Tertiary enamines hydrolysis

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

II. Kinetics and Mechanism of the Hydrolysis of Simple Tertiary Enamines 102... 

Cyclic secondary amines lead to N-cyclized tertiary enamines which are of great synthetic use. The rates of hydrolysis and the pKa values for the dissociation of N-protonated enamines decrease in the case of N-cyclic 1-TV-isobutenes in the sequence from pyrrolidino (22b) to piperidino (22c) to the morpholino (22d) derivative73, i.e. the pyrrolidino enamines hydrolyse fastest. However, enamines of 3,3-dimethylazetidine74 analogous to 22e and acyclic tertiary enamines react even faster8. 

The main elements of the mechanism proposed by Stamhuis67 and verified by Sollenberger and Martin13 have stood up very well. For this reason, and because their work covers the largest pH range (thereby revealing the variety of rate-determining steps possible for the reaction), the hydrolysis of the tertiary enamines 1-3 and 5, 12-15 will be discussed first. 

Capon and Wu have shown that the rate of hydrolysis of secondary enamines of cyclohexanone (13 and 14) is decreased only slightly by the 2) methyl group. They have therefore concluded that the methyl substituent has little effect on the ground state or the transition state conformations of secondary enamines . However, in this case there is no developing allylic strain whether the transition state is reactant-like or product-like (see also Section VIII) and pn-conjugation is uninhibited. The pn-conjuga-tion in secondary, -disubstituted acyclic enamines (15) compared to the corresponding tertiary enamines (16) is also demonstrated by the UV and NMR evidence provided by Capon and Wu . 

It remains to discuss the structure-reactivity results obtained by Capon and Wu this will be done in the context of equation 15 rate-controlling C-protonation by H30. One noteworthy result (see Table 10) is that, for the cyclohexenyl series 28, the change from a secondary to a tertiary enamine has very little effect on ky. By contrast, for series 27, the A -methylenamines are hydrolyzed at rates ranging from 20-800 times slower than the secondary analogues, while for series 29 the A-methylenamines are slower than their secondary counterparts by a factor of 15,000 to more than 400,000. For 27, L = CH3 and 29, L = CH3 it is apparently difficult to achieve the desired coplanarity of the amino and alkenyl moieties in the transition state (cf equation 4) which permits the conjugative donor properties of the amino group to be fully exploited. In agreement with this interpretation is the fact that for series 28, where the rates of hydrolysis of secondary and tertiary members are very similar, the p values for hydrolysis are also very similar = —3.45 and —3.26, respectively. For series 27 and more so... 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Furan derivatives are formed when aqueous solutions of amines react with diacetylenic alcohols and glycols. Thus when 155 is heated with aqueous dimethyl-amine, the aminofuran 158 is formed . The initial steps involve amine addition and hydration giving 156 which suffers dealdolization to give the ketone 157. In the case of tertiary glycols such as 159, a similar sequence of steps followed by hydrolysis of the intermediate enamine produces the furanone 160 . ... 

---