Synthesis of Dialkyl 5-Amino-2-hydroxy-4,6-dimethylisophthalates and Their Sulfonylation

Article abstract of DOI:10.1134/S1070428019050269

Dimethyl 5-amino-2-hydroxy-4,6-dimethylisophthalate and dimethyl 5-amino-2-hydroxy-4,6-dimethylisophthalate were obtained in the free form for the first time. The products were sulfonylated with p-toluenesulfonyl to obtain previously unknown dialkyl 5-(4-toluenesulfonamido)-2-hydroxy-4,6-dimethylisophthalates. The use of p-acetamidobenzenesulfonyl chloride as the sulfonylating agent in this reaction led to the formation of dialkyl 5-(4-acetamidobenzenesulfonamido)-2-hydroxy-4,6-dimethyl isophthalates. The synthesized sulfonamide derivatives are of interest as potentially biologically active compounds. The structure of all the obtained compounds was proved using IR and NMR spectroscopy and mass spectrometry.

Full text of DOI:10.1134/S1070428019050269

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 5, pp. 730–733. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 5, pp. 805–809.
SHORT
COMMUNICATIONS
Synthesis of Dialkyl 5-Amino-2-hydroxy-4,6-
dimethylisophthalates and Their Sulfonylation
I. G. Povarova,*, N. A. Shilenkova, I. V. Petersonb, G. A. Subocha, and M. S. Tovbisa
a Reshetnev Siberian State University of Science and Technology,
pr. imeni gazety “Krasnoyarskij rabochii” 31, Krasnoyarsk, 660037 Russia,
b Institute of Chemistry and Chemical Technology, Siberian Branch, Russian Academy of Sciences,
Akademgorodok 50/24, Krasnoyarsk, 660036 Russia
*е-mail: povarov_i@mail.ru
Received November 10, 2018; revised February 10, 2019; accepted February 17, 2019
Abstract—Dimethyl 5-amino-2-hydroxy-4,6-dimethylisophthalate and dimethyl 5-amino-2-hydroxy-4,6-
dimethylisophthalate were obtained in the free form for the first time. The products were sulfonylated with p-
toluenesulfonyl to obtain previously unknown dialkyl 5-(4-toluenesulfonamido)-2-hydroxy-4,6-
dimethylisophthalates. The use of p-acetamidobenzenesulfonyl chloride as the sulfonylating agent in this
reaction led to the formation of dialkyl 5-(4-acetamidobenzenesulfonamido)-2-hydroxy-4,6-dimethyl
isophthalates. The synthesized sulfonamide derivatives are of interest as potentially biologically active
compounds. The structure of all the obtained compounds was proved using IR and NMR spectroscopy and
mass spectrometry.
Keywords: synthesis, sulfonylation, p-toluenesulfonyl chloride, p-acetamidobenzenesulfonyl chloride,
aminoisophthalates, IR spectroscopy, NMR spectroscopy, mass spectrometry
DOI: 10.1134/S1070428019050269
At present a lot of different derivatives of amino-
phenols have been synthesized. Of great practical
importance are para-aminophenols and para-acet-
amidophenols, because their derivatives are used in
medicine as analgesics, antipyretics, and other drugs
[1]. Some persubstituted aminophenols containing
ester groups in the benzene ring exhibit analgesic, anti-
inflammatory, and antiarrhythmic activity [2, 3].
promise as potentially biologically active compounds.
To this end, we first prepared nitrosophenols
containing ester groups in the 2 and 6 positions with
respect to hydroxyl [6]. The products were reduced
and treated with p-toluenesulfonyl chloride or p-
acetamidobenzenesulfonyl chloride to isolate
previously unknown sulfonated derivative of persubs-
tituted aminophenols, whose structure was proved by
1
means of IR and H and 13C NMR spectroscopy and
Often aromatic amines are used in medicine not in
the free form but as sulfonated derivatives. Thus, the
known sulfonamide derivatives, broad-spectrum
antibacterial drugs active against both gram-positive
and gram-negative microorganisms, were introduced
into medical practice even before the discovery of
penicillins [4]. We previously synthesized a series of
hydrochlorides of persubstituted aminophenols [5]. At
the same time, free aminophenol have never been
prepared and studied.
mass spectrometry.
Dialkyl 2-hydroxy-4,6-dimethyl-5-(p-toluenesul-
fonamido)isophthalates 5a, 5b and 5-(p-acetamido-
benzenesulfonamido)-2-hydroxy-4,6-dimethyliso-
phthalates 6a, 6b (see scheme) were prepared by the
cycloaromatization of isonitrosoacetylacetone 1 and
dimethyl or diethyl acetonedicarboxylate 2a and 2b. as
a result, we obtained known persubstituted nitroso-
phenols as potassium salts 3a and 3b. These salts were
reduced with sodium dithionite by the procedure in [7]
to form corresponding aminophenols 4a and 4b. The
subsequent sulfonylation of the latter compound with
The present communication reports the first
synthesis of persubstituted aminophenols both in the
free form and as sulfonated derivatives, which hold
730

SYNTHESIS OF DIALKYL 5-AMINO-2-HYDROXY-4,6-DIMETHYLISOPHTHALATES
731
Scheme 1.
OK
O
C
O
C
ROOC
H3C
COOR
CH3
O
C
KOH
+
ROOC
COOR
H3C
C
CH3
C
C
C2H5OH
H2
H2
NOH
NO
3a_3b
1
2a_2b
OH
OH
ROOC
COOR
CH3
ROOC
H3C
COOR
CH3
ClO2S
CH3
Na2S2O4
H3C
H2O, 60oC
H2O, 60oC
NH
SO2
NH2
4a_4b
SO2Cl
H2O, 60oC
CH3
NHCOCH3
5a_5b
ROOC
CH3
HO
NH
SO2
NHCOCH3
CH3
ROOC
6a_6b
p-toluenesulfonyl chloride or p-acetamidobenzene-
sulfonyl chloride gave sulfonated derivatives 5a, 5b or
6a, 6b.
Dimethyl 5-amino-2-hydroxy-4,6-dimethyliso-
phthalate (4b). Potassium 2,6-bis(methoxycarbonyl)-
3,5-dimethyl-4-nitrosophenoxide, 0.5 g (1.87 mmol),
was dissolved in 10 mL of water at 60°C, after which
0.5 g (2.87 mmol) of sodium dithionite was added in
small portions, and the mixture was stirred for 30 min.
The mixture was then cooled to room temperature, and
the precipitate that formed was filtered off and dried
over CaCl2. Yield 0.22 g (42%). Yellow crystals, mp
77–79°C. IR spectrum, ν, cm–1: 1754 (C=O), 3373-
Diethyl 5-amino-2-hydroxy-4,6-dimethyliso-
phthalate (4a). Potassium 2,6-bis(ethoxycarbonyl)-
3,5-dimethyl-4-nitrosophenoxide, 0.5 g (1.69 mmol),
was dissolved in 10 mL of water at 60°C, after which
0.5 g (2.87 mmol) of sodium dithionite was added in
small portions, and the mixture was stirred for 60 min.
The reaction progress was monitored by TLC (toluene–
ethyl acetate, 1 : 1). The mixture was then cooled to
room temperature, and the precipitate that formed was
filtered off and dried over CaCl2. Yield 0.2 g (40%).
Yellow crystals, mp 72–75°C. IR spectrum, ν, cm–1:
1
3455 (NH2). H NMR spectrum (DMSO-d6), δ, ppm:
8.85 s (1H, OH), 4.53 s (2H, NH2), 4.15–4.39 s (4H,
COCH3), 1.19–1.33 q (6H, ester CH3). 13C NMR spec-
trum, δ, ppm: 15.5, 52.3, 121.4, 121.5, 138.2, 142.8,
168.8. Mass spectrum, m/z (Irel, %): 253 (24) [M]+ 221
(93), 189 (56), 106 (34), 77 (18), 15 (25).
1
1731 (C=O), 3373–3450 (NH2). H NMR spectrum
(DMSO-d6), δ, ppm: 8.82 s (1H, OH), 4.42 s (2H,
NH2), 4.25–4.42 q (4H, COCH2), 1.27–1.29 q (6H,
ester CH3). 13C NMR spectrum, δ, ppm: 14.3, 15.4,
61.1, 121.4, 121.6, 138.2, 143.0, 168.4. Mass
spectrum, m/z (Irel, %): 281 (34) [M]+, 235 (90), 189
(65), 106 (45), 77 (28), 29 (94). UV spectrum
(ethanol): λmax 216 nm, ε 332; λmax 388 nm, ε 86.
Diethyl 2-hydroxy-4,6-dimethyl-5-(4-methylben-
zenesulfonamido)isophthalate (5a). Compound 4a,
0.1 g (0.36 mmol), was dissolved in 4 mL of water,
after which 0.075 g (0.39 mmol) of p-toluenesulfonyl
chloride and 0.03 g (0.28 mmol) of Na2CO3 were
added in small portions over a period of 1 h under
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

POVAROV et al.
732
stirring and heating at 60°C, ensuring that the reaction
of the medium was neutral. The mixture was then
stirred for 2 h at 60°C, controlling the reaction
progress by TLC (toluene–ethyl acetate, 1 : 1), and
cooled to room temperature. To remove unreacted
aminophenol, the mixture was made acidic with HCl
(by Congo test) and stirred for 30 min. The precipitate
that formed was filtered off, washed with water until
neutral washings, and recrystallized from aqueous
alcohol. The precipitate was dried under vacuum. Yield
0.066 g (66%), light beige crystals. mp 143–145°C. IR
CH2), 1.24–1.26 t (6H, ester CH3); 1.88 s (6H,
aminophenol CH3); 2.09 s (3H, tosyl CH3). 13C NMR
spectrum, δ, ppm: 14.2, 16.5, 24.4, 61.4, 118.1, 118.9,
121.5, 126.4, 127.9, 135.2, 139.0, 143.4, 151.4, 167.3,
169.3. Mass spectrum, m/z (Irel, %): 475 (73) [M]+, 458
(15), 413 (6.91), 401 (2.52), 359 (34), 357 (59), 355
(29), 264 (20), 228 (36).
Dimethyl 5-(4-acetamidobenzenesulfonamido)-2-
hydroxy-4,6-dimethylisophthalate (6b). p-Acet-
amidobenzenesulfonyl chloride, 0.2 g (0.86 mmol),
and 0.059 g (0.56 mmol) of Na2CO3 were alternately
added in small portions over a period of 1 h to a stirred
and heated (30°C ) solution of 0.2 g (0.79 mmol) of
compound 4b in 4 mL of water. Reaction control and
further workup was similar to those described for
1
spectrum, ν, cm–1: 3232 (NH), 1380 (SO2). H NMR
spectrum (DMSO-d6), δ, ppm: 9.93 s (1H, OH), 10.13
s (1H, NH) 4.24–4.28 q (4H, COCH2), 1.24–1.26 t
(3H, ester CH3). 13C NMR spectrum, δ, ppm: 14.2,
16.5, 21.3, 61.4, 121.5, 126.2, 126.8, 130.0, 138.8,
139.0, 143.3, 151.4, 167.27. Mass spectrum, m/z (Irel,
%): 435 (50) [M]+, 390 (25), 280 (64), 234 (88), 206
(33), 91 (40), 29 (31). UV spectrum (ethanol): λmax 218
nm, ε 628; λmax 317 nm, ɛ 96.
1
compound 5a. Yield 75%, mp 200–202°C. H NMR
spectrum (DMSO-d6), δ, ppm:10.52 (1H, NH); 10.00 s
(1H, OH); 9.72 s (1H, tosyl NH); 7.70–7.85 d (4H,
tosyl ring); 3.89 s (6H, COCH3); 2.23 s (6H,
aminophenol CH3); 2.03 s (3H, tosyl CH3). 13C NMR
spectrum, δ, ppm: 16.1, 22.3, 51.4, 118.2, 118.8, 121.3,
125.3, 126.9, 134.3, 138.0, 143.0, 152.3, 166.8, 168.8.
Mass spectrum, m/z (Irel, %): 450 (74) [M]+, 372 (15),
331 (41), 317 (100), 295 (22), 236 (3), 194 (10), 135
(2), 115 (5).
Dimethyl 2-hydroxy-4,6-dimethyl-5-(4-methylben-
zenesulfonamido)isophthalate (5b). Compound 4b,
0.1 g (0.39 mmol), was dissolved in 4 mL of water,
after which 0.075 g (0.39 mmol) of p-toluenesulfonyl
chloride and 0.03 g (0.28 mmol) of Na2CO3 were
alternately added in small portions over a period of 1 h
under stirring and heating at 60°C. Reaction control
and further workup was similar to those described for
compound 5a. Yield 0.075 g (75%), light beige
crystals. mp 202–205°C. IR spectrum, ν, cm–1: 3225
The IR spectra were obtained on a Bruker Tensor-
1
27 FTIR spectrometer. The H and 13C NMR spectra
were measured on a Bruker Avance III 600 spectro-
meter at 600.13 (1H) and 150.9 (13C) MHz.
1
The mass spectra were obtained on a Shimadzu
LC/MS-2020 instrument, column RAPTORARC-18 100,
isocratic mode, flow rate 20 µL/min, column tempera-
ture 35°C, sample concentration 0.01 mg/mL; an ESI
source was operated.
(NH), 1378 (SO2). H NMR spectrum (DMSO-d6), δ,
ppm: 9.37 s (1H, OH), 10.12 s (1H, NH), 3.78 s (6H,
COCH3), 7.38–7.56 d (4H, tosyl ring), 2.39 s (3H,
tosyl CH3), 1.87 s (6H, aminophenol CH3). 13C NMR
spectrum, δ, ppm: 16.6, 21.3, 52.6, 121.4, 126.3,
126.7, 130.0, 139.0, 139.1, 143.3, 151.2, 167.7. Mass
spectrum, m/z (Irel, %): 407 (74) [M]+, 376 (21), 252
(76), 220 (96), 192 (29), 91 (49), 65 (15).
ACKNOWLEDGEMENTS
The work performed using the equipment of the
Center for Colletive Use, Krasnoyarsk Research Center,
Siberian Branch, Russian Academy of Sciences.
Diethyl 5-(4-acetamidobenzenesulfonamido)-2-
hydroxy-4,6-dimethylisophthalate (6a). Compound
4a, 0.2 g (0.71 mmol), was dissolved in 4 mL of water,
after which 0.2 g (0.86 mmol) of p-acetamido-
benzenesulfonyl chloride and 0.059 g (0.56 mmol) of
Na2CO3 were alternately added in small portions over
a period of 1.5 h under stirring and heating at 60°C.
Reaction control and further workup was similar to
those described for compound 5a. Yield 80%, mp 150–
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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