Hydrolysis of enamine

Fig. 2. Observed vs. calculated rates of hydrolysis of enamines at 24.8°. Drawn lines calculated log k values. Observed values o for 4-(2-methylpropenyl)morpholine A for l-(2-methylpropenyl)piperidine for l-(2-methylpropenyl)pyrrolidine. Values are corrected for buffer contributions (23).

The concentrations of the different intermediates are determined by the equilibrium constants. The observation of immonium ions [Eq. (5)] in strongly acidic solutions by ultraviolet and NMR spectroscopy also Indicates that these equilibria really exist (23,26). The equilibria in aqueous solutions are of synthetic interest and explain the convenient method for the preparation of 2-deuterated ketones and aldehydes by hydrolysis of enamines in heavy water (27). 

The differenee in reaction rates of the amino alcohols to isobutyraldehyde and the secondary amine in strong acidic solutions is determined by the reactivity as well as the concentration of the intermediate zwitterions [Fig. 2, Eq. (10)]. Since several of the equilibrium constants of the foregoing reactions are unknown, an estimate of the relative concentrations of these dipolar species is difficult. As far as the reactivity is concerned, the rate of decomposition is expected to be higher, according as the basicity of the secondary amines is lower, since the necessary driving force to expel the amine will increase with increasing basicity of the secondary amine. The kinetics and mechanism of the hydrolysis of enamines demonstrate that not only resonance in the starting material is an important factor [e.g., if... 

Iminium ions (2) would be expected to undergo hydrolysis quite readily, since there is a contributing form with a positive charge on the carbon. Indeed, they react with water at room temperature." Acid-catalyzed hydrolysis of enamines (the last step of the Stork reaction, 12-18) involves conversion to iminium ions " ... 

B. By Hydrolysis Reactions.—Details have appeared of the synthesis of dibenzophosphorin oxides (15) from 5-alkyldibenzophospholes, by reaction with methyl propiolate in the presence of water, and of confirmatory syntheses from phosphinic acid chlorides, as shown below. Evidence for the suggested mechanism of the ring-expansion reaction is presented. The hydrolysis of enamine phosphine oxides is an efficient, although somewhat indirect, method for the preparation of j8-ketoalkylphosphine oxides (16) [see Section 3(iii), for the preparation of enamine oxides]. Reasonable yields (48—66%) of trialkylphosphine oxides (17) have been obtained by the alkaline hydrolysis of the products from the pyrolysis at 220 °C of red phosphorus with alkyl halides, in the presence of iodine. 

Hydrolysis of enamine, kelalization and reduction of nitro group... 

Figure 3. Acid hydrolysis of enamines derived from (+) 2-methyl-...

Enantioselective reactions have also been reported for the hydrolysis of enamines containing a chiral amine moiety via protonation or of prochiral enamines by the use of a chiral acid. Other asymmetric reactions are summarized in an excellent review by Seebach and coworkers179 and by Oare and Heathcock193. 

Perhaps the simplest example of this reaction sequence is the hydrolysis of enamines, shown in equation 2. It is the purpose of this chapter to consider in detail the mechanism(s) of enamine hydrolysis. Comparison between enamines and other nucleophilic alkenes, among them enolates, enols and enol ethers, will also be made. 

The overall bonding changes which occur upon hydrolysis of enamines are shown by equation 2. Experimental studies on the protonation of enamines revealed that enamine salts are formed prior to attachment of a nucleophilic moiety. That is, protonation of enamines occurs before attack by water or any other nucleophile8,9. As is the case for alkylation7 and acylation5fl,c, protonation can occur either on nitrogen or on the / -carbon (equation 3). 

Because imines and enamines are formed by a set of reversible reactions, both can be converted back to carbonyl compounds by hydrolysis with mild acid. The mechanism of these reactions is exactly the reverse of the mechanism written for the formation of imines and enamines. In the hydrolysis of enamines, the carbonyl carbon in the product comes from the hybridized carbon bonded to the N atom in the starting material. 

Alkylation, effectively at a carboxaldehyde group, is the result of the regiocontrolled metallation, alkylation, and subsequent hydrolysis of enamine phosphonates (144) to give (2-oxoalkyl)phosphonic esters as outlined in Scheme 8,... 

The mechanism of hydrolysis of enamines has been studied kinetically over a range of pH. In alkaline solution, rate-determining C-protonation is followed by attack of hydroxide ion on the resulting iminium ion. The carbinolamine intermediate then breaks down as in imine hydrolysis. In the neutral and weakly acidic pH range, water attack on the C-protonated enamine becomes rate limiting. As in imine hydrolysis, decomposition of the tetrahedral intermediate becomes rate limiting in strongly acidic solutions. ... 

When 14 was heated in ethanol under reflux with hydrochloric acid, (Z)-[4-(5-hydroxy-3-methyl-l-phenyl-lH-pyrazol-4-ylmethyhdene)-5-oxo-l-phenyl-4,5-dihydro-lH-pyrazol-3-yl] acetate (17) was obtained in 75% yield, identical with the compound prepared from 14 and 12 in 90% yield. Apparently, partial hydrolysis of enamine 14 took place to furnish in situ pyrazole 12, which reacted as the C-nucleophile with the non-hydrolysed enaminone 14 to afford 17. Compounds 15 were heated with 2 equivalents of DMFDMA in DMF under reflux to give pyrazolo[4,3-c] pyridines 18 in moderate yields. Cyclization proceeds by incorporation of DMFDMA as a Ci synthon between the nucleophilic NH and CH2 groups. In the reaction of 15 (R =4-hydroxyphenyl) with DMFDMA, methylation of the phenolic hydroxy group also took place to give the 5-(4-methoxyphenyl)pyrazolo[4,3-c]pyridine (18 R=4-methoxyphenyl) (Scheme 7). 

SMP serves as a chiral auxiliary and can be obtained on a large scale from the amino acid proline. Hydrolysis of enamine 5 under very mild conditions releases SMP without any loss of chirality. 

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