• 10.1021/ol701432k
  • Organic Letters
  • Volume 9
  • August 2007
  • pp 3195-3197

Reproducible, but Yields Lower Than Described

Details


Summary:

An efficient method for the synthesis of diazoacetates from the coresponding bromoacetates and N,N'-ditosylhydrazine has been described. In fact, diazoacetates can be prepared from various alcohols by acylation with bromoacetyl bromide, followed by a treatment with N,N'-ditosylhydrazine without isolation of bromoacetate intermediates. Ease of operation with the stable crystalline reagent as well as a short reaction time offer a useful alternative to the conventional methods.

The Reaction of Interest:

I was using the described protocol for the synthesis of several diazocompounds. Thus, cyclohexyl diazoacetate (55-72% yield), cyclopentyl diazoacetate (60%), benzyl diazoacetate (74%), phenyl diazoacetate (58%), and diazoacetophenone (63%) were prepared via this method.

Practical Observations:

- The reaction is well-reproducible, although, yields are slightly lower then described (i.e. 58% vs 74% for phenyl diazoacetate and 74% vs 90% for benzyl diazoacetate).

- According to the protocol, 2 equiv of N,N'-ditosylhydrazine and 5 equiv of DBU are required for the reaction, which produces a lot of TsOH by-product. 

- The reaction is scalable up to 30 mmol.

Recommendations:

- Lower reagents loading can be used. Thus, the use of 1.5 equiv of N,N'-ditosylhydrazine and 3 equiv. did not decrease the yield of products. The amount of solvents also can be reduced.

- The use of inert atmosphere is generally gives slightly better yield of products.

- A significant amount of TsOH precipitate is formed upon quenching of the reaction mixture, which troubles further extraction of product. The precipitate can be removed by filtration before exctraction of a diazocompound. 

- This exact protocol is not applicable for the synthesis of diazoacetamides. However, the similar method (TMG was used instead of DBU) can be used for the synthesis of diazoacetamides, see: http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-157

 



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