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

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.

alkaloids - enaminones - heterocycles - piperidines - quinazolines

References and Notes

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<A NAME="RD35505ST-18">18</A>

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): ν_max = 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).

<A NAME="RD35505ST-19">19</A>

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

<A NAME="RD35505ST-20A">20a</A> Baker BR. Querry MV. Schaub RE. Williams JH. J. Org. Chem.  1952,  17:  58 

<A NAME="RD35505ST-20B">20b</A> For an alternative synthesis of (±)-deoxyfebrifugine from the same group, see: Baker BR. Querry MV. Kadish AF. Williams JH. J. Org. Chem.  1952,  17:  52 

<A NAME="RD35505ST-21">21</A> Baker BR. Schaub RE. Querry MV. Williams JH. J. Org. Chem.  1952,  17:  97 

<A NAME="RD35505ST-22">22</A> Ghirlando R. Howard AS. Katz RB. Michael JP. Tetrahedron  1984,  40:  2879 

<A NAME="RD35505ST-23">23</A>

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) ν_max = 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 H_bN), 4.73 (1 H, d, J = 17.4 Hz, O=CCH_a H _b N), 3.04 (2 H, 2 × m, NCH and O=CCH _a H_bCH), 2.64-2.67 (3 H, m, ring NCH ₂ and O=CCH_a H _b CH), 2.11 (1 H, br s, NH), 1.80 (1 H, br d, ring CH _a H_b), 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]

<A NAME="RD35505ST-24A">24a</A> Baker BR. Schaub RE. Williams JH. J. Org. Chem.  1952,  17:  109 

<A NAME="RD35505ST-24B">24b</A> Baker BR. Schaub RE. Williams JH. J. Org. Chem.  1952,  17:  116