Piperidine, allylic amination

Morpholine also gives the allyhc amine in high yield. The reaction is thought to involve a known hydridopaUadium-catalyzed isomerization of alkynes to aUenes followed by reaction of the latter with the hydridopalladium complex to give 1-phenyl-substituted q -allylpalladium complexes. These complexes react with amines affording the allylic amines. Primary amines give the diallylic amines. An intramolecular version has been developed for the synthesis of 2-(2-phenyl)-pyrroUdines and -piperidines [319]. 

Fig. 5. Application of dendrimeric ligand 4 in the allylic amination of crotyl acetate and piperidine using a CFMR (% conversion of crotyl acetate in the product stream vs substrate flow), (a) P/Pd = 2, (b) P/Pd = 4, Koch MPF-60 NF membrane, molecular weight cut-off = 400 Da) )18b).

The reaction proceeds well with unhindered secondary amines as both nucleophiles and bases. The yield of allylic amine formed depends upon how easily palladium hydride elimination occurs from the intermediate. In cases such as the phenylation of 2,4-pentadienoic acid, elimination is very facile and no allylic amines are formed with secondary amine nucleophiles, while phenylation of isoprene in the presence of piperidine gives 29% phenylated diene and 69% phenylated allylic amine (equation 30).84 Arylation occurs at the least-substituted and least-hindered terminal diene carbon and the amine attacks the least-hindered terminal ir-allyl carbon. If one of the terminal ir-allyl carbons is substituted with two methyl groups, however, then amine substitution takes place at this carbon. The reasons for this unexpected result are not clear but perhaps the intermediate reacts in a a- rather than a ir-form and the tertiary center is more accessible to the nucleophile. Primary amines have been used in this reaction also, but yields are only low to moderate.85 A cyclic version occurs with o-iodoaniline and isoprene.85... 

The reactions of tertiary allylic amines with vinylic halides are related closely to the allylic alcohol reactions since enamines are often major products. We have just begun work in this area and have few results to report yet. We have seen some significant differences in the products formed from tertiary allylic amines and from the related allylic alcohols. A typical example is the reaction of 2-bromopropene with N-allyl piperidine and piperdine where a 42% yield of a single enamine is obtained (6). The related reaction with allyl alcohol gives a mixture of regioisomeric enamines. 

Four-carbon-chain extensions have been very successful with conjugated dienes as the functionalized olefins. We have used a few other compounds also, but they are of limited value, such as N-3-butenylphthalimide. The last compound is only useful with aromatic or certain vinyl halides where mixtures of allylic amines would not be formed. A typical diene example is the reaction of vinyl bromide with butadiene and piperidine which gives E-N-(2,5-hexadienyl)-piper-idine in 70% yield (7). The product of this reaction can be reacted again and used to extend the carbon chains by six atoms (see below). The reactions of conjugated dienes can be used to produce conjugated trienes also (4). 

Pd-catalyzed allylic amination of crotyl acetate by piperidine, while exhibiting a reduced rate as is commonly observed for heterogenized systems (90% conversion achieved after 30 min compared with 5 min for the homogeneous system). Interestingly, the catalyst could be recycled three times via a simple filtration step. Subsequently, the catalyst was separated from the support and the support was uploaded with hydroformylation catalysts. 

Table 7 Results of the Pd-catalyzed allylic amination of crotyl acetate and piperidine, comparing the supramolecular dendrimeric catalyst with the corresponding monomer3...

The same ligand was used by Visentin and Togni [145] in the palladium catalysed allylic amination using racemic 1,3-diphenylallylethyl carbonate and either benzylamine or piperidine. The yields were rather low (32% and 58%, respectively) with very poor chiral resolution (5% ee of the S enantiomer). 

The use of enantiomerically pure iridium catalysts allows the enantioselective allylic amination of linear substrates and this has been achieved with high ee using the iridium complex of phosphoramidite (10.84) and both acyclic and cyclic amines, including pyrrolidine and piperidine. ... 

Reactions induced by ultrasonic irradiation of methyl 9,12-dioxostearate with hydrazines in water in the presenee of acidic alumina gave high yields of pyridazine fatty esters directly (95). The synthesis of novel piperidine- [25] and pyridine- [26] containing long-chain fatty ester derivatives has been reported starting from methyl wo-ricinoleate, 9-hydroxy-18 l(12Z) (96). Allylic amination of methyl oleate with bis(A-p-toluenesulfonyl)sulfodiimide gave a mixture of methyl ll-amino-(iV-p-toluenesulfonyl)-18 l(9 ) and methyl 8-amino-(Af-p-toluenesulfonyl)-18 l(9 ) (97). 

S)-Nicotine (13) is one of the many piperidine and pyrroHdine alkaloids isolated from the leaves of Nicotaiana tabacum. Welter and coworkers developed a synthesis route where 13 was obtained in only four steps from pyridinylallyl carbonate 10 involving RCM (Scheme 2.4) [17]. The synthesis commenced with an Ir-catalyzed asymmetric allylic amination of 10 to produce bis-alkene 11 in excellent enantiomeric purity when using phosphoramidate Hgand LI. Subsequently, secondary amine 11 was N-protected to produce 12 prior to RCM in order to prevent catalyst... 

Subsequently, the scope of the reaction was extended to N-nucleophiles 82. Because the inherent basicity of the substitution products 83 imposed some problems concerning catalyst decomposition, the addition of catalytic amoimts of piperidine hydrochloride (pip-HCl) proved to be necessary. Under optimized reaction conditions different aromatic amines 82 were allylated with almost exclusive regioselectivites in favor of the ipso substitution products 83 (eq. 1 in Scheme 20) [64]. 

This allows for easy reuse of the catalyst in the reaction of allylation of secondary amines like piperidine or morpholine for several runs. The leaching of palladium was less than 0.001% of the initial amount. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Substitution reactions of allylic nitro compounds often lead to rearranged products, as in palladium(0)-catalysed aminations and alkylations. Thus treatment of the nitro ester 419 with piperidine in the presence of tetrakis(triphenylphosphine)palladium yields a mixture of the unrearranged and rearranged amines 420 (R = piperidin-l-yl) and 421... 

The catalyst [Ir(COD)Cl]2/P(OPh)3 was highly effecHve also for allyhc airuna-Hons. Branched monoallylahon products were mainly obtained with primary amines as nucleophiles and Hnear fE)-allylic substrates. In contrast, mixtures of Hnear mono- and disubsHtuHon products are usually produced with Pd-catalysts. Many types of amine could be used, for example benzylairune, piperidine and anihne [14]. In terms of allyhc substrates, carbonates were more suitable than acetates. With regards to the solvent, the best results were obtained with ethanol, with complete conversion typicaUy being achieved after a reacHon time of 3 h at 50°C. The reacHons of (Z)-aUylic carbonates to give Hnear fZj-propenylamines proceeded with perfect stereospecificity. 

Trons-divinyl-pyrrolidines and -piperidines were prepared by sequential intermolecular and intramolecular aminations of bis-allylic carbonates (Scheme 9.21) [22aj. Due to double stereoselection, these reactions proceeded with high diastereoselectivity and enantioselectivity. 

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