C -H arylation reactions

Phenylazo-1,2,4-triazole were prepared from benzenediazonium chloride and 1,2,4-triazole <07SC1977>. 5-Aryltriazole acyclonucleosides 134 with various aromatic groups on the triazole ring were synthesized from precursor 133 via the Suzuki coupling reaction in aqueous solution and promoted by microwave irradiation <07TL2389>. 1-Methyl-1,2,4-triazole 135 participated in a palladium-catalyzed C-H arylation reaction with 3,5-dimethoxychlorobenzene 136 to give coupled product 137 <07OL1449>. 

Understanding the mechanistic details of the C-H activation step was a major thrust of Keith s research, and information from these studies played a key role in the methods developed by his coworkers. The Fagnou group s mechanistic studies of C-H arylation reactions are among their most highly cited work, and represent a contribution whose impact will likely be felt for years to come. In total, some 40 papers have or will appear in many of the best journals and will serve to summarize his independent career. His research program was on a rapid upward trajectory in 2008, his group published five papers in JACS. He remained a modest... 

Okamoto, K., Zhang, J., Housekeeper, J.B., Marder, S.R., Luscombe, C.K., 2013b. C—H arylation reaction atom efficient and greener syntheses of jr-conjugated small molecules and macromolecules for organic electronic materials. Macromolecules 46,8059-8078. 

Nitrogen-directed C—H activation to form C—C bonds like aryl-aryl is a relatively recent class of reactions. In 2008, Nakamura and coworkers presented the first report of an iron-catalyzed C—H arylation reaction—a homogeneous iron catalysis featuring C—C bond formation via C—H activation. As an overall synthetic transformation, it was a formal nucleophilic displacement of the ort/ o-hydrogen atom by... 

C-H arylation reaction with a triazole-based directing group [45], Although the substrate scope is relatively narrow than that with palladium catalyst, it would be helpful to explore and understand the catalytic specialty of iron. Future work will focus on the design of an efficient iron catalytic system to avoid the use of sensitive reagents enabling the reaction applicable. 

Arylation of Other Heterocycles. Y)i-tert-hutyl(methyl)phosphonium tetrafluoroborate has also been used for the C-H arylation reaction of other heterocycles. For exart5)le, the direct C5-arylation of imidazo[l,5-a]pyrazines was disclosed using this ligand, in combination with palladium acetate as the catalyst (eq 24). ... 

McNally A, Prier CK, MacMillan DWC (2011) Discovery of an a-amino C-H arylation reaction using the strategy of accelerated serendipity. Science 334 1114-1117... 

The second step in the process consisted of a palladium-catalyzed intramolecular cycliza-tion followed by an intramolecular C-H arylation reaction to afford the polycyclic indoles. While only a few examples were reported, the tolerance of the first step in the process to air coupled with the availability of all the reagents makes this an attractive approach to the synthesis of this interesting class of compounds. 

Sultones are the internal esters of hydroxy sulfonic acids and sulfur analogs of lactones. The biological activities of sultones are concerned with toxicological, skin sensitization, and antiviral properties [13]. In 2009, Majumdar developed a Pd(PPh3)4-catalyzed intramolecular C-H arylation reaction of benzenesulfonic acid 2-bromophenyl esters to afford polycyclic sultones, which are generally synthesized by elimination of the corresponding hydroxyl sulfonic acid derivatives, in up to 90% yield (Scheme 3.3, path a) [14]. TBAB was found to be critical in this reaction, and no reaction occurred in the absence of this additive. An electrophilic palladation mechanism was proposed for this transformation. 

Scheme 3.3 Pd

Scheme 16.37 Synthesis of a sodium channei inhibitor and an antimalarial agent using a pyridine W-oxide C-H arylation reaction.

Several metal cross-coupling reactions have been applied to pyrazoles. C-H Arylation of aryl tosylates or chlorides could be achieved with a ruthenium catalyst at the C-2 phenyl position of... 

Moreover, in this particular example, the distribution of mono- and bis-silylated products changes over time improved yields of the mono-silylated (sp2-functionalized product) are observed after 1 h reaction, whereas overnight reaction leads to a good yield of bis-C-H aryl- and C-H benzyl-activated product (Equation (55)).ss... 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

C in THF, which cleanly led to the formation of (amino)(aryl)carbene Xllla (Scheme 8.8). ° A NMR signal at 8 = 314.2 ppm leaves no doubt of the formation of Xllla. Carbene Xllla is stable for days in solution at —50 °C but undergoes a C—H insertion reaction at room temperature within a few hours, giving rise to the 4,6-di-ferf-butyl-l,l-dimethyl-3-(methyl-rcrt-butylamino)mdane as the major product. It is interesting to note that this reaction, typical of transient singlet and triplet carbenes, has never been observed for diamino carbenes. This striking difference demonstrates the less perturbed character of carbene Xllla. 

Until recently, intermolecular C—H insertion reactions were more a curiosity than a synthetically productive undertaking. Davies and Antoulinakis discovered in the late 1990s that aryl- and vinyldiazoacetates undergo intermolecular insertion with a wide variety of hydrocarbons in high yield. With Rh2(5-DOSP)4 (12, Ar = C12H25C6H4) moderate-to-high enantioselectivities have been achieved, but diastereoselection is often low to moderate (e.g., Eq. 32, 33 ). Note that a... 

Pyridylarenes undergo Cu(II)-catalysed diverse oxidative C-H functionalization reactions. The tolerance of alkene, alkoxy, and aldehyde functionality is a synthetically useful feature of this reaction. A radical-cation pathway (Scheme 4) has been postulated to explain the data from mechanistic studies. A single electron transfer (SET) from the aryl ring to the coordinated Cu(II) leading to the cation-radical intermediate is the rate-limiting step. The lack of reactivity of biphenyl led to the suggestion that the coordination of Cu(II) to the pyridine is necessary for the SET process. The observed ortho selectivity is explained by an intramolecular anion transfer from a nitrogen-bound Cu(I) complex.53... 

Several silver complexes have been investigated in C-H insertion reactions of carbenes. One of the earliest reports by Sulikowski and Burgess describes an intramolecular C-H insertion of a chiral aryl diazoacetate 80 as part of a study on the total synthesis of mitomycin family of natural products (Scheme 8.15).41 Among several catalysts that were screened was AgSbly, in the presence of bis(isoxazoline)-type ligands, which led to the formation of the desired insertion product 81 in moderate yield and modest diastereoselectivity. 

The C-H insertion reaction of aryldiazoacetates to furnish dihydrobenzofurans is best carried out with dimeric rhodium(ll) catalysts. Rh2(PTTL)4 has proven to be the catalyst of choice for the asymmetric version of this process, providing exclusively j-2-aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans with an ee of up to 94% (Equation 142) <2002OL3887>. 

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