Aniline derivatives natural product synthesis

Indole derivatives are biologically important natural products. Many efforts have been made to achieve the synthesis of this motif. Various innovative and powerful methodologies for the synthesis of indole derivatives have been developed. Recently, Glorius and co-workers reported an efficient oxidative synthesis of indoles from N-arylenamines using Pd(OAc)2 as a catalyst and Cu(OAc)2 as a stoichiometric oxidant (Equation 11.38) [77]. This method represents an excellent example of constructing C—C bonds by direct use of two C—H bonds. This conversion of anilines into indoles can also be carried out in a one-pot sequence. 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

Generally, the reaction works well for electron-deficient anilines. A modified approach using in situ prepared chlorosulfonium salts is preferred for more electron-rich anilines. Substituted thiol derivatives can be used to produce 3-oxindoles, which can be further reduced to 3-indole derivatives that are not available via the Gassman indole synthesis. The reaction is equally useful for the preparation of isatin derivatives vide infra). Historically, the Gassman oxindole synthesis has found applications in the preparation of heterocycles with medical or insecticidal properties. The reaction also has potential applications for the synthesis of oxindole containing natural products. ... 

Reddy and colleagues devised a novel method for the divergent synthesis of 2,3-disubstituted indoles or 2,4,5-trisubstituted pyrroles from a-diazoketone 126. In the presence of copper(II) triflate, treatment of a-diazoketone 126 with enamine 129 gave pyrrole 130 if 126 was instead treated with aniline derivative 127, indole 128 resulted. The study culminated in the formal synthesis of indole-containing natural product homofascaplysin C (130L464). 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

Indole and isoquinolone nuclei are prominent structural units frequently found in numerous natural products and pharmaceutically active compounds. Thus, the search for new methodologies to obtain these scaffolds with different substitution patterns is a current major objective in organic synthesis. Similar to benzofuran synthesis, Aluraez et al. observed that the palladium-catalyzed cascade intramolecular alkyne aminopaUadation/intermolecular Heck-type coupling reaction under oxidative conditions is an efficient methodology for the synthesis of indole 217 and isoquinolone 219 derivatives, starting from readily available aniline 216 or benzamide 218 substrates and functional alkenes [77] (Scheme 6.60). 

Carbazoles are pharmaceutically important heterocycles, and are attractive targets for organic chemists. Carbazole alkaloids are natural products exhibiting antitumor, antibacterial, antimicrobial, and antiinflammatory activities. Some carbazole derivatives display photoconducting and semiconducting properties. The nucleophylic approach can be used for the synthesis of the carbazole core. For example, intramolecular cyclization of 2-(6-substituted-3-(Z)-hexene-l,5-diyne)anilines 3.702 was accomplished for the synthesis of 5-carbazoles 3.703 in 65-85% yield (Scheme 3.76) [331]. 

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