Preparation and Reactions of Trichloromethyl-Substituted Pyridine and Pyrimidine Derivatives

Abstract

The three-component reaction of lithiated methoxyallene, nitriles and trichloroacetic acid gave three model β-keto enamides that were starting materials for the synthesis of trichloromethyl-substituted pyridine and pyrimidine N-oxide derivatives. Upon treatment with acetic anhydride, the methyl group of the prepared pyrimidine N-oxides was converted into an acetoxymethyl group by a Boekelheide rearrangement. A few typical experiments also revealed that the trichloromethyl group of the prepared pyrimidine N-oxides can be replaced by an alkoxy or a hydroxy group, or transformed into an arylthiomethyl group. An alternative approach to β-keto enamides via the corresponding β-keto enamines was also examined and provided the expected 4-hydroxy-6-(trichloromethyl)pyridine derivative in good yield.

Key words

allenes - cyclocondensation - pyridines - pyrimidines - Boekelheide rearrangement

• References


For selected reports, see:
• 1a Chupp JP. Smith LR. J. Heterocycl. Chem. 1988; 25: 1785
• 1b Chupp JP. J. Heterocycl. Chem. 1990; 27: 1697
• 1c Tiwari A. Waud WR. Struck RF. Bioorg. Med. Chem. 2002; 10: 3593
• 1d Winter E. Dal Pizzol C. Filippin-Monteiro FB. Brondani P. Silva AM. P. W. Silva AH. Bonacorso HG. Martins MA. P. Zanatta N. Creczynski-Pasa TB. Chem. Res. Toxicol. 2014; 27: 1040
• 1e Woodward EE. Hladik ML. Kolpin DW. Environ. Sci. Technol. Lett. 2016; 3: 387

For typical methods, see:
• 2a Martins P. Pereira CM. P. Zimmermann NE. A. Moura S. Sinhorin AP. Cunico W. Zanatta N. Bonacorso HG. Flores AF. C. Synthesis 2003; 2353
• 2b Zanatta N. Flores DC. Madruga CC. Flores AF. C. Bonacorso HG. Martins MA. P. Tetrahedron Lett. 2006; 47: 573
• 2c Flores AF. C. Piovesan LA. Souto AA. Pereira MA. Martins MA. P. Balliano TL. da Silva GS. Synth. Commun. 2013; 43: 2326
• 2d Lechuga-Eduardo H. Olivo HF. Romero-Ortega M. Eur. J. Org. Chem. 2014; 5910
• 2e Yavari I. Malekafzali A. Eivazzadeh-Keihan R. Skoulika S. Alivaisi R. Tetrahedron Lett. 2016; 57: 1733
• 2f Onys’ko PP. Zamulko KA. Kyselyova OI. Shalimov OO. Rusanov EB. Tetrahedron 2017; 73: 3513

For general reviews on the chemistry of alkoxyallenes, see:
• 3a Zimmer R. Synthesis 1993; 165
• 3b Reissig H.-U. Hormuth S. Schade W. Okala Amombo M. Watanabe T. Pulz R. Hausherr A. Zimmer R. J. Heterocycl. Chem. 2000; 37: 597
• 3c Reissig H.-U. Zimmer R. Donor-Substituted Allenes . In Modern Allene Chemistry . Krause N. Hashmi AS. K. Wiley-VCH; Weinheim: 2004: 425
• 3d Brasholz M. Reissig H.-U. Zimmer R. Acc. Chem. Res. 2009; 42: 45
• 3e Nedolya A. Tarasova O. Volostnykh OG. Albanov AL. Klyba LV. Trofimov BA. Synthesis 2011; 2192
• 3f Zimmer R. Reissig H.-U. Chem. Soc. Rev. 2014; 43: 2888
• 3g Tius MA. Chem. Soc. Rev. 2014; 43: 2979
• 3h Reissig H.-U. Zimmer R. Synthesis 2017; 49: 3291

For reviews, see:
• 4a Lechel T. Reissig H.-U. Pure Appl. Chem. 2010; 82: 1835
• 4b 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
• 5a Lechel T. Möhl S. Reissig H.-U. Synlett 2009; 1059
• 5b Lechel T. Reissig H.-U. Eur. J. Org. Chem. 2010; 2555
• 5c Bera MK. Reissig H.-U. Synthesis 2010; 2129
• 5d Bera MK. Dominguez M. Hommes P. Reissig H.-U. Beilstein J. Org. Chem. 2014; 10: 394
• 6 Zimmer R. Lechel T. Rancan G. Bera MK. Reissig H.-U. Synlett 2010; 1793
• 7a Lechel T. Lentz D. Reissig H.-U. Chem. Eur. J. 2009; 15: 5432
• 7b 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
• 8a Flögel O. Dash J. Brüdgam I. Hartl H. Reissig H.-U. Chem. Eur. J. 2004; 10: 4283
• 8b Lechel T. Dash J. Hommes P. Lentz D. Reissig H.-U. J. Org. Chem. 2010; 75: 726

For examples employing the trichloromethyl group as leaving group (haloform reaction), see
• 9a Signaigo FK. Adkins H. J. Am. Chem. Soc. 1936; 58: 1122
• 9b Treibs A. Dietl A. Justus Liebigs Ann. Chem. 1958; 619: 80
• 9c Bailey DM. Johnson RE. Albertson NF. Org. Synth. 1971; 51: 100
• 9d Bailey DM. Johnson RE. J. Med. Chem. 1973; 16: 1300
• 9e Barker P. Gendler P. Rapoport H. J. Org. Chem. 1978; 43: 4849
• 9f Uieara M. Zucco C. Zanette D. Rezende MC. Nome F. J. Chem. Soc., Perkin Trans. 2 1987; 175
• 9g Zucco C. Lima CF. Rezende MC. Vianna JF. Nome F. J. Org. Chem. 1987; 52: 5356
• 9h Wu P. Zhang J. Meng Q. Nare B. Jacobs RT. Zhou H. Eur. J. Med. Chem. 2014; 81: 59
• 9i Attaba N. Taylor JE. Slawin AM. Z. Smith AD. J. Org. Chem. 2015; 80: 9728
• 10a Kaberdin RV. Potkin VI. Ol’dekop YA. Russ. J. Org. Chem. 1990; 26: 1347
• 10b Guzmán A. Romero M. Talamás FX. Villena R. Greenhouse R. Muchowski JM. J. Org. Chem. 1996; 61: 2470
• 10c Romero-Ortega M. Fuentes A. González C. Morales D. Cruz R. Synthesis 1999; 225
• 10d Romero-Ortega M. Reyes H. Covarruvias-Zuiňga A. Cruz R. Avila-Zarraga JG. Synthesis 2003; 2765
• 10e Foller Larsen A. Ulven T. Org. Lett. 2011; 13: 3546
• 10f Paloque L. Verhaeghe P. Casanova M. Castera-Ducros C. Dumètre A. Mbatchi L. Hutter S. Kraiem-M’Rabet M. Laget M. Remusat V. Rault S. Rathelot P. Azas N. Vanelle P. Eur. J. Med. Chem. 2011; 54: 75
• 10g Lim FP. L. Tetrahedron Lett. 2014; 55: 6684
• 10h Romero-Reyes MA. Zaragoza-Galicia I. Olivo HF. Romero-Ortega M. J. Org. Chem. 2016; 81: 9515
• 10i Caballero-Garcia G. Romero-Ortega M. Barroso-Flores J. Phys. Chem. Chem. Phys. 2016; 18: 27500
• 11a Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas 1968; 87: 916

For the generation of 1 by a continuous flow route, see:
• 11b Seghers S. Heugebaert TS. A. Moens M. Sonck J. Thybaut JW. Stevens CV. ChemSusChem 2018;
• 12 Högermeier J. Reissig H.-U. Adv. Synth. Catal. 2009; 351: 2747
• 13 For a report describing the problems in Sonogashira reactions with trichloromethyl-substituted heterocycles, see: Kieffer C. Verhaeghe P. Primas N. Castera-Ducros C. Gellis A. Rosas R. Rault S. Rathelot P. Vanelle P. Tetrahedron 2013; 69: 2987
• 14 Eidamshaus C. Reissig H.-U. Eur. J. Org. Chem. 2011; 6056
• 15a Boekelheide V. Linn WJ. J. Am. Chem. Soc. 1954; 76: 1286
• 15b Galatsis P. In Name Reactions in Heterocyclic Chemistry . Li JJ. Corey EJ. John Wiley & Sons Inc; Hoboken, New Jersey: 2005: 340
• 15c Hommes P. Reissig H.-U. Eur. J. Org. Chem. 2016; 338
• 16 Zimmer, R.; Kurzawa, T.; Reissig, H.-U. unpublished results.
• 17a Dash J. Reissig H.-U. Chem. Eur. J. 2009; 15: 6811
• 17b Hommes P. Berlin S. Reissig H.-U. Synthesis 2013; 45: 3288
• 17c Hommes P. Fischer C. Lindner C. Zipse H. Reissig H.-U. Angew. Chem. Int. Ed. 2014; 53: 7647; Angew. Chem. 2014, 126, 7778
• 18 Eidamshaus C. Triemer T. Reissig H.-U. Synthesis 2011; 3261
• 19 Gao Y. Zhang Q. Xu J. Synth. Commun. 2004; 34: 909
• 20 Pyrimidine derivative 10c was obtained as a pure compound in low yield in a different experiment.