Preparation of 5H-pyrrolo[2,3-f]benzoxazoles, -[2,3-f]benzothiazole, and 8H-pyrrolo[3,2-g]benzothiazole

Novel compounds having either 5H-pyrrolo[2,3-f ]benzoxazole, 5H-pyrrolo[2,3-f]benzothiazole, or 8H-pyrrolo[3,2-g]benzothiazole skeletons are now available utilizing 1-hydroxyindole chemistry (Scheme 23) [39].

A simple treatment of Nb-acetyl-5-acetylamino-1-methoxytryptamine (21) with 85% HCOOH affords 7-(2-acetylamino)ethyl-2-methyl-5H-pyr-rolo[2,3-f]benzoxazole (176a, 32%), Nb-acetyl-6-acetylamino-5-hydroxy-tryptamine (177a, 16%), and Nb-acetyl-6-acetylaminotryptamine (178a, 15%). A failure of the attempt to cyclize 177a to 176a suggests that the oxygen in the molecule (176a) comes from the acetylamino oxygen of 21 [39].

Interestingly, 7-(2-acetylamino)ethyl-5H-pyrrolo[2,3-f ]benzoxazole (176c, 16%) is isolated together with 176b (23%), 177b (18%), and 178b (17%)

Scheme 23 Preparation of 5H-pyrrolo[2,3-/]benzoxazoles, -[2,3-f ]benzothiazole, and 8H-pyrrolo[3,2-g]benzothiazole

upon treatment of Nb-acetyl-5-propanoylamino-1-methoxytryptamine (179) with 85% HCOOH. Its production could be explained by the prior formation of the intermediate, Nb-acetyl-5-(N-formyl-,N-propanoyl)amino-1-methoxytryptamine (180). The structure of 176c is confirmed by direct comparison with the product obtained by the reaction of 33 with 85% HCOOH [39].

A novel intramolecular nucleophilic attack of the thioamide sulfur on the 7-position of the indole nucleus is realized to provide 7-(2-acetylamino)ethyl-2-(2-naphtyl)oxy-5ff-pyrrolo[2,3-/]benzothiazole (182,32%) and 6-(2-acetyl-amino)ethyl-2-(2-naphtyl)oxy-8ff-pyrrolo[3,2-g]benzothiazole (183, 25%), when Nb-acetyl-1-methoxy-6-N-(2-naphthyloxy)thiocarbonylaminotryptam-ine (181) is treated with 85% HCOOH [39].

X-ray Analysis, Theoretical Calculation, and Working Hypothesis

At the very beginning of the study, we had predicted in our 1-hydroxyindole hypothesis that 1-hydroxyindole compounds should undergo unprecedented nucleophilic substitution reaction and the reaction must be responsible for the generation of serotonin (melatonin, etc.) in our central nervous system [1-7].

Theoretically, however, why could 1-hydroxyindole compounds undergo nucleophilic substitution reactions? Let's consider the well-known reaction of diazonium salt (E, Fig. 3). Liberation of the nitrogen molecule leaves positive charge on the carbon initially diazonium group attached as shown in F. Because the positively charged vacant sp2 orbital is orthogonal to the p-orbitals forming a 6n-electron aromatic system, electron delocalization does not occur. As a result, resonance structures such as G and H cannot be generated.

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