Carbon–Carbon Bond Forming by Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 43

were achieved in the asymmetric cross-dehydrogenative coupling after 30-90
min milling.

2.5 Carbon-Carbon Bond Formation by
Condensation Reactions
Condensations reactions are an important tool for the formation of carbon-
carbon single and double bonds. Several reaction protocols have been de-
veloped and some famous name reactions like the Michael addition or
Knoevenagel reaction belong to this group.

2.5.1 Aldol-type Reactions
Through the reaction of enolates and carbonyl compounds, one can gain
access to a-hydroxy carbonyl compounds or a,b-unsaturated carbonyl com-
pounds. These reactions, known as aldol reaction and aldol condensation,
are valuable synthetic steps, widely used for syntheses of bioactive com-
pounds, e.g. the aldol reaction is an important part in the synthesis of
epothilone. 30
The first aldol condensation in a mixer ball mill (MBM) was published by
Raston and Scott. 31 Veratraldehyde, 4-phenylcyclohexanone and 1-indanone
were directly milled with NaOH in various combinations - prior formation of
the enolates was not necessary. The authors observed that reaction under
solvent-free ball milling conditions was much more selective than in solu-
tion and single condensation products could be achieved in good yields. The
self-condensation product was only formed in traces. In contrast, the solu-
tion based reaction protocols delivered mixtures of all possible products.
The reaction proceeds in short milling times, 2 min of milling over a period
of 10 min, yielding the crossed aldol products in 77-98%.
Waddell et al. observed that cyclohexanone undergoes an aldol type re-
action in the presence of ethyl bromide and NaOH. 32 After 17 h milling, the
aldol product was formed instead of the actually intended alkylated product.
Owing to heating of the milling vessel by grinding, ethyl bromide was in the
gas phase and therefore not available for the alkylation reaction. On this
account cyclohexanone undergoes self-aldol condensation.
While Raston found the aldol condensation product, Kaupp et al. observed
only an aldol addition product for the reaction of ninhydrin with dimedone
(Scheme 2.16). 33 After 1 h milling in a mixer ball mill they obtained the aldol

O O O

O

OH

+

OH

MBM
20-25 s -1 , 1 h

OH

O

O

O

O

Scheme 2.16 Aldol condensation of ninhydrin with dimedone.