Acetal sulfonamides, cyclization

The Bobbitt variation of the Pomeranz-Fritsch cyclization to obtain 4-hydroxytetrahydroisoquinolines continues to be a useful approach. " Jackson and co-workers have worked out a superior method for the preparation of substituted isoquinolines which involves cyclization, under mildly acidic conditions, of acetal sulfonamides. ... 

The most straightforward method for the synthesis of the sulfonamide class of 1,2-thiazines is the intramolecular amidation reaction between a sulfonyl chloride and an amine. Preparation of the sulfonyl chloride moiety via the oxidation of thiol acetate 179 and subsequent deprotection and cyclization afforded sulfonamide 180, an intermediate for the synthesis of the matrix metalloproteinase inhibitor 38 (Scheme 22) <2004JME2981>. 

Synthesis The condensation of 4-methylacetophenone with ethyl acetate by means of NaOMe in refluxing methanol gives 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione, which cyclized with 4-hydrazinophenyl-sulfonamide in refluxing ethanol (Graul et al., 1977 Talley et al. (Searle Co.), 1995. 

Intramolecular cyclization of the sulfonamide 349 gave the fused 1,2,5-thiadiazepine 351, whereas reaction of 349 with hydrazine afforded 350 (Scheme 72). The reaction of 350 with either 2-hydroxypyridine or acetic acid led to the formation of 351 <2000H(53)2163>. 

Spiro(benzoxathiazolonbenzothiazole) 25 was easily prepared by intramolecular cyclization of sulfonamide 65 with acetic anhydride-pyridine at 20 °C or with trifluoroacetic anhydride-DMF at 0-5 °C <1995CC1069>. The yield may reach 86% (Equation 11). 

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>. 

Pyrimido[5,4-6][l, 4]thiazines are synthesized by reaction of 6-amino-5-chloro-uracils with mercaptoacetic acid in alkaline solution, followed by dehydration in acetic anhydride (62JA1904). Chlorosulfonation and subsequent amination of 6-aminouracil give the corresponding 5-sulfonamides, which are cyclized to pyrimido[4,5-c][ 1,2,4]thiadiazines on heating in triethyl orthoformate (63JOC1994) (Scheme 61). 

There is one interesting example of this type of bond formation in which the bis-sulfonamide (158) can be cyclized with bis(triphenyIphosphine)palladium(II) chloride and sodium acetate to give the dibenzo[c,e][l,2]thiazine 5,5-dioxide (159). It is noteworthy that the monosulfonamide (160) is recovered unchanged under the same reaction conditions (Equation (2)) <84T1919>. 

Willoughby and coworkers reported a solid-phase strategy for the preparation of 2-arylindole combinatorial libraries in a split-and-pool format (Figure 11.61). Twenty different arylalkyl ketoacids were immobilized onto a sulfonamide resin, mixed, and separated into twenty equal portions. The Fischer indole cyclization was carried out with 20 arylhydrazines in the presence of ZnCl2 and acetic acid. The resin was mixed, separated into 80 equal portions, and finally alkylated under Mitsunobu conditions. A library of 12,800 compounds was generated, and led to the discovery of potent ligands for a variety of G-protein coupled receptors. 

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