Amides are common functional groups in organic chemistry, ubiquitous in fine chemicals, agricultural chemistry and the pharmaceutical industry.Due to the resonance stabilization of C-N bonds, the electrophilicity of carbonyl carbon of amides is weak, which makes the amide structure relatively stable, and its transformation often requires some harsh conditions. At the same time, amides are a kind of nitrogen-containing compound that has not been fully utilized. It is one of the long-term goals of synthetic chemists and a challenging research topic to convert C-C bonds into synthetically important amines via deoxygenation. In recent years, many research groups at home and abroad, including the research groups of Professor Huang Peiqiang, Professor Dixon and Professor Sato/Chida, have realized the activation and deoxygenation of amides through activation with trifluoromethanesulfonic anhydride and selective reduction with transition-metal catalysis, making outstanding contributions in this field.
In recent years, Wang Xiaoming's research group has achieved the challenging deoxygenative functionalization of amides through bimetallic relay catalysis and polymetallic mediated single-electron transfer activation. (Angew. Chem. Int. Ed. 2022, 10.1002/anie.202115497; Angew. Chem. Int.Ed. 2021, 60, 26604; Angew. Chem. Int. Ed. 2021, 60, 17088 et al.)Whether it is the classic deoxygenative functionalization of amides through multi-step reaction or the one-pot deoxygenative functionalization process developed in recent years, the electrophilic iminium ion intermediates subject to amide activation are caught by nucleophiles to obtain α-functionalized amines. At present, the types of nucleophiles available are limited, and most of the work is limited to extremely active Grignard reagents or lithium reagents, resulting in poor chemical selectivity and harsh reaction conditions. Therefore, it is an urgent need and great challenge in the field of synthetic chemistry to develop efficient and mild methods that avoid using active metallic reagents to realize the deoxygenative functionalization of amides to amines and prepare β-substituted amines.
Wang Xiaoming, a double-employed professor and research fellow from Professor Tang Yong's Studio at the HIAS School of Chemistry and Materials Science,has synthesized a series of β-substituted amines with important practical and research value by combining Ir-catalyzed selective reduction of amides with photochemical organocatalysis, based on amides and electrophilic radical precursors (Cell Rep. Phys. Sci. 10.1016/j.xcrp.2022.100955). Radical precursors (such as α-bromoketones) generate electrophilic radicals via photochemical organocatalysis under visible light, and combine with enamine intermediates produced from the hydrosilylation of amides to build new carbon-carbon bonds. The reaction conditions are mild, with good compatibility with functional groups, providing new ideas and strategies for the deoxygenative functionalization of amides.
Initial studies of catalytic reductive cross-coupling were carried out using (IrCl(CO)(PPh3)2 [Vaska's complex; 1.0 mol%] and (Me2SiH)2O [TMDS; 2.0 eq.]) for the reduction of amides, and using the radical precursor α-bromo acetophenone and catalyst potassium 5-bromo-1H-indole-1-carbodithioate (Cat-I; 10 mol %) to generate radicals under blue light emitting diode (LED) irradiation (24 W). Gladly, the reaction afforded the cross-coupling product 3aa with 68% yield, along with 6% over-reduced amine 4 in the absence of additional reductant. The γ-carbonyl aldehyde 5 was also detected with 22% yield, which was probably produced from hydrolysis of the formed iminium ion intermediate. Given this result, the authors inferred that the excess amount of TMDS from the amide reduction step might act as a reductant for the reduction of the formed iminium ion intermediate. Next, a set of reaction parameters, including reductants and solvents, was optimized to establish the optimal conditions, which were as follows: [IrCl (CO)(PPh3)2 (1 mol%) and Cat-I (10 mol%) were used as catalysts and (Me2SiH)2O (TMDS, 3.2 eq) as the reductant in CH2Cl2 at room temperature under blue LED irradiation for 12 hours.
Table 1 Screening of Conditions
Next, the scope of radical precursors and amide substrates was investigated.Alkylamines containing diverse types of functional groups were compatible with the reaction (23 cases), including cyano, methoxy, halogen, trifluoromethyl, silicon, and heterocyclic. Meantime, a variety of radical precursors could participate in the reaction, such as α-bromoketone (20 cases),ethyl 2-bromoacetate, 2-malonate and 2- bromoacetonitrile.The structure of the product was determined by single-crystal X-ray diffraction.
Figure 3: Broad Substrate Scope
In addition, the method was also used for the modification of some drug molecules.For example, amides derived from secondary amines such as maprotiline, nortriptyline and fluoxetine, amides derived from carboxylic acid oxaprozin, and bromides derived from adapalene were found compatible with the reaction, affording products with moderate to high yields.
Figure 4: Reactions of Substrates Derived from Natural Products or Drugs
At last, preliminary studies and discussions were made on the mechanism.The enamine intermediate III is produced under the Ir-catalyzed hydrosilylation of amides, which can be detected by the1H NMR spectrum. Electrophilic α-carbonyl (nitrile) C-centered radical V is generated from α-carbonyl (nitrile) bromides by use of organic catalysts under visible light. These two active intermediates combine to generate α-amino radical VII, which is further oxidized to produce iminium ion VIII. Subject to Ir-catalyzed reduction, the resulting iminium ion VIII is reduced to β-substituted amine 3 instead of aldehyde 5 by hydrolysis.
Figure 5: Reaction Path
The research was supported by the National Natural Science Foundation of China, Hangzhou Institute for Advanced Study, UCAS, Shanghai Institute of Organic Chemistry, and the State Key Laboratory of Organometallic Chemistry.
Source | School of Chemistry and Materials Science
Typesetter | Chen Xingyu
Executive Editor | Wang Xia
