Method for preparation of 4-methyl-1,2-benzoxathiine 2,2-dioxide derivatives

Full text of DOI:10.1007/s10593-012-1087-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
METHOD FOR PREPARATION OF 4-METHYL-
1,2-BENZOXATHIINE 2,2-DIOXIDE DERIVATIVES
A. Grandāne1, A. F. Mishnev1, I. V. Vozny1, and R. Žalubovskis1*
Keywords: 1,2-benzoxathiine 2,2-dioxides, 2-hydroxyacetophenones, intramolecular addition,
mesylation.
We propose an efficient method for the synthesis of 4-methyl-1,2-benzoxathiine 2,2-dioxides 4a-c from
the available 2-hydroxyacetophenones 1a-c, which undergo mesylation to give compounds 2a-c. Contrary to
literature data [1], we have found that intramolecular condensation of compound 2a [2] with formation of
compound 4a does not occur in pyridine in the presence of KOH. We have shown that this intramolecular
cyclization of compounds 2a-c occurs readily in the presence of the strong organic base 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to give presumably the intermediate hydroxy derivatives 3a-c. Subsequent
dehydration of compounds 3a-c using POCl3 gives the compounds 4a-c.
O
O
Me
O
Me
OH
R
R
R
R
Me
OH
Me
O
MsCl, Et3N
POCl3
Py
DBU
CH2Cl2
0°C
O
O
S
CH2Cl2
0°C
S
O
S
O
O
1a–c
O
4a–c
3a–c
O
Me
2a–c
a R = H, b R = OMe, c R = NO2
1
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The structure of compounds 4a-c obtained was confirmed from H NMR and C NMR spectroscopic
data, elemental analysis, and also from an X-ray structural analysis of compound 4a (Figure 1).
1H and 13C NMR spectra were recorded on a Varian 400 spectrometer (400 MHz and 100 MHz,
1
respectively) using DMSO-d6 with the residual solvent signals for reference (2.50 ppm for the H nuclei and
39.5 ppm for the 13C nuclei). Elemental analysis was carried out on an Elemental Analyzer EA 1108 apparatus.
Melting points of crystalline substances were determined using an SRS OptiMelt apparatus.
2-Acetylphenyl Methanesulfonate (2a). 2-Hydroxyacetophenone (1a) (1.77 ml, 14.70 mmol) was
dissolved in absolute CH2Cl2 (25 ml), and Et3N (2.45 ml, 17.64 mmol) was added. MeSO2Cl (1.83 ml, 23.67 mmol)
was added dropwise to the obtained mixture at 0ºC. The reaction mixture was stirred at room temperature for
4 h, then water (50 ml) was added, and the product was extracted with ethyl acetate (100 ml).
_______
*To whom correspondence should be addressed, e-mail: raivis@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 1044-1047, June, 2012. Original
article submitted February 29, 2012.
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0009-3122/12/4806-0974©2012 Springer Science+Business Media New York

Fig. 1. Structure of the compound 4a molecule with atoms represented by thermal vibrational atomic ellipsoids
of 50% probability.
The organic layer was separated, washed with NaCl solution, and dried over Na2SO4. The solvent was
evaporated in vacuo. Yield 2.88 g (99%), yellow oil. 1H NMR spectrum, , ppm (J, Hz): 2.57 (3H, s, COCH3);
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3.45 (3H, s, SO2CH3); 7.47-7.52 (2H, m, H Ar); 7.65-7.70 (1H, m, H Ar); 7.78-7.82 (1H, m, H Ar). C NMR
spectrum, , ppm: 30.2 (COCH3); 38.0 (SO2CH3); 123.4; 127.5; 130.2; 133.3; 133.5; 145.9 (C Ar); 197.9 (CO).
2-Acetyl-4-methoxyphenyl Methanesulfonate (2b). Obtained similarly to compound 2a from the
2-hydroxy-5-methoxyacetophenone (1b) (0.60 g, 3.61 mmol), Et3N (0.75 ml, 5.42 mmol), and MeSO2Cl (0.45 ml,
5.81 mmol) in absolute CH2Cl2 (10 ml). Yield 0.84 g (96%), yellow oil. 1H NMR spectrum, , ppm (J, Hz): 2.56
(3H, s, COCH3); 3.40 (3H, s, SO2CH3); 3.82 (3H, s, OCH3); 7.20 (1H, dd, J = 3.2, J = 9.0, H-5); 7.26 (1H, d,
J = 3.2, H-3); 7.41 (1H, d, J = 9.0, H-6). 13C NMR spectrum, , ppm: 30.1 (COCH3); 37.6 (SO2CH3); 55.8
(OCH3); 114.5; 118.3; 124.7; 134.4; 139.1; 157.7 (C Ar); 197.8 (CO). Found, %: C 48.91; H 4.98. C10H12O5S.
Calculated, %: C 49.17; H 4.95.
2-Acetyl-4-nitrophenyl Methanesulfonate (2c). Obtained similarly to compound 2a from the
2-hydroxy-5-nitroacetophenone (1c) (0.60 g, 3.31 mmol), Et3N (0.69 ml, 4.97 mmol), and MeSO2Cl (0.41 ml,
1
5.33 mmol) in absolute CH2Cl2 (20 ml). Yield 0.87 g (> 99%), yellow oil. H NMR spectrum, , ppm (J, Hz):
2.65 (3H, s, COCH3); 3.59 (3H, s, SO2CH3); 7.79 (1H, d, J = 9.0, H-6); 8.50 (1H, dd, J = 2.9, J = 9.0, H-5); 8.55
13
(1H, d, J = 2.9, H-3). C NMR spectrum, , ppm: 30.3 (COCH3); 38.4 (SO2CH3); 124.8; 125.3; 128.2; 133.9;
145.7; 150.0 (C Ar); 196.3 (CO). Found, % C 41.47; H 3.54; N 5.37. C9H9NO6S. Calculated, %: C 41.70; H 3.50;
N 5.40.
4-Methyl-1,2-benzoxathiine 2,2-Dioxide (4a). Compound 2a (3.37 g, 15.72 mmol) was dissolved in
absolute CH2Cl2 (11 ml), cooled to 0ºC, DBU (2.35 ml, 15.72 mmol) was added, and the reaction mixture was
stirred at 0ºC for 3.5 h. Solvent was evaporated, pyridine (8 ml) and POCl3 (1.85 ml, 19.85 mmol) were added.
The reaction product was stirred at room temperature for 3 h and then poured into water. The precipitate formed
was filtered off and recrystallized from EtOH. Yield 1.74 g (56%). Light-brown crystals, mp 87-88ºC (EtOH).
1H NMR spectrum, , ppm (J, Hz): 2.38 (3H, d, J = 1.4, CH3); 7.39 (1H, q, J = 1.4, H-3); 7.42-7.48 (2H, m,
H Ar); 7.61 (1H, dt, J = 1.5, J = 7.8, H Ar); 7.78 (1H, dd, J = 1.5, J = 7.8, H Ar). 13C NMR spectrum, , ppm:
18.9 (CH3); 118.7; 119.3; 120.5; 126.2; 127.2; 132.6; 145.5; 149.9. Found, %: C 55.12; H 4.23. C9H8O3S.
Calculated, %: C 55.09; H 4.11.
6-Methoxy-4-methyl-1,2-benzoxathiine 2,2-Dioxide (4b). Prepared similarly to compound 4a from
compound 2b (0.83 g, 3.39 mmol) and DBU (0.51 ml, 3.39 mmol) in absolute CH2Cl2 (10 ml) and POCl3 (0.95 ml,
1
10.17 mmol) in pyridine (8 ml). Yield 0.63 g (83%). Colorless crystals, mp 161-162ºC (EtOH). H NMR
spectrum, , ppm (J, Hz): 2.37 (3H, d, J = 1.4, CH3); 3.84 (3H, s, OCH3); 7.16 (1H, dd, J = 3.0, J = 9.0, H-7);
13
7.23 (1H, d, J = 3.0, H-5); 7.35-7.40 (2H, m, H-3,8). C NMR spectrum, , ppm: 18.9 (CH3); 55.9 (OCH3);
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111.5; 117.9; 119.7 (2C); 121.4; 143.6; 145.4; 156.8. Found, %: C 53.16; H 4.51. C10H10O4S. Calculated, %:
C 53.09; H 4.46.
4-Methyl-6-nitro-1,2-benzoxathiine 2,2-Dioxide (4c). Compound 2c (0.86 g, 3.31 mmol) was
dissolved in absolute CH2Cl2 (10 ml) and DBU (0.49 ml, 3.31 mmol) was added at 0ºC. The reaction mixture
was stirred at 0ºC for 3.5 h, poured into a mixture of ice and 10% HCl, extracted with ethyl acetate (330 ml),
washed with saturated aqueous ammonium chloride solution (440 ml), and dried over Na2SO4. Solvent was
evaporated, and pyridine (5 ml) and POCl3 (0.92 ml, 9.94 mmol) were added. The reaction mixture was stirred
at room temperature for 4.5 h, poured into water, and the precipitate formed was filtered off and recrystallized
from EtOH. Yield 0.27 g (34%). Light-brown crystals, mp 148-149ºC (EtOH). 1H NMR spectrum, , ppm (J, Hz):
2.48 (3H, d, J = 1.4, CH3); 7.66 (1H, q, J = 1.4, H-3); 7.74 (1H, d, J = 9.0, H-8); 8.44 (1H, dd, J = 2.8, J = 9.0,
13
H-7); 8.54 (1H, d, J = 2.8, H-5). C NMR spectrum, , ppm: 19.0 (CH3); 120.3; 120.6; 121.1; 122.8; 127.5;
144.7; 144.9; 153.7. Found, %: C 44.96; H 2.86; N 5.72. C9H7NO5S. Calculated, %: C 44.81; H 2.92; N 5.81.
X-ray Structural Analysis of Compound 4a. Single crystals of compound 4a (C9H8O3S) were grown
from ethanol solution. The unit cell parameters and intensities of 1465 independent reflections with I > 2(I)
were measured at 190 K on a Bruker-Nonius KappaCCD automatic X-ray diffractometer (MoK radiation, 
0.71073 Å). Crystals of compound 4a are monoclinic with: a 6.979(2), b 9.182(4), c 14.959(6) Å;
 114.420(17)º; V 872.8 (6) Å3; M 196.21; Z 4; dcalc 1.493 g/cm3; space group P21/c. The structure was solved
by the direct method using the SIR2008 software [3] and refined by full-matrix least-squares analysis using the
SHELXL97 software [4]. The final probability factors were R 0.0435 and Rw 0.1059. The crystallographic
parameters, atomic coordinates and their thermal parameters, bond lengths, and valence angle values for the
molecule of compound 4a have been placed in the Cambridge Crystallographic Data Center (deposit CCDC
865817).
This work was carried out with the financial support of the European Social Fund
(No. 2009/0203/1DP/1.1.2.0/09/APIA/VIAA/023).
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