Characterization of two stable degradants of palladium tbuxphos catalyst and a unique dearomatization reaction

Article abstract of DOI:10.1021/om200988f

Two stable degradants of palladium tBuXPhos catalyst have been synthesized from tBuXPhos and Pd2(dba)₃CHCl₃, isolated, and fully characterized. Complex 2 augments the known literature examples of palladacycles from this ligand family but is present as a rare four-membered-ring palladacycle, having activated the top ring of the ligand. Complex 3 is an unusual case of palladium-mediated dearomatization, whereby chloroform functionalizes the bottom ring, generating a palladium allyl complex. The mechanism is assigned to an electrophilic carbene attack where palladium directs attack of dichlorocarbene to the anti face of the bottom arene. The structures have been confirmed by NMR and single-crystal X-ray diffraction.

Full text of DOI:10.1021/om200988f

Communication
pubs.acs.org/Organometallics
t
Characterization of Two Stable Degradants of Palladium BuXPhos
Catalyst and a Unique Dearomatization Reaction
Alan M. Allgeier,*,† Bradley J. Shaw,* Tsang-Lin Hwang, Jacqueline E. Milne, Jason S. Tedrow,
and Christopher N. Wilde
Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
S
* Supporting Information
t
ABSTRACT: Two stable degradants of palladium BuXPhos
catalyst have been synthesized from tBuXPhos and
Pd2(dba)3·CHCl3, isolated, and fully characterized. Complex 2
augments the known literature examples of palladacycles from
this ligand family but is present as a rare four-membered-ring
palladacycle, having activated the top ring of the ligand.
Complex 3 is an unusual case of palladium-mediated dearo-
matization, whereby chloroform functionalizes the bottom ring,
generating a palladium allyl complex. The mechanism is
assigned to an electrophilic carbene attack where palladium
directs attack of dichlorocarbene to the anti face of the bottom
arene. The structures have been confirmed by NMR and single-crystal X-ray diffraction.
he utilization of electron-rich bulky dialkyl biphenyl
phosphine ligands for cross-coupling reactions has
cross-coupling process and represent deactivation modes of the
active catalyst. One structure provides a highly unusual case of
Pd-mediated dearomatization of a phenyl group and demon-
strates a shortcoming of using Pd2dba3·CHCl3 as a precatalyst.
In the course of our development of cross-coupling reactions,
heterogeneous metal scavengers have been employed to
remove residual palladium from organic products, driven by
the requirement to reduce concentrations of this potentially
toxic metal in drug candidate molecules.16,17 In one case,
T
significantly expanded the scope and practicality of these
transformations.1 Often the catalytically active species are
described as L−Pd0 complexes, formally 12-electron species,2,3
but characterization of catalytically relevant intermediates or
deactivation modes remains elusive. Computational methods
have been employed to gain insight into the structure of
reactive species,2,4−6 when formation of pure components and
characterization of single crystals present challenges to a study.6
The ligand 2-di-tert-butylphosphino-2′,4′,6′-tri-isopropylbi-
phenyl (tBuXPhos, 1) is an important member of the dialkyl
biphenyl phosphine ligand family with utility in amidation
reactions,5,7 primary amine coupling,8 aryl tert-butyl carbamate
synthesis,9 aryl sulfonamide synthesis,10−12 and the coupling of
hydroxide to Ar−X for phenol synthesis.13 The high reactivity
of Pd/tBuXPhos enhances catalytic activity but may make it
more challenging to isolate and characterize stable metal
complexes. It may also encourage deactivation of L−Pd, as
suggested for the coupling of aryl chlorides with carboxamides,5
and contribute to the fact that there are no known crystal
structures reported for palladium complexes of this ligand,
though an isoelectronic Ag(I) complex has recently appeared.14
A common entry into Pd/tBuXPhos-catalyzed processes
comprises use of Pd2(dba)3 as a precatalyst palladium
source,8,11,13 sometimes utilized as the crystalline chloroform
solvate.9 Activation of Pd−L precatalysts cannot be assumed to
be a rapid and simple process; indeed, differences in coupling
reaction rates are observed, depending upon the catalyst
precursor.15
t
Pd2(dba)3·CHCl3 was combined with BuXPhos (1), Cs2CO3,
and substrates in toluene under a nitrogen atmosphere before
heating to 85 °C (eq 1). After aqueous acidic workup the
product solution was treated with Silicycle thiourea scavenger
to reduce residual Pd content. Our work in removing metal
from the product16 revealed the resistance of certain Pd species
to being cleared from the product by metal scavengers. These
stable species clearly comprised a ligand field that was
substitutionally resistant to the scavengers, prompting efforts
to study and isolate the stable complexes by chromatographic
techniques. Analysis by high-pressure liquid chromatography
(HPLC) coupled with UV−vis detection, an inductively coupled
plasma/mass spectrometer (ICP/MS), and an electrospray
Herein, we report the formation and characterization of two
Received: October 15, 2011
Published: January 6, 2012
unique palladium complexes of tBuXPhos, which form during a
© 2012 American Chemical Society
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Communication
ionization mass spectrometer identified two palladium species
with exact masses 529.222 and 613.175 Da (with a 530.230
Da fragment) (Figure 1), which were present in the product
Figure 2. 31P NMR spectra of (a) cross-coupling product solution
before metal scavenger, (b) independent synthesis, (c) isolated m/z
529 fraction, and (d) isolated m/z 613 fraction.
three resonances corresponding to the top ring could be
identified and unusually strong P−H coupling for hydrogens of
the top ring were observed. No residual acetonitrile was
detected by NMR. The spectra were consistent with activation
of the ortho hydrogen of the top ring and formation of the
palladacycle 2 (eq 2; see the Supporting Information for
Figure 1. Mass spectra of species resistant to removal by metal
scavenger.
solution even after treatment with Silicycle thiourea. The species
at 529.222 Da was reduced in concentration ∼85% from the
untreated reaction mixture but not completely removed, and the
613.175 Da peak concentration was negligibly changed on
treatment with scavenger, whereas most of the Pd present in
other forms had cleared with the scavenger.
To better understand the two problematic complexes, an
independent synthesis was attempted. The Pd2(dba)3·CHCl3
precursor was reacted with t-BuXPhos (L:Pd = 2.5) at 85 °C in
deuterated toluene for 35 min in an air-free environment
followed by filtration through Celite to remove insoluble black
particles. Analysis by 31P NMR showed a mixture of three
phosphorus-containing molecules, including the free ligand
(22.4 ppm) and peaks at 75.0 and −8.2 ppm, which were the
largest peaks observed in solutions from the scavenging process
(Figure 2b). LC/ICP-MS and LC/ESI-MS also confirmed that
the solution comprised the two stable species that were
resistant to scavenging. Notably, similar behavior and spectra
were observed using L:Pd = 1.1 and no reaction was observed
between tBuXPhos and Pd2(dba)3·CHCl3 at room temperature.
Rigorous exclusion of light led to no change in the product
distribution. Additionally, mixing an HPLC diluent (200 μL of
50% H2O/50% MeCN) with 1 mL of the reaction mixture for
2 min led to no change in the spectrum and reaction mixtures
held for 3 days were stable by 31P NMR.
chemical shift assignments). Similar to the case for many
palladacycles in the literature,18 no Pd−H signal was observed
1
in the H NMR spectrum of the isolated solid or the crude
reaction mixture.
After recovery of the dried product residue of 2 from
chromatography, crystals were grown by dissolution in and
slow evaporation of acetonitrile. Single-crystal X-ray diffraction
analysis confirmed the molecular structure of 2 (Figure 3) with
Intrigued by the stability, we attempted isolation by
preparative chromatography. Using a semiprep HPLC system
with a C18 stationary phase and gradient mobile phase (MPA,
0.1% TFA in water; MPB, 0.085% TFA in 25% ACN/75%
MeOH), two peaks were isolated from multiple 110 μL
injections of the toluene reaction mixture. When the isolated
fractions were subjected back to the catalytic coupling reaction
conditions, no coupling product was observed, suggesting
that the complexes are degradants and are not catalytically
active. The isolated fractions were dried to a residue in vacuo
and analyzed by HPLC and NMR (toluene-d8 or benzene-d6;
Figure 2). The fraction corresponding to m/z 529 exhibited a
single peak at −7.6 ppm in the 31P NMR. In the 1H NMR only
Figure 3. Molecular structures of complexes 2 and 3.
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acetonitrile and trifluoroacetate as stabilizing ligands. NMR
studies of the dried product residue from chromatography in
toluene-d8 with >200 equiv of acetonitrile revealed no
interaction of acetonitrile in the solution phase, suggesting
the complex adopts a coordinatively unsaturated structure in
solution or toluene served as the stabilizing ligand before
crystallization from acetonitrile. Attempts to crystallize directly
from toluene were not fruitful. During the synthesis of 2 and
coupling reactions employing the catalyst, X may be halide
present in the system (vida infra; 2 is never observed in the
absence of 3). Complex 2 adopts a distorted-square-planar
geometry with a compressed P−Pd−C bond angle (68.4°) and
an expanded N−Pd−P bond angle (105.2°). Palladacycle
formation with bulky dialkylbiphenylphosphine ligands has
been studied19 for 2′-substituted biaryl ligands and
2′,6′-disubstituted biaryl ligands, but functionalization was limited
to the bottom ring and not observed for the top ring as in
complex 2. Additionally, in the literature example, palladacycle
formation was reversible in the presence of aliphatic amines with
β-hydrides. In the present coupling, no such β-hydrides were
accessible. The literature examples all utilized the −PCy2 moiety.
Here the −PtBu2 moiety enables activation of the top ring and
the constrained four-membered palladacycle. Notably, successive
generations of bulky dialkyl biphenyl phosphine ligands5,20,21
have been constructed to block the α position of the phosphine-
bearing aryl group to enhance reactivity. Structure 2 implies a
further benefit by eliminating one mode of catalyst deactivation.
It is notable that when complex 2 was subject to the cross-
coupling conditions no coupling product was observed.
The second fraction isolated by chromatography corre-
sponded to m/z 613 and exhibited a single peak at 74.1 ppm in
the 31P NMR (toluene-d8) and an intriguing group of peaks
around 5.43 ppm and a shift of a CHMe2 from 2.82 ppm in the
free ligand to 1.75 ppm in the product fraction in the 1H NMR
(benzene-d6). With lack of clarity on the structure, crystals were
grown by dissolution in and slow evaporation of toluene that
were suitable for single-crystal X-ray diffraction structure
analysis, establishing the molecular structure of 3 (Figure 3).
Consistent with this structure, the ESI/MS data revealed
an ionization fragment with exact mass 530.230 Da,
which corresponds to cleavage of a Cl2CH− fragment from 3
(Figure 1).
onto the triisopropyl-bearing ring, which subsequently provides
an allyl interaction with Pd. Examples of metal-mediated
dearomatization are well-known22 but are not common for the
noble metals.23 During the preparation of this paper, another
Pd-mediated dearomatization reaction for this ligand family was
reported.24
Two mechanistic possibilities were envisioned for the
formation of complex 3, each invoking a bonding interaction
between Pd and the triisopropyl arene ring (A; Scheme 1).
Such interactions have been well-established crystallographi-
cally for Pd(II)20,25 and Pd(0).26 Starting from common
intermediate A, the two possibilities are (1) oxidative addition
of chloroform to B, followed by migratory insertion of the
arene double bond into the Pd alkyl to form the Pd(II) allyl
complex, and (2) base-mediated dichlorocarbene formation
followed by cyclopropanation and Pd oxidative insertion to
form the Pd(II) allyl product 3 after protonation. In the
oxidative addition manifold, the Pd−arene interaction of
A should direct the placement of the dichloromethyl to the
syn face for an intramolecular reaction, opposite of the
orientation observed in the crystal structure. If the dichloro-
carbene mechanism is operative, the electrophilic attack would
favor the anti face. Consistent with this mechanism, addition of
5 equiv of triethylamine to the reaction mixture prevented
formation of the palladacycle 2; only free ligand and complex
3 were observed. Alternatively, addition of 0.8 equiv of HBF4
relative to phosphine led to a 65% decrease in the production
of 3 relative to 2, likely through modulation of the basicity of
the system. Uncoordinated phosphine may serve as the base
promoting dichlorocarbene formation in the independent
control synthesis, but in the case of the catalytic reaction,
exogenous base could promote dichlorocarbene formation.
In light of the elucidated structures of 2 and 3, it is
reasonable that 2 would be more likely to react with a metal
scavenger such as Silicycle thiourea because of the labile nature
of one of its coordination sites, whereas 3 is coordinatively
saturated and resistant to reaction with a metal scavenger.
Consistent with these inferences, complex 2 was significantly
but not completely cleared; about 15% remained after
scavenger treatment. On the other hand, complex 3 was
resistant to scavenging and its concentration was unchanged by
the scavenger treatment.
Complex 3 is a particularly striking example of dearomatiza-
tion, in which chloroform has been activated and substituted
In summary, we have demonstrated two degradation
pathways for Pd/tBuXPhos catalyst: palladacycle formation
Scheme 1. Mechanistic Options for Formation of 3
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Communication
(12) Rosen, B. R.; Ruble, J. C.; Beauchamp, T. J.; Navarro, A. Org.
Lett. 2011, 13, 2564.
(13) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L.
via C−H activation of the top ring of the biphenyl system
(compound 2) and dearomatization of the bottom ring of the
biphenyl system (compound 3). The dearomatization reaction
is thought to proceed via electrophilic dichlorocarbene attack.
Complexes 2 and 3 were observed after acidic workup of a
palladium-catalyzed cross-coupling reaction and independently
synthesized. The formation of 2 bears similarity to palladacycles
reported in the literature but is the first example of modification
J. Am. Chem. Soc. 2006, 128, 10694.
(14) Per
́ ́ ́
ez-Galan, P.; Delpont, N.; Herrero-Gomez, E.; Maseras, F.;
Echavarren, A. M. Chem. Eur. J. 2010, 16, 5324.
(15) (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) Bedford, R. B.; Cazin, C. S. J.; Coles,
S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E.
Organometallics 2003, 22, 987.
(16) Allgeier, A. M.; Bunel, E. E.; Correll, T.; Dilmeghani, M.; Faul,
M.; Milne, J.; Murry, J.; Payack, J. F.; Scardino, C.; Shaw, B. J.; Wang,
X. Chem. Ind.-Catal. Org. React. (Dekker) 2009, 123, 51.
(17) Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889.
(18) (a) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005,
105, 2527. (b) Ryabov, A. D. Chem. Rev. 1990, 90, 403.
(19) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
925.
(20) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(21) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel,
N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu,
B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. Chem.,
Int. Ed. 2010, 49, 5879.
t
of the top ring of BuXPhos. The reactivity pattern for
formation of 3 reveals the complications associated with
utilizing Pd2(dba)3·CHCl3 as an entry point to cross-coupling
but also lays the groundwork for extension of this work to other
electrophiles and bases.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and CIF files giving full experimental
details, compound characterization data, NMR spectra, and
crystallographic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(22) (a) Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem. Rev. 2000,
̈
100, 2917. (b) Pearson, A. J. Science 1984, 223, 895.
*E-mail: alan.m.allgeier@usa.dupont.com (A.M.A.); bshaw@
amgen.com (B.J.S.).
(23) (a) Song, D.; Sliwowski, K.; Pang, J.; Wang, S. Organometallics
2002, 21, 4978. (b) Tan, R.; Jia, P.; Rao, Y.; Jia, W.; Hadzovic, A.; Yu,
Q.; Li, X.; Song, D. Organometallics 2008, 27, 6614. (c) Feller, M.;
Ben-Ari, E.; Iron, M. A.; Diskin-Posner, Y.; Leitus, G.; Shimon, L. J. W.;
Konstantinovski, L.; Milstein, D. Inorg. Chem. 2010, 49, 1615.
(24) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y; Takase, M.
K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106. It is notable
that the reported dearomatization reaction proceeded via a different
mechanism, placing the migrating group syn to the Pd and at the
carbon meta to the biphenyl link.
Present Address
†DuPont Central Research and Development, Experimental
Station, Wilmington, DE 19880-0228.
ACKNOWLEDGMENTS
■
We thank Mr. Mike Ronk and Drs. Michal Achmatowicz, Anil
Guram, Jinkun Huang, Oliver Thiel, Kevin Turney, Xiang
Wang, and the reviewers for insightful comments and
Drs. Emilio Bunel, Janet Cheetham, Margaret Faul, and Jerry
Murry for supporting the completion of this work. Dr. Richard
Staples is acknowledged for conducting X-ray crystallography
structure determinations.
(25) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(26) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1162.
REFERENCES
■
(1) (a) Surry, D. S.; Buchwald, S. L. Angew. Chem. Intl. Ed. 2008, 47,
6338. (b) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599. (c) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(2) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
(3) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. Adv. Synth. Catal.
2006, 348, 609.
(4) (a) Barder, T. E. J. Am. Chem. Soc. 2005, 128, 898. (b) Hicks,
J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 16720.
(5) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001.
(6) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
(7) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 10767.
(8) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem. Intl. Ed. 2006, 45, 6523.
(9) Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger,
K. R. J. Org. Chem. 2009, 74, 4634.
(10) Grillo, M.; Li, A.-R.; Liu, J.; Medina, J. C.; Su, Y.; Wang, Y.;
Jona, J.; Allgeier, A. M.; Milne, J.; Murry, J.; Payack, J. F.; Storz, T.
Phenyl Acetic Acid Derivatives as Inflammation Modulators. U.S.
Patent 2009/0275659 A1, 2009.
(11) Shekhar, S.; Dunn, T. B.; Kotecki, B. J.; Montavon, D. K.;
Cullen, S. C. J. Org. Chem. 2011, 76, 4552.
522
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