Synthesis of imidazoles as novel emivirine and S-DABO analogue

Article abstract of DOI:10.1002/jhet.5570390222

5-Alkyl-4-benzyl-1,3-dihydroimidazol-2-ones (3a-d) and 5-alkyl-4-benzyl-1,3-dihydroimidazole-2-thiones (7a-d) were prepared via Dakin West reaction on DL-phenylalanine with the appropriate aliphatic acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate. Compounds 3a-d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a-d which were considered analogues of Emivirine with deletion of carbonyl group at the 4-position. Alkylation of 7a-d afforded the corresponding S-alkylated derivatives 8a-p which in a similar way were considered analogues of S-DABO. However all the imidazole derivatives were devoid of activity against HIV.

Full text of DOI:10.1002/jhet.5570390222

Mar-Apr 2002
Synthesis of Imidazoles as Novel Emivirine and S-DABO Analogues
375
Yasser M. Loksha, Per T. Jørgensen and Erik B. Pedersen*
Department of Chemistry, University of Southern Denmark, DK-5230 Odense M, Denmark
Mahmoud A. El-Badawi and Ahmed A. El-Barbary
Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
Claus Nielsen
Retrovirus Laboratory, Department of Virology, State Serum Institute, DK-2300 Copenhagen, Denmark
Received October 19, 2001
5-Alkyl-4-benzyl-1,3-dihydroimidazol-2-ones (3a-d) and 5-alkyl-4-benzyl-1,3-dihydroimidazole-2-
thiones (7a-d) were prepared via Dakin West reaction on DL-phenylalanine with the appropriate aliphatic
acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate.
Compounds 3a-d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a-d which
were considered analogues of Emivirine with deletion of carbonyl group at the 4-position. Alkylation of 7a-
d afforded the corresponding S-alkylated derivatives 8a-p which in a similar way were considered analogues
of S-DABO. However all the imidazole derivatives were devoid of activity against HIV.
J. Heterocyclic Chem., 39, 375 (2002).
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine
(HEPT) [1] showed low activity against HIV-1 but when
the hydroxy group was removed from the acyclic sugar,
the activity was increased 21 fold [2]. The activity was fur-
ther increased 55 fold when the methyl group at the 5-posi-
tion was replaced by an isopropyl group [3]. After replace-
ment of sulfur with a methylene group, the compound
6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (Emivirine
or MKC-442) [4] was chosen as a candidate for the clinical
trials on AIDS patients.
The dihydroalkoxybenzyloxopyrimidines (DABO) and
their thio analogues (S-DABO) [5-7] are closely related to
the HEPT derivatives. 6-Benzyl-4-oxopyrimidines were
synthesized as dihydrofolate reductase inhibitors and
because of their structural similarities with HEPT, they
were also tested against HIV and some were found active.
In the present report, we are interested in studying the
importance of the carbonyl group at the 4-position in
Emivirine and S-DABO analogues, for their activity
against HIV. This is done by deletion of the carbonyl group
at the 4-position (Figure 1).
Figure 1. Carbonyl group deletion in Emivirine and S-DABO.
[12]. However, we have chosen the Dakin-West reaction
[14,15] to prepare N-(1-benzyl-3-methyl-2-oxobutyl)-
isobutyramide 1d by refluxing DL-phenylalanine with
isobutyric anhydride in the presence of pyridine to induce
the acylation of the chiral CH group and subsequent decar-
boxylation in the same manner as described for 1a-c by
Cleland and Niemann [16]. For the hydrolysis of 1d, there
was used the procedure already described by Dakin and
West [15] for 1a, Sheppard et al. [17] for 1b and Cheng et
al. [18] for 1c , in which α-acylaminoketones 1a-d were
hydrolysed by 6 M HCl to afford α -aminoketone
hydrochlorides 2a-d.
1,3-Dihydroimidazol-2-ones and 1,3-dihydroimidazole-
2-thiones have been prepared by reaction of cyanate and
thiocyanate salts, respectively, with α-aminoaldehydes
[8-10] or α -aminoketones [11-13]. The unstable
α-aminoaldehydes have been prepared by reduction of
α-amino acids by sodium amalgam. However, the yield of
1,3-dihydroimidazol-2-ones by the reaction of cyanate
salts with freshly reduced α-aminoacid was low and fur-
thermore, the method is expensive because of the amounts
of sodium amalgam used. Also, there is a risk of poluting
the environment. α-Aminoketones have been prepared by
the reaction of α-haloketones with the potassium salt of
phathalimide followed by hydrolysis in acidic medium
α-Aminoketone hydrochlorides 2a-d were heated with
potassium cyanate to give 4-benzyl-5-alkyl-1,3-

376
Y. M. Loksha, P. T. Jørgensen, E. B. Pedersen,
Vol. 39
M. A. El-Badawi, A. A. El-Barbary and C. Nielsen
dazol-2-ones 3a-d. Compound 3a has previously
respectively, when the CH -N resonance in compounds 5b
dihyroimi
2
been prepared by two other methods [19,20], either by
reduction of the benzoyl group of 5-benzoyl-4-methyl-1,3-
and 5d, respectively, was irradiated.
4-Benzyl-5-alkyl-1,3-dihydroimidazole-2-thiones (7a-
d) were obtained by refluxing compounds 2a-d with potas-
sium thiocyanate in water. Compounds 7a,b have previ-
ously been prepared by Sonn [21] and Bullerwell and
Lawson [22] by the same synthetic procedure. Compounds
7a-d were alkylated by appropriate alkylating reagents to
afford the S-alkylated 1,3-dihydroimidazole-2-thiones 8a-
p which are considered as S-DABO analogues with car-
dihydroimidazol-2-one with H /Pt in acetic acid [19] or
2
by reaction of urea with 4-benzyl-3-methylisoxazol-5-
ylamine [20].
Compounds 3a-d were silylated by the action of N,O-
bis-(trimethylsilyl)acetamide (BSA) and followed by alky-
lation with ethoxymethyl chloride to afford monoalkylated
1
3
products at N 4a-d and N 5a-d (Emivirine analogues
1
3
1
with deletion of CO at the 4-position) and N ,N -dialkyl-
ated products 6a-d (Scheme 1). The assignment of struc-
tures of 4a-d and 5a-d was confirmed by NOE. Irradiation
bonyl group deletion at the 4-position (Scheme 2). H-nmr
spectra of some of these compounds 8m-p did not show
fine splitting of the peaks, which appeared as broad sin-
glets, even for aromatic protons. This is explained by an
equilibrium between the two tautomeric forms i and ii. For
the same reason, C-4 and C-5 in all the compounds 8a-p
of CH Ph in compounds 4b and 4d, respectively, did not
2
show NOE of the CH -N resonance but the same irradia-
2
tion in compounds 5b and 5d showed 2.3% and 1.6%
13
NOE, respectively, of the CH -N resonance. Also, on irra-
were never observed in the Cnmr spectra whereas, C-2
2
diation of the CH -N resonance in compounds 4b and 4d,
2
and the methylene carbon atom in the benzyl group
showed significant broadening of the peaks.
NOE was not observed at the CH Ph resonance, whereas
2
the CH Ph resonance showed 1.9% and 1.3% NOE,
2
Scheme 2
Scheme 1
1
2
1
2
8
R
R
8
R
R
a
b
c
d
e
f
Me
Et
MeSCH
MeSCH
MeSCH
MeSCH
s
s
s
s
2
2
2
2
i
j
Me
Et
Bu
Bu
Bu
Bu
Bn
Bn
Bn
Bn
Pr
Pr
k
l
m
n
o
p
Pr
Pr
i
i
i
Me
Et
Pr
Pr
Pr
Me
Et
i
i
g
h
Pr
Pr
Pr
Pr
i
i
Pr
I
The test for activity against HIV-1 was performed in
MT4 cell cultures infected with either wild type HIV-1
(strain IIIB) or non nucleoside reverse transcriptase
inhibitors (NNRTI) resistant HIV-1 (strain N119) that har-
boured a substitution of cysteine for the tyrosine at posi-
tion 181 in the reverse transcriptase enzyme (Cys181Tyr
mutant strain). The compounds 4-6 including Emivirine
analogues and 8 (S-DABO analogues) are inactive at 100
µM or inactive at subtoxic concentrations.

Mar-Apr 2002
Synthesis of Imidazoles as Novel Emivirine and S-DABO Analogues
377
37.78 (CH ), 56.60 (CH-N), 127.20, 128.57, 129.41, 134.79
In conclusion, the effect of activity against HIV has been
studied on deletion of the carbonyl group at the 4-position
for both of Emivirine and S-DABO analogues by synthe-
sizing the corresponding imidazole analogues. It was
found that deletion of the carbonyl group leads to complete
loss of the activity against HIV.
2
+
(C
), 209.81 (CO); EI ms: m/z 227 (M ).
arom
Anal. Calcd. for C
H ClNO•1.0H O (245.75): C, 58.65; H,
12 18 2
8.20; N, 5.70. Found: C, 59.55; H, 7.88; N, 5.98.
General Procedure for Preparation of 4-Benzyl-5-alkyl-1,3-dihy-
droimidazol-2-ones (3b-d).
To a hot solution of potassium cyanate (0.65 g, 8 mmoles) in
water (20 ml), 2b-d (8 mmoles) was added. The mixture was
heated at 70° for 1 hour, cooled to room temp., the solid product
formed was isolated by filtration and recrystallized from
ethanol/water to give compounds 3b-d.
EXPERIMENTALS
NMR spectra were recorded on a Varian Gemini 2000 NMR
1
13
spectrophotometer at 300 MHz for H and 75.5 MHz for
C
with TMS as an internal standard. EI mass spectra were recorded
on a Finnigan MAT SSQ 710. The silica gel (0.040−0.063 mm)
used for column chromatography was purchased from Merck.
Microanalyses were caried out at Atlantic Microlab, Inc.,
Norcross, Georgia, USA.
4-Benzyl-5-ethyl-1,3-dihydroimidazol-2-one (3b).
The compound was obtained as white crystals. Yield 1.2 g
1
(75%); mp 208−210°; H-nmr (DMSO-d ): δ 1.03 (t, 3H,
6
CH CH , J = 7.2 Hz), 2.29 (q, 2H, CH CH , J = 7.3 Hz), 3.54 (s,
3
2
2
3
2H, CH Ph), 7.15−7.29 (m, 5H, Ph), 9.57 (s, 1H, NH), 9.66 (s,
2
N-(1-Benzyl-3-methyl-2-oxobutyl)-isobutyramide (1d).
13
1H, NH); C nmr (DMSO-d ): δ 13.89 (CH ), 16.70 (CH CH ),
6
3
2
3
29.38 (CH Ph), 114.13 (C-4), 118.56 (C-5), 125.94, 128.02,
A mixture of DL-phenylalanine (6.6 g, 40 mmoles), anhydrous
pyridine (34 ml, 400 mmoles) and isobutyric anhydride (66.5 ml,
40 mmoles) was heated in an oil bath at 150° for 12 hours until
carbon dioxide was no longer evolved. After that, excess of pyri-
dine, acid anhydride and the acid formed were removed under
reduced pressure, the residue obtained was treated with an aque-
ous saturated solution of sodium bicarbonate (10 ml) to remove
the acidic components and then extracted with ether (3 × 50 ml).
After removal of solvent from the dried ether extract, the residue
was treated with petroleum ether (60−80°) (50 ml) and left at 5°
overnight. The solid product formed was isolated by filtration,
washed with petroleum ether (60−80°), dried and recrystallized
from xylene/petroleum ether (60−80°) to give N-(1-benzyl-3-
methyl-2-oxo-butyl)isobutyramide (1d) as pale yellow crystals.
2
+
128.23, 139.71 (C
), 154.32 (CO); EI ms: m/z 202 (M ).
arom
Anal. Calcd. for C
H N O (202.25): C, 71.26; H, 6.98; N,
12 14 2
13.85. Found: C, 71.09; H, 6.93; N, 13.70.
4-Benzyl-5-propyl-1,3-dihydroimidazol-2-one (3c).
The compound was obtained as white crystals. Yield 1.6 g
1
(92%); mp 146−148°; H-nmr (DMSO-d ): δ 0.84 (t, 3H, J = 7.2
6
Hz, CH CH ), 1.48 (sext., 2H, CH CH CH , J = 6.9 Hz), 2.27 (t,
3
2
3
2
2
2H, CH CH CH , J = 7.2 Hz), 3.57 (s, 2H, CH Ph), 7.21−7.32 (m,
3
2
2
2
13
5H, Ph), 9.61 (s, 1H, NH), 9.66 (s, 1H, NH); C-nmr (DMSO-d ):
6
δ 13.38 (CH ), 21.76 (CH CH ), 25.26 (CH CH CH ), 29.41
3
2
3
2
2
3
(CH Ph), 114.94 (C-4), 117.04 (C-5), 125.96, 128.07, 128.22,
2
+
139.66 (C
), 154.33 (CO); EI ms: m/z 216 (M ).
arom
1
Anal. Calcd. for C
H N O (216.28): C, 72.19; H, 7.46; N,
Yield 1.88 g (18%); mp 90−92°; H-nmr (CDCl ): δ 1.01 (d, 3H,
13 16 2
3
12.95. Found: C, 71.95; H, 7.34; N, 12.92.
CH , J = 6.6 Hz), 1.02 (d, 3H, CH , J = 6.3 Hz) 1.07 (d, 3H, CH ,
3
3
3
J = 6.6 Hz), 1.10 (d, 3H, CH , J = 6.6 Hz), 2.33 (hept., 1H,
CHCO, J = 6.9 Hz), 2.66 (hept., 1H, CHCO, J = 6.6 Hz), 2.90
(dd, 1H, HCH-CH, J = 6.0, 13.8 Hz), 3.04 (dd, 1H, HCH-CH, J =
3
4-Benzyl-5-isopropyl-1,3-dihydroimidazol-2-one (3d).
The compound was obtained as white crystals. Yield 1.0 g
1
(58%); mp 123−125°; H-nmr (DMSO-d ): δ 1.09 (d, 3H,
6.9, 13.8 Hz), 5.05 (q, 1H, PhCH CHNH, J = 7.3 Hz), 6.13 (1H,
6
2
13
(CH ) CH, J = 6.9 Hz), 2.85 (hept., 1H, (CH ) CH, J = 6.9 Hz),
d, NH, J = 6.8 Hz), 7.29−7.09 (m, 5H, Ph); C-nmr (CDCl ): δ
3 2
3 2
3
3.57 (s, 2H, CH Ph), 7.16−7.31 (m, 5H, Ph), 9.60 (s, 1H, NH),
16.95 (CH ) , 18.87 (CH ) , 35.35 (CHCONH), 37.66
2
3 2
3 2
13
9.81 (s, 1H, NH); C-nmr (DMSO-d ): δ 21.93 ((CH ) CH),
(CHCOCH), 38.61 (CH ), 56.42 (CHNH), 126.91, 128.43,
6
3 2
2
23.45 ((CH ) CH), 29.41(CH Ph), 112.93 (C-4), 122.70 (C-5),
129.19, 135.94 (C
ketone); EI ms: m/z 261 (M ).
), 176.25 (CO-amide), 212.66 (CO-
3 2
2
arom
+
125.94, 127.98, 128.23, 139.76 (C
216 (M ).
), 154.49 (C-2); EI ms: m/z
arom
+
Anal. Calcd. for C
H NO (261.36): C, 73.53; H, 8.87; N,
16 23 2
Anal. Calcd. for C
H N O•0.5H O (225.29): C, 69.31; H,
13 16 2 2
5.36. Found: C, 73.38; H, 8.77; N, 5.39.
7.16; N, 12.43. Found: C, 68.95; H, 7.34; N, 12.48.
2-Amino-4-methyl-1-phenylpentan-3-one Hydrochloride (2d).
General Procedure for Preparation of Compounds 4a-d, 5a-d and
6a-c.
A solution of 1d (5.2 g, 20 mmoles) in 6 M hydrochloric acid
(110 ml) and ethanol (60 ml) was refluxed for 10 hours, the sol-
vents were removed under reduced pressure. The residue was
left overnight, dissolved in ethanol (20 ml) and the hydrochloride
of 2-amino-4-methyl-1-phenylpentan-3-one (2d) was pecipitated
by the addition of ether (100 ml), the solid so formed was isolated
To 3a-d (5 mmoles) in chloroform (20 ml) under nitrogen
atmosphere, was added N,O-bis-(trimethylsilyl)acetamide (2.7
ml, 11 mmoles). The mixture was stirred at room temp. for 0.5
hour for complete silylation, then cooled to −10°. Ethoxymethyl
chloride (0.46 ml, 5 mmoles) was added dropwise and the mix-
ture was stirred until the dialkylated product started to appear
(tlc, high r.f. value). After ca. 0.5−1 hour, the reaction was
quenched at −10° by addition of a saturated solution of sodium
carbonate (10 ml), the mixture was filtered, the two layers were
separated and the aqueous phase was further extracted with
chloroform (20 ml). The chloroform phases were dried with
by filtration and washed with ether (50 ml). White crystals. Yield
1
3.5 g (77%); mp 140−142°; H-nmr (DMSO-d ): δ 0.83 (d, 3H,
6
CH CH, J = 6.3 Hz), 1.02 (d, 3H, CH CH, J = 6.9 Hz), 2.59
3
3
(hept., 1H, (CH ) CH, J = 6.9 Hz), 3.08 (dd, 1H, HCH-CH, J =
3 2
7.5, 14.1 Hz), 3.25 (dd, 1H, HCH-CH, J = 6.0, 14.1 Hz) 4.54 (brs,
+
1H, CH-N), 7.37−7.26 (m, 5H, Ph), 8.65 (brs, 3H, NH );
3
13
C-nmr (DMSO-d ): δ 16.41 ((CH ) C), 35.59 ((CH ) CH),
6
3 2
3 2

378
Y. M. Loksha, P. T. Jørgensen, E. B. Pedersen,
Vol. 39
M. A. El-Badawi, A. A. El-Barbary and C. Nielsen
sodium sulfate and the solvent was removed under reduced pres-
sure. The residual products were chromatographed on a column
of silica gel with methanol:chloroform (1:25, v/v) to afford com-
pounds 4a-d, 5a-d and 6a-c.
J = 6.9 Hz), 1.94 (s, 3H, CH ), 3.31 (q, 2H, CH CH O), 3.75 (s,
3 3 2
2H, CH Ph), 4.67 (s, 2H, NCH O), 7.12−7.31 (m, 5H, Ph), 9.93
2
2
13
(s, 1H, NH); C-nmr (DMSO-d ): δ 8.95 (CH ), 14.64 (CH ),
6
3
3
27.99 (CH Ph), 62.52 (CH CH O), 69.25 (NCH O), 113.89
2
3
2
2
(C-5), 115.30 (C-4), 126.12, 127.79, 128.34, 138.95 (C
153.53 (C-2); EI ms: m/z 246 (M ).
),
arom
4-Benzyl-1-ethoxymethyl-5-methyl-1,3-dihydroimidazol-2-one
(4a).
+
Anal. Calcd. for C
H N O •0.25H O (250.82): C, 67.04; H,
14 18 2 2 2
1
The compound was obtained as yellow oil. Yield 74 mg (6%); H-
7.43; N, 11.17. Found: C, 67.21; H, 7.34; N, 10.96.
nmr (DMSO-d ): δ 1.08 (t, 3H, CH CH , J = 6.9 Hz), 2.02 (s, 3H,
6
3
2
4-Benzyl-3-ethoxymethyl-5-ethyl-1,3-dihydroimidazol-2-one
(5b).
CH ), 3.41 (q, 2H, CH CH , J = 7.2 Hz), 3.59 (s, 2H, CH Ph), 4.88
3
3
2
2
13
(s, 2H, NCH O), 7.18−7.31 (m, 5H, Ph), 9.85 (s, 1H, NH); C-nmr
2
(DMSO-d ): δ 7.75 (CH ), 14.82 (CH CH ), 29.29 (CH Ph), 62.75
The compound was obtained as white crystals. Yield 234 mg
6
3
3
2
2
1
(CH CH ), 69.33 (NCH O), 113.78 (C-4), 115.01 (C-5), 126.06,
(18%); mp 91−93°; H-nmr (DMSO-d ): δ 0.97 (t, 3H, CH , J =
3
2
2
6
3
128.03, 128.29, 139.23 (C
), 153.56 (C-2); HiResMALDI m/z
6.9 Hz), 1.07 (t, 3H, CH , J = 7.5 Hz), 2.33 (q, 2H, CH CH , J =
arom
3
3
2
+
269.1249 (M + Na. C H N NaO ) requires 269.1261.
7.2 Hz), 3.29 (q, 2H, CH CH O, J = 7.2 Hz), 3.76 (s, 2H,
14 18
2
2
3
2
CH Ph), 4.66 (s, 2H, NCH O), 7.12−7.31 (m, 5H, Ph), 10.00 (s,
2
2
4-Benzyl-1-ethoxymethyl-5-ethyl-1,3-dihydroimidazol-2-one
(4b).
13
1H, NH); C-nmr (DMSO-d ): δ 13.66 (CH CH ), 14.64
6
3
2
(CH CH O), 16.72 (CH CH ), 27.94 (CH Ph), 62.55
3
2
3
2
2
The compound was obtained as yellow crystals. Yield 104 mg
(CH CH O), 69.25 (NCH O), 114.44 (C-4), 119.85 (C-5),
3 2 2
1
(8%); mp 53−55°; H-nmr (DMSO-d ): δ 1.04 (t, 3H, CH , J =
126.12, 127.73, 128.34, 138.98 (C
), 153.68 (C-2); EI ms: m/z
6
3
arom
+
7.2 Hz), 1.07 (t, 3H, CH , J = 7.2 Hz), 2.44 (q, 2H, CH CH , J =
260 (M ).
3
3
2
7.2 Hz), 3.40 (q, 2H, CH CH O, J = 7.2 Hz), 3.61 (s, 2H,
Anal. Calcd. for C
H N O (260.33): C, 69.20 ; H, 7.74; N,
3
2
15 20 2 2
CH Ph), 4.89 (s, 2H, NCH O), 7.19−7.29 (m, 5H, Ph), 9.87 (s,
10.76. Found: C, 68.79; H, 7.70;N, 10.41.
2
2
13
1H, NH); C-nmr (DMSO-d ): δ 14.46 (CH CH ), 14.80
6
3
2
4-Benzyl-3-ethoxymethyl-5-propyl-1,3-dihydroimidazol-2-one
(5c).
(CH CH ), 15.52 (CH CH ), 29.31 (CH Ph), 62.70 (CH CH O),
3
2
3
2
2
3
2
69.27 (NCH O), 114.76 (C-4), 119.68 (C-5), 126.06, 128.01,
2
128.28, 139.18 (C
283.1415 (M + Na. C
), 153.65 (C-2); HiResMALDI m/z
The compound was obtained as white crystals. Yield 137 mg
arom
+
1
H N NaO ) requires 283.1417.
(10%); mp 116−118°; H-nmr (DMSO-d ): δ 0.91 (t,
15 20 2 2
6
CH CH O3H, J = 7.2 Hz), 1.05 (t, 3H, CH CH CH , J = 6.9
3
2
3
2
2
4-Benzyl-1-ethoxymethyl-5-propyl-1,3-dihydroimidazol-2-one
(4c).
Hz), 1.56 (sext., 2H, CH CH CH , J = 7.2 Hz), 2.35 (t, 2H,
3
2
2
CH CH CH , J = 7.2 Hz), 3.38 (q, 2H, CH CH O, J = 6.9 Hz),
3
2
2
3
2
The compound was obtained as white crystals. Yield 68 mg
3.84 (s, 2H, CH Ph), 4.73 (s, 2H, NCH O), 7.20−7.38 (m, 5H,
2
2
1
13
(5%); mp 106−108°; H-nmr (DMSO-d ): δ 0.87 (t, 3H,
Ph), 10.05 (s, 1H, NH); C-nmr (DMSO-d ): δ 13.34
6
6
CH CH CH , J = 7.2 Hz), 1.09 (t, 3H, CH CH O, J = 6.9 Hz),
(CH CH CH ), 14.65 (CH CH O), 21.56 (CH CH CH ), 25.23
3
2
2
3
2
3
2
2
3
2
3
2
2
1.48 (sext., 2H, CH CH CH , J = 7.2 Hz), 2.41 (t, 2H,
(CH CH CH ), 27.98 (CH Ph), 62.53 (CH CH O), 69.28
3
2
2
3
2
2
2
3
2
CH CH CH , J = 7.1 Hz), 3.45 (q, 2H, CH CH O, J = 6.9 Hz),
(NCH O), 115.18 (C-4), 118.34 (C-5), 126.12, 127.74, 128.32,
3
2
2
3
2
2
+
3.64 (s, 2H, CH Ph), 4.91 (s, 2H, NCH O), 7.22−7.31 (m, 5H,
138.95 (C
), 153.68 (C-2); EI ms: m/z 274 (M ).
2
2
arom
13
Ph), 9.92 (s, 1H, NH); C-nmr (DMSO-d ): δ 13.51
Anal. Calcd. for C
H N O •0.25H O (278.87): C, 68.91; H,
6
16 22 2 2 2
(CH CH CH ), 14.81 (CH CH O), 22.33 (CH CH CH ), 24.15
8.13; N, 10.05. Found: C, 68.68; H, 7.85; N, 9.85.
3
2
2
3
2
3
2
2
(CH CH CH ), 29.39 (CH Ph), 62.72 (CH CH O), 69.31
3
2
2
2
3
2
4-Benzyl-3-ethoxymethyl-5-isopropyl-1,3-dihydroimidazol-2-
one (5d).
(NCH O), 115.42 (C-4), 118.07 (C-5), 126.06, 128.04, 128.25,
2
+
139.11 (C
), 153.71 (C-2); HiResMALDI m/z 297.1563 (M +
arom
Na. C
N N NaO ) requires 297.1574.
The compound was obtained as white crystals. Yield 164 mg
16 22 2 2
1
(6%); mp 118−120°; H-nmr (DMSO-d ): δ 1.00 (t, 3H,
6
4-Benzyl-1-ethoxymethyl-5-isopropyl-1,3-dihydroimidazol-2-
one (4d).
CH CH O, J = 6.9 Hz), 1.14 (d, 3H, (CH ) CH, J = 6.9 Hz), 2.88
3
2
3 2
(hept., 1H, (CH ) CH, J = 6.9 Hz), 3.34 (q, 2H, CH CH O, J =
3 2
3
2
The compound was obtained as yellow oil. Yield 96 mg (7%);
6.9 Hz), 3.81 (s, 2H, CH Ph), 4.69 (s, 2H, NCH O), 7.14−7.34
(m, 5H, Ph), 10.11 (s, 1H, NH); C-nmr (DMSO-d ): δ 14.63
6
2 2
1
13
H-nmr (DMSO-d ): δ 1.07 (t, 3H, CH CH O, J = 6.9 Hz), 1.16
6
3
2
(d, 3H, (CH ) CH, J = 6.9 Hz), 2.93 (hept., 1H, (CH ) CH, J =
(CH CH O), 21.71 ((CH ) CH), 23.42 ((CH ) CH), 27.93
3 2
3 2
3 2 3 2 3 2
7.2 Hz), 3.41 (q, 2H, CH CH O, J = 7.0 Hz), 3.66 (s, 2H, CH Ph),
(CH Ph), 62.58 (CH CH O), 69.25 (NCH O), 113.19 (C-4),
2 3 2 2
3
2
2
4.93 (s, 2H, NCH O), 7.10−7.30 (m, 5H, Ph), 9.85 (s, 1H, NH);
123.9 (C-5), 126.09, 127.66, 128.34, 139.03 (C
(CO); EI ms: m/z 274 (M ).
), 153.83
2
arom
13
+
C-nmr (DMSO-d ): δ 14.84 (CH CH O), 21.88 ((CH ) CH),
6
3
2
3 2
23.85 ((CH ) CH), 29.83 (CH Ph), 62.55 (CH CH O), 69.46
Anal. Calcd. for C
H N O •0.5H O (283.37): C, 67.82; H,
3 2
2
3
2
16 22 2 2 2
(NCH O), 114.05 (C-5), 123.24 (C-4), 126.03, 127.86, 128.26,
8.18; N, 9.89. Found: C, 67.58; H, 7.82; N, 9.87.
2
+
139.23 (C
), 153.56 (C-2); HiResMALDI m/z 297.1572 (M +
arom
4-Benzyl-1,3-bis(ethoxymethyl)-5-methyl-1,3-dihydroimidazol-
2-one (6a).
Na. C N N NaO ) requires 297.1574.
16 22
2
2
4-Benzyl-3-ethoxymethyl-5-methyl-1,3-dihydroimidazol-2-one
(5a).
The compound was obtained as yellow oil. Yield 152 mg
1
(10%); H-nmr (DMSO-d ): δ 0.97 (t, 3H, CH CH O, J = 7.2
6
3
2
The compound was obtained as white crystals. Yield 246 mg
Hz), 1.09 (t, 3H, CH CH O), 2.07 (s, 3H, CH ), 3.32 (q, 2H,
CH CH O, J = 6.9 Hz), 3.45 (q, 2H, CH CH O, J = 6.9 Hz), 3.82
3 2 3 2
3 2 3
1
(20%); mp 116−118°; H-nmr (DMSO-d ): δ 0.97 (t, 3H, CH ,
6
3

Mar-Apr 2002
Synthesis of Imidazoles as Novel Emivirine and S-DABO Analogues
379
(s, 2H, CH Ph), 4.75 (s, 2H, NCH O), 4.99 (s, 2H, NCH O),
Anal. Calcd. for C H N S (232.34): C, 67.20; H, 6.94; N,
13 16 2
12.06. Found: C, 67.21; H, 6.97; N, 12.06.
2
2
2
13
7.13−7.32 (m, 5H, Ph); C-nmr (DMSO-d ): δ 7.73 (CH ),
6
3
14.57 (CH CH O), 14.77 (CH CH O), 27.78 (CH Ph), 62.71
3
2
3
2
2
4-Benzyl-5-isopropyl-1,3-dihydroimidazole-2-thione (7d).
(CH CH O), 62.95 (CH CH O), 69.63 (NCH O), 69.76
3
2
3
2
2
(NCH O), 115.48 (C-5), 115.68 (C-4), 126.21, 127.72, 128.38,
The compound was obtained as white crystals. Yield 900 mg
2
+
1
138.58 (C
), 153.32 (C-2); EI ms: m/z 304 (M ).
(60%); mp 263−265°; H-nmr (DMSO-d ): δ 1.13 (d, 3H,
arom
6
(CH ) CH, J = 6.9 Hz), 2.94 (hept., 1H, (CH ) CH, J = 6.6 Hz),
Anal. Calcd. for C
H N O •0.5H O (313.40). C, 65.15; H,
3 2
3 2
17 24 2 3 2
3.70 (s, 2H, CH ), 7.20−7.34 (m, 5H, Ph), 11.71 (s, 1H, NH),
8.04; N, 8.93. Found: C, 64.76; H, 7.67; N, 8.85.
2
13
11.77 (s, 1H, NH); C-nmr (DMSO-d ): δ 21.78 ((CH ) CH),
6
3 2
4-Benzyl-1,3-bis(ethoxymethyl)-5-ethyl-1,3-dihydroimidazol-2-
one (6b).
23.43 ((CH ) CH ), 28.95 (CH ), 121.07 (C-4), 130.29 (C-5),
3 2
2
126.18, 128.03, 128.36, 139.22 (C
m/z 232 (M ).
), 159.08 (C-2); EI ms:
arom
+
The compound was obtained as yellow oil. Yield 318 mg (20%);
1
Anal. Calcd. for C
H N S•0.25H O (236.85): C, 65.92; H,
13 16 2 2
H-nmr (DMSO-d ): δ 0.98 (t, 3H, CH CH O, J = 7.2 Hz), 1.06 (t,
6
3
2
3H, CH CH O, J = 7.2 Hz), 1.10 (t, 3H, CH CH , J = 7.2 Hz),
7.02; N, 11.83. Found: C, 65.79; H, 6.70; N, 11.65.
3
2
3
2
2.48 (q, 2H, CH CH , J = 7.5 Hz), 3.33 (q, 2H, CH CH O, J = 7.2
3
2
3
2
General Procedure for Preparation of 4-Benzyl-5-alkyl-2-methyl-
sulfanylmethylsulfanyl-1H-imidazole (8a-d).
Hz), 3.47 (q, 2H, CH CH O, J = 6.9 Hz), 3.84 (s, 2H, CH Ph),
3
2
2
4.74 (s, 2H, NCH O), 5.01 (s, 2H, NCH O), 7.14−7.32 (m, 5H,
2
2
13
A mixture of 7a-d (2 mmoles), chloromethyl methyl sulfide
(0.168 ml, 2 mmoles) and potassium carbonate (0.276 g,
1 mmole) in dimethylformaide (10 ml) was stirred for 10 hours at
room temp. The reaction mixture was treated with ice/cold water
(50 ml). The solid product formed was isolated by filtration and
washed with petroleum ether (60−80°) (20 ml) to give com-
pounds 8a-d.
Ph); C-nmr (DMSO-d ): δ 14.22 (CH CH ), 14.57 (CH CH O),
6
3
2
3
2
14.76 (CH CH O), 15.45 (CH CH ), 27.78 (CH Ph), 62.77
3
2
3
2
2
(CH CH O), 62.93 (CH CH O), 69.66 (NCH O), 69.73
3
2
3
2
2
(NCH O), 115.34 (C-4), 121.25 (C-5), 126.21, 127.65, 128.37,
2
+
138.48 (C
), 153.46 (C-2); EI ms: m/z 318 (M ).
arom
Anal. Calcd. for C
H N O •0.5H O (327.43). C, 66.03; H,
18 26 2 3 2
8.31; N, 8.56. Found: C, 66.28; H, 8.02; N, 8.42.
4-Benzyl-5-methyl-2-methylsulfanylmethylsulfanyl-1H-imida-
zole (8a).
4-Benzyl-1,3-bis(ethoxymethyl)-5-propyl-1,3-dihydroimidazol-
2-one (6c).
The compound was obtained as white crystals. Yield 216 mg
The compound was obtained as yellow oil. Yield 162 mg
1
1
(41%); mp 130−132°; H-nmr (CDCl ): δ 2.14 (s, 3H, CH S),
(10%); H-nmr (DMSO-d ): δ 0.85 (t, 3H, CH CH O, J = 7.2
3
3
6
3
2
2.16 (s, 3H, CH ), 3.87 (s, 2H, CH Ph), 3.93 (s, 2H, SCH S),
Hz), 0.98 (t, 3H, CH CH O, J = 6.6 Hz), 1.09 (t, 3H,
3
2
2
3
2
13
7.15−7.26 (m, 5H, Ph); C-nmr (CDCl ): δ 11.07 (br, CH ),
CH CH CH , J = 6.6 Hz), 1.48 (sext., 2H, CH CH CH , J = 7.2
3
3
3
2
2
3
2
2
15.07 (CH S), 31.93 (br, CH Ph),. 41.49 (SCH S), 126.17,
Hz), 2.42 (t, 2H, CH CH CH ) , J = 7.2 Hz, 3.32 (q, 2H,
3
2
2
3
2
2
+
128.33, 128.44, 135.61 (C
); EI ms: m/z 264 (M ).
CH CH O, J = 7.2 Hz), 3.46 (q, 2H, CH CH O, J = 6.6 Hz), 3.84
arom
3
2
3
2
Anal. Calcd. for C
6.27; N, 10.25. Found: C, 57.46; H, 5.89; N, 10.03.
H N S •0.5H O (273.42): C, 57.11; H,
(s, 2H, CH Ph), 4.73 (s, 2H, NCH O), 4.99 (s, 2H, NCH O),
13 16 2 2 2
2
2
2
13
7.14−7.32 (m, 5H, Ph); C-nmr (DMSO-d ): δ 13.47
6
(CH CH CH ), 14.59 (CH CH O), 14.78 (CH CH O), 22.22
3
2
2
3
2
3
2
4-Benzyl-5-ethyl-2-methylsulfanylmethylsulfanyl-1H-imidazole
(8b).
(CH CH CH ), 24.01 (CH CH CH ), 27.89 (CH Ph), 62.75
3
2
2
3
2
2
2
(CH CH O), 62.94 (CH CH O), 69.69 (NCH O), 69.76
3
2
3
2
2
The compound was obtained as white crystals. Yield 268 mg
(NCH O), 115.97 (C-4), 119.68 (C-5), 126.22, 127.65, 128.36,
2
1
+
(54%); mp 113−115°; H-nmr (CDCl ): δ 1.08 (t, 3H, CH CH , J
138.42 (C
), 153.504 (C-2); EI ms: m/z 332 (M ).
3
3
2
arom
= 7.5 Hz), 2.06 (s, 3H, CH S), 2.47 (q, 2H, CH CH , J = 7.5 Hz),
Anal. Calcd. for C
66.42; H, 8.50; N, 8.15. Found: C, 66.18; H, 8.18; N, 8.03.
H N O •0.6H O (343.25): Calc. C,
3
3
2
19 28 2 3 2
3.82 (s, 2H, SCH S), 3.86 (s, 2H, CH Ph), 7.07−7.18 (m, 5H, Ph);
2
2
13
C-nmr (CDCl ): δ 14.31 (CH CH ), 15.07 (CH S), 18.92 (br,
3
3
2
3
General Procedure for Preparation of 4-Benzyl-5-alkyl-1,3-dihy-
droimidazole-2-thione (7c,d).
CH CH ), 31.18 (br, CH Ph), 41.49 (SCH S), 126.13, 128.41,
3
2
2
2
+
135.70 (C
), 139.76 (br, C-2); EI ms: m/z 278 (M ).
arom
Anal. Calcd. for C
6.66; N, 9.75. Found: C, 58.75; H, 6.64; N, 9.35.
H N S •0.5H O (287.45): C, 58.50; H,
A mixture of 2c,d (6.5 mmoles) and potassium thiocyanate
(0.62 g, 6.5 mmoles) in water (20 ml) was refluxed for 3 hours.
The reaction mixture was cooled and the solid product was iso-
lated by filtration and recrystallized from ethanol/water to give
compounds 7c,d.
14 18 2 2 2
4-Benzyl-5-propyl-2-methylsulfanylmethylsulfanyl-1H-imida-
zole (8c).
The compound was obtained as white crystals. Yield 340 mg
4-Benzyl-5-propyl-1,3-dihydroimidazole-2-thione (7c).
1
(58%); mp 71−73°; H-nmr (CDCl ): δ 0.89 (t, 3H,
3
CH CH CH , J = 7.2 Hz), 1.58 (sext., 2H, CH CH CH , J = 7.5
The compound was obtained as white crystals. Yield 920 mg
3
2
2
3
2
2
1
Hz), 2.14 (s, 3H, CH S), 2.49 (t, 2H, CH CH CH , J = 7.5 Hz),
(61%); mp 230−232°; H-nmr (DMSO-d ): δ 0.79 (t, 3H,
3
3
2
2
6
3.89 (s, 2H, SCH S), 3.94 (s, 2H, CH Ph), 7.16−7.29 (m, 5H,
CH CH CH , J = 7.2 Hz), 1.46 (sext., 2H, CH CH CH , J = 7.2
2
2
3
2
2
3
2
2
13
Ph); C-nmr (CDCl ): δ 13.79 (CH CH CH ), 15.07 (CH S),
Hz), 2.30 (t, 2H, CH CH CH, J = 7.2 Hz ), 3.67 (s, 2H, CH Ph),
3
3
2
2
3
3
2
2
2
23.04 (CH CH CH ), 27.57 (br, CH CH CH ), 31.91 (br,
7.16−7.31 (m, 5H, Ph), 11.69 (s, 1H, NH), 11.71 (s, 1H, NH);
3
2
2
3
2
2
13
CH Ph), 41.53 (SCH S), 126.13, 128.34, 128.39, 135.72 (C ),
C-nmr (DMSO-d ): δ 13.27 (CH ), 21.85 (CH CH CH ),
2
2
arom
6
3
3
2
2
+
139.63 (br, C-2); EI ms: m/z 292 (M ).
24.81 (CH CH CH ), 28.91 (CH Ph), 122.80 (C-4), 124.60
3
2
2
2
(C-5), 126.15, 128.09, 128.28, 139.03 (C
ms: m/z 232 (M ).
), 158.92 (C-2); EI
Anal. Calcd. for C N S •0.25H O (296.97): C, 60.67; H,
6.96; N, 9.43. Found: C, 60.92; H, 6.70; N, 9.46.
H
arom
15 20
2
2
2
+

380
Y. M. Loksha, P. T. Jørgensen, E. B. Pedersen,
Vol. 39
M. A. El-Badawi, A. A. El-Barbary and C. Nielsen
4-Benzyl-5-isopropyl-2-methylsulfanylmethylsulfanyl-1H-imi-
dazole (8d).
4-Benzyl-2-isopropylsulfanyl-5-isopropyl-1H-imidazole (8h).
The compound was obtained as white crystals. Yield 68 mg
1
(25%); mp 121−123°; H-nmr (DMSO-d ): δ 1.10 (d, 3H,
The compound was obtained as white crystals. Yield 300 mg
6
1
(CH ) CH, J =6.9 Hz), 1.20 (d, 3H, (CH ) CHS, J = 6.9 Hz),
(51%); mp 111−113°; H-nmr (CDCl ): δ 1.22 (d, 3H,
3 2
3 2
3
2.92 (hept., 1H, (CH ) CH, J = 6.9 Hz), 3.36 (hept., 1H,
(CH ) CH, J = 6.9 Hz), 2.14 (s, 3H, CH S), 2.98 (hept., 1H,
3 2
3 2
3
(CH ) CHS, J = 6.6 Hz), 3.79 (s, 2H, CH ), 7.13−7.27 (m, 5H,
(CH ) CH, J = 6.9 Hz), 3.92 (s, 2H, SCH S), 3.95 (s, 2H,
3 2
2
3 2
2
13
13
Ph), 11.94 (s, 1H, NH); C-nmr (DMSO-d ): δ 22.66
CH Ph), 7.15−7.29 (m, 5H, Ph); C-nmr (CDCl ): δ 15.08
6
2
3
((CH ) CH), 23.12 ((CH ) CHS), 24.60 (br, CH), 31.41 (br,
(CH S), 22.68 ((CH ) CH), 25.37 (br, (CH ) CH), 31.92 (br,
3 2
3 2
3
3 2
3 2
CH ), 38.75 (CH-S), 125.60, 128.00, 128.09, 134.77 (C
140.84 (br, C-2); EI ms: m/z 274 (M ).
),
CH Ph), 41.53 (SCH S), 126.10, 128.29, 128.38, 135.60 (C ),
139.70 (br, C-2); EI ms: m/z 292 (M ).
2
arom
2
2
arom
+
+
Anal. Calcd. for C
8.13; N, 10.04. Found: C, 69.21; H, 7.90; N, 9.92.
H N S•0.25H O (278.94): C, 68.90; H,
16 22 2 2
General Procedure for Preparation of 4-Benzyl-5-alkyl-2-alkyl-
sulfanyl-1H-imidazole (8e-l).
4-Benzyl-2-sec-butylsulfanyl-5-methyl-1H-imidazole (8i).
A mixture of 8a-d (1 mmole), isopropyl bromide or sec-butyl
bromide (1 mmole) and potassium carbonate (0.138 g, 1 mmole)
in dimethylformamide (5 ml) was stirred for 20 hours at room
temp. The reaction mixture was treated with ice/cold water (100
ml). The solid product formed was isolated by filtration, dried
and recrystallized from petroleum ether (60−80°) to give com-
pounds 8e-l.
The compound was obtained as white crystals. Yield 110 mg
1
(42%); mp 88−90°; H-nmr (DMSO-d ): δ 0.95 (t, 3H, CH CH ,
6
3
2
J = 7.2 Hz), 1.18 (d, 3H, CH CH, J = 6.9 Hz), 1.41−1.57 (m, 2H,
3
CH CH CH), 2.06 (s, 3H, CH ), 3.15 (hext, 1H, CH CHCH , J =
3
2
3
3
2
6.9 Hz), 3.76 (s, 2H, CH Ph), 7.12−7.27 (m, 5H, Ph), 11.92 (s,
2
13
1H, NH); C-nmr (DMSO-d ): δ 11.12 (CH CH CH and br,
6
3
2
CH at C-5), 20.67 (CH CH), 29.13 (CH CH CH), 31.59 (br,
3
3
3
2
4-Benzyl-2-isopropylsulfanyl-5-methyl-1H-imidazole (8e).
CH Ph), 45.17 (CH-S), 125.60, 128.05, 128.08, 134.28 (C
140.58 (br, C-2); EI ms: m/z 260 (M ).
),
2
arom
+
The compound was obtained as white crystals. Yield 120 mg
Anal. Calcd. for C
H N S (260.40): C, 69.19; H, 7.74; N,
1
15 20 2
(48%); mp 126−128°; H-nmr (DMSO-d ): δ 1.19 (d, 3H,
6
10.76. Found: C, 68.77; H, 7.72; N, 10.66.
(CH ) CHS, J = 6.6 Hz), 2.07 (s, 3H, CH ), 3.34 (hept., 1H,
3 2
3
(CH ) CHS, J = 6.6 Hz), 3.76 (s, 2H, CH ), 7.15−7.27 (m, 5H,
4-Benzyl-2-sec-butylsulfanyl-5-ethyl-1H-imidazole (8j).
3 2
2
13
Ph), 11.95 (brs, 1H, NH); C-nmr (DMSO-d ): δ 10.43 (br,
6
The compound was obtained as white crystals. Yield 82 mg
CH ), 23.15 ((CH ) CH), 31.34 (br, CH ), 38.71 ((CH ) CH),
3
3 2
2
3 2
1
(30%) mp 100−102°; H-nmr (DMSO-d ): δ 0.92 (t, 3H,
6
125.62, 128.06, 128.11, 134.45 (C
m/z 246 (M ).
), 140.00 (br, C-2); EI ms:
arom
CH CH CH, J = 7.2 Hz), 1.04 (t, 3H, CH CH , J = 7.2 Hz), 1.18
+
3
2
3
2
(d, 3H, CH CH, J = 6.6 Hz), 1.41−1.59 (m, 2H, CH CH CH),
3
3
2
Anal. Calcd. for C
H N S•0.25H O (250.88): C, 67.03; H,
14 18 2 2
2.39 (q, 2H, CH CH , J = 6.9 Hz), 3.17 (sext., 1H, CH CHCH ,
3
2
3
2
7.43; N, 11.17. Found: C, 66.73; H, 7.21; N, 11.14.
J = 6.6 Hz), 3.37 (s, 2H, CH Ph), 7.16−7.26 (m, 5H, Ph), 11.88
2
13
(s, 1H, NH); C-nmr (DMSO-d ): δ 11.10 (CH CH CH), 14.41
4-Benzyl-2-isopropylsulfanyl-5-ethyl-1H-imidazole (8f).
The compound was obtained as white crystals 104 mg
6
3
2
(CH CH ), 17.05 (br, CH CH ), 20.64 (CH CH), 29.13
3
2
3
2
3
(CH CH CH), 32.51 (br, CH Ph), 45.16 (CH-S), 125.39, 128.12,
3
2
2
1
(40%); mp 94−96°; H-nmr (DMSO-d ): δ 1.04 (t, 3H,
+
6
128.23, 134.43 (C
), 141 (br, C-2); EI ms: m/z 274 (M ).
arom
CH CH , J = 7.2 Hz), 1.23 (d, 3H, (CH ) CH, J = 6.6 Hz),
3
2
3 2
Anal. Calcd. for C
H N S (274.43): C, 70.03; H, 8.08; N,
16 22 2
2.44 (q, 2H, CH CH , J = 6.9 Hz), 3.34 (hept., 1H, (CH ) CH,
3
2
3 2
10.21. Found: C, 69.60; H, 8.13; N, 10.12.
4-Benzyl-2-sec-butylsulfanyl-5-propyl-1H-imidazole (8k).
J = 6.3 Hz), 3.77 (s, 2H, CH Ph), 7.14−7.24 (m, 5H, Ph), 11.92
2
13
(s, 1H, NH); C nmr (DMSO-d ): δ 14.46 (CH CH ), 18.09
6
3
2
The compound was obtained as white crystals. Yield 75 mg
(br, CH CH ), 23.14 ((CH ) CH), 31.25 (br, CH Ph), 38.69
1
3
2
3 2
2
(26%); mp 96−98°; H-nmr (DMSO-d ): δ 0.83 (t, 3H,
6
((CH ) CH), 125.60, 128.03, 128.08, 134.68 (C
(br, C-2); EI ms: m/z 260 (M ).
), 145.54
3 2
arom
CH CH CH , J = 6.9 Hz), 0.97 (t, 3H, CH CH CH, J = 7.2
3
2
2
3
2
+
Hz), 1.23 (d, 3H, CH CH, J = 6.9 Hz), 1.48−1.63 (m, 4H,
3
Anal. Calcd. for C
H N S (260.39): C, 69.19; H, 7.74; N,
15 20 2
CH CH CH and CH CH CH), 2.47 (t, 2H, CH CH CH , J =
3
2
2
3
2
3
2
2
10.76. Found: C, 68.76; H, 7.66; N, 10.71.
7.2 Hz), 3.22 (sext., 1H, CH CHCH , J = 6.6 Hz), 3.79
3
2
13
(CH Ph), 7.23−7.27 (m, 5H, Ph), 11.91 (s, 1H, NH); C-nmr
2
4-Benzyl-2-isopropylsulfanyl-5-propyl-1H-imidazole (8g).
(DMSO-d ): δ 11.12 (CH CH CH), 13.32 (CH CH CH ),
6
3
2
3
2
2
The compound was obtained as white crystals. Yield 104
20.64 (CH CH), 22.53 (CH CH CH ), 25.55 (br,
3
3
2
2
1
mg 3(8%); mp 112−114°; H-nmr (DMSO-d ): δ 0.79 (t, 3H,
6
CH CH CH ), 29.14 (CH CH CH), 32.51 (br, CH Ph), 45.18
3
2
2
3
2
2
CH CH CH , J = 7.2 Hz), 1.19 (d, 3H, (CH ) CH, J = 6.9
3
2
2
3 2
(CH-S), 125.38, 127.89, 128.16, 134.39 (C
), 141.28 (br,
arom
Hz), 1.47 (sext., 2H, CH CH CH , J = 7.5 Hz), 2.41 (t, 2H,
+
3
2
2
C-2); EI ms: m/z 288 (M ).
Anal. Calcd. for C N S (288.46): C, 70.79; H, 8.39; N,
CH CH CH , J = 7.2 Hz), 3.35 (hept., 1H, (CH ) CH, J = 6.6
3
2
2
3 2
H
17 24
2
Hz), 3.78 (s, 2H, CH Ph), 7.11−7.27 (m, 5H, Ph), 11.94 (s,
2
9.71. Found: C, 70.77; H, 8.31; N, 9.74.
13
1H, NH); C-nmr (DMSO-d ): δ 13.43 (CH CH CH ),
6
3
2
2
4-Benzyl-2-sec-butylsulfanyl-5-isopropyl-1H-imidazole (8l).
The compound was obtained as white crystals. Yield 81 mg
22.56 (CH CH CH ), 23.10 ((CH ) CH), 26.57 (br,
3
2
2
3 2
CH CH CH ), 31.34 (br, CH Ph), 38.71 ((CH ) CH),
3
2
2
2
3 2
1
125.59, 128.04, 128.05, 134.65 (C
ms: m/z 274 (M ).
), 140.70 (br, C-2); EI
(28%); mp 125−127°; H-nmr (DMSO-d ): δ 0.92 (t, 3H,
arom
6
+
CH CH CH, J = 7.2 Hz), 1.09 (d, 3H, (CH ) CH, J = 6.6 Hz), 1.18
3
2
3 2
Anal. Calcd. for C
H N S (274.42): C, 70.03; H, 8.08; N,
16 22 2
(d, 3H, CH CH-S, J = 6.9 Hz), 1.42−1.58 (m, 2H, CH CH CH), 2.95
3
3
2
10.21. Found: C, 69.98; H, 8.09; N, 10.16.
(hept., 1H, (CH ) CH, J = 7.2 Hz), 3.19 (sext., 1H, CH CHCH , J =
3 2 3 2

Mar-Apr 2002
Synthesis of Imidazoles as Novel Emivirine and S-DABO Analogues
381
6.6 Hz), 3.75 (s, 2H, CH Ph), 7.16−7.26 (m, 5H, Ph), 11.82 (s, 1H,
Anal. Calcd. for C H N S•0.25H O (326.98): Calc. C,
20 22 2 2
73.47; H, 6.94; N, 8.57. Found: C, 73.26; H, 6.75; N, 8.44.
The HIV-1 strains HTLV-IIIB [23] and the NNRTI resistant
2
13
NH); C-nmr (DMSO-d ): δ 11.10 (CH CH CH ), 20.62
6
3
2
2
(CH CHCH ), 22.43 ((CH ) CH), 24.05 (br, (CH ) CH), 29.15
3
2
3 2
3 2
(CH CH CH), 32.63 (br, CH Ph), 45.12 (CH-S), 125.36, 128.07,
strain N119 [24] were propagated in H9 cells [25] at 37°, 5% CO
3
2
2
2
+
128.21, 134.98 (C
), 141.43 (br, C-2); EI ms: m/z 288 (M ).
using RPMI 1640 with 10% heat-inactivated fetal calf serum
(FCS) and antibiotics (growth medium). Culture supernatant was
filtered (0.45 nm), aliquotted, and stored at −80° until use. Both
HIV-1 strains were obtained from NIH AIDS Research and
Reference Program.
arom
Anal. Calcd. for C
H N S•0.25H O (292.96): C, 69.70; H,
17 24 2 2
8.43; N, 9.56. Found: C, 69.62; H, 8.16; N, 9.57.
General Procedure for Preparation of 4-Benzyl-5-alkyl-2-benzyl-
sulfanyl-1H-imidazole (8m-p).
Compounds were examined for possible antiviral activity
against both strains of HIV-1 using MT4 cells as target cells. MT4
cells were incubated with virus (0.005 MOI) and growth medium
containing the test dilutions of compound for six days in parallel
with virus-infected and uninfected control cultures without com-
pound added. Expression of HIV in the cultures was indirectly
quantified using the MTT assay [26]. Compounds mediating less
than 30% reduction of HIV expression were considered without
biological activity. Compounds were tested in parallel for cyto-
toxic effect in uninfected MT4 cultures containing the test dilu-
tions of compound as described above. A 30% inhibition of cell
growth relative to control cultures was considered significant.
A mixture of 7a-d (1 mmole), benzyl bromide (0.12 ml, 1
mmole) and potassium carbonate (0.138 g, 1 mmoles) in
dimethylformamide (5 ml) was stirred for 10 hours at room temp.
The reaction mixture was treated with ice/cold water (100 ml)
and left to stand at room temperature for 3 hours. The solid prod-
uct was isolated by filtration and recrystallized from
acetone/water to give compounds 8m-p.
4-Benzyl-2-benzylsulfanyl-5-methyl-1H-imidazole (8m).
The compound was obtained as white crystals. Yield 76 mg
1
(26%); mp 105−107°; H-nmr (DMSO-d ): δ 2.07 (s, 3H, CH ),
6
3
The 50% inhibitory concentration (IC ) and the 50% cytotoxic
3.76 (s, 2H, CH Ph ), 4.16 (s, 2H, S-CH Ph), 7.20 (brs, 10H,
50
2
2
13
concentration (CC ) were determined by interpolation from the
2Ph), 11.88 (brs, 1H, NH); C-nmr (DMSO-d ): δ 10.37 (br,
50
6
plots of percent inhibition versus concentration of compound.
CH ), 31.30 (br, CH Ph), 37.81 (S-CH Ph), 125.62, 126.91,
3
2
2
128.09, 128.19, 128.61, 135.16, 138.03 (C
EI ms: m/z 294 (M ).
), 140.55 (br, C-2);
arom
+
REFERENCES AND NOTES
Anal. Calcd. for C
H N S•0.5H O (303.43): C, 71.25; H,
18 18 2 2
6.31; N, 9.22. Found: C, 71.34; H, 5.99; N, 9.19.
[1] T. Miyasaka, H. Tanaka, M. Baba, H. Hayakawa, R. T.
Walker, J. Balzarini and E. De Clercq, J. Med. Chem., 32, 2507
(1989).
[2] H. Tanaka, M. Baba, S. Saito, T. Miyasaka, H. Takashima,
K. Sekiya, M. Ubasawa, I. Nitta, R. T. Walker, H. Nakashima and E.
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Nitta, M. Baba, S. Shigeta, R. T. Walker, E. De Clercq and T.
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[4] H. Tanaka, H. Takashima, M. Ubasawa, K. Sekiya, N.
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Miyasaka, J. Med. Chem., 38, 2860 (1995).
4-Benzyl-2-benzylsulfanyl-5-ethyl-1H-imidazole (8n).
The compound was obtained as white crystals. Yield 98 mg
1
(32%); mp 138−140°; H-nmr (DMSO-d ): δ 1.04 (brs, 3H,
6
CH CH ), 2.44 (brs, 2H, CH CH ), 3.75 (s, 2H, CH Ph), 4.16 (s,
3
2
3
2
2
13
2H, S-CH Ph), 7.22 (brs, 10H, 2Ph), 11.83 (brs, 1H, NH); C-
2
nmr (DMSO-d ): δ 14.53 (CH CH ), 17.06 (br, CH CH ), 32.54
6
3
2
3
2
(br, CH Ph), 37.80 (S-CH Ph), 125.44, 125.83, 126.89, 128.16,
2
2
+
128.65, 138.07 (C
331.1238 (M + Na. C
); EI ms: m/z 308 (M ); HiResMALDI m/z
arom
+
H N NaS) requires 331.1244.
19 20 2
4-Benzyl-2-benzylsulfanyl-5-propyl-1H-imidazole (8o).
[5] M. Artico, S. Massa, A. Mai, M. E. Marongiu, G. Piras, E.
Tramontano and P. La Colla, Antiviral. Chem Chemother., 4, 361
(1993).
The compound was obtained as white crystals. Yield 216 mg
1
(67%); mp 98−100°; H-nmr (DMSO-d ): δ 0.78 (t, 3H,
6
[6] A. Mai, M. Artico, G. Sbardella, S. Quartarone, S. Massa,
A. G. Loi, A. De Montis, F. Scintu, M. Putzolu and P. La Colla, J.
Med. Chem., 40, 1447 (1997).
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Scand., 51, 426 (1997).
[8] A. Lawson, J. Chem. Soc., 1443 (1957).
[9] R. A. F. Bullerwell and A. Lawson, J. Chem. Soc., 3030
(1951).
CH CH CH , J = 7.5 Hz), 1.41−1.50 (m, 2H, CH CH CH ),
3
2
2
3
2
2
2.39 (t, 2H, CH CH CH , J = 7.5 Hz), 3.74 (s, 2H, CH Ph), 4.16
3
2
2
2
(s, 2H, S-CH Ph), 7.11−7.29 (m, 10H, 2Ph), 11.81 (s, 1H, NH);
2
13
C-nmr (DMSO-d ): δ 13.33 (CH CH CH ), 22.54 (br,
6
3
2
2
CH CH CH ), 25.57 (br, CH CH CH ), 28.30 (br, PhCH ),
3
2
2
3
2
2
2
37.84 (S-CH Ph), 125.4, 126.87, 127.90, 128.10, 128.24, 128.64,
2
+
135.17, 135.44 (C
), 141.26 (br, C-2); EI ms: m/z 322 (M ).
arom
Anal. Calcd. for C
H N S (322.46): C, 74.49; H, 6.88; N,
20 22 2
[10] S. Akabori, Chem. Ber., 66, 151 (1933).
8.69. Found: C, 74.39; H, 6.81; N, 8.61.
[11] D. Glass, A. Buschauer, H. Tenor, S. Bartel, L. Will-
Shahab and E. G. Krause, Arch.Pharm.(Weinheim Ger.), 328, 10, 709
(1995).
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Archer, J. Amer. Chem. Soc., 70, 2884 (1948).
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[15] H. D. Dakin and R. West, J. Biol. Chem., 78, 760 (1928).
[16] G. H. Cleland and C. Niemann, J. Amer. Chem. Soc., 71,
841 (1949).
4-Benzyl-2-benzylsulfanyl-5-isopropyl-1H-imidazole (8p).
The compound was obtained as white crystals. Yield 190 mg
1
(59%); mp 123−125°; H-nmr (DMSO-d ): δ 1.09 (d, 3H,
6
(CH ) CH, J = 6.6 Hz), 2.92 (hept., 1H, (CH ) CH, J = 6.0 Hz),
3 2
3 2
3.78 (s, 2H, CH Ph), 4.16 (s, S-CH Ph), 7.12−7.26 (m, 10H,
2
2
13
2Ph), 11.77 (s, 1H, NH); C-nmr (DMSO-d ): δ 22.71
6
((CH ) CH), 24.56 (br, (CH ) CH), 31.59 (br, CH Ph), 37.84 (S-
3 2
3 2
2
CH Ph), 125.58, 126.87, 128.04 128.12, 128.68, 135.27, 138.01
2
+
(C
), 140.81 (br, C-2); EI ms: m/z 322 (M ).
[17] G. S. Sheppard, A. S. Florjancic, J. R. Giesler, L. Xu, Y.
arom

382
Y. M. Loksha, P. T. Jørgensen, E. B. Pedersen,
Vol. 39
M. A. El-Badawi, A. A. El-Barbary and C. Nielsen
Guo, S. K. Davidsen, P. A. Marcotte, I. Elmore, D. H. Albert, T. J.
Magoc, J. J. Bouska, C. L. Goodfellow, D. W. Morgan and J. B.
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