An Approach to Nonsymmetric Bis(tertiary phosphine oxides) Comprising Heterocyclic Fragments via the Pd-Catalyzed Phosphorylation

Abstract

Nonsymmetric tertiary phosphine oxides with different five- and six-membered heterocyclic fragments such as pyridine, 2,2′-bipyridine, 1,10-phenantroline, quinoline, imidazole, and thiazole were synthesized in good yields via the successive introduction of phosphine oxide groups into the initial dihalogenated heterocycles by means of Pd-catalyzed phosphorylation reaction. The synthesis of pyridine-type compounds is hindered by competing double coupling, while for five-membered heterocycles the principal difficulty is the dehalogenation. Both side processes were successfully suppressed by the use of an excess of a dihalide (which can be easily recovered during the product purification step), proper phosphine ligand for palladium, and nonpolar solvent such as toluene.

Key words

cross-coupling - phosphorylation - nonsymmetric phosphine oxide - palladium - heterocycles - dehalogenation

• References and Notes

• 1 Etter MC, Baures PW. J. Am. Chem. Soc. 1988; 110: 639
• 2 Hazra S, Hoshimoto Y, Ogoshi S. Chem. Eur. J. 2017; 23: 15238
• 3 Kotani S, Nakajima M. Tetrahedron Lett. 2020; 61: 151421
• 4 Sugiura M, Nakajima M. In Encyclopedia of Reagents for Organic Synthesis. EROS; 2010
• 5 Denmark SE, Beutner GL. Angew. Chem. Int. Ed. 2008; 47: 1560
• 6 Giesbrecht E. Pure Appl. Chem. 1979; 51: 925
• 7 Platt AW. G. Coord. Chem. Rev. 2017; 340: 62
• 8 Kido J, Okamoto Y. Chem. Rev. 2002; 102: 2357
• 9 Ferreira da Rosa PP, Kitagawa Y, Hasegawa Y. Coord. Chem. Rev. 2020; 406: 213153
• 10 Xu H, Chen R, Sun Q, Lai W, Su Q, Huang W, Liu X. Chem. Soc. Rev. 2014; 43: 3259
• 11 Xu H, Sun Q, An Z, Wei Y, Liu X. Coord. Chem. Rev. 2015; 293–294: 228
• 12 Binnemans K. Chem. Rev. 2009; 109: 4283
• 13 Dam HH, Reinhoudt DN, Verboom W. Chem. Soc. Rev. 2007; 36: 367
• 14 Leoncini A, Huskens J, Verboom W. Chem. Soc. Rev. 2017; 46: 7229
• 15 Bhattacharyya A, Mohapatra Prasanta K. Radiochim. Acta 2019; 107: 931
• 16 Zakirova GG, Matveev PI, Mladentsev DY, Evsiunina MV, Tafeenko VA, Borisova NE. Mendeleev Commun. 2019; 29: 463
• 17 Matveev PI, Borisova NE, Andreadi NG, Zakirova GG, Petrov VG, Belova EV, Kalmykov SN, Myasoedov BF. Dalton Trans. 2019; 48: 2554
• 18 Bhattacharyya A, Ansari SA, Matveev PI, Zakirova GG, Borisova NE, Petrov VG, Sumyanova T, Verma PK, Kalmykov SN, Mohapatra PK. Dalton Trans. 2019; 48: 16279
• 19 Zakirova GG, Mladentsev DY, Borisova NE. Tetrahedron Lett. 2017; 58: 3415
• 20 Zakirova GG, Mladentsev DY, Borisova NE. Synthesis 2019; 51: 2379
• 21 Zawisza AM, Muzart J. Tetrahedron Lett. 2007; 48: 6738
• 22 Zawisza AM, Ganchegui B, González I, Bouquillon S, Roglans A, Hénin F, Muzart J. J. Mol. Catal. A: Chem. 2008; 283: 140
• 23 Molina de la Torre JA, Espinet P, Albéniz AC. Organometallics 2013; 32: 5428
• 24 Abbas S, Hayes CJ, Worden S. Tetrahedron Lett. 2000; 41: 3215
• 25 Scale, halide/SPO ratio, catalytic system loading, and yield are shown in Scheme 1, Table 1, and Table 2 for each tertiary phosphine oxide product. An oven-dried Schlenk flask was evacuated and back-filled with argon three times. Heteroaryl (di)halide, base (1.3 equiv relative to SPO), and a solution of an SPO in an anhydrous solvent (7 mL/mmol per halogen) were added to the flask. The solution was bubbled with argon for 10 min and Pd(OAc)₂ and a phosphine ligand were added to the flask simultaneously. The resulting mixture was stirred and heated at the indicated temperature for the given time. Workup procedures are described below for two different solvents. Final purification of crude products was achieved by column chromatography on silica gel (40–60 um) using CH₂Cl₂–MeOH as eluent. For Reactions Conducted in DMF After cooling, the reaction mixture was poured into a fourfold excess of brine. The mixture was extracted three times with CH₂Cl₂ (40 mL/mmol each). The combined organic layers were washed with brine to remove traces of DMF, dried over Na₂SO₄, and then evaporated to dryness. For reactions Conducted in Toluene After cooling, the reaction mixture was evaporated to dryness. Then, the mixture was diluted with CH₂Cl₂ (40 mL/mmol) and washed with water and brine (40 mL/mmol). The organic layer was dried over Na₂SO₄ and the CH₂Cl₂ was removed under reduced pressure. Notice that all compounds with two phosphine oxide groups are beige-to-brown solids or slowly solidifying viscous brown oils.
• 26 Analytical Data for Compound 2 ¹H NMR (400 MHz, CDCl₃): δ = 8.52–8.57 (m, 1 H, H_Quin), 8.42–8.45 (m, 1 H, H_Quin), 8.37–8.40 (m, 1 H, H_Quin), 8.06 (d, 1 H, J = 8.2 Hz, H_Quin), 7.77 (t, 1 H, J = 7.6 Hz, H_Quin), 7.66–7.71 (m, 4 H, 2-H_Ph), 7.56–7.60 (m, 2 H, 4-H_Ph), 7.45–7.49 (m, 4 H, 3-H_Ph), 1.61–1.77 (m, 4 H, H_Oct), 1.32–1.45 (m, 2 H, H_Oct), 0.97–1.27 (m, 22 H, H_Oct), 0.83 (t, 6 H, J = 7.2 Hz, H_Oct). ¹³C NMR (101 MHz, CDCl₃): δ = 157.39 (d, J = 129.3 Hz, 1 C), 146.79 (dd, J = 20.5, 7.6 Hz, 1 C), 138.68 (d, J = 4.2 Hz, 1 C), 137.55 (d, J = 9.0 Hz, 1 C), 132.44 (1 C), 132.37 (d, J = 2.4 Hz, 2 C), 132.10 (d, J = 9.8 Hz, 4 C), 131.47 (d, J = 104.8 Hz, 2 C), 131.61 (1 C), 128.65 (d, J = 12.6 Hz, 4 C), 128.30 (d, J = 4.2 Hz, 1 C), 128.01 (d, J = 10.7 Hz, 1 C), 124.08 (d, J = 21.6 Hz, 1 C), 31.70 (2 С), 30.91 (d, J = 14.6 Hz, 2 C), 29.80 (d, J = 68.9 Hz, 2 C), 29.12 (2 C), 29.01 (2 C), 22.56 (2 C), 21.34 (d, J = 4.4 Hz, 2 C), 14.05 (2 C). ³¹P NMR (162 MHz, CDCl₃): δ = 41.64, 27.76. HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₇H₄₉NO₂P₂ + H⁺: 601.3239; found: 601.3233. Analytical Data for Compound 7 ¹H NMR (400 MHz, CDCl₃): δ = 8.38 (t, 1 H, J = 6.5 Hz, 3-H_Py), 8.18 (t, 1 H, J = 5.7 Hz, 5-H_Py), 8.00–8.05 (m, 1 H, 4-H_Py), 7.76–7.81 (m, 4 H, 2-H_Ph), 7.52–7.56 (m, 2 H, 4-H_Ph), 7.42–7.46 (m, 4 H, 3-H_Ph), 1.78–1.92 (m, 4 H, H_Oct), 1.46–1.58 (m, 2 H, H_Oct), 1.08–1.33 (m, 22 H, H_Oct), 0.86 (t, 6 H, J = 7.1 Hz, H_Oct). ¹³C NMR (101 MHz, CDCl₃): δ = 157.34 (dd, J = 114.6, 17.3 Hz, 1 C), 156.98 (dd, J = 128.2, 16.0 Hz, 1 C), 136.47 (t, J = 8.0 Hz, 1 С), 131.70 (d, J = 104.8 Hz, 2 С), 132.00 (2 C), 131.90 (d, J = 8.6 Hz, 4 C), 128.94–129.33 (m, 2 С), 128.21 (d, J = 12.3 Hz, 4 C), 31.63 (2 C), 30.88 (d, J = 13.6 Hz, 2 С), 28.87–28.92 (m, 4 C), 28.54 (d, J = 69.1 Hz, 2 C), 22.49 (2 C), 21.21 (d, J = 3.7 Hz, 2 C), 13.98 (2 C). ³¹P NMR (162 MHz, CDCl₃): δ = 42.65, 21.79. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₃₃H₄₇NO₂P₂ + Na⁺: 574.2974; found: 574.2973. Analytical Data for Compound 8 ¹H NMR (600 MHz, CDCl₃): δ = 8.48 (d, 1 H, J = 8.1 Hz, H_Bipy), 8.32–8.35 (m, 1 Н, H_Bipy), 8.30 (d, 1 H, J = 8.0 Hz, H_Bipy), 8.10–8.12 (m, 1 Н, H_Bipy), 7.99 (td, 1 Н, J = 7.8, 3.8 Hz, H_Bipy), 7.90–7.93 (m, 5 Н, 2-H_Ph, H_Bipy), 7.51 (t, 2 H, J = 7.4 Hz, 4-H_Ph), 7.41–7.46 (m, 4 Н, 3-H_Ph), 1.99–2.11 (m, 4 H, H_Oct), 1.62–1.71 (m, 2 H, H_Oct), 1.36–1.45 (m, 2 H, H_Oct), 1.27–1.35 (m, 2 Н, H_Oct), 1.10–1.22 (m, 16 Н, H_Oct), 0.78 (t, 6 H, J = 6.9 Hz, H_Oct). ¹³C NMR (151 MHz, CDCl₃): δ = 156.15 (d, J = 117.5 Hz, 1 С), 155.75 (d, J = 131.0 Hz, 1 С), 155.34 (d, J = 18.9 Hz, 1 С), 155.25 (d, J = 17.4 Hz, 1 С), 137.19 (d, J = 19.2 Hz, 1 С), 137.13 (d, J = 18.1 Hz, 1 С), 132.81 (d, J = 104.3 Hz, 2 С), 132.02 (d, J = 9.5 Hz, 4 С), 131.88 (d, J = 2.0 Hz, 2 С), 128.56 (d, J = 20.0 Hz, 1 С), 128.24 (d, J = 12.1 Hz, 4 С), 128.13 (d, J = 19.0 Hz, 1 С), 122.33 (d, J = 9.7 Hz, 1 С), 122.32 (d, J = 8.8 Hz, 1 С), 31.63 (2 С), 30.84 (d, J = 13.9 Hz, 2 С), 28.89 (2 С), 28.86 (2 С), 28.46 (d, J = 68.1 Hz, 2 С), 22.46 (2 С), 21.28 (d, J = 4.0 Hz, 2 С), 13.94 (2 С). ³¹P NMR (162 MHz, CDCl₃): δ = 42.64, 21.45. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₃₈H₅₀N₂O₂P₂ + Na⁺: 651.3240; found: 651.3243. Analytical Data for Compound 9 ¹H NMR (400 MHz, CDCl₃): δ = 8.66 (dd, 1 H, J = 8.1, 4.3 Hz, 3-H_Phen), 8.46–8.59 (m, 1 H, 8-H_Phen), 8.40–8.45 (m, 2 H, 4-H _Phen), 7-H_Phen), 8.28–8.34 (m, 4 H, 2-H_Ph), 7.89–7.94 (m, 2 H, 5-H_Phen, 6-H_Phen), 7.47–7.51 (m, 2 H, 4-H_Ph), 7.41–7.45 (m, 4 H, 3-H_Ph), 2.19–2.36 (m, 4 H, H_Oct), 1.68–1.81 (m, 2 H, H_Oct), 1.40–1.53 (m, 2 H, H_Oct), 1.04–1.33 (m, 20 H, H_Oct), 0.77 (t, 6 H, J = 7.0 Hz, H_Oct). ¹³C NMR (101 MHz, CDCl₃): δ = 157.69 (d, J = 118.6 Hz, 1 C), 157.21 (d, J = 132.2 Hz, 1 C), 146.12 (d, J = 19.0 Hz, 1 C),145.85 (d, J = 20.1 Hz, 1 C), 136.05 (d, J = 25.6 Hz, 1 C), 135.96 (d, J = 24.9 Hz, 1 C), 132.79 (d, J = 103.3 Hz, 2 C), 132.03 (d, J = 9.0 Hz, 4 C), 131.62 (d, J = 2.6 Hz, 2 C), 129.29 (d, J = 2.6 Hz, 1 C), 129.22 (d, J = 2.6 Hz, 1 C), 128.18 (d, J = 12.0 Hz, 4 C), 128.17 (1 C), 127.82 (1 C), 125.99 (d, J = 18.8 Hz, 1 C), 125.88 (d, J = 21.0 Hz, 1 C), 31.59 (2 C), 30.95 (d, J = 13.6 Hz, 2 C), 28.94 (2 C), 28.92 (2 C), 28.71 (d, J = 67.8 Hz, 2 C), 22.45 (2 C), 21.40 (d, J = 4.2 Hz, 2 C), 13.93 (2 C). ³¹P NMR (162 MHz, CDCl₃): δ = 43.64, 16.55. HRMS (ESI+): m/z [M + 1/2Ca²⁺]⁺ calcd for C₄₀H₅₀N₂O₂P₂ + 1/2Ca²⁺: 672.3155; found: 672.3159. Analytical Data for Compound 13 ¹H NMR (400 MHz, CDCl₃): δ = 8.47 (dd, 1 H, J = 2.9, 2.1 Hz, 5-H_Thz), 7.83–7.88 (m, 4 H, 2-H_Ph), 7.57–7.61 (m, 2 H, 4-H_Ph), 7.46–7.51 (m, 4 H, 3-H_Ph), 1.95–2.02 (m, 4 H, H_Oct), 1.53–1.66 (m, 2 H, H_Oct), 1.20–1.41 (m, 22 H, H_Oct), 0.87 (t, 6 H, J = 7.0 Hz, H_Oct). ¹³C NMR (101 MHz, CDCl₃): δ = 167.64 (dd, J = 124.5, 17.9 Hz, 1 C), 154.96 (dd, J = 96.2, 19.9 Hz, 1 C), 134.34 (d, J = 20.3 Hz, 1 C), 132.65 (d, J = 2.4 Hz, 2 C), 131.62 (d, J = 10.1 Hz, 4 C), 130.94 (d, J = 109.8 Hz, 2 C), 128.55 (d, J = 12.9 Hz, 4 C), 31.67 (2 C), 30.83 (d, J = 14.4 Hz, 2 C), 29.55 (d, J = 69.7 Hz, 2 C), 28.95 (4 C), 22.51 (2 C), 21.35 (d, J = 3.7 Hz, 2 C), 14.02 (2 C). ³¹P NMR (162 MHz, CDCl₃): δ = 39.43, 18.92. HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₁H₄₅NO₂P₂S + H⁺: 558.2719; found: 558.2711. Analytical Data for Compound 14 ¹H NMR (600 MHz, CDCl₃): δ = 7.80–7.83 (m, 4 H, 2-H_Ph), 7.63 (s, 1 H, 5-H_Im), 7.55–7.57 (m, 2 H, 4-H_Ph), 7.45–7.48 (m, 4 H, 3-H_Ph), 4.02 (s, 1 H, H_Me), 1.83–1.94 (m, 4 H, H_Oct), 1.56–1.65 (m, 2 H, H_Oct), 1.23–1.46 (m, 22 H, H_Oct), 0.88 (t, 6 H, J = 7.1 Hz, H_Oct). ¹³C NMR (151 MHz, CDCl₃): δ = 142.66 (dd, J = 143.8, 15.2 Hz, 1 C), 136.22 (dd, J = 128.5, 14.4 Hz, 1 C), 132.98 (dd, J = 24.2, 3.4 Hz, 1 C), 131.19 (d, J = 2.8 Hz, 2 C), 131.8 (d, J = 111.7 Hz, 2 C), 131.61 (d, J = 10.2 Hz, 4 C), 128.33 (d, J = 12.9 Hz, 4 C), 35.19 (1 C), 31.72 (2 C), 30.94 (d, J = 14.5 Hz, 2 C), 29.50 (d, J = 71.1 Hz, 2 C), 29.04 (2 C), 28.99 (2 C), 22.53 (2 C), 21.42 (d, J = 4.0 Hz, 2 C), 14.02 (2 C). ³¹P NMR (243 MHz, CDCl₃): δ = 41.48, 21.10. HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₂H₄₈N₂O₂P + H⁺: 554.3191; found: 554.3186.