2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propanal synthesis

Yield:67467-96-3 77%

Reaction Conditions:

with sodium hydrogencarbonate;palladium diacetate in N,N-dimethyl-formamide at 100; for 9 h;Product distribution / selectivity;Heck Reaction;

Steps:

1.b; 2

Through a mixture of (1,1-dimethyl-propyl)-4-iodo-benzene (137.07 g, 0.50 mol), palladium(II) acetat (1.122 g, 5 mmol) and sodium bicarbonate (50.40 g, 0.60 mol) in dry DMF (500 mL) was bubbled nitrogen for 10 min. Then 2-methyl-prop-2-en-1-ol (54.083 g, 0.75 mol) was added and nitrogen was bubbled for another ten minutes. The reaction mixture was heated under nitrogen for 9 h at 100°C. The reaction was cooled and was filtered through a thin layer of Celite. The Celite was then washed with DMF (300 mL). The reaction was then partitioned between H₂O (2 L) and heptane/EtOAc (9/1) (2x1 L). The combined organic layers were washed with H₂O (1 L) and were dried over MgSO₄. The solvents were evaporated. 109.63 g of 3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propionaldehyde were isolated as crude product. This intermediate was purified by distillation at 112°C under 0.06 mbar to afford 84 g of pure 3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propionaldehyde (77% yield).. ¹H NMR (400 MHz, CDCl₃) δ: 0.69 (3H, t, J=7.45), 1.11 (3H, d, J=6.87), 1.29 (6H, s), 1.65 (2H, q, J=7.43), 2.60 (1H_AB, dd, J= 8.18, 13.52 Hz), 2.69 (1H, sex, J=7.06), 3.08 (1H, dd, J = 5.87, 13.54 Hz), 7.12 (2H, d, J = 8.27), 7.27 (2H, d, J = 8.27), 9.75 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ: 9.6 (CH₃), 13.7 (CH₃), 25.8 (CH₃), 36.6 (CH₂), 37.3 (CH₂), 38.0 (C), 48.5 (CH), 126.4 (CH_Ar), 128.6 (CH_Ar), 136.0 (C_Ar), 148.0 (C_Ar), 205.1 (C=O).; Through a mixture of (1,1-dimethyl-propyl)-4-iodo-benzene (137.07 g, 050 mol), palladium(II) acetat (1.122 g, 5 mmol) and sodium bicarbonate (50.40 g, 0.60 mol) in dry DMF (500 mL) was bubbled nitrogen for 10 min. Then 2-methyl-prop-2-en-1-ol (54.083 g, 0.75 mol) was added and nitrogen bubbled for another ten minutes. The reaction mixture was heated under nitrogen for 9 h at 100°C. The reaction was cooled (0°C)and was filtered through a thin layer of Celite. The Celite was then washed with cold DMF (300 mL). To DMF solution was added EtOH (abs. 700 mL) followed by AcOH (30 mL) and cis-2,6-dimethylmorpholine (73.9 mL). After 15 min stirring at RT, the reaction was cooled to -5°C and NaBH₄ (15.93 g, 0.42 mol) was added in portions over 1h 30 min so that temperature did not exceed 2-3°C. Stirring was continued at 0°C for 1 h and the reaction was quenched by drop-wise addition of NaOH solution in water at 0°C (30 g, 0.75 mol, /100 mL H₂O) to pH=12. The reaction was then partitioned between H₂O (2 L) and Hept/EtOAc (9/1) (2x1 L). The organic phases were combined, washed with the H₂O (1L), and dried over MgSO₄. After evaporation of the solvents, the residue (147.14 g) was dissolved in iPr₂O (500 mL) and cooled to 0°C. To this solution was added the solution of HCl gas in EtOAc (150 ml, ~4M) drop-wise (30 min) and with stirring. White precipitate was formed during HCl addition and was filtered 30 min after completion of the addition. It was washed with iPr₂O (300 mL) and was dried in vacuo at 40°C during 48 h providing 112.34 g of cis-4-{3-[4-(1,1-dimethylpropyl)-phenyl]-2-methyl-propyl}-2,6-dimethyl-morpholine hydrochloride as white powder. (64% yield) (Melting Point = 205.8°C) ¹H NMR (400 MHz, CDCl₃) δ: 0.63 (3H, t, J = 7.39 Hz), 1.12 (3H, d, J = 6.30 Hz), 1.13 (3H, d, J = 6.32 Hz), 1.24 (6H, s), 1.26 (3H, d, J = 6.65 Hz), 1.59 (2H, q, J = 7.49 Hz), 2.05 (1H, q, J = 10.77 Hz), 2.26 (1H, q, J = 10.80 Hz), 2.27-2.35 (1H, m), 2.56-2.66 (2H, m), 2.76-2.89 (2H, m), 3.22 (2H, t, J = 13.28 Hz), 4.36-4.44 (1H, m), 4.46-4.54 (1H, m), 7.06 (2H, d, J = 8.22 Hz), 7.23 (2H, d, J = 8.22 Hz), 12.55 (1H, b)

References:

EP1842848,2007,A1 Location in patent:Page/Page column 6; 7