Palladium-Catalyzed α-Arylation of Meyers’s Chiral Bicyclic Lactams and a Deprotonative Ring-Opening Sideline

Hsin-Lun Chiang; Wei-Ting Zhao; Yi-An Chen; Yi-Ching Lin; Pei-Lin Chen; Yen-Ku Wu

doi:10.1055/a-2258-3788

Synlett, Table of Contents

Synlett 2024; 35(10): 1145-1148
DOI: 10.1055/a-2258-3788

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Thieme Chemistry Journals Awardees 2023

Palladium-Catalyzed α-Arylation of Meyers’s Chiral Bicyclic Lactams and a Deprotonative Ring-Opening Sideline

Hsin-Lun Chiang‡

^aDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan

,

Wei-Ting Zhao‡

^aDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan

,

Yi-An Chen

^aDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan

,

Yi-Ching Lin

^aDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan

,

Pei-Lin Chen

^bInstrumentation Center, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan

,

Yen-Ku Wu ∗

^aDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan

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Abstract

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Abstract

Described is a deprotonative α-arylation reaction of Meyers’s chiral bicyclic lactams (MCBLs) under palladium catalysis, and a substrate-dependent post-transformation. When the bridgehead carbon of the MCBLs is substituted with a methyl or an ethyl group, the initial arylation product undergoes a further rearrangement reaction to give a conjugated framework. On the other hand, substrates bearing a bridgehead isopropyl or aryl group are converted into the corresponding exo-arylation products. Preliminary studies indicated that the rearrangement pathway was promoted by deprotonation and was independent of palladium catalysis. In addition to mechanistic interests, this study demonstrates a modular and divergent synthesis of functionalized lactams.

Key words

arylation - palladium catalysis - enolates - rearrangement - stereoselectivity - lactams

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References

References and Notes

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12 1-[(1S)-1-(Hydroxymethyl)-2-methylpropyl]-3-(4-methoxyphenyl)-5-methyl-1,5-dihydro-2H-pyrrol-2-one (3a) A 0.71 M solution of LiHMDS was prepared prior to use by adding a 2.5 M solution of BuLi in hexanes (2 mmol, 0.8 mL) to freshly distilled (TMS)₂NH (2 mmol, 0.42 mL) in THF (2 mL) at 0 °C and then stirring for 15 min. A 0.71 M solution of LDA was also prepared prior to use by adding a 2.5 M solution of BuLi in hexanes (4 mmol, 1.6 mL) to freshly distilled i-Pr₂NH (4 mmol, 0.56 mL) in THF (4 mL) at 0 °C and then stirring for 15 min. A round-bottomed flask was charged with the Meyers lactam 1a (1.0 mmol, 183 mg) and toluene (5.0 mL). The solutions of LiHMDS (1 equiv, 1.41 mL) and LDA (2.0 equiv, 2.82 mL) were added sequentially to the reaction flask at –78 °C, and the mixture was stirred for 2 h. The resulting mixture was transferred to a round-bottomed flask containing 4-bromoanisole (1.2 equiv, 1.2 mmol, 224 mg), Pd(OAc)₂ (5 mol%, 11 mg), and PAd₃ (6 mol%, 26 mg) at –78 °C. The cooling bath was removed, and the resulting mixture was stirred at r.t. for 1 h until the reaction was complete (TLC). The reaction was then quenched with aq NH₄Cl and the mixture was filtered through a pad of Celite. The filtrate was diluted with EtOAc and extracted sequentially with H₂O and brine. The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (2:1)] to give a yellow oil; yield: 142 mg (49%); R_f = 0.33 (hexanes–EtOAc, 2:1). IR (film): 3354, 3012, 2967, 2933, 2914, 2874 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 8.8 Hz, 2 H), 6.99 (d, J = 1.9 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 2 H), 5.09 (d, J = 9.7 Hz, 1 H), 4.12 (qd, J = 6.9, 1.9 Hz, 1 H), 4.04 (br s, 1 H), 3.85–3.81 (m, 4 H), 2.96 (ddd, J = 9.7, 4.8, 1.3 Hz, 1 H), 2.84–2.70 (m, 1 H), 1.32 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.54, 141.37, 138.72, 135.87, 129.24, 128.59, 127.09, 64.41, 64.33, 59.44, 26.18, 21.44, 20.48, 20.15, 17.22. HRMS (EI): m/z [M]⁺ calcd for C₁₇H₂₃NO₃: 289.1672; found: 289.1664.
13 CCDC 2309298 and 2308874 contains the supplementary crystallographic data for compounds 2f and 3b, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
14 Exo- and endo-2a were prepared in four steps from methyl (4-methoxyphenyl)acetate; see the Supporting Information for more details.

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Supplementary Material

Supporting Information