N-Functionalization of 1,2-Azaborines

Abstract

General protocols for the N-functionalization of 1,2-azaborines with C(sp³), C(sp²), or C(sp) electrophiles are described. The syntheses of a new parental BN isostere of trans-stilbene and a BN isostere of a lisdexamfetamine derivative were accomplished with the developed methodology.

Key words

azaborines - cross-coupling - BN heterocycles - N-functionalization - amination

Publication History

Received: 04 May 2023

Accepted after revision: 12 June 2023

Accepted Manuscript online:
12 June 2023

Article published online:
31 July 2023

• References and Notes

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• 16 BN-Stilbene {1-[(E)-2-Phenylvinyl]-1,2-dihydro-1,2-azaborinine} (10) In a dry box, an oven-dried 50 mL round-bottomed flask was charged with 2-benzyl-1,2-dihydro-1,2-azaborinine (7)⁶ (507 mg, 3.00 mmol) and toluene (15 mL), and the mixture was cooled to –30 °C. A 2.5 M solution of BuLi in hexane (1.26 mL, 3.15 mmol) was added at –30 °C, and the resulting mixture was stirred for 20 min while it slowly warmed to RT. Pd₂(dba)₃ (55 mg, 0.060 mmol), QPhos (170 mg, 0.240 mmol), and β-bromostyrene (476 μL, 3.60 mmol) were added, and the mixture was stirred at 85 °C for 15 h. At the completion of the reaction, the mixture was cooled to RT, then passed through an Acrodisc using CH₂Cl₂ as solvent. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, 2–10% CH₂Cl₂–pentane) to give 8 as a white solid; yield: 497 mg (61%). FTIR (thin film): 3059, 3025, 1644, 1611, 1511, 1492, 1401, 1356, 1260, 1117, 1008, 801, 751, 693, 517 cm^–1. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.70 (d, J = 14.5 Hz, 1 H), 7.60–7.54 (m, 2 H), 7.48 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.0 Hz, 2 H), 7.34–7.29 (m, 3 H), 7.25–7.22 (m, 2 H), 7.18–7.16 (m, 1 H), 6.65 (d, J = 14.0 Hz, 1 H), 6.58 (d, J = 11.5 Hz, 1 H), 6.40 (t, J = 7.0 Hz, 1 H), 2.91 (s, 2 H). ¹¹B NMR (160 MHz, CD₂Cl₂): δ = 37.9. ¹³C NMR (151 MHz, CD₂Cl₂): δ = 143.8, 143.0, 136.4, 134.1, 133.9, 131.0 (br), 129.7, 129.4, 128.9, 128.1, 126.8, 124.9, 121.5, 111.8, 27.6 (br). HRMS (DART-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₉BN: 272.16105, found: 272.16078. In a dry box, an oven-dried 20 mL microwave vial was charged with 8 (360 mg, 1.33 mmol), dodecanol (346 mg, 1.86 mmol), CuBr (19 mg, 0.13 mmol), pyridine (214 μL, 2.66 mmol), di-tert-butyl peroxide (293 mL, 1.59 mmol), and toluene (13 mL), and the mixture was stirred at 90 °C for 1 h, then cooled to RT and the solvent was removed under reduced pressure. The crude oxidized product was purified by column chromatography (silica gel 2–50% Et₂O–pentane) to isolate a mixture containing the desired product and other byproducts that was used directly to the next step. In a dry box, an oven-dried 25 mL round-bottomed flask was charged with the mixture of oxidized products and Et₂O (10 mL), which was then cooled to –30 °C. LAH (15 mg, 0.40 mmol) was added at –30 °C, and the mixture was stirred for 30 min. A 2.0 M solution of HCl in Et₂O (395 μL, 0.790 mmol) was added at –30 °C and the mixture was stirred for 30 min while it slowly warmed to RT. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, 100% pentane to 2% Et₂O–pentane) to give 10 as a white solid; yield: 91.3 mg (38% over two steps). FTIR (thin film): 3063, 3022, 2539, 1650, 1604, 1508, 1404, 1262, 1152, 973, 755, 693, 596 cm^–1. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.68–7.64 (m, 2 H), 7.48 (d, J = 14.5 Hz, 1 H), 7.45 (t, J = 8.5 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.26 (t, J = 7.5 Hz, 1 H), 6.97 (d, J = 10.5 Hz, 1 H), 6.79 (d, J = 14.5 Hz, 1 H), 6.51 (t, J = 6.5 Hz, 1 H), 5.82–4.60 (br, 1 H). ¹¹B NMR (160 MHz, CD₂Cl₂): δ = 33.2 (d, J = 109 Hz). ¹³C NMR (151 MHz, CD₂Cl₂): δ = 144.4, 136.9, 136.4, 134.1, 131.4 (br), 129.3, 127.9, 126.7, 118.8, 113.3. HRMS (DART-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₃BN: 182.11410, found: 182.11324.
• 17 Abbey ER, Zakharov LN, Liu S.-Y. J. Am. Chem. Soc. 2008; 130: 7250
• 18 The crystal structure of BN-stilbene 10 is disordered due to the apparent centrosymmetric nature of the molecule. Nevertheless, the planar geometry of the solid-state structure of 10 is clearly observed.
• 19 Goodman DW. Pharm. Ther. 2010; 35: 273
• 20 A similar effect has been reported for the 2,1-borazaronaphthalenes, see ref. 9a.