Platinum‐Catalyzed Domino Reaction with Benziodoxole Reagents for Accessing Benzene‐Alkynylated Indoles

Abstract

Indoles are omnipresent in natural products, bioactive molecules and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Herein we report a platinumcatalyzed cyclization-alkynylation domino process to obtain selectively C5-or C6-functionalized indoles starting from easily available pyrroles. Our work combines for the first time a platinum catalyst with EthynylBenziodoXole (EBX) hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.Functionalized indoles occupy a privileged position in organic chemistry, as they can be found in biomolecules, drugs, agrochemicals and materials. [1] To access these important building blocks, a first approach consists in the introduction of functional groups onto simple, commercially available indoles. In order to have a more efficient alternative to well-established cross-coupling reactions, the transition metal-catalyzed direct functionalization of C-H bond on indoles has been intensively investigated in the last two decades. Nevertheless, this approach is mostly limited to the modification of the more reactive pyrrole ring (innate reactivity, Figure 1, A). [2] The functionalization of the benzene ring has been only rarely achieved and is limited to C2,C3-disubstituted indoles. [3] One notable exception is the selective iridiumcatalyzed C7-borylation of indoles reported by Hartwig and coworkers. [4] We were particularly interested by the introduction of an alkyne onto the benzyl ring of indoles, as alkynes are key building blocks in medicinal, synthetic and material chemistry. [5] Direct alkynylation approaches can be used only to access 2-and 3-substituted indoles. [6] This is an important limitation, as 5-or 6-alkynylated indoles can be found in bioactive compounds such as 5-LOX (5-lipoxygenase) inhibitor 1, [7a] or NMDA (N-Methyl-DAspartate Receptor) antagonist 2. [7b] Alkynylated carbazoles are especially important for organic materials, such as macrocycle 3, an organic sensor for the detection of TNT. [7c] If an efficient method for the synthesis of benzene-alkynylated indoles can be developed, more complex compounds could then be easily obtained by using wellestablished C-H functionalization at the C2 or C3 positions or transformations of the triple bond. As C-H metalation of the arene ring of indoles is extremely difficult in presence of the more reactive C2 and C3 C-H bonds, we wondered if the desired reactive intermediate could be generated in situ during a metal-catalyzed cyclization step (Scheme 1). The use of such "domino" or "cascade" processes is one of the most efficient ways to increase molecular complexity in organic synthesis, [8] but it had not y...

Cyclic Hypervalent Iodine Reagents for Atom‐Transfer Reactions: Beyond Trifluoromethylation

“…[71] This transformation could not be catalyzed by either gold(I) or gold(III), but a platinum(II) catalyst was successful. Starting from 2-or 3-homopropargylic pyrroles 5-and 6-alkynylated indole derivatives 147-148 and 149 were obtained selectively.…”

Heterotetracenes: Flexible Synthesis and in Silico Assessment of the Hole‐Transport Properties

“…Recently, we developed cyclization–alkynylation domino reactions to access functionalized furans and indoles based on the use of ethynylbenziodoxole (EBX) hypervalent iodine reagents. We therefore envisaged that these reagents could be used to develop the unprecedented domino cyclization‐alkynylation process.…”

“…The conditions reported for Lautens’ domino reaction or Hashmi's benzofuran formation didn't give any desired product, independently of the hypervalent iodine reagent used (Table , entries 1–6). PtCl 2 was not efficient for this domino process (Table , entry 7). When we turned our attention to Au III catalysts, we were pleased to observe the formation of the desired product with benziodoxole 7 a (Table , entries 8–10).…”

Benziodoxol(on)e Reagents as Tools in Organic Synthesis: The Background behind the Discovery at the Laboratory of Catalysis and Organic Synthesis

“…In this case, platinum chloride was discovered as the best catalyst (Scheme 7, B). 39 Using methanol as a leaving group, the desired domino cyclization alkynylation product 30 could be obtained in 91% yield. Again, this project was not without surprise: Based on the mechanism of the cyclization reaction of Hashmi involving C2 attack and 1,2-shift of the alkoxy substituent (Scheme 7, A), we were expecting to obtain the C6-alkynylation product.…”