Synthesis and Oxidation of Myrtanethiol and Its Functional Derivatives with Chlorine Dioxide

Article abstract of DOI:10.1134/S107042801910004X

cis-Myrtanethiol and a mixture of diastereoisomeric myrtanethiols were synthesized starting from (-)-β-pinene. Their oxidation with chlorine dioxide afforded a number of derivatives such as disulfides, S-thiol-sulfonates, sulfonyl chlorides, and sulfonic acids. The effects of reaction conditions (solvent nature, reactant molar ratio, reaction time, catalyst) on the yield and ratio of the products were studied. The corresponding sulfonyl chloride was obtained in quantitative yield by oxidation of thiol in the presence of vanadyl acetyl-acetonate, and optimal conditions were found for quantitative formation of myrtanesulfonic acid.

Full text of DOI:10.1134/S107042801910004X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 10, pp. 1469–1475. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 10, pp. 1510–1519.
Synthesis and Oxidation of Myrtanethiol and Its Functional
Derivatives with Chlorine Dioxide
a
a
a
a
O. N. Grebyonkina , O. M. Lezina ,* E. S. Izmest’ev , L. L. Frolova ,
a
a
S. A. Rubtsova ,** and A. V. Kutchin
a
Institute of Chemistry, Komi Scientific Center, Ural Branch, Russian Academy of Sciences, Syktyvkar, Russia
e-mail: *lezina-om@yandex.ru; **rubtsova-sa@chemi.komisc.ru
Received March 28, 2019; revised August 10, 2019; accepted August 13, 2019
Abstract—cis-Myrtanethiol and a mixture of diastereoisomeric myrtanethiols were synthesized starting from
–)-β-pinene. Their oxidation with chlorine dioxide afforded a number of derivatives such as disulfides, S-thiol-
(
sulfonates, sulfonyl chlorides, and sulfonic acids. The effects of reaction conditions (solvent nature, reactant
molar ratio, reaction time, catalyst) on the yield and ratio of the products were studied. The corresponding
sulfonyl chloride was obtained in quantitative yield by oxidation of thiol in the presence of vanadyl acetyl-
acetonate, and optimal conditions were found for quantitative formation of myrtanesulfonic acid.
Keywords: monoterpenoids, selective oxidation, chlorine dioxide, thiol, sulfonate, sulfonyl chloride, sulfonic
acid, catalysis, vanadyl acetylacetonate.
DOI: 10.1134/S107042801910004X
Terpenes are natural biologically active compounds
possessing bactericidal, analgesic, and mucolytic prop-
erties and are used as fungicides and antiviral agents
stereoselectivity toward predominant formation of 3a,
such reaction conditions as temperature (–10 to 20°C),
solvent (methylene chloride, pyridine), and Lewis acid
(ZnCl , AlCl , LaCl ) were varied. The best result
[1]. A promising strategy in the synthesis of new bio-
2
3
3
logically active compounds is based on the combina-
tion of terpene fragments and various sulfur-containing
pharmacophoric groups [2]. We previously showed
that pinane sulfonothioates exhibit antimicrobial activ-
ity against Candida albicans, Staphylococcus aureus,
and Cryptococcus neoformans [3]. Organic sulfonic
acids and sulfonyl chlorides are known to be widely
used as intermediate products in the synthesis of
medicines [4].
In this article we report the oxidation of myrtane-
thiol with chlorine dioxide, which produced chiral
sulfur- and oxygen-containing terpenoids of the pinane
series. The effect of the reaction conditions and sub-
strate functionalization on the reactivity of the latter
was also studied.
(75% de of 3a) was obtained by carrying out the
reaction in methylene chloride at room temperature in
the presence of LaCl (Scheme 1).
3
According to published data [1], polarized lantha-
num chloride–acid complex is oriented at the sterically
more accessible side of the double bond. Due to steric
hindrances created by geminal methyl groups, the
2
approach of a bulky thioacetate anion to the C carbon
atom is hampered; therefore, small hydrogen atom
2
coordinates to C . The addition of the complex is
synchronous without formation of a carbocation, as
follows from the conservation of the pinane structure;
reactions involving species with a localized charge
usually lead to the formation of isomerization
products.
Initially, we tried to synthesize thiol 1a by addition
of thioacetic acid to the double bond of (–)-β-pinene
The reduction of mixture 3a/3b with an equimolar
amount of LiAlH [5] also afforded a chromato-
4
(
2) in the presence of a Lewis acid and subsequent
graphically inseparable mixture of diastereoisomeric
thiols (R)-1a and (S)-1b at a ratio of 7:1 (75% de)
which was determined from the intensity of the 10-H
reduction of thioacetate 3a (Scheme 1). However, the
addition products were diastereoisomeric thioacetates
(
1
R)-3a and (S)-3b which we failed to separate by
signals in the H NMR spectrum. The configuration of
column chromatography. In order to increase the
1a and 1b was proved by two-dimensional NOESY
1
469

1
470
GREBYONKINA et al.
Scheme 1.
SAc
SAc
SH
SH
1
0
2
7
AcSH, LaCl3
LiAlH4
1
+
8
Me
+
6
Me
Me
Me
Me
4
Me
Me
9
CH2
Me
3a
3b
1a
1b
Me
OH
I
Me
(
(
1) LiBH , H SO
PPh , I
3 2
benzimidazole
4
2
4
2
2) H O , NaOH
AcSK
2
2
3
a
Me
Me
Me
Me
4
5
1
0
data which revealed coupling between protons on C
goal of separating the obtained derivatives by column
chromatography. Depending on the conditions, the
main products in the oxidation of 1a and 1b were
disulfides 6, thiolsulfonates 7, sulfonyl chlorides 8,
and sulfonic acids 9 (Scheme 2). However, the (R)-
and (S)-diastereoisomers of 6–9 were characterized by
similar chromatographic mobilities, and we failed to
separate them by column chromatography. The dia-
stereoisomer ratio of 6–9 was the same as that of initial
thiols 1 (7:1).
8
and C for 1a and between 2-H and 8-H for 1b (Fig. 1).
Steric interaction between 2-H and 8-H in molecule 1b
induces a significant upfield shift of signals of these
protons and the corresponding carbon nuclei in the
NMR spectra relative to those of isomer 1a. In the
C NMR spectrum of 1b, the C and C nuclei reso-
nated at δ 38.8 and 20.1 ppm, whereas the C and C
signals of 1a were located at δ 45.3 and 23.2 ppm,
respectively; the differences in the chemical shifts of
the other carbons did not exceed 1.0–1.5 ppm.
1
3
2
8
2
8
C
C
The structure of the isolated compounds was con-
firmed by NMR, IR, and mass spectra and elemental
Since our attempts to obtain diastereomerically
pure thiol 1a according to the above described scheme
were unsuccessful, the target compound was synthe-
sized in a different way. For this purpose, (–)-β-pinene
1
3
10
analyses. In the C NMR spectra of 6–9, the C signal
appeared downfield from the corresponding signal of 1
(δ 31.4, 46.2, 70.4, 73.4, and 59.1 ppm for 1a and
C
2
was subjected to hydroboration–oxidation to
4a–9a, respectively). The IR spectra of 7a–9a contained
bands due to symmetric and antisymmetric vibrations
of the sulfonyl group at 1128, 1321 (7a), 1168, 1377
cis-myrtanol 4 [6], which was converted to iodide 5
according to a modified procedure [7], the latter was
treated with potassium thioacetate [8], and thioacetate
–
1
(8a), 1002, 1028, 1051, 1167, 1215 cm (9a).
3
a thus formed was reduced [5] to thiol 1a (Scheme 1).
We studied the effects of solvent nature, reactant
ratio, reaction time, and catalyst on the reactivity of
Thiols 1 were oxidized with chlorine dioxide ac-
cording to the procedures described by us previously
3, 9, 10] for functional derivatives 1c and 1d.
thiol 1a in the oxidation with ClO . The presence of
2
[
functional groups in the substrate molecule was also
considered by comparing the results with those ob-
tained previously for thiols 1c and 1d [3, 9]. The
reactions were carried out in anhydrous hexane,
methylene chloride, acetonitrile, and pyridine, as well
Chlorine dioxide was used a commercially available
aqueous solution or was transferred to organic sol-
vents. The oxidation was carried out with both pure
isomer 1a and diastereoisomer mixture 1a/1b with the
as with water as co-solvent when aqueous ClO was
used. It was found that the solvent nature and polarity
affect the reaction rate. In the oxidation of 1a with
2
NOE
NOE
8
8
Me
SH
H
Me
H
2
1
0
SH
Me
Me
2 equiv of ClO in hexane–water and methylene
2
chloride–water, 6–10% of the initial thiol remained
unchanged after 0.5 h (Table 1, entry nos. 3, 10), and
the major product was disulfide 6a (57–59%). The
1
a
1b
Fig. 1. Correlations in the NOESY spectra of thiols 1a and 1b.
reaction of 1a with ClO in polar aqueous acetonitrile
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND OXIDATION OF MYRTANETHIOL
1471
Scheme 2.
O
O
·
ClO
ClO2
·
S
[O]
2
·
R
·
S
S
R
S
R
R
SH
R
SH
R
R
S
R
S
–
HClO2
–
ClO2
1
a–1d
6a–6d
7a–7d
Py, H O
ClO2
2
Py, ClO2
[O]
O
O
O
O
[O]
H O
2
S
S
R
S(O) H
n
R
OH
R
Cl
A (n = 1, 2)
9a–9d
8a–8c
OH
R =
(a),
(b),
(c),
(d).
Me
Me
Me
Me
Me
Me
Me
Me
gave deep oxidation products 8a and 9a in 38 and 62%
yield, respectively (entry no. 6). Increase of the reac-
tion rate with solvent polarity indicated the formation
of polar intermediates.
0.5 h), the conversion of hydroxy thiol 1c was com-
plete, and the conversions of 1a and 1d were 71 and
39%, respectively (entry no. 2). The presence of a C=C
double bond in molecule 1d reduces the rate of oxida-
tion of intermediate compounds 6d and 7d and hence
increases the selectivity for their formation. In the
The reaction in aqueous pyridine as solvent, other
conditions being equal, gave disulfide 6a (18%) and
sulfonic acid 9a (82%), whereas 38% of 6a and 62%
of 9a were formed in anhydrous pyridine (entry
nos. 16, 19). When the reaction time was prolonged to
oxidation of 1d with 2 equiv of ClO in aqueous
2
acetonitrile, the yield of thiolsulfonate 7d was 85%
after 1 h [9], whereas thiol 1a was oxidized mainly to
compounds 8a and 9a, and no 7a was detected (entry
no. 8). The oxidation of 1d in hexane–water quantita-
tively produced the corresponding disulfide 6d, while
the yields of disulfides 6a (entry no. 4) and 6c [3]
were about 50%.
2
h, sulfonic acid 9a was obtained in quantitative yield
(
entry nos. 17, 20). No sulfonyl chloride 8a was detect-
ed in pyridine, since chlorine-containing ions arising
from the reduction of ClO are bound by the solvent;
2
therefore, chlorine dioxide acts only as oxidant.
The effects of solvent nature and thiol structure on
the stability of the oxidation products were revealed.
Presumably, the oxidation in pyridine involves
intermediate formation of sulfenic and sulfinic acids
(
A) that are stable in basic pyridine medium. In
When thiol 1d was oxidized with 2 equiv of ClO in
2
addition, nucleophilic character of the solvent hampers
methylene chloride, the reaction mixture contained
unidentified desulfurization and ring-opening products,
whereas the oxidation of 1a and 1c in methylene
chloride gave compounds 7a–9a and 7c–9c, and no
desulfurization was observed (entry no. 9).
–
solvation of ClO ion formed in the first oxidation step
2
(
Scheme 2), which makes it more active and thus
increases the reaction rate.
The product composition also depended on the
reactant molar ratio and reaction time. Increase in the
As we showed previously, the use of VO(acac) as
2
1
a–ClO ratio from 1:1 to 1:2 and of the reaction time
catalyst in the oxidation of hydroxycaranethiols [3]
and diphenyl disulfide [11] increases the selectivity
with respect to sulfonyl chlorides. Therefore, thiols 1a
and 1d were subjected to catalytic oxidation. In the
2
from 0.5 to 1 h in aqueous acetonitrile favored
hydrolysis of sulfonyl chloride 8a to sulfonic acid 9a,
so that the fraction of the latter increased from 25 to
6
3
7%, while the fraction of 8a decreased from 54 to
3% (entry nos. 5–8).
reaction of 1a with 2 equiv of ClO in methylene
2
chloride in the presence of VO(acac) , the yield of 8a
2
Comparison of the results of oxidation of thiol 1a
and its functional derivatives 1c [3] and 1d [9] with
increased from 33 to 82% in 0.5 h, and it reached 98%
after 2 h (Table 1; entry nos. 9, 12, 13). No catalytic
effect was observed when the reaction was carried out
in methylene chloride–water (yield of 8a 45%; entry
no. 14). The absence of catalytic effect in the oxidation
ClO showed that the substrate reactivity decreases in
2
the series 1c > 1a > 1d. In the oxidation of these thiols
in hexane–water (1/ClO ratio 1:0.5, reaction time
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

1
472
GREBYONKINA et al.
Table 1. Oxidation of thiol 1a with chlorine dioxide under different conditions
a
Product composition, %
Molar ratio
Reaction
time, h
No.
Solvent
1
a:ClO
2
1
a
6a
7a
8a
9a
0
0
0
0
0
0
0
0
0
1
1
1
2
3
4
5
6
7
8
9
0
1
C
C
C
C
6
6
6
6
H
H
H
H
14
1:0.5
1:0.5
1:2
0.5
0.5
0.5
1
–
70
48
57
53
–
11
10
15
21
21
–
14
04
08
04
54
38
48
33
33
10
29
82
98
45
–
05
09
10
22
25
62
38
67
41
09
22
–
14–H
2
2
2
O
O
O
29
10
–
14–H
14–H
1:2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
2
2
2
2
2
2
CN–H
CN–H
CN–H
CN–H
2
2
2
2
O
O
O
O
1:1
0.5
0.5
1
–
1:2
–
–
1:1
–
–
14
–
1:2
1
–
–
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
1:2
0.5
0.5
2
–
–
26
16
49
18
–
–H
2
O
O
1:2
06
–
59
–
–H
2
1:2
b
1
1
1
1
1
1
1
1
2
2
3
4
5
6
7
8
9
0
1:2
0.5
2
–
–
b
1:2
–
–
02
14
47
62
98
67
82
98
b
–H
2
O
1:2
2
–
–
41
06
–
C
5
C
5
C
5
C
5
C
5
C
5
H
H
H
H
H
H
5
5
5
5
5
5
N
1:0.5
1:2
0.5
0.5
2
–
47
38
–
N
N
–
–
1:2
–
–
–
N–H
N–H
N–H
1
2
O
1:0.5
1:2
0.5
0.5
2
–
33
18
–
–
–
2
O
O
–
–
–
2
1:2
–
–
–
a
According to the H NMR data.
b
2
In the presence of VO(acac) .
of thiol 1d in methylene chloride is likely to be related
to the instability of intermediates in that solvent.
methylene chloride eliminates the catalytic effect of
VO(acac) . By contrast, the presence of water in
2
pyridine accelerates the reaction and favors formation
of sulfonic acid.
The reactions of thiols 1a–1c with chlorine dioxide
in pyridine quantitatively afforded sulfonic acids
9
a–9c. The yield of 9d was lower (74%) [9] due to
Functional groups in the substrate molecules
influence their reactivity which decreases in the series
hydroxymyrtanethiol > myrtanethiol > myrtenethiol.
The reduced reactivity of the latter favors selective
formation of intermediate products, disulfide (98% in
hexane–water), and thiolsulfonate (85% in aceto-
nitrile). The oxidation of myrtenethiol in methylene
chloride is accompanied by desulfurization and ring
opening, whereas the other thiols are readily oxidized
to sulfo derivatives with retention of the pinane
structure.
formation of the corresponding pyridinium salt.
In summary, we have synthesized pure cis-myrtane-
thiol and a mixture of diastereoisomeric myrtanethiols,
and their oxidation with chlorine dioxide afforded
the corresponding disulfides, thiolsulfonates, sulfonyl
chlorides, and sulfonic acids. The effect of the reaction
medium on the product composition has been revealed,
and optimal conditions for the preparation of particular
products have been found. Disulfide 6a was synthe-
sized in 68% yield in weakly polar hexane. The maxi-
mum concentration of thiolsulfonate 7a (49%) was
observed in methylene chloride–water. The oxidation
in pyridine quantitatively afforded sulfonic acid 9a,
and sulfonyl chloride 8a was formed in almost quanti-
tative yield in methylene chloride in the presence of
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR
Prestige 21 spectrometer (Japan) with Fourier trans-
1
VO(acac) as a catalyst. The presence of water in
form from samples prepared as thin films. The H and
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND OXIDATION OF MYRTANETHIOL
1473
1
3
C NMR spectra were recorded on a Bruker Avance-
00 instrument (Germany) at 300.17 and 75.48 MHz,
2.33–2.54 m (2H, 2-H, 7β-H), 2.29 d.d (2H, 10-H, J =
1
3
3
7.9, 4.0 Hz). C NMR spectrum (CDCl ), δ , ppm:
3 C
1
0
8
3
4
respectively, using CDCl and DMSO-d as solvents.
Complete assignment of the H and C signals was
made with the aid of two-dimensional homo- ( H– H
COSY, H– H NOESY) and heteronuclear experiments
15.33 (C ), 23.09 (C ), 23.38 (C ), 25.87 (C ), 27.84
3
6
1
13
9
7
6
5
2
(C ), 33.17 (C ), 38.59 (C ), 41.20 (C ), 44.30 (C ),
1
1
1
46.81 (C ).
1
1
Reaction of β-pinene with thioacetic acid. Thio-
acetic acid, 0.076 g (1 mmol), was added with stirring
to a solution of 0.136 g (1 mmol) of β-pinene in 5 mL
of methylene chloride, and 0.021 g (0.1 mmol) of
1
13
(
H– C HSQC, HMBC). The mass spectra were
obtained on a high-performance liquid chromatograph
coupled with a Thermo Finnigan LCQ Fleet mass-
selective detector (USA) (negative ion detection;
water, methanol, and acetonitrile were used as
solvents). Analytical thin-layer chromatography was
performed on Sorbfil plates using petroleum ether–
diethyl ether (9:1) as eluent (1a, 1b, 6a, 6b, 7a, 7b,
LaCl was then added. The mixture was stirred for 2 h,
3
2
0 mL of water was added, and the mixture was
extracted with chloroform (3×15 mL). The combined
extracts were dried over Na SO , the solvent was
2
4
removed under reduced pressure, and the residue was
subjected to chromatography on silica gel using
petroleum ether as eluent. The product was a mixture
8
a, 8b); spots were visualized by treatment with a so-
lution of phosphomolybdic acid in ethanol, aqueous
potassium permanganate, or a 0.2% solution of
Bromocresol Green in ethanol (8a, 8b, 9a, 9b). The
elemental compositions were determined with an EA
2
of C -diastereoisomeric thioacetates (R)-3a and (S)-3b
at a ratio of 7:1.
S-[(1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-
1
110 CHNS-O automated analyzer. All reactions were
carried out in freshly distilled solvents. Silica gel
0.06–0.2 mm, Alfa Aesar) was used for column
2
4
2
–
3
-yl]methyl ethanethioate (3a). Yield 78%, [α]D =
22.3° (c = 0.4, CHCl ). The spectral characteristics of
3
(
a were identical to those reported in [5].
chromatography with the same solvents as in TLC;
sulfonic acids 9a and 9b were eluted with methanol.
The product ratios were determined by H NMR from
the intensity of the 10-H signals.
S-[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-
-yl]methyl ethanethioate (3b). The spectral data
1
2
were obtained from the spectra of mixture 3a/3b.
1
H NMR spectrum (CDCl ), δ, ppm: 0.80 s (3H, 8-H),
3
(
–)-β-Pinene (2) was commercial product with
2
5
0.84–0.93 m (1H, 7α-H), 1.20 s (3H, 9-H), 1.33–
a purity of 99%, [α] = –22° (from Sigma–Aldrich).
D
1
1
2
2
7
.40 m (1H, 3α-H), 1.74–1.79 m (2H, 4-H), 1.78–
.85 m (1H, 1-H), 1.87–1.94 m (1H, 5-H), 2.05–
.16 m (2H, 2-H, 3β-H), 2.31–2.42 m (1H, 7β-H),
Commercial aqueous solution of chlorine dioxide
manufactured by Mondi SLPK corporation (Russia)
was used. Organic solutions of chlorine dioxide were
prepared by extraction from aqueous solution, fol-
lowed by drying the extract over anhydrous Na SO ;
.33 s (3H, COCH ), 2.80 d.d (2H, 10-H, J = 17.6,
3
13
.4 Hz). C NMR spectrum (CDCl ), δ , ppm: 20.04
3
C
2
4
8
3
4
9
(
(
(
C ), 23.22 (C ), 24.19 (C ), 26.64 (C ), 30.61
COCH ), 33.30 (C ), 34.95 (C ), 35.14 (C ), 38.65
C ), 40.74 (C ), 45.00 (C ), 196.00 (COCH ).
the concentration of ClO was determined by titration
according to [12].
2
7
10
2
3
6
5
1
3
(
1S,2R,5S)-2-(Iodomethyl)-6,6-dimethylbicyclo-
3.1.1]heptane (5). cis-Myrtanol 4, 0.154 g (1 mmol),
was dissolved in 7 mL of toluene, and 0.314 g
1.2 mmol) of triphenylphosphine, 0.236 g (2 mmol) of
Found, %: C 67.91; H 9.41; S 15.16. C H OS.
1
2
20
[
Calculated, %: C 67.87; H 9.49; S 15.10.
Thiols 1a and 1b were synthesized according to the
(
2
2
procedure described in [5]. Yield 72%, [α] = –38.5°
D
benzimidazole, and 0.305 g (1.2 mmol) of iodine were
added with stirring. The mixture was refluxed for 1 h,
and a saturated aqueous solution of Na S O was
(
c = 0.2, CHCl ). The spectral characteristics of 1a
3
were identical to those reported in [5].
2
2
3
added in portions until the iodine color disappeared.
The mixture was extracted with chloroform, the extract
was dried over Na SO , filtered, and evaporated, and
[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-2-
yl]methanethiol (1b). The spectral data were obtained
from the spectra of mixture 1a/1b. H NMR spectrum
1
2
4
the residue was purified by silica gel chromatography
(CDCl ), δ, ppm: 0.83 s (3H, 8-H), 0.87–0.95 m (1H,
3
2
2
using petroleum ether as eluent. Yield 90%, [α]
=
7α-H), 1.22 s (3H, 9-H), 1.26–1.36 m (2H, SH, 3α-H),
1.72–1.84 m (2H, 4-H), 1.86–1.99 m (2H, 1-H, 5-H),
2.01–2.14 m (2H, 2-H, 3β-H), 2.33–2.43 m (1H,
D
1
–
42.8° (c = 0.2, CHCl ). H NMR spectrum (CDCl ),
3
3
δ, ppm: 0.92 d (1H, 7α-H, J = 9.3 Hz), 1.01 s (3H,
1
3
8
2
-H), 1.24 s (3H, 9-H), 1.43–1.60 m (1H, 3α-H), 1.85–
.00 m (3H, 4-H, 5-H), 2.01–2.17 m (2H, 1-H, 3β-H),
7β-H), 2.39–2.46 m (2H, 10-H). C NMR spectrum
8
3
4
(CDCl ), δ , ppm: 20.09 (C ), 23.27 (C ), 24.20 (C ),
3
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

1
2
474
GREBYONKINA et al.
9
10
7
6
6.65 (C ), 30.56 (C ), 33.27 (C ), 38.63 (C ), 38.82
1.00–1.09 m (1H, 7α-H), 1.03 s (3H, 8-H), 1.06 s (3H,
8′-H), 1.23 s (3H, 9-H), 1.25 s (3H, 9′-H), 1.47–1.59 m
2
5
1
(
C ), 40.89 (C ), 44.65 (C ).
(
(
2
2
7
1H, 3α-H), 1.62–1.74 m (1H, 3α′-H), 1.81–2.14 m
9H, 1-H, 1′-H, 3β-H, 4-H, 4′-H, 5-H, 5′-H), 2.15–
Oxidation of thiols with chlorine dioxide (general
procedure). The overall volume of the reaction mixture
was calculated for a thiol concentration of 0.02 M. The
progress of reactions was monitored by TLC.
.30 m (1H, 3β′-H), 2.33–2.50 m (2H, 7β-H, 7β′-H),
.75–2.98 m (2H, 2-H, 2′-H), 3.22 d (2H, 10′-H, J =
1
3
.9 Hz), 3.40–3.51 m (2H, 10-H). C NMR spectrum
a. A solution of 0.17 g (1 mmol) of thiol 1a or
mixture 1a/1b in an organic solvent was added with
stirring to an aqueous–organic solution of 0.135 g
3′
3
8
(CDCl ), δ , ppm: 21.70 (C ), 21.87 (C ), 23.13 (C ,
3 C
8′
4′
4
9′
9
C ), 25.80 (C ), 25.89 (C ), 27.53 (C ), 27.79 (C ),
3
(
4
7′
7
2′
2
2.47 (C ), 33.18 (C ), 35.29 (C ), 36.00 (C ), 37.07
(
2 mmol) of chlorine dioxide, and the mixture was kept
6′
6
5′
5
10′
C ), 37.36 (C ), 40.64 (C ), 41.05 (C ), 42.68 (C ),
5.14 (C ), 46.50 (C ), 70.28 (C ). Found, %:
for 0.5–2 h. The organic phase was separated, the
solvent was distilled off under reduced pressure, and
the residue was subjected to silica gel chromatography
to isolate compounds 6–8; sulfonic acids 9 were
isolated by evaporation of the aqueous phase.
1′
1
10
C 64.91; H 9.19; S 17.34. C H O S . Calculated, %:
2
0
34
2 2
C 64.82; H 9.25; S 17.30.
(1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-2-
yl]methanesulfonyl chloride (8a). b. Ratio 1a:ClO =
[
2
b. Thiol 1a or mixture 1a/1b, 0.17 g (1 mmol), was
dissolved in methylene chloride, 0.027 g (0.1 mmol) of
1
:2. solvent methylene chloride, reaction time 2 h.
23
Yield 96%, transparent viscous liquid, [α]D = –28.3°
VO(acac) was added with stirring, and a solution of
–1
2
(
(
(
c = 0.5, CHCl ). IR spectrum (KBr), ν, cm : 1377
3
0
.135 g (2 mmol) of ClO in methylene chloride was
1
2
SO , asym.), 1168 (SO , sym.). H NMR spectrum
CDCl ), δ, ppm: 1.01–1.12 m (1H, 7α-H), 1.05 s (3H,
2
2
then added. After 2 h, the solvent was distilled off, and
the dry residue was subjected to chromatography on
silica gel.
3
8
2
-H), 1.26 s (3H, 9-H), 1.64–1.81 m (1H, 3α-H), 1.90–
.08 m (3H, 4-H, 5-H), 2.06–2.17 m (1H, 1-H), 2.18–
Bis[(1S,2R,5S)-(6,6-dimethylbicyclo[3.1.1]hep-
2.35 m (1H, 3β-H), 2.39–2.51 m (1H, 7β-H), 2.89–
3.03 m (1H, 2-H), 3.85 d (2H, 10-H, J = 6.5 Hz).
tan-2-yl)methyl] disulfide (6a). a. Ratio 1a:ClO =
2
1
3
3
1
:0.5, solvent hexane, reaction time 0.5 h. Yield 68%.
The spectral characteristics of 6a were identical to
those reported in [13].
C NMR spectrum (CDCl ), δ , ppm: 21.37 (C ),
3
C
9
8
4
7
23.09 (C ), 25.61 (C ), 27.42 (C ), 32.31 (C ), 36.60
(
2
6
5
1
10
C ), 38.36 (C ), 40.52 (C ), 46.09 (C ), 73.38 (C ).
Found, %: C 50.79; H 7.19; S 13.61. C H ClO S.
Calculated, %: C 50.73; H 7.24; S 13.54.
Bis[(1S,2S,5S)-(6,6-dimethylbicyclo[3.1.1]-
heptan-2-yl)methyl] disulfide (6b). a. Ratio
10 17
2
(
0
7
1a/1b):ClO = 1:0.5, solvent hexane, reaction time
.5 h. Yield 68% (isomer mixture 6a/6b at a ratio of
2
[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-
-yl]methanesulfonyl chloride (8b). b. Ratio
2
(
:1). The spectral data were obtained from the spectra
1a/1b):ClO = 1:2, solvent methylene chloride, reac-
2
1
of mixture 6a/6b. H NMR spectrum (CDCl ), δ, ppm:
3
tion time 2 h. Yield of 8a/8b 95% (7:1). IR spectrum
–
1
0
9
1
3
.87 s (6H, 8-H), 1.02–1.09 m (2H, 7α-H), 1.24 s (6H,
-H), 1.28–1.36 m (2H, 3α-H), 1.76–1.87 m (4H, 4-H),
.87–2.06 m (6H, 1-H, 2-H, 5-H), 2.04–2.13 m (2H,
β-H), 2.37–2.45 m (2H, 7β-H), 2.63 d.d (4H, 10-H,
(
KBr), ν, cm : 1377 (SO , asym.), 1168 (SO , sym.).
2 2
1
H NMR spectrum (CDCl ), δ, ppm: 0.92 s (3H, 8-H),
3
0.98–1.10 m (1H, 7α-H), 1.11 s (3H, 9-H), 1.60–
1.78 m (1H, 3α-H), 1.80–1.91 m (2H, 4-H), 1.94–
2.03 m (3H, 1-H, 3β-H, 5-H), 2.36–2.48 m (1H, 7β-H),
2.83–2.91 m (1H, 2-H), 3.70 d (2H, 10-H, J = 6.6 Hz).
1
3
J = 6.9, 3.0 Hz). C NMR spectrum (CDCl ), δ , ppm:
2
(
4
3
C
8
3
4
9
0.12 (C ), 23.41 (C ), 24.26 (C ), 26.66 (C ), 32.58
C ), 38.66 (C ), 40.29 (C ), 40.86 (C ), 44.61 (C ),
5.83 (C ). Found, %: C 71.03; H 10.04; S 18.90.
7
6
2
5
1
13
8
C NMR spectrum (CDCl ), δ , ppm: 20.01 (C ),
3 C
1
0
3
4
9
7
23.20 (C ), 25.61 (C ), 26.50 (C ), 32.30 (C ), 32.62
(C ), 39.74 (C ), 40.20 (C ), 45.08 (C ), 72.53 (C ).
Found, %: C 50.79; H 7.19; S 13.61. C H ClO S.
2
6
5
1
10
C H S . Calculated, %: C 70.94; H 10.12; S 18.94.
2
0
34 2
S-[(1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-
-yl]methyl (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]-
heptan-2-yl)methanesulfonothioate (7a). a. Ratio
a:ClO = 1:2, solvent methylene chloride–water, re-
10 17
2
Calculated, %: C 50.73; H 7.24; S 13.54.
2
[(1S,2R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-
1
2-yl]methanesulfonic acid (9a). a. Ratio 1a:ClO =
2
2
action time 2 h. Yield 45%. IR spectrum (KBr), ν,
1:2, solvent pyridine–water, reaction time 2 h. Yield
–
1
1
23
cm : 1321 (SO , asym.), 1128 (SO , sym.). H NMR
98%, transparent viscous liquid, [α] = –9.6° (c = 0.3,
2
2
D
1
–
spectrum (CDCl ), δ, ppm: 0.87–0.96 m (1H, 7α′-H),
CHCl ). IR spectrum (KBr), ν, cm : 1215, 1167 (SO ,
3
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019

SYNTHESIS AND OXIDATION OF MYRTANETHIOL
1475
1
asym.), 1051, 1028, 1002 (SO , sym.). H NMR spec-
REFERENCES
2
trum (DMSO-d ), δ, ppm: 0.85–0.94 m (1H, 7α-H),
6
0
3
3
.94 s (3H, 8-H), 1.14 s (3H, 9-H), 1.48–1.67 m (1H,
α-H), 1.75–1.95 m (3H, 4-H, 5-H), 1.91–2.01 m (2H,
β-H, 1-H), 2.20–2.38 m (1H, 7β-H), 2.41–2.53 m
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(
(
2
1H, 2-H), 2.75 d (2H, 10-H, J = 6.6 Hz), 7.18 br.s
1
3
1H, OH). C NMR spectrum (DMSO-d ), δ , ppm:
6 C
3
8
4
9
2.12 (C ), 23.34 (C ), 26.22 (C ), 28.13 (C ), 32.66
7
2
6
5
1
(
C ), 36.83 (C ), 38.46 (C ), 40.88 (C ), 46.27 (C ),
1
0
5
2
9.51 (C ). Mass spectrum (ESI, 5 kV), m/z (I , %):
rel
–
17.29 (100) [M – H] , 97.00 (48) [C H ]. Found, %:
7
13
C 55.47; H 8.36; S 14.55. C H O S. Calculated, %:
1
0
18
3
C 55.05; H 8.26; S 14.68.
(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hep-
tan-2-yl]methanesulfonic acid (9b). a. Ratio
https://doi.org/10.1134/S1070428017060082
[
4
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Tupikina, V.G., and Petrov, A.Yu., RU Patent
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. Banach, A., Ścianowski, J., and Ozimek, P.,
Phosphorus, Sulfur Silicon Relat. Elem., 2014, vol. 189,
p. 274.
(
9
1
1a/1b):ClO = 1:2, solvent pyridine–water. Yield of
2
–1
a/9b 98% (7:1). IR spectrum (KBr), ν, cm : 1215,
167 (SO , asym.), 1051, 1028, 1002 (SO , sym.).
5
2
2
1
H NMR spectrum (DMSO-d ,), δ, ppm: 0.81 s (3H,
6
8
-H), 0.93–1.02 m (1H, 7α-H), 1.16 s (3H, 9-H), 1.55–
.65 m (1H, 3α-H), 1.65–1.73 m (2H, 4-H), 1.76–
.85 m (1H, 3β-H), 1.92–1.99 m (1H, 1-H), 2.20–
.38 m (2H, 5-H, 7β-H), 2.35–2.41 m (1H, 2-H),
.59 d (2H, 10-H, J = 6.6 Hz), 7.18 br.s (1H, OH).
https://doi.org/10.1080/10426507.2013.819867
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. Zheng, T.-C., Burkart, M., and Richardson, D.E.,
Tetrahedron Lett., 1999, vol. 40, p. 603.
1
1
2
7
8
2
1
3
8
C NMR spectrum (DMSO-d ), δ , ppm: 20.45 (C ),
6
C
3
4
9
2
2
3.30 (C ), 24.49 (C ), 27.03 (C ), 31.94 (C ), 32.66
7
6
5
1
10
(
C ), 38.69 (C ), 40.66 (C ), 45.15 (C ), 58.00 (C ).
Mass spectrum (ESI, 5 kV), m/z (I , %): 217.29 (100)
rel
https://doi.org/10.1016/s0040-4039(98)02545-3
–
[M – H] , 97.00 (48) [C H ]. Found, %: C 55.55;
7 13
9. Lezina, O.M., Grebenkina, O.N., Sudarikov, D.V.,
Krymskaya, Yu.V., Rubtsova, S.A., and Kutchin, A.V.,
Russ. J. Org. Chem., 2015, vol. 51, p. 1359.
H 8.41; S 14.61. C H O S. Calculated, %: C 55.05;
H 8.26; S 14.68.
1
0
18
3
https://doi.org/10.1134/S1070428015100012
FUNDING
10. Izmest’ev, E.S., Lezina, O.M., Grebyonkina, O.N.,
Patov, S.A., Rubtsova, S.A., and Kutchin, A.V., Russ.
Chem. Bull., Int. Ed., 2014, vol. 63, p. 2067.
This study was financially supported by the Ural Branch
of the Russian Academy of Sciences (project no. 18-3-3-17).
https://doi.org/10.1007/s11172-014-0702-8
11. Lezina, O.M., Rubtsova, S.A., and Kuchin, A.V., Russ.
ACKNOWLEDGMENTS
J. Org. Chem., 2011, vol. 47, p. 1249.
https://doi.org/10.1134/S1070428011080239
12. Petrenko, N.F. and Mokienko, A.V., Dioksid khlora:
primenenie v tekhnologiyakh vodopodgotovki (Chlorine
Dioxide. Application in Water Treatment Technologies),
Odessa: Optimum, 2005.
The spectral and analytical data were obtained using the
facilities of the “Chemistry” joint center at the Institute of
Chemistry, Komi Scientific Center (Ural Branch, Russian
Academy of Sciences).
1
3. Pestova, S.V., Izmest’ev, E.S., Shevchenko, O.G.,
Rubtsova, S.A., and Kuchin, A.V., Russ. Chem. Bull.,
Int. Ed., 2015, vol. 64, p. 723.
CONFLICT OF INTERESTS
The authors declare the absence of conflict of interests.
https://doi.org/10.1007/s11172-015-0926-2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 10 2019