Staudinger- Meyer reaction

Early in the last century, the Nobel Prize winning chemist Hermann Staudinger discovered a reaction between phosphines and azides, which became known as the Staudinger reaction (Staudinger and Meyer, 1919). Triphenylphosphine reacts with azides to form an intermediate iminophosphorane with the release of nitrogen gas. This intermediate quickly breaks down in aqueous environments to yield triphenylphosphine oxide and a primary amine (Figure 17.17). 

This last section underlines once again the great synthetic potential of the iminophosphorane group, as predicted by Staudinger and Meyer after their first successful synthesis of the P = N double bond. Recently, iminophosphoranes have proved to be novel and versatile heteroannulation components in their reaction with two other components heterocumulenes and heteroarenes (C=X double bonds). 

Several condensed systems, especially those combined with pyridine rings, show biological activity, e.g., in the field of crop protection and as anti-virus and anti-cancer compounds. Aza-Wittig reactions in particular should make several novel heterocyclic rings available. The aza-Wittig reaction of iminophosphoranes has to be considered as a major principle in modern synthetic chemistry, as was wisely foreseen by Staudinger and Meyer as early as 1919. 

Another method for the preparation of the 1,2,4,5-tetrazine system from a diazo compound was reported by Staudinger and Meyer (19HCA619). They reacted diaryldiazomethanes (321) with triethylphosphine and isolated the phosphazines (322). In moist benzene or chloroform these compounds were transformed into 3,3,6,6-tetraaryl-l,2,3,6-tetrahydro-1,2,4,5-tetrazines (323). This result was only obtained when triethylphosphine was used. The intermediate formation of hydrazones seems unlikely, since these compounds are stable and do not dimerize. A reaction which has a certain similarity to the above was reported by Merrill and Shechter (75TL4527). They obtained 3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine (80) when the phosphazine (324) was hydrolyzed. 

In the first report on this famous reaction, Wittig expressed a clear preference for the cyclic phosphorane intermediate 22 such as had already been formulated by Staudinger and Meyer in their earlier work. This view became generally accepted onlv many years later35). In this respect, the Wittig reaction did indeed still reflect some prominent features of the underlying research program on penta-coordinated molecules, from which it now evolved rapidly to a very active life of its own 36). 

It is rather curious that P-coupling of diazoalkanes had been found at a very early date. Staudinger and Meyer (1919) discovered that such reactions take place with trialkyl- and triarylphosphines. As shown later by Wittig and Haag (1955), even diazomethane reacts with phosphines. These couplings proceed so readily, because the P-azo product (6.8) is stabilized by acceptance of Tc-electrons into the empty d orbital of the P-atom. ... 

The formation of phosphazenes was discovered by Staudinger and Meyer in 1919 [64,65]. These authors found that when an azide was treated with aphosphine, an iminophosphorane (phosphazene) was formed. Reaction of this reactive species with carbonyl compounds resulted in the formation of the corresponding imines. The aza-Wittig reaction has been used for the synthesis of different types of azadienes [66-69] and valuable compounds [70], including natural products such as (+)-hamacanthin B [71] and mycosporine [72]. 

Meyers and co-workers have continued their studies to exploit the synthetic potential of a-lithio-formamidines and have now described an efficient synthesis of 2-aryl- or 2-heteroaryl-pyrrolidines and -piperidines (266 ). " Alkylation of formamidines (264) gives intermediates (265) which cyclize in situ after cleavage of the amidine unit. The aza-Wittig reaction has been utilized in a general synthesis of heterocyclic vinylogous ure-thanes and amides (268). Staudinger reaction of azides (267)... 

Across other double bonds The reaction of phenyl thiocyanate with P N compounds was first investigated by Staudinger and Meyer in 1919 . The reaction proceeds across the C=S bond of the isothiocyanate to give fragmentation products. For example, from ethyliminotriphenylphosphorane 67 and ethyl isothiocyanate a good yield of diethylcar-bodiimide and triphenylphosphine sulfide is obtained. The reaction most likely proceeds via the four-membered ring intermediate 68 formed in a [2+2] cycloaddition reaction. 

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