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z Organic & Supramolecular Chemistry
Metal-Free C-H Thiomethylation of Quinones Using Iodine
and DMSO and Study of Antibacterial Activity
Sakthidevi Rajasekar
+
,
[a]
T. P. Adarsh Krishna
+
,
[a]
Nagendran Tharmalingam
+
,
[b]
Ilangovan Andivelu,*
[a]
and Eleftherios Mylonakis*
[b]
A novel, transition metal-free, molecular iodine mediated
method for thiomethylation of quinones, using dimethyl
sulfoxide (DMSO) as a benign thiomethylating agent is
described. This greener reaction protocol leads to selective
mono thiomethylation in low to high yield and tolerates a
range of substituent groups. Preliminary antibacterial evalua-
tion of thiomethylated quinones, carried out against methicillin
resistant Staphylococcus aureus shows promising results. One of
the compound 3’-methyl-6-(methylthio)-[1,1’-biphenyl]-2,5-di-
one exhibited antimicrobial activity even against clinical
isolates of S. aureus and vancomycin-intermediate Staphylococ-
cus aureus (VISA).
Introduction
Quinone, an interesting structural motif with unique electronic
properties
[1]
is found among natural products,
[2]
terpenequinones,
[3]
kinamycin antibiotics
[4]
and organic
materials.
[5]
Although quinone was functionalised earlier using
pre-functionalized starting materials,
[6]
direct C H functionaliza-
tion of quinones was reported later mainly using expensive
transition metal catalysts like Pd, Ru and also inexpensive iron
salts.
[7a–c]
Nevertheless, development of metal free
[7d–f]
simple
method for direct C–H functionalization of quinones still
remains a challenge.
Over the past few years, iodine has been explored
[8]
as a
green alternative to transition metal catalysts in organic
synthesis, as iodine has diverse valence states as well as
moderate redox potentials.
[9]
Having initiated by Ishihara and
Wan, iodine has been used in carbodehydrogenative coupling
reactions for the formation of C–O, C–N and C–C bonds.
[10]
Li
and co-workers used I
2
as an alternative to transition metal
catalyst in oxidative cyclization of N-aryl enamines to indoles.
[9d]
Thioether is an important functional group found among
drugs,
[11]
novel synthetic building blocks,
[12–13]
materials
[14a–c]
and
2-alkyl and 2-arylthio-1,4-naphthaquinones which shows cho-
lestrol acyltransferase inhibition activity.
[14d–e]
Construction of
thioethers by addition of sulfur or sulfonyl radicals to C C
multiple bonds is a common strategy.
[15]
Conventional method
for preparation of thiomethyl ethers consists of directed or
heteroatom-facilitated lithiation and subsequent electrophilic
substitution with dimethyl disulfide.
[16]
An alternate approach
is, chlorosulfonylation of electron-rich rings using chlorosul-
fonic acid followed by reduction and then S-methylation with
MeI.
[17]
Several copper promoted C–H thiomethylation methods
have emerged.
1819
These include thiomethylation of 2-phenyl-
pyridine using MeSSMe Cu(OAc)
2,
[20]
arenes and hetero
arenes
[21a]
using DMSO Cu(OAc)
2
, and 2-arylpyridine using
DMSO-CuF
2
(4 equiv.).
[21b]
A new copper catalyst system for
thiolation of heteroarenes
[21c]
regioselective sulfencataylation of
flavones was also reported.
[21d]
However, the main limitation of
these transformations are the need for the presence of a
chelating hetero atom, and limited substrate scope. Interest-
ingly, iodine was used in promotion of annulation followed by
thiomethylation in construction of 3-(methylthio)-4-aryl-1H-
pyrrole-2,5-diones,
[21e]
and 6-iodo-3-(methylthio)-2-arylimidazo
[1,2-a]pyridines.
[21f]
Although, transition metal catalyzed carbon-sulfur bond
forming reactions
[22]
on different class of compounds are well
established, methods for preparation alkylthioquinones are
only very few.
[14d–e]
During the course of writing this manuscript,
Poulsen et al reported, as a part of study on heterofunctional-
ization, thioethylation of quinones using odorous EtSH and Co
(OAc)
2
catalyst. The yield is good to low and only three
examples were studied and bisthioethylated products were
formed.
[14f]
Thus an important drawback of thioalkylation of
quinones was the need for use of thiols, which are hazardous,
unstable to air, moisture sensitive and possess unpleasant
odor. Further, the hydroquinone formed in situ, should be re-
oxidized to quinone using a strong and highly toxic oxidant
like chromates. Additionally, only an isolated example on
formation of 2-(methylthio)-naphthoquinone from 1-naphthol
was reported.
[23]
Thioether derivatives are good antibacterial agents. For
example, pleuromutilin derivatives, substituted with thioether
group at the C14 side chain, show activity against Staph-
ylococcus aureus strain ATCC26112,
[24a]
and 1,3,4-oxadiazole
[a] Dr. S. Rajasekar,
+
T. P. A. Krishna,
+
Prof. I. Andivelu
School of Chemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu-
620024, India
E-mail: ilangovanbdu@yahoo.com
[b] Dr. N. Tharmalingam,
+
Prof. E. Mylonakis
Infectious Diseases Division, Warren Alpert Medical School of Brown
University, Rhode Island Hospital, Providance, RI 02903, USA
E-mail: emylonakis@lifespan.org
[
+
] Authors contributed equally
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.201803816
Full Papers DOI: 10.1002/slct.201803816
2281 ChemistrySelect 2019, 4, 2281–2287 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim