Reductions amino esters

Reduction of oximino esters, i.e. oximes of keto esters, is very useful for the preparation of amino esters. Reductions are very selective since the oximes are easily reduced by catalytic hydrogenation over 10% palladium on carbon in ethanol (yield 78-82%) I094, by aluminum amalgam in ether (yields 52-87%) [750, 70P5], or by zinc dust in acetic acid (yield 77-78%). None of these reagents attacks the ester group. The last mentioned reaction gives an N-acetyl derivative [1096. ... 

The main reaction of this type has been the reductive cyclization of nitropyridine derivatives carrying an o-amino ester or o-aminocarbonyl substituent. These cyclize in situ via the o-diamino derivative to give pyridopyrazines of known constitution, either for establishment of structure of products obtained in the ambiguous Isay synthesis (see Section 2.15.15.6.1), or in the synthesis of aza analogues of biologically active molecules. 

Claisen ester condensation, 6, 279 Thiazolecarboxylic acid chlorides reactions, 6, 279-280 Thiazolecarboxylic acid hydrazides synthesis, 6, 280 Thiazolecarboxylic acids acidity, 6, 279 decarboxylation, 6, 279 reactions, S, 92 6, 274 Thiazole-2-carboxylic acids decarboxylation, S, 92 Thiazole-4-carboxylic acids stability, S, 92 Thiazole-5-carboxylic acids decarboxylation, S, 92 Thiazole-4,5-dicarboxylic acid, 2-amino-diethyl ester reduction, 6, 279 Thiazole-4,5-dicarboxylic acids diethyl ester saponification, 6, 279 Thiazolediones diazo coupling, 5, 59 Thiazoles, 6, 235-331 ab initio calculations, 6, 236 acidity, S, 49 acylation, 6, 256 alkylation, S, 58, 73 6, 253, 256 analytical uses, 6, 328 antifogging agents... 

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

Hydrogen gas can be replaced by ammonium formate for the reduction of nitro compounds to amines. The ammonium formate method is efficient, and the rapid workup procedure by simple filtratkin makes it widely used for converting the NO to the NH. ° For example, ct-nitro esters are reduced to ct-amino esters in excellent yields on treatment v/ith HCO NH and PdAZ in methanol. ... 

N,N-Dibenzyl (z -amino a-chloroketimines 202 can be prepared from the corresponding ketones, which in turn are available by the addition of chloromethyllithium to esters of natural cz-amino acids. Reduction of 202 with sodium cyanoborohydride directly afforded a-aminoalkyl-substituted aziridines 203 with high syn diastereoselectivity, which was only moderately affected by the size of the substituent [96] (Scheme 30). A complemen-... 

Isayama described the coupling reaction of N-methylimine 157 and ethyl crotonate catalyzed by Co(acac)2 and mediated by PhSiH3 to produce Mannich product 158 in 82% with syn-selectivity (Scheme 41) [71]. The (i-laclam 159 was readily synthesized by heating 158. In 2002, Matsuda et al. reported cationic Rh complex [Rh(COD) P(OPh)3 2]OTf (1 mol%) as an active catalyst for the reductive Mannich reaction [72]. N-Tosylaldiminc 160 was coupled with methyl acrylate and Et2MeSiH (200 mol%) at 45 °C to give the b-amino ester 161 in 96% with moderate anti-selectivity 68%. 

Santagada and coworkers have disclosed a reductive amination method for the generation of a reduced peptide bond by reaction of a protected amino acid aldehyde with an N-deprotected amino ester using sodium cyanoborohydride as reducing agent [296]. 

Direct conversion of a-bromo esters into amino esters by hydride reduction of the azido ester (without isolation) produces yields in excess of 80% [7]. However, bromomalonates fail to form the azido ester under similar conditions. Instead, oxidative dimerization occurs to yield the ethene-l,l,2,2-tetracarboxylate (see Section 6.1) [10]. 

Reduction of nitro esters to amino esters is easy, since most of the reagents used for the reduction of a nitro group to an amino group do not attack the ester group. Ethyl 2-chloro-4-nitrobenzoate was quantitatively hydrogenated to either ethyl 2-chloro-4-aminobenzoate or 4-aminobenzoate over palladium [7057]. 

Reduction of Hydroxy Esters, Amino Esters, Keto Esters, Oximino Esters and Ester Acids... 

Reduction of amino esters to amino aicohols was accomplished by hydrogenation over Raney nickel at 50° and 150-200 atm with yields up to 98% [44]. 

Table 28 Reduction of hydroxy esters, amino esters, keto esters, oximino esters and add-esters...

In 2007, AntiUa and coworkers disclosed the first asymmetric organocatalytic reduction of acyclic a-imino esters (Scheme 23) [39], Chiral VAPOL phosphate (5)-16 (5 mol%) served as a catalyst for the transfer hydrogenation of the latter (62) employing commercially available dihydropyridine 44a to give both aromatic and aliphatic a-amino esters 63 in very high yields (85-98%) and enantioselectivities (94-99% ee). 

Because 3-substituted 1,2-amino alcohols and even P-alkyl-y-hydroxy-5-amino esters are potentially precursors to pharmacologically interesting materials, further investigations have been carried out to extend the methodology in this direction. Thus, the reduction of the ketone moiety of 56 by applying L-selectride or lithium tri-t-butoxyaluminum hydride opened access to the cis-amino lactones 58 (45-54% yield de = 90-94%) and the trans-amino lactones 58 (67-76% yield de > 98%), respectively (Scheme 1.1.16). Monodebenzylation with cerium ammoni-... 

The enantioselective synthesis of a somewhat more complex renin inhibitor starts with the reduction of the ester group in the chiral amino-ester (19-1) by means of diisobutyl aluminum hydride in the cold. The aldehyde product (19-2) is then reacted with prior isolation with the ylide from phosphonium salt (19-3) and a strong base... 

Aldol products do not have to come from an aldol condensation. In another example of catalysis by a small organic molecule, Jeffrey Bode of UC Santa Barbara reports (J- Am. Chem. Soc. 2004,126, 8126) that the thioazolium salt 7 effects the rearrangement of an epoxy aldehyde such as 6 to the aldol product 8. This is a net oxidation of the aldehyde, and reduction of the epoxide. As epoxy aldehydes such as 6 are readily available by Sharpless asymmetric epoxidation, this should be a general route to enantiomerically-aldol products. The rearrangement also works with an aziridine aldehyde such as 9, to give the ff-amino ester 10. 

Several synthetic methods for the reduction of a-amino esters have also been reported. The reduction of methyl or ethyl esters by diisobutylaluminum hydride (DIBAL-H) at low temperature (—78 °C) has been described as useful for the preparation of a-amino aldehydes. 1118 20 Again, this method suffers from overreduction. Reductive methods involving mild reductive agents have been described. The reduction of phenyl esters 6 21 (readily prepared from the corresponding amino acid 5) with lithium tri-ferf-butoxyaluminum hydride is efficient for the preparation of various Boc-a-amino aldehydes including Na-Boc-7V J-nitroargininal and A7a-Boc-W"-Z-argininal (Scheme 5). 

N-Methylated y-amino-p-hydroxy acids are accessible by the usual synthetic sequences, i.e. aldol condensation or y-amino-P-oxo ester reduction, starting from the corresponding N-methylated a-amino acids, but are obtained with low diastereoselectivity. 61-63 Alternatively, Brown allylboration of the ALBoc-ALMe amino aldehyde 16 (R1 = Bzl, X=Boc, Y = Me) gives the allyhc N-methylated intermediate 27 in 64% yield and 90% de (Scheme 12). 64 Oxidative cleavage of the alkenol is performed using the two-step ozonolysis and sodium chlorite oxidation sequence. 

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