# 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
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Entry** & **Catalyst** & **Ligand 1** & **Solvent** & **Temp./Time** & **Yield** & **Refs.** \\ \hline \multicolumn{7}{c}{**X = Cl (39a)**} \\ \hline
1 & Pd(AcO)\({}_{2}\) & A & THF & 110 \({}^{\circ}\)C/20 h & 79\% & [17] \\ \hline
2 & Pd(AcO)\({}_{2}\) & B & 1,4-dioxane & 100 \({}^{\circ}\)C/20 h & 84–88\% & [21] \\ \hline
3 & Pd(dppf)Cl\({}_{2}\) & - & 1,4-dioxane & 80 \({}^{\circ}\)C/on & na & [22] \\ \hline
4 & Pd\({}_{2}\)(dba)\({}_{3}\) & C & 1,4-dioxane & 85 \({}^{\circ}\)C/on & na & [23] \\ \hline \multicolumn{7}{c}{**X = Br (39b)**} \\ \hline
5 & Pd(dppf)Cl\({}_{2}\) & - & 1,4-dioxane & 100 \({}^{\circ}\)C/na or on or 2 h & 80–92\% & [24; 25; 26; 27; 28] \\ \hline
6 & Pd(dppf)Cl\({}_{2}\) & - & 1,4-dioxane & 90 \({}^{\circ}\)C/2 h & 70–85\% & [29] \\ \hline
7 & Pd(dppf)Cl\({}_{2}\) & - & 1,4-dioxane & 80 \({}^{\circ}\)C/na or 12 h–4 d & 21–78\% & [28; 29; 30; 31; 32; 33] \\ \hline
8 & Pd(dppf)Cl\({}_{2}\) & - & DMF & 90 \({}^{\circ}\)C/na & 78\% & [34] \\ \hline
9 & Pd(dppf)Cl\({}_{2}\) & - & DMF & 80 \({}^{\circ}\)C/15–16 h & 51–83\% & [35; 36] \\ \hline
10 & Pd(dppf)Cl\({}_{2}\) & - & DMSO & 80 \({}^{\circ}\)C/4–24 h & 45–61\% & [37; 38] \\ \hline
11 & Pd(dppf)Cl\({}_{2}\) & - & DMSO & 80 \({}^{\circ}\)C/on & 83\% & [39] \\ \hline
12 & Pd(dppf)Cl\({}_{2}\) & - & DME & 80 \({}^{\circ}\)C/on & 81\% & [40] \\ \hline
13 & Pd(dppf)Cl\({}_{2}\)-DCM & - & 1,4-dioxane & 80 \({}^{\circ}\)C/2 h & 77–88\% & [41] \\ \hline
14 & Pd(dppf)Cl\({}_{2}\)-DCM & - & 1,4-dioxane & 90 \({}^{\circ}\)C/12 h & na & [42] \\ \hline
15 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMF & 80 \({}^{\circ}\)C/12 h & 53\% & [43] \\ \hline
16 & CuI, Pd(dppf)Cl\({}_{2}\) & - & DMF & 90 \({}^{\circ}\)C/12 h & 82\% & [44] \\ \hline \multicolumn{7}{c}{**X = I (39c)**} \\ \hline
17 & Pd(PPh\({}_{3}\))\({}_{4}\) & - & 1,4-dioxane & 100 \({}^{\circ}\)C/12 h & 22\% \({}^{\text{2}}\) & [45] \\ \hline \multicolumn{7}{c}{**X = OTf (39d)**} \\ \hline
18 & Pd(dppf)Cl\({}_{2}\) & - & DMF & 95 \({}^{\circ}\)C/on & 86\% & [46] \\ \hline \hline \end{tabular}  
* A: 1,3-Bis(2,6-diisopropylphenyl) imidazolium chloride, B: P(Cy)\({}_{3}\), C: 2’-(Dicyclohexylphosphino)-N,N-dimethyl [1,1’-biphenyl)[2-amino. 2’ Both pinacol boronic ester and boronic acid were products of the reaction. Yield of isolated boronic acid via prep. HPLC purification. on—overnight, na—data not available.  
\end{table} 
Table 2: Miyaura borylation conditions for _para_-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol esters (**40**). final product, potassium 4-(1,3,4-oxadiazol-2-yl)phenyltrifluoraborate, is obtained in 34% yield after lyophilization and Soxhlet extraction with acetone [47]. Another common method for synthesizing 1,3,4-oxadiazol-phenylboronic acid derivatives involves a lithium borylation mechanism (Scheme 1, method A). Table 3 summarizes the reaction conditions for this methodology, including the lithium and boron sources, solvents, corresponding yields, and relevant references. The lithium borylation approach most frequently utilizes aryl bromides as starting materials (Scheme 8), which undergo halogen-metal exchange with \(n\)-butyllithium (\(n\)-BuLi) at low temperatures (from \(-78\)\({}^{\circ}\)C to \(-40\)\({}^{\circ}\)C) in Et\({}_{2}\)O (Table 3, Entry 1) or THF (Table 3, Entries 2-7). Trimethyl borate (B(OMe)\({}_{3}\)) or trisopropyl borate (B(O-\(i\)-Pr)\({}_{3}\)) is then added as a boron source to introduce the boronic ester group. Finally, an acidic workup affords the corresponding 4-(1,3,4-oxadiazol-2-yl)phenylboronic acids. Yields for this method typically range from 42% to 81% (Table 3, Entries 2-5). When isopropylboronic acid pinacol ester is used as the boron source, a six-step lithiation borylation sequence in THF with \(n\)-BuLi affords the pinacol boronic ester in 61% overall yield (Table 3, Entry 7). To improve the efficiency of this approach, a two-step, one-pot procedure has been developed (Table 3, Entries 8a-e).