Synthesis of (MeCN)2Pd(CF3)OTs, a general precursor to palladium(II) trifluoromethyl complexes LPd(CF3)X

Article abstract of DOI:10.1021/acs.organomet.9b00516

In palladium-catalyzed aryl-trifluoromethyl cross-coupling reactions, reductive elimination is often the rate-limiting step. Stoichiometric studies of reductive elimination have proved effective in evaluating the ability of various ligands to facilitate t

Full text of DOI:10.1021/acs.organomet.9b00516

Communication
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Cite This: Organometallics XXXX, XXX, XXX−XXX
Synthesis of (MeCN) Pd(CF )OTs, a General Precursor to
2
3
Palladium(II) Trifluoromethyl Complexes LPd(CF )X
3
Ryan P. King and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
*
ABSTRACT: In palladium-catalyzed aryl−trifluoromethyl cross-coupling
reactions, reductive elimination is often the rate-limiting step. Stoichiometric
studies of reductive elimination have proved effective in evaluating the ability
of various ligands to facilitate this challenging elementary step. However, the
difficulty of synthesizing palladium trifluoromethyl complexes has hindered the
use of this strategy. To address this deficiency, we herein report the synthesis
of (MeCN) Pd(CF )OTs, an air- and moisture-stable solid that can be used as
2
3
a common precursor to access various LPd(CF )X complexes. From this
3
complex we were able to prepare palladium trifluoromethyl complexes bearing many monophosphine, bisphosphine, and
diamine ligands that are known to help facilitate Ar−CF and vinyl−CF reductive elimination. Further, we found that the
3
3
anionic ligand (X) could be readily changed by modifying the NaX or AgX salt used.
In recent years, the trifluoromethyl group has received
significant attention from scientists in both the pharmaceutical
and agrochemical industries due to its effect on many
properties of organic molecules, such as lipophilicity,
installed in the final step, this strategy has the potential to
overcome the current limitations in ligand scope that would
−
otherwise arise from its displacement by CF . Specifically, our
3
method would produce compounds of the general formula
1
bioavailability, and metabolic stability. The selective incorpo-
LPd(CF )X following ligand exchange, where L is a desired
3
ration of trifluoromethyl groups on arenes has also been shown
to advantageously influence the HOMO−LUMO gap in
ancillary dative ligand and X is an anionic ligand, such as a
halide. Not only could these complexes potentially be used to
study various aryl−trifluoromethyl reductive eliminations but
they could also ultimately be used as reagents for late-stage
trifluoromethylation.
2
various photovoltaic materials and photocatalysts. Due to
the prevalence and importance of this functional group,
numerous transition-metal-mediated systems have been
3
developed to facilitate aryl−CF bond formations. In the
3
To date, only four methods exist to form complexes of this
type (Scheme 1). The first approach, reported independently
by Stone and Klabunde, involves the oxidative addition of
context of Pd-mediated trifluoromethylation, many research
groups have systematically studied the steric effects, electronic
effects, and denticity of ligands that can help promote this
challenging reductive elimination. On the basis of these
stoichiometric studies, Pd0 -catalyzed trifluoromethylation of
arenes using BrettPhos-, RuPhos-, and tri-tert-butylphosphine
4
5
6
0
9
CF X to Pd precursors. This approach provided important
3
evidence for the formation of stable complexes that contained
/II
Pd−CF linkages. Stone’s method, however, was only
3
demonstrated using triphenylphosphine (PPh ) or 1,2-bis-
t
7
3
(
P( Bu) )-ligated palladium complexes has been realized.
3
(
diphenylphosphino)ethane (dppe) as the ancillary ligand, and
Stoichiometric trifluoromethylation studies typically require
Klabunde’s method utilized vapor diffusion of Pd metal, which
is challenging to carry out in most laboratories. Sanford greatly
improved upon this approach by using trifluoroacetic
−
transmetalation of a “CF ” equivalent with a Pd oxidative-
3
addition complex. Unfortunately, the difficulty of forming
complexes bearing Pd−CF bonds in this way has been a major
3
anhydride (TFAA) as the CF source in the synthesis of
3
limiting factor in the study of the reactivity of the resultant
palladium trifluoromethyl complexes. As reported by Nau-
mann, during transmetalation with a CF3 anion source,
monodentate ligands and weakly bidentate ligands will often
dissociate, leading to the undesired formation of palladate
10
LPd(CF )OTFA complexes. As part of this study of the
3
mechanism of Pd-mediated Ar−CF coupling, it was found
3
that this complex could undergo transmetalation with diaryl
zinc reagents to form LPd(CF )Ar complexes. Furthermore,
3
8
other fluoroalkyl complexes could be easily accessed by
variation of the anhydride used in the synthesis. While
Sanford’s work is currently the most general means of
accessing various palladium fluoroalkyl complexes, this
approach requires elementary steps that involve an unstable
complexes. This significantly limits the scope of ligands that
can be employed in stoichiometric studies of reductive
elimination processes. To address this limitation, we employed
a known, but lesser used, alternative strategy to access
LPd(CF )Ar complexes starting from the synthesis of a Pd
3
complex which incorporates the Pd−CF bond but which
3
bears labile ligands that can be subsequently easily displaced by
the desired ancillary ligand. Since the desired dative ligand is
Received: July 30, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00516
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Scheme 1. Current Synthetic Approaches To Access
phines (such as BrettPhos); in the latter case, reductive
LPd(CF )X Complexes
elimination of Ar−CF occurs. Finally, Sanford, Mayer, and co-
3
3
workers reported the synthesis of N,N,N′,N′-tetramethylethy-
lenediamine-bound (TMEDA)Pd(CF )(Me), which can
3
undergo ligand exchange with 4,4′-di-tert-butyl-2,2′-bipyridyl
12
(
dtbbpy), followed by iodination to form (dtbbpy)Pd(CF )I.
3
While the dtbbpy-ligated Pd complex was the target of their
particular study, we postulated that the initial TMEDA-bound
Pd complex could be utilized as a general starting point for the
synthesis of many other LPd(CF )X complexes, as Grushin has
3
developed an efficient technique for selective abstraction and
sequestration of TMEDA from various palladium complexes
11
with the assistance of potassium bisulfate (KHSO4).
Synthesis of Pd−CF3 Precursors: (TMEDA)Pd(CF3)I
and (MeCN) Pd(CF )OTs. Starting with (TMEDA)Pd(CF )-
2
3
3
12
(
Me) (1), iodination cleanly forms (TMEDA)Pd(CF )I (2)
3
in excellent yield (Scheme 2, footnote a). While direct ligand
exchange of 2 with BrettPhos failed to form (BrettPhos)Pd-
(
CF )I (3), addition of excess KHSO to a mixture of 2 and
3 4
BrettPhos led to clean removal of TMEDA and complete
formation of 3. However, this ligand exchange strategy was not
found to be general, as the same procedure with bulkier di-tert-
butylphosphine ligands such as BuXPhos failed to deliver any
product. Analysis of the crude reaction mixture by P NMR
t
3
1
t
indicated that protonated BuXPhos was produced exclusively,
with no evidence of the desired complex 4. Thus, a proton
acyl−palladium complex and a subsequent decarbonylation
that can only proceed with a limited number of ancillary
ligands. Grushin reported a water-induced transformation of
dppe-bound (dppe)Pd(CF )Ph into (dppe)Pd(CF )I in the
presence of iodobenzene. While this reaction works excep-
tionally well for dppe-bound Pd complexes, the corresponding
reaction does not occur with diamine ligands or biarylphos-
transfer between KHSO and basic phosphines was limiting the
4
scope of ligands that could be utilized in this process. While
attempting to circumvent this issue by separating the TMEDA
abstraction and desired ligand association steps, we found that
3
3
1
1
by simply treating 2 with KHSO in acetonitrile (MeCN) led
4
to complete formation of trans-(MeCN) Pd(CF )I (5), as
2
3
1
9
assessed by F NMR. While only metastable, 5 could be
Scheme 2. Synthesis of Pd−CF Precursors and Evaluation of Ligand Exchange
3
a
b
See the Supporting Information for detailed experimental procedures for the synthesis of 1−3. Synthesis of the stable Pd−CF precursor
3
c
(MeCN) Pd(CF )OTs (6). See the Supporting Information for a detailed experimental procedure for the synthesis of 6. ORTEP diagram for 6.
2
3
Hydrogen atoms have been omitted for clarity, and ellipsoids are shown at 50% probability.
B
DOI: 10.1021/acs.organomet.9b00516
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
t
t
6a
treated with BuXPhos to form the desired ( BuXPhos)Pd-
CF3, and dtbbpy (11), which has been shown to facilitate
14
t
IV
(
CF )I (4) without the formation of protonated BuXPhos.
aryl trifluoromethylation from high-valent Pd centers.
3
Upon further optimization, we found that the addition of
silver(I) p-toluenesulfonate (AgOTs) to the reaction mixture
However, extremely bulky diadamantylphosphine ligands
such as AdXPhos did not react with 6.
containing 2 with KHSO in MeCN resulted in the formation
Synthetic Modifications To Access Various X Groups:
4
of trans-(MeCN) Pd(CF )OTs (6), an air- and moisture-
LPd(CF )X. After successfully forming the aforementioned
2
3
3
stable complex, in 88% yield (Scheme 2, footnote b). This
reaction was readily scaled to 10 mmol. Single-crystal X-ray
diffraction confirmed a square-planar palladium complex
wherein the acetonitrile ligands are trans to each other
chloride complexes, we also wanted to modify the general
procedure to generate LPd(CF )X complexes bearing a variety
3
of anionic ligands X (Scheme 4). In the modified procedure,
a
(
Scheme 2, footnote c).
Synthesis of Cl Complexes: LPd(CF )Cl. Starting from 6,
Scheme 4. Synthesis of LPd(CF )X Complexes
3
3
we synthesized and isolated several Pd−CF complexes bearing
3
ancillary ligands that were previously reported to facilitate Ar−
CF reductive elimination. While simply allowing each ligand
3
to react with 6 overnight led to complete conversion to the
desired product by 19F and P NMR, the resulting tosylate
complexes were often challenging to isolate and each required
unique purification conditions. Although these complexes
could be used directly and further modified without isolation
and purification, we sought to pursue general conditions that
31
would lead to Pd−CF complexes that were easily isolable with
3
minimal modification of the purification procedure for each
ligand. Accordingly, we found that stirring 6 with a desired
ligand and excess sodium chloride in THF cleanly formed the
chloride complex LPd(CF )Cl (Scheme 3). These complexes
3
a
Scheme 3. Synthesis of LPd(CF )Cl Complexes
3
a
Reactions were run with 2 (0.5 mmol) and L (0.6 mmol) at room
temperature. See the Supporting Information for detailed exper-
imental procedures.
(
(
TMEDA)Pd(CF )I (2) was allowed to react with a silver salt
AgX) and KHSO4 to form the trans-bis(acetonitrile)
3
intermediate complex (MeCN) Pd(CF )X. Following removal
2
3
of insoluble TMEDA and silver salts, this acetonitrile complex
was allowed to react with a ligand in the presence of a sodium
salt (NaX). As previously described, the BrettPhos complex 3
can be synthesized directly from 2. By simply omitting the use
of a sodium salt, BrettPhos and cationic 1,1′-bis(di-tert-
butylphosphino)ferrocene (DTBPF) tosylate complexes 12
and 13 were formed. By using sodium bromide (NaBr) instead
t
of NaCl, the BuXPhos bromide complex 14 could be formed
in moderate yield. Finally, by using silver trifluoroacetate
t
(
AgOTFA) instead of AgOTs, the BuXPhos trifluoroacetate
a
Reaction conditions: 6 (0.5 mmol), L (0.6 mmol), and NaCl (12.5
complex 15 could be formed. Thus, using this general strategy,
we have been able to synthesize numerous trifluoromethyl
mmol) in THF (5.0 mL) at room temperature overnight; isolated
yields reported.
complexes of the general formula LPd(CF )X, where both L
3
and X could be readily modified.
were found to be easily isolable by filtration in air and were
typically stable under ambient conditions. Using this approach,
we were able to synthesize numerous chloride complexes,
including complexes bearing the ancillary ligands BrettPhos
In conclusion, we have developed a new palladium complex,
trans-(MeCN) Pd(CF )OTs, an air- and moisture-stable
2
3
reagent that can be used as a general precursor for the
formation of Pd−CF complexes bearing one of many ancillary
3
(
7) and RuPhos (8), both previously shown to facilitate
ligands. This reagent was stable for months at 0 °C in air with
no evidence of diminished yields in the subsequent ligand
exchange. The variety of complexes accessible by this method
could enable broader and more facile stoichiometric studies of
C−CF3 reductive elimination. Studies are also underway
7a
t
catalytic trifluoromethylation of aryl chlorides, BuXPhos (9),
previously shown to facilitate catalytic trifluoromethylation of
1
3
vinyl triflates, Xantphos (10), the ligand used in the first
example of stoichiometric reductive elimination to form Ar−
C
DOI: 10.1021/acs.organomet.9b00516
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00516.
■
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ligand design for the reductive elimination of ArCF from a small bite
CCDC 1944264 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
E-mail for S.L.B.: sbuchwal@mit.edu.
■
V. CF -Ph reductive elimination from [(Xantphos)Pd(CF )(Ph)].
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(7) (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D.
ORCID
A.; Buchwald, S. L. The palladium-catalyzed trifluoromethylation of
aryl chlorides. Science 2010, 328, 1679−1681. (b) Ferguson, D. M.;
Bour, J. R.; Canty, A. J.; Kampf, J. W.; Sanford, M. S. Stoichiometric
and catalytic aryl-perfluoroalkyl coupling at tri-tert-butylphosphine
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Ryan P. King: 0000-0002-0798-313X
Stephen L. Buchwald: 0000-0003-3875-4775
Notes
The authors declare the following competing financial
interest(s): MIT has patents on ligands that are described in
this manuscript, from which S.L.B. and former co-workers
receive royalty payments.
(8) Naumann, D.; Kirij, N. V.; Maggiarosa, N.; Tyrra, W.;
Yagupolskii, Y. L.; Wickleder, M. S. Synthesen und charakterisier-
ungen der ersten tris- und tetrakis(trifluormethyl)palladate(II) und −
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platinate(II), [M(CF ) (PPh )] und [M(CF ) ] (M= Pd, Pt). Z.
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ACKNOWLEDGMENTS
(9) (a) Rosevear, D. T.; Stone, F. G. A. Perfluoroalkyl complexes of
■
palladium and platinum. J. Chem. Soc. A 1968, 164−167.
Research reported in this publication was supported by Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc. We
are grateful to Millipore-Sigma for the generous donation of
BuXPhos, RuPhos, and BrettPhos used in this work. We thank
Shane Krska (Merck) for helpful discussions. We are grateful
(
b) Klabunde, K. J.; Low, J. Y. F.; Efner, H. F. Synthesis of
bis(triethylphosphine)organonickel and organopalladium complexes
employing nickel and palladium atoms as synthetic reagents. J. Am.
Chem. Soc. 1974, 96, 1984−1985.
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to Dr. Peter Mu
̈
ller for crystallographic analysis, and we thank
catalyzed decarbonylative trifluoromethylation using trifluoroacetic
esters as the CF3 source. Organometallics 2014, 33, 2653−2660.
(b) Maleckis, A.; Sanford, M. S. Synthesis of fluoroalkyl palladium and
nickel complexes via decarbonylation of acylmetal species. Organo-
metallics 2014, 33, 3831−3839.
Richard Liu (MIT), Dr. Scott McCann (MIT), and Dr.
Christine Nguyen (MIT) for assistance in the preparation of
this manuscript.
(11) Grushin, V. V.; Marshall, W. J. Unexpected H O-induced Ar-X
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DOI: 10.1021/acs.organomet.9b00516
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