[4 + 3] Cycloadditions with Bromo-Substituted Morita–Baylis–Hillman Adducts of Isatins and N-(ortho-Chloromethyl)aryl Amides

Abstract

Efficient construction of a challenging aza-spirocycloheptane oxindole scaffold is reported through an unprecedented [4 + 3] cycloaddition reaction with bromo-substituted Morita-Baylis-Hillman adducts of isatins and N-(ortho-chloromethyl)aryl amides. Both reactive intermediates, the allylic phosphonium ylides and aza-o-quinone methides, were in situ generated, chemoselectively facilitated by a Lewis base and Brønsted base, respectively.

Transformations of Modified Morita‐Baylis‐Hillman Adducts from Isatins Catalyzed by Lewis Bases

“…In 2015, our group developed a [4+3] annulation reaction between bromo‐substituted MBH adducts 95 derived from isatins and N ‐( ortho ‐chloromethyl)aryl amides 96 mediated by tertiary phosphine and Cs 2 CO 3 (Scheme ) . Allylic P‐ylides II facilitated by Lewis base and Brønsted base, and aza‐ o ‐quinone methides (aza‐ o QMs) VI promoted by Brønsted base were generated in situ, finally delivering aza‐spirocycloheptane oxindole frameworks 97 in good yields.…”

Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers

“…virantmycin [4] and chartellin [5] ), have led to an increased awareness of these scaffolds. [8] Fort he in situ generation of aza-ortho-quinone methides various methods have been proven of value,among them the base-induced 1,4-elimination of ortho-chloromethyl aniline derivatives, [2][3][4]9] thermally induced dehydration of benzyl alcohols, [10] and photochemically induced enolizations of ortho-carbonyl anilides. [8] Fort he in situ generation of aza-ortho-quinone methides various methods have been proven of value,among them the base-induced 1,4-elimination of ortho-chloromethyl aniline derivatives, [2][3][4]9] thermally induced dehydration of benzyl alcohols, [10] and photochemically induced enolizations of ortho-carbonyl anilides.…”

“…[6] Nevertheless,a za-ortho-quinone methides,especially compared to their oxygen-containing analogous ortho-quinone methides, [7] have not been adequately investigated to date.P articularly in the area of asymmetric synthesis,only afew examples exist. [8] Fort he in situ generation of aza-ortho-quinone methides various methods have been proven of value,among them the base-induced 1,4-elimination of ortho-chloromethyl aniline derivatives, [2][3][4]9] thermally induced dehydration of benzyl alcohols, [10] and photochemically induced enolizations of ortho-carbonyl anilides. [11,12] Thev ariety of possibilities may be surprising;h owever, in reality it is limited by the predominantly harsh reaction conditions.M any substrates are not compatible with the use of overstoichiometric amounts of base,t he exposure to high temperatures (often under flash-vacuum-pyrolysis conditions), or continuous irradiation.…”

“…Thea pplication of the corresponding N-triflylphosphoramides [8d] resulted in lower enantiomeric excesses. [23] Theutilization of different solvents had agreat impact on the reaction outcome with regard to the stereoselectivity; however, no clear trend could be deduced from the results (entries [9][10][11][12]. Surprisingly,r eactions conducted in benzene and xylene provided the addition products with clearly lower ee values than in toluene,a nd also when DCM was used, no improvement was achieved.…”

Asymmetrische Brønsted‐Säure‐katalysierte Substitution von Diarylmethanolen mit Thiolen und Alkoholen zur Synthese von chiralen Thioethern und Ethern

“…Vora llem im Bereich der asymmetrischen Synthese existiert bislang nur eine Handvoll an Methoden. [8] Zur In-situ-Erzeugung von Aza-ortho-chinonmethiden haben sich im Verlauf der Jahre verschiedene Methoden bewährt, darunter vorangig baseninduzierte 1,4-Eliminierungen von ortho-Chlormethylanilinen, [2][3][4]9] thermisch realisierte Dehydratisierungen von Benzylalkoholen [10] sowie photochemisch induzierte Enolisierungen von ortho-Carbonylaniliden. [11,12] Daher stellte sich uns die Frage ob Thiole oder Alkohole enantioselektiv an Aza-ortho-chinonmethide addieren und dadurch gezielt C-S-bzw.C-O-Bindungen aufgebaut werden kçnnen (Schema 1, unten).…”