Pyrroles, fused 2-hydroxy

Ohta has developed a facile and efficient synthesis of pyrroles 42 that involves the Pd-catalyzed oxidative cyclization of hydroxy enamines such as 41 [41]. Fused pyrroles 43 and 44 were also synthesized in similar fashion. 

Unsubstituted acetone resists condensation with 2,3-diformylthiophene (71BSF1437) but, surprisingly, reacts with 3,4-diformylfuran, -thiophene, and -pyrrole or 1,2-diformylferrocene (Table II). The reactivity of hydroxy-acetone allows the preparation of heterocycle-fused tropolones. 

Lactonization of the suitable hydroxy acids or their derivatives is the most common synthetic method for benzoxepinenones with fused pyrrole rings. Therefore, reduction of the formyl group in the ester aldehyde 121 with sodium borohydride gives a mixture of alcohol 122 (80% yield) and lactone 123 (19%). Further heating of the open-chain product 122 in refluxing ethanol affords cyclic lactone 123 quantitatively (Scheme 25 (1998T11079)). 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

Equilibrium and rate constants for the keto-enol tautomerization of hydroxy heterocycles are summarized in Table 38 <1986TL3275>. The pyrroles ketonize (i.e., 226 — 230) substantially faster (103-104 times) than their sulfur or oxygen analogues, and still faster than the benzo-fused systems (indole, benzofuran, and benzothiophene). 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

A new bicyclic betaine, a pyrrolo[l,2-.7 [l,2,4]triazin-2-ium -olate 1347, was prepared by the thermolysis of a ring-expansion reaction product 1346, 2,3-di(/-butyl)-l-hydroxy-2,3-dihydropyrrolo[l,2-.7 [l,2,4]triazin-4(17/)-one, of 1,2-di(/-butyl)-l,2-diaziran-3-one 1345 with 177-pyrrole-2-carbaldehyde (Scheme 256) <1995MI1>. Its cyclization reaction with a dipolarophile such as dimethyl 2-butynedioate leads to a fused ring-enlarged compound, a triazocinone derivative 1348 in rather low yield. Heating a solution of triazocine 1348 in benzene- 6 in an NMR tube at 140 °C for 0.5 h leads to its thermal transformation into compound 1349 in 21% yield via skeletal isomerization <1999T13703>. 

When phenyl glycine ortho-caxhoxyMc acid is fused with potassium hydroxide it first loses water yielding an acid, indoi llic acid, and this loses carbon dioxide yielding indoxyl. In indoxyl the hydroxyl group is in the 3-position while in the isomeric oxindole it is in the 2-position. All of these comp>ounds are thus condensed hetero-cyclic compounds of a benzene ring and a pyrrole ring. Indole is the mother substance and the others are hydroxy or ketone derivatives. 

Indolizines (including 2-hydroxy derivatives) may be synthesized from 2-bromo(or chloro)pyridinium salts (review [1870]) and -ketoesters in the presence of DBU (review [3364]) [3277]). A fused pyrrole ring is formed in high yield when an V-(2-bromoallyl)- or -chloroallyl-arylamine is heated with meth-anolic boron trifluoride or PPA isotopic experiments show that the reaction... 

Acid-catalysed elimination of water from a side-chain hydroxy and ring-NH functions leads to the formation of a C—N bond of a fused pyrrole. 

Similarly. palladium(II)/copper(II)-catalyzed intramolecular aminocarbonylation of A-protected 3-hydroxy-4-pentenamines 6 exclusively leads to ri.s-fused hexahydro-2-oxo-2f/-furo[3,2- >]pyrroles 7 in high yield1 16. As an A-protecting group, urea is the most reactive and versatile A-nucleophile. Carbamates are less reactive, but still better than sulfonamides. The diastereose-lectivity of the cyclization is dependent on the. V-protccting group, the solvent (protic better than aprotic) and the electrophile. 

Sarkar and Mukhopadhyay have developed a three-component green methodology to synthesize ethyl/methyl 4-hydroxy-5-oxo-l,2-diaryl-2,5-dihydro-lH-pyrrole-3-carboxylates under admicellar catalysis by Ti02 nanoparticles at room temperature [59]. The catalyst in aqueous CTAB solution promotes the formation of admicelles, and the reaction occurs in admicellar environment. A number of aromatic aldehydes 51, amines 9, and diethyl/dimethyl acetylene dicarboxylate (DEAD/DMAD, 70) react to give the products 71 in good yields (Scheme 23). In this reaction, aldehydes have also been replaced with isatin 55 to give spiro-fused products. 

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