Application of the Pictet-Spengler reaction to aryl amine substrates linked to deactivated aromatic heterosystems

Three new substrates with an aryl amine moiety attached to quinoxalines, triazoles and tetrazoles either via C or N have been used for the Pictet-Spengler reaction. The substrates have been designed by applying the concept of ‘aryl amine attached to a deactivated heteroaromatic ring’ in a manner to facilitate endo cyclization. This is in contrast to the substrates used traditionally and reported earlier by us that are based on either aliphatic or aryl amine, respectively, attached to an activated heterocyclic ring. The Pictet-Spengler condensation of the three substrates with aldehydes led to the synthesis of novel N-rich polyheterocyclic system hitherto not reported. Our modified strategy opens up possibilities to design novel substrates with aryl amines linked via C or N to either deactivated or activated heterocyclic privileged structure, which in turn can be used for the synthesis of novel fused polyheterocyclic skeletons.     

Scope and limitations of Pd2(dba)3/P(i-BuNCH2CH2)3N-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides

Proazaphosphatrane ligands in combination with Pd(2)(dba)(3) generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides. In particular, commercially available P(i-BuNCH(2)CH(2))(3)N is a highly general and efficient ligand, allowing the coupling of an electronically diverse set of aryl chlorides, including chloropyridines, with a wide variety of amines using 1 mol % of Pd at 100 degrees C. Either a 1:1 or 2:1 ratio of ligand to Pd was found to be effective. This catalyst system performs exceptionally well for sterically hindered substrates, even with only 0.25 mol % of Pd. It is shown that NaOH can also be used as the base (instead of NaO-t-Bu) allowing functionalized substrates to participate in these reactions.     

Aqueous sodium hydroxide promoted cross-coupling reactions of alkenyltrialkoxysilanes under ligand-free conditions

Fluoride-free cross-coupling reactions of alkenyltrialkoxysilanes with aryl iodides, bromides, and chlorides are performed on water using sodium hydroxide as activator at 120 degrees C under normal or microwave heating. This process occurs in the presence of Pd(OAc)(2) or 4-hydroxyacetophenone oxime-derived palladacycle 1 as precatalysts under ligand-free conditions with low Pd loadings (0.01-1 mol %) and using tetra-n-butylammonium bromide as additive. Different commercially available vinylalkoxylsilanes can be cross-coupled under these reaction conditions to the corresponding styrenes, the best substrates being vinyltrimethoxy- or vinyltriethoxysilane. Alkenyltriethoxysilanes, prepared by Wilkinson-catalyzed hydrosilylation of alkynes with triethoxysilane, are stereospecifically arylated with aryl and vinyl halides under microwave irradiation in moderate to high beta/alpha regioselectivity affording unsymmetrical stilbenes, alkenylbenzenes, and conjugate dienes, respectively. This simple procedure allows the palladium recycling from the aqueous phase during three runs by extractive separation of the products, which contain very low levels of Pd (21-27.5 ppm for an aryl iodide and up to 76 ppm for a bromide).     

Copper‐Catalyzed Reductive Cross‐Coupling of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides

A copper‐catalyzed reductive cross‐coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost‐effective construction of aryl–alkyl and alkyl–alkyl C?C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo‐ or heterocycles, such as 2,3‐dihydrobenzofuran and benzochromene derivatives.     

A general strategy for the perfluoroalkylation of arenes and arylbromides by using arylboronate esters and [(phen)CuR(F)

A versatile method for the synthesis of aryl perfluoroalkanes from arenes and aryl bromides is described. Substituted arenes or aryl bromides are converted in situ to an aryl boronate ester that readily undergoes perfluoroalkylation in air with [(phen)CuR(F)]. A broad range of aryl bromide substrates were perfluoroalkylated in good yield for the first time. [(phen)CuCF(3)] is now commercially available and has been prepared on 20?g scale.     

Chiral γ‐Lactams by Enantioselective Palladium(0)‐Catalyzed Cyclopropane Functionalizations

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)‐catalyzed C? H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl–aryl couplings, palladium(0)‐catalyzed C? H functionalizations involving the formation of C(sp³)? C(sp³) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane‐fused γ‐lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane‐1‐carboxylic acid as a cocatalyst provides the γ‐lactams in excellent yields and enantioselectivities.     

Palladium-catalyzed cross-coupling of trimethoxysilylbenzene with aryl bromides and chlorides using phosphite ligands

Phosphites were employed as ligands in palladium-catalyzed Hiyama coupling reactions. The optimized reaction conditions were equimolar amounts (5 mol % each) of Pd(acac)₂ and phosphite 1 in p-xylene at 80 °C with TBAF as an additive. This catalyst system exhibited high activities in the reactions with trimethoxysilylbenzene and aryl bromides that have electron-donating or electron-withdrawing groups. In the case of aryl chlorides, substrates possessing electron-withdrawing groups gave the coupled products in high yields.     

Transition Metal‐Free One‐Pot Protocol Toward Conjugated Arylbutadiynyl Sulfides

An efficient strategy toward conjugated arylbuta‐1,3‐diynyl sulfides (Ar–C≡C–C≡C–SR) was herein reported. In the newly developed one‐pot, three‐steps protocol, the synthetically or materially significant arylbuta‐1,3‐diynyl sulfides were obtained from easily accessible 4‐hydrocarbylthio‐1‐arylbuta‐1,3‐diones, avoiding usage of expensive terminal aryl acetylenes as substrates or any transition metal complexes as catalysts. The gram‐scale experiment of the efficient methodology with acceptable yield afforded a good alternative of industrial interest.     

Palladium-catalyzed aminations of aryl halides with phosphine-functionalized imidazolium ligands

A series of 1-(2-diphenylphosphinoferrocenyl)ethyl-3-substituted imidazolium iodides [3-substituent = methyl (1a); isopropyl (1b); tert-butyl (1c); 1-adenosyl (1d); cyclohexyl (1e); 2,6-dimethylphenyl (1f); 2,4,6-trimethylphenyl (1g); 2,6-diisopropylphenyl (1h)] have been prepared and evaluated as ligands in the palladium-catalyzed aminations of aryl halides with various amines. The scope of the coupling process was carried out for various aryl bromides and chlorides with the catalysts generated in situ from a mixture of Pd(OAc)2 and in the presence of a base. NaO t Bu was found the choice of base in combination with dioxane, toluene, or DME as solvent, although NaOH or Cs2CO3 promoted the coupling of 4-bromotoluene with morpholine in moderate conversion. The steric hindrance from the 3-substituent of imidazolium in the hybrid-bidentate chelating system was found to be only beneficial to the substrates without ortho-substituents. The more sterically hindered 1d or 1h promoted the coupling of bromobenzene with morpholine in nearly quantitative conversion with 0.2 mol% of palladium loading in the presence of NaO t Bu at 110 degrees C, and 94% of conversion was afforded with the less sterical demanding 1a for a longer time. However, for the substrates with ortho-substituents, higher conversions were achieved with 1a. The Pd(OAc)2/1d catalytic system was also active for deactivated aryl chloride, and 71% isolated yield for the desired product was realized for coupling of 4-chloroanisole with morpholine at 2 mol% of catalyst loading. The developed catalyst system has been applied successfully to the synthesis of a key building block for a type of functional polymers.     

Improved synthesis of aryltrialkoxysilanes via treatment of aryl Grignard or lithium reagents with tetraalkyl orthosilicates

General reaction conditions for the synthesis of aryl(trialkoxy)silanes from aryl Grignard and lithium reagents and tetraalkyl orthosilicates (Si(OR)(4)) have been developed. Ortho-, meta-, and para-substituted bromoarenes underwent efficient metalation and silylation at low temperature to provide aryl siloxanes. Mixed results were obtained with heteroaromatic substrates: 3-bromothiophene, 3-bromo-4-methoxypyridine, 5-bromoindole, and N-methyl-5-bromoindole underwent silylation in good yield, whereas a low yield of siloxane was obtained from 2-bromofuran, and 2-bromopyridine failed to give silylated product. The synthesis of siloxanes via organolithium and magnesium reagents was limited by the formation of di- and triarylated silanes (Ar(2)Si(OR)(2) and Ar(3)SiOR, respectively) and dehalogenated (Ar-H) byproducts. Silylation at low temperature gave predominantly monoaryl siloxanes, without requiring a large excess of the electrophile. Optimal reaction conditions for the synthesis of siloxanes from aryl Grignard reagents entailed addition of arylmagnesium reagents to 3 equiv of tetraethyl- or tetramethyl orthosilicate at -30 degrees C in THF. Aryllithium species were silylated using 1.5 equiv of tetraethyl- or tetramethyl orthosilicate at -78 degrees C in ether.     

Synthesis of 1‐Aryl‐1H‐indazoles via a Ligand‐Free Copper‐ Catalyzed Intramolecular Amination Reaction

A general synthesis of 1‐aryl‐1‐H‐indazoles from o‐halogenated aryl aldehydes or ketones and aryl hydrazines was described. This protocol included an intermolecular condensation and a ligand‐free copper‐catalyzed intramolecular Ullmann‐type coupling reaction. This method was applied to a wide range of substrates to produce the indazole products in good yields.     

Mechanistic Aspects of Aryl–Halide Oxidative Addition,Coordination Chemistry,and Ring‐Walking by Palladium

This contribution describes the reactivity of a zero‐valent palladium phosphine complex with substrates that contain both an aryl halide moiety and an unsaturated carbon–carbon bond. Although η²‐coordination of the metal center to a C?C or C?C unit is kinetically favored, aryl halide bond activation is favored thermodynamically. These quantitative transformations proceed under mild reaction conditions in solution or in the solid state. Kinetic measurements indicate that formation of η²‐coordination complexes are not nonproductive side‐equilibria, but observable (and in several cases even isolated) intermediates en route to aryl halide bond cleavage. At the same time, DFT calculations show that the reaction with palladium may proceed through a dissociation–oxidative addition mechanism rather than through a haptotropic intramolecular process (i.e., ring walking). Furthermore, the transition state involves coordination of a third phosphine to the palladium center, which is lost during the oxidative addition as the C?halide bond is being broken. Interestingly, selective activation of aryl halides has been demonstrated by adding reactive aryl halides to the η²‐coordination complexes. The product distribution can be controlled by the concentration of the reactants and/or the presence of excess phosphine.     

Amination reactions of aryl halides with nitrogen-containing reagents mediated by palladium/imidazolium salt systems.

Nucleophilic N-heterocyclic carbenes have been conveniently used as catalyst modifiers in amination reactions involving aryl chlorides, aryl bromides, and aryl iodides with various nitrogen-containing substrates. The scope of a coupling process using a Pd(0) or Pd(II) source and an imidazolium salt in the presence of a base, KO(t)Bu or NaOH, was tested using various substrates. The Pd(2)(dba)(3)/IPr.HCl (1, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) system presents the highest activity with respect to electron-neutral and electron-rich aryl chlorides. The ligand is also effective for the synthesis of benzophenone imines, which can be easily converted to the corresponding primary amines by acid hydrolysis. Less reactive indoles were converted to N-aryl-substituted indoles using as supporting ligand the more donating SIPr.HCl (5, SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene). The Pd(OAc)(2)/SIPr.HCl/NaOH system is efficient for the N-arylation of diverse indoles with aryl bromides. The general protocol developed has been applied successfully to the synthesis of a key intermediate in the synthesis of an important new antibiotic. Mechanistically, palladium-to-ligand ratio studies strongly support an active species bearing one nucleophilic carbene ligand.     

N,N-dimethyl glycine-promoted Ullmann coupling reaction of phenols and aryl halides

[reaction: see text] Ullmann-type diaryl ether synthesis can be performed at 90 degrees C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.     

Studies on the Heck reaction with alkenyl phosphates: can the 1,2-migration be controlled? Scope and limitations

A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily accessible starting materials. In contrast to our earlier work exploiting P(t-Bu)3 as the ligand in the presence of PdCl2(COD), the application of Buchwald's dialkylbiarylphosphines, X-Phos, effectively promoted the vinylic substitution with a wide range of alkenyl phosphates in the presence of 10 equiv of lithium chloride. Importantly, these reaction conditions suppressed 1,2-migration of the alkenyl palladium(II) intermediate. Further studies are also reported with the catalytic system which encourages isomerization in order to determine the range of vinyl phosphates that may participate in these coupling reactions. The extent of the 1,2-migration was dependent on the C1-substituent where best results were noted for substrates possessing a C1-alkyl quaternary carbon. Hence, with certain members of this class of alkenyl phosphates either the migrated or nonmigrated Heck products may be preferentially synthesized by selection of the phosphine ligand. Finally, competition experiments between an unactivated aryl chloride and a vinyl phosphate with a palladium catalyst possessing either X-Phos or P(t-Bu)3 as ligand demonstrated the ability to carry out Heck coupling reactions selectively with the aryl halide. Oxidative addition of the metal catalyst into the aryl chloride bond rather than the C-O bond of the alkenyl phosphate is therefore preferred.     

Modern synthetic methods for copper-mediated C(aryl)[bond]O, C(aryl)[bond]N, and C(aryl)[bond]S bond formation

The copper-mediated C(aryl)[bond]N, C(aryl)[bond]O, and C(aryl)[bond]S bond formation is an important transformation and has been developed to include a wide range of substrates. This Review highlights the recent developments in the copper-mediated (both stoichiometric and catalytic) reactions of aryl boronic acids, aryl halides, iodonium salts, siloxanes, stannanes, plumbanes, bismuthates, and trifluoroborate salts as aryl donors. In particular, the recent introduction of boronic acids as reaction partners in both O- and N-arylation has been a significant discovery and will occupy centre-stage in this review. Clear improvements can be obtained by the correct choice of copper source, base, ligands, and other additives. Mechanistic investigations should provide insight into the catalytically active species, which would aid in the development of milder, more-efficient methods.     

Ru(II)- and Pt(II)-catalyzed cycloisomerization of omega-aryl-1-alkynes. Generation Of carbocationic species from alkynes and transition metal halides and its interception by an aromatic ring

The treatment of aryl-1-alkynes, such as 4-aryl-1-butyne, 5-aryl-1-pentyne, and 6-aryl-1-hexyne, with catalytic amounts of transition metal chlorides, such as PtCl(2) and [RuCl(2)(CO)(3)](2), at 80 degrees C in toluene results in cycloisomerization to give dihydronaphthalenes or dihydrobenzocycloheptenes, in which the cyclization mode is dependent on the length of the tethers. The reaction is limited to substrates containing terminal alkynes. A key step of the reaction is the intramolecular interception by an aromatic ring of the vinylmetal complex 2, which contains a cation center at the beta-position, generated from the electrophilic addition of transition metal halides toward an alkyne. The more electron-rich aryl systems are more reactive.     

A Unified and Practical Method for Carbon–Heteroatom Cross-Coupling using Nickel/Photo Dual Catalysis

While carbon–heteroatom cross-coupling reactions have been extensively studied, many methods are specific and limited to a particular set of substrates or functional groups. Reported here is a general method that allows for C−O, C−N and C−S cross-coupling reactions under one general set of conditions. We propose that an energy transfer pathway, in which an iridium photosensitizer produces an excited nickel(II) complex, is responsible for the key reductive elimination step that couples aryl bromides, iodides, and chlorides to 1° and 2° alcohols, amines, thiols, carbamates, and sulfonamides, and is amenable to scale up via a flow apparatus.     

Core size effects on the reactivity of organic substrates as monolayers on gold nanoparticles

Monolayer-protected nanoparticles (MPNs) with average core sizes of 1.7- (small), 2.2- (medium) and 4.5-nm (large) diameter have been prepared and functionalized with a variety of aryl ketone substrates, namely, 11-mercaptoundecaphenone (1), 1-(4-hexyl-phenyl)-11-mercaptoundecanone (2), 1-[4-(11-mercaptoundecyl)phenyl]hexanone (3), or 1-[4-(11-mercaptoundecyl)phenyl]undecanone (4). Upon irradiation in benzene solution, the aryl ketone-modified MPNs undergo the Norrish type II photoreaction and yield alkene- or acetophenone-modified MPNs exclusively, with no evidence for the generation of cyclobutanol. The extent of the photoreaction for the entire series of aryl ketones is dependent on the size of the MPN core. For 11-mercaptoundecaphenone, the reaction proceeds nearly to completion on the smallest MPN cores (99 +/- 1%) but occurs to a much lesser extent on medium (85 +/- 5%) and large cores (66 +/- 6%). The differences in the extents of reaction are rationalized by the decreased reactivity of substrates on terrace regions, which become increasingly larger with the core size. In lending support to this hypothesis, the edge and vertex sites of medium-sized MPNs were selectively populated with an aryl ketone probe and shown to react quantitatively, whereas selective population of the terrace sites on the same-sized MPNs results in a much lower extent of reaction. Together, these results indicate differences in reactivity of monolayer substrates on terrace versus edge/vertex sites of MPNs. The differences in reactivity with site will play a role in the design of modified MPNs for applications.     

Tunable Gold-catalyzed Reactions of Propargyl Alcohols and Aryl Nucleophiles

Gold-catalyzed transformations of 1,3-diarylpropargyl alcohols and various aryl nucleophiles were studied. Selective tunable synthetic methods were developed for 1,1,3-triarylallenes, diaryl-indenes and tetraaryl-allyl target products by C3 nucleophilic substitution and subsequent intra- or intermolecular hydroarylation, respectively. The reactions were scoped with regards to gold(I)/(III) catalysts, solvent, temperature, and electronic and steric effects of both the diarylpropargyl alcohol and the aryl nucleophiles. High yields of triaryl-allenes and diaryl-indenes by gold(III) catalysis were observed. Depending on the choice of aryl nucleophile and control of reaction temperature, different product ratios have been obtained. Alternatively, tetraaryl-allyl target products were formed by a sequential one-pot tandem process from appropriate propargyl substrates and two different aryl nucleophiles. Corresponding halo-arylation products (I and Br; up to 95 % 2-halo-diaryl-indenes) were obtained in a one-pot manner in the presence of the respective N-halosuccinimides (NIS, NBS).