Formation of 8‐Hydroxyphenanthridines by Microwave‐Mediated IMDAF Reactions; Synthesis Directed towards Lycorine Alkaloids

Abstract

8‐Hydroxyphenathridines have been synthesized efficiently from N‐propargyl‐ortho‐furylanilines employing microwave‐mediated one‐pot intramolecular Diels–Alder reaction on furans (IMDAF) reaction and subsequent aromatization. The 8‐hydroxyphenathridines were also subjected to further functionalization; O‐alkylation and conversion to the corresponding triflate followed by Suzuki coupling. N‐Propargyl‐7‐furylindole and the corresponding indoline also underwent smooth IMDAF cyclization to give, after rearomatization, 7H‐pyrrolo[3,2,1‐de]phenanthridin‐9‐ol or the 4,5‐dihydro analog. These cyclization products could be further functionalized, i.e. O‐ or N‐alkylation and oxidation at C‐6. The oxidation could lead to 6‐oxo derivatives or pyrrolo[3,2,1‐de]phenanthridin‐6‐ium salts depending on the reaction conditions and structure of the substrate. The 9‐oxy‐pyrrolophenanthridines synthesized are structurally closely related to bioactive lycorine alkaloids.

Selective C‐7 Functionalization of Phenanthridines by Microwave‐Assisted Claisen Rearrangements of 8‐Allyloxyphenanthridines

“…Additional references are cited within the Supporting Information. [21][22][23][24][25][26][27] The Supporting Information contains description of DFT calculations and procedures and spectral data for all novel compounds as well as copies of 1 H and 13 C NMR spectra of all novel compounds. ChemistryOpen…”

“…We have developed a synthetic route to phenanthridines with a microwave‐mediated IMDAF reaction of allylamino‐ ortho ‐furylarenes as a key‐step [12] . Later, we showed that propargylamino‐ ortho ‐furylarenes cyclized to 8‐hydroxyphenanthridines [13] . The hydroxyl group in the 8‐position offers possibilities for further functionalization in the C‐ring.…”

“…The hydroxyl group in the 8‐position offers possibilities for further functionalization in the C‐ring. We have previously demonstrated that the phenanthridinols can be transformed into the corresponding triflates and C‐substituents can be introduced at C‐8 by subsequent Suzuki cross‐couplings [13] . An oxygen substituent also opens the possibility for late‐stage functionalization of the neighboring unsubstituted positions.…”

Recent Applications of the Diels–Alder Reaction in the Synthesis of Natural Products (2017–2020)

“…By conveniently reacting N-alkyl-ortho-furylanilines 238, 239 and 240 in the presence of catalytic amounts of hydrochloric acid (Scheme 57), the formation of the annulated 5/6/6/6-ring system is achieved in one step via an endo-selective [4+2]-cycloaddition followed by a cycloreversion. 80 Scheme 57 A microwave-assisted intramolecular Diels-Alder reaction on furans (IMDAF) conveniently yields 8-hydroxyphenanthridines 235, 236 and 237 5 Syntheses from 2020…”

“…By conveniently reacting N -alkyl- ortho -furylanilines 238 , 239 and 240 in the presence of catalytic amounts of hydrochloric acid (Scheme 57 ), the formation of the annulated 5/6/6/6-ring system is achieved in one step via an endo -selective [4+2]-cycloaddition followed by a cycloreversion. 80…”