Synthesis of 2-arylcycloalka-2,4-dienones using sulfone-based methodology

Article abstract of DOI:10.1021/jo0523262

Addition of the anion derived from (phenylthiomethyl)phenyl sulfone to a selection of aryl ω-alkenyl ketones gives adducts that via a sequence of Lewis acid catalyzed rearrangement, α-allylation, and metathesis give rise to 2-thio-4-cycloalkenones. These in turn give cycloalkadienones upon oxidation and elimination. An attempt to develop a polymer-supported variant fails because of the reversibility of sulfone anion addition.

Full text of DOI:10.1021/jo0523262

SCHEME 1. Solution-Phase Synthesis of
2-Arylcycloalka-2,4-dienones 6a
Synthesis of 2-Arylcycloalka-2,4-dienones Using
Sulfone-Based Methodology
Saphon Hok and Neil E. Schore*
Department of Chemistry, UniVersity of California,
DaVis, California 95616
neschore@ucdaVis.edu
ReceiVed NoVember 9, 2005
a Reagents and conditions: (a) PhSO2CH(Li)SPh, Et2AlCl, THF, -78
°C, 4 h; (b) Et2AlCl, CH2Cl2, hexane, various conditions; (c) LiOEt, EtOH,
THF, 0 °C, 20 min, then CH2dCHCH2Br, 75 °C, 1 h; (d) (CyP)2-
Cl2RudCHPh, CH2Cl2, 70 °C, 48 h; (e) m-CPBA, CH2Cl2, -78 °C, 15
min, then CCl4 60 °C, 18 h.
Addition of the anion derived from (phenylthiomethyl)phenyl
sulfone to a selection of aryl ω-alkenyl ketones gives adducts
that via a sequence of Lewis acid catalyzed rearrangement,
R-allylation, and metathesis give rise to 2-thio-4-cycloalk-
enones. These in turn give cycloalkadienones upon oxidation
and elimination. An attempt to develop a polymer-supported
variant fails because of the reversibility of sulfone anion
addition.
TABLE 1. Yields (%) of Intermediates and Final Productsa
We have an ongoing interest in the adaptation of diverse
synthetic methodologies to the solid state, including but not
limited to rearrangement and cycloaddition chemistry, and with
an emphasis on organometallic methodologies. Herein, we report
the preparation of a small library of 2-arylcycloalka-2,4-dienone
derivatives, using substrates derived from (phenylthiomethyl)-
phenyl sulfone, which provides the potential for both convenient
polymer linkage as well as Lewis acid promoted rearrangement
chemistry (Scheme 1).
To obtain the necessary aryl ω-alkenyl ketones (1a-g), a
selection of 3-aryl-3-ketoesters was prepared in g95% yields
by Claisen condensations between diethyl carbonate and several
substituted acetophenones.1 Alkylation2 and decarboxylation3
gave ketones 1a-g (Table 1).
We prepared (bromomethyl)phenyl sulfone from dibro-
momethane and sodium benzenesulfinate in refluxing DMF4 and
converted the sulfone into [(phenylthio)methyl]phenyl sulfone
by treatment with sodium thiophenoxide in DMF.5 Addition of
a Yields in parentheses are based upon recovered starting material
(oxidized in the cases of 6c and 6e).
(1) (a) Nakano, J.; Katagiri, N.; Kato, T. Chem. Pharm. Bull. 1982, 30,
2590. (b) Iinuma, M.; Tanaka, T.; Hamada, K.; Mizuno, M.; Asai, F. Chem.
Pharm. Bull. 1987, 35, 3909.
(2) (a) Queignec, R.; Kirschleger, B.; Lambert, F.; Aboutaj, M. Synth.
Commun. 1988, 18, 1213. (b) Wang, E. S.; Choy, Y. M.; Wong, H. N. C.
Tetrahedron 1996, 52, 12137. (c) Saint-Dizier, A. C.; Kilburn, J. D.
Tetrahedron Lett. 2002, 43, 6201.
(3) (a) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 12, 957.
(b) Liotta, C. L.; Cook, F. L. Tetrahedron Lett. 1974, 15, 1095. (c) Krapcho,
A. P.; Jahngen, E. G. E., Jr.; Lovey, A. J.; Short, F. W. Tetrahedron Lett.
1974, 15, 1091. (d) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.;
Jahngen, E. G. E., Jr.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978,
43, 138. (e) Krapcho, A. P. Synthesis 1982, 10, 805, 893.
(4) (a) Makosza, M.; Golinski, J. J. Org. Chem. 1984, 49, 1488. (b)
Bordwell, F. G.; Clemens, A. H.; Smith, D. E.; Begemann, J. J. Org. Chem.
1985, 50, 1151.
the anion of [(phenylthio)methyl]phenyl sulfone anion to each
of the ketones 1a-g under Et2AlCl catalysis gave the corre-
sponding 1-(benzenesulfonyl)-2-aryl-1-(phenylthio)alken-2-ols
2a-g.6
Each of these alcohols consisted, by 1H NMR analysis, of a
mixture of diastereomers, one of which in each case was a solid
that was purified by recrystallization, while the other was either
(5) (a) Bordwell, F. G.; Jarvis, B. B. J. Org. Chem. 1968, 33, 1182. (b)
Langler, R. F.; Pincock, J. A. Can. J. Chem. 1977, 55, 2316. (c) Kay, D.
G.; Langler, R. F.; Trenholm, J. E. Can. J. Chem. 1979, 57, 2185. (d) Durkin,
K. A.; Langler, R. F.; Morrison, N. A. Can. J. Chem. 1988, 66, 3070.
10.1021/jo0523262 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/13/2006
1736
J. Org. Chem. 2006, 71, 1736-1738

a solid or an oil that was isolated chromatographically. In the
course of purifying 2a we realized that these compounds slowly
underwent retro-aldol-like reversion to the starting materials.
Thus, complete separation and purification of each of the two
diastereomers was not achieved in any of the cases. Nonetheless,
good to excellent combined yields of diastereomers were
obtained, especially in the cases of compounds 2c-g, whose
syntheses benefited from our prior experiences optimizing the
procedure.
Treatment of the each of the isolated 1-(benzenesulfonyl)-
2-aryl-1-(phenylthio)alken-2-ols 2a-g with Et2AlCl induced
rearrangement to the corresponding 1-aryl-1-(phenylthio)alken-
2-ones (3a-g)6,7 in variable yields. We found that each case,
although based upon Trost’s general procedure, had to be
individually optimized. The ketones 3a-g were then regiose-
lectively alkylated8 with allyl bromide to give 4-aryl-4-(phe-
nylthio)alkadien-5-ones 4a-g in good to excellent yields.
Finally, each of the alkylated ketones 4a-g was treated with
Grubbs’ I catalyst for ring closing metathesis9 to give the
corresponding 2-aryl-2-(phenylthio)cycloalk-4-enone (5a-g). In
a typical procedure, 10 mol % of catalyst solution was added
to a 2-3 µM solution of ketone in CH2Cl2. After stirring at 50
°C for 24 h, another 10 mol % of catalyst solution was added
and the cyclization allowed to proceed for another 24 h.
Generation of the seven- and eight-membered ring enones (5a-
f) proceeded satisfactorily. However, the synthesis of the nine-
membered 2-phenyl-2-(phenylthio)cyclonon-4-enone (5g) gave
only trace amounts under the same conditions. Using higher
concentrations of substrate, higher molar ratios of catalyst,
higher refluxing temperatures, and even microwave radiation
failed to improve this result.
at δ 6.4-6.5 (H4, ddt). NMR indicated that some of these
dienones (6b and 6d in particular) contained the deconjugated
2-arylcyclohepta-2,5-dienones, but in quantities too small to be
isolated or purified.11
These solution-phase syntheses demonstrated gratifying ver-
satility and diversity. We therefore attempted their adaptation
to the solid phase. Following Fre´chet’s protocol,12 we derivatized
polystyrene/2% divinylbenzene beads with arylthiol functionality
at a loading of 1.65 mmol/g.13 Deprotonation to the arylthiolate
and addition of (bromomethyl)phenyl sulfone gave the solid-
supported [(arylthio)methyl]phenyl sulfone resin 8 (IR 1326 and
1151 cm-1).14,15 Unfortunately, deprotonation of this resin-bound
sulfone followed by addition of excess aryl alkenyl ketone fails
to produce polymer-bound alcohol 9, no doubt a consequence
of the reversibility of the latter process.
In conclusion, the use of [(phenylthio)methyl]phenyl sulfone
has shown versatility in short solution-phase syntheses of several
seven- and eight-membered 2-arylcycloalka-2,4-dienones. Ad-
aptation to the solid phase was not successful.
Oxidation of cycloalkenones 5a-f with m-CPBA in dichlo-
romethane at -78 °C gave the corresponding sulfoxides,10 which
were dehydrosulfenylated by reflux in CCl4 overnight to give
the final products, 2-arylcycloalka-2,4-dienones (6a-f), in good
to excellent yields. The fully conjugated cycloalka-2,4-dienones
6a-f display three 1H NMR signals with an integration of one
proton each at ca. δ 6.6-6.7 (H2, d), at δ 6.1-6.2 (H3, dt), and
Experimental Section
Representative Procedure:6 1-(Benzenesulfonyl)-2-(4-meth-
oxyphenyl)-1-(phenylsulfanyl)hex-5-en-2-ol (2e). A hexane solu-
tion of n-BuLi (2.5 M, 24.0 mL, 60.0 mmol) was added dropwise
to a solution of [(phenylsulfanyl)methyl]phenyl sulfone (14.2 g,
53.6 mmol) in THF (400 mL) at -78 °C. The mixture turned
yellowish in color and was stirred for 30 min, whereupon a hexane
solution of diethylaluminum chloride solution in hexane (1.0 M,
80.0 mL, 80.0 mmol) was added by syringe. After 5 min, a solution
of 10.2 g of 1-(4-methoxyphenyl)pent-4-en-1-one16 (1e) (53.6
mmol) in THF (50 mL) was added dropwise. After being stirred
overnight at -78 °C, the reaction was quenched with 150 mL of
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Tanaka, K.; Matsui, S.; Kaji, A. Bull. Chem. Soc. Jpn. 1980, 53, 3619. (c)
Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1984, 106, 7260. (d) Trost,
B. M.; Mikhail, G. K. J. Am. Chem. Soc. 1987, 109, 4124. (e) Nantz, M.
H.; Radisson, X.; Fuchs, P. L. Synth. Commun. 1987, 17, 55. (f) Trost, B.
M. Bull. Chem. Soc. Jpn. 1988, 61, 107. (g) Hewkin, C. T.; Jackson, R. F.
W.; Clegg, W. Tetrahedron Lett. 1988, 29, 4889. (h) Bruckner, R.; Peiseler,
B. Tetrahedron Lett. 1988, 29, 5233. (i) Azadi-Ardakani, M.; Loftus, C.
G.; Mjalli, A. M. M.; Newton, R. F.; Roberts, S. M. J. Chem. Soc., Chem.
Commun. 1989, 1709. (j) Hewkin, C. T.; Jackson, R. F. W.; Clegg, W. J.
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N.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1994, 2289. (l) Finch,
H.; Mjalli, A. M. M.; Montana, J. G.; Roberts, S. M.; Taylor, R. J. K.
Tetrahedron 1996, 40, 4925. (m) Toyooka, N.; Okumura, M.; Takahata,
H. J. Org. Chem. 1999, 64, 2182.
(10) (a) Nozoe, T.; Mukai, T.; Tezuka, T. Bull. Chem. Soc. Jpn. 1961,
34, 619. (b) Trost, B. M.; Salzmann, T. N. J. Am. Chem. Soc. 1973, 95,
6840. (c) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976,
98, 4887. (d) Trost, B. M. Chem. ReV. 1978, 78, 363. (e) Tamura, Y.; Maeda,
H.; Choi, H. D.; Ishibashi, H. Synthesis 1982, 56. (f) Katritzky, A. R.;
Saczewski, F.; Marson, C. M. J. Org. Chem. 1985, 50, 1351. (g) Brown,
R. F. C.; Coulston, K. J.; Eastwood, F. W.; Fallon, G. D. Aust. J. Chem.
1986, 39, 189. (h) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim,
S.; Kessabi, J. Org. Lett. 1999, 1, 807.
(11) Lew, C. S. Q.; Capon, B. J. Org. Chem. 1997, 62, 5344.
(12) (a) Farral, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41, 3877.
(b) De Smet, M. D.; Frechet, J. M. J.; Farral, M. J. Polymer 1979, 20, 675.
(c) Frechet, J. M. J. Tetrahedron 1981, 37, 663. (d) Frechet, J. M. J.; Darling,
G. D.; Itsuno, S.; Lu, P.-Z.; Vivas de Meftahi, M.; Rolls, W. A., Jr. Pure.
Appl. Chem. 1988, 60, 353.
(13) Brown, H. C. Organic Synthesis Via Boranes; John Wiley and
Sons: New York, 1975; p 258.
(14) De Smet, M. D.; Frechet, J. M. J.; Farral, M. J. J. Org. Chem. 1979,
44, 1774.
(15) Cheng, W.-C.; Lin, C.-C.; Kurth, M. J. Tetrahedron Lett. 2002, 43,
2967.
(16) (a) Marvell, E. N.; Li, T. H.-C. J. Am. Chem. Soc. 1978, 100, 883.
(b) Kozikowski, A. P.; Ames, A. Tetrahedron 1985, 41, 4821.
(7) Phillipson, N.; Anson, M. S.; Montana, J. G.; Taylor, R. J. K. J.
Chem. Soc., Perkin Trans. 1 1997, 2821.
(8) (a) Ozaki, Y.; Mochida, K.; Kim, S.-W. J. Chem. Soc., Perkin Trans
I 1989, 1219. (b) Imanishi, T.; Hirokawa, Y.; Yamashita, M.; Tanaka, T.;
Miyashita, K.; Iwata, C. Chem. Pharm. Bull. 1993, 41, 31. (c) Kunz, U.;
Krimm, S.; Fischer, T.; Kottke, T.; Stalke, D.; Christl, M. Eur. J. Org.
Chem. 1998, 2171. (d) Edwards, G. L.; Sinclair, D. J. Tetrahedron Lett.
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(9) (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc.
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J. Org. Chem, Vol. 71, No. 4, 2006 1737

10% aq HCl solution at -78 °C and was allowed to warm to rt.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were washed
with water and brine, dried (MgSO4), and concentrated. Trituration
using 10% CH2Cl2 in hexane gave 14.5 g of 2e as a white solid.
The supernatant was concentrated and chromatographed using 20%
EtOAc in hexane solution to afford another 2.5 g of 2e, 2.5 g of
recovered 1e, and 3.47 g of [(phenylsulfanyl)methyl]phenyl sulfone.
The total isolated yield of 2e was 17.0 g (70%); the yield based on
unrecovered starting material was 92%. For the major diastere-
128.9, 128.9, 118.4, 115.4, 114.1, 68.8, 55.5, 38.8, 37.6, 29.1. Anal.
Calcd for C22H24O2S: C, 74.96; H, 6.86. Found: C, 75.13; H, 6.87.
Representative Procedure:9 Synthesis of 2-(4-Methoxyphe-
nyl)-2-(phenylsulfanyl)cyclohept-4-enone (5e). To a solution of
Grubbs’ catalyst (35 mg, 0.04 mmol) in CH2Cl2 (140.0 mL) was
added a solution of 150 mg (0.42 mmol) of 4e in of CH2Cl2 (10
mL). The resulting red solution was refluxed at 60-70 °C for 24
h. Another 0.1 equivt of Grubbs’ catalyst (35 mg, 0.04 mmol)
dissolved in CH2Cl2 (10 mL) was added and reflux continued for
another 24 h. After concentration, the resulting brown oil was
purified by column chromatography, eluting with 10% Et2O in
hexane to furnish 94 mg (69% isolated yield; 77% based on the
recovery of 15 mg of 4e) as a white solid: mp 127.1-129.0 °C; IR
2958, 2836, 1707, 1603 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.29-
6.77 (m, 9H), 5.69 (m, 2H), 3.80 (s, 3H), 2.95 (m, 1H), 2.83-2.73
(m, 3H), 2.28 (m, 2H); 13C NMR (CDCl3) δ 207.3, 159.0, 136.9,
131.8, 131.0, 130.8, 129.6, 129.1, 128.6, 126.3, 113.6, 71.6, 55.4,
38.5, 33.6, 26.9. Anal. Calcd for C20H20O2S: C, 74.04; H, 6.21.
Found: C, 74.29; H, 6.21.
omer: mp 163-165 °C; IR 3505, 3065, 2954, 2833, 1640 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.67-6.58 (m, 14H), 5.80 (m, 1H),
5.00-4.86 (m, 2H), 4.53 (s, 1H), 4.47 (s, 1H), 3.81 (s, 3H), 2.50
(m, 2H), 2.10 (m, 1H), 1.65 (m, 1H); MS IonSpec HiResMALDI
calcd m/z for C24H26O4S2Na ((M + Na)+) 477.1170, found
477.1524. Anal. Calcd for C25H26O4S2: C, 66.05; H, 5.76. Found:
C, 66.31; H, 5.83.
Representative Procedure:6 1-(4-Methoxyphenyl)-1-(phenyl-
sulfanyl)hex-5-en-2-one (3e). At -78 °C, 11.0 mL of a 1.0 M
solution of diethylaluminum chloride in hexane (11.0 mmol) was
added to a solution of 5.0 g of 2e (11.0 mmol) in dichloromethane
(100 mL). After 5 min, TLC showed complete consumption of
starting material, and the reaction was quenched with 50 mL of aq
satd NaHCO3. The mixture was filtered through Celite, washed with
brine, dried (MgSO4) and concentrated. Chromatography (10%
EtOAc in hexane) gave 2.81 g (81%) of 3e: IR 3070, 2904, 2837,
Representative Procedure:10 Synthesis of 2-(4-Methoxyphe-
nyl)cyclohepta-2,4-dienone (6e). A solution of 130 mg (0.40
mmol) of 5e in CH2Cl2 (80 mL) was cooled to -78 °C, and a
solution of 0.96 g of 71% m-chloroperoxybenzoic acid (4.0 mmol)
in CH2Cl2 (10 mL) was added. TLC analysis (70:30 Et2O-hexane)
showed complete loss of the starting material after 15 min. The
cold reaction mixture was poured into a separatory funnel containing
Et2O (100 mL) and 100 mL of 10% aq Na2SO3 solution. The
organic layer was separated, washed 2x with satd aq NaHCO3, dried
(MgSO4), and concentrated. The residue was added to CCl4 (20
mL) and refluxed at 50-60 °C overnight to give 57 mg of 6e (67%
isolated yield; 96% based on the recovery of 46 mg of oxidized
5e) as a faintly light green oil: IR 3003, 2958, 2837, 1658, 1604
1
1716, 1644 cm-1; H NMR (300 MHz, CDCl3) δ 7.31-6.83 (m,
9H), 5.67 (m, 1H), 4.95 (s, 1H), 4.94-4.88 (m, 2H), 3.78 (s, 3H),
2.66 (m, 2H), 2.24 (m, 2H); 13C NMR (CDCl3) δ 204.7, 159.7,
136.9, 134.1, 132.6, 130.0, 129.1, 127.9, 127.6, 115.5, 114.5, 63.4,
55.5, 39.4, 28.0. Anal. Calcd for C19H20O2S: C, 73.04; H, 6.45.
Found: C, 72.78; H, 6.37.
Representative Procedure:8 4-(4-Methoxyphenyl)-4-(phenyl-
sulfanyl)nona-1,8-dien-5-one (4e). To a mixture of EtOH (6.0 mL)
and THF (15.0 mL) cooled to 0 °C was added 4.8 mL of 2.5 M
n-BuLi in hexane (12.0 mmol). The LiOEt solution was stirred at
0 °C for 20 min, whereupon a solution of 0.66 g (2.11 mmol) of
3e in THF (30 mL) was added dropwise. After stirring and warming
to rt over 10 min, 2.90 mL (34.3 mmol) of allyl bromide was added
dropwise and the mixture heated at 75-80 °C for 3 h. The reaction
was quenched with water and extracted with EtOAc. The extracts
were washed with brine, dried (MgSO4), and concentrated. Column
chromatography (1% Et2O in hexane) gave 0.653 g (88%) of 4-(4-
methoxyphenyl)-4-(phenylsulfanyl)nona-1,8-dien-5-one (4e) as a
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.27-7.24 (m, 2H), 6.89-
6.86 (m, 2H), 6.70-6.69 (d, J ) 7.6, 1H), 6.42-6.36 (dt, 1H, J )
10.8 Hz, 5.6 Hz), 6.16-6.11 (ddt, 1H, J ) 10.8 Hz, 7.6 Hz, 1.2
Hz), 3.81 (s, 3H), 2.87-2.84 (m, 2H), 2.50-2.45 (m, 2H); 13C
NMR (CDCl3) δ 201.5, 159.4, 142.1, 138.5, 134.7, 132.0, 130.1,
126.5, 113.7, 55.5, 42.5, 23.8; MS (ESI) m/z calcd for (M + H+)
215.11, found 215.08.
Acknowledgment. We thank the National Science Founda-
tion for financial support (Grant No. CHE-0313888).
Supporting Information Available: Spectroscopic and analyti-
cal data for all compounds; experimental procedures for all
compounds and for polymer-supported experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
colorless oil: IR 3075, 2974, 2906, 2837, 1669, 1639 cm-1; H
NMR (400 MHz, CDCl3) δ 7.32-6.84 (m, 9H), 5.84-5.65 (m,
2H), 5.04-4.88 (m, 4H), 3.80 (s, 3H), 2.74 (m, 1H), 2.68-2.66
(d, J ) 6.4 Hz, 2H), 2.40 (m, 1H), 2.31-2.25 (m, 2H); 13C NMR
(CDCl3) δ 206.0, 159.2, 137.5, 136.7, 133.6, 130.7, 130.6, 129.4,
JO0523262
1738 J. Org. Chem., Vol. 71, No. 4, 2006