Pyrrolidine enamine methylation

In 1954 Stork et al. (i) reported that the alkylation of the pyrrolidine enamine of cyclohexanone (5) with methyl iodide followed by acid hydro-I ysis led to the monoalkylated ketone. It was thus obvious that the enamine (7) derived by the loss of proton from the intermediate methylated iminium cation (6) failed to undergo any further alkylation. 

That the methyl group in the pyrrolidine enamine of 2-methylcyclo-hexanone (7) is in fact axial was demonstrated by Johnson and Whitehead (8). They found that careful hydrolysis of the pyrrolidine enamine of the conformationally more stable system, i.e., 2-methyI-4-t-butylcyclohexanone (13), led to a 1 4 mixture of cis and trans isomers of the ketone (14 and 15), showing that the methyl group in the enamine is largely in the axial orientation. 

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... 

In the five-membered ring compounds, much less is known about the position of the double bond in the enamincs of 3-alkyl ketones. Demole and Stoll 43) carried out the alkylation of the pyrrolidine enamine of methyl 1 -oxo-3-cyclopentylacetate (81) with bromopentyne-2 to give a 4 5 mixture of C-2 and C-5 alkylated products (82 and 83). 

The pyrrolidine enamines of /l -3.]cetosteroids (111), on alkylation with methyl iodide, gave mainly the N-alkylated product (5,55) in nonpolar solvents such as benzene. The reaction in more polar solvents gave the 4-methylated product (5.S). The reaction of (111) with perchloryl fluoride involves attack at the C-4 atom to give, after acid hydrolysis, either 4-fluoro-zJ -3-ketone (119) or 4,4-difluoro-zJ -3-ketone 120), depending on the reaction conditions (59). 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

It is interesting to see that the addition of methyl acrylate to the pyrrolidine enamine derivative of 2-methylcyelohexanone in benzene gave equal amounts of 2-methyl-2-carbomethoxyethyl and 2-methyl-6-earbomethoxy-ethylcyclohexanone even though the less substituted double-bond isomer predominates in the starting enamine (199,200,237). In contrast, the methylation of the same enamine mixture led only to 2,6-dimethyleyclo-... 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

The same reaction sequence may be used to convert cyclo-dodecanone to cyclotetradecanone. Preparation of the pyrrolidine enamine of cyclododecanone requires 2-3 days at reflux, and reaction of the enamine with methyl propiolate is best carried out in refluxing hexane. The enamine-propiolate reaction may also be used to convert cycloheptanone to cyclononanone. In this case the procedure must be modified to provide for partial hydrogenation of the intermediate amino ester without prior hydrolysis.8 The reduced intermediate is saponified as described in the present procedure. 

Simple synthesis of ( )-17-epiyohimbol (73) has been reported by Mori et al. (214). yV-Benzyloctahydroindolo[2,3-a]quinolizinone (126), prepared according to the procedure of Novdk and Szdntay (97) was coverted to the corresponding pyrrolidine enamine, which was treated with methyl vinyl ketone to give N-benzylyohimbenone (379). Reduction of 379 with sodium in liquid ammonia... 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

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). 

Enamines of aldehydes react with alkyl vinyl ketones.212 Substituted cyclohexanones may be obtained after hydrolysis. Application of this reaction to a,j8-unsaturated aldehydes leads to substituted glutardialdehydes.269 The ratio of the products from the addition of methyl vinyl ketone to the pyrrolidine enamine derived from jS-decalone depends on the configuration of the decalone.76... 

In the pyrrolidine enamine of 2-methyl-4-f-butylcyclohexanone the methyl group is largely axial15. The morpholine enamine of 2-methyl-4-f-butylcyclohexanone exists as an isomeric equilibrium mixture of 54% trisubstituted enamines 55 and 56 and 46% tetrasubstituted enamine 57. The distribution between quasiequatorial and quasiaxial trisubstituted isomers is 1 1 (i.e. the mixture contains 27% of each)15. 

The preponderance of the A6 isomer in an equilibrium mixture of the pyrrolidine enamine of 3-methylcyclohexanone can be attributed to A(1,2) strain (2.5-3.3 kJ mol-1) between the quasiequatorial methyl group and the vinylic hydrogen atom in the A1 isomer75-77. Equilibrium between the A1 and A6 isomers of 3-substituted enamines takes place very readily at low temperatures78-80. When conjugation of the enamine with a 3-substituted aromatic ring is made possible, the A1 isomer is the predominant isomer81-89. 

Similarly, the enamine of a 2-substituted cyclohexanone is alkylated by electrophilic alkenes such as acrylonitrile or methyl acrylate at the exposition in methanol or acetonitrile. However, prolonged reaction time (66 h) of the pyrrolidine enamine of 2-methylcyclohexanone with these reagents in dioxane or benzene under reflux gives a 1 1 mixture of 2,2- and 2,6-disubstituted cyclohexanones (38 and 39)82>83 (Scheme 23). 

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. 

The high-pressure (12 kbar) reaction of isobutyraldehyde pyrrolidine enamine with benzylideneaniline or benzylidenemethylamine in f-butyl methyl ether gives azetidines... 

Methyl jasmonate (218) has a //arris-locked, 2,3-disubstituted cyclopentanone structure.297 The synthetic route devised by Sisido and co-workers, outlined in Scheme 34, is direct and requires no isomer separation.298) Reaction of the pyrrolidine enamine of methyl 2-oxycyclopent-l-yl acetate (214) with 3-bromo-2-penta-none in toluene gave 215 after hydrolysis. An intramolecular aldol condensation afforded 216 (note double bond migration) whose epoxidation followed by treat-... 

Blsannelarton see also 6, 409). Tsuji et aV have used this reagent to effect bisannelation. The product of addition of 1 to the pyrrolidine enamine of cyclohexanone gives, after hydrolysis and aldol condensation, 2 in 64% yield. The terminal double bond of 2 is oxidized with PdCU and CuCI in aqueous DMF under O2 (7, 278), and the resulting methyl ketone 3 is cyclized with base to the tricycle 4 in 60% yield from 2. 

Dunham and Lawton have shown that reaction of the pyrrolidine enamine of acetylcyclopentanone (309) with methyl a-(l-bromomethyl)acrylate (310) affords... 

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... 

The monomethylation of the pyrrolidine enamine of -tetralone shown in Scheme 41 provides a highly successful example of the reaction. Attempted alkylation of the ketone with 1 equiv. of methyl iodide in the presence of a strong base gave almost exclusively the recovered ketone and its dimethylated derivative. 

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