Diastereoselective Rhodium-Catalyzed Hydrogenation of 2-Oxindoles and 3,4-Dihydroquinolones

Abstract

The benzene ring of indolin-2-ones (2-oxindoles) and 3,4-dihydroquinol-2-ones was converted to a saturated cyclohexane ring by hydrogenation in the presence of the rhodium complex Cy (CAAC)Rh(cod)Cl. The stereoselectivity of the process was found to be high with respect to both external substituent R 1 within the saturated part of the heterocyclic ring and substituent X on the benzene ring. Twenty-one hexahydroindolin-2(3H)-ones (70−99% yield, dr = 83/17 to >99/1) and twelve octahydro-2(1H)-quinolinones (87−96% yield, dr = 64/36 to >99/1) were obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward functional groups and the compatibility with existing stereogenic centers are key features of the hydrogenation protocol presented here.Letter pubs.acs.org/OrgLett

Ru‐NHC‐katalysierte asymmetrische Hydrierung von 2‐Chinolonen zu chiralen 3,4‐Dihydro‐2‐chinolonen

“…Das Dihydro‐2‐chinolon 2 b konnte unter Verwendung von DIBAL‐H als Reduktionsmittel ohne Verlust des Enantiomerenüberschusses zu Tetrahydrochinolin 3 b reduziert werden (Schema 5). [2a] Noch beeindruckender ist, dass das dimethylsubstituierte Produkt 2 r unter dem Rh‐CAAC/H 2 ‐Katalysatorsystem diastereoselektiv zum Octahydro‐2‐chinolon 4 r reduziert werden konnte [3b, 17] …”

“…B. Aripiprazol (Antipsychotikum), Carteolol (nichtselektiver Betablocker), Vesnarinon (Kardiotonikum), Cilostazol (Phosphodiesterase-3-Hemmer) sowie Melosuavne [1c,g] Arzneimittel oder medizinisch nützliche Naturstoffe, die alle das 3,4-Dihydro-2-chinolon-Motiv enthalten (Schema 1). Darüber hinaus kçnnen Dihydrochinolone vielseitige Zwischenprodukte für die Synthese verschiedener anderer Heterozyklen wie Tetrahydrochinoline [2] oder Octahydrochinolone [3] sein.…”

Ru‐NHC‐Catalyzed Asymmetric Hydrogenation of 2‐Quinolones to Chiral 3,4‐Dihydro‐2‐Quinolones

“…In addition, dihydroquinolones could potentially become versatile intermediates which could be further transformed to several other common heterocycles such as tetrahydroquinolines [2] or octahydroquinolones. [3] Although several methods have been explored to form achiral and racemic dihydroquinolones, [4] the construction of optically active dihydroquinolones, especially dihydro-2-quinolones, is still rare and highly desirable. Currently, there are two main approaches to access chiral dihydro-2-quinolones.…”

“…[2a] More impressively, the dimethyl‐substituted product 2 r was smoothly transformed to the saturated octahydroquinolone 4 r using the Rh–CAAC/H 2 catalyst system. [ 3b , 17 ]…”

1,2,4-Trifunctionalized Cyclohexane Synthesis via a Diastereoselective Reductive Cope Rearrangement and Functional Group Interconversion Strategy

“…For example, this substitution pattern has been accessed for drug discovery from Hagemann’s ester (en route to BMS-986251) and by Diels–Alder cycloaddition (en route to CAS: 1350711-03-3). Other ways to access this and related cyclohexane substitution patterns include arene hydrogenation, − conjugate addition, − and C–H functionalization − (Figure B). That said, all of these routes have their own unique challenges and limitations (e.g., stereoselectivity, functional group compatibility).…”