1,2,3-Triazole-Mediated Synthesis of 1-Methyleneisoquinolines: A Three-Step Synthesis of Papaverine and Analogues

Abstract

A metal-free three-step synthesis toward functionalized 1-methyleneisoquinolines from readily available substrates is reported. First, acetal-containing 1,2,3-triazoles were prepared via a high-yielding triazolization reaction and quantitatively converted into triazolo­[5,1-a]­isoquinolines. Next, the acid-promoted ring opening of these fused triazoles was studied in order to obtain coupling to a diverse scope of nucleophiles, including carbon nucleophiles such as veratrole. By means of non-nucleophilic strong acids under anhydrous conditions, a series of unprecedented isoquinolines and imidazo­[5,1-a]­isoquinolines was synthesized.

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…The protocol was established over a wide range of substrates with good functional group tolerance to obtain 1‐methyleneisoquinolines in moderate yield (Scheme 336). [337] …”

Triazolization of Enolizable Ketones with Primary Amines: A General Strategy toward Multifunctional 1,2,3‐Triazoles

“…By starting from methoxy‐functionalized acetophenones 34 and aminoacetaldehyde dimethyl acetal 35 , the starting triazoles 36 could be obtained under the standard triazolization conditions (Scheme 11). [55] Thus, triazolo[5,1‐ a ]isoquinolines 37 were readily accessible via a simple, metal‐free and high yielding two‐step procedure, and further application of these substrates was sought by studying their denitrogenative ring‐opening in the presence of nucleophiles. The desired addition of nucleophiles was feasible under anhydrous conditions in the presence of a strong, non‐nucleophilic acid.…”

“…In the years after the first report, the procedure has been adapted in order to broaden the scope with respect to the amines and ketones [46–49] . Moreover, triazolization products found applicability in the large‐scale preparation of triazolium‐based ionic liquids, [50,51] in several cyclization strategies [52–55] and as potential antiviral or anticancer agents [56–59] . In this highlight, the triazolization reaction along with its modifications will be discussed.…”

Recent Advances in Denitrogenative Reactions of Pyridotriazoles

“…Recently, an acid-mediated denitrogenative reaction of 1,2,3-triazolo[5,1-a]isoquinolines 120 with nucleophiles was extensively studied by Dehaen and co-workers (Scheme 36). 30 The reactions with nucleophiles such as arenes, heteroarenes, alcohols, and thiols gave 1-methyleneisoquinolines 121 in moderate to good yields. Generally, mixtures of the regioisomeric insertion products 121 were obtained in the reactions with arenes.…”