Regiodivergent Synthesis of Brominated Pyridylthiophenes by Overriding the Inherent Substrate Bias

Abstract

A regiocontrolled functionalization of a pyridylthiophene scaffold was accomplished. Regioselectivity for deprotonation of the pyridylthiophene was switched by changing the reaction conditions, including the metal amide base and the solvent. Subsequently, in situ transmetalation and halogen dance on the corresponding organometallic species were controlled by additives and the reaction temperature, as well as by the above reaction conditions. This method successfully enabled the synthesis of four iodinated constitutional isomers from a single starting material, 2-(5-bromo-2-thienyl)pyridine.

Key words

deprotonation - halogen dance - organometallic reagents - pyridylthiophenes - regioselectivity

• References and Notes

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• 23 2-(3-Bromo-5-iodo-2-thienyl)pyridine (4) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 2-(5-bromo-2-thienyl)pyridine (1) (200.4 mg, 0.835 mmol, 1.0 equiv) and toluene (4.0 mL). The resulting solution was cooled to –78 °C, and changed into a slurry. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 1.5 equiv) was added to the Schlenk tube at –78 °C and the mixture was stirred at –78 °C for 90 min, whereupon the precipitate dissolved. I₂ (422.8 mg, 1.666 mmol, 2.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t. and stirred at r.t. for 30 min. The mixture was treated with Et₂O (20 mL) and sat. aq Na₂S₂O₃ (20 mL). After partitioning, the aqueous layer was extracted with Et₂O (20 mL). Each of the organic layers was washed with H₂O (20 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et₂O (20:1)] to give a pale yellow solid; yield: 200.6 mg (0.548 mmol, 66%); R_f = 0.37 (hexane/Et₂O = 9:1); mp 66.8–67.7 °C. IR (ATR): 1582, 1567, 1518, 1460, 1435, 1423, 1305, 1154, 994, 975, 821, 776, 738, 713, 659 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (d, 1 H, J = 4.8 Hz), 8.25 (d, 1 H, J = 7.8 Hz), 7.76 (ddd, 1 H, J = 7.8, 7.8, 1.6 Hz), 7.23 (ddd, 1 H, J = 7.8, 4.8, 1.2 Hz), 7.20 (s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.7, 149.7, 145.2, 141.3, 136.7, 123.0, 120.3, 107.3, 77.0. HRMS (EI⁺): m/z [M⁺] calcd for C₉H₅ ⁷⁹BrINS, 364.8365; found: 364.8373.
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• 25 2-(4-Bromo-5-iodo-2-thienyl)pyridine (5) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.3 mg, 0.418 mmol, 1.0 equiv), THF (1.6 mL), and DMPU (0.4 mL). The resulting solution was cooled to –78 °C. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 1.5 equiv) was added to the Schlenk tube at –78 °C and the mixture was stirred at –78 °C for 60 min. I₂ (211.4 mg, 0.833 mmol, 2.0 equiv) was added in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t. and stirred at r.t. for 30 min. The mixture was treated with Et₂O (10 mL) and sat. aq Na₂S₂O₃ (10 mL). After partitioning, the aqueous layer was extracted with Et₂O (10 mL). Each of the organic layers was washed with water (10 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et₂O (20:1)] to give a pale yellow solid; yield: 112.6 mg (0.308 mmol, 74%); R_f = 0.23 (hexane/Et₂O = 9:1); mp 101.3–103.0 °C. IR (ATR): 1584, 1564, 1461, 1433, 1408, 1321, 1289, 994, 979, 813, 772 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.56–8.53 (m, 1 H), 7.71 (ddd, J = 7.8, 7.8, 1.2 Hz, 1 H), 7.57–7.53 (m, 1 H), 7.32 (s, 1 H), 7.19 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H). ¹³C{1H} NMR (100 MHz, CDCl₃): δ = 150.80, 150.78, 149.8, 137.1, 126.7, 123.0, 120.9, 118.3, 80.3. ¹³C{1H} NMR (100 MHz, CD₃CN): δ = 152.0, 151.2, 150.4, 138.3, 127.8, 124.2, 121.4, 119.3, 81.5. HRMS (EI⁺): m/z [M⁺] calcd for C₉H₅ ⁷⁹BrINS: 364.8365; found: 364.8374.
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• 28 2-(5-Bromo-3-iodo-2-thienyl)pyridine (2) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.0 mg, 0.416 mmol, 1.0 equiv) and THF (1.0 mL). A 1.0 M solution of TMPMgCl·LiCl in THF/toluene (0.83 mL, 0.83 mmol, 2.0 equiv) was added to the Schlenk tube at r.t., and the resulting mixture was stirred at r.t. for 150 min. I₂ (211.9 mg, 0.835 mmol, 2.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was stirred at r.t. for 30 min. The mixture was then treated with Et₂O (10 mL) and sat. aq Na₂S₂O₃ (10 mL). After partitioning, the aqueous layer was extracted with Et₂O (5 mL). Each of the organic layers was washed with H₂O (5 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et₂O (9:1)] to give a pale yellow solid; yield: 80.9 mg (0.221 mmol, 53%); R_f  = 0.33 (hexane/Et₂O = 9:1); mp 45.7–46.9 °C. IR (ATR): 1583, 1567, 1509, 1460, 1435, 1424, 994, 985, 819, 802, 775, 738, 661 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.60–8.57 (m, 1 H), 8.28–8.24 (m, 1 H), 7.77 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H), 7.25 (ddd, J = 7.6, 5.0, 0.8 Hz, 1 H), 7.13 (s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 151.4, 149.7, 144.5, 139.8, 136.5, 123.1, 120.4, 116.6, 75.6. HRMS (EI⁺): m/z [M⁺] calcd for C₉H₅ ⁷⁹BrINS: 364.8365; found: 364.8370.
• 29 2-(5-Bromo-4-iodo-2-thienyl)pyridine (3) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.0 mg, 0.416 mmol, 1.0 equiv), ZnCl₂·TMEDA (315.5 mg, 1.250 mmol, 3.0 equiv), THF (3.2 mL), and DMPU (0.8 mL). The resulting solution was cooled to –50 °C. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 3.0 equiv) was added to the Schlenk tube at –50 °C, and the mixture was stirred at –50 °C for 60 min. I₂ (422.8 mg, 1.666 mmol, 4.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t and stirred at r.t. for 30 min. The mixture was then treated with Et₂O (20 mL) and sat. aq Na₂S₂O₃ (20 mL). After partitioning, the aqueous layer was extracted with Et₂O (10 mL), and each of the organic layers was washed with water (10 mL). The combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et₂O (20:1)] to give a pale yellow solid; yield: 101.1 mg (0.276 mmol, 66%); R_f = 0.27 (hexane/Et₂O = 9:1); mp 93.0–93.4 °C. IR (ATR): 1582, 1564, 1461, 1432, 1410, 1315, 1288, 1158, 995, 771 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 4.8 Hz, 1 H), 7.69 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 7.18 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.7, 149.8, 147.6, 137.0, 131.6, 122.9, 119.6, 118.3, 86.4. HRMS (EI⁺): m/z [M⁺] calcd for C₉H₅ ⁷⁹BrINS: 364.8365; found: 364.8374.
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