Chemistry Reference
In-Depth Information
S
Me
SMe
SMe
CuO, I
2
DMSO, 65 °C
KI, c. HCl
Me
2
CO, r
t
69-80%
LR
PhMe, reflux
75-85%
CH
3
Ar
Ar
Ar
Ar
Ar
Ar
Ar
65-94%
S
O
OO
OO
7
8
Scheme 9 Homo-coupling of aryl methyl ketones to prepare 1,4-di(aryl)-1,4-diketones and the
synthesis of 3-(methylthio)thiophenes [
16
]
EtO
2
C
Cl
Na powder
PhH, reflux
45%
EtO
2
C
O
O
OO
KOH
H
2
O, 95 °C
95%
P
4
S
10
,70°C
64%
S
OO
Scheme 10 Alkylation of a 1,3-keto-ester with a 2-haloketone then hydrolysis and decarboxyl-
ation to form a 1,4-diketone for thiophene ring synthesis [
20
]. N.B. The original method for
enolate formation is shown - an alternative method would be used nowadays
CO
2
Me
CO
2
Me
Et
2
Zn, CH
2
I
2
CH
2
Cl
2
CO
2
Me
PhCHO
then
PCC
t
-Bu
ZnI
t
-Bu
t
-Bu
OZnI
O
O
9
10
CO
2
Me
CO
2
Me
LR, PhMe
MW, 120 °C
50%
t
-Bu
Ph
t
-Bu
Ph
S
OO
Scheme 11 The conversion of a 1,3-keto-ester into a 2-acylmethyl derivative of a different
1,3-keto-ester; the synthesis of thiophene-3-esters [
21
]
[
17
-
19
]); Scheme
10
, from work in 1960, illustrates the venerable pedigree of this
method [
20
].
An alternative way in which
-keto-esters can be used to form 1,4-diketones is
shown in Scheme
11
[
21
]. A cyclopropyl intermediate 9 is in equilibrium with
organozinc species 10 which can then be trapped, best with an aldehyde followed
by oxidation, to give a 1,4-diketone. Note that the thiophene formation (Scheme
11
)
involves the two ketone carbonyl groups and not the ester carbonyl, although in
other cases, it can involve ester carbonyl groups (cf. Scheme
6
).
The Stetter procedure [
22
,
23
] is an excellent route to 1,4-diketones. Here,
cyanide anion, or more often a thiazolium ylide, catalyses the addition of an
aldehyde to an
ʲ
-unsaturated ketone or a precursor thereof, e.g. a Mannich
base. For example, the reaction of pyridine-4-carbaldehyde with Mannich base
11, catalysed by the ylide from 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide 12, produces the 1,4-diketone 13, from which the central thiophene ring
of 14 can be constructed (Scheme
12
)[
24
]. Comparable thiazolium ylide catalysis
α
,
ʲ
