Quinoxaline alkyl

Alkylquinoxalines have also been prepared by homolytic substitution. Thus reaction of quinoxaline with a mixture of the appropriate carboxylic acid and its sodium salt in the presence of aqueous ammonium perox-idisulfate gives the 2-alkylated quinoxaline. Alkylation can also be achieved by the use of the acid and salt in the presence of trifluoroacetic acid and lead(IV) acetate in benzene (Scheme 2-... 

Quinoline 1-oxide, hydroxy-, 360 4ff-Quinolizine, 146, 146-150, 153 9aff-Quinolizines, 143-146, 153 Quinol-2- and -4-ones, 348-352 Quinolonediols, 363 Quinol-2- and -4-thiones, 397, 398 Quinoxaline alkyl-, 428 amino-, 415 hydroxy- 378, 379, 384 reaction with dimethyl acetylenedi-carboxylate, 163-164 Quinoxaline-2-thione, 400, 402... 

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. 

Although most of the reactions of preparative importance involving the a-alkyl carbanions are usually carried out under controlled conditions with NHa /NHs being used as the base, a number of reactions using less severe conditions are known, both in the pyrazine and quinoxaline series. In the case of alkylquinoxalines, where an increased number of resonance possibilities exist, mildly basic conditions are usually employed in condensation reactions. 

Alkyl side chains in both pyrazines and quinoxalines are susceptible to halogenation by elemental halogens (28JCS1960, 68TL5931) and under radical conditions with NBS (72JOC511). Thus, bromination of 2-methylquinoxaline with bromine in the presence of sodium acetate... 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Pyrimidine-2-thiones (e.g., 206) have been shown to exist as such by comparison of their ultraviolet spectra with those of both alkylated forms.The ultraviolet spectra of pyrimidine-4-thiones are different from those of 4-alkylthiopyrimidines, therefore the former compounds exist as 207 and/or 208, the predominant form not having been determined. Infrared spectral evidence suggests that quinazoline-4-thione exists as 209 and/or 210 and has been used recently to demonstrate the thione formulation for pyrimidine-2- and -4-thione, pyrazine-2-thione, and quinoxaline-2-thione. In view of this work, the report that X-ray crystallographic evidence supports the mer-... 

Pyrazine-2-thione (213) and quinoxaline-2-thione (214) probably exist in the thione form since their ultraviolet spectra are different from those of the 2-methylthio analogs. The basicity of quinoxaline-2-thione is 1.4 pK units less than that of 2-methylthio-quinoxaline, and the ultraviolet spectra of the cations are dissimilar. Presumably quinoxaline-2-thione and its 2-methylthio derivative do not form similar cations (215, P = alkyl, H), and it would appear that either the thione gives the cation 216 or the 2-thioether gives the cation 217. Similar considerations apply to pyrazine-2-thione. 

Treatment of an alkaline solution of quinoxalin-2-one or quinoxa-line-2,3-dione with an alkyl iodide or sulfate results in A-methylation. Thus methylation of 3-aminoquinoxalin-2-one (74) with methyl sulfate and alkali gives 3-amino-l-methylquinoxalin-2-one (75) and not as previously reported the isomeric 0-methyl derivative. ... 

This chapter covers recent information on the preparation, physical properties, and reactions of quinoxaline and its C-alkyl, C-aryl, iV-alkyl, and A-aryl derivatives as well as their respective ring-reduced analogs. In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into quinoxalines already bearing substituents and the reactions specific to the alkyl or aryl groups in such compounds. For simplicity, the term alkylquinoxaline in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, and aralkylquinoxalines likewise, arylquino-xaline includes both aryl- and heteroarylquinoxalines. 

Note The C-alkylation of quinoxaline has been done by addition (with or without subsequent aromatization see also preceding subsection), by reductive alkylation, or by homolytic alkylation. 

Quinoxaline also underwent many other homolytic alkylations or arylations usually to give, for example, mixtures of 2-alkyl-, 6-alkyl-, and sometimes 2,3- or 2,6-dialkyl derivatives, according to the agent and conditions used. Percentage conversions, ratios of products, separability, and yields appear to... 

Note It is axiomatic that most hydroquinoxalines can give classical A-alkyl derivatives but quinoxalines can give only A-alkylquinoxalinium salts. 

Quinoxaline gave l,4-diethyl-l,2,3,4-tetrahydroquinoxaline by indirect reductive alkylation (AcOH, KBHai, <15°C, 1 h, then reflux, 6h 87% presumably by nuclear reduction, A-acylation, and further reduction of the acetyl groups ). ... 

Direct alkylation of unsubstituted quinoxaline has been discussed in Section 2.1.3. Such alkylation or arylation of other quinoxalines is apparently seldom satisfactory, but the following recent examples contain some procedures that may prove useful. 

The modihcation or displacement of the foregoing nuclear substituents from appropriate quinoxalines has been used to afford alkyl- or arylquinoxalines, as indicated in the following examples. 

This subsection covers not only the conversion of one simple alkylquinoxaline into another but also the conversion of a (functionally substituted alkyl)quinoxaline into another such quinoxaline provided the alkyl portion, and not just the functionality, is changed. The following classihed examples illustrate typical processes involved. 

Although A-aUcyl- and A-arylpiperazines abound in the pyrazine literature, ° the corresponding reduced quinoxalines are rarely encountered. However, reductive alkylation of quinoxaline gave products such as l,4-diethyl-l,2,3,4-tetrahydroqui-noxaline (see Section 2.1.3), and several other typical preparative routes are illustrated in the following examples. 

Some studies on the properties of alkyl- and arylquinoxalines contain data on unsubstituted quinoxaline and are therefore covered in Section 2.1.1. Other papers are mentioned briefly here. 

Alkyl-Alkylidene Tautomerism. Some 2- or 3-(substituted alkyl)quinoxalines, like 3-ethoxycarbonylmethyl-2(177)-quinoxalinone (133), have long been known to exist in equilibrium with their (substituted methylene) tautomers, for example 3-ethoxycarbonylmethylene-3,4-dihydro-2( 1 /7)-quinoxalinone (133a).The effects of solvent change, protonation, and the like on such tautomeric systems have been examined as well as the kinetics thereof. In... 

Note One or more alkyl groups on quinoxaline may become involved in annulation or other cyclization reactions. 

Note A few typical examples of the aromatization of alkylated or arylated hydroquinoxalines and of the oxidative ring fission of quinoxalines are given here. More mundane examples are given passing mention in other chapters. 

Quinoxaline (see Section 2.1.3) and many of its derivatives may be converted into A-alkylquimoxalinium or even A,A -dialkylquinoxalinediium salts by treatment with alkyl halides or the like. Occasionally, when the molecule bears a suitable acidic grouping, it may be possible to deprive the quaternary salt of its gegenion by treatment with a base to form an ylide (in which a carbon atom of the molecule bears the negative charge) or other zwitterionic entity, such as a quinoxaliniumolate. 

The straightforward formation of A-aLkylquinoxalinium halides (by dissolution of the quinoxaline in an excess of alkyl halide, with or without added solvent, at room temperature or above until complete) is now seldom, if ever, described. However, the following examples of somewhat abnormal procedures may prove useful. 

In a different way, by involving the Al-(substimted alkyl) substituent, 1-phena-cylquinoxalinium bromide (226) and acrylonitrile gave l-benzoylpyrrolo[l,2-fl]quinoxaline-3-carbonitrile (228), presumably via the tetrahydro derivative (227) (Mn02, EtsN, Me2NCHO, 85°C, 4h 48%) several analogs were... 

Most of the chemical reactions of halogenoquinoxalines consist of facile nucleophilic replacements, thus making such substrates ideal intermediates for the preparation of aU kinds of other quinoxaline derivatives. Their conversion into alkyl- or arylquinoxalines has been discussed in Section 2.2.1.2 other reactions are outlined in the following subsections. 

Many nitroquinoxalines have been prepared by primary synthesis (see Chapter 1), from halogeno quinoxalines (see Section 3.2.7), or by passenger introduction (e.g., on deoxidative alkylation of an M-oxide see Section 4.6.2.2). However, one major route and one minor preparative route remain, and they are illustrated in the following subsections. 

The foregoing processes are illustrated in the following examples, not including the 1/4-alkylation of reduced quinoxalines that has been discussed in Section 2.2.2. 

---