Stereoselective synthesis of substituted 2-(Z-Styrylsulfonyl)-1H-imidazoles and Benzothiazole

Article abstract of DOI:10.1080/00397910903009422

A novel method has been reported involving the synthesis of z-styryl sulfides by the reaction of phenylacetylene with 2-mercpto benzimidazoles and benzthiazole using NaOH as a base in absolute ethanol. On further oxidation with H2O2, these resulted in the formation of the desired styryl sulfones in good yields with retention of stereochemistry.

Full text of DOI:10.1080/00397910903009422

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Stereoselective Synthesis of Substituted
2-(Z-Styrylsulfonyl)-1H-imidazoles and
Benzothiazole
N. Guravaiah a & V. Rajeswar Rao a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Version of record first published: 22 Feb 2010.
To cite this article: N. Guravaiah & V. Rajeswar Rao (2010): Stereoselective Synthesis of Substituted
2-(Z-Styrylsulfonyl)-1H-imidazoles and Benzothiazole, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:6, 808-813
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Synthetic Communications1, 40: 808–813, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903009422
STEREOSELECTIVE SYNTHESIS OF SUBSTITUTED
2-(Z-STYRYLSULFONYL)-1H-IMIDAZOLES AND
BENZOTHIAZOLE
N. Guravaiah and V. Rajeswar Rao
Department of Chemistry, National Institute of Technology, Warangal, India
A novel method has been reported involving the synthesis of z-styryl sulfides by the reaction
of phenylacetylene with 2-mercpto benzimidazoles and benzthiazole using NaOH as a base
in absolute ethanol. On further oxidation with H2O2, these resulted in the formation of the
desired styryl sulfones in good yields with retention of stereochemistry.
Keywords: 2-Mercaptoimidazoles; phenylacetylene; styryl sulfides; sulfones
INTRODUCTION
The use of styrylsulfones in organic chemistry and medicinal chemistry has
increased dramatically.[1] Styrylsulfones have been employed in many synthetic
methodologies as intermediates, enabling the preparation of great number of
functionalized products, such as natural products and bioactive substances. The
functional group is found in numerous biologically interesting compounds. These
compounds include anticancer[2–4] and inhibitors for several enzymes such as
cyclooxygenase-2(COX-2).[5] In contrast to different methods developed for Z,Z-
and E,E-bis(styryl)sulfides and sulfones,[6] less attention was focused on stereoselec-
tive synthesis of styryl sulfones. In fact, the latter were reported earlier from our
laboratories by condensation of sodium E-styrenesulfinates with a-halocarbonyl
compounds[7] and 2-halomethyl benzimidazoles.[8] Our sustained interest in this field
led us to develop a simple and elegant methodology for a new class of stereoselective
styrylsulfones through a facile route. In the literature,[4] it has been reported that the
synthesis of the title compounds requires a multistep synthesis (five steps). The first
step involved in the preparation of 1H-benzo[d]imidazole-2-thiols is condensation of
orthophenylene diamines with CS2 in the presence of potassium hydroxide (KOH) in
ethanol. On reaction with various phenacyl halides in the presence of K2CO3 in acet-
one, these gave 2-(1H-benzo[d]imidazol-2-ylthio)-1-phenylethanones. They were
converted to 2-[{1H-bezo[d]imidazol-2-yl}sulfanyl]-1-phenyl-1-ehanols by reduction
with sodium borohydride. These compounds were oxidized to get 2-[{1H-bezo
[d]imidazol-2-yl}sulfonyl]-1-phenyl-1-ethanols. Ultimately, they were subjected to
Received February 13, 2009.
Address correspondence to V. Rajeswar Rao, Department of Chemistry, National Institute of
Technology, Warangal, AP-506 004, India. E-mail: vrajesw@yahoo.com
808

STYRYLSULFONES IN ORGANIC CHEMISTRY
809
dehydration with methanesulfonyl chloride to afford 1-{sulfonyl}2-{([E)-2-phenyl-1-
ethyl]sulfonyl} derivatives, which in turn were demesylated to 1H-benzo[d] imidaz-
ole-2-yl[(E)-2-phenyl-1-ehenyl]sulfones with 33% HBr in acetic acid. Recently, it
was reported that certain styrylsulfone derivatives like FRI-20 inhibit tumor cell
growth and viability by inhibiting the mitogen-activated protein kinase (MAPK)
signal transduction pathway. The compounds regulate the extracellular signal-
related kinase (ERK) and inhibit the proliferation of breast and prostate tumor cells
in a dose-dependent manner without affecting normal cell growth. The cell growth
inhibitory activity of this compound is dictated by the nature and position of the
functional groups. In view of the wide range of biological activities exhibited by
heteryl styrylsulfones, we report the stereoselective synthesis of some heteryl(Z)-
styryl sulfones. These methodologies are quite useful, but they have some limitations,
such as requiring the isolation of intermediates, longer reaction times, and lower
overall yields. It is thus evident that there remains a scope for the development of
clean and efficient methodologies for the preparation of the title compounds.
Herein, we report the synthesis of Z-styrylsulfones in a two-step reaction
(Schemes 1 and 2). The first step involves the nucleophilic addition of the substi-
tuted 2-mercapto benzimidazoles, 2-mercapto benzthiazoles, and 4,5 diphenyl-2-
mercapto imidazoles to phenyl acetylene in the presence of a base in ethanol.
The reflux period varies from 12 to 16 h. The progress of the reaction was mon-
itored by thin-layer chromatography (TLC). After completion of the reaction, the
mixture was cooled to room temperature, poured into crushed ice, and neutra-
lized with conc. HCl to give 3-(1-phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H-
chromen-2-ones. Oxidation of these sulfides with hydrogen peroxides in acetic
acid resulted in the formation of Z-styrylsulfones. The compounds were purified
1
by column chromatography and fully characterized by elemental analysis, IR, H
NMR, 13C NMR, and mass spectrometry.
EXPERIMENTAL
All reagents and solvents were obtained from commercial sources and used
without further purification unless otherwise stated. Reactions were monitored by
Scheme 1. R ¼ OCH3, X ¼ NH; R ¼ OCF2H, X ¼ NH; R ¼ H, X ¼ NH; R ¼ H, X ¼ s.

810
N. GURAVAIAH AND V. RAJESWAR RAO
Scheme 2. Synthesis of 4,5-diphenyl-2-(styrylsulfonyl)-1H-imidazole.
TLC on precoated silica-gel plates (E. Merck, Mumbai, India) with an ultraviolet
(UV) indicator. Column chromatography was performed with Merck 70- to
˚
230-mesh silica gel, 60 A. Yields were of purified products and were not opti-
mized. Melting points were determined in open capillaries with a Cintex
melting-point apparatus (Mumbai, India) and were uncorrected. 1H NMR and
13C NMR spectra were obtained with Bruker AM 300- and 200-MHz spectro-
meters. The chemical shifts are reported in parts per million (d) downfield using
tetramethylsilane (Me4Si) as internal standard and CDCl3 and dimethylsulfoxide
(DMSO-d6) as the solvents, except where indicated. Spin multiplicities are given
as s (singlet), d (doublet), br s (broad singlet), m (multiplet), and q (quartet).
Coupling constants (J values) were measured in hertz (Hz). CHNS analysis was
done using an Carlo Erba EA 1108 automatic elemental analyzer. Mass spectra
(EI-MS) were determined on Perkin Elmer (Sciex API-2000, ESI) instrument at
12.5 eV. 4,5-Diphenyl-2-mercaptobenzimidazole was prepared according to the
procedure reported in the literature.[9]
General Procedure for the Synthesis of 3-(1-Phenyl-2-(Z-styrylthio)-
1H-imidazol-4-yl)-2H-chromen-2-ones
2-Mercaptobenzimidazoles (1 mmol) were added portionwise to a stirred
solution of sodium hydroxide (2 mmol) in absolute ethanaol (20 mL) over a period
of 0.30 h. On completion of the addition and when the reaction was no longer
exothermic, phenylacetylene (1.25 mmol) was added, and the reaction mixture was
refluxed for 12–16 h. The reaction mixture was then poured into crushed ice and
neutralized with HCl solution. The solid was separated, filtered, washed with water,
and dried, and the crude product was purified by column chromatography
(ethylacetate=hexane 1:9) to afford the respective (Z)-styrylsulfides. All the other
compounds were prepared similarly.

STYRYLSULFONES IN ORGANIC CHEMISTRY
811
Spectral Data of the Compounds
5-Methoxy-2-(styrylthio)-1H-benzo[d]imidazole. Yield: 85%, mp 134–
136ꢀC. IR (KBr, cmax cmꢁ1): 1594 (C C), 1625 (C N), 3403 (NH), 1H NMR
(CDCl3 þ DMSO-d6, d ppm): 3.68 (s, 3H OCH3), 6.61 (d, 1H, J ¼ 12 Hz, styryl),
6.71 (d, 1H, J ¼ 2 Hz, Ar-H), 6.74 (s, 1H, Ar-H), 7.02 (d, 1H, J ¼ 12 Hz, styryl),
7.16 (m, 1H, Ar-H), 7.26–7.33 (m, 5H, Ar-H). EI-MS 282 (M þ ). 13C NMR
(CDCl3 þ DMSO-d6, d ppm) 54.9, 110.6, 119.5, 126.7, 127.3, 127.6, 127.8, 135.2,
146.1, 155.2. Anal. calcd. for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C,
68.00; H, 4.94; N, 9.95%.
=
=
5-(Difluoromethoxy)-2-(styrylthio)-1H-benzo[d]imidazole. Yield
88%,
mp 108–110ꢀC. IR (KBr, cmax cmꢁ1): 1596 (C C), 1624 (C N), 3426 (NH). H
NMR (CDCl3, d ppm): 6.85 (d, 1H, J ¼ 12 Hz, styryl), 7.27 (d, 1H, J ¼ 12 Hz, styryl),
7.31–7.39 (m, 7H, Ar-H), 7.44 (1, 1H, OCF2H), 7.53 (d, 1H, Ar-H, J ¼ 6 Hz), 9.72
(s, 1H, NH), EI-MS 319 (M þ H)þ. Anal. calcd. for C16H12F2N2OS: C, 60.37; H,
3.80; N, 8.80. Found: C, 60.33; H, 3.85; N, 8.85%.
1
=
=
2-(Styrylthio)-1H-benzo[d]imidazole. Yield 92%, mp 130–132ꢀC. IR (KBr,
1
max cmꢁ1): 1597 (C C), 1616 (C N), 3394 (NH). H NMR (CDCl3, d ppm): 6.75
=
=
c
(d, 1H, J ¼ 12 Hz, styryl), 6.85 (d, 1H, J ¼ 12 Hz, styryl), 7.10 (d, 1H, J ¼ 8 Hz
Ar-H), 7.25–7.45 (m, 8H, Ar-H). Anal. calcd. for C15H12N2S: C, 71.40; H, 4.79;
N, 11.10. Found: C, 71.45; H, 4.83; N, 11.00%.
2-(Styrylthio)benzo[d]thiazole. Yield 80%, mp 114–116ꢀC. IR (KBr,
1
max cmꢁ1): 1598 (C C), 1616 (C N), 3348 (NH). H NMR (CDCl3, d ppm): 6.65
=
=
c
(d, 1H, J ¼ 12 Hz, styryl), 6.85 (d, 1H, J ¼ 12 Hz, styryl), 7.20–7.49 (m, 9H, Ar-H).
Anal. calcd. for C15H11NS2: C, 66.88; H, 4.12; N, 5.20. Found: C, 66.84; H, 4.10;
N, 5.24%.
4,5-Diphenyl-2-(styrylthio)-1H-imidazole. Yield 78%, mp 138–140ꢀC. IR
(KBr, cmax cmꢁ1): 1595 (C C), 1623 (C N), 3448 (NH). 1H NMR (CDCl3,
d ppm): 6.76 (d, 1H, J ¼ 12 Hz, styryl), 7.01 (d, 1H, J ¼ 12 Hz, styryl), 7.28–7.51
(m, 15H, Ar-H), 12.95 (s, 1H, NH). 13C NMR (CDCl3 d ppm) 122.7, 127.2,
127.4, 127.6, 127.7, 128.2, 128.4, 128.6, 135.9, 138.7. EI-MS 355 (M þ H)þ. Anal.
calcd. for C23H18N2S: C, 77.93; H, 5.12; N, 7.90. Found: C, 77.90; H, 5.10;
N, 7.86%.
=
=
General Procedure for the Synthesis of Z-Styrylsulfones
To a solution containing Z-styrylsulfides (15 mmol) in 20 mL of glacial acetic
acid, 30% hydrogen peroxide (8 mL) was added dropwise at room temperature. After
the addition was complete, the reaction mixture was allowed to stir at room tempera-
ture for 24 h. The mixture was then poured into ice-cold water and stirred for 10 min.
The solid was separated, filtered, and dried to give the required compound. All the
other compounds were prepared similarly.

812
N. GURAVAIAH AND V. RAJESWAR RAO
Spectral Data
5-Methoxy-2-(styrylsulfonyl)-1H-benzo[d]imidazole. Yield 90%, mp
220–222ꢀC. IR (KBr, cmax cmꢁ1): 1155, 1356(SO2), 1508 (C C), 1601 (C N), 3434
(NH). 1H NMR (CDCl3, d ppm): 3.90 (s, 3H OCH3), 7.05 (d, 1H, J ¼ 12 Hz, styryl),
7.35 (d, 1H, J ¼ 12 Hz, styryl), 7.60–7.81 (m, 8H, Ar-H). EI-MS 313 (M-H)þ. Anal.
calcd. for C16H14N2O3S: C, 61.13; H, 4.49; N, 8.91. Found: C, 61.00; H, 4.38; N,
8.96%.
=
=
5-(Difluoromethoxy)-2-(styrylsulfonyl)-1H-benzo[d]imidazole. Yield 89%,
mp 198–200ꢀC. IR (KBr, cmax cmꢁ1): 1148, 1341 (SO2), 1594 (C C), 1626 (C N),
=
=
1
3588 (NH). H NMR (CDCl3, d ppm): 7.0 (d, 1H, J ¼ 12 Hz, styryl), 7.18 (d, 1H,
J ¼ 12 Hz, styryl), 7.20–7.40 (m, 9H, Ar-H). Anal. calcd. for C16H12F2N2O3S: C,
54.85; H, 3.45; N, 8.00. Found: C, 54.80; H, 3.41; N, 8.10%.
2-(Styrylsulfonyl)-1H-benzo[d]imidazole. Yield 92%, mp 213–215ꢀC. IR
(KBr, cmax cmꢁ1): 1119, 1344 (SO2), 1618 (C N), 1606 (C C), 3588 (NH). 1H
NMR (CDCl3, d ppm): 7.15 (d, 1H, J ¼ 12 Hz, styryl), 7.45 (d, 1H, J ¼ 12 Hz, styryl),
7.60–7.80 (m, 9H, Ar-H). Anal. calcd. for C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85.
Found: C, 63.39; H, 4.28; N, 9.88%.
=
=
2-(Styrylsulfonyl)benzo[d]thiazole. Yield 88%, mp 208–210ꢀC. IR (KBr,
c
max cmꢁ1): 1141, 1315 (SO2), 1626 (C N), 1606 (C C), 3392 (NH). 1H NMR
= =
(CDCl3, d ppm): 7.10 (d, 1H, J ¼ 12 Hz, styryl), 7.30 (d, 1H, J ¼ 12 Hz, styryl),
7.4 (d, 1H, J ¼ 8 Hz, Ar-H), 7.50–7.70 (m, 8H, Ar-H). Anal. calcd. for C15H11NO2S2.
C, 59.78; H, 3.68; N, 4.65. Found: C, 59.81; H, 3.70; N, 4.69%.
4,5-Diphenyl-2-(styrylsulfonyl)-1H-imidazole. Yield 85%, mp 228–230ꢀC.
1
IR (KBr, cmax cmꢁ1): 1173, 1395 (SO2), 1509 (C C), 1601 (C N), 3430 (NH). H
NMR (CDCl3, d ppm): 7.15 (d, 1H, J ¼ 12 Hz, styryl), 7.25 (d, 1H, J ¼ 12 Hz, styryl),
7.30–7.45 (m, 15H, Ar-H). EI-MS 387 (M þ H)þ. Anal. calcd. for C23H18N2SO2: C,
71.48; H, 4.69; N, 7.25. Found: C, 71.50; H, 4.72; N, 7.12%.
=
=
CONCLUSIONS
In conclusion, we have developed a simple, inexpensive, and efficient stereose-
lective synthesis of styrylsulfones without using any catalyst. The study of the bio-
logical activity of these new styrylsulfones is in progress and will be published
elsewhere.
ACKNOWLEDGMENT
This work was supported by grants from the Council of Scientific Industrial
Research (CSIR), New Delhi, for Project No. 01 (2062) 06=EMR-II.
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