thiourea
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Received in the USA March 2, 2004