Alkenes pyrrolidine derivatives

Blechert carried out a tandem reaction of enynes in the presence of olefins instead of ethylene (Scheme 21). Treatment of cyclopentenol derivative 58a with Ic in the presence of an alkene affords 59a. The five-membered ring in estrone 58b is cleaved by Ic to give 59 and an alkene part is introduced on the six-membered C ring. However, cycloalkenyl amine derivative 60 is treated in a similar manner in the presence of an allyl alcohol derivative to give pyrrolidine derivative 61, and in this case, an alkene part is introduced on the diene moiety. Presumably, ruthenium carbene complex XVI reacts with an alkyne part to produce the pyrrolidine ring with a regioselectivity opposite to the other cases. 

Platinum-catalysed intramolecular hydroamination of unactivated alkenes with secondary alkylamines has been reported. Thus, a number of y- and 5-aminoalkenes reacted in the presence of a catalytic 1 2 mixture of [PtCl2(H2C=CH2)]2 (2.5 mol%) and PPh3 in dioxane at 120 °C for 16 h to form the corresponding pyrrolidine derivatives in moderate to good yields. The reaction displayed excellent functional group compatibility and low moisture sensitivity.92... 

Application of azomethine ylides in dipolar cycloaddition reactions with alkenes provides a route to pyrrolidine derivatives, as illustrated by the generation of the intermediate 12, and its subsequent conversion to the target system 13 (Scheme 16) <1995TL9409, CHEC-III(3.03.9)327>. 

Chiral enamine derivatives have also been used as electron-rich alkenes. The oxazoline derivative 17 reacted with benzaldehyde to yield the two stereoiso-meric oxetanes 18a and 18b with a diastereomeric excess of 67% (Scheme 5) [12]. A significantly higher diastereoselectivity was observed in the case of the reaction of the pyrrolidine derivatives 19 where the enamine function is localized inside the five membered ring [13]. Then the oxetane 20a (R — n-Cgil g) was used in an asymmetric synthesis of the antifungal alkaloid (+ )-preussin. The approach of the 3n,7T excited ketone preferentially occurred syn with respect to... 

The intramolecular conjugate addition of in situ, chemoselectively generated amines 2 bearing an electrophilic double bond in the cu-position leads to functionalized pyrrolidines and piperidines 3 under very mild conditions34. The cyclization step occurs smoothly and the piperidine and pyrrolidine derivatives are obtained as a mixture of diastereomers with good diastereose-lection in most cases. The reactions are under kinetic control and the geometry of the starting alkene does not seem to have an influence on the stereochemical outcome of the cyclization step. 

Simple amines in the presence of Oxone oxidize alkenes to oxiranes. For example, Oxone, pyridine, and a 2-pyrrolidine derivative in a medium of aqueous acetonitrile selectively converts the triene in Equation (72) to a single epoxide. This process also proceeds using noncyclic alkenes. The mechanism is believed to proceed via a single-electron transfer (SET) process involving radical cation intermediates <2000JA8317>. 

From aziridines. N-Tosylaziridines, easily obtained by aziridination of the corresponding alkenes, can be opened by selenolate reagents and furnish, after straightforward N-alkylation, radical precursors suitable for the preparation of pyrrolidine derivatives [12]. The preparation of octahydro-lff-indole 24 is shown in Eq. (4). A competing process involving radical azi-doselenenylation of alkenes has also been developed and will be discussed later (Sect. 5.2). 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

Studies of different cinchona alkaloids as the chiral Bronsted bases and a metal salt showed that hydrocinchonine lh (Scheme 10.13) and AgF were the most effective combination. The scope of the [3 + 2] cydoaddition of azomethine ylides and alkenes was investigated. Selected examples are shown in Scheme 10.14. High yields and moderate enantioselectivities were obtained from a variety of a-imino esters. It was worth mentioning that most of the pyrrolidine derivatives 11 obtained from tert-butyl acrylate were solids that could be enantiomerically enriched by crystallization. 

A. Armstrong, G. Ahmed, 1. Garnett, K. Goacolou, Pyrrolidine-Derived iminium salts as catalysts for alkene epoxidation by Oxone , Synlett (1997) 1075. 

Better diastereoselectivities were achieved with dipolarophiles such as unsaturated esters that bear a chiral auxiliary297-298. For instance, cycloaddition of the EVE-azomethine ylide, generated from the following imine by metalation, with the chiral alkene (27 )-2-(2-methoxycar-bonylethenyl)-3-phenyl-l,3-diazabicyclo[3.3.0]octane affords the pyrrolidine derivative as a single regio- and stereoisomer297. 

Epoxidations. Combination of Oxone and the iminium salt derived from pyrrolidine and o-trlfluoromethylbenzaldehyde is effective for epoxidation of alkenes. In the case of an active alkene (e.g., trisubstituted alkene), pyrrolidine is an adequate catalyst. Other types of mediators include a-functionalized ketones (e.g., ot-acetaminoacetone) and the A, A -dialkylalloxans 1. ... 

Synthesis of pyrrolidine derivatives and lactones based on conjugate addition of nitroalkanes to electron-poor alkenes 05CRV933. 

Cycloaddition reactions of azomethine ylides with electron-deficient alkenes fiimish pyrrolidine derivatives, whereby up to four stereocenters are formed. Besides Re/Si discrimination endo/exo stereoselection has to be rationalized in these HOMO/LUMO controlled 1,3-dipolar cycloadditions. 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

Another plausible altemative is the metal-catalyzed coupling of amides with alkynyl bromides or 1,1-dibromo-l-alkene [196]. Scheme 4.55 shows the more significant reported results with 2-pyrrolidine derivatives. ... 

To date, many functional alkenes, such as maleates, fumarates, and vinyl phenyl sulfones, have been employed as dipolarophiles, successfully (Figure 2.1). The attractiveness of 1,3-DC reactions of azomethine ylides with alkenes is due to the fact that pyrrolidine derivatives with up to four stereocenters can be generated in a single operation from readily available starting materials. As a result, the 1,3-DC of azomethine... 

Cycloadditions have emerged as one of the most used approaches for the formation of cyclic compounds by organocatalysis [8a]. Based on the previous knowledge, [3-1-2] cycloadditions can serve as an excellent platform for the synthesis of spirocyclic compounds. For example, alkylideneindolones act as activated alkenes that react with azomethine ylides to afford pyrrolidine derivatives. Recently, several research groups have used this approach to synthesize spirooxindoles and related... 

The cation fragment nature exerts negligible impact on selectivity of the Michael reactions that involve enamine intermediates and commonly the stereochemical outcome remains high. Indeed, pyrrolidine derivatives (Figure 22.6) containing pyridinium 87a,b [98], isoquinolinium 88a,b [99], 1,2,3-triazolium 89a,b [100], benzimidazolium 90 [101], and linear 91 [102] or cyclic 92 [103] quaternary ammonium cations in combination with various anions proved efficient catalysts of asymmetric additions of carbonyl compounds to a-nitro alkenes. Desymmetriza-tion of prochiral 4-substituted cyclohexanones can be achieved by analogy [101]. The reaction efficacy was similar under neat conditions in the presence of acidic additives (catalysts 87, 89, 90, 91) or in the IL medium (commonly in [bmim]BF4) (catalysts 88a,b, 92). 

In this reaction, the tethered alkene functionality of the aniline derivatives form a Tr-allyl complex with the Pd(II) catalyst, and then the cyclization takes place via intramolecular nucleophilic attack by the N to form another Pd-complex, which reacts with CO as the electrophilic carbon source in the presence of MeOH to afford substituted bicy-clic pyrrolidine derivatives. However, these products were not stereoselective in nature. A similar type of Pd-catalyzed nonstereoselective cyclizations were also reported by Weinreb et al. and by Larock and Yang for the construction of bicyclic and bridged aza-cycles." ... 

In 2004, Wolfe et al. used a carboamination reaction for the first time for the stereoselective synthesis of substituted pyrrolidine derivatives via a Pd-catalyzed intermolecular iV-arylation followed by intramolecular cyclization reaction sequences. The reaction proceeds via an innersphere mechanism with the formation of the Pd(Ar)(NRR ) complex. In this reaction, a -(A-arylamino) alkene was treated with an aryl or heteroaryl bromide in the presence of NaO Bu as the base and Pd catalyst the corresponding 2,3- or 2,5-disubstituted pyrrolidine derivatives (Scheme 40.4) were obtained in good yields and excellent diastereoselectivity. ... 

The catalytic cycle of this reaction has been shown in Scheme 40.5. At first, the Pd(0) catalyst reacts with the aryl bromide to generate the Pd(Ar)Br complex 19 via a simple oxidative addition. Complex 19 reacts with the amino alkene in the presence of NaO Bu base to generate the Pd (Ar)amido complex 21, which after subsequent alkene insertion into the Pd N bond followed by C C bondforming reductive elimination leads to the formation of substimted pyrrolidine derivative 23 along with the regeneration of the Pd(0). 

Synthesis of anthramycin derivative 69a was achieved using RCM and alkene cross-metathesis (CM) (Scheme 6.16) [19]. L-Methionine was converted to ene-yne 61, and subsequent RCM with catalyst [Ruj-I under an atmosphere of ethylene gave pyrrolidine derivative 62. After deprotection and condensation with the commercially available acid chloride 63, the resulting amide 64 underwent reductive cyclization using Zn/AcOH followed by treatment with diluted HCl to... 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

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