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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
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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