Direct conversion of an ortho-allylphenol into a chlorosulfonyl-3-methyl-1, 2-benzoxathiin 2,2-dioxide

Article abstract of DOI:10.1515/znb-2004-0919

A one-pot synthesis of methyl 6-chlorosulfonyl-3-methyl-1,2-benzoxathiin-8- carboxylate 2,2-dioxide (9), characterized as its 6-(4-methylpiperazin-1-yl) sulfonyl derivative 10, is achieved via direct reaction of methyl 3-allylsalicylate (1) with chlorosulfonic acid at -7°C. The latter reagent converts methyl 2-methyl-2,3-dihydrobenzofuran-7-carboxylate (3) into the respective 5-chlorosulfonyl derivative 7 (identified as its 5-(4- methylpiperazin-1-yl)sulfonyl derivative 8), while contrary to literature reports, the aromatic δ-sultones 9, 10 (anticipated to be produced from 3) were not detected.

Full text of DOI:10.1515/znb-2004-0919

Direct Conversion of an ortho-Allylphenol into a
Chlorosulfonyl-3-methyl-1,2-benzoxathiin 2,2-Dioxide
Ali M. Qaisia, Mustafa M. El-Abadelahb, and Wolfgang Voelterc
a Faculty of Pharmacy, University of Jordan, Amman, Jordan
b Chemistry Department, Faculty of Science, University of Jordan, Amman, Jordan
c Abteilung fu¨r Physikalische Biochemie, Physiologisch-chemisches Institut der Universita¨t
Tu¨bingen, Hoppe-Seyler-Straße 4, D-72076 Tu¨bingen, Germany
Reprint requests to Prof. Dr. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de
Z. Naturforsch. 59b, 1059 – 1062 (2004); received March 16, 2004
A one-pot synthesis of methyl 6-chlorosulfonyl-3-methyl-1,2-benzoxathiin-8-carboxylate 2,2-
dioxide (9), characterized as its 6-(4-methylpiperazin-1-yl)sulfonyl derivative 10, is achieved via di-
rect reaction of methyl 3-allylsalicylate (1) with chlorosulfonic acid at −7 ◦C. The latter reagent con-
verts methyl 2-methyl-2,3-dihydrobenzofuran-7-carboxylate (3) into the respective 5-chlorosulfonyl
derivative 7 (identified as its 5-(4-methylpiperazin-1-yl)sulfonyl derivative 8), while contrary to liter-
ature reports, the aromatic δ-sultones 9, 10 (anticipated to be produced from 3) were not detected.
Key words: Methyl 3-Allylsalicylate, Chlorosulfonic Acid, 1,2-Benzoxathiin 2,2-Dioxide
Introduction
The 2,3-dihydrobenzofuran nucleus and the par-
ent benzo[b]furan are found to occur in several
biologically interesting natural products [1]. 2,3-
Dihydrobenzofurans are accessible from the respective
ortho-allylphenols as exemplified by the one-pot in-
tramolecular cyclization of 1 into 2 (Scheme 1) [2].
In this versatile synthetic route, the requisite o-
allylphenol precursors are readily available via the
well-known Claisen rearrangement of the correspond-
ing allyl aryl ethers [3]. Type 2 compounds were uti-
lized for further derivatizations, such as the preparation
of the respective biologically active 7-carboxamide
derivatives [4]. Complementary to a recent patent [5],
we have employed 2 and 3 for the synthesis of 5-(2,3-
dihydro-7-benzofuryl)pyrazolo[4,3-d]pyrimidone [6],
Scheme 2.
via cyclization of the ◦respective o-allylphenol pre-
cursors 4 [8]) at −7 C was reported to yield the
corresponding 8-chlorosulfonyl-1,2-benzoxathiin 2,2-
dioxides 6 (Scheme 2), useful as intermediates for sul-
fonylurea herbicides and plant growth hormones [8].
This mode of facile ring enlargement, converting 5 into
their aromatic δ-sultones (6), has spurred our interest
in cyclic sulfonates (sultones), a fundamental hetero-
cyclic system that has been the subject of a recent re-
view [9]. In particular, we sought to utilize 3 and adopt
it to Foery’s method [8] in order to prepare methyl 6-
chlorosulfonyl-3-methyl-1,2-benzoxathiin 2,2-dioxide
(9) (convertible to its sulfonamide 10, Scheme 3), con-
ceived as a suitable synthon for further manipulation.
R
an analogue of Viagraꢀ [7].
Having ( )-3 in hand [6], we have investigated
its reaction with chlorosulfonic acid as a plausible
synthetic route towards the δ-sultone 9. However,
this reaction failed to deliver the desired 6-chloro-
sulfonylsultone 9; instead, the major crude product was
Scheme 1.
The reaction of chlorosulfonic acid with substi- 7, identified as its 5-(4-methylpiperazin-1-yl)sulfonyl
tuted 2-methyl-2,3-dihydrobenzofurans (5, accessible derivative 8 (Scheme 3, vide infra). Herein we wish
c
0932–0776 / 04 / 0900–1059 $ 06.00 ꢀ 2004 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | University of Michigan-Flint
Authenticated
Download Date | 9/17/18 10:43 PM

1060
A. M. Qaisi et al. · 1,2-Benzoxathiin 2,2-Dioxide
Scheme 5.
Scheme 3.
Scheme 4.
Scheme 6.
to report on the synthesis of 10, obtainable by piper-
azinylation of 9 which is now made accessible from
the reaction of chlorosulfonic acid with methyl 3-
allylsalicylate (1) (Scheme 4).
lated 2,3-dihydrobenzofurans into the respective sul-
tones (5 → 6, Scheme 2).
Accordingly, we were prompted to puzzle this con-
trast out. In one lead experiment we have investi-
gated the reaction of chlorosulfonic acid with methyl
3-allylsalicylate 1 (precursor of 3), conducted at −5
to −7 ◦C for 5 – 6 h. Work-up of the reaction mixture
gave moderate yield of a crude solid product of the δ-
sultone 9 which was characterized by direct conversion
into the respective 6-(4-methylpiperazin-1-yl)sulfonyl
sultone 10.
Results and Discussion
Direct interaction between methyl 2-methyl-2,3-
dihydrobenzofuran-7-carboxylate ( )-3 and chlor◦o-
sulfonic acid was conducted in the cold (−5 to −7 C)
for 10 – 12 h. Work-up of the reaction mixture in the
conventional manner gave methyl 5-chlorosulfonyl-3-
methyl-2,3-dihydrobenzofuran-7-carboxylate (7) that
Based on the experimental results noted above
was directly converted into the corresponding 5- (Schemes 3 and 4), we believe that Foery’s dihy-
(4-methylpiperazin-1-yl)sulfonyl derivative 8 in 72% drobenzofurans (5) [8] were fortuitously admixed with
overall yield (Scheme 3). Comparable results were their o-allylphenol precursors 4, possibly due to in-
also obtained when the reaction was conducted at completion of the cyclization step (4 → 5, Scheme 2).
room temperature for 5 – 6 h, and at 65 – 70 ◦C for Consequently, compounds 4 seem to be the actual sub-
1 – 2 h, followed by piperazinylation. Under these re- strates that interact with chlorosulfonic acid to deliver
action conditions the putative 6-(4-methylpiperazin- the δ-sultones 6, convertible into the respective sul-
1-yl)sulfonyl derivative 10 could not be detected fonylurea derivatives. This hypothesis might explain
(Scheme 3). Apparently, the 2,3-dihydrofuran moiety the apparent discrepancy between Foery’s results and
in 3 has survived the reaction conditions and is re- our findings. Meanwhile, the reported ring-expansion
tained unchanged in the products 7 and 8. Though not process, converting 5 into 6 under the action of chloro-
unexpected , these results per se are in contrast with sulfonic acid, is questionable, and for which an amend-
literature reports [8] describing the conversion of re- ment has now been advanced.
Brought to you by | University of Michigan-Flint
Authenticated
Download Date | 9/17/18 10:43 PM

A. M. Qaisi et al. · 1,2-Benzoxathiin 2,2-Dioxide
1061
In this context, it is worth mentioning that the reac- HA part of ABX system ), 3.41 (dd, JBA = 16.0 Hz, JBX
=
9.0 Hz, 1H, C3-HB), 3.04 (br t, J = 4.7 Hz, 4H, C2’-H2/C6’-
H2), 3.92 (s, 3H, CO2CH3), 5.22 (m, 1H, C2-H), 7.65 (d,
J = 1.5 Hz, 1H, C4-H), 8.16 (d, J = 1.5 Hz, 1H, C6-H). –
13C NMR (CDCl3, 75 MHz): δ = 21.9 (C2-CH3), 35.7 (C-
3), 45.7 (N-CH3), 46.0 (C-2’/C-6’), 52.3 (OCH3), 53.9 (C-
3’/C-5’), 82.7 (C-2), 112.8 (C-7), 126.6 (C-3a), 128.1 (C-4),
131.1 (C-6), 131.2 (C-5), 163.5 (C-7a), 164.3 (-C=O). –
C16H22N2O5S (354.43): calcd. C 54.22, H 6.26, N 7.90,
S 9.05; found C 54.06, H 6.18, N 7.82, S 8.93.
tion of chlorosulfonic acid with an o-phenolic enam-
inoketone (11) at 150 ◦C was reported [10] to yield the
corresponding1,2-benzoxathiane12, whereas at 20 C,
the reaction did not proceed beyond ring – chlorosul-
fonylation to form compound 13 (Scheme 5) [11].
The formation of 9 probably involves a cascade of
plausible substitution – addition – elimination steps
tentatively depicted in Scheme 6.
◦
Experimental Section
Methyl 6-chlorosulfonyl-3-methyl-1,2-benzoxathiin 2,2-
dioxide (9)
Melting points (uncorrected) were determined on a
Gallenkamp electrothermal melting temperature apparatus.
1H and 13C NMR spectra were measured on a Bruker DPX-
300 instrument with TMS as internal reference. Mass spec-
tra (EI) and high resolution data (HRMS) were obtained us-
ing a Finnigan MAT TSQ-70 spectrometer at 70 eV; ion
source temperature = 200 ◦C. Microanalysis was performed
at the Microanalytical Laboratory-Inorganic Chemistry De-
partment, Tu¨bingen University, Germany.
Methyl 3-allylsalicylate (1) [2] (1.92 g, 10 mmol) was
added dropwise during 30 min to a stirred and cooled (−5
◦
to −7 C) chlorosulfonic acid (10 ml, 150 mmol). The re-
action mixture was stirred at that temperature for additional
5 h, then poured cautiously onto crushed ice (100 ml) and
extracted with diethyl ether (2×50 ml). The combined ether
extracts were washed with water (40 ml), dried (MgSO4)
and the solvent was evaporated. The residual crude prod-
uct 9 (thick oil) was employed as such for the preparation
of 10.
Methyl 5-chlorosulfonyl-2-methyl-2,3-dihydrobenzofuran-7-
carboxylate (7)
◦
Methyl 3-methyl-6-(4-methylpiperazin-1-yl)sulfonyl-1,2-
benzoxathiin-8-carboxylate 2,2-dioxide (10)
To a stirred and cooled (−5 to −7 C) chlorosulfonic
acid (10 g, 150 mmol) was added methyl 2-methyl-2,3-
dihydrobenzofuran-7-carboxylate (3) [6] (1.92 g, 10 mmol)
for 20 min, and the reaction mixture was stirred at that tem-
perature for 10 – 12 h. The resulting mixture was poured
cautiously onto crushed ice (100 ml) and extracted with di-
ethyl ether (2×50 ml). The combined organic extracts were
washed with water (30 ml), dried (MgSO4) and the solvent
was evaporated. The residual crude product 7 was used as
such for the preparation of 8.
To a solution of the crude 6-chlorosulfonyl derivative
9 (obtained above from 10 mmol of 1) in THF (20 ml)
was added 1-methylpiperazine (2.0 g, 20 mmol) in THF
◦
(20 ml), and the resulting mixture stirred at 20 C for 1 h.
The solvents were evaporated in vacuo, and the residue was
treated with cold water (20 ml). The resulting solid product
was collected and recrystallized form CH2Cl2/n-hexa◦ne to
give 1.54 g (37%) of compound 10; m.p. 161 – 162 C. –
MS: m/z ( % rel. int.) = 416 (2) [M+], 385 (3), 354 (4),
352 (1), 307 (3), 279 (4), 221 (2), 99 (100). – FD-MS: m/z =
416 [M+]. – HRMS: calcd. for C16H20N2O7S2: 416.071119,
Methyl 2-methyl-5-(4-methylpiperazin-1-yl)sulfonyl-2,3-
dihydrobenzofuran-7-carboxylate (8)
1
A solution of 1-methylpiperazine (2.0 g, 20 mmol) in
THF (15 ml, 150 mmol) was added to a stirred solution
of the crude 5-chlorosulfonyl derivative 7 (obtained above
from 10 mmol of 3) in THF (40 ml) at 20 ◦C, and the mix-
ture was stirred for 1 – 2 h. The solvent was then evapo-
rated, the residue treated with cold water (50 ml) and ex-
tracted with dichloromethane (2×40 ml). The combined or-
ganic extracts were dried (MgSO4), the solvent was evap-
orated and the residual solid product recrystallized from
dichloromethane/n-hexane to give 2.55 g (72%) [11] of 8 ;
found 416.07265. – H NMR (300 MHz, DMSO-d6): δ =
2.16 (s, 3H, C3-CH3), 2.37 (s, 3H, N-CH3), 2.41 (br t, 4H,
C3’-H2/C5’-H2), 2.97 (br t, 4H, C2’-H2/C6’-H2), 3.93 (s,
3H, CO2CH3), 7.65 (d, J = 1.4 Hz, 1H, C4-H), 8.16 (d,
J = 2.2 Hz, 1H, C7-H), 8.29 (d, J = 2.2 Hz, 1H, C5-H). –
13C NMR (75 MHz, DMSO-d6): δ = 15.4 (C3-CH3), 45.7
(N-CH3), 46.1 (C-2’/C-6’), 53.6 (OCH3), 53.9 (C-3’/C-5’),
121.9 (C-3), 125.2 (C-8), 131.3 (C-7), 131.4 (C-5), 132.6 (C-
4), 133.2 (C-6), 134.6 (C-4a), 151.0 (C-8a), 162.3 (-C=O). –
C16H20N2O7S2 (416.47): calcd. C 46.14, H 4.84, N 6.73,
S 15.40; found C 45.92, H 4.76, N 6.68, S 15.27.
m.p. 55 – 56 C. – MS: m/z (% rel. int.) = 354 (3) [M+],
◦
323 (2), 205 (2), 159 (1), 149 (4), 131 (4), 99 (100). – HRMS:
calcd. for C16H22N2O5S: 354.12494, found 354.13049. –
1H NMR (CDCl3, 300 MHz): δ = 1.57 (d, J = 6.3 Hz, 3H,
Acknowledgements
We wish to thank the Advanced Pharmaceutical Industries
C2-CH3), 2.28 (s, 3H, N-CH3), 2.50 (t, J = 7.4 Hz, 4H, C3’- Co. Ltd. (Amman, Jordan) and the BMBF (Bonn, Germany)
H2/C5’-H2), 2.88 (dd, JAB = 16.0 Hz, JAX = 7.4 Hz, 1H, C3- for financial support.
Brought to you by | University of Michigan-Flint
Authenticated
Download Date | 9/17/18 10:43 PM

1062
[1] G. D. McCallion, Current Org. Chem. 3, 67 (1999).
[2] P. Stanetty, H. Koller, G. Pu¨rstinger, Monatsh. Chem.
121, 883 (1990).
A. M. Qaisi et al. · 1,2-Benzoxathiin 2,2-Dioxide
[6] N. R. Al-bojuk, M. M. El-Abadelah, S. S. Sabri,
A. Michel, W. Voelter, C. M. Mo¨ssmer, Y. Al-Abed,
Heterocycles 55, 1789 (2001).
[3] A. I. Meyers, M. Reuman, R. A. Gabel, J. Org. Chem.
46, 783 (1981).
[7] a) P. Ellis, N. K. Terrett, PCT Int. Appl. WO 9, 428, 902
(1994); Chem. Abstr. 122, 187627n (1995); b) N. K.
Terrett, A. S. Bell, D. Brown, P. Ellis, Bioorg. Med.
Chem. Lett. 6, 1819 (1996).
[8] a) W. Foery, U. S. Patent, US 4, 560, 771 (1985); Chem.
Abstr. 104, 207310n (1986); b) W. Foery, Eur. Pat.
Appl. EP 177, 448 (1986); Chem. Abstr. 105, 115079m
(1986); c) J. Ehrenfreund, W. Foery, Eur. Pat. EP 128,
116 (1984); Chem. Abstr. 103, 71339y (1985).
[9] D. W. Roberts, D. L. Williams, Tetrahedron 43, 1027
(1987).
[4] a) S. Murakami, N. Marubayashi, T. Fukuda, S. Take-
hara, T. Tahara, J. Med. Chem. 34, 261 (1991);
b) T. Kuroita, M. Yasumoto, K. Inaba, M. Sakamori,
S. Takehara, T. Kawakita, Chem. Pharm. Bull.
42, 95 (1994); c) D. W. Robertson, B. Lacefield,
W. Bloomquest, W. Pfeifer, R. L. Simon, M. L. Cohen,
J. Med. Chem. 35, 310 (1992).
[5] R. J. Abdel-Jalil, Y. Al-Abed, M. M. El-Abadelah,
M. A. Khanfar, S. S. Sabri, W. Voelter, PCT Int. Appl.
WO 01 03 644 (2001); Chem. Abstr. 134, 95497 [10] W. Loewe, T. Braden, Arch. Pharm. 324, 385 (1991).
(2001).
[11] The calculated percent yield of 8 and 9 is based on the
number of mmols of the respective synthons 3 and 1.
Brought to you by | University of Michigan-Flint
Authenticated
Download Date | 9/17/18 10:43 PM