Synthesis of Azirinylammonium Salts via Alkylation of DABCO with 2-Halo-2H-azirines

Abstract

Tertiary (2H-azirin-2-yl)ammonium salts were prepared from methyl 2-halo-3-aryl-2H-azirine-2-carboxylates and 1,4-diazabicyclo[2.2.2]octane in very good to excellent yields. Both iodide and bromide salts are stable enough in crystalline form to be stored in a freezer for up to several months. The structures of the obtained salts were confirmed by NMR spectroscopy and HRMS.

1. Introduction

2H-Azirines are widely used in the synthesis of various heterocycles and acyclic nitrogen-containing compounds [1]. Their chemistry continues to attract considerable attention, which is largely driven by the availability of more than ten different synthetic approaches to the 2H-azirine ring, allowing the introduction of diverse substituents at its carbon atoms [2,3,4]. However, in most of these methods, the desired substituent must be incorporated either into the starting materials or during a multistep sequence preceding azirine ring formation.

To date, only three methods allowing direct modification of the 2H-azirine ring have been described. The first is the oxidative C2-acetoxylation of C3-substituted 2H-azirines [5,6]. The second is a recently developed radical functionalization of 2-halo-2H-azirines based on halogen-atom transfer (XAT), followed by regioselective Giese-type addition to electron-deficient alkenes [7]. The third approach involves nucleophilic substitution reactions of 2-halo- [8], 2-acyloxy- [9], or (1H-1,2,3-benzotriazol-1-yl)-substituted [10] 2H-azirines. Halogen substitution in 2-halo-2H-azirine-2-carboxylates has proven to be particularly effective for introducing various substituents at the C2 position of the azirine ring, including halogens, acyloxy, aryloxy, enyloxy, phthalimide, and various azolyl groups (Scheme 1) [8,11,12,13]. Most of these reactions proceed through an S_N2′-cascade mechanism, which imposes specific requirements on the nucleophilic reagent and therefore limits the range of compatible nucleophiles. In particular, conventional primary and secondary amines are generally unsuitable for such transformations.

In 2022, we reported the synthesis of the first stable azirines bearing an onium substituent at the C2 position, namely azirinylpyridinium salts, obtained from 2-bromoazirine-2-carboxylates and pyridines (Scheme 1) [14]. In the present work, we describe the synthesis of the first azirines containing an ammonium substituent at C2, thereby demonstrating that tertiary amines can also participate as nucleophiles in S_N2′-cascade transformations of the azirine ring.

2. Results and Discussion

Reactions of 2-halo-2H-azirines with O-, S-, and some N-nucleophiles are usually carried out in the presence of proton acceptors, in particular tertiary amines, which serve as bases for substrate deprotonation [8]. However, some of these reagents are sufficiently nucleophilic and, in principle, may react directly with the electrophilic azirine ring. In particular, the reaction of non-halogenated azirines with 1,8-diazabicyclo[5.4.0]undec-7-ene has been reported to result in ring expansion of the azirine to a pyridine system [15]. Reactions of azirines with tertiary amines have not been described in the literature. Nevertheless, considering the sufficient nucleophilicity of tertiary amines, their reactivity towards 2-haloazirines cannot be excluded. Therefore, in cases where deprotonation of a OH-, SH-, NH-substrate by a tertiary amine generates only a weak nucleophile, halogen substitution may proceed via a more complex pathway involving the initial interaction of the azirine with the amine.

To examine this possibility, we investigated the reaction of azirine 1a with triethylamine. Treatment of azirine 1a with triethylamine in diethyl ether resulted in a slow reaction that reached completion within 24 h. Although a crystalline product was formed, it proved unstable and decomposed during isolation. Nevertheless, the observed transformation suggested the possible formation of an azirinyl ammonium salt arising from substitution of the iodine atom in azirine 1a by triethylamine.

Encouraged by this result, we evaluated several tertiary amines as potential nucleophiles. The reaction of azirine 1a with diisopropyl(ethyl)amine (DIPEA) in Et₂O at room temperature for 24 h provided only traces of the product, as judged by TLC, while increasing the temperature led to the unselective decomposition of the starting compound. There is no reaction between azirine 1a and tribenzylamine. On the contrary, 1,4-diazabicyclo[2.2.2]octane (DABCO), a non-hindered base/nucleophilic tertiary amine widely used in a variety of reactions [16,17], displayed substantially higher reactivity than triethylamine and readily reacted with azirine 1a to afford azirinyl ammonium salt 2a in 93% yield (Scheme 2). Iodide salt 2b was obtained by the same method in slightly lower yield (88%), presumably due to its higher solubility in Et₂O, leading to incomplete precipitation from the reaction mixture.

To evaluate the influence of the solvent, as well as the suitability of 2-bromo-substituted azirines for this synthesis, bromoazirine 1c was reacted with DABCO in toluene to furnish ammonium salt 2c in 81% yield. In order to achieve complete conversion of azirine 1c, which is less active in this reaction than iodoazirines 1a,b, two equivalents of DABCO were used. According to the ¹H NMR spectroscopic data, compound 2c was isolated as a stable 2.5:1 solvate with toluene.

Both iodide and bromide salts are sufficiently stable in the crystalline state and can be stored at +2–5 °C for several months without noticeable decomposition. Their structures were unambiguously confirmed by ¹H and ¹³C NMR spectroscopy as well as HRMS. The ¹³C NMR spectra of these compounds display a characteristic signal corresponding to the C2 atom of the azirine ring at ca. 62 ppm, which is in good agreement with the previously reported chemical shift for this carbon atom (ca. 59 ppm) in azirinylpyridinium salts [14].

The mechanism for the formation of salts 2 from 2-haloazirines 1 (Scheme 3) was proposed on the basis of our previous experimental and computational studies on nucleophilic substitution at the C2 position of the azirine ring, including reactions with carboxylate anions and azoles [8]. The reaction is considered to proceed as a domino process initiated by nucleophilic attack of a tertiary amine on the C2 position of the 2-haloazirine, leading to S_N2′ displacement of the halogen atom and formation of an azirinium intermediate A. Given the poor leaving-group ability of the resulting ammonium fragment, the subsequent transformation is unlikely to proceed through a concerted S_N2′ pathway. Instead, it is better described as a stepwise process involving the formation of highly reactive aziridinide species B. Dissociation of this intermediate ultimately furnishes the observed azirinyl ammonium salt 2. Such a stepwise pathway is consistent, in particular, with the results of our previous quantum-chemical calculations on the nucleophilic substitution of bromine in azirines 1 by an azido group, which, similarly to the trialkylammonium group, also exhibits low nucleofugality [18].

3. Materials and Methods

3.1. General Instrumentation

The melting point was determined on a Stuart SMP30 melting-point apparatus (Cole-Parmer, Vernon Hills, IL, USA). NMR spectra were recorded on a Bruker Avance 400 spectrometer (Karlsruhe, Germany). ¹H and ¹³C{1H} NMR spectra were calibrated according to the residual signal of DMSO-d₆ (δ = 2.50 ppm for ¹H and 39.50 ppm for ¹³C) and CDCl₃ (δ = 7.28 ppm for ¹H and 77.00 ppm for ¹³C). IR spectra were recorded on a Bruker Tensor 27 instrument (Bruker Optics GmbH, Ettlingen, Germany). High-resolution mass spectra were recorded with a Bruker maXis HRMS-QTOF (Bremen, Germany), via electrospray ionization. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO₂ ALUGRAM SIL G/UV254 (Macherey-Nagel, Düren, Germany). Column chromatography was performed on silica gel 60 M (0.04–0.063 mm). Diethyl ether and toluene were distilled under sodium prior to use. Azirines 1a [19], 1b [20], and 1c [21] are known compounds prepared according to the published procedures.

3.2. Synthesis of [3-Aryl-2-(methoxycarbonyl)-2H-azirin-2-yl]-1,4-diazabicyclo[2.2.2]octan-1-ium Halides

Method A: DABCO (28 mg, 0.25 mmol, 1 equiv) was added to a solution of azirine 1 (0.25 mmol) in Et₂O (2 mL) and the mixture was stirred at room temperature for 3 h. The resulting precipitate was filtered off, washed with Et₂O (3 × 1 mL) and dried under reduced pressure.

Method B: Azirine 1 (2 mmol) was added to a solution of DABCO (224 mg, 2 mmol) in toluene (6 mL) and the mixture was stirred at room temperature for 4 h. The resulting precipitate was filtered off, washed with PhMe (3 × 1 mL) and hexane (10 mL) and dried under reduced pressure.

• 1-(2-(Methoxycarbonyl)-3-phenyl-2H-azirin-2-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium iodide (2a)

Compound 2a (96 mg, 93%; yellow solid) was obtained according to method A from azirine 1a (75 mg, 0.25 mmol).

m.p.: 60–70 °C (dec.).

IR (KBr) ν_max 3027, 2967, 2891, 1742, 1645, 1596, 1452, 1320, 1277, 1192, 1149, 1102, 1057, 1021, 999, 891, 77,4751, 687.

¹H NMR (400 MHz, DMSO-d₆), δ, ppm: 8.29–8.26 (m, 2H, Ph^ortho), 7.97–7.93 (m, 1H, Ph^para), 7.83–7.79 (m, 2H, Ph^meta), 3.73 (s, 3H, OCH₃), 3.68–3.50 (m, 6H, CH₂-N⁺), 3.11 (t, J = 7.5 Hz, 6H, CH₂-N).

¹³C{¹H} NMR (100 MHz, DMSO-d₆), δ, ppm: 164.5, 161.5, 136.7, 132.1, 130.1, 118.4, 60.7, 54.2, 52.3, 44.6.

HRMS (ESI/Q-TOF) m/z: [M]⁺ Calcd for C₁₆H₂₀N₃O₂⁺ 286.1550; found 286.1552.

• 1-(3-(4-Methylphenyl)-2-(methoxycarbonyl)-2H-azirin-2-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium iodide (2b)

Compound 2b (94 mg, 88%; yellow solid) was obtained according to method A from azirine 1b (79 mg, 0.25 mmol).

m.p.: 95–100 °C (dec.).

IR (KBr) ν_max 3028, 2956, 2890, 1741, 1645, 1604, 1461, 1276, 1148, 1101, 1057, 1027, 891, 822, 590.

¹H NMR (400 MHz, DMSO-d₆), δ, ppm: 8.16 (d, J = 7.9 Hz, 2H, Ar^ortho), 7.62 (d, J = 7.9 Hz, 2H, Ar^meta), 3.72 (s, 3H, OCH₃), 3.67–3.48 (m, 6H, CH₂-N⁺), 3.11 (t, J = 7.5 Hz, 6H, CH₂-N), 2.50 ((s, 3H, CH₃; overlaps with residual solvent signal). Compound 2b in CDCl₃ solution slowly decomposes.

¹³C{¹H} NMR (100 MHz, DMSO-d₆), δ, ppm: 164.6, 160.8, 148.1, 132.1, 130.7, 115.6, 60.7, 54.1, 52.2, 44.6, 21.6.

HRMS (ESI/Q-TOF) m/z: [M]⁺ Calcd for C₁₇H₂₂N₃O₂⁺ 300.1707; found 300.1711.

• 1-(3-(4-Bromophenyl)-2-(methoxycarbonyl)-2H-azirin-2-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide (2c)

Compound 2c (763 mg, 81%; colorless solid) as solvate with PhMe in ca. 2.5:1 ratio was obtained according to method B from azirine 1c (666 mg, 2 mmol).

m.p.: 45–60 °C (dec.).

IR (KBr) ν_max 3047, 2963, 2888, 1759, 1646, 1586, 1480, 1436, 1400, 1344, 1275, 1149, 1105, 1066, 1010, 891, 839, 587.

¹H NMR (400 MHz, CDCl₃), δ, ppm: 8.32–8.30 (m, 2H, Ar^ortho), 7.90–7.87 (m, 2H, Ar^meta), 7.25–7.12 (m, 1.22H, Ar^toluene), 4.04–3.78 (m, 6H, CH₂-N⁺), 3.72 (s, 3H, OCH₃), 3.38–3.31 (m, 6H, CH₂-N⁺), 2.33 (s, 0.8H, CH₃^toluene).

¹³C{¹H} NMR (100 MHz, CDCl₃), δ, ppm: 164.9, 161.9, 137.8 (C^toluene), 133.9, 133.7, 132.8, 128.9 (C^toluene), 128.1 (C^toluene), 125.2 (C^toluene), 116.6, 61.8, 54.3, 52.3, 45.4, 21.3 (C^toluene).

HRMS (ESI/Q-TOF) m/z: [M]⁺ Calcd for C₁₆H₁₉⁷⁹BrN₃O₂⁺ 364.0655; found 364.0663.

4. Conclusions

In summary, an efficient synthesis of tertiary (2H-azirin-2-yl)ammonium salts from methyl 3-aryl-2-halo-2H-azirine-2-carboxylates and 1,4-diazabicyclo[2.2.2]octane (DABCO) has been developed. Both 2-iodo- and 2-bromo-substituted azirines were found to be suitable substrates for this transformation, while diethyl ether proved to be the optimal solvent. The resulting iodide and bromide salts exhibit sufficient stability in the crystalline state to allow storage at +2–5 °C for several months. The synthesized compounds represent the first examples of azirines bearing an ammonium substituent directly attached to the three-membered ring.