Gold(I)-Catalyzed Benz[c]azepin-4-ol Synthesis by Intermolecular [5 + 2] Cycloaddition

Abstract

A gold(I)-catalyzed intermolecular formal [2 + 5] cycloaddition for the preparation of benzofused N-heterocyclic azepine products is presented. A number of benz[c]azepin-4-ol products were readily prepared in one step from easily accessible phenylpropargyl acetals and benzaldimine substrates in the presence of a gold(I) catalyst. A direct one-pot procedure from the propargyl and the respective aldehyde and amine substrates was successful as well. The reaction to access the benzofused azepines could be rationalized by a cascade reaction, including a nucleophilic benzaldimine N-attack at a highly reactive phenylpropargyl-gold(I) carbenoid complex, generated from propargyl acetal. A subsequent deauration step promotes ring closure by 1,7-electrocyclization through an intramolecular Pictet-Spengler-type reaction with the aldiminium moiety.

Gold(I)‐Catalysed Azepine Synthesis from Propargyl Acetals and Aryl Azides

“…The reactions required a 5:1 substrate ratio and a 10 mol-% catalyst loading of the Au III Scheme 3. This comparison demonstrates that the significantly higher reactivity of propargyl acetals [9][10][11][12][13] relative to esters enables a more convenient and efficient process for azepine synthesis. catalyst, added in two batches, to give the target azepine products (5-12 h, 50-78 % yield).…”

“…The propargyl ester method has been applied in gold-catalysed cyclopropanation reactions [2a-2x,9] (Scheme 1, a), as well as in cycloaddition reactions. [9][10][11][12][13][14] These acetal substrates 1 give particularly reactive enol ether carbenoid/allylic gold(I) intermediates I′/I′′ by gold-catalysed triple-bond activation and alkoxy migration-fragmentation. [9][10][11][12][13][14] These acetal substrates 1 give particularly reactive enol ether carbenoid/allylic gold(I) intermediates I′/I′′ by gold-catalysed triple-bond activation and alkoxy migration-fragmentation.…”

“…[9][10][11][12][13][14] These acetal substrates 1 give particularly reactive enol ether carbenoid/allylic gold(I) intermediates I′/I′′ by gold-catalysed triple-bond activation and alkoxy migration-fragmentation. [9][10][11][12][13][14] Our recent study on the gold(I)-catalysed formation of cis-1,2-oxazine derivatives from propargyl acetals 1 and nitrone 1,3-dipoles [14] (Scheme 1, f ) by an uncommon [3+3] cycloaddi-tion. The activating effect provided by the MeO-vinyl group in gold carbenoid complexes I′ and I′′ facilitates subsequent reactions, and explains the higher reactivity of propargyl acetals compared to the corresponding esters.…”

“…1,3-Dipolar compounds are versatile and powerful synthetic tools for the formation of five-membered rings by [2+3] cycloaddition reactions with dipolarophiles. [9][10][11][12][13][14] PicAu III Cl 2 (Pic = picolyl). This approach has been reported for propargyl esters and benzylic azides, which give azepine products via vinyl imine intermediates.…”

“…Azide substrates may, however, also follow alternative reaction pathways via intermediates generated through azide decomposition. We have previously developed a synthesis of benzazepines [11] through gold-catalysed [2+5] cycloaddition starting from propargyl acetals; other gold-catalysed cyclisation reactions have been used for the construction of azepines [17a-17c] and benzazepines. [15] Similar azepine products have also been synthesised directly from propargyl esters and vinyl imines.…”