Pyrrolidine enamine formation from

Formation of Enamines Investigated in Micro Reactors Organic synthesis 73 [OS 73] Stork enamine formation from cyclohexanone and pyrrolidine... 

Enamines formed in this way may be distilled or used in situ. The ease of formation of the enamine depends on the structure of the secondary amine as well as the structure of the ketone. Thus pyrrolidine reacts faster than morpholine or piperidine, as expected from a rate-controlling transition state with imonium character. Six-membered ring ketones without a substituents form pyrrolidine enamines even at room temperature in methanol (20), and morpholine enamines are generated in cold acetic acid (21), but a-alkylcyclohexanones, cycloheptanone, and linear ketones react less readily. In such examples acid catalysis with p-toluenesulfonic acid or... 

The illumination of enamines as general activa ting derivatives of ketones in alkylation reactions also threw light on their special usefulness for controlling alkylations (3), particularly in the formation of monosubstituted cyclohexanones. Thus 2-methylcyclohexanone could be obtained in 80% yield from the pyrrolidine enamine of cyclohexanone, and further alkylation, which required more drastic conditions, gave only 2,6-dimethylcyclo-hexanone (1,237). 

N-Methyl-2-hydroxypyrroIidine (246) is derived biosynthetically from ornithine (245). It functions as a source of the N- methylpyrrolinium ion (247), which in turn functions as a precursor of alkaloids such as tropine (248). The pyrrolidine enamine of cyclopentanone undergoes an interesting ring closure reaction with DMAD, resulting in the formation of a pyrrolizine (Scheme 92) (78TL1351). 

In the formation of nicotine, a pyrrolidine ring derived from ornithine, most likely as the /V-methyl-A1 -pyrrolinium cation (see Figure 6.2) is attached to the pyridine ring of nicotinic acid, displacing the carboxyl during the sequence (Figure 6.31). A dihydronicotinic acid intermediate is likely to be involved allowing decarboxylation to the enamine 1,2-dihydropyridine. 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

Loss of ethene from 67 leads to the enamine 68 which loses either a propyl radical (m/z 56) or, more easily, a methyl radical probably after pyrrolidine ring formation (cf 19 in Scheme 12) (Scheme 37). 

While it is probably reasonable to draw general trends from this series, it should be kept in mind that most of the data came from different laboratories, as indeed there are four different reports for the simple pyrrolidine enamine that account for the range from 85 to 96%. Some of the factors that contribute to determining the regioisomeric composition of enamines are A -strain, which destabilizes the more substituted isomer, and A - -strain, which destabilizes the less substituted isomer (Scheme 6). The former effect was used by Johnson to effectively convert c/j-2,4-dimethylcyclohexanone to the trans isomer through formation of the less substituted pyrrolidine enamime, where a pseudo-axial orientation of the 2-methyl group reduces the level of A - -strain (equation... 

A variety of secondary amines have been used for enamine alkylation. Nonetheless, the three most commonly used, pyrrolidine, piperidine and morpholine, appear to still represent the best compromise between ease of access to the amine and formation of the enamine and the degree of conversion to mono-alkylated product. Pyrrolidine appears to be the best amine for the specific case where the electrophilic paitner for the enamine is a Michael acceptor, such as an a, 3-unsaturated ester, - and enamines derived from this base are generally more reactive than the piperidine and morpholine analogs. The use of optically active amines for asymmetric induction will be covered in Section 4.1.2.3. 

Ketone-type enamine substrates have also been utilized, as demonstrated through the synthesis of ( )-Na-benzyl-20-desethylaspidospermidine (45, P-H) from 43 (eq. 10).20 Treatment with methyl acrylate (37) resulted in conjugate addition to the acrylate and deallylation, and subsequent reduction with NaBH4 gave 44 as a 70 30 mixture of P a diastereomers. Reduction with L1AIH4 gave 45 (75 25, P a). However, similar stepwise aza-annulation with the enamine derived from pyrrolidine and a protected 4-piperidinone resulted in only 14% product formation.21... 

A study of the conditions required for formation of the various isomers of (166), obtained by chlorination of menthone with chlorine or sulphuryl chloride, has been published. (Bromine gives only the rrans-2,4-dibromide. ) Hydro-boration of the pyrrolidine enamines of isomenthone (167), followed by pyrolysis of the corresponding N-oxide, yields a mixture of trans-carvenol (168) and iso-carvomenthone (169) from one of the enamines, and menth-2-ene from the other (Scheme 12). 

Elimination, of 6-bromocarboxyl1c acids by azide Ion, 62, 39 Enamlne formation, from pyrrolidine and cyclododecanone, 62, 191 ENAMINES, 61, 129... 

Scheme 9.66. A representation of the reversible formation of both the aminal and the enamine derived from the acid-catalyzed reaction between cyclohexanone and azacyclopen-tane (pyrrolidine). Under dehydrating conditions and with only one eqnivalent of azacyclo-pentane (pyrroUdine), only the enamine is isolated.

The formation of pyrrolidine enamines from 2-alkylcycloalkenones is highly regiospecific [14] and alfords the less substituted enamines. Thus, 2-methylcy-clohexanone yields a mixture of 6-methyl-1 -pyrrolidinocyclohexene (90%) and 2-methyl-1-pyrrolidinocyclohexene (10%), which is then converted to 3-meth-ylcyclohexene (Eq. 24.7) [13]. 

With a-substituted pyrrolidine catalysts, there are a few mechanistic issues that deserve to be mentioned. Firstly, the formation of pyrrolidine enamine with the nucleophilic partner could encounter increased steric encumbrance near the amino nitrogen that can result in reduced efficiency. Secondly, alternative mechanisms without the involvement of enamines could also be operating [40]. However, among the limited set of available computational studies on a-substituted pyrrolidines, the enamine pathway has been effective towards rationalizing the stereochemical outcome of the reaction. In most of these, a steric control driven transition state model has been invoked wherein the incoming electrophile is guided towards the enamine double bond from the face opposite to that of the bulky a-substituent. 

The magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

The formation of the same four-membered ring aminosulfone (145) from the enamine (22) and cyclohexanesulfonyl chloride in 72% yield and from N-(cyclohexylidenemethyl)pyrrolidine (146) and 2-propanesulfonyl chloride in 77 % yield proves the constitution of these cyclic sulfones (97). 

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