Īn additional drawback of the above scheme is that even the modest yields of the benzaldehyde 8 obtained by reaction of 12 with alkyl nitrites could not be reproduced by later workers. However, despite these improvements, the reported overall yield of 1 based on the starting toluidine was only 5.5%. Benzaldehyde 8 was subsequently condensed with acetone in the usual way to give dibromoindigo 1. A modest improvement was achieved via a related scheme by Rottig, who used ethyl instead of amyl nitrite for the conversion of toluene 12 to oxime 13. This synthesis of 2 is indeed shorter, but at the expense of rather low yields. The latter is then oxidatively cleaved with ferric ammonium sulfate to give the desired aldehyde 8. The substituted toluene is then condensed with amyl nitrite to give the oxime 13. In the latter procedure, 10 is nitrated in concentrated sulfuric acid to give 4-amino-2-nitrotoluene ( 11) or its sulfate, which is then diazotized and converted to 4-bromo-2-nitrotoluene ( 12) in a Sandmeyer reaction or one of its variants. Thus, van der Lee prepared 8 in 4 steps from p-toluidine ( 10) ( Scheme 2). Subsequent syntheses were accordingly based on shorter methods for the preparation of this aldehyde. This original Sachs and Kempf route is clearly inconvenient, due to the lengthy preparation of the bromonitrobenzaldehyde 8. Interestingly, the yield of dibromoindigo in the final step was not reported. Under the reaction conditions, the hydroxyketone 9 spontaneously cyclizes and undergoes oxidative coupling, but it could be isolated using trisodium phosphate instead of NaOH in the Claisen condensation. The substituted benzaldehyde 8 was prepared, in five steps starting from 2,4-dinitrotoluene ( 2), in an overall yield of about 34%. Thus, the first synthesis of 1, reported in 1903 by Sachs and Kempf ( Scheme 1), was based on the Claisen condensation of 4-bromo-2-nitrobenzaldehyde ( 8) with acetone, in analogy to the Baeyer-Drewsen process for the manufacture of indigo. ![]() Nearly all known syntheses of 6,6′-dibromoindigo ( 1) are based on the oxidative coupling of a 6‑bromoindole derivative, which is usually generated in situ. The original synthesis and its elaborations
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