2-Pyrrolidine carboxylic acid, oxidation

CH3 oxidation to alcohol and carboxylic acid oxidation and subsequent opening of the pyrrolidine ring 3-hydroxylation of the pyridine ring... 

The Kolbe electrolysis has been used by Schafer and coworkers to synthetize substituted furans or pyrrolidines in good yields by a carbon-carbon coupling reaction after co-oxidations of 6-alkenoic acids and various carboxylic acids [4, 5, 20, 21] (Schemes 2 and 15). In Scheme 15, the... 

The carboxylic group of 6-aryl-2-methylthiopyrido[2,3- s1pyrimidine-7-carboxylic acid 563 was amidated with (i )-2-(aminomethyl)-l-( /t-butoxycarbonyl)pyrrolidine 564, followed by sulfide oxidation of the resulting amide 565 and reaction with 4-morpholinoaniline to give the substituted pyridopyrimidine 566 as a kinase inhibitor (Scheme 26) <2005W02005090344>. 

Oxidations with peroxybenzoic acid are carried out in solutions in dichloromethane, chloroform, benzene, ether, or ethyl acetate at or below room temperature and include epoxidation of double bonds [295, 296, 297, 298, 299, 300, 301], oxidation of benzaldehydes to carboxylic acids or phenols [302], the Baeyer-Villiger reaction of ketones [303, 304, 305, 306, 307], and oxidation of sulfides to sulfoxides [308, 309]. Peroxybenzoic acid is also used for the anti hydroxylation of double bonds [310], the oxidation of pyrrolidines to pyrrolidones [377] and of pyrroles to succinimides [377], and the preparation of azoxy compounds from azo compounds [372]. 

The reaction of carboxylic acids with the PhI(OAc)2-iodine system may result in a decarboxylation ieading to the intermediate formation of a carbon-centered radical, which can be further oxidized to a carbocation and trapped by a nucleophile. This process has been utilized in several syntheses [97, 615,616, 617]. In a typical example, the oxidative decarboxylation of uronic acid derivatives 568 in acetonitrile under mild conditions affords acetates 569 in good yields (Scheme 3.225) [615]. A similar oxidative decarboxylation has been be used for the synthesis of 2-substituted pyrrolidines 571 from the cyclic amino acid derivatives 570 [616,617]. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

It has been established independently and simultaneously in two laboratories that ornithine is the precursor of the pyrrolidine ring in nicotine (51, 52). Adult plants of N. rustica L. maintained 14 days in hydroponic solutions containing omithine-2-C are found to contain radioactive nicotine. After oxidation, carbon 2 of the pyrrolidine ring is isolated as nicotinic acid and carbons 3, 4, and 5 are isolated as barium carbonate. Nicotinic acid contains half the radioactivity and barium carbonate the other half. Decarboxylation of the nicotinic acid shows that the radioactivity is exclusively located in the carboxylic group. It is highly probable that the second half of the radioactivity is located on carbon 5, but the separation of this carbon from carbons 3 and 4 has not been effected (51, 52). 

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