Solvent-free synthesis of new heteryl β-ketosulfones

Article abstract of DOI:10.3184/030823409X401745

A novel efficient method for the coupling of sulfinic acid salts and α-halo ketones is described. A variety of heteryl β-ketosulfones have been formed in an excellent yields at room temperature under solvent-free conditions.

Full text of DOI:10.3184/030823409X401745

JOURNAL OF CHEMICAL RESEARCH 2009
FEBRUARY, 87–89
RESEARCH PAPER 87
Solvent-free synthesis of new heteryl ȕ-ketosulfones
Nalajam Guravaiah and Vedula Rajeswar Rao*
Department of Chemistry, National Institute of Technology, Warangal 506 021, AP, India
A novel efficient method for the coupling of sulfinic acid salts and D-halo ketones is described. A variety of heteryl
E-ketosulfones have been formed in an excellent yields at room temperature under solvent-free conditions.
Keywords: ꢀꢁꢂꢃꢁEURPRDFHW\OꢄFRXPDULQꢅꢆVRGLXPDUHQHVXO¿QDWHꢅꢆE-ketosulfones, solvent-free synthesis
E-Ketosulfones are an important class of compounds in
organic synthesis.1 Several useful compounds are prepared
via the intermediacy of EꢁNHWRVXOIRQHVꢅꢆ VXFKꢆ DVꢆ ROH¿QVꢅ2-4
disubstituted acetylenes,2-4 vinyl sulfones,5 allenes,6 and
polyfunctionalised 4H-pyrans.7,8 Facile reductive elimination
of E-ketosulfones leads to the formation of ketones.9-12
Additionally, E-ketosulfones are precursors for optically
active E-hydroxy sulfones.13-15 Some of the E-ketosulfones
possess fungicidal activity.16
in 92% yield. On the other hand when the same reaction was
performed with 1 equiv. of 3-(2-bromoacetyl)coumarin and
ꢊꢉꢃꢇꢆHTXLYꢉꢆRIꢆDUHQHVXO¿QDWHVꢆDQGꢆꢊꢆHTXLYꢉꢆRIꢆ.2CO3 as base
under solid state for 20 minutes gave the condensed product
88%. Based on the above result, we concluded that using solid
state reaction involving few drops of DMF as the catalytic
system are optimised combination of the coupling reaction.
The scope of this protocol was further extended for the
synthesis of variety of substituted heteryl-E-ketosulfones.
It was observed that all the products formed in relatively
excellent yields using solid state method.
The coumarins are heterocyclic compounds, also known
as 2H-1-benzopyran derivatives, and constitute an important
group of natural products that are well known for their
biological activity and therapeutic activites.17-20 These can also
be considered as versatile building blocks and intermediates for
the synthesis of various interesting heterocyclic systems.21-23
In the literature the common routes for the synthesis of
E-ketosulfones involve oxidation of EꢁNHWRVXO¿GHVꢅ24,25
reactions of sulfonylchlorides with silylenol ethers,26
reactions of diazosulfones with aldehydes,27 alkylation
RIꢆ DUHQHꢆ VXO¿QDWHVDOWVꢆ ZLWKꢆ D-haloketones,28,29 acylation
of alkyl sulfones, reaction of alkyl sulfones with N-
acylbenzotriazoles,30 and a more recent approach involving
the reaction of sulfonyl chloride with arylacetylenes.31
Very recently Suryakiran et al.32 reported the preparation of
E-ketosulfones in ionic liquid and in PEG-40033 as solvent.
These methods require toxic substrates, multi-step synthesis
and prolonged reaction time, costly reagents and yields of the
products are moderate, Consequently, there is a need for an
alternative procedure involving milder reaction conditions.
We report here the synthesis of some novel heteryl
E-ketosulfones, we believe that these compounds may be
useful intermediates in the synthesis of biological active
compounds.
In conclusion we have disclosed a mild, inexpensive, fast
DQGꢆ HI¿FLHQWꢆ V\QWKHVLVꢆ RIꢆ E-ketosulfones under solvent-free
conditions at room temperature.
Experimental
All the reagents and solvents were pure, purchased from commercial
VRXUFHVꢆDQGꢆZHUHꢆXVHGꢆZLWKRXWꢆIXUWKHUꢆSXUL¿FDWLRQꢆXQOHVVꢆRWKHUZLVHꢆ
stated. 3-(2-Bromoacetyl) coumarin34,35 were prepared by literature
procedures. Melting points were determined in open capillaries with a
“cintex” melting point apparatus Mumbai, India and were uncorrected.
CHNS analysis was done by Carlo Erba EA 1108 automatic elemental
analyser. The purity of the compounds was checked by TLC plates
(E.Merek, Mumbai, India), IR spectra (KBr) were recorded on a
BrukerWM-4(X) spectrometer (577 model). 1H NMR spectra were
recorded on a Bruker WM-300 Spectrometer in G ppm using TMS as
internal standard. Mass spectra (EI-MS) were determined on Perkin
Elmer (SCIEX API-2000, ESI) at 12.5eV.
General procedure for the synthesis of E-keto sulfones
$ꢆ PL[WXUHꢆ RIꢆ WKHꢆ VRGLXPꢆ DUHQHVXO¿QDWHꢆ ꢂꢊꢉꢃꢇꢆ PPROꢄꢆ DQGꢆ WKHꢆ ꢀꢁ
(2-bromoacetyl)coumarin (1 mmol) was taken in mortar and
ground at room temperature for the appropriate time (see Table 2).
After completion of the reaction, as monitored by TLC, the reaction
PDVVꢆZDVꢆSRXUHGꢆLQWRꢆZDWHUꢆDQGꢆVWLUUHGꢆIRUꢆꢊꢋꢆPLQXWHVꢆWKHQꢆ¿OWHUHGꢅꢆ
GULHGꢆ DQGꢆ WKHꢆ FUXGHꢆ SURGXFWꢆ SXUL¿HGꢆ E\ꢆ FROXPQꢆ FKURPDWRJUDSK\ꢆ
(ethyl acetate/hexane, 2:8) or recrystallised from acetone. All the
other compounds were prepared similarly.
Results and discussion
3-(2-(Phenylsulfonyl)acetyl)-2H-chromen-2-one (3a): M.p. 138–
140°C. IR (KBr, Jmax cm-1): 1144, 1308(SO2), 1689 (C=O), 1727
(C=O of lactone), 1H NMR (CDCl3, G ppm): 5.12 (s, 2H CH2), 7.34–
7.36(m, 2H, ArH), 7.54–7.56(m, 2H, ArH), 7.66–7.69(m, 3H, ArH),
7.92–7.95(m, 2H, ArH), 8.50(s, 1H, C4 of coumarin proton). 13C
NMR (CDCl3 G ppm), 65.9, 117.2, 118.4, 123.7, 125.8, 128.8, 129.6,
131.1, 134.6, 135.8, 139.8, 149.6, 155.8, 159.6, 186.1. EI-MS 329
(M + H)+. Anal. Calcd. for C17H12O5S: C, 62.19; H, 3.68; S, 9.77.
Found: C, 62.00; H, 3.63; S, 9.72%.
We chose the coupling of 3-(2-bromoacetyl)coumarin with
VRGLXPꢆDUHQHVXO¿QDWHꢆDVꢆWKHꢆPRGHOꢆIRUꢆH[SORULQJꢆWKHꢆRSWLPLVHGꢆ
reaction condition. It was found that if absolute ethanol was
XVHGꢆ DORQHꢆ WKHꢆ UHDFWLRQꢆ UHTXLUHVꢆ UHÀX[ꢆ WHPSHUDWXUHꢆ ZLWKꢆ
prolonged time i.e. eight hours to get the coupling product in
RQO\ꢆꢇꢃꢈꢆ\LHOGꢉꢆ7KLVꢆLVꢆGXHꢆWRꢆORZꢆVROXELOLW\ꢆRIꢆVXO¿QDWHꢆVDOWVꢆ
in organic solvents. Note that the addition of a small amount
RIꢆZDWHUꢆꢂꢊꢋꢆꢌꢆꢃꢄꢆFRXOGꢆLPSURYHꢆWKHꢆUHDFWLRQꢆHI¿FLHQF\ꢉꢆ7KLVꢆLVꢆ
presumably due to the increased water solubility of sodium
DUHQHVXO¿QDWHꢅꢆ KHQFHꢆ WKHꢆ UHDFWLRQꢆ \LHOGꢆ LQFUHDVHGꢆ WRꢆ ꢍꢎꢈꢉꢆ
In addition to this when the same reaction was performed
under DMF as solvent, for eight hours the reaction yield was
60% only. The addition of a small amount of water (10:2)
LPSURYHGꢆ WKHꢆ UHDFWLRQꢆ HI¿FLHQF\ꢅꢆ DQGꢆ WKHꢆ UHDFWLRQꢆ \LHOGꢆ
increased to 68%.
Table 1 Optimisation of reaction condition for the formation
of 3a
Entry
Solvent
Time/h
Isolated
yield/%a
1
2
3
4
5
6
Absolute ethanol
8
52
64
Aqueous ethanol
8
DMF
Aqueous DMF
Solid state (few drops of DMF)
Solid state (1 equiv. of K2CO3)
8
8
0.20
0.20
60
68
The best results were obtained when the reaction was carried
out in the solid state with 1 equiv. 3-(2-bromoacetyl)coumarin
DQGꢆꢊꢉꢃꢇꢆHTXLYꢉꢆRIꢆDUHQHVXO¿QDWHꢆZLWKꢆIHZꢆGURSVꢆRIꢆ'0)ꢆIRUꢆ
20 minutes. We observed rapid formation of E-keto sulfones
92b
88b
aReagents and conditions: 3-(2-bromoacetyl)coumarin (1 mmol),
sodium arenesulfinate (1.25 mmol), reflux temperature in
given solvent.
bReaction was carried out at room temperature.
* Correspondent. E-mail: vrajesw@yahoo.com, nalajamorg@gmail.com

88 JOURNAL OF CHEMICAL RESEARCH 2009
6-Bromo-3-[2-(4-methylphenylsulfonyl)acetyl]-2H-chromen-2-one
(3h): M.p. 168–170°C. IR (KBr, Jmax cm-1): 1135, 1351(SO2), 1692
(C=O), 1740 (C=O of lactone), 1H NMR (CDCl3, G ppm): 2.45 (s,
3H, CH3), 5.0 (s, 2H, CH2), 7.30–7.40(m, 4H, ArH), 7.60–7.70(m,
2H, ArH), 7.85 (d, 1H, J = 8 Hz, ArH), 8.35 (s, 1H, C4 of coumarin
proton). Anal. Calcd for C18H13BrO5S: C, 51.32; H, 3.11; S, 7.61.
Found: C, 51.30; H, 3.15; S, 7.69%.
Table 2 Synthesis of E-ketosulfones by using solid state
method at room temperature
Entry
Time/min
Yield/%
3a
3b
3c
3d
3e
3f
3g
3h
3i
20
25
25
23
25
30
20
22
24
25
25
30
92
89
87
90
90
86
93
89
87
90
90
82
6,8-Dibromo-3-[2-(4-methylphenylsulfonyl)acetyl]-2H-chromen-
2-one (3i): M.p. 208–210°C. IR (KBr, Jmax cm-1): 1165, 1344(SO2),
1683 (C=O), 1728 (C=O of lactone), 1H NMR (CDCl3, G ppm): 2.5 (s,
3H, CH3), 5.05 (s, 2H, CH2), 7.30–7.45(m, 5H, ArH), 7.60–7.70 (m,
2H, ArH), 7.85(d, 1H, ArH), 8.35(s, 1H, C4 of coumarin proton). Anal.
Calcd for C18H12 Br2O5S: C, 43.22; H, 2.42; S, 6.41. Found: C, 43.19;
H, 2.38; S, 6.36%.
3j
3k
3l
6-Chloro-3-[2-(4-methylphenylsulfonyl)acetyl]-2H-chromen-2-
one (3j): M.p. 174–176°C. IR (KBr, Jmax cm-1): 1135, 1358(SO2),
1
1692 (C=O), 1734 (C=O of lactone), H NMR (CDCl3, G ppm): 2.7
(s, 3H, CH3), 5.1 (s, 2H, CH2), 7.10–7.30(m, 5H, ArH), 7.6–7.7(m,
2H, ArH), 7.95(d, 1H, ArH), 8.4(s, 1H, C4 of coumarin proton). Anal.
Calcd for C18H13ClO5S: C, 57.37; H, 3.48; S, 8.51. Found: C, 57.32;
H, 3.42; S, 8.48%.
6-Bromo-3-(2-(phenylsulfonyl)acetyl)-2H-chromen-2-one (3b): M.p.
188–190°C. IR (KBr, Jmax cm-1): 1163, 1357(SO2), 1683 (C=O),
1
1733 (C=O of lactone), H NMR (CDCl3, G ppm): 4.7 (s, 2H, CH2),
6,8-Dichloro-3-[2-(4-methylphenylsulfonyl)acetyl]-2H-chromen-
7.12–7.25(m, 8H, ArH), 8.4 (s, 1H, C4 of coumarin proton). Anal.
Calcd for C17H11BrO5S: C, 50.14; H, 2.71; S, 7.87. Found: C, 50.08;
H, 2.79; S, 7.81%.
2-one (3k): M.p. 204–205°C. IR (KBr, Jmax cm-1): 1143, 1321(SO2),
1
1683 (C=O), 1734 (C=O of lactone), H NMR (CDCl3, G ppm): 2.4
(s, 3H, CH3), 4.8 (s, 2H, CH2), 7.10–8.1(m, 6H, ArH), 8.3(s, 1H, C4
of coumarin proton). Anal. Calcd for C18H12 Cl2O5S: C, .52.57; H,
2.94; S, 7.80. Found: C, 52.51; H, 2.90; S, 7.74%.
6,8-Dibromo-3-(2-(phenylsulfonyl)acetyl)-2H-chromen-2-one
(3c): M.p. 210–212°C. IR (KBr, Jmax cm-1): 1162, 1357(SO2), 1686
(C=O), 1747 (C=O of lactone), 1H NMR (CDCl3, G ppm): 4.7 (s, 2H,
CH2), 7.25–7.45(m, 2H, ArH), 7.65–7.82(m, 5H, ArH), 8.4(s, 1H,
C4 of coumarin proton). Anal. Calcd for C17H10Br2O5S: C, 42.00; H,
2.07; S, 6.60. Found: C, 42.03; H, 2.00; S, 6.67%.
3-[2-(4-Methylphenylsulfonyl)acetyl]-2H-benzo[h]chromen-2-one
(3l): M.p. 240–242°C. IR (KBr, Jmax cm-1): 1134, 1318(SO2), 1703
(C=O), 1724 (C=O of lactone), 1H NMR (CDCl3, G ppm): 2.7 (s, 3H,
CH3), 5.1 (s, 2H, CH2), 7.2–7.30(m, 7H, ArH), 7.55–7.7(m, 2H,
ArH), 7.95(d, 1H, ArH), 8.45(s, 1H, C4 of coumarin proton). Anal.
Calcd for C22H16O5S: C, 67.33; H, 4.11; S, 8.17. Found: C, 67.30; H,
4.16; S, 8.20%.
6-Chloro-3-(2-(phenylsulfonyl)acetyl)-2H-chromen-2-one (3d):
M.p. 210–212°C. IR (KBr, Jmax cm-1): 1143, 1348(SO2), 1683 (C=O),
1
1735(C=O of lactone), H NMR (CDCl3, G ppm): 4.6 (s, 2H, CH2),
7.25–7.45(m, 2H, ArH), 7.62–7.75(m, 5H, Ar–H), 8.5(s, 1H, C4 of
coumarin proton). Anal. Calcd for C17H11ClO5S: C, 56.28; H, 3.06;
S, 8.84. Found: C, 56.34; H, 3.00; S, 8.90%.
Financial support from CSIR, New Delhi for the sanction
of the project (No.01 (2062) 06/EMR-II) is gratefully
acknowledged. We also thanks to Head analytical division,
IICT Hyderabad for analytical and spectral data.
6,8-Dichloro-3-(2-(phenylsulfonyl)acetyl)-2H-chromen-2-one
(3e): M.p. 174–175°C. IR (KBr, Jmax cm-1): 1153, 1358(SO2), 1689
(C=O), 1741(C=O of lactone), 1H NMR (CDCl3, G ppm): 4.7 (s, 2H,
CH2), 7.3–7.45(m, 2H, ArH), 7.60–7.80(m, 5H, ArH), 8.6(s, 1H, C4
of coumarin proton). Anal. Calcd for C17H10Cl2O5S: C, 51.40; H,
2.54; S, 8.07. Found: C, 51.48; H, 2.51; S, 8.0%.
Received 13 November 2008; accepted 19 December 2008
Paper 08/0292 doi: 10.3184/030823409X401745
Published online: 18 February 2009
3-(2-(Phenylsulfonyl)acetyl)-2H-benzo[h]chromen-2-one
(3f):
M.p. 182–184°C. IR (KBr, Jmax cm-1): 1152, 1357(SO2), 1682 (C=O),
1
1734 (C=O of lactone), H NMR (CDCl3, G ppm): 5.1(s, 2H, CH2),
7.10–7.45(m, 5H, ArH), 7.60–7.75(m, 5H, ArH), 8.0(d, 1H, J = 6 Hz,
ArH), 8.5 (s, 1H, C4 of coumarin proton). Anal. Calcd for C21H14O5S:
C, 66.66; H, 3.73; S, 8.47. Found: C, 66.61; H, 3.78; S, 8.40%.
3-[2-(4-Methylphenylsulfonyl)acetyl]-2H-chromen-2-one (3g): M.p.
152–154°C. IR (KBr, Jmax cm-1): 1146, 1320(SO2), 1684 (C=O), 1733
(C=O of lactone), 1H NMR (CDCl3, G ppm): 2.39 (s, 3H, CH3), 5.09 (s,
2H, CH2), 7.30–7.37 (m, 4H, ArH), 7.65–7.69 (m, 2H, ArH), 7.79–7.81
(m, 2H, ArH), 8.47 (s, 1H, C4 of coumarin proton), 13C NMR (CDCl3
G ppm), 21.4, 65.3, 116.5, 117.8, 123.2, 125.2, 128.3, 129.6, 130.3,
130.5, 135.1, 136.2, 145.1, 148.8, 155.1, 158.9, 185.6, EI-MS 343
[M + H]+. Anal. Calcd for C18H14O5S: C, 63.15; H, 4.12; S, 9.37.
Found: C, 63.10; H, 4.10; S, 9.32%.
References
1
2
3
4
5
6
N.S. Simpkins, Sulfones in organic synthesis, ed. J.E. Baldwin, Pergamon
Press, Oxford, 1993.
M. Ihara, S. Suzuki, T. Taniguchi, Y. Tokunaga and K. Fukumoto,
Tetrahedron, 1995, 51, 9873.
P.A. Bartlett, F.R. Green and E.H. Rose, J. Am. Chem. Soc., 1978,
100, 4852.
T. Mandai, T. Yanagi, K. Araki, Y. Morisaki, M. Kawada and J. Otera,
J. Am. Chem. Soc., 1984, 106, 3670.
S. Sengupta, D.S. Sarma and S. Mondal, Tetrahedron: Asym., 1998,
9, 2311.
J.E. Baldwin, R.M. Adlington, N.P. Crouch, R.L. Hill and T.G. Laffey,
Tetrahedron Lett., 1995, 36, 7925.
R1
R1
R2
O
O
O
O
O
O
Solid state
R2
SO2Na
+
O
S
O
R
Br
R
few drops of DMF
2
1
3
g) R= R1=H, R2=CH3
h) R=Br, R1=H,R2=CH3
i) R=R1=Br, R2=CH3
j) R=Cl, R1=R2=CH3
k) R=R1=Cl, R2=CH3
l) 7,8 benzo, R2=CH3
a) R= R1= R2= H
b) R=Br, R1=R2=H
c) R=R1=Br, R2=H
d) R=Cl, R1=R2=H
e) R=R1=Cl, R2=H
f) 7,8 benzo, R2=H
Scheme 1

JOURNAL OF CHEMICAL RESEARCH 2009 89
7
J.L. Marco, I. Fernandez, N. Khiar, P. Fernandez and A. Romero, J. Org.
Chem., 1995, 60, 6678.
22 A.M. Piloto, P.G.S. Costa and T.M.S. Gonclaves, Tetrahedron Lett., 2005,
46, 4757.
23 K. Sivakumar, F. Xie, B.M. Cash, S. Long, H.N. Barnhill and Q.A.Wang,
Org Lett., 2004, 6, 4603.
24 B.M. Trost and D.P. Curran, Tetrahedron Lett., 1981, 22, 1287.
25 A.-L. Fan, S. Cao and Z. Zhang, J. Heterocycl. Chem., 1997, 34, 1657.
26 N. Kamigata, K. Udodaira and T. Shimizu, J. Chem. Soc., Perkin Trans.,
1997, 783.
27 C.R. Holmquist and J.E. Roskamp, Tetrahedron Lett., 1992, 33, 1131.
28 G.E. Vennstra and B. Zwaneburg, Synthesis, 1975, 519.
29 J. Wildeman and A.M. Van Leusen, Synthesis, 1979, 733.
30 A.R. Katrizky, A.A.A. Abdel-Fattah and M. Wang, J. Org. Chem., 2003,
68, 1443.
31 C. Lai, C. Xi, Y. Jiang and R. Hua, Tetrahedron Lett., 2005, 46, 513.
3 2 N. Suryakiran, P. Prabakar, K. Rajesh, V. Suresh and Y. Venkateswarlu,
J. Mol. Catalysis A., 2007, 270, 201.
33 N. Suryakiran, T. Srikanth Reddy, K. Ashalatha, M. Lakshman and
Y. Venkateswarlu, Tetrahedron Lett., 2006, 47, 3853.
34 C.F. Koelsch, J. Am. Chem. Soc., 1950, 72, 2993.
35 V. Rajeswar Rao and T.V. Padmanabha Rao, Ind J Chem., 1986. 25B, 413.
8
9
J.L. Marco, J. Org. Chem., 1997, 62, 6575.
E.J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1964, 86, 1639.
10 M.J. Kurth and M.J. O'Brien, J. Org. Chem., 1985, 50, 3846.
11 S. Sengupta, D.S. Sarma and S. Mondal, Tetrahedron., 1998, 54, 9791.
12 H. Guo and Y. Zhang, Synth. Commun., 2000, 30, 2559.
13 A. Svatos, Z. Hunkova, V. Kren, M. Hoskovec, D. Saman, I. Valterova,
J. Vrkoc and B. Koutek, Tetrahedron: Asym., 1996, 7, 1285.
14 P. Bertus, P. Phansavath, V. Ratovelomanana-Vidal, J-P. Genet, A.R. Touati,
T. Homri and B.B. Hassine, Tetrahedron: Asym., 1999, 10, 1369.
15 V. Gotor, F. Rebolledo and R. Liz, Tetrahedron: Asym., 2001, 12, 513.
16 W.M. Wolf, J. Mol. Struct., 1999, 474, 113.
17 R. O'Kennedy and R.D. Thomas, Coumarins: biology, application, and
mode of action, Wiley, Chichester, 1997.
18 D. Yu, M. Suzyki, L. Xie, S.L. Morris-Natschke and K.H. Lee, Med. Res.
Rev., 2003, 23, 322.
19 J.M. Rollinger, A. Hornick, T. Langer, H. Stuppner and H. Prast, J. Med.
Chem., 2004, 47, 6248.
20 S. Chen, M. Cho, K. Karlsberg, D. Zhou and Y.C. Yuan, J. Biol. Chem.,
2004, 279, 48071.
21 D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo and L Vaccaro, J. Org.
Chem., 2003, 68, 9263.