Solid Wittig synthesis

Vinylpolystyrene, a useful intermediate for the preparation of various functionalized supports for solid-phase synthesis [7,57-59], has been prepared by the polymerization of divinylbenzene [7], by Wittig reaction of a Merrifield resin derived phosphonium salt with formaldehyde [59-62], or, most conveniently, by treatment of Merrifield resin with trimethylsulfonium iodide and a base [63] (Figure 5.7). 

One problem that may be encountered with this type of reaction is related to the fact that in solid-phase synthesis reagents generally have to be used in excess. This can occasionally lead to side reactions, ff, for instance, a resin-bound aldehyde is condensed under basic conditions with excess ketone, the resulting enone might undergo Michael addition with an additional equivalent of ketone (Figure 5.10). For some of these enones, the Wittig reaction may represent a superior synthetic method [75]. 

Hoesl CE, Nefzi A, Houghten RA, Parallel solid-phase synthesis of 2-Imino-4-oxo-l,3,5-triazino[l,2-a]benzimidazoles via tandem Aza-Wittig/heterocumulene-mediated annulation reaction, J. Comb. Chem., 5 155-160, 2003. 

Polymer-supported Wittig reagents have recently been developed as an extension to the traditional reagents.29 For example, polystyryldiphenylphosphine has been developed in an attempt to replace the use of triphenylphosphine in the preparation of phosphoranes (see Protocol 1). The hope is that these polymer-bound regents will overcome the practical problem of removing the triphenylphosphine oxide by-product formed in Wittig reactions. Polymer supported phosphonates and Wittig substrates have also been prepared for use in solid phase synthesis and combinatorial chemistry.30... 

Solid-phase synthesis. Two groups have reported solid-phase Wittig... 

The solid phase synthesis of trisubstituted guanidines was achieved in the research group of D.H. Drewery by utilizing the aza-Wittig reaction. The reaction of solid-supported alkyl iminophosphorane and aryl or alkyl Isothiocyanates afforded carbodiimides, which upon treatment with primary or secondary amines provided the trisubstituted guanidines. ... 

Solid-phase Wittig synthesis. Two groups3 4 have reported solid-phase Wittig synthesis. The resin is built up from styrene and the phosphine (1) with a small amount of 1,4-divinylbenzene for cross-linking. Alkylation and treatment with base gives a... 

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]. 

Highly functionalized l,4-benzazepin-5-one derivatives can be made by solid-phase synthesis incorporating aza-Wittig reactions <05MI2680 >. 

Alkenes can be considered as a class of protected carbonyl compounds since they can be converted into carbonyls by ozonolysis. Hall [69] demonstrated a practical strategy for solid phase synthesis of peptide aldehydes using an olefinic linker, which was constructed using Wittig chemistry. After normal peptide synthesis using the alkene linker, ozonolysis of the linker and subsequent workup with... 

Le Bigot, Y. Delmas, M. Gaset, A. A simplified Wittig synthesis using solid/liquid transfer processes. Synth. Commun. 1982, 12, 107-112. 

Keywords Aza-Wittig reaction Quinazolinone annelation Quinazoline alkaloids -Microwave-assisted synthesis Solid-phase synthesis... 

The topical synthetic methodologies such as iminophosphorane mediated synthesis (aza-Wittig methodology), microwave-assisted synthesis, solid-phase synthesis, and application of organometalUc reagents, etc., will be discussed retrospectively focusing on the pathways to quinazoline, quinazoline-4-one and their derivatives. 

The formation of flve-membered cyclic imines through a Staudinger/intramolecular aza-Wittig reaction can also be performed by solid-phase synthesis and has been applied for the first synthesis of lanopylin Bi (108). The total synthesis, which takes only four steps, starts with a phase-transfer alkylation of diethyl 2-oxopropylphosphonate 105 with a 2-iodoethyl azide, affording the azido phosphonate 106, which undergoes a phase-transfer Homer-Emmons Wittig reaction with heptadecanal to provide the azido enone 107. An intramolecular aza-Wittig reaction of the enone 107 with polymer-supported triphenylphosphine in toluene completed the first total synthesis of lanopylin Bi (108) in 76% yield (Scheme 15.22). 

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