The first general palladium catalyst for the Suzuki-Miyaura and carbonyl enolate coupling of aryl arenesulfonates

Article abstract of DOI:10.1021/ja036947t

The first general method for the palladium-catalyzed Suzuki-Miyaura and carbonyl enolate coupling of unactivated aryl arenesulfonates was developed utilizing XPhos, 1, and Pd(OAc)₂. This is of significant interest because aryl tosylates and aryl benzenesulfonates are more easily handled and considerably less expensive than aryl triflates. This catalyst system effects the coupling of a variety of aryl, heteroaryl, and extremely hindered arylboronic acids with different aryl tosylates, under mild conditions. The same catalyst was employed in the first carbonyl enolate coupling of aryl arensulfonates. Copyright

Full text of DOI:10.1021/ja036947t

Published on Web 09/09/2003
The First General Palladium Catalyst for the Suzuki-Miyaura and Carbonyl
Enolate Coupling of Aryl Arenesulfonates
Hanh Nho Nguyen, Xiaohua Huang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 27, 2003; E-mail: sbuchwal@mit.edu
Cross-coupling methodology to form carbon-carbon bonds has
revolutionized organic synthesis.1 The Suzuki-Miyaura coupling
is, arguably, of the greatest practical importance of these methods.2
Recently, improved catalyst systems for Suzuki-Miyaura couplings
have been described, that allow couplings to be carried out at room
temperature,3a-c to handle electron-rich aryl chlorides,3a,b and to
prepare highly substituted biaryls.3d Missing is a system capable
of handling aryl tosylates. This would be of significant interest as
tosylates are more easily handled and considerably less expensive
than aryl triflates. Aryl tosylates are relatively unreactive compared
to aryl halides and triflates. They have been reported as substrates
for other palladium-catalyzed processes, particularly in aromatic
amination.4 However, for the formation of carbon-carbon bonds
little success has been realized, and no general catalyst exists;5 some
success has been seen with Ni catalyst.6 Herein we report on our
efforts in this area.
(BINAP)Pd, that oxidative addition occurs after binding of the
amine to Pd(0) intermediate;8 such a process is unlikely for coupling
reactions involving arylboronic acids.
The use of the catalyst derived from 1 and Pd(OAc)2 in THF
demonstrated a good deal of generality and is successful for a
variety of combinations in which neither substrate contains an ortho
substitutent larger than an OMe group (Table 2). In these cases the
reactions were complete in 3 h at 80 °C (80-90% isolated yield).
Common functional groupsscyano, aldehyde, nitro and ketones
were tolerated.
Table 2. Suzuki-Miyaura Coupling of ArOTs and VinylOTs in
THFa
We recently reported that XPhos, 1,7 was an excellent supporting
ligand for the Pd-catalyzed amination of aryl benzenesulfonates.4a
During this study we also confirmed previous work which had
revealed that ferrocenyl ligands 11 and 12 were also moderate to
very good in this regard.4b Thus, we were surprised by the results
shown in Table 1. While 1 was an effective supporting ligand for
this transformation, the use of 11 or 12 provided none of the desired
Table 1. Screening of Ligands for Suzuki-Miyaura Coupling of
ArOTs
a Reaction conditions: ArOTs or VinylOTs (1 equiv), Ar′B(OH)2 (2
equiv), K3PO4‚H2O (3 equiv), 2 mol % Pd(OAc)2, 5 mol % 1, THF, 80 °C,
3 h. Isolated yield (average of two runs). b (2-Methoxy-biphenyl-4-yl)-
phenylmethanol was also isolated in 3% yield. c Reaction time 5 h.
d Reaction time 1 h. e PhB(OH)2 (1.3 equiv) at room temperature for 2 h.
For difficult substrates, complete conversion of aryl tosylates
was achieved when the cross-coupling reaction was performed with
a higher catalyst loading (3% Pd(OAc)2 and 7 mol % 1) in t-BuOH
for 6 h (Table 3). We believe that t-BuOH probably increases the
solubility of the aryl tosylates and arylboronic acids, allowing them
to proceed at rates much faster than protodeboronation. For example,
with 2,6-dimethoxyphenylboronic acid (Table 3, entry 1), a high
yield of coupling product (92%) was obtained. When THF was
employed as solvent under similar conditions, conversion of the
aryl tosylate was incomplete, and extensive deboronation of the
product. While this is not easily interpretable, one possibility is, as
we have previously shown for amination reactions catalyzed by
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J. AM. CHEM. SOC. 2003, 125, 11818-11819
10.1021/ja036947t CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 4. Enolate Arylation of Aryl Benzenesulfonates
Table 3. Suzuki-Miyaura Coupling of ArOTs in t-BuOHa
a K2CO3 as base, t-BuOH as solvent, from aryl tosylate. b Toluene was
the solvent. c Isolated yield of pure cis isomer. Ratio of cis:trans in crude
product was ∼5:1.
system can handle a wide range of substrates, including extremely
hindered arylboronic acids, under mild conditions. The same catalyst
was also used in the first example of the cross-coupling of carbonyl
enolates with aryl arenesulfonates.
Acknowledgment. We thank the National Institutes of Health
(GM 46059) for supporting this work. We are grateful to Pfizer,
Merck, Lundbeck, and Rhodia Pharmaceutical Solutions for ad-
ditional unrestricted support. H.N.N. was supported as a postdoctoral
trainee of the National Cancer Institute (NCI Training Grant CI
T32CA09112).
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 1998.
(2) (a) Miyaura, N. Topics in Current Chem. 2002, 219, 11. (b) Suzuki, A. J
Organomet. Chem. 1999, 576, 147.
a Reaction conditions: ArOTs (1 equiv), Ar′B(OH)2 (2 equiv), K3PO4‚H2O
(3.0 equiv), 3 mol % Pd(OAc)2, 7 mol % 1, t-BuOH, 80 °C, 6 h. Isolated
yield (average of two runs). b Reaction time 9 h, 89-92% conversion of
ArOTs. c Reaction time 17 h at 110 °C, 88-93% conversion of ArOTs.
(3) For example: (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J. Am. Chem. Soc. 1999, 121, 9550. (b) Littke, A. F.; Dai, C.; Fu, G.
C. J. Am. Chem. Soc. 2000, 122, 4020. (c) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (d) Yin, J.;
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(4) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Hamann, B. C.;
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boronic acid was observed. We also found that more hindered
boronic acids such as 2-methylphenylboronic acid (entries 3 and
4) and 2,6-dimethylphenylboronic acid (entries 6 and 7) could be
efficiently utilized as substrates; in THF these reactions failed to
proceed to completion. These conditions also worked well to
combine 5-(tosyloxy)-1-tetralone and pyridine-3-boronic acid (entry
5). Remarkably, 2,4,6-triisopropylphenylboronic acid, which is
exceptionally hindered, could be coupled in high yield (entry 8).
These results indicated that the transmetalation step was facile under
the conditions studied. In contrast, even a single methyl group at
the R-carbon to the tosylate was enough to prevent complete
conversion (entries 9 and 10) although very good isolated yields
were still obtained. Thus, the standard situation in which trans-
metalation is rate limiting does not hold here. Moreover, the
coupling of 2,4-dimethylchlorobenzene with PhB(OH)2 proceeded
quantitatively in 1 h at 50 °C. Thus, it is tempting to postulate that
the transition states for oxidative addition of LnPd to the tosylate
and the aryl chloride have significantly different steric requirements.
We have also demonstrated, as shown in Table 4, for the first
time that aryl benzenesulfonates can be utilized as substrates in
the arylation of enolates derived from cyclic and acyclic ketones,
â-dicarbonyl compounds, and an ester.9
(5) Suzuki-Miyaura coupling of activated aryl or vinyl tosylates: (a)
Huffman, M. A.; Yasuda, N. Synlett 1999, 471. (b) Lakshman, M. K.;
Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.; Sevova, N.; Boggess, B.
Org. Lett. 2002, 4, 1479. (c) Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.; Yang,
Z. J. Org. Chem. 2003, 68, 670. Alkyne coupling: (d) Fu, X.; Zhang, S.;
Yin, J.; Schumacher, D. P. Tetrahedron Lett. 2002, 43, 6673. (e) Wu, J.;
Liao, Y.; Yang, Z. J. Org. Chem. 2001, 68, 3642. Heck coupling: (f) Fu,
X.; Zhang, S.; Yin, J.; McAllister, T. L.; Jiang, S. A.; Tann, C.-H.;
Thiruvengadam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573. After
this manuscript was submitted, a paper on the use of aryl tosylates in
Kumada coupling processes was reported: (g) Roy, A. H.; Hartwig, J. F.
J. Am. Chem. Soc. 2003, 125, 8704.
(6) Nickel-catalyzed Suzuki-Miyaura coupling of ArOMs: (a) Percec, V.;
Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060. (b) Kobayashi, Y.;
Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531. ArOTs: (c) Zim, D.; Lando,
V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049. Iron-catalyzed
coupling of alkyl Grignard reagents with ArOTs: (d) Fu¨rstner, A.; Leitner,
A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. Stille
couplings of aryl arenesulfonates: (e) Badone, D.; Cecchi, R.; Guzzi, U.
J. Org. Chem. 1992, 57, 6321. (f) Nagatsugi, F.; Uemura, K.; Nakashima,
S.; Minoru, M.; Sasaki, S. Tetrahedron Lett. 1995, 36, 421.
(7) XPhos, ligand 1, is commercially available from Strem Chemical Co.
(8) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 14104.
(9) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7996. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234. Carbonyl enolate arylation of aryl triflates: (d) Viciu, M.
S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053.
In summary, we have disclosed the first palladium catalyst system
for the Suzuki-Miyaura coupling of unactivated aryl tosylates. This
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