New Approach to 1,4‐Benzoxazin‐3‐ones by Electrochemical C−H Amination

Abstract

1,4-Benzoxazin-3-ones are important structural motifs in naturalp roducts and bioactive compounds. Usually,t he synthesis of benzoxazinones requires transitionmetal catalystsa nd pre-functionalized substrates such as aryl halides. However,t he anodicC ÀHa mination of phenoxy acetates offers av ery efficient and sustainable access to these heterocycles. The presented electrochemical protocol can be appliedt oabroad scope of alkylated substrates. Even tert-butyl moieties or halogens ubstituents are compatible with this versatile method.The 1,4-benzoxazin-3-ones caffold has been recognized as an important heterocyclic motif in natural products as well as in pharmaceutically active compounds. [1] Naturally occurring benzoxazin-3-ones, like 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA, 1)a nd 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA, 2)w ere found in gramineousp lants like maize, wheat, rye, and rice ( Figure 1). [2, 3] Biosynthesis of DIMBOA (2)i s accomplished by the hydroxylation of indole derivatives using P450 monooxogenase. Intermediates of this reactionp athway can also be found in tryptophan biosynthesis. [4] Alternatively, benzoxazinones 3 and 4 are interesting compounds for pharmaceutical applications.T he former is an inhibitor of bacterial histidinep rotein kinase, [5] whereas the latter is ap otential agent for the treatment of anxiety and depression symptoms (Figure 1). [6,7] Common synthetic strategies to construct benzoxazin-3-ones employ ortho-substituted nitrophenols or halophenols as startingm aterials. [2, 8] Recently,E lKaïme tal. reported at hreecomponent reaction to access the benzoxazinone scaffold throughaPasserini-Smilesr earrangement, followed by hydrogenationand in situ cyclization. [9] Moreover,Liu and co-workers developed ac opper(I)-catalyzed one-pot synthesis of benzoxazinones. [6] In this approach, ortho-halophenols react with achloroacetamides in the presence of am etal promoter.H owever,adisadvantage of such approaches is the need for transition-metal catalysts as well as pre-functionalized substrates, for example, aryl halogenides or nitroaromatic compounds.I np articular,n itroaromatic starting materials are sometimes difficult to obtain selectively because nitration usually leads to regioisomericmixtures. [10] Purification of such mixturesoften is atedious process. Recently,Y oshida and co-workers reported in as eries of accountsapowerful and selectivee lectrochemical CÀNb ond-formation reactions, [11][12][13] including an ovel method for the synthesis of benzoxazoles 7 (Scheme 1). [14] The phenolic substrates for the electrochemical synthesis of oxazoles 7 were initially modified with ap yrimidine moiety. This promotesa ni ntramolecular electrochemical CÀNc oupling reaction.T he anodic amination proceeds via positivelyc harged Zinckei ntermediates 6 and 9,w hich prevent furthera nodic degradation, thus increasing the selectivity.T he corresponding amino moieties can be liberated in al ater step at non-electrolytic conditions.

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

“…321 The electrochemical formation of Zincke intermediates also allowed Yoshida, Waldvogel, and co-workers to devise an expeditious syntheses of 1,4-benzoxazin-3-ones (Figure 19D). 322 …”

Electrifying Organic Synthesis

“…53, 54 Electrochemical oxidation of phenoxyacetate substrates afforded the corresponding pyridinium derivatives. Treatment with piperidine released the primary amine, which immediately attacked the ester moiety, yielding the desired benzoxazinone.…”

“…An electrochemical route to 1,4-benzoxazin-3-ones, important structural motifs in natural products and in pharmaceutically active compounds,b ya nodic CÀHa mination of phenoxyacetate derivatives was established by the groups of Yoshida and Waldvogel (Scheme 12). [53,54] Electrochemical oxidation of phenoxyacetate substrates afforded the corresponding pyridinium derivatives.T reatment with piperidine released the primary amine,w hich immediately attacked the ester moiety,yielding the desired benzoxazinone. To enable ring closure,the amination needs to occur ortho to the carboxymethoxy substituent.…”

Electrochemical Synthesis of 3‐Bromoimidazo[1,2‐a]pyridines Directly from 2‐Aminopyridines and alpha‐Bromoketones

“…[7] Additionally, extensive efforts on electrosynthesis of N-heterocycles have been made, and great achievement has been reached. [8] In continuation of our interest in electrochemical organic synthesis, [9] herein, we report a sequential one pot electrochemical synthesis of 3-bromoimidazo[1,2-a]pyridines from 2-aminopyridines and α-bromoketones through the electrogenerated bromine. [10] (Scheme 1).…”