Synthesis of Nitrile

Nitrile is an organic compound formed by connecting carbon atoms containing hydrocarbon groups and cyano groups. It is an important drug synthesis intermediate, and the synthesis of nitrile is a very important part of organic synthesis. It is generally prepared by the following methods:

 

1. Nucleophilic substitution reaction of aliphatic halogenated hydrocarbons or sulfonates with metal cyanides

The nucleophilic substitution reaction in the aliphatic system is one of the unit reactions that attract the most attention of organic chemists. Among them, the nucleophilic substitution of aliphatic halogenated hydrocarbons or sulfonates with metal cyanides has been widely used to synthesize nitriles. The general formula is as follows:

 

 

Sometimes, when the reactivity of non-iodinated halogenated hydrocarbons is not enough, it is necessary to add KI or NaI to the reaction system to increase the reactivity of halogenated hydrocarbons. An example of the reaction is shown in the figure below:

 

 

2. Nitrilation reaction of aromatic halogenated hydrocarbons under metal catalysis

Aromatic nitrile compounds play a very important role in organic synthesis, especially in dyes, herbicides, agrochemicals, medicines, and natural products. An example of the reaction is shown in the figure below:

 

 

3. TMSCN converts hydroxyl to nitrile

For the hydroxyl group at the benzylic position of the aryl group, TMSCN can undergo various nucleophilic reactions to prepare nitriles. Examples of reactions are as follows:

 

 

4. Preparation of nitrile by dehydrogenation of amine

There are also many ways to prepare nitriles from amines. Reagents such as 2-iodobenzoic acid (IBX), sodium hypochlorite, and nicotine dichromate are realized under different conditions. Examples of reactions are as follows:

 

 

5. Dehydration of oxime to prepare nitrile

Aromatic or alkyl aldehydes can be converted to oximes and dehydrated to the corresponding nitriles. Dehydration reagents such as thionyl chloride, phosphorus tribromide, zinc oxide/acetyl chloride, etc., and substrates are dehydrated in different systems to prepare nitriles. The reaction examples are as follows:

 

 

6. Preparation of nitrile by dehydration of amide

The preparation of nitrile by amide dehydration is one of the more commonly used methods in the laboratory, and the general reaction formula is as follows:

 

 

Commonly used dehydrating agents P2O5, POCl3, SOCl2, PCl5, T3P, cyanuric chloride, trifluoroacetic anhydride, etc., the reaction examples are as follows:

 

 

Most of the above dehydration reagents react under acidic conditions and are not suitable for acid-sensitive substrates. Therefore, people have also developed many milder methods for the dehydration of amides, such as Burgess reagent (N-(triethylaminosulfur Acyl) methylcarbamate), trifluoroacetic anhydride (TFAA)-triethylamine, (COCl)2-NEt3-DMSO and other conditions can be reacted at low temperature and almost neutral conditions.

 

It is worth mentioning that the dehydrating effect of the Burgess reagent dehydrating agent has been paid attention to in the synthesis of new coronavirus therapeutic drugs. Participation responses are as follows:

 

 

In addition to the above methods, there are some unconventional methods to prepare nitriles in the experiment, such as using the Sandmeyer reaction, first diazotization and then reacting with copper cyanide to prepare aryl nitriles; Schmidt reaction with aldehyde as substrate; Van Leusen reaction; aza- Claisen rearrangement reaction and so on.

 

 

references:

1. J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484

2. J . Med. Chem. 1983, 26, 608-611

3. Bioorg. Med. Chem. 11, 18, 2003, 4093-4102.

4. Organic Process Research & Development 2001, 5, 587-592

5. J. Med. Chem. 1990, 33, 1128-1138

6. Chem Pharm Bull. 1991, 89-3201