Abstract
The present protocol describes the synthesis of di and tri-substituted s-triazine derivatives
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s-Triazine undergoes sequential nucleophilic substitution reaction but order of nucleophile is very crucial.
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It is very difficult to substitute any nucleophile except amine once amine is incorporated onto s-triazine.
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During the synthesis of O,N-type substituted s-triazine, always O-type should be incorporated first.
Keywords: Orthogonal chemoselectivity, Cyanuric chloride, Nucleophilic substitution, Amines, Alcohol
Graphical abstract
Specification Table
| Subject Area: |
• Chemistry More specific • Orthogonal chemoselective |
| Method name: | Sequential nucleophilic substitution |
| Name and reference of original method: | N/A |
| Resource availability: | N/A |
Method details
Method details involves synthesis of di- and tri- substituted s-triazine derivatives as drawn in below scheme.
Synthesis of di-substituted s-triazine using two sequential amines
Step 1: Synthesis of 4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]benzonitrile
Materials required
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Cyanuric chloride
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Potassium carbonate (K2CO3)
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4-Aminobenzonitrile
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Solvent [acetone, methanol (MeOH) and chloroform]
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Crushed ice and distilled H2O
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Rotary evaporator
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Glassware (Round bottom flask, beakers and conical flask)
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Silica-gel coated Aluminum TLC plates
Procedure
Note: Cyanuric chloride is fuming solid. So, care must be taken to weigh it. Bottle must be opened in the fume hood with exhaust on.
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(1)
Cyanuric chloride (10 mmol) and 4-aminobenzonitrile (10 mmol) were dissolved in acetone (50 mL each) separately in conical flask.
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(2)
Both solutions were cooled to 0 °C.
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(3)
K2CO3 (10 mmol) was added to cyanuric chloride solution while stirring vigorously at 0 °C in a round bottom flask.
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A cold solution of 4-aminobenzonitrile was added dropwise to the stirring solution of cyanuric chloride and K2CO3.
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The reaction was stirred for 4 h at 0 °C (Note: maintaining temperature at 0 °C is very crucial for the reaction to avoid double incorporation).
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(6)
Monitor the reaction by TLC using 20% MeOH in chloroform as mobile phase in a closed system.
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(7)
Once no starting material appears on TLC, pour the reaction mixture onto crushed ice (1 L) in a beaker.
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(8)
Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain pure product.
Note: The current procedure is applicable for all amines (In case of aromatic amines the time consumed is 4 h whereas in case of aliphatic amine it only requires 30 min)
Step 2: Synthesis of 4-[4-chloro-6-substituted(1,3,5-triazin-2-yl)amino]benzonitrile
Materials required
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K2CO3
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Piperidine
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Morpholine
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N,N’-Diethylamine
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Solvents [THF, ethyl acetate (EtOAc), hexane]
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Ice cold water and crushed ice
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Rotary evaporator
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Glassware (Round bottom flask, beakers and conical flask)
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Silica-gel coated Aluminum TLC plates
Procedure
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(1)
4,6-Dichloro (1,3,5-triazin-2-yl) aminobenzonitrile (10 mmol) and respective amine (piperidine, morpholine and diethyl amine) were dissolved in THF (50 mL each) separately in conical flask.
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(2)
K2CO3 (10 mmol) was added to 4,6-dichloro (1,3,5-triazin-2-yl) aminobenzonitrile solution while stirring vigorously at rt in a round bottom flask.
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(3)
Solution of respective amine was added dropwise to the stirring solution of 4,6-dichloro (1,3,5-triazin-2-yl) aminobenzonitrile and K2CO3.
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(4)
The reaction was stirred for 24 h at rt.
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(5)
Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.
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(6)
Once no starting material appears on TLC, THF was removed using rotary evaporator.
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(7)
Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.
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(8)
Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain product.
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(9)
The crude was recrystallized from EtOAc.
Synthesis of trisubstituted triazines containing one alkoxy substituent and two amino substituents [1]
Step 1: Synthesis of 2,4-dichloro-6-methoxy-1,3,5-triazine [2]
Materials required
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Cyanuric chloride
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Sodium bicarbonate (NaHCO3)
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Solvents (MeOH, EtOAc, hexane)
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Crushed ice and distilled H2O
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Rotary evaporator
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Glassware (Round bottom flask, beakers and conical flask)
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Silica-gel coated Aluminum TLC plates
Procedure
Note: Cyanuric chloride is fuming solid. So, care must be taken to weigh it. Bottle must be opened in the fume hood with exhaust on.
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(1)
NaHCO3 (10 mmol) was dissolved in water and cooled to 0 °C.
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(2)
MeOH (50 mL) is added to the above solution and stirred vigorously at 0 °C.
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(3)
Cyanuric chloride (10 mmol) was added to the above stirring solution.
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(4)
The reaction was stirred for 3 h at 0 °C (Note: maintaining temperature at 0 °C is very crucial for the reaction to avoid double incorporation).
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(5)
Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.
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(6)
Once no starting material appears on TLC, excess of MeOH was removed under rotary evaporator.
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(7)
The residue was poured onto crushed ice (1 L) in a beaker.
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(8)
Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain pure product.
Step 2: Synthesis of 4-chloro-6-methoxy(1,3,5-triazin-2-yl)amino)benzonitrile
Materials required
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NaHCO3
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4-Aminobenzonitrile
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Solvents (acetone, EtOAc, hexane)
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Crushed ice and distilled H2O
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Rotary evaporator
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Glassware (Round bottom flask, beakers and conical flask)
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Silica-gel coated Aluminum TLC plates
Procedure
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(1)
2,4-dichloro-6-methoxy-1,3,5-triazine (10 mmol) and 4-aminobenzonitrile (10 mmol) were dissolved in acetone (50 mL each) separately in conical flask.
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(2)
NaHCO3 (1.38 g) was added to 2,4-dichloro-6-methoxy-1,3,5-triazine solution while stirring vigorously at 0 °C in a round bottom flask.
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Solution of 4-aminobenzonitrile was added dropwise to the stirring solution of 2,4-dichloro-6-methoxy-1,3,5-triazine and NaHCO3.
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(4)
The reaction was stirred for 24 h at rt.
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(5)
Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.
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(6)
Once no starting material appears on TLC, acetone was removed using rotary evaporator.
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(7)
Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.
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(8)
Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain product.
Step 3: Synthesis of 4-substituted-6-methoxy((1,3,5-triazin-2-yl) aminobenzonitrile
Materials required
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K2CO3
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Piperidine
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Morpholine
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Pyrrolidine
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4-Methylpiparizine
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2-Hydroxyethylamine
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N,N’-Diethylaniline
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4-Bromoaniline
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4-Methoxyaniline
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Aniline
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Solvents [acetonitrile, EtOAc, ethanol (EtOH), hexane]
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Crushed ice and distilled H2O
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Rotary evaporator
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Glassware (Round bottom flask, beakers and conical flask)
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Silica-gel coated Aluminum TLC plates
Procedure
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(1)
4-chloro-6-methoxy(1,3,5-triazin-2-yl)amino)benzonitrile (10 mmol) and 4-aminobenzonitrile (10 mmol) were dissolved in acetonitrile (50 mL each) separately in conical flask.
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(2)
K2CO3 (10 mmol) was added to 4-chloro-6-methoxy(1,3,5-triazin-2-yl)amino)benzonitrile solution while stirring vigorously at rt in a round bottom flask.
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(3)
Solution of respective amine (piperidine, morpholine, pyrrolidine, N-methyl piperazine, 1-amino ethanol, N,N’-diethylamine, aniline, 4-bromoaniline and 4-methoxyaniline) dissolved in 10 mL acetonitrile was added to the stirring solution of 4-chloro-6-methoxy(1,3,5-triazin-2-yl)amino)benzonitrile and K2CO3.
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The reaction was refluxed for 18 h in an oil bath.
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Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.
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Once no starting material appears on TLC, acetonitrile was removed using rotary evaporator.
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Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.
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Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain product.
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(9)
The crude was recrystallized from 3:1 EtOAc-EtOH solvent mixture.
Method validation
All the compounds were obtained in high yields and high purity as confirmed by 1H-NMR and 13C-NMR.
Acknowledgments
Acknowledgments
The work was funded in part by the following: the Deanship of Scientific Research at King Saud University Research Group no. RGP-234, Saudi Arabia.; the National Research Foundation (NRF) (Blue Sky's Research Programme # 110960) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Science, Innovation, and Universities (CTQ2015-67870-P) and the Generalitat de Catalunya (2017 SGR 1439; Spain).
Declaration of Competing Interest
The authors declare no conflicts of interest.
Contributor Information
Muhammad Farooq, Email: fmuhammad@ksu.edu.sa.
Zainab Almarhoon, Email: zalmarhoon@ksu.edu.sa.
Mohammad A.M. Wadaan, Email: Wadaan@ksu.edu.sa.
Beatriz G. de la Torre, Email: Garciadelatorreb@ukzn.ac.za.
Fernando Albericio, Email: albericio@ukzn.ac.za.
References
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