Indoles as Substrates

A number of partly reduced arylpyrazines has been made from /V-acetyl-5-arylisatins (l-acetyl-5-aryl-2,3-indolinediones), as illustrated in the following 

A-Acetylisatin (93, R = H) was converted into a solution of the ketoester (94, R = H) (EtOH, reflux, 3 h) and thence with ethylenediamine into 3-o-acetami-dophenyl-5,6-dihydro-2(17/)-pyrazinone (95, R = H) (5 — 20°C, 1 h 85% 

Primary Syntheses from Other Heterocyclic Systems 

The only examples of this synthesis employed isoxazolopyrazine substrates that were themselves made from pyrazines. Thus l-benzyl-5,6-dihydro-2(l//)-pyrazi-none 4-oxide (99) underwent addition by ethynylbenzene to give 5-benzyl-2-phemi-6,7-dihydro-3a//-isoxazolo[2,3-a]pyrazin-4(5//)-onc (100) (60%), which subsequently underwent ring cleavage by molybdenum hexacarbonyl in wet acetonitrile to afford l-benzyl-3-phenacyl-3,4,5,6-tetrahydro-2(l//)-pyrazinone (101) in 54% yield several analogues were made similarly.1539 

Like the foregoing isomeric substrates (Section 2.2.7), these isoxazolopyrazines were frequently made from pyrazines. Thus 3-(/V-hydroxyamidino)-2(l//)-pyrazi-none (102) was converted in two stages into isoxazolo[4,5-b]pyrazin-3-aminc (103), which on vigorous treatment with acetic anhydride afforded 2-acetoxy-3-(5-methyl-l,2,4-oxadiazol-3-yl)pyrazine (104) in 78% yield the same substrate (103) in hot formic acid for 5 min gave mainly 3-(l,2,4-oxadiazol-3-yl)-2(l/7)-pyrazi-none (105) (50%) but if heating was prolonged for 3 h only 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile (106) was obtained, presumably via the oxadiazolopyrazine (105).1115 

A number of partly reduced arylpyrazines has been made from /V-ticetyl- 

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With the charged [H20-Fer7=0]+ model and indole as substrate, the C-0 bond formation was found to be remarkably facile (barrier of 6.8 kcal mol-1). This is not consistent with experimental data showing that addition of an oxygen atom to the substrate is rate limiting, or partially rate limiting, in the hydroxylation of Trp by TPH (140). An insufficient model, lacking some structural features, was indicated as the explanation of this discrepancy with experiment (117). 

A notable eight-membered ring annulation was reported by Echavarren et al. in their study of indoles as substrates for the intramolecular reaction [134]. 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

An unusually facile hydroxydemethoxylation reaction has been reported for 1-benzoyl-4-methoxynaphthalene. The use of 0-enriched hydroxide confirmed that reaction occurs by the NAr pathway rather than by cleavage of the oxygen to methyl bond. A related reaction is observed in 3-(4-methoxy-l-naphthoyl)indole derivatives. These results indicate the possibility of SnAt activation by a 4-carbonyl group the reaction is facilitated by use of a naphthyl ketone as substrate and DMSO as solvent. ... 

In 2007, two groups independently described asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylations of indoles. While You et al. chose the conventional approach and employed imines as substrates (Scheme 11), Terada and coworkers came up with a different concept and used electron-rich alkenes as precursors (Scheme 49) [73]. Enecarbamates 125 reacted with indoles 29 in the presence of BINOL phosphate (R)-io (5 mol%, R = bearing 2,4,6-triisopropyl-... 

Glycine A -acyltransferase [EC 2.3.1.13] catalyzes the reaction of an acyl-CoA derivative with glycine to produce coenzyme A and an A-acylglycine. The acyl-CoA derivative can be one of a number of aliphatic and aromatic acids. However, neither phenylacetyl-CoA nor indole-3-acetyl-CoA can act as substrates. 

Specific substrates such as diethyl a -acetylglutarate, 2-ethoxycarbonylcyclopentanone and 3-carboxypiperidone are useful for the synthesis of special classes of functionally substituted indoles, as shown in Scheme 10. When cyclization is followed by hydrolytic decarboxylation of the C-2 substituent, these cyclizations provide indoleacetic acids, indolepropionic acids and tryptamines, and 3-(2-aminoethyl)indoles, respectively <72HC(25-1)236). 

Phosphorinanones have been utilized as substrates for the preparation of alkenes,11 amines,12 indoles,5,13 and in the synthesis of a series of secondary and tertiary alcohols via reduction,10 and by reaction with Grignard6,11 and Refor-matsky11,14 reagents. Phosphorinanones have also been used as precursors to a series of 1,4-disubstituted phosphorins.15 The use of 4-amino-l,2,5,6-tetrahydro-l-phenylphosphorin-3-carbonitrile for the direct formation of phosphorino-[4,3-d] pyrimidines has been reported.16... 

Scheme 2.19 summarizes results obtained with indoles and benzofurans as substrates for H2O2 and halide-dependent CPO-catalyzed oxidations [250-252]. Indole is usually oxygenated to the corresponding lactone. An unusual double... 

The conversion of aryl hydrazones to indoles requires elevated temperatures and the addition of Br msted or Lewis acids. For example a milder conversion when iV-trifluoroacetyl enehydrazines are used as substrates. 

Light enhances decarboxylation activity by proteinoids, with pyruvic acid, glucuronic, acid, glyoxalic acid, citric acid or indole-3-acetic acid as substrates 22,23). In a typical experiment, 20 mg of proteinoid is incubated with 20 pmoles of radioactive substrate for 2-3 days in 10 ml of buffer pH 4.5 (or 7.0) at 37 °C, under the irradiation of a tungsten filament bulb with a filter of 10 % CuS04 solution the COa evolved is trapped as sodium carbonate 22). 

Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-ary I hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140]. 

This limitation was overcome, when Dy(OTf)3 was used in place of In(OTf)3. This catalyst exhibited similar activity in both [C4Ciim][BF4] and [C4Ciim][PF6], and afforded better yields and reaction rates in these solvents relative to aqueous media.[63] With either hexanal or acetone as substrates, only a slight deterioration in activity occurred after six catalytic runs. The dysprosium salt also catalysed the reaction between the indole and various imines, but with relatively low selectivity towards the condensation product. 

Nevertheless, the substrate specificity of peroxidases is so wide that secretory plant peroxidases are capable of accepting a plethora of natural compounds as substrates, such as indoles [43], porphyrins [44,45] including chlorophylls [46,47], terpenoids such as lutein [48], unsaturated lipid acids such as linoleic acid [49], alkaloids [50-52] including betacyanins [53], phenolics such as benzoic acids [54,55], DOPA [56], coumarins [38,57], stylbenes [58], catechins [36,59], chalcones [60], flavonols [61,62], isoflavones [63,64], cinnamyl alcohols and cinnamic acids [65,66], anthocyanins [67,68] and ascorbic acid [69,70],... 

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