Pentasubstituted pyridines

Boger developed his pyridine synthesis out of a need to eonstruet a pentasubstituted pyridine in an approach to the formal total synthesis of antitumor antibiotic streptonigrin 44. The requisite triazine 48 was produeed by using this methodology in an iterative sense with two different aza-heteroeyeles. Reaetion of thioamidate 46 with tetrazine 47, in a eyeloaddition/eyeloreversion sequenee, afforded 1,2,4-triaziene 48. Exposure of enamine 49 to 48 resulted in the formation of 50. This compound was elaborated into a eompound that intereepted Kende s synthesis of 44. ... 

Reaction of cyclopentadienylzirconium derivatives having C=C bonds with (NC)2C= NOTs also leads to pentasubstituted pyridines ". ... 

Fused pyridazines, such as 3, that have a chloro substituent a to the nitrogen in the pyridazine ring react with electron-rich ynamines in a reaction sequence including an inverse electron demand Diels-Alder process to give the corresponding pentasubstituted pyridines (Equation 2) <1994CPB2219>. Another isomer of the pyrrolopyridazine as well as a furopyridazine behaved similarly <1994CPB2219>. 

Pyridine/ Dewar pyridine valence isomerizations are also observed for pentasubstituted pyridines 1933 and 20.34... 

Selective cyclotrimerization of alkynes with nitriles produced pentasubstituted pyridines (1) with little formation of benzenoid products (Scheme 1) <94CB(127)2535>. 

Phthalazines containing halo substituents react with 2 equiv of alkyne and undergo N-N bond cleavage leading to pentasubstituted pyridines (Equation 200) <1996H(43)199>. 

Conjugated heterocumulenes (e.g., 308) can also act as heterodienes in [4 + 2] cycloadditions reacting with aminoalk-ynes to give pentasubstituted pyridines 309 (Scheme 156) <1997T4521>. 

Numerous transition metal-mediated [2 + 2+2] cycloadditions have been utilized in the synthesis of pyridines . Selective cyclotrimerization of alkynes with nitriles leads to pentasubstituted pyridines 310 with minimal formation of benzenoid byproducts (Scheme 157) <20000L3131>. Different alkynes can be utilized in the same strategy if a sequential approach is used (Scheme 158) <2000JA4994>. 

Suzuki, H. Sakai, N. Iwahara, R. Fujiwaka, T. Satoh, M. Kakehi, A. Konakahara, T. Novel synthesis of 7-fluoro-8-(trifluoromethyl)-l/f-l,6-naphthyridin-4-one derivatives intermolecular cyclization of an A-silyl-l-azaallyl anion with perfluoroalkene and subsequent intramolecular skeletal transformation of the resulting pentasubstituted pyridines. J. Org. Chem. 2007, 72(15),5878-5881. 

The cycloaddition of Al-vinylic heterocumulenes, such as the carbodiimide 1 with the ynamine 2 affords pentasubstituted pyridines 3 <97T4521>. The conjugated heterocumulenes act as heterodienes in the [4 + 2] cycloadditions reacting with the electron-rich aminoalkyne. If the reaction mixture is heated at 140 C the isoquinoline is obtained instead. 

By aza-Wittig reactions of iminophosphoranes with isocyanates, carbodiimide-mediated syntheses of pyrrole and indole derivatives [1270], pentasubstituted pyridines [1271], pyrimidine derivatives [1272-1274], bis( -ferrocenylvinyl)carbo-diimide [1274], amino-tetrazolyl-deoxythymidines [1275], the marine alkaloid leu-cettamine B [1276], and aza-analogues of aplysinopsins [1277] have also been accomplished. 

A rather interesting approach (Scheme 13) to streptonigrin-like pyridines has recently been described (67). The key step involves a Diels-Alder cycloaddition of a pyrimidine with an ynamine. For example, condensation of dicyanopyrimidine (89) with ynamine (90) in refluxing THF gave the pentasubstituted pyridine (92) in fair yield. Unfortunately, (89) did not react with the phenyl ynamine (91) and the desired pyridine (93) could not be produced by this method. It was suggested that (89) and (91) might react under hi pressure, but this has apparently not yet been attempted. 

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