A general and special catalyst for suzuki-miyaura coupling processes

Article abstract of DOI:10.1002/anie.201002404

(Figure Presented) Biaryl monophosphorus ligands containing a 2,3-dihydrobenzo[d][1,3]oxaphosphole framework are highly effective for the palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of a wide range of substrates. Ligand 1 has demonstrated excellent performance for coupling reactions of extremely hindered arylboronic acids.

Full text of DOI:10.1002/anie.201002404

Angewandte
Chemie
DOI: 10.1002/anie.201002404
Cross-Coupling
A General and Special Catalyst for Suzuki–Miyaura Coupling
Processes
Wenjun Tang,* Andrew G. Capacci, Xudong Wei, Wenjie Li, Andre White, Nitinchandra D. Patel,
Jolaine Savoie, Joe J. Gao, Sonia Rodriguez, Bo Qu, Nizar Haddad, Bruce Z. Lu,
Dhileepkumar Krishnamurthy, Nathan K. Yee, and Chris H. Senanayake
Since its discovery,[1] the Suzuki–Miyaura cross-coupling
phosphorus ligands 1a–d whose structures feature a 2,3-
dihydrobenzo[d][1,3]oxaphosphole framework (Figure 1).
Unlike SPhos where the dicyclohexylphosphanyl group can
À
reaction has evolved into one of most powerful carbon
carbon bond-forming transformations and has shown increas-
ing utility in synthetic organic chemistry.[2] Recent advances in
novel catalyst development[3] have enabled this transforma-
tion to be applied with a broad substrate scope, a wide
functional group tolerance, and low catalyst loadings. Palla-
dium catalysts derived from electron-rich and sterically
demanding ligands, such as trialkyl monophosphanes,[4] di-
alkyl aryl monophosphanes,[5] dialkyl biaryl monophos-
phanes,[6] N-heterocyclic carbenes,[7] and other ligands,[8]
have been particularly effective. Despite these advances,
limitations remain. For example, the Suzuki–Miyaura cou-
pling of extremely hindered arylboronic acids, such as 2,4,6-
triisopropylphenylboronic acid have been less explored. Few
successful results have been reported for the preparation of
tri-ortho-substituted biaryls from such extremely hindered
boronic acids. The development of novel, efficient, and
general catalysts for the Suzuki–Miyaura cross-coupling
reaction to address these limitations and further expand the
substrate scope has thus remained a very important area of
research.
Ligand structure defines the steric and electronic proper-
ties of the palladium catalyst and thus plays a crucial role in
the efficiency of the Suzuki–Miyaura cross-coupling reaction.
The biaryl dialkyl monophosphane ligands developed by
Buchwald and co-workers, such as SPhos, RuPhos, and Xphos
have demonstrated a broad substrate scope in the Suzuki–
Miyaura cross-coupling reaction.[3b,9] Although they all pos-
sess two cyclohexyl substituents at the phosphorus center,
reports on variations of these substituents and their impact on
reactivity are still limited.[10] The development of biaryl
monophosphorus ligands that have a rigid framework to
restrict the rotation of the phosphanyl group has rarely been
explored.[11] Herein, we report a class of novel biaryl mono-
Figure 1. Biaryl monophosphorus ligands.
freely rotate along the upper aryl ring and multiple con-
formers are present when coordinating with a metal center,[12]
the structures of ligands 1a–d completely block such rotation
and establish a well-defined orientation of the phosphorus
atom for metal coordination. We expected that these unique
steric and electronic properties of 1a–d would afford excel-
lent reactivity and substrate scope for Suzuki–Miyaura
couplings, and thus would be complementary to those
known catalytic systems.[3–8]
The syntheses of 1a–d were accomplished in two steps
from aryl triflate 2, which could be prepared on a kilogram
scale from methyldichlorophosphine using our reported
route.[13] The palladium-catalyzed Suzuki–Miyaura couplings
of triflate 2 with various arylboronic acids provided 3a–d in
[14]
75–91% yield. Reduction of 3a–d with PMHS/Ti(OiPr)4
afforded racemic ligands 1a–d in excellent yields
(Scheme 1).[15] It is noteworthy that ligands 1a–d are acces-
sible in kilogram quantities with this synthetic route, and they
were found to be highly stable in open air. For example, ligand
1d (BI-DIME) can be stored as a solid at room temperature
in air for months without observing any oxidation side-
products.
Ligands 1a–d were applied in the palladium-catalyzed
Suzuki–Miyaura coupling of sterically congested arylboronic
acids. The cross-coupling between 2,4,6-triisopropylphenyl-
boronic acid and 2-bromobiphenyl was chosen as the model
system (Scheme 2). Besides ligands 1a–d, various structurally
diverse ligands were also examined for comparison. The
reactions were carried out at 1008C in toluene for 12 hours
with [Pd2(dba)3] (0.5 mol%) as the catalyst precursor.
Whereas low conversions (< 20%) were generally observed
[*] Dr. W. Tang, A. G. Capacci, Dr. X. Wei, Dr. W. Li, N. D. Patel, J. Savoie,
J. J. Gao, Dr. S. Rodriguez, Dr. B. Qu, Dr. N. Haddad, Dr. B. Z. Lu,
Dr. D. Krishnamurthy, Dr. N. K. Yee, Dr. C. H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc.
Ridgefield, CT 06877 (USA)
Fax : (+1)203-791-6130
E-mail: wenjun.tang@boehringer-ingelheim.com
Dr. A. White
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc.
Ridgefield, CT 06877 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002404.
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Communications
excellent yield (89%). To the best of our knowledge,
this is the first high-yielding example for the prepa-
ration of a tri-ortho-substituted biaryl from 2,4,6-
triisopropylphenylboronic acid using the Suzuki–
Miyaura coupling reaction. Since both ligand 1d
and SPhos possess the same lower aryl ring, their
dramatic difference in reactivity clearly demonstrates
the influence of the steric and electronic properties of
the upper ring on the reactivity. We hypothesized that
the conformational rigidity and the relatively elec-
tron-poor nature of 1d compared to SPhos facilitates
the key transmetalation step of this reaction.[16] The
high reactivity of ligand 1d in contrast to ligands 1a–c
also indicated the importance of the two ortho-
methoxy groups in the lower aryl ring, which is
consistent with the observation by Buchwaldꢀs
group.[6d]
Scheme 1. Syntheses of monophosphorus ligands 1a–d (for experimental details,
see the Supporting Information). Tf=trifluoromethylsulfonate, dba=dibenzylide-
neacetone, Cy=cyclohexyl, SPhos=2-dicylohexylphosphino-2’,6’-dimethoxybi-
phenyl, PMHS=polymethylhydrosiloxane.
The high effectiveness of ligand 1d observed in
the coupling of 2,4,6-triisopropylphenylboronic acid
with 2-bromobiphenyl encouraged us to study the
substrate scope in the Suzuki–Miyaura coupling of
sterically congested di-ortho-substituted arylboronic
acids. As illustrated in Table 1, ligand 1d is capable of
catalyzing the coupling of hindered arylboronic acids
or esters to form tri-ortho-substituted or tetra-ortho-
substituted biaryl products in excellent yields. A
range of ortho-substituted aryl bromides were cou-
pled with 2,4,6-triisopropylphenylboronic acid to
afford the corresponding tri-ortho-substituted biaryl
products in very high yields (Table 1, entries 1–3).
3-Pyridyl bromide was also successfully employed to
provide the desired heterocyclic compound in 91%
yield (Table 1, entry 4). An extremely hindered
arylboronic acid containing an ortho-tert-butyl sub-
stituent also gave the coupling product in good yield
(Table 1, entry 5).[17] Various di-ortho-substituted
arylboronic acids were coupled with ortho-substituted
aryl chlorides or bromides to provide tri-ortho-
substituted biaryl products in excellent yields
(Table 1, entries 6–8). Two tetra-ortho-substituted
biaryls were also prepared in high yields (Table 1,
entry 9–10). Ligand 1d was also required for the
efficient cross-coupling of sterically hindered triflate
2 and 2,6-dimethoxyphenylboronic acid, and pro-
vided the desired coupling product 2d in 91% yield
(Table 1, entry 11).[18]
Besides its excellent reactivity for the coupling of
sterically hindered arylboronic acids or esters, ligand
1d is also applicable for the coupling of a broad range
of challenging substrates, including sterically con-
gested aryl halides, electron-withdrawing arylboronic
acids, and compounds containing heteroaryl moieties.
As shown in Table 2, an array of di-ortho-substituted
aryl bromides or chlorides were coupled with various
arylboronic acids to give their coupling products in
Scheme 2. Ligand screening for Suzuki–Miyaura coupling of 2,4,6-triisopropyl-
phenylboronic acid and 2-bromobiphenyl. The reactions were heated at 1008C in
toluene (2 mL) for 12 h with 2-bromobiphenyl (1 mmol), 2,4,6-triisopropylphenyl
boronic acid (1.5 mmol), and K3PO4 (3 mmol) in the presence of [Pd2dba3]
(0.5 mol%) and ligand (2 mol%). HPLC assay yields were averaged from two
runs. Ad=adamantyl.
in this challenging cross-coupling reaction with ligands such as
SPhos (4), RuPhos(5), XPhos (6), Ad2PnBu (7), PPh3 (8),
Cy3P (9), tBu3P (10), and ligands 1a–c, it is gratifying to report
that ligand 1d (BI-DIME) provided a rapid conversion and an
excellent yields (Table 2, entries 1–6). Ligand 1d provided a
superior reaction rate over SPhos in a parallel study of the
coupling of 2-bromo-1,3,5-trimethylbenzene with biphenyl-2-
ylboronic acid (Table 2, entry 1).[19] Electron-poor arylbor-
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Table 1: Sterically hindered Suzuki–Miyaura cross-couplings with di-ortho-
Table 2: Suzuki–Miyaura cross-couplings of sterically congested aryl bromides
or chlorides, electron-poor arylboronic acids, heteroaryl-containing substrates,
and at low catalyst loading with 1d as the ligand.[a]
substituted arylboronic acids or esters.[a]
Entry Aryl halide
Boronic acid
Product
Pd
Yield
[mol%] [%]
Entry Aryl halide
Boronic acid
Product
Pd
Yield
[mol%] [%]
1
1
1
96
94
1
2
0.2
1
95
95
2
3
4
1
1
89
3
4
5
0.5
0.5
1
74
95[b]
99[b]
91[b]
5
6
7
2
1
1
80[c]
87
6
7
8
1
1
1
99[b]
93
87[c]
85[b]
8
1
89
9
0.5
85[b]
9
1
3
89[b]
80[c]
10
11
12
13
1
98[b]
99
10
0.5
0.5
0.002
11
1
91[d]
99[c]
98
[a] Unless otherwise specified, the reactions were carried out at 1008C in
toluene (2 mL) for 24 h with aryl halide (1 mmol), arylboronic acid or ester
(1.5 mmol), and K3PO4 (3 mmol) as the reagents in the presence of [Pd2dba3]
and ligand 1d (Pd/1d=1:2); yields are of the isolated product. [b] Water
(1 mL) was added. [c] m-Xylene (2 mL) was employed as the solvent with a
reaction temperature of 1308C. [d] Dioxane (2 mL) as the solvent and KF
(3 equiv) as the base were employed with a reaction temperature of 1008C.
[a] Unless otherwise specified, the reactions were carried out at 1008C in
toluene (2 mL) for 24 h with aryl halide (1 mmol), arylboronic acid or ester
(1.5 mmol), and K3PO4 (3 mmol) as the reagents in the presence of [Pd2dba3]
and ligand 1d (Pd:1d=1:2); yields are of isolated products. [b] 1-Butanol
(2 mL) and water (1 mL) as the solvent. [c] Pd(OAc)2 as the catalyst precursor
with a reaction temperature of 408C.
onic acids, such as 2,4-difluorophenylboronic acid and 3-
pyridineboronic acid, were well tolerated (Table 2, entries 3
and 4). Heteroaryl substrates with strong coordinating
capabilities were also applicable (Table 2, entries 4–6). A
variety of aryl chlorides could be employed (Table 2,
entried 7–10) and a substrate containing a free amino group
was successfully coupled under the reaction conditions
(Table 2, entry 9). As well as arylboronic acids or esters, a
cyclopropaneboronic acid and a vinylboronic acid were
smoothly reacted with an aryl bromide or chloride to provide
the desired coupling product in excellent yields (Table 2,
entries 11–12). To further test the reactivity of ligand 1d, the
reaction of 1-bromo-2-methylbenzene and 2-biphenylboronic
acid was carried out in the presence of 0.002 mol% of
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Communications
palladium and 0.004 mol% of 1d to afford the di-ortho-
catalyzed cross-coupling reactions and progress towards this
end is underway within the group.[22]
substituted biaryl product in 98% yield (Table 2, entry 13).
A crystal structure of [PdCl2{(S)-1d}2] revealed the
influence of the rigid 2,3-dihydrobenzo[d][1,3]oxaphosphole
upper aryl ring of the ligand (S)-1d on the conformation of
the palladium complex (Figure 2).[20] Unlike in the structure
Received: April 23, 2010
Revised: May 27, 2010
Published online: July 15, 2010
Keywords: cross-coupling · monophosphanes · palladium ·
.
phosphorus ligands · Suzuki–Miyaura coupling
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Figure 2. X-ray structure of [PdCl2{(S)-1d}2]. The H atoms and THF
solvent molecules are omitted for clarity.
of [PdCl2(SPhos)2],[6e] where the biaryl portion of the SPhos
ligands are pointed away from the palladium center, the
conformational rigidity of (S)-1d forces a close proximity of
the biaryl moiety to the palladium center in [PdCl2{(S)-1d}2].
This orientation could lead to a greater steric impact of the
lower aryl ring on the metal complex. It is noteworthy that
[PdCl2{(S)-1d}2] can also be employed as a pre-catalyst for
Suzuki–Miyaura coupling reactions.[21]
In summary, we have developed a novel class of biaryl
monophosphorus ligands 1a–d for the Suzuki–Miyaura cou-
pling reaction by incorporating
a 2,3-dihydrobenzo[d]-
[6] a) J. P. Wolfe, R. A. Singer, B. H. Yang, J. Am. Chem. Soc. 1999,
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[1,3]oxaphosphole framework. These biaryl ligands, which
contain a well-defined orientation of the phosphorus center
for metal coordination, have provided different steric and
electronic properties in contrast to the biaryl ligands reported
by Buchwald and co-workers, which have shown special
applications for Suzuki–Miyaura coupling reactions. Besides a
very broad substrate scope, which includes sterically con-
gested aryl halides, electron-poor arylboronic acids, and
substrates containing heteroaryl substituents, ligand 1d has
demonstrated its catalytic ability for the sterically congested
Suzuki–Miyaura coupling reactions of extremely hindered
arylboronic acids. This has resulted in the first high-yielding
coupling reactions of 2,4,6-triisopropylphenyl boronic acid
with ortho-substituted aryl bromides. Accessible in kilogram
quantities and with great air-stability, ligand 1d (BI-DIME)
holds promise for practical applications in transition-metal-
5882
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[15] The same synthetic route can be employed for the synthesis of
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[16] SPhos afforded an excellent yield in the cross-coupling reaction
of 2-bromo-1,3,5-triisopropylbenzene and biphenyl-2-ylboronic
acid, see Ref. [6e]. The low reactivity observed in cross-coupling
between 2,4,6-triisopropylphenylboronic acid and 2-bromobi-
phenyl suggests that transmetalation rather than reductive
elimination is the rate-determining step.
[10] Reports on variation of the substituents at the phosphorus center
have mostly been limited to dicyclohexyl, diisopropyl, diphenyl,
and di-tert-butyl groups.
[17] There is only one high-yielding example of Suzuki–Miyaura
coupling of arylboronic acid with an ortho-tert-butyl substituent:
S. M. So, C. P. Lau, A. S. Chan, F. Y. Kwong, J. Org. Chem. 2008,
73, 7731.
[18] This procedure has been employed for the synthesis of ligand 1d
in kilogram quantities.
[11] Restriction of the rotation of the phosphanyl group to fix the
conformation of the ligand in its metal complex has appeared to
be important for reactivity. Buchwald and co-workers have
recently reported superior results for amination and amidation
reactions with biaryl monophosphanes that contain an ortho-
methyl or ortho-methoxy group on the upper aryl ring, which, to
some extent, restricts the rotation of the phosphanyl groups. See:
a) T. Ikawa, T. E. Barder, M. R. Biscoe, S. L. Buchwald, J. Am.
Chem. Soc. 2007, 129, 13001; b) B. P. Fors, D. A. Watson, M. R.
Biscoe, S. L. Buchwald, J. Am. Chem. Soc. 2008, 130, 13552; c) K.
Dooleweerdt, B. P. Fors, S. L. Buchwald, Org. Lett. 2010, 12,
2350.
[19] See the Supporting Information for details.
[20] CCDC 773967 [PdCl2{(S)-1d}2] contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] Both racemic 1d and (S)-1d provide similar reaction rates for
Suzuki–Miyaura couplings.
[22] The Supporting Information contains the experimental details,
spectroscopic data, and NMR spectra of ligands 1a–d,
[PdCl2{(S)-1d}2], and Suzuki–Miyaura coupling products.
[12] The crystal structures of the Pd/SPhos complexes revealed the
presence of two conformers of SPhos when coordinating with a
metal center, see Ref. [6e].
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