Nonsymmetric Pincer-Catalyzed Suzuki-Miyaura Arylation
TABLE 1. Suzuki Coupling of r-Bromoenone and Arylboronic
Acids Employing Complex 1
FIGURE 1. Pincer-type complex 1.
entry
Ar
3 (%)a
1
2
3
Ph
4-MeOPh
1-Naph
3a (74)
3b (90) 86
3c (38)
tion of the PCN-type palladium pincer complex 1 (Figure 1),11
which was subsequently employed in a range of standard
Hiyama, Sonogashira, and Suzuki reactions. To our delight, in
addition to a remarkably high efficiency, palladacycle 1
displayed hydrophilic properties that made it suitable for
performing transformations in aqueous media.12
a Determined by 1H NMR on the basis of the amount of starting aryl
halide. Diethylene glycol dimethyl ether was used as internal standard.
Isolated yield is shown in italics.
In principle, any carbon-halogen bond, regardless of the
carbon hybridization, is vulnerable to the attack of the nucleo-
philic partner if the appropriate metal-containing catalyst or
precatalyst is employed. Nevertheless, difficulties are often
encountered when inactivated alkyl electrophiles are employed
in Suzuki couplings, generally caused by a slower oxidative
addition of the alkyl halide, competing ꢀ-elimination side
reactions, and a more difficult reductive elimination step.13
Interestingly, when alkyl boronic esters or acids are employed
in this context, Suzuki coupling is usually interfered with by a
more troublesome transmetalation step between the boronic
counterpart and the intermediate Pd species.14
Thus, although biaryl Suzuki coupling is reasonably well
developed, the lack of efficient procedures for the reaction with
alkyl halides or primary alkyl boronic acids and other non-
standard substrates has fueled much research.14-16 In this
context, Na´jera et al. reported an elegant use of oxime-derived
palladacycles in a series of Suzuki-type reactions employing
nonactivated partners such as benzyl halides or alkylboronic
acids.17 However, concerning pincer complexes, to the best of
our knowledge, only two examples have been found in the
literature. Moreover, in the latter reports both pincers were
symmetric and each was applied to catalyze only one Suzuki
reaction with a single nonactivated substrate.18 Herein we wish
to describe the novel use of a nonsymmetric PCN pincer
complex as a Suzuki-Miyaura coupling precatalyst of such
nonactivated and unusual substrates.
Results and Discussion
To start with, we chose R-bromoenones 2 as electrophilic
partners because of two main reasons. First, a C(sp2)-C(sp2)
bond would be formed, not very dissimilar to the biaryl version
of the Suzuki coupling in which 1 had provided excellent
results.11 Second, palladium-catalyzed cross-coupling of R-ha-
loenones with arylboronic acids has been scarcely studied.19,20
In fact, this is the first report concerning the use of a pincer-
type palladacycle in the latter transformation. Thus, easily
available bromoenone 219b was reacted with several aryl
bromides in the presence of a catalytic amount of complex 1
employing Na2CO3 as base and neat water as solvent. To our
delight, the R-arylation of the stating material took place in these
conditions in moderate to good yields. It is noteworthy that the
use of neat water as solvent, apart from the previously mentioned
advantages in terms of sustainability, safety or economy,
provides a really easy workup and purification procedure.
Encouraged by the promising results obtained with R-bro-
mocetones, and in order to improve the versatility of the
complex 1, our attention then focused on C(sp2)-C(sp3) bond
construction by Suzuki coupling. First, we tested the effective-
ness of the latter palladacycle in the coupling of arylbromides
with butylboronic acid. In this regard, all our efforts to
accomplish the reaction in neat water were unsuccessful, and
although stronger reaction conditions were employed, such as
higher temperatures or catalyst loadings, in all cases the starting
materials were recovered. However, PCN pincer 1 turned out
to be highly efficient when o-xylene was used as solvent.
Accordingly, a number of electronically different aryl bromides
were effectively coupled with n-butylboronic acid, as shown in
(9) A PCN pincer applied to Heck reaction: (a) Consorti, C. S.; Ebeling, G.;
Flores, F. R.; Rominger, F.; Dupont, J. AdV. Synth. Cat. 2004, 246, 617–634.
Biaryl Suzuki couplings catalyzed by a PCN palladium complex: (b) DaSilvera
Neto, B. A.; Lopes, A. S.; Ebeling, G.; Gonzalves, R. S.; Costa, V. E. U.; Quina,
F. H.; Dupont, J. Tetrahedron 2005, 10975–10982. (c) Mancilha, F. S.; DaSilvera
Neto, B. A.; Lopes, A. S.; Moreira, P. F.; Quina, F. H.; Gonzalves, R. S.; Dupont,
J. Eur. J. Org. Chem. 2006, 4924–4033. (d) Rosa, G. R.; Rosa, C. H.; Rominger,
F.; Dupont, J.; Monteiro, A. L. Inorg. Chem. Acta 2006, 359, 1947–1954. (e)
Rosa, G. R.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Synthesis 2003, 2894–
2897. The synthesis of chiral PCN pincer complexes designed to catalyze
asymmetric reactions: (f) Motoyama, Y.; Shimozono, K.; Nisiyama, H. Inorg.
Chim. Acta 2006, 359, 1725–1730.
(10) (a) Churruca, F.; SanMartin, R.; Tellitu, I.; Dom´ınguez, E. Tetrahedron
Lett. 2006, 47, 3233–3237. (b) Churruca, F.; Sanmartin, R.; Ine´s, B.; Tellitu, I.;
Dom´ınguez, E. AdV. Synth. Catal. 2006, 348, 1836–1840. See also ref 7d.
(11) Ine´s, B.; SanMartin, R.; Churruca, F.; Dom´ınguez, E.; Urtiaga, M. K.;
Arriortua, M. I. Organometallics 2008, 28, 2833–2839.
(12) A review focused on organic reactions in aqueous media: (a) Li, C.-J.
Chem. ReV. 2005, 105, 3095–3165. For a revision on the use of aqueous
environments in Suzuki-Miyaura biaryl coupling, see: (b) Franze´n, R.; Xu, Y.
Can. J. Chem. 2005, 83, 266–272.
(13) For a minireview focused on cross-couplings with nonactivated alkyl
halides, see: Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–
688.
(14) Kataoka, N.; Shelby., Q.; Stambuli, J. P.; Hartwing, J. F. J. Org. Chem.
2002, 67, 5553–5566.
(15) Some examples of the Suzuki-Miyaura reaction employing alkyl boronic
acids: (a) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron 2004, 60, 3813–
3818. (b) Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465–1470. (c)
Andrus, M. B.; Song, M. B. Org. Lett. 2001, 3, 3761–3764.
(16) The use of benzyl halides in the Suzuki-Miyaura coupling: (a) Chang,
C.-P.; Huang, Y. L.; Hong, F.-E. Tetrahedron 2005, 61, 3835–3839. (b) Bandgar,
B. P.; Bettigeri, S. V.; Phopase, J. Tetrahedron Lett. 2004, 45, 6959–6962. (c)
Langle, S.; Abarbi, M.; Duchene, A. Tetrahedron Lett. 2003, 44, 9255–9258.
(d) Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 2865–2858.
(e) Chahen, L.; Doucet, H.; Santelli, M. Synlett 2003, 1668–1672.
(17) (a) Botella, L.; Na´jera, C. J. Organomet. Chem. 2002, 663, 46–57. (b)
Botella, L.; Na´jera, C. Angew. Chem., Int. Ed. 2002, 41, 179–181.
(18) For the use of a NCN symmetric pincer in a Suzuki coupling with one
benzyl derivative, see: (a) Luo, Q.; Eibauer, S.; Reiser, O. J. Mol. Catal. A:
Chem. 2007, 268, 65–69. (b) A PCP palladium pincer has been used in a Suzuki
coupling with bromoundecane as electrophilic partner. See ref 8d.
(19) (a) Felpin, F.-X. J. Org. Chem. 2005, 70, 8575–8578. (b) Banks, J. C.;
Van Mele, D.; Frost, C. G. Tetrahedron Lett. 2006, 47, 2863–2866. (c) Burns,
M. J.; Fairlamb, J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett. 2007,
9, 5397–5400.
(20) Suzuki-Miyaura coupling of R-haloenones catalyzed by a bentzothia-
zole-based palladium precatalyst: Dawood, K. M. Tetrahedron 2007, 63, 9642–
9651.
J. Org. Chem. Vol. 73, No. 21, 2008 8449