Synlett 2018; 29(04): 530-536
DOI: 10.1055/s-0036-1591722
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Optically Active 2,3-Disubstituted Indoline ­Derivatives through Cycloaddition Reactions between Benzynes and α,β-Unsaturated γ-Aminobutyronitriles

,
Yuta Sumii
,
Shigeaki Masuda
,
Ding Wang
,
Yuto Emi
,
Akira Takagi
,
This work was financially supported by the JSPS KAKENHI (grants numbers 23790017, 24390005, and 25460018) and by a Grant-in-Aid for JSPS (grant number 15J06024), as well as by the Platform Project for Supporting Drug Discovery and Life Science Research funded by the Japanese Agency for Medical Research and Development (AMED), the Research Foundation for Pharmaceutical Sciences, the Kobayashi International Scholarship Foundation, and the Hoansha Foundation.
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Publikationsverlauf

Received: 18. September 2017

Accepted after revision: 17. Oktober 2017

Publikationsdatum:
04.Januar 2018 (eFirst)

Abstract

We report a method for synthesizing optically active 2,3-disubstituted indolines by the cycloaddition reaction of benzynes with various 4-[(4-toluenesulfonyl)amino]-(E)-but-2-enenitriles, which are readily prepared from the corresponding l-amino acid derivatives.

Supporting Information

 
  • References and Notes


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  • 11 The use of our newly developed precursor, 2-(trimethyl­silyl)phenyl trimethylsilyl ether (see Ref. 12) instead of 5a also gave trans-1f (46%, dr = 14:1) and 6f (39%), which was very similar to Table 1, entry 6. The reaction was performed with the silyl ether (1.5 equiv), nonaflourobutane-1-sulfonyl fluoride (2.3 equiv), 3f (1.0 equiv), and CsF (4.5 equiv) in MeCN (0.10 M) at 60 °C for 26 h.
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  • 17 The corresponding diastereomer of (±)-1s was below the detection limit of 1H NMR (>50:1).
  • 18 Indolines 1ar; General ProcedureA test tube was charged with the appropriate benzyne precursor 5 (1.5 equiv) and a magnetic stir bar. THF (1.0 mL, 50 mM), which did not have to be anhydrous, was added to the tube and the mixture was stirred for a few minutes to dissolve 5. The γ-tosylamino α,β-unsaturated nitrile 3 (1.0 equiv) and 18-crown-6 (3.0 equiv) were added to the solution, and the flask was equipped with a screw cap. (This solution was stirred for 10 min at the indicated temperature when the reaction was conducted at 0 °C or below.) CsF (3.0 equiv) was quickly added to the test tube, which was then resealed with the screw cap, and the mixture was stirred at the appropriate temperature until either the α,β-unsaturated nitrile 3 or the benzyne precursor 5 was consumed (TLC). The mixture was then passed through a short pad of silica gel with elution by EtOAc, and solvents were removed under reduced pressure. The residue was subjected to 1H NMR analysis to determine the ratio of the two diastereomers (trans-1 and cis-1). The crude product was purified by flash column chromatography (silica gel) or by preparative TLC (hexane–EtOAc, hexane–CH2Cl2, or EtOAc) to afford the required substituted indoline 1 and the single-addition product 6.
  • 19 {(2S,3R)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}acetonitrile (trans-1f)According to the general procedure, a mixture of CsF (91 mg, 0.60 mmol), 18-crown-6 (0.16 g, 0.60 mmol), triflate 5a (90 mg, 0.30 mmol), and sulfonamide 3f (56 mg, 0.20 mmol) was stirred in THF (2.0 mL, 0.10 M) for 1 h at r.t. The crude product (trans-1f/cis-1f = 16:1, determined by 400 MHz 1H NMR analysis) was purified by column chromatography [silica gel, hexane–EtOAc (20:1 to 4:1)] to give a colorless solid; yield: 51 mg (72%, >99% ee); mp 139–141 °C; [α]D 25 –137.4 (c 0.12, CHCl3).The relative stereochemistry was determined by NOESY spectro­scopy, and the optical purity was determined by HPLC. HPLC: CHIRALCEL AD-3 [hexane–i-PrOH (80:20), 1.0 mL/min, 20 °C]; tr = 12.7 min (2S,3R), 9.1 min (2R,3S). IR (neat): 3446, 2964, 2251, 1597 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.81 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 1.11 (dd, J = 17.0, 9.5 Hz, 1 H), 1.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.15 (sept d, J = 7.0, 5.0 Hz, 1 H), 2.36 (s, 3 H), 3.05–3.09 (m, 1 H), 3.77 (dd, J = 5.0, 2.0 Hz, 1 H), 7.08 (dd, J = 7.5, 7.5 Hz, 1 H), 7.14 (d, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.32 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 7.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 16.4, 18.1, 21.5, 24.0, 33.3, 39.2, 72.1, 117.3, 117.5, 124.5, 125.1, 127.0, 129.5, 129.8, 132.9, 134.6, 141.6, 144.5. HRMS (MALDI): m/z [M + Na]+ calcd for C20H22N2NaO2S: 377.1294; found: 377.1291. All spectroscopic data for product (2S,3R)-1f were in good agreement with those for (±)-trans-1f, synthesized from (±)-3f.
  • 20 {(2S,3S)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}acetonitrile (cis-1f)Obtained from above-mentioned crude reaction mixture as a colorless solid; yield: 2.4 mg (3%); mp 131–133 °C; [α]D 20 –2.4 (c 0.12, CHCl3). The relative stereochemistry was determined by NOESY spectroscopy. IR (neat): 2967, 2371, 1597 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.51 (d, J = 7.0 Hz, 3 H), 1.22 (d, J = 7.0 Hz, 3 H), 1.96 (sept d, J = 7.0, 2.5 Hz, 1 H), 2.37 (s, 3 H), 2.54 (dd, J = 17.0, 9.0 Hz, 1 H), 2.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.97–3.02 (m, 1 H), 4.33 (dd, J = 8.5, 2.5 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 7.10–7.15 (m, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 8.0, 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 15.8, 17.4, 21.0, 21.6, 29.0, 40.7, 69.3, 118.2, 119.5, 121.8, 126.1, 126.9, 128.9, 129.7, 134.9, 135.2, 142.8, 144.2. HRMS (MALDI): m/z [M + Na]+ calcd for C20H22N2NaO2S: 377.1294; found: 377.1294.