Straightforward Access to Thiocyanates via Dealkylative Cyanation of Sulfoxides

Article abstract of DOI:10.1021/acs.orglett.1c00460

Thiocyanates, versatile building blocks in organic synthesis, are shown to be easily accessible via an interrupted Pummerer reaction of sulfoxides. This facile dealkylative functionalization proceeds under mild conditions through electrophilic activation of the sulfoxide partner. The resulting thiocyanate itself can serve as a handle for diversification in a straightforward one-pot procedure.

Full text of DOI:10.1021/acs.orglett.1c00460

pubs.acs.org/OrgLett
Letter
Straightforward Access to Thiocyanates via Dealkylative Cyanation
of Sulfoxides
†
†
̌
́
Uros Todorovic, Immo Klose, and Nuno Maulide*
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ABSTRACT: Thiocyanates, versatile building blocks in organic synthesis, are
shown to be easily accessible via an interrupted Pummerer reaction of sulfoxides.
This facile dealkylative functionalization proceeds under mild conditions
through electrophilic activation of the sulfoxide partner. The resulting
thiocyanate itself can serve as a handle for diversification in a straightforward
one-pot procedure.
Scheme 1. (a) Overview of Classical Thiocyanate Syntheses;
(b) Oxidative Dealkylative Thiocyanations from Sulfides
Using an Excess of Oxidants; and (c) Dealkylative
Cyanation of Sulfoxides
hiocyanates are an important compound family widely
Tencountered in medicinal chemistry and natural products,
and they constitute versatile synthetic handles.1,2 Their ability
to function as electrophilic components either on sulfur or on
carbon renders them especially attractive intermediates.3
The preparation of thiocyanates mainly relies on nucleo-
philic substitution or coupling reactions using the thiocyanate
anion (Scheme 1a).4 Alternative, less common methods
include electrophilic thiocyanations, nucleophilic or electro-
philic cyanation of suitable sulfur species, or radical processes.5
In 2015, Shi and coworkers reported the union of a sulfide, a
sulfur species that possesses neither an acidic proton nor a
designated leaving group, with a modified version of Stang’s
reagent.6 The thiocyanate products are thus formed through
oxidative cyanation followed by dealkylation (Scheme 1b). In
2019, Yang et al. showed that the same transformation could be
achieved without the hypervalent iodine reagent, employing
Selectfluor as an oxidant alongside a cyanide source.7
In this context, we speculated that the use of strong oxidants
might be avoided if one were to employ a sulfoxide as a reactant
rather than its sulfide counterpart. Such a transformation
would also further expand the toolbox for sulfoxide-mediated
transformations, a field that has seen rapid development in
recent years.8 Apart from their use as directing groups9 and
ligands,10 sulfoxides are known for their propensity toward
activation with electrophilic reagents, creating highly reactive
species that can be synthetically exploited in a variety of
reactions.11,12 In several of those reports, the sulfur residue that
remains in the final products is often an afterthought from a
synthetic point of view. Herein we report an operationally
simple dealkylative conversion of sulfoxides into thiocyanates
as well as related transformations (Scheme 1c).
Received: February 7, 2021
Published: March 16, 2021
In an initial experiment, stoichiometric trimethylsilyl cyanide
was added to a mixture of p-tolylmethylsulfoxide 1a and triflic
anhydride (i.e., an electrophilically activated sulfoxide) at low
temperature (Scheme 2). Satisfyingly, this resulted in a clean
conversion into p-tolylthiocyanate 2a, which was isolated in
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Org. Lett. 2021, 23, 2510−2513
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Letter
thiocyanate 2m. Notably, the reaction also proceeded
smoothly on Methiocarb sulfoxide 1n, a pesticide metabolite,
to give the thiocyanated derivative in 73% yield. Next, we
investigated the effect of variation of the alkyl substituent. As
might be expected from a dealkylative process, lower yields are
observed with sulfoxides carrying secondary alkyl moieties, a
clear indicator of the more challenging C−S bond-breaking
event in these cases (2a′ and 2i′). Interestingly, preferential
dealkylation of the homobenzyl substituent was observed over
a methyl substituent.13 The formation of homobenzyl
thiocyanate 2o was achieved by changing the methyl for a
benzyl and a homobenzyl substitutent, leading to a 51% yield
and quantitative (88% isolated yield) formation of 2o,
respectively. Finally, the robustness and scalability of our
methodology was demonstrated by subjecting 1j to the
standard conditions, delivering 1.03 g of 2j (88%) without
the need for column chromatography.
Scheme 2. Substrate Scope for the Dealkylative Cyanation
of Sulfoxides
a
Our proposed mechanism is outlined in Scheme 3a. After
the electrophilic activation of the sulfoxide to intermediate I1,
Scheme 3. (a) Proposed Mechanism and (b) Reaction with
Cyclic Sulfoxide
the addition of TMSCN forms cyanosulfonium triflate I2.14
This species is readily dealkylated by the counteranion to
reveal thiocyanate and the alkyl triflate.6,7 To provide further
evidence of this mechanism, we subjected cyclic sulfoxide 1p
to the reaction conditions (Scheme 3b). To our delight, the
ring-opened product was obtained in almost quantitative yield,
bearing the expected triflate group on the alkyl chain.
The simple reaction setup of this transformation led us to
investigate the possibility of functionalizing the sulfoxide
directly into diverse substituents in a one-pot fashion (Scheme
4). To this end, the crude reaction mixture of the dealkylative
cyanation was exposed to a range of conditions. For instance,
the addition of a solution of lithium alkynylide in THF
smoothly afforded thioalkyne 3 in 80% isolated yield.15
Similarly, the addition of Ruppert’s reagent (TMSCF3) and
TBAF was successful to afford trifluoromethyl sulfide 4 in one
pot.16 Lastly, sulfonyl cyanide 5 could be obtained by an
oxidation protocol developed by Landais and coworkers using
a combination of hydrogen peroxide and trifluoroacetic
anhydride (TFAA) in dichloromethane.17 These transforma-
tions highlight another advantage of the method presented
herein, namely, the relatively clean formation of the
thiocyanate even before workup of the reaction mixture,
a
Reactions were performed on a 0.1 to 0.5 mmol scale in CH2Cl2 (0.1
b
M). Yield determined by 1H NMR using an internal standard. n.d. =
not detected.
91% yield. Further changes to the temperature, time of
addition, and order of addition did not improve the outcome,
leading us directly to the exploration of the generality of this
protocol with different sulfoxides.
The desired thiocyanates were generally obtained in good to
excellent yields. In particular, hindered mesitylsulfoxide 1c
allowed the isolation of the respective thiocyanate in excellent
99% yield. Different halide substitution patterns were also well
tolerated (2d−2g), and the reaction worked well with the
extended aromatic system of 2h. Electron-rich sulfoxides
furnished the respective aryl thiocyanates cleanly in high yields,
whereas aryl sulfoxides bearing electron-withdrawing groups
afforded the respective thiocyanates 2k,2l with lower efficiency.
Furthermore, it was intriguing to investigate the regioselectivity
of the dealkylation step for a dialkylsulfoxide: In this event,
octylmethylsulfoxide 1m was selectively dealkylated at the
more sterically accessible methyl substituent to give
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Austrian Academy of Sciences. The generous support of the
University of Vienna is acknowledged. Dr. M. Riomet (U.
Vienna) is acknowledged for careful proofreading.
Scheme 4. One-Pot Dealkylative Transformations of
Sulfoxide
a
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a
Initial dealkylative cyanations were performed as in Scheme 2, which
were followed by one-pot transformations: (a) 1-hexyne, n-BuLi, 0 °C
to rt, 15 h; (b) TMSCF3, TBAF, 0 °C to rt, 15 h; (c) H2O2, TFAA, 40
°C, 16 h. See the Supporting Information for details.
which enables a range of useful downstream processes in cases
where the thiocyanate might not be the desired end product.
In summary, we have presented a straightforward method to
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00460.
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AUTHOR INFORMATION
Corresponding Author
■
Nuno Maulide − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria; orcid.org/0000-0003-
3643-0718; Email: nuno.maulide@univie.ac.at
Authors
̌
́
Uros Todorovic − Institute of Organic Chemistry, University
of Vienna, 1090 Vienna, Austria
Immo Klose − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria; orcid.org/0000-0002-
9204-2106
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00460
Author Contributions
†U.T. and I.K. contributed equally.
Notes
(7) Chen, Y.; Qi, H.; Chen, N.; Ren, D.; Xu, J.; Yang, Z. Fluorium-
Initiated Dealkylative Cyanation of Thioethers to Thiocyanates. J.
Org. Chem. 2019, 84, 9044−9050.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(8) Kaiser, D.; Klose, I.; Oost, R.; Neuhaus, J.; Maulide, N. Bond-
Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium
Salts, Sulfur Ylides, and Sulfinate Salts. Chem. Rev. 2019, 119, 8701−
8780.
This work has been supported by the Austrian Science Fund
(P30226) and the European Research Council (CoG 682002
VINCAT). I.K. is a recipient of a DOC Fellowship of the
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