Cyclization Wittig reactions

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

A new approach to indoloquinohne alkaloids from Cryptolepis sanguino-lenta has been reported based on the cyclization of an o-substituted vinyl isocyanate 244 imder microwave irradiation and further additional cyclization based on an Aza-Wittig reaction carried out in the presence of microwaves [159]. The apphcation of this synthetic scheme to the synthesis of Cryptotackienine 247 is reported in Scheme 91. 

A simple cyclization was carried out to test the ability of chloro azidoalkene cyclization to generate quinolizidines. Reduction of 6-valerolactone to the corresponding lactol was followed by a Wittig reaction onto the carbonyl function employing an appropriate phosphonium salt, and the intermediate primary alcohol thus formed afforded the chloro... 

Aminoethylidenehydrazones 161 react with triphenyl phosphine to give the azinoiminophosphorane intermediates 162 which cyclize via an aza-Wittig reaction with benzaldehydes to give the corresponding 1,2,4-triazoles 163a-j (Scheme 14 and Table 32) <2002JHC845>. 

Subsequent monosilylation and Wittig reaction furnished unsymmetrical double diene 170. The synthesis of the other Diels-Alder partner started from bromophenol 173 (prepared in three steps from dimethoxytoluene), which was doubly metalated and reacted with (S,S)-menthylp-toluenesulfinate 173. CAN oxidation delivered quinone 171, which underwent a Diels-Alder reaction with double diene 170 to give compound 175 possessing the correct regio- and stereochemistry. Upon heating in toluene the desired elimination occurred followed by IMDA reaction to adduct 176, which was obtained in an excellent yield and enantioselectivity. Both Diels-Alder reactions proceeded through an endo transition state the enantioselectivity of the first cyclization is due to the chiral auxiliary, which favors an endo approach of 170 to the sterically less congested face (top face) (Scheme 27). 

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). 

Access to pyridines from aza-l,3,5-triene units, achieved by an intramolecular aza-Wittig reaction and thermal electrocyclic cyclization with a subsequent 1,3-H shift, was mentioned in Section V,B (cf. Scheme 28) as an... 

Quinazolines have become increasingly important as biologically active principles, e.g., as antiseptics or antimalarials. An interesting approach to this class consists of a combination of the aza-Wittig reaction with photochemical processes, as shown in Scheme 76. o-Azidocinnamates (206) are cyclized with the aid of triethyl phosphite to afford 2-alkoxyquinolines... 

Finally, the synthesis of 4//-3,l-benzoxazines 239 via a tandem aza-Wittig reaction (Scheme 89) should be mentioned. Carbodiimide 238 or isocyanate generated by an intramolecular aza-Wittig reaction bears an o-hydroxymethyl group on the A(-aryl substituent this OH attacks the carbodiimide C intramolecularly with cyclization to give a 3,1-benzoxazine (91S21). 

The pharmacologically important tryptanthrine, a quinazoline alkaloid, is known for its antimycotic activity and is used against skin infections. This alkaloid is obtained from isatin (260) and o-azidobenzoyl chloride (261), as shown in Scheme 96. The adduct formed is cyclized via a Staudinger and an aza-Wittig reaction to afford tryptanthrine (262) (92H153). 

Diazepines represent an important class of bicyclic seven-membered heterocycles. They are the basis of several tranquilizers and are accessible from a-amino acid esters and o-azidobenzoyl chloride in the presence of triethylamine. The A/ -(o-azidobenzoyl)amino esters (333) formed in this way (Scheme 121) are cyclized by Staudinger and aza-Wittig reactions to give 2-ethoxy-l,4-benzodiazepin-5-ones (334) (92MI2). 

After epoxidation of the terminal olefin in syn-89 the pyrrolidine 91 was formed by reductive cleavage of the Cbz-protection and concomitant Sn2 cyclization of the free amine to epoxide 90. In five additional steps (+)-preus-sin (2) was synthesized with an overall yield of 19%. After AT-methoxycar-bonylation and oxidation of the alcohol to an aldehyde the alkyl side chain was introduced by a Wittig reaction. 

Benzofuran-2-carbaldehydes readily undergo Wittig reactions in tetra-hydrofuran at room temperature with the resonance-stabilized ylide 2-car-boxy-l-methoxycarbonylethyltriphenylphosphorane, affording high yields of ( )-4-(2-benzofuranyl)-3-methoxycarbonylbut-3-enoic acids. This method is preferable to the Stobbe condensation. The Stobbe-type intermediates undergo quantitative cyclization to methyl l-acetoxydibenzofuran-3-carboxylates on exposure to acetic anhydride at 100 C. Examples are shown in Scheme 27. The intermediate 109 has been used in a synthesis of cannabifuran (110), and the intermediate 111 has been used in a synthesis of the lichen metabolite schizopeltic acid (112). ... 

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