Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 742

(10 mol%) and JohnPhos ligand 128 (20 mol%) loadings were required to
achieve full consumption of 127, much higher than in the original publi-
cation (1-3 and 2-6 mol%, respectively; the reason for this is not clear). In
the kilogram-laboratory facility, 127 was treated with Pd(OAc) 2 , JohnPhos
ligand (128) and Et 3 N (1.5 equiv.) in 2-MeTHF-IPA (4:1 v/v) at 70-75 1C for
2.5 h. Upon completion of reaction, the hot mixture (to avoid precipitation of
129) was filtered through Celite and concentrated at reduced pressure. To
the residue was added IPA and, after heating the resulting mixture to reflux
to redissolve the solids, 129 crystallized upon cooling to 25 1C. Filtration and
IPA washing of the cake afforded 7.7 kg of 129 in 76% yield and 98.4% purity.
This material contained 100-800 ppm Pd but no efforts were made to effect
metal removal at this stage since downstream chemistry lowered the metal
content to acceptable levels ( o 20 ppm).
Several mechanisms were proposed by Hennessy and Buchwald for this
transformation based on kinetic isotope effect data (Scheme 15.28). 143 After
oxidative addition into the C-Cl bond of I (rate-determining step based on
observed isotope effect), Pd-enolate II can undergo electrophilic aromatic
substitution to provide palladacycle III followed by loss of HCl and reductive
elimination to afford oxindole V (Path A). A second possibility (Path B) is that
II undergoes carbopalladation to give species VI followed by anti-elimination
of HPdCl (or, alternatively, isomerization followed by syn-b-hydride elimin-
ation) to generate V. Hennessy and Buchwald suggested that both Paths A
and B can take place simultaneously. Finally, a true C-H activation mech-
anism is possible (Path C) that can occur via either s-bond metathesis or a

+ H

Pd

Pd

− HCl

N O

N O

R

Path A R

Cl −

Reductive
elimination

Electrophilic
substitution

III IV

ClPd

Path B

H

O O

Carbopalladation

Pd catalyst − HPdCl

O

Cl PdCl

O

N
R

N
R

N
R

N
R

V

II

I

VI

+

Cl

H

Pd

Path C

Reductive
elimination

C- H
activation

VII

N O

R

Pd

σ -bond metathesis

or

− HCl

N O

R

R

N

IV

O

VIII

PdCl

1 interaction

π , η

Scheme 15.28 Proposed mechanisms for oxindole synthesis via C-H activation.