Competitive cascade cyclization of 2′-tosyloxychalcones: An easy access to thioflavones and thioaurones

Article abstract of DOI:10.1080/00397911.2020.1775852

A new and efficient approach for the synthesis of thioflavones and thioaurones by competitive cascade cyclization of 2′-tosyloxychalcones has been developed. 2′-Tosyloxychalcones were smoothly converted into thioflavones and thioaurones by incorporation of sulfur atom using elemental sulfur and triethylamine in DMSO with good yields. The advantages of the methodology are the formation of both thioflavones and thioaurones in a single step. Easily accessible substrates, mild reaction conditions and compatibility with a broad range of functional groups make this protocol clean and inexpensive.

Full text of DOI:10.1080/00397911.2020.1775852

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Competitive cascade cyclization of 2′-
tosyloxychalcones: An easy access to thioflavones
and thioaurones
Somepalli Venkateswarlu, Gandrotu Narasimha Murty, Meka Satyanarayana
& Vidavalur Siddaiah
To cite this article: Somepalli Venkateswarlu, Gandrotu Narasimha Murty, Meka Satyanarayana
& Vidavalur Siddaiah (2020): Competitive cascade cyclization of 2′-tosyloxychalcones:
An easy access to thioflavones and thioaurones, Synthetic Communications, DOI:
10.1080/00397911.2020.1775852
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https://doi.org/10.1080/00397911.2020.1775852
SYNTHETIC COMMUNICATIONS
Competitive cascade cyclization of 20-tosyloxychalcones: An
easy access to thioflavones and thioaurones
Somepalli Venkateswarlua, Gandrotu Narasimha Murtya, Meka Satyanarayanaa, and
Vidavalur Siddaiahb
b
aDrug Discovery, Laila Impex Research Centre, Vijayawada, India; Department of Organic Chemistry,
School of Chemistry, Andhra University, Visakhapatnam, India
ABSTRACT
ARTICLE HISTORY
Received 7 January 2020
A new and efficient approach for the synthesis of thioflavones and
thioaurones by competitive cascade cyclization of 20-tosyloxychal-
cones has been developed. 20-Tosyloxychalcones were smoothly con-
verted into thioflavones and thioaurones by incorporation of sulfur
atom using elemental sulfur and triethylamine in DMSO with good
yields. The advantages of the methodology are the formation of
both thioflavones and thioaurones in a single step. Easily accessible
substrates, mild reaction conditions and compatibility with a broad
range of functional groups make this protocol clean and inexpen-
sive.
KEYWORDS
Cyclization; sulfur;
thioaurone; thioflavone;
20-tosyloxychalcone
GRAPHICAL ABSTRACT
Introduction
Thioflavones and thioaurones are the sulfur incorporated isosteres of the flavones and
aurones respectively, core constituents of natural product class of compounds[1,2]
(Fig. 1). These two sulfur class of compounds have a wide range of biological activities
and commercial applications. Thioflavone derivatives exhibit anti-malaria,[3] and anti-
microbial activities.[4] Besides this they have inhibitory effects of steroid sulfate (STS)[5]
and have specific inhibitions of ERK-MAP kinase signaling path way.[6] Moreover, sub-
stituted thioflavones exhibit highly potent antitumor and anti-carcinogenic effects.[7]
Thioaurones have valuable commercial applications, as these scaffolds are used in
dyes[2] and cosmetic industry.[8] Recently growing attention is to their applications in
photo responsive devices and photoswitches.[9] They are also served as useful
CONTACT Somepalli Venkateswarlu
drvsomepalli@gmail.com; somepalli01@rediffmail.com
Drug Discovery, Laila
Impex Research Centre, No. 1, Phase III, Jawahar Autonagar, Vijayawada 520007, India.
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2020.1775852
ß 2020 Taylor & Francis Group, LLC

2
S. VENKATESWARLU ET AL.
Figure 1. Structures of flavone, thioflavone and aurone, thioaurone.
intermediates for other bioactive sulfur containing molecules.[10] Thioflavones have
more of biological applications whereas thioaurones are known for their commercial
applications.
There are several methods for the synthesis of thioflavones and limited methods for
the synthesis of thioaurones. Thioflavones can be synthesized starting from (a) thiosali-
cylic acid,[11a–d] or 20-mercaptoacetophenone,[11e] (b) 20-chloroacetophenones,[12] (c) 2-
halobenzoyl chlorides,[13] (d) thiophenol,[14] (e) 2-(methylthio)benzoyl chloride,[15] (f)
methyl 2-mercaptobenzoate,[16] (g) 2-halochalcones,[17] (h) 1-(2-(methylthio)phenyl-3-
phenylprop-2-yn-1-one,[18a] and (i) thioisatins.[18b] Thioaurones can be synthesized by
the general condensation method of benzothiophene-3-one with aromatic aldehydes.
But it requires preparation of benzothiophene-3-one from the corresponding 2-mercap-
toacetophenone.[2] Other multi-step methods are from 2-mercaptobenzoate[16] or
metalation of 2-(methylthio)benzoic acid, ring closure, and aldol-type condensation[19]
or 20-nitrochalcones.[20] The above said methods have severe limitations including mul-
tistep synthesis, expensive starting materials/transition metal catalysts, and harsh reac-
tion conditions. So, more general and simple route to synthesize thioflavones and
thioaurones are still highly required.
As a part of our ongoing efforts toward the efficient synthetic methodologies of
aurones and isoaurones,[21] here we report the synthesis of thioflavones and thioaurones
by a cascade cyclization of 20-tosyloxychalcones with elemental sulfur and triethylamine
in DMSO.
Results and discussion
Conversion of 20-tosyloxychalcones to either thioflavones or thioaurones would be an
ideal method, as 20-hydroxychalcones are easily accessible. We envisioned that the tosyl
group is a good leaving group with sulfur nucleophile and further the rate of reaction is
increased by the ortho carbonyl functionality. Then the cyclization onto enone via b
and a attack could give either thioflavone or thioaurone, respectively. The 20-tosyloxy-
chalcones (1) were easily prepared[22] from the corresponding 20-hydroxychalcones. The
reaction of 20-tosyloxychalcone (1a) with elemental sulfur was chosen as a model

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3
Table 1. Optimization of the cyclizationa.
Yieldb (%)
Entry
Equiv. of sulfur
Base (Equiv.)
TEA (1)
Solvent
DMSO
Temp (ꢀC) Time (h) Thioflavone (2a) Thioaurone (3a)
1
2
3
4
5
6
7
8
1
2
3
5
10
5
5
5
5
5
5
5
5
5
5
80
80
80
80
80
rt
6
5
2
2
2
16
3
4
2
4
2
2
4
2
3
10
50
60
66
50
5
2
8
10
14
5
1.5
10
0
TEA (2)
TEA (3)
TEA (5)
TEA (10)
TEA (5)
TEA (5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PEG-400
DMSO
DMSO
DMSO
60
80
80
80
80
80
80
80
80
55
0
9
TEA (5)
TEA (5)
DIPEA (5)
DMAP (5)
K2CO3 (5)
57
50
40
55
56
20
60
10
10
9
12
10
2
10
11
12
13
14
15
Morpholine (5) DMSO
NMP (5) DMSO
13
aReaction conditions:
chromatography.
1
(0.5 mmol), sulfur powder, base, and solvent (2 mL). bIsolated yield after column
reaction to explore and optimize the cascade reaction, in the presence of various bases
and solvents. The results were summarized in Table 1.
Cyclization of 1a with elemental sulfur in the presence of triethylamine (TEA) at
room temperature gave a low yield of products and the reaction is not completed even
after 16 h (entry 6). Surprisingly at 80 ꢀC, the cyclization proceeded cleanly and gave
thioflavone (2a) as a major product and thioaurone (3a) as a minor product (entry 4)
by the formation of two new C(sp2)–S bonds from C(sp2)–OTs aromatic bond and
C(sp2)–H vinylic bond. Formation of C–S bond via cleavage of C–O bond using sulfur
and TEA is not known in the literature. Few initial experiments revealed that 5 Equiv.
of sulfur is required for completion of the reaction. In the absence of base, the reaction
is not progressing and hence, a base is essential for cyclization (entry 8). After establish-
ing the role of base, the cascade reaction is checked with other bases such as N,N-diiso-
propylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP), K2CO3, morpholine,
and N-methylpiperidine (NMP) in DMSO. The reaction proceeds with all the above
bases to give the desired products 2a and 3a but with lower yields than TEA/DMSO
(entry 11–15). Then the cyclization with TEA is also checked with other solvents but
obtained lower yields of products (entry 9, 10). Thus, cyclization of 20-tosyloxychalcone
(1a) with sulfur in presence of TEA in DMSO at 80 ꢀC for 2 h gave thioflavone (2a) in
66% yield and thioaurone (3a) in 14% yield. The structures of 2a and 3a have been
deduced from their spectroscopic data and finally confirmed by comparing them with
that described in the literature.

4
S. VENKATESWARLU ET AL.
Scheme 1. Thioflavones and thioaurones by cyclization of 20-tosyloxychalcones.
Table 2. Formation of thioflavones and thioaurones by cyclization of 1a.
Thioflavone (2)
Thioaurone (3)
S. No.
Chalcone
R1
R2
R3
R4
Comp No.
Yieldb (%)
Comp No.
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
OCH3
OCH3
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
NO2
H
H
H
H
OCH3
H
OCH3
Cl
CH3
H
N(CH3)2
OCH3
Br
OCH3
OCH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
67
62
63
66
64
68
67
58
66
63
3a
3b
3c
3d
3e
3f
3g
3h
3i
15
12
13
17
11
23
16
13
13
13
10
1j
H
2j
3j
aReaction conditions: 1 (1 mmol), sulfur powder (5 mmol), TEA (5 mmol), and DMSO (5 mL). bIsolated yields.
After having the optimized condition in hand, the scope and generality of the cycliza-
tion have been established as shown in Scheme 1. The generated substituted thiofla-
vones (2a–2j) and thioaurones (3a–3j) were summarized in Table 2. A wide variety of
substituents on both benzene rings of chalcone were tolerated including methoxy,
methyl, nitro, and halogens. Further, there is no striking change in the ratio of forma-
tion of thioflavones and thioaurones by both electron donating and electron withdraw-
ing substituents.
All the thioflavones (2a–2j) and thioaurones (3a–3j) were well characterized by their
physical and spectroscopic data. The geometry of thioaurones was assigned as Z, based
on the fact that the Z-isomer is thermodynamically more stable than E-isomer. Further,
the chemical shift (d) value of the vinylic proton, as well as carbon observed in the cor-
1
responding H and 13C NMR spectra are in line with the literature values.[1,2]
The mechanism of the cyclization is not very clear at this moment. In the present
method, we assumed that the C–O bond is broke down by the sulfur nucleophile gener-
ated by the attack of triethylamine on sulfur powder. This concept is indirectly sup-
ported by the C–N bond cleavage with the sulfur nucleophile[20]. Hence, a cascade of
sulfur nucleophilic substitution, cyclization and oxidation mechanism is described here.
Initially ring opening of the cyclic octa sulfur (cyclic-S8) by TEA leads to zwitterion 4.
The formed zwitterion (4) replaces highly labile aromatic tosyl group (also activated by
the ortho carbonyl functionality) to give 5. Sulfur is bivalent, so cyclization of 5 onto
enone either by path-a (b-attack) or path-b (a-attack) gives dihydro-derivatives of thio-
flavone and thioaurone (6 and 7). Finally, dehydrogenation of 6 and 7 gives desired
products thioflavone and thioaurone (2 and 3) respectively under reaction conditions as
depicted in Scheme 2. Attempts to isolate any of the intermediates by carrying out the
reaction at low temperatures were unsuccessful.

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5
Scheme 2. Tentative mechanism of cyclization.
Experimental
General procedure for cyclization
To a solution of 20-tosyloxychalcone (1, 1 mmol) in dry DMSO (5 mL) was added sulfur
powder (160 mg, 5 mmol) and triethylamine (0.69 mL, 5 mmol) at room temperature.
The mixture was stirred at 80 ꢀC for 2 h and poured into ice cold water (40 mL). The
mixture was stirred for 15 min and extracted with ethyl acetate (3 ꢁ 50 mL). The com-
bined EtOAc layer was washed with water (50 mL), brine (50 mL), and dried over
sodium sulfate. The solution was filtered and evaporated the solvent. The residue was
chromatographed over silica gel column using hexane: ethyl acetate mixture as eluents
to give thioaurone (3). Further elution of the column with the same solvent system gave
thioflavone (2).
6-Chloro-2-(3,4-dimethoxyphenyl)-4H-thiochromen-4-one (2j)
1
Pale yellow color solid (210 mg, 63%), mp 176–178 ꢀC. H NMR (400 MHz, CDCl3): d
8.51 (1H, d, J ¼ 0.8 Hz), 7.55–7.61 (2H, m), 7.30 (1H, dd, J ¼ 8.4, 2.0 Hz), 7.21 (1H, s),
7.18 (1H, d, J ¼ 2.0 Hz), 6.97 (1H, d, J ¼ 8.4 Hz), 3.97 (3H, s), 3.95 (3H, s); 13C NMR
(100 MHz, CDCl3): d 179.6, 153.0, 151.7, 149.7, 135.7, 134.3, 132.2, 131.9, 128.8, 128.2,

6
S. VENKATESWARLU ET AL.
127.8, 122.1, 120.0, 111.5, 109.7, 56.1, 56.1; LC-MS (positive ion mode): m/z 333, 335
(M þ H)þ; HRMS-(EI) (m/z): (M þ Na)þ calcd. for C17H13ClO3SNa 355.0171, 357.0142
found 355.0176, 357.0149.
(Z)-5-Chloro-2-(3,4-dimethoxybenzylidene)benzo[b]thiophen-3(2H)-one (3j)
1
Yellow color solid (42 mg, 13%), mp 182–184 ꢀC. H NMR (400 MHz, DMSO-d6): d
7.93 (1H, s), 7.85 (1H, d, J ¼ 8.4 Hz), 7.82 (1H, d, J ¼ 2.0 Hz), 7.77 (1H, dd, J ¼ 8.4,
2.0 Hz), 7.41 (1H, dd, J ¼ 8.4, 1.6 Hz), 7.38 (1H, d, J ¼ 1.6 Hz), 7.16 (1H, d, J ¼ 8.4 Hz),
3.86 (3H, s), 3.85 (3H, s); 13C NMR (100 MHz, DMSO-d6): d 186.1, 151.4, 149.0, 143.6,
135.1, 134.7, 131.6, 131.0, 127.2, 126.3, 126.2, 125.6, 125.3, 114.0, 112.2, 55.8, 55.6; LC-
MS (positive ion mode): m/z 333, 335 (M þ H)þ; HRMS-(EI) (m/z): (M þ Na)þ calcd.
for C17H13ClO3SNa 355.0171, 357.0142 found 355.0169, 357.0136.
Conclusions
In conclusion, we have demonstrated here a general and simple cascade method for the
synthesis of thioflavones and thioaurones in a single reaction by using 20-tosyloxychal-
cones as substrates with sulfur powder and triethylamine in DMSO. Readily accessible
precursors, single step and mild reaction conditions make this protocol clean and inex-
pensive in economical view. Additionally, this protocol is devoid of multistep synthesis,
malodorous sulfur substrates, and costly transition metal catalysts. We believe that this
cyclization cascade for the formation of both thioflavones and thioaurones in a single
reaction holds a potential value in the laboratory and industry in the near future.
1
General experimental details, characterization of compounds 2a–2i and 3a–3i, H
and 13C NMR spectra of 2a–2j and 3a–3j are provided. This material can be found via
the “Supplemental” section of this article’s webpage.
Acknowledgments
We sincerely thank Sri Gokaraju Ganga Raju, Chairman, and Mr. Gokaraju Rama Raju, Director,
Laila Impex Research Center, for support and encouragement.
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