A new lewis acid system palladium/TMSCl for Catalytic aldol condensation of aldehydes with ketones

Article abstract of DOI:10.1246/cl.2004.668

Palladium on charcoal effectively catalyzed the aldol condensation reactions of different ketones with aldehydes in the presence of trimethylsilyl chloride (TMSCl). The following reactions were investigated: (1) aromatic aldehydes with cycloalkanones, (2) aromatic aldehydes with aromatic ketones, (3) cycloalkanones with aliphatic aldehydes, and (4) the self-condensation reactions of aliphatic aldehydes and cycloalkanones.

Full text of DOI:10.1246/cl.2004.668

668
Chemistry Letters Vol.33, No.6 (2004)
A New Lewis Acid System Palladium/TMSCl for Catalytic Aldol Condensation
of Aldehydes with Ketones
Yulin Zhu and Yuanjiang Panꢀ
Department of Chemistry, Zhejiang University, Hongzhou 310027, P. R. China
(Received March 2, 2004; CL-040232)
Palladium on charcoal effectively catalyzed the aldol con-
cellent yields and the results of these reactions were shown in
Scheme 1. Different attempts to carry out selective mono-con-
densations of cyclopentanone or cyclohexannone were not suc-
cessful nor did we obtain a mixture of mono or di-aldol products.
Also we did not observe the formation of a self-condensation
product of a cycloalkanone in any of these reactions.
In another experiment, when cyclooctanone (1c) reacted
with different aromatic aldehydes (2a–2h), contrary to
Scheme 1, we obtained neither 2,8-bis(benzylidene)cycloocta-
none nor a mixture of mono- with di-aldol products. We only
gained a good yield with selective mono-condensation of prod-
ucts (3ca–3ch) (Scheme 2).
densation reactions of different ketones with aldehydes in the
presence of trimethylsilyl chloride (TMSCl). The following re-
actions were investigated: (1) aromatic aldehydes with cycloal-
kanones, (2) aromatic aldehydes with aromatic ketones, (3)
cycloalkanones with aliphatic aldehydes, and (4) the self-con-
densation reactions of aliphatic aldehydes and cycloalkanones.
Reactions forming carbon–carbon bonds, catalyzed by pal-
ladium, are very effective tools for synthetic chemists.1 Aldol
condensation is one of the most useful reactions in organic
chemistry.2 In this paper we present a new approach to these
condensation reactions where palladium catalyzed the cross
and self aldol condensation reactions of ketones with aldehydes
in the presence of trimethylsilyl chloride (TMSCl).
Bis(arylmethyllidene)cycloalkanones were a particularly in-
teresting class of compounds which were used as precursors for
the synthesis of bis(arylmethyllidene)cycloalkanones with bio-
active pyrimidine derivatives3 and as intermediates to form com-
pounds with particular qualities.4 Although numerous methods
for the preparation of these compounds have been reported,5–12
some difficulties have been encountered in their actual prepara-
tion, because of troublesome procedures, expensive reagents, or
poor yields. For example, the classical cross condensation reac-
tion of cycloakanones with aldehydes catalyzed by acids or bas-
es is reversible.5 Although while Ishii’s method gave satisfactory
yields, the reagent (Cp2ZrH2) was not easily prepared and self-
condensation occured as a side reaction.8 Nakano reported a
newer practical method, using Cp2TiPh2 as a catalyst and the re-
action was carried out at a higher temperature (120 ꢁC) in a
sealed ampoule.9
Scheme 2.
The reactions shown in Schemes 1 and 2 were not affected
by the substituent groups. Aromatic aldehydes or aromatic
ketones carrying either electron-donating substituents such as
–CH3, –Cl, –OCH3, or electron-withdrawing substituents such
as –F, –NO2 all reacted well, giving excellent yields.
In Scheme 3, cyclopentanne (1a) and cyclohexanone (1b)
reacted with terephthaladehyde (2i) at 75 ꢁC, and a yellow poly-
mer was obtained. Despite changing the reaction conditions,
such as the temperature (at 20 or 45 ꢁC) and using solvents such
as ether, THF, benzene, toluene, chloroform, we did not obtain
any 2,20-terephthalylidene-di-cyclopentanone nor 2,20-tereph-
thalylidene-di-cyclohexanone. However, cyclooctanone did re-
act with terephthaladehyde (2i) through two groups –CHO to
form 2,20-terephthalylidene-di-cyclooctanone (3ci) in good yield
79%.
Cyclopentanone (1a) and cyclohexanone (1b) reacted with
different aromatic aldehydes (2a–2h) such as benzaldehyde
(2a), 4-methylbenzaldehyde (2b), 4-chlorobenzaldehyde (2c),
anisaldehyde (2d), cinnamaldehyde (2e), 4-fluoraldehyde (2f),
4-nitrobenzaldehyde (2g), and furfural (2h) with 1–2 mol % of
palladium at 75 ꢁC. All the reactions were finished in 5 h with ex-
Scheme 3.
In the same reaction conditions, aromatic ketones readily re-
acted with aromatic aldehydes to give a variety of substituted
chalcones with excellent yields. These compounds were poten-
tially useful synthetic intermediates as well as having significant
pharmacological properties.13 We studied the condensation of
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.6 (2004)
669
acetophenone (1d), 4-nitroacetophenone (1e), 3-nitroacetophe-
none (1f), 3-chloroacetophenone (1g), 3-methoxyacetophenone
(1h), and acetic acid 3-acetylphenyl ester (1i) with different ar-
omatic aldehydes (2a–2h). ꢀ,ꢁ-Unsaturated ketones were isolat-
ed and identified with yields ranging between 85 and 98%, no
side reaction was observed. Compared to the reactions of 4-sub-
stituted acetophenones, 3-substituted acetophenones (1f–1i)
were more difficult.
such as cyclopentanone (1a) or cyclooctanone (1c).
TMSCl exhibited remarkable reactivity as a ‘hardsoft’ re-
agent. Reagents and all solvents were analytically pure grade
and were used without further purification. Cycloalkanones, al-
dehydes, DMF, and palladium were mixed in flask and TMSCl
was added dropwise at room temperature. After 30 min, the reac-
tion mixture was stirred at 75 ꢁC for 4.5 h. The product (3aa–3ig)
precipitated directly after the whole reaction mixture were
placed in a refrigerator for over night, filtered through a Buech-
ner funnel, washed with ethanol, and dried to give the target
compounds as a crystalloid. Otherwise the reaction mixture
was extracted with ethyl acetate; the organic layers were washed
with water, dried, filtered off and then evaporated to the com-
pounds (3aj–3cl, 3w–3z).
In conclusion, we have used palladium as a highly effective
catalyst for the cross and self-condensation reactions of alde-
hydes with ketones shown in Schemes 1–6. Our method offers
several advantages, including mild reaction conditions, higher
yields, shorter reaction time and a simpler experimental proce-
dure.
Scheme 4.
In order to investigate this catalytic feature in more details,
we researched the cross-condensation between cycloalkanones
and aliphatic aldehydes. As reported in the literature,8 it was dif-
ficult to complete the direct cross-condensation reactions. There-
fore, this method was an easier and more effective route to pre-
pare 2-alkylidenecycloalkanones. In Scheme 5, during the
reaction of cycloalkanones (1a–1c) with n-butylaldehyde (2j),
valeraldehyde (2k), and n-heptaldehyde (2l), we observed the
occurrence of small amounts of self-condensates 3x–3z and
3w (Scheme 6) as by-products.
This research was funded by NSFC of China (20375036)
and NSF of Zhejiang Province (Rc0042).
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Scheme 5.
We have extended the usefulness of this catalytic method in
the successful self-condensation reactions of cycloalkanones and
aliphatic aldehydes (Scheme 6). Self-condensation of cyclohex-
anone (1b) gave excellent yields. Also aliphatic aldehydes (2j–
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Scheme 6.
Published on the web (Advance View) May 10, 2004; DOI 10.1246/cl.2004.668