assisted one-pot three-component reactions of aromatic aldehy-
des, arylamines and terminal olefins with electron-withdrawing
groups using molecular oxygen as a sole oxidant. Besides, this
method also provides efficient access to the anti-Markovnikov
oxidative amination products of olefins via Pd-catalyzed reactions
of primary aromatic amines and alkenes under molecular oxygen.
The use of cheap and easily available starting materials and
environmentally benign oxidant would make this atom-efficient
method particularly attractive. We expect this method to be
useful in the total synthesis of more complex molecules with
potential for extensive pharmaceutical and biological applications.
Further investigation of the reaction scope including the synthesis
of unsymmetrical substituted 1,4-DHPs and its applications in
organic synthesis is ongoing in our laboratory and the results will
be reported in due course.
Scheme 2 Reaction of benzaldehyde, aniline, methyl acrylate and ethyl
3-oxobutanoate.
yield. On the basis of the above results, we proposed 7 as the key
intermediate of the reaction. There are few successful precedents
of the anti-Markovnikov oxidative amination of olefins from
primary aromatic amines and alkenes to our knowledge, because
primary aromatic amines such as anilines tend to deactivate
palladium catalyst by strong coordination to the palladium
species.12 For example, Hegedus and Bozell reported palladium-
catalyzed reactions of substituted anilines and methyl acrylate
to produce vinylogous arylamino esters with benzoquinone as
an oxidant; however, aniline failed to react completely and most
primary aromatic amines reacted poorly affording the products
in low yields.12b Therefore, this catalytic system could be used
to prepare the anti-Markovnikov oxidative amination products
of olefins from primary aromatic amines and alkenes, which are
useful synthetic intermediates, particularly in the construction of
heterocyclic compounds.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 20625205, 20772034 and 20932002),
National Basic Research Program of China (973 Program) (No.
2011CB808600), Doctoral Fund of Ministry of Education of
China (No. 20090172110014) and Guangdong Natural Science
Foundation (No. 10351064101000000).
Notes and references
A plausible mechanism is shown in Scheme 3. First, a PdII
catalyst coordinates the olefin which undergoes nucleophilic attack
by the amine to generate the s-alkylpalladium complex 6. The s-
alkylpalladium complex 6 then undergoes b-H elimination to give
an unstable palladium hydride complex and anti-Markovnikov
oxidative amination product 7. The palladium hydride complex
ultimately forms Pd0, which is reoxidized by molecular oxygen
to regenerate the PdII catalyst. Next, nucleophilic addition of
the previously formed enamine 7 to the carbonyl group of the
aldehyde occurs to form 8. Compound 8, which possibly undergoes
dehydration to imine 9, reacts with a second molecule of enamine
7 to give bisenamine (Z)-10, which would isomerize into (E)-10
and then lead to cyclized DHP 4 by nucleophilic attack of the
amino group to the enone moiety.8b
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Scheme 3 Plausible reaction mechanism.
In conclusion, we have established a novel, highly efficient proto-
col for the synthesis of 2,6-unsubstituted 1,4-DHPs via palladium-
5360 | Org. Biomol. Chem., 2011, 9, 5358–5361
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