The development of operationally straightforward and cost-effective routes for the assembly of heterocycles from simple inputs is important for many scientific endeavors, including pharmaceutical, ...agrochemical, and materials research. In this article we describe the development of a new air-stable cationic Co(III) catalyst for convergent, one-step benchtop syntheses of N-aryl-2H-indazoles and furans by C–H bond additions to aldehydes followed by in situ cyclization and aromatization. Only a substoichiometric amount of AcOH is required as an additive that is both low-cost and convenient to handle. The syntheses of these heterocycles are the first examples of Co(III)-catalyzed additions to aldehydes, and reactions are demonstrated for a variety of aromatic, heteroaromatic, and aliphatic derivatives. The syntheses of both N-aryl-2H-indazoles and furans have been performed on 20 mmol scales and should be readily applicable to larger scales. The reported heterocycle syntheses also demonstrate the use of directing groups that have not previously been applied to Co(III)-catalyzed C–H bond functionalizations. Additionally, the synthesis of furans demonstrates the first example of Co(III)-catalyzed functionalization of alkenyl C–H bonds.
A study of methods using rhodium catalysts to create carbon-carbon bonds is presented. Some hydrocarbons present low-cost alternatives as source material for the carbon-hydrogen bonded molecules used ...as source material for these reactions.
The transition-metal-catalyzed addition of C–H bonds to carbonyls, imines, and related polarized π bonds has emerged as a particularly efficient and powerful approach for the construction of an ...incredibly diverse array of heteroatom-substituted products. Readily available and stable inputs are typically employed, and reactions often proceed with very high functional group compatibility and without the production of waste byproducts. Additionally, many transition-metal-catalyzed C–H bond additions to polarized π bonds occur within cascade reaction sequences to provide rapid access to a diverse array of different heterocyclic as well as carbocyclic products. This review highlights the diversity of transformations that have been achieved, catalysts that have been used, and types of products that have been prepared through the transition-metal-catalyzed addition of C–H bonds to carbonyls, imines, and related polarized π bonds.
The chemical properties and applications of tert-butanesulinamide and other sulfinamides are examined. The addition of metalloenamies to azocarboxylates is also studied.
Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a ...paradigm shift in chemical synthesis, and today synthetic chemists can readily access carbon–carbon and carbon–heteroatom bonds from a vast array of starting compounds. Although we cannot understate the importance of these methods, the required prefunctionalization to carry out these reactions adds cost and reduces the availability of the starting reagents. The use of C–H bond activation in lieu of prefunctionalization has presented a tantalizing alternative to classical cross-coupling reactions. Researchers have met the challenges of selectivity and reactivity associated with the development of C–H bond functionalization reactions with an explosion of creative advances in substrate and catalyst design. Literature reports on selectivity based on steric effects, acidity, and electronic and directing group effects are now numerous. Our group has developed an array of C–H bond functionalization reactions that take advantage of a chelating directing group, and this Account surveys our progress in this area. The use of chelation control in C–H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. The predictability and decreased dependence on the inherent stereoelectronics of the substrate generally result in selective and high yielding transformations with broad applicability. The nature of the chelating moiety can be chosen to serve as a functional handle in subsequent elaborations. Our work began with the use of Rh(I) catalysts in intramolecular aromatic C–H annulations, which we further developed to include enantioselective transformations. The application of this chemistry to the simple olefinic C–H bonds found in α,β-unsaturated imines allowed access to highly substituted olefins, pyridines, and piperidines. We observed complementary reactivity with Rh(III) catalysts and developed an oxidative coupling with unactivated alkenes. Further studies on the Rh(III) catalysts led us to develop methods for the coupling of C–H bonds to polarized π bonds such as those in imines and isocyanates. In several cases the methods that we have developed for chelation-controlled C–H bond functionalization have been applied to the total synthesis of complex molecules such as natural products, highlighting the utility of these methods in organic synthesis.
A highly stereoselective three‐component C(sp2)−H bond addition across alkene and polarized π‐bonds is reported for which CoIII catalysis was shown to be much more effective than RhIII. The reaction ...proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp2)−H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with CoIII‐catalyzed C−H functionalization are demonstrated with three‐component C−H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C−H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.
Essential bond connections: A highly stereoselective three‐component C(sp2)−H bond addition across alkene and polarized π‐bonds is reported. Catalysis by CoIII was much more effective than by RhIII, providing products in good yield and with high diastereoselectivity for a broad range of aldehydes. The first asymmetric reactions employing CoIII‐catalyzed C−H functionalization are also reported for three‐component C−H bond addition cascades with N‐tert‐ butanesulfinyl imines.
Unprotected, α,β-disubstituted tryptamines and phenethylamines are obtained by a one-pot, metal-free sequence that proceeds by the in situ formation of aziridinium salts followed by Friedel–Crafts ...reaction with electron-rich (hetero)arenes. Both steps are facilitated by hexafluoroisopropanol as the solvent. The one-pot sequence was effective for diversely substituted indoles and 1,3,5-trimethoxybenzene, for cyclic and acyclic alkenes, and proceeded in a stereospecific fashion for both (E)- and (Z)-1,2-disubstituted alkenes. Moreover, one-pot morpholine addition to an aziridinium salt provided a diamine.
Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of ...nitrogen heterocycles through C−H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh−N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh−NHC complexes directly by treating precursors to the intermediate RhCl(PCy3)2 with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy3)2 fragment coordinates to the heterocycle before intramolecular activation of the C−H bond occurs. The resulting Rh−H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo4.2.1nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C−H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations.
Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with ...biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.
Conspectus Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal ...chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C–H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity. When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C–H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, 3 + 2 cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements. The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (−)-naltrexone, which is extensively used for the treatment of drug abuse.
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