Enantioselective Palladium-Catalyzed Oxidative β,β-Fluoroarylation of α,β-Unsaturated Carbonyl Derivatives

Article abstract of DOI:10.1002/anie.201603046

The site-selective palladium-catalyzed three-component coupling of deactivated alkenes, arylboronic acids, and N-fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step-economical approach to the stereoselective β-fluorination of α,β-unsaturated systems.

Full text of DOI:10.1002/anie.201603046

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201603046
German Edition: DOI: 10.1002/ange.201603046
Synthetic Methods
Enantioselective Palladium-Catalyzed Oxidative b,b-Fluoroarylation
of a,b-Unsaturated Carbonyl Derivatives
Javier Mirꢀ, Carlos del Pozo,* F. Dean Toste,* and Santos Fustero*
Abstract: The site-selective palladium-catalyzed three-compo-
nent coupling of deactivated alkenes, arylboronic acids, and
N-fluorobenzenesulfonimide is disclosed herein. The devel-
oped methodology establishes a general, modular, and step-
economical approach to the stereoselective b-fluorination of
a,b-unsaturated systems.
nucleophilic or electrophilic fluorinating reagents (Fig-
ure 1a).[11] The enantioselective variant has recently been
achieved through a fluorinative semipinacol rearrangement
(Figure 1b).[12] Recently reported methods explored selective
[13]
[14]
À
À
C H (Figure 1c)
and C C (Figure 1d)
activation as
a means to guide C(sp3) fluorination.
F
luorine plays a decisive role in medicinal chemistry, having
led to remarkable breakthroughs in the field.[1] Despite its
widespread distribution in nature, the presence of fluorine in
natural organic molecules is scarce, and most of the fluorine-
containing organic molecules are synthetic.[2] Given this
perspective, the development of new methodologies which
gain access to new fluorinated derivatives is always in great
demand, particularly those enabling selective fluorination on
specified positions of an organic framework.
Among current strategies for the asymmetric construction
3
of C(sp ) F bonds,[3] a-fluorination of carbonyl derivatives is
À
the strategy most commonly exploited. Distinct approaches,
including organocatalysis,[4] chiral anion phase-transfer catal-
ysis,[5] ring-opening of strained heterocycles,[6] and transition-
metal-catalyzed fluorinations[7] have been devised. In the last
[8]
À
case, C F reductive elimination is usually accomplished
from high-valent electron-deficient species,[9] since fluoride,
as a hard base, is well suited for stabilizing highly oxidized
metal centers.[10]
While great progress has been made in the assembly of
C F bonds adjacent to an electron-withdrawing group, just
Figure 1. Strategies to access to b-fluorocarbonyl-derived systems.
DG=directing group, EWG=electron-withdrawing group, FG=func-
tional group, Tf=trifluoromethanesulfonyl.
À
a few protocols incorporating fluorine at the b-position of
a carbonyl derivative have been reported, and most of them
are racemic. Seminal contributions entailed prior installation
of a functional group, for example, alcohols, halides, sulfo-
nates, or boronates, and further conversion into the corre-
sponding b-fluorinated carbonyl compounds using either
On the basis of the limited reported oxidative transition-
metal-catalyzed fluorinations[9,15] and inspired by the latest
examples on palladium-catalyzed 1,1-difunctionaliza-
tions,[15b,16] we envisioned access b-fluorinated carbonyl
derivatives by a single-step three-component Heck aryla-
tion/oxidative fluorination cascade reaction (Figure 1e).
Under this scenario, we decided to test our hypothesis by
examining the fluoroarylation of ethyl acrylate (1a) with
4-tolylboronic acid (2a) as a model reaction, under reaction
conditions similar to those previously employed in the 1,2-
fluoroarylation of styrenes[15a] (Table 1). Thus, 1a was initially
treated with 2a (2 equiv), Pd(OAc)2 (15 mol%), 1,10-phe-
nanthroline (15 mol%), and 4-tBu-catechol (4 mol%) in
DCM/H2O using Selectfluor as the electrophilic fluorine
source. However, after 20 hours only trace amounts of the
ester 3a were detected, with the major product resulting from
[*] J. Mirꢀ, Dr. C. del Pozo, Prof. S. Fustero
Departamento de Quꢁmica Orgꢂnica, Universidad de Valencia
46100 Burjassot (Spain)
E-mail: carlos.pozo@uv.es
santos.fustero@uv.es
Prof. F. D. Toste
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
E-mail: fdtoste@berkeley.edu
Prof. S. Fustero
Laboratorio de Molꢃculas Orgꢂnicas
Centro de Investigaciꢀn Prꢁncipe Felipe
46012 Valencia (Spain)
the undesired competing oxidative Heck reaction (entry 1).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201603046.
+
À
Pleasantly, switching the (N F) source to NFSI had a dra-
matic effect, thus giving rise to the exclusive formation of 3a
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Table 1: Optimization of the reaction conditions.
Entry
Variant conditions
Yield [%]
+
À
1
2
3
4
5
6
(N F) =Selectfluor
À
trace
95
–
–
–
+
(N F) =NFSI
without degassing
without water
without 1,10-phenanthroline
without 4-tBu-catechol
trace
[a] Reaction conditions: all reactions were run on 0.055 mmol scale with
respect to 1a. [b] Yields determined by 19F NMR spectroscopy by
utilizing fluorobenzene as internal standard. DCM=dichloromethane,
NFSI=N-fluorobenzenesulfonimide.
in high yield (entry 2), with complete exclusion of styrene
formation. Notably, degassing of the system was necessary to
avoid oxidation of the boronic coupling partner (entry 3).
Moreover, the reaction did not proceed in the absence of
water (entry 4). Likewise, the presence of both a bipyridine-
type ligand (entry 5), and a radical scavenger to preclude
alternative radical pathways involving the arylboronic acid
(entry 6), was critical to access the fluorinative reaction
manifold.[17]
Scheme 1. Substrate scope for the non-enantioselective process. Reac-
tion conditions: alkene (0.11 mmol), boronic acid (0.22 mmol), NFSI
(0.22 mmol); Pd(OAc)2/1,10-phenanthroline (15 mol%); DCM,
1.4 mL; H2O, 0.14 mL; RT, 20 h. Yield determined by 19F NMR spectros-
copy by utilizing fluorobenzene as an internal standard. Yield of
isolated product given within parentheses. [a] Yield after two steps:
1) b,b-fluoroarylation of 1 f and 2) reduction of 3 f. See the Supporting
Information. PMP=p-methoxyphenyl.
With these optimized reaction conditions, the scope of the
b,b-fluoroarylation protocol was evaluated (Scheme 1). We
were pleased to observe that under optimized reaction
conditions acrylic esters, amides, and ketones smoothly
provided the racemic b-fluoro derivatives 3a–d in good to
excellent yields.[18] Nevertheless, acrylic acid furnished the
benzylic fluoride 3e in diminished yield, despite increasing
the number of equivalents of arylboronic acid. Diminished
yields obtained for methyl vinyl ketone (3c) offers an
interesting mechanistic insight into the reaction manifold.
We hypothesized that this result was an indication of the
likely role displayed by the chelating carbonyl group prompt-
ing insertion while backing up the stabilization of the
palladium intermediate species. In agreement with this
hypothesis, the highly activated 4-methoxyphenyl vinyl
ketone 1d afforded 3d in a satisfactory 84% yield. The
Weinreb amide 1 f underwent smooth b,b-fluoroarylation in
98% yield. This result, besides widening the scope with
respect to the ketones, indirectly opens access to aldehyde
derivatives (3g) and, in turn, to over-reduced 3,3-fluoroaryl
alcohols.[19] In contrast, the use of a nitrile-substituted
substrate provided the g-fluoronitrile 3h in modest yield,
but the nitrile moiety had to be placed in a more distant
position. The a-substituted ethyl methacrylate 1i provided
the corresponding product 3i in good yield and modest
diastereoselectivity, but b-substituents were not tolerated.
Having achieved proof-of-principle for the b,b-fluoro-
arylation reaction, the enantioselective version was examined
next. To this end, we undertook the evaluation of a range of
various bidentate diimine chiral ligands (see the Supporting
Information). Among them, BOX 1 and PyrOX 1 were
identified as the most encouraging ligands for acrylates and
acrylamides, respectively. Attempts to increase the e.r. value
by cooling failed, but in a survey of the solvent effects,
coordinating solvents such as AcOEt, ROH, and acetone
were identified as superior in terms of enantioselectivity.
Nevertheless, the improvement in selectivity was reached at
the expense of yield, as previously observed in the reported
Heck–Matsuda arylation/Miyaura borylation cascade.[16d]
Finally, acetone and iPrOH were the solvents of choice for
esters and amides, respectively, providing a good compromise
in terms of selectivity and yield. Notably, the major byproduct
in the stereoselective reactions was the corresponding sty-
rene, that is, selected reaction conditions result in significant
termination by b-hydride elimination.
With the optimized reaction conditions in hand, a range of
boronic acids was tested (Scheme 2). To our delight the
desired b-fluoroesters and b-fluoroamides 3 were obtained in
synthetically useful yields and good enantiomeric ratios. As
shown in Scheme 2, this procedure was efficient with non-
electronically biased arylboronic acids. The b-fluorocarbonyls
3j and 3x were formed in 61 and 45% yield, respectively, thus
indicating that steric hindrance did not significantly impact
the reaction. Whereas steric effects did not have a deleterious
effect on the efficiency of the process, 3-substituted arylbor-
onic acids provided higher e.r. values. Electron-rich
4-methoxyphenylboronic acid gave trace amounts of the
desired product, most likely because of the general incom-
patibility of the anisole ring with strongly oxidative species
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Scheme 2. Scope of the enantioselective process. Reaction conditions: all reactions were run on 0.11 mmol scale with respect to alkene 1.
Enantiomeric ratio (e.r.) determined by chiral-phase HPLC. Yield determined by 19F NMR spectroscopy utilizing fluorobenzene as an internal
standard. Yield of isolated product within parentheses. [a] 0.04 M.
such as NFSI.[9b,20] The less activated 3-methoxyphenylbor-
onic acid afforded the desired products 3o and 3r in
comparably good yields and good e.r. values. In contrast,
highly deactivated arylboronic acids such as 4-CF3-phenyl-
boronic acid, failed to provide the desired b-fluorocarbonyl
adducts, but underwent the Heck coupling. Presumably,
electron-withdrawing substituents compromise the stability
of the proposed cationic p-benzyl palladium species D (see
Scheme 3), driving 1,1-difunctionalization. Additionally, the
reaction was amenable to halogen substitution (3l–n, 3q),
leaving chlorine, bromine, and even iodine[21] moieties intact
for further transformations. The protocol was also compatible
with heteroarylboronic acids, thus rendering product 3y in
46% yield and 88:12 e.r. Notably, the ester group did not have
a dramatic effect on the enantioselectivity (3p), thus provid-
ing good levels of stereoselectivity, also when more challeng-
ing steroid-derived acrylates (3t) were used. Molecular
complexity was also tolerated at the aryl coupling partner
(3u), thus showcasing that this chemistry may add to the
repertoire of late-stage functionalization methods and even to
the ready generation of fluoro bioconjugates (3v). Moreover,
the protocol was applicable to primary (3zx), secondary
(3zw), and tertiary amides (3 f). Notably, stereochemical
integrity of the products was preserved after several weeks of
storage at room temperature.[22] Moreover, when this protocol
was scaled up ten times, the catalytic charge (5 mol%) and
the amount of ArB(OH)2 (2.0 equiv) were reduced without
affecting either yields or e.r. values (3a, 3p).
A mechanistic proposal for this reaction is outlined in
Scheme 3. As noted above, the presence of a diimine ligand is
crucial for achieving the desired reaction manifold. An N,N-
ligated palladium(II) complex (A) is likely the catalytically
active species. Transmetalation with the arylboronic acid and
subsequent migratory insertion generates the b-arylated
a-palladium(II) intermediate C. Sequential b-hydride elimi-
nation and reinsertion steps yield the enantioenriched
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Acknowledgments
We gratefully thank the Spanish Ministerio de Economꢀa
y Competitividad (CTQ-2013-43310-P), Generalitat Valenci-
ana (GV/PrometeoII/2014/073), and the NIGMS (R01
GM073932) for financial support. J.M. thanks University of
Valencia for a predoctoral fellowship.
Keywords: alkenes · fluorine · palladium ·
reaction mechanisms · synthetic methods
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Scheme 4. Mechanistic experiments.
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Received: March 28, 2016
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Revised: April 30, 2016
Published online: && &&, &&&&
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J. Mirꢁ, C. del Pozo,* F. D. Toste,*
S. Fustero*
&&&& — &&&&
Enantioselective Palladium-Catalyzed
Oxidative b,b-Fluoroarylation of a,b-
Unsaturated Carbonyl Derivatives
Box in: A modular and step-economical
method for the direct b,b-fluoroarylation
of conjugated carbonyl derivatives is
reported. This approach provides access
to a range of enantioenriched b-fluori-
nated carbonyl derivatives in good yields.
BOX=bis(oxazoline), PyrOX=pyridine
oxazoline.
6
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