Carbon–Carbon Bond Forming by Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 44

addition product in quantitative yield. A subsequent dehydration to achieve
the double bond was not observed, likely due to the nature of the substrate.
Aluminium as catalyst for the self-aldol reaction of valeraldehyde was re-
ported by Heintz and co-workers. 34 Non-spherical millimeter-sized flakes of
bulk aluminium were stored together with the reactants in the milling
beaker under a nitrogen atmosphere and milled for 24 h. Yields of 467%
could be achieved. As without aluminium no reaction could be observed the
authors suppose that bare aluminium surfaces were created while milling,
leading to an acid-catalyzed aldol addition. The tentative mechanism in-
cludes an enolization of one carbonyl group and an activation step of the
coupling partner on the fresh metal surface leading to an attack of the enol
on the carbonyl group.
A reaction protocol for the asymmetric aldol reaction catalyzed by chiral
amine macrocycle-metal( II ) complexes was developed by Tanaka et al. for
reaction in a planetary ball mill. 35 The scope of reaction was demonstrated
applying several (hetero)cyclic ketones or aliphatic ketones with several
substituted aromatic aldehydes. Yields ranged from 4% to 82%. Best results
were obtained for the reaction of cyclohexanone and 4-nitrobenzaldehyde to
give (1 0 R,2S)-2-[hydroxy(4-nitrophenyl)methyl]cyclohexanone (anti : syn ¼ 60 :
40) (Scheme 2.17). The authors demonstrated that reaction in a ball mill was
superior to protocols in solution or stirring of the neat liquids. Milling for
24 h in a planetary ball mill at 100 min 1 led to yields of 82% with 93% ee. In
comparison, reaction in CH 2 Cl 2 yielded 9% with 63% ee, while under neat-
stirring conditions only 4% with 63% ee were obtained.

2.5.2 Knoevenagel Condensation
The Knoevenagel condensation is a long known and important carbon-
carbon-coupling reaction for construction of a,b-unsaturated compounds.
Traditionally, this reaction is performed in solvents like benzene or DMF
and catalyzed by weak amine bases. Wada et al. investigated the Knoevenagel
reaction of malononitrile or methyl cyanoacetate with aromatic aldehydes
catalyzed by calcite and fluoride (Scheme 2.18). 36 The reaction was per-
formed in a mixer ball mill and yields of 26-100% could be achieved within

NH HN

ligand:

O O O OH

20 mol% CoBr 2
10 mol% chiral ligand

+

HN
H N

NH

PBM
100 min -1 , 24 h

NO 2 NO 2

NH

Scheme 2.17 CoBr 2 -catalyzed aldol reaction of cyclohexanone and aromatic

aldehyde.