Regioselectivities of Diels-Alder cycloadditions to methoxy-substituted quinones

Tegmo‐Larsson, Inga‐Mai; Rozeboom, Melvin D.; Houk, K. N.

doi:10.1016/s0040-4039(01)93272-1

Cited by 24 publications

(7 citation statements)

References 5 publications

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“…In order to prepare HBADs analogous to 36 and 37 but with the opposite regiochemistry in the aromatic ring portion, the regioselectivity of the Diels-Alder reaction required alteration. Tegmo-Larsson et al 15 reported that 2,5-dimethoxybenzoquinone underwent a Diels-Alder reaction with 22 to give an adduct which, upon loss of MeOH, gave the 5,8-dihydronaphthalene with the methyl group in the desired 5-position. In our hands, this reaction proceeded slowly and was impractical for our needs.…”

Section: Aqueous Acid Hydrolysis Gave Hbads 19-21mentioning

confidence: 99%

“…The ice bath was removed, and the reaction mixture was allowed to stir at 25 °C for 20 h. NBS (1.03 g, 5.80 mmol) was added in one portion, and the reaction mixture was allowed to stir at 25 °C for 48 h. A second portion of NBS (500 mg, 2.81 mmol) was added, and the reaction mixture was allowed to stir for an additional 24 h. The reaction mixture was added to 50 mL of crushed ice, and a solution of 30% MeOH/70% CHCl3 (100 mL) was stirred in. The layers were separated, and the aqueous portion was extracted with 30% 7-Amino-3-methoxy-1H-1-benzazepine-2,5-dione (15). A mixture of 11 (250 mg, 1.01 mmol), quinoline (20 mg), and Pd/C (10%, 100 mg) in CH2Cl2/MeOH (1:1, 250 mL) was hydrogenated (Parr) at 5 psig for 1 h at 25 °C.…”

Section: -Bromo-3-methoxy-1h-1-benzazepine-25-dione (12)mentioning

confidence: 99%

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Analogs of 3-Hydroxy-1H-1-benzazepine-2,5-dione: Structure−Activity Relationship at N-Methyl-d-aspartate Receptor Glycine Sites

et al. 1996

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A series of aromatic and azepine ring-modified analogs of 3-hydroxy-1H-1-benzazepine-2,5-dione (HBAD) were synthesized and evaluated as antagonists at NMDA receptor glycine sites. Aromatic ring-modified HBADs were generally prepared via a Schmidt reaction with substituted 2-methoxynaphthalene-1,4-diones followed by demethylation. Electrophilic aromatic substitution of benzazepine 3-methyl ethers gave 7-substituted analogs. The preparation of multiply substituted 2-methoxynaphthalene-1,4-diones was effected via Diels-Alder methodology utilizing substituted butadienes with 2-methoxybenzoquinones followed by aromatization. Structural modifications, such as elimination of the aromatic ring, removal of the 3-hydroxyl group, and transfer of the hydroxyl group from C-3 to C-4, were also studied. An initial evaluation of NMDA antagonism was performed using a [3H]MK801 binding assay. HBADs demonstrating NMDA antagonist activity as indicated by inhibition of [3H]MK801 binding were further evaluated employing a [3H]-5,7-dichlorokynurenic acid (DCKA) glycine site binding assay. Selected HBADs were characterized for functional antagonism of NMDA and AMPA receptors using electrophysiological assays in Xenopus oocytes and cultured rat cortical neurons. Antagonist potency of HBADs showed good correlation between the different assay systems. HBADs substituted at the 8-position possessed the highest potency with the 8-methyl (5), 8-chloro (6), and 8-bromo (7) analogs being the most active. For HBAD 6, the IC50 in [3H]-DCKA binding assays was 0.013 microM and the Kb values for antagonism of NMDA receptors in oocytes (NR1a/2C) and cortical neurons were 0.026 and 0.048 microM, respectively. HBADs also antagonized AMPA-preferring non-NMDA receptors expressed in oocytes but at a lower potency than corresponding inhibition of NMDA receptors. HBADs demonstrating a high potency for NMDA glycine sites showed the highest steady-state selectivity index relative to AMPA receptors. Substitution at the 6-, 7-, and 9-positions generally reduced or eliminated glycine site affinity. Moving the hydroxyl group from C-3 to C-4 reduced receptor affinity, and potency was eliminated by the removal of the aromatic ring or the hydroxyl group. These data indicate that the HBAD series has specific structural requirements for high receptor affinity. With the exception of substitution at C-8, modified HBADs generally have a lower affinity at NMDA receptor glycine sites than the parent compound 3. Mouse maximum electroshock-induced seizure studies show that the three HBADs selected for testing have in vivo potency with the 6,8-dimethyl analog (52) being the most potent (ED50 = 3.9 mg/kg, iv).

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Section: Aqueous Acid Hydrolysis Gave Hbads 19-21mentioning

confidence: 99%

Section: -Bromo-3-methoxy-1h-1-benzazepine-25-dione (12)mentioning

confidence: 99%

Analogs of 3-Hydroxy-1H-1-benzazepine-2,5-dione: Structure−Activity Relationship at N-Methyl-d-aspartate Receptor Glycine Sites

et al. 1996

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“…The appearance of the products was monitored by 1 H NMR spectroscopy (Table 2). 18 A 1: 2 ratio of 8, compared to 5 in thermal reactions carried out at 110°C, 19 was observed either in LiOTf or in LiNTf 2 -acetone at room temperature. Another salient feature of the LiOTf-promoted Diels-Alder reaction is the enhancement of the endo/exo selectivity, going from 3.3:1 to 10:1 in the cycloaddition between methyl vinyl ketone and cyclopentadiene ( Table 2, entries 13 and 14).…”

Section: Methodsmentioning

confidence: 97%

Catalysis by Lithium Cation: Lithium Trifluoromethanesulfonate as a Substitute for Lithium Perchlorate in Cycloadditions

2000

Synlett

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“…Much of the recent chemistry has been involved as a key step in the synthesis of complex natural products and will be presented in a later section, The present entries deal with studies that center on the reaction itself. Those products containing quinonoid structures have employed a variety of dienes (142)(143)(144) These problems associated with predicting regioselectivity in quinone DielsAlder chemistry have been studied, and a mechanistic model based on frontier molecular orbital theory has been proposed (150). In certain cases of poor regioselectivity, eg, 2-methoxy-5-methyl-1,4-benzoquinone with alkyl-substituted dienes, the use of Lewis acid catalysts is effective (151).…”

Section: ð36þmentioning

confidence: 99%

Quinones

Finley

2016

Kirk-Othmer Encyclopedia of Chemical Technology

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Quinones, possessing two α,β‐unsaturated carbonyl groups usually in a six‐carbon atom ring, represent a unique structural unit. Their centrality in the synthesis of such important commercial substances as dyes and pharmaceuticals has resulted in extensive studies. In living matter, they are ubiquitous and vital to human metabolism. Quinones are of special interest to biochemists and to both synthetic and theoretical organic chemists. The types of reactions most often reported are nucleophilic addition, photochemistry, cycloaddition, electrophilic addition, radical alkylation, electrochemical, oxidation, and nucleophilic substitution. The synthesis of quinones is usually accomplished through oxidation of phenols or anilines.

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Regioselectivities of Diels-Alder cycloadditions to methoxy-substituted quinones

Cited by 24 publications

References 5 publications

Analogs of 3-Hydroxy-1H-1-benzazepine-2,5-dione: Structure−Activity Relationship at N-Methyl-d-aspartate Receptor Glycine Sites

Analogs of 3-Hydroxy-1H-1-benzazepine-2,5-dione: Structure−Activity Relationship at N-Methyl-d-aspartate Receptor Glycine Sites

Catalysis by Lithium Cation: Lithium Trifluoromethanesulfonate as a Substitute for Lithium Perchlorate in Cycloadditions

Quinones

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