Azabicyclo nonane derivatives

The mercuration-demercuration reaction of cw,cw-l,5-cyclooctadiene (3) has been widely studied in order to get some insight into the synthesis of 9-oxa and 9-azabicyclo-nonane derivatives. However, the results of the reaction have often been the subject of some controversy since the ratio of the two isomeric bicyclo[3.3.1]- [199 and 201] and [4.2.1]- [198 and 200] nonanes, after reduction (equation 166), strongly depended on the reaction conditions of the mercuration step168,169. 

Until recently, the intramolecular cyclization procedure had been used only to synthesize fused heterocyclic structures. The first report of a bridged product, in 1978, involved only a minor amount (9%) of an azabicyclo[3.3.1]nonane derivative obtained from the reaction of ds-carveol with acetonitrile and BFj-EtiO. However, several effective examples are now known. These all involve reaction of the nitri-lium intermediate with an internal alkenic nucleophile to yield a 1-azacyclohexene ring and a new carbe-nium ion which undergoes conventional, but stereospecific, Ritter reaction fiom the least hindered face. Such reactions are typified by formation of the multicyclic structures (64 equation 38) 5<) and (65 equation 39), 5i considerable potential in the synthesis of complex nitrogen heterocyclic systems... 

For bicyclo[3,3,l]nonane derivatives which are unsubstituted at positions 3 and 7, it has been shown in several cases that chair-chair conformations are preferred, although the cyclohexane rings are distinctly flattened with valence-angle increases (cc. 4°) beyond ideal tetrahedral values. However, derivatives with bulky endo substituents at positions 3 or 7 may adopt boat-chair conformations. Thus for 9-benzoyl-3a-bromo-9-azabicyclo[3,3,l]-nonan-2-one (74) and for the 2-hydroxy-analogue, it has been argued... 

Bohlmann et al. (118-121) observed that an infrared absorption band between 2700-2800 cm is characteristic of a piperidine derivative possessing at least two axial carbon-hydrogen bonds in antiperiplanar position to the free-electron pair on the nitrogen atom. The possibility of forming an enamine by dehydrogenation can be determined by this test. Compounds which do not fulfill this condition cannot usually be dehydrogenated (50, 122,123). Thus, for example, yohimbine can be dehydrogenated by mercuric acetate,whereas reserpine or pseudoyohimbine do not react (124). The quinolizidine (125) enamines (Scheme 4), l-azabicyclo(4,3,0)-nonane, l-azabicyclo(5,3,0)decane, l-azabicyclo(5,4,0)undecane, and l-azabicyclo(5,5,0)dodecane have been prepared in this manner (112,126). 

A wide variety of other photocyclizations have been reported, but only a few of these have any general application. The unsaturated amine 366 undergoes cyclization in cyclohexane to give the 7-azabicyclo[4.3.0]nonan-2-one 367.303 The formation of pyrrolidine derivatives by photocyclization has also been observed in JV-alkyl-2-allylanilines,304 and imidazoles have been obtained by irradiation of 2-amino-1-dialkylaminoanthraquinones.30 5... 

The derivatives of 2-azabicyclo[3.3.1]nonanes (morphane) (41) can also be used to build the framework of alkaloids with the azocino[4,3-l7]indole fragment. 7-(2-Nitrophenyl)-substituted azabicyclononanone 42 obtained from N-benzylpiperidone-4 (seven stages, total yield (10%)) under the conditions of reductive cyclization has been converted into N-benzylhexahydroazocino [4,3-1 ]-indole 43 (Scheme 10 88T2087). 

Methylene groups adjacent to the N atom in tertiary polycyclic amines were oxidised by RuO /aq. Na(IO )/CCl, depending on reaction conditions. Thus A -benzyl-9-azabicyclo-[l, 3, 3]-nonane yielded AT-benzoyl-9-azabicyclo-[l, 3, 3]-nonane (Fig. 5.5) and A -benzyl-l,3-dioxo-iso-quinoline gave the A -benzoyl compound, while A -benzyl-5,6-dihydro-llH-dibenz[b,e]azepine, which has exi and endocydic benzyl groups, were oxidised to the N-benzyl-6-oxo derivative [41]. 

The Aae values (at 60 MHz) observed for 3-azabicyclo[3.3.1]nonane and its Af-methyl derivative were 0.08 and 0.67 ppm respectively, a decrease of 0.5-0.6 ppm compared to the Aae values for the corresponding piperidines. On this evidence the conformations 15 and 16 were assigned to these compounds.37... 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

Mercuric acetate and a tertiary base in 5% aqueous acetic acid172 yield a mercurated complex, which subsequently forms mercurous acetate and acetic acid. In this manner, quinolizidine (27) and its derivatives,173 l-azabicyelo[4.3.0]nonane, l-azabicyclo[5.3.0]-... 

Azabicyclo[3.3.1]nonan-7-one derivatives, (II), effective as kappa opioid receptor antagonists, (I), were prepared by the authors (2) in an earlier investigation and used in the treatment of opioid addiction. 

Anatoxin-a, the first highly potent cyanotoxin to have its structure and absolute stereochemistry elucidated, was originally isolated from a unialgal clone of Anabaena Jlos-aquae (NRC-44h) [5]. The structure was confirmed by X-ray crystallographic data for the N-acetyl derivative [11] and additional studies have since provided further proof for the structure and stereochemistry (for example, [12]). Anatoxin-a is an unsymmetrical bicyclic secondary amine, and was the first naturally occurring alkaloid discovered to contain a 9-azabicyclo[4,2,l]nonane (homotropane) skeleton. Homotropanes are one-carbon analogs of the tropanes and, as such, are structurally closely related to the well-known alkaloid cocaine. 

Anonymous, New basic derivatives of 6,9-endoxo-3-azabicyclo-[4.3.0]-nonane. Br. Patent 973,533 (February 21, 1962, Laboratoire Lumiere, S.A.), 1964. 

The structure of yuzurine was determined to be (88) by an X-ray crystallographic study of the methiodide derivative, employing a heavy-atom method. This structure accounts for the observed chemical and physical data. The proposed biosynthetic pathway from yuzurimine-B (89) is indicated in Scheme 2. Yuzurine, which may be included in the yuzurimine class, differs from the previously isolated Daphniphyllum alkaloids in that it has no 2-azabicyclo-[3,3,l]nonane system. 

A biomimetic synthesis of the 9-azabicyclo(3.3. llnonan-3-one skeleton of the adaiine alkaloids (68) is notede6a as are syntheses of derivatives of the 3-aza-nonan- 9-one.68b 2-aza-68c and 3-aza-68d nonane relatives. Other... 

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