Staudinger Reduction

What Is Staudinger Reaction?

In 1919, Staudinger and Meyer found that the reaction of phenyl azides and tertiary phosphine (e.g., triphenylphosphine (Ph₃P)) can produce iminophosphoranes (also called aminophosphine ylide) in quantitative yield, accompanied by the release of nitrogen. Correspondingly, benzoyl azide and triphenylphosphine react to produce benzoylphosphinimine. The generated phosphinimine, as an active intermediate, can react with water, carboxylic acid, acyl chloride, etc. to obtain primary amine, amide, imine halide, and a molecule of phosphine oxide. This strong bonding tendency between phosphine and oxygen can be regarded as the driving force for these reactions to occur.

• Reagents: Trialkylphosphine or triarylphosphine, solvent (tetrahydrofuran or ether), water.
• Reactants: Organic azides.
• Product: Primary amines.
• Reaction type: Formation of N=P bonds.
• Related reactions: Appel reaction, Delbin reaction, Eschweiler-Clarke reaction, Mitsunobu reaction.

Fig 1. Staudinger reduction reaction and its mechanism. [1]

Mechanism of Staudinger Reaction

The experimental data show that no free radical or nitrene intermediate appears during the reaction. The first step of the reaction is that a pair of lone electron pairs on the phosphine attacks the α-position N of the azide to obtain phosphine azide (sometimes it can be isolated). Then the phosphine azide passes through a four-membered ring transition state and releases a molecule of nitrogen to obtain the product iminophosphorane.

Experimental Tips

The Staudinger reaction has the following characteristics:

• The reaction usually proceeds very quickly and the yield is almost quantitative.
• There are few structural restrictions on azides, and trivalent phosphorus compounds with O-alkyl, O-aryl, NH₂, NR₂, Cl, F, NCO or any combination of these ligands will also react.
• The iminophosphorane product obtained by the reaction of alkyl or aryl azide with trialkyl or aryl phosphine is relatively stable and can be separated and purified. However, when there is an alkoxy group on the phosphine, alkyl migration is likely to occur during the reaction.
• Iminophosphanes are versatile synthetic intermediates that can react with: (i) carbonyl or thiocarbonyl compounds to produce imines (aza-Wittig reaction); (ii) carboxylic acids to produce N-substituted amides; (iii) acyl halides to produce imino halides, etc.

Application Examples of Staudinger Reaction

• Example 1: Rakesh Kumar et al. synthesized 2-aminoimidazoles with different substitutions by introducing various substituents on the N1 and 2-amino functional groups via microwave-assisted tandem Staudinger/Aza-Wittig cyclization. The key step was to treat the in situ generated urea intermediate (formed by the reaction of β-aminoazide and isocyanate) with Bu₃P or polymer-supported phosphine reagents, followed by intramolecular microwave-assisted Staudinger/aza-Wittig cyclization. [2]
• Example 2: The synthesis of an antiviral marine natural product (-)-hennoxazole A was completed by Yokokawa and his collaborators. A secondary alkyl azide was subjected to phosphinidimination and subsequent hydrolysis to obtain a primary amine in high yield. [3]

Fig 2. Synthetic examples via Staudinger reduction.

Related Products

CAS No.	Structure	Product
58079-51-9		TRIPHENYLPHOSPHINE
367-21-5		3-Chloro-4-fluoroaniline
63-74-1		4-Aminobenzene-1-sulfonamide
76410-58-7		4-BORONO-L-PHENYLALANINE
150-13-0		4-Aminobenzoic acid
77385-90-1		N,N-Dibenzylglycine ethyl ester
79338-14-0		H-D-Glu-obzl
60-82-2		Phloretin
481-42-5		Plumbagin
37675-18-6		Ethyl(3S)-piperidine-3-carboxylate
3939-01-3		Methyl 1-benzyl-4-oxo-3-piperidine-carboxylate hydrochloride
5006-62-2		Ethyl nipecotate
30727-18-5		Ethyl 1-methylpipecolinate
10-99-9		Tetrahydrofuran

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 576-577.
2. Kumar R, et al. The Journal of Organic Chemistry, 2013, 78(11), 5737-5743.
3. Yokokawa F, et al. Organic Letters, 2000, 2(26), 4169-4172.