Well-defined copper(I) fluoroalkoxide complexes for trifluoroethoxylation of aryl and heteroaryl bromides

Article abstract of DOI:10.1002/anie.201501257

Copper(I) fluoroalkoxide complexes bearing dinitrogen ligands were synthesized and the structure and reactivity of the complexes toward trifluoroethoxylation, pentafluoropropoxylation, and tetrafluoropropoxylation of aryl and heteroaryl bromides were investigated. Efficiency drive: A series of copper(I) fluoroalkoxide complexes bearing N,N ligands have been prepared and structurally characterized. These well-defined complexes serve as efficient reagents for the fluoroalkoxylation of aryl and heteroaryl bromides to produce a wide range of trifluoroethyl, pentafluoropropyl, and tetrafluoropropyl (hetero)aryl ethers in good to excellent yields.

Full text of DOI:10.1002/anie.201501257

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501257
German Edition: DOI: 10.1002/ange.201501257
Synthetic Methods
Well-Defined Copper(I) Fluoroalkoxide Complexes for
Trifluoroethoxylation of Aryl and Heteroaryl Bromides**
Ronglu Huang, Yangjie Huang, Xiaoxi Lin, Mingguang Rong, and Zhiqiang Weng*
Abstract: Copper(I) fluoroalkoxide complexes bearing dini-
trogen ligands were synthesized and the structure and reactivity
of the complexes toward trifluoroethoxylation, pentafluoro-
propoxylation, and tetrafluoropropoxylation of aryl and
heteroaryl bromides were investigated.
T
he development of an efficient and convenient method for
the synthesis of fluoroorganic compounds is of paramount
significance because of their importance in the fields of
medicinal chemistry[1–3] and material sciences.[4] Over the last
few years, numerous synthetic examples of the selective
incorporation of fluorine-containing groups into organic
molecules have been developed.[5–9] Among them, trifluoro-
ethyl aryl ethers have attracted much attention because of the
high metabolic stability and significant lipophilicity of the
CF3CH2O group.[10,11] As a consequence of their various
beneficial pharmacological activities, trifluoroethyl aryl
ethers are widely used by the pharmaceutical industry in
many drugs and drug candidates.[10,12] Well-known examples
include Silodosin for the symptomatic treatment of benign
prostatic hyperplasia, Flecainide used to prevent and treat
tachyarrhythmias, as well as proton-pump inhibitor Lanso-
prazole (Scheme 1).[13]
Scheme 1. Trifluoroethyl aryl ether based drugs and bioactive com-
pounds.
high reaction temperatures, and long reaction times.[19]
Recently, Legros, Crousse, and co-workers developed
a copper-catalyzed synthesis of fluorinated aryl and vinyl
ether using neat fluoro alcohols as both the reactant and
solvent at reflux for 17 h.[20] Fluorinated aryl and vinyl ethers
were synthesized in good to excellent yields and several
aromatic substituents were tolerated. However, this proce-
dure requires a large excess of expensive fluorinated alcohols
(3–7 equiv) for effective coupling reactions. Singh and co-
workers also reported a palladium-catalyzed fluoroalkoxyla-
tion by the cross-coupling of primary fluoroalkyl alcohols
with activated aryl halides.[21] However, these reported
experiments required the use of the precious metal Pd and
phosphine ligands, and were limited to aryl substrates
containing electron-withdrawing groups.
Heteroaryl halides are a desirable class of substrates for
fluoroalkoxylation reactions because of the importance of
heterocyclic compounds in medicinal chemistry, agrochemis-
try, and materials science.[22] Therefore, there still remains
a large demand for the development of a general, practical,
and selective procedure for the fluoroalkoxylation of hetero-
aryl halides to provide trifluoroethyl heteroaryl ethers.
Our group has recently developed a novel and concise
route to synthesize copper(I) trifluoromethylthiolate/seleno-
late reagents [(bpy)Cu(SCF3)] and [(bpy)Cu(SeCF3)]2 for the
nucleophilic trifluoromethylthiolation/selenolation of organic
halides.[23] As a continuation of our work, we herein disclose
the synthesis and use of a copper(I)-OCH2RF complex for the
fluoroalkoxylation of aryl and heteroaryl bromides.
The prevalence of this structural motif in pharmaceutical
agents has resulted in methods to prepare trifluoroethyl aryl
ethers having been an important theme in organic chemistry
and drug discovery. Many interesting synthetic methods have
been developed for their synthesis,[14–16] including the nucle-
ophilic addition of a phenol to trifluoroethyl iodide[17] or
trifluoroethyl mesylate[18] in solvents such as DMSO or
hexamethyl phosphoramide (HMPA) at elevated temper-
atures (up to 1408C). An important alternative has also been
reported, where aryl halides are used to react with trifluor-
oethanol. However, these methods all depend on harsh
reaction conditions, such as the use of excess copper salts,
[*] R. Huang, Y. Huang, X. Lin, M. Rong, Prof. Dr. Z. Weng
State Key Laboratory of Photocatalysis on Energy and Environment
College of Chemistry, Fuzhou University
Fuzhou, 350108 (China)
E-mail: zweng@fzu.edu.cn
Homepage: http://chem.fzu.edu.cn/szdw/teacherinfo.asp-
x?id=99
[**] Financial support from the National Natural Science Foundation of
China (NSFC) (grant number 21372044), the Research Fund for the
Doctoral Program of Higher Education of China (grant number
20123514110003), and Fuzhou University (grant numbers 022318,
022494) is gratefully acknowledged. We thank Prof. Kuo-Wei Huang
(KAUST) for insightful discussions.
The synthesis of copper trifluoroethoxide complexes and
their higher fluorinated homologue complexes is outlined in
Scheme 2. The reaction of CuOtBu with phenanthroline
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501257.
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Table 1: Copper-mediated trifluoroethoxylation of 1-bromo-4-nitroben-
zene.
Entry Conditions
Yield [%]
86[a]
Scheme 2. Synthesis of copper(I) fluoroalkoxide complexes 1a–c.
r.t.=room temperature.
1
2
3
[(phen)2Cu][OCH2CF3] (1a) (1.2 equiv), NaOtBu,
DMF, 808C
HOCH2CF3 (1.2 equiv), NaOtBu (1.2 equiv), DMF,
808C
NR[b]
85[c]
(phen; 2 equiv) in THF, with subsequent addition of trifluor-
oethanol, led to the formation of the CuI complexes 1a–c in
91%, 82%, and 80% yields, respectively. These new fluo-
roalkoxide complexes are amenable to large-scale synthesis
(ꢀ 2 g) and may be stored indefinitely at À308C.
CF3CH2OH (7 equiv), CuI (10 mol%), ethyl 2-oxocy-
clohexanecarboxylate (20 mol%), Cs2CO3 (1.4 equiv),
788C
4
CF3CH2OH (1.5 equiv), [Pd2(dba)3] (1.0 mol%), Brett- NR[b,d]
Phos (2.5 mol%), Cs2CO3 (1.5 equiv), toluene, 858C
Few examples of structurally characterized fluorinated
copper(I) alkoxide complexes are reported in the litera-
ture,[24,25] and this prompted us to conduct single-crystal X-ray
crystallographic studies on our complexes (Figure 1).[26] The
[a] Yield of isolated product. [b] NR=no reaction. [c] Ref. [20].
[d] Ref. [21]. dba=trans,trans-dibenzylideneacetone.
Having found an effective procedure for the trifluoroe-
thoxylation, we next investigated the reaction scope with
various bromoarenes, and the results are summarized in
Scheme 3. The para-tert-butyl- and phenyl-substituted bro-
Figure 1. ORTEP diagram of 1a with thermal ellipsoids at the 40%
probability level. Cu(1)-N(1) 2.013(4), Cu(1)-N(2) 2.063(4), Cu(1)-N(3)
2.008(4), Cu(1)-N(4) 2.071(4) ꢀ.
Scheme 3. Trifluoroethoxylation of aryl bromides with 1a. Reaction
conditions: 1a (0.48 mmol), 2 (0.40 mmol), NaOtBu (0.40 mmol),
DMF (2.0 mL), 12 h, N2, 808C. Yields of isolated products are shown.
solid-state structure shows that 1a contains one cationic
tetrahedral copper center ligated by two of the dative phen
ligands and one free, unligated anionic [CF3CH2O]À moiety.
Having established the structures of the alkoxide com-
plexes, we sought to evaluate the reactivity of these com-
plexes toward fluoroalkoxylation. Our investigations began
by examining the reaction of complex 1a with 1-bromo-4-
methoxybenzene (2e). After conducting a thorough screen of
additives, solvents, temperature, and reaction time, we
observed that NaOtBu as an additive and DMF as the solvent
at 808C for 12 h afforded a good yield of the desired product
3e in 86% yield (Table 1, entry 1). The addition of NaOtBu
significantly enhanced the reaction efficiency, probably by
facilitating the formation of the active intermediate. Notably,
the reaction of 2e with HOCH2CF3 and NaOtBu did not take
place (entry 2). Likewise, the palladium-catalyzed method did
not generate the product 3e (entry 4).[21] Although the
copper-catalyzed trifluoroethoxylation gave a comparable
yield of 3e (85%), a large excess (7 equiv) of CF3CH2OH was
used (entry 3).[20]
mobenzene reacted with 1-bromonaphthalene to give the
corresponding trifluoroethoxylated products 3a, 3c, and 3d in
84%, 83%, and 90% yields, respectively. The sterically
hindered aryl bromide 2-bromotoluene furnished the product
3b in 81% yield. An aryl bromide having an electron-
donating 4-methoxy group exhibited good reactivity to afford
3e in 86% yield. Aryl bromides possessing electron-with-
drawing groups, such as nitrile, ketone, ester, and nitro, were
also good coupling partners, providing products 3 f–k in yields
of 64–96%. Meta-chloro-substituted bromobenzene was also
a good substrate under our conditions to give product 3l in
64% yield. Moreover, the reaction is not limited to aryl
bromides, it can also be performed with aryl iodides under the
same reaction conditions (see the Supporting Information).
After having established that the reaction occurred with
a wide range of substrates, the method was applied to
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Scheme 5. Fluoroalkoxylation of heteroaryl bromides with 1b and 1c.
Reaction conditions: 1b or 1c (0.36 mmol), 4 (0.30 mmol), NaOtBu
(0.30 mmol), DMF (2.0 mL), 12 h, N2, 808C. Yields of isolated prod-
ucts are shown.
strated excellent compatibility with a wide range of functional
groups, such as chloro, nitro, nitrile, and ester. The reaction
with 2-pyrimidinyl, 6-imidazo[1,2-a]pyrazinyl, and 3-ben-
zo[b]thiophenyl bromides also afforded the desired products
in good to high yields.
Scheme 4. Trifluoroethoxylation of heteroaryl bromides with 1a. Reac-
tion conditions: 1a (0.36 mmol), 4 (0.30 mmol), NaOtBu (0.30 mmol),
DMF (2.0 mL), 12 h, N2, 808C. Yields of isolated products are shown.
[a] Yield by 19F NMR spectroscopy.
Subsequently, the method was investigated in the late-
stage synthesis of an estradiol derivative (Scheme 6). The
trifluoroethoxylation of 9 with 1a provided 10 in 57% yield.
This result demonstrates that the developed method is
extendable to other pharmaceutically relevant molecules.
a variety of diverse heteroaryl bromides under the same set of
conditions (Scheme 4). The reactions of 2-bromopyridines
with either electron-withdrawing or electron-donating sub-
stituents were efficient and afforded the desired products 5a–
g in high yields. Notably, various base-labile groups such as
ester, nitrile, and chloro were tolerated. 3-Bromopyridines
proved to be less reactive than 2- and 4-bromopyridines
because of the greater electron density at the 3-position of
pyridines than at the 2- and 4-positions.[27] Nevertheless, 3-
bromopyridines were also found to react with complex 1a
under these conditions and the yields of products 5h–q were
found to be comparable to those obtained with 2-bromopyr-
idines. Furthermore, the reaction of 4-bromopyridines gave
the desired product 5r–u in high yields.
Scheme 6. Late-stage trifluoroethoxylation of an estradiol derivative.
We next explored the use of fused heterocycles, such as 3-,
5-, and 8-bromoquinoline, which furnished the corresponding
products 6a–c in yields of 89%, 96%, and 94%, respectively.
Heterocycles with more than one nitrogen atom are also
excellent substrates. 2-Bromoquinoxaline underwent
trifluoroethoxylation to furnish 6d in 92% yield. Likewise,
the reactions of 2- and 5-bromopyrimidine afforded the
expected products 6e and 6 f in yields of 90% and 72%,
respectively. Moreover, 6-bromoimidazo[1,2-a]pyrazine
underwent reaction to give 6g in 80% yield. In the case of
five-membered heterocycles, 2-bromobenzo[d]thiazole and 3-
bromobenzo[b]thiophene provided the coupling products 6h
and 6i in yields of 91% and 99%, respectively.
To demonstrate the scalability of the reaction, we
conducted the trifluoroethoxylation of 2-bromopyrimidine
with 1a on a 6.3 mmol scale. As shown in Scheme 7, the
desired trifluoroethoxylated product 6e was isolated in 87%
yield (0.99 g).
Scheme 7. Scalability of the trifluoroethoxylation of 2-bromopyrimidine.
This method can be further extended to the synthesis of
pentafluoropropyl and tetrafluoropropyl heteroaryl ethers.
As shown in Scheme 5, the reaction is also applicable to
a wide range of heterocyclic aryl bromides such as 2-pyridyl
and 3-pyridyl bromides. This transformation also demon-
A preliminary investigation of the reaction of complex 1a
with a radical probe, such as 1-(allyloxy)-2-iodobenzene
(3m),[28] indicated that only the trifluoroethoxylated product
4m was obtained (in 76% yield; 19F NMR; Scheme 8). No
cyclization product, 3-methyl-2,3-dihydrobenzofuran (11),
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Experimental Section
Preparation of [(phen)2Cu][OCH2CF3] (1a): A solution of NaOtBu
(0.48 g, 5.0 mmol) in THF (10 mL) was added to a suspension of CuCl
(0.49 g, 5 mmol) in THF (20 mL), and the resulting mixture was
stirred at room temperature for 30 min. The resulting light yellow
mixture was filtered through a layer of celite. To this filtrate was
added a solution of 1,10-phenanthroline (1.8 g, 10 mmol) in THF
(10 mL). The resulting solution turned reddish brown immediately
and was stirred at room temperature for an additional 5 min.
CF3CH2OH (0.60 g, 6.0 mmol) was added dropwise and the mixture
was further stirred at room temperature for 20 min. The solution was
filtered and the filtrate was dried under vacuum to yield a dark red
solid. The resulting solid were washed with hexanes (2 ꢀ 2 mL) and
dried under vacuum to obtain 2.39 g (91%) of 1a. 1H NMR
(400 MHz, [D6]DMSO): d = 9.10 (s, 4H), 8.64 (d, J = 7.9 Hz, 4H),
8.12 (s, 4H), 7.89 (s, 4H), 3.86 ppm (s, 2H). 13C NMR (101 MHz,
[D6]DMSO): d = 150.2 (s), 144.9 (s), 137.1 (s), 129.2 (s), 127.3 (s),
124.8 (s), 67.4 ppm (s). 19F NMR (376 MHz, [D6]DMSO): d = À75.4
(s, 3F). Elemental analysis(%) calcd for C26H18CuF3N4O·CF3CH2OH:
C 53.98, H 3.40, N 8.99; found: C 53.95, H 3.40, N 8.97.
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[26] CCDC 1048419 (1a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
À
Keywords: C O bonds · copper · cross-coupling ·
trifluoroethoxylation
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Received: February 9, 2015
Published online: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
Efficiency drive: A series of copper(I)
fluoroalkoxide complexes bearing N,N
ligands have been prepared and struc-
turally characterized. These well-defined
complexes serve as efficient reagents for
the fluoroalkoxylation of aryl and hetero-
aryl bromides to produce a wide range of
trifluoroethyl, pentafluoropropyl, and tet-
rafluoropropyl (hetero)aryl ethers in good
to excellent yields.
R. Huang, Y. Huang, X. Lin, M. Rong,
Z. Weng*
&&&& — &&&&
Well-Defined Copper(I) Fluoroalkoxide
Complexes for Trifluoroethoxylation of
Aryl and Heteroaryl Bromides
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!