Trimethylsilyl Trifluoromethanesulfonate-Promoted Cyclocondensation of β-Ketoenamides and Subsequent Nonaflation to Pyrid-2-yl and Pyrid-4-yl Nonaflates as Flexible Precursors for Polysubstituted Pyridines

Abstract

The intramolecular condensation of β-ketoenamides to 2-and/or 4-pyridone derivatives using either KOt-Bu or trimethylsilyl trifluoromethanesulfonate/Hünig's base was investigated. Subsequent nonaflation of the cyclization products allowed a facile purification and further functionalization through Suzuki-Miyaura couplings leading to new highly substituted pyridine derivatives. The dependence of the regioselectivity of cyclocondensation on the structure of the β-ketoenamides is discussed.With its ubiquitous structural motif in biologically active compounds and functional materials pyridines belong without doubt to the most important heterocycles. 1 Since the early days of organic chemistry this has been motivating chemists to search for efficient methods to synthesize functionalized pyridine derivatives. 2,3 In recent years our group developed a remarkably flexible approach for the preparation of highly functionalized pyrid-4-ones 2 by a trimethylsilyl trifluoromethanesulfonate (TMSOTf)/basepromoted intramolecular condensation of β-ketoenamides 1 (Scheme 1). A mechanistic proposal for the TMSOTfpromoted cyclocondensation has previously been presented suggesting an aldol-type step of an enolate or its equivalent with the amide carbonyl group. 4 Suitable cyclization precursors can be synthesized by a three-component reaction of lithiated alkoxyallenes, nitriles, and carboxylic acids, 5 or by N-acylation of β-ketoenamines. Suitable enamines are easily accessible via amination of 1,3-diketones, 6 or by trapping the Blaise intermediate with acetic acid anhydride. 7,8 Conversion of 4-hydroxypyridines 3 (the tautomers of 2) into the corresponding nonafluorobutanesulfonates (nonaflates) 9 allows for versatile subsequent transformations through Pd-catalyzed crosscoupling reactions. 10,11 It is known that β-ketoenamides of type 5 bearing fairly acidic protons in α-position to the amide carbonyl moiety [R 6 = (het)aryl or electron-withdrawing substituents] cyclize under basic conditions to provide pyrid-2-one derivatives 6 (Scheme 2). 12, 13 We were therefore interested, if this kind of transformation would also be possible via a TMSOTf/base-promoted condensation. Furthermore, we wanted to explore the reactivity of β-ketoenamides 7 bearing two enolizable methylene groups. We envisioned that upon treatment with TMSOTf these compounds may cyclize via intermediate 8 to give pyrid-4-ones 9 (path a) as well as via 10 to give pyrid-2-ones 11 (path b).Scheme 1 Synthesis of highly functionalized pyridine derivatives via TMSOTf-promoted cyclocondensation of β-ketoenamides 1 (Nf = nonafluorobutanesulfonyl) Scheme 2 Cyclocondensation of β-ketoenamides to pyrid-2-ones 11 and/or pyrid-4-ones 9 R 1 NH O R 2 O R 3 TMSOTf/R 3 N HN R 2 O R 3 R 1 R 4 R 4 R 1 = (het)aryl, alkenyl, refs. 4, 5 and 7 2 N R 2 R 5 R 3 R 1 R 4 4 1) NfF or Nf 2 O 2) R 5 X, [Pd]