Switchable [3+2] and [4+2] Heteroannulation of Primary Propargylamines with Isonitriles to Imidazoles and 1,6‐Dihydropyrimidines: Catalyst Loading Enabled Reaction Divergence

Abstract

Isonitrile 1 due to its carbene-like reactivity serves generally as a one-carbon synthon in a diverse set of organic transformations. We report in this article that the isocyano group can also act as a polarized triple bond to undergo, as a two-atom synthon, heteroannulation with primary propargylamines 15. In addition, we serendipitously discovered that the reaction pathways can be modulated by simply changing the catalyst loading. In the presence of 0.1 equiv of Yb(OTf)3 or TfOH, the reaction between 1 and 15 afforded exclusively imidazoles 16 by a formal [3+2] cycloaddition. At a higher catalyst loading (Yb(OTf)3 (0.4 equiv) or TfOH (0.5 equiv)) under otherwise identical conditions, the same reaction furnished 1,6-dihydropyrimidines 17 in good to excellent yields by way of a formal [4+2] cycloaddition process. Mechanistic investigations indicated that both annulations went through an amidine intermediate resulting from the insertion of the isocyano group to the NH bond of the primary amine. Subsequent catalyst-loading-dependent 5-exo-dig or 6-endo-dig cyclization provided selectively the two heterocycles, respectively.

Silver‐Catalyzed Three‐Component 1,1‐Aminoacylation of Homopropargylamines: α‐Additions for Both Terminal Alkynes and Isocyanides

“…The Ugi–Joullié‐type three‐component reaction of 1‐phenylbut‐3‐yn‐1‐amine ( 6 a ; R 1 =H, R 2 =Ph), 4 a , and trifluoroacetic acid ( 7 a ) under the above defined reaction conditions did not produce the desired proline derivatives. Competitive reactions such as protonation and/or acylation of amine, the Lewis acid catalyzed condensation of 4 a with 7 a , etc., could indeed hamper the occurrence of the desired reaction pathway. A series of control experiments (see the Supporting Information) have been performed.…”

Synthesis of Chiral Propargylamines, Chiral 1,2‐Dihydronaphtho[2,1‐b]furans and Naphtho[2,1‐b]furans with C‐Alkynyl N,N′‐di‐(tert‐butoxycarbonyl)‐aminals and β‐Naphthols

“…Three anhydrous additives, MgSO 4 , Na 2 SO 4 and 3 Å MS, were attempted (entries 10-12), and Na 2 SO 4 provided 90 % ee value (entry 11). We investigated the affection of reaction temperature and time (compare entries 9, [13][14][15][16][17], and found that 60°C and 12 h were suitable (entry 16). Other solvents were attempted, and the results showed that toluene was optimal (see Table S1).…”

“…[4] Chiral propargylamines are key precursors for the synthesis of pharmaceutical molecules. [5] The reactions with propargylamines as the substrates can provide miscellaneous heterocyclic compounds [6] such as pyrroles, [7] pyrrolines, [8] pyrrolidine, [9] pyrazines, [10] pyrazoles, [11] pyridines, [12] dihydropyridines, [13] isoxazoles, [14] oxazolidines, [15] thiazoles [16] and thiazolidines. [17] The common methods for synthesis of chiral propargylamines include the asymmetric alkynylation of imines [18,19] and the catalytic asymmetric addition of nucleophiles to previously prepared [20] or in situ generated [21,22] Calkynyl imines (Scheme 1a).…”

Fluorophores for Excited‐State Intramolecular Proton Transfer by an Yttrium Triflate Catalyzed Reaction of Isocyanides with Thiocarboxylic Acids

“…b) Twop roton transfer reactions are interconnected by aproton shutter (type B,Scheme 1b). [11] Interested in modulating the generally accepted reactivity of isocyanide, [12] we reported as ynthesis of 5-amino-4carboxamidooxazole 4 by az inc bromide-promoted condensation of carboxylic acid with isocyanide. [7] To the best of our knowledge,3-hydroxy-pipecolic acid is the only molecule belonging to this class that has been theoretically proposed and studied by ab initio methods.…”