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Synlett 2015; 26(06): 810-814
DOI: 10.1055/s-0034-1380153
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© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of (Arylethynyl)pyrrolo[2,3-d]pyrimidines by Stille Coupling

Jonas Bucevicius
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania   Email: Sigitas.Tumkevicius@chf.vu.lt
,
Sigitas Tumkevicius*
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania   Email: Sigitas.Tumkevicius@chf.vu.lt
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Further Information

Publication History

Received: 15 December 2014

Accepted after revision: 14 January 2015

Publication Date:
12 February 2015 (online)

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Abstract

An efficient synthesis of 4- and 2,4-bis(arylethynyl)pyrrolo[2,3-d]pyrimidines substituted with the same or different arylethynyl groups and 2-aryl-4-(arylethynyl)pyrrolo[2,3-d]pyrimidines by Stille coupling of 2,4-dichloro-7-methylpyrrolo[2,3-d]pyrimidine with the corresponding (arylethynyl)tributyl- or (aryl)tributylstannanes is described.

Key words

Stille reaction - heterocycles - alkynes - cross-coupling - catalysis - palladium

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1380153.
  • Supporting Information
 

  • References and Notes

  • 7 Xie H, Zeng L, Zeng S, Lu X, Zhang G, Zhao X, Cheng N, Tu Z, Li Z, Xu H, Yang L, Zhang X, Huang M, Zhao J, Hu W. Eur. J. Med. Chem. 2012; 52: 205
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  • 10 Representative Procedure for the Preparation of 4-(Aryl­ethynyl)-2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidines 2a–e; Sonogashira Coupling; Compound 2a: A solution of 1 (400 mg, 1.98 mmol) in anhyd Et3N (20 mL) was flushed with argon and Pd(PPh3)2Cl2 (28.0 mg, 0.04 mmol), PPh3 (21.0 mg, 0.08 mmol), CuI (3.8 mg, 0.02 mmol) and phenylacetylene (260 μL, 2.38 mmol) were added. The mixture was stirred under argon at 60 °C for 2–3 h. After cooling, the reaction mixture was poured into H2O (40 mL) and extracted with CHCl3. The extract was dried over Na2SO4, filtered and the solvent removed by rotary evaporation. The residue was purified by column chromatography (eluent CHCl3) and recrystallized to give compound 2a (360 mg, 68% yield); mp 175–176 °C (from 2-propanol). IR (KBr): 2213 (C≡C) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H, NMe), 6.72 (d, J = 3.6 Hz, 1 H, 5-H), 7.23 (d, J = 3.6 Hz, 1 H, 6-H), 7.44 (m, 3 H, ArH), 7.69 (dd, J = 8.0, 1.6 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 31.4, 85.2, 96.7, 100.1, 118.9, 121.3, 128.5, 129.9, 131.0, 132.5, 143.5, 152.4, 153.3. HRMS (ESI): m/z [M + H]+ calcd for C15H11ClN3: 268.0636; found: 268.0642.
  • 13 Representative Procedure for the Preparation of 4-(Aryl­ethynyl)-2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidines 2a–e; Stille Coupling; Compound 2a: A solution of 1 (400 mg, 1.98 mmol) in anhyd toluene (10 mL) was flushed with argon and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol), AsPh3 (24.5 mg, 0.08 mmol) and tributyl(phenylethynyl)tin (834 μL, 2.38 mmol) were added. The mixture was stirred under argon at 80 °C for 2 h. After cooling, the reaction mixture was poured into aq K2CO3 solution (0.5 M, 25 mL) containing CsF (50 mg). The mixture was stirred for 30 min and extracted with CHCl3. The extract was dried over Na2SO4, filtered and the solvent removed by rotary evaporation. The residue was purified by column chromatography (eluent CHCl3) to give 2a (466 mg, 88%).
  • 14 Representative Procedure for the Preparation of 2,4-Bis(aryl­ethynyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidines 3a–d; Compound 3a: A solution of 1 (100 mg, 0.495 mmol) in anhyd toluene (2 mL) was flushed with argon and Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol), AsPh3 (30.6 mg, 0.1 mmol) and tributyl(phenylethynyl)tin (452 μL, 1.29 mmol) were added and the mixture was heated to reflux under argon for 48 h. Compound 3a was isolated according to the procedure described for compound 2a. Yield: 117 mg (71%); mp 178–179 °C (from 2-propanol). IR (KBr): 2214 (C≡C) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.94 (s, 3 H, NMe), 6.74 (d, J = 3.6 Hz, 1 H, 5-H), 7.30 (d, J = 3.6 Hz, 1 H, 6-H), 7.38–7.46 (m, 6 H, ArH), 7.69–7.73 (m, 4 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 31.4, 85.7, 85.8, 88.9, 95.6, 100.2, 118.9, 121.7, 122.1, 128.2, 128.5, 129.0, 129.7, 131.5, 132.4, 132.5, 142.5, 145.4, 151.1. HRMS (ESI): m/z [M + H]+ calcd for C23H16N3: 334.1339; found: 334.1346.
  • 15 Preparation of 2,4-Bis(arylethynyl)-7-methyl-7H-pyrrolo-[2,3-d]pyrimidines 4a–g and 2-Aryl-4-(arylethynyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidines 5a–g: Compounds 4a–g and 5a–g were synthesized from the corresponding precursors 2 according to the procedure described for the synthesis of compounds 3a–g. The requisite precursor 2 (0.35 mmol), anhyd toluene (2 mL), Pd(PPh3)2Cl2 (12.3 mg, 0.0175 mmol), AsPh3 (21.4 mg, 0.07 mmol) and tributyl(arylethynyl)tin (0.525 mmol), in case of the synthesis of 4a–g, or (aryl)tributyltin (0.525 mmol) for the synthesis 5a–g were used. Compound 4e: yield: 105 mg (79%); mp 194–195 °C. IR (KBr): 2213 (C≡C) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H, NMe), 3.92 (s, 3 H, OMe), 6.70 (d, J = 3.6 Hz, 1 H, 5-H), 6.91 (d, J = 8.8 Hz, 2 H, ArH), 7.08–7.14 (m, 2 H, ArH), 7.27 (d, J = 3.6 Hz, 1 H, 6-H), 7.63–7.69 (m, 4 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 31.4, 55.3, 85.5, 86.3, 88.0, 94.2, 100.0, 113.9, 114.0, 115.9 (J = 22 Hz), 117.8 (J = 4 Hz), 118.6, 131.3, 134.1, 134.5 (J = 9 Hz), 142.3, 145.7, 151.7, 160.3, 163.3 (J = 250 Hz). 19F NMR (376 MHz, CDCl3): δ = –108.3. HRMS (ESI): m/z [M + H]+ calcd for C24H17FN3O: 382.1350; found: 382.1356. Compound 4f: yield: 97 mg (73%); mp 169–170 °C. IR (KBr): 2209 (C≡C) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H, NMe), 3.92 (s, 3 H, OMe), 6.72 (d, J = 3.6 Hz, 1 H, 5-H), 6.93 (d, J = 8.8 Hz, 2 H, ArH), 7.04–7.10 (m, 2 H, ArH), 7.27 (d, J = 3.6 Hz, 1 H, 6-H), 7.63 (d, J = 8.8 Hz, 2 H, ArH), 7.69 (dd, J = 8.8, 5.2 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 31.4, 55.3, 84.5, 84.9, 88.8, 96.3, 100.2, 113.6, 114.2, 115.7 (J = 22 Hz), 118.2 (J = 3 Hz), 118.7, 131.2, 134.1, 134.4 (J = 8 Hz), 142.8, 145.2, 151.0, 160.8, 163.0 (J = 249 Hz). 19F NMR (376 MHz, CDCl3): δ = –109.4. HRMS (ESI): m/z [M + H]+ calcd for C24H17FN3O: 382.1350; found: 382.1355. Compound 5a: yield: 89 mg (82%); mp 132–133 °C. IR (KBr): 2212 (C≡C) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.96 (s, 3 H, NMe), 6.72 (d, J = 3.2 Hz, 1 H, 5-H), 7.23 (d, J = 3.2 Hz, 1 H, 6-H), 7.42–7.49 (m, 4 H, ArH), 7.52 (t, J = 7.6 Hz, 2 H, ArH), 7.73–7.75 (m, 2 H, ArH), 8.61 (d, J = 7.6 Hz, 2 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 31.1, 86.5, 94.5, 99.7, 118.5, 122.0, 128.1, 128.40, 128.48, 129.4, 129.7, 130.4, 132.4, 138.5, 142.2, 152.0, 158.2. HRMS (ESI): m/z [M + H]+ calcd for C21H16N3: 310.1339; found: 310.1344.
  • 16 Crystal data for compound 5g: C22H13F4N3, Mw = 395.36, monoclinic, space group P21/n (#14); Z = 4, a = 7.604(13), b = 21.50(4), c = 11.22(2) Å, β = 95.07(2)o, V = 1827(6) Å3; F(000) = 808; Dx = 1.437 g/cm3; 2Θmax = 55.1o (CCD area detector, Mo Kα radiation), R = 0.0270. Crystallographic data for structure 5g have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 1038254).