Iminophosphoranes, Wittig

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). 

Phenylcyclopent[c]azcpine (33a) and 6,7-fused cyclopentazepines 33b-d are formed in moderate yields in a one-pot, two-stage process involving initial condensation of triphenyl-[(l-phenylvinyl)imino]phosphoranes 32 with 6-(dimethylamino)fulvene-2-carbaldehyde (30), followed by an intramolecular aza-Wittig reaction of the iminophosphorane with the pendant aldehyde function.5 The method fails with the unsubstituted vinylphosphorane 32 (R1 = R2 = H). 

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

A Wittig-type reaction of iminophosphorane 995 with benzoyl and ethoxycarbonyl isocyanates gave (91T6747) thiadiazolotriazines 996, whereas reaction of 995 with aromatic isocyanates afforded 997. On the other hand, iminophosphorane 995 reacted with methyl and benzyl isothiocyanates to give 998. Reaction of 995 with acid chlorides gave 999 (88H1935). All these compounds display mesoionic or zwitter ionic character (Scheme 184). 

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>. 

Within the last decades, the aza-Wittig reaction has assumed increasing importance for the specific construction of many heterocyclic systems. This first comprehensive review provides an overview of the synthetic potential exhibited by an iminophosphorane moiety. 

Although several recent reviews deal with selected aza-Wittig reactions of iminophosphoranes (910PP1 92OPP209,92T1353 94S1197), heretofore no detailed synopsis has appeared on the preparative importance of this synthetic principle for individual heterocycles with different ring size. 

For the reaction of phosphane oxide with isocyanate, the rate-determining step is the formation of the oxazaphosphetane 45 via P—O—bond formation of the intermediate betaine (44), since the stable and energetically favorable P=0 double bond is broken here. Subsequent rapid decomposition of the oxazaphosphetane 45 into iminophosphorane and carbon dioxide occurs. Within the actual aza-Wittig step, the intermediate betaine (46) is generated in a rate-determining step by nucleophilic attack of the iminophosphorane nitrogen on the carbonyl C. By P —O-bond formation, betaine (46) is then converted into an oxazaphosphetane (47), which decomposes... 

The aza-Wittig reaction offers several strategies for the syntheses of heterocyclic compounds, and in Section VI a broad choice of examples is presented. Aza-Wittig reactions can be divided into an intramolecular and an intermolecular variant, the former starting with a molecule 49 (Scheme 26) that contains both an iminophosphorane group and a carbonyl function in a geometrically favorable orientation. 

Conjugated heterocumulenes generated in situ by an aza-Wittig reaction are also capable of electrocyclic-ring closure with a subsequent 1,3-H shift. This principle, applied for the first time by Saito et al. on butadiene iminophosphorane 51 (Scheme 28) by treatment with isocyanate and isothiocya-... 

Since the electrophilic character of carbonyl groups in acid halides is more pronounced than in carboxylic anhydrides, the former are better suited for aza-Wittig reactions. Zbiral et al. studied the reaction of imino-phosphoranes with acid halides and obtained imidoyl halides (69LA29 72PS35). A -alkyl and A -aryl iminophosphoranes can be set to use in this reaction (72PS35). 

The smooth hydrolysis of imidoyl chlorides provides access to carbonam-ides from iminophosphoranes via an aza-Wittig reaction, without the occurrence of free acid or amino functions. This is of special advantage in the synthesis (Scheme 32) of sensitive substrates such as )8-lactam antibiotics (60) (77H719, 79JOC4393). 

The methods described here use oxiranes as reaction partners of imino-phosphoranes. The analogous electrophilicity of the oxiranes and the rather similar mechanism of an aza-Wittig-variant, however, justify their description within this section. Reaction of iminophosphorane 63 with phenoxymethyloxirane 64 (Scheme 36) leads at low temperature to 1,3,2-... 

A recent review on four-membered heterocycles formed from imino-phosphoranes concentrates on the preparation and the reactivity of 2,4-diimino-l,3-diazetidine and related compounds (93JPR305). As an example, the synthesis via bisiminophosphorane 85 is described in Scheme 42. The bisiminophosphorane has both a heteroaryl and a styryl site. From a mechanistic view, the reaction of the bisiminophosphorane proceeds with aryl isocyanate formation via an aza-Wittig mechanism. Intermediate car-bodiimide formation (86) occurs directly on the iminophosphorane moiety... 

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). 

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). 

An intramolecular aza-Wittig reaction of 1,3-diketones (134) and hydra-zinobis(iminophosphoranes) (133) gives pyrazole (135) on elimination of two equivalents of triphenylphosphane oxide, as shown in Scheme 53 (75CB623). 

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... 

With phenyllithium, the iminophosphoranes of benzoic acid hydrazides 157 can be deprotonated, as shown in Scheme 62.0-Acylation of the amide-enolates 158 affords intermediates 159, which are in turn cyclized by an aza-Wittig reaction to 1,3,4-oxadiazoles 160 (68JA5626). 

Under much milder conditions, the same reaction occurs with 1,2,4-triazinone 164, resulting in the formation of a l,3,4-thiadiazolo[2,3-c][l,2,4]triazinium cation 165 (Scheme 64) (88H1935). Another cationic product is obtained upon conversion of dithiocarbazate to carbodiimide, which occurs via iminophosphorane formation and aza-Wittig reaction with... 

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). 

Benzocondensed 3,l-oxazin-4-ones are also accessible via an aza-Wittig reaction (Scheme 86) (93T581). Iminophosphorane 230 affords an imidoyl chloride with aroyl chlorides. The electrophilic C atom is attacked by the ester methoxy group, and the formation of a six-membered ring 231 is thermodynamically favored. Extrusion of methyl chloride gives the stable benzoxazinone 232 (93T581). 

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... 

Kurita et al. reacted a-azidocinnamate 327 with benzoyl chloride (Scheme 119) to form benzoate 328, which upon conversion of the azide group into an iminophosphorane (329) underwent an aza-Wittig cyclization to yield 1,3-benzoxazepine (330) (92CC81). 

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. 

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. 

An alternative approach to N-S bond formation involves the aza-Wittig-type reaction of sulfoxides (Scheme 26) <2004SL101>. Initial Staudinger ligation of aryl azide 195 with triphenylphosphine afforded iminophosphorane 196, which was purified by column chromatography and then heated in anhydrous toluene, producing benzothiazines 62 and 197. The N-S bond was found to be rather sensitive to hydrolysis and cleavage to 198 was observed upon treatment of benzothiazines 62 or 197 with wet THF. 

Only one nonazapteridine (pyrimido[4,5- ]-l,2,4-triazine) derivative has been synthesized by the methods covered in this section. Thus, the reaction of the 5-amino-l,2,4-triazine-6-carboxylate 128a with triphenylphosphine/hexa-chloroethane produced the iminophosphorane 133 which underwent aza-Wittig reaction in hot benzoyl chloride in the presence of catalytic 4-dimethylaminopyridine (DMAP) to give the oxazino[6,5-< ]-l,2,4-triazine 134 as shown in Scheme 22 <2003ARK98>, which, as discussed in Section 10.20.1, constitutes an addition to the 44 ring systems covered by the remit of this chapter that were known at the time of CHEC-II(1996) <1996CHEC-II(7)785>. 

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