Benzyl Heck reaction

Bisacid 91 was used toward three different targets. For the first, a palladium-catalyzed decarboxylative Heck reaction followed by perylenequinone formation provided bis-styryl derivative 92 (Scheme 7.22) [52]. For the second, the C5,C5 -benzyl ethers were cleaved, and the more acidic carboxylic acids were then selectively benzylated using BnBr and K2CO3 (Scheme 7.22). This re-esterification... 

The choice of an ionic liquid was shown to be critical in experiments with [NBuJBr (TBAB, m.p. 110°C) as a catalyst carrier to isolate a cyclometallated complex homogeneous catalyst, tra .s-di(ri-acetato)-bis[o-(di-o-tolylphosphino) benzyl] dipalladium (II) (Scheme 26), which was used for the Heck reaction of styrene with aryl bromides and electron-deficient aryl chlorides. The [NBu4]Br displayed excellent stability for the reaction. The recycling of 1 mol% of palladium in [NBu4]Br after the reaction of bromobenzene with styrene was achieved by distillation of the reactants and products from the solvent and catalyst in vacuo. Sodium bromide, a stoichiometric salt byproduct, was left in the solvent-catalyst system. High catalytic activity was maintained even after the formation of visible palladium black after a fourth run and after the catalyst phase had turned more viscous after the sixth run. The decomposition of the catalyst and the formation of palladium... 

The main steps in the currently accepted catalytic cycle of the Heck reaction are oxidative addition, carbopalla-dation (G=G insertion), and / -hydride elimination. It is well established that both, the insertion as well as the elimination step, are m-stereospecific. Only in some cases has formal /r/ / i--elimination been observed. For example, exposure of the l,3-dibromo-4-(dihydronaphthyloxy)benzene derivative 16 and an alkene 1-R to a palladium source in the presence of a base led to a sequential intra-intermolecular twofold Heck reaction furnishing the alkenylated tetracyclic products 17 in good to excellent yields (Scheme 9). " In the rate-determining step, the base removes a proton in an antiperiplanar orientation from the benzylic palladium intermediate. The best amine base was found to be l,4-diazabicyclo[2.2.2]octane, which apparently has an optimal shape for this proton abstraction. 

The natural product, anhydrolycorinone was prepared in the palladium mediated intramolecular Heck reaction of a tetrahydroindole derivative. The coupling, which is run in air and requires the use of a stoichiometric amount of palladium, is accompanied by the dehydrogenation of the cyclohexadiene moiety and the oxidation at the benzylic position to a lactam (4.11.).12... 

The brownish-colored solid is air sensitive and should be handled and stored under inert gas atmospheres. Solutions are very air sensitive with precipitation of colloidal palladium. The 31P NMR (109.3 MHz, D20, 5°C) exhibits a singlet at <522.6 ppm. The IR displays the characteristic SO-vibrations at 1225 (sh, vst), 1200 (vst), 1039 (vst), and 622 (vst) cm-1. The compound has been intensively utilized for carbonylation of benzylic chlorides,26 aryl bromides,27 and 5-hydroxymethylfurfural,28 Heck-reactions,29 allylic substitution reactions,30 and oxidations.16... 

The Heck reaction is a palladium-catalyzed C-C bond-forming procedure that joins benzylic, vinylic, and aryl halides or the corresponding triRates with alkenes or alkyncs. The result is an alkenyl-or aiyl-substituted alkene. The mechanism below is assumed to apply to the Heck reaction.18... 

In a series of studies, Shibasaki examined the formation of chiral benzylic quaternary centers by using asymmetric intramolecular Heck reactions. The effect of double-bond stereochemistry was examined in the cyclization of aryl Inflates 9.1 and 9.3 (Scheme 8G.9) [22], As is commonly... 

In this manner, a hydroformylation/condensation sequence of 0-vinyl-anilines give indoles directly. The starting o-vinylanilines are obtained by Heck reaction of the corresponding o-haloanilines. Hydroformylation of these styrene-type olefins proceeds preferably at the benzyl carbon. Intramolecular condensation gives pharmacologically interesting tryptophols and tryptamines in mediocre to good yields (Scheme 12, Table 1) [47]. 

The presence of a good electrofugal group (L + ), such as H+ or Me3Si +, makes elimination the predominant path (Scheme 10.14, pathways a and b). When R is an aromatic ring, pathway (a) is favorable and a benzylic proton is lost to form styrenes this results in a photochemical process analogous to the Heck reaction (Scheme 10.15) [12],... 

In a similar approach, naproxen is prepared from an olefin, the product of a Heck reaction (see Section 5.3.2.1). As described above, the reaction proceeds in the presence of water and HC1, additionally copper(n)chloride is added, possibly to prevent the formation of palladium black (Scheme 5.39). Addition of HC1 to the double bond and subsequent oxidative addition reaction of the benzylic chloride with the active Pd° species initiates the catalytic cycle, which proceeds similarly to the ibuprofen synthesis [70-73]. 

As Shibasaki and co-workers demonstrated, tetralin derivatives of type 55 (with a quaternary benzylic carbon center) can also be enantioselec-tively prepared by an intramolecular Heck reaction (Scheme 14) [19]. 

Transition metal-catalyzed intramolecular cyclization has also been applied to the formation of imidazoles. Palladium-mediated amino Heck reactions of 0-pentafluorobenzoylamidoximes 1163 afford l-benzyl-4-methylimid-azoles 1164 with a range of substituents at the 2-position. This method is particularly suitable for the preparation of imidazoles with a chiral substituent at the 2-position (Scheme 283) <20050L609>. 

C-C coupling reactions include Pd-catalyzed carbonylations as well as Heck reactions. Biphasic operations are reported as being particularly efficient. Allyl and benzyl chlorides have been converted in two-phase systems to the corresponding acids with or without phase-transfer catalysts (eq. (6)) [154-157, 237]. 

The term Heck reaction summarizes catalytic C-C-coupling processes, such that a vinylic hydrogen is replaced by a vinyl, aryl, or benzyl group, with the latter being introduced from a halide or related precursor compound (cf. eq. (3)) [9 a, 14-16]. Therefore, the final step of product formation is the elimination of a hydrogen halide, and a base is thus required to bind the acid. The olefinic (vinylic) double bond is retained throughout the Heck reaction. Palladium is practically the only catalyst metal used, in the form of certain Pd and Pd" salts or complexes normally 1-5 mol % of catalyst is administered. 

In 1984, Jeffery discovered that under ligand-free conditions, Pd-catalyzed vinylation of organic halides proceeds at or near room temperature, whereas normal Heck reactions require higher temperatuies [64]. Jeffery s hgand-free conditions have been broadly applied to a variety of Heck arylations that were not feasible using more standard reaction conditions. For example, efforts to use classical Heck-reaction conditions for the conversion of Al-allyl-Al-benzyl(3-bromoquinoxalin-2-yl)amine (64) to l-benzyl-3-methylpyrrolo[2,3-/ ]quinoxaline (65), resulted in slow reactions and low yields [65], which may be attributed to the poisoning of the palladium catalyst via complexation to the aminoquinoxalines. In contrast, the Jeffery conditions afforded the desired product in 83% yield. The enhanced reactivity and yield under Jeffery s ligand-free conditions may be due to the coordination/solvation of the palladium intermediates by bromide ions present in the reaction mixture, which presumably prevents the precipitation of Pd(0). 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cychzations of266 and 267 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 266 and the TV-benzyl indole 268 [271]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 269, and they prepared a series of peripheral-type benzodiazepine receptors 270 using this chemistry. For example, 270 (n = 3, R = n-Pr) is obtained in 81% yield. 

An example is as follows. After protection as a silyl ether, amidation of benzyl A-(5,6-0-isopropylidene-4-hydroxycyclohex-2-enyl)carbamate 229 (prepared from 3-bromo-lS,2S-0-isopropylidenecyclohexa-3,5-diene) with (6-bromo-3,4-methylenedioxy)benzoyl chloride gave the protected N-benzyloxycarbonyl-A-(cyclohex-2-enyl)benzamide 230. A modified Heck reaction of 230 in anisole produced the protected lycoricidine 231 in 27% yield (two steps) by A-detosylation. Acid treatment of 231 provided (-H)-lycoricidine (204) in 85% yield (Scheme 22). 

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