2,1-benzothiazine 2,2-dioxides. 5. hydrolysis of alkyl 1-r-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzo-thiazine-3-carboxylates

Article abstract of DOI:10.1007/s10593-014-1563-7

Hydrolysis of 1-R-4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate esters in HCl-AcOH-H₂O mixture at 60°C was accompanied by decarboxylation and led to 1-R-4-oxo-3,4-dihydro-1H-2λ⁶,1-benzo-thiazine-2,2-diones. In t

Full text of DOI:10.1007/s10593-014-1563-7

Chemistry of Heterocyclic Compounds, Vol. 50, No. 7, October, 2014 (Russian Original Vol. 50, No. 7, July, 2014)
2,1-BENZOTHIAZINE 2,2-DIOXIDES. 5*. HYDROLYSIS
OF ALKYL 1-R-4-HYDROXY-2,2-DIOXO-1Н-2λ6,1-BENZO-
THIAZINE-3-CARBOXYLATES**
1
2
3
1***
I. V. Ukrainets
, L. A. Petrushova , S. P. Dzyubenko , and Liu Yangyang
Hydrolysis of 1-R-4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylate esters in HCl–AcOH–H2O
mixture at 60°С was accompanied by decarboxylation and led to 1-R-4-oxo-3,4-dihydro-1H-2λ6,1-benzo-
thiazine-2,2-diones. In the alkaline medium, regardless of the type of the substituent at position 1,
analogous structural transformations occurred at first, but the thiazine ring was also destroyed along
with the ester fragment when performing the reaction for a longer time.
Keywords: 2,1-benzothiazine-3-carboxylic acids, esters, hydrolysis.
Esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids easily react with primary and many
secondary alkyl-, aryl-, and hetarylamines forming the respective N-R-amides [2]. The reactivity of structurally
related lower alkyl 1-R-4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylates towards N-nucleophiles
was found to be much lower [1, 3]. In such a situation, it would be synthetically expedient to substitute esters
with carboxylic acids, which can be easily transformed to more reactive acylating agents than typical alkyl
esters. In this study, we attempted to establish the possibility of obtaining 1-R-4-hydroxy-2,2-dioxo-1Н-2λ6,1-
benzothiazine-3-carboxylic acids 2а-е by acidic and basic hydrolysis of esters 1а-е.
Treatment with HCl–AcOH–H2O mixture is one of the most convenient and reliable methods for
conversion of 2-carbonyl analogs of esters 1а-е, the esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxy-
lic acids, to the respective quinoline-3-carboxylic acids [4, 5]. The attempts of using this method for hydrolysis
of benzothiazine esters 1а-е showed that the change from a carbonyl to sulfo group at position 2 caused a
significant drop of the ester reactivity in this case as well, similarly to the observations during amidation [1, 3].
_______
*For Communication 4, see [1].
**Dedicated to Academician O. N. Chupakhin on the occasion of his 80th birthday.
***To whom correspondence should be addressed, e-mail: uiv-2@mail.ru.
1National University of Pharmacy, 53 Pushkinskaya St., Kharkiv 61002, Ukraine.
2N. I. Pirogov Vinnitsa National Medical University, 56 Pirogov St., Vinnitsa 21018, Ukraine; e-mail:
ser800@mail.ru
3Changchun Medical College, 6177 Jilin Road, Changchun 130031, China; e-mail: liuyy3290@yandex.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1135-1140, July, 2014. Original
article submitted April 24, 2014.
0009-3122/14/5007-1047©2014 Springer Science+Business Media New York
1047

1
Monitoring by Н NMR spectroscopy allowed to determine that at least 15 hours were necessary for
complete conversion of the starting esters 1а-е, that is, the rate of hydrolysis was approximately three times
lower compared to the quinolone analogs. However, this was not the root of the problem: the target 1-R-4-
hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylic acids 2а-е were indeed likely formed during the
reaction investigated. However, all of them were too unstable and prone to decarboxylation for being isolated
even as impurities, despite the relatively mild conditions of the synthesis. As a result, the products isolated from
the acidic hydrolysis of esters 1а-е in all cases were the corresponding 1-R-4-oxo-3,4-dihydro-1H-2λ6,1-benzo-
thiazine-2,2-diones 3а-е. Apparently, 4-oxobenzothiazine 3b (and not acid 2b) was also formed for the same
reasons in the reaction of methyl 2-{[(2-methoxy-2-oxoethyl)sulfonyl](methyl)amino}benzoate with aqueous
KОН solution at room temperature [6].
OH
O
OH
O
HCl–AcOH–H2O
60°C, 15 h
or
OAlk
OH
S
O
S O
N
R
N
R
KOH, H2O
, 20 min
O
O
1a–e
2a–e
–CO2
O
(R =/ H)
COOH
KOH, H2O
SO2Me
S
O
O
, 7 h
N
R
N
R
4b–e
3a–e
1 a Alk = Et, b–e Alk = Me; 1–4 a R = H, b R = Me, с R = Et, d R = allyl, e R = Ph
More substantial differences in the reactivity of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
esters and their 4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine analogs were found in the case of alkaline
hydrolysis. The former are known to be unusually inert towards aqueous alkali solutions [7], thus the ester
group can be cleaved only by prolonged refluxing, and this results in simultaneous decarboxylation [8, 9]. The
latter, on the other hand, undergo facile and rapid destruction under the same conditions: thus, the intermediate
acids 2а-е are completely converted to 3Н-derivatives 3а-е already after 20-minute reflux of the starting esters 1а-е
in the aqueous KОН solution. However, the situation changes substantially after increasing the reflux time to 7
1
or more hours. The Н NMR spectra of the hydrolysis products thus obtained from the N-substituted methyl
esters 1b-e contained not only broadened one-proton downfield singlets and aromatic proton signals, but also
three-proton singlets at 2.96-3.21 ppm, indicating the presence of a methyl group in the reaction products. Thus,
1
the Н NMR spectra of the starting methyl esters 1b-e and the products of their extended alkaline hydrolysis
were found to be quite similar, but certain upfield shift of methyl group signals pointed to structural changes.
The alkaline hydrolysis of benzothiazine esters 1b-е, unlike that of 4-hydroxy-2-oxoquinoline analogs, most
likely was not limited to destruction of the ester fragment. The corresponding 4-oxobenzothiazines 3b-е formed
at the first stage underwent further chemical transformation where the appearance of a new, upfield methyl
group signal relative to the СООМе group signal was possible only in association with thiazine ring cleavage at
the С(3)–С(4) bond. The same conclusion was also reached from the analysis of 1Н NMR spectra of N-phenyl-
substituted derivatives 1-4 е, which were quite informative in this regard. Thus, while the aromatic H-8 proton
in benzothiazine structures 1е and 3е was under the shielding influence of ring currents in the N-phenyl
substituent rotated relative to the bicyclic ring plane, and thus produced signals that were shifted unusually far
upfield (6.73 and 6.64 ppm, respectively), this effect was absent in the acyclic hydrolysis product 4е.
1048

The X-ray structural analysis that we performed completely confirmed this assumption, while in the
case of 4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylic acid methyl ester (1b) it was
clearly proved that prolonged refluxing of this ester in aqueous alkali not only cleaved the methoxycarbonyl
group, but also the heterocyclic moiety, resulting in 2-[methyl(methylsulfonyl)amino]benzoic acid (4b).
The substituent at the С(1) atom of this compound (Fig. 1) was rotated so that the N-methyl group was
practically orthogonal to the aromatic ring plane (the C(9)–N(1)–C(1)–C(2) torsion angle was -82.2(2)°), while
the methylsulfoxide fragment was in a +sc conformation relative to the С(1)–С(2) bond, and its S-methyl group
was perpendicular to the C(1)–N(1) bond (the S(1)–N(1)–C(1)–C(2) torsion angle was 78.0(1)°, but the
C(8)–S(1)–N(1)–C(1) angle was -84.8(1)°). The nitrogen atom had a pyramidal configuration – the sum of
valence angles involving the nitrogen atom was 357°. The carboxyl group somewhat diverged from the aromatic
ring plane (the С(1)–С(6)–С(7)–О(1) torsion angle was -24.3(2)°), despite the attraction between Н(5)···О(2)
2.40 Å (the sum of van der Waals radii [10] 2.46 Å). The presence of vicinal substituents apparently caused the
lengthening of C(1)–N(1) bond to 1.435(1) Å, compared to the average value of 1.375 Å [11].
Fig. 1. The molecular structure of acid 4b with atoms represented by thermal vibration
ellipsoids of 50% probability.
The molecules of acid 4b in the crystalline state form centrosymmetric dimers due to the intermolecular
hydrogen bond O(2)–H···O(1)' (2-x, 1-y, 1-z) H···O 1.85 Å, O–H···O 172°. The formation of a sufficiently
strong hydrogen bond causes also the lengthening of О(1)–С(7) bond to 1.244(2) Å, compared to the average
value of 1.210 Å, and shortening of the О(2)–С(7) bond to 1.293(2) Å (the average value is 1.308 Å). An
additional intramolecular hydrogen bond С(2)–Н···О(3)' (x-1, y, z) H···O 2.37 Å, C–H···O 148° was found to
exist in the crystal.
An exception to the hydrolysis trends observed among the esters studied was ester 1а, which was
unsubstituted at position 1. Remarkably, alkaline hydrolysis of its ester group was just as facile and rapid as in
the case of N-substituted analogs 1b-е. However, 4-oxobenzothiazine 3a formed at this stage was virtually inert
against further degradation. Its stability towards refluxing aqueous KOH solution was apparently explained by
the salt formation involving not only the enol OH forms common to all 4-oxobenzothiazines, but also the cyclic
sulfamide group, which was impossible in principle for the N-substituted derivatives.
Thus, our experiments based on simple examples of acidic and alkaline hydrolysis reactions clearly
demonstrated the substantial reactivity changes of 1-R-4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-
3-carboxylic esters compared to their 2-carbonyl analogs.
1049

EXPERIMENTAL
1Н NMR spectra were recorded on a Varian Mercury-400 instrument (400 MHz) in DMSO-d6 solution,
with TMS as internal standard. Elemental analysis was performed on a EuroVector EA-3000 microanalyzer.
Melting points were determined in capillaries on a Stuart SMP10 digital melting point apparatus. 1-R-4-Hydroxy-
2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic esters 1а-е were obtained by a published method [6].
Preparation of 4-Oxobenzothiazines 3а-e (General Method). А. A solution of ester 1а-е (0.01 mol)
in 20 ml of 2.8 M HCl solution in AcOH with a low water content (prepared by the reaction of calculated amounts
of Ac2O and conc. HCl [4]) was maintained for 15 h at 60°С. The reaction mixture was cooled and diluted with cold
water. The precipitate formed was filtered off, washed with cold water, and dried.
B. A solution of ester 1а-е (0.01 mol) in 20% aqueous KОН solution (20 ml) was refluxed for 20 min,
then cooled and acidified with HCl to pH 3. The precipitate formed was filtered off, washed with water, and
dried.
The 4-oxobenzothiazines 3а-e obtained were colorless crystals. Samples of compounds 3а-e obtained
by acidic (Method А) or alkaline (Method B) hydrolysis of esters 1а-e did not produce the melting point
depression in a mixture with authentic sample, and had identical 1Н NMR spectra.
4-Oxo-3,4-dihydro-1H-2λ6,1-benzothiazine-2,2-dione (3a). Yield 87% (method А), 91% (method B).
1
Mp 185-187°С (1:1 EtOH–H2O). H NMR spectra, δ, ppm (J, Hz): 11.48 (1Н, s, NH); 7.88 (1Н, dd, J = 8.0,
J = 1.6, Н-5); 7.63 (1Н, td, J = 7.7, 1.6, Н-7); 7.17 (1Н, td, J = 7.8, 1.2, Н-6); 7.08 (1Н, d, J = 8.4, Н-8); 4.77 (2Н,
s, 3-CH2). Found, %: C 48.61; H 3.45; N 7.02; S 16.35. C8H7NO3S. Calculated, %: C 48.72; H 3.58; N 7.10;
S 16.26.
1-Methyl-4-oxo-3,4-dihydro-1H-2λ6,1-benzothiazine-2,2-dione (3b). Yield 83% (method А), 94%
1
(method B). Mp 120-122°С (Et2O) (mp 120-122°С [6]). The Н NMR spectrum of compound 3b obtained
corresponded to the literature data [6].
1-Ethyl-4-oxo-3,4-dihydro-1H-2λ6,1-benzothiazine-2,2-dione (3с). Yield 79% (method А), 86%
1
(method B). Mp 84-86°С (EtOH–H2O, 1:1). H NMR spectra, δ, ppm (J, Hz): 7.99 (1Н, dd, J = 7.9, J = 1.7,
Н-5); 7.75 (1Н, td, J = 7.8, J = 1.7, Н-7); 7.45 (1Н, d, J = 8.3, Н-8); 7.26 (1Н, td, J = 7.4, J = 1.1, Н-6); 4.89
(2Н, s, 3-CH2); 4.00 (2Н, q, J = 7.2, NCH2CH3); 1.26 (3Н, t, J = 7.2, NCH2CH3). Found, %: C 53.20; H 4.83;
N 6.33; S 14.36. C10H11NO3S. Calculated, %: C 53.32; H 4.92; N 6.22; S 14.23.
1-Allyl-4-oxo-3,4-dihydro-1H-2λ6,1-benzothiazine-2,2-dione (3d). Yield 74% (method А), 83%
1
(method B). Mp 67-69°С (EtOH–H2O, 1:1). H NMR spectra, δ, ppm (J, Hz): 7.98 (1Н, dd, J = 8.0, J = 1.7,
Н-5); 7.72 (1Н, td, J = 7.8, J = 1.7, Н-7); 7.31 (1Н, d, J = 8.3, Н-8); 7.25 (1Н, td, J = 7.4, J = 1.1, Н-6);
6.08-5.87 (1Н, m, NCH2СН=CH2); 5.34 (1Н, dd, J = 17.4, J = 1.6, NCH2СН=СН-trans); 5.23 (1Н, dd, J = 10.4,
J = 1.6, NCH2СН=СН-cis); 4.95 (2Н, s, 3-CH2); 4.56 (2Н, dt, J = 4.8, J = 1.6, NCH2). Found, %: C 55.76;
H 4.54; N 5.83; S 13.42. C11H11NO3S. Calculated, %: C 55.68; H 4.67; N 5.90; S 13.51.
4-Oxo-1-phenyl-3,4-dihydro-1H-2λ6,1-benzothiazine-2,2-dione (3е). Yield 82% (method А), 88%
1
(method B). Mp 131-133°С (1:1 EtOH–H2O). H NMR spectra, δ, ppm (J, Hz): 8.05 (1Н, dd, J = 8.0, J = 1.7,
Н-5); 7.66-7.23 (7Н, m, Н-6,7, Н Ph); 6.64 (1Н, d, J = 8.5, Н-8); 5.12 (2Н, s, 3-CH2). Found, %: C 61.60;
H 3.95; N 5.21; S 11.82. C14H11NO3S. Calculated, %: C 61.53; H 4.06; N 5.12; S 11.73.
Preparation of 2-(Methylsulfonylamino)benzoic Acids 4b-e (General Method). A solution of ester
1b-е (0.01 mol) in 20% aqueous KОН solution (20 ml) was refluxed for 7 h, then cooled and filtered. The
filtrate was acidified with dilute HCl to рН 3. The precipitate formed was filtered off, washed with cold water,
dried, and recrystallized from 1:1 EtOH–H2O. Acids 4b-e were colorless crystals.
1
2-[Methyl(methylsulfonyl)amino]benzoic Acid (4b). Yield 67%. Mp 146-148°С. H NMR spectra, δ,
ppm (J, Hz): 12.98 (1H, br. s, СООН); 7.74 (1Н, dd, J = 7.4, J = 1.3, Н-6); 7.59 (1Н, td, J = 7.5, J = 1.3, Н-5);
7.50 (1Н, dd, J = 7.8, J = 1.3, Н-3); 7.43 (1Н, td, J = 7.2, J = 1.3, Н-4); 3.19 (3Н, s, NCH3); 2.98 (3Н, s, SCH3).
Found, %: C 47.26; H 4.93; N 5.98; S 14.12. C9H11NO4S. Calculated, %: C 47.15; H 4.84; N 6.11; S 13.99.
1050

2-[Ethyl(methylsulfonyl)amino]benzoic Acid (4с). Yield 64%. Mp 80-82°С. 1H NMR spectra, δ, ppm
(J, Hz): 12.95 (1H, br. s, СООН); 7.78 (1Н, d, J = 7.5, Н-6); 7.60 (1Н, t, J = 7.7, Н-5); 7.49 (1Н, d, J = 7.8,
Н-3); 7.44 (1Н, td, J = 7.3, J = 1.3, Н-4); 3.63 (2Н, q, J = 7.2, NCH2CH3); 2.96 (3Н, s, SCH3); 1.02 (3Н, t,
J = 7.2, NCH2CH3). Found, %: C 49.29; H 5.48; N 5.67; S 13.26. C10H13NO4S. Calculated, %: C 49.37; H 5.39;
N 5.76; S 13.18.
2-[Allyl(methylsulfonyl)amino]benzoic Acid (4d). Yield 60%. Mp 61-63°С. 1H NMR spectra, δ, ppm
(J, Hz): 12.87 (1H, br. s, СООН); 7.75 (1Н, dd, J = 7.6, J = 1.4, Н-6); 7.62 (1Н, td, J = 7.5, J = 1.4, Н-5); 7.53
(1Н, dd, J = 7.8, J = 1.4, Н-3); 7.44 (1Н, td, J = 7.3, J = 1.4, Н-4); 6.21-5.94 (1Н, m, NCH2СН=СН2); 5.16 (1Н,
dd, J = 17.3, J = 1.5, NCH2СН=СН-trans); 5.02 (1Н, dd, J = 10.1, J = 1.5, NCH2СН=СН-cis); 4.21 (2Н, d, J = 5.5,
NCH2); 2.99 (3Н, s, SCH3). Found, %: C 51.87; H 5.21; N 5.58; S 12.63. C11H13NO4S. Calculated, %: C 51.75;
H 5.13; N 5.49; S 12.56.
1
2-[Phenyl(methylsulfonyl)amino]benzoic Acid (4е). Yield 71%. Mp 127-129°С. H NMR spectra, δ,
ppm (J, Hz): 13.13 (1H, br. s, СООН); 7.80 (1Н, d, J = 7.7, Н-6); 7.63-7.16 (8Н, m, Н-3,4,5, Н Ph); 3.21 (3Н,
s, SCH3). Found, %: C 57.61; H 4.58; N 4.90; S 10.94. C14H13NO4S. Calculated, %: C 57.72; H 4.50; N 4.81;
S 11.01.
X-Ray Structural Investigation of Compound 4b. The crystals of compound 4b (C9H11NO4S,
М 229.26) were triclinic (EtOH), at 20°С: a 5.4472(3), b 8.4509(5), c 12.3712(7) Å; α 104.631(5), β 93.494(5),
γ 107.810(5)°; V 518.68(5) Å3; Z 2; space group P1; dcalc 1.468 g/cm3; (MoK) 0.305 mm-1; F(000) 240. Unit
cell parameters and intensities of 6066 reflections (3024 independent, Rint 0.011) were determined on an
Xcalibur-3 diffractometer (MoK-radiation, ССD-detector, graphite monochromator, ω-scanning, 2max 60°).
The structure was solved by the direct method with SHELXTL software package [12]. The hydrogen atom
positions were revealed by differential synthesis of electron density and refined isotropically. The structure was
refined by F2 with a full-matrix least-squares analysis in anisotropic approximation for the non-hydrogen atoms
to wR2 0.101 by 2983 reflections (R1 0.035 by 2588 reflections with F > 4(F), S 1.056). The full
crystallographic data set for compound 4b was deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 995042).
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