Pyrrolidines and Piperidines

The main chemical aspect in which compounds with a nitrogen in a five- or six-membered ring differ from their acyclic counterparts is that they can be dehydrogenated to the corresponding aromatic system. Dihydro-aromatic systems naturally show Ihe greatest tendency to aromatise, indeed one of the important reducing coenzymes, NADPH (a 1,4-dihydropyridine), makes use of this tendency - it is a hydride donor  

Dihydro compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then aromatisation (20.16.1.17), and similarly, electrophilic substitutions of dihydropyridines, very difficult in simple pyridines, followed by aromatisation, can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives reqnires more vigorous conditions. 

Pyrrolidine and piperidine are better nncleophiles than diethylamine, principally because the lone pair is less hindered - in the heterocycles the two alkyl snbstitnents , i.e. the ring carbons, are constrained back and away from the nitrogen lone pair, and approach by an electrophile is thus rendered easier than in diethylamine, where rotations of the C-N and C-C bonds interfere. The p/fau values of pyrrolidine (11.27) and piperidine (11.29) are typical of amine bases they are slightly stronger bases than diethylamine (10.98). Morpholine (8.3) is a somewhat weaker base than piperidine. 

Piperidines, like cyclohexanes, adopt a preferred chair conformation, where both A -hydrogen and Aralkyls take np eqnatorial conformations, thongh in the former case the equatorial isomer is favoured by only a small margin. However, alkylations at nitrogen do not necessarily reflect these ground-state conformational popnlations. 

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In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

N-Macroheterocycles and derivatives of pyrrolidine and piperidine as inhibitors of immunophillin enzymes 98JMC5119. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

This can be degraded by several mycobacteria including Mycobacterium aurum strain MOl (Combourieu et al. 1998), Mycobacterium strain RPl (Poupin et al. 1998), and Mycobacterium chelonae (Swain et al. 1991). The reaction is initiated by a cytochrome P450 monooxygenase that is also active against pyrrolidine and piperidine (Poupin et al. 1998). 

Initiation of the degradation of morpholine by a strain of Mycobacterium strain RPl (Poupin et al. 1998), and additionally of pyrrolidine and piperidine. 

The pincer complexes 89-90 (Fig. 2.14) catalyse the intramolecular hydroamination/ cyclisation of unactivated alkenes, yielding pyrrolidines and piperidines (n = 1,2, respectively). The reactions can be carried out in benzene or water with high... 

The enantioselectivity is due to the retention of the chiral sparteine in the lithiated reagent. The adducts have been used to synthesize a number of pyrrolidine and piperidine derivatives. 

Naturally occurring and synthetic polyhydroxylated pyrrolidine and piperidines have recently received considerable attention due to their biological activities. Barco has used tandem Michael-Henry reactions to synthesize 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines, from which the nitro group is removed to give the natural product, trans 2-hydroxymethyl-3-hy-droxypyrrolidine (Eq. 7.72).91... 

P-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlhL is a powerful method for the synthesis of stereodefined aziridines and azetidines <06OL1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cw-disubstituted pyrrolidines and piperidines 32 <060L1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-... 

Various schemes have been proposed to explain the production of nitrogen-containing heterocyclic compounds, such as pyrrolidines and piperidines, from proline. Nitrogen heterocyclic compounds are often potent flavouring chemicals. 

A very simple and straightforward access to enantiopure substituted pyrrolidines and piperidines was obtained by reaction of phenylglycinol 178 with co-chloroketones 179. The intermediate oxazolidines 180 were then easily converted into the desired compounds <00EJO1719>. Compound 182 was obtained by reaction of the correspondent oxazolidine with a complex alkyllithium derivatives and was the intermediate for the synthesis of... 

Intramolecular nitrile oxide—olefin cycloaddition of oxazolidine and thiazoli-dine oximes 407 (R = H, Me R1 =H, Me X = 0, S n = 1,2) proceed stereose-lectively, yielding tricyclic fused pyrrolidines and piperidines. Thus, 407 (n =2 R = H R1 =Me X=S) has been oxidized to the nitrile oxides with sodium hypochlorite, in the presence of triethylamine in methylene chloride, to give the isoxazolothiazolopyridine 408 in 68% yield. Reduction of 408 with lithium aluminum hydride affords mercaptomethylmethylpiperidine 409 in 24% yield (448). 

The Ru complex formed active catalysts in aqueous ethylenediamine, diethanolamine, pyrrolidine, and piperidine. The H2 was detected with aromatic and... 

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. 

The results are not particularly consistent here either. This last reaction, exothermic by ca —206 kJmol-1, is not consistent with either result in equation 43. We strongly doubt the principal source of error is the difference of choice of phases employed57. The difference of the hexahydrotriazine enthalpies of formation, —18 — (—132) = 114 kJmol-1, is comparable to three times the difference of liquid pyrrolidine and piperidine, 132 kJ mol-1. (The difference for other pairs of corresponding 5- and 6-membered ring species includes 166 kJ mol-1 for cyclopentane and cyclohexane, and 162 for perhydroindene and decalin.) The origin of the ca 20 and 50 kJmol-1 discrepancies remains enigmatic. 

The reductive amination of hexane-2,5-dione and heptane-2,6-dione with ammonia and primary amines RNH2 (R = PhCH2, Ph2CH, PhMeCH, Ph, 4-MeOC6H4, 2-ClC6H4 and 2,6-Me2CgH3) under the influence of sodium cyanoborohydride or sodium triacetoxyboro-hydride has been studied. The reactions yield respectively pyrrolidines and piperidines as mixtures of cis- and fraws-isomers no cyclic products were obtained when 2-chloroaniline of 2,6-dimethylaniline were employed (equation 57)168. 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

Aminolysis of 0-aryloximes shows a third-order term for both pyrrolidine and piperidine bases temperature effects on different routes are reported and explained. Hydrolysis of a-hydroxy-a-phenylbenzeneacetic acid salicylidenehydrazide (33) in aqueous ethanol proceeds via fast protonation, followed by rate-determining attack of water the results are compared with several related molecules. 

In 1971, Coulson at DuPont reported the first example of an OHA reaction catalyzed by soluble Rh and Ir complexes [5]. Secondary amines such as dimethyl-amine, pyrrolidine and piperidine were effectively added to ethylene, while primary amines, ammonia and heavier olefins were essentially unreactive (see Equation 6.3). IrCl3-3H20 proved to be an equally effective catalyst precursor in these reactions. It is probable that, under the conditions employed in this study, the Rh(III) and Ir(III) salts are reduced to monovalent, electron-rich species such as 3 (see Equation 6.6). 

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. 

Fustero has devised an intramolecular version of the iminium ion catalysed conjugate addition of nitrogen in the preparation of a series of simple pyrrolidine and piperidine derivatives [115]. The reactions proceed in chloroform to give the target heterocycles in good yield and excellent levels of stereocontrol (Scheme 32). 

Comparison of the configuration of the stannane with the prodncts of reaction reveals that primary alkyl halides that are not benzyhc or a to a carbonyl react with inversion at the lithium-bearing carbon atom. In the piperidine series, the best data are for the 3-phenylpropyl compound, which was shown to be >99 1 er. In the pyrrolidine series, the er of the analogous compound indicates 21-22% retention and 78-79% inversion of configuration. Activated alkyl halides such as benzyl bromide and teri-butyl bromoacetate afford racemic adducts. In both the pyrrolidine and piperidine series, most carbonyl electrophiles (i.e. carbon dioxide, dimethyl carbonate, methyl chloroformate, pivaloyl chloride, cyclohexanone, acetone and benzaldehyde) react with virtually complete retention of configuration at the lithium-bearing carbon atom. The only exceptions are benzophenone, which affords racemic adduct, and pivaloyl chloride, which shows some inversion. The inversion observed with pivaloyl chloride may be due to partial racemization of the ketone product during work-up. 

IV-acetyl pyrrolidines and -piperidines to the corresponding diones or ketones were similarly effected [405, 406], as were conversions of diacetyl and dibenzyl piperazines to diketo componnds by the same system (Table 5.1) [407]. Methylene groups adjacent to the N atom in tertiary polycyclic amines were oxidised by RuO /aq. NaCIO j/CCl (Fig. 5.5) [408]. A large-scale oxidation of l,4-bis(2-phenylethyl) piperazine to the dione was made by RnO /aq. Na(10 )/Et0Ac [409], and RuO /aq. Na(IO )/CCl converted dialkyl or diaryl A A -dimethyladenosines to the corresponding monoamido derivatives (Fig. 5.4) [410]. 

Because of the expected superior excretion rates of bicyclic perfluorotertiary amines as oxygen carrying emulsions, they studied the ECF of several AT-cyclo-alkyl-pyrrolidines and -piperidines, from which they reported crude yields of... 

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