Benzo-fusion

Benzo-fusion to a heterocyclic ring involved in tautomerism has the effect of steering the equilibrium in directions which tend to retain the full aromaticity of the benzene ring. 

Table 3 Heteroatom and Benzo-fusion Effects on Relative Rate Constants for N-Methylation (rs.-VHCizziri)...

Benzo-fusion onto halonitrobenzenes (Table VIII, p. 277) produces acceleration of aminations or alkoxylations (Tables XII and XIII) except for 3-halo-2-nitronaphthalenes which are analogous to 3-haloisoquinolines. 

The composite results of benzo-fusion on the rates and activation energies of ethoxylation and of piperidination are summarized in round numbers in Scheme VI to give a broad perspective. 

Even though data for a quantitative comparison are lacking, the effect of the position of benzo-fusion onto pyridazines is analogous to that with pyridines in producing the very poorly reactive 3-chloro-cinnoline (396) and highly reactive 1-chlorophthalazine (Table XV, lines 8 and 9). 

Thus, while the 3-hydroxyisoquinoline-3-isoquinolinone equilibrium (80 81) and that of the cinnoline derivatives (82 83) favour the keto forms (81, 83), the proportion of hydroxy tautomers is considerably greater than in the corresponding unfused systems. The benzo-fusion in 2- and 4-quinolinone and in 1-isoquinolinone has the effect of reducing the aromaticity of the heterocyclic ring, and consequently of lowering the proportion of the hydroxy tautomers. 

A unique example is found in 2,1-benzisoxazole (40), which undergoes N-methylation 1.9 times faster than isoxazole (37).122 This is the only known example of rate acceleration resulting from benzo-fusion. Other interesting comparisons involve 2,1,3-benzoxadiazole (benzofurazan, 41), and 1,2,5-oxadiazole (furazan, 42),123 and also isothiazole (37), and 2,1-benzisothiazole (40).122 For these two pairs essentially no change in reactivity results when the azole is converted into its benzolog. 

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... 

The Bronsted correlation for five-membered rings shows that effects of structure on reactivity and on acidity are related. Variations in rate constants for quaternization and in pKa values (Table III) are understandable in terms of resonance and inductive effects of the heteroatom X.120 The effects on the energy of a transition state leading to quaternized product are similar but smaller than those on the energy of protonated material. The following considers in more detail the influence of benzo-fusion. 

Indolo or benzo fusion at the 5,6-position in perhydropyrido[l,2-c]pyrim-idine (335-340) (Fig. 13), as in 360 and 361 shifts the equilibrium in favor of the cis-fused conformer 364 and the axial JV-methyl trans-fused con-former 362, with 54% of the equatorial iV-methyl trans-fused conformer 363 present at room temperature (CDC13 solution).284 285 The shift in equilibrium (compare corresponding shift for 192-194 compared to quinolizidine 179-181, Section III,B,3) is presumably a result of a destabilization of 362 and 363 by the peri-type interaction involving the C-l-H and either the... 

The reported examples of halogen exchange have been carried out on heterocycles activated by the presence of heteroatoms in the ring and by benzo-fusion, e.g., the preparation of 8-fluoroadenosine (137) by Kobayashi et al.212 from 8-bromoadenosine (136) and KF in acetonitrile. 

Nucleophilic attack at ring carbon occurs in benzenes only when electron-withdrawing substituents are present. Even with pyridine, only the strongest nucleophiles react. This is because the formation of the initial adduct (2) involves de-aromatization of the pyridine ring and, once formed, many such adducts tend to re-aromatize by dissociation (1 2). Benzo fusion decreases the loss in aromaticity for the formation of the adduct and thus quinoline (3) and especially acridine (4) react more readily with nucleophiles. 

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