An Investigation of the Asymmetric Huisgen ‘Click’ Reaction^[1]

Abstract

The preparation of a series of new prochiral bis-alkynes is reported. A selection of chiral ligands is examined to gain additional information about the scope of the new asymmetric Huisgen ‘click’ reaction [the desymmetrisation of bis-alkynes using chiral ligands in conjunction with the widely applied copper-catalysed azide–alkyne cycloaddition (CuAAC) triazole synthesis]. The development of a new chiral assay for (±)-methyl 2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-cyanopent-4-ynoate, and the production of this mono-triazole in up to 18% enantiomeric excess is described.

Key words

chiral ligands - copper - CuAAC reaction - asymmetric synthesis

• References and Notes

• 1 Asymmetric click chemistry, Part 1.
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• 29 Methyl 2-Cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1); Typical Procedure Methyl cyanoacetate (20 g, 202 mmol) was suspended in MeCN (600 mL). K₂CO₃ (69.7 g, 505 mmol) was added and the mixture was cooled in an ice bath. Propargyl bromide (49.5 mL, 444 mmol) was added, and the resulting orange suspension was heated at reflux temperature overnight. The deep yellow suspension was allowed to cool and worked up with H₂O (400 mL). The deep brown organic layer was separated, and the brown aqueous layer was extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with H₂O (250 mL) and brine (250 mL), and dried over anhydrous MgSO₄. After evaporating the solvents, the resulting brown oil was purified by vacuum distillation at 115–125 °C to give methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) as a colourless oil, which solidified to a white solid (25.1 g, 143 mmol, 71%). IR (neat): 3275, 2249 (nitrile), 1740 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.89 (s, 3 H), 2.94 (d, J = 2.6 Hz, 4 H), 2.24 (t, J = 2.6 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.6, 117.0, 76.0, 73.7, 54.1, 47.1, 25.6. HRMS (NSI): m/z [M + NH₄]⁺ calcd for C₁₀H₁₃O₂N₂: 193.0972; found: 193.0971. tert-Butyl 2-Cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (2) Yield: 4.0 g (53%); pale solid. IR (neat): 3289, 2989, 2979, 1728 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.86 (d, J = 2.7 Hz, 4 H), 2.19 (t, J = 2.7 Hz, 2 H), 1.50 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.8, 117.7, 85.5, 76.6, 73.6, 47.8, 27.9, 25.8. HRMS (NSI): m/z [M + NH₄]⁺ calcd for C₁₃H₁₉O₂N₂: 235.1441; found: 235.1444. Methyl 2-Acetyl-2-(prop-2-yn-1-yl)pent-4-ynoate (3) Yield: 550 mg (31%); white solid. IR (neat): 3277, 2967, 1747 (C=O), 1712 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.75 (s, 3 H), 2.90–2.95 (m, 4 H), 2.18 (s, 3 H), 2.00 (t, J = 2.7 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 200.9, 169.9, 78.6, 72.2, 62.6, 53.4, 26.3, 22.0. HRMS (NSI): m/z [M + H]⁺ calcd for C₁₁H₁₃O₃: 193.0859; found: 193.0859.
• 30 tert-Butyl ethyl malonate (1 mL, 0.994 g, 5.28 mmol), propargyl bromide (2.1 mL, 18.85 mmol) and K₂CO₃ (2.82 g, 20.39 mmol) were combined in MeCN (20 mL). The yellow suspension was heated at reflux temperature overnight. The cooled reaction mixture was worked up with H₂O (15 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H₂O (20 mL) and brine (20 mL), dried over anhydrous MgSO₄ and the solvents evaporated. Crystallisation of the residue from EtOH gave crystals of the pure product, 1-tert-butyl 4-ethyl 2,2-di(prop-2-yn-1-yl)malonate (4) (262 mg, 0.99 mmol, 19%). IR (neat): 3284, 3262, 2983, 1728 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.19 (q, J = 7.1 Hz, 2 H), 2.90 (d, J = 2.6 Hz, 4 H), 1.99 (t, J = 2.6 Hz, 2 H), 1.41 (s, 9 H), 1.23 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.1, 167.7, 82.9, 78.9, 71.7, 62.0, 56.8, 27.9, 22.6, 14.3. HRMS (NSI): m/z [M + Na]⁺ calcd for C₁₅H₂₀O₄Na: 287.1254; found: 287.1259.
• 31a Gommermann N, Gehrig A, Knochel P. Synlett 2005; 2796
• 31b For an example with copper nanoparticles, see: Orgueira HA, Fokas D, Isome Y, Chan PC.-M, Baldino CM. Tetrahedron Lett. 2005; 46: 2911
• 31c For an example with copper turnings, see: David O, Maisonneuve S, Xie J. Tetrahedron Lett. 2007; 48: 6527
• 32 General procedure for method A: benzyl azide (1–2.5 equiv) and methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (1 g, 5.71 mmol) were dissolved in t-BuOH–H₂O (2:1 v/v) (for concentrations, see Table 1) and Cu powder (2 equiv) was added. The mixture was stirred at r.t. overnight and then diluted with H₂O. After filtration through Celite to remove the Cu powder, the resulting liquid was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with H₂O and brine and then dried over anhydrous MgSO₄. The solvents were removed under reduced pressure. Representative procedure for method B with in situ generation of the benzyl azide: NaN₃ (0.412 g, 6.34 mmol) was dissolved in DMSO (25 mL) with vigorous stirring. Benzyl bromide (0.830 mL, 6.98 mmol) was added, and the mixture stirred for 2 h. Methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (1 g, 5.71 mmol) and Cu powder (0.605 g, 9.51 mmol) were added, and the mixture stirred at r.t. overnight. The mixture was diluted with H₂O. After filtration through Celite to remove the Cu powder, the resulting liquid was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with H₂O and brine, and then dried over anhydrous MgSO₄. The solvents were removed under reduced pressure.
• 33 Representative procedure for method C: methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (100 mg, 0.57 mmol), copper(I) iodide (16 mg, 0.064 mmol) and NaN₃ (46 mg, 0.705 mmol) were combined in a 5 mL microwave reactor vial. The solvent (t-BuOH–H₂O, 1:1, 4 mL) was added and the vial sealed. Benzyl bromide (0.076 mL, 0.64 mmol) was added through the septum, and the vessel was heated in a microwave reactor at 125 °C, 100 W, for 20 min. The cooled mixture was worked up with H₂O, and extracted with EtOAc. The combined organic layers were washed with H₂O and brine, and then dried over anhydrous MgSO₄. The solvents were removed under reduced pressure. The products were isolated by column chromatography, eluting with hexane–EtOAc (2:1), see references 38 and 39.
• 34 Appukkuttan P, Dehaen W, Fokin VV, Van der Eycken E. Org. Lett. 2004; 6: 4223
• 35 Cravotto G, Mendicuti F, Martina K, Tagliapietra S, Robaldo B, Barge A. Synlett 2008; 2642

Simple diynes are known to form bis-triazoles by double CuAAC reactions, see:
• 36a Park IS, Kwon MS, Kim Y, Lee JS, Park J. Org. Lett. 2008; 10: 497
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• 36d Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Org. Lett. 2004; 6: 2853
• 36e The control of mono- and bis-products from 1,3-butadiene has been studied: Aizpurua JM, Azcune I, Fratila RM, Balentova E, Sagartzazu-Aizpurua M, Miranda JI. Org. Lett. 2010; 12: 1584

Similar bis-triazole formation is possible in the CuAAC reactions of mono-alkynes though competing Glaser-type alkyne coupling processes:
• 36f Angell Y, Burgess K. Angew. Chem. Int. Ed. 2007; 46: 3649
• 36g González J, Pérez VM, Jiménez DO, Lopez-Valdez G, Corona D, Cuevas-Yañez E. Tetrahedron Lett. 2011; 52: 3514
• 37a For an example of the formation of a bis-triazole from a glycine-derived meso bis-alkyne, see: Struthers H, Mindt TL, Schibli R. Dalton Trans. 2010; 39: 675
• 37b Statistical mixtures of mono- and bis-triazoles have been reported previously for a ‘click’ reaction of a meso-diyne performed in the absence of a chiral ligand, see: Rodionov VO, Fokin VV, Finn MG. Angew. Chem. Int. Ed. 2005; 44: 2210
• 38 Methyl 2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-cyanopent-4-ynoate (5) For yields, see Table 1; mp 71–72 °C. IR (neat): 2249 (nitrile), 1748 (C=O), 1497 (C=C aromatic), 1455 (N=N), 1436 (C-H alkyne) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.49 (s, 1 H), 7.41–7.32 (m, 3 H), 7.26–7.21 (m, 2 H), 5.52 (s, 2 H), 3.80 (s, 3 H), 3.39 (s, 2 H), 2.93 (dd, J = 16.9, 2.6 Hz, 1 H), 2.81 (dd, J = 16.9, 2.6 Hz, 1 H), 2.22 (t, J = 2.6 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 167.2, 134.6, 129.1, 128.7, 128.2, 127.9, 123.3, 117.7, 76.7, 73.6, 54.1, 49.1, 32.2, 26.3. HRMS (NSI): m/z [M + H]⁺ calcd for C₁₇H₁₇N₄O₂: 309.1346; found: 309.1345.
• 39 Methyl 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-cyanopropanoate (6) For yields, see Table 1. IR (neat): 3132, 3065, 3035, 2997, 2962, 2246 (nitrile), 1740 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (s, 2 H), 7.28–7.20 (m, 6 H), 7.09–7.15 (m, 4 H), 5.39 (s, 4 H), 3.58 (s, 3 H), 3.24–3.20 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.1, 134.9, 129.2, 128.8, 128.4, 128.1, 123.6, 118.5, 54.2, 53.9, 50.4, 32.4. HRMS (NSI): m/z [M + H]⁺ calcd for C₂₄H₂₄N₇O₂: 442.1986; found: 442.1984.
• 40 Alvarez SG, Alvarez MT. Synthesis 1997; 413
• 41 (R,R)-NORPHOS (0.017 g, 0.038 mmol) and copper(I) iodide (4.76 mg, 0.025 mmol) were combined in toluene (5 mL). DIPEA (0.13 mL, 0.750 mmol) was added, and the mixture was allowed to stir at r.t. to allow the complex to form. The mixture was then cooled to –40 °C and methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (0.044 g, 0.250 mmol) and benzyl azide (0.031 mL, 0.25 mmol) were added, and the mixture stirred at –40 °C for 18 h. The mixture was filtered through silica while still cold, to prevent any further reaction occurring, and the silica pad was washed through with CH₂Cl₂ (5 mL). The solvents were evaporated, and the residue was analysed by NMR spectroscopy.
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• 43a Gaumont, A.-C.; Gulea, M.; Masson, S. unpublished results.
• 43b For the isopropyl example of this ligand series, see: Abrunhosa I, Delain-Bioton L, Gaumont A.-C, Gulea M, Masson S. Tetrahedron 2004; 60: 9263
• 43c See also: Gaumont A.-C, Gulea M, Levillain J. Chem. Rev. 2009; 109: 1371