Electron-rich Heteroarenes Research Articles

HCl/DMSO/HFIP-Mediated Chlorination of Pyrrolo[2,1-a]isoquinolines and Other Electron-Rich Heteroarenes.

An efficient oxidative chlorination of pyrrolo[2,1-a]isoquinolines has been established using HCl (aq) as the chlorine source and DMSO as the terminal oxidant in HFIP at ambient temperature. A variety of chlorinated pyrrolo[2,1-a]isoquinoline derivatives have been prepared readily in 23 to 99% yields. This chlorination strategy can be expanded to the functionalization of other electron-rich heteroarenes including substituted pyrroles, indoles, and naphthols.

Nucleophilic Aromatic Substitution of Heteroaryl Halides with Thiols.

The nucleophilic aromatic substitution (SNAr) between heteroaryl halides (Cl, Br) and thiols proceeds smoothly in DMAc under the action of K2CO3 at rt-100 °C. For most electron-deficient heteroarenes, reaction takes place without introducing an additional electron-withdrawing group. For electron-rich heteroarenes, an additional electron-withdrawing group such as a simple ester, keto, cyano, and nitro group is required to ensure the reaction completes. The reactivity trend of heteroaryl halides is highly dependent on the electronic nature of the heteroarenes and orientation of halogens. Besides thiols, a couple of functionalized thioureas and thioamides are compatible with these conditions, providing the corresponding heteroaryl thioethers in good yields.

Nickel-Catalyzed Regioselectivity-Switchable Hydroheteroarylation of Vinylarenes with Electron-Rich Heteroarenes.

We report the first example of a regioselectivity switch in the hydroheteroarylation of vinylarenes with electron-rich heteroarenes, including benzofurans, benzothiophenes, and indoles, using an expedient ligand-controlled strategy. In the presence of NaOtBu, Ni(IMesMe)[P(OEt)3]Br2 yields C2-alkylated heteroarenes with high branched selectivity, whereas the use of Ni(IPr*OMe)[P(OEt)3]Br2 favors the formation of the corresponding linear products. This robust method also provides easy access to a range of C2-alkylated electron-rich heteroarenes without employing directing groups.

Combining photoredox catalysis and hydrogen atom transfer for dearomative functionalization of electron rich heteroarenes.

Reductive dearomatization has been a broadly explored means for rapid generation of sp3 complexity from simple planar arenes. Breaking the electron rich, stable aromatic systems requires strong reduction conditions. It has been notoriously challenging to dearomatize electron even richer heteroarenes. Herein we report an umpolung strategy enabling dearomatization of such structures under mild conditions. The reversal of the reactivity of these electron rich aromatics via photoredox mediated single electron transfer (SET) oxidation generates electrophilic radical cations, which can react with nucleophiles and break the aromatic structure to form a Birch type radical species. A crucial hydrogen atom transfer (HAT) is successfully engineered into the process to efficiently trap the dearomatic radical and minimize the formation of the overwhelmingly favorable, irreversible aromatization products. Particularly, a non-canonical dearomative ring-cleavage of thiophene/furan through selective C(sp2)-S bond breaking was first discovered. The preparing power of the protocol has been demonstrated for selective dearomatization and functionalization of various electron rich heteroarenes including thiophenes, furans, benzothiophenes and indoles. Furthermore, the process offers an unrivaled capacity for simultaneously introducing C-N/O/P bonds on these structures as exemplified by various "N", "O" and "P" centered functional moieties with 96 examples.

Photoredox-Promoted Selective Synthesis of C-5 Thiolated 2-Aminothiazoles from Terminal Alkynes.

A mild photoredox approach enabling the first one-step synthesis of thiolated 2-aminothiazoles has been reported. Notably, the incorporation of thio group on electron-rich heteroarenes such as aminothiazoles via conventional nucleophilic aromatic substitution (SNAr) presents a significant challenge owing to polarity mismatch. Herein, we present a remarkable site-selective installation of thio group at the C-5 position of the electron-rich aminothiazole skeleton and successfully used them for the postfunctionalization of drugs and natural products.

Photocatalytic decarboxylative alkylation of electron-rich heteroarenes with alkyl N-hydroxyphthalimide esters

We report a direct CH alkylation of heteroarenes via photocatalytic decarboxylative couplings. A series of primary, secondary, tertiary alkyl carboxylic acids and drug-derived N-hydroxyphthalimide esters are selectively coupled with various electron-rich heteroarenes, including furans, benzofurans and thiophenes. With advantages of mild reaction conditions, broad scopes of substrates and easy handling, this transformation represents a valuable method in organic synthesis.

Crystal engineering of heterocyclic arylene(ethynylene) oligomers through programmed aromatic stacking

Electron-rich heteroarenes stack with perfluoroarene side chains and twist arylene-ethynylene conjugated oligomers, while electron deficient heterocycles do not. These trends correlate with X-ray structures, optical spectra, and computations.

Spirocyclizative Remote Arylcarboxylation of Nonactivated Arenes with CO 2 via Visible-Light-Induced Reductive Dearomatization

Spirocyclizative Remote Arylcarboxylation of Nonactivated Arenes with CO ₂ via Visible-Light-Induced Reductive Dearomatization

Base-Mediated Intramolecular Cyclization of α-Nitroethylallenic Esters as a Synthetic Route to 5-Hydroxy-3-pyrrolin-2-ones

An unprecedented Cs2CO3-mediated intramolecular cyclization/rearrangement cascade that transforms α-nitroethylallenic esters to functionalized pyrrolin-2-ones has been uncovered. This reaction provides a new and practical approach for the synthesis of medicinally privileged 5-hydroxy-3-pyrrolin-2-ones under mild conditions. The broad potential of this new method was demonstrated by an efficient Au/Ag-catalyzed heteroarylation of 5-hydroxy-3-pyrrolin-2-ones employing electron-rich heteroarenes to furnish heteroaryl-lactam derivatives.

Enantioselective Three-Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates.

Asymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron-rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3-Disubstituted tetrahydrofurans and pyrrolidines are produced in trans configuration and excellent enantiomeric ratios. The reaction proceeds via Wacker-type attack of nucleophilic heteroarenes on alkenes activated by allenyl PdII species.

Organophosphorus-catalyzed relay oxidation of H-Bpin: electrophilic C-H borylation of heteroarenes.

A nontrigonal phosphorus triamide (1, P{N[o-NMe-C6H4]2}) is shown to catalyze C–H borylation of electron-rich heteroarenes with pinacolborane (HBpin) in the presence of a mild chloroalkane reagent. C–H borylation proceeds for a range of electron-rich heterocycles including pyrroles, indoles, and thiophenes of varied substitution. Mechanistic studies implicate an initial P–N cooperative activation of HBpin by 1 to give P-hydrido diazaphospholene 2, which is diverted by Atherton–Todd oxidation with chloroalkane to generate P-chloro diazaphospholene 3. DFT calculations suggest subsequent oxidation of pinacolborane by 3 generates chloropinacolborane (ClBpin) as a transient electrophilic borylating species, consistent with observed substituent effects and regiochemical outcomes. These results illustrate the targeted diversion of established reaction pathways in organophosphorus catalysis to enable a new mode of main group-catalyzed C–H borylation.

Rhodium-Catalyzed Atroposelective Oxidative C-H/C-H Cross-Coupling Reaction of 1-Aryl Isoquinoline Derivatives with Electron-Rich Heteroarenes.

Rhodium(III)-catalyzed enantioselective oxidative C-H/C-H cross-coupling reaction between two arenes is disclosed. With the combination of a chiral CpRh(III) complex and a chiral carboxylic acid additive, the direct coupling reactions between 1-aryl isoquinoline derivatives and electron-rich heteroarenes such as thiophenes, furans, benzothiophenes, and benzofurans are realized via a double C-H functionalization process. A series of axially chiral compounds are obtained in excellent yields and enantioselectivities (up to 99% yield and 99% ee). Mechanistic studies suggest that both C-H bond cleavages may not be the turnover-limiting step.

Site-Selective Thiolation of (Multi)halogenated Heteroarenes.

A general and simple strategy for the site-selective thiolation of various pharmaceutically relevant electron-rich heteroarenes with thiols is reported. This mild and reliable photocatalytic protocol enables C-S coupling at the most electron-rich position of the (multi)halogenated substrates, complementing established methodologies. Experimental and computational studies suggest a radical chain mechanism with the key step being a homolytic aromatic substitution of the heteroaryl halide by an electrophilic thiyl radical, highlighting an underdeveloped reactivity mode.

Carbonate-promoted C-H carboxylation of electron-rich heteroarenes.

C–H carboxylation is an attractive transformation for both streamlining synthesis and valorizing CO2. The high bond strength and very low acidity of most C–H bonds, as well as the low reactivity of CO2, present fundamental challenges for this chemistry. Conventional methods for carboxylation of electron-rich heteroarenes require very strong organic bases to effect C–H deprotonation. Here we show that alkali carbonates (M2CO3) dispersed in mesoporous TiO2 supports (M2CO3/TiO2) effect CO32−-promoted C–H carboxylation of thiophene- and indole-based heteroarenes in gas–solid reactions at 200–320 °C. M2CO3/TiO2 materials are strong bases in this temperature regime, which enables deprotonation of very weakly acidic bonds in these substrates to generate reactive carbanions. In addition, we show that M2CO3/TiO2 enables C3 carboxylation of indole substrates via an apparent electrophilic aromatic substitution mechanism. No carboxylations take place when M2CO3/TiO2 is replaced with un-supported M2CO3, demonstrating the critical role of carbonate dispersion and disruption of the M2CO3 lattice. After carboxylation, treatment of the support-bound carboxylate products with dimethyl carbonate affords isolable esters and the M2CO3/TiO2 material can be regenerated upon heating under vacuum. Our results provide the basis for a closed cycle for the esterification of heteroarenes with CO2 and dimethyl carbonate.

Arylation of heterocyclic compounds by benzimidazole-based N-heterocyclic carbene-palladium(II) complexes

Specific C–H bond can be activated for arylation using aryl halide without the aid of directing the group in the case of electron-rich heteroarenes. The ability to readily generate halo substituted arylated heteroarenes is important in organic chemistry since these species are important building blocks for biochemists. In this manuscript, we report the synthesis of PEPPSI type-novel benzimidazole-based N-heterocyclic carbene-palladium(II) complexes (2a-e). All of the new compounds were fully characterized by 1H, 13C{1H} NMR and FT-IR spectra. The structures of 2c, 2d, and 2e were determined by X-ray crystallography and the prepared complexes (2a-e) were investigated as catalysts for the direct arylation of 2-n-propylthiazole, 4,5-dimethylthiazole and 2-acetylthiophene with various aryl bromides. High catalytic activity for arylation was seen reaction using only 0.5 mol% catalyst for 1 h.

Palladium(0)-Catalyzed Directed syn-1,2-Carboboration and -Silylation: Alkene Scope, Applications in Dearomatization, and Stereocontrol by a Chiral Auxiliary.

We report the development of palladium(0)-catalyzed syn-selective 1,2-carboboration and -silylation reactions of alkenes containing cleavable directing groups. With B2 pin2 or PhMe2 Si-Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono-, di-, tri- and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2-carboboration of electron-rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck-type alkene 1,2-difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio- and stereocontrol.

Photocatalyst-Free Regioselective C–H Thiocyanation of 4-Anilinocoumarins under Visible Light

In the present study, we describe the successful development of a novel and efficient C(sp2)–H thiocyanation reaction of electron-rich heteroarenes and arenes with readily available ammonium thiocy...

Quaternary Phosphonium Salts as Active Brønsted Acid Catalysts for Friedel-Crafts Reactions.

A readily available quaternary phosphonium salt containing a trifluoroacetonyl group and a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF4-) counterion was demonstrated to be a highly active Brønsted acid catalyst for Friedel-Crafts-type reactions of an array of electron-rich heteroarenes and aniline derivatives with isatin-derived ketimines, even at 0.1 mol % catalyst loadings.

Direct Carboxylation of Electron-Rich Heteroarenes Promoted by LiO-tBu with CsF and [18]Crown-6.

We herein demonstrate that the combination of LiO-tBu, CsF, and [18]crown-6 efficiently promotes the direct C-H carboxylation of electron-rich heteroarenes (benzothiophene, thiophene, benzofuran, and furan derivatives). A variety of functional groups, including methyl, methoxy, halo, cyano, amide, and keto moieties, are compatible with this system. The reaction proceeds via the formation of a tert-butyl carbonate species.

Trifluoromethyl-substituted selenium ylide: a broadly applicable electrophilic trifluoromethylating reagent

An easily available, air/moisture insensitive and broadly applicable electrophilic reagent trifluoromethyl-substituted selenium ylide 1a and its reactions with a variety of nucleophiles including β-ketoesters and silyl enol ethers, aryl/heteroaryl boronic acids, electron-rich heteroarenes and sulfinates were described.