Quinoxaline ketones preparation

The main preparative routes to quinoxaline ketones have been discussed earlier by primary synthesis (Chapter 1), by extranuclear acylation of alkylquinoxalines (Section 2.2.4), by oxidation of appropriate alkylquinoxalines (also Section 2.2.4), by displacement of a halogeno substituent (Section 3.2.7), by oxidation of... 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

This chapter covers not only nuclear and extranuclear quinoxahnecarboxylic acids (and anhydrides) but also the carboxylic esters, acyl halides, carboxamides, carbohydrazides, carbonitriles, carbaldehydes, and (ketonic) acyl derivatives of quinoxaline a few related speceis are also included. To avoid repetition, the interconversions of these quinoxaline derivatives are discussed only at the first opportunity thus the esterification of quinoxalinecarboxylic acids in covered as a reaction of carboxylic acids rather than as a preparative route to carboxylic esters, simply because the section on carboxylic acids precedes that on carboxylic esters. To minimize any confusion, appropriate cross-references have been inserted. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Treatment of 2-(l,2-dibromoethenyl)quinoxalines 57 with Na2CS3 affords thieno[2,3- ]quinoxalines 59. Addition of the thiocarbonate to the side chain generates 58. Intramolecular cyclization of 58 with loss of CS2 and NaBr leads to 59 (Scheme 14) <2001J(P1)154>. Azulenothiophenes 61 are prepared from azulene derivatives 60 by the reaction with thioacetamide (Scheme 15) <2002H(58)405>. Similar reactions of furyl ketones 62 afford thieno[3,4-3]furans 63 <1998JHC71>. 

Quinoxalinyl ketones ean be prepared by condensation of a benzene-1,2-diamine with an appropriate tricarbonyl compound yielding compounds 29. Many syntheses of quinoxaline-2-carbo.xylic acids and their derivatives arc based on the reaction of henzene-1,2-diamine with suitable tricarbonyl compounds. The formation of isomeric mixtures can prove problematic when unsymmetrical diamines arc used in this synthetic approach. 

Analogously, (quinoxalin-2-yl)methyl ketones are prepared by treating the parent quinoxaline with acetophenone and cyclohexanone, respectively, in the presence of dimethyl sulfate. ... 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

Pyrazinyl ketones have been prepared by treatment of pyrazinecarboxylic esters with an organo-metallic (alkyllithium or Grignard) reagent <84MI 603-01 >. Homolytic acylation of pyrazines and quinoxalines with a-keto acids is an important method for preparation of the acyl compounds (Section 6.03.5.6.1), but the procedure for monosubstitution needs care because the electron-withdrawing effect of the first-formed monoacyl compounds facilitates further substitution. An additional synthesis of pyrazinyl ketones is the lithiation of halogenopyrazines followed by treatment with carboxylic esters or carboxamides (Equation (8) and Scheme 24). Reaction of 2-chloropyrazine... 

Quinoxaline-thiones (144) have been prepared by heating 1,2-diamino-benzene with a-halo-ketones (RCOCH2X), sulphur, and triethylamine in dimethyl sulphoxide. ... 

Quinoxaline di-N-oxide formation (e.g., 24) has also been achieved by reaction of the dioxime with a, 8-unsaturated ketones A further extension of this reaction is the preparation of l-hydroxyquinoxalin-2-one... 

Quinoxalinyl ketones have been prepared by application of the classical quinoxaline synthesis, an o-phenylenediamine being condensed with an appropriate 1,2,3-tricarbonyl compound. Reactions of this type do not provide an unambiguous synthesis of quinoxalinyl ketones, since an alternative mode of condensation is possible leading to a benzo-1,5-diazepinone. The latter possibility is eliminated in the example cited in Scheme 1 because NMR examination of the condensation product... 

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. ... 

This reaction has wide application in the preparation of aldehydes, ketones, lactones, quinones, and quinoxalines. 

In 1997, a new synthetic route [30-34,43] made available a range of heterocyclic-substituted metallo-l,2-enedithiolate complexes (Scheme 1). The heterocycle (Het) and R group are readily varied using this method. Metallo-1,2-enedithiolate complexes with appended pyridines, 2-pyrazine, and 2-quinoxaline are now available. While the R group is limited only by the availability of the a-bromo- or tosyl ketone required for this synthesis, to date only complexes where R = H, Me, and CH2CH2OAC (and several derivatives of CH2CH2OH) [34] have been prepared. 

Two papers described novel general conversions of diamines into piperazines. Taylor et al ° reacted phenylene diamines with a-epoxy nitriles or sulphones to synthesize tetrahydro-quinoxalines in yields of between 30 and 90%, and Lai reported an interesting preparation of the l,3,3,5,5-pentasubstituted-2-piperazinones (340) and (341) from ethylene diamines (339) via a phase-transfer-catalysed reaction with ketones and chloroform this latter was... 

An interesting method for preparation of fluorinated quinoxaline AA -dioxides 1094 relies on reaction of benzofuroxanes 1093 with flnorinated p-dicarbonyl componnds - a fluoro version of the so-called Beirut reaction (named after the city where it was discovered) (Scheme 232). The reaction has attracted some attention due to the products 1094 revealed high antitumor and anti-trypanosomatid activity [665-667], The method gave satisfactory results when at least one of the starting components was symmetric otherwise, the reaction was not always regioselective. The approach was also used for simple fluorinated ketones in this case, the corresponding products 1095 were obtained in low to moderate yields (16-48 %) [668]. 

An extension of the Beirut reaction for the preparation of the first members of the quinoxaline 1,4-dioxideannulated crown ether series has been described (1985GER(E)224849, 1985ZC102). Benzofuroxan-15-crown-5 3 in MeOH reacts with various ketones in the presence ofHOCH2CH2NH2... 

Substituted quinoxalines can be also prepared by a one-pot process commencing from hydroxy ketones using a Mn02 (Raw et al. 2004), FeCla/morphoIine (Song et al. 2012), and silica gel (Jeena and Robinson 2014)-mediated tandem oxidation process (Table 2.1). 

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