Heck chlorobenzene reactions

Scheme 36, A and Turnover numbers up to approximately 500,000 were reported for the reaction of iodobenzene with methyl acrylate and an impressive nnmber (about 100,000) was also achieved with bromobenzene and 4-methoxy-bromobenzene. Characteristic featnres of these tridentate PCP catalysts are thermal stability and air stability. A competitive experiment, including 4-bromoiodobenzene, iodobenzene, 4-methyliodoben-zene, and 4-methoxy-iodobenzene with methyl acrylate provided a linear correlation with Hammet cr-valnes, which, however, exhibited a low p valne (1.39). It was concluded that nucleophilic aromatic substitution is not rate determining, bnt a snbsequent step with different electronic requirements, such as alkene insertion, may acconnt for this observation. Chlorobenzene could not be coupled with these catalyst. Very recently, Milstein s group reported new cyclopalladated, phosphine-free imine complexes as catalysts in the Heck arylation reaction (Scheme 36, The new dimeric imine complexes show... 

The long reaction times required for the previously reported copper-catalysed Mizoroki-Heck-type reactions could be significantly reduced with microwave irradiation [21] in polyethylene glycol (PEG) as solvent [22]. An induction period [23] was noted, resulting, interestingly, in improved isolated yields for the reused catalytic system in the second cycle (Scheme 10.5) [22]. Various aryl iodides, including orr/io-substituted electrophiles, were efficiently converted within 30 min. On the contrary, Ijromo- and chlorobenzene could not be converted under these reaction conditions. 

As part of comparative studies, Iyer [47] reported the use of Vaska s complex [IrCl(CO)(PPh3)2l (92) in intermolecular Mizoroki-Heck-type reactions of methyl acrylate (1) and styrene (2). Aryl iodides could be used as electrophiles, while bromobenzene, chlorobenzene and aliphatic halides gave no desired product. The catalytic activity was found to be lower than that observed when using Wilkinson s complex [RhCl(PPh3)3] (84). Thus, a higher reaction temperature of 150 °C was mostly required. In contrast to the corresponding cobalt-catalysed reaction, however, Vaska s complex (92) proved applicable to orf/io-substituted aryl iodides (Scheme 10.33). 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

Although the Heck reaction is synthetically very useful, it requires quite high molar quantities of palladium catalyst to be effective. As such, one of the main goals is to find a solvent that helps to increase the lifetime of the catalyst and consequently reduce the amount of catalyst required. In this respect, ionic liquids show considerable promise. Another key goal in this area is to be able to replace iodo- and bromoarenes, usually used as substrates in these reactions, with chloroarenes, which are more environmentally acceptable. Again, ionic liquids show some promise in this respect. Scheme 10.2 shows the Heck reaction between styrene and chlorobenzene that has been investigated in a number of ionic liquids. 

Although as described in Section 3.1.1.1, oxidative addition of chlorobenzene to Pd(0) is difficult, chlorobenzene 207, coordinated by Cr(CO)3, undergoes the facile oxidative addition to Pd(0). Then alkene insertion (Heck reaction) [53] and coupling... 

Heck and Suzuki type couplings have been described by Fu [2] et al. The reaction of chlorobenzene and styrene in refluxing dioxane in the presence of [Pd2(dba)3 ] and the electron rich tri-tert.-butyl-phosphane [eq. (a)] gives rise to trans-stilbene in 83% yield. Besides the choice of the ligand - aryl phosphanes, tri-n-butyl-phosphane or tri-cyclo-hexyl-phosphane show no conversion - the base is also crucial for success. Cesium carbonate gives the best results, although the cheaper potassium phosphate gives comparable yields. 

Heck reaction. A new catalyst system for the Heck reaction consists of (MeCNjjPdClj, Ph,PCl, NaOAc in NMP. It is highly efficient for coupling of unreactive substrates such as chlorobenzene. 

Bimetallic Pd/Ni [121] andPd/Co [122] systems have exhibited considerable catalytic activity in the Heck reaction of nonactivated chloroarenes with ethyl acrylate, acrylonitrile, and acrylic acid. For instance, ethyl acrylate and acrylonitrile reacted smoothly with chlorobenzene in the presence of Nal and catalytic amounts of NiBr2, Pd2(dba)3, and o-Tol3P in DMF to give E-isomers of ethyl cinnamate and cinnamonitrile, respectively [121]. The reaction occurred via the nickel-catalyzed halogen exchange between ArCl and Nal, followed by the conventional palladium-catalyzed olefination of the iodoarene generated in situ. 

CPG material was used as support instead of silica gel for a Heck/SAPC system [6]. There, iodobenzene was coupled with different olefins. The dependencies of different substrates and different bases on the activity were examined. The system was active for several types of olefins. The reactivity of the aryl hahdes was comparable to that of the homogeneous catalysis. Iodides reacted easily, while bromobenzene was converted inefficiently. No reaction occurred using chlorobenzene. With EtjN as base, the highest conversions were achieved. However, leaching of palladium was observed and an /Z mixture of products was isolated. When the amine was replaced by KOAc, the Heck reaction gave selectively the -isomer. No leaching was observed (detection limit approx. 0.1 ppm), but the conversion dropped to 80%. The catalytic system with KOAc as base was successfully used for five consecutive rims, with an overall TON of > 1,200. In all cases, conversion ranged from 70 to 80% and 100% selectivity of the -isomer was achieved. 

Table 10.2 Selected heterogeneously catalyzed Heck reactions of chlorobenzene.

In 1997 Ying and coworkers reported that Pd-grafted mesoporous materials are active catalysts for Heck reactions. The Pd-TMSll catalyst (prepared by gas phase reaction of volatile Pd complexes and MCM-41) was one of the very first heterogeneous catalysts that succeeded in the activation of aryl chlorides. With a catalyst amount of 0.1 mol% Pd at least 16% of chlorobenzene could be converted (TON = 64). However, 170 °C and 32 h reaction time were necessary. Only 40% selectivity to the Heck coupling products (= 6% yield) could be achieved [152, 159]. Another catalyst was prepared by Srivastava et al. by ion exchange using SAPO-31 and (NH3)4PdCl2-H20. Up to 70% of chlorobenzene could be converted at 120°C within 70 h (67% yield) [160]. 

The Suzuki-Miyaura cross-coupling reaction is a standard method for carbon-carbon bond formation between an aryl halide or triflate and a boronic acid derivative, catalyzed by a palladium-metal complex. As with the Mizoroki-Heck reaction, this cross-coupling reaction has been developed in ionic liquids in order to recycle and reuse the catalyst. In 2000, the first cross-coupling of a halide derivative with phenylboronic acid in [bmim] [BF4] was described. As expected, the reaction proceeded much faster with bromobenzene and iodobenzene, whereas almost no biphenyl 91 was obtained using the chloride derivative (Scheme 36). The ionic liquid allowed the reactivity to be increased, with a turnover number between 72 and 78. Furthermore, the catalyst could be reused repeatedly without loss of activity, even when the reaction was performed under air. Cross-coupling with chlorobenzene was later achieved - although with only a moderate yield (42%) - using ultrasound activation. 

The Heck reaction is compatible with water, and water-soluble catalysts have successfully been employed (entry 10). Alkali metal salts (NaHCOj, K2CO3, and KOAc) are effective bases in the smooth reactions of acrylic acid with o-, m-, or p-iodobenzoic acid or p-iodophenol in which water-soluble salts are formed and very high yields are encountered (entry 11). Activated heteroaryl chlorides are good arylpalladium precursors (entry 12) while nonactivated aryl chlorides have to date been considered to be less useful in the Heck reaction. In entry 13, the recent protocol devised by Littke and Fu for arylation with nonactivated chlorobenzenes is shown. ... 

Efforts to increase the catalyst turnover number are indeed another major area where further improvements can be expected. Such improvements have recently been achieved using preformed palladacycles as catalysts or by using a macrocyclic tetraphole as ligand.t Dendritic diphosphine-palladium complexes as catalysts for Heck reactions have also been reported to possess superior stability compared to the monomeric parent compounds.t °" In addition, the same research gronp could considerably activate the rate of the Heck reaction of chlorobenzene and styrene by addition of tetraphenylphosphonium salts and A/,A-dimethylglycine. Transferring snch innovations to the AHR remains an important goal. 

Various catalyst types were tested with a wide variety of substrates. For example, p-iodonitrobenzene and styrene react according to the Heck cross coupling to p-nitrostilbene with a yield of 99%. This situation is similar for many other reactions of styrene and methylacrylate with other reactants containing iodine and bromine. On the other hand, chlorobenzene reacts with styrene only in trace amounts. 

At a relatively high reaction temperature (150°C), Reetz et al. also accomplished the Mizoroki-Heck reaction of chlorobenzene with styrene in the presence of Pd(OAc)2 and phosphonium salt PI14PCI [23aj. Again, the high catalytic activity was ascribed to the presence of nanosized palladium colloids, which are beheved to be stabilized by the phosphonium salt... 

Unless very strongly activated, aryl chlorides do not undergo oxidative addition to the Pd(0) catalysts typically utilized for the Heck reaction. Chlorobenzene participates in the Heck reaction when it is reacted with Nal in the presence of NiBr2 prior to the addition of Pd-catalyst (equation 18) 64), In this example, a small equilibrium amount of iodobenzene was formed in a Ni-catalyzed... 

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