Alkoxyallene‐Based LANCA Three‐Component Synthesis of 1,2‐Diketones, Quinoxalines, and Unique Isoindenone Dimers and a Computational Study of the Isoindenone Dimerization

Abstract

A series of β‐alkoxy‐β‐ketoenamides was prepared by the well‐established LANCA three‐component reaction of lithiated 1‐(2‐trimethylsilylethoxy)‐substituted allenes, nitriles, and α,β‐unsaturated carboxylic acids. The α‐tert‐butyl‐substituted compounds were smoothly converted into the expected 1,2‐diketones by treatment with trifluoroacetic acid. A subsequent condensation of the 1,2‐diketones with o‐phenylenediamine provided the desired highly substituted quinoxalines in good overall yield. Surprisingly, the α‐phenyl‐substituted β‐alkoxy‐β‐ketoenamides investigated afford not only the expected 1,2‐diketones, but also pentacyclic compounds with an anti‐tricyclo[4.2.1.12,5]deca‐3,7‐diene‐9,10‐dione core. These interesting products are very likely the result of an isoindenone dimerization which was mechanistically studied with the support of DFT calculations. Under the strongly acidic reaction conditions, a stepwise reaction is likely leading to a protonated isoindenone as reactive intermediate. It may first form a van der Waals complex with a neutral isoindenone before the two regio‐ and diastereoselective ring forming steps occur. Interestingly, two neutral or two protonated isoindenones are also predicted to dimerize giving the observed pentacyclic product.||||||

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

“…In summary, the results of this report confirm the high versa-tility of the alkoxyallene-based 32 LANCA three-component approach to libraries of pyrimidine derivatives, complementing our earlier reports on the synthesis of highly substituted pyridines, 33 oxazoles, 34 and quinoxalines. 35 Reactions were generally performed under argon in flame-dried flasks, and the components were added by syringe. Products were purified by flash chromatography (silica gel, 230-400 mesh, Merck or Macherey & Nagel).…”

The Boekelheide Rearrangement of Pyrimidine N‐oxides as a Case Study of Closed or Open Shell Reactions ‐ Experimental and Computational Evidence for the Participation of Radical Intermediates

“…[7] This LANCA approach to intermediates F is very flexible with respect to the substitution pattern. Subsequent condensation reactions of F led to compound libraries of highly substituted pyridine, [8] oxazole, [9] pyrimidine, [10] and quinoxaline [11] derivatives. The reaction of β‐alkoxy‐β‐ketoenamides F with hydroxylamine hydrochloride proceeded particularly smoothly and directly afforded pyrimidine N ‐oxides G in good yields and in a regioselective manner [12]…”

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

“…Our group investigated in great detail a new and versatile three-component reaction which employed lithiated alkoxyallenes, nitriles and carboxylic acids (LANCA process) to deliver β-alkoxy-β-ketoenamides as key compounds (Scheme 1, upper part). [4] Under specific conditions, these intermediates undergo subsequent cyclization reactions to furnish highly substituted pyridine, [5] pyrimidine, [6] oxazole, [7] and quinoxaline [8] derivatives. Their substitution pattern allowed a variety of subsequent reactions leading to comprehensive libraries of heterocycles.…”