A New Synthetic Route to p-Methoxy-2,6-disubstituted Anilines and their Conversion into N-Heterocyclic Carbene Precursors

Abstract

The development of new N-heterocyclic carbenes (NHC) is a key feature in this now mainstream research area to access novel chemical properties and reactivity that are essential for the discovery of original applications. Up to now, only a few reliable methods have proven suitable for the preparation of methoxylated anilines to ultimately access methoxylated NHC. We are pleased to report here a straightforward and scalable approach to address this matter.

Key words

ligands - nucleophilic aromatic - copper - catalysis - carbenes

• References and Notes

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• 18 4-Iodo-2,6-di(3-pentyl)aniline (6, R = Et) A solution of aniline 2 (2.40 g, 10.3 mmol, 1.0 equiv) in cyclohexane (7.0 mL) was treated with a sat. aq solution of Na₂CO₃ (2.90 mL, ca. 5.7 mmol, 0.6 equiv) followed by solid iodine (2.90 g, 11.4 mmol, 1.1 equiv) at r.t. The reaction was stirred overnight at r.t. (11 h). The crude solution was diluted with Et₂O (15 mL) and washed with a sat. aq solution of Na₂S₂O₃ (3 × 10 mL). The organic layer was then dried over anhydrous Na₂SO₄ and concentrated under vacuum. The resulting dark greenish to black oil (4.10 g) was obtained in excellent purity but was preferably filtered through silica and eluted with a 1% solution of Et₂O in pentane to remove some of the colored impurities. Solvents were evaporated to afford the pure desired iodoaniline 6 as an orange crystalline solid (3.53 g, 96%). ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (12 H, t, J = 2 × 7.4 Hz, 4 × CH₃), 1.57 (4 H, m, 2 × CH₂), 1.70 (4 H, m, 2 × CH₂), 2.40 (2 H, m, 2 × CH), 3.64 (2 H, v br s, NH₂), 7.15 (2 H, s, H ^m-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 11.9 (4 × CH₃), 27.9 (4 × CH₂), 42.2 (2 × CH), 81.3 (I-C_IV ^Ar), 132.6 (2 × C_IV ^o-Ar), 132.7 (2 x× CH ^m-Ar), 142.5 (NC_IV ^Ar). HRMS (NSI⁺): m/z calcd for C₁₆H₂₇NI: 360.1183; found: 360.1186 [M + H]⁺. N,N′-Bis[4-iodo-2,6-di(3-pentyl)phenyl]1,4-diazabutadiene (10, R = Et) A solution of 4-iodoaniline 6 (3.53 g, 9.82 mmol, 2.0 equiv) in MeOH (20 mL) was treated with formic acid (1 drop) followed by the dropwise addition of glyoxal (40% in H₂O, 640 μL, 5.82 mmol, 1.2 equiv) at 70 °C. The solution was stirred at this temperature for 3 h, and the MeOH was evaporated under vaccum and replaced by Et₂O. The solution was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 1–5% Et₂O in pentane) to yield the pure desired diimine 10 as a bright yellow solid (3.33 g, 92%). ¹H NMR (400 MHz, CDCl₃): δ = 0.79 (24 H, t, J = 7.4 Hz, 8 × CH₃), 1.53 (8 H, m, 4 × CH₂), 1.64 (8 H, m, 4 × CH₂), 2.40 (4 H, m, 4 × CH), 7.37 (4 H, m, H ^m-Ar), 7.96 (2 H, s, 2 × CH=N). ¹³C NMR (100 MHz, CDCl₃): δ = 12.1 (8 × CH₃), 28.8 (8 × CH₂), 42.5 (4 × CH), 90.0 (2 × IC_IV ^p-Ar), 133.0 (2 × CH ^m-Ar), 136.5 (2 × C_IV ^o-Ar), 150.5 (2 × NC_IV ^Ar), 163.9 (2 × CH=N). HRMS (NSI⁺): m/z calcd for C₃₄H₅₁N₂I₂: 741.2136; found: 741.2139 [M + H]⁺. 4-Methoxy-2,6-diisopropylaniline (17, R = Me) A sealed tube was charged with MeOH (50 mL), CuI (2.46 g, 12.9 mmol, 0.5 equiv), phenanthroline (3.73 g, 20.7 mmol, 0.8 equiv), and Cs₂CO₃ (34.2 g, 105 mmol, 4.3 equiv) at r.t. To this brown mixture was added the starting diiododiimine 9 (15.4 g, 24.5 mmol, 1.0 equiv), and the reaction was stirred overnight (10 h) at 110 °C. The reaction was allowed to cool down to r.t. and was filtered through cotton wool. The remaining solid was washed with Et₂O (3 × 50 mL), and the filtrate was transferred into a separating funnel. The organic layer was washed with 10% NH₄OH (3 × 50 mL), then brine (50 mL), and was then dried over anhydrous Na₂SO₄. Concentration in vacuo afforded the crude methoxyaniline as viscous brown oil (10.4 g) that was purified by flash column chromatography (silica gel, 5–50% Et₂O in pentane). The pure desired methoxyaniline 17 was obtained as dark reddish viscous oil (7.40 g, 73%). On larger scale, the crude oil was successfully purified by distillation under reduced pressure (110–120 °C at 0.8 mbar). Our data were in full agreement with those reported in the literature.¹3b,14 ¹H NMR (400 MHz, CDCl₃): δ = 1.34 (12 H, d, J = 6.7 Hz, 4 × CH₃), 3.04 (2 H, m, 2 × CH), 3.52 (2 H, v br s, NH₂), 3.85 (3 H, s, OCH₃), 6.73 (2 H, s, H ^m-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 22.3 (4 × CH₃), 28.0 (2 × CH), 55.4 (OCH₃), 108.5 (2 × CH ^m-Ar), 133.8 (NC_IV ^Ar), 134.1 (2 × C_IV ^o-Ar), 152.6 (OC_IV ^Ar). N,N′-Bis(4-methoxy-2,6-diisopropylphenyl)1,4-diazabutadiene (13, R = Me) A solution of 4-methoxy-2,6-diisopropylaniline (17, 15.2 g, 73.4 mmol, 2.0 equiv) in MeOH (300 mL) was treated with formic acid (2 drops) followed by the dropwise addition of glyoxal (40% in H₂O, 6.43 mL, 74.4 mmol, 1.0 equiv) at r.t. The solution was stirred at this temperature for 2 h, and the MeOH was evaporated under vacuum and replaced by pentane (300 mL). The solution was dried over anhydrous Na₂SO₄, filtered, and partially concentrated in vacuo. Although good purity was obtained, the residual oil was preferably purified by flash column chromatography (silica gel, 10% Et₂O in pentane) to yield the pure desired diimine 13 as an orange solid (11.5 g, 72%). ¹H NMR (400 MHz, CDCl₃): δ = 0.81 (24 H, d, J = 6.9 Hz, 8 × CH₃), 3.04 (4 H, m, 4 × CH), 3.87 (OCH₃), 6.79 (4 H, s, 4 × H ^m-Ar), 8.14 (2 H, s, 2 × HC=N). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3 (8 × CH₃), 28.1 (4 × CH), 55.1 (2 × OCH₃), 108.6 (4 × CH ^m-Ar), 138.6 (4 × C_IV ^o-Ar), 141.6 (2 × NC_IV ^Ar), 157.2 (2 × OC_IV ^Ar), 163.5 (2 × HC=N). HRMS (NSI⁺): m/z calcd for C₂₈H₄₁O₂N₂: 437.3163; found: 437.3158 [M + H]⁺. N,N′-Bis[4-methoxy-2,6-di(3-pentyl)phenyl]1,4-diazabutadiene (14, R = Et)A sealed tube was charged with MeOH (20 mL), CuI (450 mg, 2.36 mmol, 0.5 equiv), phenanthroline (681 mg, 3.78 mmol, 0.8 equiv), and Cs₂CO₃ (6.26 g, 19.2 mmol, 4.3 equiv) at r.t. To this brown mixture was added the starting diiododiimine 10 (3.33 g, 4.50 mmol, 1.0 equiv), and the reaction was stirred overnight (10 h) at 110 °C. The reaction was allowed to cool to r.t. and was filtered through cotton wool. The remaining solid was washed with Et₂O (3 × 20 mL), and the filtrate was transferred into a separating funnel. The organic layer was washed with 10% NH₄OH (3 × 20 mL), then brine (20 mL), and was then dried over anhydrous Na₂SO₄. Concentration in vacuo afforded the crude dimethoxydiimine as viscous brown oil (2.60 g) that was filtered through silica and eluted with pentane. The filtrate was evaporated to yield the pure desired diimine 14 as brown viscous oil (2.47 g, quant.). ¹H NMR (400 MHz, CDCl₃): δ = 0.81 (24 H, t, J = 7.3 Hz, 8 × CH₃), 1.47–1.73 (16 H, m, 8 × CH₂), 2.54 (4 H, m, 4 × CH), 3.82 (OCH₃), 6.65 (4 H, s, 4 × H ^m-Ar), 8.02 (2 H, s, 2 × HC=N). ¹³C NMR (100 MHz, CDCl₃): δ = 12.1 (8 × CH₃), 28.9 (8 × CH₂), 42.6 (4 × CH), 55.1 (OCH₃), 109.2 (4 × CH ^m-Ar), 135.6 (4 × C_IV ^o-Ar), 144.8 (2 × NC_IV ^Ar), 157.0 (2 × OC_IV ^Ar), 164.4 (2 × HC=N). HRMS (NSI⁺): m/z calcd for C₃₆H₅₇O₂N₂: 549.4415; found: 549.4403 [M + H]⁺. 1,3-Bis[4-methoxy-2,6-di(3-pentyl)phenyl]imidazolium Chloride (22, R = Et, IPent^OMe·HCl) A solution of diimine 14 (2.30 g, 4.19 mmol, 1.0 equiv) in THF (164 mL) was treated with anhydrous ZnCl₂ (571 mg, 4.19 mmol, 1.0 equiv) at 70 °C and stirred for 5 min. p-Formaldehyde (132 mg, 4.40 mmol, 1.1 equiv) was subsequently added followed by the dropwise addition of anhydrous HCl (4.0 M in dioxane, 1.6 mL, 6.4 mmol, 1.5 equiv). The reaction was stirred for 3 h at 70 °C and concentrated under vacuum. The residue was dissolved in EtOAc (150 mL) and was washed with H₂O (3 × 100 mL) and brine (100 mL). The combined aqueous phases were extracted with EtOAc (50 mL), and the organic phases were combined and dried over anhydrous MgSO₄. The solvent was evaporated under vacuum, and the resulting brown solid (2.62 g) was triturated with pentane (3 × 65 mL) affording the pure desired imidazolium chloride 22 (1.62 g, 65%) as a beige solid. ¹H NMR (400 MHz, CDCl₃): δ = 0.58 (12 H, t, J = 7.4 Hz, 4 × CH₃), 0.63 (12 H, t, J = 7.4 Hz, 4 × CH₃), 1.32–1.58 (16 H, m, 8 × CH₂), 1.68 (4 H, m, 4 × CH), 3.70 (6 H, s, 2 × OCH₃), 6.56 (4 H, s, 4 × H ^m-Ar), 7.90 (2 H, s, 2 × HC=N), 8.38 (1 H, s, NCHN). ¹³C NMR (100 MHz, CDCl₃): δ = 11.9 (4 × CH₃), 12.0 (4 × CH₃), 28.0 (4 × CH₂), 28.7 (4 × CH₂), 43.2 (4 × CH), 55.2 (2 × OCH₃), 110.0 (4 × CH ^m-Ar), 125.0 (4 × C_IV ^o-Ar), 127.7 (2 × HC=N), 136.4 (NCHN), 143.6 (2 × NC_IV ^Ar), 161.4 (2 × OC_IV ^Ar). Anal. Calcd for C₃₅H₅₃ClN₂: C, 74.40; H, 9.62; N, 4.69. Found: C, 74.30; H, 9.79; N, 4.74. N,N′-Bis-(4-methoxy-2,6-diisopropylphenylamino)ethane (25) A solution of diimine 13 (11.5 g, 26.3 mmol, 1.0 equiv) in anhydrous THF (200 mL) was cooled to –20 °C and treated with LiAlH₄ (2.4 M in THF, 44.0 mL, 106 mmol, 4.0 equiv). Upon addition of LiAlH₄, the yellow solution rapidly turned very dark purple and important bubbling was observed. After 15 min at –20 °C, the color of the reaction changed back to clear orange, and the reaction was allowed to stirr for 45 min at r.t. The reaction was then cooled to 0 °C, diluted with Et₂O (200 mL), and carefully quenched with H₂O (5.0 mL). After stirring for 10 min, a 15% aqueous solution of NaOH (5.0 mL) was added, followed by H₂O (12 mL). The suspension was allowed to warm to r.t. and was stirred for 15 min before anhydrous MgSO₄ was added until a fine solid was obtained. The solids were discarded by filtration, and the filtrate was concentrated in vacuo affording a clear orange and very viscous oil (11.80 g) in excellent purity. However, the oil was preferably purified by flash column chromatography (silica, 10–20% Et₂O in pentane) to provide the pure desired diamine 25 as an orange viscous oil (11.35 g, 98%). ¹H NMR (400 MHz, CDCl₃: δ = 1.26 (24 H, d, J = 6.9 Hz, 4 × CH₃), 3.08 (6 H, v br s, 2 × CH₂ + 2 × NH), 3.40 (4 H, m, 4 × CH), 3.82 (6 H, m, 2 × OCH₃), 6.68 (4 H, s, 4 × H ^m-Ar). ¹³C NMR (100 MHz, CDCl₃: δ = 24.2 (8 × CH₃), 27.9 (4 × CH), 52.6 (2 × CH₂), 55.2 (2 × OCH₃), 108.9 (4 × CH ^m-Ar), 136.4 (2 × OC_IV ^p-Ar), 144.6 (4 × C_IV ^o-Ar), 156.2 (2 × NC_IV ^Ar). HRMS (NSI⁺): m/z calcd for C₂₈H₄₅O₂N₂: 441.3476; found: 441.3470 [M + H]⁺. 1,3-Bis-(4-methoxy-2,4-diisopropylphenyl)-imidazolinium Chloride (26, SIPr^OMe·HCl) A solution of diamine 25 (7.35 g, 16.7 mmol, 1.0 equiv) in triethyl orthoformate (60 mL) was heated to 120 °C and treated with the rapid addition of HCl (4.0 M in dioxane, 5.0 mL, 1.2 equiv). Upon addition of HCl, the clear solution immediately turned into a white suspension, and the stirring was continued for 10 min at 120 °C. The reaction was cooled to r.t. and was diluted with pentane (60 mL). The white solid was isolated by filtration and washed with pentane (3 × 60 mL). After drying under high vacuum, the desired imidazolinium chloride 25 was obtained as a bright white powder (7.80 g, 96%). ¹H NMR (400 MHz, CDCl₃): δ = 1.14 (12 H, d, J = 6.9 Hz, 4 × CH₃), 1.25 (12 H, d, J = 6.9 Hz, 4 × CH₃), 2.84 (4 H, m, 4 × CH), 3.74 (6 H, m, 2 × OCH₃), 4.58 (4 H, s, 2 × NCH₂), 6.62 (4 H, s, 4 × H ^m-Ar), 8.64 (1 H, s, N=CHN). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3 (4 × CH₃), 25.1 (4 × CH₃), 29.1 (4 × CH), 55.2 (2 × OCH₃), 109.8 (4 × CH ^m-Ar), 121.9 (2 × CH ^p-Ar), 147.4 (4 × C_IV ^o-Ar), 159.4 (NCHN), 161.1 (2 × NC_IV ^Ar). Anal. Calcd for C₂₉H₄₃ClN₂O₂: C, 71.51; H, 8.90; N, 5.75. Found: C, 71.40; H, 9.01; N, 5.85. 4-Methoxy-2,6-di(3-pentyl)aniline (18, R = Et) A solution of IPent diimine 14 (2.75 g, 5.01 mmol, 1.0 equiv) in EtOH (23 mL) was treated with a HCl solution (37% in H₂O, 11.6 mL, 120 mmol, 28 equiv) at r.t. The reaction turned brown upon the addition of HCl and after 10 min at r.t. it was allowed to stir at 100 °C for a further 10 min. The reaction was cooled to r.t. and carefully neutralized with a sat. aq solution of NaOH (6 mL). The mixture was then extracted with pentane (3 × 25 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude aniline (5.05 g) was obtained in excellent purity but was preferably purified by flash column chromatography (silica, 1–5% Et₂O in pentane) to afford the pure desired aniline 18 as an orange clear viscous oil (2.28 g, 86%). ¹H NMR (400 MHz, CDCl₃): δ = 0.84 (12 H, t, J = 7.4 Hz, 4 × CH₃), 1.51–1.78 (8 H, m, 4 × CH₂), 2.53 (2 H, m, 2 × CH), 3.34 (2 H, v br s, NH₂), 3.76 (3 H, s, OCH₃), 6.51 (2 H, s, H ^m-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 12.0 (4 × CH₃), 28.2 (4 × CH₂), 42.5 (2 × CH), 55.4 (OCH₃), 109.5 (2 × CH ^m-Ar), 132.0 (2 × C_IV ^o-Ar), 136.3 (OC_IV ^Ar), 152.7 (NC_IV ^Ar). HRMS (NSI⁺): m/z calcd for C₁₇H₃₀ON: 264.2322; found: 264.2321 [M + H]⁺ .