Zur Kenntniss der tertiären aromatischen Amine

A Perspective Distilled from Seventy Years of Research

“…This led to an extensive search of very relevant related papers of Henry Gilman and the already mentioned metalation and carboxylation of anisole and benzotrifluoride. 30 The real impetus for the benzyne work was supplied by the report by Gilman [50][51][52] that treatment of 2-bromoanisole with sodium amide resulted in exclusive formation of 3-aminoanisole that was wholly congruent with the results of Kym and Haeussermann [47][48][49] My first MIT student to do undergraduate thesis work on the mechanisms on rearrangements of this kind was Edward M. Kosower. At that time, Kosower was a very amiable, intelligent, but rather feckless, C-average student who subsequently went from MIT to a Ph.D. with Saul Winstein at UCLA and later to a very excellent academic career in physical organic chemistry, starting at Wisconsin then to Stony Brook and finally at Tel Aviv.…”

“…The real impetus for the benzyne work was supplied by the report by Gilman − that treatment of 2-bromoanisole with sodium amide resulted in exclusive formation of 3-aminoanisole that was wholly congruent with the results of Kym and Haeussermann − …”

“…To be sure, Kym’s experiment is an isolated example. In contrast, the experiments by Haeussermann − uncovered quite accurately the totality of the basic pattern of these rearrangements, as it is known today, although giving yields of only about 5% of the listed products. My interest in these rearrangements was whetted by the literature research prompted by Geissman’s suggestion that we might (but did not) investigate possible syntheses of salicylaldehyde derivatives by metalating anisole with alkyllithiums in the ortho position and running aldehyde-producing additions reactions.…”

“…With either 11 or 12 , the methoxy group is either one or two carbons removed from metalation products formed by addition of sodium amide to 10 , and the inductive effects of the methoxy group would have to be very strong to favor formation of 12 over 11 . One might guess this would be sufficiently so that formation of 13 would be at least slightly favored over 5 , but even going back to the work of Haeussermann − more than 100 years ago, the reported product ratios are quite close to 50:50 (Figure ).…”

“…With either 11 or 12, the methoxy group is either one or two carbons removed from metalation products formed by addition of sodium amide to 10, and the inductive effects of the methoxy group would have to be very strong to favor formation of 12 over 11. One might guess this would be sufficiently so that formation of 13 would be at least slightly favored over 5, but even going back to the work of Haeussermann [47][48][49] more than 100 years ago, the reported product ratios are quite close to 50:50 (Figure 2). All of this makes clear the general pattern of rearrangement products with sodium amide and 2-, 3-, and 4-chlorotoluenes, where the 1-methyl substituent has at most a minor inductive effect, meaning that if we replace methoxy with methyl and the bromo with chloro in Figure 3, we should expect little preference for formation of methyl-, chloro-substituted metalation products 2, 7, or 9.…”