Chemistry Reference
In-Depth Information
Scheme 5 Metallation of
thiophenes followed by
formylation with
N
-
formylpiperidine [
27
]
1. iPr
2
NMgCl, THF, rt
2. NFP, THF, rt
R
1
=CO
2
Et
R
1
R
1
CHO
52%
S
S
R
1
= H
84%
6
7
Scheme 6 Vinylation of
thiophene [
28
,
29
]
Pd(OAc)
2
13-90%
+
R
2
R
1
R
1
S
S
R
2
8
9
10
Table 2 Vinylation of
thiophene [
28
,
29
]
R
1
R
2
Yield
a
(%)
Ref.
24 (2:1)
b
H
CN
[
28
]
H
Ph
13
[
28
]
H
CO
2
Me
33
[
28
]
H
CO
2
Bu
83
[
29
]
Me
CO
2
Bu
87
[
29
]
OMe
CO
2
Bu
62
[
29
]
Ph
CO
2
Bu
80
[
29
]
4-MeOC
6
H
4
CO
2
Bu
87
[
29
]
H
CO
2
t
-Bu
90
[
29
]
4-MeOC
6
H
4
CO
2
t
-Bu
78
[
29
]
H
CONMe
2
85
[
29
]
Me
CONMe
90
[
29
]
OMe
CONMe
70
[
29
]
46 (2:1)
b
OMe
CN
[
29
]
a
Isolated yield of
E
-isomers
b
Ratio of
E
-to
Z
-isomers in parentheses
electrophilic directing groups. Therefore, the metallation of thiophenes with
organomagnesium compounds is a suitable alternative methodology.
For instance, the hydrogen-magnesium exchange of ethyl thiophene-2-carboxylate
6 is viable using (diisopropylamino)magnesiumchloride, without a side reaction at the
ester functionality with either the organomagnesium reagent or the arylmagnesium
intermediate (Scheme
5
)[
27
]. The metallation occurs selectively at the 5-position of
the thiophene ring. The subsequent reaction of the thienylmagnesium intermediate, as
nucleophile, for example, with
N
-formylpiperidine (NFP) gives the aldehyde 7.
2.1.4
Introduction of Allyl, Alk-1-enyl, or Alk-1-ynyl Groups
Vinylthiophenes 10 can be synthesized by direct introduction of alk-1-enyl or alk-1-
ynyl groups using equimolar amounts of palladium(II) chloride or palladium
(II) acetate (Scheme
6
, Table
2
)[
28
,
30
,
31
]. A convenient method for the prepara-
tion of mono-alkenylated thiophenes is direct alkenylation with catalytic amounts of
