Stereoselective synthesis of polyfunctionalized nitrothianes: Enhancement of stereoselectivity by microwaves

Article abstract of DOI:10.1080/00397911.2012.683970

The Michael addition of nitromethane to (Z,Z)-2,2′-thiobis(1,3- diarylprop-2-en-1-ones) in the presence of NaOEt in dimethylformamide (DMF)/alcohol under thermal conditions affords a diastereomeric mixture of 2a,6e-diaroyl-3a,5e-diaryl-4e-nitrothianes and 2e,6e-diaroyl-3e,5e-diaryl-4e- nitrothianes with a dr of ～3:1/4:1 respectively. This reaction under microwave irradiation in DMF/alcohol afforded solely 2a,6e-diaroyl-3a,5e-diaryl- 4e-nitrothianes, disclosing enhancement of stereoselectivity by microwaves. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.683970

This article was downloaded by: [University of Illinois at Urbana-Champaign]
On: 15 March 2013, At: 16:15
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Stereoselective Synthesis of Polyfunctionalised
Nitrothianes: Enhancement of Stereoselectivity by
Microwaves
Beermohamed Vinosha a , Subbiah Renuga a , Subbu Perumal b , Packianathan Thomas
Muthiah c & Kaliyaperumal Thanigaimani c
a Department of Chemistry, Fatima College, Madurai, India
b School of Chemistry, Madurai Kamaraj University, Madurai, India
c Department of Chemistry, Bharathidasan University, Tiruchirappalli, India
Accepted author version posted online: 10 Jan 2013.
To cite this article: Beermohamed Vinosha , Subbiah Renuga , Subbu Perumal , Packianathan Thomas Muthiah &
Kaliyaperumal Thanigaimani (2013): Stereoselective Synthesis of Polyfunctionalised Nitrothianes: Enhancement of
Stereoselectivity by Microwaves, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI:10.1080/00397911.2012.683970
To link to this article: http://dx.doi.org/10.1080/00397911.2012.683970
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,
proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

ACCEPTED MANUSCRIPT
Stereoselective Synthesis of Polyfunctionalised Nitrothianes: Enhancement of
Stereoselectivity by Microwaves
Beermohamed Vinosha1, Subbiah Renuga1, Subbu Perumal2, Packianathan Thomas
Muthiah3, Kaliyaperumal Thanigaimani3
1Department of Chemistry, Fatima College, Madurai, India, 2School of Chemistry,
Madurai Kamaraj University, Madurai, India, 3Department of Chemistry, Bharathidasan
University, Tiruchirappalli, India
Corresponding author: Tel.: +91 452 2668016; Fax: +91 452 2668437; Email:
s.renuga@gmail.com
Abstract
The Michael addition of nitromethane to (Z,Z)-2,2’-thiobis(1,3-diarylprop-2-en-1-ones)
in the presence of NaOEt in DMF/alcohol under thermal conditions affords a
diastereomeric mixture of 2a,6e-diaroyl-3a,5e-diaryl-4e-nitrothianes and 2e,6e-diaroyl-
3e,5e-diaryl-4e-nitrothianes with a dr of ~ 3:1 / 4:1 respectively. This reaction under
microwave irradiation in DMF/alcohol afforded solely 2a,6e-diaroyl-3a,5e-diaryl-4e-
nitrothianes disclosing enhancement of stereoselectivity by microwaves.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
O
O
O
O
O
S
S
CH NO
S
3
2
Ar
Ar
Ar
Ar
Ar
2
+
NaOEt
∆or MW
Ar'
Ar'
Ar'
Ar'
Ar'
NO
2
NO
2
Minor
Major/sole
KEYWORDS: 2,2’-thiobis(1,3-diarylprop-2-en-1-ones); Michael addition;
stereoselectivity; nitrothianes; microwave irradiation.
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
INTRODUCTION
Studies on the synthesis of thianes continue to attract keen interest[1] due to their
importance as building blocks for molecules of biological or medicinal interest.[2,3] They
exhibit important pharmacological properties such as antiulcer,[4] antimicrobial,[5]
antibacterial,[6] anti-inflammatory,[7] antihypertensive,[8] and analgesic,[9] besides their use
in industry as antiwear[10] and bleaching[11] agents and stabilizing agents in color
photography.[12] Thiane nucleus also plays a key role in the biological activities of drugs
such as cephalosporins[13] and dithiathromboxane.[14] Their scant natural occurrence[15]
further adds to the importance of thiane synthesis. The above importance of thianes and
our continued interest in the synthesis of novel heterocycles[16] from 2,2’-
thiobis/2,2’sulfonylbis(1,3-diarylprop-2-en-1-ones) as synthons prompted us now to
report the stereoselective synthesis of multi-substituted nitrothianes bearing significant
synthetic potential for elaboration into polycyclic ring systems.
RESULTS AND DISCUSSION
In the present investigation, the reaction of (Z,Z)-2,2’-thiobis(1,3-diarylprop-2-en-1-ones)
1 with nitromethane in the presence of sodium ethoxide in DMF at room temperature
afforded a diastereomeric mixture of novel 2,6-diaroyl-3,5-diaryl-4-nitrothianes
comprising 2 and 3 in good yields (Scheme 1), which were separated by column
chromatography. It is interesting to note that the diastereomer 2 with two groups, viz. an
aryl and an aroyl, axially oriented is the major product, while the diastereomer 3 having
all the five groups in equatorial orientations is the minor one, as evident from the
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
diastereomeric ratio ~ 3:1 obtained from the 1H NMR spectra of the diastereomeric
mixture in all cases. The above reaction when performed in ethyl alcohol instead of DMF
under reflux for 20–25 min. led to an improvement in overall yields with enhanced
selectivity towards 2 with dr of ~ 4:1 (Table 1), ascribable to the fact that the Michael
addition proceeding through ionic intermediates could be facilitated by the protic solvent,
alcohol.
The above reaction was also investigated under microwave irradiation with a view to
finding whether (i) the reaction could be expedited and (ii) an improvement in the
yield/selectivity occurs, as it is common to witness rate and yield enhancements under
microwave irradiation relative to thermal reactions, besides realizing different
selectivities in reactions under microwave irradiation and thermal conditions.[17–22]
In a typical reaction, nitromethane was added into a solution of sodium ethoxide,
prepared by dissolving sodium in absolute ethanol, in a 10mL quartz vial, followed by the
addition of 2,2’-thiobis(1,3-diarylprop-2-en-1-ones) and the vial was sealed and subjected
to microwave irradiation at 110°C, 15 W at 0 bar level pressure in a focused microwave
synthesiser. Within 1-2 min, the temperature reached 110°C and remained constant
thereafter. Completion of the reaction (TLC) required 8 min. of microwave irradiation.
The reaction mixture was then poured into water and the separated solid on purification
by column chromatography afforded good yields of exclusively one diastereomer, 2a,6e-
diaroyl-3a,5e-diaryl-4-nitrothianes as the only isolable product. Thus, besides significant
reduction in the reaction time, increased stereoselectivity was realized under microwave
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
irradiation compared to the thermal method. The above reaction under microwave
irradiation in DMF also led to the diastereomer 2 in comparable yields (Table 1).
The thianes were characterized by elemental analysis and IR, 1H and 13C NMR, and H,H-
COSY spectroscopic data. The 1H NMR spectrum of 2a showed five signals for the
heterocyclic ring hydrogens indicating that all these are nonequivalent. The most
downfield among them at 6.30 ppm is assignable to H-4, being attached to carbon bearing
nitro group. It appears as a doublet of doublets (J=11.7, 6.3 Hz) indicating one vicinal
hydrogen in axial and the other in equatorial orientation. The doublet of doublets at 4.35
ppm (J=6.3 and 2.4 Hz) corresponds to H-3, having a common J value of 6.3 Hz with H-
4. The small J value of 2.4 Hz indicates an e,e coupling between H-3 and H-2 implying
axial orientation of the aryl ring at C-3 and aroyl ring at C-2. Hence the signal at 4.89
ppm (J = 2.4 Hz) is assigned to H-2. The triplet at 4.56 ppm (J=11.7 Hz) is assigned to
H-5, oriented axially, from its coupling with H-4. The remaining signal, a doublet at 5.12
ppm (J=11.7 Hz) is due to H-6 in axial orientation. These hydrogen assignments are
supported by H,H-COSY correlations as well. The stereochemistry of thianes is also
corroborated by the fact that 2a exhibits twenty one carbon signals pointing to its
unsymmetrical nature. Thus the stereochemistry of 2 is assigned as 2a,6e-diaroyl-3a,5e-
diaryl-4e-nitrothianes (Figure 1).
The structure determined by an X-ray crystallographic study[23] of a single crystal of 2c
(Figure 2) confirms the stereochemistry deduced from NMR spectroscopic data. It is
pertinent to note that the J value of 6.3 Hz between H-3 and H-4 is large for vicinal
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
hydrogens, one in axial and another in equatorial orientations. This presumably suggests
deformation of the chair due to the axial orientation of benzoyl and phenyl rings at C-2
and C-3 respectively. This conclusion is also supported by the dihedral angle between H-
3 and H-4 (ϕ= 45.27°) determined by the X-ray structure, significantly smaller than 60°
expected for vicinal axial-equatorial protons. The X-ray crystallographic structure of 2c
(Figure 2) further discloses (i) a C-H…O hydrogen bonding involving the axial aroyl
group at C-2 and the H-4 and (ii) orientation of the aroyl ring away from the cyclohexane
ring plane. Such an arrangement presumably diminishes the steric interaction of the aroyl
ring with the syn axial hydrogens and enhances the stability of the conformation by the
intramolecular hydrogen bonding. Further, the other axially oriented phenyl ring at C-3
placed perpendicular to the cyclohexane ring facing one syn axial hydrogen might not
result in significant steric interaction. On the above basis, it can be inferred that the
diastereomer 2 may not be rendered significantly unstable.
The 1H NMR spectrum of 3c shows a triplet at 5.28 ppm corresponding to H-4. The two-
proton doublet at 5.19 ppm (J=10.5 Hz) and the two-proton triplet at 4.37 ppm (J=10.5
Hz) are respectively assignable to H-2,6 and H-3,5. The large J values of 10.5 Hz for all
the 1H signals of the ring indicate axial orientation of all ring hydrogens, which in turn
implies equatorial orientation for all the groups attached to the ring, viz. aryl, aroyl and
nitro of 3c (Figure 1). The other thianes 3 also displayed similar spectroscopic features.
The thianes 2 and 3 are formed presumably by two successive Michael additions of the
carbanions sequentially generated from nitromethane to 1.
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
It is also pertinent to note that the major diastereomer in the present study is the one with
two bulky groups, viz. aryl and aroyl in axial orientations. With a view to assessing the
relative thermodynamic stabilities of 2 and 3, equilibration of one representative case of
each diastereomer, viz. 2g and 3e with sodium ethoxide was investigated. It was found
that either heating or microwave irradiation of 2g or 3e in the presence of equimolar
amount of sodium ethoxide failed to facilitate equilibration. While 2g failed to react and
remained unreacted, 3e underwent decomposition both under thermal condition in
ethanol medium and under microwave irradiation. These results reveal that the
predominance of the diastereomers 2 is likely to arise from kinetic control.
The mechanism for the predominance of the diastereomer 2 is given in Scheme 2, which
involves one inter- and one intramolecular Michael additions. The latter preferentially
occurs from the anion 5 to afford 2. The formation of the diastereomer 3 presumably
arises from an initial NaOEt mediated isomerization of the (Z,Z)- into (Z,E)- via
addition-elimination mechanism, which is followed by intramolecular Michael addition.
The fact that the (E)-form is likely to be less stable than the (Z)-form explains the smaller
amount of the diastereomer in this reaction. Similar isomerisation of (Z)-C=C bond of 1
into (E)-C=C form has been found in the oxidation of (Z,Z)-1 into their (E,E)-sulfonyl
analogs via addition-elimination mechanism.[24]
The formation of disatereomer 2 solely in the reaction performed under microwave
irradiation is explicable by the fact that since microwave reactions raise the energy of the
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
reacting species rapidly, presumably before the isomerisation of the (E)-C=C bond into
its (Z)-form occurs, the intramolecular Michael addition may be completed.
CONCLUSION
The present work describes the synthesis of multifunctional thianes by conventional
reaction and microwave irradiation. In the conventional method, better yields and
selectivity were realized in alcohol compared to DMF. Microwave irradiation in the
presence of DMF/alcohol led to enhanced stereoselectivity affording solely one
diastereomer with aroyl and aryl groups at C-2 and C-3 respectively in axial orientation
apart from diminished reaction time compared to the thermal solution method.
EXPERIMENTAL
General
The melting points were measured in open capillary tubes and are uncorrected. The 1H,
13C and the 2D NMR spectra were recorded on a Bruker (Avance) 300 MHz NMR
instrument using TMS as internal standard and CDCl3 as solvent. Standard Bruker
software was used throughout. Chemical shifts are given in parts per million ( -scale)
and the coupling constants are given in Hertz. Silica gel-G plates (Merck) were used for
TLC analysis with a mixture of petroleum ether (60–80oC) and ethyl acetate as eluent.
Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer. Microwave reactions are carried out in a Biotage Microwave synthesizer.
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
SYNTHESIS OF 2,6-DIAROYL-4-NITRO-3,5-DIARYLTHIANES - GENERAL
PROCEDURE
Method 1A: By Conventional Thermal Method In DMF
Nitromethane (0.3 g, 5 mmol) was added dropwise with stirring into a solution of sodium
ethoxide prepared by dissolving sodium metal (0.12 g, 5mmol) in absolute ethyl alcohol
(4 mL). To this mixture, a solution of 2,2’-thiobis(1,3-diphenylprop-2-en-1-one) (2.2 g, 5
mmol) in dimethyl formamide (40 mL) was added with stirring and kept at room
temperature for 1 h. The reaction mixture was then poured into water and separated solid
was filtered. The solid on separation by column chromatography with petroleum ether
and ethyl acetate mixture [19:1 (v/v)] as eluent gave a mixture of 2a,6e-dibenzoyl-4e-
nitro-3a,5e-diphenylthiane and 2e,6e-dibenzoyl-4e-nitro-3e,5e-diphenylthiane in the ratio
of ~3:1.
Method 1B: By Conventional Thermal Method In Ethanol
Nitromethane (0.3 g, 5 mmol) was added dropwise with stirring into a solution of
sodium ethoxide prepared by dissolving sodium metal (0.12 g, 5mmol) in absolute
ethanol (4 mL). To this mixture, a solution of 2,2’-thiobis(1,3-diphenylprop-2-en-1-
one) (2.2 g, 5 mmol) in ethyl alcohol (40 mL) was added with stirring and refluxed
for 20 min. The reaction mixture was then poured into water and the separated solid
was filtered. The solid on separation by column chromatography with petroleum ether
and ethyl acetate mixture [19:1(v/v)] as eluent gave 2a,6e-dibenzoyl-4e-nitro-3a,5e-
diphenylthiane and 2e,6e-dibenzoyl-4e-nitro-3e,5e-diphenylthiane in the ratio 4:1.
Yields of thianes thus obtained in methods 1A and 1B are given in Table 1.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
Method 2A: By Microwave Irradiation In DMF
Nitromethane (0.3 g, 5 mmol) was added dropwise with stirring into a solution of sodium
ethoxide, (0.34 g, 5mmol) in DMF (4 mL) taken in a 10mL quartz vial. After the addition
of 2,2’-thiobis(1,3-diarylprop-2-en-1-ones) (2.2 g, 5 mmol) into the above solution, the
vial was sealed and subjected to microwave irradiation at 110°C, 15 W at 0 bar level
pressure in a Biotage microwave synthesiser. After 1-2 min, the temperature reached a
plateau of 110°C and remained constant thereafter. After 8 min., the vial was cooled to
room temperature which took about 5 min., the reaction mixture was then poured into
water and the separated solid was filtered off. The solid on purification by column
chromatography with petroleum ether and ethyl acetate mixture [19:1(v/v)] as eluent
gave 2a,6e-dibenzoyl-4e-nitro-3a,5e-diphenylthiane as a colorless solid.
Method 2B: By Microwave Irradiation In Ethanol
This experiment was repeated using ethanol as the solvent after preparing sodium
ethoxide by dissolving sodium (0.12g, 5mmol) in absolute ethanol (4 mL) and adding
mixture of the reactants as described above in method 2A. Yields of thianes thus obtained
in methods 2A and 2B are given in Table 1.
Data
2a,6e-Dibenzoyl-4e-Nitro-3a,5e-Diphenylthiane (2a)
Obtained as a colorless solid [1.5 g, (60%) in method 1A and 2.1 g, (84%) in method
2A], mp=150-152°C; IR (KBr) ν cm-1 1368, 1552, 1669, 1685; 1H NMR (300 MHz,
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
CDCl3) δH: 4.35 (dd, J=2.4, 6.3 Hz, 1H), 4.56 (t, J=11.7 Hz, 1H), 4.89 (d, J=2.4 Hz, 1H),
5.12 (d, J=11.7 Hz, 1H), 6.30 (dd, J=6.3, 11.7 Hz, 1H), 7.04-7.84 (m, 18H), 7.98 (d,
J=6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δC: 42.9, 43.6, 46.9, 47.2, 89.6, 127.8,
128.3, 128.6, 128.6 (7), 128.7(1), 128.8, 129.0, 129.4, 133.8, 134.0, 134.2, 135.3, 136.9,
138.0, 194.1, 195.0. Anal. Calcd for C31H25NO4S: C, 73.35; H, 4.96; N, 2.76%. Found:
C, 73.55; H, 4.85; N, 2.70%.
2e,6e-Dibenzoyl-4e-Nitro-3e,5e-Diphenylthiane (3a)
Obtained as a colorless solid [0.5 g, (20%) in method 1A], mp=238-240°C; IR (KBr) ν
cm-1 1368, 1558, 1668; 1H NMR (300 MHz, CDCl3) δH: 4.40 (t, J=10.8 Hz, 2H), 5.3 (m,
3H), 7.14-7.55 (m, 16H), 7.83 (d, J=8.1 Hz, 4H); 13C NMR (75 MHz, CDCl3) δC: 50.1,
50.2, 96.1, 128.0, 128.4, 128.6, 128.9, 133.8, 135.4, 135.9, 193.0. Anal. Calcd for
C31H25NO4S: C, 73.35; H, 4.96; N, 2.76%. Found: C, 73.46; H, 5.01; N, 2.83%.
2e,6e-Di(P-Chlorobenzoyl)-4e-Nitro-3e,5e-Diphenylthiane (3c)
Obtained as a colorless solid [0.7 g, (24%) in method 1A], mp=194-196°C; IR (KBr) ν
cm-1 1366, 1546, 1687; 1H NMR (300 MHz, CDCl3) δH: 4.37 (t, J=10.5 Hz, 2H), 5.19 (d,
J=10.5 Hz, 2H), 5.28 s (t, J=10.5 Hz, 1H), 7.13-7.25 (m, 10H), 7.34 (d, J=8.4 Hz, 4H),
7.74 (d, J=8.4 Hz, 4H); 13C NMR (75 MHz, CDCl3) δC: 49.9, 50.2, 95.8, 128.0, 128.6,
129.1, 129.9, 133.6, 135.8, 140.5, 191.9. Anal. Calcd for C31H23Cl2NO4S: C, 64.59; H,
4.02; N, 2.43%. Found: C, 64.48; H, 4.10; N, 2.52%.
Complete experimental details are available online in the Supporting Information.
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
ACKNOWLEDGEMENTS
S.R. and S.P thank UGC for funds under Major Research Projects. S.R. and B.V. thank
the Secretary and the Principal, Fatima College, Madurai for providing facilities. B.V.
thanks the CSIR for a Senior Research Fellowship.
REFERENCES
1.
(a) Jungong, C. S.; John, J. P.; Novikov, A. V. Formation of six-versus five-
membered cyclic sulfones by C-H insertion. Tetrahedron Lett. 2009, 50, 1954-1957; (b)
Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli,
D.; Stenta, M.; Galatini, A.; Tavani, C. A new route to thiopyran S,S-dioxide derivatives
via an overall ring-enlargement protocol from 3-nitrothiophene. Tetrahedron 2009, 65,
336-343; (c) Silveira , C. C.; Rinaldi, F.; Bassaco, M. M.; Kaufman, T. S. Synthesis of 2-
diphenylphosphinoyl-3-5-(diaryl)-3,4-dihydro-2H-thiopyrans by the reaction of a
bis[(diphenylphosphinoyl)methyl]sulfide with chalcones. Tetrahedron Lett. 2008, 49,
5782-5784; (d) Denancé, M.; Legay, R.; Gaumont, A-C.; Gulea, M. Pummerer-type
reactions in the (2-methylsulfanyl-2-phosphonyl) thiopyran-1-oxide series. Tetrahedron
Lett. 2008, 49, 4329-4332; (e) Boullosa, S.; Gándara, Z.; Pérez, M.; Gómez, G.; Fall, Y.
The furan approach to thiacyclic compounds. Stereoselective synthesis of 2,3-
disubstituted tetrahydro-thiopyrans. Tetrahedron Lett. 2008, 49, 4040-4042; (f)
Hepworth, J. D.; Heron, B. M. in Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008;
Vol. 7.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
2.
(a) Jheengut, X.; Ward, D. E. The Thiopyran Route to Polypropionates:
Enantioselective Synthesis of Membrenone B from Racemic Fragments. J. Org. Chem.
2007, 72, 7805-7808; (b) Jayabharathi, J.; Thanikachalam, V.; Thangamani, A.;
Padmavathy, M. Synthesis, AM1 calculation, and biological studies of thiopyran-4-one
and their azine derivatives. Med. Chem. Res. 2007, 16, 266-279; (c) Hollick, J. J.;
Rigoreau, L. J. M.; Cano-Soumullac, C.; Cockcroft, X.; Curtin, N. J.; Frigerio, M.;
Golding, B. T.; Guiard, S.; Hardcastle, J. R.; Hickson, I.; Hummersone, M. G.; Menear,
K. A.; Martin, N. M. B.; Matthews, I.; Newell, D. R.; Ord, R.; Richardson, C. J.; Smith,
G. C. M.; Griffin, R. J. Pyranone, Thiopyranone, and Pyridone Inhibitors of
Phosphatidylinositol 3-Kinase related Kinases. Structure-Activity Relationships for
DNA-Dependent Protein Kinase Inhibition, and Identification of the First Potent and
Selective Inhibitor of the Ataxia Telangiectasia Mutated Kinase. J. Med. Chem. 2007, 50,
1958-1972.
3.
dihydrothiopyran-4-ones. Tetrahedron Lett. 2006, 47, 5095-5097.
4. Aloup, J. C.; Bouchaudon, J.; Farge, D.; James, C.; Deregnaucourt, J.; Hardy-
Rosiak, A.; Christoffers, J. Synthesis of unsymmetrically 2,6-disubstituted 2,3-
Houis, M. Synthesis and antisecretory and antiulcer activities of derivatives and analogs
of 2-(2-pyridyl)tetrahydrothiophene-2-carbothioamide. J. Med. Chem. 1987, 30, 24-29.
5.
Dil’barkhanov, R. P.; Kudaibergenov, K. K.; Ryzhikov, V. D.; Murakhov, D. B.;
Kiyashev, D. K.; Kenzhebaeva, B. B.; Shirinkina, L. V. Vopr. Farmatsii, Alma-Ata,
1988, 39; Chem. Abstr. 1989, 111, 115365.
6.
(a) Singh, U.; Raju, B.; Lam, S.; Zhou, J.; Gadwood, R. C.; Ford, C. W.; Zurenko,
G. E.; Schaadt, R. D.; Morin, S. E.; Adams, W. J.; Friis, J. M.; Courtney, M.; Palandra,
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
J.; Hackbarth, C. J.; Lopez, S.; Wu, C.; Mortell, K. H.; Trias, J.; Yuan, Z.; Patel, D. V.;
Gordeev, M. F. New Antibacterial tetrahydro-4(2H)-thiopyran and thiomorpholine S-
oxide and S,S-dioxide phenyloxazolidinones. Bioorg. Med. Chem. Lett. 2003, 13, 4209-
4212; (b) Bozhenova, O. A.; Kharchenko, V. G.; Shebaldova, A. D. Koord Khim. 1983,
9, 1096; Chem. Abstr. 1983, 99, 132728.
7.
(a) Rovnyak, C. G. U.S. Patent 4, 128, 647, 1978; Chem. Abstr. 1979, 90, 137854;
(b) Mac Pherson, L. J.; Parker, D. T. Eur. Pat. Appl. EP, 606,046, 1994; Chem. Abstr.
1995, 122, 314456.
8.
(a) Hansen Jr., D. W.; Pilipauskas, D. R.; Clare, M. Eur. Pat. Appl. EP, 212,550,
1987; Chem. Abstr. 1987, 106, 214401; (b) Okujima, H.; Tobe, A.; Kobayashi, M.;
Betsusho, H.; Kyono, A.; Tauda, K. Jpn. Kokai Tokkyo Koho Jp. 03,07,279, 1991;
Chem. Abstr. 1991, 114, 207031.
9.
Hardy, G. W.; Doyle, P. M.; Smith, T. W. Sulphonium analogues of some
piperidine analgesics. Eur. J. Med. Chem. 1987, 22, 331-335.
10.
Wei, D. Shiyou Xuebao, Shiyou Jiagong 1988, 4, 90; Chem. Abstr. 1989, 110,
Hagiwar, S. M. Jpn. Kokai Tokkyo Koho, Jp. 01,17,057, 1988; Chem. Abstr.
41666.
11.
1989, 111, 244122.
12.
Rody, J.; Leppard, D. G. U. S. Patent 5, 149, 828, 1992.
Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage,
13.
R.; Ranganathan, S.; Vorbrüggen, H. The Total Synthesis of Cephalosporin C1. J. Am.
Chem. Soc. 1966, 88, 852-853.
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
14.
(a) Casy, G.; Lane, S.; Taylor, R. J. K. J. Chem. Soc. Perkin Trans. 1 1986, 1397-
1404; (b) Ohuchida, S.; Hamanaka, N.; Hayashi, M. Synthesis of thromboxane A2
analogs-4: (±)-Dithiathromboxane A2 sodium salt. Tetrahedron 1983, 39, 4273-4280.
15.
Boulton, A. J.; McKillop, A. Comprehensive Heterocyclic Chemistry; Pergamon:
Oxford, 1984; Vol. 3.
16.
(a) Vinosha, B.; Renuga, S.; Gnanadeebam, M.; Perumal, S.; Lycka, A. Novel
Domino Reactions of (Z,Z’)-2,2’-Thiobis(1,3-diarylprop-2-en-1-ones) with
Acetylacetone and Ethyl Acetoacetate: Stereoselective Synthesis of Highly
Functionalised Dihydrofurans. Synth. Commun. 2009, 39, 2776-2788; (b) Gnanadeebam,
M.; Selvaraj, S.; Perumal, S.; Renuga, S. Novel tandem reactions of 2,2’-sulfonylbis(1,3-
diarylprop-2-en-1-ones) with hydrazine: Formation of 3,6-diarylpyridazines and 3,5-
diarylpyrazoles. Tetrahedron 2002, 58, 2227-2230; (c) Gnanadeebam, M.; Selvaraj, S.;
Perumal, S.; Renuga, S.; Selvaraj, S. A Synthetic and stereochemical study of 2,6-
diaroyl-3,5-diaryl-4-ethyltetrahydro-1,4-thiazine-1,1-dioxides. Phosphorus, Sulfur and
Silicon. 2002, 177, 431-436; (d) Renuga, S.; Selvaraj, S.; Perumal, S.; Lycka, A.;
Gnanadeebam, M. Diastereoselective synthesis and 1H and 13C NMR study of 4-acetyl-
2,6-diaroyl-3,5-diaryl-4-ethoxycarbonylthiane-1,1-dioxides. Magn. Reson. Chem. 2001,
39, 651-653; (e) Selvaraj, S.; Renuga, S.; Gnanadeebam, M.; Perumal, S.; Sivakolunthu
S. Synthesis and stereochemical studies of some 4,4-diethoxycarbonyl- 2,6-diaroyl-3,5-
diarylthiane-1,1-dioxides. Indian. J. Chem. 1999, 38B, 376-77; (f) Gnanadeepam, M.;
Selvaraj, S.; Perumal, S.; Hewlins, M. J. E.; Lycka, A. 2,6-Diaroyl-3,5-diaryl-4-
methyltetrahydro-1,4-thiazines- A Synthetic and stereochemical study. Phosphorus,
Sulfur and Silicon. 1999, 155, 167-173; (g) Selvaraj, S.; Renuga, S.; Gnanadeepam, M.;
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
Perumal, S.; Sivakolunthu, S. Synthesis and stereochemical studies of some 2,6-diaroyl-
3,5-diaryl-4-diethoxycarbonylthiane-1,1-dioxides. Indian J. Chem. 1999, 38B, 376-377;
(h) Renuga, S.; Selvaraj, S.; Perumal, S.; Sivakolunthu, S. Synthesis and stereochemical
studies of some 4-cyano-2,6-diaroyl-3,5-diaryl-4-ethoxycarbonylthiane-1,1-dioxides.
Indian. J. Heterocycl. Chem. 1998, 8, 81-82; (i) Gnanadeepam, M.; Renuga, S.;
Selvaraj, S.; Perumal, S.; Hewlins, M. J. E. Synthesis and NMR spectral studies of 2e,6e-
diaroyl-3e,5e-diaryl-1,4-dithiane-1,1-dioxides. Phosphorus, Sulfur and Silicon. 1998,
134/135, 171-176; (j) Renuga, S.; Selvaraj, S.; Perumal, S.; Hewlins, M. J. E.
Diastereoselective Synthesis of 2,2’-Thiobis- and 2,2’-sulfonylbis-(2-aroyl-3-aryl-
oxiranes). Tetrahedron 1999, 55, 9309-9316.
17.
Regnier, T.; Lavastre, O. General and environmentally friendly synthesis of
heterocyclic multidentate molecules based on microwave assisted heating protocol.
Tetrahedron 1993, 62, 155-159.
18.
Quiroga, J.; Cruz, S.; Insuasty, B.; Abonıa, R.; Nogueras, M.; Cobo, J. Three-
component synthesis of hexahydropyridopyrimidine-spirocyclohexanetriones induced by
microwave. Tetrahedron Lett. 2006, 47, 27-30.
19.
Castagnolo, D.; Renzulli, M. L.; Galletti, E.; Corelli, F.; Botta, M. Microwave-
assisted ethylene-alkyne cross-metathesis: synthesis of chiral 2-(N-1-acetyl-1-
arylmethyl)-1,3-butadienes. Tetrahedron: Asymmetry 2005, 16, 2893-2896.
20.
Ju, Y.; Varma, R. S. Microwave-assisted cyclocondensation of hydrazine
derivatives with alkyl dihalides or ditosylates in aqueous media: Syntheses of pyrazole,
pyrazolidine and phthalazine derivatives. Tetrahedron Lett. 2005, 46, 6011-6014.
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
21.
Renuga, S.; Gnanadeebam, M.; Vinosha, B.; Perumal, S. A novel four component
tandem protocol for the stereoselective synthesis of highly functionalised thiazoles.
Tetrahedron 2007, 63, 10054-10058.
22.
(a) Loupy, A. Topics in Current Chemistry; Springer-Verlag: Berlin Heidelberg,
1999; Vol. 206; (b) Vinosha, B.; Renuga, S.; Gnanadeebam, M.; Perumal, S. A
Diastereoselective Synthesis of Novel Multifunctional Thianes. Phosphorus, Sulfur and
Silicon. 2009, 184, 2980-2988.
23.
Crystallographic data (excluding structure factors) for 2c in this article have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 765249. 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).
24.
Gnanadeebam, M.; Renuga, S.; Selvaraj, S.; Perumal, S.; Dhanabalan, A.;
Hewlins, M. J. E. Diastereosellective synthesis of 2,2’-thiobis and 2,2’-sulfonylbis-(1,3-
diarylprop-2-en-1-ones)- an oxidative configurational switch. Phosphorus, Sulfur and
Silicon. 2004, 179, 203-214.
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
Table 1. Yield and mp of diastereomeric nitrothianes
Compd Thermal Yield (%)
MW irradiation
Mp (ºC)
2
. 1
Yield (%)
2
2
3
3
DM EtO DMF EtO DMF
EtOH
F
H
H
a
b
c
d
e
f
60
66
59
66
50
59
57
70
72
75
71
66
69
65
20
21
24
19
17
19
23
17
18
18
18
16
17
16
84
83
79
81
77
78
73
85
83
85
84
80
82
78
150–152 238–240
160–162 288–290
166–168 194–196
190–192 218–220
74–76
146–148
180–182 224–226
156–158 282–284
g
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
Figure 1. Stereochemistry of the diastereomeric nitrothianes 2 and 3
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Figure 2. X-ray structure of 2c
ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
Scheme1. Synthesis of multisubstituted 4-nitrothianes
O
O
1
S
O
O
O
1
2
6
2
6
S
CH3NO2
S
Ar
Ar
Ar
Ar
Ar
3
5
5
3
2
NaOEt
∆ or MW
Ar'
Ar'
Ar'
Ar'
4
4
Ar'
NO2
NO2
1
2
3
Major
Minor
1-3
a
Ar
Ar’
C6H5
C6H5
C6H5
b
c
p-Cl-C6H4
C6H5
p-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-Me-C6H4
p-Me-C6H4
d
e
p-Cl-C6H4
p-Me-C6H4
C6H5
f
g
p-Cl-C6H4
ACCEPTED MANUSCRIPT
20

ACCEPTED MANUSCRIPT
Scheme 2. Plausible mechanism for the stereoselective formation of multisubstituted 4-
nitrothianes
O
COAr
COAr
Ar'
H
H
S
ArOC
Ar'
Ar
ArOC
H
S
2
S
H
H
CH2NO2
H
1
Ar'
Ar'
CH2NO2
4
Ar'
H
4
CH2NO2
O
C
O
C
COAr
H
Ar
Ar
ArOC
Ar'
S
H
ArOC
Ar'
ArOC
Ar'
S
H
H
S
H
H
H
C
O2N
O2N
Ar'
major or sole
2
Ar'
Ar'
H
6
N
O
5
O
ACCEPTED MANUSCRIPT
21