Synthesis of neomenthylsulfanylimidazoles

Article abstract of DOI:10.1007/s10600-012-0099-2

2-Neomenthylsulfanyl-1H-imidazole,1-methyl-2-neomenthylsulfanyl-1H- imidazole, and 2-neomenthylsulfanyl-1H-benzimidazole were synthesized.

Full text of DOI:10.1007/s10600-012-0099-2

Chemistry of Natural Compounds, Vol. 47, No. 6, January, 2012 [Russian original No. 6, November-December, 2011]
SYNTHESIS OF NEOMENTHYLSULFANYLIMIDAZOLES
1
1*
1
M. Ya. Demakova, D. V. Sudarikov, S. A. Rubtsova,
UDC 547.425.2
2
1
P. A. Slepukhin, and A. V. Kuchin
2-Neomenthylsulfanyl-1H-imidazole,1-methyl-2-neomenthylsulfanyl-1H-imidazole, and 2-neomenthyl-
sulfanyl-1H-benzimidazole were synthesized.
Keywords: L-menthol tosylate, imidazole, benzimidazoleneomenthyl sulfides, synthesis.
Heterocyclic sulfides and compounds including imidazole and benzimidazole groups possess antiviral, antibacterial,
antiulcer, anti-inflammatory, and anticancer activity. Furthermore, imidazole-containing sulfides are used as herbicides and
fungicides [1]. (–)-Menthol and its derivatives find applications in the pharmaceutical industry and the production of cosmetics
[2] and are inductors of chirality, which enables them to be used in asymmetric synthesis [3]. Therefore, the introduction of the
chiral menthane structure into a molecule with an imidazole-containing fragment raises expectations, on one hand, of the
appearance of new pharmacological properties and, on the other, of performing further asymmetric transformations with
optically active compounds.
We synthesized for the first time imidazole- and benzimidazole-containing neomenthylsulfides.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-p-toluenesulfonate (2), which was prepared from l-menthol (1) and
p-toluenesulfonylchloride by the literature method [4] in 98% yield, reacted with the heterocyclic thiols 2-mercaptoimidazole,
2-mercapto-1-methylimidazole, and 2-mercaptobenzimidazole to produce the corresponding sulfides 2-[((1S,2S,5R)-2-isopropyl-
5-methylcyclohexyl)sulfanyl]-1H-imidazole (3); 1-methyl-2-[((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)sulfanyl]-1H-
imidazole (4); and 2-[((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)sulfanyl]-1H-benzimidazole (5). Sulfides 3 and 4 were
obtained from the corresponding thiols and menthol tosylate 2 in an alcohol solution of KOH in yields of 47 and 48%,
respectively [5]. Sulfide 5 could be produced using Cs CO /tetrabutylammonium iodide (TBAI) in 68% yield [6].
2
3
7
6
TsCl
HS-R
4
1
R
2
OTs
S
OH
N
8
1
3 - 5
2
3a'
7a'
N
N
4'
5'
4'
5'
3: R =
4: R =
5: R =
2'
2'
N
H
N
N
H
7'
6'
The reactions occurred by a bimolecular nucleophilic substitution mechanism with total inversion of configuration
at C-1. This was proved using NMR spectroscopy, HPLC, and an x-ray structure analysis (XSA). Two-dimensional
1
1
H –H NOESY spectra of 3–5 showed correlations characteristic of the interaction of an isopropyl methyl and the C-1 proton
and lacked an NOE interaction for the C-1 and C-8 protons. This was characteristic of the neomenthane structure in which the
sulfanyl group is situated in the axial position. HPLC did not show impurities of diastereomeric menthyl-containing sulfides
with a sulfanyl group in the equatorial position.
1) Institute of Chemistry, Komi Scientific Center, Urals Branch, Russian Academy of Sciences, 167982, Syktyvkar,
fax: (8212) 43 66 77, e-mail: sudarikov-dv@chemi.komisc.ru; 2) I. Ya. Postovskii Institute of Organic Synthesis, Urals Branch,
Russian Academy of Sciences, Ekaterinburg. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December,
2011, pp. 789–792. Original article submitted March 30, 2011.
©
0009-3130/12/4706-0899 2012 Springer Science+Business Media, Inc.
899

TABLE 1. H-Bonds D–H…A According to XSA Data
D-H
d(D-H)
d(H..A)
<DHA
d(D..A)
A
3
N3-H3
N1A-H1
0.74 (3)
1.09 (4)
2.150 (3)
1.807 (4)
176 (3)
164 (3)
2.891 (3)
2.871 (3)
N3A [x + 1, y, z]
N1
5
N1-H1B
N1A-H1A
0.860
0.855 (14)
1.975 (3)
1.982 (14)
158.9 (3)
163 (1)
2.795 (3)
2.810 (3)
N2A [x – 1/2, -y + 3/2, –z]
N2 [x – 1/2, –y + 3/2, –z]
TABLE 2. Crystallographic Data and X-ray Structure Parameters
Parameter
3
5
Formula
C13H22N2S
238.39
C17H24N2S
288.44
MW, g/mol
System
Orthorhombic
P212121
9.9805 (5)
14.2791 (12)
19.5503 (16)
90
Orthorhombic
P212121
9.8198 (6)
17.230 (2)
20.1887 (9)
90
Space group
°
, A
a
b
°
, A
°
, A
c
ꢀ
, deg
ꢁ, deg
ꢂ, deg
90
90
90
90
° 3
, A
V
Z
2786.2 (4)
8
1.137
3415.9 (5)
8
1.122
dcalc, g/cm–3
ꢃ/mm–1
0.211
0.183
Scan range, ꢄ/ꢅ
Reflections collected
Independent reflections (
From 2.70 to 26.39
10180
3169 (0.0529)
1579
98.3 % (26.39)
297
From 2.89 to 26.38
11583
6821 (0.0364)
3434
98.9 % (26.38)
369
)
Rint
( )
ꢆ
Reflections with
2
I
I
ꢄ ꢅ
Completeness (for / )
Number of refined parameters
( ꢆ 2 ( ))
R1
I
I
0.0397
0.0407
( ꢆ 2 ( ))
0.0536
0.1083
0.0596
1.000
0.0380
0.1047
0.0415
0.959
wR2
I
I
(over all reflections)
R1
(over all reflections)
wR2
S
2
over
F
Flack parameter
–
0.10(6)
–
° 3
ꢇꢈ
min/max, e/A
0.181/–0.146
0.312/–0.179
13
PMR and C NMR spectra of 3–5 exhibited resonances for both the neomenthyl component and the heterocyclic
fragment.
The structures of 3 and 5 were established by XSA (Table 1). According to the XSA, the crystal packings of 3 and 5
were highly similar. Thus, both sulfides crystallized in a chiral space group of the orthorhombic system and the crystals were
formed by two crystallographically independent molecules with similar stereometric parameters. The molecules in the crystal
were packed in chains formed through a system of intermolecular H-bonds (IMHB) of the N–H…N type between the heterocyclic
fragments (Table 2). The direction of these chains coincided with the a axis of the unit cell. As a result, the similarity of the
N…N distances in the IMHB (Table 1) of 3 and 5 caused the a axes of the unit cells of these compounds to have similar lengths
(Table 2). Figure 1 shows general views of 3 and 5 and the atomic numbering.
900

C4
C5
C6
C7
C4A
C3
C2
C16A
C15A
C5A
N3A
C2A
S1A
C11A
C12A
C7A
C16
C17
C1
C10
N2
N1
C13A
C17A
N1A
C14A
C1
S1
C9
C7
C3A
C15
C14
C13
C8
C11
C12A
C10A
C8A
S1A
N1
C6A
S1
C13A
C8
C1A
C9A
C2
N3
N1A
C2A
C6
C9
C10
C11
N2A
C7A
C6A
C8A
C5
C11A
C3
C4
C3A
C10A
C9A
C12
C12
C1A
C13
C5A
C4A
5
3
Fig. 1. X-ray molecular structures of 3 and 5 (50% probability ellipsoids).
Thus, we prepared and characterized for the first time 2-[((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)sulfanyl]-1H-
imidazole; 1-methyl-2-[((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)sulfanyl]-1H-imidazole; and 2-[((1S,2S,5R)-2-isopropyl-
5-methylcyclohexyl)sulfanyl]-1H-benzimidazole in 50–70% yields.
EXPERIMENTAL
Melting points were determined on a Gallencamp-Sanyo instrument. HPLC analyses were performed on a Thermo
Finnigan Surveyor chromatograph using BDS Hypersil C18, Hypersil Gold, and Hypercarb columns and solvent systems
13
CH CN:H O (30:70 and 40:60, 1% HCOOH) and MeOH:H O (20:80). PMR and C NMR spectra were recorded in CDCl
3
2
2
3
1
13
on a Bruker Avance-300 spectrometer (300.17 MHz for H and 75.48 MHz for C). Resonances of CDCl were used as
3
1
13
1
1
internal standards. Resonances of H and C were fully assigned using two-dimensional homo- ( H–H COSY,
H–H NOESY) and heteronuclear experiments ( H– C HSQC, H– C HMBC). Optical rotation angles were measured on
1
1
1
13
1
13
a Kruss P3002RS automated digital polarimeter. TLC was performed on Sorbfil plates using heptane:Et O solvents
2
and phosphomolybdic acid in EtOH and KMnO solution as detectors. Elemental analysis was carried out using an EA
4
1110CHNS–O automated analyzer. All reactions were carried out using freshly distilled solvents. Commercially available
reagents were used without further purification. Column chromatography was performed over Alfa Aesar silica gel (0.06–
0.2 mm) using CHCl :Et O solvent systems.
3
2
X-ray structure analyses (XSA) of the compounds were performed on an Xcalibur 3 automated four-circle diffractometer
°
equipped with a CCD detector at 295(2) K using Mo Kꢀ-radiation (0.71073 A). Datasets were collected and processed using
the standard procedure [7]. Absorption corrections were not applied. The structures were solved and refined using the
2
SHELX programs [8] with refinement by full-matrix anisotropic least-squares methods over F for all non-hydrogen atoms.
The H atoms of C–H bonds were placed in geometrically calculated positions and refined isotropically with dependent thermal
parameters using a rider model. Those of N–H groups were solved by direct methods and refined independently (Table 1).
Table 2 presents the principal structural parameters of the experiments.
Data from the XSA were deposited in the Cambridge Crystallographic Data Centre under numbers CCDC 818566
and 818567. These data have free access and can be requested at the address www.ccdc.cam.ac.uk/data_request/cif.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-p-toluenesulfonate (menthol tosylate) (2) was prepared by the
literature method [4].
Preparation of Sulfides: 2-[((1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl)sulfanyl]-1H-imidazole (3) and 1-Methyl-
2-[((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)sulfanyl]-1H-imidazole (4). A solution of the appropriate thiol (1 mmol)
in EtOH (5 mL) at room temperature was treated with KOH solution (0.07 g, 1.2 mmol) in EtOH (3 mL), stirred for 10 min,
heated to 60°C, treated with a solution of 2 tosylate (0.37 g, 1.2 mmol) in alcohol, stirred for 24 h, evaporated in vacuo, and
extracted with CHCl . The extract was dried over Na SO . The solvent was distilled. Reaction products 3 and 4 were isolated
3
2
4
by column chromatography (CHCl eluent).
3
22
Compound 3. Transparent light-yellow crystals, 47% yield, mp 149.3°C, [ꢀ] +97.06° (c 0.85, EtOH).
D
901

PMR spectrum (300 MHz, CDCl , ꢉ, ppm, J/Hz): 0.85 (3H, d, J = 6.3, Me-7), 0.83–0.99 (1H, m, H-4a), 0.93 (6H, d,
3
J = 6.6, Me-9, Me-10), 1.11–1.25 (1H, m, H-2), 1.13–1.23 (1H, m, H-3a), 1.18–1.33 (1H, m, H-6a), 1.61–1.75 (1H, m, H-8),
1.70–1.83 (1H, m, H-4e), 1.74–1.85 (1H, m, H-3e), 1.86–2.03 (1H, m, H-6e), 1.87–2.02 (1H, m, H-5), 3.96–4.06 (1H, m,
H-1), 7.13 (2H, br.s, H-4ꢊ, H-5ꢊ), 10.18 (1H, br.s, NH).
13
C NMR spectrum (75 MHz, CDCl , ꢉ, ppm): 20.57 (C-9), 21.04 (C-10), 22.05 (C-7), 26.09 (C-3), 26.70 (C-5),
3
30.31 (C-8), 35.19 (C-4), 41.38 (C-6), 48.56 (C-2), 51.33 (C-1), 123.66 (C-4ꢊ,5ꢊ), 140.63 (C-2ꢊ). C H N S.
13 22
2
22
Compound 4. Light-yellow oily liquid, 48% yield, [ꢀ] +60.06° (c 0.93, EtOH).
D
PMR spectrum (300 MHz, CDCl , ꢉ, ppm, J/Hz): 0.85–1.01 (1H, m, H-4a), 0.89 (3H, d, J = 6.5, Me-7), 0.95 (3H, d,
3
J = 6.6, Me-10), 0.97 (3H, d, J = 6.6, Me-9), 1.12–1.26 (1H, m, H-2), 1.14–1.25 (1H, m, H-3a), 1.21–1.37 (1H, m, H-6a),
1.60–1.75 (1H, m, H-8), 1.73–1.85 (1H, m, H-4e), 1.78–1.88 (1H, m, H-3e), 1.87–2.01 (1H, m, H-6e), 3.63 (3H, m, H-6ꢊ),
4.06–4.15 (1H, m, H-1), 6.92 (1H, s, H-5ꢊ), 7.08 (1H, s, H-4ꢊ).
13
C NMR spectrum (75 MHz, CDCl , ꢉ, ppm): 20.63 (C-9), 21.06 (C-10), 22.04 (C-7), 26.42 (C-3), 27.07 (C-5),
3
30.46 (C-8), 33.13 (C-6ꢊ), 35.23 (C-4), 41.37 (C-6), 48.53 (C-2), 51.19 (C-1), 121.71 (C-5ꢊ), 129.24 (C-4ꢊ), 142.41 (C-2ꢊ).
C H N S.
14 24
2
2-[((1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl)sulfanyl]-1H-benzimidazole (5). A solution of 2-mercapto-
benzimidazole (0.15 g, 1 mmol), Cs CO (0.33 g, 1 mmol), and TBAI (0.37 g, 1 mmol) in EtOH (5 mL) was stirred at 20°C for
2
3
1 h, treated with 2 (0.34 g, 1.1 mmol), and refluxed for 24 h. The course of the reaction was followed by TLC (heptane:Et O
2
eluent, 1:2). The solvent was distilled in vacuo. The mixture was extracted with Et O (3 ꢋ 30 mL). The extracts were dried
2
over Na SO . The solvent was distilled. The reaction product 5 was isolated by column chromatography over silica gel
2
4
(CHCl eluent).
3
22
Colorless transparent crystals, 68% yield, mp 229.8°C, [ꢀ] +56.08° (c 0.51, EtOH).
D
PMR spectrum (300 MHz, CDCl , ꢉ, ppm, J/Hz): 0.83 (3H, d, J = 6.5, Me-7), 0.85–1.00 (1H, m, H-4a), 0.90 (3H, d,
3
J = 6.5, Me-9), 0.92 (3H, d, J = 6.4, Me-10), 1.02–1.19 (1H, m, H-3a), 1.19–1.32 (1H, m, H-2), 1.31–1.44 (1H, m, H-6a),
1.56–1.70 (1H, m, H-8), 1.70–1.82 (1H, m, H-4e), 1.78–1.88 (1H, m, H-3e), 1.86–2.03 (1H, m, H-6e), 1.83–1.97 (1H, m,
H-5), 4.41–4.48 (1H, m, H-1), 7.11–7.19 (2H, m, H-5ꢊ,6ꢊ), 7.43–7.50 (2H, m, H-4ꢊ,7ꢊ), 12.25 (1H, br.s, NH).
13
C NMR spectrum (75 MHz, CDCl , ꢉ, ppm): 20.50 (C-10), 20.92 (C-9), 21.89 (C-7), 26.60 (C-3), 27.22 (C-5),
3
1
13
30.55 (C-8), 35.09 (C-4), 41.45 (C-6), 48.27 (C-2), 49.12 (C-1), 121.84 (C-4ꢊ,5ꢊ,6ꢊ,7ꢊ) (assigned using H– C HSQC), 135.34
(C-3aꢊ,7aꢊ) (assigned using H– C HMBC), 151.11 (C-22). C H N S.
1
13
17 24
2
ACKNOWLEDGMENT
The work was supported financially by the RFBR (Grant 10-03-00969) and the Federal Agency for Science and
Innovation under the Federal Targeted Program Scientific and Scientific-Pedagogical Faculties of Innovation Russia (State
Contract No. 02.740.11.0081). We thank staff members of the Laboratory of Physicochemical Research Methods, Institute of
Chemistry, Komi Scientific Center, Urals Branch, RAS, E. N. Zainullina, S. P. Kuznetsov, and A. N. Alekseev for recording
the NMR spectra.
REFERENCES
1.
2.
3.
4.
5.
M. S. K. Ahmed and R. A. Youssef, Phosphorus Sulfur Silicon Relat. Elem., 181, No. 5, 1123 (2006).
R. B. Croteau, E. M. Davis, K. L. Ringer, and M. R. Wildung, Naturwissenschaften, 92, 562 (2005).
H. Oertling, A. Reckziegel, H. Surburg, and H. Bertram, Chem. Rev., 107, 2136 (2007).
A. W. Snow and E. E. Foos, Synthesis, 4, 509 (2003).
N. E. Karaulova, Synthesis of Sulfides, Thiophenes, and Thiols Found in Petroleum [in Russian], Nauka,
Moscow, 1988.
6.
7.
8.
R. N. Salvatore, R. A. Smith, A. K. Nischwitz, and T. Gavin, Tetrahedron Lett., 46, 8931 (2005).
CrysAlis CCD, Version 1.171.29.9, release 23-03-2006, Oxford Diffraction Ltd., 2006.
G. M. Sheldrick, Acta Crystallogr. Sect. A: Found. Crystallogr., 64, 112 (2008).
902