Compound 21

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InChIKey PDGZSZLMBJSDQC-BUHFOSPRSA-N

Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

A 250 mL round bottom flask equipped with a stir bar was charged with 5-methyl-2-bromoaniline (15 g, 80.620 mmol, 1 equiv) which was suspended in conc. HCl (81 ml) to obtain a white slurry. This mixture was cooled at 0 °C before a solution of NaNO₂ (8.34 g, 120.930 mmol, 1.5 equiv) in H₂O (10.4 mL) was added dropwise (Caution! Toxic gases form during this addition). The resulting yellow solution was stirred at 0 °C for 10 min after which a solution of diethylamine (6.5 g, 88.680 mmol, 1.1 equiv) in 1 M KOH (68.2 mL) was poured into the reaction flask. The reaction was allowed to proceed at 0 °C for 1h before it was quenched with 3 M NaOH (or KOH) until the pH reached 12. The product was extracted with EtOAc (3 x 75 mL). The combined organic layers were then washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The desired 2-bromotriazene intermediate (19.68 g, 91% yield) was isolated after rapid chromatography (silica gel, 49:1 hexanes/EtOAc) as a brown oil. Partial characterization data for intermediate: HRMS (m/z): calcd for C₁₁H₁₆BrN₃H⁺, [M+H]⁺, 270.0600; found, 270.0606; IR (film) ν_max = 2973, 2933, 1465, 1409, 1385, 1341, 1249, 1105, 1032, 802; ¹H NMR (600 MHz, CDCl₃) δ 7.43 (d, J = 8.1 Hz, 1 H), 7.19 (s, 1 H), 6.80 (d, J = 7.9 Hz, 1 H), 3.79 (q, J = 7.0 Hz, 4 H), 2.30 (s, 3 H), 1.31 (s, 6 H); ¹³C NMR (151 MHz, CDCl₃) δ 148.3, 137.8, 132.7, 127.1, 119.2, 116.6, 49.2, 41.9, 21.2, 14.6, 11.0. Adapted from Gross, M. L.; Blank, D. H.; Welch, W. M. The triazene moiety as a protecting group for aromatic amines. J. Org. Chem. 58, 2104-2109 (1993).

A 2 L round bottom flask equipped with a stir bar and a septum, previously flame-dried under vacuum, was charged with 2-bromotriazene intermediate (31.4 g, 116.66 mmol, 1 equiv), azeotroped from benzene (100 mL) and kept under Ar. After addition of Et₂O (1 L), the solution was cooled at –78 °C and sec-BuLi (1.4 M in cyclohexane, 140.000 mmol, 100 mL, 1.2 equiv) was added dropwise to give a red solution which was stirred for 30 min at the same temperature. After this time, SO₂(g) was condensed via cannula into the reaction flask until the mixture became a pale yellow suspension (and the color is persistent; 5–10 min). The resulting mixture was stirred for 1 h at –78 °C, then at room temperature for 5 h before the solvent was removed in vacuo to give a pale brown solid which was maintained under an atmosphere of Ar. The resulting solid (aryl sulfonate lithium salt) was dissolved in CH₂Cl₂ (1 L) and the solution was cooled at 0 °C before N-chlorosuccinimide (18.7 g, 140.000 mmol, 1.2 equiv) was added in one portion. The brown mixture was stirred at 0 °C for 10h/overnight before being quenched with a saturated solution of NH₄Cl (200 mL). The aqueous layer was extracted with EtOAc (3 x 200 mL) and the resulting organic solution was washed with brine (500 mL), dried over MgSO₄ and concentrated in vacuo. Thus TzoCl 21 (23.26 g) was isolated after column chromatography as an orange solid (silica gel, 9:1 hexane/EtOAc) (69% yield). m.p. = 74–76 ºC; HRMS (m/z): calcd for C₁₁H₁₆ClN₃O₂SH⁺ [M+H]⁺, 290.0724; found, 290.0727; IR (film) V_max = 2976, 2936, 1589, 1566, 1464, 1387, 1340, 1325, 1269, 1168, 1111; ¹H NMR (600 MHz, CDCl₃) δ 7.88 (d, J = 8.3 Hz, 1 H), 7.48 (s, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 3.94 – 3.83 (m, 4 H), 2.42 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.1 Hz, 3 H); ¹³C NMR (151 MHz, CDCl₃) δ 148.8, 147.1, 134.1, 128.9, 124.8, 118.4, 49.8, 43.0, 22.0, 14.6, 11.5.