Pentafluoroethylation of Carbonyl Compounds Using HFC-125 in a Flow Microreactor System

Article abstract of DOI:10.1021/acs.joc.1c00728

The protocol of micro-flow nucleophilic pentafluoroethylation using pentafluoroethane (HC2F5, HFC-125), a nontoxic, inexpensive, and commercially available greenhouse gas, is described. The micro-flow pentafluoroethylation by HFC-125 proceeded smoothly at

Full text of DOI:10.1021/acs.joc.1c00728

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Pentafluoroethylation of Carbonyl Compounds Using HFC-125 in a
Flow Microreactor System
Makoto Ono, Yuji Sumii, Yamato Fujihira, Takumi Kagawa, Hideyuki Mimura, and Norio Shibata*
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ABSTRACT: The protocol of micro-flow nucleophilic pentafluoroethylation using pentafluoroethane (HC2F5, HFC-125), a
nontoxic, inexpensive, and commercially available greenhouse gas, is described. The micro-flow pentafluoroethylation by HFC-125
proceeded smoothly at room temperature or at −10 °C in DMF or toluene in the presence of a potassium base, namely, t-BuOK or
KHMDS. A broad range of ketones, aldehydes, and chalcones with various substituted benzene rings were successfully converted to
the corresponding pentafluoroethyl carbinols instantly with good to high yields.
nucleophilic pentafluoroethylation reactions under fluoride
catalysis.11 In 2011, Nagaki, Amii, and Yoshida et al. elegantly
addressed this intractable problem by employing flow micro-
reactor systems.12 The flow microreactor is an effective device
for controlling unstable, reactive intermediates in organic
reactions.13 They achieved the nucleophilic pentafluoroethyla-
tion of benzaldehyde with pentafluoroethyl lithium generated
from pentafluoroethyl iodide (I-C2F5) under a flow micro-
reactor system at 0 °C (Figure 1c). Although this method is
potentially useful for various carbonyl compounds, only a
single example was reported.
INTRODUCTION
■
Organofluorine compounds have been an integral component
of pharmaceutical, agrochemical, and fine chemical industries
for more than half a century.1 Fluorination (F) and
trifluoromethylation (CF3) reactions are the two most widely
employed synthetic methods for the fluoro-functionalization of
target substrates.2,3 As a result, more than 80% of fluoro-
pharmaceuticals and fluoro-agrochemicals on the market can
be categorized into F−- and CF3-containing compounds.1,4
After fluorination (C0 unit) and trifluoromethylation (C1
unit), pentafluoroethylation (C2F5), entailing a two-carbon
extension, is the next most relevant fluoro-modification.
Among the reported pentafluoroethylation reaction methods,5
our focus is on the nucleophilic pentafluoroethylation reaction
of carbonyl compounds providing pentafluoroethyl carbinols
(RC(OH)C2F5), due to their potential broad utility in organic
synthesis. Examples of biologically attractive compounds
having a pentafluoroethyl carbinol moiety is shown in Figure
1a.6 However, taming the pentafluoroethyl anion (−C2F5) is
complicated as it is thermally unstable,7 spontaneously
decomposing into notoriously explosive tetrafluoroethylene
(TFE, CF2CF2) and fluoride (F−),8 specially in the case of
the reactive pentafluoroethyl lithium species generated by
halogen-lithium exchange reactions of pentafluoroethyl halide
(X-C2F5) (Figure 1b).9 Copper or zinc pentafluoroethyl
species (Cu-C2F5, Zn-C2F5) can be used as stable alternatives
to pentafluoroethyl anions,5a,10 but their utility is somewhat
limited owing to their low reactivity. Pentafluoroethyl
trialkylsilanes (R3SiC2F5) have been generally used for
We have recently disclosed a novel protocol for the direct
nucleophilic pentafluoroethylation of carbonyl compounds
using pentafluoroethane (HC2F5, HFC-125) in the presence
of potassium bases in glyme (Figure 1d).14 The key to this
transformation is the generation of glyme-encapsulated K+,
−
resulting in the stabilization of C2F5 derived from HFC-125
by ion separation. The encapsulation of K+ by glyme effectively
restricts contact between C2F5 and K+, preventing β-
−
−
elimination to CF2CF2 and KF. Isolated C2F5 is rather
exposed and is sufficiently nucleophilic for the pentafluor-
oethylation of various carbonyl compounds. HFC-125 is a
Special Issue: Enabling Techniques for Organic Syn-
thesis
Received: March 29, 2021
https://doi.org/10.1021/acs.joc.1c00728
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© XXXX American Chemical Society
A

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protocol enables the reaction within minutes, while the batch
system requires more than hours.14 Thus, this continuous flow
microreactor protocol for pentafluoroethylation would be
advantageous for large-scale industrial preparation.17
RESULTS AND DISCUSSION
■
Optimization of conditions for the micro-flow pentafluor-
oethylation of benzophenone (1a) as a model substrate was
investigated. On the basis of our previous report,16f we selected
a three-inlet mixer to combine the substrate, HFC-125, and
base (Table 1). It took about 2 min to stabilize the gas flow.
Table 1. Optimization of Reaction Conditions for the
Micro-flow Pentafluoroethylation of Benzophenone (1a)
Using HFC-125
a
entry
solvent
DMF
toluene
THF
DMF
DMF
DMF
triglyme
tetraglyme
base
temp
rt
rt
rt
rt
−10 °C
−50 °C
rt
rt
yield (%)
1
2
3
4
5
6
7
8
t-BuOK
t-BuOK
t-BuOK
KHMDS
t-BuOK
t-BuOK
t-BuOK
t-BuOK
92
15
33
81
89
89
74
60
Figure 1. Pentafluoroethylation using pentafluoroethyl halides or
HFC-125. (a) Biologically attractive compounds having a penta-
fluoroethyl carbinol moiety. (b) β-elimination in pentafluoroethyl
lithium, yielding TFE. (c) Micro-flow pentafluoroethylation of
benzaldehyde using I-CF2CF3 and MeLi. (d) Pentafluoroethylation
of carbonyl compounds using HFC-125 and a potassium base in
glyme. (e) Micro-flow pentafluoroethylation of carbonyl compounds
using HFC-125 and a potassium base in DMF or toluene (this work).
a
Yields were determined by 19F NMR of the crude product with
trifluorotoluene as an internal standard.
We examined the flow process time and found that 1 min is
enough to get good reproducible yields. When the reaction was
conducted by mixing 1a in DMF (0.6 M, 0.33 mL/min), t-
BuOK in DMF (2.0 equiv, 0.66 mL/min), and gaseous HFC-
125 (25 mL/min, 5.17 equiv, 0.1 MPa) at room temperature,
the desired pentafluoroethylated product 2a was obtained in
92% yield (entry 1). The use of toluene or THF as a solvent
decreased the product yield (entries 2 and 3). When KHMDS
was used instead of t-BuOK, the yield was lower (entry 4).
Decreasing the reaction temperature (−10 or −50 °C) did not
significantly affect the yield (entries 5 and 6). Despite our
expectation,14 tri- or tetraglyme as solvent was not adequate for
the micro-flow protocol (entries 7 and 8).
To reduce the amount of HFC-125, we further optimized
the concentration of 1a and the flow rates of 1a, t-BuOK, and
HFC-125 in DMF (Table 2). An increase in the concentration
of 1a resulted in a lower product yield (entries 1−3).
Decreasing the HFC-125 flow rate also resulted in a lower
yield of 2a (entries 4 and 5). A decrease in the flow rate of t-
BuOK to 0.6 mL/min (i.e., increasing the residence time)
improved the yield of 1a to 94% (entry 6). Reducing the
number of equivalents of t-BuOK (1.5 equiv) (entry 7) or the
flow rates of t-BuOK and HFC-125 (entry 8) resulted in a
lower yield (85−87%). These results suggest that the reactivity
nontoxic and inexpensive greenhouse gas, and it does not
contribute to ozone layer depletion.15 As HFC-125 is a more
atom economical reagent than C2F5I, we focused on the micro-
flow pentafluoroethylation of carbonyl compounds using HFC-
125. The advantage of being able to control an unstable anion
by harnessing the compatibility between flow microreactors
and gaseous reagents should yield an ideal method for direct
pentafluoroethylation using HFC-125. Herein, we report the
pentafluoroethylation of various carbonyl compounds using
HFC-125 in a flow microreactor system, as part of our project
aimed at devising efficient protocols that utilize fluorocarbons
in organic synthesis.16 Indeed, nucleophilic pentafluoroethyla-
tion of a broad range of ketones, chalcones, and aldehydes was
achieved in a flow microreactor system at temperatures ranging
from room temperature to −10 °C in the presence of
potassium bases such as potassium tert-butoxide (t-BuOK) and
potassium bis(trimethylsilyl)amide (KHMDS) (Figure 1e). As
expected, the use of a micro-flow system allowed for a highly
efficient pentafluoroethylation protocol, which did not require
glyme as a stabilization solvent or low-temperature conditions
ordinarily employed in batch systems. Besides, this micro-flow
B
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di-2-pyridyl ketone (1k), and 2-adamantanone (1l) proceeded
smoothly to provide the corresponding products in high yield
(2j: 90%, 2k: 85%, 2l: 85%).
Table 2. Optimization of Flow Parameters for the
Pentafluoroethylation of Benzophenone Using HFC-125
Next, we examined the micro-flow pentafluoroethylation of
aldehyde 3 (Table 3). The reaction was first conducted by
Table 3. Optimization of Reaction Conditions for the Flow
Pentafluoroethylation of Benzaldehyde Using HFC-125
flow rate (mL/min)
equiv of
HFC-125
yield
a
entry X (M)
1a
t-BuOK HFC-125
(%)
1
2
3
4
5
6
7
8
0.6
0.9
1.2
0.6
0.6
0.6
0.6
0.6
0.33
0.33
0.33
0.33
0.33
0.30
0.30
0.30
0.66
0.66
0.66
0.66
0.66
0.60
0.45
0.60
25
25
25
15
13.5
15
15
5.17
3.44
2.58
3.10
2.79
3.41
3.41
3.07
92
91
73
88
79
94
87
85
flow rate (mL/min)
equiv of
yield
a
entry X (M)
3e
t-BuOK HFC-125
HFC-125
(%)
b
b
1
2
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.9
0.33
0.33
0.33
0.33
0.33
0.33
0.30
0.30
0.30
0.30
0.66
0.66
0.66
0.66
0.66
0.50
0.60
0.45
0.33
0.30
25
25
25
15
13.5
15
13.5
13.5
13.5
20
5.17
5.17
5.17
3.10
2.79
3.10
3.07
3.07
3.07
3.03
0
75
89
93
88
92
85
84
70
89
c
13.5
3
4
5
6
7
8
9
10
a
Yields were determined by 19F NMR of crude product with
trifluorotoluene as an internal standard. 1.5 equiv of t-BuOK.
b
d
of HFC-125-mediated pentafluoroethylation is highly depend-
ent on the concentration of the reactants, viscosity, and slug
flow in the microtube.
d
e
Next, we examined the substrate generality of the flow
pentafluoroethylation protocol using various ketone substrates
with a range of substituents on the aromatic ring (Scheme 1).
Benzophenones bearing electron-donating groups or halogens
(1a−g) provided the corresponding pentafluoroethylated
products (2a−g) in high yield (85−93% yield). Substitution
with electron-withdrawing groups (1h: NO2, 1i: CF3) provided
the pentafluoroethylated products in good yield (2h: 76%, 2i:
87%). The pentafluoroethylation reaction of 9-fluorenone (1j),
a
Yields were determined by 19F NMR of the crude product with
b
trifluorotoluene as an internal standard. Reaction was performed at
c
d
room temperature. Reaction was performed at 0 °C. 1.5 equiv of t-
e
BuOK. 1.1 equiv of t-BuOK.
mixing 3a in DMF (0.6 M, 0.33 mL/min), t-BuOK in DMF
(2.0 equiv, 0.66 mL/min), and HFC-125 (25 mL/min, 5.17
equiv, 0.1 MPa) at room temperature; however, the desired
product was not observed (entry 1). This outcome could be
explained by the occurrence of the Cannizzaro reaction. Thus,
we performed the reaction at −10 °C. After a number of
attempts (entries 2−10), optimal conditions were established
as follows: 3a in DMF (0.6 M, 0.33 mL/min), t-BuOK in DMF
(1.50 equiv, 0.50 mL/min), and HFC-125 (15 mL/min, 3.10
equiv, 0.1 MPa) at −10 °C (entry 6).
Scheme 1. Flow Pentafluoroethylation of Ketones Using
HFC-125
Scheme 2 shows the substrate scope of the flow
pentafluoroethylation of substituted benzaldehydes (3a−j),
naphthalene aldehydes (3i and 3j), and heteroaryl aldehydes
(3k and 3l). Benzaldehydes bearing electron-donating groups,
halogens, and electron-withdrawing groups gave the corre-
sponding pentafluoroethylated products (4a−h) in high yield
(86−92% yield). Likewise, 1- and 2-naphthalene aldehydes (3i
and 3j) also delivered the desired products in high yield (4i:
91%, 4j: 82%). The flow pentafluoroethylation of hetero-
aromatic aldehydes (3k and 3l) afforded lower yields (4k:
65%, 4l: 69%).
The flow pentafluoroethylation of chalcone 5a was examined
next (Table 4). In this case, KHMDS was used based on the
reported batch system.14 The desired 1,2-addition product 6a
was obtained in 45% yield (entry 1). The reagent
concentrations, solvent, and HFC-125 flow rate were further
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Scheme 2. Flow Pentafluoroethylation of Aldehydes Using
HFC-125
Scheme 3. Flow Pentafluoroethylation of Chalcones Using
HFC-125
a
THF was used as the solvent.
pentafluoroethylation of nitro-substituted 5f also provided
the desired pentafluoroethylated product 6f in 72% yield when
conducted in THF instead of toluene.
Finally, we extended the protocol to the pentafluoroethyla-
tion of biologically attractive substrates (Scheme 4). The
Table 4. Optimization of Conditions for the Flow
Pentafluoroethylation of Chalcones Using HFC-125
Scheme 4. Flow Pentafluoroethylation of Bioactive
Carbonyl Derivatives
HFC-125
a
entry X (M)
solvent
flow rate (mL/min)
equiv
yield (%)
b
1
2
3
4
5
6
7
8
9
0.6
0.6
0.6
0.6
0.3
0.3
0.3
0.3
0.3
DMF
DMF
THF
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
12.5
12.5
7.5
6.5
7.5
5.17
5.17
5.17
5.17
5.17
5.17
3.10
2.69
3.10
45
65
85
85
90
90
90
85
90
c
d
a
Yields were determined by 19F NMR of the crude product with
b
trifluorotoluene as an internal standard. t-BuOK was used instead of
KHMDS. Reaction was performed at −10 °C. 1.5 equiv of KHMDS
was used.
c
d
a
b
Conditions for ketones 1 (Scheme 1). Conditions for aldehydes 3
c
d
optimized (entries 2−9), and the ideal conditions were
determined as follows: chalcone 5a in toluene (0.3 M, 0.33
mL/min), KHMDS (1.5 equiv, 0.50 mL/min) in toluene, and
HFC-125 (7.5 mL/min, 3.10 equiv, 0.1 MPa) were reacted at
room temperature to afford product 6a in 90% yield (entry 9).
Thus, we demonstrated the flow pentafluoroethylation of
chalcones 5 under optimized reaction conditions (Scheme 3).
Methoxy- (5b) and halogen-substituted (5c−e) chalcones
were converted to the corresponding 1,2-addition products
(6b−e) in good to high yields (70−88%). The flow
(Scheme 2). Conditions for chalcones 5 (Scheme 3). Modified
conditions of chalcones 5; see the details in the Experimental Section.
pentafluoroethylation of fenofibrate (7a, hypolipidemic agent)
furnished the pentafluoroethyl carbinol product 8a in good
yield (64%) by the ketone’s conditions (Scheme 1). Fragrance
aldehydes such as O-Bn-vanillin (7b) and heliotropin (7c)
were transformed into pentafluoroethyl carbinol products (8b
and 8c) in good to high yield (65% and 94%) under the
conditions for aldehydes (Scheme 2). The ABCG2 inhibitory
D
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mixer (4 direction swirl mixer, Sugiyama Shoji, SUS316, 60 μL
internal volume, 16YSM-0.8-0.5-S)23 was used for a mixing of
solutions and HFC-125. All flow stuffs (syringes, three inlets mixer,
reaction coil, tubes) were dried and filled with N2 gas before using.
The residence tube (SUS316, ID = 0.8 mm; residence volume V =
0.32 or 0.81 mL) was used for the reaction coil.
General Procedure 1: Flow Pentafluoroethylation of
Benzophenones Using HFC-125. A solution of ketone 1 (1.2
mmol, 1.0 equiv) in dry DMF (2.0 mL) was fed into a three-inlet
mixer (0.30 mL/min) using a syringe pump; simultaneously t-BuOK
(2.4 mmol, 2.0 equiv) in dry DMF (4.0 mL) was fed into the mixer
(0.60 mL/min) using another syringe pump. HFC-125 (3.41 equiv)
was introduced into the mixer at 0.1 MPa and 15 mL/min controlled
by a mass flow controller. The combined mixture was passed through
residence tubing (residence volume V = 0.32 mL) at room
temperature. After the gas flow rate stabilized (about 2 min), we
collected the product for 1 min. The product stream was quenched
with sat. NH4Cl aq. The aqueous layer was extracted with Et2O, and
the combined organic layers were washed with brine, dried over
Na2SO4, concentrated under reduced pressure, and purified by
column chromatography on silica gel to give products 2.
active chalcones (7d and 7e) gave the corresponding
pentafluoroethyl carbinols (8d and 8e) in moderated yield
(46% and 68%) by the conditions for chalcones (Scheme 3).
Interestingly, a conjugated, alkynyl ketone, 3-cyclopropyl-1-
(2,5-dichlorophenyl)prop-2-yn-1-one (7f, a building block for
the preparation of anti-HIV drug, efavirenz) was also
transformed into the desired C2F5-variant of efavirenz
precursor 8f, under the slightly modified conditions for
chalcones (1.7 equiv of KHMDS in toluene (0.3 M), 1.1
mL/min, −30 °C) in moderated yield (51%).
CONCLUSIONS
■
In summary, we have developed a micro-flow pentafluor-
oethylation method using HFC-125. Ketones, aldehydes, and
chalcones were promptly converted to the corresponding
pentafluoroethylated products in good to high yields. HFC-125
is a nontoxic, inexpensive, and commercially available green-
house gas. The reaction can be performed at room temperature
or at −10 °C, and the system does not require the use of glyme
as a stabilization solvent, nor very low-temperature conditions
employed in batch systems. While the glyme protocol is
efficient,14 the reaction should be carried out for 12 h. On the
other hand, this micro-flow protocol enables the reaction
within minutes. Besides, large-scale production can be
performed without a particular large-scale variant since the
protocol is a continuous flow system. Moreover, we never
experienced any explosions through all the experiments.8 Since
we experienced the substrates with an enolizable ketone
moiety was unreacted due to the α-deprotonation of ketones,
the issue should be the next challenge. The application of this
flow system in asymmetric pentafluoroethylation reactions is
currently under investigation.
2,2,3,3,3-Pentafluoro-1,1-diphenylpropan-1-ol (2a). Following
the general procedure 1, crude product was purified by silica gel
column chromatography with hexane/CH2Cl2 (1:1) to give the
1
product 2a (50.0 mg, 92% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 7.63−7.53 (m, 4H), 7.41−7.32 (m, 6H), 2.95−2.93
(m, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −77.6 (br s, 3F),
−116.9 (br s, 2F) ppm. MS (ESI, m/z) 301 [M − H]−. Analytical
data are consistent with reported values.13
2,2,3,3,3-Pentafluoro-1-phenyl-1-(p-tolyl)propan-1-ol (2b). Fol-
lowing the general procedure 1, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
1
product 2b (49.1 mg, 86% yield) as a colorless oil. H NMR (300
MHz, CDCl3) δ: 7.55 (d, J = 6.8 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H),
7.35−7.33 (m, 3H), 7.15 (d, J = 7.9 Hz, 2H), 2.81 (s, 1H), 2.34 (s,
3H) ppm. 19F NMR (282 MHz, CDCl3) δ: −77.5 (s, 3F), −116.9 (s,
2F) ppm. MS (ESI, m/z) 315 [M − H]−. Analytical data are
consistent with reported values.14
2,2,3,3,3-Pentafluoro-1,1-bis(4-methoxyphenyl)propan-1-ol (2c).
Following the general procedure 1, crude product was purified by
silica gel column chromatography with hexane/EtOAc (9:1) to give
the product 2c (60.8 mg, 93% yield) as a colorless oil. 1H NMR (300
MHz, CDCl3) δ: 7.45 (d, J = 8.8 Hz, 4H), 6.85 (d, J = 8.8 Hz, 4H),
3.79 (s, 6H), 2.89 (s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ:
−77.6 (s, 3F), −117.0 (s, 2F) ppm. MS (ESI, m/z) 361 [M − H]−.
Analytical data are consistent with reported values.24
EXPERIMENTAL SECTION
■
General Information. All reagents were used as received from
commercial sources unless specified otherwise. The solvents were
transferred via syringe. All reactions were monitored by thin-layer
chromatography (TLC) performed on 0.25 mm Merck silica gel (60-
F254). The TLC plates were visualized under UV light and stained
with 7% phosphomolybdic acid or KMnO4 in water, followed by
heating. Column chromatography was performed on silica gel 60N
spherical neutral size 40−50 μm (Kanto Kagaku), 64−210 μm
(FUJIFILM Wako). NMR spectra were recorded on a Varian
1-(2-Chlorophenyl)-2,2,3,3,3-pentafluoro-1-phenylpropan-1-ol
(2d). Following the general procedure 1, crude product was purified
by silica gel column chromatography with hexane/CH2Cl2 (2:1) to
give the product 2d (51.7 mg, 85% yield) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 7.99 (d, J = 7.1 Hz, 1H), 7.43−7.35 (m, 8H),
4.03 (s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −76.7 (s, 3F),
1
Mercury 300 spectrometer for H NMR (300 MHz) and 19F NMR
1
(282 MHz), and a Bruker Avance 500 for H NMR (500 MHz) and
13C{1H} NMR (125 MHz). The chemical shifts (δ) were measured in
parts per million with respect to solvent (1H: CDCl3, δ = 7.26 ppm;
19F: CDCl3, δ = −162.2 ppm with C6F6 as internal standard; 13C{1H}:
CDCl3, δ = 77.16 ppm), and coupling constants (J) are given in hertz.
The following abbreviations denoted the corresponding multiplicities:
s, singlet; d, doublet; t, triplet; q, quadruplet; dd, doublet of doublets;
td, triplet of doublets; dt, doublet of triplets; m, multiplet; br, broad.
Mass spectra were recorded using an LCMS-2020EV (ESI-MS)
system. Infrared spectra were recorded on a JASCO FT/IR-4100
spectrometer. High-resolution mass spectrometry (HR-MS) was
performed on a Waters Synapt G2 HDMS (ESI-TOF-MS) instru-
ment. Melting points were recorded using a BUCHI L3abortehnik
AG M-565 apparatus. Ketones 1, aldehydes 3, and chalcones 5a, 7b,
and 7c were purchased from Aldrich, TCI, and Wako Chemical.
Substrates 5b−f, 7b, and 7d−f were prepared according to the
reported methods.18−22
2
2
−114.0 (d, JF‑F = 275.9 Hz, 1F), −116.6 (d, JF‑F = 275.9 Hz, 1F)
ppm. 13C{1H} NMR (126 MHz, CDCl3) δ: 138.1, 137.2, 133.3,
3
132.6, 130.1, 129.1 (t, JC‑F = 5.9 Hz), 128.7, 128.0, 127.9, 126.6,
119.3 (qt, 1JC-F = 288.4, 35.0 Hz), 117.7−112.6 (m), 80.6 (t, 2JC‑F
=
23.2 Hz). ATR-FTIR (neat): ν = 3555, 3067, 1452, 1336, 1223, 1134,
1050, 910, 863, 755 cm−1. HRMS (ESI) m/z: [M − H]− calcd. for
C15H9ClF5O; 335.0262 Found: 335.0258.
1-(3-Chlorophenyl)-2,2,3,3,3-pentafluoro-1-phenylpropan-1-ol
(2e). Following the general procedure 1, crude product was purified
by silica gel column chromatography with hexane/CH2Cl2 (2:1) to
give the product 2e (52.7 mg, 87% yield) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 7.63 (s, 1H), 7.59−7.56 (m, 2H), 7.46 (d, J =
7.1 Hz, 1H), 7.39−7.29 (m, 5H), 2.97 (s, 1H) ppm. 19F NMR (282
2
Components of Flow System. A syringe pump (YMC) was used
for addition of solutions of substrate and base. The mass flow
controller (Fujikin, FCST1005MLC) was used to control the flow
rate of gaseous HFC-125. The pressure of HFC-125 was regulated by
the regulator connected to the HFC-125 cylinder. The three-inlet
MHz, CDCl3) δ: −77.6 (s, 3F), −116.4 (d, JF‑F = 279.3 Hz, 1F),
−117.6 (d, 2JF‑F = 279.3 Hz, 1F) ppm. MS (ESI, m/z) 335 [M − H]−.
Analytical data are consistent with reported values.14
1-(4-Chlorophenyl)-2,2,3,3,3-pentafluoro-1-phenylpropan-1-ol
(2f). Following the general procedure 1, crude product was purified by
E
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silica gel column chromatography with hexane/CH2Cl2 (2:1) to give
the product 2f (56.3 mg, 93% yield) as a colorless oil. 1H NMR (300
MHz, CDCl3) δ: 7.56−7.52 (m, 4H), 7.38−7.32 (m, 5H), 2.92 (s,
1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −77.6 (s, 3F), −116.5 (d,
2JF‑F = 279.3 Hz, 1F), −117.7 (d, 2JF‑F = 277.6 Hz, 1F) ppm. MS (ESI,
for 1 min. The product stream was quenched with sat. NH4Cl aq. The
aqueous layer was extracted with Et2O, and the combined organic
layers were washed with brine, dried over Na2SO4, concentrated
under reduced pressure, and purified by column chromatography on
silica gel to give products 4.
m/z) 335 [M − H]−. Analytical data are consistent with reported
2,2,3,3,3-Pentafluoro-1-phenylpropan-1-ol (4a). Following the
general procedure 2, crude product was purified by silica gel column
chromatography with hexane/CH2Cl2 (1:1) to give the product 4a
(40.3 mg, 90% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ: 7.45 (br s, 5H), 5.18−5.09 (m, 1H), 2.44 (d, J = 4.4 Hz, 1H) ppm.
19F NMR (282 MHz, CDCl3) δ: −81.7 (s, 3F), −122.3 (dd, 2JF‑F, 3JF‑F
values.14
1-(4-Bromophenyl)-2,2,3,3,3-pentafluoro-1-phenylpropan-1-ol
(2g). Following the general procedure 1, crude product was purified
by silica gel column chromatography with hexane/CH2Cl2 (1:1) to
give the product 2g (62.4 mg, 91% yield) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 7.53−7.35 (m, 9H), 2.90 (d-like, J = 6.5 Hz,
1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −77.5 (s, 3F), −116.4 (d,
2JF‑F = 277.6 Hz, 1F), −117.6 (d, 2JF‑F = 277.6 Hz, 1F) ppm. MS (ESI,
2
3
= 275.9, 6.9 Hz, 1F), −129.9 (dd, JF‑F, JF‑F = 275.9, 17.2 Hz, 1F)
ppm. MS (ESI, m/z) 227 [M + H]+. Analytical data are consistent
with reported values.14
m/z) 404 [M + Na]+. Analytical data are consistent with reported
values.14
2,2,3,3,3-Pentafluoro-1-(4-methoxyphenyl)propan-1-ol (4b).
Following the general procedure 2, crude product was purified by
silica gel column chromatography with hexane/Et2O (1:1) to give the
2,2,3,3,3-Pentafluoro-1-(4-nitrophenyl)-1-phenylpropan-1-ol
(2h). Following the general procedure 1, crude product was purified
by silica gel column chromatography with hexane/EtOAc (9:1) to
give the product 2h (47.6 mg, 76% yield) as a yellow solid. 1H NMR
(300 MHz, CDCl3) δ: 8.18 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.2 Hz,
2H), 7.54−7.52 (m, 2H), 7.39−7.37 (m, 3H), 3.16 (s, 1H) ppm. 19F
1
product 4b (46.2 mg, 91% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 7.36 (d, J = 8.8 Hz, 2H), 6.92 (d-like, J = 8.8 Hz,
2H), 5.08−4.99 (m, 1H), 3.81 (s, 3H), 2.75 (s, 1H) ppm. 19F NMR
(282 MHz, CDCl3) δ: −81.7 (s, 3F), −122.7 (dd, 2JF‑F, 3JF‑F = 274.1,
2
3
8.6 Hz, 1F), −129.9 (dd, JF‑F, JF‑F = 275.0, 16.4 Hz, 1F) ppm. MS
(ESI, m/z) 257 [M + H]+. Analytical data are consistent with
reported values.14
2
NMR (282 MHz, CDCl3) δ: −77.5 (s, 3F), −115.9 (d, JF‑F = 279.3
2
Hz, 1F), −118.0 (d, JF‑F = 279.3 Hz, 1F) ppm. MS (ESI, m/z) 346
[M − H]−. Analytical data are consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-phenyl-1-(4-(trifluoromethyl)phenyl)-
propan-1-ol (2i). Following the general procedure 1, crude product
was purified by silica gel column chromatography with hexane/EtOAc
(9:1) to give the product 2i (58.1 mg, 87% yield) as a colorless oil. 1H
NMR (300 MHz, CDCl3) δ: 7.70 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.2
Hz, 2H), 7.56−7.53 (m, 2H), 7.41−7.33 (m, 3H), 2.99 (s, 1H) ppm.
19F NMR (282 MHz, CDCl3) δ: −63.3 (s, 3F), −77.5 (s, 3F), −116.3
1-([1,1′-Biphenyl]-4-yl)-2,2,3,3,3-pentafluoropropan-1-ol (4c).
Following the general procedure 2, crude product was purified by
silica gel column chromatography with hexane/Et2O (4:1) to give the
1
product 4c (52.7 mg, 88% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 7.67−7.37 (m, 9H), 5.23−5.14 (m, 1H), 2.56 (d, J =
4.1 Hz, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −81.7 (s, 3F),
−122.2 (dd, 2JF‑F, 3JF‑F = 275.9, 6.9 Hz, 1F), −130.0 (dd, 2JF‑F, 3JF‑F
=
275.9, 17.2 Hz, 1F) ppm. MS (ESI, m/z) 303 [M + H]+. Analytical
data are consistent with reported values.14
2
2
(d, JF‑F = 279.3 Hz, 1F), −117.8 (d, JF‑F = 277.6 Hz, 1F) ppm. MS
(ESI, m/z) 369 [M − H]−. Analytical data are consistent with
reported values.14
1-(4-Chlorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (4d). Fol-
lowing the general procedure 2, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
9-(Perfluoroethyl)-9H-fluoren-9-ol (2j). Following the general
procedure 1, crude product was purified by silica gel column
chromatography with hexane/CH2Cl2 (1:1) to give the product 2j
(48.7 mg, 90% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ:
7.73−7.63 (m, 4H), 7.48 (t-like, J = 7.4 Hz, 2H), 7.35 (t-like, J = 7.5
Hz, 2H), 2.78 (s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −79.4
(s, 3F), −122.2 (s, 2F) ppm. MS (ESI, m/z) 299 [M − H]−.
Analytical data are consistent with reported values.14
1
product 4d (46.5 mg, 90% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 7.41 (br s, 4H), 5.18−5.08 (m, 1H), 2.47 (d, J = 4.1
Hz, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −81.7 (s, 3F), −122.3
2
3
2
3
(dd, JF‑F, JF‑F = 275.9, 6.9 Hz, 1F), −129.8 (dd, JF‑F, JF‑F = 275.9,
15.5 Hz, 1F) ppm. MS (ESI, m/z) 261 [M + H]+. Analytical data are
consistent with reported values.14
1-(4-Bromophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (4e). Fol-
lowing the general procedure 2, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
2,2,3,3,3-Pentafluoro-1,1-di(pyridin-2-yl)propan-1-ol (2k). Fol-
lowing the general procedure 1, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
1
product 4e (54.4 mg, 90% yield) as a white solid. H NMR (300
1
MHz, CDCl3) δ: 7.56 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H),
5.15−5.06 (m, 1H), 2.53−2.49 (m, 1H) ppm. 19F NMR (282 MHz,
CDCl3) δ: −81.7 (s, 3F), −122.2 (dd, 2JF‑F, 3JF‑F = 275.9, 6.9 Hz, 1F),
product 2k (46.4 mg, 85% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 8.60−8.58 (m, 2H), 8.24 (d-like, J = 7.9 Hz, 2H),
7.79−7.73 (m, 2H), 7.58 (s, 1H), 7.31−7.26 (m, 2H) ppm. 19F NMR
(282 MHz, CDCl3) δ: −78.5 (s, 3F), −118.3 (s, 2F) ppm. MS (ESI,
m/z) 305 [M + Na]+. Analytical data are consistent with reported
values.14
2
3
−130.0 (dd, JF‑F, JF‑F = 275.9, 17.2 Hz, 1F) ppm. MS (ESI, m/z)
306 [M + H]+. Analytical data are consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-(4-iodophenyl)propan-1-ol (4f). Follow-
ing the general procedure 2, crude product was purified by silica gel
column chromatography with hexane/CH2Cl2 (1:1) to give the
2-(Pentafluoroethyl)-2-adamantanol (2l). Following the general
procedure 1, crude product was purified by silica gel column
chromatography with hexane/Et2O (4:1) to give the product 2l (41.4
1
product 4f (64.0 mg, 92% yield) as a white solid. H NMR (300
1
MHz, CDCl3) δ: 7.76 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H),
5.14−5.05 (m, 1H), 2.52−2.49 (m, 1H) ppm. 19F NMR (282 MHz,
CDCl3) δ: −81.7 (s, 3F), −122.2 (dd, 2JF‑F, 3JF‑F = 275.9, 6.9 Hz, 1F),
mg, 85% yield) as a colorless oil. H NMR (300 MHz, CDCl3) δ:
2.27−2.12 (m, 6H), 1.92−1.75 (m, 7H), 1.61 (d, J = 12.4 Hz, 2H)
ppm. 19F NMR (282 MHz, CDCl3) δ: −78.6 (s, 3F), −117.4 (s, 2F)
ppm. MS (ESI, m/z) 269 [M − H]−. Analytical data are consistent
with reported values.24
General Procedure 2: Flow Pentafluoroethylation of
Aldehydes Using HFC-125. A solution of aldehyde 3 (1.2 mmol,
1.0 equiv) in dry DMF (2.0 mL) was fed into a three-inlet mixer (0.33
mL/min) using a syringe pump; simultaneously t-BuOK (1.8 mmol,
1.5 equiv) in dry DMF (3.0 mL) was fed into the mixer (0.50 mL/
min) using another syringe pump. HFC-125 (3.10 equiv) was
introduced into the mixer at 0.1 MPa and 15 mL/min controlled by a
mass flow controller. The combined mixture was passed through
residence tubing (residence volume V = 0.81 mL) at −10 °C. After
the gas flow rate stabilized (about 2 min), we collected the product
2
3
−129.9 (dd, JF‑F, JF‑F = 275.9, 15.5 Hz, 1F) ppm. MS (ESI, m/z)
352 [M + H]+. Analytical data are consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-(4-fluorophenyl)propan-1-ol (4g). Fol-
lowing the general procedure 2, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
1
product 4g (42.1 mg, 87% yield) as a colorless oil. H NMR (300
MHz, CDCl3) δ: 7.46 (t-like, J = 6.5 Hz, 2H), 7.12 (t-like, J = 8.5 Hz,
2H), 5.18−5.09 (m, 1H), 2.45 (d, J = 4.4 Hz, 1H) ppm. 19F NMR
(282 MHz, CDCl3) δ: −81.6 (s, 3F), −111.9 (s, 1F), −122.5 (dd,
3
2
3
2JF‑F, JF‑F = 275.9, 6.9 Hz, 1F), −129.7 (dd, JF‑F, JF‑F = 275.9, 15.5
Hz, 1F) ppm. MS (ESI, m/z) 245 [M + H]+. Analytical data are
consistent with reported values.14
F
https://doi.org/10.1021/acs.joc.1c00728
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Article
2,2,3,3,3-Pentafluoro-1-(4-(trifluoromethoxy)phenyl)propan-1-ol
(4h). Following the general procedure 2, crude product was purified
by silica gel column chromatography with hexane/CH2Cl2 (1:1) to
give the product 4h (52.8 mg, 86% yield) as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ: 7.52 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.9 Hz,
2H), 5.21−5.12 (m, 1H), 2.60 (d, J = 4.4 Hz, 1H) ppm. 19F NMR
product stream was quenched with sat. NH4Cl aq. The aqueous layer
was extracted with Et2O, and the combined organic layers were
washed with brine, dried over Na2SO4, concentrated under reduced
pressure, and purified by column chromatography on silica gel to give
products 6.
(E)-4,4,5,5,5-Pentafluoro-1,3-diphenylpent-1-en-3-ol (6a). Fol-
lowing the general procedure 3, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:2) to give the
(282 MHz, CDCl3) δ: −58.3 (s, 3F), −81.6 (s, 3F), −122.2 (dd, 2JF‑F
,
2
3
3JF‑F = 275.9, 6.9 Hz, 1F), −129.9 (dd, JF‑F, JF‑F = 276.7, 16.4 Hz,
1F) ppm. MS (ESI, m/z) 311 [M + H]+. Analytical data are
consistent with reported values.14
1
product 6a (29.0 mg, 89% yield) as a white solid. H NMR (300
MHz, CDCl3) δ: 7.65 (d, J = 7.1 Hz, 2H), 7.44−7.29 (m, 8H), 6.86
(br s, 2H), 2.74 (s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −78.2
(s, 3F), −121.0 (d, 2JF‑F = 279.3 Hz, 1F), −122.0 (d, 2JF‑F = 277.6 Hz,
1F) ppm. MS (ESI, m/z) 327 [M − H]−. Analytical data are
consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-(naphthalen-2-yl)propan-1-ol (4i). Fol-
lowing the general procedure 2, crude product was purified by silica
gel column chromatography with hexane/CH2Cl2 (1:1) to give the
product 4i (49.8 mg, 91% yield) as a white solid. 1H NMR (300 MHz,
CDCl3) δ: 7.95−7.87 (m, 4H), 7.59−7.53 (m, 3H), 5.36−5.26 (m,
1H), 2.58 (d, J = 4.7 Hz, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ:
(E)-4,4,5,5,5-Pentafluoro-3-(4-methoxyphenyl)-1-phenylpent-1-
en-3-ol (6b). Following the general procedure 3, crude product was
purified by silica gel column chromatography with hexane/EtOAc
(9:1) to give the product 6b (31.1 mg, 88% yield) as a white solid. 1H
NMR (300 MHz, CDCl3) δ: 7.55 (d, J = 9.1 Hz, 2H), 7.44−7.29 (m,
5H), 6.93 (d, J = 9.1 Hz, 2H), 6.84 (br s, 2H), 3.82 (s, 3H), 2.69 (s,
1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −78.2 (s, 3F), −121.1 (d,
2JF‑F = 277.6 Hz, 1F), −122.1 (d, 2JF‑F = 277.6 Hz, 1F) ppm. MS (ESI,
2
3
−81.7 (s, 3F), −122.1 (dd, JF‑F, JF‑F = 275.9, 6.9 Hz, 1F), −129.6
(dd, 2JF‑F, 3JF‑F = 275.9, 15.5 Hz, 1F) ppm. MS (ESI, m/z) 277 [M +
H]+. Analytical data are consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-(naphthalen-1-yl)propan-1-ol (4j). Fol-
lowing the general procedure 2, crude product was purified by silica
gel column chromatography with hexane/acetone (7:1) to give the
product 4j (44.8 mg, 82% yield) as a pale yellow solid. 1H NMR (300
MHz, CDCl3) δ: 8.02 (d, J = 7.6 Hz, 1H), 7.94−7.91 (m, 2H), 7.82
(d, J = 7.4 Hz, 1H), 7.61−7.51 (m, 3H), 6.06−5.97 (m, 1H), 2.74 (br
s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −81.8 (s, 3F), −122.1
m/z) 357 [M − H]−. Analytical data are consistent with reported
values.14
(E)-3-(4-Chlorophenyl)-4,4,5,5,5-pentafluoro-1-phenylpent-1-en-
3-ol (6c). Following the general procedure 3, crude product was
purified by silica gel column chromatography with hexane/EtOAc
(9:1) to give the product 6c (31.3 mg, 87% yield) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ: 7.58 (d, J = 8.5 Hz, 2H), 7.43−7.28
2
3
2
3
(dd, JF‑F, JF‑F = 274.1, 6.9 Hz, 1F), −130.5 (dd, JF‑F, JF‑F = 274.1,
17.2 Hz, 1F) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ: 133.8,
131.4, 130.4, 130.2, 129.1, 127.0, 126.5, 126.1, 125.3, 122.8, 119.4 (qt,
1JC‑F, 2JC‑F = 285.5, 34.4 Hz), 116.0−111.0 (m) 67.7 (dd, 2JC‑FA, 2JC‑FB
= 29.1, 21.8 Hz) ppm. ATR-FTIR (KBr): ν = 3465, 3059, 1514, 1351,
1185, 1134, 1080, 1026, 790, 720 cm−1. HRMS (ESI) m/z: [M − H]−
calcd. for C13H8F5O; 275.0495 Found: 275.0497. Mp: 45.5−46.3 °C.
2,2,3,3,3-Pentafluoro-1-(furan-2-yl)ethan-1-ol (4k). Following
the general procedure 2, crude product was purified by silica gel
column chromatography with hexane/Et2O (4:1) to give the product
4k (27.8 mg, 65% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3)
δ: 7.49 (s, 1H), 6.54 (s, 1H), 6.44 (s, 1H), 5.20−5.10 (m, 1H), 2.59
(d, J = 7.9 Hz, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −82.4 (s,
(m, 7H), 6.82 (br s, 2H), 2.84−2.81 (m, 1H) ppm. 19F NMR (282
MHz, CDCl3) δ: −78.1 (s, 3F), −121.6 (s, 2F) ppm. MS (ESI, m/z)
361 [M − H]−. Analytical data are consistent with reported values.14
(E)-3-(4-Bromophenyl)-4,4,5,5,5-pentafluoro-1-phenylpent-1-en-
3-ol (6d). Following the general procedure 3, crude product was
purified by silica gel column chromatography with hexane/EtOAc
(9:1) to give the product 6d (35.1 mg, 87% yield) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ: 7.56−7.49 (m, 4H), 7.44−7.29 (m,
5H), 6.81 (br s, 2H), 2.66 (s, 1H) ppm. 19F NMR (282 MHz,
CDCl3) δ: −78.1 (s, 3F), −121.6 (s, 2F) ppm. MS (ESI, m/z) 406
[M − H]−. Analytical data are consistent with reported values.14
(E)-4,4,5,5,5-Pentafluoro-1,3-bis(4-fluorophenyl)pent-1-en-3-ol
(6e). Following the general procedure 3, crude product was purified
by silica gel column chromatography with hexane/EtOAc (9:1) to
2
3
2
3F), −123.2 (dd, JF‑F, JF‑F = 274.1, 6.9 Hz, 1F), −129.3 (dd, JF‑F
,
3JF‑F = 275.0, 16.4 Hz, 1F) ppm. 13C{1H} NMR (126 MHz, CDCl3)
δ: 146.8, 144.0, 118.94 (qt, 1JC‑F, 2JC‑F = 286.6, 35.2 Hz), 115.1−110.1
(m), 111.0, 110.8, 66.5 (q, 2JC‑F = 17.3 Hz,) ppm. ATR-FTIR (KBr):
ν = 3407, 2927, 1507, 1363, 1192, 1138, 1015, 929, 809, 744 cm−1.
HRMS (ESI) m/z: [M + H]+ calcd. for C7H6F5O2; 217.0288 Found:
217.0278.
1
give the product 6e (25.2 mg, 70% yield) as a yellow oil. H NMR
(300 MHz, CDCl3) δ: 7.61 (dd, J = 8.8, 5.3 Hz, 2H), 7.41−7.36 (m,
2H), 7.12−7.01 (m, 4H), 6.80 (d, J = 15.9 Hz, 1H), 6.73 (d, J = 16.2
Hz, 1H), 2.71 (s, 1H) ppm. 19F NMR (282 MHz, CDCl3) δ: −78.2
(s, 3F), −113.1 to −113.0 (m, 1F), −113.6 to −113.5 (m, 1F),
−121.7 (s, 2F) ppm. MS (ESI, m/z) 363 [M − H]−. Analytical data
are consistent with reported values.14
2,2,3,3,3-Pentafluoro-1-(thiophene-2-yl)ethan-1-ol (4l). Follow-
ing the general procedure 2, crude product was purified by silica gel
column chromatography with hexane/Et2O (4:1) to give the product
4l (31.7 mg, 69% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3)
δ: 7.43 (d, J = 4.4 Hz, 1H), 7.21 (br s, 1H), 7.08−7.05 (m, 1H), 5.39
(dd, J = 16.5, 5.9 Hz, 1H), 2.69 (s, 1H) ppm. 19F NMR (282 MHz,
CDCl3) δ: −81.8 (s, 3F), −122.1 (dd, 2JF‑F, 3JF‑F = 274.1, 6.9 Hz, 1F),
(E)-4,4,5,5,5-Pentafluoro-3-(4-nitrophenyl)-1-phenylpent-1-en-3-
ol (6f). Following the general procedure 3, crude product was purified
by silica gel column chromatography with hexane/EtOAc (9:1) to
1
2
3
−130.5 (dd, JF‑F, JF‑F = 274.1, 17.2 Hz, 1F) ppm. 13C{1H} NMR
give the product 6f (26.6 mg, 72% yield) as a yellow solid. H NMR
(126 MHz, CDCl3) δ: 136.0, 128.2, 127.7, 127.1, 119.1 (qt, 1JC‑F, 2JC‑F
(300 MHz, CDCl3) δ: 8.26 (d, J = 9.1 Hz, 2H), 7.84 (d, J = 8.8 Hz,
= 287.0, 35.4 Hz), 115.1−110.1 (m), 68.5 (q, JC‑F = 17.6 Hz) ppm;
2H), 7.43−7.30 (m, 5H), 6.89−6.78 (m, 2H), 2.89 (s, 1H) ppm. 19F
2
2
ATR-FTIR (neat): ν = 3426, 2923, 1432, 1355, 1208, 1131, 1023,
809, 708 cm−1. HRMS (ESI) m/z: [M − H]− calcd. for C7H4F5OS;
230.9903 Found: 230.9911.
NMR (282 MHz, CDCl3) δ: −78.1 (s, 3F), −120.9 (d, JF‑F = 279.3
2
Hz, 1F), −122.1 (d, JF‑F = 279.3 Hz, 1F) ppm. MS (ESI, m/z) 372
[M − H]−. Analytical data are consistent with reported values.14
Flow Pentafluoroethylation of Bioactive Substrates. iso-
Propyl 2-(4-(1-(4-Chlorophenyl)-2,2,3,3,3-pentafluoro-1-
hydroxypropyl)phenoxy)-2-methylpropanoate (8a). Following the
general procedure 1, crude product was purified by silica gel column
chromatography with hexane/EtOAc (4:1) to give the product 8a
(55.4 mg, 69% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ:
7.45 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.30−7.27 (m,
2H), 6.78−6.75 (m, 2H), 5.06−4.98 (m, 1H), 3.17 (s, 1H), 1.57 (s,
6H), 1.17 (d, J = 2.1 Hz, 3H), 1.16 (d, J = 1.8 Hz, 3H) ppm. 13C{1H}
NMR (126 MHz, CDCl3) δ: 173.6, 155.9, 138.4, 134.5, 132.8, 128.8,
128.4, 128.2, 122.9−117.6 (m), 118.3, 117.8−112.8 (m), 79.3, 78.4
General Procedure 3: Flow Pentafluoroethylation of
Chalcones Using HFC-125. A solution of chalcone 5 (0.6 mmol,
1.0 equiv) in dry toluene (2.0 mL) or dry THF (2.0 mL) was fed into
a three-inlet mixer (0.33 mL/min) using a syringe pump;
simultaneously KHMDS (1.2 mmol, 1.5 equiv) in dry toluene (4.0
mL) or dry THF (4.0 mL) was fed into the mixer (0.50 mL/min)
using another syringe pump. HFC-125 (3.10 equiv) was introduced
into the mixer with 0.1 MPa, 7.5 mL/min controlled by a mass flow
controller. The combined mixture was passed through residence
tubing (residence volume V = 0.32 mL) at rt. After the gas flow rate
stabilized (about 2 min), we collected the product for 1 min. The
G
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Article
(t, J = 23.6 Hz), 69.3, 25.5, 25.4, 21.6. 19F NMR (282 MHz, CDCl3)
δ: −77.6 (s, 3F), −116.62 (d, 2JF‑F, 3JH‑F = 277.6 Hz, 1F), −117.8 (d,
syringe pump; simultaneously KHMDS (1.8 mmol, 1.7 equiv) in dry
toluene (6.0 mL) was fed into the mixer (1.1 mL/min) using another
syringe pump. HFC-125 (22.5 equiv) was introduced into the mixer
at 0.1 MPa and 50 mL/min, controlled by a mass flow controller. The
combined mixture was passed through residence tubing (residence
volume V = 0.81 mL) at −30 °C. After the gas flow rate stabilized
(about 2 min), we collected the product for 1 min. The product
stream was quenched with sat. NH4Cl aq. The aqueous layer was
extracted with Et2O, and the combined organic layers were washed
with brine, dried over Na2SO4, concentrated under reduced pressure,
and purified by column chromatography on silica gel with hexane/
EtOAc (9:1) to give products 8f (19.9 mg, 51% yield) as a colorless
oil. 1H NMR (500 MHz, CDCl3) δ: 7.90 (d, J = 2.4 Hz, 1H), 7.34 (d,
J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 2.4 Hz, 1H), 3.49 (s, 1H), 1.38−
3
2JF‑F, JH‑F = 277.6 Hz, 1F) ppm. ATR-FTIR (neat): ν = 3429, 2992,
1731, 1605, 1509, 1386, 1294, 1166, 1102, 1061, 1015, 909, 874, 828
cm−1. HRMS (ESI) m/z: [M + Na]+ calcd. for C22H22O4F5Na;
503.1024 Found: 503.1030. Mp: 94.5−94.7 °C.
1-(4-(Benzyloxy)-3-methoxyphenyl)-2,2,3,3,3-pentafluoropro-
pan-1-ol (8b). Following the general procedure 2, crude product was
purified by silica gel column chromatography with hexane/EtOAc
(4:1) to give the product 8b (46.6 mg, 65% yield) as a white solid. 1H
NMR (500 MHz, CDCl3) δ: 7.43 (d, J = 7.3 Hz, 2H), 7.39−7.36 (m,
2H), 7.34−7.30 (m, 1H), 6.97 (s, 1H), 6.85−6.60 (m, 2H), 5.13 (s,
2H), 5.01−4.96 (m, 1H), 3.84 (s, 3H), 2.87 (d, J = 4.6 Hz, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3) δ: 149.6, 149.2, 136.8, 128.7,
1.33 (m, 1H), 0.90−0.76 (m, 4H) ppm. 13C{1H} NMR (126 MHz,
1
2
128.1, 127.4, 127.1, 120.8, 119.2 (qt, JC‑F, JC‑F = 286.9, 35.8 Hz),
1
2
CDCl3) δ: 134.3, 133.0, 132.9, 131.6, 130.9, 130.6, 119.1 (qt, JC‑F
,
115.5−110.7 (m), 113.5, 111.3, 71.8 (q, JC‑F = 17.0 Hz), 71.0, 56.1.
2JC‑F = 286.4, 35.5 Hz), 112.9 (tq, 1JC‑F, 2JC‑F = 264.8, 33.3 Hz), 95.3,
2
19F NMR (282 MHz, CDCl3) δ: −81.9 (s, 3F), −122.5 (d, JF‑F
=
72.3 (t, JC‑F = 27.2 Hz), 69.3 (d, JC‑F = 5.4 Hz), 8.4, 8.3, −0.4. 19F
2
3
2
3
267.2 Hz, 1F), −130.1 (dd, JF‑F, JH‑F = 275.0, 16.4 Hz, 1F) ppm.
ATR-FTIR (neat): ν = 3673, 3425, 2967, 1721, 1466, 1387, 1235,
1130, 1040, 923, 860, 717, 650 cm−1. HRMS (ESI) m/z: [M + Na]+
calcd. for C17H15O3F5Na; 385.0839 Found: 385.0835. Mp: 85.3−85.9
°C.
2
NMR (282 MHz, CDCl3) δ: −78.3 (s, 3F), −116.9 (d, JF‑F = 270.7
Hz, 1F), −120.9 (d, 2JF‑F = 270.7 Hz, 1F) ppm. ATR-FTIR (neat): ν
= 3738, 3651, 3453, 3109, 3016, 2246, 1457, 1390, 1336, 1221, 1109,
1049, 873, 818, 630, 514 cm−1. HRMS (ESI) m/z: [M − H]− calcd.
for C14H8OF5Cl2; 356.9872 Found: 356.9873.
1-(Benzo[d][1,3]dioxol-5-yl)-2,2,3,3,3-pentafluoropropan-1-ol
(8c). Following the general procedure 2, crude product was purified
by silica gel column chromatography with hexane/EtOAc (4:1) to
ASSOCIATED CONTENT
1
■
give the product 8c (50.3 mg, 94% yield) as a white solid. H NMR
sı
(500 MHz, CDCl3) δ: 6.95 (s, 1H), 6.89 (dd, J = 7.9, 1.2 Hz, 1H),
6.82 (d, J = 7.9 Hz, 1H), 5.99 (s, 2H), 5.01 (dd, J = 16.2, 7.3 Hz, 1H),
2.67 (s, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ: 148.8, 148.1,
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00728.
1
2
127.7, 122.1, 119.2 (qt, JC‑F, JC‑F = 285.8, 36.8 Hz), 115.6−110.6
2
(m), 108.4, 108.2, 101.6, 71.9 (q, JC‑F = 16.7 Hz). 19F NMR (282
Detailed optimization of reaction conditions, photos of
flow reaction tubes, general procedures, and copies of
1H, 19F, and 13C{1H} NMR spectra of compounds 2, 4,
6, and 8 (PDF)
2
3
MHz, CDCl3) δ: −81.8 (s, 3F), −122.7 (dd, JF‑F, JH‑F = 275.0, 7.8
2
3
Hz, 1F), −130.0 (dd, JF‑F, JH‑F = 275.0, 16.4 Hz, 1F) ppm. ATR-
FTIR (neat): ν = 3372, 2911, 1855, 1507, 1450, 1308, 1258, 1105,
927, 867, 736, 683, 525 cm−1. HRMS (ESI) m/z: [M − H]− calcd. for
C10H6O3F5Na; 269.0237 Found: 269.0238. Mp: 46.7−47.0 °C.
(E)-1-(4-(Benzyloxy)-3-methoxyphenyl)-4,4,5,5,5-pentafluoro-3-
phenylpent-1-en-3-ol (8d). Following the general procedure 3, crude
product was purified by silica gel column chromatography with
toluene to give the product 8d (21.2 mg, 46% yield) as a yellow solid.
1H NMR (500 MHz, CDCl3) δ: 7.63 (d, J = 7.0 Hz, 2H), 7.43−7.35
AUTHOR INFORMATION
■
Corresponding Author
Norio Shibata − Department of Life Science and Applied
Chemistry and Department of Nanopharmaceutical Sciences,
Nagoya Institute of Technology, Nagoya 466-8555, Japan;
Institute of Advanced Fluorine-Containing Materials,
Zhejiang Normal University, 321004 Jinhua, China;
orcid.org/0000-0002-3742-4064; Email: nozshiba@
nitech.ac.jp
(m, 8H), 7.31−7.29 (m, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.90 (dd, J =
8.2, 1.8 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 15.9 Hz, 1H),
6.68 (d, J = 16.2 Hz, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 2.67 (s, 1H)
ppm. 13C{1H} NMR (126 MHz, CDCl3) δ: 149.9, 148.8, 137.7, 137.0
132.9, 129.2, 128.8, 128.7, 128.4, 128.1, 127.3, 126.8, 125.0, 120.2,
120.8−116.2 (m), 116.2−111.8 (m), 114.0, 110.1, 71.1, 56.2 (one
carbon (-C(OH)-CF2CF3) was not observed). 19F NMR (282 MHz,
CDCl3) δ: −78.2 (s, 3F), −121.4 (s, 2F) ppm. ATR-FTIR (neat): ν =
3860, 3730, 3707, 3666, 3644, 3396, 1601, 1514, 1452, 1134, 701,
516 cm−1. HRMS (ESI) m/z: [M − H]− calcd. for C25H20O3F5;
463.1333 Found: 463.1340. Mp: 69.0−69.6 °C.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-4,4,5,5,5-pentafluoro-3-phenyl-
pent-1-en-3-ol (8e). Following the general procedure 3, crude
product was purified by silica gel column chromatography with
toluene to give the product 8e (50.0 mg, 68% yield) as a yellow oil.
1H NMR (500 MHz, CDCl3) δ: 7.63 (d, J = 7.0 Hz, 2H), 7.43−7.36
Authors
Makoto Ono − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
8555, Japan
Yuji Sumii − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
8555, Japan; orcid.org/0000-0003-3900-1089
Yamato Fujihira − Department of Life Science and Applied
Chemistry, Nagoya Institute of Technology, Nagoya 466-
8555, Japan
Takumi Kagawa − Tosoh Finechem Corporation, Shunan
746-0006, Japan
Hideyuki Mimura − Tosoh Finechem Corporation, Shunan
746-0006, Japan
(m, 3H), 6.96 (d, J = 1.5 Hz, 1H), 6.84 (dd, J = 7.9, 1.5 Hz, 1H),
6.77−6.66 (m, 3H), 5.96 (s, 2H), 2.72 (s, 1H) ppm. 13C{1H} NMR
(126 MHz, CDCl3) δ: 148.3, 148.2, 137.7, 132.6, 130.1, 128.8, 128.4,
126.8, 125.0, 122.2, 119.3 (qt, 1JC‑F, 2JC‑F = 239.6, 36.0 Hz), 114.1 (tq,
1JC‑F 2JC‑F = 244.4, 34.9 Hz), 108.5, 106.1, 101.4 (one carbon
,
(−C(OH)-CF2CF3) was not observed). 19F NMR (282 MHz,
CDCl3) δ: −78.2 (s, 3F), −121.5 (s, 2F) ppm. ATR-FTIR (neat):
ν = 3459, 3072, 2915, 1604, 1451, 1220, 1072, 980, 859, 766, 703,
632, 540 cm−1. HRMS (ESI) m/z: [M − H]− calcd. for C18H12O3F5;
371.0707 Found: 371.0713.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00728
1-Cyclopropyl-3-(2,5-dichlorophenyl)-4,4,5,5,5-pentafluoropent-
1-yn-3-ol (8f). A solution of 7f (0.66 mmol, 1.0 equiv) in dry toluene
(2.0 mL) was fed into a three-inlet mixer (0.33 mL/min) using a
Notes
The authors declare no competing financial interest.
H
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J. Org. Chem. XXXX, XXX, XXX−XXX

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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI grant JP18H-
02553, 21H01933 (KIBAN B).
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