A highly active Suzuki catalyst for the synthesis of sterically hindered biaryls: Novel ligand coordination

Article abstract of DOI:10.1021/ja017082r

A catalyst system for the preparation of biaryls containing four ortho substituents via Suzuki coupling is described. The combination of a catalytic quantity of Pd₂(dba)₃ with either an electron-rich biarylphosphine or DPEPhos is effective using a wide range of substrates. The X-ray crystal structure of (dba)Pd(2-(9-phenanthryl)phenyl-dicyclohexylphosphine), in which the Pd is coordinated to the 9,10-double bond of the phenanthryl group, is also reported. Copyright

Full text of DOI:10.1021/ja017082r

Published on Web 01/29/2002
A Highly Active Suzuki Catalyst for the Synthesis of Sterically Hindered
Biaryls: Novel Ligand Coordination
Jingjun Yin, Matthew P. Rainka, Xiao-Xiang Zhang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received September 14, 2001
The Suzuki cross-coupling is among the most powerful C-C
bond-forming transformations available to synthetic organic chem-
ists.1 This transformation enjoys a broad scope and wide functional
group tolerance. In reactions involving sterically hindered substrates,
however, limited success has been realized.2,3 Thus, a general
method for the coupling of two hindered arenes where each reactant
possesses two ortho substituents has yet to be realized.1c,3,4 Johnson
and Foglesong have reported a Suzuki coupling to prepare an
unsymmetrical biaryl with tetra-ortho substitution in 12% yield.3a
In his elegant work, Fu reported an example of the preparation of
a tetra-ortho-substituted biaryl in 76% yield (Negishi coupling);
however, the two ortho substituents were smaller than a methyl
group.4e As part of our studies of the Suzuki coupling,5 we report
a general catalyst to prepare tetra-ortho-substituted unsymmetrical
biaryls. We also report new ligands for such processes and
crystallographic evidence for an unusual π-coordination mode we
previously postulated as important to catalytic efficiency.6 In initial
studies with biphenyl-based ligands 1a-c, significant amounts of
aryl bromide reduction were observed (Table 1, entries 1-3).7 The
use of ligands bearing either diisopropyl or diphenylphosphino
groups yielded increased amounts of mesitylene (entries 4, 5).
Increasing the size of the phosphine alkyl groups to tert-butyl
resulted in the production of <1% of the desired biaryl. Doubly
ortho-substituted ligand 2 furnished a slightly improved catalyst.
Phenanthrene-based ligand 3a gave superior results (entry 8). The
reaction proceeded to completion in less than 24 h with 4 mol %
Pd and 8 mol % 3a, affording the biaryl in 91% yield (GC) with
9% mesitylene. The phenanthrene ring of 3a is critical since lower
conversion and biaryl:arene ratios were observed with naphthyl-
based ligand 4 (entry 10). In all cases, <4% homocoupling of either
reactant was detected.
Figure 1. Hindered biarylphosphines.
Table 1. Ligand Effects in the Coupling of Hindered Substratesa
entry
ligand
conv (%)
biaryl (%)b
biaryl/Ar−H
1
2
1a
1b
1c
1d
1e
1f
47
20
74
68
49
21
56
100
57
20
33
10
40
34
25
<1
48
91
50
16
2.3
0.9
3
1.9
4
1.6
5
1.3
6
<0.3
7
2
5.0
8
3a
3ac
4c
10
9
7.4
4.1
10
a Reaction conditions: 1.0 equiv of ArBr, 1.4 equiv of Ar′B(OH)2, 3.0 equiv
of K3PO4, toluene, 2 mol % Pd2(dba)3, 8 mol % ligand, 110 °C, 17-24 h. b GC
yield. c 0.5 mol % Pd2(dba)3, 1.2 mol % ligand used.
Phosphine 3a and diphenyl analogue 3b proved in general to be
excellent ligands for Suzuki cross-coupling reactions to form
sterically hindered tetra-ortho-substituted biaryls in good yields
(Table 2). Ortho substituents such as methyl, primary alkyl, phenyl,
and alkoxy groups are accommodated. It was necessary to use 2.0
equiv of the boronic acid to effect complete consumption of the
aryl bromide in some cases, presumably due to competitive
protodeboronation (entries 2, 3, 5-7, 11).2 While 1a was not
suitable as a ligand for the synthesis of biaryls with four methyl
groups, it could be used to prepare products in which one or two
of the four ortho substituents were methoxy groups (entries 8, 9).
In several examples, o-xylene was superior to toluene as a solvent
(entries 2, 3, 5-7). In Pd-catalyzed couplings involving aryl
chlorides, electron-rich di- or trialkylphosphines are usually used
as ligands.2f,4,8 Thus, it was surprising that using 3b, 9-chloroan-
thracene was reacted in good yield (entry 7).
Figure 2. X-ray crystal structure of 3a/Pd(dba).
in the K3PO4 and/or boronic acid, were isolated. The use of
DPEPhos as ligand resulted in decreased phenol form-
ation, and further inhibition of this side reaction was realized by
the inclusion of freshly activated 4 Å molecular sieves. Thus, a
number of hindered aryl bromides with ortho electron-withdrawing
groups were efficiently coupled with 2,6-dimethylphenyl boronic
acid (Table 3). The DPEPhos-based system could also be used with
unactivated aryl bromides (entry 4). The 3b/Pd catalyst failed to
chemoselectively activate the bromo group. In cases directly
comparing the 3b- and DPEPhos-based systems, 3b/Pd catalyst
afforded higher conversions of the aryl halide and higher biaryl:
arene ratios.
To determine what features made 3a,b superior in these
challenging cross-couplings, we sought to prepare and characterize
a 3a/Pd complex. Mixing 3a and Pd2(dba)3 in toluene at room
temperature followed by chromatographic purification yielded the
desired complex. Crystals suitable for X-ray diffraction were grown
Unfortunately, the reaction conditions above were not suitable
when the aryl halide possessed an ortho electron-withdrawing group;
significant amounts of the phenol, presumably due to water present
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1162 VOL. 124, NO. 7, 2002 J. AM. CHEM. SOC.
10.1021/ja017082r CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Hindered Suzuki Couplings Using Biaryl-Based Ligandsa
Table 3. Suzuki Couplings of Hindered Electron-Poor Aryl Bromidesa
a Reaction conditions: 1.0 equiv of ArBr, 2.0 equiv of Ar′B(OH)2, 3.0 equiv
of K3PO4, Pd2(dba)3, DPEPhos (L:Pd ) 1.2:1), toluene, activated 4 Å molecular
sieves. Isolated yields (average of two runs) of compounds estimated to be >95%
pure as determined by 1H NMR and GC or combustion analysis.
Acknowledgment. We thank the National Institutes of Health
(GM 46059), Pfizer, Merck, and Bristol-Myers Squibb for support.
We thank Drs. Joseph M. Fox and Karen E. Torraca for the
syntheses of 3a and 3b, respectively. Dr. Alex R. Muci is thanked
for assistance in the preparation of this manuscript.
Supporting Information Available: Experimental procedures,
characterization of products, and X-ray crystal structure data for 3a/
Pd(dba) (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263. (d) Suzuki, A. J. Organomet. Chem. 1999,
576, 147.
(2) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. (b) Hoye,
T. R.; Chen, M. J. Org. Chem. 1996, 61, 7940. (c) Kamikawa, K.;
Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375. (d) Anderson,
J. C.; Namli, H.; Roberts, C. A. Tetrahedron 1997, 53, 15123. (e) Zhang,
H.; Kwong, F. Y.; Tian, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 6886.
(f) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(g) Chaumeil, H.; Signorella, S.; Le Drian, C. Tetrahedron 2000, 56, 9655.
(3) (a) Johnson, M. G.; Foglesong, R. J. Tetrahedron Lett. 1997, 38, 7001.
Two groups have each reported a single example of the preparation of a
hindered symmetrical binaphthyl: (b) Anderson, N. G.; Maddaford, S.
P.; Keay, B. A J. Org. Chem. 1996, 61, 9556. (c) Cammidge, A. N.;
Cre´py, K. V. Chem. Commun. 2000, 1723.
(4) Other Pd- or Ni-based methods: (a) Miyano, S.; Okada, S.; Suzuki, T.
Bull. Chem. Soc. Jpn. 1986, 59, 2044. (b) Hayashi, T.; Hayashizaki, K.;
Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153. (c) Saa, J. M.;
Martorell, G. J. Org. Chem. 1993, 58, 1963. (d) Terfort, A.; Brunner, H.
J. Chem. Soc., Perkin Trans. 1 1996, 1477. (e) Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 2719 and references therein.
(5) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550. (b) Yin, J.; Buchwald, S. L. J. Am. Chem Soc.
2000, 122, 12051 and references therein.
a Reaction conditions: 1.0 equiv of ArX, 1.5 equiv of Ar′B(OH)2, 3.0 equiv
of K3PO4, Pd2(dba)3, ligand, toluene, 110 °C. Isolated yields (average of two
runs) of compounds estimated to be >95% pure as determined by 1H NMR and
GC or combustion analysis. b 2.0 equiv of Ar′B(OH)2 used. c o-Xylene as solvent.
d 120 °C. e 1.0 equiv of 2,6-dimethylphenol as additive.
(6) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org.
by evaporation of a pentane solution (Figure 2). The key features
of this structure are the short C9-Pd and C10-Pd bond distances
(2.298 and 2.323 Å, respectively). Similar Pd-aryl interactions have
been reported in Pd (II) complexes.9 The C9-C10 bond of
phenanthrene is likely a better π-donor than a phenyl or naphthyl
moiety, as it resides in a less aromatically stabilized ring.10
In summary, we have described a general catalyst system for
the synthesis of tetra-ortho-substituted biaryls via the Suzuki cross-
coupling reaction. The most efficient catalyst described is based
on the phenanthrene-substituted ligand 3a. Crystallographic analysis
of 3a/Pd(dba) revealed an unusual π-coordination of the phenan-
threne moiety, the first of its type for a Pd (0) complex.
Chem. 2000, 65, 1158.
(7) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5334.
(8) (a) Bei, X. H.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen,
J. L. J. Org. Chem. 1999, 64, 6797-6803. (b) Zapf, A.; Ehrentraut, A.;
Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153. (c) Bedford, R. B.;
Welch, S. L. Chem. Commun. 2001, 129.
(9) (a) Hayashi, T.; Iwamura, H.; Naito, M.; Matsumoto, Y.; Uozumi, Y.;
Miki, M.; Yanagi, K. J. Am. Chem. Soc. 1994, 116, 775. (b) Kocovsky,
P.; Vyskocil, S.; Cisarova, I.; Sejbal, J.; Tislerova, I.; Smrcina, M.; Lloyd-
Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray, M.; Langer, V. J. Am.
Chem. Soc. 1999, 121, 7714. (c) Hayashi, T. Acc. Chem. Res. 2000, 33,
354. (d) Lloyd-Jones, G. C. Chem.-Eur. J. 2000, 6, 4348.
(10) Carroll, F. A. PerspectiVes on Structure and Mechanism in Organic
Chemistry; Brooks/Cole Publishing: Pacific Grove, 1998; p 213.
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