Secondary enamines reactions

By adhering to these conditions, Kaupp and coworkers performed a remarkable one-pot synthesis of highly substituted pyrroles [21]. When primary or secondary enamine esters 10-58 were ground with trans- 1,2-dibenzoylethene 10-59 in a ball-mill, the pyrroles 10-60 were obtained in quantitative yield (Scheme 10.15). In contrast, when in solution the yields were much lower and the reaction also required higher reaction temperatures. 

Heterocyclic secondary enamines and dicarboxylic acid dichlorides undergo complex, ring-size-dependent annulation reactions that, in the case of ester 238 and phthaloyl chloride (Scheme 57), lead to lactone-containing derivative 239 (02T2821). 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

CPCM) solvation, to study the mechanisms and stereochemistries of this important synthetic reaction. Interestingly, from these calculations, it was concluded that secondary enamine-mediated aldols have high activation energies if there is no proton source, and oxetane intermediates such as 1 can be formed (Equation 1) <2001JA11273>. 

Synthesis of lactams by reactions of primary and secondary enamines with electrophilic olefins 90MI6. 

Stable secondary enamines (21) may be prepared66 in aprotic media by partial methanolysis of organo-tin67 (32a), magnesium68 (32b) or lithium (32c)69 salts of imines and can be transferred from the reaction mixture under reduced pressure and trapped at —80 °C. These compounds are characterized by their NMR spectra and show a characteristic C=C double-bond vibration at 1670 to 1675 cm"1 and a N—H vibration around 3360 cm"1 in the IR spectrum66. 

Rearrangement of an enamine to an equilibrium mixture of isomeric enamines will occur under acid catalysis, but will not take place under neutral or basic conditions304. The reaction of non-symmetric ketones 193 with secondary enamines leads to a mixture of both possible enamines 194 and 195 (equation 20) as was shown by -NMR spectroscopy305. 

Normally the less substituted double-bond isomer (la) is the more reactive since reaction at the more substituted position It engenders severe allylic interactions (A1,3-strain5) in the transition state. Further reaction therefore occurs preferentially to give the / ,/ -disubstituted enamine or iminium salt (3) and hence the a,a -disubstituted ketone (5) on hydrolysis. However, there are exceptions to this (see Sections III.B, V and VI.D). A recent development uses the observation6 that such steric interactions do not apply to secondary enamines (Section VIII) since a conformation (2) can be adopted... 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

Acyloxylation reactions have been performed on a secondary enamine of dimedone with a series of diacyl peroxides. The isolated monoadducts could undergo further acyloxylation to yield products of acyl rearrangement50 (Scheme 34). 

The present section is briefly devoted to cyclization reactions to imines (in fact, to their secondary enamine tautomers), and will show some recent examples of the synthetic use of these hidden enamines in annulation reactions. 

Stork enamine reaction (Section 23.11) a multistep sequence whereby a ketone is converted into an enamine by treatment with a secondary amine, and the enamine is then used in Michael reactions. 

The enamine reaction was introduced by Stork and his co-workers " and is widely used in organic synthesis. Enamines are a,(B-unsaturated amines and are obtained by the reaction of an aldehyde or ketone having a-hydrogen with a secondary amine in the presence of a dehydrating agent (such as catalytic amount of p-toluenesulfonic acid). 

A number of reactions of nitrogen-containing nucleophiles with aldehydes and ketones involve addition of the nitrogen to the carbon of the carbonyl group, followed by elimination of water to produce a double bond. Common examples are reactions of primary amines to produce substituted imines, reactions of secondary amines to produce enamines, reactions of hydrazine or substituted hydrazines to produce hydrazones, reactions of semicarbazides to give semicarbazones, and reactions of hydroxylamine to produce oximes. Usually these reactions are run with an acid catalyst. 

Sevin, A., Masure, D., Giessner-Prettre, C., Pfau, M. A theoretical investigation of enantioselectivity Michael reaction of secondary enamines with enones. Helv. Chim. Acta 1990, 73, 552-573. 

Dau, M. E. T. H., Riche, C., Dumas, F., d Angelo, J. The origin of the stereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions a computational investigation. Tetrahedron Asymmetry 1998, 9, 1059-1064. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

The literature up to 1988 has been reviewed . Dienamines are usually prepared from a,j8-unsaturated aldehydes or ketones under conditions analogous to those used for preparation of the simple enamines . Reaction of secondary amines with a,)S-unsaturated ketones in the presence of p-toluenesulphonic acid is slower than that with the corresponding saturated ketones. Pyrrolidine is more reactive than morpholine. In some cases, satisfactory yields may be obtained when the water formed is removed by azeotropic distillation using a solvent such as benzene or toluene, but better results are obtained when the condensate is passed over a molecular sieve. The pyrrolidine dienamines of certain A -3-oxosteroids may be prepared by simply mixing the ketone with a secondary amine in hot methanol. Compounds with 17- or 20-oxo group are unreactive. ... 

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