# 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 Heteracyclic Linker
#### 3.3.2 Boronic Acid Derivatives of 1,3,4-Oxadiazol-2-yl-indoles  
Indole, a bicyclic aromatic heterocyclic compound, is a fundamental scaffold found in numerous natural products, pharmaceuticals, and materials science [92; 93; 94]. Its unique structural features, including a fused benzene and pyrrole ring, provide diverse opportunities for chemical modification. The indole ring is typically connected to a 1,3,4-oxadiazol at position 6, 5, or 7 of the bicyclic heterocycle (Figure 10). It is worth noting that all reported compounds contain a protected indolyl nitrogen atom, commonly using protecting groups such as SEM (2-(trimethylsilyl))ethoxymethyl), Boc (_tert_-butoxycarbonyl), or Ts (tosyl), which can be easily removed in later stages of synthesis. The boronic acid or ester groups are attached at position 2 or position 3 of the indole ring. Depending on the point of attachment, different synthetic approaches have been reported [95; 96; 97; 98; 99]. For the 2-position of the indole ring, a C-H activation approach starting from 1-Boc-6-[5-(1-(benzyloxycarbonyl)]pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]indole has been reported (Scheme 19). The reaction utilizes lithium diisopropylamide (LDA) and triisopropyl borate (B(O-\(i\)-Pr)\({}_{3}\)) in dry THF at 0 \({}^{\circ}\)C, yielding the corresponding 1-Boc-6-[5-(1-(benzyloxycarbonyl)]pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]indol-2-ylboronic acid in 47% [95; 96]. **Scheme 19. ** Borylation of 1-Boc-6-[5-(1-(benzyloxycarbonyl)]pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]indole (**80**) leading to 1-Boc-6-[5-(1-(benzyloxycarbonyl)]pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]indol-2-yl]boronic acid (**76**) via the C-H activation of indole ring: (a) B(O-\(i\)-Pr)\({}_{3}\), LDA, THF, 0 \({}^{\circ}\)C; (b) aq, HCl, rt. Figure 10: 1,3,4-Oxadiazol- and boron derivative conjugates connected by indole linkers: 1-Boc-6-(1,3,4-oxadiazol-2-yl)indol-2-ylboronic acid (**76**), 1-(-\(p\)-toluenesulffonyl)-5-(1,3,4-oxadiazol-2-yl)indol-3-ylboronic acid (**77**) and its pinacol ester (**78**), 1-SEM-7-(1,3,4-oxadiazol-2-yl)indol-3-ylboronic acid (**79**). To introduce a boronic group at the 3-position of the indole ring, a halogen-metal exchange reaction is commonly employed (method A). This involves reacting 3-iodo-1-(_p_-toluenesulfonyl)-5-(1,3,4-oxadiazol-2-yl)indole with bis(pinacolato)diboron (B\({}_{2}\)(pin)\({}_{2}\)), Pd(dppf)Cl\({}_{2}\) (bis(diphenylphosphino)ferrocene)palladium(II) dichloride), and potassium acetate (AcOK) in DMF at 90 \({}^{\circ}\)C for 1 h (Scheme 20). The resulting crude mixture of 1-(_p_-toluenesulfonyl)-5-(1,3,4-oxadiazol-2-yl)indol-3-ylboronic acid and its pinacol ester can be used directly in Suzuki coupling reactions, affording yields of 19-54% [97,98]. Alternatively, when the starting material contains a bromine atom (e.g., 1-SEM-3-bromo-7-(1,3,4-oxadiazol-2-yl)indole), the reaction is conducted in 1,4-dioxane at 80 \({}^{\circ}\)C overnight, followed by purification via reverse-phase column chromatography, yielding 1-SEM-7-(1,3,4-oxadiazol-2-yl)indol-3-ylboronic acid in 14% [99]. 3.3 Boronic Acid Derivatives of 1,3_A_-Oxadiazol-2-yl-thiophenes, 1,3,4-Oxadiazol-2-yl-furan and 1,3_A_-Oxadiazol-2-yl-ethenyl Derivatives  
Thiophene and furan are five-membered heteroaromatic rings containing a sulfur or oxygen atom, respectively. Their unique electronic, optical, and structural properties make them valuable building blocks in medicinal chemistry [100,101], agrochemistry [102], and materials science [103, 104, 105]. Two primary approaches have been reported for synthesizing thiophene-linked 1,3,4-oxadiazoles (Figure 11). The first involves a halogen-metal exchange strategy (method A), employing 2.4_M_\(n\)-BuLi in hexane and isopropyl pinacol borate in THF at -78 \({}^{\circ}\)C to synthesize symmetrical 5,5\({}^{\prime}\)-(1,3,4-oxadiazol-2,5-diyl)bis(thiophene-5,2-diyl)diboronic acid dipinaol ester. The product is obtained in 22% yield after extraction and purification by column chromatography [25].