Abstract
A direct and rapid method for the synthesis of α-iminonitriles achieved good to excellent yields. A novel intermolecular dehydration reaction between 2-aminopyridines and nitroalkenes is reported via a rare-earth-metal catalyst. The merits of this transformation include cyanide-free protocol, short reaction time, simple operation, water as the only byproduct, commercially available reagents, good functional group tolerance, etc. Moreover, nitroalkenes are demonstrated as a new “CN” source in this transformation.
Introduction
α-Iminonitriles, as attractive structural motifs, are important intermediates in organic synthesis. They have emerged as precursors for amides, amidines, aryl nitriles, α-keto acids, cyanoenamides, and N-alkylketeneimines.1 Furthermore, they are used for the construction of heterocyclic compounds through cycloaddition reaction.2 Accordingly, some synthetic methods have been reported for the synthesis of α-iminonitriles in the past decades. These protocols include the oxidation of α-aminonitriles, the Beckmann rearrangement of oxime sulfonates, nucleophilic substitution of imidoyl chloride, etc.3 Recently, several well-documented modern approaches have been developed. Zhu et al. described an 2-iodoxybenzoic acid- and tetrabutylammonium bromide-promoted three-component synthesis of α-iminonitriles from aldehydes, primary amines, and trimethylsilyl cyanide (TMSCN).4 More recently, Shen et al. have developed a palladium-catalyzed synthesis of α-iminonitriles via tert-butyl isocyanide double insertion and elimination in one pot.5 Jiao et al. reported the efficient transformation of methyl imines to α-iminonitriles by a radical pathway.6 Karade et al. demonstrated the synthesis of α-iminonitriles from imidazo[1,2-α]pyridines by using NaN3 and (diacetoxyiodo)benzene (Scheme 1a).7 However, both the traditional and modern methods often need the use of highly toxic cyanide reagents, such as CuCN, BrCN, NaCN, Hg(CN)2, Bu3SnCN, TMSCN, and so on. In addition, these approaches have some drawbacks, including the requirement of complex substrates, expensive catalysts and ligands, excess oxidants and additives, long reaction time, and low atom and step economy. From environmental and economic viewpoints, the development of new approaches toward α-iminonitriles by using easily available substrates and cheap agents with high efficiency would be highly desirable.
Scheme 1. Transformation from 2-Aminopyridines and Nitroalkenes to α-Iminonitriles.
In recent years, much attention has been devoted to the exploration of the catalytic properties of rare-earth-metal catalysts in organic synthesis.8 They have been discovered as a new kind of Lewis acid catalysts and showed some advantages, such as high efficiency, operation simplicity, eco-friendly catalytic reaction, and excellent chemo-, stereo-, and regioselectivities. Nitroalkenes, as readily available and versatile building blocks, have been widely employed in many synthetic strategies. In particular, they have attracted a great deal of attention owing to their exceptional properties in asymmertical addition reactions9 and cyclization reactions.10 Among these cyclization reactions, imidazopyridine derivatives were achieved from 2-aminopyridines and nitroalkenes in several metal catalyst systems, such as CuBr,11 Fe(NO3)3,12 and FeCl3 (Scheme 1b).13 Very recently, we have reported an expedient method for the synthesis of amides from 2-aminopyridines and nitroalkenes.14 The α-iminonitrile intermediate was detected in the transformation. Inspired by this observation, here we present a cyanide-free, Ce(OTf)3-catalyzed rapid cross-coupling reaction of 2-aminopyridines with nitroalkenes for the formation of α-iminonitriles through an intermolecular dehydration process (Scheme 1c). To our knowledge, this transformation represents the first example for α-iminonitriles using nitroalkenes as a new “CN” source.15
Results and Discussion
Our studies began with the reaction of 2-aminopyridine (1a) with nitrostyrene (2a) in the presence of Sm(OTf)3 in toluene at 120 °C, which furnished the product α-iminonitrile 3a in 69% yield (Table 1, entry 1). For further investigation, we concentrated on testing various rare-earth-metal catalysts to improve the product yields. All of the catalysts have some effects on the transformation (Table 1, entries 2–9). Among the different rare-earth-metal catalysts, it was found that Ce(OTf)3 was the most effective and provided the product in 92% isolated yield (Table 1, entry 2). Notably, the reaction could not occur without a catalyst (Table 1, entry 10). Subsequently, a variety of common solvents were evaluated at 120 or 100 °C and the results showed that solvents were essential for the transformation (Table 1, entries 11–19). When other solvents were used instead of toluene, the yields of desired products decreased rapidly. The yield decreased to 71%, when the reaction was performed at 100 °C in toluene (Table 1, entry 20). Finally, this is disadvantageous to the reaction in a longer reaction time as the product could be hydrolyzed into amide (Table 1, entry 21). These preliminary experiments indicated that the optimized condition for the formation of α-iminonitrile is using Ce(OTf)3 as the catalyst and toluene as the solvent at 120 °C for 10 min.
Table 1. Optimization of the Reaction Conditionsa.
| entry | cat. | sol. | temp. | yieldb (%) |
|---|---|---|---|---|
| 1 | Sm(OTf)3 | toluene | 120 | 69 |
| 2 | Ce(OTf)3 | toluene | 120 | 97 (92) |
| 3 | Sc(OTf)3 | toluene | 120 | 62 |
| 4 | GdCl3·6H2O | toluene | 120 | 15 |
| 5 | TbCl3·6H2O | toluene | 120 | 12 |
| 6 | TmCl3·6H2O | toluene | 120 | 18 |
| 7 | YbCl3·6H2O | toluene | 120 | 20 |
| 8 | CeCl3 | toluene | 120 | 35 |
| 9 | Ce(NO3)3·6H2O | toluene | 120 | 51 |
| 10 | toluene | 120 | N.P. | |
| 11 | Ce(OTf)3 | DMF | 120 | 8 |
| 12 | Ce(OTf)3 | DMSO | 120 | 9 |
| 13 | Ce(OTf)3 | dioxane | 120 | 50 |
| 14 | Ce(OTf)3 | HOAc | 120 | trace |
| 15 | Ce(OTf)3 | H2O | 120 | 45 |
| 16 | Ce(OTf)3 | EtOH | 100 | 43 |
| 17 | Ce(OTf)3 | DCE | 100 | 32 |
| 18 | Ce(OTf)3 | THF | 100 | trace |
| 19 | Ce(OTf)3 | MeCN | 100 | 65 |
| 20 | Ce(OTf)3 | toluene | 100 | 71 |
| 21c | Ce(OTf)3 | toluene | 120 | 62 |
Reaction conditions: 2-aminopyridine (0.2 mmol), nitrostyrene (0.2 mmol) with catalyst (10 mol %) in solvent 1.5 mL for 10 min.
Determined by gas chromatography (GC) with mesitylene as internal standard. Number in parentheses is isolated yield.
Reacted for 2 h. N.P. = no product.
To explore the scope of this rare-earth-metal-catalyzed process, various substituted 2-aminopyridines were coupled with nitrostyrene under optimized reaction conditions (Scheme 2). In general, the reaction has good functional group tolerance. Both electron-donating and electron-withdrawing substituted aminopyridines reacted well to furnish the desired products in moderate to good yields (Scheme 2, 3b–o). Substituted 2-aminopyridines with the methyl group at different positions reacted efficiently to render the corresponding products in good yields (3b–d). Interestingly, when quinolin-2-amine was used as substrate, the corresponding product 3g was generated in 81% yield. Aminopyridines bearing both weak and strong electron-deficient groups were compatible in the standard conditions (3h–n). To our delight, the bromo- or iodo-containing 2-aminopyridines were suitable substrates in the catalytic system, delivering 3k and 3l products in high yields. In particular, aryl bromide and iodide were easily further functionalized via transition-metal-catalyzed conditions and hold great potential applications in organic synthesis. In addition, the challenging substrates, trisubstituted 2-aminopyridines, also reacted smoothly to form the desired products in moderate yields (3p–r). Aliphatic nitrostyrene only gave amide product. Noteworthily, the reaction could be carried out at a 10 mmol scale and afforded the product with satisfactory yield (3a). The structure of 3p was further confirmed by X-ray crystal diffraction measurements (Figure 1).16
Scheme 2. Ce(III)-Catalyzed Synthesis of α-Iminonitriles from Aminopyridines and Nitrostyrene.
10 mmol scale of the reaction.
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), Ce(OTf)3 (10 mol %), and toluene (1.5 mL) at 120 °C for 10 min; isolated yield.
Figure 1.
X-ray crystal structure of 3p.
Next, we investigated the Ce(III)-catalyzed reaction between substituted nitroalkenes and various 2-aminopyridine derivatives, and the results are summarized in Scheme 3. First, 2-aminopyridine (1a) was examined. It was indicated that the reaction of 1a and nitrostyrene derivatives with electron-rich or electron-deficient groups on the benzene ring was smooth and produced the desired products in 58–87% yields (4a–i). Pyridine ring-bearing electron-donating (methoxy, methyl, and phenyl groups) and electron-withdrawing substituents (fluoro, chloro, bromo, iodo, and trifluoromethyl groups) all reacted well to give the corresponding products in good yields, irrespective of the nitroalkenes attached with electron-rich or electron-poor groups on the benzene ring (4j–w). It is noteworthy that the halo groups were unaffected in the standard conditions. All of these results implied that this Ce(III)-catalyzed dehydration reaction can be effective for the α-iminonitrile library.
Scheme 3. Ce(III)-Catalyzed Synthesis of α-Iminonitriles from Aminopyridines and Nitroalkenes.
Reaction conditions: 0.2 mmol of 1 and 0.2 mmol of 2 in the presence of Ce(OTf)3 (10 mol %) in toluene at 120 °C for 10 min; isolated yield.
To disclose the possible mechanistic pathway of this Ce(III)-catalyzed dehydration reaction between 2-aminopyridines and nitroalkenes, some controlled experiments were carried out under the optimized conditions. Initially, radical inhibitor (2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl was added to the reaction and the yield just decreased slightly, which suggested that this should be an ionic reaction (Scheme 4a). When benzoyl cyanide (5a) was used as raw material instead of nitrostyrene (2a) to explore the reaction, unfortunately, we found that the reaction did not give any desired product, which inferred that benzoyl cyanide was not the intermediate in this process (Scheme 4b). Moreover, aniline (6a) was reacted with nitrostyrene under the optimized conditions, and the corresponding product 7a was not detected, which indicated that the nitrogen atom of the pyridine ring is essential and serves as a base to abstract the proton (Scheme 4c).
Scheme 4. Controlled Experiments.
On the basis of previous reports as well as our experimental results, a plausible mechanism for the formation of α-iminonitriles is depicted in Scheme 5.13 Initially, the Michael addition of 2-aminopyridine with nitrostyrene forms intermediate A, which undergoes proton transfer immediately, followed by intramolecular dehydration to give intermediate C under the influence of pyridine. Then, the [1,5]H sigmatropic shift of intermediate C can yield a six-membered intermediate D, which subsequently isomerizes into intermediate E. Finally, the α-iminonitrile product is formed after the removal of water from intermediate E. Probably, the Lewis acid accelerates the Michael addition and dehydration process.
Scheme 5. Possible Reaction Mechanism.
Conclusions
In conclusion, we have explored a highly efficient and rapid coupling reaction of 2-aminopyridines and nitroalkenes catalyzed by Ce(OTf)3. A series of α-iminonitriles bearing various functional groups were obtained in moderate to high yields through an intermolecular dehydration process. This reaction features a cyanide-free process, commercially or easily available reagents, complete stereoselectivity, simple operation, etc. It is noteworthy that water is the only byproduct in this transformation. Studies regarding the scope and application of α-iminonitriles and further mechanistic studies are currently ongoing in our laboratory.
Experimental Section
General Methods
1H and 13C NMR spectra were obtained on a 400 MHz NMR spectrometer. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm, respectively; chloroform is the solvent with tetramethylsilane as the internal standard unless otherwise noted. Mass spectra were recorded on a GC-MS spectrometer at an ionization voltage of 70 eV equipped with a DB-WAX capillary column (internal diameter: 0.25 mm, length: 30 m). Elemental analyses were performed with a Vario EL elemental analyzer. High-resolution mass spectroscopy (HRMS) images were obtained from a JEOL JMS-700 instrument (EI). Silica gel (300–400 mesh) was used for flash column chromatography, by eluting (unless otherwise stated) with an ethyl acetate/petroleum ether (PE) (60–90 °C) mixture.
General Procedure for the Preparation of α-Iminonitriles
A mixture of 2-aminopyridine (0.2 mmol), nitroalkene (0.2 mmol), and Ce(OTf)3 (10 mol %) in toluene (1.5 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 120 °C for 10 min. After the reaction is complete, water (5 mL) was added and the solution was extracted with ethyl acetate (3 × 5 mL); the combined extract was dried with anhydrous MgSO4. The solvent was removed, and the residue was separated by column chromatography to give the pure sample.
(Z)-N-(Pyridin-2-yl)benzimidoyl Cyanide (3a)7
Yellow solid (38 mg, 92% yield); Rf = 0.38 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.61–8.59 (m, 1H), 8.24–8.21 (m, 2H), 7.86–7.82 (m, 1H), 7.64–7.59 (m, 1H), 7.56–7.52 (m, 2H), 7.30–7.26 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 159.2, 148.9, 141.1, 138.2, 133.6, 133.3, 129.0, 128.7, 122.9, 118.3, 111.4. MS (EI) m/z: 206, 181, 154, 127, 104, 78, 63, 51, 28.
(Z)-N-(4-Methylpyridin-2-yl)benzimidoyl Cyanide (3b)7
Yellow solid (36 mg, 82% yield); Rf = 0.39 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 4.8 Hz, 1H), 8.23–8.20 (m, 2H), 7.63–7.59 (m, 1H), 7.55–7.51 (m, 2H), 7.10–7.08 (m, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 159.4, 149.7, 148.5, 141.0, 133.7, 133.2, 129.0, 128.6, 123.9, 118.7, 111.5, 21.0. (EI) m/z: 220, 195, 168, 141, 114, 92, 77, 65, 39, 28.
(Z)-N-(5-Methylpyridin-2-yl)benzimidoyl Cyanide (3c)
Yellow solid (37 mg, 84% yield); Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 2.0 Hz, 1H), 8.23–8.20 (m, 2H), 7.65–7.57 (m, 2H), 7.54–7.50 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 156.7, 149.0, 140.2, 138.7, 133.8, 133.0, 129.1, 128.9, 128.6, 118.3, 111.8, 18.1. MS (EI) m/z: 220, 195, 168, 141, 114, 92, 77, 65, 39, 28. Anal. calcd for C14H11N3: C, 76.00; H, 5.01; N, 18.99; found: C, 75.68; H, 5.12; N, 18.83.
(Z)-N-(6-Methylpyridin-2-yl)benzimidoyl Cyanide (3d)
Yellow solid (35 mg, 79% yield); Rf = 0.44 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.23–8.20 (m, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.61–7.57 (m, 1H), 7.54–7.49 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 158.6, 158.2, 140.9, 138.4, 133.6, 133.1, 128.9, 128.6, 122.3, 114.7, 111.3, 23.8. MS (EI) m/z: 220, 195, 168, 141, 114, 92, 77, 65, 39, 28. HRMS (ESI): calcd for C14H12N3 [M + H]+ 222.1025; found 222.1021.
(Z)-N-(5-Phenylpyridin-2-yl)benzimidoyl Cyanide (3e)
Yellow solid (36 mg, 64% yield); Rf = 0.40 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.85–8.84 (m, 1H), 8.27–8.24 (m, 2H), 8.05–8.02 (m, 1H), 7.66–7.60 (m, 3H), 7.57–7.49 (m, 4H), 7.45–7.41 (m, 1H), 7.39–7.37 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.8, 147.1, 140.4, 137.0, 136.5, 136.1, 133.8, 133.2, 129.1, 129.0, 128.7, 128.3, 127.0, 118.9, 111.7. MS (EI) m/z: 282, 257, 230, 202, 179, 154, 141, 127, 114, 102, 39, 28. HRMS (ESI): calcd for C19H14N3 [M + H]+ 284.1182; found 284.1185.
(Z)-N-(4-Methoxypyridin-2-yl)benzimidoyl Cyanide (3f)
Yellow solid (36 mg, 76% yield); Rf = 0.21 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J = 7.6 Hz, 1H), 8.66–8.63 (m, 2H), 7.58–7.51 (m, 3H), 7.11 (d, J = 2.8 Hz, 1H), 6.83–6.80 (m, 1H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 165.3, 160.9, 152.8, 149.3, 131.6, 131.5, 130.7, 128.7, 128.6, 110.9, 96.6, 56.3. MS (EI) m/z: 236, 222, 199, 184, 155, 134, 105, 93, 77, 39, 28. HRMS (ESI): calcd for C14H12N3O [M + H]+ 238.0975; found 238.0965.
(Z)-N-(Quinolin-2-yl)benzimidoyl Cyanide (3g)
Yellow solid (41 mg, 81% yield); Rf = 0.44 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.28–8.26 (m, 3H), 8.13 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.77–7.73 (m, 1H), 7.65–7.61 (m, 1H), 7.58–7.54 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 158.7, 147.1, 142.0, 138.6, 133.5, 130.3, 129.2, 129.0, 128.8, 128.7, 127.5, 127.3, 126.7, 116.6, 111.3. MS (EI) m/z: 257, 231, 204, 154, 128, 115, 101, 89, 77, 63, 51, 28. Anal. calcd for C17H11N3: C, 79.36; H, 4.31; N, 16.33; found: C, 79.02; H, 4.40; N, 16.21.
(Z)-N-(5-Fluoropyridin-2-yl)benzimidoyl Cyanide (3h)
Yellow solid (33 mg, 73% yield); Rf = 0.54 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 5.45 (d, J = 2.8 Hz, 1H), 8.24–8.21 (m, 2H), 7.64–7.60 (m, 1H), 7.58–7.52 (m, 3H), 7.34–7.30 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 160.1, 156.3 (d, J = 254 Hz), 140.8, 136.8 (d, J = 26 Hz), 133.7, 133.3, 129.0, 128.7, 125.2 (d, J = 20 Hz), 120.4 (d, J = 54 Hz), 111.6. MS (EI) m/z: 224, 199, 172, 114, 96, 76, 65, 51, 39, 28. Anal. calcd for C13H8FN3: C, 69.33; H, 3.58; N, 18.66; found: C, 69.12; H, 3.65; N, 18.79.
(Z)-N-(4-Chloropyridin-2-yl)benzimidoyl Cyanide (3i)
Yellow solid (37 mg, 77% yield); Rf = 0.50 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.50–8.48 (m, 1H), 8.23–8.20 (m, 2H), 7.65–7.61 (m, 1H), 7.57–7.53 (m, 2H), 7.29–7.28 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 160.1, 149.6, 145.6, 142.2, 133.7, 133.3, 129.1, 128.8, 123.0, 118.6, 111.1. MS (EI) m/z: 240, 215, 206, 189, 179, 154, 138, 112, 103, 76, 51, 39, 28. HRMS (ESI): calcd for C13H9ClN3 [M + H]+ 242.0480; found 242.0485.
(Z)-N-(5-Chloropyridin-2-yl)benzimidoyl Cyanide (3j)
Yellow solid (33 mg, 68% yield); Rf = 0.56 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.55–8.54 (m, 1H), 8.23–8.20 (m, 2H), 7.81–7.79 (m, 1H), 7.65–7.60 (m, 1H), 7.56–7.52 (m, 2H), 7.26–7.23 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.1, 147.6, 141.3, 138.0, 133.5, 133.5, 131.1, 129.0, 128.8, 1196, 111.4. MS (EI) m/z: 240, 206, 189, 154, 112, 88, 76, 51, 28. Anal. calcd for C13H8ClN3: C, 64.61; H, 3.34; N, 17.39; found: C, 64.29; H, 3.42; N, 17.52.
(Z)-N-(5-Bromopyridin-2-yl)benzimidoyl Cyanide (3k)7
Yellow solid (48 mg, 84% yield); Rf = 0.56 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.65–8.64 (m, 1H), 8.23–8.20 (m, 2H), 7.96–7.93 (m, 1H), 7.65–7.61 (m, 1H), 7.56–7.52 (m, 2H), 7.20–7.17 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.5, 149.5, 141.3, 140.8, 133.5, 133.5, 129.0, 128.8, 120.0, 119.5, 111.3. MS (EI) m/z: 286, 259, 233, 206, 154, 127, 103, 76, 51, 28.
(Z)-N-(5-Iodopyridin-2-yl)benzimidoyl Cyanide (3l)
Yellow solid (55 mg, 83% yield); Rf = 0.56 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.78 (s, 1H), 8.20 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.8, 154.8, 146.4, 141.1, 133.5, 133.3, 128.9, 128.7, 120.4, 111.2, 91.6. MS (EI) m/z: 332, 307, 204, 154, 127, 103, 77, 64, 51, 28. HRMS (ESI): calcd for C13H9IN3 [M + H]+ 333.9836; found 333.9843.
(Z)-Methyl 2-((Cyano(phenyl)methylene)amino)isonicotinate (3m)
Yellow solid (28 mg, 53% yield); Rf = 0.32 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.74–8.73 (m, 1H), 8.25–8.22 (m, 2H), 7.84–7.82 (m, 2H), 7.66–7.62 (m, 1H), 7.57–7.54 (m, 2H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 164.9, 160.0, 149.7, 141.9, 139.9, 133.6, 133.4, 129., 128.8, 122.0, 118.1, 111.2, 52.8. MS (EI) m/z: 264, 234, 206, 155, 127, 103, 77, 51, 38, 28. HRMS (ESI): calcd for C15H12N3O2 [M + H]+ 266.0924; found 266.0929.
(Z)-N-(5-(Trifluoromethyl)pyridin-2-yl)benzimidoyl Cyanide (3n)
Yellow solid (40 mg, 72% yield); Rf = 0.38 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.86–8.85 (m, 1H), 8.24–8.21 (m, 2H), 8.07–8.04 (m, 1H), 7.67–7.63 (m, 1H), 7.58–7.54 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 161.9, 146.4 (d, J = 4.0 Hz), 142.8, 135.6, (d, J = 4.0 Hz), 134.0, 133.0, 129.1, 129.0, 127.2, 123.3 (d, J = 271.0 Hz), 117.6, 110.8. MS (EI) m/z: 274, 256, 222, 146, 126, 88, 69, 51, 39, 28. Anal. calcd for C14H8F3N3: C, 61.09; H, 2.93; N, 15.27; found: C, 60.82; H, 2.99; N, 15.44.
(Z)-N-(5-Chloro-3-iodopyridin-2-yl)benzimidoyl Cyanide (3o)
Yellow solid (58 mg, 80% yield); Rf = 0.65 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 2.4 Hz, 1H), 8.29–8.23 (m, 3H), 7.67–7.62 (m, 1H), 7.58–7.54 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 156.9, 146.9, 146.7, 141.6, 133.8, 133.2, 130.6, 129.1, 129.1, 110.9, 90.6. MS (EI) m/z: 366, 341, 240, 204, 188, 153, 111, 88, 51, 28. HRMS (ESI): calcd for C13H8ClIN3 [M + H]+ 367.9446; found 367.9447.
(Z)-N-(3,5-Dibromo-4-methylpyridin-2-yl)benzimidoyl Cyanide (3p)
Yellow solid (49 mg, 66% yield); Rf = 0.65 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1H), 8.27–8.24 (m, 2H), 7.67–7.62 (m, 1H), 7.57–7.54 (m, 2H), 2.66 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 156.2, 148.9, 148., 142.1, 133.8, 133.3, 129.1, 129.0, 121.5, 118.0, 110.9, 23.5. MS (EI) m/z: 377, 352, 298, 248, 218, 167, 115, 88, 63, 39, 27. HRMS (ESI): calcd for C14H10Br2N3 [M + H]+ 377.9236; found 377.9245.
(Z)-N-(3-Bromo-5-iodo-4-methylpyridin-2-yl)benzimidoyl Cyanide (3q)
Yellow solid (51 mg, 60% yield); Rf = 0.67 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1H), 8.28–8.26 (m, 2H), 7.66–7.62 (m, 1H), 7.56 (t, J = 7.6 Hz, 2H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 158.6, 152.1, 149.4, 141.4, 133.7, 133.3, 129.1, 129.0, 120.0, 110.9, 97.4, 29.0. MS (EI) m/z: 425, 298, 218, 167, 115, 88, 63, 51, 28. HRMS (ESI): calcd for C14H10BrIN3 [M + H]+ 425.9097; found 425.9079.
(Z)-N-(3,5-Diiodo-6-methylpyridin-2-yl)benzimidoyl Cyanide (3r)
Yellow solid (48 mg, 51% yield); Rf = 0.74 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.55 (s, 1H), 8.29–8.26 (m, 2H), 7.66–7.61 (m, 1H), 7.57–7.53 (m, 2H), 2.73 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 159.6, 157.5, 156.1, 141.4, 133.7, 133.5, 129.1, 129.1, 110.9, 94.4, 87.3, 27.5. MS (EI) m/z: 472, 445, 342, 216, 167, 115, 88, 63, 39, 28. HRMS (ESI): calcd for C14H10I2N3 [M + H]+ 473.8959; found 473.8967.
(Z)-4-Methyl-N-(pyridin-2-yl)benzimidoyl Cyanide (4a)7
Yellow solid (34 mg, 78% yield); Rf = 0.46 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.59–8.58 (m, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.85–7.80 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.28–7.23 (m, 2H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 159.4, 148.9, 144.4, 141.1, 138.2, 131.2, 129.7, 128.7, 122.6, 118.1, 111.5, 21.7. MS (EI) m/z: 220, 206, 168, 154, 109, 89, 78, 65, 39, 28.
(Z)-4-(tert-Butyl)-N-(pyridin-2-yl)benzimidoyl Cyanide (4b)
Yellow solid (45 mg, 86% yield); Rf = 0.52 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.62–8.61 (m, 1H), 8.19–8.16 (m, 2H), 7.86–7.82 (m, 1H), 7.59–7.56 (m, 2H), 7.30–7.27 (m, 2H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3): δ = 159.3, 157.3, 148.8, 140.9, 138.1, 131.0, 128.6, 126.0, 122.6, 118.1, 111.5, 35.2, 31.0. MS (EI) m/z: 262, 248, 207, 110, 78, 51. Anal. calcd for C17H17N3: C, 77.54; H, 6.51; N, 15.96; found: C, 77.28; H, 6.64; N, 15.80.
(Z)-N-(Pyridin-2-yl)-[1,1′-biphenyl]-4-carbimidoyl Cyanide (4c)
Yellow solid (37 mg, 65% yield); Rf = 0.37 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.62–8.61 (m, 1H), 8.30 (d, J = 8.4 Hz, 2H), 7.87–7.83 (m, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 159.2, 148.9, 146.1, 140.7, 139.5, 138.2, 132.6, 129.2, 129.0, 128.4, 127.6, 127.2, 122.9, 118.4, 111.6. MS (EI) m/z: 282, 230, 206, 104, 78, 51. Anal. calcd for C19H13N3: C, 80.54; H, 4.62; N, 14.83; found: C, 80.26; H, 4.78; N, 14.75.
(Z)-4-Methoxy-N-(pyridin-2-yl)benzimidoyl Cyanide (4d)7
Yellow solid (39 mg, 82% yield); Rf = 0.26 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.58–8.56 (m, 1H), 8.18–8.14 (m, 2H), 7.83–7.79 (m, 1H), 7.24–7.20 (m, 2H), 7.03–6.98 (m, 2H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 163.9, 159.6, 148.8, 140.5, 138.2, 130.7, 126.5, 122.3, 117.9, 114.4, 111.5, 55.6. MS (EI) m/z: 236, 222, 193, 170, 142, 104, 78, 51, 39, 28.
(Z)-4-Fluoro-N-(pyridin-2-yl)benzimidoyl Cyanide (4e)
Yellow solid (39 mg, 87% yield); Rf = 0.40 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.59–8.58 (m, 1H), 8.29–8.21 (m, 2H), 7.84–7.80 (m, 1H), 7.29–7.24 (m, 2H), 7.23–7.18 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 255.0 Hz), 158.8, 148.8, 139.5, 138.2, 131.1 (d, J = 9.0 Hz), 129.9 (d, J = 3.0 Hz), 123.0, 118.5, 116.3 (d, J = 22.0 Hz), 111.3. MS (EI) m/z: 224, 199, 172, 146, 132, 104, 78, 51, 39, 28. Anal. calcd for C13H8FN3: C, 69.33; H, 3.58; N, 18.66; found: C, 69.07; H, 3.65; N, 18.74.
(Z)-4-Chloro-N-(pyridin-2-yl)benzimidoyl Cyanide (4f)7
Yellow solid (41 mg, 85% yield); Rf = 0.42 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.60–8.58 (m, 1H), 8.17–8.14 (m, 2H), 7.85–7.80 (m, 1H), 7.51–7.49 (m, 2H), 7.29–7.26 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 158.6, 148.8, 139.7, 139.5, 138.2, 132.1, 129.8, 129.3, 123.2, 118.7, 111.3. MS (EI) m/z: 240, 206, 189, 154, 114, 102, 78, 51, 39, 27.
(Z)-3-Chloro-N-(pyridin-2-yl)benzimidoyl Cyanide (4g)
Yellow solid (39 mg, 81% yield); Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.61–8.60 (m, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.87–7.82 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.32–7.29 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 158.4, 148.8, 139.3, 138.3, 135.3, 133.1, 130.2, 130.1, 128.2, 127.0, 123.4, 119.0, 111.3. MS (EI) m/z: 240, 206, 154, 114, 104, 78, 51. Anal. calcd for C13H8ClN3: C, 64.61; H, 3.34; N, 17.39; found: C, 64.38; H, 3.42; N, 17.28.
(Z)-2-Chloro-N-(pyridin-2-yl)benzimidoyl Cyanide (4h)
Yellow solid (28 mg, 58% yield); Rf = 0.43 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.63–8.62 (m, 1H), 7.88–7.84 (m, 2H), 7.54–7.47 (m, 2H), 7.45–7.41 (m, 1H), 7.33–7.30 (m, 1H), 7.29–7.27 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 158.7, 149.0, 139.7, 138.3, 133.5, 133.2, 132.7, 131.5, 131.1, 127.2, 123.3, 118.2, 111.6. MS (EI) m/z: 241, 208, 181, 104, 79, 51. Anal. calcd for C13H8ClN3: C, 64.61; H, 3.34; N, 17.39; found: C, 64.25; H, 3.45; N, 17.29.
(Z)-4-Bromo-N-(pyridin-2-yl)benzimidoyl Cyanide (4i)
Yellow solid (41 mg, 72% yield); Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.60 (d, J = 4.0 Hz, 1H), 8.11–8.07 (m, 2H), 7.86–7.82 (m, 1H), 7.69–7.65 (m, 2H), 7.31–7.27 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 158.7, 148.9, 139.8, 138.3, 132.6, 132.3, 130.0, 128.4, 123.2, 118.8, 111.3. MS (EI) m/z: 286, 206, 154, 114, 104, 78, 51. Anal. calcd for C13H8BrN3: C, 54.57; H, 2.82; N, 14.69; found: C, 54.31; H, 2.90; N, 14.83.
(Z)-4-Methoxy-N-(4-methoxypyridin-2-yl)benzimidoyl Cyanide (4j)
Yellow solid (40 mg, 75% yield); Rf = 0.14 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 5.6 Hz, 1H), 8.14–8.10 (m, 2H), 6.99–6.95 (m, 2H), 6.75–6.73 (m, 1H), 6.68 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 167.2, 163.7, 161.2, 149.6, 140.4, 130.6, 126.3, 114.3, 111.4, 109.2, 102.8, 55.4, 55.3. MS (EI) m/z: 266, 252, 238, 229, 214, 135, 104, 77, 64, 40, 28. HRMS (ESI): calcd for C15H14N3O2 [M + H]+ 268.1081; found 268.1092.
(Z)-4-Fluoro-N-(6-methylpyridin-2-yl)benzimidoyl Cyanide (4k)
Yellow solid (37 mg, 78% yield); Rf = 0.57 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.26–8.21 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.23–7.19 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 255.0 Hz), 158.3 (d, J = 9.0 Hz), 139.4, 138.4, 131.0 (d, J = 9.0 Hz), 130.1 (d, J = 3.0 Hz), 122.5, 116.3, 116.1, 115.0, 111.3, 23.8. MS (EI) m/z: 239, 212, 186, 132, 118, 106, 91, 65, 39, 27. HRMS (ESI): calcd for C14H11FN3 [M + H]+ 240.0932; found 240.0946.
(Z)-4-Fluoro-N-(4-methylpyridin-2-yl)benzimidoyl Cyanide (4l)
Yellow solid (39 mg, 81% yield); Rf = 0.44 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 4.8 Hz, 1H), 8.25–8.20 (m, 2H), 7.25–7.19 (m, 2H), 7.09 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 254.0 Hz), 159.1, 149.7, 148.5, 139.5, 131.0 (d, J = 10.0 Hz), 130.1 (d, J = 3 Hz), 124.1, 118.9, 116.3 (d, J = 22.0 Hz), 111.4, 21.0. MS (EI) m/z: 238, 213, 187, 172, 132, 118, 92, 65, 39, 27. Anal. calcd for C14H10FN3: C, 70.28; H, 4.21; N, 17.56; found: C, 69.96; H, 4.32; N, 17.71.
(Z)-4-Chloro-N-(4-methylpyridin-2-yl)benzimidoyl Cyanide (4m)7
Yellow solid (41 mg, 80% yield); Rf = 0.51 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 4.8 Hz, 1H), 8.15–8.12 (m, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 158.7, 149.7, 148.4, 139.6, 139.4, 132.2, 129.7, 129.2, 124.2, 119.2, 111.3, 20.9. MS (EI) m/z: 254, 220, 203, 168, 114, 92, 65, 39, 27.
(Z)-4-Chloro-N-(5-phenylpyridin-2-yl)benzimidoyl Cyanide (4n)
Yellow solid (41 mg, 65% yield); Rf = 0.55 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.8 Hz, 2H), 8.05–8.03 (m, 1H), 7.65–7.63 (m, 2H), 7.54–7.49 (m, 4H), 7.43 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.3, 147.1, 139.7, 138.9, 136.9, 136.5, 132.4, 129.9, 129.3, 129.2, 129.1, 128.4, 127.0, 119.4, 111.6. MS (EI) m/z: 317, 291, 282, 206, 168, 112, 76, 63, 51, 28. HRMS (ESI): calcd for C19H13ClN3 [M + H]+ 318.0793; found 318.0796.
(Z)-N-(5-Fluoropyridin-2-yl)-4-methoxybenzimidoyl Cyanide (4o)
Yellow solid (32 mg, 63% yield); Rf = 0.36 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 3.2 Hz, 1H), 8.18–8.14 (m, 2H), 7.55–7.50 (m, 1H), 7.28–7.24 (m, 1H), 7.03–7.00 (m, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 163.9, 158.6 (d, J = 255.0 Hz), 155.4, 140.1, 136.6 (d, J = 26.0 Hz), 130.8, 126.6 (d, J = 3.0 Hz), 125.1 (d, J = 20.0 Hz), 119.9 (d, J = 5.0 Hz), 114.4, 111.6, 55.6. MS (EI) m/z: 254, 240, 211, 160, 96, 76, 63, 51, 28. HRMS (ESI): calcd for C14H11FN3O [M + H]+ 256.0881; found 256.0860.
(Z)-N-(4-Chloropyridin-2-yl)-4-methylbenzimidoyl Cyanide (4p)
Yellow solid (42 mg, 83% yield); Rf = 0.51 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.49–8.47 (m, 1H), 8.10–8.08 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.27–7.26 (m, 2H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 160.4, 149.6, 145.6, 144.9, 142.1, 130.9, 129.8, 1289, 122.8, 118.4, 111.2, 21.7. MS (EI) m/z: 254, 240, 220, 202, 168, 112, 76, 63, 51, 28. HRMS (ESI): calcd for C14H11ClN3 [M + H]+ 256.0636; found 256.0645.
(Z)-N-(5-Bromopyridin-2-yl)-4-methylbenzimidoyl Cyanide (4q)7
Yellow solid (48 mg, 81% yield); Rf = 0.59 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.94–7.91 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 157.8, 149.9, 144.7, 141.3, 140.8, 131.0, 129.8, 128.8, 119.8, 119.2, 111.4, 21.7. MS (EI) m/z: 300, 284, 248, 220, 204, 168, 156, 140, 103, 76, 39, 27.
(Z)-N-(5-Bromopyridin-2-yl)-4-methoxybenzimidoyl Cyanide (4r)7
Yellow solid (44 mg, 70% yield); Rf = 0.40 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.62–8.62 (m, 1H), 8.18–8.14 (m, 2H), 7.93–7.90 (m, 1H), 7.15–7.12 (m, 1H), 7.04–7.00 (m, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 164.1, 158.0, 149.8, 140.7, 140.6, 130.9, 1265, 1197, 118.9, 114.5, 111.4, 55.6. MS (EI) m/z: 315, 300, 285, 248, 220, 168, 156, 103, 76, 39, 28.
(Z)-4-Methoxy-N-(5-(trifluoromethyl)pyridin-2-yl)benzimidoyl Cyanide (4s)
Yellow solid (39 mg, 64% yield); Rf = 0.40 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.83–8.83 (m, 1H), 8.19–8.16 (m, 2H), 8.04–8.01 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.05–7.01 (m, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 165.3, 163.2, 154.4, 145.3 (d, J = 4.0 Hz), 135.7 (q, J = 4.0 Hz), 131.9, 129.3, 125.8, 122.5, 120.8 (d, J = 271.0 Hz), 114.1, 113.3, 55.4. MS (EI) m/z: 305, 290, 274, 207, 155, 134, 77, 51, 28. HRMS (ESI): calcd for C15H11F3N3O [M + H]+ 306.0845; found 306.0856.
(Z)-N-(5-Bromopyridin-2-yl)-4-fluorobenzimidoyl Cyanide (4t)
Yellow solid (52 mg, 86% yield); Rf = 0.58 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.64–8.63 (m, 1H), 8.25–8.20 (m, 2H), 7.95–7.92 (m, 1H), 7.25–7.20 (m, 2H), 7.19–7.17 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 166.0 (d, J = 256.0 Hz), 157.2, 149.9, 140.8, 139.8, 131.2 (d, J = 9.0 Hz), 129.9 (d, J = 3.0 Hz), 120.2, 119.7, 116.4 (d, J = 22.0 Hz), 111.3. MS (EI) m/z: 303, 277, 251, 224, 197, 172, 158, 132, 103, 76, 50, 38, 26. HRMS (ESI): calcd for C13H8BrFN3 [M + H]+ 303.9880; found 303.9898.
(Z)-N-(5-Bromopyridin-2-yl)-4-chlorobenzimidoyl Cyanide (4u)
Yellow solid (50 mg, 79% yield); Rf = 0.60 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 2.0 Hz, 1H), 8.17–8.14 (m, 2H), 7.97–7.94 (m, 1H), 7.54–7.47 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.1, 149.7, 140.9, 140.1, 139.9, 132.1, 130.0, 129.4, 120.5, 119.9, 111.2. MS (EI) m/z: 319, 284, 240, 204, 188, 156, 114, 76, 50, 28. HRMS (ESI): calcd for C13H8BrClN3 [M + H]+ 319.9585; found 319.9598.
(Z)-4-Fluoro-N-(5-iodopyridin-2-yl)benzimidoyl Cyanide (4v)
Yellow solid (56 mg, 80% yield); Rf = 0.54 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.78 (d, J = 2.0 Hz, 1H), 8.25–8.20 (m, 2H), 8.13–8.10 (m, 1H), 7.24–7.19 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 165.8 (d, J = 253.0 Hz), 157.6, 154.9, 146.5, 139.7, 131.2 (d, J = 9.0 Hz), 129.8 (d, J = 3.0 Hz), 120.6, 116.4 (d, J = 22.0 Hz), 111.2, 91.8. MS (EI) m/z: 351, 325, 299, 224, 204, 172, 145, 103, 77, 50, 26. Anal. calcd for C13H7FIN3: C, 44.47; H, 2.01; N, 11.97; found: C, 44.15; H, 2.13; N, 12.16.
(Z)-4-Chloro-N-(5-iodopyridin-2-yl)benzimidoyl Cyanide (4w)
Yellow solid (54 mg, 74% yield); Rf = 0.58 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3): δ = 8.79 (d, J = 1.6 Hz, 1H), 8.17–8.11 (m, 3H), 7.53–7.50 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 157.5, 154.9, 146.5, 140.1, 139.8, 132.0, 130.0, 129.4, 120.8, 111.2, 92.0. MS (EI) m/z: 365, 332, 240, 204, 188, 161, 114, 77, 50, 28. HRMS (ESI): calcd for C13H8ClIN3 [M + H]+ 367.9446; found 367.9458.
Acknowledgments
The authors are grateful for the financial support from the NSFC (21562002), the NSF of Jiangxi Province (20171ACB21048), and the NSF of Jiangxi Provincial Education Department (GJJ160924). This research was also partially supported by the Open Fund of the Key Laboratory of Functional Molecular Engineering of Guangdong Province, South China University of Technology (2017kf04).
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02214.
The authors declare no competing financial interest.
Supplementary Material
References
- a Gualtierotti J.-B.; Schumacher X.; Fontaine P.; Masson G.; Wang Q.; Zhu J. Amidation of aldehydes and alcohols through α-iminonitriles and a sequential oxidative three-component strecker reaction/thio-michael addition/alumina-promoted hydrolysis process to access β-mercaptoamides from aldehydes, amines, and thiols. Chem. - Eur. J. 2012, 18, 14812–14819. 10.1002/chem.201202291. [DOI] [PubMed] [Google Scholar]; b Chen Z.-B.; Zhang F.-L.; Yuan Q.; Chen H.-F.; Zhu Y.-M.; Shen J.-K. α-Iminonitrile: a new cyanating agent for the palladium catalyzed C-H cyanation of arenes. RSC Adv. 2016, 6, 64234–64238. 10.1039/C6RA14512D. [DOI] [Google Scholar]; c Li J.; Okuda Y.; Zhao J.; Mori S.; Nishihara Y. Skeletal rearrangement of cyano-substituted iminoisobenzofurans into alkyl 2-cyanobenzoates catalyzed by B(C6F5)3. Org. Lett. 2014, 16, 5220–5223. 10.1021/ol5026519. [DOI] [PubMed] [Google Scholar]; d You X.; Xie X.; Sun R.; Chen H.; Li S.; Liu Y. Titanium-mediated cross-coupling reactions of 1,3-butadiynes with α-iminonitriles to 3-aminopyrroles: observation of an imino aza-Nazarov cyclization. Org. Chem. Front. 2014, 1, 940–946. 10.1039/C4QO00159A. [DOI] [Google Scholar]; e Roychowdhury A.; Kumar V. V.; Bhaduri A. P. Diarylimidoylcyanides, an attractive class of intermediate: Novel synthesis of α-anilino-β-nitroenamines, N,N’-disubstituted amidines and substituted phenylglyoxate. Synth. Commun. 2006, 36, 715–727. 10.1080/00397910500446902. [DOI] [Google Scholar]
- a Amos D. T.; Renslo A. R.; Danheiser R. L. Intramolecular [4+2] cycloadditions of iminoacetonitriles: A new class of azadienophiles for hetero Diels-Alder reactions. J. Am. Chem. Soc. 2003, 125, 4970–4971. 10.1021/ja034629o. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Fontaine P.; Masson G.; Zhu J. Synthesis of pyrroles by consecutive multicomponent reaction/[4+1] cycloaddition of α-iminonitriles with isocyanides. Org. Lett. 2009, 11, 1555–1558. 10.1021/ol9001619. [DOI] [PubMed] [Google Scholar]; c Maloney K. M.; Danheiser R. L. Total synthesis of quinolizidine alkaloid (−)-217A. Application of iminoacetonitrile cycloadditions in organic synthesis. Org. Lett. 2005, 7, 3115–3118. 10.1021/ol051185n. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Rondla N. R.; Ogilvie J. M.; Pan Z.; Douglas C. J. Palladium catalyzed intramolecular acylcyanation of alkenes using α-iminonitriles. Chem. Commun. 2014, 50, 8974–8977. 10.1039/C4CC04068F. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Motorina I. A.; Fowler F. W.; Grierson D. S. Intramolecular Diels-Alder reaction of N-alkyl-2-cyano-1-azadienes: A study of the eschenmoser cycloreversion of dihydrooxazines as a route to N-alkyl-2-cyano-1-azadienes. J. Org. Chem. 1997, 62, 2098–2105. 10.1021/jo9614046. [DOI] [PubMed] [Google Scholar]; f Sisti N. J.; Zeller E.; Grierson D. S.; Fowler F. W. Intramolecular Diels-Alder reaction of 2-cyano-1-aza-1,3-butadienes. J. Org. Chem. 1997, 62, 2093–2097. 10.1021/jo961403d. [DOI] [PubMed] [Google Scholar]; g Sisti N. J.; Motorina I. A.; Dau M.-E. T. H.; Riche C.; Fowler F. W.; Grierson D. S. Reactivity of N-Phenyl-1-aza-2-cyano-1, 3-butadienes in the Diels-Alder reaction. J. Org. Chem. 1996, 61, 3715–3728. 10.1021/jo9520607. [DOI] [PubMed] [Google Scholar]; h Mir N. A.; Choudhary S.; Ramaraju P.; Singh D.; Kumar I. Microwave assisted aminocatalyzed [3+2] annulation between α-iminonitriles and succinaldehyde: synthesis of pyrrole-3-methanols and related polycyclic ring systems. RSC Adv. 2016, 6, 39741–39749. 10.1039/C6RA06831F. [DOI] [Google Scholar]
- a Jursic B. S.; Douelle F.; Bowdy K.; Stevens E. D. A new facile method for preparation of heterocyclic α-iminonitriles and α-oxoacetic acids from heterocyclic aldehydes, p-aminophenol, and sodium cyanide. Tetrahedron Lett. 2002, 43, 5361–5365. 10.1016/S0040-4039(02)00799-2. [DOI] [Google Scholar]; b Takahashi K.; Kimura S.; Ogawa Y.; Yamada K.; Iida H. A convenient synthesis of α,β-disubstituted cinnamonitriles (1-anilino-2-cyano-1,2-diphenylethenes). Synthesis 1978, 892–893. 10.1055/s-1978-24928. [DOI] [Google Scholar]; c Smith J. G.; Irwin D. C. α-Iminonitriles (imidoyl cyanides); their preparation using phase-transfer catalysis and their reductive dimerization. Synthesis 1978, 894–895. 10.1055/s-1978-24929. [DOI] [Google Scholar]; d Maruoka K.; Miyazaki T.; Ando M.; Matsumura Y.; Sakane S.; Hattori K.; Yamamoto H. Organoaluminum-promoted Beckmann rearrangement of oxime sulfonates. J. Am. Chem. Soc. 1983, 105, 2831–2843. 10.1021/ja00347a052. [DOI] [Google Scholar]; e Li L.; Wang Q.; Liu P.; Meng H.; Kan X.-L.; Liu Q.; Zhao Y.-L. DBU-mediated metal-free oxidative cyanation of α-amino carbonyl compounds: using molecular oxygen as the oxidant. Org. Biomol. Chem. 2016, 14, 165–171. 10.1039/C5OB01690H. [DOI] [PubMed] [Google Scholar]; f Li J.; Noyori S.; Nakajima K.; Nishihara Y. New entry to the synthesis of α-iminonitriles by Lewis acid mediated isomerization of cyano-substituted iminoisobenzofurans prepared by palladium-catalyzed three-component coupling of arynes, isocyanides, and cyanoformates. Organometallics 2014, 33, 3500–3507. 10.1021/om500408h. [DOI] [Google Scholar]
- Fontaine P.; Chiaroni A.; Masson G.; Zhu J. One-pot three-component synthesis of α-iminonitriles by IBX/TBAB-mediated oxidative strecker reaction. Org. Lett. 2008, 10, 1509–1512. 10.1021/ol800199b. [DOI] [PubMed] [Google Scholar]
- Chen Z.-B.; Zhang Y.; Yuan Q.; Zhang F.-L.; Zhu Y.-M.; Shen J.-K. Palladium-catalyzed synthesis of α-iminonitriles from aryl halides via isocyanide double insertion reaction. J. Org. Chem. 2016, 81, 1610–1616. 10.1021/acs.joc.5b02777. [DOI] [PubMed] [Google Scholar]
- Chen F.; Huang X.; Cui Y.; Jiao N. Direct transformation of methyl imines to α-iminonitriles under mild and transition-metal-free conditions. Chem. - Eur. J. 2013, 19, 11199–11202. 10.1002/chem.201301933. [DOI] [PubMed] [Google Scholar]
- Kalbandhe A. H.; Kavale A. C.; Karade N. N. Ring-opening reaction of imidazo[1,2-a]pyridines using (diacetoxyiodo)benzene and NaN3: The synthesis of α-iminonitriles. Eur. J. Org. Chem. 2017, 1318–1322. 10.1002/ejoc.201601480. [DOI] [Google Scholar]
- For selective reviews, see:; a Corma A.; Garcia H. Lewis acids: from conventional homogeneous to green homogeneous and heterogeneous catalysis. Chem. Rev. 2003, 103, 4307–4365. 10.1021/cr030680z. [DOI] [PubMed] [Google Scholar]; b Kobayashi S.; Sugiura M.; Kitagawa H.; Lam W. W.-L. Rare-earth metal triflates in organic synthesis. Chem. Rev. 2002, 102, 2227–2302. 10.1021/cr010289i. [DOI] [PubMed] [Google Scholar]; c Shibasaki M.; Yoshikawa N. Lanthanide complexes in multifunctional asymmetric catalysis. Chem. Rev. 2002, 102, 2187–2209. 10.1021/cr010297z. [DOI] [PubMed] [Google Scholar]; d Kobayashi S.; Manabe K. Development of novel Lewis acid catalysts for selective organic reactions in aqueous media. Acc. Chem. Res. 2002, 35, 209–217. 10.1021/ar000145a. [DOI] [PubMed] [Google Scholar]
- For recent examples, see:; a Veeraswamy V.; Goswami G.; Mukherjee S.; Ghosh K.; Saha M. L.; Sengupta A.; Ghorai M. K. Memory of chirality concept in asymmetric intermolecular michael addition of α-amino ester enolates to enones and nitroalkenes. J. Org. Chem. 2018, 83, 1106–1115. 10.1021/acs.joc.7b02315. [DOI] [PubMed] [Google Scholar]; b Feng B.; Lu L.-Q.; Chen J.-R.; Feng G.; He B.-Q.; Lu B.; Xiao W.-J. Umpolung of imines enables catalytic asymmetric regio-reversed [3 + 2] cycloadditions of iminoesters with nitroolefins. Angew. Chem., Int. Ed. 2018, 57, 5888–5892. 10.1002/anie.201802492. [DOI] [PubMed] [Google Scholar]; c Guerrero-Corella A.; Esteban F.; Iniesta M.; Martin-Somer A.; Parra M.; Diaz-Tendero S.; Fraile A.; Aleman J. 2-Hydroxybenzophenone as a chemical auxiliary for the activation of ketiminoesters for highly enantioselective addition to nitroalkenes under bifunctional catalysis. Angew. Chem., Int. Ed. 2018, 57, 5350–5354. 10.1002/anie.201800435. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Miyamura H.; Nishino K.; Yasukawa T.; Kobayashi S. Rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes: reaction mechanism and development of homogeneous and heterogeneous catalysts. Chem. Sci. 2017, 8, 8362–8372. 10.1039/C7SC03025H. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Olaizola I.; Campano T. E.; Iriarte I.; Vera S.; Mielgo A.; Garcia J. M.; Odriozola J. M.; Oiarbide M.; Palomo C. a-Hydroxy ketones as masked ester donors in Brønsted base catalyzed conjugate additions to nitroalkenes. Chem. - Eur. J. 2018, 24, 3893–3901. 10.1002/chem.201705968. [DOI] [PubMed] [Google Scholar]
- For recent examples, see:; a Chen Z.; Zhang Y.; Nie J.; Ma J.-A. Transition-metal-free [3 + 2] cycloaddition of nitroolefins and diazoacetonitrile: A facile access to multisubstituted cyanopyrazoles. Org. Lett. 2018, 20, 2120–2124. 10.1021/acs.orglett.8b00729. [DOI] [PubMed] [Google Scholar]; b Fuchs P. J. W.; Zeitler K. Nitroalkenes as latent 1,2-biselectrophiles – A multicatalytic approach for the synthesis of 1,4-diketones and their application in a four-step one-pot reaction to polysubstituted pyrroles. J. Org. Chem. 2017, 82, 7796–7805. 10.1021/acs.joc.7b00830. [DOI] [PubMed] [Google Scholar]; c Bai D.; Jia Q.; Xu T.; Zhang Q.; Wu F.; Ma C.; Liu B.; Chang J.; Li X. Rhodium(III)-catalyzed C–H activation of nitrones and annulative coupling with nitroalkenes. J. Org. Chem. 2017, 82, 9877–9884. 10.1021/acs.joc.7b01574. [DOI] [PubMed] [Google Scholar]; d Ghosh M.; Mishra S.; Hajra A. Regioselective synthesis of multisubstituted furans via copper-mediated coupling between ketones and β-nitrostyrenes. J. Org. Chem. 2015, 80, 5364–5368. 10.1021/acs.joc.5b00704. [DOI] [PubMed] [Google Scholar]; e Sathish M.; Chetna J.; Krishna N. H.; Shankaraiah N.; Alarifi A.; Kamal A. Iron-mediated one-pot synthesis of 3,5-diarylpyridines from β-nitrostyrenes. J. Org. Chem. 2016, 81, 2159–2165. 10.1021/acs.joc.5b02712. [DOI] [PubMed] [Google Scholar]; f Li J.; Yang S.; Wu W.; Jiang H. Recent advances in Pd-catalyzed cross-coupling reaction in ionic liquids. Eur. J. Org. Chem. 2018, 1284–1306. 10.1002/ejoc.201701509. [DOI] [Google Scholar]
- Yan R.-L.; Yan H.; Ma C.; Ren Z.-Y.; Gao X.-A.; Huang G.-S.; Liang Y.-M. Cu(I)-catalyzed synthesis of imidazo[1,2-a]pyridines from aminopyridines and nitroolefins using air as the oxidant. J. Org. Chem. 2012, 77, 2024–2028. 10.1021/jo202447p. [DOI] [PubMed] [Google Scholar]
- Monir K.; Bagdi A. K.; Ghosh M.; Hajra A. Unprecedented catalytic activity of Fe(NO3)3·9H2O: Regioselective synthesis of 2-nitroimidazopyridines via oxidative amination. Org. Lett. 2014, 16, 4630–4633. 10.1021/ol502218u. [DOI] [PubMed] [Google Scholar]
- Santra S.; Bagdi A. K.; Majee A.; Hajra A. Iron(III)-ctalyzed cscade reaction between nitroolefins and 2-aminopyridines: Synthesis of imidazo[1,2-a]pyridines and easy access towards zolimidine. Adv. Synth. Catal. 2013, 355, 1065–1070. 10.1002/adsc.201201112. [DOI] [Google Scholar]
- Chen Z.; Wen X.; Qian Y.; Liang P.; Liu B.; Ye M. Ce(III)-catalyzed highly efficient synthesis of pyridyl benzamides from aminopyridines and nitroolefins without external oxidants. Org. Biomol. Chem. 2018, 16, 1247–1251. 10.1039/C7OB03113K. [DOI] [PubMed] [Google Scholar]
- Chen X.; Hao X.-S.; Goodhue C. E.; Yu J.-Q. Cu(II)-catalyzed functionalizations of aryl C-H bonds using O2 as an oxidant. J. Am. Chem. Soc. 2006, 128, 6790–6791. 10.1021/ja061715q. [DOI] [PubMed] [Google Scholar]
- www.ccdc.cam.ac.uk/data_request/cif.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.