Protocol for synthesis of di- and tri-substituted s-triazine derivatives.

The present protocol describes the synthesis of di and tri-substituted s-triazine derivatives•s-Triazine undergoes sequential nucleophilic substitution reaction but order of nucleophile is very crucial.•It is very difficult to substitute any nucleophile except amine once amine is incorporated onto s-triazine.•During the synthesis of O,N-type substituted s-triazine, always O-type should be incorporated first.

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

Cyanuric chloride

Potassium carbonate (K2CO3)

4-Aminobenzonitrile

Solvent [acetone, methanol (MeOH) and chloroform]

Crushed ice and distilled H2O

Rotary evaporator

Glassware (Round bottom flask, beakers and conical flask)

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.

Cyanuric chloride (10 mmol) and 4-aminobenzonitrile (10 mmol) were dissolved in acetone (50 mL each) separately in conical flask.

Both solutions were cooled to 0 °C.

K2CO3 (10 mmol) was added to cyanuric chloride solution while stirring vigorously at 0 °C in a round bottom flask.

A cold solution of 4-aminobenzonitrile was added dropwise to the stirring solution of cyanuric chloride and K2CO3.

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).

Monitor the reaction by TLC using 20% MeOH in chloroform as mobile phase in a closed system.

Once no starting material appears on TLC, pour the reaction mixture onto crushed ice (1 L) in a beaker.

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

K2CO3

Piperidine

Morpholine

N,N’-Diethylamine

Solvents [THF, ethyl acetate (EtOAc), hexane]

Ice cold water and crushed ice

Rotary evaporator

Glassware (Round bottom flask, beakers and conical flask)

Silica-gel coated Aluminum TLC plates

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.

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.

Solution of respective amine was added dropwise to the stirring solution of 4,6-dichloro (1,3,5-triazin-2-yl) aminobenzonitrile and K2CO3.

The reaction was stirred for 24 h at rt.

Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.

Once no starting material appears on TLC, THF was removed using rotary evaporator.

Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.

Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain product.

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]

Cyanuric chloride

Sodium bicarbonate (NaHCO3)

Solvents (MeOH, EtOAc, hexane)

Crushed ice and distilled H2O

Rotary evaporator

Glassware (Round bottom flask, beakers and conical flask)

Silica-gel coated Aluminum TLC plates

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.

NaHCO3 (10 mmol) was dissolved in water and cooled to 0 °C.

MeOH (50 mL) is added to the above solution and stirred vigorously at 0 °C.

Cyanuric chloride (10 mmol) was added to the above stirring solution.

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).

Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.

Once no starting material appears on TLC, excess of MeOH was removed under rotary evaporator.

The residue was poured onto crushed ice (1 L) in a beaker.

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

NaHCO3

4-Aminobenzonitrile

Solvents (acetone, EtOAc, hexane)

Crushed ice and distilled H2O

Rotary evaporator

Glassware (Round bottom flask, beakers and conical flask)

Silica-gel coated Aluminum TLC plates

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.

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.

Solution of 4-aminobenzonitrile was added dropwise to the stirring solution of 2,4-dichloro-6-methoxy-1,3,5-triazine and NaHCO3.

The reaction was stirred for 24 h at rt.

Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.

Once no starting material appears on TLC, acetone was removed using rotary evaporator.

Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.

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

K2CO3

Piperidine

Morpholine

Pyrrolidine

4-Methylpiparizine

2-Hydroxyethylamine

N,N’-Diethylaniline

4-Bromoaniline

4-Methoxyaniline

Aniline

Solvents [acetonitrile, EtOAc, ethanol (EtOH), hexane]

Crushed ice and distilled H2O

Rotary evaporator

Glassware (Round bottom flask, beakers and conical flask)

Silica-gel coated Aluminum TLC plates

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.

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.

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.

The reaction was refluxed for 18 h in an oil bath.

Monitor the reaction by TLC using EtOAc-hexane (6:4) in a closed system.

Once no starting material appears on TLC, acetonitrile was removed using rotary evaporator.

Remaining reaction mixture was poured onto crushed ice (1 L) in a beaker.

Filter the solid product with distilled H2O (3 × 500 mL) and dry under high vacuum to obtain product.

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.

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