Cyclocondensation of α-Aminonitriles and Enones: A Short Access to 3,4-Dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-Trisubstituted Pyrroles

Abstract

The reaction of alpha,beta-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from alpha-substituted alpha-aminonitriles can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation.

Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones

“… a See [36]. b When repeated under identical conditions, a higher yield was obtained than reported in [36] (53%).…”

“…Typical procedure for the synthesis of cyanopyrrolines 6a–j: The cyanopyrrolines 6a – j were prepared according to an earlier publication [36]. As an illustrative example, compound 6e is prepared as follows: To a solution of ( E )-3-(2,3-dichlorophenyl)-1-phenylprop-2-en-1-one (2.20 g, 7.94 mmol, 1e ) in pyridine (40 mL) was added aminoacetonitrile hydrochloride (1.10 g, 11.76 mmol, 1.48 equiv, 2 ).…”

“…for the construction of γ-amino acids [32], pyrrolidines [33], as well as pyrroles [34–35]. If an additional conjugated double bond is present, the anions of α-(alkylideneamino)nitriles 3 can undergo an electrocyclic ring closure to furnish 3,4-dihydro-2 H -pyrrole-2-carbonitriles 6 after reprotonation [36]. If the products are devoid of an additional substituent in 2-position, the cyclocondensation can be simply effected by refluxing a mixture of the enone 1 and aminoacetonitrile hydrochloride ( 2 ) in pyridine.…”

Heterocycles from α‐Aminonitriles

“…[61] However, heating to 250 8C under microwave irradiation transforms compounds 108 to 2,4-disubstituted pyrroles 109 in a thermal de-hydrocyanation. For example, the Schiff bases obtained by condensation of aminoacetonitrile (104) with a,bunsaturated ketones 103, can be deprotonated in situ to form stabilized 2-azapentadienyl anions 106.…”

“…The products are kinetically stable against basic dehydrocyanation and can, for example, serve as starting materials for the preparation of 1,3,5-trisubstituted pyrrolizidines 110 by vinylogous addition to enones followed by reductive cyclization. [61] However, heating to 250 8C under microwave irradiation transforms compounds 108 to 2,4-disubstituted pyrroles 109 in a thermal de-hydrocyanation. [62] This represents the hitherto most efficient entry to this compound class.…”