Other Ring Systems

To improve these yields further, poly(ethylene glycol) (PEG) was used as support. Thus, PEG-bound aldehydes (R = PEG-connection) were mixed with ketones and 3 equiv. propanedinitrile, and NH4OAC was used as base. The three-component reaction was performed under MW irradiation for 2 min resulting in PEG bound 

6- dicyanoanilines. These were cleaved by NaOMe-MeOH to afford free polysubstituted 2,6-dicyanoanilines 62 in good yields (65-82%) [105]. 

SS -difluoride (SOF)2PCl2N3, on reaction with potassium thiocyanate, gave a mono-isothiocyanate as a mixture of two isomers, but the major product was (S0F)2P(NCS)2N3.  

A number of new silicon-containing mono- and bi-cyclic derivatives, including 

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Replacement of the benzene ring by other ring systems, or the introduction of additional substituents, decreases or aboHshes activity. 

Pyridine ring syntheses (48) can be classified into essentially two categories ring synthesis from nonheterocyclic compounds, and synthesis from other ring systems. The synthesis of pyridine derivatives by transformations on the pyridine ring atoms and side-chain atoms have been considered in the previous section. 

Synthesis From Other Ring Systems. These syntheses are further classified based on the number of atoms in the starting ring. Ring expansion of dichlorocyclopropane carbaldimine (53), where R = H and R = ryl, on pyrolysis gives 2-arylpyridines. Thermal rearrangement to substituted pyridines occurs in the presence of tungsten(VI) oxide. In most instances the nonchlorinated product is the primary product obtained (63). 

Certain thiophenes can readily be converted to other ring systems. The reversible rearrangement of thiothiophthene (86) to a thiophene... 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

Into Other Ring Systems Into Heterocycles with Ring Contraction... 

Synthesis of the other ring system ([ 1,2,4]tnazolo[3,4-r][l,2,4]tnazinc), mentioned in the title of this section, has been carried out by a procedure analogous to those shown in Scheme 52 <2004JCM174>. Thus, the diazotriazole 263 was reacted with an cr,/3-unsaturated ketone in ethanolic solution in the presence of sodium acetate at room temperature to yield the cyclized product 264 in good yield (70%). 

A number of other ring systems have been prepared by intramolecular bis-annulation procedures. Pyrrolothiadiazolines 174 were prepared by condensation between hydrazides and compound 173 (Equation 14) <1998JPR676>. The thermally induced intra-intermolecular criss-cross cycloaddition of azine 175 in the presence of phenyl isocyanate leads to heterocyclic compound 176 containing three fused five-membered rings (Equation 15) <2002TL6431>. 

Table 5.1 summarizes work done on aromatic and substituted aromatic and other ring systems. 

Substituent constants devised for substituted benzenes are often useful for substituents in meta-type (1, 3) positions in other ring systems and good correlations provide corroborating evidence for... 

Non-peptide inhibitors of thrombin (obtained by random screening procedures) include compounds based around benzothiophene (e.g. 155) and other ring systems and cyclic and linear oligocarbamate derivatives (e.g. 156). The benzothiophene derivative 155 showed antithrombotic efficacy in a rat model of thrombosis after infusion (ED50 2.3 mg/kg/h). The cyclic oligocarbamate tetramer 156 inhibited thrombin with an apparent K[ of 31 nM. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

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