Synthetic Methods DOI: 10.1002/ange.201107821 Arylsulfonylacetylenes as Alkynylating Reagents of C sp 2 À H Bonds Activated with Lithium Bases** JosØ Luis García Ruano,* JosØ Alemµn,* Leyre Marzo, CuauhtØmoc Alvarado, Mariola Tortosa, Sergio Díaz-Tendero, and Alberto Fraile Dedicated to Dr. Amelia Tito. In recent years, acetylene chemistry has become an increas- ingly attractive topic for chemists because of its importance in the synthesis of bioactive natural products and new materials as well as in biochemistry. [1] A variety of new approaches have appeared for incorporating alkyne moieties into organic molecules. The most common methods for the formation of C sp ÀC sp 2 bonds to provide aryl acetylenes and conjugated enynes are illustrated in Scheme 1, [2] the most powerful being the well-known Sonogashira cross-coupling reaction (Scheme 1 a). [3] It starts from aryl or alkenyl halides and terminal alkynes and requires the presence of a palla- dium(0) catalyst and a copper source (cocatalyst). The scope of this reaction is quite general, with its primary limitation being the availability of the starting halides. Moreover, specialized reaction conditions are often necessary to improve the poor results obtained in some couplings involving electron-rich C sp 2 components (which interfere with the oxidative addition step) or electron-poor alkynes (which do not readily form the copper acetylide intermediates). [4] A more recent strategy for the formation of aryl alkynes is the inverse-Sonogashira-type reaction (Scheme 1 b) [5] in which the alkyne source is typically a bromo alkyne and aromatic C À H activation is achieved using palladium, [5b] nickel, [5a] or copper [5c] catalysts. This method is generally restricted to substrates susceptible to C À H activation (azoles or activated aromatic rings). A third, but even less general approach is based on a gold-catalyzed Friedel–Crafts-type addition of highly electron-rich aromatic rings [6] (e.g., 2,4,6-trimethoxy- phenyl groups, [6a] thiophenes [6b] or indoles [6c] ) to electron-poor terminal alkynes or alkynyl iodonium salt derivatives (Scheme 1 c). Because all these methods suffer from problems associated with the use of expensive catalysts and harsh reaction conditions, the development of alternative methods able to circumvent these limitations would be highly desir- able. We have recently reported reactions of ortho-sulfinyl benzylcarbanions with b-monosubstituted vinylsulfones as the solution for creating carbon skeletons containing two adjacent chiral centers. [7] To evaluate the applicability of this methodology to the synthesis of quaternary centers by reaction with b-disubstituted vinylsulfones, we decided to synthesize 3aA (Scheme 2, left) by Michael addition of the orthometalated anisole (obtained with nBuLi) to the sulfo- nylacetylene 1a. Unexpectedly, only the anti-Michael [8] addition product 4aA was obtained (Scheme 2, right). Based on this unexpected behavior, we hypothesized about a new approach for the synthesis of C sp 2 À C sp bonds based on the use of sulfonyl acetylenes as general alkynylating reagents of aromatic positions activated with lithium bases to form ArLi. Taking into account that the conditions for this reaction (5 min at À78 8C) are milder than those required by Scheme 1. Approaches for the synthesis of C sp 2 ÀC sp bonds. Scheme 2. Alkynylation of anisole with arylsulfonylacetylenes. [*] Prof. Dr. J. L. García Ruano, Dr. J. Alemµn, L. Marzo, Dr. C. Alvarado, Dr. M. Tortosa, Dr. A. Fraile Departamento de Química Orgµnica (C-1) Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid (Spain) E-mail: joseluis.garcia.ruano@uam.es jose.aleman@uam.es Dr. S. Díaz-Tendero Departamento de Química (Modulo 13) Universidad Autónoma de Madrid, Cantoblanco, Madrid (Spain) [**] Financial support from the Spanish Government (CTQ-2009-12168) and CAM (“programa AVANCAT CS2009/PPQ-1634”) is gratefully acknowledged. J.A., M.T., and S.D.T thank the MICINN for “Ramon y Cajal” contracts, C.A. thanks the “Consejo Nacional de Ciencia y Tecnología de MØxico” for a postdoctoral fellowship, and L.M. thanks the Ministerio de Educación y Ciencia for a predoctoral fellowship. We gratefully acknowledge computational time provided by the “Centro de Computación Científica” at the Universidad Autónoma de Madrid CCC-UAM. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201107821. . Angewandte Zuschriften 2766  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. 2012, 124, 2766 –2770