Iminophosphoranes, Staudinger 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). 

Wilson and Pasternak reported the first asymmetric Staudinger reaction (Scheme 4) where the chiral phosphane (7) reacts with the racemic azide (8) to afford diastereomeric iminophosphoranes in different quantities, giving after hydrolysis an amine in slight enatiomeric excess. Separation of the racemate seems to be kinetically controlled, but needs optimization (90MI1). 

The Kirsanov reaction (Scheme 5) is a valuable supplement to the Staudinger reaction starting from phosphorus pentachloride and amine or amide derivatives it opens an access to P-halogenated iminophosphorane 9 (50IZV426). 

The simplest available derivatives of pyrrole in this sense are pyrrolines (97) which are accessible by simple intramolecular aza-Wittig reaction of iminophosphorane 96, the latter being formed by a Staudinger reaction from -y-azidoketones (95), as shown in Scheme 44. The process occurs under neutral conditions, so that once the double bond is formed, it cannot isomerize (86TL1031 87NKK1250). 

Imidazoles are synthesized from A-(2-azidoethyl)phthalimide (136) via the Staudinger reaction to obtain an initial intermediate iminophosphorane 137, which is then converted by an intramolecular aza-Wittig reaction and... 

The iminophosphorane 177 available from methyl azido(phenylhydrazo-no)acetate by a Staudinger reaction represents an ideal starting material for the synthesis of l//-l,2,4-triazoles (180). Two synthetic routes are possible (Scheme 68). The first is the reaction of iminophosphoranes with halides via isolable A-acylphosphonium salts (178), and imidoyl chlorides (179), leading to triazoles. The other approach involves the less reactive anhy-... 

Another approach to the syntheses of quinazolines involves 3-(o-azido-phenyl)isoxazoles (210) which are accessible from a-chloro-Z-azido benzal-doximes (209) and /3-keto esters (R = Ph, = OEt). As shown in Scheme 78, the iminophosphorane resulting from the Staudinger reaction is transformed without isolation by an aza-Wittig reaction into 3,4-disubstituted isoxazolo[4,3-c]quinolines (211) (92MI1). 

P, N-Organosubstituted iminophosphoranes are important synthetic reagents in organic chemistry. A good method for their synthesis is the reaction of tertiary phosphines with organic azides (known as Staudinger reaction, equation 1). The reaction is much used for the formation of P=N bonds. " ... 

In the first step, the triphenylphosphine reacts with an alkyl azide to form an iminophosphorane with loss of nitrogen Staudinger reaction). In the second step, the nucleophilic nitrogen of the iminophosphorane attacks the carbonyl group to form a four-membered intermediate (oxazaphosphetane) from which the product Schiff base and the byproduct triphenylphosphine oxide are released. 

The absolute configuration of the structurally unique fungal metabolite mycosporins was determined in the laboratory of J.D. White by means of enantioselective total synthesis." In the endgame of the synthetic effort, the Staudinger reaction was used to elaborate the side chain. The cyclic vinyl azide was first converted to a stable vinyl iminophosphorane, which was subsequently reacted with benzyl glyoxylate to afford the corresponding Schiff base. Reduction of the imine was achieved with sodium cyanoborohydride. 

The Staudinger reaction of azides with tertiary phosphines is one of the two major routes in the preparation of iminophosphoranes [30]. This reaction proceeds... 

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. 

In the literature, the term Staudinger reaction is actually associated with any process that involves the conversion of an azide to the iminophosphorane as its initial step. Hydrolysis is the typical fate of this intermediate, but iminophosphoranes (sometimes called phosphazenes) can also undergo a host of synthetically useful tandem reactions, most notably aza-Wittig-type reactions with carbonyl containing compounds.1-4,6-10... 

If the Staudinger reaction of an alkyl azide containing a pendant carbonyl group is heated under anhydrous conditions, the iminophosphorane can nucleophilically attack the carbonyl leading to cyclic imines (via the aza-Wittig mechanism) and liberate phosphine oxide as shown below. The reaction also works intermolecularly. 

Carbamates are one of the most widely used protecting groups for amines and the development of one-pot conversions of azides to carbamates such as Boc, Cbz, and allyl further expanded the scope of utility of the Staudinger reduction. Treatment of the Staudinger reaction iminophosphorane intermediate 26 with 1.05 equivalents of 2-t-(butoxycarbonyloximino)-2-phenylacetonitrile (Boc-on) led to Boc-protected amines 28 thru 32 in 87-100% overall yield.19 This process utilizes trimethylphosphine, which is more reactive than triphenylphosphine and provides an easier work-up because trimethylphosphine oxide is water soluble. It should be noted that the use of di-f-butyldicarbonate (B0C2O) has been investigated but leads to lower yields in comparison.20... 

Under strictly anhydrous conditions, the iminophosphorane intermediate that is formed as a result of the Staudinger reaction can react with aldehydes and ketones in an intermolecular fashion (as in the synthesis of imine 36 described above) or intramolecularly with a variety of carbonyl containing functional groups to afford a host of products. Nitrogen containing ring systems such as cyclic imines (44) represent just one of the many products one can prepare and the reaction is particularly well suited for the facile synthesis of five, six, and seven-membered rings. In addition to aldehydes and ketones, carboxylic acids, esters, thio-esters, and amides can also react in an intramolecular fashion to trap an iminophosphorane to afford a variety of heterocycles. Examples from the current literature are described in Section 2.5.5. 

The Staudinger reaction is operationally simple and is run under mild conditions. Solvents of choice are usually toluene or THF. The formation of the iminophosphorane, 1, is typically rapid, quantitative, and can be followed by thin layer chromatography. Scanning the literature, it is clear that a number of different phosphines can be employed, but triphenylphosphine, tributylphosphine, and trimethylphosphine are the most common. Reaction times, reaction temperature, and stoichiometry vary and seem to be depended upon the steric and electronic environment of the particular azide. 

Pentenenitriles and benzo[f]indoles. Ally iminophosphoranes are formed from the corresponding azides upon treatment with PPh j (Staudinger reaction). Condensation of these products with diaryl ketenes leads to 4-pentenenitriles by a sig-matropic rearrangement. In the homoallyl series the Wittig reaction is followed by an intramolecular Diels-Alder reaction. Mild dehydrogenation of the products gives ben zo[/] indoles. ... 

Recent advances in the formation of iminophosphoranes by the Staudinger reaction and their reactions have been reviewed 90 and there have been a large number of reports, some of which are minor extensions of... 

A study of the Staudinger reaction between triphenylphosphine and o-substituted aryl azides has shown that the nature of the products depends very strongly on the o-substituent. Thus, e.g., whereas with o-azidoacetophenone, the related iminophosphorane (140) is formed, the corresponding reaction of the azide (141) results in the formation of the heterocyclic system... 

T(50)3529]. An analogous procedure based on a tandem Staudinger reaction - ring closure sequence provides indazole N-iminophosphoranes (39) which react with isocyanates to afford pyrazolo[l,2-6]indoles (40) [93T(49)7599]. 

---