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CN
O
X
R
NH
2
CN
CN
Ball mill
40 min.
+
+
R
H
HN
NH
H
2
N
NH
2
X
92-98%
R =
p
-CH
3
-O-C
6
H
4
,
p
-OH-C
6
H
4
,
p
-NO
2
-C
6
H
4
,
p
-Cl-C
6
H
4
, Ph
X = S, O
Scheme 1.38 Three component condensation in a ball mill forming substituted
2-thioxo and 2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitriles.
O
O
O
H
DABCO
Ball milling
+
HO
O
Scheme 1.39 One-pot domino oxa-Michael-aldol reaction to synthesize xanthone
derivatives.
O
O
O
O
OH
Et
3
N
Ball milling
H
DABCO
Ball milling
H
H
+
OH
O
O
dihydrobenzopyran
chromene derivative
Scheme 1.40 Chemoselective base-catalyzed condensation of salicaldehyde with
a,b-unsaturated aldehydes.
in some cases resulted in different chemoselectivities compared to con-
ventional solution-phase synthesis. Xanthone and its isomers are six-
membered oxygen-containing heterocycles and can be synthesized in a ball
mill by a one-pot domino oxa-Michael-aldol reaction (Scheme 1.39).
35
Br
¨
se made a systematic study of the ball milling reaction to determine
the influence of the ratio of the reactants, the rotational frequency of the
mill, the number of balls, the milling time on the reactivity and chemos-
electivity. The best yield was obtained using salicaldehyde and cyclohex-
enone in 1 : 2 molar ratio. It has been found that increasing the reaction
time does not increase the yields linearly, probably because the high tem-
perature generated during the milling procedure can be nullified by using
water. Concerning the chemoselectivity, it has been observed that changing
the base from DABCO to Et
3
N increases the yield of dihydrobenzopyran,
while use of DABCO gives the chromene derivative as a major product
(Scheme 1.40).
35
The above experimental observation clearly established the
fact that some parameters intrinsically linked to the ball-milling process
largely influence the yield and sometimes chemoselectivity of a reaction.
Another heterocycle that contains a six-membered oxygen ring is naph-
thopyran, the derivatives of which have attracted considerable attention due
to their interesting photochromic properties and biological appli-
cations.
36-38
An ecient solid state synthesis of naphthopyran was achieved
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