Efficient, stereoselective approach to the synthesis of 3-(1-Phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-ones

Article abstract of DOI:10.1080/00397911003797874

Reaction of phenyl acetylene with 3-(1-aryl-2-mercapto-4-imidazolyl)-2H-1- benzopyran-2-ones (4) in the presence of sodium hydroxide in absolute ethanol led to the formation of 3-(1-phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H- chromen-2-ones (6) in excel

Full text of DOI:10.1080/00397911003797874

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Efficient, Stereoselective Approach
to the Synthesis of 3-(1-Phenyl-2-(Z-
styrylsulfonyl)-1H-imidazol-4-yl)-2H-
chromen-2-ones
Nalajam Guravaiah a & Vedula Rajeswar Rao a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Published online: 21 Mar 2011.
To cite this article: Nalajam Guravaiah & Vedula Rajeswar Rao (2011) Efficient, Stereoselective
Approach to the Synthesis of 3-(1-Phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-ones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:8, 1167-1174, DOI: 10.1080/00397911003797874
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Synthetic Communications1, 41: 1167–1174, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003797874
EFFICIENT, STEREOSELECTIVE APPROACH TO THE
SYNTHESIS OF 3-(1-PHENYL-2-(Z-
STYRYLSULFONYL)-1H-IMIDAZOL-4-YL)-2H-
CHROMEN-2-ONES
Nalajam Guravaiah and Vedula Rajeswar Rao
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract Reaction of phenyl acetylene with 3-(1-aryl-2-mercapto-4-imidazolyl)-2H-
1-benzopyran-2-ones (4) in the presence of sodium hydroxide in absolute ethanol led to
the formation of 3-(1-phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-ones (6)
in excellent yields. These, on further oxidation with H2O2=AcOH, gave the corresponding
sulfones (7) with retention of stereochemistry.
Keywords 3-(2-Mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-ones; phenylacety-
lene; styryl sulfides; sulfones
INTRODUCTION
Coumarins are structurally simple compounds belonging to a large class of
molecules known as benzopyrones.[1] Coumarins and related compounds have
diverse biological activities, including anticoagulant and antithrombotic proper-
ties.[2] Coumarin derivatives have also been shown to be novel lipid-lowering agents
that possess moderate triglyceride-lowering activity.[3] Many coumarin derivatives
have the unique ability to scavenge reactive oxygen species such as hydroxyl-free
radicals, superoxide radicals, and hypochlorous acid to prevent free radical injury.[4]
Received January 1, 2010.
Address correspondence to V. Rajeswar Rao, Department of Chemistry, National Institute of
Technology, Warangal 506 004, India. E-mail: vrajesw@yahoo.com
1167

1168
N. GURAVAIAH AND V. R. RAO
Scheme 1. Synthesis of 3-(1-phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-ones.
Recently, certain coumarin derivatives have been shown to function as human
immunodeficiency virus integrase inhibitors and have been evaluated in the treat-
ment of HIV infection,[5] whereas others have been evaluated as anti-invasive com-
pounds because of their inhibitory activity against some serine proteases and matrix
metalloproteases (MMPs).[6] It has been shown that 6-nitro-7-hydroxy coumarin acts
as a selective antiproliferative agent by activating p38, stress-activated protein kinase
(SAPK) and the p21WAF1=CIP1 cyclin-dependent kinase inhibitor, in the human renal
cell carcinoma cell line, A-498.[7,8] Recently, two new naturally occurring coumarins
have been isolated and shown to inhibit the polymerization of tubulin and arrest cells
in the mitotic phase by inhibiting microtubule formation.[9] These coumarins were
found to act synergistically with paclitaxel in inhibiting KB (human epidermoid
carcinoma) cell proliferation.[9] The growth-inhibitory properties of novel coumarin
sulfonamides were demonstrated using a panel of cancer cell lines.[10]
It was reported that certain styrylsulfone[11] derivatives such as FRI-20 inhibit
the tumor cell growth and viability by inhibiting the MAPK signal transduction
pathway. The compounds regulate the ERK and inhibit the proliferation of breast
tumor cells in a dose-dependent manner without affecting normal cell growth. The
cell growth–inhibitory activity of these compounds is dictated by the nature and

EFFICIENT, STEREOSELECTIVE SYNTHESIS
1169
position of the functional groups. The heteryl styryl sulfones[12] and aryl stryl sul-
fone[13] moiety has been found in numerous biologically interesting compounds.
These compounds include anticancer agents and inhibitors for several enzymes such
as cyclooxygenase-2 (COX-2). Based on these observation, we were interested in
synthesizing some of 4-coumaniyl 2-styrylsulfonyl-1-phenyl imdazoles (7), which
are expected to have more anticancer activity than aryl styrylsulfones.
In the literature, it was reported that condensation of 3-(2-bromo acetyl) cou-
marin[14] with aniline in ethanol at reflux temperature for 15–30 min resulted in the
formation of 3-(2-(phenylanliino)acetyl)-2H-chromen-2-one (3)[15] in only 70–75%
yield. On further reaction with potassiumsulfocynide in acetic acid at reflux, these
gave the 3-(2-mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-ones (4) in
62–64% yields only. Though these above methodologies are quite useful, they have
some limitations such as prolonged reaction time and moderate yields of the pro-
ducts. This is explained by the fact that they have less selectivity and low efficiency
of reactant participation in solvent media. Hence, there is a need for alternative pro-
cedures involving milder reaction conditions. In the past, we have synthesized the
heterocyclic compounds under solvent-free conditions.[16–19] In continuation of our
earlier work, we became interested in developing new methodologies for the prep-
aration of both 3-(2-phenylamino)acetyl-2H-chromen-2-ones (3) and 3-(2-mercapto-
1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-ones (4) under solvent-free conditions. In
a typical case, a mixture of 1 eq of 3-(2-bromo acetyl) coumarin and 1.25 eq of ani-
line was ground for 5–8 min in a mortar by pestle at room temperature in the pres-
ence of K2CO3 (1 eq) as a base, which gave the corresponding 3-(2-(phenylamino)
acetyl)-2H-chromen-2-one (3) in 92–96% yield. In this step, elimination of the
HBr molecule takes place in the nucleophilic substitution reaction. Various
3-(2-phenylamino)acetyl-2H-chromen-2-ones on treatment with KSCN in the pres-
ence of a few drops of acetic acid under grinding for 5–10 min gave 3-(2-mercapto-
1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-ones (4). The yields of the product in the
solid state were 90–95%. The advantage of the solid-state reactions are that the pro-
ducts are obtained with high purity, good yields, good selectivity, high efficiency,
ease of manipulation, and cleaner products. The products 3 and 4 obtained by these
two methods were shown to be identical by mixed melting-point measurements,
thin-layer chromatography (TLC), and infrared (IR). Nucleophilic addition of the
3-(2-mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-one to phenyl acetylene
in the presence of a base yielded 3-(1-phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H-
chromen-2-ones (6). This is a stereoselective synthesis involving the formation of
(z)-vinyl sulfides. In the reaction, hydrothiolation of aromatic alkyne with
3-(2-mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-one by anti-Markonikov’s
addition takes place. The sterospecific trans addition across the triple bond leads
to the formation of cis alkenes. Oxidation of these sulfides with hydrogen peroxides
in acetic acid resulted in the formation of Z-styryl sulfones (7) without any change in
the stereochemistry.
EXPERIMENTAL
All the reagents and solvents were pure, purchased from commercial sources,
and used without further purification unless otherwise stated. Melting points were

1170
N. GURAVAIAH AND V. R. RAO
determined in open capillaries with a Cintex melting-point apparatus (Mumbai,
India) and were uncorrected. CHNS analysis was done on a Carlo Erba EA 1108
automatic elemental analyzer. The purity of the compounds was checked by TLC
plates (E. Merek, Mumbai, India), IR spectra (KBr) were recorded on a Bruker
1
WM-4(X) spectrometer (577 model). H NMR spectra were recorded on Bruker
WM-300 and 200 spectrometers in d ppm using tetramethylsilane (TMS) as internal
standard. Mass spectra (EI-MS) were determined on a Perkin Elmer (Sciex
API-2000, ESI) at 12.5 eV.
3-(2-Anilinoacetyl)-2H-1-benzopyran-2-ones (3a–f)
A mixture of 3-(2-bromo acetyl) coumarin, aniline, and K2CO3 in a 1:1:1 molar
ratio were ground at room temperature for 5–8 min by monitoring TLC. After com-
pletion of the reaction, the mixture was treated with water. The solid separated was
filtered and recrystallized from suitable solvent. Yield 92–96%.[15]
3-(2-Mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-one (4a–f)
A mixture of 3-(2-(phenylamino)acetyl)-2H-chromen-2-ones (0.01 mol) and
potassium thiocyanate (0.01 mol) and a few drops of acetic acid were intimately
ground by pestle and mortar at room temperature for about 5–10 min and then
treated with water. The resultant solid was filtered and recrystallized from suitable
solvent. Yield 90–95%.[15]
3-(1-Phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-ones
(6a–f): General Procedure
3-(2-Mercapto-1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-one (1 mmol) was
added portionwise to a stirred solution of sodium hydroxide (2 mmol) in absolute
ethanol (20 mL) over a period of 0.30 h. On completion of the addition and when
the reaction was no longer exothermic, phenyl acetylene (1 mmol) was added, and
the reaction mixture was refluxed for 36 h. The reaction mixtures was then poured
into crushed ice, neutralized with HCl solution, and stirred for 10 min. The solid
separated was filtered, washed with water, and dried, and the crude product was pur-
ified by column chromatography (ethyl acetate=hexane, 1:9) to afford the respective
(Z)-styryl sulfides.
Spectral Data of Styrylsulfides (6a–f)
3-(1-Phenyl-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-one (6a).
Yield 84%, mp 142–144 ꢀC. IR (KBr, cmax cmꢁ1): 1595 (C C), 1629 (C N), 1727
=
=
1
=
(C O of lactone), H NMR (CDCl3, d ppm): 6.73 (d, 1H, J ¼ 12 Hz, styryl), 7.13
(d, 1H, J ¼ 12 Hz, styryl), 7.36–7.49 (m, 13H, Ar-H), 7.64 (d, 1H, J ¼ 6 Hz, Ar-H),
8.16 (s, 1H, imidazole), 8.66 (s,1H, C4 of coumarin proton). 13C NMR (CDCl3, d
ppm), 116.69, 120.0, 121.09, 121.22, 122.91, 125.54, 127.05, 128.11, 128.97, 129.23,
129.29, 129.50, 129.58, 131.74, 132.32, 135.01, 135.61, 135.0, 136.50, 140.0, 154.40,

EFFICIENT, STEREOSELECTIVE SYNTHESIS
1171
159.94. EI-MS 423 (MþH)þ. Anal. calcd. for C26H18N2O2S: C, 73.91; H, 4.29; N,
6.63. Found: C, 73.94; H, 4.32; N, 6.60%.
6-Bromo-3-(1-phenyl-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-one
(6b). Mp 168–170 ꢀC. IR (KBr, cmax cmꢁ1): 1562 (C C), 1612 (C N), 1714 (C O
=
=
=
1
of lactone). H NMR (CDCl3, d ppm): 6.75 (d, 1H, J ¼ 12 Hz, styryl), 7.13 (d, 1H,
J ¼ 12 Hz, styryl), 7.39–7.51 (m, 13H, Ar-H), 8.16 (s, 1H, imidazole), 8.57 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H17BrN2O2S: C, 62.28; H, 3.42; N,
5.59. Found: C, 62.34; H, 3.40; N, 5.64%.
6,8-Dibromo-3-(1-phenyl-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-
one (6c). Mp 186–188 ꢀC. IR (KBr, cmax cmꢁ1): 1596 (C C), 1724 (C O of lac-
tone), 1H NMR (CDCl3, d ppm): 6.74 (d, 1H, J ¼ 12 Hz, styryl), 7.13 (d, 1H,
J ¼ 12 Hz, styryl), 7.35–7.61 (m, 12H, Ar-H), 8.15 (s, 1H, imidazole), 8.56 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H16Br2N2O2S: C, 53.81; H, 2.78; N,
4.83. Found: C, 53.85 ; H, 2.82; N, 4.87%.
=
=
6-Chloro-3-(1-phenyl-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-one
(6d). Mp 158–160 ꢀC. IR (KBr, cmax cmꢁ1): 1560 (C C), 1595 (C N), 1721 (C O
=
=
=
1
of lactone), H NMR (CDCl3, d ppm): 6.72 (d, 1H, J ¼ 12 Hz, styryl), 7.15 (d, 1H,
J ¼ 12 Hz, styryl), 7.25–7.50 (m, 13H, Ar-H), 8.10 (s, 1H, imidazole), 8.52 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H17ClN2O2S: C, 68.34; H, 3.75; N,
6.13. Found: C, 68.38; H, 3.79; N, 6.17%.
6,8-Dichloro-3-(1-phenyl-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-
one (6e). Mp 172–174 ꢀC. IR (KBr, cmax cmꢁ1): 1595 (C C), 1654 (C N), 1751
=
=
1
=
(C O of lactone). H NMR (CDCl3, d ppm): 6.70 (d, 1H, J ¼ 12 Hz, styryl), 7.15
(d, 1H, J ¼ 12 Hz, styryl), 7.20–7.50 (m, 11H, Ar-H), 7.63 (d, 1H, J ¼ 6 Hz, Ar-H),
8.15 (s, 1H, imidazole), 8.55 (s, 1H, C4 of coumarin proton). Anal. calcd. for
C26H16Cl2N2O2S: C, 63.55; H, 3.28; N, 5.70. Found: C, 63.58; H, 3.31; N, 5.75%.
3-(1-(4-Chlorophenyl)-2-(styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-one
(6f). Mp 148–150 ꢀC. IR (KBr, cmax cmꢁ1): 1562 (C C), 1609 (C N), 1721 (C O of
=
=
=
1
lactone). H NMR (CDCl3, d ppm): 6.74 (d, 1H, J ¼ 12 Hz, styryl), 7.11 (d, 1H,
J ¼ 12 Hz, styryl), 7.22–7.49 (m, 13H, Ar-H), 8.10 (s, 1H, imidazole), 8.65 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H17ClN2O2S: C, 68.34; H, 3.75; N,
6.13. Found: C, 68.38; H, 3.78; N, 6.18%.
General Procedure for the Synthesis of 3-(1-Phenyl-
2-(Z-Styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-ones (7a–f)
To a solution containing 3-(1-Phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-yl)-
2H chromen-2-ones (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 temperature for 24 h.
The mixture was then poured into ice-cold water and stirred for 10 min. The
separated solid was filtered and dried to give the required compound.

1172
N. GURAVAIAH AND V. R. RAO
Spectral Data of Styrylsulfones (7a–f)
3-(1-Phenyl-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-one (7a).
Mp 210–212 ꢀC. IR (KBr, cmax cmꢁ1): 1152, 1316 (SO2), 1559 (C C), 1607 (C N),
=
=
1
=
1728 (C O of lactone), H NMR (CDCl3, d ppm): 7.15 (d, 1H, J ¼ 12 Hz, styryl),
7.30 (d, 1H, J ¼ 12 Hz, styryl), 7.40–7.65 (m, 14H, Ar-H), 8.20 (s, 1H, imidazole),
8.60 (s, 1H, C4 of coumarin proton). EI-MS 453 (M-H)þ. Anal. calcd. for
C26H18N2O4S: C, 68.71; H, 3.99; N, 6.16. Found: C, 68.77; H, 3.94; N, 6.13%.
6-Bromo-3-(1-phenyl-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-
2-one (7b). Mp 248–250 ꢀC. IR (KBr, cmax cmꢁ1): 1104, 1331 (SO2), 1580 (C C),
=
1612 (C N), 1718 (C O of lactone). 1H NMR (CDCl3, d ppm): 6.90 (d, 1H,
J ¼ 12 Hz, styryl), 7.10–7.55 (m, 13H, Ar-H and 1H of styryl), 8.15 (s, 1H, imidaz-
ole), 8.50 (s, 1H, C4 of coumarin proton). Anal. calcd. for C26H17BrN2O4S: C,
58.55; H, 3.21; N, 5.25. Found: C, 58.58; H, 3.24; N, 5.29%.
=
=
6,8-Dibromo-3-(1-phenyl-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-
2-one (7c). Mp 254–256 ꢀC. IR (KBr, cmax cmꢁ1): 1153, 1316 (SO2), 1564 (C C),
=
1608 (C N), 1723 (C O of lactone). 1H NMR (CDCl3, d ppm): 6.95 (d, 1H,
J ¼ 12 Hz, styryl), 7.10 (d, 1H, J ¼ 12 Hz, styryl), 7.30–7.45 (m, 12H, Ar-H), 8.05
(s, 1H, imidazole), 8.35 (s, 1H, C4 of coumarin proton). Anal. calcd. for
C26H16Br2N2O4S: C, 51.00; H, 2.63; N, 4.58. Found: C, 51.10; H, 2.68; N, 4.61%.
=
=
6-Chloro-3-(1-phenyl-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-
2-one (7d). Mp 222–224 ꢀC. IR (KBr, cmax cmꢁ1): 1149,1367 (SO2), 1598 (C C),
=
1618 (C N), 1725 (C O of lactone). 1H NMR (CDCl3, d ppm): 7.10 (d, 1H,
J ¼ 12 Hz, styryl), 7.15–7.50 (m, 14H, Ar-H), 8.19 (s, 1H, imidazole), 8.52 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H17ClN2O4S: C, 63.87; H, 3.50; N,
5.73. Found: C, 63.89; H, 3.54; N, 5.65%.
=
=
6,8-Dichloro-3-(1-phenyl-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-
2-one (7e). Mp 202–204 ꢀC. IR (KBr, cmax cmꢁ1): 1118, 1388 (SO2), 1560 (C C),
=
1610 (C N), 1743 (C O of lactone). 1H NMR (CDCl3, d ppm): 7.05 (d, 1H,
J ¼ 12 Hz, styryl), 7.20–7.60 (m, 13H, Ar-H), 7.95 (s, 1H, imidazole), 8.48 (s, 1H,
C4 of coumarin proton). Anal. calcd. for C26H16Cl2N2O4S: C, 59.66; H, 3.08; N,
5.35. Found: C, 59.69; H, 3.12; N, 5.38%.
=
=
3-(1-(4-Chlorophenyl)-2-(styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-
2-one (7f). Mp 198–200 ꢀC. IR (KBr, cmax cmꢁ1): 1118, 1366 (SO2), 1595 (C C),
=
1618 (C N), 1720 (C O of lactone). 1H NMR (CDCl3, d ppm): 6.95 (d, 1H,
J ¼ 12 Hz, styryl), 7.29 (d, 1H, J ¼ 12 Hz, styryl), 7.38–7.65 (m, 14H, Ar-H), 8.30
(s, 1H, imidazole), 8.55 (s, 1H, C4 of coumarin proton). Anal. calcd. for C26H17
ClN2O4S: C, 63.87; H, 3.50; N, 5.73. Found: C, 63.89; H, 3.58; N, 5.79%.
=
=
CONCLUSION
In conclusion, we have disclosed a mild, inexpensive, and efficient stereoselec-
tive method for the synthesis of 3-(1-phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-
yl)-2H-chromen-2-ones in good yields. The scope and synthetic application of this
novel reaction are under investigation in our laboratory.

EFFICIENT, STEREOSELECTIVE SYNTHESIS
1173
ACKNOWLEDGMENT
We are grateful for financial support from the Council of Scientific and
Industrial Research (CSIR), New Delhi, Project No. 01 (2062) 06=EMR-II.
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