Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal

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  • Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal igo rsida in ohe -am tabl system ically st in t roven ⇑ Corresponding authors. Fax: +57 2 33392440 (J.Q.); fax: +34 618907111 (M.N.). E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es (M. N NH3CX NH2 N N R H3CX NH 1 2 + + ArCH=O 3 4 Scheme 1. Tetrahedron Letters 51 (2010) 5443–5447 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier .com/ locate/ tet le t Nogueras). medicinal utility. A number of pyrrolopyrimidine derivatives struc- turally related to toyocamycin, sangivamycin, and the seco nucleo- sides of tubercidin have antiviral activity.1 As the pyrrolo[2,3-d]pyrimidine heterosystem represents a 7- deazaanalogue of biogenic purine, it is an important class of com- pounds possessing notable biological activity.2,3 We recently reported a three component one-step reaction of 6- aminopyrimidin-4-ones 1 with dimedone 2 and benzaldehydes 3, ponent synthesis of fused pyrido[2,3-d]pyrimidines.5 We report herein an extension of this three-component reaction with aminopyrimidines 1, dimedone 2, and arylglyoxales 5, which yielded the formation of unexpected several pyrrolo[2,3-d]pyrimi- dine derivatives 9a–q (Scheme 2, Table 1). The structure of all new compounds was determined on the ba- sis of their analytical techniques, 1D and 2D-NMR spectra, and MS, which agree with the proposed structures. Single crystal X-ray dif- O R O O O Ar O Keywords: Pyrrolopyrimidines Multicomponent reaction Aminopyrimidines Arylglyoxal Dimedone The pyrrolo[2,3-d]pyrimidine ring several natural products and biolog cently there has been a great intere o[2,3-d]pyrimidines due to their p 0040-4039/$ - see front matter � 2010 Elsevier Ltd. A doi:10.1016/j.tetlet.2010.08.021 is a common motif in active molecules.1a Re- he synthesis of pyrrol- biological activity and which yields pyrimido[4,5-b]quinolines4 4 via a simple, practical, and a very regioselective procedure (Scheme 1). In the course of our research aimed at the preparation of bioac- tive nitrogen-containing heterocycles, we addressed the multicom- Accepted 6 August 2010 Available online 12 August 2010 � 2010 Elsevier Ltd. All rights reserved. Jairo Quiroga a,⇑, Paola A. Acosta a, Silvia Cruz b, Rodr Justo Cobo c aGrupo de Investigación de Compuestos Heterocíclicos, Department of Chemistry, Unive bDepartment of Chemistry, Universidad de Nariño, A.A. 1175, Pasto, Colombia cDepartment of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spa a r t i c l e i n f o Article history: Received 25 May 2010 Revised 2 August 2010 a b s t r a c t A series of 6-aryl-5-(1-cycl ponent reaction between 6 cyclization process was es ll rights reserved. Abonía a, Braulio Insuasty a, Manuel Nogueras c,⇑, d del Valle, A.A. 25360, Cali, Colombia xen-1-yl)pyrrolo[2,3-d]pyrimidines 9a–qwere obtained by the three-com- inopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected ished by NMR and X-ray diffraction measurements.
  • 9a-i 9j-k N N O NH2X R N N NH2 NH2H2N O 1 NH N N NH Ar O X O OH 2 4 54a 1´ 2´ 3´ 6´ 5´ 4´ 6 R N N NH Ar NH2 H2N O OH54a 1´ 2´ 3´ 6´ 5´ 4´ 6 1 1 2 3 3 2´ 3´ 5´ 4´ OO Ar O O + + 6 R = H, CH3 X = OCH3, SCH3, NH2 7 = H 2 5 5444 J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447 N NX R R2 8 R1 = H, CH3; R2 fraction analysis of compounds 9b6 was used to corroborate the postulated structures.7 A possible mechanism route for the described three-component reaction is outlined in Scheme 3. We consider that initially the dimedone reacts with the arylglyoxal to give the intermediate 10. X = O Scheme OO + O O 52 C CH O HOHO O O 1 2 3 45 6 7 8 i o m p 10 H Scheme Table 1 Pyrrolo[2,3-d]pyrimidine derivatives Entry Pyrimidine Product 9a HN NH3CS NH2 O HN NH3CS O N H Ph O O 9b N NH3CS NH2 O H3C N NH3CS O N H Ph O OH3C 2 N N NH Ar O X O OH 2 4 54a 1´ 6´ 6 R1 3 R2 , CH3 The last one reacts with the 6-aminopyrimidine leading to the for- mation of intermediate 11, which suffers the cyclationwith loss of a watermolecule, to formfinal pyrrolopyrimidine 9. As an evidence of this is the fact that the reaction of dimedonewith phenylglyoxal led to the formation of product 10, which was isolated and character- 9l-q 2. 6,7,8 C CH O OH O N N NH2 Y X 9-H2O 11 3. Mp (�C) % m/z H 280–282 50 395 H 294–295 60 410
  • Table 1 (continued) Entry Pyrimidine Product Mp (�C) % m/z 9c HN NH3CO NH2 O HN NH3CO O N H Ph O OH 278–280 46 379 9d N NH3CO NH2 O H3C N NH3CO O N H Ph O OHH3C 296–298 60 393 9e HN NH2N NH2 O HN NH2N O N H Ph O OH 328–329 46 364 9f HN NH3CS NH2 O HN NH3CS O N H O OH Cl 299–301 43 429/431 9g N NH3CS NH2 O H3C N NH3CS O N H O OHH3C Cl 292–293 39 443/445 9h HN NH3CO NH2 O HN NH3CO O N H O OH Cl 262–263 38 413/415 9i HN NH2N NH2 O HN NH2N O N H O OH Cl 286–288 43 398/400 9j N NH2N NH2 NH2 HN NH2N O N H Ph O OH 242–243 41 363 9k N NH2N NH2 NH2 NH2N NH NH2 OH O Cl 279–281 41 397/399 (continued on next page) J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447 5445
  • H h OH n Le Table 1 (continued) Entry Pyrimidine Product 9l HN N H O NH2S HN N H O N H Ph O O S 9m N N O NH2O CH3 H3C N N O N H P O O CH3 H3C O 5446 J. Quiroga et al. / Tetrahedro ized.8 The compound 10was submitted to the reactionwith amino- pyrimidines 6 under the same conditions to give compounds 9.9 The described three-component one-step procedure is a simple, practical, and a very regioselective method for the preparation of novel pyrrolo[2,3-d]pyrimidines. The biological properties of the new compounds obtained in this research are under investigation. Acknowledgements Authors wish to thank COLCIENCIAS, Universidad del Valle, the Spanish ‘Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía’, and the Servicios Técnicos de Investigación de la Uni- versidad de Jaén for the financial support. SC thanks the Universi- dad de Nariño for her fellowship. References and notes 1. (a) Gupta, P. K.; Daunert, S.; Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32, 402; (b) Gupta, P. K.; Nassiri, M. R.; Coleman, L. A.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32, 1420. 9n HN N NH2O CH3 HN N O N H Ph O OH O CH3 9o HN N H O NH2S HN N H O N H O OH S 9p N N O NH2O CH3 H3C N N O N H O OH O CH3 H3C 9q HN N O NH2O CH3 HN N O N H O OH O CH3 Mp (�C) % m/z 246–248 44 381 299–300 55 393 tters 51 (2010) 5443–5447 2. (a) Townsend, L. B.; Lewis, A. F.; Roti Roti, L. W. US 804601, 1977; Chem. Abstr. 1978, 89, 44130.; (b) Porcari, A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach, J. M.; Vittori, S.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000, 43, 2438; (c) Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2006, 49, 1055; (d) Gangjee, A.; Lin, X.; Queener, S. F. J. Med. Chem. 2004, 47, 3689; (e) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G. J. Med. Chem. 1992, 35, 4450; (f) Edstrom, E. D.; Wei, I. J. Org. Chem. 1993, 58, 403. 3. (a) Seela, F.; Zulauf, M. Helv. Chim. Acta 1999, 82, 1878; (b) Zhang, L.; Zhang, Y.; Li, X.; Zhang, L. Bioorg. Med. Chem. 2002, 10, 907; (c) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun, J.-G.; Zhou, P. J. Org. Chem. 1997, 62, 5392; (d) Taylor, E. C.; Chaudhuri, R. P.; Watson, S. E. Tetrahedron 1999, 55, 1631; (e) Gangjee, A.; Yu, J.; McGuire, J. J.; Cody, V.; Galitsky, N.; Kisliuk, R. L.; Queener, S. F. J. Med. Chem. 2000, 43, 3837. 4. (a) Quiroga, J.; Hormaza, A.; Insuasty, B.; Ortiz, A. J.; Sánchez, A.; Nogueras, M. J. Heterocycl. Chem. 1998, 35, 231–233; For a review on multi-component reactions with 1,3-dicarbonyl compounds, see: (b) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980. 5. (a) Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A. Tetrahedron Lett. 2001, 42, 5625–5627; (b) Quiroga, J.; Rengifo, A.; Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A. Tetrahedron Lett. 2002, 43, 9061–9063; (c) Quiroga, J.; Insuasty, B.; Abonía, R.; Hernández, P.; Nogueras, M.; Sánchez, A. Heterocycl. Commun. 2000, 6, 345–350. 6. Cruz, S.; Quiroga, J.; de la Torre, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta Crystallogr., Sect. C 2006, 62, 554–556. 296–298 53 379 Cl 308–309 43 415/417 Cl 306–308 40 427/429 Cl 295–297 54 413/415
  • 7. General procedure for the preparation of pyrrolo[2,3-d]pyrimidines 9. A solution of equimolar amounts of 6-aminopyrimidine 6, 7, 8, dimedone 2, and arylglyoxal 5 in ethanol (15 mL) and amounts of catalytic acetic acid was heated for 9 h. Then, the reaction mixture was allowed to cool to ambient temperature, and the resulting solid products were collected by filtration, washed with ethanol, dried in air, and recrystallized from ethanol. Data for 5-(2-hydroxy-4,4- dimethyl-6-oxo-1-cyclohexen-1-yl)-2-(methylsulfanyl)-6-phenyl-3,7-dihydro-4H- pyrrolo[2,3-d]-pyrimidin-4-one 9a: White solid, yield 50%, 280–282 �C. 1H NMR (400 MHz DMSO-d6) d: 1.05 (s, 3H, CH3), 1.50 (s, 3H, CH3), 2.16 (s, 2H, H-50), 2.37 (s, 2H, H-30), 2.54 (s, 3H, SCH3), 7.19 (t, 1H, Hp, J = 7.36), 7.28 (t, 2H, Hm J = 7.67), 7.47 (d, 2H, Ho00 , J = 7.47), 9.86 (s, 1H, OH), 11.73 (s, 1H, H-3), 11.88 (s, 1H, H-7). 13C NMR (100 MHz DMSO-d6) d: 13.4 (SCH3), 28.3 (CH3), 28.9 (CH3), 32.1 (C-40), 43.4 (C-30), 51.1 (C-50), 106.2 (C-5), 108.1 (C-4a), 109.5 (C-10), 126.5 (Co), 126.9 (Cp), 128.6 (Cm), 129.7 (C-6), 133.0 (Ci), 148.9 (C-7a), 154.5 (C-2), 158.8 (C-4), 171.4 (C-20), 196.4(C-60). IE EM: m/z: 395 (M+, 98), 380 (100, M+�CH3), 297 (34), 270 (48), 167 (31), 140 (35). Anal. Calcd for C21H21N3O3S: C, 63.78; H, 5.35; N, 10.623; Found: C, 63.59; H, 5.18; N, 10.51. 8. Preparation of the intermediate 2,20-(2-oxo-2-phenyl-1,1-ethanediyl)bis(3- hydroxy-5,5-dimethyl-2-cyclohexen-1-one 10. This compound was obtained by a modified method described in Ref. 10. A mixture of equimolar amounts of dimedone 2, arylglyoxal 5, and amounts of catalytic CdI2 was subjected to microwave irradiation for 20 s at a temperature of 80 �C (CEM-Discovery). Then, the product obtained is treated with a mixture of ethanol–water, and the resulting solid products were collected by filtration, washed with ethanol, dried in air, and recrystallized from ethanol. White solid, yield 47%, 165–67 �C. 1H NMR (400 MHz CDCl3) d: 1.09 (s, 6H, CH3), 1.13 (s, 6H, CH3), 2.25 (s, 4H, H- 4), 2.50 (s, 4H, H-6), 5.42 (s, 1H, H-7), 7.49 (d, 2H, Ho), 7.56 (t, 2H, Hm), 8.28 (d, 1H, Hp). 13C NMR (100 MHz CDCl3) d: 27.4 (CH3), 29.0 (CH3), 32.3 (C-4), 34.2 (C- 7), 40.9 (C-5), 50.4 (C-3), 113.1 (C-1), 128.1 (Cm), 129.3 (Co) 132.8(Cp), 137.3 (Ci), 164.4 (C-2), 196.7 (C-6), 201.5 (C-8). IE EM: m/z: 396 (M+, 1), 273 (100). Anal. Calcd for C24H28O5: C, 72.71; H, 7.12. Found: C, 72.45; H, 6.78. 9. General procedure for the preparartion of pyrrolo[2,3-d]pyrimidines 9a (R = H, X = SCH3) from the intermediate 10 (di-component reaction). A solution of equimolar amounts of 6-aminopyrimidine 6 and intermediate 10 in ethanol (15 mL) and amounts of catalytic acetic acid was heated for 9 h. Then, the reaction mixture was allowed to cool to ambient temperature, and the resulting solid products were collected by filtration, washed with ethanol, dried in air, and recrystallized from ethanol. Yield 45%. 10. Prajapati, D.; Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1993, 739–740. J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447 5447 Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal Acknowledgements References and notes
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