Imines aminoalcohols

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 proline-catalyzed reaction has been extend to the reaction of propanal, butanal, and pentanal with a number of aromatic aldehydes and proceeds with high syn selectivity.197 The reaction can also be carried out under conditions in which the imine is formed in situ. Under these conditions, the conjugative stabilization of the aryl imines leads to the preference for the aryl imine to act as the electrophile. A good yield of the expected P-aminoalcohol was obtained with propanal serving as both the nucleophilic and the electrophilic component. The product was isolated as a 7-amino alcohol after reduction with NaBH4. 

The latter effect has been demonstrated by Meijer et al., who attached chiral aminoalcohols to the peripheral NH2-groups of polypropylene imine) dendrimers of different generations [100]. In the enantioselective addition of diethyl-zinc to benzaldehyde (mediated by these aminoalcohol appendages) both the yields and the enantioselectivities decreased with increasing size of the dendrimer (Fig. 28). The catalyst obtained from the 5th-generation dendrimer carrying 64 aminoalcohol groups at its periphery showed almost no preference for one enantiomer over the other. This behavior coincides with the absence of measurable optical rotation as mentioned in Sect. 3 above. The loss of activity and selectivity was ascribed to multiple interactions on the surface which were... 

A number of groups have reported the preparation and in situ application of several types of dendrimers with chiral auxiliaries at their periphery in asymmetric catalysis. These chiral dendrimer ligands can be subdivided into three different classes based on the specific position of the chiral auxiliary in the dendrimer structure. The chiral positions may be located at, (1) the periphery, (2) the dendritic core (in the case of a dendron), or (3) throughout the structure. An example of the first class was reported by Meijer et al. [22] who prepared different generations of polypropylene imine) dendrimers which were substituted at the periphery of the dendrimer with chiral aminoalcohols. These surface functionalities act as chiral ligand sites from which chiral alkylzinc aminoalcoholate catalysts can be generated in situ at the dendrimer periphery. These dendrimer systems were tested as catalyst precursors in the catalytic 1,2-addition of diethylzinc to benzaldehyde (see e.g. 13, Scheme 14). 

We saw that reaction of amines with aldehydes or ketones led to imine formation, rather than the simple aminoalcohol addition prodnct (see Section 7.7.1). This was because, in acidic solntion, the protonated aminoalcohol had two possible leaving groups, and water rather than the amine was the better leaving group. Dehydration occurs, leading to the imine. 

Phenone imines 587 were lithiated with lithium and a catalytic amount of naphthalene (8%) in the presence of different carbonyl compounds as electrophiles in THF at temperatures ranging between —78 and room temperature, giving, after hydrolysis with water, the corresponding 1,2-aminoalcohols 588 (Scheme 154). ... 

Imines 223 derived from glyoxal acetals react with various organomagnesium compounds with high diastereoselectivity (equation 152) . The 1,2-aminoalcohols 224 can be converted into the protected enantiopure aminoaldehydes 225. For these reactions toluene was found to be a superior solvent. 

It is reasonable to suppose that the carbonyl compound first forms the imine derivative by way of the aminoalcohol (see Section 16-4C), and this derivative is hydrogenated under the reaction conditions ... 

The starting aldehyde H signal (S = 10.36) was shifted to S = 5.33 as required for a change of sp2 to sp3 hybridization by passing from 4-nitrobenzaldehyde to derivative 140 (equation 27). Similar behaviour was observed for mixtures of aromatic aldehydes and of some primary amines (butylamine, t-butylamine) the presence of the 1,1-aminoalcohol (141) was observed for short times, after the imine (142)215 had been formed (equation 28). 

Many examples are known in which the co-ordination of an imine to a metal centre activates it towards nucleophilic attack by water to yield the aminol (aminoalcohol) or related derivative. In the absence of the metal ion, most aminols either dehydrate to yield imines or collapse to the parent amines and carbonyl compound. 

Figure 4-26. The aminoalcohol (aminol) intermediate in the formation of an imine.

As illustrated in Fig. 6, imines serve as important intermediates for a number of solid-phase syntheses. Additional uses for these versatile intermediates are described in Fig. 9. Resin-bound thioketene acetals have been shown to condense with imines to provide, after reductive cleavage, a route to substituted aminoalcohols 6 [45], Aminophosphinic acids 7 were prepared by allowing bis(trimethylsilyl)phosphonite to react with resin-bound imines [46],... 

Even the very efficient enantioselective catalysts used in organozinc addition reactions to carbonyl compounds failed to catalyze the corresponding addition reactions to nonactivated imines such as A-silyl-, A-phenyl-, or iV-benzyl-imines. However, enantioselective additions of diaUcylzinc compounds to more activated imines, like iV-acyl- or iV-phosphinoyl-imines, in the presence of catalytic or stoichiometric amounts of chiral (see Chiral) aminoalcohols, have been recently reported. For example, in presence of 1 equiv of (A,A-dibutylnorephedrine) (DBNE) diethylzinc reacts with masked A-acyl imines like A-(amidobenzyl)benzotriazoles, to give chiral A-(l-phenylpropyl)amides with up to 76% e.e. (equation 68). 

Radical anions of carbonyl groups and imines also seem to be produced in the presence of titanium (IV) chloride in methanol as solvent. Consecutive oxidation and deprotonation of methanol leads to hydroxymethyl radicals which combine with the carbonyl radical anions to give 1,2-diols and 1,2-aminoalcohols, respectively. The synthesis of the pheromone frontalin has been achieved in a one-pot reaction by hydroxy-methylation of a diketone [127-129]. Likewise triplet sensitizers [130] can be used for direct excitation of the substrate in methanol [131]. Chiral aldimines can be conveniently hydroxymethylated with moderate diastereoselectivity by irradiation of methanolic solutions in the presence of an excess TiCU (Scheme 34) [132]. 

A method to synthesize substituted imidazoles starts from 1,2-aminoalcohols 1081 via a four-step procedure, as demonstrated in Scheme 263. Oxidation of acylated alcohol 1082 leads to a ketone 1083, which is transformed into imine 1084. Activation of the amide bond with dehydrating agent PCls leads to intramolecular cyclization, providing... 

The most effective route to aminoalcohol (493) was established by screening various stereochemically homogeneous N,N-disubstituted-, N-monosubstitut-ed-amino alcohols and iminoalcohols as chiral additives to promote asymmetric addition of alkylzinc to N-diphenylphosphinoyl imine (492). The addition reactions that were performed in the presence of this compound resulted in excellent enantioselectivity (Figure 94a). 

The mechanism of all of the above mentioned reactions is essentially the same. However, some steps in the mechanism are still not fully understood. The following steps are believed to be involved in the Eschweiler-Clarke methylation 1) formation of a Schiff-base (imine) from the starting primary or secondary amine and formaldehyde via an aminoalcohol (aminal) intermediate 2) hydride transfer from the reducing agent (e.g., formic acid, cyanoborohydride, etc.) to the imine to get the corresponding A/-methylated amine along with the loss of CO2 and 3) if the starting amine was primary, then steps 1 and 2 are repeated. 

Noyori was subsequently able to show that triethylamine salts of formic acid (TEAF) could be used to reduce ketones to alcohols and imines to amines with high enantioselectivities [4]. The byproduct of this reaction is carbon dioxide gas and this prevents the possibility of the reverse reaction. Strangely, aminoalcohol ligands are poor in this reaction, whilst unsymmetrical 1,2-diamines have proven very effective. A particularly effective ligand is mono-N-tosyl-l,2-diphenylethylene-diamine. 

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