Pyrrolidine oxide

Bis(carbalkoxymethyl)pyrroles from N,N-dipropargylamines via 3,4-bis(carbalkoxymethylene)pyrrolidines Oxidative biscarbonylation... 

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. 

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Carbonylation of the tetrasubstituted bispropargyiic amine 23 using PdCP and thiourea under mild conditions affords the carboxylated pyrrolidine derivatives 24a and b in good yields. Thiourea is regarded as effective for the oxidative carbonylation of alkynes, but no oxidative carbonylation was observed in this case[21]. 

A variety of mono- and bi-cyclic /3-lactams have also been prepared by oxidative ring contraction of pyrrolidine-2,3-diones (180) (75JOC2356), and by the photolysis of pyrazolidin-3-ones (181) (78T1731, 75JOC3510, 75JOC3502, 75CC725). 

In 1931 Winterfeld and Kneuer, as a result of their observation that jS-lupinane can be obtained from lupanine, and the formation of 2-methyl-pyrrolidine by the oxidation of sparteine, combined these two features in a partial formula (II) for lupanine, which could be developed in various ways depending on the mode of attachment of the methylpyrrolidine residue. In view, however, of Ing s demonstration of the relationship of anagyrine, CJ5H20ON2, to Z-lupanine, CJ5H24ON2, and d-sparteine, C15H28N2, it was elearly neeessary to consider formul for lupanine derivable from the two alternati-ves, which Ing had proposed for anagyrine and which are shown below as (III) and (IV) with the formul for lupanine derived from them (V) by Ing and (VI) by Clemo and Raper. Sparteine would be represented by (V) or (VI) with the change CO CH2. 

Malhotra and Johnson (70) have further shown that 2-methylcyclo-hexanone on treatment with 1 equivalent of pyrrolidine and 1.5 equivalents of 50% deuterioacetic acid-deuterium oxide in diglyme solution for 1 hr gave a mixture of 6c-deuterated and 6,6 -dideuterated ketones. The formation of these deuterated species was explained by the mechanistic sequence outlined in Scheme 2. 

The cyclic thioketone, 3-oxotctrahydrothiophene (11), gives a mixture of enamines (12,13) when caused to react with a secondary amine such as piperidine or pyrrolidine (31). The enamine mixture can be reduced to the 3-aminotetrahydrothiophene using formic acid or oxidized to the 3-amino-thiophene using diisopentylsulfide. 

The 1,2-, 1,2,5-, 1,3,4-, and 1,2,5-substituted pyrrolidines afford the corresponding pyrrolines very readily by oxidation with mercuric acetate. In the case of 1,2,2-trimethylpyrrolidine (35), the formation of a double bond... 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

The 2,3-benzoxazepin-l(3//)-one 4 (NR2 = pyrrolidin-l-yl), a stable colorless solid, is obtained in low yield in the reaction of benzonitrile oxide with 3-(pyrrolidin-l-yl)-l//-2-benzopyran-l-one (3).5... 

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