Pyrrolidines enamine formation

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

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). 

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

Alternatively, cyclohexanone may initially be transformed into an enamine with a secondary amine, here pyrrolidine. This intermediate enamine can act as a nucleophile and can be alkylated at the P-position using methyl iodide. Finally, 2-methylcyclohexanone may be generated by hydrolysis of the iminium system, effectively a reversal of enamine formation. This gives us two routes to 2-methylcyclohexanone, a short process using the very strong base LDA and... 

In addition, acid cocatalysts can assist the formation of the enamine. With very basic, nucleophilic amines, such as pyrrolidine and its derivatives, acid catalysis is not necessarily required for enamine formation. However, with less basic amines, Brpnsted or Lewis acids are often used to assist in enamine formation (Scheme 7). 

For the general condensation reaction of secondary amines with ketones to yield enamines, pyrrolidine, piperidine, or morpholine is generally used. The rate of enamine formation depends on the basicity of the secondary amine and the steric environment of the carbonyl group [12a, b, 29], Pyrrolidine, which is more basic, usually reacts faster than morpholine. The investigation of piperazine, a disecondary amine, has only been reported recently by Benzing [45, 46] and Sandler [41]. Surprisingly, the reaction of excess -butyraldehyde with piperazine in tetrahydrofuran at — 20°C to 0°C gave mainly AM-butenyl-piperazine [41] (see Eq. 13). 

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). 

The enamine appears to be the only product in the reaction of phenyl azide with 1,2-dibenzoylethylene when it is conducted in methanol at room temperature.306 However, when heated under reflux, a mixture of enamine and pyrrolidine along with minor amounts of aziridine is obtained (Scheme 185).306 Hydrogen-bonding interactions are proposed as playing an important role in enamine formation.306,483... 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Repeating the enamine formation conditions of Holladay and coworkers38 using 4-keto-L-proline derivative 47 and pyrrolidine (1.2 equiv) in the presence of activated 5-A molecular sieves at room temperature gave essentially quantitative conversion to required enamine 51 after a reaction time of 16 h (Scheme 18). Analytical data were consistent... 

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). 

Formation of an enamine radical cation 45 was proposed as the chain initiation step in the autooxidation of enamines and SchifFs bases of a,/ -unsaturated ketones to give unsaturated 1,4-diones37. Pyrrolidine enamine of 10-methyl-A1(9)-octal-2-one (44) reacts with oxygen at room temperature to produce, after acid hydrolysis, 10-methyl-A1 (9)-octalin-2,8-dione (47) in 20% yield. Addition of a catalytic amount of FeCl3, Cu(OAc)2 or CuCl2 causes a pronounced enhancement in the oxidation rate and increases the yield to 80-85% after 1 h. 

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... 

Heyl and Herr developed an efficient method for the conversion of A -androstene-3,17-dione into testosterone involving in the first step selective enamine formation at C3. The diketone was refluxed with 4 equivalents of pyrrolidine and a trace of p-toluenesulfonic acid under a water separator, and the reaction was stopped when 1 mole of water had been collected. With the C3 carbonyl function protected," the keto group at C17 could be reduced smoothly. Hydrolysis of the enamine group with a weakly acidic buffer afforded testosterone. 

This method has been extended by Stork and his group to many ketones and a large number of applications may be found in the literature " . According to the procedure outlined by Stork, a ketone (1 equivalent), an amine (1.5-2 equivalents) and a catalytic amount of p-toluenesulphonic acid were refluxed in toluene under a Dean-Stark water trap. About 400 ml of solvent and 2 g of the catalysing acid were used per mole of ketone. The construction of a simple and inexpensive water separator for the preparation of the pyrrolidine enamine of cyclohexanone in the student organic laboratory was described. The azeotropic procedure has also been employed using one equivalent of amine with and without solvent to give the enamine directly. Various techniques in addition to azeotropic removal of water have been used to drive the enamine formation to completion, as well as to accelerate the rate of its formation. 

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