Facile Preparation and Chemical Transformations of Spirocyclopropane-Annelated Heterocycles

• Published in: European journal of organic chemistry Vol. 2003; no. 6; pp. 985 - 997
• Main Authors: Meijere, Armin de, Kuchuk, Ilya D., Sokolov, Viktor V., Labahn, Thomas, Rauch, Karsten, Es-Sayed, Mazen, Krämer, Thomas
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-03-2003; WILEY‐VCH Verlag
• Subjects: Cross-coupling reactions; Heterocycles; Homogeneous catalysis; Small-ring systems; Spiro compounds
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200390154

A productive approach has been developed to spirocyclopropane‐annelated 1,4‐benzoxathiane 17 (85%), 1,4‐benzothiazines 20−22 (56−88%) and 1,4‐benzoxazines 25, 26 (55−71%), through Michael additions of binucleophilic o‐hydroxythiophenol 15, o‐aminothiophenols 8 and o‐hydroxysulfanilides 23 onto methyl and tert‐butyl 2‐chloro‐2‐cyclopropylideneacetates (1‐Me, 1‐tBu), followed by ring closure in the intermediate of type 3 through nucleophilic substitution of the chlorine atom and, in the case of the intermediates 20, 21 and 25, elimination of benzenesulfinic acid. Reduction of 20a with LiAlH4 led to the hydroxymethyl derivative 28 (88%) with retention of the N‐phenylsulfonyl group, while that of the oxazinecarboxylate 26a‐Me gave the β‐amino alcohol 27 (87%). Selective reduction of the C=N double bond in 26a‐Me was achieved with NaBH4 in methanol. Halogen‐substituted benzoxazines 26b,c were modified further by Heck coupling with various alkenes. In the presence of a catalytic amount of triphenylphosphane, only the 6‐bromobenzoxazine underwent Heck coupling accompanied by ring opening of the spirocyclopropane moiety. The best yields of cross‐coupling products 30d−i (60−89%) retaining the spirocyclopropane ring were achieved for 6‐iodobenzoxazine 26c‐Me reacting with methyl acrylate, acrolein, and methyl vinyl ketone, respectively. By treatment with morpholine in DMF, the heterocyclic esters 26b,c undergo demethoxycarbonylation to form spirocyclopropane‐annelated 1,4‐benzoxazines 36b,c in high yields (83−98%). The 1,4‐benzoxazine 36b readily adds nucleophiles such as p‐thiocresol and hydrogen cyanide across its C=N double bond to yield compounds 37 (76%) and 38 (95%), respectively. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)