Biomedical Engineering Reference
In-Depth Information
R-Nu
R-X (R = aryl, vinyl)
L
n
Pd(0)
reductive
elimination
oxidative
addition
R
R
L
n
Pd
L
n
Pd
Nu
X
2
1
β
-elimination
R-H + L
n
Pd(0)
Base, HX
NuH, base
SCHEME 3.2
General mechanism for the Buchwald-Hartwig-type reactions.
(Pd
2
(dba)
3
), or bis(dibenzylideneacetone)palladium (Pd(dba)
2
)) with chelating phos-
phine ligands (tri(
o
-tolyl)phosphine (P(
o
-Tol)
3
), 2,2
0
-bis(diphenylphosphino)-1,1
0
-
binaphthyl (BINAP), etc.) and a stoichiometric amount of a base (
t-
BuONa, Cs
2
CO
3
,
K
3
PO
4
, etc.) at high temperatures (80-100
C, with toluene being in most cases the
solvent of choice).
3.2.2. Mechanism
Although detailed studies are available [10,15c,16], it is not intended in the context of
this chapter to give an exhaustive explanation on the mechanistic pathway of the
reaction. A general mechanism for this Pd-catalyzed cross-coupling reaction is shown
in Scheme 3.2. Hence, oxidative addition of the aryl or vinyl halide (R-X) to the Pd(0)
complex gives intermediate L
n
Pd(R)X (
1
). A base-assisted generation of the nucle-
ophile allows the transformation of the Pd(II) complex
1
into a novel L
n
Pd(R)Nu
complex
. Reductive elimination finally ends the catalytic cycle to afford the cross-
coupled product R-Nu.
2
3.2.3. Scope and Limitations
Since the pioneering work by Buchwald and Hartwig in 1995 with amine nucleo-
philes, extensive efforts have been devoted on developing new catalytic systems able
to overcome the lack of generality observed in the first stage of this cross-coupling
reaction. Thus, different classes of ligands [15a,17] (e.g., chelating diphosphine,
electron-rich monodentate phosphine, and hindered alkyl bisphosphines) have
undoubtedly resulted in a new set of reaction conditions that allows a broader scope
of these transformations (Scheme 3.3).
Nowadays, less reactive nucleophiles (such as primary alkyl amines, ammonia,
alkoxides, imines, and sulfoximines), triflates, nonaflates, and sulfonates instead of
halides, weaker bases (Cs
2
CO
3
and K
3
PO
4
instead of
t-
BuONa), and lower tem-
peratures can be successfully used in these cross-coupling reactions. In addition, in
the last decade, vinylation reactions have also appeared [18]. Nevertheless, some
functional group incompatibilities together with the high cost of palladium salts and
ligand complexity remain the main drawback for these reactions.
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