Organic Photoredox-Catalyzed Synthesis of δ-Fluoromethylated Alcohols and Amines via 1,5-Hydrogen-Transfer Radical Relay

Article abstract of DOI:10.1021/acs.orglett.9b01714

The hydrotrifluoromethylation of benzyl-protected homoallylic alcohol and amine derivatives catalyzed by 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) was developed. This reaction delivered δ-fluoromethylated free alcohols and amines with in situ deprotection of benzyl protecting group under mild irradiation conditions. 4CzIPN was found to be a competent metal-free photoredox catalyst for activating several types of fluoromethylation reagents including CF₃SO₂Cl, Togni's reagent, and 2-bromo-2,2-difluoroacetate via oxidative quenching and also CF₃SO₂Na through reductive quenching to allow direct hydrotrifluoromethylation of simple alkenes and Michael acceptors.

Full text of DOI:10.1021/acs.orglett.9b01714

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organic Photoredox-Catalyzed Synthesis of δ‑Fluoromethylated
Alcohols and Amines via 1,5-Hydrogen-Transfer Radical Relay
Huiqiao Wang,† Jinjin Zhang,† Jianxue Shi,† Fan Li,† Sheng Zhang,*,† and Kun Xu*,†,‡
†Engineering Technology Research Center of Henan Province for Photo- and Electrochemical Catalysis, College of Chemistry and
Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
‡College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China
S
* Supporting Information
ABSTRACT: The hydrotrifluoromethylation of benzyl-pro-
tected homoallylic alcohol and amine derivatives catalyzed by
2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN)
was developed. This reaction delivered δ-fluoromethylated
free alcohols and amines with in situ deprotection of benzyl
protecting group under mild irradiation conditions. 4CzIPN
was found to be a competent metal-free photoredox catalyst
for activating several types of fluoromethylation reagents
including CF3SO2Cl, Togni’s reagent, and 2-bromo-2,2-
difluoroacetate via oxidative quenching and also CF3SO2Na through reductive quenching to allow direct hydro-
trifluoromethylation of simple alkenes and Michael acceptors.
ncorporation of trifluoromethyl group into small organic
Imolecules significantly improves their metabolic stability
and lipophilicity,1 which are important biological properties of
concern in medicinal chemistry. As it was discovered that
increasing the saturation in small molecules improves the
possibility of clinical success in discovering small molecules as
effective drugs, synthetic methods that introduce a trifluor-
omethyl substituent onto an unsaturated carbon atom have
received substantial interest from the synthetic community.2,3
Among various methods to forge a C(sp3)−CF3 bond, radical
hydrotrifluoromethylation is the most straightforward and
efficient method due to its high regioselectivity and atom
economy.4 Considering the ubiquity of free alcohol and amine
structures in bioactive compounds,5 an efficient synthetic
method that selectively delivers trifluoromethylated free
alcohols and amines would be of importance in the
pharmaceutical industry, especially an operationally simple
method without recourse of expensive and toxic transition-
metal catalysts or additives. Herein, we report that by applying
an organic photoredox catalyst,6 2,4,5,6-tetra(9H-carbazol-9-
yl)isophthalonitrile (4CzIPN),7 hydrotrifluoromethylations of
benzyl-protected homoallylic alcohol and amine derivatives
using electrophilic trifluoromethylation reagent (trifluorometh-
yl sulfonyl chloride and Togni’s reagent8) deliver δ-
fluoromethylated free alcohols and amines with in situ
deprotection of a benzyl protecting group under mild
irradiation conditions. The reaction proceeds in a mixed
methanol/dioxane solvent without use of any additives and
exhibits excellent functional group compatibility. The reaction
proceeds through an oxidative quenching process to deliver a
trifluoromethyl radical followed by 1,5-hydrogen transfer relay
with in situ removal of benzyl protecting group. During this
study, we also discovered that photoexcited 4CzIPN catalyst
can also be reductively quenched by nucleophilic trifluor-
omethyl reagent an sodium triflinate to allow hydrotrifluor-
omethylation of simple alkenes and Michael acceptors. These
results reveal the general applicability of 4CzIPN photocatalyst
for activation of various trifluoromethylation reagents through
either oxidative quenching or reductive quenching due to its
larger band gap (2.4 eV) and suitable HOMO/LUMO level to
endow both strong reducing and oxidizing ability in a
photoexcited state.9
Our working hypothesis is inspired by a copper-catalyzed
anti-Markovnikov hydrofunctionalization of homoallylic alco-
hol reported by Chiba, Gagosz et al.10,11 In this work, a wide
variety of δ-fluoromethylated free alcohols were obtained
through copper-catalyzed generation of trifluoromethyl radical
following a 1,5-hydrogen transfer radical relay process. We
conceive that a suitable organic dye 4CzIPN should be able to
generate trifluoromethyl radical through oxidative quenching
of its photoexcited triplet state (E1/2(PC•+/PC*) = −1.18 V.
The generated trifluoromethyl radical can be trapped by
benzyl-protected homoallylic alcohol followed by a 1,5-
hydrogen-transfer process to generate more stable etheric
benzylic radical.12 The benzylic radical is supposed to be
oxidized by the photoredox catalyst of its oxidation form to
generate cationic intermediate ((E1/2(PC•+/PC) = +1.49 V),
which will be quenched by alcohol solvent to deliver acetal.
After aqueous workup, δ-trifluoromethylated alcohol or amine
will be delivered as the desired product (Scheme 1).
Received: May 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 1. Working Hypothesis of Organic Photoredox-
Catalyzed Synthesis of δ-Trifluoromethylated Alcohols and
Amines
Scheme 3. Scope of δ-Trifluoromethylated Alcohols
Guided by this hypothesis, we report herein that 4CzIPN, a
donor−acceptor-type organic dye, works as an effective catalyst
for this reaction due to its suitable redox potential. According
to the working hypothesis, a suitable benzyl protecting group is
important because the benzyl moiety works as a hydrogen
atom source and the substituent on benzyl affects the efficiency
of the crucial 1,5-hydrogen-transfer process. Scheme 2 showed
a
Reaction conditions: 0.2 mmol scale in dioxane/MeOH (2.0 mL, v/v
9/1) irradiated by 40 W blue LEDs (456 nm) for 12 h under Ar.
b
Isolated yields. The yields in parentheses are yields obtained using
CF3SO2Cl instead of Togni’s reagent.
Scheme 2. Investigation of Different Benzyl Protection
Groups for 1,5-Hydrogen Transfer
a
nesulfonyl chloride, probably because of the competing
alcoholysis of sulfonyl chloride. Besides linear α-substituted
homoallylic alcohol derivatives (1−8), β- and γ-substituted
homoallylic alcohol derivatives were also amenable substrates
(9−12). It is notable that chirality on both the α- and β-carbon
of homoallylic alcohol was fully retained after the reaction
(11). However, tertiary and alkyl-substituted alcohol substrates
did not work under the optimized conditions.
It was discovered that, besides trifluoromethylation, 6-
hydroxy-2,2′-difluorocarboxylate (13) could also be synthe-
sized by this method applying 2-bromo-2,2-difluoroacetate (eq
1).13 However, transesterification was observed in this
a
Reaction conditions: alkene (0.2 mmol), CF3SO2Cl (0.4 mmol),
4CzIPN (0.004 mmol) in solvent (2.0 mL) irradiated by 40 W blue
b
LEDs (456 nm) for 12 h under Ar. Isolated yields. Togni’s reagent
c
(0.3 mmol) was used instead of CF3SO2Cl. Umemoto’s reagent was
d
used. TEMPO (0.3 mmol) was added.
the results of applying various substituted benzyls as hydrogen
donating groups. 4-Cyanobenzyl appeared to be the optimal
protecting group due to its easily installation and the
appropriate electronic effect of cyano substituent to modulate
the speed of 1,5-H transfer step for a productive process (entry
3). The yield of 1 was further improved by applying Togni’s
reagent instead of CF3SO2Cl (entry 6). The use of Umemoto’s
reagent (S-(trifluoromethyl)dibenzothiophenium triflate) as
the CF3 source led to a lower yield (entry 7). The reaction was
inhibited by using TEMPO as the radical scavenger, which
suggests a radical process was involved (entry 8).
After determining 4-cyanobenzyl as the optimal protecting
group, we examined the reaction scope with respect to various
homoallylic alcohols (Scheme 3). The reaction conditions are
very simple, and the product could be easily purified. Togni’s
reagent provided generally higher yield than trifluorometha-
reaction. An experiment using α-deuterated benzyl as the
protecting group confirmed the 1,5-hydrogen-transfer process,
as deuterium was incorporated (>90%) onto the γ-position of
the trifluoromethylated alcohol product. The method offers a
synthetic route to synthesize regioselectively deuterium-labeled
trifluoromethylated alcohols, which will be useful in medicinal
chemistry study.14
We were delighted to find that the same protocol was also
applicable to hydrotrifluoromethylation of homoallyic amine
derivatives. Various N-arylated homoallylic amines perform as
amenable substrates to provide δ-trifluoromethylated N-
B
DOI: 10.1021/acs.orglett.9b01714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
arylated secondary amines in good yields (Scheme 4). A
variety of functional groups, such as bromo (20, 22), fluoro
Scheme 5. Scope of Homoallylic Amine Derivatives
Scheme 4. Scope with Respect to N-Aryl Substituents on
a
Amines
a
Reaction conditions: 0.2 mmol scale in dioxane/MeOH (2.0 mL, v/v
9/1) irradiated by 40 W blue LEDs (456 nm) for 12 h under Ar.
Isolated yields.
this catalytic reaction requires an oxidant to proceed. We
rationalize that excess amount of Langlois reagent acted as
oxidant under photoredox condition for this reaction
(E1/2(PC/PC•−) = −1.24 V).
a
Reaction conditions: 0.2 mmol scale in dioxane/MeOH (2.0 mL, v/v
9/1) irradiated by 40 W blue LEDs (456 nm) for 12 h under Ar.
Isolated yields.
Further use of difluoromethylation using CF2HSO2Na
produced unexpected hydrodifluoromethylation product with-
out removal of benzyl protecting group (eq 4). We consider
that the high reducing ability of 4CzIPN (E1/2(PC/PC•−) =
−1.24 V) allows reductive protonation of fluorinated alkyl
radical without abstraction of hydrogen through 1,5-H transfer.
Thus, we posited that the organic photoredox catalyst 4CzIPN
could be competent to catalyze hydrotrifluoromethylation of
simple alkene and Michael acceptors with CF3SO2Na, a
process previously reported by using combination of
acridinium photoredox catalyst and thiophenol hydrogen
transfer catalyst15 or iridium photoredox catalyst.16 Simply
applying 4CzIPN as photocatalyst is competent to catalyze
hydrotrifluoromethylation of aliphatic alkenes (49, 50) and
Michael acceptors (48, 51, 52, 53) with CF3SO2Na (Scheme
6). The hydride source for this hydrotrifluoromethylation
reaction may come from the MeOH solvent.16 These results
above demonstrate that 4CzIPN is a competent catalyst for
generation of trifluoromethyl radical from various trifluor-
omethylation reagents under simple irradiation conditions.
In conclusion, in this work we demonstrated an organic
photoredox method using 4CzIPN as catalyst for hydro-
trifluoromethylation without using any transition metal.
Hydrotrifluoromethylation of benzyl-protected homoallylic
alcohol and amine derivatives provides δ-fluoromethylated
free alcohols and amines with in situ deprotection of the benzyl
protecting group under mild irradiation conditions. The
reaction exhibits excellent functional group compatibility and
operational simplicity. 4CzIPN is a competent catalyst for
trifluoromethyl radical generation via oxidative or reductive
quenching of various trifluoromethylation reagents. We hope
(15), chloro (16), ester (17), amide (18), cyano (19), nitro
(21), ether (24), and even a pinacol boronate (25) substituent
on aniline moiety, were well tolerated. Tolerance of the aryl
pinacol boronate moiety shows the advantages of applying
photoredox catalysis since aryl boronate is not well survivable
in the presence of transition-metal catalyst and Togni’s reagent.
The reaction scope with respect to homoallylic amine
derivatives is shown in Scheme 5. α-Heteroarylated δ-
trifluoromethylated secondary amine could also be synthesized.
Heteroarenes including thiophene (42, 43), furan (45), and
pyridine (46) were all tolerable.
An interesting result was obtained when Langlois reagent
was used in 2.5 equiv amount instead of Togni’s reagent, as the
desired product with deprotection of benzyl protecting group
was also generated in 69% yield (eq 3). The yield of desired
product was significantly decreased when Langlois reagent was
used in 1.5 equiv amount. Judged by redox potential, it is
reasonable that Langlois reagent (E1/2 = 1.05 V vs SCE) can
reductively quench photoexcited 4CzIPN catalyst to generate
trifluoromethyl radical (E1/2(PC*/PC•−) = +1.43 V), while
C
DOI: 10.1021/acs.orglett.9b01714
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Letter
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Scheme 6. Hydrotrifluoromethylation of Simple Alkenes
and Michael Acceptors Using Langlois Reagent
a
a
Reaction conditions: 0.2 mmol scale in dioxane/MeOH (2 mL, v/v
9/1) irradiated by 40 W blue LEDs for 20 h under Ar. Isolated yields.
the method reported herein will find its use in pharmaceutical
industry to synthesize important fluorinated intermediates or
bioactive compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01714.
Experimental procedures, detailed optimization, mecha-
nistic studies, compound characterization, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shengzhang@nynu.edu.cn.
*E-mail: xukun@nynu.edu.cn.
ORCID
Sheng Zhang: 0000-0002-9686-3921
Kun Xu: 0000-0002-0419-8822
Notes
+
tion of Arylboronic Acid and CF3 Reagent. J. Am. Chem. Soc. 2019,
The authors declare no competing financial interest.
141, 1887−1892.
(4) For selected recent examples on radical trifluoromethylations of
alkenes, see: (a) Mizuta, S.; Verhoog, S.; Engle, K. M.;
Khotavivattana, T.; O’Duill, M.; Wheelhouse, K.; Rassias, G.;
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21602119 and 21702113). Financial support was
received from the Foundation of He’nan Educational
Committee (16A150057). The project was funded by the
Beijing Postdoctoral Research Foundation and the Program for
Science and Technology Innovation Talents in Universities of
Henan Province (19HASTIT033).
́
Medebielle, M.; Gouverneur, V. Catalytic Hydrotrifluoromethylation
of Unactivated Alkenes. J. Am. Chem. Soc. 2013, 135, 2505−2508.
(b) Wang, Y.-F.; Lonca, G. H.; Le Runigo, M.; Chiba, S. Synthesis of
Polyfluoroalkyl Aza-Polycyclic Aromatic Hydrocarbons Enabled by
Addition of Perfluoroalkyl Radicals onto Vinyl Azides. Org. Lett. 2014,
16, 4272−4275. (c) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.;
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DOI: 10.1021/acs.orglett.9b01714
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