An Amine Group Transfer Reaction Driven by Aromaticity

Abstract

A stereoselective domino inverse electrondemand Diels−Alder/amine group transfer reaction catalyzed by a bidentate Lewis acid provides 1-amino-1,2-dihydronaphthalenes, a core structure in many bioactive compounds. A concerted mechanism is proposed based on experimental studies as well as DFT computations demonstrating a new general reactivity scheme. The broad scope of the reaction was evaluated by variation of all three starting compounds, phthalazines, aldehydes, and amines. Scalability was demonstrated by a gram scale reaction without diminished yield.

Mechanistic Study of Domino Processes Involving the Bidentate Lewis Acid Catalyzed Inverse Electron‐Demand Diels−Alder Reaction

“…With excess of amine, the eliminated product 10 was formed nearly quantitatively after 4 d of reaction (Table 1, entry 6). However, if the reaction was stopped already after 1 d, in all cases the eliminated product 10 was the main outcome with small amounts of the rearranged product 21 , which is in contrast to our previous findings [9] . Unfortunately, the reaction cannot be conducted at lower temperatures as these temperatures are required for the less reactive ketone.…”

“…In the case of excess amine, a stepwise concerted reaction path was proposed for the amine transfer reaction, based on computations involving two amine molecules in the transition state (Scheme 5). [9] With equimolar amounts of amine, the elimination was favored, which is in accordance with this proposal. For the elimination, different mechanistic pathways are feasible (Scheme 5).…”

“…These results suggest, that monodentate Lewis acid catalysts might also be effective. In prior studies, BF 3 and others have been tested to promote the IEDDA reaction of phthalazines without success [7,9,10] . Nevertheless, in this study enamines derived from ketones are employed, which require higher temperatures (110 °C compared to max 60 °C in ref.…”

“…The following N 2 ‐extrusion occurs then after release of the catalyst to form the quinodimethane key intermediate. The elimination as well as the amine transfer reaction are very close in energy, although they proceed via different mechanisms: While for the elimination an E1‐type pathway has been shown to be most feasible, the amine transfer operates along the already published bimolecular “enforced” concerted pathway [9] . Also, the photochemical ring opening has been computed proceeding by an excitation to the first excited state, from which the electrocyclization advances nearly barrierless to the final product.…”

“…Depending on the conditions not only the substituted naphthalene product 5 is obtained, but also a dihydronaphthaleneamine 6 [9] as well as the photo‐induced ring‐opened (PIRO) product 7 corresponding to a formal insertion of the quinodimethane motif derived from phthalazine 1 into the C=C‐bond of the dienophile [10] . Although in all cases a mechanistic proposal has been presented, detailed mechanistic studies have not been conducted.…”