Birch reduction, carboxylic acid derivatives

Therefore, using either direct Birch reduction alkylation or Birch reduction-protonation-enolate formation alkylation, both followed by auxiliary removal, it is possible to prepare either enantiomer of a desired 2,5-cyclohexadiene-l -carboxylic acid derivative in excellent enantiomeric purity from the same starting materials. 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

Expanding upon these results, Schultz et al. analyzed the oxidation of enolates produced via the Birch reduction of carboxylic acid derivatives.15 It was found that when 21 was reduced and treated with (+)-5, 22 was obtained with only marginal yield and modest enantioselectivity. The enantioselectivity increased when 23 was deprotonated and then treated with (+)-5. 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

Nishino et al. found that 2-acylthiophenes are also reduced to the corresponding 2,5-dihydro derivatives (equation 24) and the intermediate anions can be intercepted with alkylating agents (equation 25). The resulting compounds can be easily converted into the corresponding 1,3-dienyl ketones (equation 25). Dmitrienko and coworkers have found that the Birch reduction of thiophene-3-carboxylic acid leads to the 2,3-dihydro derivative. ... 

Birch reduction of benzoic acids in the presence of an alcohol (proton donor) furnishes 1,4-dihydrobenzoic acids. The carboxylate salt (-CO2 M ) formed during reduction of benzoic acid derivatives is sufficiently electron rich that it is not reduced. 

Birch reduction of pyrrole carboxylic esters and tertiary amides gives dihydro-derivatives the presence of an electron-withdrawing gronp on the nitrogen serves both to remove the acidic iV-hydrogen and also to rednce the electron density on the ring. Quenching the immediate reduced species - an enolate - with an alkyl halide produces alkylated dihydropyrroles. ... 

Di- and Tetra-hydrothiophens.—Birch reduction of thiophen-2-carboxylic acid with three equivalents of lithium in liquid ammonia gave 2,5-dihydrothiophen-2-carboxylic acid and several other products. When the Birch reduction was carried out with five equivalents of lithium and with methanol as the proton source, a single product, c/s-5-mercaptopent-3-enoic acid, was obtained. Birch reduction of t-butyl 5-t-butylthiophen-2-carboxylate gave the 2,5-dihydro-derivative upon treatment with zinc dust and trimethylchlorosilane and then quenching with molar sodium hydroxide, this gave a mixture of (123) and (124) in the proportions 1 8. ... 

A final synthetic effort in the yohimbine alkaloid area concerns the studies reported by Loewenthal and his coworkers (Scheme 3.92) (143). The aim was to develop an efficient method to prepare the bicyclic enone 21, which serves as a key intermediate in the Woodward reserpine synthesis strategy (19). The route for preparation of 21 began with Friedel Crafts reaction of 2-methoxynaphthalene (523) with the oxalyl chloride equivalent 524, a process which afforded the acenaphthenoquinone 525. Oxidative-decarboxylation of 525 yielded the naphthalene-carboxylic acid 526 which was transformed by Birch reduction and esterification to the dihydro-derivative 527. Carboxyla-tion then provided geminal diester 528 which was epoxidized. Sequential lactonization and methylation afforded tricyclic lactone 529. Ester cleavage with subsequent decarboxylation gave lactone 530 which was demethylated to provide 531. While no further effort was given to the development of this... 

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