Communications
these reaction conditions, other functional groups, such as the
conversion (t1/2 ꢀ 12 m) of ester 13 to amide 14 was
observed.[10]
The above observations suggest that sodium phenoxide is
playing two distinct roles in the formation of amide 14
(Scheme 1).First, owing to its greater nucleophilicity com-
t-butyl ester and nitrile groups, remained intact (Table 3,
entries 8 and 14).Heteroaryl chlorides, such as 3-chloropyr-
idine and 2-chlorothiophene, were converted into the corre-
sponding benzamides without complications (Table 3,
entries 10–13).
To gain evidence for the proposed role of NaOPh in these
transformations, the reaction of 3-chloroanisole and di-n-
butylamine was monitored using in situ IR spectroscopy.In
the initial kinetic experiments, Pd(OAc)2 (2 mol%) and 7
(4 mol%) were used as the catalytic additives.These reac-
tions displayed a variable initiation period, presumably owing
to the reduction of Pd(OAc)2 to Pd0.To improve reproduci-
bility in the kinetic experiments, we prepared [(dcpp)PdPhCl]
(12) from dcpp and [(Ph3P)2PdPhCl] as the monotoluene
solvate.Using 12 (2 mol%) and 7 (2 mol%) as the precatalyst
eliminated the initiation period.
Scheme 1. Proposed reaction pathway for reactions involving acyclic
Figure 1 shows the reaction profile as determined by
in situ IR spectroscopy resulting from the combination of 3-
chloroanisole, di-n-butylamine, and NaOPh under catalytic
conditions at 1208C.A signal at 1736 cm À1, corresponding to
secondary amines.
pared to di-n-butylamine, NaOPh intercepts the palladium
acyl species resulting from oxidative addition of the aryl
chloride and migratory insertion of CO[11] and leads to the
formation of 13.[12,13] We suspect that this lower energy
pathway, involving intermediate ester 13, is the critical feature
that allows lower operational temperatures in this method
compared to previously reported systems that employ similar
ligand/metal systems.Second, NaOPh acts as a Brønsted base
in catalyzing the conversion of the intermediate phenyl ester
to the amide product.The phenoxide anion may also play a
role as a ligand to the metal center by displacement of
chloride.However, at this point we have no evidence to
support this suggestion.Ongoing studies are directed at
further elucidation of these subtle mechanistic details.
In conclusion, we have developed a general, practical
protocol for the aminocarbonylation of aryl chlorides at
atmospheric pressure of CO.Electron-deficient, -neutral and
-rich aryl chlorides were all successfully transformed into the
corresponding amides.Primary, a-branched primary, cyclic
secondary, acyclic secondary, and aryl amines were all
productive in the reaction.Furthermore, the process tolerates
functional groups and utilizes an inexpensive, air-stable, and
commercially available ligand salt.Like previous studies in
this area, the optimal ligand proved to be an electron-rich
bulky bisphosphine.However, the critical innovation in this
process was the use of sodium phenoxide as the basic additive.
In addition to acting as a base, this reagent facilitates acyl
transfer through the formation of phenyl esters as intermedi-
ates and catalyzes the conversion of phenyl ester into the final
amide product.This route has resulted in lower reaction
temperatures and CO pressures in the aminocarbonylation
process, which greatly improves both the practicality and
safety profile of this transformation, and for the first time has
resulted in a general method for the aminocarbonylation of
aryl chlorides.The dual role of NaOPh revealed during this
study underscores the concept that ligands alone, while
important for success in developing a method, are not the
only reaction parameter that needs to be considered.In this
case, consideration of the potential reactive intermediates
Figure 1. Kinetic profile for the reaction of di-n-butylamine and 3-
chloroanisole.
phenyl 3-methoxybenzoate 13, was observed at the beginning
of the reaction.This signal reached a maximum intensity after
about 1 h, and then slowly decayed.Additionally, a signal at
1632 cmÀ1, corresponding to amide 14, was observed a few
minutes after the beginning of the reaction and continued to
increase in intensity for approximately 5 h.At the end of the
reaction, the aryl chloride and 13 had been completely
consumed, and 14 was formed in 88% yield (determined by
GC).Thus, as predicted, phenyl ester 13 appears to be an
intermediate in the formation of amide 14.
To further confirm the intermediacy of the ester, we
examined the kinetics of the conversion of ester 13 to amide
14.Surprisingly, combining ester 13 and di-n-butylamine in
DMSO at 1208C resulted only in the very slow formation of
amide 14 (t1/2 ꢀ 10 h).However, when the same reaction was
conducted in the presence of NaOPh (1 equiv), rapid
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8460 –8463