Nickel-Catalyzed Cross-Coupling of Ethyl Chlorofluoroacetate with Aryl Bromides

Article abstract of DOI:10.1002/asia.202100348

A combinatorial nickel-catalyzed monofluoroalkylation of aryl bromides with the industrial raw regent ethyl chlorofluoroacetate has been developed. The two key factors to successful conversion are the combination of nickel with readily available nitrogen and phosphine ligands and the using of a mixture of different solvents. Mechanistic investigations indicated a new zinc regent might generated in situ and be involved in the reaction process.

Full text of DOI:10.1002/asia.202100348

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Nickel-Catalyzed Cross-coupling of Ethyl Chlorofluoroacetate
with Aryl Bromides
Authors: Xi-Sheng Wang, Han Li, Jie Sheng, Bing-Bing Wu, and Yan Li
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10.1002/asia.202100348
Chemistry - An Asian Journal
COMMUNICATION
Nickel-Catalyzed Cross-coupling of Ethyl Chlorofluoroacetate
with Aryl Bromides
Han Li,† Jie Sheng,† Bing-Bing Wu, Yan Li and Xi-Sheng Wang*[a]
[a]
H. Li, J. Sheng, B.-B. Wu, Y. Li, Prof. Dr. X.-S. Wang
Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemical
University of Science and Technology of China
Hefei, Anhui 230026 (P. R. China)
Email: xswang77@ustc.edu.cn
[†]
The authors contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: A combinatorial nickel-catalyzed monofluoroalkylation of
aryl bromides with the industrial raw regent ethyl chlorofluoroacetate
has been developed. The two key factors to successful conversion
are the combination of nickel with readily available nitrogen and
phosphine ligands and the using of a mixture of different solvents.
Mechanistic investigations indicated a new zinc regent might gener-
ated in situ and be involved in the reaction process.
Fluorine-containing organic compounds have been widely
used in pharmaceuticals and agrochemicals due to their unique
physical, chemical and biological properties[1]. Accordingly, the
development of simple and efficient methods for incorporation of
fluorine atom(s) or fluorinated moieties into parent molecules
has long been realized as a powerful strategy to discover new
biologically active compounds[2]. Among all the fluorianted motifs,
α-aryl-α-fluorocarboxylic acid derivatives have played a key role
in synthetic organofluorine chemistry and be found in many
active bioactive compounds[3]. The traditional methods to con-
struct such moieties normally underwent C-F bond formation,
including electrophilic fluorination[4] of enolates, electrochemical
routes[5] and deoxyfluorination[6] of α-hydroxyl esters, which
typically required high reactivity fluorinating agents and/or harsh
reaction conditions.
To address such issues caused by C-F bond construction,
transition-metal-catalyzed fluoroalkylation has been developed
as a complementary method to synthesize fluorinated molecules
by enabling mild conditions and general synthetic routes. Com-
pared with well-known palladium[7]- and copper[8]-catalysis, nick-
el-catalyzed fluoroalkylation has recently been established rapid-
ly due to the low cost, ready availability and low toxicity of nickel
source. Not only normal cross-coupling, but also reductive cou-
pling with two electrophiles, which avoid the preparation of metal
species, have recently been developed for nickel-catalyzed
fluoroalkylation of diverse organic molecules. With ethyl bromo-
fluoroacetate used as fluoroalkylating agent, this ‘‘building block’’
strategy has been used to synthesize α-aryl-α-fluoroacetates via
nickel-catalysis with aryl boronic acids firstly in 2015[9]. However,
this method still suffered from poor functional group tolerance,
narrow broad substrate scope, and the requirement of pre-
prepared reagents. As continuous efforts to develop novel and
efficient methods for fluoroalkylation[10], we conceive the direct
cross-coupling of fluoroacetate halides and aryl halides could
offer a step- and atom-economic path for facile construction of
this motif.
Scheme 1. Previous arts and current work.
different solvents. Mechanistic studies indicated an in-situ-
formed fluoroalkyl zinc reagent was involved in the catalytic
cycle, and magnesium dichloride played a key role to activate
chlorofluoroacetate to generate the zinc species.
We commenced our study by utilizing ethyl chlorofluoroace-
tate (2) as fluorinating agent, 4-bormo-biphenyl (1a) as coupling
partner, zinc as reductant, and MgCl2 as the additive, in the
presence of a catalytic amount of NiI2 (10 mol%) in DMA at
80 °C. Based on the experience of previous research, a system-
atic investigation of ligands was firstly performed, which clearly
indicated that ligand combinations played a key role to improve
the yield in this catalytic system. Nitrogen ligand 5,5’-dmbpy
could afford 3a in 52% yield and phosphine ligand BINAP dis-
played no reactivity (entries 1-2). The combination of 5,5’-dmbpy
with other ligands could improve the yield while the mixtures of
5,5’-dmbpy and BINAP as ligands with the optimal yield of 72%
(entries 6-8, for details, see the SI). Further attempts to improve
the efficiency of the reaction via screening of solvents were
unsuccessful (entries 9-10), however, simply mixing two different
solvents could achieve this goal (entries 11-12) and DMA/THF
was demonstrated as the best choice with a 96% isolated yield
(entry 13). Finally, several control experiments indicated that the
nickel catalyst, ligands, MgCl2 and reductant were indispensable
for the success of this catalytic system (entries 14-17).
With the viable reaction conditions established, we then
investigated the scope of this monofluoroalkylation protocol and
the results were showed in Scheme 2. First, a series of para-
substituted derivatives were tested, and they were arranged
according to their Hammett substituent constants[11]. Substrates
containing strongly electron-withdrawing functional groups, such
as sulfone (1b), cyano (1c), trifluoromethyl (1d), acetyl (1e),
Herein, we describe a combinatorial nickel-catalyzed mono-
fluoroacetation of aryl bromides with low-cost industrial regent
ethyl chlorofluoroacetate (Scheme 1c). The key factors to realize
this reaction are the combination of nickel with readily available
nitrogen and phosphine ligands and the using of a mixture of
1
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10.1002/asia.202100348
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ester (1f) were found transformed smoothly to give the desired
arenes in good to excellent yields. Aryl bromides installed with
the F and Cl (1g-1h) were well-tolerated with the corresponding
products in satisfactory yields. Likewise, substrates installed with
neutral and electron-donating groups on the aryl rings (1i-1o)
were also well tolerated in this reaction, affording the
monofluoroalkylation arenes in moderate to excellent yields.
Meanwhile,
aryl
bromides
bearing
meta-substituents
(trifluoromethyl 1p, halogen 1q-1r, methoxy 1s and phenyl 1t)
were also compatible well, furnishing the products in moderate
to good yields in this catalytic system. Additionally, aryl
bromides(1u) bearing ortho-substituent could serve as the
suitable
coupling
partner,
however,
the
yield
of
monofluoroalkylation product was relatively low affected by the
steric properties of its substituent. Although substrates bearing
active proton were found to be incompatible, aryl bromides
derived from naphthalene (1v-1w) and heterocyclic arenes, such
as quinolone (1x) and dibenzothiophene (1y) were
monofluoroalkylated successfully, in satisfactory yields under the
standard reaction conditions.
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Ligand (mol%)
Solvent
DMA
Yield (%)[b]
5,5’-dmbpy (10)
52
0
2
BINAP (10)
DMA
3
dmbpy (5)/BINAP (5)
dombpy (5)/BINAP (5)
dtbpy (5)/BINAP (5)
5,5’-dmbpy (5)/2,6-lutidine (10)
5,5’-dmbpy (5)/PPh3 (10)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
-
DMA
37
25
39
44
28
72
42
26
80
75
88 (96)
0
4
DMA
5
DMA
a
Scheme 2. Scope of aryl bromides. Unless otherwise noted, the reaction
conditions were as follows: 1 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), NiI2 (10
mol%), 5,5’-dmbpy (5 mol%), BINAP (5 mol%), MgCl2 (1.5 equiv), Zn (3.0
6
DMA
7
DMA
b
equiv), DMA (1.4 mL), THF (0.6 mL), 80 ˚C, 16 h. isolated yields were
reported. c 3Å M.S. was added.
8
DMA
9
DMF
In order to gain some insights into the mechanism of this
reaction, a series of control experiments were next carried out.
First of all, radical inhibition experiments showed the subjection
of TEMPO or BHT into the standard conditions could not quench
the reaction, and the desired product 3a were afforded in 78%
and 81%, respectively (Scheme 3a). Both results suggested that
the monofluoroalkyl radical was not involved in the catalytic
cycle, and a fluoroalkyl zinc species might generate in-situ and
couple with the aryl bromide by nickel catalysis. To confirme this
speculation, several more verification experiments were further
performed. While ethyl chlorofluoroacetate 2 was recovered
almost entirely under the treatment of zinc powder in DMA at 80
˚C and no hydrogenated product 4 was detected (Scheme 3b),
to our interests, the addition of MgCl2 along with zinc powder
under the similar conditions afforded 4 in 33% yield (Scheme 3c).
Not surprisingly, 24% yield of hydrogenated product 4 could be
detected under the standard conditions in the absence of aryl
bromides (Scheme 3d). All these results clearly implied that a
monofluoroalkyl zinc species generated in situ in the reaction,
10
11
12
13
14
15 [c]
16 [d]
17 [d]
NMP
DMA/dme
DMA/MeCN
DMA/THF
DMA/THF
DMA/THF
DMA/THF
DMA/THF
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
5,5’-dmbpy (5)/BINAP (5)
0
0
0
[a] Unless otherwise noted, the reaction conditions were as follows: 1a (0.2
mmol, 1.0 equiv), 2 (2.0 equiv), NiI2 (10 mol%), 5,5’-dmbpy (5 mol%), BINAP
(5 mol%), MgCl2 (1.5 equiv), Zn (3.0 equiv), DMA (1.4 mL), THF (0.6 mL), 80
˚C, 16 h. [b] Yields were determined by 19F NMR with benzotrifluoride as
internal standard, numbers in parentheses were yields of isolated products.
[c] Lack of NiI2. [d] Lack of MgCl2. [d] Lack of Zn.
2
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10.1002/asia.202100348
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COMMUNICATION
substrates scope and their applications in synthesis are currently
in progress.
Experimental Section
General procedure
Aryl bromine 1 (1.0 equiv, 0.2 mmol, if solid), NiI2 (10 mol %,
0.02 mmol, 6.3 mg), 5,5’-dmbpy (5 mol%, 0.01 mmol, 1.8 mg),
BINAP (5 mol%, 0.01 mmol, 6.2 mg)，MgCl2 (1.5 equiv, 0.3
mmol, 28.5 mg) and Zn (3.0 equiv, 0.6 mmol, 39.2 mg) were
combined in a 50 mL oven-dried sealing tube. The vessel was
evacuated and backfilled with N2 (repeated for 3 times), and aryl
bromine 1 (1.0 equiv, 0.2 mmol, if liquid), 2 (2 equiv, 0.4 mmol,
58.2 mg), DMA (1.4 mL) and THF (0.6 mL) were then added into
the reaction system subsequently via syringe. The tube was
sealed with a Teflon lined cap and heated in a preheated oil bath
at 80 ˚C. After stirring for 16 h, the reaction mixture was cooled
to room temperature, diluted with EtOAc and filtered through a
pad of Celite. The filtrate was added into brine and extracted
with EtOAc, the combined organic phase was dried over Na2SO4,
filtrated and concentrated under vacuum and purified by flash
column chromatography (PE/EA = 30:1) to give the desired
product 3.
Scheme 3. Control experiments.
and MgCl2 played a key role in promoting zinc power to insert
the C-Cl bond of chlorofluoroacetate 2.
Although the definite mechanism remains unclear, on the ba-
sis of above results and previous similar reports[12], a plausible
mechanism via Negishi cross-coupling is accordingly proposed
as Scheme 4. The catalytic cycle started by the oxidative addi-
tion of ArBr (1) to Ni(0) species (A), which generated by the
reduction of NiI2 with zinc power, affording the [ArNiII(Ln)Br]
intermediate B. Transmetalation of B with monofluoroalkyl zinc
regent that generated in situ by reduction of ethyl chlorofluoro-
acetate 2 with zinc powder with the assistance of MgCl2, deliv-
ered Ni(II) complex C. The final C-C bond forming reductive
elimination from C furnished the target product 3 and released
the LnNi0 (A) to complete the catalytic cycle.
In summary, the first monofluoroalkylation of aryl bromides
with ethyl chlorofluoroacetate has been successfully developed
by combinatorial nickel-catalyzed cross-coupling. This novel
method has demonstrated high catalytic reactivity, mild reaction
conditions and excellent function-group compatibility. Further
exploration of the mechanistic details and studies to expand the
Acknowledgements
We gratefully acknowledge the National Science Foundation of
China (21971228, 21772187) and China Postdoctoral Science
Foundation (2019M653580) for financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: monofluoroacetation • aryl halides • ethyl chloro-
fluoroacetate • nickel • cross-coupling
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4
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
We describe a combinatorial nickel-catalyzed monofluoroacetation of aryl bromides with low-cost industrial regent ethyl chloro-
fluoroacetate. The key factors to realize this reaction are the combination of nickel with readily available nitrogen and phosphine
ligands and the using of a mixture of different solvents. Mechanistic studies indicated an in-situ-formed fluoroalkyl zinc reagent was
involved in the catalytic cycle, and magnesium dichloride played a key role to activate chlorofluoroacetate to generate the zinc spe-
cies.
5
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