Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Nguyen, Hanh Nho; Cee, Victor J.; Deak, Holly L.; Du, Bingfan; Faber, Kathleen Panter; Günaydın, Hakan; Hodous, Brian L.; Hollis, Steven L.; Krolikowski, Paul; Olivieri, Philip R.; Patel, Vinod F.; Romero, Karina; Schenkel, Laurie B.; Geuns‐Meyer, Stephanie

doi:10.1021/jo3000628

Cited by 31 publications

(22 citation statements)

References 43 publications

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“…The general synthetic strategy to prepare new compounds 2b , 2c , and 4b takes advantage of the addition of dodecylthiophenyl lithium intermediate upon dicarboximide starting materials embedding suitable functionalities ( 1b , 1c , and 1d , respectively). For the preparation of N ‐hydroxy or N ‐methoxy‐(aza)isoindolinone derivatives 4a , 5a , and 5b , the synthesis initially consisted in the reaction of hydroxylamine or methoxylamine with (aza)phthalic anhydride 1e or 1f followed by addition of the aryllithium reagent . As previously observed for compound 1a , the addition of the alkylthiophenyl group occurs preferentially on the para carbonyl group and the regioisomers formed are readily separated by flash chromatography.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the inhibitory activity of (aza)isoindolinone‐type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

et al. 2016

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Inhibitors of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA) are considered as potential promising therapeutics for the treatment of tuberculosis. Previously, we reported that azaisoindolinone-type compounds displayed, in vitro, inhibitory activity toward InhA. Herein, we describe chemical modifications of azaisoindolinone scaffold, the synthesis of 15 new compounds and their evaluations toward the in vitro InhA activity. Based on these results, a structure-InhA inhibitory activity relationship analysis and a molecular docking study, using the conformation of InhA found in the 2H7M crystal structure, were carried out to predict a possible mode of interaction of the best (aza)isoindolinone-type inhibitors with InhA in vitro. Then, the work was extended toward evaluations of these compounds against Mycobacterium tuberculosis (Mtb) growth, and finally, some of them were also investigated in respect of their ability to inhibit mycolic acid biosynthesis inside mycobacteria. Although, some azaisoindolinones were able to inhibit InhA activity and Mtb growth in vitro, they did not inhibit the mycolic acid biosynthesis inside Mtb.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the inhibitory activity of (aza)isoindolinone‐type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

et al. 2016

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“…General procedure for the synthesis of 3-substituted 3hydroxyisoindolinones via bromine-lithium exchange (13)(14)(15)(16)(17)(18)(19). Aryl bromide (4 equiv.)…”

Section: General Procedures For the Synthesis Of 3-substituted 3hydroxmentioning

confidence: 99%

“…3-Substituted 3-hydroxyisoindolinones are usually prepared by reacting phthalimide with the corresponding organometallic reagents [14][15][16][17]. Apart from Grignard and organolithium reagents, nickel-catalyzed additions of diethylzinc to phthalimides have also been developed [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3–aryl 3–hydroxyisoindolinones by the Addition of Grignard and Organolithium Reagents to Phthalimides

Glavač

Dokli

Gredičak

2017

COC

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Background: The 3-substituted 3-hydroxyisoindolinone motif is common to a variety of compounds with potent biological activities. In recent years, they have also been increasingly used as substrates in various asymmetric transformations. Current methods for their preparation either do not tolerate wide range of functional groups, or yield 3-hydroxyisoindolinones as N-substituted products, which makes them inapplicable as substrates for the asymmetric transformations.Objective: Aim of this study was a detailed examination of the synthesis of 3-substituted 3hydroxyisoindolinones comprising various functional groups and unsubstituted phthalimide nitrogen.Method: Grignard and organolithium reagents were employed as nucleophiles for the synthesis of 3substituted 3-hydroxyisoindolinones under various reaction conditions. Results: Phenyl substituents with electron donating groups are easily introduced by employing a Grignard reaction, while electron-poor arenes require a lithium exchange or direct lithiation strategy. The protocols are tolerant of various functional groups on the nucleophile, and a wide range of 3-hydroxyisoindolinones were afforded in good to excellent yields. Conclusion:Simple and inexpensive method for the synthesis of 3-substituted 3-hydroxyisoindolinone has been developed. By tweaking the reaction conditions, described protocols are tolerant of a wide range of functional groups, and yield 3-substituted isoindolinone alcohols with unsubstituted phthalimide nitrogen.

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“…Hydrazines with phthalimide: Novel three-step method to prepare 4-substituted chlorophthalazines from phthalimide was reported [63] (Scheme 12).…”

Section: Synthesis Of Phthalazine Derivatives From Hydrazine and Hydrmentioning

confidence: 99%

Recent Developments in Chemistry of Phthalazines

El-Azm¹,

Mahmoud²,

Hekal³

2014

Organic Chem Curr Res

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El-Azm et al., Organic Chem Curr Res 2015, 4:1 http://dx.Hydrazines with 2-acyl benzoic acids: Kirill et al. [31] reported the cyclization of 2-nitro-5-chloro phenylhydrazine27 with acyl benzoic acids 28 yielded 2-(2-nitro-5-chlorobenzene)-4-substituted phthalazin-1-ones 29 (Scheme 7).Lukacs and Simig [61] adopted a novel method for the synthesis of phthalazine derivatives 32 via the reaction of benzophenones30 with chromium (VI) oxide in a mixture of acetic anhydride and sulphuric acid followed by cyclization of the products with hydrazine hydrate in refluxing ethanol (Scheme 8).Hydrazine with 1,2-diester:The dimethylphthalate derivative 33 reacted with hydrazine to yield the desired phthalhydrazide34 which undergo chlorination with phosphorus oxychloride to give 35. Subsequent treatment with sodium methoxide afforded the methoxychloride 36 [62] (Scheme 9). Hydrazines with Phthalides: Chloroformylation of 3-methoxy benzoic acid 37 and subsequently radical bromination of 38 produced 39 in good yield. Treatment with triphenyl phosphine gave 40 and wittig olefination with 3,5-dichloro-4-pyridine carboxaldehyde 41 afforded the phthalide 42. Hydrazine cyclization of 42 resulted phthalazine derivative 43 [42] (Scheme 10). Cockcroft et al. [12] synthesized the phthalazinone derivative 47 according the following (Scheme 11). AbstractThis review highlights the methods used for the synthesis of phthalazine derivatives and fused phthalazinones. Their reactivity and synthetic importance were investigated. Phthalazine derivatives can be used as building blocks for heterocycles as well as fused heterocyclic compounds. Scheme 1: Synthesis of phthalazinone derivatives 2 and 5 Scheme 2: Synthesis of phthalazinone derivatives 7-9. Reagents and conditions: (a) CHCl 3 , reflux, 5 h, 51%; (b) hydrazinehydrate, EtOH, addition at rt and then reflux, 90˚C, 2 h, 71%; (c) MeI, KOBu t , DMF, 30 min, 80%; (d) LiOH, THF:MeOH:water (1:1:1), rt, 8-10 h, 81%. Scheme 3: Synthesis of phthalazin(2H)-1-one 11, 12 Scheme 4: Synthesis of 2-[1-(4-oxo-3,4-dihydrophthalazin-1-yl)alkyl]-1Hisoindole-1,3-(2H)-diones Scheme 5: Synthesis of 1,4-disubstituted phthalazinylpiperazine derivatives 21 Scheme 6: One-pot Synthesis of thiadiazinyl-phthalazine-1,4-diones 24 and 26 Scheme 7: Synthesis of 4-substituted phthalazin-1-ones 29. Scheme 8: Synthesis of phthalazine derivatives 32 Scheme 9: Hydrazinolysis of dimethylphthalate derivative 33 Citation: El-Azm FSMA, Mahmoud MR, Hekal MH (2015) Recent Developments in Chemistry of Phthalazines. Organic Chem Curr Res 1:132. Scheme 23: Synthesis of 1H-pyrazolo [1,2-b] phthalazin-5,10-dione derivatives 92 Scheme 24: A plausible mechanism for the synthesis of 1H-pyrazolo[1,2-b] phthalazine-5,10-diones 95 Scheme 25: Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 97. Scheme 28: Synthesis of 1-{[(1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1Hpyrazolo[1,2-b] phthalazine-5,10-dione derivatives 104 Scheme 30: Synthesis of 2H-indazolo[1,2-b] phthalazine-triones 107 Scheme 29: Synthesis of 2H-indazolo[2,1-b]pht...

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Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Cited by 31 publications

References 43 publications

Evaluation of the inhibitory activity of (aza)isoindolinone‐type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

Evaluation of the inhibitory activity of (aza)isoindolinone‐type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

Synthesis of 3–aryl 3–hydroxyisoindolinones by the Addition of Grignard and Organolithium Reagents to Phthalimides

Recent Developments in Chemistry of Phthalazines

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