Pyrrolo[2,3-d]pyrimidine-Core-Extended π-Systems: Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines

Abstract

A simple and facile synthesis of novel fluorescent pyrrolo[2,3-d]pyrimidines with various aryl and heteroaryl assemblies in positions 2, 4, and 7 of the heterocycle by combination of the Suzuki cross-coupling and copper(I) iodide N-arylation reactions of chloropyrrolo[2,3-d]pyrimidines with arylboronic acids and haloarenes is described.

Key words

pyrrolo[2,3-d]pyrimidine - oligoarylenes - Suzuki coupling - N-arylation - fluorescence

References and Notes

• 1a Hughes G. Bryce MR. J. Mater. Chem.  2005,  15:  94 
• 1b Wong WY. Zhou G.-J. Yu X.-M. Kwok H.-S. Lin Z. Adv. Funct. Mater.  2007,  17:  315 
• 1c Tao Y. Wang Q. Yang C. Wang Q. Zhang Z. Zou T. Qin J. Ma D. Angew. Chem. Int. Ed.  2008,  47:  8104 
• 2a Wong K.-T. Hung TS. Lin Y. Wu C.-C. Lee G.-H. Peng S. Chou CH. Su YO. Org. Lett.  2002,  4:  513 
• 2b Wu CC. Lin YT. Chiang HH. Cho TY. Chen CW. Wong KT. Liao YL. Lee GH. Peng SM. Appl. Phys. Lett.  2002,  81:  577 
• 2c Yamaguchi Y. Kobayashi S. Wakamiya T. Matsubara Y. Yoshida Z. Angew. Chem. Int. Ed.  2005,  44:  7040 
• 2d Achelle S. Ramondenc Y. Marsais F. Ple N. Eur. J. Org. Chem.  2008,  3129 
• 2e Jaung J.-Y. Dyes Pigments  2006,  71:  245 
• 3a Petitjean A. Khoury RG. Kyritsakas N. Lehn J.-M. J. Am. Chem. Soc.  2004,  126:  6637 
• 3b Schull G. Douillard L. Fiorini-Debuisschert C. Charra F. Mathevet F. Kreher D. Attias A.-J. Adv. Mater.  2006,  18:  2954 
• 4a Bunzli J.-CG. Piguet C. Chem. Soc. Rev.  2005,  34:  1048 
• 4b Diring S. Retailleaub P. Ziessel R. Tetrahedron Lett.  2007,  48:  8069 
• 5 Seela F. Steker H. Liebigs Ann. Chem.  1984,  1719 
• 6 Berry DA. Jung K.-Y. Wise DS. Sercel AD. Pearson WH. Mackie H. Randolph JB. Somers RL. Tetrahedron Lett.  2004,  45:  2457 
• 7 Tumkevicius S. Dodonova J. Kazlauskas K. Masevicius V. Skardziute L. Jursenas S. Tetrahedron Lett.  2010,  51:  3902 
• 8a Mohamed MS. El-Domany RA. El-Hameed RHA. Acta Pharm.  2009,  59:  145 
• 8b Wiesner JB. Ugarkar BG. Castellino AJ. Barankiewicz J. Dumas DP. Gruber HE. Foster AC. Erion MD. J. Pharm. Exp. Ther.  1999,  289:  1669 
• 8c Calderwood CJ. Johnston DN. Munschauer R. Rafferty P. Bioorg. Med. Chem. Lett.  2002,  12:  1683 
• 8d Altmann E. Missbach M. Green J. Susa M. Wagenknecht H. Widler L. Bioorg. Med. Chem. Lett.  2001,  11:  853 
• 8e Widler L. Green J. Missbach M. Susa M. Altmann E. Bioorg. Med. Chem. Lett.  2001,  11:  849 
• 8f Gibson CL. Huggan JK. Kennedy A. Kiefer L. Lee JK. Suckling CJ. Clements C. Harvey AL. Hunter WN. Tulloch LB. Org. Biomol. Chem.  2009,  7:  1829 
• 8g Hess S. Muller CE. Frobenius W. Reith U. Klotz K.-N. Eger K. J. Med. Chem.  2000,  43:  4636 
• 8h Naus P. Pohl R. Votruba I. Dzubak P. Haiduch M. Ameral R. Birkus G. Wang T. Ray AS. Mackman R. Cihlar T. Hocek M. J. Med. Chem.  2010,  53:  460 
• 12 Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc.  2001,  123:  7727 

9

Representative Procedure for the Preparation of 4-Aryl-7-( tert -butoxycarbonyl)-2-chloro-7 H -pyrrolo[2,3- d ]pyrimidines 2 - Compound 2a
To a solution of compound 1a ⁷ (0.42 g, 1.83 mmol) in anhyd CH₂Cl₂ (5 mL) DIPEA (0.48 mL, 2.75 mmol), DMAP (0.07 g, 0.57 mmol), and di(tert-butyl)dicarbonate (0.6 g, 2.75 mmol) were added. The reaction mixture was refluxed for 80 min, CH₂Cl₂ was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: CHCl₃) to give compound 2a (0.37g, 61%); mp 76-77 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.74 (s, 9 H, CMe₃), 6.89 (d, J = 4.2 Hz, 1 H, 5-H), 7.58-7.61 [m, 3 H, 3′,4′,5′-H (Ph)], 7.74 (d, J = 4.2 Hz, 1 H, 6-H), 8.06-8.09 [m, 2 H, 2′,6′-H (Ph)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 28.3, 86.0, 104.1, 116.9, 128.0, 129.2, 129.3, 131.2, 136.6, 147.3, 154.4, 156.2, 160.6. HRMS: m/z calcd for C₁₇H₁₆ClN₃O₂ [M + H]⁺: 330.1004; found: 330.1000.

10

Representative Procedure for the Preparation of 2,4-Diaryl-7-( tert -butoxycarbonyl)-7 H -pyrrolo[2,3- d ]-pyrimidines 3a-c - Compound 3a A solution of compound 2a (0.07 g, 0.21 mmol) in anhyd 1,4-dioxane (5 mL) was degassed with argon, and Pd(OAc)₂ (2.0 mol%) and dicyclohexyl(2-biphenyl)phoshine (4.0 mol%) were added with stirring under argon. The mixture was stirred for 10 min, then 4-ethoxyphenylboronic acid (0.042 g, 0.25 mmol) and anhyd K₃PO₄ (0.11 g, 0.52 mmol) were added. The reaction mixture was refluxed for 4 h. Then the solvent was evaporated under reduced pressure, and H₂O (5 mL) was added to dissolve inorganic salts. The obtained solution was extracted with CHCl₃ (3 × 25 mL), the combined organic layers were dried with Na₂SO₄, filtered, and evaporated under reduced pressure to dryness. The resulting solid was purified by column chromatography (eluent: CHCl₃) to give compound 3a (0.07 g, 79%); mp 141-141.9 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.49 (t, J = 6.9 Hz, 3 H, Me), 1.81 (s, 9 H, CMe₃), 4.16 (q, J = 6.9 Hz, 2 H, OCH₂), 6.88 (d, J = 4.2 Hz, 1 H, 5-H), 7.05 [dm, J = 9.0 Hz, 2 H, 3′,5′-H (EtOC₆H₄)], 7.58-7.61 [m, 3 H, 3′,4′,5′-H (Ph)], 7.75 (d, J = 4.2 Hz, 1 H, 6-H), 8.20 [dm, J = 7.9 Hz, 2 H, 2′,6′-H (Ph)], 8.68 [dm, J = 9.0 Hz, 2 H, 2′,6′-H (EtOC₆H₄)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 15.1, 28.5, 63.7, 84.9, 104.4, 114.5, 115.9, 127.1, 129.0, 129.3, 130.1, 130.4, 131.4, 138.4, 148.6, 154.3, 158.2, 159.9, 161.1. HRMS: m/z calcd for C₂₅H₂₅N₃O₃ [M + H]⁺: 416.1969; found: 416.1962.

11

Representative Procedure for the Preparation of 2,4-Diaryl-7 H -pyrrolo[2,3- d ]pyrimidines 4a-c - Compound 4a
To a solution of compound 3a (0.1 g, 0.24 mmol) in a mixture of acetone (9 mL) and H₂O (2 mL) concd HCl (0.06 mL, 1.94 mmol) was added. The reaction mixture was refluxed with stirring for 7 d, then cooled to r.t., the precipitate was filtered off to give compound 4a (0.06g, 80%); mp 275-276 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆):
δ = 1.39 (t, J = 6.9 Hz, 3 H, Me), 4.13 (q, J = 6.9 Hz, 2 H, OCH₂), 6.90 (dd, J ^³  = 3.5 Hz, J ⁴ = 1.8 Hz, 1 H, 5-H), 7.08 [dm, J = 9.0 Hz, 2 H, 3′,5′-H (EtOC₆H₄)], 7.59-7.65 [m, 4 H, 6-H, 3′,4′,5′-H (Ph)], 8.31 [dm, J = 7.9 Hz, 2 H, 2′,6′-H (Ph)], 8.49 [dm, J = 9.0 Hz, 2 H, 2′,6′-H (EtOC₆H₄)], 12.21 (s, 1 H, NH). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 15.4, 63.9, 100.9, 113.4, 114.9, 128.4, 129.3, 129.6, 129.7, 130.8, 131.7, 138.9, 154.5, 156.1, 157.0, 160.6. HRMS: m/z calcd for C₂₀H₁₇N₃O [M + H]⁺: 316.1444; found: 316.1446.

13

Representative Procedure for the Preparation of 2,4,7-triaryl-7 H -pirolo[2,3- d ]pirimidines(5) - Compound 5a A solution of compound 4a (0.06 g, 0.19 mmol) in anhyd 1,4-dioxane (3 mL) was degassed with argon, and CuI (1 mol%) and anhyd K₃PO₄ (0.07 g, 0.33 mmol) were added. The mixture was stirred for 10 min, then 4-iodobenzonitrile (0.04 g, 0.17 mmol) and trans-1,2-diaminocyclohexane (10 mol%) were added. The reaction mixture was refluxed with stirring and after 1 h and 2 h, respectively, an additional amount of 1 mol% CuI was added. The total amount of CuI used in the reaction was 3 mol%, and total reflux time was 6 h. Then EtOAc (5 mL) was added to the reaction mixture, and the solution was filtered through a layer of silica gel. The solvents were removed under reduced pressure and the residue purified by column chromatography (eluent: hexane-EtOAc = 27:1) to give compound 5a (0.071g, 90%; mp 206.3-206.8 ˚C (from 2-PrOH-EtOAc). ^¹H NMR (300 MHz, CDCl₃): δ = 1.51 (t, J = 6.9 Hz, 3 H, Me), 4.17 (q, J = 6.9 Hz, 2 H, OCH₂), 7.04-7.09 [m, 3 H, 5-H, 3′,5′-H (4-EtOPh)], 7.61-7.62 [m, 4 H, 6-H, 3′,4′,5′-H (Ph)], 7.93 [dm, J = 9.0 Hz, 2 H, 3′,5′-H (N₇-Ph)], 8.21 [dm, J = 9.0 Hz, 2 H, 2′,6′-H (N₇-Ph)], 8.30 [m, J = 7.9 Hz, 2 H, 2′,6′-H (Ph)], 8.10 [dm, J = 9.0 Hz, 2 H, 2′,6′-H (4-EtOPh)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 15.1, 63.8, 104.2, 109.7, 114.6, 114.9, 118.8, 123.6, 126.9, 129.1, 129.3, 129.9, 130.5, 131.1, 133.7, 138.5, 141.8, 153.3, 158.5, 159.1, 161.1. HRMS: m/z calcd for C₂₇H₂₀N₄O [M + H]⁺: 417.1710; found: 417.1710.