Nucleophilic and electrophilic substitutions of difluoropropargyl bromides

Fundamental organic reactions like nucleophilic and electrophilic substitutions have seldom been studied on fluorinated propargyl or allenyl modules, when the carbon atom undergoing substitution is bonded to two fluorine atoms. Herein we report a practical synthesis of difluoropropargyl bromides from substituted acetylenes and dibromodifluorometane using a wide variety of alkyl, aryl or silyl substrates. The synthesis of O-, S- and carboxylic acid derivatives of difluoropropargyl bromide is also described. These compounds are suitable starting materials for the synthesis of electrophilically substituted difluoropropargyl derivatives via magnesium and fluoride promoted reactions. An indium-mediated reaction of silyldifluoropropargyl bromide, followed by electrophilic trapping with bromine led to a very useful bromoallene, which was then used in reactions with nucleophiles (C, O, N, P, S, Hal) to yield a de facto bimolecular nucleophilic substitution of a difluoropropargyl bromide.     

Nickel 0-catalyzed cross-coupling of alkyl arenesulfonates with aryl Grignard reagents

The nickel-catalyzed cross-coupling reactions of neopentyl arenesulfonates with arylmagnesium bromides, involving nucleophilic aromatic substitution of alkyloxysulfonyl groups by aryl nucleophiles, take place in high yields. Optimal efficiencies are obtained by adding 3 + 2 equiv of the Grignard reagent to a mixture of dppfNiCl(2) and the sulfonate in refluxing THF. Neopentyl arenesulfonates are useful sources of the electrophilic aryl groups in these transition metal-catalyzed cross-coupling reactions. Aryl sulfonates are inappropriate due to their ambident reactivity under the reaction conditions. This new cross-coupling reaction can be used for the creative elimination of alkyloxysulfonyl groups from aromatic compounds and for the preparation of unsymmetric terphenyls and oligophenyls.     

Cross‐Electrophile Coupling of Vinyl Halides with Alkyl Halides

An improved method for the reductive coupling of aryl and vinyl bromides with alkyl halides that gave high yields for a variety of substrates at room temperature with a low (2.5 to 0.5 mol %) catalyst loading is presented. Under the optimized conditions, difficult substrates, such as unhindered alkenyl bromides, can be coupled to give the desired olefins with minimal diene formation and good stereoretention. These improved conditions also worked well for aryl bromides. For example, a gram‐scale reaction was demonstrated with 0.5 mol % catalyst loading, whereas reactions at 10 mol % catalyst loading completed in as little as 20 minutes. Finally, a low‐cost single‐component pre‐catalyst, (bpy)NiI₂ (bpy=2,2′‐bipyridine) that is both air‐ and moisture‐stable over a period of months was introduced.     

An improved Cu-based catalyst system for the reactions of alcohols with aryl halides

The use of 3,4,7,8-tetramethyl-1,10-phenanthroline (Me(4)Phen) as a ligand improves the Cu-catalyzed cross-coupling reactions of aryl iodides and bromides with primary and secondary aliphatic, benzylic, allylic, and propargylic alcohols. Most importantly, by employing this catalyst system, the need to use an excessive quantity of the alcohol coupling partner is alleviated. The relatively mild conditions, short reaction times, and moderately low catalyst loading allow for a wide array of functional groups to be tolerated on both the electrophilic and nucleophilic coupling partners.     

Synthesis of substituted benzoxacycles via a domino ortho-alkylation/Heck coupling sequence

The synthesis of a variety of alkylidene benzoxacycles via a domino palladium-catalyzed ortho-alkylation/intramolecular Heck reaction is described. Under the optimized conditions [Pd(OAc)2 (10 mol %), P(2-Furyl)3 (20 mol %), norbornene (4 equiv), Cs2CO3 (2 equiv), CH3CN, 80 degrees C], aryl iodides with oxygen-tethered Heck acceptors are coupled with alkyl bromides (5 equiv) to generate a variety of six- and seven-membered-ring benzoxacyclic products.     

无配体Pd/LDH-F催化剂在Heck和Suzuki反应中的应用

 以氟离子插层的水滑石LDH-F为载体,用逐滴浸渍法制备了新型Pd/LDH-F催化剂,并用其催化溴代芳烃的Heck和Suzuki偶联反应. 用X射线衍射表征了催化剂的晶相,以等离子体发射光谱测定了溶剂中钯的流失量. 结果表明,对于Heck反应,在无配体存在和低钯用量(Pd/溴代芳烃摩尔比为0.001)的情况下, Pd/LDH-F的催化性能优于其它载体负载的Pd催化剂,显示出很高的催化活性和选择性. 在140 ℃和12 h的条件下, Pd/LDH-F催化溴苯与苯乙烯Heck反应产物的收率可达86％, 反应后催化剂经过分离,可循环使用四次其催化活性基本不变. 在DMF/水摩尔比为0.5的混合溶剂中,在室温和3 h 的条件下, Pd/LDH-F (Pd/溴代芳烃摩尔比为0.005)催化溴苯与苯基硼酸盐的Suzuki反应中,目标产物收率为99%.     

Atom-efficient metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles.

The novel metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles is described. Triorganoindium compounds (R(3)In) containing alkyl, vinyl, aryl, and alkynyl groups are efficiently prepared from the corresponding lithium or magnesium organometallics by reaction with indium trichloride. The cross-coupling reaction of R(3)In with aryl halides and pseudohalides (iodide 2, bromide 5, and triflate 4), vinyl triflates, benzyl bromides, and acid chlorides proceeds under palladium catalysis in excellent yields and with high chemoselectivity. Indium organometallics also react with aryl chlorides as under nickel catalysis. In the cross-coupling reaction the triorganoindium compounds transfer, in a clear example of atom economy, all three of the organic groups attached to the metal, as shown by the necessity of using only 34 mol % of indium. The feasibility of using R(3)In in reactions with different electrophiles, along with the high yields and chemoselectivities obtained, reveals indium organometallics to be useful alternatives to other organometallics in cross-coupling reactions.     

An efficient intermolecular BINAM-copper(I) catalyzed Ullmann-type coupling of aryl iodides/bromides with aliphatic alcohols

A wide range of alkyl aryl ethers are synthesized from the corresponding aryl iodides and aliphatic alcohols through Ullmann-type intermolecular coupling reactions in the presence of a catalytic amount of easily available BINAM-CuI complex. Less reactive aryl bromides have also been shown to react with aliphatic alcohols under identical reaction conditions to give good yields of the alkyl aryl ethers without increasing the reaction temperature and time.     

A convergent synthesis of polysubstituted aromatic nitriles via palladium-catalyzed C-H functionalization

A palladium-catalyzed C-H functionalization reaction for the synthesis of highly substituted aromatic nitriles is reported. The modularity of the reaction is demonstrated by the broad range of aryl iodides which can be coupled with metal cyanides and alkyl halides or aryl bromides.     

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of potassium aryl- and heteroaryltrifluoroborates

An extended study of the reactivity of potassium aryl- and heteroaryltrifluoroborates in Suzuki-Miyaura cross-coupling reactions is presented. The coupling of aryl- and electron-rich heteroaryltrifluoroborates with aryl and activated heteroaryl bromides proceeds readily under ligandless conditions. When deactivated aryl- and heteroaryltrifluoroborates are coupled with aryl and heteroaryl bromides and chlorides, a low loading (0.5-2%) of PdCl(2)(dppf).CH(2)Cl(2) efficiently catalyzes the reactions. Under either condition, reactions can generally be carried out in an open atmosphere.     

Nickel-catalyzed Kumada cross-coupling reactions of tertiary alkylmagnesium halides and aryl bromides/triflates

We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.     

Control of the regioselectivity in catalytic transformations involving amphiphilic bis-allylpalladium intermediates: mechanism and synthetic applications

Various dialkyl-substituted allyl chloride derivatives (2d-i) undergo regioselective palladium-catalyzed coupling reactions with allylstannanes (1a,b) and benzylidenemalonitrile (4), providing functionalized 1,7-octadienes in good yield. The catalytic reaction proceeds through an unsymmetrical amphiphilic bis-allylpalladium intermediate. An introductory electrophilic attack on the terminal position of the unsubstituted allyl moiety is followed by a nucleophilic attack on the alkyl-substituted allyl ligand. A theoretical analysis was performed by applying density functional theory at the B3PW91/DZ+P level to study the substituent effects on the electrophilic attack. According to the theoretical results, the high regioselectivity can be ascribed to the electronic effects of the alkyl substituents: The terminal alkyl groups destabilize the eta(1),eta(3)-bis-allylpalladium intermediate of the reaction; in addition, the alkyl substitution increases the activation barrier for the electrophilic attack.     

9-fluorenylphosphines for the Pd-catalyzed sonogashira, suzuki, and Buchwald-Hartwig coupling reactions in organic solvents and water

The lithiation/alkylation of fluorene leads to various 9-alkyl-fluorenes (alkyl=Me, Et, iPr, -Pr, -C18H25) in>95% yields, for which lithiation and reaction with R2PCl (R=Cy, iPr, tBu) generates 9-alkyl, 9-PR2-fluorenes which constitute electron-rich and bulky phosphine ligands. The in-situ-formed palladium-phosphine complexes ([Na2PdCl4], phosphonium salt, base, substrates) were tested in the Sonogashira, Suzuki, and Buchwald-Hartwig reactions of aryl chlorides and aryl bromides in organic solvents. The Sonogashira coupling of aryl chlorides at 100-120 degrees C leads to>90% yields with 1 mol% of Pd catalyst. The Suzuki coupling of aryl chlorides typically requires 0.05 mol% of Pd catalyst at 100 degrees C in dioxane for quantitative product formation. To carry out "green" cross-coupling reactions in water, 9-ethylfluorenyldicyclohexylphosphine was reacted in sulphuric acid to generate the respective 2-sulfonated phosphonium salt. The Suzuki coupling of activated aryl chlorides by using this water-soluble catalyst requires only 0.01 mol% of Pd catalyst, while a wide range of aryl chlorides can be quantitatively converted into the respective coupling products by using 0.1-0.5 mol% of catalyst in pure water at 100 degrees C. Difficult substrate combinations, such as naphthylboronic acid or 3-pyridylboronic acid and aryl chlorides are coupled at 100 degrees C by using 0.1-0.5 mol% of catalyst in pure water to obtain the respective N-heterocycles in quantitative yields. The copper-free aqueous Sonogashira coupling of aryl bromides generates the respective tolane derivatives in>95% yield.     

Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands.

Palladium-catalyzed reactions of aryl bromides and chlorides with two common stabilized carbanions-enolates of dialkyl malonates and alkyl cyanoesters-are reported. An exploration of the scope of these reactions was conducted, and the processes were shown to occur in a general fashion. Using P(t-Bu)(3) (1), the pentaphenylferrocenyl ligand (Ph(5)C(5))Fe(C(5)H(4))P(t-Bu)(2) (2), or the adamantyl ligand (1-Ad)P(t-Bu)(2) (3), reactions of electron-poor and electron-rich, sterically hindered and unhindered aryl bromides and chlorides were shown to react with diethyl malonate, di-tert-butyl malonate, diethyl fluoromalonate, ethyl cyanoacetate, and ethyl phenylcyanoacetate. Although alkyl malonates and ethyl alkylcyanoacetates did not react with aryl halides using these catalysts, the same products were formed conveniently in one pot from diethylmalonate by cross-coupling of an aryl halide in the presence of excess base and subsequent alkylation.     

Facile preparation of organozinc bromides using electrogenerated highly reactive zinc and its use in cross-coupling reaction

Highly reactive zinc was readily prepared by electrolysis of a DMF solution containing pyrene as a mediator with a platinum cathode and a zinc anode. Preferential reduction of pyrene occurred to generate the corresponding radical anion, which reduced zinc ions generated from anodic dissolution to give zero valent zinc with high reactivity. The reactive zinc was successfully used for an efficient transformation of bromoalkanes into the corresponding organozinc bromides. Organozinc bromides obtained were further used successfully in Pd-catalyzed cross-coupling reaction with various aryl iodides and bromides.     

Acid Chloride Synthesis by the Palladium‐Catalyzed Chlorocarbonylation of Aryl Bromides

We report a palladium‐catalyzed method to synthesize acid chlorides by the chlorocarbonylation of aryl bromides. Mechanistic studies suggest the combination of sterically encumbered PtBu₃ and CO coordination to palladium can rapidly equilibrate the oxidative addition/reductive elimination of carbon–halogen bonds. This provides a useful method to assemble highly reactive acid chlorides from stable and available reagents, and can be coupled with subsequent nucleophilic reactions to generate new classes of carbonylated products.     

One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates

In situ generated aryl, heteroaryl, alkyl, or benzylic polyfunctional zinc reagents obtained by the addition of zinc and LiCl to the corresponding organic iodides undergo smooth Pd(0)-catalyzed cross-coupling reactions with aryl bromides, chlorides, and triflates in the presence of PEPPSI as a catalyst. This procedure avoids the manipulation of water and air-sensitive organozinc reagents and produces cross-coupling products in high yields.     

An efficient intermolecular C(aryl)-S bond forming reaction catalyzed by BINAM-copper(II) complex

A wide range of diaryl thioethers and aryl alkyl thioethers are synthesized from the corresponding aryl iodides and aromatic/aliphatic thiols through Ullmann type intermolecular coupling reactions in the presence of a catalytic amount of easily available BINAM-Cu(OTf)₂ complex. Less reactive aryl bromides have also been shown to react with thiols under identical reaction conditions to give good yields of the thioethers without increasing the reaction temperature and time.     

Suzuki Coupling of Cyclopropylboronic Acid With Aryl Halides Catalyzed by a Palladium–Tetraphosphine Complex

The tetraphosphine all‐cis‐1,2,3,4‐tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp) in combination with [Pd(C₃H₅)Cl]₂ affords a very efficient catalyst for the coupling of cyclopropylboronic acid with aryl bromides and aryl chlorides. Higher reactions rates were observed with aryl bromides than with aryl chlorides; however, even in the presence of 1–0.4% of catalyst, a few aryl chlorides gave the coupling products in good yields. A wide variety of substituents such as alkyl, methoxy, trifluoromethyl, acetyl, benzoyl, formyl, carboxylate, nitro, and nitrile on the aryl halides are tolerated. The coupling reaction of sterically very congested aryl bromides such as bromomesitylene or 2,4,6‐triisopropylbromobenzene also proceeds in good yields.     

Copper‐Catalyzed Coupling of Triaryl‐ and Trialkylindium Reagents with Aryl Iodides and Bromides through Consecutive Transmetalations

An efficient copper(I)‐catalyzed coupling of triaryl and trialkylindium reagents with aryl iodides and bromides is reported. The reaction proceeds at low catalyst loadings (2 mol %) and generally only requires 0.33 equivalents of the triorganoindium reagent with respect to the aryl halide as all three organic nucleophilic moieties of the reagent are transferred to the products through consecutive transmetalations. The reaction tolerates a variety of functional groups and sterically hindered substrates. Furthermore, preliminary mechanistic studies that entailed the synthesis and characterization of potential reaction intermediates offered a glimpse of the elementary steps that constitute the catalytic cycle.