Synthesis of 2-Hydroxymethyl-1H-imidazoles from 1,3-Dihydroimidazole-2- thiones

Article abstract of DOI:10.1055/s-2003-44370

1,3-Dihydroimidazole-2-thiones 1a-d were desulfurized by hydrogen peroxide in either acid or neutral medium to afford 1H-imidazoles 3a-d. Reaction of 3b,d with dimethylsulfamoyl chloride furnished N,N-dimethylsulfamoylimidazoles 5 and 6a,b. Lithiation of 5 and 6a,b followed by formylation and reduction yielded the 2-hydroxymethyl derivatives 7 and 8a,b. 4-Alkyl-5-cyclohexylmethyl-1H- imidazol-2-yl)methanols 9a,b were obtained by hydrolysis of 7 and 8a,b.

Full text of DOI:10.1055/s-2003-44370

116
PAPER
Synthesis of 2-Hydroxymethyl-1H-imidazoles from 1,3-Dihydroimidazole-2-
thiones
S
ynthesis of 2-Hyd
a
roxymethy
s
l-1
H
-imid
s
azoles fro
e
m
1,3-Dihy
r
droimidazole-
M
2-thiones . Loksha,a Ahmed A. El-Barbary,b Mahmoud A. El-Badawi,b Claus Nielsen,c Erik B. Pedersen*a
a
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
Fax +4566158780; E-mail: ebp@chem.sdu.dk
b
c
Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
Retrovirus Laboratory, Department of Virology, State Serum Institute, Artillerivej 5, 2300 Copenhagen, Denmark
Received 12 September 2003; revised 10 November 2003
furized imidazoles 3a–d as the minor products. Treating
compounds 1a–d with hydrogen peroxide in a neutral me-
dium in ethanol furnished the desulfurized imidazoles 3a–
d as the major products and the ethyl esters of 1H-imida-
Abstract: 1,3-Dihydroimidazole-2-thiones 1a–d were desulfurized
by hydrogen peroxide in either acid or neutral medium to afford 1H-
imidazoles 3a–d. Reaction of 3b,d with dimethylsulfamoyl chlo-
ride furnished N,N-dimethylsulfamoylimidazoles 5 and 6a,b. Lithi-
ation of 5 and 6a,b followed by formylation and reduction yielded zole-2-sulfinic acids 4a–d as the minor products. The im-
the 2-hydroxymethyl derivatives 7 and 8a,b. 4-Alkyl-5-cyclohexy-
lmethyl-1H-imidazol-2-yl)methanols 9a,b were obtained by hy-
drolysis of 7 and 8a,b.
idazole-2-sulfinic acids 2a–d are somewhat stable in
acidic medium and only small amounts were converted to
the desulfinated imidazoles 3a–d through elimination of
sulfur dioxide which is further oxidized to sulfuric acid by
Key words: 1,3-dihydroimidazole-2-thiones, desulfurization, imi-
dazole-2-sulfinic acids, 2-hydroxymetylimidazoles
an excess of hydrogen peroxide. Under neutral reaction
conditions in ethanol, small amounts of the initially
formed sulfinic acids were esterified by the solvent to
Desulfurization of sulfur-containing compounds, includ-
ing thioureas, has been achieved by using a number of dif-
ferent reagents. Raney nickel has being the most often
employed;1 other methods involved the use of nickel-so-
dium hydride complexes2 and transition metal com-
pounds,3 alkali bromates and iodates,4 nitric acid,5
potassium superoxide,6 oxygen and potassium tert-butox-
ide,7 ozone,8 3,3-dimethyldioxirine,9 and a photochemical
reaction involving singlet oxygen.10,11 Alkaline hydrogen
peroxide has been used for the oxidation of pyrimidine-2-
thiones to the corresponding sulfinic acids. Subsequent re-
fluxing of the isolated sulfinic acids with sulfuric acid af-
forded the desulfinated pyrimidines.12 Alkaline hydrogen
peroxide and sodium peroxide have also been used for the
conversion of thioureas into ureas.13 In this work, hydro-
gen peroxide was used for the desulfurization reaction of
1,3-dihydroimidazole-2-thiones in acid and neutral medi-
um followed by hydroxymethylation at the 2-position. 2-
(Hydroxymethyl)imidazoles are interesting starting mate-
rials and have been used in a practical synthesis of immu-
nosuppressant compounds.14
compounds 4a–d, whereas the major part of the sulfinic
acids were converted to compounds 3a–d (Scheme 1). 5-
Benzyl-4-ethyl-1H-imidazole (3a) has been previously
synthesized by Bredereck et al.18 by an independent route
through condensation of 4-benzyl-5-ethyloxazole with
formamide.
Scheme 1
In order to activate the imidazole ring toward lithiation re-
actions, 4-alkyl-5-cyclohexylmethyl-1H-imidazoles 3b,d
were reacted with dimethylsulfamoyl chloride in toluene
in the presence of triethylamine. Coupling at N-1 or N-3
occurred when R1 was an ethyl group, while coupling oc-
curred only at N-1 when R1 was an isopropyl group due to
steric hindrance of the isopropyl group. Each of the com-
pounds 5 and 6a,b were lithiated at the 2-postion of the
imidazole ring by treatment with n-butyl lithium at 78 °C.
Subsequent formylation using dimethylformamide af-
forded the 2-formyl derivative which without isolation
was immediately reduced by sodium borohydride to fur-
nish 4-cyclohexylmethyl-5-ethyl-2-hydroxymethyl-imi-
dazole-1-sulfonic acid dimethylamide (7) and 4-alkyl-5-
4-Benzyl-5-ethyl-1,3-dihydroimidazole-2-thione (1a) has
been previously synthesized by Bullerwell and Lawson,15
4-benzyl-5-isopropyl-1,3-dihydroimidazole-2-thione
(1c)16 and 5-alkyl-4-cyclohexyl-1,3-dihydroimidazole-2-
thiones 1b,d17 have been synthesized by Loksha et al.16,17
In the present investigation we found that treatment of
1,3-dihydroimidazole-2-thiones 1a–d with hydrogen per-
oxide in an acidic medium afforded 1H-imidazole-2-
sulfinic acids 2a–d as the major products and the desul-
SYNTHESIS 2004, No. 1, pp 0116–0120
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Advanced online publication: 09.12.2003
DOI: 10.1055/s-2003-44370; Art ID: Z13503SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Hydroxymethyl-1H-imidazoles from 1,3-Dihydroimidazole-2-thiones
117
1H-Imidazole-2-sulfinic Acids 2a–d and 1H-Imidazoles 3a–d,
Method A; General Procedure
cyclohexylmethyl-2-hydroxymethylimidazole-1-sulfonic
acid dimethylamides 8a,b. For the compounds 5 and 6 and
for 7 and 8, respectively, the structural assignment was
also based on Rf values from TLC on silica. Besides the
above-mentioned influence of sterical hindrance on the
formation of 6b, we have previously observed smaller Rf
values for 4,5-disubstituted imidazoles when the more li-
pophilic substituent was next to an N1 substituent and
larger Rf values for the compounds with the interchanged
4- and 5-substituents.17 5-(Cyclohexylmethyl-4-ethyl-1H-
imidazol-2-yl)methanol (9a) was obtained by either hy-
drolysis of 4-cyclohexylmethyl-5-ethyl-2-hydroxymeth-
ylimidazole-1-sulfonic acid dimethylamide (7) or 5-
cyclohexylmethyl-4-ethyl-2-hydroxymethylimidazole-1-
sulfonic acid dimethylamide (8a) in an acidic medium
(1.5 M hydrochloric acid), while acid hydrolysis of com-
pound 8b afforded (5-cyclohexylmethyl-4-isopropyl-1H-
imidazol-2-yl)methanol (9b) (Scheme 2).
To a solution of each of the compounds 1a–d (5 mmol) in HOAc
(20 mL), 35% H2O2 (1.5 mL, 15 mmol) was added in one portion.
The reaction mixture was stirred at r.t. for 2 h. The solid product
formed was filtered off, and dried in vacuo affording the imidazole-
2-sulfinic acids 2a–d. The filtrate was evaporated in vacuo till dry-
ness, H2O (20 mL) was added to the residue, the solution was neu-
tralized with a 10% aq solution of NaHCO3, and extracted with
EtOAc (3 × 20 mL). The EtOAc extracts were collected, dried
(Na2SO4), filtered, and evaporated under reduced pressure. The re-
sidual material was dried to afford compounds 3a–d.
5-Benzyl-4-ethyl-1H-imidazole-2-sulfinic Acid (2a)
Yield: 0.6 g (48%); mp 276–278 °C.
1H NMR (300 MHz, DMSO-d6): = 1.08 (t, 3 H, J = 7.3 Hz,
CH3CH2), 2.61 (q, 2 H, J = 7.3 Hz, CH3CH2), 3.96 (s, 2 H, CH2Ph),
7.22–7.33 (m, 5 H, Ph), 14.58 (br s, 1 H, OH).
13C NMR (300 MHz, DMSO-d6):
= 13.66 (CH3CH2), 16.45
(CH3CH2), 28.66 (CH2Ph), 126.84 (C-4), 126.59, 128.17, 128.57,
137.88 (Carom), 130.72 (C-5), 145.95 (C-2).
MALDI MS: m/z = 273 (100%, M + Na+)
Anal. Calcd for C12H14N2O2S·0.25H2SO4 (274.84): C, 52.44; H,
5.32; N, 10.19. Found: C, 52.66; H, 5.08; N, 10.25.
5-Cyclohexylmethyl-4-ethyl-1H-imidazole-2-sulfinic Acid (2b)
Yield: 0.72 g (56%); mp 290–292 °C.
1H NMR (DMSO-d6): = 0.86–0.98 (m, 2 H, Hcy), 1.13–1.50 (m, 6
H, CH3CH2 and Hcy), 1.55–1.65 (m, 6 H, Hcy), 2.45 (d, 2 H, J = 5.8
Hz, CH2Cy), 2.56 (q, 2 H, J = 7.3 Hz, CH3CH2), 14.38 (br s, 1 H,
OH).
13C NMR (DMSO-d6):
= 13.79 (CH3CH2), 16.48 (CH3CH2),
25.47, 25.72, 32.04, 37.39 (Ccy), 30.17 (CH2Cy), 126.68 (C-4),
130.52 (C-5), 145.68 (C-2).
Anal. Calcd for C12H20N2O2S·0.25H2SO4 (280.89): C, 51.31; H,
7.36; N, 9.97. Found: C, 51.43; H, 7.14; N, 9.92.
5-Benzyl-4-isopropyl-1H-imidazole-2-sulfinic Acid (2c)
Yield: 0.81 g (61%); mp 285–278 °C.
1H NMR (DMSO-d6): = 1.18 [d, 6 H, J = 6.5 (CH3)2CH], 3.16
[hept, 1 H, J = 6.5 Hz, (CH3)CH], 3.98 (s, 2 H, CH2Ph), 7.20–7.32
(m, 5 H, Ph), 14.56 (br s, 1 H, OH).
13C NMR (DMSO-d6): = 21.28 [(CH3)2CH], 23.69 [(CH3)2CH],
28.68 (CH2Ph), 125.75 (C-4), 126.58, 128.07, 128.58, 138.03
(Carom), 134.78 (C-5), 146.40 (C-2).
Scheme 2
Anal. Calcd for C13H16N2O2S·0.25H2SO4 (288.87): C, 54.05; H,
5.76; N, 9.70. Found: C, 54.20, H, 5.60; N, 9.73.
Compounds 9a,b are believed to exist in a rapid equilibri-
um between the two tautomeric forms i and ii which ex-
plains why C-4 and C-5 could not be detected in 13C
NMR.
5-Cyclohexylmethyl-4-isopropyl-1H-imidazole-2-sulfinic Acid
(2d)
Yield: 0.88 g (65%); mp 295–297 °C.
1H NMR (DMSO-d6): = 0.85–0.99 (m, 2 H, Hcy), 1.11–1.31 [m, 9
H, (CH3)2CH and Hcy], 1.541.68 (m, 6 H, Hcy), 2.47 (d, 2H, J = 6.3
Hz, CH2Cy), 3.05 [hept, 1 H, J = 6.9 Hz, (CH3)2CH].
13C NMR (DMSO-d6): = 21.56 [(CH3)2CH], 23.73 [(CH3)2CH],
25.48, 25.73, 32.05, 37.51 (Ccy), 30.30 (CH2Cy), 125.64 (C-4),
134.72 (C-5), 146.20 (C-2).
NMR spectra were recorded on a Varian Gemini 2000 NMR spec-
trometer at 300 MHz for 1H and 75 MHz for 13C with TMS as the
internal standard. Cy denotes cyclohexyl. EIMS were recorded on a
Finnigan Mat SSQ 701 spectrometer, MALDI spectra were record-
ed on a Fourier Transform Ion Cyclotron Resonance Mass Spec-
trometer. Melting points were determined on a Büchi melting point
apparatus. Elementary analyses were performed at H.C. Ørsted In-
stitute, University of Copenhagen. Silica gel (0.040–0.063 mm)
used for column chromatography and analytical silica gel TLC
plates 60 F254 were purchased from Merck. Solvents for column
chromatography were distilled prior to use.
Anal. Calcd for C13H22N2O2S·0.45H2SO4 (314.53): C, 49.64; H,
7.34; N, 8.91. Found: C, 49.46; H, 7.06; N, 8.79.
Synthesis 2004, No. 1, 116–120 © Thieme Stuttgart · New York

118
Y. M. Loksha et al.
PAPER
5-Benzyl-4-ethyl-1H-imidazole (3a)
Yield: 12% (method A), 48% (method B); mp 106–108 °C (Lit.18
mp 106 °C).
1H NMR (DMSO-d6): = 1.07 (t, 3 H, J = 7.5 Hz, CH3CH2), 2.49
(q, 2 H, J = 7.5 Hz, CH3CH2), 3.79 (s, 2 H, CH2Ph), 7.11–7.27 (m,
5 H, Ph), 7.40 (s, 1 H, H-2).
5-Benzyl-4-ethyl-1H-imidazole-2-sulfinic Acid Ethyl Ester (4a)
Yield: 0.3 g (22%); oil.
1H NMR (DMSO-d6): = 1.07 (t, 3 H, J = 7.4 Hz, CH3CH2), 1.18
(t, 3 H, J = 7.1 Hz, CH3CH2), 2.54 (q, 2 H, J = 7.4 Hz, CH3CH2),
3.78 (dq, 1 H, J = 10.2, 7.1 Hz, OCHHCH3), 3.88 (s, 2 H, CH2Ph),
4.10 (dq, 1 H, J = 10.1, 7.1 Hz, OCHHCH3), 7.14–7.29 (m, 5 H,
Ph), 13.00 (br s, 1 H, NH).
13C NMR (DMSO-d6):
= 14.59 (CH3CH2), 18.01 (CH3CH2),
31.35 (CH2Ph), 125.56, 128.06, 128.14, 132.99 (Carom), 141.02 (C-
13C NMR (DMSO-d6):
= 14.20 (CH3CH2), 15.21 (CH3CH2),
2).
17.94 (br, CH3CH2), 31.06 (br, CH2Ph), 61.31 (OCH2CH3), 125.84,
128.14, 128.19, 140.02 (Carom), 144.61 (C-2).
EIMS: m/z (%) = 278 (38, M+), 233 (100).
EIMS: m/z (%) = 186 (100, M+).
5-Cyclohexylmethyl-4-ethyl-1H-imidazole (3b)
Yield: 15% (method A), 52% (method B); mp 122–124 °C.
5-Cyclohexylmethyl-4-ethyl-1H-imidazole-2-sulfinic Acid Eth-
yl Ester (4b)
Yield: 0.23 g (16%); mp 98–100 °C.
1H NMR (DMSO-d6): = 0.82–0.93 (m, 2 H, Hcy), 1.07–1.18 (m, 6
H, CH3CH2 and Hcy), 1.44–1.61 (m, 6 H, Hcy), 2.30 (d, 2 H, J = 7.0
Hz, CH2Cy), 2.42 (q, 2 H, J = 7.5 Hz, CH3CH2), 7.39 (s, 1 H, H-2).
1H NMR (CDCl3): = 0.88–0.98 (m, 2 H, Hcy), 1.11–1.32 (m, 9 H,
CH3CH2, CH3CH2O and Hcy), 1.55–1.72 (m, 6 H, Hcy), 2.44 (d, 2 H,
J = 6.8 Hz, CH2Cy), 2.59 (q, 2 H, J = 7.4 Hz, CH3CH2) 3.79 (dq, 1
H, J = 9.8, 7.1 Hz, OCHHCH3), 4.16 (dq, 1 H, J = 9.8, 7.1 Hz,
OCHHCH3), 10.70 (br s, 1 H, NH).
13C NMR (CDCl3): = 14.26 (CH3CH2), 15.32 (CH3CH2), 19.04
(br, CH3CH2), 26.12, 26.35, 38.49 (Ccy), 33.06 (CH2Cy and Ccy),
61.97 (OCH2CH3), 143.70 (C-2).
13C NMR (DMSO-d6):
= 14.69 (CH3CH2), 18.30 (CH3CH2),
25.68, 26.01, 38.08 (Ccy), 32.54 (CH2Cy and Ccy), 127.83 (C-4),
132.54 (C-2).
EIMS: m/z (%) = 192 (32, M+), 109 (100).
Anal. Calcd for C12H20N2·0.4H2O (199.51): C, 72.24; H, 10.51; N,
14.04. Found: C, 72.17; H, 10.06; N, 14.30
EIMS: m/z (%) = 284 (30, M+), 55 (100).
5-Benzyl-4-isopropyl-1H-imidazole (3c)
Yield: 12% (method A), 50% (method B); mp 152–154 °C.
Anal. Calcd for C14H24N2O2S·0.6H2O (295.23): C, 56.96; H, 8.60;
N, 9.49. Found: C, 56.73; H, 8.19; N, 9.66.
1H NMR (DMSO-d6): = 1.12 [d, 6 H, J = 7.0 Hz, (CH3)2CH], 2.97
[hept, 1 H, J = 7.0 Hz, (CH3)2CH], 3.81 [s, 2 H, CH2Ph], 7.11–7.27
(m, 5 H, Ph), 7.42 (s, 1 H, H-2).
13C NMR (DMSO-d): = 22.88 [(CH3)2CH], 24.44 [(CH3)2CH],
31.34 (CH2Ph), 125.55, 128.05, 128.11, 135.61 (Carom), 128.24 (C-
4), 132.98 (C-2), 141.05 (C-5).
5-Benzyl-4-isopropyl-1H-imidazole-2-sulfinic Acid Ethyl Ester
(4c)
Yield: 0.15 g (10%); oil.
1H NMR (DMSO-d6):
= 1.12–1.20 [m, 9 H, CH3CH2 and
(CH3)2CH], 2.20–3.00 [m, 1 H, (CH3)2CH], 3.80 (dq, 1 H, J = 10.3,
7.1 Hz, OCHHCH3), 3.90 (s, 2 H, CH2Ph), 4.09 (dq, 1 H, J = 10.3,
7.1 Hz, OCHHCH3), 7.16–7.29 (m, 5 H, Ph), 12.97 (br s, 1 H, NH).
13C NMR (DMSO-d6): = 15.20 (CH3CH2), 22.36 [(CH3)2CH],
24.83 [(CH3)2CH], 30.59 (CH2Ph), 61.36 (OCH2CH3), 125.83,
128.08, 128.23 (Carom), 144.81 (C-2).
EIMS: m/z (%) = 200 (76, M+), 185 (100).
5-Cyclohexylmethyl-4-isopropyl-1H-imidazole (3d)
Yield: 20% (method A), 68% (method B); mp 120–122 °C.
1H NMR (DMSO-d6): = 0.82–0.93 (m, 2 H, Hcy), 1.12–1.17 [m, 8
H, (CH3)2CH and Hcy], 1.43–1.61 (m, 6 H, Hcy), 2.30 (d, 2 H, J = 7.2
Hz, CH2Cy), 2.85 [hept, 1 H, J = 6.9 Hz, (CH3)2CH], 7.35 (s, 1 H,
H-2).
HRMS MALDI: m/z calcd for C15H21NaN2O2S (MH+), 293.1323;
found, 293.1317
13C NMR (DMSO-d6): = 23.11 [(CH3)2CH], 24.57 [(CH3)2CH],
25.69, 26.02, 32.57, 38.07 (Ccy), 32.49 (CH2Cy), 132.53 (C-2).
EIMS: m/z (%) = 206 (58, M+), 123 (100).
5-Cyclohexylmethyl-4-isopropyl-1H-imidazole-2-sulfinic Acid
Ethyl Ester (4d)
Yield: 0.2 g (13%); semisolid.
1H NMR (DMSO-d6): = 0.88–0.96 (m, 2 H, Hcy), 1.06–1.19 [m, 9
H, (CH3)2CH and Hcy], 1.55–1.66 (m, 6 H, Hcy), 2.39 (d, 2 H, 6.8 Hz,
CH2Cy), 2.92 [hept, 1 H, 6.9 Hz, (CH3)2CH], 3.79 (dq, 1 H,
J = 10.3, 7.1 Hz, OCHHCH3), 4.08 (dq, 1 H, J = 10.3, 7.1 Hz,
OCHHCH3).
Anal. Calcd for C13H22N2·0.25H2O (210.84): C, 74.06; H, 10.76; N,
13.29. Found: C, 74.09; H, 10.55; N, 13.54.
1H-Imidazoles 3a–d and 1H-Imidazoles-2-Sulfinic Acids Ethyl
Ester 4a–d, Method B; General Procedure
13C NMR (DMSO-d6): = 15.15 (CH3CH2), 22.56 [(CH3)2CH],
24.85 [(CH3)2CH], 25.62, 25.92, 32.40, 37.92 (Ccy), 32.37 (CH2Cy),
61.23 (OCH2CH3).
HRMS MALDI: m/z calcd for C15H27N2O2S (MH+), 299.1793;
found, 299.1792.
To a solution of each of compounds 1a–d (5 mmol) in EtOH (20
mL) was added 35% H2O2 (1.5 mL, 15 mmol) in one portion. The
mixture was stirred at r.t. for 2 h. The solvent was removed under
reduced pressure and H2O (20 mL) was added to the residual oil.
The reaction mixture was extracted with Et2O (3 × 20 mL). The
combined ether extracts were dried (Na2SO4), filtered, and evapo-
rated in vacuo to afford the ethyl ester of imidazole-2-sulfinic acids
4a–d. The H2O layer was neutralized with10% aq NaHCO3, extract-
ed with EtOAc (3 × 20 mL), the EtOAc extracts were collected,
dried (Na2SO4), filtered, and evaporated under reduced pressure.
The residual material was dried to afford compounds 3a–d. The
yields of 3a–d are given above under the products of Method A.
4-Cyclohexylmethyl-5-ethylimidazole-1-sulfonic Acid Dimeth-
ylamide (5) and 4-Alkyl-5-cyclohexylmethyl-imidazole-1-sul-
fonic Acids Dimethylamide 6a,b
To a mixture of each of the compounds 3b,d (10 mmol) and Et3N
(1.4 mL, 10 mmol) in toluene (40 mL), dimethylsulfamoyl chloride
(1 mL, 10 mmol) in toluene (10 mL) was added dropwise. The mix-
ture was stirred at r.t. for 1 h followed by refluxing for 5 h. After
cooling to r.t., H2O (50 mL) was added to the reaction mixture and
Synthesis 2004, No. 1, 116–120 © Thieme Stuttgart · New York

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Synthesis of 2-Hydroxymethyl-1H-imidazoles from 1,3-Dihydroimidazole-2-thiones
119
the two layers were separated. The organic layer was dried
(Na2SO4), filtered, and the solvent was removed under reduced
pressure. The residual material was chromatographed on a silica gel
column with CH2Cl2–EtOAc (1:1) to afford compounds 5 and 6a,b.
on a silica gel column with CH2Cl2–MeOH (1:1) to afford com-
pounds 7 and 8a,b.
4-Cyclohexylmethyl-5-ethyl-2-hydroxymethylimida-zole-1-sul-
fonic Acid Dimethylamide (7)
4-Cyclohexylmethyl-5-ethyl-imidazole-1-sulfonic Acid Dimeth-
ylamide (5)
Yield: 1 g (33%); mp 52–54 °C.
Yield: 0.15 g (30%); 100–102 °C.
1H NMR (CDCl3): = 0.85–0.92 (m, 2 H, Hcy), 1.22–1.25 (m, 6 H,
CH3CH2 and Hcy), 1.66–1.71 (m, 6 H, Hcy), 2.30 (d, 2 H, J = 6.8 Hz,
CH2Cy), 2.70 (q, 2 H, J = 7.4 Hz, CH3CH2), 3.58 (br s, 1 H, OH),
4.79 (s, 2 H, CH2OH).
13C NMR (CDCl3): = 15.04 (CH3CH2), 17.62 (CH3CH2), 26.21,
26.48, 33.28, 37.82 (Ccy), 34.39 (CH2Cy), 37.45 [(CH3)2N], 59.33
(CH2OH), 130.97 (C-4), 137.11 (C-2), 148.39 (C-5).
1H NMR (CDCl3): (ppm) = 0.88–1.00 (m, 2 H, Hcy), 1.08–1.31
(m, 6 H, CH3CH2 and Hcy), 1.67 –1.78 (m, 6 H, Hcy), 2.34 (d, 2 H,
J = 6.7 Hz, CH2Cy), 2.72 (q, 2 H, J = 7.5 Hz, CH3CH2), 2.87 [s, 6
H, (CH3)2N], 7.00 (s, 1 H, NH).
13C NMR (CDCl3): = 14.95 (CH3CH2), 17.10 (CH3CH2), 26.22,
26.49, 33.28, 37.92 (Ccy), 34.60 (CH2Cy), 37.64 [(CH3)2N], 129.05
(C-4), 136.65 (C-2), 139.47 (C-5).
EIMS: m/z (%) = 329 (19, M+), 139 (100).
Anal. Calcd for C15H27N3O3S (329.46): C, 54.68; H, 8.26; N, 12.75.
Found: C, 55.12; H, 8.31; N, 12.35.
EIMS: m/z (%) = 299 (13, M+), 109 (100).
Anal. Calcd for C14H25N3O2S·0.2H2O (303.04): C, 55.49; H, 8.45;
N, 13.87. Found: C, 55.66; H, 8.29; N, 13.81.
5-Cyclohexylmethyl-4-ethyl-2-hydroxymethylimida-zole-1-sul-
fonic Acid Dimethylamide (8a)
5-Cyclohexylmethyl-4-ethyl-imidazole-1-sulfonic Acid Dimeth-
ylamide (6a)
Yield: 0.75 g (25%); mp 96–98 °C.
Yield: 0.26 g (52%); mp 84–86 °C.
1H NMR (CDCl3): = 0.83–0.97 (m, 2 H, Hcy), 1.10–1.26 (m, 6 H,
CH3CH2 and Hcy), 1.56–1.70 (m, 6 H, Hcy), 2.45 (q, 2 H, J = 7.5 Hz,
CH3CH2), 2.54 (d, 2 H, J = 6.9 Hz, CH2Cy), 2.86 [s, 6 H, (CH3)2N],
3.77 (br s, 1 H, OH), 4.80 (s, 2 H, CH2OH).
13C NMR (CDCl3): = 13.43 (CH3CH2), 20.27 (CH3CH2), 26.26,
26.38, 33.13, 37.87 (Ccy), 31.91 (CH2Cy), 38.54 [(CH3)2N], 59.36
(CH2OH), 127.09 (C-4), 140.59 (C-2), 148.96 (C-5).
1H NMR (CDCl3): = 0.88–0.99 (m, 2 H, Hcy), 1.11–1.26 (m, 6 H,
CH3CH2 and Hcy), 1.58–1.70 (m, 6 H, Hcy), 2.48 (q, 2 H, J = 7.5 Hz,
CH3CH2), 2.55 (d, 2 H, J = 6.6 Hz, CH2Cy), 2.84 [s, 6 H, (CH3)2N],
7.03 (s, 1 H, H-2).
13C NMR (CDCl3): = 13.44 (CH3CH2), 20.41 (CH3CH2), 26.21,
26.36, 33.07, 37.94 (Ccy), 31.36 (CH2Cy), 38.47 [(CH3)2N], 125.21
(C-4), 137.07 (C-2), 142.95 (C-5).
HRMS MALDI: m/z calcd for C15H28N3O3S (MH+) 330.184, found,
330.185.
EIMS: m/z (%) = 299 (100, M+).
5-Cyclohexylmethyl-2-hydroxymethyl-4-isopropyl-imidazole-
1-sulfonic Acid Dimethylamide (8b)
Yield: 0.25 g (48%); mp 118–120 °C.
Anal. Calcd for C14H25N3O2S (299.43): C, 56.16; H, 8.42; N, 14.03.
Found: C, 56.31; H, 8.43; N, 13.99.
5-Cyclohexylmethyl-4-isopropylimidazole-1-sulfonic Acid
Dimethylamide (6b)
Yield: 1.72 g (55%); mp 122–124 °C.
1H NMR (CDCl3): = 0.88–1.02 (m, 2 H, Hcy), 1.07–1.28 [m, 9 H,
(CH3)2CH and Hcy], 1.59–1.82 (m, 6 H, Hcy), 2.56 (d, 2 H, J = 7.0
Hz, CH2Cy), 2.82–2.90 [m, 7 H, (CH3)2CH and (CH3)2N], 7.84 (s,
1 H, H-2).
1H NMR (CDCl3): = 0.86–0.97 (m, 2 H, Hcy), 1.11–1.26 [m, 9H,
(CH3)2CH and Hcy], 1.56–1.71 (m, 6 H, Hcy), 2.55 (d, 2 H, J = 6.8
Hz, CH2Cy), 2.78–2.85 [m, 7 H, (CH3)2CH and (CH3)2N], 3.79 (br
s, 1 H, OH), 4.79 (s, 2 H, CH2OH).
13C NMR (CDCl3):
= 22.35 [(CH3)2CH], 25.72 [(CH3)2CH],
26.30, 26.38, 33.11, 37.85 (Ccy), 31.67 (CH2Cy), 38.40 [(CH3)2N],
59.38 (CH2OH), 126.00 (C-4), 144.45 (C-2), 149.08 (C-5).
13C NMR (CDCl3):
= 22.41 [(CH3)2CH], 25.87 [(CH3)2CH],
EIMS: m/z (%) = 343 (57, M+), 260 (100).
26.26, 26.36, 33.07, 37.96 (Ccy), 31.56 (CH2Cy), 38.36 [(CH3)2N],
124.17 (C-4), 137.31 (C-2), 146.90 (C-5).
EIMS: m/z (%) = 313 (100, M+).
Anal. Calcd for C16H29N3O3S (343.48): C, 55.95; H, 8.51; N, 12.23.
Found: C, 55.78; H, 8.50; N, 12.11.
(5-Cyclohexylmethyl-4-alkyl-1H-imidazol-2-yl)methanols 9a,b
A suspension of each of the compounds 7 and 8a,b (3.5 mmol) in
1.5 M HCl (30 mL) was refluxed for 5 h. The solid product formed
was filtered, washed with aq NaHCO3 (20 mL), Et2O (30 mL), and
dried to afford compounds 9a,b.
Anal. Calcd for C15H27N3O2S (313.45): C, 57.48; H, 8.68; N, 13.41.
Found: C, 57.72; H, 8.67; N, 12.97.
4-Cyclohexylmethyl-5-ethyl-2-hydroxymethylimida-zole-1-sul-
fonic Acid Dimethylamide (7) and 4-Alkyl-5-cyclohexylmethyl-
2-hydroxymethylimidazole-1-sulfonic Acids Dimethylamide
8a,b
(5-Cyclohexylmethyl-4-ethyl-1H-imidazol-2-yl)methanol (9a)
Yield: 70% (obtained from hydrolysis of compound 7), 75% (ob-
tained from hydrolysis of compound 8a).
1H NMR (CDCl3): = 0.82–0.92 (m, 2 H, Hcy), 1.05–1.20 (m, 6 H,
CH3CH2 and Hcy), 1.43–1.62 (m, 6 H, Hcy), 2.25 (d, 2 H, J = 6.8 Hz,
CH2Cy), 2.37 (q, 2 H, J = 7.4 Hz, CH3CH2), 4.34 (s, 2 H, CH2OH).
13C NMR (CDCl3): = 14.80 (CH3CH2), 18.38 (CH3CH2), 26.73,
26.05, 38.11 (Ccy), 32.60 (CH2Cy and Ccy), 56.93 (CH2OH), 145.24
(C-2).
Each of the compounds 5 and 6a,b (1.5 mmol) was dissolved in
THF (20 mL) under nitrogen and the solution was cooled to –78 °C.
n-BuLi (0.81 mL, 2.2 M in n-hexane, 1.8 mmol) was added and the
mixture was stirred for 0.5 h at –78 °C. Then DMF (0.14 mL, 1.8
mmol) was added dropwise at –78 °C. The reaction mixture was al-
lowed to reach r.t. and quenched with H2O (5 mL). EtOH (10 mL)
was added to the reaction mixture followed by addition of NaBH4
(0.057g, 1.5 mmol) portion-wise. After filtration, Et2O (30 mL) was
added to the filtrate, and the two layers were separated. The organic
layer was dried (Na2SO4), filtered, and the solvent was removed un-
der reduced pressure. The residual material was chromatographed
EIMS: m/z (%) = 222 (24, M+), 139 (100).
Anal. Calcd for C13H22N2O·0.1H2O (224.13): C, 69.67; H, 9.97; N,
12.50. Found: C, 69.55; H, 10.22; N, 12.51.
Synthesis 2004, No. 1, 116–120 © Thieme Stuttgart · New York

120
Y. M. Loksha et al.
PAPER
(5-Cyclohexylmethyl-4-isopropyl-1H-imidazol-2-yl)methanol
(9b)
(5) Ainsworth, C. Org. Synth., Coll Vol. V; Wiley: New York,
1973, 1070.
Yield: 0.66 g (80%); mp 128–130 °C.
(6) Kim, Y. H.; Yon, G. H. J. Chem. Soc., Chem. Commun.
1983, 715.
(7) Kim, Y. H.; Kim, H. J.; Yon, G. H. J. Chem. Soc., Chem.
Commun. 1984, 1064.
(8) Crestini, C.; Saladino, R.; Nicoletti, R. Tetrahedron, Lett.
1993, 34, 1631.
(9) Claudia, C.; Mincione, E.; Saladino, R.; Nicoletti, R.
Tetrahedron 1994, 50, 3259.
(10) Abdou, W. M.; Sidky, M. M.; Wamhoff, H. Z. Naturforsch.,
B: Chem. Sci. 1987, 42, 1153.
(11) Crank, G.; Nursyidi, A. J. Photochem. Photobiol. A: Chem.
1992, 64, 263.
(12) Evans, R. M.; Jones, P. G.; Palmer, P. J.; Stephens, F. F. J.
Chem. Soc. 1956, 4106.
1H NMR (CDCl3): = 0.83–0.93 (m, 2 H, Hcy), 1.05–1.21 [m, 9 H,
(CH3)2CH and Hcy], 1.43–1.63 (m, 6 H, Hcy), 2.27 (d, 2 H, J = 6.9
Hz, CH2Cy), 2.81 [hept, 1 H, J = 6.8 Hz, (CH3)2CH], 4.35 (s, 2 H,
CH2OH].
13C NMR (CDCl3):
= 23.12 [(CH3)2CH], 24.66 [(CH3)2CH],
25.73, 26.05, 38.07 (Ccy), 32.06 (CH2Cy and Ccy), 56.94 (CH2OH),
145.27 (C-2).
EIMS: m/z (%) = 236 (26, M+), 153 (100).
Anal. Calcd for C14H24N2O (236.36): C, 71.14; H, 10.23; N, 11.85.
Found: C, 70.94; H, 10.55, N, 11.74.
(13) Kalm, M. J. J. Org. Chem. 1961, 26, 2925.
(14) Song, Z.; DeMarco, A.; Zhao, M.; Corley, E. G.; Thompson,
A. S.; McNamara, J.; Li, Y.; Rieger, D.; Sohar, P.; Mathre,
D. J.; Tschaem, D. M.; Reamer, R. A.; Huntington, M. F.;
Ho, G.-J.; Tsay, F.-R.; Emerson, K.; Shuman, R.;
Grabowski, J. J.; Reider, P. J. J. Org. Chem. 1999, 39, 375.
(15) Bullerwell, R. A. F.; Lawson, A. J. Chem. Soc. 1952, 1350.
(16) Loksha, Y. M.; Jørgensen, P. T.; Pedersen, E. B.; El-Badawi,
M. A.; El-Barbary, A. A.; Nielsen, C. J. Heterocycl. Chem.
2002, 39, 375.
(17) Loksha, Y. M.; El-Badawi, M. A.; El-Barbary, A. A.;
Pedersen, E. B.; Nielsen, C. Arch. Pharm. Pharm. Med.
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723.
Acknowledgment
One of the authors (Y. M. Loksha) is greatly indebted to the Danish
International Development Agency (DANIDA) for a fellowship.
References
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Synthesis 2004, No. 1, 116–120 © Thieme Stuttgart · New York