Catalytic difunctionalization of alkenes has been an ideal strategy to generate structurally complex molecules with diverse substitution patterns. Although both phosphonyl and carboxyl groups are ...valuable functional groups, the simultaneous incorporation of them via catalytic difunctionalization of alkenes, ideally from abundant, inexpensive and easy-to-handle raw materials, has not been realized. Herein, we report the phosphonocarboxylation of alkenes with CO
via visible-light photoredox catalysis. This strategy is sustainable, general and practical, providing facile access to important β-phosphono carboxylic acids, including structurally complex unnatural α-amino acids. Diverse alkenes, including enamides, styrenes, enolsilanes and acrylates, undergo such reactions efficiently under mild reaction conditions. Moreover, this method represents a rare example of redox-neutral difunctionalization of alkenes with H-P(O) compounds, including diaryl- and dialkyl- phosphine oxides and phosphites. Importantly, these transition-metal-free reactions also feature low catalyst loading, high regio- and chemo-selectivities, good functional group tolerance, easy scalability and potential for product derivatization.
Remote difunctionalization of unactivated alkenes is challenging but a highly attractive tactic to install two functional groups across long distances. Reported herein is the first remote ...difunctionalization of alkenes with CO2. This visible‐light photoredox catalysis strategy provides a facile method to synthesize a series of carboxylic acids bearing valuable fluorine‐ or phosphorus‐containing functional groups. Moreover, this versatile protocol shows mild reaction conditions, broad substrate scope, and good functional‐group tolerance. Based on DFT calculations, a radical adds to an unactivated alkene to smoothly form a new carbon radical, followed by a 1,5‐hydrogen atom‐transfer process, the rate‐limiting step, generating a more stable benzylic radical. The reduction of the benzylic radicals by an IrII species generates the corresponding benzylic carbanions as the key intermediates, which further undergo nucleophilic attack with CO2 to generate carboxylates.
Reported is the first remote difunctionalization of unactivated alkenes with CO2 by visible‐light photoredox catalysis. Mechanistic studies indicate that a 1,5‐hydrogen atom‐transfer process is the rate‐limiting step and reduction of radical intermediates generates the corresponding carbanions. Other electrophiles, including aldehydes, ketones, and benzylic bromides, are also applicable in this process, demonstrating a general strategy for redox‐neutral remote difunctionalization of unactivated alkenes.
The first cobalt-catalyzed cyanation, halogenation, and allylation via C–H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, ...and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions. Additionally, allylation proceeded efficiently with a turnover number of 2200 at room temperature, which is unprecedented for this Co(III) catalyst. Alkenyl substrates and amides have been successfully utilized in Cp*Co(III)-catalyzed C–H activation for the first time.
α‐Halo and pseudohalo ketones are used for the first time as C(sp3)‐based electrophiles in transition‐metal‐catalyzed CH activation and as oxidized alkyne equivalents in RhIII‐catalyzed ...redox‐neutral annulations to generate diverse N‐heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated.
Who needs alkynes? α‐Halo and pseudohalo ketones (as C(sp3)‐based electrophiles) are utilized as oxidized alkyne equivalents in RhIII‐catalyzed redox‐neutral annulations to efficiently generate diverse N‐heterocycles. Owing to the mild reaction conditions, a variety of functional groups are tolerated.
The first catalytic hydrocarboxylation of enamides and imines with CO2 to generate valuable α,α‐disubstituted α‐amino acids is reported. Notably, excellent chemo‐ and regio‐selectivity are achieved, ...significantly different from previous reports on β‐carboxylation of enamides, homocoupling or reduction of imines. Moreover, this transition‐metal‐free procedure exhibits low loading of an inexpensive catalyst, easily available substrates, mild reaction conditions, high efficiency, facile scalability and easy product derivatization, providing great potential for application in organic synthesis, pharmaceutical chemistry, and biochemistry.
Catalytic hydrocarboxylation of easily available enamides and imines with one atmosphere of CO2 is realized to generate valuable α,α‐disubstituted α‐amino acids under mild reaction conditions. Notably, excellent chemo‐ and regioselectivity are achieved, significantly different from previous reports. 4CzIPN=1,2,3,5‐Tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene.
Since their development in the 1970s, cross-coupling reactions catalyzed by transition metals have become one of the most important tools for constructing both carbon−carbon and carbon−heteroatom ...bonds. Traditionally, organohalides were widely studied and broadly used as the electrophile, both in the laboratory and in industry. Unfortunately, the high cost, environmental toxicity, and sluggish preparation often associated with aryl halides can make them undesirable for the large-scale syntheses of industrial applications. However, with the further development of catalytic systems, and particularly of the ligands contained therein, a variety of electrophiles have now been successfully applied to cross-coupling reactions. Oxygen-based electrophiles have attracted much attention due to their ready availability from phenol and carbonyl compounds. Initially, aryl and alkenyl triflates were used in cross-coupling reactions due to their high reactivity; however, low moisture stability and high cost hampered their application. Later, with the development of highly efficient catalytic systems, the less reactive sulfonates and phosphates were successfully employed in cross-coupling reactions. Although they have higher stability and can be easily prepared, low atom economy remains an obstacle to their broader utility. Our group has worked to directly apply the abundant and readily available oxygen-containing compounds, such as phenols, alcohols, ethers, and carbonyl compounds, to cross-coupling reactions. In this Account, we describe our recent efforts in transition-metal-catalyzed cross-coupling reactions of new O-based electrophiles via C−O bond activation. We began by developing the methylation of aryl methyl ethers and benzyl methyl ethers via Ni-catalyzed selective C−O bond cleavage. With the refined Ni-based catalytic system, we further applied aryl/alkenyl carboxylates and carbamates to Suzuki−Miyaura, Negishi, and Kumada−Tamao−Corriu reactions to construct various biaryl scaffolds and highly substituted alkenes. To further improve the carbon atom economy, we developed the diaryl sulfates as one-by-one electrophiles (that is, both aryl groups are used in the reaction). Most recently, we have achieved the first successful cross-coupling reaction of magnesium naphtholates with aryl Grignard reagents. These results extend aryl and benzyl ethers, aryl and alkenyl carboxylates/carbamates, and magnesium naphtholates as novel electrophiles in cross-coupling reactions. More importantly, these studies contribute to our better understanding the intrinsic nature of C−O bonds, which were traditionally considered “inert” but clearly show enormous synthetic potential with the proper catalysts.
Abstract
Electrochemical catalytic reductive cross couplings are powerful and sustainable methods to construct C−C bonds by using electron as the clean reductant. However, activated substrates are ...used in most cases. Herein, we report a general and practical electro-reductive Ni-catalytic system, realizing the electrocatalytic carboxylation of unactivated aryl chlorides and alkyl bromides with CO
2
. A variety of unactivated aryl bromides, iodides and sulfonates can also undergo such a reaction smoothly. Notably, we also realize the catalytic electrochemical carboxylation of aryl (pseudo)halides with CO
2
avoiding the use of sacrificial electrodes. Moreover, this sustainable and economic strategy with electron as the clean reductant features mild conditions, inexpensive catalyst, safe and cheap electrodes, good functional group tolerance and broad substrate scope. Mechanistic investigations indicate that the reaction might proceed via oxidative addition of aryl halides to Ni(0) complex, the reduction of aryl-Ni(II) adduct to the Ni(I) species and following carboxylation with CO
2
.
Reported herein is a novel visible‐light photoredox system with Pd(PPh3)4 as the sole catalyst for the realization of the first direct cross‐coupling of C(sp3)−H bonds in N‐aryl ...tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp3)−C(sp3) and C(sp2)−C(sp3) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.
Pd, just do it! A novel visible‐light photoredox system with Pd(PPh3)4 as the sole catalyst leads to the direct alkylation of C−H bonds with unactivated alkyl bromides under mild reaction conditions. These redox‐neutral reactions feature high yields, broad substrate scope (>60 examples), facile generation of quaternary centers, and good functional‐group tolerance.
Reductive carboxylation of organo (pseudo)halides with CO2 is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo‐carboxylation of unsaturated hydrocarbons ...via CO2 fixation is a highly challenging but desirable approach for structurally diverse carboxylic acids. There are only a few reports and no examples of alkenes via transition metal catalysis. We report the first asymmetric reductive carbo‐carboxylation of alkenes with CO2 via nickel catalysis. A variety of aryl (pseudo)halides, such as aryl bromides, aryl triflates and inert aryl chlorides of particular note, undergo the reaction smoothly to give important oxindole‐3‐acetic acid derivatives bearing a C3‐quaternary stereocenter. This transformation features mild reaction conditions, wide substrate scope, facile scalability, good to excellent chemo‐, regio‐ and enantioselectivities. The method highlights the formal synthesis of (−)‐Esermethole, (−)‐Physostigmine and (−)‐Physovenine, and the total synthesis of (−)‐Debromoflustramide B, (−)‐Debromoflustramine B and (+)‐Coixspirolactam A; thereby, opening an avenue for the total synthesis of chiral natural products with CO2.
A strategy is presented for nickel‐ catalyzed asymmetric reductive carbo‐carboxylation of alkenes with CO2. A variety of aryl (pseudo)halides react to produce oxindole‐3‐acetic acid derivatives bearing a C3‐quaternary stereocenter. Notably, synthesis of a range of bioactive pyrroloindolines was achieved.
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