Controllable double CF2-insertion into sp2 C-Cu bond using TMSCF3: A facile access to tetrafluoroethylene-bridged structures

Article abstract of DOI:10.1039/c9sc05018c

A highly efficient method for controllable double CF₂-insertion into pentafluorophenylcopper species using TMSCF₃ as difluoromethylene source has been developed. The newly generated fluoroalkylcopper(i) species, C₆F₅CF₂CF₂Cu, shows good reactivity towards a myriad of structurally diverse aryl, heteroaryl and alkenyl iodides. This protocol is easy to handle, ready to scale up and applicable for the synthesis of relative complex molecules, thus providing a convenient method for facile access to tetrafluoroethylene-bridged structures.

Full text of DOI:10.1039/c9sc05018c

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Controllable double CF2-insertion into sp2 C–Cu
bond using TMSCF3: a facile access to
Cite this: Chem. Sci., 2020, 11, 276
tetrafluoroethylene-bridged structures†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Qiqiang Xie, Ziyue Zhu, Lingchun Li, Chuanfa Ni and Jinbo Hu
A highly efficient method for controllable double CF2-insertion into pentafluorophenylcopper species using
TMSCF3 as difluoromethylene source has been developed. The newly generated fluoroalkylcopper(I)
species, C6F5CF2CF2Cu, shows good reactivity towards a myriad of structurally diverse aryl, heteroaryl
and alkenyl iodides. This protocol is easy to handle, ready to scale up and applicable for the synthesis of
Received 6th October 2019
Accepted 9th November 2019
DOI: 10.1039/c9sc05018c
relative complex molecules, thus providing
a
convenient method for facile access to
rsc.li/chemical-science
tetrafluoroethylene-bridged structures.
molecules with readily available, easy to handle and environ-
mentally benign reagents under mild conditions is highly
desired.
Introduction
Due to the unique physical, chemical and biological properties
of organouorine compounds, the introduction of uorine
atom(s) or uorinated moieties into organic molecules has
become a routine strategy in drug design and advanced material
development.1–4 Among various uorinated functionalities, the
tetrauoroethylene motif (–CF2CF2–) has attracted considerable
attention because of its applications in agrochemicals5 and
liquid-crystalline materials.6–8 Moreover, the introduction of
–CF2CF2– group into liquid crystals oen results in highly
advantageous properties such as high clearing temperature,
broad nematic phase range, low rotational viscosity and high
dielectric anisotropy.6–8 Therefore, it is of strong demand to
access tetrauoroethylene-bridged molecules.
Current methods for the syntheses of tetrauoroethylene-
bridged structures are mainly based on (1) deoxouorination
of 1,2-dicarbonyl compounds with SF4 and DeoxoFluor;9–11 (2)
uorination of C–C triple bonds using F2;12–14 (3) 1,2-difunc-
tionalization of tetrauoroethylene (TFE);15–23 (4) diuoro-
methylene insertion using CF2Br2 as the CF2 source;24,25 and (5)
using RCF2CF2Br as the build block.5 However, these methods
suffer from several drawbacks such as (1) using toxic, highly
reactive or hazardous reagents; (2) low functional group toler-
ance and/or (3) using explosive gaseous reagents or ozone-
depleting substances (ODS). As such, developing a new
method to incorporate –CF2CF2– structure motif into organic
(Triuoromethyl)trimethylsilane (TMSCF3), oen called
Ruppet–Prakash reagent, is arguably the most widely used
triuoromethylating agent.26–30 In 2011, our group, in collab-
oration with the Prakash group, revealed that TMSCF3 is
a good diuorocarbene precursor, which can be used in the [2
+ 1] cycloaddition reaction with alkenes and alkynes.31
Recently, our group reported that diuorocarbene generated
from TMSCF3 could undergo dimerization to give tetra-
uoroethene (TFE),32,33 which can be used for a variety of
transformations.33 Very recently, our group demonstrated that,
by using TMSCF3 as the diuoromethylene source, control-
lable CF2-insertion into CuCF3 to generate CuCF2CF3 could be
realized.34 Inspired by this C1 to C2 process, we envisioned that
it might be possible to insert CF2 into other C–M bonds.
Herein, we report our latest progress in the uorocarbon
homologation reaction using TMSCF3 as the diuoro-
methylene source. By carefully tuning the reaction conditions,
controllable double insertion of CF2 into C6F5–Cu gives rise to
C6F5CF2CF2Cu, which can be applied to the preparation of
a diverse range of tetrauoroethylene-bridged compounds
(Scheme 1).
Key Laboratory of Organouorine Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: jinbohu@sioc.ac.cn
† Electronic supplementary information (ESI) available. CCDC 1957757. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9sc05018c
Scheme
trimethylsilyl.
1
Fluorocarbon homologation with TMSCF3. TMS
¼
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Results and discussion
Our investigation commenced with the preparation of C6F5-
CF2CF2Cu from TMSC6F5 and TMSCF3. Initially, we used 1
equivalent of TMSC6F5 as the C6F5Cu precursor, 1 equivalent of
TMSCF3 as the diuorocarbene precursor, 2 equivalents of KF
as the desilylating reagent and 2.5 equivalents of CuCl as the
copper source. All these components were added simulta-
neously with DMF as the solvent, and the resulting mixture was
stirred at room temperature for 12 hours. Analysis of the
mixture by 19F NMR spectroscopy revealed that C6F5CF2CF2Cu
(21%), C6F5Cu (57%) and CuCF3 (37%) were formed; no single
CF2-insertion product C6F5CF2Cu could be detected (Table 1,
entry 1). When adding 2 equivalents of diuorocarbene source
TMSCF3, we found that the desired product C6F5CF2CF2Cu was
formed in 79% yield, in conjunction with C6F5Cu (3%), CuCF3
(10%) and CuC2F5 (5%) (entry 2).35 If 3 equivalents of TMSCF3
was used, C6F5CF2CF2Cu was formed in 83% yield, along with
CuCF3 (16%) and CuC2F5 (12%) being formed; neither C6F5Cu
nor triple CF2-insertion product C6F5CF2CF2CF2Cu could be
detected (entry 3). These results (entries 1–3) clearly indicate
that the TMSCF3-derived diuorocoppercarbene (Cu]CF2)
species34 could selectively undergo double CF2-insertion into
C6F5Cu, regardless of the amount of TMSCF3 used. This
behaviour is in accord with previous reports.24 The high selec-
tivity may be attributed to the intrinsic reactivity of different
uoroalkylcopper species toward Cu]CF2 (Scheme 2). As to the
possible intermediate, C6F5CF2Cu, its benzylic C–Cu bond is
highly reactive and tended to insert another CF2 unit to give
C6F5CF2CF2Cu;24,25 the resulting C6F5CF2CF2Cu has lower reac-
tivity than CuCF3 because of its longer uoroalkyl chain.24,25
Therefore, even in the presence of excess of TMSCF3, triple CF2-
Scheme 2 Proposed reaction mechanism.
insertion into C6F5Cu could not be observed; in that case, the
CF2-insertion into CuCF3 to generate CuC2F5 would be fav-
oured. Altogether, the relative reaction rate of each step is k3 > k2
> k1 > k4.
With this understanding in mind, we went on to optimize
the reaction conditions in order to increase the yield of C6F5-
CF2CF2Cu and minimize those of CuCF3 and CuC2F5. By using 2
equivalents of TMSCF3 and prolonging reaction time to 20
hours, C6F5CF2CF2Cu was formed in 87% yield (entry 4). When
we decreased the amount of CuCl from 4 equivalents to 3
equivalents, only trace of C6F5CF2CF2Cu was observed, with
>80% C6F5Cu and CuCF3 being recovered (entry 5). This result
revealed that the presence of excess amount of CuCl is crucial
for the Cu]CF2 generation, which is consistent with our
previous report.34 As CuCF3 was always observed, we tried to
speed up the decomposition of CuCF3 at elevated temperatures.
ꢀ
However, when the reaction was carried out at 50 C, although
no CuCF3 was observed, a larger amount of CuC2F5 was detec-
ted, and C6F5CF2CF2Cu was obtained in relatively lower yield
(entry 6 vs. entry 4). Next, we attempted to add TMSCF3 into the
reaction mixture aer the preparation of C6F5Cu. Gratifyingly,
the yield of C6F5CF2CF2Cu was increased slightly (entry 7). In
light of the decomposition of CuCF3 to Cu]CF2 would release
a
Table 1 Optimization of reaction conditions for the double CF2 insertion into C6F5Cu with TMSCF3
Yield (%)
Entry
TMSC6F5 : CuCl : KF : TMSCF3
t (h)
T (ꢀC)
C6F5C2F4Cu
C6F5Cu/CuCF3/CuC2F5
1b
1 : 2.5 : 2 : 1
1 : 4 : 3 : 2
1 : 5.5 : 4 : 3
1 : 4 : 3 : 2
1 : 3 : 3 : 2
1 : 4 : 3 : 2
1 : 4 : 3 : 2
1 : 4 : 2 : 2
1 : 4 : 3 : 2
1 : 4 : 3 : 2
1 : 4 : 3 : 1.9
1 : 4 : 3 : 1.9
1 : 4 : 3 : 1.9
12
12
12
20
20
10
28
28
28
28
28
36
28
rt
rt
rt
rt
rt
50
rt
rt
rt
rt
rt
rt
rt
21
79
83
87
1
75
91
76
91
93
92
86
89
57/37/n.d.
3/10/5
n.d./16/12
4/2/4
87/82/n.d.
1/n.d./23
<1/<1/4
n.d./2/5
n.d./6/2
n.d./8/2
2/4/2
2b
3b
4b
5b
6b
7
8
9c
10d
11e
12e
13e,f
3/4/2
n.d./1/2
a
Reactions were performed on 0.2 mmol TMSC6F5 (1.0 equiv.) scale. Yields were determined by 19F NMR spectroscopy using PhOCF3 as an internal
standard. n.d. ¼ not detected. b TMSC6F5 and TMSCF3 were added simultaneously without the pre-preparation of C6F5Cu. c TMSCF3 was added in
three portions for every 4 hours. d TMSCF3 was added in three portions for every 6 hours. e TMSCF3 was added in two portions for every 6 hours.
f
Aer reacted at rt for 28 hours, the reaction mixture was stirred at 60 ꢀC for another 2 hours.
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uoride ions, we surmised that the amount of externally added of CuC2F5, we envisaged that adding TMSCF3 in batches to
KF could be reduced. However, lowering down KF to 2 equiva- decrease the concentration of CuCF3 might be helpful. Aer
lents gave inferior result (entry 8). To further decrease the yield some brief optimizations and decreasing the amount of
TMSCF3 to 1.9 equivalents (entries 9–11), C6F5CF2CF2Cu was
formed in 92% yield, together with 2% of C6F5Cu and 4% of
CuCF3 being formed (entry 11). Prolonging the reaction time to
36 hours did not have any benecial effect (entry 12). Finally,
when the reaction was coꢀnducted at room temperature for 28
hours, then stirred at 60 C for 2 hours, no C6F5Cu and little
amounts of CuCF3 (1%) and CuC2F5 (2%) could be detected,
with C6F5CF2CF2Cu being formed in 89% yield (entry 13).
With the optimized conditions (Table 1, entry 13) in hand,
the reactivity of this TMSCF3-derived C6F5CF2CF2Cu towards
aryl iodides was studied. A variety of structurally diverse
(hetero)aryl and alkenyl iodides are all viable substrate, giving
the desired tetrauoroethylene-bridged products in moderate
to good yields (Scheme 3). The electronic character of aryl
iodides do not have obvious inuence on the reaction effi-
ciency, and both electron-decient (2a–i) and electron-rich
(2k–p, 2r–s) substrates were readily transformed to the
desired products in good yields. Common functional groups
such as nitro (2a–c, in ortho, meta and para positions), acetyl
(2d), ester (2e), cyano (2f), sulfonamide (2h) and sulfone (2i)
were compatible with the reaction conditions, and good yields
of products were observed. Notably, because of the mildness of
the reaction conditions, some sensitive functionalities
including aldehyde (2g, 2ab–ac), alcohol (2m) and unprotected
NH group (2u, 2ab), were also tolerated. Heterocycles, such as
pyrazole (2p), coumarin (2q), carbazole (2r), benzothiophene
(2s), quinoline (2t) and indole (2u) were competent under the
reaction conditions, as demonstrated by the formation of
tetrauoroethylene-bridged products in high yields. Moreover,
heteroaryl iodides, including iodopyridine (2w–x), iodoimida-
zole (2y), iodoisoxazole (2z), iodothiophene (2aa), iodopyrrole
(2ab) and iodofuran (2ac), participated in this per-
uorophenylethylation to afford corresponding products in
moderate to good yields (54–84%). Iodoalkene 1ad also
showed good reactivity towards C6F5CF2CF2Cu, furnishing the
desired product 2ad in 88% yield. This protocol is also
Scheme
3 Perfluorophenylethylation of (hetero)aryl iodides with
a
TMSCF3-derived C6F5CF2CF2Cu. Unless otherwise noted, reactions
were performed on 0.5 mmol of 1 (1.0 equiv.) scale, and TMSCF3 was
added in two portions every 6 h; 1.5 equivalents of TMSC6F5 was used;
b
the molar ratio of TMSC6F5 : CuCl : KF : TMSCF3 ¼ 1 : 4 : 3 : 1.9. 1.6
equivalent of TMSC6F5 was used. c 1.8 equivalent of TMSC6F5 was used. Scheme 4 Gram-scale synthesis.
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Fig. 1 (a) The single crystal structure and (b) packing diagram of 2n.36
effective for the peruorophenylethylation of relatively providing an easy access to a variety of –CF2CF2– bridged
complex compounds and pharmaceutical intermediates 1ae molecules. Compared with previous methods for the construc-
and 1af, giving the corresponding products 2ae and 2af in 96% tion of –CF2CF2– unit, this approach owns several merits such
and 88% yields, respectively. The broad scope of this reaction as utilizing commercially available and environmentally benign
underscores the great potential of its application in the reagents as the CF2 source, easy to handle, broad substrate
synthesis of a ra of valuable –CF2CF2– bridged molecules.
scope and mild conditions. This double CF2-insertion strategy
The inherent value of our controllable double CF2-insertion represents the second generation of uorocarbon homologa-
strategy with TMSCF3 for the introduction of tetrauoro- tion reactions via diuoromethylene insertion using TMSCF3
ethylene bridge is further demonstrated by its applicability to (the rst generation is single CF2-insertion into CuCF3). Further
gram-scale synthesis. For example, when iodoisoxazole 1z was efforts to seek aer novel CF2-insertion reactions using TMSCF3
scaled up to 5 mmol (1.12 g), the desired product 2z was ob- are currently underway in our laboratory.
tained in 83% yield (1.50 g). Analogously, pharmaceutical
intermediates 1ae and 1af were also successfully scaled up to
5 mmol, with the yields comparable to that on 0.5 mmol scale
Conflicts of interest
(Scheme 4).
There are no conicts to declare.
It is worthwhile to note that the tetrauoroethylene-bridged
product 2n possesses interesting conformation and intermo-
lecular interaction. As shown in Fig. 1,36 the single crystal
structure of product 2n shows that the dihedral angle of C10–
C11–C12–C13 is 174.1ꢀ, and two aromatic (the naphthalenyl
and pentauorophenyl) rings in 2n are almost parallel to each
other (see Fig. 1a, also see ESI†). The packing diagram shows
there are extensive intermolecular p–p stackings between
naphthalenyl and pentauorophenyl rings of 2n (Fig. 1b), which
might nd useful applications in crystal engineering and
materials science.
Acknowledgements
This work was supported by the National Basic Research
Program of China (No. 2015CB931900, 2016YFB0101200), the
National Natural Science Foundation of China (No. 21632009,
21421002), the Key Programs of the Chinese Academy of
Sciences (No. KGZD-EW-T08), the Key Research Program of
Frontier Sciences of CAS (No. QYZDJ-SSW-SLH049), and
Shanghai Science and Technology Program (No. 18JC1410601).
Notes and references
Conclusions
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The resulting C6F5CF2CF2Cu species showed high reactivity
towards various (hetero)aryl iodides and alkenyl iodides,
2006.
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35 The chemical shis of these uoroalkylcopper/
uoroarylcopper species were assigned as follows (in ppm):
C6F5CF2CF2Cu, ꢁ101.1 (t, 2F), ꢁ106.6 (s, 2F), ꢁ139.4 (m,
2F), ꢁ153.1 (t, 1F), ꢁ163.9 (t, 2F); C6F5Cu, ꢁ111.0 (d, 2F),
ꢁ163.3 (t, 1F), ꢁ164.3 (t, 2F); CuCF3, ꢁ26.7 (s, 3F); CuC2F5,
ꢁ84.0 (s, 3F), ꢁ112.4 (s, 2F).
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1957757†
contains
the
supplementary
S. Ogoshi, Angew. Chem., Int. Ed., 2017, 56, 11911–11915. crystallographic data for compound 2n.
280 | Chem. Sci., 2020, 11, 276–280
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