Angewandte
Chemie
tion. For example, a catalyst based upon Pd(OAc)2 and 2
allowed for the borylation of 4-chloroanisole in 97% yield at
room temperature (Table 3, entry 1). This approach was also
applicable to sterically hindered aryl chlorides, such as 2-
chloro-p-xylene and 2-chloro-m-xylene (Table 3, entries 4 and
5). It is noteworthy that with the latter substrate, a signifi-
cantly higher yield was obtained using one-half the amount of
palladium precatalyst than when the reaction was carried out
at 1108C.[7] Furthermore, activated aryl chlorides such as 4-
chlorobenzophenone were efficiently converted to the corre-
sponding pinacol boronate esters (Table 3, entry 6). This
protocol represents the first Pd-catalyzed method for trans-
forming aryl chlorides to aryl boronate esters at room
temperature.
Although aryl boronate esters can be precursors to a
variety of compounds, their primary application is in the
synthesis of biaryl species via the Suzuki–Miyaura reaction
with an aryl halide or sulfonate.[1] However, the boronate
ester is typically prepared and isolated prior to the cross-
coupling step. Although a few reports have utilized a “one-
pot” reaction protocol combining borylation and Suzuki–
Miyaura steps to synthesize biaryl compounds, these methods
employ catalysts that neither display prolonged stability nor a
high level of activity.[8] Consequently, previous efforts have
been unsuccessful when attempting to utilize relatively
unreactive aryl chlorides for the one-pot biaryl synthesis.
Moreover, the addition of a second portion of palladium
catalyst is necessary for the reaction to go to completion.
In our initial studies on the borylation of aryl chlorides
(see above), we found that when employing bases such as
K3PO4, approximately 15–20% of the aryl halide was
converted directly to the symmetrical biaryl compound.[9]
Furthermore, if K3PO4·H2O was utilized, this product was
isolated in high yield. A Pd-to-ligand ratio of 1:4 was found to
be optimal in order to maintain catalyst stability. Using the
conditions given in Table 4, 4-n-butylchlorobenzene was
directly converted to the symmetrical biaryl product in
near-quantitative yield (Table 4, entry 1). This method was
then applied to the homocoupling of an electron-rich chloride
(2-chloroanisole, entry 2), a relatively hindered cloride (2-
chloro-p-xylene, entry 3), and a heteroaryl chloride (3-chlor-
othiophene, entry 4), all of which were readily converted to
the corresponding symmetrical biaryl compounds.
Although this method was useful for the preparation of
symmetrical biaryl compounds, we sought to develop con-
ditions for the direct synthesis of their unsymmetrical
counterparts. In this endeavor, a catalyst system based upon
[Pd2dba3] and 2 proved to be effective for the borylation as
well as for the subsequent Suzuki–Miyaura reaction. In this
process, the substrate was subjected to standard Pd-catalyzed
borylation conditions with subsequent addition of the second
aryl chloride and aqueous K3PO4. No workup was performed
nor was catalyst added prior to conducting the second
reaction of the sequence. This protocol was used successfully
with a variety of aryl chlorides and with a vinyl chloride
(Table 5). In addition, heteroaryl chlorides could be
employed in the first step (Table 5, entry 7) or in the second
step (Table 5, entries 2 and 3) while maintaining good or
excellent yields of the biaryl products. However, these
standard conditions could not be used with many ketones,
as significant a-arylation of the substrate was observed.[10]
However, if KOAc was replaced with K3PO4 in the first step,
then the biaryl species was obtained in good yield (Table 5,
entry 8). These methods represent the first processes for the
direct synthesis of symmetrical and unsymmetrical biaryl
compounds from two aryl chlorides.
To help determine what effect biaryl phosphine ligands
may have on the Pd-catalyzed borylation of aryl halides with
A, we turned to computational chemistry. Specifically, we
were interested in the common use of KOAc in Pd-catalyzed
borylation reactions. All of the calculated structures de-
scribed below were optimized using Gaussian 03[11] and the
B3LYP[12] functional in combination with the 6-31G(d) basis
set for all nonmetal atoms and LANL2DZ + ECP[13] for the
Pd center.
It is possible that the use of KOAc in Pd-catalyzed
borylation reactions facilitates the formation of an [LPd(Ar)-
OAc] compound from an oxidative addition species (e.g.
[LPd(Ar)Cl], complex 6, Scheme 2). This type of metathesis
was shown to occur in the Pd-catalyzed borylation reactions
of aryl iodides and bromides by Miyaura in 1995.[14] Although
the calculated free energy of reaction is + 9.2 kcalmolÀ1, this
metathesis may still occur because
of concurrent generation and pre-
cipitation of KCl, thus shifting the
Table 4: Palladium-catalyzed preparation of symmetrical biaryl compounds.[a]
reaction equilibrium to the product
(Scheme 2).
On the basis of our previous
Entry
1
Product
Yield [%][b]
98[c,d]
Entry
3
Product
Yield [%][b]
77[c,d]
study of oxidative addition inter-
mediates involving biaryl phos-
phine ligands, it is very likely that
transmetalation of bis(pinacolato)-
diboron occurs when complex 7
(Scheme 2) is in a geometry such
that the Pd center is distal to the
non-phosphine-bearing ring of the
ligand.[15] The necessity for this
situation is the extreme crowding
around the Pd center when the
Pd center is coordinated to the
2
70
4
87
[a] Reaction conditions: 1 equiv of aryl or heteroaryl chloride, 0.50 equiv of A, 3 equiv of K3PO4·H2O,
dioxane (4 mL(mmol halide)À1), cat. [Pd2dba3], Pd/1=1:4. [b] Yield of isolated product based upon an
average of two runs. [c] K3PO4 used instead of K3PO4·H2O. [d] H2O (0.50 mL) added to the reaction
mixture by syringe after 6 h.
Angew. Chem. Int. Ed. 2007, 46, 5359 –5363
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5361