1.3- Diazepines fused

Much work has been done on the photochemical ring-expansion of pyridine A -imides to 1,2-diazepines, but it has previously not proved possible to extend this reaction to the formation of 2,3-benzodiazepines (58) from isoquinoline A -imides (57). Now, however, it has been shown that this reaction can be effected in 30-50% yield if it is done in the presence of base. Full reports have now been published on the photolysis of thieno-, furo-, and pyrrolo-[ ]- and -[c]-pyridine A -imides. These reactions give both 1,2-and 1,3-diazepines fused to the heteroaromatic rings (see these Reports, Volumes 2 and 3). 

I.3.3.2.3. 1,4-Diazepines Fused to Heteroaromatic Rings 4.I.3.3.2.3.I. Synthesis By Ring-Closure Reactions... 

By use of the versatile reactivity of the copper catalysts, the Ohno group expanded their three-component indole formation (Scheme 19.78) to a one-pot synthesis of diazepine-fused indoles [152]. After formation of 2-(aminomethyl)indoles 307 using 2-ethynyl-At-mesylanilines 305, formaldehyde, and 2-bromobenzylamines 288b, addition of NaOMe furnishes removal of Ms group and spontaneous copper-catalyzed N-arylation to produce indole-fused 1,4-diazepines 308 (Scheme 19.82). 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Diazepines alkylation, 7, 617 electrophilic reactions, 7, 615 with fused heterocyclic rings... 

The result of condensation of (3-dicarbonyl compounds with 3,4-diaminofurazan depends on the reaction conditions. With metal ions as templates, 14-membered rings 188 were formed exclusively (91MI2), whereas in the absence of these ions, only fused diazepines 189 were formed (Scheme 122) (89UKZ1064). 

In contrast to the iV-imines 11, which yield solely bicyclic 1,2-diazepines 12 on irradiation, the [c]-fused pyridine /V-imincs 13 give mixtures of condensed 1,2- and 1,3-diazepines, 14 and 15, accompanied by condensed pyridines 16 (if R3 = H).145... 

The imine 13d gives only the fused 1,2-diazepine 14d, and compounds 13e and I3f yield solely the corresponding bicyclic 1,3-diazepines 15e and 15f.145... 

Monocyclic and benzo-fused 1,3-diazepines are rare and have been reported only recently. For a review, see ref 67a. 

The formation of 5//-dibenzo[r/,/][l,3]diazepin-6(7//)-one (13, R = H) in good yield by fusing biphenyl-2,2 -diamine with urea was reported in 1901177 and has since been extended to the preparation of numerous analogs.178 Selected examples are given yields were generally not reported.177-179... 

Aminopyrimidines are also known to undergo Michael additions to a,P-unsaturated carbonyl compounds. This methodology was utilized by Insuasty and co-workers using triaminopyrimidines 70 with conjugated ketones 71 to produce a variety of pyrimidine-fused diazepines 72 <00JHC193,00JHC401>. 

SEVEN MEMBERED SYSTEMS CONTAINING TWO HETEROATOMS 7.3.1 Diazepines and fused diazepines and derivatives... 

A range of azole-fused 1,4-diazepine derivatives have also been reported, for example the [l,2,5]selenadiazolo[3,4-e][l,4]diazepines 107 (eg. R = H) <00JHC1269>. 

Interest continues in the preparation of pyrimido-fused diazepines. In this context, a number of new 6-amino and 6,8-diamino-4-aryl-2,3-dihydropyrimido[4,5- >][l,4]diazepines were synthesised by the highly regioselective condensation of 4,5,6-triaminopyrimidine and 2,4,5,6-tetraaminopyrimidine respectively with 3-dimethylaminopropiophenones <00JHC401>. 

The diazepine with fused pyrrole ring 250c is the product of the condensation of orflzo-phenylenediamine with pyrrole carbaldehyde 249 in 36% yield (Equation (31) (2006T6018)). 

As for benzo[f7]pyrrolo[3,4-e][l,4]diazepin-3(4H)-ones 241, a fused thiophene (X = S) can be synthesized using a two-step reaction sequence (Scheme 51, Section 3.1.1.3 (1991CE495)). 

Pyrrolo-benzoxazepines with other fusion modes. As with diazepine, benzoxazepine with the fused pyrrole ring 250a can be prepared by condensing ortho-amino phenol (X = O) with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 (2006X6018)). 

Lithium hydroxide hydrolysis of the ester of pyrrolo[l,2-l7][l,2,5]benzothia-diazepine 5,5-dioxide 346 afforded the acid, subsequently reduced with lithium aluminum hydride-aluminum chloride to alcohol 348 (Scheme 73, Section 4.2 (2006JMC5840)). Pyrrolo[l,2- 7][l,2,5]benzothiadiazepine acid 347 gives easy access to a variety of esters and amides 407, while treatment with TFAA produces fused lactam 408 (Scheme 85 (1996FES425)). 

Amino methyl substituted pyrrolo-benzodiazepine 215 forms a cyclic aminal with aldehydes that can be further oxidized with Mn02 to fused 3-substituted imidazole 216. Alternatively, cyclic imine 217 can be submitted to TosMlC cycli-zation to afford unsubstituted 9H-benzo[e]imidazo[5,l-c]pyrrolo[l,2-fl][l,4]-diazepine 218 (Scheme 45, Section 3.1.1.2 (1993JHC749)). 

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. 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

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