Flash vacuum pyrolysis, the key step in the synthesis of a novel oxadiazolopyrimidinone library

The synthesis of previously unexplored ring systems is of particularly high interest, especially in the pharmaceutical industry. Yet, it has been shown that medicinal chemists employ a relatively small chemical technology toolbox,¹ and only a minor part of the synthetically tractable small aromatic systems can be found in the literature.²
STATE OF THE ART: Thermal cyclizations in batch are normally performed in solvents with high boiling points (e.g. diphenyl ether, b.p. 258°C). However, such processes are often hampered by side-reactions and by difficult workup.^5,6 Beneficially, high temperature / high pressure flow chemistry (e.g. in the Phoenix Flow Reactor) allows to apply low boiling point solvents (e.g. CH₃CN, THF) in combination with the precise control of residence time.⁶ Although flash vacuum pyrolysis is not a generally accepted method in pharmaceutical R&D, it is often advantageous when other methods afford low selectivity or the synthesis is problematic (e.g. due to clogging) in microor mesofluidic flow reactors.³ In this application note we show how the flash vacuum pyrolysis technique is used as a key step in the synthesis of a novel oxadiazolo-pyrimidinone library.^3,4

2,2-Dimethyl-5-{[(4-methyl-1,2,5-oxadiazol-3-yl)amino]methylidene}-1,3-dioxane-4,6-dione (1).
Meldrum’s acid (680 mg, 4.72 mmol) and triethyl orthoformate (4.7 mL, 28.26 mmol) were combined in a 25 mL round bottom flask equipped with a reflux condenser. The mixture was stirred and heated at 145°C for 2 h. The dark yellow solution was cooled to room temperature, and 4-methyl-1,2,5-oxadiazole-3-amine (430 mg, 4.34 mmol) was added. The mixture was stirred at room temperature for 1.5 h, and then the solution was concentrated under vacuum. The crude product was washed with water and cold ethanol. The white crystals were dried under vacuum over P₂O₅. Yield: 700 mg (2.76 mmol, 64%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 8.41 (s, 1H), 2.42 (s,3H), 1.70 (s, 3H). ¹³C{1H} NMR (101 MHz, DMSO): δ 163.4, 162.3, 155.3, 153.4, 147.2, 105.1, 90.6, 26.8, 7.8. HRMSESI calcd for C7H6N3O4, 196.0358 [M-C₃H₆O+H]+; found, 196.0356 [M-C₃H₆O+H]+.

Ethyl 3-((4-methyl-1,2,5-oxadiazol-3-yl)amino)but-2-enoate (2).
4-methyl-1,2,5-oxadiazol-3-amine (500 mg, 5.05 mmol), ethyl 3-oxobutanoate (808 µL, 6.41 mmol) and catalytic amount of PTSA (17 mg. 0.1 mmol) were combined in a 25 mL round bottom flask equipped with a Dean-Stark distillation trap. The mixture was stirred in refluxing toluene (14 mL) overnight. The mixture was cooled and concentrated under vacuum. The residue was purified by column chromatography (silica, heptane/EtOAc 1:1) to yield the product as a white solid (498 mg, 2.36 mmol, 47%). 1H NMR (300 MHz, CDCl3): δ 10.96 (s,1H), 5.0 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 2.39 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 169.8, 156.6, 152.1, 146.8, 92.6, 59.8, 21.5, 14.7, 7.5. HRMS ESI calcd for C9H14N3O3, 212.1035 [M+H]+; found, 212.1032 [M+H]+.

3-Methyl-7H-[1,2,5]oxadiazolo[2,3a]pyrimidin-7-one (3).
FVP of 1 (220 mg, 0.869 mmol, Tf = 450°C, Ti = 125°C, P = 2.9x10^-2 - 1x10^-3 mbar, t = 5 min, 30x2 cm) gave 3 as a white sticky solid. The product was purified by column chromatography (silica, hexane - diethyl ether) to give a white crystalline solid (96 mg, 0.635 mmol, 73% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.31 (d, J = 6.5 Hz,1H), 6.59 (d, J = 6.5 Hz, ¹H), 2.53 (s, 3H). ¹³C{¹H} NMR (¹⁰¹ MHz, DMSO-d₆): δ 155.6, 152.7, 152.3, 147.2, 110.2, 8.6. ¹⁵N NMR (extracted from ¹H/¹⁵N HMBC, DMSO-d₆): δ 377, 263, 226. HRMS ESI calcd for C6H6N3O2, 152.0460 [M+H]⁺; found, 152.0481 [M+H]⁺.

3,5-dimethyl-7H-[1,2,5]oxadiazolo[2,3-a]pyrimidin7-one (4).
FVP of 2 (1.27 g, 6.01 mmol, T_f = 450°C, T_i = 150°C, P = 2.5x10^-2 mbar, t = 50 min, 30×2 cm) gave 4 as a white solid. The product was scraped out from the tube and purified by column chromatography (silica, hexane : ethyl acetate = 3:2) to give 4 as a white solid (726 mg, 4.51 mmol, 73% yield). ¹H NMR (300 MHz, CDCl₃): δ 6.34 (s, 1H), 2.59 (s, 3H), 2.47 (s, 3H). ¹³C{1H} NMR (101 MHz, DMSO-d₆): δ 166.4, 152.4, 152.1, 146.2, 107.9, 23.3, 8.7. HRMS ESI calcd for C7H7N3O2, 166.0617 [M+H]⁺; found, 166.0612 [M+H]⁺.

The synthesis of 3 was carried out by vacuum distillation of substrate 1 through the heated quartz reactor tube (450°C furnace temperature, 30×2 cm tube dimensions) of the FVP unit of the Flash Reactor Plus^™. The ringclosed product (3) was collected after the reactor tube in a cooled trap at -78°C (dry ice/acetone). The structural confirmation of compound 3 was established by detailed NMR spectroscopic analysis (¹H, ¹³C{¹H }, ¹H-¹⁵N HMBC, ¹H-¹³C HSQC, ¹H-¹³C HSQMBC), and its elemental composition was confirmed by HRMS spectrometric analysis. All analytical data was in correspondence with the proposed structure. Synthesis and characterisation of compound 4 was done analogously. Next, compounds 3 and 4 were treated with N-bromosuccinimide under standard batch conditions to afford the brominated products (not shown on the scheme). Subsequent Suzuki-coupling with aryl boronic acids afforded 5.

We demonstrated how the flash vacuum pyrolysis technique can afford previously non-described heterocycles. These heterocycles were then derivatized to afford a library of more than 20 oxadiazolo-pyrimidinones.^{3, 4}

This study was undertaken in the laboratories of ComInnex Inc. and ThalesNano Inc.