Regioselectivity enamine formation

The excellent regioselectivity was explained by highly regioselective enamine formation by the hydroxyacetone, because of the hydroxy group. This n-donating hydroxyl group stabilizes the hydroxyl enamine by interacting with the n -orbital of the C=C double bond [93]. 

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 deprotonation of an iminium ion (formula A in Figure 7.27) to give an enam-ine is reversible under the usual reaction conditions. Therefore, the most stable enam-ine possible is produced preferentially. Figure 7.28 emphasizes this using the example of an enamine formation from a-methylcyclohexanone (i.e., from an asymmetrical ketone). The enamine with the trisubstituted double bond is produced regioselectively and not the enamine with the tetrasubstituted double bond. Since the stability of olefins usually increases with an increasing degree of alkylation, this result is at first... 

Regioselectivity of formation of enamines Lithium enolates and silyl enol ethers Regioselective Aldol Reactions... 

The diketo-aldehyde 37 has four electrophilic carbon atoms (A-D) and three positions for enolisation (1-3). Cyclisation could occur in twelve different ways. Three can be regioselectively realised by different conditions.6 With morpholine catalysis, the aldehyde forms an enamine which does a Michael addition on the enone (B) to give 39. Enamine formation with PhNHMe also gives the aldehyde enamine, but this time it does an aldol condensation with the simple ketone (D) to give 38. 

Hexachloroacetone acts as a source of positive chlorine on reaction with enamines, furnishing, after acid hydrolysis, good yields of a-chloro-ketones. Thus the regioselectivity of enamine formation dictates the regioselectivity of chlorination.Similarly, cyclic enamines react with N2F2 to give the a-fluorocyclo-alkanone after hydrolysis. ... 

The exquisite regioselectivity possible in enamine formation or a-formylation of cycloalkanones, followed hy a,a-dithianation and ring cleavage, has been exploited in several natural product syntheses (eqs 2-4). ... 

Extension of this work by reacting 5-nitropyrimidine with 0,0-ketene acetals and with other cyclic and non-cyclic enamines showed that also with these electron-rich dienophiles the addition is regioselective and gives rise to the formation of 2-mono- or 2,3-disubstituted 5-nitropyridines (Scheme 30). Thus, reaction of 5-nitropyrimidine with the cyclic N,S-ketene acetals 4,5-dihydro-1 -methyl-2-methylthiopyrrole and 4,5,6,7-tetrahydro-1 -methyl-2-methylthioazepine gives in low yields 2,3-dihydro-1-methyl-5-nitropyr-olo[2,3-h]pyridine and the 5,6,7,8-tetrahydro-9-methyl-3-nitropyrido [2,3-Z)]azepine, respectively (89T2693) (Scheme 30). 

The formation of iminium ions of 20-epipandoline occurred only under Polo-novski-Potier conditions. Thus on treatment of the TV-oxide of 165 with tri-fluoroacetic anhydride followed by an aqueous solution of KCN, the iminium ion 329 was obtained, readily isolated as the corresponding a-amino nitrile 331 (Scheme 17). The reaction was completely regioselective and no traces of the enamine 332 could be obtained. This made the synthesis of spiroketone 333... 

The nudeophile is activated by the formation of a titanium(IV)-imido complex 19. The next step is a [2 + 2] cydoaddition with one of the jt-bonds of the allene, depending on the regioselectivity leading to either 20 or 22. Compound 20 then delivers 21 by twofold stepwise proto-demetallation and the latter enamine tau-tomerizes to the imine 24 (Scheme 15.3). Compound 22, on the other hand, should provide allylamines 23, but as we shall see, there are no examples of that mode of reaction known so far. 

Momiyama and Yamamoto have recently demonstrated that acid cocatalysts can even influence the outcome of enamine-mediated reactions [63]. In their studies of the acid-catalyzed O- and A-nitroso aldol reaction, they found that the nature of the acid catalyst dictates the regioselectivity of the reaction between preformed enamine species A carboxylic acid catalyst promoted the 0-nitroso aldol reaction whereas a hydrogen bonding catalyst catalyzed the formation of an A-adduct, both in high enantioselectivities(Scheme 10). 

Nitroso-Aldol Reaction In the course of the Yamamoto group s studies on the nitroso-aldol (NA) reachon of enamines substantial rate increases were observed upon addihon of stoichiometric amounts of achiral Br0nsted acid. Furthermore, exclusive regioselective formation of the N- versus 0-adducts could be controlled by the choice of MeOH or AcOH, respechvely, as Br0nsted acids (Scheme 5.60) [113]. Subsequently, enantioselechve versions of both N- and 0-nitroso aldol... 

Similarly, (S4N4.SbCl5) reacted with alkyl methyl ketoximes 84 in aromatic solvents (e.g benzene and toluene) to give 3-alkyl-4-methyl-l,2,5-thiadiazoles 85, albeit in low yields (3-37%). A mechanism for the formation of 85 was proposed and the regioselective formation of 85 ascribed to the stability of an enamine intermediate. Suprisingly, this appears to be only the second example of a synthesis of a 3,4-dialkyl-l,2,5-thiadiazole that has been reported in the literature <99H147>. 

The alkylation of asymmetric acyclic ketones takes place regioselectively on the most-substituted carbon, thus affording the syn isomers as major products. a-Hydroxyketones showed anti selective additions similar to that observed in related aldol, and Mannich-type additions (Scheme 2.39). Such selectivity is due to the preferred formation of the Z-enamine intermediate, stabilized by intramolecular hydrogen bonding between the hydroxy group and the tertiary amine of the catalyst [23]. 

Fig. 9.30. Regioselective formation of an enamine from an asymmetrical ketone.

Bach and coworkers investigated the photocycloaddition of 7V-acyl, 7V-alkyl enamines 125 with benzaldehyde [125]. The 3-amido oxetanes 126 were formed with excellent regioselectivity (analogous to reactions with enolethers—vide supra) and good diastereoselectivity (Sch. 41). Enamines, not deactivated by acylation at the nitrogen atom are poor substrates for Paterno-Buchi reactions due to preferred electron transfer reactivity (formation of the corresponding enamine radical cation and subsequent reactions). 

A major breakthrough in the regioselectivity of enamine reactions followed from the observation by Pfau and Ughetto-Monfrin391 that the cyclohexylamine imine of acetone 191 underwent a,a-bis-alkylation to give 196, in addition to products 195 and 197 derived from self-condensation (Scheme 199). There was no evidence for the formation of the a,a -bis-alkylated product 194. Clearly, as we pointed out in 1982, this can be attributed... 

An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

Enaminolysis of pyranylidene complexes affords cyclohexadiene annulation products.26 For example, steroid-like molecules 83 are obtained most straightforwardly by this route if the chromanylidene complex 81 is added to the enamine 82. The annulation is highly regioselective, exemplified by the formation of compound 86 from chromanylidene complex 85 and enamine 84, and also by the straightforward generation of the sterically... 

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