Efficient Synthesis of Polysubstituted Pyrroles Based on [3+2] Cycloaddition Strategy Utilizing [1,2]‐Phospha‐Brook Rearrangement under Brønsted Base Catalysis

Abstract

An efficient method for the synthesis of polysubstituted pyrroles was established based on the [3+2] cycloaddition strategy utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The less-explored approach of the [3+2] cycloaddition, that is, the reaction of a C3 subunit with imines, was successfully achieved by making use of newly designed C3 subunits containing the requisite umpolung. The two-step formal [3+2] cycloaddition involves the catalytic generation of an α-oxygenated propargyl anion through the [1,2]-phospha-Brook rearrangement followed by γ-addition to the imine under Brønsted base catalysis and the subsequent intramolecular cyclization mediated by Au catalyst or a halogenation reagent to afford polysubstituted pyrroles having a variety of substituents in a positional selective manner. The pyrroles thus synthesized were amenable to further transformations, such as palladium-catalyzed cross-coupling reactions. The operationally very simple method with readily available substrates provides new access to a diverse array of well-organized polysubstituted pyrroles.

Gold-Catalyzed Reactions of Specially Activated Alkynes, Allenes, and Alkenes

“…The reaction was shown to be efficient (78–87%) and highly diastereoselective. A related transformation was reported later on by Terada and coworkers (Scheme , part B) . In this case, pyrroles 425 were produced from allenylphosphonates 423 by an addition/elimination sequence.…”

“…A related transformation was reported later on by Terada and coworkers (Scheme 95, part B). 174 In this case, pyrroles 425 were produced from allenylphosphonates 423 by an addition/ elimination sequence. First, there is intramolecular addition of the pendant NHBoc moiety at position α to the allenamide nitrogen atom.…”

Synthesis of Tetrasubstituted Furans through One-Pot Formal [3 + 2] Cycloaddition Utilizing [1,2]-Phospha-Brook Rearrangement

“…Indeed, several efficient approaches have been established in the synthesis of multisubstituted pyrroles because various types of nitrogen-containing subunits, such as imines, enamides, and azomethyne ylides, and their reaction partners are easily available . In this regard, we have recently established a method for the synthesis of polysubstituted pyrroles, which is based on the [3 + 2] cycloaddition strategy utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis (Scheme a) . The formal [3 + 2] cycloaddition involves the construction of a pyrrole ring from propargyl alcohols 1 as a C3 subunit containing the requisite umpolung and imines as a two-atom subunit containing nitrogen, providing a diverse array of well-organized polysubstituted pyrroles.…”

“…As the initial substrate, 1a having a phenyl group at the propargylic position and a butyl group at the alkyne terminus was used. Treatment of 1a and benzaldehyde ( 2a ) with 10 mol % P1- t Bu in DMF at −60 °C was carried out according to the reaction conditions for our previous pyrrole synthesis (Table , entry 1) . The reaction provided desired allenyl alcohol 3aa as the major product in 65% NMR yield along with some byproducts including propargyl alcohol 5aa , which was formed through the addition of the propargyl anion to 2a at the α-position followed by the migration of the dimethoxyphosphoryl moiety, as well as allenyl phosphate 6a and propargyl phosphate 7a , which were formed by the direct protonation of propargyl anion at the γ- and α-positions, respectively.…”

“…9 In this regard, we have recently established a method for the synthesis of polysubstituted pyrroles, which is based on the [3 + 2] cycloaddition strategy utilizing the [1,2]phospha-Brook rearrangement under Brønsted base catalysis (Scheme 1a). 10 The formal [3 + 2] cycloaddition involves the construction of a pyrrole ring from propargyl alcohols 1 as a C3 subunit containing the requisite umpolung and imines as a two-atom subunit containing nitrogen, providing a diverse array of well-organized polysubstituted pyrroles.…”