An Improved Synthesis of N-Isocyanoiminotriphenylphosphorane and Its Use in the Preparation of Diazoketones

Abstract

An improved synthesis of N-isocyanoiminotriphenylphosphorane is reported. This reagent is a safe, stable, solid alternative to diazomethane and TMS-diazomethane in the Arndt-Eistert synthesis of diazoketones.

diazoketone - diazomethane - isonitrile - iminophosphorane

References

1 Arndt F. Eistert B. Chem. Ber.  1935,  68:  200 

2a Aoyama T. Shioiro T. Tetrahedron Lett.  1980,  21:  4461 

2b Aoyama T. Shioiro T. Chem. Pharm. Bull.  1981,  29:  3249 

3 Proctor LD. Warr AJ. Org. Process Res. Dev.  2002,  6:  884 ; and references therein

4 Aller E. Molina P. Lorenzo Á. Synlett  2000,  526 

5

It should be noted that diazoketones themselves are often unstable compounds, thus great care should be taken whenever diazoketones or diazoalkanes are being formed.

6

A further advantage of Aller’s procedure is that the isolation of pure diazoketones from reaction is often simpler than from reactions using TMSCHN₂ or CH₂N₂. Diazoketones formed from both diazo reagents invariably are contaminated with α-chloroketones and, in the case of TMSCHN₂, the α-TMS ketone, both of which are difficult to remove because they usually impart a polarity similar to that of the diazoketone functionality. Using 1 to form diazoketones gives none of these difficult to remove impurities. In our experience in using 1, the overall yield of diazoketone from acid is consistently higher than when TMSCHN₂ or CH₂N₂ is used.

7a Aller and co-workers reference the following paper for the synthesis of 1: Weinberger B. Fehlhammer WP. Chem. Ber.  1985,  118:  42 

7b

To the best of our knowledge no other syntheses of 1 have been reported.

8 Appel has studied the reaction of tertiary phosphoranes and CCl₄ in detail and notes the acceleration of the reaction in MeCN specifically: Appel R. Angew. Chem., Int. Ed. Engl.  1975,  14:  801 

9

Compound 1 showed no degradation by HPLC analysis after more than 3 d in MeCN-H₂O (1:1) or in MeCN-0.01% K₂HPO₃ (1:1) aqueous solution.

10

The addition of more water anti-solvent led to high isolated yield but lower quality material.

11

The synthesis of 6 will be published at a later date.

12

A cursory cost calculation based on quotes obtained for bulk quantities of formic hydrazide, PPh₃, CCl₄ and DBU give a raw material cost of $0.54/gram N-isocyanotriphenyl-iminophosphorane.

13 For a review see: Ye T. McKervey A. Chem. Rev.  1994,  94:  1091 

14 Aside from the papers mentioned in ref., we have found only a single additional mention of this compound in the literature: Zinner G. Beck G. Fehlhammer WP. Wilberg N. J. Organomet. Chem.  1989,  368:  23 

15

Adding seed to the reaction is necessary only if no crystalline material has precipitated upon cooling to 35 °C. The initial seed may be obtained by removing a few millilitres of the reaction solution and cooling it to r.t.

16

After 40 min the reaction was complete by HPLC assay; a reaction sample quenched into MeOH show ca 99% conversion to the methyl ester.

17

Concentration and flush with fresh DCE removes excess oxalyl chloride.