A Novel Route towards Bicyclo[1.1.1]pentane Sulfoxides from a Bench-Stable Starting Material

Lukas S. Langer; Mareen Stahlberger; Robin M. Bär; Stefan Bräse

doi:10.1055/a-2210-0893

Synlett, Table of Contents

Synlett 2024; 35(09): 1023-1027
DOI: 10.1055/a-2210-0893

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Chemical Synthesis and Catalysis in Germany

A Novel Route towards Bicyclo[1.1.1]pentane Sulfoxides from a Bench-Stable Starting Material

Lukas S. Langer

^aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany

,

Mareen Stahlberger

^aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany

,

Robin M. Bär

^aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany

,

Stefan Bräse ∗

^aInstitute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany

^bInstitute of Biological and Chemical Systems - Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany

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Abstract

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Abstract

Bicyclopentanes (BCPs) are non-classical bioisosteres that have gained a lot of interest in drug discovery as non-conjugated rigid hydrocarbons. There has been substantial progress in the synthesis of carbon- and nitrogen-substituted derivatives using [1.1.1]propellane as a precursor, while sulfur-substituted BCPs are rather underdeveloped. This work investigates a new method for the synthesis of BCP-sulfoxides. Herein, a previously reported bench-stable sodium BCP-sulfinate precursor is converted, using a range of aryl and alkyl magnesium bromides, into unsymmetrical BCP-sulfoxides via a convenient one-pot procedure. Furthermore, the conversion of the obtained sulfoxides into sulfoximines is explored.

Key words

bicyclo[1.1.1]pentane - sulfoxide - sulfoximine - bioisostere - one-pot - Grignard reagent

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References

References and Notes
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13 Sulfoxides 8a–j; General Procedure Na-6 (1.00 mmol, 1.00 equiv.) was dissolved in 2-MeTHF (2.00 mL) under argon. TMSCl (1.50 mmol, 1.50 equiv.) was added and the mixture was heated to 50 °C for 1 h. RMgBr (1.00 mmol, 1.00 equiv.) was added and the reaction was stirred for 1 h at 50 °C. The reaction was quenched with saturated NH₄Cl solution and the aqueous layer was extracted with EtOAc (×3). The organic layers were collected and dried by the addition of Na₂SO₄. The mixture was filtered through a glass funnel and the solvent evaporated under reduced pressure. The crude residue was adsorbed on a small amount of Celite and was purified via column chromatography (cyclohexane/EtOAc, 5:1). Products 8a–j were isolated in yields of 19–79%. Bicyclo[1.1.1]pentyl 4-Methoxyphenyl Sulfoxide (8b) Yield: 76.0 mg (68%); yellow oil; R_f = 0.10 (cyclohexane/EtOAc, 2:1). IR (ATR): 3452, 2969, 2915, 2880, 2840, 1594, 1493, 1460, 1407, 1302, 1248, 1203, 1130, 1085, 1026, 868, 830, 796, 773, 557, 524, 493, 463, 441, 387 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.45 (m, 2 H, H_aromatic ), 7.04–7.00 (m, 2 H, H_aromatic ), 3.86 (s, 3 H, OCH₃ ), 2.82 (s, 1 H, C(CH₂)₃CH), 1.89 (s, 6 H, C(CH₂ )₃CH). ¹³C NMR (101 MHz, CDCl₃): δ = 161.8 (C_q, C_aromatic ), 132.6 (C_q, C_aromatic ), 126.0 (+, 2 C, C_aromatic H), 114.4 (+, 2 C, C_aromatic H), 55.5 (C_q, C(CH₂)₃CH), 55.5 (+, OCH₃), 48.7 (–, 3 C, C(CH₂)₃CH), 27.7 (+, C(CH₂)₃ CH). MS (EI, 70 eV, 50 °C): m/z (%) = 222 (2) [M]⁺, 169 (4) [C₈H₈O₂S + H]⁺, 156 (14) [C₇H₇O₂S + H]⁺, 155 (8) [C₇H₇O₂S]⁺, 139 (6) [C₇H₇OS]⁺, 108 (3) [C₇H₇O + H]⁺, 100 (13) [C₅H₇S]⁺, 67 (3) [C₅H₇]⁺. HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₄O₂S⁺: 222.0715; found: 222.0714.

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