Eine neue Methode zur Addition von Aldehyden an aktivierte Doppelbindungen, IV. Addition von aromatischen und heterocyclischen aldehyden an α,β‐ungesättigte Ketone

Stetter, Hermann; Schreckenberg, Manfred

doi:10.1002/cber.19741070805

Cited by 44 publications

(8 citation statements)

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“…Therefore, the benzyl substituent was introduced by a Stetter reaction 37. 38 The highest yield (49 %) of ketonitrile 11 was obtained by the reaction of the α,β‐unsaturated nitrile 5 with benzaldehyde and NaCN at 35 °C (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

et al. 2014

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In accordance with a novel strategy for generating the 2-benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.

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Section: Resultsmentioning

confidence: 99%

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

et al. 2014

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“…1,4-Diketones are important intermediates in the synthesis of five-membered carbocyclic 1 and heterocyclic 2 compounds, including the preparation of derivatives of terthiophene and other conjugated, five-membered heterocycles, which are being intensively investigated at present as monomers for electroconductive polymers. 3 Among the most convenient methods for the synthesis of symmetrical and asymmetrical 1,4-diketones, [4][5][6][7][8][9][10][11][12][13][14][15][16][17] the Michael-Stetter addition of aldehydes to a,b-unsaturated ketones, [8][9][10][11][12] as well as alkylation of stabilized alkaline metal enolates, 12-15 enamines 15, 16 and tin enolates by a-halocarbonyl compounds should be mentioned.…”

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One-Step Preparation of Symmetrical 1,4-Diketones from α-Halo Ketones in the Presence of Zn-I₂ as a Condensation Agent

Ceylan¹,

Gürdere²,

Budak³

et al. 2004

Synthesis

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O n e -S t e p P r e p a r a t i o n o f S y m m e t r i c a l 1 , 4 -D i k e t o n e s f r o m a -H a l o K e t o n e s Abstract: Eleven 1,4-diphenylbutane-1,4-diones have been prepared in one step from the corresponding a-halo acetophenones under the action of Zn-I 2 as a condensation agent with moderate to high yields. The mechanistic pathway of the reaction can be explained by the Wurtz-like self-condensation of a-halo ketones. Similarly, 3-chloropentane-2,4-dione gave 3,4-diacetylhexane-2,5-dione, a Wurtz-like condensation product.1,4-Diketones are important intermediates in the synthesis of five-membered carbocyclic 1 and heterocyclic 2 compounds, including the preparation of derivatives of terthiophene and other conjugated, five-membered heterocycles, which are being intensively investigated at present as monomers for electroconductive polymers. 3 Among the most convenient methods for the synthesis of symmetrical and asymmetrical 1,4-diketones, 4-17 the Michael-Stetter addition of aldehydes to a,b-unsaturated ketones, 8-12 as well as alkylation of stabilized alkaline metal enolates, 12-15 enamines 15,16 and tin enolates by a-halocarbonyl compounds should be mentioned.In this paper, we present a new and simple procedure for the generation of twelve symmetrical 1,4-diketones directly from the corresponding a-halo ketones. The reaction of a-halo ketones 1a-m with zinc dust in the presence of a small amount of I 2 at 65 °C gave the corresponding 1,4-diketones 2a-l, Wurtz-like condensation products, in moderate to high yields (Scheme 1, Table 1). Scheme 1The synthesis of compound 2a and similar products by different methods has been reported, but in only one 18 was the Zn-Cu couple (10 mol equiv) used in the presence of NaI (10 mol equiv). The reaction was carried out at high temperatures (90 and 170 °C), and resulted in 32 and 40% yields, respectively. Moreover, 2f and 2i were formed at 70 and 170 °C only in 32 and 25% yields, respectively.In our method, zinc dust was used as a reagent in the presence of a small amount of iodine, while activated zinc dust (Zn-Cu/NaI) was used in the above method. 18 The reactions were performed at a lower temperature (65 °C), and resulted in higher yields of 2a (67%), 2f (98%) and 2i (32%) ( Table 1).In the presence of a small amount of I 2, the reactions of ahalo ketones 1a-m with zinc were completed at 65 °C in 16 hours. Very mild and almost neutral reaction conditions allowed us to obtain mostly good results by using different starting compounds containing halogen or methoxy functional groups. The structure of 1,4-diketones 2a-l was elucidated from spectral data (NMR, IR, GC-MS, elemental analysis).Some limitations of this procedure should also be mentioned. Moderate yields were obtained with electron-rich ketone (p-methoxy, 1i) and o-substituted ketones 1d and 1g. Reductive removal of the functional groups from asubstituted carbonyl compounds is commonly known and a concerted mechanism has been suggested for this process. 19 The mechanism can be adopted to o-substituted ke...

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“…1,4-Diketones are useful synthetic intermediates for the preparation of five-membered carbocyclic and heterocyclic compounds. 1 Among the most convenient methods for the synthesis of asymmetrical 1,4-diketones, [2][3][4][5][6][7][8][9][10][11][12][13][14][15] the Michael-Stetter addition of aldehydes to a,b-unsaturated ketones, [6][7][8][9][10] as well as alkylation of stabilized alkaline metal enolates, [10][11][12][13] enamines, 13,14 and tin enolates 15 by a-halocarbonyl compounds should be mentioned. However, to our knowledge, the Michael-Stetter method does not give satisfactory results with electron-poor aromatic substrates, 10 and the last three methods are restricted mainly by aromatic or symmetrical aliphatic starting nucleophiles, which should be prepared from the corresponding carbonyl compounds.…”

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One Step Preparation of 1,4-Diketones from Methyl Ketones and α-Bromomethyl Ketones in the Presence of ZnCl2 · t-BuOH · Et2NR as a Condensation Agent

2000

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1,4-Diketones have been prepared in one step from methyl ketones and a-bromomethyl ketones under the action of ZnCl 2 ·t-BuOH·Et 2 NR as a condensation agent with moderate to high yields. The mechanistic pathway of the reaction is proposed to go through aldol condensation of ketones followed by 1,3-dehydrobromination of aldol products and cleavage of activated cyclopropyl intermediates.1,4-Diketones are useful synthetic intermediates for the preparation of five-membered carbocyclic and heterocyclic compounds. 1 Among the most convenient methods for the synthesis of asymmetrical 1,4-diketones, 2-15 the Michael-Stetter addition of aldehydes to a,b-unsaturated ketones, 6-10 as well as alkylation of stabilized alkaline metal enolates, 10-13 enamines, 13,14 and tin enolates 15 by a-halocarbonyl compounds should be mentioned. However, to our knowledge, the Michael-Stetter method does not give satisfactory results with electron-poor aromatic substrates, 10 and the last three methods are restricted mainly by aromatic or symmetrical aliphatic starting nucleophiles, which should be prepared from the corresponding carbonyl compounds.Recently, we have reported a new simple and regioselective method for the preparation of 1,4-diketones directly from methyl ketones and a-bromo ketones. 16,17 This method is based on the thermodynamically controlled cross aldol condensation of methyl ketones with a-bromo ketones followed by 1,3-dehydrobromination of the aldol products and cleavage of the corresponding intermediate activated cyclopropyl derivatives to 1,4-diketones. Using this approach, we have developed two main preparative procedures. The first is based on the application of two separate stages: aldol condensation of methyl ketones with a-bromo ketones in the presence of magnesium bases, and subsequent conversion of the aldol products into 1,4-diketones by treatment with tertiary amine. 16 In the second procedure, we have succeeded in combining these both stages into one using titanium isopropoxide as the condensation agent. 17In this paper, we propose another simple one step procedure for the preparation of 1,4-diketones 5a-r from methyl ketones 1a-n and a-bromo ketones 2a-g, which gives better results for the synthesis of products with strong a Compounds 3−5: R 1 , R 2 , see Table 1.

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Eine neue Methode zur Addition von Aldehyden an aktivierte Doppelbindungen, IV. Addition von aromatischen und heterocyclischen aldehyden an α,β‐ungesättigte Ketone

Cited by 44 publications

References 4 publications

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

One-Step Preparation of Symmetrical 1,4-Diketones from α-Halo Ketones in the Presence of Zn-I₂ as a Condensation Agent

One Step Preparation of 1,4-Diketones from Methyl Ketones and α-Bromomethyl Ketones in the Presence of ZnCl2 · t-BuOH · Et2NR as a Condensation Agent

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Eine neue Methode zur Addition von Aldehyden an aktivierte Doppelbindungen, IV. Addition von aromatischen und heterocyclischen aldehyden an α,β‐ungesättigte Ketone

Cited by 44 publications

References 4 publications

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

Synthesis, σ Receptor Affinity, and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

One-Step Preparation of Symmetrical 1,4-Diketones from α-Halo Ketones in the Presence of Zn-I2 as a Condensation Agent

One Step Preparation of 1,4-Diketones from Methyl Ketones and α-Bromomethyl Ketones in the Presence of ZnCl2 · t-BuOH · Et2NR as a Condensation Agent

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One-Step Preparation of Symmetrical 1,4-Diketones from α-Halo Ketones in the Presence of Zn-I₂ as a Condensation Agent