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Method for realizing selective N-methylation of primary amine

A methylated primary amine, selective technology, applied in the field of selective N-methylated primary amine, to achieve broad development prospects and industrial value, high economic efficiency, wide substrate versatility

Inactive Publication Date: 2013-06-26
NANJING UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it is still a challenging problem to use methanol as a versatile and efficient methylation reagent to achieve selective N-methylation of primary amines.

Method used

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  • Method for realizing selective N-methylation of primary amine
  • Method for realizing selective N-methylation of primary amine
  • Method for realizing selective N-methylation of primary amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 4-Chloro-N-methylaniline

[0028] 4-chloro-N-methylbenzonamine

[0029]

[0030] 4-Chloroaniline (255 mg, 2 mmol), [Cp*IrCl 2 ] 2 (1.6 mg, 0.002 mmol, 0.1 mol%), sodium hydroxide (80 mg, 2 mmol) and methanol (1 ml, 790 mg, 24.7 mmol, 12.4 equiv.) were sequentially added to a 20 ml Schlenk reaction flask. The reaction mixture was at 150 o After 12 h at C, cool to room temperature. The solvent was removed by rotary evaporation, and then the pure target compound was obtained by column chromatography (developing solvent: ethyl acetate / petroleum ether), yield: 96%. The H NMR and C NMR spectra of the product are as follows: figure 1 with figure 2 as shown,

[0031] 1 H NMR (500 MHz, CDCl 3 ) δ 7.11 (d, J = 8.8 Hz, 2H, ArH), 6.51 (d, J = 8.8 Hz, 2H, ArH), 3.69 (br s, 1H, NH), 2.79 (s, 3H, CH 3 ); 13 C NMR (125 MHz, CDCl 3 ) δ 147.8, 128.8, 121.5, 113.3, 30.6.

Embodiment 2

[0033] 3-Chloro-N-methylaniline

[0034] 3-chloro-N-methylbenzonamine

[0035]

[0036] 3-Chloroaniline (255 mg, 2 mmol), [Cp*IrCl 2 ] 2 (1.6 mg, 0.002 mmol, 0.1 mol%), sodium hydroxide (80 mg, 2 mmol) and methanol (1 ml, 790 mg, 24.7 mmol, 12.4 equiv.) were sequentially added to a 20 ml Schlenk reaction flask. The reaction mixture was at 150 o After 12 h at C, cool to room temperature. The solvent was removed by rotary evaporation, and then the pure target compound was obtained by column chromatography (developing solvent: ethyl acetate / petroleum ether). Yield: 90%.

[0037] 1 H NMR (500 MHz, CDCl 3 ) δ 7.06 (t,J = 8.1 Hz, 1H, ArH), 6.65 (d, J = 7.9 Hz, 1H, ArH), 6.55 (s, 1H, ArH), 6.45 (dd, J = 8.3 Hz and 2.3Hz, 1H, ArH), 3.76 (br s, 1H, NH), 2.79 (s, 3H, CH 3 ); 13 C NMR (125 MHz, CDCl 3 ) δ 150.3, 134.9, 130.0, 116.8, 111.8, 110.7, 30.4.

Embodiment 3

[0039] 4-Bromo-N-methylaniline

[0040] 4-bromo-N-methylbenzonamine

[0041]

[0042] 4-Bromoaniline (344 mg, 2 mmol), [Cp*IrCl 2 ] 2 (1.6 mg, 0.002 mmol, 0.1 mol%), sodium hydroxide (80 mg, 2 mmol) and methanol (1 ml, 790 mg, 24.7 mmol, 12.4 equiv.) were sequentially added to a 20 ml Schlenk reaction flask. The reaction mixture was at 150 o After 12 h at C, cool to room temperature. The solvent was removed by rotary evaporation, and then the pure target compound was obtained by column chromatography (developing solvent: ethyl acetate / petroleum ether), yield: 88%

[0043] 1 H NMR (500 MHz, CDCl 3 ) δ 7.24 (d, J = 8.9 Hz, 2H, ArH), 6.46 (d, J = 8.9 Hz, 2H, ArH), 3.70 (br s, 1H, NH), 2.79 (s, 3H, CH 3 ); 13 C NMR (125 MHz, CDCl 3 ) δ 148.1, 131.7, 113.8, 108.5, 30.5.

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Abstract

The invention relates to a method for realizing selective N-methylation of primary amine, which comprises the following steps: in a nitrogen gas protective atmosphere or in the air, adding a primary amine derivative, a metal iridium or ruthenium complex, methanol and alkali into a reaction vessel; reacting the reaction mixture at 100-150 DEG C for several hours, and then cooling to room temperature; and performing rotary evaporation to remove the solvent, and then performing column separation to obtain a target compound. Compared with the prior art, the reaction shows the following remarkable advantages: 1) the methanol is used as an alkylation agent, thereby avoiding the use of virulent haloalkane and dimethyl sulfate; 2) the reaction only generates water as the byproduct, thereby causing no environmental hazard; 3) the reaction is high in atom economy; 4) the reaction shows absolute selectivity, and the reaction only generates mono-methyl products and generates no bis-methyl products; and 5) the reaction shows wide substrate universality and is effective for various primary amine derivatives.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis chemistry, and in particular relates to a method for selectively N-methylating primary amines. Background technique [0002] N-methylated primary amines are an important class of organic synthesis reactions, widely used to synthesize natural products, fine chemicals, pharmaceuticals and key intermediates. ((a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry , 4th ed.; Kluwer Academic: New York, 2001; Part B, Chapter 3.2.5. (b) Aurelio, L.; Brownlee, R. T. C.; Hughes A. B. Chem. Rev. 2004, 104 , 5823-5846). The traditional method of N-methylating primary amine is to use highly toxic and dangerous methyl halide and dimethyl sulfate as methylating reagents, and complete it with the participation of alkali. This reaction is also difficult to control because the monomethylated product produced by the reaction is more nucleophilic than the primary amine, so it is easy to react to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/52C07C209/18C07C217/84C07C213/08C07C317/36C07C315/04C07C211/48C07C211/58C07C311/29C07C311/16C07C303/40C07D213/74C07D241/20C07D277/42C07D277/82C07D263/58C07D235/30
Inventor 李峰单海霞孙春楼
Owner NANJING UNIV OF SCI & TECH
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