Research Letter | Open Access
Rukhsana I. Kureshy, Irshad Ahmad, Kavita Pathak, N. H. Khan, Sayed H. R. Abdi, H. C. Bajaj, Eringathodi Suresh, "Solvent-Free Microwave Synthesis of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides", Organic Chemistry International, vol. 2009, Article ID 109717, 5 pages, 2009. https://doi.org/10.1155/2009/109717
Solvent-Free Microwave Synthesis of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides
The ring opening reaction of aryloxyepoxides with isopropylamine under solvent-free microwave irradiation produced therapeutically useful -blockers-aryloxypropanolamines in excellent yield (up to 98%) in 10 minutes which is considerably less than the time taken in classical heating ( hours).
Aryloxypropanolamines are important class of β-adrenergic blocking agents (β-blockers) and extensively used in medicinal chemistry for the treatment of hypertension, angina pectoris, glaucoma, anxiety, and obesity [1, 2]. The oxirane ring  due to its inherent polarity and strain is susceptible to the attack of nucleophiles to give propan-2-ol 3 (Scheme 1), which is known for their β-adrenoceptor antagonist activity. One of the most straightforward synthetic approaches for the preparation of β–blockers involves the heating of epoxides with an excess of amines at elevated temperature [4–7]. In recent years, various metal salts as catalysts have been reported for epoxide ring opening reaction with amine and amine derivatives giving good-to-poor regioselectivity [8–12].
Microwave-assisted organic synthesis is currently gaining ground in synthetic chemistry largely due to the dramatic reduction in reaction time (from days or hours to minutes or even seconds) and advancement in the need-based design of microwave reactors [13, 14]. As a part of our ongoing research in ring opening of epoxides with amines [15–19], herein we report solvent-free microwave-assisted synthesis of aryloxypropanolamines by ring opening of aryloxyepoxides with isopropylamine. Excellent yields (up to 98%) of aryloxypropanolamines were achieved in shorter time (10 minutes) with substantially reduced quantity of amine as compared to method used under classical thermal conditions . Quanitiative yields of 2-aminoalcohols have been reported earlier in the ring opening of epoxides with aliphatic and aromatic amines using montmorillonite K-10, metal salts and metal salts supported on montmorillonite K-10 as catalyst [21–23].
2. Results and Discussion
The ring opening of 3-(1-naphthoxy)-1,2-epoxy propane 1a with isopropylamine 2 in solvent-free condition was used as a representative reaction to see the effect of strength of microwave wattage and duration of its exposure on % yield of aryloxypropanolamine. Data from Table 1 shows that with an increase in microwave output power as well as reaction time, there is an increase in the formation of the product (Table 1, entries 2–9). Best result (yield, 98%) was achieved in 10 minutes at 400 W of microwave output (Table 1, entry 9) at 50°C temperature hence these conditions were used for our rest of experiments with different aryloxyepoxides 1a–f to give excellent yield (up to 98%) in 10 minutes (Figure 1). Main advantage of the present microwave-assisted epoxide ring opening protocol lies in substantial decrease in the quantity of isopropylamine (1.5 equivalent) as compared to the classical approach where the amine was used in large excess (10–15 equivalents at rt to reflux temperature)with longer duration of reaction time 4-5 hours.
Isolated yield after chromatographic separation.|
(b) Reaction carried out for 16 hours.
The regioselectivity of the product aryloxypropanolamines was confirmed by NMR analysis of the crude product. Single crystals X-ray analysis of representative products 3c, 3d, and 3f (Figure 1, entries 3, 4, 6) further confirmed that the desired regioisomers (Figure 2) were obtained under our microwave-assisted solvent-free epoxide ring opening reaction procedure.
1H and 13C NMR spectra were recorded on Bruker F113V. FTIR spectra were recorded on Perkin Elmer Spectrum GX spectrophotometer in KBr window. Microanalysis was done on a Perkin Elmer model 2400 CHNS analyzer. High-resolution mass spectra were obtained with an LC-MS (Q-TOF) LC (Waters), MS (Micromass) instruments. For the product purification, flash chromatography was performed using silica gel 60–200 mesh. ETHOS 1600 Advanced Microwave Lab station was used to conduct experiment under microwave irradiation. CCDC-612074 to-612077 contains the supplementary crystallographic data in CIF format for all the three compounds 3c, 3d, and 3f. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/datarequest/cif/.
The aryloxyepoxides were synthesized by the modified reported procedure [3d] given as supplementary materials.
3.1. Procedure for The Preparation of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides under Solvent-Free Mw Irradiation
Aryloxyepoxides 1a–f (5 mmol) and isopropylamine 2 (7.5 mmol) were taken in a closed Teflon reactor. The reactor was placed in a microwave oven at a selected power (400 W) for 10 minutes. After cooling the reactor to room temperature, excess amine was removed by distillation under reduced pressure. The purification of the reaction products was carried out by flash chromatography on silica gel using CH2Cl2:MeOH (95:5), dried over anhydrous Na2SO4. All products 3a–f were characterized by 1H and 13C NMR spectroscopy and data is given as follows.
3.1.1. 1-[(1-Methylethyl) Amino]-3-(1-Naphthoxy)-2-Propanol (propranolol) (3a)
Yield 1.27 g (98%); mp: 95–97°C; IR (KBr): ν = 765 (CH wagging, NH bending), 1029 (CN streching), 1582 (aromatic CC stretching), 2835 (CH stretch), 3271 (OH stretch) cm−1; 1H NMR (200 MHz, CDCl3): δ 8.22–8.27 (m, 1H, 8-CH), 7.75–7.80 (m, 1H, 11-CH), 7.29–7.48 (m, 4H, 7, 9, 10-, and 12-CH), 6.77 (d, 1H, J = 7.4 Hz, 6-CH), 4.07–4.18 (m, 3H, OH, and 3-CH2), 2.75–3.0 (m, 5H, NH, 1-CH2, 2-CH, 2′-CH), 1.07 (d, 6H, J = 6.2 Hz, 3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.7 (2 × 3′-CH3), 49.7 (2′-CH), 50.4 (1-CH2), 69.3 (2-CH), 71.6 (3-CH2), 105.8 (6-CH), 121.3 (12-CH), 122.6 (9-CH), 126.0 (11-CH), 126.4 (10-CH), 126.6 (8-CH), 127.1 (7a-c), 128.3(11a-c), 135.3 (7-CH), (155.2 5-C); LC-MS m/z 260 [M + H]; analytical calculation for C16H21NO2: C, 74.10; H, 8.16; N, 5.40 found C, 74.0; H, 8.10; N, 5.30.
3.1.2. 1-[4-(2-Methoxyethyl) Phenoxy]-3-[(1-Methylethyl) Amino]-2-Propanol (metoprolol) (3b)
Yield 1.249 g (97%); mp: 96–98°C; IR (KBr): ν = 828(CH wagging, NH bending), 1113(CN streching), 1512(aromatic CC stretching), 2869(CH stretch), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J = 8.2 Hz, 7- and 9-CH), 6.79 (d, 2H, J = 8.2 Hz, 6- and 10-CH), 4.14 (m, 2H, 3-CH2), 3.90 (m, 3H, OH, NH, and 2′-CH), 3.53 (t, 2H, J = 7.0 Hz, 8a-CH2), 3.32 (s, 3H, 8d-CH3), 2.79 (t, 2H, J = 7.0 Hz, 8b-CH2), 2.76 (m, 3H, 2-CH, 1-CH2), 1.05 (d, 6H, J = 6.2 Hz, 2 × 3′-CH3);13 C NMR (50 MHz, CDCl3): δ 23.2 (2 × 3′-CH3), 35.6 (8a-CH2), 49.2 (2′-CH), 50.1(1-CH2), 58.9 (8d-CH3), 68.7 (2-CH), 71.3 (3-CH2), 74.2 (8b-CH2), 114.8 (6 and 10-CH), 130.1 (7- and 9-CH), 131.7 (8-C), 157.6 (5-C); LC-MS m/z 269; analytical calculation for C15H25NO3: C, 67.38; H, 9.42.; N, 5.24 found C, 67.12; H, 9.23; N, 5.12.
3.1.3. 1-[(1-Methylethyl) Amino]-3-(1-Phenoxy)-2-Propanol (3c)
Yield 0.993 g (95%); mp: 75–78°C; IR (KBr): ν = 802(CH wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH stretch), 3308(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.25 (m, 2H, 7- and 9-CH), 6.91 (m, 3H, 6-, 8-, and 10-CH), 4.11 (m, 3H, 3-CH2, and 2-CH), 3.94 (m, 1H, 2′-CH), 3.56 (bs, 1H, OH), (m, 3H, NH, 1-CH2), 1.07 (d, 6H, J = 6.4 Hz, 2 × 3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.2 (2 × 3′-CH3), 49.5 (2′-CH), 50.1 (1-CH2), 68.8 (2-CH), 71.2 (3-CH2), 115.1 (6- and 10-CH), 121.5 (8-CH), 130.0 (7- and 9-CH), 159.2 (5-C); LC-MS m/z 211; analytical calculation for C12H19NO2: C, 68.87; H, 9.15; N, 6.69 found C, 68.58; H, 9.00; N, 6.59.
3.1.4. 1-[(1-Methylethyl) Amino]-3-(4-Methylphenoxy)-2-Propanol (3d)
Yield 1.048 g (94%); mp: 75–77°C; IR (KBr): ν = 803(CH wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH stretching), 3308 (OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J = 8.4 Hz, 7- and 9-CH), 6.81 (d, 2H, J = 8.4 Hz, 6- and 10-CH), 4.08 (m, 2H, 3-CH2), 3.92 (m, 2H, OH, and 2-CH), 3.28 (bs, 1H, NH), (m, 3H, 1-CH2, 2- and 2′-CH), 2.27 (s, 3H, 8a-CH3), 1.10 (d, 6H, J = 6.2 Hz, 2 × 3′-CH3); 13C NMR (50 MHz, CDCl3): δ 21.0 (8a-CH3), 23.4 (2 × 3′-CH3), 49.5 (2′-CH), 50.1(1-CH2), 69.0(2-CH), 71.4 (3-CH2), 115.0 (6- and 10-CH), 130.5 (8-C), 130.7 (7- and 9-CH),157.2 (5-C); LC-MS m/z 224; analytical calculation for C13H21NO2: C, 69.92; H, 9.48; N, 6.27 found C, 69.86; H, 9.38; N, 6.20.
3.1.5. 1-[(1-Methylethyl) Amino]-3-(4-Cynophenoxy)-2-Propanol (3e)
Yield 1.123 g (96%); mp: 108–110°C; IR (KBr): ν = 839(CH wagging, NH bending), 1173(CN streching), 1508(aromatic CC stretching), 2932(CH stretching), 3504(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.58 (d, 2H, J = 8.2, 7- and 9-CH), 7.01 (d, 2H, J = 8.2 Hz, 6- and 10-CH), 4.22 (m, 2H, 3-CH2), 4.02 (bs, 1H, OH), 3.30 (bs, 1H, NH), (m, 4H, 1-CH2, 2- and 2′-CH), 1.08 (d, 6H, J = 6.2 Hz, 2 × 3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.3 (2 × 3′-CH3), 49.4 (2′-CH), 49.7 (1-CH2), 68.6 (2-CH), 71.5 (3-CH2), 104.5 (8-C), 115.8 (6- and 10-CH), 118.0 (8a-CN), 134.4 (7- and 9-CH), 162.5(5-C); LC-MS m/z 235; analytical calculation for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96 found C, 66.51; H, 7.60; N, 11.88.
3.1.6. 1-[(1-Methylethyl) Amino]-3-(4-Methoxyphenoxy)-2-Propanol (3f)
Yield 1.123 g (94%); mp: 80–82°C; IR (in KBr): ν = 830(CH wagging, NH bending), 1115(CN streching), 1525(aromatic CC stretching), 2928(CH stretching), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 6.8 (s, 4H, 6, 7, 9-, and 10-CH), 4.08 (m, 2H, OH, 3-CH2), (m, 1H, 2-CH), 3.73 (s, 3H, 8b-CH3), (bs, 1H, NH), (m, 4H, 1-CH2, 2- and 2′-CH), 1.06 (d, 6H, J = 6.2 Hz, 2 × 3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.4 (2 × 3′-CH3), 49.4 (2′-CH), 50.2 (1-CH2), 56.1 (8b-CH3), 69.1(2-CH), 72.1(3-CH2), 115.2 (6- and 10-CH), 116.0 (7- and 9-CH), 153.5 (5-C), 154.5 (8-C); LC-MS m/z 240 [M + H]+; analytical calculation for C13H21NO3: C, 65.25; H, 8.84; N, 5.85 found C, 65.20; H, 8.69; N, 5.78.
R. I. Kureshy is thankful to DST and CSIR Net Work Project on Catalysis.
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