Electronic and Steric Effects on the Mechanism of the Inverse Electron Demand Diels−Alder Reaction of 2-Aminopyrroles with 1,3,5-Triazines: Identification of Five Intermediates by ¹H, ¹³C, ¹⁵N, and ¹⁹F NMR Spectroscopy

Abstract

The inverse electron demand Diels-Alder (IEDDA) reaction of 1-tert-butyl-2-aminopyrrole with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine in THF-d(8) to give a pyrrolo[2,3-d]pyrimidine was studied by (1)H, (13)C, (15)N, and (19)F NMR spectroscopy, and five intermediates were identified. A zwitterion was the first intermediate detected, and it cyclized to a tricyclic adduct and its conjugate acid. It also gave a neutral imine via a proton switch. The tricyclic adduct underwent a retro-Diels-Alder reaction, but the expected CF(3)CN was not detected. NMR indicated that the amino group of the 2-aminopyrrole was bonded to the CF(3)CN to form a trifluoroacetoamidinium ion. The products of the retro-Diels-Alder reaction reacted rapidly with each other to give the final intermediate observed. Acid-catalyzed loss of an amidine gave the final aromatic product. This is the first study in which direct experimental evidence for the order of the steps in the IEDDA cascade reaction of 1,3,5-triazines with amino-containing dienophiles has been obtained. This study and analogous 1,3-dipolar cycloaddition reactions, in which zwitterions have been detected or proposed, have two factors in common: electronic effects that stabilize the zwitterions and steric effects that inhibit their cyclization.

Inverse‐Electron‐Demand Diels–Alder Reactions: Principles and Applications

“…The De Rosa group has performed extensive research on the reaction of aminopyrroles with 1,3,5‐triazines. As many as five intermediates have been identified by 1 H NMR, 13 C NMR, 15 N NMR, and 19 F NMR spectroscopy . On this basis, a stepwise mechanism has been proposed (Figure ).…”

“…As many as five intermediates have been identified by 1 HNMR, 13 CNMR, 15 NNMR, and 19 FNMR spectroscopy. [6,7] On this basis, astepwise mechanism has been proposed( Figure 1). The first intermediate is zwitterion 3.Z witterions have also been isolated in other iEDDA experiments involving tetrazine.…”

“…[8] In general,t hese zwitterionsa re detected if there are stabilizing electronic factors and steric factors inhibiting their cyclization. [7] Ad ensity functional theory (DFT) study performed on similar compounds [9] suggestst hat the 2-aminos ubstituent helps to stabilizet he zwitterionic intermediate by delocalizing the positive charge, which thus allows hydrogen bondingb etween the triazine ni-trogen atom and the amino hydrogen atom. Ac ertain amount of stabilization of the zwitterion has also been attributed to solvatione nergy.H owever,n od irect evidenceh as been found for zwitterion 3.I nstead, its tautomer,z witterion 4a,h as been detected.…”

“…Zwitterions have also been isolated in other iEDDA experiments involving tetrazine . In general, these zwitterions are detected if there are stabilizing electronic factors and steric factors inhibiting their cyclization . A density functional theory (DFT) study performed on similar compounds suggests that the 2‐amino substituent helps to stabilize the zwitterionic intermediate by delocalizing the positive charge, which thus allows hydrogen bonding between the triazine nitrogen atom and the amino hydrogen atom.…”

Reaction mechanisms : Part (ii) Pericyclic reactions

“…de Rosa and Arnold examined the inverse electron demand Diels-Alder (IEDDA) reaction of 1-tert-butyl-2-aminopyrrole with 2,4,6-tris(trifluoromethyl)1,3,5-triazine in perdeuterated THF to yield pyrrolo [2,3-d]pyrimidine (Scheme 36, R = t-C 4 H 8 ). 44 Scheme 33 Scheme 34…”