Synthesis of New Fused Benzothiadiazepines and Macrocyclic Sulfamides Starting from N,N-Disubstituted Sulfamides and N(Boc)-Sulfamides

Herein, we describe an efficient one-step synthesis of new fused benzothiadiazepine-1,1-dioxides and macrocyclic sulfamides. The synthesis of these compounds was achieved in moderate yields starting from previously described N,N′-disubstituted symmetric sulfamides and N-tert-butoxycarbonyl, N′-alkyl sulfamide. The chemical structures of all the new compounds reported in this work were confirmed by NMR, IR, and mass spectrometry. These compounds are beneficial building blocks that can be used in deriving new chemical entities that exert a wide spectrum of pharmacological activities.

In particular, we report the synthesis and spectroscopic properties of novel macrocyclic rings containing the sulfamide unit, which was incorporated by a direct reaction between m-dibromomethylbenzene derivatives and N,Ndisubstituted symmetric sulfamide. This strategy provides a ready access to a broad range of products. Beyond their pivotal role in the development of supramolecular chemistry [19,20], this class of molecules has also served as the basis for designing various receptors of organic molecules [21]. Moreover, they have become useful building blocks for constructing nanoporous structures [22,23].

Results and Discussion
Our earlier studies involved the synthesis of heterocyclic compounds containing sulfonyl groups [9,10,15,16]. Chlorosulfonyl isocyanate (CSI) and sulfuryl chloride (SO 2 Cl 2 ) have been shown to be versatile reagents in the synthesis of heterocyclic chemistry. They have been used in the direct introduction of sulfonyl groups into heterocycles. Several total syntheses of N,N -disubstituted symmetric sulfamides (1a-d) have been reported in the literature including the original synthetic approaches [24][25][26][27]. Thus, the starting material, sulfuryl chloride, was treated with an excess of the corresponding amine in dichloromethane for 24 h (Scheme 1), and this resulted in the formation of products 1a-d in moderate yields. The synthesis of the key intermediates N(Boc), N -alkyl-sulfamide (2a-f) and N-((Boc)sulfamoylamino)carboxylates (2g-j) was accomplished as shown in Scheme 1. The carbamylation of chlorosulfonyl isocyanate with tert-butyl alcohol at 0 • C in dichloromethane followed by in situ sulfamoylation with the corresponding amine, amino acid ester hydrochloride, or diamine in the presence of triethylamine (TEA) gave the desired N(Boc), N (alkyl)sulfamide (2a-b), N(Boc), Nsufamoylamino acid esters (2g-j) or bis-carboxylsulfamides (2c-f) [28,29]. As outlined in Scheme 2, the N,N -disubstituted symmetric sulfamides (1a-d) are a suitable starting material for the synthesis of an array of new benzocondensed scaffolds (4a-c) in good yields 75-79%. The starting materials, N,Ndisubstituted symmetric sulfamides 1a-d, were condensed with 1,2,4,5-tetrakis(bromomethyl)benzene (0.5 equiv) by refluxing in acetonitrile for 10 h in the presence of potassium carbonate (K 2 CO 3 ) to afford fused Benzo-di-thiadiazepines 4a-c.
In the second route, after replacing N,N -disubstituted sulfamides by N(Boc)sulfamides derivatives (2a-j) under the same conditions, products 4d-f and 4d -f were formed. Both isomers (symmetric and asymmetric) were separated by flash chromatography using dichloromethane as an eluant. The products were obtained in different yields as summarized in Table 1. Notably, the percentage yields of the asymmetric fused benzothiadiazepines 4d -f were relatively low. These yields seem to be strongly dependent upon the reaction conditions (solvent, temperature, and steric effect). Therefore, further optimization of the reaction conditions might improve the yield of these reactions.
The prepared N(Boc)-protected compounds (2a-j) have traditionally been a starting point for the design of novel benzocondensed derivatives (3a-e) by condensation with α,α -dibromo-o-xylene in acetonitrile in the presence of potassium carbonate (K 2 CO 3 ) (Scheme 2).
The presence of the tert-butoxycarbonyl (Boc) group, which activates the sulfamide nitrogen nucleophilicity, was required for substitution. This protecting group was removed by trifluoroacetic acid to yield the unprotected fused cyclic sulfamides [30]. These deprotected compounds were considered excellent starting materials for preparation of biomolecule analogues employing different types of reactions such as regioselective Mitsunobu reaction (DEAD, PPh 3 , THF at room temperature, 2 h) [31,32]. The structures of fused compounds were confirmed by IR, mass spectrometry, and NMR ( 1 H, 13 C), and the results are presented in Table 1.
The IR spectra of compounds 3a-e displayed the characteristic absorption bonds near 1370 for SO 2 , near 1140 cm −1 for SO 2 and strong absorption in the vicinity of 1740 cm −1 due to C=O stretching. If the substituent R is an ester group, there must also be an intense stretch in the carbonyl region of the spectrum near to 1750 cm −1 . At ambient temperature, the 1 H-NMR spectra of the benzothiadiazepines showed sharp signals near 1.40 ppm indicating the presence of Boc group. The aromatic proton signals appear at 7 ppm as one multiplet of 4H for (3a-c) and 9H for (3d-e). ESI-MS spectra of the compounds 3a-e showed ion peaks due to [M+Na] + and [M+2Na] + .
The structures of fused a, b, and c compounds were supported by analysis of the mass spectra ESI-MS, which showed peaks respectively at m/z 509, 567, and 710 indicating molecular masses of ions [M+Na] + . As shown in Table 1, all the H 1 NMR spectra showed one singlet peak near 7 ppm, which is a strong indication of the presence of aromatic protons. In the infrared data, all spectra showed bands near 1150 and 1350 cm −1 due to SO 2 stretching. In the ESI-MS spectra, all the prepared fused compounds 4d-f exhibit intense peaks corresponding to the molecular weight [M+Na] + . Since the symmetric and asymmetric fused compounds have the same molecular weight, it was difficult to extract all the rich structural information from the mass spectra. In the IR spectra (Table 1), there are peaks at about (1140-1170) and (1368-1390) cm −1 , due to the sulfonyl group (SO 2 ) stretching, and at about 1715-1732 cm −1 , due to C=O stretching vibrations. For the compounds containing an ester group, IR spectra showed also bands near 1700 cm −1 due to C=O stretching. The one difference in the 1 H NMR spectra between the symmetric and asymmetric fused is the aromatic region. The 1 H NMR spectra of symmetric fused 4d-f showed resonances attributed a two aromatic protons, which appeared as one singlet with a relative integration of 2 indicating the equivalency of the two hydrogens. However, ISRN Organic Chemistry   for the asymmetric fused derivatives, the 1 H-NMR spectra showed two different kinds of aromatic protons with relative integration of 1 : 1.

Synthesis of New Macrocyclic Sulfamides
There are many strategies available for the synthesis of benzylic amide macrocycles that involve the reaction of an ester group with an amino group [33][34][35]. In this work, we also investigated the synthesis of new macrocyclic containing the sulfamide unit. As shown in Scheme 3, the desired macrocyclic sulfamides 5 were synthesized in one step [2+2] condensation under high dilution conditions [36]. A solution of 1-methoxy-4-tert-butyl-(2,6-dibromomethyl)benzene (1 equiv) in 20 mL of acetonitrile and a solution of N,Ndisubstituted symmetric sulfamide (1 equiv) in 20 mL of CH 3 CN were added dropwise using two mechanically driven syringes over 5 h into solution of K 2 CO 3 (4.5 equiv) in 130 mL of CH 3 CN under nitrogen with stirring at reflux for 24 h. The reaction mixture was subsequently cooled down, and the solvent was removed. Dichloromethane was added to the obtained crude, and this solution was washed with 2 N HCl then with water and dried with magnesium sulfate. The solvent was evaporated to give the macrocycle 5a in 58% yield. In the macrocyclization reactions, it was critical to find suitable reaction conditions that maintain the correct condensation, while keeping the reactions fast enough to prevent buildup of reactive intermediates. The structure of macrocyclic compounds 5a was unambiguously confirmed by IR, mass spectrometry, and NMR ( 1 H, 13 C) spectroscopy. The infrared spectrum showed characteristic bands at 1148 and 1361 cm −1 , which were assigned to the sulfonyl group (SO 2 ). A molecular peak of 952 [M+Na] + was observed by ESI mass spectrometry. In addition, the 300 MHz 1 H spectrum, measured on a sample dissolved in CDCl 3 , showed a relative integration of 4 : 20 for the two sets of peaks at 6.78 and 7.30-7.45 ppm. These signals were assigned to the aromatic regions of product.

Conclusion
In summary, we have successfully synthesized and characterized a new series of N-protected fused benzothiadiazepines, which offer good starting materials for the synthesis of new molecules with interesting biological activities. In the second part, we described an efficient method for the synthesis of new macrocycle with sulfamide moiety with potential diverse applications in supramolecular chemistry and as starting materials for further synthetic transformations. The synthetic example presented in this work is one of the simplest and most efficient macrocyclization reactions based on the technique of high-dilution conditions. The biological evaluation of the compounds synthesized in this work is currently being carried out.

Instrumentals and Characterization
. NMR spectra were acquired on commercial instruments (Bruker Avance 300 MHz or Bruker AMX 400 MHz) and chemical shifts (δ) are reported in parts per million downfield from internal Me 4 Si (s = singlet, d = doublet, dd = double of doublet, t = triplet, q = quartet, m = multiplet). Mass spectrometry data were obtained with an HP MS apparatus 5989A, at 70 eV for EI spectra and with methane as reagent gas for CI spectra. The ESI-MS were obtained on Mariner (ESI TOF) and API 365 (ESI 3Q) mass spectrometers with methanol as a spray solvent. UV-Vis spectra were taken on a PerkinElmer Lambda 20 spectrometer. Melting points (not corrected) were determined using a Reichert Thermovar or Electrothermal 9200 Apparatus. The microwave oven was a monomode discover MW reactor. All reactions were done in a 10 mL glass tube sealed with a Teflon stopper unless stated otherwise. (1a-d) prepared as described in the literature [15]. The reaction was carried out by dropwise addition of a solution of sulfuryl chloride (1 equiv) in 20 mL of dichloromethane to a solution of the corresponding amine (4-6 equiv) in 50 mL of CH 2 CL 2 at 0 • C in darkness. Gas evolution was observed during the addition. The reaction mixture was warmed to room temperature (rt), stirred for 24 h, and monitored by TLC (SiO 2 ). The crude was washed by HCl (2 N, 2 × 20 mL) water (2 × 30 mL) and dried over Na 2 SO 4 . The solution was filtered and then concentrated under reduced pressure to leave yellow solid as the crude product. Column chromatography (CH 2 Cl 2 , MeOH 95 : 5) afforded the N,N -dialkyl sulfamide.

General Procedure A for the Synthesis of N,N -Disubstituted Symmetric Sulfamides
N,N -Dipropylsulfamide (1a). This compound was prepared according to the general procedure A, using a solution of propylamine (6 equiv) in CH 2 Cl 2 and SO 2 Cl 2 (1 equiv) in CH 2 Cl 2 . Yield = 60% (was obtained as a white solid);

General Procedure B for the Synthesis of N-tert-Butyloxycarbonyl, N -Alkyl Sulfamide: Carbamoylation-Sulfamoylation (2a-f).
To a stirred solution of CSI (1 equiv, 10 mmol, 1.4153 g) in 20 mL of anhydrous dichloromethane at 0 • C was added a solution of tert-butyl alcohol (1 equiv, 10 mmol, 0.7412 g) in 20 mL of dried CH 2 Cl 2 . After being stirred for 30 min, the resulting solution of N(Boc)-sulfamoyl chloride and triethylamine (TEA) in 20 mL dichloromethane was added dropwise to a solution of amine (1 equiv) or (diamine 0.5 equiv) in 20 mL of CH 2 Cl 2 . The reaction temperature did not rise above 5 • C. The resulting reaction solution was allowed to warm up to rt over 3 h. The reaction mixture was diluted with dichloromethane and washed with 0.1 N HCl and brine. The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo to give the crude product. Recrystallization from CH 2 Cl 2 at low temperature afforded the expected compounds in 70-85% yield. 2a and 2b were prepared according to the general procedure B; see [29].  (2g-j). To a suspension of the amino acid ester hydrochloride (1 equiv, 10 mmol) was added triethylamine (1 equiv, 10 mmol, 1.0119 g) in 20 mL of dichloromethane. Simultaneously the tert-butyl chlorosulfonyl carbamate was prepared by addition of tert-butyl alcohol (1 equiv, 10 mmol, 0.7412 g) in 20 mL of CH 2 Cl 2 to an ice-cooled solution containing CSI (1 equiv, 10 mmol, 1.4153 g) in 20 mL of dichloromethane. The obtained reagent solution was slowly added to the solution of amino acid ester hydrochloride in 30 mL of dichloromethane at the same time as of Et 3 N (1 equiv, 10 mmol, 1.0119 g). The reaction was monitored by TLC. The mixture was then diluted with CH 2 Cl 2 (100 mL) and washed with 2 portions of 1 M HCl and water. The solution was then dried with Na 2 SO 4 and concentrated in vacuum to give the crude product. Recrystallization from CH 2 Cl 2 at low temperature or chromatography on silica gel (eluent: CH 2 Cl 2 /MeOH, 9 : 1) afforded the pure carboxyl sulfamide.