Reactions of 6-Halodihydrodiazepines with Nucleophiles

As mentioned in Section VIII, 6-iododihydrodiazepines may be prepared by reaction of their 6-bromo analogs with sodium iodide in methanol.35 Similarly, 6-bromodihydrodiazepines react readily with methoxide ions to give the corresponding 6-methoxy derivatives.26,36 Other 6-alkoxy-, 6-aryloxy-, and 6-aminodihydrodiazepines have been prepared by nucleophilic substitution.35 

This ready nucleophilic substitution is surprising, since in the normal tautomeric form 18 the 6-position should be deactivated towards nucleophilic attack indeed, as discussed in Section VIII, this position is a site where electrophilic substitution takes place readily. It is possible that in the presence of base prototropic rearrangement via the dihydrodiazepenide anion 19 to the tautomer 20 takes place. Although the equilibrium concentration of 20 is likely to be very small it would be strongly electrophilic at the 6-position owing to the effects of the bromine atom and the two azomethine groups, and it could well be the reactive species in the nucleophilic substitution of the bromine atom. A tautomer of this structure 

Although the mechanism of this reaction is uncertain it seems likely that the bisazomethine tautomer 20 is again involved, nucleophilic attack on the bromine atom by base leading to an anion which, in turn, extracts a proton from the solvent or from another diazepine molecule [Eq. (7) ].36 

The involvement of this tautomer is particularly suggested by the fact that under identical conditions iV-methyldihydrodiazepines do not undergo this reaction. 

The evidence available suggests that, in a general way, steric factors affect the course of the reaction. Increase in the size of substituents at positions 5 or 7 or in the size of the nucleophile appears to favor protode-bromination over nucleophilic substitution, Furthermore it appears that 6-iododihydrodiazepines undergo protodeiodination rather than nucleophilic substitution irrespective of the size of the nucleophile or of 5(7)-substituents, whereas 6-chlorodihydrodiazepines are less susceptible to protodchalogenation.64 Thus with thiourea 6-bromodihydrodiazepines undergo protodebromination, whereas 6-chlorodihydrodiazepines form 6-isothiouronium salts, in contrast to the normally more ready formation of isothiouronium salts from bromo compounds than from chloro compounds. It is not unreasonable that protodehalogenation should be favored for more bulky dihydrodiazepines or nucleophiles since this reaction has less steric demands than nucleophilic substitution. Similarly, both for 

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