HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 3, 2010, pp. 637-648
Received, 13th December, 2009, Accepted, 15th January, 2010, Published online, 18th January, 2010.
DOI: 10.3987/COM-09-11884

■ Iodotrimethylsilane and Catalytic Iodine Promoted Cyclization for the Facile Synthesis of 3-Monoarylated Five-Membered Benzosultams

Yue-Hui Dong, Qiong-Wei Ni, Shu-Tao Ma, and Zhao-Peng Liu*

Department of Organic Chemistry, School of Pharmaceutical Sciences, Shandong University, No. 44, WenHua XiLu, Jinan 250012, China

Abstract

3-Monoarylated five-membered benzosultams with various functional groups were prepared by simple and convenient two-step procedures. N-t-Bu-benzenesulfonamides were lithiated and reacted with substituted aromatic aldehydes to form the corresponding carbinols, which were converted to the cyclic compounds via a sequence of consecutive processes mediated by TMSCl-NaI-MeCN reagent and catalytic amount of iodine. Iodine played a crucial role in the eliminating the reductive side reaction in the cyclization processes.

1. INTRODUCTION
The sulfonamide functional group stands out as one of the most important pharmacophores and is widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications.1 Recently, high interest has also been directed to their conformationally constrained cyclic counterparts, the sultams, which display a vast array of biological activities, act as nonsteroidal antiinflammatory agents, agonists of 5-HT1A receptors, novel serine inhibitors, zinc enzyme carbonic anhydrase inhibitors, etc.2 3-substituted five-membered benzosultams have also received attention as potent modulators of neurotransmitters,3 HIV-1 inhibitors,4 and serotonin antagonists.5 In addition to their significance in the treatment of diseases, sultams have also been succesfully applied as chiral auxiliaries in asymmetric versions of several reactions, including alkylations, acylations, aldol reactions, Diels-Alder reactions and azidations.6 Design and synthesis of N-fluorobenzosultam based on sultam templates have also become one of the important strategies for the development of novel electrophilic fluorinating agents.7
As part of a program to study the biological activities of highly functionalized cyclic sulfonamides, we
are interested in the development of an efficient method for the construction of 3-monoarylated five-membered benzosultams. An often used method for the preparation of such kind of compounds includes two steps from saccharin: (1) the direct nucleophilic addition to the carbonyl carbon using strong nucleophiles such as aryllithium reagents or Grignard reagents to form a cyclic N-sulfonylimine; (2) reduction of the sulfonylimine through Pd/C catalyzed hydrogenation.8 But this method has limitations owning to the unavailability of some of the functionalized organometallic species, or the poor reactivities of some hindered organometallic reagents with saccharin. In addition, substituted saccharins on the aromatic ring are not readily available and usually take several steps to prepare.9 In fact, only a limited number of 3-monoarylated five-membered benzosultams have been prepared in this way. In recent years, metal (Fe, Mn, Ru, Cu, Rh, Co) complexes catalyzed intramolecular C−H amination and intramolecular aziridination have been investigated for the synthesis of five- and six-membered benzosultams.10 However, a simple and general procedure to generate 3-monoarylated five-membered benzosultams, which can tolerate a wide variety of functional groups, remains elusive. In previous researches, we developed a novel cyclization method mediated by iodotrimethylsilane (Me3SiI, TMSI), generated in situ by mixing chlorotrimethylsilane (TMSCl) with sodium iodide (NaI) in acetonitrile (MeCN) solution, for the efficient construction of 3,3-disubstituted five-membered benzosultams, 3-monosubstituted and 3,3-disubstituted six-membered benzosultams.11 To study the mechanism, the scope and limitations of this novel methodology, we want to adopt the same two-step strategy for the preparation of 3-monoarylated five-membered benzosultams (Scheme 1). We here report our new findings in the synthesis of 3-monoarylated benzosultams.

2. RESULTS AND DISCUSSION
The first step takes advantage of the powerful sulfonamide directed ortho metalation (DoM) effect.12 N-t-Butylbenzenesulfonamides 1 or 2 underwent ortho metalation, as well as N-metalation, with two equivalents of BuLi in anhydrous THF at 0 °C for 30 min under a nitrogen atmosphere to generate dilithiosulfonamide, which was reacted with an aldehyde to form a carbinol. Keen to test the generality of our strategy, a variety of aromatic aldehydes with different functional groups were applied, and the corresponding carbinol sulfonamides 3a-m were obtained in general good yields, ranging from 58 to 96% (Table 1). In next step, we first tested the TMSCl-NaI-MeCN reagent system to effect the cyclization. When carbinol sulfonamides 3a and 3b were treated with two equivalents of TMSCl-NaI in acetonitrile under reflux conditions for one hour respectively, to our surprise, in addition to the normal cyclization products 4a and 4b, there were also the unexpected deoxygenated products 5a and 5b formed (Scheme 2), and the ratio of 4a to 5a is 1:2, while 4b to 5b is 5:1! (Table 2, entries 1 and 2). When we run the same reaction with substrate 3a at room temperature, the cyclic N-t-butylbenzosultam 4a’, together with the deoxygenated N-t-butylbenzenesulfonamide 5a’ were isolated, the ratio of 4a’ to 5a’ is 1:2 (Table 2, entriy 5). It is clear now, in the TMSCl-NaI-MeCN reagent promoted synthesis of five-membered benzosultams, the cyclization goes first, while the removal of the t-butyl protective group runs second, and the later needs heating to go to completion. It is also apparent that the reductive reaction is competitive with the cyclization, but how is the reduction product generated?

It is well known that alcohols can be converted to iodides by the iodotrimethylsilane rather rapidly.13 Therefore the novel cyclization mediated by iodotrimethylsilane can be visulised to proceed via a sequence of consecutive processes, involving in the conversion of the hydroxy group to iodide, an intramolecular necleophilic substitution for the cyclization, and finally the removal of the t-butyl protective group (Scheme 3). In the formation of an iodide, an alcohol first reacts with one molecule of iodotrimethylsilane to form trimethylsilyl ether 6, and in this process, one molecule of HI is always generated.14 We postulate that the hydrogen iodide might account for the formation of the deoxygenated product, as HI is known to reduce an alkyl iodide to an alkane. Comparing with 4a to 5a, the reversed ratio of 4b to 5b also supports our hypothesis, since the dimethylamine group in the substrate 3b may trap part of the HI, so the deoxygenated product 5b was much less than 5a, while the cyclization product 4b was predominant.

To prove our above assumptions, we first used triethylamine as HI scavenger. When carbinol sulfonamides 3a was reacted with two equiv of TMSCl and NaI in acetonitrile and one equiv of triethylamine under reflux conditions (Table 2, entry 3), indeed, there were no deoxygenated products 5a or 5a’ detected, however, the reaction did not go completely, with 76% of 3a recovered, and the cyclic product was identified by 1H NMR analysis as N-t-butylbenzosultam 4a’. It is clear that HI do play an important role in the formation of the deoxygenated products and triethylamine is an effective HI scavenger. But triethylamine can also interact directly with iodotrimethylsilane, reducing its lewis acidity and nucleophilicity,15 thus affect the formation of the iodide 7 and the cyclization process. When one more equiv of TMSCl-NaI were added to above reaction mixture, the transformation was completed in less than one hour, but in addition to the normal cyclic product 4a, there were still about 10% deoxygenated products 5a produced (Table 2, entry 4). Other HI scavengers like N,N-dimethylaniline, cyclohexene and sodium carbonate did not give any better results than triethylamine. Inspired by the report that iodine exerts a catalytic effect in the conversion of aromatic esters with iodotrimethylsilane,16 we tested iodine as a catalyst for this reaction. When 0.5 equiv of iodine was coexistence in the iodotrimethylsilane reagent system, the cyclization went smoothly with no reduced products 5a or 5a’ detected by TLC analysis, and the sultam 4a was obtained in 90% yield after silica gel chromatography (Table 2, entry 6). Though the exact role of iodine needs further experiments to elucidate, it is suggested that iodine sets up an equilibrium with TMSI to form trimethylsilyl triiodide (TMSI3).16 The triiodide-silicon bond would be expected to be more polarizable than the silicon-iodine bond in iodotrimethylsilane, and we suppose it would behave differently with TMSI, possibly via an alternative pathway involving a six-centered transition state in the transformation of alcohol into the iodide, with the release of Me3SiOH and I2, but accompanying no HI formation in this process, thus avoids the formation of the reduction products. There is another possibility that iodine might trap HI through the direct formation of HI-I2 complex or hydrogen triiodide,17 affecting the reductive ability of hydrogen iodide.
The scope of this novel cyclization was studied with various carbinol sulfonamides. When 3b-m were subject to two equiv of TMSCl-NaI and 0.5 equiv of iodine in acetonitrile under reflux conditions for 1 h, sultams 4b-m were obtained in high yields (Table 1). It was seen that the novel process mediated by TMSI in the presence of catalytic amounts of iodine was effective and tolerant to a broad range of functional groups. It is also of note that the five-membered polymethoxyphenolic benzosultams, the potentially biologically interesting molecules that have the structural features to combine the important sulfonamide pharmacophore and the common polymethoxyphenolic units existed in many bioactive natural products, are readily prepared by this novel method.
In conclusion, we have developed a simple two-step synthesis of 3-monoarylated five-membered benzosultams via the novel cyclization mediated by iodotrimethylsilane and a catalytic amount of iodine. This method makes 3-monoarylated five-membered benzosultams having diverse functional groups easily preparable in two steps.

EXPERIMENTAL
Melting points were determined on an X-6 micro-melting point apparatus (Beijing Tech. Co., Ltd) and were uncorrected. IR spectra (cm–1) were recorded on a Perkin-Elmer 1600 spectrometer. 1H NMR (600 MHz) spectra were recorded at room temperature for CDCl3. All chemical shifts were reported as δ values (ppm) relative to Me4Si (0.00 ppm) as internal standards for 1H spectra. Electrospray-ionization mass spectrometry (ESI-MS) was performed on an API 4000 instrument. Microanalyses were performed with a YANAKO CHN-coder MT-5. Column chromatography was performed on silica gel (200-300 mesh). All reactions involving oxygen- or moisture-sensitive compounds were carried out under a dry N2 atmosphere. Unless otherwise noted, reagents were added by syringe. THF was distilled from sodium/benzophenone immediately prior to use.
Typical Procedure for the Preparation of Carbinol Sulfonamide 3a-m. A 2.5 M solution of BuLi (6.5 mL, 16 mmol) in hexane was added dropwise to a stirred solution of N-t-Bu-benzenesulfonamide 1 (1.70 g, 8 mmol) in THF (8 mL) under nitrogen at 0 °C. After stirring for 30 min, another solution of 4-chlorobenzaldehyde (1.12 g, 8 mmol) in THF (5 mL) was added. The mixture was stirred for 1 h and quenched by saturated aqueous NH4Cl. The mixture was then extracted with EtOAc, and the combined organic layers were dried (Na2SO4), concentrated in vacuo. Crystallization from EtOAc/petroleum ether gave 3a as a white solid (2.56 g, 91%), mp 109–111 °C; IR (KBr) 3484, 3270, 1489, 1393, 1300, 1152, 1012, 861, 762 cm–1; 1H NMR δ 8.05 (dd, J = 7.9, 1.2 Hz, 1H), 7.46 (td, J = 7.9, 1.2 Hz, 1H), 7.38 (td, J = 7.7, 1.0 Hz, 1H), 7.31–7.32 (m, 4H), 7.22 (dd, J = 7.7, 1.0 Hz, 1H), 6.71 (s, 1H), 4.91 (s, 1H), 3.51 (s 1H), 1.20 (s, 9H) ; MS (ESI) m/z 376.4 [M+Na]+. Anal. Calcd for C17H20ClNO3S: C, 57.70; H, 5.70; N, 3.96. Found: C, 57.79; H, 5.81; N, 3.91.
N-t-Butyl-2-[1-(4-dimethylaminophenyl)-1-hydroxy]methylbenzenesulfonamide 3b. White solid; mp 117–118 °C; IR (KBr) 3494, 3272, 1613, 1518, 1442, 1302, 1153, 770 cm–1; 1H NMR δ 8.08 (dd, J = 8.3, 1.1 Hz, 1H), 7.54 (td, J = 7.5, 1.0 Hz, 1H), 7.41 (td, J = 7.7, 1.2 Hz, 1H), 7.26–7.30 (m, 3 H,), 6.75 (d, J = 1.5 Hz, 2H), 6.67 (d, J = 3.5 Hz, 1H), 4.22 (d, J = 3.5 Hz, 1H), 2.97 (s, 6 H), 1.06 (s, 9H); MS m/z 363 [M+H]+. Anal. Calcd for C19H26N2O3S: C, 62.96; H, 7.23; N, 7.73. Found: C, 62.71; H, 7.26; N, 7.68.
N-t-Butyl-2-[1-(4-methylphenyl)-1-hydroxy]methylbenzenesulfonamide 3c. White solid; mp 100–101 °C; IR (KBr) 3477, 3273, 1511, 1471,1390, 1152, 1004, 820, 767 cm–1; 1H NMR δ 8.07 (dd, J = 5.9, 0.9 Hz, 1H), 7.38–7.53 (m, 3H), 7.30 (d, J = 6.0 Hz, 2H), 7.19 (d, J = 5.9 Hz, 2H), 6.68 (s, 1H), 2.35 (s, 3H), 1.11 (s, 9H); MS m/z 356.5 [M+Na]+. Anal. Calcd for C18H23NO3S: C, 64.84; H, 6.95; N, 4.20. Found: C, 64.75; H, 6.99; N, 4.15.
N-t-Butyl-2-[1-(4-methoxylphenyl)-1-hydroxy]methylbenzenesulfonamide 3d. White solid; mp 103–104 °C; IR (KBr) 3424, 3237, 1614, 1512, 1320, 1245, 1150, 1036, 841, 764 cm–1; 1H NMR δ 7.74 (dd, J = 4.7, 1.6 Hz, 1H), 7.42–7.46 (m, 2H), 7.33–7.37 (m, 2H), 7.02–7.04 (m, 1H), 6.84–6.87 (m, 2H), 5.60 (s, 1H), 3.78 (s, 3H), 1.45 (s, 9H); MS m/z 372.3 [M+Na]+. Anal. Calcd for C18H23NO4S: C, 61.87; H, 6.63; N, 4.01. Found: C, 61.69; H, 6.53; N, 4.05.
N-t-Butyl-2-[1-(3,4-dimethoxylphenyl)-1-hydroxy]methylbenzenesulfonamide 3e. White solid; mp 133–135 °C; IR (KBr) 3494, 3270, 1606, 1511, 1305, 1265, 1144, 1120, 1037, 812, 757 cm–1; 1H NMR δ 7.75 (dd, J = 4.4, 1.4 Hz, 1H), 7.39–7.51 (m, 3H), 7.06–7.08 (m, 1H), 6.98 (d, J = 1.5 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 5.58 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 1.46 (s, 9H); MS m/z 402.5 [M+Na]+. Anal. Calcd for C19H25NO5S: C, 60.14; H, 6.64; N, 3.69. Found: C, 60.01; H, 6.57; N, 3.65.
N-t-Butyl-2-[1-(3,4,5-triimethoxylphenyl)-1-hydroxy]methylbenzenesulfonamide 3f. White solid; mp
122–124 °C; IR (KBr) 3498, 3218, 1592, 1505, 1332, 1230, 1144, 1122, 863, 810, 771 cm–1; 1H NMR δ 8.08 (dd, J = 7.9, 0.9 Hz, 1H), 7.52 (td, J = 7.5, 1.0 Hz, 1H), 7.40–7.43 (m, 2H), 6.68 (s, 2H), 6.66 (s, 1H), 3.85 (s, 3H), 3.83 (s, 6H), 1.17 (s, 9H); MS m/z 427.5 [M+NH4]+. Anal. Calcd for C20H27NO6S: C, 58.66; H, 6.65; N, 3.42. Found: C, 58.45; H, 6.78; N, 3.36.
N-t-Butyl-6-[1-(4-chlorophenyl)-1-hydroxy]methyl-benzo[d][1,3]dioxole-5-sulfonamide 3g. White solid; mp 132.5−134.5 °C; IR (KBr) 3524, 3256, 1625, 1597, 1297, 1254, 1139, 814, 768 cm–1; 1H NMR δ 7.70 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 7.6, 2.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 6.09 (d, J = 1.2 Hz, 1H ), 6.01 (d, J = 1.2 Hz, 1H), 1.13 (s, 9H); MS m/z 396.3 [M−H]−. Anal. Calcd for C18H20ClNO5S: C, 54.34; H, 5.07; N, 3.52. Found: C, 54.24; H, 5.15; N, 3.47.
N-t-Butyl-6-[1-(4-methoxyphenyl)-1-hydroxy]methyl-benzo[d][1,3]dioxole-5-sulfonamide 3h. White solid; mp 84−86 °C; IR (KBr): 3522, 3264, 1610, 1512, 1297, 1136, 830, 768 cm–1; 1H NMR δ 7.45 (dd, J = 7.7, 2.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 10.7, 2.0 Hz, 2H), 6.01 (d, J = 1.3 Hz, 1H), 5.92 (d, J = 1.3 Hz, 1H), 5.62 (s, 1H ), 3.80 (s, 3H), 1.43 (s, 9H); MS m/z 392.5 [M−H]−. Anal. Calcd for C19H23NO6S: C, 58.00; H, 5.89; N, 3.56. Found: C, 58.14; H, 5.93; N, 3.47.
N-t-Butyl-6-[1-(3,4,5-trimethoxyphenyl)-1-hydroxy]methyl-benzo[d][1,3]dioxole-5-sulfonamide 3i. White solid; mp 96−98 °C; IR (KBr) 3507, 3365, 1594, 1506, 1331, 1309, 1250, 1128, 1060, 901, 759 cm–1; 1H NMR δ 7.71 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.70 (s, 2H), 6.45 (s, 1H), 6.16 (d, J = 1.4 Hz, 1H), 6.08 (d, J = 1.4 Hz, 1H), 3.85 (s, 9H), 1.08 (s, 9H); MS m/z 452.5 [M−H]−. Anal. Calcd for C21H27NO8S: C, 55.62; H, 6.00; N, 3.09. Found: C, 55.45; H, 6.10; N, 3.02.
N-t-Butyl-6-[1-(3,4-dimethoxyphenyl)-1-hydroxy]methyl-benzo[d][1,3]dioxole-5-sulfonamide 3j. White solid; mp 84.5−86.5 °C; IR (KBr): 3573, 3274, 1593, 1518, 1304, 1258, 1132, 1000, 898, 758 cm–1; 1H NMR δ 7.30 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 9.3, 2.0 Hz, 1H), 6.92 (d, J = 8.1Hz, 1H), 6.84 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 1.3 Hz, 1H), 5.95 (d, J = 1.3 Hz, 1H), 5.62 (s, 1H ), 3.88 (s, 3H), 3.86 (s, 3H), 1.46 (s, 9H); MS m/z 422.4 [M−H]−. Anal. Calcd for C20H25NO7S: C, 56.72; H, 5.95; N, 3.31. Found: C, 56.53; H, 6.03; N, 3.19.
N-t-Butyl-6-[1-(4-methylphenyl)-1-hydroxy]methylbenzo[d][1,3]dioxole-5-sulfonamide 3k. White solid; mp 123−125 °C; IR (KBr) 3538, 3246, 1597, 1459, 1299, 1252, 1139, 1004, 901, 816, 766 cm–1; 1H NMR δ 7.68 (d, J = 8.4 Hz, 1H) , 7.33 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 10.4 Hz, 1H), 6.13 (d, J = 1.2 Hz, 1H), 6.07 (d, J = 1.2 Hz, 1H), 4.45 (d, J = 10.7 Hz, 1H), 3.53 (s, 1H), 2.35 (s, 3H), 1.02 (s, 9H); MS m/z 376.6 [M−H]−. Anal. Calcd for C19H23NO5S: C, 60.46; H, 6.14; N, 3.71. Found: C, 60.31; H, 6.25; N, 3.65.
N-t-Butyl-6-[1-(4-fluorophenyl)-1-hydroxy]methylbenzo[d][1,3]dioxole-5-sulfonamide 3l. White solid; mp 127−129 °C; IR (KBr) 3439, 3260, 1603, 1509, 1459, 1297, 1253, 1137, 1057, 935, 838, 764 cm–1; 1H NMR δ 7.70 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 5.5 Hz, 2H), 7.05 (td, J = 7.7, 2.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 6.09 (d, J = 1.2 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 3.90 (s, 1H), 1.12 (s, 9H); MS m/z 380.6 [M−H]−. Anal. Calcd for C18H20FNO5S: C, 56.68; H, 5.29; N, 3.67. Found: C, 56.56; H, 5.33; N, 3.53.
N-t-Butyl-6-[1-(3-chlorophenyl)-1-hydroxy]methylbenzo[d][1,3]dioxole-5-sulfonamide 3m. White solid; mp 130−132 °C; IR (KBr) 3528, 3317, 1596, 1462, 1300, 1254, 1177, 1135, 991, 900, 818, 767 cm–1; 1H NMR δ 7.70 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.27 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 9.5 Hz, 1H), 6.11 (d, J = 1.2 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 4.13 (d, J = 9.5 Hz, 1H), 3.84 (s, 1H), 1.12 (s, 9H); MS m/z 396.3 [M−H]−. Anal. Calcd for C18H20ClNO5S: C, 54.34; H, 5.07; N, 3.52. Found: C, 54.29; H, 5.09; N, 3.45.
TMSCl-NaI-MeCN Reagent Promoted Cyclization of 3a and 3b under Reflux Conditions. Chlorotrimethylsilane (0.26 mL, 2 mmol) was added dropwise to a stirred solution of 3a (354 mg, 1 mmol) and sodium iodide (300 mg, 2 mmol) in MeCN (10 mL) under nitrogen at room temperature. The mixture was heated under reflux for 1 h, after which it was cooled and 10% sodium thiosulfate solution was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo. The residue was purified by preparative TLC (Hex-EtOAc, 5:1) to give 4a (90 mg, 32%) and 5a (190 mg, 67%).
In the same way, from 3b (880 mg, 2.43 mmol), chlorotrimethylsilane (0.63 mL, 4.86 mmol) and sodium iodide (730 mg, 4.86 mmol) in MeCN (20 mL), 4b (560 mg, 80%) and 5b (120 mg, 17%) were isolated by silica gel chromatography (CH2Cl2-Et2O, 40:1).
3-(4-Chlorophenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4a. White solid; m.p. 181–182 °C; IR (KBr) 3436, 3281, 1487, 1391, 1290, 1169, 839, 758 cm–1; 1H NMR δ 7.85 (dd, J = 5.8, 1.5 Hz, 1H), 7.56–7.59 (m, 2H), 7.37 (dd, J = 6.9, 1.1 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 6.5 Hz, 1H), 5.71 (d, J = 3.6 Hz, 1H), 4.95 (d, J = 3.6 Hz, 1H); MS m/z 280.3 [M+H]+. Anal. calcd for C13H10ClNO2S: C, 55.82; H, 3.60; N, 5.01. Found: C, 55.80; H, 3.58; N, 4.99.
2-(4-Chlorobenzyl)benzenesulfonamide 5a. White solid; mp 137–138 °C; IR (KBr) 3346, 3249, 1489, 1151, 899, 755 cm–1; 1H NMR δ 8.09 (dd, J = 5.9, 1.0 Hz, 1H), 7.53 (td, J = 5.7, 1.0 Hz, 1H), 7.40 (td, J = 5.6, 0.9 Hz, 1H), 7.27–7.30 (m, 3H), 7.15 (d, J = 6.3 Hz, 2H), 4.31 (s, 2H), 4.46 (s, 2H) ; MS m/z 282.0 [M+H]+. Anal. calcd for C13H12ClNO2S: C, 55.42; H, 4.29; N, 4.97. Found: C, 55.36; H, 4.23; N, 4.89.
3-(4-Dimethylaminophenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4b. White solid; mp 137–139 °C; IR (KBr) 3437, 3259, 1623, 1532, 1450, 1324, 1302, 1278, 1164, 818, 765 cm–1; 1H NMR δ 7.85 (dd, J = 7.1, 1.0 Hz, 1 H), 7.53–7.58 (m, 2 H), 7.16–7.20 (m, 3 H), 6.72 (s, 2 H), 5.66 (d, J = 3.9 Hz, 1 H), 4.70 (d, J = 3.9 Hz, 1 H), 2.98 (s, 6 H); MS m/z 289 [M+H]+. Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C, 62.21; H, 5.56; N, 9.68.
2-(4-Dimethylaminobenzyl)benzenesulfonamide 5b. White solid; mp 209–210 °C; IR (KBr) 3494, 3269, 1511, 1463, 1389, 1305, 1285, 1143, 978, 812, 758 cm–1; 1H NMR δ 8.06 (dd, J = 8.2, 1.5 Hz, 1H), 7.55 (td, J = 7.5, 1.2 Hz, 1H), 7.39 (d, J = 7.0 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 4.14 (s, 2H), 2.93 (s, 6H); MS m/z 289.4 [M–H]–. Anal. Calcd for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.00; H, 6.21; N, 9.67.
TMSCl-NaI-MeCN Reagent Promoted Cyclization of 3a at RT. Chlorotrimethylsilane (0.26 mL, 2 mmol) was added dropwise to a stirred solution of 3a (354 mg, 1 mmol) and sodium iodide (300 mg, 2 mmol) in MeCN (10 mL) under nitrogen at room temperature. The mixture was stirred for 1 h. 10% sodium thiosulfate solution was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo. The residue was purified by preparative TLC (Hexane-EtOAc, 5:1) to give 4a’ (100 mg, 29%) and 5a’ (200 mg, 60%).
N-t-Butyl-3-(4-chlorophenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dione 4a’. White solid; mp 135–136 °C; IR (KBr) 3323, 3281, 3251, 1487, 1300, 1291, 1169, 839, 758 cm–1; 1H NMR δ 8.10 (dd, J = 4.0, 0.7 Hz, 1H), 7.50 (td, J = 3.8, 0.7 Hz, 1H), 7.43 (td, J = 3.8, 0.7 Hz, 1H), 7.38 (s, 4H), 7.27–7.29 (m, 1H), 6.73 (s, 1H), 1.23 (s, 9H); MS m/z 358.3 [M+Na]+. Anal. Calcd for C17H18ClNO2S: C, 60.80; H, 5.40; N, 4.17. Found: C, 60.73; H, 5.43; N, 4.14.
N-t-Butyl-2-(4-chlorobenzyl)benzensulfonamide 5a’. White solid; mp 102–103 °C; IR (KBr) 3301, 1473, 1441, 1307, 1150, 796, 760 cm–1; 1H NMR δ 8.08 (dd, J = 6.0, 0.9 Hz, 1H), 7.47 (td, J = 5.7, 1.0 Hz, 1H), 7.36 (td, J = 8.0, 0.8 Hz, 1H), 7.27–7.30 (m, 2H), 7.19 (d, J = 5.7 Hz, 1H), 7.14 (d, J = 6.3 Hz, 2H), 4.43 (s, 2H), 3.97 (s, 1H), 1.08 (s, 9H); MS m/z 360.4 [M+Na]+. Anal. Calcd for C17H20ClNO2S: C, 60.43; H, 5.97; N, 4.15. Found: C, 60.46; H, 5.99; N, 4.09..
TMSCl-NaI-MeCN Reagent Promoted Cyclization of 3a in the Presence of Et3N under Reflux Conditions. Chlorotrimethylsilane (0.65 mL, 5 mmol) was added dropwise to a stirred solution of 3a (900 mg, 2.55 mmol), sodium iodide (765 mg, 5.10 mmol) in MeCN (20 mL) and triethylamine (0.36 mL, 2.55 mmol) under nitrogen at room temperature. The mixture was heated under reflux for 1 h, after which it was cooled and 10% sodium thiosulfate solution was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2-Et2O, 40:1) to give 4a’ (174 mg, 21%) and recovered 3a (684 mg, 76%).
Typical Procedure for the Preparation of 3-Monoarylated Benzosultam 4 Promoted by Iodotrimethylsilane and Catalytic Amount of Iodine. Chlorotrimethylsilane (0.26 mL, 2 mmol) was added dropwise to a stirred solution of 3a (0.36 g, 1 mmol), iodine (0.12 g, 0.5 mmol) and sodium iodide (0.30 g, 2 mmol) in MeCN (10 mL) under nitrogen at room temperature. The mixture was heated under reflux for 1 h, after which it was cooled and 10% sodium thiosulfate solution was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo. Recrystallizion from EtOAc/hexane gave 4a as a white solid (0.25 g, 90%).
3-(4-Methylphenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4c. White solid; mp 166–168 °C; IR (KBr): 3277, 3036, 1511, 1454, 1391, 1279, 1168, 1048, 833, 751 cm–1; 1H NMR δ 7.84 (td, J = 2.7, 1.1 Hz, 1H), 7.55 (td, J = 2.7, 1.1 Hz, 2H), 7.18–7.25 (m, 4H), 7.12–7.14 (m, 1H), 5.68 (d, J = 2.9 Hz, 1H), 4.77 (d, J = 2.9 Hz, 1H), 2.36 (s, 3H); MS m/z 260.3 [M+H]+. Anal. Calcd for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40. Found: C, 64.67; H, 5.11; N, 5.36.
3-(4-Methoxyphenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4d. White solid; mp 143–144 °C; IR (KBr) 3252, 3010, 1615, 1515, 1292, 1276, 1251, 1165, 1028, 919, 838, 763 cm–1; 1H NMR δ 7.85 (dd, J = 4.2, 1.8 Hz, 1H), 7.55–7.57 (m, 2H), 7.25 –7.26 (m, 2H), 7.14 (d, J = 6.5 Hz, 1H), 6.90–6.92 (m, 2H), 5.68 (d, J = 3.4 Hz, 1H), 4.77 (d, J = 3.4 Hz, 1H), 3.81 (s, 3H); MS m/z 276.5 [M+H]+. Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 60.89; H, 4.87; N, 4.93.
3-(3,4-Dimethoxyphenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4e. White solid; mp 184–185 °C; IR (KBr) 3276, 3068, 1598, 1519, 1452, 1377, 1279, 1162, 1027, 864, 752 cm–1; 1H NMR δ 7.86 (dd, J = 6.7, 1.7 Hz, 1H), 7.56–7.61 (m, 2H), 7.17–7.19 (m, 1H), 6.96 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 5.69 (d, J = 3.9 Hz, 1H), 4.86 (d, J = 3.9 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H); MS m/z 306.4 [M+H]+. Anal. Calcd for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59. Found: C, 58.86; H, 4.97; N, 4.45.
3-(3,4,5-Trimethoxyphenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 4f. White solid; mp 192–194 °C; IR (KBr) 3213, 3006, 1597, 1507, 1467, 1342, 1285, 1165, 1062, 995, 856, 782, 756 cm–1; 1H NMR δ 7.85 (dd, J = 4.8, 1.4 Hz, 1H), 7.56–7.61 (m, 2H), 7.20–7.22 (m, 1H), 6.59 (s, 2H), 5.64 (s, 1H), 4.88 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H); MS m/z 336.5 [M+H]+. Anal. Calcd for C16H17NO5S: C, 57.30; H, 5.11; N, 4.18. Found: C, 57.15; H, 5.20; N, 4.09.
3-(4-Chlorophenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4g. White solid; mp 188−190 °C; IR (KBr) 3307, 3098, 2910, 1601, 1491, 1467, 1261, 1188, 1039, 899, 832, 743 cm–1; 1H NMR δ 7.37–7.43 (m, 5H), 7.02 (d, J = 8.1 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.71 (d, J = 3.6 Hz, 1H), 4.86 (d, J = 3.6 Hz, 1H); MS m/z 324.4 [M+H]+. Anal. Calcd for C14H10ClNO4S: C, 51.94; H, 3.11; N, 4.33. Found: C, 51.88; H, 3.09; N, 4.29.
3-(4-Methoxyphenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4h. White solid; mp 177−179 °C; IR (KBr) 3224, 3010, 1613, 1514, 1468, 1269, 1251, 1187, 1140, 1031, 897, 831, 705 cm–1; 1H NMR δ 7.39 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 6.8, 1.9 Hz, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.92 (dd, J = 6.8, 1.9 Hz, 2H), 6.01 (d, J = 1.2 Hz, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 4.69 (d, J = 4.0 Hz, 1H), 3.83 (s, 3H); MS m/z 320.3 [M+H]+. Anal. Calcd for C15H13NO5S: C, 56.42; H, 4.10; N, 4.39. Found: C, 56.56; H, 4.08; N, 4.28.
3-(3,4,5-Trimethoxyphenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4i. White solid; mp 213.5−215.5 °C; IR (KBr) 3266, 3007, 1593, 1518, 1472, 1299, 1139, 1036, 877, 773 cm–1; 1H NMR δ 7.39 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.72 (s, 2H), 6.06 (d, J = 1.2 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 5.67 (d, J = 4.0 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 3.86 (s, 9H); MS m/z 380.5 [M+H]+. Anal. Calcd for C17H17NO7S: C, 53.82; H, 4.52; N, 3.69. Found: C, 53.67; H, 4.56; N, 3.56.
3-(3,4-Dimethoxyphenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4j. White solid; mp 175−177 °C; IR (KBr) 3265, 3006, 1593, 1518, 1472, 1298, 1265, 1139, 1035, 907, 877, 817, 758 cm–1; 1H NMR δ 7.39 (d, J = 8.1 Hz, 1H), 7.00-7.02 (m, 2H), 6.97 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.68 (d, J = 4.0 Hz, 1H), 4.79 (d, J = 4.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H,); MS m/z 350.4 [M+H]+. Anal. Calcd for C16H15NO6S: C, 55.01; H, 4.33; N, 4.01. Found: C, 54.89; H, 4.41; N, 3.89.
3-(4-Methylphenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4k. White solid; mp 218−220 °C; IR (KBr) 3426, 3213, 3095, 1498, 1471, 1287, 1139, 1037, 899, 827, 741 cm–1; 1H NMR δ 7.39 (d, J = 8.1 Hz, 1H), 7.33 (dd, J = 7.9, 4.2 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.1Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.69 (d, J = 4.0 Hz, 1H), 4.72 (d, J = 4.0 Hz, 1H), 2.38 (s, 3H); MS m/z 304.4 [M+H]+. Anal. Calcd for C15H13NO4S: C, 59.39; H, 4.32; N, 4.62. Found: C, 59.21; H, 4.29; N, 4.65.
3-(4-Fluorophenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4l. White solid; mp 195.5−197.5 °C; IR (KBr) 3422, 3187, 1604, 1512, 1473, 1292, 1144, 1029, 898, 841, 820, 741 cm–1; 1H NMR δ 7.44−7.46 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.09 (td, J = 8.1, 2.3 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.72 (d, J = 4.0 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H); MS m/z 308.6 [M+H]+. Anal. Calcd for C14H10FNO4S: C, 54.72; H, 3.28; N, 4.56. Found: C, 54.68; H, 3.29; N, 4.52.
3-(3-Chlorophenyl)-2,3-dihydro[1,3]dioxolo[4,5-f][1,2]benzisothiazole 1,1-dioxide 4m. White solid; mp 146−148 °C; IR (KBr) 3289, 1593, 1500, 1465, 1290, 1184, 1146, 1035, 899, 796 cm–1; 1H NMR δ 7.46 (d, J = 8.1 Hz, 1H), 7.38−7.39 (m, 1H), 7.36−7.37 (m, 1H), 7.34−7.35 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 1.2 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 5.70 (d, J = 4.5 Hz, 1H), 4.99 (d, J = 4.5 Hz, 1H); MS m/z 324.4 [M+H]+. Anal. Calcd for C14H10ClNO4S: C, 51.94; H, 3.11; N, 4.33. Found: C, 51.78; H, 3.09; N, 4.36.

ACKNOWLEDGEMENTS
This work was supported by the Natural Science Foundation of China (Grant No. 30873134) and Natural Science Foundation of Shandong Province (Y2007C125).

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