A New Method for the Preparation of 2-Thio Substituted Furans by Methylsulfanylation of γ-Dithiane Carbonyl Compounds

Abstract

Several related methods for the preparation of differentially substituted 2-thiofurans are described. The general procedure involves the formation of a thionium ion from a gamma-dithianyl substituted carbonyl compound followed by cyclization of this reactive intermediate onto the tethered carbonyl group. Two methods for thionium ion generation were explored. One of these involved an acid-catalyzed reaction of beta-ketenedithioacetals, prepared from the condensation of 2,2-bis(methylsulfanyl)acetaldehyde with a variety of ketones. Cyclization followed by loss of methane thiol gave 2-thiofurans 17, 18 and 23, 24 in 70-90% yield. Attempts to prepare 5-heteroatom substituted 2-thiofurans from the corresponding beta-ketenedithioacetal amides or esters were unsuccessful, leading to 1,2-thio rearranged products. A more successful route involved the reaction of beta-acetoxy-gamma-thianyl carbonyl compounds with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). Treatment of the dithiane with this reagent resulted in the smooth generation of a thionium ion. Cyclization followed by loss of acetic acid afforded thiofurans 17, 18, 23, 47-49, 51, and 61-64 in 40-100% yield. The N-butenyl substituted thioamido furan furnished a rearranged hexahydropyrroloquinolin-2-one in high yield when heated at 110 degrees C.

Recent developments of ketene dithioacetal chemistry

“…For example, intramolecular annulation of a-carbamoyl ketene dithioacetals via PIFA-mediated N-S bond formation to give substituted isothiazol-3(2H)-ones (PIFA: phenyliodine(III) bis(trifluoroacetate)), 202 synthesis of 2-benzylthio-5-phenyl-3,4-disubstituted thiophenes through intramolecular condensation of a-oxo ketene dibenzylthioacetals, 203 synthesis of N-aryl-substituted 3,4-dihydro-2-pyridones from TiCl 4 -Et 3 N promoted cyclization of 2-(2-acetyl-1-methyl-3-oxobutyl)-N-aryl-3,3-bis(ethylthio)acrylamides, 204 and the synthesis of 2,3,5-trisubstituted furans 367 from a-formyl ketene dithioacetals 77 (Scheme 28) via Wittig reaction (to give 366) and subsequent NBS-mediated cyclization (Scheme 95, NBS: N-bromosuccinimide) are known. 140,205,206…”

“…257 Later, they developed a general procedure for the synthesis of 2-thio substituted furans by using DMTSF-mediated cyclization (DMTSF: dimethyl-(methylthio)sulfonium tetrafluoroborate) via a thionium ion intermediate. 81,206,[258][259][260] Such a strategy was successfully used for the total synthesis of asteriscunolide D. 258 In a recent research focusing on the development of a new domino reactions based on methyl isocyanides 18,151,152,[261][262][263][264][265] in our lab, it was found that fused pyrroles 267 (Scheme 75) 151 and fused oxazolines 274 (Scheme 76) 152 could be, respectively, obtained from the reaction of a-alkenoyl ketene dithioacetals 265a with tosylmethyl isocyanides (TosMICs) and ethyl isocyanoacetate in a single step (Fig. 13).…”

Linked Pummerer-Mannich Ion Cyclizations for Heterocyclic Chemistry

“…N-Acylation at nitrogen (74) followed by thionium ion gen-eration using the DMSTF reagent afforded good yields of the desired cyclic amidofurans (75). 24 Having assembled the required ring systems, the question becomes whether the IMDAF cycloaddition would work? Much to our delight, the cascade chemistry proceeded quite well (Scheme 24).…”

Total Synthesis of (−)-Preussochromone A

“…Unfortunately, subsequent glycolate aldol and related reactions did not give any desired product 17 under various (basic, Brønsted acidic, and Lewis acidic) conditions. Although (Mukaiyama-)­aldol reactions with simple α-thioaldehydes are known, most likely enolization of the aldehyde may have prevented a successful aldol reaction in our system . As aldehyde 16 did not show the desired reactivity, we examined another strategy.…”