Oxalate ester reduction

Reissert indole synthesis. Condensation of an o-nitrotoluene with oxalic ester, reduction to the amine, and cyclization to the indole. 

Oxalates can be reduced to glyoxylates 533), in analogy to the oxalic acid reduction. Ester reductions have also been used for syntheses of cephalosporins 534 535>. 

During the time frame covered by this chapter, stannanes have been reported to have been involved in radical chemistry not involving the more traditional functionalities. For example, Marzi and coworkers reported that the reduction of cyclic thionocarbonates (e.g. 82) with Bu3SuH under standard radical conditions affords cyclic acetals that can then be further transformed into 1,2-diols (equation 57). This transformation represents a new approach to the protection of these diols. Zehl and Cech described the use of Bu3SnH in the reduction of azide (83) to the corresponding amine (equation 58) , while Hanessian and his associates reported the Ph3SnH-mediated free-radical reduction of the tertiary oxalate (84) (equation 59) . This transformation represents a departure from the more typical reduction of a pyridinethioneoxycarbonyl (PTOC) oxalate ester. ... 

In aprotic conditions, diethyl oxalate is reduced reversibly, and its relatively stable anion radical has been well characterized by epr spectroscopy [81,82]. Not all oxalate esters give reversible reduction the anion radicals of several (e.g., dibenzyl oxalate) undergo rapid fragmentation [72,83]. 

Ban s synthesis of quebrachamine (5) (282-284) (Scheme 44) was readily modified to afford syntheses of several aspidospermidine derivatives. Thus, angular alkylation of the tetracyclic lactam 478, followed by appropriate reduction and cyclization stages, afforded ( )-lV-acetylaspidospermidine (26), whereas acylation at the future C-20 by means of oxalic ester provided a route to ( )-deoxylimapodine (479) and ( )-N-acetylaspidoalbidine (480). ( )-Deoxyaspidodispermine (481) was obtained by C-20 hydroxyla-tion of 478 by means of oxygen and LDA, followed by reduction and cyclization stages (4,282-284). 

Thus, as shown by the example in Scheme 42, sequential treatment of the trime-thylsilyl ethers of a variety of tertiary alcohols with oxalyl chloride and the parent thionohydroxamic acid furnishes mixed oxalate esters which undergo reductive deoxygenation on subsequent reaction with a tertiary thiol in refluxing benzene [46]. The selectivity of this method for tertiary alcohols arises as a consequence of the relativity slow rates of decarboxylation of primary and secondary alkoxycarbonyl radicals. 

The CO insertion into nitrite-substituted alkoxy-palladium bonds to give a Pd(COORONO)2 species followed by reductive elimination of dinitrite-substituted oxalate ester was proposed as a mechanism in this Pd-catalyzed carbonylation of alkane dinitrite (Scheme ll).[ ],[vo]... 

NOTE. Many esters reduce Fehling s solution on warming. This reduction occurs rapidly with the alkyl esters of many aliphatic acids, but scarcely at all with similar esters of aromatic acids (f.g., ethyl oxalate reduces, but ethyl benzoate does not). Note also that this is a property of the ester itself thus both methyl and ethyl oxalate reduce Fehling s solution very rapidly, whereas neither oxalic acid, nor sodium oxalate, nor a mixture of the alcohol and oxalic acid (or sodium oxalate), reduces the solution. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The reduction of o-nitrophenyl acetic acids or esters leads to cyclization to oxindoles. Several routes to o-nitrophenylacetic acid derivatives arc available, including nitroarylation of carbanions with o-nitroaryl halides[2l,22] or trif-late[23] and acylation of o-nitrotoluenes with diethyl oxalate followed by oxidation of the resulting 3-(u-nitrophenyl)pyruvate[24 26]. 

From their structures, it appears that the hydrolytic stability of macrocyclic lactones must necessarily be inferior to macrocyclic polyethers. Ease of synthesis of the cyclic esters is therefore one of the aspects which commend them to interest. It is probably for this reason that such lactones have not been made more often by the interesting approach of Kdgel and Schroder . These workers report the ozonolysis of dibenzo-18-crown-6 in a mixture of methanol and dichloromethane at —20°. Reduction of the ozon-ide at —75° using dimethylsulfide followed by warming and addition of acetone led to formation of 6 in 14% yield. The bis-oxalate had mp 164—165° from acetone, very similar to that of the starting crown. The transformation is illustrated below in Eq. (5.9). 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Several total syntheses of antirhine (11) and 18,19-dihydroantirhine (14) have been developed during the last decade. Wenkert et al. (136) employed a facile route to ( )-18,19-dihydroantirhine, using lactone 196 as a key building block. Base-catalyzed condensation of methyl 4-methylnicotinate (193) with methyl oxalate, followed by hydrolysis, oxidative decarboxylation with alkaline hydrogen peroxide, and final esterification, resulted in methyl 4-(methoxycar-bonylmethyl)nicotinate (194). Condensation of 194 with acetaldehyde and subsequent reduction afforded nicotinic ester derivative 195, which was reduced with lithium aluminum hydride, and the diol product obtained was oxidized with manganese dioxide to yield the desired lactone 196. Alkylation of 196 with tryptophyl bromide (197) resulted in a pyridinium salt whose catalytic reduction... 

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