One‐Pot and Regioselective Gold‐Catalyzed Synthesis of 2‐Imidazolyl‐1‐pyrazolylbenzenes from 1‐Propargyl‐1H‐benzotriazoles, Alkynes and Nitriles through α‐Imino Gold(I) Carbene Complexes

Abstract

Abstract.A three-components gold(I)-catalyzed synthesis of 2-imidazoyl-1-pyrazolylbenzenes from 1-propargyl-1H-benzotriazole is described here. Initially benzotriazole derivative suffers an intramolecular 5-endo-dig cyclization to form a triazapentalene. This dipolar compound is able to perform an intermolecular and regioselective attack to a gold-activated alkyne. After triazole breakage, pyrazole ring and -imino gold carbene complex are formed. Finally, iminocarbene is captured by a nitrile to form an imidazole ring. Keywords: gold catalysis; alkynes; iminocarbenes; imidazoles; pyrazolesThe synthesis of azoles, as pyrazoles [1] or imidazoles, [2] is a common target due to their appearance in the structure of natural products, biologically active compounds and also ligands in coordination chemistry. On the other hand, goldcatalyzed reactions involving -carbophilic gold alkyne activation represent an important step forward in heterocyclic synthesis. [3] Although the use of methodologies involving -oxo gold carbenes has been widely described, [4] their nitrogenated counterparts, the -imino gold carbenes, have received less attention [5] (Figure 1). This type of intermediates was first proposed by Toste and coworkers in a gold-catalyzed intramolecular pyrrole synthesis from homopropargyl azides as nitrene equivalents. [6] Since that seminal contribution, the most extended procedure for the access to -imino gold carbenes as intermediates is based on intramolecular transformations of azides with goldactivated alkynes. [7] In addition, a few intermolecular approaches have been carried out, although they require the use of heteroatom-polarized alkynes as ynamides. [8] The use of other nucleophilic nitrenoids as pyridine-N-aminides [9] or 2H-azirine derivatives, [10] has recently emerged as an elegant alternative to azides, however these methodologies present similar limitations in terms of intermolecular reactivity. Finally, isoxazoles [11] Herein we describe a catalytic methodology, involving three components, for the formation of 2-imidazolyl-1-pyrazolylbenzene derivatives. The synthesis is triggered by a 5-endo-dig cyclization of a 1-propargyl-1H-benzotriazole that generates a dipolar triazapentalene derivative (azomethine imine type). [12] The nucleophilicity of the dipole allows its 2 intermolecular attack to a gold-activated alkyne, to initiate a second catalytic cycle that involves the participation of a -imino gold carbene intermediate.In the course of our work in gold catalysis with alkynyl compounds, [13] we observed that treatment of 1-propargyl-1H-benzotriazole [14] 1a with 5 mol% of IPrAuNTf 2 in 1,2-dichloroethane at 70ºC for 4h, give rise to benzofusedtriazapentalene 2a in 78% yield. [15] This result indicates a 5-endo-dig nucleophilic attack from the central nitrogen atom of the triazole [16] to the gold-activated triple bond. However, when this reaction was performed in acetonitrile at room temperature, we observed, after 30 minutes, the formation of a precipitate. Upon filtration, a yellow so...

α‐Imino Gold Carbene Intermediates from Readily Accessible Sulfilimines: Intermolecular Access to Structural Diversity

“…Chemists can benefit from exploiting such methodologies for rapid synthesis or late‐stage modification of biologically important compounds. Under this principle, a series of cyclic nitrenoid precursors, including 2 H ‐azirines, isoxazoles, 1,2,4‐oxadiazoles, 1,4,2‐dioxazoles, 4,5‐dihydro‐1,2,4‐oxadiazoles, 2,1‐benzisoxazoles, 1,2‐benzisoxazoles, pyrido[1,2‐ b ]indazoles, and triazapentalenes have been developed for the direct introduction of nitrogen‐containing heterocyclic frameworks, whereas the corresponding gold carbenes generally underwent a limited number of transformations (Scheme A). By contrast, azides and pyridium aza‐ylides potentially provide more opportunities to obtain reaction and product diversity (Scheme B).…”

Dioxazoles, a new mild nitrene transfer reagent in gold catalysis: highly efficient synthesis of functionalized oxazoles

“…3 These highly reactive gold-species are mainly accessed through gold-catalyzed nitrene transfer to alkynes using azides as the nitrene equivalent, as reported by Toste, 4a Gagosz, 4b Zhang 4c-e and others. 4 Recently, 2H-azirines, 5 N-iminopyridium ylides, 6 isoxazoles, 7 benzoisoxazoles 8 and triazapentalene 9 have also been used as nitrene equivalents. Despite the impressive progress made so far, the development of new methods for the generation of a-imino gold carbenes involving the utilization of less reactive/ sensitive nitrene transfer reagents with high chemo-and regioselectivities under milder reaction conditions is still highly desired.…”

“…Various commonly used gold catalysts also catalyze the desired cyclization efficiently, furnishing 3a in lower yields of 72-87% (entries 6-8). The reaction could also be performed smoothly in the DCM, THF, toluene or CH 3 CN solvents (entries [9][10][11][12]. No reaction was observed catalyzed by IPrAuCl or AgNTf 2 alone or in the absence of any catalyst (entries 13-15).…”

Regiodivergent Control in the Gold(I) Catalyzed Synthesis of 7‐Pyrazolylindoles from 1‐Propargyl‐1H‐benzotriazoles and Ynamides through α‐Imino Gold(I) Carbene Complexes

“…We started our study using benzofused triazapentalene 1 a (R 1 = p Tol; R 2 =Ph), easily accessible from the corresponding 1‐propargyl‐1 H ‐benzotriazole, and N ‐methyl‐ N ‐tosylynamide 2 a (R 3 =Ph), as the starting materials (Scheme ). The reaction was performed at 70 °C, in 1,2‐dichloroethane (DCE) and using IPrAuNTf 2 (IPr=1,3‐bis(2,6‐diisopropylphenyl)‐2,3‐dihydro‐1 H ‐imidazol‐2‐ylidene) as the gold catalyst.…”

“…Thus, pyridine-N-aminides, [6] 2H-azirine derivatives, [7] isoxazoles, [8] oxadiazoles, [9] dioxazoles, [10] indazoles [11] or directly from a gold-catalyzed decomposition of diazo compounds [12] have demonstrated to be alternatives. On the other hand, we have recently reported in this field an efficient procedure for the synthesis of 2-imidazolyl-1-pyrazolylbenzenes from propargylbenzotriazoles, alkynes and nitriles (Figure 1), [13] with the participation of isolable triazapentalenes as nucleophiles. Exploration of this reaction in absence of the nitrile compounds resulted in the decomposition of the starting materials.…”