Mo(VI) complex catalysed synthesis of sulfonees and their modification for anti-HIV activities

Article abstract of DOI:10.1016/j.catcom.2020.105931

An efficient method for the synthesis of sulfones has been developed using sugar derived cis-dioxo molybdenum(VI) complex as catalyst and urea hydrogen peroxide as oxygen source. Present method is highly specific for sulfide oxidation irrespective of presence of alkene and aldehyde groups in the same molecule. Synthesis of fifteen sulfones have been reported with 82–98% isolated yields and the catalyst has been reused five times without any loss in its activity. 2-(Phenylsulfonyl)aniline has been condensed with eight different aromatic aldehydes and the products are being explored for HIV-1 reverse transcriptase inhibition activities.

Full text of DOI:10.1016/j.catcom.2020.105931

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Mo(VI) complex catalysed synthesis of sulfonees and their
modification for anti-HIV activities
Vimal Kumar Madduluri, Noorullah Baig, Subhash Chander,
Sankaranarayanan Murugesan, Ajay K. Sah
PII:
S1566-7367(20)30006-6
DOI:
https://doi.org/10.1016/j.catcom.2020.105931
CATCOM 105931
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
2 December 2019
31 December 2019
13 January 2020
Please cite this article as: V.K. Madduluri, N. Baig, S. Chander, et al., Mo(VI) complex
catalysed synthesis of sulfonees and their modification for anti-HIV activities, Catalysis
Communications (2019), https://doi.org/10.1016/j.catcom.2020.105931
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Mo(VI) complex catalysed synthesis of sulfones and their
modification for anti-HIV activities
Vimal Kumar Madduluria, Noorullah Baiga, Subhash Chanderb, Sankaranarayanan Murugesanb
and Ajay K. Saha*
aDepartment of Chemistry, Birla Institute of Technology and Science, Pilani, Pilani Campus,
Rajasthan 333031, India.
bDepartment of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus,
Rajasthan 333031, India.
*Corresponding author. Email: asah@pilani.bits-pilani.ac.in
Abstract
An efficient method for the synthesis of sulfones has been developed using sugar
derived cis-dioxo molybdenum(VI) complex as catalyst and urea hydrogen peroxide as oxygen
source. Present method is highly specific for sulfide oxidation irrespective of presence of alkene
and aldehyde groups in the same molecule. Synthesis of fifteen sulfones have been reported
with 82 – 98 % isolated yields and the catalyst has been reused five times without any loss in its
activity. 2-(Phenylsulfonyl)aniline has been condensed with eight different aromatic aldehydes
and the products are being explored for HIV-1 reverse transcriptase inhibition activities.
Keywords
Molybdenum; Homogeneous catalysis; Sulfide oxidation; Sulfones; Anti-HIV agent.

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1. Introduction
Organic sulfones are one of the important classes of molecules that have been used in
various fields like medicine [1], agrochemicals [2], electronics [3], polymers [4], etc. Therapeutic
application of sulfones has been started with Promin (sodium glucosulfone) for treating leprosy
[5]. Currently, several sulfone containing drugs are available in the market, including Dapsone
[6] for leprosy, Casodex [7] for prostate cancer, Relpax [8] for migraine, etc. Diaryl sulfone
derivatives like 2-amino-6-arylsulfonylbenzonitrile, pyrrylarylsulfone and indolylaryl sulfones
have been reported to inhibit HIV-1 reverse transcriptase (RT) enzyme [9]. Besides biological
and pharmaceutical applications, sulfones have also been used in organic synthesis to form
heterocycles [10] and stereo selective C–C bonds [11]. Owing to their implication in various
fields of science, several methodologies have been developed to synthesize the sulfones via C–
S coupling or oxidation of sulfides [12]. Direct C–S coupling approach provides a broad
substrate scope; however, its major drawbacks are harsh reaction conditions and low atom
economy [13]. An alternate method of sulfone synthesis is oxidation of sulfides using oxidants
like potassium permanganate, hydrogen peroxide, oxone and m-chloroperoxybenzoic acid in
presence/absence of metal catalysts [12]. Recently we have reported cis-di-oxo
molybdenum(VI) complex catalyzed oxidation of organic sulfides to sulfoxides using one
equivalent of urea hydrogen peroxide (UHP) as oxygen source [14] and noticed the formation of
sulfone in presence of excess of oxidising agent. Versatile use of sulfones inspired us to
develop its synthetic methodology using our catalyst and explore the activity of the resultant
molecules. Along this line, we have optimised the conditions for synthesis of sulfone using
thioanisole and following the optimum conditions, fifteen molecules have been prepared. One of
these sulfones has also been condensed with aromatic aldehydes to form a series of new
molecules having imine linkage and evaluation of their anti-HIV abilities are under progress.

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Hence, this article presents the optimized conditions for Mo(VI) complex catalyzed
synthesis of sulfones along with recyclability of the catalyst, synthesis of imine derivatives of 2-
(phenylsulfonyl)aniline and in silico evaluation of the resultant molecules as an anti-HIV agent.
2. Experimental
The catalyst (D-glucose derived cis-dioxo molybdenum(VI) complex) [15] and selected
sulfide derivatives (for entry O6-O9 [16], O10 [17], O11 [18] and O12 [19] under Table 2) were
prepared following the reported procedure.
2.1 General procedure for catalytic oxidation of organic sulfides to sulfones
Organic sulfide (1.0 mmol), UHP (5.0 mmol) and catalyst (0.05 mmol) were stirred in
ethanol (5 mL) at room temperature and the progress of the reaction was monitored using thin
layer chromatography (TLC). After completion of the reaction, precipitate formed was filtered off,
washed with cold ethanol and dried to obtain the pure organic sulfone. In case of soluble
organic sulfones, solvent was evaporated under reduced pressure; residue was triturated with
dichloromethane (5 mL) and filtered to remove the insoluble urea and catalyst. The filtrate
containing sulfone was dried and recrystallized from dichloromethane/hexane mixture.
2.2 Synthesis of N1-N8 by condensation of 2-(phenylsulfonyl)aniline (N0) with aromatic
aldehydes
2-(Phenylsulfonyl)aniline (1.0 mmol) and aromatic aldehyde (1.02 mmol) were refluxed
in ethanol (5 mL) for 8 hours. Solid product formed was filtered and washed with cold ethanol to
afford the pure desired compound.

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In the case of benzaldehyde, toluene (5 mL) was used instead of ethanol and reaction
mixture was refluxed for 24 hours. After cooling the reaction mixture, solvent was evaporated,
residue was triturated with hexane and filtered to obtain the pure solid product.
Single crystals suitable for X-ray diffraction studies were generated by layering
technique with solvent combinations dichloromethane/hexane for N3 and N5, while dimethyl
sulfoxide/methanol for N8.
3. Results and discussion
3.1 Oxidation of organic sulfides to sulfones
Catalytic activities of sugar derived molybdenum complexes are limited and we have
noticed reports on epoxidation [20, 21], sulfoxidation [14] and bis(indolyl)methanes [22]
synthesis. Fridgen et al. [20] and Sui et al. [21] have explored the epoxidation reactions using
tert-butylhydroperoxide and cumene hydroperoxide respectively as oxidants while
Mohammadnezhad et al. used hydrogen peroxide to achieve sulfoxidation. Recently, we have
explored Mo(VI) complex catalysed oxidation of organic sulfides to sulfoxides and stability of the
catalyst [23]. The robust nature of the catalyst and versatile use of sulfones prompted us to
explore the conditions for selective oxidation of sulfides to sulfones and along this line, we
performed several control reactions on thioanisole as summarized in Table 1. The progress of
the reaction was monitored using TLC and the formation of products was confirmed by HRMS
analysis. Catalyst (5 mol%) and five equivalents of UHP with respect to substrate were found to
be suitable for sulfone formation under normal conditions and shorter reaction time (15 Min).
Under optimum reaction conditions, fifteen aliphatic and aromatic sulfides, including
amino acid (methionine), were oxidized to sulfones in good to excellent isolated yields (82-
98%). The details of sulfone formation are summarized in Table 2, which clearly supports the
negligible effect of aromatic substituents on reaction time and yield. The reaction proceeds with
sulfoxide intermediate and solubility of this intermediate affect the overall reaction time. This fact

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was established while monitoring the reactions for the formation of O4 and O5 with respect to
others. Since excess of UHP was used during the reaction, stability and reusability of catalyst
was one of the major concerns and the same was tested on 2-(phenylthio)aniline as substrate.
After completion of reaction, solid sulfone was isolated through filtration and the filtrate was
charged with fresh substrate and UHP for next cycle. This procedure was repeated for five times
and sequential yield was recorded as 92, 98, 97, 97 and 98 % respectively, confirming the
stability and reusability of the homogeneous catalyst. A slight increase in the yields of sulfone
during the recycling process may be attributed to the saturation of the mother liquor with sulfone
after the first cycle. Our protocol is suitable for gram-scale synthesis as we performed the
oxidation of 2-(phenylthio)aniline in 3 g scale and isolated corresponding 3.4 g sulfone (N0;
98%).
As oxidation of sulfide to sulfones is a well-established reaction, we compared our
methodology with the existing reports. A handful of literature reports are available on
molybdenum compound catalysed sulfones synthesis using oxidants like hydrogen peroxide
[24-27]. The major demerits of these syntheses include complexity in synthesizing the catalysts,
elevated temperatures, long reaction time and use of column chromatography for product
purification, which restricts gram scale synthesis. Reports are also available on UHP assisted
sulfone production in combination with volatile and unstable acid anhydrides [28]. To the best of
our knowledge, only one report is available on molybdenum-UHP combination for synthesizing
di-n-pentyl, methylphenyl and diphenyl sulfones [29]. The major demerit of the procedure
mentioned in this paper is the decomposition of catalyst due to the excess oxidant used during
the reaction. Hence, our method has several advantages like short reaction time (15 minutes),
recyclable catalyst and applicability in large scale synthesis. This method has excellent
chemoselectivity towards sulfide group over various other functional groups like alkene,
aldehyde, amine, etc. as no side products were formed during oxidation of sulfide substrates
containing these functional groups. Oxidation reactions were also set on styrene and 4-
chlorobenzaldehyde under optimised reaction condition (using Mo(VI) catalyst and 5 equivalent

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UHP) and progress of reaction was monitored. We did not observe any oxidation reaction in
either case even after 24 hours, which confirms the chemoselectivity.
3.2 Synthesis of N1-N8 by condensation of N0 with aromatic aldehydes
Compounds N1-N8 were synthesized by condensing N0 with aromatic aldehydes, as
described in section 2.2. FTIR spectral analysis of compounds N1–N7, revealed strong
absorbance in the range of 1600–1625 cm-1 and 1145–1155 cm-1 corresponding to C=N
stretching and S=O symmetric stretching respectively. Proton NMR spectra of these compounds
showed singlet peaks corresponding to imine CH around δ 8-9 ppm and phenolic OH above δ
12 ppm. All these results supported the formation of anticipated products and further
confirmation was accomplished by HRMS data along with single-crystal X-ray diffraction studies
of N3 and N5 (Fig. 1(a) and 1(b)). Analogous reaction with 2-carboxybenzaldehyde afforded
cyclized product (N8) instead of expected Schiff base and similar report is also available in
literature [30]. Racine reported the structure of condensed product to be open-chain Schiff base
[31], which was challenged by Kubota et al. [32]. Our finding aligns with the result reported by
Kubota et al. and we succeeded in establishing the structure of this molecule using single-
crystal X-ray diffraction studies. The crystallographic data confirms the lactam structure (Fig.
1(c)) with C(Ar)–N and C(Lactam)–N bond distances 1.383(2) and 1.417(2) Å respectively. The
C(1)N(1)C(9) is found to be 122.26(13)°, which may be attributed to the planar geometry
about nitrogen due to the involvement of lone pair electrons in resonance with the aromatic ring.
This resonance is further supported by the shorter bond distance between C(Ar)–N, which was
noticed by Odabasoglu et al. [33], while solving the structure of 3-anilinoisobenzofuran-1(3H)-
one.
3.3 In silico HIV-1 RT inhibition study

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McMahon et al. in 1993 illustrated the in vitro HIV-1 RT inhibition potential of several
diphenyl sulfones wherein nitro derivatives were more active than amine derivatives [34].
Recently GlaxoSmithKline group patented the amide derivative of 2-(phenylsulfonyl)aniline
consisting of tetrazole moiety for treating HIV [35]. Since our compounds (N0-N8) have similarity
in structure with above mentioned active compounds, out of curiosity, we are exploring the HIV-
1 RT inhibition capability of these molecules. In this direction, we started with in silico docking
study using Schrödinger software (details provided in supplementary information section 3.1).
Docking results (Fig. 2) of synthesised compounds are comparable with that of the commercially
marketed drug Rilpivirine. Notably, binding energies (-10.07 to -12.16 kcal/mol) for modified
compounds (N1-N8) are more than that of starting sulfone (N0, -8.39 kcal/mol). The highest
binding energy (-12.16 kcal/mole) was obtained for methoxy derivative (N3), while it is –14.26
kcal/mole for Rilpivirine under identical conditions.
4. Conclusion
This is the first report, where sugar derived molybdenum(VI) complex has been used as
a catalyst for selective synthesis of sulfones. The catalyst is stable and reusable in presence of
excess (5 equivalents) of urea hydrogen peroxide and the method of transformation is mild. The
reactions have been carried out at room temperature in ethanol, and 82–98 % isolated yield of
sulfones was recorded within 15 minutes. The catalyst combination is highly specific for sulfide
oxidation irrespective of presence of alkene and aldehyde groups; however, hydrolysis of imine
bond has been noticed for sulfides having this functionality. One of the catalysed products
containing amine group has also been condensed with aromatic aldehydes to generate a series
of new molecules and currently we are exploring their anti-HIV activities. Here we are also
reporting brief outcome of our in silico result in this direction along with crystal structures of
three synthesised compounds.

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Acknowledgements
A. K. Sah is grateful to Angshuman R. Choudhury and X-ray facility IISER Mohali for
crystallographic data collection and refinement. We are also thankful to DST FIST and UGC
SAP for their financial support in procuring the instruments and developing the research
infrastructure.
Appendix A. Supplementary material
Supplementary information including details of synthesis, analytical data, details of in
1
silico studies, H, 13C NMR spectra, crystallographic data and docking poses of N3 and
Rilpivirine along their interactions with wild HIV-1 RT enzyme can be found online at xxxxxxxx.
Crystallographic data of N3, N5 and N8 have been deposited to Cambridge Crystallographic
Data Centre and their CCDC deposition numbers are 1968356, 1966960 and 1966961
respectively.
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Table 1. Optimization of reaction conditions for selective oxidation of thioanisole to
methylphenyl sulfone
Catalyst
(% mol)a
UHP
(equivalents)a
Time
(Hr)
Sulfone
(% yield)b
Sulfoxide
(% yield)b
S. No.
1
2
5
5
1
2
3
5
7
5
5
5
5
5
4
4
trace
92
81
13
3
5
4
42
51
4
5
0.25
0.25
24
8
92
trace
trace
trace
<5
5
5
93
6
0
0
7
1
88
8
2
4
87
<5
9
3
1
94
91
trace
trace
10
10
0.25
a with respect to sulfide substrate(0.001 mol)
b isolated yields

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Table 2. Sulfone synthesis using Mo(VI) complex–UHP system in ethanol using
optimised conditions
Entry
Sulfone
Yield %a
92
O1
O2
O3
95
82
O4
O5
O6
87b
86b
90
O7
O8
O9
88
93
94
O10
O11
93
97

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O12
O13
O14
92
93
91
N0
98c
a isolated yields after 15 minutes
b isolated yields after 30 minutes
c 3 g of 2-(phenylthio)aniline was taken

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Scheme 1. Synthesis of N1-N8 by condensation of N0 with aromatic aldehydes.

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Fig. 1. ORTEP diagrams of (a) N3, (b) N5 and (c) N8 with 50% thermal ellipsoid probability.

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Fig. 2. Glide scores for compounds N0-N8 and co-crystallised ligand (Rilpivirine) when docked
in the HIV-1 RT enzyme (PDB ID: 3MEE).

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CRediT author statement
Vimal Kumar Madduluri: Conceptualization, Methodology, Investigation, Data curation, Writing-
Original draft preparation
Noorullah Baig: Conceptualization, Methodology
Subhash Chander: Software, Investigation
Sankaranarayanan Murugesan: Validation, Writing- Original draft preparation, Supervision
Ajay K. Sah: Validation, Writing- Reviewing and Editing, Supervision, Project administration

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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Declarations of interest: none

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Mo(VI) complex catalysed synthesis of sulfones and their modification for anti-HIV activities
Vimal Kumar Madduluria, Noorullah Baiga, Subhash Chanderb, Sankaranarayanan Murugesanb and Ajay K. Saha*

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Highlights



First report on selective sulfone synthesis using D-glucose derived Mo(VI) catalyst
Gram scale synthesis through homogenous catalysis using UHP as oxygen source
Catalyst has been recycled for five times without appreciable loss in activity
 Structure of three sulfones has been established using X-ray crystallographic data