Brønsted acid catalyzed regioselective aza-Ferrier reaction: a novel synthetic method for alpha-(N-Boc-2-pyrrolidinyl) aldehydes

The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)pyrrolidines is shown to proceed with high (1E,3E)-stereoselectivity to afford N-Boc-2-(1,3-dienyloxy)pyrrolidines; the Br?nsted acid catalyzed aza-Ferrier reaction of the N-Boc-2-(1,3-dienyloxy)pyrrolidines (3) provides alpha-(N-Boc-2-pyrrolidinyl) aldehydes in excellent yields with high alpha-regioselectivities.     

Acid-catalyzed cyclization of vinylsilanes bearing an amino group. Stereoselective synthesis of pyrrolidines

[reaction: see text] In the presence of an acid catalyst, vinylsilanes 1 bearing an amino group protected by an electron-withdrawing group were smoothly cyclized to 2-(silylmethyl)pyrrolidines 2. This cyclization was utilized for the stereoselective synthesis of 2,n-disubstituted pyrrolidines (n = 3-5). The cyclized products could be converted to the corresponding alcohols by oxidative cleavage of the carbon-silicon bond with TBAF and H2O2.     

Divergent chemical synthesis of prolines bearing fluorinated one-carbon units at the 4-position via nucleophilic 5-endo-trig cyclizations

N-[3-(Trifluoromethyl)homoallyl]sulfonamides, prepared via ring opening of (S)-glycidyl ethers or 2-aryloxiranes with 1-(trifluoromethyl)vinyllithium, underwent intramolecular addition or S(N)2'-type reaction in the normally disfavored 5-endo-trig fashion, leading to 2-substituted 4-(trifluoromethyl)- or 4-(difluoromethylene)pyrrolidines. Both alpha- and beta-face-selective hydrogenation of the 4-difluoromethylene group afforded syn- and anti-4-(difluoromethyl)pyrrolidines, respectively. These sequences, followed by the oxidation of a 2-hydroxymethyl or 2-aryl group, successfully provided prolines with a trifluoromethyl, difluoromethylene, or difluoromethyl group at the 4-position, including optically active prolines.     

Reduction of 5-(bromomethyl)-1-pyrrolinium bromides to 2-(bromomethyl)pyrrolidines and their transformation into piperidin-3-ones through an unprecedented ring expansion-oxidation protocol

3,3-Dialkyl-5-(bromomethyl)-1-pyrrolinium bromides, prepared via bromocyclization of N-(2,2-dialkyl-4-pentenylidene)amines by means of bromine in dichloromethane, were reduced to 4,4-dialkyl-2-(bromomethyl)pyrrolidines for the first time using borane dimethyl sulfide in dichloromethane. Furthermore, the latter 2-(bromomethyl)pyrrolidines were transformed into the corresponding piperidin-3-ones through an unprecedented ring expansion-oxidation protocol in dimethylsulfoxide in the presence of potassium carbonate. Reduction of 5,5-dialkylpiperidin-3-ones by means of sodium borohydride in methanol afforded 5,5-dialkyl-3-hydroxypiperidines in good yields.     

diastereoselective intramolecular Alder-Ene reaction on chiral perhydro-1,3-benzoxazines. a rapid entry to enantiopure cis-3,4-disubstituted pyrrolidines

Chiral 3-acryloyl-2-vinyl-substituted 1,3-perhydrobenzoxazines derived from (-)-8-aminomenthol participate in an ene reaction leading to 3,4-disubstituted pyrrolidinone derivates with excellent diastereoselectivity. The cycloadducts were transformed into enantiopure 3,4-disubstituted pyrrolidines after elimination of the chiral adjuvant.     

A new synthesis of pyrrolidines via imino-aldol reaction of (2-trimethylsilylmethyl)cyclopropyl ketones with imines

A new synthesis of 2,3,5-trisubstituted pyrrolidines from the imino-aldols formed from Lewis acid-mediated reactions of (2-trimethylsilylmethyl)cyclopropyl ketones with benzylimines is described. The ring closure of the imino-aldols formed from the benzylimines of 2-chloro-, 2-fluoro-, and 2-trifluoromethylbenzaldehydes proceeds with predominantly 2,5-anti selectivity to generate the corresponding pyrrolidines in moderate yields.     

Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot decarboxylation-alkylation reaction as the key step. In this reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule. In this way, optically pure alkaloid analogues and iminosugars were prepared.     

Double reduction of cyclic aromatic sulfonamides: a novel method for the synthesis of 2- and 3-aryl-substituted cyclic amines

The facile double reduction of bicyclic aromatic sulfonamides was used to synthesize a variety of 2- and 3-aryl-substituted pyrrolidines and 2-phenylpiperidine. The method features a combined nitrogen protection and a traceless tether for the transposition of the aromatic moiety from nitrogen to carbon.     

Sequential addition reaction of lithium acetylides and Grignard reagents to thioiminium salts from thiolactams leading to 2,2-disubstituted cyclic amines

The reaction of thioiminium salts derived from γ- and δ-thiolactams with lithium acetylides and Grignard reagents proceeded sequentially to give 2,2-disubstituted pyrrolidines and piperidines in moderate to high yields. In the initial step of the reaction, 2-(methylthio)pyrrolidines and -piperidines may be formed. The use of lithium (trimethylsilyl)acetylide gave the products most effectively. Aryl-, alkyl-, and allylmagnesium halides were used as Grignard reagents. Silylcarbocyclization of N-allyl 2-ethynyl cyclic amines with HSiMe₂Ph in the presence of a catalytic amount of Rh₄(CO)₁₂ was carried out to give trisubstituted hexahydro-1H-pyrrolizines and octahydroindolizines.     

Synthesen und pharmakologische Eigenschaften von 2,2-Dialkyl-5-aryl-3-pyridylpyrrolidinen

Syntheses and Pharmacological Properties of 2,2-Dialkyl-5-aryl-3-pyridylpyrrolidines Reaction of the photochemically generated benzonitrile methylides 2 with vinylpyridines yields 2-aryl-4-pyridyl-1-pyrrolines 3. Depending on reduction methods, the compounds 3 are selectively transformed to the corresponding cis- or the trans-substituted pyrrolidines 10 or 11 , respectively. Furthermore, a non-photochemical synthesis has been developed: the easily available nitro-ketones 8 provide through reductive cyclization the pyrrolines 3 or directly the pyrrolidines 11. Twenty-seven compounds of types 10 and 11 have been evaluated in the writhing, hot plate and kaolin tests; especially the cis-pyrrolidines 10 exhibit a valuable antinociceptive activity. Some of the pyrrolines and pyrrolidines have been separated into their enantiomers, which are easily interconverted.     

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.     

Synthesis of 1-(arylsulfonyl)pyrrolidines from phenols and 1-[(4-chlorophenyl)sulfonyl]-2-ethoxypyrrolidine

Acid-catalyzed reaction of 1-[(4-chlorophenyl)sulfonyl]-2-ethoxypyrrolidine with phenols leads to the formation of new 1-(arylsulfonyl)pyrrolidines. The reaction proceeds under mild conditions and may be used as a convenient method for the synthesis of pyrrolidine-1-sulfonylarene derivatives containing a phenol fragment in the position 2.     

Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines,pyrrolidines, and pyrimidinones

(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.     

Synthesis of 2-Arylpyrrolidines by Reactions of 3-Arylidene-1-pyrrolines with Phenols

Russian Journal of General Chemistry - The reaction of 3-arylidene-1-pyrrolines with phenols yielded 2-arylpyrrolidines. The proposed method makes it possible to obtain pyrrolidines containing a...     

On the scope of Pd-catalyzed carboamination reactions—synthesis of 2,4-disubstituted pyrrolidines and 2-substituted piperidines and morpholines

The scope of the palladium-catalyzed carboamination reaction for the synthesis of 2-substituted pyrrolidines, piperidines, and morpholines was investigated. Formation of a 2,4-disubstituted pyrrolidine proceeded in high yield but with a diastereoisomeric ratio of only 2:5, favoring the cis-isomer. The diastereoselectivity is hence significantly smaller than that observed previously in the formation of 2,3- and 2,5-disubstituted pyrrolidines. The yields of substituted piperidines and morpholines were lowered by competing Heck arylation reactions. Both the N-substituent and the choice of phosphine ligand for the palladium-catalyzed reaction were determining for the outcome.     

2-(diphenylphosphinoyl) pyrrolidines; versatile reagents for the synthesis of heterocyclic enamines and enamides.

A method is described for the preparation of N-substituted 2-(diphenylphosphinoyl) pyrrolidines. Application of these phosphine oxides in the Horner-Wittig reaction affords heterocyclic enamines and enamides in good yields.     

Stereoselective synthesis of polyhydroxylated pyrrolidines: a route to novel 3,5-bis(hydroxymethyl)pyrrolidines from 2-azabicyclo[2.2.1]hept-5-enes

An efficient preparation of racemic and chiral 2-functionalized-3,5-bis(hydroxymethyl)pyrrolidines is described. The method uses 2-azabicyclo[2.2.1]hept-5-enes, readily obtained from glyoxylates of aliphatic amines and cyclopentadiene, as starting material. The hydroxylation of the double bond followed by the oxidative cleavage of the six-membered ring and in situ reduction of the dialdehyde intermediate gives the title pyrrolidines.     

Regioselective Synthesis of Novel Spirooxindolo and Spiroindano Nitro Pyrrolidines Through 3+2 Cycloaddition Reaction

β‐Nitro styrene reacts with nonstabilized azomethine ylides generated from isatin/ninhydrin with sarcosine, resulting in the formation of a series of spiroxindolo nitro pyrrolidines, and spiroindano nitro pyrrolidines, respectively, in good yields. It was noted that in a one‐pot 3+2 cycloaddition reaction, the azomethine ylides generated from isatin and ninhydrin have reacted with the β‐nitro styrenes regiochemically in opposite ways.     

Synthesis and structure of new 2-aryl-substituted pyrrolidines containing phosphine oxide group

2-Aryl-substituted pyrrolidines containing phosphine oxide group have been obtained by the reaction of P-(4,4-diethoxybutylaminomethyl)- P,P-di-p-tolylphosphine oxide with polyatomic phenols.     

Reactivity of 1,1,2,2-tetracyano-3-(2,2-dimethylhydrazino)cyclopentanes Toward Amines

Substituted 1,1,2,2-tetracyano-3-(2,2-dimethylhydrazino)cyclopentanes were reacted with amines to synthesize substituted 1,5,5-tricyano-4-(2,2-dimethylhydrazino)-1-cyclopentenes and 5-cyano-2-(dicyanomethylene)-1-(dimethylamino)pyrrolidines.