Hydroxyindole derivatives

The Nenitzescu process is presumed to involve an internal oxidation-reduction sequence. Since electron transfer processes, characterized by deep burgundy colored reaction mixtures, may be an important mechanistic aspect, the outcome should be sensitive to the reaction medium. Many solvents have been employed in the Nenitzescu reaction including acetone, methanol, ethanol, benzene, methylene chloride, chloroform, and ethylene chloride however, acetic acid and nitromethane are the most effective solvents for the process. The utility of acetic acid is likely the result of its ability to isomerize the olefinic intermediate (9) to the isomeric (10) capable of providing 5-hydroxyindole derivatives. The reaction of benzoquinone 4 with ethyl 3-aminocinnamate 35 illustrates this effect. ... 

VI. Studies towaid Biologically Active 1-Hydroxyindole Derivatives. 146... 

Gong and co-workers employed an intermolecular Nenitzescu reaction, a type lice transformation, for the condensation of a P-amino-a,(3-unsaturated ester with 1,4-benzoquinone to afford a 5-hydroxyindole derivative <06BMC911>. 

The synthesis of 3- and 7-substituted indoles (184 and 185) by [3,3]-sigmatropic rearrangement of A-hydroxyindole derivatives (181) was reported (equation 54). A-hydroxyindole 181 in the presence of cyanogen bromide (182, R = Br, = N) and base afforded 183 that rearranged to the NCO substituted at position 3 and position 7, leading to two isomeric isocyanates, 184 and 185, respectively. Different behaviour was found when an acetylenic sulfone 182, R =11, R = CTos, was used where the 3-substituted indole 186 was the only rearrangement product identified. 

The removal of the semicarbazide residue from aminochrome mono-semicarbazones by alkaline degradation has been reported.303 The resulting 6-hydroxyindole derivatives could be readily isolated as their methyl ethers.303... 

Table 11 Synthesis of 1-Hydroxyindole Derivatives by Reductive Cyclization...

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

E. Naturally Occurring 1-Hydroxyindole Derivatives 1. Simple Indoles... 

The UV-spectrum of mitragynine differs notably from the spectra of the other Mitragyna alkaloids. Whereas the absorption of the latter indicate the presence of oxindole nuclei, the spectrum of mitragynine shows a greater resemblance to that of the ajmalicine group of alkaloids (5). The presence of an indole nucleus is also suspected from its color reactions (2) and confirmed by the isolation of indole derivatives (so far unidentified) and 5-methoxy-9-methylharman (I) from the products of zinc dust distillation (6). The identification by synthesis (51) of this degradation product is of some interest, since the alkaloid itself does not apparently contain an iV-methyl group. Moreover, this was the first demonstration of the occurrence of a 4-hydroxyindole derivative in nature. 

Hydroxyindoles may be accessed using the Nenitzescu reaction, as illustrated by preparation of the indole 381 from the enamine 382 and 1,4-benzoquinone (Equation 107) <1996JOC9055>. Additional applications of this strategy encompass syntheses of 1 -alkyl-5 -hydroxynaltrindole derivatives <2005JME635>, and lO-hydroxy-5,6-dihydroindolo[2,l- ]isoquinolines <2001JOC4457>. An alternative approach to 5-hydroxyindole derivatives involves Lewis acid-mediated reactions of benzoquinone monoimines with enol ethers <1997TL6135>. 

Kucklaender, U. Mechanism of the Nenitzescu reaction, IV. Synthesis of benzindole derivatives. Liebigs Ann. Chem. 1978,129-139. Kucklaender, U. Mechanism of the Nenitzescu reaction, V. Synthesis of naphthofuran derivatives. Liebigs Ann. Chem. 1978, 140-149. Kucklaender, U., Huehnermann, W. Studies on the mechanism of the Nenitzescu reaction. Synthesis of 6-hydroxyindole derivatives. Arch. Pharm. (Weinheim, Ger.) 1979, 312, 515-526. 

A two-step synthesis of 4-hydroxyindole derivatives (87) has also been reported and involves photorearrangement of isoquinoline iV-oxides (88) via oxaziridines (89) to the benzoxazepines (90), followed by treatment with acid, as shown in Scheme 9. In a separate study, 3,1-benzoxazepines have been shown to undergo... 

Simple treatment of 6-hydroxyindole derivatives with ferf-prenol in the presence of Bp3-Et20 does not appear to be selective, since mixtures of prenylated and ferf-prenylated products were obtained [225]. 

This reaction was first reported by Nenitzescu in 1929. It is the synthesis of a 5-hydroxyindoie derivative involving the condensation between a 1,4-benzoquinone and a /3-amino-a ,/3-unsaturated compound and subsequent cyclization. Therefore, this reaction is generally known as the Nenitzescu indole synthesis, Nenitzescu reaction, j or Nenitzescu synthesis.Occasionally, it is also referred to as the Nenitzescu cyclization, Nenitzescu condensation, s.2i qj. Nenitzescu process. It should be pointed out that the synthesized indole derivatives by this reaction are restricted to those with an electron-withdrawing group at position 3, such as an ester or a carbonyl group. In addition, the completion of this reaction requires an appropriate oxidizing agent to convert the initial adduct into the indole derivative. i From monosubstituted quinone, 4-, 6- and 7-substituted 5-hydroxyindole derivatives all are possible products, but 6-substituted isomer is the one normally obtained. ... 

This reaction is particularly useful for the preparation of 5-hydroxyindole derivatives. 

Another example of the reaction proceeding in a similar manner is the conversion of 2-(5-chloro-2-nitrophenyl)-3-phenylpropionitrile into A-hydroxyindole derivative (Scheme 71) [189]. The intermediate vinyl nitroso compound undergoes electrocyclization, resulting in the formation of nitrone (2//-indole N-oxide), which is tautomerized into A-hydroxyindole. 

Phosphonium ylide, generated from allyl triphenylphosphonium chloride, is capable of addition to 1-nitronaphthalene or 5-nitro-8-methoxyquinoline in the presence of DBU and titanium tetraisopropoxide to form unstable A -hydroxyindole derivative, which is transformed by action of ethyl bromoacetate into benzo- or pyridoindoles (Scheme 80) [200]. 

Polyfunctional N-hydroxyindole derivatives 32 have been synthesized by using the sequence of reactions, involving the VNS of hydrogen, alkylation, and base-catalyzed cyclization [39] (Scheme 18). 

Nevertheless, there are several other oxidation (dehydrogenation) routes to indoles from indolines. In a series of papers, Somei and colleagues used sodium tungstate to synthesize A-hydroxyindole derivatives from the corresponding indolines (Scheme 11, equations 1 and 2) [64, 103-107]. The simple l-hydroxy-6-nitroindole [106] and 4-, 6-, and 7-ethoxy-l-methoxyindoles were synthesized in similar fashion [107]. Pedras and coworkers employed the Somei method to prepare the natural phytoalexin methyl l-methoxyindole-3-carboxylate [108], and McNab and... 

Under similar reaction conditions, 35 generates many products such as 7-bromo- (59), 2,7-dibromotryptamines (60), 57, 7-bromo- (61), 5-bromo-2-oxindoles (62), 56,2-bromotryptamine (63), and 58, depending on the bromination conditions (entries 1-3). l-Hydroxy-Wh-methoxycarbonyltryptamine (52) shows almost the same results as 35. It should be noted that the ratio of all of the 7-brominated indoles to the total products, observed in the bromination of 1-hydroxyindole derivatives (35 and 52), is much higher than that of the N(l)-H compound (55). 

From the point of view of developing an anti-cancer drug, some potent 1-hydroxyindole derivatives have been discovered through the test using human tumor cells. Further study is in progress (Somei and co-workers, personal communication, 2006). 

Synthesis of 5-hydroxyindole derivatives by condensation ofp-benzoquinone with p-aminocrotonic esters ... 

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