A new procedure for the synthesis of 4-substituted-2H-1,2,3- benzothiadiazine 1,1-dioxides via directed ortho-lithiation of N 1-arylsulfonylhydrazonates

Article abstract of DOI:10.1016/j.tetlet.2013.05.082

N¹-Arylsulfonylhydrazonates, which are readily available from commercial N¹-arylsulfonylhydrazides, undergo directed ortho-lithiation with an excess of lithium diisopropylamide and tetramethylethylenediamine to provide new 2H-1,2,3-b

Full text of DOI:10.1016/j.tetlet.2013.05.082

Tetrahedron Letters 54 (2013) 4023–4025
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Tetrahedron Letters
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A new procedure for the synthesis of 4-substituted-2H-1,2,3-benzo-
thiadiazine 1,1-dioxides via directed ortho-lithiation of N1-
arylsulfonylhydrazonates
⇑
Yakdhane Kacem, Béchir Ben Hassine
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, Faculté des Sciences, Université de Monastir, Avenue de l’environnement, 5019 Monastir, Tunisia
a r t i c l e i n f o
a b s t r a c t
N1-Arylsulfonylhydrazonates, which are readily available from commercial N1-arylsulfonylhydrazides,
undergo directed ortho-lithiation with an excess of lithium diisopropylamide and tetramethylethylenedi-
amine to provide new 2H-1,2,3-benzothiadiazine 1,1-dioxide derivatives in yields ranging from 43% to
85%.
Article history:
Received 3 March 2013
Revised 30 April 2013
Accepted 17 May 2013
Available online 23 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
N1-Arylsulfonylhydrazonates
Ortho esters
Directed ortho-lithiation
2H-1,2,3-Benzothiadiazine 1,1-dioxides
Sulfonamides have found many important applications in or-
ganic synthesis for examples, as protecting groups,1 chiral auxilia-
ries2–6 and directed metalation groups (DMGs).7,8 In addition, the
sulfonamide functionality is present in many biologically active
compounds where it can function as a stable amide equivalent.9,10
In particular, cyclic sulfonamides, of which there are many varia-
tions, are well documented in the literature. For example, amino-
thiadiazole 1,1-dioxides have shown antihypertensive and
vasodilating properties,11 whilst diuretic activity was found for
several 1,2,4-benzothiadiazine 1,1-dioxide derivatives.12 Sedative
and mild tranquilizer activities have been reported for benzothi-
adiazine dioxides.13 Particular mention should be made of 2H-
1,2,3-benzothiadiazine 1,1-dioxides with a basic side chain at the
2-position, which are useful as central nervous system stimulants
and as intermediates for the preparation of moth-proofing agents,
pickling inhibitors and herbicides.14
reactions for the synthesis of biologically active compounds,17–21
we report in this communication the successful transformation of
readily prepared N1-arylsulfonylhydrazonates into 2H-1,2,3-benzo-
thiadiazine 1,1-dioxide derivatives via an in situ sequence involving
directed ortho-lithiation-cyclization reactions. These heterocycles
were required for biological activity evaluations and as starting
materials to prepare potential new drugs.
The starting N1-arylsulfonylhydrazonates were prepared from
the corresponding arylsulfonylhydrazides (Scheme 1). Treatment
of arylsulfonylhydrazide 1 with a triethyl ortho ester in the pres-
ence of a catalytic amount of acetic acid gave the corresponding
N1-arylsulfonylhydrazonates 2 in high yields. Deprotonation of
compounds 2 with NaH in THF followed by the addition of methyl
iodide afforded the corresponding N-methyl-N-arylsulfonylhyd-
razonates 3 in good yields (Table 1).
A few reports have been published concerning the synthesis of
2H-1,2,3-benzothiadiazine 1,1-dioxide derivatives. The usual pro-
cedure for their preparation is a two-step approach involving chlo-
rosulfonation of either o-formylbenzenesulfonate15 or o-
aminobenzophenones,16 followed by ring-closure with hydrazine.
We were unaware of any reports in the literature in which the
1,2,3-benzothiadiazine ring system has been synthesized directly
from readily available N1-arylsulfonylhydrazonates. As part of our
continued efforts to develop synthetically useful anionic aromatic
O
O
O
O
OEt
OEt
AcOH
S
S
N
R'
OEt
NH-NH2
N
R'
+
H
80-90 °C
OEt
R
R
1
2
O
O
S
N
R'
OEt
1) NaH, THF, 0 °C
2) MeI
N
Me
3
R
⇑
Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
E-mail address: bechirbenhassine@yahoo.fr (B.B. Hassine).
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.082

4024
Y. Kacem, B. B. Hassine / Tetrahedron Letters 54 (2013) 4023–4025
Table 1
Table 2
Synthesis of N1-arylsulfonylhydrazonates 2a–e and 3a–e
Synthesis of 2H-1,2,3-benzothiadiazine 1,1-dioxides 4a–j
Product
R
R0
Mp (°C)
Yield (%)
Product
R
R0
R00
Mp (°C)
Yield (%)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
H
H
H
Me
Me
H
H
H
Me
Et
123–125
135–137
152–154
180–182
135–137
97–99
113–115
100–102
155–157
161–163
93
87
92
90
95
76
78
84
90
78
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
Me
Me
H
H
H
Me
Et
H
H
H
H
179–181
150–151
166–168
99–101
170–172
132–134
153–155
184–186
147–149
188–189
61
55
48
49
43
85
77
69
52
47
Ph
Me
Ph
Me
Et
Ph
Me
Ph
Ph
Me
Ph
Me
Et
Ph
Me
Ph
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
4j
The directed aromatic ortho-metalation reaction22 has been
developed into a broadly useful protocol for the regioselective con-
struction of polysubstituted aromatic compounds, and has been
used for the efficient synthesis of several heterocyclic ring systems
and bioactive molecules.23,24 Sulfonamides constitute powerful but
under developed directing groups.25 Hauser first achieved the
metalation of secondary and tertiary arylsulfonamides and then
described the synthesis of heteroannelation products.26–29 Also, in-
ter- and intramolecular anionic Friedel–Crafts equivalent conden-
sations of arylsulfonamides have been described by Snieckus.30–
We speculate that the reaction, possibly driven by the complex-
induced proximity effect40,41 (CIPE), proceeds via ortho-lithiation of
the aryl sulfonamide. The resulting carbanion then attacks the imi-
nic carbon group which leads to the cyclized product.
In summary, the efficient process described in this Letter has
enabled us to prepare 4-substituted 2H-1,2,3-benzothiadiazine
1,1-dioxides from inexpensive and readily available N1-aryl-
sulfonylhydrazides. The potential anti-inflammatory activity of
these new products is under investigation in our laboratory.
34
The protocol reported herein constitutes a mild method for the
Acknowledgments
LDA-TMEDA mediated conversion of N1-arylsulfonylhydrazonates
2a–e and 3a–e into 4-substituted-2H-1,2,3-benzothiadiazine 1,1-
dioxides 4a–j (Scheme 2).
The authors thank the DGRST (Direction Générale de la Recher-
che Scientifique et de la Rénovation Technologique) of the Tunisian
Ministry of Higher Education and Scientific Research for financial
support of this research.
Initially, an optimization of the reaction conditions for the syn-
thesis of compounds 4a–j was undertaken. Treatment of 2a with
different equivalents of LDA at either ambient or low temperatures
failed, in all cases, to provide any of the desired products, and only
recovered starting sulfonylhydrazonate 2a was obtained. As the
regioselectivity in ortho-metalation reactions is influenced by addi-
tives,35,36 and by variation of the metalating agent,37 compound 2a
was treated with 3 equiv of LDA-TMEDA, at 0 °C followed by
quenching with NH4Cl to afford the corresponding benzothiadi-
azine 1,1-dioxide 4a with a conversion of 61%. The combination
of n-BuLi-TMEDA yielded only 18% of the cyclized product. At-
tempts to enhance the yield through the use of an alternative base
(LHMDS) and additive (HMPA), and higher reaction temperatures
provided no significant benefit. Increasing the number of equiva-
lents of LDA-TMEDA afforded the desired product 4a along with
a complex mixture of by-products.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.082.
References and notes
1. Greene, T. H.; Wuts, P. G. M. Protective Groups in Organic Synthesis, third ed.;
Wiley: New York, 1999.
2. Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett.
1990, 31, 4117.
3. Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J. Tetrahedron Lett. 1990,
31, 5015.
4. Oppolzer, W.; Rodriguez, I.; Starkemann, C.; Walther, E. Tetrahedron Lett. 1990,
31, 5019.
5. Ahn, K. H.; Ham, C.; Kim, S. K.; Cho, C. W. J. Org. Chem. 1997, 62, 7047.
6. Ahn, K. H.; Baek, H. H.; Lee, S. J.; Cho, C. W. J. Org. Chem. 2000, 65, 7690.
7. MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001, 66, 3662.
8. Familoni, O. B. Synlett 2002, 1181.
9. Aran, V. J.; Goya, P.; Ochoa, C. Adv. Heterocycl. Chem. 1988, 44, 81.
10. Choi, S. Y.; Lee, S. G.; Yoon, Y. J.; Kim, W. K. J. Heterocycl. Chem. 1989, 26, 1073.
11. Stegelmeier, E.; Niemers, E.; Rosentreter, U.; Knorr, A.; Garthoff, B. Ger. Patent
3,309,655, 1984; Chem. Abstr. 1985, 102, 24633.
12. Selleri, R.; Caldini, O. Boll. Chim. Farm. 1961, 100, 323.
13. Houlihan, W. J. U.S. Patent 3,278,532, 1966; Chem. Abstr. 1966, 20154.
14. Wright, J. B. U.S. Patent 3,407, 198, 1966; Chem. Abstr. 1969, 28960.
15. King, J. F.; Huston, B. L.; Hawson, A.; Komery, J.; Deaken, D. M.; Harding, D. R. K.
Can. J. Chem. 1971, 49, 936.
Application of the LDA-TMEDA conditions38 (3 equiv for 2a–e
and two equivalents for 3a–e) yielded the corresponding 1,2,3-
benzothiadiazine 1,1-dioxides in good yields (Table 2).
The results shown in Table 2 indicate the scope and potential
limitations of this process. N-Methyl-N-arylsulfonylhydrazonates
3a–e provided respectable yields of the products, whereas the cor-
responding N-arylsulfonylhydrazonates 2a–e reacted less effi-
ciently. Although p-methyl deprotonation occurs7,39 in the
presence of excess LDA conditions, products 4d, 4e, 4i and 4j illus-
trate the successful cyclization of secondary and tertiary aryl-
sulfonylhydrazonates, albeit in variable yields.
16. Wright, J. B. J. Heterocycl. Chem. 1968, 5, 453.
17. Kacem, Y.; Kraiem, J.; Kerkani, E.; Bouraoui, A.; Ben Hassine, B. Eur. J. Pharm. Sci.
2002, 16, 221.
18. Kacem, Y.; Bouraoui, A.; Vidal, R. V.; Genêt, J. P.; Ben Hassine, B. C.R. Chim. 2002,
5, 611.
19. Ould Aliyenne, A.; Khiari, J. E.; Kraiem, J.; Kacem, Y.; Ben Hassine, B.
Tetrahedron Lett. 2006, 47, 6405.
20. Ould Aliyenne, A.; Kraiem, J.; Kacem, Y.; Ben Hassine, B. Tetrahedron Lett. 2008,
49, 1473.
21. Kacem, Y.; Ben Hassine, B. Tetrahedron Lett. 2012, 53, 5608.
22. Snieckus, V. Chem. Rev. 1990, 90, 879.
R'
O
O
1) LDA, TMEDA
THF, 0 ° to 25 °C
R
S
N
R'
OEt
N
N
N
R"
2) NH4Cl (aq.)
S
R"
R
O
O
2a-e: R"=H
23. Gschwend, H. W.; Rodriguez, J. R. Org. React. 1979, 26, 1.
24. Snieckus, V. Pure Appl. Chem. 1990, 62, 2047.
3a-e: R"=Me
4a-j
25. Hellwinkel, D.; Karle, R. Synthesis 1989, 394.
Scheme 2.

Y. Kacem, B. B. Hassine / Tetrahedron Letters 54 (2013) 4023–4025
4025
26. Watanabe, H.; Gay, R. L.; Hauser, C. R. J. Org. Chem. 1968, 33, 900.
27. Watanabe, H.; Mao, C.-L.; Barnish, I. T.; Hauser, C. R. J. Org. Chem. 1969, 34, 919.
28. Watanabe, H.; Mao, C.-L.; Hauser, C. R. J. Org. Chem. 1969, 34, 1786.
29. Watanabe, H.; Schwarz, R. A.; Hauser, C. R.; Lewis, J.; Slocum, D. W. Can. J.
Chem. 1969, 47, 1543.
30. Fu, J. M.; Zhao, B. P.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991, 56, 1683.
31. Grey, M.; Chapell, B.; Taylor, N. J.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1996,
35, 1558.
32. Familoni, O. B.; Ionica, I.; Bower, J.; Snieckus, V. Synlett 1997, 1081.
33. Bakker, W. I.; Familoni, O. B.; Padfield, J.; Snieckus, V. Synlett 1997, 1079.
34. Blanchet, J.; Macklin, T.; Ang, P.; Metallinos, C.; Snieckus, V. J. Org. Chem. 2007,
72, 3199.
35. Mongin, F.; Maggi, R.; Schlosser, M. Chimia 1996, 50, 650.
36. Bailey, W. F.; Tao, Y. Tetrahedron Lett. 1997, 38, 6157.
cooled to 0 °C and treated dropwise with a freshly prepared solution of LDA
(2.31 mmol, in 5 mL of THF) precooled to 0 °C. The resulting yellow solution
was stirred at 0 °C for 1.5 h, and then warmed to room temperature and
quenched with saturated aqueous NH4Cl (10 mL). The mixture was
concentrated in vacuo and the aqueous phase extracted with ethyl acetate
(3 ꢀ 20 mL). The organic phase was washed with brine (3 ꢀ 5 mL), dried over
MgSO4 and concentrated in vacuo. The crude residue was purified by column
chromatography on silica gel (30% EtOAc:70% hexane) to afford 85 mg of 4-
methyl-2H-1,2,3-benzothiadiazine 1,1-dioxide (4a). Mp = 179–181 °C; IR
(cmꢁ1): 3220 (NH), 1650 (C@N), 1334 and 1168 (SO2). 1H NMR (300 MHz,
CDCl3): d 2.38 (s, 3H, N@C–CH3), 7.84–7.99 (m, 4H, ArH), 11.36 (s, 1H, NH). 13
C
NMR (75 MHz, CDCl3): d = 20.25, 122.37, 127.88, 128.24, 132.04, 132.44,
133.66, 150.21. HRMS (ES) found MH+ m/z = 197.0519, C8H9N2O2S requires
197.0511.
37. Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
39. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 29.
40. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
41. Whistler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004,
43, 2206.
38. Typical cyclization procedure: A flame-dried, argon-flushed, round-bottomed
flask containing a solution of ethyl N1-phenylsulfonyl acetohydrazonate (2a)
(172 mg, 0.71 mmol) and TMEDA (0.32 mL, 2.31 mmol) in THF (10 mL) was