Synthesis of Condensed Heterocycles by the GouldâJacobs Reaction

Article pubs.acs.org/OPRD

Synthesis of Condensed Heterocycles by the Gould−Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor László Csaba Lengyel,*,†,‡ Gellért Sipos,§ Tamás Sipőcz,§ Teréz Vágó,† György Dormán,§ János Gerencsér,‡ Gergely Makara,‡ and Ferenc Darvas§ †

ComCIX Inc., Záhony u. 7. H-1031 Budapest, Hungary ComInnex Inc., Záhony u. 7. H-1031 Budapest, Hungary § ThalesNano Inc., Záhony u. 7. H-1031 Budapest, Hungary ‡

S Supporting Information *

ABSTRACT: In the present paper we report the synthesis of condensed pyrimidone heterocycles (including novel ones) prepared by the Gould−Jacobs reaction using an in-house-built vacuum-to-high pressure multipurpose “three-mode” pyrolysis reactor. Four of the ring systems have not been described in the literature to date. The pyrolysis reactor has (i) a flash vacuum pyrolysis (FVP) module that applies high vacuum (10−3 mbar), letting the starting material through the reactor chamber heated up to 1000 °C; (ii) a pneumatic spray pyrolysis (PSP) module that can inject nonvolatile reactants to the heated reactor zone; and (iii) a high-pressure pyrolysis (HPP) continuous-flow module that operates from atmospheric to 400 bar pressure and between room temperature and 600 °C. The capabilities of the pyrolysis reactor were demonstrated by comparison experiments on two different condensed pyrimidone bicyclic ring systems, and the established reaction conditions were then successfully applied to the synthesis of another six condensed pyrimidone bicyclic systems.

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INTRODUCTION The synthesis of novel heterocyclic frameworks is of particularly high interest, especially in the pharmaceutical industry’s pipeline drought observed throughout the past decade. While a number of avenues are available to organic and medicinal chemists for the synthesis of these structures, it has also been shown that chemists employ a relatively small chemical technology toolbox.1 Moreover, an analysis by Pitt et al.2 revealed that only a minor part of the synthetically tractable small aromatic systems can be found in the literature or in compound databases. Previously unexplored chemical classes not only represent intellectual property opportunities but also expand the chemical matter available to interrogate challenging protein targets. Hence, new technologies that enable the rapid and efficient synthesis of novel core structures are valuable for the chemical community. The overwhelming majority of organic reactions are carried out between −78 and 250 °C and between 0.01 and 100 bar pressure, and therefore, one of the attractive possibilities to access novel heterocyclic systems is the extension of the parameter space currently used to perform organic reactions. Our team has particular interest in extending both the temperature and pressure ranges that can be applied to synthesis. For the former, pyrolysis techniques such as flash vacuum pyrolysis (FVP) are an effective tool, while for the latter, flow reactors can be the answer. FVP conditions are particularly suitable for thermal cyclizations, and the technique could be the method of choice because of its green nature and its ability to affect transformations at high temperature in a very short reaction time (1 s or less), which reduces or eliminates decompositions. As a standard practice, thermolytic ring closures that normally require temperatures above 250 °C are © 2015 American Chemical Society

executed in high-boiling-point solvents (e.g., Dowtherm ATM, diphenyl ether (DPE), etc.)3 or under neat solvent-free conditions over hours or days as batch procedures. Also, microwave reactors are a standard solution today to reach high reaction temperatures.4 In the past decade, the use of continuous-flow devices has become a routine practice in many high-temperature organic and medicinal chemistry laboratories.5 We previously described the thermolytic synthesis of pyridopyrimidones, hydroxyquinolines, and aromatic naphthol and phenol derivatives in a liquid-phase high-temperature (160−350 °C)/high-pressure (90−180 bar) mesoreactor as a continuous-flow system called X-Cube Flash.6 Recently Kappe and co-workers demonstrated that X-Cube Flash employing near- or supercritical fluids as reaction media (a process they termed “flash flow pyrolysis”) can mimic gasphase FVP protocols, providing a good alternative.7 While such substitution for FVP is certainly very promising and provides a feasible solution in many cases, it has some limitations and drawbacks, as also pointed out by the authors. These include a temperature limitation (99 >99 >99 >99 >99

76 67 60 45 40 85

− − − 30 31 −

>99

−

83

80 >99 >99 70

68 88 75 55

− − − −

Isolated yields (solution concentration 0.05 M). DOI: 10.1021/op500354z Org. Process Res. Dev. 2015, 19, 399−409

Article

Organic Process Research & Development Table 3. Optimization of the flow conditions for Table 2 by the Simplex optimization method based on the Nelder− Mead algorithm10

were recorded at room temperature. High-resolution mass spectra were recorded on an Agilent 6230 TOF instrument equipped with a JetStream ESI ion source. Microwave-assisted syntheses were carried out in a CEM Explorer microwave instrument. Unless otherwise noted, reagents and solvents were used as purchased from commercial suppliers; diethyl ethoxymethylene malonate was purchased from Sigma-Aldrich. Thinlayer chromatography (TLC) was performed using silica gel 60 plates (F254) and visualized by UV light (254 nm). Synthesis of Precursors. Diethyl 2-((Thiazol-2-ylamino)methylene)malonate (1a).14 Thiazol-2-amine (2.0 g, 20 mmol) and diethyl ethoxymethylene malonate (4.25 g, 24 mmol) were dissolved in ethanol (40 mL). The mixture was refluxed for 5 h, cooled to room temperature, and then concentrated under vacuum. The residue was purified by column chromatography (chloroform) to give 1a (3.2 g, 59% yield) as off-white crystals. 1H NMR (300 MHz, DMSO-d6): δ 11.32 (d, J = 7.0 Hz, 1H), 8.70 (d, J = 7.0 Hz, 1H), 7.43 (d, J = 3.5 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.18−1.33 (m, 6H). 13C NMR (75 MHz, DMSO-d6): δ 165.5, 164.5, 161.4, 146.8, 138.9, 114.9, 97.1, 59.9, 59.8, 14.1, 14.0. HRMS: 270.0679 (calcd for C11H14N2O4S), 270.0674 (found). 2,2-Dimethyl-5-((pyrimidin-2-ylamino)methylene)-1,3-dioxane-4,6-dione (1b). Meldrum’s acid (4.54 g, 31.5 mmol) and triethyl orthoformate (10.5 mL, 63.0 mmol) were combined in a 50 mL round-bottom flask equipped with a reflux condenser. The mixture was stirred at 145 °C for 2 h. The dark-yellow solution was cooled to room temperature, and pyrimidine-2-amine (2.0 g, 21 mmol) was added. The mixture was stirred at room temperature for 1 h and then at 70 °C for another hour. The solution was cooled to room temperature, upon which the product precipitated. The precipitate was filtered off and washed with water and cold ethanol to give 1b (4.2 g, 80% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.05 (d, J = 13.6 Hz, 1H), 9.11 (d, J = 13.6 Hz, 1H), 8.81 (d, J = 4.8 Hz, 2H), 7.42 (t, J = 4.9 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 164.0, 162.1, 159.3 (2C), 155.3, 151.1, 118.8, 105.0, 89.8, 26.6 (2C). HRMS: 191.0331 (calcd for C11H11N3O4 − C3H6O), 191.0330 (found). 5-{[(1,2,5-Thiadiazol-3-yl)amino]methylene}-2,2-dimethyl1,3-dioxane-4,6-dione (1c). Meldrum’s acid (1.11 g, 7.7 mmol) and triethyl orthoformate (2.6 mL, 15.4 mmol) were combined in a 25 mL round-bottom flask equipped with a reflux condenser. The mixture was stirred at 145 °C for 2 h. The dark-yellow solution was cooled to room temperature, and 1,2,5-thiadiazol-3-amine (520 mg, 5.15 mmol) was added. The mixture was stirred at room temperature for 2 h. The precipitated solid was filtered and washed with cold ethanol to furnish 1c (591 mg, 45% yield) as light-yellow crystals. 1H NMR (400 MHz, DMSO-d6): δ 12.02 (d, J = 13.5 Hz, 1H), 8.90 (s, 1H), 8.83 (d, J = 13.5 Hz, 1H), 1.69 (s, 6H). 13C NMR (100 MHz, DMSO-d6): δ 162.65, 162.59, 154.16, 152.41, 143.16, 104.61, 99.50, 89.98, 26.60. HRMS: 196.9895 (calcd for C9H9N3O4S − C3H6O), 196.9892 (found). 2,2-Dimethyl-5-[(1,2,4-triazin-3-ylamino)methylidene]1,3-dioxane-4,6-dione (1d). Meldrum’s acid (1.44 g, 10.0 mmol) and triethyl orthoformate (3,3 mL, 20.0 mmol) were combined in a 25 mL round-bottom flask equipped with a reflux condenser. The mixture was stirred at 145 °C for 2 h. The dark-yellow solution was cooled to room temperature, and 3-amino-1,2,4-triazine (1.00 g, 10.4 mmol) was added. The mixture was stirred at room temperature for 1 h and then at 70

yield (%)a Simplex optimization point no.

T (°C)

P (bar)

flow rate (mL/min)

conv. (%)

2a

3

1 2 3 4 5 6 7 8 9 10 11

150 150 250 350 350 150 350 450 500 500 500

50 200 80 80 80 80 80 80 80 80 80

2 2 2 6 10 0.5 20 28 10 20 30

24 24 >99 >99 >99 >99 >99 >99 >99 >99 90

17 15 17 47 50 − 70 85 42 60 65

− − 75 51 46 83 13 − 30 8 −

a

Isolated yields.

were performed in the FVP system using the conditions established during the validation experiments. Rewardingly, all six condensed pyrimidone templates could be synthesized in good to excellent yields (Scheme 4) using the standard protocol without optimization.

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CONCLUSIONS The three-mode reactor system presented in this paper proved to be an efficient addition to the chemical technology toolbox available to chemists. We have demonstrated the capabilities of the pyrolysis instruments by applying the Gould−Jacobs reaction for the synthesis of different fused pyrimidone heterocyclic systems that require the reaction to cross a high activation barrier. Although such rings can be synthesized under conventional batch conditions as well, the rapid energy transfer and very low contact time significantly improved the yields of the intramolecular condensation reactions. Furthermore, the generality of pyrolysis for this reaction was also demonstrated via the application of just one set of conditions to eight different reactions, all of which furnished the desired products without solvent or a significant workup. We investigated the stability and the incorporation of diversity-building functional elements of the produced heterocycles. On the basis of those results, we selected the Suzuki− Miyaura cross-coupling reaction, which was followed by halogenation., The generated new heterocyclic compounds formed an 18-member library. The synthesis of novel heterocyclic templates via pyrolysis and their use in parallel synthesis of chemical libraries will be reported elsewhere. In our opinion, pyrolysis in general and specifically our threemode system can be considered a new and effective tool for accessing an expanded parameter space for organic reactions that can be exploited for the synthesis of novel heterocyclic systems that will benefit the chemical and pharmaceutical community.

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EXPERIMENTAL DETAILS General Methods and Instruments. 1H and 13C NMR spectra were recorded on either a Bruker Avance II 300 (75) MHz or a Bruker Avance III 400 (100) MHz spectrometer with a Prodigy BBO probe or on a Bruker Avance III 500 MHz spectrometer with a cryo probe. For the calibration of spectra, solvent-peak and tetramethylsilane signals were used. Spectra 404

DOI: 10.1021/op500354z Org. Process Res. Dev. 2015, 19, 399−409

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Organic Process Research & Development

Figure 4. LC−MS spectra for selected entries in Table 3 (Simplex optimization points 8, 6, and 5).

ethanol to give 1d (1.63 g, 65% yield) as a beige crystalline solid. 1H NMR (400 MHz, DMSO-d6): δ 11.30 (d, J = 13.2 Hz, 1H), 9.35 (d, J = 2.4 Hz, 1H), 9.08 (d, J = 13.2 Hz, 1H), 8.87 (d, J = 2.4 Hz, 1H), 1.71 (s, 6H). 13C NMR (75 MHz, DMSOd6): δ 163.9, 161.9, 156.6, 151.4, 150.7, 148.0, 105.3, 91.3, 26.6, (2C). HRMS: 192.0283 (calcd for C10H10N4O4 − C3H6O), 192.0286 (found). Diethyl 2-((Pyridazin-3-ylamino)methylene)malonate (1e). Pyridazine-3-amine (500 mg, 5.2 mmol) and diethyl ethoxymethylene malonate (1.35 g, 6.2 mmol) were dissolved in ethanol (20 mL). The mixture was stirred at reflux

Scheme 3. Synthesis of 4H-pyrimido[1,2-a]pyrimidin-4-one (2b)

°C for another hour. The solution was cooled to room temperature, upon which the product precipitated. The precipitate was filtered off and washed with water and cold 405


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14.3. HRMS: 265.1063 (calcd for C12H15N3O4), 265.1060 (found). Diethyl 2-(((4-(Ethoxycarbonyl)oxazol-2-ylamino)methylene)malonate (1f). A mixture of ethyl 2-aminooxazole-4-carboxylate (200 mg, 1.28 mmol) and diethyl ethoxymethylene malonate (305 mg, 1.41 mmol) was stirred at 110 °C overnight. The mixture was allowed to cool and then concentrated. The residue was purified by column chromatography (20% ethyl acetate in heptane) to give 1f (303 mg, 73% yield) as a yellow crystalline product. 1H NMR (300 MHz, DMSO-d6): δ 11.07 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 4.10− 4.33 (m, 6H), 1.17−1.34 (m, 9H). 13C NMR (75 MHz, DMSO-d6): δ 165.0, 163.9, 160.0, 155.0, 145.3, 141.8, 132.1, 100.5, 60.6, 60.5, 60.2, 14.1, 14.0, 13.9. HRMS: 326.1114 (calcd for C14H18N2O7), 326.1112 (found). 5-(((1,3-Dimethyl-1H-pyrazol-5-ylamino)methylene)-2,2dimethyl-1,3-dioxane-4,6-dione (1g). Meldrum’s acid (389 mg, 2.7 mmol) and triethyl orthoformate (0.9 mL, 5.4 mmol) were combined in a 5 mL round-bottom flask equipped with a reflux condenser. The mixture was stirred at 145 °C for 2 h. The dark-yellow solution was cooled to room temperature, and 1,3-dimethyl-1H-pyrazol-5-amine (200 mg, 1.8 mmol) was added. The mixture was stirred at 60 °C overnight. The solution was cooled to room temperature, upon which the product precipitated. The precipitate was filtered off and washed with water and cold ethanol to give 1g (425 mg, 89% yield) as yellow crystals. 1H NMR (300 MHz, CDCl3): δ 11.25 (d, J = 13.5 Hz, 1H), 8.32 (d, J = 13.5 Hz, 1H), 5.98 (s, 1H), 3.78 (s, 3H), 2.24 (s, 3H), 1.76 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 165.9, 162.7, 154.5, 148.5, 138.4, 105.7, 94.6, 88.8, 35.1, 27.2 (2C), 13.9. HRMS: 207.0644 (calcd for C12H15N3O4 − C3H6O), 207.0655 (found). Diethyl 2-((Thieno[3,2-d]pyrimidin-4-ylamino)methylene)malonate (1h). A mixture of thieno[3,2-d]pyrimidin-4-amine (150 mg. 1.03 mmol) and diethyl ethoxymethylene malonate (233 mg, 1.07 mmol) was stirred at 120 °C overnight. The mixture was cooled to room temperature and then concentrated. The crude residue was purified by column chromatography (2.5% methanol in chloroform), giving 1h (152 mg, 48% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.01 (d, J = 11.7 Hz, 1H), 9.08 (d, J = 11.7 Hz, 1H), 8.80 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 5.5 Hz, 1H), 4.29 (q,

Table 4. Validation results for pyrimidinopyrimidinones using two pyrolysis reactors, a flow microreactor, and traditional batch techniques entry

technique

parameters

1 2 3 4

batch (ref 12) batch MW flow reactorb

5

flow reactorb

6 7 8 9

FVP FVP FVP PSP

Dowtherm A, >250 °C, 8 min DPE, 250 °C, 10 min DPE, 250 °C, 5 min MeCN, 350 °C, 6 mL/min, 80 bar, 4 mL loop MeCN, 450 °C, 6 mL/min, 80 bar, 4 mL loop 350 °C, 2.5 × 10−1 mbar 450 °C, 2.5 × 10‑1 mbar 500 °C, 2.5 × 10−1 mbar MeCN, 450 °C, 3.7 L/min N 2 carrier gas

conv. (%)

yield of 2b (%)a

N/A >99 >99 >99

59 66 61 60

>99

30

60 >99 >99 >99

48 86 75 44

a

Isolated yields (solution concentration 0.05 M). bFor optimization of the flow conditions, see Table 5.

Table 5. Optimization of the flow conditions for Table 4 with the Simplex method under constant pressure [80 bar] Simplex optimization point no.

T (°C)

P (bar)

flow rate (mL/min)

conv. (%)

yield of 2b (%)a

1 2 3 4 5 6 7

150 150 150 250 350 450 350

50 200 80 80 80 80 80

1 1 1 7 5 6 6

35 40 37 >99 >99 >99 >99

20 22 21 40 55 30 60

a

Isolated yields.

temperature for 6 h, cooled to room temperature, and then concentrated. The crude residue was crystallized from diethyl ether and hexane, giving 1e (700 mg, 51% yield) as white crystals. 1H NMR (300 MHz, CDCl3): δ 11.27 (d, J = 12.4 Hz, 1H), 9.29 (d, J = 12.4 Hz, 1H), 8.96 (d, J = 4.6 Hz, 1H), 7.40− 7.51 (m, 1H), 7.09 (d, J = 8.7 Hz, 1H), 4.21−4.39 (m, 4H), 1.28−1.44 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 168.8, 164.8, 153.4, 148.5, 148.4, 128.6, 116.6, 98.3, 61.0, 60.5, 14.4,

Scheme 4. Selected molecular frameworks 2c−h with their synthetic precursors 1c−h and the isolated yields for the prepared analogues

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407

147.0433 (calcd for C7H5N3O), 147.0421 (found)

(300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.19 (d, J = 4.5 Hz, 1H), 7.69 (d, J = 4.5 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H)

(300 MHz, CDCl3) δ 9.32 (dd, J = 7.16, 2.26 Hz, 1H), 9.06 (dd, J = 4.1, 2.5 Hz, 1H), 8.47 (d, J = 6.5 Hz, 1H), 7.12−7.23 (m, 1H), 6.51 (d, J = 6.5 Hz, 1H)

2a

2b

(75 MHz, DMSO-d6) δ 167.0, 163.7, 157.2, 154.3, 123.1, 115.4, 106.5, 60.2, 14.1 (75 MHz, CDCl3) δ 161.9, 157.9, 157.1, 152.4, 136.4, 111.8, 105.9

H NMR

1

compound

Table 6. Structural identification and analytical characterization of products 2a and 2b

13

C NMR

HRMS

J = 7.0 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 1.23−1.35 (m, 6H). 13 C NMR (75 MHz, DMSO-d6): δ 166.5, 163.9, 162.2, 154.0, 151.4, 145.1, 137.0, 124.6, 117.2, 100.1, 60.7, 14.1, 13.9. HRMS: 321.0783 (calcd for C14H15N3O4S), 321.0779 (found). Cyclization Reactions. Structural identification and analytical characterization data for the product compounds 2a and 2b are presented in Table 6, and their syntheses by various methods are described in the following sections. The syntheses of 2c−h by FVP are also described. Batch Reactions. Ethyl 5-Oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (2a). A solution of diethyl 2((thiazol-2-ylamino)methylene)malonate (1a) (135 mg, 5 mmol) in DMF (10 mL) was refluxed for 3 h. The mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, and the organic phase was dried over MgSO4 and then concentrated. The residue was purified by column chromatography (2% methanol in DCM) to give 2a (75 mg, 67% yield) as white crystals. 4H-Pyrimido[1,2-a]pyrimidin-4-one (2b). A solution of 2,2dimethyl-5-((pyrimidin-2-ylamino)methylene)-1,3-dioxane-4,6dione (1b) (125 mg, 5 mmol) in DPE (10 mL) was refluxed for 10 min. The mixture was cooled and subjected to column chromatography (10% ethyl acetate in heptanes) to give 2b (58 mg, 78%) as orange crystals. Microwave-Assisted Syntheses. Ethyl 5-Oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (2a). A solution of 1a (27 mg, 5 mmol) in DMF (2 mL) was irradiated at 150 °C for 30 min. The mixture was cooled to room temperature, and water was added. The resulting mixture was extracted with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (2% methanol in DCM) to give 2a (14 mg, 60% yield) as white crystals. Ethyl 5-Oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (2a). A solution of 1a (27 mg, 5 mmol) in DPE (2 mL) was irradiated at 250 °C for 5 min. The mixture was cooled and purified by column chromatography (10% ethyl acetate in heptane) to give 2a (9 mg, 40% yield) as white crystals. 4H-Pyrimido[1,2-a]pyrimidin-4-one (2b). A solution of 1b (25 mg, 5 mmol) in DPE (2 mL) was irradiated at 250 °C for 5 min. The mixture was cooled to room temperature and subjected to column chromatography (10% ethyl acetate in heptane) to give 2b (9 mg, 61% yield) as orange crystals. Flash Thermolysis in Flow. The flow conditions are quoted as follows: reactor temperature (Rf), system pressure (P), flow rate (Fr), reaction time (t), reactor volume (V). Ethyl 5-Oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (2a). A solution of 1a (135 mg, 0.5 mmol) in acetonitrile (10 mL) was subjected to flash thermolysis (Rf = 450 °C, P = 80 bar, Fr = 28 mL/min, t = 8.5 s, V = 4 mL). The solution was concentrated under vacuum, and the residue was purified by column chromatography (2% methanol in DCM) to give 2a (95 mg, 85% yield) as white crystals. 5H-Thiazolo[3,2-a]pyrimidin-5-one (3). A solution of 1a (150 mg, 5 mmol) in acetonitrile (10 mL) was subjected to flash thermolysis (Rf = 150 °C, P = 80 bar, Fr = 0.5 mL/min, t = 8 min, V = 4 mL). The solution was concentrated under vacuum, and the residue was purified by column chromatography (2% methanol in DCM) to give 3 (70 mg, 83% yield) as an off-white powder. 1H NMR (300 MHz, CDCl3): δ 8.10− 7.90 (m, 2H), 7.03 (d, J = 4.9 Hz, 1H), 6.3 (d, J = 6.4 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ 163.3, 158.5, 153.2, 122.0,

224.0256 (calcd for C9H8N2O3S), 224.0257 (found)



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DMSO-d6): δ 8.79 (s, 1H), 8.63 (s, 1H), 4.37 (q, J = 7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.24−1.35 (m, 6H). 13C NMR (75 MHz, DMSO-d6): δ 163.8, 159.7, 157.0, 153.9, 140.6, 120.4, 109.6, 63.0, 60.9, 14.7, 14.4. HRMS: 280.0695 (calcd for C12H12N2O6), 280.0696 (found). 1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-ol (2g). Compound 1g (63.4 mg, 0.24 mmol) was subjected to vacuum flash pyrolysis (Tf = 450 °C, Ti = 150 °C, P = 2.7 × 10−2 mbar, t = 5 min, 30 cm × 2 cm). The product 2g (31 mg, 77% yield) was collected from the tube as pale-yellow crystals and characterized without further purification. 1H NMR (300 MHz, DMSO-d6): δ 7.84 (d, J = 5.7 Hz, 1H), 6.11 (d, J = 5.7 Hz, 1H), 3.80 (s, 3H), 2.50 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 167.0, 152.5, 147.6, 139.9, 107.7, 104.2, 33.1, 13.9. HRMS: 163.0746 (calcd for C8H9N3O), 163.0743 (found). Ethyl 7-Oxo-7H-pyrimido[1,2-c]thieno[2,3-e]pyrimidine-8carboxylate (2h). Compound 1h (45.6 mg, 0.14 mmol) was subjected to vacuum flash pyrolysis (Tf = 500 °C, Ti = 150 °C, P = 1 × 10−1 mbar, t = 5 min, 30 cm × 2 cm). The product 2h (30 mg, 75% yield) was collected from the tube as a yellow solid and characterized without further purification. 1H NMR (300 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.86 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 4.29 (q, J = 6.6 Hz, 2H), 1.31 (t, J = 6.4 Hz, 3H). 13C NMR (75 MHz, DMSO-d6): δ 163.3, 159.8 (2C), 155.7, 154.2, 150.1, 139.8, 125.2, 108.6, 60.3, 14.1. HRMS: 275.0365 (calcd for C12H9N3O3S), 275.0362 (found).

111.5, 105.9. HRMS: 152.0044 (calcd for C6H5N2OS), 152.0049 (found). 4H-Pyrimido[1,2-a]pyrimidin-4-one (2b). A solution of 1b (125 mg, 5 mmol) in acetonitrile (10 mL) was subjected to flash thermolysis (Rf = 350 °C, P = 80 bar, Fr = 6 mL/min, t = 30 s, V = 4 mL). The mixture was cooled to room temperature and concentrated, and the residue was purified by column chromatography (10% ethyl acetate in heptane) to give 2b (45 mg, 60% yield) as orange crystals. FVP Reactions. The pyrolysis conditions are quoted as follows: furnace temperature (Tf), inlet temperature (Ti), pressure (range if appropriate) (P), pyrolysis time (t), tube dimensions (length × inner diameter). Ethyl 5-Oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (2a). Compound 1a (100 mg, 0.37 mmol) was subjected to vacuum flash pyrolysis (Tf = 450 °C, Ti = 140 °C, P = 2.5 × 10−1 mbar, t = 30 min, 30 cm × 2 cm). The product 2a (73 mg, 88% yield) was collected from the tube as white crystals and characterized without further purification. 4H-Pyrimido[1,2-a]pyrimidin-4-one (2b). Compound 1b (100 mg, 0.4 mmol) was subjected to vacuum flash pyrolysis (Tf = 450 °C, Ti = 140 °C, P = 5 × 10−1 mbar, t = 20 min, 30 cm × 2 cm). The product 2b (51 mg, 86% yield) was collected from the tube as orange crystals. 7H-[1,2,5]Thiadiazolo[2,3-a]pyrimidin-7-one (2c). Compound 1c (100 mg, 0.39 mmol) was subjected to flash vacuum pyrolysis (Tf = 450 °C, Ti = 150−160 °C, P = 10−3 mbar, t = 1.5 h, 30 cm × 2 cm). The product 2c (58 mg, 96% yield) was collected from the tube as white crystals and characterized without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.39 (d, J = 6.3 Hz, 1H), 6.37 (d, J = 6.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 157.66, 155.92, 155.13, 149.34, 104.97. HRMS: 152.9997 (calcd for C5H3N3OS), 152.9993 (found). 8H-Pyrimido[1,2-b][1,2,4]triazin-8-one (2d). Compound 1d (106 mg, 0.42 mmol) was subjected to vacuum flash pyrolysis (Tf = 450 °C, Ti = 130 °C, P = 10−3 mbar, t = 4 h, 30 cm × 2 cm). The product 2d (51 mg, 81% yield) was collected from the tube as light-yellow crystals and characterized without further purification. 1H NMR (500 MHz, DMSO-d6): δ 9.04 (d, J = 1.5 Hz, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.35 (d, J = 6.5 Hz, 1H), 6.63 (d, J = 6.5 Hz, 1H). 13C NMR (125 Hz, DMSOd6): δ 157.38, 155.39, 154.65, 149.81, 141.28, 110.45. HRMS: 148.0385 (calcd for C6H4N4O), 148.0382 (found). Ethyl 4-Oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxylate (2e).15 Compound 1e (100 mg, 0.38 mmol) was subjected to vacuum flash pyrolysis (Tf = 450 °C, Ti = 120 °C, P = 2.5 × 10−1 mbar, t = 1 h, 30 cm × 2 cm). The product 2e (63 mg, 76%) was collected from the tube as a pale-brown solid and characterized without further purification. 1H NMR (300 MHz, CDCl3): δ 8.99 (s, 1H), 8.81 (dd, J = 4.2, 1.8 Hz, 1H), 8.00 (dd, J = 9.2, 1.7 Hz, 1H), 7.62−7.66 (m, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 163.9, 158.1, 154.4, 152.3, 145.7, 135.2, 128.9, 111.7, 61.5, 14.3. HRMS: 219.0644 (calcd for C10H9N3O3), 219.0639 (found). Diethyl 5-Oxo-5H-oxazolo[3,2-a]pyrimidine-3,6-dicarboxylate (2f). Compound 1f (100 mg, 0.31 mmol) was subjected to vacuum flash pyrolysis (Tf = 500 °C, Ti = 150 °C, P = 8.5 × 10−2 to 1 × 10−1 mbar, t = 10 min, 30 cm × 2 cm). The crude product was collected from the tube and purified by column chromatography (25% ethyl acetate in heptane) to give 2f (63 mg, 73% yield) as pale-yellow crystals. 1H NMR (300 MHz,

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ASSOCIATED CONTENT

S Supporting Information *

Detailed description of the three-function high-temperature reactor system and analytical data including 1H NMR, 13C NMR, and HRMS data for compounds 1a−h, 2a−h, and byproduct 3. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Hungarian Government and financed by the Research and Technology Innovation Fund (Grant KMR_12-1-2012-0218). HRMS and 13 C NMR measurements were performed at Analytical Department of Servier Research Institute of Medicinal Chemistry, Budapest. The authors thank Dr. András Simon for recording the 1H NMR spectra.

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REFERENCES

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Synthesis of Condensed Heterocycles by the GouldâJacobs Reaction

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