Dedicated to Professor E. J. Corey on the occasion of his 80th birthday Enantioselective CÀH activation has been a longstanding challenge in catalysis and organic chemistry. The insertion of metal-bound carbenes or nitrenes into CÀH bonds has been employed to develop highly enantioselective carbon-carbon and carbon-nitrogen bond-forming reactions.[1] The enantioselective lithiation of C(sp 3 ) À H bonds adjacent to the nitrogen atom in N-tert-butyloxycarbonylpyrrolidine using secBuLi/(À)sparteine has provided a broadly useful method for the differentiation of prochiral C(sp 3 )ÀH bonds.[2] Investigations into the biomimetic oxidation of CÀH bonds using chiral metal-porphyrin complexes [3] and other synthetic catalysts [4] continue to provide inspiration for the development of methods for the asymmetric oxidation of C À H bonds. Remarkable progress in understanding the fundamental mechanisms of CÀH activation by means of metal insertion [5] has spurred the development of metal-catalyzed carboncarbon and carbon-heteroatom bond-forming reactions in organic molecules containing functional groups.[6] Such reactions will impact synthetic and medicinal chemistry in the context of retrosynthetic analysis [7] by providing unprecedented and more efficient strategic disconnections.[8] A major hurdle remaining in Pd II -catalyzed CÀH activation reactions, however, is the need for an external ligand that coordinates to the Pd II species and controls the chemo-, regio-, and stereoselectivity of its insertion into C À H bonds. With this in mind, we embarked on the development of a Pd II -catalyzed enantioselective CÀH activation/CÀC coupling reaction, a process previously unknown owing to the difficulty in differentiating prochiral CÀH bonds through metal insertions.
Pd(II)-catalyzed meta-olefination of highly electron deficient arenes is achieved through the use of a rationally designed mutually repulsive ligand. The combination of directed and non-directed C-H functionalization of arenes provides a versatile route for the synthesis of highly sought-after 1,2,4-trisubstituted arenes.Since the discovery of the Pd-catalyzed olefination of benzene by Fujiwara, substantial progress has been made to improve the efficiency and practicality of this reaction. 1 To date, reactivity is still limited to electron rich arenes, 1-4 except for a single example using chlorobenzene, a moderately electron deficient arene. 1c Furthermore, olefination of monosubstituted arenes gives an approximately even mixture of ortho-, meta-and para-olefinated products, 1c limiting possible synthetic applications. The ortho-olefination of benzoic acids and anilides via directed C-H activation reported by Miura and de Vries, respectively, represents an important approach to control the regioselectivity of this reaction. 5,6 Herein, we report the first example of a meta-selective olefination process of highly electron deficient arenes. This reaction is promoted by a novel mutually repulsive 2,6-dialkylpyridine ligand, yu200@scripps.edu. Supporting Information Available: Experimental procedure and characterization of all new compounds (PDF). This material is available free of charge via the Internet at
Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC(6)F(5), sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions.
Pd(II)-catalyzed ortho-hydroxylation of variously substituted benzoic acids under 1 atm of O(2) or air is achieved under nonacidic conditions. Extensive labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen.
Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acid substrates has been achieved through the use of mono-protected chiral amino acid ligands. The absolute configuration of the resulting olefinated products is consistent with that of a proposed C-H insertion intermediate.Despite substantial progress in developing various Pd-catalyzed C-heteroatom and C-C bond forming reactions via C-H activation,1 achieving enantioselectivity in these reactions through a stereoselective Pd insertion step remains a significant challenge.2 -9 In our ongoing studies to design and evaluate new ligands to effect asymmetric C-H cleavage, two major problems have become apparent. First, the simultaneous binding of both the substrate and the chiral ligand to the Pd(II) center is often difficult to achieve. Second, even if such complexes are assembled, the ligand often strongly inhibits C-H activation, either because it induces an unwanted conformational change or adversely affects the electronic properties of the Pd(II) center.yu200@scripps.edu. Supporting Information Available: X-ray diffraction analysis for 2e, experimental procedure and characterization of all new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2011 January 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have recently found that mono-protected amino acid ligands and 2-benzylpyridine substrates coordinate with Pd(II) in a one-to-one ratio with high fidelity. 3 Importantly, the resulting chiral Pd(II) complexes were found to induce asymmetric C-H cleavage with high enantioselectivity (up to 95% ee). Of critical importance for the viability of this process is the precise match between the binding ability of the pyridine substrate and the chiral ligand. This observation, however, calls into question whether this chiral ligand scaffold is broadly applicable to synthetically useful substrates, including those that contain weakly coordinating functional groups. Herein, we report an enantioselective C-H olefination reaction of α,α-diphenylacetic acids using mono-protected amino acids as chiral ligands. This new development represents an encouraging step towards the realization of synthetically useful Pdcatalyzed enantioselective C-H activation reactions.We previously reported that both inorganic and organic cations dramatically accelerate carboxyl-directed C-H activation reactions.10 Our current hypothesis, based on the structure of a C-H insertion intermediate, 10b is that the σ-chelation of the carbonyl oxygen of the carboxylate salt with Pd(II) is responsible for the facile C-H cleavage promoted by the complexinduced proximity effect. Following this hypothesis, we anticipated that a chiral carbon-Pd intermediate B could be formed in analogy to intermediate A, which is formed following enantioselective C-H activation using a pyridyl directing group. Subsequently, we envisioned t...
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