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

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 molecules^1,2. Among the various N-heterocycles, 1,2,3-thiadiazoles^3,4 and 1,4,5,6-tetrahydropyridazines^5,6 are the most important molecules, which are utilized as versatile intermediates in the synthetic chemistry (Figure 1). Since modification of thei....

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. ....

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, 2H, CH

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.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
2,4'-Dibromoacetophenone	ENERGY	D0500850050
2'-bromo-4-chloroacetophenone	ENERGY	A0500400050
2-Bromo-4'-fluoroacetophenone	ENERGY	A050037-5g
2-Bromoacetophenone	ENERGY	A0500870050
4-Bromobenzhydrazide	ENERGY	B0103390010
4-Chlorobenzhydrazide	ENERGY	D0511130050
4-Fluorobenzhydrazide	ENERGY	B010461-5g
5 W blue LED	PHILIPS	29237328756
Benzoyl hydrazine	ENERGY	D0500610250
CH2Cl2	SINOPHARM	80047360
CH3CN	SINOPHARM	S3485101
CH3OH	SINOPHARM	100141190
Cs2CO3	ENERGY	E060058-25g
Ethyl acetate	SINOPHARM	40065986
freeze dryer	LABCONCO	7934074
HPLC	Agilent	1260 Infinity II
KSCN	ENERGY	E0104021000
Na2SO4	SINOPHARM	51024461
organic microfiltration membrane	SINOPHARM	92412511
S-7 medium			Gluose 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 tub	Synthware	F891910
sephadex LH-20 column	GE	17009001
shaker	Lab Tools	BSH00847
silica gel	ENERGY	E011242-1kg
tBuOK	ENERGY	E0610551000
vacuum bump	Greatwall	SHB-III
vacuum evaporator