1 Introduction
Multi-component reactions (MCRs) play an important role in combinatorial chemistry because of their ability to synthesize small drug-like molecules with several degrees of structural diversity. These reactions allow compounds to be synthesized in few steps and usually in a one-pot manner [1]. Being time and energy saving while having simple procedures, high bond forming efficiency and low expenditures are among the advantages of these reactions [2]. Therefore finding and designing new MCRs has been the subject of extensive research.
Compounds containing 1,3-amino-oxygenated functional groups are frequently found in biologically active natural products and potent drugs such as nucleoside antibiotics and HIV protease inhibitors [3–6]. Furthermore, 1-amidoalkyl-2-naphthols can be converted to useful and important biological building blocks and to 1-aminomethyl-2-naphthols, which exhibit depressor effects and bradycardia [7,8], by an amide hydrolysis reaction.
The preparation of 1-amidoalkyl-2-naphthols can be carried out by condensation of aryl aldehydes, β-naphthol, and acetonitrile or amides in the presence of Lewis or BrØnsted acid catalysts such as montmorillonite K10 clay [9], Ce(SO4)2 [10], iodine [11], K5CoW12O40.3H2O [12], p-TSA [13], sulfamic acid [14], cation-exchanged resins [15], FeCl3.SiO2 [16], silica-sulfuric acid [17], BrØnsted acidic ionic liquid [18], Fe(HSO4)3 [19], Sr(OTf)2 [20], PPA-SiO2 [21], oxalic acid [22], molybdophosphoric acid [23], ZrOCl2 [24], and thiamine hydrochloride [25].
However, most of the synthetic protocols for 1-amidoalkyl-2-naphthol reported so far suffer from drawbacks such as unsatisfactory yields, long reaction times, and the production of environmental pollutants. Therefore, a great demand still exists for versatile, simple, and environmentally friendly processes whereby 1-amidoalkyl-2-naphthols may be formed under simple and practical conditions.
Herein, we report a convenient, mild and efficient procedure for a one-pot three-component synthesis of new 1-amidoalkyl 2-naphthol derivatives from various aryl and alkyl aldehydes, β-naphthol and different amides in the presence of DPA [26] as an effective and cost efficient catalyst under solvent-free conditions (Scheme 1).
2 Results and discussion
Initially, to optimize and find the best conditions, the reaction of β-naphthol (1 mmol), 4-nitrobenzaldehyde (1 mmol) as the test substrate and benzamide (1.2 mmol) in the presence of DPA (0.1 mmol) was performed in different solvents, such as H2O, EtOH/H2O (1:1), toluene, acetonitrile, and ethyl acetate (Table 1, entries 2–6) under reflux conditions. The reaction did not proceed at all in any of the solvents except in toluene in which the desired product was obtained in 48% yield. Then the model reaction was investigated under solvent-free conditions in the presence of DPA (10 mol%) at 90 °C and the desired product was formed in 88% yield (Table 1, entry 1). Decreasing of the yield was observed when the reaction was repeated in the presence of 5 mol% of the catalyst (Table 1, entry 7). Enhancement of the catalyst loading to 20 mol% did not show any effect on the yield or the reaction time (Table 1, entry 8).
Investigated conditions for preparation of 1-amidoalkyl-2-naphthol using of dodecylphosphonic acid (DPA) as catalyst.
| Entry | Solvent | Catalyst (mol%) | Temp. (°C) | Time (min) | Yield (%)a |
| 1 | Solvent-free | DPA (10 mol%) | 90 | 20 | 88 |
| 2 | H2O | DPA (10 mol%) | Reflux | 120 | – |
| 3 | EtOH: H2O | DPA (10 mol%) | Reflux | 120 | – |
| 4 | Toluene | DPA (10 mol%) | Reflux | 120 | 48 |
| 5 | Acetonitrile | DPA (10 mol%) | Reflux | 120 | – |
| 6 | Ethyl acetate | DPA (10 mol%) | Reflux | 120 | – |
| 7 | Solvent-free | DPA (5 mol%) | 90 | 20 | 45 |
| 8 | Solvent-free | DPA (20 mol%) | 90 | 20 | 90 |
| 9 | Solvent-free | DPA (10 mol%) | 50 | 20 | 45 |
| 10 | Solvent-free | DPA (10 mol%) | 100 | 20 | 85 |
a Isolated yields.
Also the effect of temperature was studied and the results indicated that the best yield was provided at 90 °C (Table 1, entries 1, 9 and 10). At lower temperatures than that, the reaction did not proceed properly and most of the initial substances remained unreacted.
These optimized reaction conditions were then applied on the preparations of 1-amidoalkyl-2-naphthols with a variety of aromatic and aliphatic aldehydes (Table 2). Aromatic aldehydes bearing electron-donating and withdrawing substituents led to good yields of the desired 1-amidoalkyl-2-naphthols (Table 2, entries 1–6). Even hindered polynuclear aromatic aldehydes such as 2-naphthaldehyde, phenantherene-9-carbaldehyde and pyrene-1-carbaldehyde gave good yields under the same condition (Table 2, entries 9–11). In contrast to the previously reported methods in literature [11,19,23], in which aliphatic aldehydes were not transformed to the corresponding 1-amidoalkyl-2-naphtols, also in our study they were converted to the desired product in good yields when mixed with β-naphthol and benzamide in the presence of DPA under solvent-free conditions at 90 °C (Table 2, entries 12 and 13).
The reaction of β-naphthol, amides and aldehydes in solvent-free conditions.
| Entry | R1 | R2 | Product | Time (min) | Yielda (%) | Mp (lit.(°C) |
| 1 | 4-NO2C6H4 | C6H5 | 4a | 20 | 88 | 240 (239–241 [22]) |
| 2 | 3-NO2C6H4 | C6H5 | 4b | 20 | 90 | 241 (240–242 [27]) |
| 3 | C6H5 | C6H5 | 4c | 20 | 90 | 235 (235–237 [24]) |
| 4 | 4-CH3OC6H4 | C6H5 | 4d | 20 | 85 | 196 (197–199 [23]) |
| 5 | 4-(CH3)2CHC6H4 | C6H5 | 4e | 20 | 90 | 210 |
| 6 | 2-BrC6H4 | C6H5 | 4f | 20 | 88 | 229 (228–230 [14]) |
| 7 | C6H5CH2CH2 | C6H5 | 4g | 30 | 80 | 158 |
| 8 | C6H5CH = CH | C6H5 | 4h | 30 | 85 | 234 |
| 9 | 9-Phenanthryl | C6H5 | 4i | 20 | 81 | 251 |
| 10 | 1-Pyrenyl | C6H5 | 4j | 20 | 86 | 246 |
| 11 | 2-Naphtyl | C6H5 | 4k | 20 | 90 | 218 |
| 12 | CH3(CH2)10 | C6H5 | 4l | 30 | 70 | 166 |
| 13 | CH3CH2 | C6H5 | 4m | 30 | 60 | 226 |
| 14 | 9-Anthryl | C6H5 | 4n | 60 | N.R | – |
| 15 | C6H5 | CH3 | 4o | 20 | 88 | 230 (228–230 [11]) |
| 16 | C6H5CH = CH | CH3 | 4p | 20 | 81 | 173 (174–175.5 [23]) |
| 17 | 9-Phenantryl | CH3 | 4q | 20 | 86 | 273 |
| 18 | 2-BrC6H4 | CH3 | 4r | 20 | 88 | 204 |
| 19 | CH3(CH2)10 | CH3 | 4s | 30 | 72 | 110 |
a Isolated yields.
Using acetamide as an aliphatic amide, instead of benzamide, resulted in the corresponding 1-amidoalkyl-2-naphthols in good yields when it was treated with β-naphthol and aromatic or aliphatic aldehydes in the presence of DPA at 90 °C (Table 2, entries 15–19).
For showing efficiency of DPA compared to the reported catalysts in literature, including Lewis acids and BrØnsted acids, a study was designed on the reaction of β-naphthol, acetamide, and benzaldehyde as a model. These data, which are shown in Table 3, revealed that DPA is a better catalyst than most of the conventional catalysts mentioned, with the exception being the protocols that were aided by microwave or ultrasound (Table 3, entry 2 and 10).
A comparison among efficiency of dodecylphosphonic acid (DPA) and some reported acids on the reaction of β–naphthol, benzaldehyde and acetamide.
| Entry | Catalyst | Mole % | Time/yield (%)/condition |
| 1 | Fe(HSO4)3 | 5 | 65 min/83/solvent-free (85 °C) [19] |
| 2 | Fe(HSO4)3 | 5 | 7 min/90/solvent-free/microwave [19] |
| 3 | FeCl3.SiO2 | 0.025 g | 11 min/86/solvent-free (120 °C) [16] |
| 4 | K5CoW12O40.3H2O | 1 | 2 h/90/solvent-free (125 °C) [12] |
| 5 | K-10 clay | 0.1 g | 1.5 h/89/solvent-free (125 °C) [9] |
| 6 | I2 | 5 | 4.5 h/87/solvent-free (125 °C) [11] |
| 7 | Molybdophosphoric Acid | 0.12 g | 3.5 h/94/ethylacetate (65 °C) [23] |
| 8 | PPA-SiO2 | 0.03 g | 5 min/80/solvent-free (120 °C) [21] |
| 9 | PTSA | 10 | 15 h/89/ClCH2CH2Cl (rt) [13] |
| 10 | Sulfamic acid | 50 | 15 min/89/solvent-free/sonication[14] |
| 11 | Sulfamic acid | 50 | 4 h/72/solvent-free (28–30 °C) [14] |
| 12 | [TEBSA][HSO4] | 5 | 10 min/81/solvent-free (120 °C) [18] |
| 13 | ZrOCl2 | 10 | 11 h/79/ClCH2CH2Cl (rt) [24] |
| 14 | Thiamine.HCl | 10 | 4 h/88/EtOH [25] |
| 15 | Cyanuric chloride (TCT) | 10 | 50 min/93/solvent-free (100 °C) |
| 16 | DPA | 10 | 20 min/88/solvent-free (90 °C) |
3 Conclusion
In summary, we have therefore established a catalytic, environmental friendly route for the one-pot preparation of a range of new 1-amidoalkyl-2-naphthols with aromatic and aliphatic aldehydes by using DPA, which is commercially available and easy to produce, that has not been reported before. In addition, this method offers several significant advantages such as: high conversions, easy handling, short reaction times, easy and green work up, cost efficient and versatility. These advantages, in general, highlight this protocol as a useful and attractive methodology, among the methods reported in the literature, for the rapid synthesis of 1-amidoalkyl-2-naphthols as precursors of biological active 1-aminoalkyl-2-naphthols.
4 Experimental
The 1H and 13C NMR spectra were recorded on Bruker Advance DPX FT spectrometer at 250 and 62.9 MHz, respectively, and with TMS as an internal standard. Elemental analyses were performed on Thermofinnigan 1112 flash EA. The synthesized 1-amidoalkyl-2-naphthols were fully characterized with 1H-NMR, 13C-NMR spectroscopy and CHN analysis.
4.1 General procedure for the synthesis of 1-amidoalkyl-2-naphthols with dodecylphosphonic acid (DPA)
A mixture of β-naphthol (1 mmol), aromatic aldehyde (1 mmol) and amide (1.2 mmol) and DPA (0.1 mmol) in 5 mL round bottomed flask, which was equipped with a condenser, was heated at 90 °C. After completion of the reaction (monitored by TLC), the resulted powder was dissolved in 20 mL of hot ethanol. Then 20 mL of water was added to the reaction mixture. The resulting precipitate was filtered. Then the solid product was purified by recrystallization in aqueous ethanol.
4.2 Spectral data for new compounds
N-((2-Hydroxynaphthalen-1-yl) (4-isopropylphenyl) methyl)benzamide (4e, C27H25NO2): white solid, m.p 210 °C, 1H NMR (250 MHz, DMSO-d6): δ = 1.10 (d, 6H), 2.72 (m, 1H), 7.00 (d, 1H), 7.09 (m, 6H), 7.42 (m, 4H), 7.75 (m, 4H), 8.08 (d, 1H), 9.01 (d, 1H), 10.34 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 23.81, 32.97, 49.11, 118.34, 122.61, 126.06, 126.49, 126.69, 127.02, 127.39, 128.13, 128.30, 128.45, 128.55, 129.20, 131.14, 131.34, 132.25, 134.30, 139.28, 146.64, 153.05, 165.50. Anal. Calcd: C, 82.00; H, 6.37; N, 3.54. Found: C, 81.89; H, 6.28; N, 3.48.
N-(1-(2-Hydroxynaphthalen-1-yl)-3-phenylpropyl) benzamide (4 g, C26H23NO2): white solid, m.p 158 °C, 1H NMR (250 MHz, DMSO-d6): δ = 2.04 (m, 2H), 2.74 (t, 2H), 5.98 (d, 1H), 7.13–7.24 (m, 6H), 7.40–7.47 (m, 4H), 7.66–7.82 (m, 4H), 8.02 (d,1H), 8.66 (d, 1H), 10.16 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 32.46, 35.60, 46.70, 118.59, 119.62, 122.38, 125.66, 126.22, 126.96, 127.33, 128.18, 128.26, 128.35, 128.45, 128.52, 131.13, 132.02, 134.63, 141.68, 152.90, 165.55. Anal. Calcd: C, 81.86; H, 6.08; N, 3.67. Found: C, 81.86; H, 5.98; N, 3.52.
(E)-N-(1-(2-Hydroxynaphthalen-1-yl)-3-phenylallyl benzamide (4 h, C26H21NO2): white solid, m.p 234 °C, 1H NMR (250 MHz, DMSO-d6): δ = 7.08 (1H, d), 7.17 (d, 1H), 7.21 (m, 4H), 7.41 (m, 3H), 7.75 (m, 3H), 8.07 (d, 1H), 9.01 (d, 1H), 10.43 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 48.15, 123.51, 127.61, 128.30, 131.27, 132.47, 133.60, 135.81, 137.28, 141.84, 158.24, 165.54. Anal. Calcd: C, 82.30; H, 5.58; N, 3.69. Found: C, 82.27; H, 5.55; N, 3.66.
N-((2-Hydroxynaphthalen-1-yl)(phenanthren-9-yl)methyl) benzamide (4i, C32H23NO2): Pink solid, m.p 251 °C, 1H NMR (250 MHz, DMSO-d6): δ = 7.06 (m, 7H), 7.59 (m, 6H), 7.80 (m, 6H), 8.31 (d, 1H), 8.75 (d, 1H), 8.88 (s, 1H), 9.27 (d, 1H), 10.19 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 48.15, 117.47, 118.80, 122.46, 122.62, 123.53, 124, 126.53, 126.61, 126.89, 127.07, 127.44, 128.19, 128.48, 128.63, 129.69, 130.41, 130.71, 131.23, 134.18, 153.83, 165.37. Anal. Calcd: C, 84.74; H, 5.11; N, 3.09. Found: C, 84.68; H, 5.05; N, 3.04.
N-((2-Hydroxynaphthalen-1-yl)(pyren-1-yl)methyl) benzamide (4j, C34H23NO2): Yellow solid, m.p 246 °C, 1H NMR (250 MHz, DMSO-d6): δ = 7.22 (d, 1H), 7.25–7.46 (m, 5H), 7.80–8.49 (m, 14H), 8.85 (d, 1H), 9.37 (d, 1H), 10.33 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 48.29, 117.96, 122.51, 122.93, 124.46, 125.20, 125.34, 126.18, 127.10, 127.22, 127.40, 127.76, 128.25, 128.50, 130.07, 130.19, 130.68, 134.15, 134.81, 153.68, 165.41. Anal. Calcd: C, 85.51; H, 4.85; N, 2.93. Found: C, 85.49; H, 4.81; N, 2.89.
N-((2-Hydroxynaphthalen-1-yl)(naphthalen-1-yl)methyl) benzamide (4k, C28H21NO2): Pink solid, m.p 218 °C, 1H NMR (250 MHz, DMSO-d6): δ = 7.30 (d, 1H), 7.41–7.48 (m, 7H), 7.76–7.80 (m, 7H), 7.88 (d, 1H), 8.14 (d, 1H), 9.12 (d, 1H), 10.47 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 49.44, 118.14, 118.66, 122.70, 124.37, 125.25, 125.64, 126.09, 127.15, 127.30, 127.64, 127.80, 128.38, 128.48, 128.63, 129.52, 131.45, 131.89, 132.67, 139.52, 153.28, 165.90. Anal. Calcd: C, 83.35; H, 5.25; N, 3.47. Found: C, 83.32; H, 5.19; N, 3.44.
N-(1-(2-Hydroxynaphthalen-1-yl)dodecyl)benzamide (4l, C29H37NO2): white solid, m.p 167 °C, 1H NMR (250 MHz, DMSO-d6): δ = 0.88 (t, 3H), 1.23 (m, 18H), 1.67 (m, 2H), 6.02 (t, 1H), 7.21 (d, 1H), 7.36 (t, 1H), 7.53 (t, 3H), 7.65 (d, 1H), 7.83 (d, 2H), 8.23 (d, 1H), 8.64 (d, 1H), 10.18 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 13.86, 22, 26.22, 28.87, 31.19, 33.76, 46.79, 118.54, 119.78, 122.33, 126.20, 126.84, 128.33, 131.06, 132.07, 134.63, 152.81, 165.29. Anal. Calcd: C, 80.70; H, 8.64; N, 3.25. Found: C, 80.74; H, 8.58; N, 3.24.
N-(1-(2-Hydroxynaphthalen-1-yl)propyl)benzamide (4 m, C20H19NO2): white solid, m.p 226 °C, 1H NMR (250 MHz, DMSO-d6): δ = 0.90 (t, 3H), 1.89 (m, 2H), 5.85 (t, 1H), 7.09 (d, 1H), 7.29 (dd, 1H), 7.43 (m, 4H), 7.66 (d, 1H), 7.75 (m, 3H), 8.18 (d, 1H), 8.61 (d, 1H), 10.08 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 11.35, 26.91, 48.49, 118.57, 119.53, 122.34, 126.22, 126.87, 128.19, 131.06, 132.23, 134.71, 152.85, 165.37. Anal. Calcd: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.65; H, 6.20; N, 4.55.
(E)- N-(1-(2-Hydroxynaphthalen-1-yl)-3-phenylallyl) acetamide (4p, C21H19NO2): white solid, m.p 173 °C, 1H NMR (250 MHz, DMSO-d6): δ = 1.89 (s, 3H), 6.48 (d, 1H), 6.52 (m, 2H), 7.16 (m, 7H), 7.43 (m, 1H), 7.70 (m, 1H), 7.76 (m, 1H), 8.10 (d, 1H), 8.35 (d, 1H), 10.02 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 27.87, 52.53, 123.51, 127.61, 128.30, 131.27, 132.47, 133.60, 135.81, 137.28, 141.84, 158.24, 173.93. Anal. Calcd: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.38; H, 5.98; N, 4.33.
N-(2-Hydroxynaphthalen-1-yl)(phenanthren-9-yl) methyl) acetamide (4q, C27H21NO2): white solid, m.p 273 °C, 1H NMR (250 MHz, DMSO-d6): δ = 1.89 (s, 3H), 7.08 (m, 7H), 7.59 (m, 6H), 7.80 (m, 6H), 8.31 (d, 1H), 8.78 (d, 1H), 8.87 (s, 1H), 9.27 (d, 1H), 10.20 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 28.87, 48.18, 117.47, 118.80, 122.46, 122.62, 123.53, 124, 126.53, 126.61, 126.89, 127.07, 127.44, 128.19, 128.48, 128.63, 129.69, 130.41, 130.71, 131.23, 134.18, 154.83, 173.17. Anal. Calcd: C, 82.84; H, 5.41; N, 3.58. Found: C, 82.78; H, 5.34; N, 3.42.
N-((2-Bromophenyl)(2-hydroxynaphthalen-1-yl)methyl)acetamide (4r, C19H16BrNO2): white solid, m.p. 204 °C, 1HNMR (250 MHz, DMSO-d6): δ = 1.87 (s, 3H), 6.91 (d, 1H), 7.06–7.29 (m, 5H), 7.47 (t, 2H), 7.69 (m, 2H), 7.92 (d, 1H), 8.54 (d, 1H), 9.73 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 22.28, 49.84, 116.95, 118.57, 122.18, 122.69, 122.78, 126.21, 126.82, 128.20, 128.42, 128.50, 129.31, 130.15, 132.49, 132.89, 141.26, 153.59, 168.42. Anal. Calcd: C, 61.64; H, 4.36; N, 3.78. Found: C, 61.58; H, 4.28; N, 3.74.
N-(1-(2-Hydroxynaphthalen-1-yl)dodecyl)acetamide (4 s, C24H35NO2): white solid, m.p. 110 °C, 1HNMR (250 MHz, DMSO-d6): δ = 0.79 (t, 3H), 1.15 (m, 18H), 1.80 (s, 3H), 1.91 (m, 2H), 5.68 (t, 1H), 7.11(d, 1H), 7.20 (m, 1H), 7.37 (m, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 7.98 (d, 1H), 8.00 (d, 1H), 9.82 (s, 1H). 13C NMR (62 MHz, DMSO-d6): δ = 13.87, 22.02, 22.67, 26.23, 28.62, 28.77, 28.90, 31.22, 33.56, 45.73, 118.49, 119.74, 122.13, 122.47, 125.98, 128.14, 128.24, 128.41, 132.23, 152.92, 168.36. Anal. Calcd: C, 78.00; H, 9.55; N, 3.79. Found: C, 77.94; H, 9.48; N, 3.75.
Acknowledgement
We gratefully acknowledge the support of this work by Shiraz University Research Council.