Electrochemical ⍺-C─H Functionalization of Nitramines for Accessing Bifunctional Energetic Heterocycles

Abstract

The synthesis of energetic materials (EMs) often involves hazardous reagents and harsh conditions, raising safety and environmental concerns. We herein present an electrochemical method for the ⍺-C─H azolation of nitramines, enabling the integration of nitramines and various nitrogen-rich azoles as dual energetic components within the same molecule. To enhance the practicality of the overall synthesis, we developed a tandem two-step process that transforms free amines into nitramines using stable and readily available reagents, which was complemented by subsequent electrochemical azolation to complete a streamlined, scalable preparation of bifunctional energetic compounds. Finally, a continuous flow system was employed to further improve the practicality of the electrosynthetic method, which substantially reduced electrolyte usage and increased productivity. Computational and experimental data revealed that the introduction of azoles, particularly those with additional nitro substituents, improves the energy density and thermal stability of nitramines. This work provides a proof of concept that the reported electrochemical azolation reaction may not only offer a safer and more sustainable alternative to traditional approaches for energetic material synthesis, but it will also provide a platform for the discovery of novel compounds with favorable energetic properties.

Keywords: Azolation; Electrochemistry; Electroflow; Energetic compound; Nitramine.

Scheme 1

Electrochemical α‐C─H functionalization of nitramines. RDX = 1,3,5‐trinitro‐1,3,5‐triazinane. HMX = 1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocane. HNIW = hexanitrohexaazaisowurtzitane. TEX = 4,10‐dinitro‐2,6,8,12‐tetraoxa‐4,10‐diazatetracyclo[5.5.0.0^5,9.0^3,11]‐dodecane. TNAZ = 1,3,3‐trinitroazetidine. ABTr = 4,4′‐azobis[1,2,4‐triazole]. DAT = 1,5‐diamino‐tetrazole. DNP = 3,4‐dinitropyrazole. DDF = 4,4′‐dinitro‐3,3′‐diazenofuroxan. TNBI = 4,4′,5,5′‐tetranitro‐2,2′‐biimidazole. Oxone = potassium peroxymonosulfate.

Scheme 2

Nitramine synthesis under nitric‐acid‐free conditions. ^a)With NaNO₂ (3 equiv), HCl (2.2 equiv) in dichloromethane at 0 °C for 1 h. ^b)With Oxone (2 equiv), in acetonitrile/H₂O (1:1.5) at 40 °C for 16 h.

Scheme 3

Development and optimization of reaction conditions for the azolation of nitramines. ^a)Conducted with 1 (0.25 mmol), 2 (2 equiv), electrolyte (0.4 M) in presence of TFA (10 equiv) or BF₃·OEt₂ (2 equiv) in solvent (2.5 mL) at room temperature; constant current i = 8 mA, 6 F mol⁻¹, 5 h; undivided cell (ElectraSyn 2.0); isolated yields; diastereomeric ratio (dr) determined by ¹H NMR analysis of crude mixture. ^b)Working electrode: glassy carbon disk; counter electrode: Pt wire; pyrazole (10 mM); solvent: MeCN; electrolyte: TBAClO₄ (0.1 M); υ = 100 mV s⁻¹. Boc = tert‐butoxycarbonyl. Cbz = benzyloxycarbonyl. Ac = acetyl. Bz = benzoyl. Ts = p‐toluenesulfonyl. Ns = 2‐nitrobenzenesulfonyl. TBA = tetrabutylammonium. MsOH = methanesulfonic acid. TCA = trichloroacetic acid. TFA = trifluoroacetic acid. BzOH = benzoic acid. AcOH = acetic acid. HFIP = hexafluoroisopropanol. TfOH = trifluoromethanesulfonic acid. RVC = reticulated vitreous carbon.

Scheme 4

Scope for electrochemical α‐C─H azolation of nitramines. ^a)Conducted with a 0.25 mmol scale with azole (2 equiv), TBAClO₄ (0.4 M) in presence of TFA (0.2 mL) or BF₃·OEt₂ (2 equiv) in acetonitrile (2.5 mL) at room temperature; constant current i = 8 mA, 6 F mol⁻¹, 5 h; platinum wire; undivided cell (ElectraSyn 2.0); isolated yields; diastereomeric ratio (dr) determined by ¹H NMR analysis of crude mixture. ^b)Relative configuration determined by X‐ray crystallography. ^c)Yields determined by ¹H NMR spectroscopy. ^d)With LiClO₄ (0.4 M). ^e)Conducted with a 0.25 mmol scale with alcohol (2 equiv), LiClO₄ (0.4 M) in the presence of HFIP (0.4 mL) in acetonitrile (2.1 mL) at room temperature; constant current i = 10 mA, 5 F mol⁻¹, 3 h and 21 min; RVC anode and glassy carbon (GC) cathode; undivided cell (ElectraSyn 2.0); isolated yields.

Scheme 5

α‐C─H functionalizations via tandem Shono oxidation for the introduction of energetic functionalities. ^a)With TBAClO₄ (0.4 M) in TFE at room temperature; constant current i = 5 mA, 2.5 F mol⁻¹, 3 h and 21 min; RVC anode and Pt foil cathode; undivided cell (ElectraSyn 2.0). ^b)With TMSN₃ (3 equiv), BF₃·OEt₂ (3 equiv) in MeCN at room temperature. ^c)With TMSCN (3 equiv), BF₃·OEt₂ (3 equiv) in MeCN at room temperature. ^d)With NaN₃ (3 equiv), NH₄Cl (3 equiv) in DMF at 100 °C. ^e)With nitroacetate (3 equiv), AlCl₃ (3 equiv) in DCM at room temperature. Diastereomeric ratio (dr) determined by ¹H NMR analysis of crude mixture. ^f)The isolated compound (65:35 dr) underwent isomerization in chloroform‐d, increasing the dr to 92:8. The relative configuration at C3 could not be confidently assigned.

Scheme 6

Telescoped reaction for scalable synthesis. ^a)With NaNO₂ (3 equiv), HCl (2.2 equiv) in dichloromethane at 0 °C for 1 h. ^b)With Oxone (2 equiv), in acetonitrile/H₂O (1:1.5) at 40 °C for 16 h. ^c)With azole (2 equiv), TBAClO₄ (0.4 M) in the presence of TFA (10 equiv) in acetonitrile at room temperature; Constant current i = 8 mA, 6 F mol⁻¹, 5 h; platinum wire; undivided cell; isolated yield.

Scheme 7

Electroflow system for the synthesis of functionalized nitramines.

Scheme 8

Comparison of physical properties across nitramine derivatives. ^a)Based on experimental measurements. ^b)Based on computation. T _dec = onset temperature of decomposition. T _m = onset temperature of melting. Ω _CO2 = CO₂ oxygen balance.^{[ 103 ]} Δ_f H°_gas = gas‐phase heat of formation.^{[ 104 ]} ρ = crystal density.^{[ 105 ]} BDE = bond‐dissociation energy. 1,3‐DNAZ = 1,3‐dinitroazetidine. TNAZ = 1,3,3‐trinitroazetidine. 1,4‐DNP = 1,4‐dinitropiperazine. RDX = 1,3,5‐trinitro‐1,3,5‐triazinane. DSC = differential scanning calorimetry. TGA = thermal gravimetric analysis.