One step entry to P,O- and P,N-type heterocyclic tertiary phosphine ligands and application in Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1039/c1ob05426k

A direct synthesis of conformationally mobile P,O- and P,N-type heterocyclic phosphine ligands is described involving radical-mediated addition of diisobutylphosphine to olefinic-heterocycles. Palladium complexes of the P,N-ligand were determined to be highly active in the Suzuki-Miyaura cross-coupling reactions, including deactivated aryl chlorides.

Full text of DOI:10.1039/c1ob05426k

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One step entry to P,O- and P,N-type heterocyclic tertiary phosphine ligands
and application in Suzuki–Miyaura cross-coupling reactions†
Ehsan Ullah,a James McNulty,*a Christine Kennedyb and Al Robertsonb
Received 17th March 2011, Accepted 20th April 2011
DOI: 10.1039/c1ob05426k
A direct synthesis of conformationally mobile P,O- and P,N-
type heterocyclic phosphine ligands is described involving
radical-mediated addition of diisobutylphosphine to olefinic-
heterocycles. Palladium complexes of the P,N-ligand were
determined to be highly active in the Suzuki–Miyaura cross-
coupling reactions, including deactivated aryl chlorides.
The development of novel phosphine ligands has been of central
importance to advances in palladium-mediated cross-coupling
reactions (C–C, C–O, C–N etc.) over the last few decades.1–4
Successful substrate activation and progression through the cat-
alytic cycle is often highly dependent on the nature of the ligand
employed.2 The general mechanism of palladium catalyzed cross-
Fig. 1 Examples of P,O and P,N type ligands.
coupling processes with aryl or vinyl halides (or equivalents) is well
understood, however the relative importance of the contributing
steps is variable. In addition to the ligand, the nature of the halide (I
introduced by Kamer8e and Pfaltz8f respectively. Bidentate ligands
containing different soft and hard donor substituents (i.e. hemi-
labile ligands) have great potential in homogenous catalysis.1d,6,7,8,9
Such ligands possess one weakly coordinating group that can
provide unsaturation at the metal center through dissociation
during the catalytic cycle.
> Br > Cl), including its steric and electronic environment, is often
critical, with electron rich, hindered aryl/vinyl chlorides being the
most challenging. Sterically hindered, electron-rich phosphines
have proved to be useful in effecting both oxidative addition
and reductive elimination processes in these catalytic cycles and
many ligands incorporating this feature have been developed.5–9
Among these, the Buchwald-type biaryl ligands1b,2,5 and di-tert-
butyl-alkyl phosphine and related ligands introduced by Fu and
co-workers1c,2e–g have proven to be of great value in activating
difficult substrates and uncovering novel chemoselectivity.
Related to these monodentate ligands are a growing number
of monophosphine P,N and P,O- type ligands that incorporate
a sterically hindered phosphine in conjunction with a weaker,
tunable n- or p-lewis basic donor substituent.1d,6,7,8 A few examples
are shown in Fig. 1. Kwong and co-workers reported the synthesis
and application of indolylphosphines A and B for Suzuki–
Miyaura and other coupling reactions.1d,6 Guram and co-workers
introduced the ketal-containing P,O-type ligand C for Suzuki–
Miyaura cross-coupling of aryl chlorides.8 P,N-type ligands in-
clude the pyridine-phosphine D and phosphine-oxazoline ligand E
Our group has been involved in the design and application of
new hindered phosphine ligands over the last few years.10,11 The
synthesis of the P,O-type hemi-labile ligand F, incorporating a
novel conformational feature into the ligand design, was recently
reported.12 A key consideration in the design of ligand F was
the introduction of dual-functionality through conformational
mobility. The ligand is expected to function as an electron-rich
monodentate ligand assisting oxidative addition in one conformer
(i.e. L2Pd to LPd involves only a conformational change). The
hydroxyl appendage would become engaged through a chair–boat
conformational flip, converting to a bidentate ligand, assisting
ligand exchange/reductive elimination processes. Pd-complexes of
ligand F proved to be very efficient in effecting Suzuki–Miyaura
cross-coupling reactions on challenging, hindered and electron
rich aryl chlorides. The success of this ligand prompted us to
explore other ligand architectures that might allow synthesis
of hemilabile P,O and P,N-type ligands. Herein we report the
synthesis of the novel (tetrahydrofuran-3-yl)phosphine ligand 3
and 2-[(diisobutylphosphinyl-ethyl)-pyridine ligand 4 and their ap-
plication in challenging Pd-mediated Suzuki–Miyaura reactions.
The design features of these new ligands are outlined in Fig. 2.
We were attracted to the incorporation of a tetrahydrofuranyl
core given the role played by ethereal solvents such as THF
aDepartment of Chemistry, McMaster University, Hamilton, Ontario,
Canada, L8S 4M1. E-mail: jmcnult@mcmaster.ca; Fax: (+1)-905-522
2509; Tel: (+1)-905-525-9140 Ext. 27393
bCytec Canada, Inc., P.O. Box 240, Niagara Falls, Ontario, Canada, L2E
6T4
† Electronic supplementary information (ESI) available: General experi-
mental details, procedures, NMR and MS data for all new compounds.
See DOI: 10.1039/c1ob05426k
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Table 1 Suzuki–Miyaura cross coupling reaction of aryl halides with
ligand 3a
Isolated yield
Entry R-X
1
Boronic acid
Product 7
of 7 (%)b
96%
Fig. 2 Bi- and monodentate complexes of ligands 3 and ligand 4 (R =
iBu).
2
78%
as weakly coordinating ligands in transition metal and s-block
metal complexation. We envisioned that a bulky electron-rich
phosphine (R = Cy, tBu, iBu etc.) could be incorporated onto
a tetrahydrofuranyl core to give 3 or onto a 2-vinylpyridine to
give 4. The hemi-labile nature of the ligands would involve the
two contributing envelope-type conformers shown (top) for the
furan 3, and a fused-bicylo to monodentate exchange in the case
of ligand 4.
3
4
97%
85%
The synthesis of ligands 3 and 4 is outlined in Scheme 1. The
ligands were synthesized by the addition of diisobutylphosphine
to 2-vinylpyridine and dihydrofuran in the presence of AIBN
(or VAZO 67) in toluene.9,13 Both ligands are reported here
for the first time. Derivatives of ligand 4 (D, Fig. 1) have
been previously reported prepared via multi-step routes involving
either a hydrophosphination oxidation/reduction sequence,8e or
via an Arbuzov reaction, phosphine oxide reduction sequence.14
While the synthesis of ligand 3 proved uneventful, the radical-
mediated addition of the secondary phosphine to 2-vinylpyridine
was initially problematic due to polymerization. Satisfactory
conditions were eventually found, involving the slow addition of
both initiator and 2-vinylpyridine to the secondary phosphine at
90 ◦C in toluene. The desired ligands could be readily accessed on
either a laboratory or multi-gram scale (>750g) via this simple,
single step procedure from commercially available precursors.
5
89%
6
7
93%
75%
8
9
98%
10%
10
95%
a Reaction conditions. Aryl halide (3.18 mmol), phenylboronic acid
(6.36 mmol), ligand 3 (3.00 mol%), Pd(OAc)2 (1.00 mol%), K3PO4·H2O
(9.54 mmol) in t-BuOH at 110 ◦C, 12 h. b Isolated yield after column
chromatography.
and bromides (Table 1). Aryl chlorides proved very difficult to
activate using ligand 3 under these conditions and various mod-
ifications. For example, activated 4-chloroacetophenone yielded
only 10% of the biaryl adduct under the standard condition.
Ligand 4 was next investigated in the cross-coupling reaction
with aryl boronic acids and met with immediate success, the
overall results of which are summarized in Table 2. Deactivated
4-methoxychlorobenzene was smoothly coupled using ligand 4
under these conditions in toluene at 110 ◦C. A wide range of
electron deficient, electron rich and hindered ortho-substituted
chlorobenzene derivatives could readily be activated with the Pd-
complex of 4 and coupled with arylboronic acids (entries 1 to
Scheme 1 Synthesis of phosphine ligands 3 and 4.
A catalyst system employing ligand 3 and Pd(OAc)2 was
screened for the Suzuki–Miyaura cross-coupling of phenylboronic
acids with a range of aryl halides, the overall results of which are
collected in Table 1. The reaction with bromobenzene (entry 1)
was attempted with different solvents and bases to optimize the
coupling. Pre-complex formation6b using freshly distilled Et3N and
dichloromethane, generated a highly active catalytic system that
provided the biphenyl product in 96% isolated yield. This same
protocol was successfully applied to a series of Suzuki–Miyaura
cross-couplings with both activated and non-activated aryl iodides
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Table 2 Suzuki–Miyaura cross coupling reaction of aryl halides with
pyridine ligand 4a
Table 3 Suzuki–Miyaura cross coupling reaction of aryl halides with
hindered phenyl boronic acidsa
Isolated yield
Isolated yield
Entry R-X
1
Boronic acid
Product 7
of 7 (%)b
Entry R-X
1
Boronic acid
Product 7
of 7 (%)b
74%
60%
2
3
4
78%
70%
90%
2
3
4
64%
57%
62%
5
6
86%
72%
5
6
7
50%
55%
61%
7
8
78%
81%
9
80%
95%
a Reaction conditions. Aryl halide (0.70 mmol), phenylboronic acid (1.40
mmol), ligand 4 (6.0 mol%), Pd(OAc)2 (2.0 mol%), Cs2CO3 (2.10 mmol)
in toluene at 110 ◦C, 24 h. b Isolated yield after column chromatography.
10
a Reaction conditions. Aryl halide (0.70 mmol), phenylboronic acid (1.40
mmol), ligand 4 (3.0 mol%), Pd(OAc)2 (1.0 mol%), Cs2CO3 (2.10 mmol)
in toluene at 110 ◦C, 12 h. b Isolated yield after column chromatography.
In conclusion, while the furano-ligand 3 proved unable to acti-
vate challenging aryl halides, ligand 4 clearly has much potential
in Pd-mediated cross-coupling chemistry. Both ligands share a
monodentate diisobutylphosphino appendage, the difference lies
in their ability to function as hemi-labile ligands based on the
conformational features described. It appears ligand 3 is unable to
function as a hemi-labile ligand, perhaps due to steric constraints
within the bidentate envelope conformer. The enhanced catalytic
activity seen with ligand 4 clearly illustrates the effectiveness of the
2-ethano-pyridyl substituent in its ability to activate challenging
aryl halides and assisting progress of the intermediates through the
catalytic cycle. Ligand 4 is also very attractive given its one-step
synthesis and availability on a multi-gram scale. Further extension
of related hemi-labile systems based on this new lead is under active
investigation in our laboratories.
5). An interesting example was the efficient cross-coupling of
the electron poor 4-acetylphenylboronic acid with chlorobenzene
(entry 6). Bromo- and iodobenzene derivatives (entries 7–10)
provided the corresponding biaryls in high yield as expected.
The most challenging cases in the Suzuki–Miyaura cross-
coupling reaction involve the synthesis of hindered biaryls from the
reaction of unactivated aryl halides (particularly readily available
chlorides) and ortho-substituted hindered phenylboronic acids.
Pd-complexes of ligand 4 also proved to be highly effective in
promoting such cross-coupling reactions, although these reactions
were expectedly slower. The standard reaction time was extended
to 24 h and catalyst loading increased to 2.0 mol%. Table 3 summa-
rizes selected examples of these challenging cases employing ligand
4. The results outlined in Tables 2 and 3 represent a snapshot of the
possibilities achievable with ligand 4 under one set of prescribed,
unoptimized conditions.
Acknowledgements
We thank NSERC, Cytec Canada Inc. and McMaster University
for financial support of this work.
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