Imine and Enamine Derivatives

Heterocycle formation through aza-annulation with acrylate esters was accomplished with both imine and enamine derivatives of aldehydes. Treatment of 36 with methyl acrylate (37) resulted in both mono and bisalkylation at the nucleophilic site, and selective bisalkylation to form 38 could be enhanced through the use of two equivalents of 37 (eq. 8).18 Subsequent cyclization of 38 generated the corresponding aza-annulation product 39. Selective monoalkylation was more... 

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). 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

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. 

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-... 

In all of these reactions, a nucleophile adds to a positively polarized carbonyl carbon to form a tetrahedral intermediate. There are three possible fates for the tetrahedral intermediate (1) The intermediate can be protonated, as occurs in Grignard reactions, reductions, and cyanohydrin formation. (2) The intermediate can lose water (or OH), as happens in imine and enamine formation. (3) The intermediate can lose a leaving group, as occurs in most reactions of carboxylic acid derivatives. 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

List and coworkers developed an excellent approach to synthesize p branched amines in optically active forms by combining the enamine and reductive amination processes (Scheme 3.45) [96]. The reductive amination of unsymmetrically a,a disubstituted aldehydes and aniline derivatives proceeded through a tautomerization between imine and enamine forms. Dynamic kinetic resolution occurred under the... 

Using a similar strategy, the research groups of Repo and Rieger reported the catalytic hydrogenation of imines and enamines using a linked amine-borane species derived from 2,2,6,6-tetramethylpiperidine [57]. In this case, the link... 

Ammonia and the amines may be regarded as nitrogen analogs of water and alcohols. Do they add to aldehydes and ketones In fact, they do, giving products corresponding to those just studied. We shall see one important difference, however. The products of addition of amines and their derivatives lose water, furnishing either of two new derivatives of the original carbonyl compounds imines and enamines. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Primary and secondary halides do not perform well, mostly because N-alkylation becomes important, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF ... 

Tautomeric equilibrium between imine 18 and enamine 19 forms of 2(l//)-quinoxalinonyl acetic acid derivatives (Scheme 4) has been recognized already but found to be affected by the substituent R on the side chain. When R is hydrogen and X is alkoxy or arylamino group, both tautomers 18 and 19 exist in DMSO-r4 or CDCI3 <1994ZOR1681,... 

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