Synergistic Gold(I)/Trimethylsilyl Catalysis: Efficient Alkynylation of N,O‐Acetals and Related Pro‐Electrophiles

Abstract

We report a unique mechanism-guided reaction that enhances and expands the chemical space that readily generated gold(I) acetylides currently operate in. Our strategy exploits the propensity of gold(I) carbophilic catalysts with specific counteranions (LAuX -X = triflate or triflimidate) to efficiently activate and desilylate trimethylsilylalkynes, thereby mediating the in situ formation of equal and catalytic quantities of a silyl Lewis acid (TMSX) of tunable strength and a nucleophilic gold(I) acetylide. This unprecedented manifold opens avenues for developing synergistic silyl-gold(I)-catalyzed alkynylation strategies of diverse pro-electrophiles which were heretofore unattainable, the proof of concept being principally exemplified herein with the first catalytic alkynylation of N,O-acetals. The reaction proceeds at low catalyst loading, employs mild reaction conditions, is easily scalable, and affords propargylic lactam products in good to excellent yields. Fur-thermore, it is fully amenable to a diverse array of structure and function substrates, and also expands to other pro-electrophiles beyond N,O-acetals. Control experiments have been carried out that strongly support our dual reaction mechanism proposal which, furthermore, itself outlines an inextricable link between the strength of the ancillary silyl Lewis acid (TMSOTf versus TMSNTf 2 ) and the coordinating ability of the gold counter anion employed. This underlying feature of our system underscores its significant potential and flexibility, which indeed manifests with the demonstration that by carefully selecting the gold counter ion, it is possible to manipulate the strength of the ancillary silyl Lewis acid so that it can be tailored to the ionizing ability of a particular pro-electrophile.

Counterion Effects in Homogeneous Gold Catalysis

“…The choice of the counterion proved to be of pivotal importance also in the alkynylation of N , O -acetals . In this regard, Dalla and co-workers reported on the direct intermolecular condensation between trialkylsilylalkynes 33 and acetals 32 under mild conditions (CF 3 C 6 H 5 , 40 °C), in the presence of in-situ-formed PPh 3 AuOTf (1–3 mol %).…”

“…The choice of the counterion proved to be of pivotal importance also in the alkynylation of N,O-acetals. 64 In this regard, Dalla and co-workers reported on the direct intermolecular condensation between trialkylsilylalkynes 33 and acetals 32 under mild conditions (CF 3 A specific case in which the counterion proved to be fundamental in gold(I)-mediated processes, documented by Zhang and co-workers, employed the gold counterion as one of the reaction partners in the synthesis of methanesulfonyloxymethyl ketones 38. 65 The protocol involves the oxidation of terminal alkynes with quinoline N-oxide derivatives 37, 66 delivering the corresponding α-oxo gold carbenes XXV that were trapped by MsO − .…”

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron‐Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N‐Acyliminium Ion Chemistry

“…As iron-catalyzed alkynylation of N-acyliminium ions was not described before, we initially focused on the alkynylation of N-acyliminium ions. Based on the mechanism proposed by Dalla, [8] the activation of N,O-acetals, and trimethylsilylphenylacetylene by iron Lewis acids was presumed to generate a Fe-acetylide intermediate, which through an amidoalkynylation reaction can provide the expected alkyne compounds. This proposed mechanism was supported by previous studies on spÀ sp 3 CÀ C bond formation via Fe-catalyzed coupling reactions of alkynes [6,24] and our previous work on N-acyliminium ions chemistry.…”

“…Recently, Dalla and coworkers have reported the catalytic alkynylation of N,O-acetals using synergic silyl-gold(I) catalysis and various silicon-based alkyne nucleophiles [Scheme 1, Equation (4)]. [8] Despite the advances and elegance of the above synthetic methodology, several limitations exist: (i) The method relies on the use of pre-functionalized starting materials (acetoxylactams) whereas the direct substitution of hydroxylactams would be an ideal substrate for atom-economy and environmentally friendly processes; (ii) The alkynylation reaction employs costly noble metals whereas the use of cheap catalysts would be very desirable; (iii) Only endocyclic N-acyliminium ions were used, while the use of exocyclic and bis N-acyliminium ions could offer a vast array of possible combinations resulting in multiple synthetic opportunities.…”

Catalytic Alkynylation of Cyclic Acetals and Ketals Enabled by Synergistic Gold(I)/Trimethylsilyl Catalysis

“…To reach this goal we sought to exploit a synergistic gold­(I)–silicon catalysis concept recently introduced. − The latter is characterized by two interlaced catalytic cycles capable of producing in situ and simultaneously small amounts of a silicon-based Lewis superacid dedicated to the activation of a pro-electrophile, and a gold alkynylide intended for trapping the resulting intermediate promptly due to an improved nucleophilicity compared with the parent alkynylsilane. We have launched this concept by reporting the first catalytic alkynylation of N,O-acetals. , Assuming that our approach is transposable to a wider range of transformations, and thus bears the potential to become a truly general catalytic alkynylation methodology, we next identified the non trivial and challenging alkynylative ring-opening of cyclic acetals/ketals as new platform (Scheme ). We now report the successful realization of these ideas to provide diol monopropargylic ethers with perfect regiocontrol and moderate diastereocontrol.…”