Catalytic Selective Oxidative Coupling of Secondary N-Alkylanilines: An Approach to Azoxyarene

Abstract

Azoxyarenes are among important scaffolds in organic molecules. Direct oxidative coupling of primary anilines provides a concise fashion to construct them. However, whether these scaffolds can be prepared from secondary N-alkylanilines is not well explored. Here, we present a catalytic selective oxidative coupling of secondary N-alkylaniline to afford azoxyarene with tungsten catalyst under mild conditions. In addition, azoxy can be viewed as a bioisostere of alkene and amide. Several “azoxyarene analogues” of the corresponding bioactive alkenes and amides showed comparable promising anticancer activities.

Dienedioic acid as a useful diene building block via directed Heck-decarboxylate coupling

“…Azoxymycin A, B, and C are quite unique natural products containing diarylazoxy scaffolds isolated from Streptomyces chattanoogensis by Li 2 . Interestingly, the proposed biosynthetic pathway 35 is quite similar to our research in tungstate-catalyzed azoxy synthesis 9 .…”

“…16). Meanwhile, methyl sorbate (1-16) bearing similar steric and electronic properties as those of sorbic acid, afforded no ɑand β-selective products (5)(6)(7)(8)(9)(10)(11)(12)(13)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Instead, the δ-selective product 5-15 was observed by H-NMR, in consistent with Heck's discovery 42 (Fig.…”

“…Heteroarenes are frequently encountered in medicinal chemistry, and it is important to develop novel access to their functionalization. Therefore, several heteroaryl bromides were selected and tested in this reaction, including benzofuran (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), benzothiophene (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), pyridine (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(1...…”

“…Of note, pyridine (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and isoquinoline bearing Lewis basic nitrogen can be well tolerated, although they could coordinate to palladium. However, 2-bromopyridine failed to afford the desired coupling product (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…Therefore, a late-stage biomimetic synthesis of azoxymycin C was conducted (see Supplementary Note 1), utilizing both the decarboxylative coupling and tungstate-catalyzed azoxy formation 9 developed in our lab. After installing the diene moiety, deprotonation, and azoxy formation from compound 1-2, the desired product 7-1 was isolated as a yellow solid in moderate yield (Fig.…”