S-Arylation of thiols with masked o-benzoquinones: Synthesis of alkyl aryl/diaryl sulfides

Article abstract of DOI:10.1039/c4nj01381f

A novel, efficient, and metal-free C-S bond formation of masked o-benzoquinones with thiols is reported. This protocol involves the synthesis of unsymmetrical alkyl aryl/diaryl sulfides in excellent yields under mild and catalyst-free conditions. This journal is

Full text of DOI:10.1039/c4nj01381f

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S-Arylation of thiols with masked
o-benzoquinones: synthesis of alkyl
aryl/diaryl sulfides†
Cite this:DOI: 10.1039/c4nj01381f
Received (in Montpellier, France)
15th August 2014,
Santosh Kumar Reddy Parumala, Seshi Reddy Surasani and Rama Krishna Peddinti*
Accepted 20th August 2014
DOI: 10.1039/c4nj01381f
www.rsc.org/njc
A novel, efficient, and metal-free C–S bond formation of masked
o-benzoquinones with thiols is reported. This protocol involves the
synthesis of unsymmetrical alkyl aryl/diaryl sulfides in excellent
yields under mild and catalyst-free conditions.
Over the last several years organosulfur chemistry has received
significant relevance in organic synthesis due to the role of sulfur in
both environmental and biological fields.1 Among all the sulfur
compounds, aryl sulfides and their derivatives have broad applica-
tions in organic synthesis, the pharmaceutical industry as well as in
materials science.2 The diaryl sulfide unit is an integral part of many
drugs which are employed for inflammatory, malarial, Parkinson’s,
Alzheimer’s, cancer, and HIV diseases (Fig. 1).3
Fig. 1 Some of the diaryl sulfide containing biologically active molecules.
Conventionally these diaryl sulfides can be synthesized by boronic acids is an another alternative.12 Recently Lee et al.
the cross-coupling of aryl halides with thiophenols. Traditional reported an N-chlorosuccinimide promoted one-pot approach
methods for the synthesis of these compounds require harsh for the synthesis of aryl sulfides through the cross-coupling
conditions involving elevated temperatures (4200 1C) and between thiols and Grignard reagents.13 However, there are still
high boiling polar solvents such as DMF, HMPA, quinoline or some limitations in the cross-coupling of aryl halides with
N,N-dimethylacetamide and also require strong reducing thiophenols. Pd catalysts are air sensitive, Cu promoted reactions
agents like LiAlH4 and DIBAL-H for the reduction of sulfoxides require the usual stoichiometric amount of copper salts, high
and sulfones.4 When compared to the catalytic formation of temperature, and long reaction time whereas Co, Ni catalysts are
C–O and C–N bonds, the formation of a C–S bond remains associated with toxicity and also all these reactions require expen-
scarce because sulfur readily undergoes oxidative S–S bond sive ligands. Moreover metal contamination is a serious issue in the
formation leading to disulfide by-products and also has a great pharmaceutical industry. For this purpose environmentally-
tendency to coordinate with metals which deactivates the metal friendly, inexpensive, mild, and efficient protocols are still desirable
catalysts.5 To overcome these problems, several methods were in this area.
reported for the cross-coupling of aryl halides and thiophenols
Dearomatization of phenols is an important event in the field
which were catalyzed by transition metals such as palladium,6 of biosynthesis which involves the synthesis of many natural
nickel,7 cobalt,8 iron,9 copper or copper-based enzyme laccase10 products. o-Benzoquinone monoketals commonly called masked
and related metals.11 Chan–Lam type S-arylation of thiols with o-benzoquinones (MOBs) are versatile intermediates in the
synthesis of many natural products,14 which can be easily
Department of Chemistry, Indian Institute of Technology, Roorkee-247667,
Uttarakhand, India. E-mail: ramakpeddinti@gmail.com, rkpedfcy@iitr.ac.in;
Fax: +91 133 227 3560; Tel: +91 133 228 5438
obtained by the oxidation of 2-methoxyphenols in methanol
using hypervalent iodine reagents such as diacetoxyiodobenzene
(DIB). These linearly conjugated dienes can easily undergo the
Diels–Alder reaction with various dienophiles, self-dimerization
in the absence of external reactants and conjugate addition
with nucleophiles.15 Naphthoquinone monoketals belong to a
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data, copies of 1H NMR and 13C NMR are provided. CCDC
972198. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4nj01381f
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Table 1 Synthesis of diaryl sulfides from MOBs and thiophenols
Scheme 1 Working hypothesis.
promising class of compounds which are an integral part of
several antibiotics such as angucyclines or angucyclinones.16
These naphthoquinone monoketals can be obtained by the
oxidation of b-naphthols in methanol using DIB. Recently, we
reported a Lewis acid mediated anti-Michael addition reaction
for the synthesis of unsymmetrical oxygenated biaryls by adding
the electron-rich arenes to these electron deficient MOBs.17a To
further exploit the reactivity of MOBs,17 we were interested to add
some of the non-carbon nucleophiles such as thiols to these
MOBs. In continuation of our green protocols for the formation of
carbon and hetero atom bonds,18 herein, we report the catalyst-
free, eco-friendly method for the construction of the C–S bond to
synthesise unsymmetrical alkyl aryl/diaryl sulfides. This protocol
involves the oxidative dearomatization of 2-methoxyphenols/
b-naphthols into quinone monoketals and subsequent conjugate
addition with thiols. The working hypothesis for the addition of
thiophenols to MOBs is depicted in Scheme 1.
In an initial experiment, 1 equiv. of DIB was added to a
solution of creosol (1a) in dry methanol and stirred at room
temperature for 5 min to generate the corresponding MOB (2a).
To the in situ generated MOB, 1 equiv. of thiophenol was added.
As expected the unsymmetrical diaryl sulfide was obtained in
91% yield in 15 min. This reaction proceeds through Michael
addition of nucleophilic thiophenol to electrophilic MOB 2a
followed by prototropic shift leading to the formation of
unsymmetrical diaryl sulfide 3a. To probe the scope of the
reaction, we have tested a series of thiophenols and all the
reactions underwent cleanly to furnish diaryl sulfides in excellent
yields 84–93%. Similarly the same reaction was performed with
eugenol (1b), 4-chloro- and 4-bromo-guaiacols (1c and 1d) and
thioarenols under similar conditions. In the case of eugenol (1b)
the reactions reached completion in 20 min to afford the unsym-
metrical diaryl sulfides in excellent yields (90–95%) whereas in the
case of 4-chloro- and 4-bromo-guaiacols (1c and 1d) the reactions
reached completion in 45 min, and the corresponding diaryl
sulfides obtained in very high to excellent yields ranging from
73–92% which are shown in Table 1. The structure of the products
Fig. 2 ORTEP plot of 7a.
was confirmed by 1H and 13C NMR. The protons corresponding to benzyl thiol the reactions reached completion in 15–20 min
2-methoxyphenols appear as singlets in 1H NMR which indicates whereas in the case of ester functionalized thiols, the reactions
that there is no ortho-coupling. This supported the observation reached completion in 2 h and the corresponding alkyl aryl
that the thiophenol attacks at position 3 of MOB instead of thiols were obtained in very high yields (Table 2).
position 5. The structure of 7a was further confirmed by single
At this juncture, we turned our attention to the addition of
thiols to naphthoquinone monoketals 2e and 2f derived from
crystal X-ray analysis (Fig. 2).19
As evident from the above reactions the S-arylation of the oxidation of b-naphthols in methanol using 2.2 equiv. of
thiophenols via Michael addition to MOBs is facile. To ensure DIB. In this experiment, 1 equiv. of thioarenol/alkyl thiol was
that the current protocol is compatible with aliphatic thiols, we added to a solution of naphthoquinone monoketal in methanol
performed the reactions of 2-methoxyphenols 1a and 1b with and stirred the reaction mixture at room temperature for
benzyl thiol and ester functionalized thiols. In the case of 2.5–3 h (6 h in the case of functionalized thiols). In all the reactions,
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Table 2 Synthesis of aryl sulfides from MOBs and thiols
Fig. 3 Fukui functions for nucleophilic attack on MOBs.
of the LUMO indicates the preferred site for a nucleophilic
attack in the molecule.
Table 3 Reactions of naphthoquinones with thiols
In MOBs 2a–d three electrophilic sites (C-1, C-3, C-5) and in
naphthalenones 2e and 2f, two electrophilic sites (C-1, C-3) are
available on which nucleophiles may attack. From the analysis
of electrophilic Fukui functions for MOBs 2a–d and naphtho-
quinone monoketals 2e and 2f, the C-3 position has larger electro-
+
philic activation (fk = 0.18–0.21) (Fig. 3) on which nucleophilic
attack takes place. Thus the calculated Fukui functions support the
experimentally observed regioselectivity from the attack of nucleo-
philes (thiol) on the C-3 position of MOBs studied.
In summary, we have developed a rapid method for the synthesis
of aryl sulfides through the reaction of in situ generated masked
o-benzoquinones with thiols under aerobic and catalyst-free
conditions. The significant features of the reactions are short
reaction times, high yields, operational simplicity, and the absence
of toxic/expensive reagents.
Acknowledgements
This work was supported by the Science and Engineering
Research Board (DST), New Delhi [Research grant No. SR/S1/
OC-38/2011]. We thank DST for providing HRMS facility in the
DST-FIST program, and Prof. V. R. Peddinti, IIT Bhubaneswar,
for X-ray crystallographic assistance. S. K. R. P. thanks CSIR for
a research fellowship.
the naphthoquinone monoketals were transferred into the
corresponding diaryl/alkyl aryl sulfides in high to excellent
yields ranging from 78–94% (Table 3).
Notes and references
In order to understand the observed regiochemistry in the
attack of thiols on MOBs, the condensed Fukui functions have
been evaluated for MOBs. These calculations have been done
at the B3LYP/6-31G* level of theory using the Gaussian09
program. In Fukui’s frontier molecular orbital theory, the
relative nucleophilicity or electrophilicity at different sites of
the molecule is interpreted in terms of the highest occupied
molecular orbital (HOMO) or lowest unoccupied molecular
orbital (LUMO) electron density.20 If HOMO electron density
is more at a particular site of a molecule an electrophilic attack
will take place at that position. Similarly, largest Fukui function
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