Pyrrole versus quinoline formation in the palladium catalyzed reaction of 2-alkynyl-3-bromothiophenes and 2-alkynyl-3-bromofurans with anilines. A combined experimental and computational study

Abstract

Benzofuroquinolines were prepared by a new type of Pd catalyzed annulation reaction. In the first step, 2-alkynyl-3-bromobenzofurans were prepared by Sonogashira reactions of 2,3-dibromobenzofuran. Their Pd catalyzed reaction with electron-rich anilines afforded benzofuroquinolines by a domino C-N coupling/annulation process. This reaction proceeds as a C,N-cyclization via the nitrogen atom and the ortho-carbon of the aniline. Similarly, furoquinolines were prepared from 2,3-dibromofuran. In contrast, benzofuropyrroles and furopyrroles were formed by N,N-cyclization when electron-poor anilines were used. Earlier, we reported results related to the thiophene and benzothiophene series. Quinolines were formed from 2,3-dibromobenzothiophene when electron rich anilines were used. In contrast, pyrroles were obtained in the case of electron-poor anilines. On the other hand, pyrroles were generally obtained, not depending on the type of aniline, when 2,3-dibromothiophene was employed as the starting material. In the present article, a detailed DFT study related to the mechanism (quinoline versus pyrrole formation) is reported which provides a rationalization of the selectivities observed for the furan, benzofuran, thiophene and benzothiophene series and for the different selectivities observed for electron-rich and -poor anilines.

Computational Studies of Synthetically Relevant Homogeneous Organometallic Catalysis Involving Ni, Pd, Ir, and Rh: An Overview of Commonly Employed DFT Methods and Mechanistic Insights

“…In even more challenging scenarios, the preferred mechanism may depend on reaction conditions, ligands, and additives . While experimental chemistry can give sufficient insights, often the interpretation of these results may end up being inconclusive. , In such situations, turning to computational chemistry may allow to gain greater understanding of a specific chemical problem. − More recently, many studies have emerged where computational chemistry has given new insight even before any experiments have been conducted . In recent years numerous reviews have been published that cover the contributions of computational chemistry to palladium catalysis.…”

Synthesis of Nitrogen Heterocycles by Domino C–N Coupling/Hydroamination Reactions

“…The Sonogashira reaction of 2,3-dibromofuran ( 5 ) with arylalkynes afforded 2-alkynyl-3-bromofurans 6a – c in good yields (Scheme 3 ). 10 The cyclization proceeded similarly to the corresponding benzofuran derivatives 2a – c and afforded furo[3,2- b ]quinolines 7a – f in case of electron-rich anilines, such as unsubstituted aniline, 4-toluidine, and 4-anisidine (Scheme 3 ). In case of electron-poor 4-nitroaniline, furo[3,2- b ]pyrrole 8 was obtained.…”

“…The Sonogashira reaction of 2,3-dibromobenzofuran ( 1 ) with arylalkynes afforded 2-alkynyl-3-bromobenzofurans 2a – c in good yields (Scheme 2 ). 10 Interestingly, Ghazwan A. Salman and Munawar Hussain found that the subsequent Pd-catalyzed domino C–N coupling/hydroamination reaction of 2a – c with a variety of anilines took an unexpected path. In most cases, benzofuro[3,2- b ]quinolines 3a – u rather than the expected benzofuro[3,2- b ]pyrroles were obtained.…”

Palladium-Catalyzed Transformations of Salvinorin A, a Neoclerodane Diterpene from Salvia divinorum

“…Employing conditions previously used for Sonogashira couplings on bromofurans, 16 several alkynyl substitutions were synthesized (Table 3). Despite an increase in the reaction temperature and large excess of base, no epimerization was observed.…”

“…To extend the method from sp 2 - and sp 3 -hybridized substitutions to alkyne substitutents, Sonogashira couplings were also investigated. Employing conditions previously used for Sonogashira couplings on bromofurans, several alkynyl substitutions were synthesized (Table ). Despite an increase in the reaction temperature and large excess of base, no epimerization was observed.…”