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Abstract

Polysubstituted furan has been found as a key structural unit in many bioactive natural products and pharmaceuticals. [1] It is also a reactive species that, upon appropriate activation, can be engaged in complex chemical transformations. [2] The development of efficient furan syntheses has thus attracted chemists for decades and continues to be an active and rewarding research area. [3,4] Besides polysubstituted furans, various annulated derivatives such as benzo-, thieno-, isoxazolo-, furo-, pyridino-, pyridazino-, and indolofuran have been synthesized and their properties investigated. [5] Cyclization of acyclic precursors and derivatization of an appropriately functionalized furan ring are two main strategies used for the elaboration of polysubstituted furans. New technologies such as solid-phase synthesis [6] and multicomponent reactions [7] have recently been developed for the preparation of this heterocycle.Furoquinoline alkaloids, typical constituents of the Rutaceae and Solanaceae plant species, are the most widely distributed of quinoline alkaloids. [8] Antimicrobial, antitumor, and antiemetic activities have been attributed to both natural and synthetic analogues of these molecules. [9] While several synthetic routes to individual furoquinolines have been developed, most of them were linear and involved harsh reaction conditions. [10,11] In connection with our ongoing project aimed at using oxazoles as a starting point to reach diverse druglike heterocycles, [12] we report herein a conceptually novel multicomponent domino synthesis of furo[2,3c]quinoline 1 (Scheme 1) from readily available substrates. [13,14] Using methyl 3-(2-aminophenyl)prop-2-ynoate (2 a), heptanal (3 a), and isocyanoacetamide (4 a) as substrates, a survey of reaction conditions is summarized in Table 1. The reaction proceeded in refluxing toluene to provide the desired furoquinoline 1 a (R 1 ¼ H, R 2 ¼ CO 2 CH 3 , R 3 ¼ (CH 2 ) 5 CH 3 , NR 4 R 5 ¼ morpholinyl), albeit in low yield. Both lithium bromide [15] and camphorsulfonic acid were detrimental to the desired transformation, while ammonium chloride [16] promoted the reaction sequence efficiently, providing 1 a in 75 % yield.The scope of this novel multicomponent reaction was examined using three ortho-alkynyl anilines, [17] five aldehydes, and three isocyanoacetamides as substrates (Scheme 2). Some representative furoquinolines synthesized are shown in Scheme 3. The potential and general applicability of this novel three-component domino process is readily seen from these selected examples. Aniline derivatives bearing both electronically poor and electronically neutral acetylene units participated in the reaction. For the aldehyde substrate, aliphatic aldehydes, including sterically hindered isobutyraldehyde, and aromatic aldehydes bearing electron-donating or -withdrawing groups were suitable. Various substituted amino groups were easily incorporated by varying the isocyanoacetamide substrate. The presence of aryl bromide and ester functional groups in furoquinolines sho...

Computational Assessment of the Electronic Structure of 1‐Azacyclohexa‐2,3,5‐triene (3δ2‐1H‐Pyridine) and Its Benzo Derivative (3δ2‐1H‐Quinoline) as well as Generation and Interception of 1‐Methyl‐3δ2‐1H‐quinoline

“…A palladium‐catalyzed aromatization of three‐component‐coupling products, which is based on a new transfer hydrogenation reaction, is the key step of the described method. The sequential combination of a three‐component‐coupling reaction and a domino deprotection/aromatization reaction leads to the straightforward synthesis of polysubstituted anilines with diverse substitution patterns 24. The overall procedure utilizes simple, readily available starting materials and is unique in that it allows the (regio)selective introduction of substituents in one ortho , one meta , and para position, as well as electron‐deficient substituents in the other ortho and meta positions.…”

Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry

“…A three-component reaction to give furoquinolines 83 in 75% yield simply by heating a toluene solution of methyl 3-(2-aminophenyl)prop-2-ynoate 82, heptanal 75, and isocyanoacetamide 70 at reflux in the presence of ammonium chloride was described in Scheme 19. 62 At least six distinct reactions, including condensation between aldehyde and amine, nucleophilic addition of isocyanide to imine, ringchain tautomerization of the nitrilium intermediate, intramolecular Diels-Alder cycloaddition of oxazole, retro-Diels-Alder reaction, and oxidation, occurred in this onepot process. Anilines bearing both electronically poor and neutral acetylene units participated in the reaction.…”

Domino Ring‐Opening/Recyclization Reactions of Doubly Activated Cyclopropanes as a Strategy for the Synthesis of Furoquinoline Derivatives

“…Recently, in conjunction with drug development, new synthetic routes to furoquinoline derivatives have been developed 5. For example, furoquinolines were synthesized in a single step by a multicomponent domino reaction of an ortho ‐alkynyl aniline, an isocyanoacetamide, and an aldehyde5a and by the tandem radical annulation of unsaturated N ‐aryl thiocarbamates,5b although there are limitations in terms of the starting materials, expensive reagents are involved, and the regioselectivity is not controllable in some cases. Herein, we report a new strategy for the synthesis of furo[2,3‐ b ]quinoline derivatives 2 in a single step from doubly activated cyclopropane precursors in the form of readily available 1‐acyl N ‐aryl cyclopropanecarboxamides 1 (Scheme 1).…”