Pyrrolidines as catalysts

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

These studies were expanded by Yang and coworkers [48], who uses fluorinated chiral pyrrolidine as catalysts, such that the epoxidation of l-phenylcydohexene was achieved with an enantioselectivity of up to 61% ee (Scheme 7.14). 

The synthesis of heterocycles by means of Lewis bases has been carried out using the reactions described above. For instance, the dipole resulting from the reaction of pyridine with DMAD was intercepted with phenylisocyanate giving a 1,4 dipole that ultimately led to pyrimidindione derivatives. Wang and coworkers have described the synthesis of benzoxazoles by reaction of ynals with N-protected-2-aminophenols using pyrrolidine as catalyst. Salicylaldehyde has been the starting material for the synthesis of many benzoheterocycles. When using DBU as catalyst, it was transformed into benzopyran derivatives by reaction with 2,2-disubstituted allene esters. When DABCO is used as catalyst, the reaction of AT-tosylimines with ethyl... 

In 2014 Phiko, Papai et al. tested a series of (25,55)-2,5-disubstituted pyrrolidines as catalysts for enantioselective Mukaiyama-Michael reactions between 2-silylo qr-furans and a,p-unsaturated aldehydes and found that 33, used in the presence of 4-nitro-benzoic acid as the cocatalyst, was the best catalyst in terms of selectivity (Scheme 11.31). Since 33 is not so sterically hindered, the authors also performed a detailed high-level DPT computational study to rationalise the stereochemical outcome, which was found to be controlled not by steric effects, but by the sum of a number of attractive noncovalent interactions involving the catalyst aromatic rings and the furan system. 

The general rule has been formulated (P) that the less substituted enamine is formed from unsymmetrical ketones such as the 2-alkylcyclohexanones. In enamine 21 the R, group and the N-alkyl groups would interfere with one another if overlap is to be maintained between the nitrogen unshared electrons and the double bond. There would be less repulsion if the isomeric enamine (22) were formed. 2-Phenylcyclohexanone and pyrrolidine with p-toluenesulfonic acid as catalyst in refluxing benzene gave enamine... 

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. 

In 1998, Ruiz et al. reported the synthesis of new chiral dithioether ligands based on a pyrrolidine backbone from (+ )-L-tartaric acid. Their corresponding cationic iridium complexes were further evaluated as catalysts for the asymmetric hydrogenation of prochiral dehydroamino acid derivatives and itaconic acid, providing enantioselectivities of up to 68% ee, as shown in Scheme 8.18. 

In 2003, Livinghouse et al. also reported that chelating bis(thiophosphonic amidates) complexes of lanthanide metals, such as yttrium or neodymium, were able to catalyse intramolecular alkene hydroaminations. These complexes were prepared by attachment of the appropriate ligands to the metals by direct metalation with Ln[N(TMS)2]3- When applied to the cyclisation of 2-amino-5-hexene, these catalysts led to the formation of the corresponding pyrrolidine as a mixture of two diastereomers in almost quantitative yields and diastereos-electivities of up to 88% de (Scheme 10.81). 

Another new example using titanocene as catalyst has been revealed by Malacria and coworkers. Here, a previously unknown combination of radical cyclizahon involving an epoxide-opening of 3-154 and a 3-phosphinoyl-elimination takes place to furnish various pyrrolidines 3-155, bearing a tetrasubstituted exo-double bond, in good yields (Scheme 3.41) [66]. 

Toluenesulfonic acid, as catalyst in reaction of cyclooctanone and pyrrolidine, 48, 57... 

Oxazines are prone to hydrogenolysis since the relatively weak N-O bond is easily cleaved. This reaction has often been employed for the transformation of this cycle (generally obtained from nitrones) into amino alcohols in a stereocontrolled manner. For example, reaction of 57 with hydrogen and palladium on charcoal as catalyst (Equation 1) furnished the expected substituted pyrrolidine 58 in moderate yields <2003EJ01153>. 

Success was obtained with Ru3(CO)i2 as catalyst precursor [6], but the most efficient catalysts were found in the RuCl2(arene)(phosphine) series. These complexes are known to produce ruthenium vinylidene spedes upon reaction with terminal alkynes under stoichiometric conditions, and thus are able to generate potential catalysts active for anti-Markovnikov addition [7]. Similar results were obtained by using Ru(r]" -cyclooctadiene)(ri -cyclooctatriene)/PR3 as catalyst precursor [8]. (Z)-Dienylcarba-mates were also regio- and stereo-selectively prepared from conjugated enynes and secondary aliphatic amines (diethylamine, piperidine, morpholine, pyrrolidine) but, in this case, RuCl2(arene) (phosphine) complexes were not very efficient and the best catalyst precursor was Ru(methallyl)2(diphenylphosphinoethane) [9] (Scheme 10.1). 

The Co-catalyzed reaction of azepane 264 n = 3) at 220 °C and 54 atm of CO gave the normal ring-expansion product 265 ( = 3) in 42% yield (Scheme 39). However, when Ru3(CO)i2 was used as co-catalyst of Co2(CO)s under the same conditions, azepanone 266 ( = 3) was obtained as the sole product in 72% yield (Scheme 39).The attempted reaction only with Ru3(CO)i2 as catalyst under the same conditions resulted in the recovery of the substrate 264 (n = 3). Thus, this unique rearrangement requires both Co and Ru catalysts. A proposed mechanism for the formation of 266 is illustrated in Scheme 40, which proposes that the origin of the lactam oxygen is the carbonyl oxygen of the A7-pivaloylmethyl group of pyrrolidine 264. ... 

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

In several cases the application of other basic catalysts is described, but such reactions often are followed by numerous side reactions or proceed in another direction. For example, in the reaction of malononitrile 107 with dimethylami-nochalcone 111 in the presence of pyrrolidine as the catalyst, instead of the expected cyanopyridines being formed the heterocycle 5-amino-7-(pyrrolidin-l-yl)-l,6-naphthyridine-8-carbonitrile 112 [118] is produced (Scheme 3.34). 

Shibasaki et al. described the first direct three-component catalytic enantioselec-tive Mannich reaction [3], wherein propiophenone 1, paraformaldehyde 2 and pyrrolidine 3 were reacted using (R)-LaLi tris(binaphthoxide) [(R)-LLB, 4] as catalyst to form Mannich product 5 with 64% ee and in 16% yield (Scheme 9.2). 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

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