N-Substituted piperidines

Spiroaziridinium compounds have also been synthesized under photochemical conditions. For example, the photolysis of piperidine 83 in acetonitrile resulted in 3-azoniaspirooctane 85 (Equation 19) <1997JOC6903>. Its presence was detected by H NMR spectroscopy and mass spectrometry. This azoniaspiro species was thought to be transient and went on to form N-substituted piperidines which were qualitatively identified by gas liquid chromatography (GLC). 

Good yields of secondary amines are achieved using both the methods in the reactions of aromatic and aliphatic aldehydes as well as of diaUcyl ketones and cycloalkanones with aliphatic and alicyclic amines (and ammonia). Anilines give low yields, but when 2 equiv is used in the sodium hydrogen telluride method, the yields are improved. In the reaction of ammonia with aldehydes, symmetrical secondary amines are obtained, whereas glu-taraldehyde and amines lead to N-substituted piperidines. 

The Aae criterion was applied to the problem of the piperidine equilibrium (10 11) by examining the H-NMR spectrum of the deutero derivatives 12, 13, and 14 at — 85°C when ring inversion is slow on the NMR time scale.37 The Aae values are recorded in Table I. The preferred conformation for the N-substituted piperidines 13 and 14 was assigned as lone-pair axial because for these compounds Aae values were similar to those in quinolizidine. However, in piperidine (12), where the Aae value is similar to that in cyclohexane, the lone pair was assumed to occupy the equatorial position in the preferred conformation. In support of this contention, protonation of... 

N-Heterocyclization.1 1,5-Pentanediol reacts with primary amines at 150-180° in the presence of a ruthenium catalyst to form N-substituted piperidines. For the reaction with aromatic amines RuC I QHs) is the catalyst of choice. On the other hand, the most effective catalyst for the reaction with aliphatic amines is RuC13 combined with either tributylphosphine or triethylphosphine. 

RuCl2(PPh3)3 catalyzes coupling reactions of primary amines with 1,5-diols to give N-substituted piperidines, morpholines, and piperazines in high yields (Eq. 14.6) [76]. 

According to a method of Miyano and Abe AT-arylenaminones bearing an ortho-amino-substituent can be cyclocondensed to pharmaceutically useful dibenzo-l,4-dia-zepine derivatives . The same enaminones with benzoyl chloride derivatives give first the benzoylated derivative which by intramolecular condensation gave the same ring system (equation 24). An extension of this reaction to heterocyclic enaminones derived from N-substituted piperidine-3,5-diones is also known . 

Preparation of aromatic amines by the reaction of aryl halides with aliphatic and aromatic amines has been regarded as a difficult reaction. Recently a facile synthetic method for aromatic amines by amination of aryl halides has been discovered, and rapid progress has occurred in the Pd-catalyzed reaction of amines with aryl halides [1]. One simple example which shows the usefulness of the new method is cited here. The commercially important arylpiperazines 1 have been synthesized by intramoleular N-alkylation of aniline derivatives with N,N-di-(2-chloroethyl)amine (2), which is highly carcinogenic. Now the amines 3 can be prepared efficiently by coupling aryl iodides, bromides or chlorides with N-substituted piperidines. This example provides a big contribution to synthetic chemistry by the new Pd-catalyzed efficient preparative method for arylamines, which are usefial in medicinal and material chemistry. 

Chang, D., Feiten, H.-J., Witholt, B., and li, Z. (2002) Regio- and stereoselective hydroxylation of N-substituted piperidin-2-ones with Sphingomonas sp. HXN-200. Tetrahedron Asyrmnetry, 13 (19), 2141-2147. 

Reaction takes place on nitrogen when the electrophilic center is an sp carbon, particularly if it is charged. Thus Mannich reaction yields the N-substituted compound (71 and 72) (Scheme 34) (54. 157-159). The same reaction is reported with piperidine, o-toluidine. and methylaniline (158). 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Enantiopure (7 )-3-alkylpiperidines (38, R = Me, Et) were obtained when perhydropyrido[2,l-Z)][l,3]benzoxazin-9-ones (37, R = H, Me) were treated first with an excess of AIH3, then with PCC, followed by a 2.5 N solution of KOH (99TL2421). Treatment of optically active perhydropyr-ido[2,l-Z)][l,3]benzoxazines 39 and 40 with LAH in the presence of AICI3 and DIBALH (if R = COOEt) yielded 3-substituted piperidines 41 (00TA2809). 

Secondary amines such as dibenzylamine or 4-substituted piperidines are readily formylated in yields of up to 94% at room temperature by excess N,N-di-methylformamide (DMFj/MesSiCl 14/imidazole with formation of HCl and HMDSO 7 [32aj. 

Similar to pyrrolo-benzodiazepines, pyrrolo-benzotriazepines 225 (X = NMe) with a spiro piperidine moiety have been reported (Scheme 47, Section 3.1.1.3 (1992JHC241)). Their synthesis included direct reaction of hydrazine 224 (X = NMe) with N-substituted 4-piperidones to afford 225 in 42-63% yields. 

N-Alkyl-substituted piperidines react autocatalytically at room temperature (in 82-84% yields). However, in the case of acceptor substituents (COMe, C02pt) a basic catalyst is required (triethylamine, yields 64-79%). In addition to EtsN, an electrogenerated base from n-Bu4NBr in CH3CN was applied, enlarging yields by 12-15%. Charge consumption was 0.03-0.05 Faradays/mol, consistent with the catalytic mechanism. The other advantage of the three-component... 

Stereoselective synthesis of trans 4-chloro-2-substituted piperidines can be achieved by the reaction of epoxides and N-protected homoallyllic amines using BiCl3 as the Lewis acid catalyst (Fig. 3). This method furnishes very good generality with respect to various epoxides with a regioselectivity that favors the trans-... 

These conclusions are reinforced by measurement of natural abundance 15N chemical shifts in piperidines and decahydroquinolines (77JA8406,78JA3882,78JA3889). Lack of correlation between 13C shifts of cyclohexanes and 1SN shifts of piperidines bearing the same methyl substituents are attributed to, among other factors, solvent effects and the difference between H-lone pair and H-H interactions. Protonation served to cancel these stereoelec-tronic effects. Correspondence between 1SN shifts in N- and C- methyl substituted piperidines and decahydroquinoline hydrochlorides and the analogous 13C values were, however, generally much closer than for saturated aliphatic amines. 

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