Pyrrolines 2,5-disubstituted

Racemic 2,5-disubstituted 1-pyrrolines were kinetically resolved effectively by hydrogenation with a chiral titanocene catalyst 26 at 50% conversion, which indicates a large difference in the reaction rate of the enantiomers (Table 21.19, entries 4 and 5), while 2,3- or 2,4-disubstituted 1-pyrrolines showed moderate selectivity in the kinetic resolution (entries 6 and 7) [118]. The enantioselectivity of the major product with cis-configuration was very high for all disubstituted pyrrolidines. The high selectivity obtained with 2,5-disubstituted pyrrolines can be explained by the interaction of the substituent at C5 with the tetrahydroinde-nyl moieties of the catalyst [Eq. (17)]. 

Racemic 2,5-disubstituted 1-pyrrolines were successfully resolved by hydrosilylation with PMHS in the presence of 11. For instance, reduction of 5-methyl-2-phenyl-l-pyrroline with a five equivalents of PMHS using (R)-ll (substrate Ti=40 l) in the presence of a three equivalents of i-C4H9NH2 in THF at 70 °C followed by purification by chromatography resulted in the S unreacted imine in 98.7% ee (42% yield) and the 2R,5R amine in 98.5% ee (43% yield) accompanied by a small amount of (R)-2-methyl-5-phenyl-l-pyrroline in 98% ee (Scheme 15)... 

The chiral titanocene catalyst 34 is very effective for the kinetic resolution of racemic 2,5-disubstituted 1-pyrrolines. When hydrogenation of racemic 5-methyl-2-phenyl-1-pyrroline with (Y)-34 is interrupted at ca. 50% conversion, unreacted R substrate with 99% ee is obtainable with a (2S,5S)-cA-pyrrolidine derivative with 99% ee (Scheme 1.98) [353], As summarized in the table, some other racemic substrates can be resolved in >95% optical yield. 

This method for preparing 2-phenyl-1-pyrroline, and assorted 2-substituted 1-pyrrolines, is one of the best currently available, particularly because it reproducibly affords clean materials. Generally, the procedure is amenable to various aromatic esters 2 it has also been applied successfully to aliphatic esters (Table I).3 An advantage of this method is the use of readily available, inexpensive N-vinyl-pyrrolidin-2-one as a key starting material. This compound serves effectively as a 3-aminopropyl carbanion equivalent. The method illustrated in this procedure has been extended to include the synthesis of 2,3-disubstituted pyrrolines. Thus, alkylation of the enolate of the intermediate keto lactam, followed by hydrolysis, leads to various disubstituted pyrrolines in good yields (see Table II).3... 

The stereoselective construction of nitrogen heterocycles remains a topic of intense synthetic interest [39]. Evans and Robinson described the combination of the stereospecific aUylic amination with ring-closing metathesis as a strategy for the constmction of mono- and disubstituted azacycles, which they demonstrated with the stereospecific construction of cis- and tra s-2,5-disubstituted pyrrolines [40]. Furthermore, this approach provided an ideal system for the determination of whether the enantiospecific rhodium-catalyzed aUyhc amination with an enantiomerically enriched nucleophile experiences a matched and a mismatched reaction manifold. 

Scheme 10.9 Stereospecific approach to cis- and trans-disubstituted pyrrolines.

Titanium, Zirconium, Hafnium - The catalytic asymmetric hydrogenation of imines has been reported using a chiral titanocene catalyst. " An enantiopure titanocene catalyst has been used in the catalytic asymmetric hydrogaution of disubstituted enamines. Kinetic resolution of a racemic disubstituted pyrroline has been effected by asymmetric reduction with a chiral titanocene catalyst. Poly(methylhydrosiloxane) has been used as a stoichiometric... 

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

The reaction of alkenylcarbene complexes and imines in the presence of a Lewis acid generates pyrroline derivatives as a result of a [3C+2S] cyclisation process [76]. This reaction has been extended to an asymmetric version by the use of chiral alkenylcarbene complexes derived from several chiral alcohols. However, the best results are found when (-)-8-phenylmenthol-derived complexes are used and catalytic amounts of Sn(OTf)2 are added to the reaction. In these conditions high levels of trans/cis selectivity are achieved and the hydrolysis of the major tram diastereoisomers allows the preparation of optically pure 2,5-disubstituted-3-pyrrolidinone derivatives (Scheme 29). 

Akiyama developed a novel [3+2] cycloaddition reaction of alkenyl Fischer carbene complexes 11 with simple imines 12 in the presence of a catalytic amount of GaCb to produce 3-alkoxy-2,5-disubstituted-3-pyrroline derivatives 13 <00JA11741>. 

Pyrrolines. This diene undergoes a [4 + ljannelation with primary amines to form a pyrrolidine 2 that can be converted to a 3-(3-phenylsulfonyl)pyrroline (3) in high yield. These pyrrolines are oxidized by DDQ to pyrroles (4), which can be converted readily to 2,3-disubstituted pyrroles (5). 

The flash vacuum pyrolysis of isopropylidene N./V-disubstituted ami-nomethylenemalonates (e.g., 1235, 1237) was studied by McNab et al. [83CC957 85CC213 86JCS(P1)1465 87CC138 88JCS(PI)863, 88JCS(P1)869, 88JCS(P2)759], They obtained 1,5,5-trisubstituted 2-pyrrolin-4-ones (e.g., 1236, 1238) in 38-75% yields. 

Flash vacuum pyrolysis of other isopropylidene /V,/V-disubstituted aminomethylenemalonates (1244) also gave 1-substituted pyrrolin-4-ones (1245) [84HCA1402 85CC213 88JCS(P 1)863]. 

C (70-82% yield) methanolysis of the latter resulted in the formation of 3,4-disubstituted-5-trimethylsilyl-l-pyrrolines 9 as the sole stereoisomer (68-93% yield). 

Oxidation of conjugated dienes in CH3CN-NaC104 in the presence of 1,3-dimethylurea gives a mixture of the possible 4,5-disubstituted 1,3-di-methylimidazolidin-2-ones in about 40% yield.103 Anodic oxidation of 2,4-hexadiene, 1,3-butadiene, and 1,3-cyclohexadiene in CH3CN-H20-NaC104 yields diols, 2-oxazolines, and 3-pyrrolines.104 The product distribution is influenced by the supporting electrolyte. 

The reduction of pyrroles by zinc in acetic acid or hydrochloric acid gives, initially, as the major product, A-pyrroline, together with A1- and A2-pyrrolines, all of which are further reduced to pyrrolidine (Scheme 54) (B-77MI30507). Reduction of 2,5-disubstituted pyrroles produces both the cis- and the trans- A3-pyrrolines, (206) and (207). 

The same thioimidate can be reacted with unsymmetrical dipolarophiles to give mixtures of two regioisomeric pyrroline derivatives where the 2,3-disubstituted compound is predominant.453... 

From a preparative point of view, Lukes s140 observation that the perchlorates of pyrrolines and piperideines and the picrates of 2,2-disubstituted saturated bases crystallize well is important, for these types of bases may thus be isolated. Some authors who repeated the experiments of Luke did not isolate both types, probably because of... 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

The 2,5-disubstituted pyrrolidines (and pyrrolines) are well known as constituents of ant venoms, particularly ants of the myrmicine genera Solenopsis, Monomorium, and Megalomyrmex 158). More than 20 such compounds have been identified in myrmicine ants 134,149,158-161). These include the /rans-pyrrolidine 197B. Incidentally, all ant pyrrolidines so far detected are of the trans configuration. A trans-2-n-butyl-5-n-heptylpyrrolidine (cf. 225C) occurs in ants, but a 2,5-di-/i-butylpyrrolidine (cf. 183B) has not been reported. 

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