Pyrrolidines preparation

Nagel, U., Rieger, B., and Bublewitz, A., Enantioselective catalysis. VII. Complexes from [P(R/S),3R,4R,P (R,S)]-3,4-bis(phenylphosphino)pyrrolidine. Preparation of optically pure 1,2-biphosphine ligands with four stereocenters containing additional functional groups, /. Organomet. Chem., 370, 223, 1989. 

Investigation of the inhibitory effects on glycosidases has been carried out for the hydroxylated pyrrolidines [65] and piperidines [73]. Among the pyrrolidines prepared only the l,4-dideoxy-l,4-imino-L-allitol (23) (Scheme 7) and its C-5 isomer showed any remarkable effects. They inhibited lysosomal a-manno-sidase rather than the processing a-mannosidases I and II [65], and their specificity is in accord with the structural requirements of azafuranose analogues of mannose for inhibiting mammalian a-o-mannosidases [80]. 

The diamine (99) was prepared from (S)-proline90b) or (S)-glutamic acid I15) maintaining the asymmetric center. Racemic 2-(anilinomethyl)pyrrolidine, prepared from (RS)-5-oxopyrrolidine-2-carboxylic acid, was effectively resolved into a pair of enantiomers by fractional crystallization of its mandelic acid salt U6). Moreover, the preferential crystallization of its 4-hydrobenzoic acid salt was found to produce both enantiomers in high optical purities by alternate seeding116). 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

Asymmetric rearrangement of cyclohexene oxide Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyl)pyrrolidines prepared from (S)-proline are almost as stereoselective.3... 

Better results have been obtained using the 3-(2-pyrrolidinylidene)indolenine intermediate 13.3A which can be prepared from indole-3-carboxaldehyde and pyrrolidine[16]. 

A variety of mono- and bi-cyclic /3-lactams have also been prepared by oxidative ring contraction of pyrrolidine-2,3-diones (180) (75JOC2356), and by the photolysis of pyrazolidin-3-ones (181) (78T1731, 75JOC3510, 75JOC3502, 75CC725). 

The present preparation illustrates a general and convenient irethod for ring contraction of cyclic ketones. The first step is the usual procedure for the preparation of enamines. The second step involves 1,3-dipolar cycloaddition of diphenyl phosphorazidate to an enamine followed by ring contraction with evolution of nitrogen. Ethyl acetate and tetrahydrofuran can be used as a solvent in place of toluene. Pyrrolidine enamines from various cyclic ketones smoothly undergo the reaction under similar reaction conditions. Diphenyl (cycloalkyl-1-pyrrolidinylmethylene)phosphoramidates with 5,6,7, and 15 members in the ring have been prepared in yields of 68-76%. 

Steroidal A -dienamines are formed with a high degree of selectivity in the presence of 17- or 20-ketones. Preparation of morpholine and pyrrolidine enamines is achieved by azeotropic removal of water with or without a catalyst. Pyrrolidine enamines are also formed efficiently by addition of the base to the hot solution of the ketone in methanol followed by immediate cooling. ... 

Malhotra et al. (5pyrrolidine enamine of 3-methyl-cyclohexanone, prepared under equilibrating conditions, is a 3 7 mixture of A and A isomers (67 and 68) on the basis of NMR spectral data. The preponderance of the A isomer in the mixture was attributed to strain between the equatorial methyl group and the vinylic hydrogen atom... 

The piperidine, pyrrolidine, and morpholine enamines of cyclohexanone substituted in the 3-position by methyl, phenyl, and l-butyl have been prepared (49). The complexity of the NMR spectra in the ethylenic hydrogen region indicated a mixture of isomeric enamines. Estimation of the per cent of each isomer by examination of the NMR spectra was not possible, nor were the isomeric enamines separable by vapor-phase chromatography. 

Partial hydrogenation of pyrrole derivatives and partial dehydrogenation of pyrrolidines afford /I -pyrrolines (80-82). However, because of the complex nature of the reaction, it is of little preparative value. The same is true for isomerization of /) -pyrrolines to /) -pyrrolines (83). A photodehydrogenation of 2,6-dimethylpiperidine (26) has been observed recently, affording 2,6-dimethyl-3,4,5,6-tetrahydropyridine (27) in a good yield (84)-... 

The best procedure for the preparation of zl -pyrroline (31, n = l)and /I -piperideine (31, = 2) consists of dehydrohalogenation of N-chloro-pyrrolidine and N-chloropiperidine, respectively, by means of potassium hydroxide (106). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

This sulfonate, prepared from B0CNHCH2CH2C(CH3)2CH20H and the sulfonyl chloride (Pyr, 100% yield) is cleaved by initial BOC cleavage to release the free amine after pH adjustment to 7-8. Intramolecular displacement occurs to release the sulfonate and a pyrrolidine. ... 

Ammonia treatment removes the TFA group, which then releases the phosphate and pyrrolidine through intramolecular cyclization. The analogous pentyl derivative was also prepared. ... 

In conclusion, the Hofmann-Loffler-Freytag reaction tends to give moderate and sometimes poor yields for the preparation pyrrolidines under the classic conditions. Nonetheless, the utility of this reaction to functionalize molecules via the aminyl radical mechanism plays an unique role in the tool box for the organic chemist, enabling transformations not easily achievable using other means. Furthermore, milder conditions and better yields can be achieved by taking advantages of the newer developments such as the Suarez modification. 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

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