Straightforward Novel One-Pot Enaminone and Pyrimidine Syntheses by Coupling-Addition-Cyclocondensation Sequences

Abstract

The coupling of acid chlorides 1 with terminal alkynes 2 using only one equivalent (!) of triethylamine under Sonogashira conditions followed by subsequent addition of primary or secondary amines 4 to the intermediate alkynones 3 represents a straightforward one-pot three component access to enaminones 5 under mild conditions and in excellent yields. Furthermore, 2,4-di-and 2,4,6-trisubstituted pyrimidines 7 can be synthesized in moderate to good yields according to a highly flexible coupling-addition-cyclocondensation sequence.Pyrimidines represent an important class of heterocycles 1 and their structural framework is not only a key constituent of nucleic bases, alkaloids, and numerous pharmacophores with antibacterial, 2 antimicrobial, antifungal, 3 antimycotic, 4 antiviral, and antitumor activity, 5 but also functions as a central unit in grid-forming ligands for supramolecular scaffolds. 6,7 As a consequence, many pyrimidine syntheses are known, the most efficient of them applying cyclocondensations of 1,3-dicarbonyl compounds or their synthetic equivalents with amidines as a key step. 8,9 Among these approaches the reaction of alkynones and amidinium salts 10,11 represents an intriguing entry to pyrimidines, in particular, since alkynones can readily be formed in catalytic way by a Sonogashira coupling of an acid chloride with a terminal alkyne. 12,13 As part of our program directed to design novel multi-component reactions based on in situ activation of alkynes by Sonogashira coupling, 13,14 we have now focused on coupling-amination sequences as an entry to heterocycle sequences. Here, we wish to report three-component syntheses of enaminones and 2,4-and 2,4,6-substituted pyrimidines with a flexible substitution pattern.The most elegant and atom-economic way of transforming acid chlorides into alkynones is the cross coupling of terminal alkynes under the conditions of the Sonogashira coupling. In turn, the resulting ynones are highly reactive Michael acceptors that readily react with all kinds of nucleophiles. Just recently, we discovered that adding only one equivalent of triethylamine as the hydrochloric acid scavenging base proves to be most favorable, in particular, for the successful coupling of (TMS)acetylene. 13Probing ynones generated under cross-coupling conditions for the feasibility in a consecutive aminovinylation, 15 the addition of primary and secondary amines should give rise to b-enaminones in a one-pot fashion. Besides their enormous synthetic potential as well-established three-carbon building blocks for cyclocondensations in heterocyclic chemistry, 16 enaminones 17 in their own right are highly pharmacologically active and reveal a pronounced anticonvulsant 18 and nonsteroidal antiinflammatory activity. 19 Therefore, in the sense of a consecutive three-component one-pot reaction, after reacting various acid chlorides 1 with terminal alkynes 2 under modified Sonogashira conditions for 1 hour at room temperature to furnish the expected alkynones 3, and subsequently adding methanolic solutio...

Aroylacetylene-Based Amino-Yne Click Polymerization toward Nitrogen-Containing Polymers

“…To systematically explore the polymerization conditions of this catalyst-free amino-yne click polymerization, bis­(aroylacetylene) monomer 2a was first designed and synthesized via a convenient and simple process (Scheme S1). ,, By Sonogashira reaction of the bis­(aroylchloride) derivative and trimethylsilylacetylene at room temperature, trimethylsilyl group-protected bis­(aroylacetylene) could be obtained. Then, the bis­(aroylacetylene) monomer can be easily prepared after deprotection of it in dilute borax solution.…”

Palladium-catalyzed Sonogashira coupling reactions in γ-valerolactone-based ionic liquids

“…From the environmental point of view, the Sonogashira reactions are usually performed in fossil-based common organic reaction media having high vapor pressure even at higher temperatures, toxicity, flammability, etc., which could result in several serious environmental concerns, especially when they are released into the atmosphere. According to the FDA guidelines [9], the typical solvents of Sonogashira reactions such as toluene [10], THF [11], DMF [12], NMP [13], DMA [14], or MeCN [15] are classified into Class 2, of which applications should be strictly limited, particularly in pharmaceutical industry. To develop an environmentally benign alternative of this useful method, the reaction has been extended to green solvents such as water [16], fluorous solvents [17], supercritical CO 2 [18], and very recently γ-valerolactone [19].…”

Synthesis of Highly Substituted 3-Acylpyrroles by a Four-Component Sonogashira Alkynylation–Amine Addition–Nitroalkene Michael Addition–Cyclocondensation

“…The selected combination of catalysts is commonly used in the generation of ynones and enaminones. [25] The consecutive fourcomponent alkynylation-addition-addition-cyclocondensation sequences furnishes 17 products with various functional groups were obtained in modest to good yield (Scheme 2).…”