Formation of amides: one-pot condensation of carboxylic acids and amines mediated by TiCl4 (2023)

General experimental details

All reagents were purchased commercially without further purification. Solvents were purified according to well-known laboratory methods and freshly distilled prior to use. Reaction were carried out in a tightly sealed screw-capped vial. Reactions were magnetically stirred and monitored by thin layer chromatography using Merck-Kieselgel 60 F254 plates. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 300 instrument at 300MHz and 75MHz, respectively. Spectroscopic analysis was performed at 293K on diluted solutions of each compound by using CDCl₃ and DMSO-d₆ as the solvents. Chemical shifts (δ) are reported in ppm. Coupling constants (J) are reported in Hertz (Hz) (Additional file 1). GC–MS analyses were performed with a DB-35MS (20m×0.18mm, 35% Phenyl 65% dimethylpolysiloxane) capillary column. The mass detector was operated in the electron impact ionization mode (EI/MS) with an electron energy of 70eV. The injection port was heated to 250°C. The oven temperature program was initially set at 70°C with a hold of 2min and ramped to 280°C at 20°C/min with a hold of 10min. Chiral GC–MS analyses of enantiomeric compounds 27–28 were performed by using a 25m×0.25mm, Diethyl tertbutyldimethylisilyl-β-cyclodextrine chiral capillary column. The injection port was heated to 250°C. The oven temperature program was initially set at 50°C, with a hold of 2min, ramped to 250°C at 0.5°C/min with a hold of 5min.

General procedure for the synthesis of amides 1–28

TiCl₄ (3mmol) and the amine (1mmol) were added to a solution of carboxylic acid (1mmol) in pyridine (10mL). The tightly sealed screw-capped vial containing the reaction mixture was then heated at 85°C. After magnetic stirring for about 2h, TLC analysis (chloroform/methanol 90:10 v/v) of the reaction mixture showed complete conversion of the carboxylic acid precursor. The reaction mixture was then cooled, and after removing pyridine by co-evaporation with toluene, was treated with an aqueous 1N HCl solution (10mL) and extracted with methylene chloride (3×10mL). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (3×10mL), dried (Na₂SO₄), and evaporated to dryness under reduced pressure to afford the corresponding amides 1–28 with yields ranging from 56 to 98%.

N-phenylbenzamide (1)

Solid (98%); mp=163–165°C; Rf=0.70; ¹H NMR (300MHz, DMSO-d₆) δ: 10.23 (s, 1H), 7.99–7.95 (m, 2H), 7.81–7.78 (m, 2H), 7.56–7.52 (m, 3H), 7.38–7.32 (m, 2H), 7.12–7.07 (m, 1H); ¹³C-NMR (75MHz, DMSO-d₆) δ: 166.0, 139.7, 135.5, 131.9, 129.0, 128.8, 128.1, 124.1, 120.9; GC/MS (EI) m/z (% rel.): 197 [M^+∙] (46), 105 (100), 77 (46); 65 (4), 51 (9).

4-nitro-N-phenylbenzamide (2)

Solid (98%); mp=218–220°C; Rf=0.65; ¹H NMR (300MHz, DMSO-d₆) δ: 10.53 (s, 1H), 8.35 (d, J=9.0Hz, 2H), 8.18 (d, J=9.0Hz,2H), 7.78 (d, J=7.5Hz, 2H), 7.46–7.27 (m, 2H), 7.13 (t, J=7.4Hz, 1H); ¹³C-NMR (75MHz, DMSO-d₆) δ: 164.3, 149.6, 141.1, 139.2, 129.7, 129.1, 124.6, 124.0, 121.0; GC/MS (EI) m/z (% rel.): 242 [M^+∙] (75), 150 (100), 120 (21), 104 (32), 92 (20), 76 (25).

4-methoxy-N-phenylbenzamide (3)

Solid (95%); mp=177–179°C; Rf=0.69; ¹H NMR (300MHz, DMSO-d₆) δ: 10.06 (s, 1H), 7.99–7.88 (m, 2H), 7.80–7.74 (m, 2H), 7.39–7.24 (m, 2H), 7.13–6.99 (m, 3H), 3.83 (s, 3H); ¹³C-NMR (75MHz, DMSO-d₆) δ: 165.4, 162.4, 139.9, 130.0, 129.0, 127.5, 123.9, 120.9, 114.1, 55.9; GC/MS (EI) m/z (% rel.): 227 [M^+∙] (21), 135 (100), 107 (6), 92 (11), 77(12).

4-chloro-N-phenylbenzamide (4)

Solid (95%); mp=205–207°C; Rf=0.78; ¹H NMR (300MHz, DMSO-d₆) δ: 10.28 (s, 1H), 8.06–7.88 (m, 2H), 7.82–7.71 (m, 2H), 7.64–7.53m, 2H), 7.40–7.28 (m, 2H), 7.10 (t, J=7.4Hz, 1H); ¹³C-NMR (75MHz, DMSO-d₆) δ: 164.9, 139.5, 136.9, 134.1, 130.1, 129.1, 128.9, 124.3, 120.9; GC/MS (EI) m/z (% rel.): 231 [M^+∙] (31), 139 (100), 111 (31), 75 (12).

N,2-diphenylacetamide (5)

Solid (95%); mp=105–107°C; Rf=0.73; ¹H NMR (300MHz, CDCl₃) δ: 7.63 (s_broad, 1H), 7.49–7.42 (m, 2H), 7.39–7.21 (m, 7H), 7.09 (t, J=7.4Hz, 1H), 3.70 (s, 2H); ¹³C-NMR (75MHz, CDCl₃) δ: 169.4, 137.8, 134.6, 129.5, 129.1, 128.9, 127.6, 124.4, 120.0, 44.7; GC/MS (EI) m/z (% rel.): 211 [M^+∙] (49), 119 (11), 91(68), 93 (100), 77 (11), 65 (21).

N-phenylcinnamamide (6)

Solid (91%); mp=155–157°C; Rf=0.72; ¹H NMR (300MHz, CDCl₃) δ: 8.09 (s, 1H), 7.75 (d, J=15.6Hz, 1H), 7.69–7.59 (m, 2H), 7.52–7.39 (m, 2H), 7.38–7.23 (m, 5H), 7.12 (t, J=7.4Hz, 1H), 6.66 (d, J=15.6Hz, 1H).; ¹³C-NMR (75MHz, CDCl₃) δ: 164.7, 142.2, 138.2, 134.6, 129.9, 129.1, 128.8, 128.0, 124.5, 121.2, 120.4; GC/MS (EI) m/z (% rel.): 223 [M^+∙] (25), 131 (100) 103 (36), 93 (19), 77 (24).

N-phenylpalmitamide (7)

Solid (88%), mp=88–90°C; Rf=0.81; ¹H NMR (300MHz, CDCl₃) δ: 7.53 (d, J=8.3Hz, 2H), 7.40 (s, 1H), 7.36–7.22 (m, 2H), 7.11 (m, 1H), 2.42–2.29 (m, 2H), 1.80–1.60 (m, 2H), 1.41–1.13 (m, 24H,), 0.89 (t, J=6.7Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.7, 137.9, 129.0, 124.2, 119.8, 37.8, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 25.7, 22.7, 14.2; GC/MS (EI) m/z (% rel.): 331 [M^+∙] (2), 135 (19), 93 (100), 77 (2).

N-(2-fluorophenyl)-2-phenylacetamide (8)

Solid (72%), mp=100–102°C; Rf=0.85; ¹H NMR (300MHz, CDCl₃) δ: 8.29 (t, J=8.0Hz, 1H), 7.53–7.30 (m, 6H), 7.16–7.06 (m, 1H), 7.06–6.95 (m, 2H), 3.78 (s, 2H); ¹³C-NMR (75MHz, CDCl₃) δ: 169.2, 152,1 (d, J=242.5Hz), 134.1, 129.5, 129.3, 127.8, 126.2 (d, J=10.3Hz), 124.54 (d, J=3.8Hz), 124.51 (d, J=7.6Hz), 121.7, 114.7 (d, J=19.4Hz), 44.8; GC/MS (EI) m/z (% rel.): 229 [M^+∙] (25), 118 (24), 111 (100), 91 (76), 65 (13).

2-phenyl-N-(p-tolyl)acetamide (9)

Solid (98%), mp=108–110°C; Rf=0.73; ¹H NMR (300MHz, CDCl₃) δ: 7.52 (s_broad, 1H), 7.43–7.28 (m, 7H), 7.07 (d, J=8.3Hz, 2H), 3.69 (s, 2H), 2.29 (s, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 169.3, 135.2, 134.7, 134.0, 129.5, 129.4, 129.1, 127.5, 120.1, 44.6, 20.9; GC/MS (EI) m/z (% rel.): 225 [M^+∙] (49), 133 (12), 107 (100), 91 (46), 77 (9), 65 (12).

N-propylbenzamide (10)

Solid (91%); mp=83–85°C; Rf=0.64; ¹H NMR (300MHz, CDCl₃) δ: 7.82–7.69 (m, 2H), 7.52–7.27 (m, 3H), 6.60 (s_broad, 1H), 3.42–3.31 (m, 2H), 1.70–1.51 (m, 2H), 0.93 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 167.6, 134.8, 131.1, 128.4, 126.8, 41.7, 22.8, 11.3; GC/MS (EI) m/z (% rel.): 163 [M^+∙] (28), 134 (7), 105 (100), 77 (30).

4-nitro-N-propylbenzamide (11)

Solid (92%); mp=102–104°C; Rf=0.50; ¹H NMR (300MHz, CDCl₃) δ: δ: 8.21 (d, J=8.8Hz, 2H), 7.92 (d, J=8.8Hz, 2H), 6.74 (s_broad, 1H), 3.44–3.34 (m, 2H), 1.74–1.53 (m, 2H), 0.95 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 165.6, 149.5, 140.5, 127.6, 123.5, 41.96, 22.6, 11.3; GC/MS (EI) m/z (% rel.): 208 [M^+∙] (21), 193 (12), 179 (12), 150 (100), 104 (23), 76 (15).

4-methoxy-N-propylbenzamide (12)

Solid (78%); mp=58–60°C; Rf=0.54; ¹H NMR (300MHz, CDCl₃) δ: 7.74 (d, J=8.8Hz, 2H,), 6.87 (d, J=8.8Hz, 2H), 6.45 (s_broad, 1H), 3.81 (s, 3H), 3.42–3.28 (m, 2H), 1.70–150 (m, 2H), 0.94 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 167.1, 162.0, 128.7, 127.1, 113.6, 55.4, 41.7, 22.9, 11.5; GC/MS (EI) m/z (% rel.): 193 [M^+∙] (19), 151 (10), 135 (100), 107 (5), 92 (10), 77 (12).

4-chloro-N-propylbenzamide (13)

Solid (96%); mp=96–98°C; Rf=0.58; ¹H NMR (300MHz, CDCl₃) δ: 7.75–7.65 (m, 2H), 7.41–7.28 (m, 2H), 6.55 (s_broad, 1H), 3.43–3.28 (m, 2H), 1.70–1.50 (m, 2H), 0.94 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 166.5, 137.4, 133.2, 128.6, 128.3, 41.8, 22.7, 11.3; GC/MS (EI) m/z (% rel.): 197 [M^+∙] (25), 168 (6), 139 (100), 111 (23), 75 (11).

2-phenyl-N-propylacetamide (14)

Solid (95%); mp=66–69°C; Rf=0.68; ¹H NMR (300MHz, CDCl₃) δ: 7.42–7.17 (m, 5H), 5.65 (s_broad, 1H), 3.55 (s, 2H), 3.22–3.07 (m, 2H), 1.58–1.31 (m, 2H), 0.82 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.0, 135.1, 129.4, 129.0, 127.3, 43.8, 41.3, 22.7, 11.2; GC/MS (EI) m/z (% rel.): 177 [M^+∙] (18), 92 (100), 91 (87), 86 (10), 65 (13), 43 (23).

N-propylcinnamamide (15)

Solid (97%); mp=75–77°C; Rf=0.71; ¹H NMR (300MHz, CDCl₃) δ: 7.62 (d, J=15.6Hz, 1H), 7.54–7.41 (m, 2H), 7.38–7.25 (m, 3H), 6.50 (d, J=15.6Hz, 1H), 6.34 (sbroad, 1H), 3.47–3.26 (m, 2H), 1.71–1.49 (m, 2H), 0.94 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 166.1, 140.5, 134.9, 128.7, 127.7, 127.7, 121.1, 41.4, 22.8, 11.4; GC/MS (EI) m/z (% rel.): 189 [M^+∙] (27), 131 (100), 174 (5), 146 (24), 103 (40), 77 (24).

N-propylpalmitamide (16)

Solid (94%), mp=74–76°C; Rf=0.81; ¹H NMR (300MHz, CDCl₃) δ: 5.49 (s_broad, 1H), 3.27–3.14 (m, 2H), 2.20–2.09 (m, 2H), 1.73–1.58 (m, 2H), 1.57–1.41 (m, 2H), 1.40–1.11 (m, 24H), 0.98–0.78 (m, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 173.1, 41.2, 37.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 25.9, 22.9, 22.7, 14.1, 11.4; GC/MS (EI) m/z (% rel.): 297 [M^+∙] (3), 268 (3), 239 (3), 114 (24), 101 (100), 43 (14).

N,N-diethylbenzamide (17)

Viscous oil (64%); Rf=0.75; ¹H NMR (300MHz, CDCl₃) δ: 7.41–7.10 (m, 5H), 3.43 (s_broad, 2H), 3.14 (s_broad, 2H), 1.27–0.89 (m, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.1, 137.1, 128.9, 128.2, 126.1, 43.1, 39.1, 14.0, 12.7; GC/MS (EI) m/z (% rel.): 177 [M^+∙] (21), 162 (2), 148 (7), 176 (61), 105 (100), 77 (27).

N,N-diethyl-4-nitrobenzamide (18)

Solid (80%); mp=54–56°C; Rf=0.73; ¹H NMR (300MHz, CDCl₃) δ: 8.26 (d, J=8.8Hz, 2H), 7.53 (d, J=8.8Hz, 2H), 3.73–3.36 (m, 2H), 3.34–3.01 (m, 2H), 1.25 (t, J=6.9Hz, 3H), 1.11 (t, J=6.9Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 168.9, 148.3, 143.4, 127.3, 123.9, 43.3, 39.5, 14.2, 12.8; GC/MS (EI) m/z (% rel.): 222 [M^+∙] (17), 221 (42), 205 (7), 175 (4), 150 (100), 120 (13), 104 (25), 92 (8), 76 (14).

N,N-diethyl-4-methoxybenzamide (19)

Oil (56%); Rf=0.65; ¹H NMR (300MHz, CDCl₃) δ: 7.22 (d, J=8.7Hz, 2H), 6.77 (d, J=8.7Hz, 2H), 3.68 (s, 3H,), 3.29 (s_broad, 4H), 1.05 (s_broad, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.1, 160.1, 129.3, 128.0, 113.5, 55.1, 43.0, 39.7, 13.5; GC/MS (EI) m/z (% rel.): 207 [M^+∙] (15), 206 (34), 135 (100), 107 (4), 92 (11), 77 (9).

4-chloro-N,N-diethylbenzamide (20)

Oil (77%); Rf=0.65; ¹H NMR (300MHz, CDCl₃) δ: 7.41–7.24 (m, 4H, ArH), 3.50 (s_broad, 2H), 3.22 (s_broad, 2H), 1.31–0.98 (m, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 170.2, 135.6, 135.1, 128.7, 127.8, 43.1, 39.1, 14.1, 12.7; GC/MS (EI) m/z (% rel.): 211 [M^+∙] (15), 210 (34), 139 (100), 111 (23), 75 (9).

N,N-diethyl-2-phenylacetamide (21)

Oil (85%); Rf=0.73; ¹H NMR (300MHz, CDCl₃) δ: 7.36–7.15 (m, 5H), 3.69 (s, 2H), 3.38 (q, J=7.1Hz, 2H), 3.28 (q, J=7.1Hz, 2H), 1.16–1.02 (m, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 170.2, 135.5, 128.7, 128.6, 126.6, 42.4, 40.9, 40.1, 14.2, 12.9; GC/MS (EI) m/z (% rel.): 191[M^+∙] (38), 118 (3), 100 (100), 91 (46), 72 (50).

N,N-diethylcinnamamide (22)

Solid (87) %); mp=58-60°C; Rf=0.73; ¹H NMR (300MHz, CDCl3) δ: 7.55 (d, J=15.4Hz, 1H), 7.41–7.27 (m, 2H), 7.24–7.04 (m, 3H), 6.68 (d, J=15.4Hz, 1H), 3.42–3.15 (m, 4H), 1.16–0.92 (m, 6H); ¹³C-NMR (75MHz, CDCl₃) δ: 165.4, 141.9, 135.3, 129.2, 128.6, 127.5, 117.7, 42.1, 40.9, 14.9, 13.0; GC/MS (EI) m/z (% rel.): 203 [M^+∙] (32), 188 (8), 131 (100), 126 (8), 103 (35), 77 (12).

N,N-diethylpalmitamide (23)

Oil (91) %); Rf=0.73; ¹H NMR (300MHz, CDCl₃) δ: 3.42–3.21 (m, 4H), 2.35–2.19 (m, 2H), 1.71–1.51 (m, 2H), 1.39–0.99 (m, 30H), 0.87 (t, J=6.7, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 172.4, 41.9, 40.0, 33.2, 31.9, 29.7, 29.6, 29.5, 29.4, 25.5, 22.7, 14.4, 14.1, 13.1; GC/MS (EI) m/z (% rel.): 311 [M^+∙] (8), 128 (26), 115 (100), 100 (23).

N-phenylpivalamide (24)

Solid (90%); mp=133–135°C; Rf=0.82; ¹H NMR (300MHz, CDCl₃) δ: 7.57–7.50 (m, 2H), 7.43 (s_broad, 1H), 7.36–7.25 (m, 2H), 7.14–7.04 (m, 1H), 1.32 (s, 9H); ¹³C-NMR (75MHz, CDCl₃) δ: 176.6, 138.0, 128.9, 124.2, 120.0, 39.6, 27.6; GC/MS (EI) m/z (% rel.): 177 [M^+∙] (90), 120 (7), 93 (100), 77 (12), 57 (95).

N-propylpivalamide (25)

Oil (75%); Rf=0.84; ¹H NMR (300MHz, CDCl₃) δ: 5.73 (s, 1H), 3.23–3.11 (m, 2H), 1.58–1.40 (m, 2H), 1.16 (s, 9H), 0.88 (t, J=7.4Hz, 3H); ¹³C-NMR (75MHz, CDCl₃) δ: 178.4, 41.2, 38.6, 27.6, 22.8, 11.3; GC/MS (EI) m/z (% rel.): 143 [M^+∙] (54), 128 (19), 114 (7), 100 (14), 86 (41), 85 (26), 57 (100), 43 (59).

N,N-diethylpivalamide (26)

oil (9%); Rf=0.65; ¹H NMR (300MHz, CDCl₃) δ: 3.48–3.32 (m, 4H), 1.29–1.18 (m, 15H); GC/MS (EI) m/z (% rel.): 157 [M^+∙] (25), 142 (7); 100 (100), 72 (62), 57 (53).

(S)-2-(N-tert-Butoxycarbonylamino)-N-phenylpropanamide (27)

Oil (88%); Rf=0.80; ¹H NMR (300MHz, CDCl₃) δ: 8.86 (s_broad, 1H), 7.58–7.45 (m, 2H), 7.36–7.19 (m, 2H), 7.13–7.01 (m, 1H), 5.50 (d, J=7.5Hz, 1H), 4.53–4.31 (m, 1H), 1.48–1.38 (m, 12H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.2, 155.9, 137.9, 128.9, 124.2, 119.9, 80.4, 50.4, 28.3, 17.8; GC/MS (EI) m/z (% rel.): 264 [M^+∙] (17), 208 (25), 191 (29), 144 (18), 120 (28), 93 (100), 77 (25), 57 (87).

(R)-2-(N-tert-Butoxycarbonylamino)-N-phenylpropanamide (28)

Oil (87%); Rf=0.80; ¹H NMR (300MHz, CDCl₃) δ: 8.69 (s_broad, 1H), 7.61–7.42 (m, 2H), 7.33–7.21 (m, 2H), 7.11–7.02 (m, 1H), 5.31 (d, J=8.0Hz, 1H), 4.49–4.27 (m, 1H), 1.51–1.38 (m, 12H); ¹³C-NMR (75MHz, CDCl₃) δ: 171.1, 156.1, 137.8, 128.9, 124.2, 119.9, 80.7, 51.7, 28.3, 17.5; GC/MS (EI) m/z (% rel.): 264 [M^+∙] (17), 208 (24), 191 (28), 144 (18), 120 (28), 93 (100), (77 (25), 57 (92).