Pseudo five-component synthesis of 2,5-di(hetero)arylthiophenes via a one-pot Sonogashira-Glaser cyclization sequence.
ABSTRACT: Based upon a consecutive one-pot Sonogashira-Glaser coupling-cyclization sequence a variety of 2,5-di(hetero)arylthiophenes were synthesized in moderate to good yields. A single Pd/Cu-catalyst system, without further catalyst addition, and easily available, stable starting materials were used, resulting in a concise and highly efficient route for the synthesis of the title compounds. This novel pseudo five-component synthesis starting from iodo(hetero)arenes is particularly suitable as a direct access to well-defined thiophene oligomers, which are of peculiar interest in materials science.
Project description:2,5-Di(hetero)arylfurans are readily accessible in a pseudo five-component reaction via a Sonogashira-Glaser coupling sequence followed by a superbase-mediated (KOH/DMSO) cyclization in a consecutive one-pot fashion. Besides the straightforward synthesis of natural products and biologically active molecules all representatives are particularly interesting due to their bright blue luminescence with remarkably high quantum yields. The electronic structure of the title compounds is additionally studied with DFT computations.
Project description:Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp<sup>3</sup>)-C(sp) coupling of unactivated C(sp<sup>3</sup>)-H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp<sup>3</sup>)-H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C(sp<sup>3</sup>)-H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C(sp<sup>3</sup>)-H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C(sp<sup>3</sup>)-C(sp), C(sp<sup>3</sup>)-C(sp<sup>2</sup>), and C(sp<sup>3</sup>)-C(sp<sup>3</sup>) bonds when allied with follow-up transformations.
Project description:A method for the radical chlorodifluoromethylation of (hetero)arenes using chlorodifluoroacetic anhydride is reported. This operationally simple protocol proceeds under mild photochemical conditions with high functional group compatibility and complements the large body of literature for the trifluoromethylation of (hetero)arenes. Introduction of the chlorodifluoromethyl motif enables rapid diversification to a wide array of aromatic scaffolds. This work showcases the chlorodifluoromethyl group as an attractive entryway to otherwise synthetically challenging electron-rich difluoromethyl(hetero)arenes. Furthermore, facile conversion of the CF2Cl moiety into the corresponding aryl esters, gem-difluoroenones, and ?-keto-esters is demonstrated.
Project description:Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.
Project description:A Cu-catalyzed strategy has been developed that harnesses a radical relay mechanism to intercept a distal C-centered radical for C-C bond formation. This approach enables selective ? C-H (hetero)arylation of sulfonamides <i>via</i> intramolecular hydrogen atom transfer (HAT) by an N-centered radical. The radical relay is both initiated and terminated by a Cu catalyst, which enables incorporation of arenes and heteroarenes by cross-coupling with boronic acids. The broad scope and utility of this catalytic method for ? C-H arylation is shown, along with mechanistic probes for selectivity of the HAT mechanism. A catalytic, asymmetric variant is also presented, as well as a method for accessing 1,1-diaryl-pyrrolidines <i>via</i> iterative ? C-H functionalizations.
Project description:DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify chemical starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C-N coupling is a valuable synthetic method for the construction of DECL chemical matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide and bromide electrophiles. We developed conditions utilizing an <i>N</i>-heterocyclic carbene-palladium catalyst that extends this reaction to the coupling of DNA-conjugated (hetero)aromatic chlorides with (hetero)aromatic and select aliphatic amine nucleophiles. In addition, we evaluated steric and electronic effects within this catalyst series, carried out a large substrate scope study on two representative (hetero)aryl bromides, and applied this newly developed method within the construction of a 63 million-membered DECL.
Project description:The construction of (hetero)biaryls, which are ubiquitous scaffolds among medical substances, functional materials, and agrochemicals, constitutes a key application of cross-coupling methods. However, these usually require multiple synthetic steps. Herein, we report a simple photoinduced and catalyst-free C-H/C-H (hetero)arylation cross-coupling through aryl thianthrenium salts, which are formed site-selectively by direct C-H functionalization. The key to this approach is the UV-light, which can disrupt the C-S bond to form thianthrene radical cations and aryl radicals.
Project description:Trifluoromethoxylated (hetero)arenes are of great interest for several disciplines, especially in agro- and medicinal chemistry. Radical C-H trifluoromethoxylation of (hetero)arenes represents an attractive approach to prepare such compounds, but the high cost and low atom economy of existing <sup>.</sup> OCF<sub>3</sub> radical sources make them unsuitable for the large-scale synthesis of trifluoromethoxylated building blocks. Herein, we introduce bis(trifluoromethyl)peroxide (BTMP, CF<sub>3</sub> OOCF<sub>3</sub> ) as a practical and efficient trifluoromethoxylating reagent that is easily accessible from inexpensive bulk chemicals. Using either visible light photoredox or TEMPO catalysis, trifluoromethoxylated arenes could be prepared in good yields under mild conditions directly from unactivated aromatics. Moreover, TEMPO catalysis allowed for the one-step synthesis of valuable pyridine derivatives, which have been previously prepared via multi-step approaches.
Project description:We developed a one-pot, two-stage synthetic route to substituted 4-aminoquinolines involving an imidoylative Sonogashira coupling followed by acid-mediated cyclization. This three-component reaction affords pharmaceutically valuable 4-aminoquinolines in a one-pot procedure from readily available starting materials. The reaction tolerates various substituents on the arene as well as the use of secondary and even primary isocyanides. Additionally, the wide tolerance for functionalized isocyanides allows for the one-pot synthesis of various substituted chloroquine analogues as well as other medicinally relevant products.
Project description:Applications of TEMPO<sup>.</sup> catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO<sup>.</sup> -catalyzed, redox-neutral C-H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO<sup>.</sup> /TEMPO<sup>+</sup> redox catalytic cycle. Mechanistic studies also suggest that Li<sub>2</sub> CO<sub>3</sub> plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO<sup>.</sup> catalysis.