Indoles and Indolines

The same strategy of using sulfone intermediate 30 was applied by Fluryn, Wipf, and coworkers (15MI1225) in the synthesis of the ATPases associated with diverse cellular activities ATPase p97 inhibitor 35, which contains a 2-aryl-5-SF5-indole fragment as one of the molecule 

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Indole and indoline alkaloids —C(0)(CH2)4C02CH3 from dimethyl adipate (CH30C(0)C=CHC(0)CH3)... 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

The introduction of phosphoryl fragment at position 5 of indole and indoline molecules was described in [35], 5-Bromo-2-methylindoline reacts with an excess of phosphite, which acts as solvent and reagent, in the presence of nickel chloride, giving 5-diethoxyphosphoryl-2-methylindoline (58). 5-Bromo-2-methylindole reacts with triethyl phosphite in mesitylene (catalyst nickel chloride) with the formation of 5-diethoxyphosphoryl-2-methylindole (59) ... 

N. Neuss, Physical Data of Indole and Indoline Alkaloids, Vol. II. Eli Lilly and Company, Indianapolis, 1962. 

Mass spectrometry has been very successfully applied to alkaloids, especially those of the indole and indoline series. Even complicated alkaloids frequently give simple spectra with significant key fragments sometimes this permits structure determination with only a minute amount of sample. The occurrence of a great number of alkaloids having the same skeleton, and differing only in the substituents, makes the comparison technique, briefly mentioned in the introduction to Section III, extremely useful. Since its first application in alkaloid chemistry in 1960 by Biemann,60 the structures of nearly a hundred unknown alkaloids have been elucidated with the aid of mass spectrometry. A comprehensive review on the mass spectra of alkaloids can be found in the book of Budzikiewicz, Djerassi, and Williams.61... 

Figure 40 (a) Vinblastine 14 consists of two half-molecules, cleavamine and vindoline the CD spectra of the component molecules, (b) Left The sum CD spectrum (dotted line) = CD(deavamine) + CD(vindoline) and CD spectrum of vinblastine Center Electric transition moments of indole and indoline chromophores Right Difference CD = CD(vinblastine) - [CD(cleavamine) + CDfvindoline)]. Redrawn from C. A. Parish J.-G. Dong W. G. Bornmann J. Chang K. Nakanishi N. Berova, Tetrahedron 1998, 54, 15739-15758. 

The synthesis of optically active substituted indolines 46 has been achieved via C. antarctica lipase A catalyzed resolution using 3 methoxyphenyl allyl carbonate 47 as the acylating agent (Figure 14.17) [23]. Indole and indoline cores are present in a variety of natural products, biologically active alkaloids, and pharmaceuticals. Ex cellent selectivity values ( > 200) were achieved. 

Several other nonsteroidal compounds have been developed as novel and selective aromatase inhibitors, including 4-(4 -aminobenzyl)-2-oxazo-lidinones , 7-(alpha-azolylbenzyl)-lH-indoles and indolines of which l-ethyl-7-[(imidazol-l-yl) (4-chlorophenyl)methyl]-lH-indole 12c exhibited the most promising potency, 4-imidazolylfla-vans , and anastrozole (Arimidex Figure 7.31). Of these anastrozole has recently been approved in the United States and several other countries for... 

Marchand, P., M. Le Borgne, M. Palzer, G. Le Baut, and R.W. Hartmann (2003). Preparation and pharmacological profile of 7-(alpha-Azolylbenzyl)-1H-indoles and indolines as new aromatase inhibitors. Bioorg. Med. Chem. Lett. 13, 1553-1555. 

Suggestive of indole and indoline chromophores. j3-Anilinoacrylate ehromophore. 

As a result of the large number of indole and indoline alkaloids present in the literature, many reports and reviews have emerged demonstrating the capabilities of radical cyclization to furnish fused indole structures [25-30]. 

Synthesis of Other Five-Membered and Six-Membered Ring Fused Indoles and Indolines... 

Fuwa H, Sasaki M (2009) Synthesis of 2-substituled indoles and indolines via Suzuki—Miyaura coupling/5-endo-trig cyclization strategies. J Org Chem 74 212-221... 

This reaction has general application for the synthesis of indole and indoline derivatives. 

New strategies for the synthesis of 2-substituted indoles and indolines (101) using acyclic, imide-derived enol phosphates (100), which were readily prepared from o-haloanilides, have been developed based on Suzuki-Miyaura coupling-cyclization sequences by Fuwa and Sasaki (Scheme 22)." ... 

Based on the early studies of radical generation from organotin hydrides and their addition to multiple bonds [1-3], particnlarly in cyclization [4-7], several groups applied this chemistry to the synthesis of indoles and indolines. For example, in 1975 Beckwith and colleagues found that < -(A -allyl-Af-methylamino)iodobenzene was converted to 1,3-dimethylindoline (78% yield) upon treatment with tri-n-butylstannane (prepared by the reduction of tri-n-butyltin chloride with LiAlH ) in the presence of AIBN (azobisisobutyronitrile) and benzene at 130°C in a sealed tube [4],... 

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