Use of Thiazoles in the Halogen Dance Reaction:  Application to the Total Synthesis of WS75624 B

Abstract

The total synthesis of the pyridine-thiazole-containing natural product WS75624 B (1) is described. This synthesis proceeds via the Stille coupling of appropriately functionalized pyridine and thiazole components, and this paper details our studies on the use of the halogen dance reaction to prepare the desired thiazole. Various halogen dance reactions on thizoles are described, including a novel one-pot multistep reaction in which 2-bromothiazole is treated with LDA in the presence of a silyl chloride at -78 degrees C and quenched with an electrophile to provide the highly functionalized thiazole derivatives 27.

Lithiation of 2-bromo-4-(1,3-dioxolan-2-yl)-1,3-thiazole

“…For the introduction of an aldehyde group, morpholin-4-carbaldehyde was used, and N-methoxy-N-methylacetamide was used to introduce an acetyl group, which led to 2-bromo-4-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbaldehyde 4 ( [21][22][23] To confirm the structure of compounds (2-6) and to study a possibility of the Halogen Dance Reaction, we performed lithiation of 1,3-thiazole 1 in the above conditions using water as the electrophile. As a result, we obtained the starting compound 1 with a quantitative yield.…”

Polyarylated Thiazoles via a Combined Halogen Dance – Cross‐Coupling Strategy

“…Unfortunately, the introduction of bromine to obtain 4,5-dibrominated product 8b worked only in comparably moderate yields (50 %). Even by applying 1,2-dibromo-1,1,2,2-tetrachloroethane instead of Br 2 , a method successful in the oxazole series, [10] did not improve the yield (30 %). On the other hand, the introduction of tributyltin (with Bu 3 SnCl) worked well and the desired compound 8e was isolated in 65 % yield (entry 6).…”

“…HD reactions were successfully performed on a number of heterocyclic systems [8] but only recently oxazole [9] and thiazole have been added to this list. The first HD on thiazole was performed by Stangeland and Sammakia [10] and recently two more examples, from our group, were published. [11] In a very recent example, we reported preliminary data on the formation of polyhalogenated thiazoles via the HD reaction as starting materials for cross-coupling reactions.…”

Metalated heterocycles in organic synthesis: Recent applications

“…359 In addition, thiazoles stannylated at C-4 are usually obtained by sequential halogen-lithium-tin exchange, and have been used for instance in Stille couplings for the synthesis of epothilone B analogues, 360 as well as the total synthesis of the antifungal agents cystothiazoles A and B 361 and the fermentation broth metabolite WS75624 B. 362 In some cases, 4-stannylthiazoles are prepared by palladium-catalyzed cross-coupling of the corresponding bromide using bis(trimethyltin), as in the synthesis of the heterocyclic core of the GE2270 antibiotic, a Stille coupling being a key step. 363 Finally, 5-stannylated thiazoles can be prepared by direct lithiation-stannylation if a substituent blocks the 2-position, an example of their use in a Stille coupling being reported in the design of artificial nucleobases for molecular recognition.…”