A regioselective synthesis of novel functionalized organochalcogen compounds by chalcogenocyclofunctionalization reactions based on Chalcogen halides and natural products

Article abstract of DOI:10.3390/molecules26123729

The regioselective synthesis of novel functionalized condensed organochalcogen compounds by chalcogenocyclofunctionalization reactions based on chalcogen halides and the natural products thymol and carvacrol has been developed. The reactions of selenium d

Full text of DOI:10.3390/molecules26123729

molecules
Article
A Regioselective Synthesis of Novel Functionalized
Organochalcogen Compounds by Chalcogenocyclofunctionalization
Reactions Based on Chalcogen Halides and Natural Products
Maxim V. Musalov , Vladimir A. Potapov * , Vladimir A. Yakimov, Maria V. Musalova, Arkady A. Maylyan,
Sergey V. Zinchenko and Svetlana V. Amosova
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of The Russian Academy of Sciences,
1 Favorsky Str., 664033 Irkutsk, Russia; musalov_maxim@irioch.irk.ru (M.V.M.); yakimov@irioch.irk.ru (V.A.Y.);
musalova@irioch.irk.ru (M.V.M.); maylyan@irioch.irk.ru (A.A.M.); svz@irioch.irk.ru (S.V.Z.);
amosova@irioch.irk.ru (S.V.A.)
* Correspondence: v.a.potapov@mail.ru
Abstract: The regioselective synthesis of novel functionalized condensed organochalcogen com-
pounds by chalcogenocyclofunctionalization reactions based on chalcogen halides and the natural
products thymol and carvacrol has been developed. The reactions of selenium dibromide with
allyl thymol and allyl carvacrol proceeded in methylene chloride at room temperature in the pres-
ence of NaHCO3 affording bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and
bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenides in 90–92% yield. Similar
sulfides were obtained in 70–72% yields by the reaction of sulfur dichloride in chloroform under
reflux. Trihalotellanes containing the same organic moieties were synthesized from allyl thymol,
allyl carvacrol and tellurium tetrachloride or tetrabromide in quantitative yields. Corresponding
functionalized ditellurides were prepared in 91–92% yields by the reduction of the trichlorotellanes
with sodium metabisulfite in two-phase solvent system. The comparison of reactivity of sulfur,
selenium and tellurium halides in chalcogenocyclofunctionalization and distinguishing features of
each reaction were discussed.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Musalov, M.V.; Potapov,
V.A.; Yakimov, V.A.; Musalova, M.V.;
Maylyan, A.A.; Zinchenko, S.V.;
Amosova, S.V. A Regioselective
Synthesis of Novel Functionalized
Organochalcogen Compounds by
Chalcogenocyclofunctionalization
Reactions Based on Chalcogen
Halides and Natural Products.
Molecules 2021, 26, 3729. https://
doi.org/10.3390/molecules26123729
Keywords: thymol; carvacrol; selenium dibromide; tellurium tetrachloride; tellurium tetrabromide;
sulfur dichloride
Academic Editor: Luana Bagnoli
1. Introduction
Received: 1 June 2021
Accepted: 17 June 2021
Published: 18 June 2021
Natural products and their derivatives play an important role in the discovery of
new drugs [1–5]. Many modern drugs have been developed from natural products, and
synthesis of novel functionalized compounds based on natural products is promising in
terms of the possible manifestation of biological activity.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
The present work is devoted to regioselective synthesis of novel condensed function-
alized organochalcogen compounds by chalcogenocyclofunctionalization reactions based
on selenium dihalides, tellurium tetrahalides and sulfur dichloride and natural products,
thymol (2-isopropyl-5-methylphenol) and carvacrol (5-isopropyl-2-methylphenol). Thymol
and carvacrol are isomeriC-Natural monoterpenoid phenols, found in essential oils of
Thymus vulgaris (thyme) and Origanum vulgare (oregano) and extracted from various other
kinds of plants.
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
The thyme herb has been used in folk traditional medicine as a sedative and antiseptic
since ancient times [6]. Ancient Egyptians used thyme for embalming. The ancient Greeks
used it in their baths and burned it as incense in their temples, believing it was a source of
courage. The spread of thyme throughout Europe was thought to be due to the Romans,
as they used it to purify their rooms and to give an aromatic flavor to some food and
liqueurs [7]. Its extract was used as a natural antibacterial gargle for sore throat and colds.
Molecules 2021, 26, 3729. https://doi.org/10.3390/molecules26123729
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3729
2 of 15
Not only thymol and carvacrol derivatives, but these natural products themselves
show various types of biological activity [
dustry and pharmacotherapy due to its antibiotic [
and antileishmanial [14] properties and general non-genotoxicity or cytotoxicity on hu-
man cells [15 17]. Besides, thymol is applied as an active antiseptic ingredient in some
toothpastes, medicinal ointments and drugs for inhalation. This natural product is also
proposed as an environmental-friendly, rapidly degrading and non-persisting pesticide [ ].
Derivatives of thymol and carvacrol exhibit a variety of biological activities [18–37] includ-
ing antibacterial [18 22 24], antifungal [27 29], antitubercular [32] and anticancer [35–37]
8
–18]. Thymol is widely used in the chemical in-
9,
10], anticancer [11], insecticidal [12,13]
–
8
,
–
–
properties (some examples of biologically active thymol and carvacrol derivatives are
presented in Figure 1). Simplest derivatives of these natural products such as allyl ether of
thymol and allyl-substituted thymol (4-allyl-2-isopropyl-5-methylphenol) display antibac-
terial activity [18].
H
N
OH
O
N
O
S
OH
O
O
O
OH
OH
O
O
Antibacterial activity
Anticancer activity
Anticancer activity
N
O
N
O
SO2NH2
O
O
OH
O
N
O
O
O
S
N
H
S
Cl
HN
N
OH
H
O
O
Antibacterial activity
Anticancer activity
Antifungal activity
23], anticancer [18 35 37] and antifun-
Figure 1. Known derivatives of thymol and carvacrol exhibiting antibacterial [18
,22
,
,
–
gal [27] activities.
The discovery of the biological role of selenium gave a powerful impetus to the rapid
development organoselenium chemistry, which is currently occupied an important place
in chemical research. It is worth noting that organoselenium compounds and especially
selenium-containing heterocycles show a variety of biological activities including an-
tibacterial, antitumor, anti-inflammatory, neuroprotective and glutathione peroxidase-like
actions [38–47].
In recent years, chalcogen-induced cyclization and especially selenocyclofunctional-
ization reactions have acquired particular importance as valuable tools for modern organic
synthesis. The growing interest in selenocyclofunctionalization was demonstrated in
excellent books and reviews [45–54].
Similar methodology of intramolecular halocyclization of alkenes containing nucle-
ophilic functions which afford useful heterocyclic compounds including nitrogen heterocy-
cles are well documented in the literature [55–57]. However, opportunities of selenocyclo-
functionalization reactions have not yet been fully realized.
Addition products of selenenyl halides to alkenes are very reactive in nucleophilic
substitution reactions since halogen atoms in β-haloorganyl selenides are activated by

Molecules 2021, 26, 3729
3 of 15
anchimeric assistance of the selenium atom [58]. The high anchimeric assistance effect
of the selenium atom plays an important role in selenocyclofunctionalization reactions
which include intramolecular nucleophilic substitution. This effect leads to considerable
activation of halogen atoms to nucleophilic substitution and intramolecular cyclization
reactions proceed very smoothly. It has been found that the anchimeric assistance effect of
the selenium atom is approximately two orders of magnitude greater than the analogous
effect of the sulfur and nitrogen atoms [58].
Previously, we first introduced selenium dihalides in organic synthesis for preparation
of organoselenium compounds [59–61] and used these reagents for selenocyclofunctional-
ization reactions [62 69]. The application of selenium dihalides in selenocyclofunctional-
–
ization allows to carry out two heterocyclization processes in one molecule and to obtain
selenides containing two heterocyclic moieties [62–69].
Previously we studied annulation reactions of selenium dihalides with allyl thymyl
and allyl carvacryl ethers (Scheme 1) [70,71]. A novel methodology to accelerate annulation
reactions leading to condensed selenium heterocycles was developed. The reactions of sele-
nium dihalides with allyl thymyl and allyl carvacryl ethers (as well as with methyleugenol,
allyl 1-naphthyl and 1-naphthyl propargyl ethers) were carried out in solvent systems
CH2Cl2/ROH or CHCl3/ROH. It was found that addition of alcohol to methylene chloride
or chloroform considerably accelerated annulation reactions [70,71]. In solvent systems
CH2Cl2/MeOH or CHCl3/MeOH, the reactions proceeded as annulation–methoxylation af-
fording condensed methoxylated heterocycles. In the presence of isopropanol, the reactions
were not accompanied by alkoxylation giving condensed halogen-containing products
(Scheme 1). The annulation–acetoxylation reaction of selenium dibromide with allyl car-
vacryl ether in the solvent system CH2Cl2/acetic acid affording bicylic acetoxy derivative in
98% yield was also developed [71]. Novel condensed functionalized products, 2,3-dihydro-
1,4-benzoxaselenine derivatives, bearing methoxy, acetoxy and halogen-containing groups
were synthesized in high yields from selenium dihalides and allyl thymyl and allyl car-
vacryl ethers using this novel methodology (Scheme 1) [70,71].
O
SeBr2
SeX2
O
O
CH2Cl2/MeOH
CH2Cl2/i-PrOH
X
OMe
Se
Se
RT
RT
86-90%
90%
O
SeBr2
SeBr2
O
O
CH2Cl2/MeOH
CH2Cl2/AcOH
OAc
OMe
Se
Se
RT
RT
98%
98%
X = Cl, Br
Scheme 1. Synthesis of novel condensed products by the annulation reactions of selenium dibromide with allyl carvacryl
and allyl thymyl ethers.
2. Results and Discussion
The aim of this research is to develop an efficient regioselective synthesis of novel con-
densed functionalized organochalcogen compounds by chalcogenocyclofunctionalization
reactions based on chalcogen halides and natural products thymol (1) and carvacrol (2).
Starting compounds allyl ethers of thymol and carvacrol were prepared by the reaction of
thymol and carvacrol with allylbromide in the presence of a base. Usually strong bases

Molecules 2021, 26, 3729
4 of 15
as sodium hydroxide or potassium carbonate are often used in alkylation reactions of
phenols [72]. We developed efficient green chemistry synthesis of allyl thymyl ether
3
and allyl carvacryl ether in near quantitative yields (97–98%) at room temperature using
4
environmentally tolerant sodium hydrocarbonate (NaHCO3, baking soda, E number food
additive code is E500) instead of strong bases like alkalis or carbonates (Scheme 2).
200 oC
Br
DMSO/NaHCO3
NaHCO3
71%
OH
O
OH
RT
97%
5
3
1
200 oC
Br
DMSO/NaHCO3
NaHCO3
70%
OH
O
OH
RT
98%
2
6
4
and allyl carvacrol
2 with allyl bromide followed by Claisen rearrangement of compounds 3 and 4.
Scheme 2. Synthesis of allyl thymol
5
6
by the reaction of thymol
1
and carvacrol
The conversion of allyl ethers
developed using Claisen rearrangement (Scheme 2). It was established that the products
and were formed in 75–80% yields when the reaction was carried out by heating
allyl ethers and
at 200 ◦C for 2 h in sealed tubes. The reaction is a [3,3]-sigmatropic
3 and 4 to corresponding allyl phenols 5 and 6 was
5
6
3
4
rearrangement which leads to the formation of new carbon-carbon bond. It was found
that an additive of sodium hydrocarbonate increases selectivity of the rearrangement.
Pure products
yields (Scheme 2). Minor amounts of allyl ethers
rearrangement, however, products
separated from them.
5
and
6
were isolated by column chromatography on silica gel in 70–71%
and remained unconverted in Claisen
containing a polar hydroxyl group can be easily
3
4
5 and 6
We studied the reactions of selenium dihalides with allyl thymol
5 and allyl carvacrol
6
and found that selenium dibromide is more efficient than selenium dichloride in seleno-
cyclofunctionalization. The reactions smoothly proceeded in methylene chloride at room
temperature. After completing the first stage (electrophilic addition of selenium dibromide
to the double bond of allyl thymol 5 and allyl carvacrol 6), sodium hydrocarbonate as a mild
base was added to the reaction mixture in order to catalyze intramolecular nucleophilic
substitution of the bromine atom by the hydroxyl group with the formation of bis[(7-
isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and bis[(4-isopropyl-7-methyl-
2,3-dihydro-1-benzofuran-2-yl)methyl] selenides
7 and 8 in 90–92% yield (Scheme 3). In
the case of using selenium dichloride, the yields of products 7 and 8 were 67–70%.

Molecules 2021, 26, 3729
5 of 15
CH2Cl2/NaHCO3
+ SeBr2
RT
Se
OH
O
O
90%
7
5
CH2Cl2/NaHCO3
+ SeBr2
RT
Se
OH
92%
O
O
8
6
Scheme 3. Synthesis of selenides
and allyl carvacrol 6.
7 and 8 by the reaction of selenium dibromide with allyl thymol 5
The reaction of sulfur dichloride with allyl thymol
sluggish under the same conditions as synthesis of selenium analogues
5
and allyl carvacrol
and
6
was very
7
8. Heating
under reflux in chloroform was found to be necessary in order to accelerate the reaction.
Besides, using a 20% excess of sulfur dichloride is advisable, otherwise a part of allyl
thymol
5 and allyl carvacrol 6 stayed unconverted. After heating under reflux, sodium
hydrocarbonate was added in order to catalyze intramolecular nucleophilic substitution
and the reaction mixture was stirred overnight at room temperature. Bis[(7-isopropyl-4-
methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and bis[(4-isopropyl-7-methyl-2,3-dihydro-
1-benzofuran-2-yl)methyl] sulfides 9 and 10 were isolated by column chromatography on
silica gel in 70 and 72% yields, respectively (Scheme 4).
CHCl3/NaHCO3
+ SCl2
S
Reflux
70%
OH
O
O
9
5
CHCl3/NaHCO3
+ SCl2
S
Reflux
72%
OH
O
O
10
6
Scheme 4. Synthesis of sulfides 9 and 10 by the reaction of sulfur dichloride with allyl thymol 5 and allyl carvacrol 6.
We suppose that heating accelerates isomerization of primarily formed anti-Markovnikov
adducts
A into Markovnikov products B followed by intramolecular nucleophilic substitu-
tion with the formation of (2,3-dihydro-1-benzofuran-2-yl)methyl moiety (Scheme 5). It is
known that electrophilic addition of sulfenyl halides to 1-alkenes leads predominantly to
anti-Markovnikov products [73–75].

Molecules 2021, 26, 3729
6 of 15
Alk
Alk
R
Alk
R
Heating
Y
+ YX2
OH
X X
HO
OH
R
5, 6
A
Alk
O
Alk
O
Alk
R
Alk
Y
NaHCO3
X
X
Y
HO
OH
R
R
R
B
7-10
YX2 = SeBr2, SeCl2 (7, 8); YX2 = SCl2 (9, 10); Alk = Me, R = i-Pr (5, 7, 9); Alk = i-Pr, R = Me (6, 8, 10)
Scheme 5. A supposed pathway of the reactions of SeBr2, SeCl2 and SCl2 with allyl thymol 5 and allyl carvacrol 6.
We suppose that similar consequence of transformations (Scheme 5) also takes place
in selenocyclofunctionalization reactions (Scheme 3). The isomerization process and in-
tramolecular nucleophilic substitution proceed smoothly at room temperature due to
high anchimeric assistance effect of the selenium atom, which activates halogen atoms
in β-haloorganyl selenides B (Scheme 5) [58]. Previously, we observed the formation of
anti-Markovnikov adducts in the reactions of selenium dibromide with 1-alkenes and
their isomerization into thermodynamically more stable Markovnikov products at room
temperature [76,77]. The bromine atom is better leaving group compared to the chlorine
atom in nucleophilic substitution and selenium dibromide is more efficient than selenium
dichloride in these reactions.
Tellurium tetrachloride and tetrabromide were used in the cyclofunctionalization
reactions with allyl thymol
reactions with each of these tellurium-centered electrophilic reagents were established.
We found that the reactions of tellurium tetrachloride with allyl thymol and allyl car-
vacrol
proceeded smoothly in methylene chloride at the temperature 35–40 ◦C affording
5 and allyl carvacrol 6, and conditions for efficient selective
5
6
trichlorotellanes 11 and 12 bearing the (2,3-dihydro-1-benzofuran-2-yl)methyl moiety in
quantitative yields (Scheme 6).
CH2Cl2
+ TeCl4
35_40 oC
~100%
TeCl3
OH
O
11
5
CH2Cl2
+ TeCl4
35_40 oC
~100%
TeCl3
OH
O
12
6
Scheme 6. Synthesis of tellanes 11 and 12 by the reaction of tellurium tetrachloride with allyl thymol
5 and allyl carvacrol 6.

Molecules 2021, 26, 3729
7 of 15
The disadvantage of using tellurium tetrabromide is the low solubility of this reagent
in most common organic solvents (chloroform, methylene chloride, benzene, diethyl ether,
carbon tetrachloride). However, we found that the reactions of tellurium tetrabromide with
allyl thymol
5 and allyl carvacrol 6 can be efficiently carried out in acetonitrile at room
temperature affording tribromotellanes 13 and 14 in quantitative yield (Scheme 7).
MeCN
+ TeBr4
RT
TeBr3
OH
O
~100%
13
5
MeCN
+ TeBr4
RT
TeBr3
OH
~100%
O
14
6
Scheme 7. Synthesis of tellanes 13 and 14 by the reaction of tellurium tetrabromide with allyl thymol
5 and carvacrol 6.
The intramolecular substitution is activated by anchimeric assistance of the selenium
atom in the reactions with selenium dibromide (Scheme 3), however, in the case of tel-
lurium tetrachloride and tetrabromide (Schemes 6 and 7), the halogen atom in the addition
products is very reactive due to high electron-withdrawing effect of trichlorotellanyl and
tribromotellanyl groups.
It is worth noting that reactions of tellurium tetrachloride and tetrabromide with allyl
thymol 5 and allyl carvacrol 6 proceeded with high selectivity in a regiospecific manner
affording only monoadducts 11–14 in quantitative yields (Schemes 6 and 7).
Finally, we obtained functionalized ditellurides 15 and 16 bearing the (2,3-dihydro-1-
benzofuran-2-yl)methyl moiety in 91–92% yields by the reduction of trichlorotellanes 11
and 12 with sodium metabisulfite (Scheme 8). The reactions were selectively carried out in
the two-phase solvent system of water and methylene chloride at room temperature giving
the products 15 and 16, which did not require additional purification.
CH2Cl2/H2O/Na2S2O5
TeCl3
Te Te
RT
O
O
O
91%
11
15
CH2Cl2/H2O/Na2S2O5
RT
92%
TeCl3
Te
Te
O
O
O
12
16
Scheme 8. Synthesis of ditellurides 15 and 16 by the reduction of trichlorotellanes 11 and 12 with sodium metabisulfite.

Molecules 2021, 26, 3729
8 of 15
The obtained products represent a new family of organochalcogen compounds bearing
(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl and (4-isopropyl-7-methyl-
2,3-dihydro-1-benzofuran-2-yl)methyl moieties with promising biological activity.
The structural assignments of the synthesized compounds were made using 1H-, 13C-,
77Se- and 125Te-NMR spectroscopy and confirmed by elemental analysis. The compounds
7–10, 15, 16 consist of two diastereomers (dl and meso) approximately in an equimolar ratio.
Two closely spaced signals which correspond to two diastereomers were observed in the
77Se NMR spectra of compounds 7 and 8.
The signals of the CH2TeCl3 and CH2TeBr3 groups in 13C-NMR spectra of compounds
11–14 manifest themselves in the downfield region (66.0–66.3 and ~61.5 ppm) due to high
electron-withdrawing effect of trichlorotellanyl and tribromotellanyl groups. The signals of
the CH2Te group in 13C-NMR spectra of ditellurides 15 and 16 are observed in the upfield
region (~11.8 ppm).
The tellurium atom of the CH2TeCl3 group in 125Te NMR spectra of compounds 11
and 12 resonated in the downfield region (1206.3 and 1204.0 ppm) due to the presence
of three electronegative chlorine atoms. However, the signals in 125Te-NMR spectra of
ditellurides 15 and 16, which were obtained by the reduction of compounds 11 and 12
,
were observed in the upfield region (77.9 and 84.0 ppm).
3. Experimental Section
3.1. General Information
The 1H (400.1 MHz), 13C (100.6 MHz), 77Se (76.3 MHz) and 125Te (126.4 MHz) NMR
spectra (see Supplementary Materials) were recorded on a Bruker DPX-400 spectrometer
(Bruker BioSpin GmbH, Rheinstetten, Germany) in CDCl3 and d6-DMSO solutions and
referred to the residual solvent peaks of CDCl3 (
δ
= 7.27 and 77.16 ppm in 1H- and 13C-
NMR, respectively) and d6-DMSO (
δ
= 2.50 and 39.5 ppm in 1H- and 13C-NMR) or Me2Se
(77Se-NMR, external) and Me2Te (125Te-NMR, external). Elemental analysis was performed
on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan,
Italy). Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A
apparatus (Wagner & Munz GmbH, Munich, Germany). The organic solvents were dried
and distilled according to standard procedures. Silica gel (0.06–0.20 mm (70–230 mesh, Alfa
Aesar, Heysham, Lancashire, United Kingdom) was used for column chromatography.
3.2. Synthesis of Starting Compounds 5 and 6
2-Allyl-6-isopropyl-3-methylphenol (
and dry powdered NaHCO3 (1 g, 12 mmol) was heated at 200 ◦C for 2 h in a sealed tube
under argon. Compound (2.84 g, 71% yield) was isolated as a colourless liquid by column
5). A mixture of allyl thymyl ether 3 (4 g, 21 mmol)
5
chromatography on silica gel (eluent: hexane, then hexane/methylene chloride 1:10).
1H-NMR (CDCl3): 1.39 (d, 6H, CH3CH, J = 7 Hz), 2.41 (s, 3H,CH3CAr), 3.26–3.35 (m,
1H, CH3C
6.06–6.16 (m, 1H, CH2=C
13C-NMR (CDCl3): 19.7 (
H2=CH), 122.5 (CHAr), 123.2 (CH2CAr), 123.9 (CHAr), 132.4 (CHCAr), 134.9 (CH3CAr),
135.7 (CH2= H), 151.6 (CArOH). Anal. calcd for C13H18O (190.28): C 82.06, H 9.53%.
H
), 3.55–3.58 (m, 2H, CH2CAr), 5.10 (s, 1H, OH), 5.21–5.27 (m, 2H, CH2=CH),
), 6.91 (d, 1H, CHAr, J = 7.8 Hz), 7.15 (d, 1H, CHAr, J = 7.8 Hz).
H3CAr), 22.8 ( H3CH), 27.0 (CH3 H), 31.3 ( H2CAr), 116.0
H
C
C
C
C
(
C
C
Found: C 82.31, H 9.38%.
2-Allyl-3-isopropyl-6-methylphenol (6) was obtained as a colourless liquid (2.80 g, 70%
yield) from allyl carvacryl ether 4 (4 g, 21 mmol) and dry powdered NaHCO3 (1 g, 12 mmol)
by heating the mixture at 200 ◦C for 2 h in a sealed tube followed by isolation by column
chromatography on silica gel (eluent: hexane, then hexane/methylene chloride 1:10).
1H-NMR (CDCl3): 1.34 (d, 6H, CH3CH, J = 7 Hz), 2.34 (s, 3H,CH3CAr), 3.19–3.25 (m,
1H, CH3C
6.08–6.18 (m, 1H, CH2=C
13C-NMR (CDCl3): 15.9 (
H2=CH), 117.3 (CHAr), 121.1 (CH3CAr), 122.1 (CH2CAr), 128.9 (CHAr), 136.6 (CH2=C
H
), 3.60–3.63 (m, 2H, CH2CAr), 5.03 (s, 1H, OH), 5.16–5.25 (m, 2H, CH2=CH),
), 6.95 (d, 1H, CHAr, J = 7.9 Hz), 7.14 (d, 1H, CHAr J = 7.9 Hz
H3CAr) 24.1 ( H3CH), 29.3 (CH3 H), 30.1 ( H2CAr), 115.8
H),
H
C
,
)
C
C
C
(C

Molecules 2021, 26, 3729
9 of 15
146.1 (CHCAr), 152.4 (CArOH). Anal. calcd for C13H18O (190.28): C 82.06, H 9.53%. Found:
C 82.24, H 9.67%.
3.3. Synthesis of Products 7–16
Bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenide (7). A solution
of selenium dibromide (0.5 mmol) was prepared from selenium (0.04 g, 0.5 mmol) and
bromine (0.08 g, 0.5 mmol) in methylene chloride (2 mL). The obtained solution of selenium
dibromide (0.5 mmol) was added dropwise to a solution of allyl thymol
5 (0.19 g, 1 mmol)
in methylene chloride (10 mL). The mixture was stirred for 7 h at room temperature
and NaHCO3 (0.17 g, 2 mmol) was added. The mixture was stirred overnight (14 h) at
room temperature. The mixture was filtered and the solvent was removed by a rotary
evaporator. The residue was subjected to column chromatography on silica gel (eluent:
hexane, then hexane/chloroform 1:10). Compound
as a colourless viscous oil. H-NMR (CDCl3): 1.26 (d, 12H, CH3CH, J = 6.8 Hz), 2.19 (d,
7 (0.206 g, 90% yield) was isolated
1
6H,CH3CAr
3.10–3.20 (m
2H, CHAr
J = 7.7 Hz), 6.95 (d, 2H, CHAr, J = 7.7 Hz). 13C-NMR (CDCl3): 15.1 (
15.1 ( H3CAr), 23.0 ( H3CH), 23.0 ( H3CH), 29.7 (CH2Se), 30.0 (CH2Se), 31.4 (CH3
35.0 (
,
J = 7.2 Hz), 2.83–2.91 (m, 2H, CH3C
2H, CH2Se), 3.35–3.43 (m, 2H, CH2CAr), 5.02–5.09 (m, 2H, CHO), 6.71 (d,
H3CAr),
H),
H), 2.93–3.06 (m, 4H, CH2Se, CH2CAr),
,
,
C
C
C
C
C
C
H2CAr), 82.5 (CHO), 117.0 (CHAr), 123.2 (CH2CAr), 123.2 (CH3CAr), 129.7 (CHAr),
143.0 (CHCAr), 157.4 (CArO). 77Se-NMR (CDCl3): 103.1, 104.4. Anal. calcd for C26H34O2Se
(457.51): C 68.26, H 7.49, Se 17.26%. Found: C 68.48, H 7.64, Se 17.49%.
Bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenide (
as a colourless viscous oil (0.211 g, 92% from selenium dibromide (0.5 mmol) and allyl
carvacrol (0.19 g, 1 mmol) in methylene chloride under the same conditions as compound
1H-NMR (CDCl3): 1.27 (d, 12H, CH3CH, J = 6.8 Hz), 2.25 (s, 6H,CH3CAr), 2.94–3.02
(m, 4H, CH3CH, H2Se), 3.06–3.19 (m, 4H, CH2Se, CH2CAr), 3.29–3.36 (m, 2H, CH2CAr),
5.05–5.09 (m, 2H, CHO), 6.69 (d, 2H, CHAr, J = 7.6 Hz), 6.97 (d, 2H, CHAr, J = 7.6 Hz).
13C-NMR (100 MHz,CDCl3): 18.7 (
H3Ar), 22.6 ( H3CH), 28.2 (CH3 H), 29.7 (CH2Se),
30.0 (CH2Se), 35.1 ( Ar), 125.1 (HCAr), 127.9
8) was obtained
6
7.
C
C
C
C
C
H2Ar), 82.5 (CHO), 121.6 (HCAr), 124.9 (CH2C
(CHCAr), 132.0 (CH3CAr), 156.4 (OCAr). 77Se NMR (,CDCl3): 106.4, 108.2. Anal. calcd for
C26H34O2Se (457.51): C 68.26, H 7.49, Se 17.26%. Found: C 67.98, H 7.65, Se 17.47%.
Bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] sulfide (
sulfur dichloride (0.62 g, 0.6 mmol) in methylene chloride (2 mL) was added dropwise to a
solution of allyl thymol (0.19 g, 1 mmol) in methylene chloride (10 mL). The mixture was
9). A solution of
5
stirred for 1 h at room temperature and refluxed for 7 h. NaHCO3 (0.25 g, 3 mmol) was
added and the mixture was stirred overnight (14 h) at room temperature. The mixture was
filtered and the solvent was removed by a rotary evaporator. The residue was subjected
to column chromatography on silica gel (eluent: hexane, then hexane/chloroform 1:10).
Compound
(CDCl3): 1.25 (d, 12H, C
9
(0.144 g, 70% yield) was isolated as a colourless viscous oil. 1H-NMR
H
3CH, J = 6.6 Hz), 2.24 (s, 6H,CH3CAr), 2.88–2.96 (m, 2H, CH3CH),
2.97–3.02 (m, 2H, CH2S), 3.05–3.08 (m, 2H, CH2CAr), 3.09–3.16 (m, 2H, CH2S), 3.25–3.31
(m, 2H, CH2CAr), 4.98–5.06 (m, 2H, CHO), 6.68 (d, 2H, CHAr, J = 7.9 Hz), 6.96 (d, 2H,
CHAr H), 34.3
,
J = 7.9 Hz). 13C-NMR (CDCl3): 18.7 (
C
H3CAr), 22.6 (
CH3CH), 28.2 (CH3
C
(
CH2CAr), 37.7 (CH2S), 38.1 (CH2S), 82.1 (CHO), 121.6 (CHAr), 124.8 (CH2CAr), 125.1
(CHAr), 127.9 (CHCAr), 132.1 (CH3CAr), 156.4 (CArO). Anal. calcd for C26H34O2S (410.61):
C 76.05, H 8.35, S 7.81%. Found: C 76.28, H 8.19, S 7.65%.
Bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] sulfide (10) was obtained
as a colourless viscous oil (0.148 g, 72% yield) from sulfur dichloride (0.62 g, 0.6 mmol)
and allyl carvacrol 6 (0.19 g, 1 mmol) in methylene chloride under the same conditions as
compound 9. 1H-NMR (CDCl3): 1.23 (d, 12H, CH3CH, J = 6.5 Hz), 2.16 (d, 6H,CH3CAr
,
J = 10.8 Hz), 2.81–2.95 (m, 4H, CH3C
H2S), 3.30–3.36 (m, 2H, CH2CAr), 4.95–5.02 (m, 2H, CHO), 6.68 (d, 2H, CHAr
6.91 (d, 2H, CHAr, J = 7.5 Hz). 13C-NMR (CDCl3): 15.1 (
H3CAr), 15.1 ( H3CAr), 23.0
H3CH), 23.0 ( H3CH), 31.5 ( H2CAr), 34.3 (CH3 H), 37.8 (CH2S), 38.2 ( H2S), 82.3
H
, C
H
2S), 2.99–3.06 (m, 2H, CH2CAr), 3.09–3.15 (m
, 2H,
C
,
J = 7.5 Hz),
C
C
(
C
C
C
C
C

Molecules 2021, 26, 3729
10 of 15
(CHO), 117.0 (CH3CAr), 117.1 (CHAr), 123.2 (CH2CAr), 129.7 (CHAr), 143.0 (CHCAr), 157.4
(CArO). Anal. calcd for C26H34O2S (410.61): C 76.05, H 8.35, S 7.81%. Found: C 75.91, H
8.54, S 7.76%.
Trichloro[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-
solution of allyl thymol (0.19 g, 1 mmol) in methylene chloride (2 mL) was added dropwise
λ
4-tellane (11). A
5
to a stirred mixture of tellurium tetrachloride (0.27 g, 1 mmol) and methylene chloride
◦
(
10 mL). The obtained mixture was stirred at room temperature for 2 h and at 35–40 C for
6 h. The solvent was removed by a rotary evaporator and the residue was dried in vacuum.
Compound 11 (0.423 g, quantitative yield) was isolated as a grey viscous oil.
1H-NMR (CDCl3): 1.20 (d, 3H, C
H
3CH, J = 7.1 Hz), 1.29 (d, 3H, C
2.28 (s, 3H,CH3CAr), 2.97–3.04 (m, 1H, CH3C ), 3.26–3.33 (m, 1H, CH2CAr), 3.51–3.57
(m, 1H, CH2CAr), 4.54–4.65 (m, 2H, CH2Te), 5.85–5.93 (m, 1H, CHO), 6.85 (d, 1H, CHAr
J = 7.7 Hz), 7.08 (d, 1H, CHAr, J = 7.7 Hz). 13C-NMR (DMSO-d6): 18.5 (
H3CAr), 22.4
H2CAr), 66.3 (CH2Te), 79.2 (CHO), 121.6
H3CH, J = 7.1 Hz),
H
,
C
(CH3CH), 22.5 (CH3CH), 27.8 (CH3CH), 35.3 (C
(CHAr), 124.7 (CH2CAr), 124.8 (CHAr), 127.1 (CHCAr), 131.7 (CH3CAr), 155.4 (CArO). 125Te-
NMR (DMSO-d6): 1206.3. Anal. calcd for C13H17OCl3Te (423.23): C 36.79, H 4.05, Cl 25.13,
Te 30.15%. Found: C 36.96, H 3.98, Cl 25.29, Te 29.98%.
Trichloro[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-
obtained as a colourless viscous oil (0.423 g, quantitative yield) from tellurium tetrachloride
(0.27 g, 1 mmol) and allyl carvacrol (0.19 g, 1 mmol) in methylene chloride under the
same conditions as compound 11. 1H-NMR (CDCl3): 1.20 (d, 3H, CH3CH, J = 6.9 Hz), 1.30
(d, 3H, CH3CH, J = 6.9 Hz), 2.22 (s, 3H,CH3CAr), 2.88–2.96 (m, 1H, CH3C ), 3.31–3.38
λ
4-tellane (12) was
6
H
(m, 1H, CH2CAr), 3.54–3.62 (m, 1H, CH2CAr), 4.50–4.61 (m, 2H, CH2Te), 5.86–5.93 (m, 1H,
CHO), 6.90 (d, 1H, CHAr, J = 7.8 Hz), 7.08 (d, 1H, CHAr, J = 7.8 Hz). 13C-NMR (DMSO-d6):
15.0 (CH3CAr), 22.7 (CH3CH), 23.0 (CH3CH), 30.0 (CH3CH), 35.1 (CH2CAr), 66.0 (CH2Te),
79.2 (CHO), 116.2 (CHAr), 117.1 (CH2CAr), 122.9 (CH3CAr), 129.3 (CHAr), 142.6 (CHCAr),
156.4 (CArO). 125Te-NMR (DMSO-d6): 1204.0. Anal. calcd for C13H17OCl3Te (423.23): C
36.89, H 4.15, Cl 25.13, Te 30.15%. Found: C 37.08, H 4.03, Cl 24.92, Te 30.32%.
Tribromo[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-
solution of allyl thymol (0.19 g, 1 mmol) in acetonitrile (2 mL) was added to a stirred
λ
4-tellane (13). A
5
mixture of tellurium tetrabromide (0.27 g, 1 mmol) in acetonitrile (8 mL). The obtained
mixture was stirred at room temperature overnight (16 h). The solvent was removed
by a rotary evaporator and the residue was dried in vacuum. Compound 13 (0.423 g,
1
quantitative yield) was obtained as a light orange powder, mp 61–63 ◦C (decomp.). H-
NMR (CDCl3): 1.03 (d, 3H, CH3CH, J = 6.8 Hz), 1.05 (d, 3H, CH3CH, J = 6.8 Hz), 2.04
(s, 3H,CH3CAr), 2.82–2.92 (m, 1H, CH3CH), 3.09–3.16 (m, 1H, CH2CAr), 3.27–3.33 (m, 1H,
CH2CAr), 3.87–3.96 (m, 1H, CH2Te), 4.04–4.15 (m, 1H, CH2Te), 5.48–5.55 (m, 1H, CHO),
6.46 (d, 1H, CHAr, J = 7.9 Hz), 6.73 (d, 1H, CHAr, J = 7.9 Hz). 13C-NMR (CDCl3/DMSO-d6):
18.1 (CH3CAr), 21.9 (CH3CH), 27.4 (CH3CH), 34.9 (CH2CAr), 61.5 (CH2Te), 79.5 (CHO),
121.0 (CHAr), 124.2 (CH2CAr), 124.2 (CHAr), 127.1 (CHCAr), 131.5 (CH3CAr), 155.2 (CArO).
Anal. calcd for C13H17OBr3Te (556.58): C 28.05, H 3.08, Br 43.07, Te 22.93%. Found: C 27.78,
H 2.99, Br 43.34, Te 23.17%.
Tribromo[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl]-
quantitative yield) was obtained as a light orange powder, mp 59–61 ◦C (decomp.) from
tellurium tetrabromide (0.27 g, 1 mmol) and allyl carvacrol (0.19 g, 1 mmol) in acetonitrile
under the same conditions as compound 13. 1H-NMR (CDCl3): 0.95 (d, 3H, CH3CH,
J = 6.8 Hz), 0.96 (d, 3H, C 3CH, J = 6.8 Hz), 1.89 (s, 3H,C 3CAr), 2.56–2.67 (m, 1H, CH3C ),
λ ,
4-tellane (14) (0.423 g
6
H
H
H
3.20–3.26 (m, 2H, CH2Te) 3.81–3.88 (m, 1H, CH2CAr), 3.99–4.03 (m, 1H, CH2CAr), 5.38–5.45
(m, 1H, CHO), 6.40 (d, 1H, CHAr, J = 7.8 Hz), 6.63 (d, 1H, CHAr, J = 7.8 Hz). 13C-NMR
(CDCl3/DMSO-d6): 14.5 (
CH3CAr), 22.2 (CH3CH), 22.4 (CH3CH), 30.6 (CH3CH), 34.5
(
CH2CAr), 61.5 (CH2Te), 79.6 (CHO), 116.0 (CHAr), 116.4 (CH2CAr), 122.5 (CH3CAr), 128.7
(CHAr), 142.5 (CHCAr), 156.2 (CArO). Anal. calcd for C13H17OBr3Te (556.58): C 28.05, H
3.08, Br 43.07, Te 22.93%. Found: C 28.16, H 3.13, Br 43.29, Te 23.14%.

Molecules 2021, 26, 3729
11 of 15
Bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] ditelluride (15). A solution
of Na2S2O5 (1.2 g, 6.3 mmol) in water (8 mL) was added to a stirred mixture of trichlorotel-
lane 11 (0.423 g, 1 mmol) in methylene chloride (10 mL). The obtained mixture was stirred
at room temperature for 6 h. The organic layer was separated and the aqueous phase
was extracted by methylene chloride (8 mL). The combined organic phase was dried over
CaCl2, the solvent was removed by a rotary evaporator and the residue was dried in
vacuum. Compound 15 (0.288 g, 91% yield) was obtained as a dark orange viscous oil.
1H-NMR (CDCl3): 1.15 (d, 12H, C
CH2CAr), 2.89–2.98 (m, 2H, CH3C
3.54–3.60 (m, 2H, CH2Te), 4.83–4.90 (m, 2H, CHO), 6.55 (d, 2H, CHAr, J = 7.3 Hz), 6.83 (d,
2H, CHAr, J = 7.3 Hz). 13C-NMR (CDCl3): 11.8 (CH2Te), 18.6 (
H3CAr), 22.3 ( H3CH), 22.5
H2CAr), 83.7 (CHO), 121.5 (CHAr), 124.8 (CH2 Ar), 125.0
H3CH, J = 6.9 Hz), 2.11 (s, 6H,C
H3CAr), 2.76–2.83 (m, 2H,
H
), 3.18–3.24 (m, 2H, CH2CAr), 3.42–3.47 (m, 2H, CH2Te),
C
C
(CH3CH), 28.2 (CH3
C
H), 35.6 (
C
C
(CHAr), 127.8 (CHCAr), 131.9 (CH3CAr), 156.2 (CArO). 125Te-NMR (100 MHz, CDCl3): 77.9.
Anal. calcd for C26H34O2Te2 (633.75): C 49.27, H 5.41, Te 40.27%. Found: C 49.49, H 5.46,
Te 40.08%.
Bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] ditelluride (16) was ob-
tained as a dark orange viscous oil (0.291 g, 92% yield) from trichlorotellane 12 (0.423 g,
1 mmol) and Na2S2O5 (1.2 g, 6.3 mmol) in the two-phase solvent system of water (8 mL)
and methylene chloride (10 mL). 1H-NMR (CDCl3): 1.14 (d, 12H, CH3CH, J = 7.0 Hz), 2.08
(s, 6H,CH3CAr), 2.71–2.78 (m, 2H, CH3CH), 2.83–2.89 (m, 2H, CH2CAr), 3.25–3.32 (m, 2H,
CH2CAr), 3.40–3.48 (m, 2H, CH2Te), 3.56–3.63 (m, 2H, CH2Te), 4.84–4.91 (m, 2H, CHO), 6.59
(d, 2H, CHAr, J = 7.7 Hz), 6.83 (d, 2H, CHAr, J = 7.7 Hz). 13C-NMR (CDCl3): 11.8 (CH2Te),
15.1 (CH3CAr), 23.0 (CH3CH), 23.0 (CH3CH), 31.4 (CH3CH), 35.7 (CH2CAr), 84.0 (CHO),
117.1 (CH2CAr), 123.2 (CH3CAr), 128.4 (CHAr), 129.8 (CHAr), 143.0 (CHCAr), 157.4 (CArO).
125Te-NMR (100 MHz, CDCl3): 84.0. Anal. calcd for C26H34O2Te2 (633.75): C 49.27, H 5.41,
Te 40.27%. Found: C 49.51, H 5.58, Te 40.53%.
4. Conclusions
There are no works in the literature studying chalcogenocyclofunctionalization re-
actions of sulfur, selenium and tellurium halides on the same substrates and comparing
the reactivity of these electrophilic reagents. The present work described regioselective
synthesis of novel functionalized condensed organochalcogen compounds by chalcogeno-
cyclofunctionalization reactions based on chalcogen halides and natural products thymol
and carvacrol. The conditions for efficient chalcogenocyclofunctionalization by reactions
of selenium dihalides, sulfur dichloride and tellurium tetrahalides with allyl thymol and
allyl carvacrol were found. Attempts were made to reveal the distinguishing features of
each reaction and to compare the reactivity of sulfur, selenium and tellurium halides in
chalcogenocyclofunctionalization.
The reactions of tellurium tetrachloride and tetrabromide with allyl thymol and allyl
carvacrol proceeded with high selectivity in a regiospecific manner affording monoadducts
in quantitative yield.
The obtained products represent a new family of organochalcogen compounds bearing
(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl and (4-isopropyl-7-methyl-
2,3-dihydro-1-benzofuran-2-yl)methyl moieties with promising biological activity.
Supplementary Materials: The following are available online: examples of the NMR spectra of the
obtained compounds.
Author Contributions: Methodology, M.V.M. (Maxim V. Musalov) and V.A.P.; conceptualization,
M.V.M. (Maxim V. Musalov) and V.A.P.; investigation (research experiments on selenocyclofunction-
alization reactions), V.A.Y.; investigation (research experiments on the synthesis of organotellurium
compounds), M.V.M. (Maria V. Musalova); investigation (research experiments on the synthesis of
organosulfur compounds), A.A.M.; investigation (NMR experiments), S.V.Z.; supervision, S.V.A.
and V.A.P.; data curation, S.V.A.; writing—original draft preparation, V.A.P. and M.V.M. (Maxim V.
Musalov); writing—review and editing, V.A.P. All authors have read and agreed to the published
version of the manuscript.

Molecules 2021, 26, 3729
12 of 15
Funding: The research on selenocyclofunctionalization reactions was funded by Russian Foundation
for Basic Research, grant 19-33-90214 Aspiranty.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data is available in this article and supplementary information.
Acknowledgments: The authors thank the Baikal Analytical Center SB RAS for providing the
instrumental equipment for structural investigations.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.
References
1.
Koehn, F.E.; Carter, G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 2005, 4, 206–220.
[CrossRef]
2.
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 2007, 70, 461–477.
[CrossRef]
3.
4.
Harvey, A.L. Natural products in drug discovery. Drug Discov. Today 2008, 13, 894–901. [CrossRef] [PubMed]
Chhetri, B.K.; Lavoie, S.; Sweeney-Jones, A.M.; Kubanek, J. Recent trends in the structural revision of natural products. Nat. Prod.
Rep. 2018, 35, 514–531. [CrossRef]
5.
Beghyn, T.; Deprez-Poulain, R.; Willand, N.; Folleas, B.; Deprez, B. Natural compounds: Leads or ideas? Bioinspired molecules
for drug discovery. Chem. Biol. Drug Design 2008, 72, 3–15. [CrossRef] [PubMed]
6.
7.
8.
9.
D’Andrea, J. Ancient Herbs in the J. Paul Getty Museum Gardens; Getty Publications: Malibu, CA, USA, 1982; p. 84.
Tilford, G.L. Edible and Medicinal Plants of the West; Mountain Press Publishing: Missoula, MT, USA, 1997; p. 240.
Nieto, G. Biological Activities of Three Essential Oils of the Lamiaceae Family. Medicines 2017, 4, 63. [CrossRef] [PubMed]
Marchese, A.; Orhan, I.E.; Daglia, M.; Barbieri, R.; Di Lorenzo, A.; Nabavi, S.F.; Gortzi, O.; Izadi, M.; Nabavi, S.M. Antibacterial
and Antifungal Activities of Thymol: A Brief Review of the Literature. Food Chem. 2016, 210, 402–414. [CrossRef] [PubMed]
10. Krepker, M.; Shemesh, R.; Danin Poleg, Y.; Kashi, Y.; Vaxman, A.; Segal, E. Active Food Packaging Films with Synergistic
Antimicrobial Activity. Food Control 2017, 76, 117–126. [CrossRef]
11. Mezzoug, N.; Elhadri, A.; Dallouh, A.; Amkiss, S.; Skali, N.S.; Abrini, J.; Zhiri, A.; Baudoux, D.; Diallo, B.; El Jaziri, M.; et al.
Investigation of the Mutagenic and Antimutagenic Effects of Origanum Compactum Essential Oil and Some of Its Constituents.
Mutat. Res. Toxicol. Environ. Mutagen. 2007, 629, 100–110. [CrossRef]
12. Kong, J.; Zhang, Y.; Ju, J.; Xie, Y.; Guo, Y.; Cheng, Y.; Qian, H.; Quek, S.Y.; Yao, W. Antifungal Effects of Thymol and Salicylic Acid
on Cell Membrane and Mitochondria of Rhizopus Stolonifer and Their Application in Postharvest Preservation of Tomatoes. Food
Chem. 2019, 285, 380–388. [CrossRef] [PubMed]
13. Nagoor Meeran, M.F.; Javed, H.; Al Taee, H.; Azimullah, S.; Ojha, S.K. Pharmacological Properties and Molecular Mechanisms of
Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development. Front. Pharmacol. 2017, 8, 380. [CrossRef]
[PubMed]
14. De Morais, S.M.; Vila-Nova, N.S.; Bevilaqua, C.M.L.; Rondon, F.C.; Lobo, C.H.; Moura, A.D.A.A.N.; Sales, A.D.; Rodrigues, A.P.R.;
de Figuereido, J.R.; Campello, C.C.; et al. Thymol and Eugenol Derivatives as Potential Antileishmanial Agents. Bioorg. Med.
Chem. 2014, 22, 6250–6255. [CrossRef] [PubMed]
15. Llana-Ruiz-Cabello, M.; Pichardo, S.; Maisanaba, S.; Puerto, M.; Prieto, A.I.; Gutiérrez-Praena, D.; Jos, A.; Cameán, A.M. In Vitro
Toxicological Evaluation of Essential Oils and Their Main Compounds Used in Active Food Packaging: A Review. Food Chem.
Toxicol. 2015, 81, 9–27. [CrossRef]
16. Llana-Ruiz-Cabello, M.; Gutiérrez-Praena, D.; Pichardo, S.; Moreno, F.J.; Bermúdez, J.M.; Aucejo, S.; Cameán, A.M. Cytotoxicity
and Morphological Effects Induced by Carvacrol and Thymol on the Human Cell Line Caco-2. Food Chem. Toxicol. 2014, 64,
281–290. [CrossRef]
17. Llana-Ruiz-Cabello, M.; Maisanaba, S.; Puerto, M.; Prieto, A.I.; Pichardo, S.; Jos, Á.; Cameán, A.M. Evaluation of the Mutagenicity
and Genotoxic Potential of Carvacrol and Thymol Using the Ames Salmonella Test and Alkaline, Endo III- and FPG-Modified
Comet Assays with the Human Cell Line Caco-2. Food Chem. Toxicol. 2014, 72, 122–128. [CrossRef]
18. Dheer, D.; Singh, D.; Kumar, G.; Karnatak, M.; Chandra, S.; Verma, V.P.; Shankar, R. Thymol Chemistry: A Medicinal Toolbox.
Curr. Bioact. Compd. 2019, 15, 454–474. [CrossRef]
19. Rajput, J.D.; Bagul, S.D.; Bendre, R.S. Design, synthesis, biological screenings and docking simulations of novel carvacrol and
thymol derivatives containing acetohydrazone linkage. Res. Chem. Intermed. 2017, 43, 4893–4906. [CrossRef]
20. Narkhede, H.P.; More, U.B.; Dalal, D.S.; Mahulikar, P.P. Solid-Supported Synthesis of Bio-active Carvacrol Compounds Using
Microwaves. Synth. Commun. 2008, 38, 2413–2418. [CrossRef]
21. Bkhaitan, M.M.; Alarjah, M.; Mirza, A.Z.; Abdalla, A.N.; El-Said, H.M.; Faidah, H.S. Preparation and biological evaluation of
metronidazole derivatives with monoterpenes and eugenol. Chem. Biol. Drug Design. 2018, 92, 1954–1962. [CrossRef]

Molecules 2021, 26, 3729
13 of 15
22. Nostro, A.; Blanco, A.R.; Cannatelli, M.A.; Enea, V.; Flamini, G.; Morelli, I.; Sudano Roccaro, A.; Alonzo, V. Susceptibility of
methicillin-resistant staphylococci to oregano essential oil, carvacrol and thymol. FEMS Microbiol. Lett. 2004, 230, 191–195.
[CrossRef]
23. Zhao, J.; Li, Y.; Liu, Q.; Gao, K. Antimicrobial activities of some thymol derivatives from the roots of Inula hupehensis. Food Chem.
2010, 120, 512–516. [CrossRef]
24. El-Miligy, M.M.M.; Hazzaa, A.A.; El-Zemity, S.R.; Al-Kubeisi, A.K. Synthesis of Thymol Derivatives as Potential Non-Irritant
Antimicrobial and Insecticidal Agents. Curr. Bioactive Comp. 2019, 15, 125–137. [CrossRef]
25. Mastelic, J.; Jerkovic, I.; Blazevic, I.; Poljak-Blazi, M.; Borovic, S.; Ivancic-Bace, I.; Smrecki, V.; Zarkovic, N.; Brcic-Kostic, K.;
Vikic-Topic, D. Comparative Study on the Antioxidant and Biological Activities of Carvacrol, Thymol, and Eugenol Derivatives. J.
Agricult. Food Chem. 2008, 56, 3989–3996. [CrossRef]
26. Piombino, C.; Lange, H.; Sabuzi, F.; Galloni, P.; Conte, V.; Crestini, C. Lignosulfonate microcapsules for delivery and controlled
release of thymol and derivatives. Molecules 2020, 25, 866. [CrossRef] [PubMed]
27. Bagul, S.D.; Rajput, J.D.; Tadavi, S.K.; Bendre, R.S. Design, synthesis and biological activities of novel 5-isopropyl-2-
methylphenolhydrazide-based sulfonamide derivatives. Res. Chem. Intermed. 2017, 43, 2241–2252. [CrossRef]
28. Wang, K.; Jiang, S.; Pu, T.; Fan, L.; Su, F.; Ye, M. Antifungal activity of phenolic monoterpenes and structure-related compounds
against plant pathogenic fungi. Nat. Prod. Res. 2019, 33, 1423–1430. [CrossRef] [PubMed]
29. Pricopie, A.-I.; Ionu, I.; Marc, G.; Arseniu, A.-M.; Vlase, L.; Grozav, A.; Gaina, L.I.; Vodnar, D.C.; Pirnau, A.; Tiperciuc, B. Design
and synthesis of novel 1,3-thiazole and 2-hydrazinyl-1,3-thiazole derivatives as anti-Candida agents: In vitro antifungal screening,
molecular docking study and spectroscopic investigation of their binding interaction with bovine serum albumin. Molecules 2019
24, 3435. [CrossRef] [PubMed]
,
30. Koshti, S.M.; Patil, P.A.; Patil, C.B.; Patil, A.S. Synthesis and characterization of prodrugs of sulfonamides as an azo derivatives of
carvacrol. Pharma. Chem. 2018, 10, 1–15.
31. Sobotta, L.; Lijewski, S.; Dlugaszewska, J.; Nowicka, J.; Mielcarek, J.; Goslinski, T. Photodynamic inactivation of Enterococcus
faecalis by conjugates of zinc (II) phthalocyanines with thymol and carvacrol loaded into lipid vesicles. Inorg. Chim. Acta. 2019
,
489, 180–190. [CrossRef]
32. Jeankumar, V.U.; Sridevi, J.P.; Matikonda, S.S.; Peddi, S.; Alvala, M.; Yogeeswari, P.; Sriram, D. Identification and Structure–
Activity Relationship Study of Carvacrol Derivatives as Mycobacterium Tuberculosis Chorismate Mutase Inhibitors. J. Enzyme
Inhib. Med. Chem. 2014, 29, 547–554.
33. Talavera-Aleman, A.; Rodriguez-Garcia, G.; Lopez, Y.; Garcia-Gutierrez, H.A.; TorresValencia, J.M.; del Rio, R.E.; Cerda-Garcia-
Rojas, C.M.; Joseph-Nathan, P.; Gomez-Hurtado, M.A. Systematic evaluation of thymol derivatives possessing stereogenic or
prostereogenic centers. Phytochem. Rev. 2016, 15, 251–277. [CrossRef]
34. Cherkasov, R.A.; Nizamov, I.S.; Gabdullina, G.T.; Almetkina, L.A.; Shamilov, R.R.; Sofronov, A.V. Dithiophosphoric and
Dithiophosphonic Acids and Their Derivatives on the Basis of Thymol: Synthesis and Antimicrobial Activity. Phosphorus Sulfur.
Silicon Relat. Elements 2013, 188, 33–35. [CrossRef]
35. Chen, L.C.; Lee, T.H.; Sung, P.J.; Shu, C.W.; Lim, Y.P.; Cheng, M.J.; Kuo, W.L.; Chen, J.J. New thymol derivatives and cytotoxic
constituents from the root of Eupatorium cannabinum ssp. asiaticum. Chem. Biodivers. 2014, 11, 1374–1380. [CrossRef]
˙
36. Kulabas¸, N.; Tatar, E.; Bingöl Özakpınar, Ö.; Özsavci, D.; Pannecouque, C.; De Clercq, E.; Küçükgüzel, I. Synthesis and
antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells.
Eur. J. Med. Chem. 2016, 121, 58–70. [CrossRef]
37. Rajput, J.D.; Bagul, S.D.; Bendre, R.S. Synthesis, biological activities and molecular docking simulation of hydrazone scaffolds of
carvacrol, thymol and eugenol. Res. Chem. Intermed. 2017, 43, 6601–6616. [CrossRef]
38. Tiekink, E.R.T. Therapeutic potential of selenium and tellurium compounds: Opportunities yet unrealized. Dalton Trans. 2012, 41,
6390–6395. [CrossRef] [PubMed]
39. Nogueira, C.W.; Zeni, G.; Rocha, J.B.T. Organoselenium and Organotellurium Compounds: Toxicology and Pharmacology. Chem.
Rev. 2004, 104, 6255–6286. [CrossRef] [PubMed]
40. Ruberte, A.C.; Sanmartin, C.; Aydillo, C.; Sharma, A.K.; Plano, D. Development and Therapeutic Potential of Selenazo Compounds.
J. Med. Chem. 2020, 63, 1473–1489. [CrossRef] [PubMed]
41. Yu, S.-C.; Kuhn, H.; Daniliuc, C.-G.; Ivanov, I.; Jones, P.G.; du Mont, W.-W. 5-Selenization of salicylic acid derivatives yielded
isoform-specific 5-lipoxygenase inhibitors. Org. Biomol. Chem. 2010, 8, 828–834. [CrossRef] [PubMed]
42. Potapov, V.A. Organic diselenides, ditellurides, polyselenides and polytellurides. Synthesis and reactions. In Patai’s Chemistry of
Functional Groups. Organic Selenium and Tellurium Compounds; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, UK, 2013;
Volume 4, pp. 765–843.
43. Braga, A.L.; Rafique, J. Synthesis of biologically relevant small molecules containing selenium. Part B. Anti-infective and
anticancer compounds. In Patai’s Chemistry of Functional Groups. Organic Selenium and Tellurium Compounds; Rappoport, Z., Ed.;
John Wiley and Sons: Chichester, UK, 2013; Volume 4, pp. 1053–1117.
44. Azad, G.K.; Tomar, R.S. Ebselen, a promising antioxidant drug: Mechanisms of action and targets of biological pathways. Mol.
Biol. Rep. 2014, 41, 4865–4879. [CrossRef]
45. Woollins, J.D.; Laitinen, R.S. (Eds.) Selenium and Tellurium Chemistry. From Small Molecules to Biomolecules and Materials; Springer:
Berlin/Heidelberg, Germany, 2011; p. 334.

Molecules 2021, 26, 3729
14 of 15
46. Santi, C. (Ed.) Organoselenium Chemistry: Between Synthesis and Biochemistry; Bentham Science Publishers: Sharjah, United Arab
Emirates, 2014; p. 563.
47. Mugesh, G.; du Mont, W.W.; Sies, H. Chemistry of Biologically Important Synthetic Organoselenium Compounds. Chem. Rev.
2001, 101, 2125–2180. [CrossRef] [PubMed]
48. Lenardao, E.J.; Santi, C.; Sancineto, L. New Frontiers in Organoselenium Compounds; Springer International Publishing AG: Cham,
Switzerland, 2018; 189p.
49. Petragnani, N.; Stefani, H.A.; Valduga, C.J. Recent advances in selenocyclofunctionalization reactions. Tetrahedron 2001, 57,
1411–1448. [CrossRef]
50. Kostic´, M.D.; Divac, V.M.; Bugarcˇic´, Z.M. Electrophilic Selenocyclofunctionalization in the Synthesis of Biologically Relevant
Molecules. Curr. Org. Chem. 2016, 20, 2606–2619. [CrossRef]
51. Kostic´, M.D.; Divac, V.M.; Bugarcˇic´, Z.M. An introduction to the kinetics of the triethylamine-mediated selenocyclofunctionaliza-
tion of 4-pentenoic acid. J. Mol. Struct. 2019, 1175, 24–27. [CrossRef]
52. Nieto, J.; Andres, C.; Perez-Encabo, A. 7-Endo Selenocyclization reactions on chiral 3-prenyl- and 3-cinnamyl-2-hydroxymethylperhydro-
1,3-benzoxazine derivatives. A way to enantiopure 1,4-oxazepanes. Org. Biomolec. Chem. 2015, 13, 9118–9126. [CrossRef]
53. Pedrosa, R.; Andres, C.; Mendiguchia, P.; Nieto, J. Diastereoselective Synthesis of Enantiopure Morpholines by Electrophilic
Selenium-Induced 6-exo Cyclizations on Chiral 3-Allyl-2-hydroxymethylperhydro-1,3-benzoxazine Derivatives. J. Org. Chem.
2006, 71, 8854–8863. [CrossRef]
54. Stefani, H.A.; Costa, I.M.; Silva, D.D.O.; Menezes, P.H.; Rodrigues, A. Selenocyclofunctionalization of
β-ketoamides: Synthesis of
substituted dihydrofurans. Phosphorus Sulfur. Silicon Relat. Elements 2001, 171–172, 395–406. [CrossRef]
55. Saikia, I.; Borah, A.J.; Phukan, P. Use of Bromine and Bromo-Organic Compounds in Organic Synthesis. Chem. Rev. 2016, 116,
6837–7042. [CrossRef]
56. Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B.J. Iodide-Catalyzed Halocyclization/Cycloaddition/Elimination Cascade Reaction. J.
Org. Chem. 2013, 78, 2751–2756. [CrossRef]
57. Parker, P.D.; Lemercier, B.C.; Pierce, J.G. Synthesis of Quaternary-Substituted Thiazolines via Halocyclization of S-Allyl Thioimi-
date Salts. J. Org. Chem. 2018, 83, 12–22. [CrossRef] [PubMed]
58. Accurso, A.A.; Cho, S.-H.; Amin, A.; Potapov, V.A.; Amosova, S.V.; Finn, M.G. Thia-, Aza-, and Selena[3.3.1]bicyclononane
Dichlorides: Rates vs Internal Nucleophile in Anchimeric Assistance. J. Org. Chem. 2011, 76, 4392–4395. [CrossRef]
59. Potapov, V.A.; Amosova, S.V.; Belozerova, O.V.; Albanov, A.I.; Yarosh, O.G.; Voronkov, M.G. Synthesis of 3,6-dihalo-4,4-dimethyl-
1,4-selenasilafulvenes. Chem. Heterocycl. Compd. 2003, 39, 549–550. [CrossRef]
60. Potapov, V.A.; Amosova, S.V. New Methods for Preparation of Organoselenium and Organotellurium Compounds from Elemental
Chalcogens. Russ. J. Org. Chem. 2003, 39, 1373–1380. [CrossRef]
61. Abakumov, G.A.; Piskunov, A.V.; Cherkasov, V.K.; Fedushkin, I.L.; Ananikov, V.P.; Eremin, D.B.; Gordeev, E.G.; Beletskaya, I.P.;
Averin, A.D.; Bochkarev, M.N.; et al. Organoelement chemistry: Promising growth areas and challenges. Russ. Chem. Rev. 2018
87, 393–507. [CrossRef]
,
62. Musalov, M.V.; Potapov, V.A.; Musalova, M.V.; Amosova, S.V. Regioselective synthesis of bis[(2,3-dihydro-1-benzofuran-2-
yl)methyl]selenide. Russ. J. Org. Chem. 2014, 50, 1702–1703. [CrossRef]
63. Musalov, M.V.; Ishigeev, R.S.; Udalova, S.I.; Musalova, M.V.; Kurkutov, E.O.; Khabibulina, A.G.; Albanov, A.I.; Potapov, V.A.;
Amosova, S.V. Synthesis of Fused Compounds on the Basis of Chalcogen Chlorides and 2-Allylphenols. Russ. J. Org. Chem. 2018
54, 1035–1040. [CrossRef]
,
64. Kurkutov, E.O.; Potapov, V.A.; Musalov, M.V.; Amosova, S.V. Bis(1,3-dioxolan-2-ylmethyl)selenide. Russ. J. Gen. Chem. 2017, 87,
357–358. [CrossRef]
65. Musalov, M.V.; Potapov, V.A. Selenium dihalides: New possibilities for the synthesis of selenium-containing heterocycles. Chem.
Heterocycl. Comp. 2017, 53, 150–152. [CrossRef]
66. Potapov, V.A.; Kurkutov, E.O.; Musalov, M.V.; Amosova, S.V. Effective synthesis of bis(1,4-dioxan-2-ylmethyl)selenide and
selenoxide. Russ. J. Org. Chem. 2016, 52, 1715–1716. [CrossRef]
67. Musalov, M.V.; Ishigeev, R.S.; Potapov, V.A.; Amosova, S.V. Reaction of selenium dihalides with 2-(allylsulfanyl)ethanol. Russ. J.
Org. Chem. 2016, 52, 1533–1534. [CrossRef]
68. Potapov, V.A.; Kurkutov, E.O.; Musalov, M.V.; Amosova, S.V. Efficient method for the synthesis of bis(tetrahydro-2H-pyran-2-
ylmethyl) selenide. Russ. Chem. Bull. 2015, 64, 2973–2974. [CrossRef]
69. Potapov, V.A.; Musalov, M.V.; Kurkutov, E.O.; Musalova, M.V.; Albanov, A.I.; Amosova, S.V. Synthesis of new functionalized
organoselenium compounds by heterocyclization of selenium dihalides with pent-4-en-1-ol. Russ. J. Org. Chem. 2016, 52, 339–342.
[CrossRef]
70. Musalov, M.V.; Yakimov, V.A.; Potapov, V.A.; Amosova, S.V.; Borodina, T.N.; Zinchenko, S.V. A novel methodology for the
synthesis of condensed selenium heterocycles based on the annulation and annulation–methoxylation reactions of selenium
dihalides. New J. Chem. 2019, 43, 18476–18483. [CrossRef]
71. Musalov, M.V.; Yakimov, V.A.; Potapov, V.A. Synthesis of Functional Dihydro-1,4-benzoxaselenines from Carvacrol Allyl Ether
and Selenium Dihalides. Russ. J. Org. Chem. 2020, 56, 2258–2262. [CrossRef]
72. Coleman, M.T.; LeBlanc, G. Use of Diethoxymethane as a Solvent for Phase Transfer-Catalyzed O-Alkylation of Phenols. Org.
Proc. Res. Develop. 2010, 14, 732–736. [CrossRef]

Molecules 2021, 26, 3729
15 of 15
73. Smit, V.A.; Zefirov, N.S.; Bodrikov, I.V.; Krimer, M.Z. Episulfonium ions: Myth and reality. Acc. Chem. Res. 1979, 12, 282–288.
[CrossRef]
74. Abu-yousef, I.A.; Harpp, D.N. New Sulfenyl Chloride Chemistry: Synthesis, Reactions and Mechanisms toward Carbon-Carbon
Double Bonds. Sulfur. Rep. 2003, 24, 255–282. [CrossRef]
75. Rasteikiene, L.; Greiciute, D.; Lin’kova, M.G.; Knunyants, I.L. The Addition of Sulphenyl Chlorides to Unsaturated Compounds.
Russ. Chem. Rev. 1977, 46, 548–564. [CrossRef]
76. Musalov, M.V.; Potapov, V.A.; Kurkutov, E.O.; Musalova, M.V.; Khabibulina, A.G.; Amosova, S.V. Regioselective syntheses of
bis(2-haloalkyl) selenides and dihalo[bis(2-haloalkyl)]-
nenylation reaction. Arkivoc 2017, iii, 365–376. [CrossRef]
λ
4-selanes from selenium dihalides and 1-alkenes, and the methoxysele-
77. Potapov, V.A.; Musalov, M.V.; Amosova, S.V. Reactions of selenium dichloride and dibromide with unsaturated ethers. Annulation
of 2,3-dihydro-1,4-oxaselenine to the benzene ring. Tetrahedron Lett. 2011, 52, 4606–4610. [CrossRef]