Thiophenes with iminium salts

Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 C give the relative rates thiophene (1.0), furan (1.4 x 10 ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). Similar values, thiophene (1.0), furan (3.0 x 10 ) and pyrrole (5.0 x 10 ) are obtained for reactions with [C6H7Fe(CO)3]. We have already discussed the fact that thiophene does undergo the Mannich reaction using preformed methyleneiminium salts and therefore it is not surprising that furan also affords the aminomethyl derivatives in reactions with iminium salts. 

Acid-catalyzed hydroxyalkylation with aldehydes or ketones is not a viable route to hydroxyalkyl thiophenes, since these are unstable under the reaction conditions. However, chloromethylation with CH2O/HCI andaminometiiylation with iminium salts are reported. 

The key intermediate 21 is in principle accessible in any of several ways. Thus reaction of thiophenecarbox-aldehyde with amninoacetal would lead to the Schiff base treatment with acid would result in formation of the fused thiophene-pyridine ring (21). Alkylation of that intermediate with benzyl chloride gives the corresponding ternary iminium salt. Treatment with sodium borohydride leads to reduction of the quinolinium ring and thus formation of ticlopidine (24). ... 

Thiophene-2-carbaldehyde has become extremely cheap and easily available through the Vilsmeier formylation of thiophene. The reactions of thiophene substrates with several iminium salts have been investigated (B-76MI31400). 3-Phenylthiophene gives 4-phenylthiophene-2-carbaldehyde with chloromethylene iminium ion. In the case of 2-methoxy-5-methylthiophene, a dealkylation takes place above 50-70 °C. If the intermediate iminium salt (91) is formed at 20 °C and then hydrolyzed, the aldehyde (92) is obtained. 

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-... 

Oxidation of the salt (125) with active manganese dioxide gives a high yield of thiophene-2-carbaldehyde (67G397). Amines, both primary and secondary, readily cleave the ring with expulsion of hydrogen sulfide and generation of the iminium species (128) in up to 90%... 

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