Reductive amidation

Adipic acid undergoes the usual reactions of carboxyflc acids, including esterification, amidation, reduction, halogenation, salt formation, and dehydration. Because of its biflmctional nature, it also undergoes several industrially significant polymerization reactions. 

Anhydrides are reduced with relative ease. McAlees and McCrindle 20) established the following increasing order of difficulty for various carbonyls acid chlorides > aldehydes, ketones > anhydrides > esters > carboxylic acids > amides. Reduction may proceed by 1,2-addilion of hydrogen or by cleavage of an oxygen-carbonyl bond. If 1,2-addition to the carbonyl occurs, as in the presence of strong protic acids over palladium, 1,1-diesters are formed by acylation 26). 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of 5 2 displacement with C followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

Phenyllactic acid is converted to the (S)-( - )-hydroxyketone via its ester and amide. Reduction of the (- )-epoxychalcone yields the ( + )-rotating a-hydroxyketone. Therefore the configuration of the a-carbon of the epoxy-chalcone must be R. Since epoxychalcones are derived from /rans-chalcones, the configuration of the (3-carbon in the epoxychalcone must be 5, as shown in Figure 12. 

Given the wide utility of biocatalysis in the fine chemical industry, why is there such an in-house reliance on classical methods of enantioseparation In fact, why is biocatalysis not applied more generally as a replacement for atom-inefficient or hazardous reactions that are intensively used in the pharmaceutical industry, such as amidation, reduction and oxidation ... 

Silylformylation and hydroformylation reactions figured prominently in Ojima s approach to isoretronecanol and trachelanthamidine [40]. Thus, silylformylation of alkyne 70 proceeded smoothly to produce aldehyde 71 (Scheme 5.26). Reduction and protodesilylation provided allylic alcohol 72, which was protected to give 73. Hydroformylation in the presence of HC(OEt)3 led to a 2 1 mixture of 74 and 75. Deprotection and amide and amidal reduction then provided the target compounds. 

Kano and co-workers.Once the 2,4-oxazolidinedione moiety has been incorporated, amide reduction then affords an a-hydroxy lactam, the key N-acyliminium ion precursor. Representative examples of 2,4-oxazolidinediones and the products derived from A -acyliminium ion cyclization are shown in Schemes 6.61-6.63, pp. 110-112. 

N.J Turner (work on the biocatalytic J. Xiao (amide reductions without... 

Amide reduction with lithium aluminum hydride, 39, 19 Amine oxide formation, 39, 40 Amine oxide pyrolysis, 39, 41, 42 -Aminoacetanilide, 39, 1 Amino adds, synthesis of, 30, 7 2-Amino-4-anilino-6-(chloro-METHYl) -S-TRIAZINE, 38, 1 -Aminobenzaldehyde, 31, 6 hydrazone, 31, 7 oxime, 31, 7 phenylhydrazone, 31, 7 > -Aminobenzoic add, 36, 95 2-Aminobenzophenone, 32, 8 c-Aminocaproic acid, 32, 13 6-Aminocaproic acid hydrochloride,... 

In benzene, Mowah observed some differences between symmetrical amides RCONR2 and unsymmetrical amide RCON(CII3)R. The influence of the dose on >u(vu was stronger for. V-mcthyl-A -alkyl amides (reduction of factor 4 compared to factor 1.7—1.8 for RCONR() (192), related to the extractant s lower stability. 

Many enzymes are both active and stable in carbon dioxide and have been used to conduct a number of reactions. Several different types of reactions have been examined, including hydrolysis (Lee et al., 1993 Randolph et al., 1985 Zheng and Tsao, 1996), oxidation (Hammond et al., 1985 Randolph et al., 1988), and esterification/transesterification (Kamihira et al., 1987 Nakamura et al., 1986 Rantakyla and Aaltonen, 1994), but there are other types of reactions that would make worthwhile investigations in carbon dioxide. These include preparation of amides, reduction of ketones, preparation of cyanohydrins from aldehydes, aldol reactions, hydroxylation reactions, and Baeyer-Villiger oxidation. 

The alkylation of ammonia, Gabriel synthesis, reduction of nitriles, reduction of amides, reduction of nitrocompounds, and reductive amination of aldehydes and ketones are methods commonly used for preparing amines. 

The nitrile 70 gives a stabilised anion with NaH that reacts with the tosylate with inversion as expected. The rather unusual sulfonamide deprotection with HBr in phenol gave the amine 72 that was coupled to the rest of the molecule as an amide. Reduction of the amide to the amine and, finally, hydrolysis of the nitrile to the amide gave darifenacin 63. 

Esters are preferred over amides reduction to the alcohol is not tolerated... 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

Specifically, the tetrahedral intermediates B and D are formed in amide reductions with LiAlH4 and DIBAL, respectively. Their decomposition in principle could affect the C—O bond (—> —> —> amine) or the C—N bond (—> —> —> alcohol). There are two factors that provide an advantage for the C—O bond cleavage ... 

Reduction with zinc dust in glacial acetic acid yields deoxymycelia-namide, C22H28O3N2, ferric chloride negative, with infra red spectrum reminiscent of unstrained cyclic amides. Reduction with sodium and methanol in liquid ammonia gives an unsaturated hydrocarbon side chain ("mycelene ) characterized as a 2,6-dimethylocta-2,6-diene. Mycelianamide believed to consist of a cyclic bis-acylhydroxylamino nucleus substituted by the hydrocarbon side chain (12, 13). 

In the amide reduction scheme on p. 618, the step framed in green gives an iminium ion. Stopping the reaction here would therefore provide a way of making aldehydes from amides. Because these tetrahedral intermediates are rather more stable than those from ester reduction, this can often be achieved simply by carrying out the amide reduction, and quenching, at 0°C (-70 °C is usually needed to stop esters overreducing to alcohols). 

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