Enamines thermodynamic control

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). 

These results have led to the conclusion (11) that the formation of enammonium salts is kinetically controlled, while the protonation on the 3-carbon atom is subject to thermodynamic control, t Only tertiary enamines will be considered,... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The partial steps of the conjugate addition in aminocatalytic reactions are in dynamic equilibrium, and thus products are formed under thermodynamic control. This fact is translated also in the geometry of the enamine intermediates, leading to the product, which can be either E or Z (Fig. 2.9). The geometry of the enamine depends on the catalyst structure and also on the substrate. Whilst proline-catalyzed reactions form preferentially, with a-alkyl substituted ketones, the. E-isomer, enamines derived from pipecolic acid afford an approximate 1 1 mixture of the E and Z isomers [6], In turn, small- and medium-sized cyclic ketones afford the E isomer. 

Bronsted acid (Scheme 2.42) [26-28]. (For experimental details see Chapter 14.9.4). These catalysts mediate the addition of ketones to nitroalkenes at room temperature in the presence of a weak acid co-catalyst, such as benzoic acid or n-butyric acid or acetic acid. The acid additive allows double alkylation to be avoided, and also increases the reaction kinetic. The Jacobsen catalyst 24 showed better enantio- and diastereoselectivity with higher n-alkyl-ethyl ketones or with branched substrates (66 = 86-99% dr = 6/1 to 15/1), and forms preferentially the anti isomer (Scheme 2.42). The selectivity is the consequence of the preferred Z-enamine formation in the transition state the catalyst also activates the acceptor, and orientates in the space. The regioselectively of the alkylation of non-symmetric ketones is the consequence of this orientation. Whilst with small substrates the regioselectivity of the alkylation follows similar patterns (as described in the preceding section), leading to products of thermodynamic control, this selectivity can also be biased by steric factors. 

The original ketone here is unsymmetrical, so two enamines are possible. However, the formation of solely the less substituted enamine is typical. The outcome may be explained as the result of thermodynamic control enamine formation is reversible so the less hindered enamine predominates. 

The recorded reports of the synthesis of enamines which can exist as geometric isomers are generally characterized by the absence of discussion of the stereochemical constitution of the products. It is likely that, where possible, mixtures of stereoisomers are obtained when employing the general procedures, whose composition is the result of thermodynamic control. 

Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equation 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 2]-cycloadducts, followed by retro-Diels-Alder reaction or rearrangement under thermodynamic control which leads diastereo-selectively to aminocyclopentenes. The reaction is called [3 + 2]-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration325 (equation 243). 

In principle, a solvent may favour protonation at the N site over the C site through solvating effects in fact, —NH3 sites are known to be more readily solvated than —CHJ sites6,45 so that enammonium ions will also be easier to solvate than will iminium cations. Bearing in mind that many enamines are nitrogen bases in the gas phase, it is not very surprising that a number of enamines are initially protonated in solution at the nitrogen, not only by kinetic but also by thermodynamic control. 

Evidence for the two-step nature of the dihydropyran formation follows from the observation that both cis- and fraws-dibenzoylethene gave the same dihydropyran96, under conditions where cis-trans isomerism of the electrophilic alkene did not occur. On heating, the dihydropyrans rearrange into a mixture of the corresponding alkylated enamines (44 and 45) (Scheme 29). This is kinetically rather than thermodynamically controlled, since the equilibrium composition was obtained only after treatment with acid96, and can therefore be regarded as irreversible in an aprotic solvent (benzene) at 80°C. 

The reaction was shown to be triggered by protonation of the ketone and reduction to 139. Cyclisation of the carbon centred radical to the pyridinium ring next produced radical cation 140. Addition of a second electron then gave enamine 141, which underwent reversible protonation to iminium salt 138. Further cathodic reduction completes the sequence (Scheme 38). Interestingly, such cyclisations appear to be reversible as the product mixtures attained better reflect a reaction under thermodynamic control than one under kinetic control <03EJO2919>. 

The reaction of CH )NH2 with 2-methylpropanal can give three possible products two isomeric imines and an enamine. Since the products form reversibly, the reaction is thermodynamically controlled. Use SpartanView to obtain the energies of imine A, iminc B, and the enamine, and predict which is likely to be formed. What factors are responsible for the energy differences between the possible products ... 

However, the maximum level of stereochemical control in these processes with a variety of electrophiles (CH =CHC02Me, CH2—CHCN, BrCH2CH=CH2, BrCH2C02Et) was below 60% optical purity (corresponding to a ratio no better than 4 1). These results appear to be the result of kinetic control in the transition state for carbon-carbon bond formation. On the other hand, reactions with methyl vinyl ketone can be run under either kinetic or thermodynamic control and the level of stereochemical control is higher under the conditions. - Likewise, the enamine from 2-methoxymethylpyrrolidine... 

In contrast to the results of base-catalyzed alkylations of sodium or potassium enolates under thermodynamic control, alkylations of enamines of unsymmetrical ketones occur largely or exclusively at the less-substituted a-position. More-substituted ketone enamines are destabilized relative to the less-substituted isomers by A - -strain involving the substituents on the nitrogen atom and at the 3-carbon atom. Although in most systems some of the more-substituted enamine is present in equilibrium with the less-substituted isomer, the former is less reactive toward C-alkylation because steric effects prevent effective overlap of the lone pair of electrons on nitrogen with the carbon-carbon ir-bond. 

The most obvious methods of activating the y-position would involve enamines19 and silyl enol ethers.20 These are the more stable of the various specific enol equivalents (chapter 10) and thus are more suited to thermodynamic control. Extended enamines 55 are easy to make and are excellent electron-rich dienes for the Diels-Alder reaction but react in the a-position with most alkylating agents. 

With ketone enolates, issues of site selectivity arise. Generation of enolates under conditions of kinetic control results in preferential amination at the less substituted a-carbon (product 49, Eq. 87 388 Eq. 88217) unless one of the a-positions is benzylic (Eq. 89).134 Trialkylsilyl groups may also be used to direct animations (Eq. 90).156 On the other hand, in reactions involving ketone enamine intermediates under thermodynamic control, amination at the more highly substituted a-carbon predominates, but as the bulk at that position increases, reaction times increase and selectivity decreases (products 51 and 52, Eq. 91).228 A potential solution to this problem that apparently has not been explored extensively is to selectively generate silyl enol ethers and treat them with one of the reagents that are known to aminate these derivatives. The lone example of this approach is shown in Eq. 92.173... 

Significant asymmetric induction (18-60% e.e.) is observed in the alkylation of the chiral alkyl complexes [Fe(T7-C5H5)(CO)(L)(CH2Cl)] [(5) L = PPh3 or tri(o-biphenyl)phosphite] by the prochiral nucleophiles sodium r-butyl acetoacetate and pyrrolidine cyclohexanone enamine. The product diastereomer ratio in the former case was shown to be thermodynamically controlled, while kinetic control was assumed in the latter reaction. 

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