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.     

Spirans XXII. Synthesis of 4,4-dialkyl-4-germacyclohexanone and 8,8-dialkyl-8-germaazaspiro [4.5] decanes

4,4-Dialkyl-4-germacyclohexanones have been synthesized and their reactions studied. The diethyl ketone has been converted into N-(-dimethylaminopropyl)-2 aza-8,8-diethyl-8-germaspiro[4.5]decane ( 16 ). The biological properties of 16 have been examined in some detail. The reactions of this new ketone with some other reagents are reported.     

Synthesis of oxa-aza spirobicycles by intramolecular hydrogen atom transfer promoted by N-radicals in carbohydrate systems

The nitrogen-centred radical generated by reaction of an N-phosphoramidate or N-cyanamide, attached to a tri- or tetramethylene tether extended from the C-1 of a carbohydrate, with (diacetoxyiodo)benzene (DIB) and iodine can undergo a regio- and stereoselective intramolecular hydrogen atom transfer (HAT) reaction to furnish four different oxa-azaspirobicyclic systems: 1-oxa-6-azaspiro[4.4]nonane, 1-oxa-6-azaspiro[4.5]decane, 6-oxa-1-azaspiro[4.5]decane and 1-oxa-7-azaspiro[5.5]undecane. A tandem 1,5- or 1,6-HAT-oxidation-nucleophilic cyclisation mechanism is proposed.     

Synthesis of sulfur‐containing heterocycles: spiropyrimidinetriones,thioxopyrimidinediones, pyrazolidinediones,and isoxazolidinediones—part ii

1‐Aroyl‐2‐styrylsulfonylethene is the precursor for 4,4‐dimethoxycarbonyl‐2′,5‐diaryl‐3‐(1′,3′‐dioxolano)‐1‐thia‐1,1‐dioxide ( 4 ), which is the key intermediate for the synthesis of 7‐aroyl‐11‐aryl‐2,4‐diazaspiro[5,5]undecane‐1,3,5‐trione‐9‐thia‐9,9‐dioxide( 10 )/3‐thioxo‐1,5‐dione‐9‐thia‐9,9‐dioxide ( 11 ), 6‐aroyl‐10‐aryl‐2,3‐diazaspiro[4,5]decane‐1,4‐dione‐8‐thia‐8,8‐dioxide ( 12 )/2‐oxo‐3‐azaspiro [4,5]decane‐1,4‐dione‐8‐thia‐8,8‐dioxide ( 13 ). The new compounds were characterized by IR and ¹H NMR spectral data. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:131–135, 2001     

One-Step Synthesis of the 1-Azaspiro[5.5]undecane Skeleton Characteristic of Histrionicotoxin Alkaloids from Linear Substrates via Hg(OTf)2-Catalyzed Cycloisomerization

Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1-azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1-azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six-membered carbo- or azacycle. Herein, we report the direct one-step construction of the 1-azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N-methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)₂)-catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX-235A and HTX-283A, respectively, from the azaspirocycle.     

The reduction and hydrolysis of some 7,7-diethylpyrazolo[1,2-a]-pyridazine-6,8(7H)dione derivatives

The chemistry of several of the Diels-Alder adducts formed by the reaction of 4,4-diethylpyrazoline-3,5-dione ( 1 ) with conjugated dienes was studied with respect to reduction (hydride and catalytic) and reaction with base. Reaction of the 2,3-dimethyl-1,3-butadiene adduct with lithium aluminum hydride followed by hydrogenation gave 1,3,5,6,7,8-hexahydro-cis-endo-6,7-dimethyl-2,2-diethylpyrazolo[1,2-a]pyridazine ( 11 ). Attempted conversion of this compound to 3,3-diethyl-cis-7,8-dimethyl-1,5-diazacyclononane ( 12 ) gave instead a compound which has been tentatively identified as N-(2,3-dimethyl-4-aminobutyl)-2-ethyl-2-methylbutanaldimine ( 14 ). Lithium aluminum hydride reduction of 4,4-diethylpyrazolidine-3,5-dione ( 22 ) or the adducts formed from 1 and cyclopentadiene or 1,3-cyclohexadiene gave good yields of 4,4-diethylpyrazolidine ( 21 ). This later reduction gave a new and efficient synthetic route to the pyrazolidine ring system. Lithium aluminum hydride reduction of 5,6,7,8-tetrahydro-5,8-ethano-2,2-diethylpyrazolo[1,2-a]pyridazine-1,3(2H)dione ( 26 ) followed by hydrogenolysis led to a high yield of 4,4-diethyl-2,6-diazabicyclo[5.2.2]undecane ( 28 ) which is the first reported example of this ring system. Reaction of several of the adducts with ethanolic potassium hydroxide resulted in the opening of the five-membered ring.     

Chiral macrocyclic polyethers incorporating a tetraoxaspiro[5.5]undecane or trioxa-azaspiro[5.5]undecane moiety

New macrocyclic polyethers possessing chirality due to a spiro ring junction are prepared from 2,8-dihydroxymethylated (+)-1,4,7,10-tetraoxaspiro[5.5]undecane 1 and (+)-1,4,7-trioxa-10-azaspiro[5.5]undecane 2, both (E,E). N-Functionalization of compounds derived from 2 is also examined. The complexing properties of representative ligands 3, 4, 5 measured by spectrophotometry in THF, for alkaline and alkaline-earth cations, indicate that these spheric positively-charged species are weakly associated.     

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.     

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.     

Organoboron compounds : CCCXCIX. The matteson-pasto rearrangement in the series of 3-borabicyclo[3.3.1]nonane compounds

Bromination of 3-isopropyl-7-methyl- and 3-isopropyl-7-bromomethyl-3-borabicyclo[3.3.1]nonane leads to corresponding 3-(2-bromo-2-propyl) derivatives, which, on treatment with alcohols or pyridine as well as on heating, undergo the Matteson-Pasto rearrangement to convert into 3-X-4,4,8-trimethyl- and 3-X-4,4-dimethyl-8-bromomethyl-3-borabicyclo[4.3.1]decane (X = Br, OR). Interaction between triethylamine and 3-(2-bromo-2-propyl)-7-methyl-3-borabicyclo[3.3.1]nonane is accompanied by dehydrobromination leading to 3-isopropenyl-7-methyl-3-borabicyclo[3.3.1]nonane. Carbonylation of 3,4,4,8-tetramethyl-3-borabicyclo[4.3.1]decane at 140°C is accompanied by migration of two alkyl groups from the boron to the carbon atom, and subsequent oxidation with H₂O₂ produces 1-(2-hydroxy-2-methyl-1-propyl)-3-acetonyl-5-methyl-cyclohexane. Under more forcing conditions (180-195°C), the third alkyl group also migrates to give, after oxidation, a mixture of isomeric 3,4,4,8-tetramethylbicyclo[4.3.1]decan-3-ols. 3-n-Butoxy-4,4-dimethyl-8-bromomethyl-3-borabicyclo[4.3.1]decane, on treatment with Lì, undergoes cyclization to afford 4,4-dimethyl-3-borahomoadamantane, carbonylation and subsequent oxidation of which gave 4,4-dimethylhomoadamantan-3-ol.     

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.     

Stereoselective synthesis of 2e-phenyl-4e-hydroxy-1-azaspiro[5.5]undecane

6-Phenylspiro(1-aza-7-oxabicyclo[2.2.1]heptane-2-cyclohexane) was synthesized by cyclization of N-benzylidene-1-allyl-1-cyclohexylamine N-oxide, and its reduction splitting yielded 2e-phenyl-4e-hydroxy-1-azaspiro[5.5]undecane.Russian People's Friendship University, Moscow 117198. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 77–80, January, 1998.     

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.     

Flexible synthesis of enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes from propargylic and homopropargylic alcohols

A new approach to enantiomerically pure 2,8-dialkyl-1,7-dioxaspiro[5.5]undecanes and 2,7-dialkyl-1,6-dioxaspiro[4.5]decanes is described and utilizes enantiomerically pure homopropargylic alcohols obtained from lithium acetylide opening of enantiomerically pure epoxides, which are, in turn, acquired by hydrolytic kinetic resolution of the corresponding racemic epoxides. Alkyne carboxylation and conversion to the Weinreb amide may be followed by triple-bond manipulation prior to reaction with a second alkynyllithium derived from a homo- or propargylic alcohol. In this way, the two ring components of the spiroacetal are individually constructed, with deprotection and cyclization affording the spiroacetal. The procedure is illustrated by acquisition of (2S,5R,7S) and (2R,5R,7S)-2-n-butyl-7-methyl-1,6-dioxaspiro[4.5]-decanes (1), (2S,6R,8S)-2-methyl-8-n-pentyl-1,7-dioxaspiro[5.5]undecane (2), and (2S,6R,8S)-2-methyl-8-n-propyl-1,7-dioxaspiro[5.5]undecane (3). The widely distributed insect component, (2S,6R,8S)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane (4), was acquired by linking two identical alkyne precursors via ethyl formate. In addition, [(2)H(4)]-regioisomers, 10,10,11,11-[(2)H(4)] and 4,4,5,5-[(2)H(4)] of 3 and 4,4,5,5-[(2)H(4)]-4, were acquired by triple-bond deuteration, using deuterium gas and Wilkinson's catalyst. This alkyne-based approach is, in principle, applicable to more complex spiroacetal systems not only by use of more elaborate alkynes but also by triple-bond functionalization during the general sequence.     

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 spirocyclic benzo[f]quinoline derivatives by cascade heterocyclization of dimedone, 2-naphthylamine, and formaldehyde

The three-component condensation of dimedone, 2-naphthylamine, and formaldehyde in aliphatic alcohols under mild conditions gives in high yields the corresponding N-alkoxymethyl benzo[f]quinoline derivatives having a substituted 2-azaspiro[5.5]undecane fragment. The reaction involves formation of three new carbon-carbon bonds, two carbon-nitrogen bonds, and one carbon-oxygen bond, and the initial β-dicarbonyl system is conserved.     

Five-Membered 2,3-dioxoheterocycles: XCV. Recyclization of 4-benzoyl-5-phenylfuran-2,3-dione at the action of substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes. Crystal and molecular structure of substituted 5-(2-azaspiro[4.5]dec-1-ylidene)cyclopent-3-ene-1,2-dione

4-Benzoyl-5-phenylfuran-2,3-dione reacts with 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one and 8-(2-methoxy-5-methylphenyl)-1,3,3,9-tetramethyl-2-azaspiro[4.5]deca-1,7-dien-6-one with the formation of (Z)-3-benzoyl-5-(5′,5′-dimethyl-4-oxo-4H-spiro[naphthalene-1,3′-pyrrolidin]-2′-ylidene)-4-phenylcyclopent-3-ene-1,2-dione, whose structure was proved by XRD analysis, and of (Z)-3-benzoyl-5-{8-(2-methoxy-5-methylphenyl)-3,3,9-trimethyl-6-oxo-2-azaspiro[4.5]dec-7-en-1-ylidene}-4-phenylcyclopent-3-ene-1,2-dione.     

Fused indoles. 2. Synthesis and reactions of imidazo[1,2-a]- and pyrimido[1,2-a]-indoles

The alkylation of 2-chloroindole-3-carboxaldehyde ( 1 ) and 3-acetyl-2-chloroindole ( 5 ) with 3-chloro-N,N-dimethyl-1-propylamine, 3-chloro-N,N-diethyl-1-propylamine and 2-chloro-N,N-dimethyl-1-ethylamine is described. Following alkylation, demethylation occurs and furnishes imidazo[1,2,-a]- and pyrimido[1,2-a]indoles ( 3a,6,8,10 ). Pyrimido-indole 3a , on treatment with lithium aluminum hydride, furnishes the bis-indole 12 . Analogous reaction with diborane affords the reduced product 14 , while reaction with methyllithium yields the deformylated product 13 . Spectral data of the resulting compounds are also discussed.     

Electrophysiological Responses of Bactrocera kraussi (Hardy) (Tephritidae) to Rectal Gland Secretions and Headspace Volatiles Emitted by Conspecific Males and Females

Pheromones are biologically important in fruit fly mating systems, and also have potential applications as attractants or mating disrupters for pest management. Bactrocera kraussi (Hardy) (Diptera: Tephritidae) is a polyphagous pest fruit fly for which the chemical profile of rectal glands is available for males but not for females. There have been no studies of the volatile emissions of either sex or of electrophysiological responses to these compounds. The present study (i) establishes the chemical profiles of rectal gland contents and volatiles emitted by both sexes of B. kraussi by gas chromatography–mass spectrometry (GC–MS) and (ii) evaluates the detection of the identified compounds by gas chromatography–electroantennogram detection (GC–EAD) and –electropalpogram detection (GC–EPD). Sixteen compounds are identified in the rectal glands of male B. kraussi and 29 compounds are identified in the rectal glands of females. Of these compounds, 5 were detected in the headspace of males and 13 were detected in the headspace of females. GC–EPD assays recorded strong signals in both sexes against (E,E)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane, 2-ethyl-7-mehtyl-1,6-dioxaspiro[4.5]decane isomer 2, (E,Z)/(Z,E)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane, and (Z,Z)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane. Male antennae responded to (E,E)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane, 2-methyl-6-pentyl-3,4-dihydro-2H-pyran, 6-hexyl-2-methyl-3,4-dihydro-2H-pyran, 6-oxononan-1-ol, ethyl dodecanoate, ethyl tetradecanoate and ethyl (Z)-hexadec-9-enoate, whereas female antennae responded to (E,E)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane and 2-methyl-6-pentyl-3,4-dihydro-2H-pyran only. These compounds are candidates as pheromones mediating sexual interactions in B. kraussi.     

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.