Indium-Catalyzed Regioselective β-Alkylation of Pyrroles with Carbonyl Compounds and Hydrosilanes and Its Application to Construction of a Quaternary Carbon Center with a β-Pyrrolyl Group

Abstract

Treatment of N-substituted pyrroles with carbonyl compounds and nucleophiles under indium catalysis was found to be a promising method for preparing β-alkylpyrroles without contamination by α-alkylpyrroles. With this methodology, a variety of alkyl groups, which are primary, secondary, and tertiary as well as cyclic and functionalized types, can be introduced in place onto the pyrrole ring. The simplicity performable as a catalytic one-step process is one of the important features of this reaction. The substituent on the nitrogen atom of the product β-alkylpyrrole can be removed easily by literature procedures. Therefore, the indium-catalyzed β-alkylation plus the N-deprotection is a powerful system for all six variations, which are N-substituted and N-unsubstituted β-alkylpyrroles having primary, secondary, and tertiary alkyl groups. Our method is applicable to synthesizing, albeit in two steps, β-pyrrolyl-group-connected unsymmetrical tetraarylmethanes that have not been addressed thus far. Mechanistic studies showed the following three aspects: (1) dipyrrolylalkanes produced in situ from the pyrrole and carbonyl compound are key intermediates, (2) the selective β-alkylation is attributed to the selective elimination of an α-pyrrolyl group from the dipyrrolylalkane intermediates, and (3) the indium Lewis acid catalyst is indispensable for the progress of both stages.

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…Mechanistic invetigations demonstrated the subsequent three perspectives: (1) dipyrrolylalkanes delivered in situ from the pyrrole and carbonyl compound are chief intermediates, (2) the selective β‐alkylation is ascribed to the selective removal of α‐pyrrolyl group from the dipyrrolyl alkane intermediates, and (3) the indium Lewis acid catalyst is irreplaceable for the advancement of both the steps [115] …”

A series of (E)-5-(arylideneamino)-1-tert-butyl-1H-pyrrole-3-carbonitriles and their reduction products to secondary amines: syntheses and X-ray structural studies

“…The wide range of biological properties displayed by the pyrrole moiety has attracted considerable interest in the field of drug discovery and in the pharmaceutical industry. For example, Atorvastatin (marketed by Pfizer as Lipitor 1 ) is a blockbuster drug widely used as a cholesterol-lowering agent, Zomepirac is an effective nonsteroidal anti-inflammatory drug and Sunitinib is used as a multitargeted receptor tyrosine kinase inhibitor for the treatment of renal cancer (Khajuria et al, 2016;Ye et al, 2017;Nomiyama et al, 2017). While a plethora of methods for the synthesis of this scaffold have been developed, there still remains a great need to find noncatalytic eco-compatible and efficient methodologies for the synthesis of functionalized pyrroles from inexpensive and available starting materials, as well as their use as building blocks for the preparation of new pyrrole-fused heterocycles (Esté vez et al, 2014;Mohamed & Fatahala, 2014).…”

Indium-Catalyzed Annulation of o-Acylanilines with Alkoxyheteroarenes: Synthesis of Heteroaryl[b]quinolines and Subsequent Transformation to Cryptolepine Derivatives

“…On the other hand, we have recently reported a new C(heteroaryl)–N bond-forming reaction by reacting electron-rich methoxyheteroarenes with amines via a nucleophilic aromatic substitution (S N Ar) reaction [ 54 ]. In addition to this, we have also developed several new C(heteroaryl)–C bond-forming reactions by reacting alkynes [ 55 , 56 , 57 ] or carbonyl compounds [ 58 , 59 , 60 ] with heteroarenes. All of these reactions are effectively catalyzed by a salt of an indium(III) Lewis acid, which has been also employed for various organic transformations by other research groups [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”