Armitage, Georgina Kate (2017) The Zav'yalov Pyrrole Synthesis Revisited: Some Derivatives of 3-Hydroxy- and 3-Amino-Pyrroles. Doctoral thesis, University of Huddersfield.

The objective of this study was to investigate the acylative-cyclisation-decarboxylation reactions of enamino acids derived from 1,3-difunctional compounds. Remarkably little is known regarding the generality of these variants of the Zav’yalov pyrrole synthesis, despite their considerable scope for the synthesis of functionalised pyrroles.
The cyclisation of diethyl 2-(1-carboxyalkylaminomethylene)malonates provided access to a range of 5-(un)substituted-4-acetoxypyrrole-3-carboxylates. However, in some instances the corresponding 4-ethoxypyrrole-3-carboxylates also accounted for up to 20% of the reaction product. 1-Acetyl-4-ethoxy-5-ethylpyrrole-3-carboxylate was characterised by X-ray crystallography. Some of the (aminomethylene)malonates from bifunctional α-amino acids provided anomalous products. For example, the glutamine-derived enamino malonate gave a 5-acetylpyrrolidin-2-one via a Dakin-West-type reaction. The asparagine-enamino malonate cyclised to 4-acetoxy-1-acetyl-5-cyanomethylpyrrole-3-carboxylate probably via an isosuccinimide intermediate. Several mechanisms for the formation of the pyrrole products have been discussed. A 13C-labelling experiment confirmed that the carboxyl function in the starting material is not incorporated in the product. Evidence for the involvement of a 1,3-oxazolium-5-olate (münchnone) accrued from cyclisation of diethyl 2-(1-carboxymethylaminomethylene)malonate with Ac2O in the presence of dimethyl acetylenedicarboxylate which provided a novel 1-alkenylpyrrole, characterised by X-ray crystallography. An alternative pathway supervenes in the Zav’yalov reaction when α,α-disubstitution of the amino acid prevents münchnone and thus pyrrole formation to afford an N-alkenyloxazolidin-5-one.
Novel ethyl 4-(di)acetamido-5-(un)substituted-pyrrole-3-carboxylates and the corresponding 3-carbonitriles have been obtained in good yields via the cyclisation of ethyl 2-(1-carboxyalkylaminomethylene)cyanoacetates and (1-carboxyalkylaminomethylene)malononitriles respectively. Evidence for a different cyclisation pathway, in the former, involving intramolecular acylation of the enaminonitrile moiety was observed. Thus, ethyl (2R*,3S*)-1-acetyl-3-cyano-2,4-diacetoxy-5-methyl-2,3-dihydropyrrole-3-carboxylate was characterised by X-ray crystallography.
A wide range of novel 2-alkanoyl- and 2-aroyl-3-(1-carboxyalkylamino)acrylonitriles has been obtained via aminomethylenation of β-ketonitriles. The products from their cyclisations (Ac2O-NEt3) were largely independent of the nature of the acyl group but determined by the substituent in the α-amino acid moiety. The 3-(1-carboxy-1-phenylmethylamino)acrylonitriles provided mixtures of 3-acyl-4-(di)acetamido-5-phenylpyrroles in which the 4-acetamido- derivatives predominated. Contrasting behaviour was displayed by the 3-(1-carboxyalkylamino)acrylonitriles derived from alanine, 2-aminobutyric acid and valine in which the cyclisation followed an unexpected course, via enaminone acylation, to the novel 4-acetoxy-1-acetyl-5-alkylpyrrole-3-carbonitriles in high yields. The acylative cyclisation of the 2-acyl-3-(1-carboxymethylamino)acrylonitriles furnished mixtures of pyrroles. In two cases, 3-acetamido-6-aryl-5-cyanopyran-2-ones, generated by a unique cyclisation pathway were isolated. The structure of the 6-phenyl- derivative was confirmed by unambiguous synthesis. The synthesis and acylative cyclisation of (Z)-2-benzoyl-3-(1-carboxyalkylamino)crotononitriles was investigated. Whereas the 3-(1-carboxyethylamino)- derivative provided 4-acetoxy-1-acetyl-2,5-dimethylpyrrole-3-carbonitrile exclusively, the 3-(1-carboxy-1-phenylmethylamino)crotononitrile afforded a mixture of pyrroles. A remarkable minor component was characterised as 4-acetoxy-1-benzoyl-2-methyl-5-phenylpyrrole-3-carbonitrile, the result of sequential [1,5]-benzoyl migrations of a 3H-pyrrole intermediate.
The acylative cyclisation of 3-(1-carboxyalkylamino)-2-tosylacrylonitriles provides access to hitherto unknown 3-diacetamido-4-tosyl- and 3-acetamido-4-tosylpyrroles. Cyclisation of 2-(1-carboxyalkylaminomethylene)dibenzoylmethanes offers an excellent, complementary approach to access 5-(un)substituted-3-benzoyl-4-phenylpyrroles, to the existing tosylmethyl isocyanide-based protocols.

FINAL THESIS - Armitage.pdf - Accepted Version
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