Environmentally‐Safe Conditions for a Palladium‐Catalyzed Direct C3‐Arylation with High Turn Over Frequency of Imidazo[1,2‐b]pyridazines Using Aryl Bromides and Chlorides

Pd(OAc)₂ was found to catalyze very efficiently the direct arylation of imidazo[1,2‐b]pyridazine at C3‐position under a very low catalyst loading and phosphine‐free conditions. The reaction can be performed in very high TOFs and TONs employing as little as 0.1–0.05 mol % catalyst using a wide range of aryl bromides. In addition, some electron‐deficient aryl chlorides were also found to be suitable substrates. Moreover, 31 examples of the cross couplings were reported using green, safe, and renewable solvents, such as pentan‐1‐ol, diethylcarbonate or cyclopentyl methyl ether, without loss of efficiency.     

Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene

The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-dimethylamides including easily enolizable amides at −20 °C within 27 sec, producing highly functionalized ketones in 48–90 % yield (36 examples). This method was well suited for the preparation of α-chiral ketones such as naproxene and ibuprofen derived ketones with 99 % ee. A one-pot stepwise bis-addition of two different lithium organometallics to 1,1,3,3-tetramethyurea (TMU) provided unsymmetrical ketones in 69–79 % yield (9 examples).     

Heck reactions of aryl halides with alk‐1‐en‐3‐ol derivatives catalysed by a tetraphosphine–palladium complex

cis,cis,cis‐1,2,3,4‐Tetrakis(diphenylphosphinomethyl)cyclopentane–[PdCl(C₃H₅)]₂ efficiently catalyses the Heck reaction of alk‐1‐en‐3‐ol with a variety of aryl halides. In the presence of hex‐1‐en‐3‐ol or oct‐1‐en‐3‐ol, the β‐arylated carbonyl compounds were selectively obtained. Turnover numbers up to 84 000 can be obtained for this reaction. Linalool and 2‐methylbut‐3‐en‐2‐ol led regio‐ and stereoselectively to the corresponding (E)‐1‐arylalk‐1‐en‐3‐ol derivatives. A minor electronic effect of the substituents of the aryl bromide was observed. Quite similar reaction rates were generally observed in the presence of activated aryl bromides such as bromoacetophenone and deactivated aryl bromides such as bromoanisole, indicating that, with these alkenols and this catalyst, the oxidative addition of aryl bromides to palladium is not the rate‐limiting step. It should be noted that this reaction also proceeds with sterically very congested aryl bromides such as 9‐bromoanthracene or 2,4,6‐triisopropylbromobenzene or with a vinyl bromide. On the other hand, low yields were obtained with aryl chlorides. Copyright © 2006 John Wiley & Sons, Ltd.     

Practical one-pot conversion of aryl bromides and β-bromostyrenes into aromatic nitriles and cinnamonitriles

Various aryl bromides were efficiently converted into the corresponding aromatic nitriles in good yields by the treatment with Mg turnings and subsequently DMF, followed by treatment with molecular iodine and aq NH₃. The same treatment of aryl bromides, which are weakly reactive to Mg turnings, with ⁱPrMgCl·LiCl and subsequently DMF, followed by the treatment with molecular iodine and aq NH₃ also afforded the corresponding aromatic nitriles in good yields. On the other hand, when N-formylpiperidine was used instead of DMF, p-substituted β-bromostyrenes were converted into the corresponding p-substituted cinnamonitriles, i.e., α,β-unsaturated nitriles, in good to moderate yields by the same procedure. The reactions were carried out by means of a simple experimental procedure and did not require any toxic metal cyanides or expensive rare metals. Therefore, the present reactions are practical and environmentally benign one-pot methods for the preparation of aromatic nitriles, cinnamonitriles, and aliphatic nitriles from aryl bromides, β-bromostyrenes, and alkyl bromides, respectively, through the formation of Grignard reagents and their DMF or N-formylpiperidine adducts.     

Copper(I)-catalyzed arylselenylation of aryl bromides and iodides

A new protocol to prepare unsymmetrical diarylselenides using the reaction of aryl bromides and iodides with easily available Bu₃SnSeAr catalyzed by Cu(I) complexes under rather mild conditions and with a very high yield is described.     

A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C: in quest of an industrially viable process

Preparation of aryl nitrile 2a through classical Rosenmund-von Braun reaction of aryl bromide 1a resulted in a poor yield (61%) due to a high reaction temperature (165 °C) and a lack of efficient procedure for separating 2a from a large quantity of heavy metal waste (Cu salts). To address these issues, a practical synthesis of multifunctional aryl nitriles through cyanation of aryl bromides has been developed with heterogeneous Pd/C used as the catalyst. Treatment of aryl bromides 1 with Zn(CN)₂ in the presence of Pd/C, Zn, ZnBr₂ and PPh₃ in DMA provided aryl nitriles 2 involving those carrying sterically demanding electron-rich substituent in good yields and in highly reproducible manner. The activity of Pd/C is highly dependent on the properties of the Pd/C. Oxidic thickshell type catalyst Pd/C D5 was found to furnish the highest rate acceleration and yield. The use of heterogeneous Pd/C might anchor and disperse Pd over the solid support of the catalyst, at least in the initial stage of the reaction, to assure the formation of monomeric Pd complex without precipitating to inactive Pd black. The use of a slightly excess of Zn(CN)₂ (0.6 equiv) and air oxidation of phosphine ligand, after end of the reaction, converted Pd species to insoluble phosphine-free Pd cyanides, from which Pd was recovered in high yield through simple filtration followed by usual recovery process involving combustion.     

Palladium-Catalyzed Aminocarbonylation of Aryl Halides with N,N-Dialkylformamide Acetals

We developed a protocol for the palladium-catalyzed aminocarbonylation of aryl halides using less-toxic formamide acetals as bench-stable aminocarbonyl sources under neutral conditions. Various aryl (including heteroaryl) halides reacted with N,N-dialkylformamide acetals in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and xantphos to give the corresponding aromatic carboxamides at 90–140 °C without any activating agents or bases in up to quantitative chemical yield. This protocol was applied to aryl bromides, aryl iodides, and trifluoromethanesulfonic acid, as well as to relatively less-reactive aryl chlorides. A wide range of functionalities on the aromatic ring of the substrates were tolerated under the aminocarbonylation conditions. The catalytic aminocarbonylation was used to prepare the insect repellent N,N-diethyl-3-methylbenzamide as well as a synthetic intermediate of the dihydrofolate reductase inhibitor triazinate.     

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.     

Nickel-promoted ligand-free palladium-catalyzed Suzuki coupling reaction

Summary A Ni-promoted ligand free palladium catalyst system for Suzuki coupling of aryl bromides has been developed in high efficiency under mild reaction conditions. It was obtained in situ by introducing NiCl₂ to PdCl₂/PVP using a parallel high-throughput screening technique. A wide range of aryl bromides bearing a variety of functional groups was evaluated.     

Synthesis of Alkyl-Aryl Ethers by Copper-catalyzed Etherization Reactions of Aryl Fluorides with Tetraalkylammonium Bromides and H2O

Synthesis of alkyl aryl ethers via copper‐catalyzed etherizations of electron‐deficient aryl fluorides with quaternary ammonium bromides and water has been developed. In the presence of Cu(OAc)₂, POPh₃ ( L4 ) and Cs₂CO₃, a variety of electron‐deficient aryl fluorides underwent the reaction with quaternary ammonium bromides and H₂O in moderate to good yields. The mechanism was also discussed.     

Synthesis of Aromatic Nitriles Using Nonmetallic Cyano‐Group Sources

Aromatic nitriles are prepared efficiently through transition‐metal‐mediated cyanation of aryl (pseudo)halides with metallic cyano‐group sources, such as CuCN, KCN, NaCN, Zn(CN)₂, TMSCN, or K₄[Fe(CN)₆]. However, this approach often suffers from drawbacks, such as the formation of stoichiometric amounts of metal waste, the poisoning of the metal catalysts, or the generation of toxic HCN gas. As a result, a range of “nonmetallic” organic cyano‐group sources have been explored for the cyanation of aryl halides and arene C? H bonds. This Minireview summarizes types of nonmetallic cyano‐group sources and their applications in the preparation of aryl nitriles.     

Biaryl and Aryl Ketone Synthesis via Pd‐Catalyzed Decarboxylative Coupling of Carboxylate Salts with Aryl Triflates

A bimetallic catalyst system has been developed that for the first time allows the decarboxylative cross‐coupling of aryl and acyl carboxylates with aryl triflates. In contrast to aryl halides, these electrophiles give rise to non‐coordinating anions as byproducts, which do not interfere with the decarboxylation step that leads to the generation of the carbon nucleophilic cross‐coupling partner. As a result, the scope of carboxylate substrates usable in this transformation was extended from ortho‐substituted or otherwise activated derivatives to a broad range of ortho‐, meta‐, and para‐substituted aromatic carboxylates. Two alternative protocols have been optimized, one involving heating the substrates in the presence of Cu^I/1,10‐phenanthroline (10–15 mol %) and PdI₂/phosphine (2–3 mol %) in NMP for 1–24 h, the other involving Cu^I/1,10‐phenanthroline (6–15 mol %) and PdBr₂/Tol‐BINAP (2 mol %) in NMP using microwave heating for 5–10 min. While most products are accessible using standard heating, the use of microwave irradiation was found to be beneficial especially for the conversion of non‐activated carboxylates with functionalized aryl triflates. The synthetic utility of the transformation is demonstrated with 48 examples showing the scope and limitations of both protocols. In mechanistic studies, the special role of microwave irradiation is elucidated, and further perspectives of decarboxylative cross‐couplings are discussed.     

Short communication: An alternative and effective catalyst in the stereo‐specific reaction of Z‐1‐aryl‐1‐stannyl‐2‐silylethenes with allyl bromide

The Pd(dba)₂‐catalyzed reaction of Z‐1‐aryl‐1‐(tributylstannyl)‐2‐(trimethylsilyl)ethenes with allyl bromide in the presence of copper(I) iodide is reported for the first time. The reaction in the presence of 0.5 mol% Pd(dba)₂ and 8 mol% CuI in dimethylformamide takes place at room temperature to give E‐2‐aryl‐1‐(trimethylsilyl)penta‐1,4‐dienes exclusively in isolated yields of 62–99%. A putative reaction mechanism is proposed. Copyright © 2005 John Wiley & Sons, Ltd.     

氯化钯在氟化四丁基铵中当场生成纳米钯：一种高效、可回收的催化体系，在无配体和无溶剂条件下催化Suzuki-Miyaura反应

氯化钯在氟化四丁基铵中当场生成纳米钯,该钯催化剂在Suzuki-Miyaura交叉偶联反应中显示很高的催化效率。在氯化钯和氟化四丁基铵存在下,许多芳基卤代烃可以顺利与芳基硼酸发生偶联反应,得到中等到高的产率。此外,在Suzuki-Miyaura偶联反应中该氯化钯/氟化四丁基铵催化体系可以回收重复使用多次,并且芳基溴代烃可以在15-60分钟内反应完全。值得指出的是,该反应是在无溶剂、无配体和催化体系可回收重复使用的条件下进行的。这和无配体条件下TBAB中钯催化卤代芳烃与芳基硼酸的Suzuki-Miyaura交叉偶联反应方法。该氯化钯/氟化四丁基铵催化反应的反应机理也进行了讨论。     

Efficient cyanation of aryl bromides with K4[Fe(CN)6] catalyzed by a palladium-indolylphosphine complex

This study describes a general palladium-catalyzed cyanation of aryl bromides using K₄[Fe(CN)₆] as the cyanide surrogate. The reactions can be successfully conducted under mild reaction conditions (at 50 °C) in mixed solvents (water/MeCN = 1:1) without any surfactant additives, and afford the desired aryl nitriles in good-to-excellent yields. Particularly noteworthy is that this system allows the mildest reaction temperature reported so far for palladium-catalyzed cyanation of aryl bromides with K₄[Fe(CN)₆] source in general. Common functional groups, including keto, aldehyde, free amine, and heterocyclic substrates are compatible under this system. Interestingly, the phosphine ligands bearing -PCy₂ moiety, which usually show excellent activity in aryl halide couplings, are found less effective than the corresponding ligands with -PPh₂ group.     

Mild and efficient copper-catalyzed cyanation of aryl iodides and bromides

An efficient copper-catalyzed cyanation of aryl iodides and bromides is reported. Our system combines catalytic amounts of both copper salts and chelating ligands. The latter, which have potential nitrogen- and/or oxygen-binding sites, have never previously been used in this type of reaction. A protocol has been developed that enables the cyanation of aryl bromides through the copper-catalyzed in situ production of the corresponding aryl iodides using catalytic amounts of potassium iodide. Aryl nitriles are obtained in good yields and excellent selectivities in relatively mild conditions (110 degrees C) compared with the Rosenmund-von Braun cyanation reaction. Furthermore, the reaction is compatible with a wide range of functional groups including nitro and amino substituents. The protocol reported herein involves two main innovations: the use of catalytic amounts of ligands and the use of acetone cyanohydrin as the cyanating agent in copper-mediated cyanation reactions.     

无配体、水相中钯催化的卤代芳烃与苯硼酸的Suzuki偶联反应

溴代(碘代)芳烃与苯硼酸在以Li OH为碱、水为反应溶剂、醋酸钯为催化剂、90℃条件下反应24h后,可以较高收率得到二芳基产物。该方法具有收率好,操作方便以及催化体系便宜又简单的优点。     

Copper(I)‐Catalyzed Intramolecular Direct C‐Arylation of Azoles with Aryl Bromides

A concise route to access 5H‐imidazo[2,1‐a]isoindole heterofused compounds by copper(I)‐catalyzed intramolecular coupling of non‐activated aryl bromides with azoles is reported. With CuI as catalyst, 1,10‐phenanthroline as ligand, and K₃PO₄ as base, the reactions of 1‐(2‐bromobenzyl)‐1H‐imidazoles in DMF/o‐xylene (1:1, V:V) at 145°C afford the corresponding substituted 5H‐imidazo[2,1‐a]isoindoles in high yields via intramolecular C‐arylation.     

A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C

An industrially viable cyanation of aryl bromides with Zn(CN)₂ was accomplished in the presence of inexpensive and readily accessible Pd/C, Zn dust, ZnBr₂, and PPh₃ in DMA to provide functionalized aryl nitriles in moderate to high yields.     

醋酸钯催化甲苯中无配体的 Suzuki 反应

 报道了一种甲苯中醋酸钯催化无配体的 Suzuki 反应体系. 以 K₃PO₄·7H₂O 为碱, 在该体系中可高效进行芳基溴代物和芳基硼酸的 Suzuki 反应, 且具有反应条件温和、无需惰性气体保护等特点. 在 n(ArBr) = 0.5 mmol, n(ArB(OH)₂) = 0.75 mmol, x(Pd(OAc)₂) = 1 mol%, n(K₃PO₄·7H₂O) = 1.0 mmol, v(甲苯) = 2 ml 的优化条件下, 4-溴硝基苯和苯硼酸在 75 °C 反应 5 min, 分离收率即达 99%, TOF 高达 1 188 h?1.