Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-dien-8-ones and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones by condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles

Abstract

1-Substituted 3, 3,7,9-tetramethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones and 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized by three-component condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles in concentrated sulfuric acid.Compounds having a 2-azaspiro[4.5]decane skeleton rarely occur in nature. Examples of such structures are annosqualine isolated from the Stems of Annona squamosa [1], spirostaphylotrichins produced by Staphylotrichum coccosporum [2][3][4], triticones (spirocyclic lactams from the fungal plant pathogen Drechslera tritici-repentis [5]), and spiro-arogenate (a spiro-γ-lactam produced by Neurospora crassa from prephenic acid [6,7]). Some 2-azaspiro[4.5]decanes attract certain interest from the viewpoints of medicinal and synthetic organic chemistry. Some synthetic analogs of natural 2-azaspirane derivatives showed high immunosupressive activity [8]. Kazmierski et al. [9] proposed novel HIV-1 protease inhibitors on the basis of a spirocyclic pyrrolidone. It was also found that 2-azaspiranes are formed as intermediate products in the Bischler-Napieralski [10,11] or Ritter [12] syntheses of isoquinolines and phenanthridines. Several synthetic approaches to 2-azaspiro[4.5]-decane derivatives have been reported. Some procedures imply building of 2-azaspiro[4.5]decane skeleton from cyclohexanone or cyclohexene fragments. 2-Azaspiranes can be synthesized according to BuchwaldHartwig via intramolecular cyclization of the corresponding cyclohexanone derivatives [13] and by radical cyclization of N,N-diallyl-2-oxocyclohexanecarboxamides in the presence of Mn(OAc) 3 [14] or of 2-bromo-substituted diene amides, e.g., N-benzyl-2-bromo-N-[1-(cyclohex-1-en-1-yl)vinyl]propanamide, in the presence of CuBr-(C 5 H 5 N) 3 N [15]. A group of methods for the preparation of 2-azaspirane systems is based on dearomatization of arenes with simultaneous construction of pyrrolidinone fragment. Acid-catalyzed intramolecular ipso-cyclization of electron-rich aromatic diazoacetamides [16] or thionium ions generated by reaction of N-benzylglyoxamides with thiols [17] leads to the formation of spirocyclic lactams. 2-Azaspiranes can also be obtained by oxidative radical ipsocyclization of N- [p-methoxy(hydroxy)benzyl]acetamides [18] and substituted N-benzyltrichloroacetamides [19]. developed a procedure for the synthesis of 2-azaspiranes via aromatic nucleophilic substitution in the presence of (η 6 -arene)RuCp + complexes. Another possible way to 2-azaspiranes is based on the reaction of tricarbonyl (η 5 -1-alkyl-4-methoxycyclohexadienylium)iron with difunctional nucleophiles [25]. Intramolecular ene-type [6 + 2]-cyclization of Fe(CO) 3 -(cyclohexa-1,3-diene) complexes having a pendant double bond was reported to afford spirocyclic systems [26][27][28]. 2-Azaspiro[4.5]-deca-6,9-diene-3,8-diones were synthesized by tandem Ugi reaction and intramolecular Michael 5-exoaddition [29].

Theoretical Investigation of Regioselectivity and Stereoselectivity in AIBN/HSnBu3-Mediated Radical Cyclization of N-(2-Iodo-4,6-dimethylphenyl)-N,2-dimethyl-(2E)-butenamide

“…Radical cyclization is an important aspect of radical reactions . Recognition of the importance of radical cyclization in organic synthesis has increased − with the development of radical chemistry. − Presently, such a technique often enables access to very complex carbocyclic − and heterocyclic compounds. − In various radical cyclizations, investigators have found that some given axially chiral radicals can cyclize to give ring-closure products with not only high regioselectivity but also high stereoselectivity, , that is, the axially chiral element disappears in the reaction processes, accompanied by the formation of a certain stereocenter in the resulting product structure, often termed a “transfer of chirality”. − Chirality transfer is a type of “memory of chirality”, in which the stereochemical elements in the products and reactants are different.…”

Atom Transfer Radical Cyclization of Trichloroacetamides to Electron-Rich Acceptors Using Grubbs’ Catalysts: Synthesis of the Tricyclic Framework of FR901483

“…We began by examining the feasibility of applying the G-2 -mediated ATRC to anisole derivatives bearing a trichloroacetamide handle (i.e., 1 ) to achieve 1-azaspiro[4.5]decane compounds. , On the basis of our previous results in dearomatizing radical spirocyclization upon inactivated benzene promoted by Cu(I), we used the tert -butyl derivative 1a as the substrate. The required trichloroacetamide 1a was prepared through imine formation from 4-methoxybenzaldehyde and tert -butylamine, followed by reduction and trichloroacetylation.…”

Acylation of the enamino tautomer of 2-azaspiro[4.5]deca-1,6,9-trien-8-ones with 5-arylfuran-2,3-diones. Crystal and molecular structure of (2Z,5Z)-3-Hydroxy-5-(6,9-dimethoxy-3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)-1-phenylpent-2-ene-1,4-dione

“…In continuation of our studies on the reactions of 5-arylfuran-2,3-diones with spirans of the 2-azaspiro- [4.5]deca-1,6,9-trien-8-one series in the present work we examined how additional substituents in positions 3 and 6 of the latter affect the direction of their reaction with the former. 5-Arylfuran-2,3-diones Ia and Ib reacted with 2-azaspiro [4.5]deca-1,6,9-trien-8-ones IIa-IId [8][9][10] at a molar ratio of 1 : 1 on heating in boiling benzene (3-6 h, TLC monitoring) to afford (2Z,5Z)-1-aryl-3hydroxy-5-(5′,5′-dimethyl-4-oxo-2′H,4H-spiro[naphthalene-1,3′-pyrrolidin]-2′-ylidene)pent-2-ene-1,4-diones IIIa and IIIb and substituted (2Z,5Z)-3-hydroxy-5-(3,3-dimethyl-8-oxo-2-azaspiro [4.5]deca-6,9-dien-1ylidene)-1-phenylpent-2-ene-1,4-diones IIIc-IIIe (Scheme 1). The structure of compound IIIe was confirmed by X-ray analysis.…”