Phoenix Flow Reactor™ Application Note
Modern flow chemistry methods offer new chemical space for drug discovery programs: novel compounds can be synthesized in dedicated high temperature/high pressure (high T/p) reactors, while reaction times can be shortened dramatically.1,2
State of the art: Thermal electrocyclic ringopening reactions traditionally require high temperatures and prolonged heating.3Due to effective heat transfer and precise control of the parameters, the application of high T/p continuous flow technology enables these reactions to proceed with significantly shorter reaction times compared to batch or microwave methods. Tsoung and coworkers described a new approach for GouldJacobs reactions in their publication, which exploits the advantages of the Phoenix Flow ReactorTM, as the part of an inhouse modified automated system.4
In this application note, we present their new achievements with this instrument: first, highly reactive dienes (orthoquinodimethanes) were in situ generated by thermal electrocyclic ringopening of benzocyclobutanes and related cyclic moieties, then benzoisoindoles, benzocyclobutanes and other tripleannulated, biologically active heterocyclic fragments were synthesized in DielsAlder cycloaddition (DA) reactions, applying high T/p continuous flow techno logy within short residence times (< 4 minutes, Scheme 1.).5
Phoenix Flow ReactorTM is designed to perform reactions up to 450 °C. The pressure range can exceed up to 200 bar applying a back pressure regulator.
The Phoenix Flow ReactorTM (5, with a 2 mL stainless steel coil reactor) was supplemented with the following (Figure 1.): a solvent reservoir (1), an automated sample processor (2), an HPLC pump (3, to ensure the continuous flow of the reagents), a 10port injector valve with a pair of 5 mL stainless steel loops (4), a back pressure regulator (6, for keeping the organic solvents in liquid phase even above their boiling points) and a fraction collector (7).
Risk assessment and hazards: Always use the system in a well ventilated fume hood to avoid inhalation of solvent vapors. Never open it at high pressure or temperature, the overheated or pressurized solvents can cause injuries. Avoid contact with the heated parts.
Figure 1. Schematic view of the applied instrument 3, 4
1. Solvent reservoir; 2. Autosampler; 3. HPLC pump; 4. Injection loop; 5. Phoenix Flow ReactorTM; 6. Back pressure regulator; 7. Fraction collector.
The synthesis of 3 (intermolecular DA):
13a-phenyl-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-a]isoquinoline-13-carbonitrile (3): 1-benzocyclobutanecarbonitrile (1, 19.0 mg, 0.15 mmol) and 3,4-dihydroisoquinoline (2, 2.0 equiv., 39 mg, 0.30 mmol) were dissolved in 750 μL tetrahydrofuran (THF). The Phoenix Flow ReactorTM was set to 120 bar pressure, 300 °C temperature and 4.0 mLmin-1 flow rate. After the system reached the stable state, the mixture was injected to the reactor. The crude reaction mixture was collected, concentrated and purified by column chromatography. Product 3 was formed in a 1.3:1 cis/trans ratio, confirmed by 1H NMR analysis, in 85% yield (33 mg, 0.13 mmol). Crystallization from dichloromethane/diethyl ether afforded the cis product.
1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.15 (m, 8H), 4.37 (d, J = 3.2 Hz, 1H), 4.17 (d, J = 15.2 Hz, 1H), 4.03 – 3.92 (m, 1H), 3.79 (d, J = 15.2 Hz, 1H), 3.32 (ddd, J = 17.3, 12.2, 5.2 Hz, 1H), 3.22 (ddd, J = 10.9, 5.2, 2.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 136.1, 134.8, 133.4, 129.3, 129.3, 128.4, 128.4, 127.2, 127.1, 126.8, 126.6, 125.3, 119.1, 61.3, 57.7, 50.3, 39.3, 29.3. HRMS (ESI/TOFQ) m/z: [M+H]+ calcd for C18H17N2: 261.1386; found: 261.1393
The synthesis of 5 (intramolecular DA):
2-methyl-2,3,4,5-tetrahydro-1H-benzo[e]isoindol-1-one (5): NmethylN(prop2yn1yl)bicyclo[4.2.0]octa1,3,5triene7carboxamide (4) (30 mg, 0.15 mmol) was dissolved in 3.0 mL of THF. Subsequently, 100 bar, 300 °C and 4.0 mLmin1 flow rate was set on the Phoenix Flow ReactorTM. After the system reached the stable state, the mixture was injected to the 2 mL stainless steel reactor. The crude reaction mixture was collected, concentrated and purified by preparative HPLC (15-45% NH4OAc/ACN method) to afford the product in 79% yield (24 mg, 0.12 mmol).
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.30 – 7.13 (m, 3H), 3.97 (s, 2H), 3.11 (s, 3H), 2.98 (t, J = 8.2 Hz, 2H), 2.61 (t, J = 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 169.9, 149.9, 134.4, 129.2, 129.2, 127.7, 127.5, 126.9, 123.6, 54.0, 29.0, 27.9, 22.9. HRMS (ESI/TOFQ) m/z: [M+Na]+ calcd for C13H13NNaO: 222.0889; found: 222.089
The synthesis of 3 (intermolecular DA)
The synthesis of 5 (intermolecular DA)
Results and discussion
The intermolecular Diels-Alder cycloaddition of different imine dienophiles to 1benzocyclobutanecarbonitrile (1) was investigated in the Phoenix Flow ReactorTM at 300 °C and 120 bar. The reactions were regiospecific (cis/trans ratios were determined by 1H NMR spectroscopic analysis of the crude reaction mixture) and complete conversion was achievable in just 30 seconds in all cases. (In comparison, the batch and microwave processes required 6 hours (7% conversion) and 1 hour (complete conversion) at 180 °C, respectively). In the tested intramolecular reactions olefins and acetylenes gave only the cisproducts in good yields (79% for product 5). Reactions with siloxy compounds were also tested, affording alkyl silyl ether and vinyl silyl ether. Aldehydes and nitriles also participated in the DielsAlder reaction in moderate yields. In case of 1,2disubstituted alkenes, the formation of both diastereomers of the product were observed. To avoid the dimerization of the starting compounds in the synthesis of benzoisoindolinelike products more dilute (0.05 M) conditions were needed.
Dihydrobenzothiophene2,2dioxides and benzoisothiazoline-2,2-dioxides can also serve as precursors of orthoquinodimethanes which can be generated via thermal cheletropic extrusion of SO2. They were also tested in the intramolecular DielsAlder reactions with olefins and acetylenes: the expected products were obtained in good yields but the reactions required longer residence times (4 minutes
Through the selected examples from the research of Tsoung and coworkers, we demonstrated the advantages of the Phoenix Flow ReactorTM in various DielsAlder cycloaddition reactions. The synthesis of different biologically active fused heterocyclic compounds was achieved by the electrocyclic ring opening reactions of benzocyclobutanes, benzothiophene2,2dioxides and benzoisothiazoline2,2dioxides and the subsequent DA reactions with several dienophiles. The application of high T/p flow methodology allowed full conversion in less than 4 minutes in a safe and reliable process.
1) Darvas, F.; Hessel, V.; Dormán, Gy. (Eds.); Flow Chemistry Volume 1: Fundamentals, 2014, Berlin/Boston, De Gruyter
2) Sipos, G.; Gyollai, V.; Sipőcz, T.; Dormán, Gy.; Kocsis, L.; Jones, R.V.; Darvas, F.; J. Flow Chem.2013, 3, 51–58.
3) Kametani, T.; Yukawa, H.; Suzuki, Y.; Honda, T.; J. Chem. Soc., Perkin Trans. 11985, 2151–2154.
4) Tsoung, J.; Bogdan, A. R.; Kantor, S.; Wang, Y.; Charaschanya, M.; Djuric, S. W.; J. Org. Chem. 2017, 82, 1073–1084.
5) Tsoung, J.; Wang, Y.,; Djuric, S. W.; React. Chem. Eng.2017, 2, 458–461.
ThalesNano would like to thank the authors for their contribution.