Nenitzescu reaction

Olefins and cycloolefins give unsaturated ketones with acyl hahdes (the Nenitzescu reaction) (170). Saturated chloroketones are formed as intermediates followed by elimination of HCl. Similar products may be obtained by using acid... 

The procedure was largely ignored until the 1950s when interest in melanin-related substances and recognition of serotonin as a 5-hydroxy derivative stimulated exploration of the scope of the reaction. Nowadays, the Nenitzescu reaction is one of the most efficient processes for the preparation of 5-hydroxyindoles. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

The Nenitzescu reaction generally occurs under relatively mild reaction conditions. Moreover mono-, di-, and tri-substituted quinones react with equal facility. Many enamines including p-aminoacrylonitriles, p-aminoacrylamides, and p-amino-a,p-unsaturated ketones react with quinones to form indole nuclei as well. The mild reaction conditions and the availability of the starting material render it attractive even in those instances where the yield of the product is low. ... 

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. ... 

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>. 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

Nazarov cyclization, 45, 1 Nef reaction, 38, 3 Nenitzescu reaction, 20, 3 Nitriles ... 

Methyl isatogenate and 2-(2-pyridyl)isatogen react with ethyl 3-(n-butylamino)crotonate to give stable crystalline nitroxide radicals. The structures 15317 have been assigned from preliminary ESR studies and by analogy with the Nenitzescu reaction involving quinones and this reagent.101... 

The use of aromatic amines having electron-attracting groups as the enamine component of the Nenitzescu reaction have been reported. This reaction leads to carbazoles. The yields, however, are very low (equation 111) (80JOC1493). 0... 

One of the most widely used synthetic approaches to 5-hydroxyindoles is the Nenitzescu reaction. A classical example is the interaction of p-benzoquinone and its derivatives with various enamines. In the present contribution, only the most recent papers devoted to the Nenitzescu reaction will be discussed because a detailed review on this topic has been published recently [93KFZ(6)37] and this topic has received considerable attention in one of the chapters in a monograph (94MI1). One study involves the reaction of benzoquinone with indane enamines (36) (94AP137) leading to 2-hydroxybenzo[b] carbazole derivatives (37). 

Condensation reactions of enaminoesters, enaminoketones, and enam-inonitriles with benzo- and chloronaphthoquinones have been described (94JIC281). Utilization of diamines (38) as novel synthons in the Nenitzescu reaction has resulted in a new synthesis of 2-(3-benzofuryl)indoles (40) [95KFZ(9)47,95MC69].The pathway in the scheme leading to 40 has... 

In the case of enaminoketone (77) and /j-benzoquinone, there are two parallel reactions in the /3-position of the enamine 77 and in the 8-position of the tautomeric dienamine 77a [93MC40 94KFZ(2)36]. The first pathway (common in the Nenitzescu reaction) gives a dibenzofuran derivative (78), the second affords an unusual product—a jpiro[benzofuran-3,l cyclohexene] derivative (79). The likely pathways are indicated. The... 

A convenient method for the production of phosphorus-containing indoles with P-O-C bond may be the reaction of hydroxyindoles with the chlorides of phosphorus acids [59, 60, 158], 5-Hydroxyindole, obtained by the Nenitzescu reaction [160, 161], and amidophosphite (toluene, 110°C) form the unstable 5-phosphitoindoles 62 (132-124 ppm), which are isolated in the form of thiophosphates 63 (62-64 ppm) [159] ... 

Synthesis of 5- and 6-hydroxyindoles using the Nenitzescu reaction 93KFZ(6)37. 

Benzoquinones reacted with four equivalents of isonitriles to form benzo[c c ]dipyrroles <84LA1003>, and variations of the Nenitzescu reaction, i.e. of quinones with enamines, have been useful synthetic approaches to benzo[l,2-6 4,5-6 ]dipyrroles <71T503J, 73T921). 

Several JV-(quinonylalkyl)enaminones have served as model compounds for an intramolecular Nenitzescu reaction demonstrating the ambident reactivity of both the enaminone and the quinone. The compounds cyclized unexpectedly, mainly to heterocyclic spiro-compounds146,147. A phenanthridinium salt and benzofuranoazocine are also obtained, depending on the length of the chain connecting the quinone and the enaminone moieties (equation 95). 

The use of quinone monoketals in the reaction with an exocyclic enaminoester is a new variation150. It is not a typical Nenitzescu reaction since an enamine anion is used. Tricyclic intermediates are obtained, which nevertheless formally give typical Nenitzescu products in high yield and regioselectively (equation 58). In this way annelated indoles of mitomycin type become accessible. 

Other extensions of the Nenitzescu reaction are the use of a-ketoenamines (see equations 233-235) which mainly yield non-indolic compounds. Another extension is the application to -substituted aminomethylene ketones leading to compounds with indole-2-one structure by rearrangement (see Section II.B, equations 158-160). 

The first step in the reaction of aminocycloalkenones with quinones is a normal Michael addition to yield hydroquinone adducts, as is known from the Nenitzescu reaction with / -ketoenamines. However, the consecutive cyclization is quite different, and the structure of the heterocycles formed depends on the substitution at the nitrogen and the size of the cycloalkane ring. 

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>. 

Bisagni and co-workers (113,116) also explored several synthetic routes to the tricyclic y-carbolines (5//-pyrido[4,3-i>]indole ring system). Unfortunately, the attractive one-step Nenitzescu reaction (114) proceeded in only 6% yield to afford 286 (113). The Fischer indolization sequence was far more efficient (Scheme 46) (113). Thus, condensation of phenylhydrazine with 279 in boiling diphenyl ether gave in one step the desired y-carboline 287 in excellent yield. Chlorination of the pyridone functionality gave chloropyridine 288, which was converted to the target amine-substituted y-carbolines 289—291 by heating with the appropriate amines. 

Friedel-Crafts acylation of alkenes (Daizens-Nenitzescu reaction ) with unsaturated acylium ions generated from acid halides and Lewis acids constitutes a general synthesis of divinyl ketones. 

Lyubchanskaya, V. M., Alekseeva, L. M., Granik, V. G. The first example of dienediamine utilization in the Nenitzescu reaction. Mendeleev Commun. 1995, 68-69. 

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