Ruthenium catalyzed deuteration involving nitrogen atom as directing groups

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H/D exchange reactions catalyzed by iridium complexes

Among all the metal catalysts used for the H/D exchange procedures, iridium complexes are the most wildly studied. 42 Many research groups have been working on iridium catalyzed H/D exchange reactions and great achievements have been obtained in this field.32a In recent years, numerous novel methods based on HIE have been developed for the selective deuterium/tritium labeling of various organic compounds catalyzed by iridium complexes.

Iridium catalyzed deuteration involving oxygen atom as directing groups

Oxygen is a common coordinating atom to many metals. It can coordinate in the form of different functional groups, such as alcohols, ketones, esters, carboxylic acids, amides or nitro group. Therefore, many works on H/D exchange have been achieved involving oxygen atom as directing groups catalyzed by iridium complexes.
Among the research groups working on iridium catalyzed H/D exchange reactions, W. J. Kerr’s group has made huge contributions.40a, 41d-e, 42, 43d-k In 2008, Kerr reported40a the synthesis of a series of iridium complexes stabilized by bulky N-heterocyclic carbene (NHC) and their applications in the regioselective H/D exchange reactions (Figure 1.14). Excellent levels of labeling had been achieved over short reaction times and at low catalyst loadings. Moreover, these complexes were all air- and moisture-stable solids, which could be stored under air for more than 8 months without loss of catalytic activity.

Iridium catalyzed deuteration involving nitrogen atom as directing group

Compared with oxygen, nitrogen atom displays stronger coordinating ability to transition metal catalysts because N-ligands are generally stronger Lewis bases than O-ligands, thus the coordination bond between transition metal and nitrogen is stronger than the one between transition metal and oxygen. Nitrogen can participate as coordinating atom in various functional groups, such as amines, sulfonamides and a series of N-heterocycles. Numerous works have been published recently based on the nitrogen directing groups.
Apart from the works of the deuteration involving oxygen atom, Kerr also applied his catalysts in the
labeling of N-heterocycles41e, 43h and primary sulfonamides. 41d For the labeling of N-heterocycles such as pyrimidine, imidazole, oxazole, oxazoline, isoxazole, thiazole, benzimidazole, benzoxazole and benzothiazole, catalyst 1.4.1a proved to be the most efficient (Scheme 1.6, a);43h while for the labeling of unprotected tetrazoles, catalyst 1.4.2 worked best with the addition of Cs2CO3 as base since the reaction was a concerted metalation-deprotonation (CMD) pathway (Scheme 1.6, b).41e Moreover, through the optimization of reaction conditions, deuteration of complex molecules 1.4.7-1.4.9 and deuteration/tritiation of valsartan 1.4.10, an angiotensin receptor blocker, were also achieved using the two catalysts separately (Figure 1.16).

Iridium catalyzed deuteration of various compounds with distinct functional groups

For the works described above, the catalysts could catalyze the H/D exchange of compounds with comparable functional groups. However, there are some more general catalysts that are able to catalyze H/D exchange of various compounds with different types of functional groups, such as Kerr’s catalysts.42, 43e, f, j, 45.
For catalysts containing an NHC and a chlorine ligands, after screening catalysts with different substituents on carbene ligand (Figure 1.18), Kerr discovered that catalyst 1.4.12 was able to deuterate various aryl ketones efficiently.42 The catalyst could also deuterate amides with moderate deuterium incorporation, and N-heterocycles with high deuterium incorporation.
For catalysts containing an NHC and a phosphine ligands, Kerr showed that all the catalysts (Figure 1.18) were active toward the labeling of aryl ketones, aryl amides and N-heterocycles, despite a little difference of activities was observed among different substrates.43e, f One could choose different catalyst according to the functional groups of substrates. Kerr even succeeded to tritiate various molecules with different functional groups using catalysts 1.4.1a-1.4.1c respectively. Replacing the phosphine ligand with pyridine (Figure 1.18, 1.4.1f) also had similar catalytic activities towards various compounds with different functional groups.

Iridium catalyzed deuteration of aromatic compounds

In 2012, R. H. Grubbs reported a PNP-pincer iridium dihydride complex (compound 1.4.26, Figure 1.21) which catalyzed H/D exchange for aromatic substrates using D2O or C6D6.43a Complete incorporation of deuterium into sterically accessible CAr-H bonds was observed at 80 °C after 3 days.
According to the authors, steric factors played an important role in the deuteration process, since nodeuterium incorporation was observed at α-position of methyl group in the arenes. Heteroarenes such as furan and thiophene were also deuterated efficiently under these conditions; however, substrates with strong coordinating atom such as pyridine were not able to be deuterated by this method, due to deactivation of the catalyst by pyridine’s coordination to the metal center.

H/D exchange reactions catalyzed by ruthenium catalysts

Compared with iridium catalyzed H/D exchange reactions, ruthenium catalyzed H/D exchange reactions is another research hotspot. Thanks to the excellent coordinating ability of many functional groups (alcohol, amine, ester, amide, alkene, (hetero)arene…and so on) to the ruthenium atom, many catalysts based on ruthenium have been developed allowing the efficient and selective C-H deuteration of various organic compounds.

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Ruthenium catalyzed deuteration involving oxygen atom as directing groups

As mentioned above, oxygen is an excellent coordinating atom to many metals, including ruthenium complexes. Since it exists in various functional groups such as alcohols and carbonyl groups, many H/D exchange processes based on oxygen directing groups have been achieved catalyzed by ruthenium complexes.
Carbohydrates are important components of living organisms, and all of them contain certain number of hydroxyl groups which can act as directing groups. In 2010, H. Sajiki’s group developed a method for the regioselective deuteration of primary and secondary alcohols as well as diols and triols catalyzed by Ru/C in D2O under 1 bar of H2 gas.47 Based on this work, the same group reported a stereo- and regioselective deuterium labeling of various sugars catalyzed by Ru/C in D2O under a hydrogen atmosphere.48 The direct H/D exchange reaction could selectively proceed on carbons adjacent to the free hydroxyl groups. A series of pyranosides were deuterated with high isotopic enrichment and high isolated yield (Scheme 1.11). The products were transferred into the corresponding acetates in order to better analyze them by 1H NMR. However, the deuteration of furanosides failed because they were easily hydrolyzed under heated aqueous conditions.

Table of contents :

Chapter 1 Deuterium and Tritium Labeling of Bioactive Thioethers
1 Introduction and background
1.1 Deuterium and applications of deuterated compounds
1.2 Tritium and applications of tritiated compounds
1.3 Synthesis of deuterium or tritium labeled compounds
1.4 H/D exchange reactions catalyzed by iridium complexes
1.4.1 Iridium catalyzed deuteration involving oxygen atom as directing groups
1.4.2 Iridium catalyzed deuteration involving nitrogen atom as directing group
1.4.3 Iridium catalyzed deuteration of various compounds with distinct functional groups
1.4.4 Iridium catalyzed deuteration of alkenes
1.4.5 Iridium catalyzed deuteration of aromatic compounds
1.5 H/D exchange reactions catalyzed by ruthenium catalysts
1.5.1 Ruthenium catalyzed deuteration involving oxygen atom as directing groups
1.5.2 Ruthenium catalyzed deuteration involving nitrogen atom as directing groups
1.5.3 Ruthenium catalyzed deuteration of various compounds with distinct functional groups
1.5.4 Ruthenium catalyzed deuteration of other types of organic molecules
1.6 H/D exchange reactions catalyzed by other metals
1.6.1 Palladium catalyzed H/D exchange reactions
1.6.2 Rhodium catalyzed H/D exchange reactions
1.6.3 Platinum catalyzed H/D exchange reactions
1.6.4 Iron catalyzed H/D exchange reactions
1.6.5 H/D exchange reactions catalyzed by mixed metal catalysts
2.1 The investigation of the H/D exchange of thioethers
2.2 Attempts to apply our method in quantitative LC-MS analysis
2.3 Application of our method in tritium labeling
2.4 Mechanistic studies of the H/D exchange of thioethers
2.5 Summary and perspective
2.6 Exploring the catalytic activities of different kinds of ruthenium catalysts
3 Experimental section
3.1 Reagents and General Procedures
3.2 Experimental details and characterization for compounds 2.1 to 2.15’
3.3 Data of mass analyses for compounds 2.1 to 2.15’
Chapter 2 Ru/C catalyzed homocoupling of 2-arylpyridines
1 Introduction and background
1.1 C-C bond formation through heterogeneously catalyzed C-H functionalization
1.1.1 C-C bond formation based on heterogeneous palladium catalysts
1.1.2 C-C bond formation based on heterogeneous ruthenium catalysts
1.1.3 C-C bond formation based on heterogeneous platinum catalysts
1.2 C-C bond formation through heterogeneously catalyzed CDC reactions
1.2.1 C-C bond formation through heterogeneously catalyzed dehydrogenative alkylation
1.2.2 C-C bond formation through heterogeneously catalyzed dehydrogenative alkenylation
1.2.3 C-C bond formation through heterogeneously catalyzed dehydrogenative arylation .
1.2.4 C-C bond formation through heterogeneously catalyzed dehydrogenative alkynylation
1.2.5 C-C bond formation through heterogeneously catalyzed dehydrogenative homocoupling
1.3 Summary and perspectives of CDC reactions through heterogeneous catalysis
2 The discovery of new C-H activation reactions
2.1 Exploring new C-H activation reactions catalyzed by ruthenium heterogeneous catalyst
2.2 Literature review for the homocoupling of 2-arylpyridines
3 Results and discussions
3.1 Optimization of reaction conditions
3.2 Substrate scope of the homocoupling reactions
3.3 Experiments for mechanism studies
3.4 Applications of the homocoupling products
3.4.1 Perspectives
3.4.2 Conclusion
4 Experimental section
4.1 Reagents and General Procedures
4.2 Experimental details and characterization for synthesized compounds
Chapter 3 Pd-catalyzed C-H activation intramolecular arylation via concerted metalation-deprotonation
1 Introduction and background
1.1 Synthesis of polycyclic biaryls through intramolecular arylation involving CMD process
1.2 Synthesis of polycyclic biaryls through intramolecular arylation involving pyridine derivatives
2 Results and discussions
3 Experimental section
3.1 Reagents and General Procedures
3.2 Experimental details and characterization for synthesized compounds

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