Facile Preparation of Λ-Shaped Building Blocks: Hünlich Base Derivatization

Abstract

Hünlich’s base modification has resulted in introducing a series of versatile Λ-shaped building blocks presented in this work. The methods are optimized to provide convenient approaches in the quicker production of these new building blocks in low-cost and low-risk.

Key words

amines - bicyclic compounds - azo compounds - diazo compounds - nucleophilic aromatic substitution - phenols - protecting groups - thiols

• References and Notes

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• 35 Synthesis and Characterization of Compound 1 Hünlich’s base (0.56 g, 2.0 mmol, 1.0 equiv) solution in H₂SO₄ (6.5%, 30 mL) was cooled down to –5 °C. A NaNO₂ solution (0.30 g, 4.4 mmol, 2.2 equiv in 5 mL cold H₂O) was dropped into the reaction flask and stirred for 30 min. The resulting yellowish solution was poured into a solution consisting N-benzylmethylamine (3 mL, excess), Na₂CO₃ (4.5 g), H₂O (60 mL), and MeCN (30 mL) chilled at –10 °C. The stirring was continued for 3 h meanwhile the temperature was gradually raised to r.t.; afterward, a beige precipitate was extracted from the aqueous mixture by CH₂Cl₂ (3 × 50 mL). The CH₂Cl₂ layers were combined, dried over Na₂SO₄, and filtered. The evaporation of the CH₂Cl₂ gave the crude product which was then purified by chromatography to furnish the purified bistriazene compound 1 as a light-yellow solid. Yield 0.65 g (1.2 mmol, 60%); R_f = 0.3 (silica gel; MeOH–CH₂Cl₂, 2% v/v). IR (neat): 3027, 2941, 2893, 2844, 1610, 1486, 1441, 1341, 1173, 1047, 921, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.38 (m, 12 H, CH), 6.74 (s, 2 H, CH), 4.91–5.02 (q, J = 16.1 Hz, 4 H, NCH₂), 4.66–4.70 (d, J = 16.6 Hz, 2 H, CH₂), 4.36 (s, 2 H, NCH₂N), 4.22–4.26 (d, J = 16.8 Hz, 2 H, CH₂), 3.15 (b, 6 H, NCH₃), 2.30 (s, 6 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 147.9, 146.3, 137.1, 129.0, 128.7, 128.6, 128.0, 127.7, 125.1, 112.7, 67.3, 58.8, 34.4, 17.2. MS (ESI⁺; i-PrOH): m/z [M + H]⁺ calcd for [C₃₃H₃₇N₈]⁺: 545.31; found: 545.2. UV-vis: (EtOAc): λ (lg ε) = 297 (4.465) nm. Anal. Calcd for C₃₃H₃₆N₈: C, 72.77; H, 6.66; N, 20.57. Found: C, 72.56; H, 6.85; N, 20.18.
• 36 Synthesis and Characterization of Compound 2 The bistriazene compound 1 (0.54 g, 1.0 mmol, 1.0 equiv) was poured into a 50 mL round-bottom flask containing CH₂Cl₂ (20 mL). A solution of trichloroacetic acid (5.0 g, 30 mmol, excess, in CH₂Cl₂ (20 mL)) was added and stirred for 2 min. Afterward, Na₂S (0.70 g, 9 mmol, excess) was slowly added to the reaction flask, as shown in the following figure, and remained sealed when stirred for 2 hours at r.t. The volume of the resulting yellowish suspension was then reduced to half by nitrogen gas flow and then refluxed for 30 min. The reaction mixture cooled down to r.t. and diluted with CH₂Cl₂ (100 mL), and filtered. The CH₂Cl₂ layer was rinsed with cold H₂O (5 × 100 mL), dried over Mg₂SO₄, and filtered. The CH₂Cl₂ was removed, and the residue was purified by column chromatography to obtain a pale-lemon substance with a mild rotten-egg odour which was then stored under argon in darkness. Yield 0.06 g (0.19 mmol, 19%); R_f = 0.2 (silica gel, MeOH–CH₂Cl₂, 4% v/v). IR (neat): 2896, 2847, 2560, 1608, 1492, 1474, 1205, 1091, 1010, 811 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (br, 2 H, SH), 6.65 (s, 2 H, CH), 6.17 (s, 2 H, CH), 4.56–4.60 (d, J = 16.7 Hz, 2 H), 4.28 (s, 2 H, NCH₂N), 4.17–4.13 (d, J = 16.8 Hz, 2 H), 2.10 (s, 6 H, 2CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 143.8, 134.5, 128.6, 127.4, 126.8, 124.7, 67.1, 58.4, 20.9. MS (ESI⁺; i-PrOH–EtOAc–H₂O/0.5% HCO₂Na = 90:5:5): m/z [M + Na]⁺ calcd for [C₁₇H₁₈N₂S₂Na]⁺: 337.08; found: 337.0. MS (ESI^–): m/z [M – H]^– calcd for [C₁₇H₁₇N₂S₂]^–: 313.09; found: 313.1. MS (ESI⁺; MeCN/Δ): m/z [M + 2MeCN + H]⁺ calcd for [C₂₁H₂₅N₄S₂]⁺: 397.14; found: 397.1. UV-vis: (EtOAc): λ (lg ε) = 277 (3.583) nm. Anal. Calcd for C₁₇H₁₈N₂S₂: C, 64.93; H, 5.77; N, 8.91; S, 20.39. Found: C, 65.08; H, 5.83; N, 9.22.
• 37 Synthesis and Characterization of Compound 3 Hünlich’s base (0.56 g, 2.0 mmol, 1.0 equiv) was dissolved in H₂SO₄ (6.5%, 90 mL), then cooled down to –5 °C. A NaNO₂ solution (0.30 g, 4.4 mmol, 2.2 equiv) in cold H₂O (10 mL) was dropped into the reaction flask and stirred for 30 min. Afterward, the solution’s temperature was gradually raised to boil, over 2 h (attention: this step releases nitrogen gas; hence, rapid heating and sealing the container may lead to explosion). The reaction mixture was cooled down to r.t., its pH was adjusted to 5 (by adding Na₂CO₃ sat. solution) and extracted with EtOAc (5 × 30 mL), the organic layers were combined, dried over Na₂SO₄, and evaporated to dryness to obtain the product as a light-grey powder. Yield 0.54 g (1.9 mmol, 96%). R_f = 0.3 (silica gel, MeOH–CH₂Cl₂, 8% v/v). IR (neat): 3649, 3549, 3012, 2948, 2904, 2857, 1620, 1508, 1368, 1081, 910 cm⁻¹. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.06 (s, 2 H, OH), 6.56 (s, 2 H, CH), 6.45 (s, 2 H, CH), 4.39–4.43 (d, J = 16.4 Hz, 2 H, CH₂), 4.07 (s, 2 H, NCH₂N), 3.81–3.85 (d, J = 16.4 Hz, 2 H, CH₂), 1.97 (s, 6 H, CH₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.1, 146.5, 128.2, 119.9, 117.9, 110.0, 66.5, 57.8, 15.5. MS (ESI⁺; EtOH–EtOAc–H₂O, 90:5:5): m/z [M + H]⁺ calcd for [C₁₇H₁₉N₂O₂]⁺: 283.14; found: 283.1. MS (ESI^–): m/z [M – H]^– calcd for [C₁₇H₁₇N₂O₂]^–: 281.14; found: 281.1. UV-vis: (EtOAc): λ (lg ε) = 292 (3.643) nm. Anal. Calcd for C₁₇H₁₈N₂O₂: C, 72.32; H, 6.43; N, 9.92; O, 11.33. Found: C, 72.21; H, 6.61; N, 9.74.