Microwave-Assisted Cleavage of Aryl Methyl Ethers with Lithium Thioethoxide (LiSEt)

Abstract

Lithium thioethoxide (LiSEt), a white solid easily prepared from EtSH and n-BuLi in hexane, was identified as a highly efficient reagent for the cleavage (O-demethylation) of aryl methyl ethers, i.e. methyl-protected phenols. Of particular synthetic value are applications in the double deprotection of 1,2-dimethoxyarenes (to give catechols) and in the selective monodeprotection of di- and trimethoxyarenes. The thermal reactions, which are usually performed in DMF as a solvent, can be greatly accelerated through microwave irradiation. In this case, the monodemethylated products are usually formed in high (80-99%) yield within only 15 minutes.

Key words

lithium - thioethanolate - phenol protecting groups - ­microwave irradiation - S_N2 reactions - demethylation

References and Notes

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43

DMF (99.8%, Fluka) was stored over molecular sieves. GC-MS measurements were carried out on an Agilent HP6890 instrument with MS detector 5937 N using an Optima 1 MS (Macherey-Nagel) 30 m × 0.25 mm capillary column with H₂ as carrier gas. NMR data were measured on Bruker DPX 300 and AC 250 instruments. Chemical shifts (δ) are given in ppm relative to the solvent reference as the internal standard. Reactions under microwave irradiation were performed in a CEM Discover instrument (300 W) in glass tubes with temperature and pressure control.
Preparation of the Reagent (LiSEt): In a dry 500-mL Schlenk flask a solution of n-BuLi (1.3 M) in hexane (120 mL, 160 mmol) was diluted with hexane (150 mL) under an argon atmosphere. The solution was cooled to 0 ˚C and under rapid stirring EtSH (200 mmol, 1.25 equiv, 15 mL) was added dropwise, whereupon a white precipitate formed. The reaction mixture was stirred at 0 ˚C for 10 min and at r.t. for 30 min. After removal of the solvent (always ensuring inert conditions) the residue was dried in vacuo to give LiSEt as a white solid (10.6 g, 156 mmol, 97%). The product was stored under argon at ambient temperature. C₂H₅SLi; M = 68.06 g/mol. ^¹H NMR (250 MHz, DMSO): δ = 1.06 (t, ^³ J = 7.2 Hz, 3 H, H2), 2.27 (q, ^³ J = 7.3 Hz, 2 H, H1).
General Procedure: The substrate (0.6 mmol, 1 equiv) and LiSEt (1.2 mmol, 2 equiv) were weighed into the reaction vessel (either a Schlenk tube or a microwave reactor), which was then evacuated and flushed with argon three times before DMF (5 mL) was added and the reaction mixture was heated/irradiated as specified in Table  [¹] . Reactions were monitored by TLC and/or GC-MS. For workup, the mixture was cooled to r.t. and partitioned between 2 N aq HCl (5 mL) and MTBE (5 mL). The aqueous layer was re-extracted with MTBE (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, filtered through a pad of silica and solvents were evaporated. The residue was flash chromatographed on silica gel with c-hexane-EtOAc (4:1).
3-Methoxyphenol (10): colorless oil. ^¹H NMR (CDCl₃): δ = 3.76 (s, 3 H), 5.03 (br s, 1 H), 6.40-6.43, 6.46-6.50 (m, 3 H), 7.09-7.14 (m, 1 H). ^¹³C NMR (CDCl₃): δ = 55.3 (q), 101.5, 106.4, 107.9 (3 × d), 130.1 (d), 156.7 (s), 160.9 (s). HRMS (EI, 70 eV): m/z calcd for C₇H₈O₂: 124.0524; found: 124.053.
3-Methoxy-2-methylphenol (12): white solid; mp 42-43 ˚C. ^¹H NMR (CDCl₃): δ = 2.11 (s, 3 H), 3.81 (s, 3 H), 4.80 (s, 1 H), 6.44 (d, ^³ J = 8.5 Hz, 1 H), 6.47 (d, ^³ J = 8.5 Hz, 1 H), 7.02 (ψt, ^³ J = 8.5 Hz, 1 H). ^¹³C NMR (CDCl₃): δ = 7.9 (q), 55.6 (q), 103.0 (d), 108.0 (d), 112.1 (s), 126.4 (d), 154.3 (q), 158.6 (q). HRMS (EI, 70 eV): m/z calcd for C₈H₁₀O₂: 138.0681; found: 138.068.
2-Hydroxy-6-methoxybenzonitrile (14): white solid; mp 163-164 ˚C. ^¹H NMR (CD₃OD): δ = 3.87 (s, 3 H), 6.50 (d, ^³ J = 8.4 Hz, 1 H), 6.52 (d, ^³ J = 8.4 Hz, 1 H), 7.34 (ψt, ^³ J = 8.5 Hz, 1 H). ^¹³C NMR (CD₃OD): δ = 56.7 (q), 90.6 (s), 102.9 (d), 109.0 (d), 115.4 (s), 136.1 (d), 163.0 (s), 163.9 (s). IR (ATR): 3220 (br m), 2230 (s), 1607 (s), 1594 (s), 1476 (s) cm^-¹. HRMS (EI, 70 eV): m/z calcd for C₈H₇NO₂: 149.0477; found: 149.047.
3,5-Dimethoxybenzoic acid (16): GC-MS and NMR data matched those of an authentic(commercial) sample.
1-(4-Hydroxy-3,5-dimethoxyphenyl)ethanone (20): colorless oil. ^¹H NMR (CDCl₃): δ = 2.54 (s, 3 H), 3.92 (s, 6 H), 6.03 (br s, 1 H), 7.22 (s, 2 H). ^¹³C NMR (CDCl₃): δ = 26.2 (q), 56.4 (q), 105.7 (d), 128.8 (s), 139.7 (s), 146.7 (s), 200.3 (s). IR (ATR): 3350 (br m), 1728 (s) cm^-¹. HRMS: m/z calcd for C₁₀H₁₂O₄: 196.0736; found: 196.074.
5-Bromo-2,3-dimethoxyphenol (22a): white solid; mp 68-70 ˚C. ^¹H NMR (CDCl₃): δ = 3.82 (s, 3 H), 3.85 (s, 3 H), 5.83 (br s, 1 H), 6.59 (d, ⁴ J = 2.1 Hz, 1 H), 6.75 (d, ⁴ J = 2.1 Hz, 1 H). ^¹³C NMR (CDCl₃): δ = 56.5 (q), 60.9 (q), 107.9 (d), 111.6 (d), 116.4 (s), 134.8 (s), 149.9 (s), 152.8 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one bromine atom): m/z (%) = 234 (95) [M]⁺, 232 (100) [M]⁺, 219 (95), 217 (97), 191 (46), 189 (55), 173 (29), 171 (31), 110 (14), 67 (41). HRMS: m/z calcd for C₈H₉O₃ ⁷⁹Br: 231.9735; found: 231.974.
4-Bromo-2,6-dimethoxyphenol (22b): white solid; mp 90-92 ˚C. ^¹H NMR (CDCl₃): δ = 3.86 (s, 6 H), 5.42 (br s, 1 H), 6.70 (s, 2 H). ^¹³C NMR (CDCl₃): δ = 56.4 (q), 108.4 (d), 111.04 (s), 138.9 (s), 147.5 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one Br atom): m/z (%) = 234 (93) [M]⁺, 232 (100) [M]⁺, 219 (37), 217 (41), 191 (27), 189 (30), 176 (16), 174 (16), 110 (13), 67 (19), 50 (16). HRMS: m/z calcd for C₈H₉ ⁷⁹BrO₃: 231.9735; found: 231.974.
2-Bromo-4,6-dichloro-3-methoxy-5-methylphenol (24): white solid; mp 128 ˚C. ^¹H NMR (CDCl₃): δ = 2.44 (s, 3 H), 3.85 (s, 3 H), 5.91 (s, 1 H). ^¹³C NMR (CDCl₃): δ = 18.1 (q), 60.6 (q), 103.7 (s), 117.0 (s), 121.2 (s), 134.9 (s), 148.0 (s), 152.5 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one Br and two Cl atoms): m/z (%) = 290 (6) [M]⁺, 288 (44) [M]⁺, 286 (100) [M]⁺, 284 (63) [M]⁺, 273 (14), 271 (31), 269 (20), 245 (23), 243 (56), 241 (34), 179 (15), 177 (14). HRMS: m/z calcd for C₈H₇O₂ ⁷⁹Br^³5Cl₂: 283.9006; found: 283.901.