JACS: carbon dioxide mediated C (SP3) - H arylation of amine substrates

Amino group is a key functional group in medicine, agricultural chemicals and materials, so the synthesis of amines has attracted much attention Although transition metal catalyzed C-H activation can effectively install functional groups on inert C-H bonds, due to the poor reactivity of amines, it is difficult for amine derivatives to undergo C-H activation At present, there are a few palladium catalyzed activation of C (SP 3) - h in 1 º and 2 º free amine substrates, but most of them are more active C (SP 2) - H activation or intramolecular cyclization Recently, the Michael C young group of University of Toledo in the United States solved the above problems They reported the method to promote the intermolecular γ - C (SP 3) - H arylation of amine substrates by using the dry ice form of CO 2 Relevant articles were published on j.am Chem SOC (DOI: 10.1021 / JACS 8b05061) (source: j.am Chem SOC.) 1 ° and 2 ° amines usually need to introduce guiding group (DG) to promote C (SP 3) - H activation One method is to use static guiding group, the other is to use transient guiding group However, both methods have some disadvantages The static guide group needs additional stoichiometric reagents and lacks atom and step economy The use of transient guiding group will produce imine intermediates which are sensitive to oxidation In addition, both static and transient guiding groups are rarely used for C-H activation of primary amines In order to avoid the above shortcomings, the author tries to explore a mixed guiding group strategy CO2 contains a carbonyl group which can react reversibly with amines, and carbamates can easily coordinate with palladium The chemical stability of the coordination products is higher than that of imines In addition, CO2 was previously reported as a traceless guide group for C-H activation at the phenol site Therefore, the author speculates that CO2 can be used as a transient guide group in the presence of suitable nucleophiles (such as amines), which can not only be used as a protective group to prevent substrate oxidation, but also coordinate with palladium to achieve site-selective C-H bond breaking As a guide group, the transient carbamate will activate the C-H bond of 1 ° amine under the condition of stronger oxidation, and the method can also be extended to 2 ° amine (source: j.am Chem SOC.) the author first used tert amylamine and iodobenzene as model substrates It is satisfactory that γ - arylated tertiary amines can be obtained successfully in CO2 atmosphere with silver trifluoroacetate as additive and acetic acid as solvent As expected, the absence of any reaction condition will lead to the termination of the reaction Although the reaction can be carried out at 1 atmospheric pressure, dry ice is chosen as the CO 2 source in order to optimize the reaction conditions Interestingly, no other foreign ligands are needed to promote transformation Under the optimal reaction conditions, the author first investigated the substrate range of aryl iodide (Table 1) Even aryl iodides with electron acceptor and electron acceptor can obtain the product of γ - arylation in good yield The more complex heterocyclic iodide can also participate in the reaction (1P and 1q), but the yield is reduced Although the orthofunctional groups other than chelates are not compatible under the standard conditions, the reaction can be carried out successfully when the silver additive is converted to agotf (source: j.am Chem SOC.) then the author examined the substrate range of amines (Table 2) The substrates containing saturated (2A - 2D) and unsaturated (2e) carbon rings obtained the corresponding products with relatively high yield Although 2E has a more reactive γ - C (SP 2) - H bond, the author only observed the selective arylation of C (SP 3) - H bond, which may be due to the fact that the non curable thick ring hinders the coordination of the more reactive C-H bond with palladium catalyst (source: j.am Chem SOC.) next, the author continued to explore whether CO 2 can promote the γ - C (SP 3) - H arylation of 2 ° amines (Table 3) Up to now, the C (SP 3) - H arylation of 2 ° amines requires highly substituted substrates β - functionalization rather than γ - functionalization products are usually obtained in the reaction Moreover, the imine type guide group can not promote the C (SP 3) - H arylation It is gratifying that the C (SP 3) - H arylation of 2 ° amines can proceed smoothly by increasing the amount of CO 2 Excessive CO2 is the key to the reaction When the concentration of CO2 is low, not only the yield of the product will be reduced, but also the raw material will be oxidized The secondary amines with different length alkyl substituents and various benzyl substituents can selectively form the product of γ - C (SP 3) - H arylation in medium yield (source: j.am Chem SOC.) Summary: Michael C young team reported the first method of CO 2-mediated activation of amine C-H the process of CO 2 transient formation of carbamate can be used not only for C-H activation, but also for other guided group mediated reactions.