Pyrrolidines nucleophilic addition reactions

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). 

The nucleophilic addition of lithiated methoxyallene to N-tosylimines delivers tosylamides 174. Treatment of the latter with AgN03 leads cleanly to dihydropyrroles 175, which under acidic conditions provide pyrrolidin-3-ones 176. Another example is the reaction of 177 to 178 (Scheme 15.55) [113]. 

Nucleophilic additions were studied using the same TSIL with pyrrolidine and thiophenol as models. As with the Diels-Alder reaction above, the reaction gave the required adducts which were then transesterified to give the final products. Heck coupling catalyzed by a transition metal and the Stetter reaction, Scheme 30, to prepare 1,4-dicarbonyl compounds were also studied by the same group using similar TSILs. 

A ruthenacyclopentane 48 has been proposed as an intermediate in this reaction, after coordination of the allene and enone. Exocyclic /1-hydride elimination led to the 1,3-dienes. This ruthenacycle possessed a o-bound ruthenium allyl, allowing nucleophilic additions by alcohols or amines. Alkylative cycloetherification [29] (Eq. 20) and synthesis of pyrrolidine and piperidine [30] were thus achieved. 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

Rapopoit found that 5-(2-pyridyl) thioates such as (28) did not function as selective acylating agents, and substantial amounts of tertiary alcohol were formed through overaddition (equation 16). Presumably, the tetrahedral intermediate, derived from nucleophilic addition to the S-(2-pyridyl) thioate, was not a stable entity in the reaction mixture. As will be discussed shortly, the lability of these intermediates had been recognized previously. The novel dimethylpyrazolide moiety of substrate (29) also did not confer any additional stability to the tetrahedral intermediate and tertiary alcohol was the major product (equation 16). Tertiary amides, such as those derived from pyrrolidine or dimethylamine, were reactive towards lithium adkynides in the presence of BF3, but analysis of the product indicated that it had undergone substantial racemization. ... 

Cycloadditions of acylnitropyrrolidine derivatives [272] of 1.64 or 1.65 give interesting results, as do reactions of alkoxyimminium salts [295] or of 2-pyrrolidinobutadienes [296], The same pyrrolidine derivatives have been used in asymmetric Michael reactions of aminochromium carbene anions [297] and in nucleophilic additions to arenemanganese tricarbonyl complexes [298],... 

As mentioned before (Section 2.5.5.2), only primary and secondary amines are able to give a nucleophilic addition to fuUerenes. Tertiary amines, on the other hand, exclusively enter into radical additions. Usually these are initiated photo-chemically, and they are very hard to control. However, the isolation of a triethyl-amine-adduct with Cgo (see below) succeeded when oxygen was scmpulously excluded, while in its presence a completely different product featuring a pyrrolidine ring was generated. Moreover, the aerobic thermal reaction of C > with NEts has successfully been performed just recently. It yields the 3-N,N-diethylamino-5-... 

Chiral pyrrolidines constitute the first class of organocatalysts which have been successfully used to catalyse various domino Michael addition reactions involving other-than-C-nucleophiles. As an example, Wang et al. have reported highly enantio- and diastereoselective domino aza-Michael-Michael reactions of ot,p-unsaturated aldehydes with a trans 4-amino protected cx,p-unsaturated ester catalysed by diphenylprolinol silyl ether combined with NaOAc as a base. As summarised in Scheme 1.75, the corresponding trisubstituted synthetically useful, highly functionalised chiral pyrrolidines were produced in high yields and diastereoselectivities of up to 94% de combined with almost complete enantioselectivity in all cases of substrates. 

Two C-C Bond-Forming Events In 2008, Frechet and coworkers described an impressive asymmetric cascade reaction promoted by soluble star polymers with core-confined catalytic entities [10]. The encapsulation of catalysts into soluble star polymers allowed the use of incompatible catalysts and prevented undesired interactions between these catalytic systems. The organocascade corresponded to a nucleophilic addition of Af-methylindole to a,p-unsaturated aldehydes followed by a Michael addition of the adduct to methylvinylketone (MVK) in the presence of H-bonding additive (Scheme 12.5). Each catalyst - imidazolidinone 8 for the nucleophilic addition and diphenylprolinol methyl ether 9 for the Michael addition - or their combination cannot mediate both reaction steps. In particular, p-toluenesulfonic acid (p-TSA) diminished the ability of the chiral pyrrolidine 9 to effect enamine activation. Therefore, p-TSA and 9 were encapsulated in the core of star polymers, which cannot penetrate each other. Imidazolidone 8 was added to the acid star polymer and diffused to the core to form the salt, which allowed the iminium activation and catalyzed the first step. The second step was catalyzed by the pyrrolidine star polymer in presence of the H-bonding additive 10, which... 

The mechanism of the formation of lff-pyrrole-2,3-diones 494 involves first the Michael-type attack of nitrogen atom of NH2 group of the urea derivative on C(5) in the furandione ring. Later, the molecule of water was eliminated and compound 494 was obtained. Nucleophilic addition of 1,2-DABs 155 to pyrrole-2,3-dione 494 lead to quinoxalin-2-ones 495. These compounds arise fi om the sequential attacks of 1,2-DABs at the C(3) and C(2) atoms of pyrrolidine, respectively, followed by the elimination of water and pyrrole ring opening, and the basic hydrolysis of this intermediate provides the final product 495. A possible reaction scenario is outlined in Scheme 2.111. 

The mechanisms of the reactions of the cluster Ru3(CO)i2 with halide ions, alkoxide ions and amines, all of which involve initial rapid nucleophilic addition at a carbonyl hgand, have been reviewed.In a related study, addition of 5-proline methylester or 5-methoxymethyl pyrrolidine to a carbonyl ligand of Ru3(CO)j2 has yielded chiral carbamoyl clusters of the type (84) R = C02Me or CH20Me, Eq. (16). Such chiral clusters may have potential as new enantioselective catalysts, as shown by the observation that cluster (84), R = CH20Me) catalyzes the isomerization of the prochiral allylic alcohol nerol to give the chiral aldehyde citronellal with an enantiomeric excess of 12%. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

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