Synlett 2024; 35(09): 1023-1027
cluster
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
a
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
,
Mareen Stahlberger
a
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
,
Robin M. Bär
a
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
,
a
Institute of Organic Chemistry (IOC), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
b
Institute of Biological and Chemical Systems - Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany
› Author Affiliations The authors acknowledge support from the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy - 3DMM2O (EXC-2082/1-390761711).
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
Supporting Information
Supporting information for this article is available online at https://doi.org/10.1055/a-2210-0893.
Supporting Information
Publication History
Received: 19 September 2023
© 2023. Thieme. All rights reserved
Georg Thieme Verlag KG
References and Notes
1
Locke GM,
Bernhard SS,
Senge MO.
Chem. Eur. J. 2019; 25: 4590
2
Levin MD,
Kaszynski P,
Michl J.
Chem. Rev. 2000; 100: 169
3a
Stepan AF,
Subramanyam C,
Efremov IV,
Dutra JK,
O’Sullivan TJ,
DiRico KJ,
McDonald WS,
Won A,
Dorff PH,
Nolan CE.
J. Med. Chem. 2012; 55: 3414
3b
Makarov IS,
Brocklehurst CE,
Karaghiosoff K,
Koch G,
Knochel P.
Angew. Chem. Int. Ed. 2017; 56: 12774
4
Taylor RD,
MacCoss M,
Lawson AD.
J. Med. Chem. 2014; 57: 5845
5a
Mykhailiuk PK.
Org. Biomol. Chem. 2019; 17: 2839
5b
St Jean DJ. Jr,
Fotsch C.
J. Med. Chem. 2012; 55: 6002
6a
Frings M,
Bolm C,
Blum A,
Gnamm C.
Eur. J. Med. Chem. 2017; 126: 225
6b
Xiong F,
Yang B.-B,
Zhang J,
Li L.
Molecules 2018; 23: 2680
7
Bär RM,
Langer L,
Nieger M,
Bräse S.
Adv. Synth. Catal. 2020; 362: 1356
8
Bär RM,
Kirschner S,
Nieger M,
Bräse S.
Chem. Eur. J. 2018; 24: 1373
9
Semmler K,
Szeimies G,
Belzner J.
J. Am. Chem. Soc. 1985; 107: 6410
10
Lenstra DC,
Vedovato V,
Ferrer Flegeau E,
Maydom J,
Willis MC.
Org. Lett. 2016; 18: 2086
11
Bär RM,
Gross PJ,
Nieger M,
Bräse S.
Chem. Eur. J. 2020; 26: 4242
12
Pickford HD,
Ripenko V,
McNamee RE,
Holovchuk S,
Thompson AL,
Smith RC,
Mykhailiuk PK,
Anderson EA.
Angew. Chem. Int. Ed. 2023; 62: e202213508
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 NH4 Cl solution and the aqueous layer was extracted with EtOAc (×3). The organic layers were collected and dried by the addition of Na2 SO4 . 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; Rf
= 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 . 1 H NMR (400 MHz, CDCl3 ): δ = 7.49–7.45 (m, 2 H, Haromatic
), 7.04–7.00 (m, 2 H, Haromatic
), 3.86 (s, 3 H, OCH3
), 2.82 (s, 1 H, C(CH2 )3 CH ), 1.89 (s, 6 H, C(CH2
)3 CH). 13 C NMR (101 MHz, CDCl3 ): δ = 161.8 (Cq , Caromatic
), 132.6 (Cq , Caromatic
), 126.0 (+, 2 C, Caromatic
H), 114.4 (+, 2 C, Caromatic
H), 55.5 (Cq , C (CH2 )3 CH), 55.5 (+, OC H3 ), 48.7 (–, 3 C, C(C H2 )3 CH), 27.7 (+, C(CH2 )3
C H). MS (EI, 70 eV, 50 °C): m /z (%) = 222 (2) [M]+ , 169 (4) [C8 H8 O2 S + H]+ , 156 (14) [C7 H7 O2 S + H]+ , 155 (8) [C7 H7 O2 S]+ , 139 (6) [C7 H7 OS]+ , 108 (3) [C7 H7 O + H]+ , 100 (13) [C5 H7 S]+ , 67 (3) [C5 H7 ]+ . HRMS (EI): m /z [M]+ calcd for C12 H14 O2 S+ : 222.0715; found: 222.0714.
14a
Evans DA,
Andrews GC,
Sims CL.
J. Am. Chem. Soc. 1971; 93: 4956
14b
Rayner DR,
Miller EG,
Bickart P,
Gordon AJ,
Mislow K.
J. Am. Chem. Soc. 1966; 88: 3138
15a
Wimmer A,
König B.
Org. Lett. 2019; 21: 2740
15b
Bolm C,
Hildebrand JP.
J. Org. Chem. 2000; 65: 169
15c
Andresini M,
Tota A,
Degennaro L,
Bull JA,
Luisi R.
Chem. Eur. J. 2021; 27: 17293
