A facile one-pot synthesis of β-keto sulfones from ketones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.04.076

An easy solvent-free method is described for the conversion of ketones into β-keto sulfones in high yields that involves the in situ generation of α-tosyloxyketones, followed by nucleophilic substitution with sodium arene sulfinate in the presence of tetra-butylammonium bromide at room temperature. The salient features of this one-pot protocol are short reaction times, cleaner reaction profiles, and simple work-up that precludes the use of toxic solvents.

Full text of DOI:10.1016/j.tetlet.2006.04.076

Tetrahedron Letters 47 (2006) 4197–4199
A facile one-pot synthesis of b-keto sulfones from ketones
under solvent-free conditions
a,
a
a
b,
*
*
Dalip Kumar, Swapna Sundaree, V. S. Rao and Rajender S. Varma
a
Chemistry Group, Birla Institute of Technology and Science, Pilani 333 031, India
b
Clean Processes Branch, Sustainable Technology Division, National Risk Management Research Laboratory, US
Environmental Protection Agency, 26 W. Martin Luther King Dr., MS 443. Cincinnati, OH 45268, USA
Received 20 March 2006; revised 7 April 2006; accepted 10 April 2006
Abstract—An easy solvent-free method is described for the conversion of ketones into b-keto sulfones in high yields that involves the
in situ generation of a-tosyloxyketones, followed by nucleophilic substitution with sodium arene sulfinate in the presence of tetra-
butylammonium bromide at room temperature. The salient features of this one-pot protocol are short reaction times, cleaner reac-
tion profiles, and simple work-up that precludes the use of toxic solvents.
Ó 2006 Elsevier Ltd. All rights reserved.
b-Keto sulfones are an important class of compounds in
organic synthesis. Several useful compounds are pre-
sis of heterocyclic compounds under solvent-free
conditions.
1
15
pared via the intermediacy of b-keto sulfones, such as
2
2
3
olefins, disubstituted acetylenes, vinyl sulfones, al-
Organic reactions under solvent-free conditions are
advantageous because of their enhanced selectivity and
efficiency, ease of manipulation, cleaner product forma-
4
5
lenes, and polyfunctionalized 4H-pyrans. Facile reduc-
tive elimination of b-keto sulfones leads to the
6
16
formation of ketones. Additionally, b-keto sulfones
tion, and toxic or often volatile solvents are avoided.
7
are precursors for optically active b-hydroxy sulfones.
Since many hypervalent iodine reagents have low
solubility in most of the organic solvents, the develop-
ment of solvent-free reactions will further widen the
utility of these reagents in organic synthesis. In continu-
ation of our interest to develop greener protocols, herein
we report one-pot synthesis of b-keto sulfones from
the corresponding ketones, using relatively benign
[hydroxy(tosyloxy)iodo]benzene and sodium arene sulf-
inates in the presence of phase transfer catalyst under
solvent-free conditions (Scheme 1). Initial efforts to syn-
thesize b-keto sulfones by in situ generation of a-tosyl-
oxyacetophenone from the reaction of acetophenone
with [hydroxy(tosyloxy)iodo]benzene, followed by the
Some of the b-keto sulfones are found to possess fungi-
8
cidal activity. The common routes to b-keto sulfones
9
involve oxidation of b-keto-sulfides, reactions of sulfo-
1
0
nyl chlorides with silyl enol ethers, reactions of diazo
1
1
sulfones with aldehydes, alkylation of arene sulfinate
1
2
salts with a-haloketones, acylation of alkyl sulfones,
1
3
reaction of alkyl sulfones with N-acylbenzotriazoles,
and a more recent approach involving the reaction of
1
4
sulfonyl chloride with arylacetylenes. Some of these
methods require toxic substrates, multi-step synthesis,
and prolonged reaction time, and yields of the products
are moderate, at best. Consequently, there is a need for
an alternative procedure involving milder reaction con-
ditions. In the past, we have delineated the utility of
hypervalent iodine reagents, particularly for the synthe-
O
O
PhI(OH)OTs
SO2R'
Keywords: b-Keto sulfones; Solvent-free synthesis; [Hydroxy(tosyl-
R
R
oxy)iodo]benzene; Phase transfer catalyst.
R'SO Na, TBAB
2
*
Corresponding authors. Tel.: +91 1596 245073; fax: +91 1596 244183
D.K.); e-mail addresses: dalipk@bits-pilani.ac.in; varma.rajender@
rt
(
epa.gov
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.076

4198
D. Kumar et al. / Tetrahedron Letters 47 (2006) 4197–4199
addition of sodium benzene sulfinate in the same pot,
failed to generate the product; b-keto sulfones were
not formed even in trace amounts after 48 h and upon
using the excess of sodium benzene sulfinate. Encour-
aged by our synthesis of azides promoted by phase
transfer catalysts (PTC), we explored the reaction
by adding an equimolar quantity of tetrabutylammo-
nium bromide (TBAB) to the above reaction mixture
and intimately grinding the contents together for
3 min. We observed exclusive and rapid formation of
1
7
b-keto sulfones in high yields (Table 1, entry 1), as con-
1
8
firmed by their spectral analysis. Various phase trans-
fer catalysts, such as triethylbenzylammonium chloride,
trimethylcetylammonium bromide, and tetrabutylam-
monium hydrogen sulfate, were also examined for this
conversion. TBAB proved to be most effective in terms
a
Table 1. Synthesis of b-keto sulfones from ketones using hydroxy(tosyloxy)iodobenzene
b
Entry
Substrate
Product
Time (min)
7
Yield (%)
O
O
O
S
1
91
92
87
89
88
90
84
85
82
O
O
O
O
S
2
3
4
5
6
7
8
9
8
5
5
8
7
6
5
6
O
CH3
O
O
O
O
O
S
O
Cl
Cl
Cl
Cl
O
S
O
CH3
O
O
O
S
O
H C
H C
3
3
O
O
O
S
O
CH3
H C
3
H C
3
O
O
S
O
H C
3
H C
3
CH3
O
O
O
O
S
H C
3
H C
3
CH3
O
CH3
O
O
O
S
O
O
O
O
S
10
7
81
O
O
O
a
Reactions conducted at room temperature using 1 mol equiv of TBAB.
Yields refer to pure isolated products, which were identified by the comparison of IR and NMR spectral data with those of the known compounds.
b

D. Kumar et al. / Tetrahedron Letters 47 (2006) 4197–4199
4199
of reaction time and yield of the product. The addition
of PTC converts the solid reaction mixture to a semi-
solid state, thus facilitating the attack of a nucleophile
on the ensuing a-tosyloxyketone substrates. Further,
Kurth, M. J.; O’Brien, M. J. J. Org. Chem. 1985, 50, 3846;
d) Fuju, M.; Nakamura, K.; Mekata, H.; Oka, S.; Ohno,
(
A. Bull. Chem. Soc. Jpn. 1988, 61, 495; (e) Sengupta, S.;
Sarma, D. S.; Mondal, S. Tetrahedron 1998, 54, 9791; (f)
Guo, H.; Zhang, Y. Synth. Commun. 2000, 30, 2564.
. (a) Svatos, A.; Hunkova, Z.; Kren, V.; Hoskovec, M.;
S y¨ aman, D.; Valterova, I.; Vrkoc, J.; Koutek, B. Tetra-
hedron: Asymmetry 1996, 7, 1285; (b) Bertus, P.; Phan-
savath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P.;
Touati, A. R.; Homri, T.; Hassine, B. B. Tetrahedron:
Asymmetry 1999, 10, 1369; (c) Gotor, V.; Rebolledo, F.;
Liz, R. Tetrahedron: Asymmetry 2001, 12, 513.
the enhanced nucleophilicity of the ArSO anion in the
2
7
salt form, ArSO N(t-But) , generated from TBAB and
2
4
ArSO Na may be responsible for the facile reaction.
2
Subsequently, the molar ratio of TBAB was varied and
it was found that the 25 molar percentage is adequate to
complete the reaction rapidly; with lesser amounts of
TBAB, the reaction gets completed but takes longer
time (10–48 h). The scope of this protocol was further
extended for the synthesis of a variety of substituted
b-keto sulfones (Table 1, entries 2–10). It was observed
that all the ketones require almost the same reaction
time, and yields are relatively better in the case of ace-
tophenone and its derivatives.
8
9
. Wolf, W. M. J. Mol. Struct. 1999, 474, 113.
. (a) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22,
1
287; (b) Fan, A.-L.; Cao, S.; Zhang, Z. J. Heterocycl.
Chem. 1997, 34, 1657.
1
1
1
0. Kamigata, N.; Udodaira, K.; Shimizu, T. J. Chem. Soc.,
Perkin Trans. 1 1997, 783.
1. Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992,
3
3, 1131.
2. (a) Vennstra, G. E.; Zwaneburg, B. Synthesis 1975, 519;
(b) Wildeman, J.; Van Leusen, A. M. Synthesis 1979,
733.
3. Katrizky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J.
Org. Chem. 2003, 68, 1443.
4. Lai, C.; Xi, C.; Jiang, Y.; Hua, R. Tetrahedron Lett. 2005,
In conclusion, we have developed a rapid, one-pot and
high yielding protocol for the synthesis of b-keto sulf-
ones from readily available ketones via in situ genera-
tion of a-tosyloxyketones, followed by nucleophilic
substitution with sodium arene sulfinates, under sol-
vent-free conditions.
1
1
1
1
4
6, 513.
5. Varma, R. S.; Kumar, D.; Liesen, P. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 4093.
6. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (b)
Varma, R. S. Green Chem. 1999, 43; (c) Varma, R. S. Pure
Appl. Chem. 2001, 73, 193.
Acknowledgments
1
1
7. Varma, R. S.; Naicker, K. P.; Kumar, D. J. Mol. Catal. A:
Chem. 1999, 149, 153.
Financial support from the institute is gratefully
acknowledged.
8. A representative procedure is as follows: A neat mixture of
p-chloroacetophenone (1 mmol) and [hydroxy(tosyl-
oxy)iodo]benzene (1.1 mmol) was ground together for
3 min, using a pestle and mortar at room temperature.
Subsequently, sodium benzene sulfinate (1 mmol) and
TBAB (0.25 mmol) were added, and the grinding process
continued further for 2 min. The semi-solid reaction
mixture was taken into water and extracted with dichlo-
romethane (5 mL). Organic phase was dried over anhy-
drous sodium sulfate, and the solvent was removed under
reduced pressure. The residue was percolated through a
column of silica gel using ethyl acetate/hexane (1:9, v/v) as
References and notes
1
2
. Simpkins, N. S. In Sulfones in Organic Synthesis; Baldwin,
J. E., Ed.; Pergamon Press: Oxford, 1993.
. (a) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.;
Fukumoto, K. Tetrahedron 1995, 51, 9873; (b) Bartlett, P.
A., ; Green, F. R., III; Rose, E. H. J. Am. Chem. Soc.
1
978, 100, 4852; (c) Mandai, T.; Yanagi, T.; Araki, K.;
Morisaki, Y.; Kawada, M.; Otera, J. J. Am. Chem. Soc.
984, 106, 3670; (d) Lythgoe, B.; Waterhouse, I. Tetrahe-
1
eluent to afford the pure product 3, yield 91%, mp 130–
1
dron Lett. 1978, 29, 2625.
32 °C; H NMR (300 MHz, CDCl
3
) d 4.70 (2H, s, CH
2
),
C
1
3
3
4
5
. Sengupta, S.; Sarma, D. S.; Mondal, S. Tetrahedron:
Asymmetry 1998, 9, 2311.
7.45–7.71 (5H, m, Ar–H), 7.81–7.94 (4H, m, Ar–H);
NMR (CDCl ) d 186.81, 141.17, 138.56, 134.36, 134.05,
130.74, 129.27, 129.24, 128.54, 63.61. Compound 4, yield
89%, mp 136–38 °C; H NMR (300 MHz, CDCl
(3H, s, CH ), 4.68 (2H, s, CH ), 7.35 (2H, dd, J = 1.8,
3
. Baldwin, J. E.; Adlington, R. M.; Crouch, N. P.; Hill, R.
L.; Laffey, T. G. Tetrahedron Lett. 1995, 36, 7925.
. (a) Marco, J.-L.; Fernandez, I.; Khiar, N.; Fernandez, P.;
Romero, A. J. Org. Chem. 1995, 60, 6678; (b) Marco, J. L.
J. Org. Chem. 1997, 62, 6575.
1
3
) d 2.46
3
2
7.2 Hz, Ar–H), 7.47 (2H, dd, J = 1.8, 6.9 Hz, Ar–H), 7.75
(2H, dd, J = 1.8, 6.6 Hz, Ar–H), 7.91 (2H, dd, J = 1.8,
1
3
6
. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964,
3
6.6 Hz, Ar–H); C NMR (CDCl ) d 186.99, 145.54,
8
6, 1639; (b) Trost, B. M.; Arndt, H. C.; Strege, P. E.;
141.10, 135.59, 134.11, 130.78, 129.89, 129.20, 128.55,
Verhoeven, T. R. Tetrahedron Lett. 1976, 27, 3477; (c)
63.77, 21.70.