Imines and Enamines

Imines, the nitrogen analogs of ketones and aldehydes, are commonly prepared using primary amines and dehydrating conditions [50] as exem-plihed in Equation 6.30, where the water was removed as a benzene azeotrope [51]. 

If a secondary amine is used with a ketone or aldehyde, elimination cannot occur between the nitrogen and the former carbonyl carbon. Elimination then occurs between the carbonyl carbon and an a carbon to form anenamine [52] (Eq. 6.31) [53]. 

Pyrrolidine, piperidine, and morpholine are commonly used. Enamines and enolate anions from imines are useful in carbon-carbon bond formahon (Sections 3.5 and 8.3). 

Acetals [54] are derivatives of aldehydes and ketones wherein the oxidahon level remains the same but the hybridization of the carbon changes to This renders the former carbonyl carbon unattractive to nucleophiles and the acetal is therefore a temporary protecting group. 

Aldehydes are converted to acetals by treating with excess alcohol and an acid catalyst. The reaction is reversible, and the equilibrium is driven toward the acetal by the excess alcohol or by the removal of the water as it is produced. If a 1,2- or 1,3-diol is used, the cyclic acetal forms readily, even exothermically, but can be difficult to remove. 

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Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the for mation of imines and enamines Carbocation (Section 4 8) Positive ion in which the charge re sides on carbon An example is tert butyl cation (CH3)3C Carbocations are unstable species that though they cannot normally be isolated are believed to be intermediates in certain reactions... 

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the formation of imines and enamines. 

In contrast to the five-membered ring, conformational factors would be expected to influence the equilibrium between the imine and enamine forms in the case of the six-membered-ring piperideine derivatives (154). 

Nucleophilic Addition of Amines Imine and Enamine Formation... 

Imine and enamine formation are slow at both high pH and low pH but reach a maximum rate at a weakly acidic pH around 4 to 5. For example, the profile of pH versus rate shown in Figure 19.9 for the reaction between acetone and hydroxylamine, NH2OH, indicates that the maximum reaction rate is obtained at pH 4.5. 

The spiro compound 206 was prepared in five steps from (S)-l-naphthyl-ethylamine and was composed of a mixture of imine and enamine tautomers. Reduction of the imine function by sodium borohydride occurred on the less hindered si face, leading to the diamine with the R configuration of the newly formed stereo center, then the N-benzyl substituent was removed by hydrogenolysis to give 207 with good overall yield [98] (Scheme 30). 

TiCl4 also effectively promotes formation of imines and enamines from carbonyl compounds (Scheme 31). The combination of imine formation using TiCl4 and reduction leads to reductive alkylation of an amine moiety.113,114... 

It has been shown by Varma et al. [61] that reaction of primary and secondary amines with aldehydes and ketones is substantially accelerated by microwaves under solvent-free conditions in the presence of montmorillonite K10 clay, affording high yields of imines and enamines (Eq. 10). 

MW-expedited dehydration reactions using montmorillonite K 10 clay [70] (Schs. 6.20 and 6.21) or Envirocat reagent, EPZG [71] (Schs. 6.20 and 6.21) have been demonstrated in a facile preparation of imines and enamines via the reactions of primary and secondary amines with aldehydes and ketones, respectively. The generation of polar transition state intermediates in such reactions and their enhanced... 

Early transition-metal complexes have been some of the first well-defined catalyst precursors used in the homogeneous hydrogenation of alkenes. Of the various systems developed, the biscyclopentadienyl Group IV metal complexes are probably the most effective, especially those based on Ti. The most recent development in this field has shown that enantiomerically pure ansa zirconene and titanocene derivatives are highly effective enantioselective hydrogenation catalysts for alkenes, imines, and enamines (up to 99% ee in all cases), whilst in some cases TON of up to 1000 have been achieved. 

Table 34.4 Selected results for the enantioselective hydrogenation of N-alkyl imines and enamines (for structures, see Fig. 34.7) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

Despite the remarkable enantioselectivities observed with the Ti-ebthi catalyst for the imine and enamine hydrogenation, we consider its technical potential rather low. The ligand is difficult to prepare, the activation of the catalyst precursor is tricky, for the moment the catalytic activity is far too low for preparative purposes, and last - but not least - its tolerance for other functional groups is low. 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

Imines and enamines under hydroformylation conditions can also be reduced to give saturated amines. With or without additional reduction, these conversions can be used in synthesis of various types of heterocycles. 

Similar to the formation of AT.A/ -acetals under hydroformylation conditions attack of the carbonyl carbon by primary or secondary amines can lead to imines and enamines, respectively (Scheme 11). 

Scheme 11 Basic principle for imine and enamine formation under hydroformylation conditions...

In the reduction of imines and enamines with hydrogen telluride and sodium hydrogen telluride, hydrolysis leading to primary amines and carbonyl compounds is frequently competitive with the reduction. This undesired side reaction is minimized by the addition of triethylamine, in the case of hydrogen telluride. ... 

For general reviews of imines and enamines see P. Y. Sollenberger and R. B. Martin, in The Chemistry of the Amino Group, S. Patai, ed., John Wiley Sons, 1968, Chapter 7 G. Pitacco and E. Valentin, in The Chemistry of Amino, Nitroso and Nitro Groups and Their Derivatives, Part 1, S. Patai, ed., John Wiley Sons, New York, 1982, Chapter 15 P. W. Hickmott, Tetrahedron 38 3363 (1982) A. G. Cook, edEnamines Synthesis, Structure and Reactions, Marcel Dekker, New York, 1988. 

The reaction of or//io-substituted anilines containing substituent groups, e.g., phenyl, cyano, and nitro, gives rise to simple enamine fumarates these in turn can be cyclized to the corresponding 4-quinolones. " Aromatic diamines such as o-phenylenediamine and 2,3-diaminonaphthalene, however, react with DMAD to give tetra-hydroquinoxaline derivatives (7) [Eq. (2)]. ° It has been suggested that these tetrahydroquinoxalines exist in tautomeric equilibrium between the imine and enamine forms and that the enamine form (7) is more favored in inert organic solvents. On the other hand, an iso-... 

V-Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position to give products of type (229) (82TL1201). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (230), thus examplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. 

Catalytic hydrogenation of nitriles over Raney nickel leads to primary amines with variable amounts of secondary and tertiary amines depending on reaction conditions (Ref. 1). These by-products result from hydrogenation of secondary imines and enamines respectively. 

Varma, R.S. and Dahiya, R., Microwave-assisted facile synthesis of imines and enamines using envirocat EPZG as a catalyst, Synlett, 1997, 1245. 

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