Furan electrophilic substitution reactions involving

Electrophilic substitution reactions of furans take place predominately at the C2 (C5) position. In many cases reaction at the C3 position is only favored when the C2 and C5 positions are already occupied or severe sterics are involved. 

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

Furfuryl alcohol in an acid medium gives rise to reactions of polycondensation reactions of successive electrophilic substitutions involving furan molecules. This reaction is identical to the reaction described for benzyl alcohol on p.256 and represents the same dangers. It is carried out under the same conditions, ie in a sulphuric medium. The electrophilic species that comes into play is very similar to the benzyl cation. 

The most important reactions involve electrophilic attack on ring carbon atoms, a wide variety of which are known for pyrroles, -furans and thiophenes. Most frequently, such electrophilic attack is followed by proton loss, resulting in overall substitution. 

The relative reactivities of all four unsubstituted rings have been subsequently determined in another electrophilic substitution trifluoroacetylation by trifluoroacetic anhydride in dichloroeth-ane.142 143 The relative rates, obtained by a competitive procedure, are in good agreement with the bromination data (Table V) and confirm, in particular, the big jump in reactivity from furan to pyrrole. The great reactivity of pyrrole cannot be ascribed to a reaction involving the anion C4H4N, since V-methylpyrrole is still more reactive than pyrrole by a factor of about 2. 

For reactions involving side-chain carbocations, the order of transmission of substituent effects is quite different to the electrophilic substitutions, being furan > pyrrole > thiophene > benzene > tellurophene. 

Similarly, the reaction of an electrophile will involve the HOMO of the reactant, i.e. the reaction should occur preferentially on the atom having the largest HOMO coefficient. The coefficients for furan shown in Figure 15.3 indicate that electrophilic substitution preferentially should occur at the 2-position, again in agreement with... 

A preparation of 5-formyl-2-[(diethoxyphosphinyl)methyl]furan in 40% yield by electrophilic substitution has been described. It involves the reaction between diethyl 2-furylmethylphosphonate and the complex DMF-POCI3 at 50°C.-- 5 A related methodology allows the preparation of 5-substituted dietliyl 2-furylmethylphosphonates (Scheme 5.57). In this case diethyl 2-furylmethylphosphonate is... 

Similarly to the synthesis of C3-functionalized benzo[i)]furans (Scheme 9.2), Nakamura employed the Zn/Cu-mediated cydization-substitution strategy for a facile assembly of 2,3-disubstituted indoles 130 (Scheme 9.49) (79,80]. This reaction involves the initial formation of 3-zincindole 128, which undergoes transmetalation with CuCN-LiCl complex to give the corresponding cuprate 129. The latter, upon reaction with a suitable electrophile, furnishes indole 130. 

A new approach to the synthesis of 2,4-disubstituted furans involves protection of the 2-position in 3-substituted furans such as furan-3-carboxylic acid <91SL33,9iJCS(Pl)2600> and 3-furylmethanol <94TL5335> as the 2-/-butyldimethylsilyl-derivatives. Metallation at low temperature followed by reaction with an electrophile and removal of the silicon protecting group then gives the required... 

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