Chemistry Reference
In-Depth Information
Br Ph
(Ph
3
P)
4
P
d
NMe
2
NMe
2
n
-BuLi
ortho
-metallation
NMe
2
Ph
Li
2.44
2.45
2.46
Scheme 2.16
EtMgBr
Pd(PPh
3
)
4
n
-C
6
H
13
I
n
-C
6
H
13
Et
2.48
2.47
Scheme 2.17
Br
Ph
PhMgBr
dpppNiCl
2
Br
2
, NaOAc,
AcOH
N
N
N
N
N
N
2.49
2.50
2.51
Scheme 2.18
S
BrMg
NiCl
2
, dppbenz
S
S
+
Br
Br
S
S
2.53
2.52
2.54
Scheme 2.19
is sufficiently reactive that coupling is fast, surprisingly good functional-group tolerance can be achieved.
Nevertheless, this reaction is most often used for the synthesis of molecules with little functionality. With
vinyl halides, alkene geometry is retained.
A nickel-catalysed coupling of a Grignard reagent with a bromopyrazole
2.50
was employed as the last
step in a synthesis of withasomnine
2.51
(Scheme 2.18).
20
Nickel catalysis was also employed to make
terthiophene on a 700 g scale (Scheme 2.19).
21
The Kumada reaction was employed for the synthesis of dendralenes, cross-conjugated alkenes, which
show interesting reactivity (Scheme 2.20).
22
The products even include the labile [3]dendralene
2.56
which
has a half-life of just 10 h at 25
◦
C.
A Kumada allylation gave the desired isoindoline
2.59
on a multigramme scale (69.5g as its HCl salt)
accompanied by small amounts of the isomerization product
2.61
(Scheme 2.21). Transition-metal catalysed
isomerization is discussed in Section 11.4. Formation of this by-product could be minimized by correct choice
of ligand and the metal:ligand ratio.
23
Kumada coupling reactions of alkyl chlorides, possessing
-hydrogens also proceed using palladium
catalysis in the presence of either electron-rich phosphines
24
and NHC ligands (Scheme 2.22).
25
Simple
dienes, such as butadiene, may also act as useful ligands in promoting coupling of this sort (Schemes 2.23
and 2.24).
26
This form of catalysis shows a surprising preference for primary alkyl halides over aryl halides.
Grignard reagents are also formed during addition of nucleophiles, with magnesium counter ions, to
benzynes. A Grignard reagent, generated in this way, was employed in a synthesis of Dictyodendrin A.
27
Given the array of aryl groups in this telomerase inhibitor natural product, it is no surprise that palladium-
catalysed coupling was also used later in the synthesis (Schemes 2.25 and 2.26).
