Electrooxidative Metal-Free Dehydrogenative α-Sulfonylation of 1H-Indole with Sodium Sulfinates

Article abstract of DOI:10.1002/ejoc.201700269

A method for the electrochemical α-sulfonylation of 1H-indole with arenesulfinates was developed. A variety of indoles underwent this sulfonylation smoothly at room temperature under metal-free and chemical-oxidant-free conditions to afford indolyl aryl sulfones in good to high yields. This reaction was found to tolerate a variety of functional groups, including halides and cyclopropyl, ether, ester, and aldehyde groups. It was applied to the synthesis of biologically active 5-HT6 modulators.

Full text of DOI:10.1002/ejoc.201700269

A Journal of
Accepted Article
Title: Electrooxidative Metal-free Dehydrogenative ꢀ-Sulfonylation of
1-H-Indole with Sodium Sulfinates
Authors: Xiao-Qi Yu, Mei-Lin Feng, Long-Yi Xi, and Shan-Yong Chen
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10.1002/ejoc.201700269
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Electrooxidative Metal-free Dehydrogenative -Sulfonylation of 1-H-Indole with
Sodium Sulfinates
Mei-Lin Feng, Long-Yi Xi, Shan-Yong Chen* and Xiao-Qi Yu*[a]
toxic reagents under mild conditions.
Abstract: An electrochemical -sulfonylation of 1-H-indole with
arenesulfinates has been developed. A variety of indoles underwent
this sulfonylation smoothly at room temperature under metal- and
chemcial oxidant-free conditions, affording indolyl aryl sulfones in
good to high yields. This reaction tolerates a variety of functional
groups including halides, cyclopropyl, ether, ester and aldehyde. It
can be applied to the syntheis of biologically active 5-HT6
modulators.
Introduction
Organic electrosynthesis, which employs electrons as
reagents, presents an attractive alternative to traditional
chemical processes in a large apart owing to the fact that the
former uses less chemical reagents and generates less waste
than the latter. Dehydrogenative coupling serves as a step- and
atom-economical method for building complex molecules. The
combination of electrolysis and dehydrogenative coupling
provides a new strategy for green organic synthesis. Therefore,
electrooxidative dehydrogenative coupling has gained increasing
interest in recent years.[1] In spite of these breakthroughs,
Figure 1. Examples of biologically active indolyl aryl sulfones.
electrooxidative dehydrogenative coupling was mainly applied to
constructing C-N or C-C bonds.[2] Reports on C-S formation
through electrooxidative dehydrogenative coupling are
Results and Discussion
especially rare.[3]
The heteroaromatic sulfone moiety exists widely in medicinally
active compounds, such as enzyme inhibitors,[4] antagonists,[5]
and antimicrobial agents.[6] Among them, indolyl aryl sulfones
have gained great attention due to their prominent biological
activity, such as serving as 5-HT6 modulators,[7] HIV-1 non-
nucleoside reverse transcriptase inhibitor,[8] Ca2+ antagonists in
cardiac myocytes,[9] canabinoid receptor angonisists(Figure 1).[10]
3-sulfonylindoles are traditionally prepared by oxidation of the
corresponding arylthioindole.[11] Direct sulfonylation of indoles
with aryl sulfonyl halides or aryl sulfonic acids is an alternative
approach for 3-sulfonylindoles.[12] It is well-known that the C3-
position of indoles has priority in functionalization over the C2-
position. Literature methods for the installation of the sulfur
moiety at the C2-position of indoles often involve multistep
synthesis and the use of highly dangerous alkyllithium reagents.
1-H-indole (1a) and sodium benzenesulfinate (2a) were chosen
to optimize reaction conditions. Initially, these two starting
materials
were
treated
in
a
solution
of
TBAI
(tetrabutylammonium iodide) and acetic acid in CH3CN/H2O (1:1)
mixture solvent in an undivided cell equipped with a pair of Pt foil
electrodes (0.25 cm2 each) under a constant current (10 mA) at
room temperature. After stirring for 8 h, indole transformed
completely and product 3a was obtained in a yield of 69% (Table
1, entry 1).The structure was confirmed by single-crystal X-ray
diffraction studies (Figure 2). [15] When LiClO4 was used as the
supporting electrolyte instead of TBAI, no obvious product
formation was observed (Data not shown), suggesting that TBAI
is not only a supporting electrolyte but also a catalyst. Changing
the current or increasing the amount of TBAI did not improve the
efficiency (Entries 2-4). We thought the low efficiency may result
from the oxidation of indole at high potential. Then we turned our
attention to performing this reaction under a constant potential.
After optimizing the potential we found that 1.5 V (vs Ag/AgCl)
gave the best result, affording the product in 81% yield (Entries
5-7). We further found the amount of TBAI can be reduced by
half (Entry 8 vs entries 7-9). Other iodide catalysts, such as NaI
and KI were sluggish (Entries 10-11). Attempts to reduce the
amounts of acetic acid or sulfinate as well as changing the
solvent were not successful. Finally, we found that the yield
increased to 92% when half volume of the mixture solvent was
used.
[13]
Recent limited examples afford an alternative method for the
synthesis of 2-sulfonylindoles. However, excess of oxidants and
large amounts of acid were required, which limit their application
in large scale preparation.[14] Herein we report
a
novel
electrooxidative
dehydrogenative
coupling
strategy to
exclusively generate 2-sulfonylindoles in good to high yields
using only a catalytic amount of TBAI and acetic acid without
[a]
M.-L. Feng, L.-Y. Xi, S.-Y. Chen, Prof. Dr. X.-Q. Yu
Key Laboratory of Green Chemistry and Technology, Ministry of
Education,
Department College of Chemistry,
Sichuan University
Chengdu, 610064, P. R. China
E-mail: chensy@scu.edu.cn
1
We monitored the reaction using H NMR and found that the
xqyu@scu.edu.cn
yield of 3a increased with time and the maximum appeared at
about 8 h (Figure 3).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700269
European Journal of Organic Chemistry
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Table 1. Optimization of reaction conditions.[a]
oxidation has its unique advantage over current chemical
process.
Catalyst
(mol %)
Currency
Potential
Yiled
[%][b]
Entry
Solvent
1
TBAI (40)
TBAI(40)
TBAI(80)
TBAI(40)
TBAI(40)
TBAI(40)
TBAI(40)
TBAI(20)
TBAI(10)
NaI(20)
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
H2O
10 mA
5 mA
10 mA
10 mA
1.5 V
1 V
69
2
35
3
66
4[c]
5
56
81
6
65
Figure 3. Concentration profile of 3a during the electrolysis process.
Table 2. The scope of indole substrates.[a]
7
2.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
1.5 V
81
8
81
9
15
10
11
12[d]
13[e]
14
15
16[g]
17[h]
20
KI(20)
39
TBAI(20)
TBAI(20)
TBAI(20)
TBAI(20)
TBAI (20)
TBAI (20)
76
70
trace
trace
67
Ionic liquid[f]
CH3CN/H2O
CH3CN/H2O
92
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), acetic acid (0.5 mmol),
CH3CN (4 mL), H2O (4 mL), Ag/AgCl as the reference electrode at room
temperature, 8 h. [b] Isolated yield. [c] 0.75 mmol of 2a. [d] Acetic acid (0.6
mmol). [e] Acetic acid (0.3 mmol). [f] 1-Butyl-3-methylimidazolium
tetrafluoroborate. [g] 1.5 equiv of 2a (0.45 mmol). [h] CH3CN (2 mL), H2O (2
mL).
Figure 2. X-ray structure of the product 3a.
The optimal reaction conditions were then applied to various
indoles as summarized in Table 2. A variety of indoles bearing
electron-donating or electron-withdrawing groups underwent
smoothly, affording the corresponding products in moderate to
good yields. When C2-position of the indole ring was occupied,
only trace of 3-indoyl sulfone was detected (3f), indicating that
this electrochemical oxidative sulfonylation was highly selective
for the C2-position. This reaction tolerates a variety of functional
groups including halides, ether, ester and aldehyde (3g-3l, 3o
and 3p). Halogen-containing indoles gave indolyl aryl sulfones in
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), TBAI (0.06 mmol), acetic
acid (0.5 mmol), CH3CN (2 mL), H2O (2 mL), Pt foil electrodes (0.25 cm2 each),
Ag/AgCl as the reference electrode, constant potential (1.5 V vs Ag/AgCl),
undivided cell, air, room temperature, 8h. Isolated yield.
moderate
yields,
providing
opportunity
for
further
Several sodium arenesulfinates containing weak electron-
withdrawing and electron-donating functionalities were also
evaluated. Most of the tested substrates afforded the
functionalization (3g-3l). It is well-known that aldehyde group is
hardly kept in a chemical oxidation. While, aldehyde functional
group survived in this process (3o), showing electrochemical
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10.1002/ejoc.201700269
European Journal of Organic Chemistry
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corresponding products in good to excellent yields. Functional
groups such as halides, ester and cyclopropyl could survive well
sodium benzene sulfinate, affording 5c in 62% yield. This
method avoids the protection step and the use of dangerous
under the standard reaction condition (Table 3, 4e, 4f, 4i and 4k). reagents.
Sodium 2-naphthalenesulfinate and sodium 2-thiophenesulfinate
also gave indolyl aryl sulfones in good yields (4d and 4g). In
addition, alkyl sulfinate, such as methyl and cyclopropyl
underwent smoothly, affording the corresponding indolyl alkyl
sulfones in excellent yields (4j and 4k). Sodium
trifluoromethanesulfinate and sodium 4-nitropheny sulfinate did
not undergo this transformation (date not shown).
Table 3. The scope of sulfinates.[a]
Scheme 2. Electrochemical synthesis of the precursor of 5d.
It has been known that unsaturated system can be
sulfonylated through a radical process. [17] To gain insight into
the mechanism, competition reactions between styrene and
indole with sodium benzene sulfinate were carried out. Vinyl
sulfone and indolyl sulfone were isolated in 8% and 33% yields
respectively using 2a as the limiting reagent. However, the yield
of vinyl sulfone was high up to 99% in the presence of excess 2a
(Scheme 3). We suspected that a sulfonyl radical might be
involved.
Scheme 3. Competition reactions.
A gram scale reaction was conducted to assess the
scalability of this electrochemical sulfonylation under standard
condition in a beaker (Scheme 1). Indolyl aryl sulfone 3a was
obtained in 70% yield, which was only slightly decreased in
comparison with that of a smaller scale.
Based on the above experimental results and literatures, [14]
a
possible mechanism was outlined in Scheme 4. Firstly,
sulphonyl radical A is directly generated from sulfinate through
electrolysis in the presence of acetic acid.[18] And then the
addition of the sulphonyl radical to indole affords an intermediate
radical B. This radical is stabilized by the p-conjugation, which
is responsible for the selectivity for the C2-position. The reaction
of B with I2 generated through electrolysis at the anode affords
intermediate C. Lastly, the elimination of HI gives the product 3a.
[19] Protons are reduced at the cathode to release H2.
[a] Reaction conditions: 1a (10 mmol), 2a (20 mmol), TBAI (20 mol%), acetic
acid (16 mmol), CH3CN (66 mL), H2O (66 mL), Pt foil electrodes (1.5 cm2
each), Ag/AgCl as the reference electrode, constant potential (1.5 V vs
Ag/AgCl), undivided cell, air, room temperature, 36h. Isolated yield.
Scheme 1. Gram scale synthesis of 3a. [a]
To demonstrate the utility of this electrochemical sulfonylation,
we applied it to prepare biologically active molecules.
Compound 5d can serve as the 5-HT6 receptor modulator. The
reported method to prepare 5d requires the protection of the
amino group on the indole ring and the use of a dangerous
reagent sec-BuLi. [16] Even so, only 10% yield of 5c was obtained
(based on 5b). In our method, 5b was directly sulfonylated with
Scheme 4. Proposed radical mechanism.
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10.1002/ejoc.201700269
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8 hours, electrodes were removed. A saturated Na2S2O3 solution
(30 mL) and ethyl acetate (30 mL) were added to the resulted
mixture. The phases were separated and the aqueous phase
was extracted with ethyl acetate (2 x 30 mL). The combined
organic solution was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was
chromatographed through silica gel eluting with ethyl
acetate/hexanes to give the product.
On the other hand, during the process, we observed the
formation of 3-iodo-1H-indole (see Supporting information),
which could react with azole nucleophiles to afford 2-(azol-1-
yl)indoles according to
a
previous report by Beaulieu.[20]
Therefore, we suspected that sodium benzenesulfinate also
reacted with 3-iodo-1H-indole in the same mode. The reaction of
1a with 1b did give product 3a in 60% yield by stirring the
mixture under nitrogen atmosphere without electricity (Scheme
5). We further observed the formation of 3-iodo-1H-indole in the
absence of 2a during electrolysis. Based on the above results,
another possible mechanism was proposed (Scheme 6). The
iodogenation of indole gives 3-iodo-1H-indole during the
Acknowledgements
electrolysis. Subsequent protonation of 3-iodo-1H-indole affords
This work was supported financially by the National Program on
Key Basic Research Project of China (973 Program,
2013CB328905) and the National Science Foundation of China
(Grant 21202107).
[20]
a
cationic intermediate D,
which then interacts with
nucleophilic 2a and gives intermediate C. The release of HI
furnishes the desired product 3a.
Keywords: electrochemical oxidation
•
sulfonylation
•
electrolysis • indolyl sulfone • dehydrogenative coupling
Scheme 5. The reaction of 3-iodo-1H-indole with 2a.
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Scheme 6. Another possible mechanism.
Conclusions
In conclusion, we have developed an electrochemical -
sulfonylation of 1-H-indoles with sodium sulfinates under metal-
and chemical oxidant-free conditions. This reaction tolerates a
variety of functional groups including halides, ether, ester and
aldehyde. This transformation can be applied to the synthesis of
biologically active 5-HT6 modulators. In comparison with the
current chemical synthesis, this sulfonylation have great
advantages including step-economy, good efficiency and
avoiding the use of highly dangerous reagents.
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Experimental Section
The electrochemical sulfonylation of 1a with 2a: The
electrolysis was carried out in a one-compartment cell. Pt foils
(0.25 cm2 each) were chosen as the electrodes and an Ag/AgCl
served as the reference electrode. To a one-compartment cell
were added 1a (0.3 mmol), 2a (0.6 mmol), n-(Bu)4NI (0.06 mmol)
acetic acid (0.5 mmol), CH3CN (2 mL), H2O (2 mL). The solution
was electrified under a constant potential of 1.5 V (vs Ag/AgCl)
at room temperature under air atmosphere. After electrolysis for
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[18] The sulfonyl radical may result from the hemolytic cleavage of sulfonyl
iodine generated in situ from the reaction of sulfinate and iodine.
[19] The standard electrode potential of I-/I2 is 0.535V.
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10.1002/ejoc.201700269
European Journal of Organic Chemistry
FULL PAPER
Mei-Lin Feng, Long-Yi Xi,
Shan-Yong Chen* and Xiao-Qi
Yu*
Page No. – Page No.
ElectrochemicalSulfonylation of indoles: An electrochemical -sulfonylation of
1-H-indole with arenesulfinates was developed. A variety of indoles underwent this
sulfonylation smoothly at room temperature under metal-free conditions, affording 2-
indolyl sulfones in good to high yields. This reaction tolerates a variety of functional
groups including halides, cyclopropyl, ether, ester and aldehyde.
Metal-free Electrochemical -
Sulfonylation of 1-H-indole with
Arenesulfinates
This article is protected by copyright. All rights reserved.