Amides reduction with complex metal hydrides

Reduction with complex metal hydrides. Useful reduction systems are those nvolving NaBHy 68 and LiAlH4/69. Synthesis of chiral a-hydroxy carboxylic acids -on take advantage of forming esters or amides with chiral auxiliaries. Typical examples are i picted by 70, 3 71,and 72. ... 

In less repetitive syntheses, it is possible to use remote functional groups as "control elements", a technique which depends more upon the opportunist tactics developed in the course of a synthesis rather than of a premeditated strategy. Such is the case, for instance, of the synthesis of strychnine (i) by Woodward [2], in which after synthesising the intermediate 2 a hydrogen at C(8) must be introduced onto the P-face (4), i.e., onto the most hindered concave face of the molecule (Scheme 8.1). Usually the reduction with a metal hydride would lead to the a-C(8)-H isomer (i.e., the hydride ion will atack from the less hindered face of the molecule), however in the present case the P-OH group at C(21) acts as a control element and, besides the reduction of the amide at C(20), a hydride ion attacks at C(8) from the P-face by an intramolecular transfer of the complex C(21)-0-Al-H (3). 

Amides seem to behave differently, with complex metal hydride reduction giving an amine, effectively converting the carbonyl group to a methylene (see Section 7.11). 

The reduction of nitriles and amides to the amines is a very important, but not so easy, organic transformation. Several methods for the reduction of nitriles and amides with complex metal hydrides have been reported so far. 

The saturated uronates 201, 202, 206, and 207 were separated, and converted into their crystalline amides. In addition, reduction of the methoxycarbonyl group with a complex metal hydride led to the corresponding deoxyhexopyranosides (203, 204, 208, and 209). The proportion of the C-5 epimers obtained on saturation of the enolacetal double... 

The mechanism of this reaction is complex and may vary with the number of alkyl groups on the amide nitrogen. However, the first step is certainly the same as in the other reductions by metal hydrides the hydride adds to the carbonyl to give an alkoxide that is coordinated to a metal (Fig. 18.43). Now, the metal oxide is lost with formation of an iminium ion. There are several possible ways to describe the formation of the iminium ion, but once it is produced, reduction by the metal hydride to give the amine is sure to be rapid. 

The problem is apparently due to some residual aluminum that is hard to remove. If, however, the reduction is carried out in a iV-methylmorpholine solution, followed by addition of potassium tartrate, a pure product can be isolated. A -Methylmorpholine is a good solvent for reductions of various macromolecules with metal hydrides.In addition, the solvent permits the use of strong NaOH solutions to hydrolyze the addition complexes that form. Other polymers that can be reduced in it are those bearing nitrile, amide, imide, lactam, and oxime pendant groups. Reduction of polymethacrylonitrile, however, yields a product with only 70% of primary amine groups. Complete reductions of pendant carbonyl groups with LiAlH4 in solvents other than A -methyl-morpholine, however, were reported. Thus, a copolymer of methyl vinyl ketone with styrene was fully reduced in tetrahydrofuran. ... 

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

First, solvent molecules, referred to as S in the catalyst precursor, are displaced by the olefinic substrate to form a chelated Rh complex in which the olefinic bond and the amide carbonyl oxygen interact with the Rh(I) center (rate constant k ). Hydrogen then oxidatively adds to the metal, forming the Rh(III) dihydride intermediate (rate constant kj). This is the rate-limiting step under normal conditions. One hydride on the metal is then transferred to the coordinated olefinic bond to form a five-membered chelated alkyl-Rh(III) intermediate (rate constant k3). Finally, reductive elimination of the product from the complex (rate constant k4) completes the catalytic cycle. 

Sodium borohydride (160) was found to serve as a hydrogen donor in the asymmetric reduction of the presence of an a,pi-unsaturated ester or amide 162 catalyzed by a cobalt-Semicorrin 161 complex, which gave the corresponding saturated carbonyl compound 163 with 94-97% ee [93]. The [i-hydrogen in the products was confirmed to come from sodium borohydride, indicating the formation of a metal enolate intermediate via conjugate addition of cobalt-hydride species (Scheme 2.17). 

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