Reaction of difluorocarbene with 2H-azirines: generation and transformations of strained azomethine ylides -- aziriniodifluoromethanides

The reaction of difluorocarbene with azirines affords a new type of azomethine ylides, viz., strained aziriniodifluoromethanides. 1,3-Dipolar cycloadditions of ylides derived from 2-unsubstituted 3-arylazirines to dimethyl acetylenedicarboxylate and aldehydes give derivatives of 2,2-difluoro-1-azabicyclo[3.1.0]hex-3-ene-3,4-dicarboxylic acids and 1,4-oxazin-3(4H)-ones, respectively. Ylides derived from 2-mono- and 2,2-disubstituted azirines undergo isomerization to 2-aza-1,3-diene derivatives. 2,2-Difluoro-1-azabicyclo[3.1.0]hex-3-enes are transformed into 2-fluoropyridine derivatives in high yields and react with amines to give 2,4-diamino-1-azabicyclo[3.1.0]hex-2-ene derivatives.     

Stereoselective synthesis of cis and trans 2-substituted 1-phenyl-3-azabicyclo[3.1.0]hexanes

The Stereoselective synthesis of cis and trans 2-methyl-1-phenyl-3-azabicyclo[3.1.0]hexanes and 1,2-diphen-yl-3-azabicyclo[3.1.0]hexanes from 2-oxo-1-phenyl-3-azabicyclo[3.1.0]hexane is described. The relative stereochemistry of the products was established by nuclear magnetic resonance and molecular modeling studies.     

Reaction of nitrenes with strained olefins. Preparation and reactions of some 6-azabicyclo[3.1.0]hexanes

A number of examples of the 6-azabicycIo[3.1.0]hexane ring system have been prepared by the oxidation of N-aminophthalimide or 3-amino-2-methyl-4-quinazoIone with lead tetraacetate in the presence of variously substituted cyclopentenes. Thus, 6-phthalimidyl-6-azabicyclo[3.1.0]hexane, dimethy 1–6-phthalimidyl-6-azabicyclo[3.1.0]-hexane-1,5-dicarboxylate, 2,3-benzo-6-phthalimidyl-6-azabicycIo[3.1.0]hexane and N-3-(2-methyl-4-quinazolyl)-6-azabicyclo [3.1.0]hexane were prepared for the first time. All of the new compounds were found to be stable in refluxing carbon tetrachloride and chlorobenzene. Refluxing 6-phthalimidyl-6-azabieyclo[3,1.0]hexane in acetic acid for 24 hours resulted in quantitative rearrangement to a phthalohydrazide, 8 .     

An efficient stereoselective synthesis of 1-iodo- or 1-phenyl selenenyl-2-aryl-3-azabicyclo[3.1.0]hexane via electrophilic cyclization of benzyl-2-arylmethylidenecyclopropylmethyl-amines

The reaction of benzyl-2-arylmethylidenecyclopropylmethyl-amine 1 with iodine in the presence of potassium carbonate or PhSeBr stereoselectively gives ring-closure product 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexane or 1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]hexane in good yields at room temperature. A plausible reaction mechanism has been proposed.     

Novel synthesis of 3-azabicyclo[3.1.0]hexanes by unusual palladium(0)-catalyzed cyclopropanation of allenenes

Novel stereoselective synthesis of 3-azabicyclo[3.1.0]hexanes from allenenes is presented. Treatment of N-protected 4-alkyl-4-(N-allyl)amino allenes with allyl carbonate and a catalytic amount of Pd(2)(dba)(3).CHCl(3) in MeCN leads to stereoselective formation of the 3-azabicyclo[3.1.0]hexane framework in moderate to good yields. [reaction: see text]     

Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.     

Reaction of Substituted 6,8-Dioxo-2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 6,8-Dioxo-1,2,7-triazaspiro[4.4]non-2-ene-3-carboxylates with N-Fluoropyridinium Tetrafluoroborate

Substituted 6,8-dioxo-2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylates react with N-fluoropyridinium tetrafluoroborate to give mixtures of exo and endo isomers of 6-fluoro-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylates. Analogous reaction of 6,8-dioxo-1,2,7-triazaspiro[4.4]non-2-ene-3-carboxylates results in formation of syn,anti-isomeric 1-fluoro-4,6-dioxo-5-azaspiro[2.4]heptane-1-carboxylates.     

Thermolysis of the esters of substituted 3,7-triazabicydo[3.3.0]oct-3-ene-4-carboxylic acids

Heating to 190–200‡C of the esters of substituted 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylic acids afforded esters of 3-azabicyclo[3.1.0]hexane-6-carboxylic acids as a mixture of exo and endo isomers. The reaction carried out in chlorobenzene at 130‡C in the presence of copper stearate yielded only exo isomers. The study was carried out under financial support of the Russian Ministry of Education (grant no. 97-0-9.4-118).     

Unexpected formation of new bicyclic γ-lactams by dimerization of α-chloroacetoacetanilides

Novel and unusual dimerization reaction of α-chloroacetoacetanilide under basic reaction condition to give structurally unique 6-oxa-3-azabicyclo[3.1.0]hexane was described.     

A new synthetic route to substituted 1-fluoro-1-cyclopropanecarboxylates

Substituted 6-fluoro-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylates were obtained as a mixture of the exo- and endo-isomers by reaction of substituted 6,8-dioxo-2,3,7-triazabicyclo[3.3.0]oct-3-en-4-carboxylates with N-fluoropyridinium tetrafluoroborate.     

Reaction of Substituted Methyl 2,3,7-Triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-Triazaspiro[4.4]non-2-ene-3-carboxylates with Iodinating Agents

Substituted methyl 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-triazaspiro[4.4]non-2-ene-3-carboxylates react with N-iodosuccinimide (or the system iodine-silver trifluoroacetate) to give, respectively, methyl 6-iodo-3-azabicyclo[3.1.0]hexane-6-carboxylates or methyl 1-iodo-4,6-dioxo-5-azaspiro[2.4]heptane-1-carboxylates as mixtures of exo and endo isomers.     

Reactions of 2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles with nucleophiles

2′-Oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles reacted with oxygencentered nucleophiles to form addition products at the cyano groups with conservation of the three-membered ring. Reactions of the title compounds with alcohols required the presence of base catalyst, and the products, 2-amino-4,4-dialkoxy-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles, were converted into the corresponding 2-imino-2′,4-dioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles and 2,2′,4-trioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles by the action of acetic and sulfuric acids, respectively. The reactions with ketone oximes occurred in the absence of a catalyst, yielding 2-amino-4,4-bis(alkylideneaminooxy)-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles. The reactions with thiols, aliphatic amines, and anilines were accompanied by opening of the three-membered ring. In the reactions with triphenylphosphine and thiols 2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)malononitrile was obtained, while morpholine and N,N-dimethylaniline gave rise, respectively, to 3,3-diaryl-and 3,3-dimorpholino-1H-indol-2(3H)-ones and tri- and dicyanoethylene derivatives.     

Reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with O-centered nucleophiles

The reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with primary aliphatic alcohols lead to the formation of alkyl 2,2,3,3-tetracyanocyclopropanecarboxylates; the reactions of the same compounds with ketone oximes give 2-amino-4,4-bis(alkylideneaminooxy)-6-(alkylidene-aminooxycarbonyl)-3-azabicyclo[3.1.0]hex-2-ene-1,5-dicarbonitriles, while with aldehyde oximes 2-amino-2-oxo-1,5-dicyano-3-azabicyclo[3.1.0]hex-2-ene-6-carboxylic acid is formed.     

Reactions of Substituted 2,3,7-Triazabicyclo[3.3.0]oct-2-enes and 1,2,7-Triazaspiro[4.4]non-1-enes with Halogens

Halogenation of 1-substituted 7-aryl-2,3,7-triazabicyclo[3.3.0]oct-2-ene-6,8-diones gives different products, depending on the substituent in position 1 (R¹): when R¹ = Ar, 6-chloro-3-azabicyclo[3.1.0]hexanes are formed, while compounds with R¹ = H or Me give rise to 2- or 4-chloro-2,3,7-triazabicyclo[3.3.0]oct-2-ene-6,8-diones whose thermolysis leads to formation of the corresponding 6-chloro-3-azabicyclo[3.1.0]hexanes. Chlorination of 7-aryl-1,2,7-triazaspiro[4.4]non-1-ene-6,8-diones yields 3-chloro-1,2,7-triazaspiro[4.4]non-1-ene-6,8-diones, and thermolysis of the latter affords 1-chloro-5-azaspiro[2.4]heptanes.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005, pp. 78–88.Original Russian Text Copyright © 2005 by Molchanov, Stepakov, Kostikov.     

Copper-mediated aerobic synthesis of 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles from N-allyl/propargyl enamine carboxylates

Synthetic methods for 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles have been developed that use copper-mediated/catalyzed reactions of N-allyl/propargyl enamine carboxylates under an O(2) atmosphere and involve intramolecular cyclopropanation and carbooxygenation, respectively. These methodologies take advantage of orthogonal modes of chemical reactivity of readily available N-allyl/propargyl enamine carboxylates; the complementary pathways can be accessed by slight modification of the reaction conditions.     

Reactions of tetracyanocyclopropyl ketones with ammonia and primary amines

Reactions of aliphatic 2,2,3,3-tetracyanocyclopropyl ketones with aqueous ammonia afforded 4-alkyl- 4-amino-2-oxo-3-azabicyclo[3.1.0]hexane-1,6,6-tricarbonitriles with conservation of the three-membered ring. Reactions of the same compounds with primary amines were accompanied by opening of the cyclopropane ring, and they led to the formation of 5-amino-6,6a-dimethyl-2-oxo-1,2,6,6a-tetrahydropyrrolo[2,3-b]-pyrrole-3,4-dicarbonitriles as a result of successive heterocyclizations.     

Kinetics of dehydrohalogenation of N-chloro-3-azabicyclo[3,3,0]octane in alkaline medium. NMR and ES/MS evidence of the dimerization of 3-azabicyclo[3,3,0]oct-2-ene

The formation of 3-azabicyclo[3,3,0]oct-2-ene in the course of the synthesis of N-amino-3-azabicyclo[3,3,0]octane using the Raschig process results from the following two consecutive reactions: chlorine transfer between the monochloramine and the 3-azabicyclo[3,3,0]octane followed by a dehydrohalogenation of the substituted haloamine. The kinetics of the reaction were studied by HPLC and UV as a function of temperature (15 to 44°C), and the concentrations of NaOH (0.1 to 1 M) and the chlorinated derivative (1 to 4×10⁻³ M). The reaction is bimolecular (k=103×10⁻⁶ M⁻¹ s⁻¹; ΔH^0#=89 kJ mol⁻¹; and ΔS^0#=−33.6 J mol⁻¹ K⁻¹) and has an E2 mechanism. The spectral data of 3-azabicyclo[3,3,0]oct-2-ene were determined. IR, NMR, and ES/MS analysis show dimerization of the water-soluble monomer into a white insoluble dimer. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 129–136, 1998.     

Reactions of Substituted 2,3,7-Triazabicyclo[3.3.0]oct-3-ene-4-carboxylic Acid Esters with Halogens

Substituted 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylic acid esters react with chlorine and bromine to give the corresponding 4-halo-2,3,7-triazabicyclo[3.3.0]oct-2-ene-4-carboxylates. Heating of the latter to 120°C under reduced pressure leads to elimination of nitrogen molecule and formation of 6-halo-3-azabicyclo[3.1.0]hexane-6-carboxylates.     

Ruthenium-catalysed synthesis of fluorinated bicyclic amino esters through tandem carbene addition/cyclopropanation of enynes

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF(3))(CO(2)R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp*=C(5)Me(5) , PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N(2)CHSiMe(3), whereas N(2)CHCO(2)Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions.     

Reactions of Aliphatic Diazo Compounds: IV. Reaction of Diphenyldiazomethane with Substituted Imides of Maleic and Itaconic Acids

Diphenyldiazomethane regioselectively adds to 2-R-substituted maleimides to yield 1-pyrazoline derivatives, 1-R-7-aryl-6,8-dioxo-4,4-diphenyl-2,3,7-triazabicyclo[3.3.0]oct-2-enes that on heating liberate nitrogen to afford substituted 3-azabicyclo[3.1.0]hexanes. To the N-arylsubstituted imides of itaconic acid the diphenyldiazomethane adds to furnish 5-aryl-4,6-dioxo-1,1-diphenyl-5-azaspiro[2.4]heptanes.