Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-diene-8-ones and 2-azaspiro[4.5]deca-1,6,9-triene-8-ones by a three-component condensation of 1,2,3-, 1,2,4- or 1,3,5-trimethoxybenzene with isobutyric aldehyde and nitriles

A three-component condensation of 1,2,3- or 1,2,4-trimethoxybenzene with isobutyric aldehyde and alkyl cyanoacetates in the presence of sulfuric acid resulted in the formation of substituted 2-azaspiro[4.5]deca-6,9-diene-8-ones. The same reaction of aromatic nitriles yielded 2-azaspiro[4.5]deca-1,6,9-triene-8-ones; in the case of 1,2,3-trimethoxybenzene corresponding Ritter amides were also observed. The condensation of 1,3,5-trimethoxybenzene with isobutyric aldehyde and alkyl cyanoacetates provided the compounds of the formal Knöevenagel condensation.     

Synthesis and Rearrangement of 1-Substituted 3,3,7-Trimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

Russian Journal of Organic Chemistry -     

Ritter reaction. Synthesis of 1-substituted 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-6,9-dien- and -1,6,9-trien-8-ones and 7-methoxy-3,3,6,8-tetramethyl-3,4-dihydroisoquinolines

1-(4-Methoxy-3,5-dimethylphenyl)-2-methylpropan-1-ol reacted with nitriles [MeSCN, PhCN, MeCN, EtOC(O)CH₂CN] in the presence of concentrated sulfuric acid to give both 1-R-3,3,7,9-tetramethyl-2-azaspiro[4,5]deca-6,9-dien- and -1,6,9-trien-8-ones and 1-R-7-methoxy-3,3,6,8-tetramethyl-3,4-dihydroisoquinolines. The reaction with 3,4-dimethoxyphenylacetonitrile afforded 10,11-dimethoxy-1,3,6,6-tetramethyl-1,5,6,12b-tetrahydrodibenzo[d,f]indole-2,8-dione. Three-component condensation of 2-methoxy-1,3-dimethylbenzene with isobutyraldehyde and nitriles led to the formation of spirocyclic systems and 3,4-dihydroisoquinoline derivatives in lower yield.     

Spirocyclohexadienones. 4. Synthesis and dienone-phenolic rearrangement of 1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

The reactions of 1-(p-methoxyphenyl)-2-methylpropan-1-ol or -cyclohexyl-p-methoxybenzyl alcohol with nitriles RCN in concentrated sulfuric acid afforded 1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones. The stability of the latter toward the dienone-phenolic rearrangement depends on the nature of the substituent R. The reaction mechanism was studied by the semiempirical quantum-chemical AM1 method.     

A simple and efficient route for the synthesis of novel isoxazolyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

A new, simple and efficient method for the synthesis of novel isoxazolyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones is described by the intramolecular ipso-cyclization of 5-[(E)-2-(4-methoxyphenyl)-1-ethenyl]-3-methyl-4-nitroisoxazole with nitriles. In presence of 5-[(E)-2-(4-methoxyphenyl)-1-ethenyl]-3-methyl-4-nitroisoxazole, a variety of nitriles underwent the intramolecular ipso-cyclization smoothly, affording title compounds in moderate to good yields.     

Spirocyclohexadienones. 6. Three-component synthesis of 1-R-3,3-dimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

1-R-3,3-Dimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized through three-component condensation of anisole, isobutyraldehyde, and a corresponding nitrile in dichloromethane in the presence of concentrated sulfuric acid.     

Retropinacol rearrangement in the synthesis of 3,3,4-trimethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-one derivatives

Russian Journal of Organic Chemistry -     

Design,Synthesis, and Antitumor Activity of a Series of Novel 4-(Aromatic Sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-ones

Many sulfonamides show anticancer activity. Based on benzenesulfonylazaspirodienone (HL-X9) identified in our previous work, we optimized the lead compound for better efficacy, thereby synthesizing a series of novel 4-(aromatic sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-one derivatives through a key step of metal-catalyzed cascade cyclization. The preliminary antiproliferative tests have shown that the anticancer activities of acetyl-protected mannose-linked sulfonylazaspirodienone derivatives (7i–7l) have been greatly improved. Among them, 7j is the most potent derivative, with IC₅₀ values of 0.17 µM, 0.05 µM, and 0.07 µM for A549, MDA-MB-231, and HeLa cell lines, respectively. Flow cytometry analysis shows that 7j arrests MDA-MB-231 cells in the G2/M phase and has a certain effect on the apoptosis of MDA-MB-231 cells. In addition, the acute toxicity of 7j was lower than that of adriamycin.     

Synthesis of 1-substituted (R,S)-8-(2-methoxy-5-methylphenyl)-3,3,9-trimethyl-2-azaspiro[4.5]deca-1,7-dien-6-ones

Reactions between p-methylanisole, isobutyraldehyde, and nitriles (acetonitrile, methyl thiocyanate, or ethyl cyanoacetate) in conc. H₂SO₄ yield 1-substituted (R,S)-8-(2-methoxy-5-methylphenyl)-3,3,9-trimethyl-2-azaspiro[4.5]deca-1,7-dien-6-ones.     

Synthese des 6- und 7-Methyl-spiro[4.5]deca-6,9-dien-8-ons

Zusammenfassung Es werden die Synthesen folgender Verbindungen beschrieben: -(4-Hydroxy-3-methylphenyl)buttersäure, 4-(4-Hydroxy-3-methylphenyl)-1-butanol, 7-Methyl-spiro[4.5]deca-6,9-dien-8-on, -(4-Hydroxy-2-methylphenyl)buttersäure und dessen Methylester, 4-(4-Hydroxy-2-methylphenyl)-1-butanol und 6-Methyl-spiro[4.5]deca-6.9-dien-8-on.

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The synthesis of the following compounds is described: -(4-hydroxy-3-methylphenyl)-butyric acid, 4-(4-hydroxy-3-methylphenyl)-butanol-(1), 7-methyl-spiro[4.5]deca-6.9-dien-8-one, -(4-hydroxy-2-methylphenyl)-butyric acid and its methyl ester, 4-(4-hydroxy-2-methylphenyl)-butanol-(1) and 6-methyl-spiro[4.5]deca-6.9-dien-8-one.

     

Synthesis of 8-oxa-2-azaspiro[4.5]decane

A convenient synthesis of new 8-oxa-2-azaspiro[4.5]decane from commercially available reagents based on tetrahydropyran-4-carbonitrile and 1-bromo-2-fluoroethane has been developed. This compound is promising for the production of important biologically active compounds.

     

Spirocyclohexadienones: XII. Dienone-phenol rearrangement of 1-substituted 2-azaspiro[4.5]undeca-1,6,9-trienes and their analogs

Hydrolytic cleavage of 1-substituted 2-azaspiro[4.5]undeca-1,6,9-trienes in acid medium is accompanied by dienone-phenole rearrangement with formation of substituted N-[2-(p-hydroxyphenyl)ethyl] carboxylic acid amides. 1,2-Dimethoxy-3-oxo-15-phenyl-14-azadispiro[5.1.5.2]pentadeca-1,4,14-triene and 2′-R-7a′-methyl-3a′,4′,5′,6′,7′,7a′-hexahydrospiro[cyclohexa[2,5]diene-1,3′-indol]-4-ones undergo analogous cleavage.     

Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones from l-proline derivatives

An enantioselective synthesis of protected 1-azaspiro[4.5]dec-6-en-8-one derivatives was achieved using an alkylidene carbene 1,5-CH insertion reaction as the key step.     

Synthesis of enantiopure 3-amino-1-azaspiro[4.5]decan-8-ones by halonium promoted cyclization of amino-tethered cyclohexenes

Haloaminocyclization reactions of polysubstituted γ-aminocyclohexenes give 3-amino-1-azaspiro[4.5]decan-8-one derivatives. The stereocontrol, chemoselectivity (N-attack vs O-attack), and influence of the halonium ion are discussed.     

Synthesis and Structure Elucidation of 8-Methyl- and 9-Methyl-exo-2-carbomethoxy-endo-tricyclo[5.2.1.02,6]deca-3,8-dien-5-ones

A mixture of 1-methyl- and 2-methyl-1,4,4a,8a,-tetrahydro-endo-1,4-methano-naphthalene-5,8-diones ( 2 & 3 ) was chemically transformed into separable methyl substituted tricyclo[5.2.1.0^2,6]decadienones 7 , 8 & 9 . The structure of 8 & 9 were elucidated via Cope rearrangement of their corresponding allylic alcohols ( 10 & 11 ) to furnish 12 & 13 respectively.     

Synthesis of 3-Amino-2,2-dimethyl-8-thia-1-azaspiro[4.5]decane

The synthesis of 3-amino-2,2-dimethyl-8-thia-1-azaspiro[4.5]decane is described. Key steps include the addition of prenyl magnesium bromide to a 4-methoxybenzylimine without reversal of stereochemistry and the iodine-initiated aminocyclization to form the azaspirocycle.     

Spirocyclohexadienones: VIII. 1-R-3,3-Dimethyl-2-azaspiro[5.5]undeca-1,7,10-trien-9-ones

1-R-3,3-Dimethyl-2-azaspiro[5.5]undeca-1,7,10-trien-9-ones were synthesized by condensation of 4-(p-methoxyphenyl)-2-methylbutan-2-ol with nitriles RCN in the presence of a concn. sulfuric acid.     

pi-Facial stereoselectivity in Diels-Alder cycloadditions to 1-oxaspiro[4.5]deca-6,9-dien-8-one. The strong directive effect of ether oxygen in a cross-conjugated ketone setting

[reaction: see text] The title compound 1, prepared from 1,4-cyclohexanedione monoethylene ketal, was treated with several reactive dienes, including diphenylisobenzofuran and 9,10-dihydro-11,12-dimethylene-9,10-ethanoanthracene. These [4 + 2] cycloadditions proceed with a strong kinetic bias for bonding to the dienophile from the direction syn to the tetrahydrofuranyl oxygen and consequently hold value in stereoselective synthesis.     

Five-membered 2,3-dioxo heterocycles: XCII. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with ethyl (2Z)-(3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)ethanoate. Synthesis of bridged analogs of pyrrolizidine alkaloids

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with ethyl (2Z)-(3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)acetate to give ethyl 6′-aryl-2′-(2-hydroxyphenyl)-11′,11′-dimethyl-3′,4,4′,13′-tetraoxospiro[2,5-cyclohexadiene-1,9′-(7′-oxa-2′,12′-diazatetracyclo[6.5.1.0^1,5.0^8,12]tetradec-5′-ene)]-14′-carboxylates whose structure was confirmed by X-ray analysis. The products may be regarded as bridged analogs of pyrrolizidine alkaloids, 7′-oxa-2′,12′-diazatetracyclo[6.5.1.01,5.08,12]tetradecanes.