5- pyrrolinones

Furan undergoes 1,4-addition with ethoxycarbonyinitrene to give, after rearrangement, the pyrrolinone (121). The corresponding reaction with pyrrole gives a mixture of (122) and (123) (64TL2185). 

The general form of metal-assisted cycloaddition as shown in Scheme 31 can be readily elaborated using monohaptopropargyl complexes (Scheme 32)61 specific examples illustrating the synthesis of A3-pyrrolinone derivatives are shown in Scheme 33.59... 

A3-Pyrrolinones have also been obtained from metal-mediated cyclooligomerization processes in which concomitant hydrolytic or carbonyl insertion occurs. For example, tert-butyl isocyanide is converted in aqueous methanol by zerovalent nickel compounds e.g., Ni(t-BuNC)4, Ni(CO)4, into a di(alkylamino)-A3-pyrrolinone in moderate yield (Scheme 34). The reaction takes a different course in anhydrous methanol in which a di-tert-butylamino)ethylene derivative is formed, albeit in poor yield (Scheme 34).62... 

Acrylic acid diallylamide is transformed by palladium chloride into A3-pyrrolinone derivatives but the synthetic utility of this type of cyclization is limited because of the formation of a complex product mixture containing pyrrolidones (Scheme 37).65... 

The enol form 10 of pyrrolam A 10 could not be detected despite its aromatic character <2004JOC6105>. Also, its pyrrolinone analogues 34 exist mainly as /3-enaminones <1985TL833> the tautomeric hydroxypyrrole 34 was only observed when R = C02Et (Scheme 1) <1988JOC5680>. 

The 02-oxidation of hydroquinone into quinone, which is very slow in the absence of a catalyst, was found to be accelerated by the addition of the ce-pyrrolinonate-bridged Pt(2.5 + )4 (19) (117). The detailed kinetic investigation revealed that the Pt(2.0+)2 species formed according to Eq. (1) plays a major role as the catalyst. The reaction rate of the quinone formation is higher than that of 02 oxidation of Pt(2.0+)2 into Pt(3.0 + )2 and was found to be rather linear to the hydroquinone concentration. Therefore, it was suggested that the quinone formation proceeds via a certain intermediate formed between the Pt(2.0+)2 species and molecular oxygen (e.g., peroxo species). The possible schematic mechanism is illustrated in Eq. (12). 

With related substrates 159 and a silver catalyst, the furanylidenamines 160 were formed with other substitution patterns as in 161 similar products 162 were accompanied by pyrrolinones 163 (Scheme 15.51) [105]. 

In a study of the flash vacuum pyrolysis of chiral isopropylidene N-isopropyl-N-(a-methylbenzyl)aminomethylenemalonates, (/ )- and (S)-(1239), McNab and Monahan demonstrated the existence of another intermediate (1242) in the reaction pathway from the methyleneketene (1240) to the pyrrolinone (1243) [87CC138 88JCS(P 1)869]. Pyrolysis of the enantiomers (R) and (S) of compound 1239 resulted in the formation of an enantiomeric mixture of l-isopropyl-5-methyl-5-phenyl-2-pyrrolin-5-one (1243), where incomplete chirality loss was observed (see Scheme 50). 

The flash vacuum pyrolysis of isopropylidene (1-ally 1-1-azacycloalk-2-ylidene)malonate (1277) at 460-680°C and 10 5-10 3 torr yielded a mixture of bicyclic azepines (1278) and pyrrolinones (1279) (85TL833) (Scheme 53). The ratio of 1278 and 1279 shifted towards the lower homologue (1279) at higher reaction temperature. 

When subjected to mercury acetate the ynone 78 underwent a 5-endo-dig cyclization and after work-up with aqueous sodium chloride, furnished the pyrrolinones 79 and 80 in a ratio of 89/11. The mixture of pyrrolinones was reduced directly with sodium borohydride to the iST-Boc-pyrrolidinol 81 which was obtained as a single diastereoisomer. Reduction of the carbamate with lithium aluminum hydride gave (+)-preussin (2) in 37% overall yield. 

The action of phosphorus halides on pyrrolinones and related compounds offers an alternative route to chloropyrroles. Yields of around 60% of 2,5-dichloropyrroles were obtained in this way from N-substituted succinimides (82ZC126). Vilsmeier reaction of N-alkylsuccinimidals formed chlorinated pyrrole aldehydes in modest yields (90CJC791), and there are other examples [66YZ158 81H(15)547]. A useful synthesis of chloropyrrole-2-carboxylates employed the action of phosphorus pentachloride on pyrrolidin-2-one-5-carboxylates (40) (87CB45) (Scheme 15), and in a Pummerer-type reaction pyrrol-3-yl sulfoxides were transformed by thionyl chloride into chloropyrroles. Yields were increased to >80% by the use of oxalyl chloride (88JOC2634) (Scheme 15). 

Whenever only primary amines need to be derivatized, fluorescamine often constitutes the reagent of choice. Fluorescamine, although nonfluorescent itself, can react with primary amines forming highly fluorescent pyrrolinones (139-144). Aliphatic primary amines favor derivatization reaction at pH 8-9, whereas primary aromatic amines exhibit optimal reactivity at pH 3-4. Secondary amines are also fully reactive with fluorescamine but their products do not fluoresce. However, secondary amines can be detected with fluorescamine if they are converted to primary amines by oxidation with N-chlorosuccinimide prior to their fluorescamine derivatization (145, 146). Alcohols can also interact with fluorescamine but this reaction is reversible as a result, alcohols just slow down the reaction rate of fluorescamine with primary amines. On the other hand, tertiary amines and guanidines are not reactive at all with fluorescamine. 

Methyl-2-furylcarbamate (138) on standing in benzene solution at room temperature undergoes autoxidation to the hydroxypyrrolinone (139) <81H(16)1157>. Treatment of (139) with trifluoroacetic acid at 0 °C for 30 min gave (140) in 70% yield, a compound identical to the naturally occurring antitumor pyrrolinone alkaloid jatropham (Scheme 31). 

A new /3-lactam synthesis has been devised which relies on the formal ring contraction of the A3-pyrrolinone (271), readily prepared from commercially available mucochloric... 

The base-catalyzed reaction at the activated methylene positions of the pyrrolinones and indolinones with aromatic aldehydes is a general reaction producing the benzylidene derivatives. Products of the Ehrlich reaction with pyrrolinones are generally yellow-orange... 

The C-2 and C-3 hydroxy derivatives of pyrrole are special in the sense that the tautomeric equilibria favor the pyrrolinone structures (see Section 3.04.6.2). Furthermore, the general synthetic methods are not usually applicable so that we will call attention in this section not only to the methods of directly introducing these substituents, which are rare, but also to those ring construction processes which specifically give the pyrrolinones and indolinones. The indole derivatives have widely used trivial names, oxindole (5) for indolin-2-one and indoxyl (6) for indolin-3-one, Carbocyclic hydroxy substituents in indole and carbazole, on the other hand, for the most part act as normal aromatic phenolic groups. These compounds are usually prepared by application of the standard ring syntheses. 

Pyrrolinones are best obtained by cyclizative condensation of y-keto esters with ammonia or a primary amine (reaction 195). Alternatively, the 2-pyrrolinones may be obtained by cyclization of preformed a-keto amides as shown in reaction (196) (71CC346). Preexisting lactones (2H- or 5H-furanones) also react with amines to give pyrrolinones (reaction 197). Jones and Bean give references to specific examples of these methods as well as to more specialized examples (B-77MI30610). 

Two general syntheses of 3-pyrrolinones which utilize easily available starting materials are known. One involves acylation and cyclization of /3-aminoacrylates by reaction with chloroacetyl chloride, as shown in reaction (198). The condensation of /3-keto esters with ethyl glycinate (reaction 199) also appears to be a reasonably general route to 3-pyrrolinones. Other methods, which are summarized by Jones and Bean (B-77MI0610), lead to specialized products or require unusual starting materials. 

Several pyrrolopyrrole derivatives were prepared by the cyclization of amides under the influence of basic reagents such as potassium hydroxide, potassium f-butoxide or even ammonium hydroxide. For example, the pyrrolinone amide (190) cyclized to give the pyrrolopyrrole derivative (21/22) under basic conditions (Scheme 68) (71JOC3929). Compound (21/22) exists mainly in the keto form in the solid state, but largely as the enol in polar solvents. Strictly speaking, neither tautomer is a true pyrrolopyrrole, since one ring is always in the form of pyrrolenine. 

An interesting approach to the treatment of autoimmune diseases is design of peptide mimics that bind into the antigen-binding groove of specific MHC proteins. For example, a protease-resistant pyrrolinone-peptide hybrid has been designed to bind to the rheumatoid-arthritis-associated HLA-DR1.326... 

An entire series of heterocyclizations is based on a-cyano-/3,/3-bis(acetyl)enamines (84JOC4696). When treated with weak bases, compounds 28 give amidine intermediates (29), which undergo cyclization yielding five-membered ring derivatives (30). The subsequent hydrolysis of 30 affords high yields of pyrrolinones (31). 

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