Synthesis and application of palladium precatalysts that accommodate extremely bulky Di-tert-butylphosphino biaryl ligands

Article abstract of DOI:10.1021/ol401208t

A series of palladacyclic precatalysts that incorporate electron-rich di-tert-butylphosphino biaryl ligands is reported. These precatalysts are easily prepared, and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of these palladium sources to various C-N and C-O bond-forming processes is also described.

Full text of DOI:10.1021/ol401208t

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis and Application of Palladium
Precatalysts that Accommodate
Extremely Bulky Di-tert-butylphosphino
Biaryl Ligands
Nicholas C. Bruno and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, United States
sbuchwal@mit.edu
Received April 29, 2013
ABSTRACT
A series of palladacyclic precatalysts that incorporate electron-rich di-tert-butylphosphino biaryl ligands is reported. These precatalysts are easily
prepared, and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of
these palladium sources to various CÀN and CÀO bond-forming processes is also described.
Dialkylphosphino biaryl compounds have emerged as
privileged ligands for a wide range of palladium-catalyzed
cross-coupling processes. Di-tert-butylphosphino biaryls
represent a subset of this ligand class with catalysts based
upon them having demonstrated a unique ability to induce
extremely challenging and important processes efficiently,
including the construction of CÀC,1 CÀN,2 CÀO,3 and
CÀF bonds.4 In general, structural features of these
ligands facilitate difficult reductive eliminations, thus con-
tributing to their overall effectiveness. The formation of
the catalytically active LPd(0) species, however, is less
efficient when using these ligands. Two common methods
have been utilized to overcome this issue: (1) water-mediated
reduction of Pd(II) precursors5 and (2) ligand and Pd2(dba)3
premixing.6 Neither approach is ideal, as they both require
an extra equivalent of ligand, and more importantly, the
catalyst activation step involves an additional operation
conducted in a second reaction vessel. Thus, we sought a
simple, general approach to generating active catalysts based
on these ligands.
Addressing the difficulty of efficient formation of active
catalytic species, we have developed a family of air- and
moisture-stable palladacycles, shown in Scheme 1, that
allow for quantitative formation of the desired monoli-
gated Pd(0) species.7 These precatalysts are easily prepared
using standard techniques and provide highly active cata-
lysts for use in a broad array of synthetic applications.
Under the basic conditions commonly employed in cross-
coupling reactions, these complexes undergo deprotona-
tion and reductive elimination to generate LPd(0) along
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(c) Ueda, S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51, 10364. (d)
Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron
2009, 65, 6576. (d) Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L.
J. Am. Chem. Soc. 2012, 51, 11132.
(5) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.
2008, 10, 3505.
(3) (a) Salvi, L.; Davis, N. R.; Ali, S. Z.; Buchwald, S. L. Org. Lett.
2012, 14, 170. (b) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2011, 50, 9943. (c) Anderson, K. W.; Ikawa, T.; Tundel, R. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.
(4) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(6) Ueda, S.; Su, M.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 132,
700.
(7) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 14073. (c) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L.
Chem. Sci 2013, 4, 916.
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10.1021/ol401208t
XXXX American Chemical Society

with relatively inert indoline (generation 1) or carbazole
(generation2 and 3). While precatalysts basedona number
of important ligands (including R3P, Ar3P, BINAP, Xant-
Phos, and dialkylphosphino biaryls) can be prepared, a
means to access precatalysts based on di-tert-butylpho-
sphino biaryl ligands has remained elusive. Herein, we
report a general method for the synthesis of precatalysts
based on these ligands and demonstrate the high catalytic
efficiency of these complexes in several challenging cross-
coupling reactions.
Scheme 2. Preparation of Methanesulfonate Precatalysts with
L1ÀL5
Scheme 1. Palladacyclic Precatalysts Previously Developed in
Our Laboratory and Their General Activation
We recently reported the third-generation precatalysts
wherein dimeric 2-aminobiphenylpalladium methanesul-
fonate complex 1 can be treated with a range of phosphine
ligands to provide methanesulfonate precatalysts, 2. These
palladium sources are particularly useful; they allow for
the direct incorporation of a range of ligands from a single
intermediate and are efficiently converted to the active
catalysts under very mild conditions.7c Initially the re-
ported conditions for 2 were not successful for the forma-
tion of precatalysts with ligands L1 À L5. As a result, we
investigated a series of palladacyclic triflate precatalysts
for these ligands.8
Figure 1. Crystallographically determined X-ray structure of 2a
(thermal ellipsoid plot at 50% probability, hydrogen atoms are
omitted for clarity).
However, after reexamining the reaction conditions for
preparing 2 we found that the use of chlorinated solvents
(CH2Cl2 or CHCl3) could be used for the incorporation of
L1ÀL5.9 Thus, stirring μ-OMsdimer 1 witht-BuBrettPhos
(L1) in CH2Cl2 for 12 h at room temperature, followed by
trituration of the crude material with diethyl ether, cleanly
afforded the desired precatalyst in 90% yield. Addition-
ally, this protocol could be used to form precatalyst 2
bearing L2ÀL5 in uniformly high yields (Scheme 2). The
structure of 2a was confirmed by X-ray crystallography
and is shown in Figure 1. As previously described,7c the
palladium center is cationic with the fourth coordination
Scheme 3. Comparison of Catalytic Activities of 2a and Water
Activation in the Arylation of a Primary Amidea
a General Conditions: ArCl (1 mmol), amide (1.05 À 1.2 mmol),
K3PO4 (1.4 mmol), 2a (1 mol %), tBuOH (2 mL), 110 °C, 1.5 h, isolated
yields. b Previously reported yield.2d
site being occupied through coordinating to the ipso
carbon of triisopropyl ring of the ligand.
Our reported procedure for the palladium-catalyzed
amidation reaction of aryl chlorides employed a catalyst
(8) Palladacyclic triflate precatalyst analogues have also been pre-
pared. They exhibit similar reactivity but silver triflate is necessary for
their preparation. See the Supporting Information for details.
(9) The formation of precatalysts 2aÀe only went to completion in
chlorinated solvents (CH2Cl2 and CHCl3)
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 4. Arylation of Primary Amides with 2aa
Scheme 6. Arylation of Aliphatic Alcohols with 2ba
a General Conditions: aryl halide (1 mmol), alcohol (1.5 mmol),
Cs2CO3 (2 mmol), 2b (1À2 mol %) PhMe (1 mL), 90 °C, 24 h; isolated
yields, average of two runs. b 3 equiv of alcohol. c 1.05 equiv of alcohol.
a General Conditions: ArCl (1 mmol), amide (1.05 À 1.2 mmol),
K3PO4 (1.4 mmol), 2a (1 mol %), tBuOH (2 mL), 110 °C, 1.5 h; isolated
yields, average of two runs.
catalyst system.3a This original procedure involved the
use of 0.25À3 mol % of Pd, excess L4, at between ambient
temperature and 100 °C. However, when 2d was used in
place of [(cinnamyl)PdCl]2/L4 (Scheme 5), the diaryl ether
products were formed in good yields, under mild reaction
conditions (ambient to 60 °C, 1.5À2 mol % of Pd) and
without the need to add excess ligand. Similarly, utilizing a
precatalysts (2b) derived from RockPhos (L2), which was
previously described to be an excellent supporting ligand
for the Pd-catalyzed arylation of aliphatic alcohols,3b we
were able to couple a variety of primary alcohols with aryl
halides (Scheme 6). Aryl alkyl ethers were obtained in good
to excellent yields, comparable to our previously described
results.10
Scheme 5. Arylation of Phenols with 2da
In summary, we have developed a series of ligated
palladium precatalysts that incorporate extremely bulky
ligands (L1ÀL5). The use of these precatalysts address a
number of issues in catalyst activation. They are signifi-
cantly more convenient to use and obviate the need to use
excess ligand to generate active LPd(0) species. These
precatalysts are bench stable and easily synthesized on a
large scale (10 g for 2a). We expect that their use will
expand the scope of known transformations and facilitate
the discovery of new Pd-catalyzed processes.
a General Conditions: aryl halide (1 mmol), phenol (1.5 mmol),
K3PO4 (1.5 mmol), 3d (1.5À2 mol %) 3:2 PhMe/DME (1 mL), rt À60 °C,
16 h; isolated yields, average of two runs.
based on L1.2d The procedure was efficient, requiring only
1 mol % palladium and relatively short reaction times;
however, use of the water-mediated preactivation method
was necessary to generate the active catalyst. To evaluate the
efficacy of 2a, we utilized 1 mol % of 2a in the reaction of
benzamide with 2-chloro-1,4-dimethoxybenzene (Scheme 3).
Under otherwise identical conditions, the secondary amide
product was obtained in slightly higher yield than previously
obtained when using 2a. As shown in Scheme 4, we further
evaluated the efficiency of 2a toward more functionalized
aryl chlorides and primary amides. In general, the use of 2a
exhibited good functional group tolerance; we observed no
competitive CÀO bond formation or N-arylation of indole
in the cases of 3b and 3d, respectively.
Acknowledgment. We thank the National Institutes of
Health for financial support (GM46059 and GM58160).
This activity was also supported, in part, by an educational
donation provided by Amgen, for which we are grateful.
We thank Phillip J. Milner (MIT) for growing crystals of
€
2a and 7a and Dr. Peter Muller (MIT) for X-ray structural
analysis. We thank Dr. Nathan Jui (MIT) and Dr. J. Robb
(10) Maligres, P. E.; Li, J.; Krska, S. W.; Schreier, J,. D.; Raheem,
I, T. Angew. Chem., Int. Ed. 2012, 51, 9071. This report notes that in
difficult couplings, such as in 5a, L2/Pd2(dba)3 was only effective when
the palladium and ligand were premixed and molecular sieves were used.
The use of 2b circumvents these issues and provides the desired product
in comparable yields without molecular sieves or premixing.
We were also interested in assessing the performance of
the new precatalysts in Pd-catalyzed CÀO bond-forming
reactions. We previously demonstrated the coupling of
aryl halides and phenols using a [(cinnamyl)PdCl]2/L4
Org. Lett., Vol. XX, No. XX, XXXX
C

DeBergh (MIT) for helpful discussions and assistance in
the preparation of this manuscript. The Varian 500 and
300 MHz NMR instruments used for portions of this work
were supported by the National Science Foundation
(Grant Nos. CHE 9808061 and DBI 9729592, respectively).
The content of this manuscript is solely the responsibility of
the authors and does not necessarily represent the official
views of the National Institute of Health.
Supporting Information Available. Experimental pro-
cedures along with experimental and spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare the following competing financial interest(s):
MIT has patents on the ligands used in this paper from which S.L.B.
receives royalty payments and has also filed patents on the methane-
sulfonate precatalysts.
D
Org. Lett., Vol. XX, No. XX, XXXX