Wittig reaction with iminophosphoranes

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. 

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). 

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... 

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. 

The marine alkaloid almazole C 112 was synthesised through an iminophosphorane derivative in an aza-Wittig reaction with an acyl chloride 114 <07SL324>. 

The aza-Wittig reaction of iminophosphoranes 60 with isocyanates affords the carbodiimides 61, which undergo ring closure to give 2-aminopyridine derivatives 62. ... 

Various hetero-, for example (205) 25 and (206), 26 and carbo-(2 07) 25 cycles have been prepared by aza-Wittig reactions of iminophosphoranes with isocyanates and diphenylketene, respectively, followed by cyclization. The reaction of triphenylphosphine with o-azidobenzaldimines (208) followed by hydrolysis has been used to prepare 2,3-diamino-2H-indazole derivatives (209) (Scheme 30). 27... 

Resin-bound iminophosphoranes 103 derived from the reaction of resin-bound 2-aminobenzimidazole 102 with triphenylphosphine oxide were reacted with aryl isocyanates in an abnormal aza-Wittig reaction with a chemoselectivity that depends on the reaction temperature and the nature of the aryl isocyanate (Scheme 22). The mechanism considered for the solid phase synthesis reaction involves the loss of triphenylphosphin-imide instead of triphenylphosphine oxide, resulting in the formation of isocyanates instead of carbodiimides as intermediates. Optimization studies revealed that employing electron-poor aryl isocyanates at high temperature leads to 95% of the abnormal aza-Wittig products 3-aryl 2,4-dioxo-l,3,5,-triazino[l,2-fl]benzimidazoles 104 [76]. 

Carbodimides 92, obtained from aza-Wittig reactions of iminophosphorane and aromatic isocyanates, reacted with primary amines to give isolable intermediate guanidines 93. Cyclization afforded selectively regjoisomer 94 with sodium ethoxide, whereas in its absence another regioisomer 95 was obtained <05CL1022>. 

A series of new l//-pyrazolo[3,4- /]pyrimidin-4(5/f)-ones 84a-l has been regioselectively synthesized in four steps, via a tandem aza-Wittig reaction. The iminophosphorane 81, prepared from 5-aminopyrazole 80, reacted with phenyl isocyanate to give carbodiimide 82, which by reaction with primary or secondary alkylamines, afforded intermediate guanidines 83 that cyclized to the corresponding pyrazolopyrimidinones <04JHC393>. 

One example of a successful application of solid-phase chemistry constitutes the highly versatile synthesis of quinazolinones 300/301 which efficiently combines an aza.-Wittig reaction with a multidirectional cyclisation cleavage. Iminophosphoranes were shown to be useful intermediates in organic synthesis, particularly for the preparation of different heterocyclic systems containing an endocyclic C,N double bond. In these cases, an aza-Mfrig-mediated anellation reaction was involved as the key step. 27-i29... 

Syntheses of 2-anilino-3-arylsulfonylindoles from 2-arylsulfonylmethylanilines have been accomplished by reaction of iminophosphoranes with phenyl isocyanate [1264]. Iminophosphoranes 1714 are obtained in 82-95% yield by treating the azides 1713 with triphenylphosphine. Carbodiimides 1716 are formed in 66-98% yield by the aza-Wittig reaction of iminophosphoranes 1714 and phenyl isocyanate 1715. The ring closure of carbodiimides 1716 under strongly basic conditions to afford 2-anilinoindoles 1717 proceeds in 68-83% yield. 

By aza-Wittig reactions of iminophosphoranes with isocyanates, carbodiimide-mediated syntheses of pyrrole and indole derivatives [1270], pentasubstituted pyridines [1271], pyrimidine derivatives [1272-1274], bis( -ferrocenylvinyl)carbo-diimide [1274], amino-tetrazolyl-deoxythymidines [1275], the marine alkaloid leu-cettamine B [1276], and aza-analogues of aplysinopsins [1277] have also been accomplished. 

A-Vinylic phosphazenes, are useful building blocks, that have been used in Aza-Wittig reactions with unsaturated aldehydes to form 3-azatrienes through a [2 -I- 21-cycloaddition-cycloreversion sequence. " The presence of an alkyl substituent in position 3 of A-vinylic phosphazenes increases the steric interactions, and [4 + 2] periselectivity (1,4 addition) is observed." Other Aza-Wittig reactions include the reaction of iminophosphorane (60) with aromatic isocyanates to obtain, inter alia, useful carbodiimides for the selective synthesis of pyrimidones." Also the iminophosphorane (61) was reacted with furan-2-carbaldehyde, thiophene-2-carbaldehyde, furan-3-carbaldehyde, and thiophene-3-carbaldehyde to give, depending on temperature and aldehyde, trans imines or mixtures of trans and cis imines." " The... 

A synthetic method for 2-alkoxy-3H-quinazolin-4-ones was reported by Ding et al. in 2004 [54], In this study, 12 novel 2-alkoxy-3H-quinazolin-4-ones were synthesized from carbodiimide, which was obtained from aza-Wittig reaction of iminophosphorane with aromatic isocynate (Scheme 13.13). 

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). 

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>. 

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 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-... 

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). 

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). 

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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