Synthesis of 2-Aminonicotinonitriles via Photodecarboxylation of Azirine-2-Carboxylic Acids

Abstract

2-Aminonicotinonitriles represent an important class of heterocycles with diverse biological activities. Herein, we report an unexpected photochemical transformation of azirine-2-carboxylic acids leading to the formation of 2-aminonicotinonitrile derivatives. Optimization of the reaction conditions enabled the synthesis of the target products in moderate yields. The structure of the obtained product was confirmed by NMR spectroscopy, HRMS, and single-crystal X-ray diffraction analysis.

1. Introduction

Pyridine derivatives represent an important class of nitrogen-containing heterocycles widely found in natural products, pharmaceuticals, and biologically active molecules [1,2,3,4,5]. Among these compounds, 2-aminonicotinonitrile derivatives constitute a valuable structural motif that has been extensively explored in medicinal chemistry. These molecules exhibit a broad spectrum of biological activities and have been reported as inhibitors of several biologically relevant targets, including SIRT1 [6], IKKβ [7], and A2A adenosine receptors [8] (Scheme 1). In addition, various 2-aminonicotinonitrile derivatives demonstrate antibacterial [9], antiviral [10], anti-inflammatory [11], and antitumor properties [12]. Beyond their biological properties, APNs have also shown promise as fluorescent sensors for monitoring photopolymerization processes [13] and steel corrosion inhibitors [14].

Several synthetic approaches toward 2-aminonicotinonitrile derivatives have been reported. The classical method involves multicomponent condensation reactions of aldehydes or ketones with malononitrile and ammonia or ammonium salts, often referred to as a Chichibabin-type pyridine synthesis [15]. More recently, improved protocols have been developed, including Cu-catalyzed cyclization of oxime esters [16], annulation reactions of α-keto vinyl azides with α,α-dicyanoalkenes [17], or even direct modification of 2-amino-3-bromopyridines [18].

2. Results and Discussion

Recently, we reported a radical strategy for the generation of 2H-azirin-2-yl radicals under halogen-atom transfer (XAT) conditions from readily available 2-bromo-2H-azirine-2-carboxylic esters. These highly reactive intermediates undergo regioselective Giese-type additions to electron-deficient alkenes, including 2-benzylidenemalononitrile, providing densely functionalized azirine adducts while preserving the azirine ring [19]. Encouraged by these results, we sought to extend this strategy to non-functionalized azirinyl radicals by turning to photodecarboxylation methods [20,21,22] for their generation. However, when azirine-2-carboxylic acid 1a [23] was employed as an azirinyl radical precursor in the reaction with 2-benzylidenemalononitrile 2 under UV-LED (450 nm) irradiation, the reaction pathway changed dramatically (Scheme 2). Instead of the expected Giese-type product, the transformation proceeded further, leading to the formation of 2-aminonicotinonitrile derivative 3a. The structure of 3a was established by NMR, HRMS, and XRD methods. The NMR data were in full agreement with the literature data for this compound [24].

To optimize the reaction conditions, the reaction between azirine-2-carboxylic acid 1a and 2-benzylidenemalononitrile 2 was investigated under visible-light irradiation (

Table 1. Optimization of the reaction conditions.

Entry 1	Photocatalyst (3 mol %)	Base	Time	Yield of 3a
1	PC-1	Cs2CO3, 20 mol %	24 h	17%
2	PC-2	Cs2CO3, 20 mol %	24 h	16%
3	PC-3	Cs2CO3, 20 mol %	24 h	17%
4	PC-1	Cs2CO3, 5 mol %	24 h	23%
5	PC-1	Bn3N, 5 mol %	24 h	24%
6	PC-1	Bn3N, 5 mol %	48 h	32%
7	PC-1	Bn3N, 5 mol %	96 h	34%

¹ Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), PC (3 mol%), base, MeCN (1 mL), 450 nm, rt.

and extended Supplementary Materials Table S1 in the Supporting Information). Initial experiments in the presence of PC-1 and 20 mol% of Cs₂CO₃ showed that the use of an equimolar amount of acid 1a resulted in a 5% yield of target compound 3, whereas increasing its amount to 2 equiv led to a gradual improvement in yield, reaching 17% (Table S1, entries 1–5). Control experiments under daylight or in the dark resulted in only trace product formation (Table S1, entries 7–8).

Screening of several photocatalysts (PC-1–3) revealed only a minor effect on the reaction outcome (Table 1, entries 1–3). Similarly, the reaction was found to proceed even in the absence of base, giving a 15% yield (Table S1, entry 11), indicating that the base is not strictly required but influences the efficiency of the transformation. A moderate improvement was observed upon decreasing the loading of Cs₂CO₃ from 20 mol % to 5 mol %, increasing the yield to 23% (Table S1, entry 12), whereas higher base loadings (50–300 mol %) led to a substantial decrease in yield (Table S1, entries 13–16).

Further evaluation of different bases showed that organic amines are generally more effective, with Bn₃N (5 mol %) providing the best result (24%, Table S1, entry 17), while other bases such as DMAP, K₃PO₄, DBU, TMG, and DABCO gave lower yields (Table S1, entries 18–22). The reaction concentration also had an effect, with both dilution and increased concentration leading to diminished yields (Table S1, entries 23–24).

Finally, extending the reaction time led to a gradual increase in the yield, reaching 34% after 96 h under otherwise identical conditions (Table 1, entries 4–6). Under the optimized conditions, full consumption of the starting materials was observed, but no significant amounts of well-defined side products were isolated.

Structure of 3a was unambiguously confirmed by single-crystal X-ray diffraction analysis (Figure 1).

The moderate yield of 3a (34%) can likely be attributed to the limited stability of the azirin-2-yl radical generated after the photochemical decarboxylation step. To increase the stability of this intermediate, we introduced an additional substituent into the azirine ring. When the more substituted azirine-2-carboxylic acid 1b was employed under the optimized reaction conditions, the yield of the corresponding 2-aminonicotinonitrile 3b increased to 47% (Scheme 3). Nicotinonitrile 3b is a new compound; its structure was confirmed by NMR spectroscopy and HRMS methods.

3. Materials and Methods

3.1. General Instrumentation

The melting point was determined on a Stuart SMP30 melting-point apparatus. NMR spectra were recorded on a Bruker Avance 400 spectrometer (Karlsruhe, Germany) in CDCl₃. ¹H and ¹³C{1H} NMR spectra were calibrated according to the residual signal of CDCl₃ (δ = 7.28 ppm for ¹H and 77.00 ppm for ¹³C). 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). All solvents were distilled and dried prior to use. Single crystals of compound 3a were grown by slow evaporation of its solution in a diethyl ether–hexane–dichloromethane mixture. Crystallographic data were collected on a SuperNova, single source at offset/far, HyPix3000 diffractometer (Rigaku, Wroclaw, Poland) using graphite monochromatic Cu–Kα radiation (λ = 1.54184 A). The crystal was kept at 100.01(11) K during data collection. Using the Olex2 version 1.5 [25], the structure was solved with the ShelXT [26] structure solution programme using the Intrinsic Phasing method and refined with the ShelXL [27] refinement package using Least Squares minimization. CCDC 2534715 contains crystallographic data for compound 3a. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures (accessed on 6 April 2026).

3.2. Synthesis of 2-Aminonicotinonitriles

A stirred solution of 2-benzylidenemalononitrile 2 (30.8 mg, 0.2 mmol), azirine-2-carboxylic acid 1 (0.4 mmol, 2 equiv), Bn₃N (2.9 mg, 0.01 mmol, 5 mol%), and PC-1 (2.8 mg, 0.006 mmol, 3 mol%) in MeCN (1 mL) was irradiated at 450 nm under an Ar atmosphere for 96 h. After the reaction completion, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (benzene–EtOAc) to give 2-aminonicotinonitrole 3.

• 2-Amino-4,6-diphenylnicotinonitrile 3a

Compound 3a (18.4 mg, 0.068 mmol, 34%; grey solid) was obtained according to the general procedure from azirine-2-carboxylic acid 1a (64.5 mg, 0.4 mmol).

Mp: 184–185 °C.

¹H NMR (400 MHz, CDCl₃), δ, ppm: 8.04–8.02 (m, 2H), 7.67–7.65 (m, 2H), 7.58–7.49 (m, 6H), 7.23 (s, 1H), 5.43 (s, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃), δ, ppm: 160.2, 159.8, 155.1, 137.9, 136.9, 130.2, 129.8, 128.9, 128.8, 128.1, 127.3, 117.1, 111.2, 88.3.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ Calcd for C₁₈H₁₄N₃⁺ 272.1182; found 272.1185.

• 2-Amino-6-(4-methoxyphenyl)-4,5-diphenylnicotinonitrile 3b

Compound 3b (34.3 mg, 0.094 mmol, 47%; grey solid) was obtained according to the general procedure from azirine-2-carboxylic acid 1b (106.9 mg, 0.4 mmol).

Mp: 210–212 °C.

¹H NMR (400 MHz, CDCl₃), δ, ppm: 7.26–7.21 (m, 5H), 7.11–7.09 (m, 2H), 7.04–7.03 (m, 3H), 6.81–6.79 (m, 2H), 6.73–6.71 (m, 2H), 5.36 (s, 2H), 3.77 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃), δ, ppm: 160.3, 159.7, 158.2, 155.0, 136.9, 136.5, 131.9, 131.6, 131.2, 129.1, 128.3, 128.0, 127.7, 126.5, 125.8, 116.7, 113.1, 90.5, 55.2.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺ Calcd for C₂₅H₂₀N₃O⁺ 378.1601; found 378.1608.

4. Conclusions

In summary, we have discovered an unexpected photochemical transformation of azirine-2-carboxylic acids with benzylidenemalononitriles, leading to the formation of 2-aminonicotinonitrile derivatives. This transformation reveals a previously unexplored reactivity of azirinyl radicals and provides an alternative approach to functionalized 2-aminonicotinonitriles. The structure of compound 3a was confirmed by single-crystal X-ray diffraction analysis. The developed method was used to synthesize a new representative of the 2-aminonicotinonitrile series, compound 3b.