Palladium and nickel catalysed Suzuki cross-coupling of sterically hindered aryl bromides with phenylboronic acid

Article abstract of DOI:10.1016/S0040-4039(00)00186-6

Nickel and palladium catalysts for the Suzuki cross-coupling of aryl halides bearing two ortho substituents with phenylboronic acid have been developed and used for the synthesis of sterically hindered biaryls. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00186-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2487–2490
Palladium and nickel catalysed Suzuki cross-coupling of
sterically hindered aryl bromides with phenylboronic acid
Clare Griffiths and Nicholas E. Leadbeater ∗
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 15 July 1999; revised 20 January 2000; accepted 25 January 2000
Abstract
Nickel and palladium catalysts for the Suzuki cross-coupling of aryl halides bearing two ortho substituents with
phenylboronic acid have been developed and used for the synthesis of sterically hindered biaryls. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Suzuki cross-coupling; biaryls; palladium; nickel; steric hindrance.
Palladium and nickel mediated cross-coupling reactions have evolved into versatile methods for
carbon–carbon bond formation.1,2 Of particular interest is the coupling of aryl halides and aryl boronic
acids, the so-called Suzuki reaction (Scheme 1), due to the fact that the biaryl unit and its homologues
are found in natural products, polymers, liquid crystals and advanced materials.3,4 The coupling of di-
ortho substituted boronic acids with aryl halides has been reported previously.5 It is however not easy
to prepare these sterically hindered acids and so our attention has been focused on coupling di-ortho
substituted aryl halides with simple boronic acids. In this letter we describe two methods by which Suzuki
cross-couplings of sterically crowded aryl bromides and phenylboronic acid proceed in good yield using
commercially available reagents.
Scheme 1.
The palladium complex, Pd2(dba)3 [dba=dibenzylideneacetone], when used in the presence of a
tertiary phosphine ligand and a base, has been shown to behave as an active catalyst for Suzuki coupling
reactions.6,7 As a starting point for our studies, we decided to develop this catalyst mixture for synthesis
of sterically hindered biaryls from phenylboronic acid and aryl bromides bearing alkyl and aryl groups in
∗
Corresponding author. Current address: Department of Chemistry, King’s College London, The Strand, London WC2R 2LS,
UK. E-mail: nicholas.leadbeater@kcl.ac.uk (N. E. Leadbeater)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00186-6
tetl 16466

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the two ortho positions. The coupling reaction between 2,6-dimethylbromobenzene and phenylboronic
acid to form 2,6-dimethylbiphenyl (1) was studied first.8 As shown in Tables 1 and 2, the best results are
obtained using 3 mol% Pd2(dba)3, 6 mol% trimethyl phosphite and two equivalents of K3PO4 in dioxane,
heating the reaction mixture at 95°C for 8 h. This is in contrast to previous investigations showing that,
when coupling less sterically demanding aryl halides with Pd2(dba)3, the use of tributyl phosphine and
Cs2CO3 gives the best results.3 We find that, using PtBu3, poor yields of sterically crowded biaryl are
obtained. We rationalise our observations in terms of the difference in cone angle9 between PtBu3 (182°)
and P(OMe)3 (107°) and hence the distance to which the Pd complex can approach the aryl halide; the
P(OMe)3 complex being able to access and react with the sterically hindered halide, the PtBu3 not.
Table 1
Effect of P-donor ligand on the Pd-catalysed Suzuki cross-coupling of 2,6-dimethyl bromobenzene
with phenylboronic acid to form 1a)
Table 2
Effect of base on the Pd-catalysed Suzuki cross-coupling of 2,6-dimethyl bromobenzene with phenyl-
boronic acid to form 1a)
To develop the synthetic protocol and also identify possible limits of steric hindrance beyond which
the reaction would not occur, we studied the coupling of 2-ethyl-6-methylbromobenzene,10,11 2,6-
diethylbromobenzene, 4-bromobiphenyl,12 and 9-bromoanthracene13 with phenylboronic acid, using
the Pd2(dba)3/P(OMe)3 catalyst mixture with the aim of forming 2-ethyl-6-methylbiphenyl (2), 2,6-
diethylbiphenyl (3), o-terphenyl (4) and 9-phenylanthracene (5), respectively (Table 3).
Our route to substituted biaryls offers a significant improvement over previously reported methods.
It is not necessary to use aryl phosphines where, in addition to their steric bulk retarding the process,
unwanted by-products are often formed by reaction of ligand-bound phenyl groups with the boronic
acid.14 It is not necessary to use labilised aryl triflates or mesylates in order to get a reasonable yield of
product, nor is it necessary to use other metal transfer agents such as arylmagnesium halides.5,15 As a
consequence it is possible to form the desired biaryl, quickly, efficiently and from simple, unmodified,
starting materials.
Although a number of sterically crowded biaryls can be formed using the Pd2(dba)3/P(OMe)3 catalyst
mixture, we find that a limit comes when both ortho substituents on the aryl halide are equal to or more

2489
Table 3
Scope of the Pd2(dba)3/P(OMe)3-catalysed Suzuki cross-coupling of sterically hindered aryl
bromidesa)
sterically demanding than ethyl groups. This may attribute to the difficulty of the catalyst to get close
enough to the aryl halide for the initial oxidative addition to occur. This led us to look at some nickel
catalysts for the synthesis of 1–5. We felt that, using nickel complexes such as Ni(dppf)Cl2 [dppf=1,10-
bis-diphenylphosphino ferrocene] and Ni{P(OMe)3}2Cl2, it may be possible to facilitate the coupling of
more sterically demanding aryl halides.16 As the results in Table 4 show, this is unfortunately not the
case. As with the palladium system, sterically crowded biaryls can be formed but the limit to this comes
at the same point.17 A key advantage of the nickel catalysts over the Pd2(dba)3/P(OMe)3 mixture is the
much greater ease of separation of product from catalyst mixture at the end of the reaction. As the nickel
complex added is the catalyst for reaction, the addition of free phosphine or phosphite is not necessary
as it is in the case of Pd2(dba)3. Other advantages of the nickel systems include the air stability, cost
and ease of preparation of the catalyst, all of which are important when considering the scale-up of the
reaction.
Table 4
Scope of the nickel catalysed Suzuki cross-coupling of sterically hindered aryl bromidesa)
In summary, we have developed catalyst mixtures for the Suzuki cross-coupling of aryl halides bearing
two ortho substituents with phenylboronic acid. Our catalyst systems, which employ readily available
components, allow for the synthesis of sterically crowded biaryls in good yields and open up new
routes for the synthetic chemist when attempting to prepare compounds containing this structural motif,
including a range of natural products.

2490
Acknowledgements
Financial support from AstraZeneca plc and the University of Cambridge is acknowledged with thanks.
Girton College Cambridge is thanked for a College Research Fellowship (N.E.L.).
References
1. Tsuji, J. Palladium Reagents and Catalysis; Wiley: New York, 1995.
2. Stanforth, S. P. Tetrahedron 1998, 54, 263.
3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
4. Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
5. Wanatabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
6. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1998, 37, 3387.
7. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
8. Preparation of 2,6-dimethylbiphenyl (1): A solution of 2,6-dimethylbromobenzene (0.5 g, 0.37 ml, 2.7 mmol) in dioxane (5
ml) and a solution of P(OMe)3 (22 mg, 0.016 ml) in dioxane (5 ml) were added in turn to a flask charged with Pd2(dba)3
(82 mg), phenylboronic acid (360 mg, 3.0 mmol) and K3PO4 (1.26 g) under a nitrogen atmosphere. The reaction mixture
was then stirred at 95°C, monitoring the reaction regularly by removing aliquots of the solution and analysing them by
LC-MS. After 8 h, the reaction mixture was cooled to room temperature, diluted with Et2O, filtered through a pad of Celite,
concentrated and purified by flash chromatography using hexane/ethyl acetate as eluent. 1 (393 mg) was recovered in 80%
yield. 1H NMR (CDCl3, 250 MHz): δ 2.0 (s, 6H), 7.21 (m, 2H), 7.26 (m, 2H), 7.33 (m, 2H), 7.38 (m, 1H), 7.41(m, 1H). MS
(ES) m/z 182 (calcd 182.2).
9. Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 2956.
10. 2-Ethyl-6-methylbromobenzene was prepared by the published procedure (Bultsma, T.; Mejer, J. F.; Pauli, F. I.; Ramacker,
J. P.; Nauta, W. T. Eur. J. Med. Chem.–Chim. Ther. 1977, 12, 427).
11. Preparation of 2-ethyl-6-methylbiphenyl (2): Method as with 1 but using 2-ethyl-6-methylbromobenzene (537 g, 2.7 mmol)
as the aryl halide. 2 (286 mg) was recovered in 56% yield. 1H NMR (CDCl3, 250 MHz): δ 1.23 (t, 3H), 2.25 (s, 3H), 2.75
(q, 2H), 7.21 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.49 (m, 1H), 7.51 (m, 1H). MS (ES) m/z 196 (calcd 196.2).
12. Preparation of o-terphenyl (4): Method as with 1 but using 2-bromobiphenyl (629 mg, 0.45 ml, 2.7 mmol) as the aryl halide.
4 (447 mg) was recovered in 72% yield. 1H NMR (CDCl3, 250 MHz): δ 7.4 (m, 4H), 7.16 (m, 10H). MS (ES) m/z 230 (calcd
230.3). Mp 56°C (lit. 56–58°C).
13. Preparation of 9-phenylanthracene (5): Method as with 1 but using 9-bromoanthracene (693 mg, 2.7 mmol) as the aryl
halide. 5 (404.6 mg) was recovered in 59% yield. 1H NMR (CDCl3, 250 MHz): δ 8.42 (m, 1H), 7.95 (m, 2H), 7.62 (m, 2H),
7.51 (m, 4H), 7.42 (m, 3H), 7.3 (m, 2H). MS (ES) m/z 254 (calcd 254.3). Mp 154°C (lit 153–155°C).
14. Kamikawa, T.; Hayashi, T. Synlett 1997, 207.
15. Johnson, M. G.; Foglesong, R. J. Tetrahedron Lett. 1997, 38, 7002.
16. Ni(dppf)Cl2 has been used in cross-coupling reactions before with some considerable success. See: Indolese, A. F.
Tetrahedron Lett. 1997, 38, 3513.
17. Preparations of 1–5 using Ni catalysts: In a reaction, 5 molthe nickel complex (Ni(dppf)Cl2 or Ni(P(OMe)3