Modular Access to Tetrasubstituted Imidazolium Salts through Acid‐Catalyzed Addition of Isocyanides to Propargylamines

Abstract

Propargylamines, prepared through A3‐coupling of primary amines, aldehydes and terminal alkynes, react with isocyanides in an HCl‐catalyzed process to yield tetrasubstituted imidazolium salts. The key step of the mechanism involves the generation of an amidine intermediate, from the isocyanide insertion into the N–H bond of the propargylamine, which in situ evolves by cyclization upon the alkyne moiety. The scope of the process is analyzed and only shows restrictions for aliphatic amines, whereas it is quite general regarding the aldehyde, alkyne and isocyanide inputs. The protocol allows the preparation of a wide array of adducts, tandem one‐pot processes being also feasible. Mechanistic studies using selected substrates have been used to determine the profile of the reaction and some substitution and functional group limitations. Some post‐synthetic transformations of the imidazolium salts have been performed as well.

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

“…As a matter of fact, regioselective cyclization of structurally related substrates such as 2‐alkynyl benzoic acid 26 , 2‐alkynyl benzamides 27 , propargyl ureas 28 , and propargyl guanidines 29 has been extensively studied and conditions have been established for performing either a 5‐ exo ‐dig or a 6‐ endo ‐dig cyclization (Figure ). However, the cyclization of amidine 19 has been far less investigated and to the best of our knowledge, only 5‐ exo ‐dig cyclization leading to imidazole is known . Indeed, in this case, the 5‐ exo ‐dig cyclization furnishes an aromatic compound 16 after facile double‐bond isomerization of the primary cyclization product 30 , providing, therefore, additional thermodynamic driving force (pathway a, Scheme )…”

“…Increasing the loading of TfOH to 0.5 equiv,1 ,6dihydropyrimidine 17 a was formedi n7 8% isolated yield (entry 13). [30] It is worth noting that both Lavilla [21] and Hulme [31] have previously demonstrated that acid-catalyzedisocyanidei nsertion into the NH bond, while effective with anilines, failed with aliphatic amines.F inally,t ributylammonium triflate (nBu 3 NH + TfO À ), aw hite solid easily preparedf rom nBu 3 Na nd TfOH, was also able to catalyzet he [2+ +3] heteroannulationb etween 1a and 15 a (entry 14). On the other hand, tetrabutylammoniumt riflate was devoid of catalytic activity (entry 15).…”

“…Ytterbium triflate catalyzed the insertion of isocyanide to the NH bond, silver triflate catalyzed the 5‐ exo ‐dig cyclization of the resulting propargyl amidines, and potassium triflate underwent salt metathesis with the hypothetical vinyl silver species to regenerate the catalytic species. Concurrently, Lavilla and co‐workers independently reported a hydrochloride‐promoted heteroannulation between 1 and 13 to afford the same product 14 . In both cases, a secondary amine was used as a nucleophile to initiate the heteroannulation sequence.…”

“…[20] In this multicatalytic process, three taskspecific metal salts acted cooperatively to channel the reaction towardst he formation of 1,3,4,5-tetrasubstituted imidazolium salts 14.Y tterbium triflate catalyzed the insertion of isocyanide to the NH bond, silver triflate catalyzed the 5-exo-dig cyclization of the resulting propargyl amidines, and potassium triflate underwent salt metathesis with the hypothetical vinyl silver speciest or egenerate the catalytic species. Concurrently,L avilla and co-workers [21] independently reported ah ydrochloride-promoted heteroannulation between 1 and 13 to afford the same product 14.Inboth cases,asecondary aminewas used as anucleophile to initiatet he heteroannulation sequence. To enlarge the scope of this novel heteroannulation process, we set out to examine the reaction between isonitriles 1 and primary propargylamines 15.W es erendipitously discovered that the reactionb etween 1 and 15 can be channeled towards the formation of either imidazoles 16 or 1,6-dihydropyrimidines 17 by simply adjusting the catalystl oading (Eq.…”

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

“…[9] Thehomopropargyl amine 3a (R 1 = R 2 = Ph, R 3 = H) and tert-butyl isocyanide (4a)w ere chosen as test substrates (Scheme 2). [12] To our delight, reaction of 3a and 4a in toluene in the presence of AgOTf indeed afforded the proline amide 5a (16 %) resulting from aformal 1,1-gem difunctionalization of the terminal alkyne.Systematic survey of reaction conditions [*] Dr.S .T ong, [ varying the silver salt, the solvent, and the temperature allowed us to obtain 5a in 82 %y ield (d.r.1 :1) under the following optimized reaction conditions:AgOAc (0.1 equiv), toluene,4 0 8 8C, then FCC on SiO 2 (see the Supporting Information for details). [10] While many transition metals promote this transformation efficiently, [11] we have recently shown that as ilver salt, because of its high alkynophilicity,p referred to coordinate to the triple bond of the propargylamine,t herefore inhibiting the N À Hi nsertion process.…”