Friedlander annulation reaction

Beier and Pastyrikova (13MI411) reported that reductive ring opening of SFs-substituted benzisoxazoles 78a, 79a using iron in aqueous AcOH resulted in excellent yields of ori/ o-aminobenzophenones 100, 101, which can be used as precursors for the synthesis of other SFs-substituted heterocycles such as quinazoHnes (see Section 2.8), as weU as for the synthesis of SFs-substituted quinolines. Thus 6-SFs-quinoline 102 was prepared in high yield by the Friedlander annulation reaction of 101 with excess ethyl acetoacetate in the presence of catalytic cerium (IV) ammonium nitrate (CAN). Similarly, aminoketone 100 was condensed in good yield with cyclohexanone to provide 7-SFs-quinoline 103 (Scheme 25). 

The Friedlander annulation is one of the most straightforward approaches towards poly-substituted quinolines. Thus, a 22-membered library of quinolines was synthesized in a TsOH-catalyzed cyclocondensation-dehydration of 2-aminoaryl ketones and 2-aminoarylaldehydes with ketones in a household microwave oven (with power control) under solvent-free conditions [112]. It was observed that the Friedlander reaction occurred readily also in an oil-bath (at 100 °C). To compare the conventional and dielectric heating conditions precisely, a purpose-built monomode microwave system with temperature control was employed instead of the household oven. The experiments at 100 °C under otherwise identical conditions demonstrated that the dielectric heating protocol was only slightly faster. Products were isolated by a simple precipitation-neutralization sequence (in the case of solid products) or neutralization-extraction for oily or low melting point products (Scheme 43). 

Major modifications to the Friedlander reaction frequently involve different starting materials that deviate from the conventional examples. A one-pot combination of a modified Friedlander annulation and a Knoevenagel condensation have provided 2-styrilquinolines 152 in the presence of 1-methylimidazolium trifluoroacetate ([HmimJTFA) (Scheme 28) (08TL5366). 

Several variations on a Friedlander reaction strategy were investigated for the construction of palbociclib, one of which is shown in Scheme 9. In this approach, pyrimidine 28 was treated with cyclopentylamine, which provided aminopyridine 29. Heck reaction with n-butyl vinyl ether provided 30, which was hydrolyzed with aqueous trifluoroacetic acid to give the ketone 31. Palladium-catalyzed amination, with aminopyridine 22, then provided the key ketone intermediate 32. The Friedlander annulation was then evaluated using a variety of acetoacetate and diketene analogs. 

Proline potassium salt is a superior catalyst for Friedlander annulations, compared to proline. " Copper(II) catalysis of the Friedlander reaction has been studied by DFT. " ... 

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