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Synlett 2006(16): 2559-2564  
DOI: 10.1055/s-2006-951484
LETTER
© Georg Thieme Verlag Stuttgart · New York

Aryl Alkyl Ketones in a One-Pot Gewald Synthesis of 2-Aminothiophenes

Victor M. Tormyshev*a, Dmitry V. Trukhina, Olga Yu. Rogozhnikovaa, Tatiana V. Mikhalinaa, Tatiana I. Troitskayaa, Anthony Flinn*b
a Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentjev Ave., 630090 Novosibirsk, Russia
Fax: +7(383)3309752; e-Mail: torm@nioch.nsc.ru;
b Onyx Scientific Ltd, Silverbriar, Sunderland Enterprise Park East, Sunderland SR5 2TQ, UK
Fax: +44(191)5166526; e-Mail: tonyflinn@onyx-scientific.com;
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Publication History

Received 30 June 2006
Publication Date:
22 September 2006 (online)

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Abstract

2-Aminothiophene-3-carboxylates bearing various aryl groups at the 4-position are readily obtained in good to moderate yields by the one-pot Gewald reaction of aryl alkyl ketones with ethyl cyanoacetate and elemental sulfur in the presence of mor­pholinium acetate and excess morpholine.

Key words

Gewald reaction - aryl alkyl ketones - 4-aryl-2-amino­thiophene-3-carboxylates

    References and Notes

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13

To dissolve crystalline ammonium salts a small amount of 95% ethanol was added (0.5 mL per 1 mmol of acetophenone). DMF was also shown to be a good choice.

14

Replacement of morpholine with alternative amines or acetic acid with TFA caused a substantial drop in the conversion of acetophenone. Thus, changing the amine from morpholine to diethylamine produced a heavily contaminated reaction mixture with only 18% conversion. At the same time employing half the amount of morpholine (1.5 equiv) and acetic acid (0.5 equiv) with acetophenone cyanoacetate (1 equiv) and sulfur (1 equiv) resulted in only a small decrease in ketone conversion (57%).

17

We were also interested in investigating if the combination of organic base and acid were essential for the formation of 3a and if we could reach a similar equilibrium in the absence of acetic acid, that is, under conditions generally used in classical one-pot Gewald reaction (see ref. 1). In contrast to the former experiment, even heating for 12 hours was insufficient for the mixture of acetophenone, ethyl cyano-acetate, and morpholine (1:1:3) to give any condensation products at detectable concentrations. The same result was obtained for the reaction of acetophenone, ethyl cyano-acetate, and acetic acid in the absence of morpholine. Kinetic measurements and further experiments made it possible to consider that the acid-base ‘catalyst’, morpholinium acetate, was required in high concentrations to enhance the rate of the process leading to nitriles 3a, which in turn was a key intermediate for the latter steps of thiolation and ring closure.

18

Heterocyclization; Typical Conditions: A 25-mL round-bottomed two-necked flask equipped with a magnetic stirring bar and argon inlet tube was charged with acetophenone (2.40 g, 20.0 mmol), ethyl cyanoacetate (3.39 g, 30.0 mmol), 95% EtOH (5 mL), morpholine (2.61 g, 30.0 mmol), and glacial AcOH (0.60 g, 10 mmol). The mixture was stirred at 55 °C (temperature of bath) for 3 h. Finely powdered sulfur (3 × 0.32 g, 10 mmol) was then added in equal portions. After addition of each new portion the mixture was flushed with argon and left stirring at 55 °C for 10-12 h (overall reaction time 36-40 h). The mixture was transferred to a separating funnel containing CH2Cl2 (30 mL) and H2O (30 mL). The organic layer was separated, washed with brine (4 × 10 mL), filtered through a short plug of silica, and concentrated in vacuo to give 4.62 g of the crude product. 1H NMR spectroscopy indicated 92% conversion of acetophenone to 2a.Purification; Method A: Column chromatography (silica gel; CHCl3) gave 2a (3.38 g, 68%); off-white plates; mp 98-99 °C (hexane, Lit. [1b] mp 98 °C).Method B: The crude product was dissolved in EtOAc (10 mL), and a solution of anhyd HCl (2.2 M) in anhyd EtOAc (15 mL, 33 mmol of HCl) was added to furnish a resinous cake. The cake was thoroughly triturated until crystallization began. The mixture was allowed to stand in a refrigerator overnight. The crystalline hydrochloride was collected by filtration, then washed with EtOAc (3 × 3 mL), and dried in air to give 3.92 g of crude hydrochloride. The residue was suspended in 5% aq NH3 (10 mL) in CH2Cl2 (20 mL). The organic layer was separated, filtered through a short plug of silica, and concentrated in vacuo to give 2a (3.14 g, 64%.1H NMR (400 MHz, CDCl3): δ = 0.92 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.02 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.58 (br s, 2 H, NH2), 6.04 (s, 1 H, thiophene-CH), 7.28 (app s, 5 H, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.61 (q), 59.38 (t), 105.47 (d), 106.31 (s), 126.74 (d), 127.18 (d), 128.91 (d), 138.46 (s), 141.68 (s), 163.70 (s), 165.66 (s). HRMS: m/z calcd for C13H13NO2S [M+]: 247.0667; found: 247.0678.Thiophenes 2b-n were prepared analogously.Compound 2b: Purified by method A (CH2Cl2); yield: 56%; white powder; mp 105-107 °C (EtOH). 1H NMR (400 MHz, CDCl3): δ = 0.97 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.04 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.94 (br s, 2 H, NH2), 6.04 (s, 1 H, thiophene-CH), 7.21 (d, AB system, 2 H, J = 8.8 Hz, ArH), 7.25 (d, AB system, 2 H, J = 8.8 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.63 (q), 59.40 (t), 105.64 (d), 105.76 (s), 127.23 (d), 130.14 (d), 132.59 (s), 136.82 (s), 140.21 (s), 163.86 (s), 165.34 (s). HRMS: m/z calcd for C13H12NO2SCl [M+]: 281.0277; found: 281.0281.Compound 2c: Purified by method B; yield: 52%; white powder; mp 120-121 °C (hexane). 1H NMR (400 MHz, CDCl3): δ = 0.96 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.04 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.88 (br s, 2 H, NH2), 6.02 (s, 1 H, thiophene-CH), 7.14 (d, 2 H, J = 8.4 Hz, ArH), 7.41 (d, 2 H, J = 8.4 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.67 (q), 59.44 (t), 105.65 (d), 105.73 (s), 120.72 (s), 130.21 (d), 130.51 (d), 137.31 (s), 140.23 (s), 163.89 (s), 165.35 (s). HRMS: m/z calcd for C13H12NO2SBr [M+]: 324.9773; found: 324.9791.Compound 2d: Purified by method B; yield: 70%; white powder; mp 105-106.5 °C (toluene). 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.03 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.08 (br s, 2 H, NH2), 6.11 (s, 1 H, thiophene-CH), 7.45 (dd, 1 H, J = 8.4, 8.4 Hz, ArH), 7.62 (ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 8.12 (ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 8.16 (dd, 1 H, J = 1.2, 1.2 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.56 (q), 59.51 (t), 105.14 (s), 106.67 (d), 121.57 (d), 123.96 (d), 127.92 (d), 134.96 (d), 138.77 (s), 139.87 (s), 147.35 (s), 164.36 (s), 165.04 (s). HRMS: m/z calcd for C13H12N2O4S [M+]: 292.0518; found: 292.0519.Compound 2e: Purified by method A (CHCl3); yield: 52%; white powder; mp 126-127 °C (EtOH). 1H NMR (400 MHz, CDCl3): δ = 0.94 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.03 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.04 (br s, 2 H, NH2), 6.06 (s, 1 H, thiophene-CH), 7.39 (ddd, 1 H, J = 8.4, 8.4, 0.6 Hz, ArH), 7.51 (ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 7.56 (ddd, 1 H, J = 8.4, 1.2, 1.2 Hz, ArH), 7.59 (ddd, 1 H, J = 1.2, 1.2, 0.6 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.59 (q), 59.46 (t), 105.27 (s), 106.42 (d), 111.29 (s), 118.74 (s), 127.93 (d), 130.18 (d), 132.54 (d), 133.31 (d), 138.96 (s), 139.59 (s), 164.28 (s), 165.04 (s). HRMS: m/z calcd for C14H12N2O2S [M+]: 272.0619; found: 272.0621.Compound 2f: Purified by method A (CH2Cl2-hexane, 1:2); yield: 64%; white powder; mp 102-103 °C (hexane). 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 1.37 (t, 3 H, J = 7.1 Hz, CH 3CH2O), 4.01 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 4.36 (q, 2 H, J = 7.1 Hz, CH3CH 2O), 5.95 (br s, 2 H, NH2), 6.07 (s, 1 H, thiophene-CH), 7.36 (dd, 1 H, J = 7.6, 7.6 Hz, ArH), 7.47 (ddd, 1 H, J = 7.6, 1.0, 1.0 Hz, ArH), 7.97 (ddd, 1 H, J = 7.6, 1.0, 1.0 Hz, ArH), 7.98 (dd, 1 H, J = 1.0, 1.0 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.53 (q), 14.20 (q), 59.36 (t), 60.75 (t), 104.67 (s), 105.89 (d), 127.12 (d), 127.89 (d), 129.57 (s), 130.06 (d), 133.26 (d), 138.58 (s), 140.47 (s), 163.99 (s), 165.45 (s), 166.45 (s). HRMS: m/z calcd for C16H17NO4S [M+]: 319.0878; found: 319.0869.Compound 2g: Prepared using EtOH-DMF (1:1) as the solvent and purified by method B; yield: 37%; white powder; mp 127-128 °C (EtOH). 1H NMR (400 MHz, CDCl3): δ = 0.99 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.06 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.65 (br s, 1 H, OH), 5.99 (s, 1 H, thiophene-CH), 6.06 (br s, 2 H, NH2), 6.75 (d, 2 H, J = 8.4 Hz, ArH), 7.14 (d, 2 H, J = 8.4 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.72 (q), 59.58 (t), 105.11 (d), 105.94 (s), 114.11 (d), 130.08 (d), 130.80 (s), 141.16 (s), 154.72 (s), 163.82 (s), 165.84 (s). HRMS: m/z calcd for C13H13NO3S [M+]: 263.0616; found: 263.0624.Compound 2h: Purified by method A (CHCl3); yield: 45%; white powder; mp 115-116 °C (hexane). 1H NMR (400 MHz, CDCl3): δ = 0.95 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 4.03 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.80 (br s, 3 H, NH2, OH), 6.04 (s, 1 H, thiophene-CH), 6.74 (dd, 1 H, J = 1.0, 1.0 Hz, ArH), 6.75 (ddd, 1H, J = 8.5, 1.0, 1.0 Hz, ArH), 6.84 (ddd, 1 H, J = 8.5, 1.0, 1.0 Hz, ArH), 7.15 (dd, 1 H, J = 8.5, 8.5 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.56 (q), 59.49 (t), 105.56 (d), 106.32 (s), 113.69 (d), 115.95 (d), 121.48 (d), 128.32 (d), 139.83 (s), 141.01 (s), 154.61 (s), 163.70 (s), 165.74 (s). HRMS: m/z calcd for C13H13NO3S [M+]: 263.0616; found: 263.0626.Compound 2i: Purified by method B; yield: 45%; white powder; mp 73-75 °C (toluene-hexane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.98 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.81 (s, 3 H, OCH3), 4.05 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.99 (s, 1 H, thiophene-CH), 6.04 (br s, 2 H, NH2), 6.84 (d, 2 H, J = 8.8 Hz, ArH), 7.21 (d, 2 H, J = 8.8 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.72 (q), 55.14 (q), 59.29 (t), 104.92 (d), 105.40 (s), 112.57 (d), 129.89 (d), 130.90 (s), 141.12 (s), 158.56 (s), 163.72 (s), 165.61 (s). HRMS: m/z calcd for C14H15NO3S [M+] : 277.0773; found: 277.0778.Compound 2j: Purified by method B; yield: 20%; white powder; mp 123-124 °C (MeOH). 1H NMR (400 MHz, CDCl3): δ = 1.00 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.87 (s, 3 H, OCH3), 4.06 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 5.55 (br s, 1 H, OH), 5.95 (br s, 2 H, NH2), 6.06 (s, 1 H, thiophene-CH), 6.81 (d, AB system, 1 H, J = 8.6 Hz, ArH), 6.82 (s, 1 H, ArH), 6.86 (d, AB system, 1 H, J = 8.6 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 13.82 (q), 55.80 (q), 59.35 (t), 105.02 (d), 105.96 (s), 111.79 (d), 113.19 (d), 121.82 (d), 130.55 (s), 141.27 (s), 144.59 (s), 145.29 (s), 163.72 (s), 165.66 (s). HRMS: m/z calcd for C14H15NO4S [M+]: 293.0722; found: 293.0710.Compound 2k: Prepared using DMF as the solvent; purified by recrystallization (EtOH); yield: 63%; white powder; mp 193-195 °C (EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 0.94 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 2.05 (s, 3 H, CH 3CO), 3.97 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.11 (s, 1 H, thiophene-CH), 7.15 (d, 2 H, J = 8.4 Hz, ArH), 7.34 (s, 2 H, NH2), 7.50 (d, 2 H, J = 8.4 Hz, ArH), 9.88 (s, 1 H, NHCO). 13C NMR (400 MHz, DMSO-d 6): δ = 13.77 (q), 23.92 (q), 58.56 (t), 102.89 (s), 104.62 (d), 117.73 (d), 128.76 (d), 132.89 (s), 137.84 (s), 140.17 (s), 164.68 (s), 165.00 (s), 168.08 (s). HRMS: m/z calcd for C15H16N2O3S [M+]: 304.0882; found: 304.0892.Compound 2l: Purified by method A (CHCl3); yield: 44%; white powder; mp 189-190 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.47 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.61 (s, 2 H, CH2), 4.44 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.12 (br s, 2 H, NH2), 7.40 (dd, 1 H, J = 8.4, 0.8 Hz, ArH), 7.52 (d, 1 H, J = 0.8 Hz, ArH), 8.06 (d, 1 H, J = 8.4 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 14.56 (q), 34.09 (t), 60.05 (t), 101.15 (s), 118.03 (s), 122.99 (d), 125.54 (s), 126.97 (d), 129.39 (d), 138.82 (s), 141.28 (s), 148.05 (s), 165.41 (s), 167.02 (s). HRMS: m/z calcd for C14H12NO2SBr [M+]: 336.9773; found: 336.9764.Compound 2m: Purified by method B; yield: 49%; white powder; mp 96-97 °C (EtOH). 1H NMR (400 MHz, CDCl3): δ = 1.40 (d, 3 H, J = 7.2 Hz, CH 3CH), 1.49 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.73 (q, 1 H, J = 7.2 Hz, CH3CH), 4.45 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.12 (br s, 2 H, NH2), 7.17 (m, 1 H, ArH), 7.27 (m, 1 H, ArH), 7.36 (br d, 1 H, J = 7.6 Hz, ArH), 8.16 (br d, 1 H, J = 7.2 Hz, ArH). 13C NMR (400 MHz, CDCl3): δ = 14.59 (q), 18.61 (q), 40.40 (d), 59.96 (t), 101.24 (s), 121.78 (d), 122.69 (d), 124.23 (d), 126.52 (d), 132.62 (s), 138.88 (s), 139.79 (s), 151.76 (s), 165.75 (s), 166.85 (s). HRMS: m/z calcd for C15H15NO2S: 273.0823; found: [M+] 273.0821.Compound 2n: Purified by method B; yield: 25%; white powder; mp 187-188 (dec., EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 1.38 (t, 3 H, J = 7.2 Hz, CH 3CH2O), 3.52 (s, 2 H, CH2), 4.34 (q, 2 H, J = 7.2 Hz, CH3CH 2O), 6.64 (dd, 1 H, J = 8.0, 0.8 Hz, ArH), 7.09 (dd, 1 H, J = 8.0, 8.0 Hz, ArH), 7.44 (s, 2 H, NH2), 7.69 (dd, 1 H, J = 8.0, 0.8 Hz, ArH), 9.25 (s, 1 H, OH). 13C NMR (400 MHz, DMSO-d 6): δ = 14.42 (q), 31.22 (t), 59.07 (t), 98.07 (s), 111.71 (d), 113.38 (d), 124.44 (s), 127.33 (d), 130.77 (s), 141.02 (s), 141.13 (s), 152.27 (s), 164.63 (s), 168.32 (s). HRMS: m/z calcd for C14H13NO3S [M+]: 275.0616; found: 275.0611.