Aryl ethers Heck reaction

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

Regarding bis-NHC chelating ligands, several structures that differ in the motifs used for the enlargement of the tether have been proposed as catalysts for the Mizoroki-Heck reaction. They range from non-functionalised aliphatic chains [23-25] to phenyl [26], biphenyl [27], binaphthyls [28] and to chains containing additional coordination positions like ethers [29], amines [30], and pyridines in an evolution towards pincer complexes [31-35], In most cases, the activity of aryl bromides in Mizoroki-Heck transformations was demonstrated to be from moderate to high, while the activation of chlorides was non-existent or poor (Scheme 6.7). 

Another important type of reactivity of palladium, namely oxidative addition to Pd(0), is the foundation for several methods of forming carbon-carbon bonds. Aryl126 and alkenyl127 halides react with alkenes in the presence of catalytic amounts of palladium to give net substitution of the halide by the alkenyl group. The reaction, known as the Heck reaction,128 is quite general and has been observed for simple alkenes, aryl-substituted alkenes, and substituted alkenes such as acrylate esters, vinyl ethers, and A-vinylamides.129... 

Tietze and coworkers [60] observed a combination of a Heck reaction and a C-H-activation by treatment of the alkyne 6/1-111 with Pd°. These authors aimed at compound 6/1-112, but 6/1-110 was obtained as a single product in high yield (Scheme 6/1.29). It can again be assumed that after oxidative addition a cis-carbopalladation of the triple bond takes place to give an alkenyl Pd intermediate which undergoes the C-H-insertion into the neighboring naphthalene and not into the aryl ether moiety. 

Lamaty and coworkers described a straightforward combination of three Pd-cata-lyzed transformations first, an intermolecular nucleophilic substitution of an al-lylic bromide to form an aryl ether second, an intramolecular Heck-type transformation in which as the third reaction the intermediate palladium species is intercepted by a phenylboronic acid [124]. Thus, the reaction of a mixture of 2-iodophenol (6/1-253), methyl 2-bromomethylacrylate 6/1-254 and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-di-hydrobenzofuran 6/1-255 (Scheme 6/1.66). In addition to phenylboronic acid, several substituted boronic acids have also been used in this process. 

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

Traditional Heck arylation of the corresponding ethyl vinyl ether afforded high yields with most of the aryl bromides investigated (Eq. 11.11). Under continuous singlemode microwave treatment the transformations were complete within 10-12 min [25], Heck reactions without solvent in a domestic microwave oven have been examined by Diaz-Ortiz [26]. The reactions were conducted in closed vessels with reported temperatures of 150 °C. A study was performed in which reactions performed with microwave irradiation were compared with oil-bath-heated reactions with identical reaction times and temperatures. The isolated yields tended to substantially favor the microwave-heated reactions (Eq. 11.12). 

An interesting organometallic reaction is the Heck Arylation (Eqn. 1) (ref. 5), which is commonly run using a Pd(OAc>2 catalyst. This reaction is used to prepare aryl enol ethers which can be valuable synthetic intermediates in that they can be hydrolyzed to aldehydes or ketones, species which can be useful themselves or as intermediates in further reactions. The influence of reaction parameters on the rate and selectivity of this reaction was reported in a series of papers (refs. 2, 3). In these a brief mention in some tables was made that Pd/C was able to catalyze this reaction but no discussion of the use of this catalyst was included. We have found, though, that this reaction is readily promoted over dispersed Pd catalysts. When run with Pd(OAc)2 as the catalyst, the Heck reaction gives as the primary products the E (1) and Z (2) aryl P enol ethers in about a 2 1 ratio. The a isomer, 3, and ester, 4, are also produced but in much smaller amounts. When the reaction is run over Pd/A Oj, the same products are obtained but the P enol ethers 1 and 2 are produced in nearly a 3 1 ratio. Table 1 lists the product compositions of these reactions. 

When a series of STO characterized Pd/A Og catalysts were used to promote the Heck reaction (Eqn. 1) the amount of the fi aryl enol ethers, 1 and 2, formed after a 60 minute reaction was directly related to the comer site densities on these catalysts. Thus, this reaction and presumably, others such as the diene cyclization shown in Eqn. 2, which require the adsorption of two reactive species on a single surface atom, must take place on the more coordinatively unsaturated comer atoms. 

Scheme 2 shows a similar mechanistic pathway for a Heck reaction taking place on a Pd octahedral comer. This mechanism is based on that established for soluble Pd catalysts (ref. 5). Adsorption of the aryl halide (or aryl acid chloride after decarbonylation) gives the aryl Pd halide, 15, by way of the adsorbed intermediate, 14. Vinyl ether adsorption, as in 16, takes place as described in Scheme 1. Aryl insertion gives the halometalalkyl, 17, which on f) elimination to the available 4dxy orbital gives the aryl enol ether, 2 (or 1 depending on which hydrogen is eliminated in 17). The resulting halo palladium hydride, 18, then reacts with the tertiary amine to give the amine hydrochloride and regenerates the octahedral comer for further reaction.

Since 1,4 addition of a variety of appropriate aryl caibanions to 36 failed, an intramolecular version of the Heck reaction was examined. With this end in view, the ketone 36 was reduced stereospecifically to the corresponding allyl alcohol which was then protected as its p-methoxybenzyl ether 37. The amine, obtained on reduction of the azide 37, was condensed with 6-bromopiperonylic acid to furnish the amide 38. 

In order to prepare the bicyclic compound 9, an intramolecular Heck reaction under Grigg s conditions (Pd(OAc)2, K2CO3, Bu4NBr) is carried out (see Chapter 13).7 Starting from aryl iodide 8 a six-membered ring formation occurs providing intermediate 28, which reacts to alkene 29. Finally double bond isomerization to compound 9 is forced by the formation of a thermodynamically more stable enol ether. 

An orf/io-directed lithiation allows the conversion of 25 to aryl iodide 40. Reductive ether formation of aldehyde 40 with crotyl alcohol yields compound 41. Intramolecular Heck reaction of 41 affords a mixture of the olefins 42 and 43. The undesired alkene 42 can be isomer-ized quantitatively to the desired enol ether 43 with Wilkinson s catalyst. Sharpless dihydroxylation ee 94 %) of the enol ether 43 provides lactol 44, which is oxidized directly to lactone 45. Finally, the pyridone-O-methyl ester is cleaved under acid conditions (45 — 7). 

Unlike 13-26, the Heck reaction is not hmited to activated substrates. The substrate can be a simple alkene, or it can contain a variety of functional groups, such as ester, ether, carboxyl, phenolic, or cyano groups. Couphng with vinyl ethers has been reported, C=C OR C=C(Ar)OR. The Heck reaction can be done with heterocychc compounds, and the C C unit of compounds, such as indene, react with aryl iodides and palladium catalyst without the need for... 

Danishefsky and co-workers exploited a 6-exo intramolecular vinylic Heck substitution reaction en route to a total synthesis of ( )-FR-900482 (76) (Scheme 6-12) [26]. The efficient conversion of aryl iodide 70 to tetracycle 71 is illustrative of the impressive functional-group tolerance displayed by the Heck reaction. During the development of this synthesis, attempts were made to introduce the oxygenation present at C —13 at an earlier stage [27]. Enol ethers 72 and 74 were prepared and subjected to Heck conditions. 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

In 2002, Trost and Tang reported the chiral total synthesis of (-)-codeine in short reaction steps using a palladium-catalyzed asymmetric allylic alkylation (AAA) [53] as the key transformation [54], In 2005, a detailed full account of their synthesis was published [55]. The key features of their synthesis are (1) a preparation of an aryl ether with high optical purity by the Pd-catalyzed AAA reaction, (2) the intramolecular Heck reaction to generate the A-C-E benzofuran skeleton, (3) the second intramolecular Heck reaction of Z-vinyl bromide providing the phenan-throfuran core, and (4) the intramolecular hydroamination for the construction of D-ring by the action of LDA and visible light. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

Halofurans and halobenzofurans readily participate in Heck reactions with alkenes, and it is possible to synthesize benzofurans via intramolecular Heck reactions of aryl vinyl ethers. The heteroaromatic behavior of furans enable them to undergo heteroaryl Heck reactions to provide substituted furans. 

The immobilization of SCS pincer ligands has attracted considerable attention. An SCS ligand was attached to an MeO-PEG backbone via an aryl ether linkage to give 315 which was then metallated by treatment with Pd(PhCN)2-CI2 yielding 316. " Although active in the Heck reaction, 316 slowly decomposed during the course of the reaction... 

Scheme 5 Remarkable dendritic effect in the Heck reaction using aryl ether dendrons on PS solid support...

A dendritic spacer of poly(aryl benzyl ether) was used for incorporation of phosphine ligands onto a PS resin support [116,117]. Thus, the condensation of 4-(diphenylphosphino)benzoic acid with Wang resin bearing poly(aryl benzyl ether) (generation 1-3) gave the PS-supported dendritic phosphine 86. Treatment of the dendritic phosphine 86 with Pd(dba)2 in THF afforded the bisphosphine-palladium complex 87 (Scheme 29) [ 118]. The PS-supported palladium complex exhibited a positive dendritic influence on the Heck reaction of bromobenzene with methyl acrylate. 

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