Regioselective Synthesis of 2,3,4- or 2,3,5-Trisubstituted Pyrroles via [3,3] or [1,3] Rearrangements ofO-Vinyl Oximes

Abstract

The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base. When enolization is favored, a [3,3] rearrangement followed by a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the [3,3] rearrangement or the [1,3] rearrangement product with β-ester O-allyl oxime substrates.

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

“…Therefore, the regioselectivity of pyrrole formation in this transformation can be controlled by either the nature of the α-substituent or by addition of a base. 357 …”

Investigation of the Synthesis of Benzofuroindolines from N-Hydroxyindoles: An O-Arylation/[3,3]-Sigmatropic Rearrangement Sequence

“…13 Transient 16a could also be generated by the O-addition of N-arylhydroxylamines to alkynes or allenes 14 or by the Chan-Lam coupling between N-arylhydroxylamines and alkenyl boronic acids. 15 20 Recently, the Bartoli reaction has been extended to the synthesis of 2-amino-2′-hydroxy-1,1′-biaryls 20 through the generation of N,O-diarylhydroxylamines 16d by addition of aryl Grignard reagents to nitroarenes. 21 Somei described only one example of the SNAr-sigmatropic rearrangement sequence from N-hydroxyindoles.…”

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

“…[1] Due to the privileged nature of these heterocycles,m any methods have been developed to access these important scaffolds. [3] This approach is appealing because of the potential to simultaneously set several contiguous stereocenters in the tetrahydrofuran ring and the latent modularity of the precursor.A nalogous transformations have been reported for the synthesis of dihydrobenzofurans from O-aryloxime ethers,w hich are easily prepared via oxime arylation or condensation of the corresponding O-arylhydroxylamine with the appropriate ketone. [3] This approach is appealing because of the potential to simultaneously set several contiguous stereocenters in the tetrahydrofuran ring and the latent modularity of the precursor.A nalogous transformations have been reported for the synthesis of dihydrobenzofurans from O-aryloxime ethers,w hich are easily prepared via oxime arylation or condensation of the corresponding O-arylhydroxylamine with the appropriate ketone.…”

“…[3] This approach is appealing because of the potential to simultaneously set several contiguous stereocenters in the tetrahydrofuran ring and the latent modularity of the precursor.A nalogous transformations have been reported for the synthesis of dihydrobenzofurans from O-aryloxime ethers,w hich are easily prepared via oxime arylation or condensation of the corresponding O-arylhydroxylamine with the appropriate ketone. [6] Herein we describe the synthesis of 2-aminotetrahydrofurans such as 8a with three contiguous carbon stereocenters through acopper-catalyzed N-alkenylation of N-Boc-siloxyamine 1,followed by generation of N,O-dialkenyl-hydroxylamine 6a via deprotection of 3a and addition of 4a to allene 5a,which precipitates aspontaneous [3,3]-rearrangement and cyclization sequence (Scheme 1C). Due to our interest in advancing the reactivity of unsaturated hydroxylamines and nitrones,wewondered if we could leverage our understanding of oxime and hydroxylamine alkenylation to design am odular route to N,Odialkenylhydroxylamines.…”

“…[6] Herein we describe the synthesis of 2-aminotetrahydrofurans such as 8a with three contiguous carbon stereocenters through acopper-catalyzed N-alkenylation of N-Boc-siloxyamine 1,followed by generation of N,O-dialkenyl-hydroxylamine 6a via deprotection of 3a and addition of 4a to allene 5a,which precipitates aspontaneous [3,3]-rearrangement and cyclization sequence (Scheme 1C). Synthesis of 2-aminodihydrobenzofurans and 2-aminotetrahydrofurans via [3,3]-sigmatropic rearrangements. [7][8][9] We initiated our studies towards the generation of N,Odialkenylhydroxylamines 6 for the synthesis of 2-aminotetrahydrofurans 8 through the development of conditions for the N-alkenylation of N-Boc-siloxyamine 1.U sing previous studies of hydrazodiformates as as tarting point, coppercatalyzed conditions for the N-alkenylation of 1 were optimized and the reaction was determined to work best in the presence of 10 mol %CuI and DMEDA(N,N'-dimethylethylenediamine) (Scheme 2).…”