Formation of 3-Halobenzyne:  Solvent Effects and Cycloaddition Adducts

Coe, Jotham W.; Wirtz, Michael; Bashore, Crystal G.; Candler, John

doi:10.1021/ol049655l

Cited by 59 publications

(39 citation statements)

References 36 publications

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“…Reaction of 18 with n -BuLi in PhMe11 at −78 °C presumably resulted in selective metal–halogen exchange at C-7 and elimination to give the 4-bromo-6,7-indolyne 22 , which was trapped with cyclopentadiene to afford the desired 4-bromoindole 23 in 89% yield. Although the possibility of some metal–halogen exchange occurring at the 4-bromo position cannot be rigorously excluded at this time, it is important to note that no evidence for the formation of compound 24 has been found thus far.…”

mentioning

confidence: 99%

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Brown

Luo

Decapo

et al. 2009

Tetrahedron Letters

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We describe herein an efficient new route to the trikentrins and their related structures using a tandem 6,7-indolyne cycloaddition/Negishi cross-coupling reaction starting from a 4,6,7-tribromoindole (obtained in good yield via the Bartoli indole synthesis). The key step of this second generation route to the trikentrins is based on our observation that the 7-bromo substituent appears to undergo selective metal-halogen exchange and elimination to give the 6,7-indolyne, which is trapped in the presence of excess cyclopentadiene. Subsequent Negishi cross-coupling at the 4-bromoindole position with Et 2 Zn gave directly the same intermediate obtained from our previous work. Application of this chemistry to the construction of trikentrin-related libraries using this general cycloaddition/crosscoupling tactic will also be described.Arynes derived from all three benzenoid positions of the ubiquitous indole nucleus (indolynes 1-3, Fig. 1) represent potentially attractive and powerful new tools for the total synthesis of complex alkaloid natural products such as the trikentrins, 1 herbindoles, 1a,c teleocidins, 2 cytoblastin, 3 and lyngbyatoxin 4 (Fig. 2). Our group recently discovered the first successful and general route to these intermediates via metal-halogen exchange of o-dihalides 5 and later, via fluoride-induced decomposition of o-silyltriflates.6 We subsequently examined the regioselectivity of indolynes in Diels-Alder reactions with 2-substituted furans. 6a These studies quickly led to the first application of indolynes in the construction of natural products and culminated in a concise synthesis of (±)-cis-trikentrin A 7 and (±)-herbindole A, 9. 7 This work clearly validated the utility of indolynes to gain quick access to architecturally challenging structures. 8 We now describe an efficient and flexible new route to the trikentrins using a novel tandem intermolecular 6,7-indolyne cycloaddition/Negishi cross-coupling reaction starting from a versatile 4,6,7-tribromoindole, which itself was obtained via the Bartoli indole synthesis. 9 Application of this general cycloaddition/cross-coupling tactic to the construction of novel small-molecule libraries will also be introduced. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe were intrigued by the idea of using a potentially new scaffold, namely, a 4,6,7-tribromoindole 11 for the synthesis of the antibacterial cis-trikentrin A as well as libraries derived from it (Scheme 1).Based on our earlier work with the various reaction manifolds of 6,7-indolynes, 6a it occurred to us that it might be possible to generate selectively the 6,7-indolyne as described previously 5,6a without simultaneously inducing metal-halogen exchange at the 4-bromo position. In this manner indolyne cycloaddition would be followed by further elaboration of the scaffold at the 4-bromo position of 12 by any of the several metal-mediated coupling strategies (e.g., Buchwald-Hartwig, Heck, Negishi, Sonogashira, Stille, and Suzuki). We are now pleased to rep...

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mentioning

confidence: 99%

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Brown

Luo

Decapo

et al. 2009

Tetrahedron Letters

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“…15 Our synthesis of the required starting material 11 began with a Diels-Alder reaction between cyclopentadiene (8) and benzyne which can easily be generated in situ from 1,2-dibromobenzene (7) and n-butyllithium. 16 After the resulting benzonorbornadiene (9) had been obtained in moderate yield of 58 % an oxymercuration and a subsequent Swern oxidation gave access to ketone 11 in 68 % combined yield over these two steps. For the final photochemical ring opening, ketone 11 was then irradiated with UV-light in diethyl ether using a 450 W mercury high pressure lamp.…”

Section: Resultsmentioning

confidence: 99%

“…Tricyclo[6.2.1.0 2,7 ]undeca-2,4,6,9-tetraene (9). 16 A flame-dried 500 mL three-necked roundbottom flask equipped with a Teflon ® -coated oval stirring bar (2.5 cm), a septum, an argon-inlet and a dropping-funnel was charged with 1,2-dibromobenzene (7, 50.00 g, 212.0 mmol), freshly distilled cyclopentadiene (8,14.01 g, 212.0 mmol) and toluene (250 mL). The flask was cooled to 0 °C and a solution of n-butyllithium (58.50 g, c = 2.5 mol·L −1 in hexanes, 212.0 mmol) was added dropwise over a period of 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

Highly flexible synthesis of indenylethylamines as ligand precursors for titanium complexes

Ross¹,

Rohjans²,

Schmidtmann³

et al. 2015

Arkivoc

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Dedicated to Professor Jürgen Martens in honor of his outstanding contribution to synthetic organic chemistry DOI: http://dx.doi.org/10.3998/ark.5550190.p008.859 AbstractVarious indenylethylamines are synthesized for the first time by reductive amination of 2-(1H-inden-1-yl)acetaldehyde with commercially available primary amines. In addition, a new twostep synthesis of 2-(1H-inden-1-yl)acetaldehyde that uses inexpensive indene and 2-bromo-1,1-diethoxyethane as starting materials is presented. Finally, a selected indenylethylamine is used as a ligand precursor for the synthesis of a corresponding indenylethylamido titanium complex. The latter result paves the way for applications of corresponding complexes as catalysts for important chemical reactions.

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“…Moreover, the corresponding reaction of iodide 8c having a fluorine atom at 2-position as a leaving group gave moderate yield of 6a (entries 5-6). These results indicate that halogen-lithium exchange selectively occurred at the more electropositive iodine atom in iodo-halides 8a-8c (Type 1 in Scheme 3), smoothly generating (2-halo)phenyllithiums, respectively, whereas the dibromoisobenzofuran 1 and the dibromocycloadduct 6a almost untouched under these conditions [33][34][35][36]. As for the moderate yield of the cycloadduct 6a in the reaction of the dihalides 8b and 8c, the lower leaving ability of halogen (Cl and F) in comparison with bromine in aryllithium species would affect the elimination of lithium halide and subsequent generation of benzyne B [37].…”

Section: Scheme 2 Previous Study On the [2+4] Cycloaddition Of Benzymentioning

confidence: 90%

Selective Halogen-Lithium Exchange of 1,2-Dihaloarenes for Successive [2+4] Cycloadditions of Arynes and Isobenzofurans

Eda

Hamura

2015

Molecules

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Formation of 3-Halobenzyne: Solvent Effects and Cycloaddition Adducts

Cited by 59 publications

References 36 publications

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

New synthesis of (±)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development

Highly flexible synthesis of indenylethylamines as ligand precursors for titanium complexes

Selective Halogen-Lithium Exchange of 1,2-Dihaloarenes for Successive [2+4] Cycloadditions of Arynes and Isobenzofurans

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