Steric crowding makes challenging Csp3 - F reductive eliminations feasible

Article abstract of DOI:10.1021/om200515f

A high-yielding fluorination of (triphos)Pt-R⁺ has been achieved using an array of F⁺ sources, with XeF₂ yielding R-F in minutes. The C-F coupling proved to be a stereoretentive process that proceeds via a concerted reductive elimination from a putative dicationic Pt(IV) center. The larger the steric congestion of the (triphos)Pt-C_sp3⁺ complexes, the more efficient the fluorination, seemingly a result of sterically accelerated C-F reductive elimination along with simultaneous deceleration of its competing processes (β-H elimination).

Full text of DOI:10.1021/om200515f

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pubs.acs.org/Organometallics
Steric Crowding Makes Challenging Csp3ÀF Reductive
Eliminations Feasible
Shu-Bin Zhao,† Jennifer J. Becker,‡ and Michel R. Gagnꢀe*,†
†Caudill Laboratories, Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
‡U.S. Army Research Office, P.O. Box 12211, Research Triangle Park, North Carolina 27709, United States
S Supporting Information
b
ABSTRACT: A high-yielding fluorination of (triphos)PtÀR+ has been achieved using an
array of F+ sources, with XeF2 yielding RÀF in minutes. The CÀF coupling proved to be
a stereoretentive process that proceeds via a concerted reductive elimination from a
putative dicationic Pt(IV) center. The larger the steric congestion of the (triphos)PtÀ
+
Csp3 complexes, the more efficient the fluorination, seemingly a result of sterically
accelerated CÀF reductive elimination along with simultaneous deceleration of its competing processes (β-H elimination).
rganofluorine compounds are pervasive in pharmaceuticals,
catalytic cyclization/fluorination reaction,13 we utilized com-
pounds like 1 to study key issues retarding progress on the PtÀC
fluorination step. We report, herein, a PtÀCsp3 bond fluorination
reaction that is stereoretentive and provide evidence suggesting
that it is steric congestion in a putative Pt(IV)-fluoride that
benefits the critical CÀF reductive elimination over competing
reactions.
We began by examining the electrophilic fluorination of
1 (eq 1),10e which generated 2 in >80% yields with an array of
F+ reagents (Table 1),14 the mass balance being the known β-H
elimination product 3.10c Electron-rich N-fluoropyridinium tetra-
fluoroborates were unreactive or required elevated temperatures,
while the more aggressive 2,6-dichloro derivative and Selectfluor
provided 2at roomtemperature. Most remarkablewasXeF2, which
gave complete conversion within 3 min at 0 °C. N-Fluorobenze-
nesulfonimide (NFSI, entry 6) was also effective, and in contrast to
the CÀN bond formations reported by Michael15 and Liu6b,c for
PdII/IV chemistry, it provided 2 in good yields.
O
agrochemicals, biomedical imaging agents, and materials.1
This has led to significant interest in developing metal-catalyzed
CÀF bond forming reactions.1À7 While transition metal mediated
CÀF couplings with FÀ are underdeveloped,1d,3 methods based
on “F+” reagents have proven more tractable,4À6 in part due to
their propensity to generate high-valent organometallic MÀF
intermediates (e.g., Pd(IV), Ag(III), Au(III)), which may be
more prone to CÀF coupling.1f,8
Electrophilic Pt(II) dications catalyze CÀC bond forming
reactions that propagate via cation-olefin sequences which parallel
sterol biosynthesis9,10 and proceed through PtÀCsp3 intermedi-
ates. It would be desirable to convert such PtÀC bonds into FÀC
bonds, as C3-fluoro steroids are bioactive and fluoro-carbocycles
in general are difficult to synthesize.1 Despite the ease of accessing
the tetravalent oxidation state with Pt-organometallics (e.g., the
Shilov reaction),11 Pt analogues of the above CÀF couplings are
rare. For example, adding F+ to P2PtR2 complexes affords only
the product of CÀC (RÀR, R = Me, Ph) and not CÀF
coupling.7 As the transformation of a PtÀC bond into an FÀC
bond was unknown, we initiated a study aimed at rectifying this
situation.
These fluorination reactions worked equally well in a variety
of solvents including MeCN, CH2Cl2, and MeNO2. Monitor-
1
ing reactions with H and 19F NMR spectroscopy revealed
that 2 was produced as a single diastereomer (19F: δ = À170.4
1
2
ppm; H for the geminal H: δ = 4.67 ppm, JFÀH = 48 Hz).
NOESY analysis and X-ray diffraction showed the F atom
in 2 to be equatorial,14 indicating that the fluorination was
stereoretentive (Figure 1). Several representative C3-plati-
nated carbocycles generated by cation-olefin cyclizations10e,f
were tested; N-fluoropyridinium salts, Selectfluor, XeF2, and
NFSI all led to the expected stereoretentive CÀF couplings, with
XeF2 again being particularly effective (Table 2, entries 1À4).
Such organofluorine compounds would otherwise be difficult to
access.1a
As illustrated in eq 1, wherein PPP = bis(2-diphenylpho-
sphinoethyl)phenylphosphine (i.e., triphos), pincer ligands
inhibit β-H elimination and enable the isolation of relevant
cyclization intermediates.10,12 With the eventual goal of a
Received: June 22, 2011
Published: July 01, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/om200515f Organometallics 2011, 30, 3926–3929
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Table 1. Fluorination of 1 with a Variety of “F+” Reagentsa
Figure 1. X-ray structure of 2, showing the equatorially disposed
CÀF bond.
a
Table 2. Fluorination of Platinated Alkyls with XeF2
These initial data suggested a PtÀC fluorination that was
general and uniformly high yielding; however, simple acyclic
(triphos)PtÀR+ complexes were unexpectedly complex. While
R = cyclohexyl was only slightly diminished compared to entries
1À4 (Table 2), the isopropyl and ethyl complexes underwent
preferential β-H elimination, producing only 14% and 41% of
the fluorocarbon product, respectively. The benzyl complex, which
lacks β-hydrogens, gave exclusively benzyl fluoride, while the methyl
complex reacted with XeF2 to yield a complex mixture of methyl
Pt(IV) fluoro complexes but no CH3ÀF (entry 9). Fluorinations
using NFSI (70 °C, CD3CN) were comparable to XeF2
(fluorocyclohexane: 76%; 2-fluoropropane: <5%; benzyl fluoride:
>94%), except for the R= Me and Et complexes, which preferentially
formed CÀN products (eqs 2 and 3).14
reaction of (triphos)PtÀMe+ with XeF2 yields Pt(IV) fluoro
complexes.
Several mechanisms have been considered, with reaction path-
ways involving direct backside SE2 attack of F+ onto the PtÀC σ
bond being ruled out, as these processes would be invertive CÀF
couplings. While direct attack of F+ onto the PtÀC bond would be
retentive, this later mechanism does not explain the increased rates
of β-H elimination and the CÀN bond forming products for R =
Me and Et. The mechanism, based in large part on precedence
established by Ritter,4d Sanford,4e Vigalok,7b and mechanistic
commonalities to Shilov-type reactions,11 and best able to explain
the observations, is outlined in Scheme 1.16 Initiating F+ attack
generates the common intermediate A, a dicationic Pt(IV) fluoride.
When the steric demand of the alkyl is high, rapid (concerted) CÀF
reductive elimination follows;17,18 when lessened, β-H elimination
becomes competitive, or even favorable.19 Finally, when the alkyl
The reactivity of PtÀR complexes therefore depends on
both the identity of the R group and (partially) on the F+
source. From data analysis emerge several generalizations:
(1) XeF2 fluorinates bulky alkyls (with retention) more effi-
ciently than less bulky ligands; (2) the NSFI reagent fluor-
inates (with retention) bulky alkyls with similar fluorocarbon:
alkene ratios to XeF2; however, Me and Et ligands are
preferentially amidated by the [N(SO2Ph)2À] counterion;
(3) fluorination conditions make otherwise stable (triphos)-
PtÀR+ complexes susceptible to β-H elimination; and (4) the
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Scheme 1. Proposed Mechanistic Pathways for Fluorinations
To investigate the role of supporting ligation on CÀF coupling,
the fluorination (XeF2, RT, CH3CN) of several additional Pt-cyclo-
hexyl complexes was investigated.14 Variable quantities of fluorocy-
clohexane were observed for the different ligand sets, with the
yield steadily improving as the steric congestion around the Pt
center increased.25
of (triphos)PtÀR+
Also illuminating wereexperiments to investigate the possibility
that the preferential CÀN formation observed by Michael15 and
Liu6b,c using NSFI was a metal effect (i.e., Pd vs Pt). In a direct
parallel to 1, fluorination of palladium alkyl 510e with NFSI gave a
76% yield of 2 (XeF2 gave 82% yield in minutes at 0 °C), with 3
again providing the mass balance (eq 4). These experiments
demonstrate that CÀF vs CÀN bond formation is not a conse-
quence of metal choice but the overall steric encumbrance of the
putative tetravalent organometallic intermediate.
Scheme 2. Cyclometalation of a Putative Pt(IV) Fluoride
Intermediate
In summary, PtIIÀCsp3 bonds can be efficiently fluorinated by
electrophilic F+ reagents when the coordination environment of the
putative Pt(IV) intermediate is congested. These data suggest that
CÀF reductive elimination is sterically accelerated over the compet-
ing processes of β-H elimination and/or nucleophilic attack of the
F+’s counterion. Taken together these studies suggest strategies for
optimizing the propensity of high-valent Pd and Pt reactive inter-
mediates to undergo desirable CÀF coupling reactions.
(Me, Et) is sterically susceptible to nucleophilic attack by the
counterion, the SN2-type amidation can become dominant.11,18
Overall, these data suggest that A can be coaxed away from β-H
elimination and CÀN coupling by enhancing the size of the R
group, the consequence of which is to apparently accelerate CÀF
reductive elimination and slow β-H elimination and CÀN bond
formation (for NFSI).20
Evidence supporting the intermediacy of A was sought through
low-temperature trapping studies in acetonitrile.21 Only in the case of
R = Et were spectroscopic data consistent with solvated (triphos)-
Pt(Et)(F)2+ observable (XeF2, À20 °C); 31P and 19F NMR spec-
troscopic data established its similarity to the unreactive methyl
analogue (entry 9, Table 2).14 Additionally, it undergoes a slow β-H
elimination and competing CÀF coupling at À20 °C. Similarly
informative were reactions of (triphos)Pt-CH2Ph+ and XeF2 in
melting acetonitrile. In addition to the expected PhCH2F and
(triphos)Pt2+ species,22 ∼10% of a cyclometalated benzyl Pt(IV)
fluoride complex was spectroscopically identified (4, Scheme 2);23,24
a seemingly related cyclometalated benzyl Pt(IV) fluoro species was
invoked by Vigalok and co-workers to account for their fluorination
of a ligand benzyl CÀH bond.7b While stable for a time at RT, 4
could not be isolated, and its structure was deduced by 1H, 31P, and
19F NMR spectroscopy as well as HRMS.14
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, characteri-
b
zation data, and complete X-ray diffraction data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mgagne@unc.edu.
’ ACKNOWLEDGMENT
The NIH (GM-60578) and Army Research Office Staff
Research Program are thanked for their generous support. S.Z.
thanks NSERC of Canada for a Postdoctoral Fellowship.
These in situ experiments together support the notion that
Pt(IV) fluoro intermediates (i.e., A) are involved. Moreover, they
demonstrate that steric effects significantly affect the rate of CÀF
reductive elimination in A, with R = Me being negligible, R = Et being
observable at À20 °C, and R larger than Et being too rapid to observe
the intermediate.
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