Enamines kinetic control

A further example is the contrathermodynamic isomerization of e.w-3,6,6-trimethylbicy-clo[3.1.1]heptan-2-one to the eWo-isomer. The e.vo-isomer is first converted to the enamine. Kinetically controlled protonation furnishes the e.vo-salt which isomerizes quantitatively to the endo-isomer on standing. Final hydrolysis then gives the endo-ketone 2132. 

Anotheranalogy between the enolate anions derived from a,)3-unsatura ted ketones and the corresponding enamines is encountered in their alkylation reactions (57), which proceed by the kinetically controlled attack at the a-carbon atom. For instance, Stork and Birnbaum (51) found that the alkylation of the morpholine enamine of /J -octalone-2 (117) with methyl iodide gave the C-1 methylated derivative (118). 

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,... 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

Reaction of aryl azide with cis-trans mixtures of enamines yields, under kinetically controlled conditions, only the trans-triazolines, as shown by NMR studies. At higher temperatures or in the presence of acid, however, the trans-triazoline epimerizes to give a cis-trans equilibrium mixture the isomer ratio at equilibrium is dictated by steric repulsions in the triazoline ring, and the size of the substituents does not seem to exert a significant effect.211 The proposed mechanism involves the breaking of the N-l/C-5 bond (Scheme 54), although an N-l/N-2 rupture is equally feasible. 

When enamines are produced by the titanium tetrachloride method of White and Weingarten1,2, the kinetically controlled product is formed. 

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). 

When organometallic enamines 35 and imines 36 prepared from imines50 are treated with an insufficient amount of methanol (75% of the theoretical amount), they give quantitatively enamines 37 as the kinetic-controlled products of the reaction. These enamines are stable in strictly aprotic media and can be distilled from the reaction... 

Reaction of a-ketoenamines with a series of cyclic and acyclic nitroolefins gave aminocyclopentene derivatives with high diastereoselectivity, as products of kinetic control instead of the expected 1,2-oxazine N-oxides (see Section III.D.2)45,46. For example, ketoenamine 62 when reacted with cyclic nitroalkene 61 afforded 65 as a single diastereoisomer46, first through the dipolar intermediate 63 and later through the betaine-type intermediate 64. Hydrolysis of this enamine furnished the cyclopentanone derivative 66, also as a single diastereoisomer (equation 11). 

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 palladium catalyst generally used is Pd(PPhj)4, which can be formed in situ from Pd(OAc)2 and PPhj. The most often used allylic substrates are those having an ester or a carbonate as a leaving group, although -OPO(OR)2, -OPh, -Cl, or -Br will also work. Soft nucleophiles of the malonate-type generally give the best results for carbon-carbon bond formation. The reaction is usually in eversible and thus proceeds under kinetic control. Other soft carbon nucleophiles are anions from nitromethane, enolates, and enamines. 

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... 

Enamines (e.g. 377) have been shown to react with conjugated nitroolefins 378 to give mainly dihydro-l,2-oxazine A -oxide derivatives 379 as products of kinetic control (sometimes a cyclobutane ring is formed in these reactions see Section II.B). The stability of these heterocycles is largely dependent on the parent enamine and the type of substituent used on the nitro olefin as has been extensively studied by Valentin and coworkers " . Usually they open into the corresponding nitroalkylated enamines 380 (equation 82), in particular in a solution of methanol or deuteriated chloro-and often an equilibrium between the two forms is established. Stable 1,2-oxazine A -oxides have been obtained in the reaction of 2-nitro-l,3-dienes with cyclic enamines . 

The stereochemical assignments for the cyclization of 25.1 were based on conversion into synthetic intermediates for the synthesis of (— )-ajmalicine (25.6), (— )-tetrahydroalstonine (25.7), and ( — )-(10K)-hydroxydihydroquinine (25.8). No details of the stereochemical assignment of 25.5 were reported. These results can be rationalized by transition state 25.9, which allows for association of the donor and acceptor portions of the substrate. Attack occurs from the face of the enamine opposite to the phenyl group. As in the intermolecular reactions of similar imines, these reactions are probably under kinetic control. 

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... 

When the pre-existing stereocenter is adjacent to the iminium ion carbon atom, Pictet-Spengler cyclization most commonly occurs from the face opposite the substituent, as in the conversion of (42) to (43) (Scheme 20). A related example is the cyclization of the disubstituted A -tetrahydropyridine (44), which was treated with hydrogen chloride gas in anhydrous methanol to produce three of the four possible diastereomeric products in the indicated abundances (Scheme 21). The relative stereochemistry at C-1 is set by protonation of the enamine, while that at C-12b is determined in the cyclization step. The authors argue that protonation is kinetically controlled and occurs preferentially from the... 

Stereoselective protonation of enamines of the following type yield immonium salts under kinetic control which are subsequently transformed by cleavage of the / -diketones into the keto acids 3133. 

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