A synthesis of orixiarine

Article abstract of DOI:10.3987/com-01-9413

A synthesis of the quinoline alkaloid, orixiarine was achieved starting from N-methylaniline and isopropyl methyl ketone.

Full text of DOI:10.3987/com-01-9413

HETEROCYCLES, Vol. 57, No. 2, 2002, pp. 357-360, Received, 3rd December, 2001
A SYNTHESIS OF ORIXIARINE
Raju Nandha Kumar, Senniappan Thamarai selvi, Thangaraj Suresh, and
Palathurai Subramaniam Mohan*
Department of Chemistry, Bharathiar University, Coimbatore 641 046,
Tamil Nadu, India
E-mail: ps_mohan_in@yahoo.com
Fax: +91-422-422387
Abstract – A synthesis of the quinoline alkaloid, orixiarine was achieved starting
from N-methylaniline and isopropyl methyl ketone.
A hemiterpenoid quinoline alkaloid, named orixiarine was recently isolated in 1998 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.3
OCH3
O
O
N
CH3
1
Herein we report our approach resulting in a synthesis of orixiarine (1). As shown in the Scheme 1, the
synthesis of 1 was realized through, a five-step procedure based on condensation reactions.
As the first step, 1-bromo-3-methyl-2-butanone (3) was obtained by bromination of isopropyl methyl ketone (2)
and on further treatment with sodium methoxide and diethyl malonate, the bromo compound was converted
to diethyl 2’-oxoisopentylmalonate (4) in moderate yields.4
Adapting the general method of the synthesis of 2,4-dihydroxyquinoline5 the compound (4) was reacted
with N-methyl substituted anilines. Ring closure6 by thermal cyclization of the resulting dianilide compound
(5) in refluxing diphenyl ether for 1 h gave 1-methyl-3-(3-methyl-2-oxobutyl)-4-hydroxy-2-quinolinone (6).
Reaction of 6 with phosphorous oxychloride under reflux conditions7,8 for 3 h led to conversion of 6 to
its chloro derivative (7) in 90% yield. Finally on treatment with sodium methoxide and after analysis
1
13
the H-NMR and C-NMR spectra of the methoxy product (1) have been found identical with that isolated
from Skimmia laureola.1

Scheme 1
O
O
O
Br
COOC2H5
COOC 2H5
i
ii
2
3
4
iii
NH
CH3
5
Cl
OH
iv
O
O
O
N
O
N
CH3
CH3
7
6
v
OCH3
O
O
N
CH3
1
(i) Br2, CH3OH, rt, stirring, 61 % (ii) CH2(COOC2H5)2, Na, CH3OH, 80 o C, 3 h, 70 %
(iii) Ph2O, NMA, reflux, 1 h, 65 % (iv) POCl3, reflux, 3 h, 90 % (v) Na, CH3OH,
reflux, 2.5 h, 80 %.
Thus, we have developed a facile route for the synthesis of the terpenoid quinoline alkaloid, orixiarine in
good yield, which could pave a path for its biological evaluation.
EXPERIMENTAL
TLC was used to access the reactions and purity of products. mps were determined on a Boetius
Microheating Table and Mettler-FP5 Melting apparatus and were uncorrected. IR spectra were recorded in
Shimadzu – 8201-FT instrument in KBr pellets and only noteworthy absorption levels (reciprocal
centimeter) are listed. 1H-NMR spectra were recorded in a AMX-400 MHz spectrometer in CDCl3 solution;
chemical shifts are expressed in ppm (δ) relative TMS, coupling constants (J) in Hz. Satisfactory
microanalyses were obtained on Carlo Erba 1106 and Perkin Elmer models 240 CHN analyzer. Mass
spectra were recorded on a Jeol – 300 mass spectrometer.
Diethyl 2’-oxoisopentylmalonate (4): Sodium methoxide, prepared from sodium (1.15 g, 0.05 mol) and 20
mL of dry methanol was added to diethyl malonate (7.6 mL, 0.05 mol) during 30 min with continuos
stirring. After all diethyl malonate had been introduced, the mixture was heated on a water bath for 15 min
and allowed to cool. 1-Bromo-3-methyl-2-butanone (3) (5.6 mL, 0.05 mol) was then added over a period of
10 min and kept on a water bath for 3 h for the completion of the reaction. Besides distilling off the
methanol, the residue was diluted with water and extracted with ether. The ether extract dried over

anhydrous sodium sulfate was filtered and concentrated to give diethyl 2’-oxoisopentylmalonate (4) (yield
(3.9 mL, 70 %)). bp 175-178 o C. IR (KBr, γmax) 2980, 1760, 1270 cm-1. 1H-NMR (CDCl3, 400 MHz) δ 1.10 –
1.45 (m, 12H, 4 CH3), δ 2.67 (m, 1H, -CH-(CH3)2), δ 3.15 (d, 2H, -CH2-CH, J = 7.58 Hz), δ 3.39 (t, 1H, CH-
CH2), δ 4.28 (m, 4H, 2-O-CH2-CH3). MS [70 eV, m/z (M+)] 244. Anal. Calcd for C11H18O5: C, 59.05; H, 8.16.
Found: C, 59.01; H, 8.19.
1-Methyl-3-(3-methyl-2-oxobutyl)-4-hydroxy-2-quinolinone (6): A solution of N-methylaniline (5) (1.10 mL,
0.01 mol) and diethyl 2’-oxoisopentylmalonate (4) (2.3 mL, 0.01 mol) in 10 mL of diphenyl ether was
o
refluxed at 200 C for 1 h. The reaction mixture was cooled gradually and washed several times with
petroleum ether. The gummy residue was further washed three times with benzene (3x 50 mL) to give a
o
colorless powder (6). It was then recrystallized with CHCl3. mp >300 C; yield 65 %; IR (KBr, γmax
)
1680, 1643, 3350 cm-1. 1H-NMR (CDCl3, 400 MHz) δ 1.15 (s, 3H, CH3), δ 1.21 (s, 3H, CH3), δ 2.89 (h, 1H,
-CH-(CH3)2, J =7.56 Hz), δ 3.80 (s, 3H, -N-CH3), δ 4.05 (s, 2H, CH2), δ 7.30 (t, 1H, C7-H, J = 7.48 Hz), δ
7.40 (d, 1H, C8-H, J = 8.44 Hz), δ 7.60 (t, 1H, C6-H, J = 7.62 Hz), δ 8.20 (d, 1H, C5-H, J = 7.84 Hz), δ 12.50 (s,
1H, -OH). 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.
1-Methyl-3-(3-methyl-2-oxobutyl)-4-chloro-2-quinolinone (7): 1-Methyl-3-(3-methyl-2-oxobutyl)-4-hydroxy-
2-quinolinone (6) (0.26 g, 0.001 mol) was directly refluxed in phosphorous oxychloride (3 mL, 0.02 mol) for 3 h.
After cooling, it was poured in to 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 with silica gel column
chromatography with petroleum ether-ethyl acetate yielded the product (7) at (98:2). mp 215 o C (CHCl3).
IR (KBr, γmax) 1705, 1665. 1H-NMR (CDCl3, 400 MHz) δ 1.25 (s, 3H, CH3), 1.32 (s, 3H, CH3), 2.97 (h, 1H,
CH-(CH3)2, J= 8.04 Hz), 3.95 (s, 3H, N-CH3), 4.20 (s, 2H, CH2), 7.40-8.35 (m, 4H, Ar-H). MS [70 eV, m/z
(M+)] 278.
1-Methyl-3-(3-methyl-2-oxobutyl)-4-methoxy-2-quinolinone (orixiarine) (1): A solution of 1-Methyl-3-
(3-methyl-2-oxobutyl)-4-chloro-2-quinolinone (7) (0.56 g, 0.002 mol) and sodium methoxide (0.0515 g, 0.0025
mol) in 20 mL of dry methanol was refluxed for 2.5 h. Upon cooling, the solid separated was filtered and
1
recrystallized with methanol, to furnish 1 (Yield 80 %). The H-NMR and 13C-NMR spectrum of the
product was essentially identical to the corresponding spectra that have been reported1 previously for authentic.
mp 173-178 o C. IR (KBr, γmax) 1665, 1630. MS [70 eV, m/z (M+)] 273. Anal. Calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.13 Found: C, 70.18; H, 6.89; N, 5.21.
ACKNOWLEDGEMENTS
RNK thanks CSIR, New Delhi for the award of Senior Research Fellowship. SIF, Indian Institute of Science,
Bangalore and Central Drug and Research Institute, Lucknow supported the spectral details.

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