1 Ru Carbene Insertion Csp3-H Bonds DOI: 10.1002/anie.200((will be filled in by the editorial staff)) Cyclization by Catalytic Ruthenium Carbene Insertion into sp 3 C–H Bonds Fermín Cambeiro, Susana López, Jesús A. Varela, and Carlos Saá* [∗] Fermín Cambeiro, Dra. Susana López, Dr. Jesús A. Varela, Prof. Carlos Saá Departamento de Química Orgánica y Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS) Universidad de Santiago de Compostela 15782 Santiago de Compostela, Spain Fax: (+)34−881815704 E−mail: carlos.saa@usc.es Homepage: http://www.usc.es/gi1603/saa [∗∗] We thank the MICINN [Projects CTQ2008-06557, CTQ2011-28258, Consolider Ingenio 2010 (CSD2007-00006)] and Xunta de Galicia (2007/XA084 and CN2011/054) for financial support. F. C. thanks the Xunta de Galicia and MICINN for a predoctoral grant. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Novel reactions that can selectively functionalize carbon-hydrogen bonds are very important because they offer new strategic approaches in synthesis. [1] A remarkable methodology for such carbon-hydrogen functionalization involves the insertion of metal carbenes into C–H bonds. [2] The regioselectivity in these C–H insertions is governed by electronic, steric and conformational factors. [3] Typically, in non-constrained systems, metal-catalyzed intramolecular C–H insertion reactions predominantly afford five-membered rings (1,5-insertions). [2,4] Formation of lower and higher rings is achieved only when geometrical constraints or activated C–H bonds are involved. [5] Usually, Rh [6] - and Cu [7] -catalyzed C–H insertions have shown amazing versatility in both intramolecular and intermolecular reactions, but it would be a challenging goal to discover other metals and tethers that facilitate the construction of rings by Csp3–H functionalization. Recently, special attention has been paid to Pt [8] - and Au-catalyzed [9] intramolecular coupling between terminal unactivated alkynes and sp 3 C–H bonds in alkynyl ethers and amines to produce complex spiro or fused bicyclic systems in a tandem 1,5-hydride shift/cyclization sequence. [10] The above methods require temperatures as high as 100–120 ºC for good performance and Pt only allows the formation of 5-exo methylene bicyclic structures. We report herein a mild procedure based on a novel tandem Ru-catalyzed carbene addition to terminal alkynes/insertion of Csp3–H bonds in alkynyl acetals, ethers and amines to form complex spiro and fused bicyclic structures in 1,5- and 1,6-hydride shift/cyclization sequences (Scheme 1). [11] Cyclization of dioxolane 1a was the first reaction examined under various catalytic conditions (Table 1). After some preliminary experimentation, [12] the well-known Dixneuf’s conditions for the preparation of Ru carbenes starting from alkynes were employed. [13] Thus, a 1,5-hydride shift/cyclization sequence to give the functionalized spiro[5,5] compound 2a gave a moderate yield of 40% on stirring at 60 ºC a dioxane solution of 1a (0.15 M) in the presence of 1 equiv of N2CHTMS (2M in hexanes) and 10 mol% Cp*Ru(cod)Cl as catalyst (entry 1), with the linear hydroxyester 3a being the major isolated product in 50% yield. Lower overall yield and similar amounts of 2a and 3a were obtained when the reaction was performed in dioxane at rt (entry 2). Gratifyingly, the desired spiro compound 2a or its desilylated analogue 2a' [13e,g] were isolated in fairly good yields (66-80%) when the reactions were carried out in diethyl ether or MeOH at rt (entries 3 and 4). [14] However, other typical solvents like THF and toluene gave either lower yields and/or longer reaction times (entries 5 and 6). Changes in the electronic and steric nature of the neutral Ru(II) catalyst on using CpRu(cod)Cl strongly affected the course of the reaction by increasing the time duration and decreasing conversion and yield (entry 7). [15] More challenging substituted dioxolanes 1 were also examined (Table 2). Thus, spiro compound 2b was obtained in low yield when the formation of the putative Ru carbene was hindered by a C-sp substituent in dioxolane 1b (Table 2, entry 1). The nature of Z (see Scheme 1) had a significant effect on the course of the reaction, [16] with hydroxyester 3c the major isolated product in the case of 1c, Z = (CH2O)2CMe2 (Table 2, entry 2). [17] The course of the reaction was also influenced by stereoelectronic effects on the activated C–H bond. [18] Thus, rigid cyclic acetal 1a afforded a higher yield of spiro compound 2a (Table 1, entry 3) in comparison to the linear acetals 1d and 1e (Table 2, entries 3 and 4). Gratifiyngly, a diastereoselective C-H activation of ethers took place to give smoothly the