Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation

Abstract

Abstract2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free –NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.

Mapping Ambiphile Reactivity Trends in the Anti‐(Hetero)annulation of Non‐Conjugated Alkenes via PdII/PdIV Catalysis

“…Product ratios were assayed at two time points, low (<40 %) conversion and full (>95 %) conversion, and the data shown in Scheme 2B is calculated based on the product ratio at low conversion. Consistent with reactivity trends seen in Tables 2–4, a carbon‐pronucleophile (−CH(CO 2 Et) 2 ) was incorporated in preference to nitrogen nucleophile (−NHTs), which in turn was incorporated in preference to an oxygen nucleophile (−OH) [14, 21, 30, 31] . Ambiphile N1 was next competed against N19 , N21 , and N30 , where the relative reactivities were found to be Alkenyl−I (terminal)>Alkenyl−I (internal)≈Aryl−I>Alkyl−I.…”

“…The reaction mechanism is similar to the previous [3+2] annulation reaction, [12] involving reversible nucleopalladation, intramolecular Pd(II)/Pd(IV) oxidative addition, and reductive elimination. We carried out control experiments to exclude the alternative hydrofunctionalization/C-H cyclization pathway that could be envisioned (Scheme 3).…”

“…This indicates that protodepalladation is prohibitively high‐energy under these conditions. Furthermore, the fact that no C−N coupled byproducts (e.g., from aza‐Wacker coupling) were detected suggests that the initial nucleopalladation step may be endergonic [14] . Consistent with these findings, when independently prepared 2 aa’ was subjected to the standard conditions, intramolecular cyclization was not observed, indicating that it is not a competent intermediate (Scheme 3B).…”

“…During the past five years, we and others have reported various palladium‐catalyzed functionalizations of non‐conjugated alkenes by leveraging strongly coordinating bidentate directing auxiliaries, such as 8‐aminoquinoline (AQ)‐based amides [11–13] . By applying this substrate directivity strategy, we recently described a Pd II ‐catalyzed [3+2] annulation method to prepare dihydrobenzofurans, indolines, and indanes (Figure 1B) [14] . In contrast to classical Larock‐type Pd 0 chemistry, which nearly always results in syn ‐selective addition, [6] this reaction proceeds in an anti ‐selective fashion as a consequence of its nucleopalladation‐first mechanism.…”

Palladium‐Catalyzed Selective Hydroamination of Aliphatic Alkenes with Hydrazides

“…[15] More recently, Engle and co-workers diclosed the Pd-catalyzed [3 + 2] annulation of alkenes with ortho-iodoanilines/phenols acted as both nucleophiles and electrophiles. [16] Despite these significant advancements, considering the importance of γand δ-hydrazide substituted carboxylic acid moiety in the repertoire of pharmaceuticals and organic synthesis, the exploration and development of a simple and efficient method for the hydroamination of unactivated alkenes with readily accessible hydrazide remains a challenge. Inspired by the above encouraging achievements and our continuous endeavour of directing group-assisted transitionmetal-catalyzed reactions, [17] we explored the possibility of the diverse γand δ-hydrazide substituted carboxylic acid construction from unactivated alkenes by palladium catalysis.…”