Mechanism of benzoquinone-promoted palladium-catalyzed oxidative cross-coupling reactions

Article abstract of DOI:10.1021/ja901952h

(Chemical Equation Presented) This communication describes mechanistic studies of the Pd-catalyzed oxidative cross-coupling of benzo[h]quinoline with simple arenes. Through a series of experiments, including determination of the order of the reaction in v

Full text of DOI:10.1021/ja901952h

Published on Web 07/01/2009
Mechanism of Benzoquinone-Promoted Palladium-Catalyzed Oxidative
Cross-Coupling Reactions
Kami L. Hull and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109
Received March 13, 2009; E-mail: mssanfor@umich.edu
The development of mild, efficient, and selective transition-metal
catalysts for the direct oxidative cross-coupling of simple arenes
remains a significant challenge in organic synthesis.1-8 Such
transformations represent an atom-economical alternative to tradi-
tional Ar-X/Ar-M coupling reactions, which require the use of
two prefunctionalized arene starting materials.1 As shown in Scheme
1, a general mechanism for oxidative cross-coupling would involve
sequential C-H activation of two different arene substrates followed
by C-C bond-forming reductive elimination to release a biaryl
product. A key challenge in these reactions is to control the
selectivity of each C-H activation step.
that the quinone acts as a ligand during the selectivity-determining
step.6 Thus, a key goal of these mechanistic studies was to more
clearly elucidate the role of the quinone in these transformations.
A general reaction pathway for the Pd-catalyzed oxidative
coupling between benzo[h]quinoline and Ar-H involves (i) cy-
clometalation of benzo[h]quinoline to afford intermediate 1, (ii)
BQ-promoted Ar-H activation/Ar-Ar′ coupling to liberate 2 and
Pd0, and finally (iii) oxidation of Pd0 to PdII with AgI (Scheme 2).
On the basis of this pathway, we focused our mechanistic studies
on the stoichiometric reaction between palladacycle 1 and 1,2-
dimethoxybenzene (3) (eq 1):
Scheme 1. General Mechanism for Ar-H/Ar′-H Cross-Coupling
This stoichiometric reaction was chosen because it allows for direct
kinetic interrogation of the key Ar-H actiVation and C-C bond-
forming steps [(ii) in Scheme 2], while eliminating complications
from cyclometalation and oxidation processes. Arene 3 was selected
for these studies because it reacts cleanly under both stoichiometric
and catalytic conditions to afford a single biaryl product, 4, in high
yield.
We considered three mechanisms for the Ar-H activation/
Ar-Ar′ coupling steps of this Pd-mediated oxidative coupling
(Scheme 3). Mechanism 1, which was proposed in our initial paper,6
involves reversible coordination of π-acidic BQ to Pd followed by
Ar-H activation and then reductive elimination to form the new
Ar-Ar′ bond. Mechanism 2 proceeds by reversible formation of
an agostic Ar-H/Pd adduct (intermediate B), then BQ-promoted
Ar-H activation, and finally reductive elimination. Mechanism 3
involves reversible Ar-H activation to form intermediate C
followed by coordination of BQ and then reductive elimination to
release the biaryl product. Notably, in each case, we assume that
C-C coupling from intermediate D is fast and that the slow step
is either Ar-H activation or BQ coordination.9
Several recent reports have described exciting progress in the
development of Pd-catalyzed reactions for chemo- and regioselec-
tive Ar-H/Ar′-H cross-coupling.4-8 For example, couplings
between activated heteroarenes and arenes,5 between cyclometa-
lating substrates and arenes,6,7 and between simple Ar-H deriva-
tives8 have been communicated over the past two years. These
studies represent important advances in the field; however, the
reactions remain limited by modest substrate scope, low turnover
numbers, and the inability to rationally tune selectivity. These
limitations are due, in large part, to a lack of fundamental
mechanistic information about the factors controlling reactivity and
selectivity in these systems. This communication describes the first
detailed mechanistic investigation of a Pd-mediated oxidative cross-
coupling reaction. The work provides key insights into the
selectivity-determining step(s) of this transformation.
Scheme 2. General Pathway for Pd-Catalyzed Cross-Coupling
Scheme 3. Possible Detailed Mechanisms for Ar-H Activation/
C-C Bond Formation from 1 Promoted by BQ
Our investigations focused on the Pd-catalyzed coupling of
benzo[h]quinoline with simple arenes (Ar-H) (Scheme 2).6 These
transformations proceed with very high chemoselectivity for the
formation of cross-coupled (vs homocoupled) products. Further-
more, like many related reactions, they afford modest to excellent
selectivity for coupling at the least sterically hindered site of 1,2-
and 1,3-disubstituted arenes.6,7 However, this system is unique in
that a substoichiometric quantity of a 1,4-benzoquinone (BQ)
derivative is required to promote the oxidative coupling reaction.
Furthermore, the structure of this quinone has a profound influence
on the regioselectivity of coupling with certain arenes, suggesting
A variety of experiments were conducted to distinguish between
mechanisms 1, 2, and 3.10 Initial kinetic investigations revealed
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C O M M U N I C A T I O N S
Scheme 4. H/D Exchange between 3 and CD3CO2D Catalyzed by
1
that the oxidative coupling between 1 and 3 is half-order with
respect to 1 and first-order with respect to 3 and exhibits saturation
kinetics with respect to BQ (Figure 1). This data could potentially
be consistent with all of the mechanisms in Scheme 3.
result is consistent only with mechanism 3, since no H/D exchange
would be expected if mechanisms 1 or 2 were operating.12,13
We next sought to take advantage of the observed saturation
kinetics to directly probe the mechanism of Ar-H activation. These
studies were all conducted under saturation conditions ([BQ] > 0.15
M), ensuring that C-H activation is rate-limiting. We first
determined the intermolecular kinetic isotope effect (KIE) for Ar-H
activation by comparing the initial reaction rate for 3 to that for
3-d2 (Scheme 5). The KIE was found to be 3.39 ( 0.10, which
indicates that the transition state involves significant Ar-H bond
breaking.14
Figure 1. Saturation kinetics in benzoquinone.
The order of 0.5 with respect to 1 indicates cleavage of the native
dimer to a kinetically competent monomeric species prior to the
rate-determining step. The saturation kinetics with respect to BQ
could result from two possible scenarios. For mechanism 1,
saturation could be observed if equilibration between 1 + BQ and
A were much faster than the subsequent Ar-H activation. At
saturation (∼0.2 M in BQ), Keq would be expected to be
significantly greater than 1 (see the Supporting Information);
therefore, the Pd-BQ adduct A should be detectable. However,
1H NMR spectroscopic analysis of the reaction in the presence of
up to 0.5 M BQ did not show formation of a new PdII complex or
the diagnostic signals associated with a coordinated quinone.12c
These results suggest that mechanism 1 is unlikely.
Instead, we propose that the saturation kinetics are due to the
formation of a steady-state (SS) intermediate that undergoes
subsequent reaction with BQ. Such a scenario is consistent with
either mechanism 2 (with the SS intermediate being agostic complex
B) or mechanism 3 (with the SS intermediate being bisaryl complex
C).
Scheme 5. Kinetic Isotope Effect Study
The effect of electronically varying the carboxylate ligand was
studied next by examining the reaction of para-substituted benzoate
complexes with 3 in the presence of 20 equiv of BQ. The Hammett
plot obtained from this data showed a F value of -0.94 ( 0.16
(Figure 3). This indicates that the carboxylate ligand stabilizes
positive-charge buildup in the transition state for C-H activation.
Figure 3. Hammett plot for variation of the carboxylate ligand.
Scheme 6. Arene Electronic Effects on the C-H Activation Step
Figure 2. Inverse-first-order kinetics with respect to AcOH.
Experiments were next designed to differentiate between mech-
anisms 2 and 3. First, we measured the effect of 0.1-0.5 equiv of
AcOH on the initial reaction rate in the presence of 1 equiv of BQ
(nonsaturation conditions). This transformation showed an inverse-
first-order dependence on AcOH (Figure 2), suggesting that AcOH
is lost during formation of the SS intermediate. This is consistent
with mechanism 3 (where AcOH is released in the generation of
SS intermediate C) but not with mechanism 2 (where AcOH is
formed only during the reaction of SS intermediate B with BQ).
Further support for mechanism 3 was obtained from the H/D
exchange reaction between 1, 3, and CD3CO2D in the absence of
BQ (Scheme 4). 2H NMR spectroscopic analysis of this transforma-
tion after 12 h at 130 °C showed significant D incorporation into
3, presumably via reversible C-H activation/deuteration.11 This
Finally, the influence of Ar-H electronics was examined using
the reaction depicted in Scheme 6. The competition between 7 and
8 afforded a 1.3:1 ratio of products 9 and 10, demonstrating that
the relative rate of C-H activation is slightly larger for the electron-
rich arene 7. The observed chemoselectivity provides evidence
against a mechanism involving Ar-H deprotonation, since such
reactions are typically much faster with more acidic C-H bonds.15
Further, the modest magnitude of this electronic effect is incon-
sistent with an SEAr mechanism.16 On the basis of this result, along
with the KIE and Hammett data, we hypothesize that C-H
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activation in this system proceeds by an intermediate mechanism
that resembles σ-bond metathesis.17 Computational studies to further
assess the nature of this transition state are ongoing.
systematic tuning of both reactivity and selectivity in these
transformations.
Acknowledgment. This material is based upon work supported
by the U.S. Department of Energy, Office of Basic Energy Sciences
(DE-FG02-08ER 15997). K.L.H. acknowledges the ACS Division
of Organic Chemistry and Novartis for fellowships. We also thank
Dr. Bala Ramanathan for performing preliminary Hammett studies
and Thomas Lyons for editorial and experimental assistance.
The results of the mechanistic studies detailed herein have
important implications for the future development of this oxidative
coupling reaction. Most notably, they suggest that the chemo- and
regioselectivity of these transformations can be tuned by rational
modification of the reaction conditions. In the presence of a large
excess of BQ, Ar-H activation should not be reversible; therefore,
the observed selectivity should reflect that inherent to the C-H
activation step. However, as the amount of BQ is decreased and/or
as AcOH is added, the Ar-H activation step should become highly
reversible. Under these Curtin-Hammett-type conditions, the
selectivity should approach that intrinsic to the BQ-promoted
reductive elimination step.
Supporting Information Available: Experimental details and
spectroscopic data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV
2002, 102, 1359.
(2) Li, C. J. Acc. Chem. Res. 2009, 42, 335, and references therein.
(3) For Pd-catalyzed homocoupling, see: (a) Hull, K. L.; Lanni, E. L.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 14047. (b) Mori, A.; Sugie, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548. (c) Xia, J. B.; Wang, X. Q.; You, S. L. J.
Org. Chem. 2009, 74, 456. (d) Rong, Y.; Li, R.; Lu, W. Organometallics
2007, 26, 4376.
(4) For stoichiometric Pd-mediated oxidative cross-coupling, see: (a) Itahara,
T. Synthesis 1979, 151. (b) Itahara, T.; Kawasaki, K.; Ouseto, F. Bull. Chem.
Soc. Jpn. 1984, 57, 3488. (c) Itahara, T. J. Org. Chem. 1985, 50, 5272.
(5) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Dwight, T. A.;
Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(c) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
12072. (d) Potavathri, S.; Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.;
Hammann, J. M.; DeBoef, B. Tetrahedron Lett. 2008, 49, 4050. (e) Fagnou,
K.; Liegault, B. Organometallics 2008, 27, 4841. (f) Liegault, B.; Lee, D.;
Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022.
(6) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
(7) (a) Xia, J.; You, S. Organometallics 2007, 26, 4869. (b) Cai, G.; Fu, Y.;
Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (c) Brasche,
G.; Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207.
(8) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973.
Figure 4. 10/9 ratio as a function of [BQ].
(9) The assumption that C-C coupling from D is fast is based on (1)
calculations and experiments showing that coordination of BQ to PdII(R)2
complexes dramatically lowers the barrier for C-C bond-forming reductive
elimination and (2) the fact that observable PdII(BQ) complexes are
extremely rare in the literature (see ref 12c), presumably because they are
highly reactive towards reductive elimination. See: (a) Pe´rez-Rodr´ıguez,
M.; Braga, A. A. C.; Garcia-Melchor, M.; Pe´rez-Temprano, M. H.; Casares,
J. A.; Ujaque, G.; de Lera, A. R.; Alvarez, R.; Maseras, F.; Espinet, P.
J. Am. Chem. Soc. 2009, 131, 3650. (b) Szabo, K. J. Organometallics 1998,
17, 1677.
(10) DMSO (4 equiv) was added in each of the mechanistic experiments for
consistency with the catalytic reactions (ref 6). Order studies revealed that
the reaction is zeroth-order with respect to this additive (see the Supporting
Information for details).
(11) The control reaction in the absence of Pd showed <1% D incorporation.
(12) BQ-promoted reductive elimination at PdII is well-precedented. For
examples, see ref 9 and: (a) Temple, J. S.; Riediker, M.; Schwartz, J. J. Am.
Chem. Soc. 1982, 104, 1310. (b) Backvall, J. E.; Bystrom, S. E.; Nordberg,
R. E. J. Org. Chem. 1984, 49, 4619. (c) Albeniz, A. C.; Espinet, P.; Martin-
Ruiz, B. Chem.sEur. J. 2001, 7, 2481. (d) Chen, M. S.; Prabagaran, N.;
Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (e) Chen,
X.; Li, J.; Hao, X.; Goodhue, C. E.; Yu, J. J. Am. Chem. Soc. 2006, 128,
78.
(13) Analysis of the crude reaction mixture did not show the presence of any
hydroquinone, suggesting that the BQ plays a non-redox role in this
transformation. The major Pd-containing product appears to be Pd black,
which precipitates from solution over the course of the C-C coupling.
(14) (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (b) Yoneyama,
T.; Crabtree, R. H. J. Mol. Catal. A 1996, 108, 35. (c) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496. (d) Desai, L. V.; Stowers, K. J.;
Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285.
(15) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066. (b) Lafrance, M.; Rowley, C. N.; Woo,
T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (c) Gorelsky, S. I.;
Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.
(16) (a) Ryabov, A. D. Chem. ReV. 1990, 90, 403. (b) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (c) Park, C. H.; Ryabova,
V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159.
(17) For calculations describing a related mechanism, see: Davies, D. L.; Donald,
S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754.
(18) Similar effects were observed in the catalytic reaction (using AgOAc as a
stoichiometric oxidant). With 0.25 equiv of BQ, 10/9 ) 1.45:1, while with
25 equiv of BQ, 10/9 ) 1:1.2. This suggests that these stoichiometric
mechanistic studies are relevant and applicable to the catalytic transformation.
Figure 5. 10/9 ratio as a function of [AcOH].
For a preliminary demonstration of this powerful concept, we
examined the chemoselectivity of the competition reaction between
1 and 7/8 under the two limiting scenarios. As shown in Figure 4,
when [BQ] was increased from 0.00625 M (0.25 equiv) to 0.625
M (25 equiv), the chemoselectivity of the reaction was reversed
from favoring product 10 (10/9 ) 2.3:1 with [BQ] ) 0.00625 M)
to favoring 9 (10/9 ) 1:1.3 with [BQ] ) 0.625 M). The former
selectivity reflects that of the BQ-promoted Ar-Ar′ coupling
reaction, while the latter represents that for Ar-H activation at 1.18
As expected, similar results were obtained when AcOH (0 to 0.625
M) was added to the reaction, with the 10/9 ratio changing from
1:1 at [AcOH] ) 0 M to 2.5:1 at [AcOH] ) 0.625 M (Figure 5).
In conclusion, this communication has described detailed mecha-
nistic investigations of the Pd-mediated cross-coupling between
benzo[h]quinoline and simple arenes (Ar-H). These studies all
support a mechanism involving pre-equilibrium Ar-H activation
followed by BQ-promoted Ar-Ar′ reductive elimination to release
the cross-coupled product. This work serves as a foundation for
the rational design of reaction conditions and catalysts for the
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