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Research Article Volume 1 Issue 5
Synthesis of 5-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid
Kimberly Chinea, Dioni A Arrieche, Ajoy K Banerjee
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Venezuelan Institute of Scientific Research (IVIC), Venezuela
Correspondence: Ajoy K Banerjee, Centro de Química, Venezuelan Institute of Scientific Research, Apartado-21827, Caracas-1020A, Venezuela, Tel +5802125041324, Fax +5802125041350
Received: August 26, 2017 | Published: September 26, 2017
Citation: Chinea K, Arrieche DA, Banerjee AK. Synthesis of 5-methoxy-1, 2, 3, 4- tetrahydro -2-naphthoic acid. MOJ Biorg Org Chem. 2017;1(5):145-146. DOI: 10.15406/mojboc.2017.01.00027
Abstract
A four-step synthesis of 5-methoxy-1, 2, 3, 4-tetrahydro-2-naphthoic acid 5 from 5-methoxy-2-tetralone 1 has been developed. The acid 5 has been considered to be a potential intermediate for optically active 11-deoxyanthracycline antibiotics.
Keywords: 2-naphthoic acid, 5-methoxy-β-tetralone, trimethylsilylcyanide, catalytic hydrogenation
Introduction
The route developed1 for the title acid 5 from 2-naphthoic acid in five steps (bromination, esterification, methoxylation, alkaline hydrolysis, Birch reduction followed by acid hydrolysis) afforded with an overall yield of 33%. Johnson & Mander2 have also reported the same acid from 5-methoxy-1-tetralone in three steps (carboxylation, hydrogenolysis, alkaline hydrolysis) in high overall yield. In this procedure the first two steps were not purified and thus it is very difficult to say the exact overall yield of the pure acid. Moreover the hydrogenolysis experiment was achieved by overnight hydrogenation at high pressure. The process is not recommendable because if the flow of hydrogen is not controlled, it may cause explosion.
The acid 5 was converted by the same authors1 to amine as hydrogen chloride salt 6. The α-agonist, α-the androgenic, antifungal and dopamine-like activity of the aminotetralin and its N-alkyl substituents are well documented.3-7 The interesting biological activities of aminotetralin prompted us to develop an easy route to obtain the acid 5. The details of our efforts are described in present article (Scheme 1).
Scheme 1 Reagents and Conditions: (i) TMSCN, C6H6ZNI2, rt, 12h; (ii) NaOH-H2O (50%); (iii) H2, Pd-C (10%), EtOH.
Results and discussion
Tetralone 1 on treatment with trimethylsilyl cyanide8 in benzene in presence of zinc iodide as catalyst yielded the α,β - unsaturated nitrile 2 in 91% yield which is superior compared to the yield (67%) reported.9 The absence of the nitrile 3 was clearly indicated in its 1H NMR spectrum. Heating the nitrile 2 under reflux in microwave oven for 2 hours with an aqueous solution of potassium hydroxide (50% KOH in water) yielded the acid 4 in 96% yield (overall yield 87%) whose alternative synthesis10 from 5-methoxy-1-tetralone in four steps (carboxylation, metal hydride reduction, dehydration and alkaline hydrolysis) was reported in an overall yield of 44%. The acid 4 has been considered to be a potential intermediate for optically active 11-deoxyanthracycline antibiotics.10 The catalytic hydrogenation over Pd/C (10%) in absolute ethanol yielded the acid 5 in 99% yield whose spectroscopic data confirmed the structure assigned. The overall yield of the acid 5 was 87% which is higher than that published1 yield (33%).
Experimental
Unless otherwise stated all melting points are uncorrected and were determined on an Electrothermal melting point apparatus. Infrared (IR) spectra were recorded on a Nicolet-Fourier Transform (FT) instrument and NMR (1H and 13C) spectra were determined on a Bruker AM-300 spectrometer in CDCl3. Chemical shifts (d) are expressed in ppm and multiplicity is defined as s (singlet), d (doublet), t (triplet) or m (multiplet) . Mass spectra (MS) were determined on a Dupont 21-492B. Column chromatography was carried out on silica gel 60 (Merck). Thin layer chromatography (TLC) plates were coated with silica gel and the spots were visualized using ultraviolet light. All organic solvents were dried over anhydrous MgSO4 and solvents were evaporated in vacuo. Microwave irradiations were carried out using a CEM Discovery Labmate microwave oven (2.45 GHZ, 300W), using flask (100 mL) made of Pyrex glass (No 4320), size 24/40 mm. Oberon chemically resistant safety goggles (Aldrich Chemical Company) were utilized for carrying out experiments with microwave irradiations and reactions with trimethylsilyl cyanide were carried out in well-ventilated hood using appropriate aprons and hand gloves. Elemental analyses were performed on a Carlo-Erba 1108 Elemental Analyser.
5-Methoxy-2-cyano-3, 4-dihydronaphthalrne (2)
To a solution of the tetralone 1 (0.51 g, 2.84 mmol) in dry benzene (20 mL) was added zinc iodide (40 mg, 0.12mmol) and trimethylsilyl cyanide (0.5 mL, 4.3 mmol) and stirred at room temperature for 12 hours under nitrogen atmosphere. The progress of the reaction was monitored by TLC. To the resulting solution was added pyridine (3 mL) and phosphorous oxychloride (0.8 mL, 8.5 mmol) and the mixture was heated under reflux for 8 hours. The dark solution was cooled, poured into cold hydrochloric acid (10%) and extracted with ether (3 x 10 mL). The organic extracts were washed with brine, dried, evaporated and chromatographed (hexane: ethyl acetate; 6:4) to obtain the nitrile 2 (481 mg, 91%), as a colorless solid; Rf 0.27 (hexane: ether 7:3), m.p.42-43oC (from hexane) (lit.9 43-44oC); IR (cm-1): 2214 (CN); MS (m/z):185 (M+), 170 (M+- Me) and 154 (M+- OMe); 1H NMR (300 MHz) d(ppm): 7.15-7.17 (t, 1H, J=8.25 Hz), 7.12- 7.13 (t, 1H, ArH-7, J= 1.62 Hz), 6.86-6.88 (d, 1H, J=7.51 Hz), 6.75-6.67 (d, 1H, J=7.51 Hz), 3.82 (s, 3H, OMe), 2.84-2.87 (t, 2H, J= 8.81 Hz ), 2.45- 2.52 (t, 2H, J= 8.81 Hz); 13C NMR (75 MHz) d(ppm): 156.2 (C-5), 141.6 (C-1), 132.1 (C-9), 127.4 (C-7), 123.3 (C-10),120.5 (C-8), 119.7 (CN), 112.7 (C-6), 109.8(C-2), 55.6(OMe) ,24.2 (C-3), 19.1 (C-4). Anal. Calcd. for C12H11NO: C, 77.83; H, 5.94. Found: C, 78.02; H, 6.06.
5-Methoxy-3,4- dihydro-2-naphthoic acid (4)
A mixture of the nitrile 2 (201 mg, 1.08 mmol) and an aqueous solution of potassium hydroxide (15 mL, 50%) was heated under reflux in a microwave oven at 60W for 2 hours at 120oC. The reaction mixture was cooled, diluted with water, neutralized with aqueous HCl (10%) and extracted with ether (2 x 10 mL). The organic extracts were washed, dried and evaporated. The resulting solid on crystallization afforded the acid 4 (212 mg, 96%), m.p 172-1740C (from ether) (lit.10 m.p.177-179oC), Rf 0.31(ether), nmax (cm-1):1725 (CO); MS (m/e) 204 (M+), 159 (M+-COOH) and 144 (M+- COOH- Me); 1H NMR (300 MHz) d(ppm): 7.61 (s, 1H, H-1), 7.14-7.21 (m, 1H, H-7), 6.88-6.83 (d, 2H, J= 8.1 Hz, H-6, H-8), 3.83 (s, 2H, OMe), 2.91-2.85 (t, 2H, J= 8.7 Hz), 2.61 -2.55 (t, 2H, J= 8.8 Hz) (C-3, C-4); 13C NMR (75 MHz) d(ppm): 175.25 (CO), 156.27 (C-5), 138.71 (C-1), 133.28 ( C-9), 128.43 (C-2), 127.08 (C-7), 125.09 (C-10), 112.42 (C-6), 55.68 (OMe), 21.31 (C-3), 19.90 (C-4). Anal. Calcd for C12H12O3: C, 70.58; H, 5.92. Found: C, 70.74; H, 6.04.
5-Methoxy-1, 2, 3, 4-tetrahydro-2-naphthoic acid (5)
The acid 4 (208 mg,) in absolute ethanol (20 mL) was hydrogenated in presence of Pd-C (2 mg, 10%) at room temperature for 24 hours at atmospheric pressure. Removal of the catalyst by filtration and evaporation yielded the acid 5 (221 mg, 99%), white crystals, Rf 0.91 (ether), m.p. 148-150oC (from CHCl3). (lit.1 147-149oC). nmax(cm-1): 3548 (OH), 1710 (CO); MS (m/z): 206 (M+), 160 (M+1- COOH); 1H NMR (300 MHz) d(ppm): 7.11 -7.107 (t, 1H, J= 7.8 Hz, ArH-7), 6.72-6.71 (d, 1H, J=7.7 Hz, ArH-8), 6.66-6.65 (d, 1H, J= 8.1 Hz, ArH-6), 3.79 (s, 3H, OMe), 3.01- 2.89 (m, 3H), 2.76-2.71 (m, 1H), 2.61 - 2.54 (ddd, J= 17.4 Hz, J= 10.9 Hz, J =6.2 Hz, 1H, H-2), 2.28-2.25 (m, 1H), 1.85 -1.77 (m, 1H); 13C NMR (75 MHz) d(ppm): 182.5 (CO), 157.3 (C-5), 136.2 (C-9), 126.5 (C-7), 124.8 (C-10), 121.4 (C-8), 107.5 (C-6), 55.4 (OMe), 39.7 (C-2), 31.7 (C-1), 25.6 (C-3), 22.6 (C-4). Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.07; H, 6.96.
Conclusion
In conclusion, a very convenient approach for the synthesis of the acid 5 has been developed. To the best of our knowledge this is the first report of the acid 5 with a high overall yield. The starting material is commercially available. The present method can be utilized in the synthesis of acid 5 in gram quantities.
Acknowledgements
Financial support from our institute is gratefully acknowledged.
Conflict of interest
The author declares no conflict of interest.
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