Synthesis of Pentafluoroethyl Ethers by Silver-Mediated Oxidative Pentafluoroethylation of Alcohols and Phenols

Article abstract of DOI:10.1021/acs.joc.7b00190

A silver triflate (AgOTf)-mediated oxidative pentafluoroethylation of alcohols and phenols with nucleophilic (pentafluoroethyl)trimethylsilane (TMSCF₂CF₃) using selectfluor as oxidant under mild reaction conditions was developed. This oxidative coupling protocol utilizes broadly available substrates and easily handled reagents to afford various pentafluoroethyl ethers in moderate to excellent yields. Furthermore, this method was extended to the oxidative heptafluoropropylation and ethoxycarbonyldifluoromethylation of alcohols and phenols for preparation of the corresponding fluoroalkyl ethers.

Full text of DOI:10.1021/acs.joc.7b00190

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Article
Synthesis of Pentafluoroethyl Ethers by Silver-Mediated
Oxidative Pentafluoroethylation of Alcohols and Phenols
Mao-Lin Fu, Jian-Bo Liu, Xiu-Hua Xu, and Feng-Ling Qing
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00190 • Publication Date (Web): 14 Mar 2017
Downloaded from http://pubs.acs.org on March 16, 2017
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The Journal of Organic Chemistry
1
Synthesis of Pentafluoroethyl Ethers by Silverꢀ
Mediated Oxidative Pentafluoroethylation of Alcohols
and Phenols
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Mao-Lin Fu,† Jian-Bo Liu,† Xiu-Hua Xu,† and Feng-Ling Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North
Renmin Lu, Shanghai 201620, China
Eꢀmail: flq@mail.sioc.ac.cn
Table of Graphic Contents
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Abstract
A silver triflate (AgOTf)ꢀmediated oxidative pentafluoroethylation of alcohols and phenols with
nucleophilic (pentafluoroethyl)trimethylsilane (TMSCF2CF3) using Selectfluor as oxidant under mild
reaction conditions was developed. This oxidative coupling protocol utilizes broadly available substrates
and easily handled reagents to afford various pentafluoroethyl ethers in moderate to excellent yields.
Furthermore, this method was extended to the oxidative heptafluoropropylation and
ethoxycarbonyldifluoromethylation of alcohols and phenols for preparation of the corresponding
fluoroalkyl ethers.
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Introduction
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The demand for organofluorine compounds is rapidly increasing because of their prevalence in
pharmaceuticals, agrochemicals and material science.1 Consequently, research interests are ever
increasing concerning not only the fluorine atom, but also the fluoroalkyl, fluoroalkylthio, and
fluoroalkoxy groups.2 As a typical fluoroalkoxy group, trifluoromethoxy (OCF3) is prevalent in
bioactive compounds and functional materials.3 Thus, various methods have been reported for the
preparation of OCF3ꢀcontaining compounds.4 Compared with the well studied OCF3 group, its bulkier
analogue, pentafluoroethoxy (OC2F5) group, has been much less explored. In fact, OC2F5 has similar
properties to OCF3 in electronic effect, lipophilicity, and metabolic stability,5 which makes it attractive
in drugs and agrochemicals discovery process. For example, Jimonet and coꢀworkers evaluated the
effect of different polyfluoroalkoxy substituents in the 6ꢀposition of 2ꢀbenzothiazolamine on the in vivo
“antiglutamate” activity.6 The ED50 values, the doses of drugs (mg/kg) that totally protected 50% of the
rats from clonic convulsions, clearly showed that the OC2F5ꢀsubstituted compound is more active than
Riluzole and other polyfluoroalkoxy (OCF2H,7 OCH2CF3,8 and OCF2CF2H9) substituted derivatives
(Figure 1).
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Figure 1. “Antiglutamate” activities of 6ꢀfluoroalkoxyꢀ2ꢀbenzothiazolamines.
Traditionally, pentafluoroethyl ethers are synthesized by nucleophilic fluorination of
trifluoroacetates,10a fluorohaloalkyl ethers10b or trifluoromethyl dithioorthoesters10c with toxic
fluorinating reagents (Scheme 1a), all of which suffer from the necessity of prefunctionalized substrates
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and/or harsh reaction conditions. In 1980, Lerman and Rozen disclosed a novel method for the
introduction of OC2F5 group by the addition of C2F5OF to olefins (Scheme 1b).11 But this protocol also
employed poisonous and corrosive C2F5OF. Recently, the reaction of alkyl halides with
pentafluoroethoxide has been reported as an alternative synthetic method (Scheme 1c),12 however, the
reversible decomposition of pentafluoroethoxide anion hampered the wide application of this method. It
is noteworthy that pentafluoroethyl ethers cannot be prepared by nucleophilic substitution of
pentafluoroethyl iodide, which is attacked on the iodine atom rather than the carbon atom of
pentafluoroethyl group because of the reversed electron density.13 Obviously, the efficient and practical
synthesis of pentafluoroethyl ethers remains a big challenge. Inspired by our recent discoveries on silverꢀ
mediated oxidative trifluoromethylation of phenols and alcohols for direct synthesis of trifluoromethyl
ethers,4e,4g we envisioned that oxidative pentafluoroethylation of alcohols and phenols would provide a
potentially valuable strategy for the preparation of pentafluoroethyl ethers. Herein, we disclose the
preparation of these compounds by silverꢀmediated oxidative pentafluoroethylation of alcohols and
phenols with safe and stable TMSC2F5 (Scheme 1d).
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Scheme 1. Approaches to Pentafluoroethyl Ethers
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Results and Discussion
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Initially, we investigated the oxidative pentafluoroethylation of 5ꢀphenylpentanꢀ1ꢀol (1a) with
TMSC2F5 in the presence of KF, AgOTf, 2ꢀfluoropyridine and Selectfluor in EtOAc according to the
optimized reaction conditions of oxidative trifluoromethylation of alcohols.4g However, the desired
pentafluoroethyl ether (2a) was obtained in only 19% yield along with a byproduct trifluoroacetate ester
(3a) in 27% yield (Table 1, entry 1). We reasoned that the byproduct 3a was formed by the reaction of
alcohol 1a with trifluoroacetyl fluoride. To change the ratio of 2a and 3a, a number of reaction
conditions were screened. First, the reaction was carried out at lower concentration, and 2a was
produced in higher yield (entry 2). However, further decreasing the concentration did not improve the
yield (entry 3). Then, the lessꢀpolar solvents PhCH3 and PhCF3 or more polar solvent DMF were
examined (entries 4ꢀ6). No better result was obtained. A binary solvent mixture was beneficial for the
chemoselectivity of this reaction (entries 7ꢀ11), and EtOAc/PhCF3 (1:1) was the ideal solvent system to
give 2a in 53% yield (entry 9). The observed solvent effect might be due to the solubility of reagents. To
improve the reaction yield further, we increased the amounts of reagents. Although a higher yield of 2a
was observed, a larger amount of byproduct 3a was simultaneously formed (entry 12). Finally, different
additives including LiBr, LiOTf, NaOTf, and LiNTf2 were added to the reaction mixture (entries 13ꢀ16).
Among these salts, only LiOTf was beneficial for this reaction to afford compound 2a in 84% yield
(entry 14). However, the exact role of LiOTf for promoting the reaction is unclear at the present stage.
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Table 1. Optimization of Reaction Conditionsa
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Entry
1c
Solvent
Additive
yield (2a/3a, %)b
EtOAc
─
19/27
30/16
29/15
29/14
trace/31
8/4
2
EtOAc
─
3d
4
EtOAc
─
PhCH3
─
5
PhCF3
─
6
DMF
─
7
EtOAc/PhCH3 (1:1)
EtOAc/CH2Cl2 (1:1)
EtOAc/PhCF3 (1:1)
EtOAc/PhCF3 (2:1)
EtOAc/PhCF3 (1:2)
EtOAc/PhCF3 (1:1)
EtOAc/PhCF3 (1:1)
EtOAc/PhCF3 (1:1)
EtOAc/PhCF3 (1:1)
EtOAc/PhCF3 (1:1)
─
44/8
8
─
36/2
9
─
53/2
10
11
12e
13e
14e
15e
16e
─
42/2
─
48/2
─
68/16
51/19
84/14
38/10
32/54
LiBr
LiOTf
NaOTf
LiNTf2
aReaction conditions: 1a (0.1 mmol), TMSC2F5 (0.2 mmol), KF (0.3 mmol), Selectfluor (0.15 mmol), AgOTf (0.2
b
mmol), 2ꢀfluoropyridine (0.2 mmol), additive (0.1 mmol), solvent (1.0 mL), under N2, rt, 12 h. Yields determined by
19F NMR spectroscopy using trifluoromethoxybenzene as an internal standard. Solvent (0.5 mL). Solvent (2.0 mL).
c
d
eTMSC2F5 (0.3 mmol), KF (0.4 mmol), Selectfluor (0.2 mmol), AgOTf (0.3 mmol).
Under the optimized reaction conditions (Table 1, entry 14), the scope of this oxidative
pentafluoroethylation was next investigated. As shown in Scheme 2, a variety of alcohols were
transformed to the corresponding alkyl pentafluoroethyl ethers in moderate to excellent yields. In most
cases the undesired trifluoroacetate esters were formed in low yields, and in some cases the oxidation
products (aldehydes) were detected. The primary (1aꢀh), benzyl (1iꢀp), and secondary (1rꢀt) alcohols are
almost equally effective in this protocol. The allylic alcohol (1q) underwent this reaction to give ether
2q in low yield (49%). However, the tertiary alcohols are not suitable substrates for this reaction.
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Different functional groups, such as ether, ketone, ester, amide, chloro, bromo, and iodo, are well
tolerated under the mild reaction conditions.
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Scheme 2. Oxidative Pentafluoroethylation of Alcoholsa
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KF (4.0 equiv)
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AgOTf (3.0 equiv)
2-fluoropyridine (2.0 equiv)
R OH
TMSC2F5
(3.0 equiv)
R OC2F5
+
Selectfluor (2.0 equiv)
LiOTf (1.0 equiv)
EtOAc/PhCF3, rt
1
2
OC2F5
( )3 OC2F5
O
OC2F5
Br
2a, 78%
2b, 76%
2c, 75%
OC2F5
OC2F5
NHBoc
OC2F5
NHBoc
2e, 91%
N
Boc
2d, 83%
2f, 62%
O
OC2F5
MeO
MeO
OC2F5
Me
O
2g, 80%
2h, 80%
OC2F5
OC2F5
OC2F5
OC2F5
Ph
MeO2C
t-Bu
2i, 74%
2j, 75%
2k, 68%
OC2F5
Cl
OC2F5
I
Br
2l, 55%
2m, 80%
2n, 76%
Cl
OC2F5
2q, 49%
OC2F5
2o, 66%
OC2F5
2p, 72%
OC2F5
OC2F5
OC2F5
2t, 68%
BocN
2s, 62%
2r, 75%
aReaction conditions: 1 (0.5 mmol), TMSC2F5 (1.5 mmol), KF (2.0 mmol), Selectfluor (1.0 mmol), AgOTf (1.5 mmol),
2ꢀfluoropyridine (1.0 mmol), LiOTf (0.5 mmol), EtOAc/PhCF3 (1:1, 5.0 mL), under N2, rt, 12 h, isolated yields.
Notably, complex substrates including rosuvastatin derivative and epiandrosterone were compatible
with the reaction conditions to afford pentafluoroethyl ethers (2u and 2v) in good yields (Scheme 3).
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These results demonstrated that this oxidative pentafluoroethylation protocol could be applied in the
lateꢀstage drug development.
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Scheme 3. Late-Stage Oxidative Pentafluoroethylation
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Subsequently, we explored the oxidative heptafluoropropylation of alcohols (Scheme 4). The
reaction of several primary, benzyl, and secondary alcohols with TMSCF2CF2CF3 proceeded well to
give the corresponding heptafluoropropyl ethers 4 in moderate to high yields. Similar to the oxidative
pentafluoroethylation, this reaction also gave the byproducts (pentafluoropropanoate esters) in low
yields. Moreover, the oxidative ethoxycarbonyldifluoromethylation of alcohols 1d and 1e with
TMSCF2CO2Et afforded ethers 4d and 4e in moderate yields. However, the analogous oxidative
difluoromethylation with TMSCF2H failed to give the desired product.
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Scheme 4. Oxidative Heptafluoropropylation and Ethoxycarbonyldifluoromethylation of Alcohols
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KF, AgOTf
2-fluoropyridine
R OH
+
TMSRf
R ORf
Selectfluor, LiOTf
EtOAc/PhCF3, rt
Rf = CF2CF2CF3
CF2CO2Et
1
4
9
OCF2CF2CF3
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4a, 77%a
OCF2CF2CF3
4n, 72%a
OCF2CF2CF3
4j, 53%a
MeO2C
I
OCF2CF2CF3
OCF2CF2CF3
4t, 66%a
4p, 61%a
OCF2CO2Et
OCF2CO2Et
NHBoc
4e, 57%b
NHBoc
4d, 40%b
aReaction conditions: 1 (0.5 mmol), TMSCF2CF2CF3 (1.25 mmol), KF (2.0 mmol), Selectfluor (1.0 mmol), AgOTf (1.5
mmol), 2ꢀfluoropyridine (1.0 mmol), LiOTf (0.5 mmol), EtOAc/PhCF3 (1:1, 5.0 mL), under N2, rt, 12 h, isolated
yields. Reaction conditions: 1 (0.5 mmol), TMSCF2CO2Et (1.5 mmol), KF (2.0 mmol), Selectfluor (1.0 mmol),
AgOTf (1.5 mmol), EtOAc/PhCF3 (1:1, 5.0 mL), under N2, rt, 12 h, isolated yields.
b
The phenols were also applicable to this oxidative perfluoroalkylation protocol (Scheme 5). For
example, the reaction of phenols 5a and 5b with TMSCF2CF3 and TMSCF2CF2CF3 gave the
corresponding aryl perfluoroalkyl ethers 6a and 7b in moderate yields respectively (for the optimization
of reaction conditions: see Table S1 in the Supporting Information). However, the metaꢀsubstituted
phenol (5c) was converted to pentafluoroethylated product 6c in low yield. In the cases of the phenols
substituted with an electronꢀdonating group (5d) or bromine (5e), the desired products (6d and 6e) were
also obtained in low yields.
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Scheme 5. Oxidative Perfluoroalkylation of Phenolsa
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aReaction conditions: 5 (0.5 mmol), TMSRf (2.0 mmol), NMe4F (2.5 mmol), Selectfluor (1.0 mmol), AgOTf (2.0
b
mmol), 2ꢀfluoropyridine (1.0 mmol), toluene (7.5 mL), under air, rt, 16 h, isolated yields. Yields determined by 19F
NMR spectroscopy using trifluoromethoxybenzene as an internal standard.
To probe for the possible reaction mechanism, preliminary mechanistic experiments were
performed. First, treatment of TMSC2F5 with KF, AgOTf and 2ꢀfluoropyridine in EtOAc generated
AgC2F5 (19F NMR: δ ꢀ84.9 ppm, s, 3F; ꢀ109.0 ppm, s, 2F).14 Unlike AgCF3 which easily
disproportionates to Ag(CF3)4 anion,4g,15 the AgC2F5 in solution is stable under inert atmosphere. Then,
AgC2F5 reacted with 1a in the presence of Selectfluor to give product 2a in 28% yield (Scheme 6a). This
result revealed that AgC2F5 probably is the reaction intermediate. Furthermore, the reaction of 1a and
TMSC2F5 in EtOAc under O2 gave ester 3a in 78% yield (Scheme 6b), which indicated that O2 was the
source of the oxygen atom of trifluoroacetyl group. This result was further confirmed by the 18Oꢀlabeling
experiment (Scheme 6c).
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Scheme 6. Mechanistic Investigations
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Based on the above results and previous reports, we proposed a plausible reaction mechanism
(Scheme 7). First, the initiation of TMSCF2Rf by fluoride and subsequent reaction with AgOTf
produced Ag(I)CF2Rf A. Then the oxidation of A with Selectfluor followed by ligand exchange with
alcohol 1 or phenol 5 afforded silver complex B, which underwent reductive elimination to give the
desired products 2, 4, 6 and 7. On the other hand, intermediate A might be converted into acyl fluoride
D after several transformations in the presence of oxygen. The byproduct 3 was formed by the reaction
of alcohol 1 with D.
Scheme 7. Proposed Reaction Mechanism
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Conclusion
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In summary, we have developed a new method for the preparation of potentially useful but less
explored pentafluoroethyl (heptafluoropropyl) ethers. The silverꢀmediated oxidative coupling of simple
alcohols and phenols with safe and stable nucleophilic TMSCF2CF3 (TMSCF2CF2CF3) reagents
provides a convenient access to the target compounds. Further investigation of the reaction mechanism
and extension of oxidative fluoroalkylation reactions are currently in progress.
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Experimental Section
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General Experimental Methods. H NMR (TMS as the internal standard), C NMR, and F NMR
spectra (CFCl3 as the outside standard and low field is positive) were recorded on a 400 MHz
spectrometer. Chemical shifts (δ) are reported in ppm and coupling constants (J) are in Hertz (Hz). The
following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. HRMS data using EI were obtained on a GCꢀTOF mass spectrometer. Substrates
were purchased from commercial sources and used as received. Unless otherwise noted, all reagents
were obtained commercially and used without further purification.
General procedure for pentafluoroethylation of alcohols
To a reaction tube that was equipped with a stirring bar, AgOTf (385.4 mg, 1.5 mmol, 3.0 equiv),
Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv), KF (116.5 mg, 2.0 mmol, 4.0 equiv), and LiOTf (78.0 mg,
0.5 mmol, 1.0 equiv) were added in a nitrogenꢀfilled glovebox. Then the reaction tube was removed
from the glovebox. Alcohol (0.5 mmol, 1.0 equiv), ethyl acetate (2.5 mL), PhCF3 (2.5 mL), TMSCF2CF3
(288.3 mg, 1.5 mmol, 3.0 equiv), and 2ꢀfluoropyridine (145.5 mg, 1.5 mmol, 3.0 equiv) were added
successively under N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was filtered through a plug of silica (eluted with ethyl acetate). The filtrate was
concentrated, and the product was purified by column chromatography on silica gel to give the alkyl
pentafluoroethyl ether.
(5-(Perfluoroethoxy)pentyl)benzene (2a). Compound 2a was obtained as a colorless liquid (110.0 mg,
78%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 7.31ꢀ7.17
19
(m, 5H), 4.01 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 1.77ꢀ1.63 (m, 4H), 1.48ꢀ1.40 (m, 2H). F
NMR (376 MHz, CDCl3) δ ppm ꢀ86.2 (s, 3F), ꢀ90.7 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 142.2,
128.4, 128.3, 125.8, 116.8 (qt, J = 282.5, 45.3 Hz), 115.3 (tq, J = 267.6, 41.1 Hz), 65.4 (t, J = 4.8 Hz),
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35.7, 30.9, 28.7, 25.1. IR (thin film) v 3028, 2938, 2861, 1454, 1217, 1102, 1031, 735, 698 cmꢀ1. MS
(EI): m/z 282 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C13H15F5O: 282.1043; Found: 282.1031.
((3-(Perfluoroethoxy)propoxy)methyl)benzene (2b). Compound 2b was obtained as a colorless liquid
(108.1 mg, 76%), hexane/Et2O = 10:1 as eluent for the column chromatography. 1H NMR (400 MHz,
CDCl3) δ ppm 7.35ꢀ7.28 (m, 5H), 4.50 (s, 2H), 4.15 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.01ꢀ
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1.95 (m, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ86.2 (s, 3F), ꢀ90.8 (s, 2F). C NMR (100 MHz,
CDCl3) δ ppm 138.1, 128.4, 127.7, 127.6, 116.8 (qt, J = 282.5, 45.4 Hz), 115.3 (tq, J = 268.1, 41.1 Hz),
73.2, 65.6, 62.5 (t, J = 5.3 Hz), 29.3. IR (thin film) v 3033, 2929, 2864, 1496, 1479, 1454, 1216, 1101,
735, 698 cmꢀ1. MS (EI): m/z 284 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C12H13F5O2: 284.0836;
Found: 284.0841.
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1-Bromo-4-(2-(perfluoroethoxy)ethyl)benzene (2c). Compound 2c was obtained as a colorless liquid
(120.8 mg, 75%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
7.43 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.17 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H). 19F
NMR (376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F), ꢀ90.9 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 135.6,
131.7, 130.6, 120.9, 116.6 (qt, J = 283.1, 44.8 Hz), 115.1 (tq, J = 268.4, 41.0 Hz), 65.4 (t, J = 5.3 Hz),
34.8. IR (thin film) v 3028, 2972, 2926, 2855, 1594, 1490, 1422, 1218, 1104, 1074, 1013, 964, 818, 736,
517 cmꢀ1. MS (EI): m/z 318 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C10H8BrF5O: 317.9679;
Found: 317.9683.
Tert-butyl (S)-(1-(perfluoroethoxy)-3-phenylpropan-2-yl)carbamate (2d). Compound 2d was obtained
as a white solid (154.2 mg, 83%), hexane/ethyl acetate = 7:1 as eluent forthe column chromatography.
Mp: 72ꢀ74 oC. 1H NMR (400 MHz, CDCl3) δ ppm 7.32ꢀ7.17 (m, 5H), 4.65 (s, 1H), 4.08ꢀ3.89 (m, 3H),
2.88ꢀ2.81 (m, 2H), 1.41 (s, 9H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ85.9 (s, 3F), ꢀ90.3ꢀ(ꢀ91.2) (m, 2F).
13C NMR (125 MHz, CDCl3) δ ppm 155.1, 136.7, 129.2, 128.7, 126.9, 116.7 (qt, J = 282.8, 45.0 Hz),
115.1 (tq, J = 268.4, 41.0 Hz), 79.9, 65.3, 50.5, 37.1, 28.2. IR (thin film) v 3350, 3030, 2979, 1712,
1498, 1421, 1393, 1250, 1177, 1059, 968, 878, 700 cmꢀ1. MS (EI): m/z 369 [M+]. HRMS (EIꢀTOF): m/z
[M+] Calculated for C16H20F5NO3: 369.1363; Found: 369.1372.
Tert-butyl (S)-(3-methyl-1-(perfluoroethoxy)butan-2-yl)carbamate (2e). Compound 2e was obtained as
a yellow oil (145.5 mg, 91%), hexane/ethyl acetate = 7:1 as eluent for the column chromatography. 1H
NMR (400 MHz, CDCl3) δ ppm 4.62ꢀ4.60 (m, 1H), 4.05ꢀ4.01 (m, 2H), 3.60 (s, 1H), 1.85ꢀ1.80 (m, 1H),
1.42 (s, 9H), 0.96ꢀ0.93 (m, 6H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ86.0 (s, 3F), ꢀ90.5ꢀ(ꢀ91.3) (m, 2F).
13C NMR (125 MHz, CDCl3) δ ppm 155.5, 116.6 (qt, J = 282.6, 45.5 Hz), 115.1 (tq, J = 268.4, 41.1 Hz),
79.5, 65.3, 54.4, 28.9, 28.1, 19.1, 18.3. IR (thin film) v 3347, 2972, 2879, 1707, 1502, 1421, 1393, 1231,
1174, 1101, 1024 cmꢀ1. MS (EI): m/z 306 [MꢀCH3]+. HRMS (EIꢀTOF): m/z [MꢀCH3]+ Calculated for
C11H17F5NO3: 306.1129; Found: 306.1135.
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Tert-butyl 3-((perfluoroethoxy)methyl)piperidine-1-carboxylate (2f). Compound 2f was obtained as a
colorless liquid (101.4 mg, 62%), hexane/Et2O = 3:1 as eluent for the column chromatography. 1H NMR
(400 MHz, CDCl3) δ ppm 3.89ꢀ3.82 (m, 4H), 2.86 (s, 2H), 1.90ꢀ1.84 (m, 1H), 1.80ꢀ1.76 (m, 1H), 1.68ꢀ
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1.60 (m, 1H), 1.42 (s, 10H), 1.30ꢀ1.20 (m, 1H). F NMR (376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F), ꢀ91.0
(s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 154.8, 116.7 (qt, J = 282.5, 44.9 Hz), 115.1 (tq, J = 267.6,
41.1 Hz), 79.6, 66.9, 46.3, 44.0, 35.2, 28.2, 26.7, 23.8. IR (thin film) v 2978, 2860, 1696, 1423, 1393,
1212, 1152, 1100, 972, 736 cmꢀ1. MS (EI): m/z 333 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for
C13H20F5NO3: 333.1363; Found: 333.1354.
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2,3-Dimethoxy-5-methyl-6-(10-(perfluoroethoxy)decyl)cyclohexa-2,5-diene-1,4-dione (2g). Compound
2g was obtained as a yellow oil (182.5 mg, 80%), hexane/Et2O = 5:1 as eluent for the column
chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 4.00ꢀ3.97 (m, 7H), 2.45ꢀ2.41 (m, 2H), 1.99 (s, 3H),
1.71ꢀ1.64 (m, 2H), 1.33ꢀ1.19 (m, 14H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ86.2 (s, 3F), ꢀ90.7 (s, 2F).
13C NMR (100 MHz, CDCl3) δ ppm 184.7, 184.1, 144.3, 143.0, 138.6, 116.7 (qt, J = 282.5, 45.4 Hz),
115.2 (tq, J = 267.6, 41.1 Hz), 65.5 (t, J = 4.8 Hz), 61.0, 29.7, 29.3, 29.2, 29.1, 28.9, 28.7, 28.6, 26.3,
25.3, 11.7. IR (thin film) v 2930, 2857, 1651, 1611, 1458, 1380, 1266, 1214, 1157, 1096, 1003, 948, 744
cmꢀ1. MS (EI): m/z 456 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C21H29F5O5: 456.1935; Found:
456.1926.
9-((Perfluoroethoxy)methyl)-9H-fluorene (2h). Compound 2h was obtained as a colorless liquid (125.7
mg, 80%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (d,
J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.50ꢀ7.47 (m, 2H), 7.41ꢀ7.37 (m, 2H), 4.30 (s, 3H). 19F NMR
(376 MHz, CDCl3) δ ppm ꢀ85.9 (s, 3F), ꢀ90.9 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 142.8, 141.4,
128.2, 127.4, 125.2, 120.2, 117.1 (qt, J = 282.2, 45.2 Hz), 115.4 (tq, J = 269.1, 41.3 Hz), 67.6 (t, J = 4.8
Hz), 46.7. IR (thin film) v 3069, 1610, 1478, 1420, 1324, 1216, 1099, 810, 737 cmꢀ1. MS (EI): m/z 314
[M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C16H11F5O: 314.0730; Found: 314.0728.
1-(Tert-butyl)-4-((perfluoroethoxy)methyl)benzene (2i). Compound 2i was obtained as a colorless
liquid (130.1 mg, 74%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ
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ppm 7.43 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.02 (s, 2H), 1.34 (s, 9H). F NMR (376 MHz,
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CDCl3) δ ppm ꢀ85.9 (s, 3F), ꢀ90.1 (s, 2F). C NMR (100 MHz, CDCl3) δ ppm 152.1, 130.9, 128.1,
125.7, 116.8 (qt, J = 282.5, 44.3 Hz), 115.4 (tq, J = 268.6, 41.2 Hz), 66.9 (t, J = 6.8 Hz), 34.6, 31.2. IR
(thin film) v 2966, 2871, 1518, 1466, 1365, 1216, 1100, 1020, 818, 732, 669 cmꢀ1. MS (EI): m/z 282
[M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C13H15F5O: 282.1043; Found: 282.1046.
Methyl 4-((perfluoroethoxy)methyl)benzoate (2j). Compound 2j was obtained as a yellow liquid (106.5
mg, 75%), hexane/ethyl acetate = 8:1 as eluent for the column chromatography. 1H NMR (400 MHz,
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CDCl3) δ ppm 8.04 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H), 3.90 (s, 3H). F NMR
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(376 MHz, CDCl3) δ ppm ꢀ86.2 (s, 3F), ꢀ90.7 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 166.5, 138.8,
130.6, 129.9, 127.4, 116.8 (qt, J = 282.2, 44.1 Hz), 115.3 (tq, J = 269.1, 41.3 Hz), 66.1 (t, J = 5.5 Hz),
52.0. IR (thin film) v 2958, 2849, 1727, 1580, 1418, 1220, 1021, 967, 841, 757 cmꢀ1. MS (EI): m/z 284
[M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C11H9F5O3: 284.0472; Found: 284.0466.
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4-((Perfluoroethoxy)methyl)-1,1'-biphenyl (2k). Compound 2k was obtained as a white solid (102.7 mg,
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68%), hexane as eluent for the column chromatography. Mp: 54ꢀ56 C. H NMR (400 MHz, CDCl3) δ
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ppm 7.63ꢀ7.58 (m, 4H), 7.47ꢀ7.34 (m, 5H), 5.08 (s, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ85.9 (s,
3F), ꢀ90.1 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 141.9, 140.4, 132.8, 128.9, 128.6, 127.6, 127.5,
127.2, 116.8 (qt, J = 283.2, 44.8 Hz), 115.4 (tq, J = 269.6, 41.8 Hz), 66.9 (t, J = 5.7 Hz). IR (thin film) v
3033, 2965, 1489, 1467, 1216, 1100, 1008, 826, 743 cmꢀ1. MS (EI): m/z 302 [M+]. HRMS (EIꢀTOF):
m/z [M+] Calculated for C15H11F5O: 302.0730; Found: 302.0741.
1,3-Dichloro-5-((perfluoroethoxy)methyl)benzene (2l). Compound 2l was obtained as a colorless liquid
(80.8 mg, 55%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.37 (t, J = 1.6 Hz, 1H), 7.24 (d, J = 2.0 Hz, 2H), 4.98 (s, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ
86.0 (s, 3F), ꢀ90.7 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 137.1, 135.4, 129.0, 126.0, 116.6 (qt, J =
283.2, 44.0 Hz), 115.2 (tq, J = 270.2, 41.8 Hz), 65.2 (t, J = 5.7 Hz). IR (thin film) v 3084, 2927, 2856,
1575, 1413, 1220, 1108, 855, 740 cmꢀ1. MS (EI): m/z 294 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated
for C9H5Cl2F5O: 293.9638; Found: 293.9644.
1-Bromo-4-((perfluoroethoxy)methyl)benzene (2m). Compound 2m was obtained as a colorless liquid
(121.6 mg, 80%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.52 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.98 (s, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ
86.0 (s, 3F), ꢀ90.3 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 132.9, 131.9, 129.6, 123.1, 116.6 (qt, J =
283.2, 44.8 Hz), 115.2 (tq, J = 270.3, 41.0 Hz), 66.2 (t, J = 5.7Hz). IR (thin film) v 2964, 2927, 2855,
1598, 1491, 1408, 1217, 1102, 1014, 806, 736 cmꢀ1. MS (EI): m/z 304 [M+]. HRMS (EIꢀTOF): m/z [M+]
Calculated for C9H6BrF5O: 303.9522; Found: 303.9516.
1-Iodo-4-((perfluoroethoxy)methyl)benzene (2n). Compound 2n was obtained as a colorless liquid
(133.8 mg, 76%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.72 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.96 (s, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ
86.0 (s, 3F), ꢀ90.3 (s, 2F).13C NMR (100 MHz, CDCl3) δ ppm 137.9, 133.6, 129.8, 116.7 (qt, J = 282.5,
44.6 Hz), 115.3 (tq, J = 269.1, 41.1 Hz), 94.8, 66.4 (t, J = 5.6 Hz). IR (thin film) v 2963, 2925, 2854,
1594, 1404, 1218, 1101, 1009, 951, 803 cmꢀ1. MS (EI): m/z 352 [M+]. HRMS (EIꢀTOF): m/z [M+]
Calculated for C9H6F5IO: 351.9384; Found: 351.9382.
2-((Perfluoroethoxy)methyl)naphthalene (2o). Compound 2o was obtained as a white solid (91.1 mg,
o
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66%), hexane as eluent for the column chromatography. Mp: 58ꢀ60 C. H NMR (400 MHz, CDCl3) δ
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ppm 7.87ꢀ7.81 (m, 4H), 7.52ꢀ7.49 (m, 2H), 7.46ꢀ7.43 (m, 1H), 5.18 (s, 2H). F NMR (376 MHz,
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CDCl3) δ ppm ꢀ85.9 (s, 3F), ꢀ90.0 (s, 2F). C NMR (100 MHz, CDCl3) δ ppm 133.4, 133.1, 131.3,
128.7, 128.1, 127.8, 127.5, 126.7, 126.6, 125.4, 116.8 (qt, J = 282.5, 44.9 Hz), 115.4 (tq, J = 269.1, 41.1
Hz), 67.3 (t, J = 5.6 Hz). IR (thin film) v 3060, 3029, 2966, 1603, 1511, 1420, 1272, 1100, 961, 857,
743 cmꢀ1. MS (EI): m/z 276 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C13H9F5O: 276.0574;
Found: 276.0563.
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1-((Perfluoroethoxy)methyl)naphthalene (2p). Compound 2p was obtained as a colorless liquid (99.4
mg, 72%), hexane as eluent for the column chromatography. 1H NMR (500 MHz, CDCl3) δ ppm 8.05 (d,
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J = 8.5 Hz, 1H), 7.96ꢀ7.93 (m, 2H), 7.66ꢀ7.53 (m, 3H), 7.51ꢀ7.49 (m, 1H), 5.54 (s, 2H). F NMR (376
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MHz, CDCl3) δ ppm ꢀ85.9 (s, 3F), ꢀ90.6 (s, 2F). C NMR (125 MHz, CDCl3) δ ppm 133.8, 131.4,
130.1, 129.4, 128.8, 127.6, 127.0, 126.2, 125.2, 123.0, 116.9 (qt, J = 283.0, 44.6 Hz), 115.6 (tq, J =
269.2, 41.7 Hz), 65.6 (t, J = 6.2 Hz). IR (thin film) v 3052, 1601, 1513, 1420, 1216, 1101, 930 744 cmꢀ1.
MS (EI): m/z 276 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C13H9F5O: 276.0574; Found:
276.0582.
(E)-(3-(Perfluoroethoxy)prop-1-en-1-yl)benzene (2q). Compound 2q was obtained as a colorless liquid
(61.8 mg, 49%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.42ꢀ7.24 (m, 5H), 6.70 (d, J = 16.0 Hz, 1H), 6.30ꢀ6.23 (m, 1H), 4.69 (d, J = 6.8 Hz, 2H). F NMR
(376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F), ꢀ90.1 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 135.7, 135.4,
128.7, 128.5, 126.8, 116.8 (qt, J = 282.2, 44.5 Hz), 115.4 (tq, J = 269.1, 41.2 Hz), 66.1 (t, J = 7.3 Hz).
IR (thin film) v 3086, 3031, 2960, 1498, 1450, 1217, 1098, 966, 745, 691 cmꢀ1. MS (EI): m/z 252 [M+].
HRMS (EIꢀTOF): m/z [M+] Calculated for C11H9F5O: 252.0574; Found: 252.0573.
Tert-butyl 4-(perfluoroethoxy)piperidine-1-carboxylate (2r). Compound 2r was obtained as a colorless
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liquid (118.1 mg, 75%), hexane/Et2O = 4:1 as eluent for the column chromatography. H NMR (400
MHz, CDCl3) δ ppm 4.58ꢀ4.52 (m, 1H), 3.67ꢀ3.61 (m, 2H), 3.28ꢀ3.22 (m, 2H), 1.88ꢀ1.82 (m, 2H), 1.75ꢀ
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1.67 (m, 2H), 1.41 (s, 9H). F NMR (376 MHz, CDCl3) δ ppm ꢀ86.5 (s, 3F), ꢀ88.4 (s, 2F). C NMR
(100 MHz, CDCl3) δ ppm 154.6, 116.6 (qt, J = 282.5, 45.9 Hz), 115.5 (tq, J = 268.6, 41.7 Hz), 79.8,
73.1(t, J = 5.0 Hz), 40.2, 31.6, 28.2. IR (thin film) v 2976, 2934, 2873, 1701, 1421, 1325, 1248, 1136,
1016, 734 cmꢀ1. MS (EI): m/z 319 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C12H18F5NO3:
319.1207; Found: 319.1215.
(Perfluoroethoxy)cyclododecane (2s). Compound 2s was obtained as a colorless liquid (150.0 mg,
62%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 4.59ꢀ4.53
(m, 1H), 1.86ꢀ1.77(m, 2H), 1.66ꢀ1.58 (m, 2H), 1.59ꢀ1.36 (m, 18H). 19F NMR (376 MHz, CDCl3) δ ppm
ꢀ86.5 (s, 3F), ꢀ87.7 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 116.8 (qt, J = 282.9, 45.4 Hz), 115.5 (tq,
J = 266.9, 40.9 Hz), 30.0, 23.9, 23.8, 23.2, 23.1, 20.5. IR (thin film) v 2934, 2866, 1471, 1447, 1251,
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1214, 1152, 1095, 733 cmꢀ1. MS (EI): m/z 302 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for
C14H23F5O: 302.1665; Found: 302.1669.
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2-(Perfluoroethoxy)-2,3-dihydro-1H-indene (2t). Compound 2t was obtained as a colorless liquid
(85.7mg, 68%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.27ꢀ7.22 (m, 4H), 5.30ꢀ5.25 (m, 1H), 3.38ꢀ3.32 (m, 2H), 3.23ꢀ3.17 (m, 2H). F NMR (376 MHz,
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CDCl3) δ ppm ꢀ86.3 (s, 3F), ꢀ88.6 (s, 2F). C NMR (100 MHz, CDCl3) δ ppm 139.2, 127.2, 124.6,
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116.8 (qt, J = 283.0, 45.2 Hz), 115.5 (tq, J = 268.3, 41.1 Hz), 77.6 (t, J = 5.4 Hz), 39.9. IR (thin film) v
3029, 2962, 1484, 1414, 1250, 1216, 1097, 998, 824, 738 cmꢀ1. MS (EI): m/z 252 [M+]. HRMS (EIꢀ
TOF): m/z [M+] Calculated for C11H9F5O: 252.0574; Found: 252.0571.
N-(4-(4-fluorophenyl)-6-isopropyl-5-((perfluoroethoxy)methyl)pyrimidin-2-yl)-N-
methylmethanesulfonamide (2u). Compound 2u was obtained as a white solid (149.8 mg, 64%),
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hexane/ethyl acetate = 5:1 as eluent for the column chromatography. Mp: 128ꢀ130 C. H NMR (400
MHz, CDCl3) δ ppm 7.63ꢀ7.60 (m, 2H), 7.17 (t, J = 8.6 Hz, 2H), 5.00 (s, 2H), 3.56 (s, 3H), 3.50 (s, 3H),
3.35ꢀ3.28 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F), ꢀ91.5 (s,
2F), ꢀ110.4ꢀ(ꢀ110.5) (m, 1F). 13C NMR (100 MHz, CDCl3) δ ppm 178.7, 167.7, 163.9 (d, J = 249.2 Hz),
158.9, 133.2(d, J = 3.6 Hz), 131.1 (d, J = 8.1 Hz), 116.6 (qt, J = 282.6, 44.2 Hz), 115.0 (tq, J = 270.8,
41.6 Hz), 115.7 (d, J = 21.7 Hz), 114.5, 60.7 (t, J = 11.7 Hz), 42.5, 33.1, 31.7, 22.0. IR (thin film) v
3079, 2877, 1605, 1510, 1420, 1336, 1209, 1095, 998, 821 cmꢀ1. MS (EI): m/z 471 [M+]. HRMS (EIꢀ
TOF): m/z [M+] Calculated for C18H19F6N3O3S: 471.1051; Found: 471.1054.
(3S,5S,8R,9S,10S,13S,14S)-10,13-Dimethyl-3-(perfluoroethoxy)hexadecahydro-17H-
cyclopenta[a]phenanthren-17-one (2v). Compound 2v was obtained as a white solid (159.3 mg, 78%),
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hexane/ethyl acetate = 7:1 as eluent for the column chromatography. Mp: 153ꢀ155 C. H NMR (400
MHz, CDCl3) δ ppm 4.33ꢀ4.25 (m, 1H), 2.44ꢀ2.37 (m, 1H), 2.08ꢀ1.99 (m, 1H), 1.93ꢀ1.42 (m, 11H),
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1.35ꢀ0.90 (m, 8H), 0.83 (s, 6H), 0.71ꢀ0.64 (m, 1H). F NMR (376 MHz, CDCl3) δ ppm ꢀ86.4 (s, 3F), ꢀ
13
87.2ꢀ(ꢀ88.0) (m, 2F). C NMR (100 MHz, CDCl3) δ ppm 221.0, 116.8 (qt, J = 282.6, 46.1 Hz), 115.4
(tq, J = 267.3, 41.5 Hz), 77.0 (t, J = 26.2 Hz), 54.3, 51.4, 47.7, 44.7, 36.7, 35.8, 35.4, 35.2, 35.0, 31.5,
30.7, 28.6, 28.2, 21.7, 20.4, 13.8, 12.1. IR (thin film) v 2960, 2856, 1740, 1474, 1384, 1214, 1092, 958,
734 cmꢀ1. MS (EI): m/z 408 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C21H29F5O2: 408.2088;
Found: 408.2082.
General procedure for heptafluoropropylation of alcohols
To a reaction tube that was equipped with a stirring bar, AgOTf (385.4 mg, 1.5 mmol, 3.0 equiv),
Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv), KF (116.5 mg, 2.0 mmol, 4.0 equiv), and LiOTf (78.0 mg,
0.5 mmol, 1.0 equiv) were added successively in a nitrogenꢀfilled glovebox. Then the reaction tube was
removed from the glovebox. Alcohol (0.5 mmol, 1.0 equiv), ethyl acetate (2.5 mL), PhCF3 (2.5 mL),
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TMSCF2CF2CF3 (303.0 mg, 1.25 mmol, 2.5 equiv), and 2ꢀfluoropyridine (145.5 mg, 1.5 mmol, 3.0
equiv) were added successively under N2 atmosphere. The reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was filtered through a plug of silica (eluted with ethyl
acetate). The filtrate was concentrated, and the product was purified by column chromatography on
silica gel to give the alkyl haptafluoropropyl ether.
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(5-(Perfluoropropoxy)pentyl)benzene (4a). Compound 4a was obtained as a colorless liquid (127.1 mg,
77%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 7.33ꢀ7.20
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(m, 5H), 4.05 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 1.79ꢀ1.65 (m, 4H), 1.49ꢀ1.42 (m, 2H). F
NMR (376 MHz, CDCl3) δ ppm ꢀ81.5ꢀ(ꢀ81.6) (m, 3F), ꢀ86.6ꢀ(ꢀ86.7) (m, 2F), ꢀ129.6ꢀ(ꢀ129.7) (m, 2F).
13C NMR (100 MHz, CDCl3) δ ppm 142.3, 128.4, 128.3, 125.8, 122.2ꢀ103.9 (m), 65.5 (t, J = 5.1 Hz),
35.7, 30.8, 28.6, 25.0. IR (thin film) v 3065, 2938, 2861, 1496, 1341, 1236, 1097, 992, 744 cmꢀ1. MS
(EI): m/z 332 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C14H15F7O: 332.1011; Found: 332.1006.
Methyl 4-((Perfluoropropoxy)methyl)benzoate (4j). Compound 4j was obtained as a yellow liquid (88.6
mg, 53%), hexane/ethyl acetate = 8:1 as eluent for the column chromatography. 1H NMR (400 MHz,
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CDCl3) δ ppm 8.05 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 5.10 (s, 2H), 3.91 (s, 3H). F NMR
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(376 MHz, CDCl3) δ ppm ꢀ81.4ꢀ(ꢀ81.5) (m, 3F), ꢀ86.4ꢀ(ꢀ86.5) (m, 2F), ꢀ129.4ꢀ(ꢀ129.5) (m, 2F). C
NMR (100 MHz, CDCl3) δ ppm 166.6, 138.7, 130.6, 130.0, 127.3, 122.1ꢀ104.2 (m), 66.3 (t, J = 5.7 Hz),
52.2. IR (thin film) v 2958, 1727, 1617, 1438, 1340, 1284, 1192, 1109, 998, 785 cmꢀ1. MS (EI): m/z 334
[M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C12H9F7O3: 334.0440; Found: 334.0436.
1-Iodo-4-((perfluoropropoxy)methyl)benzene (4n). Compound 4n was obtained as a colorless liquid
(143.3 mg, 72%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.75 (d, J = 6.8 Hz, 2H), 7.10 (d, J = 6.8 Hz, 2H), 5.02 (s, 2H). F NMR (376 MHz, CDCl3) δ ppm ꢀ
13
81.7ꢀ(ꢀ81.8) (m, 3F), ꢀ86.5ꢀ(ꢀ86.6) (m, 2F), ꢀ129.8 (s, 2F). C NMR (100 MHz, CDCl3) δ ppm 138.0,
133.5, 129.6, 121.7ꢀ103.8 (m), 94.7, 66.4 (t, J = 5.9Hz). IR (thin film) v 2965, 2911, 1594, 1487, 1385,
1231, 1105, 1060, 997, 801, 742 cmꢀ1. MS (EI): m/z 402 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated
for C10H6F7IO: 401.9352; Found: 401.9364.
1-((Perfluoropropoxy)methyl)naphthalene (4p). Compound 4p was obtained as a colorless liquid
(100.0 mg, 61%), hexane as eluent for the column chromatography. 1H NMR (500 MHz, CDCl3) δ ppm
8.00ꢀ7.89 (m, 3H), 7.62ꢀ7.45 (m, 4H), 5.53(s, 2H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ81.3ꢀ(ꢀ81.4) (m,
13
3F), ꢀ86.4ꢀ(ꢀ86.5) (m, 2F), ꢀ129.3ꢀ(ꢀ129.4) (m, 2F). C NMR (125 MHz, CDCl3) δ ppm 133.7, 131.3,
130.1, 129.3, 128.8, 127.4, 126.8, 126.2, 125.2, 122.9, 119.8ꢀ103.8 (m), 65.6 (t, J = 6.2 Hz). IR (thin
film) v 3035, 1513, 1336, 1235, 1190, 1102, 993, 773 cmꢀ1. MS (EI): m/z 326 [M+]. HRMS (EIꢀTOF):
m/z [M+] Calculated for C14H9F7O: 326.0542; Found: 326.0545.
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2-(Perfluoropropoxy)-2,3-dihydro-1H-indene (4t). Compound 4t was obtained as a colorless liquid
(100.0 mg, 66%), hexane as eluent for the column chromatography. 1H NMR (400 MHz, CDCl3) δ ppm
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7.28ꢀ7.23 (m, 4H), 5.34ꢀ5.30 (m, 1H), 3.40ꢀ3.36 (m, 2H), 3.23ꢀ3.19 (m, 2H). F NMR (376 MHz,
CDCl3) δ ppm ꢀ81.4ꢀ(ꢀ81.5) (m, 3F), ꢀ84.5ꢀ(ꢀ84.6) (m, 2F), ꢀ129.6 (s, 2F). 13C NMR (100 MHz, CDCl3)
δ ppm 139.2, 127.2, 124.6, 121.8ꢀ104.2 (m), 77.7 (t, J =4.6 Hz), 39.9. IR (thin film) v 3088, 2963, 1484,
1382, 1251, 1100, 981, 778 cmꢀ1. MS (EI): m/z 302 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for
C12H9F7O: 302.0542; Found: 302.0541.
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General procedure for ethoxycarbonyldifluoromethylation of alcohols
To a reaction tube that was equipped with a stirring bar, AgOTf (385.4 mg, 1.5 mmol, 3.0 equiv),
Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv), and KF (116.5 mg, 2.0 mmol, 4.0 equiv) were added
successively in a nitrogenꢀfilled glovebox. Then the reaction tube was removed from the glovebox.
Alcohol (0.5 mmol, 1.0 equiv), ethyl acetate (2.5 mL), PhCF3 (2.5 mL), and TMSCF2CO2Et (294.4 mg,
1.5 mmol, 3.0 equiv) were added successively under N2 atmosphere. The reaction mixture was stirred at
room temperature for 12 h. The reaction mixture was filtered through a plug of silica (eluted with ethyl
acetate). The filtrate was concentrated, and the product was purified by column chromatography on
silica gel to give the corresponding ether.
Ethyl (S)-2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-2,2difluoroacetate (4d). Compound 4d
was obtained as a yellow oil (74.6 mg, 40%), hexane/ethyl acetate = 5:1 as eluent for the column
chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 7.30ꢀ7.19 (m, 5H), 4.75 (s, 1H), 4.38ꢀ4.32 (m, 2H),
4.04 (s, 1H), 3.93ꢀ3.83 (m, 2H), 2.87ꢀ2.83 (m, 2H), 1.40ꢀ1.35 (m, 12H). 19F NMR (376 MHz, CDCl3) δ
ppm ꢀ79.9 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 160.1 (t, J = 42.5 Hz), 155.1, 137.1, 129.4, 128.6,
126.7, 114.7 (t, J = 268.6 Hz), 79.7, 64.8, 63.4, 50.7, 37.3, 28.3, 13.9. IR (thin film) v 3336, 2933, 1714,
1498, 1368, 1169, 1061, 855, 701 cmꢀ1. MS (EI): m/z 317 [MꢀC4H8]+. HRMS (EIꢀTOF): m/z [M+]
Calculated for C14H17F2NO5: 317.1075; Found: 317.1074.
Ethyl (S)-2-(2-((tert-butoxycarbonyl)amino)-3-methylbutoxy)-2,2-difluoroacetate (4e). Compound 4e
was obtained as a yellow oil (92.5 mg, 57%), hexane/ethyl acetate = 6:1 as eluent for the column
chromatography. 1H NMR (400 MHz, CDCl3) δ ppm 4.66ꢀ4.64 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.03ꢀ
3.92 (m, 2H), 3.58ꢀ3.55 (m, 1H), 1.86ꢀ1.81 (m, 1H), 1.41(s, 9H), 1.35ꢀ1.32 (m, 2H), 0.93 (t, J = 7.2 Hz,
2H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ80.2 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 160.0 (t, J =
41.7 Hz), 155.6, 114.6 (t, J = 268.4 Hz), 79.4, 64.9, 63.3, 54.6, 29.0, 28.3, 19.3, 18.5, 13.9. IR (thin
film) v 3346, 2976, 1777, 1506, 1342, 1175, 973, 778 cmꢀ1. MS (EI): m/z 282 [MꢀC3H7]+. HRMS (EIꢀ
TOF): m/z [M+] Calculated for C11H18F2NO5: 282.1153; Found: 282.1161.
Phenyl 4-(perfluoroethoxy)benzoate (6a). To a reaction tube that was equipped with a stirring bar,
AgOTf (513.9 mg, 2.0 mmol, 4.0 equiv), Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv), NMe4F (232.9
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mg, 2.5 mmol, 5.0 equiv), and phenyl 4ꢀhydroxybenzoate (107.1 mg, 0.5 mmol, 1.0 equiv) were added
in a nitrogenꢀfilled glovebox. Then the reaction tube was removed from the glovebox. PhCH3 (7.5 mL),
TMSCF2CF3 (384.4 mg, 2.0 mmol, 4.0 equiv), and 2ꢀfluoropyridine (194.2 mg, 2.0 mmol, 4.0 equiv)
were added successively under Air atmosphere. The reaction mixture was stirred at room temperature
for 16 h. The reaction mixture was filtered through a plug of silica (eluted with ethyl acetate). The
filtrate was concentrated, and the product was purified by column chromatography (silica gel,
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hexane/ethyl acetate = 15:1) to give compound 6a as a white solid (85.3 mg, 51%). Mp: 78ꢀ80 C. H
NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 7.28 (t, J = 7.2 Hz, 1H), 8.26 (d, J = 7.6 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F),
ꢀ87.9 (s, 2F). 13C NMR (100 MHz, CDCl3) δ ppm 164.0, 152.4, 150.7, 132.1, 129.5, 128.2, 126.1, 121.6,
121.2, 116.5 (qt, J = 283.5, 43.4 Hz), 114.3 (tq, J = 275.0, 41.8 Hz). IR (thin film) v 3017, 2929, 2854,
2258, 1592, 1493, 1409, 1321, 1235, 1149, 989, 909, 768 cmꢀ1. MS (EI): m/z 332 [M+]. HRMS (EIꢀ
TOF): m/z [M+] Calculated for C15H9F5O3: 332.0472; Found: 332.0460.
(3r,5r,7r)-1-(4-(Perfluoroethoxy)phenyl)adamantine (6d). To a reaction tube that was equipped with a
stirring bar, AgOTf (513.9 mg, 2.0 mmol, 4.0 equiv), Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv),
NMe4F (232.9 mg, 2.5 mmol, 5.0 equiv), and 4ꢀ(1ꢀadamantyl)phenol (114.2 mg, 0.5 mmol, 1.0 equiv)
were added in a nitrogenꢀfilled glovebox. Then the reaction tube was removed from the glovebox.
PhCH3 (7.5 mL), TMSCF2CF3 (384.4 mg, 2.0 mmol, 4.0 equiv), and 2ꢀfluoropyridine (194.2 mg, 2.0
mmol, 4.0 equiv) were added successively under Air atmosphere. The reaction mixture was stirred at
room temperature for 16 h. The reaction mixture was filtered through a plug of silica (eluted with ethyl
acetate). The filtrate was concentrated, and the product was purified by column chromatography (silica
gel, hexane) to give compound 6d as a white solid (40.1 mg, 23%). Mp: 40ꢀ42 oC. 1H NMR (400 MHz,
CDCl3) δ ppm 7.36 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.10 (s, 3H), 1.89 (s, 6H), 1.76 (q, J =
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11.7 Hz, 6H). F NMR (376 MHz, CDCl3) δ ppm ꢀ86.1 (s, 3F), ꢀ87.7 (s, 2F). C NMR (100 MHz,
CDCl3) δ ppm 150.1, 146.1, 126.2, 121.0, 116.8 (qt, J = 283.4, 44.2 Hz), 114.3 (tq, J = 271.9, 41.5 Hz),
43.1, 36.6, 36.0, 28.8. IR (thin film) v 2909, 2360, 1508, 1345, 1213, 1085, 835, 807 cmꢀ1. MS (EI): m/z
346 [M+]. HRMS (EIꢀTOF): m/z [M+] Calculated for C18H19F5O: 346.1356; Found: 346.1359.
1-(Methylsulfonyl)-4-(perfluoropropoxy)benzene (7b). To a reaction tube that was equipped with a
stirring bar, AgOTf (513.9 mg, 2.0 mmol, 4.0 equiv), Selectfluor (354.3 mg, 1.0 mmol, 2.0 equiv),
NMe4F (232.9 mg, 2.5 mmol, 5.0 equiv), and 4ꢀ(methylsulfonyl)phenol (86.1 mg, 0.5 mmol, 1.0 equiv)
were added in a nitrogenꢀfilled glovebox. Then the reaction tube was removed from the glovebox.
PhCH3 (7.5 mL), TMSCF2CF2CF3 (484.4 mg, 2.0 mmol, 4.0 equiv), and 2ꢀfluoropyridine (194.2 mg, 2.0
mmol, 4.0 equiv) were added successively under Air atmosphere. The reaction mixture was stirred at
room temperature for 16 h. The reaction mixture was filtered through a plug of silica (eluted with ethyl
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acetate). The filtrate was concentrated, and the product was purified by column chromatography (silica
gel, hexane/ethyl acetate = 2:1) to give compound 7b as a white solid (90.6 mg, 53%). Mp: 96ꢀ98 oC. 1H
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NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J = 8.8 Hz, 2H), 7.39(d, J = 8.4 Hz, 2H), 3.06 (s, 3H). F
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NMR (376 MHz, CDCl3) δ ppm ꢀ81.6ꢀ(ꢀ81.7) (m, 3F), ꢀ84.0 (s, 2F), ꢀ129.7ꢀ(ꢀ129.8) (m, 2F). 13C NMR
(100 MHz, CDCl3) δ ppm 152.2, 139.2, 129.7, 122.1, 119.1ꢀ104.4 (m), 44.5. IR (thin film) v 3020, 2930,
2258, 1493, 1340, 1232, 1208, 1150, 989, 768, 738 cmꢀ1. MS (EI): m/z 340 [M+]. HRMS (EIꢀTOF): m/z
[M+] Calculated for C10H7F7O3S: 340.0004; Found: 340.0007.
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Acknowledgment
This work was supported by the National Natural Science Foundation of China (21421002, 21332010)
and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000,
XDB20020000).
Supporting Information Available: Optimization of reaction conditions for oxidative
pentafluoroethylation of phenols, preliminary mechanistic experiments, as well as copies of 1H, 19F, and
13C NMR spectra. These material are available free of charge via the Internet at http://pubs.acs.org.
References
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B.; Pazenok, S.; Vors, J. P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140. (f) Landelle, G.;
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