A practical ligand-free copper(I) bromide-catalyzed fluoroalkoxylation of unactivated aryl bromides

Article abstract of DOI:10.1007/s11164-015-2165-4

An efficient ligand-free fluoroalkoxylation of unactivated aryl bromides has been developed, with special attention focused on practicability of the reaction. Without precious metal and organic ligand, the reaction was carried out under the catalytic system of inexpensive copper(I) bromide as a catalyst, N,N-dimethyl formamide as a cocatalyst, and the corresponding stoichiometric sodium fluoroalkoxide as a nucleophilic reagent. The facile approach avoids the drawbacks associated with cost, separation and pollution of ligand to enable sustainable access to aryl fluoroalkyl ethers from readily available bromoarenes.

Full text of DOI:10.1007/s11164-015-2165-4

Res Chem Intermed
DOI 10.1007/s11164-015-2165-4
A practical ligand-free copper(I) bromide-catalyzed
fluoroalkoxylation of unactivated aryl bromides
Ying Guo1 Yu-Dao Li1 Cheng Chen1
•
•
•
Jian-Hong Zhao1 Hong-Wei Liu1
Dao-Hua Liao1 Ya-Fei Ji1
•
•
•
Received: 4 June 2015 / Accepted: 4 July 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract An efficient ligand-free fluoroalkoxylation of unactivated aryl bromides
has been developed, with special attention focused on practicability of the reaction.
Without precious metal and organic ligand, the reaction was carried out under the
catalytic system of inexpensive copper(I) bromide as a catalyst, N,N-dimethyl
formamide as a cocatalyst, and the corresponding stoichiometric sodium fluo-
roalkoxide as a nucleophilic reagent. The facile approach avoids the drawbacks
associated with cost, separation and pollution of ligand to enable sustainable access
to aryl fluoroalkyl ethers from readily available bromoarenes.
Keywords Fluoroalkoxylation Á Ligand-free catalysis Á Unactivated aryl
bromides Á Copper(I) bromide Á Aryl fluoroalkyl ethers
Introduction
Incorporation of various fluorinated moieties into organic molecules has been an
attractive topic, due to the widespread applications of fluorine-containing
compounds in materials science, agricultural chemicals and drug discovery [1–6].
In fact, substitution of hydrogen with fluorine will usually give rise to dramatic
enhancement in the resulting compounds of physical, chemical and biological
properties including solubility, lipophilicity, metabolic and oxidative stability, as
well as bioavailability [7–10]. Remarkably, aryl fluoroalkyl ethers have emerged as
common fluorinated building blocks in the pharmaceutical industry. For instance,
trifluoroethoxylated aromatics have appeared in the commercial drugs with
excellent metabolic stability and lipophilicity [11], such as the alpha
&
Ya-Fei Ji
jyf@ecust.edu.cn
1
School of Pharmacy, East China University of Science and Technology, Shanghai 200237,
China
123

Y. Guo et al.
1-adrenoreceptor antagonist silodosin [12], the atrial fibrillation therapeutic agent
flecainide [13] and the proton pump inhibitor lansoprazole (Fig. 1) [14]. Further-
more, the compounds bearing aryl 2,2,3,3-tetrafluoropropyl ether moieties were
disclosed as serotonin 5-HT6 antagonists [15] and cholesteryl ester transfer protein
(CETP) inhibitors (Fig. 1) [16]. Therefore, the construction of aryl fluoroalkyl
ethers has received considerable attention.
Owing to the unavoidable drawbacks involving cost, separation and pollution
issues, substantial efforts have been devoted to approaches without the need for
precious metals and organic ligands to the fluoroalkoxylated aromatics. Typically,
fluoroalkyl sulfonates [15, 17] or halides [18, 19] as preinstalled electrophiles can
easily condense with phenols to offer aryl fluoroalkyl ethers under basic conditions.
Base-mediated nucleophilic reaction undergoing an aromatic SN1 mechanism
between activated aryl halides and fluoroalkanols is another class of common
methods [16, 20–22]. The use of prefunctionalized fluoroalkyl derivative and
activated aryl halides greatly limits the substrate scope in the preparation of aryl
ethers. In addition, the ligand-based copper-catalyzed etherifications of aryl halides
and aryl trifluoroborate salts with fluoroalkanols also provide feasible access to
fluoroethoxylated aromatics [23–25]. However, the employment of ligands, iodides
or superstoichiometric fluoroalkanols raised the concerns of cost, separation and
pollution.
In contrast, the ligand-free copper-catalyzed etherification strategies with
stoichiometric fluoroalkanols are considered to be more economical in large-scale
applications for fluoroalkoxylation of unactivated aryl bromides (no strong electron-
withdrawing groups like NO2, CN, CF3, etc. on aromatic ring), due to less expensive
substrates as well as omission of precious metals and organic ligands. Although
having an example of ligand-free copper(I) iodide-catalyzed trifluoroethoxylation of
iodobenzene [26], the use of iodides is still beyond our consideration. In this
context, we report a practical and convenient ligand-free fluoroalkoxylation herein,
Fig. 1 Pharmaceutically active molecules bearing aryl fluoroalkyl ether moieties
123

A practical ligand-free copper(I) bromide-catalyzed…
which features the use of inexpensive aryl bromides and stoichiometric sodium
fluoroalkoxides as reactants, along with copper(I) bromide as a catalyst and with
N,N-dimethyl formamide (DMF) as a cocatalyst.
Results and discussion
Considering their high boiling points, troublesome workup and reproductive health
hazards [27], the polar aprotic solvents DMF, N-methyl-2-pyrrolidinone (NMP)
dimethylsulfoxide (DMSO) and hexamethylphosphoric triamide (HMPT) were only
allowed as cocatalysts in the current study. Furthermore, DMF holding lower
boiling point was preferentially used in the preliminary investigations [28, 29]. We
commenced the optimization process with the trifluoroethoxylation of 1-bromo-3-
methoxybenzene as a model reaction, employing copper(I) bromide (10 mol%) as a
catalyst and DMF (1.5 equiv) as a cocatalyst under 110 °C (Table 1).
Firstly, the screening of solvents showed that acetonitrile worked poorly to
provide the desired product 1 with 32 % yield (entry 1). Whereas, the ethereal
solvent 2-methyltetrahydrofuran (2-MeTHF) proved to be a better choice furnishing
1 in 85 % yield (entry 2). Furthermore, tetrahydrofuran (THF) and 1,4-dioxane
equally delivered excellent yield of 92 % (entries 3 and 4). Given better dissolving
Table 1 Optimization of the reaction conditions
OCH3
OCH3
Cu(I) salt (n1 mol%)
DMF (n2 equiv)
+
CF3CH2ONa
solvent (5 mL)
110 oC, T (h)
OCH2CF3
Br
1
model substrate
Entry
Solvent
Cu salt (n1 mol%)
DMF (n2 equiv)
Time (h)
Yield (%)a
1
CH3CN
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuCl (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (8)
1.5
1.5
1.5
1.5
1.5
1.5
1.0
0.75
1.0
1.0
6
6
6
6
6
6
6
6
6
5
32
85
92
92
84
90
92
78
81
88
2
2-MeTHF
THF
3
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
5
6b
7
8
9
10
CuBr (10)
Reaction conditions: a CF3CH2ONa solution [6.0 mmol, freshly prepared from CF3CH2OH (6.6 mmol)
and Na (6.0 mmol) in solvent (5 mL)], 1-bromo-3-methoxybenzene (3.0 mmol), Cu(I) salt (n1 mol%) and
DMF (n2 equiv) in a Teflon-lined sealed tube at 110 °C for specified time
Bold indicates the standard reaction condition
a
Isolated yield (%)
b
DMF replaced by NMP
123

Y. Guo et al.
capacity to the following sodium fluoroalkoxides, we gave preference to 1,4-
dioxane as the ideal solvent.
Afterwards, an attempt to replace copper(I) bromide by copper(I) chloride
resulted in a diminished yield of 84 % (entry 5), indicating that copper(I) bromide
possesses higher catalytic activity. Besides, a slightly reduced yield of 90 % was
observed when using NMP as a cocatalyst instead of DMF (entry 6). The further
survey of catalyst loadings identified the optimal amounts of copper(I) bromide and
DMF at the levels of 10 mol% and 1.0 equiv, respectively (entry 7 vs. entries 8 and
9). Shortening reaction time to 5 h led to a slightly weakened efficiency (88 %,
entry 10). On the basis of these results, the standard reaction conditions (entry 7)
were established to probe the substrate scope of the fluoroalkoxylation.
Next, various commercially available unactivated aryl bromides and fluoroalka-
nols were assessed for this Ullmann-type C–O coupling reaction (Table 2).
Primarily, with regard to the shortest carbon-chain trifluoroethanol, the substrates
Table 2 Substrate scope of the fluoroalkoxylation
a
b
b
b
Reaction conditions: a 1,4-dioxane solution of RFONa [3.0(n ? 1) mmol, freshly prepared from RFOH
(3.3(n ? 1) mmol) and Na (3.0(n ? 1) mmol) in 1,4-dioxane (5 mL)], ArBrn (3.0 mmol), CuBr
(0.3n mmol) and DMF (3.0n mmol) in a Teflon-lined sealed tube at 110 °C for 6 h
a
Isolated yield (%)
b
The substrate with phenolic hydroxyl group needing additional one equiv of RFONa
123

A practical ligand-free copper(I) bromide-catalyzed…
containing both electron-donating and weak electron-withdrawing substituents all
underwent the approach smoothly to achieve the corresponding products, with
excellent yields of more than 90 % (1–6). A series of strong electron-donating
substituents tending to impairment of the nucleophilic reaction, like methoxy,
ethoxy and hydroxy groups, did not give rise to any detrimental influence. In all the
cases, no significant amounts of byproducts were observed, validating an excellent
functional group tolerance for this method. It was noteworthy that the dibromoare-
nes 2,4-dibromo-1-methoxybenzene and 2,6-dibromo-4-methylphenol also pro-
ceeded successfully to deliver the di-trifluoroethoxylated products with good yields
of 85 and 86 %, respectively (7 and 8).
The scope of nucleophilic partners was further extended to sodium fluoro-
propoxides (9–16). Although 3,3,3-trifluoropropoxide anion owns the higher
electron density at the oxygen atom and has stronger reductive ability to
copper(I) ion among these fluoroalkoxide anions [28, 29], sodium 3,3,3-trifluoro-
propoxide was still compatible with the approach, offering the corresponding
products in yields of 58 and 60 %, respectively (9 and 10). In contrast, for 2,2,3,3-
tetrafluoropropoxide anion owning lower electron density at the oxygen atom, the
protocol efficiently submitted the tetrafluorinated ethers in excellent yields of
92–94 % with good functional group tolerance (11–15). These outcomes could
illustrate the fact that sodium 2,2,3,3-tetrafluoropropoxide was more favorable to the
fluoroalkoxylation than sodium 3,3,3-trifluoropropoxide, attributed to its distinct
reductive capabilities to copper(I) ion [29]. Pleasingly, 2,4-dibromo-1-methoxy-
benzene was subjected to the di-2,2,3,3-tetrafluoropropoxylation, providing the
target compound 16 in good yield of 83 %.
Finally, the fluoroalkanol containing five carbon atoms was investigated. With
regard to the highly fluorinated sodium 2,2,3,3,4,4,5,5-octafluoropentyloxide, the
bromoarenes smoothly suffered from the protocol to attain the octafluorinated ethers
with satisfactory yields of 72 and 85 %, respectively (17 and 18). It was noted that
the increase of alkoxide carbon chain would impair the reaction outcome.
Obviously, weak electron-withdrawing substituent was liable to the reaction in
comparison with electron-donating substituent (18 vs. 17).
Flecainide has clinically served as a classical anti-arrhythmic agent [13]. To
evaluate the synthetic utility of this protocol, the synthesis of the key intermediate of
flecainide, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (22, Scheme 1), was carried
out on a multigram scale through a new route by virtue of our method. Gratifyingly,
the commercially inexpensive 1,4-dibromobenzene (19) underwent the crucial di-
fluoroalkoxylation to accomplish the fluorinated product 20 with good yield of
Scheme 1 Synthesis of the key intermediate of flecainide on a multigram scale
123

Y. Guo et al.
82 %. Then, the acylation of 20 presented a usual yield of 83 % to the
acetophenones 21, which was followed by the haloform reaction to efficiently
access the desired product 22 at 89 % yield. Impressively, this ligand-free protocol
unfolded a potential practicality for convenient preparation of high-value aryl
fluoroalkyl ether derivatives.
Conclusion
In summary, we have developed a ligand-free transition metal-catalyzed fluo-
roalkoxylation of unactivated aryl bromides, utilizing inexpensive copper(I) bromide
as a catalyst and DMF as a co-catalyst. The sustainable reaction is characterized by
operational simplicity and reagent economy. Its synthetic utility was highlighted by
a multigram-scale preparation of the key intermediate of flecainide. We anticipate
that the approach developed here will provide a useful tool in academia and
industry.
Experimental
Unless otherwise indicated, all reagents were obtained from commercial sources and
used as received without further purification. All reactions were carried out in a
Teflon-lined, stainless steel, sealed tube or autoclave. All solvents were only dried
˚
over 4 A molecular sieves. Reaction products were purified via column
chromatography on silica gel (300–400 mesh). Melting points were determined
using an open capillaries and uncorrected. Nuclear magnetic resonance (NMR)
spectra were determined on a Bruker AV400 in CDCl3 or DMSO-d6 with TMS as
1
internal standard for H NMR (400 MHz), 13C NMR (100 MHz) and 19F NMR
(376 MHz), respectively. HRMS were measured on a QSTAR Pulsar I LC/TOF MS
mass spectrometer or Micromass GCTTM gas chromatograph-mass spectrometer.
General fluoroalkoxylation procedure (Table 2)
The Teflon-lined sealed tube (20 mL) was charged with a 1,4-dioxane solution of
sodium fluoroalkoxide RFONa [freshly prepared from fluoroalkanol RFOH (3.3
(n ? 1) mmol) and Na (3.0 (n ? 1) mmol) in 1,4-dioxane (5 mL)], unactivated aryl
bromide ArBrn (3.0 mmol), CuBr (0.3n mmol) and DMF (3.0n mmol). The sealed
tube was heated to 110 °C and stirred for 6 h. After the completion of reaction, the
concentration of the mixture in vacuo gave a residue, to which was added methyl
tert-butyl ether (MTBE, 20 mL) and diluted hydrochloric acid (10 mL, 1.0 mol/L).
The organic phase was separated, and the aqueous phase was extracted with MTBE
(10 mL 9 3). The combined organic layer was dried over anhydrous MgSO4, and
then concentrated in vacuo to supply a crude product. Lastly, the purification of the
crude product provided the desired product via column chromatography on silica gel
(eluents: petroleum ether/ethyl acetate 20:1).
123

A practical ligand-free copper(I) bromide-catalyzed…
1-methoxy-3-(2,2,2-trifluoroethoxy)benzene (1)
Pale yellow oil, 0.57 g (92 %); 1H NMR (400 MHz, CDCl3), d (ppm): 3.80 (s, 3H,
OCH3), 4.33 (q, JHF = 8.0 Hz, 2H, CH2), 6.51–6.54 (m, 2H, Ar), 6.59–6.63 (dd,
3
J = 8.8 Hz, 2.4, 1H, Ar), 7.20–7.25 (m, 1H, Ar); 13C NMR (100 MHz, CDCl3), d
2
(ppm): 55.3, 65.8 (q, JCF = 35.5 Hz), 101.6, 106.6, 108.2, 123.4 (q,
1JCF = 276.3 Hz), 130.2, 158.6, 161.0; 19F NMR (376 MHz, CDCl3), d (ppm):
-74.0 (t, 3JHF = 8.2 Hz, 3F); HRMS (EI): m/z [M?] calcd. for C9H9O2F3 206.0555,
found 206.0551.
1-ethoxy-4-(2,2,2-trifluoroethoxy)benzene (2)
1
Pale yellow oil, 0.60 g (91 %); H NMR (400 MHz, CDCl3), d (ppm): 1.40 (t,
J = 6.8 Hz, 3H, CH3), 3.99 (q, J = 6.8 Hz, 2H, CH2), 4.29 (q, 3JHF = 8.0 Hz, 2H,
CH2), 6.86 (q, J = 8.8 Hz, 4H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 14.9,
64.0, 67.0 (q, 2JCF = 35.1 Hz), 115.5 (2C), 116.4 (2C), 123.4 (q, 1JCF = 276.7 Hz),
151.6, 154.5; 19F NMR (376 MHz, CDCl3), d (ppm): -74.1 (t, 3JHF = 8.2 Hz, 3F);
HRMS (EI): m/z [M?] calcd. for C10H11O2F3 220.0711, found 220.0713.
2,4-dimethyl-1-(2,2,2-trifluoroethoxy)benzene (3)
Pale yellow oil, 0.56 g (92 %); 1H NMR (400 MHz, CDCl3), d (ppm): 2.23 (s, 3H,
CH3), 2.28 (s, 3H, CH3), 4.32 (q, JHF = 8.0 Hz, 2H, CH2), 6.69 (d, J = 8.0 Hz,
3
1H, Ar), 6.96 (d, J = 8.0 Hz, 1H, Ar), 6.99 (s, 1H, Ar); 13C NMR (100 MHz,
2
CDCl3), d (ppm): 15.8, 20.5, 66.5 (q, JCF = 35.1 Hz), 112.1, 123.6 (q,
1JCF = 276.4 Hz), 127.1, 127.4, 131.7, 132.0, 153.7; 19F NMR (376 MHz,
3
CDCl3), d (ppm): -74.2 (t, JHF = 8.2 Hz, 3F); HRMS (EI): m/z [M?] calcd. for
C10H11OF3 204.0762, found 204.0761.
1-methoxy-4-methyl-2-(2,2,2-trifluoroethoxy)benzene (4)
Pale yellow oil, 0.61 g (93 %); 1H NMR (400 MHz, CDCl3), d (ppm): 2.28 (s, 3H,
CH3), 3.84 (s, 3H, CH3), 4.38 (q, 3JHF = 8.4 Hz, 2H, CH2), 6.82–6.86 (m, 3H, Ar);
13C NMR (100 MHz, CDCl3), d (ppm): 20.6, 56.1, 68.1 (q, 2JCF = 34.7 Hz), 112.7,
118.7, 123.6 (q, 1JCF = 277.0 Hz), 124.3, 130.7, 146.8, 148.3; 19F NMR (376 MHz,
3
CDCl3), d (ppm): -74.1 (t, JHF = 8.2 Hz, 3F); HRMS (EI): m/z [M?] calcd. for
C10H11O2F3 220.0711, found 220.0712.
4-methyl-2-(2,2,2-trifluoroethoxy)phenol (5)
Pale yellow oil, 0.57 g (93 %); 1H NMR (400 MHz, CDCl3), d (ppm): 2.29 (s, 3H,
CH3), 4.40 (q, 3JHF = 8.0 Hz, 2H, CH2), 5.35 (br s, 1H, OH), 6.68 (s, 1H, Ar), 6.77
(d, J = 8.0 Hz, 1H, Ar), 6.87 (d, J = 8.0 Hz, 1H, Ar); 13C NMR (100 MHz,
2
CDCl3), d (ppm): 20.9, 60.8 (q, JCF = 35.6 Hz), 113.7, 115.5, 123.2 (q,
1JCF = 276.4 Hz), 123.9, 130.0, 143.6, 144.2; 19F NMR (376 MHz, CDCl3), d
123

Y. Guo et al.
3
(ppm): -74.1 (t, JHF = 8.2 Hz, 3F); HRMS (EI): m/z [M?] calcd. for C9H9O2F3
206.0555, found 206.0553.
1-chloro-4-(2,2,2-trifluoroethoxy)benzene (6)
White solid, 0.59 g (94 %), m.p. 31–33 °C; 1H NMR (400 MHz, CDCl3), d (ppm):
4.32 (q, JHF = 8.0 Hz, 2H, CH2), 6.88 (d, J = 8.0 Hz, 2H, Ar), 7.28 (d,
3
J = 8.0 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 66.1 (q,
1
2JCF = 35.6 Hz), 116.3 (2C), 123.2 (q, JCF = 276.4 Hz), 127.6, 129.7 (2C),
156.0; 19F NMR (376 MHz, CDCl3), d (ppm): -74.0 (t, 3JHF = 8.2 Hz, 3F); HRMS
(EI): m/z [M?] calcd. for C8H6ClOF3 210.0059, found 210.0061.
1-methoxy-2,4-bis(2,2,2-trifluoroethoxy)benzene (7)
Pale yellow oil, 0.77 g (85 %); 1H NMR (400 MHz, CDCl3), d (ppm): 3.84 (s, 3H,
CH3), 4.29 (q, 3JHF = 8.0 Hz, 2H, CH2), 4.39 (q, JHF = 8.4 Hz, 2H, CH2), 6.60 (d,
J = 8.8 Hz, 1H, Ar), 6.67 (s, 1H, Ar), 6.86 (d, J = 8.8 Hz, 1H, Ar); 13C NMR
2
(100 MHz, CDCl3),
d
(ppm): 56.5, 66.7 (q, JCF = 35.3 Hz), 67.9 (q,
2JCF = 35.1 Hz), 106.6, 109.0, 113.4, 123.3 (q, JCF = 276.5 Hz), 123.4 (q,
1JCF = 276.9 Hz), 146.0, 147.7, 151.7; 19F NMR (376 MHz, CDCl3), d (ppm):
-74.1 to -74.0 (m, 6F); HRMS (EI): m/z [M?] calcd. for C11H10O3F6 304.0534,
found 304.0535.
1
4-methyl-2,6-bis(2,2,2-trifluoroethoxy)phenol (8)
White solid, 0.77 g (86 %), m.p. 49–51 °C; 1H NMR (400 MHz, CDCl3), d (ppm):
2.27 (s, 3H, CH3), 4.42 (q, JHF = 8.0 Hz, 4H, CH2), 5.32 (br s, 1H, OH), 6.52 (s,
3
2
2H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 21.1, 67.5 (q, JCF = 35.3 Hz,
1
2C), 111.2 (2C), 123.3 (q, JCF = 276.7 Hz, 2C), 129.5, 134.6, 145.3 (2C); 19F
NMR (376 MHz, CDCl3), d (ppm): -74.2 (t, 3JHF = 8.2 Hz, 6F); HRMS (ESI): m/z
[M–H]- calcd. for C11H9O3F6 303.0456, found 303.0446.
1-methoxy-3-(3,3,3-trifluoropropoxy)benzene (9)
1
Pale yellow oil, 0.38 g (58 %); H NMR (400 MHz, CDCl3), d (ppm): 2.56–2.68
(m, 2H, CH2), 3.80 (s, 3H, CH3), 4.18 (t, 3JHF = 6.8 Hz, 2H, CH2), 6.46 (s, 1H, Ar),
6.48 (d, J = 8.4 Hz, 1H, Ar), 6.55 (d, J = 8.4 Hz, 1H, Ar), 7.20 (t, J = 8.4 Hz, 1H,
2
Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 34.1 (q, JCF = 28.7 Hz), 55.3, 60.9
3
1
(q, JCF = 3.7 Hz), 101.2, 106.5, 107.0, 125.9 (q, JCF = 275.0 Hz), 130.0, 159.3,
160.9; 19F NMR (376 MHz, CDCl3), d (ppm): -74.1 (t, 3JHF = 8.2 Hz, 6F); HRMS
(EI): m/z [M?] calcd. for C10H11O2F3 220.0711, found 220.0712.
1-ethoxy-4-(3,3,3-trifluoropropoxy)benzene (10)
1
Pale yellow oil, 0.42 g (60 %); H NMR (400 MHz, CDCl3), d (ppm): 1.39 (t,
J = 7.0 Hz, 3H, CH3), 2.53–2.66 (m, 2H, CH2), 3.98 (q, 3JHF = 6.8 Hz, 2H, CH2),
123

A practical ligand-free copper(I) bromide-catalyzed…
4.15 (t, J = 7.0 Hz, 2H, CH2), 6.83 (s, 4H, Ar); 13C NMR (100 MHz, CDCl3), d
(ppm): 14.9, 34.1 (q, JCF = 28.5 Hz), 61.7 (q, JCF = 3.6 Hz), 64.0, 115.5 (2C),
2
3
1
115.7 (2C), 126.0 (q, JCF = 274.9 Hz), 152.1, 153.7; 19F NMR (376 MHz,
3
CDCl3), d (ppm): -64.7 (t, JHF = 10.9 Hz, 3F); HRMS (EI): m/z [M?] calcd. for
C11H13O2F3 234.0868, found 234.0869.
1-methoxy-3-(2,2,3,3-tetrafluoropropoxy)benzene (11)
Pale yellow oil, 0.66 g (92 %); 1H NMR (400 MHz, CDCl3), d (ppm): 3.80 (s, 3H,
CH3), 4.33 (t, 3JHF = 11.6 Hz, 2H, CH2), 6.07 (t, 2JHF = 49.6 Hz, 1H, CHF2), 6.49
(s, 1H, Ar), 6.51 (d, J = 8.4 Hz, 1H, Ar), 6.61 (d, J = 8.4 Hz, 1H, Ar), 6.86 (t,
J = 8.4 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 55.4, 65.3 (t,
2JCF = 29.7 Hz), 101.4, 106.5, 108.1, 109.0 (tt, 1JCF = 248.4 Hz, 2JCF = 33.9 Hz),
1
2
114.6 (tt, JCF = 248.6 Hz, JCF = 26.7 Hz), 130.2, 158.5, 161.0; 19F NMR
2
3
(376 MHz, CDCl3), d (ppm): -139.6 (dt, JHF = 53.0 Hz, JFF = 3.8 Hz, 2F),
-125.4 to -125.3 (m, 2F); HRMS (EI): m/z [M?] calcd. for C10H10O2F4 238.0617,
found 238.0618.
1-ethoxy-4-(2,2,3,3-tetrafluoropropoxy)benzene (12)
1
Pale yellow oil, 0.70 g (93 %); H NMR (400 MHz, CDCl3), d (ppm): 1.40 (t,
J = 6.8 Hz, 3H, CH3), 3.99 (q, J = 6.8 Hz, 2H, CH2), 4.29 (t, 3JHF = 12.0 Hz, 2H,
2
3
CH2), 6.06 (tt, JHF = 53.2 Hz, JHF = 4.8 Hz, 1H, CHF2), 6.85 (s, 4H, Ar); 13C
2
NMR (100 MHz, CDCl3), d (ppm): 14.9, 64.0, 66.3 (t, JCF = 29.7 Hz), 109.1 (tt,
1JCF = 248.2 Hz, JCF = 33.9 Hz), 114.6 (tt, JCF = 248.4 Hz, JCF = 26.7 Hz),
2
1
2
115.5 (2C), 116.0 (2C), 151.5, 154.4; 19F NMR (376 MHz, CDCl3), d (ppm):
2
3
-139.7 (dt, JHF = 53.0 Hz, JFF = 3.8 Hz, 2F), -125.5 to -125.4 (m, 2F);
HRMS (EI): m/z [M?] calcd. for C11H12O2F4 252.0773, found 252.0775.
1-methoxy-4-methyl-2-(2,2,3,3-tetrafluoropropoxy)-benzene (13)
Pale yellow oil, 0.69 g (92 %); 1H NMR (400 MHz, CDCl3), d (ppm): 2.28 (s, 3H,
CH3), 3.83 (s, 3H, CH3), 4.36 (t, JHF = 12.0 Hz, 2H, CH2), 6.17 (t,
3
2JHF = 53.2 Hz, 1H, CHF2), 6.76–6.85 (m, 3H, Ar); 13C NMR (100 MHz,
CDCl3),
d
(ppm): 20.6, 56.0, 67.7 (t, 2JCF = 29.4 Hz), 109.1 (tt,
1JCF = 248.0 Hz, 2JCF = 33.1 Hz), 112.6, 114.6 (tt, 1JCF = 248.9 Hz,
2JCF = 26.3 Hz), 117.9, 124.1, 130.7, 146.8, 148.2; 19F NMR (376 MHz, CDCl3),
2
3
d (ppm): -139.7 (dt, JHF = 53.0 Hz, JFF = 3.8 Hz, 2F), -125.6 to -125.5 (m,
2F); HRMS (EI): m/z [M?] calcd. for C11H12O2F4 252.0773, found 252.0777.
4-ethyl-2-(2,2,3,3-tetrafluoropropoxy)phenol (14)
1
Pale yellow oil, 0.70 g (93 %); H NMR (400 MHz, CDCl3), d (ppm): 1.21 (t,
J = 7.6 Hz, 3H, CH3), 2.58 (q, J = 7.6 Hz, 2H, CH2), 4.43 (t, 3JHF = 12.0 Hz, 2H,
2
3
CH2), 5.30 (br s, 1H, OH), 6.00 (tt, JHF = 53.2 Hz, JHF = 3.6 Hz, 1H, CHF2),
6.73 (d, J = 1.6 Hz, 1H, Ar), 6.80 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H, Ar), 6.89 (d,
123

Y. Guo et al.
J = 8.4 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 15.8, 28.4, 66.1 (t,
1
2
2JCF = 28.6 Hz), 109.5 (tt, JCF = 248.7 Hz, JCF = 36.5 Hz), 112.7, 114.4 (tt,
1JCF = 248.4 Hz, JCF = 27.9 Hz), 115.5, 122.7, 136.8, 143.7, 144.4; 19F NMR
2
2
3
(376 MHz, CDCl3), d (ppm): -139.5 (dt, JHF = 53.0 Hz, JFF = 4.0 Hz, 2F),
-125.5 to -125.4 (m, 2F); HRMS (ESI): m/z [M–H]- calcd. for C11H11O2F4
251.0695, found 251.0676.
1-chloro-4-(2,2,3,3-tetrafluoropropoxy)benzene (15)
1
Pale yellow oil, 0.68 g (94 %); H NMR (400 MHz, CDCl3), d (ppm): 4.32 (tt,
3JHF = 12.0 Hz, 4JHF = 1.6 Hz, 2H, CH2), 6.04 (tt, 2JHF = 52.8 Hz,
3JHF = 4.8 Hz, 1H, CHF2), 6.87 (dt, J1 = 3.6 Hz, J2 = 8.8 Hz, 2H, Ar), 7.28 (dt,
J1 = 3.6 Hz, J2 = 8.8 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 65.5 (t,
1
2
2JCF = 29.6 Hz), 109.0 (tt, JCF = 248.4 Hz, JCF = 34.4 Hz), 114.4 (tt,
1JCF = 248.7 Hz, JCF = 27.0 Hz), 116.1 (2C), 127.6, 129.7 (2C), 156.0; 19F
2
2
3
NMR (376 MHz, CDCl3), d (ppm): -139.3 (dt, JHF = 53.0 Hz, JFF = 4.0 Hz,
2F), -125.0 to -124.9 (m, 2F); HRMS (EI): m/z [M?] calcd. for C9H7ClOF4
242.0122, found 242.0121.
1-methoxy-2,4-bis(2,2,3,3-tetrafluoropropoxy)benzene (16)
1
Pale yellow solid, 0.92 g (83 %), m.p. 29–31 °C; H NMR (400 MHz, CDCl3), d
(ppm): 3.82 (s, 3H, CH3), 4.29 (t, JHF = 12.0 Hz, 2H, CH2), 4.37 (t,
3
2
3
3JHF = 12.0 Hz, 2H, CH2), 6.04 (tt, JHF = 53.2 Hz, JHF = 4.8 Hz, 1H, CHF2),
2
3
6.13 (tt, JHF = 53.2 Hz, JHF = 4.8 Hz, 1H, CHF2), 6.57 (dd, J1 = 8.8 Hz,
J2 = 2.4 Hz, 1H, Ar), 6.60 (d, J = 2.4 Hz, 1H, Ar), 6.85 (d, J = 8.8 Hz, 1H, Ar);
13C NMR (100 MHz, CDCl3), d (ppm): 56.5, 66.1 (t, JCF = 29.5 Hz), 67.4 (t,
2
2JCF = 29.3 Hz), 105.7, 108.2, 109.1 (tt, JCF = 248.1 Hz, JCF = 34.0 Hz, 2C),
1
2
1
2
1
113.2, 114.5 (tt, JCF = 248.7 Hz, JCF = 26.7 Hz), 114.6 (tt, JCF = 248.8 Hz,
2JCF = 26.6 Hz), 145.9, 147.8, 151.6; 19F NMR (376 MHz, CDCl3), d (ppm):
-139.8 (dt, JHF = 53.0 Hz, JFF = 4.1 Hz, 2F), -139.3 (dt, JHF = 53.0 Hz,
3JFF = 4.0 Hz, 2F), -125.6 to -125.5 (m, 2F), -125.1 to -125.0 (m, 2F); HRMS
(EI): m/z [M?] calcd. for C13H12O3F8 368.0659, found 368.0660.
2
3
2
1-methoxy-3-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)-benzene (17)
Pale yellow oil, 0.73 g (72 %); 1H NMR (400 MHz, CDCl3), d (ppm): 3.84 (s, 3H,
CH3), 4.48 (t, 3JHF = 12.8 Hz, 2H, CH2), 6.04 (tt, 2JHF = 52.0 Hz, 3JHF = 5.6 Hz,
1H, CHF2), 6.54–6.58 (m, 2H, Ar), 6.63–6.67 (m, 1H, Ar), 7.24–7.30 (m, 1H, Ar);
2
13C NMR (100 MHz, CDCl3), d (ppm): 55.4, 65.1 (t, JCF = 26.4 Hz), 101.6,
2
107.0, 107.6 (t, JCF = 30.0 Hz), 108.2, 110.0 (d, JCF = 30.7 Hz), 112.2 (d,
2
2
2JCF = 30.5 Hz), 114.9 (t, JCF = 30.9 Hz), 130.2, 158.6, 161.0; 19F NMR
(376 MHz, CDCl3), d (ppm): -137.3 to -137.1 (m, 2F), -130.3 to -130.2 (m,
2F), -125.3 (quint, 3JFF = 8.2 Hz, 2F), -119.8 to -119.7 (m, 2F); HRMS (EI): m/
z [M?] calcd. for C12H10O2F8 338.0553, found 338.0555.
123

A practical ligand-free copper(I) bromide-catalyzed…
1-chloro-4-((2,2,3,3,4,4,5,5-octafluoropentyl)oxy)ben-zene (18)
1
Pale yellow oil, 0.87 g (85 %); H NMR (400 MHz, CDCl3), d (ppm): 4.44 (t,
2
3
3JHF = 12.8 Hz, 2H, CH2), 6.08 (tt, JHF = 52.0 Hz, JHF = 5.6 Hz, 1H, CHF2),
6.89 (d, J = 8.8 Hz, 2H, Ar), 7.29 (d, J = 8.8 Hz, 2H, Ar); 13C NMR (100 MHz,
2
2
CDCl3), d (ppm): 65.5 (t, JCF = 26.7 Hz), 104.9 (t, JCF = 27.9 Hz), 107.6 (t,
2JCF = 31.0 Hz), 110.1 (d, JCF = 27.2 Hz), 114.6 (d, JCF = 21.1 Hz), 116.3
2
2
(2C), 127.7, 129.7 (2C), 156.1; 19F NMR (376 MHz, CDCl3), d (ppm): -137.3 to
-137.1 (m, 2F), -130.1 to -130.0 (m, 2F), -125.2 (quint, JFF = 8.2 Hz, 2F),
3
-119.8 to -119.7 (m, 2F); HRMS (EI): m/z [M?] calcd. for C11H7ClOF8 342.0058,
found 342.0057.
Procedure for the synthesis of the key intermediate of flecainide
on a multigram scale (Scheme 1)
1,4-bis(2,2,2-trifluoroethoxy)benzene (20)
The Teflon-lined autoclave (100 mL) was charged with CF3CH2ONa [freshly
prepared from CF3CH2OH (3.58 mL, 1.382 g/mL, 49.5 mmol) and Na (1.04 g,
45 mmol) in 1,4-dioxane (35 mL)], CuBr (0.43 g, 3.0 mmol), DMF (2.3 mL,
0.944 g/mL, 30 mmol) and 1-bromo-3-methoxybenzene (19, 3.54 g, 15 mmol). The
autoclave was heated to 110 °C and stirred for 6 h. After the completion of reaction,
the mixture was concentrated in vacuo to give a residue. Diethyl ether (50 mL) and
diluted hydrochloric acid (1.6 M, 50 mL) were added to the residue. The organic
phase was separated, and the aqueous phase was extracted with diethyl ether
(20 mL 9 3). The combined organic layer was dried over anhydrous MgSO4, and
then concentrated in vacuo to supply a crude product, which was separated via
column chromatography on a silica gel (eluents: petroleum ether/ethyl acetate 20:1)
1
to provide the desired product 20. White solid, 3.37 g (82 %), m.p. 76–78 °C; H
NMR (400 MHz, CDCl3), d (ppm): 4.31 (q, 3JHF = 8.4 Hz, 4H, CH2), 6.91 (s, 4H,
2
Ar); 13C NMR (100 MHz, CDCl3), d (ppm): 66.8 (q, JCF = 35.5 Hz, 2C), 116.4
1
(4C), 123.3 (q, JCF = 276.6 Hz, 2C), 152.9 (2C); 19F NMR (376 MHz, CDCl3), d
3
(ppm): -74.1 (t, JHF = 8.2 Hz, 6F); HRMS (EI): m/z [M?] calcd. for C10H8O2F6
274.0428, found 274.0430.
1-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)ethanone (21)
A three-necked flask was charged with the above product 20 (3.37 g, 12.3 mmol),
anhydrous AlCl3 (3.28 g, 24.6 mmol) and dichloromethane (DCM, 15 mL). Acetyl
chloride (1.05 mL, 1.11 g/mL, 14.8 mmol) was added dropwise to the mixture at
0 °C. Then the mixture was further stirred at room temperature for 6 h. After
completion of the reaction, the mixture was poured into diluted hydrochloric acid
(1.6 M, 20 mL) at 0 °C. The organic phase was separated and the aqueous phase
was extracted with DCE (10 mL 9 3). The combined organic layer was washed
with brine (30 mL), dried over anhydrous MgSO4, and then concentrated in vacuo
to supply a crude product, which was separated via column chromatography on a
123

Y. Guo et al.
silica gel (eluents: petroleum ether/ethyl acetate 15:1) to provide the desired product
1
21. White solid, 3.21 g (83 %), m.p. 91–92 °C; H NMR (400 MHz, CDCl3), d
(ppm): 2.64 (s, 3H, CH3), 4.35 (q, JHF = 8.4 Hz, 2H, CH2), 4.42 (q,
3
3JHF = 8.4 Hz, 2H, CH2), 6.88 (d, J = 8.8 Hz, 1H, Ar), 7.13 (dd, J1 = 8.8 Hz,
J2 = 3.2 Hz, 1H, Ar), 7.37 (d, J = 3.2 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3),
2
2
d (ppm): 31.7, 66.1 (q, JCF = 30.0 Hz), 66.8 (q, JCF = 29.7 Hz), 114.4, 115.7,
121.5, 123.0 (q, 1JCF = 276.3 Hz), 123.2 (q, 1JCF = 276.6 Hz), 129.2, 151.7, 152.5,
197.8; 19F NMR (376 MHz, CDCl3), d (ppm): -74.0 (t, 3JHF = 8.0 Hz, 3F), -73.6
3
(t, JHF = 8.2 Hz, 3F); HRMS (ESI): m/z [M ? Na?] calcd. for C12H10O3F6Na
339.0432, found 339.0435.
2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (22)
A three-necked flask was charged with the above product 21 (3.21 g, 10.2 mmol),
NaOH (0.61 g, 15.3 mmol) and water (15 mL), then the mixture was heated to
95 °C. To the mixture, aqueous sodium hypochlorite solution (45 g, 10 %,
61.2 mmol) was added dropwise over 1 h. Subsequently, the mixture was further
stirred for 8 h at 95 °C. After completion of the reaction, the mixture was cooled to
room temperature and hydrochloric acid (1.6 mL, 30 %) was added to give a
precipitation. The precipitation was washed with water, and then dried in vacuo at
50 °C to supply the desired product 22. White solid, 2.89 g (89 %), m.p.
1
3
122–123 °C; H NMR (400 MHz, CDCl3), d (ppm): 4.39 (q, JHF = 8.0 Hz, 2H,
3
CH2), 4.51 (q, JHF = 8.0 Hz, 2H, CH2), 7.05 (d, J = 9.2 Hz, 1H, Ar), 7.21 (dd,
J1 = 9.2 Hz, J2 = 3.2 Hz, 1H, Ar), 7.66 (d, J = 3.2 Hz, 1H, Ar); 13C NMR
2
2
(100 MHz, CDCl3), d (ppm): 66.4 (q, JCF = 35.7 Hz), 68.5 (q, JCF = 35.6 Hz),
117.8, 118.0, 120.8, 122.7, 122.8 (q, 1JCF = 276.8 Hz), 123.0 (q, 1JCF = 276.4 Hz),
152.4, 153.1, 166.9; 19F NMR (376 MHz, CDCl3), d (ppm): -74.1 (t,
3JHF = 8.2 Hz, 3F), -73.5 (t, JHF = 8.2 Hz, 3F); HRMS (ESI): m/z [M ? Na?]
3
calcd. for C11H8O4F6Na 341.0224, found 341.0226.
Acknowledgments The authors are grateful to the National Natural Science Foundation of China
(Project Nos. 21176074 and 21476074), and the Research Fund for the Doctoral Program of Higher
Education of China (Project No. 20130074110009) for financial support.
References
1. B.E. Smart, J. Fluorine Chem. 109, 3 (2001)
¨
2. H.J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, U.O. Sander, M. Stahl, Chem-
¨
BioChem 5, 637 (2004)
3. F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 105, 827 (2005)
4. P. Jeschke, ChemBioChem 5, 570 (2004)
5. S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37, 320 (2008)
6. D. Barnes-Seeman, J. Beck, C. Springer, P. Jeschke, Curr. Top. Med. Chem. 14, 855 (2014)
}
7. M. Morgenthaler, E. Schweizer, A.H. Roder, F. Benini, R.E. Martin, G. Jaeschke, B. Wagner, H.
Fischer, S. Bendels, D. Zimmerli, J. Schneider, F. Diederich, M. Kansy, K. Mu¨ller, ChemMedChem
2, 1100 (2007)
8. W.K. Hagmann, J. Med. Chem. 51, 4359 (2008)
9. T. Liang, C.N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52, 8214 (2013)
123

A practical ligand-free copper(I) bromide-catalyzed…
´
10. J. Wang, M.S. Rosello, J.L. Acen˜a, C. del Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H.
Liu, Chem. Rev. 114, 2432 (2014)
11. J. Irrupe, J. Casas, A. Messeguer, Bioorg. Med. Chem. Lett. 3, 179 (1993)
12. P.C. Yan, X.Y. Zhang, X.W. Hu, B. Zhang, X.D. Zhang, M. Zhao, D.Q. Che, Y.Q. Li, Q.L. Zhou,
Tetrahedron Lett. 54, 1449 (2013)
13. E. Aliot, A. Capucci, H.J. Crijns, A. Goette, J. Tamargo, Europace 13, 161 (2011)
14. H. Satoh, Curr. Pharm. Des. 19, 67 (2013)
15. A. Pasternak, M.J. Szymonifka, U.S. Patent 2009073118 (2009)
16. M.E. Salvati, H. Finlay, L.S. Harikrishnan, J. Jiang, J.A. Johnson, M.G. Kamau, R.M. Lawrence,
M.M. Miller, J.X. Qiao, T.C. Wang, Y. Wang, W. Yang, U.S. Patent 2007062314 (2007)
17. F. Camps, J. Coll, A. Messeguer, M.A. Pericas, Synthesis 9, 727 (1980)
18. A. Kamal, T.B. Pratap, K.V. Ramana, A.V. Pamana, A.H. Babu, Tetrahedron Lett. 43, 7353 (2002)
19. X.J. Tang, Q.Y. Chen, Org. Lett. 14, 6214 (2012)
20. Z.L. Liu, J. Zhang, T.F. Li, Z.N. Yu, S.Z. Zhang, J. Fluor. Chem. 147, 36 (2013)
21. H. Suzuki, T. Matuoka, I. Ohtsuka, A. Osuka, Synthesis 5, 499 (1985)
22. V. Dichiarante, A. Salvaneschi, S. Protti, D. Dondi, M. Fagnoni, A. Albini, J. Am. Chem. Soc. 129,
15919 (2007)
23. T.D. Quach, R.A. Batey, Org. Lett. 5, 1381 (2003)
24. D. Vuluga, J. Legros, B. Crousse, D.B. Delpon, Eur. J. Org. Chem. 21, 3513 (2009)
25. R. Huang, Y. Huang, X. Lin, M. Rong, Z. Weng, Angew. Chem. Int. Ed. 54, 1 (2015)
26. I. Gu¨ell, X. Ribas, Eur. J. Org. Chem. 15, 3188 (2014)
27. Y. Guo, S.Z. Ji, C. Chen, H.W. Liu, J.H. Zhao, Y.L. Zheng, Y.F. Ji, Res. Chem. Intermed. (2014).
doi:10.1007/s11164-014-1917-x
28. V.C. Papadimitriou, D.K. Papanastasiou, V.G. Dtefanopoulos, A.M. Zaras, Y.G. Lazarou, P.
Papaginnakopoulos, J. Phys. Chem. A 111, 11608 (2007)
29. M.A. Keegstra, T.H.A. Peters, L. Brandsma, Tetrahedron 48, 3633 (1992)
123