# 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
In this method, the starting 2-(4-bromophenylyl)-1,3,4-oxadiazol (R\({}_{1}\) = H) is initially deprotonated with a weaker base (e.g., Me \begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Entry** & **Lithium Source** & **Boron Source 1** & **Solvent** & **Temp.** & **Yield** & **Product** & **Ref.** \\ \hline
1 & \(n\)-BuLi & A & E\({}_{2}\)O & na & na & **44** & [48,49] \\ \hline
2 & \(n\)-BuLi & A & THF & \(-40\)\({}^{\circ}\)C to \(-78\)\({}^{\circ}\)C & 81\% & **44** & [18] \\ \hline
3 & \(n\)-BuLi & A & THF & \(-50\)\({}^{\circ}\)C & 42\% & **44** & [50] \\ \hline
4 & \(n\)-BuLi & A & THF & \(-78\)\({}^{\circ}\)C & 74\% & **44** & [51] \\ \hline
5 & \(n\)-BuLi & A & Toluene/THF & \(-78\)\({}^{\circ}\)C & 62\% & **44** & [39] \\ \hline
6 & \(n\)-BuLi & B & Toluene/THF & \(-78\)\({}^{\circ}\)C & na & **44** & [15] \\ \hline
7 & \(n\)-BuLi & C & THF & Na & 61\%\({}^{\text{2}}\) & **40** & [52] \\ \hline
8a & 1. MeLi & B & THF & \(-65\)\({}^{\circ}\)C & 82\% & **44** & \\  & 2. \(n\)-BuLi & & B & THF & \(-35\)\({}^{\circ}\)C to \(-65\)\({}^{\circ}\)C & 89\% & **44** & \\ \hline
8b & 1. Li, 2-chlorotoluene, biphenyl & A & THF & \(-30\)\({}^{\circ}\)C to \(-65\)\({}^{\circ}\)C & 60\% & **44** & [53] \\  & 2. \(n\)-HexLi & & & & & \\ \hline
8c & 1. Li, 2-chlorotoluene & A & THF & \(-30\)\({}^{\circ}\)C to \(-65\)\({}^{\circ}\)C & 76\% & **44** & \\  & 2. \(n\)-HexLi & & & & & \\ \hline
8e & 1. Li, chlorobenzene, biphenyl & A & THF & \(-30\)\({}^{\circ}\)C to \(-65\)\({}^{\circ}\)C & 84\% & **44** & \\  & 2. \(n\)-HexLi & & & & & \\ \hline \hline \end{tabular}  
* A: trimethyl borate, B: trisopropyl borate, C: isopropylboronic acid pinacol ester. \({}^{\text{2}}\) Total yield after six-step synthesis.  
\end{table} 
Table 3: Lithiation borylation conditions for the synthesis of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acids (**44**) or its pinacol esters (**40**). 2-Li-toluene, Li-benzene), followed by halogen-metal exchange with a stronger base (e.g., \(n\)-BuLi, \(n\)-HexLi). Subsequent bordism with trimethyl borate or triisopropyl borate and acidic workup affords the desired 4-(1,3,4-oxadiazol-2-yl)phenylboronic acids in 60-89% yield [53]. The third approach (Scheme 3, method C) involves the formation of the 1,3,4-oxadiazol ring from starting materials already containing a boronic ester moiety (Scheme 9). For example, a pinacol boronic ester can be attached to a carboxylic acid (R1 = OH) or a hydrazide reagent (R2 = NHNHH2) via a phenylene linker. Cyclization is achieved using trichloroacetonitrile and triphenylphosphine in acetonitrile at 130 \({}^{\circ}\)C under microwave irradiation, followed by hydrolysis of the 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester using ammonium acetate and sodium periodate in an acetone/water mixture or aqueous sulfuric acid (Scheme 9A) [15]. Alternatively, 4-(hydrazinecarbonyl)phenylboronic acid pinacol ester can be reacted with triethyl orthoformate under reflux to form the corresponding 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (44). Figure 8: Transformation of 1,3,4-oxadiazol-containing aryl bromides (39b) into the corresponding 4-(1,3,4-oxadiazol-2-yl)phenylboronic acids (44) or its pinacol esters (40). yl)phenylboronic acid pinacol ester in 84% yield. Hydrolysis of the resulting boronic ester with 5% acetic acid affords 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid in 94% yield (Scheme 9B) [16]. Optionally, 4-(hydroxzinccarbonyl)phenylboronic acid pinacol ester can be treated with an \(S\)-ethylated thioamide in refluxing \(n\)-butanol to generate a 1,3\(A\)-oxadiazol ring as a 22% byproduct during triazole synthesis [54]. The structure of this byproduct was confirmed by NMR and X-ray crystallography. [PERSON] et al. aimed to obtain boronic acids as ligands for potential luminescent sensors; the synthesized 4-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]phenylboronic acid pinacol ester was converted into a more stable trifluoroborate potassium salt.