Synthesis of Indene[1,2-c]isoquinoline-11-one by Rhodium-catalyzed Benzimide-directed C—H Activation
Indene[1,2-c]isoquinoline is a novel non-camptothecin-like Topol inhibitor,and possesses good antitumour effect on lung cancer,lymphoma,etc.Thus,the development of new methodologies to construct indene[1,2-c]isoquinoline and its derivatives has been a hot topic in organic chemistry.In recent years,benzimidate has been widely used as a building block in the construction of nitrogen-containing heterocycles via transition metal-catalyzed C(sp2)—H bond activation and subsequent cyclization reaction with different reagents,such as alkyne,alkene,carbenes.Meanwhile,α-diazo carbonyl compounds have been widely used as C2 synthons in organic synthesis.In particular,with cyclic α-diazo-1,3-diketones,fused polycyclic compounds could also be prepared via Rh(Ⅲ)-catalyzed[4+2]oxidative annulations.Herein,we report the construction of indene[1,2-c]isoquinoline-ll-one using benzimidate and α-diazo carbonyl compounds as the starting material.The reaction proceeds via a rhodium-catalyzed C—H activation/carbenoid insertion/dehydration process.The protocol showed high atom economy,excellent functional group tolerance,and heterocycle compatibility,giving the indene[l,2-c]isoquinoline-ll-one in moderate-to-good yields.Wolff-Kishner reduction of the product withN2H4·H2Oaffords the indene[1,2-c]isoquinoline.To demonstrate the synthetic utility of this protocol,gram-scale synthesis and late-stage modification of drug molecule were showcased.The KIE value of 3.4∶1 indicated that the C—H cleavage step is probably involved in the rate-determined step.A typical general procedure for the synthesis of indene[1,2-c]isoquinoline-l l-one 3a is described as the following:To a solu-tion of ethyl benzimidate(0.1 mmol),[Cp*RhCl2]2(1.5 mg,2.5 mol％),and AgOAc(3.2 mg,20 mol％)in hexafluoroisopro-panol(2 mL)was added diazooxindole(0.11 mmol)under N2.The mixture was stirred at 100 ℃ for 12 h.Then the reaction mixture was cooled to room temperature.The mixture was filtered through Celite,and the filtrate was evaporated to give the crude product which was then purified by flash column chromatography on silica gel with a gradient eluent of petroleum ether/ethyl acetate(V/V,10/1)to give the product 3a.
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