2-Azabicyclo hexanes

Addition of bromine to the gew-diphenyl substituted <5,8-unsaturated amines 28 was shown to afford mixtures of the pyrrolidinium and piperidinium salts, 29 and 30, which were converted into the 1-azabicyclo-hexanes 31 by treatment with sodium hydride in dimethylformamide. 

Azabicyclo[2.2.0]hexa-2,5-diene, pentakis-(pentafluoroethyl)-synthesis, 2, 304 2-Azabicyclop.2.0]hexadiene reactivity, 7, 360 thermal isomerization, 7, 360 2-Azabicyclo[2.2.0]hexa-2,5-diene synthesis, 2, 304 1 -Azabicyclo[3.2.0]hexadiene synthesis, 7, 361 1 - Azabicyclo[2.2.0]hexane reactions, 7, 344 ring strain... 

Phenyl-2-oxa-3-azabicyclo[3.2.0]hepta-3,6-diene (11 0.200 g, 1.17 mmol) in hexane was irradiated in a quartz vessel using a Rayonet photoreactor to give the product as a yellow oil yield 0.160 g (SO %). The compound can be distilled below 100 C at 10 4Torr. It gradually resinifies when kept in air at 20 C. 

Bromonitromethane is used for the preparation of nitrocyclopropane. The reaction of /V-be 11 zylmaleimide and bromonitromethane in the presence of base gives the azabicyclo[3.1.0] hexane ring system. Many bases have been tried to improve the yield however, amidine base, particularly 1,2-dimethyl-l, 4, 5, 6-tetrahydropyrimidine (DMTHP), gives the best yield... 

C2S2-C3S 2,4-Dithia-bicyclo[ 1.1.1 ]pentane 2, 836 C3N-C3N 1-Azabicyclo[2.2.0]hexane As... 

The structurally related 1-amino-substituted azabicyclo[3.1.0]hexanes 132 were prepared by intramolecular cyclopropanation of N -allylaminoacetic acid N,N-dimethylamides 131 as diastereomeric mixtures (Scheme 11.34) [127]. 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

Scheme 6.67 Reactions of N-substituted 6,6-dichloro-3-azabicyclo-[3.1.0]hexanes (309, 310) with n-butyllithium.

The ORD curves and ECD spectra of a number of chiral methyl-substituted cyclic amines, aziridine, azetidine, pyrrolidine and piperidine, and their A-mcthyl, A-halo and A-cyano derivatives, and of (5 )-l-azabicyclo[3.1.0]hexane [(5 )-115] were measured96. 

A similar ab initio computational and VCD study in the 800-1500 cm-1 range using (55)-1 -azabicyclo[3.1.0]hexane (55 )-115] gave VCD spectra calculated at three different computational levels which are well reproduced in the experimental VCD spectrum151. 

Domino-Heck Reactions-General Procedure 5.6 mg (25 pmol) of palladium(II) acetate and 55 pmol of the arsine ligand were dissolved in 3 ml of dry dimethyl formamide and the solution was stirred at 65°C (40°C for trimethylsilylacetylene) for 15 mitt Then, 127 mg (1.35 mmol) N-Benzoyl-2-azabicyclo[2.2.1]hept-5-en-3-one, 1 mmol of the aryl compound. Four hundred and eighty-eight microliters (3.50 mmol) of triethylamine, and 3.00 mmol of the phenylacetylene (or silylmethyl-acetylene) were added rapidly in one portion. The mixture was heated at the same temperature for 24 h. After cooling down to room temperature 50 ml of brine were added, the reaction mixture was extracted with ethyl acetate and dried over MgSO. The solvent was evaporated, the residue purified by column chromatography (n-Hexan-Ethyl acetate 4 1). 

A-Boc-4-tosyloxypiperidine (161) undergoes, upon (—)-sparteine-mediated deprotonation, cycloalkylation to form via the lithium compound 162 the l-azabicyclo[3.1.0]hexane 163. 163 is subsequently deprotonated at the bridged-head carbon atom and lithium compound 164 is trapped by silylation the yield of 165 and the e.r. are low (equation 37)" " . 

For the most part the parent unsubstituted bicyclic azetidines have not been reported. Those unsubstituted ring systems which have been reported are l-azabicyclo[2.2.0]hexane (4) (64HCA2145), l-azabicyclo[4.2.0]octane (5) (60JA2609) and the cis- and trans-6-azabicyclo[4.2.0]octanes (6) (66JOC1372). 

The primary mode of electrophilic attack on the azetidine of fused-ring derivatives is acid-catalyzed opening of the bridging bond. For example, l-azabicyclo[2.2.0]hexane (4) gives 4-chloropiperidine (21) on treatment with hydrogen chloride (64HCA2145). 

The free bases of the 2-azabicyclo[2.2.0]hexanes are relatively stable to HC1 but their Af-acyl derivatives (26) react rapidly to give ring-opened cyclobutenes (79JA6677). 

Azetidinones having a ring fused at the N-l/C-4 atoms usually are more susceptible to hydrolysis than those compounds in which the ring fusion is at C-3/C-4. The 2-azabicyclo[2.2.0]hexan-3-one (115) is cleaved with ethanolic HC1 to give ring-opened products (equation 6) (72CB2780). 

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