New 5‐Alkoxypyrimidine Derivatives from β‐Alkoxy β‐Keto Enamides and Ammonium Salts

Abstract

A series of highly substituted β-alkoxy β-keto enamides were prepared by a multi-component reaction combining lithiated alkoxyallenes, nitriles and carboxylic acids. Apt conditions were developed for their conversion into 5-alkoxypyrimidine derivatives. This synthesis is highly flexible with respect to the substitution pattern at C-2 and C-4 of the pyrimidine core. The corresponding pyrimidin-5-yl nonaflates allowed subsequent transformations at C-5 by palladium-catalyzed

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

“…Next, we investigated the cyclocondensation of bis(β-ketoenamides) 13 – 15 to pyrimidines ( Scheme 4 ) using ammonium acetate as ammonia source. Initially we subjected enamide 13 to conditions that had been optimized for mono-β-ketoenamides [ 48 – 49 ], in this case resulting in incomplete conversion: after heating 13 with 8 equiv of ammonium acetate in a sealed tube we obtained a 1:1 mixture of bis(pyrimidine) derivative 23a and pyrimidine 23b still containing one β-ketoenamide unit with an overall yield of 68%. However, full conversion of 13 into 23a was achieved by increasing the amount of ammonium acetate to 16 equiv and using a higher reaction temperature, raising the yield of 23a from 34% to 55% yield.…”

“…as biologically active compounds) the development of efficient protocols for the preparation of functionalized pyridine [ 10 – 20 ] and pyrimidine derivatives [ 21 – 33 ], in particular by MCRs, is of permanent high interest. In the course of exploring the reactivity of alkoxyallenes and their utilization as C-3 building blocks [ 34 – 37 ] our group developed a highly flexible method to synthesize β-alkoxy-β-ketoenamides of type 1 that are remarkably versatile cyclization precursors for the synthesis of functionalized heterocycles such as 4-hydroxypyridines [ 38 – 44 ], furopyridines [ 45 ], 5-acetyloxazoles [ 46 – 47 ], pyrimidines [ 43 , 48 – 49 ] and their corresponding N -oxides [ 50 ] ( Scheme 1 ). This approach – discovered and mechanistically elucidated by Oliver Flögel – features a three-component reaction that employs alkoxyallenes, nitriles and carboxylic acids: upon treatment with n -butyllithium the allene is lithiated in α-position to the alkoxy moiety; the addition of a nitrile as electrophile to this highly reactive nucleophile results in the formation of an iminoallene adduct [ 38 ] that is protonated and subsequently acylated by the addition of a carboxylic acid furnishing a β-alkoxy-β-ketoenamide 1 .…”

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

“…Cyclocondensation reactions with ammonium salts in methanol afford these versatile heterocycles in good to excellent yields (Scheme 8). In most cases, ammonium acetate gave the best results (method A) and in a few examples ammonium bicarbonate was tested as alternative (method B) [29,33]. The plausible mechanism of this transformation involves the formation of an α,β-unsaturated imine G and its cyclization to H followed by water elimination.…”

“…In Scheme 9 additional examples PM31 – 34 having stereogenic centers are presented, that were obtained from β-ketoenamides KE37 , KE38 , KE40 and KE41 (see Scheme 5 ) [ 43 ]. The pyrimidine PM35 is derived from β-ketoenamide KE78 (see Scheme 7 ) and bears a benzyl group at C-4 instead of the standard methyl group [ 33 ].…”

Electrophilic alkylation of arenes with 5-bromopyrimidine en route to 4-aryl-5-alkynylpyrimidines

“…9 Conveniently, structures of this type are accessible via Pd-catalyzed cross-coupling reaction involving terminal alkynes and hetaryl halides or sulfonates 2 (Scheme 1). 10,11 Alternatively, a decarboxylative cross-coupling of alkynyl halides with hetarylcarboxylic acids can be employed. 12 Although the synthetic route involving 2 as an electrophilic component in the Sonogashira reaction seems very straightforward, access to these starting materials typically relies on another transition metal-catalyzed cross-coupling step, usually chemoselective Suzuki reaction between arylboronic acid 3 and hetaryl dihalide 4 (Scheme 1).…”