Sulfonamide substitution-cyclization reaction

Acylic syn-1,4-chloroacetates were used in a similar sulfonamide substitution-cyclization reaction for their transforaiation to stereodefined 2,5-disubstituted pyrrolidines (Scheme 8-24] [83]. Some of these 2,5-disiibstitiited pyrrolidines are ant venom pheromones and are also found in the skin of frogs. 

An anionic equivalent of the Friedel-Crafts cyclization reaction has been developed for the formation of the C /C-5 bond of the 1,2-benzothiazine structure (Equation 35 Table 5) <1997SL1079>. In this reaction, directed metalation of sulfonamide-substituted aromatic systems 233 with an excess of LDA affords aryl lithium species 234 in a regiocontrolled fashion. This intermediate then reacts in situ with a proximal amide to form l,2-benzothiazine-4-one 1,1-dioxides 235. The yields of this transformation appear to be highly dependent upon the substitution pattern in 233. The authors attribute the low yield when = methyl and = H to a-deprotonation of the amide moiety. 

The Paal-Knorr method can be applied to the synthesis of a variety of 1-substituted pyrroles using commercially available 2,5-dialkoxytetrahydrofurans as a butane-1,4-dial equivalent. When an appropriate tetrahydrofuran derivative is available, the reaction can be used for more highly substituted pyrroles. Aliphatic and aromatic amines react readily and even weakly nucleophilic sulfonamides undergo cyclization (equation 66) (73SC303). 

Several synthetic approaches to the l,2-benzothiazin-3-ones have been described. Usually, an ortho-substituted sulfonamide was cyclized to form the thiazine ring. For example, Lombardino and Wiseman14,38 treated /V-methyl-o-toluenesulfonamide (45) with butyllithium the dianion with CO 2 produced o-sulfamoylphenylacetic acid 46 which was cyclodehydrated to 3,4-dihydro-2-alkyl-l,2-benzothiazin-3(2H)-one 1,1-dioxide (47) in good yield (Eq. 10). This same reaction sequence was applied to analogs of 47 such as the 7-methyl, the 7-chloro, and the 2-benzyl derivatives.38... 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

Substitution of the acetate group at the C-3 position of the /3-sultam 105 can occur by reaction with silyl enol ethers in the presence of zinc iodide or zinc chloride. When the diazo compound is used, after desilylation with tetrabutyl-ammonium fluoride (TBAF), photochemical cyclization gives the bicyclic /3-sultam 106 as a mixture of two cis/ fra -diastereoisomers. When silyl enol ethers derived from cyclic ketones are used, the substitution product is stabilized by a retro-Michael-type reaction leading to open-chained sulfonamides 107 (Scheme 31) <1997LA1261>. 

Heck reactions involving nonaromatic components are particularly versatile synthetic processes. For example, 1,2,4-trienes and l,2-dien-4-ynes are readily prepared from propargyl carbonates." Intramolecular Heck cyclization followed by Diels-Alder or nucleophilic attackleads to bicyclic products. Substituted pyrrolidines and piperidines are formed by coupling of alkenyl sulfonamides with vinylic halides. ... 

The chloroacetoxylation approach was also used for the stereoselective synthesis of tropine and pseudotropine employing a sulfonamide as the nucleophile [91]. Using the same approach, scopine and pseudoscopine were synthesized (Scheme 11.26) [92]. The chloroacetoxylation of 6-benzyloxy-l,3-cycloheptadiene was highly diastereoselective, and produced only the diastereoisomer 73 shown. Transformation of the chloroacetate 73 to 74 was realized by a Pd(0)-catalyzed substitution of the chloride by a sulfonamide, which occurred with retention of configuration. Reaction of the aUyUc chloride with the sulfonamide salt in DMSO-water at 80 °C afforded the inversion product 75. Subsequent stereoselective epoxidation, cyclization, and deprotection afforded the target molecules scopine and pseudoscopine. 

Reaction outcomes have been reported for 1,6-hexadiene (W=CH2, X=Br, I), diallyl sulfide (W=S, X=Br, I), diallyl ether (W=0, X=Br, diallyl sulfone (W=S02, X=Br, I), diallylmalonates [W=C(C02R)2, X=C1, Br, ], diallyl sulfonamide (W=N-Ts, X=C1, Br), and diallyl carboxyamide (W=N-C02R, X=C1, Br, ). Changing the steric and electronic character of the olefins can infiuence the regiochemical outcome in these systems. Less-substituted olefins (eq 3), electron-rich acetylenes (eq 4), and allenes (eq 5) react preferentially. Bis-allenic and 1,6-diyne systems also undergo radical cyclization. These factors are exemplified below. 

Pd-catalyzed cyclization was also applied to the stereocontrolled preparation of chiral substituted tetrahydrofurans. The synthesis of optically active tetrahydrofurans was pioneered by Stork and Poirier,who described effective chirality transfer in the Pd-assisted cyclization of y-hydroxy allylic esters. Williams and Meyer deployed a variant of the 0-capture of 7r-allylpalladium complexes in the reactions of substimted trimethylenemethane palladium complexes developed by Trost, using aUylstannane (Scheme 32). A key intermediate 156 in the synthesis of amphidinolide K, a marine nam-ral product, was therefore synthesized starting from enantiopure diastereomer 160. Compound 160 was prepared by in situ transmetallation using the Corey chiral sulfonamide 159 with optically active aUylstannane 157 and then condensation with functionalized aldehyde 158. Formation of the c -2,5-disubstituted tetrahydrofuran 156 occurred with an excellent diastereoselectivity (cis/trans 13 1) and a good yield (88%) from the syn-1,4-precursor 160. 

Among chemical methods for the separation of amines, those of Hinsberg (reaction with / -toluenesulfonyl chloride) and of Alexander (94) (reaction with 3-nitrophthalic anhydride) are most commonly used. Tertiary amines do not react with the reagents mentioned and they can be separated after the reaction — for example, by extraction. Derivatives of primary amines with p-toluenesulfonyl chloride are soluble in alkali hydroxide solutions, in contrast to sulfonamides of secondary amines this is utilized for their separation. When primary and secondary amines are separated by reacting them with 3-nitrophthalic anhydride, use is made of the fact that only phthal-imine acids derived from primary amines can be cyclized. Practical utilization of both procedures is demonstrated by the separated of a mixture of aniline, ethylaniline, and diethylaniline. However, it should be mentioned that in a number of cases the procedures fail or do not lead to a sufficiently sharp separation. Negatively substituted amines which do not react with / -toluenesulfonyl chloride can be separated with 3-nitrophthalic anhydride. Some p-toluenesulfonamides of primary amines are poorly soluble in alkali. The derivative of primary amine with 3-nitrophthalic anhydride is cyclized merely by boiling in benzene, and the phthalimide formed is soluble in benzene and can be isolated together with the tertiary amine. 

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