Phosphines, Staudinger reduction

Reduction of amides is an important preparative method for the synthesis of primary amines. Reducing agents used for this purpose include lithium aluminum hydride, sodium borohydride, triphenyl-phosphine (Staudinger reduction), and thiols. In the present case it is important to consider the compatibility of the reduction system with the carboxylic and methanesulfonic acid functions. Platinum and palladium arc often used for catalytic reduction. 

In the first step a Staudinger reduction of the azide to the amine takes place, wherein triphenylphosphine reacts with the azide and forms a phosphazide, which then loses N2 and forms the iminophosphorane. Aqueous workup then generates the amine with phosphine oxide as a side product. The amine formed then undergoes macrolactonization to 63 with loss of acetone. 

Azides react with tertiary phosphines under mild conditions to form iminophosphoranes (1), which are versatile synthetic intermediates that have found a number of applications.1- 0 Upon treatment with water, an iminophosphorane will hydrolyze to form a primary amine and phosphine oxide in what is referred to as the Staudinger reaction or Staudinger reduction. 

Figure 17.17 The Staudinger reaction involves the reduction of an azide to a primary amine with loss of N2 and the concomitant oxidation of a phosphine derivative to a phosphine oxide.

There now are available a number of alkyl azide compounds that may be used in click chemistry reactions and the Staudinger ligation processes. It is not recommended, however, to use aryl azide compounds, as these are light sensitive and photoreactive as well as highly susceptible to reduction in the presence of thiols. Unfortunately, at the time of this writing there are fewer choices in aryl phosphine compounds to participate in this reaction, as commercial sources of labeling reagents are limited. 

Treatment of enecarbamate 344 with sodium azide and ceric ammonium nitrate (CAN) in acetone furnished azidocarbazole 345. The low yield in this oxidative cychzation reaction is due to formation of the diastereomer consisting of stereochemical inversion at the azide-substituted carbon. At this point, azide reduction employing the Staudinger conditions of triphenyl-phosphine in a mixture of water and THF led to an amine, which was subjected to trichloroacetyl chloride in a solution of dichloromethane and triethylamine to yield amide 346 (Scheme 49). 

The synthesis of phosphorous-functionalized click ligands also requires special conditions. Phosphine building blocks need be protected as either the corresponding borane complex (l-2a and 4-5a) or oxide (l-2b and 4—5b) in order to prevent an undesirable Staudinger reaction with the azide synthons (Scheme 1). A range of bi-and tridentate P,N click ligands have been synthesized, and the free clickphines (3 and 6) are liberated by a final deprotection of the phosphine group with either DABCO in the case of the borane complexes [86-90] or reduction with tri-chlorosilane [88-92] in the case of the phosphine oxides. 

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