Synthesis of pyrrolidines

Hollinshead [32] used polymer-bound enones for the synthesis of highly functionalized pyrrolidines. 3-Hydroxyacetophenone was immobilized on chlorinated Wang resin and transformed into polymer-bound enones upon a Knoevenagel reaction with aldehydes. Pyrrolidines were then formed in the addition of azomethinylides, generated from imines, LiBr and DBU (Fig. 6.24). 

The secondary amino function was modified with acid chlorides and sulphonyl chlorides, and the final products were cleaved from the resin with 50% TFA. Four pyrrolidines were synthesized, with isolated yields between 31 % and 68%. 

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HOFMANN - LOEFFLER FREYTAG Pyrrolidine Synthesis Synthesis of pyrrolidines or piperidines from N-haloamlnes (free radical reaction). 

Diastereoselective synthesis of pyrrolidine derivatives using chiral and non-racemic A-cyanomethyloxazolidines 99CSR383. 

The so-called Hofmann-Loeffler-Freytag reaction" " of TV-chloroamines 9 proceeds by a similar mechanism, and is for example used for the synthesis of pyrrolidines 11 ... 

Nitro compounds have been extensively used for synthesis of pyrrolidines as discussed in Chapter 4 on the Michael addidon and Chapter 8 on cycloaddidon. Tandem [2 + 4 /[2 + 3 ... 

Scheme 1.30. Cationic cyclization/aziridinium ion formation/nucleophilic ring-opening procedure for the synthesis of pyrrolidines.

Scheme 3.17. Synthesis of pyrrolidines and indolizidines as well as of the lycopodium alkaloid 13-desoxyserratine (3-65).

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

Scheme 2-16. Synthesis of pyrrolidine. Reagents and conditions a TCDI (1,1-thiono-carbonyldiimidazole), THF b P(OEt)3, DEAD c H2, Rh/Al203, EtOH d TsOH, aq. MeOH e Bu2SnO, toluene, reflux BnBr, BmN Br f TsCl, Py, 0°C g BnNH2, A h H2, Pd(OH)2/C, EtOH.

Two types of ring contractions have been used in the synthesis of pyrrolidines. The older one, an analogous Favorskii process, is the key step of Honjo s a-allokainic acid synthesis. The general lines of this approach are given in Scheme 29 (173). 

C Pothion, J-A Fehrentz, A Aumelas, A Loffet, J Martinez. Synthesis of pyrrolidine-2,4-diones from urethane N-carboxyanhydridess (UNCAs). Tetrahedron Lett 37, 1027, 1996. 

Punniyamurthy, T. Iqbal, J. Polyaniline Supported Cobalt(II) Salen Catalyzed Synthesis of Pyrrolidine Containing a-Hydroxyamide Core Structures as Inhibitors for HIV Proteases, Tetrahedron Lett. 1997, 38, 4463. 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

The synthesis of pyrrolidines by the free radical transformation of (V-chloroamines, the Hofmann-Loeffler-Freytag reaction, is of preparative significance. The key step is the formation of a radical cation which abstracts hydrogen intramolecularly to form a carbon-based radical (Scheme 21(a)). This species then abstracts chlorine from another TV-chloroamine (60JA1657, 50JA2118). The observed positional selectivity for hydrogen abstraction is a consequence of the preferred adoption of a six-membered transition state. A typical conversion achieved is indicated in Scheme 21(b). 

Most cyclizations to form five-membered rings involve the 5-exo mode of cyclization. An exception has been reported in the intramolecular sulfenoamination of 3-alkenylamines used in the synthesis of pyrrolidine alkaloids (equation 102).215 229 Other examples include the aminomercurations of Af-sub-stituted-l-amino-3-butenes162,23° and the methylsulfenilium ion-initiated cyclization of 0-(2-propenyl)-/V-tosylaniline 231... 

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the y-position react with azome-thine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc (equation 171)612-614. This reaction may also be done using other alkene-containing substrates615,616. 

Ma and co-workers have reported the selective synthesis of pyrrolidine derivatives through a three-component reaction based on a conceptually related strategy (Scheme 8.29) [72], Beginning with the catalytic intermolecular carbopalladation of y-allenic malonate 57 in the presence of a base, they succeeded in intercepting the internal carbonucleophile 58 with an imine such as the N-benzylidene p-toluenesulfonamide 59. The attack of the newly formed heteronucleophile on the 7r-allyl palladium intermediate affords the functionalized pyrrolidine 60 with high... 

Synthesis of pyrrolidin-2-ones by cyclization through the generally disfavored 5-endo-trig mode has been reported [95JCS(P1)1115]. Treatment of the disulfanyl acetal 133 under reductive conditions furnished continine 134, a nicotine metabolite in high yield. Reaction of the corresponding dichloro or monochloro compound gave none or very small amounts of the cyclized compounds. 

A practical method for the synthesis of pyrrolidines and piperidines. Tetrahedron Letters, 30, 6059—6062. 

Other reports also demonstrate the efficiency of this reaction for the synthesis of pyrrolidine prostacyclin analogues [183], ( )-indolizidine 209B [184], pyridinones [185] and pyrrolidine-2-ylidene esters [186], though in one case the structure of the substrate had to be modified to avoid an undesired reaction [187]. 

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