Pyrrolidine, 2- 5.5- dimethyl

N1 - PYRROLIDINE, 2 2-DIMETHYL-l-l2-( p-(6-HETHOXY-2-PHENYL-2-INDENYDPHENOXY)ETWYL)-HYDROCHLORIDE... 

Johnson and Whitehead have further shown that the reductive elimination of the pyrrolidine group from the pyrrolidine enamine of 2,4-dimethyl-cyclohexanone (16), which involved treating it with a mixture of lithium aluminum hydride and aluminum chloride (9), gave the trans isomer of 3,5-dimethyl-/l -cyclohexene (17) which on subsequent hydrogenation on a platinum catalyst led to the // onr-3,5-dimethylcyclohexane (18). 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

Partial hydrogenation of pyrrole derivatives and partial dehydrogenation of pyrrolidines afford /I -pyrrolines (80-82). However, because of the complex nature of the reaction, it is of little preparative value. The same is true for isomerization of /) -pyrrolines to /) -pyrrolines (83). A photodehydrogenation of 2,6-dimethylpiperidine (26) has been observed recently, affording 2,6-dimethyl-3,4,5,6-tetrahydropyridine (27) in a good yield (84)-... 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The addition of ethyl acrylate to 1,2-dimethyl- -piperideine 163), l-methyl-2-ethyl-zJ -piperideine 164), and 1,2-dimethyl- -pyrrolidine 216,217) occurs, yielding both possible enamine structures (138 and 139, n=I,2). 

In practice, the [2 + 2] cycloadduct of 3-(pyrrolidin-l-yl)-l-benzothiophene (3) and dimethyl acetylenedicarboxylate isomerizes at 40°C to give the 3,4,5-trisubstituted 1-benzothiepin 5.12 In this synthesis cycloadduct 4 is not isolated. 

Dimethyl 5-(Pyrrolidin-l-yl)-l-benzothiepin-3,4-dicarboxylate (5) Single Procedure 11... 

The best result is obtained with the (.S )-2-(2,6-dimethyl benzyl (pyrrolidine complex (see Appendix) at — 109 °C. On quenching with acid, this yields 79% of a 78 22 kinelically controlled... 

In 20%iger Schwefelsaure wird Methyl-(4-oxo-pentyl)-amin an Blei-Kathoden reduk-tiv zu 1,2-Dimethyl-pyrrolidin (65% d.Th.) cyclisiert3. In verdiinnter Schwefelsaure fiihrt die Coelektrolyse von Aceton mit Allylalkohol zu 2,2-Dimethyl-tetrahydrofuran (95% d.Th.)4. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Pyrrolidines have been prepared by 1,3-dipolar cycloaddition of N-(benzyli-dene)trimethylsilylamine/TMSOf 20 and methyl acrylate, N-methylmaleimide, or dimethyl maleate [35]. More recently, methyl trans-3-cyanociruiamate 1479 was reacted with N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether 1480 and trifluoroacetic acid in CH2CI2 at 0°C and 24°C to afford, via 1481, the pyrrolidine derivative 1482 in high yield and MeOSiMe3 13a [35a] (Scheme 9.20). Several... 

Direct GC Injection of Amines. Morpholine, 2,6-dimethyl-morpholine, or pyrrolidine in methanol (2.6 to 2.8 g/ml) solutions were injected directly into the GC inlet at 210 C. Portions of these solutions were exposed to ultraviolet radiation (366 nm) for 16 hours prior to injection. 

An X-ray analysis has confirmed the structure of the product (39) formed when 2-aminobenzamide is heated with P S q in pyridine (there is no reaction in toluene). In the presence of alkali, dimethyl sulphate converts (39) into (40 R=SMe) which, in turn, yields (40 R=C HgN or PhNH) by reaction with pyrrolidine or aniline. 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

We also studied the structure of poly(N.N-dimethyl-diallyl-ammonium bromide) using poly(N,N-dimethy1-3,4-dimethylenepyrroli-dinium bromide) as a model system (16). These studies unequivocally confirmed that polydiallyl quaternary ammonium system consisted predominantly, if not exclusively, of five-membered rings linked mainly in a 3,4-cis configuration. By investigating synthetic polymers with defined structures and composition, it is hoped that some relationship between the polymeric structure and properties could be clarified. We now wish to report the 1,4-polymerization of N-pheny1-3,4-dimethylene pyrrolidine and the effects of oxidation and reduction of this polymer. 

Valence Isomerization of the 2-Thiabicyclo[3.2.0]heptadiene Moiety In principle, a valence isomerization of thiabicyclo[3.2.0]heptadiene skeleton would lead to a thiepin ring system. Wynberg et al. 23) reported that the photochemical adduct (28) from benzo[6]thiophene and dimethyl acetylenedicarboxylate was not thermally stable. When heated in diglyme, it loses sulfur to give dimethyl 1,2-naphthalenedicarboxylate. This reaction presumably proceeds via ring opening of 28 to 2,3-dimethoxycarbonylbenzo[6]thiepin (29) which readily eliminates sulfur. This synthetic route was successfully applied to the reaction of electron-deficient acetylenes with enamines of 2,3-dihydrobenzo[fe]thiophen-3-ones in which the enamine moiety constitutes part of a thiophene system. When 3-pyrrolidin-l-yl-benzo[6]thiophene (30) was allowed to react with dimethyl acetylenedicarboxylate... 

In the context of preparing analogues of chiral l,2-dimethyl-3-(2-naphthyl)-3-hy-droxy-pyrrolidines, which are known non-peptide antinociceptive agents, Collina and coworkers have reported the solvent-free dehydration of hydroxypyrrolidines to pyrrolines under microwave conditions (Scheme 6.141) [278]. In a typical experiment, the substrate was adsorbed onto a large excess of anhydrous ferric(III) chloride on silica gel and then irradiated as a powder under microwave conditions for 30 min at 150 °C. The microwave method leads to dehydration without racemiza-tion and provides higher yields in considerably shorter times than the conventionally heated process. 

Diaz-Ortiz described the cycloaddition of 4,6-dimethyl-l,2,3-triazine (105) with en-amines to give condensed pyridine systems [82]. These reactions were performed in a monomode reactor at a power of 270 W for 20 min at 15 °C. The reactions can also be performed with pyrrolidine, with cyclic ketones used as precursors of the enam-... 

The /V -hydroxylamino compounds (404) and (405), obtained from the reaction of tert-butyl acetate with 3,4-dihydroisoquinoline-A-oxide or 5,5-dimethyl-pyrroline-/V-oxide, when boiled in methylene chloride in the presence of triphenylphosphine, carbon tetrachloride and triethylamine, are transformed to (1,2,3,4- tetrahydroisoquinolin-l-ilidene) acetate (406) or (pyrrolidin-2-ilidene) acetate (407) (Scheme 2.181) (645). 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Thus, derivatives of structure 84 were treated with iV-methylmaleinide to give the cycloadducts 85 in high yields. In accordance with the concerted nature of this process, the pyrazoles and pyrrolidine-dione had a rxr-fusion. Similar cycloaddition was also experienced with dimethyl acetylenedicarboxylate (DMAD) to afford 86 containing the partially unsaturated pyrazole ring. 

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