Novel Synthesis of N-Methyl-1,2-benzosultams, an Unsuspected Demethylative Intramolecular Cyclization Reaction

Full text of DOI:10.1021/jo971053a

2348
J . Org. Chem. 1998, 63, 2348-2350
Notes
Novel Syn th esis of
N-Meth yl-1,2-ben zosu lta m s, a n
Un su sp ected Dem eth yla tive In tr a m olecu la r
Cycliza tion Rea ction
Chengde Wu*
F igu r e 1.
Texas Biotechnology Corporation, 7000 Fannin,
Suite 1920, Houston, Texas 77030
zenesulfonic acid (6) was converted to the corresponding
sulfonyl chloride 7 rather uneventfully. Compound 7 was
coupled with the bromoisoxazole2 to afford sulfonamide
8.
Received J une 11, 1997
During work on the synthesis of endothelin receptor
antagonists,1-3 we sought to study the structure-activity
relationships of benzene sulfonamides, in particular the
2,5-disubstituted system (Figure 1). To synthesize 2-(di-
methylamino)-5-methylbenzenesulfonamides, we needed
to make 2-(dimethylamino)-4-methylbenzenesulfonyl chlo-
ride (Figure 1).
Typical ways of synthesizing aromatic sulfonyl chlo-
rides are by reacting the sulfonic acid with SOCl2,4
POCl3,5 PCl5,6 PCl5/POCl3,7 or chlorosulfonic acid.8 In our
hands, the PCl5/POCl3 method had been most effective
and appeared to be applicable to aromatic systems
substituted with a dimethylamino group.
We attempted to make the sulfonyl chloride from
commercially available 2-amino-4-methylbenzenesulfonic
acid (Scheme 1). The aniline 1 was dimethylated with
aqueous formaldehyde under catalytic hydrogenation
conditions in essentially quantitative yield, while the
other standard procedures failed on this substrate.9
When this sulfonic acid 2 was heated at 60-80 °C for
4-6 h with phosphorus oxychloride in the presence of
phosphorus pentachloride,10 we did not obtain any of the
desired (dimethylamino)benzenesulfonyl chloride. In-
stead, the dimethylamino group was monodemethylated
and the four-membered-ring sultam 3 was obtained in
good yield. Sultam 3 is insoluble in water and can be
stored at -20 °C for at least 1 week. This demethylation
reaction was not expected because under the same
experimental conditions 5-(dimethylamino)-2-methylben-
We speculated that the following mechanisms might
be operative. The sulfonic acid group of 2 first reacted
with phosphorus pentachloride to give intermediate 13,
which then formed a six-membered ring with the neigh-
boring dimethylamino group with the release of a mol-
ecule of chloromethane (Scheme 2). This intermediate
14 then upon heating extruded phosphorus oxytrichloride
to give the sultam 3. Alternatively, the expected di-
methylamino sulfonyl chloride 15 maybe did form but
underwent an internal nucleophilic attack on the sulfonyl
chloride to produce intermediate 16, which upon dem-
ethylation led to 3. This represents a novel synthesis of
such a four-membered benzosultam, the literature meth-
ods of synthesis being by extrusion of dinitrogen from a
1,1-dioxo-1,2,3,4-thiatriazole formed via intramolecular
capturing of an aromatic diazonium with an ortho sul-
fonamide11,12 or by intramolecular radical cyclization.13
Considering the strain of this four-membered ring
sultam, it is probable that it may be opened by the attack
of a nucleophile. Indeed, when the sultam 3 was treated
with 5-amino-4-chloro-3-methylisoxazole,2 the ring was
opened to give the corresponding sulfonamide 4, which
was fully characterized. To show that this was a general
reaction, we subjected both 2-(dimethylamino)benzene-
sulfonic acid (9) and 2-aminobenzenesulfonic acid (11) to
the cyclization conditions, and the corresponding sultams
10 and 12 were obtained. Compound 10 had essentially
no solubility in water and was quite stable when stored
at -20 °C, while compound 11 was moderately soluble
in warm water but prolonged storage at -20 °C caused
significant decomposition. Sultam 12 could not be coupled
with an amine and was only destroyed.
* To whom correspondence should be addressed. Tel.: (713) 796-
8822. Fax: (713) 796-8232. E-mail: cwu@tbc.com.
(1) Wu, C.; Chan, M. F.; Stavros, F.; Raju, B.; Okun, I.; Mong, S.;
Keller, K. M.; Brock, T.; Kogan, T. P.; Dixon, R. A. F. J . Med. Chem.
1997, 40(11), 1690-1697.
(2) Wu, C.; Chan, M. F.; Stavros, F.; Raju, B.; Okun, I.; Castillo, R.
S. J . Med. Chem. 1997, 40(11), 1682-1689.
(3) Chan, M. F.; Raju, B.; Kois, A.; Castillo, R. S.; Verner, E. J .; Wu,
C.; Hwang, E.; Okun, I.; Stavros, F.; Balaji, V. N. Bioorg. Med. Chem.
Lett. 1996, 6(20), 2393-2398.
(4) Campbell, R. W.; Hill, H. W. J . Org. Chem. 1973, 38, 1047.
(5) Snyder, H. R.; Heckert, R. E. J . Am. Chem. Soc. 1952, 74, 2006.
(6) Adams, R.; Marvel, C. S. Org. Synth. 1941, 1, 84.
(7) Flelding, H. C.; Shirley, I. M. J . Fluorine Chem. 1992, 59, 15-
31.
(8) Spryskov, A. A.; Apar’Eva, N. A. J . Gen. Chem. USSR (Engl.
Transl.) 1949, 19, 1576.
(9) Procedures tried: NaCNBH3/THF/HCHO, HCHO/HCO2H/reflux,
MeI/K2CO3/THF/MeOH, MeOH/concd H2SO4/sealed tube, or MeI/
NaOH/MeOH/100-110 °C.
(10) Even when the reaction was stirred at room temperature, 3
was the sole product only with lower yield; higher temperature also
gave 3 but with lower purity.
In summary, we have serendipitously discovered a
facile synthesis of benzosultams via a demethylative
cyclization. This sultam ring can be readily opened by
coupling with an amine and functions as a sulfonyl
chloride substitute.
Exp er im en ta l Section
Gen er a l Meth od s. For compounds 3, 10, and 12, melting
points were determined using a Fisher-J ohns hot-stage ap-
paratus and are uncorrected. Proton NMR (1H NMR) spectra
(11) Ao. M. S.; Burgess, E. M. J . Am. Chem. Soc. 1971, 93, 5298.
(12) Ege, G.; Beisiegel, E. J ustus Liebigs Ann. Chem. 1972, 763, 46.
(13) Nikishin, G. I.; Troyansky, E. I.; Lazareva, M. I. Tetrahedron
1985, 41, 4279.
S0022-3263(97)01053-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/05/1998

Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2349
Sch em e 1
Sch em e 2
were recorded on a J EOL 400 MHz spectrometer. Elemental
analyses were performed by Oneida Research Services, Inc.
(Whitesboro, NY) and were within 0.4% of theoretical values
unless otherwise indicated. For descriptions of analytical
instruments for other compounds, spectral data formats, and
standard calibrations, see ref 1.
2-(Dim et h yla m in o)-5-m et h ylb en zen esu lfon ic Acid (2).
To a suspension of 1 (10 g, 53.4 mmol) in methanol (100 mL)
was added formaldehyde (17 mL, 37% in water, 213.7 mmol).
The mixture was subjected to catalytic hydrogenation conditions
(Pd/C, 40 psi) overnight. The solids were filtered off, and the
filtrate was concentrated to give 2 as a white powder (8.94 g,
78% yield): mp 220 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (s,
1H), 7.37 (m, 2H), 3.42 (s, 6H), 2.42 (s, 3H). Anal. Calcd for
C9H13NO3S: C, 50.22; H, 6.09; N, 6.51. Found: C, 49.84; H,
6.12; N, 6.46.
N-5-Dim eth yl-1,2-ben zosu lta m (3). To a suspension of 2
(8.94 g, 41.6 mmol) in POCl3 (50 mL) was slowly added PCl5 (44
g, 213.6 mmol). The resulting mixture was heated at 70 °C for
5 h before it was allowed to cool to room temperature and poured
onto crushed ice. The icy aqueous mixture was stirred vigorously
at 0 °C for 40 min, and the resulting yellow precipitate was
filtered, washed with water and dried on lyopholyzer. This
material was chromatographed (10% CH2Cl2 in hexanes) to give
3 as a bright yellow solid (3.8 g, 49% yield): mp 68-69 °C; Rf )
0.45 in 10% CH2Cl2 in hexanes; 1H NMR (400 MHz, CDCl3) δ

2350 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
7.59 (d, 1H, J ) 1.6 Hz), 7.34 (dd, 1H, J ) 8.6, 1.6 Hz), 6.71 (d,
1H, J ) 8.6 Hz), 2.97 (s, 3H), 2.27 (s, 3H); 13C NMR (400 MHz,
CDCl3) δ 145.66, 138.98, 129.11, 125.23, 124.94, 112.90, 29.76
(NCH3), 19.40 (ArCH3); HRMS for C8H10NO2S (M + H)+ calcd
184.0432, found 184.0449.
It should be noted that if this procedure is followed, a violent
exotherm may result depending on the amount of ice present.
A safer method for quenching these quantities of POCl3 is to
add the reaction mixture slowly to warm water (35-45 °C) with
good agitation, thus hydrolyzing the POCl3 almost instanta-
neously.
3-methylisoxazole and 7 were used in place of 4-chloro-5-amino-
3-methylisoxazole and 3, respectively. Compound 8 was obtained
as a white powder (76 mg, 58% yield): mp 128-129 °C; 1H NMR
(300 MHz, CDCl3) δ 7.35 (d, 1H), 7.16 (d, 1H), 6.81 (dd, 1H),
2.95 (s, 6H), 2.55 (s, 3H), 2.20 (s, 3H); HRMS for C13H16BrN3O3S
(M+) calcd 373.0096, found 373.0095. Anal. Calcd for C13H16
-
BrN3O3S: C, 41.72; H, 4.31; N, 11.23; S, 8.57. Found: C, 41.80;
H, 4.43; N, 11.03; S, 8.65.
N-Meth yl-1,2-ben zosu lta m (10). Compound 10 was syn-
thesized in the same fashion as for 3 except that 9 was used
instead of 2 and the crude material was chromatographed (10%
CH2Cl2 in hexanes): 56% yield; mp 60-62 °C; Rf ) 0.45 in 10%
N-(4-Ch lor o-3-m et h yl-5-isoxa zolyl)-2-(a m in om et h yl)-5-
m eth ylben zen esu lfon a m id e (4). To a solution of 4-chloro-5-
amino-3-methylisoxazole2 (1.74 g, 13.1 mmol) in anhydrous THF
(30 mL) was added sodium hydride (874 mg, 21.9 mmol, 60%
dispersion in mineral oil) at 0 °C. The mixture was stirred for
30 min at 0 °C before the addition of 3 (800 mg, 4.4 mmol). The
resulting mixture was stirred for 30 min at 0 °C and an
additional 3 h at room temperature. The reaction was quenched
with saturated NH4Cl (aqueous, 10 mL), and THF was evapo-
rated in vacuo. The aqueous residue was extracted with EtOAc,
and the organic layer was concentrated. A fraction of the residue
was subjected to HPLC purification to give 4 as a brown powder
(60 mg, ∼66% yield): mp 132-135 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.39 (1H, d), 7.26 (1H, dd), 7.69 (1H, d), 2.80 (3H,
s), 2.19 (3H, s), 2.12 (3H, s); HRMS for C12H14ClN3O3S (M+) calcd
315.0444, found 315.0466; IR (KBr pellet) 3416, 1634, 1522,
1
CH2Cl2 in hexanes; H NMR (400 MHz, CDCl3) δ 7.80 (dd, 1H,
J ) 1.5, 8.1 Hz), 7.52 (ddd, 1H, J ) 1.5, 6.2, 8.1 Hz), 6.79 (d,
1H, J ) 8.4 Hz), 6.74 (ddd, 1H, J ) 1.1, 5.8, 8.1 Hz), 3.00 (s,
3H); 13C NMR (400 MHz, CDCl3) δ 147.53, 137.73, 129.81,
125.29, 115.65, 112.75, 29.68 (NCH3); HRMS for C7H8NO2S (M
+ H)+ calcd 170.0276, found 170.0280.
5-Meth yl-1,2-ben zosu lta m (12). Compound 12 was syn-
thesized in the same fashion as for 3 except that 11 was used
instead of 2 and this material was chromatographed (10% EtOAc
in hexanes): 48% yield; mp 38-40 °C; Rf ) 0.3 in 10% EtOAc
in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J ) 0.7 Hz,
1H), 7.23 (dd, J ) 8.4, 0.7 Hz, 1H), 6.70 (d, J ) 8.4 Hz, 1H),
2.27 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 143.52, 138.58,
128.40, 127.71, 125.79, 118.76, 19.56 (ArCH3); HRMS for C7H8-
NO2S (M + H)+ calcd 170.0276, found 170.0315.
1341, 1412, 1154 cm-1
. Anal. Calcd for C12H14ClN3O3S: C,
45.64; H, 4.47; N, 13.31. Found: C, 45.59; H, 4.43; N, 13.09.
5-(Dim eth yla m in o)-2-m eth ylben zen esu lfon yl Ch lor id e
(7). Compound 7 was synthesized in the same fashion as for 2
with the exception that 5 and 6 were used instead of 1 and 2:
1H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 7.26 (dd, 1H), 7.05
Ack n ow led gm en t. The author wishes to thank Dr.
Ming Fai Chan for helpful discussions and thank Dr.
Timothy P. Kogan for critical review of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of 3
and 10 (6 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(d, 1H), 3.05 (s, 6H), 2.68 (s, 3H). Anal. Calcd for C9H12
-
ClNO2S: C, 46.25; H, 5.18; N, 5.99. Found: C, 45.95, H, 5.14;
N, 5.95.
N-(4-Br om o-3-m et h yl-5-isoxa zolyl)-5-(d im et h yla m in o)-
2-m eth ylben zen esu lfon a m id e (8). Compound 8 was synthe-
sized in the same fashion as for 4 except that 4-bromo-5-amino-
J O971053A