Heck reaction benzyl chlorides

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 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... 

Heck and co-workers have reported the catalytic carbonylation of aryl and vinyl bromides and iodides and of benzyl chlorides in the presence of alcohols to give esters.479 The general reaction is summarized in equation (107) in which RX represents the above organic halides. 

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]. 

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]. 

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). 

The Heck reaction can be used to couple alkenyl, aryl, allyl (the intramolecular Heck reaction on aUyUc substrates is called a palladaene reaction),f ° t f benzyl, methyl, alkoxycarbonyhnethyl, alkynyl, certain alkyl, and silyl fragments to a variety of alkenes. The nature of the leaving group greatly affects the reaction rate aryl iodides react faster than bromides, and aryl chlorides are notoriously unreactive unless special catalysts or ligands and elevated temperatures are used to enhance the reaction rate. This has been taken to indicate that the oxidative addition of the haloarene (haloalkene) to pal-ladium(O) is the rate-determining step. " It has been shown that the Heck reaction can be performed with aryldiazonium salts, A -nitroso-Af-arylacetamides, and hy-pervalent iodo compounds " at room temperature. 

Mechanistic studies performed with Freeh s pincer catalyst in the Heck reaction excluded catalytic cycles with the involvement of homogeneous palladium(O) species, as indicated by the results obtained from the (recently developed) dibenzyl-test, which is directly applicable under the reactions conditions applied [24aj. Dibenzyl formation was - in contrast to Heck reactions catalyzed by palladium(O) complexes of type [Pd(PR3)2, where Pd /Pd" cycles are operative - not detectable by gas chromatography-mass spectrometry (GC/MS) when reaction mixtures of aryl bromide, olefin, benzyl chloride ( 10 mol% relative to aryl bromide), catalyst, and base were thermally treated. On the other hand, experimental observations, such as quantitative poisoning experiments with metallic mercury and CS2, which were shown to eflfidently inhibit catalysis, as well as analysis of the reaction profiles showed sigmoidal-shaped kinetics with induction periods and hence indicated that palladium nanoparticles are the catalytically active form... 

Scheme 14.19 Ni-catalysed Heck reaction of benzyl chlorides.

In contrast to PPhs, P(c -Tol)3 cannot reduce Pd (OAc)2 to a Pd(0) complex, but a P,C-palladacycle, rran5-di(/r-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipaIladium (5) is formed via a cyclometallation [27, 55]. The palladacycle 5 is an efficient catalyst for Mizoroki-Heck reactions involving aryl bromides and activated aryl chlorides (i.e. substituted by EWGs) [lj,l,o,s-v, 27, 55]. When 5 is used as catalyst in C—N crosscoupling reactions, Louie and Hart wig [56] have established that the true catalyst is aPd(0) complex, Pd P(o-Tol)3 2 formed by reduction of the palladacycle by the nucleophile (a secondary amine as a hydride donor in the presence of a strong base). 

The reaction of 5-acetoxy-5,6,7,8-tetrahydroisoquinoline 109 with Mel followed by reduction afforded the octahydroisoquinoline 110, which upon treatment with ethyl chloroformate followed by hydrolysis gave 111. The condensation of 111 with 2-bromoisovanillin afforded 112, which was reduced to give the benzyl alcohol intermediate 113. Heck reaction of 113 led to the formation of 0-ring affording 115. The yield of the above intramolecular cyclization was increased significantly via prior protection of the alcohol in 113 as silyl ether 114. Conversion of 115 to benzyl chloride 116 was achieved via the treatment with NCS and triphenylphosphine. Further, Heck reaction of 116 afforded the tertiary amine 117 via an intramolecular A -benzylation. The amine 117 was converted into the corresponding iV-methylammonium iodide 118, which was then subjected to Stevens rearrangement with PhLi to afford ( )-desoxycodeine 119 in 83 % yield. ... 

Greaney et al. introduced the Heck reaction to the benzyne three-component coupling to prepare 1,2-functional-ized arenes 28 and 29. Alternatives to allyl chlorides as the initial carbopalladation electrophile were presented, that is, methyl bromoacetate and benzyl bromides, thus avoiding the formation of benzyne/benzyne/allyl by-products and therefore improving the efficiency of the reaction [39], When using aryl iodides as the electrophilic partners, highly functionalized biaryl compounds 30 are obtained (Scheme 3.20) [40]. 

Palladium bromide is also an efficient Pd(0) catalyst precursor for the aminocarbonylation of benzyl chlorides (eq 46), car-bonylative Heck reaction of aryl bromides with vinyl ethers (eq 47), and carbonylation of halogenoalkynes (eq 48). ... 

The adduct resulting from this Ugi-Smiles coupling contains an N-aryl unit that offers great synthetic potential for further functionalization. Scheme 5.26 shows just one such an example. The reaction of 2-iodo-4-nitrophenol (90) with allylamine, 3-methylbutanal, and benzyl isocyanide in the presence of ammonium chloride afford the Ugi-Smiles adduct 91, which, without purification, underwent palladium-catalyzed Heck cydization to afford indole 92 in 72% yield. Trifluoroacetic add (O.lequiv.) was introduced before addition of the palladium catalyst in order to destroy any remaining isocyanide, which was harmful to the subsequent cydization due to catalyst poisoning [51]. 

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