5-Oxygenated indoles, synthesis

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]. 

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 ... 

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-... 

There is no need to restrict our discussion to carbon and oxygen atoms. We shall finish this section with two useful reactions that use other elements. The most famous synthesis of indoles is a nineteenth century reaction discovered by Emil Fischer—the Fischer indole synthesis—and it would be a remarkable discovery even today. Reaction of phenylhydrazine with a ketone in slightly acidic solution gives an imine (Chapter 14) called a phenylhydrazone. 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

Benzofurans and Other Annelated Furans.-A new synthesis of benzofurans (73) is by the reaction of the phosphonium salt (72) with acid chlorides RCOCl in the presence of triethylamine. The benzofuran (74) results from the condensation of hexafluorobenzene with acetylacetone. Three instances of the formation of benzofurans from O-aryl-hydroxylamines, i.e. the oxygen analogue of the Fischer indole synthesis, have been reported O-phenylhydroxylamine hydrochloride and benzenesulphonylacetone give a 2 1 mixture of compounds (73 R = CH2S02Ph) and (75), the oxime ether (76) is converted into the aldehyde (77 ... 

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... 

One of the simplest methods for indole synthesis was accomplished when meta-nitroanilines 51 were treated with carbonyl compounds in the presence of base (Scheme 27). The authors have suggested that the intermediate c -complexes undergo oxidation by atmospheric oxygen followed by cycUzation into indoles 52 [54]. 

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. 

These annulations can be extended bqrond indole syntheses. For example, the analogous reaction with ortho-iodophenols can provide an effective method to build up benzofurans (Scheme 6.50) [67]. Presumably due to the lower nudeophilicity of the phenolic oxygen, these reactions generally require higher reaction temperatures. Nevertheless, similar regioselectivity was found here as with the indole synthesis, and, in particular, 2 -silyl-substituted benzofuran is often obtained with high selectivity. This same approach can be applied to the construction of pyrroles and furans [68]. 

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. 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

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... 

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