Fluoroazaindolines by an Uncommon Radical ipso-Substitution of a C-F Bond

Abstract

Trifluoroazaindoline derivatives are prepared using the first synthetically useful radical ipso-substitution of a fluorine atom. The initial procedure has been improved to allow the gram scale synthesis of these building blocks, which can be regioselectively substituted by nucleophiles under mild conditions to rapidly access a library of new molecules. Oxidation to the corresponding fluoroazaindole core has also been accomplished.

Menaquinone Biosynthesis: The Mechanism of 5,8-Dihydroxy-2-naphthoate Synthase (MqnD)

“…This type of reductive ipso substitution of fluoride has been previously reported. 25,26 Analogous halogen-enhanced product yields have been observed in the NosL-catalyzed reaction. 27 A recombinant plasmid encoding MqnD from Bacillus halodurans was transformed into Escherichia coli BL21(DE3), and His 6 -MqnD was overexpressed and purified (Figure S3).…”

The Xanthate Route to Indolines, Indoles, and their Aza Congeners

“…The same oxidizing system can be appliedt od ifluoroazaindoline 88,b elonging to the first series (see Schemes 12 and 14) and prepared from trifluoroazaindoline 73 a followed by cleavage of the acetyl group. [43] Notice that in this case the fluorine atom on C-6 is not replaced by am ethoxy group from the methanols olvent, no doubt because of increased steric hindrance at this position in comparison to C-2 in 84 m + 85 m. The modest yield in the aromatization into azaindole 89 reflects once againt he unfavorable influenceo ft he fluorine atoms.…”

“…[42] Under somewhat forcing conditions, namely heatingw ith di-tert-butyl peroxidei nr efluxing chlorobenzene or amyl acetate, ar are homolytic ipso substitution of af luorine takes place to give azaindoline 76.T he sequence proceeding via intermediates 74 and 75 and final extrusion of af luorine atom appears to be the mostl ikely pathway,a sa ll other alternatives are less reasonable. [42][43][44] Homolytic rupture of a carbon-fluorineb ond is very rare, but the substantial increase in entropyi nt he last fragmentation step and, especially, the restoration of aromaticity are strong driving forces.…”

“…Thus, starting with compound 76 a,avariety of nitrogen, oxygen and sulfur nucleophilesc ould be regioselectively introduced to give substituted indolines 80 a-i,( Scheme14). [43] In the case of primary and secondary amines (80 a-f), no addition of base is necessary.W ith imidazole andp henol (80 g and 80 h), the anion is generated with sodium hydride and the basic conditions of the reaction caused cleavage of acetyl group. This loss of the acetyl group is not observed with thiophenol adduct (80 i).…”

“…This variant is shown on adduct 83 m,d erived by addition of xanthate 63 to acetamide 86 (Scheme 16). [43,44] Cyclisation furnishes am ixture of 84 m and 85 m,f rom whicht he acetyl group is cleaved by treatment with potassium carbonate in ethanol. Under these conditions, the fluorine in the 2-position is substituted by an ethoxy group.…”