Pyrrolidines bond reduction

Similar to 2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine, Birch reduction-alkylation of pyrrolobenzodiazepine-5,ll-diones 1 leads to reduction of two double bonds and a-alkylation with the creation of two new stereocenters3. The chemical yields are moderate to good and the diastereomeric ratios are generally >85 15. The products are easily purified by recrystallization. In some cases y-alkylation products, with two double bonds in the reduced ring, are obtained as side products31. 

A -Benzyl-C-glycosyl nitrones reacted with acrylate to give glycosyl isoxazolidines which were easily converted to glycosyl pyrrolidines by reduction of the N-0 bond with Zn in acetic acid. The best result was obtained with pyranosyl nitrone 88 which quantitatively afforded the cycloadduct 89 with complete regio- and stereoselectivity <03TA3731>. 

Similar to the results discussed for the silylcarbocyclizations of carbon-carbon multiple bonds, reductive cyclizations in the presence of carbonyl compounds are readily achieved. Crowe has developed a titanium-catalyzed procedure for the intramolecular reductive coupling of i5, -unsaturated carbonyl compounds in the presence of triethoxysilane (eq 18).The electronic advantage of triethoxysilane is demonstrated by the lack of reductive coupling in the presence of less reactive silanes, such as triethylsilane and diphenylsilane. With this method, Mori has utilized nickel(O) catalysts to generate five- and six-membered carbocycles and pyrrolidine derivatives. Furthermore, coordination of a chiral phosphine ligand to the nickel catalyst renders the reaction moderately enantioselective. ... 

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

The M-aUylated compounds may serve as precursors to the M-unsubstituted pyrrolidines by a mild Pd(0) catalyzed deallylation procedure [451. The deallylation may be more straightforward than hydrogenolysis of the M-benzylated product in which complications due to the presence of the oxime and the other Bn moiety (1,2 bond in the pyrrolidine ring) may arise during reduction. Attempts to prepare piperidine and azepine systems following the above procedure were unsuccessful. 

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl-phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N-0 bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

Organoelement groups like the phenylthio- or diphenylarsanyl group can be removed reductively from alkyl residues very well by Raney-Nickel (Scheme 8). But the transfer of this splitting reaction to our products of anionic cycloadditions - pyrrolidine derivatives - led to difficulties because, as demonstrated in Scheme 8, in addition to the splitting of the element carbon bond ring opening or aromatization occured. 

Birch reduction-alkylation of (2S)-2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine (1) gives products 2 in high diastereoselectivities29. In contrast to the previous examples, only one double bond remains in the product (if one equivalent of rm-butyl alcohol is used as proton donor). Formally this procedure is a stereoselective cis addition, and is thus particularly useful. Thus, two stereogenic centers are created in the same reaction step with high diastereoselectivities. Subsequent hydrolysis furnishes acids, whereas reaction with methyllithium yields chiral ketones29. 

It is known that electrochemical reduction of oximes in protic media occurs in two steps the N—O bond is first reduced to form an imine and the latter is then reduced to afford a primary amine1,29. Tallec has shown that the amine from oxime 33 can be trapped intramolecularly (equation 16)35. Interestingly, the SS diastereomer predominates the chiral pyrrolidine ring derivative serves to control the stereochemistry of formation of the new benzylic chiral center. Electrochemical reductive cross-coupling of O-methyl oximes with carbonyl compounds in isopropanol at a tin cathode affords adducts (equation 17) which can be reduced further to 2-amino alcohols36. In this fashion, menthone could... 

The reduction of azetidin-2-one 302 containing a thioacetal moiety at C-4 to the corresponding acetal azetidine, followed by diethylaluminium chloride promoted C(2)-N(l) bond cleavage, afforded bicyclic pyrrolidines 303 and pyrroles 304 (Equation 98) <1999JOC9596, 1998TL467>. 

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