4- Hydroxy-3-pyrrolin-2-one

Newer investigations deal with the conversion of a-ketoalkynes to highly functionalized 3,5-substituted 5-hydroxy-3-pyrrolin-2-ones in a regioselective synthesis with KCN catalyzed by tetracyanonickelate(O) formed in situ from the system Ni(CN)2/CO/KCN in alkaline aqueous medium. This study is based on the catalytic hydrocyanation of alkynes in the presence of Ni(CN)4" introduced by Funabiki and co-workers [66]. 

Oxidative decarboxylation of pyrrole-2-carboxylic acids Reaction of pyrrolc-2-carboxylic acids such as 1 and 2 with singlet oxygen in i-PrOH or CH3CN and water (3 1) results in 5-hydroxy-3-pyrrolin-2-ones in high yield. 

The Dittami group developed a cyclocondensation approach to 5-hydroxy-3-pyrroHn-2-ones from y-oxoenamides (Scheme 45 1995TL4197, 1995 TL4201). For example, irradiation of ( )-enamide 202 produced 5-hy-droxy-3-pyrroHn-2-one 204 via the isomerized intermediate (Z)-enamide 203. An alternate approach to (Z)-enamides, and subsequendy to 5-hydroxy-3-pyrroHn-2-ones, was discovered by Nagoa and coworkers (2000TL2419). They utilized the hydrolysis of a-hydroxy-a-(p-propiola-mide)malonates to produce 5-carboethoxy-5-hydroxy-3-pyrrolin-2-ones, inhibitors of cathepsin B. 

One of the oldest reports of a synthesis of a highly substituted 3-pyrrolin-2-one involved a type e cyclization. Bashour and Lindwall treated y-oxo-P-hydroxycarboxamide 205 with HCl and obtained a product presumed to be 5-hydroxy-3-pyrrolin-2-one 206 (Scheme 46 1935JA178). Given the similarity of reactions that have been reported since then (e.g.. Scheme 42), this probably was the correct structural assignment. Moon later reported a synthesis of 4-acyl-3-pyrrolin-2-ones via thermal cyclization of y-ketocar-boxamides (1977JOC2219). 

Quai and coworkers utilized a [4+1] cycloaddition with isocyanide to prepare highly substituted 3-pyrroHn-2-ones (Scheme 60 2004TL1413). Treatment of benzylidene-1,3-diketone 243 with tert-butyl isocyanide (244) gives 5-hydroxy-3-pyrrolin-2-ones 246 (Scheme 24). The authors propose an oxidative rearrangement mechanism for the conversion of initial adduct 245 to the observed product 246. Similar reactions have been reported by others in the synthesis of 3-aryl-4-carboethoxy-5-hydroxy-3-pyrrolin-2-ones (2007T8987) and 3,5-diaryl-5-hydroxy-3-pyrrolin-2-ones (2007TL8056). 

Rosas and coworkers developed two related approaches to 3-pyrrolin-2-ones that employ metal-mediated cyanation reactions of ynones (19970M2726, 2005OM4893). Regarding the first approach, treatment of ynone 339 with potassium cyanide in the presence of a Ni catalyst gives 5-hydroxy-3-pyrrolin-2-one 341 via cyanide-derived Michael adduct 340 (Scheme 87 19970M2726). 

A novel three-component reaction sequence leading to 5-hydroxy-3-pyrrolin-2-ones has been reported by Liang and coworkers (Scheme 108 2007T8987). Mixing arylaldehyde 410, 2,4-pentanedione (361), and cyclohexyl isocyanide (260) with piperidine gives the 3-pyrrolin-2-one 411. The reaction proceeds via the formation of2-aminofuran intermediates followed by a Dimroth-type rearrangement to the corresponding 3-pyrrolin-2-ones. 

Bonete and Najera prepared a 5-hydroxy-3-pyrrolin-2-one via a DBU-mediated elimination of a tosyl group from a 3-tosylpyrrohdin-2-one (1995T2763). 

In a similar fashion, 5-alkoxy-butyrolactones can undergo addition and elimination to give substituted 3-pyrrolin-2-ones. In 1973, Farina and coworkers found that 5-methoxyfuran-2-one 575 treated with aqueous ammonia gives 5-hydroxy-3-pyrrolin-2-one 576 (Scheme 165 1973S167). Ten years later. Farina and coworkers showed that primary amines, such as benzylamine, give 5-hydroxy-3-pyrrolin-2-ones when stirred with 2-chloro-5-methoxyfuran-2-one (1983H(20)1761). The transformation... 

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