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

Abstract

Convergentr outes to av ariety of indolines, indoles, oxindoles, and their aza analogues involving radical additions of xanthates are described. Three approaches are summarized. The first is the least general and relies on the generation of aryl or heteroaryl radicals startingf rom diazonium salts. The second involves radical addition to N-allylanilines followed by ring-closure onto the aromatic core. A large varietyo fi ndolines and azaindolines can thus be obtained and, in many cases, converted into the corresponding indoles and azaindoles by variousm ethods. Thes ynthesiso f novel fluoroazaindolines and fluoroazaindoles by ar are homolytic ipso-substitution of fluorine atoms is particularly noteworthy.T he last approachh inges on the direct modification of indoles by radical addition to the pyrrole subunit of the indolen ucleus. Application of this methodology to the total synthesis of melatonin andt he alkaloids mersicarpine, caulerpine, and the pentacyclic skeleton of tronocarpine is briefly discussed. Mosto ft he compounds described herein would be difficult to obtain by more traditional routes.

Radical chain monoalkylation of pyridines

“…This issue could be efficiently circumvented by using the more stable O-ethyl xanthate radical precursors (type I). [55][56][57][58] Theses xanthates 48a-d were prepared by adding ethyl 2-((ethoxycarbonothioyl)thio)acetate to 1-nonene, allyltrimethylsilane, vinyl acetate, and vinyl butyl ether. Reaction of these three radical precursors with different Nmethoxypyridium salts 1i-k have been examined and results are reported in Scheme 6.…”

“…This approach is expected to complement the related photoredox catalyzed approaches involving N-methoxypyridinium salts, [35][36][37] lepidinium and quinaldinium trifluoroacetate, 63 as well as quinoxalin-2(1H)ones. 64 As the xanthates 48a-d are prepared by radical mediated xanthate transfer addition to the corresponding alkenes, [55][56][57][58] all products presented in Scheme 6 result formally from a two-step carbopyridinylation reaction. Since electrophilic radicals are not expected to react with the Nmethoxypyridinium salts 1, a one-pot process appears feasible.…”

A Practical Route to Cyclobutanols and Fluorocyclobutanes

“…Addition to N ‐allyl‐ N ‐mesyl‐ p ‐methoxyaniline furnishes the normal adduct 12l in a synthetically useful yield. Further exposure to stoichiometric amounts of peroxide regenerates the intermediate radical which is now forced to cyclize onto the aromatic ring to give indoline 16 in good yield [36] . Trivial saponification of the acetate produces the corresponding cyclobutanol 17 , perhaps a medicinally more interesting compound.…”

“…The fact that the intermediate xanthate 12l can be isolated reflects the faster transfer of the xanthate group as compared to the cyclization step. Nevertheless, both steps could have been performed in the same pot, if so desired [36] …”

Synthesis of Indoles via Sigmatropic Rearrangements and Olefin Isomerization

“…Indoles are a major type of heterocyclic ring that are found in many pharmaceuticals, agrochemicals, and natural products, including proteins. [1][2][3][4][5][6][7][8] Owing to their importance, many methodologies for chemical synthesis of indoles have been proposed, [9][10][11][12][13][14][15][16][17][18][19][20][21][22] such as the Bartoli, Fukuyama, Larock, Madelung and Nenitzescu methods. However, many of these methods suffer from quantitative (sometimes excess) byproducts, and harsh reaction conditions, which often have a high environmental burden.…”