Carbon(sp3)-fluorine bond-forming reductive elimination from palladium(IV) complexes

Article abstract of DOI:10.1002/anie.201107816

Pd^IV-fluoride complexes, some of which are remarkably insensitive to water, have been synthesized and used in the title reaction, which proceeds with high selectivity to give the product of the C(sp ³)-F coupling (see scheme, TfO=tri

Full text of DOI:10.1002/anie.201107816

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Angewandte
Communications
DOI: 10.1002/anie.201107816
Fluorination
3
À
Carbon(sp ) Fluorine Bond-Forming Reductive Elimination from
Palladium(IV) Complexes**
Joy M. Racowski, J. Brannon Gary, and Melanie S. Sanford*
The development of transition-metal-catalyzed reactions for
could be displaced by pyridine or water to generate cationic
products 3 and 4, respectively. An analogue of 3 with a BF4
counterion (3-BF4) was also prepared by oxidation of 1 with
À
À
the formation of C F bonds has been an area of intense
research over the past decade.[1–3] Traditionally, the C F
À
coupling step of these sequences has proven challenging
N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate
À
because of the high kinetic barrier for C F bond-forming
reductive elimination from most transition-metal centers.[1]
Our approach to address this challenge has involved the use
of PdII catalysts in conjunction with F+-based oxidants. Since
2006, a variety of PdII-catalyzed reactions of F+ reagents have
been developed to introduce fluorine at both C(sp2) and
C(sp3) centers.[4–6] These transformations have been proposed
À
to proceed through C F bond-forming reductive elimination
from transient, highly reactive PdIV alkyl/aryl fluoride inter-
mediates.
A detailed understanding of the high-valent organopalla-
À
dium species that are involved in the key C F coupling step
has lagged considerably behind the development of catalytic
3
À
reactions. In particular, the feasibility of C(sp ) F bond
formation from PdIV complexes (a crucial step in the Pd-
catalyzed fluorination of benzylic/alkyl C H bonds[4c] and the
À
fluorination of olefins)[5] has not yet been established. Several
recent reports have described detailed investigations of
2
À
related C(sp ) F bond-forming reductive elimination from
PdIV aryl fluoride complexes.[7] In addition, both Vigalok[8]
and Gagne[9] and their respective co-workers have demon-
strated that PtII alkyl complexes react stoichiometrically with
Scheme 1. Synthesis of PdIV fluoride complexes 2–5. TfO=trifluorome-
thanesulfonate.
F+ reagents to form alkyl fluorides. Both groups proposed
3
À
C(sp ) F bond-forming reductive elimination from a high-
valent Pt center as a key step; however, no intermediates were
isolated in either of these transformations. Our goal was to
design a system with which we could access PdIV alkyl fluoride
(NFTPB) in the presence of pyridine. The PdIV complexes
2–4 were all formed as a single detectable stereoisomer
(established by 1H NMR spectroscopic analysis). Notably,
unlike most other palladium–fluoride complexes,[14] 2–4 are
not sensitive to water. They were routinely synthesized under
ambient conditions and could be stored on the bench top for
several hours (and in a freezer at À358C for several weeks)
without noticeable decomposition. The fluoride ligand of 2–4
appears as a sharp doublet at À336.17 ppm (J = 15 Hz) in the
19F NMR spectrum. In all cases, the fluoride is coupled to one
of the a hydrogen atoms of the s alkyl ligand (coupling to the
other a hydrogen atom is not observed, presumably because
of the small magnitude of this second coupling constant). The
sharpness of this 19F NMR signal and the insensitivity of the
complex to adventitious moisture both suggest that there are
no interactions of the fluoride ligand with H2O in solution.[14]
X-ray quality crystals of 4 were obtained by slow diffusion
of pentane into a solution of 3 in wet acetone at À358C. The
crystal structure of 4 shows that the s alkyl group of the
cyclometalated ligand is trans to the labile H2O ligand,
whereas the s aryl and fluoride ligands are trans to the
bipyridine unit (Figure 1).
À
complexes and directly study their reactivity toward C F
bond-forming reductive elimination. We report herein the
first direct observation and study of this important trans-
formation from a Group 10 metal center.[10,11]
We targeted the cyclometalated bipyridine–PdII complex
1[12] as a precursor to stable PdIV alkyl fluoride adducts. The
oxidation of 1 with NFTPT (N-fluoro-2,4,6-trimethylpyridi-
nium triflate)[13] afforded the PdIV complex 2 in 94% yield
(Scheme 1). The triflate ligand of 2 was highly labile and
[*] J. M. Racowski, J. B. Gary, Prof. Dr. M. S. Sanford
Department of Chemistry, University of Michigan
930 N. University Ave, Ann Arbor, MI 48109 (USA)
E-mail: mssanfor@umich.edu
[**] We thank the National Science Foundation (CHE-0545909 and CHE-
1111563) for support of this work. We are also grateful to Dr. Jeff
Kampf for X-ray crystallographic analysis of compound 4.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107816.
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3
À
Scheme 2. C(sp ) F bond-forming reductive elimination from 3 and 5.
Figure 1. ORTEP drawing of complex 4.[27] Thermal ellipsoids are
drawn at 50% probability, and hydrogen atoms are omitted for clarity.
Selected bond lengths [ꢀ]: Pd–F 1.979(5), Pd–C11 2.008(9), Pd–N1
2.015(7), Pd–C18 2.025(9), Pd–N2 2.151(8), Pd–O 2.229(6), C11–C16
1.383(13), C17–C18 1.522(13). Selected bond angles [8]: F-Pd-C11
85.9(3), F-Pd-N1 175.8(3), C11-Pd-N1 98.3(3), F-Pd-C18 89.2(3), F-Pd-
N2 96.1(2), F-Pd-O 90.1(2), C11-Pd-O 100.6(3), N1-Pd-O 89.8(2).
from a palladium center.[10] Remarkably, the reactions were
3
À
both highly selective for C(sp ) F coupling, and the analo-
gous aryl fluorides 6b and 7b were not detected under any
conditions examined. This is a reversal of the “normal”
selectivity of reductive elimination (for example, at PdII and
most other metal centers C(sp2) ligands are typically much
more reactive toward reductive elimination than their non-
allylic C(sp3) analogues).[18] This result highlights an impor-
tant and complementary feature of PdIV-mediated fluorina-
tions[4–6] compared to analogous transformations at PdII
centers.[2]
The triflate ligand of 2 could also be readily replaced with
fluoride. For example, the treatment of 1 with NFTPT for
15 minutes followed by the addition of 1.6 equivalents of
NMe4F afforded the difluoride complex 5 in 93% yield
(Scheme 1). The 19F NMR spectrum of 5 shows two distinct
fluorine resonances, a doublet at À201.42 ppm and a doublet
of doublets at À336.73 ppm. Complex 5 could also be
prepared in high yield by the direct reaction of PdIV triflate
complex 2 with 1.6 equivalents of NMe4F.
Stacked 19F NMR spectra for the conversion of 3-BF4 to 6-
BF4 are shown in Figure 2. The disappearance of starting
material proceeded with clean first order kinetics (k = 3.5 ꢀ
Difluoride PdIV complex 5 had very different properties
than 2–4. Complex 5 was extremely sensitive to water, and
attempts to synthesize 5 without rigorous exclusion of
moisture resulted in the formation of mixtures of unidentified
products. Given the strong trans influence of the s alkyl
ligand, the trans-fluoride of 5 is likely labile and highly
susceptible to H-bonding interactions with H2O.
We next sought to study the reactivity of these PdIV
À
fluoride complexes toward C F bond-forming reductive
elimination. There are several potential challenges to con-
sider for these transformations. First, 2–5 all contain both
s aryl and s alkyl ligands; thus, it was not clear whether
Figure 2. Stacked 19F NMR spectra of reductive elimination from 3-BF4.
10À4 sÀ1 at 458C), and no intermediates were detected by 19F
selectivity could be achieved in the reductive elimination
3
À
processes. Second, C(sp ) heteroatom bond-forming reduc-
tive eliminations from PdIV complexes generally proceed by
outer-sphere mechanisms that involve an SN2-type attack of
a nucleophile on the s alkyl ligand.[15] However, it is well-
known in organic chemistry that fluoride is a poor nucleophile
for SN2 reactions,[16] thus suggesting that such a pathway might
À
NMR spectroscopy. The rate of C F bond-forming reductive
elimination from 3-BF4 slowed dramatically upon the addi-
tion of pyridine. For example, in the absence of added
pyridine, reductive elimination was complete after 30 minutes
at 808C.[19] In contrast, under analogous conditions but with
50 equivalents of added pyridine, no reaction was observed. A
quantitative study of kobs versus concentration of pyridine is
shown in Figure 3. An excellent linear fit was observed for
not be viable in these systems. In addition, the high degree of
3
À
b substitution at the C(sp ) Pd bond in 2–5 was expected to
further disfavor SN2-type processes.
We were pleased to find that, despite these potential
À
challenges, both 3 and 5 underwent clean C F bond-forming
a plot of kobs versus 1/[C5D5N].
3
À
reductive elimination at 808C. Heating 3 for 30 minutes at
808C produced 6 in 93% yield (Scheme 2a); 3-BF4 showed
similar reactivity and gave 6-BF4 in 58% yield. Similarly, 5
was converted cleanly to 7 upon heating at 808C for
On the basis of these studies, we propose that C(sp ) F
bond-forming reductive elimination proceeds by the mecha-
nism shown in Scheme 3. The inverse first-order dependence
on the concentration of pyridine implicates dissociation of the
pyridine ligand prior to the rate-determining step. Following
15 minutes (Scheme 2b).[17] These are the first examples of
a non-allylic C(sp ) F bond-forming reductive elimination
3
À
À
this dissociation, C F coupling could potentially occur either
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related transformations).[13b] We first compared proposed
intermediate 8 to isomeric complex 8-I (which contains the
C(sp2) of the cyclometalated ligand at the axial position and
the C(sp3) at the equatorial position). The optimized geo-
metries of both complexes are approximately square-pyrami-
dal, and 8 is the lower-energy structure (DH298 lowered by
3.2 kcalmolÀ1).
3
2
À
À
Transition states for both C(sp ) F and C(sp ) F bond-
forming reductive elimination were optimized from 8 and 8-I.
3
À
In both cases, low-energy transition states for C(sp ) F
coupling were found; for example, DH° from 8 is 15.2 kcal
298
Figure 3. Plot of kobs versus 1/[C5D5N] for reductive elimination from
molÀ1 (Scheme 5). The C(sp ) F coupling was kinetically
3
À
3-BF4 to form 6-BF4 in CD2Cl2 at 458C. y=(5.65ꢁ10À7)xÀ1.39ꢁ10À5
;
R2 =0.979.
3
2
À
À
Scheme 5. Calculated energies for C(sp ) F versus C(sp ) F bond-
forming reductive elimination from 8 (ts=transition state).
Scheme 3. Proposed reaction pathway for complex 3.
by direct reductive elimination from 8 (shown in Scheme 3) or
by dissociation of fluoride from 8 to generate a PdIV dication
followed by SN2-type attack of FÀ on the s alkyl ligand. While
we cannot definitively distinguish these possibilities at this
time, we favor the direct reductive elimination pathway for
several reasons. First, as discussed above, fluoride is generally
a poor nucleophile for SN2 reactions, and SN2 reactions are
typically slow in systems with high degrees of b substitu-
tion.[16] Second, dissociation of fluoride to generate a 14eÀ
dicationic PdIV species is expected to be unfavorable,
favored for both complexes (DDH° was 12.7 and 5.8 kcal
298
molÀ1 for 8 and 8-I, respectively).[26] These results strongly
suggest that the observed chemoselectivity is not a conse-
quence of the geometry of 8 (which contains the C(sp3) ligand
at the axial position). Instead, they indicate that this
selectivity reflects an inherent preference of this PdIV center.
In conclusion, we have demonstrated the synthesis of
a series of PdIV fluoride complexes, including several (2–4)
that are remarkably insensitive to water. We have also
3
particularly in the relatively non-polar solvent CH2Cl2.[20]
reported the first example of a C(sp ) F bond formation
À
3
À
Third, stereochemical studies have implicated direct C(sp )
from a palladium center. This reaction proceeds with high
selectivity for C(sp ) F bond formation despite the potential
for competing C(sp ) F coupling. Preliminary studies are
3
À
F bond-forming reductive elimination (with retention of
configuration at carbon) at related PtIV and AuIII centers.[9,10]
2
À
À
À
For example, Gagne demonstrated retention in the C F
consistent with a mechanism that involves direct C F bond
formation rather than SN2-type attack on the PdIV alkyl bond.
À
coupling reaction shown in Scheme 4, and consequently
proposed a reaction pathway that involves direct reductive
elimination from the transient PtIV intermediate 9.[9]
We anticipate that further investigations of this system and
related ones will initiate the development of new PdII/IV
-
catalyzed alkane/alkene fluorination processes.
Received: November 7, 2011
Revised: January 23, 2011
Published online: February 28, 2012
Keywords: chemoselectivity · fluorinated ligands ·
.
homogeneous catalysis · palladium · redox chemistry
3
À
Scheme 4. C(sp ) F bond formation proceeds with retention of stereo-
chemistry from putative PtIV intermediates (triphos=bis(2-diphenyl-
phosphinoethyl)phenylphosphine).
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A final series of studies were conducted to evaluate the
mechanism (Scheme 3) by using DFT calculations. In partic-
ular, we sought to gain insights into the origin of the
3
2
À
À
preference to form C(sp ) F over C(sp ) F bonds in this
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2
3
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[19] Reductive elimination from 5 is inhibited by added NMe4F. For
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À
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À
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3
À
[10] For a recent example of C(sp ) F bond-forming reductive
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À
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3
À
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