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Chemoselective synthesis of 1,3,4-thiadiazoles from acyl hydrazines and nitroalkanes using elemental sulfur

26 August 2025

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Introduction

In medicinal chemistry, the 1,3,4-thiadiazole ring is a privileged pharmacophore found in numerous therapeutic agents, including the antibacterial cefazedone, the antipsychotic candidate MK-8189, and the anti-NASH drug BI-3231 (Fig. 1a). Traditional syntheses, however, rely on highly toxic P₂S₅ or Lawesson’s reagent under harsh anhydrous conditions and exhibit limited substrate scope, severely restricting their application to complex molecules. Developing a mild, modular route to these motifs has therefore become a critical unmet need.

Professor Jing Li’s group at Xi’an Jiaotong University reports in Nature Communications a breakthrough that achieves one-step annulation of nitroalkanes with acyl hydrazides using cheap elemental sulfur (S₈) (Fig. 1c). The protocol employs an Na₂S·9H₂O/DMF catalytic system that efficiently forges the 1,3,4-thiadiazole core under ambient conditions.

Key innovations include:

1. Mild reaction conditions—room temperature, transition metal-free;
2. Generation of thioacyl intermediates from primary nitroalkanes;
3. High functional-group tolerance and excellent scalability;
4. Complete stereochemical integrity of chiral amino acids (e.g., >99% ee for product 3r);
5. Applicability to late-stage functionalization of complex drug molecules and peptides.

Figure 1. a Application of 1,3,4-Thiadiazoles in pharmaceuticals and pesticides. b Traditional synthetic routes and limitations; c This work: mild and modular synthesis 1,3,4-thiadiazole directly from nitroalkanes and acyl hydrazines using elemental sulfur.

Reaction discovery and optimization

Primary nitroalkanes are readily available for synthesis and used as carbonyl precursors to form carboxylic, amides, esters. Elemental sulfur (S8) is abundant in nature, non-toxic, non-volatile, nonhygroscopic and odorless, making it an ideal sulfur source. At the outset, researchers selected commercially available benzoyl hydrazine 1a and nitroethane 2a as simple starting materials. Under mild conditions (room temperature, DMF or DMF/H2O), the 1,3,4-thiadiazole core is assembled in a single, high-yielding step. Initial experiments delivered 76 % yield (Table 1, entry 1), and subsequent systematic optimization of the solvent and the hydration state of Na2S further increased the yield while enabling compatibility with polar solvents, thus overcoming the traditional limitation of anhydrous, non-polar systems.

Table 1. Optimization of 1,3,4-thiadiazole synthesis from nitroethane 2a and benzoylhydrazine 1a

Substrate scope for 1,3,4-thiadiazole formation

Next, the authors systematically evaluated the substrate scope of the reaction.
The substrate scope of various acyl hydrazines: Acyl hydrazines carrying aliphatic, aromatic, alcohol, CF3, amine, furan, thiophene, pyridine, pyrimidine, aromatic amine, electron-deficient amine, free acid, and OH units were all tolerated well under the reaction conditions, providing the 1,3,4-thiadiazole products in high yields (3a–3r). Importantly, the α-amino product 3r was produced with complete stereochemical integrity (Fig. 2a).

Changing the primary nitroalkane to bear valuable functionalities such as hydroxyl group, ester, amide, ketone, acetal and triazole, similarly furnished the corresponding thiadiazoles 4a-4j from benzoyl hydrazine 2a in good yields (Fig. 2b). When using chiral nitroalkanes, reactions proceeded in moderate yield with minimal epimerization at −10 ˚C with iPrO-S-S-OiPr (e.g., 4k, 96% ee).

Figure 2. a Scope of acyl hydrazines; b Scope of nitroalkanes; c Analogue functionalization of bioactive compounds.

Peptide applications break through traditional limitations

Using solid phase peptide synthesis (SPPS), nitro-peptides (7) and peptide hydrazides (6) were prepared. Coupling hydrazide-bearing fragment 6 with nitro-containing fragment 7 in the S₈/Na₂S·9H₂O system efficiently furnished 2,5-disubstituted 1,3,4-thiadiazoles 8a–8c, while tolerating fluorophore or biotin (8d–8e) (Fig. 3a). A linear “nitro-hydrazide” precursor 9, also synthesized by SPPS, underwent direct intramolecular cyclization under the same conditions to give a 20-membered cyclic peptide 10 in 50% yield (Fig. 3c), offering a new strategy for cyclic peptide construction.

Figure 3. a Late-stage C-terminal functionalization of peptide hydrazines; b Peptide ligation between nitroalkane and hydrazine fragments; c Intramolecular cycloaromative formation of cyclic peptide.

Significant industrial value

Compared with the traditional 7-step synthesis of BI-3231 (requiring Pd/Cu catalysts), the new route delivers the target in only three steps from intermediate 11. The yield of the key MK-8189 intermediate 15 is increased to 73%. Kilogram-scale preparation of the ACKR3 modulator key intermediate 19 likewise avoids the malodorous Lawesson reagent (Fig. 4).

Figure 4. a Synthetic route of BI-3231; b Synthetic route of MIK-8189; c Synthetic route of 19.

AmBeed's Products Support Related Research:

AmBeed supplies a complete range of high-purity building blocks and reagents for the synthetic route described above—including the acyl hydrazines, primary nitroalkanes, and 1,3,4-thiadiazoles mentioned in the article—fully meeting your experimental needs and powering your research forward.

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References

[1]Wang, X., Yu, X., Qian, R. et al. Chemoselective synthesis of 1,3,4-thiadiazoles from acyl hydrazines and nitroalkanes using elemental sulfur. Nat Commun 2025, 16, 6127.

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