A Novel Assembly of Substituted Pyrroles by Acid‐Catalyzed Sequential Three‐Component Reaction of Amines, Alkynoates, and 1,2‐Diaza‐1,3‐dienes

Abstract

A novel protocol for the assembly of polysubstituted pyrroles has been developed through the acid-catalyzed, sequential three-component reaction of primary aliphatic amines, alkynoates and 1,2-diaza-1,3-dienes (DDs). This methodology proceeds with complete chemo-/regioselectivity involving first formation of an enamino ester intermediate, in situ Michael addition with azo-ene compounds and subsequent intramolecular ring closure.

One‐Pot Synthesis of Biheterocycles Based on Indole and Azole Scaffolds Using Tryptamines and 1,2‐Diaza‐1,3‐dienes as Building Blocks

“…Encouraged by the successful incorporation of DDs 2 as annulation reaction partners in the 1,5‐electrocyclization, we next explored the possibility of assembling a pyrrole nucleus instead of an imidazole unit. Thus, treatment of Tryps 1a , 1d – 1f , and 1h with alkynoates 5a and 5b in CH 2 Cl 2 , followed by addition of DDs 2a and 2b in toluene at reflux with acid catalysis gave indole–pyrroles 6 (Table ) . Commercially available tryptamine ( 1a ) or easily prepared bis(indolyl)ethanamino derivatives 1d – 1f , and 1h could be successfully used together with either methyl or ethylpropiolate 5a and 5b and DDs 2a and 2b following the procedure described above.…”

“…The mechanism for the formation of the indole–pyrrole system probably involves the initial formation of a tryptamine‐derived enamino ester through conjugate addition of Tryp to the alkynoate, followed by in‐situ Michael addition with the 1,2‐diaza‐1,3‐diene compound, and subsequent intramolecular ring closure with loss of carbazate …”

“…Thus, treatment of Tryps 1a, 1d-1f, and 1h with alkynoates 5a and 5b in CH 2 Cl 2 , followed by addition of DDs 2a and 2b in toluene at reflux with acid catalysis gave indole-pyrroles 6 ( Table 2). [17] Commercially available tryptamine (1a) or easily prepared bis(indolyl)ethanamino derivatives 1d-1f, and 1h could be successfully used together with either methyl or ethylpropiolate 5a and 5b and DDs 2a and 2b following the procedure described above. The mechanism for the formation of the indole-pyrrole system probably involves the initial formation of a tryptaminederived enamino ester through conjugate addition of Tryp to the alkynoate, followed by in-situ Michael addition with the 1,2diaza-1,3-diene compound, and subsequent intramolecular ring closure with loss of carbazate.…”

“…The mechanism for the formation of the indole-pyrrole system probably involves the initial formation of a tryptaminederived enamino ester through conjugate addition of Tryp to the alkynoate, followed by in-situ Michael addition with the 1,2diaza-1,3-diene compound, and subsequent intramolecular ring closure with loss of carbazate. [17] Finally, inspired by Westermann's previous study [18] on the Sakai reaction, [19] we focused on the construction of the indole-triazole structure (i. e., 8), which is a recurrent motif in pharmaceutical compounds.…”

Regioselective [1N+2C+2C] Assembly of Fully Decorated Pyrroles from Primary Amines, 1,2‐Diaza‐1,3‐dienes, and 2,3‐­Allenoates

“…In this context, the assembly of regioselectively substituted pyrroles through sequential three‐component reaction of readily available starting materials has been achieved by our research group 9. Considering the mutual reactivity of one set of reagents, the process was realized either by sequential addition of primary amines, 1,2‐diaza‐1,3‐dienes (DDs)10 and acetylenedicarboxylates,9a,9b (Scheme , Path A) or by sequential addition of primary amines, alkynoates, and DDs (Scheme , Path B) 9c. Thus, simply by changing the order of addition of the two electrophilic partners (i.e., alkynoate derivatives and DDs) it was possible to accomplish divergent regioselective synthesis of fully functionalized pyrroles.…”