Synthesis of 3-amino-1,2,4-benzothiadiazine 1,1-dioxides via a tandem aza-Wittig/heterocumulene annulation

Article abstract of DOI:10.1021/jo051843h

Reaction of o-azidobenzenesulfonamides with polymer-supported triphenylphosphine affords the corresponding iminophosphoranes. Subsequent reaction with isocyanates gives 3-amino-1,2,4-benzothiadiazine 1,1-dioxides in high yields and purities. The reaction

Full text of DOI:10.1021/jo051843h

Synthesis of 3-Amino-1,2,4-benzothiadi-
azine 1,1-Dioxides via a Tandem
Aza-Wittig/Heterocumulene Annulation
Christopher Blackburn,* Abe Achab, Amy Elder,
Shomir Ghosh, Jianping Guo, Geraldine Harriman, and
Matthew Jones
Department of Medicinal Chemistry,
Millennium Pharmaceuticals, 35 Landsdowne Street,
Cambridge, Massachusetts 02139
FIGURE 1. Typical syntheses of 3-amino-1,2,4-benzothiadi-
azine 1,1-dioxides.
chris.blackburn@mpi.com
Received August 31, 2005
FIGURE 2. Synthesis of quinazolinones via intramolecular
aza-Wittig reaction.
tion of the resultant iminophosphoranes with isocyanates
in an aza-Wittig reaction14 affording the desired 6 via
cyclization of the diimide intermediate.
Reaction of o-azidobenzenesulfonamides with polymer-sup-
ported triphenylphosphine affords the corresponding imi-
nophosphoranes. Subsequent reaction with isocyanates gives
3-amino-1,2,4-benzothiadiazine 1,1-dioxides in high yields
and purities. The reaction has been successfully applied to
the synthesis of derivatives with various substituents at the
2- and 3-positions and in the benzenoid ring.
Recently, iminophosphoranes have been prepared from
polymer-supported triphenylphosphine by reaction with
an o-aminobenzamide11 in the presence of C2Br2Cl4 (Kir-
sanov conditions) or, in our own laboratories, by reaction
with an o-azidobenzamide.12 In each case, subsequent re-
action with isocyanates at elevated temperatures re-
leased quinazolinones 6 into solution. The high yields we
achieved in this reaction12 (Figure 2) prompted us to
investigate analogous transformations starting from the
corresponding o-azidosulfonamides, which we report
herein, leads to a short and high yield route to 5. In addi-
tion, we show that primary sulfonamides undergo the
same reaction opening up a new route to compounds of
type 1.
Sulfonamides bearing an o-azido group were prepared
beginning with the diazotization of the appropriate
orthanilic acid derivative followed by reaction with
sodium azide to give sulfonic acids 7a-c. Conversion to
the corresponding sulfonyl chlorides 8a-c by treatment
with oxalyl chloride followed by reaction with the ap-
propriate amines gave the requisite sulfonamides 9-11
(Scheme 1).15 To simplify isolation, we investigated
iminophosphorane formation using commercially avail-
3-Amino-1,2,4-benzothiadiazine 1,1-dioxides, which have
been shown1 to exist predominantly in the tauto-
meric form 1, possess diverse biological activities includ-
ing potassium1-4 and calcium channel5 modulation and
adrenergic antagonism6 effects. These compounds are
typically prepared (Figure 1) by reaction of amines with
thioethers 2 or their sulfone derivatives. The thioethers
2 are obtained either by cyclization of a chlorosulfonyl-
thiourea or by reaction of o-aminobenzenesulfonamides
3 (R2 ) H) with CS2 (or an equivalent reagent) followed
by methylation.4-6 2-N-Alkyl derivatives 5 can only be
accessed by this second route from 3 (R2 ) alkyl) because
reaction of 2 with alkylating agents takes place at the
4-position.3 Hence, analogues 5 are quite rare despite
their isosteric relationship to the well studied quinazoli-
none system 6.7-12 The synthetic route to compound class
6 introduced by Molina8 and subsequently used by
Eguchi9 entails a Staudinger reaction13 of o-azidoaryl-
carboxamides with triphenyphosphine followed by reac-
(7) (a) Ding, M. W.; Zeng, G. P.; Wu, T. J. Synth. Commun. 2000,
30, 1599. (b) Okawa, T.; Eguchi, S. Synlett 1994, 555. (c) Villalgordo,
J. M.; Obrecht, D.; Chucholowsky, A. Synlett 1998, 1405.
(8) (a) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1988,
29, 3849. (b) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron 1989, 45,
4263.
* To whom correspondence should be addressed. Tel: +1-617-761-
6811. Fax: +1-617-444-1483.
(9) Okawa, T.; Kawase, M.; Eguchi, S.; Kakehi, A.; Shiro, M. J.
Chem. Soc., Perkin Trans. 1 1998, 15, 2277.
(1) de Tullio, P.; Ouedraogo, R.; Dupont, L.; Somers, F.; Boverie, S.;
Dogne, J. M.; Delarge, J.; Pirotte, B. Tetrahedron 1999, 55, 5419.
(2) de Tullio, P.; Pirotte, B.; Lebrun, P.; Fontaine, J.; Dupont, L.;
Antoine, M. H.; Ouedraogo, R.; Khlelili, S.; Maggetto, C.; Masereel,
B.; Diouf, O.; Podona, T.; Delarge, J. J. Med. Chem. 1996, 39, 937.
(3) de Tullio, P.; Becker, B.; Boverie, S.; Dabrowski, M.; Wahl, P.;
Antoine, M. H.; Somers, F.; Sebille, S.; Ouedraogo, R.; Hansen, J. B.;
Lebrun, P.; Pirotte, B. J. Med. Chem. 2003, 46, 3342.
(10) Makino, S.; Okuzumi, T.; Tsugi, T.; Nakanishi, E. J. Comb.
Chem. 2003, 5, 756.
(11) Zhang, W.; Mayer, J. P.; Hall, S. E.; Weigel, J. A. J. Comb.
Chem. 2001, 3, 255.
(12) Jones, M.; Ghosh, S.; Elder, A.; Achab, A.; Guo, J.; Mani, U.;
Blackburn, C.; Harriman, G. Abstracts of Papers. 228th ACS National
Meeting, Philadelphia, August 2004; American Chemical Society:
Washington, DC, 2004; ORGN-697.
(4) Peat, A. J.; Townsend, C.; Worley, J. F.; Allen, S. H.; Garrido,
D.; Mertz, R. J.; Pgohl, J. L.; Terry, C. M.; Traux, J. F.; Veasey, R. L.;
Thomson, S. A. Bioorg. Med. Chem. Lett. 2002, 12, 2977.
(5) Ouedraogo, R.; Becker, B.; Boverie, S.; Somers, F.; Antoine, M.
H.; Pirotte, B.; Lebrun, P.; de Tullio, P. Biol. Chem. 2002, 383, 1759.
(6) Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.;
Yen, M. H.; Chien, S. L.; Rong, J. K. J. Med. Chem. 1998, 41, 3128.
(13) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
(14) a) Scriven, E. F. V. Chem. Rev. 1988, 88, 297. (b) Molina, P.;
Vilaplana, M. J. Synthesis 1994, 1192. (c) Wahrnhoff, H.; Richardt,
G.; Stolben, S. Adv. Heterocycl. Chem. 1995, 159. (d) Drewry, D. H.;
Gerritz, S. W.; Linn, J. A. Tetrahedron Lett. 1997, 38, 3377. (e) Wang,
F.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 8651.
10.1021/jo051843h CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
10206
J. Org. Chem. 2005, 70, 10206-10209

TABLE 1. Synthesis of
SCHEME 1. Synthesis of 2-N-Alkyl-3-amino-1,2,4-
benzothiadiazine 1,1-Dioxidesa
3-N-Alkylamino-1,2,4-benzothiadiazine 1,1-Dioxides from
Polymer-Supported Iminophosphoranes and Isocyanates
a Reagents and conditions: (a) (i) NaNO2, H2SO4, 0 °C, (ii) NaN3,
25 °C, 16 h; (b) (COCl)2, DMF, CH2Cl2, reflux, 2 h; (c) R3NH2,
DIEA, CH2Cl2, 25 °C; (d) PS-PPh2, CH2Cl2, 25 °C, 16 h; (e) R3NCO,
C2H4Cl2, 80 °C, 8 h.
able polymer-supported triphenylphosphine (loading 1.5
mmol/g). Treatment of o-azidosulfonamide 9a with poly-
mer-supported triphenylphosphine led to nitrogen evolu-
tion with formation of the corresponding polymer-bound
iminophosphorane 12.
Subsequent treatment with n-butylisocyanate in re-
fluxing dichloroethane afforded 5a in good yield (Table
1, entry 1) and analytical purity after filtration through
a plug of silica gel. Somewhat lower yields of 5b and 5c
were obtained by reaction of 12 with arylisocyanates
(Table 1, entries 2 and 3) but the sulfonylisocyanate
(entry 4) afforded 5d in high yield and purity. Azides 9b
and 9c derived from less hindered N-benzyl- and N-
alkylsulfonamides also afforded polymer-supported imi-
nophosphoranes 13 and 14, respectively, which on treat-
ment with the same isocyanates gave the corresponding
heterocycles 5e-k in generally higher yields than the
isopropyl derivatives (Table 1, entries 5 to 10). Spectro-
scopic data for all compounds were in accord with
structure 5 including the observation of coupling between
the protons of the alpha methylene group and the NH of
the 3-n-butylamino derivatives. Derivatives with sub-
stituents in the benzenoid ring could also be accessed.
Thus, azides 10 and 11 readily formed supported imino-
phosphoranes 15 and 16 which afforded 5l-p on reaction
with isocyanates or sulfonyl isocyanates (Table 1).
This synthesis could also be adapted to the preparation
of analogues that are unsubstituted at the 2-nitrogen
atom (Scheme 2). Thus, azides 1716 bearing ortho primary
sulfonamide groups formed the corresponding polymer-
supported iminophosphoranes 18 on reaction with poly-
mer supported triphenylphosphine; subsequent reaction
with isocyanates afforded 1a-e in good to moderate
yields. This reaction contrasts that of the corresponding
primary carboxamides which do not afford the quinazoli-
nones but rather give nitriles arising from cyclization of
the carbonyl oxygen onto the diimide followed by ring
opening.8
a Isolated yield of pure product calculated over two steps.
SCHEME 2. Synthesis of
3-Amino-1,2,4-benzothiadiazine 1,1-Dioxidesa
a Reagents and conditions: (a) 2 M NH3 in MeOH, CH2Cl2, 25
°C; (b) PS-PPh2, CH2Cl2, THF, 25 °C, 24 h; (c) R3NCO, THF,
C2H4Cl2, 80 °C, 16 h.
(15) Saeed, A.; Rama, N. H. J. Chem. Soc. Pak. 1997, 19, 236.
(16) Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou,
C. Tetrahedron Lett. 2000, 41, 10107.
In summary, we have shown that reaction of o-azidoben-
zenesulfonamides with polymer-supported triphenylphos-
J. Org. Chem, Vol. 70, No. 24, 2005 10207

The crude product was filtered over a plug of silica gel eluting
with 50% ethyl acetate in hexane and the solvent evaporated to
give 5a: 63 mg (65%); colorless oil; IR (neat) νmax 3371, 1613
phine affords iminophosphoranes that undergo a tandem
aza-Wittig heterocummulene annulation with isocyan-
ates or sulfonylisocyanates releasing 3-amino-1,2,4-ben-
zothiadiazine 1,1-dioxides into solution in good yields.
1
cm-1; H NMR (400 MHz, CD3OD, 25 °C) δ 7.65 (dd, J ) 9 Hz,
J ) 3 Hz, 1H), 7.53 (t, 1H) 7.24 (d, J ) 9 Hz, 1H), 7.18 (dd, J )
9 Hz, J ) 3 Hz, 1H), 4.19 (m, 1H), 3.44 (m, 2H), 1.67 (m, 2H),
1.46 (m, 2H), 1.20 (d, J ) 7 Hz, 6H), 0.98 (t, 3H); 13C NMR (100
MHz, CD3OD, 25 °C) δ 152.9, 146.6, 134.5, 128.2, 126.4, 123.0,
122.6, 55.6, 42.6, 32.4, 22.2, 21.4, 14.2; HRMS (ESI+) calcd for
Experimental Section:
General Considerations and Synthesis of 2-Azidoben-
zenesulfonic Acids 7a-c. See the Supporting Information.
General Procedure for the Synthesis of 2-Azido-N-
benzylbenzenesulfonamide (9b). To a suspension of 2-azi-
dobenzenesulfonic acid 7a (0.225 g, 1.13 mmol) in dichlo-
romethane (10 mL) were added 2 M oxalyl chloride in CH2Cl2
(2.83 mmol) and DMF (50 µL). The resulting mixture was heated
under reflux for 3 h and then evaporated under reduced
pressure. The residue (IR: νmax 2125 cm-1) was dissolved in
dichloromethane (10 mL), treated with DIEA (0.39 mL, 2.26
mmol) and benzylamine (0.18 mL, 1.7 mmol, 1.5 equiv), and
stirred at ambient temperature for 6 h and then washed with 1
N HCl followed by water and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue subjected to
chromatography on silica gel eluting with a hexanes-ethyl
acetate gradient from 15% ethyl acetate to 60% ethyl acetate to
give 9b 0.257 g (79%) as a light tan solid: mp 80-82 °C (lit.15
C
14H21N3O2S + H, 296.1433, found 296.1443.
2-N-Isopropyl-3-phenylamino-2H-1,2,4-benzothiadi-
azine 1,1-dioxide (5b) was purified by preparative TLC on
neutral alumina eluting with 20% ethyl acetate in hexane. The
major UV-active band was extracted with ethyl acetate and the
solvent evaporated to give 5b: 46%; white solid; mp 119-122
°C; IR (neat) νmax 3363, 2924, 1608 cm-1 1H NMR (400 MHz,
;
CD3OD, 25 °C) δ 7.75 (d, J ) 8 Hz, 1H), 7.66 (m, 3H), 7.40-
7.32 (m, 4H), 7.22 (t, 1H), 4.29 (m, 1H), 1.25 (d, J ) 7 Hz, 6H);
13C NMR (100 MHz, CD3OD, 25 °C) δ 150.5 (br), 145.3 (br), 140.5
(br), 134.8, 130.5 (br), 130.1, 126.8 (br), 125.4, 125.1, 122.7, 122.2,
56.9, 22.2; HRMS calcd for C16H17N3O2S + H, 316.1120, found
316.1131.
2-N-Isopropyl-3-(3-fluoro-4-methylphenylamino)-2H-1,2,4-
benzothiadiazine 1,1-dioxide (5c) was purified as described
for 5b: 40%; white solid; mp 111-114 °C; 1H NMR (400 MHz,
CD3OD, 25 °C) δ 7.74 (d, 1H), 7.62 (m, 2H), 7.39-7.29 (m, 3H),
7.19 (1H, t), 4.23 (1H, m), 2.24 (3H, s), 1.22 (6H, d); 13C NMR
(100 MHz, CD3OD, 25 °C) δ 162.5, 150.1, 145.4, 134.8, 132.5,
130.3, 127.0, 125.6, 122.8, 121.0, 117.2, 108.7, 57.0, 22.2, 14.0;
HRMS calcd for C17H18FN3O2S + H 348.1182, found 348.1196.
2-N-Isopropyl-3-(4-fluorophenylsulfonylamino)-2H-1,2,4-
benzothiadiazine 1,1-dioxide (5d) was purified as described
for 5a: 70%; white solid; mp 128-130 °C; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 10.76 (br, 1H), 7.95 (m, 2H), 7.81 (d, 1H), 7.69
(t, 1H), 7.36 (t, 1H), 7.20 (m, 3H), 4.95 (m, 1H), 1.47 (d, J ) 7
Hz, 6H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 165.7, 149.5, 138.6,
135.3, 134.0, 129.6, 125.9, 125.7, 123.0, 118.6, 117.0, 116.8, 51.8,
50.3; HRMS calcd for C16H16FN3O4S2 + H 398.0645, found
398.0661.
2-N-Benzyl-3-n-butylamino-2H-1,2,4-benzothiadiazine 1,1-
dioxide (5e) was purified as described for 5a: 76%; white solid;,
mp 87-88 °C; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.79 (dd, 1H),
7.52 (dd, 1H), 7.36 (m, 5H), 7.32 (d, 1H), 7.18, (t, 1H), 4.94, (s,
2H), 4.61 (br, 1H), 3.34 (br, 2H), 1.37 (m, 2H), 1.15 (m, 2H), 0.82
(t, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 149.9, 145.0, 136.1,
134.1, 130.0, 129.1, 127.9, 126.7, 126.6, 123.4, 121.9, 49.5, 42.2,
31.6, 20.5, 14.3; HRMS calcd for C18H21N3O2S + H 344.1433,
found 344.1435.
2-N-Benzyl-3-(3-fluoro-4-methylphenylamino)-2H-1,2,4-
benzothiadiazine 1,1-dioxide (5f) was purified as described
for 5b: 63%; white solid; mp 137-138 °C; 1H NMR (400 MHz,
CD3OD, 25 °C) δ 7.76 (d, J ) 9 Hz, 1H), 7.53 (t, 1H), 7.44-7.00
(m, 8H), 6.83 (m, 2H), 5.12 (m, 2H), 2.18 (s, 3H); 13C NMR (100
MHz, CD3OD, 25 °C) 162.4, 148.7, 144.7, 139.7, 136.0, 134.6,
132.6, 129.7, 129.5, 129.2, 129.0, 127.0, 125.4, 122.3, 120.8, 117.0,
108.6, 108.3, 51.7, 14.0; HRMS calcd for C21H18FN3O2S + H
396.1182, found 396.1193.
2-N-Benzyl-3-(4-fluorophenylsulfonylamino)-2H-1,2,4-
benzothiadiazine 1,1-dioxide (5g) was purified as described
for 5b: 75%; white solid; mp 183-185 °C; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 10.76 (s, 1H), 7.94 (d, 1H), 7.70 (m, 2H), 7.40 (t,
1H), 7.15 (m, 9H), 5.14 (s, 2H); 13C NMR (100 MHz, CDCl3, 25
°C) 165.6, 149.3, 138.2, 135.7, 135.6, 133.6, 131.5, 129.6, 129.5,
129.1, 129.0, 128.6, 126.1, 124.6, 123.5, 118.7, 116.80, 116.6, 46.3;
HRMS calcd for C20H16FN3O4S2 + H 446.0639, found 446.0633.
2-N-(2-Methoxyethyl)-3-n-butylamino-2H-1,2,4-benzo-
thiadiazine 1,1-dioxide (5h) was prepared and purified as
described for 5a: 61%; colorless oil; 1H NMR (300 MHz, CDCl3,
25 °C) δ 7.70 (d, 1H), 7.50 (t, 1H), 7.40 (d, 1H), 7.16 (t, 1H), 6.92
(br, 1H), 3.96 (t, 2H), 3.80 (t, 2H), 3.50 (m, 5H), 1.60 (m, 2H),
1.42 (m, 2H), 0.96 (t, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
134.5, 126.7, 125.3, 124.2, 121.6, 74.1, 60.1, 48.0, 43.3, 31.7, 20.6,
14.4; HRMS calcd for C14H21N3O3S + H 312.1376, found
312.1367.
mp 78-79 °C); IR (neat) νmax 3290, 2107 cm-1 1H NMR (400
;
MHz, CDCl3) δ 8.00 (d, 1H), 7.55 (t, 1H), 7.30-7.14 (m, 7H),
5.26 (m, 1H), 4.11 (d, 2H); 13C NMR (100, MHz, CDCl3) δ 138.2,
136.6, 134.6, 131.3, 130.6, 129.2, 128.6, 128.5, 125.5, 119.9, 48.3.
2-Azido-N-isopropylbenzenesulfonamide (9a): 90%; white
solid; mp 106-109 °C; IR (neat) νmax 3292, 2134, 2100 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 7.92 (d, J ) 9 Hz, 1H), 7.52 (dd, J )
9 Hz, J ) 9 Hz, 1H), 7.20 (m, 2H), 4.82 (m, 1H), 3.37 (m, 1H),
1.02 (d, 6H); 13C NMR (100, MHz, CDCl3) δ 138.1, 134.4, 131.9,
131.0, 125.5, 120.1, 47.1, 24.2; MS (ESI-) 239 (M - H+).
2-Azido-N-(2-methoxyethyl)benzenesulfonamide (9c):
75%; oil; IR (neat) νmax 3307, 2131, 2101 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.90 (d, J ) 9 Hz, 1H), 7.52 (dd, J ) 9 Hz, J ) 9 Hz,
1H), 7.20 (m, 2H), 5.42 (br, 1H), 3.30 (t, 2H), 3.20 (s, 3H), 3.02
(t, 2H); 13C NMR (CDCl3, 100 MHz) δ 138.4, 134.6, 131.2, 130.6,
125.4, 120.0, 70.9, 59.5, 43.9; MS (ESI-) 255 (M - H+).
2-Azido-5-methoxy-N-(2-methoxyethyl)benzenesulfon-
1
amide (10): 65%; oil; IR (neat) νmax 3305, 2122 cm-1; H NMR
(CDCl3, 300 MHz) δ 7.46 (d, J ) 3 Hz, 1H), 7.20 (d, J ) 9 Hz,
1H), 7.12 (d, J ) 9 Hz, 1H), 5.52 (t, 1H), 3.83 (s, 3H), 3.37 (t,
2H), 3.34 (s, 3H), 3.07 (t, 2H); 13C NMR (CDCl3, 100 MHz) δ
157.1, 131.0, 130.3, 121.3, 120.8, 115.4, 70.8, 59.4, 56.6, 43.8;
ESI-MS 285 (M - H)-.
2-Azido-4-chloro-N-(2-methoxyethyl)-5-methylbenzene-
sulfonamide (11): 75%; white solid; mp 104-106 °C; IR (neat)
νmax 3299, 2133 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.82 (s, 1H),
7.30 (s, 1H), 5.42 (br, 1H), 3.40 (t, 2H), 3.29 (s, 3H), 3.07 (t,
2H), 2.39 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 140.5, 136.8,
133.9, 133.0, 128.8, 120.1, 70.9, 59.5, 43.9, 20.1; MS (ESI-) 303
(M - H+).
General Procedure for Synthesis of 2-N-Alkyl-3-ami-
no-1,2,4-benzothiadiazine 1,1-Dioxides 5. 2-N-Isopropyl-
3-n-butylamino-1,2,4-benzothiadiazine 1,1-Dioxide 5a. Tri-
phenylphosphine resin (220 mg, 0.33 mmol) was washed with
several times with anhydrous THF followed by anhydrous
dichloromethane and treated with a solution of 9a (80 mg, 0.33
mmol) in dichloromethane (1.5 mL), resulting in evolution of
nitrogen gas. The reaction mixture was shaken at ambient tem-
perature for 16 h and then filtered and washed with dichloro-
methane and dichloroethane. The resin was then resuspended
in dichloroethane (1.5 mL), treated with n-butyl isocyanate (30
mg, 34 uL, 0.30 mmol, 0.9 equiv), and heated in a sealed vial at
80 °C for 16 h. The solvent was decanted and the resin
resuspended in dichloroethane and treated with further n-butyl
isocyanate (0.3 equiv) at 80 °C for 8 h. This procedure improved
the yield of the title compound while minimizing further reaction
of the product with the isocyanate. The resin was filtered and
washed thoroughly with dichloromethane (12 × 4 mL), and the
combined filtrates were treated with polystyrene trisamine resin
(3 equiv) and allowed to stand for 3 h at ambient temperature.
10208 J. Org. Chem., Vol. 70, No. 24, 2005

2-N-(2-methoxyethyl)-3-phenylamino-2H-1,2,4-benzo-
thiadiazine 1,1-dioxide (5i) was prepared and purified as
described for 5b: 85%; white solid; mp 108-110 °C; 1H NMR
(400 MHz, CDCl3, 25 °C) δ 7.80 (d, 1H), 7.64-7.26 (m, 7H), 7.15
(t, 1H), 4.02 (t, 2H), 3.82 (t, 2H), 3.56 (s, 3H); 13C NMR (100
MHz, CDCl3, 25 °C) δ 148.4, 143.5, 138.6, 134.3, 129.9, 129.9,
127.6, 125.9, 125.9, 125.0, 124.8, 121.7, 121.0, 73.6, 60.1, 48.1;
HRMS calcd for C16H17N3O3S + H 332.1069, found 332.1081.
2-N-(2-methoxyethyl)-3-(3-fluoro-4-methylphenylamino)-
2H-1,2,4-benzothiadiazine 1,1-dioxide (5j) was purified as
described for 5b: 72%; white solid; mp 117-119 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ 9.05 (br, 1H), 7.78 (d, 1H), 7.60 (m,
2H), 7.48 (d, 1H), 7.27 (t, 1H), 7.12 (m, 2H), 4.00 (t, 2H), 3.86 (t,
2H), 3.60 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3, 25
°C) δ 161.8 (d, J ) 234 Hz), 146.9, 144.4, 138.4, 134.1, 131.9,
127.7, 127.1, 124.4, 121.5, 120.3, 115.6, 107.9, 74.5, 60.3, 47.9,
14.7; HRMS calcd for C17H18FN3O3S + H 364.1131, found
364.1146.
2-N-(2-Methoxyethyl)-3-(4-fluorophenylsulfonylamino)-
2H-1,2,4-benzothiadiazine 1,1-dioxide (5k) was purified as
described for 5a: 73%; white solid; mp 133-134 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ 10.80 (s, 1H), 7.98 (m, 2H), 7.86 (d,
1H), 7.70 (t, 1H), 7.42 (t, 1H), 7.20 (m, 3H), 4.16 (t, 2H), 3.56 (t,
2H), 3.22 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 165.7,
149.9, 138.4, 135.4, 133.8, 129.7, 126.1, 124.9, 123.2, 118.8, 117.0,
116.7, 70.0, 59.3, 43.0; HRMS calcd for C16H16FN3O5S2 + H
414.0588, found 414.0586.
2-N-(2-Methoxyethyl)-3-n-butylamino-7-methoxy-2H-1,2,4-
benzothiadiazine 1,1-dioxide (5l) was purified as described
for 5a: 71%; white solid; mp 86-89 °C; 1H NMR (300 MHz,
CDCl3, 25 °C) δ 7.23 (d, J ) 10 Hz, 1H), 7.08 (dd, J ) 10 Hz, 3
Hz, 1H), 6.61 (br, 1H), 3.91 (t, 3H), 3.82 (s, 2H), 3.78 (t, 3H),
3.48 (s, 3H), 3.40 (d of t, 2H), 1.60 (m, 2H), 1.42 (m, 2H), 0.96 (t,
3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 155.6, 149.4, 139.3,
127.9, 126.7, 122.4, 103.7, 74.5, 60.0, 56.5, 47.4, 42.0, 31.9, 20.7,
14.5; HRMS calcd for C15H23FN3O4S + H 342.1482, found
342.1480.
2-N-(2-Methoxyethyl)-3-(3-fluoro-4-methylphenyl)-7-meth-
oxy-2H-1,2,4-benzothiadiazine 1,1-dioxide (5m) was purified
as described for 5b: 54%; white solid; mp 128 °C; 1H NMR (300
MHz, CDCl3, 25 °C) δ 9.00 (br, 1H), 7.62 (d, 1H), 7.42 (d, 1H),
7.23-7.05 (m, 4H), 4.00 (t, 2H), 3.89 (t, 3H), 3.88 (s, 3H), 3.65
(s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 161.9
(d, J ) 242 Hz), 156.8, 145.7, 138.7, 137.8, 131.9, 128.5, 127.7,
122.3, 119.9 (d, J ) 17 Hz), 115.4, 107.4 (d, J ) 27 Hz), 103.9,
74.5, 60.3, 56.6, 47.9, 14.7; HRMS calcd for C18H20FN3O4S + H
394.1237, found 394.1249.
2-N-(2-Methoxyethyl)-3-(4-fluorophenylsulfonyl)-7-meth-
oxy-2H-1,2,4-benzothiadiazine 1,1-dioxide (5n) was purified
as described for 5a: 66%; white solid; mp 196-198 °C; 1H NMR
(300 MHz, CDCl3, 25 °C) δ 10.64 (s, 1H), 7.96 (d, 1H), 7.30-
7.16 (m, 6H), 4.14 (t, 2H), 3.92 (s, 3H), 3.56 (t, 2H), 3.22 (s, 3H);
13C NMR (100 Hz, CDCl3, 25 °C) δ 165.5 (d, J ) 253 Hz), 157.7,
149.7, 138.6, 129.6, 127.0, 125.5, 123.3, 120.3, 116.9, 105.7, 70.1,
59.4, 56.8, 43.0; HRMS calcd for C17H18FN3O6S2 + H 444.0699,
found 444.0709.
2-N-(2-Methoxyethyl)-3-(3-fluoro-4-methylphenyl)-6-chlo-
ro-7-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (5o) was
purified as described for 5b: 45%; white solid; mp 190-191 °C;
1H NMR (300 MHz, CDCl3, 25 °C) δ 9.10 (br, 1H), 7.62 (m, 2H),
7.58 (s, 1H), 7.10 (m, 2H), 4.00 (t, 2H), 3.86 (t, 2H), 3.62 (s, 3H),
2.43 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) δ
161.8 (d, J ) 234 Hz), 147.9, 142.9, 140.5, 133.2, 132.2, 132.1,
126.8, 126.0, 123.0, 120.6, 120.2, 115.8, 107.9 (d, J ) 28 Hz),
74.2, 60.3, 48.1, 20.4, 14.8; HRMS calcd for C18H19ClFN3O3S +
H 412.0898, found 412.0901.
2-N-(2-methoxyethyl)-3-(4-fluorophenylsulfonyl)-6-chloro-
7-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (5p) was
purified as described for 5a: 80%; white solid; mp 160-165 °C;
1H NMR (300 MHz, CDCl3, 25 °C) δ 10.70 (br, 1H), 7.96 (m, 2H),
7.69 (s, 1H), 7.32 (s, 1H), 7.20 (m, 2H), 5.11 (m, br, 1H), 4.09 (t,
2H), 3.50 (t, 2H), 3.20 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 165.8 (d, J ) 255 Hz), 149.7, 141.9, 138.8, 138.2,
135.0, 132.4, 129.8, 124.6, 123.2, 119.3, 117.0, 69.9, 59.3, 43.1,
20.4; HRMS calcd for C17H17ClFN3O5S2 + H 462.0360, found
462.0370.
2-Azidobenzenesulfonamide 17a.16 2-Azidobenzenesulfonyl
chloride (0.65 g, 3 mmol) in dichloromethane (20 mL) was treated
dropwise with 0.5 M NH3 in dioxane (20 mL) and stirred at
ambient temperature for 3 h. The mixture was evaporated to
dryness, dissolved in ethyl acetate, and filtered through a short
silica gel column washing with ethyl acetate. Evaporation of the
solvent afforded 19a (0.54 g, 81%) as a white solid: mp 175-
177 °C dec; 1H NMR (300 MHz, CD3OD) δ: 7.93 (d, 1H), 7.64 (t,
1H), 7.46 (d, 1H), 7.29 (t, 1H), 4.88 (s, 2H).
2-Azido-4-chloro-5-methylbenzenesulfonamide 17b was
prepared from 8c and purified as described for 17a: 75%; white
1
solid; mp 180-182 °C dec; IR (neat) νmax 3270, 2125 cm-1; H
NMR (400 MHz, CD3OD) δ: 7.82 (s, 1H), 7.47 (s, 1H), 2.39 (s,
3H); MS (ESI-) 245 (M - H+).
3-n-Butylamino-1,2,4-benzothiadiazine 1,1-dioxide (1a)
was prepared as described for 5a except that the resin capture
and aza-Wittig reactions were conducted in dichloromethane-
THF (1:4) and dichloroethane-THF (1:1), respectively. The
reaction solvent was evaporated and the product triturated with
ether to give 1a: 85%; white solid; mp 175-176 °C; IR (neat)
1
νmax 3298, 3184, 3114, 1626 cm-1; H NMR (400 MHz, CD3OD,
25 °C) δ 7.74 (dd, 1H), 7.54 (t, 1H), 7.27 (t, 1H), 7.10 (d, 1H),
3.34 (dt, 2H), 1.59 (m, 2H), 0.96 (t, 3H); 13C NMR (100 MHz,
CD3OD, 25 °C) δ 153.1, 137.4, 133.9, 125.2, 124.3, 123.5, 117.4,
41.9, 32.5, 21.0, 14.1; HRMS calcd for C11H15N3O2S + H
254.0963, found 254.0976.
3-(3-Fluoro-4-methylphenylamino)-2H-1,2,4-benzothia-
diazine 1,1-Dioxide (1b). Following the solid-supported aza-
Wittig reaction, the reaction mixture was filtered and the white
solid occluded in the resin was dissolved in DMSO and subjected
to preparative reverse-phase chromatography (see the Support-
ing Information) to give 1b (65%): white solid; mp 325-330 °C;
1H NMR (400 MHz, DMSO-d6, 25 °C) δ 9.50 (br, 1H), 7.70 (d,
1H), 7.59 (t, 1H), 7.40 (dd, 1H), 7.32-7.23 (m, 3H), 7.15 (dd,
1H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ 160.2,
(d, J ) 240 Hz), 148.0, 137.0, 135.8, 132.6, 131.6, 131.5, 124.2,
122.9, 122.5, 119.2, 117.4, 116.7, 107.8, (d, J ) 26 Hz), 13.7;
HRMS calcd for C14H12FN3O2S + H 306.0713, found 306.0723.
3-(4-Fluorophenylsulfonylamino)-2H-1,2,4-benzothiadi-
azine 1,1-dioxide (1c) was prepared as described for 1a and
purified by chromatography on silica gel eluting with ethyl
acetate: 45%; white solid; mp 264-266 °C; 1H NMR (THF-d8) δ
9.88 (br, 1H), 8.08 (dd, 2H), 7.70 (d, 1H), 7.39 (t, 1H), 7.10 (m,
4H); 13C NMR (100 MHz, THF-d8, 25 °C) δ 164.0 (d, J ) 248
Hz), 153.1, 141.2, 137.3, 131.6, 129.5, 123.1, 122.2 (d, J ) 8 Hz),
115.8, 114.4 (d, J ) 22 Hz); HRMS calcd for C13H10FN3O4S2 +
H 356.0175, found 356.0188.
3-n-Butylamino-6-chloro-7-methyl-2H-1,2,4-benzothiadi-
azine 1,1-dioxide (1d) was prepared and purified as described
1
for 1a: 55%; white solid; mp 274-275 °C; H NMR (DMSO-d6)
δ 10.49 (br, 1H), 7.67 (s, 1H), 7.25 (br, 2H), 3.20 (m, 2H), 2.32
(s, 3H), 1.49 (m, 2H), 1.32 (m, 2H), 0.92 (t, 6H); 13C NMR (100
MHz, DMSO-d6, 25 °C) δ 150.9, 136.8, 134.8, 131.1, 124.8, 121.5,
116.4, 40.0, 30.8, 19.4, 18.8, 13.6; HRMS calcd for C12H16ClN3O2S
+ H 302.0730, found 302.0271.
6-Chloro-7-methyl-3-(4-fluorophenylsulfonylamino)-2H-
1,2,4-benzothiadiazine 1,1-dioxide (1e) was prepared as
described for 1a and purified by chromatography on silica gel
eluting with ethyl acetate: 45%; white solid; mp 281-283 °C;
1H NMR (400 MHz, CD3OD, 25 °C) δ 8.01 (m, 2H), 7.54 (s, 1H),
7.15 (m, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CD3OD, 25 °C)
δ 165.7, (d, J ) 249 Hz), 154.4, 141.2, 139.4, 137.4, 132.4, 131.3,
(d, J ) 9 Hz), 125.9, 121.4, 117.3, 115.9 (J ) 22 Hz), 19.5; HRMS
calcd for C14H11ClFN3O4S2 + H 403.9942, found 403.9951.
Supporting Information Available: 1H NMR and 13C
NMR spectra of compounds 9-11, 5a-p, and 1a-e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051843H
J. Org. Chem, Vol. 70, No. 24, 2005 10209