Iodine-Mediated Electrophilic Cyclization of 2-Alkynyl-1-methylene Azide Aromatics Leading to Highly Substituted Isoquinolines and Its Application to the Synthesis of Norchelerythrine

Abstract

The reaction of 2-alkynyl-1-methylene azide aromatics 1 with iodine and/or other iodium donors, such as the Barluenga reagent (Py2IBF4/HBF4) and NIS, gave highly substituted cyclization products, namely, the 1,3-disubstituted 4-iodoisoquinolines 2, in good to high yields. Not only simple 2-alkynyl benzyl azides 1a-j and their substituted analogues 1k-u and 6 but also heteroaromatic analogues, including pyridine 8, pyrroles 10a-c, furane 10d, and thiophenes 10e-g, gave the corresponding isoquinoline derivatives in excellent to allowable yields. Electron-donating and electron-accepting substituents on the aromatic ring were equally tolerated, and either acidic or basic (or even neutral) reaction conditions, depending on the reactivity of the substrate, could be applied to smoothly convert the azide starting materials into the desired isoquinoline products in moderate to good yields. Limits were found only in connection with the substituent at the alkyne terminus, where electron-neutral or electron-donating substituents are clearly favored. The iodine-mediated electrophilic cyclization of 1 most probably proceeds through the iodonium ion intermediate 4 followed by nucleophilic cyclization of the azide and subsequent elimination of N2. This new methodology was successfully applied to the short synthesis of norchelerythrine.

Copper‐Catalyzed Asymmetric Allylic Alkylation of Halocrotonates: Efficient Synthesis of Versatile Chiral Multifunctional Building Blocks

“…(a)] could be obtained. [41,42] 2,4-Disubstituted 3-butyrolactones [43] (Scheme 7) are interesting building blocks for natural product synthesis and have been used, for example, in the synthesis of jasplakinolide. [44] We envisioned constructing these highly versatile structures with three contiguous [c] 10 mol% HG-II and 20 mol% 2,6-dichlorobenzoquinone were used.…”

Synthesis of substituted isoquinolines utilizing palladium-catalyzed α-arylation of ketones

“…It is also imperative to develop routes to highly-substituted isoquinolines to fully explore this chemical space, for example, for potential pharmaceutical targets. While recent synthetic efforts have greatly expanded the diversity of isoquinoline motifs available (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), new routes to isoquinolines are still highly desirable, particularly ones with the ability to directly access the isoquinoline moiety in a range of oxidation levels and which do not require highly-specialized starting materials.…”

Silver‐Catalyzed One‐Pot Cyclization Reaction of Electron‐ Deficient Alkynes and 2‐Yn‐1‐ols: An Efficient Domino Process to Polysubstituted Furans

“…It is especially noteworthy that a novel 2,3,5-trisubstituted 4-ynylfuran was formally formed in an extremely direct manner without tedious stepwise synthesis. [13] The above studies dealt with 1a, 1b, 1c, 1d, and 1e as the starting materials. As an extension of the above study (Table 2), we devised other electronic-deficient compounds, such as substituted aryl alkynyl ketones (1e-1h), to investigate the possibility of this transformation.…”

“…Different from previous work, [13] the 2,3,5-trisubstituted 4-ynyl-furan was obtained from electron-deficient alkynes (1c-1e) and 2n or 2o in a one-pot manner. The reaction proceeds efficiently under mild conditions with commercially available catalysts.…”