Benzylic palladium catalyzed

In addition to benzylations, palladium-catalyzed C-H allylation reactions have also been described, but they usually involve the electrophilic substitution of an electron-rich (hetero)arene with a 7t-allyl palladium complex and therefore deviate from the scope of this chapter [41, 42]. In contrast, the palladium/copper-catalyzed allylation of polyfluoroarenes with allyl carbonates (Scheme 19.27) has been reported to occur through a different mechanism [43]. Thus, base-induced cupration of the arene would give rise to intermediate 15 that was previously characterized by X-ray crystallography [44]. Attack of the in sitw-generated JT-allyl... 

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... 

In order to account for the high regioselectivities observed in the rhodium-catalyzed hydroboration of styrenes, Hayashi proposed a modified mechanism which proceeds through 73-benzyl-rhodium complex 22 as a key intermediate (Scheme 7). Reductive elimination from this 73-benzyl-rhodium complex 22 produces the secondary alkylborane regioselectively.12 A related 73-benzyl-palladium complex was recently isolated by Hartwig in studies of hydroamination.75... 

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... 

The added advantage of the C (1 )-stannylated glycals is their abUity to participate in palladium-catalyzed coupling reactions with organic halides, a process independently reported by Beau [75] and Friesen [81]. Vinyl stannane 237 can be benzylated, allylated or acylated provided that appropriate catalysts are used [75,77] and representative examples are given in Scheme 59. The C-arylation of... 

The annelation of benzo rings on pyridazines was covered in CHEC-II(1996) <1996CHEC-II(6)1>. Maes and Matyus reported new examples in their synthesis of the dibenzo[// ]phthalazin-l(27r)-one and dibenzo[//]cinnolin-3(27/)-one skeleton. Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one yielded 2-benzyldibenzo[/,4]phthalazin-l(2//)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl) -phenylpyridazin-3(2//)-one via a Pschorr-type reaction was also investigated. Similarly, the con-stmction of 2-methyldibenzo[/, ]cinnolin-3(2//)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(27T)-one and 2-methyl-5-(2-aminophenyl)-6-phenyl-pyridazin-3(2//)-one was performed <2003T5919>. 

The same product was obtained when 4-chloro-5-methyl-2-(methylthio)pyrimidine 236 was reacted with benzyl-zinc bromide, due to selective palladium-catalyzed displacement of the 2-methylthio group, followed by nucleophilic displacement of the 4-chloro substituent of the intermediate 237 by the liberated zinc thiomethoxide <2000SL905>. 

Conditions for controlling the regiochemistry of the addition reactions between benzyl zinc reagents and 2,4-dichloroquinoline under palladium-catalyzed conditions were developed <99JOC453>. Similarly, the regiochemistry of the palladium-catalyzed carbonylation of 4,7-dichloroquinoline was evaluated <99TL3719>. 

A series of pyrido[2,3-rf pyrimidine-2,4-diones bearing substituents at C-5 and/or C-6 were synthesized using palladium-catalyzed coupling of uracil derivative 417 with vinyl substrates or allyl ethers to give the regioisomeric mixtures of 418/419 and 420/421, respectively. The ratio of the isomeric structures was dependent on the substituent R. In the case of the reaction with -butyl vinyl ether, only the product 419 was obtained. However, the reactions with acrylonitrile, ethyl acrylate, 2-trifluoromethylstyrene, and 3-nitrostyrene afforded only 418. Also, reaction with allyl phenyl ether gave only 420. The key intermediate 417 was prepared by the reaction of 6-amino-l-methyluracil with DMF-DMA (DMA = dimethylacetamide), followed by N-benzylation with benzyl chloride and vinyl iodination with iV-iodosuccinimide (NIS) (Scheme 15) <2001BML611>. 

Novel palladium-catalyzed transformations of allylic alcohol and its derivatives are developed by Yamamoto and his co-workers. Bis(7r-allyl)palladium complexes are considered to be the key intermediates for the allylation of benzyl-idenemalonitrile and benzyl chloride (Scheme 29) (for examples see Refs 176,176a-176d). Asymmetric version of these reactions is being awaited. 

Palladium-catalyzed asymmetric cyclization/hydrosilylation tolerated a number of functional groups including benzyl and pivaloyl ethers as well as benzyl and methyl esters (Table 8, entries 1-4). Furthermore, the protocol tolerated substitution at one of the two /ra/zi -terminal alkenyl positions and at one of the two allylic positions of the 1,6-diene (Table 8). As was the case with diene cyclization/hydrosilylation catalyzed by achiral palladium... 

Other Alkyl Ethers. Sucrose has been selectively etherified by electrochemical means to generate a sucrose anion followed by reaction with an alkyl halide (21,22). The benzylation of sucrose using this technique gives 2-O-benzyl- (49%), T-O-benzyl- (41%), and 3 -O-benzyl- (10%) sucrose (22). The benzylation of sucrose with benzyl bromide and silver oxide in DMF also produces the 2-O-benzyl ether as the principal product, but smaller proportions of T- and 3 -ethers (23). Octadienyl ether derivatives of sucrose, intermediates for polymers, have been prepared by a palladium-catalyzed telomerization reaction with butadiene in 2-propanol—water (24). 

Fig. 35. Effect of phase behavior on palladium-catalyzed oxidation of benzyl alcohol to benzaldehyde in supercritical CO2 characterized by transmission- and ATR-IR spectroscopy combined with video monitoring of the reaction mixture (102). The figure at the top shows the pressure dependence of the reaction rate. Note the strong increase of the oxidation rate between 140 and 150 bar. The in situ ATR spectra (middle) taken at 145 and 150 bar, respectively, indicate that a change from a biphasic (region A) to a monophasic (B) reaction mixture occurred in the catalyst surface region in this pressure range. This change in the phase behavior was corroborated by the simultaneous video monitoring, as shown at the bottom of the figure.

The 2,3-dichloro-4-hydroxyphenyl derivative of aripiprazole was prepared to confirm the structure of a primary metabolite of aripiprazole (Scheme 21). The synthesis began with the protection of 4-bromo-2,3-dichlorophenol as its benzyl ether 71. Palladium-catalyzed amination of 71 with piperazine proceeded regioselectively in excellent yield. Alkylation of the piperazine 72 with 69 in the presence of K2CO3 and... 

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