Alkynylation, Alkenylation of R,ꢀ-Unsaturated Aldehydes
A R T I C L E S
the ketone functionality, the alkynylation process proceeds by
a novel enolate-type Smiles rearrangement, initiated by depro-
tonation of the weakly acidic ꢀ-keto sulfone functionality of
the key intermediate (see mechanistic details below). In contrast
to the classical Julia-Kocienski reaction, where products lacking
a stereocenter are formed, our method provides access to highly
enantioenriched alkynylic and alkenylic functionalities. Fur-
thermore, in contrast to the Julia-Kocienski transformation,
which converts a highly valuable carbonyl group into an
alkenylic compound, the present alkynylation method leaves the
carbonyl untouched. In case of alkenylation, the oxidation state
is simply altered into an alcohol, which can easily be reoxidized
to the aldehyde using standard procedures.
concentration and temperature in toluene led to an improvement
and yielded the intermediate 4 with 88 and 96% ee, respectively
(entries 4-6). Other catalysts were found to be less effective
for the addition reaction. The use of L-proline 3c failed
completely (entry 8), whereas catalysts 3b and 3d gave
diminished enantioselectivity (entries 7 and 9). Ready access
to both product enantiomers was possible simply by choosing
the appropriate catalyst (entries 5 and 6). To state the importance
of the heterocyclic moiety, we also reacted ꢀ-keto tolyl sulfone
1c with 2a. Full conversion was obtained in the organocatalyzed
addition step; however, no product formation via the Smiles
rearrangement could be observed (entry 10).
Alkynylation. With the optimized conditions in hand, we
turned our attention to the envisaged transformations of the
ꢀ-keto heterocyclic sulfone moiety in intermediate 4. First
attempts to form the alkynylated product under basic conditions
starting from 4 resulted in unsatisfactory yields of ca. 30%,
presumably due to an intramolecular reaction with the aldehyde
functionality, forming an undesired and stable pyranose struc-
ture. To prevent this side reaction, the in situ protection as
diethylacetal was conducted before treatment with base. To our
delight, the alkyne was formed under these conditions with high
conversion, and we developed a one-pot procedure for a
Herein, we disclose the one-pot and metal-free highly
stereoselective organocatalytic conjugate formal alkynylation
and alkenylation of R,ꢀ-unsaturated aldehydes, as a simple
process to these privileged classes of optically active compounds
(Scheme 2).
Scheme 2. Conjugate Addition of ꢀ-Keto Heterocyclic Sulfones to
R,ꢀ-Unsaturated Aldehydes and Transformation into the
Alkynylated or Alkenylated Products
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Results and Discussion
Optimization of the Organocatalytic Conjugate Addition. The
synthesis of these new nucleophilic reaction partners was
achieved in a straightforward synthesis, as outlined in Scheme
3. After alkylation of the commercially available heterocyclic
sulfides with different R-bromoketo compounds, the correspond-
ing ꢀ-keto heterocyclic sulfones 1 were obtained in a range of
45-95% overall yield after oxidation with m-CPBA.
Scheme 3. Synthesis of the ꢀ-Keto Heterocyclic Sulfones 1
For initial screening studies, the different ꢀ-keto heterocyclic
sulfones 1 were reacted with (E)-pent-2-enal 2a using 10 mol
% of the commercially available 2-[bis(3,5-bistrifluorometh-
ylphenyl)trimethylsilylanyloxymethyl]pyrrolidine 3a16 as cata-
lyst and m-chlorobenzoic acid as additive (Table 1). We
commenced with ꢀ-keto BT-sulfone 1a, but unfortunately this
substrate gave no conversion to the desired adduct (entry 1).
Therefore, we turned our attention to the utilization of the ꢀ-keto
PT-sulfone 1b and were pleased to achieve full conversion after
3 h with an enantioselectivity of 83% ee in toluene as the solvent
(entry 2). Changing the solvent to CH2Cl2 resulted in decreased
enantiomeric excess (entry 3), whereas lowering the reaction
9
J. AM. CHEM. SOC. VOL. 131, NO. 30, 2009 10583