Pyrolytic cyclisation reactions of 3-azolylpropenyl alcohols; unexpectedly facile thermal decomposition of 5H-pyrrolo[2,1-a]isoindole

Clark, Bernard A. J.; Despinoy, Xavier L. M.; McNab, Hamish; Sommerville, Craig C.; Stevenson, Elizabeth

doi:10.1039/a904884g

Cited by 9 publications

(8 citation statements)

References 10 publications

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“…The mixture of 19 and 1 was completely converted into 1 by FVP at 800 • C. This result confirms that the extreme temperatures required for the formation of 1 by FVP of 7 are due to the high energy barrier of the sigmatropic shift to give 10, (which is the first step of the cascade sequence) rather than the ketene generation step (Scheme 3). Lithium aluminium hydride reduction of 1 under the conditions used for 3, 23 gave the alcohol 22 (76%); similar ring-opening has been reported for a substituted isoindolo[2,1-a]indol-6-one. 3 In contrast to the behaviour of 20, FVP of the alcohol 22 at 800-950 • C gave two products in varying ratio (Scheme 6).…”

Section: Introductionsupporting

confidence: 72%

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Isoindolo[2,1-a]indol-6-one—a new pyrolytic synthesis and some unexpected chemical properties

et al. 2008

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Isoindolo[2,1-a]indol-6-one 1 is formed by a sigmatropic shift-elimination-cyclisation cascade by flash vacuum pyrolysis (FVP) of methyl 2-(indol-1-yl)benzoate 7 at 950 degrees C. The dihydro compound 16 is easily obtained by catalytic reduction of 1, but the reaction is very sensitive to steric effects at the 11-position. Attempted ring-opening of 1 in basic methanol provides an equilibrium of isoindolo[2,1-a]indol-6-one 1 and the ester 19. Lithium aluminium hydride reduction of 1 provides the alcohol 22 which can be dehydrated to a mixture of 23 and 24 by FVP at 800-950 degrees C.

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Section: Introductionsupporting

confidence: 72%

“…Scheme 4 Reagents and conditions: (i) MeOH, Hunig's base.We have shown that reduction of the benzopyrrolizinone 3 followed by FVP of the resulting 2-(pyrrol-2-yl)benzyl alcohol 20 causes elimination of water and cyclisation to form benzopyrrolizine 21 (Scheme 5), thereby providing a two-step deoxygenation of the lactam starting material 23. …”

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confidence: 99%

Isoindolo[2,1-a]indol-6-one—a new pyrolytic synthesis and some unexpected chemical properties

et al. 2008

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“…One recrystallisation of the picrate gave the picrate salt of isoretronecanol 6, mp 186-188 The free base has the following spectroscopic data: d H 4.54 (1H, br, OH), 3.62 (2H, dd, n J 7.3 and 2.0), 3.43 (1H, td, n J 6.9 and 9.9), 3.06 (1H, ddd, n J 9.3, 6.5 and 3.5), 2.93 (1H, ddd, n J 11.1, 9.2 and 6.4), 2.56 (1H, ddd, n J 11.1, 7.7 and 3.4), 2.32-2.49 (2H, m) and 1. 22 (10), 124 (17), 110 (11), 97 (6), 84 (12), 83 (100), 82 (43), 70 (11) and 55 (32).…”

Section: Isoretronecanolmentioning

confidence: 99%

Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines

Despinoy

McNab

2009

Org. Biomol. Chem.

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Pyrrolizin-3-ones (e.g. 1) can be easily hydrogenated to their hexahydro (pyrrolizidin-3-one) derivatives in the presence of heterogeneous catalysts. Good diastereoselectivity (up to >97:3, depending on catalysts and solvent) can be achieved if the pyrrolizin-3-one is substituted at the 1- (or 7-) position(s), but the selectivity is reduced if both positions are substituted. Subsequent deoxygenation of the pyrrolizidin-3-ones provides concise, diastereoselective routes to the necine bases (+/-)-heliotridane 5, (+/-)-isoretronecanol 6 and (+/-)retronecanol 7.

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“…Sporadic reports of 3H-pyrrolizin-3-ones have appeared in the literature but little remains known about their chemistry and biological activity. [8][9][10][11][12][13] Complex structures incorporating a 3H-pyrrolizin-3-one-type core have been reported, including tricyclic pyrrolo-indolones, pyrrolo-isoindolones, tetracyclic isoindoloindolones and other polycyclic heterocycles. [14][15] A number of these are marine natural products or their derivatives.…”

Section: Synthesis and Preliminarymentioning

confidence: 99%

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Kirk

Bezos

Willis

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (7), 1813-1816. Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors Abstract Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that nonindoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of nonindoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors. Disciplines Medicine and Health Sciences Publication DetailsKirk, N. S., Bezos, A., Willis, A. C., Sudta, P., Suksamrarn, S., Parish, C. R., Ranson, M. & Kelso, M. J. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors.

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Pyrolytic cyclisation reactions of 3-azolylpropenyl alcohols; unexpectedly facile thermal decomposition of 5H-pyrrolo[2,1-a]isoindole

Cited by 9 publications

References 10 publications

Isoindolo[2,1-a]indol-6-one—a new pyrolytic synthesis and some unexpected chemical properties

Isoindolo[2,1-a]indol-6-one—a new pyrolytic synthesis and some unexpected chemical properties

Hydrogenation of pyrrolizin-3-ones; new routes to pyrrolizidines

Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

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