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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

Summary

New routes for the synthesis of nitrogen-containing heterocycles utilizing cercosporin as a metal-free photocatalyst were developed.

Abstract

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. Traditionally, they were synthesized through thermal cycloaddition reactions, whereas today, photocatalysis is preferred due to the mild and efficient conditions. With this focus, a new photocatalytic method for the synthesis of nitrogen-containing heterocycles is highly desired. Here, we report a protocol for the biosynthesis of cercosporin, which could function as a metal-free photocatalyst. We then illustrate cercosporin-photocatalyzed protocols for the synthesis of nitrogen-containing heterocycles 1,2,3-thiadiazoles through annulation of azoalkenes with KSCN, and synthesis of 1,4,5,6-tetrahydropyridazines [4+2] through cyclodimerization of azoalkenes under mild conditions, respectively. As a result, there is a new bridge between the microbial fermentation method and organic synthesis in a mild, cost-effective, environmentally friendly and sustainable manner.

Introduction

Nitrogen-containing heterocycles have drawn much attention since they are not only important skeletons for a wide range of natural products with bioactivities, but also the synthetic precursors for agrochemicals and drug molecules1,2. Among the various N-heterocycles, 1,2,3-thiadiazoles3,4 and 1,4,5,6-tetrahydropyridazines5,6 are the most important molecules, which are utilized as versatile intermediates in the synthetic chemistry (Figure 1). Since modification of their functional groups always induces distinctive pharmacological activities, extensive efforts have been devoted to developing effective strategies for the synthesis of nitrogen-containing heterocycles and they were mostly synthesized through thermal cycloaddition reactions7,8,9,10. Nowadays, to meet the requirements of sustainable development and green chemistry, photocatalysis has exerted great importance and advantages11,12,13,14, which includes effectiveness15,16,17,18,19 and avoidance of stoichiometric reagents for the activation20,21. The powerful and versatile four-unit intermediates, azoalkenes (1,2-diaza-1,3-dienes)22,23,24,25,26,27,28,29, have been employed as precursors in metal-based Ru(bpy)3Cl2-photocatalyzed reactions with high efficiency for the annulation of halogeno hydrazine and ketocarbonyls30. Furthermore, it was also used in the metal-free Eosin Y photocatalyzed system, but affording the desired product in only 7% yield. Since metal-free photocatalysts show great advantage over transition metal-based photocatalysts, regarding to the environmental factor as well as the cheaper prices18,19, it is highly important to develop new metal-free photocatalytic systems for the synthesis of N-heterocycles.

Cercosporin31,32,33,34,35, hypocrellin36,37,38,39,40, elsinochrome41 and phleichrome42,43 (Figure 2) belong to perylenequinonoid pigments (PQPs) in nature and are produced by endophytic fungi, which have been widely investigated regarding to their photophysical and photobiological properties, and applied in photodynamic therapy and photophysical diagnosis, due to their strong absorption in UV-vis region and unique properties of photosensitization36,44,45,46,47. Upon irradiation, those PQPs can be prompted to excited state and then generate active species through energy transfer (EnT) and electron transfer (ET)35,38,44,48,49,50,51,52,53,54. Thus, we envisioned that these natural PQPs may be utilized as "metal-free" photocatalysts to drive organic reactions, which have rarely been investigated55,56,57,58,59.

Herein, we report the protocol for the biosynthesis of cercosporin from liquid fermentation and then apply it as a metal-free photocatalyst for the [4+1] annulation reaction of azoalkenes and KSCN, as well as the [4+2] cyclodimerization of azoalkenes, which supply 1,2,3-thiadiazoles and 1,4,5,6- tetrahydropyridazines with high efficiency under mild conditions, respectively (Figure 3).

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Protocol

NOTE: α-Halo-N-acyl-hydrazones were prepared according to a published procedure60. All the solvents and other chemical reagents were obtained from commercial sources without further purification. We first described the synthesis of α-Halo-N-acyl-hydrazones and the biosynthesis of cercosporin as a metal-free photocatalyst. Next, we illustrated the protocols of the cercosporin-photocatalyzed reactions for the synthesis of 1,2,3-thiadiazoles and 1,4,5,6-tetrahydropyridazines.

CAUTION: All the manipulation should be conducted cautiously wearing gloves, lab-coat, and goggles. It is highly recommended to carefully read the MSDS for each chemical and solvent used in those reactions and purification process. Chemicals can be weighed out on a balance on the bench. All the organic reactions should be set up in the fume hood and the purification process should also be carried out in a fume hood.

1. Preparation of α-Halo-N-acyl-hydrazones

  1. Weigh out 10 mmol of ketone and 10 mmol of benzoyl hydrazine into a flask.
  2. Add 20 mL of CH3OH to the flask.
  3. Equip the flask with a rubber stopper and a stirring bar.
  4. Inject 0.25 mL of HCl slowly into the mixture.
  5. Incubate the flask in the air at room temperature for 4 h.
  6. Collect the precipitate after reaction by filtration and wash with acetone.
  7. Dry the product by vacuum and identify by NMR.

2. Preparation of cercosporin

  1. Charge a 3 L shake flask with 1 L of S-7 medium.
  2. Inoculate the cercosporin-producing strain56 into the shake flask.
  3. Culture the mixture under light conditions at 135 r/min, 25 °C for 2 weeks.
  4. Subject the fermentation broth to vacuum filtration using a vacuum pump to obtain the supernatant and pellet.
  5. Collect the pellet and dry it in a freeze dryer.
  6. Extract the pellet and the supernatant separately with 3 x 50 mL of dichloromethane.
  7. Combine the organic phases and wash with water 2-3 times.
  8. Concentrate the organic phase under vacuum.
  9. Re-dissolve the residue with analytical methanol, and filter through a 0.18 µm organic microfiltration membrane.
  10. Purify the cercosporin with a Sephadex LH-20 column and identify by HPLC.

3. Preparation of 1,2,3-thiadiazoles

  1. Weigh out the α-Halo-N-acyl-hydrazone (0.2 mmol, 1.0 eq), 1 mg of cercosporin (0.002 mmol, 0.01 equiv.), 27 mg of tBuOK (1.2 equiv) and 39 mg of KSCN (2 equiv) into a 10 mL Schlenk tub equipped with a rubber stopper and a stirring bar.
  2. Purge the Schlenk tube with O2 three times.
  3. Inject dry CH3CN (2 mL) to the Schlenk tube.
  4. Subject the Schlenk tube to a 5 W blue LED from the bottom for 16 h.
  5. Wash with 4 x 15 mL of saturated NaCl solution and combine the aqueous phase.
  6. Re-extract the aqueous phase with 4 x 15 mL of ethyl acetate.
  7. Combine organic phase and dry with anhydrous Na2SO4.
  8. Remove the solvent with vacuum evaporator.
  9. Purify the product 3 by silica gel column chromatography (eluent, petroleum: ethyl acetate = 10:1) and identify by NMR.

4. Preparation of 1,4,5,6-tetrahydropyridazine

  1. Weigh out the α-Halo-N-acyl-hydrazone (0.5 mmol), 2.7 mg of cercosporin (0.01 equiv), and 195 mg of Cs2CO3 (1.2 equiv) into a 10 mL Schlenk tub equipped with a rubber stopper and a stirring bar.
  2. Purge the Schlenk tube with N2 three times.
  3. Inject CH3CN/H2O (10:1, 2 mL) to the Schlenk tube.
  4. Subject the Schlenk tube to a 5 W blue LED from the bottom for 16 h.
  5. Wash with 4 x 15 mL of saturated NaCl solution and combine the aqueous phase.
  6. Re-extract the aqueous phase with 4 x 15 mL of ethyl acetate.
  7. Combine organic phase and dry with anhydrous Na2SO4.
  8. Remove the solvent with vacuum evaporator.
  9. Purify the product 4 by silica gel column chromatography (eluent, petroleum: ethyl acetate = 10:1) and identify by NMR.

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Results

Synthesis of α-Halo-N-acyl-hydrazones: They are synthesized according to Protocol 1.

Synthesis of cercosporin: It was synthesized and purified according to Protocol 2. 1H NMR (400 MHz, CDCl3): δ ppm 14.82 (s, 2H, ArH), 7.06 (s, 2H, ArH), 5.57 (s, 2H, CH2), 4.20 (s, 6H, 2OCH3), 3.62-3.57 (m, 2H, CH2), 3.42-3.37 (m,...

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Discussion

Nitrogen-containing heterocycles are important motifs for many new drugs and were traditionally synthesized through thermal cycloaddition reactions. Due to great interest, a new photocatalytic method for the synthesis of these compounds is highly desired. To take advantage of the excellent photosensitization properties of cercosporin, we applied cercosporin as a metal-free photocatalyst in two categories of annulation reactions to synthesize nitrogen-containing heterocycles.

First, we reported...

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Disclosures

The authors have nothing to disclose.

Acknowledgements

We thank for the National Key R&D Program of China (2018YFA0901700), Natural Science Foundation of Jiangsu Province (Grants No. BK20160167), the Thousand Talents Plan (Young Professionals), the Fundamental Research Funds for the Central Universities (JUSRP51712B), the National First-class Discipline Program of Light Industry Technology and Engineering (LITE2018-14) and Postdoctoral Foundation in Jiangsu Province (2018K153C) for the funding support.

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Materials

NameCompanyCatalog NumberComments
2,4'-DibromoacetophenoneENERGYD0500850050
2'-bromo-4-chloroacetophenoneENERGYA0500400050
2-Bromo-4'-fluoroacetophenoneENERGYA050037-5g
2-BromoacetophenoneENERGYA0500870050
4-BromobenzhydrazideENERGYB0103390010
4-ChlorobenzhydrazideENERGYD0511130050
4-FluorobenzhydrazideENERGYB010461-5g
5 W blue LEDPHILIPS29237328756
Benzoyl hydrazineENERGYD0500610250
CH2Cl2SINOPHARM80047360
CH3CNSINOPHARMS3485101
CH3OHSINOPHARM100141190
Cs2CO3ENERGYE060058-25g
Ethyl acetateSINOPHARM40065986
freeze dryerLABCONCO7934074
HPLCAgilent1260 Infinity II
KSCNENERGYE0104021000
Na2SO4SINOPHARM51024461
organic microfiltration membraneSINOPHARM92412511
S-7 mediumGluose 1g; Fructose 3g; Sucrose 6g; Sodium acetate 1g; Soytone 1g; Phenylalanine 5mg; Sodium benzoate 100mg; 1M KH2P04 buffer ph6.8; Biotin 1mg; Ca(NO3)2 6.5mg; Pyridoxal 1mg; Calcium pantothenate 1mg; Thiamine 1mg; MnCl2 5mg; FeCl3 2mg; Cu(NO3)2 1mg; MgSO4 3.6mg; ZnSO4 2.5mg
Schlenk tubSynthwareF891910
sephadex LH-20 columnGE17009001
shakerLab ToolsBSH00847
silica gelENERGYE011242-1kg
tBuOKENERGYE0610551000
vacuum bumpGreatwallSHB-III
vacuum evaporator

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