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OMe
OMe
OMe
OMe
Pd(OAc)
2
(1.2 equiv)
NaOAc
N
N
MeO
Pd
Cl
O
Me
(1) CO (40 atm) MeOH
(2) SiO
2
, CHCl
3
OMe
OMe
+
NH
O
NH
O
Scheme 10.75 Oxidative carbonylation for lactam synthesis.
Pd(OAc)
2
(10 mol%)
CuO (1 equiv)
CO (1 atm)
AcOH, 110 °C, 23 h
O
NH
R
'
NH
R
'
H
R"
N
R"
Scheme 10.76
Intramolecular carboxamidation.
recent literature. A wide variety of functional groups, such as amide, pyri-
dine, imine, ketone and carboxylate, can function in this way. In addition,
this coordination also serves to direct reaction to a specific C-H site and thus
deliver the regioselectivity that is so important to the transformation of the
complex molecules that are of interest to the pharmaceutical industry. An
early application of this approach in natural product synthesis was provided
by Sames and co-workers (Scheme 10.75).
93
They used the stoichiometric
reaction of a Schiff base with palladium chloride to form the palladacycle,
with subsequent reaction with CO (40 atm) and then acid hydrolysis to give
the lactam in a one-pot reaction.
The ready formation of palladacycles from N-alkyl-o-arylalkylamines is
another example of C
sp
2
-H activation. Combining this with carbon mon-
oxide (balloon pressure), oxygen and Cu(OAc)
2
while heating in toluene
proved effective for the formation of benzolactams.
94
The reaction proceeds
much more rapidly when forming the five- rather than the six-membered
ring and is also accelerated by the presence of other potentially chelating
donor atoms such as oxygen in a 3,4-methylenedioxy group. This study
was later extended as a method to provide ureas, carbamates and 1,3-
oxazolidinones and also benzolactams.
95
With ethanol as the nucleophile,
N,N-dimethylbenzylamines are carbonylated to yield ortho-substituted
carboxylate esters with lithium chloride being added as a Lewis acid to
promote the insertion of CO into the Pd-C bond.
96
In a similar reaction, Zhu
and co-workers reported the intramolecular carboxamidation of N-arylami-
dines to yield quinazolin-4(3H)-one derivatives (Scheme 10.76).
97
Enabling
these reactions to be carried out under milder conditions is advantageous
for maximizing the selectivity of the reaction, in addition to avoiding the
degradation of sensitive substrates.
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