A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes

Article abstract of DOI:10.1073/pnas.1304346110

We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate β-amino- and β-aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid-liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation-cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step.

Full text of DOI:10.1073/pnas.1304346110

A combination of directing groups and chiral anion
phase-transfer catalysis for enantioselective
fluorination of alkenes
Jeffrey Wu, Yi-Ming Wang, Amela Drljevic, Vivek Rauniyar, Robert J. Phipps, and F. Dean Toste1
Department of Chemistry, University of California, Berkeley, CA 94720
Edited by Stephen L. Buchwald, Massachusetts Institute of Technology, Cambridge, MA, and approved July 11, 2013 (received for review March 6, 2013)
opportunity to combine the principle of transition-state organiza-
tion with our recently reported chiral anion phase-transfer system,
with the hypothesis that an allylic hydrogen-bonding DG could
effectively direct an ion-paired chiral phosphate species for the
enantioselective electrophilic fluorination of alkenes (Fig. 1
E and F).
Our recent enantioselective halocyclization methods (18–20)
used chiral anion phase-transfer catalysis, in which metathesis
between an insoluble electrophilic salt (such as Selectfluor) and
a chiral lipophilic phosphate anion derived from catalysts such as
3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydro-
genphosphate (TRIP) generates a soluble electrophile in a chiral
environment (Fig. 2). In addition, we reported the enantiose-
lective fluorinations of enamides, using the same phase-transfer
system (21, 22). In the latter examples, hydrogen bonding between
the reacting enamide functional group and the phosphate catalyst
is hypothesized to facilitate the fluorination reaction.
On the basis of our previous success with amides as pendant
nucleophiles, we posited that allylic amides could be used as DGs
for direct alkene fluorination to provide access to allylic fluoride
products (23). The synthesis of enantioenriched allylic fluorides is
a synthetic challenge for which only a handful of approaches have
been disclosed. Recently reported general methods for the
enantioselective synthesis of allylic fluorides include the reaction
of allylic chlorides with palladium catalysts (24, 25) as well as the
fluorination of allylsilanes using cinchona alkaloid catalysis (26,
27). Furthermore, we envisioned that, upon removal of the amide
directing group, this method would provide access to enantioen-
riched β-fluoroamines bearing a fluorinated quaternary center,
a privileged bioactive motif and longstanding synthetic challenge
(28–33).
In initial experiments, enantioselective fluorination of sub-
strates containing no hydrogen-bond donor functionality was
attempted (23). As expected, in the absence of a suitable DG,
enantioselectivities no higher than 10% enantiomeric excess (ee)
were obtained. In stark contrast, under typical chiral anion phase
transfer conditions, allylic amide 1a underwent fluorination to
provide allylic fluoride 1b in 82% yield and 85% ee, along with
cyclized side product 1c (Table 1, Entry 1). Switching the solvent to
toluene increased selectivity for the desired allylic fluoride over 1c,
as well as enantioselectivity (Table 1, Entry 2). Finally, use of the
recently developed 12-hydroxy-1,10-bis(2,4,6-triisopropyphenyl)-
4,5,6,7-tetrahydrodiindeno[7,1-de:1′,7′-fg][1,3,2]dioxaphosphocine
12-oxide (STRIP) (3, see Table 1) in place of TRIP (2) as catalyst
further increased enantioselectivity and chemoselectivity in favor
We report a catalytic enantioselective electrophilic fluorination
of alkenes to form tertiary and quaternary C(sp3)-F bonds and
generate β-amino- and β-aryl-allylic fluorides. The reaction takes
advantage of the ability of chiral phosphate anions to serve as
solid–liquid phase transfer catalysts and hydrogen bond with
directing groups on the substrate. A variety of heterocyclic, carbo-
cyclic, and acyclic alkenes react with good to excellent yields and
high enantioselectivities. Further, we demonstrate a one-pot, tan-
dem dihalogenation–cyclization reaction, using the same catalytic
system twice in series, with an analogous electrophilic brominat-
ing reagent in the second step.
asymmetric organocatalysis hydrogen-bonding
|
|
n the history of asymmetric catalysis, directing groups (DGs)
have been instrumental for the achievement of selectivity in
I
transformations of great synthetic utility. DGs have likewise been
shown to play a central role in transition-metal catalysis, having
recently been used for site-selective C-H activation (1–6). The
advantage of using a DG lies in the ability to functionalize
nonpolar bonds (such as in alkenes) while maintaining beneficial
polar interactions between the substrate and chiral source;
however, DGs have rarely been used in organocatalysis. In this
context, the Miller research group reported the epoxidation re-
action of allylic alcohols, using an amino acid catalyst capable of
hydrogen bonding with the alcohol DG, and conducted elegant
studies delineating the importance of hydrogen-bonding inter-
actions for this and related systems (7–9) (Fig. 1). The Tan re-
search group has elaborated this idea through the concept of
induced intramolecularity, in which the catalyst reduces the en-
tropic cost of reaction by bringing together reactants and organiz-
ing the transition state through favorable binding interactions (10).
The peptide catalysts in Miller’s studies facilitate reaction
through organization of the reactants in the transition state (Fig.
1) rather than through formation of covalent adducts or lowest
unoccupied molecular orbital-lowering protonation (or hydrogen
bonding), which has generally required substrates containing
carbonyl or imine moieties (11–13). This generalization applies
to chiral phosphoric acids, which have been predominantly used
in activation of the electrophile, although hydrogen bonding to
the nucleophile has also been implicated as a key component
(14). More recently the anionic conjugate bases of chiral phosphoric
acids (i.e., chiral phosphate anions) have received attention as
counterions for positively charged electrophilic intermediates,
wherein ion pairing with the phosphate anion provides a suitable
chiral environment for subsequent enantioselective transformations
of the electrophilic species (11–13). The generality of the concept of
ion pair catalysis has allowed the application of these highly tunable
scaffolds to a diverse range of transformations in which carbonyl or
imine activation is clearly inapplicable (15–17). As part of both
aforementioned modes of reactivity, hydrogen bonds between chiral
phosphoric acids or phosphate anions and reacting functionality are
often invoked as crucial interactions for achieving high levels of
enantioselectivity (11–14). We speculated that hydrogen-bonding
interactions with substrate functionality may play a key role, via
transition state organization, even when the interacting functionality
does not directly participate in the transformation. We saw an
Author contributions: J.W., V.R., R.J.P., and F.D.T. designed research; J.W., Y.-M.W., A.D.,
V.R., and R.J.P. performed research; J.W., Y.-M.W., A.D., V.R., R.J.P., and F.D.T. analyzed
data; and J.W., Y.-M.W., and F.D.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and X-ray structures have been deposited in the
Cambridge Structural Database, Cambridge Crystallographic Data Centre, Cambridge CB2
1EZ, United Kingdom (CSD reference nos. 927904, 927905, and 947493).
1To whom correspondence should be addressed. E-mail: fdtoste@berkeley.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1304346110/-/DCSupplemental.
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Fig. 2. A source of electrophilic fluorine soluble in hydrophobic nonpolar
solvents, via solid–liquid phase transfer. Both solubility and chirality are
imparted by the organophosphate catalyst ion paired with the positively
charged 1,4-diazabicyclo[2.2.2]octane-fluorine moiety.
our hypothesis that a hydrogen bond donor is required to direct
the fluorination, the N-methylated analog of 1a was unreactive
(<10% conversion) under otherwise identical conditions. Fur-
thermore, homoallylic amide 1a′ reacted to deliver allylic fluo-
ride 1b′ in only 12% ee, suggesting that there is a distance
requirement for the directing group (Table 1, Entry 6). We
considered several possible pathways in which 1b could form
from 1a (Fig. 3). We first considered the possibility that allylic
fluoride 1b formed from E2 elimination of initially formed
cyclization product 1c (Fig. 3A). However, subjecting 1c to
standard reaction conditions did not result in the formation
of 1b.
We next considered the possibility that a carbocationic in-
termediate could be formed upon initial fluorination, followed
by loss of a proton to generate 1b (Fig. 3B). Indeed, previous
studies of the kinetics of Selectfluor-mediated fluorofunction-
alization of alkenes in polar solvents supported a stepwise
mechanism involving the rate-determining formation of a fluo-
rocarbocation, followed by rapid nucleophilic trapping (35).
Fig. 1. (A and B) Modes of reactivity in chiral phosphoric acid/phosphate
anion chemistry. (C and D) Substrate–catalyst interactions in directed allylic
alkene functionalizations. (E and F) Chiral phosphate anions in directed
asymmetric transformations.
of the desired allylic fluoride (Table 1, Entry 3) (34). The crystal
structure of STRIP confirms earlier suggestions that it may have
a tighter binding pocket than TRIP, which may in turn contribute
to the enhanced enantioselectivities observed for some systems.
Interestingly, under homogeneous conditions (MeCN), cycli-
zation product 1c predominates, regardless of the presence of
catalyst 3, illustrating the unique reactivity achievable under
anionic phase transfer conditions (Table 1, Entries 4 and 5).
A few experiments and observations allowed us to gain some
insight into the mechanism of this transformation. In accord with
Table 1. Optimization of product distribution and enantioselectivity
Entry
n
1
1
1
1
1
2
Catalyst
(S)-2
(S)-2
(R)-3
(R)-3
None
(R)-3
Solvent
PhF
1b:1c
5:1
% ee 1b or 1b (% ee 1c)
1
2
3
4
5
6
85 (48)
89
PhMe
PhMe
MeCN
MeCN
PhMe
8:1
10:1
1:4
90
0
1:4
—
—
12
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Wu et al.

was observed with increased steric bulk (t-Bu > i-Pr > Me;
Table 2, Entries 1–3). Identical enantioselectivities were achieved
with CH3 and CHF2 substrates (Table 2, Entries 1 and 5). It
was, however, observed that one additional fluorine increased
enantioselectivity dramatically (Table 2, Entry 5 vs. Entry 6).
This may be due to a conformation attained with rotation of
the CHF2 group to minimize steric interactions that is not
possible with the larger CF3 group. In line with this proposal,
an increase in size to CCl3, constituting a trichloroacetamide
(TCA) group, improved enantioselectivity to 93% ee. Thus,
both steric and electronic parameters affect enantioselectivity,
although steric factors may be more important. More substantial
changes such as the use of the more electron-withdrawing p-
toluenesulfonamide as the directing group provided product with
67% conversion by NMR analysis and only 18% ee. In addition to
being highly efficient for the desired transformation, the TCA
group was readily hydrolyzed with potassium hydroxide to provide
free amine in 90% yield with no racemization of the fluorinated
stereocenter, thus allowing access to primary β-fluoroamines and
Fig. 3. (A–C) Possible mechanisms for the formation of allylic fluoride 1b
from substrate 1a.
On the basis of these studies, if a stepwise mechanism were
operative in the allylic fluorination reaction, the formation of
the fluorocarbocation intermediate would be expected to be rate
determining as well, especially considering the low polarity of the
reaction medium (toluene). Under this scenario the fluorination
step would also be enantiodetermining, and products 1b and 1c
should be formed with the same level of enantioselectivity.
However, the observed enantioselectivity of the cyclization product
(1c) is considerably lower (48% ee) than that of the allylic fluoride
(1b, 85% ee; Table 1, Entry 1). This observation suggests that
fluorination to give 1b is unlikely to take place through a step-
wise fluorination–deprotonation mechanism. Therefore, we
propose that this transformation most likely occurs through a
concerted process in which fluorination and loss of proton, po-
tentially assisted by the phosphate catalyst or substrate amide,
occur in the same step (Fig. 3C).
We anticipated that better understanding of the properties
required for an effective DG would aid in identification of a
readily cleaved amide DG. Thus, investigations of the impact of
steric and electronic changes to amide DGs on enantioselectivity
were performed (Table 2). Halogenated acetyl derivatives pro-
vided insight into the influence of changing electronegativity,
whereas alkyl derivatives revealed the effect of electronically
negligible changes in steric bulk. Increased enantioselectivity
Table 2. Studies on electronic and steric factors using amide
DGs
Entry
1
R =
% ee
30
2
3
4
51
75
92
5
6
7
30
82
93
Fig. 4. Scope of amide DG substrates. a, reaction run at room temperature;
b, product isolated with cyclized by-product in 10:1 ratio; c, reaction run for
36 h; d, all stereochemistry defined in analogy to compound 14b (see SI
Appendix for crystallography details).
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Fig. 6. (A–C) Further reactions with fluorinated products.
Fig. 5. 2-Hydroxyphenyl DG effective for various alkenes. a, Selectfluor
(1.35 eq), Na2CO3 (1.45 eq), (R)-STRIP (0.1 eq), tol, rt, 18 h; b, reaction run for
36 h; c, catalyst A (39) used instead of (R)-STRIP.
hydrogen bonding with the catalysts. We anticipate that the
enantioselective construction of both β-amino and β-aryl sp3-C-F
bonds will be valuable in drug discovery (38).
potential derivatives not necessarily containing the DGs presented
here (see Fig. 6A).
Our previously reported electrophilic bromination reagent
22 (19) could be used to further functionalize the product
from the title reaction via bromocyclization. This reaction
shows the capability of chiral anion phase-transfer catalysis
to operate sequentially in one pot to facilitate orthogonal
reactions through the use of reagents with differing reactivity.
Although Selectfluor did not further react with fluorination
product 8b, it was found that bromocyclization of 8b took
place in the presence of reagent 22 under phase-transfer
conditions. With phase-transfer bromination verified step-
wise, 8a was subjected to the standard fluorination conditions
for 18 h (“F+”), followed by addition of 22 (“Br+”) and base.
(This was operationally simple: The cap to the vial was opened
and 22 was added without exclusion of air.) Gratifyingly, indeno-
1,3-oxazine 20 formed in good yield and high diastereo- and
enantioselectivity with the creation of two adjacent stereocenters
and two carbon–halogen bonds. Heterocyclic substrate 14a also
underwent fluorination with high selectivity, providing highly
functionalized tricyclic product 21 (Fig. 6).
A catalytic, enantioselective direct fluorination of alkenes to
provide a variety of β-amino and β-phenolic allylic fluorides
has been presented. The utilization of solid–liquid chiral anion
phase-transfer catalysis and the implementation of DGs were
instrumental to achieving enantioselectivity. More generally, the
ability of chiral phosphate anions to interact with the cationic
electrophiles and with the substrate DGs through hydrogen
bonding offers the potential to greatly expand the scope of elec-
trophilic alkene functionalization reactions.
In addition to the studies described above, substrates with
different ring sizes, benzamide substitution patterns, substitu-
tions on the bicyclic core, and heterocyclic substrates were ex-
amined (Fig. 4). With modifications to dihydronaphthalene-
derived substrate 5a, we found that both 3,5- and 4-position
substitution patterns of strongly electron-withdrawing groups
on the benzamide were well tolerated (Fig. 4, Entries 6 and 7).
Good yields and high enantioselectivities were maintained with
benzosuberene- and indene-derived substrates, allowing access
to a variety of ring sizes (Fig. 4, Entries 3 and 4). Neither elec-
tron-withdrawing nor electron-donating groups present on the
fused benzene ring resulted in diminished enantioselectivity,
(Fig. 4, Entries 8 and 10). Fluorination of chromanone-
derived heterocyclic substrates 9a and 14a proceeded with
good yield and high enantioselectivity (96% ee and 97% ee,
respectively).
In addition to amides, 2-hydroxyphenyl was found to be a suit-
able DG to promote enantioselective fluorination of a variety of
alkenes under similar reaction conditions (Fig. 5). We had re-
cently seen phenol act as a competent hydrogen-bond donor in
enantioselective fluorinative dearomatization reactions (36). In
the examples shown here we observe that increased substitution
on the alkene changes the chemoselectivity, and fluorination on
the alkene is seen exclusively rather than fluorination of the
phenol, as in our previous studies. Both β-phenolic tertiary and
quaternary fluorides with alkyl, aryl, or heteroaryl substituents
were obtained with good to high enantioselectivity. Further,
fluorinated piperidine product 19b can be obtained in moderate
yield and enantioselectivity—a facile synthesis of a fluorinated
scaffold that has been previously shown to be a privileged core of
various biologically active compounds (37). In agreement with
previous results, conversion was severely diminished (<10%)
when the phenol group was methylated, presumably due to the
inability of the methyl ether moiety to effectively participate in
ACKNOWLEDGMENTS. We thank Natalja Früh and Hunter Shunatona for
synthesis of some intermediate materials. We thank William J. Wolf for obtain-
ing X-ray crystallographic data for 3. We thank the University of California for
financial support. Y.-M.W. thanks Amgen for a graduate fellowship and
R.J.P. thanks the European Commission for a Marie Curie International
Outgoing Fellowship.
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