Synthesis of Deuterated Allylaniline Intermediate

A solution of LiAlD₄ (3.6 g, 85.6 mmol, 1.6 equiv) in dry Et₂O (285 mL) was cooled to −10°C and a solution of propargyl alcohol (3.0 g, 53.5 mmol, 1 equiv) in Et₂O (33 mL) was added through an addition funnel over 30 min. The resulting solution was warmed to room temperature and stirred for 14 h. The mixture was cooled to 0°C and was quenched slowly with H₂O (4.0 mL). The solution was stirred for another 15 min and then 15% aqueous NaOH solution (4.0 mL) and H₂O (4.0 mL) were added. The white slurry was filtered through a short pad of Celite and was washed with Et₂O (300 mL). The filtrate was concentrated in vacuo to give the crude allyl-2-d₁ alcohol⁴ as a yellow oil (3.0 g). ¹H NMR (500 MHz, CDCl₃): δ = 5.22 (s, 1H), 5.09 (s, 1H), 4.08 (s, 2H), 3.0 ppm (brs, 1H).
The crude allyl-2-[D₁] alcohol (3.0 g, 50.8 mmol, 1 equiv) was added to a stirring solution of PBr₃ (2.4 mL, 25.5 mmol, 0.5 equiv) in Et₂O (21 mL) dropwise at 0°C. The resulting solution was stirred at 0°C for 1 h and then carefully quenched by the addition of brine (12 mL). The layers were separated and the combined organic extracts were washed with a saturated solution of NaHCO₃, brine and dried over Na₂SO₄. Excess solvent was removed via careful distillation (45–50°C). The crude allyl-2-[D₁] bromide was obtained as colorless liquid (2.1 g, 32% yield over 2 steps).^{[5 ] 1}H NMR (500 MHz, CDCl₃): δ = 5.31 (s, 1H), 5.14 (s, 1H), 3.94 ppm (s, 2H).
Into an oven-dried round bottom flask were added the crude allyl-2-[D₁] bromide (1.5 mL, 12.5 mmol, 1.0 equiv), aniline (4.5 mL, 37.0 mmol, 3.0 equiv), K₂CO₃ (5.0 g, 37.0 mmol, 3.0 equiv) and DMF (20 mL).^{[6 ]} The flask was equipped with a stopper and the reaction mixture was heated to 70°C overnight. The mixture was allowed to cool to room temperature and was washed with water (20 mL). The aqueous phase was extracted with Et₂O (3 × 20 mL). The combined organic layers were washed with brine, dried with Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography on SiO₂ (10% EtOAc in hexanes) gave compound N-allyl-2-[D₁] aniline (0.7 g, 45% yield). Data: ¹H NMR (500 MHz, CDCl₃): δ = 7.18 (t, J = 7.5 Hz, 2H), 6.72 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 5.29 (s, 1H), 5.17 (s, 1H), 3.78 ppm (s, 2H); ¹³C NMR (75 Hz, CDCl₃): δ = 148.0, 135.1 (t, J = 23.0 Hz), 129.2, 117.5, 116.1, 112.9, 46.4 ppm; HRMS (ESI): m/z calcd for [M]⁺ C₉H₁₁DN₁: 135.1027, found: 135.1022.
To an oven-dried pressure tube were added N-allyl-2-[D₁] aniline (0.7 g, 5.2 mmol, 1 equiv) and xylenes (13 mL). The solution was cooled to −78°C and BF₃·Et₂O (1.3 mL, 10.4 mmol, 2.0 equiv) was added dropwise. The resulting solution was warmed to room temperature and was heated to 160°C for 4 h.^{[7 (link)]} The reaction mixture was then cooled to room temperature and was placed in an ice–water bath and was quenched with 2M NaOH (6 mL). The organic layer was separated and aqueous layer was extracted with Et₂O (3 × 10 mL). The organics were combined, dried with Na₂SO₄, filtered and concentrated in vacuo. Purification by flash chromatography on SiO₂ (10% EtOAc in hexanes) gave o-allyl-2-[D₁] aniline (0.5 g, 70% yield). ¹H NMR (500 MHz, CDCl₃): δ = 7.05 (t, J = 8.0 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.12 (s, 1H), 5.10 s, 1H), 3.66 (brs, 2H), 3.30 ppm (s, 2H); HRMS (ESI): m/z calcd for [M+ H]⁺ C₉H₁₁DN₁: 135.1012, found: 135.1009.
The o-allyl-2-[D₁] aniline (0.5 g, 3.7 mmol, 1 equiv) was dissolved in dry CH₂Cl₂ (20 mL) and the solution was treated with pyridine (1.18 mL, 14.9 mmol, 4 equiv) followed by p-toluenesulfonyl chloride (0.85 g, 4.5 mmol, 1.2 equiv). The mixture was stirred at room temperature for 24 h, washed with 1N HCl (15 mL) and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Flash chromatography of the resulting crude compound on SiO₂ (5–10% EtOAc in hexanes) afforded compound [D]-1b as white solid (1.0 g, 96% yield). M.p. 62–65°C; ¹H NMR (500 MHz, CDCl₃): δ = 7.61 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.19 (m, 1H), 7.13–7.05 (m, 2H), 6.55 (b. s., 1H), 5.11 (s, 1H), 4.93 (s, 1H), 3.00 (s, 2H), 2.39 ppm (s, 3H); ¹³C NMR (75 Hz, CDCl₃): δ = 143.7, 136.7, 135.2 (t, J = 24 Hz), 134.9, 131.9, 130.4, 129.5, 127.6, 127.0, 126.2, 124.4, 116.9, 36.0, 21.5 ppm; IR (neat): ν̃ = 3266, 3076, 3030, 2967, 2913, 2849, 2243, 1922, 1623, 1596, 1492, 1451, 1401, 1333, 1161, 1089, 1039, 1016, 921, 817, 754, 663 cm⁻¹; HRMS (ESI): m/z calcd for [M]⁺ C₁₆H₁₆DO₂N₁S₁: 288.1037, found: 288.1036.