Kishanpal Singha,
Neetu Singhb,
Harvinder Singh Sohal*b,
Baljit Singh*a,
Fohad Mabood Husainc,
Mohammed Arshadd and
Mohd Adile
aDepartment of Chemistry, Punjabi University, Patiala 147002, Punjab, India
bMedicinal and Natural Product Laboratory, Department of Chemistry, Chandigarh University, Gharuan 140413, Mohali, Punjab, India. E-mail: drharvinder.cu@gmail.com
cDepartment of Food Science and Nutrition. College of Food and Agriculture Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia
dDental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Kingdom of Saudi Arabia
eDepartment of Environmental Sciences, Dalhousie University, Truro, NS, Canada
First published on 1st November 2023
In the present report, the authors describe a synthetic route for the generation of N-phenyl amino acid derivatives using CO2 via a C–C coupling reaction in an undivided cell containing a combination of Mg–Pt electrodes. The reactions were completed in a short time without the formation of any other side product. The final products were purified via a simple recrystallization procedure. The structures of the newly prepared compounds were established using advanced spectroscopic techniques including 1H, 13C NMR, IR, and ESI-MS. All the prepared derivatives show good-to-excellent activity when tested against bacterial and fungal strains. Interestingly, it was observed that the presence of polar groups (capable of forming H-bonds) such as –OH (4d) and –NO2 (4e) at the para position of the phenyl ring show activity equivalent to the standard drugs.
Furthermore, these 20 important amino acids have been connected to a number of substrates to achieve potent biological activities, such as antibacterial,8 antifungal,9 anticancer10 inhibition of Type B monoamine oxidase,11 and anti-fibrotic12 activities. It has also been observed that N-substituted amino acids are more potent for a number of activities, such as PPAR γ-agonist,13 hyperalphalipoproteinaemic,14 anti-inflammatory,9 anti-phlogistic,10 anti-hypertensive,15 anti-oxidant,16 and anti-phlogistic activity.17
To date, a number of methods have been proposed for the formulation of amino acids, including simple refluxing,18 visible light irradiation,19 microwave irradiation,20 and ultraviolet irradiation,21 but these methods all have limitations. In continuation of our work on electro-carboxylation,22–24 in the present report, we introduced a synthetic route for the production of N-substituted amino acids via an environmentally friendly electrochemical C–C coupling method using carbon dioxide.
Entry | Sacrificial anode | Conc. (mmol L−1) | SRP (volts) | Yield (%) |
---|---|---|---|---|
1 | Ni | 0.64 | −0.19 | 64 |
2 | Ni | 1.12 | −0.19 | 53 |
3 | Ni | 1.53 | −0.19 | 41 |
4 | Ni | 2.15 | −0.19 | 30 |
5 | Al | 0.59 | −1.62 | 72 |
6 | Al | 1.05 | −1.62 | 63 |
7 | Al | 1.61 | −1.62 | 59 |
8 | Al | 2.15 | −1.62 | 47 |
9 | Mg | 0.54 | −2.36 | 92 |
10 | Mg | 1.05 | −2.36 | 89 |
11 | Mg | 1.59 | −2.36 | 77 |
12 | Mg | 2.15 | −2.36 | 65 |
Entry | Current density (mA cm−2) | Temperature (°C) | Yielda (%) |
---|---|---|---|
a Yield refers to combined yield from all the crops. | |||
1 | 10 | 0 | 61 |
2 | 10 | 5 | 65 |
3 | 10 | 10 | 69 |
4 | 10 | 15 | 75 |
5 | 10 | 20 | 79 |
6 | 10 | 25 | 75 |
7 | 15 | 0 | 63 |
8 | 15 | 5 | 74 |
9 | 15 | 10 | 79 |
10 | 15 | 15 | 80 |
11 | 15 | 20 | 90 |
12 | 15 | 25 | 92 |
13 | 20 | 0 | 65 |
14 | 20 | 5 | 69 |
15 | 20 | 10 | 73 |
16 | 20 | 15 | 75 |
17 | 20 | 20 | 81 |
18 | 20 | 25 | 79 |
Various substitutions on the aldehyde moiety in the imine derivatives were reacted with CO2 under similar reaction conditions for the generalization of the reaction, and it was discovered that the reactions proceeded smoothly and the desired molecules were collected in high yield as well as high purity. Finally, all the collected synthesized compounds were purified by simple recrystallization in ethanol.
The synthesis of amino acid derivative 4a was confirmed by the downfield shift in the signal of the aromatic protons from δ 7.25 to δ 7.60, and also the singlet peak for the proton of N–H at δ 9.59 ppm. 13C-NMR exhibits signals at δ 180.5 for the carboxylic group, with other peaks δ 129.5, 129.2, 128.9, 120.8, 113.5, and 64.3 confirming the formation of the targeted compound. In the IR spectrum, an additional broad peak at 3356 cm−1 demonstrates the –OH of the carboxylic group and a peak at 2873 cm−1 validates the C–H group. Furthermore, ESI-MS fragmentation generated [M+1] and [M+2] peaks at 262 and 263 m/z respectively, confirming the formation of the desired amino acid derivative.
Compound | Gram (+ve) bacteria | Gram (−ve) bacteria | Fungi | |||||
---|---|---|---|---|---|---|---|---|
B. subtilis | S. pyogenes | E. coli | K. pneumonia | S. aureus | A. janus | A. niger | A. sclerotiorum | |
4a | 16 | 8 | 8 | 8 | 16 | 8 | 16 | 8 |
4b | 16 | 16 | 8 | 16 | 16 | 16 | 8 | 16 |
4c | 16 | 32 | 32 | 16 | 32 | 16 | 8 | 32 |
4d | 8 | 4 | 8 | 4 | 8 | 16 | 8 | 16 |
4e | 4 | 4 | 4 | 8 | 4 | 4 | 4 | 8 |
4f | 8 | 8 | 16 | 8 | 16 | 16 | 16 | 8 |
4g | 16 | 16 | 8 | 8 | 16 | 8 | 16 | — |
4h | 64 | 16 | 32 | 16 | 32 | 32 | 32 | 16 |
4i | 16 | 32 | 32 | 32 | 16 | 32 | 32 | 32 |
4j | 32 | 16 | 8 | — | 16 | 32 | 16 | 16 |
4k | 8 | 16 | 16 | 32 | — | 16 | 16 | 32 |
4l | 8 | 8 | 8 | 16 | 8 | 16 | 32 | 16 |
Amoxicillin | 4 | 4 | 4 | 4 | 4 | — | — | — |
Fluconazole | — | — | — | — | — | 2 | 2 | 2 |
As an inert cathode and sacrificial anode electrode, platinum gauze and magnesium electrodes with dimensions of 1 cm × 1 cm × 0.1 cm and 1 cm diameter and 5 cm length, respectively, were employed. Using a DC power supply, the cathode and anode were eventually connected to the positive and negative ends of the electric circuit, respectively.
Entry | Product | R | Rf | Yielda (%) | Melting point (°C) | Literature melting point (°C) |
---|---|---|---|---|---|---|
a Yield refers to total mass of collection from different crops. | ||||||
1 | 3a | 4-Cl C6H4 | 0.61 | 98 | 62 | 62–64 (ref. 25) |
2 | 3b | C6H5 | 0.66 | 98 | 55 | 54 (ref. 25) |
3 | 3c | 4-Me C6H4 | 0.63 | 96 | 39–41 | 38–40 (ref. 25) |
4 | 3d | 4-OH C6H4 | 0.69 | 95 | 96–97 | 94–96 (ref. 25) |
5 | 3e | 4-NO2 C6H4 | 0.71 | 97 | 90–93 | 90–92 (ref. 25) |
6 | 3f | 3-NO2 C6H4 | 0.68 | 98 | 64–65 | 65–66 (ref. 25) |
7 | 3g | 4-OMe C6H4 | 0.62 | 93 | 64–66 | 63–65 (ref. 25) |
8 | 3h | 4-Br C6H4 | 0.63 | 95 | 75–77 | 76–77 (ref. 25) |
9 | 3i | C6Hs CH![]() |
0.65 | 89 | 103–105 | 106–108 (ref. 25) |
10 | 3j | 2-Furyl | 0.67 | 91 | 56–58 | 55–57 (ref. 25) |
11 | 3k | 2-Thiophenyl | 0.63 | 92 | 61–63 | — |
12 | 3l | 2-Pyridyl | 0.59 | 90 | 65–66 | — |
3a: yield 98%, colourless solid, mp 62 °C. IR spectrum, ν, cm−1: 3149 (sp2 C–H), 3029 (Ar–H), 1597 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.44 (s, 1H, CH), 7.13–7.44 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 216 (M+1), 217 (M+2).
3b: yield 98%, colourless solid, mp 55 °C. IR spectrum, ν, cm−1: 3060 (sp2, C–H), 3028 (Ar–H), 1590 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.13 (s, 1H, CH), 7.10–7.35 (m, 10H, Ar–H). Mass spectrum, m/z (Irel, %): 182 (M+1).
3c: yield 96%, colourless solid, mp 39–41 °C. IR spectrum, ν, cm−1: 3140 (sp2 C–H), 3030 (Ar–H), 1586 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.28 (s, 1H, CH), 7.06–7.26 (m, 9H, Ar–H), 2.14 (s, 3H, CH3). Mass spectrum, m/z (Irel, %): 196 (M+1).
3d: yield 95%, colourless solid, mp 96–97 °C. IR spectrum, ν, cm−1: 3315 (O–H), 3142 (sp2 C–H), 3010 (Ar–H), 1584 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 9.1 (s, 1H, OH), 8.28 (s, 1H, CH), 7.09–7.27 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 198 (M+1).
3e: yield 97%, pale yellow solid, mp 90–93 °C. IR spectrum, ν, cm−1: 3170 (sp2 C–H), 3039 (Ar–H), 1610 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.59 (s, 1H, CH), 7.23–7.84 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 227 (M+1).
3f: yield 98%, pale yellow solid, mp 64–65 °C. IR spectrum, ν, cm−1: 3152 (sp2 C–H), 3033 (Ar–H), 1608 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.52 (s, 1H, CH), 7.22–7.79 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 227 (M+1).
3g: yield 93%, colourless solid, mp 64–66 °C. IR spectrum, ν, cm−1: 3122 (sp2 C–H), 3019 (Ar–H), 1582 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.24 (s, 1H, CH), 7.09–7.23 (m, 9H, Ar–H), 3.92 (s, 3H, OCH3). Mass spectrum, m/z (Irel, %): 212 (M+1).
3h: yield 95%, colourless solid, mp 75–77 °C. IR spectrum, ν, cm−1: 3148 (sp2 C–H), 3024 (Ar–H), 1599 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.27 (s, 1H, CH), 7.15–7.42 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 261 (M+1), 262 (M+2).
3i: yield 89%, yellow solid, mp 103–105 °C. IR spectrum, ν, cm−1: 3149 (sp2 C–H), 3015 (Ar–H), 1581 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.27 (s, 1H, CH), 6.89 (s, 1H,
CH), 7.27 (s, 1H,
CH), 7.11–7.34 (m, 10H, Ar–H). Mass spectrum, m/z (Irel, %): 208 (M+1).
3j: yield 91%, yellow solid, mp 56–58 °C. IR spectrum, ν, cm−1: 3144 (sp2 C–H), 3033 (Ar–H), 1601 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.43 (s, 1H, CH), 7.17–7.45 (m, 8H, Ar–H). Mass spectrum, m/z (Irel, %): 172 (M+1).
3k: yield 92%, yellow-brown solid, mp 61–63 °C. IR spectrum, ν, cm−1: 3140 (sp2 C–H), 3025 (Ar–H), 1599 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.47 (s, 1H, CH), 7.16–7.48 (m, 8H, Ar–H). Mass spectrum, m/z (Irel, %): 188 (M+1).
3l: yield 90%, brown solid, mp 65–66 °C. IR spectrum, ν, cm−1: 3132 (sp2 C–H), 3029 (Ar–H), 1597 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 8.46 (s, 1H, CH), 7.14–7.51 (m, 9H, Ar–H). Mass spectrum, m/z (Irel, %): 183 (M+1).
Following this, the excess solvent was reduced under low pressure, while the solid residue was retained. Furthermore, to eliminate ionic residues from the solid, the extraction was carried out in a separating funnel with diethyl ether, and the product was left to dry using anhydrous MgSO4. Finally, compound 4a was obtained by recrystallizing the isolated crude product with ethanol (Scheme 2). Similarly, the other imine derivatives 3b–l were converted into amino acid derivatives 4b–l using the same procedure (Table 6).
Entry | Product | R1 | Rf | Yielda (%) | Melting point (°C) |
---|---|---|---|---|---|
a Yield refers to total mass of collection from different crops. | |||||
1 | 4a | 4-Cl C6H4 | 0.66 | 92 | 196–197 |
2 | 4b | C6H5 | 0.69 | 91 | 183–185 |
3 | 4c | 4-Me C6H4 | 0.61 | 86 | 174–175 |
4 | 4d | 4-OH C6H4 | 0.72 | 84 | 216–217 |
5 | 4e | 4-NO2 C6H4 | 0.70 | 91 | 210–212 |
6 | 4f | 3-NO2 C6H4 | 0.64 | 89 | 191–192 |
7 | 4g | 4-OMe C6H4 | 0.66 | 86 | 206–208 |
8 | 4h | 4-Br C6H4 | 0.69 | 85 | 178–180 |
9 | 4i | C6Hs CH = CH | 0.73 | 82 | 225–226 |
10 | 4j | 2-Furyl | 0.66 | 87 | 199–201 |
11 | 4k | 2-Thiopehyl | 0.67 | 86 | 188–190 |
12 | 4l | 2-Pyridyl | 0.63 | 83 | 178–181 |
4a: yield 92%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3356 (OH), 2970 (Ar–H), 2873 (C–H), 1619 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.85 (s, 1H, OH), 9.59 (s, 1H, NH), 8.54 (s, 1H, CH), 7.14–7.80 (m, 9H, ArH). 13C NMR spectrum, δ, ppm: 180.5, 145.9, 135.0, 133.1, 129.5, 129.2, 128.9, 120.8, 113.5, 64.3. Mass spectrum, m/z (Irel, %): 262 (M+1), 263 (M+2).
4b: yield 91%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3455 (OH), 3052 (Ar–H), 2825 (C–H), 1628 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.79 (s, 1H, OH), 9.62 (s, 1H, NH), 8.23 (s, 1H, CH), 7.22–7.53 (m, 10H, ArH). 13C NMR spectrum, δ, ppm: 188.3, 145.9, 136.9, 129.7, 129.5, 129.1, 127.5, 120.8, 113.5, 64.3. Mass spectrum, m/z (Irel, %): 228 (M+1).
4c: yield 86%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3440 (OH), 3031 (Ar–H), 2978 (C–H), 1610 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.83 (s, 1H, OH), 9.51 (s, 1H, NH), 8.37 (s, 1H, CH), 7.14–7.739 (m, 9H, ArH), 2.23 (s, 3H, CH3). 13C NMR spectrum, δ, ppm: 180.5, 155.9, 147.2, 143.9, 139.6, 139.5, 139.4, 130.8, 123.5, 74.3, 31.3. Mass spectrum, m/z (Irel, %): 242 (M+1).
4d: yield 84%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3428 (OH), 3031 (Ar–H), 2978 (C–H), 1625 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.87 (s, 1H, OH), 9.55 (s, 1H, NH), 8.42 (s, 1H, CH), 7.21–7.43 (m, 9H, ArH). 13C NMR spectrum, δ, ppm: 180.5, 157.3, 145.9, 129.5, 128.9, 120.8, 116.3, 113.5, 64.3. Mass spectrum, m/z (Irel, %): 244 (M+1).
4e: yield 91%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3478 (OH), 3057 (Ar–H), 3020 (C–H), 1612 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 13.15 (s, 1H, OH), 9.87 (s, 1H, NH), 8.69 (s, 1H, CH), 7.38–8.03 (m, 9H, ArH). 13C NMR spectrum, δ, ppm: 180.5, 146.7, 145.9, 143.0, 129.5, 128.9, 127.9, 120.8, 113.5, 64.3. Mass spectrum, m/z (Irel, %): 273 (M+1).
4f: yield 89%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3470 (OH), 3053 (Ar–H), 3017 (C–H), 1628 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 13.03 (s, 1H, OH), 9.83 (s, 1H, NH), 8.63 (s, 1H, CH), 7.37–7.99 (m, 9H, ArH). 13C NMR spectrum, δ, ppm: 180.5, 148.3, 145.9, 136.8, 135.8, 130.0, 129.5, 123.5, 122.7, 120.8, 113.5, 63.3. Mass spectrum, m/z (Irel, %): 273 (M+1).
4g: yield 86%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3421 (OH), 3039 (Ar–H), 2983 (C–H), 1605 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.80 (s, 1H, OH), 9.51 (s, 1H, NH), 8.37 (s, 1H, CH), 7.22–7.53 (m, 9H, ArH), 3.98 (s, 3H, OMe). 13C NMR spectrum, δ, ppm: 180.5, 159.4, 145.9, 129.5, 129.2, 128.5, 120.8, 114.7, 113.5, 64.3, 55.8. Mass spectrum, m/z (Irel, %): 258 (M+1).
4h: yield 85%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3446 (OH), 3037 (Ar–H), 2989 (C–H), 1622 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.89 (s, 1H, OH), 9.62 (s, 1H, NH), 8.42 (s, 1H, CH), 7.22–7.57 (m, 9H, ArH), 5.34 (d, 2H). 13C NMR spectrum, δ, ppm: 180.5, 145.9, 135.9, 132.0, 131.9, 129.5, 121.9, 120.8, 113.5, 64.3. Mass spectrum, m/z (Irel, %): 307 (M+1), 308 (M+2).
4i: yield 82%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3442 (OH), 3050 (Ar–H), 2987 (C–H), 1616 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.92 (s, 1H, OH), 9.63 (s, 1H, NH), 8.61 (s, 1H, =CH), 7.48 (s, 1H, CH), 7.23–7.58 (m, 10H, ArH), 6.91 (s, 1H,
CH). 13C NMR spectrum, δ, ppm: 184.1, 147.6, 136.4, 129.5, 128.6, 128.5, 127.9, 123.3, 120.8, 113.5, 72.3. Mass spectrum, m/z (Irel, %): 254 (M+1).
4j: yield 87%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3434 (OH), 3049 (Ar–H), 2997 (C–H), 1633 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.95 (s, 1H, OH), 9.57 (s, 1H, NH), 8.62 (s, 1H, CH), 7.28–7.68 (m, 8H, ArH). 13C NMR spectrum, δ, ppm: 178.5, 145.9, 142.8, 139.3, 129.5, 120.8, 118.6, 113.5, 110.7, 60.0. Mass spectrum, m/z (Irel, %): 218 (M+1).
4k: yield 86%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3439 (OH), 3047 (Ar–H), 2998 (C–H), 1628 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.87 (s, 1H, OH), 9.58 (s, 1H, NH), 8.61 (s, 1H, CH), 7.23–7.62 (m, 8H, ArH). 13C NMR spectrum, δ, ppm: 178.5, 145.9, 137.5, 129.5, 128.1, 126.1, 121.3, 120.8, 113.5, 65.5. Mass spectrum, m/z (Irel, %): 234 (M+1).
4l: yield 83%, colourless solid, mp 183–185 °C. IR spectrum, ν, cm−1: 3445 (OH), 3055 (Ar–H), 3002 (C–H), 1615 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 12.93 (s, 1H, OH), 9.65 (s, 1H, NH), 8.63 (s, 1H, CH), 7.34–7.79 (m, 9H, ArH). 13C NMR spectrum, δ, ppm: 178.5, 155.4, 148.6, 145.9, 136.2, 129.5, 121.9, 120.9, 120.8, 113.5, 72.9. Mass spectrum, m/z (Irel, %): 229 (M+1).
TPAC | Tetrapropylammonium chloride |
TPAB | Tetrapropylammonium bromide |
TBABF4 | Tetrapropylammonium tetrafluoroborate |
MIC | Minimum inhibitory concentration |
SRP | Standard reduction potential |
ATR | Attenuated total reflectance |
TLC | Thin layer chromatography |
Footnote |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ra03592a |
This journal is © The Royal Society of Chemistry 2023 |