The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

Abstract

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to β-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-β-ketoenamides. β-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of β-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of β-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile β-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key β-ketoenamides show a unique substitution pattern – not easily accomplishable by alternative methods – and therefore many subsequent reactions are possible.

Recent advances in catalytic silylation of hydroxyl‐bearing compounds: A green technique for protection of alcohols using Si–O bond formations

“…As mild Lewis bases, pyridine N-oxides can result in activating Lewis acid parts of molecules and also increasing the reactivity of nucleophilic part toward different reactions with electrophiles. [115][116][117][118] Pyridines have been highly significant in catalyzing reactions, as reported in a study by Yoshida and coworkers. In this regard, they reported that when TBDPSCl, DIPEA, and pyrrolidinopyridine N-oxide (PPYO) catalyst are combined, it would bring about silylating different secondary alcohols in CH 2 Cl 2 at r.t. with excellent yields.…”

Synthesis of Heterocyclic Compounds with Pyrimidine-4-carbaldehydes as Key Intermediates

“…A very interesting option to highly substituted pyrimidines and other functionalized heterocycles is offered by the LANCA three-component approach [LANCA = LA (lithiated alkoxyallenes) + N (nitriles) + CA (carboxylic acids)] to β-alkoxy-β-ketoenamides A (Scheme 1 ), discovered and developed by our group. 6 7 The reaction of these versatile intermediates with hydroxylamine hydrochloride smoothly provides 4-methyl-substituted pyrimidine N -oxides B under mild conditions, 8 whereas the heating of A with ammonium salts furnishes the corresponding pyrimidine derivatives C in good yields (Scheme 1 ). 9 The subsequent Boekelheide rearrangement of B with carboxylic acid anhydrides converts these compounds into 4-carbonyloxy-substituted pyrimidine derivatives, 10 and, after saponification, hydroxymethyl-substituted pyrimidines D are available with good efficiency (Scheme 1 ).…”

A Proline and 4‐Hydroxyproline Based Approach to Enantiopure Pyrrolidin‐2‐yl‐Substituted Pyridine and Pyrimidine Derivatives

“…Their substitution pattern allowed a variety of subsequent reactions leading to comprehensive libraries of heterocycles. [9] The successful application of β-alkoxy-β-ketoenamides for the synthesis of hundreds of new compounds motivated our group to study the behavior of simple β-ketoenamides (Scheme 1, lower part) which are very easily available in two steps from ammonia, 1,3diketones and carboxylic acids. Analogous cyclization reactions led indeed to formation of pyridine, bipyridine, terpyridine and pyrimidine derivatives in good yields.…”