Palladium-Catalyzed Enantioselective 1,1-Fluoroarylation of Aminoalkenes

Article abstract of DOI:10.1021/jacs.5b07795

The development of an enantioselective palladium-catalyzed 1,1-fluoroarylation of unactivated aminoalkenes is described. The reaction uses arylboronic acids as the arene source and Selectfluor as the fluorine source to generate benzylic fluorides in good yields with excellent enantioselectivities. This transformation, likely proceeding through an oxidative Heck mechanism, affords 1,1-difunctionalized alkene products.

Full text of DOI:10.1021/jacs.5b07795

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Enantioselective 1,1-Fluoroarylation
of Aminoalkenes
Ying He,†,‡,§ Zhenyu Yang,†,§ Richard T. Thornbury,† and F. Dean Toste*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Institute of Chemistry and BioMedical Science, Nanjing University, Nanjing 210046, China
S
* Supporting Information
alkenes with arylstannanes (Figure 1b) in the absence of a
directing group on the alkene.13 Inspired by these reports, we
have developed a catalytic enantioselective 1,1-arylfluorination
of alkenes with arylboronic acids and Selectfluor (Figure 1c).
On the basis of the interest in fluorine-containing amines,14
we began our investigation by examining the fluoroarylation
of protected allylamine 1a with phenylboronic acid (2a). Using
these substrates, conditions similar to those previously em-
ployed in the 1,2-fluoroarylation of styrenes10 afforded
the 1,1-fluoroarylation product 3a, albeit with moderate yield
(Table 1, entry 1). Notably, the product derived from the
ABSTRACT: The development of an enantioselective
palladium-catalyzed 1,1-fluoroarylation of unactivated amino-
alkenes is described. The reaction uses arylboronic acids as
the arene source and Selectfluor as the fluorine source to
generate benzylic fluorides in good yields with excellent
enantioselectivities. This transformation, likely proceeding
through an oxidative Heck mechanism, affords 1,1-
difunctionalized alkene products.
he unique properties engendered by fluorine1 have in-
Tspired a number of strategies for the enantioselective con-
struction of C−F bonds employing either electrophilic or
nucleophilic fluorine sources.2−5 The difunctionalization of
alkenes has emerged as an attractive strategy for the simul-
taneous formation of C−F and C−X (X = C, N, P, etc.)
bonds.6,7 However, while great progress has been made in
fluorocyclization of alkenes,8 intermolecular difunctionalization
of alkenes as a means for enantioselective construction of
C−F bonds remains challenging.9 We recently reported a
palladium-catalyzed asymmetric 1,2-fluoroarylation of styrenes
with boronic acids and Selectfluor as the fluorine source
(Figure 1a).10 Key to this transformation was the placement of
a
Table 1. Selected Optimization of Reaction Conditions
b
entry
variation from “standard conditions”
yield (%)
1
2
3
4
5
6
7
8
9
none
50
44
2,2′-bipyridine as ligand
NFSI instead of Selectfluor
Ts instead of Ns in 1a
Mbs instead of Ns in 1a
Ms instead of Ns in 1a
no water
trace
44
40
42
no catalyst or no ligand
MeCN (0.1 mL) as additive
c
75
a
Reaction conditions: all reactions were run on 0.1 mmol scale with
respect to 1a. Ligand: 4,4′-ditert-butyl-2,2′-bipyridine; CH2Cl2, 1.0 mL;
b
H2O, 0.2 mL. 1H NMR yield using 1,3,5-trimethoxybenzene as
c
internal standard. Isolated yield. Ns = 4-nitrobenzenesulfonyl, Ts =
4-methylbenzenesulfonyl, Mbs =4-methoxybenzenesulfonyl, Ms =
methanesulfonyl.
1,2-fluoroarylation of 1a was not observed.15 Encouraged by
this discovery, we set out to further optimize the reaction con-
ditions. Modification of the ligand afforded little change in the
yield (Table 1, entry 2). The use of N-fluorobenzenesulfoni-
mide (NFSI) as an alternative source of fluorine resulted in
only trace yield of 3a (Table 1, entry 3). Changing the nitrogen
protecting group did not have a dramatic impact on the yield of
this transformation (Table 1, entries 4−6). No 1,1-fluoroary-
lated product was formed when water (Table 1, entry 7),
Figure 1. Pd-catalyzed arylhalogenation of alkenes.
a directing group on the alkene, which disfavored the oxidative
Heck reaction11 and allowed for C−F bond formation via a
high-valent palladium intermediate.12 In contrast, Sanford has
described the 1,2 or 1,1-arylchlorination/bromination of
Received: July 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b07795
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ligand, or palladium (Table 1, entry 8) were removed from the
reaction. However, the addition 0.1 mL of MeCN resulted in an
increase in yield to 75% (Table 1, entry 9).
Table 3. Selected Optimized Conditions of Enantioselective
1,1-Fluoroarylation
a
With the optimized conditions in hand, we investigated the
scope of the palladium-catalyzed 1,1-arylfluorination (Table 2).
b
% ee
c
a
Table 2. Substrate Scope
entry
Pd
ligand
solvent
nitrile
(yield )
1
2
3
4
5
6
7
8
9
Pd(OAc)2
L1
L1
L1
L1
L1
L2
L3
L1
L1
L1
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
(trace)
MeCN
iPrCN
BnCN
BnCN
BnCN
BnCN
66 (68%)
82
84
81
55
80
benzene/H2O BnCN
benzene/H2O BnCN
87
d
10
90 (46%)
a
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), Selectfluor
(0.3 mmol); Cat., 10 mol %; ligand, 13 mol %; solvent, 0.8 mL; H2O,
b
0.8 mL; nitrile, 0.1 mL; rt, 18 h. % ee determined by chiral HPLC.
c
d
1H NMR yields in parentheses. The reaction was carried out at 4 °C
for 18 h, isolated yield in parentheses.
In light of the described results, we investigated the enantio-
selective palladium-catalyzed 1,1-fluoroarylation. Selected opti-
mization studies are shown in Table 3 (for additional details,
see the Supporting Information). Both Pd(OAc)2 and
Pd(MeCN)2Cl2 gave disappointing results without added
nitrile (Table 3, entries 1 and 2); however, the reaction pro-
ceeded smoothly in the presence of acetonitrile as an additive,
affording γ-fluoroamine 3a in 68% yield and 66% ee (Table 3,
entry 3). On the basis of this initial result, examination of a
variety of nitriles (see Supporting Information for full details)
revealed that use of benzyl nitrile as an additive produced the
desired product with the highest enantioselectivity (Table 3,
entries 4 and 5). We then surveyed the effect of ligand, solvent,
and temperature on the reaction and found that the enantio-
meric excess of 3a was improved to 90% ee when using a
solvent mixture of benzene/water at 4 °C for 18 h (Table 3,
entries 6−10).17
The substrate scope of the enantioselective transformation
was explored under these optimized conditions. The reaction
tolerated substitution in both the para- and meta- positions of
the boronic acid coupling partner, producing the corresponding
fluoroamines in 86−91% ee (Table 4, 3a−3g, 3x). With respect
to the substitution at nitrogen, aniline-derived substrates bearing
electron-donating or electron-withdrawing groups at the para-
and meta- positions furnished the corresponding products in
good to excellent enantioselectivities (3j−3n, 3w). Addition-
ally, a heteroaryl group on nitrogen was also tolerated under the
enantioselective conditions, affording the 1,1-fluoroarylation
adduct 3u in 81% ee, albeit in 35% yield. Substrates with
O-methyl and alkyl groups on nitrogen also provided the
products in 81% ee to 84% ee (3q, 3r, and 3v); however, when
a longer chain alkene was used, the product (3t) was obtained
in 66% ee.
a
Reaction conditions: alkene (0.1 mmol), boronic acid (0.2 mmol),
Selectfluor, (0.2 mmol), ligand: 4,4′-ditert-butyl-2,2′-bipyridine; CH2Cl2,
1.0 mL; H2O, 0.2 mL; MeCN, 0.1 mL; yield of isolated products.
The reaction was amenable to halogen and alkyl substitution in
the para- and meta-positions of the arylboronic acids (3a−3h).
Additionally, the coupling of an arylboronic acid substituted
with an electron-withdrawing ester group afforded benzyl fluo-
ride 3i in 48% yield. With respect to the alkene scope, sub-
stitution at nitrogen with aryl moieties bearing either electron-
donating or electron-withdrawing groups in the para- or
meta- position was well tolerated (3j−3n). Notably, γ-fluoroamine
3l was also obtained in good yield, leaving the iodo group intact
for further transformations. Moreover, substrates derived
from hindered anilines proved competent in this transformation
(3o and 3p). The reaction was not limited to aniline derived
substrates. Substrates with alkyl, O-alkyl, and heteroaryl-
substitution at nitrogen also furnished the desired products in
good yields (3q, 3r, and 3u).
Use of a substrate derived from ( )-2-phenylglycine provided
the corresponding product in excellent yield and a modest
diastereomeric ratio (1.8:1) (3s). A longer chain alkene was
also effective in the 1,1-fluoroarylation reaction, affording the
desired δ-fluoroamine (3t) in 60% yield.16
To demonstrate potential application of these chiral benzylic
fluorides, removal of the nosyl group of 3a was carried out.
The deprotection proceeded smoothly at room temperature,
B
DOI: 10.1021/jacs.5b07795
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Journal of the American Chemical Society
Communication
Table 4. Substrate Scope of Enantioselective
1,1-Fluoroarylation
ACKNOWLEDGMENTS
■
ab18
We are grateful for financial support from the NIHGMS
(RO1 GM073932), the National Natural Science Foundation of
China (21332005), and Jiangsu Innovation Programs of China.
We gratefully acknowledge the College of Chemistry CheXray
(NIH Shared Instrumentation Grant No. S10-RR027172) and
Dr. Antonio DiPasquale for X-ray crystallographic data. We also
thank Andrew Neel for assistance with variable temperature
NMR experiments.
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In conclusion, we have disclosed a palladium-catalyzed
1,1-fluoroarylation of unactivated amino-alkenes by a three-
component coupling of alkenes, arylboronic acids, and
Selectfluor. Moreover, the reaction was extended to an asym-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b07795.
■
S
Crystallographic data (CIF)
Experimental procedures; compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
*fdtoste@berkeley.edu
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Author Contributions
§Y.H. and Z.-Y.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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Communication
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(15) The observance of no product derived from the 1,2-
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experiments (see Supporting Information).
(16) Substrates bearing longer methylene tethers (those derived from
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ylation adducts in low yield (<20%).
(17) The major byproduct in this case was the corresponding styrene
derived from an oxidative Heck reaction.
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(e.g., o-chlorophenyl and (o-tolyl)boronic acid) gave low yields of the
desired product under both the racemic and asymmetric reaction
conditions.
D
DOI: 10.1021/jacs.5b07795
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX