Synthesis of β-fluorophenethyl halopyridyl thiourea compounds as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Article abstract of DOI:10.1081/SCC-120039500

Synthesis of β-fluorophenethylamines was accomplished in three steps with an overall yield of 50%. Condensation of β-fluorophenethylamine hydrochloride with thiocarbonylimidazole derivative derived from halopyridyl amines in dimethylformamide furnished the desired thiourea compounds as crystalline solids. Several of the β-fluorophenethyl thiourea compounds inhibited HIV-1 reverse transcriptase (RT) at nanomolar to low micromolar concentrations.

Full text of DOI:10.1081/SCC-120039500

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Synthesis of
β‐Fluorophenethyl Halopyridyl
Thiourea Compounds as
Non‐nucleoside Inhibitors of
HIV‐1 Reverse Transcriptase
T. K. Venkatachalam a & F. M. Uckun M.D., Ph.D. b
c d e
a Department of Chemistry , Parker Hughes
Institute , Roseville, Minnesota, USA
b Drug Discovery Program , Parker Hughes
Institute , Roseville, Minnesota, USA
c Department of Virology , Parker Hughes
Institute , Roseville, Minnesota, USA
d Department of Immunology , Parker Hughes
Institute , Roseville, Minnesota, USA
e Drug Discovery Program , Parker Hughes Clinics ,
2699 Patton Road, St. Paul, MN, 55113, USA
Published online: 10 Jan 2011.
To cite this article: T. K. Venkatachalam & F. M. Uckun M.D., Ph.D. (2004) Synthesis
of β‐Fluorophenethyl Halopyridyl Thiourea Compounds as Non‐nucleoside Inhibitors
of HIV‐1 Reverse Transcriptase, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:13, 2463-2472, DOI:
10.1081/SCC-120039500

To link to this article: http://dx.doi.org/10.1081/SCC-120039500
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2463–2472, 2004
Synthesis of b-Fluorophenethyl Halopyridyl
Thiourea Compounds as Non-nucleoside
Inhibitors of HIV-1 Reverse
Transcriptase
T. K. Venkatachalam1 and F. M. Uckun2,3,4,
*
2
1Department of Chemistry, Drug Discovery Program,
4
3Department of Virology, and Department of Immunology,
Parker Hughes Institute, Roseville, Minnesota, USA
ABSTRACT
Synthesis of b-fluorophenethylamines was accomplished in three steps
with an overall yield of 50%. Condensation of b-fluorophenethylamine
hydrochloride with thiocarbonylimidazole derivative derived from halo-
pyridyl amines in dimethylformamide furnished the desired thiourea
compounds as crystalline solids. Several of the b-fluorophenethyl thiourea
compounds inhibited HIV-1 reverse transcriptase (RT) at nanomolar to low
micromolar concentrations.
*
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.
2463
DOI: 10.1081/SCC-120039500
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2464
Venkatachalam and Uckun
Key Words: b-Fluorophenethylamines; Thiourea; HIV-1; Reverse tran-
scriptase.
INTRODUCTION
Several thiourea compounds has been found to inhibit HIV reverse
transcriptase (RT).[1–6] In a systematic search for non-nucleoside inhibitors
of HIV RT, we prepared 30 b-fluorophenethyl halopyridyl thiourea
compounds.
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 nitrogen atmosphere. 1H and 13C NMR spectra were obtained on
a 300 MHz Varian Mercury 300 instrument at ambient temperature in
either CDCl3 or DMSO-d6. Chemical shifts are reported as d values in
parts per million downfield from tetramethylsilane (d ¼ 0.0 ppm) as an
internal standard in the case of CDCl3 or from the residual dimethylsufloxide
1
signal (d ¼ 2.49ppm for H NMR or d ¼ 39.7ppm for 13C NMR). 19F NMR
spectra were obtained using either of the above solvents and a capillary
containing 0.1% trifluoroacetic acid in water which served as internal
standard. Chemical shifts for fluorine NMR are based on the trifluoroacetic
acid signal referenced at 0.0 ppm. 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 spectrometer
(KBr pellet). 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.
HPLC was done using
a Hewlett–Packard 1100 series instrument
consisting of an automatic sampler, an 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 the eluent was 35: 65, H2O (0.1%
ACOH): acetonitrile. 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 varied depending on the

b-Fluorophenylethyl Halopyridyl Thiourea Compounds
2465
compound and included either one or a combination of the following:
ethylacetate, methanol, chloroform, hexane, methylene chloride, tetrahydrofuran
(THF), and ether.
RESULTS AND DISCUSSION
The thiourea compounds were prepared by condensing b-fluorophenethyl-
amines and thiocarbonylimidazole derivatives of 5- or 6-substituted amino
pyridines in anhydrous dimethylformamide (Sch. 1). Substituted b-fluoro-
phenethylamines were synthesized using the procedure described here.
The amines were used as hydrochloride salt. Thiazolyl- and benzothiazolyl-
substituted thioureas were prepared in a similar fashion using thiocarba-
imidazole derivatives derived from either substituted amino thiazoles or
benzothiazoles, respectively.
Scheme 1. Synthetic scheme.

2466
Venkatachalam and Uckun
General Example for the Preparation of 2-Fluoro-Substituted
Phenethylamines
Preparation of 2-fluoro-2-arylacetonitrile (1). Anhydrous ZnI2 (40 mg)
was placed in a 250 mL three-necked round-bottomed flask fitted with a
60 mL addition funnel under nitrogen atmosphere. Using a syringe, an aryl
aldehyde (0.080 mol) was added and the contents were stirred at room
temperature. In the case of solid aryl aldehydes, 5–10 mL of anhydrous
methylene chloride was used to form a homogenous mixture. The mixture
was cooled to 08C using an ice bath and trimethylsilylcyanide (10.67 mL,
0.080 mol) was added to the vigorously stirred reaction mixture. After
addition, the ice bath was removed and the reaction mixture was allowed to
stir at room temperature for 18 hr. After the reaction, CH2Cl2 (100 mL) was
added and the mixture cooled to 08C. In the meantime, the additional funnel
was charged with a solution of diethylamino sulfurtrifluoride (11.63 mL,
0.088 mol) in CH2Cl2 (40 mL). This solution was added dropwise to the
stirring mixture. Upon completion of addition, the ice bath was removed
and the reaction was allowed to warm to room temperature overnight, poured
into ice water (500 mL), and the organic layer was separated from the aqueous
layer. The organic layer was sequentially washed with water (250 mL), 0.5 N
HCl (250 mL), water (250 mL), sat. NaHCO3 (250 mL), and water (250 mL).
The organic layer was dried over anhydrous MgSO4, filtered, and concentrated
using a rotary evaporator to yield a viscous liquid. This product was further
purified by column chromatography, using solvent mixture consisting of 7%
ethylacetate and 93% hexane as eluent.
Preparation of 2-fluoro-2-arylethylamine hydrochloride (2). A round-
bottomed flask was charged with one-equivalent of 2-fluoro-2-arylacetonitrile
and anhydrous THF (50 mL) and cooled to 08C. Using a dry syringe, two
equivalents of 1.0 M borane–THF solution was added and the reaction was
allowed to stir overnight. The reaction was quenched using ethanol and acidified
with ethanolic HCl. Rotary evaporation of the solvent under vacuum furnished
the required hydrochloride.
Preparation of b-fluorophenethyl thioureas (4). Based on previously
published synthetic procedures[1,4,5] the synthesis of the thiourea compounds
(Table 1) was accomplished as shown in the scheme using one equivalent of
both the thiocabonylimidazole derivatives (3) derived from the respective
amino heterocyles and b-fluorophenylethylamine hydrochloride salt in DMF.
Anhydrous potassium carbonate (30–40 mg) was added to the mixture. The
contents was sitrred and heated to 1008C over an oil bath for 15–20 hr. The
solution was cooled and poured into ice water. The precipitated product was
filtered, washed with water, and dried. The product was then redissolved
in chloroform, transferred into a separatory funnel, and washed thoroughly

b-Fluorophenylethyl Halopyridyl Thiourea Compounds
2467
Table 1. Chemical properties of b-fluorophenylethyl thiourea derivatives.
Compound no.
X
R
Mp (8C)
565
566
H
H
5-Bromopyridyl
5-Chloropyridyl
4-Methylbenzothiazolyl
5-Methylpyridyl
Pyridyl
185–186
183–184
198–199
142–144
158–160
195–196
188–189
126–128
159–160
175–177
156–157
148–150
111–112
137–138
172–173
149–150
150–151
165–166
171–172
189–190
159–160
185–186
144–145
141–142
170–171
191–192
119–120
168–169
143–145
136–137
1,054
1,063
1,072
1,089
1,090
1,091
1,092
1,093
1,096
1,122
1,123
1,125
1,126
1,127
1,128
1,129
1,174
1,175
1,176
1,177
1,178
1,179
1,180
1,181
1,182
1,184
1,185
1,188
3-F
3-F
3-F
3-F
6-Chlorobenzothiazolyl
6-Methoxybenzothiazolyl
4-Methyleneethoxythiazolyl
Thiazolyl
3-F
3-F
3-F
3-F
6-Flurobenzothiazolyl
4,6-Dimethylpyridyl
5-Bromopyridyl
4-Methylenethoxythiazolyl
Thiazolyl
3-F
4-Br
4-Br
4-Br
4-Br
4-Br
H
5,6-Dimethylbenzothiazolyl
Pyridyl
3,4-Dimebenzothiazolyl
6-Methoxybenzothiazolyl
6-Methylpyridyl
5-Methylpyridyl
Benzothiazolyl
4-Br
2-Br
3-F
4-Cl
4-Cl
2-Cl
3-Cl
3-Cl
2-Cl
3-Cl
4-Br
3-Cl
H
5-Methylpyridyl
Thiazolyl
Thiazolyl
5-Bromopyridyl
4-Methylbenzothiazolyl
5-Methylpyridyl
5-Chloropyridyl
5-Chloropyridyl
Pyridyl
with brine and water. The organic layer was separated and dried over anhydrous
MgSO4. Filtration and rotary evaporation of the solvent under vacuum furnished
a residue which was column chromatographed using slica gel and solvent mix-
ture consisting of 20% THF and 80% hexane as eluent. The compounds were
finally recrystallized from ethanol to give thioureas as cyrstalline solids. The
purity of the compounds was determined using various analytical techniques.

2468
Venkatachalam and Uckun
Physical Constants of Selected Thiourea Derivatives
DDE 565. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
mp. 185–1868C, 1H NMR (CDCl3): 11.63 (bs, 1H), 8.76 (bs, 1H), 8.24–8.23
(m, 1H), 7.76–7.46 (m, 1H), 7.44–7.40 (m, 5H), 6.73–6.70 (m, 1H), 5.94–
5.91 (m, 1/2H), 5.78–5.74 (m, 1/2H), 4.57–4.40 (m, 1H), 3.98–3.84
(m, 1H), 13C NMR (CDCl3): 179.9, 151.3, 146.7, 141.3, 137.1, 136.9, 128.8,
128.7, 128.5, 125.4, 125.3, 113.2, 113.1, 93.2, 90.9, 51.6, 51.3; IR n: 3219,
3161, 3087, 3030, 2924, 1602, 1560, 1533, 1479, 1458, 1340, 1307, 1232,
1178, 1137, 1111, 1012, 916, 855, 868, 825, 758, 700 cm21; MALDI-TOF
m/z: 356 (M þ 2); Anal. calcd. for: C14H13N3SFBr: C, 47.46; H, 3.67; N,
11.86. Found: C, 47.75; H, 3.66; N, 11.50.
DDE 566. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
mp. 183–1848C, 1H NMR (CDCl3): 11.63 (bs, 1H), 8.76 (bs, 1H), 8.24–8.23
(m, 1H), 7.76–7.46 (m, 1H), 7.44–7.40 (m, 5H), 6.73–6.70 (m, 1H), 5.94–
5.91 (m, 1/2H), 5.78–5.74 (m, 1/2H), 4.57–4.39 (m, 1H), 3.98–3.84
(m, 1H); 13C NMR (CDCl3): 179.9, 151.5, 146.6, 141.3, 137.1, 136.9, 128.7,
128.5, 125.4, 125.3, 113.5, 113.0, 93.1, 90.8, 51.5, 51.1; IR n: 3224, 3157,
3024, 2925, 2858, 2742, 1822, 1595, 1537, 1477, 1340, 1306, 1197, 1178,
1140, 1093, 1070, 1014, 918, 885, 823, 758, 700 cm21; UV (MeOH): 251,
267 nm, MALDI-TOF m/z: 311.8 (M þ 2) Anal. calcd. for: C14H13N3SFCl:
C, 54.19; H, 4.19; N, 13.54. Found: C, 49.97; H, 4.58; N, 21.15.
DDE 1063. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
1
mp. 142–1448C; H NMR (DMSO-d6) d 11.89 (t, 1H), 10.67 (s, 1H), 7.94
(s, 1H), 7.57 (dd, 1H, J ¼ 2.1, 8.7 Hz), 7.47 (q, 1H), 7.28 (d, 1H, J ¼ 8.4 Hz),
7.21 (t, 1H), 7.06 (d, 1H, J ¼ 8.4 Hz), 5.99 (dd, 1/2H, J ¼ 3.3, 7.2 Hz), 5.83
(dd, 1/2H, J ¼ 3.0, 6.6 Hz), 4.21 (m, 1H), 7.03 (m, 1H), 2.18 (s, 1H); 13C
NMR (DMSO-d6) d 180.1, 163.7, 160.5, 151.7, 144.7, 140.3, 140.1 (d), 139.8
(d), 130.7 (d), 127.1, 121.8 (t), 115.6 (d), 112.6 (m), 92.4, 90.1, 50.0, 49.7,
17.4; IR n: 3222, 3174, 3020, 2935, 1592, 1556, 1492, 1446, 1342, 1234,
11914, 1029 cm21; MALDI-TOF m/z: 309.5 (C15H15F2N3S þ 2Hþ); HPLC
Rt: 7.66min. Single peak in HPLC (AUC) purity 99.5%. Anal. calcd. for:
C15H15N3SF2: C, 58.62; H, 4.92; N, 13.67. Found: C, 58.73; H, 4.93; N, 13.61.
DDE 1072. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
1
mp. 158–1608C; H NMR (DMSO-d6) d 11.96 (t, 1H), 10.76 (s, 1H), 8.11
(d, 1H, J ¼ 5.1 Hz), 7.75 (m, 1H), 7.47 (q, 1H), 7.29 (d, 2H, J ¼ 8.4 Hz),
7.22 (d, 1H, J ¼ 9.0 Hz), 7.16 (d, 1H, J ¼ 8.7 Hz), 7.01 (m, 1H), 6.01
(d, 1/2H, J ¼ 5.7 Hz), 5.85 (d, 1/2H, J ¼ 5.4 Hz), 4.26 (m, 1H), 4.03 (m, 1H);
13C NMR (DMSO-d6) d 180.3, 163.7, 160.5, 153.6, 145.4, 140.0 (q), 139.1,
130.8 (d), 121.8 (q), 118.1, 115.6 (d), 112.6 (q), 92.3, 90.0, 50.0 (d); 19F
NMR (DMSO-d6) d 236.5 (t), 2105.9 (m); IR n: 3455, 3239, 3110, 2987,
1604, 1560, 1537, 1481, 1269, 1186, 784 cm21; MALDI-TOF m/z 292.3

b-Fluorophenylethyl Halopyridyl Thiourea Compounds
2469
(C14H13F2N3S 2 Hþ); HPLC Rt: 6.01min. Single peak in HPLC (AUC) purity
98.4%. Anal. calcd. for C14H13N3SF2: C, 57.33; H, 4.47; N, 14.33. Found: C,
57.43; H, 4.44; N, 14.32.
DDE 1092. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
1
mp. 159–1608C; H NMR (DMSO-d6) d 11.79 (s, 1H), 9.94 (s, 1H), 7.47
(q, 1H), 7.38 (d, 1H, J ¼ 3.6 Hz), 7.27 (d, 2H, J ¼ 7.8 Hz), 7.21 (t, 1H),
7.10 (d, 1H, J ¼ 3.0 Hz), 5.96 (dd, 1/2H, J ¼ 2.7, 7.5 Hz), 5.79 (dd, 1/2H,
J ¼ 3.0, 7.5 Hz), 4.24–3.91 (m, 2H); 13C NMR (DMSO-d6) d 178.9, 163.7,
161.9, 160.5, 139.9 (dd), 136.4, 130.8 (d), 121.9 (dd), 115.6 (d), 112.7 (dd),
112.3, 92.4, 90.1, 49.5; IR n: 3417, 3185, 3041, 2935, 1583, 1513, 1450,
1346, 1276, 1184, 1141, 1033, 688 cm21; HPLC Rt: 5.20 min. Single peak
in HPLC (AUC) purity 99.2%. Anal. calcd. for C12H11N3S2F2: C, 48.15; H,
3.70; N, 14.04. Found: C, 48.35; H, 3.81; N, 13.89.
DDE 1093. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
1
mp. 175–1778C; H NMR (DMSO-d6) d 12.01 (s, 1H), 9.95 (s, 1H), 7.80
(d, 1H, J ¼ 9.0 Hz), 7.57 (q, 2H), 7.47 (q, 1H), 7.29 (d, 2H, J ¼ 8.1 Hz),
7.22 (d, 1H, J ¼ 8.7 Hz), 5.99 (d, 1/2H, J ¼ 4.2 Hz), 5.83 (d, 1/2H,
J ¼ 4.2 Hz), 4.09 (m, 2H); 13C NMR (DMSO-d6) d; IR n: 471, 3178, 3043,
2939, 1560, 1537, 1454, 1270, 1201, 1139, 865 cm21; HPLC Rt: 10.52 min.
Main peak in HPLC (AUC) purity 90.1%, isomer shoulder peak (AUC)
8.0% Anal. calcd. for C16H12N3S2F3: C, 52.31; H, 3.29; N, 11.44. Found:
C, 52.69; H, 3.28; N, 11.42.
DDE 1122. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
1
mp. 148–1508C; H NMR (DMSO-d6) d 11.44 (t, 1H), 10.89 (s, 1H), 8.23
(t, 1H), 7.97 (m, 1H), 7.62 (d, 2H, J ¼ 7.5 Hz), 7.39 (d, 2H, J ¼ 8.1 Hz), 7.13
(dd, 1H, J ¼ 0.9, 9.0 Hz), 5.97 (dd, 1/2H, J ¼ 2.7, 7.25Hz), 5.81 (dd, 1/2H,
J ¼ 2.4, 7.2 Hz), 4.20 (m, 1H), 4.03 (m, 1H); 13C NMR (DMSO-d6) d 179.9,
152.2, 145.9, 141.6, 136.6 (d), 131.6, 127.8 m(d), 122.0, 114.7, 112.36, 92.4,
90.1, 50.1, 49.8; 19F NMR (DMSO-d6) d -105.6 (7); IR n: 3448, 3224, 3022,
2925, 1592, 1564, 1529, 1340, 1305, 1180 cm21; MALDI-TOF m/z 457.6
(C14H12Br2FN3S þ Na þ Hþ); HPLC Rt: 14.37 min. Main peak in HPLC (AUC)
purity 86.8%, isomer peak (AUC) 12.8%. Anal. calcd. for C14H12N3SFBr2: C,
38.82; H, 2.79; N, 9.70. Found: C, 38.21; H, 2.69; N, 10.23.
DDE 1127. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
1
mp. 149–1508C; H NMR (DMSO-d6) d 11.95 (t, 1H), 10.76 (s, 1H), 8.13
(d, 1H, J ¼ 5.1 Hz), 7.76 (m, 1H), 7.63 (d, 2H, J ¼ 8.4 Hz), 7.41 (d, 2H,
J ¼ 8.4 Hz), 7.15 (d, 1H, J ¼ 8.1 Hz), 7.03 (q, 1H), 5.98 (dd, 1/2H, J ¼ 3.0,
6.9 Hz), 5.82 (dd, 1/2H, J ¼ 3.0, 6.9 Hz), 4.22 (m, 1H), 4.02 (m, 1H);
13CNMR (DMSO-d6) d 180.2, 153.6, 145.4, 139.1, 136.7 (d), 131.6, 127.9
(d), 122.0, 118.1, 112.7, 92.5, 90.2, 49.9 (d); 19F NMR (DMSO-d6) d 2105.4
(7); IR n: 3423, 3234, 3010, 2929, 1604, 1538, 1479, 1319, 1180, 1031,
773 cm21; MALDI-TOF m/z 397.3 (C14H13BrFN3S þ K þ Na 2 Hþ); HPLC

2470
Venkatachalam and Uckun
Rt: 8.54min. Single peak in HPLC (AUC) purity 98.8%. Anal. calcd. for
C14H13N3SFBr: C, 47.47; H, 3.70; N, 11.86. Found: C, 47.57; H, 3.77; N, 11.73.
DDE 1174. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
1
mp. 171–1728C; H NMR(DMSO-d6) d 12.29 (m, 1H), 10.67 (s, 1H), 7.71
(m, 1H), 7.64–7.63 (m, 1H), 7.61–7.56 (m, 1H), 7.45 (t, 1H), 7.32 (t, 1H),
7.02–6.99 (d, 1H, J ¼ 9.0 Hz), 6.95–6.87 (m, 1H), 6.10–6.07 (m, 1/2H),
5.94–5.91 (m, 1/2H), 4.34–4.08(m, 2H), 2.31 (s, 3H); 13C NMR (DMSO-
d6) d 180.3, 176.7, 154.3, 153.2, 139.4, 136.1, 135.8, 132.9, 131.0, 128.2,
127.9, 127.8, 121.3, 117.2, 109.5, 92.2, 89.9, 48.2, 47.9, 23.8, 23.7; IR n:
3227, 3198, 3048, 3029, 1613, 1595, 1561, 1538, 1471, 1449, 1380, 1334,
1311, 1227, 1198, 1162, 1153, 785, 755 cm21; UV (MeOH): 204, 248, 266,
301 nm; HPLC Rt: 9.32 min. Main peak in HPLC (AUC) purity 97.0%, isomer
peak HPLC (AUC) purity 1.7%. Anal. calcd. for C14H12N3SFBr2: C, 48.92; H,
4.11; N, 11.41. Found: C, 53.79; H, 4.54; N, 11.50.
DDE 1177. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
mp. 185–1868C; 1H NMR (DMSO-d6) d 11.88 (bs, 1H), 10.66 (bs, 1H), 7.95–
7.94 (d, 1H, J ¼ 3.0 Hz), 7.61–7.58 (dd, 1H, J ¼ 8.0, 9.0 Hz), 7.57–7.47
(m, 4H), 7.08–7.05 (d, 1H, J ¼ 9.0 Hz), 5.99–5.96 (m, 1/2H), 5.83–5.80
(m, 1/2H), 4.28–3.93 (m, 2H), 2.20 (s, 3H); 13C NMR (DMSO-d6) d 180.0,
151.7, 144.7, 139.9, 136.4, 136.2, 133.4, 128.7, 127.7, 127.6, 127.1, 112.3,
92.5, 90.2, 50.0, 49.7, 17.5; IR n: 3229, 3176, 3019, 2939, 1611, 1596,
1550, 1533, 1341, 1309, 1255, 1235, 1186, 1178, 1092, 1029, 1014,
824 cm21; UV (MeOH): 203, 207, 247, 270 nm; HPLC Rt: 9.38 min. Single
peak in HPLC (AUC) purity 97.8% Anal. calcd. for C15H15N3SFCl: C,
55.64; H, 4.67; N, 12.98. Found: C, 55.77; H, 4.75; N, 12.92.
DDE 1180. Column chromatography (hexane/THF, 80 : 20), Xst EtOH;
1
mp. 170–1718C, H NMR (DMSO-d6) d 11.44 (m, 1H), 10.88 (m, 1H)
8.23–8.19 (m, 1H), 7.98–7.91 (m, 2H), 7.48–7.39 (m, 3H), 7.15–7.10
(m, 1H), 6.01–5.98 (m, 1/2H), 5.85–5.82 (m, 1/2H), 4.27–3.98 (m, 2H);
13C NMR (DMSO-d6) d 180.1, 152.3, 145.9, 141.6, 139.9, 139.6, 133.0,
130.7, 128.8, 125.7, 125.6, 124.4, 124.3, 114.8, 112.4, 92.3, 89.9, 50.3,
49.9; IR n: 3236, 3156, 3086, 3037, 2943, 1592, 1498, 1476, 1469, 1431,
1389, 1311, 1227, 1183, 1030, 827, 709 cm21; UV (MeOH): 205, 255, 276,
306 nm; MALDI-TOF m/z: 389.1 (M þ 1); HPLC Rt: 11.6 min. Single peak
in HPLC (AUC) purity 97.5% Anal. calcd. for C14H12N3SFBr Cl: C, 43.26;
H, 3.11; N, 10.81. Found: C, 42.88; H, 3.07; N, 10.89.
DDE 1182. Column chromatography (hexane/THF, 80: 20), Xst EtOH;
1
mp. 119–1208C; H NMR (DMSO-d6) d 11.88 (m, 1H), 10.65 (bs, 1H), 7.94
(s, 1H), 7.60–7.59 (d, 1H, J ¼ 3.0 Hz), 7.49 (s, 1H), 7.45–7.42 (m, 3H),
7.07–7.04 (d, 1H, J ¼ 9.0 Hz), 6.02–5.97 (m, 1/2H), 5.84–5.81 (m, 1/2H),
4.30–3.95 (m, 2H), 2.19 (s, 3H); 13C NMR (DMSO-d6) d 180.1, 151.7,
144.8, 139.7, 139.5, 133.4, 130.7, 128.8, 127.3, 125.7, 125.6, 124.5, 124.4,

b-Fluorophenylethyl Halopyridyl Thiourea Compounds
2471
112.4, 92.4, 90.2, 50.2, 49.9, 17.5; IR n: 3424, 3287, 3172, 3099, 3033, 3013,
2966, 2933, 1613, 1592, 1563, 1534, 1491, 1431, 1345, 1314, 1238, 1223,
1185, 1028, 833, 776, 689, 678 cm21; UV (MeOH): 209, 246, 270, 299 nm;
MALDI-TOF m/z: 325.9 (M þ 2); HPLC Rt: 9.17min. Single peak in HPLC
(AUC) purity 98.0%. Anal. calcd. for C15H15N3SFCl: C, 55.64; H, 4.67; N,
12.98. Found: C, 55.88; H, 4.63; N, 13.13.
CONCLUSIONS
Novel b-fluorophenethyl thiazolyl as well as halopyridyl thioureas were
synthesized as NNRTI candidates. Synthesis of b-fluorophenethylamines
was accomplished in three steps with an overall yield of 50%. Further conden-
sation with thiocarbonylimidazole derivative derived from halopyridyl- or
thiazolyl-substituted amines in dimethylformamide gave the desired thiourea
compounds. The unsubstituted phenyl group compounds exhibited potent
anti-HIV activity. Our lead compounds HI-565 (b-fluoro[2-phenethyl]-N0-
[2-(5-bromopyridyl)]-thiourea and HI-566 (b-fluoro[2-phenethyl]-N0-[2-(5-
chloropyridyl)]-thiourea were more potent inhibitors of HIV replication in
peripheral blood mononuclear cells than several of the known compounds
in the literature.
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Received in the USA March 2, 2004