Pyrrole Chemistry. XV. The Chemistry of Some 3,4-Disubstituted Pyrroles

Abstract

The syntheses of a variety of 3,4-disubstituted pyrroles including the antimitotic agent Verrucarin E are described. 3,4-Pyrroledicarboxylic esters were prepared through a Diels–Alder reaction. Partial hydrolysis of the diesters gave the 4-ester-3-acids which were modified to achieve the synthesis of a variety of unsymmetrically 3,4-disubstituted pyrroles. Raney nickel reduction of a thiolester gave hydroxymethyl under conditions which left acyl or carbalkoxy substituents unaffected. Pyrrole reactions involving carbanionic reagents are complicated by 1-proton abstraction. Therefore, when necessary, the nitrogen was protected by an N-benzyloxymethyl substituent which can be cleaved to the N-hydroxymethyl derivative by aluminum chloride or by hydrogenolysis. Subsequent treatment with benzyltrimethylammonium hydroxide gave back the pyrrole.

Chemistry of 7-Azabicyclo[2.2.1]hepta-2,5-dienes, 7-Azabicyclo[2.2.1]hept-2-enes, and 7-Azabicyclo[2.2.1]heptanes

“…Further decarbonylation of 59 afforded 3,4-disubstituted pyrroles which are difficult to prepare by the conventional methods. [71][72][73][74] High temperatures were often required for the retrocycloaddition reaction of the 7-azabicycloheptadienes 58. As a result, the decomposition of the diene has been a competitive pathway which has limited the scope of this method.…”

“…The thermolysis of the 7-azabicyclo[2.2.1]heptadienes 58 have been reported to undergo a retrocycloaddition reaction with loss of acetylene to furnish the pyrroles 59 (Scheme ). Further decarbonylation of 59 afforded 3,4-disubstituted pyrroles which are difficult to prepare by the conventional methods. − High temperatures were often required for the retrocycloaddition reaction of the 7-azabicycloheptadienes 58 . As a result, the decomposition of the diene has been a competitive pathway which has limited the scope of this method.…”

“…The instability of the 7-azabicyclo[2.2.1]heptadiene and 7-azabicyclo[2.2.1]heptene ring systems have been exploited as synthetic approaches for the preparation of a variety of substituted pyrroles. The [71][72][73][74] High temperatures were often required for the retrocycloaddition reaction of the 7-azabicycloheptadienes 58. As a result, the decomposition of the diene has been a competitive pathway which has limited the scope of this method.…”

Nouvelle méthode de synthèse de pyrroles sous micro-ondes

“…Les dCrivCs pyrroliques disubstituks, uniquement en positions 3 et 4, sont d'un accks difficile. On peut les prCparer 2 partir du succinate d'Cthyle (20)(21)(22), du tosylmethyl isonitrile (23)(24)(25) ou enfin par retro Diels-Alder (26)(27)(28).…”

Azanorbornadienes as Thiol-Reactive Cleavable Linkers

“…N-Acylpyrroles have long been known to participate in Diels–Alder reactions with electron-deficient dienophiles, − but no information on thiol-triggered rDA reactivity appeared in the literature until a recent report from Moreno-Vargas, Bernardes, and colleagues on the chemistry of N-Boc pyrrole adducts of tosylacetylene ( 2 , R 1 -R 4 = H, R 5 = Boc, R 5 = SO 2 p -tolyl, R 6 = H) . An important advantage to this system is the avoidance of potential furan-associated metabolic toxicity because acylpyrroles are less likely to undergo analogous P450 processing .…”