Isoquinoline has many interesting chemical properties, the most representative of which is that it can carry out many types of reactions. Isoquinoline can also be oxidized to quinolinane, or reduced to 1- or 2-methyl-quinoline. Isoquinoline is also slightly alkaline and only slightly acidic. Natural-like products are a class of alkaloids widely found in plants and animals. They generally have good pharmacological activities, including sedative, analgesic, antitumor, antiviral, and antibacterial effects. Typical examples include morphine, phenothiazines, quinolines and the like. Due to the pharmacological activity of natural products, isoquinoline compounds have become an important basis for drug design and synthesis. For example, lidocaine is a local anesthetic used in surgery, and its synthesis involves the conversion of isoquinoline compounds. Amoxicillin is an antibiotic used to treat bacterial infections, a key precursor of which is also Isoquinoline. Overall, isoquinoline is one of the important organic compounds with wide applications in natural products, pharmaceutical synthesis and organic chemistry. The study of isoquinoline can not only deeply explore its unique chemical properties, but also is expected to bring some beneficial application value.
Isoquinoline is a widely used aromatic compound, which has important value in medicine and material application. Therefore, its synthetic method has attracted much attention. This article will review all the synthesis methods of isoquinoline, including Pictet-Spengler synthesis, Bischler-Napieralski synthesis, Gattermann-Skita synthesis, Pd-catalyzed C-H functionalization, etc.
1. Pictet-Spengler synthesis
Isoquinoline is an important nitrogen-containing heterocyclic compound with a wide range of biological activities and pharmacological effects. Pictet-Spengler synthesis is a commonly used method for synthesizing Isoquinoline.
The steps of the Pictet-Spengler synthesis method:
1. Synthesis of amide compounds. Aromatic amines and acid anhydrides are condensed in a reaction solvent to generate amide compounds. The reaction can be carried out at room temperature, and the catalyst can be DCC (1,3-Dicyclohexylcarbodiimide) or EEDQ (N-aminobutoxycyano), etc.
2. Synthesis of aromatic cyclopropanones. The synthesized amide compound is reacted with another aromatic amine under basic conditions to generate an aromatic cycloacetone intermediate. General catalysts include sub-alkaline oxidants such as CuCl2, or metal bases such as NaH.
3. Generating the target product via light protonation and cyclization. Firstly, the generated aromatic cyclopropanone intermediate is lightly protonated under weakly acidic conditions, and then the cyclization reaction is carried out to obtain the Isoquinoline product. A molecule of water may be released during the reaction, and the conditions for cyclization can use acids such as HCl, or reducing agents such as pyrophosphoric acid.
Reaction mechanism:
The reaction mechanism of the Pictet-Spengler synthesis can be divided into two main steps. In the first step, aromatic amine and acid anhydride are condensed in a reaction solvent to form an amide compound. The mechanism of this condensation reaction is considered to be a nucleophilic addition-elimination reaction. In this mechanism, the lone electron pair on the nitrogen heteroatom acts as a nucleophilic attack on the hydroxyl-like group of the anhydride, during which a carbonyl group is transferred to the nitrogen, producing an intermediate amide and releasing formic acid which serves as the other part of the acetic anhydride.
The second step, the formation of the aromatic cyclopropanone intermediate, is by simple combination of two different molecules followed by decarboxylation. In this mechanism, the amine in the first molecule acts as a nucleophile to attack a carbene carbon in the ketone, yielding intermediate A, which can be de-handled depending on the conditions. Intermediate A is then subjected to the action of an acid or reducing agent to produce the Isoquinoline product.
In conclusion, the Pictet-Spengler synthesis method is an important chemical synthesis method that can efficiently synthesize Isoquinoline. Its steps are simple, the reaction conditions are mild, easy to control, and the obtained product has high purity, so it is widely used in the field of organic synthesis.
2. Bischler-Napieralski synthesis
The Bischler-Napieralski synthesis is a method for synthesizing isoquinoline compounds, which uses amides as starting materials and converts them into target compounds by cyclization and dehydration. The synthesis method was first invented by Bischler and Napieralski in 1893 and has been widely used in the preparation of plants and synthetic drugs.
Reaction mechanism:
The Bischler-Napieralski reaction consists of an acid-catalyzed cyclization step and a base-catalyzed dehydration step. The reaction mechanism can be summarized by the following steps:
(1) The amide molecule is protonated under the action of an acidic catalyst to generate an intermediate, which is an organic cation in which the N atom is positively charged. This step requires a sufficiently strong acidic catalyst, such as hydrochloric acid or ferric chloride.
(2) An electrophilic attack occurs between the N atom of the intermediate and the adjacent C atom, resulting in a five-membered ring intermediate. This step is achieved through intramolecular nucleophilic substitution. The π electrons in the group move to the C atom in the five-membered ring to develop a new C-C bond, and the C atom in the center of the five-membered ring is positively charged.
(3) The five-membered ring intermediate is deprotonated to generate a six-membered ring intermediate. This step usually requires a certain temperature and time to promote the deprotonation reaction.
(4) The alkyl-substituted six-membered ring intermediate undergoes a base-facilitated dehydration reaction to form the final isoquinoline product and release water molecules at the same time.
Generally speaking, there are many synthesis methods of isoquinoline, and different methods are suitable for different reaction conditions. These methods can be adjusted and selected according to actual needs.