Name: cercosporin-photocatalyzed [4+1]- and [4+2]-annulations of azoalkenes under mild conditions
Uploaded: 2020-07-17T13:00:00.000+00:00
Duration: 7 min 12 s
Description: Watch this Scientific Journal Video about Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions at JoVE.com

We thank for the National Key R&#38;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.

NOTE: &#945;-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 &#945;-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 &#945;-Halo-N-acyl-hydrazones
<ol>
	<li>Weigh out 10 mmol of ketone and 10 mmol of benzoyl hydrazine into a flask.</li>
	<li>Add 20 mL of CH3OH to the flask.</li>
	<li>Equip the flask with a rubber stopper and a stirring bar.</li>
	<li>Inject 0.25 mL of HCl slowly into the mixture.</li>
	<li>Incubate the flask in the air at room temperature for 4 h.</li>
	<li>Collect the precipitate after reaction by filtration and wash with acetone.</li>
	<li>Dry the product by vacuum and identify by NMR.</li>
</ol>
2. Preparation of cercosporin
<ol>
	<li>Charge a 3 L shake flask with 1 L of S-7 medium.</li>
	<li>Inoculate the cercosporin-producing strain56 into the shake flask.</li>
	<li>Culture the mixture under light conditions at 135 r/min, 25 &#176;C for 2 weeks.</li>
	<li>Subject the fermentation broth to vacuum filtration using a vacuum pump to obtain the supernatant and pellet.</li>
	<li>Collect the pellet and dry it in a freeze dryer.</li>
	<li>Extract the pellet and the supernatant separately with 3 x 50 mL of dichloromethane.</li>
	<li>Combine the organic phases and wash with water 2-3 times.</li>
	<li>Concentrate the organic phase under vacuum.</li>
	<li>Re-dissolve the residue with analytical methanol, and filter through a 0.18 &#181;m organic microfiltration membrane.</li>
	<li>Purify the cercosporin with a Sephadex LH-20 column and identify by HPLC.</li>
</ol>
3. Preparation of 1,2,3-thiadiazoles
<ol>
	<li>Weigh out the &#945;-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.</li>
	<li>Purge the Schlenk tube with O2 three times.</li>
	<li>Inject dry CH3CN (2 mL) to the Schlenk tube.</li>
	<li>Subject the Schlenk tube to a 5 W blue LED from the bottom for 16 h.</li>
	<li>Wash with 4 x 15 mL of saturated NaCl solution and combine the aqueous phase.</li>
	<li>Re-extract the aqueous phase with 4 x 15 mL of ethyl acetate.</li>
	<li>Combine organic phase and dry with anhydrous Na2SO4.</li>
	<li>Remove the solvent with vacuum evaporator.</li>
	<li>Purify the product 3 by silica gel column chromatography (eluent, petroleum: ethyl acetate = 10:1) and identify by NMR.</li>
</ol>
4. Preparation of 1,4,5,6-tetrahydropyridazine
<ol>
	<li>Weigh out the &#945;-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.</li>
	<li>Purge the Schlenk tube with N2 three times.</li>
	<li>Inject CH3CN/H2O (10:1, 2 mL) to the Schlenk tube.</li>
	<li>Subject the Schlenk tube to a 5 W blue LED from the bottom for 16 h.</li>
	<li>Wash with 4 x 15 mL of saturated NaCl solution and combine the aqueous phase.</li>
	<li>Re-extract the aqueous phase with 4 x 15 mL of ethyl acetate.</li>
	<li>Combine organic phase and dry with anhydrous Na2SO4.</li>
	<li>Remove the solvent with vacuum evaporator.</li>
	<li>Purify the product 4 by silica gel column chromatography (eluent, petroleum: ethyl acetate = 10:1) and identify by NMR.</li>
</ol>

The authors have nothing to disclose.

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 the protocol of cercosporin-photocatalyzed [4+1] annulation of azoalkenes with KSCN under standard conditions: &#945;-halo-N-acyl-hydrazone 1 (0.2 mmol), tBuOK (1.2 equiv), KSCN 2 (2 equiv), cercosporin (0.01 equiv), dry CH3CN (2 mL), and the resulting mixtures were subjected to 5 W blue LED for 16 h under an O2 atmosphere. KSCN functionalized as an ambident nucleophilic unit here. Cercosporin, tBuOK, blue light and O2 were all prerequisites for this reaction. CH3 CN supplied the best yield of product and 0.01 equiv. of cercosporin was the optimized ratio.
Second, we reported the protocol of cercosporin-photocatalyzed [4+2] annulation of azoalkenes under standard conditions: &#945;-halo-N-acyl-hydrazone 1 (0.5 mmol), Cs2CO3 (1.2 equiv), cercosporin (0.01 equiv) (CH3CN/H2O = 10:1) 2 mL, and the resulting mixtures were subjected to a 5 W blue LED for 16 h under a N2 atmosphere. The control experiments have been done for the [4+2] reaction as it was for the [4+1] reaction. In this protocol, the addition of water and Cs2CO3 was critical for the self-condensation of &#945;-halo-N-acyl-hydrazone. The ratios of water and Cs2CO3 were also critical to provide best yield for the product.
In summary, we have reported the biosynthesis protocol for cercosporin and then applied it as a metal-free photocatalyst for the synthesis of N-heterocycles 4-aryl-1,2,3-thiadiazoles and 1,4,5,6-tetrahydropyridazines under mild conditions, through [4+1] annulation of azoalkenes with KSCN and [4+2] annulation of azoalkenes, respectively. Those reactions made use of cost-effective 5 W LED and could be processed easily, which supplied a new application in synthesis. Most importantly, we built a bridge between biosynthesis and organic synthesis for the design of N-heterocycles in a mild, cost-effective, environmentally friendly and sustainable manner.

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 &#34;metal-free&#34; 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).

<table><tbody><tr><td>2,4&#039;-Dibromoacetophenone</td><td>ENERGY</td><td>D0500850050</td><td></td></tr><tr><td>2&#039;-bromo-4-chloroacetophenone</td><td>ENERGY</td><td>A0500400050</td><td></td></tr><tr><td>2-Bromo-4&#039;-fluoroacetophenone</td><td>ENERGY</td><td>A050037-5g</td><td></td></tr><tr><td>2-Bromoacetophenone</td><td>ENERGY</td><td>A0500870050</td><td></td></tr><tr><td>4-Bromobenzhydrazide</td><td>ENERGY</td><td>B0103390010</td><td></td></tr><tr><td>4-Chlorobenzhydrazide</td><td>ENERGY</td><td>D0511130050</td><td></td></tr><tr><td>4-Fluorobenzhydrazide</td><td>ENERGY</td><td>B010461-5g</td><td></td></tr><tr><td>5 W blue LED</td><td>PHILIPS</td><td>29237328756</td><td></td></tr><tr><td>Benzoyl hydrazine</td><td>ENERGY</td><td>D0500610250</td><td></td></tr><tr><td>CH&lt;sub&gt;2&lt;/sub&gt;Cl&lt;sub&gt;2&lt;/sub&gt;</td><td>SINOPHARM</td><td>80047360</td><td></td></tr><tr><td>CH&lt;sub&gt;3&lt;/sub&gt;CN</td><td>SINOPHARM</td><td>S3485101</td><td></td></tr><tr><td>CH&lt;sub&gt;3&lt;/sub&gt;OH</td><td>SINOPHARM</td><td>100141190</td><td></td></tr><tr><td>Cs&lt;sub&gt;2&lt;/sub&gt;CO&lt;sub&gt;3&lt;/sub&gt;</td><td>ENERGY</td><td>E060058-25g</td><td></td></tr><tr><td>Ethyl acetate</td><td>SINOPHARM</td><td>40065986</td><td></td></tr><tr><td>freeze dryer</td><td>LABCONCO</td><td>7934074</td><td></td></tr><tr><td>HPLC</td><td>Agilent</td><td>1260 Infinity II</td><td></td></tr><tr><td>KSCN</td><td>ENERGY</td><td>E0104021000</td><td></td></tr><tr><td>Na&lt;sub&gt;2&lt;/sub&gt;SO&lt;sub&gt;4&lt;/sub&gt;</td><td>SINOPHARM</td><td>51024461</td><td></td></tr><tr><td>organic microfiltration membrane</td><td>SINOPHARM</td><td>92412511</td><td></td></tr><tr><td>S-7 medium</td><td></td><td></td><td>Gluose 1g; Fructose 3g; Sucrose 6g; Sodium acetate 1g; Soytone 1g; Phenylalanine 5mg; Sodium benzoate 100mg; 1M KH&lt;sub&gt;2&lt;/sub&gt;P0&lt;sub&gt;4&lt;/sub&gt; buffer ph6.8; Biotin 1mg; Ca(NO&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt; 6.5mg; Pyridoxal 1mg; Calcium pantothenate 1mg; Thiamine 1mg; MnCl&lt;sub&gt;2&lt;/sub&gt; 5mg; FeCl&lt;sub&gt;3&lt;/sub&gt; 2mg; Cu(NO&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt; 1mg; MgSO&lt;sub&gt;4&lt;/sub&gt; 3.6mg; ZnSO&lt;sub&gt;4&lt;/sub&gt; 2.5mg</td></tr><tr><td>Schlenk tub</td><td>Synthware</td><td>F891910</td><td></td></tr><tr><td>sephadex LH-20 column</td><td>GE</td><td>17009001</td><td></td></tr><tr><td>shaker</td><td>Lab Tools</td><td>BSH00847</td><td></td></tr><tr><td>silica gel</td><td>ENERGY</td><td>E011242-1kg</td><td></td></tr><tr><td>&lt;em&gt;&lt;sup&gt;t&lt;/sup&gt;&lt;/em&gt;BuOK</td><td>ENERGY</td><td>E0610551000</td><td></td></tr><tr><td>vacuum bump</td><td>Greatwall</td><td>SHB-III</td><td></td></tr><tr><td>vacuum evaporator</td><td></td><td></td><td></td></tr></tbody></table>

cercosporin-photocatalyzed [4+1]- and [4+2]-annulations of azoalkenes under mild conditions

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.

Synthesis of &#945;-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): &#948; 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, 2H, CH2), 2.93-2.88 (m, 2H, CH2), 0.63 (d, 6H, J = 8 Hz, 2CH3) (Figure 4). 13C NMR (101 MHz, CDCl3): &#948; ppm 207.0, 181.8, 167.4, 163.4, 152.8, 135.4, 130.6, 127.9, 112.9, 109.3, 108.2, 92.6, 68.1, 61.2, 42.2, 19.3. HRMS (ESI-Q-TOF) exact mass calcd for C29H25O10 [M-H]- 533.1448, found 533.1468.
Synthesis of 4-Phenyl-1,2,3-thiadiazole (3a): It was synthesized and purified using Protocol 3 with 88% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 8.66 (s, 1H), 8.07-8.05 (m, 2H), 7.55-7.44 (m, 3H) (Figure 5). 13C NMR (100 MHz, CDCl3): &#948; ppm 162.9, 130.8, 129.9, 129.4, 129.2, 127.4 (Figure 6). HRMS (ESI-Q-TOF) exact mass calcd for C8H7N2S [M+H]+ 162.0330, found 163.0349.
Synthesis of 4-(4-Fluorophenyl)-1,2,3-thiadiazole (3b): It was synthesized and purified using Protocol 3 with 72% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 8.60 (s, 1H), 8.09-8.02 (m, 2H), 7.19-7.19 (m, 2H). 13C NMR (100 MHz, CDCl3): &#948; ppm 164.3-161.9 (d, JC-F = 240 Hz), 161.3, 133.6, 129.8 (d, JC-F = 9.0 Hz), 127.8 (d, JC-F = 3.0 Hz), 116.7 (d, JC-F = 22.0 Hz). HRMS (ESI-Q-TOF) exact mass calcd for C8H6FN2S [M+H]+ 181.0196, found 181.0191.
Synthesis of 4-(4-Chlorophenyl)-1,2,3-thiadiazole (3c): It was synthesized and purified using Protocol 3 with 87% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 8.65 (s, 1H), 8.00 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3): &#948; ppm 162.6, 135.5, 132.4, 129.4, 128.9, 128.7. HRMS (ESI-Q-TOF) exact mass calcd for C8H6ClN2S [M+H]+ 196.9940, found 196.9940.
Synthesis of 4-(4-Bromophenyl)-1,2,3-thiadiazole(3d): It was synthesized and purified using Protocol 3 with 78% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 8.66 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3): &#948; ppm 161.2, 134.3, 132.7, 130.4, 129.6, 119.1. HRMS (ESI-Q-TOF) exact mass calcd for C8H6BrN2S [M+H]+ 240.9435, found 240.9429.
Synthesis of (3,6-Diphenyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl)methanone (4a): It was synthesized and purified using Protocol 4 with 80% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 7.84-7.82 (m, 2H), 7.60-7.58 (m, 2H), 7.49-7.44 (m, 3H), 7.33-7.30 (m, 5H), 7.26-7.24 (m, 1H), 7.18 (d, J = 8 Hz, 2H), 6.09 (s, 1H), 2.71-2.67 (m, 1H), 2.43-2.16 (m, 3H) (Figure 7).
Synthesis of (3,6-Bis(4-fluorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)methanone (4b): It was synthesized and purified using Protocol 4 with 72% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 7.80-7.78 (m, 2H), 7.57-7.55 (m, 2H), 7.52-7.43 (m, 3H), 7.16-7.12 (m, 2H), 7.03-6.97 (m, 4H), 6.05 (s, 1H), 2.69-2.65 (m, 1H), 2.40-2.25 (m, 2H), 2.18-2.13 (m, 1H). 13C NMR (100 MHz, CDCl3): &#948; ppm 170.2, 163.4 (d, 1JC-F = 248.1 Hz), 162.0 (d, 1JC-F = 244.1 Hz), 146.0, 135.5 (d, 4JC-F = 3.1 Hz), 135.1, 133.2 (d, 4JC-F = 3.2 Hz), 130.4, 129.9, 127.5, 127.2 (d, 3JC-F = 8.2 Hz), 127.1 (d, 3JC-F = 8.0 Hz), 115.7 (d, 2JC-F = 21.5 Hz), 115.4 (d, 2JC-F = 21.6 Hz), 50.9, 24.0, 18.7. 19F NMR (376 MHz, CDCl3) (ppm) -111.7, -115.5. HRMS (ESI-Q-TOF) exact mass calcd for C23H19F2N2O [M+H]+ 377.1465, found 377.1482.
Synthesis of (3,6-Bis(4-chlorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)methanone (4c): It was synthesized and purified using Protocol 4 with 70% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 7.78 (d, J = 4 Hz, 2H), 7.50-7.43 (m, 5H), 7.30-7.26 (m, 5H), 7.10 (d, J = 8 Hz, 2H), 6.03 (s, 1H), 2.68-2.63 (m, 1H), 2.39-2.26 (m, 2H), 2.20-2.11 (m, 1H). 13C NMR (100 MHz, CDCl3): &#948; ppm 170.2, 145.8, 138.3, 135.4, 135.3, 134.9, 133.2, 130.5, 129.9, 129.0, 128.6, 127.5, 126.9, 126.6, 51.2, 29.7, 19.8, 18.6. HRMS (ESI-Q-TOF) exact mass calcd for C23H19Cl2N2O [M+H]+ 409.0874, found 409.0864.
Synthesis of (3,6-Bis(4-bromophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)methanone (4d): It was synthesized and purified using Protocol 4 with 82% yield. 1H NMR (400 MHz, CDCl3): &#948; ppm 7.78 (d, J = 8 Hz, 2H), 7.52-7.40 (m, 9H), 7.04 (d, J = 8 Hz, 2H), 6.01 (s, 1H), 2.67-2.62 (m, 1H), 2.39-2.25 (m, 2H), 2.20-2.11 (m, 1H). 13C NMR (100 MHz, CDCl3): &#948; ppm 170.2, 145.9, 138.9, 135.8, 134.8, 132.0, 131.6, 130.5, 129.9, 127.5, 127.2, 126.9, 119.6, 121.2, 51.3, 29.7, 19.8, 18.5. HRMS (ESI-Q-TOF) exact mass calcd for C23H19Br2N2O [M+H]+ 498.9845, found 498.9799.
These representative results demonstrate how 4-aryl-1,2,3-thiadiazoles and 1,4,5,6-tetrahydropyridazines can be conveniently synthesized by cercosporin-catalyzed photocatalytic reactions from &#945;-Halo-N-acyl-hydrazone (Figure 8).
4-aryl-1,2,3-thiadiazoles were obtained with those conditions: 1 (0.2 mmol), KSCN (0.4 mmol), tBuOK (0.24 mmol), CH3CN (2.0 mL), cercosporin (1 mol%), 5 W blue LED, 16 h, at room temperature under O2 atmosphere (Figure 3 and Figure 8). The procedure was suitable for substrates bearing both electron-donating and electron-accepting groups on the phenyl ring, providing the desired products with moderate to good yields.
1,4,5,6-tetrahydropyridazines were obtained with those conditions: 1 (0.5 mmol), Cs2CO3 (1.2 equiv) and cercosporin (1 mol%) in the mixture of MeCN and H2O (10:1) under N2 atmosphere (Figure 3 and Figure 8). The desired products were obtained in good to excellent yields.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60786/60786fig1.jpg" /> 
Figure 1: Bioactive molecules with N-heterocycles motifs. Adapted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/60786/60786fig2.jpg" /> 
Figure 2: Representative perylenequinonoid pigments in nature. Adapted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/60786/60786fig3.jpg" /> 
Figure 3: Cercosporin-Catalyzed Synthesis of 1,2,3-Thiadiazoles and 1,4,5,6- Tetrahydropyridazines. Adapted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/60786/60786fig4.jpg" /> 
Figure 4: 1H-NMR spectrum of cercosporin (400 MHz, CDCl3). Reprinted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/60786/60786fig5.jpg" /> 
Figure 5: Representative 1H-NMR spectrum of 3a (400 MHz, CDCl3). Reprinted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/60786/60786fig6.jpg" /> 
Figure 6: Representative 13C-NMR spectrum of 3a (400 MHz, CDCl3). Reprinted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/60786/60786fig7.jpg" /> 
Figure 7: Representative 1H-NMR spectrum of 4a (400 MHz, CDCl3). Reprinted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig7large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/60786/60786fig8.jpg" /> 
Figure 8: Cercosporin-Catalyzed Synthesis of 4-aryl-1,2,3-thiadiazoles and 1,4,5,6-tetrahydropyridazines. Adapted with permission from Zhang Y., Cao Y., Lu L. S., Zhang S. W., Bao W. H., Huang S. P., Rao Y. J. Perylenequinonoid-Catalyzed [4+1]-and [4+2]-Annulations of Azoalkenes: Photocatalytic Access to 1, 2, 3-Thiadiazole/1, 4, 5, 6-Tetrahydropyridazine Derivatives, Journal of Organic Chemistry. 84 (12), 7711-7721, (2019). Copyright (2019) American Chemical Society. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60786/60786fig8large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions at JoVE.com

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

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

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. ...

cercosporin-photocatalyzed-4-1-4-2-annulations-azoalkenes-under-mild

Nanyang Technological University

Research

JoVE Journal

Chemistry

6.2K Views.  Jiangnan University. Dit protocol kan worden gebruikt voor de biosynthese van cercosporines door middel van microbiële fermentatie, die op zijn beurt kan worden gebruikt om stikstofhoudende heterocycles te synthetiseren in de groene en milde omstandigheden. Een voordeel van deze techniek is dat het kan worden gebruikt als een brug tussen de microbiële fermentatiemethoden en de organische gesynthetiseerde processen. Stikstofhoudende heterocycles zijn niet alleen belangrijk skelet voor veel natuurlijke producten ...

Video: Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Preparation of a Corannulene-functionalized Hexahelicene by Copper(I)-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar polyaromatic units, which are two corannulene moieties and a racemic hexahelicene linking them. The compound described in this work is a good host for fullerenes. Several common organic reactions, such as free-radical reactions, C-C coupling or click chemistry, are employed demonstrating the versatility of functionalization that this compound can accept. All of these reactions work for planar aromatic molecules. With subtle modifications, it is possible to achieve similar results for nonplanar polyaromatic compounds.

Preparation of a Corannulene-functionalized Hexahelicene by CopperI-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

Here, we present a protocol to synthesize a complex organic compound comprised of three nonplanar polyaromatic units, assembled easily with reasonable yields.

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar ...

Controlled Photoredox Ring-Opening Polymerization of O-Carboxyanhydrides Mediated by Ni/Zn Complexes

Here, we describe an effective protocol that combines photoredox Ni/Ir catalysis with the use of a Zn-alkoxide for efficient ring-opening polymerization, allowing for the synthesis of isotactic poly(&#945;-hydroxy acids) with expected molecular weights (&#62;140 kDa) and narrow molecular weight distributions (Mw/Mn &#60; 1.1). This ring-opening polymerization is mediated by Ni and Zn complexes in the presence of an alcohol initiator and a photoredox Ir catalyst, irradiated by a blue LED (400 - 500 nm). The polymerization is performed at a low temperature (-15 &#176;C) to avoid undesired side reactions. The complete monomer consumption can be achieved within 4 - 8 hours, providing a polymer close to the expected molecular weight with narrow molecular weight distribution. The resulted number-average molecular weight shows a linear correlation with the degree of polymerization up to 1000. The homodecoupling 1H NMR study confirms that the obtained polymer is isotactic without epimerization. This polymerization reported herein offers a strategy for achieving rapid, controlled O-carboxyanhydrides polymerization to prepare stereoregular poly(&#945;-hydroxy acids) and its copolymers bearing various functional side-chain groups.

Controlled Photoredox Ring-Opening Polymerization of O-Carboxyanhydrides Mediated by Ni/Zn Complexes

A protocol for the controlled photoredox ring-opening polymerization of O-carboxyanhydrides mediated by Ni/Zn complexes is presented.

Here, we describe an effective protocol that combines photoredox Ni/Ir catalysis with the use of a Zn-alkoxide for efficient ring-opening polymerization, ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond&#8211;forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the &#945;-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

Photogeneration of N-Heterocyclic Carbenes: Application in Photoinduced Ring-Opening Metathesis Polymerization

We report a method to generate the N-heterocyclic carbene (NHC) 1,3-dimesitylimidazol-2-ylidene (IMes) under UV-irradiation at 365 nm to characterize IMes and determine the corresponding photochemical mechanism. Then, we describe a protocol to perform ring-opening metathesis polymerization (ROMP) in solution and in miniemulsion using this NHC-photogenerating system. To photogenerate IMes, a system comprising 2-isopropylthioxanthone (ITX) as the sensitizer and 1,3-dimesitylimidazolium tetraphenylborate (IMesH+BPh4-) as the protected form of NHC is employed. IMesH+BPh4- can be obtained in a single step by anion exchange between 1,3-dimesitylimidazolium chloride and sodium tetraphenylborate. A real-time steady-state photolysis setup is described, which hints that the photochemical reaction proceeds in two consecutive steps: 1) ITX triplet is photo-reduced by the borate anion and 2) subsequent proton transfer takes place from the imidazolium cation to produce the expected NHC IMes. Two separate characterization protocols are implemented. Firstly, CS2 is added to the reaction media to evidence the photogeneration of NHC through formation of the IMes-CS2 adduct. Secondly, the amount of NHC released in situ is quantified using acid-base titration. The use of this NHC photo-generating system for the ROMP of norbornene is also discussed. In solution, a photopolymerization experiment is conducted by mixing ITX, IMesH+BPh4-, [RuCl2(p-cymene)]2 and norbornene in CH2Cl2, then irradiating the solution in a UV reactor. In a dispersed medium, a monomer miniemulsion is first formed then irradiated inside an annular reactor to produce a stable poly(norbornene) latex.

We describe a protocol to photogenerate N-heterocyclic carbenes (NHCs) by UV irradiation of a 2-isopropylthioxanthone/imidazolium tetraphenylborate salt system. Methods to characterize the photoreleased NHC and elucidate the photochemical mechanism are proposed. The protocols for ring-opening metathesis photopolymerization in solution and miniemulsion illustrate the potential of this 2-component NHC photogenerating system.

We report a method to generate the N-heterocyclic carbene (NHC) 1,3-dimesitylimidazol-2-ylidene (IMes) under UV-irradiation at 365 nm to characterize IMes ...

[(DPEPhos)(bcp)Cu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the activation of a broad variety of organic halides, including unactivated ones. These can then participate in various radical transformations such as reduction and cyclization reactions, as well as in the direct arylation of several (hetero)arenes. These transformations provide a straightforward access to a range of small molecules of interest in synthetic chemistry, as well as to biologically active natural products. Altogether, [(DPEPhos)(bcp)Cu]PF6 acts as a convenient photoredox catalyst which appears to be an attractive, cheap and complementary alternative to the state-of-the-art iridium- and ruthenium-based photoredox catalysts. Here, we report a detailed protocol for the synthesis of [(DPEPhos)(bcp)Cu]PF6, as well as NMR and spectroscopic characterizations, and we illustrate its use in synthetic chemistry for the direct arylation of (hetero)arenes and radical cyclization of organic halides. In particular, the direct arylation of N-methylpyrrole with 4-iodobenzonitrile to afford&#160;4-(1-methyl-1H-pyrrol-2-yl)benzonitrile and the radical cyclization of N-benzoyl-N-[(2-iodoquinolin-3-yl)methyl]cyanamide to afford natural product luotonin A are detailed. The scope and limitations of this copper-based photoredox catalyst are also briefly discussed.

[DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst

Detailed and general protocols are presented for the synthesis of [(DPEPhos)(bcp)Cu]PF6, a general copper-based photoredox catalyst, and for its use in synthetic chemistry for the direct arylation of C-H bonds in (hetero)arenes and radical cyclization of organic halides.

Our group recently reported the use of [(DPEPhos)(bcp)Cu]PF6 as a general copper-based photoredox catalyst which proved efficient to promote the ...

Developing Photosensitizer-Cobaloxime Hybrids for Solar-Driven H2 Production in Aqueous Aerobic Conditions

Developing photocatalytic H2 production devices is the one of the key steps for constructing a global H2-based renewable energy infrastructure. A number of photoactive assemblies have emerged where a photosensitizer and cobaloxime-based H2 production catalysts work in tandem to convert light energy into the H-H chemical bonds. However, the long-term instability of these assemblies and the need for hazardous proton sources have limited their usage. Here, in this work, we have integrated a stilbene-based organic dye into the periphery of a cobaloxime core via a distinct axial pyridine linkage. This strategy allowed us to develop a photosensitizer-catalyst hybrid structure with the same molecular framework. In this article, we have explained the detailed procedure of the synthesis of this hybrid molecule in addition to its comprehensive chemical characterization. The structural and optical studies have exhibited an intense electronic interaction between the cobaloxime core and the organic photosensitizer. The cobaloxime was active for H2 production even in the presence of water as the proton source. Here, we have developed a simple airtight system connected with an online H2 detector for the investigation of the photocatalytic activity by this hybrid complex. This photosensitizer-catalyst dyad present in the experimental setup continuously produced H2 once it was exposed in the natural sunlight. This photocatalytic H2 production by the hybrid complex was observed in aqueous/organic mixture media in the presence of a sacrificial electron donor under complete aerobic conditions. Thus, this photocatalysis measurement system along with the photosensitizer-catalyst dyad provide valuable insight for the development of next generation photocatalytic H2 production devices.

Developing Photosensitizer-Cobaloxime Hybrids for Solar-Driven H2 Production in Aqueous Aerobic Conditions

We have directly incorporated a stilbene-based organic dye into a cobaloxime core to generate a photosensitizer-catalyst dyad for photocatalytic H2 production. We have also developed a simple experimental setup for evaluating the light-driven H2 production by photocatalytic assemblies.

Developing photocatalytic H2 production devices is the one of the key steps for constructing a global H2-based renewable energy infrastructure. A number ...

Easy Access to Aliphatic Sulfonamides using Sulfamoyl Chlorides Under Visible Light Activation

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due to their unique biological properties. Recently, several methods for the synthesis of aryl sulfonamides have been developed, but little effort has focused on developing one-step methodologies to access sulfonamides flanked by two alkyl groups. This protocol describes a practical and facile method for the net hydrosulfamoylation of electron-deficient alkenes using sulfamoyl chlorides as radical precursors under blue-light activation. This practical and cost-effective methodology is performed in the presence of the metal-free photocatalyst Eosin Y and uses light as a clean and traceless energy source. The procedure is scalable, displays a broad functional group tolerance, and can be applied for late-stage functionalization. All reagents used in this protocol are commercially available. Simple reaction set-up, the absence of work-up and easy purification, demonstrate the convenience of this protocol. The reaction is best applied to electron-deficient alkenes.

Presented here is a protocol for the easy synthesis of aliphatic sulfonamides using sulfamoyl chlorides, (TMS)3SiH and Eosin Y under blue-light irradiation.

Sulfonamides are prevalent motifs in marketed drugs and natural products. Their synthesis represents a great interest to the pharmaceutical industry, due ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

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