Electronic nature of N-heterocyclic carbene ligands: Effect on the Suzuki reaction

Article abstract of DOI:10.1021/ol050471w

(Chemical Equation Presented) Suzuki reactions of aryl chlorides and arylboronic acids with a range of electronically different N-heterocyclic carbene ligands derived from N,N-diadamantylbenzimidazolium salts are reported. Results indicate that an electron-rich NHC ligand enhances the rate of oxidative addition. However, reductive elimination is unchanged by the electronic nature of the supporting ligand and is primarily affected by the steric environment.

Full text of DOI:10.1021/ol050471w

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1991-1994
Electronic Nature of N-Heterocyclic
Carbene Ligands: Effect on the Suzuki
Reaction
Niloufar Hadei, Eric Assen B. Kantchev, Christopher J. O’Brien, and
Michael G. Organ*
Department of Chemistry, York UniVersity, 4700 Keele Street,
Toronto, M3J 1P3, Canada
organ@yorku.ca
Received March 4, 2005
ABSTRACT
Suzuki reactions of aryl chlorides and arylboronic acids with a range of electronically different N-heterocyclic carbene ligands derived from
N,N-diadamantylbenzimidazolium salts are reported. Results indicate that an electron-rich NHC ligand enhances the rate of oxidative addition.
However, reductive elimination is unchanged by the electronic nature of the supporting ligand and is primarily affected by the steric environment.
The coupling reaction of organoboron derivatives with aryl-,
vinyl-, or alkyl halides, named the Suzuki1 reaction, has
emerged as one of the most important carbon-carbon bond-
forming methods in the synthesis of pharmaceutical agents,
organic materials, and natural products.2 The activation of
unreactive substrates such as chloroarenes has only recently
become reality with the advent of bulky, electron-rich phos-
phines, introduced by the groups of Beller,3 Buchwald,4 and
Fu.5
ing the Suzuki reaction.6 However, only very recently have
NHC ligands reached a level of activity comparable with
that of phosphines.7
Caddick, Cloke et al. recently published a Suzuki reaction
of aryl chlorides with a Pd-NHC catalyst based on the bulky
N,N-di-(2,6-diisopropylphenyl)-imidazoylidene ligand (IPr,
1, Figure 1) at 40 °C using tetra-n-butylammonium bromide
as a cocatalyst.8 Nolan et al. reported an air-stable palladium
complex of ligand 1 that coupled aryl chlorides, but high
In recent years, N-heterocyclic carbenes (NHCs) have
emerged as alternatives to phosphines as ligands for a variety
of transition metal-catalyzed cross-coupling reactions, includ-
(4) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Buchwald, S. L.
Org. Lett. 2004, 6, 2642. (c) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 3820. (d) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 1162. (e) Old, D. W.; Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 9722.
(1) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20,
3437.
(2) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002.
(3) (a) Audreu, M. G.; Zapf, A.; Beller, M. Chem. Commun. 2000, 2475.
(b) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39,
4153.
(5) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 17, 3387.
(6) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
(7) Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201.
(8) Arentsen, K.; Caddick, S.; Cloke, F. G. N.; Herring, A. P.; Hitchcock,
P. B. Tetrahedron Lett. 2004, 45, 3511.
10.1021/ol050471w CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/09/2005

Scheme 1. Accepted Mechanism for Palladium-Catalyzed
Cross-Coupling Reactions
Figure 1. Active NHC ligands for the Suzuki reaction.
temperatures were required to achieve acceptable yields.9
Lebel et al. found that N,N-di-(2,4,6-trimethylphenyl)-imid-
azoylidene (IMes, 2) also functioned as an effective support-
ing ligand, but again elevated temperatures were required.10
Herrmann et al. reported the use of N,N-diadamantylimi-
dazoylidene (IAd, 3) in Suzuki reactions at room temperature
with aryl chlorides, although ortho-substitued chloroarenes
failed to couple.11 The admantyl groups in IAd are extremely
sterically demanding and are believed to be responsible for
its activity. Glorius and co-workers similarly reported a
Suzuki reaction of aryl chlorides at ambient temperature,12
including ortho-substituted aryl chlorides and arylboronic
acids, with the pentacyclic carbene 4; the activity of this
ligand was attributed to flexible steric bulk.
of the product concomitant with the regeneration of the
catalyst; however, if the ligand is too sterically demanding,
the rate of oxidative addition can be adversely affected.14b
It is clear that a subtle balance between steric and
electronic factors has to be achieved for a highly active
catalyst system to be created.
In an attempt to provide an answer to the role of electronic
effects in Pd-NHC-mediated couplings, we decided to
synthesize a range of NHC ligands (Figure 2) and explore
their activity in Suzuki couplings of aryl chlorides.
Thus, the recurrent theme in NHC ligand design has been
to adjust the steric environment around the metal center. The
electronic nature of the carbene ligand and how it might
affect the overall performance of the Pd-NHC catalyst has
received almost no attention at all. Batey et al. reported a
single example of an NHC-carbene bearing an electron-
withdrawing carbonyl substituent on the ring nitrogen atom;
a Pd complex of this carbene was shown to be a competent
catalyst in the Sonogashira reaction.13 However, no mecha-
nistic studies or comparison with similar ligands have
appeared as yet. Moreover, investigations of the electronic
properties of the central palladium atom, which is ultimately
responsible for the chemistry taking place, are virtually
nonexistent for the Pd-NHC catalysts.
The accepted mechanism for Pd-catalyzed cross-coupling
reactions (Scheme 1) involves three discrete steps: oxidative
addition, transmetalation, and finally reductive elimination.
For facile oxidative insertion into the strong carbon-chlorine
bond of aryl chlorides, an electron-rich ligand is needed.
Whether the active species for this step is a mono- or
diligated palladium complex is still under debate.14 The steric
bulk of the ligand is believed to aid the reductive elimination
Figure 2. Proposed tunable benzimidazolidine NHC ligands.
Even though benzimidazolidines have received scant
attention as NHC ligands,15 they provide a suitable platform
for tuning the electron density on the carbene carbon.
Introducing electronically different substituents at positions
5 and 6 would remotely alter the electronic character of the
palladium metal center without any steric interference from
the substituent itself. At the same time, the presence of
N-adamantyl groups ensures the required steric bulk for facile
reductive elimination is in place.
Synthesis of the NHC precursor benzimidazolium salts
followed a protocol developed by Diver and co-workers.16
A Buchwald-Hartwig amination of the required 1,2-dibro-
moarene (5-7) with excess 1-adamantylamine and sodium
tert-butoxide followed by cyclization with ethyl orthofor-
(9) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem. 2004,
69, 3171.
(10) Lebel, H.; Janes, M. K.; Charette, A. B.; Nolan, S. P. J. Am. Chem.
Soc. 2004, 126, 5046.
(11) Gsto¨ttmayr, C. W. K.; Bo¨hm, V. P. W.; Herdtweck, E.; Grosche,
M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363.
(12) (a) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew.
Chem., Int. Ed. 2003, 42, 3690. (b) Altenhoff, G.; Goddard, R.; Lehmann,
C.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15196.
(13) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411.
(14) (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
(b) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 5749.
(15) (a) Metallinos, C.; Barrett, F. B.; Chaytor, J. L.; Heska, M. E. A.
Org. Lett. 2004, 6, 3641. (b) Perry, M. C.; Burgess, K. Tetrahedron:
Asymmetry 2003, 14, 951.
1992
Org. Lett., Vol. 7, No. 10, 2005

suggest that the transmetalation and reductive elimination
steps are unaffected by the electronic nature of the carbene
ligand. Electron-deficient ligands are believed to accelerate
the reductive elimination step.2 However, reactions conducted
with the most electron-deficient ligand 13 consistently
yielded the lowest amount of product, while the most
electron-rich ligand 11 was found to give the highest yields.
These results indirectly corroborate the theory that the
reductive elimination step is primarily governed by the steric
nature of the NHC ligand.
Scheme 2. Benzimdazolium Salt Synthesis
Next, we investigated whether the electronic nature of the
aryl halide had an effect on the cross-coupling reaction with
ligands 11-13. The results (Table 2) demonstrate that ligand
mate/HCl yielded the benzimidazolium chlorides (11-13)
in good yields in two steps (Scheme 2).
Table 2. Suzuki Cross-Coupling Reactions with Electronically
Different Aryl Chloridesa
With the salts 11-13 in hand, we submitted them to the
Suzuki reaction using conditions developed by Lebel.10 First,
we were interested in whether there would be a difference
in reactivity when 4-chlorotoluene was coupled with electron-
rich and electron-deficient boronic acids (Table 1). Results
Table 1. Suzuki Cross-Coupling Reactions with Electronically
Different Boronic Acidsa
a Reaction conditions: 0.5 mmol of aryl chloride, 0.75 mmol of p-tolyl
boronic acid, 1 mmol of Cs2CO3, in duplicate. b GC yield against calibrated
internal standard (undecane). Isolated yields in parentheses.
11, the most electron rich, yielded the most cross-coupling
product, followed, respectively, by 12 and 13, the most
electron deficient.
a Reaction conditions: 0.5 mmol of 4-chlorotoluene, 0.75 mmol of
arylboronic acid, 1 mmol of Cs2CO3, in duplicate. b GC yield against a
calibrated internal standard (undecane). Isolated yields in parentheses.
(16) (a) Rivas, F. M.; Riaz, U.; Diver, S. T. Tetrahedron: Asymmetry
2000, 11, 1703. (b) Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.;
Diver, S. T. Org. Lett. 2001, 3, 2673.
Org. Lett., Vol. 7, No. 10, 2005
1993

Assuming that oxidative addition is the rate-determining
step and its rate is increased by an electron-rich metal center,2
these results can be explained by assuming that rate of
oxidative addition of the palladium complexes is in the order
11 > 12 > 13, which is in agreement with the current
mechanistic theories detailed above.
In conclusion, the studies on the Pd-NHC-catalyzed
Suzuki reaction presented here help further clarify the
mechanistic picture of the overall process. The oxidative
addition is primarily affected by the electronic nature of
the palladium metal center, while the reductive elimination
step is not unduly affected by the electronic nature of the
supporting ligand but by the steric environment it imparts.
These results imply that NHC ligand design should focus
on creating an electron-rich carbene ligand with a carefully
selected steric environment. The topography created by the
neighboring N-substituents must not retard the oxidative
addition but be sufficient to ensure rapid elimination of the
product and thus turnover of the catalysts.17
and Varian Canada for their collaborative in-kind donation
(in part) of the GCMS/MS 4000 to conduct the analyses in
this report.
Note Added after ASAP Publication. Erroneous values
were listed for the isolated yields of 4-methyl-4′-methoxy-
biphenyl and 4-fluoro-4′-methylbiphenyl in the Supporting
Information (p S6) published ASAP April 9, 2005; the
corrected version was published April 13, 2005.
Supporting Information Available: Procedures for the
preparation and full characterization of compounds 8-13 and
a representive procedure for the coupling reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050471W
(17) We are currently involved in computation studies that we hope will
allow rationale design of the NHC carbene ligand. These studies will be
published in due course.
Acknowledgment. We would like to thank the ORDC
and NSERC (Canada) for financially supporting our program
1994
Org. Lett., Vol. 7, No. 10, 2005