Studying the synthesis of 4-tert-Butyl-1,3-dihydroimidazol-2-ones and their corresponding thiones

Article abstract of DOI:10.1002/jhet.5570400406

4-tert-Butyl-1,3-dihydroimidazol-2-ones and 1,3-dihydroimidazol-2-thiones were synthesized from 1-amino-3,3-dimethylbutanone and subjected to alkylation reactions. The latter compounds were S-alkylated with iodoacetamide under alkaline conditions. The N¹,N³-unsubstituted derivative was iodinated and subsequently alkylated with alkylation reagents which previously have been used for the synthesis of anti-HIV active imidazoles. Unfortunately, the present products were devoid of activity against HIV.

Full text of DOI:10.1002/jhet.5570400406

Studying the Synthesis of 4-tert-Butyl-1,3-
593
Jul-Aug 2003
dihydroimidazol-2-ones and Their Corresponding Thiones
*
Yasser M. Loksha and Erik B. Pedersen
†
Nucleic Acid Center , Department of Chemistry, University of Southern Denmark,
DK-5230 Odense M, Denmark
Ahmed A. El-Barbary and Mahmoud A. El-Badawi
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 March 4, 2003
4-tert-Butyl-1,3-dihydroimidazol-2-ones and 1,3-dihydroimidazol-2-thiones were synthesized from
1-amino-3,3-dimethylbutanone and subjected to alkylation reactions. The latter compounds were S-alkyl-
ated with iodoacetamide under alkaline conditions. The N1,N3-unsubstituted derivative was iodinated and
subsequently alkylated with alkylation reagents which previously have been used for the synthesis of anti-
HIV active imidazoles. Unfortunately, the present products were devoid of activity against HIV.
J. Heterocyclic Chem., 40, 593(2003).
1,3-Dihydroimidazol-2-ones are used as cardiotonic
the action of N,O-bis-(trimethylsilyl)acetamide (BSA) and
followed by N -alkylation of 1b with ethoxymethyl chlo-
ride to afford monoalkylated imidazolone 2 and dialkyl-
ated imidazolone 3. The silylation step induced protection
3
agents [1-4] and 1-substituted 1,3-dihydroimidazole-2-
thione derivatives are used for the treatment of thyroid
disorder [5], arthritis [6,7] and cardiovascular disorders
[8,9]. 1-Substituted 1H-imidazole derivatives are used as
HIV-1 reverse transcriptase inhibitors [10,11]. In addi-
tion, anti-inflammatory activities [12] and, more recently,
antioxidant properties [13] have been reported as well. In
the present report, we are exploring the chemistry of tert-
butyl substituted imidazoles which could be possible
intermediates for the synthesis of imidazole derivatives
with potential activity against HIV. We found tert-butyl
derivatives interesting because an ethyl or an isopropyl
group seems to be a prerequisite for activity against HIV
of both AG1549 (5-(3,5-dichlorophenyl)thio-4-iso-
propyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl
carbamate) [11] and in SJ-3366 (1-(3-cyclopenten-1-yl)-
methyl-6-(3,5-dimethylbenzoyl)-5-ethyl-2,4-pyrimidine-
dione) [14].
1
3
at the N position of 1b rather than N due to steric
hindrance of the tert-butyl group. In this way the lone pair
3
at N of 1b was available for attack on the alkylating
reagent. An alternative explanation for the formation of 2
could be via dealkylation of 3 at the least hindered site
(Scheme 1). Assignment of the structure of compound 2
was confirmed by NOE. Irradiation of NCH O showed
2
4.7% NOE in (CH ) C, and no NOE in H-4 was observed.
3 3
1-Alkyl-5-tert-butyl-1,3-dihydroimidazole-2-thiones
4a-c were obtained by condensation of 1-amino-3,3-
dimethylbutan-2-one hydrochloride with aliphatic isothio-
cyanate derivatives (methyl, ethyl, and cyclohexyl, respec-
tively). Compound 4a has previously been prepared by
Doney and Altland [17] by the same synthetic procedure.
The potassium salt of compounds 4a-c were treated with
2-iodoacetamide to afford 2-(1-alkyl-5-tert-butyl-1H-imi-
dazol-2-ylsulfanyl)acetamides 5a-c (Scheme 1). This is an
a -Aminoketone hydrochlorides were heated with potas-
sium cyanate to give 4-alkyl-1,3-dihydroimidazol-2-ones
1a,b as previously described by Lawson [15] for 1a and by
Jackman et al [16] for 1b. Compound 1b was silylated by
1
effective way to prepare N ,S-dialkylated-1H-dihydroimi-
dazol-2-thiones 5a-c which have a substituent in the
2-position with some resemblance to the one in AG1549.
2-[(4-tert-Butyl-1H-imidazol-2-yl)thio]acetamide 6 was
synthesized by reaction of the potassium salt of the com-
mercial available 4-tert-butyl-1,3-dihydroimidazole-2-
thione 1c with 2-iodoacetamide in methanol. Compound 6
was coupled with dimethylsulfamoyl chloride to get 2-[(4-
tert-butyl-1-dimethylsulfamoyl-1H-imidazol-2-
yl)thio]acetamide 7. It was attempted to introduce a cyclo-
hexylthio substituent to the 5-position of 7 by lithiation
with n-butyl lithium at –78° followed by addition of cyclo-
hexyl disulfide. However, the product was elucidated to be
Figure 1. Chemical Structure of SJ-3366 and AGI 549.

594
Y. M. Loksha, E. B. Pedersen, A. A. El-Barbary, M. A. El-Badawi and C. Nielsen
Vol. 40
group. Formation of sodium salt of compound 10 was
obtained by its treatment with sodium hydride in anhy-
drous dimethylformamide under ice cooling. By portion-
wise addition of 4-pyridylmethyl chloride hydrochloride
to the salt of 10, 2-[(4-tert-butyl-5-iodo-1-(pyridin-4-
ylmethyl)-1H-imidazol-2-yl)thio]acetamide (12) was
formed (Scheme 3). It was clear that steric hindrance of
the tert-butyl group at the 4-position inhibited coupling at
the 3-position of the imidazole ring
The sodium salt of 3,5-dimethylthiophenol was treated
with compound 11b in dimethylformamide in order to
introduce the 3,5-dimethylphenylthio group in the 5-posi-
tion of the imidazole ring. The products separated from the
reaction mixture using column chromatography were elu-
cidated to be 2-[(1-benzyloxymethyl-4-tert-butyl-1H-imi-
dazol-2-yl)thio]acetamide (13), 1-benzyloxymethyl-4-
tert-butyl-1,3-dihydroimidazole-2-thione (14), and 2,2-
bis-(3,5-dimethylphenylthio)acetamide (15) and not the
desired substitution product (Scheme 4).
2-[(4-tert-butyl-1H-imidazol-2-yl)thio]-2-dimethylsul-
famoylacetamide 8 and not the desired 2-[(4-tert-butyl-5-
cyclohexylsulfanyl-1-dimethylsulfamoyl-1H-imidazol-2-
yl)thio]acetamide 9 (Scheme 2). Both tautomers of com-
1
13
pound 8 were observed in H-nmr and C-nmr where
double signals were observed for nearly all the atoms. In
all other cases with tautomeric structures in this investiga-
tion, the tautomerisation in the imidazole ring resulted in
line broadening and/or disappearance of imidazole car-
13
bons in C-nmr.
Phase transfer iodination of compound 6 by treatment
with a mixture of methylene chloride, aqueous sodium
hydroxide and methanol followed by addition of iodine
solution in methanol and methylene chloride afforded 2-
[(4-tert-butyl-5-iodo-1H-imidazol-2-yl)thio]acetamide
(10). Coupling of compound 10 with ethoxy (or benzyl-
oxy) methyl chloride in the presence of N-ethyldiisopropy-
It is believed that a deiodination reaction of 11b takes
place by a nucleophilic attack of sulfide on iodine forming
a 3,5-dimethylphenyl sulfenyliodide that in turn is
believed to be an iodination reagent. Iodination can then
take place in the a -position of the acetamide side chain
1
lamine (EDIA) as a bulky base gave N substituted 2-[(4-
tert-butyl-5-iodo-1H-imidazol-2-yl)thio]acetamides 11a,b
as the sole product due to steric hindrance of the tert-butyl

Jul-Aug 2003
Studying the Synthesis of 4-tert-Butyl-1,3-dihydroimidazol-2-ones
595
dazol-2-ylmethyl)benzamide (17). Phase transfer iodina-
tion of compound 17 furnished N-(4-tert-butyl-5-iodo-1H-
imidazol-2-ylmethyl)benzamide (18). Lithiation of com-
pound 18 by n-butyl lithium at –78° followed by addition
of cyclohexyl disulfide was tried, but the isolated product
was compound 17 (Scheme 5).
because an anion here easily can be formed due to the
neighboring sulfur atom. A series of subsequent reaction
will then lead to the main compound 15.
4-Alkyl-1,3-dihydroimidazol-2-ones 1a,b were acyl-
ated by benzoyl chloride under the Friedel-Crafts condi-
tions using nitrobenzene as a solvent and aluminum
chloride as a catalyst to furnish 5-alkyl-4-benzoyl-1,3-
dihydroimidazol-2-ones 19a,b (Scheme 6). The yield of
the reaction in the case of isopropyl group was higher
than that of tert-butyl group due to the steric hindrance
of the tert-butyl group. This seems so far to be the only
route for synthesizing 4-tert-butyl substituted imidazole
derivatives with an aryl containing substituent in the
5-position. Further work is progress of utilizing such
compounds as intermediates in the synthesis of potential
anti-HIV compounds.
Benzoylaminoacetonitrile was prepared by treatment of
aminoacetonitrile with benzoyl chloride in pyridine under
ice cooling as described by Goldberg and Kelly [18].
Benzoylaminoacetonitrile was converted to ethyl 2-ben-
zoylaminoacetamidate hydrochloride (16) by passing
hydrogen chloride gas through a solution of benzoyl-
aminoacetonitrile and absolute ethanol in methylene chlo-
ride under ice cooling [19]. Refluxing compound 16 with
1-amino-3,3-dimethylbutan-2-one hydrochloride and
triethylamine in ethanol afforded N-(4-tert-butyl-1H-imi-
The test for activity against HIV-1 was performed in
MT4 cell cultures infected with wild type HIV-1 (strain
IIIB) using the assay as previously described [20]. The
compounds were inactive at 100mM or inactive at subtoxic
concentrations.

596
Y. M. Loksha, E. B. Pedersen, A. A. El-Barbary, M. A. El-Badawi and C. Nielsen
Vol. 40
EXPERIMENTAL
5-tert-Butyl-1-ethyl-1,3-dihydroimidazole-2-thione (4b).
This compound was obtained as white crystals. Yield 1.1 g
(30%); mp 160–162°; 1H-nmr (DMSO-d6): d 1.19–1.28 (m, 12H,
(CH3)3C and CH3CH2), 4.09 (q, 2H, CH3CH2, J = 6.3 Hz), 6.53
(s, 1H, H-4), 11.93 (s, 1H, NH); 13C-nmr (DMSO-d6): d 13.50
(CH3CH2), 29.45 ((CH3)3C), 30.63 ((CH3)3C), 40.11 (CH2N),
109.68 (C-4), 137.90 (C-5); EI MS: m/z 184 (M+).
NMR spectra were recorded on a Varian Gemini 2000 NMR
spectrometer at 300 MHz for 1H and 75.5 MHz for 13C with TMS
as an internal standard. EI mass spectra were recorded on a
Finnigan MAT SSQ 710. The progress of the reactions was mon-
itored by TLC (analytical silica gel plates 60F254). The silica gel
(0.040x0.063 mm) used for column chromatography was pur-
chased from Merck. Microanalyses were carried out at
Microanalytical Department, Chemical Laboratory II at the
University of Copenhagen, Denmark.
Anal. Calcd. for C9H16N2S•0.25H2O (188.81): C, 57.25; H,
8.54; N, 14.84. Found: C, 57.23; H, 8.62; N, 14.72.
5-tert-Butyl-1-cyclohexyl-1,3-dihydroimidazole-2-thione (4c).
This compound was obtained as white crystals. Yield 4.1 g
(86%); mp 198–200°; H-nmr (CDCl3): d 1.18–1.46 (m, 13H,
5-tert-Butyl-1-ethoxymethyl-1,3-dihydroimidazol-2-one (2) and
4-tert-Butyl-1,3-bis(ethoxymethyl)-1,3-dihydroimidazol-2-one
(3).
1
(CH3)C and Hcy), 1.66–1.96 (m, 4H, Hcy), 3.36–3.48 (m, 2H,
Hcy), 4.13–4.24 (m, 1H, Hcy), 6.41 (s, 1H, H-4), 11.81 (s, 1H,
NH); 13C-nmr (CDCl3): d 24.81, 26.39, 27.88, 58.35 (Ccy), 29.68
((CH3)C), 30.93 ((CH3)C), 109.95 (C-4), 139.51 (C-5), 159.20
(C=S); EI MS: m/z 238 (M+).
To a solution of compound 1b (0.7 g, 5 mmoles) in chloroform
(20 ml) under nitrogen atmosphere, was added N,O-bis-
(trimethylsilyl)acetamide (4.3 ml, 17.5 mmoles). The mixture
was stirred at room temp. for 0.5 hour, then ethoxymethyl chlo-
ride (0.7 ml, 7.5 mmoles) and cesium iodide (2 g, 7.5 mmoles)
were added dropwise and the mixture was stirred for 3 hours. The
reaction was quenched by addition of a saturated solution of
sodium carbonate (10 ml), the mixture was filtered, the two lay-
ers were separated and the aqueous phase was further extracted
with chloroform (20 ml). The chloroform phases were dried with
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 (1:10, v/v) to afford com-
pounds 2 and 3.
Anal. Calcd. for C13H22N2S•0.25H2O (242.9): C, 64.28; H,
9.13; N, 11.53. Found: C, 64.68; H, 9.37; N, 11.65.
General Procedure for Preparation of 2-[(1-Alkyl-5-tert-butyl-1-
methyl-1H-imidazol-2-yl)thio]acetamides 5a-c.
To a solution of potassium hydroxide (0.28 g, 5 mmoles) in
methanol (15 ml), compound 4a-c (1.3 g, 5 mmoles) was added
and the mixture was stirred for 0.5 hour. 2-Iodoacetamide (0.93
g, 5 mmoles) was added to the reaction mixture, and the reaction
was stirred at room temp. for an additional hour. The solvent was
removed under reduced pressure, water (25 ml) was added to the
residual material. The solid product was collected and recrystal-
lized from ethanol/water to give 5a-c.
5-tert-Butyl-1-ethoxymethyl-1,3-dihydroimidazol-2-one (2).
The compound was obtained as white crystals. Yield 0.08 g
2-[(5-tert-Butyl-1-methyl-1H-imidazol-2-yl)thio]acetamide (5a).
1
(8%); mp 83–84°; H-nmr (CDCl3): d 1.12 (t, 3H, CH3CH2, J =
7.1 Hz), 1.23 (s, 9H, (CH3)3C), 3.54 (q, 2H, CH3CH2, J = 7.1
Hz), 5.17 (s, 2H, NCH2O), 5.92 (s, 1H, H-4), 10.41 (brs, 1H,
NH); 13C-nmr (CDCl3): d 14.97 (CH3CH2), 29.58 ((CH3)3C),
31.15 ((CH3)3C), 63.66 (CH3CH2O), 71.14 (NCH2O), 103.68
(C-4), 132.61 (C-5),156.56 (C-2); EI MS: m/z 198 (M+).
This compound was obtained as white crystals. Yield 0.68 g
(60%); mp 94–96°; H-nmr (CDCl3): d 1.35 (s, 9H, (CH3)3C),
1
3.63 (s, 2H, CH2S), 3.68 (s, 3H, CH3N), 5.79 (brs, 1H, HNH),
6.77 (s, 1H, H-4), 8.46 (brs, 1H, HNH); 13C-nmr (CDCl3): d
29.33 ((CH3)3C), 31.01 ((CH3)3C), 33.03 (CH2S), 35.95
(CH3N), 124.43 (C-4), 142.36 (C-5), 142.68 (C-2), 172.14
(C=O). EI MS: m/z 227 (M+).
4-tert-Butyl-1,3-bis(ethoxymethyl)-1,3-dihydroimidazol-2-one
(3).
Anal. Calcd. for C10H17N3OS (227.32): C, 52.84; H, 7.54; N,
18.48. Found: C, 52.35; H, 7.57; N, 18.25.
The compound was obtained as an oil. Yield 0.2 g (15%);
1H-nmr (CDCl3): d 1.17–1.25 (m, 6H, 2 ´ CH3CH2O), 1.32 (s,
9H, (CH3)3C), 3.54–3.65 (m, 4H, 2 ´ CH3CH2O) 5.01 (NCH2O),
5.25 (NCH2O), 6.08 (s, 1H, H-5); 13C-nmr (CDCl3): d 14.85
(CH3CH2O), 14.95 (CH3CH2O), 29.50 ((CH3)3C), 31.20
((CH3)3C), 63.86 (CH3CH2O), 64.24 (CH3CH2O), 71.52
(NCH2O), 72.72 (NCH2O), 105.49 (C-5), 132.78 (C-5), 156.28
(C-2); EI MS: m/z 256 (M+).
2-[(5-tert-Butyl-1-ethyl-1H-imidazol-2-yl)thio]acetamide (5b).
This compound was obtained as white crystals. Yield 0.7 g
1
(58%); mp 103–105°; H-nmr (CDCl3): d 1.32–1.39 (m, 12H,
(CH3)3C and CH3CH2), 3.65 (s, 2H, CH2S), 4.09 (q, 2H,
CH3CH2, J = 7.2 Hz), 5.76 (brs, 1H, HNH), 6.70 (s, 1H, H-4),
8.62 (brs, 1H, HNH); 13C-nmr (CDCl3): d 15.95 (CH3CH2),
30.03 ((CH3)3C), 31.14 ((CH3)3C), 35.89 (CH3CH2), 40.37
(CH2S), 124.36 (C-4), 141.98 (C-2 and C-5), 172.39 (C=O); EI
MS: m/z 241 (M+).
General Procedure for Preparation of 1-Alkyl-5-tert-butyl-1,3-
dihydroimidazole-2-thiones 4b,c.
A mixture of 1-amino-3,3-dimethylbutan-2-one hydrochloride
(3.03 g, 20 mmoles), isothiocyanate derivative (ethyl, and cyclo-
hexyl) (20 mmoles), and triethylamine (2.8 ml, 20 mmoles) in
dry benzene (20 ml) was refluxed for 3 hours. The solvent was
removed under reduced pressure, and acetic acid (20 ml) was
added to the residual material and the mixture was refluxed for 2
hours. The solvent was concentrated to 5 ml, then water (30 ml)
was added and the solid product formed was collected, washed
with ether (30 ml), and dried to afford compounds 4b,c.
Anal. Calcd. for C11H19N3OS (241.35): C, 54.74; H, 7.93; N,
17.40. Found: C, 54.73; H, 8.04; N, 17.35.
2-[(5-tert-Butyl-1-cyclohexyl-1H-imidazol-2-yl)thio]acetamide
(5c).
This compound was obtained as white crystals. Yield 1.13 g
(77%); mp 182–184°; 1H-nmr (DMSO-d6): d 1.09–1.44 (m, 13H,
(CH3)3C and Hcy), 1.66–1.88 (m, 4H, Hcy), 2.26–2.38 (m, 2H,
Hcy), 3.78 (s, 1H, CH2S), 6.60 (s, 1H, H-4), 7.12 (brs, 1H, HNH),

Jul-Aug 2003
Studying the Synthesis of 4-tert-Butyl-1,3-dihydroimidazol-2-ones
597
7.69 (brs, 1H, HNH); 13C-nmr (DMSO-d6): d 24.63, 25.67,
30.36, 55.58 (Ccy), 29.77 ((CH3)3C), 30.63 ((CH3)3C), 37.04
(CH2S), 123.54 (C-5), 139.66 (C-2), 141.38 (C-4), 169.50
(C=O);. EI MS: m/z 295 (M+).
Anal. Calcd. for C15H25N3OS (295.44): C, 60.98; H, 8.53; N,
14.22. Found: C, 60.91; H, 8.59; N, 14.24.
The compound was obtained as white crystals. Yield 0.1 g
(30%); mp 185–187°; 1H-nmr (DMSO-d6): d 1.21 (s, 9H,
(CH3)3C), 1.22 (s, 9H, (CH3)3C), 2.77 (s, 6H, (CH3)2N), 2.81 (s,
6H, (CH3)2N), 5.45 (s, 1H, CHS), 5.59 (s, 1H, CHS), 6.68 (s, 1H,
H-5), 6.88 (s, 1H, H-5), 7.63 (brs, 2H, HNH), 8.02 (brs, 1H,
HNH), 8.06 (brs, 1H, HNH), 12.17 (s, 1H, NH), 12.26 (s, 1H,
NH); 13C-nmr (DMSO-d6): d 29.56, 30.06 ((CH3)3C), 30.23,
31.53 ((CH3)3C), 37.35, 37.54 ((CH3)2N), 68.63, 68.88 (CHS),
112.55, 123.51 (C-5), 134.18, 143.03 (C-4), 152.41 (C-2),
164.07, 171.50 (CONH2); EI MS: m/z 320 (M+).
2-[(4-tert-Butyl-1H-imidazol-2-yl)thio]acetamide (6).
To a solution of potassium hydroxide (0.56 g, 10 mmoles) in
methanol (15 ml), compound 4-tert-butyl-1,3-dihydroimidazole-
2-thione 1c (1.56 g, 10 mmoles) was added and the mixture was
stirred for 0.5 hour. 2-Iodoacetamide (1.86 g, 10 mmoles) was
added to the reaction mixture and the reaction was stirred at room
temperature for an additional hour. The solvent was removed
under reduced pressure, and water (25 ml) was added to the resid-
ual material and the solid product formed was collected and
recrystallized from ethanol/water to give compound 6.
The compound was obtained as white crystals. Yield 1.34 g
(63%); mp 145–147°; 1H-nmr (DMSO-d6): d 1.19 (s, 9H,
(CH3)3C), 3.63 (s, 2H, CH2S), 6.69 (brs, 1H, H-5), 7.17 (s, 1H,
HNH), 7.76 (brs, 1H, HNH), 11.96 (brs, 1H, NH); 13C-nmr
(DMSO-d6): d 29.83 ((CH3)3C), 36.66 (CH2S), 137.56 (C-2),
170.12 (C=O); EI MS: m/z 213 (M+).
Anal. Calcd for C11H20N4O3S2•0.6H2O (331.24): C, 39.89; H,
6.45; N, 16.91. Found: C, 39.66; H, 6.00, N, 16.62.
2-[(4-tert-Butyl-5-iodo-1H-imidazol-2-yl)thio]acetamide (10).
To a solution of sodium hydroxide (0.6 g, 15 mmoles) in water
(15 ml) were added methylene chloride (15 ml) and compound 6
(3.2 g, 15 mmoles). A solution of iodine (3.84 g, 15 mmoles) in
methylene chloride (15 ml) and methanol (10 ml) was added
dropwise under ice cooling. After 15 min. the mixture was fil-
tered and the precipitated material was washed with ether (30 ml)
and dried to give a pure solid of compound 10.
The compound was obtained as white crystals. Yield 2.9 g
(57%); mp 158–160°; 1H-nmr (DMSO-d6): d 1.33 (s, 9H,
(CH3)3C), 3.68 (s, 2H, CH2S), 7.23 (brs, 1H, HNH), 7.66 (s, 1H,
HNH), 12.09 (s, 1H, NH); 13C-nmr (DMSO-d6): d 29.67
((CH3)3C), 36.38 (CH2S), 169.91 (C=O). EI MS: m/z 339 (M+).
Anal. Calcd for C9H14IN3OS×0.25H2O (343.70): C, 31.45; H,
4.25; N, 12.23. Found: C, 31.13; H, 3.87; N, 11.81.
Anal. Calcd for C9H15N3OS•0.25H2O (217.81): C, 49.63; H,
7.17; N, 19.70. Found: C, 49.83; H, 6.96; N, 19.34.
2-[(4-tert-Butyl-1-dimethylsulfamoyl-1H-imidazol-2-yl)thio]-
acetamide (7).
To a mixture of compound 6 (0.53 g, 2.5 mmoles) and triethy-
lamine (0.35 ml, 2.5 mmoles) in toluene (20 ml), dimethylsul-
famoyl chloride (0.26 ml, 2.5 mmoles) in toluene (5 ml) was
added dropwise. The mixture was stirred at room temp. for 1 hour
followed by refluxing for 5 hours. After cooling to room temp.,
water (30 ml) was added to the reaction mixture and the two lay-
ers were separated. The organic layer was dried over sodium sul-
fate, and the solvent was removed under reduced pressure. The
residual material was chromatographed on a column of silica gel
with CH2Cl2:EtOAc (1:1, v/v) to afford compound 7.
The compound was obtained as white crystals. Yield 0.38 g
(48%); mp 120–122°; 1H-nmr (CDCl3): d 1.24 (s, 9H, (CH3)3C),
2.95 (s, 6H, (CH3)2N), 3.77 (s, 2H, CH2S), 5.84 (brs, 1H, HNH),
6.95 (s, 1H, H-5), 7.81 (brs, 1H, HNH); 13C-nmr (CDCl3): d
29.36 ((CH3)3C), 31.89 ((CH3)3C), 35.09 (CH2S), 38.54
((CH3)2N), 114.54 (C-5), 143.34 (C-4), 151.81 (C-2), 171.88
(CONH2); HiResMALDI m/z 321.1049 (M+H+. C11H20N4O3S2)
requires 321.1055.
General Procedure for Preparation of 2-[(1-Alkoxymethyl-4-tert-
butyl-5-iodo-1H-imidazol-2-yl)thio]acetamide (11a,b).
Compound 10 (1.36 g, 4 mmoles) was dissolved in methylene
chloride (20 ml) under nitrogen atmosphere. N-Ethyldiiso-
propylamine (EDIA) (0.72 ml, 4 mmoles) was added to the reac-
tion mixture followed by addition of ethoxy or benzyloxy methyl
chloride (4 mmoles). The reaction mixture was stirred for 3 hours
at room temp. and quenched with water (20 ml). Methylene chlo-
ride (30 ml) was added and the two layers were separated. The
organic layer was dried using sodium sulfate, and the solvent was
removed under reduced pressure. The residual material was chro-
matographed on a column of silica gel with ethyl acetate to afford
compounds 11a,b.
2-[(4-tert-Butyl-1-ethoxymethyl-5-iodo-1H-imidazol-2-
yl)thio]acetamide (11a).
The compound was obtained as white crystals. Yield 1.14 g
(72%); mp 95–97°; 1H-mnr (CDCl3): d 1.21 (t, 3H, CH3CH2, J =
7.0 Hz), 1.40 (s, 9H, (CH3)3C), 3.54 (q, 2H, CH3CH2, J = 7.0
Hz), 3.63 (s, 2H, CH2S), 5.31 (s, 1H, NCH2O), 5.69 (brs, 1H,
HNH), 8.68 (brs, HNH); 13C-mnr (CDCl3): d 14.84 (CH3CH2),
29.83 ((CH3)3C), 32.94 ((CH3)3C), 36.42 (CH2S), 64.46
(CH3CH2O), 65.82 (C-5), 75.71 (NCH2O), 142.94 (C-4), 152.40
(C-2), 172.20 (C=O); EI MS: m/z 397 (M+).
2-[(4-tert-Butyl-1H-imidazol-2-yl)thio]-2-dimethylsulfamoyl-
acetamide (8).
Compound 7 (0.32 g, 1 mmole) was dissolved in tetrahydrofu-
ran (20 ml) under nitrogen atmosphere, and the solution was
cooled to –78°. n-Butyl lithium (1.8 ml, 4 mmoles) was added to
the solution at –78°. The mixture was stirred for 0.5 hour at –78°,
then cyclohexyl disulfide (0.69 g, 3 mmoles) was added dropwise
at –78°. The mixture was left to reach room temp. and the reac-
tion was quenched with water (10 ml). The reaction mixture was
filtered and ether (30 ml) was added to the filtrate before separat-
ing the two layers. The organic layer was dried over sodium sul-
fate. The solvents were removed under reduced pressure and the
residual material was chromatographed on a column of silica gel
with CH2Cl2:MeOH (15:1, v/v) to afford compound 8.
Anal. Calcd. for C12H20IN3OS (397.27): C, 36.28; H, 5.07; N,
10.58. Found: C, 36.53; H, 5.05; N, 10.35.
2-[(1-Benzyloxymethyl-4-tert-butyl-5-iodo-1H-imidazol-2-
yl)thio]acetamide (11b).
The compound was obtained as white crystals. Yield 1.38 g
(75%); mp 104–106°; 1H-mnr (CDCl3): d 1.39 (s, 9H, (CH3)3C),
3.59 (s, 2H, CH2S), 4.58 (s, 2H, CH2Ph), 5.36 (s, 2H, NCH2O),

598
Y. M. Loksha, E. B. Pedersen, A. A. El-Barbary, M. A. El-Badawi and C. Nielsen
Vol. 40
5.67 (s, 1H, HNH), 7.26-7.35 (m, 5H, Ph), 8.62 (s, 1H, HNH);
13C-nmr (CDCl3): d 29.83 ((CH3)3C), 32.94 ((CH3)3C), 36.36
(CH2S), 65.72 (C-5), 70.78 (CH2Ph), 75.38 (NCH2O), 127.59,
128.02, 128.44, 136.52 (Carom), 143.08 (C-4), 152.64 (C-2),
172.14 (C=O); EI MS: m/z 459 (M+).
4.68 (s, 2H, CH2Ph), 5.52 (s, 2H, NCH2O), 6.47 (s, 1H, H-5),
7.27-7.38 (m, 5H, Ph), 11.71 (brs, 1H, NH); 13C-nmr (CDCl3): d
29.29 ((CH3)3C), 30.50 ((CH3)3C), 71.43 (OCH2Ph), 75.39
(NCH2O), 110.99 (C-5), 127.88, 127.89, 128.38, 137.19 (Carom),
139.59 (C-4), 161.43 (C-2); EI MS: m/z 276 (M+).
Anal. Calcd. for C17H22IN3OS (459.35): C, 44.45; H, 4.83; N,
9.15. Found: C, 45.06; H, 4.76; N, 8.92.
2,2-Bis(3,5-dimethylphenylthio)acetamide (15).
The compound was obtained as white crystals.Yield 120 mg
(36%); mp 138–140°; 1H NMR (CDCl3): d 2.28 (s, 12H, 4 ´
CH3), 4.79 (s, 1H, CH), 5.67 (brs, 1H, HNH), 6.39 (brs, 1H,
HNH), 6.92 (s, 2H, Ph), 7.08 (s, 4H, Ph); 13C-nmr (CDCl3): d
21.15 (4 ´ CH3), 58.03 (CH), 129.81, 130.27, 132.39, 138.85
(Carom), 170.26 (C=O); EI MS: m/z 331 (M+).
2-[(4-tert-Butyl-5-iodo-1-pyridin-4-ylmethyl-1H-imidazol-2-
yl)thio]acetamide (12).
Compound 10 (1.36 g, 4 mmoles) was dissolved in dimethylfor-
mamide (15 ml), sodium hydride (0.35 g, 8 mmoles) was added to
the solution portionwise under ice cooling. After stirring for
0.5 hour, 4-pyridylmethyl chloride hydrochloride (1.7 g, 10
mmoles) was added portionwise to the reaction mixture under ice
cooling, and the reaction mixture was left to be stirred at room
temp. for 4 hours. The solvent was removed under reduced pressure
and the residual material was treated with water (30 ml) and filtered.
The precipitate was dried and chromatographed on a column of
silica gel with EtOAc:MeOH (20:1, v/v) to give compound 12.
The compound was obtained as white crystals. Yield 0.9 g
(52%); mp 135–137°; 1H-mnr (CDCl3): d 1.42 (s, 9H, (CH3)3C),
3.57 (s, 2H, CH2S), 5.19 (s, 2H, CH2N), 5.77 (s, 1H, HNH), 6.94
(d, 2H, Hpy, J = 6.0 Hz), 8.58 (d, 2H, Hpy, J = 6.0 Hz), 8.64 (s, 1H,
HNH); 13C-mnr (CDCl3): d 29.79 ((CH3)3C), 32.99 (CH3)3C),
36.56 (CH2S), 66.46 (C-5), 121.29, 144.38, 150.26 (Cpy), 142.15
(C-4), 153.13 (C-2), 171.87 (C=O); EI MS: m/z 430 (M+).
Anal. Calcd for C15H19IN4OS (430.31): C, 41.87; H, 4.45; N,
13.02. Found: C, 42.13; H, 4.39; N, 12.69.
Anal. Calcd. for C18H21NOS2 (331.49): C, 65.22; H, 6.39; N,
4.23. Found: C, 64.78; H, 6.39; N, 4.29.
N-(4-tert-Butyl-1H-imidazol-2-ylmethyl)benzamide (17).
A mixture of compound 16 (4.85 g, 20 mmoles), 1-amino-3,3-
dimethylbutan-2-one hydrochloride (3.03 g, 20 mmoles), and
triethylamine (5.6 ml, 40 mmoles) was refluxed in ethanol (30
ml) for 6 hours. The reaction mixture was cooled to room temp.
and the solvent was removed under reduced pressure. The residue
was treated with water (50 ml) and extracted with ether (3 x 25
ml). The ether extracts were dried (sodium sulfate), and concen-
trated to 10 ml. Petroleum ether (50 ml) was added to the concen-
trated solution and the solid product formed was collected and
dried to furnish compound 17.
The compound was obtained as white crystals. Yield 1.6 g
(31%); mp 168–170°; 1H-nmr (CDCl3): d 1.24 (s, 9H, (CH3)3C),
4.58 (d, 2H, CH2NH, J = 5.4 Hz), 6.61 (s, 1H, H-5), 7.26?7.47
(m, 3H, Ph), 7.93 (d, 2H, Ph, J = 7.5 Hz), 9.56 (brs, 1H, NH);
13C-nmr (CDCl3): d 30.12 ((CH3)3C), 30.85 ((CH3)3C), 37.43
(CH2), 127.44, 128.34, 131.56, 133.65 (Carom), 145.59 (C-2),
169.01 (CONH); EI MS: m/z 257 (M+).
2-[(1-Benzyloxymethyl-4-tert-butyl-1H-imidazol-2-yl)thio]-
acetamide (13), 1-Benzyloxymethyl-4-tert-butyl-1,3-dihydroimi-
dazole-2-thione (15) and 2,2-Bis(3,5-dimethylphenylthio)-
acetamide (14).
3,5-Dimethylthiophenol (0.13 ml, 1 mmole) was dissolved in
dimethylformamide (10 ml), and sodium hydride (44 mg, 1 mmole)
was added to the solution portionwise under ice cooling. After stir-
ring for 0.5 hour, compound 11b (0.46 g, 1 mmole) was added por-
tionwise to the reaction mixture under ice cooling, and the reaction
mixture was left to be stirred at room temp. for 4 hours. The solvent
was removed under reduced pressure and the residual material was
treated with water (20 ml) and filtered. The precipitate was dried
and chromatographed on a column of silica gel with
CH2Cl2:EtOAc (6:1, v/v) to furnish compounds 13, 14and 15.
Anal. Calcd for C15H19N3O•0.15H2O (260.04): C, 69.28; H,
7.48; C, 16.16. Found: C, 69.27; H, 7.34; N, 15.93.
N-(4-tert-Butyl-5-iodo-1H-imidazol-2-ylmethyl)benzamide (18).
To a solution of sodium hydroxide (0.2 g, 5 mmoles) in water
(10 ml) was added methylene chloride (10 ml) and compound 17
(1.3 g, 5 mmoles). A solution of iodine (1.28 g, 5 mmoles) in
methylene chloride (10 ml) and methanol (5 ml) was added drop-
wise under ice cooling. After 15 min. the mixture was filtered,
and the precipitated material was washed with ether (20 ml) and
dried to give a pure solid of compound 18.
2-[(1-Benzyloxymethyl-4-tert-butyl-1H-imidazol-2-yl)thio]-
acetamide (13).
The compound was obtained as white crystals. Yield 0.85 g
1
(44%); mp 215–217°; H-nmr (CDCl3): d1.36 (s, 9H, (CH3)3C),
The compound was obtained as an oil. Yield 50 mg (15%); 1H-
nmr (CDCl3): d 1.65 (s, 9H, (CH3)3C), 3.52 (s, 2H, CH2S), 4.43
(s, 2H, CH2Ph), 5.18 (s, 2H, NCH2O), 5.73 (brs, 1H, HNH), 6.66
(s, 1H, H-5), 7.20-7.29 (m, 5H, Ph), 8.75 (brs, 1H, HNH); 13C-
nmr (CDCl3): d 29.78 ((CH3)3C), 31.78 ((CH3)3C), 36.29
(CH2S), 70.63 (OCH2Ph), 74.69 (NCH2O), 115.17 (C-5),
127.75, 128.10, 128.48, 136.35 (Carom), 141.16 (C-4), 152.71 (C-
2), 172.45 (C=O); MS HiResMALDI m/z 334.1576
(M+H+.C17H23N3O2S) requires 334.1583.
4.45 (d, 2H, CH2NH, J = 5.1 Hz), 7.44?7.56 (m, 3H, Ph), 7.90 (d,
2H, Ph, J = 6.9 Hz), 8.87 (t, 1H, CH2NH, J = 5.1 Hz); 13C-nmr
(CDCl3): d 29.77 ((CH3)3C), 30.31 ((CH3)3C), 36.46 (CH2),
77.01 (C-5), 127.26, 128.18, 131.21, 137.99 (Carom), 133.98 (C-
4), 145.25 (C-2), 165.97 (CONH); EI MS: m/z 383 (M+).
Anal. Calcd for C15H18IN3O (283.23): C, 47.01; H, 4.73; N,
10.96. Found: C, 46.86; H, 4.62; N, 10.76.
5-Alkyl- 4-benzoyl-1,3-dihydroimidazol-2-ones 19a,b.
Benzoyl chloride (0.6 g, 5 mmoles) was added dropwise to a
mixture of anhydrous aluminum chloride (1.33 g, 10 mmoles),
4-alkyl-1,3-dihydroimidazol-2-one 1a,b (5 mmoles) in nitroben-
zene (10 ml) over 15 min. The mixture was stirred for 6 hours at
60–65° and then poured onto ice (100 g). The resulting solid was
1-Benzyloxymethyl-4-tert-butyl-1,3-dihydro-imidazol-2-thione
(14).
The compound was obtained as white crystals. Yield 50 mg
(18%); mp 110–112°; 1H-nmr (CDCl3): d 1.29 (s, 9H, (CH3)3C),

Jul-Aug 2003
Studying the Synthesis of 4-tert-Butyl-1,3-dihydroimidazol-2-ones
599
Ingebretsen and E. Cantor, J. Med. Chem., 32, 1173 (1989).
collected, washed with water and ether (20 ml) and recrystallized
[4] K. J. Shaw, P. W. Erhardt, A. A. Hagedorn III, C. A. Pease,
W. R. Ingebretsen and J. R. Wiggins, J. Med. Chem., 35, 1267
(1992).
from ethanol/water to give compounds 19a,b.
4-Benzoyl-5-isopropyl-1,3-dihydroimidazol-2-one (19a).
[5] R. C. Haynes Jr and F. Murad, in The Pharmaceutical
Basis of Therapeutics, ed, by A. G. Gilman, L. S. Goodman and F.
Murad, Macmillan, New York, 1401 (1985).
[6] T. D. Hill, US4188397; Chem. Abstr., 92: 215444 (1980).
[7] S. C. Cherkofsky and T. R. Sharp, GP2805166; Chem.
Abstr., 90, 23051 (1979)).
[8] L. I. Kruse, C. Kaiser, W. E. DeWolf, J. A. Frazee, L. E.
Hilbert, S. T. Ross, K. E. Flaim and J. L. Sawer, J. Med. Chem., 33,
781 (1990).
[9] L. I. Kruse, C. Kaiser, W. E. DeWolf, J. S. Frazee, S. T.
Ross, J. Wawro, M. Wise, K. E. Flaim, J. L. Sawer, R. W. Erickson,
M. Ezekiel, E. H. Ohlstein and B. A. Berkowitz, J. Med. Chem., 30,
486 (1987).
[10] E. J. Saloski, Tetrahedron Lett., 36, 1387 (1995).
[11] T. Fujiwara, A. Sato, M. El-Farrash, S. Miki, K. Abe, Y.
Isaka, M. Kodama, Y. Wu, B. L. Chen, H. Harada, H. Sugimoto, M.
Hatanaka and Y. Hinuma, Antimicrob. Agents Chemother., 42,
1961(1998).
[12] S. Maeda, M. Suzuki, T. Iwasaki, K. Masumoto and I
Iwasawa, Chem. Pharm. Bull., 32, 2536(1984).
[13] R. C. Smith and J. C. Reeves, Biochem. Pharmacol., 36,
1457 (1987).
The compound was obtained as white crystals. Yield 0.4 g
(35%); mp 254–256°; 1H-nmr (DMSO-d6): d 1.05 (d, 6H,
(CH3)2CH, J = 6.8 Hz), 2.56 (hept., 1H, (CH3)2CH, J = 6.8 Hz),
7.47–7.61 (m, 5H, Ph), 10.31 (s, 1H, NH), 11.01 (s, 1H, NH);
13C-nmr (DMSO-d6): d 20.98 ((CH3)2CH), 24.63 ((CH3)2CH),
117.24, 127.66, 128.29, 131.46, 139.61 (C-4, Carom), 141.06 (C-
5), 153.27 (C-2), 183.93 (COPh); EI MS: m/z 230 (M+).
Anal. Calcd. for C13H14N2O2•0.3H2O (235.67): C, 66.25; H,
6.24; N, 11.89. Found: C, 66.21; H, 5.98; N, 11.60.
4-Benzoyl-5-tert-butyl-1,3-dihydroimidazol-2-one (19b).
The compound was obtained as white crystals. Yield: 0.2 g
(16%); mp 215–217°; 1H-nmr (DMSO-d6): d 1.25 (s, 9H,
(CH3)3C), 7.48–7.72 (m, 5H, Ph), 10.14 (s, 1H, NH), 10.66 (s,
1H, NH); 13C-nmr (DMSO-d6): d 28.85 ((CH3)3C), 31.91
((CH3)3C), 115.79, 128.44, 128.96, 132.51, 138.56 (C-4, Carom),
139.42 (C-5), 152.41 (C-2), 186.11 (COPh); EI MS: m/z 244
(M+).
Anal. Calcd. for C14H16N2O2 (244.30): C, 68.83; H, 6.60; N,
11.47. Found: C, 68.78; H, 6.59; N, 11.51.
Acknowledgement.
[14] R. W. Buckheit Jr., K. Watson, V. Fliakas-Boltz, J. Russell,
T. L. Loftus, M. C. Osterling, J. A. Turpin, L. A. Pallansch, E. L.
White, J.W. Lee, J.-W. Oh, H.-S. Kwon, S.-G. Chung and E.-H. Cho,
Antimicrob. Agents Chemother., 45, 393 (2001).
One of the authors (Y. M. Loksha) is greatly indebted to the
Danish International Development Agency (DANIDA) for grant-
ing a fellowship.
[15] A. Lawson, J. Chem. Soc., 1443 (1957).
[16] M. Jackman, M. Klenk, B. Fishburn, B. F. Tullar and S.
Archer; J. Am. Chem. Soc., 70, 2884 (1948).
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