Stoichiometric and Catalytic Aryl-Perfluoroalkyl Coupling at Tri-tert-butylphosphine Palladium(II) Complexes

Article abstract of DOI:10.1021/jacs.7b05216

This Communication describes studies of Ph-R_F (R_F = CF₃ or CF₂CF₃) coupling at Pd complexes of general structure (P^tBu₃)Pd^II(Ph)(R_F). The CF₃ analogue participates in fast Ph-CF₃ coupling (<5 min at 80 °C). However, the formation of side products limits the yield of this transformation as well as its translation to catalysis. DFT and experimental studies suggest that the side products derive from facile α-fluoride elimination at the 3-coordinate Pd^II complex. Furthermore, they show that this undesired pathway can be circumvented by changing from a CF₃ to a CF₂CF₃ ligand. Ultimately, the insights gained from stoichiometric studies enabled the identification of Pd(P^tBu₃)₂ as a catalyst for the Pd-catalyzed cross-coupling of aryl bromides with TMSCF₂CF₃ to afford pentafluoroethylated arenes.

Full text of DOI:10.1021/jacs.7b05216

Communication
pubs.acs.org/JACS
Stoichiometric and Catalytic Aryl−Perfluoroalkyl Coupling at
Tri-tert-butylphosphine Palladium(II) Complexes
Devin M. Ferguson,† James R. Bour,† Allan J. Canty,‡ Jeff W. Kampf,† and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 N University Avenue, Ann Arbor, Michigan 48109, United States
‡School of Physical Sciences, University of Tasmania, Hobart, Tasmania 7001, Australia
S
* Supporting Information
three ligands, Xantphos,5c dfmpe,5d and BrettPhos,4a have been
ABSTRACT: This Communication describes studies of
shown to enable high-yielding aryl−RF coupling from isolated
PdII complexes (Figure 1b).6 Furthermore, only BrettPhos and
Ph−RF (RF = CF3 or CF2CF3) coupling at Pd complexes
of general structure (PtBu3)PdII(Ph)(RF). The CF3
analogue participates in fast Ph-CF3 coupling (<5 min at
80 °C). However, the formation of side products limits the
yield of this transformation as well as its translation to
catalysis. DFT and experimental studies suggest that the
side products derive from facile α-fluoride elimination
at the 3-coordinate PdII complex. Furthermore, they show
that this undesired pathway can be circumvented by
changing from a CF3 to a CF2CF3 ligand. Ultimately, the
insights gained from stoichiometric studies enabled the
identification of Pd(PtBu3)2 as a catalyst for the Pd-catalyzed
cross-coupling of aryl bromides with TMSCF2CF3 to afford
pentafluoroethylated arenes.
related RuPhos have been successfully translated to Pd0/II
-
catalyzed aryl-fluoroalkylation processes.4a
We sought to identify new ligands that promote aryl−RF
coupling at PdII centers. Additionally, we aimed to identify key
obstacles to the translation of stoichiometric aryl−RF coupling
reactions to catalysis. We noted that BrettPhos forms mono-
phosphine PdII complexes of general structure A (Figure 1c),
which are stabilized by a hemilabile PdII−O interaction.4a,7
Inspired by the work of Hartwig,8 we hypothesized that
PtBu3 would form related 3-coordinate monophosphine com-
plexes (1) that might be even more reactive toward aryl−RF
coupling.8−11 Herein, we describe DFT and experimental
studies of (PtBu3)PdII(Ph)(RF) (RF = CF3 or CF2CF3).
We show that both complexes undergo Ph−RF coupling
under mild conditions (within 15 min at 80 °C). However,
studies of the CF3 analogue reveal that an α-fluoride elimi-
nation pathway limits the selectivity and efficiency of both
stoichiometric and catalytic transformations. We demonstrate
that this pathway can be circumvented by moving from RF =
CF3 to RF = CF2CF3. Ultimately, these stoichiometric studies
enabled the development of the Pd(PtBu3)2-catalyzed penta-
fluoroethylation of aryl bromides.
We first studied complex 1-CF3 using DFT calculations
involving the dispersion functional B3LYP-D3.12 The lowest
energy ground-state structure is T-shaped, with the fluoroalkyl
ligand trans to PtBu3 (Figure 2). The isomer with the Ph ligand
trans to PtBu3 (1-I-CF3) is 5.8 kcal/mol higher in energy,
consistent with the stronger trans influence of Ph versus
CF3.4a,5a−d The formation of PhCF3 from 1-CF3 can occur via
two distinct pathways, both of which have been proposed pre-
viously for related systems.7,13 The first involves direct Ph−CF3
coupling via the concerted transition state TS-1-CF3-RE,
with a calculated barrier of 27.0 kcal/mol.14 The second
involves initial α-fluoride elimination to form difluorocarbene
intermediate A.5b,15 Subsequent phenyl migration to form
difluorobenzyl complex B16 is followed by C−F coupling via
TS-B-CF3-RE to yield PhCF3. The highest energy transition
state in this latter sequence is for the phenyl migration step
(21.8 kcal/mol). Overall, these calculations predict that 1-CF3
could form PhCF3 via either pathway under relatively mild
conditions.
luoroalkyl (RF) groups, such as CF3 and CF2CF3, appear
F
in a variety of pharmaceuticals1 and agrochemicals.2 These
substituents are commonly appended to aromatic rings to
enhance the lipophilicity and oxidative stability of bioactive
molecules. A variety of synthetic methods have been developed
to form aryl−RF bonds.3 Among these, Pd0/II-catalysis is the
least developed, despite the widespread utility of other Pd0/II
-
catalyzed C−C coupling processes.4 This has largely been
attributed to challenges associated with the product-release step
of the catalytic cycle, which involves aryl−RF coupling from
LnPdII(Aryl)(RF) intermediates (Figure 1a).4a,5 To date, only
Received: May 19, 2017
Figure 1. (a) Challenging aryl−RF coupling step; (b) ligands known to
promote aryl−RF coupling; (c) this study.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05216
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. (a) Thermolysis of 1-CF3; (b) Proposed pathway
to 2 and 3; (c) Independent synthesis of 3
Figure 2. Reaction coordinate from DFT calculations of 1-CF3.
Energies ΔG (ΔH) in kcal/mol.
To test this experimentally, 1-CF3 was synthesized via the
treatment of [P(o-tol)3]2PdII(CF3)(OC(O)CF3)17 with PtBu3
followed by Ph2Zn (eq 1). The X-ray structure of 1-CF3 shows
23
from 1-CF3 and, further, that these could be problematic in
catalysis.24
Literature reports suggest that CF2CF3 ligands are less
susceptible to α-fluoride elimination relative to their CF3
counterparts.25 Indeed, DFT studies of 1-CF2CF3 predict a
34.7 kcal/mol barrier for α-fluoride elimination/phenyl migra-
tion (Figure 3).26 This is almost 14 kcal/mol higher than the
a T-shaped complex with the CF3 ligand trans to PtBu3 (eq 1).
A Pd−H−C agostic interaction is predicted from placing the H
atoms in idealized positions (Pd−H = 2.18 Å).8c The P−Pd
bond distance (2.372 Å) is significantly longer than that in
(PtBu3)PdII(Ph)(Br) (2.285 Å),8c reflecting the greater trans
influence of CF3 versus Br. In solution, 1-CF3 shows a 19F
NMR resonance at −28 ppm (d) and a 31P NMR resonance at
55 ppm (q). No agostic interaction is detected by 1H NMR spec-
troscopy down to −70 °C in CD2Cl2.
Heating a benzene solution of 1-CF3 in the presence of
5 equiv of PtBu3 at 80 °C for 5 min resulted in the complete
consumption of the starting material and the formation of
PhCF3 in 41% yield (Scheme 1a).18−20 Notably, these condi-
tions are similarly mild to those required for aryl−CF3 coupling
from (BrettPhos)PdII(aryl)(CF3) (t1/2 = 22−24 min at 80 °C).4a
The high conversion of 1-CF3 but modest yield of PhCF3 in
our system suggests that there are competing decomposition
pathways. Indeed, 19F NMR spectroscopic analysis shows the
presence of two major side products: difluorodiphenylmethane
(2, 20% yield) and PdII difluorobenzyl complex 3 (8% yield).21,22
We hypothesize that 2 and 3 are formed from the α-fluoride
elimination/phenyl migration intermediate B. As shown in
Scheme 1b, transmetalation between B and LnPd(CF3) would
form side product 3. Analogous exchange with LnPd(Ph) would
yield C, and subsequent C−C coupling from C would release 2.
Notably, the Pd-fluoride intermediate B was not detected
by 19F NMR spectroscopy during this reaction. However, we
hypothesized that B could be trapped in situ with TMSCF3 to
generate 3.5c Indeed, allowing 1-CF3 to stand at 25 °C in the
presence of excess TMSCF3 afforded 3 in 19% isolated yield
(Scheme 1c). Overall, the formation of 2 and 3 provides strong
evidence that α-fluoride elimination pathways are accessible
Figure 3. Reaction coordinate from DFT calculations of 1-CF2CF3.
Energies ΔG (ΔH) in kcal/mol.
analogous transformation at 1-CF3. In contrast, the predicted
barrier for concerted Ph−CF2CF3 coupling from 1-CF2CF3 is
very similar to that from 1-CF3 (27.5 kcal/mol vs 27.0 kcal/mol,
respectively).27
On this basis, we hypothesized that reductive elimination
from 1-CF2CF3 would proceed selectively via this latter
pathway to afford PhCF2CF3 in increased yield and selectivity
relative to that of 1-CF3. Complex 1-CF2CF3 was prepared
in 74% yield via an analogous procedure to that for 1-CF3.
B
DOI: 10.1021/jacs.7b05216
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Consistent with our hypothesis, heating 1-CF2CF3 for 5 min at
80 °C in C6D6 in the presence of 5 equiv of PtBu3 afforded
PhCF2CF3 in 92% yield (with 95% conversion of the starting
material). Heating for an additional 5 min resulted in 96% yield
of PhCF2CF3 with quantitative conversion (eq 2).19 No products
conditions (10 mol % of Pd(PtBu3)2, 2 equiv of TMSCF2CF3,
2 equiv of KF in dioxane at 80 °C for 16 h), 6 was obtained in
73% isolated yield.31 A preliminary evaluation of substrate
scope showed that this transformation proceeds with electroni-
cally diverse aryl and heteroaryl bromides to afford 6-21 in
yields ranging from 53 to 80% (Figure 4).32
In summary, this Communication describes aryl−RF coupling
reactions at PdII complexes of general structure (PtBu3)-
PdII(Ph)(RF). With RF = CF3, the complex is susceptible to
α-fluoride elimination. DFT calculations suggest that this pathway
provides a kinetically viable route to PhCF3. However, experi-
mental studies show that competitive side reactions preclude
selective Ph-CF3 coupling. In contrast, an α-fluoride elimination
pathway is not accessible with the CF2CF3 derivative. As such,
this system can be leveraged to achieve the first example of
Pd0/II-catalyzed pentafluoroethylation of aryl bromides.
derived from α-fluoride elimination were detected by NMR
spectroscopy or GC−MS.
To translate these results to catalysis, we first explored the
cross-coupling of 1-butyl-4-chlorobenzene with TESCF3 using
various PtBu3-ligated Pd catalysts (Table S4). The best result
was obtained with 10 mol % of Pd(PtBu3)2 at 120 °C for 20 h,
which afforded 4 in 22% yield (eq 3a).28 Consistent with the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05216.
Experimental details, characterization data for new
compounds, and DFT calculations(PDF)
Data for C1-CF3(CIF)
AUTHOR INFORMATION
Corresponding Author
*mssanfor@umich.edu
■
stoichiometric studies, difluorodiarylmethane 5 was detected as
a side product of this reaction. This suggests that α-fluoride
elimination intermediate B may be formed and undergo
undesired side reactions under catalytic conditions.29,30
We next explored the catalytic coupling of 1-butyl-4-
chlorobenzene with TMSCF2CF3. Under otherwise identical
conditions, this transformation afforded 6 in 64% yield (eq 3b).
The increase in yield relative to trifluoromethylation is con-
sistent with the stoichiometric studies. We also note that this
is the first reported example of Pd0/II-catalyzed pentafluo-
roethylation of an aryl halide. Additional optimization revealed
that aryl bromides afford higher yields than aryl chlorides
and that catalysis proceeds at 80 °C. Under the optimized
ORCID
Allan J. Canty: 0000-0003-4091-6040
Melanie S. Sanford: 0000-0001-9342-9436
Funding
This work was supported by the NSF (CHE 1361542, CHE
0840456 for X-ray instrumentation, and a graduate fellowship
to J.R.B.) and the Australian Research Council.
Notes
The authors declare no competing financial interest.
REFERENCES
(1) (a) Andrzejewska, M.; Yep
A.; Vilpo, L.; Vilpo, J.; Kazimierczuk, Z. Eur. J. Med. Chem. 2002, 37,
973. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320.
■
́
ez-Mulia, L.; Cedillo-Rivera, R.; Tapia,
(2) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Jeschke, P. Pest
Manage. Sci. 2010, 66, 10. (c) Fujiwara, T.; O’Hagan, D. J. Fluorine
Chem. 2014, 167, 16.
(3) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475. (b) Chen, P.; Liu, G. Synthesis 2013, 45, 2919. (c) Alonso, C.; de
Marigorta, E. M.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
(4) (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D.
A.; Buchwald, S. L. Science 2010, 328, 1679. (b) Samant, B. S.; Kabalka,
G. W. Chem. Commun. 2011, 47, 7236.
(5) (a) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
(b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 4632.
(c) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644.
(d) Nielsen, M. C.; Bonney, K. J.; Schoenebeck, F. Angew. Chem., Int.
Ed. 2014, 53, 5903.
(6) Aryl−RF coupling from (RuPhos)PdII(Aryl)(RF) has also been
reported, albeit in moderate yield. See: Maleckis, A.; Sanford, M. S.
Organometallics 2014, 33, 2653.
(7) Zhang, S.-L.; Huang, L.; Sun, L.-J. Dalton Trans. 2015, 44, 4613.
Figure 4. Scope of Pd(PtBu3)2-catalyzed pentafluoroethylation of aryl
(8) (a) Stambuli, J. P.; Buhl, M.; Hartwig, J. F. J. Am. Chem. Soc.
̈
b
bromides. a 19F NMR yield. 24 h.
2002, 124, 9346. (b) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
C
DOI: 10.1021/jacs.7b05216
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
125, 13944. (c) Stambuli, J. P.; Incarvito, C. D.; Buhl, M.; Hartwig, J.
(32) For a comparison with literature methods for arene
pentafluoroethylation, see p. S40.
̈
F. J. Am. Chem. Soc. 2004, 126, 1184. (d) Yamashita, M.; Hartwig, J. F.
J. Am. Chem. Soc. 2004, 126, 5344.
(9) For theoretical investigations of reductive elimination from PdII,
see: (a) Tatsumi, K.; Hoffmann, R.; Yamamoto, A.; Stille, J. K. Bull.
Chem. Soc. Jpn. 1981, 54, 1857. (b) Ananikov, V. P.; Musaev, D. G.;
Morokuma, K. Eur. J. Inorg. Chem. 2007, 2007, 5390. (c) Ariafard, A.;
Yates, B. F. J. Am. Chem. Soc. 2009, 131, 13981.
(10) Moncho, S.; Ujaque, G.; Lledos
2008, 14, 8986.
́
, A.; Espinet, P. Chem. - Eur. J.
(11) For aryl−CF3 coupling from 3-coordinate AuIII, see: Winston,
M. S.; Wolf, W. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136, 7777.
(12) B3LYP-D3 has been used for related systems. See: Lyngvi, E.;
Sanhueza, I. A.; Schoenebeck, F. Organometallics 2015, 34, 805.
́ ́
(13) Bakhmutov, V. I.; Bozoglian, F.; Gomez, K.; Gonzalez, G.;
Grushin, V. V.; Macgregor, S. A.; Martin, E.; Miloserdov, F. M.;
Novikov, M. A.; Panetier, J. A.; Romashov, L. V. Organometallics 2012,
31, 1315.
(14) Reductive elimination from the other isomer of this complex (1-
I-CF3) occurs with a similar overall energy (26.6 kcal/mol).
(15) For examples of α-fluoride elimination, see: (a) Brothers, P. J.;
Roper, W. R. Chem. Rev. 1988, 88, 1293. (b) Harrison, D. J.; Gorelsky,
S. I.; Lee, G. M.; Korobkov, I.; Baker, R. T. Organometallics 2013, 32,
12. (c) Pell, C. J.; Zhu, Y.; Huacuja, R.; Herbert, D. E.; Hughes, R. P.;
Ozerov, O. V. Chem. Sci. 2017, 8, 3178.
(16) Similar insertion reactions at Pt/Ir: (a) Appleton, T. G.; Hall, J.
R.; Mathieson, M. T.; Neale, D. W. J. Organomet. Chem. 1993, 453,
307. (b) Hughes, R. P. J. Fluorine Chem. 2010, 131, 1059.
(17) Maleckis, A.; Sanford, M. S. Organometallics 2014, 33, 3831.
(18) The addition of PtBu3 improved the reaction yield (Table S1). A
previous report on the reductive elimination of triarylamines from PdII
PtBu3 complexes also used 5 equiv of PtBu3 (ref 8d).
(19) The major Pd0 product of this reaction is Pd(PtBu3)2 (as
determined by 31P NMR spectroscopy). No Pd black is observed.
(20) Attempts to increase the yield of PhCF3 by variation of the
temperature, solvent, and/or concentration were unsuccessful.
(21) Another possible competing side reaction would be exchange
between the substituents on phosphorus and the phenyl or CF3
ligands of Pd. However, GC−MS analysis of the reaction mixtures
showed no products consistent with this reaction.
(22) The reported products account for 66% of the fluorine mass
balance. The crude reaction mixtures were analyzed by 19F NMR
spectroscopy and GC−MS; however, the rest of the fluorine could not
be accounted for (see p. S12 for details).
(23) Efforts to probe the operating mechanism of PhCF3 formation
from 1-CF3 were inconclusive. See p. S17 for details.
(24) This side reaction may be limited with BrettPhos based on its
hemilabile nature.
(25) Leclerc, M. C.; Bayne, J. M.; Lee, G. M.; Gorelsky, S. I.; Vasiliu,
M.; Korobkov, I.; Harrison, D. J.; Dixon, D. A.; Baker, R. T. J. Am.
Chem. Soc. 2015, 137, 16064.
(26) Notably in this system the α-fluoride elimination/phenyl
migration is concerted, and no fluorocarbene intermediate could be
located.
(27) Rotation of the CF2CF3 ligand was found to occur prior to
reductive elimination via TS-1-CF2CF3-RE.
(28) No TESCF3 remains after 20 h. However, after 11 h the yield of
ArCF3 is nearly identical (22%), whereas 52% of TESCF3 remains.
This suggests that the reaction yield is not limited by the decom-
position of TESCF3.
(29) Difluorobenzyl complex 3 is catalytically inactive for the Pd-
catalyzed aryl trifluoromethylation of Ar-Cl. As such, the formation of
this side product appears to be a dead-end for catalysis. See p. S22 for
details.
(30) For a discussion of other potential issues that might limit
catalytic turnover, see p. S28.
(31) Translating these conditions to the trifluoromethylation of 1-
butyl-4-bromobenzene with TMSCF3 afforded 3% of the trifluor-
omethylated arene as determined by 19F NMR.
D
DOI: 10.1021/jacs.7b05216
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX