Abstract:Iron-assisted S(N)Ar reactions were performed for the first time on solid phase, and a library of 36 unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesized with this novel strategy. The scope of iron-assisted S(N)Ar reactions on solid phase was investigated, and reactions of representative nucleophiles from groups VI (O, S, and Se) and V (N and P) of the periodic table were examined. Decomplexation of resin-bound iron complexes was achieved with 1,10-phenanthroline under irradi… Show more
“…Merrifield resin was used as a solid support in the solid-phase synthesis outlined in Scheme . The first diversifying element was introduced by attachment of symmetrical, secondary diamines, as exemplified with piperazine, resulting in the resin-bound piperazine 1 . , 1 …”
Section: Resultsmentioning
confidence: 99%
“…The combination of a piperazinyl moiety with an aryl or hetaryl moiety (often in close proximity to each other) has been found to be a structural key element in the architecture of many biologically active compounds. Recently, we have reported a general solid-phase synthesis of substituted N -phenylpiperazines via iron-assisted nucleophilic aromatic substitution on solid phase . A number of N -monoarylated piparazines are known as ligands for G-protein-coupled receptors, such as nefazodone used in the treatment of depression as well as N , N‘-diarylated piperazines, such as the antifungal drug itraconazole .…”
Novel nonsymmetrical N-bi- and N-terarylpiperazines were synthesized on solid phase via three consecutive palladium-catalyzed cross-coupling reactions in which C-N, C-B, and C-C bonds are formed consecutively.
“…Merrifield resin was used as a solid support in the solid-phase synthesis outlined in Scheme . The first diversifying element was introduced by attachment of symmetrical, secondary diamines, as exemplified with piperazine, resulting in the resin-bound piperazine 1 . , 1 …”
Section: Resultsmentioning
confidence: 99%
“…The combination of a piperazinyl moiety with an aryl or hetaryl moiety (often in close proximity to each other) has been found to be a structural key element in the architecture of many biologically active compounds. Recently, we have reported a general solid-phase synthesis of substituted N -phenylpiperazines via iron-assisted nucleophilic aromatic substitution on solid phase . A number of N -monoarylated piparazines are known as ligands for G-protein-coupled receptors, such as nefazodone used in the treatment of depression as well as N , N‘-diarylated piperazines, such as the antifungal drug itraconazole .…”
Novel nonsymmetrical N-bi- and N-terarylpiperazines were synthesized on solid phase via three consecutive palladium-catalyzed cross-coupling reactions in which C-N, C-B, and C-C bonds are formed consecutively.
“…[311][312][313] Iron-catalyzed arylation of Merrifield resin-bound piperazine was also achieved (11-72% yields). 314 Wang and Huang adapted a palladium-catalyzed threecomponent coupling of aryl halides, dienes, and amines to SPS on Rink resin (~35-81% yields). 315 Yamazaki et al prepared indoles in an on-resin intramolecular cyclization by palladium-catalyzed amination, 316 and microwave-assisted aryl aminations on solid phase were reported by Weigand and Pelka.…”
Aliphatic and aromatic amino functionalities are present in a wide variety of natural products and drugs, as well as in synthetic small molecular probes with therapeutic and/or diagnostic potential in drug discovery. As solid-phase synthesis and combinatorial chemistry have emerged as important tools for generation of compound libraries, development of broad-scope and efficient chemistry for the introduction of various functional groups into resinanchored substrates is highly important. Herein, we present a review of the literature concerning formation of the amino functionality on solid phase.
“…A second substitution can be achieved after neutralization with an equivalent amount of acid. If the first nucleophile is attached to the solid phase, a library of substituted arenes can be generated [77]. With h 6 -(o-dichlorobenzene)FeCp + and a bis-heteroatom nucleophile, benzo-fused heterocycles (e.g., 34) are obtained after pyrolytic demetallation [78].…”
Section: S N Ar With Heteroatom Nucleophilesmentioning
Transition metals coordinated to the pi system of arenes function as strong electronwithdrawing groups and favor nucleophilic addition to the arene to give cyclohexadienyl-metal complexes. The regioselectivity of addition is influenced in subtle and indirect ways, compared to the powerful effect on both reactivity and regioselectivity of electron-withdrawing groups attached to the sigma bond system of the arene. The intermediate cyclohexadienyl complexes can be processed in several ways, leading to several distinct synthesis methods. Useful reactivity is known for several metal systems and each is discussed for specific reaction types. The presence of a fluoro or chloro substituent on the arene allows an effective analog of classical S N Ar reactivity, with a wide range of nucleophiles including simple amines, alkoxides, and carbon anions. Another general process is the addition/protonation protocol, where a hydrogen substituent on the arene is replaced by a nucleophile. This opens new questions of regioselectivity since the typical arene ligand has several hydrogens which are candidates for substitution. The formation of five-and six-membered rings by both general mechanisms are known. Less general indirect mechanisms (e.g., tele substitution) have also been defined.
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