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

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.

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

References and Notes

<A NAME="RD19106ST-1A">1a</A> Gewald K. Z. Chem.  1962,  2:  305 

<A NAME="RD19106ST-1B">1b</A> Gewald K. Schinke E. Böttcher H. Chem. Ber.  1966,  99:  94 

<A NAME="RD19106ST-1C">1c</A> Sabnis RW. Rangnekar DW. Sonawane ND. J. Heterocycl. Chem.  1999,  36:  333 ; and references therein

<A NAME="RD19106ST-2">2</A> Hagen H, Nilz G, Walter H, and Landes A. inventors; German Patent  4039734.  ; Chem. Abstr. 1992, 117, 106370

<A NAME="RD19106ST-3">3</A> Press JB. Pelkey ET. In Progress in Heterocyclic Chemistry   Vol. 9:  Gribble GW. Gilchrist TW. Pergamon; New York: 1997.  p.77 

<A NAME="RD19106ST-4">4</A> Koike K. Jia Z. Nikaido T. Liu Y. Zhao Y. Guo D. Org. Lett.  1999,  1:  197 

<A NAME="RD19106ST-5A">5a</A> Duval E. Case A. Stein RL. Cuny GD. Bioorg. Med. Chem. Lett.  2005,  15:  1885 

<A NAME="RD19106ST-5B">5b</A> Andersen HS. Olsen OH. Iversen LF. Sørensen ALP. Mortensen SB. Christensen MS. Branner S. Hansen TK. Lau JF. Jeppesen L. Moran EJ. Su J. Bakir F. Judge L. Shahbaz M. Collins T. Vo T. Newman MJ. Ripka WC. Møller NP. J. Med. Chem.  2002,  45:  4443 

<A NAME="RD19106ST-5C">5c</A> Fujita M. Hirayama T. Ikeda N. Med. Chem. Lett.  2002,  10:  3113 

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<A NAME="RD19106ST-8">8</A> Microwave irradiation was reported to be an efficient tool for the one-pot microscale synthesis of N-acylated thiophenes 2 from acetophenones (ref. 5a). However, earlier attempts to use the microwave technique showed that acetophenone was unreactive in the one-pot Gewald reaction: Hoener APF. Henkel B. Gauvin J.-C. Synlett  2003,  63 

<A NAME="RD19106ST-9">9</A> Cope AA. Hofmann CH. Wyckoff C. Hardenbergh E. J. Am. Chem. Soc.  1941,  63:  3452 

<A NAME="RD19106ST-10">10</A> Similar yields of 9-43% were reported for a series of 4-aryl-substituted thiophenes 2 resulted from the two-step Gewald reaction: Shvedov VI. Ryzhkova VK. Grinev AN. Khim. Geterotsikl. Soedin.  1967,  3:  239 ; Chem. Abstr. 1967, 67, 73464

<A NAME="RD19106ST-11A">11a</A> Le Moal H. Carrié R. Foucaud A. Bargain M. Sévellec C. Bull. Soc. Chim. Fr.  1966,  1033 

<A NAME="RD19106ST-11B">11b</A> Prager RH. Were ST. Aust. J. Chem.  1983,  36:  1441 

<A NAME="RD19106ST-12">12</A> Ionic liquids were shown to be very efficient in the case of the Gewald synthesis with aliphatic and alicyclic ketones: Hu Y. Chen Z.-C. Le Z.-G. Zheng Q.-G. Synth. Commun.  2004,  34:  3801 

<A NAME="RD19106ST-13">13</A>

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.

<A NAME="RD19106ST-14">14</A>

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%).

<A NAME="RD19106ST-15">15</A> Peet NP. Sunder S. Barbuch RJ. J. Heterocycl. Chem.  1986,  23:  129 

<A NAME="RD19106ST-16">16</A> Resonances of methyl groups adjacent to double bonds in authentic (E)- and (Z)-nitriles 3a: Zhu X.-Q. Liu Y.-C. Li J. Wang H.-Y. J. Chem. Soc., Perkin Trans. 2  1997,  2191 

<A NAME="RD19106ST-17">17</A>

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.

<A NAME="RD19106ST-18">18</A>

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.

<A NAME="RD19106ST-19">19</A> Elslager EF. Jacob P. Werbel LM. J. Heterocycl. Chem.  1972,  9:  775