Air-tolerant C–C bond formation via organometallic ruthenium catalysis: diverse catalytic pathways involving (C 5 Me 5 )Ru or (C 5 H 5 )Ru are robust to molecular oxygen Lukáš Severa, Jan Vávra, Anna Kohoutová, Martina C ˇ íz ˇková, Tereza Šálová, Jakub Hy ´ vl, David Šaman, Radek Pohl, Louis Adriaenssens, Filip Teply ´ * Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo n. 2, Prague 166 10, Czech Republic article info Article history: Received 26 January 2009 Revised 15 May 2009 Accepted 22 May 2009 Available online 27 May 2009 abstract Ruthenium-catalyzed substitutions of carbon pronucleophiles, various [2+2+2] cycloadditions, and addi- tion of a diazo compound to an alkyne are shown to proceed in the presence of air. Notably diverse cat- alytic manifolds remain supported under conditions generally regarded as prohibitive. Building on rare reports from the literature we show that a range of organometallic transformations based on reaction intermediates derived from (C 5 Me 5 )Ru or (C 5 H 5 )Ru moieties are air-compatible. Ó 2009 Elsevier Ltd. All rights reserved. Ruthenium organometallic catalysis has emerged as an impor- tant method for forming various types of bonds in organic synthe- sis. 1 The majority of these reactions, and indeed the majority of all reactions involving organometallic catalysis, are described under the strict exclusion of air. In this context, the search for oxygen-tol- erant reactions catalyzed by organometallics has emerged as a new challenge at the forefront of synthetic chemistry. 2 Although, air- tolerant ruthenium-catalyzed carbon-heteroatom bond formations are known, 3 C-C bond formation catalyzed by molecular ruthenium complexes in the presence of dioxygen has, until very recently, re- mained generally unrecognized. 4 Trost’s ruthenium-catalyzed alkene-alkyne coupling was one of the first examples of an air-tolerant C–C bond formation via ruthe- nium organometallic catalysis. 4a In spite of the fact that the authors point to the oxygen tolerance of their benchmark Alder- ene-type transformations, such reactions are invariably run under an inert atmosphere. 1e,5 As there was no yield reported for the open-flask set-up, we decided to test the efficiency of this simpli- fied procedure. Interestingly, the yields of two representative al- kene-alkyne couplings performed in the presence of air with no effort taken to exclude moisture compared very well with the re- sults obtained using traditional air-free conditions (Scheme 1). 5c,5e Based on this initial study we speculated that other reactions proceeding via ruthenacyclic intermediates might be air tolerant. Furthermore, catalytic manifolds involving ruthenacyclic interme- diates 1e,7 offer a varied set of known C–C bond forming reactions as a testing ground for our investigation of air-compatibility. Recently, Fokin and co-workers reported that ruthenium-cata- lyzed azide-alkyne cycloaddition (RuAAC) 3b is considerably air tol- erant. Although RuAAC 8 is not a C–C bond forming process, a putative mechanistic analogy 3b,8a between RuAAC and ruthe- nium-catalyzed [2+2+2] cycloadditions 9 led us to investigate the feasibility of a model [2+2+2] cycloaddition 10 under aerobic conditions. Initially, we attempted a [2+2+2] intermolecular cycloaddition of dimethyl acetylenedicarboxylate (9) using catalyst 1 (1 mol%) in reagent grade 1,2-dichloroethane (DCE) under an atmosphere of air (Scheme 2). The starting material was consumed within 1 h and hexamethylmellitate (10) was isolated in 85% yield (cf. 88% yield of 10 under anhydrous conditions and an atmosphere of argon 9a ). A series of [2+2+2] cycloadditions leading to benzene deriva- tives 12, 9a 15, 9a 17, 9a 18 9c and 20, 9d (Schemes 2 and 3) and pyridines 22 9e and 23 9e (Scheme 4), also exhibited excellent toler- ance to air as was evident by comparison with results previously obtained with exclusion of air. 9 This is in line with the working 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.05.079 * Corresponding author. Tel.: +420 220 183 412; fax: +420 220 183 578. E-mail address: teply@uochb.cas.cz (F. Teply ´ ). 2 3 4 r.t., 15 min OH Ph Ph [Cp*Ru(cod)Cl] 1 5 mol% O Ph O 5 81% (85%) 6 7 8 r.t., 1 h NHBoc [CpRu(MeCN)3]PF6 NHBoc acetone, air 64% (78%) neat, air 4:5 7:3 5 mol% Scheme 1. Alkene–alkyne couplings in air. 6 The yields in parentheses are literature yields 5c,e for reactions run with exclusion of air. Cp * = pentamethylcyclopentadie- nyl, Cp = cyclopentadienyl, cod = 1,5-cyclooctadiene. Tetrahedron Letters 50 (2009) 4526–4528 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet