No abstract

Amides are common functional groups that have been well studied for more than a century.1 They serve as the key building blocks of proteins and are present in an broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to resonance stability of the amide bond.1,2 Whereas Nature can easily cleave amides through the action of enzymes, such as proteases,3 the ability to selectively break the C–N bond of an amide using synthetic chemistry is quite difficult. In this manuscript, we demonstrate that amide C–N bonds can be activated and cleaved using nickel catalysts. We have used this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory (DFT) calculations provide insight into the thermodynamics and catalytic cycle of this unusual transformation. Our results provide a new strategy to harness amide functional groups as synthons and are expected fuel the further use of amides for the construction of carbon–heteroatom or carbon–carbon bonds using non-precious metal catalysis.

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.

Amides have been widely studied for decades, but their synthetic utility has remained limited in reactions that proceed with rupture of the amide C–N bond. Using Ni catalysis, we have found that amides can now be strategically employed in several important transformations: esterification, transamidation, Suzuki–Miyaura couplings, and Negishi couplings. These methodologies provide exciting new tools to build C–heteroatom and C–C bonds using an unconventional reactant (i.e., the amide), which is ideally suited for use in multi-step synthesis. It is expected that the area of amide C–N bond activation using nonprecious metals will continue to flourish and, in turn, will promote the growing use of amides as synthons in organic synthesis.

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 distortion/interaction model has been used to explain and predict reactivity in a variety of reactions where more common explanations, such as steric and electronic factors, do not suffice. This model has also provided new fundamental insight into regioselectivity trends in reactions of unsymmetrical arynes, which in turn, has fueled advances in aryne methodology and natural product synthesis. This article describes a systematic experimental and computational study of one particularly important class of arynes, 3-halobenzynes. 3-Halobenzynes are useful synthetic building blocks whose regioselectivities have been explained by several different models over the past few decades. Our efforts show that aryne distortion, rather than steric factors or charge distribution, are responsible for the regioselectivities observed in 3-haloaryne trapping experiments. We also demonstrate the synthetic utility of 3-halobenzynes for the efficient synthesis of functionalized heterocycles, using a tandem aryne trapping/cross-coupling sequence involving 3-chlorobenzyne.

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.

Material and Methods. Unless stated otherwise, reactions were performed in flame-dried glassware under a nitrogen or argon atmosphere using dry, deoxygenated solvents. All other commercially obtained reagents were used as received. Solvents were dried by passage through an activated alumina column under argon. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV or anisaldehyde staining. ICN Silica gel (particle size 0.032-0.063 mm) was used for flash chromatography. Disposable SepPak C 18 Vac Cartridges were purchased from Waters and used for all reversed-phase filtrations.HPLC analysis was performed on a Beckman Gold system using a Rainin C 18 , Microsorb MV, 5mm, 300 x 4.6 mm reversed-phased column in 0.1% (wt/v) TFA with acetonitrile as eluent and a flow rate of 1.0 mL/min, gradient elution of 1.25% acetonitrile/min. Preparatory reversed-phase HPLC was performed on a Beckman HPLC with a Waters DeltaPak 25 x 100 mm, 100 mm C 18 column equipped with a guard, 0.1% (wt/v) TFA with acetonitrile as eluent, and gradient elution of 0.50% acetonitrile/min. For all reversed-phase purifications, water (18MW) was obtained from a Millipore MiliQ water purification system and TFA from Halocarbon, Inc.