1.2- Benzisoxazole, quaternization

Sheads studied the reactivity of over 100 alcohols with 2,1-benzisoxazoles with 70% aqueous perchloric acid in nitromethane 74DIS(B)147). The rates of quaternization by reaction with Mel in DMSO were also studied and the dynamics of the reaction investigated <74AJC122l). 

All these special cases involve benzologs with an ortho quinonoid structure. But even this pattern is not universal, a deviation being 2-methylindazole (40), which quaternizes 2.2 times more slowly than its parent compound 1-methylpyrazole (37).122 Indeed, except for the molecules just considered and 1,2-benzisothiazole,122 benzo-fusion is rate retarding. Thus, 1,2-benzisoxazole (indoxazene, 39), reacts 3.2 times, and 1-methylindazole (39) 7.1 times, more slowly than their parent compounds.122 Fusing a benzene ring onto an azole where the heteroatoms are situated 1,3 leads to decreases in rate constants by factors of 5.0, 6.3, and 6.8, respectively, when X of 38 is NMe, S, and O.122 These factors are not much smaller than that obtained from a comparison of pyridine and quinoline reactivities.61,78,79... 

Fio. 1. Bronsted plot for azoles reacting with methylating agents in quaternization reactions. Pyridine is the reference substrate. 1, 1-methylimidazole 2, 1-methylbenzimidazole 3, thiazole 4, 1-methylpyrazole 5, 2-methylindazole 6, benzo-thiazole 7, oxazole 8, 1-methylindazole 9, benzoxazole 10, 2,1-benzisothiazole 11, isothiazole 12, 2,1-benzisoxazole 13, isoxazole and 14, 1,2-benzisoxazole. 

Sections VI,A, B, D, and E give information about indazoles, oxazole, benzoxazole, isoxazole, benzisoxazoles, isothiazole, benziso-thiazoles, and benzothiazole. In addition, Sections II and VI,F,1 refer to quaternization reactions of isoxazole and benzisothiazoles, respectively. 

Azoles having heteroatoms in the 1,3-orientation are more reactive than those in which the arrangement is 1,2. However, the magnitude of the factor varies, thus oxazole is 68 times more reactive than isoxazole, whereas benzox-azole quaternizes 26 times faster than does 1,2-benzisoxazole. 

Deprotonation can occur at the -GH of pyrazole A-alkyl groups for example 1-methylpyrazole with -BuLi. Such proton loss is facilitated in cationic azido rings, and the ylides so formed sometimes undergo rearrangement. Thus, quaternized 1,2-benzisoxazoles 796 lose a proton and then rearrange to 1,3-benzoxazines, e.g., 797. Quaternized derivatives of benzofuroxan formed in situ undergo rearrangement to 1-hydroxybenzimidazole A-oxides 798. Reactions of this type are also known for A-alkylazolinones. 

Alkylation. Rates of quaternization of isothiazole and its 2,1 and 1,2-benzologues have been examined as a part of a wider study on azoles. The isothiazoles react with methyl iodide in DMSO, and with dimethyl sulphate, affording novel A -methyl derivatives. Benzo-fusion exerts a rate-diminishing effect, but this influence is very small in 1,2-benzisothiazole. The stability of the heterocycles apparently increases in the order 2,1-benzisoxazole < iV -methylindazole < 2,1-benzisothiazole, which parallels the well-established order of stability and aromaticity of furan < pyrrole < thiophen. ... 

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