CuI-Catalyzed Pentafluoroethylation of Aryl Iodides in the Presence of Tetrafluoroethylene and Cesium Fluoride: Determining the Route to the Key Pentafluoroethyl CuI Intermediate

Article abstract of DOI:10.1002/chem.201802415

The Cu(I)-catalyzed pentafluoroethylation of iodoarenes via the fluorocupration of tetrafluoroethylene (TFE) is disclosed. The active species, (phen)CuC₂F₅, was isolated and its molecular structure confirmed by a single-crystal X-ray diffraction analysis. The key to the successful suppression of the competing oligomerization of TFE is to refrain from stirring the reaction mixture. A mechanistic study clearly discarded the possibility that the catalytic reaction proceeds via a radical pathway.

Full text of DOI:10.1002/chem.201802415

A Journal of
Accepted Article
Title: Cu(I)-Catalyzed Pentafluoroethylation of Aryl Iodides in
the Presence of Tetrafluoroethylene and Cesium Fluoride:
Determining the Route to Key Pentafluoroethyl Cu(I) Intermediate
Authors: Masato Ohashi, Naoyoshi Ishida, Kota Ando, Yu Hashimoto,
Anna Shigaki, Kotaro Kikushima, and Sensuke Ogoshi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201802415
Link to VoR: http://dx.doi.org/10.1002/chem.201802415
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10.1002/chem.201802415
Chemistry - A European Journal
Cu(I)-Catalyzed Pentafluoroethylation of Aryl
Iodides in the Presence of Tetrafluoroethylene and
Cesium Fluoride: Determining the Route to Key
Pentafluoroethyl Cu(I) Intermediate
Masato Ohashi*, Naoyoshi Ishida, Kota Ando, Yu Hashimoto, Anna Shigaki, Kotaro Kikushima, and
Sensuke Ogoshi*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
ohashi@chem.eng.osaka-u.ac.jp (M.O.); ogoshi@chem.eng.osaka-u.ac.jp (S.O)
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Continuous efforts have been devoted to the development of novel strategies for the preparation of
organofluorine compounds, mostly on account of their applications in a variety of research areas that
include pharmaceutical, agrochemical, and materials sciences.1 Especially, fluorine is an often-used
substituent in drug design, owing to its unique combination of electronegativity, size, and lipophilicity.
Among such fluorinated compounds, trifluoromethylated aryl compounds (Ar–CF3) are one of the
most attractive structural motifs in biologically active compounds.2 Therefore, a variety of synthetic
routes to trifluoromethyl copper(I) species (Cu–CF3) have been developed and subsequently used as
key intermediates in trifluoromethylation reactions of aromatic compounds.2,3 In comparison with such
trifluoromethylation reactions, the introduction of longer-chain perfluoroalkyl groups employing the
corresponding copper(I) species remains largely unexplored.4 The comparatively limited synthetic
access to the pentafluoroethyl copper(I) key intermediate (Cu–C2F5) can be divided into three main
routes: a) a transmetallation of pentafluoroethyl anion equivalents with copper salts,4a-f b) a
deprotonation of C2F5H,4g,h and c) a reaction with penta-fluoroethylpropionate derivatives.4i,j Although
fluorinated and tri-fluoromethylated aromatic compounds account for the majority of fluorine-
containing drugs, only very few biologically active compounds that contain the pentafluoroethyl group
have been reported to date.5 Therefore, the development of practical, cost-effective, and reliable
methods for the pentafluoroethylation of aromatic compounds is highly desirable.
Our group has been developing a series of transformations of tetrafluoroethylene (TFE; CF2=CF2)
into valuable organofluorine compounds; our interest in TFE is due to the fact that TFE i) is employed
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as a monomer for the preparation of tetrafluoroethylene-based polymers,6 and ii) represents a cost-
efficient and environ-mentally benign feedstock with negligible GWP100 and ODP values.7 Indeed, we
have already demonstrated that TFE can serve as an ideal C2 building block for the introduction of
fluorinated functional groups, such as -CF=CF2,8 -CF2CF2H,9 or -CF2CF2-,10 into organic molecules.
In the Cu-mediated transformation of TFE into 1,2-diaryl-tetrafluoroethane derivatives, the
carbocupration of TFE is a key elementary step (Scheme 1a).10a In addition, we have demonstrated
that the carbocupration can be successfully expanded to the related oxycupration of TFE, which led to
a variety of fluoroalkylethers (Scheme 1b).10b After our manuscript on this oxycupration chemistry
was published online, we noted that during roughly the same period, Hu and co-workers had developed
related (aryloxy)tetrafluoroethylation and pentafluoroethylation reactions, in which TFE was prepared
in situ from CF3SiMe3.11 Although they demonstrated the related synthetic utility of
pentafluoroethylations employing TFE, special efforts to distinguish two possible routes to the key
Cu–C2F5 intermediates, i.e., the fluorocupration of TFE12,13 or the transmetallation between CsC2F5
and copper(I) halide,3b,14 were not undertaken. In addition, applications of these Cu-catalyzed penta-
fluoroethylations were not carried out. In this manuscript, we focused our attention in particular on
disclosing that the fluorocupration of TFE affords indeed a Cu–C2F5 species and the first examples of
the Cu(I)-catalyzed pentafluoroethylation of aryl iodides (Scheme 1c).15
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Scheme 1. Carbocupration, oxycupration, and fluorocupration of TFE.
Based on our results on the carbocupration and the oxycupration of TFE, we initially investigated
a stoichiometric reaction between (phen)CuF (1)16 and TFE. Exposure of a CH2Cl2 solution of 1 to 5.0
atm of TFE at room temperature for 6 h induced the desire fluorocupration to yield (phen)Cu(C2F5)
(2) in 54% isolated yield as an orange solid (Scheme 2). Monitoring the reaction by 19F NMR
spectroscopy demonstrated a smooth and quantitative progress of the fluorocupration. A further
carbocupration of TFE, i.e., another addition of the Cu–C bond in 2 across the C=C bond of another
molecule of TFE, did not occur, not even after prolonged heating to 60 ºC. We also confirmed that the
thermolysis of 2 under an atmosphere of N2 (in DMF, 60 °C, 18 h) did not result in - or -fluorine
elimination reactions. As previously reported,3c,d,4b,d,10 2 exists in DMF as a mixture of a neutral form
([(phen)Cu(C2F5)]; 2neutral) and an ionic form ([(phen)2Cu][Cu(C2F5)2]; 2ionic).17
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Scheme 2. Preparation of (phen)CuC2F5 (2) via the fluorocupration of TFE and
pentafluoroethylation of iodobenzene (3a) using 2.
In contrast to the fluorocupration of TFE, neither the related chlorocupration with [(phen)CuCl]18
nor the cyanocupration with [(phen)CuCN]19 proceeded, not even at 80 ºC. In addition, other alkenes,
such as ethylene, chlorotrifluoroethylene, and vinylidene fluoride, did not participate in the
fluorocupration of 1 to yield the corresponding ethylcopper derivatives.17 The molecular structure of
2 was unambiguously determined by single-crystal X-ray diffraction analysis (Figure 1).20 In the
crystal lattice, the Y-shaped coordination geometry of 2, which manifests in an N–Cu–N bond angle
of 80.79(8)º, is considerably distorted, which is also reflected in the C–Cu–N bond angles
[147.28(10)º/131.64(10)º] and the Cu–N bond distances [2.101(2) Å/2.013(4) Å], while the degree of
distortion in 2 is slightly smaller than that observed in (bpy)CuC2F5 (bpy = 2,2’-bipyridyl).4h
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Figure 1. ORTEP drawing of 2 with thermal ellipsoids set to 30% probability; all
hydrogen atoms have been omitted for clarity, and only selected atoms have been
labelled.
In agreement with the report by Hu,11 treatment of 2 with iodobenzene (3a) in DMF at 60 ºC yielded
pentafluoroethylbenzene (4a) in 85% yield (Scheme 2). In response to the result of the stoichiometric
reaction, our subsequent efforts were devoted to the development of a Cu(I)-catalyzed
pentafluoroethylation of iodoarenes in the presence of metal fluoride as a source of fluoride anions.
When 3a was treated with TFE in DMF at 80 ºC in the presence of 1 (20 mol %) and CsF (300 mol %),
4a was obtained in 81%.21
With the optimal reaction conditions in hand,21 the catalytic reaction was then conducted on a larger
scale (1.0 mmol of 4-iodo-biphenyl 3b) using a 50 mL autoclave reactor.22 In the presence of 1, a DMF
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solution of 3b was heated to 60 °C for 16.5 h with stirring, leading to a diminished yield of 4-
pentafluoroethybiphenyl (4b; 30%) and a considerable oligomerization of TFE (Scheme 3a). In this
reaction, all TFE monomers were transformed into oligomers, whereby the major component of the
resulting oligomer mixture was the pentamer. The occurrence of such oligomerizations was confirmed
by treating a DMF solution of CsF with TFE in theautoclave reactor with stirring.17 Graham has also
reported that a similar oligomerization of TFE in diglyme was facilitated by the addition of CsF.23
Based on the fact that the oligomerization did not occur in the high-pressure NMR tube, the reaction
was carried out without stirring, which led to the isolation of 4b in 97% yield (Scheme 3b, Table 1).
The undesired oligomerization was thus completely suppressed when the reaction mixture was not
stirred, which clearly indicates that the dissolved concentration of TFE is a key factor for suppressing
the oligomerization of TFE.24,25
Scheme 3. Cu(I)-catalyzed pentafluoroethylation of 3b in the presence of TFE and CsF.
Each reaction was conducted in a 50 mL glass autoclave reactor (a) with stirring or (b)
without stirring. a Estimated by 19F NMR spectroscopy. b Isolated yield.
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Subsequently, we investigated the scope and limitations in the Cu(I)-catalyzed
pentafluoroethylation (Table 1). Initially, the substrate scope was investigated by chiefly employing
iodoarenes with relatively-higher molecular weight, given the ease of isolation of 4, which exhibits
high volatility. The reaction with monoiodobiphenyl derivatives (3b,c) allowed isolating the
corresponding pentafluoroethylated products (4b,c) in good to excellent yield. The reaction with 1-
iodonaphthalene (3d) furnished 1-pentafluoroethyl-naphthalene (4d) in 76% yield. 9-
Iodophenanthrene (3e) and 1-iodo-pyrene (3f) also gave the corresponding products (4e,f) in excellent
yield. Furthermore, the use of 2-iododibenzofuran (3g), N-phenyl-3-iodo-carbazole (3h), and 2-iodo-
9,9-dimethyl-fluorene (3i) led to the almost quantitative formation of the corresponding products (4g-
i). However, using 2-iodofluorene (3j), which contains weakly acidic protons (pKa = 22.6 in DMSO26)
at the C9 position, did not afford the expected 2-pentafluoroethylfluorene (4j).
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Table 1. Substrate scope in the Cu(I)-catalyzed pentafluoroethylation of iodoarenes
(3) in the presence of TFE and CsF
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We then further investigated the electronic influence of the ring substituents in monoaromatic
compounds on the catalytic activity. It should be noted that the isolated yield of some products
decreased considerably due to their high volatility. When iodobenzene 3a was employed, the catalytic
reaction proceeded quantitatively to yield 4a. The use of electron-rich aryl iodides, such as p-t-butyl-
(3k), p-benzyloxy- (3l), and p-methoxy-iodoarene (3m), afforded the corresponding products (4k-m)
in excellent yield. In contrast, the reactions with p-iodo-ethylbenzoate (3n) and o-iodo-pyridine
derivative (3o) proceeded sluggishly. In addition, the reactions with iodoarenes bearing a nitro group
(3p-r) proceeded slowly, whereas a stoichiometric treatment of 3p-r with in-situ-generated 2 resulted
in the clean formation of 4p-r.11 In this catalytic system, the electron-withdrawing group, especially
the nitro substituent, might impede the regeneration of the key intermediates 1 and/or 2. Moreover,
diiodoarene derivatives (3s,t) could be employed as substrates for the preparation of
bis(pentafluoroethyl)arenes (4s,t), while an increased catalyst loading was required. When 2-bromo-
8-iodo¬dibenzofuran (3u) was employed, 2-bromo-8-(pentafluoroethyl)dibenzofuran (4u) was
obtained as the major product, albeit that trace amount of 4s were also detected due to a
pentafluoroethylation of the C(sp2)–Br bond.
A plausible reaction mechanism for the Cu-catalyzed pentafluoroethylation is shown in Scheme 4.
As demonstrated in Scheme 2, the fluorocupration step of TFE (step a) occurs smoothly, even at room
temperature, and generates 2. Based on the fact that addition of fluoride did not retarded the
fluorocupration of TFE, the fluorocupration mechanism might not have involved the so-called outer
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sphere mechanism, a dissociation of fluoride from (phen)CuF (1), a coordination of TFE to the copper
center, and then a subsequent nucleophilic attack of the fluoride to TFE that coordinates to the copper.17
In addition to the previous reports regarding the reactivity of 2 toward aryl iodides,3b,4b,f,11 the
stoichiometric reaction between 2 and 3a delivered compelling evidence for the occurrence of the
pentafluoroethylation (step b). The existence of the regeneration step from (phen)CuI to (pehn)CuF
(1) (step c) was confirmed by monitoring of the reaction by UV-Vis spectroscopy. When a DMF
solution of (phen)CuI was treated with 15 equiv of CsF at 80 ºC for 3 hours, the UV-Vis spectrum of
the crude reaction mixture revealed the regeneration of 1.17 Another possible route leading to the key
intermediate 2, in which (phen)CuI directly undergoes a transmetalation with CsC2F5,3b cannot be ruled
out completely at this time, given that the competing oligomerization of TFE occurred, which suggests
the generation of CsC2F5 in situ.14,22 A stoichiometric pentafluoroethylation employing 2-
(allyloxy)iodobenzene (3v) clearly discarded the possibility that this catalytic system proceeds via a
radical pathway.3b,17
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Scheme 4. Plausible reaction mechanism for the Cu(I)-catalyzed pentafluoroethylation
of iodearenes in the presence of TFE and CsF.
In conclusion, we have demonstrated that the fluorocupration of TFE occurs in the presence of phen
as an auxiliary ligand, resulting in the clear formation of (phen)CuC2F5. We moreover reconfirmed
that the stoichiometric pentafluoroethylation of iodoarenes with (phen)CuC2F5 proceeded smoothly.
Furthermore, the resulting (phen)CuI is transformed into (phen)CuF in the presence of an excess of
CsF. We have thus reported the first examples for a Cu(I)-catalyzed pentafluoroethylation of aryl
iodides in the presence of TFE and CsF, in which refraining from stirring the reaction mixture is the
key to suppressing the competing oligomerization of TFE. This reaction allows the effective use of
TFE as a starting material for the preparation of pentafluoroethylated aromatic compounds that have
potential value as biologically active compounds.
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[**] This work was partially supported by Grant-in-Aid for Scientific Research (A) (No.
A16H02276) and (B) (Nos. 16KT0057 and 17H03057) from Japan Society for the Promotion of
Science (JSPS). The authors acknowledge the help of Prof. Dr. N. Tohnai and Prof. Dr. Y. Takeda for
collecting X-ray diffraction data and for measuring UV-vis spectroscopy, respectively.
Keywords: pentafluoroethylation · copper· fluorine· catalytic reaction · fluorocupration
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[15]
A part of our pentafluoroethylation chemistry was presented at several domestic and
international conferences: a) N. Ishida, K. Kikushima, M. Ohashi, S. Ogoshi, The 66th Conference
of Japan Society of Coordination Chemistry, Fukuoka, Japan, September, 2016, 1PD-16. b) N.
Ishida, K. Kikkushima, M. Ohashi, S. Ogoshi, International Symposia on Organometallic
Chemistry Directed Towards Organic Synthesis (OMCOS 19), Jeju, Korea, June, 2017, PP1-131.
[16]
Complex 1 was prepared from the previously reported N-heterocyclic carbene analogue
(SIPr)CuF. See, a) C. M. Wyss, B. K. Tate, J. Bacsa, M. Wieliczko, J. P. Sadighi, Polyhedron 2014,
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10.1002/chem.201802415
Chemistry - A European Journal
84, 87. Cuprous fluorides ligated with a substituted phenanthroline derivative: see, b) Y. Liu, C.
Chen, H. Li, K.-W. Huang, J. Tan, Z. Weng, Organometallics 2013, 32, 6587. It might be worth
mentioning that CuF itself is a compound which does not exist, because it disproportionates Cu
and CuF2.
[17]
For details, see the Supporting Information.
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2015, 7, 1539.
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Engelhardt, C. Pakawatchai, V. A. Patrick, A. H. White, J. Chem. Soc., Dalton Trans. 1985, 839.
[20]
CCDC 1835390 (2) contains the supplementary crystallographic data for this paper. This data
can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/ data_request/cif.
[21]
For the optimization of the Cu(I)-catalyzed pentafluoroethylation reaction (conducted in a
pressure-tight NMR tube), see the Supporting Information.
[22]
Since the isolation of 4a was hampered by its high volatility, 3b was used for the scale-up test.
a) D. P. Graham, J. Org. Chem. 1969, 31, 955; b) R. H. Haszeldine, B. Hewitson, A. E.
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Tipping, J. Chem. Soc., Perkin Trans. 1 1976, 1178.
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10.1002/chem.201802415
Chemistry - A European Journal
[24]
We have recently demonstrated that CO gas itself has been utilized in a nickel(0)-catalyzed
[2+2+1] carbonylative cycloaddition, in which refraining from stirring the reaction mixture is the
key to suppressing a rapid CO saturation that leads to catalytic deactivation. Y. Hoshimoto, K.
Ashida, Y. Sasaoka, R. Kumar, K. Kamikawa, X. Verdaguer, A. Riera, M. Ohashi, S. Ogoshi,
Angew. Chem. Int. Ed. 2017, 56, 8206.
[25]
Although there still remains a room for improvement of the catalytic efficiency, it would be
improved by introduction of the gas flow control system to regulate the TFE concentration strictly.
At this stage, such a flow control system for TFE gas was not available.
[26]
F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456.
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10.1002/chem.201802415
Chemistry - A European Journal
for table of contents use only
Cu(I)-Catalyzed Pentafluoroethylation of Aryl Iodides in the Presence of Tetrafluoroethylene
and Cesium Fluoride: Determining the Route to Key Pentafluoroethyl Cu(I) Intermediate
Masato Ohashi*, Naoyoshi Ishida, Kota Ando, Yu Hashimoto, Anna Shigaki, Kotaro Kikushima,
and Sensuke Ogoshi*
The Cu(I)-catalyzed pentafluoroethylation of iodoarenes via the fluorocupration of tetrafluoroethylene
(TFE) is disclosed. The active species, (phen)CuC2F5, was isolated and its molecular structure
confirmed by a single-crystal X-ray diffraction analysis. The key to the successful suppression of the
competing oligomerization of TFE is to refrain from stirring the reaction mixture. A mechanistic study
clearly discarded the possibility that the catalytic reaction proceeds via a radical pathway.
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