Isothiazole aromaticity

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Table 7 also indicates that the rate enhancements for a 3- and 5-methyl group vary significantly among 1,2-azoles. The difference between the increments in log units for a 3-and 5-methyl group, which should vary directly with bond fixation in the ground state, is larger for isoxazole (1.4) than for pyrazole (0.7) and for isothiazole (0.2). This indicates that the aromaticity increases in the same order and contributes the first quantitative evidence that the 1,2-azoles follow the same aromaticity order as furan < pyrrole < thiophene. 

The possible structures for isothiazoles are discussed in Section 4.01.1, and attention in this chapter will be directed mainly towards the aromatic systems, as defined in Section 4.01.1. The saturated isothiazole 1,1-dioxides (5) are known as sultams, and bicyclic compounds of structure (6) are called isopenems. Isothiazoles readily coordinate to metals (76MI41703, 78MI41701, 79MI41700, 80MI41701). Coordination usually takes place through the nitrogen atom, but sulfur coordination can occur with soft metals such as cadmium or mercury. Some specific coordination complexes are discussed in later sections. 

Representative chemical shifts from the large amount of available data on isothiazoles are included in Table 4. The chemical shifts of the ring hydrogens depend on electron density, ring currents and substituent anisotropies, and substituent effects can usually be predicted, at least qualitatively, by comparison with other aromatic systems. The resonance of H(5) is usually at a lower field than that of H(3) but in some cases this order is reversed. As is discussed later (Section 4.17.3.4) the chemical shift of H(5) is more sensitive to substitution in the 4-position than is that of H(3), and it is also worth noting that the resonance of H(5) is shifted downfield (typically 0.5 p.p.m.) when DMSO is used as solvent, a reflection of the ability of this hydrogen atom to interact with proton acceptors. This matter is discussed again in Section 4.17.3.7. 

The NMR chemical shifts of non-aromatic isothiazoles can be predicted with reasonable accuracy using standard substituent increments. A particular usefulness of NMR is its ability to distinguish between very similar compounds, and for this reason NMR finds application in pharmaceutical and other analyses. As an example CNMR allows ready distinction of the dlastereolsomers of dehydromethionine (14) and the possibility of detection of one dlastereolsomer in the presence of the other (79JOC2632). 

Alternative ( soft ) ionization techniques are not usually required for aromatic isothiazoles because of the stability of the molecular ions under electron impact. This is not the case for the fully saturated ring systems, which fragment readily. The sultam (25) has no significant molecular ion under electron impact conditions, but using field desorption techniques the M + lY ion. is the base peak (73X3861) and enables the molecular weight to be confirmed. 

Isothiazole behaves as a typical stable aromatic molecule. Thermolysis of substituted isothiazoles at 590 °C leads to the formation of thioketenes (80MI41700) and phenyl-isothiazoles undergo photoisomerism (Section 4.17.6.2) (73BSF1743, 81T3627). 1,2-Benzisothiazole boils at 220 °C without appreciable decomposition, and the 2,1-isomer... 

The stability of isothiazole derives from the fact that it has an aromatic delocalized ir-electron system. The NMR chemical shifts, which depend, inter alia, on ring currents, and the high stability of the molecular ions in mass spectrometry, are typical of aromatic compounds, and X-ray measurements confirm the partial double bond character of all the bonds of the ring. 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

A powerful method of introducing a CF3 group into aromatics is the conversion of C02H with SF4. The use of SF4 with heterocyclics is not as widespread but it has been applied to imidazoles [81JFC(17)179], thiazoles, isothiazoles [91 JFC(55) 173], and furans (86BSF974). 

The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively <06JHC1045>. The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Aromatic pyrrolo[ 1,2-A isothiazoles are not known and only a sulfone analog of tetrahydro and one perhydro derivative have been prepared. 

Sulfur. Thiophene and benzo[ >] thiophene are both aromatic heterocycles, as discussed earlier in this review. Isothiazole is a planar molecule with an aromaticity comparable with those of thiazole and pyrazole, and higher than those of isoxazole and oxazole,122 140 as evaluated on the basis of Bird s aromaticity index A, based upon the statistical degree of uniformity of the bond orders of the ring periphery. Theoretical calculations and experimental data in connection with the aromaticity of isothiazole have been reviewed.141 Thiazole is also viewed as an aromatic molecule, similar to thiophene. It lacks an experimental aromaticity value, but the heat of formation together with bond lengths and angles have been calculated by various computational meth-... 

Thiophene-1-oxide and 1 -substituted thiophenium salts present reduced aromaticity.144 A variety of aromaticity criteria were used in order to assess which of the 1,1-dioxide isomers of thiophene, thiazole, isothiazole, and thiadiazole was the most delocalized (Scheme 46).145 The relative aromaticity of those molecules is determined by the proximity of the nitrogen atoms to the sulfur, which actually accounts for its ability to participate in a push-pull system with the oxygen atoms of the sulfone moiety. The relative aromaticity decreases in the series isothiazole-1,1-dioxide (97) > thiazole-1,1 -dioxide (98) > thiophene-1-dioxide (99) then, one has the series 1,2,5 -thiadiazole-1,1 -dioxide (100) > 1, 2,4-thiadiaz-ole-1,1-dioxide (101) > 1,2,3-thiadiazole-1,1 -dioxide (102) > 1,3,4-thiadiazole-l,1-dioxide (103) in the order of decreasing aromaticity. As 1,2,5-thiadiazole-1,1-dioxide (100) was not synthesized, the approximations used extrapolations of data obtained for its 3,4-dimethyl-substituted analogue 104 (Scheme 46). 

TT-Electron delocalization in isoxazole seems to be more effective than in oxazole however, isothiazole is less aromatic than thiazole thus it is not a general rule that 1,2-diazoles possess higher aromaticity in comparison with 1,3-diazoles. Oxygen-containing heterocycles are always less aromatic than their sulfur and nitrogen counterparts, e.g. thiazole > imidazole > > oxazole. At the same time, the relative aromaticity of S- and N-containing heterocycles can interchange (pyrazole > isothiazole > isoxazole). 

Chloride ion in benzyl(triethyl)ammonium chloride can activate a nitrile group in dicyanomethylenedithiazole 42 which then cyclizes onto S-l to form the aromatic isothiazole ring and a new cyano group (Equation 17) <1997J(P1)3345>. The yield of isothiazole 86 is quantitative. 

The organo-lithium reagent can be made by exchange of Li for a halide or by deprotonation. With di-iodide 24, one iodine may be exchanged with one equivalent of BuLi and the aldehyde 25 is the product.6 The aromatic heterocycle isothiazole 26 has its most acidic hydrogen (marked) next to sulfur and it gives one aldehyde 27 in good yield.7... 

They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole (see Chapter 4). Their aromaticity derives from delocalisation of a lone pair from the second heteroatom, 3.4a-e. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

Dithiolium salts, particularly with aromatic substituents, readily form isothiazoles on treatment with ammonia58-62 and a mechanism (Scheme 21) has been proposed by Olofson et al. °... 

The isothiazoles possess the typical properties of a heterocyclic aromatic system without the ring lability so characteristic of the analogous isoxazoles.87 The chemistry reflects the relative inertness of the 3-position, the susceptibility of the 4-position to electrophilic attack, and the susceptibility of the 5-position to nucleophilic attack. The ring nitrogen is only weakly basic, but can be induced to form quaternary derivatives, and the N-S bond may be cleaved under certain circumstances. 

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