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Synlett 2003(1): 0063-0066
DOI: 10.1055/s-2003-36229
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel One-Pot Microwave Assisted Gewald Synthesis of 2-Acyl Amino Thiophenes on Solid Support

Annabelle P. Frutos Hoener*a, Bernd Henkelb, Jean-Christophe Gauvina
a Morphochem AG, Schwarzwaldallee 215, 4058 Basel, Switzerland
Fax: +41(61)6952122; e-Mail: annabelle.frutos-hoener@morphochem.ch;
b Morphochem AG, Gmunder Strasse 37-37a, 81379 München, Germany
Further Information

Publication History

Received 7 October 2002
Publication Date:
18 December 2002 (online)

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Abstract

A new efficient variation of the Gewald reaction is described. A number of tetrasubstituted 2-acyl aminothiophenes have been prepared via a one-pot microwave assisted Gewald reaction on solid support. This reaction proceeds in good yields within only a few hours rendering diverse products in a time-effective manner. The scope and limitations of the reaction have been investigated.

Key words

solid-phase thiophene synthesis - microwave chemistry - Gewald-synthesis - combinatorial chemistry - acylations

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16

Typical Procedure for the Microwave Assisted Gewald-Synthesis of 12:
Isovalerylaldehyde (462 µL, 4.28 mmol) and DBU (21 µL, 0.14 mmol) were added to cyanoacetic acid Wang resin (96 mg, 1.46 mmol/g) and elemental sulfur (137 mg, 4.28 mmol) in toluene (2 mL). The reaction mixture was heated in a sealed 5mL Smith Process glass vial upon stirring at 120 °C for 20 min in the microwave (Smith Creator from Personal Chemistry).
Diisopropylethylamine (249 µL, 1.56 mmol) followed by benzoyl chloride (165 µL, 1.42 mmol) was added and the reaction mixture heated again at 100 °C for 10 min in the microwave.
After cooling to r.t., the reaction mixture was filtered and the resin washed three times each with methanol, CH2Cl2, DMF and again with dichloromethane. Resin was immediately treated for 2 h at r.t. with a mixture of 1:2:37 H2O:CH2Cl2:TFA to obtain 37 mg of the acylated thiophene (90% yield) after filtration and evaporation.

17

The 4-butyl analogue resulting from the reaction of 2-hexanone was not isolated but only detected by NMR analysis.
Entry 2: 1H NMR (400 MHz, DMSO-d 6): δ = 12.17 (s, 1 H, -COOH), 6.95 (s, 1 H, =CH-Thiophene), 6.87 (s, 1 H, -NH), 3.87 (s, 3 H, -CH3), 3.09 [septet, J = 6.85 Hz, 1 H,
-CH(CH3)2], 1.26 [d, J = 6.85 Hz, 6 H, -CH(CH3)2]. 13C NMR (100 MHz, DMSO-d 6): δ = 165.87, 159.38, 152.63, 143.23, 124.83, 119.09, 115.04, 53.63, 30.33, 24.06.
Entry 3: 1H NMR (400 MHz, DMSO-d6): δ = 12.07 (s, 1 H, -COOH), 6.95 (s, 1 H, =CH-Thiophene), 3.88 (s, 3 H, -CH 3 ), 1.33 [s, 9 H, -(CH3)3]. 13C NMR (100 MHz, DMSO-d 6):
δ = 165.87, 159.31, 152.55, 147.21, 143.18, 118.46, 114.88, 53.69, 33.78, 31.67.
Entry 4: 1H NMR (400 MHz, DMSO-d 6): δ = 12.69 (s, 1 H, -COOH), 7.68 (m, 2 H -Ar), 7.60 (s, 1 H, -NH), 7.41 (m, 2 H, -Ar), 7.31 (m, 1 H, -Ar), 6.87 (s, 1 H, =CH-Thiophene), 3.88 (s, 3 H, -CH3). 13C NMR (100 MHz, DMSO-d 6): δ = 165.80, 159.19, 152.99, 144.70, 133.73, 132.73, 129.19, 127.80, 125.12, 120.57, 53.73.
Entry 5: 1H NMR (400 MHz, DMSO-d 6): δ = 12.46 (s, 1 H, -COOH), 6.68 (s, 1 H, -NH), 3.90 (s, 3 H, -OCH3), 2.70 (t, J = 7.04 Hz, 2 H, -CH 2-CH2-CH3), 2.28 (s, 3 H, -CH3), 1.60 (m, J = 7.04 Hz, 2 H, -CH2-CH 2-CH3), 0.95 (t, J = 7.04 Hz, 3 H, -CH2-CH2-CH 3). 13C NMR (100 MHz, DMSO-d 6): δ = 167.68, 160.43, 152.40, 140.12, 130.73, 128.98, 125.85, 54.63, 35.32, 21.98, 14.88, 14.40.
Entry 6: 1H NMR (400 MHz, DMSO-d 6): δ = 12.39 (s, 1 H, -COOH), 6.86 (s, 1 H, -NH), 3.86 (s, 3 H, -CH3), 2.73 (m, 2 H, -CH2), 2.63 (m, 2 H, -CH2), 1.72 (m, 4 H, -CH2-CH2-). 13C NMR (100 MHz, DMSO-d 6): δ = 166.53, 163.11, 159.32, 143.86, 131.70, 127.46, 124.79, 53.59, 30.32, 25.71, 23.74, 22.04
Entry 8: 1H NMR (400 MHz, DMSO-d 6): δ = 12.69 (s, 1 H, -COOH), 9.49 (m, 2 H, -Ar), 7.45 (m, 5 H, -Ar), 3.87 (s, 3 H, -OCH3), 2.37 (s, 3 H, -CH3-Thiophene). 13C NMR (100 MHz, DMSO-d 6): δ = 165.80, 159.19, 152.99, 144.70, 133.73, 132.73, 129.39, 128.74, 125.12, 120.57, 53.73, 15.01.
Entry 10: 1H NMR (400 MHz, DMSO-d 6): δ = 11.03 (s, 1 H, -COOH), 6.85 (s, 1 H, =CH-Thiophene), 6.83 (s, 1 H,
-NH), 3.06 [septet, J = 7.04 Hz, 1 H, -CH(CH3)2], 2.21 (s, 3 H, -CH3), 1.24 [d, J = 7.04 Hz, 6 H, -CH(CH 3)2]. 13C NMR (100 MHz, DMSO-d 6): δ = 167.01, 165.88, 1145.27, 141.03, 124.83, 118.22, 112.19, 30.33, 28.53, 24.06.
Entry 11: 1H NMR (400 MHz, CDCl3): δ = 10.70 (s, 1 H,
-COOH), 6.92 (s, 1 H, =CH-Thiophene), 3.05 [septet, J = 5.48 Hz, 1 H, -CH(CH3)2], 2.48 (dd, J = 7.04, 3.91 Hz, 2 H, -NHCOCH2-), 1.80 (m, 2 H, -NHCOCH2CH2-), 1.31 [d, J = 5.48 Hz, 6 H, -CH(CH 3)2], 1.02 (t, J = 7.04 Hz, 3 H,
-NHCOCH2CH2CH 3 ). 13C NMR (100 MHz, CDCl3): δ = 170.04, 148.67, 142.86, 117.74, 110.69, 76.99, 38.56, 29.40, 24.18, 18.69, 13.66.
Entry 12: 1H NMR (400 MHz, DMSO-d 6): δ = 12.04 (s, 1 H, -COOH), 7.91 (d, J = 7.04 Hz, 2 H, -Ar) 7.68 (m, 1 H,
-Ar), 7.62 (m, 2 H, -Ar), 6.92 (s, 1 H, =CH-Thiophene), 3.09 [septet, J = 6.26 Hz, 1 H, -CH(CH3)2], 1.31 [dd, J = 6.26, 1.57 Hz, 6 H, -CH(CH 3)2]. 13C NMR (100 MHz, DMSO-d 6): δ = 166.70, 162.46, 145.47, 141.84, 132.75, 131.88, 129.18, 126.97, 118.51, 113.41, 28.65.
Entry 13: 1H NMR (400 MHz, DMSO-d 6): δ = 12.0 (s, 1 H, -COOH), 7.36 (d, J = 7.04 Hz, 2 H, -Ar), 7.29 (m, 3 H, -Ar), 4.29 (q, J = 6.26 Hz, 2 H, -CH 2-CH3), 4.11 (s, 2 H, -CH2-), 3.90 (s, 3 H, -CH3), 1.27 (t, J = 7.04 Hz, 3 H, -CH2-CH 3). 13C NMR (100 MHz, DMSO-d 6): δ = 165.94, 160.28, 154.44, 145.225, 140.25, 136.28, 129.81, 129.65, 129.49, 126.08, 114.72, 62.32, 54.96, 34.027, 15.02.