CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 449-453 DOI: 10.1055/s-0037-1610389
Copyright with the author
Complex Boron-Containing Molecules through a 1,2-Metalate Rearrangement/anti -S
N
2′ Elimination/Cycloaddition Reaction Sequence
Chloe Tillin
,
Raphael Bigler
,
Renata Calo-Lapido
,
Beatrice S. L. Collins
,
Adam Noble
,
› Author Affiliations This work was financially supported by the EPSRC (EP/I038071/1), H2020 ERC (670668), and the University of Bristol. R.B. thanks the Swiss National Science Foundation fellowship program (P2EZP2_165268). R.C.L. was funded by Xunta de Galicia and European Social Fund.
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
Supporting Information
Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610389.
Supporting Information
References and Notes
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(±)-(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 Procedure Boronic 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. ClCO2 CMe2 CCl3 (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 H2 O (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, Rf
= 0.47 (EtOAc–pentane, 15:85).IR (liquid film): 2927, 1771, 1710, 1397, 1138, 908, 727, 644 cm–1 . 1 H 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, =CH H), 5.26–5.21 [m, 2 H, =CH H (1 H) + CH N (1 H)], 5.11 (dd, 3
J
H,H′ = 5.5 Hz, 4
J
H,H′ = 1.7 Hz, 1 H, CH N), 2.08–2.00 (m, 1 H, CH H), 1.79–1.61 (m, 4 H, CH H), 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) + CH H (5 H)]. 13 C{1 H} NMR (101 MHz, CDCl3 ): δ = 155.8 (C O), 155.3 (C O), 142.9 (=C ), 131.8 (arom.), 129.9 (=C H), 129.0 (2 C, arom.), 128.6 (=C H), 128.0 (arom.), 125.4 (2C, arom.), 113.9 (=CH
2 ), 84.2 [2 C, OC (CH3 )2 ], 59.0 (CH N), 57.0 (CH N), 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, C H3 (pin)], 24.4 [2 C, C H3 (pin)]. Carbons attached to boron were not observed due to quadrupolar relaxation. 11 B{1 H} NMR (128 MHz, CDCl3 ): δ = 33.5 (br s). HRMS (ESI): m/z [M + Na]+ calcd for C27 H34 BN3 NaO4 : 498.2535; found: 498.2554.