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

An extension of the substrate scope of the Flögel-three-component reaction of lithiated alkoxyallenes, nitriles and carboxylic acids is presented. The use of dicarboxylic acids allowed the preparation of symmetrical bis(β-ketoenamides) from simple starting materials in moderate yields. Cyclocondensations of these enamides to 4-hydroxypyridine derivatives or to functionalized pyrimidines efficiently provided symmetrically and unsymmetrically substituted fairly complex (hetero)aromatic compounds containing up to six conjugated aryl and hetaryl groups. In addition, subsequent functionalizations of the obtained heterocycles by palladium-catalyzed couplings or by oxidations are reported. We also describe the simple synthesis of a structurally interesting macrocyclic bispyrimidine derivative incorporating a 17-membered ring, whose configuration was elucidated by DFT calculations and by subsequent reactions.

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Preparation and Reactions of Trichloromethyl-Substituted Pyridine and Pyrimidine Derivatives

Synthesis ◽

10.1055/s-0037-1609576 ◽

2018 ◽

Vol 50 (20) ◽

pp. 4071-4080 ◽

Cited By ~ 2

Author(s):

Reinhold Zimmer ◽

Hans-Ulrich Reissig ◽

Lina Unger ◽

Matteo Accorsi ◽

Christian Eidamshaus ◽

...

Keyword(s):

Acetic Anhydride ◽

Good Yield ◽

Trichloroacetic Acid ◽

Pyridine Derivative ◽

Pyrimidine Derivatives ◽

Methyl Group ◽

Alternative Approach ◽

Three Component Reaction ◽

Trichloromethyl Group ◽

Pyridine And Pyrimidine Derivatives

The three-component reaction of lithiated methoxyallene, nitriles and trichloroacetic acid gave three model β-keto enamides that were starting materials for the synthesis of trichloromethyl-substituted pyridine and pyrimidine N-oxide derivatives. Upon treatment with acetic anhydride, the methyl group of the prepared pyrimidine N-oxides was converted into an acetoxymethyl group by a Boekelheide rearrangement. A few typical experiments also revealed that the trichloromethyl group of the prepared pyrimidine N-oxides can be replaced by an alkoxy or a hydroxy group, or transformed into an arylthiomethyl group. An alternative approach to β-keto enamides via the corresponding β-keto enamines was also examined and provided the expected 4-hydroxy-6-(trichloromethyl)pyridine derivative in good yield.

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

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.15.61 ◽

2019 ◽

Vol 15 ◽

pp. 655-678 ◽

Cited By ~ 6

Author(s):

Tilman Lechel ◽

Roopender Kumar ◽

Mrinal K Bera ◽

Reinhold Zimmer ◽

Hans-Ulrich Reissig

Keyword(s):

Carboxylic Acids ◽

Functional Groups ◽

Condensation Reaction ◽

Hydroxylamine Hydrochloride ◽

Dicarboxylic Acids ◽

Alkoxy Group ◽

Alternative Methods ◽

Substitution Pattern ◽

Three Component Reaction ◽

Acid Labile

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.

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Access to Highly Substituted Pyrimidine N-Oxides and 4-Acetoxymethyl-Substituted Pyrimidines via the LANCA Three-Component Reaction–Cyclocondensation Sequence

Synthesis ◽

10.1055/s-0040-1706020 ◽

2021 ◽

Author(s):

Reinhold Zimmer ◽

Hans-Ulrich Reissig ◽

Luise Schefzig ◽

Timon Kurzawa ◽

Giaime Rancan ◽

...

Keyword(s):

Carboxylic Acids ◽

Room Temperature ◽

Hydroxylamine Hydrochloride ◽

Trifluoroacetic Anhydride ◽

Pyrimidine Derivatives ◽

Mild Conditions ◽

Structural Variety ◽

Three Component Reaction ◽

Sterically Demanding ◽

Synthetic Utility

AbstractThe LANCA three-component reaction of lithiated alkoxyallenes (LA), nitriles (N), and carboxylic acids (CA) smoothly provides β-alkoxy-β-ketoenamides in broad structural variety. The subsequent cyclocondensation of these compounds with hydroxylamine hydrochloride afforded a large library of pyrimidine N-oxides under mild conditions and in good yields. Their synthetic utility was further increased by the Boekelheide rearrangement leading to 4-acetoxymethyl-substituted pyrimidines. With trifluoroacetic anhydride the rearrangement proceeds even at room temperature and directly furnishes 4-hydroxymethyl-substituted pyrimidine derivatives. The key reactions are very robust and work well even in the presence of sterically demanding substituents.

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Synthesis of highly functionalised 5-membered ring fused pyrimidine derivatives using an isocyanide-based one-pot, three component reaction

Tetrahedron Letters ◽

10.1016/j.tetlet.2020.151796 ◽

2020 ◽

Vol 61 (17) ◽

pp. 151796

Author(s):

Reagan L. Mohlala ◽

E. Mabel Coyanis ◽

Manuel A. Fernandes ◽

Moira L. Bode

Keyword(s):

Membered Ring ◽

Pyrimidine Derivatives ◽

One Pot ◽

Three Component Reaction

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Ligand-Enabled γ-C(sp3)–H Olefination of Free Carboxylic Acids

10.26434/chemrxiv.11857857 ◽

2020 ◽

Author(s):

Kiron Kumar Ghosh ◽

Alexander Uttry ◽

Francesca Ghiringhelli ◽

Arup Mondal ◽

Manuel van Gemmeren

Keyword(s):

Reaction Mechanism ◽

Carboxylic Acids ◽

Michael Addition ◽

Kinetic Studies ◽

Wide Range ◽

Palladium Catalyzed

We report the ligand enabled C(sp3)–H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael-addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.<br>

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Direct and Selective Synthesis of Adipic and Other Dicarboxylic Acids by Palladium‐Catalyzed Carbonylation of Allylic Alcohols

Angewandte Chemie International Edition ◽

10.1002/anie.202008916 ◽

2020 ◽

Vol 59 (46) ◽

pp. 20394-20398

Author(s):

Ji Yang ◽

Jiawang Liu ◽

Yao Ge ◽

Weiheng Huang ◽

Helfried Neumann ◽

...

Keyword(s):

Dicarboxylic Acids ◽

Allylic Alcohols ◽

Selective Synthesis ◽

Palladium Catalyzed

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A Palladium-Catalyzed Oxa-(4+4)-Cycloaddition Strategy Towards Oxazocine Scaffolds

Synlett ◽

10.1055/s-0040-1706038 ◽

2021 ◽

Author(s):

Julian Garrec ◽

Alexis Archambeau ◽

Anaïs Scuiller ◽

Xueyang Liu ◽

Marie Cordier

Keyword(s):

Dft Calculations ◽

Palladium Catalyzed

AbstractA Pd-catalyzed oxa-(4+4)-cycloaddition between 1-azadienes and (2-hydroxymethyl)allyl carbonates is described. Aurone-derived azadienes furnished polycyclic 1,5-oxazocines in good yields. Interestingly, linear azadienes have also been involved and yielded monocyclic heterocycles with complete regioselectivity. DFT calculations were carried out to gain insight on this observation.

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