Acylation-cycloalkylation. Reaction of phenylacetyl chloride with cyclohexene

Valko, Joseph T.; Wolinsky, Joseph

doi:10.1021/jo01323a029

Cited by 9 publications

(4 citation statements)

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“…Intriguingly, Friedel–Crafts-type reactions of alkenes have also been found to enable remote functionalization of alkenes (Fig. 1b , bottom); such transformations, however, invariably suffer from undefined selectivity—often giving mixtures of 1,2- and 1,3-functionalization products 24 – 27 —or are possible only under substrate control or on specialized substrates 28 – 30 . Thus, although the corresponding reactivity, at its core that of the Friedel–Crafts reaction, has been explored, little is known about the factors governing the selectivity or predictability of such transformations, and the direct and general 1,3-difunctionalization of unactivated and unfunctionalized alkenes remains an unmet challenge.…”

Section: Mainmentioning

confidence: 99%

“…4b ) we believe that the 1,3-difunctionalizations presented above rely on a rapid isomerization event. This converts, under thermodynamic control, what would be the first intermediate of electrophilic addition 23 , 24 , 27 , the β-keto cation, into the rearranged, cyclic oxocarbenium ion rac -I 45 – 50 —with the formation of rac -I constituting a locking event to prevent further isomerization and non-selective product formation. This common intermediate is then intercepted either in hydrolytic fashion at the carbonyl (affording the syn -configured products) or through invertive displacement at the secondary sp 3 -centre C3 with other nucleophiles, resulting in the formation of the anti -configured products described above.…”

Section: Mainmentioning

confidence: 99%

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Stereodivergent 1,3-difunctionalization of alkenes by charge relocation

Brutiu,

Iannelli,

Riomet

et al. 2024

Nature

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Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene—1,2-difunctionalization—is part of chemistry curricula worldwide1. Although difunctionalization at distal positions has been reported2–4, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation5–7. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed ‘charge relocation’, which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.

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Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Stereodivergent 1,3-difunctionalization of alkenes by charge relocation

Brutiu,

Iannelli,

Riomet

et al. 2024

Nature

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“…fur C20H,,N0,(313,43): C 76,64,H 8,68,N 4,47;gef. : C 76,3,H 8,5,N 4,7. N- Cyclopropylmethy1-3-methoxy-4bN-dimethyl-cis-4b,5,6,7,8,8a,9.10-octahydrophenanthren-9-amin (4e und 3e). In 80 ml THF wurden 6,5 g (0,17~) LiAlH, unter Riickfluss vorgelegt und innert 1 Std.…”

Section: -Mefhoxy-4b-me~hylunclassified

Synthese von neuen Morphin‐Teilstrukturen des Typs 15,16‐Secomorphinan

Révész

1984

Helvetica Chimica Acta

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Synthesis of the New Morphine Partial Structure 15,16-Secomorphinan SummaryThe synthesis of a new morphine partial structure, 15,16-secomorphinan, is described. One of the series, (f)-l5,16-secocyclorphan (9, has the analgesic potency of morphine and exhibits good binding to the opiate receptor.1. Einleitung. -Die Entdeckung endogener Opiate (Enkephaline, Endorphine und Dynorphine) hat der Opiatforschung in den letzten Jahren neue Impulse gegeben [ 11. Die biologische Funktion dieser endogenen opioiden Peptide beschrankt sich nicht nur auf Dampfung der Schmerzsignale; Enkephaline beispielsweise spielen auch eine wichtige Rolle als Neurotransmitter im Zentralnervensystem [2] bei der Steuerung der Sekretion von Hypophysenhormonen [3]. Mit exogenen Opiat-Agonisten bzw. -Antagonisten kann in die Regulierung derselben Hormone eingegriffen werden [4].Entsprechend unserem Interesse an analgetisch bzw. endokrinologisch wirksamen Opioiden haben wir (+)-15,16-Secocyclorphan (5) und dessen Isomer 6 als Zielmolekule gewahlt. Anhand der einfach zuganglichen Modellverbindung 5 war es moglich, die Auswirkungen der Offnung des Morphinan-Piperidinrings zwischen C( 15) und C( 16) auf die biologische Aktivitat zu studieren und mit dem entsprechenden Morphinanderivat Cyclorphan [5] zu vergleichen. Trotz starker Zunahme an Flexibilitat im Molekul besass 5 erhebliche Affinitat zum Opiat-Rezeptor (lC,, = 51 nM; [3H]-Naloxon) und war analgetisch gleich stark (ED,, = 2,7 mg/kg; 'hot plate'; S.C. Maus) wirk-Sam wie Morphin, jedoch schwacher als Cyclorphan'). Antagonistische Eigenschaften wie in Cyclorphan konnten in 5 nicht nachgewiesen werden. Uberraschend ist die gute Rezeptor-Affinitat des Isomers 6 (IC,o = 35 nM) und dessen analgetische Wirkung (ED,, = 17 mg/kg; 'hot plate'; S.C. Maus). 2. Synthese. -@-Methoxypheny1)acetylchlorid (1) wurde unter Friedel-Crafts-Bedingungen [7] mit 1-Methyl-1-cyclohexen behandelt und das entstandene Keton als Oxim 2 isoliert. Die cis-Konfiguration von 2 wurde im 'H-NMR-Spektrum mittels nuklearem Overhauser-Effekt (NOE) zwischen der CH,-Gruppe an C(4b) und H-C(8a) nachgewiesen. Reduktion von 2 lieferte mit der 5fachen Gewichtsmenge ') (&)-Cyclorphan: ED,, = 0,12 mg/kg, 'writhing' Test, s.c., Maus; S.C. =: subcutane Applikation. H~LVETICA CHIMICA ACTA -Val. 67 (1984) Experimenteller TeilAllgemeines. Schmelzpunkte (Schmp.) sind nicht korrigiert. IR-Spektren: Perkin-Elmer 21, lmax in cm-'. 'H-NMR-Spektren: Bruker WH-360; chemische Verschiebung in ppm relativ zu TMS ( = 0 ppm). Kopplungskonstanten J in Hz; s = Singulett, d = Dublett, I = Tripiett, m = Multiplett, br. = breit. Zur NMR-Analyse gelangten 3a und 4a als Salze, 3e, 4e, 5 und 6 als freie Basen.

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“…[4] The majority of the traditional approaches available for the assembly of these molecules involve multistep transformations and harsh reaction conditions. [5] In contrast, transition metal-catalyzed cyclization reactions provide a straightforward access to these benzoxepines. For example, Lu [6] reported the synthesis of 1-benzoxepines by two cationic palladium-catalyzed [5 + 2] annulation reactions.…”

mentioning

confidence: 99%