Aminoalcohol with aldehyde

Aspects of the scale-up of aminoalcohol-catalyzed organozinc reactions with aldehydes have been investigated using A lV-diethylnorephedrine as a catalyst.153 In addition to examples with aromatic aldehydes, 3-hexanol was prepared in 80% e.e. 

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. 

Nitroalkanols are intermediate compounds that are used extensively in many important syntheses 142). They can be converted by hydrogenation into / -aminoalcohols, which are intermediates for pharmacologically important chemicals such as chloroamphenicol and ephedrine. They are obtained by Henry s reaction by the condensation of nitroalkanes with aldehydes. The classical method for this transformation involves the use of bases such as alkali metal hydroxides, alkoxides, Ba(OH)2, amines, etc. 142-144). However, these catalysts give predominantly dehydrated products—nitroalkenes— which are susceptible to polymerization (Scheme 16). The reaction proceeds by the nucleophilic addition of the carbanion formed by the abstraction of a proton from the nitro compound to the carbon atom of the carbonyl group, finally forming the nitroaldol by abstraction of a proton from the catalyst. 

Chiral aminoalcohols both catalyze reactions of simple dialkylzinc reagents with aldehydes and also induce a high degree of enantioselectivity, even when used in only catalytic amounts. Two examples are given below. Indicate how the aminoalcohols can have a catalytic effect. Suggest transition states for the examples show which would be in accord with the observed enantioselectivity. 

Fig. 17.2. Properties profile of the products in the oxazolidine library formed with all available reagents (blacKj and after filtering the reagents (grefl based on the product properties with GLARE. The multi-objective thresholds are illustrated by the dashed vertical lines. The initial library is formed by 651 x 637 x 143 products and the filtered library by 144 x 143 x 92 products (aminoalcohols x aldehydes x sulfonyl chlorides).

D. Chambers, Extractive derivatization of primary amines and beta-aminoalcohols with aromatic aldehydes to form Schiff base or oxa-zolidine products for analysis by electron capture gas chromatography, Diss. Abstr. Int. b. 44(7) 2148, (1984). 

Allylsilacycles bearing a chiral 1,2-diol, /3-aminoalcohol, or 1,2-diamine ligand have been utilized for enantioselective allylation of aldehydes. 102>102a,i03,i06,l06a menti0ned above, they react with aldehydes spontaneously. Among them, allylsilacycles 16 show the highest enantioselectivity (Equation (24)). 

This method has been extended to the reaction of PhCsCZnBr with aldehydes in the presence of stoichiometric amounts of the lithium alcoholate of 1.14 (R = Me). Divinylzincs (RCH=CH)2Zn react under similar conditions, or also in the presence of other lithium alcoholates [650]. Under precise experimental conditions, PhMgBr adds to aliphatic or aromatic aldehydes in the presence of zinc salts and 1.14 (R = n-Bu). The enantiomeric excesses in these additions are higher than 75%. Diaiylzincs react with aldehydes in the presence of aminoalcohols bearing a ferrocene skeleton 2.47 with a very high enantioselectivity [651, 652], Schiff bases have also been used as catalysts in such reactions [367], as have some titanium complexes (see below) [559,653,654,655],... 

Lewis add complexes formed by the reactions of various aminoalcohols with Et2AlG [778, 824] or by the reaction of Et2Zn with a chiral sulfamide [806] have displayed a low efficiency in the asymmetric condensations of ketene and thioketene silyiacetals derived from acetic acid with aldehydes. Disappointing se-lectivities have also been observed with some binaphtol-titanium complexes [778]. However, Mikami and Matsukawa [1296] recently performed the enantioselective condensation of various aldehydes with acetic acid derivatives in the presence of a chiral binaphtol-titanium complex. Good selectivities were observed when the reaction was performed at 0°C in toluene (Figure 6.95). Quaternary ammonium fluorides derived from cinchona alkaloids have been proposed as catalysts to perform additions of enoxysilanes derived from ketones to PhCHO, but the observed selectivities are modest [1303],... 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56). Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated P-aminoalcohols stereoselectively. Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57). Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58). Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

A collection of results obtained with the most effective catalyst systems is summarized in Figure 6.4. Noteworthy examples include the oxidation of a-aminoalcohols with no loss in enantiopurity and the oxidation of cis-allyhc alcohols without Z E isomerization. Stahl also demonstrated the chemoselective oxidation of primary diols to form lactones [22]. While ABNO provides efficient oxidation of symmetric diols, TEMPO discriminates between subtle steric differences in nonsymmetrical substituted diols. Cu/nitroxyl catalysts have also been applied to a variety of tandem reactions [23], perhaps the most noteworthy of which is the conversion of primary alcohols to nitriles via in situ condensation of ammonia with the aldehyde and subsequent dehydrogenation of the primary imine to the nitrile (Figure 6.5) [24]. 

A different kind of moisture-activated IK urethane adhesive utilizes a moisture-activated curing agent such as oxazolidine (51). Oxazolidines are formed by dehydration and subsequent ring closure of aminoalcohols by aldehydes or ketones. When the presence of water causes that reaction to reverse, hydroxyl and amine groups are formed. These react readily and directly with isocyanates. Monooxazolidines are useful primarily as water scavengers, but bisoxazolidines can participate in the curing reactions of urethane adhesives. 

Recently, Kobayashi and co-workers reported an interesting variant for the synthesis of homoallylic amines, dubbed an ammonia fixation reaction [128]. With this method, allylboronates are reacted with aldehydes in a solution of ethanolic ammonia. Despite the highly basic conditions, optically pure protected a-hydroxy aldehydes such as 89 can be employed without any observed racemization, and this approach was apphed to the synthesis of aminosugar derivatives via aminoalcohol product 90 (Equation 47). Unfortunately, the addition of a chiral camphor-based allylboronate to benzaldehyde led only to a low enantioselectivity (34% ee). Reactions with the ( )- and (2)-pinacol crotylboronates lead to the same diastereoselectivity seen in the corresponding reactions with aldehydes, affording the respective anti and syn products from a reaction mechanism that most likely involves the intermediacy of primary imines. 

In 2003, Barbas and coworkers described a one-pot synthesis of functionalized P-aminoalcohols from aldehydes, acetone, and dibenzyl azodicarboxylate [2], This enzyme-like direct asymmetric assembly process was catalyzed with 20 mol% of L-proline (l-Pto) and provided the optically active products 1. This was the first example of an assembly reaction that used directly both an aldehyde and a ketone as donors in a single vessel. The success of the assembly reaction can be attributed to the higher reactivity of aldehydes over ketones in the L-Pro-catalyzed a-amination. The reaction of propionaldehyde, acetone, and dibenzyl azodicarboxylate in acetonitrile produced the expected aminoalcohol 1 in 85% yield (Scheme 12.1). The two diastereomers were obtained with an anti/syn ratio of 54 46 and with an enantioselectivity of >99% for the anti product. The authors explored the scope of the assembly reaction using various aldehydic donors, and this transformation was applied to the expedient synthesis of a potent renin inhibitor. 

High degrees of enantioselectivity have been observed when alkylzinc reagents react with aldehydes in the presence of chiral aminoalcohols. The enantioselectivity is the result of chelation by the aminoalcohol. The aminoalcohols also serve to activate the organozinc reagent. 

The Henry reaction, or nitroaldo reaction, is one of the classic carbon-chain formation methods utilized in organic synthesis. It involves the condensation of nitroalkanes with aldehydes or ketones in the presence of bases (often catalytic amount) to afford the mixtures of diastereomeric 2-nitroalcohols, which in turn can be converted into other useful synthetic intermediates, such as 2-aminoalcohols, a-hydroxyketones, homologous ketones, and perhaps most importantly, nitroalkenes through various functional transformations. 

The first work about polymer-supported P-aminoalcohol used in the asymmetric nucleophilic addition to aldehydes was reported by Frechet [113]. The best result (95% ee) was obtained by using a polymeric catalyst derived finm AA -dialkylated (-)-3-exo-aminoisobomeol 124b for the asymmetric addition of diethylzanc to o-methoxybenzaldehyde in toluene at 0°C (Scheme 64). This catalyst was prepared through reaction of aminoalcohols with 1-2% crosslinked chloromethylated polystyrene. The ehiral polymeric catalyst of the reaction could be used several times in fmther asymmetric reactions. 

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. 

Diamines, aminothiols, and aminoalcohols are well suited for quantitative solid-state cyclizing condensations with simple aldehydes and ketones. As yet only quantitative gas-solid reactions with acetone and solid-solid reactions with paraformaldehyde (that will monomerize upon the milling) have been profited from. An early remarkable reaction type involving two molecules of... 

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