cyclic sulfamides and their analogues have been the subject of many organic and medicinal chemistry studies due to their interesting biological activities that include anti - hiv and serine protease [ 14 ] . in addition , some cyclic sulfamide derivatives have been reported as nonhydrolyzable peptidomimetics [ 5 , 6 ] , metalloprotease inhibitors , and constrained peptides [ 810 ] . the benzothiadiazepine ring system has been considered as cyclic sulfamides , and these derivatives have been the subject , especially in the field of medicinal chemistry , because many useful therapeutic agents contain this heterocyclic system . for example , the nevirapine analogs , the pyrrolo[1,2-b]benzothiadiazepine-1,1-dioxides ( pbtds ) and the pyrrolo[2,1-d]benzothiadiazepine-1,1-dioxides , were tested and reported as potential nonnucleosidic reverse transcriptase inhibitors . furthermore , the pyrrolo[1,2-b]benzothiadiazepine ( pbtd ) derivatives were also reported to exert potent anticancer activities . considering the diverse biological properties of this class of compounds and as part of continuous work on the synthesis of biologically active heterocycles , we herein report simple and efficient procedures for the synthesis of a new class of fused benzothiadiazepine derivatives ( a ) , ( b ) , ( c ) ( figure 1 ) . these derivatives include two thiadiazepine rings and macrocyclic molecules containing a sulfamide functionality ( n  so2n ) , which were synthesised using previously described n , n - disubstituted symmetric sulfamides and n(boc ) , n(alkyl)sulfamide [ 1418 ] . 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 , n-disubstituted 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 . moreover , they have become useful building blocks for constructing nanoporous structures [ 22 , 23 ] . our earlier studies involved the synthesis of heterocyclic compounds containing sulfonyl groups [ 9 , 10 , 15 , 16 ] . chlorosulfonyl isocyanate ( csi ) and sulfuryl chloride ( so2cl2 ) have been shown to be versatile reagents in the synthesis of heterocyclic chemistry . several total syntheses of n , n-disubstituted symmetric sulfamides ( 1a - d ) have been reported in the literature including the original synthetic approaches [ 2427 ] . 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 0c 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 ) , n-sufamoylamino 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 7579% . the starting materials , n , n-disubstituted 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 ( k2co3 ) 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 ) 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 ,-dibromo - o - xylene in acetonitrile in the presence of potassium carbonate ( k2co3 ) ( 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 . these deprotected compounds were considered excellent starting materials for preparation of biomolecule analogues employing different types of reactions such as regioselective mitsunobu reaction ( dead , pph3 , thf at room temperature , 2  h ) [ 31 , 32 ] . the structures of fused compounds were confirmed by ir , mass spectrometry , and nmr ( h , c ) , and the results are presented in table 1 . the ir spectra of compounds 3a - e displayed the characteristic absorption bonds near 1370 for so2 , near 1140  cm for so2 and strong absorption in the vicinity of 1740  cm 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 . at ambient temperature , the 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 hnmr 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 due to so2 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 ( 11401170 ) and ( 13681390 ) cm , due to the sulfonyl group ( so2 ) stretching , and at about 17151732  cm , due to c = o stretching vibrations . for the compounds containing an ester group , ir spectra showed also bands near 1700 cm due to c = o stretching . the one difference in the h nmr spectra between the symmetric and asymmetric fused is the aromatic region . the 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 , for the asymmetric fused derivatives , the h - nmr spectra showed two different kinds of aromatic protons with relative integration of 1  :  1 . there are many strategies available for the synthesis of benzylic amide macrocycles that involve the reaction of an ester group with an amino group [ 3335 ] . in this work as shown in scheme 3 , the desired macrocyclic sulfamides 5 were synthesized in one step [ 2 + 2 ] condensation under high dilution conditions . a solution of 1-methoxy-4-tert - butyl-(2,6-dibromomethyl)benzene ( 1 equiv ) in 20  ml of acetonitrile and a solution of n , n-disubstituted symmetric sulfamide ( 1 equiv ) in 20  ml of ch3cn were added dropwise using two mechanically driven syringes over 5  h into solution of k2co3 ( 4.5 equiv ) in 130  ml of ch3cn 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 ( h , c ) spectroscopy . the infrared spectrum showed characteristic bands at 1148 and 1361  cm , which were assigned to the sulfonyl group ( so2 ) . in addition , the 300 mhz h spectrum , measured on a sample dissolved in cdcl3 , showed a relative integration of 4  :  20 for the two sets of peaks at 6.78 and 7.307.45  ppm . 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 . nmr spectra were acquired on commercial instruments ( bruker avance 300  mhz or bruker amx 400  mhz ) and chemical shifts (  ) are reported in parts per million downfield from internal me4si ( 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 . melting points ( not corrected ) were determined using a reichert thermovar or electrothermal 9200 apparatus . all reactions were done in a 10  ml glass tube sealed with a teflon stopper unless stated otherwise . 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 ( 46 equiv ) in 50  ml of ch2cl2 at 0c in darkness . the reaction mixture was warmed to room temperature ( rt ) , stirred for 24  h , and monitored by tlc ( sio2 ) . the crude was washed by hcl ( 2 n , 2  20  ml ) water ( 2  30  ml ) and dried over na2so4 . the solution was filtered and then concentrated under reduced pressure to leave yellow solid as the crude product . column chromatography ( ch2cl2 , meoh 95  :  5 ) afforded the n , n-dialkyl sulfamide . n , n-dipropylsulfamide ( 1a)this compound was prepared according to the general procedure a , using a solution of propylamine ( 6 equiv ) in ch2cl2 and so2cl2 ( 1 equiv ) in ch2cl2 . yield = 60% ( was obtained as a white solid ) ; rf = 0.45 [ sio2 , ch2cl2/meoh ( 95  :  5 ) ] ; mp 6465c ( described : 6263c ) . ir ( kbr ,   cm ) : 3280 ( nh ) , 1333 and 1150 ( so2 ) . h nmr ( cdcl3 ) : 0.95 ( t , j = 7.2  hz , 6h , ch3 ) , 1.57 ( sext , j = j = 7.1  hz , 4h , -ch2 ) , 2.99 ( q , 4h , -ch2 ) , 4.27 ( t broad , 2h , nh ) . c nmr ( cdcl3 ) : 11.26 ( -c ) , 22.89 ( -c ) , 44.95 ( -c ) . lrms ( ci ) : 181 [ m+h ] . this compound was prepared according to the general procedure a , using a solution of propylamine ( 6 equiv ) in ch2cl2 and so2cl2 ( 1 equiv ) in ch2cl2 . yield = 60% ( was obtained as a white solid ) ; rf = 0.45 [ sio2 , ch2cl2/meoh ( 95  :  5 ) ] ; mp 6465c ( described : 6263c ) . ir ( kbr ,   cm ) : 3280 ( nh ) , 1333 and 1150 ( so2 ) . h nmr ( cdcl3 ) : 0.95 ( t , j = 7.2  hz , 6h , ch3 ) , 1.57 ( sext , j = j = 7.1  hz , 4h , -ch2 ) , 2.99 ( q , 4h , -ch2 ) , 4.27 ( t broad , 2h , nh ) . c nmr ( cdcl3 ) : 11.26 ( -c ) , 22.89 ( -c ) , 44.95 ( -c ) . n , n-dibutylsulfamide ( 1b)yield = 58% ( was obtained as a white solid ) ; rf = 0.36 [ ( sio2 , ch2cl2 ) ) ] ; mp : 126127c ( described 126.5c ) . ir ( kbr ,   cm ) : 3281 ( nh ) , 1314 and 1145 ( so2 ) . h nmr ( cdcl3 ) : 4.33 ( t broad , 2h , nh ) , 3.04 ( m , 4h , -ch2 ) , 1.54 ( m , 4h , -ch2 ) , 1.38 ( m , 4h , -ch2 ) , 0.93 ( t , j = 7.1  hz , 6h , ch3 ) . c nmr ( cdcl3 ) : 43.2 ( -c ) , 31.7 ( -c ) , 20.11 ( -c ) , 13.88 ( ch3 ) . lrms ( ci ) : 209 [ m+h ] . yield = 58% ( was obtained as a white solid ) ; rf = 0.36 [ ( sio2 , ch2cl2 ) ) ] ; mp : 126127c ( described 126.5c ) . ir ( kbr ,   cm ) : 3281 ( nh ) , 1314 and 1145 ( so2 ) . h nmr ( cdcl3 ) : 4.33 ( t broad , 2h , nh ) , 3.04 ( m , 4h , -ch2 ) , 1.54 ( m , 4h , -ch2 ) , 1.38 ( m , 4h , -ch2 ) , 0.93 ( t , j = 7.1  hz , 6h , ch3 ) . c nmr ( cdcl3 ) : 43.2 ( -c ) , 31.7 ( -c ) , 20.11 ( -c ) , 13.88 ( ch3 ) . lrms ( ci ) : 209 [ m+h ] . n , n-di(2methoxyethyl)sulfamide ( 1c)yield = 61% ( was obtained as a viscous oil ) ; rf = 0.36 [ sio2 , ch2cl2/meoh ( 95  :  5 ) ] ; ir ( kbr ,   cm ) : 3279 ( nh ) , 1316 and 1147 ( so2 ) . h nmr ( cdcl3 ) : 3.22 ( q , 4h , -ch2 ) , 3.36 ( s , 6h , ch3 ) , 3.52 ( m , 4h , -ch2 ) , 5.28 ( t , 2h , nh ) , c nmr ( cdcl3 ) : 42.67 ( -c ) , 58.57 ( ch3 ) , 70.93 ( -c ) . lrms ( ci ) : 213 [ m+h ] . 
  yield = 61% ( was obtained as a viscous oil ) ; rf = 0.36 [ sio2 , ch2cl2/meoh ( 95  :  5 ) ] ; ir ( kbr ,   cm ) : 3279 ( nh ) , 1316 and 1147 ( so2 ) . h nmr ( cdcl3 ) : 3.22 ( q , 4h , -ch2 ) , 3.36 ( s , 6h , ch3 ) , 3.52 ( m , 4h , -ch2 ) , 5.28 ( t , 2h , nh ) , c nmr ( cdcl3 ) : 42.67 ( -c ) , 58.57 ( ch3 ) , 70.93 ( -c ) . n , n-dibenzylsulfamide ( 1d)yield = 59% ( was obtained as a white solid ) ; rf = 0.37 ( sio2 , ch2cl2 ) ; mp : 182184c ( described 180182c ) . ir ( kbr ,   cm ) : 3270 ( nh ) , 3034 ( ch - ar ) , 1350 and 1143 ( so2 ) . h nmr ( cdcl3 ) : 4.17 ( d , 4h , ch2 ) , 4.37 ( t broad , 2h , nh ) , 7.287.34 ( m , 10h , ar - h ) . lrms ( ci ) : 277 [ m+h ] , 199 , 91 . yield = 59% ( was obtained as a white solid ) ; rf = 0.37 ( sio2 , ch2cl2 ) ; mp : 182184c ( described 180182c ) . ir ( kbr ,   cm ) : 3270 ( nh ) , 3034 ( ch - ar ) , 1350 and 1143 ( so2 ) . h nmr ( cdcl3 ) : 4.17 ( d , 4h , ch2 ) , 4.37 ( t broad , 2h , nh ) , 7.287.34 ( m , 10h , ar - h ) . to a stirred solution of csi ( 1 equiv , 10  mmol , 1.4153  g ) in 20  ml of anhydrous dichloromethane at 0c was added a solution of tert - butyl alcohol ( 1 equiv , 10  mmol , 0.7412  g ) in 20  ml of dried ch2cl2 . 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 ch2cl2 . 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 ( na2so4 ) and concentrated in vacuo to give the crude product . n , n-bis(tert - butoxycarbonylsulfamoyl)-1,2-diaminoethane ( 2c)this compound was prepared according to the general procedure b using a solution of 1,2-ethan diamine ( 0.5 equiv , 5  mmol , 0.6010  g ) in ch2cl2 . yield = 70% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2-meoh 95  :  5 ] ; ir(kbr ,   cm ) : 3286 and 3311(nh ) ; 1709 ( c = o ) ; 1346 and 1141 ( so2 ) . h nmr ( dmso - d6 ) : 10.90 ( s , 2h , nhboc ) ; 7.65 ( s , 2h , nh ) ; 2.98 ( s , 4h , ch2 ) ; 1.43 ( s , 18h , tbu ) . hrms esi : m / z : 441 [ m+na ] . this compound was prepared according to the general procedure b using a solution of 1,2-ethan diamine ( 0.5 equiv , 5  mmol , 0.6010  g ) in ch2cl2 . yield = 70% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2-meoh 95  :  5 ] ; ir(kbr ,   cm ) : 3286 and 3311(nh ) ; 1709 ( c = h nmr ( dmso - d6 ) : 10.90 ( s , 2h , nhboc ) ; 7.65 ( s , 2h , nh ) ; 2.98 ( s , 4h , ch2 ) ; 1.43 ( s , 18h , tbu ) . n , n-bis(tert - butoxycarbonylsulfamoyl)-1,3-diaminopropane ( 2d)this compound was prepared according to the general procedure b using a solution of 1,3-propandiamine ( 0.5 equiv , 5  mmol , 0.3706  g ) in dichloromethane yield = 70% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2-meoh 95  :  5 ] ; mp : 175177c . ir ( kbr ,   cm ) : 3266 and 3212(nh ) ; 1697 ( c = o ) ; 1348 and 1138 ( so2 ) . h nmr ( dmso - d6 ) : 10.79 ( s , 2h , nhboc ) ; 7.52 ( t , 2h , nh ) ; 2.89 ( q , 4h , ch2-n ) ; 1.63 ( m , 2h , ch2 ) ; 1.42 ( s , 18h , tbu ) . hrms . esi : m / z : 455 [ m+na ] , 887 [ m*2+na ] . this compound was prepared according to the general procedure b using a solution of 1,3-propandiamine ( 0.5 equiv , 5  mmol , 0.3706  g ) in dichloromethane yield = 70% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2-meoh 95  :  5 ] ; mp : 175177c . ir ( kbr ,   cm ) : 3266 and 3212(nh ) ; 1697 ( c = o ) ; 1348 and 1138 ( so2 ) . h nmr ( dmso - d6 ) : 10.79 ( s , 2h , nhboc ) ; 7.52 ( t , 2h , nh ) ; 2.89 ( q , 4h , ch2-n ) ; 1.63 ( m , 2h , ch2 ) ; 1.42 ( s , 18h , tbu ) . esi : m / z : 455 [ m+na ] , 887 [ m*2+na ] . 
 compound ( 2e)this compound was prepared according to the general procedure b using a solution of l - cystine methyl ester dihydrochloride ( 0.5 equiv , 5  mmol , 1.7064  g ) in ch2cl2 and triethylamine ( 2 equiv , 20  mmol , 2.0238  g ) . yield = 71% ( was obtained as a white solid ) ; rf = 0.37 [ sio2 , ch2cl2-meoh 95  :  5 ] ; ir ( kbr ,   cm ) : 3289 and 3240(nh ) ; 1709 and 1748 ( c = o ) ; 1364 and 1139 ( so2 ) . h nmr ( dmso - d6 ) : 10.98 ( s , 2h , nhboc ) ; 8.40 ( d , 2h , nh ) ; 4.22 ( q , 2h , ch ) ; 3.66 ( s , 6h , ch3 ) ; 3.00 ( d , 4h , ch2 ) ; 1.41 ( s , 18h , tbu ) . hrms esi : m / z : 659 [ m+na ] , 1275 [ m*2+na ] . this compound was prepared according to the general procedure b using a solution of l - cystine methyl ester dihydrochloride ( 0.5 equiv , 5  mmol , 1.7064  g ) in ch2cl2 and triethylamine ( 2 equiv , 20  mmol , 2.0238  g ) . yield = 71% ( was obtained as a white solid ) ; rf = 0.37 [ sio2 , ch2cl2-meoh 95  :  5 ] ; ir ( kbr ,   cm ) : 3289 and 3240(nh ) ; 1709 and 1748 ( c = o ) ; 1364 and 1139 ( so2 ) . h nmr ( dmso - d6 ) : 10.98 ( s , 2h , nhboc ) ; 8.40 ( d , 2h , nh ) ; 4.22 ( q , 2h , ch ) ; 3.66 ( s , 6h , ch3 ) ; 3.00 ( d , 4h , ch2 ) ; 1.41 ( s , 18h , tbu ) . hrms esi : m / z : 659 [ m+na ] , 1275 [ m*2+na ] . dimethyl-5,5-oxybis(2-(n-(tert - butoxycarbonyl)sulfamoylamino)pentanoate ) ( 2f)this compound was prepared according to the general procedure b using a solution of 1,3-propan diamine ( 0.5 equiv , 5  mmol , 0.661  g ) . yield = 73% ( was obtained as a white solid ) ; rf = 0.49 [ sio2 , ch2cl2-meoh 95  :  5 ] ; mp : 132134c . ir ( kbr ,   cm ) : 3296 ( nh ) ; 1713 and 1738 ( c = o ) ; 1371 and 1143 ( so2 ) . h nmr ( cdcl3 ) : 7.52 ( s , 2h , nhboc ) ; 5.79 ( t , 2h , nh ) ; 3.57 ( t , 4h , ch2o ) ; 3.20 ( q , 4h , ch2n ) ; 1.84 ( m , 4h , ch2 ) ; 1.49 ( s , 18h , tbu ) . hrms esi : m / z : 514 [ m+na ] , 1004 [ m*2+na ] . this compound was prepared according to the general procedure b using a solution of 1,3-propan diamine ( 0.5 equiv , 5  mmol , 0.661  g ) . yield = 73% ( was obtained as a white solid ) ; rf = 0.49 [ sio2 , ch2cl2-meoh 95  :  5 ] ; mp : 132134c . ir ( kbr ,   cm ) : 3296 ( nh ) ; 1713 and 1738 ( c = o ) ; 1371 and 1143 ( so2 ) . h nmr ( cdcl3 ) : 7.52 ( s , 2h , nhboc ) ; 5.79 ( t , 2h , nh ) ; 3.57 ( t , 4h , ch2o ) ; 3.20 ( q , 4h , ch2n ) ; 1.84 ( m , 4h , ch2 ) ; 1.49 ( s , 18h , tbu ) . hrms esi : m / z : 514 [ m+na ] , 1004 [ m*2+na ] . 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 ch2cl2 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 et3n ( 1 equiv , 10  mmol , 1.0119  g ) . the mixture was then diluted with ch2cl2 ( 100  ml ) and washed with 2 portions of 1  m hcl and water . the solution was then dried with na2so4 and concentrated in vacuum to give the crude product . recrystallization from ch2cl2 at low temperature or chromatography on silica gel ( eluent : ch2cl2/meoh , 9  :  1 ) afforded the pure carboxyl sulfamide . the synthesis of the compounds , starting from csi , tert - butyl alcohol and methyl esters of amino acids ( l - alanine 2j and l - phenylalanine 2  h ) has been previously reported [ 9 , 10 ] . 
 ethyl [ n,(n-tert - butyloxycarbonyl)-sulfamoyl]-acetate ( 2 g ) this compound was prepared according to the general procedure c using a solution of glycine ethyl ester hydrochloride ( 1 equiv , 10  mmol , 1.396  g ) . yield = 72% ( was obtained as a white solid ) ; rf = 0.60 [ sio2 , ch2cl2-meoh 9  :  1 ] ; mp 122123c . ir ( kbr ,   cm ) : 1352 and 1126 ( so2 ) , 1735 and 1675 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.5 ( s , 9h , tbu ) , 1.30 ( t , 3h , ch3 ) , 3.96 ( d , 2h , n - ch2 ) , 4.24 ( q , 2h , ch2 ) , 5.63 ( t , 1h , nh - ch2 ) , 7.25 ( s , 1h , nhboc ) . this compound was prepared according to the general procedure c using a solution of glycine ethyl ester hydrochloride ( 1 equiv , 10  mmol , 1.396  g ) . yield = 72% ( was obtained as a white solid ) ; rf = 0.60 [ sio2 , ch2cl2-meoh 9  :  1 ] ; mp 122123c . ir ( kbr ,   cm ) : 1352 and 1126 ( so2 ) , 1735 and 1675 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.5 ( s , 9h , tbu ) , 1.30 ( t , 3h , ch3 ) , 3.96 ( d , 2h , n - ch2 ) , 4.24 ( q , 2h , ch2 ) , 5.63 ( t , 1h , nh - ch2 ) , 7.25 ( s , 1h , nhboc ) methyl [ n,(n-tert - butyloxycarbonyl)-sulfamoyl]-2-phenyglycynate ( 2i)this compound was prepared according to the general procedure c using a solution of phenyl glycine methyl ester hydrochloride ( 1 equiv , 10  mmol , 2.0165  g ) . yield = 76% ( was obtained as a white solid ) ; rf = 0.70 [ sio2 , ch2cl2-meoh 9  :  1 ] ; mp 144146c . ir ( kbr ,   cm ) : 1362 and 1141 ( so2 ) , 17351712 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.44 ( s , 9h , tbu ) , 3.74 ( s , 3h , o - ch3 ) , 5.27 ( d , 1h , ch ) , 6.27 ( d , 1h , nh ) , 7.36 ( s , 5h , ph ) , 7.44 ( s , 1h , nhboc ) . this compound was prepared according to the general procedure c using a solution of phenyl glycine methyl ester hydrochloride ( 1 equiv , 10  mmol , 2.0165  g ) . yield = 76% ( was obtained as a white solid ) ; rf = 0.70 [ sio2 , ch2cl2-meoh 9  :  1 ] ; mp 144146c . ir ( kbr ,   cm ) : 1362 and 1141 ( so2 ) , 17351712 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.44 ( s , 9h , tbu ) , 3.74 ( s , 3h , o - ch3 ) , 5.27 ( d , 1h , ch ) , 6.27 ( d , 1h , nh ) , 7.36 ( s , 5h , ph ) , 7.44 ( s , 1h , nhboc ) . to a stirring solution of [ n - tert - butyloxycarbonyl , n-alkyl]-sulfamide ( 1 equiv , 1  mmol ) in ch3cn ( 50  ml ) in a 100  ml round bottom flask was added k2co3 ( 2.5 equiv , 2.5  mmol , 0.34552  g ) and ,-dibromo - o - xylene ( 1 equiv , 1  mmol , 0.26396  g ) . the resulting mixture was stirred at reflux for 4 hours then cooled to room temperature . the residue was dissolved in ch2cl2 , washed with 2 portions of hcl ( 1  m ) and water and dried with na2so4 , and the solvent was removed under reduced pressure to give the crude oil . flash chromatography on silica gel ch2cl2 to furnish the pure fused cyclic sulfamide in 7085% yields the following . 1,5-dihydro-2-tert - butoxycarbonyl-4-benzylbenzo[d]thiadiazepine-3,3-dioxides ( 3a)this compound was prepared according to the general procedure d , using a solution of 2a ( 1 equiv , 1  mmol , 0.28635  g ) . yield = 71% ( was obtained as a viscous oil ) ; rf = 0.36 [ sio2 , ch2cl2 ] . ir ( kbr ,   cm ) : 1389 and 1141 ( so2 ) , 1732 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 9h , tbu ) , 4.14 ( s , 2h , ch2-n ) , 4.37 ( s , 2h , ch2-n - boc ) , 4.91 ( s , 2h , ch2-ph ) , 7.037.37 ( m , 9h , h - ar ) . this compound was prepared according to the general procedure d , using a solution of 2a ( 1 equiv , 1  mmol , 0.28635  g ) . yield = 71% ( was obtained as a viscous oil ) ; rf = 0.36 [ sio2 , ch2cl2 ] . ir ( kbr ,   cm ) : 1389 and 1141 ( so2 ) , 1732 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 9h , tbu ) , 4.14 ( s , 2h , ch2-n ) , 4.37 ( s , 2h , ch2-n - boc ) , 4.91 ( s , 2h , ch2-ph ) , 7.037.37 ( m , 9h , h - ar ) . 1,5-dihydro-2-tert - butoxycarbonyl-4-(cyclohexyl)benzo[d]thiadiazepine-3,3-dioxides ( 3b)this compound was prepared according to the general procedure d , using a solution of 2b ( 1 equiv , 1  mmol , 0.27837  g ) . yield = 80% ( was obtained as a white solid ) ; rf = 0.42 [ sio2 , ch2cl2 ] ; mp 9698c . ir ( kbr ,   cm ) : 1376 and 1145 ( so2 ) , 1726 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.231.72 ( m , 10h , cyclohexyl ) ; 1.41 ( s , 9h , tbu ) , 3.94 ( m , 1h , ch ) , 4.58 ( s , 2h , ch2 ) , 4.88 ( s , 2h , ch2 ) , 7.207.28 ( m , 4h , h - ar ) . this compound was prepared according to the general procedure d , using a solution of 2b ( 1 equiv , 1  mmol , 0.27837  g ) . yield = 80% ( was obtained as a white solid ) ; rf = 0.42 [ sio2 , ch2cl2 ] ; mp 9698c . ir ( kbr ,   cm ) : 1376 and 1145 ( so2 ) , 1726 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.231.72 ( m , 10h , cyclohexyl ) ; 1.41 ( s , 9h , tbu ) , 3.94 ( m , 1h , ch ) , 4.58 ( s , 2h , ch2 ) , 4.88 ( s , 2h , ch2 ) , 7.207.28 ( m , 4h , h - ar ) . 1,5-dihydro-2-tert - butoxycarbonyl-4-((ethoxycarbonyl)methyl)benzo[d]thiadiazepine-3,3-dioxides ( 3c)this compound was prepared according to the general procedure d , using a solution of 2  g ( 1 equiv , 1  mmol , 0.28231  g ) . yield = 79% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2 ] ; mp 9192c . ir ( kbr ,   cm ) : 1382 and 1134 ( so2 ) , 1729 and 1748 2(c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.28 ( t , 3h , ch3 ) , 1.41 ( s , 9h , tbu ) , 3.77 ( s , 2h , ch2co ) , 4.23 ( q , 2h , ch2-o ) , 4.72 ( s , 2h , ch2-n ) , 4.88 ( s , 2h , ch2-n - boc ) , 7.207.35 ( m , 4h , h - ar ) . hrms esi : m / z : 407 [ m+na ] , 791[m*2+na ] . this compound was prepared according to the general procedure d , using a solution of 2  g ( 1 equiv , 1  mmol , 0.28231  g ) . yield = 79% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2 ] ; mp 9192c . ir ( kbr ,   cm ) : 1382 and 1134 ( so2 ) , 1729 and 1748 2(c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.28 ( t , 3h , ch3 ) , 1.41 ( s , 9h , tbu ) , 3.77 ( s , 2h , ch2co ) , 4.23 ( q , 2h , ch2-o ) , 4.72 ( s , 2h , ch2-n ) , 4.88 ( s , 2h , ch2-n - boc ) , 7.207.35 ( m , 4h , h - ar ) . hrms esi : m / z : 407 [ m+na ] , 791[m*2+na ] . 1,5-dihydro-2-tert - butoxycarbonyl-4-(benzyl(methoxycarbonyl)methyl)benzo[d]thiadiazepine-3,3-dioxides ( 3d)this compound was prepared according to the general procedure d , using a solution of 2  h ( 1 equiv , 1  mmol , 0.35841  g ) . yield = 76% ( was obtained as a viscous oil ) ; rf = 0.37 [ sio2 , ch2cl2 ] . ir ( kbr ,   cm ) : 1368 and 1142 ( so2 ) , 1735 and 1742 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.40 ( s , 9h , tbu ) , 3.25 ( s , 3h , ch3o ) , 5.01 ( t , 1h , ch ) , 4.76 ( d , 2h , ch2-ph ) , 4.73 ( s , 2h , ch2n  boc ) , 4.65 ( s , 2h , ch2n ) , 7.087.28 ( m , 9h , ar - h ) . hrms esi : m / z : 483 [ m+na ] , 944[m*2+na ] . this compound was prepared according to the general procedure d , using a solution of 2  h ( 1 equiv , 1  mmol , 0.35841  g ) . yield = 76% ( was obtained as a viscous oil ) ; rf = 0.37 [ sio2 , ch2cl2 ] . ir ( kbr ,   cm ) : 1368 and 1142 ( so2 ) , 1735 and 1742 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.40 ( s , 9h , tbu ) , 3.25 ( s , 3h , ch3o ) , 5.01 ( t , 1h , ch ) , 4.76 ( d , 2h , ch2-ph ) , 4.73 ( s , 2h , ch2n  boc ) , 4.65 ( s , 2h , ch2n ) , 7.087.28 ( m , 9h , ar - h ) . hrms esi : m / z : 483 [ m+na ] , 944[m*2+na ] . 1,5-dihydro-2-tert - butoxycarbonyl-4-(phenyl(methoxycarbonyl)methyl)benzo[d]thiadiazepine-3,3-dioxides ( 3e)this compound was prepared according to the general procedure d , using a solution of 2i ( 1 equiv , 1  mmol , 0.34438  g ) . yield = 66% ( was obtained as a white solid ) ; rf = 0.38 [ sio2 , ch2cl2 ] ; mp : 9092c . ir ( kbr ,   cm ) : 1314 and 1138 ( so2 ) , 1732 and 1708 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 9h , tbu ) , 3.66 ( s , 3h , ch3-o ) , 5.96 ( s , 1h , ch ) , 6.987.32 ( m , 9h , h - ar ) , 4.384.80 ( dd , 2h , chahb - n ) , 4.855.05 ( dd , 2h , chahb - n - boc ) , 6.987.32 ( m , 9  h , h - ar ) . hrms esi : m / z : 469 [ m+na ] , 915[m*2+na ] . this compound was prepared according to the general procedure d , using a solution of 2i ( 1 equiv , 1  mmol , 0.34438  g ) . yield = 66% ( was obtained as a white solid ) ; rf = 0.38 [ sio2 , ch2cl2 ] ; mp : 9092c . ir ( kbr ,   cm ) : 1314 and 1138 ( so2 ) , 1732 and 1708 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 9h , tbu ) , 3.66 ( s , 3h , ch3-o ) , 5.96 ( s , 1h , ch ) , 6.987.32 ( m , 9h , h - ar ) , 4.384.80 ( dd , 2h , chahb - n ) , 4.855.05 ( dd , 2h , chahb - n - boc ) , 6.987.32 ( m , 9  h , h - ar ) . an acetonitrile solution ( 50  ml ) containing n , n-disubstituted symmetric sulfamide ( 2 equiv , 2  mmol ) , 2,3,4,5-tetrakis(bromomethyl)benzene ( 1 equiv , 1  mmol , 0.44980  g ) , and anhydrous k2co3 ( 4.5 equiv , 4.5  mmol , 0.6219  g ) was heated at reflux for 10 hours . the reaction mixture was cooled to room temperature , filtered , and after removal of the solvent under reduced pressure a solid was obtained . the solid was redissolved in dichloromethane ( ch2cl2 ) , washed with 2 portions of hcl 1  m ( 2  20  ml ) followed with water ( 2  30  ml ) , and dried with na2so4 . the residue was purified by chromatography on silica gel using ch2cl2 to yield fused symmetric and asymmetric benzothiadiazepines 
 compound ( 4a)this compound was prepared according to the general procedure e , using a solution of 1a ( 2 equiv , 2  mmol and 0.36054  g ) . yield = 76% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2 ] ; mp 264266c . ir ( kbr ,   cm ) : 1339 and 1148 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 0.90 ( t , 12h , ch3 ) , 1.58 ( m , 8h , -ch2 ) , 2.91 ( t , 8h , -ch2 ) , 4.46 ( s , 8h , n - ch2-ar ) , 7.15 ( s , 2h , h - ar ) . c nmr ( cdcl3 ) : 11.02 ( -c ) , 21.08 ( -c ) , 48.90 ( -c ) , 50.03 ( ch2 ) , 132.50 and 136.85 ( car ) . lrms ( ci ) : 487 [ m+h ] ; hrms esi : m / z : 509 [ m+na ] . this compound was prepared according to the general procedure e , using a solution of 1a ( 2 equiv , 2  mmol and 0.36054  g ) . yield = 76% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2 ] ; mp 264266c . ir ( kbr ,   cm ) : 1339 and 1148 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 0.90 ( t , 12h , ch3 ) , 1.58 ( m , 8h , -ch2 ) , 2.91 ( t , 8h , -ch2 ) , 4.46 ( s , 8h , n - ch2-ar ) , 7.15 ( s , 2h , h - ar ) . c nmr ( cdcl3 ) : 11.02 ( -c ) , 21.08 ( -c ) , 48.90 ( -c ) , 50.03 ( ch2 ) , 132.50 and 136.85 ( car ) . lrms ( ci ) : 487 [ m+h ] ; hrms esi : m / z : 509 [ m+na ] . compound ( 4b)this compound was prepared according to the general procedure e , using a solution of 1b ( 2 equiv , 2  mmol and 0.41664  g ) . yield = 79% ( was obtained as a white solid ) ; rf = 0.29 [ sio2 , ch2cl2 ] ; mp 141143c . ir ( kbr ,   cm ) : 1354 and 1149 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 0.91 ( t , 12h , ch3 ) , 1.34 ( m , 8h , -ch2 ) , 1.52 ( m , 8h , -ch2 ) , 2.94 ( t , 8h , -ch2 ) , 4.46 ( s , 8h , n - ch2 ) , 7.16 ( s , 2h , h - ar ) . c nmr ( cdcl3 ) : 13.68 ( -c ) , 19.58 ( -c ) , 29.79 ( -c ) , 46.82 ( -c ) , 49.97 ( ch2 ) , 132.49 and136.85 ( car ) . lrms ( ci ) : 543 [ m+h ] ; hrms esi : m / z : 567 [ m+na ] . this compound was prepared according to the general procedure e , using a solution of 1b ( 2 equiv , 2  mmol and 0.41664  g ) . yield = 79% ( was obtained as a white solid ) ; rf = 0.29 [ sio2 , ch2cl2 ] ; mp 141143c . ir ( kbr ,   cm ) : 1354 and 1149 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 0.91 ( t , 12h , ch3 ) , 1.34 ( m , 8h , -ch2 ) , 1.52 ( m , 8h , -ch2 ) , 2.94 ( t , 8h , -ch2 ) , 4.46 ( s , 8h , n - ch2 ) , 7.16 ( s , 2h , h - ar ) . c nmr ( cdcl3 ) : 13.68 ( -c ) , 19.58 ( -c ) , 29.79 ( -c ) , 46.82 ( -c ) , 49.97 ( ch2 ) , 132.49 and136.85 ( car ) . lrms ( ci ) : 543 [ m+h ] ; hrms esi : m / z : 567 [ m+na ] . compound ( 4c)this compound was prepared according to the general procedure e , using a solution of 1d ( 2 equiv , 2  mmol and 0.5527  g ) . yield = 75% ( was obtained as a white solid ) ; rf = 0.46 [ sio2 , ch2cl2 ] ; mp 313314c . ir ( kbr ,   cm ) : 1364 and 1157 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 4.25 ( s , 8h , ch2-ph ) , 4.35 ( s , 8h , n - ch2 ) , 6.79 ( s , 2h , h - ar ) , 7.287.37 ( m , 20h , ph ) . this compound was prepared according to the general procedure e , using a solution of 1d ( 2 equiv , 2  mmol and 0.5527  g ) . yield = 75% ( was obtained as a white solid ) ; rf = 0.46 [ sio2 , ch2cl2 ] ; mp 313314c . ir ( kbr ,   cm ) : 1364 and 1157 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 4.25 ( s , 8h , ch2-ph ) , 4.35 ( s , 8h , n - ch2 ) , 6.79 ( s , 2h , h - ar ) , 7.287.37 ( m , 20h , ph ) . hrms esi : m / z : 701 [ m+na ] . compound ( 4d)this compound was prepared according to the general procedure e , using a solution of 2a ( 2 equiv , 2  mmol , 0.5727  g ) . yield = 55% ( was obtained as a white solid ) ; rf = 0.22 [ sio2 , ch2cl2 ] ; mp 160162c . ir ( kbr ,   cm ) : 1392 and 1150 ( so2 ) , 1715 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.42 ( s , 18h , tbu ) , 4.05 ( s , 4h , ch2-n - bn ) , 4.39 ( s , 4h , ch2-n - boc ) , 4.90 ( s , 4h , ch2-ph ) , 7.13 ( s , 2h , h - ar ) , 7.367.44 ( m , 10h , ph ) . this compound was prepared according to the general procedure e , using a solution of 2a ( 2 equiv , 2  mmol , 0.5727  g ) . yield = 55% ( was obtained as a white solid ) ; rf = 0.22 [ sio2 , ch2cl2 ] ; mp 160162c . ir ( kbr ,   cm ) : 1392 and 1150 ( so2 ) , 1715 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.42 ( s , 18h , tbu ) , 4.05 ( s , 4h , ch2-n - bn ) , 4.39 ( s , 4h , ch2-n - boc ) , 4.90 ( s , 4h , ch2-ph ) , 7.13 ( s , 2h , h - ar ) , 7.367.44 ( m , 10h , ph ) . hrms esi : m / z : 721 [ m+na ] . compound ( 4d)yield = 15% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2 ] ; mp 159161c . ir ( kbr ,   cm ) : 1371 and 1155 ( so2 ) , 1715 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.45 ( s , 18h , tbu ) , 4.17 ( s , 4h , ch2-n - bn ) , 4.40 ( s , 4h , ch2-n - boc ) , 4.90 ( s , 4h , ch2-ph ) , 6.75 ( s,1h , h - ar ) , 7.27 ( s , 1h , h - ar ) , 7.367.44 ( m , 10h , ph ) . hrms esi : m / z : 721 [ m+na ] . yield = 15% ( was obtained as a white solid ) ; rf = 0.25 [ sio2 , ch2cl2 ] ; mp 159161c . ir ( kbr ,   cm ) : 1371 and 1155 ( so2 ) , 1715 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.45 ( s , 18h , tbu ) , 4.17 ( s , 4h , ch2-n - bn ) , 4.40 ( s , 4h , ch2-n - boc ) , 4.90 ( s , 4h , ch2-ph ) , 6.75 ( s,1h , h - ar ) , 7.27 ( s , 1h , h - ar ) , 7.367.44 ( m , 10h , ph ) . hrms esi : m / z : 721 [ m+na ] . compound ( 4f)this compound was prepared according to the general procedure e , using a solution of 2j ( 2 equiv , 2  mmol , 0.5646  g ) . yield = 37% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2 ] ; mp 169171c . ir ( kbr ,   cm ) : 1368 and 1144 ( so2 ) , 1732 and 1745 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.44 ( s , 18h , tbu ) , 1.34 ( d , 6h , ch3 ) , 3.53 ( s , 6h , o - ch3 ) , 4.65 ( q , 2h , ch ) , 4.86 ( s , 4h , n - ch2-ar ) , 5.00 ( s , 4h , ch2-n - boc ) , 7.13 ( s , 2h , h - ar ) . this compound was prepared according to the general procedure e , using a solution of 2j ( 2 equiv , 2  mmol , 0.5646  g ) . yield = 37% ( was obtained as a white solid ) ; rf = 0.20 [ sio2 , ch2cl2 ] ; mp 169171c . ir ( kbr ,   cm ) : 1368 and 1144 ( so2 ) , 1732 and 1745 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.44 ( s , 18h , tbu ) , 1.34 ( d , 6h , ch3 ) , 3.53 ( s , 6h , o - ch3 ) , 4.65 ( q , 2h , ch ) , 4.86 ( s , 4h , n - ch2-ar ) , 5.00 ( s , 4h , ch2-n - boc ) , 7.13 ( s , 2h , h - ar ) . compound ( 4f)yield = 34% ( was obtained as a white solid ) ; rf = 0.24 [ sio2 , ch2cl2 ] ; mp 168170c . ir ( kbr ,   cm ) : 1390 and 1144 ( so2 ) , 1732 and 1750 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.42 ( s , 18h , tbu ) , 1.30 ( d , 6h , ch3 ) , 3.47 ( s , 6h , o - ch3 ) , 4.63 ( q , 2h , ch ) , 4.84 ( s , 4h , n - ch2-ar ) , 4.96 ( s , 4h , ch2-n - boc ) , 7.00 ( s , 1h , h - ar ) , 7.24 ( s , 1h , h - ar ) . yield = 34% ( was obtained as a white solid ) ; rf = 0.24 [ sio2 , ch2cl2 ] ; mp 168170c . ir ( kbr ,   cm ) : 1390 and 1144 ( so2 ) , 1732 and 1750 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.42 ( s , 18h , tbu ) , 1.30 ( d , 6h , ch3 ) , 3.47 ( s , 6h , o - ch3 ) , 4.63 ( q , 2h , ch ) , 4.84 ( s , 4h , n - ch2-ar ) , 4.96 ( s , 4h , ch2-n - boc ) , 7.00 ( s , 1h , h - ar ) , 7.24 ( s , 1h , h - ar ) . compound ( 4e)this compound was prepared according to the general procedure e , using a solution of 2  g ( 2 equiv , 2  mmol , 0.5646  g ) . yield = 48% ( was obtained as a white solid ) ; rf = 0.18 [ sio2 , ch2cl2 ] ; mp 181183c . ir ( kbr ,   cm ) : 1380 and 1139 ( so2 ) , 1723 and 1751 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.40 ( s , 18h , tbu ) , 1.29 ( t , 6h , ch3 ) , 3.75 ( s , 4h , ch2co ) , 4.22 ( q , 4h , ch2ch3 ) , 4.73 ( s , 4h , ch2 ) , 4.86 ( s , 4h , ch2-n - boc ) , 7.21 ( s , 2h , h - ar ) . hrms esi : m / z : 713 [ m+na ] . this compound was prepared according to the general procedure e , using a solution of 2  g ( 2 equiv , 2  mmol , 0.5646  g ) . yield = 48% ( was obtained as a white solid ) ; rf = 0.18 [ sio2 , ch2cl2 ] ; mp 181183c . ir ( kbr ,   cm ) : 1380 and 1139 ( so2 ) , 1723 and 1751 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.40 ( s , 18h , tbu ) , 1.29 ( t , 6h , ch3 ) , 3.75 ( s , 4h , ch2co ) , 4.22 ( q , 4h , ch2ch3 ) , 4.73 ( s , 4h , ch2 ) , 4.86 ( s , 4h , ch2-n - boc ) , 7.21 ( s , 2h , h - ar ) . hrms esi : m / z : 713 [ m+na ] . compound ( 4e)yield = 24% ( was obtained as a white solid ) ; rf = 0.22 [ sio2 , ch2cl2 ] ; mp 179181c . ir ( kbr ,   cm ) : 1380 and 1139 ( so2 ) , 1723 and 1755 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 18h : tbu ) , 1.28 ( t , 6h : ch3 ) , 3.77 ( s , 4h , ch2co ) , 4.20 ( q , 4h , ch2ch3 ) , 4.71 ( s , 4h , ch2 ) , 4.90 ( s , 4h , ch2-n - boc ) , 7.05 ( s , 1h , h - ar ) , 7.32 ( s , 1h , h - ar ) . yield = 24% ( was obtained as a white solid ) ; rf = 0.22 [ sio2 , ch2cl2 ] ; mp 179181c . ir ( kbr ,   cm ) : 1380 and 1139 ( so2 ) , 1723 and 1755 ( c = o ) . h nmr ( 300  mhz , cdcl3 ) : 1.43 ( s , 18h : tbu ) , 1.28 ( t , 6h : ch3 ) , 3.77 ( s , 4h , ch2co ) , 4.20 ( q , 4h , ch2ch3 ) , 4.71 ( s , 4h , ch2 ) , 4.90 ( s , 4h , ch2-n - boc ) , 7.05 ( s , 1h , h - ar ) , 7.32 ( s , 1h , h - ar ) . hrms esi : m / z : 713 [ m+na ] . a solution of 1-methoxy-4-tert - butyl-(2,6-dibromomethyl)benzene ( 1 equiv , 1  mmol , 0.350  g ) in 20  ml of anhydrous ch3cn and a solution of n , n - disubstituted sulfamide 1d ( 1 equiv , 1  mmol , 0.2763  g ) in ch3cn ( 20  ml ) were slowly added by syringe pump over several 5 hours at the same rate to a mixture of k2co3 ( 4.5 equiv , 4.5  mmol , 0.622  g ) and ch3cn ( 150  ml ) . after stirring at reflux for 24  h , the residue was dissolved in ch2cl2 , washed with hcl ( 0.1  n ) ( 2  20  ml ) water ( 2  30  ml ) , and dried with na2so4 and the solvent was evaporated under reduced pressure . the residue was purified by chromatography on silica gel using ch2cl2 to yield the pure macrocyclic sulfamide 5a . macrocyclic sulfamide ( 5a)yield = 58% ( was obtained as a white solid ) ; rf = 0.47 [ sio2 , ch2cl2 ] ; mp > 350c . ir ( kbr ,   cm ) : 1361 and 1148 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 1.35 ( s , 18h , tbu ) , 3.10 ( s , 6h , ch3 ) , 3.8 ( br , 8h , n - ch2 ) , 4.85 ( br , 8h , ch2-ph ) , 6.78 ( s , 4h , h - ar ) , 7.307.45 ( m , 20h , ph ) . yield = 58% ( was obtained as a white solid ) ; rf = 0.47 [ sio2 , ch2cl2 ] ; mp > 350c . ir ( kbr ,   cm ) : 1361 and 1148 ( so2 ) . h nmr ( 300  mhz , cdcl3 ) : 1.35 ( s , 18h , tbu ) , 3.10 ( s , 6h , ch3 ) , 3.8 ( br , 8h , n - ch2 ) , 4.85 ( br , 8h , ch2-ph ) , 6.78 ( s , 4h , h - ar ) , 7.307.45 ( m , 20h , ph ) .
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 .