Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents

Article abstract of DOI:10.1021/jacs.8b04902

A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C-F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross-coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation.

Full text of DOI:10.1021/jacs.8b04902

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Copper-Catalyzed Defluoroalkylation Using
Arylboronate-Activated Alkyl Grignard Reagents
Minyan Wang, Xinghui Pu, Yunfei Zhao, Panpan Wang, Zexian Li, Chendan Zhu, and Zhuangzhi Shi*
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed system has been
introduced for the enantioselective defluoroalkylation of
linear 1-(trifluoromethyl)alkenes through C−F activation
to synthesize various gem-difluoroalkenes as carbonyl
mimics. For the first time, arylboronate-activated alkyl
Grignard reagents were uncovered in this cross-coupling
reaction. Mechanistic studies confirmed that the tetraor-
ganoborate complexes generated in situ were the key
reactive species for this transformation.
odern drug discovery relies on improvements in
Mchemical synthesis to address the many challenges
that result from the design of new pharmaceutical agents. One
such challenge arises from the presence of important but
sensitive functional groups in pharmaceutical compounds, such
as carbonyl moieties,1 which are easily reduced to the
corresponding alcohols during phase I metabolism by
mammalian NAD(P)H-dependent reductases leading to
diminished bioavailability.2 gem-Difluoroalkenes have emerged
as a useful carbonyl mimic that has steric and electronic
profiles that are similar to those of ketones, aldehydes, and
esters, and consequently, they have been used extensively as
carbonyl isosteres.3 Therefore, a commonly used synthetic
Figure 1. Development of an enantioselective defluoroalkylation
protocol to construct gem-difluoroalkene carbonyl mimics.
strategy to prevent in vivo metabolism involves the
replacement of a carbonyl in drug candidates with the
corresponding gem-difluoroalkene moiety.4 For instance, gem-
enantioselectivity in defluorinative functionalization still
remains a challenge.13 To the best of our knowledge, the
corresponding defluoroalkylation reaction has not been
difluoromethylene−artemisinins have been designed to mimic
artemisinin and show better antimalarial activity.5 Further-
more, this motif has proved beneficial in diverse downstream
transformations; thus, rapid the construction of various novel
gem-difluoromethylene−artemisinin derivatives is an attractive
target (Figure 1a).6 Typically, the α-position of a gem-
difluoromethylene substituent on a drug candidate is an
alkyl-substituted chiral carbon center.7 In this context, various
strategies that can access gem-difluoroalkenes have been
actively pursued, and some elegant methods for the formation
of alkyl-substituted gem-difluoroalkenes have been reported.6,8
Defluorinative alkylation9 of α-trifluoromethyl alkenes is one
of the most promising processes owing to the ready availability
of substrates10 as well as the high efficiency of the reactions.
This transformation historically requires the addition of carbon
(RLi or RMgBr) nucleophiles in an SN2′ manner through the
cleavage of a C−F bond.11 Very recently, a catalytic variant was
developed by using a photocatalyst in conjunction with alkyl-
radical precursors (Figure 1b).12 However, control over the
developed. Here, we report a mild and operationally simple
strategy for a copper-catalyzed enantioselective defluoroalky-
lation of linear 1-trifluoromethyl alkenes using commercially
available alkyl Grignard reagents (Figure 1c). Organoboronate-
derived “ate” complexes14 with alkyl Grignard reagents or
alkyllithium reagents have been widely applied in transition-
metal-catalyzed cross-coupling reactions in which an aryl group
is usually the coupling partner (Figure 1d).8a,15 Remarkably,
the key to our success is the discovery of the reactivity of
arylboronate-activated alkyl Grignard reagents.
To begin our studies, we chose (E)-4-(3,3,3-trifluoroprop-1-
en-1-yl)-1,1′-biphenyl (1a) and EtMgBr (2a) as the model
substrates (Table 1). In presence of 7 mol % CuTc, 8 mol %
NHC ligand L1, and 20 mol % NaOtBu at room temperature
Received: May 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b04902
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Reaction Development
Table 2. Substrate Scope
b
c
entry
[Cu]
base
activator
L*
ee (%)
yield (%)
1
2
3
4
5
6
7
8
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuBr
CuBr
CuBr
CuBr
CuBr
−
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOPh
−
−
−
−
−
−
−
−
−
−
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
10
2
30
18
0
58
42
51
32
82
23
52
7
2
44
49
52
83
90
92
92
0
9
12
50
62
10
11
12
13
14
PhBpin
PhBnep
PhBnep
PhBnep
−
d
90 (87)
15
0
NaOMe
a
Reaction conditions: 7 mol % [Cu], 8 mol % NHC ligand, 20 mol %
base, 1a (0.20 mmol), 2a (0.60 mmol), activator (0.20 mmol) in 1
b
mL of toluene for 24 h under argon. Enantiomeric excesses were
c
determined by chiral HPLC analysis. Yields were determined by GC
d
analysis. Isolated yield. PhBpin = phenylboronic acid pinacol ester;
PhBnep = phenylboronic acid neopentyl glycol ester.
under an argon atmosphere in toluene, defluoroalkylation
product 3aa was generated in 58% yield with 10% ee (entry 1).
To improve the result, we evaluated various ligands, but only
NHC-type ligands were effective (entries 2−8). Among the
tested ligands, bidentate NHC ligand L816 provided the best
enantioselectivity (7% yield, 49% ee, entry 8). A range of
copper salts were also tested, and CuBr afforded the best yield
and enantioselectivity (12% yield, 52% ee, entry 9).
Interestingly, the reaction efficacy was enhanced by the
addition of PhBpin as an activator, which provided the desired
product in 50% yield and 83% ee (entry 10). The enantiomeric
excess of 3aa could be increased to a high level by using
PhBnep as the activator (62%, 90% ee, entry 11). Under these
conditions, using a catalytic amount of NaOPh as the base
increased the yield to 90% with 92% ee, and no
defluoroarylation byproduct was detected (entry 12). Finally,
control experiments revealed that in the absence of base, the
yield dramatically decreased (entry 13), and the reaction was
unsuccessful using 2a directly (entry 14).
With the optimized reaction conditions in hand, we first
examined the scope of this defluoroalkylation reaction. Cross-
coupling reactions of EtMgBr (2a) with a broad range of 1-
(trifluoromethyl)alkenes 1 were examined (Table 2). In most
cases, this novel defluoroalkylation reaction proceeded
efficiently to give the corresponding gem-difluoroalkenes in
moderate to good yields with excellent enantioselectivities.
Ortho-substituted substrates 1g lead to the best results (3ga,
a
Reaction conditions: 7 mol % CuBr, 8 mol % L8, 20 mol % PhONa,
1a (0.20 mmol), 2a (0.60 mmol), PhBnep (0.20 mmol) in 2 mL of
toluene, at room temperature, 24 h, under argon; Isolated yields with
b
c
ee values were determined by chiral HPLC. At 0 °C. Using 10 mol
% CuBr and 12 mol % L8.
91%, 95% ee), suggesting that the increased steric congestion
does not impair the reactivity. Notably, the chemoselectivity of
the chiral copper catalyst was not affected by halo substituents,
such as Cl and Br, on the substrates (3ia−3na), highlighting
the potential uses of this process in combination with further
conventional cross-coupling transformations. Naphthalene-
containing substrates were also well-tolerated in the present
reaction conditions, and they afforded products 3oa−3pa in
73−78% yields and 89−93% ees. Notably, the couplings of
substrates with heterocyclic aromatic motifs like benzofuran
(1q), benzo[b]thiophene (1r), and even isoquinoline (1s)
were also tolerable and afforded 3qa−3sa in 88−99% ees. To
B
DOI: 10.1021/jacs.8b04902
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Journal of the American Chemical Society
Communication
further explore functional group compatibility of this method,
an additive-based robustness screen was also performed.17
We next examined the scope of this defluoroalkylation
process with respect to the Grignard reagents. Grignard
reagents possessing longer (3ab−3ad) alkyl chains also
resulted in excellent enantioselectivity. However, the enantio-
selective defluoroalkylation with MeMgBr failed (not shown in
phenylboroxine with Et2Zn in toluene (Figure 2b).21 With the
increase of EtMgBr, the 11B NMR spectrum showed three
i
the table). Bulky Grignard reagents, such as PrMgBr (3ae,
c
96%, 96% ee) and PentMgBr (3af, 73%, 92% ee), also
provided good results under these conditions. Unfortunately,
t
hindered BuMgCl only generated product 3ag in low yield.
This defluoroalkylation process is not only limited to
(het)aryl-substituted trifluoromethylalkenes, alkyl-substituted
substrate 4 was also effective and provided desired product 5 in
80% yield and 83% ee (Scheme 1a). The bulky substituent
a
Scheme 1. Further Investigations
Figure 2. 11B NMR studies of the reaction intermediates.
peaks at −12, −14, and −16 ppm, consistent with
tetraorganoborate anions21a such as [BEt4]− and [BPhEt3]−
with different counterion, most likely [BrMg(solv)x]+ (Figure
2c). Addition of the rest of the reaction components to this
1B/3Mg mixture immediately lead a decrease in the intensity
of the signal at −14 and −16 ppm (Figure 2d). At the end of
the reaction (∼10 h), the signals at −16 and −14 ppm in the
11B NMR spectrum almost vanish and the intensity of the
signal of Et3B increases while that of the peak at −12 ppm
remains constant (Figure 2e). To further clarify the role of
these formed boronate complexes, we tried to synthesize these
compounds separately. Interestingly, performing the reaction
of Et3B and PhMgBr (1:1) formed a boronate probably with
[BPhEt3]− species, consistent with the left peak at −12 ppm
(Figure 2f). After addition of 1.0 equiv EtMgBr to the above
system, the middle and right peaks increased, indicating these
two compounds should contain [BEt4]− anion or related
structure (Figure 2g). Pleasingly, the mixture of EtBnep and
EtMgBr (1:3) only generated the boronate at −16 ppm,
confirming our speculation (Figure 2h). Finally, this boronate
mixture with a different proportion of each component
compared to 1B/3Mg could also be produced from a
pregenerated PhBEt2 and EtMgBr (Figure 2i).
We found the reaction efficacy was closely related to the
boronate complexes at −14 and −16 ppm. As shown in
Scheme 2, the use of Et3B as ethyl source did not work (entry
1) and the combination of Et3B and PhMgBr only gave the
desired product 3aa in trace amount (entry 2). As long as the
mixture contains the compound at −14 and/or −16 ppm
(Figure 2g−i), excellent enantioselectivities in the product 3aa
were observed in which the more the coupling components,
the higher the yield that could be detected (entries 3−5).
Notably, reducing the proportion of PhBnep to 0.5 equiv only
led to a slightly lower yield and ee (entry 6), however,
employing 0.2 equiv or 1.5 equiv PhBnep in our reaction
affected the result dramatically (entries 7−8).
a
For details, see Supporting Information.
adjacent to the olefin is crucial for the enantioselectivity of
products, and long alkyl chain substituted substrates lead to
dramatically decreased ee value.18 This method could be
applied to 1,3-diene substrate 6, which afforded chiral 1,4-
diene 7 in 51% yield and 93% ee with perfect regioselectivity.
Moreover, our preliminary experiments revealed that the
reaction between enyne 8 and Grignard reagent 2a could form
desired 1,1-difluoropenta-1,4-enyne 9 in 67% yield with 71%
ee. As shown in Scheme 1b, the reduction of the formed 3aa
with Red Al afforded E-fluoroalkene 10 as the major product.
Alternatively, utilizing our recently developed method of
copper-catalyzed hydrodefluorination of gem-difluoroalkenes
with water could afford Z-fluoroalkene 11 in 94% yield with no
erosion of the ee.19 The double bond in 3aa could be
hydrogenated to yield CF2H-substituted alkane12 in 84%
yield. Finally, cross-coupling of 3aa with excess methyl
Grignard reagent, MeMgBr, proceeded in the presence of a
nickel catalyst to provide methylation product 13 in high yield.
With a series of experiments, we investigated the pivotal role
of the activator. As demonstrated by 11B NMR, the 2:1 ratio of
PhBnep (δ = 27 ppm) and EtMgBr in toluene generated two
new compounds confirmed as Et3B (δ = 87 ppm) and PhBEt2
(δ = 78 ppm)20 in line with B−Zn transmetalation of
On the basis of the above experimental results, a possible
mechanism has been proposed as shown in Figure 3. Similar to
the known process of boron-to-zinc transmetalation,21 the B−
Mg transmetalation between PhBnep and EtMgBr can form
EtBnep (I) and PhMgBr along with a byproduct PhBEt2 (II).
C
DOI: 10.1021/jacs.8b04902
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Journal of the American Chemical Society
Communication
a
Scheme 2. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b04902.
■
S
Experimental procedures, characterization data, and
spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*shiz@nju.edu.cn
■
ORCID
Zhuangzhi Shi: 0000-0003-4571-4413
Notes
a
For details, see Supporting Information.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the “1000-Youth Talents Plan”, the National Natural
Science Foundation of China (grant 2167020084), and the
National Natural Science Foundation of Jiangsu Province
(grant BK20170632) for their financial supports.
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