Palladium-catalyzed benzylation

Very recently another reaction, which involves a palladium-catalyzed benzyl halide carbonylation step, has been commercialized by Clariant AG. Here, the carbonylation of 1,2-xylyl dichloride in the presence of a palladium-phosphine catalyst yields isochromanone (eq. (10)) [54]. 

Few investigations have been devoted to the scope of palladium-catalyzed benzylic oxidation. Electron-donating substituents, e.g. MeO, in the aromatic ring have a promoting effect no reaction was observed with /7-nitrotoluene... 

Scheme 19.21 Palladium-catalyzed benzylation of (benz)oxazoles with benzyl phosphate.

Scheme 19.22 Palladium-catalyzed benzylation of azoles with benzyl carbonates.

A particularly significant and useful contribution of transition metals in fine organic synthesis as well at the industrial level is based on their use as catalysts. This aspect is of course particularly important with expensive transition metals (Rh, Os, Pd, etc.). Indeed, there are numerous examples of selective processes which have never been developed up to the industrial stage because of catalyst costs, especially when some (even minor) loss of the catalyst could not be avoided. This was, for example, the case for palladium-catalyzed benzylic acetoxylation reactions, and several rhodium-catalyzed reactions, such as the direct ethylene glycol production from syngas (prohibitive pressures being an additional major drawback in this latter case). 

Oxygen Nucleophiles. A reagent such as permanganate oxidizes toluene to benzoic acid, whereas benzylic oxidation by palladium acetate results in benzyl alcohol derivatives. The oxidation is favored by electron-releasing substituents in the phenyl ring. Catalytic amounts of palladium acetate and tin diacetate, in combination with air, effects an efficient palladium-catalyzed benzylic oxidation of toluene and xylenes. For the latter substrates, the Q, Q -diacetate is the main product.A mixed palladium diacetate-copper diacetate catalyst has also been found to selectively catalyze the benzylic acyloxylation of toluene (eq 64). ... 

Only one example of palladium-catalyzed benzylation of 1,2,3 triazoles has been reported by the group of late Fagnou (Scheme 43) [98], The presence of pivalic acid... 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperatiue with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAIH, amd weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed bydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Rcist, 1964). 

An unusual by-product was obtained in small yield in palladium-catalyzed reduction of 2-amino-4,5-dimethoxyindanone hydrochloride, The reduction was done in two stages first, a rapid absorption of 1 mol of hydrogen at 38 C to give the amino alcohol, and then a much slower reduction in the presence of HCIO4 at 70 "C. The rearranged by-product was shown to arise from attack of acid on the amino alcohol (50), Resistance to hydrogenolysis is characteristic of / -amino aromatic alcohols (56), a fact that makes reduction of aromatic oximino ketones to amino benzyl alcohols a useful synthetic reaction. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

Palladium-catalyzed hydrosilylation of styrene derivatives usually proceeds with high regioselectivity to produce benzylic silanes, 1-aryl-1-silyle thanes, because of the... 

The palladium-catalyzed opening of an oxazolidine ring followed by the hydrogenolysis of a benzylic OH group was performed over 5% Pd/C in ethanol at 140 atm H2 in 45 hours (Scheme 4.17).35... 

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... 

As part of the same study, the capacity of this novel resin to act as an allyl cation scavenger was demonstrated in a palladium-catalyzed O-alloc deprotection of O-alloc benzyl alcohol (Scheme 7.107) [125], Benzyl alcohol was obtained in high yield with only trace amounts of by-product, thereby eliminating the need for further purification. The resulting C-allylation of the resin was evident from the presence of C-allyl signals in the relevant MAS-probe 1H NMR spectrum. 

Scheme 7.107 Palladium-catalyzed deprotection of O-alloc benzyl alcohol employing the scavenging resin CHD-SR.

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Palladium-catalyzed directed intramolecular activations of aryl C-H bonds have been reported, as in the phenyla-tion of heterocycle analogs. Palladacycles are proposed intermediates, acting as effective catalysts, and the mechanism is likely to proceed via oxidation of Pd(ll) to Pd(iv) by the iodonium salt, as for the Equation (57), which described the activation of benzylic i/-CH bonds (Equations (121)—(123).109... 

The palladium-catalyzed reaction of benzol]quinoline in the presence of PhI(OAc)2 as an oxidant in MeCN gives an 11 1 mixture of 10-acetoxy- and 10-hydroxybenzo[ ]quinolines in 86% yield (Equation (98)).135 This chelation-directed oxidation can be extended to the benzylic C-H bond of 8-methylquinoline. The inactivated sp3 C-H bonds of oximes and pyridines undergo the same palladium-catalyzed oxidation with PhI(OAc)2 (Equation (99)).1... 

The palladium-catalyzed C-Se bond formation79-81 and the platinum-catalyzed carboselenation of alkynes with selenoesters have been reported in analogy with the thiolate chemistry. An electron-withdrawing or electron-donating group on the aromatic residue leads to the formation of the desired carboselenation product with acceptable yields. Functionalities like benzyl, hydroxyl, or nitrile group are tolerant with the reaction conditions. This method provides a new access to the functionalized vinylselenide 60,82 molecules of interest as key intermediate (Scheme 19) 85... 

The asymmetric hydrosilylation that has been most extensively studied so far is the palladium-catalyzed hydrosilylation of styrene derivatives with trichlorosilane. This is mainly due to the easy manipulation of this reaction, which usually proceeds with perfect regioselectivity in giving benzylic silanes, 1-aryl-1-silylethanes. This regioselectivity is ascribed to the formation of stable 7t-benzylpalladium intermediates (Scheme 3).1,S Sa It is known that bisphosphine-palladium complexes are catalytically much less active than monophosphine-palladium complexes, and, hence, asymmetric synthesis has been attempted by use of chiral monodentate phosphine ligands. In the first report published in 1972, menthyldiphenylphosphine 4a and neomenthyldiphenylphosphine 4b have been used for the palladium-catalyzed reaction of styrene 1 with trichlorosilane. The reactions gave l-(trichlorosilyl)-l-phenylethane 2 with 34% and 22% ee, respectively (entries 1 and 2 in Table l).22 23... 

Secondary phosphine oxides are known to be excellent ligands in palladium-catalyzed coupling reactions and platinum-catalyzed nitrile hydrolysis. A series of chiral enantiopure secondary phosphine oxides 49 and 50 has been prepared and studied in the iridium-catalyzed enantioselective hydrogenation of imines [48] and in the rhodium- and iridium-catalyzed hydrogenation functionalized olefins [86]. Especially in benzyl substituted imine-hydrogenation, 49a ranks among the best ligands available in terms of ex. 

Common protectors of hydroxyls are benzyl and 2-bromobenzyl for Boc chemistry and tert-butyl for Fmoc chemistry. Trityl provides a third level of selectivity for both chemistries because it can be removed by mild acid (1% CF3C02H in CH2C12), which does not affect tert-butyl based protectors. O-Allyl is not removable by palladium-catalyzed allyl transfer, so it is not appropriate. Protection by acyl such as benzyloxycarbonyl is possible, but 0 -acyl protectors can be problematic because of their tendency to shift to adjacent amino groups (see Section 6.6) and... 

The Boots Hoechst Celanese (BHC) ibuprofen process involves palladium-catalyzed carbonylation of a benzylic alcohol (IBPE). More recently, we performed this reaction in an aqueous biphasic system using Pd/tppts as the catalyst (Figure 9.6 tppts = triphenylphosphinetrisulfonate). This process has the advantage of easy removal of the catalyst, resulting in less contamination of the product. 

Salcedo A, Neuville L, Zhu JP (2008) Palladium-catalyzed intramolecular C-arylation of benzylic carbon synthesis of 3-benzoxazolylisoindolinones by a sequence of Ugi-4CR/ postfunctionalization. J Org Chem 73 3600-3603... 

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