Synthesis of iminophosphoranes

The ready synthesis of iminophosphorane 767 from 766 and its subsequent conversion to benzylidene derivative 768 and aza-Wittig reaction... 

Since many functional groups react with phosphorus pentachloride, the synthesis of iminophosphoranes (10) from dihalogenophosphoranes and primary amines (Scheme 6) represents one of the most versatile routes to this class of compounds (59LA142 66MI1). 

The isolation of phosphatriazenes (R—N=N—N=PR3 ), the intermediates in the synthesis of iminophosphoranes, has been reported in several cases... 

The synthesis of larger rings has also been accomplished including the fully unsaturated azolo-fused 1,3-diazepines (222) from bis(iminophosphoranes) (221) and novel cyclic carbodiimides (e.g. 223). Iminophosphoranes are also intermediates in the synthesis of macrolactams (e.g. 225) from the reaction of co-azido acid anhydrides (e.g. 224) with tributylphosphine. The synthesis of iminophosphorane-containing cryptands and a spherand-type structure have been reported. 

Another total synthesis used the rich chemistry of iminophosphoranes (95AHC159). The /3-(3-indolyl)vinyl iminophosphorane 354 underwent an aza-Wittig/electrocyclic ring closure reaction to give the carboline 355 which was hydrolyzed with lithium hydroxide (Scheme 106). A selective reduction, deprotection, decarboxylation and diazotation followed by ring closure gave Fascaplysine (353) (94TL8851). 

A general synthesis of the secondary amines RNHMe and RNHEt has been developed starting from the iminophosphoranes (181). Alkylation with methyl or ethyl iodides (all other halides gave olefins) gave the salts (182) from which secondary amines were obtained on alkaline hydrolysis. 

Reduction of azides is a classical approach to primary amine synthesis. Treatment of 17 with sodium azide in DMF or in THF/H2O mixtures in the presence of phase transfer catalysts effects a quantitative conversion to the corresponding polymeric azide, 27. Recently the reduction of azides to primary amines via hydrolysis of iminophosphoranes produced by interaction of the azide with triethyl phosphite was reported.30 Application of this technique to the azidomethyl polymer, 27, as shown below, failed to produce a soluble polyamine. 

An aza-Wittig reaction-cycloaddition reaction sequence was utilized for the synthesis of pyridotriazines 94. Treatment of iminophosphorane 92 with phenylisocyanate leads to the formation of the corresponding carbodiimide intermediate, which with another molecule of isocyanate affords 94 in [4+2] heterocycloaddition reactions (Equation 13) <1997T16061>. 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

An efficient solid-phase synthesis of [l,2,4]triazolo[l,5-7]indazoles has been described starting from bis(azide) 367. The coupling of this compound with polymer-bound triphenylphosphine gives compound 368. This unprecedented bis(iminophosphorane) reacts with various isothiacyanates to give the corresponding iminophosphoranes 215 (unreported yields) attached to the resin (Scheme 37) <2000SL1411>. 

As early as 1919 Staudinger and Meyer reported for the first time the synthesis of an iminophosphorane (3) from triphenylphosphane (2) and organic azides (1) with simultaneous nitrogen extrusion (Scheme 1) (19HCA635). A modern graphic representation of the first Staudinger iminophosphorane is shown in Fig. 1. A facsimile of the original paper published in Helvetica Chimica Acta is shown in Fig. 2. 

An interesting l,3-oxazol-2-one synthesis of 126 starts from propargyl alcohol 125, CO2, and primary amines with n-butylphosphane as a catalyst (Scheme 50). It is not yet clear if the phosphane reacts by formation of an iminophosphorane followed by an aza-Wittig reaction with CO2 (90TL1721). 

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-... 

The synthesis of 4//-pyrano[2,3-d]pyrimidines, a class of compounds important in crop protection, is presented in Scheme 91. Dichlorotriphenyl-phosphorane affords iminophosphorane 247 with ethyl 2-amino-4//-pyran-3-carboxylate (246). Phenyl isocyanate cyclizes under alkoxide migration to afford pyrano[2,3-d]pyrimidines (248) (90LA995). 

Rossi et al. have used the tandem aza-Wittig principle (88TL3849 89T4263 91T5819, 91TL5379 92JOC6703, 92T4601) in the synthesis of quinazolines (Scheme 98). In the primary step, iminophosphorane 267 is... 

An interesting variation of this quinoxaline synthesis is outlined by the synthesis of sydnoquinoxalines shown in Scheme 103. The starting material is phenylsydnone 288 with an iminophosphorane group in an o-position. With isocyanate or isothiocyanate carbodiimide intermediates 289 are formed by an electrophilic aromatic substitution at the sydnone ring (4 position), the 4-(arylamino)sydno[3,4-a]quinoxalines (290) are obtained (91S745). 

Molina et al. were able to prepare the mesoionic thiadiazole (292) from iminophosphorane 297 and carbon disulfide. As Scheme 106 shows, 298 reacts with a,w-dihalo compounds to form dimer 299 [91JCS(P1)1159]. The synthesis of the mesoionic thiazolo[2,3-6][l,3,4]thiadizole is described in (92T1285). 

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). 

Although this review is by no means exhaustive, it should present an impression of the importance of iminophosphoranes as versatile synthons in heterocyclic synthesis. Much attention was paid to the aza-Wittig reaction, which enables the preparation of a wide range of simple and complex heterocyclic systems. 

A comprehensive overview of the multifaceted use of iminophosphoranes as versatile reagents in heterocyclic synthesis is provided by H. Wamhoff, G. Richardt, and S. Stdiben (Bonn, Germany). 

TABLE 7.33. SYNTHESIS OF UNSATURATED 5(4//)-OXAZOLONES VIA CYCLIZATION OF a,P-UNSATURATED IMINOPHOSPHORANES OR a,p-UNSATURATED ISOCYANIDES... 

Photolysis of tris(dimethylamino)azidophosphonium hexafluorophosphate (14) leads, via release of nitrogen, to the iminophosphenium salt 15 (synthesis of the first stable iminophosphenium salt36) (equation 8)37. The photoreaction of cation 14 shows a high dependence on the anion. The hexafluorophosphate achieves the results shown in equation 8, but the bromide yields the iminophosphorane 16. When the anion is a good... 

The synthesis of iV-substituted-S -trimethylenepyrazoles (45) from iminophosphoranes and 2-azido-l-cyclopentene-l-carboxaldehyde has been described (R = Ph, CH2Ph, CH2C02Et) (88S742). 

Peptides. A new amide or peptide synthesis is based on the formation of iminophosphoranes, R N=PR3, from the reaction of azides with a tertiary phosphine. These phosphoranes react with carboxylic acids to form amides.1 Ethyl diphenylphosphinite is more useful than a triarylphosphine because the by-product is hydrolyzed to diphenylphosphinic acid, which can be readily removed. The iminophosphorane 2, derived from 1 and ethyl azidoacetate, reacts with CboGly-L-Phe-OH to give optically pure 3 in 70% yield.2... 

A convenient synthesis of l//-indolyl-2-benzothiazoles in moderate yield by the direct conversion of indole-2- and 5-carboxylates with in situ generated trimethylaluminum-2-aminothiophenol was described. [95H1045] 2-Substituted 1,3-benzothiazoles having a variety of substituents can be prepared from 2-methylthio-N-triphenylphosphoranylideneaniline and acid chlorides by iminophosphorane-mediated cyclization. [95H455]... 

When jV-protected indole-3-carboxaldehydes were allowed to react with tosylmethyl isocyanide, 3-(oxazol-5-yl)-indoles were obtained in satisfactory yields and applied to the synthesis of novel indole-based IMPDH inhibitors <02BMCL3305>. In the same context, a modified approach to 2-(JV-aryl)oxazoles employing an iminophosphorane/ isothiocyanate-mediated methodology and its application to the synthesis of the potent IMPDH inhibitor BMS-337197, was reported <020L2091>. 

The synthesis of N-substituted-3,4-trimethylenepyrazoles 67 from iminophosphoranes 66 and 2-azidocyclopentene-l-carbaldehyde has been described (Scheme 41) <1988S742>. 

Iminophosphoranes can also be used to synthesize symmetrical carbodiimides. In this case they are reacted with carbon dioxide, thereby mimicking the synthesis of carbodiimides from amines and carbon dioxide. Another useful synthesis of unsymmetrical carbodiimides, not requiring the use of carbonyl chloride, is the reaction of carbonimidoyl dihalides with amines. The synthesis and chemistry of carbonimidoyl halides was reviewed in 1968. ... 

The reaction of a-chloroisocyanates 3 with iminophosphoranes is a mild and efficient method of synthesis of o -halocarbodiimides 4 ... 

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