Facile synthesis of coumarin bioisosteres - 1,2-benzoxathiine 2,2-dioxides

Article abstract of DOI:10.1016/j.tet.2012.04.080

A simple and reproducible procedure for the synthesis of bioisosteres of coumarin - 1,2-benzoxathiine 2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of derivatives of mesylsalicyl aldehydes in the presence

Full text of DOI:10.1016/j.tet.2012.04.080

Tetrahedron 68 (2012) 5541e5546
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Facile synthesis of coumarin bioisosteresd1,2-benzoxathiine 2,2-dioxides
*
Aiga Grandane, Sergey Belyakov, Peteris Trapencieris, Raivis Zalubovskis
Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and reproducible procedure for the synthesis of bioisosteres of coumarind1,2-benzoxathiine
2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of
derivatives of mesylsalicyl aldehydes in the presence of strong organic bases, where best results were
obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It has been shown that depending on the na-
ture of the substituent in the aromatic ring, intermediate aldol adducts (3,4-dihydro-1,2-benzoxathiin-4-
ol 2,2-dioxides) in different ratios with title compound are formed. Dehydration of the intermediate
aldols with POCl3 led to full conversion into 1,2-benzoxathiine 2,2-dioxide derivatives. The scaffold of
1,2-benzoxathiine 2,2-dioxide is unequivocally proven by a single-crystal X-ray structure.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 19 December 2011
Received in revised form 3 April 2012
Accepted 23 April 2012
Available online 28 April 2012
Keywords:
Heterocycles
Cyclization
Coumarin
Bioisoster
1,2-Benzoxathiine 2,2-dioxide
1. Introduction
In this paper we wish to report a general and reproducible
method for the synthesis of 1,2-benzoxathiine 2,2-dioxides utiliz-
The ability of coumarins to inhibit carbonic anhydrases (CA, EC
4.2.1.1) was recently discovered,1 and in order to improve selec-
tivity towards tumour associated CA IX and CA XII, a series of
coumarin derivatives have been synthesized.2,3 For further de-
velopment of selective new type CA inhibitors it was of interest to
prepare a series of coumarin (1) bioisosteresd1,2-benzoxathiine
2,2-dioxide (2), where the carbonyl group in the coumarin ring
would be replaced by a sulfonyl group (Fig. 1).
Only a few examples of 3,4-unsubstituted 1,2-benzoxathiine
2,2-dioxides are reported in the literature where a base catalyzed
intramolecular aldol condensation was utilized with mesylsalicyl
aldehydes.4,5 Unfortunately the literature procedure was not re-
producible4 in our hands, and might be substrate specific or ana-
lytical data are not presented.5 Therefore there is a need for
a general and reproducible synthetic route for the preparation of
3,4-unsubstituted 1,2-benzoxathiine 2,2-dioxides.
ing the intramolecular aldol reaction.
2. Results and discussion
Our choice of starting material was based on two possible ways
of intramolecular cyclization: firstdcyclization of O-mesylated
derivatives of widely accessible substituted 2-hydroxy benzalde-
hydes (salicylaldehyde) 3, and seconddcyclization of unsaturated
derivatives of sulfonic acid 4. Since the preparation of unsaturated
sulfonic acids might be time consuming and low yielding and the
product formed would contain a trans-double bond, which in turn
requires cisetrans isomerization for the intramolecular cycliza-
tion, and to the best of our knowledge there are no reported
procedures for the preparation of 4-like sulfonic acids in the lit-
erature, our preference was for O-mesylated derivatives
(Scheme 1).
3
O
O
O
S
OH
S
O
O
O
O
O
O
S
1
2
OH
O
S
O
O
Fig. 1. Coumarin (1) and its bioisostered1,2-benzoxathiine 2,2-dioxide (2).
O
O
3
2
4
* Corresponding author. Tel.: þ371 67014826; fax: þ371 67550338; e-mail ad-
Scheme 1. Retrosynthetic scheme for the preparation of 1,2-benzoxathiine
2,2-dioxide (2).
dress: raivis@osi.lv (R. Zalubovskis).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.080

5542
A. Grandane et al. / Tetrahedron 68 (2012) 5541e5546
Our initial efforts to utilize literature conditions4 for the cycli-
Table 2
DBU catalyzed cyclization of mesylsalicyl aldehyde derivatives (6)
zation of mesyl derivative 3 in the presence of NEt3 at various re-
action times resulted in no cyclic compound 5 and/or 2 formation
(Table 1, entry 1). The use of other common organic bases, pyridine
(Py), diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine
(DMAP) and tetramethyl piperidine (TMP), also did not provide the
title compound (Table 1, entries 2e5). The situation was not
changed when strong bases BuLi and LDA were used (Table 1, en-
tries 6e8).
OH
O
R
R
R
POCl
DBU
CH Cl
3
O
O
S
S
Py, r. t., 3 h
2
2
O
S
O
O
O
O
0 °C, 2 h
O
O
6a-g
7a-g
8a-g
Entry
6
Substrate
8
Yield of 8a (%)
Table 1
Base catalyzed cyclization of mesylsalicyl aldehyde (3)
O
OH
O
O2N
POCl3
O
1
6a
8a
65
Base
S
O
O
S
S
O
Py, r. t., 3 h
O
O
S
O
O
O
O
O
O
O
O
O
3
5
2
S
O
2
3
6b
6c
8b
8c
54
32
O
S
Entry
Base
Temp [ꢀC]
Solvent
Yielda [%]
O
O
1
2
3
4
5
6
7
8
NEt3
Py
DMAP
DABCO
TMP
BuLi
0 or 20
20
20
20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
0
0
0
0
0
O
Cl
O
20
S
O
ꢁ78 to 20
O
BuLi
LDA
ꢁ78 to 20
Cl
ꢁ78 to 20
9
DBUb
DBNb
TBDb
TMGb
0
0
0
0
71
67
53
39
O
O
10
11
12
O
4
6d
8d
39
S
a
Isolated yields. Yields are given with respect to 3.
Reaction time 2 h.
O
O
b
OMe
O
BnO
Br
However, with the organic base 1,8-diazabicyclo[5.4.0]undec-7-
5
6
6e
6f
8e
8f
38
63
30
ene (DBU), a mixture of cyclic products 2 and 5 (ratio 1:5) was
obtained. Further treatment of the mixture with POCl3 resulted in
formation of the title compound 2 in 71% yield with respect to 3
(Table 1, entry 9). In order to investigate the influence of other or-
ganic bases, structurally related 1,5-diazabicyclo[4.3.0]non-5-ene
(DBN) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) were applied
in the reaction. In both cases a mixture of 2 and 5 in different ratios
1:10 and 1:3, respectively, was obtained, but treatment of the
mixture with POCl3 resulted in slightly lower yields of 2 67% and
53%, respectively, with respect to 3 (Table 1, entries 10 and 11).
Utilization of tetramethyl guanidine (TMG) provided a mixture of
cyclic compounds 2 and 5 in remarkable ratio 1:15, but, after de-
hydration the isolated yield of 2 was not superior to the bicyclic
bases used above (Table 1, entry 12).
S
O
O
O
O
S
O
O
O
7
6g
8g
O
S
O
O
With the optimized conditions in hand, we extended substrates
to a series of 2-mesyloxy benzaldehydes 6. A variety of mesyl
compounds 6aeg with electron-withdrawing or -donating groups
were submitted to the DBU catalyzed cyclization reaction. In all
cases complete conversion of 6 was observed. A significant differ-
ence in the isolated yields of the title compounds 8aeg (30e65% in
respect to 6), most probable, was due to crystallization from eth-
anol (Table 2). However, it is worth commenting that the main
difference was observed in the formation of cyclic intermediates 7.
The presence of electron-withdrawing groups in compound 6a
gave a 1:2 ratio of 7a and 8a after the cyclization step according to
the 1H NMR spectra. At the same time, naphthalene 6g gave single
hydroxyl derivative 7g. Derivatives with electron-donating groups
6d or 6e gave the product (7 and 8) ratio in favour of the hydrox-
ylated product 7d or 7e 5:1 or 1:1, respectively, (see the
Experimental section).
a
Isolated yields after recrystallization from EtOH. Yields are given with respect
to 6.
All 1,2-benzoxathiine 2,2-dioxides 8 were fully characterized by
1H and 13C NMR spectroscopy, MS and elemental analysis. 1H NMR
spectra in DMSO-d6 displayed the expected signals including two
doublets with coupling constants between 10.3 and 10.6 Hz for 3-
and 4-H in the oxathiine ring. The final unequivocal identification
of the scaffold of 1,2-benzoxathiine 2,2-dioxide was established by
a single-crystal X-ray structure for compound 8f, shown in Fig. 2.
It has been demonstrated, that in the case of coumarin de-
rivatives the 6-substituent plays a crucial role in the inhibitory
activity towards CA.2 Therefore it was of interest to develop
a method of synthesis of 1,2-benzoxathiine 2,2-dioxides not only

A. Grandane et al. / Tetrahedron 68 (2012) 5541e5546
5543
Fig. 2. Single-crystal X-ray structure of 8f (CCDC deposition number 831986). Thermal ellipsoids are drawn at the 50% probability level.
with hydrogen bond acceptors at the 6-position (compound 8a),
but also with hydrogen bond donors NH2 and OH.
4. Experimental section
4.1. General
In order to obtain 6-aminoderivative 9, hydrogenation of the
NO2-group in compound 8a was attempted under regular condi-
tions employing H2 over Pd/C. Unfortunately all the hydrogenation
attempts resulted in inseparable mixtures of desired amino com-
pound 9 and the product of further double bond hydrogenationd6-
amino 3,4-dihydro 1,2-benzoxathiine 2,2-dioxide. In contrast, per-
forming an alternative reduction of the NO2-group with Fe, the
desired compound 9 was isolated in 88% yield (Scheme 2).
Reagents and starting materials were obtained from commercial
sources and used as received. The solvents were purified and dried
by standard procedures prior to use; petroleum ether of boiling
range 40e60 ꢀC was used. Flash chromatography was carried out
using Merck silica gel (230e400 mesh). Thin-layer chromatography
was performed on silica gel, spots were visualized with UV light
(254 and 365 nm). NMR spectra were recorded on a Varian Mercury
(400 MHz) spectrometer with chemical shift values (d) in parts per
H N
2
R=NO
a
2
million relative to TMS using the residual DMSO-d6 signal as an
internal standard. Elemental analyses were performed on a Carlo
Erba CHNSeO EA-1108 apparatus. GCeMS analyses were per-
formed as gas chromatographic analysis using Agilent Technologies
7890A gas chromatographic system with Agilent Technologies
5975C MSD detector. IR spectra were measured on a Shimadzu FTIR
IR Prestige-21 spectrometer.
O
O
S
O
O
R
O
9
O
S
O
O
HO
R=OSO Me
2
8a, b
S
b
O
10
4.2. General procedure for the synthesis of methanesulfonate
derivatives: preparation of 2-formylphenyl methanesulfonate
(3)7
Scheme 2. Synthesis of 6-amino (9) and 6-hydroxy (10) 1,2-benzoxathiine 2,2-dioxide.
(a) Fe, AcOH, EtOH, 75 ꢀC, 1 h, 88%; (b) LDA, THF, ꢁ78 ꢀC, 5.5 h, 27%.
To a solution of 2-hydroxybenzaldehyde (1.50 g, 12.3 mmol) in
dry CH2Cl2 (50 mL) triethylamine (2.01 mL, 14.7 mmol) was added.
The mixture was cooled to 0 ꢀC and mesyl chloride (1.52 mL,
19.7 mmol) was added. The reaction was stirred at 0 ꢀC for 10 min
and then for 22 h at room temperature. The mixture was diluted
with H2O (50 mL) and extracted with EtOAc (1ꢂ120 mL). The or-
ganic phase was washed with brine and dried over Na2SO4, and the
solvent was evaporated to yield 3 as a yellow oil (3.14 g, 99%). 1H
Since hydrogenation over Pd/C resulted in the unwanted hy-
drogenation of the double bond (see above), we have used com-
pound 8b instead 8e for the synthesis of phenol-compound 10.
Therefore cleavage of mesyl group in compound 8b was performed
using LDA according to Carreira’s protocol6 and 6-hydroxy de-
rivative was isolated in 27% yield (Scheme 2).
NMR (400 MHz, DMSO-d6):
d
¼10.24 (s, 1H), 7.94e7.90 (m, 1H),
3. Conclusions
7.85e7.80 (m, 1H), 7.60e7.54 (m, 2H), 3.59 (s, 3H). 13C NMR
(100 MHz, DMSO-d6):
d
¼188.7, 149.7, 136.1, 129.2, 129.0, 128.0,
We have demonstrated that 1,2-benzoxathiine 2,2-dioxides are
efficiently prepared from the corresponding mesylsalicyl aldehydes
in an organic base mediated cyclization reaction with subsequent
dehydration. It has been also demonstrated that the method de-
veloped is reproducible and applicable for a broad scope of sub-
strates with electron-withdrawing and -donating substituents. The
nature of the substituent on the aromatic ring plays a remarkable
role in the ratio of the title compounds and their hydrated form in
the cyclization step.
123.8, 37.8. MS (EI, 70 eV): m/z¼200 (29) [M]þ, 121 (100), 104 (60),
93 (22), 79 (17), 65 (57).
4.3. 2-Formyl-4-nitrophenyl methanesulfonate (6a)8
Compound 6a was obtained from 2-hydroxy-5-nitrobenzaldehyde
(3.00 g, 18.0 mmol) in dry CH2Cl2 (70 mL), triethylamine (2.99 mL,
21.5 mmol) and mesyl chloride (2.24 mL, 28.9 mmol) as a yellow solid

5544
A. Grandane et al. / Tetrahedron 68 (2012) 5541e5546
(4.89 g, 99%). Mp 90e91 ꢀC (98e99 ꢀC, CCl4).8 1H NMR (400 MHz,
Calcd for C15H14O5S (306.33): C 58.81, H 4.61. Found: C 59.12, H
4.55.
DMSO-d6):
d
¼10.26 (s, 1H), 8.62 (dd, J¼2.9 and 9.0 Hz, 1H), 8.58 (d,
J¼2.9 Hz, 1H), 7.84 (d, J¼9.0 Hz, 1H), 3.70 (s, 3H). 13C NMR (100 MHz,
4.8. 4-Bromo-2-formylphenyl methanesulfonate (6f)14
DMSO-d6):
d¼187.3,153.2,146.2,130.3,129.7,125.4,124.1, 38.2. MS (EI,
70 eV): m/z¼245 (9.0) [M]þ,166 (100),149 (53),120 (34),103 (9.3), 92
(22), 79 (86).
Compound 6f was obtained from 5-bromo-2-hydroxyben-
zaldehyde (3.00 g, 14.9 mmol) in dry CH2Cl2 (70 mL), triethylamine
(2.49 mL, 17.9 mmol) and mesyl chloride (1.86 mL, 24.0 mmol) as
a yellow solid (4.99 g, 99%). Mp 76e77 ꢀC. 1H NMR (400 MHz, DMSO-
4.4. 2-Formy-4-(methylsulfonyl)phenyl methanesulfonate
(6b)9
d6):
d
¼10.16 (s, 1H), 8.04e7.98 (m, 2H), 7.53 (d, J¼8.4 Hz, 1H), 3.60 (s,
3H). 13C NMR (100 MHz, DMSO-d6):
d¼187.6, 148.7, 138.4, 131.4, 130.8,
Compound 6b was obtained from 2,5-dihydroxybenzaldehyde
(1.00 g, 7.24 mmol) in dry CH2Cl2 (100 mL), triethylamine
(2.42 mL, 17.4 mmol) and mesyl chloride (1.80 mL, 23.3 mmol) as
a pink crystalline solid (2.74 g, 99%). Mp 89e90 ꢀC. IR (KBr):
126.2, 120.5, 37.8. MS (EI, 70 eV): m/z¼280 (43) [M]þ, 278 (41), 200
(100), 184 (24), 182 (24), 173 (29), 171 (29), 145 (41), 143 (43), 79 (20).
nmax¼1696, 1361, 1351, 1332, 1178, 1162, 1132 cmꢁ1
.
1H NMR
4.9. 1-Formylnaphthalen-2-yl methanesulfonate (6g)
(400 MHz, DMSO-d6):
d
¼10.20 (s, 1H), 7.83e7.78 (m, 2H), 7.72e7.68
(m, 1H), 3.63 (s, 3H), 3.48 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
Compound 6g was obtained from of 2-hydroxynaphthalene-1-
carbaldehyde (3.00 g, 17.4 mmol) in dry CH2Cl2 (120 mL), triethyl-
amine (2.90 mL, 20.9 mmol) and mesyl chloride (2.20 mL,
28.1 mmol) as a light-pink solid (3.86 g, 99%). Mp 118e119 ꢀC. IR
(neat): nmax¼1686, 1355, 1345, 1174, 1153 cmꢁ1. 1H NMR (400 MHz,
d
¼187.7, 147.9, 147.6, 130.6, 129.7, 126.1, 122.1, 37.8, 37.5. MS (EI,
70 eV): m/z¼294 (30) [M]þ, 215 (29), 198 (8.1), 137 (85), 108 (10), 79
(100).
4.5. 2,4-Dichloro-6-formylphenyl methanesulfonate (6c)
DMSO-d6):
d
¼10.65 (s, 1H), 9.10 (d, J¼8.6 Hz, 1H), 8.42 (d, J¼9.0 Hz,
1H), 8.12 (d, J¼8.4 Hz, 1H), 7.82e7.76 (m, 1H), 7.72e7.67 (m, 2H),
Compound 6c was obtained from 3,5-dichloro-2-hydroxybe-
nzaldehyde (3.00 g, 15.7 mmol) in dry CH2Cl2 (70 mL), triethyl-
amine (2.62 mL,18.9 mmol) and mesyl chloride (1.96 mL, 25.3 mmol)
as a white solid (4.93 g, 99%). Mp 110e111 ꢀC. IR (KBr): nmax¼1693,
3.68 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d¼190.9, 151.9, 137.2,
131.9, 130.1, 130.0, 128.8, 127.3, 124.8, 122.9, 121.6, 38.2. MS (EI,
70 eV): m/z¼250 (49) [M]þ, 170 (52), 154 (35), 143 (18), 126 (11), 115
(100), 89 (11), 63 (8.8). Anal. Calcd for C12H10O4S (250.27): C 57.59,
H 4.03. Found: C 57.51, H 3.80.
1350, 1329, 1183, 1147 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d¼10.08
(s, 1H), 8.22 (d, J¼2.7 Hz, 1H), 7.83 (d, J¼2.7 Hz, 1H), 3.72 (s, 3H). 13C
NMR (100 MHz, DMSO-d6):
d¼186.8, 144.5, 135.4, 132.9, 132.5, 129.8,
127.2, 39.1. MS (EI, 70 eV): m/z¼270 (23) [M]þ, 268 (33),192 (49),190
(100),174 (9.0),172 (14),163 (8.4),161 (13),135 (46),133 (73), 97 (38),
79 (25). Anal. Calcd for C8H6Cl2O4S (269.10): C 35.71, H 2.25. Found: C
35.39, H 2.33.
4.10. General procedure for the synthesis of 1,2-
benzoxathiine 2,2-doxides. Preparation of 3,4-dihydro-1,2-
benzoxathiin-4-ol 2,2-dioxide (5) and 1,2-benzoxathiine 2,2-
dioxide (2)
4.6. 2-Formyl-6-methoxyphenyl methanesulfonate (6d)10
Method A.5 A solution of 3 (0.18 g, 0.89 mmol) in dry CH2Cl2
(10 mL) was cooled to 0 ꢀC and DBU (0.13 mL, 0.89 mmol) was
added. The reaction was stirred at 0 ꢀC for 2 h under argon atmo-
sphere and poured into the mixture of ice and 10% HCl and
extracted with Et2O (3ꢂ30 mL). The organic phase was dried over
Na2SO4, and the solvent was evaporated to yield a mixture of 2 and
5 (0.17 g) in ratio 1:5 as a white crystalline solid. 5 in mixture: 1H
Compound 6d was obtained from 2-hydroxy-3-methoxybenz-
aldehyde (1.00 g, 6.57 mmol) in dry CH2Cl2 (40 mL), triethylamine
(1.10 mL, 7.88 mmol) and mesyl chloride (0.82 mL, 10.6 mmol). The
crude product was purified by silica gel chromatography (EtOAc/pe-
troleum ether 1:3) affording yellow oil 6d (1.36 g, 90%). 1H NMR
(400 MHz, DMSO-d6):
d
¼10.18 (s, 1H), 7.57 (dd, J¼1.6 and 8.2 Hz, 1H),
NMR (200 MHz, DMSO-d6):
d
¼7.66e7.58 (m, 1H), 7.47e7.27 (m,
7.50 (dd, J¼7.8 and 8.2 Hz,1H), 7.43 (dd, J¼1.6 and 7.8 Hz,1H), 3.93 (s,
2H), 7.15 (dd, J¼1.3 and 7.8 Hz, 1H), 6.42 (d, J¼7.1 Hz, 1H), 5.22e5.05
(m, 1H), 4.28 (dd, J¼6.2 and 13.7 Hz, 1H), 3.67 (dd, J¼9.3 and
13.7 Hz, 1H).
3H), 3.52 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d¼188.4, 152.1, 139.4,
130.7,128.4,119.4,119.2, 56.5, 39.0. MS (EI, 70 eV): m/z¼230 (34) [M]þ,
151 (100), 136 (20), 123 (8.6), 108 (28), 93 (20).
A solution of mixture of 2 and 5 (0.17 g) in pyridine (7 mL) was
cooled to 0 ꢀC and POCl3 (0.10 mL, 1.5 mmol) was added. The re-
action was stirred for 3 h at room temperature then poured into
mixture of ice and water. Precipitate was collected by filtration and
recrystallized from EtOH to yield 2 (0.12 g, 71%) as a white crys-
talline solid. Mp 82e83 ꢀC. IR (neat): nmax¼1367, 1352, 1182,
4.7. 4-(Benzyloxy)-2-formylphenyl methanesulfonate (6e)
Compound 6e was obtained from 5-(benzyloxy)-2-
hydroxybenzaldehyde (0.24 g, 1.06 mmol) in an inseparable mix-
ture with 2,5-bis(benzyloxy)benzaldehyde derivative ratio 1:1.7
(prepared according modified literature procedure)11e13 in dry
CH2Cl2 (30 mL), triethylamine (0.48 mL, 3.47 mmol) and mesyl
chloride (0.36 mL, 4.65 mmol) as a mixture of 6e (0.34 g, 98%) and
2,5-bis(benzyloxy)benzaldehyde in ratio 1:1.7 as a chromato-
graphically (on a preparative scale) inseparable mixture that was
carried on to the next step without further purification. The ana-
lytically pure sample of 6e was obtained by HPLC (column: YMC-
Pack ODS-A, 150ꢂ10 mm, elution with MeOH/H2O). Mp
1167 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d¼7.74e7.68 (m, 2H),
7.62e7.57 (m, 1H), 7.51 (d, J¼10.3 Hz, 1H), 7.46e7.39 (m, 2H). 13C
NMR (100 MHz, DMSO-d6):
d
¼150.8, 136.6, 132.6, 130.0, 126.3,
122.7, 118.9, 118.4. MS (EI, 70 eV): m/z¼182 (100) [M]þ, 118 (82), 89
(74), 63 (31), 51 (9.5). Anal. Calcd for C8H6O3S (182.20): C 52.74, H
3.32. Found: C 52.33, H 3.28.
Method B. Compound 2 was obtained from 3 (0.21 g, 1.05 mmol),
DBN (0.13 mL, 1.02 mmol) (mixture of 2 and 5 in ratio 1:10) and
POCl3 (0.09 mL, 0.95 mmol) as a white crystalline solid (0.12 g, 67%).
Method C. Compound 2 was obtained from 3 (0.21 g, 1.05 mmol),
TBD (0.15 g, 1.05 mmol) (mixture of 2 and 5 in ratio 1:3) and POCl3
(0.06 mL, 0.67 mmol) as a white crystalline solid (0.074 g, 39%).
101e102 ꢀC. IR (neat): nmax¼1686, 1369, 1347, 1155 cmꢁ1
.
1H NMR
(400 MHz, DMSO-d6):
d
¼10.18 (s, 1H), 7.52e7.31 (m, 8H), 5.21 (s,
2H), 3.54 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d
¼188.4, 157.2,
143.4, 136.4, 130.0, 128.5, 128.1, 127.8, 125.3, 122.8, 112.8, 69.9, 37.5.
Method D. Compound
2.50 mmol), TMG (0.31 mL, 2.50 mmol) (mixture of 2 and 5 in ratio
2 was obtained from 3 (0.50 g,
MS (EI, 70 eV): m/z¼306 (6.2) [M]þ, 91 (100), 79 (2.4), 65 (6.1). Anal.

A. Grandane et al. / Tetrahedron 68 (2012) 5541e5546
5545
1:15) and POCl3 (0.28 mL, 2.96 mmol) as a white crystalline solid
(0.23 g, 53%).
5.18e5.04 (m, 1H), 4.25 (dd, J¼6.2 and 13.7 Hz, 1H), 3.83 (s, 3H),
3.64 (dd, J¼9.3 and 13.7 Hz, 1H).
Following treatment of mixture of 7d and 8d (0.60 g) with
mixture POCl3 (0.31 mL, 3.27 mmol) in pyridine (1.5 mL) and re-
crystallization from EtOH yielded 8d (0.39 g, 39%) as a white crys-
talline solid. Mp 128e129 ꢀC. IR (neat): nmax¼1369, 1356, 1178,
4.11. 6-Nitro-1,2-benzoxathiine 2,2-dioxide (8a)
Compound 8a was prepared according to Method A from 6a
(3.00 g, 12.23 mmol) in dry CH2Cl2 (20 mL) and DBU (1.83 mL,
12.23 mmol) with the following treatment of intermediate mixture
(contains 7a and 8a in ratio 1:2) with POCl3 (1.14 mL, 12.23 mmol)
in pyridine (12 mL). Recrystallization from EtOH yielded 8a (1.77 g,
64%) as a yellow crystalline solid. Mp 181e182 ꢀC. IR (KBr):
1164 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d
¼7.68 (d, J¼10.3 Hz,
1H), 7.51 (d, J¼10.3 Hz, 1H), 7.38e7.32 (m, 2H), 7.24 (dd, J¼2.8 and
6.4 Hz, 1H), 3.90 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d¼148.1,
139.6, 136.7, 126.3, 122.9, 120.9, 119.6, 115.7, 56.3. MS (EI, 70 eV): m/
z¼212 (100) [M]þ, 148 (27), 133 (76), 118 (17), 77 (63) 51 (35). Anal.
Calcd for C9H8O4S (212.22): C 50.94, H 3.80. Found: C 51.01, H 3.56.
nmax¼1367, 1344, 1174 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
¼8.73
d
(d, J¼2.8 Hz, 1H), 8.42 (dd, J¼2.8 and 9.0 Hz, 1H), 7.92 (d, J¼10.5 Hz,
1H), 7.78 (d, J¼10.5 Hz, 1H), 7.72 (d, J¼9.0 Hz, 1H). 13C NMR
4.15. 6-(Benzyloxy)-1,2-benzoxathiine 2,2-dioxide (8e)
(100 MHz, DMSO-d6):
d
¼154.5, 144.9, 135.5, 127.4, 125.7, 124.1,
120.0, 119.3. MS (EI, 70 eV): m/z¼227 (100) [M]þ, 163 (12), 117 (23),
89 (40). Anal. Calcd for C8H5NO5S (227.20): C 42.29, H 2.22, N 6.17.
Found: C 42.61, H 2.42, N 6.03.
Compound 8e was prepared according to Method A from 6e
(0.34 g, 1.11 mmol) in dry CH2Cl2 (19 mL) and DBU (0.47 mL,
3.12 mmol) with following treatment of intermediate mixture
(contains 7e and 8e in ratio 1:1) with POCl3 (0.25 mL, 2.68 mmol) in
pyridine (15 mL). Purification by silica gel chromatography (EtOAc/
petroleum ether 1:2) yielded 8e (0.12 g, 38%) as a yellow crystalline
4.12. 4-Hydroxy-2,2-dioxido-3,4-dihydro-1,2-benzoxathiin-6-
yl methanesulfonate (7b) and 2,2-dioxido-1,2-benzoxathiin-6-
yl methanesulfonate (8b)
solid. Mp 150e151 ꢀC. IR (KBr): nmax¼1361, 1348, 1173, 1160 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d
¼7.63 (d, J¼10.3 Hz, 1H), 7.50 (d,
Compounds 7b and 8b were prepared according to Method A
from 6b (1.00 g, 3.40 mmol) in dry CH2Cl2 (40 mL) and DBU
(0.51 mL, 3.40 mmol). A mixture (0.78 g) of 7b and 8b was obtained
J¼10.3 Hz,1H), 7.48e7.44 (m, 2H), 7.43e7.32 (m, 5H), 7.22 (dd, J¼3.1
and 9.1 Hz, 1H), 5.15 (s, 2H). 13C NMR (100 MHz, DMSO-d6):
d
¼155.8, 144.6, 136.5, 136.3, 128.5, 128.1, 127.8, 123.2, 119.6, 119.5,
in a ratio 2:1. 7b in mixture: 1H NMR (400 MHz, DMSO-d6):
d
¼7.56
119.0, 114.8, 69.9. MS (EI, 70 eV): m/z¼288 (2.8) [M]þ, 91 (100).
Anal. Calcd for C15H12O4S (288.32): C 62.49, H 4.20. Found: C 62.45,
H 4.17.
(d, J¼2.8 Hz, 1H), 7.41 (dd, J¼2.8 and 8.9 Hz, 1H), 7.30 (d, J¼8.9 Hz,
1H), 6.57 (br s, 1H), 5.19e5.12 (m, 1H), 4.33 (dd, J¼6.2 and 13.7 Hz,
1H), 3.74 (dd, J¼9.6 and 13.7 Hz, 1H), 3.43 (s, 3H).
Following treatment of mixture (0.78 g) of 7b and 8b with POCl3
(0.31 mL, 3.33 mmol) in pyridine (15 mL) and recrystallization from
EtOH yielded 8b (0.51 g, 54%) as a white crystalline solid. Mp
4.16. 6-Bromo-1,2-benzoxathiine 2,2-dioxide (8f)5
Compound 8f was prepared according to Method A from 6f
(1.09 g, 3.90 mmol) in dry CH2Cl2 (10 mL) and DBU (0.58 mL,
3.90 mmol) with the following treatment of mixture (contains 7f
and 8f in ratio 3:1) with POCl3 (0.46 mL, 4.91 mmol) in pyridine
(12 mL). Recrystallization from EtOH yielded 8f (0.64 g, 63%) as
a white crystalline solid. Mp 143e144 ꢀC. IR (neat): nmax¼1363,
130e131 ꢀC. IR (KBr): nmax¼1375, 1363, 1185, 1170, 1139 cmꢁ1
.
1H
NMR (400 MHz, DMSO-d6):
d
¼7.80e7.78 (m, 1H), 7.74 (d, J¼10.4 Hz,
1H), 7.64 (d, J¼10.4 Hz,1H), 7.60e7.58 (m, 2H), 3.47 (s, 3H). 13C NMR
(100 MHz, DMSO-d6):
d¼149.1, 146.0, 135.7, 126.3, 123.6, 123.5,
120.4, 120.0, 37.5. MS (EI, 70 eV): m/z¼276 (42) [M]þ, 212 (3.0), 197
(100), 133 (17), 77 (33), 51 (21). Anal. Calcd for C9H8O4S (212.22): C
39.12, H 2.92. Found: C 38.97, H 2.64.
1342, 1168 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d
¼8.00 (d,
J¼2.5 Hz, 1H), 7.78 (dd, J¼2.5 and 8.8 Hz, 1H), 7.68 (d, J¼10.4 Hz,
1H), 7.61 (d, J¼10.4 Hz, 1H), 7.44 (d, J¼8.8 Hz, 1H). 13C NMR
4.13. 6,8-Dichloro-1,2-benzoxathiine 2,2-dioxide (8c)
(100 MHz, DMSO-d6):
d
¼149.9, 135.4, 134.9, 132.2, 123.7, 120.7,
118.0. MS (EI, 70 eV): m/z¼262 (100), 260 (98) [M]þ, 198 (40), 196
(42), 170 (5.5), 168 (5.6), 117 (34), 89 (90). Anal. Calcd for C8H5BrO3S
(261.09): C 36.80, H 1.93. Found: C 36.96, H 1.94.
Compound 8c was prepared according to Method A from 6c
(0.30 g, 1.11 mmol) in dry CH2Cl2 (3 mL) and DBU (0.17 mL,
1.11 mmol) with the following treatment of intermediate mixture
(contains 7c and 8c in ratio 2:1) with POCl3 (0.10 mL, 1.11 mmol) in
pyridine (2.3 mL). Recrystallization from EtOH yielded 8c (0.089 g,
32%) as a white crystalline solid. Mp 105e106 ꢀC. IR (neat):
4.17. 1,2-Dihydronaphtho[1,2-e][1,2]oxathiin-1-ol 3,3-dioxide
(7g)
nmax¼1369, 1347, 1173 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
¼8.01
Compound 7g was prepared according to Method A from 6g
(1.00 g, 4.00 mmol) in dry CH2Cl2 (30 mL) and DBU (0.60 mL,
4.00 mmol). Obtained 7g (0.48 g, 48%) as a light crystalline solid.
(d, J¼2.5 Hz,1H), 7.88 (d, J¼2.5 Hz,1H), 7.76 and 7.72 (AB, J¼10.4 Hz,
2H). 13C NMR (100 MHz, DMSO-d6):
d¼145.4, 135.5, 131.9, 130.3,
128.4, 124.3, 123.4, 121.4. MS (EI, 70 eV): m/z¼252 (48), 250 (70)
[M]þ, 188 (54), 186 (84), 151 (5.0), 125 (33), 123 (100), 87 (19). Anal.
Calcd for C8H4Cl2O3S (251.09): C 38.27, H 1.61. Found: C 38.37, H
1.56.
Mp 156e157 ꢀC. IR (KBr): nmax¼3452, 1376, 1360, 1175, 1158 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d
¼8.28 (d, J¼8.6 Hz, 1H), 8.03 (d,
J¼9.1 Hz, 1H), 7.99 (d, J¼8.2 Hz, 1H), 7.70e7.54 (m, 2H), 7.31 (d,
J¼9.1 Hz, 1H), 6.18 (d, J¼7.2 Hz, 1H), 5.85e5.79 (m, 1H), 4.32 (dd,
J¼5.7 and 14.6 Hz, 1H), 4.00 (dd, J¼4.3 and 14.6 Hz, 1H). 13C NMR
4.14. 8-Methoxy-3,4-dihydro-1,2-benzoxathiin-4-ol 2,2-
dioxide (7d) and 8-methoxy-1,2-benzoxathiine 2,2-dioxide (8d)
(100 MHz, DMSO-d6):
d
¼147.9,131.3,131.1,128.5,127.4,125.8,124.9,
118.1, 63.3, 52.2. Anal. Calcd for C12H10O4S (250.27): C 57.59, H 4.03.
Found: C 57.79, H 3.85.
Compounds 7d and 8d were prepared according to Method A
from 6d (1.00 g, 4.34 mmol) in dry CH2Cl2 (30 mL) and DBU
(0.65 mL, 4.34 mmol). The reaction was stirred at 0 ꢀC for 2 h under
argon atmosphere. The mixture (0.60 g) of 7d and 8d was obtained
4.18. Naphtho[1,2-e][1,2]oxathiine 3,3-dioxide (8g)
Following treatment of 7g (0.48 g, 1.91 mmol) with POCl3
(0.22 mL, 2.41 mmol) in pyridine (3.0 mL) and recrystallization
from EtOH yielded 8g (0.28 g, 62% [30% in respect to 6g]) as a white
in a ratio 5:1. 7d in mixture: 1H NMR (200 MHz, DMSO-d6):
d
¼7.23
(d, J¼7.8 Hz, 1H), 7.18e7.07 (m, 2H), 6.39 (d, J¼7.2 Hz, 1H),

5546
A. Grandane et al. / Tetrahedron 68 (2012) 5541e5546
crystalline solid. Mp 152e153 ꢀC. IR (neat): nmax¼1369, 1178 cmꢁ1
.
extracted with EtOAc (3ꢂ70 mL), washed with water and brine. The
organic phase was dried over Na2SO4, and the solvent was evapo-
rated. The mixture was purified by silica gel chromatography (t-
BuOMe) yielding 10 (0.15 g, 27%), a yellow crystalline solid. Mp
1H NMR (400 MHz, DMSO-d6):
d
¼8.53 (d, J¼10.6 Hz, 1H), 8.46 (d,
J¼8.4 Hz, 1H), 8.22 (d, J¼9.1 Hz, 1H), 8.08 (d, J¼8.4 Hz, 1H),
7.79e7.73 (m, 1H), 7.70e7.64 (m, 2H), 7.60 (d, J¼9.1 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6):
d
¼150.1, 133.8, 133.1, 130.7, 129.4, 129.0,
146e147 ꢀC. IR (KBr): nmax¼3498, 1340, 1169, 1155 cmꢁ1
.
1H NMR
128.8, 126.7, 122.9, 122.0, 117.7, 113.3. MS (EI, 70 eV): m/z¼232 (80)
[M]þ, 168 (65), 139 (100), 113 (9.3), 102 (12). Anal. Calcd for
C12H8O3S (232.26): C 62.06, H 3.47. Found: C 61.99, H 3.32.
(400 MHz, DMSO-d6):
d
¼9.93 (s, 1H), 7.60 (d, J¼10.3 Hz, 1H), 7.43
(d, J¼10.3 Hz, 1H), 7.25 (d, J¼8.9 Hz, 1H), 7.03 (d, J¼2.9 Hz, 1H), 6.94
(dd, J¼2.9 and 8.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6):
¼155.1,
d
143.4, 136.6, 122.8, 119.6, 119.4, 119.0, 115.1. MS (EI, 70 eV): m/z¼198
(99) [M]þ, 134 (100), 105 (27), 78 (51), 64 (3.6), 51 (7.0). Anal. Calcd
for C8H6O4S (198.20): C 48.48, H 3.05. Found: C 48.13, H 3.11.
4.19. 1,2-Benzoxathiin-6-amine 2,2-dioxide (9)
To a solution of 8a (3.04 g, 13.4 mmol) in acetic acid (0.46 mL),
water (33 mL) and ethanol (22 mL) was added iron powder (4.48 g,
80.3 mmol). The mixture was stirred at 75 ꢀC for 1 h, cooled to
room temperature and 300 mL EtOAc was added. The organic layer
was washed with saturated NaHCO3 solution, dried over Na2SO4,
and the solvent was evaporated affording 9 (2.33 g, 88%) as a yellow
crystalline solid. Mp 139e140 ꢀC. IR (KBr): nmax¼3494, 3400, 1361,
Acknowledgements
This project was financed by European Social Fund (No. 2009/
0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
References and notes
1344, 1166, 1130 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6):
d¼7.51 (d,
1. Maresca, A.; Temperini, C.; Vu, H.; Pham, N. B.; Poulsen, S.-A.; Scozzafava, A.;
Quinn, R. J.; Supuran, C. T. J. Am. Chem. Soc. 2009, 131, 3057.
2. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C. T.
J. Med. Chem. 2010, 53, 335.
3. Maresca, A.; Scozzafava, A.; Supuran, C. T. Bioorg. Med. Chem. Lett. 2010, 20,
7255.
J¼10.2 Hz,1H), 7.32 (d, J¼10.2 Hz,1H), 7.08 (d, J¼8.7 Hz,1H), 6.74 (d,
J¼2.7 Hz, 1H), 6.71 (dd, J¼2.7 and 8.7 Hz, 1H), 5.39 (s, 2H). 13C NMR
(100 MHz, DMSO-d6):
d
¼147.0, 141.3, 137.0, 122.5, 119.3, 118.9, 117.0,
112.8. MS (EI, 70 eV): m/z¼197 (52) [M]þ, 133 (100), 104 (61), 78
(28), 52 (13). Anal. Calcd for C8H7NO3S (197.21): C 48.72, H 3.58; N
7.10. Found: C 48.71, H 3.55, N 6.79.
4. Edwards, D. J.; Hadfield, J. A.; Wallace, T. W.; Ducki, S. Org. Biomol. Chem. 2011, 9,
219.
5. Ehrenfreund, J.; Foery, W. U.S. Patent 4,589,911, 1986.
6. Ritter, T.; Stanek, K.; Larrosa, I.; Carreira, E. M. Org. Lett. 2004, 6, 1513.
7. Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741.
8. Belokon’, Y. N.; Tararov, V. I.; Belikov, V. M. Polym. Sci. U.S.S.R. 1978, 20, 1467.
9. Dinsmore, C. J.; Bergman, J. M.; Graham, S. L.; Nguyen, D. N.; Stokker, G. E.;
Williams, T. M.; Zartman, C. B. U.S. Patent 6,562,823, 2003.
10. Cotterill, A. S.; Moody, C. J.; Roffey, J. R. A. Tetrahedron 1995, 51, 7223.
4.20. 1,2-Benzoxathiin-6-ol 2,2-dioxide (10)6
A solution of diisopropylamine (0.63 mL, 4.45 mmol) in dry THF
(15 mL) was cooled to ꢁ78 ꢀC and 2.5 M butyllithium in hexane
(2.22 mL, 5.56 mmol) was added. The mixture was stirred at ꢁ78 ꢀC
for 10 min under argon atmosphere. Compound 8b (0.77 g,
2.78 mmol) in THF (35 mL) was added to LDA solution. The reaction
was stirred under argon at ꢁ78 ꢀC for 5.5 h. Saturated NH4Cl so-
lution (20 mL) was added to the reaction mixture. The mixture was
ꢀ
11. Barrero, A. F.; Quílez del Moral, J. F.; Herrador, M. M.; Arteaga, P.; Cortes, M.;
ꢀ
Benites, J.; Rosellon, A. Tetrahedron 2006, 62, 6012.
12. Haraldsson, G. G.; Baldwin, J. E. Tetrahedron 1997, 53, 215.
13. Khupse, R. S.; Erhardt, P. W. Org. Lett. 2008, 10, 5007.
14. Ryu, S. E.; Kim, S. J.; Jeong, D. G.; Lee, S. H.; Jung, S. K.; Kim, H. M.; Park, S. K.;
Lee, K. H.; Lee, C. W.; Choi, J. K.; Ahn, J. H. WO Patent 081091, 2007.