Complex Boron-Containing Molecules through a 1,2-Metalate Rearrangement/anti-S _N 2′ Elimination/Cycloaddition Reaction Sequence

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

The three-component coupling of benzylamines, boronic esters, and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD) is reported. The boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes a stereospecific 1,2-metalate rearrangement/anti-S _N 2′ elimination in the presence of an N-activator to provide a dearomatized tertiary boronic ester. Interception of this dearomatized intermediate with a dienophile leads to stereopredictable cycloaddition reactions to generate highly complex three-dimensional boron-containing molecular structures. When enantioenriched α-methyl-substituted benzylamines are employed, the corresponding cycloaddition adducts are formed with excellent enantiospecificities.

Key words

cycloaddition - 1,2-metalate rearrangement - phenyltriazoledione - benzylamines - boronic esters - multicomponent reaction

• References and Notes

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• 13 (±)-(5S,8R,11S)-11-Cyclohexyl-10-methylene-2-phenyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,8-dihydro-1H-5,8-ethano[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (3aa) Typical ProcedureBoronic ester 2a (500 μmol) was added to the ortho-lithiated benzylamine Li–1a (525 μmol, 1.05 equiv; prepared from 1a) in THF (2 mL) at –78 °C, and the solution was stirred at –78 °C for 15 min, after which the cooling bath was removed, and the mixture was stirred for a further 15 min. ClCO₂CMe₂CCl₃ (132.0 mg, 550 μmol, 1.10 equiv) was added at –78 °C, and the solution was stirred for 15 min at –78 °C, after which the cooling bath was removed and the mixture was stirred for a further 5 min. PTAD (96.3 mg, 550 μmol, 1.10 equiv) was added, and the solution was stirred for 1 h at r.t. CHCl₃ (50 mL) was added and the solution was washed with H₂O (25 mL) and sat. aq NaCl (25 mL), then dried (MgSO₄), filtered, and concentrated under reduced pressure. Purification by flash column chromatography [silica gel. EtOAc–pentane (15:85)] gave a white solid; yield: 121 mg (50%), dr = 17:1; mp 86 °C, R_f  = 0.47 (EtOAc–pentane, 15:85).IR (liquid film): 2927, 1771, 1710, 1397, 1138, 908, 727, 644 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.36 (m, 4 H, Ar-H), 7.34–7.28 (m, 1 H, Ar-H), 6.50 (ddd, ³ J _H,H′ = 7.7, 5.5 Hz, ⁴ J _H,H′ = 1.8 Hz, 1 H, =CH), 6.43 (ddd, ³ J _H,H′ = 7.7, 5.4 Hz, ⁴ J _H,H′ = 1.7 Hz, 1 H, =CH), 5.39 (s, 1 H, =CHH), 5.26–5.21 [m, 2 H, =CHH (1 H) + CHN (1 H)], 5.11 (dd, ³ J _H,H′ = 5.5 Hz, ⁴ J _H,H′ = 1.7 Hz, 1 H, CHN), 2.08–2.00 (m, 1 H, CHH), 1.79–1.61 (m, 4 H, CHH), 1.26 [s, 6 H, CH ₃ (pin)], 1.24 [s, 6 H, CH ₃ (pin)], 1.23–1.02 [m, 6 H, CH (1 H) + CHH (5 H)]. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 155.8 (CO), 155.3 (CO), 142.9 (=C), 131.8 (arom.), 129.9 (=CH), 129.0 (2 C, arom.), 128.6 (=CH), 128.0 (arom.), 125.4 (2C, arom.), 113.9 (=CH ₂), 84.2 [2 C, OC(CH₃)₂], 59.0 (CHN), 57.0 (CHN), 44.4 (CH), 31.0 (CH ₂), 29.8 (CH ₂), 27.3 (CH ₂), 27.1 (CH ₂), 26.4 (CH ₂), 25.1 [2 C, CH3 (pin)], 24.4 [2 C, CH3 (pin)]. Carbons attached to boron were not observed due to quadrupolar relaxation. ¹¹B{¹H} NMR (128 MHz, CDCl₃): δ = 33.5 (br s). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₄BN₃NaO₄: 498.2535; found: 498.2554.