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Synlett 2009(13): 2172-2176  
DOI: 10.1055/s-0029-1217569
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Mariella Pattarozzi*a, Franco Ghelfia, Fabrizio Roncagliaa, Ugo M. Pagnonia, Andrew F. Parsonsb
a Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax: +39(059)373543; e-Mail: mariella.pattarozzi@unimore.it;
b Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
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Publication History

Received 28 April 2009
Publication Date:
15 July 2009 (online)

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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, CHaxH), 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, CHeqH), 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, CHeqH), 2.94 (t d, J = 13.2, 3.0 Hz, 1 H, CHaxH), 3.17 (t d, J = 13.2, 3.0 Hz, 1 H, CHaxH), 3.29 (t, J = 7.0 Hz, 2 H, CH2), 4.11 (br d, J = 13.2 Hz, 1 H, CHeqH) 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.