Palladium-catalyzed reductive ortho -arylation: Evidence for the decomposition of 1,2-dimethoxyethane and subsequent arylpalladium(II) reduction

Article abstract of DOI:10.1021/ol1019037

A palladium-catalyzed crossed biaryl coupling/reduction sequence enables the formation of meta-substituted biaryls via solvent-mediated arylpalladium(II) reduction. Isotope labeling studies determined that the decomposition of 1,2-dimethoxyethane (DME) is

Full text of DOI:10.1021/ol1019037

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5186-5188
Palladium-Catalyzed Reductive
ortho-Arylation: Evidence for the
Decomposition of 1,2-Dimethoxyethane
and Subsequent Arylpalladium(II)
Reduction
Andrew Martins, David A. Candito, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80
St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received September 14, 2010
ABSTRACT
A palladium-catalyzed crossed biaryl coupling/reduction sequence enables the formation of meta-substituted biaryls via solvent-mediated
arylpalladium(II) reduction. Isotope labeling studies determined that the decomposition of 1,2-dimethoxyethane (DME) is indeed involved in
the reductive process.
Reductive processes in metal-catalyzed organic synthesis are
often well understood when common reducing agents such
as molecular hydrogen, formates, and activated alcohols are
used.1 When reduction products are formed, often unexpect-
edly, in the absence of these traditional reducing agents, the
reductive mechanism can be unclear. Such a process was
recently discovered in our laboratories.2 Our research into
reductive ortho-benzylation reactions of aryl iodides found
that reduction of the terminal arylpalladium(II) species
occurred through hydride transfer from coupling partners in
addition to an undefined process. We believed that the solvent
(1,2-dimethoxyethane, DME) was the likely reductant,
prompting us to develop a system where hydride transfer
from DME would be the predominant pathway. Herein, we
report the development and study of a highly selective
palladium-catalyzed process involving crossed ortho-aryla-
tion of aryl iodides followed by reduction to afford meta-
substituted biaryls (Scheme 1). Deuterium isotope labeling
studies further revealed that reduction of the terminal
arylpalladium(II) species involves DME.
Building upon the studies in our laboratories and that of
Catellani regarding palladium-catalyzed homo and crossed
ortho-arylation reactions of aryl iodides,3 we chose to
develop a crossed reductive ortho-arylation where, unlike
our previous system,2 obvious R- and/or ꢀ-elimination
pathways for arylpalladium(II) reduction are absent. Begin-
ning our studies with the reaction of methyl 2-iodobenzoate,
we were pleased to obtain unsymmetrical homobiaryl 3a in
quantitative yield under our optimized conditions (Table 1,
entry 1). This result confirmed our belief that arylpalla-
dium(II) reduction can occur without the addition of
traditional reductants.4 Furthermore, careful control of
(1) (a) Tsuji, J. In Palladium Reagents and Catalysts: New PerspectiVes
for the 21st Century; Tsuji, J., Ed.; Wiley-VCH: Weinheim, 2004. (b)
Negishi, E.-I. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley-VCH: Weinheim, 2002. (c) De Meijere,
A.; Diederich, F. In Metal-Catalyzed Cross-Coupling Reactions; De Meijere,
A., Diederich, F., Ed.; Wiley-VCH: Weinheim, 2004.
(3) (a) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr. Chem.
2010, 1. (b) Catellani, M. Top. Organomet. Chem. 2005, 14, 21.
(2) Martins, A.; Lautens, M. Org. Lett. 2008, 10, 4351.
10.1021/ol1019037  2010 American Chemical Society
Published on Web 10/15/2010

crossed reductive arylation were derivatives of methyl
2-bromobenzoate. Using functionalized ortho-substituted aryl
iodides, and commercially available methyl 2-bromoben-
zoates, a variety of meta-substituted biaryls were synthesized
in good to excellent yields (entries 2-10). We were also
able to use methyl 2-bromo-3-thiophene carboxylate (entries
12 and 13) as well as methyl 4-bromobenzoate (entry 14) as
reaction partners, albeit in moderate yields.
Scheme 1. Generalized Reaction Mechanism
Our next focus was to seek out potential reductants and
determine whether or not they contribute to the reductive
arylation sequence. We quickly excluded norbornene as we
found that catalytic amounts of norbornene could be used with
comparable yields, implying that it is not consumed in the
reductive process.6 Next, we used deuterium labeled aryl iodide
47 as a presumptive source of CsDCO3 (Scheme 2) under the
Scheme 2. Deuterium Labeling Experiments
palladium ligation and temperature favors the desired ortho-
arylation/reduction sequence over the ortho-arylation/CdO
addition sequence that we previously reported.5 We further
extended this method to a crossed reductive arylation
sequence by employing electron-deficient aryl halide cou-
pling partners. We found that the best coupling partners for
Table 1. Homo and Crossed Domino ortho-Arylation/Reduction
reaction conditions. We obtained the reduction product; how-
ever, analysis revealed no deuterium incorporation.
During the course of our studies, we observed the presence
of methanol in 1H NMR spectra of the crude reaction
mixtures. The methanol formed may be derived either from
decomposition of the ester or DME. We excluded decom-
position of the ester by subjecting deuterated ester 5 to our
reaction conditions and obtaining product with no detectable
deuterium incorporation at the ipso position and no erosion
of deuterium content in the ester. The higher concentration
of this reaction (0.2 M with respect to aryl iodide) can
account for the lower yield. We further determined that DME
is the source of methanol through a trapping experiment.
Replacing the bromobenzoate coupling partner with 4-ni-
trobenzoyl chloride (Scheme 3), we obtained methyl 4-ni-
trobenzoate in addition to a norbornene incorporation
(4) Catellani reported a homo ortho-arylation/reduction of aryl iodides
using benzyl alcohol as a stoichiometric reductant. See: Deledda, S.; Motti,
E.; Catellani, M. Can. J. Chem. 2005, 83, 741.
a Isolated yield (%). b Using 2 equiv of aryl iodide with respect to
norbornene, and no aryl bromide was added.
(5) Zhao, Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 1849.
Org. Lett., Vol. 12, No. 22, 2010
5187

there is a preference for the metal catalyst to transfer the
methylene hydrogen atoms from the solvent. Although partial
hydride transfer has been previously reported using ethereal
solvents such as 1,4-dioxane in the presence of palladium
catalysts,9 to the best of our knowledge, hydride transfer has
not been observed with 1,2-dimethoxyethane. Furthermore,
a preference for the abstraction of methylene versus methyl
hydrogens in ethereal solvents under palladium catalysis has
not been described.
Scheme 3. Methanol Trapping Experiment
Although we have determined the source of reducing
hydrogens, the mechanism of hydride transfer and the
formation of methanol remain unclear. Keay has proposed
a ꢀ-hydride elimination pathway for 1,4-dioxane, which is
plausible in the present system. We believe that the stoichi-
ometry of the base is important to the reductive process, as
using less than 2 equiv of Cs2CO3 leads to a drastic reduction
in product yields. Further research is required to fully
elucidate the reductive mechanism.
In summary, we have developed and studied a method
for the synthesis of meta-substituted biaryls through a
reductive ortho-arylation sequence. Through investigation of
the reduction using deuterium-labeled reagents and solvents,
we have determined that palladium-catalyzed decomposition
of DME is responsible for the reduction of the terminal
arylpalladium(II) species.
product. Further control experiments determined that the
nitrobenzoate is not formed in the absence of palladium
catalyst. From these experiments, we can conclude that
methanol is derived from DME under the reaction conditions.
Although our observation of methanol in crude spectra
led us to believe that it is not consumed in the reductive
process, a recent report of deuterium transfer by CD3OD
under palladium catalysis8 prompted us to add it in the
reaction with deuterated ester 5. This substrate was chosen
as the undeuterated ester was found to irreversibly exchange
to the deuterated ester in the presence of CD3OD under the
reaction conditions. When 1 equiv of CD3OD was added to
the reaction of 5, we obtained product with no more than
10% deuterium at the ipso position and believe that it is not
a major contributor to the reductive pathway.
Finally, we synthesized two different isotopomers of DME:
one with deuterium atoms on the methyl carbons (d6-DME)
and the other completely deuterated (d10-DME). Under the
optimized conditions, d6-DME did not afford any observable
ipso deuteration. Conversely, when d10-DME was used, we
observed 80% deuteration of the ipso carbon based upon both
Acknowledgment. We would like to thank the University
of Toronto, the Natural Sciences and Engineering Research
Council of Canada, and Merck Inc. for financial support in
the form of an Industrial Research Chair.
2
1H and H NMR spectra. This result confirmed that the
Supporting Information Available: Experimental details
and characterization data for compounds 3b-3n, 5, d6-DME,
and d10-DME. This material is available free of charge via
the Internet at http://pubs.acs.org.
solvent was involved in the reduction of the terminal
arylpalladium(II) species. Furthermore, it appears as though
(6) Under the optimized conditions with 25 mol % norbornene, 3d was
OL1019037
obtained in 75% isolated yield. Norbornene was also observed in near
1
quantitative amounts in crude H NMR analyses.
(7) Martins, A.; Lautens, M. Org. Lett. 2008, 10, 5095.
(8) Wisily, A.; Nguyen, Y.; Fillion, E. J. Am. Chem. Soc. 2009, 131,
15606.
(9) Lau, S. Y. W.; Andersen, N. G.; Keay, B. A. Org. Lett. 2001, 3,
181. Up to 1:1 H:D ratios reported. Under our conditions, d8-dioxane only
afforded traces of product and did not incorporate deuterium.
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Org. Lett., Vol. 12, No. 22, 2010