Benzoquinones reactions with enamines

Arylation of enamines with p-benzoquinones takes a somewhat different course (70). The enamine (16) reacts exothermally with p-benzoquinone in benzene solution to give 2-(dimethylamino)-2,3-dihydro-3,3-dimethyl-5-benzofuranol (92). The reaction of enamines with quinone dibenzenesul-fonimide proceeds similarly (68). The product from the enamine (28) is the tetrahydrocarbazole derivative (93). 

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). 

Benzo[6]furans and 2,3-dihydrobenzo[6]furans have been obtained by condensation of quinones with compounds having an active methylene group (B-74MI31201) and 2-aminobenzo[6 ]furan derivatives are obtained with malononitrile (68M2359). The reaction of p-benzoquinone with enamines also affords benzo[6]furans. 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

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). 

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>. 

The synthesis of benzofuranols has been accomplished by reaction ofp-benzoquinones with enamines For example, when silylenamine 217 was allowed to react with /)-benzoquinone 216, a 1,3-cycloaddition took place to give dihydrofuranol 218, which after treatment with acid was transformed to benzofuranol 219 (equation 47). 

Tetronic acid has been prepared in three steps from enamines derived from 4-chIoroacetoacetate, and 2,4-dialkyltetronic acids are produced in good yield by ozonolysis of 2,6-dialkyl-3,5-dihydroxy-l,4-benzoquinones. ° The vinyl-lithium (72) can be obtained from the parent enamine by reaction with Bu Li. ° Subsequent condensation with alkaryl ketones and cyclization leads to the tetronic acid derivatives (73) in 20—50% yield. 

The best yields of 5-hydroxyindoles are obtained when equimolar amounts of the quinone and enamine are used. An excess of enamine gives rise to non-indolic products derived from reaction of two enamine units and one quinone unit or the product which results from the initial Michael addition of the enamine to the quinone. Use of excess quinone has been reported less frequently, but limited studies indicate no advantage. When 2,5-dichloro-l,4-benzoquinone (32) was treated with a 50% excess of ethyl 3-... 

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). 

Recent work176 shows that route A is more probable. Acetoacetic ester, vinyl ethers, and enamines react analogously with acetyl-benzoquinone. The reaction of acetoacetic ester probably goes via the enol form, as the reaction rate is solvent-dependent, i.e., it depends on the enol content176 ... 

V. Enamines. Reactions of the enamines from condensation of piperidine or morpholine with an aldehyde with p-benzoquinone gives 2,3-dihydro-5-hydroxy-2-piperidino(or morpholino)benzofurans (146),... 

In general, the reaction of heteroaromatic JV-imines with a,/ -unsaturated carbonyl compounds gives cycloaddition products as described later (Section IV,C). However, in some cases they can act as nucleophiles. Thus, pyridine N-ethoxycarbonylimine, in the presence of silicic acid, reacts with fumarate, maleic anhydride, (V-phenylmaleimide, p-benzoquinone, and a-naphthoquinone to give the corresponding enamines in good yields (Eq. 23).176 Pyridine JV-imine also reacts with dimethyl maleate to give dimethyl aminofumarate.164... 

This reaction was first reported by Haddadin and Issodorides in 1965. It is the preparation of quinoxaline-1,4-dioxides from the cycloaddition between benzofuroxan (i.e., benzofu-razan A -oxide) and dienes, a.y -unsaturated ketones, enamines, or enolates. Unfortunately, this reaction is not named after the authors who discovered it instead it is known as the Beirut reaction after the city in which the inventors carried out is the initial work. In most cases, ketones," /3-diketones, j8-ketoesters, )8-ketonitrile, LS-dinitrile, and/8-ketoamides all are suitable for this reaction, and the corresponding enolates can be easily prepared in the presence of a weak base such as triethylamine. In addition, even phenolic enolates from phenol, resorcinol, hydroquinone, or benzoquinone undergo a similar dehydrative condensation with benzofuroxan under mild conditions (e.g., Na0H/H20, H2O, MeOH/RNH2, Si02/MeCN at room temperature), to give phenazine iV,iV -dioxide derivatives. ... 

When using aliphatic aldehydes tethered to arene motifs as substrates, an enan-tioselective sequential aza-hetero-Diels-Alder and Friedel-Crafts reaction was successfully achieved by the same group [63]. Similarly, optically active lactone[3,3-b] piperidine skeletons 140 can be obtained by tandem aza-hetero-Diels-Alder reaction-hemiacetal formation-oxidation from a,P-unsaturated imines 136 and glutaraldehyde (139) (Scheme 38.41) [64]. Enamine catalysis of the inverse-electron-demand aza-hetero-Diels-Alder reaction was further extended to o-benzoquinone diimide 141 by Chen s group [65]. Various hydroquinoxalinones 142 can be obtained in high yields with excellent enantioselectivities (Scheme 38.42). 

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