Regioselective palladium-catalyzed arylation of 3-carboalkoxy furan and thiophene

[reaction: see text] The regioselective palladium(0)-catalyzed arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides is described. Conditions were developed that allow for the selective synthesis of either 2-aryl or 5-aryl products.     

Regioselective palladium-catalyzed arylation of 2-furaldehyde

An efficient regioselective method for the direct arylation of 2-furaldehyde to provide a range of pi-diverse 5-aryl-2-formylfuran derivatives is described. The method employs functionalized aryl halides and a catalytic amount of palladium(II) chloride under relatively mild conditions.     

Regioselective palladium-catalyzed arylation of 4-chloropyrazoles

A highly regioselective Pd-catalyzed arylation of N-methylpyrazoles with aryl bromides is described. This transformation was studied extensively via automated reaction screening. A Design of Experiments (DoE) approach for optimizing the critical parameters was applied, resulting in excellent conditions for preparing selectively 5-arylpyrazoles in moderate to excellent yields under mild conditions.     

Arylation of adamantanamines: VI. Palladium-catalyzed arylation of amines and diamines of the adamantane series with 3-bromopyridine

Palladium-catalyzed amination of 3-bromopyridine with amines of the adamantane series in the presence of Pd(dba)₂/L [L = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or 2-dimethylamino-2′-dicyclohexylphosphinobiphenyl] gave the desired N-(pyridin-3-yl)-substituted amines in 74–97% yields. Diamines of the adamantane series reacted with 2 equiv of 3-bromopyridine in a complicated fashion to produce mono- and triaryl-substituted derivatives as by-products, while the yields of N,N′-diarylation products were 18–56%.     

Regioselective arylation of unsaturated silanes under phase transfer catalysis conditions

Conclusions The regioselective arylation of unsaturated compounds was carried out under metal complex and phase transfer conditions by the action of aryl iodides.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1180–1183, May, 1988.     

Regioselective palladium-catalyzed CH arylation of 4-alkoxy and 4-thioalkyl pyrazoles

A methodology for the palladium-catalyzed regioselective CH arylation of electron rich pyrazoles has been developed. New ligands and mild conditions (70–90?°C) have been identified for this transformation. An intramolecular application of the methodology provided a novel synthetic route for the regioselective synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles.     

Regioselective Heck arylation of unsaturated alcohols by palladium catalysis in ionic liquid

In contrast to almost all of the known examples of Heck arylation of unsaturated alcohols, which yield predominately beta-arylated products, arylation under the Pd-DPPP catalysis in ionic liquid leads preferentially to aryl substitution at the alpha carbon, providing an easy pathway to this valuable class of olefins.     

Meerwein arylation with 3-fluorobutenone

3-Fluorobutenone (7) reacts with aryl triazenes in the presence of zinc iodide to give 4-aryl-3-fluoro-3-iodo-2-butanones (9a-9f) in moderate yields. The products arise from a free radical process that terminated by iodination of an alkyl radical. The process yields unusual geminal iodo-fluoro compounds.     

Palladium-mediated arylation of 3-aminopiperidines and 3-aminopyrrolidines

This paper describes the palladium-catalyzed arylation of 1-substituted 3-aminopyrrolidines or piperidines. Palladium(0) (1-2 mol %) in conjunction with "Buchwald's ligand" [2-(dimethylamino)-2'-(dicyclohexylphosphine)biphenyl] was shown to be the catalyst of choice for the coupling with aryl bromides or chlorides. When bromobenzene was used, a strong temperature effect was noticed. Whereas no reaction occurred at 100 degrees C, yields higher than 85% were obtained at 130 degrees C for each substrate. Such an effect was not observed when diphosphines were used. Whereas Xantphos and, to a lesser extent BINAP, were moderately efficient in the coupling of all diamines, the palladium-mediated arylation in the presence of monophosphines was strongly dependent on the substrate. The results suggest the participation of both nitrogens of the aminoheterocycle in the reactive intermediate. This participation could also account for the highly selective arylation of the endocyclic nitrogen of unsubstituted 3-aminopyrrolidine or piperidine. Optimal conditions were found for the arylation using 2- or 4-substituted electron-poor or enriched aryl halides.     

Regioselective synthesis of 1,5-diaryl-1H-imidazoles by palladium-catalyzed direct arylation of 1-aryl-1H-imidazoles

[reaction: see text] A variety of 1,5-diaryl-1H-imidazoles have been regioselectively synthesized by direct coupling of 1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and a catalyst precursor consisting of a mixture of Pd(OAc)2 and AsPh3. The data obtained in this synthetic study support a reaction mechanism involving an electrophilic attack of an arylpalladium(II) halide species onto the imidazole ring. Interestingly, some imidazole derivatives synthesized in this study have been found to exhibit significant cytotoxic activity against human tumor cell lines.     

Regioselective alkynylation of 2-aryl-4-chloro-3-iodoquinolines and subsequent arylation or amination of the 2-aryl-3-(alkynyl)-4-chloroquinolines

Palladium-CuI catalyzed Sonogashira coupling of 2-aryl-4-chloro-3-iodoquinolines with terminal acetylenes (1 equiv) in triethylamine afforded the 2-aryl-3-(alkynyl)-4-chloroquinolines as sole products. The 2-aryl-4-chloro-3-iodoquinolines coupled with excess terminal acetylenes (2.5 equiv) in dioxane/water to yield the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-pot operation. The 2-aryl-3-(alkynyl)-4-chloroquinolines were, in turn, subjected to arylation via Suzuki cross-coupling with arylboronic acid derivatives or amination with methylamine, respectively. The structures of the products of successive Sonogashira and Suzuki cross-couplings were also confirmed by X-ray crystallography.     

Direct palladium-catalyzed C-3 arylation of indoles

An efficient protocol for palladium-catalyzed direct C-3 arylation of indoles containing unprotected heterocyclic nitrogen atom has been developed.     

A study on the BF3 directed lithiation of 3-chloro- and 3-bromopyridine

The BF₃-directed lithiation of 3-chloro- and 3-bromopyridine (1a and 1b, respectively) has been investigated. The reactions of 3-chloro- or 3-bromopyridine–BF₃ adduct with LDA (1.3/1.1 equiv) followed by quenching with benzaldehyde or iodine exclusively gave the C-2 substituted products. However, when 2.2 equiv of LDA and dimethyl disulfide was used, a C-6 substituted product was obtained. Dilithiation of 1a and 1b has been studied with and without the involvement of BF₃ complexation. The role of Li?F(BF₃) interactions has been investigated by experimental and DFT calculations.     

Regioselective Diels-Alder reactions of 3-indolylquinones

6-(3-Indolyl)quinolinequinone derivatives gave regioselective Diels-Alder reactions with a variety of dienophiles, yielding polycyclic carbazole derivatives. One-pot reactions, proceeding through a cascade of reactions including regioselective Michael and Diels-Alder steps, gave heptacyclic derivatives starting from indoles and 2,5,8(1H)-quinolinetriones. Double Diels-Alder reactions of 6-(3-indolyl)quinolinequinones and dihalobenzoquinones gave eleven-cycle products in one step.     

Regioselective N-9 arylation of purines employing arylboronic acids in the presence of Cu(II)

9-Arylpurines are efficiently formed with complete regioselectivity when purines are treated with arylboronic acids in the presence of copper(II) acetate. A variety of substituents on both coupling partners are well tolerated.     

Regioselective B(3,4)–H arylation of o-carboranes by weak amide coordination at room temperature

Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.

B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides.

o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.¹ The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,² medicine,³ optoelectronics,⁴ nanomaterials,⁵ boron neutron capture therapy agents⁶ and organometallic/coordination chemistry.⁷ In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).⁸ Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),⁹ with major contributions by the groups of Xie,¹⁰ and Yan,¹¹ among others.¹² Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),¹³ and amide-assisted B(4,7,8)–H arylations¹⁴ (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.^15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.¹⁷ Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.¹⁸ In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.¹⁹ Within our program on sustainable C–H activation,²⁰ we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1^†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)₂ and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).²¹ Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag₂O, K₂HPO₄, and Na₂CO₃ failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI^†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag₂CO₃ resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditions^a

Regioselective synthesis of 2-chloro-3-pyridinecarboxylates

2-Chlorocyanoacetate was found to undergo base-catalyzed Michael addition to ,β-unsaturated ketones or aldehydes to afford 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and useful in the synthesis of 2,3-disubstituted pyridines.     

Regioselective synthesis of 2-substituted 3-diarylmethylenylpiperidines

A simple three-step synthetic routes toward 2-substituted 3-diarylmethylenylpiperidines 7 (Y = CN) and 8 (Y = allyl) starting with 3-diarylmethylenylpiperidines 9 is described. The process was carried out by the bromomethoxylation of skeleton 9 with NBS in MeOH at reflux for 2 h, regioselective α-dehydrobromination with DBU in THF at reflux for 10 h, and BF₃·OEt₂-catalyzed cross-coupling of the corresponding enamine with trimethylsilyl-based nucleophiles (TMS-Y) in DCM at rt for 2 h. α-Amino ester 18 and β-amino acid 19 are also synthesized via the simple three-step synthetic protocol.