From Simple Furans to Complex Nitrogen‐Bearing Aromatic Polycycles by Means of a Flexible and General Reaction Sequence Initiated by Singlet Oxygen

Abstract

All-in-one: A new and general one-pot reaction sequence initiated by singlet oxygen that transforms simple furan substrates into complex nitrogen-bearing aromatic polycycles having all the structural features of a number of important natural products (for example, the erythrina alkaloids; see scheme, RB = rose Bengal) is reported. The reaction sequence itself uses mild conditions and has wide functional group tolerance.

Singlet oxygen-mediated transformation of furans into aromatic nitrogen-containing polycycles in water

“…It shows how water is expected to participate as a reactant and why the use of water as solvent might cause a serious deviation from what had been accomplished previously. [22][23][24] Singlet oxygen, generated photochemically, typically first undergoes a [4+2]-cycloaddition with the furan substrate to give an ozonide (not shown). It is reasonable to suggest that the solvent, in this case water, might open the ozonide adduct to give a hydroxy-hydroperoxy intermediate B.…”

“…31 Under aqueous conditions, we propose that the equilibria between B, C and D is sidelined by the collapse of the open chain hydroperoxy ketone C affording the unsaturated keto-aldehyde E, which would in turn be the subject of an attack by the newly introduced amine (E → F). It should be emphasized here that no reductant (such as the Me 2 S utilized in such sequences [21][22][23][24] ) shall be used as an additive, thus the new protocol will not only be undertaken in an environmentally benign solvent, but will also work in a more succinct manner and have a reduced number of additives/reagents than previous methods. A series of reorganizing equilibria could then afford cation H, deprotonation of which affords the isolable, but fairly fragile, intermediate I that had been observed in previous studies.…”

“…A series of reorganizing equilibria could then afford cation H, deprotonation of which affords the isolable, but fairly fragile, intermediate I that had been observed in previous studies. [21][22][23][24] Since the last stages of this mechanistic analysis are common to the Pictet-Spengler reaction in methanol 22 the first and most important task was to validate the early steps of the proposed sequence. To this end, the simple furan 1a was photooxygenated using our standard conditions: bubbling oxygen through the reaction solution containing catalytic rose Bengal at 5 °C while irradiating with visible spectrum light (Scheme 2).…”

“…[15][16][17] Beyond its many advantages as a green reagent, singlet oxygen is an ideal player in sustainable chemistry because it is both highly selective in its reactions, which eliminates the need for protecting groups and non-strategic redox manipulations, 17 and because it readily initiates one pot reaction sequences that can accomplish dramatic increases in molecular complexity in a single operation. [18][19][20] Recently, we have explored ways to include basic nitrogen components in such sequences, [21][22][23][24] so that not only polyoxygenated, but also nitrogen-bearing, polycycles can be targeted. In a new method, 22,23 we combined the singlet oxygenphotooxidation of simple furans with the introduction into the reaction sequence of both a basic nitrogen reactant and a Pictet-Spengler cyclisation; [25][26][27] thus, affording in one operation various aromatic nitrogen containing-polycycles that are present in many natural products and other bioactive targets.…”

“…[18][19][20] Recently, we have explored ways to include basic nitrogen components in such sequences, [21][22][23][24] so that not only polyoxygenated, but also nitrogen-bearing, polycycles can be targeted. In a new method, 22,23 we combined the singlet oxygenphotooxidation of simple furans with the introduction into the reaction sequence of both a basic nitrogen reactant and a Pictet-Spengler cyclisation; [25][26][27] thus, affording in one operation various aromatic nitrogen containing-polycycles that are present in many natural products and other bioactive targets. This method, however, required the use of methanol and chlorinated solvents, neither of which can be part of a complete sustainable paradigm.…”