3,5-Bis(trifluoromethyl)phenyl sulfones in the direct Julia-Kocienski olefination

Article abstract of DOI:10.1021/jo050852n

3,5-Bis(trifluoromethyl)phenyl (BTFP) sulfones 7 have been employed in the Julia-Kocienski olefination reaction with carbonyl compounds. Sulfones 7 are readily prepared in high yields (64-97%) from commercially available 3,5-bis(trifluoromethyl)thiophenol through an alkylation/oxidation two-step sequence. The stability of metalated BTFP sulfones has been studied and compared with heteroaryl benzothiazol-2-yl (BT), 1-phenyl-1H-tetrazol-5-yl (PT), and 1-tert-butyl-1H-tetrazol-5-yl (TBT) sulfones 9-11 under different reaction conditions. The Julia-Kocienski olefination between alkyl BTFP sulfones 7 and a wide variety of aldehydes affords the corresponding 1,2-disubstituted alkenes and dienes in good yields and stereoselectivities. This one-pot protocol can be performed using KOH at room temperature or the phosphazene bases P2-Et and P4-t-Bu at -78 °C or rt and has been successfully used in a high-yielding and stereoselective synthesis of various methoxylated stilbenes such as trimethylated resveratrol. These new reaction conditions for the Julia-Kocienski olefination reaction have been also studied with BT, PT, and TBT sulfones, giving poorer results. Methylenation of aliphatic and aromatic aldehydes, ketones, and 1,2-dicarbonyl compounds is carried out through the modified Julia olefination using BTFP methyl sulfone 7d to give terminal alkenes and dienes. Mechanistic studies of the olefination reaction between benzyl BTFP sulfone 7a and aromatic aldehydes performed by KOH-induced Smiles rearrangement of stereodefined syn- and anit-β-hydroxyalkyl BTFP sulfones indicate that the stereocontrol of the reaction is determined in the elimination step. 2005 American Chemical Society.

Full text of DOI:10.1021/jo050852n

3,5-Bis(trifluoromethyl)phenyl Sulfones in the Direct
Julia-Kocienski Olefination
Diego A. Alonso, Mo´nica Fuensanta, Carmen Na´jera,* and Montserrat Varea
Departamento de Quı´mica Orga´nica and Instituto de S´ıntesis Orga´nica (ISO), Facultad de Ciencias,
Universidad de Alicante, Apartado 99, E-03080 Alicante, Spain
cnajera@ua.es
Received April 27, 2005
3,5-Bis(trifluoromethyl)phenyl (BTFP) sulfones 7 have been employed in the Julia-Kocienski
olefination reaction with carbonyl compounds. Sulfones 7 are readily prepared in high yields (64-
97%) from commercially available 3,5-bis(trifluoromethyl)thiophenol through an alkylation/oxidation
two-step sequence. The stability of metalated BTFP sulfones has been studied and compared with
heteroaryl benzothiazol-2-yl (BT), 1-phenyl-1H-tetrazol-5-yl (PT), and 1-tert-butyl-1H-tetrazol-5-
yl (TBT) sulfones 9-11 under different reaction conditions. The Julia-Kocienski olefination between
alkyl BTFP sulfones 7 and a wide variety of aldehydes affords the corresponding 1,2-disubstituted
alkenes and dienes in good yields and stereoselectivities. This one-pot protocol can be performed
using KOH at room temperature or the phosphazene bases P2-Et and P4-t-Bu at -78 °C or rt and
has been successfully used in a high-yielding and stereoselective synthesis of various methoxylated
stilbenes such as trimethylated resveratrol. These new reaction conditions for the Julia-Kocienski
olefination reaction have been also studied with BT, PT, and TBT sulfones, giving poorer results.
Methylenation of aliphatic and aromatic aldehydes, ketones, and 1,2-dicarbonyl compounds is carried
out through the modified Julia olefination using BTFP methyl sulfone 7d to give terminal alkenes
and dienes. Mechanistic studies of the olefination reaction between benzyl BTFP sulfone 7a and
aromatic aldehydes performed by KOH-induced Smiles rearrangement of stereodefined syn- and
anti-â-hydroxyalkyl BTFP sulfones indicate that the stereocontrol of the reaction is determined in
the elimination step.
Introduction
son,4 Johnson,5 and classical Julia6 reactions. These
methodologies have played prominent roles in the syn-
thesis of natural products containing the E- or Z-alkene
moiety. The classical Julia olefination, also known as the
Julia-Lythgoe olefination, was developed nearly 30 years
ago and is based on a reductive elimination process of
â-acyloxy alkyl sulfones.7 Since its discovery, significant
improvements have been made in the reaction, and it has
become a crucial step in the synthesis of many natural
products.8 A new variant of the classical Julia reaction,
The stereoselective synthesis of alkenes has repre-
sented one of the long-standing challenges in organic
chemistry. During several decades, a variety of ap-
proaches to the synthesis of olefins have been developed
attempting to address their regio- and stereochem-
ical demands. The most generally applicable methods
involve the direct olefination of carbonyl compounds, as
in the Wittig,1 Horner,2 Wadsworth-Emmons,3 Peter-
(1) (a) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953, 580,
44-68. (b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-
927.
(2) (a) Horner, L.; Hoffmann, H.; Wipel, H. C.; Klahre, G. Chem.
Ber. 1959, 92, 2499-2505. (b) Clayden, J.; Warren, S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 241-270.
(3) (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733-1738. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974,
74, 87-89.
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Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31,
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(5) Johnson, C. R.; Shanklin, J. R.; Kirchhoff, R. A. J. Am. Chem.
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(6) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833-4836.
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Yus, M. Tetrahedron 1999, 55, 10547-10658.
10.1021/jo050852n CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/02/2005
6404
J. Org. Chem. 2005, 70, 6404-6416

BTFP Sulfones in Direct Julia-Kocienski Olefination
SCHEME 1
the Julia-Kocienski olefination, also called modified or
one-pot Julia olefination,9,10 has recently emerged as a
powerful tool for olefin synthesis. The process involves
the replacement of the aryl sulfone moiety, traditionally
used in the classical reaction, with different heteroaryl
sulfones, thus allowing the direct olefination process.
Since the initial exploration by Julia and co-workers of
the reaction of metalated benzothiazol-2-yl sulfones (BT
sulfones, 1) with carbonyl compounds,9a the versatility
of these derivatives has been fully demonstrated through
their application in the total synthesis of a large number
of biologically active natural products9c such as rapamy-
cin,11 (+)-herboxidiene A,12 (-)-13 and (+)-lasonolide A,14
rhizoxin D,15 phorboxazole A16 and B,17 peridin,18 (-)-
colombiasin A,19 and (-)-elisapterosin B.19 In addition,
other heterocyclic derivatives have also provided useful
levels of stereoselectivity in the one-pot Julia olefination,
such as pyridin-2-yl (PYR, 2),20 1-phenyl-1H-tetrazol-5-
yl (PT, 3),21 and 1-tert-butyl-1H-tetrazol-5-yl (TBT, 4),22
all of them developed with the aim of increasing the
stability of the corresponding metalated sulfones and
applied, especially in the case of the 1-phenyl-1H-tetrazol-
5-yl derivatives, to the stereoselective synthesis of the
alkene moiety in complex natural products.23 The Julia-
Kocienski reaction has also been used as a C-C coupling
methodology in numerous total syntheses after hydro-
genation of the newly formed double bond. The presence
of an electrophilic imine-like moiety in the heterocyclic
derivatives 1-4 is responsible for the different reactivity
and reaction pathway observed in the one-pot Julia
olefination, involving a Smiles rearrangement,24 and
spontaneous elimination of sulfur dioxide and the corre-
sponding hydroxy-substituted heterocycle (Scheme 1). As
depicted for PT derivatives in Scheme 1, the deprotona-
tion of these sulfones must be carried out with strong
anhydrous non-nucleophilic bases such as LDA or KH-
MDS. We have recently shown that the 3,5-bis(trifluo-
romethyl)phenylsulfonyl (BTFP sulfonyl), is a strong
electron-withdrawing group and an excellent nucleofuge
in base-promoted â-elimination processes. Thus, R-aryl-
sulfonyl acetates 5 are very soft nucleophiles that can
be easily dialkylated under very mild phase-transfer-
catalyzed (PTC) conditions, and its reaction with ethyl
bromoacetate allows the direct synthesis of (E)-aconitates
via an alkylation-elimination integrated process.25 On
the other hand, â-arylsulfonyl ethanol 6 is an efficient
protecting group for carboxylic acids, easily removed with
aqueous NaHCO3.26 As part of a program aimed at
developing useful applications of 3,5-bis(trifluoromethyl)-
phenyl sulfones in organic synthesis, we have very
recently communicated the successful use of alkyl BTFP
sulfones 7a-c in the Julia-Kocienski olefination reaction
under very simple reaction conditions.27 In this article,
we report the full account on the evaluation and optimi-
zation of the synthetic applications of alkyl BTFP sul-
fones 7 in the Julia-Kocienski reaction of carbonyl
compounds.
(8) Prilezhaeva, E. N. Russ. Chem. Rev. 2000, 69, 367-408.
(9) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175-1178. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.;
Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336-357. (c) Baudin,
J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr.
1993, 130, 856-878.
(10) For a recent review, see: Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563-2585.
(11) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Syn-
thesis 1996, 285-296.
(12) Kocienski, P. Synthesis 1996, 652-666.
(13) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo,
J. M. J. Am. Chem. Soc. 2004, 124, 384-385.
(14) (a) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.-W.; Jun, H.-
S.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed. 2003,
42, 4779-4782. (b) Kang, S. H.; Kang, S. Y.; Choi, H.-W.; Kim, C. M.;
Jun, H.-S.; Youn, J.-H. Synthesis 2004, 1102-1114.
(15) (a) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J.
W. Tetrahedron Lett. 1999, 40, 4145-4148. (b) Lafontaine, J. A.;
Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68,
4215-4234. (c) Jiang, Y.; Hong, J.; Burke, S. D. Org. Lett. 2004, 6,
1445-1448.
(16) (a) Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Tetrahedron Lett. 1998, 40, 6099-6102. (b) Pattenden, G.; Gonza´lez,
M. A.; Little, P. B.; Millan, D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Org. Biomol. Chem. 2003, 1, 4173-4208. (c) Pattenden, G.; Gonza´lez,
M. A. Angew. Chem., Int. Ed. 2003, 42, 1255-1258.
(17) (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P.
S. Angew. Chem., Int. Ed. 2000, 39, 2533-2536. (b) Li, D. R.; Tu, Y.
Q.; Lin, G.-Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 8729-8732. (c)
Li, D. R.; Sun, C. Y.; Su, C.; Lin, G.-Q.; Zhou, W.-S. Org. Lett. 2004, 6,
4261-4264.
(18) (a) Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.;
Katsumura, S. J. Org. Chem. 2004, 69, 7949-7959. (b) Vaz, B.; Alvarez,
R.; Bru¨ckner, R.; de Lera, A. R. Org. Lett. 2005, 7, 545-548.
(19) Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O.
Angew. Chem., Int. Ed. 2005, 44, 1221-1222.
(20) (a) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron
Lett. 2001, 42, 5149-5153. (b) Corrigendum: Charette, A. B.; Ber-
thelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 6619.
(21) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26-28.
FIGURE 1. Heteroaryl groups and BTFP sulfones.
(24) Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970,
18, 99-215.
(25) (a) Alonso, D. A.; Na´jera, C.; Varea, M. Tetrahedron Lett. 2001,
42, 8845-8848. (b) Alonso, D. A.; Na´jera, C.; Varea, M. Helv. Chim.
Acta 2003, 85, 4287-4305.
(26) Alonso, D. A.; Na´jera, C.; Varea, M. Synthesis 2003, 277-287.
(27) (a) Alonso, D. A.; Na´jera, C.; Varea, M. Tetrahedron Lett. 2004,
45, 573-577. (b) Alonso, D. A.; Fuensanta, M.; Na´jera, C.; Varea, M.
Phosphorus, Sulfur, and Silicon Relat. Elem. 2005, 180, 1119-1131.
(22) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365-
366.
(23) For the latest applications of PT sulfones in total synthesis,
see: (a) Cramer, N.; Laschat, S.; Baro, A.; Schwalbe, H.; Richter, C.
Angew. Chem., Int. Ed. 2005, 44, 820-822. (b) Gao, X.; Hall, D. G. J.
Am. Chem. Soc. 2005, 127, 1628-1629. (c) Jasper, C.; Wittenberg, R.;
Quitschalle, M.; Jakupovic, J.; Kirschning, A. Org. Lett. 2005, 7, 479-
482.
J. Org. Chem, Vol. 70, No. 16, 2005 6405

Alonso et al.
SCHEME 2
TABLE 1. Stability of Sulfones 7 and 9-11a
a Isolated yield after flash chromatography. b Isolated crude yield, pure by 1H NMR. c Isolated yields of 5 and 64% of 3,5-
bis(trifluoromethyl)phenol and stilbene (12aa) (Z/E: 12/88), respectively, were also obtained. d Isolated yields of 25 and 26% of
benzo[d]thiazol-2-ol and stilbene (12aa) (Z/E: 20/80), respectively, were also obtained. e Only decomposition products and small amounts
of stilbene (Z/E: nd) were observed in the crude reaction mixture. f A 10% isolated yield of 1,2-bis(3,5-dimethoxyphenyl)ethene (12ba)
(Z/E: 17/83) was also obtained. g 3,5-Bis(trifluoromethyl)phenol (55%) was also obtained.
Results and Discussion
On the basis of our previously reported studies of the
R,R-dialkylation of R-arylsulfonyl acetates 5 under PTC
conditions employing K2CO3 as base, we first carried out
a stability analysis of the sulfonyl carbanions derived
from the BTFP sulfones 7 under different basic conditions
(Table 1). Benzylic heteroaryl sulfones 9a-11a, prepared
following literature methods,21,22 were also included in
the screening to compare their stability with 3,5-bis(tri-
fluoromethyl)phenyl sulfones under the tested reaction
conditions. As depicted in Table 1, sulfones 7 and 9a-
11a were treated with different bases such as LDA (1.1
equiv, THF, -78 °C), KHMDS (1.1 equiv, DME, -60 °C),
the phosphazene (triaminoiminophosphorane) base P4-
BTFP Sulfones Preparation, Stability, and Reac-
tivity under Basic Conditions. Different representa-
tive π-deficient BTFP sulfones 7a-e were prepared in
high yields by reaction of 3,5-bis(trifluoromethyl)ben-
zenethiol28 with alkyl bromides or iodides using NaH as
base in CH3CN at room temperature to afford the
corresponding sulfides 8, which were oxidized without
further purification with 30% H2O2 in the presence of
substoichiometric amounts of MnSO4‚H2O (1 mol %) and
29
a buffer solution of NaHCO3 to the corresponding
sulfones 7 (Scheme 2).
(28) Alonso, D. A.; Na´jera, C. 3,5-Bis(trifluoromethyl)benzenethiol.
In Encyclopedia of Reagents for Organic Synthesis; Wiley & Sons. http://
www.mrw.interscience.wiley.com/eros, in press.
(29) This is a simple, green, and general method for the oxidation
of sulfides to sulfones: Alonso, D. A.; Na´jera, C.; Varea, M. Tetrahedron
Lett. 2002, 43, 3459-3461.
6406 J. Org. Chem., Vol. 70, No. 16, 2005

BTFP Sulfones in Direct Julia-Kocienski Olefination
t-Bu30 (1.2 equiv, THF, -78 °C), and KOH [9 equiv, THF,
tetrabutylammonium bromide (TBAB, 10 mol %), rt], for
24 h, and the amount of remaining starting material after
quenching the reaction with water was determined.
When using metalated bases such as LDA and KHMDS,
the sulfone recovery clearly showed that benzylic TBT
sulfone 11a was the most stable system under these
conditions. With respect to BTFP sulfones 7, the recovery
of the crude material was also satisfactory, but a signifi-
cant decrease in the isolated yield was observed after
flash chromatography. This problem, which was also
observed in the case of benzyl phenyltetrazolyl sulfone
10a, was not detected when using P4-t-Bu as base in THF
at -78 °C, all the systems giving place to recoveries
between 55 and 88%. Furthermore, in no case were self-
condensation products proceeding from an ipso reaction
of the metalated carbanion of the BTFP sulfones with
itself or with the starting material detected. This fact
allows us to carry out the deprotonation step in the
absence of the electrophile, thus extending the scope of
the olefination reaction to base-sensitive carbonyl com-
pounds. In addition, an inorganic base such as KOH
under solid-liquid PTC conditions was also employed in
the sulfone stability study. As shown in Table 1, the
sulfone recovery after 24 h was much lower than that in
the case of the previously mentioned bases. This behavior
is in part due to the ipso nucleophilic substitution
between the base and the arylsulfonyl moiety, leading
to the corresponding hydroxy-BT, PT, and TBT deriva-
tives, and 3,5-bis(trifluoromethyl)phenol in the case of
the methyl BTFP sulfone 7d. This unwanted side reac-
tion was not observed in shorter metalation times, a 90%
of sulfone recovery being obtained after stirring 7a for
15-20 min in THF at room temperature in the presence
of 9 equiv of KOH and TBAB (1 mol %). Furthermore, in
the case of the benzyl BTFP sulfones 7a and 7b, the
formation in variable amounts of symmetrical stilbenes
12 was also observed under the tested PTC reaction
conditions. A plausible mechanism for the stereoselective
formation of 12 would involve nucleophilic substitution
on the benzylic sulfones by the formed R-sulfonyl car-
banions to give intermediates 13, which suffer a â-elim-
ination of arylsulfinate under basic conditions to afford
stereoselectively the corresponding stilbenes (Scheme
3).31
SCHEME 3
With respect to benzylic sulfones, only the Ni- and Te-
catalyzed protocols have been shown to be efficient for
the preparation of the corresponding symmetrical stil-
benes with moderate stereoselectivity. Furthermore, the
homocoupling reactions are always carried out under
inert atmosphere and either under reflux conditions33 or
employing substoichiometric amounts of catalyst.34 We
carried out an optimization study of the reaction with
benzylic sulfone 7a to improve the yield and stereoselec-
tivity of the homocoupling reaction (Table 2). The opti-
mization of the base, which was studied with THF as
solvent at room temperature, showed t-BuOK (5 equiv)
as the base of choice in terms of both yield and stereo-
selectivity (80% yield, Z/E: 3/97) (Table 2, entry 2). Other
inorganic bases such a K2CO3 and organic bases such as
1,1,3,3-tetramethylguanidine (TMG), P4-t-Bu, or P2-Et
failed to promote efficiently the reaction (Table 2, entries
3-6). With respect to the solvent, lower yields were
obtained when the dimerization of sulfone 7a was carried
out in DME instead of in THF (Table 2, entries 2 and 8).
BTFP sulfones 7b and 7e also afforded the corresponding
sym-stilbenes 12bb and 12ec in 85 and 17% yields,
respectively, when treated with t-BuOK in THF at room
temperature in high E-selectivities (Table 2, entries 9 and
10). The low yield obtained with sulfone 7e is due to the
low stability of this sulfone under the reaction conditions.
When the reaction with sulfone 7e was carried out in
DME, the yield was improved although the selectivity
was lower (Table 2, entry 11). Finally, it is significant to
mention that benzylic BT, PT, and TBT sulfones 9-11
did not afford significant amounts of stilbene under the
optimized conditions (Table 2, entries 12-14). It can be
concluded that benzyl BTFP sulfones are the most
appropriate systems for the diastereoselective prepara-
tion of (E)-sym-stilbenes using t-BuOK as base and THF
as solvent.
The oxidative homocoupling of metalated sulfones
(mainly Li and Mg) has been previously reported under
Cu-,32 Ni-,33 Te-,34 Fe-,35 and O236-catalyzed conditions.
(30) (a) Schwesinger, R. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 6, p 4110.
(b) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.;
Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.;
Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji,
G.-Z.; Peters, E. M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs
Ann. Chem. 1996, 1055-1081. (c) Seebach, D.; Beck, A. K.; Studer, A.
Modern Synthetic Methods 1995, 7, 1-178.
Julia-Kocienski Olefination with BTFP Sul-
fones: Synthesis of 1,2-Disubstituted Olefins. The
Julia-Kocienski olefination of carbonyl compounds with
BTFP sulfones 7 was first evaluated through the coupling
between benzyl BTFP sulfone 7a and PhCHO. In this
study, different reaction conditions were employed: LDA,
KHMDS, KOH, DBU, t-BuOK, and the phosphazene
(31) Uguen has proposed the formation of carbene species from
benzyl sulfone carbanions to explain the observed formation of stilbenes
in very low yields in the reduction with sodium amalgam of benzyl
sulfones: Jolivet, B.; Uguen, D. Tetrahedron Lett. 2002, 43, 7907-
7911.
(32) Julia, M.; Le Thuillier, G.; Rolando, Ch.; Saussine, L. Tetrahe-
dron Lett. 1982, 23, 2453-2456.
(33) (a) Julia, M.; Verpeaux, J.-N. Tetrahedron Lett. 1982, 23, 2457-
2460. (b) Gai, Y.; Julia, M.; Verpeaux, J.-N. Bull. Soc. Chim. Fr. 1996,
133, 805-816.
(36) Heathcock has noticed the oxygen-catalyzed oxidative coupling
of two alkyl sulfone anions to give an alkene after the reductive
elimination of a bis sulfone intermediate: Heathcock, C. H.; Finkel-
stein, B. L.; Jarvi, E. T.; Radel, P. A.; Hadley, C. R. J. Org. Chem.
1988, 53, 1922-1942.
(34) Engman, L. J. Org. Chem. 1984, 49, 3559-3563.
(35) Jin, L.; Julia, M.; Verpeaux, J. N. Synlett 1994, 215-216.
J. Org. Chem, Vol. 70, No. 16, 2005 6407

Alonso et al.
TABLE 2. Synthesis of 1,2-Diarylethylenes 12
reaction conditions
alkene
entry
Ar
Ar′
sulfone No.
base (equiv)
solvent
No.
yield (%)a
Z/Eb
1
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BTFP
BT
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7a
7a
7a
7a
7a
7a
7a
7a
7b
7e
KOH (9)c
t-BuOK (5)
K2CO3 (5)c
TMG (5)
THF
THF
THF
THF
THF
THF
DME
DME
THF
THF
DME
THF
THF
THF
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12bb
12ec
12ec
12aa
12aa
12aa
65
80
<5
<5
10d
8d
12/88
3/97
nd
2
3
4
nd
5
P4-t-Bu (5)
P2-Et (5)
50/50
50/50
17/83
1/99
1/99
1/99
14/86
-
6
7
KOH (9)c
41
25
85
17
36
0e
8
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
9
3,5-(MeO)2C6H3
10
11
12
13
14
4-NO2C6H4
4-NO2C6H4
Ph
Ph
Ph
7e
9a
10a
11a
PT
15d
<5f
23/77
nd
TBT
a Isolated yield of (E)-12 after flash chromatography. b Determined by GC over the crude reaction mixture. c TBAB (0.1 equiv) was
added to the reaction mixture. d Mainly decomposition products were observed by 1HNMR in the crude reaction mixture. e A 100% conversion
to benzo[d]thiazol-2-ol was observed by 1HNMR in the crude reaction mixture. f The starting sulfone 11a was the main product observed
by 1H NMR in the crude reaction mixture.
SCHEME 4
TABLE 3. Julia-Kocienski Olefination of Benzaldehyde
Employing Sulfones 7a and 9a-11a
reaction conditions
12aa
entry Ar
base (equiv) solvent T (°C) yield (%)a Z/Eb
bases P2-Et and P4-t-Bu,37 either at room temperature
(KOH, DBU, t-BuOK) or at low temperatures (-78 °C
for LDA, P2-Et, and P4-t-Bu and -60 °C for KHMDS) in
THF, CH2Cl2, and DME as solvents (Scheme 4, Table 3).
For comparative purposes, the study was extended to
sulfones 9a-11a. The sulfone was treated with the
corresponding base for 15-20 min prior to the addition
of the aldehyde, except in the case of using t-BuOK where
the reaction was carried out under Barbier-type condi-
tions (slow addition of the base to a mixture of the
aldehyde and sulfone), due to the propensity of sulfone
7a to give stilbene (see Table 2), thus avoiding secondary
reactions, especially in the case of using KOH as base
(see Table 1). As shown in Table 3 (entries 1-8), the
yields of the olefination reaction with KOH at room
temperature and the Schwesinger bases at -78 °C were
good. However, when 1.1 equiv of LDA, KHMDS, DBU,
and t-BuOK were used as base, very low yields were
obtained. No improvement was observed in the case of
using LDA by adding 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) as additive or larger amounts
of base (2.2 equiv). This could be explained by an
aromatic metalation in the much-activated BTFP ring.
However, after addition of D2O to a THF solution of
metalated 7a, only dideuteration in the benzylic position
was observed (80% deuterium incorporation by 1H NMR).
With respect to the (E)-stereoselectivity of the reaction,
this was not sensitive to changes of base, and only in the
presence of KOH (Table 3, entry 3) did it slightly
1
2
3
4
5
6
7
8
9
BTFP LDA (1.1)
THF
-78
<5c
20c
78
nd
BTFP KHMDS (1.1) DME
-60 to rt
rt
1/99
16/84
nd
BTFP KOH (9)e
BTFP DBU (1.2)
BTFP t-BuOK (5)
BTFP P2-Et (2.2)
THF
CH2Cl2 rt
THF
THF
<5
<5
67d
65d
78d
35
rt
nd
-78
-78
-78
-78
rt
3/97
2/98
5/95
5/95
40/60
25/75
15/85
34/66
5/95
BTFP P4-t-Bu (1.2) THF
BTFP P4-t-Bu (1.2)f THF
TBT P4-t-Bu (1.2) THF
10 TBT KOH (9)e
THF
THF
53
11 BT
12 BT
13 PT
14 PT
KOH (9)e
rt
45
P4-t-Bu (1.2) THF
KOH (9)e
THF
P4-t-Bu (1.2) THF
-78
rt
55
50
-78
30
a Isolated yield of 12aa after flash chromatography (hexane).
b Determined by GC over the crude reaction mixture. c Similar
results were obtained in the presence of 1.1 equiv of DMPU or
using 2.2 equiv of LDA. d Isolated yield of (E)-stilbene. e TBAB (0.1
equiv) was added to the reaction mixture. f HMPA (1.2 equiv) was
added to the reaction mixture.
decrease, probably due to the room temperature condi-
tions. Both P2-Et (2.2 equiv) and P4-t-Bu (1.2 equiv) at
-78 °C in THF gave satisfactory results in terms of yield
and stereoselectivity (Table 3, entries 6 and 7). We also
studied the effect of employing HMPA as an additive on
the reaction behavior. The presence of this additive (1.2
equiv) in the reaction medium when using P4-t-Bu (1.2
equiv) as base involved an increase in the reaction yield,
still with a high (E)-selectivity (Table 3, entry 8). Benzylic
1-tert-butyl-1H-tetrazol-5-yl TBT sulfone 11a gave poorer
results in terms of yield (P4-t-Bu as base, Table 3, entry
9) or selectivity (KOH, Table 3, entry 10). Under the same
reaction conditions, BT and PT sulfones 9a and 10a also
gave lower yields and stereoselectivities than the BTFP
sulfone, as shown in Table 3, entries 11-14. From these
(37) Benzyl sulfones have been successfully deprotonated by phos-
phazene base P4-t-Bu in the diastereoselective aldol reaction with
aldehydes: (a) Solladie´-Cavallo, A.; Roche, D.; Fischer, J.; De Chian,
A. J. Org. Chem. 1996, 61, 2690-2694. (b) Costa, A.; Na´jera, C.;
Sansano, J. M. J. Org. Chem. 2002, 67, 5216-5225.
6408 J. Org. Chem., Vol. 70, No. 16, 2005

BTFP Sulfones in Direct Julia-Kocienski Olefination
TABLE 4. Julia-Kocienski Olefination of Aldehydes with BTFP Sulfones 7
sulfone
reaction conditions
base (equiv) T (°C)
alkene
yield (%)a
entry
No.
R1
R2CHO
No.
Z/Eb
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7c
7c
7c
7c
7c
7c
7c
7c
Ph
PhCHO
KOH (9)c
rt
-78
rt
12aa
12aa
12ad
12ad
12ac
12ac
12ae
12ae
12ae
12ca
12ca
12ca
12cf
78
16/84
2/98
14/86
6/94
2
Ph
PhCHO
P4-t-Bu (1.2)
65d
52
3
Ph
4-MeOC6H4CHO
4-MeOC6H4CHO
4-NO2C6H4CHO
4-NO2C6H4CHO
C6H11CHO
KOH (9)c
4
Ph
P4-t-Bu (1.2)
KOH (9)c
-78
rt
76d
12
5
Ph
34/66
60/40
66/34
75/25
50/50
33/67
25/75
25/75
88/12f
50/50f
25/75
10/90
15/85
6
Ph
P4-t-Bu (1.2)
0
67
7
Ph
KOH (9)c
rt
14
8
Ph
C6H11CHO
P2-Et (2.2)
P4-t-Bu (1.2)
KOH (9)c
rt
75
9
Ph
C6H11CHO
rt
86
10
11
12
13
14
15
16
17
Bun
Bun
Bun
Bun
Bun
Bun
Bun
Bun
PhCHO
rt
70
PhCHO
KOH (9)c,e
P4-t-Bu (1.2)
KOH (9)c
rt
40
PhCHO
rt
45
(E)-PhCHdCHCHO
(E)-PhCHdCHCHO
C6H11CHO
rt
30
P4-t-Bu (1.2)
-78
rt
12cf
28
KOH (9)c
12ce
12ce
12ce
50g
70g
60g
C6H11CHO
C6H11CHO
P2-Et (2.2)
P4-t-Bu (2.2)
rt
rt
a Isolated yield after flash chromatography (hexane). b Determined by GC over the crude reaction mixture. c TBAB (0.1 equiv) was
added to the reaction mixture. d Isolated yield of (E)-isomer. e The reaction was carried out under Barbier-type conditions. f EZ/EE ratio
determined by GC over the crude reaction mixture. g Conversion versus decane.
SCHEME 5
ates via a retroaddition/addition process and a lower
energy barrier for the syn isomer in the Smiles rear-
rangement, which drives to the Z-isomer. In fact, it has
been demonstrated that the base-mediated elimination
of syn-â-hydroxy-BT sulfones is more facile as compared
with that of their anti counterparts (see below).9b The
same reaction using P4-t-Bu as base at room temperature
gave a 1/1 mixture of diastereoisomers (Table 4, entry
9). The olefination of (E)-cinnamaldehyde with sulfone
7a was never successful irrespective of the base used,
obtaining intractable crude reaction mixtures that were
not analyzed.
The condensation of pentyl BTFP sulfone 7c toward
benzaldehyde, (E)-cinnamaldehyde, and cyclohexanecar-
boxaldehyde (Table 4, entries 10-17) was carried out
employing KOH, P2-Et, and P4-t-Bu as bases. The (E)-
selectivity of the olefination reaction with sulfone 7c was
in general good, except for the coupling with (E)-cinna-
maldehyde. The reaction with benzaldehyde employing
KOH as base was also carried out in the presence of the
electrophile (Barbier-type conditions), with a small im-
provement in the E-selectivity, although a noticeable
decrease in yield was also observed (Table 4, compare
entries 10 and 11). When the same olefination reaction
was performed in the presence of P4-t-Bu as base, a
similar yield (45%) was obtained (Table 4, entry 12).
Moderate yields were obtained in the olefination reaction
of (E)-cinnamaldehyde with KOH and P4-t-Bu to give
diene 12cf, although in the former case a good Z-
selectivity was obtained (Table 4, entries 13 and 14). High
levels of Z-selectivity in the synthesis of conjugated 1,2-
disubstituted alkenes via the condensation of metalated
alkyl PYR sulfones with R,â-unsaturated aldehydes have
also been observed.20 With respect to the coupling of 7c
with cyclohexanecarboxaldehyde, the best result was
obtained when the reaction was carried out at room
temperature using 2.2 equiv of P2-Et (Table 4, entry 16).
P4-t-Bu gave similar results (entry 17), and KOH af-
forded the lowest yield and selectivity (Table 4, entry 15).
Unlike the coupling between sulfone 7a and cyclohexan-
ecarboxaldehyde, the reaction with sulfone 7c was more
stereoselective.
studies, it can be concluded that KOH is an appropriate
base to carry out the Julia-Kocienski olefination between
benzyl BTFP sulfone 7a and benzaldehyde, even though
higher selectivities are obtained using the phosphazene
base P4-t-Bu in THF at -78 °C.
The olefination of different aromatic and aliphatic
aldehydes with the benzyl sulfone 7a and the pentyl
sulfone 7c was then performed according to the optimized
conditions (Scheme 5, Table 4). The olefination process
was successful when coupling benzyl sulfone 7a with
benzaldehyde and para-substituted electron-rich and
electron-deficient benzaldehydes in the presence of P4-
t-Bu or KOH as bases (Table 4, entries 1-6). With respect
to the selectivity of the reaction, electron-rich p-meth-
oxybenzaldehyde and benzaldehyde gave very similar
results under these conditions (compare entries 1-4),
affording better E-selectivities with P4-t-Bu as base. The
olefination reaction with p-nitrobenzaldehyde employing
KOH as base yielded the corresponding alkene 12ac in
a low 12% yield and as a 1/2 mixture of Z/E stereoiso-
mers. The use of P4-t-Bu increased the yield of the
reaction up to 67% and inverted the selectivity of the
process in favor of the Z-isomer (Table 4, entry 6). The
poor performance obtained with p-nitrobenzaldehyde has
been previously observed with BT sulfones with LDA as
base in THF, where the E-stereoselectivity of the process
increases with the electron-donating ability of the para
substituent on the benzaldehyde.9c Regarding aliphatic
aldehydes, benzyl BTFP sulfone 7a condensed with
cyclohexanecarboxaldehyde in the presence of KOH in a
low 14% yield and moderate selectivity (Table 4, entry
7). Higher Z-selectivity was obtained when using the
phosphazene base P2-Et at room temperature (Table 4,
entry 8), affording alkene 12ae in a 75% yield. The
reversed selectivity presented by an aliphatic aldehyde
can be attributed to a diastereomeric equilibration be-
tween the syn- and anti-â-alkoxyalkyl sulfone intermedi-
J. Org. Chem, Vol. 70, No. 16, 2005 6409

Alonso et al.
TABLE 5. Synthesis of Resveratrol Analogues With BTFP Sulfone 7b
a The reactions were performed under Barbier-type conditions. b Isolated yield after flash chromatography (hexane). In parentheses
isolated yield of (E)-1,2-bis(3,5-dimethoxyphenyl)ethene. c Determined by GC over the crude reaction mixture. d TBAB (0.1 equiv) was
added to the reaction mixture. e Isolated yield of (E)-isomer. f HMPA (1.2 equiv) was added to the reaction mixture. g Isolated yield of
(E)-isomer after isomerization of the mixture with I2.
SCHEME 6
We can conclude with respect to the olefination of
aliphatic and conjugated aldehydes with BTFP sulfones
7a and 7c that, under the studied reaction conditions,
the benzyl sulfone 7a performs better with aromatic
aldehydes in the Julia-Kocienski reaction in terms of
yield and selectivity with the phosphazene base P4-t-Bu
at low temperature, giving the corresponding stilbenes
with E-configuration. However, P2-Et at room temper-
variety of unique and useful biological antioxidant,
ature is the appropriate condition in the case of the
antimutagenic, and lifespan extension properties.38 Meth-
coupling between benzyl sulfone 7a and an aliphatic
oxylated stilbenoids39 such as the trimethylated resvera-
aldehyde. Regarding aliphatic sulfone 7c, the olefination
with aromatic aldehydes gives very similar results ir-
(38) (a) Siemann, E. H.; Creasy, L. L. Am. J. Enol. Vitic. 1992, 43,
respective of the base used. However, R,â-unsaturated
and aliphatic aldehydes afford better yields and selectivi-
ties when employing KOH and P2-Et at room tempera-
ture, respectively.
The benzyl BTFP sulfone 7b was employed for the
synthesis of methoxylated stilbenoids (Scheme 6, Table
5). Hydroxylated E-stilbenoids are natural polyphenols
widely present in nature, especially in medicinal plants
and food products, which have been shown to exhibit a
49-52. (b) Soleas, G. J.; Diamandis, E. P.; Goldberg, D. M. Clin.
Biochem. 1997, 62, 4821-4826. (c) Jang, M.; Cai, L.; Udenai, G. O.;
Slowing, K. V.; Thomas, C. F.; Beecher, C. W. W.; Fong, H. H. S.;
Farnsworth, N. R.; Kinghorn, A. D.; Mehta, R. G.; Moon, R. C.; Pezzuto,
J. M. Science 1997, 275, 218-220. (d) Orsini, F.; Pelizzoni, F.; Verotta,
L.; Aburjai, T.; Rogers, C. B. J. Nat. Prod. 1997, 60, 1082-1087. (e)
Fremont, L. Life Sci. 2000, 66, 663-673. (f) Gusman, J.; Malonne, H.;
Atassi, G. Carcinogenesis 2001, 22, 1111-1117. (g) Howitz, K. T.;
Bitterman, K. J.; Cohen, H. Y.; Lamming, D. W.; Lavu, S.; Wood, J.
G.; Zipkin, R. E.; Chung, P.; Kisielewski, A.; Zhang, L. L.; Scherer, B.;
Sinclair, D. A. Nature 2003, 425, 191-196. (h) Lamming, D. W.; Wood,
J. G.; Sinclair, D. A. Mol. Microbiol. 2004, 53, 1003-1009.
6410 J. Org. Chem., Vol. 70, No. 16, 2005

BTFP Sulfones in Direct Julia-Kocienski Olefination
SCHEME 7
trol show higher activity against several human cancer
cell lines than resveratrol itself.40 After an extensive
study of different bases, solvents, and temperatures, we
found that the reaction between sulfone 7b and p-
methoxybenzaldehyde with KOH in the presence of
TBAB yielded, under Barbier-type conditions, the corre-
sponding trimethylated resveratrol 12bd in a 81% yield
and with a moderate E-selectivity (Z/E ) 25/75) (Table
5, entry 1). This result could be a consequence of the
presence of two electron-donating groups in BTFP sulfone
7b, which may prevent the diastereomeric equilibration
through a retroaddition/addition process, due to the lower
stability of the corresponding benzylic carbanion, com-
pared with 7a. The reaction had to be carried out
necessarily under Barbier-type conditions due to the low
stability of sulfone 7b under the basic reaction conditions
(see Table 1). The phosphazene base P4-t-Bu in THF at
-78 °C gave a very poor yield, although with an excellent
selectivity (Table 5, entry 2). However, when this reaction
was performed in the presence of HMPA, trimethylated
resveratrol 12bd was obtained with an excellent yield
and selectivity (Table 5, entry 3). This strong positive
effect of using HMPA in the reaction was not observed
using other additives such as DMPU and is probably due
to favorable interactions between the additive and the
P4-t-Bu-derived carbanion, which could modify its struc-
ture and, hence, the reactivity of the system.41 Several
polymethoxylated stilbenes were synthesized following
this protocol, although moderate yields were usually
obtained (Table 5, entries 4-7), the best reaction condi-
tions involving the use of KOH as base. The Julia-
Kocienski olefination of 2,4-dimethoxybenzaldehyde af-
forded significant amounts of (E)-bis(2,4-dimethoxy-
phenyl)ethene (17%) even working under Barbier-type
conditions (Table 5, entry 4). Better yields were obtained
when sulfone 7b was coupled with 2-thiophenecarboxal-
dehyde and 4-pyridine carboxaldehyde, substrates that
afforded stilbenes 12bj and 12bl, respectively. These
derivatives along with 12bg present human cytochrome
P450 1B1 inhibitory activity.42 Even though both (Z/E)
isomers of the corresponding stilbenes were obtained
usually in different ratios following the Julia-Kocienski
protocol with sulfone 7b, it was possible to isomerize
those mixtures after equilibration with catalytic iodine
to furnish exclusively the E-stilbene, as shown for
compound 12bj (Table 5, entry 8). Therefore, the syn-
thesis of resveratrol derivatives with sulfone 7b employ-
ing KOH as base is a general process that works with a
wide variety of aromatic aldehydes with moderate yields
and good selectivities. The reaction has to be performed
under Barbier-type conditions to avoid homocoupling of
sulfone 7b to the sym-stilbene 12bb.
minal alkenes from carbonyl compounds is a very im-
portant reaction in organic synthesis.43 The interest in
the methylenation reaction of carbonyl compounds con-
tinues to generate many diverse methylenation reagents,
such as Tebbe’s reagent44 and Grubbs’ titanacyclobu-
tane.45 Recently, a few approaches to transition metal-
catalyzed olefinations have also been disclosed.46 We
found out that BTFP methyl sulfone 7d is a good reagent
to perform methylenation reactions of carbonyl com-
pounds through the Julia-Kocienski protocol47 (Scheme
7, Table 6). In this case, the olefination reaction proved
to be much more efficient when Barbier-type conditions
were used. Thus, an equimolar mixture of BTFP sulfone
7d and 4-methoxybenzaldehyde in THF at room temper-
ature was treated with KOH (9 equiv) and a substoichio-
metric amount of TBAB (10 mol %) for 16 h to yield the
corresponding alkene in a 60% isolated yield (Table 6,
entry 1). In addition, 2-vinyl-6-methoxynaphthalene
(14b), a key intermediate for the production of naproxen
in the Albermale process, was obtained by reaction of
sulfone 7d with 6-methoxy-2-naphthaldehyde under simi-
lar reaction conditions in an 80% isolated yield (Table 6,
entry 2). A comparable yield was obtained when the
phosphazene base P4-t-Bu in THF was employed at -78
°C for 16 h (Table 6, entry 3). Moderate yields were
obtained when either an aliphatic or an R,â-unsaturated
aldehyde was submitted to the methylenation protocol
employing P4-t-Bu or KOH as bases, respectively (Table
6, entries 4 and 5). In these particular reactions, the
selection of the reaction conditions was based on the
results obtained in the olefination reactions of similar
substrates with pentyl BTFP sulfone 7c (see Table 4).
In the case of cinnamaldehyde, (E)-1-phenyl-1,3-butadi-
ene (14d) was obtained as a single isomer in 50% yield
(Scheme 7, Table 6, entry 5).
Several attempts to carry out the Julia-Kocienski
olefination of acetophenone with benzyl BTFP sulfone 7a
employing different reaction conditions and bases (KOH,
(43) Kelly, S. E. Alkene Synthesis. In Comprehensive Organic
Synthesis; Trost, B. M. Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 1, p 729.
(44) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613.
(45) Pine, S. H.; Zahier, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270-3272.
(46) (a) Mo-catalyzed: Lu, X. Y.; Fang, H.; Ni, Z. J. J. Organomet.
Chem. 1989, 373, 77-84. (b) Re-catalyzed: Zhang, X. Y.; Chen, P.
Chem.-Eur. J. 2003, 9, 1852-1859 and references therein. (c) Fe-
catalyzed: Aggarwal, V. K.; Fulton, J. R.; Sheldon, C. G.; de Vicente,
J. J. Am. Chem. Soc. 2003, 125, 6034-6035 and references therein.
(d) Ru-catalyzed: Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J.
Org. Chem. 2003, 68, 3714-3717 and references therein. (e) Rh-
catalyzed: Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320-
328 and references therein.
Julia-Kocienski Methylenation of Aldehydes and
Ketones with BTFP Sulfones. The synthesis of ter-
(39) For a very recent synthesis of methoxylated stilbenoids employ-
ing Heck chemistry in our group, see: Botella, L.; Na´jera, C. Tetra-
hedron 2004, 60, 5563-5570.
(40) (a) Pettit, G. R.; Grealish, M. P.; Jung, M. K.; Hamel, E.; Pettit,
R. K.; Chapuis, J.-C.; Schmidt, J. M. J. Med. Chem. 2002, 45, 2534-
2542. (b) Lion, C. J.; Matthews, C. S.; Stevens, F. G.; Westwell, A. D.
J. Med. Chem. 2005, 48, 1292-1295.
(41) For a discussion about the nature of P4-t-Bu enolates, see:
Fruchart, J.-S.; Gras-Masse, H.; Melnyk, O. Tetrahedron Lett. 2001,
42, 9153-9155.
(42) Kim, S.; Ko, H.; Park, J. E.; Jung, S.; Lee, S. K.; Chun, Y.-J. J.
Med. Chem. 2002, 45, 160-164.
(47) For the methylenation reaction of carbonyl compounds employ-
ing BTSO2Me, see refs 9a,c and Gueyrard, D.; Haddoub, R.; Salem,
A.; Bavar, N. S.; Goekjian, P. G. Synlett 2005, 520-522.
J. Org. Chem, Vol. 70, No. 16, 2005 6411

Alonso et al.
TABLE 6. Julia-Kocienski Methylenation of Aldehydes and Ketones With Methyl BTFP Sulfone 7d
a The reactions were carried out under Barbier conditions. b Isolated yield after flash chromatography (hexane). c TBAB (0.1 equiv)
was added to the reaction mixture. d 75% yield was obtained when non-Barbier conditions were used. e (E)-isomer. f A 50% isolated yield
of 3,5-(bistrifluoromethyl)phenol was also obtained. g Conversion versus decane. h Two equivalents of 7d were used. i Four equivalents of
7d were used.
P4-t-Bu, P2-Et, KHMDS, and LDA) were unsuccessful,
and sulfone recovery was always observed except when
KOH was used, where significant amounts of 3,5-bis-
(trifluoromethyl)phenol were obtained. However, under
Barbier-type conditions, ketones could be condensed with
BTFP methyl sulfone (7d). When the reaction was
performed with 4-tert-butylcyclohexanone using KOH as
base under Barbier conditions (Table 6, entry 6), very
low yields of methylenated ketone were obtained due to
the formation of 3,5-bis(trifluoromethyl)phenol as the
main product. However, both aliphatic and aromatic
ketones were converted into the corresponding terminal
alkenes (14e-h) in moderate to good yields through
methylenation with 1 equiv of 7d and the phosphazene
base P4-t-Bu at 0 °C to room temperature in THF. The
observed low isolated yields of compounds 14c-f appear
associated with their volatility as indicated by the high
reaction conversions observed. For the methylenation of
benzophenone, the yield could be improved by increasing
the amount of sulfone 7d (Table 6, entry 9). Finally, it is
worthy mentioning that 1,2-diketone derivatives such as
benzil could be dimethylenated under the above-men-
tioned reaction conditions to the corresponding 1,3-diene
14i using an excess of sulfone 7d (Scheme 7, Table 6,
entry 11). This type of diene-bearing aryl group has
recently been studied as branched π-systems with po-
tential applications in the development of materials with
multiple conduction channels.48
Therefore, it can be concluded that the methylenation
reaction of aromatic and R,â-unsaturated aldehydes with
sulfone 7d gives good results when using KOH as base
at room temperature. For aromatic aldehydes, the reac-
tion can be carried out with P4-t-Bu, which also gives
good isolated yields, whereas P4-t-Bu is the base of choice
when a methylenation reaction with sulfone 7d of
aliphatic aldehydes and ketones is required.
The olefination reaction of BTFP sulfones 7 can be
performed with aromatic, R,â-unsaturated, and aliphatic
aldehydes, as well as aliphatic and aromatic ketones, the
stereoselectivity of the process being influenced by a
variety of factors, such as the carbonyl and sulfone
structure, as well as the base, solvent, and additives
employed (Table 7). In general, stabilized metalated
benzyl sulfones 7a,b stereoselectively afforded (E)-olefins
when neutral or electron-rich aromatic aldehydes are
employed in the reaction, whereas lower or reversed
stereoselectivities were observed when using electron-
poor aromatic or aliphatic aldehydes. The benzylic sul-
(48) Van der Wiel, B. C.; Williams, R. M.; van Walree, C. A. Org.
Biomol. Chem. 2004, 2, 3432-3433.
6412 J. Org. Chem., Vol. 70, No. 16, 2005

BTFP Sulfones in Direct Julia-Kocienski Olefination
TABLE 7. Selected Olefination Conditions for BTFP Sulfones
SCHEME 8
fone 7b has been successfully used in the stereo-
selective synthesis of a wide variety of methoxyl-
ated stilbenes using KOH as base and working under
Barbier-type conditions. Pentyl BTFP sulfone 7c, which
does not afford a stabilized carbanion intermediate,
usually showed low stereoselectivity, the observed E/Z
ratio being very dependent on the reaction conditions.
BTFP methyl sulfone 7d has been shown to be a good
methylenation reagent for aliphatic and aromatic alde-
hydes, ketones, and 1,2-dicarbonyl compounds, working
under Barbier-type conditions and employing P4-t-Bu as
base.
Table 8 includes a comparison among the results
obtained for selected examples with BTFP sulfones with
those for related BT, PT, and TBT sulfones under the
particular conditions that have been optimized for these
sulfones. With respect to benzylic sulfones 7a and 9a,9c
better yields and similar or higher (E)-selectivities were
obtained when employing BTFP sulfone 7a with cyclo-
hexanecarboxaldehyde and 4-methoxybenzaldehyde. In
the case of pentyl sulfones 7c-11c, good yields and
excellent selectivities have been obtained in the olefina-
tion reaction of cyclohexanecarboxaldehyde and benzal-
dehyde with the phenyltetrazolyl derivative 10c employ-
ing KHMDS as base.22 BTFP sulfone 7c afforded moderate
to good yields and selectivities with these substrates
working under room temperature conditions and using
phosphazene base P2-Et and KOH as bases, respectively.
When comparing BTFP and BT methyl sulfones 7d and
9d, their reaction with the aromatic 4-methoxybenzal-
dehyde afforded good yields in both cases of the terminal
olefin. However, BTFP sulfone 7d gives much better
yields in the case of the olefination reaction of cyclic
ketones such as 4-tert-butylcyclohexanone.
Mechanistic Studies. As mentioned above, after
completion of the olefination reaction, we have observed
in the crude reaction mixtures the formation of 3,5-bis-
(trifluoromethyl)phenol as a side product, which supports
the postulated pathway for the modified Julia olefination
(Scheme 8): addition of the sulfonyl carbanion to the
J. Org. Chem, Vol. 70, No. 16, 2005 6413

Alonso et al.
TABLE 8. Olefination Conditions for Selected Examples With BT, PT, TBT, and BTFP Sulfones
SCHEME 9
aldehyde, Smiles rearrangement, and spontaneous sulfur
dioxide and 3,5-bis(trifluoromethyl)phenolate elimina-
tions.9c
olefination process under the tested reaction conditions
(see Table 4, entry 1): a 13/87 and 15/85 mixtures of (Z)-
and (E)-stilbene (12aa), respectively. These results and
the presence of PhCHO and 3,5-bis(trifluoromethyl)-
phenol in the crude reaction mixture demonstrate an
equilibration between the syn- and anti-â-alkoxyalkyl
sulfone diastereomers via a retroaddition/addition pro-
cess with the carbonyl compound.
Regarding the stereoselectivity of the Julia-Kocienski
reaction employing BTFP sulfones, an investigation of
the base-mediated elimination of stereodefined anti- and
syn-â-hydroxyalkyl BTFP sulfones 15 was carried out
(Scheme 9). Hydroxyalkyl sulfones 15, which were pre-
pared from trans- and cis-stilbene epoxides in 40 and 30%
isolated yields, respectively (Scheme 9),49 gave place
stereoselectively to the same results obtained in the
(49) All attempts to isolate or detect â-hydroxy sulfones 15 from the
reaction between sulfone 7a and benzaldehyde under different condi-
tions were unfruitful due to the fast Smiles rearrangement and
elimination of SO2 that these systems suffer from.
6414 J. Org. Chem., Vol. 70, No. 16, 2005

BTFP Sulfones in Direct Julia-Kocienski Olefination
SCHEME 10
The lack of total stereospecificity, although affording
mostly the (E)-alkene, seems to involve zwitterionic inter-
mediates created by direct loss of 3,5-bis(trifluoromethyl)-
phenolate, as proposed by Julia.9c Conformational equili-
bration of these betaine intermediates favors the forma-
tion of the trans-alkene upon loss of SO2 (Scheme 10).
In the case of the reaction between pentyl BTFP
sulfone 7c with aliphatic aldehydes (Table 4, entries 15-
17), the â-alkoxyalkyl sulfone intermediate does not
suffer a retroaddition/addition process due to the lower
stability of the R-metalated sulfone, and therefore, the
E/Z ratio of the product olefin accurately reflects the anti/
syn ratio of the initial nucleophilic addition.
Experimental Section
Typical Procedure for the Synthesis of sym-(E)-1,2-
Diarylethylenes 12. To a stirred solution of t-BuOK (56 mg,
0.5 mmol) in anhydrous THF or DME (1 mL) under argon
atmosphere was added dropwise a previously prepared solu-
tion of the corresponding sulfone (0.1 mmol) in anhydrous THF
or DME (1 mL). After being stirred at room temperature for
16 h, the reaction mixture was quenched with a saturated
aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2
× 10 mL), the organic phase was dried (Na2SO4), and the
solvent was evaporated, affording crude sym-olefins 12, which
were purified by flash chromatography (hexane).
(E)-1,2-Bis(3,5-dimethoxyphenyl)ethene (12bb):42 Solid;
Rf (hexane/EtOAc: 2/1) 0.66; mp 129-131 °C; IR (KBr) νmax
1616, 1461, 1425, 1282, 1058; 1H NMR δ 7.01 (s, 2H), 6.66 (d,
J ) 2.3, 4H), 6.40 (t, J ) 2.2, 2H), 3.83 (s, 12H); 13C NMR δ
160.9, 139.1, 129.2, 104.6, 100.1, 55.4; MS m/z 300 (M+, 100),
270 (11), 269 (29), 254 (12).
Conclusions
The 3,5-bis(trifluoromethyl)phenyl sulfonyl (BTFP sul-
fonyl) group has been shown to be a very stable and
excellent activator for the synthesis of olefins through
the Julia-Kocienski olefination reaction using very
simple reaction conditions. From studies on the stability
and reactivity of BTFP sulfones in different reactions, it
can be concluded that KOH and the phosphazene deriva-
tives P2-Et and P4-t-Bu are the most appropriate bases
for this type of coupling. Under these reaction conditions,
BTFP sulfones were better substrates than the heteroaryl
BT, PT, and TBT sulfones in terms of stability and
reactivity. The olefination reaction of BTFP sulfones 7
could be performed with aromatic, R,â-unsaturated, and
aliphatic aldehydes, as well as aliphatic and aromatic
ketones, the stereoselectivity of the process being influ-
enced by a variety of factors, such as the carbonyl and
sulfone structure, as well as the base, solvent, and
additives employed. The stereochemical behavior of BTFP
sulfones in the olefination reaction seemed to be very
similar to that presented by BT sulfones. Thus, the
â-alkoxyalkyl sulfone intermediates from benzyl sulfones
such as 7a equilibrated via a retroaddition/addition
process involving a zwitterionic sulfinate generated by
direct loss of 3,5-bis(trifluoromethyl)phenolate in the
spirocyclic intermediates. Additional applications of BTPF
sulfones in olefination and other reactions are currently
under investigation.
General Olefination Procedure with BTFP Sulfones
in THF. To a stirred solution of the corresponding sulfone (0.1
mmol) in THF (2 mL) at the corresponding temperature (see
Tables 3-6) under argon atmosphere (except for KOH) was
added the suitable base (see Tables 3-6). After being stirred
at the same temperature for 30 min, the corresponding
aldehyde (0.11 mmol) was added. The reaction mixture was
stirred overnight, quenched with a saturated aqueous NH4Cl
solution (5 mL), and extracted with EtOAc (2 × 10 mL), and
the organic phase was dried (Na2SO4). The solvent was
evaporated to give crude olefins, which were purified by flash
chromatography (hexane) to afford pure compounds 12aa,
12ac, 12ad, 12ae, and 12ca. In the case of compound 12cf
the THF was distilled off and the residue was washed with
pentane, which was evaporated, and the obtained residue was
purified by flash chromatography (pentane) to afford pure
compound 12cf. For compounds 12ce and 14e the conversion
of the reaction was determined by GLC over the crude reaction
mixture by adding 0.1 mmol of internal standard (decane). In
the case of compound 14d the THF was distilled off, the
residue was washed with pentane, and distillation of pentane
afforded pure compound 14d. For compounds of Tables 5 and
6, the reaction was carried out under Barbier conditions, that
is, addition of the base to a stirred mixture of the sulfone and
the corresponding carbonyl compound in THF (2 mL).
(E)-2-[2-(3,5-Dimethoxyphenyl)vinyl]thiophene (12bj):42
Oil; Rf (hexane/EtOAc: 2/1) 0.72; IR (KBr) νmax 3055, 2951,
2918, 2847, 1580, 1454, 1421, 1279, 1203, 1159, 1061, 957, 837,
689; 1H NMR δ 7.17-7.10 (m, 2H), 6.99 (d, J ) 3.3, 1H), 6.92
(dd, J ) 3.5, 5.1, 1H), 6.78 (d, J ) 16.1, 1H), 6.54 (d, J ) 2.2,
J. Org. Chem, Vol. 70, No. 16, 2005 6415

Alonso et al.
2H), 6.31 (t, J ) 2.2, 1H), 3.74 (s, 6H); 13C NMR δ 160.9, 142.6,
138.9, 128.2, 127.6, 126.3, 124.5, 122.3, 104.3, 100.0, 55.3; MS
m/z 246 (M+, 17), 245 (100), 244 (26), 230 (71), 215 (24), 199
(16), 187 (27), 171 (21), 115 (13), 97 (15).
BQU) and the University of Alicante. M.F. thanks the
University of Alicante for a predoctoral fellowship.
Supporting Information Available: General experimen-
tal methods and analytical and spectral characterization data
for compounds 7a-d, 8a-d, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This article is dedicated to Pro-
fessor Joaqu´ın Plumet on the occasion of his 60th
birthday. This work has been supported by the Direccio´n
General de Investigacio´n of the Ministerio de Educacio´n
y Ciencia (BQU2001-0724-CO2-01 and CTQ2004-00808/
JO050852N
6416 J. Org. Chem., Vol. 70, No. 16, 2005