Background and Originality Content
Indole substructures have always been the most important and appealing structural core for the discovery of new drug candidates.[1] In particular, tetrahydrocarbazol-4-one represents a kind of privileged drug scaffold in numerous bioactive molecules, marketed pharmaceuticals and natural products (Figure 1),[2] which greatly promoted the development of its expedient methods, mainly including classic Fischer indole cyclization,[3] Heck-type coupling reactions,[4] oxidative cyclization,[5] and acid-catalyzed cyclization,[6] etc. However, the reported routes often suffer from multi-step processes, harsh conditions, or limited substrate scope. Therefore, it is urgent need to develop an efficient and concise synthetic method.
Figure 1 Bioactive compounds and natural products containing tetrahydrocarbazol-4-one scaffold.
Transition-metal-catalyzed direct C–H functionalization has apparently provided simple and practical pathways for preparing complex molecules form readily available starting materials with the advantage of eliminating the need for prefunctionalization of substrates. Recently, several efforts to construct indole scaffolds have been made in theN- nitroso-directed C–H activation and cyclization with different coupling partners, such as alkynes,[7]alkynols,[8] diazo compounds,[9] sulfoxonium ylides,[10] and cyclopropenones[11] by a traceless, step-economic and cascade approach. However, the discovery of new routes that meet green synthesis goals from readily available raw materials is still desirable. Iodonium ylides, inexpensive, readily available, safe and stable highvalent iodine reagents compared to dangerous and explosive diazonium compounds, were used as effective synthons in few C–H activation.[12] In 2020, Rh(III)-catalyzed C–H bond activation of N -methoxybenzamide with hypervalent iodonium ylides deployed as a carbene precursor has been reported by Maheswari and co-workers.[13] More recently, Kanchupalli’ group developed another Rh(III)-catalyzed [4+2] and [3+3] annulations between indoles and iodonium ylides for rapid synthesis of diverse N -heterocylces.[14]
Based on the continuous efforts of our group in building drug-like heterocyclic compounds through transition-metal-catalyzed C–H bond activation, we further accomplished an efficient synthesis of the tetrahydrocarbazol-4-one scaffold via a Rh(III)-catalyzed traceless and cascade reaction of hypervalent iodonium ylides withN -nitrosoanilines under mild reaction conditions (Scheme 1). More importantly, the tetrahydrocarbazol-4-one derivatives constructed by the first-step C–H activation provided valuable templates for further modification, fulfilling the rapid and modular generation of molecular complexity through sequential multicomponent C–H activation. For example, C5 -selective alkylation, alkenylation, amidation and (hetero)arylation of tetrahydrocarbazol-4-one derivatives have successfully been achieved by sequential transition metal catalyzed C–H functionalization with commercially available materials. To the best of our knowledge, Rh(III)-catalyzed annulation ofN -nitrosoanilines with iodonium ylides and sequentialC5 -H functionalization of tetrahydrocarbazol-4-ones have not been reported previously. We believe the desired analogues may help in the search of new biologically active compounds and drug discovery by creation of diverse chemical space.
Scheme 1 Design of Rh(III)-catalyzed annulation ofN -nitrosoanilines with iodonium ylides and sequential C–H functionalization.
Results and Discussion
As a starting point, we conducted the annulation reaction betweenN -nitroso-N -methylaniline (1a ) and 2-(phenyl-λ 3-iodaneylidene)cyclohexane-1,3-dione (2a ) in the presence of [Cp*RhCl2]2 and AgSbF6 in DCE at 80 oC as the initial catalytic conditions, and fortunately isolated the desired product3aa in 29% yield (Table 1, entry 1). Among the tested catalysts, [Cp*RhCl2]2 still showed the highest catalytic activity (entries 2−5). Further reaction optimization by examining Ag salts revealed that AgBF4was conducive to this reaction, providing 3aa in 40% yield (entries 6-10). Then, a screening of additives demonstrated that PivOH gave a better yield (entries 11-14), and the yield of 3aa was increased to 57% when the reaction was conducted in acetone (entries 15 and 16). Subsequently, performing the reaction at 90oC exhibited a higher reaction efficiency with 72% isolated yield (entry 17). Briefly, the optimal results could be obtained when 1a (0.4 mmol) and 2a (0.6 mmol, 1.5 equiv.) in acetone were treated with 8 mol% [Cp*RhCl2]2, AgBF4(0.6 mmol, 1.5 equiv.) and PivOH (0.8 mmol, 2 equiv.) at 90oC under Ar for 12 h.
Table 1. Optimization of Reaction Condition Aa