# 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
#### 3.2.2 Derivatives of Meta-Substituted (1,3,4-Oxadiazol-2-yl)phenylboronic Acid
\begin{table}
\begin{tabular}{c c c c c c c} \hline
**Entry** & **Catalyst** & **Ligand 1** & **Solvent** & **Temp./Time** & **Yield** & **Refs.** \\ \hline \multicolumn{8}{c}{**X = Br (53a)**} \\ \hline
1 & Pd(dppf)Cl\({}_{2}\) & - & 1\(\mathcal{A}\)-dioxane & 120 \({}^{\circ}\)C/20 min or on & 44–90\% & [55] \\ \hline
2 & Pd(dppf)Cl\({}_{2}\) & - & 1\(\mathcal{A}\)-dioxane & 100 \({}^{\circ}\)C/6 h & 53–80\% & [56] \\ \hline
3 & Pd(dppf)Cl\({}_{2}\) & - & 1\(\mathcal{A}\)-dioxane & 90 \({}^{\circ}\)C/on & 99\% & [57] \\ \hline
4 & Pd(dppf)Cl\({}_{2}\) & - & 1\(\mathcal{A}\)-dioxane & 85 \({}^{\circ}\)C/on & 88–90\% & [58] \\ \hline
5 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMSO & 130 \({}^{\circ}\)C/45 min & 62\% & [59] \\ \hline
6 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMSO & 80 \({}^{\circ}\)C/16 h & na & [60,61] \\ \hline
7 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMSO & 80 \({}^{\circ}\)C/18 h & na & [62] \\ \hline
8 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMF & 90 \({}^{\circ}\)C/15 h & 76\% & [63] \\ \hline
9 & Pd(dppf)Cl\({}_{2}\)-DCM & - & DMF & 80 \({}^{\circ}\)C/12 h & 71\% & [40] \\ \hline
10 & Pd(dppf)Cl\({}_{2}\) & - & THF & 85 \({}^{\circ}\)C/12 h & 80\% & [64] \\ \hline
11 & Pd(dppf)Cl\({}_{2}\) & - & dimethoxyethane & 101 \({}^{\circ}\)C/14 h or 120 \({}^{\circ}\)C/45 min & na & [65,66] \\ \hline
12 & Pd(PPh\({}_{3}\))\({}_{2}\)Cl\({}_{2}\) & - & 1,4-dioxane & n/a & 35\% 2  & [67] \\ \hline
13 & Pd(PPh\({}_{3}\))\({}_{2}\)Cl\({}_{2}\) & - & DMSO & 80 \({}^{\circ}\)C/4.5 h & 22\% & [68] \\ \hline
14 & Pd(AcO)\({}_{2}\) & A & THF & 101 \({}^{\circ}\)C/2 h & n/a & [61] \\ \hline
15 & Pd(AcO)\({}_{2}\) & A & THF & 75 \({}^{\circ}\)C/2 h & 78\% & [69] \\ \hline
16 & Pd(AcO)\({}_{2}\) & A & THF & 75 \({}^{\circ}\)C/3 h & 84\% & [70] \\ \hline \multicolumn{8}{c}{**X = I (53b)**} \\ \hline
17 & Pd(AcO)\({}_{2}\) & - & DMF & 85 \({}^{\circ}\)C/3 h & na & [71] \\ \hline
18 & Pd(dppf)Cl\({}_{2}\) & - & DMF & 80 \({}^{\circ}\)C/4 h & na & [72] \\ \hline \multicolumn{8}{c}{**X = CI (53c)**} \\ \hline
19 & Pd(AcO)\({}_{2}\) & B & 1\(\mathcal{A}\)-dioxane & 101 \({}^{\circ}\)C & 79–85\% & [21] \\ \hline \end{tabular}  
* A: 1,3-Bis(2,6-disopropylphenyl)imidazol chloride, B: P(Cy)\({}_{3}\). 2 Yield after three-step synthesis. on—overnight, na—data not available.  
\end{table} 
Table 4: Miyaura borylation conditions for _meta_-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester (54). 2,5-bis(2,6-diisopropylphenyl)imidazolium chloride in refluxing THF gave the desired product in 78-84% yield (Table 4, Entries 14-16). Aryl iodides can also be used as starting materials. Reactions conducted in the presence of Pd(OAc)\({}_{2}\) in DMF at 85 \({}^{\circ}\)C for 3 h, or Pd(dppf)Cl\({}_{2}\) in DMF at 80 \({}^{\circ}\)C for 4 h, led to the formation of 3-(1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester (Table 4, Entries 17-18). While less common, aryl chlorides can also be employed as substrates. Pd(AcO)\({}_{2}\), tricyclohexylphosphine (P(Cy)\({}_{3}\)), and AcOK in refluxing 1,4-dioxane can convert aryl chlorides to pinacol boronic esters in 79-85% yield (Table 4, Entry 19). A different synthetic route (method C) involves 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated desulfurative cyclization of the acyl thiosemicarbazide intermediate in a THF/MeOH mixture at 65 \({}^{\circ}\)C [73]. This method follows a two-step process involving thiourea formation and carbodiimide-mediated cyclization. The reaction employs 3 equivalents of EDC, with 1.5 equivalents promoting \(N\)-acyl-thiosemicarbazide formation and the remaining 1.5 equivalents driving the cyclodesulfurization step. The reaction is completed within 2 h, affording the 3-[5-(phenylamino)-1,3,4-oxadiazol-2-yl]phenylboronic acid pinacol ester in 85-91% yield (Scheme 12). Cyclization of diacyl hydrazide, in particular 3-(2-acylhydrazzinccarbonyl) phenylboronic acid pinacol ester, can be achieved using toyl chloride as a dehydrating agent in the presence of \(N\),\(N\)-diisopropylplativamine (DIPEA).