Aminoketones bicyclic

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

A further rearrangement route to bicyclic aminoketones has been investigated by Padwa et al. (128-134) (Scheme 1.19). Building on the allene-nitrone cycloadditions reported by Tufariello, the alkenylisoxazolidine adducts 90 and 91 were... 

During attempts to synthesize a series of optically active, bicyclic a-aminoketones (195-198), Kuneida and co-workers found that racem-ization invariably took place during the saponification and decarboxylation of the /9-ketoester intermediates, prepared via Dieckmann reactions [Eqs. (26) and (27)].253... 

A special type of ring enlargement is found in the electrolytic reduction of bicyclic a-aminoketones (lead cathode, 30% sulfuric acid, 60°C) to monocyclic products.102 103 Thus, 1-ketoquinolizidine (107) under these conditions gave 59% 5-hydroxyazacyclodecane (108) and 4.5% l-azabicyclo[5.3.0]decane (109) (Scheme 13). 

Piperidine-based aminoketones similar to 456 also featured in syntheses of (+ )-427 by Munchhof and Meyers (Scheme 57) 412), and by Solladie and Chu (Scheme 58) 413). In the former, the enantiomerically pure bicyclic oxazolidine-thione 457 underwent Eschenmoser sulfide contraction under forcing conditions to produce the vinylogous urethane 458, which was simultaneously hydrogenated and hydrogenolyzed over Pearlman s catalyst to give the 2,6-c/s-disubstituted piperidine... 

Lhommet and co-workers synthesized (- )-436 by the route shown in Scheme 66 [422). Wittig-Homer reaction between the 2,5-rrans -disubstituted pyrrolidine aldehyde 509, made from (S)-pyroglutamic acid [423), and the protected keto-phosphonate 510 introduced all the skeletal carbon atoms of the target. Simultaneous hydrogenation and //-deprotection of enone 511 gave the aminoketone 512, which spontaneously formed the bicyclic enamine 513 in 98% yield when exposed to trifluoroacetic acid—apparently the first time that such an intermediate has actually been isolated en route to indolizidines. Reduction with sodium cyanoborohydride in acidic medium acid produced a diastereomeric mixture (92 8) of (- )-436 and (+ )-437. The former was isolated in 84% yield after chromatography on silica gel. The overall yield of this 15-step sequence was 8% based on (S)-pyroglutamic acid. 

The 1,3-dipolar cycloaddition follows with the regiochemistry shown 146a and the product is a bicyclic compound 147 with an N-0 single bond that is easily reduced to give a seven-membered cyclic aminoketone 148 with stereochemistry. 

The synthesis of 14,15-dehydroaspidospermine (184), which affords a third route to the important group of alkaloids containing a double bond in ring D, involved the synthesis " of the unsaturated bicyclic aminoketone (185) (Scheme 33), and completion of the synthesis by the route adopted by Stork and Dolfini in the original aspidospermine synthesis. 

Mannich reaction of acetophenone with formaldehyde and piperidine results into the formation of an aminoketone, which on grignardization with bicyclic halide and subsequent neutralization with HCl affords the offieial eompound biperiden hydrochloride. 

The reductive ring opening of 5,6-fused ring systems has proved to be a valuable means of entry to nine-membered heterocycles. Leonard showed that bicyclic a-aminoketones (288) and (289) could be electrolyzed at a lead cathode to give octahydroazoninols (290) and (291) (Scheme 35) <52JA4620>. 

A soln. of startg. (3-chloroketimine in /cr/-butanol treated with 2 eqs. KOBu-r, stirred under reflux for 12 h, after cooling the mixture diluted with pentane, and stirred for 1 h 2-methylene-3,3-dimethyl-l-phenylazetidine. Y 90%. The method is restricted to N-aryl-derivs., N-benzyl-derivs. affording cyclopropanes (Synth. Meth. 42, 952) and N-alkyl-derivs. giving p-aminoketones. F.e. inch spiro and bicyclic compds. s. P. Sulmon et al., J. Org. Chem. 53, 4462-5 (1988). 

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