Startseite Atom- and step-economic synthesis of biaryl-substituted furocoumarins, furoquinolones and furopyrimidines by multicomponent reactions and one-pot synthesis
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Atom- and step-economic synthesis of biaryl-substituted furocoumarins, furoquinolones and furopyrimidines by multicomponent reactions and one-pot synthesis

  • Asha Kadam

    Asha Kadam is a senior PhD student in Professor Wei Zhang’s group at the University of Massachusetts Boston. She received her MS degree in Organic Chemistry from the University of Mumbai, India. Her current research comprises multicomponent synthesis, fluorous chemistry, and Grignard reactions.

         , Stephanie Bellinger

    Stephanie Bellinger is a graduate student at the University of Massachusetts Boston. She is currently in Professor Rochford’s research group investigating chromophores for use as dye sensitizers and molecular photoacoustic contrast agents.

         und Wei Zhang

    Dr. Wei Zhang is Professor and Director of the Center for Green Chemistry at the University of Massachusetts Boston. He was a Senior Chemist at DuPont and Director at Fluorous Technologies, Inc. He has 150 publications on fluorous chemistry, free radical chemistry, and green chemistry.

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Abstract

Atom-efficient multicomponent reactions (MCR) and step-efficient one-pot synthesis are developed for the synthesis of biaryl-substituted furocoumarins, furoquinolones, and furopyrimidines. Furocoumarin and furoquinolone derivatives are synthesized by a three-component reaction, followed by the Suzuki coupling reaction. Furopyrimidine derivatives are prepared by the Suzuki coupling and then the three-component reaction. The bromobenzaldehydes are the key bifunctional molecules for the multicomponent and Suzuki coupling reactions.

Keywords: atom economy; furocoumarin; furopyrimidine; furoquinolone; multicomponent reaction; one-pot synthesis; step economy

1 Introduction

Synthetic efficiency is important for atom economy and reducing chemical waste. A multicomponent reaction (MCR) is highly atom economic, which generates multiple chemical bonds in a simple operation. All of the reagents are introduced spontaneously and no distinguishable intermediate can be isolated from the MCR. One-pot synthesis is step economic, because no intermediates need to be separated from multi-step reactions. Introduced in this paper, is the combination of MCR and one-pot synthesis for the preparation of biaryl-substituted heterocyclic compounds, including furocoumarins, furoquinolones, and furopyrimidines.

Furocoumarins, furoquinolones, and furopyrimidines are furan-fused coumarin, quinolone, and pyrimidine systems. Conjugated furans have unique photophysical and electrochemical properties and have been investigated as fluorescent dyes, photosensitizers, organic light emitting diodes, two-photon absorption materials, second and higher order nonlinear optics, and supramolecular materials [1–4]. Coumarin, quinolone, and pyrimidine are privileged-ring systems found in numerous natural products and synthetic compounds which have a wide range of biological activities and developed as antifungal, antibacterial, antiviral, antimicrobial, and anticonvulsant agents [5–13]. The combination of furan with coumarin, quinolone, or pyrimidine could result in unique heterocyclic molecules for photophysical, photochemical and biological studies.

We introduce in this paper a new strategy for atom- and step-economic synthesis of furocoumarin, furoquinolone, and furopyrimidine derivatives. The synthesis of furocoumarin and furoquinolone derivatives 6 was accomplished by a three-component reaction, followed by the one-pot Suzuki coupling reaction (Scheme 1). The synthesis of furopyrimidine derivatives 9 was accomplished by the Suzuki coupling of bromobenzaldehydes, followed by the three-component reaction (Scheme 2). All the reactions shown in Schemes 1 and 2 were promoted by microwave (μw) heating to reduce reaction time and increase synthetic efficiency.

Scheme 1 One-pot synthesis of furocoumarins (X=O) and furoquinolones (X=NMe).
Scheme 1

One-pot synthesis of furocoumarins (X=O) and furoquinolones (X=NMe).

Scheme 2 Synthesis of furopyrimidines.
Scheme 2

Synthesis of furopyrimidines.

2 Experimental section

2.1 General information

All chemicals and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used as received. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on a Varian NMR spectrometer. LC-MS were performed on an Agilent 2100 system (Santa Clara, CA, USA) with a C18 column (5.0 μm, 6.0×50 mm). The mobile phases were MeOH and water, both containing 0.05% trifluoroacetic acid. A linear gradient was started from 75:25 MeOH/H2O to 100% MeOH in 5 min at a flow rate of 0.7 ml/min. The chromatograms were recorded at UV 210 nm, 254 nm, and 365 nm. Low resolution mass spectra were recorded in atmospheric pressure chemical ionization (APCI). High resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer. Flash chromatography separations were performed on YAMAZEN AI-580 system (San Bruno, CA, USA) with Agela silica gel (Wilmington, DE, USA) (12 g or 20 g, 230–400 μm) cartridges. The μw reactions were performed on a Biotage Initiator 8 system (Charlotte, NC, USA). NMR, LC-MS, and HRMS spectra for the representative final compounds can be found in the supporting information.

2.2 Synthesis of furocoumarins and furoquinolones 6

2.2.1 Representative procedure for the synthesis of compound 6a

In a 10 ml μw vial equipped with a magnetic stirrer, a mixture of 4-hydroxycoumarin (0.162 g, 1.0 mmol), 4-bromobenzaldehyde (0.185 g, 1.0 mmol) and cyclohexyl isocyanide (0.124 g, 1.15 mmol) was mixed with 0.40 ml of toluene. The mixture was heated under μw at 80°C for 20 min to give 4a. To the same reaction vial, phenyl boronic acid (0.181 g, 1.5 mmol), Pd(dppf)Cl2 (0.040 g, 3 mol%), Cs2CO3 (0.650 g, 2.0 mmol), and 0.40 ml of 4:4:1 acetone/toluene/water were added. The mixture was heated under μw at 130°C for 20 min. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. Purification of the crude product by flash column chromatography (7:3 hexanes/EtOAc) gave 6a (0.296 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.34–7.14 (m, 2 H), 7.61–7.58 (m, 2 H), 7.50–7.20 (m, 9 H), 3.64–3.42 (m, 1 H), 2.01 (d, J=11.7 Hz, 2H), 1.70 (d, J=13.4 Hz, 2 H), 1.58 (d, J=12.5 Hz, 1 H), 1.21 (ddd, J=40.4, 19.9, 7.8 Hz, 5 H). 13C NMR (75 MHz, CDCl3) δ 25.0, 25.6, 34.3, 53.8, 97.4, 111.0, 112.9, 117.0, 119.6, 124.3, 125.7, 127.4, 127.4, 127.7, 128.5, 128.8, 128.9, 129.2, 131.2, 141.2, 141.6, 150.0, 151.4, 155.1. LC-MS (APCI+): m/z=436 [M+1]+. HRMS (ES+): m/z [M+H]+ calcd for C29H26NO3: 436.1906; found: 436.1913.

2.2.2 Representative procedure for the synthesis of compound 9a

In a 10 ml μw vial equipped with a magnetic stirrer, 0.40 ml of 4:4:1 acetone/toluene/water was added to a mixture of 4-bromobenzaldehyde (0.185 g, 1.0 mmol), 4-methoxy phenyl boronic acid (0.181 g, 1.5 mmol), Pd(dppf)Cl2 (0.040 g, 3%), and Cs2CO3 (0.650 g 2.0 mmol). The mixture was heated under μw at 130°C for 20 min. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. Purification of the crude product by flash column chromatography (7:3 hexanes/EtOAc) gave 7a (0.202 g, 95%). A mixture of 7a (0.106 g, 0.5 mmol), 1,3-dimethylbarbituric acid (0.078 g, 0.5 mmol), and 4-chlorobenzyl isocyanide (0.086 g, 0.57 mmol) in 0.40 ml of toluene was heated under μw at 80°C for 20 min. The crude product was filtered and washed with a minimum amount of toluene to give 9a as a yellow solid (0.232 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.10–7.19 (m, 4 H), 7.50–7.20 (m, 8 H), 4.21 (d, 2 H), 4.06 (m, 1 H), 3.44 (s, 3H), 3.31 (s, 3H), 2.32 (s, 3H). 13C NMR (75 MHz, CDCl3): δ=21.2, 28.4, 29.5, 51.1, 96.3, 100.4, 118.1, 126.9, 127.9, 127.9, 128.8, 128.9, 129.6, 129.6, 137.2, 138.1, 138.5, 139.9, 149.0, 150.5, 150.7, 152.8, 158.3. LC-MS (APCI+): m/z=486 [M+1]+.

3 Results and discussion

3.1 Optimization of the MCR for the synthesis of furocoumarin 4a

The MCR of 4-hydroxycoumarin 1a with 4-bromobenzaldehyde 2a and cyclohexyl isocyanide 3a for the synthesis of furocoumarin 4a was optimized using different solvents and under different reaction temperature and times [14, 15] (Table 1). Toluene was found to be a good solvent for the MCR (Table 1). The next step Suzuki coupling also used toluene as a solvent. It was found that the MCR gave unexpected non-condensed byproducts in polar solvents such as MeOH, EtOH, and DCM-MeOH (Table 1).

Table 1

Optimization of multicomponent reaction (MCR) for the synthesis of furocoumarin 4a.

EntrySolventTemp (°C) Time (min)Yield (%)a
1DMF1001085
2DMF1201088
3Toluene801597
4Toluene1201095
5EtOH8015Uncondensed productb
6MeOH8015Uncondensed productb
7DCM-MeOH8015Uncondensed productb

aIsolated yield.

bReaction with 1,3-dimethylbarbituric acid.

DMF, N,N-Dimethylformamide; DCM, Dichloromethane.

3.2 One-pot MCR and Suzuki coupling for the synthesis of furocoumarins and furoquinolones 6

The one-pot synthesis of compounds 6 were accomplished by the MCR followed by the Suzuki coupling reactions (Table 2). The optimized MCR was carried under μw heating at 80°C for 15 min to obtain furocoumarins 4 with >96% conversion, as detected by LC-MS. It was found that cycloaddition reactions for the furoquinolone intermediate 4f using N-methyl quinolone required more time and a higher temperature for completion. Sequential Suzuki coupling reactions of 4 with phenyl boronic acids [16] to form 6 were conducted in the same vial, without isolation of the intermediate. The Suzuki reactions were carried out using Pd(dppf)Cl2 as a catalyst, 4:4:1 acetone/toluene/water as a co-solvent, and Cs2CO3 as a base under μw heating at 130°C for 30 min. Fourteen compounds 6 were prepared in 40–70% yields after flash chromatography purification. The structures of the final products were characterized by LC-MS, 1H and 13C NMR analysis.

Table 2

One-pot synthesis of furocoumarin and furoquinolone derivatives 6.

Table 2 One-pot synthesis of furocoumarin and furoquinolone derivatives 6.

3.3 Synthesis of furopyrimidine derivatives 9

We also attempted the synthesis of furopyrimidine derivative 9a by the one-pot MCR and Suzuki coupling reaction sequence. The MCR of 1,3-dimethylbarbituric acid with 4-bromobenzaldehyde and cyclohexyl isocyanide afforded the desired product 10 in 94% yield. However, the Suzuki reaction of 10 under our conditions was not able to give the product 9a (Table 3). The furopyrimidine ring was decomposed during the reaction. We developed an alternative pathway for the synthesis of 9 by first performing the Suzuki coupling reaction of 4-bromobenzaldehyde 2a with the boronic acid. The coupling product 7a was then used for the MCR with 1,3-dimethylbarbituric acid 8 and cyclohexyl isocyanide 3a under μw heating at at 80°C for 20 min to give 9a in 98% yield (Scheme 3). Using this approach, we completed the synthesis of seven furopyrimidine derivatives 9a–g in 95–98% yields.

Scheme 3 Synthesis of pyrimidine compound 9a.
Scheme 3

Synthesis of pyrimidine compound 9a.

Table 3

Synthesis of furopyrimidine derivatives 9.

Table 3 Synthesis of furopyrimidine derivatives 9.

4 Conclusions

In summary, we have developed an atom- and step-efficient synthesis of biaryl substituted furocoumarin and N-methyl quinolone derivatives 6, by conducting a sequential three-component reaction and the Suzuki coupling reaction in one pot. We also developed an alternative method for the synthesis of furopyrimidine derivatives 9, by conducting the Suzuki reaction first followed by the three-component reaction. All the reactions were conducted under μw heating to further increase the reaction efficiency.

Corresponding author: Wei Zhang, Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA, e-mail:

About the authors

Asha Kadam

Asha Kadam is a senior PhD student in Professor Wei Zhang’s group at the University of Massachusetts Boston. She received her MS degree in Organic Chemistry from the University of Mumbai, India. Her current research comprises multicomponent synthesis, fluorous chemistry, and Grignard reactions.

Stephanie Bellinger

Stephanie Bellinger is a graduate student at the University of Massachusetts Boston. She is currently in Professor Rochford’s research group investigating chromophores for use as dye sensitizers and molecular photoacoustic contrast agents.

Wei Zhang

Dr. Wei Zhang is Professor and Director of the Center for Green Chemistry at the University of Massachusetts Boston. He was a Senior Chemist at DuPont and Director at Fluorous Technologies, Inc. He has 150 publications on fluorous chemistry, free radical chemistry, and green chemistry.

We thank the University of Massachusetts Boston Joseph P. Healy Grant for supporting this work.

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Received: 2013-7-19
Accepted: 2013-8-20
Published Online: 2013-09-14
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/gps-2013-0064
Schlagwörter für diesen Artikel
atom economy; furocoumarin; furopyrimidine; furoquinolone; multicomponent reaction; one-pot synthesis; step economy
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Artikel in diesem Heft

  1. Masthead
  2. Masthead
  3. Graphical abstracts
  4. In this issue
  5. Editorial
  6. “Teamed Science” – the Future, and is 1+1=3?
  7. CoPIRIDE
  8. EU FP7 Project CoPIRIDE – towards new production and factory concepts for a sustainable and competitive European chemical industry
  9. Investigations on the anionic polymerization of butadiene in capillaries by kinetic measurements and reactor simulation
  10. Supercritical fluid technology in biodiesel production: pilot plant design and operation
  11. Supercritical fluid technology in biodiesel production
  12. Selective epoxidation of soybean oil with performic acid catalyzed by acidic ionic exchange resins
  13. Multi-injection microstructured reactor for intensification of fast exothermic reactions: proof of concept
  14. Novel manufacturing techniques for microstructured reactors in industrial dimensions
  15. Bridging sustainability and intensified flow processing within process design for sustainable future factories
  16. Process intensification in gas-to-liquid reactions: plasma promoted Fischer-Tropsch synthesis for hydrocarbons at low temperatures and ambient pressure
  17. Original articles
  18. Atom- and step-economic synthesis of biaryl-substituted furocoumarins, furoquinolones and furopyrimidines by multicomponent reactions and one-pot synthesis
  19. Development of a continuous emulsification process for a highly viscous dispersed phase using microstructured devices
  20. Conference announcements
  21. Ecochem: Free Conference & Exhibition on Sustainable Chemistry & Engineering (MCH Congress Center, Basel, Switzerland, November 19–21, 2013)
  22. 3rd Industrial Green Chemistry World: Convention & Ecosystem (IGCW-2013; Mumbai, India, December 6–8, 2013)
  23. 52nd Eastern Analytical Symposium and Exposition (EAS2013): Analytical in Motion: Knowledge, Network, and Career (Somerset, NJ, USA, November 18–20, 2013)
  24. 2nd International Flow Chemistry Asia Conference and Tradeshow, held in association with the Flow Chemistry Society (Singapore, November 14–15, 2013)
  25. 15th Brazilian Meeting on Organic Synthesis (15th BMOS): Applied Organic Synthesis in Action: Strategies and Process Development (Campos do Jordão, Brazil, November 10–13, 2013)
  26. 1st International Symposium on Nanoparticles/Nanomaterials and Applications (ISN2A-2014; Costa de Caparica, Portugal, January 20–22, 2014) and 1st International Conference on Ultrasonic-based Applications: from Analysis to Synthesis. (ULTRASONICS2014; Costa de Caparica, Portugal, September 15–17, 2014)
  27. Sustainable Oil and Gas 2013 (Edinburgh, Scotland, November 25–26, 2013)
  28. Conferences 2013–2017
  29. Book reviews
  30. Biomimetics: a molecular perspective
  31. Right first time in fine-chemical process scale-up
  32. Chemical photocatalysis
  33. Industrial separation processes: fundamentals
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