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Preface Quaternary carbon stereocenters–carbon atoms to which four distinct carbon substituents are attached–are common features of molecules found in nature. However, prior to recent advances in chemical catalysis, there were few methods available for constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for synthesizing organic molecules containing such carbon atoms. This progress now makes it possible to selectively incorporate quaternary stereocenters in many high-value organic molecules for use in medicine, agriculture, and other areas.

The first Suzuki–Miyaura cross-coupling reactions of the synthetically versatile O-aryl carbamate and O-sulfamate groups is described. The transformations utilize the inexpensive, bench-stable catalyst NiCl2(PCy3)2 to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups (EDGs, EWGs) are tolerated, in addition to those that possess ortho substitutents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative additions with carbamates and sulfamates occur via a five-centered transition state, resulting in the exclusive cleavage of the Ar–O bond. Water is found to stabilize the Ni–carbamate catalyst resting state, and thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of polysubstituted aromatic compounds of natural product and bioactive molecule interest.

The first Suzuki-Miyaura cross-coupling of carbamates, carbonates, and sulfamates is described. The method presented provides a powerful means to use simple derivatives of phenol as precursors to polysubstituted aromatic compounds, as exemplified by a concise synthesis of the antiinflammatory drug flurbiprofen.Transition metal-catalyzed cross-coupling reactions continue to play a vital role in modern synthetic chemistry. 1 Although cross-couplings of aryl halides and triflates are most common, recent studies have demonstrated the successful cross-coupling of simple and affordable phenolic derivatives. In 2008, notable achievements in this area include the Suzuki-Miyaura coupling of electron deficient aryl methyl ethers by Chatani, 2 and the Suzuki-Miyaura coupling of aryl pivalates, 3 which was reported simultaneously by our group, 4a and the group of Shi. 4b A conceptual advantage of these technologies, compared to methodologies involving halides and sulfonates, is the potential to direct the installation of other functional groups onto an aromatic ring prior to cross-coupling (Figure 1). In practice, however, the ability to use methyl ethers (R = Me) and pivalates (R = OC(O)CMe 3 ) in this sense is somewhat limited. 5 Given the importance of polyfunctionalized aromatics in medicine, ligands for catalysis, and materials chemistry, we sought to address this problem. In this communication, we describe the first Suzuki-Miyaura couplings of aryl carbamates, carbonates, and sulfamates. Moreover, we disclose a concise synthesis of the anti-inflammatory drug flurbiprofen (1) 6 using this methodology.neilgarg@chem.ucla.edu. Supporting Information Available: Detailed experimental procedures and compound characterization data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. Of the potential phenolic derivatives to be studied, aryl carbamates and sulfamates were considered ideal because of their ready availability and pronounced stability to a variety of reaction conditions. Furthermore, these substrates can be used to direct the installation of functional groups at both the ortho and para positions (via ortho-lithiation chemistry pioneered by Snieckus7 and electrophilic aromatic substitution,8 respectively). Although nickelcatalyzed Kumada couplings of these substrates have been documented, 7b,9 cross-coupling under milder, more attractive Suzuki-Miyaura conditions have not been reported. Of note, the oxidative addition of a metal into the aryl C-O bond of an aryl carbamate or sulfamate presents a considerable challenge. NIH Public AccessDespite this difficulty, we have found that the Suzuki-Miyaura coupling of aryl carbamates with aryl boronic acids proceeds in the presence of NiCl 2 (PCy 3 ) 2 , K 3 PO 4 , and heat, with toluene as solvent (Table 1). That NiCl 2 (PCy 3 ) 2 could be used to facilitate the desired transformation is advantageous,10 as this readily available complex shows marked stability to air and water, and can be used on the bench-top rather than in a gl...

The first cross-coupling of acylated phenol derivatives has been achieved. In the presence of an air-stable Ni(II) complex, readily accessible aryl pivalates participate in the Suzuki-Miyaura coupling with arylboronic acids. The process is tolerant of considerable variation in each of the cross-coupling components. In addition, a one-pot acylation/cross-coupling sequence has been developed. The potential to utilize an aryl pivalate as a directing group has also been demonstrated, along with the ability to sequentially cross-couple an aryl bromide followed by an aryl pivalate, using palladium and nickel catalysis, respectively.