Imines, alkylation reduction

Hydrolysis of enol esters 0-83 Reduction of acyl halides 0-84 Reduction of carboxylic acids, esters, or anhydrides 0-85 Reduction of amides 0-95 Alkylation and hydrolysis of imines, alkylation of aldehydes 0-97 Alkylation and hydrolysis of dithi-anes... 

The strategies presented in Table 8.1 can be generalized in the following manner (1) carbanion addition to aldimine or ketimine derivatives (2) sequential amination-alkylation of aldehydes (carbanion addition to in situ formed aldimine derivatives) (3) transfer hydrogenation or hydrogenation of imines (4) reductive amination of ketones and (5) N-acetylenamide reduction. Because of the difficulty of their synthesis, a-alkyl,-alkyl substituted amines are highlighted whenever possible. 

Cyclic imine 88 was also used in the synthesis of several natural products (Scheme 8). Aza-annulation of 88 with 97 led to the formation of 98, which was then transformed to the key intermediate 99 by alkylation, reduction, and decarboxylation.39 Compound 99 was subsequently converted to ( )-tubulosine (100),40 ( )-dihydroprotoemetine (101),39 and ( )-emetine (102).39... 

Graphite reacts with alkali metals - potassium, cesium and rubidium - to form lamellar compounds with different stoichiometries. The most widely known intercalate is the potassium-graphite which has the stoichiometry of CgK. In this intercalate the space between the graphite layers is occupied by K atoms. CgK functions as a reducing agent in various reactions such as reduction of double bonds in a,fl-unsaturated ketones [19], carboxylic acids and Schiff bases alkylation of nitriles [20], esters and imines [21] reductive cleavage of carbon-sulfur bonds in vinylic and allylic sulfones [22]. The detailed reaction mechanism of CgK is not known, and the special properties which are ascribed to the intercalate come either from the equilibrium between K+/K [23], or topochemical observations (the layer structure) [24]. 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

The reductive alkylation of a primary amine with ketone leads to the formation of a stable imine. In the presence of hydrogen and a hydrogenation catalyst, the imine is reduced to a secondary amine. Similarly, a diamine reacts stepwise to form dialkylated secondary amines. However, several side reactions are possible for these reactions as outlined by Greenfield (12). The general scheme depicting the reaction between primary amine or diamine to yield secondary amine through a Schiff base is shown in Figure 17.1. 

The BS2 catalyst was more selective toward the formation of the dialkylated product than the Pd catalysts tested. The activity of BS2 for DAE-MIBK reaction was slower than that with acetone due to steric effects posed by the larger ketone. Here again, the imine tends to rapidly cychze to form imidazolidines or pyrimidines. Figure 17.2 shows the stepwise formation of various side products observed during the reductive alkylation of DAE with acetone. 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

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 is necessary for the intermediate cation or complex to bear considerable car-bocationic character at the carbon center in order for effective hydride transfer to be possible. By carbocationic character it is meant that there must be a substantial deficiency of electron density at carbon or reduction will not occur. For example, the sesquixanthydryl cation l,26 dioxolenium ion 2,27 boron-complexed imines 3, and O-alkylated amide 4,28 are apparently all too stable to receive hydride from organosilicon hydrides and are reportedly not reduced (although the behavior of 1 is in dispute29). This lack of reactivity by very stable cations toward organosilicon hydrides can enhance selectivity in ionic reductions. 

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