DOI: 10.1002/chem.201200116 A Silver-Catalyzed Spirocyclization of Alkynyl Silyl Enol Ethers Christian Schäfer, Michel Miesch, and Laurence Miesch* [a] Spiro compounds are of great interest because of their special conformational features and their structural implica- tions on biological systems. [1] The presence of the sterically constrained spiro structure in various natural products sub- stantially promotes interest in the investigation of spiro compounds. [2] The Conia-ene cyclization is one of the pro- cesses during which a quaternary center is formed by the pericyclic reaction of an enolizable carbonyl group with an alkyne. However, the need for high temperatures limits the synthetic utility of this reaction. [3] On the other hand, transi- tion-metal-catalyzed versions [4] proceed under mild condi- tions at lower temperatures. Toste and co-workers have re- ported a phosphine–gold(I)-catalyzed version for the intra- molecular addition of a b-ketoester to an unactivated alkyne. [5] In a similar reaction, Davies and Detty-Mambo demonstrated the cycloisomerization of unactivated ketones with alkynes under gold catalysis. [6] In recent years, silver salts have gained increasing interest in homogeneous cataly- sis owing to their mildness and efficiency. [7] More recent re- views discuss the current revolution in silver chemistry. Cat- alysis with silver salts has become widespread due to the s and p Lewis acidic properties of silver(I) complexes, [8] which lead to a variety of chemical transformations. [9] There- fore, exploring new catalytic reactions with silver complexes is of great interest. For this reason, we focused on silver-cat- alyzed cycloisomerization to study the behavior of alkynyl silyl enol ethers. Mainly used as cocatalysts in gold catalysis, silver salts, such as AgBF 4 , AgSbF 6 , and AgPF 6 , are very hygroscopic, causing difficulties in properly weighing the reagent and keeping the reaction medium nonacidic. In contrast, AgNTf 2 (Tf = triflyl) [10] is known to be more stable and easier to handle than its congeners. Thus, this reagent proved to be an efficient catalyst for nucleophilic additions to alkynes. [11] For this purpose, we envisaged the use of AgNTf 2 as a poten- tially valuable candidate for the cycloisomerization of silyl alkynyl enol ethers. We began our investigation by examining the cyclization using various silver catalysts with different solvents for the reaction of compound 1 (Table 1). Interestingly, the use of AgNTf 2 alone led to spiro compounds 2a and 2b with the same yield as that observed under gold catalysis (Table 1, entry 3). Furthermore, the yield could be improved by using CH 2 Cl 2 or toluene as the solvent (Table 1, entries 4 and 7). Control experiments revealed that silver carbonate or the corresponding free amine, that is, triflimide, could not cata- lyze the reaction of silyl alkynyl enol ethers to form spiro compounds, and no reaction occurred under metal-free con- ditions. Likewise, the unsilylated ketones could not be trans- formed into the spiro compounds. Having found that Ag I -catalyzed cycloisomerization favors the 5-exo-dig cyclization process, we evaluated the scope of the reaction by using various alkynyl cycloalka- nones. The reaction proved to be quite general, although the yield is dependent upon both the substrate and the solvent (Table 2, entries 1, 2, 13–16, and 19). Interestingly, in most cases that use CH 2 Cl 2 as the solvent, the exo regioisomer is favored, except for entries 6, 18, and 22 in Table 2, whereas the endo compound is obtained in toluene except for cyclo- [a] Dipl.-Ing. C. Schäfer, Dr. M. Miesch, Dr. L. Miesch Laboratoire de Chimie Organique SynthØtique, Institut de Chimie UMR 7177, UniversitØ de Strasbourg, 1 rue Blaise Pascal BP 296/R8, 67008 Strasbourg-Cedex (France) Fax: (+) 33368851754 E-mail : l.miesch@unistra.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200116. Table 1. Screening of solvents and catalysts (IPr = 1,3-bis(2,6-diisopropyl- phenyl)imidazol-2-ylidene). Entry Catalyst Solvent T [8C] Yield [%] [b] 2a/2b 1 IPrAuCl/AgOTf ClCH 2 CH 2 Cl 84 12 (63) 100:0 2 IPrAuCl/AgNTf 2 ClCH 2 CH 2 Cl 84 66 2.5:1 3 AgNTf 2 ClCH 2 CH 2 Cl 20 67 17:1 4 AgNTf 2 CH 2 Cl 2 20 78 16:1 5 AgNTf 2 THF 20 41 (40) 20:1 6 AgNTf 2 acetone 20 – [c] – 7 AgNTf 2 toluene 20 76 9:1 8 AgNTf 2 CH 3 CN 82 7 (65) 1:5 9 AgNTf 2 ClCH 2 CH 2 Cl/MeOH 20 – [c] – 10 AgNTf 2 toluene [a] 20 56 (12) 1:38 11 AgNTf 2 ClCH 2 CH 2 Cl 20 – [c] – 12 Ag 2 CO 3 ClCH 2 CH 2 Cl 20 – [c] – 13 – ClCH 2 CH 2 Cl 20 – [d] – [a] Toluene was not distilled before use. [b] Yields in parentheses corre- spond to the deprotected starting material. [c] Only deprotection of the starting material occurred. [d] The starting material was recovered.  2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2012, 18, 8028 – 8031 8028