1.4- Diketones reductive amination

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

Catalytic hydrogenation of the unstable pyrroles (281a-c), which are prepared by heating the 1,4-diketones (280a-c) with an excess of ammonium carbonate at 120°C, gives 2,5-dialkylpyrrolidines (lOa-c) (cis trans = 85 15, 85% conversion) (Scheme 25) 133). Reductive amination of 1,4-diketones (282b,f,h,i) with ammonium acetate and sodium cyanoborohydride produces 2,5-dialkylpyr-rolidines (10b,f,h,i) identical to natural products in 50-90% yields. Each pyrrolidine is an approximately 1 1 mixture of cis and trans isomers (Scheme 26) 25,138). 

Dialkylpyrrolidines. These compounds can be prepared by reductive amination of 1,4-diketones with sodium cyanoborohydride and ammonium acetate (4, 448-449). 1-Pyrrolines are usually formed also, but they can be reduced to pyrrolidines by NaBH4 in a second step.1... 

The principal component of the secretion of the poison gland of the European thief ant (Solenopsis fugax) is rrarcs-2-n-butyl-5-n-heptylpyrrolidine, identified by mass spectrometry and synthesis.5 The reductive amination of 1,4-diketones with sodium cyanoborohydride and ammonium acetate has yielded various 2,5-dialkyl-pyrrolidines that occur in the poison glands of ants of Monomorium spp.6... 

Rather surprisingly this strategy works.5 It was better to use the diketone 36 (rather than 33), made by acylation of the morpholine enamine 35 of 34 and reductive amination of with 3-aminopropanol to give 37 that is dehydrated in acid to the amine 38. A Mitsunobu-like treatment with Ph3P-Br2 converts the OH to Br whereupon cyclisation of 32 X = Br gives 31. 

Accordingly, 14 was converted under standard dihydroxylation conditions to hemiketal 45 in 80% yield. Selective benzylation of 45 provided benzyl ether 46, which was transformed to the diketone 47, over two steps ketone reduction, and subsequent reoxidation of the resultant diol. Treatment of 47 under our standard reductive amination conditions (1.2 equivalents NH4HCO2, NaCNBH3, dry MeOH, 4A MS, 2h) provided the aza-p-C-galactoside 12 in 72% yield. The structure of 12 was confirmed by HCOSY, 13CNMR and MS analysis. No diastereomeric products were observed within the limits of NMR detection (Scheme 7). 

Other reactions dealing with the reduction of -diketonates by amines have been reported by Nemykin and coworkers, such as the reduction of LnPc(dik)2, Ln = Sm, Eu, Gd and Lu, with aliphatic amines with formation of amine radicals identified by EPR, and by Yamamoto and coworkers , stating that pyridine promotes the reduction of NiR(acac)(PPh3), R = Me, Et, to Ni(PPh3)2(C2H4) with formation of methane or ethane, depending on R. 

Reductions of aromatic carbonyl compounds a-substituted carbonyl compounds a-hydroxy ketones p- and y-substituted carbonyl compounds ketones and a- and p-diketones P-keto acids and esters, y-kcto esters masked carbonyl compounds activated double bonds (hydrogenation) acyclic and cyclic ketones reductive amination of keto acids BY BY BY, glycerolDH BY BY, An, Cr, Cu, Gc, Ha, Ks, Mi, Mr, Ns, Pd, Pm, Rn, Y1 BY, Ao, Cb, Cg, Cu, Ct, Gc, Hp, Lk, Mj, Pf, Pm, Pv, Rr, Td, glycerolDH BY BY, An, Gc, Pc HLADH, TBADH, other ADHs, HSDHs AADH, GluDH, PheDH... 

In view of the tiresome zinc reduction of fully aromatized isoquinolines like 80, attempts were made to avoid these stable intermediates by biomimetically incorporating the nitrogen in the sense of a reductive amination with pyridox-amine (88) (cp. Scheme 4, Section IV,A,4). In vitro reaction of the diketone 75 with the amine form 88 of vitamin Bg, however, did not even give traces of the desired product pair 87/89, but an A/-pyridoxylisoquinolinium salt 90, instead, which as seen before (see Scheme 19) for the/V-benzyl compound 86, would not have been accessible by N-alkylation on the preformed isoquinoline 80. Reduction of 90 to 91—now possible with NaBH4 owing to the positive charge—... 

The P-homonojirimycin derivative 63, has been made by reductive amination of the corresponding 2,6-diketone. Compound 63, after deprotection, was converted into the homoaza methylcellobioside 64. ... 

In some cases the intermediate imine is so labile that unwanted by-products are formed before reduction can occur. There are at least two important variations of the reductive amination process that can improve the yield of amine one involves conversion of the aldehyde or ketone to an oxime and the other involves their conversion to a hydrazone. When keto-acid 1.96 was treated with hydrazine, oxime 1.97 was forraed.54 In this approach, a second step was required to convert the oxime to an amine. Catalytic hydrogenation is the most common procedure that is used, as in the reduction of 1.98 to 7-aminooctanoic acid, 1.99. In this particular example, the starting material for this sequence was diketone 1.96, which was cleaved with aqueous hydroxide to give 7-oxooctanoic acid, i.9754 (see chapter two, section 2.1). 

As detailed in Sections 42.2 and 42.3, both covalent and non-covalent organocatalytic activation modes have provided efficient strategies to design asymmetric MCRs. A quite recent study by Zhou and list has demonstrated the feasibility of combining asymmetric Bronsted acid catalysis with aminocatalysis to design even more sophisticated reaction sequences toward the synthesis of useful complex molecules. Specifically, they developed a highly enantioselective approach to pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones 223 via an aldolization/dehydration/conjugate reduction/reductive amination domino... 

Cascade reactions triggered by the combination of chiral amines and achiral Brpnsted acid were well documented on the basis of enamine and iminium ion formation, while examples with the combination of a chiral amine catalyst and a chiral Brpnsted acid were rare, hi 2(X)7, Zhou and List reported an elegant cascade intramolecular aldol-reduction process to prepare chiral 3-substituted cyclohexyl-amines by combining achiral enamine catalysis and chiral phosphoric acid catalysis [38]. Unusually, achiral aryl primary amine was exploited as an amino catalyst to generate a transient enamine intermediate to facilitate an intramolecular aldolization-dehydration process, while chiral phosphoric acid was harnessed to accelerate the following conjugate reduction-reductive amination cascade. Starting from readily available 2,6-diketones and aryl amines, pharmaceutically relevant 3-substituted cyclohexyamine derivatives were readily produced in satisfactory yield and excellent enantioselectivity (Scheme 9.42). 

Diketimines can be prepared by condensation of 1,2-diketones with 2 equiv of an amine, or 1 equiv of a 1,2-diamine, by azeotropic removal of water. Either a chiral diketone or a chiral amine/diamine can be used in order to obtain a chiral diimine. In both cases, the use of 1,2-diamines is expected to provide better stereocontrol, because of the rigidity of the derived cyclic diimines. For example, the reaction of camphor 1,2-diketone 275 and racemic 1,2-diphenylethylenediamine (d,l)-26 gave the diimine 276 as a mixture of two diastereomers (Scheme 45) [138]. Reduction of 276 with sodium borohydride followed by hydrogenolysis of the N substituents afforded the camphordiamine, which was isolated as the dihydrochloride... 

Recently ECL reactions of Ru(bpy)32+ with other reducing agents have been documented, such as various P-diketone and some methylene compounds that have cyano and carbonyl groups [40], Hence with further research, analytical applications should arise for many classes of compounds other than amines that can act as reductants, or electrochemical precursors of reductants, capable of reacting with Ru(bpy)33+ to produce ECL. 

Aqueous solutions of vanadous chloride (vanadium dichloride) are prepared by reduction of vanadium pentoxide with amalgamated zinc in hydrochloric acid [213], Reductions are carried out in solution in tetrahydrofuran at room temperature or under reflux. Vanadiiun dichloride reduces a-halo ketones to ketones [214], a-diketones to acyloins [215], quinones to hydroquinones [215], sulfoxides to sulfides [216] and azides to amines [217] (Procedure 40, p. 215). 

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