5-oxygenated indoles

A general and efficient synthesis of 5-oxygenated indoles 126 and 128 has been reported by Kita et al. (92H503). The method involves intramolecular imine formation from p-benzoquinones 125 and p-benzoquinone monoacetals 127 bearing the 2-aminoethyl side chain. Compounds 125 and 127 are prepared by the oxidation of 124 with IBTA in acetonitrile in the presence of water and methanol, respectively (Scheme 35). 

In the previous reaction when the solvent was changed to acetonitrile-methanol, quinone monoacetals were formed. Both products were used for the synthesis of 5-oxygenated indoles [11], This type of transformation also occurred using DIB (Section 3.3) however, the use of BTI activated 4-alkyl phenols which reacted not only with methanol but also with other nucleophiles, simple ones such as water and fluoride, or more complex, according to the general scheme ... 

While the Engler indole synthesis has not been pursued by others, Kita and coworkers developed a related intramolecular amine cyclization onto benzoquinones leading to 5-oxygenated indoles (Scheme 4) [7]. The yields are excellent, and several examples are shown (yields are overall from the starting quinones or quinone acetal). 

Kita has described an excellent synthesis of 5-oxygenated indoles viathephenyliodine (III) bis(trifluoroacetate) (PIFA) oxidation of 2-aminoethyl oxygenated phenols (Scheme 2, equations 1 and 2) [5]. This method was extended to the preparation of 5-hydroxyindole, 5-methoxyindole, and 7-bromo-5-hydroxyindole in 65% to 100% yield from the requisite quinone or quinone acetal. 

The infrared spectra of over 20 1-oxygenated indoles have been collected [79MI1 see also 78JCS(P1)1117]. In the 1-hydroxy compounds, the positions of the HO bands are sensitive to both the conditions of measurement and to the other substituents present, and hydrogen bonding may or may not be observed. For example, l-hydroxy-2-methylindole in nujol shows a sharp peak at 3415 cm-1 and a broad band between 2230 and 3385 cm-1, while in carbon tetrachloride, the corresponding bands for nonbon-ded and bonded hydroxyl appear 3510 and 2300-3450 cm-1. The range for unbonded and bonded hydroxyl appears to be between 3100 and 3510 cm"1 and (broad absorption) between 2230 and 3450 cm"1, respectively. 

Through the years, widespread interest in the synthesis of natural products and their analogs bearing the oxygenated indole nucleus has led to ihe development of several routes to protected hydroxylated indoles. However, 4-benzyloxy1ndole was first prepared relatively recently in modest overall yield by the Reissert method, which involves condensation of 6-benzyloxy-2-... 

Sewarine, from Rhazya stricta, was shown to be 10-hydroxyakuammicine (66a) by spectral comparison with akuammicine (66b) and with other a ring oxygenated indole alkaloids. " Preakuammicine (67a), an isomer of precondylocarpine (67b), has been isolated from young Vinca rosea seedlings. " The retroaldol loss of formaldehyde and the formation of akuammicine was base catalysed. Boro-hydride reduction, as well as causing some retroaldolisation, gave rise to stemmadenine (65). 

The word indole is derived from the word India a blue dye imported from India was known as indigo in the sixteenth century. Chemical degradation of the dye gave rise to oxygenated indoles (see 20.13), which were named indoxyl and oxindole indole itself was first prepared in 1866 by zinc-dust distiUation of oxindole. 

In 2002, Zhao et al. reported the first enantiospecific synthesis of the ring A-oxygenated indole alkaloids (-h)-majvinine (187), (+)-10-methoxyafFini-sine (151) and (+)-Na-methylsarpagine (188) as well as the total synthesis of... 

Photoredox catalysis was utilized by Rueping et al. to effect the intramolecular C—H functionalization of tertiary amine 114. When conducted in the presence of oxygen, indole 115 was isolated as the major product in good yields. Depending on the substrate and reaction conditions, tetrahy-droquinohne derivatives or substituted anilines could also be obtained (13JA1823). 

R. H. Kenten, Bioehem. J. 61, 353 (1955). A similar enzyme has been studied in medium from cultures of the mold Omphalla flavida. This enzyme, which acts most rapidly near pH 3.5, carries out an oxidation that is followed by several secondary reactions. The properties of the principal product are consistent with the structure of an oxygenated indole [P. M. Ray and K. V. Thimann, Arch. Bioehem. Biophys. 64, 175 (1956) P. M. Ray, Arch. Bioehem. Biophys. 64, 193 (1966)]. 

Murakami, Y, Takahashi, H., Nakazawa, Y, Koshimizu, M., Watanabe, T, and Yokoyama, Y. (1989) The improved synthesis of 7-oxygenated indoles by Fischer indolization and its application to the first total synthesis of eudistomidin A. Tetrahedron Lett., 30, 2099-2100. 

From the perspective of laboratory practice, the sensitivity of many indoles to acids, oxygen and light prescribes the use of an inert atmosphere for most reactions involving indoles and the avoidance of storage with exposure to light. This sensitivity is greatly attenuated by electron-withdrawing (EW) substituents. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

The oxygen analogue of the Fischer cyclization requires the formation of 0-vinyl derivatives of iV-arylhydroxylarnines. These are readily converted to indoles but are less readily accessible than the arylhydrazones used for the Fischer cyclization. 

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

Oxidation. As a 7t-excessive heterocycle, indole is susceptible to oxidation a variety of oxidation intermediates and products have been observed. With oxygen as the oxidant, the key intermediate is normally a 3-hydroperoxy-3ff-indole. These intermediates ate observable for 2,3-disubstituted indoles but are unstable for less substituted derivatives. Figure 1 indicates typical reactivity patterns toward oxygen. 

Note Indoles, that are substituted with oxygen in position 2 or 3, do not react [11]. The reagent can be employed on silica gel, kieselguhr and Si 50 000 layers. Aluminium oxide layers are not suitable [3]. 

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