A Novel Highly Site-Selective Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines by a Combination of Palladium(0)-, Nickel(0)-, and Copper(I)-Catalyzed Cross-Coupling Reactions

Abstract

An efficient highly site-selective synthesis of 2,4,7-triarylpyrrolo[2,3-d]pyrimidines from 4-chloro-2-methylthiopyrrolo[2,3-d]pyrimidine has been developed. The proposed synthetic pathway is based on three sequential arylation reactions: Suzuki coupling at position 4 of pyrrolo[2,3-d]pyrimidine, copper(I)-catalyzed N(7)-arylation and nickel(0)-catalyzed desulfitative reaction of 2-methylthio group with aryl Grignard reagents.

Key words

arylation - cross-coupling - heterocycles - transition metals - catalysis - desulfitative C-arylation

• References and Notes

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• 8 7-(tert-Butoxycarbonyl)-4-chloro-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (2) To a solution of 1 (100 mg, 0,50 mmol) in anhyd CH₂Cl₂ (2 mL) DIPEA (77.4 mg, 0.60 mmol), DMAP (12.2 mg, 0.10 mmol), and Boc₂O (164 mg, 0,752 mmol) was added. The reaction mixture was stirred at r.t. for 30 min. After evaporation of CH₂Cl₂ the residue was dissolved in CHCl₃ and filtered through a layer of silica gel. After evaporation of the CHCl₃ the solid was recrystallized to give 142 mg (95%) of compound 2; mp 104–105 °C (from 2-PrOH). IR (KBr): ν = 1748 (C=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.71 [s, 9 H, C(CH₃)₃], 2.67 (s, 3 H, SCH₃), 6.57 (d, J = 4 Hz, 1 H, 5-H), 7.61 (d, J = 4 Hz, 1 H, 6-H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.9, 28.4, 85.8, 103.1, 116.3, 126.2, 147.9, 152.7, 152.8, 167.6. Anal. Calcd for C₁₂H₁₄ClN₃O₂S: C, 48.08; H, 4.71; N, 14.02. Found: C, 48.07; H, 4.73; N, 13.68.
• 9 Representative Procedure for the Preparation of 4-Aryl-7-tert-butoxycarbonyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidines 3a–c Compound 3a: A solution of 2 (100 mg, 0.33 mmol) in anhyd dioxane (2 mL) was flushed with argon and 2-biphenyldicyclohexylphosphine (4 mol%) and Pd(OAc)₂ (2 mol%) were added. The mixture was stirred for 10 min, then phenylboronic acid (48.8 mg, 0.4 mmol) and K₃PO₄ (169.8 mg, 0.8 mmol) were added under argon flow, and the reaction mixture was refluxed for 1 h. After cooling the solvent was removed to dryness, the residue dissolved in H₂O (5 mL), and the solution obtained was extracted with CHCl₃. The extract was dried over Na₂SO₄, filtered, and the CHCl₃ was removed on the rotary evaporator. The residue was purified by column chromatography (eluent CHCl₃) to give 93.5 mg (83%) of compound 3a; mp 82.5–83 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.72 [s, 9 H, C(CH₃)₃], 2.73 (s, 3 H, SCH₃), 6.78 (d, J = 4 Hz, 1 H, 5-H), 7.52–7.54 (m, 3 H, ArH), 7.62 (d, J = 4 Hz, 1 H, 6-H), 8.05 (d, J = 9 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.9, 85.2, 104.3, 125.9, 129.0, 129.2, 130.6, 137.5, 148.4, 153.8, 158.6, 167.4. Anal. Calcd for C₁₈H₁₉N₃O₂S: C, 63.32; H, 5.61; N, 12.31. Found: C, 62.95; H, 5.63; N, 12.03
• 10 Representative Procedure for the Preparation of 4-Aryl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidines 4a–c Compound 4a: To a solution of 3a (270 mg, 0.79 mmol) in anhyd CH₂Cl₂ (5 mL) TFA (8.5 mL, 114.6 mmol) was added. The reaction mixture was stirred for 30 min, then concentrated to dryness under reduced pressure. H₂O was added to the residue, and the solid obtained was recrystallized to give 165 mg (86%) of compound 4a; mp 221–222 °C (from 2-PrOH). ¹H NMR (300 MHz, CDCl₃ + DMSO-d ₆): δ = 2.59 (s, 3 H, SCH₃), 6.66 (dd, J = 4, 2 Hz, 1 H, 5-H), 7.21 (dd, J = 4, 2 Hz, 1 H, 6-H), 7.44–7.51 (m, 3 H, ArH), 8.08 (d, J = 8 Hz, 2 H, ArH), 11.69 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃ + DMSO-d ₆): δ = 14.8, 100.6, 112.3, 125.9, 129.0, 129.1, 130.4, 138.4, 154.3, 156.8, 163.6. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₃H₁₂N₃S: 242.0746; found: 242.0745.
• 11 Representative Procedure for the Preparation of 4,7-Diaryl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidines 5a–g Compound 5a: To a solution of 4a (100 mg, 0.41 mmol) in anhyd dioxane (2 mL) CuI (1 mol%), K₃PO₄ (154 mg, 0,72 mmol), iodobenzene (71.4 mg, 0,35 mmol), and trans-cyclohexane-1,2-diamine (10 mol%) were added. The reaction mixture was refluxed for 4 h. Then every hour CuI (1.0 mol%) was added to the mixture until the total amount of CuI reached 10 mol%. The total reaction time was 13 h. Then, after cooling to r.t., EtOAc (5 mL) was added to the reaction mixture and the resulting solution was filtered through a layer of silica gel, eluting with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using CHCl₃ as eluent to give 110 mg (99%) of compound 5a; mp 102–103 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.70 (s, 3 H, SCH₃), 6.92 (d, J = 4 Hz, 1 H, 5-H), 7.40 (t, J = 8 Hz, 1 H, ArH), 7.47 (d, J = 4 Hz, 1 H, 6-H), 7.53–7.62 (m, 5 H, ArH), 7.84 (d, J = 8 Hz, 2 H, ArH), 8.18 (d, J = 8 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.8, 102.6, 113.6, 123.8, 126.9, 127.3, 129.0, 129.3, 129.6, 130.5, 137.9, 138.1, 152.7, 158.4, 165.5. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₆N₃S: 318.1059; found: 318.1056.
• 12 Representative Procedure for the Preparation of 2,4,7-Triaryl-7H-pyrrolo[2,3-d]pyrimidines 6a–h Compound 6f: To a suspension of 5c (100 mg, 0.25 mmol) and NiCl₂(dppp) (5 mol%) in anhyd THF (2 mL) a solution of PhMgBr prepared from bromobenzene (0.13 mL, 1.24 mmol) and Mg (31 mg, 1.3 mmol) in anhyd THF (1 mL) was added under stirring and argon flow. For activation of magnesium 1,2-dibromoethane (0.005 mL, 0.06 mmol) was used. The reaction mixture was stirred at r.t. for 2 h. Then poured into 15% NH₄Cl aq solution (15 mL) and extracted with CHCl₃. The extract was dried over Na₂SO₄. After evaporation of CHCl₃ the residue was purified by column chromatography using a mixture CHCl₃–hexane (2:1) as an eluent to give 86 mg (79%) of compound 6f; mp 232–233 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.51 (s, 3 H, CH₃), 7.06 (d, J = 4 Hz, 1 H, 5-H), 7.42–7.55 (m, 3 H, ArH), 7.60 (d, J = 4 Hz, 1 H, 6-H), 7.86 (m, 2 H, ArH), 8.42 (d, J = 8 Hz, 2 H, ArH), 7.57–7.88 (m, 9 H, ArH), 8.73 (d, J = 8 Hz, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.4, 102.2, 115.1, 124.0, 127.5, 127.7, 128.0, 128.5, 128.6, 129.1, 129.2, 129.8, 130.0, 130.2, 135.6, 136.8, 137.8, 139.1, 140.9, 143.1, 152.9, 157.4, 158.5. ESI-HRMS: m/z [M + H]⁺ calcd for C₃₁H₂₄N₃: 438.1965; found: 438.1956.