Cyclohexanone with pyrrolidine

Propose a mechanism for the acid-catalyzed reaction of cyclohexanone with pyrrolidine. 

Pyrrolidine enamines of cyclic ketones have been prepared from cyclobutanone to cyclononanone. In the reaction of unsymmetrical 2-methyl or 2-phenyl cyclohexanone with pyrrolidine, of the two regio isomers 50a and 50b the less substituted enamine (50a) is formed preferentially . This is in contrast to the behaviour of enol derivatives, where the most stable regio isomer is the more substituted one. The reason for the destabilization of 50b is the steric interference of the 2-substituent with a CH2 group of the pyrrolidine ring in a coplanar cis arrangement at the C=C double bond. 

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. 

Stork and Borowitz (36) have reported that the reaction of the pyrrolidine enamine of cyclohexanone with aromatic sulfonyl chloride led to the tetrasubstituted isomer of the sulfonated enamine (63). 

The enamines derived from cyclic ketones give the normal alkylated products, although there is some evidence that unstable cycloadducts are initially formed (55b). Thus the enamine (28) derived from cyclohexanone and pyrrolidine on reaction with acrylonitrile, acrylate esters, or phenyl vinyl sulfone gave the 2-alkylated cyclohexanones (63) on hydrolysis of the intermediates (31,32,55,56). These additions are sensitive to the polarity of the solvent. Thus (28) in benzene or dioxane gave an 80% yield of the... 

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). The... 

Nitrilimines can be produced by treating halogenated hydrazones with a base such as triethylamine. These nitrilimines undergo 1,3 cycloaddition with enamines to form pyrazoles (181-183). This is shown by the reaction of the pyrrolidine enamine of cyclohexanone with diphenyinitrilimine to... 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

Cyclohexanone, for example, reacts with pyrrolidine in the following way... 

Condensation of the pyrrolidine enamine of cyclohexanone with l,l-dicyano-2,2-dimethylcyclopropane proceeds smoothly in refluxing dry xylene and gives the expected adduct in 76% yield. Recrystallisation of the adduct from 95% ethanol, however, gave a 91% yield of a product which no longer contained the pyrrolidine group but whose spectral data clearly showed the presence of a ketone group and an enaminonitrile function. Hydrolysis of this latter product with phosphoric acid/acetic acid gave 5-(2-oxo-4,4-dimethylcyclopentyl)pentanoic acid in 83% yield. 

Steric interactions of bulky substituents may also prevent the enamine system from assuming a planar arrangement. Unfortunately, no basicity and spectral data for such compounds have been reported. The course of reactions, e.g. of alkylation, of enamines obtained from pyrrolidine and 2-substituted cyclohexanones with a sufficiently bulky substituent could demonstrate decreased participation of the polarized mesomeric form.40... 

Enamines are formed when aldehydes or ketones react with secondary amines. The mechanism is given in Chapter 11. The mechanism below shows how they react with alkylating agents to form new carbon-carbon bonds the enamine here is the one derived from cyclohexanone and pyrrolidine. The product is at first not a carbonyl compound it s an iminium ion or an enamine (depending on whether an appropriate proton can be lost). But a mild acidic hydrolysis converts the iminium ion or enamine into the corresponding alkylated carbonyl compound. 

In these two examples enamines from cyclohexanone formed with pyrrolidine and morpholine add in good yield to an a, 3-unsaturated carbonyl compound with an extra electron-withdrawing methylthio or phenylsulfonyl group. 

Cyclohexanone and related cyclic ketones generally gave poor results with L-proline catalyst. L-Azetidinone carboxyhc acid catalyst (4) showed improved enantioselectivities (88-90% ee. Table 11.2) for the a-amination of cyclohexanone with DEAD or dibenzyl azodicarboxylate (DEAD) [13]. The benzimidazole-pyrrolidine (EIP) catalyst 5 was comparable to L-proUne in terms of enantioselectivity with cyclohexanone and l-silacyclohexa-4-one as substrates [14]. In a comparison between the efficiencies of L-proUne and 4-silyloxyproline 6 in the a-amination of cyclohexanone and derivatives, catalyst 6 provided higher yields and enantioselectivities [15]. 

The Stork variation was pioneered by Stork and co-workers in 1963. It entails the reaction of pyrrolidine or morpholine enamine derived from unsymmetrical cyclohexanones with methyl vinyl ketones. The alkylation is directed to the less substituted carbon opposite to the alkylation regioisomer formed by the standard Robinson annulation conditions. Cyclization to the corresponding octalone then occurs. The morpholine enamine is less reactive than the pyrrolidine and hence pyrrolidine enamine has been mostly used for this approach. An example of such annulation is shown in the s mthesis of 8-methyl-2-oxo-A octalone (19). The pyrrolidine enamine of 2-methylcyclo-hexanone is refluxed in benzene with MVK for 24 h followed by the addition of an acetate buffer and reflux for 4 h, and after the reaction is worked up purification gives 19 in 45% yield. 

The reaction of NO with the double bonds of enamines also produces compounds containing the diazeniumdiolate functional group bound to carbon, and some of the compounds prepared in this way have the potential to serve as spontaneous NO donors [43]. The compounds chosen for study were enamines 1-4 derived from condensation of cyclopentanone or cyclohexanone with morpholine or pyrrolidine. When these enamines were dissolved in acetonitrile and treated with NO gas (5-atm pressure) at room temperature, a vigorous exothermic reaction resulted, accompanied by high uptake of NO and formation of a brown precipitate. Attempts to isolate the solid precipitates often resulted in rapid decomposition, with the release of large volumes of gaseous NO. At -78 °C in diethyl ether, the reaction of 4-(l-cyclohexen-l-yl) morpholine (IX) afforded a good yield of crystalline NO addition product (X) ... 

Treatment of the diketone 78 with pyrrolidine afforded cyclohexanone derivative 79 exclusively. Other bases (piperidine, KOH) also led to the C-4 and C-5 epimer of 79. 

Enamines act as Michael donors in conjugate addition reactions (Section 21.12). Draw the structure of the product formed by reaction of the enamine of cyclohexanone and pyrrolidine with methyl vinyl ketone. 

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