A Pyrrolines derivs

The recent synthesis of ( ) 8-coniceine (190) involved a pyrroline derivative (191) as a key intermediate as it was relatively stable. It was cyclized with methanolic hydrogen chloride, desulfurized with Raney... 

Metabolic N-demethylation of methadone occurs since incubation of levo methadone with rat liver slices results in the formation of formaldehyde at a rate only marginally less than that obtained with pethidine as substrate. °2) The reason for the failure of early attempts to isolate the corresponding secondary amine is now well established as due to the facile cyclization of N-desmethylmethadone to a pyrroline derivative. Chemical studies have confirmed the cyclic structure 3 (13) the corresponding free base is an exocyclic alkene 2 that exists as an approximately 50 50 mixture of c-t isomers.(14)... 

A partial synthesis of 12-substituted derivatives of iV-demethyl-5a-con-20(iV)-en-3-one from holarrhenine has been reported. ° Furthermore, it has been shown that treatment of the methoxylated 20-imino-steroid (427) with methyl-magnesium iodide afforded the steroid A -pyrroline derivative (428). In... 

C,H,7N0 Mr 267.25. An amino sugar acid isolated from gangliostdes and named by Klenk. N. is unstable and cyclizes spontaneously to furnish a pyrroline derivative. However, it is widely distributed in N- and O-acylated forms. N-Acetylneuraminic acid (NeuSAc, Neu/VAc, NANA) C,H NO Mr 309.27, mp. 185-187°C, [a]o -33 (HjO). 

Thiols are easily oxidised using a mercury electrode, but the analysis of thiol drugs poses special problems and is discussed in Chapter 5. Solutions of pheno-thiazines, particularly those without an electron withdrawing substituent at the 2-position, become coloured on storage due to oxidation. EC oxidation of these compounds at carbon electrodes is possible at +0.8 V vs Ag/AgCl. Dihydro-pyridines and other reduced aromatic compounds are also often oxidizable at moderate potentials and HPLC-ED methods for nifedipine, other 1,4-dihydro-pyridines, and pirprofen, a pyrroline derivative which can be oxidised to a pyrrole at + 0.8 V vs Ag/AgCl, have been described. 

A -Pyrroline-5-carboxylate reductase catalyzes the reduction of this compound to proline. In the rat liver enzyme DPNH and, less effectively, TPNH serve as hydrogen donors 115,120,123). In the Neurospora enzyme TPNH is sixteen times as effective as DPNH 124). A -Pyrroline-S-car-boxylate reductase has been observed in various mammalian tissues 120, 123) and in a variety of microorganisms 116, 123-126). The enzyme has been purified about thirtyfold, from Neurospora 126) and about eightyfold in the writer s laboratory from animal tissue 126). The enzyme is active on a number of A -pyrroline derivatives. The optimum activity of the liver and Neurospora enzymes is at about pH 7.0. The reductase is an SH enzyme and it is strongly inhibited by the usual SH reagents. Estimation of the kinetic constants of the liver enzyme yielded X values of 2.0 X 11" M for pyrroline-5-carboi late and 2.5 X 10 M for DPNH. 

The mechanism of acid degradation and humin formation is undoubtedly complex. A A -pyrroline derivative was proposed (Gottschalk, 1960) as an initial cyclization product, and this was later substantiated by identification of 4-hydroxy-5-(l,2,3,4,-tetrahydroxybutyl)-A -pyrroline-2-carboxylic acid (XXVI) (Gielen, 1967a). This compound is... 

Scheme 22 Synthesis of tricyclic A -pyrroline derivatives substituent-dependent...

Finally a general approach to synthesize A -pyrrolines must be mentioned. This is tl acid-catalyzed (NH4CI or catalytic amounts of HBr) and thermally (150°C) induced tea rangement of cyclopropyl imines. These educts may be obtained from commercial cyan> acetate, cyclopropyl cyanide, or benzyl cyanide derivatives by the routes outlined below. Tl rearrangement is reminiscent of the rearrangement of 1-silyloxy-l-vinylcyclopropancs (p. 7 83) but since it is acid-catalyzed it occurs at much lower temperatures. A -Pyrrolines constitut reactive enamines and may be used in further addition reactions such as the Robinson anei lation with methyl vinyl ketone (R.V. Stevens, 1967, 1968, 1971). 

These observations can be extrapolated to the pyrrole series the 2-amino derivatives are very unstable whereas 3-aminopyrroles appear to be more stable. 3-Amino-l-tritylpyr-role (162) appears to exist in solution exclusively in the imino-A -pyrroline form (163) (83JCS(P1)93). 2-Aminoindole (164) is unusual in that it exists mainly as the 3//-tautomer (165). 4-Alkylaminoindoles (166) undergo an unexpected rearrangement to 4-amino-1-alkylindoles (167) when heated with p-toluenesulfonic acid hydrate (82CC1356). 

Reaction of 2-alkyl- -pyrrolines and 2-alkyl- -piperideines with acid chlorides leads to ring-opening and formation of N-acylated amino ketones (131, = 1, 2) (211-213). Ketene reacts with J -piperideine to form a tricyclic derivative (132) (214). 

By means of and NMR spectroscopy it was found that 2-(meth-ylamino)-l-pyrroline (R = Me) is present in solution mainly in the amino form. For the corresponding A -phenyl derivative an equilibrium between 2-aminopyrroline, imino, and 2-amino-4,5-dihydropyrrole tautomers is found (Scheme 20) (87MI5). 

Rolgamidine (14) is a dihydropyrrole derivative which has antidiarrheal activity It can be synthesized by alkylation of trans 2,5-dimethyl-3 pyrroline (12) with methyl bromoacefate to give 13 An amide-ester exchange reaction with guanidine hydrochloride completes the synthesis of rolgamidine (14) [3]... 

Thermal rearrangement of 2-vinylaziridine 203, with an electron-withdrawing substituent on the nitrogen atom, at reflux in decalin predominantly yielded 2-pyr-roline 204 along with some 3-pyrroline derivatives 205 (Scheme 2.50) [79]. A similar reaction was also observed with l-alkyl-2-phenyl-3-vinylaziridines 206 [80]. From these observations, the nature of the products formed depends on the natures of the substituents on the aziridine ring if the ring carbon carries a phenyl substituent, the thermolysis in most cases preferentially yields 2-pyrrolines. 

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). 

Microwave irradiation in solvent-free conditions induces the cleavage of the 2,3-bond of 2-aroyl-aziridines 135 to give an azomethine ylide intermediate, which subsequently undergoes cycloadditions to a multiple bond and leads to oxazolidine, imidazoline, naphthooxazole and pyrroline derivatives 136 in good yields (Scheme 9.41) [32b], Reactions were performed at atmospheric pressure in an Erlenmeyer flask placed in a commercial domestic oven. The reactions were complete in 10-15 min while the conventional method requires 18-20 h. 

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>. 

Addition of (4-methoxybenzyl)magnesium chloride to the pyrroline derivative (312) is a key step in the stereoselective synthesis of antibiotics (—)-anisomicine... 

Chromium carbene complexes have also been known to react with imine equivalents to afford /3-lactam derivatives234. Furthermore, [3 + 2]-cycloaddition of an alkenylchromium carbene 133 with imines proceeded to afford 3-pyrroline derivatives 134 in the presence of a Lewis acid catalyst (Equation (21)),235 where GaClj or Sn(OTf)2 were efficient promoters. Alkenylcarbenes bearing chiral auxiliaries afforded the desired cycloadduct in optically pure form. 

The reaction of l-methyl-2-(methylmercapto)-2-pyrroline (282) with DMAD is known to give a dihydroazepine derivative (283) (Eq. (38)1. The recent report of the reaction of 1-methyl-2-pyrrolidone dimethyl-acetal (284) with DMAD to give products like 286, 287, 288, and 289 may be interpreted as essentially the reaction of the enamine system (285) (Scheme 45). Other examples of the reaction of enamines include the reaction of the pyrrolidinopentenone (290) to give the phthalate (293)... 

The cyano-substituted nitrile ylides 123 have been generated via 1,1-elimination reactions. For example, the benzyhdene derivative 122 (R=Ph) eliminated benzene on vapor phase pyrolysis to give 123 (R=Ph), which reacted via 1,5-electrocycli-zation [see also (66)] to give the isoindole 124 (41%) (67). In a similar way, 122 [R=(CH2)3CH=CH2] gave the corresponding nitrile yhde that reacted via intramolecular cycloaddition to give the pyrroline derivative 126. 

The palladium catalysed substitution reaction of allylic systems has also been utilised in the formation of five membered rings. Intramolecular nucleophilic attack of the amide nitrogen atom on the allylpalladium complex formed in the oxidative addition of the allyl acetate moiety on the catalyst led to the formation of the five membered ring (3.63.). In the presence of a copper(II) salt the intermediate pyrroline derivative oxidized to pyrrole.80... 

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