Synthesis of the Disubstituted Maleic Anhydride Frame Using a Novel Tandem Radical-Polar Reaction

Abstract

An unreported 5-endo-trig atom-transfer radical cyclization of cyclic N-α-dichloroacyl-ketene-N,S-acetals, which evolves as a tandem radical-polar process, is described. The reaction, which is carried out in the presence of a Cu(I) complex catalyst (10 mol%) and an inorganic base (i.e., carbonate), can be exploited as the key step for a novel, short, and versatile synthesis of the 3,4-disubstituted maleic anhydride nucleus.

Key words

cyclizations - imides - radical reactions - sulfur - tandem reactions

References and Notes

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• 23 Compound 13b (0.73 mmol, 300 mg), wet SiO₂ 60% (w/w, 365 mg), NaNO₃ (1.46 mmol, 124 mg), and silica-sulfuric acid (1.46 mmol, 400 mg) were weighed into a vial, then CH₂Cl₂ (3 mL) was added. The vial was closed with a screw cap, and the mixture was stirred at 45 ˚C for 17 h and then cooled down to r.t. Et₂O (10 mL) was added, and the suspension was stirred at r.t. for 30 min and then filtered. The solid was washed with Et₂O (3 × 10 mL), then the combined organic layers were concentrated under vacuum into a Schlenk tube. Glacial AcOH (1.5 mL) and 2 M aq H₂SO₄ (1.5 mL) were added to the crude product, then the tube was closed with a screw cap. The mixture was stirred at 140 ˚C for 65 h and then cooled down to r.t. Water (15 mL) was added, and the solution was extracted with Et₂O (4 × 20 mL). The solvent was removed under vacuum. Chromatography of the crude product on silica, eluting with a PE-Et₂O gradient from 9:1 to 5:5, afforded 3-ethyl-2-methyl maleic anhydride (12, 61 mg, 60%). Characterizations were in agreement with literature values: Poigny S. Guyot M. Samadi M. J. Chem. Soc., Perkin Trans. 1  1997,  2175 
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18

3-(2,2-Dichlorobutanoyl)-2-ethylidene-1,3-thiazolidine (5a)
Yellow oil. R _f  = 0.64 (PE-Et₂O, 1:1). ^¹H NMR (200 MHz, CDCl₃): δ = 1.23 (t, J = 7.1 Hz, 3 H, CH₃), 1.74 (d, J = 6.8 Hz, 3 H, CH₃), 2.50 (q, J = 7.1 Hz, 2 H, CH₂), 3.05 (t, J = 6.2 Hz, 2 H, CH₂), 4.48 (t, J = 6.2 Hz, 2 H, CH₂), 6.26 (q, J = 7.1 Hz, 1 H, CH) ppm. ^¹³C NMR (50 MHz, CDCl₃): δ = 9.6, 15.8, 28.1, 39.4, 53.1, 87.2, 109.1, 135.0, 162.3 ppm. MS (EI, 70 eV): m/z (%) = 253 (22) [M]⁺, 218 (100), 190 (28). IR (film): 1670 (C=O) cm^-¹.
3-(2,2-Dichlorobutanoyl)-2-ethylidene-1,3-thiazine (5b)
Yellowish oil. R _f  = 0.56 (PE-Et₂O, 1:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.19 (t, J = 7.1 Hz, 3 H, CH₃), 1.84 (d, J = 6.8 Hz, 3 H, CH₃), 2.08 (br m, 2 H, CH₂), 2.49 (q, J = 7.1 Hz, 2 H, CH₂), 2.85 (br m, 2 H, CH₂), 4.22 (br m, 2 H, CH₂), 6.07 (br m, 1 H, CH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 9.7, 14.4, 26.3, 29.5, 40.1, 49.8, 85.7, 130.6, 132.2, 163.5 ppm. MS (EI, 70 eV): m/z (%) = 267 (2) [M]⁺, 232 (42), 156 (96), 128 (100). IR (film): 1669 (C=O) cm^-¹.

20

Typical Procedure for the ATRC
Compound 5b (2 mmol, 536 mg), CuCl (10 mol%, 20 mg), and Na₂CO₃ (2 mmol, 212 mg) were weighed into a Schlenk tube, then dry MeCN (3 mL) and TMEDA (20 mol%, 60 µL) were added under Ar. The mixture was stirred at 30 ˚C and after 17 h diluted with H₂O and extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were concentrated under vacuum. Chromatography of the crude product on silica, eluting with a PE-Et₂O gradient from 9:1 to 4:6, afforded 1-{3-[(7-ethyl-8-methyl-6-oxo-3,4-dihydro-2H-pyrrolo[2,1-b][1,3]thiazin-6 (8aH)-yl)sulfanyl]propyl}-3-ethyl-4-methyl-1H-pyrrole-2,5-dione (13b) as yellow oil (327 mg, 80%) and 1,1′-(disulfanediyldipropane-2,1-diyl)bis(3-ethyl-4-methyl-1H-pyrrole-2,5-dione) (14b) as orange oil (60 mg, 14%).
Compound 13b: R _f  = 0.12 (PE-Et₂O, 1:1). ^¹H NMR (400 MHz, CDCl₃): δ = 0.92 (t, J = 7.6 Hz, 3 H, CH₃), 0.98 (t, J = 7.6 Hz, 3 H, CH₃), 1.44 (q t, J = 13.2 Hz, 3.0 Hz, 1 H, CH_axH), 1.51 (quin, J = 7.0 Hz, 2 H, CH₂), 1.62-1.77 (m, 2 H, CH₂), 1.78-1.90 (m, 1 H, CH_eqH), 1.80 (s, 3 H, CH₃), 1.88 (s, 3 H, CH₃), 2.17 (q, J = 7.6 Hz, 2 H, CH₂), 2.24 (q, J = 7.6 Hz, 2 H, CH₂), 2.54 (br d t, J = 13.2 Hz, 1 H, CH_eqH), 2.94 (t d, J = 13.2, 3.0 Hz, 1 H, CH_axH), 3.17 (t d, J = 13.2, 3.0 Hz, 1 H, CH_axH), 3.29 (t, J = 7.0 Hz, 2 H, CH₂), 4.11 (br d, J = 13.2 Hz, 1 H, CH_eqH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 8.4, 10.2, 12.6, 13.1, 17.0, 26.2, 26.8, 27.7, 27.9, 35.6, 37.0, 73.8, 134.5, 136.5, 142.1, 150.1, 167.6, 171.6, 172.1 ppm. HRMS: m/z calcd for C₂₀H₂₈N₂NaO₃S₂ [M + Na]⁺ 431.1434; found: 431.1438. IR (film): 1685 (C=O) cm^-¹.
Compound 14b: R _f  = 0.33 (PE-Et₂O, 1:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.12 (t, J = 7.6 Hz, 6 H, 2 CH₃), 1.90-2.00 (m, 4 H, 2 CH₂), 1.95 (s, 6 H, 2 CH₃), 2.39 (q, J = 7.6 Hz, 4 H, 2 CH₂), 2.64 (t, J = 7.0 Hz, 4 H, 2 CH₂), 3.56 (t, J = 7.0 Hz, 4 H, 2 CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 8.5, 12.6, 17.1, 28.3, 36.0, 36.7, 136.5, 142.2, 171.8, 172.2 ppm. HRMS: m/z calcd for C₂₀H₂₈N₂NaO₄S₂ [M+Na]⁺: 447.1383; found: 447.1385. IR (film): 1700 (C=O) cm^-¹.
All other compounds show spectral data (^¹H NMR, ^¹³C NMR, HRMS, and IR) consistent with their structures.

22

1-[3-({[3-(3-Ethyl-4-methyl-2,5-dioxo-2,5-dihydro-1 H -pyrrol-1-yl)propyl]sulfonyl}sulfanyl)propyl]-3-ethyl-4-methyl-1 H -pyrrole-2,5-dione (17)
Yellow oil. R _f  = 0.10 (PE-Et₂O, 1:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.11 (t, J = 7.6, 6 H, 2 CH₃), 1.94 (s, 6 H,2 CH₃), 2.00 (quin, J = 6.8 Hz, 2 H, CH₂), 2.14 (quin, J = 7.2 Hz, 2 H, CH₂), 2.38 (br q, J = 7.6 Hz, 4 H, 2 CH₂), 3.07 (br t, J = 6.8 Hz, 2 H, CH₂), 3.31 (br t, J = 7.2 Hz, 2 H, CH₂), 3.57 (br t, J = 6.8 Hz, 2 H, CH₂), 3.61 (br t, J = 7.2 Hz, 2 H, CH₂) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 8.4, 12.5, 17.0, 23.4, 28.9, 33.5, 35.8, 36.1, 60.2, 136.6, 136.7, 142.28, 142.32, 171.6, 171.7, 172.0, 172.1 ppm. HRMS: m/z calcd for C₂₀H₂₉N₂O₆S₂ [M + H]⁺: 457.1462; found: 457.1470. IR (film): 1700 (C=O) cm^-¹.