Synthesis of Substituted Benzofurans by the Tandem One-Pot Intramolecular Carbolithiation–Cyclization–Substitution Sequence

Abstract

A convenient methodology for the synthesis of 3-sustituted-2,3-dihydrobenzofurans was developed based on the tandem intramolecular carbolithiation–cyclization of 2-bromophenyl-3-phenylprop-2-enyl ether, followed by trapping of the new lithiated intermediate by suitable electrophiles. Several electrophiles were tested, affording good to excellent yields. Alkyl bromides show better results than chlorides and when doubly halogenated alkyl chains are used as electrophiles only one position reacts, affording substituted benzofurans conveniently functionalized to undergo further reactions. The performance of both butyl and phenyllithium as lithiating agents was examined.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

GRAPHICAL ABSTRACT

Keywords:

• Alkylation
• benzofurans
• intramolecular carbocyclization
• intramolecular carbolithiation
• organolithium

ACKNOWLEDGMENTS

The authors are grateful to Graciela Garcia. The financial support from the Agency for the Promotion of Science and Technology (ANPCyT) and the National Research Council of Argentine (CONICET) is gratefully acknowledged.

Notes

^a 1.5 equivalent BuLi was added to a solution of 1 at −85°C in THF. After 5 min the E was added. The reaction mixture was warmed up to rt, and then it was quenched with MeOH after 5 min.

^b Relative yields determined by NMR and GC.

^c In all cases 8 eq. of E were used.

^d dr, determined by NMR.

^a Reactions were carried out under the same conditions describe for BuLi, adding different equivalents of PhLi according to the [PhLi]:[1] ratio given in the table.

^b Relative yields determined by NMR and GC.

^c In all cases 8 equivalents of E were used.

^d dr, determined by NMR.