Palladium-catalyzed direct benzylation

Scheme 19.20 Palladium-catalyzed direct benzylation of heteroarenes.

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... 

Campeau L-C, Schipper Dl, Fagnou K (2008) Site-selective sp2 and benzylic sp3 palladium-catalyzed direct arylation. 1 Am Chem Soc 130 3266-3267... 

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... 

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>. 

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... 

Metal-mediated approaches to the synthesis of imidazoles have been reported. PaUadium(ll)-catalyzed intermolecular 1,2-diamination of conjugated dienes with ureas led to 4-alk enyl-2-imidazolones in good yields rmder mild conditions <05JA7308>. Palladium-catalyzed cyclization of O-pentafluorobenzoylamidoximes 74 furnished l-benzyl-2-substituted-4-methylimidazoles 75 <050L609>. Direct copper(I)-chloride mediated reaction of nitriles 76 with a-amino acetals 77 followed by acidic reaction led to a variety of 2-substituted imidazoles 78 <05TL8369>. 

In a substrate-dependent, palladium-catalyzed domino N-benzylation/ intramolecular direct arylation process, tosylamides 133 and 2-bromobenzyl bromides 134 reacted to form dibenzo-l,2-thiazepine dioxides 135 exclusively, or gave mixtures that also contained 6,7-dihydro-5H-dibenzo[c,e] azepines 136 (14JOC10899). 

Intramolecular palladium-catalyzed alkylations of (hetero)arenes have been pioneered by Wong and Song [25], who described in 1994 a direct benzylation of furans within a domino sequence starting with the intermolecular Suzuki- Miyaura coupling of furylboroxines with o-bis(bromomethyl)arenes (Scheme 19.14). Mixtures of the cross-coupled product and the corresponding homocoupled furan were almost always obtained. 

Cunico and Pandey reported the palladium-catalyzed preparation of a-aryl tertiary amides using benzylic halides and carbamoylsilane [87], and, in this report, a disadvantage of using aminocarbonylation of benzyl halides was also described [90]. Accordingly, to expand the scope of this chemistry, we next focused on the use of benzylic organometallic reagents to develop a facile route for the synthesis of a-aryl tertiary amides. Since the appropriate benzylzinc halides were easily prepared via the direct insertion of highly active zinc, they were employed in the... 

The ready availability of arylboronates by an aromatic C-H borylation provides a synthetic link to the well-established palladium-catalyzed cross-coupling reactions, rhodium-catalyzed 1,4-addition to a,p-unsaturated carbonyl compounds, and other bond forming reactions using arylboronic esters (Scheme 2.12). Borylation of 1,3-dichlorobenzene with pinacolborane is followed directly by a cross-coupling reaction with methyl p-bromobenzoate for the synthesis of a biaryl product in 91% yield [60]. Pinacol esters of arylboronic acids react much slower than the free acids [62], but both derivatives achieve high isolated yields and comparable enantioselectivities (91% ee) in asymmetric 1,4-addition to N-benzyl crotonamides [63]. Borylation of arenes followed by oxidation of the C-B bond is synthetically equivalent to an aromatic C-H oxidation to phenols [64]. Oxidation of the resulting arylboronates with Oxone in a 1 1 acetone-water solution is completed within 10 min at room temperature. 

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). 

Another typical example for the direct oxidative transformation of methyl arenes were developed by Wang and co-workers [118]. In this palladium catalyzed reaction, tert-butyl nitrite (TBN) was employed as both nitrogen source and oxidant N-hydroxyphthalimide (NHPI) was used as precursor of the active phthalimide N-oxyl (PINO) radical, which initiates the reaction to give benzylic radical A by grabbing hydrogen atom from the substrate. In the interaction between TBN and NHPI, TBN decomposes to NO radical and tert-butyl alcohol. NO radical would trap benzylic radical A to give nitrosomethyl benzene B, which isomerizes to aldoxime C [119]. Finally, nitrile product would be generated fitom C by palladium catalysis (Scheme 4.21). 

The palladium catalyzed Heck reaction of 2-pyridyl tosylates would not only provide access to the a-arylated olefins but also act as direct precursors to the attractive chiral benzylic amine and amide derivatives often found in bioactive compounds. 

The aforementioned methods to construct benzofurans are all achieved by activation of C(sp )-H bond. In 2012, based on the alkynoxy-directed synthesis of 2-methylidene-2H -chromene derivatives [28], Hiyama and coworkers developed a palladium-catalyzed hydrobenzylation of ortho-tolyl alkynyl ethers to construct 2-methylidene-2,3-dihydrobenzofurans via the activation of benzylic C(sp )-H bond [34]. 

The palladium-catalyzed double C-H activation of simple benzyl phenyl sulfoxides to synthesize dibenzothiophenes (DBTs) was described by Antonchick and coworkers (Scheme 4.3) [7]. They proposed that the sulfoxide functionalized as a directing group to undergo the first ortho-C-H activation in the benzyl phenyl... 

---