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

Abstract

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 ...

Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins

“…The synthesis of two of the most potent members of a new class of tricyclic seven-membered lactam (SE-III-468 and SE-III-525) was carried out using the aryne cycloaddition strategies developed in the Buszek laboratories (Scheme 2) (5–9). In this manner, a collection of tertiary diene amides (prepared in four steps from Danheiser’s aldehyde) (10) was subjected to fluoride-induced decomposition of a tethered o-silyltriflate moiety to give the benzyne, which then underwent a facile intramolecular cycloaddition to afford directly the desired compounds.…”

“…Bound conformers of ligands interacting with the substrate binding sites of HMG-CoA reductase, including (A) the docked conformer of DL-II-D4, and (B) crystallographically resolved positions of mevastatin (lower left) and NADP + (upper right) as derived by superimposing relevant crystal structures 1HW8 (9) and 1DQ9 (10) onto our receptor model. All ligands are rendered as CPK-colored sticks.…”

o-Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors

“…In 2009, Buszek and co-workers developed a Fischer indole synthesis strategy to prepare Kobayashi precursors of 4,5-, 5,6-, and 6,7-indolynes . As shown in Scheme , hydrazine hydrochloride salt 12-53 could be prepared in 51% overall yield from 4-nitro-2-(trimethylsilyl)­phenol ( 12-52 ), which was then subjected to Fischer’s cyclization conditions with phenylacetaldehyde to afford indole products 12-54 and 12-55 in a 1:5 ratio.…”

Oxidative para-Triflation of Acetanilides

“…Valuable amidosubstituted aryne precursor 5 2o could be isolated in a modest 41% yield, which remains synthetically useful when compared to lengthy traditional methods for its preparation (typically 5À6 steps from commercially available o-halophenol). 14 The presence of electron-neutral or -donating alkyl or methoxy groups on the aromatic ring proved to be more challenging, owing to the formation of unidentified oxidative byproducts. Indeed, 3-methyl and 2-methyl aryltriflates 2h and 2p were obtained in 28 and 26% yield, respectively.…”