Biheterocycles

Acidic hydrolysis of these compounds regenerates the initial 2-aminothiazole (510). The reduction of 2-thiazolylamidines provides a good synthetic route to secondary 2-aminothiazoles (see Section I.l.E). They can be used as starting materials to obtain biheterocyclic products such as l-(5-nitro-2-thiazolyl)-2-thioxoimidazolidine (275) (Scheme 169) (511). 

Tautomerism of [6.6]biheterocycles was not covered in the previous review (76AHCS1). Since then, several surveys appeared on pyrazino[2,3-djpyrimidines or pteridines (135) with some coverage of tautomerism, with the most recent by Pfieiderer [96CHEC(7)679, and references therein],Tire results on pteridines not included in the previous surveys, are discussed in this section. Limited data on other heterocycles are also covered. 

Synthesis, structure, and properties of aromatic biheterocycles 97AHC(67)1. 

The reactions presented below involve cyclization of an unfused biheterocycle at two ring nitrogen atoms adjacent to the torsional bond by an electrophilic reagent to give a fluorene analogue such as compound 197 from 2,2 -bipyridyl 196 (Equation 19) <1998AGE344>. 

Many investigations are devoted to INOCs leading to fused biheterocyclic systems. 

Fig. 6. Solid-phase synthesis of biheterocyclic dihydroimidazole derivatives from resin-bound diamines.

Steel, P. J., Aromatic Biheterocycles Syntheses, Structures, and Properties,... 

Condensation of dibromomethane with the 1,2,4-triazepine 194 in phase-transfer catalysis conditions provides efficient and facile access to the biheterocyclic triazepine 42 with high regioselectivity (Equation 19) <1997TL2087>. 

Sodium borohydride reduction of cyclic ketone 109 produced alcohol 110 <1997BMC1327> (Equation 19). Biheterocyclic 2-hydroxyphosphonates 111 were synthesized by reactions of phospha-bicyclodecanones 112 with dimethylphosphonates in the presence of NaOH/MeOH <1996RJC567> (Equation 20). 1-Cyclohexylphosphin-4-one 113 was reduced to the corresponding alcohol 114 by sodium borohydride <2004TL407> (Equation 21). 

Under physiological conditions and at all reasonable values of pH the biheterocycle form is favored. 

This nucleophilic reactivity of 2-aminothiazoles has been used to prepare biheterocyclic compounds. Thus 2-aminothiazole reacts with chlorovinyl methyl ketone yielding 5-methyl-thiazolo[3,2-a]pyrimidinium chloride (Scheme 109). In the presence of formaldehyde, aminothiazoles react with ends affording condensation products, through the intermediacy of Mannich bases (Scheme 110). In acidic medium and at higher temperatures, condensation of 4-aryl-2-aminothiazole with benzaldehyde takes place at the C-5 position (Scheme 111). The same orientation is observed when 2-amino-4-methylthiazole is alkylated by secondary or tertiary alcohols in 85% sulfuric acid (Scheme 112). 

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