Unexpected regioselective diels-alder cycloaddition reactions between 3-fluorobenzyne and 2-alkylfurans

Gribble, Gordon W.; Keavy, Daniel J.; Branzt, Stephen E.; Kelly, William J.; Pals, M. A.

doi:10.1016/s0040-4039(00)82311-4

Cited by 28 publications

(15 citation statements)

References 25 publications

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“…The structure was unequivocally confirmed via NOESY and COSY analysis. The formation of the more sterically crowded product can be rationalized in terms of a previously observed polarization phenomenon that has been invoked for substituted benzynes in which fluorine acts as powerful regiochemical director 13–15. The effect correlates with electronegativity values and is reduced with methoxy substiutents14 and finally reversed with electron-donating groups such as methyl 15.…”

mentioning

confidence: 65%

Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

Brown

Luo

VanderVelde

et al. 2009

Tetrahedron Letters

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The regioselectivity of Diels-Alder cycloadditions of indole arynes (indolynes) at all three benzenoid positions was examined. Cycloadditions with the 4,5-and 5,6-indolynes, derived via metal-halogen exchange from the corresponding o-dibromo indoles, showed essentially no selectivity with 2-tbutylfuran. In contrast, the 6,7-indolyne displayed virtually complete preference for the more sterically congested cycloadduct. This same cycloadduct undergoes a facile acid-catalyzed rearrangement to afford the annulated enone, or alternatively, undergoes hydrolysis and oxidation in the presence of air to give the indolobenzoquinone. The 5,6-difluoroindoles show anomolous behavior and give either 5-fluoro-6,7-indolynes with n-BuLi in ether, or 5,6-indolynes with n-BuLi in toluene. We have also demonstrated that benzenoid indolynes can be easily and conveniently generated by the fluoride-induced decomposition of o-trimethylsilyl triflates.Unlike the familiar benzenoid arynes such as benzyne 1, 1 the naphthalynes (2a and 2b), 2 and the pyridynes (3a and 3b) (Figure 1), 3 all of which have been known for at least 40 years, the tetrad of arynes 4-7 derived from the ubiquitous indole aromatic nucleus was until recently unknown. [4][5] The absence of these arynes from the literature was surprising given the potential utility of these reactive intermediates for an attractive entry into the indole alkaloid class of complex natural products such as the trikentrins, 6 herbindoles, 6a,c teleocidins, 7 cytoblastin, 8 and lyngbyatoxin 9 (Figure 2).We recently reported the existence of and first Diels-Alder cycloaddition examples with all three indole arynes derived from the benzenoid part of the indole nucleus. 4 We are now pleased to follow that communication with this report on the regiochemical behavior of these cycloadditions. 10 The 4,5-, 5,6-, and 6,7-indolynes were generated from the corresponding o-dibromoindoles in the manner previously described. 4 Treatment of 8 with 2.2 eq of n-BuLi in either ether or toluene 11 at −78 °C in the presence of an excess of 2-t-butylfuran was found to give an * Corresponding author. Tel.: +1-816-235-2292; fax: +1-816-235-5502;, buszekk@umkc.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptTetrahedron Lett. Author manuscript; available in PMC 2010 November 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript approximate 1:1 mixture of regioisomers 9 and 10 (Scheme 1). 12 In a similar fashion, the generation of the 5,6-indolyne from 11 and trapping in the same manner also afforded a ...

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confidence: 65%

Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

Brown

Luo

VanderVelde

et al. 2009

Tetrahedron Letters

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“…The reactions favored the formation of the syn- cycloadduct, the regioselectively major product, consistent with previous findings. 24 Diimide reduction and subsequent acid-catalyzed dehydration quantitatively gave the bromonaphthalene ‘anchors’ for Heck coupling. Catalytic hydrogenation and ester hydrolysis gave the desired final ‘8-alkyl’ products.…”

Section: Resultsmentioning

confidence: 99%

A Modified ToxT Inhibitor Reduces Vibrio cholerae Virulence in Vivo

et al. 2018

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We have previously designed and synthesized small-molecule inhibitors that reduce Vibrio cholerae virulence in vitro by targeting the transcription factor ToxT. Here we report the synthesis and biological activity of derivatives of our previous bicyclic, fatty acid-like inhibitors. All of the synthesized derivatives show antivirulence activity in vitro. For the most potent compounds, a concentration of 5 μM completely inhibited ToxT-mediated tcpA expression as measured in the β-galactosidase assay. One indole compound, 3-(1-butyl-1 H-indol-7-yl)propanoic acid (8), was also effective at inhibiting intestinal colonization in the infant mouse. These modified compounds may serve as good candidates for further anti-cholera drug development.

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“…This method features the use of the robust tert ‐butyldimethylsilyl (TBDMS) group for two different purposes, namely, the silicon‐directing Diels–Alder reactions of 3‐TBDMS‐benzynes and the Hiyama coupling of the TBDMS‐substituted cycloadducts. The Diels–Alder reactions of the 3‐TBDMS‐benzynes and the 2‐substituted furans possibly take place through a nonsynchronous concerted mechanism5a that reflects the regioselectivity of the reaction. Further investigations into the detailed mechanism and expansion of the scope of the reaction are now underway.…”

Section: Diels–alder Reactions Of 3‐substituted Benzynes 3 Generatedmentioning

confidence: 99%

Synthesis of Biaryl Compounds through Three‐Component Assembly: Ambidentate Effect of the tert‐Butyldimethylsilyl Group for Regioselective Diels–Alder and Hiyama Coupling Reactions

Akai¹,

Ikawa²,

Takayanagi³

et al. 2008

Angewandte Chemie

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Unexpected regioselective diels-alder cycloaddition reactions between 3-fluorobenzyne and 2-alkylfurans

Cited by 28 publications

References 25 publications

Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

A Modified ToxT Inhibitor Reduces Vibrio cholerae Virulence in Vivo

Synthesis of Biaryl Compounds through Three‐Component Assembly: Ambidentate Effect of the tert‐Butyldimethylsilyl Group for Regioselective Diels–Alder and Hiyama Coupling Reactions

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