Synthesis of 2(3H)-furanones via electrophilic cyclization

Abstract

The electrophilic cyclization of functionally-substituted alkynes is a very promising route to an extraordinary range of medicinally-interesting, functionally-substituted heterocycles and carbocycles. A variety of highly substituted 2(3H)-furanones are readily prepared from 3-alkynoate esters and the corresponding acids via electrophilic cyclization. This highly efficient approach proceeds under mild conditions, tolerates various functional groups, and generally provides 2(3H)-furanones in good to excellent yields. The cyclizations of 3-alkynoate esters and the corresponding acids have been performed using an excess of the electrophile at room temperature using either methylene chloride or acetonitrile as the solvent. Successful electrophiles in this process include I 2 , ICl, and PhSeCl. The iodine functionality introduced into the heterocycle facilitates further elaboration by Pd-catalyzed chemistry. 1 GENERAL INTRODUCTION The electrophilic cyclization of functionally-substituted alkynes has proven to be a very promising route to an extraordinary range of medicinally-interesting, functionallysubstituted heterocycles and carbocycles. Previous work by our group and others has shown that iodine and other electrophiles can be used for the synthesis of benzo[b]furans, benzo[b]thiophenes, indoles, isoquinolines and a number of other heterocycles and carbocycles. This highly efficient approach to heterocycles and carbocycles proceeds under mild reaction conditions, accommodates various functional groups in the starting alkyne, and the iodo-substituted products can be further elaborated by Pd-catalyzed chemistry. Our interest in electrophilic cyclization has led us to further explore the generality of this approach for the synthesis of highly substituted 2(3H)-furanones. We have extensively studied the reaction of 3-alkynoate esters and the corresponding acids with various electrophiles and obtained highly substituted 2(3H)-furanones in fair to excellent yields. Dissertation Organization This thesis is composed of one main chapter. The chapter describes the synthesis of various 2(3H)-furanones from 3-alkynoate esters and the corresponding acids. The cyclization proceeds under relatively mild reaction conditions. Some 3-alkynoate esters give fair to good yields of 2(3H)-furanones, whereas other 3-alkynyl esters with more than one nucleophilic center failed to give the desired 2(3H)-furanones. The unsuccessful 3-alkynoate ester substrates can be easily transformed to the corresponding 3-alkynoic acids. These 3-alkynoic acids cyclize in the presence of various electrophiles to give fair to excellent

Zinc-mediated carboxylations of allylic and propargylic halides in flow: synthesis of β-lactones via subsequent bromolactonization

“…We next studied bromination of the propargylic acid 7e and allenic acid 6e (3 : 1 ratio), to determine the regioselectivity of bromolactonization. Similar transformations using iodine were previously reported by Larock, 27 with an array of substituted propargyl acids and thus our expectation was that only the propargylic acid would react. When carboxylic acids 6e and 7e were subjected to bromolactonization conditions (Scheme 2), this led to the exclusive generation of furanones 8a and 8b via the favorable 5- endo -dig cyclization in accord with results by Larock in 55% combined yield.…”

Parallel Synthesis of an Imidazole-4,5-dicarboxamide Library Bearing Amino Acid Esters and Alkanamines

“…The same information is also available for each compound at the project website [18]. Additional synthetic efforts that are part of the NIH Roadmap are now being reported [19-31]. …”