1. Introduction
1.4 Transition Metal-Catalyzed C–C Functionalizations
1.4.1 Transition Metal-Catalyzed C─C Functionalizations
The fist example of C─C activation by transition metal insertion was reported by Tipper in 1955 (Scheme 1.4.3).[130] The C─C bond of cyclopropane (135) was activated by [H2PtCl6] generating a platinacyclobutane intermediate 141 (structure was corrected by Chatt in 1961, Tipper thought it reacted with“PtCl2”)[131] via an oxidative addition step.
Introduction
Scheme 1.4.3 Stoichiometric C–C cleavage cyclopropane via oxidative addition.
Inspired by the pioneering work of Tipper and Chatt, strained ring systems have thus emerged as role models for a number of C─C cleaving transformations.[123] For example, in 2013, Bower and coworkers developed rhodium-catalyzed multicomponent synthesis of N-heterobicyclic enones 144 and 145 by carbonylative C─C bond activation of aminocyclopropanes 143 (Scheme 1.4.4).[132] A plausible pathway was postulated. Firstly, the rhodium catalyst activates the proximal C─C bond of cyclopropane with the aid of N-protecting group, and then undergoes CO insertion generating the rhodacyclopentanone intermediate 146. Finally, the desired product was obtained by the alkyne insertion and C─C bond reductive elimination.
Scheme 1.4.4 Rhodium-catalyzed carbonylative C─C activation of aminocyclopropanes.
Meanwhile, other unstained substrates were also successfully employed for C─C activations, such as C─C bond cleavage assisted by chelation. Recently, Ackermann and coworkers reported an unprecedented ruthenium-catalyzed C─C arylations as well as C─C alkylations on decorated pyrazoles 148.[133] The robust and unique ruthenium catalyst was reflected by fully tolerating valuable functional groups, including nitriles, cyano, free NH2, halides, alkenes, esters, and ketones.
The leaving group for C─C bond cleavage is not limited to the amide. Indeed, the decarboxylative C─C arylations and C─C alkylations were also successfully achieved under the optimal conditions.
Introduction
40
Detailed mechanistic studies indicated a facile and reversible C─C metalation step (Scheme 1.4.5a).
Moreover, the pyrazole group could be easily removed by ozonolysis,[134] providing the arylated anilides 151 in moderate yields (Scheme 1.4.5b).
Scheme 1.4.5 Ruthenium(II)-catalyzed C─C functionalizations by Ackermann and coworkers.
In 2011, Shi and coworkers developed a rhodium-catalyzed selective C─C bond activation of secondary alcohols 152 with the aid of a pyridinyl group via β-carbon elimination.[135] This C─C alkenylation features a broad reaction scope and highly functional group tolerance. Inter- and intra-molecular competition experiments both supported that C─C bond activation was much faster than the direct C─H activation under the optimal conditions. This strategy offered a mild and efficient process for C─C cleavage (Scheme 1.4.6a). Thereafter, the same group also reported the rhodium-catalyzed C─C arylation under an oxidative condition, and reductive cleavage of the C(sp2)-C(sp3) bond in the presence of H2 as the reducing agent, respectively (Scheme 1.4.6b and c).[136]
Introduction
Scheme 1.4.6 C─C bond activation via β-carbon elimination.
Compared to the noble metals, such as rhodium, cobalt is an alternative candidate for C─C bond activation due to its benefits of Earth-abundant, nontoxic. In 2015, Morandi and coworkers developed the C─C cleavage by using inexpensive cobalt as catalyst through a β-carbon elimination step.[137] The electronic and steric effects of the substrates both had little influence on the transformation of C─C cleavage. The secondary and tertiary alcohols underwent the reaction smoothly, but the primary alcohol could not achieve the C─C bond activation (Scheme 1.4.7a).
Moreover, when the cyanating reagent NCTS (47a) was selected as the reaction partner, the desired product was obtained in 91% yield (Scheme 1.4.7b). Two possible pathways were proposed for the cobalt(III)-catalyzed C─C cyanation reaction. The cobalt intermediate 157 was firstly generated by the initial β-carbon elimination, and then underwent the cyanation directly, delivering the final product (Path A, direct C─C activation). Alternatively, the intermediate 157 could be trapped by proton providing the phenylpyridine firstly, then underwent the C─H functionalization and gave the desired product (Path B, C─C activation and then C─H functionalization) (Scheme
Introduction
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1.4.7c).
Scheme 1.4.7 Cobalt(III)-catalyzed C─C bond activation by Morandi and coworkers.
Objectives
2 Objectives
Transition metal-catalyzed C─H functionalizations have emerged as increasingly powerful tools for sustainable organic syntheses.[81b, 138] Remarkable advances in this area have been achieved by Prof.
Dr. Lutz Ackermann and coworkers, which is mainly focused on the development of chemo- and site-selective syntheses of valuable organic molecules, with applications to pharmaceutical chemistry, materials sciences and peptide assembly.[80, 139] Within this context, major efforts were made to develop novel C─H or C─C activation reactions by environmentally-benign, less expensive and Earth-abundant versatile cobalt(III)/manganese(I) catalysts.
In the past few years, alkyne annulations by C─H/N─O functionalizations have proven to be instrumental for the step-economical assembly of various heterocycles with activities of relevance to medicinal chemistry and biology.[109c, 140]
In addition, in light of the beneficial features of naturally abundant 3d transition metals, focus has shifted in recent years to the use of environmentally-benign, less expensive base metal catalysts for the C─H activation processes, such as cobalt catalyst. Therefore, it was of great interest to establish a novel approach for cobalt(III)-catalyzed C─H/N─O functionalization for the redox-neutral preparation of isoquinolines (Scheme 2.1).[141]
Scheme 2.1 Cobalt(III)-catalyzed C─H/N─O functionalization of O-acyl oximes 158.
Substituted indoles are important structural motifs widely found in compounds of relevance to medicinal chemistry, crop protection, and drug discovery, among others.[142] Although the recent years have witnessed the emergence of C─H functionalization as increasingly powerful tools for the direct synthesis of indoles, these protocols largely required precious 4d and 5d transition metals.[143]
In this regard, an Earth-abundant and environmentally-benign cobalt catalyst would be desired to be used for the synthesis of unprotected indoles by site-selective C─H activation (Scheme 2.2).[144]
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Scheme 2.2 Selective synthesis of indoles by cobalt(III)-catalyzed C–H/N–O functionalization with nitrones 159.
Biologically relevant N-heterocycles, such as pyrazoles, oxazolines, pyrimidines, or pyridines, can strongly coordinate to the active transition metals, in some cases, resulting in C─H activation at undesired position or catalyst poisoning,[145] which severely limits the application of these reactions in material sciences or drug discovery. In 2014, Yu reported the palladium-catalyzed position-selective C─H functionalizations of the substrates containing two different directing groups, which the N-heterocycles, such as pyridine, quinolone, pyrazine, pyrimidine, pyrazole, thiazole, and oxazoline, are fully tolerant.[146] Although major advances in cobalt(III)-catalyzed C─H functionalizations have been accomplished in recent years, no example was reported for cobalt(III)-catalyzed C─H activation fully tolerating strongly coordinating N-heterocycles. Herein, we would plan to establish cobalt(III)-catalyzed C─H amidation by the assistance of imidate that tolerated strongly coordinating N-heterocycles (Scheme 2.3).[147]
Scheme 2.3 Strongly coordinating N-heterocycles were fully tolerated in cobalt-catalyzed C─H amidations.
Despite significant progress of Cp*Co(III)-catalyzed C─H activation has been accomplished recently, large transformations still largely continue to simply mirror the activities and selectivities observed
Objectives
from their analogous Cp*Rh(III) counterparts. Herein, a first cobalt(III)-catalyzed domino reaction comprising C─H/N─H allylation for the direct synthesis of isoquinolines has been developed, which notably could not be achieved by Rh(III) catalysis (Scheme 2.4).[148]
Scheme 2.4 Cobalt-catalyzed domino C─H/N─H allylations of imidates 161.
In 2016, Ackermann and coworkers reported an unprecedented manganese(I)-catalyzed substitutive C─H allylation with allyl carbontates 53.[104] Based on this work, further expansion for manganese-catalyzed C─H allylation in water using dioxolanones 110 as the allyl source was investigated (Scheme 2.5).[149]
Scheme 2.5 Manganese(I)-catalyzed C─H activation for decarboxylative C─H/C─O cleavages.
Flow chemistry bears huge potential to address the needs of sustainable synthesis, facilitating challenging synthetic transformations and providing additional advantages, such as safer and faster reactions, clean products, and easy scale-up.[150] In addition, remarkable advances have been achieved with the aid of less toxic manganese catalysis over the last decade.[83] Nevertheless, all manganese(I)-catalyzed functionalization of substrates, bearing leaving groups in proximity to the C─C multiple bond, thus far resulted in β-heteroatom eliminations.[104-107, 151]
Therefore, it is of great significance to develop a new versatile protocol, combining with continuous flow for manganese(I)-catalyzed C─H alkenylations without concurrent β-O elimination (Scheme 2.6).[152]
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Scheme 2.6 Manganese(I)-catalyzed synergistic C─H activation for chemoselective hydroarylation in flow.
Recent years have witnessed great sucssess in transition-metal-catalyzed C─C bond activations, offering new opportunities to the synthesis of valuable and novel organic moleculars.[119] However, precious metals, such as rhodium, ruthenium and palladium, have always played a predominant role in this field, which limites their further application in synthetic chemistry due to the high cost and toxicity of these metals. In this regard, catalysts based on Earth-abundant metals, for example manganese, are highly desirable for C─C bond functionalization. In addition, organic synthesis reactions catalyzed in water is consistent with the requirements of green chemistry.[29] However, to date, transition-metal-catalyzed C─C functionalizations in water have proven elusive. Within our program on sustainable C–C functionalizations,[153] herein, we disclosed the first versatile C–C activation by inexpensive and less toxic manganese catalyst in water (Scheme 2.7).[154]
Scheme 2.7 Chelation-assisted manganese-catalyzed C─C activations in H2O.
Results and Discussion