Chiral Amines

Chiral Amines

A product which one or more hydrogen atoms in an ammonia molecule are replaced by a hydrocarbon group is referred to as an amine. The amine can be classified into a primary amine, a secondary amine, and a tertiary amine depending on the number of hydrogen atoms substituted in the amine molecule. For example: CH₃CH₂NH₂ (primary amine), (CH₃CH₂)₂NH (secondary amine) and (CH₃CH₂)₃N (tertiary amine). Amines are widely found in the biological world and have extremely important physiological activities and biological activities. Among them, an amine attached to a chiral carbon atom is referred to as a chiral amine.

Applications

• Catalytic Diels-Alder reaction: Some scholars have reported that chiral secondary amine hydrochloride catalyst can catalyze the Diels-Alder reaction between cyclopentadiene and (E)-cinnamaldehyde. It promotes the reaction in the molecule by catalytically activating the alkenal, and the product obtains good yield and high optical purity.

  Figure 1. Asymmetry Diels-Alder reaction between acrolein or crotonaldehyde and dienes

• Catalytic Michael reaction: The guanamine can activate the nitro group by hydrogen bonding, and the secondary amine can activate the unsaturated ketone to form the corresponding dienamine intermediate, attack the β position of the nitrone, and generate the Michael addition reaction of the olefin. The corresponding imine intermediate is obtained, and then the intermediate undergoes intramolecular Michael addition to finally obtain a chiral four-membered ring compound.
• Catalytic cycloaddition reaction: The cyclic dienyl aldehyde forms a cross-triamine intermediate in situ under the catalysis of a chiral secondary amine. This intermediate is reacted with 3-alkyl-2-indanone to give the corresponding [4+2] cycloaddition product with excellent enantioselectivity.
• Catalytic Aldol reaction: The cinchona base-derived chiral primary amine can catalyze the Aldol series reaction of an anthrone with a cyclic dienone. A high yield, high enantioselectivity (up to 97% ee) chiral spiro compound is obtained by activation of the phenylenimine cation.
• Catalytic asymmetric Mannich reaction: Catalytic asymmetric Mannich reaction is one of the most important reactions in organic chemistry. Chiral amine catalysts have been widely used in asymmetric Mannich reactions of aldehydes and imines. For example, under the action of a chiral primary amine catalyst, the α-substituted aldehyde reacts with the erythridone imine to form a trans product, which produces a cis product under the action of a chiral secondary amine catalyst. In addition, chiral primary amine catalysts can also be used to catalyze the asymmetric Mannich reaction of acetaldehyde with trifluoromethylketimine.

  Figure 2. Asymmetry Mannich reaction between acetaldehyde and trifluoromethylketimine.

Classification

Among many organic catalysts, organic amine catalysts are undoubtedly the darling of organic catalysts. According to the type of amine, it can be divided into three categories.

• Chiral primary amine catalyst: Further, by type, it can be subdivided into a primary amino acid-derived primary amine catalyst, a chiral diamine-derived primary amine catalyst, a cinchona base-derived primary amine catalyst, and a binaphthol-based primary amine catalyst and so on. They form an enamine or imine intermediate with the carbonyl group in the substrate, thereby increasing the HOMO energy of the molecule or reducing the LUMO energy of the molecule to catalyze the reaction. At present, Aldol reaction, Mannich reaction, Diels-Alder reaction, and Michael addition reaction, amination reaction and a series reaction of olefin are successfully realized by using chiral primary amine catalyst.
• Chiral secondary amine catalyst: L-valine is the earliest secondary amine catalyst, and the diphenyl-mercapto-silicone ether derived therefrom is the most commonly used chiral secondary amine catalyst. In addition, MacMillan's Imidazolinone secondary amine catalyst. They can be catalyzed by reactions with acids, bases, metals, oxidants, and the like.
• Chiral tertiary amine catalyst: The main function is a tertiary amine-thiourea bifunctional catalyst, including a cinchona base-derived tertiary amine-thiourea catalyst, a cyclohexanediamine-derived tertiary amine-thiourea catalyst, and other tertiary amine hydrogen bond catalysts. In the catalytic system, the basicity of the tertiary amine activates the nucleophile, and the thiourea moiety activates the substrate by hydrogen bonding. The two parts work together to complete the entire catalytic reaction.

References

1. Enders, Raabe, G.( 1992). “Diastereo- and Enantioselective Synthesis of 4-Nitrocyclohexanones by [4+2] Cycloaddition of a Chiral 2-Aminobutadiene to Nitroalkenes.” Synthesis. 1992, 1242-1244.
2. Thayumanavan, R. Dhevalapally. (2002). “.Aminecatalyzed Direct Diels-Alder Reactions of ap-Unsaturated Ketones with Nitro Olefins.”Tetrahedron Lett. 2002, 43, 3817-3820.
3. List, B..( 2006). “The ying and yang of asymmetric aminocatalysis.” Chem. Commun. 2006, 819-824.