Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation

Article abstract of DOI:10.1002/anie.201803228

A combinatorial nickel-catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross-coupling has been developed. This method demonstrated high efficiency, mild conditions, and excellent functional-group tolerance, thus enabling the late-stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine-type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel-catalyzed reductive cross-coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.

Full text of DOI:10.1002/anie.201803228

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Accepted Article
Title: Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with
Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation
Authors: Xi-Sheng Wang, Jie Sheng, Hui-Qi Ni, Hao-Ran Zhang, Kai-
Fan Zhang, and Yi-Ning Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803228
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10.1002/anie.201803228
Angewandte Chemie International Edition
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Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with
Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation
Jie Sheng,+ Hui-Qi Ni,+ Hao-Ran Zhang, Kai-Fan Zhang, Yi-Ning Wang and Xi-Sheng Wang*
Abstract: A combinatorial nickel-catalyzed monofluoroalkylation of
aryl halides with unactivated fluoroalkyl halides via reductive cross-
coupling has been developed firstly. This method has demonstrated
high efficiency, mild conditions, and excellent functional group
tolerance, thus enabling the late-stage monofluoroalkylation of
diversified drugs. The key to success is the combination of diverse
readily available nitrogen ligands bidendate and monodate pyridine-
type ligands to nickel, which in-situ generated a variety of easily
tunable catalysts to promote the fluoroalkylation with broad scopes of
both coupling partners. This combinatorial catalysis strategy will offer
a solution for nickel-catalyzed reductive cross-coupling reactions and
provide an efficient way to synthesize fluoroalkylated drug-like
molecules for drug discovery.
construct such monofluoroalkylated arenes. However, neither of
the two methods is efficient enough for late-stage fluoroalkylation
of complex molecules, because of the important functional group
incompatibility and/or relatively harsh reaction conditions. As an
efficient alternative approach to normal cross-coupling between
electrophilic and nucleophlic partners, nickel-catalyzed reductive
crossing-coupling of two electrophiles has recently emerged as a
powerful strategy to forge C-C bonds, which has demonstrated
high atom- and step-economy and easy handling by avoiding the
use of organometallic reagents generally synthesized from
organic halides.[8] Despite of its great progress made in this field,
the synthetic potential of this method has never been
demonstrated for -fluoroalkylation of aryl halides.[9,16]
Herein, we described an efficient and mild nickel-catalyzed
reductive cross-coupling between aryl halides and unactivated
monofluoroalkyl halides. This method has demonstrated high
catalytic reactivity and broad scope, thus enabling the late-stage
fluoroalkylation of different drugs. The key to success is the
combination of diverse readily available bidentate and
monodentate pyridine-type ligands to nickel,[7k,10] which could
generate a number of highly active catalysts to promote the cross-
coupling between broad scopes of both electriphiles. This
strategy based on combinatorial catalysis will offer a new solution
to nickel-catalyzed reductive cross-coupling reactions and
provide a new way for facile synthesis of -fluoroalkylated arenes.
Fluorine-containing organic compounds have been widely used
as pharmaceuticals and agrochemicals, for the incorporation of
fluorine or fluorinated moieties into organic molecules could often
remarkably enhance the lipophilicity, metabolic stability, and
bioavailability of the parent molecules.[1] As a result, the selective
introduction of fluorine or fluorinated moieties into durg-like
molecules has long been realized as a powerful strategy to study
the structure-activity relationships for drug design and
discovery.[2] While the conventional approaches access such
fluorine-containing compounds typically via mutistep syntheses,
late-stage fluoroalkylation of candidate drug molecules offers a
perfect alternative solution to open a new way for their syntheses
in medicinal chemistry.[3] Considering polyfunctional complex
molecules are normally used as starting materials for modification
with important chemical groups, broad functional group tolerance
and mild conditions are the necessary requirements to enable
these late-stage transformations.[4]
As an important fluroinated moieties with unique properties for
medicinal chemsitry, diversity-oriented syntheses (DOS) of
monofluoroalkylated arenes (ArCHFR, R = alkyl or H) has drawed
increasing attentions in the past years, but the relevant synthetic
methods were still very limited.[5] Till date, directly fluorination of
benzylic C-H bonds of alkyl arenes[6] and transition-metal-
catalyzed cross-coupling of monofluoroalkyl halides with aryl
metal species[7] have been developed as the only methods to
Scheme 1. Transition-metal-catalyzed cross-coupling for facile synthesis of
monofluoroalkylated arenes
Our study commenced with phenyl iodide 1a as the pilot
substrate and 1-fluoro-1-iodo ethylbenzene 2a as the coupling
partner in the presence of a catalytic amount of NiI2 (10 mol%)
and Mn (2.0 equiv) in dimethylacetamide (DMAc) at 40 °C .
Fortunately, the desired fluoroalkylated product 3 was obtained in
21% yield when dmbpy (10 mol%) was used as ligand. Different
kinds of nitrogen and phosphine ligands were next examined, but
all giving only pretty low yields or even none of 3 (entries 1-8, for
details, see the SI). Inspired by our previous results on
combinatorial nickel catalysis,[7n] various combinations of N/P and
N/N ligands were then investigated extensively. To our delight,
the mixture of pyridine and dmbpy (N/N) as a simple ligand
combination improved the yield obviously to 71% (entry 9), while
the ligand combinations consist of N/P ligands were ineffective
[*] J. Sheng, H.-Q. Ni, H.-R. Zhang, Y.-N. Wang, Prof. Dr. X.-S. Wang
Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry
Center for Excellence in Molecular Synthesis of CAS
University of Science and Technology of China
96 Jinzhai Road, Hefei, Anhui 230026, China
E-mail: xswang77@ustc.edu.cn
[+] The authors contributed equally
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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(entries 10, for more details, see the SI), which indicated that N/N
ligand combination was the key choice to realize this reductive
cross-coupling. To further improve the yield, other monodentate
and bidentate nitrogen ligand combinations were next examined,
and dmbpy/4-CN-Py was demonstrated as the optimal choice
with 82% yield (entries 12-13, for details, see the SI). As reaction
monitoring showed 2a was completely consumed in the reaction,
slightly increasing 2a to 1.1 equiv could further improve the yield
to 91% (entry 14). Additionally, careful screening of solvents and
nickel sources indicated DMAc and NiI2 were still the best choices
(entries 15-17, for details, see the SI). Lastly, control experiments
confirmed that none of the desired product 3 was detected in the
absence of nickel catalyst or ligands (entries 18-19).
combinations, including dmbpy/Py, dmbpy/4-CN-Py, dtbpy/4-CN-
Py, dmbpy/2,6-Lutidine and dombpy/2,6-(MeO)2-Py could furnish
3 with excellent yields (~90%), and 5 more combinations could
give good yields (~80%). It is worth noting that the diversified
combinations of readily available ligands provided us an efficient
approach to tune the properties of nickel complex from the
perspective of both electronic and steric effects, which thus
offered a reliable method to improve the catalytic activity for the
transformation to tolerate broad scope of functional groups.
With these optimized conditions and catalysts in hand, a variety
of aryl iodides were next tested. As shown in Table 2, a variety of
para- and meta-substituted aryl iodides furnished the desired
monofluoroalkylated arenes with excellent yields. Indeed, aryl
iodides installed with both electron-donating groups, including Me
(4, 5), t-Bu (6), Ph (7, 8), MeO (9) and TMS (10), and electron-
withdrawing groups, such as CF3 (11), CN (12), CO2Me (13), CHO
(14), Ac (15), Ms (16) and ketone (17, 18) on the phenyl rings
were fluoroalkylated smoothly to give the desired products with
high yields in our catalytic system. Remarkably, aryl iodides
containing F (19, 20), Cl (21, 22), Br (23), and free hydroxy group
(24) were also suitable coupling partners, which clearly
demonstrated excellent functional group tolerance of our method
and offered synthetic potential for further transformation. To our
delight, ortho-substituents including not only small groups like Me
(25), F (26) and Cl (27), but also bigger groups like Ph (28) and
CO2Me (29), which were less reactive in known
systems,[7n,10b,10g,11] were well tolerated with excellent yields.
Furthermore, aryl iodides derived from polycyclic (30, 31) or
heterocyclic (32-34) arenes were also compatible with this
reaction. Of note is that aryl bromides worked also well in this
reaction system, although a higher temperature (80 °C ) and
addition of extra NaI (1 equiv) were required (3, 7, 11, 15, 17).
Table 1. Nickel-catalyzed monofluoroalkylation: optimization of conditions.[a]
Entry
1
Ligands (mol%)
bpy (10)
Solvent
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMPU
DMF
Yield (%)[b]
17
2
dmbpy (10)
21
3
dtbpy(10)
17
4
dombpy(10)
16
5
Pyridine (20)
0
6
4-CN-Py (20)
0
To further demonstrate the scope of -fluoroalkyl halides,
various kinds of monofluoroalkyl iodides (2b-2h) were examined
in this catalytic system. Not surprisingly, the length of alkyl chain
on 2 had no obvious influence on the reaction efficiency (35-37).
Meanwhile, polycyclic arenes on the fluoroalkylating reagents
could be well tolerated in this transformation (38, 39). Additionally,
the electronic properties of aromatic rings in fluoroalkyl iodides 2e
and 2f had almost no effect on the reaction efficiency (40-44).
Meanwhile, 1-fluoro-1-iodoalkanes (2g, 2h) installed with ethers
(45-47) and long-chain alkanes (48, 49) were also compatible with
this reaction. To our excitement, this reductive cross-coupling
system could also been applied to monofluoromethylation of aryl
iodides with BrCFH2, a commercial raw material, albeit a slightly
higher amount of gaseous BrCFH2 (1.5 equiv) was required.
Importantly, not only electron-rich (50) and electron-poor (51) aryl
rings, but also heteroarenes (52), could be well tolerated in this
mild transformation. As the monofluoromethyl group (CFH2) are
widely used as a key motif to improve the biological properties of
candidate drug molecules,[12] this method provides a new strategy
for facile synthesis of monofluoromethylated arenes to meet the
demand of drug screen.
7
DMAP (20)
0
0
8
PPh3 (20)
9
dmbpy (10)/Py (20)
dmbpy (10)/PPh3 (20)
dmbpy (10)/DMAP (20)
dmbpy (10)/4-CN-Py (20)
dmbpy (10)/4-CN-Py (20)
dmbpy (10)/4-CN-Py (20)
dmbpy (10)/4-CN-Py (20)
dmbpy (10)/4-CN-Py (20)
-
71(71)
20
10
12
13
14c
15c
16c
17c
18c
19c,d
40
80 (82)
88 (91)
31
68
NMP
20
DMAc
DMAc
0
dmbpy (10)/4-CN-Py (20)
0
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (1.0 equiv), NiI2 (10
mol%), ligand (10-20 mol%), Mn (2.0 equiv), solvent (1.0 mL), 40 °C, 24 h. [b]
Yield was determined by 19F NMR using PhCF3 as an internal standard;
numbers in parentheses were isolated yields. [c] 2a (1.1 equiv). [d] No NiI2.
Considering ligand combination played the decisive role in this
transformation, different kinds of readily available monodentate
and bidentate pyridine-type ligands have been collected for
combinatorial screening to find the optimal catalysts (for details,
see the SI). Among all these choices we examined, six ligand
Given that excellent functional group tolerance and mild
conditions have been well demonstrated in this catalytic system,
the synthetic potential of this method were next elucidated via
late-stage monofluoroalkylation of several drugs with structural
diversity. Indeed, different functional groups in complex
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Table 2. Nickel-catalyzed monofluoroalkylation via reductive cross-coupling.[a]
[a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (1.1 equiv), NiI2 (10 mol%), dmbpy (10 mol%)/4-CN-pyridine (20 mol%), Mn (2.0 equiv), DMAc (1.0 mL), 40 °C,
24 h. [b] dmbpy (10 mol%)/pyridine (20 mol%). [c] dombpy (10 mol%)/2,6-(MeO)2-pydidine (20 mol%). [d] dtbpy (10 mol%)/4-CN-pyridine (20 mol%). [e] Reaction
was performed in a 5 mL sealed tube in the presence of 1.5 equiv of BrCFH2. [f] Aryl bromine (1.0 equiv) and NaI (1.0 equiv) was used instead of aryl iodide under
80 °C . [g] 1-Fluoro-1-bromo ethylbenzene (1.1 equiv). [h] Reactions were performed under the reported conditions.[10a]
biologically active molecules, such as halides, hydroxyl and
amino, could be transformed to iodide smoothly, which thus
offered a great number of aryl coupling partners for the late-stage
fluoroalkylation via this reductive cross-coupling reaction. As
shown in Table 2, different aryl iodides derived from various
pharmaceuticals, such as Ezetimibe, Estrone, Indometacin,
Fenofibrate and Procaine, could be monofluoroalkylated smoothly
with excellent yields. Importantly, monofluoromethylation could
also be realized for direct incorporation of CFH2 group into these
drug molecules. All these late-stage modifications of complex
molecules clearly indicated the great potential of this method in
drug discovery and development as an efficient and expedient
tactic for synthesis of fluorine-containing analogues. It is worth
noting that the reported nickel-catalytic system for reductive
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cross-coupling of non-fluorinated alkanes[10a] afforded only pretty
low yields (5-24%, 3, 56-59).
of Mn gave only trace amount of 25 (Eq. 4). Additionally, both
reactions using stoichimetric or catalytic amount of 73 under
standard conditions furnished only trace amount of 25 in the
absence of 4-CN-Py (Eq. 3-4), which further confirmed the critical
role of ligand combination. Finally, several verified experiments
were then performed to rule out the possible in-situ generation of
monofluoroalkyl manganese species between BnCHFI 2a and Mn
(For details, see the SI). Actually, none of monofluoroalkyl
manganese species were detected by reaction of 2a with
manganese power in DMAc at 40 °C , or subjection of 2a into
standard conditions in the absence of aryl iodide, while only 2a
was recovered in both cases. On the basis of all above results
and previous reports,[8,15,16] a nickel-based reductive cross-
coupling catalytic cycle is still the most reasonable to be proposed
for this transformation (For possible catalytic cycles, see the SI).
Table 3. Nickel-catalyzed alkylation via reductive cross-coupling.[a]
[a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (1.1 equiv), NiI2 (10 mol%),
dmbpy (10 mol%), 4-CN-pyridine (20 mol%), Mn (2.0 equiv), DMAc (1.0 mL),
40 °C, 24 h. [b] Reported yields.[10a] [c] Reactions were performed under the
reported conditions.[10a]
Considering the high efficiency of this transformation, this
combinatorial nickel catalysis strategy was next extended to non-
fluorinated alkyl halides. Not surprisingly, the cross coupling of
different kinds of phenyl iodide 1 and 1-iodooctane 2j proceeded
smoothly to afford the desired product in good yields (61-66).
Meanwhile, secondary alkyl iodides (2k, 2l) were also well
compatible with this reaction to give the alkylated arenes (68, 69).
Most notably, aryl iodides derived from various pharmaceuticals,
including Fenofibrate and Ezetimibe, offered various aryl coupling
partners for efficient late-stage alkylation via this nickel-catalyzed
combinational nickel-catalytic reductive cross-coupling system
(69, 70). In contrast, while the known method[10a] gave almost the
same yields for the simple aryl iodides, the late-stage alkylation of
complex molecules under the reported conditions demonstrated
still lower efficiency (41% yield for 69 and 35% yield for 70).
Scheme 2. Mechanistic studies
In summary, we have developed a combinatorial nickel-
catalyzed monofluoroalkylation of aryl halides with unactivated
To gain some insights into the mechanism of this transformation, fluoroalkyl halides via reductive cross-coupling. This novel
a series of control experiments were next carried out. First, the
subjection of radical clock 71 into the standard conditions afforded
the cycle-opening product 72 in 21% yield (Eq. 1, Scheme 2),
indicating a free monofluoroalkyl radical might be involved in the
catalytic cycle.[13] Next, the use of Ni(0) species instead of NiI2 as
the catalyst under standard conditions furnished 3 in almost the
same yield (93%, Eq. 2). Inspired by this result, aryl nickel
complex [(dtbpy)NiII(2-tolyl)I] (73) was prepared and tested in both
stoichiometric and catalytic reactions.[14,16] As a 76% yield of 25
was obtained by treatment of complex 73 with 2a (Eq. 3), the use
of 73 as a precatalyst also furnished 2a in 81% yield (Eq. 4). Both
of the results are comparable with the yield obtained by using
dtbpy/NiI2/4-CN-Py catalytic system (85%, 25, Table 2), which
demonstrated the complex 73 might serve as a key intermediate
in the catalytic cycle. While the stoichiometric reaction between
73 and 2a without Mn could also give 25 in an obviously reduced
yield (34%, Eq. 3), the catalytic reaction without the participation
method has demonstrated mild conditions, broad scope of both
coupling partners, excellent functional group tolerance, and thus
enabled the late-stage monofluoroalkylation of diversified drugs.
This combinatorial catalysis strategy will offer a solution for nickel-
catalyzed reductive cross-coupling reactions and provides an
efficient way to synthesize fluoroalkylated drug-like molecules for
drug discovery. Further exploration of the mechanistic details and
application of this method to fluorine-containing modification of
complex biologically active molecules are still ongoing in our
laboratory.
Acknowledgements
We gratefully acknowledge the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Basic Research Program of China
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of China (21522208, 21772187, 21372209) for financial support.
Keywords: combinatorial catalysis • nickel • reductive cross-
coupling • monofluoroalkylation • aryl halides
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10.1002/anie.201803228
Angewandte Chemie International Edition
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COMMUNICATION
J. Sheng,+ H.-Q. Ni,+ H.-R. Zhang, K.-F.
Zhang, Y.-N. Wang and X.-S. Wang*
Page No. – Page No.
Nickel-Catalyzed Reductive Cross-
Coupling of Aryl Halides with
Monofluoroalkyl Halides for Late-
Stage Monofluoroalkylation
A combinatorial nickel-catalyzed monofluoroalkylation of aryl halides with unactivated
fluoroalkyl halides via reductive cross-coupling has been developed firstly. This
method has demonstrated high efficiency, mild conditions, and excellent functional
group tolerance, thus enabling the late-stage monofluoroalkylation of diversified
drugs. The key to success is the combination of diverse readily available nitrogen
ligands bidendate and monodate pyridine-type ligands to nickel, which in-situ
generated a variety of easily tunable catalysts to promote the fluoroalkylation with
broad scopes of both coupling partners. This combinatorial catalysis strategy will
offer a solution for nickel-catalyzed reductive cross-coupling reactions and provides
an efficient way to synthesize fluoroalkylated drug-like molecules for drug discovery.
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