A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides

Article abstract of DOI:10.1021/jacs.5b09308

A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.

Full text of DOI:10.1021/jacs.5b09308

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Article
A Fluorinated Ligand Enables Room Temperature and Regioselective
Pd-Catalyzed Fluorination of Aryl Triflates and Bromides
Aaron Sather, Hong Geun Lee, Valentina Y. De La Rosa, Yang Yang, Peter Müller, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09308 • Publication Date (Web): 28 Sep 2015
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A Fluorinated Ligand Enables Room Temperature and Regi-
oselective Pd-Catalyzed Fluorination of Aryl Triflates and
Bromides
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Aaron C. Sather,† Hong Geun Lee,† Valentina Y. De La Rosa,† Yang Yang, †,‡ Peter Müller,† and
Stephen L. Buchwald†,*
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Supporting Information Placeholder
ABSTRACT: A new biaryl monophosphine ligand (AlPhos, L1) allows for the room temperature Pd-catalyzed
fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are
prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl
fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as
density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with
L1.
orine sources (“F+”) have been employed to oxidize
INTRODUCTION
the metal center to Pd(III) or Pd(IV) intermediates
from which reductive elimination is more facile.10
The preparation of fluorine-containing aromatic
compounds (ArF) has been a long-standing chal-
lenge in organic synthesis.1 While these compounds
are highly prized in the pharmaceutical2 and agro-
chemical industries,3 methods to access aryl fluo-
rides selectively, under mild and general reaction
conditions, remain elusive. Since the advent of the
Balz-Schiemann4 reaction and the Halex5 process,
significant advances have been made toward this
end,6 especially with regard to transition metal-
catalyzed methods.7 In analogy to the practicality,
simplicity, and generality of Pd(0)/Pd(II)-catalyzed
aryl carbon–heteroatom bond-forming processes,
the coupling of aryl (pseudo)halides with simple
metal fluoride salts ("F–") (Figure 1a) would be ideal.
However, several challenges associated with develop-
ing such a process have been revealed both experi-
mentally8 and theoretically.9 Among these difficul-
ties are the formation of stable [LPd(II)F]2 dimers
and competitive P–F and P–C bond formation, which
suggests a high barrier for C–F reductive elimination
(Figure 1a). To circumvent the difficult reductive
elimination from Pd(II) complexes, electrophilic flu-
The desired C–F reductive elimination from
[LPdAr(F)] is unique to biaryl monophosphine-
ligated complexes, and has been observed stoichio-
metrically,11 albeit at high temperatures and with
substrates that contain activated12 aryl groups. Sub-
sequently, it was discovered that incorporating a sub-
stituent at the C3´ position of the biaryl monophos-
phine ligand e.g, as in HGPhos ((L2), Figure 1 b)
gives rise to a more active catalyst system.13
Figure 1. a) The proposed catalytic cycle for Pd-
catalyzed fluorination. b) A Pd(II) complex with L2
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with t-BuLi at -78 °C followed by the addition of
CuCl and Ad2PCl then heating to 140 °C overnight
furnished L1 in 82% yield (25 % yield over 5 steps).
The synthesis was amenable to scale up as more than
10 g of L1 was prepared in a single batch.
highlighted in red. The interaction between ligand
bound Pd(II) and C1´ is shown by a dashed line. c) Biar-
yl monophosphine ligand (Alphos, L1).
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While these discoveries have shown that Pd(II)-
catalyzed fluorination is indeed viable, several prob-
lems remain. Most importantly, the generation of
regioisomeric by-products14 (presumably through a
Pd–benzyne intermediate) lowers the yield of the
desired product and renders purification difficult or
even impossible. Additionally, the use of elevated
reaction temperatures is required to achieve full con-
version of the starting materials. To address these
issues, which we ascribe to the difficult C–F reductive
elimination from Pd(II) complexes, we sought to de-
sign a ligand to improve this elementary step as well
as the overall efficiency of the catalytic transfor-
mation. As shown in Figure 1b, biaryl monophos-
phine ligands coordinate to the Pd(II) metal center
in a bidentate fashion, making contacts through
both the phosphine and the C1´ carbon of the adja-
cent aromatic ring.15 Since reductive elimination
from Pd(II) complexes is typically favored from a
three-coordinate intermediate,16 we hypothesized
that modification at C3´ with an electron-
withdrawing group would diminish the donation of
electron density from C1´ to the Pd(II) metal center,
providing an intermediate with more three-
coordinate character and thereby generating a more
active catalyst.
Scheme 1. Synthesis of L1 and Pd(0) Precatalyst 1a
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aReagents and conditions: (a) THF, -78 °C, n-BuLi, 1
h; added to C6F6 in THF, 0 °C – rt, 2 h, 87%. (b) THF,
-78°C, n-BuLi, 30 min, 99% (c) AcOH, EtOAc,
H2SO4, N-Iodosuccinimide, 50 °C,17 h, 80%. (d) THF,
-78 °C, t-BuLi, 1 h; added to 3-fluoroanisole and n-
BuLi in THF, -78 °C to -25 °C, 44%. (e) THF, -78 °C, t-
BuLi, 1 h; CuCl -78°C to rt; Ad2PCl, toluene, 140 °C, 18
h, 82%. (f) [COD•Pd(CH2TMS)2], pentane, rt, 48 h,
78%.
The highly active Pd(0) precatalyst [(L1Pd)2•COD]
(1), was prepared in 78% yield by treating L1 with an
equivalent of [COD•Pd(CH2TMS)2] in pentane,
which could be easily isolated and stored under an
inert atmosphere (Scheme 1).18,19 Due to the electron-
rich nature and high reactivity of biaryl monophos-
phine-ligated Pd(0) complexes, there exist only a few
structurally characterized examples.20 We have pre-
viously described several Pd(0) precatalysts, of which
indirect evidence was obtained suggesting an empir-
ical formula of [(LPd)n•COD] (n = 1-2), however the
insolubility these complexes precluded structural
characterization by single crystal X-ray diffrac-
tion.18,13c Single crystals of 1 suitable for x-ray diffrac-
tion were obtained providing the first structural evi-
dence for this class of precatalyst (Figure 2). Complex
1 crystallizes in the triclinic centrosymmetric space
group P-1 with half a molecule of 1 and three mole-
cules of benzene per asymmetric unit. The second
half of 1 is generated by the crystallographic inver-
sion center. The full molecule is a binuclear complex
in which each Pd atom is chelated by one L1 ligand.
Located between the two palladium centers is a cy-
clooctadiene molecule (COD), which coordinates
through its two double bonds to the metal atoms in a
side-on fashion that can be described as η2. This re-
RESULTS AND DISCUSSION
To test our hypothesis, we designed and synthe-
sized a ligand that was less electron-rich than the
previously reported L2. This was accomplished by
removing the methoxy group adjacent to the dial-
kylphosphino group on the "upper" aromatic ring
and replacing the hydrogen atoms of the pendant 4-
(n-Bu)Ph group at C3´ with fluorines17 (Figure 1c).
The synthesis of L1 is described in Scheme 1. Lithi-
um-halogen
exchange
of
2,4,6-
triisopropylbromobenzene with n-BuLi followed by
nucleophilic addition into hexafluorobenzene pro-
vides perfluoro biaryl L1a. To improve solubility of
the final ligand and prevent subsequent nucleophilic
additions into the activated perfluoro aromatic, n-
BuLi was added at -78 °C to give the alkylated prod-
uct via SNAr, which was then halogenated using N-
iodosuccinimide and H2SO4 to yield L1b. Terphenyl
L1c was prepared by nucleophilic addition of L1b
into a benzyne intermediate, generated from 3-
fluoroanisole, followed by quenching the resulting
aryl anion with bromine at -30 °C. Treatment of L1c
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sults in a distorted trigonal planar coordination envi-
ronment for the palladium atoms with the following
angles: P-Pd-C1´: 88°, P-Pd-COD: 135°, and C1´-Pd-
COD: 137°.
1
2
3
4
The enhanced reactivity in the stoichiometric pro-
cess exhibited by the L1-supported Pd(Ar)F complex
was successfully extended to the catalytic reaction.
By using 1, a variety of activated (hetero)aromatic
triflates (Table 1) were transformed to the fluoride
derivatives at room temperature.22 A range of func-
tional groups were tolerated in this transformation,
including nitro (2), formyl (3), methyl ketone (4),
redox active anthraquinone (5), and sulfona-
mide/tertiary amine (6). Heteroaryl triflates were
also competent substrates as flavone 7, quinolines 8
and 9, and quinazoline 10 derivatives were prepared
in high yields. Notably, XAV939,23 a tankyrase inhibi-
tor and potential cancer therapeutic, could be fluor-
inated to give 11, demonstrating the applicability of
this method to fluorinate medicinally relevant com-
pounds. Additionally, aryl triflates can be selectively
transformed in the presence of aryl chlorides, leaving
a reactive handle for downstream modifications (12-
14). While the long reaction times at room tempera-
ture speak to the stability of the catalyst, the trans-
formation can be completed in 24 hours by increas-
ing the temperature even while lowering the catalyst
loading (Table 1, 7 and 9).
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Figure 2. Crystal structure of [(L1Pd)2•COD] (1). Ther-
mal ellipsoids are shown at 50% probability; hydrogen
atoms and residual benzene molecules are omitted for
clarity.
Table 1. Room Temperature Fluorination of Aryl Tri-
flatesa
The reactivity of L1 and L2 was compared by pre-
paring analogous [LPdAr(F)] complexes and examin-
ing the formation of the ArF resulting from the stoi-
chiometric C–F reductive elimination from the Pd(II)
intermediates at room temperature (Scheme 2). The-
se reactions were performed in the presence and ab-
sence of added aryl bromide, which serves as a trap-
ping agent for the resulting Pd(0) that is formed after
reductive elimination.21,13a After a period of 12 hours
the L1-supported complex provides approximately
twice the amount of the desired product than the
one bearing L2. Both L1- and L2-ligated complexes
provided the ArF product and are the first examples
of room temperature C–F reductive elimination from
isolated [LPd(Ar)F] complexes.
Scheme 2. Stoichiometric C–F Reductive Elimination
From Pd(II) Complexes at Room Temperature
aIsolated yields are reported as an average of two runs.
Reaction conditions unless otherwise noted: Aryl tri-
flate (1 mmol), CsF (3 mmol), tol or 2-MeTHF (10 mL).
d
b0.50 mmol scale. c19F NMR yield. Aryl bromide (0.5
mmol), KF (0.25 mmol), AgF (1.0 mmol), tol (5 mL).
tol=toluene, 2-MeTHF=2-methyl tetrahydrofuran.
aYields determined by 19F NMR. bNo ArBr added.
cArBr (R = C(O)n-Bu). dArBr (R = n-Bu).
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flates and bromides converted to the corresponding
1
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aryl fluorides in high yield with >100:1 selectivity for
the desired regioisomer (15-21, 23-25). Previously,
substrates with strongly electron-donating groups in
the para position, such as -OMe, have been the most
challenging substrates for this methodology. For ex-
With our previously described catalyst sys-
tems,11,13,14 mixtures of regioisomeric aryl fluorides
are sometimes formed during the Pd-catalyzed nu-
cleophilic fluorination reaction.14 In general, sub-
strates with para electron-donating groups or meta
substitution are plagued by this undesired reaction
pathway. Previously, by using cyclohexane as the sol-
vent, the amount of regioisomer formation could be
reduced. In some instances, however, the quantity of
undesired regioisomer formed was still significant.
ample,
4-methoxyphenyl
triflate15
and
4-
bromoanisole13c have previously been shown to form
the undesired meta isomer as the major product.
Using 1, the observed selectivity is reversed and the
desired product dominates (22). Several fluorinated
analogues of biologically active compounds were also
prepared to give (±)-naproxen 23, diethylstilbesterol
24, and tyrosine 25 derivatives with exceptional se-
lectivity. No loss in stereochemical integrity was ob-
served with 25 under the reaction conditions and
reduction (ArH) was only observed for 16 (0.75%), 19
(0.64%), and 22 (0.52%) (see the Supporting Infor-
mation).24
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To probe the effectiveness of catalysts derived from
1 to further suppress the formation of regioisomeric
byproducts, we examined 4-(n-Bu)PhOTf (X=OTf)
and 4-(n-Bu)PhBr (X=Br) as model substrates (Table
2). With either aryl electrophile, the L2-supported
precatalyst provides substantial amounts of unde-
sired isomer B (entry 1). The enhanced reactivity of 1,
however, allows for the use of lower reaction temper-
atures than were previously possible (entry 2,
X=OTf), revealing a temperature dependence on the
formation of B (entries 3-5, X=OTf). The same tem-
perature dependence is not observed for aryl bro-
mides although using 1 diminishes the amount of B
formed. Currently we have no explanation for this
dichotomy.
Table 3. Regioselective Fluorinationa,b,c
Table 2. Temperature Dependence on Regioisomer
Formationa,b
aIsolated yields are reported as an average of two
runs. Reaction conditions unless otherwise noted:
Aryl triflate (1 mmol), CsF (3 mmol), cy (10 mL). bAr-
yl bromide (1 mmol), KF (0.5 mmol), AgF (2.0
aYields were determined by 19F NMR. Numbers in pa-
renthesis indicate % conversion of the starting materi-
al. bThe reaction time was 48 h.
c
mmol), cy (10 mL). 0.5 mmol scale. d19F NMR yield.
eNo
regioisomer
cy=cyclohexane.
detected
by
19F
NMR.
The success of 1 in suppressing the formation of B
with 4-(n-Bu)phenyl triflate or bromide prompted us
to study the reaction of a number of substrates that
are prone to give regioisomeric mixtures of ArF
products. As shown in Table 3, a variety of aryl tri-
To gain further insight into the enhanced reactivity
of 1, we prepared the [LPd(Ar)Br] complexes, from
the reaction of 4-(n-Bu)PhBr and CODPd(CH2TMS)2
using L1 and L2 as supporting ligands (Figure 3) (see
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the Supporting Information). The respective com-
plexes were characterized in the solid state using sin-
1
2
3
4
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7
8
gle crystal X-ray diffraction. The initial hypothesis
from which the design of L1 derived predicts that
significant lengthening of the C1´–Pd bond would be
observed with the more electron-deficient support-
ing ligand (L1). In fact, only a slight increase in this
bond length in D was apparent, compared to that
seen with C (see the Supporting Information).
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By overlaying the crystal structures of C and D, a
more subtle difference was, however, revealed (Fig-
ure 3c). With C, the pendant 4-(n-Bu)Ph group of
the ligand is shifted towards the Pd-bound bromide
to form an aromatic CHꢀꢀꢀBr contact of 3.874(3) Å
(measured from C to Br), which is in agreement with
typical aromatic CHꢀꢀꢀBr interaction distances found
in the solid state (3.7-4.2 Å; measured from C to
Br).25 The perfluorinated aryl group of D lacks the
required hydrogen atom to achieve the same attrac-
tive interaction, giving a CꢀꢀꢀBr distance of 4.370(2)
Å. The analogous [LPd(Ar)F] complexes were synthe-
sized (E and F) and single crystal X-ray analysis of E
shows that this behavior is conserved, with E exhibit-
ing an aromatic CHꢀꢀꢀF interaction distance of
3.387(3) Å (measured from C to F) (Figure 3d). Typi-
cal aromatic CHꢀꢀꢀF interaction distances found in
the solid state range from 3.3 to 3.7 Å (measured
from C to F).25 Unfortunately all attempts to obtain
single crystals of F suitable for X-ray diffraction
yielded decomposition and/or pseudo-crystalline
material.
Figure 3. a) Schematic of [L2Pd(Ar)X] complexes C and
E where L2 is highlighted in red. b) Schematic of
[L1Pd(Ar)X] complexes D and F. c) Crystal structure
overlay of C and D. C is shown in red. Hydrogen atoms
and an isopropyl group omitted for clarity. d) Crystal
structure of E highlighting the intramolecular CHꢀꢀꢀ
F
contact. Hydrogen atoms and the n-butyl group on the
Pd-bound aryl omitted for clarity. Thermal ellipsoids
are shown at 50% probability.
Short CHꢀꢀꢀF contacts are frequently observed in
structurally characterized Pd–F complexes. They
serve to stabilize the Pd–F bond by alleviating elec-
tronic repulsions between the lone pairs on the fluo-
ride atom and the filled d-orbitals of Pd.8 As shown
in the solid state, E achieves this Pd–F bond stabili-
zation intramolecularly while F cannot. The lack of
an intramolecular CHꢀꢀꢀF interaction in F results in
ground state destabilization relative to E, which may
account for the observed enhancement in reactivity.
Density functional theory (DFT) calculations were
carried out to compare complexes E and F and gain
further insight into the stabilizing CHꢀꢀꢀF interaction
that was observed in the solid state structure of E. To
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plex F´ showing the lack of an intermolecular stabiliz-
ing interaction.
reduce conformational complexity, the Pd-bound 4-
1
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(n-Bu)Ph of complexes E and F was replaced with a
phenyl group in our computational study, giving
complexes E´ and F´, respectively. The calculated
ground state structure of E´ is in good agreement
with the crystallographic data of E, exhibiting an at-
tractive CHꢀꢀꢀF contact (3.24 Å, measured from C to
F) (Figure 4a). Furthermore, NPA (natural popula-
tion analysis) charge calculations of complex E´
showed that the Pd–bound fluorine atom bears a
partial negative charge of -0.700 and the hydrogen
atom at the 2 position of the pendant 4-(n-Bu)Ph
group carries a partial positive charge of +0.251. Tak-
en together, these analyses clearly indicate the pres-
ence of an intramoleuclar stabilizing interaction. As
anticipated, this interaction is absent in complex F´,
which lacks the necessary hydrogen atom required
for this attractive interaction (Figure 4b). In addi-
tion, NPA charge analysis of complex F´ reveals that
both the Pd-Bound fluorine atom and the fluorine
atom at the 2 position of the pendant 4-(n-Bu)Ph
group carry a partial negative charge (-0.690 and -
0.318, respectively), further demonstrating the lack
of an attractive interaction in complex F´.
Additionally we performed DFT calculations of the
C–F bond forming reductive elimination step for
complexes E´ and F´ (Figure 5). This process involves
a three membered transition state where the C–F
bond is being formed while the Pd–F and the Pd–C
bonds are being broken in a concerted fashion. The
calculations showed that the C–F reductive elimina-
tion of complex F´ (Figure 5b) has an activation bar-
rier (ΔG‡) of 0.7 kcal/mol lower than that of complex
E´ (Figure 5a), which is in agreement with the exper-
imentally observed enhanced reactivity of the L1-
based catalyst.
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Figure 5. Energies were computed at the M06/6-
311+G(d,p)-SDD(Pd)/SMD(toluene) level of theory with
geometries optimized at the B3LYP/6-31G(d)-SDD(Pd)
level. Hydrogen atoms are omitted for clarity. a) Transi-
tion state minimization of complex E´. b) Transition
state minimization of complex F´.
Figure 4. Computed ground state structures of com-
plexes E´ and F´. Geometries were optimized at the
B3LYP/6-31G(d)-SDD(Pd) level of theory. Hydrogen
atoms are omitted for clarity. a) The CHꢀꢀꢀF interaction
of complex E´ is 3.24 Å, measured from C to F. b) Com-
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CONCLUSION
REFERENCES
1
2
3
4
5
6
7
8
9
A new ligand (L1) that allows for room tempera-
ture C–F reductive elimination from [LPd(Ar)F] has
been developed. The enhanced reactivity was ex-
ploited to provide aryl fluorides from aryl triflates
and bromides with greater than 100:1 selectivity for
the desired regioisomer. Crystallographic analysis of
several Pd complexes revealed that L2 provides a sta-
bilizing intramolecular aromatic CHꢀꢀꢀF interaction,
which is not accessible with L1, giving rise to a more
active catalyst system. Finally, DFT calculations were
performed comparing complexes E´ and F´ corrobo-
rating the observations made in the solid state. This
study provides insights into ligand structure, which
should aid in the discovery and design of more effec-
tive catalysts for C–F bond formation.
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ASSOCIATED CONTENT
Additional procedural, crystallographic, and spectral
data are provided. “This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
Notes
The authors declare the following competing financial
interest(s): MIT has obtained patents the lig-
ands/precatalysts that are described in the paper from
which S.L.B. and former/current coworkers receive roy-
alty payments.
(8) (a) Grushin, V. V. Acc. Chem. Res. 2009, 43, 160. (b) Grushin,
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Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
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M.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2014, 136,
4097. (f) Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131,
3796. (g) Furuya, T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.;
Tang, P.; Goddard, W. A.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
3793. (h) Ding, Q.; Ye, C.; Pu, S.; Cao, B. Tetrahedron 2014, 70,
409. (i) Lou, S.-J.; Xu, D.-Q.; Xia, A.-B.; Wang, Y.-F.; Liu, Y.-K.;
Du, X.-H.; Xu, Z.-Y. Chem. Commun. 2013, 49, 6218.
(11) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(12) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232.
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M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106. (b)
Milner, P. J.; Maimone, T. J.; Su, M.; Chen, J.; Müller, P.; Buch-
wald, S. L. J. Am. Chem. Soc. 2012, 134, 19922. (c) Lee, H. G.;
Milner, P. J.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 3792.
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Chem. Soc. 2014, 136, 15757.
ACKNOWLEDGMENT
Dedicated to the grandfather of A.C.S. (Albert B.
Sather; AlPhos, L1). We thank Drs. Yiming Wang, Mi-
chael Pirnot, and John Nguyen for assistance with the
preparation of the manuscript. We thank the National
Institutes of Health (NIH) for financial support of this
research (R01GM46059). A.C.S. thanks the NIH for a
postdoctoral fellowship (1F32GM108092-01A1). The con-
tent is solely the responsibility of the authors and does
not necessarily represent the official views of the NIH.
V.Y.D thanks the MIT UROP program. We thank Prof.
Peng Liu (University of Pittsburgh) for help with com-
putational studies. Calculations were performed at the
Center for Simulation and Modeling at the University of
Pittsburgh. The X-ray diffractometer was purchased
with the help of funding from the National Science
Foundation (CHE 0946721).
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(15) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
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Milner, P. J.; Buchwald, S. L. Org. Lett. 2013, 15, 5602.
(19) The unreacted ligand could be reisolated from the reaction
mixture, allowing 1 to be prepared on the gram scale without
losing appreciable amounts of L1 (see the Supporting Infor-
mation).
(20) (a) Tschan, M. J. L.; García-Suárez, E. J.; Freixa, Z.; Launay,
H.; Hagen, H.; Benet-Buchholz, J.; van Leeuwen, P. W. N. M. J.
Am. Chem. Soc. 2010, 132, 6463. (b) Barder, T. E.; Walker, S. D.;
(21) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937.
(22) [(L1Pd)2•COD] (1) and [(L2Pd)2•COD] were compared as
precatalysts for the conversion of an aryl bromide (4-
bromovalerophenone) and an aryl triflate (4-pentanoylphenyl
trifluoromethanesulfonate) to the corresponding aryl fluoride
(4-fluorovalerophenone) at room temperature. The reactions
were analyzed after 24 hours and these experiments revealed
that the use of 1 catalyzes the transformation approximately
three times faster than the use of [(L2Pd)2•COD] (see the Sup-
porting Information).
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(23) Huang, S.-M. et al. Nature 2009, 461, 614.
(24) The reduction content (ArH) of 2, 21, and 10 was not deter-
mined.
(25) Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061.
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Figure 1. a) The proposed catalytic cycle for Pd-catalyzed fluor-ination. b) A Pd(II) complex with L2
highlighted in red. The interaction between ligand bound Pd(II) and C1´ is shown by a dashed line. c) Biaryl
monophosphine ligand (Alphos, L1).
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Figure 2. Crystal structure of [(L1Pd)2•COD] (1). Thermal ellipsoids are shown at 50% probability; hydrogen
atoms and residual benzene molecules are omitted for clarity.
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Figure 3. a) Schematic of [L2Pd(Ar)X] complexes C and E where L2 is highlighted in red. b) Schematic of
[L1Pd(Ar)X] complexes D and F. c) Crystal structure overlay of C and D. C is shown in red. Hydrogen atoms
and an isopropyl group omitted for clarity. d) Crystal structure of E highlighting the intramolecꢀular CH●●●F
contact. Hydrogen atoms and the nꢀbutyl group on the Pdꢀbound aryl omitted for clarity. Thermal ellipsoids
are shown at 50% probability.
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Figure 4. Computed ground state structures of complexes E´ and F´. Geometries were optimized at the
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molecular stabilizing interaction.
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Figure 5. Energies were computed at the M06/6-311+G(d,p)-SDD(Pd)/SMD(toluene) level of theory with
geometries opti-mized at the B3LYP/6-31G(d)-SDD(Pd) level. Hydrogen at-oms are omitted for clarity. a)
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aReagents and conditions: (a) THF, -78 °C, n-BuLi, 1 h; add-ed to C6F6 in THF, 0 °C – rt, 2 h, 87%. (b)
THF, -78°C, n-BuLi, 30 min, 99% (c) AcOH, EtOAc, H2SO4, N-Iodosuccinimide, 50 °C,17 h, 80%. (d) THF, -
78 °C, t-BuLi, 1 h; added to 3-fluoroanisole and n-BuLi in THF, -78 °C to -25 °C, 44%. (e) THF, -78 °C, t-
BuLi, 1 h; CuCl -78°C to rt; Ad2PCl, toluene, 140 °C, 18 h, 82%. (f) [COD•Pd(CH-2TMS)2], pentane, rt, 48
h, 78%.
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aYields determined by 19F NMR. bNo ArBr added. cArBr (R = C(O)n-Bu). dArBr (R = n-Bu).
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aYields were determined by 19F NMR. Numbers in parenthesis indicate % conversion of the starting
material. bThe reaction time was 48 h.
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aIsolated yields are reported as an average of two runs. Re-action conditions unless otherwise noted: Aryl
triflate (1 mmol), CsF (3 mmol), cy (10 mL). bAryl bromide (1 mmol), KF (0.5 mmol), AgF (2.0 mmol), cy
(10 mL). c0.5 mmol scale. d19F NMR yield. eNo regioisomer detected by 19F NMR. cy=cyclohexane.
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