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Synlett 2006(3): 0383-0386  
DOI: 10.1055/s-2006-926233
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Synthesis of (±)-Deoxyfebrifugine, an Antimalarial Alkaloid Analogue, and Related Compounds

Joseph P. Michael*, Charles B. de Koning, Daniel P. Pienaar
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, PO Wits 2050, South Africa
Fax: +27(11)7176749; e-Mail: jmichael@aurum.wits.ac.za;
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Publication History

Received 25 November 2005
Publication Date:
06 February 2006 (online)

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Abstract

The title compound was prepared by a simple route involving Eschenmoser sulfide contraction between 3-(3-bromo-2-oxopropyl)quinazolin-4(3H)-one (11) and piperidine-2-thione (13) followed by chemoselective catalytic hydrogenation. This short but flexible procedure also permitted access to N-alkyl analogues, and to analogues in which the piperidine ring was replaced by other ­saturated nitrogen-containing heterocycles.

Key words

alkaloids - enaminones - heterocycles - piperidines - quinazolines

18

Synthesis of 3-[(3 Z )-2-Oxo-3-(piperidin-2-ylidene)propyl]quinazolin-4 (3 H )-one ( 15).
A mixture of 3-(3-bromo-2-oxopropyl)quinazolin-4 (3H)-one (11, 395 mg, 1.41 mmol) and piperidine-2-thione (13, 163 mg, 1.41 mmol) in dry THF (30 mL) was stirred at r.t. for 48 h until salt precipitation was complete. After evaporation of the solvent in vacuo, dry MeCN (25 mL), triphenylphosphine (PPh3, 0.92 g, 3.5 mmol) and 1-methylpiperidine (0.44 mL, 3.5 mmol) were sequentially added to the residue. Stirring was continued at r.t. for another 18 h. After evaporation of the solvent in vacuo, the residue was dissolved in CH2Cl2 (50 mL) and extracted with aq HCl (2 M, 3 × 20 mL). The combined aqueous extracts were washed with CH2Cl2 (10 mL), then made basic with concd aq NH3 solution. Extraction with CH2Cl2 (3 × 15 mL) was followed by washing of the combined organic extracts with brine (10 mL). Drying (Na2SO4), filtering and evaporation to dryness yielded crude product as a light brown solid, which was purified by column chromatography (EtOAc-hexane, 4:1) to afford 15 as a colourless solid (254 mg, 64%), mp 167.5-170 °C (from EtOAc-hexane) (lit. mp of the putative tautomer 16, [20] 167-170 °C; 176-178 °C after recrystallisation). MS: m/z calcd for C16H17N3O2: 283.1321; found: 283.1326 [M+]. IR (CHCl3): νmax = 2948, 2869, 1673 (s, quinazolinone C=O), 1607 (s, enaminone C=O), 1578, 1526, 1474 cm-1. 1H NMR (300 MHz, CDCl3): δ = 11.11 (1 H, br s, NH), 8.31 (1 H, d, J = 8.3 Hz, H-5), 8.04 (1 H, s, H-2), 7.71-7.78 (2 H, m, H-7 and H-8), 7.45-7.51 (1 H, m, H-6), 4.93 (1 H, s, NC=CH), 4.64 (2 H, s, O=CCH 2), 3.32 (2 H, dt, J = 5.7, 2.3 Hz, ring NCH 2), 2.39 (2 H, t, J = 6.2 Hz, NCCH 2), 1.67-1.81 (4 H, m, 2 × ring CH 2). 13C NMR: δ = 186.0 (enaminone C=O), 166.5 (NC=CH), 161.1 (quinazolinone C=O), 148.3, 147.2, 134.1, 127.4, 127.0, 126.8, 122.1, 90.2 (NC=CH), 52.4 (O=CCH2), 41.1 (ring NCH2), 28.5, 21.9, 18.9. MS (EI): m/z (%) = 283 (9) [M+], 255 (2), 220 (3), 124 (100), 82 (4), 55 (3).

19

Results of a more extensive crystallographic survey that includes 15 and representative examples of compounds 19 and 21 will be published elsewhere.

23

Synthesis of (±)-Deoxyfebrifugine ( 5).
Enaminone 15 (190 mg, 0.671 mmol) was dissolved in a mixture of MeOH (15 mL) and aq HCl (8.5 N, 0.20 mL). The solution was stirred over pre-hydrogenated PtO2·xH2O (Adams catalyst, 26 mg) under H2 gas (3 atm) for 6 h. After filtering through Celite®, the solvent was removed under reduced pressure and the residue was triturated with EtOH-MeOH (5:1), cooled down and left to precipitate overnight in the freezer. After filtering, the precipitate was identified as the dihydrochloride salt of (±)-deoxyfebrifugine, 5·2HCl (138 mg, 58%), mp 218-221 °C (decomp.) [lit. mp 228-230 °C (decomp.) [20] ]. 1H NMR (300 MHz, D2O): δ = 8.65 (1 H, s, H-2), 8.28 (1 H, d, J = 8.1 Hz, H-5), 8.04 (1 H, m, H-6), 7.74-7.83 (2 H, m, H-7 and H-8), 5.20 (2 H, s, O=CCH 2N), 3.70 (1 H, m, J = 7.1 Hz, NCH), 3.05-3.49 (4 H, m, ring NCH 2 and O=CCH 2CH), 1.92-2.11 (3 H, m, 1.5 × ring CH 2), 1.59-1.75 (3 H, m, 1.5 × ring CH 2). 13C NMR (50 MHz, D2O): δ = 204.4, 163.5, 151.7, 144.6, 139.2, 132.0, 129.4, 125.9, 122.5, 58.2, 54.7, 47.6, 45.1, 30.7, 24.3, 24.0. The salt was dissolved in sat. K2CO3 solution (5 mL), and the resulting solution was extracted with EtOAc (3 × 10 mL). The combined extracts were dried (MgSO4), filtered and evaporated in vacuo to give the free base as a cream-coloured solid which could be repeatedly recrystallised from EtOAc-hexane to afford (±)-deoxyfebrifugine (5) in quantitative yield from the hydrochloride salt; colourless needles, mp 127.5-129 °C (lit. [10] mp 139-141 °C; lit. [20] 138-140 °C). MS: m/z calcd for C16H20N3O2: 286.1556; found: 286.1559 [MH+]. IR (film) νmax = 3063 (w), 2930 (m), 2854 (w), 1729 (m), 1677 (s), 1613 (s), 1563 (w), 1474 (m) cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.28 (1 H, d, J = 8.1 Hz, H-5), 7.89 (1 H, s, H-2), 7.72-7.80 (2 H, m, H-7 and H-8), 7.51 (1 H, dt, J = 7.3, 1.4 Hz, H-6), 4.84 (1 H, d, J = 17.4 Hz, O=CCH a HbN), 4.73 (1 H, d, J = 17.4 Hz, O=CCHa H b N), 3.04 (2 H, 2 × m, NCH and O=CCH a HbCH), 2.64-2.67 (3 H, m, ring NCH 2 and O=CCHa H b CH), 2.11 (1 H, br s, NH), 1.80 (1 H, br d, ring CH a Hb), ca. 1.64, 1.40, 1.23 (2 H, 2 H, 1 H, 3 × m, remaining ring CH 2). 13C NMR: δ = 202.1, 160.9, 148.2, 146.2, 134.5, 127.6, 127.4, 126.7, 121.8, 54.8, 52.7, 47.7, 46.7, 32.7, 26.0, 24.5. FAB-MS: m/z (%) = 286 (25) [MH+], 180 (5), 154 (100), 136 (74), 124 (9), 120 (13), 115 (5), 107 (26). The 1H NMR spectroscopic data agree with those reported in the literature. [10]