Regiospecific synthesis, X-ray crystal structure and biological activities of 5-bromothiophenethyl thioureas

Article abstract of DOI:10.1016/S0040-4039(01)01290-4

The regiospecific synthesis of 5-bromothiophenethyl thioureas was accomplished in four steps with an overall yield of 40-60%. The requisite regioselectivity for bromination of the thiophene ring was achieved using bromine in acetic acid at low temperatures. The resulting 5-bromothiophenethylamine hydrobromide is an important precursor for the preparation of substituted thioureas. The X-ray crystal structure demonstrates that the bromine atom is indeed located at the 5-position of the thiophene ring.

Full text of DOI:10.1016/S0040-4039(01)01290-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6629–6632
Regiospecific synthesis, X-ray crystal structure and biological
activities of 5-bromothiophenethyl thioureas
Taracad K. Venkatachalam, Elise A. Sudbeck and Fatih M. Uckun*
Departments of Chemistry, Structural Biology and Virology, Parker Hughes Institute, 2665 Long Lake Road, Roseville,
MN 55113, USA
Received 18 June 2001; accepted 10 July 2001
Abstract—The regiospecific synthesis of 5-bromothiophenethyl thioureas was accomplished in four steps with an overall yield of
40–60%. The requisite regioselectivity for bromination of the thiophene ring was achieved using bromine in acetic acid at low
temperatures. The resulting 5-bromothiophenethylamine hydrobromide is an important precursor for the preparation of
substituted thioureas. The X-ray crystal structure demonstrates that the bromine atom is indeed located at the 5-position of the
thiophene ring. © 2001 Elsevier Science Ltd. All rights reserved.
The potent anti-HIV activities displayed by several
thiourea derivatives has led to comprehensive efforts in
preparing and evaluating the biological activities of
many other substituted thioureas. Since the first class of
phenethyl thiazolyl thioureas was reported in 1995,1,2
several new derivatives have been synthesized and
proven to be effective anti-HIV agents.3–6 We have
the thiophene ring, however. We describe here a
method for regioselectively brominating the thiophene
ring.
Commercially available 2-thiophenethylamine was pro-
tected using a tboc group. Subsequent reaction with
bromine in acetic acid at 0°C yielded 5-bromothio-
phenethylamine hydrobromide in a regiospecific fashion
(Scheme 1). Alternatively, we can use the hydrochloride
or bromide salt of thiophenethylamine as starting mate-
rial. Condensation with a thiocarbaimidazole derivative
of a pyridyl-substituted amine generated the final
product (Scheme 1). Purification was achieved by
column chromatography and recrystallization from
ethanol.
previously
reported7
that
thiophene-substituted
thioureas inhibit both wild-type and multidrug-resistant
strains of HIV. To explore the structure–activity rela-
tionships of thiophene-substituted thioureas, the effects
of substituents on the thiophene ring on the anti-HIV
activities of the thioureas must be examined. The lack
of commercially available precursors requires the devel-
opment of new synthetic approaches for functionalizing
Scheme 1. Synthesis of 5-bromothiophenethyl thioureas. (a) CHCl3, (BOC)2O, reflux, 6 h; (b) AcOH, 0°C, Br2/AcOH, rt,
overnight; (c) 1,1%-thiocarbonyldiimidazole, ACN, rt, 12 h; (d) K2CO3, DMF, 100°C, 15 h.
Keywords: HIV; reverse transcriptase; non-nucleoside inhibitor; thiophene thiourea.
* Corresponding author. Tel.: (651) 697-9228; fax: (651) 697-1042; e-mail: fatih uckun@ih.org
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01290-4

6630
T. K. Venkatachalam et al. / Tetrahedron Letters 42 (2001) 6629–6632
Of the eleven 5-bromothiophenethyl thioureas studied,
six exhibited significant anti-HIV activity (nanomolar
to micromolar IC50 values against recombinant reverse
transcriptase; Table 1). Two of the compounds were
Electrophilic substitution on thiophene generally occurs
at the 2- and 5-positions since the allylic cation interme-
diate can be stabilized by charge delocalization. Substi-
tution at the 3- or 4-position would lead to a much less
stable intermediate. Accordingly, bromination of thio-
phene yields 2-bromothiophene and 2,5-dibromothio-
phene as the major products.8–10 Thus, the
regioselective bromination of 2-ethylaminothiophene at
the 5-position was expected since the 2-position is
already occupied.
Table 2. X-Ray crystal structure data and refinement
statistics for DDE935. Data collected at room temperature
,
(u=0.71073 A), refined using full-matrix least-squares
refinement on F2, and corrected for absorption using mul-
tiscan data (see text)
The regioselectivity of the reaction was confirmed by
X-ray crystallography. Crystals of DDE 935 (N-[2-(5-
Unit cell
,
a (A)
8.3549(4)
8.7416(4)
10.9337(5)
78.7300(10)
86.0410(10)
61.9620(10)
bromo-2-thienyl)ethyl]-N%-[2-(pyridyl)]thiourea)
were
,
b (A)
grown from dichloromethane by slow evaporation at
room temperature. A crystal was mounted on a glass
fiber using epoxy and X-ray diffraction data for a
0.25×0.25×0.02 mm crystal were collected at room tem-
perature using a SMART 1K CCD X-ray detector
(Bruker Analytical X-ray Systems, Madison, WI).
Structure solution and refinement was performed using
the SHELXTL suite of programs.11 X-Ray crystal
structure data and refinement statistics for DDE 935
are listed in Table 2. The refined small molecule X-ray
crystal structure of DDE 935 is shown in Fig. 1 and
atomic coordinates are listed in Table 3. All non-hydro-
gen atoms were refined using anisotropic displacement
parameters. Hydrogen atoms were placed at ideal posi-
tions and refined as riding atoms with relative isotropic
displacement parameters except for H1 and H3 (Fig. 1),
which were located in the electron density difference
map and refined isotropically. The crystal structure
clearly indicated the presence of a bromine atom on the
C5 carbon of the thiophene ring. No evidence for a
bromine atom on the C3 or C4 carbons of the thio-
phene ring was observed in the crystal structure.
,
c (A)
h (°)
i (°)
k (°)
(
Space group
Unit cell volume (A )
Z
q Range for data collection (°)
Limiting indices (°)
P1
3
,
690.99(6)
2
1.90–28.27
−115h510
−115k511
−145l513
8240
3209 (Rint=0.031)
3209/0/171
1.046
R1=0.038, wR2=0.10
R1=0.052, wR2=0.11
3.261
0.9376, 0.4961
1.01, −0.53
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I\2|(I)]
R indices (all data)
Absorption coefficient (mm−1
Max. and min. transmission
Largest difference peaks (e A
)
−3
,
)
2
2
R
int=ꢀꢁFo2−ŽFo ꢁ/ꢀꢁFo ꢁ, R1=ꢀꢁꢁFoꢁ−ꢁFcꢁꢁ/ꢀꢁFoꢁ.
wR2={ꢀ[w(Fo2−Fc2)2]/ꢀ[w(Fo2)2]}1/2
.
GooF=S={ꢀ[w(Fo2−Fc2)2]/(n−p)}1/2, where n=reflections and p=
parameters.
Table 1. Anti-HIV activity of nine 5-bromothiophenethyl thioureas
Compound no.
X
Y
Z
IC50 rRT (mM)
IC50 HTLVIIIB (mM)
DDE 933
DDE 934
DDE 935
DDE 946
DDE 949
DDE 950
DDE 951
DDE 954
DDE 1009
Delavirdine
Nevirapine
5-Me
Cl
H
NA
NA
NA
NA
NA
NA
H
NA
Me
NA
NA
NA
NA
NA
NA
NA
NA
NA
H
0.60
0.10
1.24
0.92
12.5
0.16
0.012
0.015
0.05
0.24
ND
0.31
ND
ND
Br
6-Me
4,6-Me
NA
NA
NA
NA
NA
\100
10.0
\100
4.3
NA
NA
NA
NA
NA
0.01
0.04
NA, not applicable; ND, not determined.

T. K. Venkatachalam et al. / Tetrahedron Letters 42 (2001) 6629–6632
6631
DDE 934 was the most potent anti-HIV agent. In
addition, DDE934 was three times more potent than
Nevirapine (Table 1).
In summary, 5-bromothiophenethyl thioureas were syn-
thesized from the commercially available 2-thio-
phenethylamine in four simple steps with an overall
yield of 50%. Regioselective bromination at the 5-posi-
tion of the thiophene ring was accomplished using
acetic acid and bromine at low temperatures and was
verified by X-ray crystallography. The intermediate 5-
bromothiophenethylamine hydrobromide may be a use-
ful building block in the preparation of a variety of
biologically active compounds. The presence of a halo-
gen atom may also facilitate the synthesis of thio-
phenethyl thioureas substituted with other functional
groups.
Figure 1. X-Ray crystal structure of DDE 935, which clearly
shows the bromine atom present at the C5-position of the
thiophene ring (30% ellipsoids, room temperature data).
Physical constants:
Table 3. Atomic coordinates (×104) and equivalent
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(5-methylpyridyl)]-
thiourea (DDE 933). Mp 159–160°C; 1H NMR
(DMSO-d6) l 11.70 (t, 1H), 10.53 (s, 1H), 7.90 (s, 1H),
7.57 (d, 1H, J=8.1 Hz), 7.06 (s, 1H), 7.03 (s, 1H), 6.79
(d, 1H, J=3.0 Hz), 3.82 (q, 2H), 3.10 (t, 2H), 2.18 (s,
3H); 13C NMR (DMSO-d6) l 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 w 3563, 3220, 3035, 2935, 1608, 1565, 1535, 1488,
1330, 1188 cm−1; MALDI-TOF m/z 357.5
(C13H14BrN3S2+2H+); HPLC Rt: 12.42 min.
3
,
isotropic displacement parameters (A×10 ) for DDE 935
based on the X-ray crystal structure at room temperature.
U(eq) is defined as one-third of the trace of the orthogo-
nalized Uij tensor
Atom
x
Y
z
U(eq)
Br1
S1
S2
C10
N3
C12
N4
N1
C2
C14
C6
C4
C5
C13
C8
C9
C7
C11
H1
H3
440(1)
1514(1)
9142(1)
3268(1)
5780(4)
5663(3)
4731(5)
4143(3)
7193(3)
7198(3)
2804(4)
2693(4)
5457(4)
3511(4)
3029(5)
949(4)
1832(4)
1467(4)
6128(4)
8240(50)
4840(40)
4928
1039(1)
−3614(1)
41(1)
64(1)
54(1)
52(1)
40(1)
43(1)
56(1)
46(1)
44(1)
39(1)
54(1)
48(1)
48(1)
55(1)
57(1)
56(1)
49(1)
56(1)
49(1)
60(10)
40(8)
67
2057(1)
2882(1)
1839(4)
3594(3)
800(4)
2963(3)
1752(3)
2520(4)
2994(5)
4319(4)
4534(4)
5524(4)
1941(5)
2864(5)
2077(4)
4133(5)
745(4)
970(50)
3760(40)
70
−5527(2)
−3304(2)
−6969(3)
−4963(2)
−5058(2)
−3993(2)
−5413(3)
−1193(3)
−2171(3)
−1583(3)
−6389(3)
−1056(3)
−114(3)
−1670(3)
−6546(3)
−5430(30)
−3580(30)
−7647
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(5-chloropyridyl)]-
thiourea (DDE 934). Mp 115–116°C; 1H NMR
(DMSO-d6) l 11.29 (t, 1H), 10.77 (s, 1H), 8.11 (t, 1H),
7.85 (dd, 1H, J=3.0, 9.3 Hz), 7.17 (d, 2H, J=8.7 Hz),
7.07 (d, 1H, J=3.6 Hz), 6.80 (d, 1H, J=3.0 Hz), 3.81
(q, 2H), 3.11 (t, 2H); 13C NMR (DMSO-d6) l 179.3,
152.0, 143.5, 138.9, 130.2, 126.7, 123.8, 114.1, 108.8,
46.0, 28.9; IR w 3490, 3212, 3039, 2923, 1592, 1554,
1531, 1473, 1226 cm−1; MALDI-TOF m/z 378.3
(C12H11BrClN3S2+2H+); HPLC Rt: 14.04 min.
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(pyridyl)]thiourea
1
(DDE 935). Mp 156–157°C; H NMR (DMSO-d6) l
11.78 (s, 1H), 10.61 (s, 1H), 8.08 (d, 1H, J=3.0 Hz),
7.74 (t, 1H), 7.13 (d, 1H, J=8.4 Hz), 7.06 (t, 1H), 7.01
(t, 1H), 6.81 (d, 1H, J=3.0 Hz), 3.83 (q, 2H), 3.12 (t,
2H); 13C NMR (DMSO-d6) l 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 w
3452, 3220, 3050, 2931, 1600, 1562, 1535, 1477, 1199,
775 cm−1; MALDI-TOF m/z 343.8 (C12H12BrN3S2+
3H+); HPLC Rt: 9.29 min.
H12
H14
H4A
H4B
H5A
H5B
H13
H8
3783
3670
5396
6376
6218
1985
2606
1658
6114
5915
2875
3377
2065
110
−5033
−1592
−2362
−2175
−858
−6659
−1274
65
58
58
67
67
68
67
H7
4785
1001
−2347
68
H11
−7
7282
−6934
59
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(5-bromopyridyl)]-
thiourea (DDE 946). Mp 163–164°C; 1H NMR
(DMSO-d6) l 11.29 (t, 1H), 10.73 (s, 1H), 8.17 (d, 1H,
J=2.4 Hz), 7.93 (dd, 1H, J=3.0, 9.0 Hz), 7.10 (d, 1H,
J=9.0 Hz), 7.04 (d, 1H, J=3.9 Hz), 6.79 (d, 1H, J=3.6
Hz), 3.81 (q, 2H), 3.10 (t, 2H); 13C NMR (DMSO-d6) l
179.4, 152.4, 145.9, 143.7, 141.6, 130.3, 126.9, 114.7,
inactive. Six of the 5-bromothiophenethyl thioureas
inhibit replication of the HIV-1 strain HTLVIIIB in the
12–300 nM range in human peripheral blood mononu-
clear cells (PBMC). Among the derivatives examined,

6632
T. K. Venkatachalam et al. / Tetrahedron Letters 42 (2001) 6629–6632
112.2, 108.9, 46.2, 29.0; IR w 3506, 3212, 3037, 2925,
1591, 1552, 1529, 1473, 1227, 796 cm−1; MALDI-TOF
m/z 423.3 (C12H11Br2N3S2+2H+); HPLC Rt: 15.18 min.
d6) l 178.4, 161.4, 143.5, 130.2, 126.6, 108.8, 106.1,
45.5, 28.9, 16.7; IR w 3455, 3174, 3016, 1585, 1562,
1531, 1506, 1270, 1211 cm−1; MALDI-TOF m/z 364.1
(C11H12BrN3S3+2H+); HPLC Rt: 4.03 min.
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(6-methylpyridyl)]-
thiourea (DDE 949). Mp 125–126°C; 1H NMR
(DMSO-d6) l 11.92 (t, 1H), 10.54 (s, 1H), 7.61 (t, 1H),
7.03 (d, 1H, J=3.6 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.84
(d, 1H, J=7.8 Hz), 6.78 (d, 1H, J=3.6 Hz), 3.90 (q,
2H), 3.11 (t, 2H), 2.25 (s, 3H); 13C NMR (DMSO-d6) l
179.6, 154.4, 153.2, 143.9, 139.1, 130.2, 126.5, 116.9,
109.4, 108.8, 45.5, 29.2, 23.5; IR w 3442, 3047, 2919,
1610, 1560, 1452, 1226, 1157, 783 cm−1; MALDI-TOF
m/z 357.0 (C13H14BrN3S2+2H+); HPLC Rt: 12.41 min.
References
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N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(4,6-dimethyl-
1
pyridyl)]thiourea (DDE 950). Mp 167–168°C; H NMR
(DMSO-d6) l 11.99 (d, 1H, J=5.1 Hz), 10.45 (d, 1H,
J=4.8 Hz), 7.03 (q, 1H), 6.77 (t, 1H), 6.81 (dd, 2H,
J=3.6, 14.7 Hz), 3.88 (m, 2H), 3.09 (q, 2H), 2.19 (t,
6H); 13C NMR (DMSO-d6) l 179.7, 153.9, 153.3, 149.8,
143.9, 130.2, 126.5, 118.2, 109.4, 108.7, 45.5, 29.2, 23.3,
20.9; IR w 3444, 3052, 2917, 1616, 1540, 1446, 1213, 833
cm−1; MALDI-TOF m/z 372.1 (C14H16BrN3S2+3H+);
HPLC Rt: 18.77 min.
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(thiazolyl)]thiourea
1
(DDE 951). Mp 146–147°C; H NMR (DMSO-d6) l
11.66 (s, 1H), 9.64 (s, 1H), 7.34 (t, 1H), 7.08 (s, 1H),
7.04 (t, 1H), 6.77 (s, 1H), 3.75 (d, 2H), 3.07 (t, 2H); 13C
NMR (DMSO-d6) l 178.3, 161.9, 143.4, 136.5, 130.2,
126.6, 112.1, 108.8, 45.4. 28.9; IR w 3484, 3079, 2993,
1560, 1513, 1235, 1178 cm−1; MALDI-TOF m/z 350.3
(C10H10BrN3S3+2H+); HPLC Rt: 7.98 min.
7. Uckun, F. M.; Mao, C.; Pendergrass, S.; Maher, D.; Zhu,
D.; Tuel-Ahlgren, L.; Venkatachalam, T. K. Bioorg.
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13, 235.
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(benzothiazolyl)]-
thiourea (DDE 954). Mp 179–180°C; 1H NMR
(DMSO-d6) l 1.93 (s, 1H), 10.21 (s, 1H), 7.88 (d, 1H,
J=7.2 Hz), 7.57 (br s, 1H), 7.39 (t, 1H), 7.25 (t, 1H),
7.06 (d, 1H, J=3.6 Hz), 6.83 (s, 1H), 3.12 (t, 2H), 2.48
(d, 2H, J=2.1 Hz); 13C NMR (DMSO-d6) l 178.8,
161.1, 148.7, 143.4, 130.2, 126.7, 126.3, 123.7, 121.9,
119.7, 112.8, 112.0, 108.9, 45.7, 28.8; IR w 3463, 3029,
1569, 1527, 1207, 754 cm−1; MALDI-TOF m/z 400.0
(C14H12BrN3S3+3H+); HPLC Rt: 16.04 min.
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of Area Detector Data, University of Go¨ttingen, Ger-
many.
N-[2-(5-Bromo-2-thienyl)ethyl]-N%-[2-(4-methylthia-
1
zolyl)]thiourea (DDE 1009). Mp 151–152°C; H NMR
(DMSO-d6) l 11.60 (s, 1H), 9.90 (s, 1H), 7.05 (d, 1H,
J=3.9 Hz), 6.79 (d. 1H, J=3.6 Hz), 6.62 (s, 1H), 3.78
(q, 2H), 3.07 (t, 2H), 2.16 (s, 3H); 13C NMR (DMSO-