Takashi Nishikata

Cationic Palladium(II) Catalysis: C-H Activation/Suzuki-Miyaura Couplings at Room Temperature

Cationic palladium(II) catalyst realized facile C-H activation of aryl urea with arylboronic acids at room temperature. This reaction is extremely mild to carry out aromatic C-H activations through electrophilic substitution.

Cationic Pd(II)-catalyzed Fujiwara-Moritani reactions at room temperature in water.

Pd(II)-catalyzed Fujiwara-Moritani reactions can be carried out without external acid at room temperature and in water as the only medium. A highly active cationic Pd(II) catalyst, [Pd(MeCN)(4)](BF(4))(2), easily activates aromatic C-H bonds to produce electron-rich cinnamates in good yields.

Room temperature C-H activation and cross-coupling of aryl ureas in water.

Palladium-catalyzed cross-coupling reactions of aryl halides with aromatic C–H bonds have emerged as a powerful method for the preparation of biaryls.[1,2] Despite substantially increased attention to the field, typical reaction conditions still require high temperatures (> 120°C) for insertion into aromatic C–H bonds, which can be viewed as a major drawback to this chemistry. Such forcing conditions often appear to be critical to overcoming the low reactivity of aryl C–H bonds. A much milder C–H activation reaction at ambient temperatures would, in particular, likely be more dependent on activation by the catalyst.[3] Although there are many ortho-directing groups for C–H activation reactions,[1] the amide residue in anilides is especially attractive as a coupling partner for the synthesis of valuable aniline derivatives. In 1984, Tremont and co-workers used acetanilides for C–H alkylation with alkyl iodides, albeit promoted by stoichiometric Pd(OAc)2.[4] Both the Daugulis[5] and Sanford[6] groups have demonstrated Pd-catalyzed ortho-arylations of anilides with aryl iodides or iodonium salts at temperatures above 100°C. Moreover, ortho-directed C–H activation can suffer from double arylations with respect to the directing group.[1,5] C–H arylations of reactive indoles have been reported at room temperature,[7] but to the best of our knowledge C–H arylation of anilide derivatives with aryl halides at ambient temperatures have not yet been achieved.[1,8] Herein, we describe the first room temperature mono-C–H activation of urea derivatives and their cross-couplings with aryl iodides in water (Scheme 1). This methodology provides a convenient route to various aniline derivatives by means of C–H activation under mild conditions. Scheme 1 C–H activation at room temperature in water. Optimization studies employed the combination of anilides (1a–f) and 4-iodoanisole (2a, 2 equiv) in the presence of Pd(OAc)2 (10 mol%), AgOAc (2 equiv) and aqueous HBF4 (5 equiv) in 2 wt% surfactant/water solutions at room temperature (Table 1). The effectiveness of various directing groups was initially examined, and among a number of different anilide derivatives 1a–f explored, only the aromatic urea 1f smoothly underwent C–H arylation at room temperature (Table 1, runs 1–6). Recently, Lloyd-Jones and Booker-Milburn have also found aryl ureas to be more active coupling partners for C–H functionalizations than other anilides.[9] Acetanilide 1a reacted with 2a only upon heating to 50°C. Pivaloylanilide 1c has been reported as an effective directing group at 130°C,[1,2,5] but gave a low yield under these room temperature conditions (run 3). Generally, acetic acid or trifluoroacetic acid (TFA) is required to carry out C–H activation;[1,2] in this case, HBF4 was found to be critical for generation of biaryl 3 in good yield (run 6). Table 1 Optimization of C–H arylations at room temperature.[a] Although use of the surfactant PTS[10] gave good yields, comparable results were realized with several commercially available amphiphiles. Best yields were obtained using 2 wt% Brij35 in water (Table 1, runs 7–13). Reduced amounts of HBF4, silver salt, or palladium catalyst led to lower yields. A plausible rationale for these results involves generation of a highly active cationic palladium species (Scheme 2).[7c,11] Scheme 2 Generation of a cationic palladium(II) species. As illustrated by several representative examples in Table 2, the scope of this transformation is broad, applying to aryl urea derivatives and aryl iodides bearing a variety of functional groups with yields in the 70–97% range, all done in water at room temperature. Under these mild conditions, only mono-arylated products of net substitution were typically obtained. Table 2 Products from reactions of aryl ureas with aryl iodides.[a] Especially noteworthy are aniline derivatives lacking ortho- or meta-substitution, which have previously been shown to be prone to double arylation. Under these conditions, couplings are selective for singly arylated products (3f, 3r, 3s, 3v). Only reactions of the aryl urea bearing a 4-sec-butyl group with phenyliodide and 4-tolyl iodide produced small amounts (10–15% yields) of doubly arylated products. Reduced aryl iodide loading or reaction time, however, suppressed double arylation to less than 3% (3t, 3u). While current reaction conditions were effective for a variety of substrates, products resulting from sterically hindered aryl iodides having ortho-substituents, such as 2-anisyl iodide and 2-tolyl iodide, were not formed (3b, 3n). The reactivity of N-methyl substituted ureas (e.g., 3x) appears to be much lower than that of their non-N-methyl-substituted analogues, possibly due to palladium coordination in the initial C–H activation step. Electron-deficient ureas (e.g., 3q) were also inert, suggesting that electrophilic attack of cationic palladium may be critical for activating aromatic C–H bonds. The reactivity of aryl iodides possessing electron-rich groups is also much higher than that of more electron-withdrawing aryl iodides (3a vs. 3e). Further advantage can also be taken of the reaction conditions associated with these cross-couplings to allow for tandem processes. Thus, in the presence of silver nitrate, arylation afforded a product of type 3 exclusively, following standard treatment with hydrogen carbonate (Scheme 3). Without exposure to this aqueous workup, nitrated biaryl 4 was isolated. Since use of silver acetate gave only arylated product 3a regardless of quenching conditions, the potential for carrying out secondary electrophilic aromatic substitution could readily be demonstrated. Simple introduction of bromine prior to workup afforded the C-arylated, regiospecifically brominated adduct 5 in good overall isolated yield (70%). The identities of products 3a and 4 were confirmed by X-ray analyses (see Supporting Information). Scheme 3 Tandem C–H arylation–electrophilic trapping. While the exact reaction mechanism is currently unclear, one possibility involves a cationic PdII complex-catalyzed electrophilic C–H activation step.[7,11] Nevertheless, the reaction of 1f and 2a (see Table 2) in the presence of [Pd(MeCN)4](BF4)2, a commercially available cationic palladium(II) complex, did not result in the formation of product (Scheme 4, top). It was found, however, that adding 40 mol% MeCN under the standard, optimized, and otherwise successful conditions (cf. Table 2, product 3a; 76% yield), only traces of product formation was observed (Scheme 4, bottom). This suggests that the low reactivity of the pre-formed cationic palladium complex may actually be due to suppression of the reaction by MeCN coordination to the Lewis acidic PdII. Scheme 4 Effect of cationic palladium species. With the goal of generating a highly active cationic PdII complex without the aid of strong acid, and in the absence of coordinating ligands, the combination of Pd(OAc)2 and AgBF4 was examined (Scheme 5). As expected, these conditions led to C–H activation. Unlike the reaction with AgOAc, the reaction with AgBF4 produced the corresponding C–H arylated product 3a without assistance of external acid at room temperature. This result, under such mild conditions, is indicative of the potential for highly active cationic palladium species to serve as especially effective catalysts for C–H arylation reactions. The silver salt may not only weaken the C–I bond and/or function as halogen scavenger, but may also play an important role in the generation of cationic palladium(II) species. Scheme 5 C–H activation without acids at room temperature in water. In summary, the first room temperature C–H arylation of anilides with aryl iodides to give biaryl derivatives in good yields is described. These are accomplished using aryl urea derivatives, and are all done in water in the absence of phosphine ligands. Further studies of metal-catalyzed C–H activation reactions at room temperature, including both Heck couplings and mechanistic studies, are currently under investigation.

Allylic ethers as educts for Suzuki-Miyaura couplings in water at room temperature.

The first examples of Suzuki-Miyaura couplings of allylic ethers are reported. These can be done not only under very mild room-temperature conditions but also in water as the only medium. The process is made possible by micellar catalysis using the designer surfactant PTS.

1,4-Additions of arylboron, -silicon, and -bismuth compounds to α,β-unsaturated carbonyl compounds catalyzed by dicationic palladium(II) complexes

An enantioselective synthesis of cyclic and acyclic β-aryl ketone and aldehydes via Pd(II)-catalyzed 1,4-addition of Ar-m [m = B(OH)2, BF3K, Si(OMe)3, SiF3, BiAr2] to α,β-unsaturated ketones or aldehydes is described. The catalytic cycle involves transmetallation between Ar-m and Pd complexes as a key process, the mechanism of which is discussed on the basis of characterization of the transmetallation intermediate and electronic effect of the substituents. The enantioselection mechanism and efficiency of a chiraphos ligand for structurally planar α,β-unsaturated ketones are discussed on the basis of the X-ray structure of the catalyst and results of density functional theory (DFT) computational studies on the model of coordination of the substrates to the phenylpalladium(II)/(S,S)-chiraphos intermediate.

Pd-catalyzed synthesis of allylic silanes from allylic ethers.

Allylic phenyl ethers serve as electrophiles toward Pd(0) en route to a variety of allylic silanes. The reactions can be run at room temperature in water as the only medium using micellar catalysis.

Aminations of allylic phenyl ethers via micellar catalysis at room temperature in water.

Especially mild, organic solvent-free conditions have been found that allow for allylic ethers to undergo Pd-catalyzed aminations.

General and Facile Method for exo-Methlyene Synthesis via Regioselective C–C Double-Bond Formation Using a Copper–Amine Catalyst System

In this study, for distal-selective β-hydride elimination to produce exomethylene compounds with a newly formed Csp(3)-Csp(3) bond between tertiary alkyl halides and α-alkylated styrenes, a combination of a Cu(I) salt and a pyridine-based amine ligand (TPMA) is found to be a very efficient catalyst system. The yields and regioselectivities were high, and the regioselectivity was found to be dependent on the structure of the alkyl halide, with bulky alkyl halides showing the highest distal selectivities.

Site‐Selective Tertiary Alkyl–Fluorine Bond Formation from α‐Bromoamides Using a Copper/CsF Catalyst System

A copper-catalyzed site-selective fluorination of α-bromoamides possessing multiple reaction sites, such as primary and secondary alkyl-Br bonds, using inexpensive CsF is reported. Tertiary alkyl-F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF2 is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α-bromocarbonyl compound and a copper(I) salt.

A Copper-Catalyzed Formal [3 + 2]-Cycloaddition for the Synthesis of All Different Aryl-Substituted Furans and Thiophenes

A highly efficient formal [3 + 2]-cycloaddition was established using a copper catalyst. The resulting dihydrofurans were subjected to oxidation followed by arylations to produce tetraarylfurans. In addition, the dihydrofuran can be converted to diaryldihydrothiophene by using Lawessons reagent. This protocol will facilitate the synthesis of all different aryl-substituted furans and thiophenes.