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