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

Annabelle P. Frutos Hoener; Bernd Henkel; Jean-Christophe Gauvin

doi:10.1055/s-2003-36229

LETTER

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

Annabelle P. Frutos Hoener*^a, Bernd Henkel^b, Jean-Christophe Gauvin^a
^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

Abstract

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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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References

<A NAME="RG29102ST-1">1</A> Gewald K. Angew. Chem. 1961, 73: 114

<A NAME="RG29102ST-2">2</A> Sabnis RW. Rangnekar DW. Sonawane ND. J. Heterocycl. Chem. 1999, 36: 333

<A NAME="RG29102ST-3">3</A> Buchstaller H.-P. Siebert CD. Lyssy RH. Frank I. Duran A. Gottschlich R. Noe CR. Monatsh. Chem. 2001, 132: 279

<A NAME="RG29102ST-4">4</A> Castanedo GM. Sutherlin DP. Tetrahedron Lett. 2001, 42: 7181

<A NAME="RG29102ST-5">5</A> Pinto IL. Jarvest RL. Serafinowska HT. Tetrahedron Lett. 1999, 41: 1597

<A NAME="RG29102ST-6">6</A> Koike K. Jia Z. Nikaido T. Liu Y. Zhao Y. Guo D. Org. Lett. 1999, 1: 197

<A NAME="RG29102ST-7">7</A> Gottschlich R, Leibrock J, Noe CR, Berger M, and Buchstaller H.-P. inventors; Eur. Pat. Appl. EP 717044, 1996; Chem. Abstr. . , 125, 114585

<A NAME="RG29102ST-8">8</A> Modica M. Santiagati M. Russo F. Parotti L. Gioia LD. Selvaggini C. Salmona M. Mennini T. J. Med. Chem. 1997, 40: 574

<A NAME="RG29102ST-9">9</A> Gutschow M. Kuerschner L. Neumann U. Peitsch M. Loser R. Koglin N. Eger K. J. Med. Chem. 1999, 42: 5437

<A NAME="RG29102ST-10">10</A> Iversen LF. Anderson HS. Branner S. Mortensen SB. Peters GH. Norris K. Olsen OH. Jeppesen CB. Lundt BF. Ripka W. Moller KB. Moller NPH. J. Biol. Chem. 2000, 275: 10300

<A NAME="RG29102ST-11">11</A> Webb TR. Melman N. Ji X. Jacobson KA. Chem. Lett. 2000, 10: 31

<A NAME="RG29102ST-12">12</A> Fujita M. Hirayama T. Ikeda N. Bioorg. Med. Chem. 2002, 10: 3113

<A NAME="RG29102ST-13">13</A> McKibben BP. Cartwright CH. Castelhano AL. Tetrahedron Lett. 1999, 40: 5471

<A NAME="RG29102ST-14">14</A> Arya VP. Ghate SP. Indian J. Chem. 1971, 9: 1209

<A NAME="RG29102ST-15">15</A> Peet NP. Sunder S. Barbuch RJ. J. Heterocycl.Chem. 1985, 23: 129

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.

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,
-NHCOCH₂CH₂CH₃). 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.