Syntheses of Some Arylamino- and Arylguanidinopyrimidines
About: This article is published in Journal of Organic Chemistry.The article was published on 1960-11-01. It has received 5 citations till now.
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TL;DR: A complementary approach has been developed for the Pd-mediated attachment of heterocyclic groups to a dihalogenated porphyrin, thereby avoiding the acid-catalyzed condensations with heterocyClic aldehydes.
Abstract: Tailoring the perimeter of the porphyrin macrocycle with diverse substituents in defined patterns is essential for studies in biomimetic and materials chemistry.1,2 Small nitrogen heterocycles are substituents of particular interest,3 providing sites for metal coordination, hydrogenbonding, alkylation (water solubilization), and modulation of the electronic properties of the porphyrin. Indeed, pyridine substituents have yielded a broad array of metal-coordinated multiporphyrin architectures,4 imidazole groups have yielded stacked multiporphyrin assemblies,5 and quinoline,6 pyrimidine/purine,7,8 or pyrazole9 units have enabled molecular recognition and selfassembly studies of porphyrins with complementary molecules. In these diverse architectures, a recurring pattern entails the incorporation of one heterocyclic group and three nonheterocyclic groups at the four meso positions of a porphyrin. Despite the widespread attraction of porphyrins bearing a single nitrogen heterocyclic group,10 the synthesis of such porphyrins has presented vexing challenges. The prevalent method of synthesis involves a mixed aldehyde condensation with pyrrole via the Adler method in refluxing propionic acid.11 This statistical approach affords a mixture of up to six porphyrins, from which the desired porphyrin is typically separated by laborious chromatography. For many nonheterocyclic aldehydes the milder conditions of the two-step one-flask synthesis (at room temperature in CH2Cl2 with TFA or BF3-etherate followed by oxidation with DDQ) are attractive, generally affording higher yields and more tractable non-porphyrin byproducts.1 However, small heterocyclic aldehydes generally fail in this method, which has been attributed to the poor solubility of the heterocyclic aldehyde (or its intermediate reaction products with pyrrole) in acidified CH2Cl2 or CHCl3. Indeed, the room-temperature pyrrolealdehyde condensation has succeeded with more soluble heterocyclic aldehydes, such as pyrimidinecarboxaldehydes bearing bulky groups adjacent to both nitrogens,12 pyrazolecarboxaldehydes bearing protecting groups (benzyl, SEM) on one of the nitrogens,13 or benzaldehydes to which heterocycles are attached.1 A complementary approach has been developed for the Pd-mediated attachment of heterocyclic groups to a dihalogenated porphyrin, thereby avoiding the acid-catalyzed condensations with heterocyclic aldehydes.14 Still, a direct and nonstatistical method is required to avoid performing additional synthetic steps and extensive chromatographic separation of multiple porphyrin products. We now report such a method for the preparation of porphyrins bearing one nitrogen heterocycle. Our approach builds on our recent success in developing two reactions: (1) a one-flask synthesis of dipyrromethanes and (2) the condensation of the dipyrromethane and a dipyrromethane-dicarbinol. For both reactions we have identified conditions (solvent, catalyst, temperature) that are suitable for the heterocyclic substrates. Dipyrromethanes are available via the one-flask roomtemperature condensation of an aldehyde with excess pyrrole (in the absence of any solvent) in the presence of TFA or BF3-etherate. This reaction has been used to prepare dipyrromethanes bearing a wide variety of substituents.1 The dipyrromethane-forming reaction also can be performed at elevated temperature in the absence of added acid, albeit in lower yield than with acid at room temperature.16 Upon application of the standard procedure at room temperature with acid to a set of heterocyclic aldehydes (2-, 3-, or 4-pyridinecarboxaldehyde, quinoline-3-carboxaldehyde, imidazole-2-carboxaldeyde, uracil-5-carboxaldehyde) with pyrrole, no dipyrromethane was obtained.17 While the “high-temperature no-acid” conditions have had no utility with aryl or aliphatic aldehydes, we felt the ability to forego any acid warranted examination in this case, given that identifying a suitable acidic medium for heterocyclic aldehydes has proved so problematic. Upon performing the pyrrole-aldehyde (1) Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M.; Smith, K. M.; Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 45-118. (2) Lindsey, J. S. In Metalloporphyrin-Catalyzed Oxidations; Montanari, F.; Casella, L., Eds.; Kluwer Academic Publishers: The Netherlands, 1994; pp 49-86. (3) Chambron, J.-C.; Heitz, V.; Sauvage, J.-P. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 6, pp 1-42. (4) (a) Ding, L.; Casas, C.; Etemad-Moghadam, G.; Meunier, B.; Cros, S. New J. Chem. 1990, 14, 421-431. (b) Sari, M. A.; Battioni, J. P.; Dupre, D.; Mansuy, D.; Le Pecq, J. B. Biochemistry 1990, 29, 42054215. (c) Fleischer, E. B.; Shachter, A. J. Heterocycl. Chem. 1991, 28, 1693-1699. (d) Fleischer, E. B.; Shachter, A. M. Inorg. Chem. 1991, 30, 3763-3769. (e) Drain, C. M.; Lehn, J.-M. J. Chem. Soc., Chem. Commun. 1994, 2313-2315. (f) Milgrom, L.; Hill, J. P.; Dempsey, P. J. F. Tetrahedron 1994, 50, 13477-13484. (g) Yuan, H.; Thomas, L.; Woo, L. K. Inorg. Chem. 1996, 35, 2808-2817. (h) Takeuchi, M.; Imada, T.; Ikeda, M.; Shinkai, S. Tetrahedron Lett. 1998, 39, 7897-7900. (i) Gerasimchuk, N. N.; Mokhir, A. A.; Rodgers, K. R. Inorg. Chem. 1998, 37, 5641-5650. (j) Funatsu, K.; Imamura, T.; Ichimura, A.; Sasaki, Y. Inorg. Chem. 1998, 37, 4986-4995. (k) Alessio, E.; Geremia, S.; Mestroni, S.; Iengo, E.; Srnova, I.; Slouf, M. Inorg. Chem. 1999, 38, 869-875. (5) (a) Milgrom, L. R.; Dempsey, P. J. F.; Yahioglu, G. Tetrahedron 1996, 52, 9877-9890. (b) Kobuke, Y.; Miyaji, H. Bull. Chem. Soc. Jpn. 1996, 69, 3563-3569. (6) (a) Mizutani, T.; Kurahashi, T.; Murakami, T.; Matsumi, N.; Ogoshi, H. J. Am. Chem. Soc. 1997, 119, 8991-9001. (b) McCurry, J.; Roberts, J. E. Polyhedron 1990, 9, 2527-2531. (7) Sessler, J. L.; Wang, B.; Harriman, A. J. Am. Chem. Soc. 1995, 117, 704-714. (8) Drain, C. M.; Fischer, R.; Nolen, E. G.; Lehn, J.-M. J. Chem. Soc., Chem. Commun. 1993, 243-245. (9) Ikeda, C.; Nagahara, N.; Motegi, E.; Yoshioka, N.; Inoue, H. Chem. Commun. 1999, 1759-1760. (10) A Web of Science search of pyrid* and porph* elicited over 500 papers. (11) (a) Little, R. G.; Anton, J. A.; Loach, P. A.; Ibers, J. A. J. Heterocycl. Chem. 1975, 12, 343-349. (b) Little, R. G. J. Heterocycl. Chem. 1981, 18, 129-133. (12) Motmans, F.; Ceulemans, E.; Smeets, S.; Dehaen, W. Tetrahedron Lett. 1999, 40, 7545-7548. (13) Werner, A.; Sanchez-Migallon, A.; Fruchier, A.; Elguero, J.; Fernandez-Castano, C.; Foces-Foces, C. Tetrahedron 1995, 51, 47794800. (14) DiMagno, S. G.; Lin, V. S.-Y.; Therien, M. J. J. Org. Chem. 1993, 58, 5983-5993. (15) Lee, C. H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427-11440. (16) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391-1396. 2249 J. Org. Chem. 2000, 65, 2249-2252
86 citations
TL;DR: Pyrimidine derivatives have been found to possess fungicidal, antibacterial, antimitotic, antithyroid and surface-anaesthesia activities, with the exception of pyrimidine antibiotics.
Abstract: Publisher Summary The beginning of pyrimidine chemistry may be traced back to the isolation of alloxan, a pyrimidine derivative. The synthesis of barbituric acid from urea and malonic acid perhaps marked the next major event in the development. Since then pyrimidines have occupied a unique and important place in the fields of biological and medicinal chemistry. It is well known that uracil, thymine, and cytosine are essential constituents in nucleic acids; thiamine that possesses antiberiberi activity was the first vitamin discovered in the B series; barbiturates are widely used as sedatives; pyrimethamine is highly potent against erythrocytic parasites in antimalarial study; aminometradine (Mictine) is an orally effective diuretic; and the 5-halogen-substituted uracils and derivatives have recently been reported as antitumour or antiviral agents, or both. Other pyrimidine derivatives have been found to possess fungicidal, antibacterial, antimitotic, antithyroid and surface-anaesthesia activities. With the exception of pyrimidine antibiotics, in this chapter, pyrimidines are classified based on special structural features and functional groups. The chapter discusses the following areas: 2,4- diaminopyrimidines, halogenated pyrimidines, sulphur-substituted pyrimidines, 2-substituted 4-amino-5-hydroxymethylpyrimidines, pyrimidine sulphonamides and pyrimidine antibiotics.
58 citations
TL;DR: In this article, the synthesis and structure of N-8-phenyl substituted pterins is described on the basis of u. v. r. and n. m. spectra as well as pKa values.
Abstract: Die Synthese von vorwiegend N-8-phenylsubstituierten Pterinen wird beschrieben. Die komplexen Strukturverhaltnisse der verschiedenen Molekulformen in Abhangigkeit vom pH-Wert werden anhand von UV- und NMR-Spektren sowie pK-Werten besprochen. Durch die Isolierung des 3.6-Dimethyl-8-phenyl-7-methylen-7.8-dihydro-pterins (62) konnte sichergestellt werden, das 8-substituierte 6.7-Dimethyl-pteridin-Derivate im alkalischen Bereich nicht unter Ringoffnung sondern unter Deprotonierung an 7-CH3 reagieren.
Pteridines, XLIV. Synthesis and Structure of N-8 Substituted Pterins and Lumazines
The synthesis of mainly N-8-phenyl substituted pterins is described. The structural complexity of the various molecular species in dependence of the pH value is discussed on the basis of u. v. and n. m. r. spectra as well as pKa values. Isolation of 3.6-dimethyl-7-methylen-8-phenyl-7.8-dihydropterin (62) proved for the first time that 8-substituted 6.7-dimethyl-pteridine derivatives do not react in basic medium with ring opening but with deprotonation at 7-CH3.
36 citations
TL;DR: 2,4-Bis(arylamino)-6-hydroxypyrimidines have been found to be the most active of the series and their inhibitory activity seems to be partially due to their interference with the pyrimidine metabolism of the microorganisms.
8 citations
TL;DR: 2,4_bis-@-chloroanilino)-pyrimidine, being the most potent inhibitor of growth of yeasts and bacteria, was chosen for studies on the mechanism of its action and is found to have a partial uncoupling effect on oxidative phosphorylation.
4 citations