Synthesis,including asymmetric synthesis,of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon–hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.     

Highly regioselective Pd-catalyzed intermolecular aminoacetoxylation of alkenes and evidence for cis-aminopalladation and S(N)2 C-O bond formation

Synthetic methods that achieve oxidative 1,2-difunctionalization of alkenes are very powerful in organic chemistry. Here we report the first examples of intermolecular Pd-catalyzed aminoacetoxylation of alkenes with phthalimide as the nitrogen source and PhI(OAc)2 as the stoichiometric oxidant and source of acetate. These reactions are highly regio- and diastereoselective, and mechanistic studies reveal that the reaction proceeds via cis-aminopalladation of the alkene followed by oxidative cleavage of the intermediate Pd-C bond with inversion of stereochemistry.     

Diastereoselective synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes

A general method was developed for the synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes via intramolecular aminomethylation of the NH group of the diaziridine ring by the reactions of 3-aminomethyl-1,3-dimethyldiaziridine with aliphatic, aromatic, and heteroaromatic carbonyl compounds. These reactions with aldehydes proceeded diastereoselectively to form mixtures of two racemates, viz., 1R*,2R*,5R*,6R* and 1R*,2S*,5R*,6R*, in a ratio of (3—20) : 1, the predominant diastereomer being isolated in all cases. The reactions with symmetrical ketones gave rise exclusively to the (1R*,5R*,6R*) racemate. The predominant diastereomer 1R*,2R*,5R*,6R*-2-(2-bromothien-5-yl)-1,3,6-triazabicyclo[3.1.0]hexane crystallized as a conglomerate. The structure of one of its enantiomers was established by X-ray diffraction analysis.     

Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: a general methodology for the synthesis of potent and selective mGluR2/3 agonists

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.     

A domino palladium-catalyzed C-C and C-O bonds formation via dual O-H bond activation: synthesis of 6,6-dialkyl-6H-benzo[c]chromenes

An efficient Pd-catalyzed domino reaction of α,α-dialkyl-(2-bromoaryl)methanols to 6,6-dialkyl-6H-benzo[c]chromenes is presented. Their formation can be explained via a five membered Pd(II)-cycle that efficiently involves a domino homocoupling with the second molecule, β-carbon cleavage, and finally intramolecular Buchwald-Hartwig cyclization. This domino process effectively involves breaking of five σ-bonds (2C-Br, 2O-H, and a C-C) and formation of two new σ-bonds (C-C and C-O). This mechanistic pathway is unprecedented and further illustrates the power of transition metal catalysis.     

Diastereoselective cascade synthesis of azabicyclo[3.1.0]hexanes from acyclic precursors

The diastereoselective synthesis of azabicyclo[3.1.0]hexanes bearing different substituents on all positions of the cyclopropane ring has been achieved in moderate to good yields.     

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.     

Unusual carbon shielding effects of cyclopropanes and double bonds in strained bicyclo[3.1.0]hexanes and cyclopentenes

Carbon-13 shieldings and one-bond ¹³C? H coupling constants of bicyclo[2.1.1]hexane, bicyclo[2.1.1]hex-2-ene, tricyclo[3.1.1.0^2,4]heptane and benzvalene are presented and compared to the data of related compounds. If a bicyclo[3.1.0]hexane system is part of a rigid skeleton, the cyclopropane ring exerts specific γ substituent effects of two kinds. In the case of the bicyclohexane boat form an upfield shift of the C-3 signal is observed and in the case of the chair form a downfield shift of 15–20 ppm. Compared to the corresponding cyclopentanes the double bond in strained cyclopentenes causes downfield shifts of the C-4 absorption. This effect increases with increasing strain, reaching a 45.9 ppm maximum in benzvalene. Hence it is the only known bicyclo[1.1.0]butane having a reversed order of carbon shieldings. The downfield shifts are explained by means of simple orbital interaction schemes.     

The photosensitized rearrangement of aryl-substituted tricyclo[2.2.0.02,6]hexanes to bicyclo[3.1.0]hex-2-enes

The triplet sensitized irradiation of 3-allyl-diaryl-substituted cyclopropenes to bicyclo[3.1.0]hex-2-enes proceeds via an intramolecular [2+2]-cycloaddition followed by a subsequent rearrangement of the initially formed tricyclo[2.2.0.0^2,6]hexane skeleton.     

Synthesis and transformations of 1,3,5-triazabicyclo[3.1.0]hexanes

The conditions for the condensation of 1,2-nonsubstituted diaziridines with CH₂O and NH₃ (or AlkNH₂) to the corresponding 1,3,5-triazabicyclo[3.1.0]hexanes have been found and 3-phenylsulfonyl, 3-trimethylsilyl, 3-nitroso, and 3-nitro derivatives of the latter have been obtained.For the previous communication, see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2091–2095, December, 1993.     

Stereochemical assignments of the 6-phenyl-2-oxabicyclo[3.1.0]hexanes

Preparation and stereochemical assignments of the 6-phenyl-2-oxabicyclo[3.1.0]hexanes are reported. The stereochemical assignments are based on chemical as well as nmr data.     

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]     

One-pot palladium-catalyzed synthesis of 2,3-disubstituted bicyclo[2.2.1]heptanes and bicyclo[2.2.1]hept-5-enes

A new and highly stereoselective palladium-catalyzed synthesis is reported, based on two subsequent insertions of the bicyclo[2.2.1]heptene system into an aryl or vinylpalladium bond, formed in situ from aryl or vinyl bromides.     

A new synthesis of 2-azabicyclo[2.1.1]hexanes

An efficient synthesis of the 2-azabicyclo[2.1.1]hexane ring system has been accomplished starting from cis-cyclobut-3-ene-1,2-dicarboxylic anhydride 7, which was prepared using a photochemical method. The key step of this new strategy involved a stereoselective electrophilic addition of phenylselenyl bromide to the double bond of cyclobutene dicarbamate 16 derived from 7. The subsequent ring closure of 17a in the presence of sodium hydride afforded the 2-azabicyclohexane compound 18 with a satisfying overall yield. Reductive removal of the phenylselenyl group and subsequent deprotection led rapidly to the amino derivative 4a functionalized on the carbon ring. Syntheses of the hydroxy and carboxylic derivatives 4b,c were then achieved from the intermediary disulfonamide 23. Displacement of the activated amino group by potassium acetate yielded hydroxy derivative 4b after three additional steps. Finally, oxidation of the alcohol function of 4b under Jones conditions followed by hydrogenolysis afforded the carboxylic derivative 4c, which is the first reported beta-isomer of 2,4-methanoproline 1.     

Bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene

The formation and trapping of bicyclo[3.1.0]hex-(1,5)-ene and bicyclo[4.1.0]hept-(1,6)-ene from the corresponding vicinal dibromides is described.     

Acylation of bicyclo[3.1.0]hexane and bicyclo[5.1.0]octane with pivaloyl tetrafluoborate

Conclusions When bicyclo[3.1.0]hexane and bicyclo[5.1.0]octane are acylated with pivaloyl tetrafluoborate the three-membered ring is opened to respectively give 2-methylpivaloylcyclopentane and 2-methylpivaloylcycloheptane derivatives.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2614–2616, November, 1975.     

An atom-economic synthesis of bicyclo[3.1.0]hexanes by rhodium N-heterocyclic carbene-catalyzed diastereoselective tandem hetero-[5+2] cycloaddition/Claisen rearrangement reaction of vinylic oxiranes with alkynes

The first synthetic application of a vinylic oxirane as a heteroatom-containing five-atom component in transition-metal-catalyzed cycloaddition reactions is reported. A new, efficient, diastereoselective tandem intramolecular hetero-[5+2] cycloaddition/Claisen rearrangement of vinylic oxirane-alkyne substrates that uses a rhodium NHC complex and provides strategically novel, atom-economic, regiospecific, and diastereoselective access to [3.1.0] bicyclic products has been developed.     

Synthesis of bicyclo[3.1.0]hexanes functionalized at the tip of the cyclopropane ring. Application to the synthesis of carbocyclic nucleosides

[reaction: see text] A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a carbene-mediated intramolecular cyclopropanation reaction on the corresponding diazo intermediate. This combined methodology allowed the diastereoselective introduction of chemically diverse substituents at the tip of the cyclopropane group, except in cases where the substituents consisted of electron-withdrawing groups where a competing [3 + 2] cycloaddition predominated.     

Stereoselective synthesis of 1-nitrobicyclo[3.1.0]hexanes and fused isoxazoline-N-oxides from primary nitro compounds

The one-step preparation of 1-nitrobicyclo[3.1.0]hexane and bicycloisoxazoline-N-oxide was readily achieved from conjugate adducts of nitro alkenes and allylmalonates by treatment with Ag(2)O and iodine under basic conditions. We observed that when a primary alkyl group was present at the β-position of the nitro group, bicyclo[3.1.0]hexane was preferentially formed, whereas if a secondary alkyl group occupied that position, isoxazoline-N-oxide was predominantly produced. High cis-selectivity was observed for the formation of cyclopentane units for both reactions. An iodomethyl adduct, considered an intermediate of the cyclization, was isolated, and its conversion to isoxazoline-N-oxide was successfully achieved. The isoxazoline-N-oxide underwent 1,3-dipolar cycloaddition with alkenes to yield tricycloheterocyclic compounds, which were readily converted to spirolactam in good yield by reductive cleavage of N-O bonds using Raney-Ni. On the other hand, 1,3-dipolar cycloaddition of the isoxazoline-N-oxide to terminal alkynes yielded tricyclic aziridines stereoselectively.