Chemistry Reference
In-Depth Information
> 95%
P(
t
-Bu)
2
D
D
1.1 mol% Cat, C
6
H
12
2. D
2
O, 75 ° C, 3 d
H
2
N
Ru
H
S
D
D
H
S
> 95%
P(
t
-Bu)
2
1
3
2
Scheme 3 Transition metal-catalyzed H/D exchange [
6
]
R
1
R
1
BuLi, hexane
Li
S
4
S
5
Scheme 4 Selective 2-lithiation
Table 1 Selective
2-lithiation
R
1
Ref.
H
[
16
]
OMe
[
17
]
O
t
-Bu
[
18
,
19
]
F
[
20
]
CN
[
21
]
CH
2
NMe
2
[
22
]
CO
2
Li
[
23
,
24
]
of halogenated thiophenes, LDA is the metallating agent of choice because its weak
nucleophilicity allows the selective substitution of hydrogen with lithium instead of a
possible halogen-metal exchange [
10
]. Next to chemoselectivity issues, substituents
on the thiophene skeleton also have a strong influence on the regioselectivity of the
hydrogen-lithium exchange process [
11
,
12
]. Thus, thiophenes bearing substituents at
the 2-position usually form 2,5-disubstituted products with organolithium com-
pounds, whereas metallation of 3-alkyl thiophenes leads to a mixture of 2- and
5-lithiated products [
13
-
15
]. The selective 2-lithiation, which gives rise to
2,3-disubstituted derivatives (Scheme
4
,Table
1
), is possible with substituents at
C-3 such as alkoxy, fluoro, cyano, carboxylate, or dimethylaminomethyl [
17
-
23
,
25
,
26
]. The last can direct the lithium atom into a specific position due to coordination
with nitrogen. The dianionic lithium 2-lithiothiophene-3-carboxylate comprises a
useful
tool
for
the further
synthesis of
thiophenecarboxylic acid or ester
derivatives [
24
].
2.1.3
Introduction of Formyl Groups by Metallation and Subsequent
Reaction with
N
-Formylpiperidine
The application of hydrogen-lithium exchange reactions is limited due to possible
reactions of nucleophilic organolithium reagents or aryllithium intermediates with
