2- alkyl pyrrolidine

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

Pyrrolidine alkaloids a group of Alkaloids (see) with simple structmes. P.a. are either derivatives of proline (e.g. stachydrin and its diastereoisomer, beto-nicin), or they are derived from a Af-methyl-2-alkyl-pyrrolidine (e.g. hygrin and cuskhydrin). The latter occur together with the tropane alkaloid with which they share the same biogenetic precursors, ornithine and acetate. 

Treatment of N-alkyl-pyrrolidines and -indoles with a fivefold excess of complex 220 in chloroform for 48 h at room temperature gave regioselectively... 

Man kann bei diesen Reaktionen auch von geeigneten tertiaren, silylierten Aminen aus-gehen, die man mittels Trifluormethansulfonsaure-trimethylsilylester/Casiumfluorid in Iminium-methylide uberfuhrt die Addition von aktivierten Alkenen ergibt dann substituierte 1-Alkyl-pyrrolidine z.B. 1-Cyclohexyl- 3,4-dime thoxy carbonyl-pyrrolidin... 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

Because of the expected superior excretion rates of bicyclic perfluorotertiary amines as oxygen carrying emulsions, they studied the ECF of several AT-cyclo-alkyl-pyrrolidines and -piperidines, from which they reported crude yields of... 

Pathway A employed a reductive cyclization [21] to form 3-carboxy-4-alkyl-pyrrolidin-2-one (17), which could then be converted to pregabalin under acidic conditions pathway B employed a hydro lysis/reduction/decarboxylation analogous to the one used in the first-generahon route via intermediate 18 [7], and pathway C involving a heat-mediated decarboxylation to intermediate 19 followed by a hydrolysis/reduchon sequence to yield pregabalin. In pathway A, the hydro-genahon of 13 was performed in predominantly aqueous medium at neutral pH, with catalyhc amounts of Raney nickel, and afforded 17 in >95% isolated yield. The reduction could be performed at relatively high substrate loads (0.5-1.OM),... 

Heating or photolytic treatment of A,A-dialkyl-A-haloamine in sulfuric acid or trifluoroacetic acid, followed by neutralization with a base, generates a pyrrolidine or piperidine skeleton. This is the Hofmann-Loffler-Frey tag reaction, and the reaction comprises of the formation of an electrophilic aminium radical, 1,5-H shift (6-membered transition state) or 1,6-H shift (7-membered transition state), formation of 4-haloalkyl ammonium or 5-haloalkyl ammonium, and its polar cyclization by neutralization with a base. Eq. 6.16 shows the formation of A-alkyl pyrrolidine (31) from A-chloro-A-alkyl-A-butylamine (30) in sulfuric acid [46, 47]. 

Reaction with N-protected 2-hydroxypyrrolidines or -piperidines. The Wittig reaction with these substrates provides a-alkylated pyrrolidines or piperidines after base-catalyzed intramolecular Michael addition.1... 

The exception - alkylation oflithiated N-alkyl pyrrolidines and piperidines inversion (SE2inv)... 

In this reaction, the formation of two series of compounds is proposed because in the chromatographic separations of polypeptide pyrolysates, an additional peak is noticed for each 3-alkenyl-5-alkyl-pyrrolidin-2,4-dione. This second peak is assigned to the corresponding 2,4-dialkyl-3,5-diketopyrroline (position isomers are not possible when R2 and R3 are identical) [1]. The list of different compounds from these two classes that may be formed during laser irradiation of different mammalian tissues [13a] due to peptide (protein) pyrolysis and the amino acid pair that can generate them is given in Table 12.2.3. 

Table 12.2.3. 3-Alkenyl-5-alkyl-pyrrolidin-2,4-diones and 2,4-dialkyl-3,5-diketopyrrolines that can be formed from laser pyrolysis of mammalian tissues [13a].

In the Hofmann-Loffler reaction an A-alkyl-A-haloamine is heated under acidic conditions to give the/V-alkyl-pyrrolidine or A-alkyl-piperidine product. A related process is the Barton reaction, in which a methyl group that is 5 to a hydroxyl group is oxidised into an aldehyde. 

The exo-succinimido moiety in l-(morpholinobicyclo[n.l.0]alkyl)pyrrolidine-2,5-diones is readily displaced by strongly basic amines such as morpholine. Heating the starting material in morpholine gave 4,4 -bicyclo[n.l.0]alkanediyldimorpholines 5. No cisitrans isomerization of the bicyclic system was observed. 

A suspension of l-(morpholinobicydo[n.l.0]alkyl)pyrrolidine-2,5-dione(10mmol) in morpholine (20 mL) was refluxed for several hours (see table above). Then excess morpholine was evaporated in vacuo at 20 °C. The residue was extracted with pentane (3 x 50 mL). Evaporation of the pentane gave crude products which were recrystallized from MeCN. 

EljN (1.52 g, 15 mmol) was added to cooled formic acid (0.69 g, 15 mmol) at — 20°C. Then 1-(aminobicycIo[n.l.0]alkyl)pyrrolidine-2,5-dione (5 mmol) was added at 20°C and the mixture was stirred for 5 h at 140°C. The amine was isolated by extraction of the cooled mixture at 20°C with pentane (3 X 20 mL) and purified by addition of 5% HCl (20 mL), removal of the pentane extract, basification of the aqueous layer with 5% KOH and extraction with pentane (3 x 20 mL). The pentane solution was washed with citrate buffer (pH = 3.75 or 4.5 see table above). Pure amine was obtained from the pentane solution by evaporation of the solvent and distillation of the residue in a Kugelrohr apparatus. 

In a further study the prospects of a series of alkylated pyrrolidine side-chains was explored [149]. All compounds prepared showed good binding affinity and ERa... 

Polyfluoro-imines have also been encountoed in work on perfluoro-vinyl iso< anates (see Schemes 38, 39), peifluoro-jV-fluoromorpholine (see Schmes 21, 22), 4 electrochemical fluorination of -alkyl-pyrrolidines and -piperidines (see Schranes 18,19), fluorination of 1,3,3-trichloroisoindolenines (see Sdione 20), fluorinated isocyanates (see p. 227),. fluoro-ol ns (see pp. 71, 73), fluorinated... 

Another group of Solenopsis (thief ants) and some species of Mono-morium ants have alkyl-pyrrolidines and -pyrrolines (Figure 9.7). The sting of these ants does not seem to be so painful, but whether this is due to the alkaloids or the protein part of the sting is not known. More recently some of the same and similar pyrrolidines have been found in Megalomyrmex ants. Their biosynthesis is not yet known. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

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