SCHEME 1
Improved Julia-Kocienski Conditions for the
Methylenation of Aldehydes and Ketones
Christophe A¨ıssa
Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/Ruhr, Germany
SCHEME 2. Synthesis of 3a
ReceiVed August 10, 2005
a Reagents and conditions: (a) NaN3, i-PrOH/H2O, reflux, 77%. (b) (1)
NaH, MeI, THF; (2) Mo7O24(NH4)6, H2O2, EtOH, 91%.
zolylmethyl sulfone 2 has been used in the formal total synthesis
of (-)-agelastatin A.10 Motivated by our general interest for
this reaction, we embarked on a more comprehensive study of
the methylenation of ketones and aldehydes under modified
Julia-Kocienski conditions.
Kocienski isolated products of the intermolecular ipso nu-
cleophilic attack of R-lithiated BT-alkyl sulfones onto the
heteroaryl moiety.11 It is reasonable to assume that a BT-methyl
sulfone like 1 has an even stronger reactivity in this degradative
pathway, as the steric hindrance around the carbon atom attached
to sulfur atom is reduced. Furthermore, Kocienski demonstrated
also that TBT-alkyl sulfones are more stable to this autocon-
densation reaction than their PT or BT counterparts. We chose
in consequence to prepare the sulfone 3 for our work. This was
realized in a classical fashion on a 10 g scale in 91% yield from
the mercaptan 412 in two steps by alkylation and subsequent
oxidation (Scheme 2).
It became rapidly clear that a Barbier-type procedure was
convenient, the generation of the premetalate of the sulfone
leading only to low conversion to the terminal alkene and
important degradation. Two different sets of conditions have
emerged from the initial optimization study. With conditions
A, NaHMDS was used as a base in THF at low temperature.
With conditions B, Cs2CO3 was used in a THF/DMF mixture
at reflux. The use of Cs2CO3 is precedented for a Julia-
Kocienski olefination reaction, but on activated methylene
substrates.13 Other inorganic bases were totally inefficient,
except for K3PO4, which however remained inferior. Under
those second conditions (B), the choice of solvent is also
important. DMF must be present and is superior to other polar
cosolvents such as MeCN.
The scope of the reaction appears in Table 1. Aldehydes and
ketones reacted smoothly to furnish the desired terminal olefins
in good to excellent isolated yields. The reaction displayed a
good functional group compatibility as esters, lactones, car-
bamates, acetals, silyl, and p-methoxybenzyl ethers were toler-
ated. Moreover, aromatic and aliphatic substrates are equally
The scope of the methylenation of aldehydes and ketones
under optimized Julia-Kocienski conditions is broadened
by using 1-tert-butyl-1H-tetrazol-5-ylmethyl sulfone. Two
different Barbier-type procedures are applied with NaHMDS
at -78 °C or Cs2CO3 at 70 °C. The latter conditions are
also adapted for the preparation of 1,2-disubstituted olefins
and intramolecular olefination reactions.
Terminal olefins have received particular interest among
alkenes, and methods ranging from anionic reactions developed
by Wittig,1 Johnson,2 and Peterson3 to other stoichiometric
methods based on gem-dimetallic reagents have been reported.4
A rhodium-catalyzed methylenation of aldehydes also has been
developed recently.5 The Julia-Kocienski reaction is a very
efficient method to transform carbonyl compounds into olefins,
as illustrated by the recent total synthesis of the triester of
Viridiofungin A, A2, and A46 among others.7 Surprisingly, the
methylenation of carbonyl compounds under Julia-Kocienski
conditions has been studied only briefly by Julia and co-workers
with the benzothiazol-2-ylmethyl sulfone 18 (Scheme 1) and
more recently by Na´jera’s group.9 Additionally, phenyltetra-
(1) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44-57.
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Soc. 1982, 104, 7041-7044.
(3) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784.
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1978, 2417-2420. (b) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am.
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2004.
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Org. Chem. 2005, 70, 5579-5591.
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F. Org. Lett. 2003, 5, 2927-2930.
(7) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585.
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1991, 32, 1175-1178.
(11) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365-
366.
(12) Quast, H.; Bieber, L. Chem. Ber. 1981, 114, 3253-3272.
(13) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem.
2005, 1365-1368.
(9) Alonso, D. A.; Fuensanta, M.; Na´jera, C.; Varea, M. J. Org. Chem.
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10.1021/jo051693a CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2005
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J. Org. Chem. 2006, 71, 360-363