CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N-Sulfonylimines

Article abstract of DOI:10.1002/anie.202001262

An unprecedented electrochemical trifluoromethylation/SO₂ insertion/cyclization process has been achieved in an undivided cell in an atom-economic fashion. The protocol relies on tandem cyclization of N-cyanamide alkenes by using Langlois’ reagent as a source of both CF₃ and SO₂ under direct anodically oxidative conditions, in which two C?C bonds, two C?X bonds (N?S and S?C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N-sulfonylimines from readily accessible materials.

Full text of DOI:10.1002/anie.202001262

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Accepted Article
Title: CF3SO2Na Acted as a Bifunctional Reagent: Electrochemical
Trifluoromethylation of Alkenes Accompanied by SO2-Insertion to
Access Trifluoromethylated Cyclic N-Sulfonylimines
Authors: Wei-Wei Liao, Zheng Li, Ling-Cong Jiao, Yun-Hai Sun, Ze-
Ying He, and Zhonglin Wei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001262
Angew. Chem. 10.1002/ange.202001262
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10.1002/anie.202001262
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CF3SO2Na Acted as a Bifunctional Reagent: Electrochemical
Trifluoromethylation of Alkenes Accompanied by SO2-Insertion to
Access Trifluoromethylated Cyclic N-Sulfonylimines
Zheng Li,+ Lingcong Jiao,+ Yunhai Sun, Zeying He, Zhonglin Wei, Wei-Wei Liao*
Abstract:
An
unprecedented
electrochemical
trifluoromethylation/SO2-insertion/cyclization process has been
achieved in an undivided cell in an atom-economic fashion. The
protocol relies on tandem cyclization of N-cyanamide alkenes by
using Langlois reagent as CF3 and SO2 sources under direct
anodically oxidative conditions, in which two C−C bonds, two C-X
bonds (N-S and S-C) and two rings were formed in a single
operation. This transformation enabled efficient construction of
various trifluoromethylated cyclic N-sulfonylimines from readily
accessible materials.
SO2 as waste
Decoration small molecules with trifluoromethyl (CF3) group
has gained growing attentions both from industrial and academic
communities, due to the unique physical properties of
trifluoromethylated
compounds
such
as
lipophilicity,
bioavailability and metabolic stability and their frequent
Scheme 1. Existing and new approach for trifluoromethylation of alkenes with
CF3SO2Na.
occurrence in pharmaceuticals, agrochemicals and performance
[1]
materials.
As a consequence, development of efficient and
practical protocols to rapidly access trifluoromethylated molecules
continues to be highly demanded. [2]
trifluoromethylation of heterocycles under direct electrolytic
[6]
conditions,
electrochemically oxidative difunctionalization of
The trifluoromethylation of alkenes with the simultaneous
formation of C−C or C−X bonds represents one of the most
practical and powerful strategies for preparing acyclic or cyclic
alkenes involving the simultaneous formation of C−CF3 and C−O,
C-N, C-C bonds has aroused as a highly attractive strategy to
streamline the access for CF3-containing compounds by employing
trifluoromethyl-containing building blocks for bioactive
[2b-2i]
readily available trifluoromethanesulfinates as the radical
compounds.
Various either electrophilic (e.g., Umemoto’s
[3]
precursors.
However, all of trifluoromethanesulfinates-based
reagent or Togni’s reagents) or nucleophilic trifluoromethylating
reagents (e.g., Langlois’ reagent and Baran’s reagent) enabled a
diversity of trifluoromethylation of alkene transformations in
which most of them were based on a radical mechanism, to access
reagents acted exclusively as a sole CF3 source regardless of
conventional oxidative, photoredox or electrochemical pathway,
and the concomitantly generated SO2 was discarded as a waste
(Scheme 1a).
structurally diverse trifluormethylated molecules. Owing to recent
[2h-2i]
remarkable advances on photoredox
approaches,
and electrochemical
Recently, rapidly developed protocols on the preparation of
sulfonyl compounds by means of SO2-insertion have drawn
increasing attention. [7] In particular, the incorporation of in situ
[3a-3b]
the trifluoromethylation of alkenes can be
performed environmental-friendly by avoiding the utilization of
stoichiometric quantities of chemical oxidants or reductants and the
[3c-3i,
4]
generation
of
hazardous
waste.
Sodium
trifluoromethanesulfinate (Langlois reagent), which is an
inexpensive, bench-stable, and easily handled trifluoromethyl
source, has been regarded as an attractive trifluoromethylating
reagent and received more attention. [5] In particular, since Baran
and co-workers’ pioneer contribution on the radical
[*] Z. Li, L. Jiao, Y, Sun, Z. He, Dr. Z. Wei, Prof. W.-W. Liao
Department of Organic Chemistry, College of Chemistry, Jilin University
Changchun 130012, (P. R. China)
Prof. W.-W. Liao
E-mail: wliao@jlu.edu.cn
Figure 1. Selective examples of bioactive and synthetically useful molecules
containing six-membered cyclic N-sulfonylimine-related motifs.
[+] These authors contributed equally to this work.
[] Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202001262
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generated sulfur dioxide from surrogates into the organic
frameworks in aminosulfonylative reactions via a radical pathway
afforded an attractive strategy to construct a series of sulfonamides,
constant electric current of 3 mA for 6 h, led to the formation of
cyclic N-sulfonylimine 3a concomitantly incorporating both
trifluoromethyl and SO2 moieties in 64% isolated yield as the sole
product (Table 1, entry 1). In this case, two C−C bonds, two C-X
bonds (N-S and S-C) and two rings were formed with Langlois
reagent (2a) as CF3 and SO2 sources in a single operation. The
lower electricity and long reaction time gave the similar result to
that of the reaction with 3 mA and 6 hours, while the high
electricity led to a reduced yield (Table 1, entries 2-3). Inert
atmosphere was not essential, since the outcome of electrochemical
reaction was not improved under nitrogen atmosphere (Table 1,
entry 4). The reduced amount of 2a resulted in the deteriorative
[8]
which are valuable structural motifs in medicinal and
[9]
agrochemical agents.
direct
Among them, Wu et al. have reported
of alkynes through
vicinal difunctionalization
trifluoromethylation (or difluoroalkylation) and aminosulfonylation
by employing fluorinating reagent, alkynes, sulfur dioxide of
surrogates and hydrazines via an insertion of sulfur dioxide under
[10]
catalyst-free or photoinduced conditions.
Inspired by the
advances of radical trifluoromethylation and the insertion of sulfur
dioxide and environmentally friendly nature of electrochemical
organic synthesis due to its tunability over electron transfer
processes and use of electrons as traceless reagents, [11] we envision
that readily available CF3SO2Na may act as a bifunctional reagent,
namely, both as a radical (•CF3) source and a sulfating reagent
(SO2) in a tandem cyclization of N-cyanamide alkene process
under direct anodically oxidative conditions (Scheme 1b), which
could extremely extend the application of Langlois reagent on
efficient construction of fluorinated molecules with advanced
sulfonyl complexities by concomitant incorporation of in situ
generated trifluoromethyl and sulfur dioxide in an atom
economical fashion. Herein, we report the application of this
strategy on the electrochemical preparation of six-membered cyclic
N-sulfonylimine derivatives bearing CF3 units in an undivided cell,
which are both synthetically useful [12] and medicinally important
(Figure 1), [13] in an environment-friendly manner.
production
of
3a
(Table
1,
entry
5).
Zinc(II)
bis(trifluoromethanesulfinate) (Zn(SO2CF3)2, Baran’s reagent) can
also serve as CF3 and SO2 sources to deliver the desired product 3a
with comparable efficacy (Table 1, entry 6). In addition, control
experiment suggested that electricity was indispensable (Table 1,
entry 7) (see the SI for full detailed). Notably, other possibly cyclic
compounds such as 4a or 5a via alternatively possible radical
pathway were not observed.
With the optimized reaction conditions in hand, the substrate
scope of this tandem electrosynthesis was investigated (Table 2).
First, we examined a diverse range of N-aryl cyanamides 1 bearing
unactivated terminal alkene moiety. A broad range of substituents
on the aromatic ring system of cyanamides, such as para-fluoro,
para-chloro, para-bromo, para-methyl, para-methoxy and para-t-
butyl were well tolerated and afforded both CF3 and SO2
incorporated cyclic N-sulfonylimines 3b-3g in this transformation.
However, cyanamides 1 bearing strong electronic withdrawing
groups such as CF3 and CO2Et on the para-position of aromatic
ring, failed to give any desired products (3h-3i). Both ortho- or
meta-substitution of the aromatic ring system of cyanamides were
tolerated (3j, 3l), and meta-substituted analogue afforded a 1.2:1
mixture of regioisomers (3l). Disubstituted cyanamides were also
evaluated, and N-(3,4-dimethylphenyl) cyanamide gave the desired
product 2n with regioselectivity 1.7/1, while the expected tandem
reaction of 3,4-dimethoxyl analogue with 2a did not occur (3o)
with the recovery of the most of starting material. Besides, either
N-α- or β-naphthyl substituted cyanamides can also serve as
suitable substrates to furnish the desired trifluoromethyl cyclic N-
sulfonylimines (3k, 3m) as sole regioisomers. Notably,
heterocyclic moiety like 5-substituted indole was amenable to this
electrochemical transformation, and the desired product 3q can
obtained in moderate yield with high regioselectivity along with
small amount of by-product 3q’ which may stem from the
trifluoromethylation/cyclization without SO2-insertion. N-Aryl
cyanamides 1 bearing disubstituted alkene moiety were also
evaluated, and N-(3-methylbut-3-en-1-yl)-N-phenylcyanamide
gave the desired product 3p in 33% yield, while phenyl-substituted
analogue did not react with 2a to give the desired cyclic
sulphonamide (3r) under the optimized reaction conditions. The
structure of trifluoromethylated cyclic N-sulfonylimine was
unambiguously confirmed by single crystal X-ray analysis of
compound 3a.
Table 1: Selected optimization of reaction conditions. [a]
Entry
Deviation from standard conditions
none
Yield (%) [b]
1
2
3
4
5
6
7
66 (64)
61
1.5 mA, 12 h
6 mA, 3 h
53
under nitrogen atmosphere
CF3SO2Na (2.0 equiv.)
(CF3SO2)2Zn (1.5 equiv.)
No electricity
61
48
56
nd
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), Bu4NBF4 (0.3 mmol)
and DCM/H2O (5/1) (c = 0.03 M) in an undivided cell with graphite rod anode
(Φ 6 mm), Pt plate cathode (10 × 10 × 0.1 mm), constant current = 3.0 mA,
30 °C, 6 h. 2.2 F/mol. [b] Determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as the internal standard. Isolated yield in parenthesis.
Initially, N-(but-3-en-1-yl)-N-phenylcyanamide 1a was chose
as the model substrate to evaluate the feasibility of the
electrochemical
trifluoromethylation/SO2-insertion/cyclization
process using Langlois reagent (2a) as possible CF3 and SO2
sources in an undivided cell.[14] After extensive screening of
reaction conditions, we found that anodically electrolyzing 2a and
cyanamide 1a bearing a terminal alkene moiety as the radical
acceptor at 30 °C in a cosolvent of DCM/H2O = 5/1, including
Bu4NBF4 as electrolyte and C(+)/Pt(-) as the electrodes with a
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10.1002/anie.202001262
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Table 2: Substrates scope. [a]
alkenyl moieties of cyanamides. For examples, N-(2, 2-
dimethylbut-3-enoyl) substituted cyanamide (1w), N-cinnamoyl
Table 3: Substrates scope. [a]
O
O
CN
C (+)/Pt (-), cc 3 mA
S
N
N
N
undivded cell
Bu4NBF4 (0.03 M)
DCM/H2O (5/1)
30 oC, 6 h
Ar
+
CF3SO2Na
(3.0 equiv.)
Ar
O
R
CF3
R
1
2a
3
O
O
O
X
S
S
N
N
N
N
CF3
CF3
3b
3c
3d
3a
(X = F): 58%
(X = Cl): 51%
(X = Br): 44%
: 64 %
O
O
O
O
O
O
Me
S
tBu
MeO
S
S
N
N
N
N
N
N
CF3
CF3
CF3
3e
: 62%
3f
: 50%
3g: 61%
O
O
O
O
O
O
R
S
N
S
N
S
N
N
N
N
CF3
CF3
CF3
Me
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Bu4NBF4 (0.3 mmol) and
solvent (c = 0.03 M) in an undivided cell with graphite rod anode (Φ 6 mm), Pt
plate cathode (10 ×10 × 0.1 mm), constant current = 3.0 mA, 30 °C, 6 h. [b]
Constant current = 5.0 mA, 30 °C, 6 h.
3h
(R = CF3): nd
3i (R = CO2Et): nd
3j
3k:
: 53 %
30 %
Me
O
O
O
O
O
O
S
N
S
N
S
N
N
N
+
Me
N
CF3
CF3
CF3
substituted cyanamide (1x), N-cinnamyl substituted cyanamide
(1y) or N-(pent-4-en-1-yl)- substituted cyanamide (1z) cannot
participate in this tandem electrochemical cyclization to afford the
desired products, while N-benzoyl substituted cyanamide 6
delivered CF3-substituted quinazolinone 8 in 32% yield instead of
N-sulfonylimine 7 with SO2-insertion (eq-1), which can also
3m: 29 % [b]
3l:
1.2/1
47 %,
R
O
O
O
O
O
O
R
R
S
R
S
N
S
N
N
N
N
+
N
CF3
CF3
CF3
Me
prepared from copper-catalyzed trifluoromethylation/cyclization of
[14a]
3n
(R = Me): 40 %,
3p
: 33%
6 by using Togni’s reagent.
In addition, cyanamide moiety
3o (R = MeO): nd
seemed to be pivotal to this electrolytic sequence, since
electrochemical reaction between N-arylacrylamide with
CF3SO2Na (2a) furnished trifluoromethylated oxindole 11 instead
of CF3-incorporated cyclic N-sulfonylimine 10 under the current
electrolysis conditions (eq-2).[3e, 3g-3h]
O
O
O
O
CF3
9
Ts
N
S
S
N
N
N
+
NC
N
N
CF3
CF3
N
Ph
Ts
[b]
3r
3q:
3q':
: nd
47 %
15 %
O
O
N
O
O
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Bu4NBF4 (0.3 mmol) and
DCM/H2O (5/1) (c = 0.03 M) in an undivided cell with graphite rod anode (Φ 6
mm), Pt plate cathode (10 ×10 × 0.1 mm), constant current = 3.0 mA, 30 °C,
6 h. Isolated yields. [b] Constant current = 5.0 mA, 30 °C, 6 h.
S
standard reaction
conditions
N
Me
CN
N
N
eq-1
eq-2
CF3
+
CF3
N
Me
Me
O
7: nd
6
8: 32% yield
O
O
Me
CF3
standard reaction
conditions
S
Besides, to our delight, the electrolytic trifluoromethylation/SO2-
insertion/cyclization tandem sequence was applicable to N-aryl
cyanamides 1 containing unactivated internal alkene moiety under
the standard reaction conditions. By virtue of Langlois reagent (2a)
as a bifunctional reagent, trifluoromethylated N-sulfonylimines 3s-
3v incorporating spiro-cyclic moieties can be readily assembled
O
CF3
Me
O
O
+
N
N
N
Me Me
Me
Me
9
10: nd
11: 29% yield
Besides, this electrochemical approach was also applicable to
difluoromethylation/SO2-insertion/cyclization sequence, which was
from N-aryl cyanamides
1
containing cyclopentene and
cyclohexene moieties as sole diastereoisomers (Table 3). Further
investigations revealed that this tandem sequence was susceptive to
the substitution and the length of the linkage between N and
exemplified by the reaction between 1a and
sodium
difluoromethanesulfinate 2b. The desired difluoromethylated
cyclic N-sulfonylimine 3ab can be obtained in 28% yield under the
slightly modified reaction conditions.
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10.1002/anie.202001262
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COMMUNICATION
intermediate II can deliver sulfonyl radical III, which undergoes
further cyclization to give intermediate IV. Finally, further anodic
oxidation followed by aromatization affords the corresponding
product.
In summary, we have developed an unprecedented
electrochemical
trifluoromethylation/SO2-insertion/cyclization
process in an undivided cell. By utilizing Langlois reagent as CF3
and SO2 sources, this protocol enabled efficient construction of
various trifluoromethylated cyclic N-sulfonylimines from readily
accessible materials in a single operation in an atom-economic
Scheme 2. Electrochemical difluoromethylation/SO2-insertion/cyclization
sequence of 1a and 2b.
fashion.
The
difluoromethylation/SO2-insertion/cyclization
sequence and synthetic application were also demonstrated. We are
currently studying the application of this approach to other
sulfonylative reactions.
To evaluate the potential application of this protocol, the
electrolytic reaction of 1a (7.5 mmol, 1.29 g) with 2a could be
performed on a gram scale with acceptable yield (1.03 g, 45%)
(Scheme 3).[15] On the other hand, cyclic N-sulfonylimine 3a could
be readily converted to functionalized trifluoromethylated cyclic
sulfonamides (12 and 13) by using LiAlH4 and Grignard reagent
respectively.
Acknowledgments
We gratefully acknowledge financial support from the NSFC (no.
21772063).
Conflict of interest
The authors declare no conflict of interest.
Keywords: Electrochemical reaction • trifluoromethylation •
SO2-insertion • cyclization • atom-economy
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the Supporting Information for details.
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10.1002/anie.202001262
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Zheng Li, + Lingcong Jiao, + Yunhai Sun,
Zeying He, Zhonglin Wei, Wei-Wei Liao*
Page No. – Page No.
CF3SO2Na Acted as a Bifunctional
Reagent: Electrochemical
Trifluoromethylation of Alkenes
Accompanied by SO2-Insertion to
Access Trifluoromethylated Cyclic N-
Sulfonylimines
Text for Table of Contents
Two birds with one stone: An electrochemical trifluoromethylation/SO2-insertion/cyclization process is presented in an undivided
cell in an atom-economic fashion. Various trifluoromethylated cyclic N-sulfonylimines can be readily accessed from readily available
materials by using Langlois reagent as CF3 and SO2 sources in a single operation under direct anodically oxidative conditions.
This article is protected by copyright. All rights reserved.