Piperidine derivatives bond formation

Dehydrohalogenation of the 314 proceeded in excellent yield under the action of morpholine or piperidine at rt, during double bond formation between the C-l and C-2 atoms <2003CHE640>. The active methylene group of 3,4-dihydro-1 ///>//-[ 1,4 oxazino[3,4- quinazolin-6-onc 315 readily condensed with aromatic aldehydes at 160 °C in a melt to give the 1-benzylidenes, and coupled with aryldiazonium chlorides to give the arylhydrazono derivatives <1996BMC547>. 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

Rate and equilibrium constants have been reported for the reactions of butylamine, pyrrolidine, and piperidine with trinitrobenzene, ethyl 2,4,6-trinitrophenyl ether, and phenyl 2,4,6-trinitrophenyl ether in acetonitrile, hi these reactions, leading to cr-adduct formation and/or nucleophilic substitution, proton transfer may be rate limiting. Comparisons with data obtained in DMSO show that, while equilibrium constants for adduct formation are lower in acetonitrile, rate constants for proton transfer are higher. This probably reflects the stronger hydrogen bonding between DMSO and NH+ protons in ammonium ions and in zwitterions.113 Reaction of 1,3,5-trinitrobenzene with indole-3-carboxylate ions in methanol has been shown to yield the re-complex (26), which is the likely precursor of nitrogen- and carbon-bonded cr-adducts expected from the reaction.114 There is evidence for the intermediacy of adducts similar to (27) from the reaction of methyl 3,5-dinitrobenzoate with l,8-diazabicyclo[5.4.0]undec-8-ene (DBU) cyclization eventually yields 2-aminoindole derivatives.115... 

Related reactions of acyclic unsaturated amide derivatives S show a reversal of the diastereofa-cial selection according to the geometry of the double bond. This is in contrast to the carbamate series (vide infra)13 which is dependent on the nature of the nucleophile68. The most remarkable feature is the formation of 1,2-syvj-products 6B from the A-isomers. This may be best explained by the steric repulsion between the ester and acyl groups. This complementary and effective diastereoselection provides a stereodivergent synthesis of 2,3-disubstituted piperidines (see also Section D.7.3.1.1.2.2.). 

The A -l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde 22, R = Me) and A -l-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl (22, R = iBu) derivatives of diamino acids are stable towards trifluoroacetic acid, piperidine/DMF (20% piperidine in NMP for 117 min cleaves the Dde group to an extent of only 2.1% ) and DBU, but are easily cleaved with 2% hydrazine in DMF. The preferential protection of primary versus secondary amines is explained by the formation of hydrogen bonds in the product. Further deriv-... 

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