Linear versus Angular Fischer Indole Annulation: Relative Configuration Determines Regioselectivity

Abstract

Fischer indole synthesis with bicyclic ketones yields regioselectively linear annulated tetracyclic products when starting from ketones with a relative trans configuration. On the other hand, starting materials with a relative cis configuration give exclusively angular annulated indole derivatives. The starting materials were prepared in optically active form in three steps by a sequence of asymmetric Michael reaction, aldol condensation, and catalytic hydrogenation. The last step yields a mixture of cis and trans diastereoisomers which can be separated by column chromatography. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Dihydropyridazine Derivatives with Cyclopenta‐, Benzo‐, Furo‐, Thiopyrano‐ and Pyrido‐Annulation

“…[1] In contrast to our proposed mechanism of azocanone formation through intermediate 3 (see Scheme 1), hydrazine 5a preferentially reacted with the endocyclic carbonyl group of compound 1a. [10] Because we were aiming to avoid the latter process, we started to look for alternative conditions. [1] Our attempts to transfer that earlier result to hydrazone 6b, which was obtained from cyclohexanone derivative 1b in 74 % yield, led to indole annulation product 9b instead of a pyridazine.…”

“…This was not surprising, because the reaction conditions were typical for a Fischer indolization. [10] Because we were aiming to avoid the latter process, we started to look for alternative conditions. Finally, the conversion of oxo ester 1b with hydrazine 5a under acidic conditions in polar aprotic solvent and without isolation of any hydrazone gave 1,4-dihydro-5H-pyridazine derivative 7b in excellent yield.…”

Synthesis and structure–activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors

“…Compound 30 was prepared by Fischer indole synthesis of S3 with phenylhydrazine (Scheme 3). 16 S3 was formylated with HCOOEt in the presence of MeONa to produce S4, which reacted with hydroxylamine hydrochloride in EtOH, followed by debenzylation to give isoxazole derivative 31. 17 Treatment of S4 with hydrazine hydrochloride to afford the pyrazole derivative S5, which reacted with appropriate acyl chloride, followed by debenzylation to yield corresponding compounds 32-36 (Scheme 3).…”

“…Base on the initial SAR studies of AKBA derivatives (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), in order to investigate the impact of different groups introduced at C-2,3 position on anti-proliferation activities against HUVECs, a series of heterocycle substituted AKBA derivatives at C-2,3 position were synthesized as Scheme 3. The screening results of antiproliferation activities against HUVECs in Table 4 indicated that pyrazole substituted AKBA derivative (19, IC 50 = 2.13 lM) showed greater potency than indole (30, IC 50 = 8.22 lM) and isoxazole (31, IC 50 = 9.92 lM) substituted AKBA derivatives.…”

“…Subsequently, in order to evaluate whether AKBA derivatives synthesized can truly inhibit VEGFR-2, we conducted in vitro kinase inhibition assay studies on all compounds (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). All the compounds were tested at 50 lM.…”