Synthetic Approaches to 1,3,4-Oxadiazole-Containing Boronic Derivatives

Abstract

1,3,4-Oxadiazoles containing boronic acid moieties are promising as a highly versatile class of compounds with significant utility across various scientific domains. The diverse synthetic methodologies for their preparation make these compounds valuable precursors for developing novel entities with tailored properties in medicinal chemistry, agrochemistry, and materials science. This review systematically compiles and discusses synthetic methods for the direct and indirect incorporation of boronic acid derivatives into 1,3,4-oxadiazole scaffolds. Understanding these strategies is particularly important because of their key role in modern synthetic transformations, especially Suzuki–Miyaura cross-coupling reactions, which enable easy access to a new generation of structurally diverse 1,3,4-oxadiazole-based compounds. The synthetic procedures and reactions discussed are based on the currently available literature, offering a comprehensive overview of this rapidly evolving field.

1. Introduction

Boron, the fifth element in the periodic table, is a small atom and a semimetal from the p-block, containing three valence electrons. This leads to remarkable potential in its chemistry, especially in the field of organoboron compounds [1]. Elemental boron is used as a dopant in semiconductors, while its derivatives are widely exploited in the production of glass, ceramics and glass fibers, wood preservatives and insecticides, as well as detergents and bleaching agents [1,2]. It also plays a fundamental role in organic synthesis. Boronic acids (Figure 1) are organic derivatives of boric acid, B(OH)₃, in which one hydroxyl group is replaced by an alkyl or aryl group (represented as R in the general formula R–B(OH)₂). Boronic esters, such as the well-known pinacol boronic ester, are formed by the reaction of boronic acids with alcohols. In addition to traditional boronic acids and esters, new classes of organoboron compounds—including trifluoroborate salts and MIDA (methyliminodiacetic acid) boronic ester (Figure 1)—have been developed, offering improved stability and reactivity in various synthetic applications [3].

Boronic acids are a versatile class of reagents due to their unique properties: they act as mild Lewis acids, exhibit good stability, and are relatively easy to handle. Furthermore, their low toxicity and biodegradability into boric acid make them environmentally friendly and “green” compounds [4].

The acids in question and their esters are known to form from both saturated and unsaturated organic compounds [1]. However, arylboronic acids represent the most prominent class in organic chemistry. Organoboron compounds are widely used in the synthesis of pharmaceuticals, materials, and other valuable molecules. They serve as powerful building blocks in modern organic chemistry, especially in carbon–carbon cross-coupling reactions such as Suzuki–Miyaura, Petasis, Chan–Lam, and Liebeskind–Srogl couplings. Furthermore, organoboron compounds play crucial roles in catalysis, materials science, biology, and imaging [4,5].

Over the past decades, oxadiazoles—classified as five-membered aromatic heterocyclic systems—have attracted considerable scientific interest [6]. Compounds of this type belong to the diazole family and contain two nitrogen atoms and one oxygen atom within their structure. Four isomers of oxadiazoles are known, differing in the relative positions of heteroatoms (Figure 2).

Unlike the unstable 1,2,3-oxadiazoles (Figure 2), sydnones (1,2,3-oxadiazol-3-ium-5-olate) are recognized as their stable derivatives [7]. The other three isomers—1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole—are actively being investigated by both medicinal and materials chemists, who are keenly interested in achieving specific properties through optimized substitution patterns. However, 1,3,4-oxadiazole and 1,2,4-oxadiazole are favored by researchers and have been extensively studied for their significant chemical and biological properties (Figure 3).

Derivatives of both 1,2,4- and 1,3,4-oxadiazoles exhibit activity against bacteria, fungi, parasites, and viruses. These compounds are also being explored in research related to anti-inflammatory, anticancer, antidiabetic, antioxidant, and neurological applications [6,8]. The properties of compounds containing 1,2,4- and 1,3,4-oxadiazole strongly depend on the substitution patterns, but some general trends can be recognized. For example, in medicinal chemistry applications, 1,3,4-oxadiazoles demonstrate enhanced properties compared to 1,2,4-oxadiazoles, including an order of magnitude lower lipophilicity (LogD), improved metabolic stability and aqueous solubility, and decreased hERG inhibition [9].

In materials science, 1,3,4-oxadiazoles find primary applications in polymers, particularly in heat-resistant materials, insulators/semiconductors, macromolecular scintillators, and organic light-emitting devices (OLEDs). Their photoluminescent and electrochromic properties, stability, and organosolubility make them valuable as hole-transporting and electrochromic materials, as well as in blue-light-emitting diodes and low-band-gap applications [8]. Furthermore, incorporating electron-deficient 1,3,4-oxadiazole moieties into polymer side chains has been shown to enhance photovoltaic cell efficiency [6]. In contrast, 1,2,4-oxadiazoles are primarily utilized in liquid crystal applications and in emissive materials, where the unsymmetrical atom distribution and electron density within the 1,2,4-oxadiazole ring structure play an important role [8]. Figure 4 illustrates several examples of compounds featuring a 1,3,4-oxadiazole core, with applications across agrochemistry (e.g., Oxadiazone), medicine (e.g., Raltegravir, Zibotentan, Nesapidil), and materials science (e.g., highly conjugated derivatives) [6].

Due to the continuous and growing interest in 1,3,4-oxadiazoles across diverse disciplines, and the significant potential of their boronic acid derivatives for fine-tuning properties in both medicinal chemistry and materials science (Figure 5), a comprehensive review of synthetic approaches is presented. This paper summarizes the achievements since 2000 in synthesizing organoboron derivatives directly or indirectly linked to the 1,3,4-oxadiazole core.

2. General Approaches for the Synthesis of Organoboron Derivatives

The three most popular synthetic approaches to 1,3,4-oxadiazole-containing organoboron derivatives were identified in the literature:

(a)

Halogen–metal–boron exchange in aromatic compounds (method A),

(b)

Miyaura borylation of aryl and vinyl halides using bis(pinacolato)diboron (method B),

(c)

formation of the 1,3,4-oxadiazole ring from acyclic reagents already containing a boronic ester moiety (method C).

2.1. Method A: Lithium/Magnesium–Boron Exchange

One of the earliest and most common methods for synthesizing arylboronic acids involves a three-step sequence, presented in Scheme 1, comprising halogen–metal (lithium or magnesium) exchange in aryl halide, followed by electrophilic trapping with a trialkylborate (typically methyl or isopropyl borate). This reaction is usually performed at low temperatures to minimize over-alkylation, which can lead to the formation of borinic acids (R₂B(OH)). The reaction is then quenched with water in an acidic solution to yield the desired boronic acid [10,11,12].

2.2. Method B: Miyaura Borylation

Miyaura borylation is a well-established method for the synthesis of boronic esters, developed by the research group of Norio Miyaura (Scheme 2). It involves the cross-coupling of bis(pinacolato)diboron (B₂(pin)₂) with aryl or vinyl halides at 80 °C. This method offers several advantages, particularly its mild reaction conditions (e.g., high functional group tolerance, temperature up to 100 °C, without highly reactive organometallic bases), which are beneficial for the preparation of boronic esters that are not accessible through traditional lithium- or Grignard-based borylation approaches. Furthermore, the Miyaura borylation exhibits a broad substrate scope and wide functional group tolerance [13,14].

The role and importance of reaction components in the Miyaura borylation were defined by Miyaura in 1995 and have remained largely unchanged since then. Potassium acetate (AcOK), a weak base, is widely recognized as the optimal choice, providing high yields and selectivity. Employing stronger bases, such as K₃PO₄ and K₂CO₃, can lead to side reactions, such as competitive coupling of the boronic ester with the aryl halide, resulting in undesired Suzuki reaction products. The reaction proceeds more rapidly in polar solvents, with DMSO generally exhibiting the highest reactivity, followed by DMF, dioxane, and toluene. Furthermore, Pd(dppf)Cl₂ has proven to be the most effective catalyst [13].

2.3. Method C: 1,3,4-Oxadiazole Ring Formation

Another popular approach for the synthesis of 1,3,4-oxadiazole derivatives bearing a boronic acid/ester or MIDA moiety is the formation of the 1,3,4-oxadiazole ring from acyclic starting materials already containing a boronic acid or ester group. The boron-containing group is usually attached to a hydrazine or carboxylic acid reagent. Three of the most popular methods include the cyclization of diacylhydrazides (Scheme 3, method C1) [15], thiosemicarbazides (Scheme 3, method C2) [16], and the oxidative cyclization of acylhydrazones (Scheme 3, method C3) [17].

3. Synthesis of Boronic Derivatives from Reagents Containing 1,3,4-Oxadiazole Moiety

3.1. Direct Connection of Boron with 1,3,4-Oxadiazole Ring

There are relatively few direct methods reported in the literature for synthesizing 1,3,4-oxadiazole boronic derivatives. This is likely due to the inherent challenges associated with introducing a boronic group onto the oxadiazole ring. These challenges arise from the electron-deficient nature of the 1,3,4-oxadiazole ring [6], which makes electrophilic substitution difficult at the C2 and C5 positions. The most common approach involves 2-bromo-1,3,4-oxadiazole as a starting material and proceeds via a two-step process: metal–halogen exchange followed by electrophilic substitution with a trialkylborate (Scheme 4). The first step, bromide–lithium exchange, is performed in the presence of a strong base, n-BuLi, at low temperature (below −40 °C) in an inert solvent such as THF or toluene. The resulting lithium intermediate then reacts with trimethyl or triisopropyl borate to introduce the boronic group. Next, the esters are cleaved under acidic conditions to obtain the boronic acid product (R = H) in yields of 84% [18] and 71% [19].

Another useful boron derivative of oxadiazole is the MIDA boronic ester, which can be prepared via a convenient, one-pot, two-step synthesis from carboxy-MIDA boronic ester and either benzhydrazide or thiosemicarbazide. Subsequent cyclization, mediated by toluenesulfonyl chloride, affords corresponding oxadiazoles in 64% and 56% yield, respectively (Scheme 5A). The carboxy-MIDA boronic ester is synthesized from ethynyl- MIDA boronic ester through oxidation with excess periodic acid, catalyzed by RuCl₃·3H₂O in MeCN (Scheme 5B) [20]. MIDA boronic esters offer several advantages: they are stable, easily handled, compatible with various reaction conditions, and tolerant of harsh reagents [10].

3.2. Indirect Connection of Boron with 1,3,4-Oxadiazole Ring via Phenylene Linker

1,3,4-Oxadiazole rings linked to boronic derivatives through a benzene ring are common motifs in the synthesis of molecules for OLEDs and biological applications. While meta- and para-substituted compounds are well established, examples of ortho-substituted analogues are less common (

Table 1. Publications on boronic acid and its derivatives linked to 1,3,4-oxadiazole via ortho-, meta-, and para-substituted phenyl groups as determined via the SciFinder database (accessed on 3 March 2025).

Publication Type	para	meta	ortho
Journals	18	7	0
Patents	28	29	2

, Figure 6).

3.2.1. Derivatives of Para-Substituted (1,3,4-Oxadiazol-2-yl)phenyl)boronic Acid

Para-phenylene-linked 1,3,4-oxadiazole boronic acids or esters can be synthesized via various methods, starting from the appropriate aryl halides (Scheme 6).

Table 2. Miyaura borylation conditions for para-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol esters (40).

Entry	Catalyst	Ligand 1	Solvent	Temp./Time	Yield	Refs.
X = Cl (39a)
1	Pd(AcO)2	A	THF	110 °C/20 h	79%	[17]
2	Pd(AcO)2	B	1,4-dioxane	100 °C/20 h	84–88%	[21]
3	Pd(dppf)Cl2	-	1,4-dioxane	80 °C/on	na	[22]
4	Pd2(dba)3	C	1,4-dioxane	85 °C/on	na	[23]
X = Br (39b)
5	Pd(dppf)Cl2	-	1,4-dioxane	100 °C/na or on or 2 h	80–92%	[24,25,26,27,28]
6	Pd(dppf)Cl2	-	1,4-dioxane	90 °C/2 h	70–85%	[29]
7	Pd(dppf)Cl2	-	1,4-dioxane	80 °C/na or 12 h–4 d	21–78%	[28,29,30,31,32,33]
8	Pd(dppf)Cl2	-	DMF	90 °C/na	78%	[34]
9	Pd(dppf)Cl2	-	DMF	80 °C/15–16 h	51–83%	[35,36]
10	Pd(dppf)Cl2	-	DMSO	80 °C/4–24 h	45–61%	[37,38]
11	Pd(dppf)Cl2	-	DMSO	80 °C/on	83%	[39]
12	Pd(dppf)Cl2	-	DME	80 °C/on	81%	[40]
13	Pd(dppf)Cl2·DCM	-	1,4-dioxane	80 °C/2 h	77–88%	[41]
14	Pd(dppf)Cl2·DCM	-	1,4-dioxane	90 °C/12 h	na	[42]
15	Pd(dppf)Cl2·DCM	-	DMF	80 °C/12 h	53%	[43]
16	CuI, Pd(dppf)Cl2	-	DMF	90 °C/12 h	82%	[44]
X = I (39c)
17	Pd(PPh3)4	-	1,4-dioxane	100 °C/12 h	22% 2	[45]
X = OTf (39d)
18	Pd(dppf)Cl2	-	DMF	95 °C/on	86%	[46]

¹ A: 1,3-Bis(2,6-diisopropylphenyl) imidazolium chloride, B: P(Cy)₃, C: 2′-(Dicyclohexylphosphino)-N,N-dimethyl [1,1′-biphenyl]-2-amine. 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.

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 = OTf) using bis(pinacolato)diboron (B₂(pin)₂) in the presence of AcOK (method B) [17,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46].

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)imidazolium chloride or P(Cy)₃ (tricyclohexylphosphine), Pd(dppf)Cl₂ (bis(diphenylphosphino)ferrocene)palladium(II) dichloride), or Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium) 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)Cl₂ 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. 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(PPh₃)₄ (tetrakis(triphenylphosphine)palladium) can be used as a catalyst in 1,4-dioxane at elevated temperatures. However, Bachand 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)Cl₂ catalyst can be used with aryl triflates. Conducting the reaction in DMF at 95 °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′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)), AcOK, and tetrahydroxydiboron (B₂(OH)₄) in EtOH at 80 °C for 2 h. After simple extraction, the crude boronic acid is converted to the trifluoroborate salt using an aqueous KHF₂ solution. The final product, potassium 4-(1,3,4-oxadiazol-2-yl)phenyltrifluoroborate, is obtained in 34% yield after lyophilization and Soxhlet extraction with acetone [47].

Another common method for synthesizing 1,3,4-oxadiazole–phenylboronic acid derivatives involves a lithium borylation mechanism (Scheme 1, method A).

Table 3. Lithiation borylation conditions for the synthesis of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acids (44) or its pinacol esters (40).

Entry	Lithium Source	Boron Source 1	Solvent	Temp.	Yield	Product	Ref.
1	n-BuLi	A	Et2O	na	na	44	[48,49]
2	n-BuLi	A	THF	−40 °C to −78 °C	81%	44	[18]
3	n-BuLi	A	THF	−50 °C	42%	44	[50]
4	n-BuLi	A	THF	−78 °C	74%	44	[51]
5	n-BuLi	A	Toluene/THF	−78 °C	62%	44	[39]
6	n-BuLi	B	Toluene/THF	−78 °C	na	44	[15]
7	n-BuLi	C	THF	Na	61% 2	40	[52]
8a	1. MeLi 2. n-BuLi	B	THF	−65 °C	82%	44	[53]
8b	1. Li, 4-chlorotoluene 2. n-HexLi	B	THF	−35 °C to −65 °C	89%	44
8c	1. Li, 2-chlorotoluene, biphenyl 2. n-HexLi	A	THF	−30 °C to −65 °C	60%	44
8d	1. Li, 2-chlorotoluene 2. n-HexLi	A	THF	−30 °C to −65 °C	76%	44
8e	1. Li, chlorobenzene, biphenyl 2. n-HexLi	A	THF	−30 °C to −65 °C	84%	44

¹ A: trimethyl borate, B: triisopropyl borate, C: isopropylboronic acid pinacol ester. ² Total yield after six-step synthesis.

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 °C to −40 °C) in Et₂O (Table 3, Entry 1) or THF (Table 3, Entries 2–7). Trimethyl borate (B(OMe)₃) or triisopropyl 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). In this method, the starting 2-(4-bromophenyl)-1,3,4-oxadiazole (R₁ = H) is initially deprotonated with a weaker base (e.g., MeLi, 4-Li-toluene, 2-Li-toluene, Li-benzene), followed by halogen–metal exchange with a stronger base (e.g., n-BuLi, n-HexLi). Subsequent borylation 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-oxadiazole 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 = NHNH₂) via a phenylene linker. Cyclization is achieved using trichloroacetonitrile and triphenylphosphine in acetonitrile at 130 °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 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-(hydrazinecarbonyl)phenylboronic acid pinacol ester can be treated with an S-ethylated thioamide in refluxing n-butanol to generate a 1,3,4-oxadiazole ring as a 22% byproduct during triazole synthesis [54]. The structure of this byproduct was confirmed by NMR and X-ray crystallography. Hashemzadeh 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. This transformation was achieved by treating the boronic ester with potassium hydrogen fluoride (KHF₂) in methanol, yielding the desired product in 77%. Subsequent hydrolysis of the trifluoroborate group using lithium hydroxide afforded the 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid derivative in 52% yield (Scheme 9C) [54].

An alternative approach to synthesizing 1,3,4-oxadiazole–phenyl boron derivatives is presented in Scheme 10 and involves the cyclization of N¹-benzoylthiosemicarbazide in the presence of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in DMSO at 50–60 °C. The final product can be either a [4-(5-amino)-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid derivative (R₁ = B(OH)₂) or its boronic acid pinacol ester (R₁ = B(pin)), depending on the specific functional groups present on the starting material [17].

3.2.2. Derivatives of Meta-Substituted (1,3,4-Oxadiazol-2-yl)phenylboronic Acid

1,3,4-Oxadiazole–phenylboronic acid derivatives bearing a boronic group in the meta position relative to the oxadiazole ring can be synthesized via three methods similar to those used for para-substituted derivatives.

Table 4. Miyaura borylation conditions for meta-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester (54).

Entry	Catalyst	Ligand 1	Solvent	Temp./Time	Yield	Refs.
X = Br (53a)
1	Pd(dppf)Cl2	-	1,4-dioxane	120 °C/20 min or on	44–90%	[55]
2	Pd(dppf)Cl2	-	1,4-dioxane	100 °C/6 h	53–80%	[56]
3	Pd(dppf)Cl2	-	1,4-dioxane	90 °C/on	99%	[57]
4	Pd(dppf)Cl2	-	1,4-dioxane	85 °C/on	88–90%	[58]
5	Pd(dppf)Cl2·DCM	-	DMSO	130 °C/45 min	62%	[59]
6	Pd(dppf)Cl2·DCM	-	DMSO	80 °C/16 h	na	[60,61]
7	Pd(dppf)Cl2·DCM	-	DMSO	80 °C/18 h	na	[62]
8	Pd(dppf)Cl2·DCM	-	DMF	90 °C/15 h	76%	[63]
9	Pd(dppf)Cl2·DCM	-	DMF	80 °C/12 h	71%	[40]
10	Pd(dppf)Cl2	-	THF	85 °C/12 h	80%	[64]
11	Pd(dppf)Cl2	-	dimethoxyethane	101 °C/14 h or 120 °C/45 min	na	[65,66]
12	Pd(PPh3)2Cl2	-	1,4-dioxane	n/a	35% 2	[67]
13	Pd(PPh3)2Cl2	-	DMSO	80 °C/4.5 h	22%	[68]
14	Pd(AcO)2	A	THF	101 °C/2 h	n/a	[61]
15	Pd(AcO)2	A	THF	75 °C/2 h	78%	[69]
16	Pd(AcO)2	A	THF	75 °C/3 h	84%	[70]
X = I (53b)
17	Pd(AcO)2	-	DMF	85 °C/3 h	na	[71]
18	Pd(dppf)Cl2	-	DMF	80 °C/4 h	na	[72]
X = Cl (53c)
19	Pd(AcO)2	B	1,4-dioxane	101 °C	79–85%	[21]

¹ A: 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, B: P(Cy)₃. ² Yield after three-step synthesis. on—overnight, na—data not available.

summarizes the reaction conditions, catalysts, ligands, solvents, and corresponding yields, along with relevant references. The most common approach, based on metal-catalyzed borylation, typically utilizes aryl bromides (X = Br) (Scheme 11, method B). These reactions are usually carried out at elevated temperatures (>90 °C) using bis(pinacolato)diboron (B₂(pin)₂) as the boron source, potassium acetate (AcOK) as the base, and palladium catalysts such as Pd(dppf)Cl₂ or its DCM adduct (Table 4, Entries 1–11). Reactions conducted in 1,4-dioxane afforded the derivatives of 3-(1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester in yields ranging from 44% to 99% (Table 4, Entries 1–4). Alternatively, the reaction can be performed in DMSO (Table 4, Entries 5–7), although only a single publication reports the yield (62%) for this solvent system (Table 4, Entry 5). Reactions in DMF have yielded 76% (Table 4, Entry 8) and 71% (Table 4, Entry 9), while THF has been used to achieve an 80% yield (Table 4, Entry 10). Additionally, the reaction can be conducted in refluxing dimethoxyethane (Table 4, Entry 11).

A broader range of catalysts can be used for the conversion of 2-(3-bromophenyl)-1,3,4-oxadiazole to meta-substituted 1,3,4-oxadiazole–phenylboronic acid derivatives. For example, Pd(PPh₃)₂Cl₂ (bis(triphenylphosphine)palladium chloride) in 1,4-dioxane can be utilized to obtain the desired product in 35% overall yield over three steps, including hydrazide formation and 1,3,4-oxadiazole ring cyclization (Table 4, Entry 12). Alternatively, the same catalyst can be used in DMSO at 80 °C for 4.5 h to afford the boronic ester in 22% yield (Table 4, Entry 13). As another option, Pd(OAc)₂ (palladium(II) acetate) with 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 °C for 3 h, or Pd(dppf)Cl₂ in DMF at 80 °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 °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-acylhydrazinecarbonyl)phenylboronic acid pinacol ester, can be achieved using tosyl chloride as a dehydrating agent in the presence of N,N-diisopropylethylamine (DIPEA). The reaction can be carried out in dichloromethane at room temperature to yield the 3-[5-(phenylamino)-1,3,4-oxadiazol-2-yl]phenylboronic acid pinacol ester in 77% yield [74], or in acetonitrile at 40 °C to afford the product in 62% yield (Scheme 13) [67].

The third approach to synthesizing meta-substituted phenylboronic acid derivatives of 1,3,4-oxadiazole is the metal–halogen exchange reaction (method A). Commonly, 2-(3-bromophenyl)-1,3,4-oxadiazole derivatives are used as starting materials and reacted with n-BuLi as a strong base and triisopropyl borate (B(O-i-Pr)₃) as the boron source at −78 °C in dry THF. Subsequent acidic hydrolysis of the resulting boronic esters yields the desired 3-(1,3,4-oxadiazol-2-yl)phenylboronic acids in 60–80% yield [69,75]. A similar method can be applied for bis-meta-bromo substitution using trimethyl borate (B(OMe)₃) (Scheme 14) [76].

Alternatively, meta-iodophenyl derivatives such as 2-(3-iodophenyl)-1,3,4-oxadiazole can be employed to form Grignard reagents (Scheme 14). Isopropylmagnesium chloride (i-PrMgCl) can be used for metal–halogen exchange, followed by substitution with triisopropyl borate. Subsequent acidic hydrolysis leads to meta-substituted (1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester derivatives in 37–66% yield. The reaction is typically carried out in THF under milder conditions (−10 °C) compared to the lithium-based approach [77,78,79].

3.2.3. Derivatives of Ortho-Substituted (1,3,4-Oxadiazol-2-yl)phenylboronic Acid

The 2-(1,3,4-oxadiazol-2-yl)phenylboronic acid or its pinacol ester derivative can be obtained via three approaches (methods A, B, and C). The first, method A, involves a lithiation borylation sequence of 2-(2-bromophenyl)-1,3,4-oxadiazole derivatives using n-BuLi and triisopropyl borate in a toluene/THF mixture at −78 °C, followed by acidic hydrolysis (Scheme 15) [15].

An alternative method involves the Miyaura borylation reaction (Scheme 15, method B). (2-Bromophenyl)-1,3,4-oxadiazole intermediate can be coupled with bis(pinacolato)diboron using Pd(dppf)₂Cl₂ as a catalyst, AcOK as a base, and DMSO as a solvent at 80 °C for 2–8 h. The resulting 2-(1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester can then be hydrolyzed using 0.2M sulfuric acid to yield 2-(1,3,4-oxadiazol-2-yl)phenylboronic acid [15]. (2-Chlorophenyl)-1,3,4-oxadiazoles can also be used as substrates in Miyaura borylation reactions. These reactions typically utilize Pd(OAc)₂ as the catalyst, AcOK as the base, and tricyclohexylphosphine as the ligand. Refluxing the reaction mixture in 1,4-dioxane for 2 h affords the pinacol boronic ester in 75–86% yield [21].

A third strategy involves the formation of the 1,3,4-oxadiazole ring from a precursor containing a boronic ester group (Scheme 16, method C). The derivatives of benzhydrazide or benzoic acid bearing a boronic ester group can be cyclized using trichloroacetonitrile and triphenylphosphine in acetonitrile at 130 °C. Subsequent hydrolysis of 2-(1,3,4-oxadiazol-2-yl)phenylboronic acid pinacol ester with ammonium acetate and sodium periodate in an acetone/water mixture affords the desired boronic acid [15].

3.3. Indirect Connection of Boron with 1,3,4-Oxadiazole Ring via Heterocyclic Linker

Beyond phenyl derivatives, the linkers connecting 1,3,4-oxadiazole and boronic acid units also include a diverse range of heteroaromatic compounds. A literature review demonstrates that, among heterocyclic linker-containing scaffolds, pyridine derivatives are the most commonly reported (48%), followed by indoles (24%) and thiophene rings (12%) (Figure 7).

3.3.1. Boronic Acid Derivatives of (1,3,4-Oxadiazol-2-yl)pyridines

The pyridine ring is one of the most important heteroaromatic rings, present in many organic compounds with a wide range of applications in pharmaceuticals and agrochemicals, and is also found in certain vitamins such as B₆ and B₃ [80,81,82,83].

The pyridine ring attached to the 1,3,4-oxadiazole ring was functionalized with boronic esters or acids at four possible positions (Figure 8). For clarity, boronic acids/esters located at the 6-position relative to the nitrogen (6-(1,3,4-oxadiazol-2-yl)pyridin-2-ylboronic acid (65)) atom are referred to as 2-pyridinylboronic acids, while those at the 5-position (5-(1,3,4-oxadiazol-2-yl)pyridin-3-ylboronic acid (66)) are classified as 3-pyridinylboronic acids, based on their nitrogen–boron positional relationship.

There are limited reported syntheses of 1,3,4-oxadiazol-2-ylpyridine boronic acid derivatives. This is likely due to the instability of 2-pyridinyl boronic acids, which readily undergo protodeboronation [84]. To improve their stability, strategies such as the use of alternative boronate species—including N-methyliminodiacetic acid (MIDA) boronates and N-phenyldiethanolamine (PDEA) boronates—one-pot or in situ generation, or the addition of copper salts as stabilizing agents are commonly employed [84]. However, these methods have not yet been reported for the synthesis and stabilization of 1,3,4-oxadiazol-2-ylpyridine boronic acid derivatives. 2-Pyridinylboronic esters, however, are much more stable than the corresponding acids [85]. One method (Scheme 17) describes the successful Miyaura borylation (method B) of a 1,3-bis(5-(6-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)benzene to form the desired 6,6′-(5,5′-(1,3-phenylene)bis(1,3,4-oxadiazole-5,2-diyl))bis(pyridine-6,2-diyl)diboronic acid dipinacol ester in 81% yield. This approach utilizes bis(pinacolato)diboron (B₂(pin)₂) as the boron source, tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) as the catalyst, and AcOK as the base in 1,4-dioxane at 110 °C [86,87].

Several studies focus on the synthesis of 1,3,4-oxadiazole–pyridine derivatives bearing a boron atom at the 3-position relative to the pyridinyl nitrogen (Figure 9) [69,88,89,90,91]. Two general approaches have been employed: Miyaura borylation (method B) and halogen–metal exchange via lithiation (method A).

Table 5. Miyaura borylation conditions for (1,3,4-oxadiazol-2-yl)pyridines (71–73).

Entry	Product	Catalyst	Solvent	Base	Temp./Time	Yield	Ref.
1	71a, R1 = NH2	Pd(dppf)Cl2·DCM	1,4-dioxane 1	AcOK	120 °C/45 min	na	[88]
2	71b, R1 = H	Pd(dppf)Cl2	ACN 1	AcOK	160 °C/15 min	na	[89]
3	71b, R1 = H	Pd(dppf)Cl2	DMSO	AcOK	80 °C/24h	15%	[69]
4	72	Pd(PPh3)2Cl2	1,4-dioxane	AcOK	70 °C/12.5h	76%	[90]
5	73	Pd(dppf)Cl2·DCM	DMSO	AcOK, Et3N	80 °C/2h	35%	[91]

¹ Microwave irradiation. na—not available.

summarizes the reaction conditions, catalysts, solvents, bases, and the corresponding yields, together with relevant references. The Miyaura borylation protocol involves the cross-coupling of 3-bromopicolic acid derivatives with bis(pinacolato)diboron (B₂(pin)₂). Common catalysts for this reaction leading to derivative 5-(1,3,4-oxadiazol-2-yl)-pyridin-3-ylboronic acid pinacol ester include Pd(dppf)Cl₂ (bis(diphenylphosphino)ferrocene)palladium(II) dichloride) or its DCM adduct. Solvents such as DMSO, acetonitrile, or 1,4-dioxane are typically used in conjunction with potassium acetate as the base (Table 5, Entries 1–3). Microwave irradiation can accelerate the reaction in some cases (Table 5, Entries 1–2). However, yield data are often absent from the literature. One notable exception reports a 15% yield for a reaction conducted in DMSO at 80 °C (Table 5, Entry 3). For 4-(1,3,4-oxadiazol-2-yl)pyridin-3-ylboronic acid pinacol ester, the synthesis involves PdCl₂(PPh₃)₂ (bis(triphenylphosphine)palladium(II) dichloride), potassium acetate, and triethylamine in 1,4-dioxane at 100 °C, yielding the boronic ester in 76% yield (Table 5, Entry 4). A single example describes a 6-(1,3,4-oxadiazol-2-yl)pyridin-3-ylboronic acid pinacol ester, synthesized using Pd(dppf)Cl₂·DCM and potassium acetate in DMSO at 80 °C. A 35% yield was obtained after 2 h of heating and standard workup (Table 5, Entry 5).

The second method for preparing boronic acids linked to a 1,3,4-oxadiazole ring via a pyridine moiety is based on a lithium borylation mechanism (method A). This method, applicable to 5-bromo-2-(1,3,4-oxadiazol-2-yl)pyridine, employs n-butyllithium in hexane and triisopropyl borate (B(O-i-Pr)₃) (Scheme 18). The reaction is conducted in THF or a 4:1 mixture of toluene and THF at –78 °C. The reaction can be quenched with water, followed by boronic ester hydrolysis using 50% HCl and subsequent boronic acid precipitation. Alternatively, quenching with 2N aqueous HCl, extraction, and crystallization can be employed to isolate the 6-(1,3,4-oxadiazol-2-yl)pyridin-3-ylboronic acid [15].

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-oxadiazole 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 °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].

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 (B₂(pin)₂), Pd(dppf)Cl₂ (bis(diphenylphosphino)ferrocene)palladium(II) dichloride), and potassium acetate (AcOK) in DMF at 90 °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 °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].

3.3.3. Boronic Acid Derivatives of 1,3,4-Oxadiazol-2-yl-thiophenes, 1,3,4-Oxadiazol-2-yl-furan and 1,3,4-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 2.4M n-BuLi in hexane and isopropyl pinacol borate in THF at −78 °C to synthesize symmetrical 5,5′-(1,3,4-oxadiazole-2,5-diyl)bis(thiophene-5,2-diyl)diboronic acid dipinacol ester. The product is obtained in 22% yield after extraction and purification by column chromatography [25].

The second approach is based on the formation of a 1,3,4-oxadiazole ring from a carboxythiophene boronic ester and an appropriate hydrazide (method B). This reaction is carried out in the presence of polystyrene-supported triphenylphosphine (PPh₃) and trichloroacetonitrile in dry acetonitrile under microwave irradiation at 130 °C for 2 h. The resulting thienyl boronic ester (with the boron atom at the 2- or 3-position relative to the sulfur atom) is subsequently converted to the corresponding boronic acids: 5-(1,3,4-oxadiazol-2-yl)thiophen-3-ylboronic acid (84), 5-(1,3,4-oxadiazol-2-yl)thiophen-2-ylboronic acid (85), 3-(1,3,4-oxadiazol-2-yl)thiophen-2-ylboronic acid (86) using sodium periodate and ammonium acetate in an acetone/water mixture. The boronic acid can be isolated using various methods, including precipitation with 1N HCl, extraction, recrystallization, trituration, or flash column chromatography. This approach has also been successfully applied to the derivatives containing furan and ethenylbenzene linkers such as 4-(1,3,4-oxadiazol-2-yl)furan-2-ylboronic acid and 2-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenylboronic acid (Figure 11) [15].

3.3.4. Other Boronic Acid Derivatives of 1,3,4-Oxadiazole Substituted with Dibenzothiophene, Dibenzofuran, Naphthalene, and Biphenyl

Dibenzo[b,d]furan and dibenzothiophene have also been used as heterocyclic linkers between 1,3,4-oxadiazole and boronic esters [21,31,32]. These compounds were synthesized via Miyaura borylation of the corresponding chloro derivatives using bis(pinacolato)diboron (B₂(pin)₂), potassium acetate (AcOK) as the base, palladium(II) acetate (Pd(OAc)₂) as the catalyst, and tricyclohexylphosphine (P(Cy)₃) as the ligand. The reactions were conducted in refluxing 1,4-dioxane, yielding the desired products containing dibenzofuran and dibenzothiophene linkers in 85% and 71% yields (Figure 12). The same approach was also applied to naphthalene and biphenyl linkers [21]. Boronic esters of biphenyl derivatives of 1,3,4-oxadiazole: 4′-(5-phenyl-1,3,4-oxadiazol-2-yl)biphenyl-4-ylboronic acid pinacol ester and 3′-(5-phenyl-1,3,4-oxadiazol-2-yl)biphenyl-2-ylboronic acid pinacol ester (Figure 12) were synthesized in 90% [32] and 59% [31] yields, respectively. The reactions were conducted in 1,4-dioxane in the presence of bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl₂) and potassium acetate (AcOK).

4. Conclusions

This review focuses on effective methods for preparing boronic acids and their derivatives conjugated with 1,3,4-oxadiazole scaffolds, either directly or via a linker. The three most frequently reported synthetic approaches in the literature were highlighted, utilizing a broad spectrum of available reagents. Their key features are summarized in

Table 6. A summary of three approaches for the synthesis of 1,3,4-oxadiazole-containing organoboron derivatives.

	Method A	Method B	Method C
Advantages	Wide range of aromatic and heteroaromatic compounds The main byproducts are inorganic salts and alcohols Relatively low costs of organometallic base for larger scale Simple work-up/purification via precipitation or pH-dependent extraction Provide direct access to boronic acid	High functional group tolerance Mild reaction conditions without highly reactive organometallic bases Relatively mild temperatures (up to 100 °C) Catalytic amounts of palladium, resulting in less metal waste Direct production of the more stable boronic pinacol esters, which are easier to purify and handle than free boronic acids	Compatible with various functional groups Multiple synthetic routes available for oxadiazole core synthesis Mild reaction conditions
Limitations	Very low functional group tolerance Harsh conditions (cryogenic temperatures, strong bases, and potent nucleophiles) Sensitive to moisture and oxygen Utilizes highly reactive organometallic bases that react violently with water Possibility of competing side reactions (e.g., Wurtz-type coupling)	Relatively high costs of palladium catalysts and bis(pinacolato)diboron for large-scale synthesis Removal of palladium traces can be challenging Requires an inert atmosphere	Requires precursors with a boronic ester moiety for complex targets
Average yield	22–88%	40–99%	43–77%
Applicability	Bromides, Iodides	Chlorides, Bromides, Iodides, Triflates	Carboxylic acids, Hydrazides, Thiosemicarbazides

.

For instance, halogens or pseudo-halogens can be strategically employed in well-established reactions such as metal–boron exchange (method A) or Miyaura borylation (method B). Meanwhile, carboxylic acids or their derivatives play a key role in the cyclization process that forms the 1,3,4-oxadiazole ring itself (method C). These synthetic strategies enable the formation of 1,3,4-oxadiazole-containing boronic derivatives, which are powerful tools with significant potential applications across various fields, such as optoelectronics (e.g., OLEDs, semiconductors), luminescent and fluorescent chemosensors, and advanced polymers. In biological contexts, they show promise for bioimaging and targeted drug delivery (e.g., in oncology and the central nervous system (CNS)). The versatility of these boron reagents allows for further derivatization and broad diversification of 1,3,4-oxadiazole-based cores. The resulting strategies demonstrate significant potential across various scientific disciplines, including medicinal chemistry (e.g., as drug candidates with diverse pharmacological activities), agrochemistry (e.g., as herbicides, insecticides, and fungicides), and materials science (e.g., in optoelectronic applications and advanced polymers). Ongoing investigation of these boronic acid derivatives of 1,3,4-oxadiazoles is accelerating the discovery and development of next-generation oxadiazole-based compounds with tailored properties and expanded utility, opening doors to future innovations.