Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides

Article abstract of DOI:10.1002/chem.202001815

Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.

Full text of DOI:10.1002/chem.202001815

Accepted Article
Accepted Article
Title: Electrophilic Chlorine from Chlorosulfonium Salts: A Highly
Chemoselective Reduction of Sulfoxides
Authors: Paola Acosta-Guzmán, Camilo Mahecha-Mahecha, and
Diego Gamba-Sánchez
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001815
Link to VoR: https://doi.org/10.1002/chem.202001815
01/2020

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
Electrophilic Chlorine from Chlorosulfonium Salts: A Highly
Chemoselective Reduction of Sulfoxides
Paola Acosta-Guzmán,[a] Camilo Mahecha-Mahecha[a] and Diego Gamba-Sánchez*[a]
[a]
Dr. P. Acosta-Guzmán, M.Sc. C. Mahecha-Mahecha, Dr. D. Gamba-Sánchez
Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department
Universidad de los Andes
Cra 1 No. 18A-12 Q:305. Bogota 111711 (Colombia)
E-mail: da.gamba1361@uniandes.edu.co
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we describe a selective late-stage deoxygenation
of sulfoxides based on a novel application of chlorosulfonium salts
and, a new process using them generated in situ from sulfoxides as
the source of electrophilic chlorine. The use of highly nucleophilic
1,3,5-trimethoxybenzene (TMB) as the reducing agent is described
for the first time and applied successfully in the deoxygenation of
simple and functionalized sulfoxides. The method is easy to handle,
economic, appropriate for gram scale and decidedly appropriate for
poly-functionalized molecules, as demonstrated with more than 45
examples, including commercial medicines and analogues. We also
report some competition experiments to define the more reactive
sulfoxide and a mechanistic proposal based on substrate and product
observations.
reducing agent is molecular hydrogen (produced in situ or
inserted), are usually catalyzed by expensive transition metal
catalysts and are impractical with unsaturated or reducible
functions; reductions, (Scheme 1b)[13e-h] when the reducing agent
is a hydride, usually a silane, and catalysts include boron
compounds or transition metals; the functional group tolerance for
reductions is fairly poor since other electrophilic groups react with
the reductive mixture. Finally, deoxygenations,[13i-p] (Scheme 1c)
which are promoted by the activation of a sulfoxide with strong
electrophiles, need low temperatures and, in most cases,
stoichiometric amounts of base. An alternative photocatalytic
deoxygenation was described very recently.[13q] It is noteworthy
that deoxygenations methods produce strong acids, making them
traditionally incompatible with labile acid and nucleophilic
functional groups. In addition, an oxygen trap or a reducing agent
is also in the reaction mixture.
Introduction
a. Hydrogenation
H2
Pd, Ru, Fe Catalyst
Organosulfur compounds, particularly sulfides, are found in
nature[1] and produced synthetically;[2] their significance is
undeniable in many fields, including biochemistry,[3]
agrochemistry and organic materials,[4] among others.[5] Many
sulfides are also used as therapeutic agents[6] or as synthetic
intermediates.[7] Despite the major advances in sulfur organic
chemistry, the discovery of practical methods for making mutual
transformations between oxygenated functional groups is an area
of continuous growth, and amazing results continuously appear in
the literature.[8]
b. Reduction
R3SiH
O
O
S
R1 R2
S
S
R1 R2
R1 R2
Cat.
R3SiOSiR3 + H2
c. Deoxygenation
E+, Oxygen trap (Y)
(COCl)2
CO2, CO, Cl-
EOY
The direct relationship among sulfides, sulfoxides and
sulfones has promoted the development of valuable methods for
Cl
TMB
Key
d. Dehalogenation
selective sulfur oxidation in sulfides to sulfoxides[9] or sulfones[10]
;
S
Intermediate
R1 R2
unfortunately, the reduction of oxygenated functional groups to
sulfides has suffered from several drawbacks,[11] principally the
unsatisfactory chemoselectivity. Insufficient chemoselectivity is
particularly important since several sulfides and sulfoxides are
used in current medicine and their oxidation or reduction is
necessary for metabolic studies of these active molecules.[12]
Unfortunately, the current methods for sulfoxide reductions are
based on the use of highly electrophilic reagents, making them
unsuitable for late-stage transformations.[13]
During the course of our research program, we became
interested in the chemoselective reduction of highly functionalized
sulfoxides. Regrettably, we could not find a general and
inexpensive method applicable in late-stage transformations.
Actually, the existing methods to reduce sulfoxides can be divided
in three categories: hydrogenations (Scheme 1a),[13a-c] when the
2-Cl-TMB
Scheme 1. Traditional reduction of sulfoxides and association with our
approach.
Inspired by the abovementioned difficulties, we report herein
the development of a new (Scheme 1d), practical, economic and
highly chemoselective method for the reduction of sulfoxides that
can be easily applied to polyfunctionalized substrates. The
reported method is compatible with oxygen- and nitrogen-
protecting groups, unsaturated functional groups, chiral centers
near the sulfoxide, and most importantly, can be applied in late-
stage functionalization, as demonstrated with commercial drugs,
drug precursors and some drug derivatives. This method is based
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
on the use of oxalyl chloride (COCl)2, which reacts as an
electrophile and as a chloride source to produce an intermediate
chlorosulfonium salt (the key intermediate in Scheme 1d). Then,
1,3,5-trimethoxybenzene (TMB) is used as a chlorine trap,
producing a chlorinated aromatic and equimolar amounts of
hydrogen chloride. In other words, we propose the use of
(COCl)2/TMB as the reductive couple.
the ketone as the oxidized functional group. Previously, we have
described an intramolecular reductive chlorination of some
special sulfoxides,[15] but we did not identify the utility of
chlorosulfonium salts in intermolecular reductions. Herein, we
hypothesize that using strong nucleophilic aromatics could
eliminate the use of the base (Scheme 2b). Put differently, we
propose the use of aromatics as reducing agents, and the re-
aromatization step of an electrophilic aromatic substitution as the
driving force for the reduction of sulfoxides. Sulfonium salt II is
somehow stable at temperatures below -60ºC, so carrying out the
reaction at higher temperatures should promote the spontaneous
generation of chlorosulfonium salt V by the nucleophilic reaction
of chlorine with II. Then, the reaction of V with the aromatic should
be fast enough to prevent the spontaneous degradation of the
sulfonium. Consequently, the temperature may be higher than in
previous methods, thus making our proposal inexpensive for large
scale operations. The use of chlorosulfonium salts as the source
of electrophilic chlorine is fairly rare.[16] Usually, the reaction of
halosulfonium salts with nucleophiles leads to the substitution on
the more electrophilic sulfur atom, generating another sulfonium
salt;[7d] it has been described as the spontaneous degradation of
halosulfonium salts by the action of nucleophilic halides to
generate molecular halogens and the corresponding sulfide.[16b]
However, the yields of sulfides are very low, and the reaction
needs alkenes as halogen scavengers. Halogenations of
aromatics with halosulfonium salts have only recently appeared
in the literature[17] and apparently evolve by the in situ formation
of molecular halogens. However, their potential application as
halogenating agents needs
a good balance between the
electrophilic character of the halogen linked to the sulfur and the
nucleophilic character of the aromatic counterpart.
Results and Discussion
Scheme 2. Mechanistic hypothesis and comparison between previous studies
and the current work.
Table 1. Optimization Experiments[a]
Graczyk and coworkers[13k] vaguely explored the use of oxalyl
chloride in combination with low-molecular weight alcohols in the
deoxygenation of sulfoxides. The method was based on the
mechanism of Swern oxidation;[14] basically, in this classic
reaction, DMSO is reduced by an alcohol, so the use of other
sulfoxides can be complemented with low molecular weight
alcohols. Unfortunately, this method has several drawbacks. First,
it uses excess organic bases and very low temperatures (-78ºC).
Also, the reaction is incompatible with aryl-aryl sulfoxides since,
according to the proposed mechanism, α-hydrogens on sulfur
atoms are imperative for the reaction; thus, α-chiral centers will
result in racemization. Our primary hypothesis is compared with
the previous work shown in Scheme 2.
As mentioned before, the methods based on electrophilic
activation need an oxygen trap, in other words, a reducing agent.
Scheme 2a shows the proposed mechanism for the
deoxygenation of sulfoxides promoted by (COCl)2/Et3N/iso-
propanol. The low temperature promotes the stability of sulfonium
salt II. The reaction of II with the nucleophilic secondary alcohol
helps in the formation of the sulfonium salt III, which has at least
one acidic proton. Therefore, the base is essential for carrying out
entry
(COCl)2:TMB:a1
1.2:1:1
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Yield (%) b1[b]
1
2
3
4
5
6
7
8
92
92[c]
90[d]
87
1.2:0.8:1
1.2:0.5:1
1:0.5:1
0.8:0.5:1
1.2:0.8:1
1.2:0.8.1
1.2:0.8:1
33[e]
49
Et2O
25
CHCl3
90
[a] All the reactions were performed at the 0.15M concentration of sulfoxide. [b]
Isolated yields. [c] Reaction time, 10 min. [d] Reaction time, 1 hour. [e] The
starting material was recovered after a reaction time of 8 hours.
the
deprotonation
to
IV,
and
the
intramolecular
Based on our previous observations, we reasoned that any
chlorosulfonium salt might be able to be used as a source of
protonation/deoxygenation leads to the sulfide as the product and
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
electrophilic chlorine if it can react with a very strong aromatic
nucleophile; different options appear plausible. However, 1,3,5-
trimethoxybenzene TMB is solid, inexpensive, stable to oxidation
in air, does not form stable radicals, is easy to handle, has low
toxicity, can be stored dry without special conditions and has three
reactive nucleophile positions. Therefore, TMB seems to be a
very good alternative to act as the chlorine scavenger. To our
delight, the reaction proceeded smoothly, and only few
experiments for optimization were required.
a base in the rearomatization producing HCl. Careful analysis of
the crude 1H NMR spectra showed variable amounts of 2-
chloroTMB and 2,4-dichloroTMB. However, the α-chlorinated
sulfide was not observed. This product has been described in the
absence of nucleophiles or in some reductions performed with
chlorinated reagents, such as SOCl2,[13m] since the Pummerer
reaction is often in competition when basic species are present.
The optimal conditions required a molar ratio of 1.2:0.8:1 (entry
2), and the reaction was completed within 10 minutes in excellent
yield. Changing the solvent to THF or ethyl ether resulted in lower
yields (entries 6 and 7), but CHCl3 can be used without a
significant loss of effectiveness. It is noteworthy that even if TMB
can accept three chlorine atoms, 2-chloroTMB is less nucleophilic
Table 1 shows the optimization of the reaction conditions. We
started
with
a
molar
ratio
of
1.2:1:1
(oxalyl
chloride:TMB:substrate). The reaction worked very well (entry 1),
so we decided to reduce the quantity of TMB (entries 2 and 3)
since each molecule has the ability to accept three chlorine atoms. than TMB. Consequently, with highly nucleophilic substrates, the
Reducing the quantity of TMB resulted in longer reaction times
but comparable yields. When decreasing the quantity of oxalyl
chloride, the yield dropped, and some starting material was
recovered (entries 4 and 5), showing that each molecule of oxalyl
chloride reacts only with one molecule of sulfoxide. Consequently,
the production of CO2, CO and Cl- is well supported. It is
noteworthy that the Cl- remains in solution and eventually acts as
use of low amounts of TMB should result in competitive reactions,
which is why we decided to use the conditions described in entry
2
in all subsequent experiments, even though we found
comparable results in entries 3 and 4. However, as we will
mention (vide infra), with highly nucleophilic substrates, we were
forced to increase the quantity of TMB to avoid the
aforementioned competition.
Scheme 3. Selective reduction of sulfoxides to sulfides. [a] One equiv. of TMB was used. [b] Approximately 10% of the doubly reduced product was observed. [c]
This product was obtained from the monosulfoxide. [d] Two point four equiv. of Et3N was added to the reaction mixture to neutralize the liberated HCl. [e] This
product was obtained from a21 without using Et3N. [f] The corresponding ester was obtained under the presence of low-molecular weight alcohols
According to these results, we started our study of the reaction
scope using simple sulfoxides. The results are summarized in
Scheme 3. The reaction with a2 was performed with two different
quantities of TMB; as we anticipated, using a molar ratio of
1.2:0.8:1 was problematic for deoxygenation since the substrate
is in competition with TMB. Consequently, a low yield was
observed. However, increasing the amount of TMB (molar ratio
1.2:1:1) allowed us to isolate compound b2 in good yield; this
particular issue was not observed in the reaction with less
activated (compound b3) or deactivated substrates (see products
b4-b6), and products were obtained in good to excellent yields.
Products b7 and b8 were isolated in very good yields and
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
therefore proved the compatibility of our method with unsaturated
functional groups. Also, these products are the first evidence of
our proposed mechanism since no chlorination of the double bond
was observed nor did chlorination occur in the allylic position. -
deprotonation in compounds a8 or b8 might produce the
corresponding allene, which was not observed. Aliphatic-aliphatic
sulfoxides were easily reduced (products b9, b10, b15, b16, b17
and b26). Compound b9 was obtained after the reduction of the
bis-sulfoxide. It is noteworthy that approximately 10% of the
doubly reduced product was observed. On the other hand, b10
was obtained from the monosulfoxide.
We then turned our attention to more functionalized and
potentially problematic substrates. Compatibility with commonly
used protecting groups is illustrated with compounds b11-b14 for
nitrogen-protecting groups and b15-b18 for oxygen-protecting
groups; in all cases, the desired sulfide was obtained in good yield
and no deprotection was observed, which is particularly important
for labile acid functional groups, such as small silylated groups
(TES in compound b18), in that case a small excess of
triethylamine is use to neutralize the HCl. Chemoselective
reduction of compounds a19 and a20 was accomplished without
any particular issue. The aldehyde functional group showed null
reactivity under the reaction conditions, as well as the ketone.
Acetal a21 required the addition of two equivalents of Et3N since
HCl is formed during the reaction; it cleaves the acetal, producing
aldehyde b22 in excellent yield. The addition of triethylamine
resulted in the easy isolation of acetal b21. Potentially reactive
functional groups such as free acids a23, free OH and NH2 groups
(sulfoxides a24 and a25) were also tested. Free carboxylic acids
may form the corresponding acyl chloride, making them
incompatible with previous deoxygenations since the
corresponding ester was isolated when low molecular weight
alcohols were added to the reaction mixture. Nevertheless,
product b23 was isolated in excellent yield when using alcohol-
free solvent. Free OH or NH2 groups are vulnerable to acylation
reactions when using acyl chlorides, so we were curious to see
whether any by-product was obtained in those cases. The careful
analysis of crude 1H NMR showed some products issued from
halogenation of the hydroxylated or aminated ring (as minor
products). Nonetheless, the addition of a small excess of TMB
(molar ratio 1.2:1:1) proved effective, affording the corresponding
sulfides b24 and b25 in good yields. We then turned our attention
to amino acid derivatives and found very good results (product
b26). The use of sulfoxides without -hydrogens was impossible
with the previous use of oxalyl chloride; in our case, the reaction
proceeded smoothly with compounds a27, a28 and a29. With the
use of an aromatic sulfoxide, compound a27 was reduced to the
corresponding sulfide, giving further evidence of our proposed
mechanism; on the other hand, substrates a28 and a29 may be
problematic since conjugated additions or vinylogous Pummerer
reactions may be in competition. Fortunately, the sulfides b28 and
b29 were obtained as the sole products and in good yields.
Scheme 4. Selective reduction of more complex sulfoxides. [a] The reaction was carried out in CHCl3 as the solvent because of the low solubility of the substrate
in CH2Cl2. [b]The reaction was performed at the 1 g scale.
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
Oxalyl chloride has been used as an activator in Pummerer
reactions.[15, 18] In these types of reactions, -chlorinated sulfides
were observed, demonstrating that they can react with Lewis
acids or bases, leading to the formation of thionium ions or
nucleophilic substitutions. According to careful analysis of the
crude 1H NMR spectra in all the cases described in Scheme 3, we
hypothesize that the addition of TMB to the chlorosulfonium
intermediate is so fast that the Pummerer reaction does not occur
in this context. Nonetheless, even if we did not observe an -
chlorosulfide in any of the previous examples, we were curious to
determine the behavior of our method with sulfoxides that can
undergo a Pummerer cyclization reaction, that is, with substrates
that can produce something more stable than chlorinated sulfides.
On the other hand, it was also necessary to demonstrate the
compatibly of the method with highly functionalized molecules
and with asymmetric centers near the sulfur atom. Consequently,
we performed the reduction on several sulfoxides issued from
commercial drugs and some other sulfoxides described
previously as suitable Pummerer substrates.
The results are summarized in Scheme 4. All the products
showed great reactivity, and sulfoxides a30-a43 were
deoxygenated in good to excellent yields. Product b30 was
obtained without racemization, providing the third piece of
evidence of our proposed mechanism since any alternative route
should result in the loss of stereochemistry in the chiral center.
Moreover, sulfoxides a31 to a35 have been described previously
as being reactive in Pummerer reactions, producing oxazolines or
chromanes and thus preventing alternative proposals for
mechanisms via thionium ions. Product b35 also proved the
compatibility of this method with the Fmoc protecting group.
Proton pump inhibitors used for the treatment of
gastroesophageal reflux, peptic ulcers and Zollenger-Ellison
syndrome, such as a36 and a37 (omeprazole[19] and
lansoprazole,[20] respectively), were reduced in very good yields,
obtaining the corresponding sulfides b36 and b37. These
molecules, along with albendazole,[21] b38, a medicine used to
treat parasitic infections, showed the compatibility of our method
with nitrogen-heterocycles, small carbamates and basic
functional groups.
pressure, in some cases for diabetic kidney disease and hearth
failure; a41 was reduced in very good yield. Quinine[26]
modification afforded a42, and its reduction produced the
corresponding sulfide b42 as the sole product in excellent yield;
quinine is an antimalaria used mainly for infections produced by
Plasmodium Falciparum which is resistant to chloroquine or when
other drugs are not available.[27] It is noteworthy that malaria is an
infectious disease touching mainly the developing countries;[28]
consequently, the production of synthetic analogues of
commercial antimalarials seems a primary approach to partially
address this important issue; also, quinine is an essential
medicine worldwide and among the most effective and safest
pharmaceuticals. Finally, we obtained a43 from commercial
lovastatin,[29] a medication from the statins group used to reduce
the risk of cardiovascular diseases by reducing high cholesterol.
The reduction of the synthetic analogue was accomplished with
excellent results, yielding b42.
Finally, we turned our attention to competition experiments.
During the course of our research, we observed that, even if the
common reaction time was 10 min, some substrates were
completely consumed in shorter reaction times. Consequently, we
performed three experiments to determine the selectivity between
different kinds of sulfoxides and between sulfoxides and sulfones.
The results of these experiments are summarized in Scheme 5;
as expected, the reaction is completely selective to sulfoxides
over sulfones (product b44). This was easily predictable since
sulfones are less nucleophilic than sulfoxides, and their reduction
usually requires metallic hydrides[30] (Scheme 5a). The
competition between dialkyl sulfoxides and alkyl-aryl sulfoxides
proved slightly difficult. Clearly, alkyl-aryl sulfoxide reacts faster
than dialkyl sulfoxide (see product b45); however, approximately
15% of the doubly reduced product was observed. On the other
hand, the reaction of alkyl-aryl sulfoxides over diaryl sulfoxides is
much faster and completely selective (product b46). These
results also indicate that dialkyl sulfoxides react faster than diaryl
sulfoxides.
The sulfoxide a39 was obtained by the derivatization of
podophyllotoxin,[22] a nonalkaloid natural toxin used in the
treatment of genital warts and molluscum contagiosum. a39 was
reduced selectively over other oxygenated functional groups
without affecting the highly activated aromatic rings. One of the
most important issues in the reduction of sulfoxides is the use of
expensive or highly toxic reagents or catalysts. Therefore,
performing the reaction at a large scale (grams) is potentially
problematic for the researcher and the environment. Also, if the
molecule is highly functionalized, it can be very awkward from an
economical point of view since most of the methods use strong
reaction conditions. Keeping all these issues in mind, we
performed the reduction of a39 at the gram scale with comparable
success to the reaction performed at the milligram scale, and
negligible quantities of by-products were observed. We also
obtained the testosterone derivative a40. Testosterone is the
principal male sex hormone, it is used as a medication for the
treatment of some types of breast cancer,[23] so analogues may
have a potential as anticancer new drugs.[24] The reduction of a40
proceeded smoothly yielding b40 in excellent yield. Continuing
with our exploration of late-stage reductions we used the losartan
derivative a41; losartan[25] is a medication used to treat high blood
Scheme 5. Competition experiments [a] Approximately 15% of the doubly
reduced product was observed.
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
247; e) V. H. Le, M. Inai, R. M. Williams, T. Kan, Nat. Prod. Rep. 2015,
32, 328-347.
Conclusion
[2]
See, for instance: a) S. A. Vizer, E. S. Sycheva, A. A. A. Al Quntar, N. B.
Kurmankulov, K. B. Yerzhanov, V. M. Dembitsky, Chem. Rev. 2015, 115,
1475-1502; b) T. Kondo, T.-a. Mitsudo, Chem. Rev. 2000, 100, 3205-
3220; c) P. Chauhan, S. Mahajan, D. Enders, Chem. Rev. 2014, 114,
8807-8864; d) V. Tyagi, G. Sreenilayam, P. Bajaj, A. Tinoco, R. Fasan,
Angew. Chem. Int. Ed. 2016, 55, 13562-13566; Angew. Chem. 2016, 128,
13760-13764; e) H. Wang, Q. Lu, C. Qian, C. Liu, W. Liu, K. Chen, A.
Lei, Angew. Chem. Int. Ed. 2016, 55, 1094-1097; Angew. Chem. 2016,
128, 1106-1109; f) H. Li, C. Shan, C.-H. Tung, Z. Xu, Chem. Sci. 2017,
8, 2610-2615; g) C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. A. Hor, X. Liu,
Chem. Soc. Rev. 2015, 44, 291-314; h) X.-C. Liu, X.-L. Chen, Y. Liu, K.
Sun, Y.-Y. Peng, L.-B. Qu, B. Yu, ChemSusChem 2020, 13, 298-303.
a) K. L. Dunbar, D. H. Scharf, A. Litomska, C. Hertweck, Chem. Rev.
2017, 117, 5521-5577; b) C. Jacob, Nat. Prod. Rep. 2006, 23, 851-863;
c) R. Bentley, Chem. Soc. Rev. 2005, 34, 609-624.
In summary, we describe a simple, inexpensive and highly
chemoselective method for the deoxygenation of sulfoxides. The
method is compatible with many other reducible functional groups
and can be applied at any stage of synthesis, including late stages.
The most important result of this investigation is the use, for the
first time, of a tandem sulfoxide activation and an electrophilic
aromatic substitution as the reduction reaction. The oxidized
functional group, in this case, is a chlorinated aromatic that can
be easily separated from the reaction mixture. The efficiency of
this method was illustrated with more than 45 examples, including
commercial drugs as substrates and as precursors. The
uniqueness of this method might facilitate its application in other
deoxygenations in both industry and academia as well as in the
development of new halogenation reactions. Related studies are
currently ongoing in our laboratory.
[3]
[4]
a) G. E. Poirier, Chem. Rev. 1997, 97, 1117-1128; b) T.-J. Yue, W.-M.
Ren, L. Chen, G.-G. Gu, Y. Liu, X.-B. Lu, Angew. Chem. Int. Ed. 2018,
57, 12670-12674; Angew. Chem. 2018, 130, 12852-12856; c) J. Guo, Y.
Cao, R. Shi, G. I. N. Waterhouse, L.-Z. Wu, C.-H. Tung, T. Zhang, Angew.
Chem. Int. Ed. 2019, 58, 8443-8447; Angew. Chem. 2019, 131, 8531-
8535.
Experimental Section
[5]
[6]
X. Jiang, Sulfur Chemistry, Vol. Topics in Current Chemistry, Springer,
Berlin, 2018.
General procedure for deoxygenation of sulfoxides: To a solution
of the corresponding sulfoxide (1 equiv.) in dry DCM (0.15 M) at
0°C, trimethoxybenzene (0.8 equiv.) and oxalyl chloride (1.2
equiv.) were added. The mixture was stirred at the same
temperature for around 10 minutes (complete conversion was
checked by TLC). The reaction was neutralized with NaOH (1M).
The aqueous layer was extracted with DCM (3 x 15 mL), the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude mixture was purified using flash
chromatography to afford the pure product. The products were
obtained with yields between 61 and 97%.
a) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57, 2832-
2842; b) B. Li, F. Zheng, J.-P. R. Chauvin, D. A. Pratt, Chem. Sci. 2015,
6, 6165-6178; c) P. Rose, M. Whiteman, P. K. Moore, Y. Z. Zhu, Nat.
Prod. Rep. 2005, 22, 351-368.
[7]
[8]
[9]
a) L. Wang, W. He, Z. Yu, Chem. Soc. Rev. 2013, 42, 599-621; b) T.
Castanheiro, J. Suffert, M. Donnard, M. Gulea, Chem. Soc. Rev. 2016,
45, 494-505; c) S. Otocka, M. Kwiatkowska, L. Madalińska, P.
Kiełbasiński, Chem. Rev. 2017, 117, 4147-4181; d) D. Kaiser, I. Klose,
R. Oost, J. Neuhaus, N. Maulide, Chem. Rev. 2019, 119, 8701-8780; e)
K. Gao, H. Yorimitsu, A. Osuka, Angew. Chem. Int. Ed. 2016, 55, 4573-
4576; Angew. Chem. 2016, 128, 4649-4652; f) J. Santandrea, C. Minozzi,
C. Cruché, S. K. Collins, Angew. Chem. Int. Ed. 2017, 56, 12255-12259;
Angew. Chem. 2017, 129, 12423-12427; g) S. Otsuka, K. Nogi, H.
Yorimitsu, Angew. Chem. Int. Ed. 2018, 57, 6653-6657; Angew. Chem.
2018, 130, 6763-6767; h) F. Dénès, C. H. Schiesser, P. Renaud, Chem.
Soc. Rev. 2013, 42, 7900-7942; i) B. Cheng, Y. Li, T. Wang, X. Zhang,
H. Li, Y. Li, H. Zhai, Chem. Commun. 2019, 55, 14606-14608.
Selected examples for switchable oxidations to sulfoxides and sulfones:
a) Y. Li, S. A.-e.-A. Rizvi, D. Hu, D. Sun, A. Gao, Y. Zhou, J. Li, X. Jiang,
Angew. Chem. Int. Ed. 2019, 58, 13499-13506; Angew. Chem. 2019, 131,
13633-13640; b) K.-J. Liu, J.-H. Deng, J. Yang, S.-F. Gong, Y.-W. Lin,
J.-Y. He, Z. Cao, W.-M. He, Green Chem. 2020, 22, 433-438; c) Z. Cheng,
P. Sun, A. Tang, W. Jin, C. Liu, Org. Lett. 2019, 21, 8925-8929; d) G.
Laudadio, N. J. W. Straathof, M. D. Lanting, B. Knoops, V. Hessel, T.
Noël, Green Chem. 2017, 19, 4061-4066; e) X. Lang, W. R. Leow, J.
Zhao, X. Chen, Chem. Sci. 2015, 6, 1075-1082; f) S. Doherty, J. G.
Knight, M. A. Carroll, J. R. Ellison, S. J. Hobson, S. Stevens, C. Hardacre,
P. Goodrich, Green Chem. 2015, 17, 1559-1571; g) F. Brockmeyer, J.
Martens, ChemSusChem 2014, 7, 2441-2444; h) B. Karimi, M. Khorasani,
ACS Catal. 2013, 3, 1657-1664.
Acknowledgements
Financial support for this work was provided by The Faculty of
Science of Universidad de los Andes (INV-2019-84-1813). P. A.-
G and C. M.-M acknowledge the Universidad de los Andes and
especially the Chemistry Department for their fellowships. Pierre
Hubert, Alvaro Rodriguez-Lopez and Sandra Ortiz are
acknowledged for the isolation of some starting materials,
preliminary experiments and HRMS studies, respectively.
Conflict of Interest
a) H. Hao, Z. Wang, J.-L. Shi, X. Li, X. Lang, ChemCatChem 2018, 10,
4545-4554; b) X. Chen, K. Deng, P. Zhou, Z. Zhang, ChemSusChem
2018, 11, 2444-2452; c) D. Chao, M. Zhao, ChemSusChem 2017, 10,
3358-3362; d) A. Casado-Sánchez, R. Gómez-Ballesteros, F. Tato, F. J.
Soriano, G. Pascual-Coca, S. Cabrera, J. Alemán, Chem. Commun.
2016, 52, 9137-9140; e) X. Lang, W. Hao, W. R. Leow, S. Li, J. Zhao, X.
Chen, Chem. Sci. 2015, 6, 5000-5005; f) G. K. Surya Prakash, A.
Shakhmin, K. E. Glinton, S. Rao, T. Mathew, G. A. Olah, Green Chem.
2014, 16, 3616-3622; g) S.-I. Murahashi, D. Zhang, H. Iida, T. Miyawaki,
M. Uenaka, K. Murano, K. Meguro, Chem. Commun. 2014, 50, 10295-
10298; h) A. Bottoni, M. Calvaresi, A. Ciogli, B. Cosimelli, G. Mazzeo, L.
Pisani, E. Severi, D. Spinelli, S. Superchi, Adv. Synth. Catal. 2013, 355,
191-202; i) P. Zhang, Y. Wang, H. Li, M. Antonietti, Green Chem. 2012,
There are no conflicts to declare.
Keywords: Chemoselectivity • Deoxygenation • sulfides •
Sulfonium salts • sulfoxides
[1]
Selected examples of naturally occurring sulfides can be found in: a) C.-
R. Jan, H.-R. Lo, C.-Y. Chen, S.-Y. Kuo, J. Nat. Prod. 2012, 75, 2101-
2107; b) R. X. Tan, P. R. Jensen, P. G. Williams, W. Fenical, J. Nat. Prod.
2004, 67, 1374-1382; c) C. S. Kim, J. Oh, L. Subedi, S. Y. Kim, S. U.
Choi, K. R. Lee, J. Nat. Prod. 2018, 81, 2129-2133; d) O. Goethe, A.
Heuer, X. Ma, Z. Wang, S. B. Herzon, Nat. Prod. Rep. 2019, 36, 220-
6
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
14, 1904-1908; j) F. Rajabi, S. Naserian, A. Primo, R. Luque, Adv. Synth.
Catal. 2011, 353, 2060-2066.
B. Julie, F. Sebastien, B. Kevin, L. Valerie, A. Eric, B. Gervais, Medicinal
Chemistry 2015, 11, 531-539.
[10] a) M. Jereb, Green Chem. 2012, 14, 3047-3052; b) S. K. Karmee, L.
Greiner, A. Kraynov, T. E. Müller, B. Niemeijer, W. Leitner, Chem.
Commun. 2010, 46, 6705-6707; c) R. G. Almeida, R. L. de Carvalho, M.
P. Nunes, R. S. Gomes, L. F. Pedrosa, C. A. de Simone, E. Gopi, V.
Geertsen, E. Gravel, E. Doris, E. N. da Silva Júnior, Catal. Sci. Technol.
2019, 9, 2742-2748; d) Y.-L. Hu, X.-B. Liu, D. Fang, Catal. Sci. Technol.
2014, 4, 38-42; e) L. Xu, J. Cheng, M. L. Trudell, J. Org. Chem. 2003, 68,
5388-5391; f) B. M. Choudary, C. R. V. Reddy, B. V. Prakash, M. L.
Kantam, B. Sreedhar, Chem. Commun. 2003, 754-755.
[25] N. Katsiki, K. Tsioufis, D. Ural, M. Volpe, J. Clin. Hypertens. 2018, 20,
1153-1159.
[26] M. Saito, M. E. Gilder, F. Nosten, R. McGready, P. J. Guérin, Malar. J.
2017, 16, 488.
[27] R. Skrzypek, R. Callaghan, Essays Biochem. 2017, 61, 167-175.
[28] a) M. Baghbanzadeh, D. Kumar, S. I. Yavasoglu, S. Manning, A. A.
Hanafi-Bojd, H. Ghasemzadeh, I. Sikder, D. Kumar, N. Murmu, U. Haque,
Sci. Total. Environ. 2020, 712, 136368; b) S. Bauhoff, J. Busch, World
Dev. 2020, 127, 104734.
[11] Reviews on deoxygenation of sulfoxides: a) L. Shiri, M. Kazemi, Res.
Chem. Intermed. 2017, 43, 6007-6041; b) J. Drabowicz, H. Togo, M.
Mikołajczyk, S. Oae, Org. Prep. Proced. Int. 1984, 16, 171-198; c) M.
Madesclaire, Tetrahedron 1988, 44, 6537-6580.
[29] K. C. L. Mulder, F. Mulinari, O. L. Franco, M. S. F. Soares, B. S.
Magalhães, N. S. Parachin, Biotechnol. Adv. 2015, 33, 648-665.
[30] a) J. N. Gardner, S. Kaiser, A. Krubiner, H. Lucas, Can. J. Chem. 1973,
51, 1419-1421; b) E. Akgün, K. Mahmood, C. A. Mathis, J. Chem. Soc.,
Chem. Commun. 1994, 761-762.
[12] a) H. Cho, B. V. Plapp, Biochemistry 1998, 37, 4482-4489; b) M.
Nishimura, K. Yamaoka, S. Naito, T. Nakagawa, Biol. Pharm. Bull. 1997,
20, 1285-1289; c) A. W. Craig, H. Jackson, R. M. V. James, Br. J.
Pharmacol. 1963, 21, 590-595.
[13] Recent selected examples: a) A. Gevorgyan, S. Mkrtchyan, T. Grigoryan,
V. O. Iaroshenko, ChemPlusChem 2018, 83, 375-382; b) T. Mitsudome,
Y. Takahashi, T. Mizugaki, K. Jitsukawa, K. Kaneda, Angew. Chem. Int.
Ed. 2014, 53, 8348-8351; Angew. Chem. 2014, 126, 8488-8491; c) R.
Ma, A.-H. Liu, C.-B. Huang, X.-D. Li, L.-N. He, Green Chem. 2013, 15,
1274-1279; d) N. García, P. García-García, M. A. Fernández-Rodríguez,
D. García, M. R. Pedrosa, F. J. Arnáiz, R. Sanz, Green Chem. 2013, 15,
999-1005; e) D. Porwal, M. Oestreich, Synthesis 2017, 49, 4698-4702; f)
S. Enthaler, Catal. Sci. Technol. 2011, 1, 104-110; g) J. M. S. Cardoso,
B. Royo, Chem. Commun. 2012, 48, 4944-4946; h) S. Enthaler,
ChemCatChem 2011, 3, 666-670; i) N. García, P. García-García, M. A.
Fernández-Rodríguez, R. Rubio, M. R. Pedrosa, F. J. Arnáiz, R. Sanz,
Adv. Synth. Catal. 2012, 354, 321-327; j) Y. Kuwahara, Y. Yoshimura, K.
Haematsu, H. Yamashita, J. Am. Chem. Soc. 2018, 140, 9203-9210; k)
G. S. Bhatia, P. P. Graczyk, Tetrahedron Lett. 2004, 45, 5193-5195; l) M.
Abbasi, M. R. Mohammadizadeh, Z. Moradi, Tetrahedron Lett. 2015, 56,
6610-6613; m) Y. Jang, K. T. Kim, H. B. Jeon, J. Org. Chem. 2013, 78,
6328-6331; n) K. C. Nicolaou, A. E. Koumbis, S. A. Snyder, K. B.
Simonsen, Angew. Chem. Int. Ed. 2000, 39, 2529-2533; Angew. Chem.
2000, 112, 2629-2633; o) K. Bahrami, M. M. Khodaei, A. Karimi,
Synthesis 2008, 2008, 2543-2546; p) X. Zhao, X. Zheng, B. Yang, J.
Sheng, K. Lu, Org. Biomol. Chem. 2018, 16, 1200-1204; q) A. K. Clarke,
A. Parkin, R. J. K. Taylor, W. P. Unsworth, J. A. Rossi-Ashton, ACS Catal.
2020, 5814-5820.
[14] a) A. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43, 2480-
2482; b) K. Omura, D. Swern, Tetrahedron 1978, 34, 1651-1660.
[15] P. Acosta-Guzmán, A. Rodríguez-López, D. Gamba-Sánchez, Org. Lett.
2019, 21, 6903-6908.
[16] a) G. E. Wilson, Tetrahedron 1982, 38, 2597-2625; b) Y. Guindon, J. G.
Atkinson, H. E. Morton, J. Org. Chem. 1984, 49, 4538-4540; c) G. A.
Olah, M. Arvanaghi, Y. D. Vankar, Synthesis 1979, 1979, 721-721.
[17] a) S. Song, X. Sun, X. Li, Y. Yuan, N. Jiao, Org. Lett. 2015, 17, 2886-
2889; b) H. Kajita, A. Togni, ChemistrySelect 2017, 2, 1117-1121; c) X.
Ma, J. Yu, M. Jiang, M. Wang, L. Tang, M. Wei, Q. Zhou, Eur. J. Org.
Chem., doi:10.1002/ejoc.201900794.
[18] L. Becerra-Cely, J. Rueda-Espinosa, A. Ojeda-Porras, D. Gamba-
Sánchez, Org. Biomol. Chem. 2016, 14, 8474-8485.
[19] M. Forgerini, S. Mieli, P. d. C. Mastroianni, Sao Paulo Med J. 2018, 136,
557-570.
[20] R. A. Blum, Am. J. Health-Syst. Pharm. 1996, 53, 1401-1415.
[21] F. Movahedi, L. Li, W. Gu, Z. P. Xu, Nanomedicine 2017, 12, 2555-2574.
[22] X. Zhang, K. P. Rakesh, C. S. Shantharam, H. M. Manukumar, A. M.
Asiri, H. M. Marwani, H.-L. Qin, Bioorg. Med. Chem. 2018, 26, 340-355.
[23] a) E. Fels, J. Clin. Endocrinol. Metab. 1944, 4, 121-125; b) S. Witherby,
J. Johnson, L. Demers, S. Mount, B. Littenberg, C. D. Maclean, M. Wood,
H. Muss, The Oncologist 2011, 16, 424-431; c) C. Boni, M. Pagano, M.
Panebianco, A. Bologna, N. M. A. Sierra, R. Gnoni, D. Formisano, G.
Bisagni, Anticancer Res 2014, 34, 1287-1290.
[24] a) M. Jabeen, M. I. Choudhry, G. A. Miana, K. M. Rahman, U. Rashid,
H.-u. Khan, Arshia, A. Sadiq, Steroids 2018, 136, 22-31; b) M. Nathalie,
7
This article is protected by copyright. All rights reserved.

10.1002/chem.202001815
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
Late-Stage Deoxygenation
S
S
(COCl)2
MeO OMe
O
O
O
N
O
O
OMe
N
N
DCM, 0ºC, 10 min
O
O
>45 examples
Up to 98% yield
N
A highly chemoselective late-stage deoxygenation of sulfoxides is described; this is a new process using chlorosulfonium salts
generated in situ from sulfoxides. The reaction is easy to handle, economic and showed great functional-group tolerance. It is
appropriate for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial drugs and some
analogues.
8
This article is protected by copyright. All rights reserved.