Gas/Liquid-Phase Micro-Flow Trifluoromethylation using Fluoroform: Trifluoromethylation of Aldehydes, Ketones, Chalcones, and N-Sulfinylimines

Article abstract of DOI:10.1002/open.201800286

A micro-flow nucleophilic trifluoromethylation of carbonyl compounds using gaseous fluoroform was developed. This method also allows the first micro-flow transformation of N-sulfinylimines into trifluoromethyl amines with excellent diastereoselectivity. To demonstrate the synthetic utility of this micro-flow synthesis, the formal micro-flow synthesis of Efavirenz is described.

Full text of DOI:10.1002/open.201800286

Communications
DOI: 10.1002/open.201800286
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Gas/Liquid-Phase Micro-Flow Trifluoromethylation using
Fluoroform: Trifluoromethylation of Aldehydes, Ketones,
Chalcones, and N-Sulfinylimines
Kazuki Hirano,[a] Satoshi Gondo,[a] Nagender Punna,[a] Etsuko Tokunaga,[a] and
Norio Shibata*[a, b]
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these, the majority of nucleophilic trifluoromethylation reac-
tions is performed using the RuppertÀ Prakash reagent
(CF3SiMe3), i.e., a nucleophilic trifluoromethylation agent, which
is not atom economical.[3] Towards more practical and industri-
ally more efficient nucleophilic trifluoromethylation transforma-
tions, two improvements should be considered: i) novel
practical methods and ii) atom-economical alternatives for the
RuppertÀ Prakash reagent that exhibit similar reactivity.
A micro-flow nucleophilic trifluoromethylation of carbonyl
compounds using gaseous fluoroform was developed. This
method also allows the first micro-flow transformation of N-
sulfinylimines into trifluoromethyl amines with excellent diaster-
eoselectivity. To demonstrate the synthetic utility of this micro-
flow synthesis, the formal micro-flow synthesis of Efavirenz is
described.
Although traditional organic synthesis is generally per-
formed in round-bottomed flasks (batch system), new micro-
flow technologies for the synthesis of organic compounds have
recently emerged.[4] Flow synthesis based on special flow
devices is considered more beneficial than batch reactions, as
the former are faster and safer than the latter, reduce the
energy consumption, and are easily scaled up (mg to kg).[5]
However, performing batch reactions in micro-flow mode is not
always easy and, depending on the reaction and substrates,
many factors may have to be precisely optimized.[4,5,6] Given the
rapid progress of a variety of flow reactions and flow reactors,
the development of micro-flow trifluoromethylation processes
has also attracted much attention. In 2016, our group
demonstrated the first flow and micro-flow nucleophilic trifluor-
omethylation of carbonyl species using the RupertÀ Prakash
reagent.[7] While our (micro-)flow method efficiently produces
trifluoromethylated carbinols, including the anti-HIV drug
Efavirenz and the 11β-hydroxysteroid dehydrogenase type 1
inhibitor HSD016, in good to high yield, the fundamental green
chemistry aspect of using trifluoromethylation reagents that are
more atom-economical than the RuppertÀ Prakash reagent
remains unresolved.
Fluoroform (CF3H) is a highly atom-economical gaseous
source of CF3 groups for the introduction in organic molecules
that is readily available, given that fluoroform is a chemical
waste product that accumulates during the manufacturing of
Teflon®. Another critical aspect of fluoroform is the existing
restrictions regarding its emission into the environment follow-
ing the Kyoto protocol due to its very large global warming
potential (GWP), which is 11,700-fold that of carbon dioxide,
and an atmospheric lifetime of 264 years.[8] Thus, the develop-
ment of efficient trifluoromethylation methods that use fluoro-
form instead of the RupertÀ Prakash reagent would have a great
impact both from a synthetic and environmental perspec-
tive.[9,10] Although the use of fluoroform for trifluoromethyla-
tions via the deprotonation with strong bases has been
reported more than a quarter of a century ago by Shono and
co-workers,[9a] taming fluoroform for trifluoromethylations has
Fluorine plays a unique role in pharmaceuticals and agro-
chemicals, as its introduction at key positions of biologically
attractive organic molecules alters their original properties,
sometimes enhancing their therapeutic efficacy.[1] Especially the
trifluoromethyl (CF3) group has garnered much attention due to
its versatile biological activity (Figure 1).[2]
Figure 1. Representative biologically active molecules containing a trifluor-
omethyl group.
The preparation of CF3-containing drugs usually requires
expensive trifluoromethylation reagents regardless of the type
of transformation (electrophilic, nucleophilic, or radical). Among
[a] K. Hirano, S. Gondo, N. Punna, E. Tokunaga, Prof. Dr. N. Shibata
Department of Life Science and Applied Chemistry, Department of Nano-
pharmaceutical Sciences
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555, Japan
E-mail: nozshiba@nitech.ac.jp
[b] Prof. Dr. N. Shibata
Institute of Advanced Fluorine-Containing Materials
Zhejiang Normal University
688 Yingbin Avenue, 321004 Jinhua, China
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201800286
©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution Non-Commercial NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
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remained challenging. In 2011, Grushin and co-workers made a
breakthrough on this matter by the direct cupration of fluoro-
Table 1. Optimization of the micro-flow reaction using fluoroform and
benzophenone
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form with a dialkoxycuprate, which was generated from CuCl
[10a]
and tBuOK, that afforded CuCF3
and thus significantly
wide variety of
facilitated the use of fluoroform for
a
trifluoromethylations.[10] In 2012, Prakash et al. reported nucleo-
philic trifluoromethylations with fluoroform via a deprotonation
using potassium bases.[9e] Since then, numerous protocols have
been reported that use fluoroform as a trifluoromethylation
reagent.[9,10] Thus, we turned our attention on applying fluoro-
form as a trifluoromethylation reagent in a micro-flow system.[4e]
Micro-flow methods should present several advantages in the
gas/liquid phase due to the small volume of the micro reactors,
which facilitates the mixing of the gaseous with the liquid
phase.[11] In 2018, the groups of Kappe and Ley successfully
used fluoroform in micro-flow systems for trifluoromethylation
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Entry Conc. Solvent
[M]
Fluoroform
Flow rate
Yield[a]
[%]
Pressure X [equiv]
[MPa]
[mLminÀ 1
]
1
2
3
4
5
6
7
8
9
0.14
0.14
0.14
0.14
0.14
0.3
0.6
0.8
0.6
DMF/THF 25
DMF/THF 25
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
8.0
8.0
8.0
8.0
8.0
3.6
1.7
1.5
1.1
93
94
99
47
15
99
99
82
68
DMF
THF
25
25
25
25
25
25
15
[11c]
and difluoromethylation[11d] reactions; however, the sub-
Toluene
DMF
DMF
DMF
DMF
strate scope of these methods was severely limited. Herein, we
disclose a micro-flow trifluoromethylation process using fluoro-
form that rapidly transforms a wide variety of carbonyl
substrates, including diaryl ketones, aryl alkyl ketones, and
aldehydes into the corresponding trifluoromethylated alcohols
in good yield. Moreover, these micro-flow conditions also allow
the regioselective 1,2-addition of chalcones. Furthermore, this
method can be used for the highly stereoselective trifluorome-
thylation of non-racemic chiral N-sulfinylimines. The synthetic
utility of this new method was demonstrated by the formal
synthesis of the anti-HIV drug Efavirenz.
We started our experiments with benzophenone (1a) as the
model substrate and tBuOK as the base in a mixture of DMF/
THF at room temperature. Initially, 1a (1 equiv) and tBuOK
(2 equiv) were dissolved in a DMF/THF, then the mixture was
pumped through a mixer where it as mixed with the other
stream. Via a different channel, fluoroform (8 equiv) was passed
through the mixer (micro-flow rate: 25 mLminÀ 1; pressure:
0.2 MPa), which afforded the corresponding trifluoromethylated
product (2a) in excellent yield (93%; Table 1, Entry 1). Reducing
the pressure to 0.1 MPa did not affect the product yield
(Table 1, Entry 2).
To evaluate the solvent effect, the same reaction was carried
out in DMF, THF, and toluene. This screening revealed that DMF
is superior to the other solvents, as it furnished the targeted
product in quantitative yield. Subsequently, we increased the
concentration of 1a up to 0.8 M (Table 1, Entries 6–8), and
discovered that a concentration of 0.6 M affords the corre-
sponding product in quantitative yield (99%, Table 1, Entry 7).
We also performed the micro-flow reaction at a reduced micro-
flow rate (15 mLminÀ 1), which furnished the desired product in
moderate yield (Table 1, Entry 9). In all the cases, we detected
the gas phase exists as large bubbles in the tube. Thus, the
reaction would proceed as slug flow.
With the optimized reaction conditions in hand (Table 1,
Entry 7), we screened the substrate scope for the trifluorome-
thylation of ketones using this micro-flow reaction system.
Ketones 1a–l with different electronic properties were smoothly
transformed into the desired trifluoromethylated products (2a–
l) in good yield (Scheme 1). Substrates bearing an electron-
[a] Yields were calculated based on the 19F NMR spectra of the crude
reaction mixture using PhCF3 as the internal standard.
Scheme 1. Substrate scope with respect to ketones.
donating methoxy group were tolerated very well under the
applied conditions, and the corresponding products were
obtained in good yield (2b: 74%; 2h: 74%), whereas a substrate
with an electron-withdrawing CF3 group (1f) afforded the
desired product in excellent yield (2f: 92%). Furthermore,
halogen-substituted 1c (4-F), 1d (4-Cl), 1e (4-Br), and 1g (2-Cl)
were also smoothly converted into the desired products in
good to very good yield (2c: 70%; 2d: 81%; 2e: 84%; 2g:
74%). However, phenyl-tert-butyl-ketone 1k afforded the corre-
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sponding product in low yield (2k: 35%), while adamantyl
ketone 1l furnished 2l in moderate yield (59%).
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2
Encouraged by these results, we turned our attention to the
trifluoromethylation of aldehydes using the micro-flow reaction
system. In this protocol, the base and substrate were separately
deposited in the mixer in order to avoid the formation of the
corresponding Cannizzaro product (for the details of the
optimization, cf. Table S1). Substrates bearing electron-donat-
ing, electron-withdrawing, or halogen substituents on the
phenyl ring underwent the micro-flow reaction smoothly to
provide the corresponding trifluoromethylated carbinols in
good yield of up to 87% (Scheme 2). Moreover, heterocyclic
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Scheme 3. Micro-flow trifluoromethylation of chalcones using fluoroform.
variety of N-sulfinylimines (7a–k), and all the substrates (with
either electron-donating or -withdrawing substituents) under-
went the reaction to afford the corresponding trifluoromethy-
lated products in poor to moderate yield (up to 53%) with high
diastereoselectivity (up to 35:1). N-sulfinylimines bearing chloro
(7b) and bromo (7c) substituents furnished the products in fair
yield (8b: 48%; 8c: 43%) with good selectivity (8b: 21:1; 8c:
16:1). The configuration of the desired products (Ss,S) was
confirmed based on our previous report (Scheme 4).[9l]
Scheme 2. Substrate scope of with respect to aldehydes. [a] Yields were
calculated based on the 19F NMR spectra of the crude reaction mixture using
PhCF3 as the internal standard.
aldehyde furfural (3g) and extended π-conjugated aldehydes
(naphthalene-3i and anthracene-3d) also tolerated the micro-
flow reaction to afford the desired products in moderate to
good yield (4g: 56%; 4d: 77%; 4i: 74%).
The regioselective 1,2-addition of fluoroform to chalcone 5a
also smoothly afforded the desired product (6a) in 61% yield
under different optimized conditions using KHMDS in toluene
(for the optimization details, cf. Table S2). Substrates bearing
chloro (5b) and fluoro (5c) substituents afforded the corre-
sponding products in moderate to good yield (6b: 67%; 6c:
66%) (Scheme 3).
Subsequently, we turned our attention to the trifluorome-
thylation of N-sulfinylimines via this micro-flow reaction system.
Based on our recent report,[9l] we chose potassium bis
(trimethylsilyl)amide (KHMDS) as the base and toluene as the
solvent at room temperature; however, the reaction did not
proceed. The reaction conditions were thus optimized by
Scheme 4. Substrate scope with respect to imines. The dr values were
calculated based on the crude 19F NMR spectra.
Finally, we evaluated the potential application of this
protocol for the micro-flow synthesis of Efavirenz. After a brief
optimization of the reaction conditions including the base
°
changing the temperature (À 10 C), substrate concentration
(0.3 M), and base equivalents (3.3 equiv), which afforded the
desired product in moderate yield (53%) and high diastereose-
lectivity (20:1) (for the optimization details, cf. Table S3). With
the optimized reaction conditions in hand, we examined a
(1.7 equiv of KHMDS), solvent (toluene), micro-flow rate
À 1
°
(50 mLmin ), and temperature (À 30 C) (cf. Table S4), aryl
alkenyl ketone 9 was rapidly converted into the corresponding
trifluoromethylated carbinol 10 in moderate yield (52%). As 10
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stream was quenched with sat. NH4Cl aq. The aqueous layer was
extracted with Et2O, and the combined organic layers was washed
with brine, dried over Na2SO4 and concentrated under reduced
pressure, and purified by column chromatography on silica gel to
give the products 4. Residence time is 1.3 s (see SI).
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General Procedure for the Trifluoromethylation to Chalcones
in Flow (Procedure C)
A solution of the Chalcone 5 (0.6 mmol) in dry toluene (2.0 mL) was
fed into three inlets mixer (SUS316, ID=0.5 mm, 60 μL internal
volume, 0.33 mLminÀ 1) using syringe pump (YMC), simultaneously
KHMDS (2.0 mmol) in dry toluene (6.6 mL) was fed into the mixer
(1.1 mLminÀ 1) using another syringe pump (YMC). Fluoroform was
introduced into the mixer with 0.1 MPa, 25 mLminÀ 1 controlled by
mass flow controller (MFC) using Flow Factory (EYELA). The
combined mixture went through a residence tubing (SUS316, ID=
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Scheme 5. Trifluoromethylation of 9 to afford Efavirenz intermediate 10.
has already been converted into Efavirenz via a micro-flow
reaction by Seeberger et al.,[12] the transformation of 9 into 10
outlined here completes the formal micro-flow synthesis of
Efavirenz (Scheme 5).
In summary, we have successfully developed a gas/liquid-
phase micro-flow trifluoromethylation method for ketones,
aldehydes, chalcones, and imines using the gaseous chemical
waste fluoroform. We have also demonstrated the utility of this
protocol for the formal total micro-flow synthesis of the anti-
HIV drug Efavirenz. Further applications of this protocol in
asymmetric micro-flow trifluoromethylation reactions are cur-
rently under investigation.
°
0.8 mm, residence volume, V=0.23 mL) at À 10 C. After gas flow
rate was stabilized, we collected the product for 1 minute. The
product stream was quenched with sat. NH4Cl aq. The aqueous
layer was extracted with Et2O, and the combined organic layers was
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure, and purified by column chromatography on silica
gel to give the products 6. Residence time is 0.5 s (see SI).
General Procedure for the Trifluoromethylation to
N-Sulfinylimines in Flow (Procedure D)
A solution of the N-sulfinylimine 7 (0.6 mmol) in dry toluene
(2.0 mL) was fed into three inlets mixer (SUS316, ID=0.5 mm, 60 μL
internal volume, 0.33 mLminÀ 1) using syringe pump (YMC), simulta-
neously KHMDS (2.0 mmol) in dry toluene (6.6 mL) was fed into the
mixer (1.1 mLminÀ 1) using another syringe pump (YMC). Fluoroform
was introduced into the mixer with 0.1 MPa, 25 mLminÀ 1 controlled
by mass flow controller (MFC) using Flow Factory (EYELA). The
combined mixture went through a residence tubing (SUS316, ID=
Experimental Section
General Procedure for the Trifluoromethylation to Ketones in
Flow (Procedure A)
°
0.8 mm, residence volume, V=0.23 mL) at À 10 C. After gas flow
A solution of the ketone 1 (1.2 mmol) and tBuOK (2.4 mmol) in dry
DMF (2.0 mL) was fed into two inlets mixer (SUS316, ID=0.5 mm,
60 μL internal volume, 1.0 mLminÀ 1) using syringe pump (YMC).
Fluoroform was introduced into the two inlets mixer with 0.1 MPa,
25 mLminÀ 1 controlled by mass flow controller (MFC) using Flow
Factory (EYELA). The combined mixture went through a residence
tubing (SUS316, ID=0.8 mm, residence volume V=0.23 mL) at rt.
After gas flow rate was stabilized, we collected the product for 1
minute. The product stream was quenched with sat. NH4Cl aq. The
aqueous layer was extracted with Et2O, and the combined organic
layers was washed with brine, dried over Na2SO4 and concentrated
under reduced pressure, and purified by column chromatography
on silica gel to give the products 2. Residence time is 0.5 s (see
Supporting Information (SI)).
rate was stabilized, we collected the product for 1 minute. The
product stream was quenched with sat. NH4Cl aq. The aqueous
layer was extracted with Et2O, and the combined organic layers was
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure, and purified by column chromatography on silica
gel to give the products 8. Residence time is 0.5 s (see SI).
Procedure for the Trifluoromethylation to
1-(2,5-Dichlorophenyl)-3- cyclopropylprop-2-yn-1-one (9)
(Procedure E)
A solution of the 1-(2,5-Dichlorophenyl)-3-cyclopropylprop-2-yn-1-
one 9 (0.6 mmol) in dry toluene (2.0 mL) was fed into three inlets
mixer (SUS316, ID=0.5 mm, 60 μL internal volume, 0.33 mLminÀ 1
)
using syringe pump (YMC), simultaneously KHMDS (1.0 mmol) in
dry toluene (6.6 mL) was fed into the mixer (1.1 mLminÀ 1) using
another syringe pump (YMC). Fluoroform was introduced into the
mixer with 0.1 MPa, 50 mLminÀ 1 controlled by mass flow controller
(MFC) using Flow Factory (EYELA). The combined mixture went
General Procedure for the Trifluoromethylation to Aldehydes
in Flow (Procedure B)
A solution of the aldehyde 3 (0.6 mmol) in dry DMF (1.0 mL) was
fed into three inlets mixer (SUS316, ID=0.5 mm, 60 μL internal
volume, 0.33 mLminÀ 1) using syringe pump (YMC), simultaneously
tBuOK (1.2 mmol) in dry DMF (2.0 mL) was fed into the mixer
(0.66 mLminÀ 1) using another syringe pump (YMC). Fluoroform was
introduced into the mixer with 0.1 MPa, 10 mLminÀ 1 controlled by
mass flow controller (MFC) using Flow Factory (EYELA). The
combined mixture went through a residence tubing (SUS316, ID=
0.8 mm, residence volume, V=0.23 mL) at rt. After gas flow rate
was stabilized, we collected the product for 1 minute. The product
through
a
residence tubing (SUS316, ID=0.8 mm, residence
°
volume, V=4.0 mL) at À 30 C. After gas flow rate was stabilized, we
collected the product for 4 minutes. The product stream was
quenched with sat. NH4Cl aq. The aqueous layer was extracted with
Et2O, and the combined organic layers was washed with brine,
dried over Na2SO4 and concentrated under reduced pressure, and
purified by column chromatography on silica gel to give 2-(2,5-
dichlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol 10. Resi-
dence time is 4.7 s (see SI).
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This work was supported by the Asahi Glass Foundation as well as
by JSPS KAKENHI grants JP18H02553 (KIBAN B) and JP18H04401
(Middle Molecular Strategy). We also would like to thank Tosoh
Finechem Corporation for their support.
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Conflict of Interest
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The authors declare no conflict of interest.
Keywords: flow chemistry · trifluoromethyl · fluoroform · micro-
flow · gaseous
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Manuscript received: December 13, 2018
Revised manuscript received: January 9, 2019
ChemistryOpen 2019, 8, 1–6
www.chemistryopen.org
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© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA

Communications
COMMUNICATIONS
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Go with the flow: A gas/liquid-phase
micro-flow nucleophilic trifluoro-
methylation of carbonyl compounds
using gaseous fluoroform is
developed. This method also allows
the first micro-flow transformation of
N-sulfinylimines into trifluoromethyl
amines with excellent diastereoselec-
tivity. To demonstrate the synthetic
utility of this micro-flow synthesis,
the formal micro-flow synthesis of
Efavirenz is described.
K. Hirano, S. Gondo, N. Punna, E.
Tokunaga, Prof. Dr. N. Shibata*
1 – 6
Gas/Liquid-Phase Micro-Flow Tri-
fluoromethylation using Fluoro-
form: Trifluoromethylation of
Aldehydes, Ketones, Chalcones, and
N-Sulfinylimines
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