Use of highly reactive, versatile and air-stable palladium-phosphinous acid complex [(t-Bu)2P(OH)]2PdCl2 (POPd) as a catalyst for the optimized Suzuki-Miyaura cross-coupling of less reactive heteroaryl chlorides and arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2004.05.010

Using highly reactive air-stable palladium-phosphinous acid complex [(t-Bu)₂P(OH)]₂PdCl₂ (POPd) as a catalyst, synthesis of heteroaryl-aryl cross-coupled products via palladium-catalyzed Suzuki-Miyaura coupling of less reactive substituted 3-chloropyridines with arylboronic acids was achieved in high yields.

Full text of DOI:10.1016/j.tetlet.2004.05.010

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5283–5286
Use of highly reactive, versatile and air-stable palladium–
phosphinous acid complex [(t-Bu)2P(OH)]2PdCl2 (POPd)
as a catalyst for the optimized Suzuki–Miyaura cross-coupling
of less reactive heteroaryl chlorides and arylboronic acids
Subhash P. Khanapure* and David S. Garvey
NitroMed, Inc., Department of Chemistry, 12 Oak Park Drive, Bedford, MA 01730, USA
Received 12 March 2004; revised 3 May 2004; accepted 4 May 2004
Abstract—Usinghighly reactive air-stable palladium–phosphinous acid complex [( t-Bu)2P(OH)]2PdCl2 (POPd) as a catalyst, syn-
thesis of heteroaryl–aryl cross-coupled products via palladium-catalyzed Suzuki–Miyaura couplingof less reactive substituted
3-chloropyridines with arylboronic acids was achieved in high yields.
Ó 2004 Elsevier Ltd. All rights reserved.
In the past decade, the synthesis of biaryl compounds by
palladium-catalyzed cross-couplingreaction between
aryl triflates or aryl halides with arylboronic acids,
commonly referred to as the Suzuki–Miyaura coupling
has developed into an extremely powerful synthetic
method in organic synthesis.1;2 It is noteworthy to
mention that besides the published work in scientific
journals,3;4 the patent literature on the utilization of
Suzuki–Miyaura cross-couplingreaction is extensive.
For example, pharmaceutical companies utilized this
cross-couplingas a cornerstone reaction in generating
extensive libraries of ortho-diarylsubstituted five- or six-
membered ringcompounds for the development of po-
tent cyclooxygenase-2 (COX-2) selective inhibitors. The
biaryl group is also a key pharmacophore in the sartan
class of anti-hypertensive drugs.5;6 Of the various cross-
couplingreactions, Suzuki–Miyaura cross-couplinghas
a practical advantage over other cross-coupling methods
due to the commercial availability of a wide variety of
arylboronic acids, which are nontoxic, as well as air- and
moisture-stable.
eroaryl chlorides. To overcome this limitation, a ver-
satile catalyst Pd2(dba)3/P(t-Bu)3 that catalyzes the
couplingreaction of less reactive aryl chlorides and
arylboronic acids under mild conditions,7 and the use
of sterically hindered ligands such as 2-(dicyclo-
hexylphosphino)biphenyl8 were later discovered. Li and
co-workers developed the air-stable palladium–phosph-
inous acid complexes, for example, [(t-Bu)2P(OH)]2-
PdCl2, [(t-Bu)P(OH)PdCl2]2, and {[(t-Bu)2PO–H–OP(t-
Bu)2]PdCl}2 abbreviated as POPd, POPd1, and POPd2,
that were investigated and found to be efficient catalysts
for a variety of cross-couplingreactions of less reactive
aryl chlorides and arylboronic acids.9–11
Duringthe course of our efforts to synthesize novel
cyclooxygenase-2 selective inhibitors12 the need to find
efficient conditions for the Suzuki–Miyaura cross-cou-
plingreaction of substituted 3-halopyridines with aryl-
boronic acids was required.13 Although bromide
displacements are facile in pyridine systems independent
of the position of the halide usinga traditional palla-
dium catalyst14 such as Pd(PPh3)4, the bromopyridines
are available commercially only in small quantities and
are expensive.
One of the early limitations of the Suzuki–Miyaura
cross-couplingreaction was the poor reactivity of het-
Accordingly, we devised a method optimizing the reac-
tion conditions for the less reactive chloropyridyl com-
pounds. We found that substituted-2-chloropyridines
reacted with arylboronic acids usingthe classical
Keywords: Suzuki–Miyamura; 3-Chloropyridines; Arylboronic acids;
POPd; Cyclooxygenase.
* Correspondingauthor. Tel.: +1-781-6859711; fax: +1-781-2751127;
e-mail: skhanapure@nitromed.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.010

5284
S. P. Khanapure, D. S. Garvey / Tetrahedron Letters 45 (2004) 5283–5286
Pd(PPh3)4 catalyst and sodium carbonate as a base to
give the desired products in high yields, as shown in Eq.
1 (Figure 1).13 However, under the identical conditions,
reactions of 3-chloropyridines with arylboronic acids
failed to yield any of the desired products (Eq. 2). While
one might anticipate that 2-position of pyridine would
be more electron deficient than the 3-position, and
therefore substituted 2-chloropyridines would be better
substrates usingthe Pd(PPh 3)4 catalyst, the total lack of
reactivity for substituted 3-chloropyridines was unex-
pected. Very recently, a similar observation has been
reported (2% yield) duringthe reaction of 3-chloro-
pyridine and phenylboronic acid usinga heterogeneous
catalyst, palladium/charcoal.14 However, the yield of the
reaction was dramatically improved14 usingthe palla-
dium/charcoal catalyst and a sterically hindered ligand
2-(dicyclohexylphosphino)biphenyl.8
phine ligands. Recently, POPd, POPd1, and POPd2
catalysts have been utilized in Stille reactions of 4-chlo-
roquinolines and aryl stannanes, in Heck additions of
aryl chlorides to t-butyl acrylates,15 and in regioselective
Suzuki couplingof 2,6-dichloronicotin amides. 16
The principal goal of this study was to explore the
possibility of usingthe air-stable POPd catalysts, 17 in the
Suzuki–Miyaura cross-couplingreaction of substituted
3-chloropyridines with arylboronic acids to afford het-
eroaryl–aryl frameworks that were either not possible or
difficult to generate using other Pd-catalysts. In this
paper, we report the cross-couplingreactions of substi-
tuted-3-chloropyridines with a variety of arylboronic
acids where the POPd catalysts played a significant role
in giving the desired cross-coupled products in high
yields, as shown in Eq. 4.
OH
Cl
Cl
Cl
P
P
P
P
Cl
O
O
P
O
O
Pd
Pd
Pd
Pd
H
H
HO
P
Pd
P
OH
P
Cl
Cl
Cl
Cl
HO
POPd2
POPd
POPd1
When we used the Pd2(dba)3/(t-Bu)3P catalyst,7 reactions
did not go to completion, and the desired cross-coupling
products were obtained in low, variable yields (15–20%)
(Eq. 3).13 It has been reported that the 1:1 ratio of
Pd2(dba)3 catalyst and (t-Bu)3P, which generates in situ
the reactive palladium–monophosphine complex is also
critical to give the optimum yields since the use of catalyst
and phosphine reagent in a 1:2 ratio leads to an extremely
slow reaction. From synthetic and process-development
viewpoint, it appeared to us that it would be advanta-
geous to explore further the scope and limitations of the
POPd catalysts.11 Direct use of POPd as a catalyst would
also be practical consideringthe difficulties and vari-
ability associated with the generation of active catalysts
in situ and the handlingof extremely air-sensitive phos-
The substituted 3-chloropyridine 1 coupled with a
variety of arylboronic acids such as 2a–d to give corre-
spondingcross-coupled products 3a–d in good yields
(75–98%) (Table 1). The scope and limitations of this
reaction were further investigated by performing the
reactions of various 3-chloropyridines 4, 7, and 10 with
a variety of arylboronic acids 5, 8, and 2a. The results
are summarized in Table 1. The yields mentioned in the
Table 1 are for either recrystallized or chromatograph-
ically purified products and we have not made attempts
to investigate use of other bases or the solvents in the
reaction to further optimize the yields.
It is important to note that 3d could be obtained in 98%
18
yield usingPOPd as the catalyst in the reaction.
N
Cl
N
Ar
2
Pd(PPh )
3 4
Good yields
Eq. 1
Eq. 2
Ar B(OH)
2
+
2
Ar
1
Ar
1
R
Na CO
R
R
2
3
R
1
R
2
R
R
2
1
Pd(PPh )
3 4
R
Cl
Ar
2
+
Ar B(OH)
2
2
Ar
Ar
1
1
N
N
R
1
R
2
R
1
Na CO
R
2
2
3
R
R
Cl
R
R
Ar
2
Pd (dba)
2
3
Low yields
Good yields
Eq. 3
Eq. 4
+
+
Ar B(OH)
2
2
Ar
Ar
1
1
N
N
Cs CO
N
N
2
3
R
R
R
2
R
1
R
1
2
Cl
Ar
2
POPd
Ar B(OH)
2
2
Ar
1
Ar
1
R
2
1
R
1
R
2
Figure 1.

S. P. Khanapure, D. S. Garvey / Tetrahedron Letters 45 (2004) 5283–5286
5285
a
Table 1. Examples of Suzuki–Miyaura cross-couplingproducts usingPOPd as a catalyst
Substrate
Arylboronic acid
Product
Yieldb (%)
R
3
F C
3
Cl
B(OH)
2
R
2
N
F C
3
R
1
R
1
R
3
R
2
N
2a; R1 = R2 = R3 = H
OMe
2b; R1 = R3 = H; R2 = F
2c; R1 = R2 = H; R3 = F
2d; R1 = R3 = H; R2 = SO2Me
1
OMe
3a; R1 = R2 = R3 = H
91
3b; R1 = R3 = H; R2 = F
3c; R1 = R2 = H; R3 = F
3d; R1 = R3 = H; R2 = SO2Me
75
94
98
F
F C
Cl
O
B(OH)
2
3
N
F C
3
F
F
F
79
O
N
5
4
6
F C
3
Cl
B(OH)
SMe
2
F C
3
N
OMe
98
N
OMe
SMe
7
8
9
2a
Cl
Cl
N
74c
N
10
11
a All reactions were conducted using1.5 equivalents of arylboronic acid, 3 equivalents of Cs 2CO3, and 0.025 mol % POPd. Most reactions were >1/2
complete in 1 h and complete in 4 to 8 h, but can be allowed to run overnight for convenience.
b Isolated yields of pure products.
c 3 Equivalents of arylboronic acid, 4 equivalents of Cs2CO3, and 0.05 mole% POPd were used.
In comparison, the traditional Pd(PPh3)4 catalyst under
the standard Suzuki reaction conditions completely
failed to give any of the coupled product (Eq. 2). When
the Pd2(dba)3/(t-Bu)3P catalyst was employed, the
reaction did not go to completion and the desired
product was obtained in low yield (Eq. 3). It is inter-
estingto note that in the presence of POPd catalyst, the
reaction of 3,5-dichloropyridine 10 with phenylboronic
acid 2a afforded 11 in 74% yield. This demonstrates that
the arylboronic acid can effectively cross-couple with
both deactivated positions of the pyridine ringwhen this
catalyst is employed in the cross-couplingreaction. In
regard to comparisons of catalytic effects of POPd,
POPd1, and POPd2, we performed the reaction of
compounds 7 and 8 (Table 1), usingthese catalysts. The
cross-couplings were equally effective under identical
conditions of concentration and temperature. Based
upon these results, the POPd catalysts have been found
to be superior reagents in the cross-coupling reactions of
3-chloropyridines with arylboronic acids. Additionally,
due to the air-stability of the POPd catalysts, they are
much more convenient to handle and thus offer an
attractive alternative for the chemists interested in
exploringtheir use in the Pd-catalyzed reactions in
organic synthesis.
In conclusion, we have demonstrated that Suzuki–
Miyaura couplingof less reactive 3-chloropyridines with
a variety of arylboronic acids proceeds in high yield
usingthe palladium–phosphinous acid complex POPd
as a catalyst. The further usefulness of this catalyst for
the synthesis of COX-2 selective inhibitors is currently
under investigation in our laboratories.
Acknowledgements
We thank Dr. Li, at CombiPhos Catalysts, Inc.,
Princeton, NJ, for helpful discussions regarding the use
of POPd catalyst.

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13. Khanapure, S. P.; Augustyniak, M.; Garvey, D. S.;
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18. Representative experimental procedure: To a solution of 1
(2 mmol) in DME (8 mL) was added 2d (500 mg, 2.5 mmol)
followed by Cs2CO3 (5 mmol) and POPd (25 mg,
0.05 mmol, 0.025 mol %). The reaction mixture was re-
fluxed for 4 h, then filtered, and the filtrate was evaporated
at reduced pressure. The residue was extracted with ethyl
acetate, washed with aqueous saturated Na2CO3, water,
brine, and then dried. The solvent was evaporated, and the
residue obtained was triturated with hexane–ether (9:1) to
give pure product 3d (98%) as a colorless solid, mp 104–
107 °C. 1H NMR (CDCl3) d 8.97 (s, 1H), 8.06 (d,
J ¼ 8:3 Hz, 2H), 7.79 (s, 1H), 7.47 (d, J ¼ 8:3 Hz, 2H),
6.91 (d, J ¼ 8:6 Hz, 2H), 6.8 (d, J ¼ 8:6 Hz, 2H), 4.15 (s,
2H), 3.81 (s, 3H), 3.17 (s, 3H); LRMS (APIMS) m=z 422
(MþH)þ.