Ring contraction pyrroles

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

There are several examples of the formation of pyridazines from other heterocycles, such as azirines, furans, pyrroles, isoxazoles, pyrazoles or pyrans and by ring contraction of 1,2-diazepines. Their formation is mentioned in Section 2.12.6.3.2. 

The base-promoted ring contraction of 3-bromo-2-pyrones to 2-furoic acids cf. Scheme llOd) is a well exemplified reaction 01CB1992,69JCS(C)1950,73JCS(P1)1130> which has also been applied to the obtention of benzofuran-2-carboxylic acids frorn 3-bromocoumarins 08CB830,70KGS(S2)166), Similar base treatment of 3-amino-2-pyrones provides pyrrole-2-carboxylic acids (Scheme IlOe) 75JHC129). 

Into Other Ring-Contracted Systems To Furan and Pyrrole Derivatives... 

Cold, aqueous sodium hydroxide brings about the collapse of diethyl 2,7-dimelhyl-4//-azepine-3,6-dicarboxylate (3) to the 1-substituted pyrrole 4,29 whereas with aqueous ethanolic ammonia solution ring contraction is accompanied by loss of the butenoic acid side chain and formation of ethyl 2-methylpyrrole-3-carboxylate (94% mp 77-78cC). 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

When acted upon by phosphorous acid, the polymethylenediamides (60) afford the novel diphosphonic acids (61),53 while lactams are converted into the related compounds (63).64 The pyrrol idonebis(phosphonic acid) (62) is evidently obtained by ring contraction of the acid (61 n = 2).55... 

The reaction of oxime 323 with concentrated aqueous HCl proceeded with a ring contraction and afforded pyridazine 324 as a single product (equation 140) . On the contrary, the rearrangement of pyrrol-3-one oxime in the presence of hydrazine proceeded with ring enlargement and led to l//-pyridazin-4-one oxime . ... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

Ring contraction with desulfurization occurs when the 4//-l,3-thiazines 131 are reacted with potassium /-butoxide (Scheme 7) <2004TL5913>. The bis(methoxycarbonyl)pyrroles 132 are not isolated but instead give the 4-oxo, 5 dihydro-2//-pyrrolo[3,4-c]quinolines 133 and 134. 

Boger has reported efficient total syntheses of the marine alkaloids ningalin A, lamellarin O, lukianol A, and stomiamide A each of which possess a common 3,4-diaryl-substituted pyrrole nucleus bearing 2- or 2,5-carboxylates <99JA54>. A key step in each of these syntheses utilized a zinc mediated reductive ring contraction of 1,2-diazines such as 29 to pyrrole 30, a precursor in... 

The photolytic Wolff ring contraction of diazopyridones (181) is a synthesis of pyrrole-2-carboxylic acids via carbene (182) and ketene (183) intermediates (76S754). 

For a triazepine into pyrrole ring contraction see Section 3.5.2.1. 

Several other ring contractions which lead to pyrroles are summarized in the reviews of Patterson (76S281) and Jones and Bean (B-77M130602), but none appear to have the generality or efficiency that would be required to be of broad synthetic applicability. 

Diels-Alder reactions pyrrolesThis azadiene undergoes [4 + 2] cycloaddi-non with unactivated dienophiles to form dimethyl l,2-diazine-3,6-dicarboxylates, hich are reduced by zinc in acetic acid with ring contraction to dimethyl pyrrole-1.5-dicarboxylates. 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

The photolytic Wolff ring contraction of diazopyridones 247 leads to pyrrole-2-carboxylic acids 250 via carbene 248 and ketene 249 intermediates <1976S754>. The thermolysis of 2-azidopyridine A-oxides 251 affords A-hydroxy-2-cyano-pyrroles 252 (Scheme 137) <1973JOC173> (see also Section 3.4.3.11). 

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