Intermolecular Heck arylation

Xiao et al. [213] recently reported that the intermolecular Heck arylation with several electron-rich olefins can be effected with both aryl bromides and iodides in a highly regioselective manner by the use of ionic liquids. Regioselectivity towards the branched cr-olefin was up to 99/1 and there was no need for additional halide scavenger. In this case the ionic liquid seems to serves not only as a quite polar solvent but also as halide scavenger. 

Wu, J., Marcoux, J.-R, Davies, I.W. and Reider, P.J. (2001) Beta-regioselective intermolecular Heck arylation of V,V-disubstituted allylamines. Tetrahedron Lett., 42, 159-62. 

S,7R)-5,6-Dehydro-de-0-methyl- Intermolecular Heck arylation with [278[... 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

Normally, the oxidative addition of an aryl chloride to Pd(0) is reluctant to take place. But such a process is greatly accelerated in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(/-Bu)3 or tricyclohexylphosphine]. In late 1990s, Reetz [76] and Fu [77] successfully conducted intermolecular Heck reactions using arylchlorides as substrates, as exemplified by the conversion of p-chloroanisole to adduct 77 [77], The applications of this discovery will surely be reflected on future Heck reactions of non-activated heteroaryl chlorides. 

In 1995 Herrmann discovered highly efficient palladacyde catalysts in Heck and related reactions of aryl halides with catalyst turnover numbers (TONs) up to 500,000 [ 117]. Later, TONs of the intermolecular Heck reaction reached up to 8,900,000 [ 118]. On the other hand, few syntheses of chiral palladacyde catalysts were envisioned and most of these attempts failed. Recently, the first AHR using a chiral phosphapalladacycle catalyst was reported by Buono et al. [ 119]. The chiral phosphapalladacycle catalyst 129, which was prepared from Pd(OAc)2... 

Ishiyama and Hartwig disclosed a set of rhodium(I)-catalyzed intermolecular Heck-type reactions between aryl iodides and N-heterocyclic aldimines to form the corresponding ketimines. Ishiyama T, Hartwig J (2000) 122 12043... 

These cationic conditions are also used for intermolecular Heck olefinations in which the chiral centers are generated via double-bond migration. The synthesis of 2-aryl-2,3-dihydrofurans 17 is a good example (Scheme 9) [26]. 

In the presence of a catalyst system of [Pd2dba3] and proazaphospha-trane (107) Verkade and Nandakumar [94,95] have achieved a double-amination-intermolecular Heck reaction sequence in a one-pot fashion with 4-amino styrene and various aryl halides to furnish the triarylated products 108 in moderate to excellent yields (Scheme 37). 

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

The total synthesis of the potent anticancer macrocyclic natural product lasiodiplodin was achieved in the laboratory of A. Furstner. The key macrocyclization step was carried out by the alkene metathesis of a styrene derivative, which was prepared in excellent yield via an intermolecular Heck reaction between an aryl triflate and high-pressure ethylene gas. 

The first detailed study of alkyl to aryl palladium migrations, reported in 2004, involved homobenzylic to phenyl migration (Table 5) [58], The process was demonstrated using aryl iodides tethered to an olefin. An additional hap, either intramolecular arylation or intermolecular Heck olefination, was used to hap the migrated palladium. The reaction gives high yields of the desired polycyclic products. 

Ozawa et al. reported the Pd(OAc)2-BlNAP catalysed asymmetric intermolecular Heck reaction of aryl triflate and 2,3-dihydrofiiran in the presence of a base [34]. In this reaction, the enantiomeric excess was significantly affected by the base, and Proton Sponge (1) gave the best results among the various bases, such as triethylamine, diisopropylethylamine, pyridine derivatives and inorganic bases (Table 8.9). 

Table 8.9 Asymmetric intermolecular Heck reaction of aryl triflate... 

Intramolecular or intermolecular Heck-type reactions were also used in the synthesis of poly-substituted quinoline compounds. Palladium-catalyzed reaction between vinyl or aryl halides and ortAo-allyl-substituted-A -tosyl-anilides produces dihydroquinolines in an intermolecular fashion, where reaction of acrylates intramolecularly affords 4-quinolones. ° ° ... 

B.xiv.c. Intermolecular Heck Reactions on Polymeric Support. Combinatorial chemistry has initiated a reappraisal and consequent renaissance in synthesis of compounds attached to polymeric supports. Therefore, it comes as no surprise that Pd-catalyzed reactions are among the most widely explored reactions for the generation of combinatorial libraries on solid phase. The first example of the intermolecular Heck reaction on solid phase was reported in 1994. In this article, 4-vinylbenzoic acid was attached to Wang resin and coupled with aryl halides/triflates under catalysis with Pd(OAc)2 (Scheme 45). Similar... 

Mariampillai, B., Herse, C. and Lautens, M. (2005) Intermolecular Heck-type coupling of aryl... 

Accordingly, catalytic and stoichiometric amounts of cuprous salts were employed for Mizoroki-Heck-type reactions of various conjugated alkenes [ 19]. Intermolecular catalytic arylations of methyl acrylate (1, not shown) and styrene (2) were accomplished under ligand-free conditions using CuBr (3) or Cul (4) as catalyst in A-methyl-2-pyrrolidinone (NMP) as solvent various aryl iodides could be employed (Scheme 10.2). On the contrary, aryl bromides and chlorides, as well as aliphatic halides, were found to be unsuitable substrates. The reactions employing an alkenyl bromide, methylmethacrolein or methyl methacrylate required stoichiometric amounts of copper salts. 

The reaction is initiated by oxidative addition of Pd(0) to aryl bromide followed by intermolecular Heck reaction, generating the intermediate 15 (Scheme 3.3). 

Scheme 7.15 Ligand-induced enantioselective intermolecular Mizoroki-Heck arylation of 2,3-dihydrolliran.

Figure 7.1 Chiral ligands tested in asymmetric intermolecular Mizoroki-Heck arylations (nd = not determined).

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