1,2,4-Triazepines, fused

Reactions of this type are of value in the synthesis of 1,2,4-triazepines fused to various heterocyclic ring systems. Reactants of type (464) combine with /3-keto esters to give products such as (465) (75JHC661, 1095, 79LA639). Similarly compounds of type (466) react with /3-halogenoacyl halides, /3-diketones and /3-keto esters to give a variety of triazepines and triazepinones, e.g. (467) (77AJC2053). 

Some triazepinones in which one of the nitrogen atoms belongs to a fused azole moiety have been reported. For instance, compound 63 was prepared (74JHC751) and its X-ray structure determined (75CSC317). Similarly, and NMR spectra and X-ray structural determination of 64 revealed that this compound exists as a 3//-tautomer with the 1,2,4-triazepine ring in a distorted boat conformation (88T7185). 

Nitrile imines have been added to 1,4-diazepines (246) (143,144), 1,2, 4-triazepines (247) (145), 1-benzazepines (248) (146), 1,4-benzodiazepines (249-251) (147-149), 1,5-benzodiazepines (252, 253) (X = NH) (143,150-153), 1,5-benzothiazepines (253) (X=S) (153). Interest in this area has been stimulated by the known pharmacological activity of many compounds with five-membered heterocyclic rings fused to a benzodiazepine skeleton. 

The indeno fused compounds (521) have been prepared in moderate yield by the photochemical reaction of 2,5-diaryl-l,3,4-oxadiazoles (519) with indene (77JOC1496) the reaction is thought to proceed via a diradical or betaine (520). These products react with isocyanates (RNCO) to give the triazepine system, e.g. (522) (76H(4)989). 

Concerning the theoretically accessible triazepine systems, the respective 1,2,3-analogues are the least studied. Despite several computational studies published since CHEC(1996), the synthesis of both monocyclic and fused 1,2,3-triazepines remains elusive. 

Reactions of 1,2-diaminobenzimidazole 72 with 1,3-diketones, acetocetic acid, and its derivatives to obtain fused triazepines were studied <2002CHE598>. The obtained products are depicted in Scheme 18. 

Fused l,2,5-triazepine-3,6-diones 88-90 were synthesized from (2 S )-proline methyl ester 205 by treating the latter with bromoacetic acid 206 in the presence of tiro-butyl chloroformate 207 (Scheme 46). The resultant bromoacetamide 208 on further treatment with hydrazine hydrate in EtOH gave 88-90 via cyclization through displacement of bromine <1996CC85>. 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

Prototropic tautomerism of pyrimidinedione-fused 1,3,5-triazepine 16 (Figure 3) and analogs was studied by measuring ultraviolet (UV) spectra in various solvents. Solution in MeOH showed a strong negative Cotton effect... 

Reaction of various aromatic or heteroaromatic diamines with iV-acyl isothiocyanates gave the corresponding benzo- or heterocycle-fused l,3,5-triazepine-2-thiones, for example, 16 (Figure 3) from 5,6-diamino-1,3-dimethyl-uracil and D-gluconyl isothiocyanate <1981CPB1832>. Cycloaddition of iVjiV -disubstituted ethylenediamines with bis(isocyanato)dimethylsilane or bis(isothiocyanato)dimethylsilane followed by treatment with 1,1 -carbonyldi-imidazole or 1,1 -thiocarbonyldiimidazole afforded a series of 1,5-disubstituted l,3,5-triazepine-2,4-diones, -2,4-dithiones, and 4-oxo-l,3,5-triazepine-2-thiones <1980AGE327>. 

All the approaches discussed in Sections 13.16.9 and 13.16.10 were widely applied to the synthesis of 1,3,5-triazepine heterocyclic ring. For the monocyclic and fused compounds, the [1+6] and [3+4] cyclization reaction and the azine ring expansion are the most popular routes (for additional information on the early reports, see CHEC-II(1996)). The bridged derivatives, such as hexaazaisowurtzitanes 5 (Figure 1), are available by multicomponent condensation. 

The photolysis of 4-azidopyridazines gives significant yields of the ring-expansion products, unsaturated 1,2,5-triaze-pines. Thus, 3-methoxy derivative 801 reacts, via formation of a nitrene and ring opening of an intermediate fused azirine, with methoxide or diethylamine to give 4-methoxy (or4-diethylamino)-l,2,5-triazepines 802 (X = OMe, NEt2). 

Further applications of the use of the versatile starting material, diaminomaleonitrile 166, in the synthesis of heterocyclic derivatives have been reported. For example, reaction of 166 with chlorocarbonylisocyanate 167 in the presence of triethylamine gave the isocyanate 168 which, on heating in the presence of sodium hydroxide, cyclised to the l,3,5-triazepine-2,5-dione 169. This heterocycle then served as a precursor for the synthesis of a range of other ring fused triazepinediones <04MI71>. 

Imidazo-fused analogues 174 of the 1,2,4-triazepine system have been synthesised from pre-formed imidazoles 173. Reaction of 173 with iV,iV -dimethylhydrazine.2HCl and the appropriate orthoformate then resulted in the triazepine derivatives 174 the formation of the imidates 175 is proposed to occur initially, followed by the ring closed intermediates 176. Reaction of 176 with the alcohol would then give 174 <04JMC1044>. 

---