Synthesis of 2,3-Dihydrobenzo[1,4]dioxins and -oxazins via a Domino Wacker-Heck Reaction

Abstract

All reactions were performed under argon in flame-dried flasks.All solvents were dried and distilled prior to use by usual laboratory methods.All reagents obtained from commercial sources were used without further purification.Thin-layer chromatography (TLC) was performed on precoated silica gel SIL G/UV 254 plates (Macherey-Nagel GmbH & Co. KG) and silica gel 60 (0.032-0.063 mm, Merck) was used for column chromatography.Phosphomolybdic acid in methanol (PMA) or vanillin in methanolic sulfuric acid were used as staining reagents for TLC.UV spectra were taken in CH 3 CN or MeOH with a Perkin-Elmer Lambda 2 spectrometer.IR spectra were recorded as KBr pellets or as films with a Bruker IFS 25 spectrometer. 1H-and 13 C-NMR spectra were recorded with or AMX 300 (Bruker) spectrometer.Chemical shifts are reported in ppm with tetramethylsilane (TMS) as internal standard.Multiplicities of 13 C-NMR peaks were determined with the APT pulse sequence.Mass spectra were measured with a Finnigan MAT 95, TSQ 7000 or LCQ instrument. GENERAL PROCEDURESGeneral Procedure A: Allylation using K 2 CO 3 : A suspension of anhydrous K 2 CO 3 (0.95-1.1 eq.) and KI (1.1 eq.), or alternatively TBAI (cat.), in acetone (2 mL/mmol substrate) was treated with the respective substrate and stirred at room temperature until the end of gas release.Afterwards the allyl halide (1.1-2.0 eq.) was added and the resulting mixture stirred for 0.5-6 h at 25-60 °C.(TLC-Control).Then H 2 O (5 mL/mmol) was added, the solution was neutralised with 1 N HCl and the aqueous phase was extracted with Et 2 O (3 × 5 mL/mmol).The combined organic layers were dried over MgSO 4 , the solvent removed under vacuum and the crude product purified by column chromatography on silica.General Procedure B: Allylation using NaH: The substrate, dissolved in dry DMF (3 mL/mmol), was carefully treated with NaH (0.95 eq.) at 0 °C.After warming up to room temperature and the end of gas release, the respective ally halide as well as TBAI (cat.) were added and the reaction mixture stirred for 2-24 h at 25-80 °C (TLC-Control).Then H 2 O (5 mL/mmol) was added, the solution neutralised with 1 N HCl and the aqueous phase extracted with Et 2 O (3 × 5 mL/mmol).The combined organic layers were washed with H 2 O (15 mL/mmol) and saturated NaCl-solution, dried over MgSO 4 and the solvent removed under reduced pressure.The crude product was purified by column chromatography on silica.General Procedure C: Domino Wacker-Heck Reaction: A mixture of palladium trifluoroacetate (0.1 eq.) and p-benzoquinone (4.0 eq.) in CH 2 Cl 2 (0.4-0.5 mL/mmol substrate) was stirred for 10 min at room temperature.Then a solution of the phenol (1.0 eq.) and the respective coupling partner (2.0-5.0 eq.) in CH 2 Cl 2 (0.4-0.5 mL/mmol) was added to the suspension and the mixture was stirred for 5 h-4 d at 25-60 °C.(TLC-Control).At the end of the reaction the mixture was treated with 1N HCl (50 mL/mmol) and the aqueous phase extracted with Et 2 O (3 x 50 mL/mmol).The combined organic phases were washed with 1N NaOH (3 x 50 mL/mmol), dried over MgSO 4 and the solvent was removed under reduced pressure.The crude product was purified by column chromatography on silica. SYNTHESIS OF THE MONOALLYL ETHERS 10-252-(2-Methylallyloxy)-phenol (10): According to general procedure A, catechol (1) (5.01 g, 45.5 mmol) was treated with K 2 CO 3 (6.92g, 50.1 mmol, 1.1 eq.), KI and 3-chloro-2-methylpropene (26) (4.94 g, 54.6 mmol, 5.34 mL, 1.2 eq.) under reflux for 4 h.After column chromatography on silica (P/EtOAc = 50:1 → 10:1) the desired compound 10 (3.90 g, 23.8 mmol, 52 %) was obtained as a colorless liquid. 1 H-NMR (300 MHz, CDCl 3 ): δ = 1.85 (s, 3 H, 2'-CH 3 ), 4.51 (s, 2 H, 1'-H 2 ), 5.03 (m c , 1 H, 3'-H), 5.10 (m c , 1 H, 3'-H), 5.70 (s, 1 H, OH), 6.79-6.99(m, 4 H, Ar-H) ppm. 13C-NMR (75.6 MHz, CDCl 3 ): δ = 19.37 (2'-CH 3 ), 72.59 (C-1'), 113.30(C-3'), 112.11, 114.62 (C-3, C-6), 120.02, 121.63 (C-4, C-5), 140.38 (C-2') 145.60, 145.78 (C-1, C-2) ppm.IR (Film): ν ~= 3536, 2919, 1597, 1501, 1454, 1373, 1259, 1219 cm -1 .UV (CH 3 CN): λ max (lg ε) = 197.0(4.582), 199.5 (4.582), 215.5 (3.798), 276.0 (3.424) nm.MS (EI, 70 eV): m/z (%) = 164 (57) [M] + , 109 (30) [M-C 4 H 7 ] + , 55 (100) [C 4 H 7 ] + .Calcd for C 10 H 12 O 2 : 164.0837,Found: 164.0837 (EI-HRMS). 5-Methyl-2-(2-methylallyloxy)-phenol (11), 4-Methyl-2-(2-methylallyloxy)-phenol (19):According to general procedure A, 4-methoxycatechol (2) (6.24 g, 50.3 mmol) was treated with K 2 CO 3 (6.95g, 50.3 mmol, 1.0 eq.), KI and 3-chloro-2-methylpropene (26) (5.01 g, 55.3 mmol, 5.41 mL, 1.1 eq.) under reflux for 4 h.After purification by column chromatography on silica (P/EtOAc = 60:1) a 1:1 mixture of the two regioisomers 11 and 19 (5.68 g, 31.9 mmol, 63 %) was obtained as a colorless liquid. 1 H-NMR S-3