Titanocene(II)-Promoted Intramolecular Olefination of Thiol Esters: A New Route to Substituted 2,3-Dihydrothiophenes

Abstract

The treatment of S- [3,3-bis(phenylthio)propyl] thioalkanoates with the low-valent titanium species Cp 2 Ti[P(OEt) 3 ] 2 in THF produced 5-substituted 2,3-dihydrothiophenes in good yields. These thiophene derivatives were found to be susceptible to photoirradiation and easily isomerized into 2-alkylidenetetrahydrothiophenes.2,3-Dihydrothiophene is one of the most fundamental sulfur-containing heterocycles and is employed for protection of hydroxy group, 1 the synthesis of certain 2,3-dispirocyclohexanones containing tetrahydrothiophene rings, 2 and the preparation of 4-thio-1,2-dideoxy-ribose. 3 The chemistry of this reactive compound and its derivatives is, however, relatively unexplored. This is apparently due to the lack of appropriate method for their preparation, and the instability of the compounds. As for the preparation of unsubstituted 2,3-dihydrothiophene, several methods including the thermal decomposition of 2-acyloxytetrahydrothiophene have been developed. 1,4 Although Paquette et al. reported the preparation of 5-substituted derivatives by the reaction of 5-lithio-2,3-dihydrothiophene with aldehydes, 2 the yields of adducts were only moderate. The improved procedure using 5-tributylstannyl-2,3-dihydrothiophene was reported by O'Neil and co-workers. 3 However the preparation of the requisite starting material is rather complicated.Recently we developed a new method for the carbonyl olefination using a thioacetal-Cp 2 Ti[P(OEt) 3 ] 2 system. We tentatively assume that the key intermediate of this transformation is a titanium-carbene complex. 5 Then we have investigated the preparation of 5-substituted 2,3-dihydrothiophenes 1 by the intramolecular carbonyl olefination of thiol esters 2 outlined in Scheme 1. Scheme 1The starting thiol esters possessing a diphenyl thioacetal moiety 2 were easily prepared by the reaction of the corresponding acyl chlorides with 3,3-bis(phenylthio) propanethiol 4 or 4,4-bis(phenylthio)-2-butanethiol 5 (1.1 equiv/triethylamine; 1.1 equiv/THF/0°C-room temperature/15-30 min) (2a; quant, 2b; 92%, 2c; 82%, 2d; 85%, 2e; 88%, 2f; 82%, 2g; 87%, 2h; 78%). The thiol 4 was prepared from commercially available 3,3-dimethoxypropionic acid methyl ester (6) (Scheme 2). The ester 6 was treated with thiophenol (2 equiv) in the presence of BF 3 ◊OEt 2 (2 equiv) in CHCl 3 (0°C-room temperature/1 h) to produce the thioacetal which was then reduced with lithium aluminum hydride (0.5 equiv/THF/ 0°C/1 h) to give the alcohol 7. The transformation of 7 to the tosylate (TsCl; 1.1 equiv/pyridine/0°C/overnight) followed by the reaction with thiourea (1.5 equiv/methanol/ reflux/3 h) and the hydrolysis of the resulting S-thiouronium salt (10% NH 4 OH/reflux/1.5 h) gave the thiol 4. The secondary thiol 5 was prepared according to the method reported by Fochi et al. 6 using the tosylate prepared from the alcohol 8 (TsCl; 1.1 equiv/pyridine/0°C-room temperature/overnight). The alcohol 8 was obtained by the reaction of bis(phenylthio)methyllithium with propylene oxide (1 equiv/THF/0°C/15 min) (Scheme 3).

Titanium reagents for the alkylidenation of carboxylic acid and carbonic acid derivatives

“…of low-valent titanium complex 83 in THF produced 5-substituted 2,3-dihydrothiophenes. 96 Yields were best when there was a branch α to the carbonyl group as in thioester 107 (Scheme 59).…”

Unusual formation of a thiacyclopent‐2‐ene by the reaction of 4,4′‐dimethoxythiobenzophenone with tetracyanoethylene

“…Thiacyclopent-2-enes were previously prepared in many ways: for example, in five steps from ␣-acetyl c-lactones [7], in five steps from cysteine [8], by the partial hydrogenolysis of thiophene [9], by Michael reaction of a sulfonium ylide with an unsaturated thioamide [10], by a free radical intramolecular cyclization of enynes [11], and by the the reaction of S-3,3-bis(phenylthio)propylthioalkanoates with a low-valent titanium species [12]. The present result offers the formation of a thiacyclopent-2-ene from TCNE by novel types of [2 ‫ם‬ 2] and [4 ‫ם‬ 2] sequential cycloadditions.…”

The Society for Cardiovascular Angiography and Interventions' 27th Annual Scientific Sessions

“…One of the characteristic features of our method is that the starting materials, thioacetals, are typical protected aldehydes and are fairly stable under either acidic or basic conditions. Therefore, the carboxylic acid derivatives having a thioacetal moiety 15 were readily synthesized using various starting materials and reactions and subjected to intramolecular carbonyl olefination to produce a variety of unsaturated carbo‐ and heterocycles 16 (Scheme ) 15,21. The intramolecular reaction of 15 was found to be extremely useful for the construction of seven‐ to nine‐membered medium rings.…”

“…The intramolecular reaction of 15 was found to be extremely useful for the construction of seven‐ to nine‐membered medium rings. In the case of amides, however, the initially formed cyclic enamines were reduced to cyclic amines depending on the substrate structure and workup conditions 15,21d. This new intramolecular carbonyl olefination was employed in the synthesis of ciguatoxin by Hirama et al22…”