4-Chloro-2-Fluoro-5-Nitrobenzoic Acid as a Possible Building Block for Solid-phase Synthesis of Various Heterocyclic Scaffolds

Abstract

4-Chloro-2-fluoro-5-nitrobenzoic acid is a commercially available multireactive building block that can serve as a starting material in heterocyclic oriented synthesis (HOS) leading to various condensed nitrogenous cycles. This work describes its ability for the preparation of substituted nitrogenous heterocycles having 5-7-membered cycles via polymer-supported o-phenylendiamines. Immobilization of this compound on Rink resin followed by further chlorine substitution, reduction of a nitro group and appropriate cyclization afforded benzimidazoles, benzotriazoles, quinoxalinones, benzodiazepinediones and succinimides. The method developed is suitable for the synthesis of diverse libraries including the mentioned types of heterocycles, which have significant importance in current drug discovery. In this paper, we also report limitation of these method and unsuccessful attempt to prepare an 8-membered benzodiazocine cycle.

Veni, Vidi, Vici: Immobilized Peptide-Based Conjugates as Tools for Capture, Analysis, and Transformation

“…The solid-supported synthesis of peptides allows not only for a quick and efficient assembly of peptide chains, there are also multiple procedures for the on-resin modification of peptides directed at the formation of heterocyclic structures (Figure 9A,B) [140,141]. The relatively easy method for producing novel arrangements of structural features was explored in the design and synthesis of combinatorial libraries aimed at optimizing the complex stability [142][143][144]. The distribution of functional groups in peptide scaffold allows not only for the N-terminal and C-terminal tethering of the ligand moiety, but also for the attachment to specific side chains using the existing functionalities or the application of nonproteinaceous amino acids, including the formation of pincer structures [145][146][147][148].…”

Solid-Phase Synthesis of 4,7,8-Trisubstituted 1,2,3,4-Tetrahydro-benzo[e][1,4]diazepin-5-ones

“…For similar reaction we have previously developed a procedure consisting in heating with amine solution in DMSO to 120 °C. 2 In our case, the reaction had to be very carefully optimized due to relatively low reactivity of the starting material toward nucleophilic substitution at position 4 and simultaneous sensitivity of ester toward nucleophilic adition resulting in amide formation. We tested different reaction temperatures and solvents (such as DMSO, N-methylpyrrolidone NMP, diethylene glycole diethyl ether), but the products were contaminated by the corresponding amides in each case in spite of the substitution being carried out at lower temperature 80 °C (conventional heating).…”

“…Except applicability of the developed method for simple preparation of diverse 4,7,8-substituted benzodiazepinones the approach can be applied for combinatorial synthesis of libraries of BFHs (Scheme 1) with use of 4-chloro-2-fluoro-5-nitrobenzoic acid and previously described procedures. 2 ■ ASSOCIATED CONTENT * S Supporting Information Supporting Information contains details of experimental synthetic and analytical procedures and spectroscopic data for synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org.…”

“…1 The second contribution was focused on the "left side" heterocycle formation and methodology for the preparation of various nitrogen-containing scaffolds was developed (Figure 1). 2 In this contribution, we focused on an expansion of the right side heterocycles group to increase the number of scaffolds available for future synthesis of BFHs library. We aimed at the 1,2,3,4-tetrahydro-benzo[e] [1,4]diazepin-5-one derivatives I (Figure 1).…”

Palladium(II)‐Catalyzed Direct Arylations of Quinoxalin‐2(1H)‐ones with Arylsulfonyl Chlorides

“…Intrigued by the fascinating biological properties of 3arylquinoxalin-2(1H)-ones, different annulation strategies were developed for their construction, including the acylations/ cyclizations of o-phenylenediamines with phenylglyoxylic acid, [7] visible-light-induced cycloadditions of o-phenylenediamines with terminal alkynes, [8] and the cleavage of immobilized oxazolones with o-phenylenediamine nucleophiles. [9] Recent novel strategies for the construction of C3-functionalized quinoxalinones have emphasized the direct manipulation of readily accessible quinoxalin-2(1H)-ones.…”