Reactions of 3,5-di-tert-butyl-1,2-benzoquinone with mercapto carboxylic acids

Article abstract of DOI:10.1007/s11172-016-1363-6

Heating of an equimolar mixture of 3,5-di-tert-butyl-1,2-benzoquinone with thiosalicylic acid led to 2-[(4,6-di-tert-butyl-2,3-dihydroxyphenyl)thio]benzoic acid. In the case of β-mercaptopropionic acid, 2-[(4,6-di-tert-butyl-2,3-dihydroxyphenyl)thio]propi

Full text of DOI:10.1007/s11172-016-1363-6

Russian Chemical Bulletin, International Edition, Vol. 65, No. 3, pp. 727—730, March, 2016
727
Reactions of 3,5ꢀdiꢀtertꢀbutylꢀ1,2ꢀbenzoquinone
with mercapto carboxylic acids
L. Yu. Ukhin,a K. Yu. Suponitsky,b E. N. Shepelenko,c L. V. Belousova,a D. V. Alekseenko,a
G. S. Borodkin,a and L. N. Etmetchenkoa
aInstitute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 Rostov on Don, Russian Federation.
Fax: +7 (863) 243 4700. Eꢀmail: may@ipoc.sfedu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: kirshik@yahoo.com
c Southern Scientific Center, Russian Academy of Sciences,
41 ul. Chekhova, 344006 Rostov on Don, Russian Federation.
Eꢀmail: dubon@ipoc.sfedu.ru
Heating of an equimolar mixture of 3,5ꢀdiꢀtertꢀbutylꢀ1,2ꢀbenzoquinone with thiosalicylic
acid led to 2ꢀ[(4,6ꢀdiꢀtertꢀbutylꢀ2,3ꢀdihydroxyphenyl)thio]benzoic acid. In the case of βꢀmerꢀ
captopropionic acid, 2ꢀ[(4,6ꢀdiꢀtertꢀbutylꢀ2,3ꢀdihydroxyphenyl)thio]propionic acid was formed,
which upon reflux in Ac2O was converted to 6,8ꢀdiꢀtertꢀbutylꢀ9ꢀhydroxyꢀ3,4ꢀdihydroꢀ2Hꢀ1,5ꢀ
benzoxathiepinꢀ2ꢀone.
Key words: 3,5ꢀdiꢀtertꢀbutylꢀ1,2ꢀbenzoquinone, mercapto carboxylic acids, lactonization,
6,8ꢀdiꢀtertꢀbutylꢀ9ꢀhydroxyꢀ3,4ꢀdihydroꢀ2Hꢀ1,5ꢀbenzoxathiepinꢀ2ꢀone.
3,5ꢀDiꢀtertꢀbutylꢀ1,2ꢀbenzoquinone (1) is easily availꢀ
able and promising compound1,2 due to its ability to be
involved in different reactions, leading to unexpected strucꢀ
tures. The formation of βꢀtropolones in the reaction of 1 with
2ꢀmethylquinoline derivatives3,4 is one of the examples.
Another interesting example was the conversion of
3ꢀ[(2ꢀaminophenyl)amino]ꢀ5,5ꢀdimethylcyclohexꢀ2ꢀenꢀ
1ꢀone in the reaction with quinone 1 to earlier unknown
macrolactone of the oxonine series.5 In these examples,
the reaction begins from the attack by Cꢀ or Nꢀnucleoꢀ
phile on the quinone C(2)ꢀcarbonyl carbon atom.
In the reaction with Sꢀnucleophiles, the attack was
directed on another electrophilic center of quinone 1: the
C(6) carbon atom (see Refs 2 and 6), thus following the
Michael addition reaction. In the case of thioglycolic acid,
4,6ꢀdiꢀtertꢀbutylꢀ2,3ꢀdihydroxyphenylthioacetic acid was
obtained, undergoing ready lactonization to 5,7ꢀdiꢀtertꢀ
butylꢀ8ꢀhydroxyꢀ1,4ꢀbenzoxathiinꢀ2(3H)ꢀone. These both
compounds possess antioxidant properties, especially proꢀ
nounced in the lactone, which is regarded by the authors
as the structural analogue of tocopherol.2 Apart from that,
the acid and its complex with AgI exibit antimicrobial
activity.7 We did not find information in the literature on
the reaction of quinone 1 with thiosalicylic acid (2).
We found that an equimolar mixture of quinone 1 and
thiosalicylic acid (2) triturated in a mortar and subjected
to heating, after partial melting undervent conversion to
a loose colorless mass without complete melting. The IR
and mass spectra of the material obtained indicate the
formation of a linear product of addition of thiosalicylic
acid to quinone at position C(6). However, the 1H NMR
spectrum of the product recrystallized from MeCN exhibꢀ
ited signals conflicting with the structure.
The Xꢀray diffraction study of the crystal grown
from MeCN unambiguously confirmed that this is 2ꢀ[(4,6ꢀ
diꢀtertꢀbutylꢀ2,3ꢀdihydroxyphenyl)thio]benzoic acid (3,
Scheme 1, Fig. 1). The cause of the discrepancy of the
1H NMR spectrum was the presence of disulfide 4 in the
sample. Compound 4 was formed simultaneously with the
main product by the oxidation of thiosalicylic acid. The
impurity of disulfide 4 cannot be removed by recrystallizaꢀ
tion from MeCN.
The spectrally pure product 3 was obtained by recrysꢀ
tallization of the reaction mixture from acetone. The comꢀ
pound is very poorly soluble in refluxing acetic acid, but
crystallizes from a mixture of AcOH—Ac2O (6 : 1). Reꢀ
fluxing acetic anhydride decomposes compound 3.
The asymmetric unit cell of compound 3 contains one
molecule. The phenyl rings bound by a sulfide bridge are
arranged almost perpendicular to each other because of
the steric factor. Both hydroxy groups are almost coplanar
to the phenyl ring, to which they are attached. The hydroꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0727—0730, March, 2016.
1066ꢀ5285/16/6503ꢀ0727 © 2016 Springer Science+Business Media, Inc.

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Ukhin et al.
leads to the formation of centrosymmetric dimers bound
by a hydrogen bond typical of carboxylic acids.8—10
It was found that a shortꢀtime heating of quinone 1
with 2ꢀmercaptopropionic acid (5) led to 5,7ꢀdiꢀtertꢀbuꢀ
tylꢀ8ꢀhydroxyꢀ3ꢀmethylꢀ1,4ꢀbenzoxantiinꢀ2(3H)ꢀone (7)
(Scheme 2).
C(15)
C(17)
C(16)
O(1)
C(14)
C(10)
C(9)
C(11)
Scheme 2
C(12)
C(13)
O(2)
C(19)
C(8)
C(6)
C(18)
C(20)
C(21)
C(5)
C(7)
C(4)
C(2)
O(3)
C(3)
C(1)
O(4)
Fig. 1. General view of compound 3 in representation of atoms
by ellipsoids of atomic displacements with 50% probability.
Apparently, compound 7 is formed by lactonization of
the intermediate acid 6, similarly to the reaction of 1 with
thioglycolic acid.2
The product of heating of quinone 1 with 3ꢀmercaptoꢀ
propionic acid (8) was 3ꢀ[4,6ꢀdiꢀtertꢀbutylꢀ(2,3ꢀdihydrꢀ
oxyphenyl)thio]propionic acid (9). Its reflux in Ac2O causꢀ
es lactonization to the earlier undescribed 6,8ꢀdiꢀtertꢀbuꢀ
tylꢀ9ꢀhydroxyꢀ3,4ꢀdihydroꢀ2Hꢀbenzꢀ1,5ꢀoxathiepinꢀ2ꢀ
one (10) (Scheme 3).
Scheme 1
Scheme 3
gen atoms of these groups are not involved in the formaꢀ
tion of intermolecular hydrogen bond (because of the steric
hindrance posed by the close tertꢀbutyl groups), but form
the weak intramolecular bonds O(2)—H(2)...S(1) (O—H,
0.82(2), O...S, 2.920(2), H...S, 2.35(2), <OHS, 127(2)°),
O(1)—H(1)...O(2) (O—H, 0.81(2) Å, O...O, 2.619(2) Å,
H...O, 2.13(2) Å, <OHO, 118(2)°). At the same time, the
proton of the carboxy group is involved in the strong direct
intermolecular Hꢀbond O(4)—H(4)...O(3) (O—H 0.83(2),
O...O, 2.683(2) Å, H...O, 1.86(2), <OHO, 173(2)°), which
Compound 10 is isomeric to compound 7. If a suggestꢀ
ed intermediate compound 6 undergoes lactonization just
upon heating, the acid 9 remains unchanged upon reflux
in acetic acid, from which it can be recrystallized. The
1
structure of 10 was inferred from its H and 13C NMR

Reactions of oꢀquinones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 3, March, 2016
729
captopropionic acid (0.2 mL) was heated until dissolution and
turning colorless and cooled, resulting in solidification of the
mixture. Light petroleum ether (3 mL) was added, the precipiꢀ
tate was triturated, filtered, and washed with light petroleum
ether to obtain a colorless compound with m.p. 161—165 °C
(from light petroleum ether), the yield was 0.25 g (77%).
Found (%): C, 62.73; H, 8.28; S, 9.61. C17H26O4S. Calculatꢀ
ed (%): C, 62.54; H, 8.03; S, 9.82. IR, ν/cm–1: 3539, 3342 (OH);
spectra by the complete assignment of the signals (see
Experimental). The complete assignment of chemical
shifts in the 1H NMR spectra was made using a 2D pulse
sequence COSY.
The complete assignment of chemical shifts in the
13C NMR spectra was made using a 2D pulse sequences
HSQC and HMBC.
1
2953 (But); 1698 (CO). H NMR (300 MHz, CDCl3), δ: 1.40
(s, 9 H, But); 1.49 (s, 9 H, But); 2.74 (t, 2 H, CH2, J = 6.6 Hz); 2.92
(t, 2 H, CH2, J = 6.6 Hz); 5.65 (br.s, 1 H, OH); 6.91 (s, 1 H,
C(5)H); 7.50 (br.s, 1 H, OH). 13C NMR (600 MHz, DMSOꢀd6),
δ: 29.24, 30.75, 31.27, 33.02, 34.59, 36.31, 114.68, 116.70, 135.07,
141.54, 142.18, 147.39, 173.35. MS, m/z: 326 [M]+.
Experimental
IR spectra were recorded on a Varian Excalibur 3100 FTꢀIR
1
spectrometer using FTIR method. H NMR spectra were reꢀ
corded on a Varian UNITYꢀ300 spectrometer. Mass spectra were
obtained on a Shimadzu GCMSꢀQP2010 SE spectrometer with
direct injection of the sample into the source of ions (EI 70 eV).
The signals in the NMR spectra of compound 9 were assigned
based on the experiments recorded on a Bruker Avanceꢀ600
spectrometer, which was also used for recording 13C NMR spectra
for compounds 7 and 9. The starting compounds and solvents
were purchased from Alfa Acear.
2ꢀ[(4,6ꢀDiꢀtertꢀbutylꢀ2,3ꢀdihydroxyphenyl)thio]benzoic acid
(3). A mixture of quinone 1 (0.44 g, 2 mmol) and thiosalicylic
acid (0.31 g, 2 mmol) was triturated in a mortar, then placed into
a 25ꢀmL roundꢀbottom flask, and heated in a heater with the
temperature set to 300 °C. A partially melted mixture, without
complete melting, turned to a loose colorless mass. After coolꢀ
ing, ethyl acetate (5 mL) was added, a precipitate formed was
triturated, filtered, sequentially washed with ethyl acetate, diꢀ
ethyl ether, and light petroleum ether. The yield of the product
containing a disulfide 4 admixture was 0.4 g (53%). To obtain
spectrally pure compound, the product was recrystallized from
acetone, hotꢀfiltered through a dense filter to obtain a colorꢀ
6,8ꢀDiꢀtertꢀbutylꢀ9ꢀhydroxyꢀ3,4ꢀdihydroꢀ2Hꢀ1,5ꢀbenzoxaꢀ
thiepinꢀ2ꢀone (10). A mixture of compound 9 (0.293 g, 0.89 mmol)
and Ac2O (1 mL) was heated to reflux, a clear solution formed
was cooled. Light petroleum ether (3 mL) was added to the
reaction mixture with a precipitate formed. The precipitate was
filtered, washed with light petroleum ether, and dried. The yield
of crude product was 0.115 g (42%). Recrystallization from light
petroleum ether (70—100 °C) (15 mL) gave chemically pure
compound 10 (0.081 g, 29%), a colorless compound, m.p. 194 °C
(from light petroleum ether). Found (%): C, 65.94; H, 8.03;
S, 10.02. C17H24O3S. Calculated (%): C, 66.20; H, 7.84; S, 10.40.
IR, ν/cm–1: 3370 (OH); 2991, 2959 (But); 1757 (CO). 1H NMR
(600 MHz, CDCl3), δ: 1.41 (s, 9 H, But); 1.51 (s, 9 H, But); 2.76
(t, 2 H, C(3)H2, J = 7.1 Hz); 3.17 (t, 2 H, C(4)H2, J = 7.1 Hz);
5.91 (s, 1 H, OH); 7.27 (s, 1 H, C(7)H). 13C NMR, δ: 29.23
(C(8)—C(CH3)3); 31.20 (C(6)—C(CH3)3); 31.61 (C(4)); 32.75
(C(3)); 35.46 (C(8)—CMe3); 37.00 (C(6)—CMe3); 118.09 (C(5a));
122.20 (C(7)); 137.66 (C(8)); 142.95 (C(9)); 143.25 (C(9a));
144.06 (C(6)); 169.46 (C(2)). MS, m/z: 308 [M]+.
Xꢀray diffraction study of compound 3. Crystals C21H26O4S at
120 K are monoclinic, space group P21/c: a = 10.5940(4) Å,
less compound with m.p. 245 °C (from acetone). IR, ν/cm–1
:
1
3527, 3365 (OH); 2961 (But); 1681 (CO). H NMR (300 MHz,
b = 9.9657(4) Å, c = 17.9939(7) Å, β = 92.4570(10)°, V =
DMSOꢀd6), δ: 1.36 (s, 9 H, But); 1.38 (s, 9 H, But); 6.43 (d, 1 H,
3
= 1897.99(13) Å , Z = 4, M = 374.48, dcalc = 1.311 g cm–3
,
CHarom, J = 8.4 Hz); 6.93 (s, 1 H, C(5´)H); 7.09 (t, 1 H, CHarom
,
wR2 = 0.0841, the structure was solved on F2 and on 4139
hkl
J = 7.5 Hz); 7.30 (dt, 1 H, CHarom, 3J = 8.4 Hz, J = 1.5 Hz); 7.91
(dd, 1 H, 3J = 7.5 Hz, J = 1.5 Hz); 8.12 (s, 1 H, OH); 8.45 (s, 1 H,
OH); 13.05 (s, 1 H, OH). MS, m/z: 374 [M]+.
independent reflections with 2θ < 54°, GOOF = 1.032
(R = 0.0330, was solved on Fhkl on 3679 reflections with
I > 2σ(I)). Crystallographic data (except structural factors) for
this the structure were deposited with the Cambridge Crystalloꢀ
graphic Data Center (CCDC 1411565).
5,7ꢀDiꢀtertꢀbutylꢀ8ꢀhydroxyꢀ3ꢀmethylꢀ1,4ꢀbenzoxathiinꢀ2(3H)ꢀ
one (7). A mixture of quinone 1 (0.22 g, 1 mmol) and 2ꢀmercaptoꢀ
propionic acid (0.15 mL) was heated until dissolution and turnꢀ
ing colorless, followed by addition of EtOH (2 mL). Then, the
mixture was heated to homogenization and cooled, resulting in
solidification of the mass. The material obtained was placed on
a filter, washed with cold EtOH, light petroleum ether, and dried
to obtain a colorless compound (0.11 g) with m.p. 150—152 °C
(from EtOH). The filtrate was treated with water to precipitate
another 0.12 g of the compound with an identical IR spectrum.
A total yield was 0.23 g (74%). Found (%): C, 66.34; H, 7.93;
S, 10.28. C17H24O3S. Calculated (%): C, 66.20; H, 7.84; S, 10.40.
IR, ν/cm–1: 3438 (OH); 2965, 2954 (But); 1763 (CO). 1H NMR
(300 MHz, CDCl3), δ: 1.37 (s, 9 H, But); 1.41 (s, 9 H, But); 1.56
(d, 3 H, CH3, J = 6.9 Hz); 3.40 (q, 1 H, CH, J = 6.9 Hz); 5.76
(s, 1 H, OH); 7.08 (s, 1 H, C(6)H). 13C NMR (600 MHz, CDCl3),
δ: 13.81, 29.31, 30.26, 35.17, 36.15, 36.29, 116.87, 120.01, 134.22,
138.15, 139.23, 141.42, 166.23. MS, m/z: 308 [M]+.
Spectroscopic studies were carried out using facilities
of the Molecular Spectroscopy Multiꢀaccess Center of the
Southern Federal University.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation within
the Project part of the State Assignment in Academic Area
for the Southern Federal University according to the
Theme 4.196.2014/К.
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Received August 28, 2015;
in revised form December 23, 2015