Practical Solvent‐Free Ruthenium Trichloride‐Mediated Benzannulation Approach to Fused Functionalized Arenes

Abstract

Thes olvent-andl igand-free [2+ +2+ +2] ruthenium-promoted cycloaddition of a,wdiynes and alkynes provides af acile and efficient strategy for the synthesis of substitutedb enzene-derived systems.T he search for the optimal reaction conditions revealedt he unprecedented catalytic activity of ruthenium trichloridef or benzannulation reactions and this atom-economicalp rocess allowed the synthesis of fused arenes including dihydrobenzofurans,i soindolines,i ndanes in good to high yields.T his practical protocola lso gave rise to the preparation of pentasubstituted aromatic derivatives and was applied to the one-gram scale synthesis of af unctionalized heterocycle.Benzannulationi sa na tom-economical andastraightforward approach to access complexs tructures starting from relatively simple materials. Tr ansition metalcatalyzed [2+ +2+ +2] cycloadditions have proven to be ap owerful tooli nt he construction of highly substituted arenes.Indeed, the [2+ +2+ +2] cycloaddition hasbeen widelyr eported with several metals,t he most common being cobalt, nickel, iridium, rhodium and ruthenium. [1] Ruthenium-catalyzed [2+ +2+ +2] cycloadditions [2][3][4][5] have been reported using mainly elaborated and expensive Ru complexes such as Cp*Ru(cod)Cl, [RuCp(MeCN) 3 ]PF 6 ,[ RuCl 2 (p-cymene)] 2 , [Cp*RuCl 2 ] 2 ,Grubbs(Iand II), Hoveyda-Grubbscatalysts (Grubbs III), or Ru(ethene)(CO) 4 ,R u 3 (CO) 12 (Scheme 1) combined with organic solvents, additional ligands,s upported systems or microwavea ssistance. Due to environmental concerns to makec hemical processesg reener, the development of atom-economical synthetic procedures involving, for instance,s olvent-free conditions hasbecome crucial. [6] To the best of our knowledge,s olventless metal-catalyzed [2+ +2+ +2] cycloadditions of diynes have been scarcelyd escribeda lthough the search for environmentally friendly protocols is essential. [7] To complete our recent interest in [2+ +2+ +2] cycloaddition reactions, [8] we were wondering if am ore practical strategy couldb ee nvisaged to access fused arenesi nt he absence of solvent andi nt he absenceo fa dditional ligand by using the commercially available,c heap and easy to handle RuCl 3 ·n H 2 O. Noteworthy,M itsudo and Tanakar eported the inefficiency of RuCl 3 and the RuCl 3 /amine system toward [2+ +2+ +2] cycloadditions of terminal alkynes with dimethyl acetylenedicarboxylate andc yclotrimerization of ethyl phenylpropiolate. [9] We and others previouslyd emonstrated the efficiency of RuCl 3 ·n H 2 Oi nC À H, C À C, C À Na nd C À Ob ondf orming processes. [10,11] In this context, we report here the first efficientR uCl 3 -catalyzed [2+ +2+ +2] cycloaddition reactions of a,w-diynesa nd alkynes under solvent-freec onditions. Scheme 1. Selected[ Ru] catalysts for [2+ +2+ +2] cycloaddition reactionsofa,w-diynes.

Recent Developments in the Cyclization of Alkynes and Nitrogen Compounds for the Synthesis of Indole Derivatives

“…The authors observed that the microwave irradiation enhanced the reactivity; however, it did not affect the regioselectivity [224] . Amide‐tethered diynes, [225] N ‐benzenesulfonamide 1,6‐diynes, [226] and bis‐1,3‐diynes [227] were used as efficient substrates to [2+2+2] cycloisomerization reactions to give the corresponding isoindolines in good yields.…”

Ruthenium-Catalyzed Cycloadditions to Form Five-, Six-, and Seven-Membered Rings

“…254 Finally, in 2015 and 2016, Ratovelomanana-Vidal and Michelet developed a cost-effective intermolecular [2+2+2] cycloaddition of α,ω-diynes with alkynes to construct benzene and fluorenone derivatives, catalyzed by RuCl 3 •nH 2 O in the absence of ligand under solvent-free conditions (not shown). 255,256 3.2.3. [2+2+2] Cycloadditions of Alkynes+Alkenes.…”

“…In contrast, in 2012 Holthausen and Ghosh explored the use of arachno -[(Cp*RuCO) 2 B 2 H 6 ] as a catalyst for intermolecular alkyne cyclotrimerization, and their computational studies implicated a mechanism in which the transient ruthenacyclopentadiene is converted to a benzene derivative through a Diels–Alder-type [4+2] cycloaddition with the third alkyne (not shown) . Finally, in 2015 and 2016, Ratovelomanana-Vidal and Michelet developed a cost-effective intermolecular [2+2+2] cycloaddition of α,ω-diynes with alkynes to construct benzene and fluorenone derivatives, catalyzed by RuCl 3 ·nH 2 O in the absence of ligand under solvent-free conditions (not shown). , …”

Transition metal-catalyzed [2 + 2 + 2] cycloaddition of nitrogen-linked 1,6-diynes: a straightforward route to fused pyrrolidine systems

“…This procedure was applied on the gram-scale without sacricing the yield or outcome of the methodology. 19 Other applications of Ru catalysts in [2 + 2 + 2] cycloaddition of di(3-iodopropargyl)amine with alkynes to afford 4,7-diiodoisoindoline derivatives are also known. 20 Yamamoto and co-workers were able to demonstrate that a series of regioisomeric isoindolinones 28 and 29 be efficiently synthesized from the cyclization of amide-tethered diynes 27 with terminal alkynes 6 by treatment with [Cp*Ru(cod)Cl] in DCM.…”