Unusual sulfanylation through ring transformation of arene-tethered 2H-pyran-2-ones by in situ built Michael adduct

Article abstract of DOI:10.1016/j.tetlet.2006.03.119

A novel synthesis of highly functionalized alkylsulfanylmethyl arenes 8a-m through the ring transformation of 6-aryl-4-methyl/ethylsulfanyl-2H-pyran-2-one-3-carbonitriles 1a-j, by reaction with methyl vinyl ketone 2, is delineated and illustrated. To asce

Full text of DOI:10.1016/j.tetlet.2006.03.119

Tetrahedron Letters 47 (2006) 3759–3762
Unusual sulfanylation through ring transformation of
arene-tethered 2H-pyran-2-ones by in situ built Michael adduct I
Diptesh Sil,a Ramendra Pratap,a Rishi Kumar,b P. R. Maulikb and Vishnu Ji Rama,*
aDivisions of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
bMolecular and Structural Biology, Central Drug Research Institute, Lucknow 226 001, India
Received 30 January 2006; revised 7 March 2006; accepted 17 March 2006
Abstract—A novel synthesis of highly functionalized alkylsulfanylmethyl arenes 8a–m through the ring transformation of 6-aryl-4-
methyl/ethylsulfanyl-2H-pyran-2-one-3-carbonitriles 1a–j, by reaction with methyl vinyl ketone 2, is delineated and illustrated. To
ascertain the course of reaction, 3-arylsulfanylmethyl-2-methyl-6-methylsulfanyl-4-phenylbenzonitriles 8k–m were also prepared
from the reaction of 1 with 4-arylsulfanyl-butan-2-ones 7c,d.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The biaryl system serves as a central building block in
various natural products of therapeutic significance.1
The synthesis of highly congested biaryls, particularly
those with hindered rotation, is highly demanding not
only in the construction of natural products, but also
in asymmetric syntheses,2 crown ethers,3 chiral liquid
crystals,4 chiral phases for chromatography5 and
agrochemicals.6
transformation of suitably functionalized 2H-pyran-
2-one-3-carbonitriles24 1a–j with methyl vinyl ketone 2.
Our attempt to construct hindered biaryls 3 with an aryl
or heteroaryl linked to a styrenyl group through the ring
transformation of 2H-pyran-2-ones 1a–j with methyl
vinyl ketone 2, failed. The isolated product, showed three
1
singlet signals in the H NMR due to CH3, SCH3 and
CH2 protons, but no vinyl signals. The molecular ion
and mass spectral fragmentation pattern also did not
match with the anticipated product 3. The structure of
the isolated compound 8a was unambiguously con-
firmed by single crystal X-ray diffraction analysis as
2-methyl-6-methylsulfanyl-3-methylsulfanylmethyl-4-
phenylbenzonitrile. The formation of products 8a–m is
only possible if the ring transformation of 1 involves
4-alkyl/arylsulfanyl-butan-2-one 7, formed by Michael
addition of alkylthiol or thiophenol to methyl vinyl
ketone.
Earlier, biaryls have been synthesized by coupling of
aromatic moieties using a variety of expensive metal
catalysts.7–20 Villemin et al.21 synthesized asymmetrical
biaryls efficiently by microwave irradiation of an aro-
matic halide and a tetraaryl borate in DMF. These have
also been prepared22 by dihydrooxazole-mediated cou-
pling, but with a limitation on the substituent in the phen-
yl ring and difficulty in obtaining some Grignard
reagents. Very recently, we have reported23 the synthesis
of non-sulfanylated biaryls from the reaction of suitably
functionalized 2H-pyran-2-ones and malonodinitrile.
The liberation of alkylthiol in situ could occur in two
ways: via a substitution reaction at position 4 of the
pyran ring by a carbanion, generated from methyl vinyl
ketone to form 4, or through the ring transformation of
2H-pyran-2-one by 2 with ring opening followed by
Michael addition of an enolate to C-3-C-4 of the pyran
ring, with the elimination of alkylthiol and formation
of pyran-2-ylidene 6. Our best efforts to isolate either
of the envisaged products 4 or 6 failed. Based on our
past observations on the ring transformations of 2H-
pyran-2-ones, the reaction is possibly initiated by
The wide-ranging applications of biaryl systems necessi-
tated the development of an easy access to the synthesis
of alkyl/arylsulfanylmethylbiaryls 8a–m through the ring
Keywords: Sulfanylated arenes; 2H-Pyran-2-one; Ring transformation
reactions.
q Communication No. 6721.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: vjiram@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.119

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D. Sil et al. / Tetrahedron Letters 47 (2006) 3759–3762
substitution at C-4 with liberation of alkylthiol followed
by an unusual in situ Michael addition to methyl vinyl
ketone 2, which in turn acts as a source of a carbanion
for the further ring transformation reactions. The carb-
anion formation could occur at either C-1 or C-3 of 4-
alkylsulfanyl-butan-2-one 7, but C-3 is more susceptible
due to the combined inductive effects of the acetyl
and methylsulfanylmethyl groups. The formation of
products 8a–i is only possible if the ring transformation
involves a carbanion generated at C-3 from 7a. In
support of our previous findings, an independent ring
transformation reaction from 4-ethylsulfanyl-6-phenyl-
2H-pyran-2-one-3-carbonitrile 1j with methyl vinyl
ketone was carried out under similar reaction condi-
tions and an analogous product, 6-ethylsulfanyl-3-ethyl-
sulfanylmethyl-2-methyl-4-phenylbenzonitrile 8j, was
isolated.
7c and 7d independently from the reaction of methyl
vinyl ketone with thiophenol and 4-thiocresol,
respectively.25
The reaction of 6-aryl-4-methylsulfanyl-2H-pyran-2-
one-3-carbonitriles 1a,d with 7c and 7d separately led
to the expected analogous products 8k–m in moderate
yields because of the competitive reactions of the
Michael adducts 7c,d at the C-4 and C-6 electrophilic
centres of 2H-pyran-2-ones 1. In support of our pro-
posed mechanism, an independent reaction was carried
out stirring a mixture of 4-methylsulfanyl-6-phenyl-
2H-pyran-2-one-3-carbonitrile 1a, methyl vinyl ketone
2 and ethanethiol in the presence of powdered KOH
in DMF at room temperature for 24 h. On usual work
up and chromatographic purification, a mixture of two
cross-over products was isolated and distinguished by
1H NMR spectra as 6-ethylsulfanyl-2-methyl-3-meth-
ylsulfanylmethyl-4-phenylbenzonitrile and 3-ethylsulfa-
nylmethyl-2-methyl-6-methylsulfanyl-4-phenylbenzonit-
rile in a ratio of almost 40:60. These experiments further
support our view that the liberated alkylthiol is used up
in the formation of the Michael adduct from methyl
vinyl ketone, which then participates in the ring trans-
formation reactions.
This experiment indicated that the liberated alkylthiol
acts as a nucleophile to form an adduct in situ on reac-
tion with 2. The reason for the moderate yields of the
isolated compounds 8a–j in the range of 37–48% is
possibly due to the limited availability of methyl vinyl
ketone for the formation of the Michael adduct. In
another set of experiments, we prepared Michael adducts
SR
CN
O
O
+
Ar
O
1
2
X
X
O
SR
CN
CN
CN
O
O
RSH
+
Ar
Ar
O
Ar
O
3
5
4
6
O
R1SH
+
SR1
R1
5
7
7
2
a
b
c
CH3
C2H5
C6H5
4-CH3C6H4
O
O
CN
OH
d
O
RS
CN
O
O
RS
1 + 7
CH3
SR1
CH3
Ar
Ar
H
SR1
Ar
R1
8
a
b
c
d
e
f
g
h
i
Yield (%)
phenyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C6H5
40
38
45
47
47
40
45
37
37
48
40
4-methylphenyl
4-fluorophenyl
4-chlorophenyl
4-bromophenyl
4-methoxyphenyl
3,4-dichlorophenyl
2-furanyl
2-thienyl
phenyl
phenyl
phenyl
SR
CN
Ar
CH3
SR1
j
k
l
8
4.CH3.C6H4 48
C6H5 45
4-chlorophenyl
m
R = C2H5 for 8j otherwise CH3
Scheme 1.

D. Sil et al. / Tetrahedron Letters 47 (2006) 3759–3762
3761
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Figure 1. The ORTEP (30% probability) diagram of 8a with the
atomic numbering scheme.
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2H-Pyran-2-one 1 has three electrophilic centres at C-2,
C-4 and C-6 in which the latter is highly vulnerable to
nucleophilic attack owing to extended conjugation and
the presence of an electron withdrawing substituent
(CN) at position 3 of the pyran ring. Thus, the carban-
ion generated in situ from 4-alkyl/arylsulfanyl-butan-2-
one attacks at C-6 with ring closure followed by the
elimination of carbon dioxide and water affording 8,
as shown in Scheme 1. Thus, a mixture of 2H-pyran-2-
one 1, methyl vinyl ketone 2 and powdered KOH in
DMF was stirred at room temperature for 24 h to give
8a–j. All the synthesized compounds were character-
ized26 by spectroscopic and elemental analysis.
Figure 1 shows the crystal structure of 8a.26 The mole-
cule consists of two phenyl rings with one twisted at
C-6 by 54.2(1)ꢁ from the least-squares mean plane
through the substituted phenyl ring. The crystal packing
reveals the presence of weak intermolecular SÁ Á ÁAr
interactions between S2 and the centroid of the substi-
25. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
2109.
˚
tuted phenyl ring [1 À x, 1 À y, 1 À z; S2Á Á ÁCg: 3.857 A].
26. Typical procedure for the synthesis of 8: A mixture of 2H-
pyran-2-one 1 (1 mmol), methyl vinyl ketone 2 (1.5 mmol)
and powdered KOH (1.5 mmol) in dry DMF was stirred
for 24 h at room temperature. The reaction mixture was
poured onto ice water and neutralized with 10% HCl. The
separated solid was filtered, washed with water and dried.
The crude product was purified by silica gel column
chromatography to afford 8 in moderate yield. Compound
8a: Yield 40%; mp 106–108 ꢁC; IR (KBr) m 2213 cmÀ1
Our procedure provides an easy access for the synthesis
of sulfanylated asymmetrical hindered biaryls in a single
step.
Acknowledgement
1
(CN); H NMR (200 MHz, CDCl3) d 1.95 (s, 3H, CH3),
D.S. is thankful to CSIR for Senior Research Fellow-
ship.
2.51 (s, 3H, SCH3), 2.72 (s, 3H, SCH3), 3.59 (s, 2H, CH2),
6.98 (s, 1H, ArH), 7.42–7.44 (m, 5H, ArH); MS (FAB) 300
(M++1). Anal. Calcd for C17H17NS2: C, 68.18; H, 5.72; N,
4.68. Found: C, 68.40; H, 5.66; N, 4.44. Compound 8b:
Yield 38%; mp 104–106 ꢁC; IR (KBr) m 2212 cmÀ1 (CN);
1H NMR (200 MHz, CDCl3) d 1.96 (s, 3H, CH3), 2.43 (s,
3H, CH3), 2.50 (s, 3H, SCH3), 2.71 (s, 3H, SCH3), 3.60 (s,
2H, CH2), 6.97 (s, 1H, ArH), 7.23–7.33 (m, 4H, ArH); MS
(FAB) 314 (M++1). Anal. Calcd for C18H19NS2: C, 68.96;
H, 6.11; N, 4.47. Found: C, 69.29; H, 5.86; N, 4.35.
Compound 8c: Yield 45%; mp 110–112 ꢁC; IR (KBr) m
References and notes
´
1. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
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1112.
4. (a) Yamamura, K.; Ono, S.; Tanshi, I. Tetrahedron Lett.
1988, 29, 1797–1798; (b) Yamamura, K.; Ono, S.; Ogoshi,
H.; Masuda, H.; Kuroda, Y. Synlett 1989, 18–19.
5. Mikes, F.; Boshart, G. J. Chromatogr. 1978, 149, 455–464.
6. Hassan, J.; Sevignon, M.; Gozzi, C.; Shulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
1
2214 cmÀ1 (CN); H NMR (200 MHz, CDCl3) d 1.99 (s,
3H, CH3), 2.51 (s, 3H, SCH3), 2.71 (s, 3H, SCH3), 3.56 (s,
2H, CH2), 6.95 (s, 1H, ArH), 7.10–7.19 (m, 2H, ArH)
7.37–7.44 (m, 2H, ArH); MS (FAB) 318 (M++1). Anal.
Calcd for C17H16FNS2: C, 64.32; H, 5.08; N, 4.41. Found:
C, 63.85; H, 4.91; N, 3.96. Compound 8j: Yield 48%;
mp 77–79 ꢁC; IR (KBr) m 2216 cmÀ1 (CN); 1H NMR
(200 MHz, CDCl3) d 1.09 (t, J = 7.40 Hz, 3H, CH3), 1.35
7. Ulman, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.
8. Fanta, P. E. Synthesis 1974, 9–21.

3762
D. Sil et al. / Tetrahedron Letters 47 (2006) 3759–3762
(t, J = 7.40 Hz, 3H, CH3), 2.39 (q, J = 7.32 Hz, 2H,
tions measured (Rint = 0.027), 2856 unique, Rw = 0.131
for all data, conventional R = 0.053 [(D/r)max = 0.000] on
F values of 1369 reflections with I > 2r(I), S = 0.997 for all
SCH2), 2.73 (s, 3H, CH3), 3.01 (q, J = 7.32 Hz, 2H,
SCH2), 3.62 (s, 2H, CH2), 7.09 (s, 1H, ArH), 7.42–7.44 (m,
5H, ArH), MS (FAB) 328 (M++1). Anal. Calcd for
C19H21NS2: C, 69.68; H, 6.46; N, 4.28. Found: C, 69.86;
H, 6.84; N, 4.01. Compound 8l: Yield 48%; mp 90–92 ꢁC;
IR (KBr) m 2214 cmÀ1 (CN); 1H NMR (200 MHz,
CDCl3) d 2.31 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.70 (s,
3H, SCH3), 3.94 (s, 2H, CH2), 6.97 (s, 1H, ArH), 7.01–
7.11 (m, 4H, ArH), 7.37–7.39 (m, 5H, ArH); MS (FAB)
376 (M++1). Anal. Calcd for C23H21NS2: C, 73.56; H,
5.64; N, 3.73. Found: C, 73.18; H, 5.52; N, 4.06. Crystal
data of Compound 8a: C17H17NS2, M = 299.44, mono-
clinic, P21/n, a = 9.874(1), b = 8.183(1), c = 20.009(3), b =
data and 184 parameters, Dqmax = 0.231 and Dqmin
=
À0.178. Unit cell determination and intensity data collec-
tion (2h = 50ꢁ) was performed on a Bruker P4 diffracto-
meter at 293(2) K. Structure solution by direct methods
and refinements by full-matrix-least-squares methods on
F2. Programs: XSCANS [Siemens Analytical X-ray Instru-
ments Inc.: Madison, Wisconsin, USA 1996] was used for
data collection and data processing, SHELXTL-NT
[Bruker AXS Inc.: Madison,Wisconsin, USA 1997] was
used for structure determination, refinements and mole-
cular graphics. Further details of the crystal structure
investigation can be obtained from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK (CCDC deposit No: 275438).
3
90.1(1)ꢁ, V = 1616.7(4) A , Z = 4, Dc = 1.230 g cmÀ3
,
˚
l (Mo-Ka) = 0.319 mmÀ1, F(000) = 632, colourless rect-
angular crystal, size = 0.3 · 0.15 · 0.125 mm, 4150 reflec-