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Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

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ABSTRACT

Starting from γ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally defined the structure of crucial cyclization products. The relative configuration of the precursor compounds is essentially transferred to that of the products and the formed hydroxy group in the newly generated cyclohexane ring is consistently in trans-arrangement with respect to the methoxycarbonyl group. A transition-state model is proposed to explain the observed stereochemical outcome. This palladium-catalyzed Barbier-type reaction requires a reduction of palladium(II) back to palladium(0) which is apparently achieved by the present triethylamine.

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Palladium-catalyzed reactions of methyl ketone 1 to tetralin derivative 7 and of isopropyl-substituted ketone 2 to compounds 8, 9 and 10.
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C3: Palladium-catalyzed reactions of methyl ketone 1 to tetralin derivative 7 and of isopropyl-substituted ketone 2 to compounds 8, 9 and 10.

Mentions: We start our report with the palladium-catalyzed reactions of simple alkyl ketones 1 and 2 leading to bicyclic products and then continue with the transformations of cyclic ketones 3–6 that led to tricyclic compounds. Methyl ketone 1 provided under the reaction conditions (2 mol % Pd(PPh3)4, 3.5 equivalents NEt3, DMF, 110 °C, 3 d) that had been optimized with compound 4 a moderate yield of the tetralin derivative 7 formed as a single diastereomer (Scheme 3). Although the configurational assignment is ambiguous in this case, the NMR data and the fact that no γ-lactone is formed strongly support the trans-arrangement of the two functional groups as depicted. Under similar conditions (5 mol % Pd(PPh3)4, 90 °C, 3 d) the isopropyl-substituted ketone 2 furnished a mixture of the related trans-compound 8 (11%) together with the de-iodinated product 9 (25%) and the indane derivative 10 as major component (62%). The C–C coupling reaction to 8 seems to be hindered in this case, probably due to the steric bulk of the isopropyl group. The formation of indane derivative 10 occurs by an intramolecular enolate arylation, a reaction that has been discovered by our group some years ago [11–12]. Apparently, under the reaction conditions a ketone enolate of 2 reacts with the iodoarene moiety to form the five-membered ring of 10. The configurational assignments of compounds 7 and 8 are in agreement with those discussed below, where X-ray crystal structure analyses unequivocally confirmed the relative configurations of cyclization products.


Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups
Palladium-catalyzed reactions of methyl ketone 1 to tetralin derivative 7 and of isopropyl-substituted ketone 2 to compounds 8, 9 and 10.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4979759&req=5

C3: Palladium-catalyzed reactions of methyl ketone 1 to tetralin derivative 7 and of isopropyl-substituted ketone 2 to compounds 8, 9 and 10.
Mentions: We start our report with the palladium-catalyzed reactions of simple alkyl ketones 1 and 2 leading to bicyclic products and then continue with the transformations of cyclic ketones 3–6 that led to tricyclic compounds. Methyl ketone 1 provided under the reaction conditions (2 mol % Pd(PPh3)4, 3.5 equivalents NEt3, DMF, 110 °C, 3 d) that had been optimized with compound 4 a moderate yield of the tetralin derivative 7 formed as a single diastereomer (Scheme 3). Although the configurational assignment is ambiguous in this case, the NMR data and the fact that no γ-lactone is formed strongly support the trans-arrangement of the two functional groups as depicted. Under similar conditions (5 mol % Pd(PPh3)4, 90 °C, 3 d) the isopropyl-substituted ketone 2 furnished a mixture of the related trans-compound 8 (11%) together with the de-iodinated product 9 (25%) and the indane derivative 10 as major component (62%). The C–C coupling reaction to 8 seems to be hindered in this case, probably due to the steric bulk of the isopropyl group. The formation of indane derivative 10 occurs by an intramolecular enolate arylation, a reaction that has been discovered by our group some years ago [11–12]. Apparently, under the reaction conditions a ketone enolate of 2 reacts with the iodoarene moiety to form the five-membered ring of 10. The configurational assignments of compounds 7 and 8 are in agreement with those discussed below, where X-ray crystal structure analyses unequivocally confirmed the relative configurations of cyclization products.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Starting from γ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally defined the structure of crucial cyclization products. The relative configuration of the precursor compounds is essentially transferred to that of the products and the formed hydroxy group in the newly generated cyclohexane ring is consistently in trans-arrangement with respect to the methoxycarbonyl group. A transition-state model is proposed to explain the observed stereochemical outcome. This palladium-catalyzed Barbier-type reaction requires a reduction of palladium(II) back to palladium(0) which is apparently achieved by the present triethylamine.

No MeSH data available.