Imidazo azepine

A multicomponent reaction involving 84, 85, and 86 has been realized in the high yielding synthesis of the imidazole 87, which could be converted in turn into the novel imidazo azepine 88 via a ring closing metathesis process <05TL9049>. 

The azepino-indole (600 E = COjMe) is produced by thermolysis of methyl 2-azidodiphenylmethane4 -carboxylate, N3C6H4CH2C6H4C02Me. Treatment of the pyrrolo-azepine (601) with benzoylmethylenetriphenyl-phosphorane, PhCOCH=PPh3, yields the bridged compound (602) by successive Michael addition and intramolecular Wittig reaction The imidazo-azepine (604) is formed from (603) by ring-expansion with diazomethane.Addition of dimethyl acetylenedicarboxylate to the cyclo-... 

I CN 9,13b-dihydro-l//-dibenz[c/ imidazo[l,5-a]azepin-3-amine monohydrochloride ( epinastine... 

CN ( )-r-[3-(3-chloro-10,l I-dihydro-5//-dibenz[6/ azepin-5-yI)propyl]hexahydrospiro[imidazo[l,2-a]pyridine-3(2//),4 - piperidin]-2-one... 

Additionally, uracil 6-iminophosphorane, isocyanate, and o-methyl-e-caprolactim ether join to form the intensely yellow pyrimido[4 5 4,5] pyrimido[6,l-n]azepine (360), as shown in Scheme 130. Upon ring closure, methanol is spontaneously eliminated. Diethyl azodicarboxylate affords with the other components pyrimido[4,5-e][l,2,4]triazoline (361), which is closely related to the alkaloid isofervenuline. The imidazo[5, -/][ ,2,4]tria-zine (362) results in a known Michael-type rearrangement sequence by treatment with diethyl acetylenedicarboxylate (86JOC149, 86JOC2787) in this latter case, the Michael-type addition occurs much faster than the expected three-component reaction [93H(35)1055]. 

Tetralins — see also Naphthalenes, tetrahydro-thermochemistry, 2, 368 Tetralones Schmidt reaction azepine synthesis by, 7, 531 Tetramisole—see Imidazo[2,I-6]thiazoie, ( )-2,3,5,6-tetrahydro-6-phenyl-... 

CN (Z)-6-(2-chlorophenyl)-2,4-dihydro-2-[(4-methy 1-1 -piperazinyl)methylene]-8-nitro-1 A/-imidazo[ 1,2-a ][ 1,4 Jbenzodi azepin-1 -one... 

The formation of amidines from lactim ethers and amines proceeds readily with high yields,8, >18,21,70-70 e.g., in the synthesis of imidazo-[l,2-6]azepine derivatives reported by Stolle et al.77 (Scheme 9), and in the preparation of the pyrimido[l,2-a]-azepine derivative (Scheme 10).70... 

Pyrazole-3-acetonitrile (370)117 and imidazole-4(5)-acetonitrile (375)118 react by just this means to pyrazolo( 1,5-a)pyridine-4-carbonitriles (312) and imidazo(l,5-a)-pyridine-8-carbonitriles (318) respectively. Only (310) can be reacted with (7m), giving pyrazolo(l,5-c)pyrimidine-4-carbonitrile (313) mp. 164°, colorless plates (150°, 3 h in quinoline, 56%) and yielding with (44) red needles of the pyrazolo(l,5-a)-cyclopent(e)azepine-4-carbonitrile (314) mp. 160-161° (150°, 4 h in quinoline 15%). 

To a solution of 1.68 g diphenyltetrazine (7.18 mmol) in 15 mL dimethyl sulfoxide was added 0.219 g DBU (1.44 mmol). This mixture was then heated at reflux under nitrogen for 2 h. The solution was cooled to room temperature, and 20 mL dichloromethane was added followed by 15 mL H2O. The aqueous layer was removed, and the organic layer was washed twice with H2O. The white precipitate, if any, was filtered and washed with several small amounts of dichloromethane. The concentrated organic layer was submitted to flash chromatography on silica gel with EtOAc followed by EtOAciMeOH (9 1) to afford 0.295 g 2,8,ll-triphenyl-37/,47/,57/,67/,7//-imidazo[4,5,l-e/][l,3]-diazaperhydroino[l,2-/] pyridazino[4,5-J]azepine as a yellow solid, m.p., 245-248°C (dec.). 

H.-R. Pan, X.-R. Wang, C.-X. Yan, Z.-X. Sun, Y. Cheng, Org. Biomol. Chem. 2011, 9, 2166—2174. The multicomponent reaction of imidazo[l,5-a]pyridine carbenes with phthalal-dehydes and dimethyl acetylenedicarboxylate a facile construction of benzo[d]furo[3,2-h]azepines. 

O-Methylcaprolactim added to powdered a-aminopropiophenone hydrochloride, stirred intermittently at room temp, during 6 hrs. with portionwise addition of alcohol to keep the thick slurry stirrable, then allowed to stand 4 days at room temp. -> 2,3,6,7,8,9-hexahydro-2-methyl -3-phenyl -5H- imidazo[1,2-a] azepin-3- ol hydrochloride. Y 68-79%. F. e. s. G. P. Claxton, J. M. Grisar, and N. L. Wiedi, J. Med. Chem. 17, 364 (1974). 

Ceratamines A (249) and B (250) both had IC50 values of 10 pg/ml in the cell-based antimitotic assay. They are the first two representatives of a novel family of antimitotic heterocychc alkaloids. The imidazo[4,5,d]azepine core heterocycle in the ceratamines appears to have no precedent at any oxidation level among known natural products or synthetic compounds (151). 

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