Hetero-Diels−Alder Reactions of Homochiral 1,2-Diaza-1,3-butadienes with Diethyl Azodicarboxylate under Microwave Irradiation. Theoretical Rationale of the Stereochemical Outcome

Abstract

The stereoselective normal electron demand Diels-Alder reactions of chiral 1,2-diaza-1,3-butadienes, derived from acyclic carbohydrates having different configurations (1-6), with diethyl azodicarboxylate (DEAD) are disclosed. Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation to form the corresponding functionalized 1,2,3,6-tetrahydro-1,2,3,4-tetrazines (7-18) in good yields. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1′,2′. Thus, 1,2-diazoalkenes derived from per-Oacylated sugars having threo configuration at C-1′,2′ give tetrazines with a high facial selectivity, whereas those having erythro configuration at C-1′,2′ afford products in lower diastereomeric ratios. The facial diastereoselection has been rationalized by a PM3 computational study. These results prove that in the transition structures (TSs) the reacting azoalkene exhibits formal negative charges at C-3 and N-2, the former being of greater magnitude, while the heterodienophile displays a partial positive charge at the substituent attached to the nitrogen atom. Accordingly, a stabilizing electrostatic interaction will only occur in TSs involving an endo orientation of the azodicarboxylate in its approach to the azadiene, a fact consistent with the experimental observations.

Synergic Effect of Vicinal Stereocenters in [3 + 2] Cycloadditions of Carbohydrate Azadipolarophiles and Mesoionic Dipoles: Origin of Diastereofacial Selectivity

“…12 As we shall see, and in a counter-intuitive way, it appears that the second stereocenter exerts a strong stereoface directing effect with respect to the heterocyclic dipole. Again, a computational study at a semiempirical level is sufficient to provide a satisfactory rationale of the stereochemical outcome, thereby validating models previously suggested for the interpretation of [3 + 2] cycloadditions.…”

“…8,12 The main argument, illustrated in Scheme 3, for the observed face selectivity is based on the assumption that the acyloxy group attached to the first stereocenter moves away from the heterocyclic dipole. It is worth noting that in acyclic sugar heterodienes in which the first stereocenter has the opposite configuration, the face exposed for attack has been observed to be the Si,Si face.…”

Heterocyclic Chemistry Using Microwave‐Assisted Approaches

“…This property of graphite has been exploited in the microwave-assisted one-pot synthesis of cyanuric acid ( [1,3,5] triazine-2,4,6-triol), prepared via pyrolysis of urea in the absence of water and organic solvents (Scheme 3.39) 64 . The authors suggested that the higher yields and short reaction rates observed in this study were the direct consequence of localised superheating (often called 'hot spots' Avalos et al has reported the microwave-assisted synthesis of tetrazine derivatives by a hetero Diels-Alder reaction of homochiral 1,2-diaza-1,3-butadienes with diethyl azodicarboxylate (Scheme 3.40) 65 . Under conventional conditions, reactions could be performed in benzene solution at room temperature.…”

Environmentally Benign Solvent Systems: Toward a Greener [4+2] Cycloaddition Process

“…26 The dienes are reacted with DEAD to give the corresponding hetero-Diels-Alder cycloadducts in good to excellent yields (87 -96%) and good diastereoselectivities. …”