# Synthetic Approaches to 1,3,4-Oxadiazole-Containing Boronic Derivatives
## 3 Synthesis of Boronic Derivatives from Reagents Containing 1,3,4-Oxadiazole Moiety
### Indirect Connection of Boron with 1,3,4-Oxadiazole Ring via Phenotype Linker
#### 3.2.1 Derivatives of Para-Substituted (1,3,4-Oxadiazol-2-yl)phenyl)boronic Acid  
_Para-phenylene-linked 1,3,4-oxadiazol boronic acids or esters can be synthesized via various methods, starting from the appropriate aryl halides (Scheme 6). Table 2 summarizes the reaction conditions, catalysts, ligands, solvents, and corresponding yields, along with relevant references. Boronic esters can be prepared from aryl halides (X = Cl, Br, I) or pseudohalides (X = Off) using bis(pinacolato)diboron (B\({}_{2}\)(pin)\({}_{2}\)) in the presence of AcOK (method B) [17; 21; 22; 23; 24; 25; 26]._  
For aryl chlorides used as reactants (Table 2, Entries 1-4), catalyst systems such as Pd(OAc)\({}_{2}\) (palladium(II) acetate) with 1,3-bis(2,6-diisopropylphenyl)imidazol chloride or P(Cy)\({}_{3}\) (tricyclohexylphosphine), Pd(dppf)Cl\({}_{2}\) (bis(diphenylphosphino)ferrocene) palladium(II) dichloride), or Pd\({}_{2}\)(dba)\({}_{3}\) (tris(dibenzylideneacetone)di palladium) with 2'-(dicyclohexylphosphino)-\(N\),\(N\)-dimethyl [1,1'-biphenyl]-2-amine can be employed in solvents such as THF or 1,4-dioxane to afford the desired _para_-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol esters in 79-88% yield (Table 2, Entries 1-2). Bromides are the most commonly used species for Miyaura borylation reactions. Palladium catalysts, particularly Pd(dppf)Cl\({}_{2}\) or its DCM adduct, are frequently employed to carry out the coupling reaction. Solvents such as 1,4-dioxane, DMF, or DMSO are typically used, and elevated temperatures are often required to drive the reaction to completion. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Publication Type** & & & \\  & _para_ & & \\  & _para_ & & \\ \hline  & 18 & 7 & 0 \\  & 28 & 29 & 2 \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Publications on boronic acid and its derivatives linked to 1,3,4-oxadiazol via _ortho-, meta-_, and _para_-substituted phenyl groups as determined via the SciFinder database (accessed on 3 March 2025). Figure 6: Distribution of publication types concerning _ortho_, _meta_, and _para_ isomers of boronic acid and its derivatives linked to 1,3,4-oxadiazol via a phenylene linker, as determined via the SciFinder database (accessed 3 March 2025). Yields typically range from 45% to 92% (Table 2, Entries 5-16). In some cases, the addition of copper(I) iodide (CuI) as an additive can improve yields (82%, Table 2, Entry 16). For aryl iodide substrates, Pd(PPh\({}_{3}\))\({}_{4}\) (tetrakis(triphenylphosphine)palladium) can be used as a catalyst in 1,4-dioxane at elevated temperatures. However, [PERSON] et al. reported that the reaction yielded a mixture of boronic acid and ester. To isolate the desired boronic acid, preparative HPLC was necessary, and the yield of the isolated boronic acid was 22% (Table 2, Entry 17). The Pd(dppf)Cl\({}_{2}\) catalyst can be used with aryl trifilates. Conducting the reaction in DMF at 95 \({}^{\circ}\)C overnight affords the desired boronic ester in 86% yield (Table 2, Entry 18). Due to potential issues with the isolation and stability of boronic acids and esters during long-term storage, their direct conversion to crystalline trifluoroborate salts can be advantageous (Scheme 7). A two-step, one-pot approach involves the initial formation of boronic acid using the catalytic system XPhos Pd G2 (chloro(2-dicyclohexylphosphino-2\({}^{\prime}\),4\({}^{\prime}\),6\({}^{\prime}\)-triisopropyl-1,1\({}^{\prime}\)-biphenyl)[2-(2\({}^{\prime}\)-amino-1,1\({}^{\prime}\)-biphenyl)]] palladium(II)), AcOK, and tetrahydroxylboron (B\({}_{2}\)(OH)\({}_{4}\)) in EtOH at 80 \({}^{\circ}\)C for 2 h. After simple extraction, the crude boronic acid is converted to the trifluoroborate salt using an aqueous KHF\({}_{2}\) solution. The