Asymmetric electrophilic fluorination using an anionic chiral phase-transfer catalyst

Article abstract of DOI:10.1126/science.1213918

The discovery of distinct modes of asymmetric catalysis has the potential to rapidly advance chemists'ability to build enantioenriched molecules. As an example, the use of chiral cation salts as phase-transfer catalysts for anionic reagents has enabled a vast set of enantioselective transformations. Here, we present evidence that a largely overlooked analogous mechanism wherein a chiral anionic catalyst brings a cationic species into solution is itself a powerful method. The concept is applied to the enantioselective fluorocyclization of olefins with a cationic fluorinating agent and a chiral phosphate catalyst. The reactions proceed in high yield and stereoselectivity, especially considering the scarcity of alternative approaches. This technology can in principle be applied to the large portion of reaction space that uses positively charged reagents and reaction intermediates.

Full text of DOI:10.1126/science.1213918

Asymmetric Electrophilic Fluorination Using an Anionic Chiral
Phase-Transfer Catalyst
Vivek Rauniyar et al.
Science 334, 1681 (2011);
DOI: 10.1126/science.1213918
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REPORTS
could be uniquely advantageous. In this con-
text, procedures for the construction of carbon-
fluorine bonds are highly prized because of the
scarcity of methods and the value of the products
across applied chemistry (12–15). Electrophilic
reagents have proven to be one of the most ap-
plicable vehicles for introducing fluorine into
organic molecules (16–21). Unfortunately, the
mechanism of these reactions offers little room
for the addition of a chiral catalyst. Many of the
most effective published enantioselective fluo-
rination protocols require formation of a nucleo-
Asymmetric Electrophilic Fluorination
Using an Anionic Chiral
Phase-Transfer Catalyst
Vivek Rauniyar,* Aaron D. Lackner,* Gregory L. Hamilton, F. Dean Toste†
The discovery of distinct modes of asymmetric catalysis has the potential to rapidly advance chemists’
ability to build enantioenriched molecules. As an example, the use of chiral cation salts as phase-transfer philic chiral enolate equivalent (22–30), including
one report of formation through chiral cationic
phase-transfer catalysis (26). On the other hand,
the catalytic generation of a chiral electrophile
has proven quite challenging; usually a stoichi-
ometric amount of chiral promoter is necessary
catalysts for anionic reagents has enabled a vast set of enantioselective transformations. Here, we present
evidence that a largely overlooked analogous mechanism wherein a chiral anionic catalyst brings a
cationic species into solution is itself a powerful method. The concept is applied to the enantioselective
fluorocyclization of olefins with a cationic fluorinating agent and a chiral phosphate catalyst. The
reactions proceed in high yield and stereoselectivity, especially considering the scarcity of alternative
approaches. This technology can in principle be applied to the large portion of reaction space that uses to suppress the racemic background reaction
(31–34). With the current limitations in mind, we
envisioned a chiral anion phase-transfer approach
to electrophilic fluorination through the use of an
positively charged reagents and reaction intermediates.
n the years since Knowles and co-workers could be quite useful. Nelson and colleagues
demonstrated that synthetic catalysts could appreciated this possibility when they titled a insoluble cationic electrophilic fluorination re-
agent in conjunction with a chiral phosphate
catalyst.
Specifically, we targeted Selectfluor (1, Fig. 1)
I
approach the levels of absolute stereocontrol 2003 publication “Towards phase-transfer cata-
achieved by enzymes (1), chemists have made lysts with a chiral anion” (6). Although this report
remarkable progress on the synthesis of optically nicely demonstrated some asymmetric induction
active molecules using catalytic chiral inputs. by a chiral borate anion in a ring opening of
Despite the advances, the subset of reactions that prochiral aziridinium intermediates, no catalysis
can be performed with enantioselective methods (phase-transfer or otherwise) was investigated.
still represents only a fraction of the pool of known The challenge of rendering this reaction catalytic
organic transformations. One reason for this dis- and highly enantioselective seemed to us to be an
crepancy is that, although new ligand designs and excellent testing ground for the possibility of
catalyst variants have been reported at a striking chiral anion phase-transfer catalysis. We realized
rate, a slower pace has been set for devising this goal using a chiral phosphate anion catalyst
alternative underlying approaches to inducing and Ag+ (in the form of silver carbonate) as the
as a versatile cationic fluorinating agent that would
normally be insoluble in nonpolar media. We hy-
pothesized that lipophilic, bulky chiral phosphate
anions such as 2 (Fig. 1) could exchange with one
or both of the tetrafluoroborate anions associated
with Selectfluor to bring the reagent into solution.
The resulting chiral ion pair could then mediate
an asymmetric fluorination of an organic substrate
in solution. Given its insolubility, no appreciable
background reaction between Selectfluor and sub-
strate would be anticipated.
To properly test our idea, it also seemed logical
to investigate a previously unexplored reaction
that would not be amenable to chiral nucleophile–
based methods. We noted that fluorocyclizations,
wherein a pendant nucleophile attacks a p-bond
activated by an electrophilic fluorine source, are
much less common than the analogous reactions
of heavier halogens (35), and enantioselective var-
asymmetry.
insoluble stoichiometric promoter (7). Essential
Among the distinct strategies that comple- to our success was the previous discovery that
ment the traditional metal-chiral ligand methods, binaphthol-derived phosphates could convey
asymmetric phase-transfer catalysis has undoubt- asymmetry during reactions of cationic species
edly been one of the most successful. In this (8–10) independent of their ability to act as chiral
mode of catalysis, a lipophilic chiral cation salt Brønsted acids and hydrogen-bond donors (11).
mediates the reaction between a substrate in
Although this previous report hinted at the
organic solution and an anionic reagent in a promise of the underlying concept, we hoped
separate aqueous or solid phase. Ion pairing to find an area of chemistry with broader utility
with the cation solubilizes the anionic reagent where charge-inverted phase-transfer catalysis
or reaction intermediate in the bulk organic
phase, while also providing a chiral environ-
ment for the desired reaction with the substrate.
Application of this simple logic has yielded a
diverse array of operationally simple, highly
enantioselective protocols (2–5).
However, almost no consideration has been
given to an analogous charge-inverted strategy
in which the salt of a chiral anion brings an in-
soluble cationic promoter into solution. Positive-
ly charged reagents and reaction intermediates
are certainly quite common, so in principle this
neglected other half of phase-transfer catalysis
Department of Chemistry, University of California, Berkeley, CA
94720, USA.
Fig. 1. Catalytic formation of a chiral fluorination reagent via
chiral anion–mediated phase transfer in nonpolar solvents.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-mail:
fdtoste@berkeley.edu
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REPORTS
iants are almost unknown (34). Based on prece-
dent showing that enol ethers react efficiently
with Selectfluor, we first focused on dihydropyran
substrates tethered to various nucleophilic traps.
Initial experimentation revealed that benzamide
nucleophiles perform particularly well under the
designed catalytic conditions (Fig. 2). These sub-
strates display an interesting mode of reactivity
wherein, upon fluorination of the enol ether, the
amide carbonyl attacks the nascent oxocarbenium
ion to form a spiro-fused oxazoline.
After brief optimization of the reaction pa-
rameters, the product from the model substrate 3a
could be obtained in 86% yield with exceptional
enantio- and diastereoselectivity (92% ee, >20:1
diasteromer ratio) (Fig. 2). The inclusion of Pro-
ton Sponge [1,8-bis(dimethylamino)naphthalene]
as a base served a dual purpose of generating the
anionic phosphate catalyst in situ from its conju-
gate acid 2b as well as neutralizing the equivalent
of acid generated during the reaction. Consistent
with our design plan, the hydrophobic alkyl chains
attached to the backbone of the catalyst proved
beneficial: Use of the unsubstituted catalyst (2c)
reduced the enantioselectivity to 87%. Addition-
ally, products with a variety of substituents on the
benzamide ring—including halides, nitro, and alkyl
groups—could be obtained in very good yields
with enantioselectivities above 95% (products 4b
to 4f). Substitutions at the 2- or 3-positions of the
aryl ring gave rise to slightly more variability in
terms of yield and stereoselectivity but were gen-
erally well tolerated (4g to 4i). The absolute stereo-
chemistry of product 4c as shown in Fig. 2 was
determined by single-crystal x-ray diffraction
(see the supporting online material for crystal-
lographic data), and all other products were as-
signed by analogy.
Fig. 2. Enantioselective synthesis of fluorinated heterocycles from dihydropyran-derived substrates.
*Reaction run at –5°C.
We were naturally eager to extend the meth-
odology to less electron-rich alkenes. However,
this represented quite a challenge, as previously
reported catalytic asymmetric electrophilic fluo-
rination methods have largely relied on enol,
enolate, or other strongly activated nucleophiles.
Thus, it was encouraging to find that our tech-
nology enabled the efficient fluorocyclization of
dihydronaphthalene and chromene substrates
(Fig. 3A). Excellent enantioselectivities were ob-
tained even at room temperature (92 to 96% ee),
although in this case a slightly higher catalyst load-
ing gave optimal results. Even more remarkably,
an unactivated olefin with only alkyl substituents
also delivered a good yield of fluorinated product,
albeit with modestly reduced enantioselectivity
(Fig. 3B). Fluorination of these less-reactive sub-
strates was accomplished most effectively using
inorganic bases such as sodium carbonate.
An unanticipated benefit of the phase-transfer
protocol is an improved tolerance toward sensi-
tive functionality. When treated with Selectfluor
under homogeneous conditions, benzothiophene
substrates 10a and 10b were converted to a com-
plex mixture of products with only trace con-
version to desired product (Fig. 3C). However,
Fig. 3. (A) Fluorocyclization of dihydronaphthalenes and chromenes. (B) Successful extension to an
unactivated alkene. (C) The phase-transfer procedure displays improved chemoselectivity over ho-
when the chiral anion–mediated phase-transfer mogeneous conditions.
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REPORTS
Fig. 4. (A) Nonlinear relationship between the optical activity of catalyst and product in the fluorocyclization reaction. (B) The proposed catalytic cycle
supported by the observed nonlinear effect.
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and high optical purity. This improved chemo-
Like its chiral cation cousin, the anion-based
selectivity may be due to a combination of the phase-transfer procedure is appealing because
slow introduction of the fluorinating agent into it avoids the use of transition metals and the need
solution and possibly a reduction in reactivity in to rigorously exclude air and moisture. More im-
nonpolar solvent. This result is in contrast to a portant, it offers a mechanism for robust catalyst
recent report from Lectka and co-workers, where- turnover and suppression of the racemic back-
in increased reactivity of Selectfluor was observed ground reaction. This makes it particularly advan-
through a postulated counterion exchange in ace- tageous for transformations like halocyclizations,
tonitrile (36).
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In considering the mechanism of the reaction, methods have often suffered from insufficient
we were interested in discerning the precise na- rate acceleration over the background reactivity.
ture of the active fluorinating species: specifical-
The highly enantioselective fluorocyclizations
ly, whether one or both of the tetrafluoroborate demonstrated here exemplify the potential of
counteranions of Selectfluor are exchanged for the strategy. The method generates heterocyclic
chiral phosphate anions. The presence of multiple products with two stereogenic centers, including
chiral components in a reaction transition state a carbon-fluorine stereocenter that would be very
often results in a nonlinear relationship between difficult to construct using alternative approaches.
the enantiopurity of catalyst and product (37). Furthermore, the reactivity of the present system
Such nonlinear effects thus offer a convenient allows less electron-rich olefins to be fluorinated
tool for studying new catalyst formulations. To relative to previous reports. The enhanced reactiv-
carry out the study, catalyst 2c was prepared in ity fortunately does not trade off with the stereo-
six different levels of enantiopurity and used in selectivity, which compares favorably with other
the reaction of substrate 5a (Fig. 4A) (see table chiral electrophile–based fluorination methods.
S1 and accompanying text for further details). A Finally, the chiral anion phase-transfer catalysis
nonlinear effect was observed, supporting a path- scheme can be superimposed on any number of
way in which both tetrafluoroborate anions are transformations involving cationic reagents or
exchanged for chiral phosphates before the re- reaction intermediates. Its successful application
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We therefore propose the following catalytic very few catalyst systems have achieved with con-
mechanism (Fig. 4B): Two equivalents of phos- sistently high enantioselectivities, suggests that it
phate 2a undergo salt metathesis with dicationic may find utility in other areas of chemistry as well.
Selectfluor to generate chiral ion pair 12. Now solu-
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References and Notes
ble in the nonpolar reaction solvent, 12 is available
to mediate the fluorocyclization of alkene substrate
5. Upon reaction, one equivalent of phosphoric
acid 2b is generated along with one equivalent of
the defluorinated monocationic ion pair 13. The
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Supporting Online Material
www.sciencemag.org/cgi/content/full/334/6063/1681/DC1
Materials and Methods
SOM Text
Tables S1 to S6
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Acknowledgments: We gratefully acknowledge the
University of California, Berkeley, and Amgen for
financial support. V.R. thanks the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
a postdoctoral fellowship. A.D.L. thanks J. Lee for initial
investigations. Structural parameters for compound 4c
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13 September 2011; accepted 11 October 2011
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Angular Momentum Conservation
Focusing on the energy transfer step, the total
spin angular momenta spanned by the coupled
reactants (SRT) and products (SPT) can be described
according to
in Dipolar Energy Transfer
Dong Guo,* Troy E. Knight,* James K. McCusker†
jSRTj ¼ SD* þ SA ¼ jSD* þ SAj,
jSD* þ SA − 1j,:::,jSD* − SAj ð2Þ
Conservation of angular momentum is a familiar tenet in science but has seldom been invoked to
understand (or predict) chemical processes. We have developed a general formalism based on Wigner’s
original ideas concerning angular momentum conservation to interpret the photo-induced reactivity of two
molecular donor-acceptor assemblies with physical properties synthetically tailored to facilitate
intramolecular energy transfer. Steady-state and time-resolved spectroscopic data establishing excited-
state energy transfer from a rhenium(I)-based charge-transfer state to a chromium(III) acceptor can be fully
accounted for by Förster theory, whereas the corresponding cobalt(III) adduct does not undergo an
analogous reaction despite having a larger cross-section for dipolar coupling. Because this pronounced
difference in reactivity is easily explained within the context of the angular momentum conservation model,
this relatively simple construct may provide a means for systematizing a broad range of chemical reactions.
jSPTj ¼ SD þ SA* ¼ jSD þ SA*j,
jSD þ SA* − 1j,:::,jSD − SA*j ð3Þ
where |SD|, |SD*|, |SA|, and |SA*| represent the
magnitudes of the spin angular momenta of the
ground and excited states of the donor and ac-
ceptor, respectively. This formalism is identical
to the vector coupling of spin angular momenta
onservation of angular momentum ap- tion, the relative energies of the spin-coupled used to describe magnetic exchange interactions
pears to be a fundamental property of reactant-product states must also be considered in among weakly coupled paramagnetic species (7).
nature (1). It is widely manifest in settings order to define the thermodynamic viability of the In the present context, a spin-allowed reaction is
C
as varied as astrophysics, in which the idea of reaction in question. A straightforward way to possible if (i) there exists a value of S common
coupled momenta can be used to infer the pres- illustrate this idea is to envision a generic energy to both the reactant and product manifolds (i.e.,
ence of satellites, and figure skating, where skat- transfer reaction between an electronically excited DS = 0 for the reaction), and (ii) the energy of
ers spin faster and faster as they draw their arms donor species (D*) and an energy acceptor (A):
that common state is lower in the product man-
ifold (DG < 0). This concept has been invoked
explicitly for the interpretation of collisional frag-
mentation reactions in the gas phase (8–10) and
more implicitly in the context of spin effects in
in. In chemistry, the principle figures prominently
hn
D þ A
D* þ A
D þ A*
energy transfer
in the interpretation of optical spectra. For exam-
ple, conservation of spin angular momentum (2)
forms the basis of the so-called spin selection rule
whereby radiative transitions between two states
of differing spin multiplicity are forbidden (3). A
familiar manifestation of this phenomenon is the
(relatively) long lifetime of an electronic excited
state with spin angular momentum different from
that of the ground state. This condition leads to
the observation of phosphorescence and has
recently found application in the development
of organic light-emitting diodes (OLEDs) (4) as well
as the creation of charge-separated excited states
that form the conceptual underpinning of many
current approaches to solar energy conversion (5).
In 1927, Wigner introduced the notion of spin
conservation in chemical reactions (6) whereby a
process would be designated “spin-allowed” if
the spin angular momentum space spanned by
the reactants intersects the spin angular momen-
tum space spanned by the products. Although not
explicitly stated in Wigner’s original presenta-
ð1Þ
Department of Chemistry, Michigan State University, East
Lansing, MI 48824, USA.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-mail:
jkm@chemistry.msu.edu
Fig. 1. Molecular structure of the cation of [M(pyacac)3{Re(bpy)(CO)3}3](OTf)3 prepared for this study. 1,
M = CrIII; 2, M = CoIII; 3, M = GaIII.
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