Neber rearrangement

What is Neber rearrangement?

The Neber rearrangement is a chemical reaction that involves the formation of α-amino ketones. This is achieved through the treatment of sulfonic esters of ketoximes with potassium ethoxide, followed by hydrolysis.

Neber rearrangement
Neber rearrangement

Experimental Procedure

The compound PhCH2C(:NOH)Me, which has a melting point of 68-70 ºC, can be converted into a p-toluenesulfonic ester (I) with a melting point of 78 ºC. When 3 grams of this compound are shaken with 50 cc. of absolute EtOH for 24 hours, filtered, pulverized, and then shaken again with 30 cc. of EtOH for 24 hours, benzylamine p-toluenesulfonate with a melting point of 180 ºC is obtained. If the crude compound I is allowed to stand in an open vessel at room temperature, it becomes liquid in 5 days, and after several days it becomes crystalline, yielding acetylbenzylamine p-toluenesulfonate with a melting point of 81-82 ºC. The free amine with a melting point of 61 ºC can be obtained by treating the sulfonate with NaOH.

Saponification of compound I with EtONa yields 2,5-dimethyl-3,6-diphenyl-1,4-diazine. When 6 grams of I is dissolved in EtOH-EtOK, followed by filtration of the resulting MeC6H4SO3K and acidification of the filtrate with AcOH, the product obtained is α-amino-β-diethoxy-α-phenylpropane acetate (II), which melts at 141 °C. II can form yellow picrate (m.p. 142 °C) or p-toluenesulfonate (m.p. 124 °C). When II is treated with dilute HCl, it forms the HCl salt of PhCH(NH2)COMe, which melts at 208 °C. The benzoyl derivative of this compound has a melting point of 98 °C. A reaction between II and BzCl in C5H3N gives α-benzoylamino-β-diethoxy-α-phenylpropane, which melts at 13 °C. Treatment of this product with HCl results in the formation of its benzoyl derivative, which has a melting point of 98 °C. When II is treated with MeOH, the corresponding di-MeO derivative is obtained, which melts at 111 °C. Finally, α-[o-nitrobenzylmethylkeloxime] p-toluenesulfonate (III) has a melting point of 109 °C.

The reaction of the benzenesulfonate with EtOH yields o-nitrobenzylamine benzenesulfonate with a melting point of 167 ºC. Treatment with EtOH-NH3 leads to the formation of 2,5-dimethyl-3,6-dihydro-3,6-di-[o-nitrophenyl]-1,4-diazine (IV), which is straw-yellow and has a melting point of 186 ºC. IV can also be obtained from III. The di-Bz derivative has a melting point of 158 ºC, and the di-Ac derivative has a melting point of 84-5 ºC. Treatment of IV with EtOK, followed by AcOH, then HCl, leads to the formation of α-amino-β-keto-α-[o-nitrophenyl]propane-HCl with a melting point of 184 ºC. When IV is treated with NH2 in dilute EtOH, it remains unchanged.

References

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