Tetrahedron Letters
Synthesis and investigation of 1,6-bis-di-tert-butylphosphinohexane
and its application in Suzuki–Miyaura coupling
⇑
John M. Mitchell, William S. Brown
Department of Chemistry, 1201 Jones Hall, Murray State University, Murray, KY 42071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium catalysts have excellent compounds used in generating difficult carbon–carbon bonds. The
development of these palladium catalysts has been the attention of much research. The use of alkyl-phos-
phines has led to many very active, bulky ligands for palladium catalysts. We report a convenient
synthesis of 1,6-bis-di-tert-butylphosphinohexane (DTBPH) and its evaluation in palladium catalyzed
Suzuki–Miyaura coupling. The combination of DTBPH and palladium has led to excellent productivity
when used as catalyst for Suzuki coupling.
Received 9 November 2012
Revised 8 January 2013
Accepted 14 January 2013
Available online 30 January 2013
Keywords:
Published by Elsevier Ltd.
Cross-coupling
Suzuki–Miyaura
Palladium
Bidentate ligand
Palladium catalysts have emerged as an excellent tool for
organic synthesis and their use in Suzuki–Miyaura couplings has
become one of the most widely used methods for creating
carbon–carbon bonds in the synthesis of biaryls.1–3 Over the course
of many years it has become widely accepted that strong electron-
donating, sterically-demanding ligands produce extremely active
catalysts (including tri-aryl, tri-alkyl, N-heterocyclic carbenes,
and chelating ligands).4–6 To fully understand the nature of the
ligand effect on the catalyst, it is necessary to follow the catalytic
cycle mechanism. According to Shaughnessy, sterically bulky
ligands promote ligand dissociation from a PdL2 resting state.7,8
This dissociation is necessary to generate a highly active PdL
complex (Scheme 1).
is favored over the 9-atom macrocycle (3, Scheme 1).10 We postu-
lated that, regardless of which intermediate complex (2 or 3) is
generated, this complex may break open to generate the catalyti-
cally active PdL species (4, Scheme 1).
To synthesize DTBPH, di-tert-butyl phosphine (5) in dioxane
was combined with 1,6-dibromohexane (6, Scheme 2) and the
reaction mixture was heated to reflux until a white solid precipi-
tated. This solid was filtered and found to be a 3:1 mixture of the
target 1 and di-tert-butylphosphepanium bromide (7). It was found
that while 7 is insoluble in chloroform, 1 has excellent solubility in
this solvent, allowing for a simple separation by filtration to pro-
vide target phosphonium salt 1 in high purity and 41% yield as
an air-stable white solid.
Because of the importance of dissociation in the catalytic cycle,
we were interested in designing a bidentate chelating ligand that
might readily interconvert between the catalytically active PdL
species and the resting state PdL2. Previously, Bickelhaupt modeled
this type of chelation using ZORA-BLYP/TZ2P calculations to show
that a six carbon bridge and tert-butyl end groups provide an opti-
mal bite angle when coordinated via a chelate to palladium.9 Based
on this, we wished to explore the use of 1,6-bis-di-tert-buty-
lphosphinohexane (DTBPH) (1, Scheme 1) as a reversible bidentate
ligand for palladium catalysis. This compound had been previously
prepared by Shaw and co-workers, who reported that, when cou-
pled with palladium, a dimerization of the palladium/ligand (2)
Upon successful synthesis and purification, this ligand was
tested in Suzuki–Miyaura coupling of 4-bromoanisole (8) and
phenylboronic acid (16) into 40-methyoxybiphenyl, using the con-
ditions described in Scheme 3.8,11 It was observed this reaction
went on smoothly and in 99% yield under the employed conditions.
Upon examining the reaction with electron-rich (8, 9, and 12, Ta-
ble 1) and electron-deficient (10, 13, and 15, Table 1) aryl bro-
mides, excellent conversion to product at room temperature was
observed. When evaluating more sterically demanding substrates
(12 and 14, Table 1), the same excellent conversion was obtained.
When both aryl bromide and boronic acid possessed sterically
demanding ortho-substituents (14 and 17, Table 1), a modest
amount of coupling was observed at room temperature. When
the coupling was examined at elevated temperatures, it was found
that the yield improved upon heating to 45 °C, but no further yield
increase was noted at 60 °C. It is postulated that the absence of
⇑
Corresponding author. Tel.: +1 270 809 66626; fax: +1 270 809 6474.
0040-4039/$ - see front matter Published by Elsevier Ltd.