Traceless Removal of the Pyrazole Group

Finally, the synthetic utility of this C─C activation strategy was investigated by the traceless removal of the pyrazole group, delivering the corresponding anilines 209 in moderate to good yields, which could be easily transformed into other useful compounds (Scheme 3.7.13).

Results and Discussion

Scheme 3.7.13 Traceless removal of the pyrazole group.

Summary and Outlook

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4 Summary and Outlook

Metal-catalyzed C─H and C─C functionalizations have become an increasingly viable approach, which allows the direct formation of C─C and C─heteroatom bonds in an atom- and step-economical manner. However, the significant accomplishments in this field have heavily relied on the use of precious transition metals, such as rhodium, palladium, ruthenium, and iridium, over the last few decades. The high cost and potential toxicity of these metals limit the applications in pharmaceutical and fine chemical industries. Therefore, developing efficient and economic C─H and C─C functionalization by inexpensive and Earth-abundant metals is highly desirable. In this thesis, we summarize our recent achievements in direct C─H and C─C bond transformations by cobalt(III)- and manganese(I)-catalysis.

In the first project, a cobalt(III)-catalyzed C─H/N─O functionalization was achieved for the synthesis of substituted isoquinolines derivatives (Scheme 3.8.1). Notable features of this developed annulation reaction were a wide substrate scope applicable and tolerance of various functional groups. The N─O bond of the oxime was successfully utilized as the internal oxidant in this process.

Importantly, the reaction was not limited to the symmetrical alkynes, but also unsymmetrical and terminal alkynes could be employed in the reaction to afford the isoquinolines in good yields with high regio-selectivities. In many cases, the annulation products were obtained high yields within only 15 min. The mechanistic findings, including H/D exchange, competition experiments and KIE studies, revealed a reversible and facile BIES-type C─H metalation pathway was involved.

Scheme 3.8.1 Cobalt(III)-catalyzed C─H/N─O functionalization for the synthesis of isoquinolines.

Summary and Outlook

In the second project, a good site- and regio-selective cobalt(III)-catalyzed C─H annulation of various nitrones approached the novel and useful indole synthesis (Scheme 3.8.2). The versatile cobalt(III) catalyst proved to be particularly effective for challenging unsymmetrically substituted alkynes, when employing a catalytic amounts of Piv-Leu-OH as ligand, delivering unprotected indoles in good yields with excellent levels of regioselectivity. Detailed mechanistic studies, such as H/D exchange and KIE experiments, provided strong support for a rate-determining C─H metalation step.

Scheme 3.8.2 Cobalt(III)-catalyzed C─H/N─O functionalization for the synthesis of indoles.

In the third project, we developed the first cobalt(III)-catalyzed position-selective C─H functionalization, which fully tolerated strongly coordinating heterocycles, such as pyridines, pyrimidines, and pyrazoles (Scheme 3.8.3). This reaction was showed a wide substrate scope with various functional groups tolerance, such as chloro, fluoro, ester, ketone, nitro, and thiophene. The preliminary mechanistic studies, especially the H/D exchange experiments, indicated that the positional selectivity of this C─H amination is determined in the C─N bond forming step.

Summary and Outlook

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Scheme 3.8.3 Cobalt(III)-catalyzed position-selective C─H functionalization.

In the fourth project, a cobalt(III)-catalyzed domino C─H/N─H allylation reaction of aryl imidates with dioxolanones was accomplished (Scheme 3.8.4). The reaction was performed under mild reaction conditions with water and generated CO2 as the only byproducts. This step-economic method using an earth-abundant cobalt catalyst provided expedient access to decorated vinyl 3,4-dihydroisoquinolines, which could not be obtained using a rhodium catalysis.^[181]

Aryl-substituted imidates bearing various electron-donating and electron-withdrawing groups are compatible with the reaction conditions, delivering the cyclization products 164 in good yields with high levels of regio-selectivity. Furthermore, the obtained product 164 could be easily transformed to dihydroisoquinolone 191 and acetylated isoquinoline 192.

Scheme 3.8.4 Cobalt(III)-catalyzed domino C─H/N─H allylation.

In the fifth project, a manganese(I)-catalyzed decarboxylative C─H/N─O allylation in water was

Summary and Outlook

developed (Scheme 3.8.5). When indole substrates were employed, the reaction features a broad substrate scope and good functional group tolerance. This organometallic C─H activation was also tolerant to air and water. The organomanganese intermediate 193 could be isolated and showed high catalytic efficiency in both catalytic and stoichiometric experiments. The detailed mechanistic findings including competition experiments, H/D exchange and KIE studies strongly support a facile and reversible C─H metalation step. At last, this versatile C─H allylation was also successfully applied to the amino acids and aryl ketimines, delivering the allylation products in good yields with high levels of chemo- and regio-selectivities.

Scheme 3.8.5 Manganese(I)-catalyzed decarboxylative C─H/N─O functionalization.

In the sixth project, a synergistic Brønsted acid/manganese(I)-catalyzed C─H hydroarylation with high chemo- and regio-selectivities in continuous flow was accomplished (Scheme 3.8.6). With the assistance of carboxylic acid, the undesired β-O elimination could be avoided and provided a robust access to allylic carbonates in high yields with excellent chemo- and regio-selectivities. Moreover, this catalytic system tolerated a variety of valuable functional groups, including chloro, bromo, iodo, ether, carboxylic acid, and ester. The first manganese(I)-catalyzed C─H activation in continuous flow could be conducted within only 20 minutes under an atmosphere of air. Mechanistic findings indicated that a fast organometallic C─H metalation step, as well as an intramolecular proton transfer were involved.^[152] Furthermore, late-stage diversification of the allylic carbonates 167ba could be achieved, giving rise to a plethora of valuable building blocks.

Summary and Outlook

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Scheme 3.8.6 Synergistic manganese(I)-catalyzed C─H hydroarylation in continuous flow.

In the last project, we have developed versatile C─C activations in water by inexpensive and Earth-abundant manganese catalysis (Scheme 3.8.7). The organometallic C─C functionalizations, including C─C allylations, C─C alkenylations, and C─C alkylations, occurred efficiently in environmentally-benign solvent with excellent levels of chemo-, regio-, and position-selectivities.

The unique manganese(I)-catalyzed C─C activation was characterized by a broad substrate scopes, functional group tolerance and position-selective synthesis. Competition and H/D exchange experiments clearly showed that the C─C cleavage is much faster than the C─H activation under the optimal condition. This result was showcased by the synthesis of 1,2,3-tri-substituted arenes, which could not be achieved by C─H activation. Importantly, the pyrazole group could be easily removed, furnishing the synthetically useful anilines 209.

Summary and Outlook

Scheme 3.8.7 Manganese(I)-catalyzed C─C functionalizations in water.

Experimental Section

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5 Experimental Section