A simple total synthesis of the quinoline alkaloid, orixiarine was achieved from N-methylaniline and 1-bromo-3-methyl-2-butanone.
In the recent past, a hemiterpenoid quinoline alkaloid, named orixiarine (Graph 1) was isolated from Skimmia laureola (Rutaceae), which is an aromatic gregarious evergreen shrub found in Western Himalayas and Kashmir [1,2]. The plant is used for the treatment of smallpox [
Earlier, our program of synthesis of quinoline alkaloids, in particular the hemiterpenoid quinoline alkaloid [
Thin layer chromatography was used to access the reactions and the purity of products. Melting Points were determined on a Boetius Microheating
Preparation of 4-hydroxy-1-methylquinolin-2-one (3): 4-Hydroxy-1-methylquinolin-2-one (3) was prepared by reported procedure [8,9].
Preparation of 1-bromo-3-methyl-2-butanone (4): A solution of 3-methyl-2-butanone (8.6 g, 10.5 mL, 0.01 mol) and 60 mL of anhydrous methanol was stirred and cooled in an ice-salt bath from 0˚C - 5˚C and 5.46 mL (0.01 mol) of bromine was added in a rapid steady stream from the dropping funnel. During this time, the temperature was allowed to rise but was not permitted to exceed 10˚C. The reaction temperature was then maintained at 10˚C throughout the remaining reaction time. The red colour of the solution faded gradually in about 45 min, 30 mL of water was then added and the mixture was stirred at room temperature overnight. To this solution,
Graph 1. Orixiarine.
Scheme 1. Reagents & Conditions: (a) Ph2O, reflux, 5 h (85%); (b) 4% NaOH, stirring, 70˚C - 80˚C (85%); (c) MPTSA, DMF, K2CO3, RT, stirring, 8 h (80%)
90 mL of water was added and the mixture was washed with four little portion of ether. The ether layers were combined and washed with 20 mL of aq 10% potassium carbonate and then twice with 20 mL portions of water. The ether layer was dried for 15 min over a few gram of sodium sulfate and the ether was evaporated to get 1-bromo-3-methyl-2-butanone. (yield: 10.0 g, 6.8 mL, bp 83˚C - 85˚C) [
Preparation of 4-hydroxy-1-methyl-3-(3’-methyl-2’- oxobutyl)-quinolin-2-one (5): 4-Hydroxy-1-methylquinolin-2-one (3) (0.700 g, 0.004 mol) and 1-bromo-3- methyl-2 butanone (4) (0.66 mL, 0.004 mol) was stirred in 4% sodium hydroxide solution at 70˚C - 80˚C for 7 - 8 hr. The solid separated from the reaction mixture was filtered, dried and separated by column chromatography using pet. ether-ethyl acetate (95:5) which gave two products. Specific details on each product (5 and 6) are as follows.
Data for 5: mp 234˚C; yield 85%; IR (KBr, gmax) 1618, 1680, 3350 cm−1. 1H-NMR (CDCl3, 400 MHz) d 1.0 (d, 3H, CH3, J = 6.02 Hz), d 1.2 (d, 3H, CH3, 6.02 Hz), d 2.8 (m, 1H, -CH-(CH3)2), d 3.6 (s, 3H, N-CH3), d 3.8 (s, 2H, CH2), d 7.28 (dd, 1H, C6-H, J = 7.84 Hz), d 7.7 (d, 1H, C5-H, J = 6.02 Hz), d 7.9 (dd, 1H, C7-H, J = 7.84 Hz), d 8.15 (d, 1H, C8-H, J = 6.02 Hz), d 12.5 (s, 1H, -OH). 13C NMR (CDCl3, 500 MHz): 207, 174.3, 162.1, 161.8, 141, 135, 126, 122.8, 122.4, 115, 114, 106, 42.3, 31.6, 30, 29. MS [70 eV, m/z (M+)] 259; Anal. Calcd for C15H17NO3:C, 69.46; H, 6.61; N, 5.41 Found: C, 69.41; H, 6.55; N, 5.34.
Data for 6: mp 170˚C; yield 7%; IR (KBr, gmax) 1672, 1635, 1610 cm−1. 1H-NMR (CDCl3, 400 MHz) d 1.00 (6H, m), 1.2 (6H, m), 3.6 (2H, h, J = 7.37 Hz), 3.4 (4H, s), 3.4 (3H, s), 7.25 (1H, t, J = 7.64 Hz), 7.6 (1H, d, J = 8.22 Hz), 7.8 (1H, t, J = 7.60 Hz), 8.00 (1H, d, J = 7.64 Hz). Anal. Calcd for C20H25NO4:C, 69.95; H, 7.34; N, 4.08 Found: C, 69.45; H, 7.66; N, 4.14.
Synthesis of 4-methoxy-1-methyl-3-(3’-methyl-2’- oxobutyl)-quinolin-2-one [Orixiarine] (1) 4-Hydroxy- 1-methyl-3-(3’-methyl-2’-oxobutyl)-quinolin-2-one (5)
(0.259 g, 0.001 mol) was stirred with p-methyltoluenesulphonate (0.186 mL. 0.001 mol) and K2CO3 (250 mg) at room temperature for 6 - 8 hr. After completion of reaction, monitored by tlc, it was poured into crushed ice and allowed to stand overnight. The mixture was then extracted using ethyl acetate and the extract was dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (pet. ether/EtOAc) yielded the product 1 as brownish powder. Yield 80%; mp. 173˚C - 178˚C; IR (KBr, υmax) −1665, 1630 cm−1 1H NMR (CDCl3) [d ppm] −1.2 (d, 3H, CH3, J = 6.45 Hz), 1.31 (d, 3H, CH3, J = 6.45 Hz), 2.8 (m, 1H, CH-(CH3)2), 3.6 (s, 3H, N-CH3), 3.7 (s, 3H, OCH3), 3.9 (s, 2H, CH2), 7.28 (dd, 1H, C6-H, J = 5.82 Hz), 7.35 (d, 1H, C5-H, J = 5.34 Hz), 7.64 (dd, 1H, C7-H, J = 5.82 Hz), 8.0 (d, 1H, C8-H, J = 5.34 Hz). 13C NMR (CDCl3, 500 MHz)-210.65, 168.91, 162.3, 140.6, 138, 123,122.6,116, 115, 113, 52.25, 40.18, 38, 31.58, 30.4, and 17.48. MS (m/z)-273. CHN Analysis (%)-Calcd: C 70.31, H 7.01, N 5.12. (C16H19NO3) Found: C 70.18, H 6.89, N 5.21.
In conclusion, a simple synthesis of the hemiterpenoid quinoline alkaloid, orixiarine was achieved and characterized. This paves the path for further exploration of the compound towards various potential biological studies.
TS thanks CSIR, New Delhi for the award of Senior Research Fellowship, PSM thanks CSIR-New Delhi for financial assistance (CSIR-Project). Authors thank SIF, IISc, Bangalore and IICT, Hyderabad for providing the spectral and analytical data.