Indole-Derived Arynes and Their Diels−Alder Reactivity with Furans

Abstract

Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (Cl, Br, F) were synthesized and reacted under metal-halogen exchange conditions to give Diels-Alder cycloadducts in high yield with furan. The use of an excess of tert-butyllithium resulted in the rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with furan.

Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions

“…Extremely high levels of regioselectivity are observed experimentally (Table 6), and even azide cycloaddition gives very high selectivity. The 6,7-indolynes also display remarkably high regioselectivity in cycloadditions with 2-substituted furans, unlike 4,5- and 5,6-indolynes 12e. Complementary to our rationalization based on the distortion energies required to achieve the transition state geometry, Buszek and Cramer have also shown that regioselectivity of additions of electron-rich furans to indolynes are influenced by the computed polarization of the C≡C bond 12e.…”

“…The 6,7-indolynes also display remarkably high regioselectivity in cycloadditions with 2-substituted furans, unlike 4,5- and 5,6-indolynes 12e. Complementary to our rationalization based on the distortion energies required to achieve the transition state geometry, Buszek and Cramer have also shown that regioselectivity of additions of electron-rich furans to indolynes are influenced by the computed polarization of the C≡C bond 12e. This polarization is related to the unsymmetrical bending distortions of the indolyne.…”

“…The field of indolyne chemistry lay dormant for over four decades,11 until our groups and Buszek’s laboratory entered the area. In 2007, Buszek’s laboratory demonstrated that C3-substituted indolynes could be generated from dihaloindoles in the presence of butyllithium reagents 12a. The presumed indolyne intermediates were trapped with furan to afford Diels–Alder products (e.g., 23 + 24 → 26 ).…”

“…The presumed indolyne intermediates were trapped with furan to afford Diels–Alder products (e.g., 23 + 24 → 26 ). Further studies have been reported by Buszek,12 which include indolyne Diels–Alder reactions of substituted furans and cyclopentadiene, the total synthesis of trikentrin A and herbindole A using an indolyne Diels–Alder reaction, and access to N - and C3-substituted indolynes from silyltriflate precursors for use in the furan Diels–Alder reaction.…”

Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions

“…3 (Figure 2). We recently discovered the first successful and general route to these reactive intermediates via metal–halogen exchange of o -dihalides 4 and later via fluoride-induced decomposition of o -silyltriflates. 5 We subsequently examined the regioselectivity of indolynes in Diels–Alder reactions with 2-substituted furans.…”