Me₃(OMe)tBuXPhos: A Surrogate Ligand for Me₄tBuXPhos in Palladium-Catalyzed C–N and C–O Bond-Forming Reactions

Abstract

A new biaryl phosphine ligand, Me₃(OMe)tBuXPhos (L3), was designed as a surrogate for Me₄tBuXPhos (L1). The Me₃(OMe)tBuXPhos could be prepared in a chromatography-free manner from inexpensive and readily available 2,3,6-trimethylphenol. Comparative studies demonstrated that a catalyst based on Me₃(OMe)tBuXPhos displayed the same reactivity as a catalyst based on Me₄tBuXPhos for Pd-catalyzed C–N and C–O bond-forming processes.

Me₄tBuXPhos (L1) is a useful ligand in Au-catalyzed carbocyclization1 and Pd-catalyzed arylation reactions of nitrogen/oxygen nucleophiles, including amides,² benzimidazoles,³ phenols⁴ and water.⁵ We recently demonstrated that the combination of Pd and L1 was the most effective catalyst system for the highly N²-selective arylation of 1,2,3-triazoles⁶ and completely N¹-selective arylation of unsymmetric imidazoles.⁷ L1 is synthesized from 1,2,3,4-tetramethylbenzene via dibromination and then a one-pot biaryl phosphine synthesis protocol, which proceeds through a benzyne intermediate.^4,5 However, the high cost and limited availability of the 1,2,3,4-tetramethylbenzene⁸ could potentially prevent the utilization of Pd/L1 systems, as well as the future development of methods using L1 as a supporting ligand for various metals. To circumvent this problem, the development of an inexpensive and robust alternative to L1 is highly desirable.

Mechanistic investigations by our group on Pd-catalyzed aryl amidation with L1 indicated that the 3-methyl substituent of the ligand restricts rotation of the Ar–P bond and fixes the Pd center over the triisopropylphenyl ring.^2a In addition, it was postulated that 6-methyl group of L1 increases conformational rigidity in the Pd-ligand complex and possibly accelerates the rate of reductive elimination.³ Based on these two features it was proposed that the utility of L1 was superior to that of non-methylated ligand tBuXPhos (L2) in several Pd-catalyzed C–N bond-forming reactions.^2,6–7 We felt that ligand, L3, which possesses both 3- and 6-methyl substitutents and is accessible from inexpensive and readily available 2,3,6-trimethylphenol⁹ might be a suitable surrogate for L1. Herein, we report a synthesis of L3 and its utilization in the Pd-catalyzed arylation reactions of nitrogen and oxygen nucleophiles.

The synthesis of L3 is described in Scheme 1. Dibromide 2 was prepared from 2,3,6-trimethylphenol via dibromination and O-methylation. Notably, both 1 and 2 were crystalline solids and could be isolated in pure form without chromatography. Dibromide 2 was treated with Mg and 2,4,6-triisopropylphenyl magnesiumbromide in THF at 60 ° C for 1.5 h and then allowed to react with CuCl and ClP(tBu)₂ to give L3 in 61% yield. ¹H NMR analysis showed that L3 was an approximately a 1:1 mixture of two regioisomers, suggesting that addition of the aryl Grignard reagent to the benzyne generated from 2 was unselective.

Scheme 1.

Preparation of L3

In order to compare the activity of the Pd/L1 and Pd/L3 systems, the reaction progress of the N-arylation of nitrogen heterocycles was investigated (Schemes 2 and 3). Previously, the N-arylation of 4-methylimidazole and bromobenzene with Pd/L1 gave N-arylated product 3a in 95% yield with complete N¹-selectivity.⁷ The same N-arylation reaction using Pd/L3 showed similar progress and the N-arylated product was obtained in 96% yield with complete N¹-selectivity. Similarly, almost identical yields (90% with L1, 89% with L3) and N²-selectivity (N²:N¹ = 97:3 for both L1 and L3) were observed for the N-arylation of 1,2,3-triazole.⁶ These results demonstrate that a catalyst based on L3 shows identical reactivity to a catalyst based on L1, indicating that it is excellent surrogate for C–N cross-coupling reactions.

Scheme 2.

Comparison of catalysts based on L1 and L3 for the N-arylation of 4-methylimidazole

Scheme 3.

Comparison of catalysts based on L1 and L3 for the N-arylation of 1,2,3-triazole

We next explored the scope of the Pd/L3 system using variety of aryl halides and N/O-nucleophiles (Scheme 4). We found that the use of Pd/L3 gave comparable yields to those obtained with Pd/L1 in all reactions examined. It should be noted that N¹-aryl-4-methylimidazoles 3c and 3d, which are key intermediate for the synthesis of GSK2137305¹⁰ and nilotinib (Tasigna®)¹¹ were prepared in high yield as single regioisomers at 0.3 or 0.5 mol % Pd loadings.

Scheme 4.

Comparison of catalysts based on L1 and L3 for the N- and O-arylation reactions^a

^a Reactions were carried out in 1.0 mmol scale. Isolated yields, average of two runs. ^b Condition: Pd₂(dba)₃ (L/Pd = 1:1), 4-methylimidazole (2 mmol), K₃PO₄ (2 mmol), toluene- dioxane (1:1), 130 ° C, 6 h. ^d Condition: Pd₂(dba)₃ (L/Pd = 1:1), 4-methylimidazole (2.4 mmol), K₃PO₄ (2 mmol), toluene-tBuOH (1:1), 120 ° C, 8 h. ^d Condition: Pd₂(dba)₃ (L/Pd = 1:1), imidazole derivative (1.2 mmol), K₃PO₄ (2 mmol), toluene-dioxane (5:1), 120 ° C, 5 h. ^e Condition: Pd₂(dba)₃ (L/Pd = 1:2.5), benzamide (1.2 mmol), K₃PO₄ (1.2 mmol), tBuOH, 110 ° C, 16 h. ^f Condition: Pd₂(dba)₃ (L/Pd = 1:2), KOH (3 mmol), H₂O-dioxane (1:1), 100 ° C, 16 h. ^g Condition: Pd(OAc)₂ (L/Pd = 1:1.5), phenol (1.2 mmol), K₃PO₄ (2 mmol), toluene, 100 ° C, 16 h.

In summary, we have designed and synthesized a new biaryl phosphine ligand, Me₃(OMe)tBuXPhos (L3). The ligand L3 could be prepared in a chromatography-free manner from inexpensive and readily available 2,3,6-trimethylphenol. Comparative studies of L1 and L3 demonstrated that L3 could indeed serve as a surrogate for the Me₄tBuXPhos (L1). We expect wide use and large-scale application of L3 as an efficient substitute for L1 in a variety of Pd-catalyzed C–N and C–O bond-forming reactions.

Experimental Section

General Information

Pd₂(dba)₃ and Pd(OAc)₂ was purchased from Strem Chemicals Inc. Anhydrous tribasic potassium phosphate was stored in a glovebox. Small portions were removed and stored in a desiccator for up to 2 weeks (All reactions were set-up outside of the glovebox). L1^4a was prepared by literature procedure. Reactions were monitored by GC and thin-layer chromatography (TLC) using UV light. Flash chromatography was performed using silica gel (230–400 mesh). All ¹H NMR experiments are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform (7.26 ppm) or dimethylsulfoxide-d6 (2.50 ppm) in the deuterated solvent. All ¹³C NMR spectra are reported in ppm relative to deuterochloroform (77.23 ppm) or dimethylsulfoxide-d6 (39.52 ppm), unless otherwise stated, and all were obtained with 1H decoupling. The pure compounds are estimated to be ≥ 95% pure as determined by ¹H NMR or GC analysis.

3,4-Dibromo-2,5,6-trimethylphenol (1)

To a stirred solution of 2,3,6-trimethylphenol (20.4 g, 150 mmol) and I₂ (381 mg, 1.5 mmol) in CH₂Cl₂ (150 mL), Br₂ (17.0 mL, 330 mmol) was added dropwise (1 drop/1 sec) at room temperature. After the addition of Br₂ was complete, the reaction mixture was stirred at room temperature for 3 h then a saturated aqueous solution of Na₂SO₃ (150 mL) was added to quench the residual Br₂. The organic phase was separated and washed with brine, dried over MgSO₄, and concentrated in vacuo to give a white solid which was triturated with hexanes and collected by filtration. The white solid was dried in vacuo to give 40.1 g (92% yield) of the title compound. Mp 142–144 °C; ¹H NMR (400 MHz, CDCl₃): δ 4.73 (s, 1H), 2.43 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 151.23, 136.5, 125.3, 123.3, 122.7, 119.4, 22.3, 18.3, 13.7; IR (film) νmax: 3376, 1699, 1652, 1558, 1541, 1456, 1388, 1290, 1199, 1081, 970, 784, 731 cm⁻¹; Anal. Calcd. For C₉H₁₀Br₂O: C, 36.77; H, 3.43. Found: C, 36.63; H, 3.39.

1,2-Dibromo-4-methoxy-3,5,6-trimethylbenzene (2)

A 250 mL round bottom flask, which was equipped with a stir bar, was charged with 3,4-dibromo-2,5,6-trimethylphenol (14.7 g, 50 mmol) and K₂CO₃ (8.3 g, 60 mmol). Acetone (80 mL) and dimethyl sulfate (5.68 mL, 60 mmol) were added to the mixture and then the flask was equipped with a reflux condenser. The reaction mixture was stirred at 75 °C for 6 h. After cooling to room temperature, an aqueous KOH solution (2.0 M, 100 mL) was added and the mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated to remove acetone and then, extracted with Et₂O, washed with brine, dried over MgSO₄ and concentrated under reduced pressure to give the title compound as a white solid (15.0 g, 97% yield, GC purity of 99.5% area %). Mp 63–65 °C; ¹H NMR (400 MHz, CDCl₃): δ 3.65 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 156.3, 137.1, 131.2, 130.3, 125.6, 123.4, 60.5, 22.2, 18.6, 14.1; IR (film) νmax: 2924, 1652, 1540, 1449, 1375, 1213, 1092, 1002, 972, 902, 755, 668 cm⁻¹; Anal. Calcd. For C₁₀H₁₂Br₂O: C, 38.99; H, 3.93. Found: C, 38.82; H, 3.86.

Di-tert-butyl(2′,4′,6′-triisopropyl-5-methoxy-3,4,6-trimethyl[1,1′-biphenyl]-2-yl)phosphine/di-tert-butyl(2′,4′,6′-triisopropyl-4-methoxy-3,5,6-trimethyl-[1,1′-biphenyl]-2-yl)phosphine (L3)

An oven-dried 250 mL round bottom flask, which was equipped with a stir bar and charged with Mg shavings (1.02 g, 42 mmol) was fitted with a reflux condenser, a glass stopper and a rubber septum. The flask was purged with argon and then 2-bromo-1,3,5-triisopropylbenzene (5.07 mL, 20 mmol) and anhydrous THF (40 mL) were added via syringe. The reaction mixture was heated to 60 °C and 1,2-dibromoethane (50 μL) was added via syringe. The reaction was stirred at 60 °C for 1.5 h. 1,2-Dibromo-4-methoxy-3,5,6-trimethylbenzene (6.16 g, 20 mmol) was added portion wise to the reaction mixture over 30 min period under a stream of argon. After the addition of 1,2-dibromo-4-methoxy-3,5,6-trimethylbenzene was complete, the reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was cooled to room temperature and CuCl (1.98 g, 20 mmol) and ClPtBu₂ (4.6 mL, 24 mmol) were quickly added under a stream of argon. The reaction mixture was heated to reflux at 75 °C for 30 h. The reaction mixture was cooled to room temperature, diluted with Et₂O, washed three times with 30% NH₄OH, dried over MgSO₄ and concentrated under reduced pressure to give a pale yellow crude oil. The crude oil was diluted with EtOAc (5 mL) and then, MeOH (50 mL) was added. The mixture was cooled to 0 °C and the white precipitate that had formed was collected by filtration, washed two times with cold MeOH and dried in vacuo to yield a white powder (6.03 g, 61% yield, mp 130–132 °C) as an approximately 1:0.98 mixture of two isomers as determined by methoxy proton signals (methoxy proton signal of major isomer: 3.75 ppm, minor isomer: 3.68 ppm). ¹H NMR (400 MHz, CDCl₃) δ 6.95/6.94 (s, 2H), 3.76/3.68 (s, 3H), 2.97-2.86 (m, 1H), 2.57/2.53 (s, 3H), 2.48-2.33 (m, 2H), 2.26/2.20 (s, 3H), 1.76/1.73 (s, 3H), 1.31-1.25 (m, 6H), 1.23-1.19 (m, 6H), 1.16-1.09 (m, 18H), 0.93/0.89 (d, J = 6.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 157.7, 155.8, 150.0, 149.6, 147.5, 147.5, 146.5, 146.5, 146.2, 141.6, 141.6, 138.1, 137.8, 137.7, 136.1, 136.0, 134.0, 133.9, 130.5, 130.4, 129.0, 128.9, 127.6, 120.7, 120.6, 59.7, 59.6, 34.7, 34.6, 34.3, 34.3, 34.2, 32.8, 32.6, 31.0, 31.0, 31.0, 26.2, 26.2, 25.5, 25.5, 24.8, 24.7, 24.7, 24.7, 24.4, 24.4, 21.9, 21.9, 21.1, 21.0. (Observed complexity is due to C-P splitting); ³¹P NMR (121 MHz, CDCl₃): δ 39.17, 38.16; IR (film) νmax: 2956, 2362, 1542, 1461, 1381, 1311, 1208, 1166, 1090, 1011, 911 cm⁻¹; Anal. Calcd. For C₃₃H₅₃OP: C, 79.79; H, 10.75. Found: C, 79.71; H, 10.69.

4-Methyl-1-phenyl-1H-imidazole (3a)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (6.9 mg, 0.0075 mmol) and L1 or L3 (0.018 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous toluene (0.83 mL) and anhydrous 1,4-dioxane (0.17 mL) were added via syringe The resulting dark purple mixture was stirred at 120 °C for 3 min, at this point the color of the mixture turned to red-brown. A second oven-dried vial, which was equipped with a stir bar, was charged with 4-methylimidazole (98 mg, 1.2 mmol) and K₃PO₄ (424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times) and then bromobenzene (106 μL, 1.0 mmol) and the pre-heated catalyst solution were added via syringe to the second vial. The reaction mixture was heated at 120 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc/MeOH, 50:1) to provide the title compound as a pale-yellow solid (152 mg, 96% (with L3)), mp 60 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 1.6 Hz, 1H), 7.36-7.29 (m, 2H), 7.25-7.17 (m, 3H), 6.89 (s, 1H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 139.4, 137.3, 134.4, 129.7, 126.9, 120.8, 114.4, 13.6; IR (film) νmax 3385, 3108, 2921, 1599, 1507, 1448, 1392, 1366, 1291, 1241, 1070, 1003, 969, 817, 759, 692 cm⁻¹; Anal. Calcd. For C₁₀H₁₀N₂: C, 75.92; H, 6.37. Found: C, 76.04; H, 6.33.

2-Phenyl-1,2,3-triazole (3b)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (6.9 mg, 0.0075 mmol) and L1 or L3 (0.018 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous toluene (1.0 mL) was added via syringe and the resulting dark purple mixture was stirred at 120 °C for 3 min, at this point the color of the mixture turned to red-brown. A second oven-dried vial, which was equipped with a stir bar, was charged with K₃PO₄ (424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times) and then bromobenzene (106 μL, 1.0 mmol), 1,2,3-triazole (70 μL, 1.2 mmol) and the pre-heated catalyst solution were added via syringe to the second vial. The reaction mixture was heated at 120 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (Hexanes/EtOAc, 9:1) to provide the title compound as colorless oil (129 mg, 89% (with L3)). ¹H NMR (400 MHz, CDCl3) δ 8.12-8.06 (m, 2H), 7.80 (s, 2H), 7.51-7.44 (m, 2H), 7.38-7.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 140.0, 135.6, 129.4, 127.6, 119.1; IR (film) νmax 3128, 3059, 2362, 1745, 1598, 1500, 1410, 1376, 1259, 1152, 1069, 953, 820, 757, 692, 668, 510, 455 cm⁻¹; Anal. Calcd. For C8H7N3: C, 66.19; H, 4.86. Found: C, 66.23; H, 4.91.

3-(4-(4-Methyl-1H-imidazol-1-yl)phenyl)-1,4-diazaspiro[4.4]non-3-en-2-one (3c)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol) and L1 or L3 (0.01 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of 3 times). Anhydrous toluene (0.6 mL) was added via syringe and the resulting dark purple mixture was stirred at 130 °C for 3 min. A second oven-dried vial which was equipped with a stir bar was charged with 3-(4-chlorophenyl)-1,4-diazaspiro[4.4]non-3-en-2-one⁷ (249 mg, 1.0 mmol), 4-methylimidazole (164 mg, 2.0 mmol) and K₃PO₄ (424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). The pre-heated catalyst solution (0.18 mL, 0.3 mol% Pd) was transferred to the second vial via syringe and then toluene (0.5 mL) and dioxane (0.5 mL) were added (a total 1.18 mL of solvent). The reaction mixture was heated at 130 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc-MeOH, 15:1) to provide the title compound as a white solid (268 mg, 91% (with L3)), mp 194–195 °C. ¹H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 2.17 (s, 3H), 2.00-1.77 (m, 8H); ¹³C NMR (100 MHz, DMSO-d6) δ 164.1, 158.8, 138.9, 138.8, 134.7, 129.4, 128.5, 119.3, 113.8, 89.6, 37.1, 23.9, 13.6; IR (film) ν3max 3854, 3745, 3158, 3050, 2962, 2360, 1704, 1606, 1518, 1442, 1254, 1191, 1063, 963, 848, 752, 540 cm⁻¹; Anal. Calcd. For C₁₇H₁₈N₄O: C, 69.37; H, 6.16. Found: C, 69.21; H, 6.12.

3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (3d)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (2.3 mg, 0.0025 mmol) and L1 or L3 (0.0025 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Then, anhydrous toluene (0.5 mL) was added via syringe. This dark purple mixture was stirred at 120 °C for 3 min. The color of the mixture turns to dark brown after 3 min. A second oven-dried vial which was equipped with a stir bar was charged with 3-amino-5-bromobenzotifluoride (240 mg, 1.0 mmol), 4-methylimidazole (197 mg, 2.4 mmol) and K₃PO₄ (424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of 3 times). The pre-heated catalyst solution, followed by anhydrous toluene (0.5 mL) and tBuOH (1.0 mL), were added via syringe to the second vial (a total 2 mL of toluene-tBuOH 1:1 solution). The reaction was heated at 120 °C for 8 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄, concentrated in vacuo and purified via flash chromatography (Et₂O/EtOAc/MeOH, 125:125:1) to provide the title compound as a white solid (219 mg, 91% (with L3)), mp 125 °C. ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 6.96 (s, 1H), 6.85 (s, 1H), 5.91 (s, 2H), 2.16 (s, 3H); ¹³C NMR (100 MHz, DMSO-d6) δ 150.9, 138.5, 134.8, 131.3 (q, J = 38 Hz), 124.1 (q, J = 272 Hz), 114.2, 107.9, 103.3 (q, J = 4 Hz), 13.5; IR (film) νmax 3854, 3745, 3414, 3215, 2362, 1620, 1509, 1412, 1328, 1293, 1254, 1199, 1158, 1115, 843, 807, 735, 691, 621 cm⁻¹; Anal. Calcd. For C₁₁H₁₀F₃N₃: C, 54.77; H, 4.18. Found: C, 54.61; H, 4.11.

2-(1-(6-Methoxypyridin-2-yl)-1H-imidazol-4-yl)acetonitrile (3e)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (2.3 mg, 0.0025 mmol) and L1 or L3 (0.005 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous toluene (0.41 mL) and anhydrous 1,4-dioxane (0.19 mL) were added via syringe. The resulting dark purple mixture was stirred at 120 °C for 3 min, at this point the color of the mixture turned to red brown. A second oven-dried vial, which was equipped with stir bar, was charged with 4-cyanomethylimidazole (64 mg, 0.6 mmol) and K₃PO₄ (212 mg, 1.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times) and then 6-bromo-2-methoxypyridine (61 μL, 0.5 mmol) and the preheated catalyst solution were added via syringe to the second vial. The reaction mixture was heated at 120 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc) to provide the title compound as a white solid (94 mg, 87% (with L3)), mp 77–78 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 1.2 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.58 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 163.8, 146.5, 141.2, 135.2, 133.0, 117.4, 114.0, 109.2, 103.6, 53.8, 17.9; IR (film) νmax 3397, 2954, 1614, 1580, 1481, 1452, 1421, 1321, 1253, 1091, 1035, 1000, 860, 793 cm⁻¹; Anal. Calcd. For C₁₁H₁₀N₄O: C, 61.67; H, 4.71. Found: C, 61.65; H, 4.77.

1-(Pyrimidin-5-yl)-1H-benzimidazole (3f)

An oven-dried vial was equipped with a magnetic stir bar and charged with Pd₂(dba)₃ (2.3 mg, 0.0025 mmol) and L1 or L3 (0.005 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous toluene (0.3 mL) was added via syringe. The resulting dark purple mixture was stirred at 120 °C for 3 min, at this point the color of the mixture turned to red-brown. A second oven-dried vial, which was equipped with a stir bar, was charged with benzimidazole (142 mg, 1.2 mmol), 5-bromopyrimidine (159 mg, 1.0 mmol) and K₃PO₄ (424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times) and then the pre-heated catalyst solution, toluene (0.53 mL) and dioxane (0.17 mL) were added to the second vial. The reaction mixture was heated at 120 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (EtOAc/MeOH, 15:1) to provide the title compound as a white solid (190 mg, 97% (with L3)), mp 137–139 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.95 (s, 2H), 8.07 (s, 1H), 7.86-7.81 (m, 1H), 7.47-7.41 (m, 1H), 7.37-7.31 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 157.7, 151.9, 144.1, 141.3, 133.0, 132.0, 124.7, 123.8, 121.2, 109.6; IR (film) νmax 3745, 3065, 2362, 1698, 1652, 1558, 1497, 1464, 1429, 1291, 1245, 1208, 881, 725, 615 cm⁻¹; Anal. Calcd. For C₁₁H₈N₄: C, 67.34; H, 4.11. Found: C, 67.42; H, 4.20.

N-(3-Methoxyphenyl)benzamide (3g)

An oven-dried vial was equipped with a magnetic stir bar and charged with benzamide (145 mg, 1.2 mmol), K₃PO₄ (254 mg, 1.2 mmol), Pd₂(dba)₃ (4.6 mg, 0.005 mmol) and L1 or L3 (0.02 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Bromobenzene (106 μL, 1.0 mmol) and tBuOH (2.0 mL) were added via syringe and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (hexanes/EtOAc, 3:1) to provide the title compound as a white solid (206 mg, 91% (with L3)), mp 117–119 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.81-7.75 (m, 2H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 2H), 7.19-7.11 (m, 2H), 6.67-6.61 (m, 1H), 3.67 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 160.1, 139.4, 134.9, 131.7, 129.6, 128.6, 127.2, 112.9, 110.5, 106.3, 55.2; IR (film) νmax 3304, 1652, 1607, 1540, 1492, 1455, 1420, 1305, 1276, 1200, 1160, 1046, 854, 775, 690 cm⁻¹; Anal. Calcd. For C₁₄H₁₃NO₂: C, 73.99; H, 5.77. Found: C, 73.73; H, 5.75.

2-Methyl-5-phenoxybenzo[d]thiazole (3i)

An oven-dried vial was equipped with a magnetic stir bar and charged with 5-chloro-2-methylbenzothiazole (184 mg, 1.0 mmol), phenol (113 mg, 1.2 mmol), K₃PO₄ (424 mg, 2.0 mmol), Pd(OAc)₂ (4.5 mg, 0.02 mmol) and L1 or L3 (0.03 mmol). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of three times). Toluene (1.5 mL) was added via syringe and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified via flash chromatography (hexanes/EtOAc, 7:1) to provide the title compound as colorless oil (224 mg, 93% (with L3)). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.37-7.30 (m, 2H), 7.14-7.02 (m, 4H), 2.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.8, 157.4, 156.3, 154.6, 130.3, 129.9, 123.6, 122.1, 119.0, 117.3, 112.1, 20.3; IR (film) νmax 3064, 2922, 1590, 1558, 1522, 1489, 1453, 1311, 1266, 1216, 1169, 1133, 1069, 1002, 950, 872, 810, 752, 693, 643 cm⁻¹; Anal. Calcd. For C₁₄H₁₁NOS: C, 69.68; H, 4.59. Found: C, 69.63; H, 4.64.

Figure 1.

Structures of biaryl phosphine ligands