Domino Pd⁰‐Catalyzed C(sp³)–H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates

Abstract

The Pd 0 -catalyzed C(sp 3 )-H arylation of 2-bromo-N-methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4p electrocyclic ringopening and 6p electrocyclization. The introduction of abulky, non-activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

“…We were motivated by prior observations that o-bromo-N-methylanilines tend to undergo demethylation under Pd 0 /ligand-catalyzed conditions,p resumably through 1,4-Pd shift and iminium formation. [16] Gratifyingly,t his undesired demethylation could be avoided upon deactivation of the nitrogen atom with at rifluoroacetyl substituent (substrate 6a), and after reoptimization of the reaction conditions (cat. AdCO 2 H/stoich.…”

Remote Construction of N‐Heterocycles via 1,4‐Palladium Shift‐Mediated Double C−H Activation

“…We set out to explore the reactivity of several o ‐bromoaniline substrates using three different catalytic systems, which proved successful in previous Pd 0 ‐catalyzed C(sp 3 )−H activation reactions, i.e. [Pd(π‐allyl)Cl] 2 /NHC (NHC=N‐heterocyclic carbene), [16] Pd 2 dba 3 /PR 3 [4, 9] and Pd(PPh 3 ) 4 [10] (Table 1, entries 1–5, see Table S1 for details). As a result, IBioxMe 4 [16b, 17] was identified as the optimal ligand to convert substrate 7 a to the desired indoline 8 a in 99 % NMR yield, and minimize the formation of the direct C(sp 2 )−H arylation product 9 a , N‐demethylated product 10 a , and proto‐dehalogenated product 11 a (entry 1).…”

“…The latter is unstable under the reaction conditions and undergoes a 4π/6π electrocyclic cascade to furnish product 2 [4] . In addition, N‐demethylation was observed when an N ‐alkyl substituent was present instead of the carbonyl group, which presumably occurs through reversible reprotonation of palladacycle A to furnish σ‐alkylpalladium intermediate C and demetallation via formation of an iminium species [4, 5] . The formation of σ‐alkylpalladium complex C from the oxidative addition complex arising from 1 a and the active Pd 0 catalyst formally results in a 1,4‐Pd shift.…”

“…For instance, the reaction of 2‐bromo‐ N ‐methyl anilines 1 a equipped with a bulky carbonyl substituent on the nitrogen atom was shown to produce benzoxazines 2 via C(sp 3 )−H activation at the N ‐methyl group (Scheme 1a), giving rise to 5‐membered palladacycle A , which upon reductive elimination generates benzazetidine B . The latter is unstable under the reaction conditions and undergoes a 4π/6π electrocyclic cascade to furnish product 2 [4] . In addition, N‐demethylation was observed when an N ‐alkyl substituent was present instead of the carbonyl group, which presumably occurs through reversible reprotonation of palladacycle A to furnish σ‐alkylpalladium intermediate C and demetallation via formation of an iminium species [4, 5] .…”

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

“…[16] Gratifyingly,t his undesired demethylation could be avoided upon deactivation of the nitrogen atom with at rifluoroacetyl substituent (substrate 6a), and after reoptimization of the reaction conditions (cat. We were motivated by prior observations that o-bromo-N-methylanilines tend to undergo demethylation under Pd 0 /ligand-catalyzed conditions,p resumably through 1,4-Pd shift and iminium formation.…”