Modern Heck Reactions - New Trends in Cross-Coupling: Theory and Applications - page 433

R R

COOH Pd(OAc) 2 (5 mol%)

O 2, Ac-Ile , KHCO 3
t-A my lOH , 90° C , 2 h

COOH

CO 2 Et

R=CF 3 (99%)
R=Me(98%)

Scheme 9.120 Alkenylation directed by a carboxylic group. Ac-Ile ¼ N-acetyl-L-
isoleucine.

O

O

COOtBu
P d(OAc) 2 (1 0 mol%)
bathophen, O 2
toluene, 110°C, 24 h

NHTs

NHTs

F 3 C F 3 C

CO 2 tBu

Ph Ph

O

NTs

N N

F 3 C

bathophen

64%

CO 2 tBu

Scheme 9.121 N-Tosylamide-directed alkenylation.

Subtle effects were revealed on comparing kinetic parameters - relative
rate constants and H/D isotope effects, which were established to be
dependent on the substituents in phenylacetic acid and the ligand used, e.g.
with N-Boc-L-valine ligand o-methylphenylacetic acid is slightly more re-
active than the o-trifluoromethyl derivative (k CF 3 /k Me ¼ 0.9), whereas with N-
acetyl-L-isoleucine the opposite was observed (k CF 3 /k Me ¼ 1.38). Given that
the variations observed are rather small and dependent on a slight variation
in reactivity, this case nicely illustrates the variable nature of the reaction
pathway of directed palladation.
N-Tosylbenzamides were demonstrated by Zhu and Falck to be excellent
substrates for directed alkenylation, allowing for both electron-rich and
electron-withdrawing aryl rings and both electron-rich and electron-with-
drawing alkenes. 367 Oxygen is used as terminal oxidant, being superior to
benzoquinone, and 4,7-diphenylphenanthroline (bathophenanthroline) de-
rivative as the ligand of choice. The products of the reaction are not the
initially formed alkenes, but the products of cyclization. Electron-deficient
alkenes give the respective Michael adducts (Scheme 9.121).
Electron-rich alkenes give the products of Wacker-type palladium-assisted
conjugate addition as a mixture of exo and endo cyclization products, with
the exo adduct being the major one (Scheme 9.122).
The involvement of a palladacycle was explicitly established and studied
by Brown and co-workers. 368 The reaction of acetanilides with acrylate in the
presence of strong acid and benzoquinone as terminal oxidant involves
the respective palladacycles, which can be isolated and reintroduced into the
catalytic cycle (Scheme 9.123).