Pyrazine 1-oxides halogenation

Isoxazolo[4,5-6]pyrazine (176) is resistant to electrophilic halogenation because the potentially reactive site is at the ring junction. The 7-oxide, though, was converted into the 6-chloro derivative of 176 on heating with phosphoryl chloride (73JHC181). 

The presence of an N-oxide function in pyrazine is not sufficient in itself to promote electrophilic halogenation, and even the presence of other weak donor groups may fail to promote reaction unless they can act in concert. Although 2-methoxypyrazine 1-oxide could not be bromi-nated, the 3-methoxy isomer [and 3-aminopyrazine 1-oxide (54)] was bro-minated in the 2- and 6-positions (ortho to oxide and ortho or para to the amino group cf. Scheme 47). Similarly, 2-aminopyrazine was brominated more readily than its Af-oxide (55 R = H) where the two groups are in opposition [83JOC1064 84H(22) 1195]. 

With the exception of those halogenopyrazines made by primary synthesis (see Chapters 1 and 2), most chloropyrazines have been made recently by the reaction of tautomeric pyrazinones with a phosphorus chloride or by the reaction of pyrazine iV-oxides with phosphoryl chloride in contrast, most other halogenopyrazines have been made by direct halogenation or by transhalogenation of chloropyrazines. A single interesting example of the conversion of a methoxy- into a chloropyrazine is included at the end of Section 4.1.1. 

Nuclear Halogenopyrazines by Deoxidative Halogenation of Pyrazine A -Oxides H105)... 

Halogenated pyrazine N-oxides are more reactive than the parent halo-pyrazines toward oxygen (85JHC1291), nitrogen, and sulfur nucleophiles (84H11O5). 

Aluminum Reagents. Alanes are effective donors of an alkyl group to Pd(II) after the palladium insertion into a carbon-halogen or a carbon-oxygen bond. All carbon positions in pyrazine are electrophilic. Therefore, chloropyrazines can be used as substrates for the methylation with trimethylalanes as in the preparation of the methylpyrazine A-oxides 250 and 251 (Scheme Triflated 5-hydroxy-l,3-... 

In concentrated sulphuric acid solution, chlorinated pyrazines and quinoxalines are regiospecifically oxidized by peroxysulphuric acid (Caro s acid) at the nitrogen adjacent to the halogen-bearing carbon.This procedure does in fact provide the first direct, high-yield synthesis of the hitherto difficultly accessible 2-chloropyrazine 1-oxides. Pyrazine-based cyclophanes, e.g. (230), have been prepared and, under standard conditions, methylate only at N-4. This property has been used to construct the 1,3,5-bridged cyclophane (231) from (230) and 1,4-di-iodobutane. 

---