Synthesis of 2‘-Substituted 4-Bromo-2,4‘-bithiazoles by Regioselective Cross-Coupling Reactions

Abstract

The synthesis of the title compounds (1) was achieved in two steps starting from readily available 2,4-dibromothiazole (2). In a regioselective Pd(0)-catalyzed cross-coupling step, compound 2 was converted into a variety of 2-substituted 4-bromothiazoles 3 (10 examples, 65-85% yield). Alkyl and aryl zinc halides were employed as nucleophiles to introduce an alkyl or aryl substituent. The Sonogashira protocol was followed to achieve an alkynyl-debromination. Bromo-lithium exchange at carbon atom C-4 and subsequent transmetalation to zinc or tin converted the 4-bromothiazoles 3 into carbon nucleophiles which underwent a second regioselective cross-coupling with another equivalent of 2,4-dibromothiazole (2). The Negishi cross-coupling gave high yields of the 2'-alkyl-4-bromo-2,4'-bithiazoles 1a-g (88-97%). The synthesis of the 2'-phenyl- and 2'-alkynyl-4-bromo-2,4'-bithiazoles 1h-j required a Stille cross-coupling that did not proceed as smoothly as the Negishi cross-coupling (58-62% yield). The title compounds which were accessible in total yields of 38-82% are versatile building blocks for the synthesis of 2,4'-bithiazoles.

Total Synthesis of Cystothiazole A by Microwave‐Assisted Olefin Cross‐Metathesis

“…CM of 9 with 2 under our optimized conditions then furnished the key intermediate 10 in an acceptable yield of 55 %. As expected, final C-2 arylation of 10 with the known stannane 11 [8] [Pd(PPh 3 ) 4 , PhMe, reflux] proceeded smoothly and afforded cystothiazole A (1) as the only product in 83 % yield. In both cases the spectroscopic and physical data of 1 are identical with those reported for the natural product {[α] D 20 = +110 (c = 0.5, CHCl 3 ); ref.…”

“…Accordingly, the synthesis of cystothiazole A (1) began with the preparation of the bithiazolyl bromide 7 which can be obtained from 5 by two consecutive Negishi cross-coupling reactions as described by Bach et al [8] However, in our approach, an alternative Stille cross-coupling reaction between isopropylthiazole 6 [9] and 5 furnished the known bromide 7 in a slightly improved yield of 78 % (Scheme 2). [10] Scheme 2.…”

Total Syntheses of the Thiopeptides Amythiamicin C and D

“…[32] For the further assembly of key intermediate 6, a regioselective Stille reaction [33] with 2,4-dibromothiazole (19) was performed [14] upon converting 4-bromothiazole 23 to the respective stannane by a Pd-catalyzed stannyl-debromination with hexamethylditin. [34] For the stannylation, a high temperature (100 8C) and a short reaction time (1.5 h) proved to be beneficial.…”

“…[12] Our own synthetic work in the area of thiopeptides was triggered by methodology studies concerning the regioselectivity of cross-coupling reactions [13] on certain heterocycles, specifically on pyridines and thiazoles. A strategy for the preparation of 2',4-disubstituted 2,4'-bithiazoles [14] was implemented in the total synthesis of cystothiazole E and the formal syntheses of cystothiazoles A and C.…”

Five‐Membered Heterocycles: 1,3‐Azoles

“…4-Stannylated thiazoles are usually obtained by a sequential halogen-lithium-tin interchange [248], although after lithiation of 4-bromo-2-stannylthiazoles, to give the 4-stannylated heterocycles, rearrangements were observed [249]. In some cases, 4-stannylthiazoles are prepared by palladium-catalyzed cross-coupling of the corresponding bromide using bis (trimethyltin) [250].…”