Metal-free addition of aliphatic carboxylic acids to cyanopropargyl alcohols: an access to new families of functionalized dihydrofurans and 3(2H)-furanones

Abstract

The metal-free Et 3 N-mediated addition of cyanopropargyl alcohols to aliphatic carboxylic acids provides for straightforward efficient access to 4-cyano-[(Z)-3-cyanomethylene]-2,3-dihydrofurans and 4-cyano-3(2H)furanones of pharmaceutical value. By comparison to analogous reactions using aromatic and heteroaromatic carboxylic acids, this synthesis is implemented under much milder conditions (room temperature vs. 100 °C and microwave assistance) to give essentially higher relative content of 2,3-dihydrofurans (2:1 assembly products).

Cyanoacetylenic Alcohols: Molecules of Interstellar Relevance in the Synthesis of Essential Heterocycles, Amino Acids, Nucleobases and Nucleosides

“…The addition of aliphatic carboxylic acids 25 to cyanoacetylenic alcohol 1 ensured the straightforward entry to 3(2H)furanones 26, 2,3-dihydrofurans 27, and keto esters 28 (Scheme 22). 37 Scheme 22 Reaction of cyanoacetylenic alcohol 1 with aliphatic carboxylic acids 25 (at 1.2:1 reactant ratio)…”

“…Then two competitive reactions take place: (i) intramolecular cyclization of intermediates 28 to 3(2H)-furanones 26 or (ii) the nucleophilic attack of carbanions C on the triple bond of the second molecule of cyanoacetyle 1 and cyclization of carbanions D to 2,3-dihydrofurans 27 (Scheme 23). 37 Template for SYNTHESIS © Thieme Stuttgart • New York 2021-04-28 page…”

“…Generally, the reaction of cyanoacetylenic alcohols with carboxylic acids is chemoselective, 37,53,54,59 though in few cases, trace amounts of side products are detected. These products were identified as 2,3-dihydrofurans, i.e.…”

“…Stepwise formation 3(2H)-furanones 26 and 2,3-dihydrofurans 27 37 It is noteworthy that functionalized derivatives of dihydrofurans are currently the focus of synthetic organic chemistry. [38][39][40] These structures are closely related to the ribose fragment of nucleosides, and consequently, to DNA and other ribose-tailored life-sustaining structures including diverse dehydro and deoxy sugars.…”

“…The addition of aliphatic carboxylic acids 25 to cyanoacetylenic alcohol 1a allowed a straightforward entry to 3(2H)-furanones 26, 2,3-dihydrofurans 27, and keto esters 28 (Scheme 22). 37 Scheme 22 Reactions of cyanoacetylenic alcohol 1a with aliphatic carboxylic acids 25 (in a 1.2:1 reactant ratio) When a two-fold molar excess of cyanoacetylenic alcohol 1a relative to carboxylic acids 25a-e was used, the product ratio changed in favor of 2,3-dihydrofurans 27a-e (27-59%), with 3(2H)-furanones 26a-e and intermediates 28b,c,e being minor products (6-20% and 6-19%, respectively). Unlike in the reactions directed to obtain 3(2H)-furanones 26a-e as the major products, these syntheses were implemented without solvent.…”