Quinoxaline nucleophilic substitution

Nucleophilic displacement of 2-chloro-3-phenylquinoxaline with methylamine at 100°-150° and with sodium phenoxide in excess of phenol of 100° gives the expected 2-methylamino- and 2-phenoxy-3-phenylquinoxalines. 2-Chloroquinoxaline and its 3-phenyl derivative undergo ring closure with aminoacetaldehyde dimethylacetal to an imidazo[l,2-a]quinoxaline. Nucleophilic substitution of 2-chloro-quinoxaline with hydroxide ion in water is accelerated by cationic micelles and retarded by anionic micelles. These results were correlated with reactions of l-chloro-2,4-dinitrobenzene, and the characteristics of their transition states were discussed. ... 

Pyrazine and quinoxaline fV-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine fV-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine fV-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

The effect of nuclear substituents on nucleophilic substitution of quinoxalines is included in Section II, E, and in section III, A,... 

The Stille reaction featuring bromoquinoxaline 84 and vinylstannane delivered vinylquinoxaline 85. In addition, 85 was further manipulated to a 5-aminomethylquinoxaline-2,3-dione 86 as an AMPA receptor antagonist [47]. Pd-catalyzed nucleophilic substitution on the benzene ring has also been described [48]. Thus, transformation of 5,8-diiodoquinoxalines to quinoxaline-5,8-dimalononitriles with sodium malononitrile was promoted by PdCl2,(Ph3P)2. 

Intramolecular deoxidative nucleophilic substitution of 2-(Tmethylhydrazino)quinoxaline 4-oxides 62 to tricyclic heteroaromatics has been extensively researched by Kurasawa e( al. <1995JHC1085, 2000JHC1257, 2002H(56)291, 2002H(58)359, 2003JHC837>. The cyclization consists of initial formation of hydrazone followed by nucleophilic... 

Although the most commonly used reactive systems involve the halotriazine and sulfa-toethyl sulfone (vinyl sulfone) groups, halo-genated pyrimidines, phthalazines, and quinoxalines are also available (Fig. 13.14). For all of these systems, alkali is used to facilitate dye-fiber fixation, and fixation occurs either by nucleophilic substitution or addition (Figs. 13.15-13.16). 

In quinoxaline A -oxides, ring substituents show enhanced reactivity towards nucleophilic substitution relative to the unoxidized compounds, in particular in the position a to the 7V-oxide moiety. 

Carbanions of a-haloalkyl aryl sulfones, sulfonates and sulfonamides react with quinoxalines according to two general pathways vicarious nucleophilic substitution of hydrogen and/or bis-annulation to bis(azirino)quinoxaline derivatives. The charge distribution in the anionic (T-adducts and reaction conditions influence the direction of these reactions. ... 

Quinoxalines are more reactive towards nucleophilic substitution than quinolines as a result of inductive activation by the additional ring nitrogen. If substituents are present in both the benzenoid and heteroaromatic ring, monosubstitution occurs predominantly in the latter. 

Quinoxaline A -oxides substituted in the 2,3-positions undergo facile nucleophilic displacement. 2-Chloroquinoxaline 1-oxide undergoes nucleophilic substitution much more readily than 2-chloroquinoxaline itself. 

Phenylquinoxalin-2(l/f)-one reacts with 3-dimethylaminopropylmagnesium chloride at the carbonyl carbon to give 2-(3-dimethylaminopropyl)-3-phenylquinoxaline in 30% yield. Nucleophilic substitution of the methoxy group in 2-meihoxyquinoxaline (19) with phenyl-acetonitrile in the presence of sodium hydride yields a-phenyl-a-(quinoxalin-2-yl)acetonitrile (20). "" ... 

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