Nickel-Catalyzed Reductive Coupling for Transforming Unactivated Aryl Electrophiles into β-Fluoroethylarenes

Article abstract of DOI:10.1002/asia.201901490

We report herein a facile synthetic method for converting unactivated (hetero)aryl electrophiles into β-fluoroethylated (hetero)arenes via nickel-catalyzed reductive cross-couplings. This coupling reaction features the involvement of FCH₂CH

Full text of DOI:10.1002/asia.201901490

CHEMISTRY
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Accepted Article
Title: Nickel-Catalyzed Reductive Coupling for Transforming
Unactivated Aryl Electrophiles into β-Fluoroethylarenes
Authors: Yi Yang, Gen Luo, Youlin Li, Xia Tong, Mengmeng He,
Hongyao Zeng, Yan Jiang, Yingle Liu, and Yubin Zheng
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10.1002/asia.201901490
Chemistry - An Asian Journal
FULL PAPER
Nickel-Catalyzed
Reductive
Coupling
for
Transforming
Unactivated Aryl Electrophiles into β-Fluoroethylarenes
Yi Yang,*[a] Gen Luo,[a] Youlin Li,[a] Xia Tong,[a] Mengmeng He,[a] Hongyao Zeng,[b] Yan Jiang,[a] Yingle
Liu,*[a] and Yubin Zheng[a]
Abstract: We report herein a facile synthetic method for converting
unactivated (hetero)aryl electrophiles into β-fluoroethylated
(hetero)arenes via nickel-catalyzed reductive cross-couplings. This
coupling reaction features the involvement of FCH2CH2 radical
intermediate rather than β-fluoroethyl manganese species which
provides effective solutions to the problematic β-fluoride side
eliminations. The practical value of this protocol is further
demonstrated by the late-stage modification of several complex ArCl
or ArOH-derived bioactive molecules.
Introduction
The selective introduction of fluorine atoms or fluorine-
containing groups into organic molecules has represented as
popular tactics for drug discovery and received substantial
attentions within the pharmaceutical and agrochemical
communities.1 Numerous practices of drug modification
demonstrated that the precisely-controlled introduction of
fluorine atoms could be highly beneficial for improving the
pharmacological properties of candidate compounds such as
lipophilicity, metabolic stability and binding affinity.2 It is therefore
of great interest to develop novel methods to achieve efficient
Scheme 1. Strategy toward nickel-catalyzed reductive coupling between 1,2-
and site-specific fluorine incorporations. Versus the difficulties of
controlling chemo- and regio-selectivity in the methods of direct
fluorination on the unbiased and inactive C-H bonds of aliphatic
chains,3 transition metal catalyzed fluoroalkylations become an
alternative but effective approach to install the fluorine(s) pre-
decorated alkyl moieties.4 These methods are highlighted by the
mildness of reaction conditions and the synthetic convergences
from widely available fluorine-containing building blocks such as
fluoroolefin5 and fluoroalkyl halides.6 Although important
fluorohaloethane and aryl halide.
“R-[M]”) and electrophilic carbon (Cδ+ or “R-[X]”), the reductive
cross-coupling reactions provide the linkages of two electrophilic
carbon based on the turnover of transiton metal catalysts in the
presence of sacrificial reductant. Given the mentioned paucity of
fluoroalkylmetallics and the ubiquity of fluoroalkyl halides, we
envisage that the reductive coupling strategy could provide an
elegant approach for the monofluoroalkylation reaction
development with omitting the preparation step of problematic
fluoroalkylmetallics.13
Recently, Wang group disclosed a nickel-catalyzed reductive
monofluoroalkylation reaction for access to benzylic fluorides
(ArCHFR, R = H or alkyl) from Ar-X (X= Br or I) and YCHFR (Y =
Br or I) electrophiles (Scheme 1a).14 Their reaction was
highlighted by utilizing gem-dihaloalkane as starting material and
bypassing the generation of elusive Y-M-CHFR metallic
nucleophiles. Inspired by these seminal results, it is anticipated
that the isomeric 1,2-fluorohaloethanes (FCH2CH2Y, a vicinal
dihalide) could be coupled with the widely available aryl
electrophiles to furnish the value-added ArCH2CH2F structural
motifs15 through this flourishing nickel-catalyzed reductive
coupling stragegy (Scheme 1b-d). Although the construction of
homobenzylic fluoride (ArCH2CH2F) has been concisely
achieved by nickel catalyzed Suzuki-type coupling between
ArB(OH)2 and FCH2CH2I in our group (Scheme 1c-II),16 this
method still pertains to the following restrictions: limited patterns
of arylborons especially those bearing complex bioactive
structural units which requires lengthy preliminary synthetic
progress
has
been
achieved
on
the
theme
of
polyfluoroalkylations,7 the direct introduction of partially
fluorinated alkyl motifs especially monofluoroalkyl into organic
products remains underdeveloped8 owing to the situation of
limited availability of fluoroalkyl metallic reagents9-10 for coupling
with other electrophiles.
On the other hand, the transition-metal-catalyzed reductive
cross-coupling reactions between two electrophiles have
emerged as powerful tools for the construction of carbon-carbon
bonds over the recent few years.11-12 Unlike the conventional
couplings which relied on the union of nucleophilic carbon (Cδ- or
[a]
Dr. Y. Yang, G. Luo, Y. Li, X. Tong, M. He, Dr. Y. Jiang, Dr. Y. Liu,
Dr. Y. Zheng
College of Chemistry and Environmental Engineering, Sichuan
University of Science & Engineering, 180 Xueyuan Street, Huixing
Lu, Zigong, Sichuan 643000 (China)
E-mail: yangyiyoung@163.com; liuyingleyou@163.com
Dr. H. Zeng
College of Chemistry, Leshan Normal University, 778 Binghe
Road, Leshan, Sichuan 614000 (China)
Supporting information for this article is given via a link at the end
of the document.
[b]
[*]
steps,
unfavored
group
tolerance
and
competitive
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FULL PAPER
Table 1. Optimization of the reductive coupling reaction conditions[a]
protodeboronation caused by basic activators.17 Undoubtedly,
the nickel-catalyzed reductive coupling between ArX and
FCH2CH2Y electrophiles could address these limitations and
constitute a superior and complementary method with high step-
efficiency. To be specific, the current reductive coupling reaction
system needs to meet these following requirements: (i) The NiLn
catalytic system should be adequately active to ensure the
carbon-halogen bond clevage of unactivated aryl electrophiles
and 1,2-fluorohaloethanes, then fulfill the subsequent reductive
elimination of aryl and fluoroethyl groups; (ii) The competitive
hydrodehalogenation18 and β-fluoride elimination19 of 1,2-
fluorohaloethanes should be suppressed by proper choice of
metallic catalytic species and reductant; (iii) The further
conversion of aliphatic homobenzylic C-F bond20 of ArCH2CH2F
product should be precluded in the reaction system. Based on
the above considerations, we explore the feasibility of reductive
fluoroethylation reaction development in the step-efficient
manner and report its use for the structural modifications of Ar-
Cl or Ar-OH derived scaffolds in the present paper.
Entry
Ligand/(x mol%)
Additive/(y eq.)
Yield/%[b]
1
2
dmbpy (x = 10)
dmbpy (x = 10)
None
14
8
TMSCl (y = 1.5)
NaI (y = 1.5)
3
dmbpy (x = 10)
29
22
8
4
dmbpy (x = 10)
KI (y = 1.5)
5
dmbpy (x = 10)
ZnCl2 (y = 1.5)
LiCl (y = 1.5)
6
dmbpy (x = 10)
56
61
45
45
38
56
51
30
67
65
68
77/73[c]
29
0
7
dmbpy (x = 10)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
MgCl2 (y = 1.5)
8
dmbpy (x = 10)/Py (x′= 10)
dmbpy (x = 10)/4-CN-Py (x′ = 10)
dmbpy (x = 10)/4-CF3-Py (x′ = 10)
dmbpy (x = 10)/2-CN-Py (x′ = 10)
dmbpy (x = 10)/DMAP (x′ = 10)
dmbpy (x = 10)/4-MeO-Py (x′ = 10)
bpy (x = 10)
Results and Discussion
9
10
11
12
13
14
15
16
17
18
19[d]
We commenced the study with examining the effectiveness of
the designed transformation by utilizing 4-chlorobiphenyl and
FCH2CH2I as coupling partners in the presence of a catalytic
loading of NiBr2/4,4'-dimethyl-2,2'-bipyridine (dmbpy, a privileged
ligand in Wang’s monofluoroalkylation13) and stoichiometric
reductant Mn (Table 1). Through a systematic examination of
reaction parameters (See SI), we found that the addition of
additive was crucial for the effective conversion of 4-
chlorobiphenyl in this nickel-catalyzed reductive coupling
chemistry. Similar to some reported examples of Gong12j,21 and
Zhang’s13b reductive couplings, MgCl2 was proved to be the
most effective which improved the yield from 14% to 61%. Other
additives like TMSCl12f-12g, NaI, KI, ZnCl2 and LiCl showed
inferior or deleterious effects in promoting this coupling (Table 1,
entries 2-7). Attempts to improve the reaction outcome via
employing combinatorial ligand system14 were unsuccessful by
screening within a series of pyridinyl monodentate ligands which
are decorated by either electron-donating or electron-
withdrawing groups (Table 1, entries 8-13). Further interrogation
on the structural motifs of bidentate nitrogen ligands indicated
that the electron-rich 4,4'-dimethoxy-2,2'-bipyridine (dmobpy)
with steric-unhindered coordination site was optimal and
improved the coupling yield to 77% (Table 1, entries 14-18).
Finally, control experiment indicated that both the nickel salts
and supporting ligands were indispensable for the success of
this coupling (Table 1, entry 19).
phen (x = 10)
dtbpy (x = 10)
dmobpy (x = 10)
6,6-dmbpy (x = 10)
-
[a] General Reaction conditions: 4-chlorobiphenyl (0.2 mmol, 1.0 equiv),
FCH2CH2I (0.3 mmol, 1.5 equiv), NiBr2 (0.02 mmol, 10 mol%), ligand
(10-20 mol%), Mn (0.8 mmol, 4.0 equiv). [b] Isolated yield. [c]Gram-scale
synthesis (6.0 mmol scale). [d] Reaction without NiBr2 or supporting
ligand.
nitrile 1j-1k) on the para-position on the phenyl ring were also all
compatible well and they were not reduced under the current
reductive coupling conditions. Interestingly, the active and acidic
hydrogen in alcohol 1n did not disrupt the reaction efficiency,
furnishing the product 3n in moderate yield. Furthermore, the
meta-substituted substrates (1o-1r) were proved to be viable
under the current reaction systems regardless of the
substituents’ electron-rich or electron-poor properties. However,
this reductive fluoroethylation displayed high steric sensitivity
and failed to realize the coupling when utilizing the ortho-
substituted substrates (1u-1v), and only the linear and
uncongested ortho-cyano substrate 1t delivered the
corresponding product 3t in 62% yield. Collectively, the coupling
condition A was generally amenable to the aryl chlorides.13b
While using the more active aryl bromides and aryl iodides as
electrophiles, we found that the addition of MgCl2 as promoter
was not necessary and only required few adjustments of
reaction conditions (condition B and C) which featured the
With the optimized reaction conditions established, the scope
of the aryl eletrophiles was subsequently investigated (Scheme
2). A variety of para- and meta-substituted aryl halides (Ar-X)
were found to couple smoothly with FCH2CH2Y to give the
desired β-fluoroethylated arenes. For example, the electron-rich
or -neutral aryl halides (1a-1d) could provide the corresponding
fluoroethylation products (3a-3d) in moderate to good yield.
Likewise, the electron-withdrawing functional groups including
(aldehyde 1e, ketone 1f-1g, 1l-1m, ester 1h, sulfone 1i, and
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FULL PAPER
CH2CH2F
X
NiBr2, Ligand, additive
Mn, NMP, 80oC
YCH2CH2F
R
R
1
2
3a-3v
CH2CH2F
CH2CH2F
CH2CH2F
tBu
3b, 59%a, 55%c
CH2CH2F
Ph
3a, 77%a, 77%b, 89%c
MeO
3c, 38%a, 48%c
CH2CH2F
CH2CH2F
O
O
Ac
OHC
3e, 41%a, 73%c
3d, 35%b
3f
a
b
c
, 60% , 71% , 65%
CH2CH2F
CH2CH2F
CH2CH2F
O
Ph
S
EtO2C
3h, 60%a, 40%b, 64%c
H3C
O
O
3i, 61%a
CH2CH2F
3g, 63%a
CH2CH2F
CH2CH2F
NC
NC
O
O
3k, 27%a
CH2CH2F
3l, 55%a
3j, 48%a
CH2CH2F
MeO
CH2CH2F
Scheme 3. Substrate scope expansion to the fused-ring aromatic and
heteroaromatic electrophiles.[a] Condition A for Ar-Cl; isolated yield. [b]
Condition B for Ar-Br. [c] Condition C for Ar-I.
OH
O
3m, 29%a
3n, 32%a
3o, 40%a
stage modification of several Ar-Cl derived medicinal molecules
(clofibrate 4g, fenofibrate 4h, and Loratadine 4i), leading to β-
fluoroethylated products in satisfactory yields (5g-5i) (Scheme 3).
Thus, these successes demonstrated the potential application of
this methodology in drug discovery and development.
CH2CH2F
NC
CH2CH2F
Ac
CH2CH2F
MeO
OMe
3q, 46%a
3p, 61%a, 74%b
3r, 62%a, 50%b, 48%c
Further extension of this protocol to other vicinal
halofluorinated scaffolds (2c-2d) was also productive which
delivered the more complicated homobenzylic fluorides
correspondingly (Scheme 4). Interestingly, the phenol
derivatives such as aryl triflate and tosylate (pseudo-halides)22
could serve as the suitable coupling partners via C-O bond
scission under the coupling conditions. Similar to the previous
reports,22 the aryl triflate displayed better reactivity order than
the counterpart tosylate (3a and 5a). Importantly, a series of
para-electron-neutral or electron-withdrawing groups were well
tolerated (3a, 3f, 3h and 3j) in these examples whereas the
electron-donating groups such as methoxyl and tert-butyl greatly
retarded the coupling reactions. This phenomenon might be
ascribed to the difficulties in the C-O cleavage (oxidative
addition) with the increasing of electron density23. Finally, the
fluoroethylated cross-coupling product of estrone 5j was
successfully synthesized which further exhibit the utility and
practicality of this method in the functionalization of phenol-
derived bioactive molecules.
CH2CH2F
R
CH2CH2F
OMe
CH2CH2F
MeO
CN
3u (R=Ph), NDa
3v (R=iPr), NDa
3s, 52%b
3t, 62%b
Scheme 2. Scope of aryl halides. [a] General reaction conditions: Ar-Cl (0.2
mmol, 1.0 equiv), FCH2CH2I 2a (0.3 mmol, 1.5 equiv), NiBr2 (0.02 mmol, 10
mol %), dmobpy (0.02 mmol, 10 mol%), Mn (0.8 mmol, 4 equiv), MgCl2 (0.3
mmol, 1.5 equiv), NMP (1.0 mL), 80 oC, N2, isolated yield. Abbreviated as
condition A. [b] Ar-Br (0.2 mmol, 1.0 equiv), FCH2CH2Br 2b (0.3 mmol, 1.5
equiv), NiBr2 (0.02 mmol, 10 mol%), dmbpy (0.02 mmol, 10 mol%), Mn (0.8
mmol, 4 equiv), tetrabutylammonium iodide (0.04 mmol, 0.2 equiv), NMP (1.0
mL), 80 oC, N2. Abbreviated as condition B. [c] Ar-I (0.2 mmol, 1.0 equiv),
FCH2CH2I (0.3 mmol, 1.5 equiv), NiBr2 (0.02 mmol, 10 mol %), dmbpy (0.02
mmol, 10 mol%), Mn (0.8 mmol, 4 equiv), NMP (1.0 mL), 80 oC, N2.
Abbreviated as condition C.
utilization of less electron-rich dmbpy as supporting ligands.
The facile access to the fluorinated fused-ring and
heterocyclic aromatic compounds was highly relevant with
material science and medicinal chemistry. Gratifyingly, the
naphthalene (4a-4b), pyridine (4c), quinoline (4d-4e) and
benzooxazole (4f) rings-containing substrates were smoothly
installed with the β-fluoroethyl motifs under the opitimized
conditions. Notably, this protocol can also extended to the late-
To probe whether the viable fluoroethylation species was free
radical or nucleophilic organometallic intermediate, a series of
radical inhibition experiments were initially conducted. It was
found that the coupling reaction was completely quenched upon
the subjection of radical inhibitor TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) under the standard reaction conditions (Scheme
5a).13a In addition, this reaction was readily inhibited by the
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F
Radical inhibition experiments
X
F
Y
NiBr2, ligand
Mn, NMP, 80 o
Ar
+
Ar
TEMPO (1.0 equiv)
C
Ar-CH2CH2F
(a) Ar-Cl
+
FCH2CH2I
condition A
3
1
2c or 2d
1a
3a, 0%
1,4-dinitrobenzene
(1.0 equiv)
Other vicinal halofluoride
F
Ar-CH2CH2F
(b) Ar-Cl
+
FCH2CH2I
Ph
Ph
Ph
condition A
1a
3a, 0%
Ph
F
F
F
Ph
OHC
Ac
3y, 39%a
3w, 39%a
3x, 46%b, 41%c
3z, 31%d
Radical clock experiment
CH2CH2F
Ar-Cl 1a
Phenol derivatives (X=OTf or OTs)
condition A
Ph
+
3a
15%
+
(c)
CH2CH2F
CH2CH2F
CH2CH2F
CH2CH2F
FCH2CH2I
6
7 (GC-MS)
Ph
Ac
Ac
EtO2C
NC
3a, 51%e, 16%f
3h, 39%e
CH2CH2F
3f, 43%e
3j, 48%e
Experiments for ruling out the generation of fluoroethyl manganese species
O
H
H
Mn (4 equiv)
NMP, 80 oC
CH2CH2F
1M HCl
1M HCl
CH2CH2F
FCH2CH3
(d)
[FCH2CH2MnI]
FCH2CH2I
H
quantitative recovery
8, 0%
FH2CH2C
3q, 21%e
5j, 35%e
5a, 44%e, 37%f
5b, 75%e
NiBr2 (10 mol%)
dmobpy (10 mol%)
Mn (4 equiv), MgCl2 (1.5 equiv)
FCH2CH3
(e)
FCH2CH2I
quantitative recovery
Scheme 4. Further extension of the scope of vicinal halofluorides and aryl
electrophiles. [a] Condition B, using Ar-Br and PhCH(F)CH2Br 2c instead;
isolated yield. [b] Condition B, using Ar-I and PhCH(F)CH2Br 2c instead. [c]
Condition C, using Ar-I and PhCH(F)CH2Br 2c instead. [d] Condition A, using
Ar-I and 1-fluoro-2-iodocyclohexane 2d instead. The trans configuration of the
racemic product 3z was determined by 1H–1H COSY spectra. [e] Condition A,
using Ar-OTf and 1-fluoro-2-iodoethane 2a instead. [f] Condition A, using Ar-
OTs and 1-fluoro-2-iodoethane 2a instead.
NMP, 80 o
C
8, 0%
Scheme 5. Control experiments for verifying the intermediacy of fluoroethyl
radicals.
manganese thus provided effective solutions for the frequently-
encountered problematic β-fluoride side eliminations.19
Based on the above experimental observation of the key
FCH2CH2● radical intermediate involving in this coupling reaction
and the previous similar reports12c,13-14, the putative reaction
mechanisms were accordingly proposed (Scheme 6). The left
catalytic cycle started with the oxidative addition between the Ar-
X electrophile and LnNi0 (A) (generated from the reduction of NiII
salt precusors) to deliver the LnNiII(Ar)(X) intermediate B. This
divalent nickel complex B was reduced by the manganese to
produce an arylated univalent nickel species C which underwent
stepwise oxidative addition with FCH2CH2Y (a halogen
abstraction/FCH2CH2● radical cage-rebound process) to afford
LnNiIII(Ar)(Y)(CH2CH2F) D. Further reductive elimination of D
gave the target product ArCH2CH2F and released the univalent
LnNiI(Y) E which proceeded 1e reduction into LnNi0 (A) to
complete the catalytic cycle. Alternatively, the interception of
LnNiII(Ar)(X) intermediate B by the diffused FCH2CH2● radical
(cage-escaped radical) could also be possible. The prodcuced
trivalent intermediate LnNiIII(Ar)(X)(CH2CH2F) D′ underwent
reductive elimination to deliver the ArCH2CH2F product and
LnNiI(X) E′. The further grabbing of halogen Y atom from
FCH2CH2Y provided LnNiII(X)(Y) F and FCH2CH2● radical that
escaped from the solvent cage to attach with the anterior
intermediate B. At last, conversion of LnNiII(X)(Y) F into LnNi0 (A)
via 2e reduction regenerated LnNi0 (A) to fulfill the right catalytic
cycle.
addition of electron transfer scavenger 1,4-dinitrobenzene
(Scheme 5b). These results were indicative of SET process
(single electron transfer) and the involvement of radical
intermediates within the catalytic cycle. Further evidence was
obtained from the radical clock experiment (Scheme 5c). The
interfering effects of radical clock α-cyclopropylstyrene 6 led to
the suppression of reductive fluoroethylation reaction and the
formation of FCH2CH2 radical attaching/cyclopropane ring-
openning product 7.
With the above evidence about the intermediacy of FCH2CH2
radical identified, several verification experiments were further
implemented to rule out the possible generation of fluoroethyl
manganese species (a hypothesized intermediate that could
result in problematic beta-fluorine elimination).14 We found that
the β-fluoroalkyl electrophile (FCH2CH2I) kept untouched under
o
the treatment of manganese powder in NMP at 80 C (Scheme
5d) or under the standard condition A in the absence of aryl
chloride (Scheme 5e). These results indicated that the
generation of homobenzylic fluoride product from the cross-
coupling between β-fluoroethyl manganese species and aryl
chloride was less likely. The alternative reaction intermediate in
the form of β-fluoroethyl radical rather than β-fluoroethyl
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Scheme 6. Proposed reaction mechanisms: (a) radical-cage-rebound process or (b) radical chain process.
2011, 54, 2529-2591; e) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C.
del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu,
Chem. Rev. 2014, 114, 2432-2506.
[2]
For selected review and examples, see: a) N. A. Meanwell, J. Med.
Chem. 2018, 61, 5822-5880; b) M. Berninger, C. Erk, A. Fuß, J. Skaf, E.
Al-Momani, I. Israel, M. Raschig, P. Güntzel, S. Samnick, U. Holzgrabe,
Eur. J. Med. Chem. 2018, 152, 377-391; c) P. Bentler, N. Erdeljac, K.
Bussmann, M. Ahlqvist, L. Knerr, K. Bergander, C. G. Daniliuc, R.
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Czerwinski, X. Du, E. L. Ged, G. Han, H. Tan, T. Wong, S. Xie, J. A.
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Gangjee, J. Med. Chem. 2018, 61, 4228-4248.
Conclusions
In conclusion, we have reported a nickel-catalyzed reductive
coupling protocol for facile installing β-fluoroethyl into aromatic
rings from readily accessible aryl chlorides and 1,2-
fluorohaloethane. This novel catalytic method features the
mildness of reaction conditions, broad scope with respect to
both the aryl and β-monofluoroalkyl electrophiles, and excellent
group compatibilities towards free proton or reducible group
containing substrates, thus offering an efficient approach for the
late-stage functionalization of complex Ar-Cl or Ar-OH derived
bioactive molecules. We believe that the success of suppressing
β-fluorine side elimination via the fluoroalkyl radical intermediate
during the coupling reaction could draw more attention towards
the derivatization of fluoroalkyl halides. Further explorations of
this reaction strategy to more diversified fluoroalkylated
electrophiles for access to the precisely-controlled construction
of complicated fluorine-added organoproducts are ongoing in
our laboratory, and the results will be reported in due course.
[3]
For selected examples and reviews, see: a) M. B. Nodwell, A. Bagai, S.
D. Halperin, R. E. Martin, H. Knust, R. Britton, Chem. Commun. 2015,
51, 11783-11786; b) D. Liang, Y. Li, S. Gao, R. Li, X. Li, B. Wang, H.
Yang, Green Chem. 2017, 19, 3344-3349; c) J.-B. Xia, C. Zhu, C.
Chen, J. Am. Chem. Soc. 2013, 135, 17494-17500; d) H. Tu, S. Zhu,
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We thank National Natural Science Foundation of China
(21502131), Science & Technology Department of Sichuan
Province (2018JZ0061, 2018HH0128), Education Department of
Sichuan Province (18CZ0024), Key Laboratory of Vanadium and
Titanium of Sichuan Province (2018FTSZ03), and Sichuan
University of Science and Engineering (2017RCL03) for funding
this work.
Keywords: Nickel • Reductive Coupling • Unactivated bond •
Homobenzylic Fluoride • Methodology and Reactions
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Layout 2:
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Yi Yang,* Gen Luo , Youlin Li, Xia Tong,
Mengmeng He, Hongyao Zeng, Yan
Jiang, Yingle Liu,* and Yubing Zheng
Page No. – Page No.
Nickel-Catalyzed Reductive Coupling
for Transforming Unactivated Aryl
We report herein a facile synthetic method for converting unactivated (hetero)aryl
electrophiles into β-fluoroethylated (hetero)arenes via nickel-catalyzed reductive
cross-couplings. This method can be applied for the late-stage modification of
several complex ArCl or ArOH-derived bioactive molecules with high efficiency.
Electrophiles
into
β-
Fluoroethylarenes
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