1,1-Difluoroethyl chloride (CH3CF2Cl), a novel difluoroalkylating reagent for 1,1-difluoroethylation of arylboronic acids

Article abstract of DOI:10.1039/c9ra06406k

1,1-Difluoroethylated aromatics are of great importance in medicinal chemistry and related fields. 1,1-Difluoroethyl chloride (CH₃CF₂Cl), a cheap and abundant industrial raw material, is viewed as an ideal 1,1-difluoroethylating reagent, but the direct introduction of the difluoroethyl (CF₂CH₃) group onto aromatic rings using CH₃CF₂Cl has not been successfully accomplished. Herein, we disclose a nickel-catalyzed 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl for the synthesis of (1,1-difluoroethyl)arenes.

Full text of DOI:10.1039/c9ra06406k

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1,1-Difluoroethyl chloride (CH3CF2Cl), a novel
difluoroalkylating reagent for 1,1-
difluoroethylation of arylboronic acids†
a
Cite this: RSC Adv., 2019, 9, 28409
Jianchang Liu,a Jida Zhang,a Chaolin Wu,a Hefu Liu,a Hui Liu,
Fenggang Sun,a
a
ab
*
Yueyun Li,
Yuying Liu,a Yunhui Donga and Xinjin Li
1,1-Difluoroethylated aromatics are of great importance in medicinal chemistry and related fields. 1,1-
Difluoroethyl chloride (CH3CF2Cl), a cheap and abundant industrial raw material, is viewed as an ideal
1,1-difluoroethylating reagent, but the direct introduction of the difluoroethyl (CF2CH3) group onto
aromatic rings using CH3CF2Cl has not been successfully accomplished. Herein, we disclose a nickel-
catalyzed 1,1-difluoroethylation of arylboronic acids with CH3CF2Cl for the synthesis of (1,1-difluoroethyl)
arenes.
Received 16th August 2019
Accepted 3rd September 2019
DOI: 10.1039/c9ra06406k
rsc.li/rsc-advances
Organic uorine compounds have attracted extensive attention diuoroalkylating reagents for synthesis of (1,1-diuoroethyl)
in recent years, since the introduction of uorine atom(s) into arenes.
organic molecules oen results in dramatic changes in phys-
1,1-Diuoroethyl chloride (CH3CF2Cl; HCFC-142b; bp ¼
ical, chemical and biological properties.1,2 Among them, ꢀ9.5 ꢁC), a cheap and abundant industrial raw material used for
aromatic compounds containing the diuoroethyl (CF2CH3) vinylidene uoride (VDF),13 is viewed as an ideal source to
group are of great importance, because it mimics the steric and prepare diuoroethylated derivatives.14 We envisioned that the
electronic features of a methoxy group, which makes it direct introduction of CF2CH3 onto aromatic rings could be
a signicant group for drug design.3 For instance, a tri-
azolopyrimidine-based
dihydroorotate
dehydrogenase
(DHODH) inhibitor4 shows remarkable advantage in terms of
potency due to the replacement of a methoxy group by
a diuoroethyl group (Scheme 1A). LSZ102,5 a clinical agent, is
currently applied in phase I/Ib trials for the treatment of
estrogen receptor alpha-positive breast cancer (Scheme 1A).
Thus, the invention of reagents or methods for the synthesis of
(1,1-diuoroethyl)arenes is a very appealing and pretty mean-
ingful task.
The synthesis of such compounds are generally accom-
plished by two strategies:6 one is the transformation of a func-
tional group to a diuoromethylene (CF2) group or a CF2CH3
moiety, such as nucleophilic uorination of ketones or their
derivatives,7 dihydrouorination of terminal arynes,8 and
benzylic C–H uorination;9 the other is the direct introduction
of a CF2CH3 moiety onto aromatic rings, including nucleo-
philic,10 electrophilic11 and radical 1,1-diuoroethylation12
(Scheme 1B). In spite of these important accomplishments, it is
still a key challenge to develop low-cost and easily available
aCollege of Chemistry and Chemical Engineering, Shandong University of Technology,
266 West Xincun Road, Zibo, 255000, China. E-mail: lixj@sdut.edu.cn
bKey Laboratory of Organouorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/c9ra06406k
Scheme 1 (A) Difluoroethyl-containing bioactive and drug molecules;
(B) strategies for synthesis of (1,1-difluoroethyl)arenes. M ¼ metal; (C)
application of 1,1-difluoroethyl chloride.
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through transition-metal-catalyzed 1,1-diuoroethylation of to 15% (Table 1, entry 2), while diNH2-bpy (L2) and ditBu-bpy
arylboronic acids with CH3CF2Cl (Scheme 1C). Although (L3) gave poor yields of 3a (Table 1, entry 3 and 4). 1,10-Phe-
transition-metal-catalyzed diuoroalkylation of aromatics using nanthroline (phen), commonly used in copper-catalyzed reac-
activated diuoroalkyl halides (RCF2X, R ¼ p system) has been tions, led to a negative result in current reaction (Table 1, entry
successfully reported,15 the use of unactivated RCF2X (R ¼ alkyl) 5). With the optimal combination of Ni and ligand established
for synthesis of diuoroalkylarenes was rarely reported.11,16 To (for details, see ESI†), we next investigated the inuence of
the best of our knowledge, the use of CH3CF2Cl to prepare Ar– additives and solvent. As previously reported,16,17 pyridine
CF2CH3 compounds through a Suzuki-type cross-coupling derivatives could promote Ni-catalyzed Suzuki–Miyaura cross-
reaction has not been reported and remains challenges coupling reactions. Thus, we attempted the current reaction
because of the difficulties in activating the inert C–Cl bond of in the presence of pyridine and its derivatives. As expected, the
CH3CF2Cl and in suppressing homo-coupling and deborona- use of 4-(N,N-dimethylamino)pyridine (DMAP) afforded
tion of arylboronic acids. Herein, we wish to disclose a nickel- a higher yield of 3a (Table 1, entry 8), while pyridine (Py) and 4-
catalyzed 1,1-diuoroethylation of arylboronic acids with cyanopyridine (4-CNPy) proved to be ineffective for the reaction
CH3CF2Cl.
(Table 1, entry 6 and 7). To improve the yield of 3a, we increased
At the onset of our investigation, 4-biphenylboronic acid (2a) the loading of DMAP to 50 mol% and the yield was corre-
was chosen as the model substrate for the nickel-catalyzed 1,1- spondingly enhanced to 49% (Table 1, entry 9). Consequently,
diuoroethylation reaction (Table 1). To our delight, the the use of 70 mol% of DMAP provided the desired product in
product 3a was obtained in 5% yield in the presence of NiCl2(- 61% yield (Table 1, entry 10). In addition, when 3 mol% of
PPh3)2 (5 mol%), 2,20-bipyridine (5 mol%), K2CO3 (2.0 equiv.) in NiCl2(PPh3)2 and ligand were employed in the reaction, the
DME at 110 ꢁC (Table 1, entry 1). The low yield should be due to yield of 3a was increased to 70% and did little change by pro-
the residual 2a and the formed homo-coupling and deborona- longing reaction time (Table 1, entry 12). However, only trace of
tion of 2a (determined by GC-MS). To improve the reaction the product was formed in the absence of ligand L1 (Table 1,
efficiency, different diamine ligands were examined (Table 1, entry 13), indicating that the diamine ligand is essential in the
entries 2–5). As a result, diOMe-bpy (L1) improved the yield of 3a Ni-catalyzed 1,1-diuoroethylation of arylboronic acids. For
further insight the reactivity of other ligands in the presence of
DMAP, we conducted the reactions with ligands L2 and L3
under the optimized conditions (Table 1, entry 14 and 15). The
results showed that the combination of ligand L2 with DMAP
offered a low yield of 24% due to the residue of 2a, and ligand L3
gave a yield of 61% because of a little more deboronation of 2a.
For solvent screening (for details, see ESI†), it was found that
1,4-dioxane and DMF were inferior to DME (Table 1, entry 16
and 17).
Table 1 Optimization of reaction conditionsa
With the optimised conditions in hand, we further explored
the substrate scope of the 1,1-diuoroethylation of arylboronic
acids with CH3CF2Cl (Scheme 2). The reaction can tolerate
a variety of functional groups, such as methyl, methoxyl, tri-
uoromethyl, triuoromethoxy and substituted morpholine
(Scheme 2, 3d–3h). Generally, the substituent group of aryl-
boronic acids with p-system showed good reactivity toward
CH3CF2Cl, affording the desired product in moderate to good
yields (Scheme 2, 3a, 3b, 3m–3o). It was found that the reaction
afforded slightly low yields with sterically hindered arylboronic
acids under the standard conditions (Scheme 2, 3c, 3k, 3l). In
addition, this transformation was also applicable to 4-(9H-
carbozol-9-yl)phenylboronic acid and the 1,1-diuoroethylated
product was obtained in 62% yield (Scheme 2, 3j).
To investigate the substituent effect of uoroalkyl chlorides
on the Suzuki-type reaction, we conducted comparative experi-
ments using HCF2Cl (1b), PhCF2Cl (1c) and CF3CF2Cl (1d)
under the standard conditions (Scheme 3A). When arylboronic
acids and 1b were subjected to the standard conditions, the
reaction provided diuoromethylated products (4a–4c) in
moderate yields. However, the use of 1c and 1d gave poor yields
of the corresponding products 4d and 4e, respectively. These
results indicate that the reactivity of RCF2Cl in the reaction with
2a decreases in the following order: CH3CF2Cl > HCF2Cl >
Entry Ligand (mol%) Additive (mol%) Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
bpy (5)
L1 (5)
L2 (5)
L3 (5)
Phen (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (5)
L1 (3)
—
—
—
—
—
—
Py (10)
4-CNPy (10)
DMAP (10)
DMAP (50)
DMAP (70)
DMAP (100)
DMAP (70)
DMAP (70)
DMAP (70)
DMAP (70)
DMAP (70)
DMAP (70)
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
MME
DME
DME
5
15
7
7
Trace
Trace
Trace
30
49
61
9
10
11
12c
13c
14c
15c
16c
17c
59
70 (69)d
Trace
24
L2 (3)
L3 (3)
L1 (3)
L1 (3)
61
1,4-Dioxane 31
DMF 21
a
Reaction conditions: 2a (0.2 mmol, 1.0 equiv.), 1a (2.0–2.6 mmol),
NiCl2(PPh3)2 (5 mol%), K2CO3 (2.0 equiv.), solvent (2 mL), 110 ꢁC, N2,
5 h. Isolated yield. NiCl2(PPh3)2 (3 mol%). The reaction was
conducted for 12 h. bpy
phenanthroline, DME
dimethylamino)pyridine.
b
c
d
¼
2,20-bipyridine, phen
1,2-dimethoxyethane, DMAP
¼
1,10-
4-(N,N-
¼
¼
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CF3CF2Cl z PhCF2Cl. Next, we intended to explore the uorine
effect on the reaction. Comparative experiments by the use of
H2CFCl (1e) and ClCH2CH2Cl (1f) were conducted under the
standard conditions (Scheme 3B). It was found that the reaction
of 1e with 2a afforded monouoromethylated product 4f in
a low yield, while b-chloroethylarenes (4g, 4h) were obtained in
good yields under the standard conditions. These results indi-
cate that the reactivity of RCl in the reaction with 2a decreases
in the following order: ClCH2CH2Cl z CH3CF2Cl > H2CFCl.
To examine the role of DMAP in the reaction, we prepared
nickel complexes NiCl2(diOMebpy) and NiCl2(DMAP)4. Both of
them could serve as precatalysts and offered 3a in 50% and 15%
yield, respectively (Scheme 4A and B). However, NiCl2(-
diOMebpy) provided 3a in a low yield (5%) in the absence of
DMAP (Scheme 4A) and the use of NiCl2(DMAP)4 resulted in no
product without diOMebpy (Scheme 4B). It was noted that the
additional DMAP did enhance the yield from 15% to 50%
(Scheme 4C). These results demonstrate that one of the roles of
DMAP may function as a co-ligand in the Ni-catalyzed reaction.
Apparently, the combination of diOMebpy as a bidentate ligand
with 70 mol% of DMAP facilitates the Ni-catalyzed 1,1-diuor-
oethylation of arylboronic acids with CH3CF2Cl.
In order to obtain some insight into the mechanism of the
current reaction, radical inhibition and radical clock experi-
ments were conducted (Scheme 5). In the presence of 2,2,6,6-
tetramethylpiperidine-1-oxy (TEMPO) as a radical scavenger, the
reaction was readily inhibited and compound 5 was detected by
19F NMR and GC-MS. Furthermore, when diallyl ether was
added to the reaction under the standard conditions, a ring-
closing product 6 was formed (determined by 19F NMR and
GC-MS), along with 9% yield of 3a (for details, see ESI†). These
results demonstrate that a 1,1-diuoroethyl radical is indeed
generated in the reaction.
Scheme 2 Scope of 1,1-difluoroethylation of arylboronic acids with
CH3CF2Cl. Reaction conditions (unless otherwise specified):
2
(0.2 mmol, 1.0 equiv.), 1a (1.3 M in DME, 2.6 mmol, 13.0 equiv.), DME (2
mL), 110 ꢁC, N2, 5 h. Isolated yields. aYields were determined by 19F
NMR spectroscopy using PhCF3 as an internal standard.
On the basis of these results and previous reports,16,18
a plausible mechanism involving Ni(I)/Ni(III) catalytic cycle was
proposed for the 1,1-diuoroethylation reaction (Scheme 6).
The LnNi(I)Cl intermediate (A) is supposed to be generated via
the comproportionation of initially formed LnNi(0) species and
the remaining LnNi(II)Cl2,19 followed by transmetalation with
arylboronic acids. The formed LnNi(I)Ar species (B) reacts with
CH3CF2Cl through a SET pathway to produce 1,1-diuoroethyl
Scheme 3 Ni-catalyzed cross-coupling of arylboronic acids with alkyl
halides. Reaction conditions: 2 (0.2 mmol, 1.0 equiv.), 1 (2.0 mmol, 10
equiv.), DME (2 mL). Isolated yields. a1 (1.0 mmol, 5.0 equiv.). b1
(0.2 mmol, 1.0 equiv.), 2 (0.3 mmol, 1.5 equiv.).
Scheme 4 The role of DMAP. Isolated yields.
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(No. 4041-416021) and open project foundation of Key Labora-
tory of Organouorine Chemistry, Chinese Academy of
Sciences. We thank Professor Jinbo Hu (SIOC) for helpful
discussions.
Notes and references
´
´
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Scheme 6 Proposed reaction mechanism.
radical and LnNi(II)(Ar)(Cl) species (C). Subsequently, the
resulting LnNi(III)(Ar)(CF2CH3)(Cl) species (D) undergoes
reductive elimination to give the coupling product 3 and
regenerates LnNi(I)Cl to complete the catalytic cycle. It is noted
that DMAP may not only function as a co-ligand to coordinated
to the nickel center,16,20 but also activate the arylboronic acids to
facilitate the transmetalation.17a
In conclusion, the rst transition-metal-catalyzed 1,1-
diuoroethylation of arylboronic acids with the cheap and
easily available CH3CF2Cl has been successfully developed. This
method can tolerate methyl, methoxyl, triuoromethyl and
heteroarenes, affording 1,1-diuoroethylated products in
moderate to good yields. The reactivity of different alkyl chlo-
rides in the reaction was also investigated. Initial mechanism
study showed the nickel-catalyzed 1,1-diuoroethylation prob-
ably involves a NiI/III process. Current efforts are to develop
catalytic system for improving yields and novel reactions with
CH3CF2Cl as cheap uorine source.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
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