2024 Volume 72 Issue 12 Pages 1061-1064
We have investigated the base-induced long-range halogen dance reactions of 4,5-dibromo- or 4-bromo-5-iodothiazoles bearing sulfur-containing aromatic heterocycles at the C2-position. We have found that the reaction occurs in bithiazole regioisomers or (thiophenyl)thiazole derivatives, in which the C-5 halo group on the thiazole halogen donor regioselectively migrates to a halogen acceptor ring after treatment with lithium bis(trimethylsilyl)amide. The substrate with a thiophen-2-yl substituent required highly basic P4-t-Bu to induce the halogen dance reaction.
Halogenated heterocycles are versatile building blocks for synthesizing pharmaceutical compounds or natural products. However, the regiocontrol of the halogenation is difficult, causing the production of undesired by-products. Halogen dance reactions are base-induced migrations of halogen groups on aromatic and heteroaromatic rings. They are often utilized as a method of halogenation at positions that are difficult to modify using other methods.
Typically, halogen migration occurs as 1,2- or 1,3-halogen shifts around a ring, with few examples of 1,4-halogen shifts.1–11) To the best of our knowledge, no reports existed on regioselective long-range halogen dance reactions longer than a 1,5-halogen shift until our previous report.12) We observed a long-range halogen dance reaction in 4,5-dibromo-2,4′-bithiazole, where the C5-bromo group migrated to the C2′-position on another thiazole ring (Chart 1). The conversion corresponds with a rare transannular 1,6-halogen shift. The reaction occurs via the initial generation of carbanion, followed by a cascade of metal–halogen exchange reactions according to a reported reaction mechanism.13) In the 2,4′-bithiazole system, the conversion of the reactive C2′-carbanion into a relatively stable C5-carbanion seems to be the driving force of the reaction.
We expected similar long-range halogen dance reactions to occur if appropriate halogen donors and acceptors were employed (Chart 2).
Herein, we report the long-range halogen dance reactions observed in other biheterocyclic compounds, where 4,5-dibromo- or 4-bromo-5-iodothiazole play a role as a halogen donor and several sulfur-containing heterocycles work as halogen acceptors.
First, we demonstrated the long-range halogen dance reaction of an iodo group using iodinated 2,4′-bithiazole. Thereafter, substrate 2, bearing an iodine donor, was synthesized by the iodination of 4-bromo-2,4′-bithiazole (1)12) with N-iodosuccinimide (NIS) in the presence of an In(OTf)3 catalyst in MeCN. The reaction proceeded regioselectively at the C5 position of 2,4′-bithiazole ring with an 84% yield. The long-range halogen dance reaction of the iodinated bithiazole (2) was carried out using lithium bis(trimethylsilyl)amide (LiHMDS). As expected, the C5-iodo group migrated regioselectively to the C2′-position, affording 2′-iodobithiazole (3) in 54% yield (Chart 3).
The migration of the iodine group was confirmed by the disappearance of the C2′-proton (δ 8.83 ppm) and the appearance of the C5-proton (δ 7.71 ppm) in 1H-NMR spectral data of 3 in acetone-d6.
Reaction of the Ring-Substituted Regioisomers of 2,4′-BithiazoleNext, we examined the halogen dance reaction of the ring-substituted regioisomers of 2,4′-bithiazole. Further, 4,5-dibromo-2′-(triisopropylsilyl)-2,5′-bithiazole (6) was synthesized by Stille coupling with 2,4,5-tribromothiazole (4) and 5-(tributylstannyl)-2-(triisopropylsilyl)thiazole (5)14) in 77% yield. The triisopropylsilyl protection of 6 was removed with tetra-n-butylammonium fluoride (TBAF) in a 4 : 1 mixture of tetrahydrofuran (THF) and water, giving the protonated 4,5-dibromo-2,5′-bithiazole (7) in 80% yield. Without water, the yield decreased to 45%, presumably because of a partial halogen dance reaction (Chart 4).
Here, 4,5-dibromo-2,2′-bithiazole (9) was synthesized from 2-(tributylstannyl)thiazole (8)15) and 4 with a Pd(PPh3)4 catalyst in refluxing 1,4-dioxane, with 69% yield (Chart 4).
With two kinds of 4,5-dibromobithiazoles, we examined the long-range halogen dance reaction using LiHMDS at −90 °C according to the reaction conditions for the 2,4′-bithiazole. In both the 2,5′- and 2,2′-bithiazoles (7 and 9), the C5-bromo group migrated selectively to the position neighboring the sulfur atom in another thiazole ring, like the 2,4′-bithiazole regioisomer, affording halogen dance products 10 and 11a in 85 and 74% yields, respectively.16) The structures were confirmed by the disappearance of the proton at the brominated position as well as the appearance of the C5 proton in 1H-NMR spectral data. In addition, in 13C-NMR spectral data, chemical shift changes of approximately 10 ppm were consistently observed at the carbons involved in the bromine shift, with a downfield shift at the bromine-releasing carbon and an upfield shift at the bromine-accepting carbon. The long-range halogen dance reaction of both 7 and 9 was initiated by the deprotonation of the acidic proton neighboring sulfur atom, and the C5-bromo group on another thiazole ring migrated to the deprotonated position.17) Notably, even 9 without the C2′-H flanked by two heteroatoms underwent the long-range halogen dance reaction after treatment with LiHMDS (Chart 5). Further, the C-5 carbanion intermediate generated from the substrate 9 was trapped with N-bromosuccinimide (NBS) to afford 2′,4,5-tribromo-2′,4-bithiazole (11b) in excellent yield.
Finally, we examined the long-range halogen dance reaction in substrates bearing a halogen acceptor other than thiazole. As the halogen dance reaction proceeded in 9, a CH group flanked by two hetero atoms was not always necessary for the LiHMDS-induced halogen dance reaction. Therefore, we chose three thiophene derivatives as a halogen acceptor, such as benzo[b]thiophen-3-yl, thiophen-3-yl, and thiophen-2-yl groups. The halogen dance precursors were synthesized by the Stille coupling of the appropriate heterocyclic stannans and 4. The reaction of sterically hindered benzo[b]thiophen-3-yltributylstannane (12)18) was very slow in refluxing 1,4-dioxane (bp 101 °C), and almost no coupling product was produced even after 6 h. However, when the reaction was conducted with 1.5 equivalent (equiv.) of 12 in xylene at 125 °C, the coupling product (13) was obtained in 61% yield.
Conversely, the Stille coupling of 4 with 3-thienylstannane (14)19) or 2-thienylstannane (16)20) proceeded considerably fast, requiring the decrease of the stannans to 1.2 equiv. to prevent overreaction, affording products 15a and 17 in 45% and 68% yields, respectively. For comparison with 15a, the bithiophene analog 15b was also synthesized in 46% yield at 120 °C in xylene (Chart 6).
As expected, the LiHMDS-induced halogen dance reaction of the benzo[b]thiophen derivative (13) proceeded smoothly even in the halogen acceptor without a nitrogen atom. Further, in this case, the C5-bromo group on the thiazole ring was rearranged to the C2′-position neighboring sulfur atom to afford 18 in 65% yield.
The substrate (15a) with a thiophen-3-yl halogen acceptor has two C–H bonds neighboring a sulfur atom. Our interest was which proton was replaced with a bromo group. On treatment with LiHMDS, the C5 bromo group selectively migrated to the C2′-position to produce 19 in 62% yield. The regioselectivity was confirmed by a vicinal coupling between the C4′ and C5′-protons (J = 5.9 Hz) in 19. The bromination of the C5′-position was not observed. We assumed that the thiazole ring worked as a directing group and induced deprotonation at the C2′-position, thereby achieving high regioselectivity. In contrast, the nitrogen-free analog 15b did not react with LiHMDS and was quantitatively recovered. The reaction mixture was quenched with methanol-d4, but the hydrogen was not deuterized. These results support the role of the thiazole ring as a directing group and the importance of the nitrogen atom in regioselective deprotonation.
The orientation of the thiophene ring affected the reactivity. Further, 2-(thiophen-2-yl)thiazole (17) did not react with LiHMDS or lithium diisopropylamide (LDA). When the reaction mixture of thiazole 17 with LDA was quenched with methanol-d4, no deuteration was observed in the recovered substrate. This was presumably because of the insufficient acidity of the thiophene ring, in which the 5′-thienyl proton neighboring a sulfur atom in 17 was not activated by the 2-thiazolyl group, such as 13 and 15a. However, the long-range halogen dance reaction could be induced by employing a highly basic phosphazene base (P4-t-Bu), producing 4-bromo-2-(5-bromothiophen-2-yl)thiazole (20) in 36% yield along with 4-bromo-2-(thiophen-2-yl)thiazole (21) in 25% yield.21) The result was in sharp contrast that the halogen dance reaction in 9 proceeded smoothly with LiHMDS. The results showed that the C3′-nitrogen atom in 9 played an important role in enhancing the acidity at the C5′-position (Chart 7).
We found that base-induced long-range halogen dance reactions occurred in various bithiazole regioisomers or (thienyl)thiazole derivatives. Here, the C-5 halogen group (Br or I) of 4,5-dibromo- or 4-bromo-5-iodothiazoles migrated regioselectively to the position neighboring the sulfur atom in another heterocyclic ring on treatment with LiHMDS. Even the less-reactive substrate with a thiophen-2-yl substituent induced the long-range halogen dance reaction using highly basic P4-t-Bu as a base.
This research was financially supported by a Grant from Osaka Ohtani University. We also thank the Ultra-trace Elemental Analysis Research Center, A-Rabbit-Science Japan Co., Ltd., for performing elemental analysis.
The authors declare no conflict of interest.
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