Efficient Synthesis of Substituted Tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones by a Double Annulation Strategy from Dialkenoylketene Dithioacetals

Abstract

E f f i c i e n t S y n t h e s i s o f S u b s t i t u t e d T e t r a h y d r o t h i o p y r a n o [ 2 , 3 -b ] t h i o p y r a n -4 , 5 -d i o n e sAbstract: An efficient synthetic procedure for substituted 2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones by a double annulation strategy is described. The ring systems are made in good yields from readily available dialkenoylketene dithioacetals in the presence of either sodium sulfide nonahydrate/N,N-dimethylformamide (DMF) or a sodium hydride/DMF/amine system.Thiopyrones have emerged as key units in medicinal chemistry and versatile intermediates in organic synthesis. 1 As representatives of this kind of sulfur-containing heterocycle, 2,3-dihydrothiopyran-4-ones have been used in the synthesis of tetrahydrodicranenone B, 2 pheromones, 3 thromboxanes, 4 cyclopentanoids, 5 and related natural products. A variety of synthetic procedures are readily available for the preparation of 2,3-dihydrothiopyran-4-ones, including (i) cycloaddition of structurally appropriate acetylenic/divinyl ketones with hydrogen sulfide, 3,6 (ii) intramolecular Michael addition of a thiolate to an a,b-unsaturated carbonyl group, 7 (iii) DielsAlder cycloadditions involving thiophosgene and donorsubstituted thioaldehydes, 8,9 (iv) conjugate additions to thiopyran-4-ones or oxidation of tetrahydrothiopyran-4-ones with N-chlorosuccinimide (NCS), 2,5d and (v) dimsyl anion (DMSO anion) mediated tandem fragmentation-cyclization reactions of alkenoyl cyclic ketene dithioacetals. 10 Nevertheless, it is still of continued interest and great importance to explore novel and efficient synthetic approaches to six-membered thia-heterocycles, especially methods with broad general applicability to achieve more flexible substitution patterns.During the course of our studies on the chemistry of aoxo-substituted ketene dithioacetals, 11,12 we noted that the readily available alkenoylketene dithioacetals showed promising structural features as novel organic intermediates in annulation reactions. Accordingly, new synthetic strategies were developed for the construction of highly substituted phenols and six-membered aza-and thiaheterocycles, relying on the use of alkenoylketene dithioacetals as five-carbon 1,5-dielectrophilic species in formal [5+1] annulations with various carbon, nitrogen, and sulfur nucleophiles, respectively. 13 Considering the important synthetic utility of alkenoylketene dithioacetals, we recently investigated the aldol condensation reaction of 3-(1,3-dithiolan-2-ylidene)pentane-2,4-dione with various selected aromatic aldehydes in water and successfully obtained the symmetric and unsymmetrical double condensed products, dialkenoylketene dithioacetals. 14 To explore the synthetic potential of the easily available intermediates, dialkenoylketene dithioacetals, in our ongoing research, efficient synthesis of substituted 2,3,6,7-tetrahydrothiopyrano[2,3-b]thiopyran-4,5-diones has been achieved in good yields by treatment of dialkenoylketene dithioacetals 3 either with sodium sulfide...

A Facile and Divergent Synthesis of Substituted Pyridine-2,4(1H,3H)-diones and 4H-Thiopyran-4-ones from α-Alkenoyl-α-carbamoyl Ketene-S,S-acetals

“…Considering the synthetic importance of α-alkenoyl ketene-S,S-acetals, we recently investigated the aldol condensation reaction of 3-(1,3-dithiolan-2-ylidene)pentane-2,4-dione in water and obtained both mono-and double condensed products, [10] which were in turn further used for the synthesis of thiopyrano [2,3-b]thiopyran-4,5-diones via a double formal [5 + 1] annulation. [11] In connection with our previous work and our continuing interest in the synthesis of valuable heterocycles, we synthesized a series of α-dimethylaminopropenoyl-α-carbamoyl ketene-S,S-acetals, and examined their reaction behaviour under different conditions. As a result, we achieved a facile and divergent synthesis of substituted pyridine-2,4(1H,3H)-diones and 4H-thiopyran-4-ones from readily available α-oxo ketene-S,S-acetals.…”

[4+2] Annulation – Convenient Synthesis of Substituted Dihydropyranones in Aqueous Media

“…[14] Considering the important synthetic utility of α-alkenoyl ketene S,S-acetals, we recently investigated the aldol condensation reaction of 3-(1,3-dithiolan-2-ylidene)pentane-2,4-dione in water and obtained both mono-and double-condensed products, [15] which were further used for the synthesis of thiopyrano [2,3-b]thiopyran-4,5-diones by a double formal [5+1] annulation. [16] In connection with our previous work and our continuing interest in the synthesis of valuable heterocycles, we examined the aldol reactions of α-oxo ketene S,S-acetals 1 with aldehydes 2 in aqueous media. As a result, we achieved a convenient one-pot synthesis of substituted dihydropyranones by a base-promoted formal [4+2] annulation of 1 with 2 in the presence of NaOH in water.…”

[5+1]-Annulation Strategy Based on Alkenoyl Ketene Dithioacetals and Analogues

“…in high yields (Scheme 17) 26. This reaction provides an alternative method to the [5C+1S] annulation using the easily available alkenoyl cyclic ketene dithioacetals as the 1,5-bielectrophilic components.Divinyl ketones are typically associated with the Nazarov and related reactions.…”