Solid-phase synthesis of β-keto sulfones

Article abstract of DOI:10.1055/s-2006-942382

A novel method for the preparation of β-keto-sulfones through the use of organoselenium reagents in the solid phase by polystyrene-supported benzeneselenosulfonate or tolueneseleno-sulfonate with acetylenes has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942382

1934
SHORT PAPER
Solid-Phase Synthesis of b-Keto Sulfones
S
olid-Phase
Synth
a
esis of
b
-K
e
to Sulfones Qian,a,b Xian Huang*b,a
a
Department of Chemistry, 521 Mail Box, Hangzhou Normal College, Hangzhou 310036, P. R. of China
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, P. R. of China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn; E-mail: qianhao@mail.hz.zj.cn
b
Received 27 January 2006; revised 27 February 2006
where the vinyl C–Se bond serves as the substrate-resin
tether.
Abstract: A novel method for the preparation of b-keto-sulfones
through the use of organoselenium reagents in the solid phase by
polystyrene-supported benzeneselenosulfonate or tolueneseleno-
sulfonate with acetylenes has been developed.
Solution-phase experiments were conducted as outlined
in Scheme 1. Phenylacetylene with benzeneselenosul-
Key words: b-keto sulfones, solid-phase synthesis, selenosul- fonate or tolueneselenosulfonate reacted under AIBN ca-
fonate, polymer reagent
talysis in benzene to give b-(phenylseleno)vinyl sulfones
(1)19, which was then converted to the b-keto sulfones (2)
in good yields by trifluoroacetic acid catalyzed hydrolysis
(Table 1).
Solid-phase reactions play an important role in parallel
synthesis and combinatorial chemistry, particularly in the
area of medicinal chemistry, where their potential has
emerged as a result of the possibility of automation.1 Sul-
fones are of great importance generally in organic synthe-
sis and, among their derivatives, b-keto sulfones
particularly have widespread synthetic applications. Such
ketones are utilized as intermediates in the synthesis of
disubstituted acetylenes,2 olefins,3 allenes,4 vinyl sul-
fones,5 polyfunctionalized 4H-pyrans,6 and ketones.7 In
addition, b-keto sulfones are precursors for optically ac-
tive b-hydroxy sulfones8 and certain b-keto sulfone deriv-
atives exhibit fungicidal activity.9 Available synthetic
methods to b-keto sulfones include: (i) alkylation of me-
tallic arene sulfinates with either a-halo-ketones10 or
a-tosyloxy ketones;11 (ii) oxidation of b-keto sulfides,
b-keto sulfoxides or b-hydroxy sulfones;12 (iii) reactions
of diazo sulfones with aldehydes catalyzed by SnCl2;13
(iv) reactions of sulfonyl chlorides with silyl enol ethers
catalyzed by a ruthenium(II) complex;14 (v) free-radical
rearrangement of enol sulfonates;15 (vi) acylation of alkyl
sulfones;16 and (vii) reaction of sulfonyl chlorides with
arylacetylenes catalyzed by sulfonic acid. 17
Following our published protocol,18a polystyrene-support-
ed benzeneselenosulfonate or tolueneselenosulfonate (3)
were prepared with a loading of 1.33 mmol/g (S), as deter-
mined by elemental analysis. Resin 3, acetylenes and cat-
PhSeSO2Ar
PhSe
R
H
R
H
AIBN, PhH
SO2Ar
a: Ar = Tol
b: Ar = Ph
1
TFA
O
SO2Ar
R
2
Scheme 1 Solution-phase synthesis of b-keto sulphones (for R, see
Table 1)
Table 1 Hydrolysis of b-(Phenylseleno)vinyl Sulfones Catalyzed
by Trifluoroacetic Acid
Our research group has been interested in the application
of organoselenium reagents in organic synthesis for many
years.18 Herein we would like to report a simple method
for preparation of b-ketosulfones by polystyrene-support-
ed benzeneselenosulfonate and tolueneselenosulfonate.
Products
2a
R
Ar
Yield (%)a
Ph
p-MeC6H4
Ph
85
84
75
71
83
80
85
83
2b
Ph
2c
n-C4H9
n-C4H9
p-MeC6H4
p-MeC6H4
p-BrC6H4
p-BrC6H4
p-MeC6H4
Ph
With the continuing evolution of solid-phase organic syn-
thesis (SPOS) comes a growing appreciation for the im-
portance of linker technology, which ideally must
accommodate a wide variety of synthetic transformations
and yet allow for ready product cleavage in the final solid-
phase transformation. b-(Phenylseleno)vinyl sulfones (1)
appear to be ideally suited for SPOS linker application
2d
2e
p-MeC6H4
Ph
2f
2g
p-MeC6H4
Ph
2h
SYNTHESIS 2006, No. 12, pp 1934–1936
Advanced online publication: 11.05.2006
DOI: 10.1055/s-2006-942382; Art ID: F01606SS
x
x.
x
x
.
2
0
0
6
a Based on pure isolated compounds. The products were identified by
mp and 1H NMR, MS and IR spectra.
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Solid-Phase Synthesis of b-Keto Sulfones
1935
a Bruker Avance 400 with TMS as internal standard. Mass spectra
were recorded by EI on HP5989B. Infrared spectra were recorded
using a Bruker Tensor-27 spectrometer. (E)-1-Phenyl-1-(phenyl-
seleno)-2-(p-toluenesulfonyl)ethene (1a) was prepared according to
the literature.19
alytic AIBN were combined and refluxed for 20 h in
benzene (Scheme 2). The reaction mixture was filtered
and washed, and the resultant resin 4 could be converted
to the corresponding b-keto sulfones 2 by trifluoroacetic
acid catalyzed hydrolysis, in good yield. Almost pure ke-
tones 2 were obtained upon direct filtration of the polymer
(Table 2). Resin (5) could be regenerated.18d
Solution-Phase Synthesis of b-Keto Sulfones (2); Typical Proce-
dure
A solution of 1a (83 mg, 0.2 mmol) in THF (5mL) and TFA (2 mL)
was heated at 50 °C for 5 h. The mixture was cooled, diluted with
CH3Cl (20 mL) and H2O (10 mL). The organic layer was washed
with NaHCO3 (10%, 20 mL), H2O (20 mL), dried over MgSO4 and
concentrated in vacuo. Preparative TLC gave 2a (46 mg, 85%).
3
SeSO2Ar
Se
R
H
R
H
AIBN, PhH
SO2Ar
a: Ar = Tol
b: Ar = Ph
4
Solid-Phase Synthesis b-Keto Sulfones (2); Typical Procedure
To a suspension of the swelled resin 3b (0.5 g) in dry benzene (8
mL), under a nitrogen atmosphere, was added phenylacetylene (3
mmol, 306 mg) and AIBN (0.15 mmol, 24mg). The mixture was re-
fluxed for 20 h then the resin 4b was collected by filtration and
washed with benzene (2 × 10 mL), MeOH (2 × 10 mL), THF
(2 × 10 mL) and CH2Cl2 (2 × 10 mL). The washed resin 4b was sus-
pended in TFA (2 mL) and the mixture was stirred at 50–60 °C for
10 h. The reaction was quenched with H2O (20 mL), and the mixture
was filtered to remove the resin 5, which was washed with CHCl3
(3 × 15 mL). The organic layer was washed with NaHCO3 (10%, 20
mL), H2O (20 mL), dried over MgSO4 and evaporated to dryness in
vacuum to afford of the almost pure 2-benzenesulfonyl-1-phenyl-
ethanone 2b (104 mg, 60%).
TFA
O
SO2Ar
+
Se
R
2
2
5
Scheme 2 Solid-phase synthesis of b-keto sulfones (For R, see
Table 2)
Table 2 Solid-Phase Synthesis of b-Keto Sulfones
1-Phenyl-2-(toluene-4-sulfonyl)ethanone (2a)
Products
5a
R
Ar
Yield (%)a
Yield: 64%; white solid; mp105–106 °C (Lit.19 105–107 °C).
Ph
p-MeC6H4
Ph
64
60
55
51
69
68
73
69
IR (KBr): 3060, 2999, 2924, 1679, 1596, 1448,1320, 1309, 1272,
1211, 1152, 1086, 995, 824, 749, 590, 536, 502 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3 H), 4.72 (s, 2 H), 7.34
(d, J = 7.93 Hz, 2 H), 7.48 (t, J = 7.37 Hz, 2 H), 7.62 (t, J = 7.48 Hz,
1 H), 7.76 (d, J = 8.28 Hz, 2 H), 7.95 (d, J = 7.25 Hz, 2 H).
MS (EI, 70 eV): m/z = 274 [M]+, 210, 155, 139, 108, 105, 91, 77,
65.
5b
Ph
5c
n-C4H9
n-C4H9
p-MeC6H4
p-MeC6H4
p-BrC6H4
p-BrC6H4
p-MeC6H4
Ph
5d
5e
p-MeC6H4
Ph
5f
2-Benzenesulfonyl-1-phenylethanone (2b)
Yield: 60%; white solid; mp 92–93 °C (Lit.19 93–94 °C).
5g
p-MeC6H4
Ph
IR (KBr): 3063, 2998, 2958, 2941, 1676, 1597, 1582, 1448, 1308,
1275, 1228, 1155, 1084, 1006, 750, 686, 537 cm–1.
5h
1H NMR (400 MHz, CDCl3): d = 4.74 (s, 2 H), 7.48 (t, J = 7.53 Hz,
2 H), 7.55 (t, J = 8.01 Hz, 2 H), 7.61–7.67 (m, 2 H), 7.89–7.95 (m,
4 H).
a Yields of products based on the loading of the resin. Products were
identified by mp and 1H NMR, MS, IR spectra.
MS (EI, 70 eV): m/z = 260 [M]+, 196, 152, 141, 119, 105, 91, 77,
65, 51.
We also investigated the influence of different reaction
conditions on the hydrolysis (HClO4–THF, TFA–THF,
TFA–CHCl3 and neat TFA). However, only when resin 4
was treated with neat TFA at 50–60 °C for 10 h, followed
by filtration and washing, did the reaction afford the b-
keto sulfone 2 as almost pure product.
1-(Toluene-4-sulfonyl)hexan-2-one (2c)
Yield: 55%; white solid; mp 54–55 °C (Lit.20 56–56.5 °C).
IR (KBr): 3040, 2959, 2931, 2873, 1719, 1597, 1458, 1402, 1322,
1153, 1087, 1044, 815, 566, 515 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.33 Hz, 3 H), 1.26–
1.35 (m, 2 H), 1.51–1.58 (m, 2 H), 2.46 (s, 3 H), 2.70 (t, J = 7.25 Hz,
2 H), 4.12 (s, 2 H), 7.36 (d, J = 7.97 Hz, 2 H), 7.75 (d, J = 8.29 Hz,
2 H).
In conclusion, we have developed a novel method for the
preparation of b-keto sulfones using polystyrene-support-
ed benzeneselenosulfonate and tolueneselenosulfonate. A
distinct advantage of the polymer reagents is the conve-
nience of handling and odorless nature of the procedure as
compared to the non-polymer-supported reagents.
MS (EI, 70 eV): m/z = 255 (100%) [M + 1]+, 239, 212, 189, 155,
148, 139, 130, 105, 98, 91, 85, 65, 57.
1-Benzenesulfonylhexan-2-one (2d)
yield: 51%; oil.
Melting points were recorded on a Kofler melting point apparatus
and are uncorrected. 1H NMR (400 MHz) spectra were recorded on
IR (neat): 3063, 2958, 2928, 2872, 1720, 1585, 1448, 1379, 1322,
1154, 1085, 1044, 743, 688, 529 cm–1.
Synthesis 2006, No. 12, 1934–1936 © Thieme Stuttgart · New York

1936
H. Qian, X. Huang
SHORT PAPER
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.37 Hz, 3 H), 1.25–
1.33 (m, 2 H), 1.53–1.58 (m, 2 H), 2.70 (t, J = 7.21 Hz, 2 H), 4.14
(s, 2 H), 7.58 (m, 2 H), 7.68 (m, 1 H), 7.89 (m, 2 H).
MS (EI, 70 eV): m/z = 241 [M + 1]+, 198, 141, 134, 125, 116, 98,
85, 77, 57, 43.
(2) (a) Lythgoe, B.; Waterhouse, I. Tetrahedron Lett. 1978, 19,
2625. (b) Bartlett, P. A.; Green, F. R. III; Rose, E. H. J. Am.
Chem. Soc. 1978, 100, 4852. (c) Mandai, T.; Yanagi, T.;
Araki, K.; Morisaki, Y.; Kawada, M.; Otera, J. J. Am. Chem.
Soc. 1984, 106, 3670.
(3) Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.;
Fukumoto, K. Tetrahedron 1995, 51, 9873.
2-(Toluene-4-sulfonyl)-1-p-tolylethanone (2e)
(4) Baldwin, J. E.; Adlington, R. M.; Crouch, N. P.; Hill, R. L.;
Laffey, T. G. Tetrahedron Lett. 1995, 36, 7925.
(5) Sengupta, S.; Sarma, D. S.; Mondal, S. Tetrahedron:
Asymmetry 1998, 9, 2311.
(6) (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.
Yield: 69%; white solid; mp 114–116 °C (Lit.20 116–117 °C).
IR (KBr): 3062, 3001, 2947, 2905, 1674, 1606, 1330, 1314, 1289,
1182, 1173, 1148, 1138, 1086, 810, 775, 735, 702, 557, 514 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H), 2.44 (s, 3 H), 4.68
(s, 2 H), 7.28 (d, J = 8.01 Hz, 2 H), 7.33 (d, J = 8.01 Hz, 2 H), 7.75
(d, J = 8.32 Hz, 2 H), 7.84 (d, J = 8.32 Hz, 2 H).
(7) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964,
86, 1639. (b) Trost, B. M.; Arndt, H. C.; Strege, P. E.;
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3846. (d) Fuju, M.; Nakamura, K.; Mekata, H.; Oka, S.;
Ohno, A. Bull. Chem. Soc. Jpn. 1988, 61, 495.
MS (EI, 70 eV): m/z = 289 [M + 1]+, 288 [M]+, 224, 155, 139, 119,
108.
2-Benzenesulfonyl-1-p-tolylethanone (2f)
Yield: 68%; white solid; mp 122–124 °C (Lit.20 122–124 °C).
IR (KBr): 3061, 2991, 2937, 1668, 1604, 1571, 1448, 1413, 1321,
1307, 1281, 1162, 1085, 1067, 791, 754, 733, 686, 527 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H), 4.71 (s, 2 H), 7.27
(d, J = 8.01 Hz, 2 H), 7.54 (t, J = 8.05 Hz, 2 H), 7.66 (t, J = 7.49 Hz,
1 H), 7.84 (d, J = 8.29 Hz, 2 H), 7.89 (d, J = 7.25 Hz, 2 H).
MS (EI, 70 eV): m/z = 275 [M + 1]+, 274, 210, 165, 141, 119, 105,
91, 77, 65, 51.
(e) Sengupta, S.; Sarma, D. S.; Mondal, S. Tetrahedron
1998, 54, 9791. (f) Guo, H.; Zhang, Y. Synth. Commun.
2000, 30, 2564.
(8) (a) Svatos, A.; Hunkova, Z.; Kren, V.; Hoskovec, M.;
Saman, D.; Valterova, I.; Vrkoc, J.; Koutek, B. Tetrahedron:
Asymmetry 1996, 7, 1285. (b) Bertus, P.; Phansavath, 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.
(9) Wolf, W. M. J. Mol. Struct. 1999, 474, 113.
(10) (a) Vennstra, G. E.; Zwaneburg, B. Synthesis 1975, 519.
(b) Wildeman, J.; van Leusen, A. M. Synthesis 1979, 733.
(11) Xie, Y.-Y.; Chen, Z.-C. Synth. Commun. 2001, 31, 3145.
(12) (a) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22,
1287. (b) Fan, A.-L.; Cao, S.; Zhang, Z. J. Heterocycl.
Chem. 1997, 34, 1657.
1-(4-Bromophenyl)-2-(toluene-4-sulfonyl)ethanone (2g)
Yield: 73%; white solid; mp144–146 °C.
IR (KBr): 3056, 3003, 2947, 2922, 2857, 1679, 1584, 1567, 1419,
1395, 1314, 1291, 1276, 1148, 1083, 1069, 1001, 849, 780, 751,
720, 695, 540 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3 H), 4.67 (s, 2 H), 7.34
(d, J = 8.09 Hz, 2 H), 7.63 (d, J = 8.61 Hz, 2 H), 7.74 (d, J = 8.29
Hz, 2 H), 7.82 (d, J = 8.61 Hz, 2 H).
(13) Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992,
33, 1131.
(14) Kamigata, N.; Udodaira, K.; Shimizu, T. J. Chem. Soc.,
Perkin Trans. 1 1997, 783.
MS (EI, 70 eV): m/z = 354 [M, 81Br]+, 352 [M, 79Br]+, 290, 288,
185, 183, 157, 155, 139, 108, 91, 77, 65.
2-Benzenesulfonyl-1-(4-bromophenyl)ethanone (2h)
Yield: 69%; white solid; mp134–136 °C.
(15) Nagata, W.; Wakabayashi, T.; Hayase, Y.; Narisada, M.;
Kamata, S. J. Am. Chem. Soc. 1970, 92, 3203.
IR (KBr): 3060, 2950, 2908, 1691, 1583, 1448, 1328, 1299, 1206,
1169, 1140, 1084, 1070, 986, 812, 748, 686, 555, 526 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.69 (s, 2 H), 7.56 (t, J = 7.81 Hz,
2 H), 7.62–7.71 (m, 3 H), 7.82 (d, J = 8.61 Hz, 2 H), 7.88 (d, J =
7.45 Hz, 2 H).
MS (EI, 70 eV): m/z = 341 [M + 1,81Br]+, 340 [M, 79Br]+, 339 [M +
1, 79Br]+, 338 [M, 79Br]+, 276, 274, 185, 183, 171, 169, 157, 155,
141, 125, 94, 90, 89, 77, 63, 51.
(16) (a) Truce, W. E.; Knospe, R. H. J. Am. Chem. Soc. 1955, 77,
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Org. Chem. 1962, 27, 2821. (d) Thomsen, M. W.;
Handwerker, B. M.; Katz, S. A.; Belser, R. B. J. Org. Chem.
1988, 53, 906. (e) Ibarra, C. A.; Rodriguez, R. C.; Monreal,
M. C.; Navarro, F. J.; Tesorero, J. M. J. Org. Chem. 1989,
54, 5620. (f) Katritzky, A. R.; Abdel-Fattah, A. A.; Wang,
M. Y. J. Org. Chem. 2003, 68, 1443.
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Acknowledgment
(18) (a) Qian, H.; Huang, X. Synlett 2001, 1913. (b) Qian, H.;
Huang, X. Tetrahedron Lett. 2002, 43, 1059. (c) Qian, H.;
Huang, X. J. Comb. Chem. 2003, 5, 569. (d) Huang, X.;
Sheng, S. R. Tetrahedron Lett. 2001, 42, 9035.
(19) Back et al. reported that b-(phenylseleno)vinyl sulfones
were converted to the unprotected b-keto sulfones in
moderate yields by perchloric acid catalyzed hydrolysis (two
examples), see: Back, T. G.; Collins, S.; Kerr, R. G. J. Org.
Chem. 1983, 48, 3077.
We are grateful to the National Natural Science Foundation of Chi-
na (Project No. 29932020) and the Science Foundation of Hang-
zhou Normal College (No. 131901 and No. 131001) for financial
support.
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Synthesis 2006, No. 12, 1934–1936 © Thieme Stuttgart · New York