Regioselective functionalizations, pyridine

Regioselective functionalization of unreactive carbon-hydrogen bonds, in particular, arylation of pyridines by using aryl iodide, silver acetate, and catalytic palladium acetate 06SL3382. 

Regioselective functionalization of pyridines using a directed metalation or a halogen/metal exchange 13ZN411. 

Highly efficient rhodium-catalyzed direct arylations were accomplished through the use of 2,2, 6,6 -tetramethylpiperidine-N-oxyl (TEMPO) as terminal oxidant [17]. Thereby, a variety of pyridine-substituted arenes was regioselectively functionalized with aromatic boronic acids (Scheme 9.5). However, in order for efficient catalysis to proceed, 4equiv. of TEMPO were required. The use of molecular oxygen as terminal oxidant yielded, unfortunately, only unsatisfactory results under otherwise identical reaction conditions. However, a variety of easily available boronic acids could be employed as arylating reagents. 

Dudnik, A. S. Weidner, V. L. Motta, A. Delferro, M. Marks, T. J. Atom-efficient regioselective 1,2-dearomatization of functionalized pyridines by an earth-abundant organolanthanide catalyst. Nat. Chem. 2014, 6, 1100-1107. 

The regioselective functionalization of pyridines using metallation or halogen/metal exchange reactions has been reviewed. There has been a detailed mechanistic study of the ort/io-lithiation of 2-fluoro- and 2,6-difluoro-pyridines by lithium diisopropy-lamide (LDA) in tetrahydrofuran at -78°C where aggregation and aggregate-exchange phenomena are critical.The mono-lithiation of the boron trifluoride adduct of 3-chloro- and 3-bromo-pyridines results in reaction at the 2-position. However, with two equivalents of LDA, the 2,6-dilithiated derivatives may be formed. Subsequent reaction with electrophiles may result in the formation of 2-, 6-, or 2,6-substituted products. " ... 

In connection with trifluoromethyl chemistry, one has, from the synthetic point of view, to mention the large-scale preparation of numerous trifluo-romethoxypyridines. They can, via regioselective functionalization, provide large libraries of fluoro-substituted pyridine building blocks [260]. 

The regioselective functionalization of pyridine at the C4 position remains a challenge. A recent example illustrates a selective C4 silaboration under palladium catalysis (eq 28). Pyridine can be reacted with Me2PhSi-B(pin) in the presence of al-lyl PdCl(PCy3) (2 mol%) in benzene at 50 °C. The resulting sUylated dihydropyridine product is obtained in 79% yield ( H-NMR yield confirmed by isolation) and it can be aromatized to the C4 silylated pyridine in 92% yield when using... 

The nature of the nitrogen protecting group also played a significant role in the chemoenzymatic total synthesis ofepibatidine, which shall be outlined as an example for the synthetic elaboration of the regioselective biooxidation product of a nonnatural precursor. B. bassiana mediated hydroxylation of the aza-norbornane system enabled functionalization for the subsequent introduction of the pyridine system (Scheme 9.10) [82,83]. 

The cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

Other calculations were aimed at predicting the reactivity of some bicyclic 5-6 systems. For instance, the rare [l,4,2]diazaphospholo[4,5- ]pyridine 22 (Scheme 2) was examined for its reactivity (C=P bond) toward dienes in cycloaddition reactions <2005T10521>. The results of density functional theory (DFT) calculations were in good agreement with the experimentally obtained regioselectivity when using unsymmetrical dienes. 

Halofluorinations take place, as a rule, regioselectively (Markovnikov addition), the olefinic carbons can be substituted with a variety of substituents ranging from alkyl or aryl groups to different electron-withdrawing functions see for example refs 31 and 178-180. Bromo-fluorination of 4-/m-butyl-l-methylcyclohexene with /V-bromosuccinimide in 70% hydrogen fluoride/pyridine gave two stereoisomers 1 and 2.181... 

Palladium-catalysed directed C-H oxidation with (diacetoxy)iodobenzene of a series of meta -substituted aryl pyridine and aryl amide derivatives resulted in the formation of the corresponding acetoxy compounds. The reactions generally proceed with high levels of regioselectivity for functionalization of the less sterically hindered ortho-C-H bond.144 The mechanism shown in Scheme 4 has been proposed for the oxidation of 2,6-dimethylphenol with (diacetoxyiodo)benzene for the formation of 3,5,3, 5 -tetramethyl-biphenyl-4,4 -diol, via C-C coupling.145... 

Pd-catalysed chelate-directed acetoxylation of meta -substituted arenes has been studied.61 Many substituted groups are tolerated by this process and the reaction shows a high degree of regioselectivity for the less sterically hindered ortfto-position. For example, 2-(3-nitrophenyl)pyridine forms 2-(2-acetoxy-3-nitrophenyl)pyridine. Finally, density functional calculations62 on the palladium acetate-promoted cyclomet-allation of dimethylbenzylamine suggest that reaction occurs via an agostic C-H complex rather than a Wheland intermediate. An intramolecular H-transfer to a coordinated acetate via a six-membered transition state follows. 

Regioselective reactions in systems which contain multiple functional groups are an area ideally suited for biocatalysis. Linhardt and co-workers at the University of Iowa s Division of Medicinal and Natural Products Chemistry recently published the synthesis of a series of 1 -O-acyl sucrose derivatives [31], Using Chiro-CLEC -BL (the CLC of subtilisin) and vinyl esters of the acylating agent in pyridine as solvent, the authors prepared l -O-lauryl sucrose, l -O-myristyl sucrose, and l -O-stearyl sucrose in 80-90% yield (Fig. 9). Their method represents a green alternative to the tin chemistry previously used [32],... 

In the presence of alkylchloroformate esters, Ws(tributylstannyl)acetylene has been used in the 2-ethynylation of pyridines <94T(50)13089>. An unexpected regioselectivity has been observed in the rearrangement of 3-pyridyl thiophosphates to 2- and 4-pyridyl thiophosphonates <94ZOK(64)610>. A method for introduction of acyl carbon functional groups using trimethylstannyl pyridine (45) was explored and applied to making fusaric acid (46) (Scheme 34) <95H(41)817>. 

---