Dual Nickel- And Photoredox-Catalyzed Reductive Cross-Coupling to Access Chiral Trifluoromethylated Alkanes

Article abstract of DOI:10.1021/acs.orglett.1c01420

A dual nickel/photoredox-catalyzed enantioselective reductive cross-coupling of aryl halides with CF3-substituted racemic alkyl electrophiles has been established. The approach accommodates a broad palette of aryl iodides and alkyl bromides to access a va

Full text of DOI:10.1021/acs.orglett.1c01420

pubs.acs.org/OrgLett
Letter
Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling to
Access Chiral Trifluoromethylated Alkanes
Pan Zhou, Xinxuan Li, Dong Wang, and Tao XU*
Cite This: Org. Lett. 2021, 23, 4683−4687
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ABSTRACT: A dual nickel/photoredox-catalyzed enantioselective reductive
cross-coupling of aryl halides with CF3-substituted racemic alkyl electrophiles
has been established. The approach accommodates a broad palette of aryl
iodides and alkyl bromides to access a variety of chiral CF3-containing
compounds. The exceptionally mild conditions (visible light, ambient
temperature, no strong base) and no need for Grignard reagents or
stoichiometric metallic reductants provide this transformation huge potential
in the application of the late-stage functionalization of complex molecules.
iven that the incorporation of the trifluoromethyl (CF3)
group into biologically active molecules in pharmaceut-
using nickel catalysis to generate the benzylic chiral C−CF3
bond. In addition, an enantioselective palladium-catalyzed
coupling of aryl halides with an in-situ-generated α-
trifluoromethylated alkylsilver species was reported by Zhang’s
group to deliver chiral CF3-bearing molecules.8 Despite these
advances, these works usually focused on the premade or in-
situ-formed air-sensitive organometallic reagents, thus com-
monly limiting the substrate scopes and the functional group
tolerance. To address these issues, the reductive cross-coupling
of two easily available electrophiles would provide a convenient
route.9 As part of our ongoing research interest in the dual Ni/
photoredox-catalyzed reductive cross-coupling (RCC) reac-
tions,10 we speculated if this mild condition could be applied in
this chiral C−CF3 bond construction. Very recently, when this
work was almost finished, the Wang group reported an elegant
asymmetric RCC trifluoroalkylation of aryl iodides.11 How-
ever, this approach still relied on the use of stoichiometric
amounts of manganese reductant to compete for the catalytic
cycle. Thus efforts toward exploring alternative reducing agents
and novel catalytic systems are still highly beneficial to broaden
the utility of this RCC reaction.
G
ical and agricultural chemistry has a significant effect on their
properties,1 the exploration of trifluoromethylation reactions,
especially on the construction of chiral structures containing
C−CF3 bonds, has drawn much attention.2 Although many
achievements in asymmetric nucleophilic or electrophilic
trifluoromethylations have been made during the last several
decades, transition-metal-catalyzed cross-couplings of CF3-
substituted electrophiles with organometallic reagents also
represent one of the highly efficient and straightforward routes
(Scheme 1).3 Among them, arylzinc,4 arylboronic,5 arylsilyl,6
and aryltitanic7 reagents have been employed in succession as
partners with CF3-containing alkyl halides or pseudohalides
Scheme 1. Asymmetric Cross-Couplings to Access the
a
Chiral Benzylic CF3 Molecules
Visible-light-induced photoredox catalysis has been proven
to be a powerful tool in methodology development and organic
synthesis.12 In the past decade, the combination of photoredox
catalysis and transition-metal catalysts, termed as “metal-
laphotoredox”,13 has been an emerging mode to construct
carbon−carbon bonds and carbon−heteroatom bonds that
were unfeasible or difficult to achieve with a single catalytic
Received: April 26, 2021
Published: June 2, 2021
a
TM, transition-metal. PC, photoredox catalyst.
https://doi.org/10.1021/acs.orglett.1c01420
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4683−4687
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system.14 Although a number of asymmetric studies on such a
cooperative regime have been developed upon the cross-
couplings, especially with nickel, they are largely limited to
redox-neutral reactions.15 The dual nickel/photoredox-cata-
lyzed asymmetric reductive cross-coupling is still much less
observed.16 Recently, by this strategy, we demonstrated an
enantioselective RCC of aryl iodides with α-chloroboranes
under exceptionally mild conditions.10b Herein we would like
to facilitate this route further to create chiral CF3-bearing
molecules.
Initial exploration into this dual Ni/photoredox-catalyzed
process focused on using 1a as the sp2-hybridized electrophile
and racemic CF3-containing precursor 2a as another partner.
After a systematic evaluation of all of the reaction parameters,
product 3a was concertedly afforded in high yield with good
enantioselectivity under the conditions listed in entry 1 of
Table 1. The change of nickel catalyst to Ni(cod)2 or NiI2 led
to a lower yield but had no distinct influence on the
enantioselectivity (entries 2 and 3, Table 1). The ligand with
CF3 substitution on the aryl group (L2) gave only the product
with a decreased yield, highlighting the importance of the
electron property of the ligand (entry 4, Table 1). A higher
yield was observed but a lower enantioselectivity was given
with a dual chiral center ligand L3, whereas the popular
bis(oxazolines) ligand L4 afforded the benzyl CF3 product in
an obviously diminished yield (entries 5 and 6, Table 1). Other
photoredox catalysts only gave lower conversions (entries 7
and 8, Table 1). The further examination of several solvents
confirmed the best outcome with CPME (entries 9 and 10,
Table 1). The same conclusion regarding the Et3N selection
was also deduced after systematic tests with organic or
inorganic bases (entries 11 and 12, Table 1). Control
experiments in the absence of Hantzsch ester (HEH), Et3N,
nickel catalyst, photoredox 4CzIPN, or light resulted in no
detectable product formation (entries 13 and 14, Table 1),
strengthening the essential role of each of these components in
this asymmetric reductive cross-coupling process.
With the optimized conditions in hand, we investigated the
scopes of this dual nickel/photoredox-catalyzed reductive
cross-coupling (Scheme 2). In general, the aryl iodides with
either electron-donating or electron-withdrawing functional
groups on the meta and para positions can react smoothly to
give the corresponding products in moderate to high yields
with good enantioselectivities. The aryl bromide can also be
utilized as a partner to give the product in the same enantiomer
ratio and a bit lower yield (3a). A variety of versatile functional
groups that have great potential in the further transformation,
such as nitrile (3a), ester (3b), aldehyde (3c), and ketone (3d,
3e), were well tolerated in this RCC process. The sulfur-
containing group including thioether (3f) and sulfone (3g) in
the benzene ring did not influence the high yields and
enantioselectivities. The aryl iodides bearing an ether on the
para position could give the corresponding product without a
significant reduction in yield but a decreased er value (3h),
thus giving some insights into the electronic effect on this
transformation. In addition, the substrates processing a meta
substituent (3i−3l) as well as the multiple substituted
candidates (3m, 3n) can be employed to afford the chiral
CF3-containing products in undiminished yields and selectiv-
ity. When moving to the heterocyclic iodides, in an effort to
showcase the mild nature of this method, the reactions still
readily proceeded under the optimized conditions (3o, 3p).
Then, the method was applied to the α-trifluoromethyl
bromides for a further study of the scope of this dual-catalytic
regime (3q−3z). Identically, a diverse set of functional groups,
including ester (3q, 3r, 3u), amide (3s), alcohol (3t), alkyl
(3v), ether (3w), protected phenol (3x), thiazole (3y), and
ferrocene (3z), were tolerated. These results serve to highlight
the broad scope and high chemoselectivity of the current
method.
a
Table 1. Optimization Conditions
entry
changes
yield (%)
er
93:7
b
1
no change
82
2
using Ni(cod)2
45
93:7
3
using NiI2
50
91:9
4
5
L2 instead of L1
L3 instead of L1
6
98
88.5:11.5
91:9
6
L4 instead of L1
38
95:5
7
8
9
10
11
12
13
14
[Ir(dFCF3ppy)dtbbpy]PF6 as PC
Ru(bpy)3Cl2·6H2O as PC
TBME as solvent
46
n.d.
82
20
14
n.d.
n.d.
n.d.
93:7
To further illustrate the utility of this method, this dual
nickel/photoredox-catalyzed reductive cross-coupling was
applied for the rapid, late-stage modification of natural
products and drug molecules, which typically requires mild
reaction conditions and high functional-group tolerance. Aryl
iodides derived from drugs such as clofibrate (3aa) and
aniracetam (3bb) were transformed into the corresponding
chiral CF3-containing products with this strategy. The alkyl
bromides or aryl iodides bearing multiple stereocenters, such
as 3cc, a chiral L-menthol derivative, and 3dd, a steroidal
framework, were all amenable for this process. In addition, the
components (3ee−3gg) with an indomethacin skeleton
underwent smooth transformations as well. The successful
late-stage functionalization of these natural products and drugs,
many of which contain sensitive ester, amide, aryl chloride, and
92.5:7.5
94:6
92.5:7.5
DMA as solvent
DIPEA instead of Et3N
Na2CO3 instead of Et3N
no HEH/Et3N
no Ni/4CzIPN/light
a
Reaction conditions: 1a (0.15 mmol), 2a (0.1 mmol), NiBr2(DME)
(10 mol %), L1 (12 mol %), 4CzIPN (1 mol %), HEH (2 equiv),
Et3N (5 equiv), CPME (2 mL), blue LED lamp (30 W), room
temperature, 8−10 h. The yields were determined by GC with
ndodecane as an internal standard. The enantiomer ratio (er) values
b
were determined by HPLC. 75% isolated yield. CPME, cyclopentyl
t
methyl ether. TBME, butyl methyl ether. DIPEA, N,N-diisopropy-
lethylamine.
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a
Scheme 2. Scopes of Dual Ni/Photoredox-Catalyzed Reductive Cross-Coupling
a
Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), NiBr2(DME) (10 mol %), L1 (12 mol %), 4CzIPN (1 mol %), HEH (2 equiv), Et3N (5
equiv), CPME (4 mL), blue LED lamp (30 W), room temperature, 8−10 h. Isolated yields are given. The er values were determined by HPLC.
b
c
d
Reaction on a 1 mmol scale gave the product in 68% yield (93:7 er). 4-Bromobenzonitrile was utilized. Compounds 1 (0.2 mmol) and 2 (0.3
mmol) were used.
heterocyclic groups, underscores the high potential of this
methodology in the late-stage functionalization of complex
molecules.
To give some insights into the features and mechanism of
the coupling, we performed some experiments. Although both
electron-rich and electron-poor aryl iodides can be employed
in this transformation, the substrates with electron-with-
drawing groups take overwhelming precedence over the ones
with richer electronic properties, as evidenced by the
competing reaction with 1a (para-CN, σ = 0.66) and 1h
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Scheme 3. Competition Experiments and Mechanistic Studies
(para-OMe, σ = −0.27). Even for the two competitors with
very close electronic densities, such as 1a (para-CN, σ = 0.66)
and 1d (para-Ac, σ = 0.50), the selectivity was still very high,
thus illustrating the strong influence on the oxidative addition
step from the component electronic property in this process
(Scheme 3A). Moreover, when the reaction was conducted in
the presence of 2 equiv of 2,2,6,6-tetramethylpiperidinooxy
(TEMPO), the product was obtained in only 12% yield, which
was much lower than that observed under the standard
conditions. When compound 4 was treating with 1a under the
standard conditions, the ring cyclization products 5a and 5b
were obtained in 44 and 45% yield, respectively, highly
suggesting that a radical mechanism was probably involved in
this scenario (Scheme 3B).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01420.
■
sı
Experimental procedures and spectroscopic data for new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tao XU − Shanghai Key Laboratory of Chemical Assessment
and Sustainability, School of Chemical Science and
Engineering, Tongji University, Shanghai 200092, P. R.
China; orcid.org/0000-0002-4228-4895; Email: taoxu@
tongji.edu.cn
Meanwhile, the luminescence quenching experiment with
substrate 2a was investigated, and the results showed that it is
unlikely to quench the excited state of 4CzIPN (Scheme 3C).
Combined with our previous results,10b it is still possible that
HEH is responsible for quenching the active state [4CzIPN]*.
In addition, the model reaction with 1a and 2a under the
standard conditions was stirred for 3 h, alternating between 30
min periods of blue LED light irradiation and 15 min periods
of a complete lack of light irradiation (Scheme 3D). It was
observed that the reaction progressed steadily with blue LED
light irradiation, but it abruptly stalled when the light source
was removed, thus clearly showcasing the necessity and
importance of the light irradiation in this dual catalysis system.
In summary, we have reported a dual nickel/photoredox-
catalyzed regime to accomplish a wide array of enantiocon-
vergent reductive cross-couplings of aryl halides with CF3-
substituted racemic alkyl electrophiles. Compared with tradi-
tional strategies to construct this kind of enantiomerically
enriched trifluoromethylated compound, the approach can
proceed under very mild conditions and exhibits excellent
catalytic efficiency. It accommodates a broad scope of many
functional groups, thus highlighting the potential of this
methodology in the late-stage functionalization of complex
molecules.
Authors
Pan Zhou − Shanghai Key Laboratory of Chemical Assessment
and Sustainability, School of Chemical Science and
Engineering, Tongji University, Shanghai 200092, P. R.
China
Xinxuan Li − Shanghai Key Laboratory of Chemical
Assessment and Sustainability, School of Chemical Science
and Engineering, Tongji University, Shanghai 200092, P. R.
China
Dong Wang − Shanghai Key Laboratory of Chemical
Assessment and Sustainability, School of Chemical Science
and Engineering, Tongji University, Shanghai 200092, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01420
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NFS of China (grant nos. 22071183, 21801188),
the “Thousand Youth Talents Plan”, and Tongji University for
financial support.
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pubs.acs.org/OrgLett
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Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Fluoroalky-
lation. Angew. Chem. 2021, 133, 10035.
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