Pd-catalyzed synthesis of 1-(hetero)aryl-2,2,2-trichloroethanols using chloral hydrate and (hetero)arylboroxines

1-(Hetero)aryl-2,2,2-trichloroethanols are useful key intermediates for the synthesis of various bioactive compounds. Herein, we describe N-heterocyclic carbene (NHC)-coordinated cyclometallated palladium complex (CYP)-catalyzed (hetero)aryl addition of chloral hydrate using (hetero)arylboroxines, providing a new approach to 1-(hetero)aryl-2,2,2-trichloroethanols. Notably, PhS-IPent-CYP which coordinated the bulky yet flexible 2,6-di(pentan-3-yl)aniline (IPent)-based NHC showed good catalytic activities and promoted the transformation in 24–97% yields.

N-heterocyclic carbene (NHC)-coordinated cyclometallated palladium complex (CYP) catalyzed (hetero)aryl addition of chloral hydrate using (hetero)arylboroxines, providing a new approach to 1-(hetero)aryl-2,2,2-trichloroethanols.     

Transesterification of (hetero)aryl esters with phenols by an Earth-abundant metal catalyst

Readily available and inexpensive Earth-abundant alkali metal species are used as efficient catalysts for the transesterification of aryl or heteroaryl esters with phenols which is a challenging and underdeveloped transformation. The simple conditions and the use of heterogeneous alkali metal catalyst make this protocol very environmentally friendly and practical. This reaction fills in the missing part in transesterification reaction of phenols and provides an efficient approach to aryl esters, which are widely used in the synthetic and pharmaceutical industry.

Readily available and inexpensive Earth-abundant alkali metal species are used as efficient catalysts for the transesterification of aryl or heteroaryl esters with phenols which is a challenging and underdeveloped transformation.     

Direct sulfonamidation of (hetero)aromatic C–H bonds with sulfonyl azides: a novel and efficient route to N-(hetero)aryl sulfonamides

N-Aryl sulfonamides belong to a highly important class of organosulfur compounds which are found in a number of FDA-approved drugs such as dofetilide, dronedarone, ibutilide, sotalol, sulfadiazine, sulfamethizole, vemurafenib, and many more. There is therefore continuing interest in the development of novel and convenient protocols for the preparation of these pharmaceutically important compounds. Recently, direct sulfonamidation of (hetero)aromatic C–H bonds with easily available sulfonyl azides has emerged as an attractive and powerful strategy to access N-(hetero)aryl sulfonamides where non-toxic nitrogen gas forms as the sole by-product. This review highlights recent advances and developments (2012–2020) in this fast growing research area with emphasis on the mechanistic features of the reactions.

N-Aryl sulfonamides belong to a highly important class of organosulfur compounds which are found in a number of FDA-approved drugs such as dofetilide, dronedarone, ibutilide, sotalol, sulfadiazine, sulfamethizole, vemurafenib, and many more.     

Ruthenium-catalyzed decarboxylative C–S cross-coupling of carbonothioate: synthesis of allyl(aryl)sulfide

A novel ruthenium-catalyzed decarboxylative cross-coupling of carbonothioate is disclosed. This method provides straightforward access to the corresponding allyl(aryl)sulfide derivatives in generally good to excellent yields under mild conditions and features a broad substrate scope, wide group tolerance and in particular, no need to use halocarbon precursors.

A method for the construction of a C–S bond via the ruthenium-catalyzed decarboxylative cross-coupling of carbonothioate under mild conditions is described.     

Addition of 1,3-dicarbonyl compounds to terminal alkynes catalyzed by a cationic cobalt(iii) complex

The Nakamura reaction using a cationic cobalt(iii) complex, [Cp*Co(CH₃CN)₃][SbF₆]₂ as the catalyst under neutral and aerobic conditions at 110 °C has been described. In solution, the complex is expected to lose a hemilabile acetonitrile ligand to produce a highly electron-deficient cobalt(iii) center, and the Lewis acidic nature of the cobalt center has been exploited for the enolization of the dicarbonyl compounds. The reaction of 1,3-dicarbonyl compounds with alkynes affords the corresponding alkenyl derivative. However, the reaction of phenylacetylene and its derivatives with β-ketoesters affords corresponding terphenyl compounds. Details of the mechanisms of the reactions have been proposed based on in situ LCMS measurements.

The Nakamura reaction using the complex, [Cp*Co(CH₃CN)₃][SbF₆]₂ as the catalyst has been described. Alkynes on reaction with β-ketoesters afford tetrasubstituted benzenes.     

Cu-catalyzed cross-coupling reactions of vinyl epoxide with organoboron compounds: access to homoallylic alcohols

Copper-catalyzed cross-coupling reactions of vinyl epoxide with arylboronates to obtain aryl-substituted homoallylic alcohols are described. The reaction selectivity was different to that of previously reported vinyl epoxide ring-opening reactions using aryl nucleophiles. The reaction proceeded under mild conditions, affording aryl-substituted homoallylic alcohols with high selectivity and in good to excellent yields. The reaction provides convenient access to aryl-substituted homoallylic alcohols from vinyl epoxide

Copper-catalyzed cross-coupling reactions of vinyl epoxide with arylboronates to obtain aryl-substituted homoallylic alcohols are described.     

Electrochemically driven,cobalt–carbon bond-mediated direct intramolecular cyclic and acyclic perfluoroalkylation of (hetero)arenes using X(CF2)4X

A proof-of-concept for the one-step, synthetically challenging cyclic and acyclic perfluoroalkylation of (hetero)arenes driven by the valence change of a vitamin B₁₂ derivative as a cobalt catalyst in the presence of fluoroalkylating reagents (X(CF₂)₄X) is presented. The consecutive formation of cobalt–carbon bonds and generation of fluoroalkyl radicals by homolysis are the key steps for the reaction to proceed.

A proof-of-concept for synthetically challenging cyclic and acyclic perfluoroalkylation of (hetero)arenes driven by the valence change of a cobalt catalyst with X(CF₂)₄X is demonstrated.

The cobalt–carbon (Co–C) bond is recognized as a crucial catalytic intermediate, and has been extensively studied for radical-mediated reactions in the fields of bioinorganic and organometallic chemistry.^1–7 In particular, fluorine substitution of aromatic compounds is an interesting research topic due to the dramatic impact of this reaction on the physical, chemical, and biological properties of the substrates.^8–11 In this context, methods for the stoichiometric or catalytic mono-, di-, and trifluoromethylation, and other perfluoroalkylations of (hetero)arenes have been extensively studied.^12–20 Nonetheless, catalytic radical fluoroalkylation mediated by Co–C intermediates is still less explored. Recently, our group has investigated electrochemically driven, radical fluoroalkylation reactions using the vitamin B₁₂ derivative, heptamethyl cobyrinate perchlorate [Cob(ii)7C₁ester]ClO₄ (C1), as a cobalt catalyst and fluoroalkylating reagents such as BrCF₂COOEt, CF₃I, and R_fI (Scheme 1(a and b)).^21,22 These reactions proceed as follows: first, the Co(i) species is generated from C1 by controlled-potential electrolysis at −0.8 V vs. Ag/AgCl, and it quickly reacts with the fluoroalkylating reagent, e.g., R_fI, to form a Co(iii)–R_f complex. The Co(iii)–R_f complex releases a R_f radical under visible-light irradiation (≥420 nm). Finally, the generated R_f radical reacts with nonactivated (hetero)arenes to afford the fluoroalkylated product. Despite these advances, the radical fluoroalkylation via homolysis of a Co–C bond cannot be clearly distinguished from the reaction obtained by directly reducing fluoroalkylating agents with conventional photoredox catalysts. This situation motivated us to explore in more detail the radical-generating ability from the homolysis of a Co–C bond. Herein, we investigated the intramolecular fluoroalkylating cyclization of (hetero)arenes promoted by formation of a Co–C bond and subsequent generation of fluoroalkyl radicals by homolysis in the presence of the dihalogenated fluoroalkylating reagents X(CF₂)₄X (Scheme 1(c)).Open in a separate windowScheme 1(a) Molecular structure of C1. (b) Trifluoromethylation, perfluoroalkylation and difluoroacylation of (hetero)arenes catalyzed by C1. (c) This work.We selected X(CF₂)_nX as alkylating reagents because, although the –(CF₂)_n– moiety is becoming increasingly important for a diverse array of functional compounds,^23–27 methods for the construction of fluoroalkyl-containing rings on aromatic compounds are still scarce. Although a number of studies have been reported in this regard, stoichiometric or harsh conditions are normally required.^23,25,28,29 To the best of our knowledge, Co–C bond mediated one-step catalytic C–H intramolecular fluoroalkylating cyclization of unactivated (hetero)arenes through an electrocatalytic method under mild conditions has not been explored yet.In this study, we demonstrate an electrolysis-driven, intramolecular fluoroalkylating cyclization of (hetero)arenes using dihalogenated fluoroalkylating reagents (X(CF₂)₄X; X = I, Br) and the vitamin B₁₂ derivative (C1) as cobalt catalyst under mild conditions. We also present that X(CF₂)_nX (n = 4, 6) can serve as a –(CF₂)_nH source especially in the presence of methanol (CH₃OH) solvent, leading to an acyclic perfluoroalkylated compound containing the –(CF₂)_nH functional group (Scheme 1(c)). This is the first report on catalytic Co–C bond-mediated intramolecular cyclic and acyclic perfluoroalkylation of (hetero)arenes through an electrochemical method, which provides a new method for the preparation of a large number of synthetically important functional compounds. Although the electrochemically enabled fluoroalkylation strategies^30–35 have increasingly emerged in recent years, this work should provide a new insight into various fields.To investigate the abovementioned fluoroalkylation reactions, we firstly focused on the redox behaviour of C1 as catalyst in the presence or absence of octafluoro-1,4-diiodobutane (1,4-C₄F₈I₂) in CH₃OH by cyclic voltammetry (CV) at a scan rate of 100 mV s⁻¹ under nitrogen (Fig. S1^†). We observed a reversible Co(ii)/Co(i) redox couple of C1 at −0.63 V vs. Ag/AgCl. After adding 2 eq. 1,4-C₄F₈I₂ to C1, the voltammetric pattern was changed, and a new irreversible reduction wave at ca. −0.76 V vs. Ag/AgCl appeared. This can be ascribed to the reduction of the fluoroalkylated derivative of C1, which suggested the suitability of C1 for this molecular transformation. Subsequently, we conducted the fluoroalkylation of (hetero)arenes using 1,4-dimethoxybenzene (1) as the model substrate and 1,4-C₄F₈I₂ as a perfluoroalkylating source in the presence of C1 (1 mol%) catalyst at room temperature employing an electrochemical approach (Fig. S2^†). The CV results indicated that the electrolysis potential at −0.8 V vs. Ag/AgCl is suitable for this fluoroalkylation reaction, which was in associating with our previous work.²¹The optimized results of the reaction are summarized in †). The results initially provided us with some optimal reaction conditions, such as carbon felt as the cathode, C1 as the cobalt catalyst and visible-light irradiation. Subsequently, we firstly continued to perform the reaction with the flow rate of 1,4-C₄F₈I₂ (0.5 eq. of substrate per 1 h, 6 eq. in total) for 12 h, yielding the desired products 1a (13%) and 1b (22%) (†). Using other alcohol solvents and DMSO all led to incomplete conversions and lower yields (†). These results indicate that some radical intermediates were formed during the reaction process. On the basis of these results, the optimized condition for the controlled-potential electrolysis was established at −0.8 V vs. Ag/AgCl in CH₃OH with 6 eq. 1,4-C₄F₈I₂ reagent of aromatic substrate in the presence of C1 catalyst (1 mol%) for 12 h at room temperature (

Rh(iii)-catalyzed spiroannulation of 3-arylquinoxalin-2(1H)-ones with alkynes: practical access to spiroquinoxalinones

The Rh(iii)-catalyzed synthesis of spiroquinoxalinone derivatives from 3-arylquinoxalin-2(1H)-ones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been developed. This method, featuring low catalyst loading, was amenable to Gram scale synthesis and tolerated a variety of functional groups and substitution patterns on the aryl rings, providing the target products in good to excellent yields.

The use of imines as a H acceptor for Rh(iii)-catalyzed spirocyclization of 3-arylquinoxalinones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been achieved.     

Palladium-catalyzed hydroboration reaction of unactivated alkynes with bis (pinacolato) diboron in water

A highly efficient and mild palladium-catalyzed hydroboration of unactivated internal alkynes in water is described. Both aryl- and alkyl-substituted alkynes proceeded smoothly within the reaction time to afford the desired vinylboronates in moderate to high yields. Bis (pinacolato) diboron was used to afford α- and β-hydroborated products in the presence of HOAc. These reactions showed high reactivities and tolerance, thus providing a promising method for the synthesis of alkenyl boron compounds.

A highly efficient and mild palladium-catalyzed hydroboration of unactivated internal alkynes in water.     

A green route for the cross-coupling of azide anions with aryl halides under both base and ligand-free conditions: exceptional performance of a Cu2O–CuO–Cu–C nanocomposite

A convenient, inexpensive and effective route for the preparation of a Cu₂O–CuO–Cu–C nanocomposite is described here by applying Cu(ii) as a source of copper. Characterization of the nanocomposite was performed with X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), high-resolution TEM (HR-TEM), field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and energy-dispersive X-ray spectroscopy (EDX). Analysis of the data showed that the particles of the nanocomposite are uniformly distributed and show high catalytic activity in the cross-coupling of sodium azide with various aryl iodides and bromides. This nanocomposite has a high level of performance, and even led to the synthesis of the products at room temperature. In addition, this is the first report of the synthesis of aryl azides under both base- and ligand-free conditions. For the first time, both ligand- and base-free conditions were applied for the synthesis of aryl azides, which implies exceptional performance of the Cu₂O–CuO–Cu–C nanocomposite. Simultaneous removal of the base and ligand in a green solvent is the main advantage of this reaction. Unfortunately, aryl bromides and aryl iodides with electron-withdrawing functional groups in their scaffold did not give the desired aryl azides.

Ligand-free and base-free conditions were used for the preparation of aryl azides using the cross-coupling of sodium azide and aryl halides catalysed by Cu₂O–CuO–Cu–C.     

Palladium(ii)-catalyzed synthesis of indenones through the cyclization of benzenecarbaldehydes with internal alkynes

The palladium(ii)-catalyzed carbocyclization of benzenecarbaldehydes with internal alkynes to afford 2,3-disubstituted indenones was reported. The annulation reaction proceeded through the transmetalation of Pd(ii) with an aromatic aldehyde and the insertion of internal alkynes, followed by cyclization via the intramolecular nucleophilic addition of intermediate organopalladium(ii) species to the aldehyde group. This reaction proceeded in moderate to good yields with high regioselectivity.

The palladium(ii)-catalyzed carbocyclization of benzenecarbaldehydes with internal alkynes to afford 2,3-disubstituted indenones was reported.     

Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins.

Hydrogels were formed by conjugate addition of polyethylene glycol (PEG) multiacrylates and dithiothreitol (DTT) for encapsulation and sustained release of protein drugs; human growth hormone (hGH) was considered as an example. Prior to encapsulation, the hGH was precipitated either by Zn2+ ions or by linear PEG, to protect the hGH from reaction with the gel precursors during gelation. Precipitation by Zn2+ ions yielded precipitates that dissolved slowly and delayed release from even highly permeable gels, whereas linear PEG yielded rapidly dissolving precipitates. To independently protect the protein and delay its release, linear PEG precipitation was adopted, and release control via modulation of the PEG gel mesh size was sought. By varying the molecular weight of the multiarm PEG acrylates, control over gel swelling and hGH release, from a few hours to a few months, could be obtained. Protein release from the swollen and degrading PEG-based gel networks was modeled as a diffusion process with a time-dependent diffusion coefficient, calculated from swelling measurements and theoretical mesh sizes. Release following zero-order kinetics was obtained by the counter influences of decreasing protein concentration and increasing protein diffusion coefficient over time.     

1,2-Benzoxathiin-4(3H)-one 2,2-dioxide – new enol nucleophile in three-component interaction with benzaldehydes and active methylene nitriles

The reactivity of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide was studied in multicomponent type reactions for the first time, namely, in a three-component interaction with active methylene nitriles and aromatic aldehydes in order to construct condensed 2-amino-4H-pyran derivatives. The reaction outcome strongly depended on the nature of an active methylene nitrile and an arenecarbaldehyde. Application of malononitrile resulted in novel 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides in most cases, whereas the utilization of ethyl cyanoacetate resulted in a complex mixture of products. In the last case, three different products were isolated depending on the arenecarbaldehyde used, namely ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carboxylate 5,5-dioxides, ethyl 2-cyano-3-arylacrylates, and salts of 3,3′-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-dioxides). Attempts to obtain separately ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carboxylate 5,5-dioxides enabled us to propose reaction pathways leading to these products. The salts were obtained for the first time. The preparative method for the synthesis of triethylammonium salts of 3,3′-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-dioxides) was proposed by the direct interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with arenecarbaldehydes. The application of ammonium acetate as a catalyst allowed us to synthesize 7-aryl-7,14-dihydrobenzo[5,6][1,2]oxathiino[4,3-b]benzo[5,6][1,2]oxathiino[3,4-e]pyridine 6,6,8,8-tetraoxides containing a novel heterocyclic system. These facts, combined with our past investigations, allowed us to assert that the reactivity of enol nucleophiles that include the COCH₂SO₂X fragment has not been reported previously.

Reactivity of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide was for the first time studied in multicomponent type reactions involving active methylene nitriles and aromatic aldehydes.     

Thiourea fused γ-amino alcohol organocatalysts for asymmetric Mannich reaction of β-keto active methylene compounds with imines

Catalytic functionality of new optically active thiourea fused γ-amino alcohols was examined in the asymmetric Mannich reaction of β-keto active methylene compounds with imines to afford chiral Mannich products, β-amino keto compounds, with continuous chiral centers, that are versatile synthetic intermediates for deriving various biologically active compounds. In particular, the thiourea fused γ-amino alcohols showed satisfactory catalytic activity in this reaction and afforded chiral Mannich products in excellent chemical yield (up to 88%) and stereoselectivities (up to syn : anti/93 : 7 dr, up to 99% ee).

Catalytic functionality of new optically active thiourea fused γ-amino alcohols was examined in the asymmetric Mannich reaction of β-keto active methylene compounds with imines to afford chiral Mannich products, β-amino keto compounds..     

Effects of active addition of bacterial cultures in fermented milk to patients with chronic bowel discomfort following irradiation

Radiotherapy is a cornerstone in the treatment of malignancies in the pelvis. Consequently, there is usually exposure of the intestine and especially the lower colon and rectum, with ensuing disturbances in bowel habits at different times following radiotherapy. The main problem is diarrhoea associated with lactose intolerance, bile salt absorption and fat malabsorption. Bacterial contamination has also been described. In the present study we have evaluated the influence of the active administration of specific bacterial cultures in fermented milk, which inhibit the growth of potentially pathogenic micro-organisms, to 40 consecutive patients with chronic alteration in their bowel habits caused by previous radiotherapy of pelvic malignancies. The results suggest that intake of fermented milk products could be of value in decreasing chronic bowel discomfort following radiotherapy of pelvic malignancies. However, a more extensive study is warranted in order to very the significance of the results and to find the optimal product.     

A facile method for Rh-catalyzed decarbonylative ortho-C–H alkylation of (hetero)arenes with alkyl carboxylic acids

A facile and effective method for Rh-catalyzed direct ortho-alkylation of C–H bonds in (hetero)arenes with commercially available carboxylic acids has been developed. This strategy was initiated by in situ conversion of carboxylic acids to anhydrides which, without isolation, underwent Rh-catalyzed direct decarbonylative cross-coupling of aryl carboxamides containing 8-aminoquinoline. The reaction proceeds with high regioselectivity and exhibits a broad substrate scope as well as functional group tolerance.

A facile and effective method for Rh-catalyzed direct ortho-alkylation of C–H bonds in (hetero)arenes with commercially available carboxylic acids has been developed.

Alkylation of (hetero)arenes¹ is one of the most fundamental reactions in synthetic chemistry, leading to ubiquitous alkylated scaffolds and revealing itself to be of great significance with widespread application in fine chemicals, pharmaceuticals, agrochemicals and so forth. One of the classical methods for the C–H alkylation of arenes is the Friedel–Crafts reaction,² one of the oldest organic transformations and still a commonly used protocol nowadays which, however, suffers from severe limitations such as poor reactivity of electron-poor aromatic substrates, undesired cationic rearrangement, and low chemo- and/or regioselectivity. Recently, oxidative decarboxylative coupling of aliphatic carboxylic acids^3,4 has provided complementary access to Friedel–Crafts reactions with opposite reactivity and selectivity. However, in this decarboxylative coupling, the substrate scopes of carboxylic acids were mainly restricted to arylacetic acids, secondary and tertiary alkyl acids, or alkyl acids with a stabilized atom (such as N, O, S) at the α-position of the carboxyl group. Additionally, regioselectivity in simple (hetero)arenes remains challenging.These well-established limitations have encouraged the development of alternative metal-catalyzed directed alkylation of (hetero)arenes C–H bonds,⁵ one of the most accurate and effective tools, therein, highly regioselectivity mostly relies on the use of a directing group by allowing the metal center proximally close to the target C–H bonds in the starting (hetero)arenes. To date, this directed C–H alkylation of (hetero)arenes undergoes with diverse alkylating agents within which alkenes^5j,l,p and alkyl halides^5c are mostly used reagents. To avoid the multiple steps or limitations in synthesis of these agents from available starting materials, as well as to reduce the discharge of poisonous by-products, there is a need to explore novel and convenient alkyl donors beyond these commonly used reagents. Carboxylic anhydrides⁶ thereof have attracted considerable attention not only owing to their low cost and nontoxicity, but also the easy obtainment from commercially available carboxylic acids. Driven by their electron deficiency, the activated anhydrides may serve as potent alkylating sources in the metal-catalyzed direct decarbonylative coupling reaction of (hetero)arenes which is triggered by metal-catalyzed oxidative addition of a C(acyl)–O bond. Notably, this direct decarbonylative alkylation no longer confined to the use of ortho-substituted aromatic carboxylic acids which are required in conventional decarboxylative cross-coupling reactions.⁷ Following their first example of the decarbonylative methylation of arenes with benzoic acids via Rh^I/(tBuCO)₂O catalytic system,^6c Z.-J. Shi and co-workers further extended this concept to afford alkylated products, enabling to introduce methyl, ethyl, benzyl and phenethyl groups onto cyclic enamines,^6d and later achieved methylation of indoles.^6e In their research, the presence of a monodentate N-directing groups and the in situ generation of mixed anhydrides were crucial. Using a similar protocol, Z. Shi and co-workers developed Rh-catalyzed methylation of indoles with Ac₂O in the presence of a P^III-directing groups.^6g P. Walsh and co-workers demonstrated an analogous access to Rh-catalyzed C6-alkylated 2-pyridones with the assist of pyridine as the directing group, installing long chains and cyclic rings onto N-heteroarenes (Scheme 1a).^6h Despite these significant progresses in recent years, there is still much room for improvement of this decarbonylative alkylation, particularly in terms of substrate scopes and functional group tolerance for both the starting (hetero)arenes and alkyl sources.Open in a separate windowScheme 1Transition-metal-catalyzed chelation-assisted decarbonylative alkylation reactions of (hetero)arenes with alkyl carboxylic acids or anhydrides.Encouraged by Daugulis''s pioneering work and others'' previous studies,⁵ herein we select 8-aminoquinoline (AQ), an excellent N,N-bidentate directing group in catalytic functionalization of C–H bonds,^8,9 as the installed moiety on the starting (hetero)arenes, and expect to develop a general method for Rh-catalyzed decarbonylative C–H alkylation of (hetero)arenes with in situ generated alkyl carboxylic acid anhydrides (Scheme 1b).Based on our knowledge, we initially chose N,N′-dicyclohexylcarbodiimide (DCC) as the additive for the stoichiometric conversion of alkyl carboxylic acids into the corresponding anhydrides,¹⁰ and began our studies with a thorough optimization for this Rh-catalyzed C–H alkylation of AQ-substituted benzamide 1a with propionic acid 2a (†). Na₂CO₃ was identified as potent base when compared with NaHCO₃ and K₂CO₃ (entries 5 and 6). Using N,N′-diisopropylcarbodiimide (DIC) as an additive in the activation of carboxylic acid led to a drop in yield (entry 7). Lowing the reaction temperature hindered the reaction, probably because the high temperature was required for the decarbonylation step (entries 8 and 9). The use of polar solvent such as 1,4-dioxane gave a decreased yield (entry 10). Interestingly, this reaction still occurred in air, albeit with a lower yield, indicating its promising application in the practical synthesis (entry 11).Selected results from optimization of reaction conditions^a

Palladium-catalyzed direct C(sp3)–H arylation of indole-3-ones with aryl halides: a novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones

A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp³)–H arylation of indole-3-ones with aryl halides has been developed. Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction of C2-quaternary indolin-3-one skeletons.

A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp³)–H arylation of indole-3-ones with aryl halides has been developed.

2,2-Disubstituted indole-3-ones (trivially known as pseudo-indoxyl) are privileged core heterocyclic structural motifs that occur in a great number of biologically active natural products.(Fig. 1, (−)Isatisine A,^1a–c Aristotelone,^1e Fluorocarpamine^1d).¹ In addition, they can be used as a key synthetic intermediate in the synthesis of many natural products (Fig. 1, Hinckdentine A,^2a–c Lapidilectine B^2d,e and (−)-Trigonoliimine C^2f–j).² Owing to its interesting structure and biological activity, the pseudo-indoxyl scaffold has attracted extensive attention from both synthetic and medicinal chemists. Numerous elegant synthetic protocols have been developed for the construction of the 2,2-disubstituted indole-3-one scaffold.^2c,3,4 Recently, nucleophilic indole-3-ones have been demonstrated to be very reliable building blocks for the enantioselective or racemic construction of C2-quaternary indolin-3-one skeletons.^3d,4 Among these significant advances, one of the key substrates was nucleophilic 2-monoarylated indole-3-ones (Scheme 1a).^3d,4aOpen in a separate windowFig. 1Natural products containing the C2-quaternary indolin-3-ones fragment and representative natural products that were synthesized with using 2,2-disubstituted indole-3-one as the key intermediate.Open in a separate windowScheme 1Reported approaches toward the synthesis of C2-quaternary indolin-3-one skeletons and palladium-catalyzed direct C(sp³)–H arylation reaction of indole-3-ones with aryl halides.So far, much of the effort has been focused on the synthesis of C2-quaternary indolin-3-one skeletons,^2c,3,4 however, the routes for the synthesis of nucleophilic 2-monoarylated indole-3-ones have been challenging and are rare (Scheme 1a).^3d,4a,5 Although some useful methods were developed via Baeyer–Villiger oxidation of C-3 phenyl substituted indole derivatives (A and B) and direct arylation of indolin-3-one 1a with aryllead triacetate, it should be noted that the application of these methods is restricted by the limited number of available substrates and the low yields (Scheme 1b).⁵ In 2015, a method for the potassium tert-butoxide mediated direct C2-arylation of indolin-3-ones 1 was reported by Liu et al., however, diaryliodonium salts were required as the arylating agents and lower yields (up to 70%) were obtained.^3d In addition, the “Selective Problem” arose due to the use of unsymmetric diaryliodonium salts as the arylating agents and the mixtures of two C2-arylation products were produced (Scheme 1c).^3d Therefore, more efficient methods for the synthesis of nucleophilic 2-monoarylated indole-3-ones are highly desired.Palladium-catalyzed α-arylation of carbonyl and related compounds has served as a powerful tool for the quick construction of C–C bonds.⁶ Although palladium-catalyzed C-3 arylation of 2-oxindole has been reported by Willis et al.,^6c palladium-catalyzed direct C(sp³)–H arylation of indole-3-ones with aryl halides remains unexplored.^3d With our ongoing interest in the study of palladium-catalyzed coupling reactions^6d,7 and indolin-3-one chemistry,^4d,e we developed an efficient procedure for this transformation for the synthesis of nucleophilic 2-monoarylated indole-3-ones 3 (Scheme 1c).1-Acetylindolin-3-one 1a and bromobenzene 2a were used as the model substrate for the initial study and the results are summarized in EntryCat. [Pd]LigandBaseSolventYield^b (%)1Pd(dba)₂L1K₂CO₃THF<102Pd(dba)₂L2K₂CO₃THF263Pd(dba)₂L3K₂CO₃THF874Pd(dba)₂L4K₂CO₃THFNR^c5Pd(dba)₂L5K₂CO₃THFNR^c6Pd(dba)₂L6K₂CO₃THF<107Pd(dba)₂L7K₂CO₃THF<108Pd(OAc)₂L3K₂CO₃THF<109PdCl₂L3K₂CO₃THF<1010Pd(TFA)₂L3K₂CO₃THF2411Pd(dba)₂L3KHMDSTHF<1012Pd(dba)₂L3 ^t BuOKTHF—^d13Pd(dba)₂L3CsCO₃THF<1014Pd(dba)₂L3K₃PO₄THF3215Pd(dba)₂L3AcONaTHFNR^c16Pd(dba)₂L3 ^t BuONaTHF—^d17Pd(dba)₂L3K₂CO₃Dioxane5318ⁱPd(dba)₂L3K₂CO₃Toluene2419^fPd(dba)₂L3K₂CO₃THF8020^gPd(dba)₂L3K₂CO₃THF7321^hPd(dba)₂L3K₂CO₃THF6622^jPd(dba)₂L3K₂CO₃THF84Open in a separate window^aReactions performed on a 0.25 mmol scale using 1a (1.0 equiv.) and 2a (1.1 equiv.) in 2.0 ml of the solvent for 14 h, reaction performed at 70 °C under an high pure nitrogen atmosphere.^bIsolated yield.^cNR = no reaction.^dDecomposition observed based on TLC.^f1.0 ml THF was used as the solvent.^g3.0 ml THF was used as the solvent.^hReaction time = 10 h.ⁱReaction performed at 100–110 °C and 1.0 ml solvent was used.^jReaction time = 18 h.With the reaction conditions optimized, we next investigated the substrate scopes of indole-3-ones 1 and aryl halides 2 ( Open in a separate window^aUnless otherwise specified, all reactions were carried out with using 1 (0.25 mmol, 1.0 equiv.) and 2 (1.1 equiv.) in 2.0 mL of the THF for 14 h at 70 °C under an high pure nitrogen atmosphere and all the yields were isolated yield.^bReaction performed at 110 °C and 1.0 ml PhMe was used as the solvent.^cPd(dba)₂ (10 mol%) and Xphos (10 mol%) was used.^dAryl bromides (2.0 equiv.) and K₂CO₃ (2.0 equiv.) was used.To investigate the potential utility of this strategy, the large-scale synthesis of 3a was also performed under the optimized conditions. The reaction proceeded smoothly to afford the corresponding 2-monoarylated indole-3-one 3a product albeit with the actual yield decreased to 72% (Scheme 2). In addition, the 2-monoarylated indole-3-one 3 could be used as a kind of key nucleophilic substrate for the chiral or achiral synthesis of C2-quaternary indolin-3-one skeletons.^3d,4aOpen in a separate windowScheme 2The large-scale synthesis of the product 3a.As shown in Scheme 3, a possible reaction mechanism for this palladium-catalyzed α-arylation of indole-3-ones was proposed based on the reported mechanisms of the similar palladium-catalyzed α-arylation of carbonyl and related compounds with aryl halides.⁶ The oxidative addition of a palladium complex into the C–X bond of aryl halides first occurs and the palladium complex intermediate 4 is formed. At the same time the enolate intermediate 5 is also produced by indole-3-one 1 in the presence of a base, which reacts with intermediate 4 to get the arylpalladium enolate complex 6 and its isomerism intermediate 6′. Finally, anionic palladium intermediate 7 is formed by above isomerism intermediate 6′ in the presence of a base,^6e,f which then undergoes a reductive elimination to form the desired 2-monoarylated indole-3-one 3, at the same time restores the original palladium catalyst and completes the catalytic cycle.Open in a separate windowScheme 3A proposed mechanism for the palladium-catalyzed direct C(sp³)–H arylation of indole-3-ones with aryl halides.In conclusion, we have developed an efficient method for the synthesis of 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp³)–H arylation of indole-3-ones with aryl halides. The nucleophilic 2-monoarylated indole-3-ones were obtained in moderate to good yields (up to 95%). The products could be used as building blocks for the enantioselective or racemic synthesis of C2-quaternary indolin-3-one skeletons. Further investigation and application of the nucleophilic 2-monoarylated indole-3-one derivatives are ongoing in our laboratories.     

In vitro activity of Proveblue (methylene blue) on Plasmodium falciparum strains resistant to standard antimalarial drugs

The geometric mean 50% inhibitory concentration (IC50) for Proveblue, a methylene blue complying with the European Pharmacopoeia, was more active on 23 P. falciparum strains than chloroquine, quinine, mefloquine, monodesethylamodiaquine, and lumefantrine. We did not find significant associations between the Proveblue IC50 and polymorphisms in the pfcrt, pfmdr1, pfmdr2, pfmrp, and pfnhe-1 genes or the copy numbers of the pfmdr1 and pfmdr2 genes, all of which are involved in antimalarial resistance.     

One-step preparation of novel 1-(N-indolyl)-1,3-butadienes by base-catalysed isomerization of alkynes as an access to 5-(N-indolyl)-naphthoquinones

A series of novel 1-(N-indolyl)-1,3-butadienes, as (1 : 1) mixtures of the (E) and (Z) dienes, was prepared in one step by base-catalysed isomerization of N-alkylindoles with a terminal butyne chain. The reaction conditions are mild, and in all cases the yields were very high (>90%). The (E) and (Z) dienes were separable by preparative TLC and could be fully characterized. This isomerization proceeded readily in the case of a butynyl chain, but didn''t take place with a pentynyl chain. A mechanism was proposed for this reaction, based on previous studies on the isomerization of alkynes in basic media, and a key intermediate that supports the proposed mechanism could be isolated and fully characterized. A theoretical study of the proposed mechanism was performed by computational methods and the results validated the proposal. The reactivity of the synthesized dienes was studied in Diels–Alder reactions with p-benzoquinone, to obtain a small library of new 5-(N-indolyl)-1,4-naphthoquinones.The lack of reactivity in the case of the (Z) isomers was explained by calculation of the rotational curves of the central bond of the (Z) and (E) dienes. Finally, the cytotoxicity of the new 5-(N-indolyl)-1,4-naphthoquinones was tested against a panel of three cell lines.

A series of novel 1-(N-indolyl)-1,3-butadienes, was easily prepared in one step and used for the synthesis of 5-(N-indolyl) naphthoquinones.