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Ph
Ph
MM100, 30 Hz, 3 h
+
CO
2
t
Bu
HCl
.
H
2
N
N
NH
CO
2
t
Bu
2 steel balls, 7 mm O
Ph
Ph
17
18
19,
98%
KOH (2 equiv)
20 Hz, 1-2 h
20
(10 mol%)
R
1
X (1 equiv)
O
N
R
2
= anthracene
Br
R
2
N
R
1
20
Ph
CO
2
t
Bu
N
Ph
R
2
= Alkyl, Aryl
21,
92-97%,
ee
36-75%
11 examples
Scheme 6.6
Solvent-free synthesis of glycine Schiff base and enantioselective alkyla-
tion under PTC-conditions.
6.2.4 Synthesis of Unsaturated Amino Acids
Unsaturated unnatural amino acid derivatives 23 were also obtained using
the ball-milling technique by performing a Horner-Wadsworth-Emmons
reaction
25
or a Heck-Jeffery protocol,
26,27
and used as platform to access
2-carbonylindoles 26 (Scheme 6.7).
28
High yields of Boc-protected unsaturated amino-esters were obtained by
grinding amino-phosphoryl acetate 22 and various aromatic or aliphatic
aldehydes in a planetary ball-mill based on a Horner-Wadsworth-Emmons
reaction, with a conversion close or equal to 100% (Scheme 6.7).
25
The (Z)/(E)
selectivity was always very high (100 : 0) with exclusive formation of the (Z)-
isomer using aromatic aldehydes and hindered ortho-substituted substrates,
except in one case (with naphthaldehyde the selectivity was lower, (Z)/(E)82:
18). Linear aliphatic aldehydes were also tested: in most cases high yields (up
to 90%) and 100% selectivity in favor of the (Z)-isomer were obtained, while
branched or sterically hindered aldehydes were less suitable, with in-
complete conversion of starting material, while ketones were unreactive.
A comparative experiment starting from aminophosphoryl acetate 22 and
3,5-dimethoxybenzaldeyde (with Cs
2
CO
3
as base) was carried out in a flask
with a stir bar. After 7 h, incomplete conversion (43%) was obtained, as well
as by heating the mixture at 50 1C (45% conversion). Under the same con-
ditions, mechanochemical activation led to full conversion and 94% yield
for unsaturated Boc-protected amino ester 23 (R
1
ΒΌ
3,5-dimethoxyphenyl),
showing the importance of ball-milling activation for this transformation.
Exclusive (Z)-selectivity was also observed when dehydrophenylalanine
derivatives 23 were prepared using solvent- and phosphine-free Heck-Jeffery
protocol
26,27
in a planetary mill under phase transfer conditions involving
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