Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers

Article abstract of DOI:10.1002/anie.201805927

The first transition-metal-free, site-specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp³)–SCF₃ coupling under redox-neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL-based phosphorothiols can site-selectively cleave tertiary sp³ C(sp³)–O ether bonds in complex molecules initiated by a polarity-matching hydrogen-atom-transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp³)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site-selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.

Full text of DOI:10.1002/anie.201805927

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Accepted Article
Title: Synergistic Catalysis for the Umpolung Trifluoromethylthiolation
of Tertiary Ethers
Authors: Jin Xie
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805927
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10.1002/anie.201805927
Angewandte Chemie International Edition
COMMUNICATION
Synergistic Catalysis for the Umpolung Trifluoromethylthiolation
of Tertiary Ethers
Wentao Xu, Junyang Ma, Xiang-Ai Yuan, Jie Dai, Jin Xie* and Chengjian Zhu*
Abstract: The first transition metal-free, site-specific umpolung
trifluoromethylthiolation of tertiary alkyl ethers has been developed,
achieving the challenging tertiary C(sp3)-SCF3 coupling under redox-
neutral conditions. The synergism of organophotocatalyst 4CzIPN
and BINOL-based phosphorothiols can site-selectively cleave
tertiary sp3 C-O ether bonds in complex molecules initiated by a
polarity-matching hydrogen atom transfer (HAT) event. The
incorporation of several competing benzylic and methine C(sp3)-H
bonds in alkyl ethers has little influence on the regioselectivity.
Selective difluoromethylthiolation of C-O bonds has also been
achieved. This represents not only an important step forward in
trifluoromethylthiolation but also a promising means for site-selec-
tive C-O bond functionalization of unsymmetrical tertiary alkyl ethers.
efficient construction of a tertiary C(sp3)-SCF3 bond from
unreactive coupling partners remains a challenge.[5] The major
reason for this is the significant steric hindrance effect in δ+/δ-
bonding regimes.
The radical C(sp3)-SCF3 coupling was first reported in 1962
by Harris,[6] but this strategy attracted little attention[7] until 2014
when a Ag-catalyzed decarboxylative radical trifluoromethyl-
thiolation reaction was disclosed.[8] Subsequently, transition
metal-catalyzed, hydrogen atom transfer (HAT)-controlled
C(sp3)-H radical trifluoromethylthiolation was successfully
achieved based on the bond-dissociation energy (BDE) of
benzylic or methine C-H bonds.[9] Despite this important
advance, site-specific tertiary C(sp3)-CF3 coupling remains a
major barrier to C(sp3)-H trifluoromethylthiolation when the
substrates contain several competing C(sp3)-H bonds with
comparable BDE or electronic properties. This again results in
uncontrollable selectivity. The use of transition-metal
catalysts[8,9a-d] and/or external strong oxidants[8,9a-c] also
compromises the substrate’s utility in late-stage modification
reactions. Ethers are readily available, non-toxic and widely
used electrophiles in the C-O activation scenario.[10] To the best
of our knowledge, selective C-O trifluoromethylthiolation of
unsymmetrical aliphatic ethers has rarely been studied. Herein,
we report a metal-free, site-specific umpolung (reversed polarity)
trifluoromethylthiolation of unactivated tertiary alkyl ethers
initiated by a polarity-matching HAT process (Scheme 1b).
Organofluorine compounds are used widely in all fields of
science.[1] The strongly electron withdrawing and highly lipophilic
(πR = 1.44) trifluoromethylthio group (SCF3) is a privileged
bioisoster, which can substantially improve cell-membrane
permeability and metabolic stability of parent drug molecules.[2]
Besides metal-catalyzed C(sp2)- and C(sp)-SCF3 coupling,[3] the
direct nucleophilic or electrophilic trifluoromethylthiolation of alkyl
precursors, alkenes and even directed C(sp3)-H bonds is
currently of great interest to those seeking to construct primary
and secondary C(sp3)-SCF3 bonds (Scheme 1a).[4] However, the
Scheme 1. General strategies for direct C(sp3)-SCF3 formation.
Scheme 2. Mechanistic hypothesis.
W. Xu, J. Ma, Dr. J. Dai, Prof. Dr J. Xie, and Prof. Dr C. Zhu
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, National Demonstration
Center for Experimental Chemistry Education, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing 210023 (P.
R. China)
In 2018, we reported the first inverse hydroborylation of
imines with NHC-boranes via synergistic catalysis.[11] This was
enabled by combining iridium-based photoredox catalysis with
organocatalysis. As part of our ongoing interest in photoredox
catalysis,[12] a new review of this promising combination revealed
a site-selective umpolung trifluoromethylthiolation of tertiary
ether C-O bonds. To achieve site-selective C-O cleavage of
unsymmetrical tertiary alkyl ethers, the polar matching
strategy[13] is taken into account to initiate an exclusive HAT
event of a C-H bond adjacent only to an oxygen atom. In this
context, the electrophilic thiyl radical would be liable to undergo
homolytic cleavage of the hydridic α-C(sp3)-H bond of ethers
(BDE ~93 kcal/mol[14]) even in the presence of weaker neutral C-
H bonds such as a benzylic C-H (BDE ~90 kcal/mol[15]; Scheme
Email: xie@nju.edu.cn; cjzhu@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/xie/
Prof. Dr. X.-A. Yuan
School of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165 (P. R. China)
Prof. Dr C. Zhu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Shanghai 200032 (P. R. China)
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/anie.201805927
Angewandte Chemie International Edition
COMMUNICATION
1b). Since about half of the top-selling 200 pharmaceutical
products contain a benzylic structural motif,[16] the compatibility
of benzylic C-H bonds makes this protocol practical for
enhancement of bioisosteric lead screening.
calculations, the BINOL-based phosphorothiyl radical (2g.) has
the highest electrophilic reactivity amongst the thiyl radicals
examined. Combining this organocatalyst (2g) with an
organophotocatalyst (4CzIPN), several unsymmetrical tertiary
alkyl ethers were investigated (Scheme 3b). The optimized
reaction conditions require 2 mol% 4CzIPN, 2 mol% (2g), 0.1
equiv. K2CO3 as base and DCM as solvent at room temperature
under irradiation from blue LEDs (see Supporting Information for
optimization details).
We found that shelf-stable and easily available
methoxymethyl (MOM)-type tertiary alkyl ethers[19] (1d, 1e) could
undergo the expected reaction to afford the desired product (3a)
in 76% and 57% yields respectively. Other substrates (1a-c)
gave little or no trifluoromethylthiolation product (Scheme 3b).
Control experiments revealed that 4CzIPN, thiol and light were
crucial to a successful transformation. Benzylic C-H bonds are
entirely compatible with the reaction, although it remains highly
challenging for HAT-controlled C(sp3)-H functionalization
precedents.[20] We rationalized that the stronger hydridic C-H
bond in MOM-type ethers could facilitate the site-selective
C(sp3)-H abstraction steered by a polar matching effect.
The scope of the tertiary ether substrates was examined
(Scheme 4). The protocol has a broad substrate scope and can
achieve the site-specific C-O bond trifluoromethylthiolation of
tertiary alkyl ethers even when the substrate has several
competing electronically similar C-H bonds. For example, a wide
array of tertiary alkyl ethers bearing weak benzylic C-H bonds
were found to be competent coupling partners. These included
the derivatives of oxaprozin, ibuprofen and flurbiprofen (3o-q,
Scheme 4). Electron-withdrawing and -donating substituents in
the ortho, meta- and para-position of phenyl rings were tolerated
and substrates bearing -Me (3j), -Et (3k) or -CH2TMS (3l) at the
tertiary carbon center performed well. Heteroaromatic rings were
also compatible (3n) and the bistrifluoromethylthiolation product
(3m) was successfully obtained in 70% yield.
Scheme 3. Reaction development.
As shown in Scheme 2, the photoexcited PC*, an oxidant
undergoes single electron transfer (SET) with thiolate anion to
give a thiyl radical (4) via a reductive quenching pathway. The
resulting highly electrophilic thiyl radical (4) rapidly undergoes a
HAT event with the most hydridic -C-H group of the ether to
generate an alkoxyl radical (5). This then cleaves the C-O
bond[17] homolytically to form a tertiary alkyl radical (6). There
are two plausible pathways, paths A and B (Scheme 2) for
tertiary alkyl radical trifluoromethylthiolation. In path A, the
resulting Phth-SCF3 radical anion (7) undergoes radical-radical
coupling[18] with the tertiary alkyl radical (6) to afford the desired
product (3), releasing Phth- anion. In path B, the tertiary alkyl
radical addition to the electrophilic Phth-SCF3 reagent occurs
first and is followed by SET reduction of the phthalimide radical,
producing a Phth- anion. In both cases, the resulting Phth- ion
can abstract one proton from the thiol organocatalyst to yield
phthalimide and thiolate anion and so restart the catalytic cycle.
Subsequently, we examined substrates containing
competing hydridic C-H bonds. The reaction showed satisfactory
tolerance of a wide range of versatile functional groups, such as
ketone (3r), ester (3s, 3t, 3w), amide (3v), heteroaromatic ether
(3u) and halogen (3w). Notably, most HAT-controlled aliphatic
C-H trifluoromethylthiolation reactions usually occurred at the
methine C-H bonds.[9] In our case, the polarity-matching
principle enabled these methine C(sp3)-H bonds to survive (3x-
aa) and offered an effective route to site-specific construction of
a tertiary C(sp3)-SCF3 bond from C-O bonds under redox-neutral
reaction conditions. In addition, other kinds of cyclic, linear and
branched alkyl ethers can undergo this useful transformation to
afford the corresponding products (3bb-hh) in 47-75% yields.
Interestingly, when the substrate contains both secondary and
tertiary MOM ether units, the tertiary MOM ether moiety was
preferentially trifluoromethylthiolated (3ii).
The presence of a suitable thiol organocatalyst in the
catalytic combination should be a factor crucial to the umpolung
trifluoromethylthiolation. The reason for this is that the resulting
thiyl radical (4) should be capable of achieving a site-selective
HAT event with a hydridic C-H bond to initiate the C-O homolytic
cleavage. Aside from the kinetic polarity matching effect, the
thiyl radical reactivity would, to a certain extent, control the H-
atom abstraction efficiency. Accordingly, the singly occupied
molecular orbital (SOMO) energies of several kinds of thiyl
radicals were computed. Different thiyl radicals have significantly
different SOMO energies, indicative of variable reactivity
towards the HAT process (Scheme 3a). According to our DFT
In view of the prevalence of the difluoromethylthio group in
pharmaceuticals and agrochemicals, we successfully applied
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10.1002/anie.201805927
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COMMUNICATION
Scheme 4. The ether scope: isolated yields are given. [a] 1 mmol scale. [b] 6 mmol scale (gram-scale). [c] PhthSCF3 (2 equiv). [d] 19F NMR yield.
this synergistic catalysis to site exclusive difluoromethylthiolation
of C-O bonds (Scheme 5). Among the tertiary alkyl ethers
examined, only the MOM-type ethers underwent this
difluoromethylthiolation smoothly (See Supporting Information).
Although the direct nucleophilic substitution of primary and
secondary alcohols with AgSCF3 can occur smoothly, Qing et al.
reported that tertiary alcohols fail to undergo this
transformation.[4b] To further demonstrate the practicality of this
protocol, a complementary trifluoromethylthiolation of complex
tertiary alcohols was achieved (Scheme 6). The MOM-type ether
was obtained by treatment of complex tertiary alcohols (8, 9)
with chloromethyl methyl ether (MOMCl), and was used directly
in the subsequent trifluoromethylthiolation procedure without
purification. The consecutive synthetic route provides an
important access to trifluoromethylated alkylthioethers from
unreactive tertiary alcohols in acceptable yields.
Scheme 5. Site-specific difluoromethylthiolation of C-O bond in tertiary ethers.
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10.1002/anie.201805927
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COMMUNICATION
C-H bonds in isobutylbenzene appeared to be trifluoromethyl-
thiolated simultaneously (3a:3a’ = 45:55). Both reactive tertiary
alkyl oxalates[22] and carboxylic acids[23] however cannot
undergo this transformation (Eq. 4, 5). These investigations
further underscore the synthetic advantages of our protocol.
In conclusion, we have developed
a
synergistic
organophotoredox catalysis and organocatalysis for the first site-
selective trifluoromethylthiolation and difluoromethylthiolation of
tertiary C(sp3)-O ether bonds under mild reaction conditions. The
polar matching principle enables competing benzylic, methine
and hydridic C(sp3)-H bonds to survive during the HAT-initiated
C-O bond functionalization event, and this highlights the
excellent regioselectivity and functional group compatibility of
this protocol. Furthermore, the implementation of challenging
tertiary C(sp3)-SCF3 coupling in complex molecules represents a
significant advance in future lead screening. Exploration of this
new alkyl radical source for the construction of chiral quaternary
carbon stereocenters by means of visible-light photoredox
catalysis is in progress in our laboratory.
Scheme 6. Consecutive procedures for trifluoromethylthiolation of complex
tertiary alkyl alcohols.
Further experiments were carried out to gain insight into the
mechanism of this reaction (see Supporting Information). Stern–
Volmer quenching studies showed that photoexcited 4CzIPN*
was quenched by thiolate anions. Significantly, the postulated
tertiary alkyl radical could be successfully trapped by TEMPO
and BHT. Analysis of the 1H NMR spectrum of the model
reaction mixture clearly revealed the generation of methyl
formate along with the product (3a). Comparison of the potential
Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (21702098, 21732003, 21672099 and 21703118),
“1000-Youth Talents Plan”, the Fundamental Research Funds
for the Central Universities (No. 020514380158, 020514380131)
of the photocatalyst [1/2E(4CzIPN/4CzIPN-1) = -1.21 V vs SCE][21]
and Shandong Provincial Natural Science Foundation (No.
ZR2017MB038) and open traning program of undergraduate
organic experiment course for financial support. We are grateful
to Professor Qilong Shen at Shanghai Institute of Organic
Chemistry for generously providing PhthSCF2H.
1/2
and Phth-SCF3
[
E
reduction
= - 0.80 V vs SCE], showed that
although the SET event to generate Phth-SCF3 radical anion (7)
seems thermodynamically favorable (Path A, Scheme 2),
nucleophilic alkyl radical addition to highly electrophilic Phth-
SCF3 (Path B, Scheme 2)[9d] still cannot be ruled out. However,
a radical chain pathway is unlikely because the quantum yield of
a model reaction was determined to be only 2.4%.
Conflict of interest
The authors declare that one Chinese patent has been applied..
Keywords: cooperative catalysis • umpolung • polarity matching
effect • trifluoromethylthiolation • C-O bond activation
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10.1002/anie.201805927
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
W. Xu, J. Ma, X.-A. Yuan, J. Dai, J. Xie*
and C. Zhu*
Page No. – Page No.
Synergistic Catalysis for the
Umpolung Trifluoromethylthiolation
of Tertiary Ethers
The weaker survive: The first transition metal-free, site-specific umpolung
trifluoromethylthiolation of tertiary ethers has been developed, achieving the
challenging tertiary C(sp3)-SCF3 coupling under mild conditions. The polarity-
matching effect enables competing benzylic, methine and hydridic C(sp3)-H bonds
to survive during a HAT-initiated C-O bond functionalization event.
This article is protected by copyright. All rights reserved.