8,10-Dimethyl-7,13-dioxa-10-azaspiro[5.7]tridecane — the first representative of perhydro-1,3-dioxa-6-azocines

The first representative of perhydro-1,3-dioxa-6-azocines, 8,10-dimethyl-7,13-dioxa-10-azaspiro[5.7]tridecane, was synthesized by the reaction of 4-methyl-1-oxa-4-azaspiro[4.5]decane with propylene oxide. The structure of the compound has been confirmed by IR and¹H and¹³C NMR spectroscopy and mass spectrometry.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1838–1839, September, 1995.     

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.

     

Spirans XX. Synthesis of 8,8-dialkylazaspiro[4.5] decanes and 9,9-dialkylazaspiro[5.5]undecanes

N-(2-Dimethylaminopropyl)-8,8-dimethyl-2-azaspiro[4.5]decane ( 1 ), N-(2-dimethylaminopropyl)-8,8-diethyl-2-azaspiro[4.5]decane ( 2 ), N-(3-dimethylaminopropyl)-9,9-dimethyl-3-azaspiro[5.5]undecane ( 3 ), and N-(3-dimethylaminopropyl)-9,9-diethyl-3-azaspiro[5.5]undecane ( 4 ) have been synthesized from 4,4-dimethylcyclohexanone ( 5 ) and 4,4-diethylcyclohexanone ( 6 ). Biological evaluation of these amines showed significant inhibition of cancer cell growth in human cancer cells grown in tissue culture.     

Synthesis of a New Spiro System: 1-Oxa-7-thia-4-azaspiro[4.5]decane 7,7-Dioxide

Dihydro-2H-1λ⁶-thiopyran-1,1,3(4H)-trione reacted with N-substituted 2-aminoethanols to give derivatives of a new spiro system, 1-oxa-7λ⁶-thia-4-azaspiro[4.5]decane-7,7-diones. No spirocyclic product was obtained by the reaction with unsubstituted 2-aminoethanol, but the corresponding enamine was formed as in the reactions with other primary amines.     

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.     

Hydrolysis and acylation of imino group in E/Z-isomers of 3,4-dialkyl-8-amino-1-imino-6-morpholin-4-yl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles

Acid-catalyzed hydrolysis of 3,4-dialkyl-substituted 8-amino-1-imino-6-morpholin-4-yl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles under mild conditions led to the formation of 8-amino-6-morpholin-4-yl-1-oxo-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles, and their acylation afforded N-(8-amino-9-cyano-6-morpholin-4-yl-2-oxa-7-azaspiro-[4.4]nona-3,6,8-trien-1-ylidene)acetamides. The NMR spectra of compounds synthesized in contrast to the spectra of initial N-unsubstituted imins contained no doubled proton and carbon signals.     

Intramolecular hydrogen abstraction promoted by amidyl radicals. Evidence for electronic factors in the nucleophilic cyclization of ambident amides to oxocarbenium ions

A tandem 1,5-hydrogen atom transfer/radical oxidation/nucleophilic cyclization mechanism is proposed for the intramolecular hydrogen abstraction reaction promoted for primary carboxamidyl radicals. The electron-withdrawing capacity of the C-5 substituent can switch the reaction to give exclusively bicyclic spirolactams (6-oxa-1-azaspiro[4.5]decan-2-one) when R(1) = H or spirolactones (1,6-dioxaspiro[4.5]decan-2-one) when R(1) = OAc. With a substituent of medium polarity (R(1) = OMe), a mixture of lactones and lactams is formed.     

Enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

The enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 1 to either of the corresponding (R)- or (S)-6-hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-diones 2 and 3 is described.     

The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide

An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is demonstrated by the synthesis of N-Boc-2,3-methano-β-proline. The amino acid was prepared through a three-step synthesis from easily available reagents in an overall yield of 15%.     

Spirans XXI. Synthesis of silaazaspiro[4.5]decanes and silaazaspiro[5.5]undecanes

N-(2-Dimethylaminopropyl)-8,8-dimethyl-8-sila-2-azaspiro[4.5]decane ( 1 ) and N-(3-dimethyl-aminopropyl)-9,9-dimethyl-9-sila-3-azaspiro[5.5]undecane ( 2 ) have been synthesized from 4,4-dimethyl-4-silacyclohexanone ( 5 ). Biological evaluation of 1 and 2 indicated cytotoxic action against human cancer cells grown in tissue culture.     

Synthesis and Crystal Structure of 4-(Dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane

<正>The title compound 4-(dichloroacetyl)-1-oxa-4-azaspiro[4. 5] decane (CAS number 71526-07-3, C10H15Cl2NO2, Mr= 252.13) was obtained by the reaction of dichloroacetic acid with 1-oxa-4-azaspiro[4. 5] decane. The crystal is of monoclinic, space group P21ln with the unit cell constants: a = 5.9619(4),b= 10.0066(8), c = 20.0986(4) A,β = 90.194(3)°, V= 1199(4) A3,Z = 4, Dc= 1.397 g/cm3, F(000) = 528, μ(MoKα) = 0.522 mm-1, R = 0.0611 and wR = 0.1656 for 1276 observed reflections (I > 2σ(I)). X-ray analysis reveals that the cyclohexyl adopts a chair conformation and the compound is a chiral one.     

Efficient synthesis of the azaspirocyclic core structure of halichlorine and pinnaic acid by intramolecular acylnitroso ene reaction

[reaction: see text] A new efficient strategy for the construction of the 6-azaspiro[4.5]decane ring system was developed using intramolecular ene reaction of the acylnitroso compound. The spirocyclic ene product obtained as a single diastereomer was subsequently subjected to highly stereoselective ethynylation, leading to the azaspirodecane core of halichlorine and the pinnaic acids.     

Asymmetric synthesis of 1-azaspiro[4.5]decanes via intramolecular dipolar cycloaddition of nitrones containing the bornane-10,2-sultam chiral auxiliary

The intramolecular 1,3-dipolar cycloaddition of a cyclic nitrone, prepared by an asymmetric electrophilic enolate hydroxyamination using the (2R)-bornane-10,2-sultam chiral auxiliary, proceeds to give bridged and fused cycloadducts with total diastereocontrol. Reduction of the fused isoxazolidine provides a 1-azaspiro[4.5]decane as a potential intermediate in the asymmetric synthesis of the cylindricine alkaloids.     

Synthesis of 3-oxatricyclo[4.4.0.02,7]decene derivatives

Unsaturated haloethers of norpinane structure were prepared by reaction of N-iodo-and N-bromosuccinimides with 1-phenyltricyclo[4.1.0.0^2,7]-heptane in the presence of unsaturated propargyl or allyl alcohol. The iodopropargyloxy derivative underwent reductive 6-exo-cyclization when treated with tributyltin hydride resulting in 5-methylene-3-oxa-2-phenyltricyclo[4.4.0.0^2,7]decane, and the iodoallyloxy derivative on heating in the presence of benzoyl peroxide suffered isomerization into 5-iodomethyl-3-oxa-2-phenyltricyclo[4.4.0.0^2,7]decene. Bromopropargyloxy and bromoallyloxy derivatives failed to undergo the reductive cyclization under the treatment with a system cobaloxime(III)-sodium borohydride, but suffered hydrogenetion at the multiple carbon-carbon bond.     

Synthesis, Structure, and Growth-Regulating Activity of 1-(6,9-Dimethyl-1,4-dioxa-8-azaspiro[4,5]dec-8-ylmethyl)-1H-pyridin-2-one

1-(6,9-Dimethyl-1,4-dioxa-8-azaspiro[4,5]dec-8-ylmethyl)-1H-pyridin-2-one was prepared by the Mannich reaction from 6,9-dimethyl-1,4-dioxa-8-azaspiro[4,5]decane, formaldehyde, and pyridin-2-one in alcohol. Its structure was proved by NMR spectroscopy. This compound exhibits a growth-regulating activity.     

Reaction of methyl 1-bromocyclopentane-1-carboxylate with zinc and 3-aryl-2-cyanoprop-2-enamides

Reformatsky reaction of methyl 1-bromocyclopentane-1-carboxylic acid with 3-aryl-2-cyanoprop-2-enamides and their N-methyl derivatives afforded 10-aryl-6,8-dioxo-7-azaspiro[4.5]decane-9-carbonitriles and 10-aryl-7-methyl-6,8-dioxo-7-azaspiro[4.5]decane-9-carbonitriles, respectively.     

Synthesis of some substituted 1,3-thiazolines and 1,3-thiazolidines

Sodium salts of 2, 2-dimethyl-4-mercapto-5-oxo-1,3-thiazoline and 2-oxo-3-mercapto-1-thia-4-azaspiro[4.5]dec-3-ene, obtained from a solvate of sodium cyanodithioformate with three molecules of dimethylformamide, acetone, or cyclohexanone in the presence of morpholine, react with chlorothioformic dimethylamide with the formation of 2,2-dimethyl-5-oxo-4-(dimethylaminothiocarbonylthio)-1,3-thiazoline and 2-oxo-3-(dimethylaminothiocarbonylthio)-1-thia-4-azaspiro[4.5]dec-3-ene, respectively, and during acidolysis by hydrochloric acid they are converted to 2,2-dimethyl-5-oxo-4-thiono-1,3-thiazolidine and 2-oxo-3-thiono-1-thia-4-azaspiro[4.5]decane. The latter compounds are facilely phosphorylated by dialkyl chlorophosphonates at the nitrogen atom. The reaction of the solvate of sodium cyanodithioformate with three molecules of dimethylformamide with chloroacetone in the presence of morpho-line occurs anomalously with the formation of cyanothioformic morpholide.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2590–2593, November, 1990.     

Synthesis of spirodienones by intramolecular ipso-cyclization of N-methoxy-(4-halogenophenyl)amides using [hydroxy(tosyloxy)iodo]benzene in trifluoroethanol

Spirodienones bearing the 1-azaspiro[4.5]decane ring system have been synthesized from N-methoxy-(4-halogenophenyl)amides by the intramolecular ipso attack of a nitrenium ion generated with [hydroxy(tosyloxy)iodo]benzene in trifluoroethanol.     

Regioselective cycloaddition of C-aryl- and C-carbamoylnitrones to methyl 2-benzylidenecyclopropanecarboxylate

C-Aryl- and C-carbamoylnitrones reacted with methyl 2-benzylidenecyclopropanecarboxylate in highly regioselective fashion to give the corresponding 1,3-dipolar cycloaddition products, substituted methyl 5-oxa-6-azaspiro[2.4]heptane-1-carboxylates as mixtures of two diastereoisomers.     

Manganese(III)-mediated facile synthesis of 3,4-dihydro-2(1H)-quinolinones: selectivity of the 6-endo and 5-exo cyclization

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1H)-quinolinones 2 were easily synthesized by the oxidative 6-endo-trig cyclization of 2-[2-(N-arylamino)-2-oxoethyl]malonates 1 with manganese(III) acetate in good to excellent yields. The same reaction of N-(2,4-dimethoxyphenyl)-substituted malonate 1t exclusively produced the 5-exo-cyclized 4,4-bis(ethoxycarbonyl)-1-azaspiro[4,5]deca-6,9-diene-2,8-dione 5t instead of the corresponding dihydroquinolinone. The regioselectivity during the cyclization could be explained by the difference in the activation energy of the transition state of the 6-endo/5-exo cyclization.