Facile domino reactions for the stereoselective assembly of highly functionalized bis-(trans-2,3-dihydrofuranyl) sulfides

Article abstract of DOI:10.1016/j.tetlet.2013.03.088

A facile stereoselective synthesis of a series of nineteen novel bis-(trans-2,3-dihydrofuranyl) sulfides from the reaction of (Z,Z)-2,2′-thiobis(1,3-diarylprop-2-en-1-ones) with substituted phenacyl bromides and pyridine in the presence of K₂CO₃ in acetonitrile via domino reactions is described. This transformation presumably occurs via pyridinium salt formation/ylide generation/Michael addition/intramolecular annulation domino sequence, involving the formation of two C-C and two C-O bonds and four stereocentres in a single step with complete stereoselectivity affording only one diastereomer.

Full text of DOI:10.1016/j.tetlet.2013.03.088

Tetrahedron Letters 54 (2013) 2837–2840
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Tetrahedron Letters
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Facile domino reactions for the stereoselective assembly of highly
functionalized bis-(trans-2,3-dihydrofuranyl) sulfides
Beer Mohamed Vinosha a, Subbu Perumal a, , Subbiah Renuga b, Abdulrahman I. Almansour c
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Department of Chemistry, Fatima College, Madurai 625018, India
c Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile stereoselective synthesis of a series of nineteen novel bis-(trans-2,3-dihydrofuranyl) sulfides from
the reaction of (Z,Z)-2,20-thiobis(1,3-diarylprop-2-en-1-ones) with substituted phenacyl bromides and
pyridine in the presence of K2CO3 in acetonitrile via domino reactions is described. This transformation
presumably occurs via pyridinium salt formation/ylide generation/Michael addition/intramolecular
annulation domino sequence, involving the formation of two C–C and two C–O bonds and four stereocen-
tres in a single step with complete stereoselectivity affording only one diastereomer.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 December 2012
Revised 18 March 2013
Accepted 20 March 2013
Available online 27 March 2013
Keywords:
Bis-(trans-2,3-dihydrofuranyl) sulfides
(Z,Z)-2,20-Thiobis(1,3-diarylprop-2-en-1-
ones)
Pyridinium ylide
Stereoselectivity
Michael addition
Aryl sulfides are known to have broad significance in the phar-
maceutical and material science arena, besides serving as impor-
tant intermediates in organic synthesis. Their derivatives, viz.
sulfoxides and sulfones are common functionalities in pharmaceu-
tical agents like nonsteroidal anti-inflammatory agents,1 selective
M2 muscarinic receptor antagonists,2 HIV protease inhibitors,3 his-
tone deacetylase inhibitors,4 fatty acid amide hydrolase inhibitors,5
etc. It is also pertinent to note that furans possess important bio-
logical activities such as anti-cancer,6 anti-inflammatory,7 analge-
sic,8 anti-fungal9 and anti-rheumatic.10 They also find application
as agrochemicals, pharmaceuticals, and in the food industry,11 be-
sides serving as potential intermediates in organic synthesis.12
These applications stimulated widespread interest in the synthesis
of furans.13–16
A perusal of the literature shows that no study has been re-
ported yet on the synthesis of any compound belonging to
bis(dihydrofuranyl) sulfides, while only one report exists on the
synthesis of unsubstituted bis(3-tetrahydrofuranyl) sulfide.17 This
is the first time, the synthesis of a series of bis(2,3-dihydrofuranyl)
sulfides has been realized (Scheme 1), that too with complete ste-
reoselectivity affording solely one diastereomer 4, despite the
presence of four stereocentres. A plausible rationalization for the
observed stereoselectivity has been provided (vide infra). These
compounds bearing six aryl rings, offer great potential for generat-
3
Ar''
Ar''
N
O
O
O
O
Ar'
S
Ar'
S
K2CO3 (2 equiv)
Ar
Ar'
Ar
O
2 Ar''COCH2Br
+
O
CH3CN, rt, 12 h
2
Ar'
Ar
1
Ar
Scheme 1. One pot synthesis of bis-(trans-2,3-dihydrofuranyl) sulfides 4.
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.088

2838
B. M. Vinosha et al. / Tetrahedron Letters 54 (2013) 2837–2840
Table 1
Influence of base in acetonitrile on the yield of 4e
O
O
H
Ar''
Ar''
Ar'
H
H
O
O
Ar'
*
*
H
S
O
O
O
O
S
Ar
Ar
Ar = Ar' = Ph; Ar' '= p-ClC6H4
Figure 2. Possible diastereomer of 4 (viz. 40) differing in relative configurations at
starred carbons [not formed].
Entry
Base
mol (%)
Reaction time (h)
Yield of 4e (%)
a
a
1
2
3
4
5
K2CO3
K2CO3
Et3Na
DBUa
100
200
200
200
200
12
12
12
12
12
39
79
73
42
In this work, the bis-(trans-2,3-dihydrofuranyl) sulfides 4 were
obtained in good yields from the pseudo three-component reaction
of (Z,Z)-2,20-thiobis(1,3-diarylprop-2-en-1-ones) 1 with phenacyl
bromide 2 and pyridine 3 in the presence of K2CO3 in CH3CN at
room temperature (Scheme 1). The data presented in Table 1 show
that (i) the reaction fails to occur when pyridine alone, in the ab-
sence of any added base and that (ii) the base added and its quan-
tity, in addition to pyridine, influences the yield of 4 significantly. It
is also found that a maximum yield of the product was obtained,
when 1 mol of (Z,Z)-2,20-thiobis(1,3-diaryl-prop-2-en-1-ones) was
reacted with 2 mol each of phenacyl bromide, K2CO3, and pyridine
in acetonitrile solvent (Table 1).
Consequently, all subsequent reactions were performed typi-
cally by reacting a mixture of (Z,Z)-2,20-thiobis(1,3-diaryl-prop-2-
en-1-ones) (1 mmol) 1, phenacyl bromide (2 mmol) 2, and pyridine
(2 mmol) 3 in the presence of K2CO3 (2 mmol) in acetonitrile at
room temperature19 for 12 h. The solid product upon filtration,
washing with petroleum ether and recrystallization from dichloro-
methane–ethanol mixture afforded bis-(trans-2,3-dihydrofuranyl)
sulfides 4 in good yields in a pure state (68–80%) (Scheme 1,
Table 2).
The structure of 4 is in accord with the results of elemental
analyses and 1H, 13C, and 2D NMR spectroscopic data as illustrated
for 4d. In the 1H NMR spectrum of 4d (Fig. 1), the methyl group of
the p-tolyl ring appears as a singlet at 2.32 ppm, which showed (i)
HMBC with ipso carbon of the p-tolyl ring at 137.5 ppm and (ii)
C,H-COSY correlation with the carbon signal at 21.1 ppm. The
hydrogens, H-2 and H-3, related by a H,H-COSY correlation, ap-
peared as doublets, respectively at 5.75 and 4.10 ppm (J = 4.2 Hz)
revealing their trans-relationship. These hydrogens showed HMBCs
(Fig. 1) with C-4 at 105.8 ppm and C-5 at 154.2 ppm and also
showed, respectively C,H-COSY correlations with the carbon sig-
nals at 86.2 and 56.0 ppm enabling their assignments to C-2 and
C-3. The H-3 showed HMBCs with the carbonyl carbon at
194.4 ppm and C-2 at 86.2 ppm. The H-2 showed HMBCs with C-
3 at 56.0 ppm. Two diastereomeric structures, 4 and 40 (Fig. 2), dif-
fering in their relative configurations at the benzylic carbons of the
b
Pyridine
—
a
In these reactions, 200 mol % of pyridine was also employed.
Product not obtained.
b
Table 2
Yield and melting point of bis-(trans-2,3-dihydrofuranyl) sulfides 4
Compd
Ar
Ar0
Ar00
mp (°C)
Yield (%)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
C6H5
C6H5
p-ClC6H4
p-ClC6H4
C6H5
C6H5
p-ClC6H4
C6H5
p-CH3C6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
p-FC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
p-FC6H4
C6H5
p-ClC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
160–162
204–206
194–196
228–230
239–241
212–214
240–242
246–248
180–182
230–232
206–208
207–209
174–176
214–216
186–188
196–198
222–224
104–108
230–232
73
72
70
80
79
71
78
72
76
69
75
69
71
78
79
68
72
77
74
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-FC6H4
a
Obtained yield after filtration.
ing a library of densely functionalized sulfides and their deriva-
tives, sulfoxides and sulfones, which could, in turn, be attractive
for investigating biological and material properties. This transfor-
mation occurring via one pot domino reactions furnishing good
yields of 4 (considering the number of steps involved) stems as a
part of our recently embarked research on the synthesis of novel
heterocycles employing domino, multicomponent, and green
transformations.18
H3C
CH3
CH3
H3C
O
O
H
H
H
O
O
H
O
H
3'
2
H
H
3
H
2'
1'
3
4
4'
O
S
2
O
4
1
S
5
O
5'
5
Cl
Cl
Figure 1. Selected HMB correlations and chemical shifts in 4d.
Cl
Cl

B. M. Vinosha et al. / Tetrahedron Letters 54 (2013) 2837–2840
2839
furan-4,2-diyl))bis(arylmetha-nones) 4. Presumably, the sulfur
atom of 1 with its low-lying vacant -orbitals and the consequent
D
–R-effect stabilizes the transition state of Michael addition and
facilitates the formation of the Michael adduct (Scheme 2). On the
contrary, in the nitrogen analog of 1, the nitrogen by its +R-effect
could diminish the electrophilicity and render the Michael addition
difficult. This conclusion is supported by the fact that the reaction of
a model compound comprising one
a,b-unsaturated carbonyl
moiety with nitrogen at -position, viz. (Z)-1,3-diaryl-2-(N-methy-
a
lanilino)-2-propen-1-ones with phenacyl bromide and pyridine
under the reaction conditions employed for the synthesis of 4 failed
to furnish the analogous furan derivatives.
It is pertinent to note that only one stereoisomer, 4 is formed,
despite the presence of four stereocentres showing that the reac-
tion is highly stereoselective. The trans-relationship between the
Ar0 and COAr00 groups in the dihydrofuran ring of 8 is ascribable
to the facile annulation via displacement of pyridine from the Mi-
chael adduct 7, while the cis stereochemical relationship requires
annulation via the other possible Michael adduct 70, a diastereomer
of 7, that could be present in the equilibrium mixture, which would
have gauche interactions between aryl ring with aroyl as well as
pyridinium ring rendering 70 difficult to react. This trans-relation-
ship between the Ar0 and COAr00 is also in accord with higher stabil-
ity of 4 relative to its diastereoisomer with Ar0 and COAr00 in
cis-relationship. The reaction of 8 with 6 furnishing 4 with the
trans-relationship between Ar0 and COAr00 in the second dihydro-
furanlyl ring is also explicable similarly.
Figure 3. ORTEP diagram of 4b.
dihydrofuranyl rings are in accord with 1H, 13C NMR, and HRMS
mass spectra. Further distinction among them (4 and 40) is enabled
by an X-ray crystallographic study of a single crystal of 4b20
(Fig. 3), which discloses that the product has the relative stereo-
chemistry at stereocentres shown in structure 4 (Fig. 1).
A plausible mechanism depicted in Scheme 2 involves the for-
mation of phenacylpyridinium salt 5 in the first step, which is sub-
sequently deprotonated to yield the pyridinium ylide, 6. The
Michael addition of this pyridinium ylide 6 to (Z,Z)-2,20-thi-
obis(1,3-diaryl-prop-2-en-1-ones) 1 affords pyridinium enolates
7, which undergo annulation to form 8. Similar domino reactions
The relative configuration of the two benzylic carbon (Ar0CH)
stereocentres, one in each dihyrofuranyl ring, as shown on struc-
ture 4 is not readily apparent. This is tentatively ascribable to the
preferred attack of the phenacylpyridinium ylide 6 on 8 from the
less hindered side as shown in Scheme 2 affording intermediate
9, which upon annulation via substitution furnishes 4.
involving the other a,b-unsaturated C@C bond of 8 with pyridinium
ylide 6 ultimately affords trans(4,40-thiobis(3,5-diaryl-2,3-dihydro-
- Br
base
Ar''COCH2Br
+
6
N
N
N
2
5
CH2COAr''
CHCOAr''
Ar''
O
Ar'
Ar'
N
H
Ar''
O
N
H
H
6
Ar'
O
Ar'
Ar'
H
O
H
S
H
H
O
Ar'
O
O
Ar
1
S
Ar
S
7
7'
Ar
Ar
O
Ar
Ar
less stable
-Py
Ar''
N
H
6
O
Ar''
Ar''
Ar
Ar'
Ar'
+Py
Ar'
O
H
O
O
H
Ar'
H
Ar'
H
Ar'
H
H
Ar''
H
H
O
H
S
O
O
S
O
O-
S
Ar
-
Ar
Ar
Ar
Ar
O
6
7''
9
8
Michael adduct
stabilized by sulfur
O
Ar''
Ar''
O
Ar'
Ar'
O
O
S
Ar
Ar
4
Scheme 2. Plausible mechanism for the stereoselective formation of bis-(trans-2,3-dihydrofuranyl) sulfides 4.

2840
B. M. Vinosha et al. / Tetrahedron Letters 54 (2013) 2837–2840
9. Kemp, M. S.; Burden, R. S. Phytochemistry 1986, 25, 1261–1269.
In conclusion, we have described a facile synthesis of trans-
10. Da Silva Filho, A. A.; Albuquerque, S.; Silva, M. L. A.; Eberlin, M. N.; Tomazela, D.
M.; Bastos, J. K. J. Nat. Prod. 2004, 67, 42–45.
11. Hislop, J.-A.; Hunt, M. B.; Fielder, S.; Rowan, D. D. J. Agric. Food Chem. 2004, 52,
7075–7083.
12. (a) Garzino, F.; Meou, A.; Brun, P. Eur. J. Org. Chem. 2003, 1410–1414; (b)
Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819.
13. (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955–2020; (b) Kirsch, S. F. Org. Biomol. Chem.
2006, 4, 2076–2080.
14. (a) Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995, 117, 7255–7256; (b)
Brown, R. D. Angew. Chem., Int. Ed. 2005, 44, 850–852; (c) Garrido, J. L.; Alonso,
I.; Carretero, C. J. Org. Chem. 1998, 63, 9406–9413; (d) Yoshida, M.; Morishita,
Y.; Fujita, M.; Ihara, M. Tetrahedron Lett. 2004, 45, 1861–1864.
15. Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95–98.
16. Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S.
Angew. Chem., Int. Ed. 2003, 42, 2681–2684.
(4,40-thiobis(3,5-diaryl-2,3-dihydrofuran-4,2-diyl))bis(arylmetha-
nones) from pseudo three-component domino reactions of
(Z,Z)-2,20-thiobis(1,3-diaryl-prop-2-en-1-ones), substituted phena-
cyl bromides, and pyridine. This transformation occurs via two C–C
and two C–O bond formations and the generation of four stereo-
centres in a completely stereoselective manner with the exclusive
formation of one diastereomer.
Acknowledgment
S.P. and A.I.M. acknowledge the Deanship of Scientific Research
at the King Saud University for funding through the research Grant
RGP-VPP-026.
17. Zaidlewicz, M.; Kanth, J. V. B.; Brown, H. C. J. Org. Chem. 2000, 65, 6697.
18. (a) Indumathi, S.; Perumal, S.; Anbananthan, N. Green Chem. 2012, 14, 3361; (b)
Devi Bala, B.; Michael Rajesh, M.; Perumal, S. Green Chem. 2012, 14, 2484; (c)
Gunasekaran, P.; Balamurugan, K.; Sivakumar, S.; Perumal, S.; Menendez, J. C.;
Almansour, A. I. Green Chem. 2012, 14, 750; (d) Michael Rajesh, S.; Bala, B. D.;
Perumal, S.; Menéndez, J. C. Green Chem. 2011, 13, 3248; (e) Prasanna, P.;
Balamurugan, K.; Perumal, S.; Menéndez, J. C. Green Chem. 2011, 13, 2123; (f)
Michael Rajesh, S.; Perumal, S.; Menéndez, J. C.; Pandian, S.; Murugesan, R.
Tetrahedron 2012, 68, 5631; (g) Indumathi, S.; Perumal, S.; Menendez, J. C. J.
Org. Chem. 2010, 75, 472.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.088.
19. General procedure for the synthesis of (4,40-thiobis(3,5-diaryl-2,3-dihydrofuran-
4,2-diyl))bis(arylmethanones) (4)
References and notes
A mixture of (Z,Z)-2,20-thiobis(1,3-diaryl-prop-2-en-1-ones) 1 (1 mmol) with
a
-phenacyl bromides 2 (2 mmol), pyridine 3 (2 mmol), and K2CO3 (2 mmol) in
1. Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem.
1982, 25, 1065–1070.
2. Wang, Y.; Chackalamannil, S.; Hu, Z.; Clader, J. W.; Greenlee, W.; Billard, W.;
Binch, H. I. I. I.; Crosby, G.; Ruperto, V.; Duffy, R.; McQuade, R.; Lachowicz, J. E.
Bioorg. Med. Chem. Lett. 2000, 10, 2247–2250.
3. Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.;
Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B.
A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muessing, M. A.;
Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979–
3985.
4. Marson, C. M.; Savy, P.; Rioja, A. S.; Mahadevan, T.; Mikol, C.; Veerupillai, A.;
Nsubuga, E.; Chahwan, A.; Joel, S. P. J. Med. Chem. 2006, 49, 800–805.
5. Hardouin, C.; Kelso, M. J.; Romero, F. A.; Rayl, T. J.; leung, D.; Hwang, I.; Cravatt,
B. F.; Boger, D. L. J. Med. Chem. 2007, 50, 3359–3368.
acetonitrile was stirred at room temperature for 12 h. The solid precipitated
from the reaction mixture was filtered, washed with petroleum ether (2 ml), and
recrystallized from dichloromethane–ethanol mixture (3:2 (v/v), 5 ml) to give
trans-(4,40-thiobis(3,5-diaryl-2,3-dihydrofuran-4,2-diyl))bis(arylmethanones)
4
in good yields. Spectroscopic data for a representative compound 4d are given
below.
4,40-Thiobis(5-(4-chlorophenyl)-3-p-tolyl-2,3-dihydrofuran-4,2-diyl)bis-
(phenylmethanone) (4d). Obtained as white solid; yield: 80%; mp 228–230 °C;
1H NMR (300 MHz, CDCl3) dH: 2.32 (s, 6H, CH3), 4.10 (d, 2H, J = 4.2 Hz, H-3),
5.75 (d, 2H, J = 4.2 Hz, H-2), 6.95 (br s, 8H, ArH), 7.18 (d, 4H, J = 8.7 Hz, ArH),
7.41 (t, 4H, J = 7.8 Hz, ArH), 7.59 (t, 2H, J = 7.8 Hz, ArH), 7.67 (d, 8H, J = 8.7 Hz,
ArH); 13C NMR (75 MHz, CDCl3) dC: 21.1, 56.0, 86.2, 105.8, 127.9, 128.0 (2C),
128.6, 128.8, 129.1, 129.3, 133.6, 134.8, 137.2, 137.5, 154.2, 194.4. Anal. Calcd
for C48H36Cl2O4S: C, 73.93; H, 4.65; Found: C, 73.81; H, 4.71.
6. (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C. J. Nat. Prod. 2001, 64,
134–135; (b) Joseph, H.; Gleye, J.; Moulis, C.; Mensah, L. J.; Roussakis, C.;
Gratas, C. J. Nat. Prod. 1988, 51, 599–600.
7. Cho, J. Y.; Baik, K. U.; Yoo, E. S.; Yoshikawa, K.; Park, M. H. J. Nat. Prod. 2000, 63,
1205–1209.
20. Crystallographic data (excluding structure factors) for compound 4b in this
letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 814421. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
8. Borsato, M. L. C.; Grael, C. F. F.; Souza, G. E. P.; Lopes, N. P. Phytochemistry 2000,
55, 809–813.