A -Pyrroline

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). 

Pyrrole oxidizes in air to red or black pigments of uncertain composition. More usehil is the preparation of 2-oxo-A -pyrrolines, which is best carried out by oxidation of the appropriate pyrrole with in pyridine (37), eg, 3,5-dimethyl-ethyl-3-pyrrolin-2-one [4030-24-4] from... 

Complex reactions occur on the autoxidation of pyrroles (see Section 3.05.1.4) predictably, susceptibility to autoxidation increases with increasing alkyl substitution, llie photosensitized reaction of pyrrole and oxygen yields 5-hydroxy-A -pyrrolin-2-one, probably by way of an intermediate cyclic peroxide (Scheme 28) (76JA802). 

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). 

Among the less widely exploited interconversion processes are those involving thermal reactions with ethyl azidoformate, which convert furan into A-ethoxycarbonyl-A -pyrrolin-2-one, and thiophenes into A-ethoxycarbonylpyrroles (Scheme 96a) (64TL2185). The boron trifluoride catalyzed reaction of l,3-diphenylbenzo[c]furan with A-sulfinylaniline results in the replacement of the oxygen by an iV-phenyl group (Scheme 96b) 63JOC2464). 

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. 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

The original compound, maleimide (2,5-dioxo-A -pyrroline), is synthesized by the cyclo-condensation of ammonia and maleic acid. Similarly, primary amine is added to maleic anhydride, followed by cyclocondensation, to form N-substituted maleimide (Fig. 2). This reaction is applied to the preparation of bis-maleimides (BMl) [1]. At first, BMI was used as a crosslinking agent for natural rubber (NR). An o-dichlorobenzene solution of NR was crosslinked by BMI at I08-150°C in the presence of peroxides. The radicals generated from peroxides react with the double bonds of both BMI and NR [ 1 ]. 

A -Pyrroline has been prepared in low yield by oxidation of proline with sodium hypochlorite (71), persulfate (102), and periodate (103). A -Pyrroline and A -piperideine are products of enzymic oxidation via deamination of putrescine and cadaverine or ornithine and lysine, respectively (104,105). This process plays an important part in metabolism and in the biosynthesis of various heterocyclic compounds, especially of alkaloids. 

A -Pyrroline-N-oxides when unsubstituted in the 2 position readily add hydrogen cyanide. The 1 -hydroxy-2-cyanopyrrolidines thus formed undergo oxidation to 2-cyano-J -pyrroline-N-oxides. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Condensation of A -pyrroline with o-aminobenzaldehyde leads to dihydroquinazolinium salt 202 on acidification, which in turn can be reduced to desoxyvasicine (203). 

The same rearrangement was observed somewhat later by the irradiation of 5,5-dimethyl-A -pyrroline oxide (13)/ The product (11% yield) was shown to be identical with the oxazirane (14) synthesized from 5,5-dimethyl-A -pyrroline and hydrogen peroxide. 

There is no associated impairment of hydroxyprohne catabolism. The metabolic block in type II hyperpro-linemia is at glutamate-7-semiaIdeliyde dehydrogenase, which also functions in hydroxyprohne catabolism. Both proline and hydroxyprohne catabohsm thus are affected and A -pyrroline-3-hydroxy-5-carboxylate (see Figure 30-10) is excreted. 

Muramatsu H, H Mihara, R Kakutani, M Yasuda, M Ueda, T Kurihara, N Esaki (2005) The putative malate/ lactate dehydrogenase from Pseudomonas putida is an NADPH-dependent ALpiperideine-2-carboxyl-ate/A -pyrroline-2-carboxylate reductase involved in the catabolism of L-lysine and D-proline. J Biol Chem 280 5329-5335. 

A3-Pyrroline formation with carbonyl insertion also occurs during the reaction of /V-sulfinylarylamines with diphenylcyclopropenone in the presence of nickel carbonyl (Scheme 36).64 Phenyl isocyanate does not give a pyrroline product under these reaction conditions, hence the SO-CO exchange probably occurs within an intermediate metallocycle. The reaction... 

Ultrasound irradiation of mixtures of amines RNH2 (R = PI1CH2, Ph or Ar) and methyl pyruvate results in the 3-pyrrolin-2-ones 322377. The silver tetrafluoroborate-catalysed cyclization of the allenic amines 323 leads either to a pyrroline 324 or tetrahydropyridine 325, depending on the structure of the amine. The former is formed from 323 (R = H), the latter from 323 (R = Me)378. 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

In the case of class-II inhibitors, the acyl-enzyme undergoes either normal deacylation (Fig. 5.3, Pathway c) or a chemical re-arrangement in which the enamine tautomerizes to an imine, generating an acyl-enzyme with a A -pyrroline structure (Fig. 5.3, Pathway b). This second acyl-enzyme intermediate hydrolyzes at a much slower rate, and the decreased tum°ver cacis t0 transient inhibition of the enzyme [22] [50]. 

Additional communications deal with the synthesis of pyrrolo[l,2-cjquinazolines by treatment of methyl 3-alkyl-l,3-dihydro-2-oxo-3-(triphenylphosphoranylidenamino)-2//-indole-l-carboxylates (275) with ketones to afford A -pyrrolin-4-ones (276). As Scheme 100 shows, 276 can... 

Maleylacetoacetate Fumarylacetoacetate Acetoacetate ( Glutamate 4-semialdehyde A -Pyrroline-5-carboxylate... 

A -Pyrroline (12i) is emitted by sexually mature male Mediterranean fruit flies (Ceratitis capitate), together with 2-ethyl-3,5-dimethylpyrazine (21b) (Tables II and III). This cyclic imine (12i) is the key component in the sexual attraction of virgin female flies to males (102). Xanthommatin (58) and two pteridines (81 and 84) are also found in this fruit fly (Tables V and VI). 

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