Pyrrolizidines substituted, reactions

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

A wide application of Newcomb s method provides a variety of N-heterocyc-lic systems, such as perhydroindoles, pyrrolizidines and aza-brigded bicycles [59, W, 146], The mild reaction conditions are compatible with several funtional groups of the substrate and several trapping agents to functionalize the cyclized product. 2-Substituted pyrrolizidines 132 are accessible by tandem cyclization of iV-allyl-substituted PTOC carbamate 131. In this case the allyl group on the nitrogen serves as an internal trap for the intermediate carbon radical. The Af-methylcyclohept-4-enaminium radical cation, produced from the corres-... 

Plumet et al. described domino metathesis of propargyl (2-endo-7-oxanorborn-5-enyl) ethers 62a-62c with allyl acetate in the presence of Grubbs ruthenium catalyst Ic (Scheme 22). The reaction proceeds stereoselectively to produce substituted m-fused bicyclic ethers 63a-63c. In a similar manner, indolizidinone derivative 64 is obtained from compound 62d instead of pyrrolizidine derivative 63d. ... 

In an interesting fragmentation reaction, the hexahydroazocine (23) is formed by solvolysis of (22) in the presence of NaBHt in 94% yield (75TL2613). A related compound (24) can be prepared from 4-cycloheptenone oxime tosylate via the unsaturated lactam (25) (79JOC287). Whereas (25) adds bromine to the double bond, (24) undergoes a transannular reaction to give a 1-substituted pyrrolizidine (26). The latter type of reaction also occurs... 

The synthesis of pyrrolizidine developed by LukeS and Sorm31 and by Micheel and Flitsch32 starts with furylacrylic acid (56) which is converted by the Markwald reaction into y-ketopimelic acid (57). The carbonyl group in 57 is replaced by an amino group via the oxime or by the Leuckart-Wallach reaction this substitution results immediately in the formation of the lactam 58, which can be converted by heat into 3,5-dioxopyrrolizidine (59). The latter compound yields pyrrolizidine... 

B) Reactions of hydroxy-, oxo-, car boxy-, and other substituted pyrrolizidines. 

B. Reactions of Hydroxy,- Oxo-, Carboxy-, and Other Substituted Pyrrolizidines... 

The hydroxy groups of pyrrolizidine amino-alcohols are readily replaced by chlorine atoms upon treatment with thionyl chloride (see, e.g., refs. 101 and 103). In this reaction, the allylic hydroxyl group is more reactive and can be selectively replaced by chlorine.79 In some particular cases, methoxyl groups can also be substituted for halogen e.g., l/3-methoxymethyl-8a-pyrrolizidine, when treated with hydro-bromic acid, gives rise to the corresponding bromo derivative.104... 

Cyclopropanone equivalent. Unlike cyclopropanone, which is difficult to isolate, 1 is stable, easily obtained from 3-chloropropionic acid (Aldrich), and is a useful substitute for the ketone. Thus reaction of the silyl ether 2 with RMgBr provides adducts in which the OH group of 1 is replaced by R. The carbinol 1 is also a useful precursor to pyrroles, pyrrolines, and pyrrolizidines (equation I). 

Benzophenones have been described as useful sensitisers for PET catalysed conjugate addition reactions of a-amino alkyl radicals to enones (Bertrand et al. 2000). We tried to modify this reaction and synthesised the pyrrolidinylethyl-substituted quinolone 35 from the known bromide (Bauer et al. 2005). Upon electron transfer from the pyrrolidine to a given acceptor, a radical cyclisation occurs (Scheme 15), which after electron and proton transfer generates a pyrrolizidine. We found 4,4/-dimethoxybenzophenone to be a suitable catalyst for this reaction. Remarkably, the reaction proceeded with excellent simple diastereos-electivity and a single diastereoisomeric product rac-36 was obtained. With 10 mol% of the catalyst, a chemical yield of 71% was achieved. 

The scope of the lanthanide-mediated, intramolecular amination/cyclization reaction has been determined for the formation of substituted quinolizidines, indolizidines, and pyrrolizidines,1046 as well as tricyclic and tetracyclic aromatic nitrogen heterocycles.1047 The amide derivative OT ro-[ethylene-bis(indenyl)]ytterbium(m) bis(trimethyl-silyl)amide catalyzes the hydroamination of primary olefins in excellent yields.701 A facile intramolecular hydroamination process catalyzed by [(C5H4SiMe3)2Nd(/r-Me)]2 has also been reported. The lanthanide-catalyzed hydroamination enables a rapid access to 10,1 l-dihydro-5//-dibenzo[tf,rf]cyclohepten-5,10-imines (Scheme 283).1048... 

Dipolar cycloadditions of pyrroHne N-oxides, which could be regarded as cycHc nitrones , on electron-poor aUcenes, represent a viable method to obtain highly substituted pyrrolizidines. Enantiopure (S)-3-alkoxypyrroline N-oxide (170), on the other hand, has been exploited in stereoselective cycloaddition reactions with solid-supported unsaturated esters (169) [266]. A both regio- and stereoselective cycloaddition took place in this case, affording the desired compound (171) as a single isomer (Scheme 36). 

Reaction of vinyl Wittig reagents with carbonyl-substituted pyrroles has been used to generate the pyrrolizine ring system, from which pyrrolizidines are available by reduction. In this way, Schweizer and Light prepared... 

A similar approach was utilized by Brandange and Lundin in their synthesis of the endo- and exo-isomers of 1-substituted pyrrolizidines. The glyoxylate ester (84) was prepared at low temperature in an improved yield of 64% (Scheme 6). Wittig reaction of this ester with the allyl salt used by Schweizer and Light, gave mainly the pyrrolizine ester (85), possibly... 

Two entirely different methods utilizing A -pyrrolines as intermediates have been published. Storesund and Kolsaker prepared heavily substituted pyrrolizidines by base-catalyzed dimerization of nitriles. Initial reaction of the dinitrile starting material (97) is presumed to generate a cyclopropane... 

The total synthesis of (+ )-dehydroheliotridine (4), a toxic metabolite of the pyrrolizidine alkaloids (e.g. lasiocarpine and heliotrine), has also been described.2 The pyrrole ring was obtained by reaction of l,6-dihydroxy-2,5-dicyanohexa-l,3,5-triene-l,6-dicarboxylic ester (5) with j3-alanine, which afforded the N-substituted pyrrole ester (6), together with the appropriate amide of oxalic acid. Careful hydrolysis of (6) with dilute alkali afforded the related tricarboxylic acid, which was converted, by Dieckmann cyclization, hydrolysis and decarboxylation, into the keto-acid (7). Esterification of (7) with diazomethane, followed by reduction with lithium aluminium hydride, finally afforded ( )-dehydroheliotridine (4), identical, except in optical rotation, with dehydroheliotridine obtained earlier by Culvenor et al.3... 

Coleman and Goheen409 found it better to use iV-chloro amines rather than the A-bromo compounds for synthesis of pyrrolidines and in this way achieved yields of around 75% of substituted pyrrolidines. The method has also proved valuable for synthesis of bicyclic tertiary amines.410"412 Schmitz413 applied it to N,N-dibromo derivatives of primary amines from iV,JV-dibromo-l-propylbutylamine he obtained pyrrolizidine in 35% yield,414 the best yields being obtained here, as in other cases,412 415 416 when the reaction is carried out with irradiation in ultraviolet light. Recently ring closure was also achieved with JV-monochloro derivatives of primary amines 417 pyrrolidine (70%) was obtained from butylamine, 2-methylpyrrolidine (80%) from pentylamine, and 2-propylpyrrolidine (50% and 70%, respectively) from heptylamine or 1-pro-pylbutylamine.417 The mechanism of the Hofmann-Loffler reaction has been discussed by Wawzonek and Culbertson.416... 

Tetrahydropyrrolizines (210) and (211) can be formed via radical scission of either bond a or b in the intermediate vinyl-aziridine (208) but yields are moderate at best and the major product is the monocyclic pyrroline (209), formed by a 1,5-homo-dienyl rearrangement. The route therefore could provide a useful access to the pyrrolizidine framework if conditions could be identified which would allow more controlled and efficient breakdown of (208). The synthesis of substitute pyrrolines by ring expansion of vinyl aziridine derivatives has also been accomplished in a palladium-catalysed reaction. N -Tosyl-2-vinyl five- and six-membered nitrogen heterocycles (213) ace obtained in generally high yields under mild conditions from precursor dienyl nitrogen heterocycles (212) in the presence of a catalytic amount of [Pd(PPh ) ]. The complete diene unit is required for the... 

An efficient synthesis of dispiro-oxindolopyrrohdines and pyrrolizidines were reported through [3+2] cyeloaddition reaction of azomethine ylides with [E]-2-ox-oindolino-3-ylidene acetophenones under microwave irradiation in presence of ZiOCl. SHjO (Babu et al., 2007) while Wilson et al. (2001) have developed a novel method for the rapid synthesis of a hbraiy of substituted prolines by microwave-assisted [3+2] cycloaddition reaction. In this process, a-aminoesters and aldehydes generates imines under mierowave irradiation resulting into the [3+2] eycloadducts. 

---