Synthesis of Heterocyclic Compounds with Pyrimidine-4-carbaldehydes as Key Intermediates

Dedicated to Professor Hiriyakkanavar Ila in great admiration of her creative contributions to heterocyclic chemistry

Abstract

With the motivation to expand the compound library of specifically substituted pyrimidine derivatives, we prepared several pyrimidine-4-carbaldehydes. In most cases, the chemoselective oxidation of 4-hydroxymethyl-substituted pyrimidine derivatives could be achieved in good yields to provide the desired compounds. Alternatively, the aldehydes were prepared by Riley oxidation with selenium dioxide from the corresponding 4-methylpyrimidines. The formyl group of these compounds was employed as handle to generate alkynyl, cyano, oxazol-5-yl or β-ketoester substituents. Furthermore, two methods were found to prepare furo[3,2-d]pyrimidines. A serendipitously discovered reaction to a 6-(pyrimidin-4-yl)furo[3,2-d]pyrimidin-7-ol derivative involves a mechanistically interestingly ‘dimerization’ process with a benzoin addition as key step. Other compounds in this series contain amino, azido, or 1,2,3-triazol-1-yl groups. All these transformations to highly substituted pyrimidine derivatives demonstrate the synthetic versatility of pyrimidine-4-carbaldehydes and similar compounds.

Key words

azides - furo[3,2-d]pyrimidines - nitriles - oxazoles - oxidation - pyrimidine-4-carbaldehyde - triazoles

Publication History

Received: 02 April 2024

Accepted after revision: 30 April 2024

Article published online:
22 May 2024

• References


For selected examples, see:
• 1a Malik I, Ahmed Z, Reimann S, Ali I, Villinger A, Langer P. Eur. J. Org. Chem. 2011; 2088
• 1b Hadad C, Achelle S, García-Martinez JC, Rodríguez-López J. J. Org. Chem. 2011; 76: 3837
• 1c Achelle S, Robin-le Guen F. Tetrahedron Lett. 2013; 54: 4491
• 1d Fecková M, le Poul P, Robin-le Guen F, Roisnel T, Pytela O, Klikar M, Bureš F, Achelle S. J. Org. Chem. 2018; 83: 11712
• 1e Achelle S, Rodríguez-López J, Larbani M, Plaza-Pedroche R, Robin-le Guen F. Molecules 2019; 24: 1742
• 1f Pérez-Caaveiro C, Moreno Oliva M, López Navarrete JT, Pérez Sestelo J, Martínez MM, Sarandeses LA. J. Org. Chem. 2019; 84: 8870
• 2a Lagoja IM. Biodiversity 2005; 2: 1
• 2b Pathak V, Maurya HK, Sharma S, Srivastava KK, Gupta A. Bioorg. Med. Chem. Lett. 2014; 24: 2892
• 2c Reddy DS, Hosamani KM, Devarajegowda HD. Eur. J. Med. Chem. 2015; 101: 705
• 2d Ahmed K, Choudhary MI, Saleem RS. Z. Eur. J. Med. Chem. 2023; 259: 115701
• 2e Songsri S, Harkis AH, Sutherland A. J. Org. Chem. 2023; 88: 13214
• 2f Nammalwar B, Bunce RA. Pharmaceuticals 2024; 17: 104
• 3a Undheim K, Benneche T. In Comprehensive Heterocyclic Chemistry II, Vol. 6. Katritzky AR, Rees CW, Scriven EF. V, McKillop A. Pergamon Press; Oxford: 1996: 93
• 3b von Angerer S. In Science of Synthesis, Vol. 16. Yamamoto Y. Thieme; Stuttgart: 2004: 379
• 3c von Angerer S. In Science of Synthesis, Knowledge Update, Vol. 16. Carreira EM. Thieme; Stuttgart: 2011: 103

For other reviews, see:
• 4a Hill MD, Movassaghi M. Chem. Eur. J. 2008; 14: 6836
• 4b Radi M, Schenone S, Botta M. Org. Biomol. Chem. 2009; 7: 2841
• 4c Mahfoudh M, Abderrahim R, Leclerc E, Campagne J.-M. Eur. J. Org. Chem. 2012; 2856
• 4d Aparna EP, Devaky KS. ACS Comb. Sci. 2019; 21: 35
• 4e Stopka T, Adler P, Hagn G, Zhang H, Tona V, Maulide N. Synthesis 2019; 51: 194
• 4f Maji PK. Curr. Org. Chem. 2020; 24: 1055
• 4g Elkanzi NA. A, Zahou FM. Heterocycl. Lett. 2020; 10: 131
• 4h Nagata T, Obora Y. Asian J. Org. Chem. 2020; 9: 1532
• 4i Mishra S, Raikwar S, Baire B. Chem. Asian J. 2023; 18: e202300316
• 4j Díaz-Fernández M, Calvo-Losada S, Quirante J.-J, Sarabia F, Algarra M, Pino-González M.-S. Catalyst 2023; 13: 180
• 4k Bhatnagar A, Pemawat G. Org. Prep. Proced. Int. 2024; 56: 1
• 4l Eid EM. Curr. Org. Synth. 2024; 21: 127
• 4m Maikhuri VK, Mathur D, Chaudhary A, Kumar R, Parmar VS, Sing BK. Top. Curr. Chem. 2024; 382: 4
• 4n Rezaeifard A, Bakherad M, Navidpour L, Bajestani MA, Onagh G. ChemistrySelect 2024; 9: e202302345

For selected recent examples, see:
• 5a Mastalir M, Glatz M, Pittenauer E, Allmaier G, Kirchner K. J. Am. Chem. Soc. 2016; 138: 15543
• 5b Vidal M, García-Arriagada M, Rezende MC, Domínguez M. Synthesis 2016; 48: 4246
• 5c Fuji M, Obora Y. Org. Lett. 2017; 19: 5569
• 5d Yang K, Dang Q, Cai P.-J, Gao Y, Yu Z.-X, Bai X. J. Org. Chem. 2017; 82: 2336
• 5e Jalani HB, Cai W, Lu H. Adv. Synth. Catal. 2017; 359: 2509
• 5f Shi T, Qin F, Li Q, Zhang W. Org. Biomol. Chem. 2018; 16: 9487
• 5g Chu X.-Q, Cheng B.-Q, Zhang Y.-W, Ge D, Shen Z.-L, Loh T.-P. Chem. Commun. 2018; 54: 2615
• 5h Wang P, Zhang X, Liu Y, Chen B. Asian J. Org. Chem. 2019; 8: 1122
• 5i Belyaev DV, Chizhov DL, Rusinov GL, Charushin VN. Russ. J. Org. Chem. 2019; 55: 879
• 5j Reddy ML. C, Khan FR. N, Saravanan V. ChemistrySelect 2019; 4: 9573
• 6 For discovery, see: Flögel O, Dash J, Brüdgam I, Hartl H, Reissig H.-U. Chem. Eur. J. 2004; 10: 4283
• 7 For a review, see: Lechel T, Kumar R, Bera MK, Zimmer R, Reissig H.-U. Beilstein J. Org. Chem. 2019; 15: 655
• 8a Zimmer R, Lechel T, Rancan G, Bera MK, Reissig H.-U. Synlett 2010; 1793
• 8b Unger L, Accorsi M, Eidamshaus C, Reich D, Zimmer R, Reissig H.-U. Synthesis 2018; 50: 4071
• 8c Schefzig L, Kurzawa T, Rancan G, Linder I, Leisering S, Bera MK, Gart M, Zimmer R, Reissig H.-U. Synthesis 2021; 53: 2067
• 9a Lechel T, Möhl S, Reissig H.-U. Synlett 2009; 1059
• 9b Lechel T, Reissig H.-U. Eur. J. Org. Chem. 2010; 2555
• 9c Bera MK, Reissig H.-U. Synthesis 2010; 2129
• 10 For a mechanistic investigation, see: Kurzawa T, Zimmer R, Würthwein E.-U, Reissig H.-U. Chem. Eur. J. 2023; 29: e202204015
• 11 See examples in refs. 9a and 9c.
• 12a Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
• 12b Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
• 13a Frigerio M, Santagostino M. Tetrahedron Lett. 1994; 35: 8019
• 13b Frigerio M, Santagostino M, Sputore S, Palmisano G. J. Org. Chem. 1995; 60: 7272
• 14 For oxidation with activated MnO₂, see: Fieser LF, Fieser M. Reagents for Organic Synthesis, 1st ed. John Wiley & Sons; New York: 1967: 637
• 15 For Stahl oxidation, see: Hoover JM, Stahl SS. J. Am. Chem. Soc. 2011; 133: 16901
• 16 Müller S, Liepold B, Roth GJ, Bestmann J. Synlett 1996; 521
• 17 Lechel T, Dash J, Brüdgam I, Reissig H.-U. Eur. J. Org. Chem. 2008; 3647
• 18a Huisgen R. Angew. Chem. Int. Ed. Engl. 1963; 2: 565 ; Angew. Chem. 1963, 75, 604
• 18b For a recent review, see: Breugst M, Reissig H.-U. Angew. Chem. Int. Ed. 2020; 59: 12293 ; Angew. Chem. 2020, 132, 12389
• 19a Tongkate P, Pluempanupat W, Chavasiri W. Tetrahedron Lett. 2008; 49: 1146
• 19b Eidamshaus C, Reissig H.-U. Eur. J. Org. Chem. 2011; 6056

For selected reviews, see:
• 20a Bräse S, Gil C, Knepper K, Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188 ; Angew. Chem. 2005, 117, 5320
• 20b Meldal M, Tornøe CW. Chem. Rev. 2008; 108: 2952
• 20c Sletten EM, Bertozzi CR. Angew. Chem. Int. Ed. 2009; 48: 6974 ; Angew. Chem. 2009, 121, 7108
• 20d Bräse S, Banert K. Organic Azides – Syntheses and Applications . John Wiley & Sons; Chichester: 2010
• 20e Tanimoto H, Kakiuchi K. Nat. Prod. Commun. 2013; 8: 1021
• 20f Dommerholt J, Rutjes FP. J. T, van Delft FL. Top. Curr. Chem. 2016; 374: 16
• 20g Stanovnik B. Adv. Heterocycl. Chem. 2020; 130: 145
• 21 Tzanetou EN, Kasiotis KM, Haroutounian SA. Am. J. Org. Chem. 2012; 2: 35
• 22 Koóš P, Reissig H.-U. Synthesis 2024; 56: 795
• 23 Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Org. Lett. 2004; 6: 2853
• 24 van Leusen AM, Hoogenboom BE, Siderius H. Tetrahedron Lett. 1972; 23: 2369
• 25 Krishna PR, Prapurna YL, Alivelu M. Eur. J. Org. Chem. 2011; 5089
• 26 Nie Z, Yang T, Su M, Luo W, Liu Q, Guo C. Adv. Synth. Catal. 2022; 364: 2989
• 27 Xia A, Qi X, Mao X, Wu X, Yang X, Zhang R, Xiang Z, Lian Z, Chen Y, Yang S. Org. Lett. 2019; 21: 3028
• 28 Modak A, Naveen T, Maiti D. Chem. Commun. 2013; 49: 252
• 29 Riley HL, Morley JF, Friend NA. C. J. Chem. Soc. 1932; 1875
• 30 Bera MK, Hommes P, Reissig H.-U. Chem. Eur. J. 2011; 17: 11838
• 31 Bera MK, Dominguez M, Hommes P, Reissig H.-U. Beilstein J. Org. Chem. 2014; 10: 394

For reviews on alkoxyallene chemistry of our group, see:
• 32a Zimmer R. Synthesis 1993; 165
• 32b Brasholz M, Reissig H.-U, Zimmer R. Acc. Chem. Res. 2009; 42: 45
• 32c Zimmer R, Reissig H.-U. Chem. Soc. Rev. 2014; 43: 2888
• 32d Reissig H.-U, Zimmer R. Synthesis 2017; 49: 3291
• 32e Schmiedel VM, Reissig H.-U. Curr. Org. Chem. 2019; 23: 2976

For reviews, see:
• 33a Lechel T, Reissig H.-U. Pure Appl. Chem. 2010; 82: 1835
• 33b Lechel T, Reissig H.-U. In Targets in Heterocyclic Systems – Chemistry and Properties, Vol. 20. Attanasi OA, Merino P, Spinelli D. Italian Society of Chemistry; Rome: 2016: 1
• 34a Lechel T, Lentz D, Reissig H.-U. Chem. Eur. J. 2009; 15: 5432
• 34b Lechel T, Gerhard M, Trawny D, Brusilowskij B, Schefzig L, Zimmer R, Rabe JP, Lentz D, Schalley CA, Reissig H.-U. Chem. Eur. J. 2011; 17: 7480
• 35 Kumar R, Bera MK, Zimmer R, Lentz D, Reissig H.-U, Würthwein E.-U. Eur. J. Org. Chem. 2020; 1753