Unexpected cyclization of ortho-nitrochalcones into 2-alkylideneindolin-3-ones

Abstract

An original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from ortho-nitrochalcones is described. The featured transformation is a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer–Drewson reaction.

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Introduction

It would be hard to overstate the importance of 2-alkylideneindolin-3-one derivatives in modern medicinal chemistry. The bis-indole indirubin, a main component of “Tyrian purple” dye, is also a known active component of a traditional Chinese herbal medicine, while its numerous synthetic derivatives show potent and highly selective pharmacological inhibition of glycogen synthase kinases and cycline-dependent kinases.^1–6 These molecules induce apoptosis of human cancer cells and have promising potential for applications in the treatment of several neurodegenerative conditions, such as Alzheimer's disease.^1–6 Indirubin, as well as other related dyes, can be easily prepared via base-assisted condensation of ortho-nitrobenzaldehydes with acetone according to the classical Baeyer–Drewson reaction.^7–9 2-Alkylideneindolin-3-one derivatives possessing a single indoline subunit (or two remotely positioned subunits) also occur in nature and also exhibit a wide spectrum of important biological properties (Fig. 1).^10–17 Normally, preparation of such compounds relies heavily on the chemistry of isatins, which makes synthetic approaches to certain substitution patterns hardly accessible. An alternative synthetic platform for assembling indoline alkaloids and related non-natural, biologically active target molecules has also emerged, relying on the chemistry of 2-alkylidene-3-oxindoles.^18–23 Various synthetic approaches to these synthons have been developed based on the aldol condensation of 3H-indol-3-ones with carbonyl compounds (path A, Scheme 1),^24–28 transition metal-catalyzed carbonylative coupling of ortho-iodoanilines to acetylenes (path B, Scheme 1),^29–32 and cascade reactions of anilines with α-ketoesters involving an electrophilic aromatic substitution step (path C, Scheme 1)^10,33 Herein we wish to report on our recent serendipitous discovery of the unexpected one-pot cascade transformation of ortho-nitrochalcones 1 via a Baeyer–Drewson-like pathway, but affording 2-alkylideneindolin-3-ones 2 rather than indigo-like dimers (Scheme 1).

Fig. 1 Biologically active 2-alkylideneindolin-3-ones.

Scheme 1 Synthetic approaches to 2-alkylideneindolin-3-ones.

Results and discussion

In the frame of our ongoing project dealing with the synthesis of nitrogen-based heterocyclic compounds and evaluation of their biological activity, we were interested in the preparation of a series of minaprine analogs 4,^34–37 possessing an additional amino-group handle at C-2′.^38,39 To tackle this task, we decided to employ a routine cyclocondensation of hydrazine with 3-cyanoketone 3 bearing an ortho-nitro group, which was supposed to be routinely reduced and properly modified in subsequent steps (Scheme 2). We planned to access precursor 3 via conjugate addition of hydrogen cyanide to α,β-unsaturated ketones 1.^40–43 Although hydrocyanation of conjugate carbonyl compounds is unknown for specific substrates of type 1, possessing ortho-nitro functionality, we did not initially expect any problems with this well-established chemistry.

Scheme 2 Unexpected assembly of 2-benzylideneindolin-3-one 2a.

To evaluate the planned synthetic route, chalcone 1aa – prepared by aldol condensation of ortho-nitroacetophenone (6a) with benzaldehyde (7a) – was treated with KCN in EtOH in the presence of acetic acid (1.3 equiv.) at room temperature. Unexpectedly, this reaction provided only marginal yields, which was initially attributed to poor solubility of 1aa in ethanol. To address this situation, we tried to perform this reaction in methanol at elevated temperature, which also failed (Table 1, entry 1). In one of the trial experiments, a mixture of chalcone 1aa and KCN was pre-heated in MeOH to reflux prior to addition of the acetic acid. To our great surprise, within 15 min the reaction mixture turned emerald green. The starting material (m/z 276, M + Na) disappeared, but the expected product 3aa (m/z 303, M + Na) did not form, while cyclic hydroxylamine product 5aa was detected in MS (m/z 285, M + Na) and NMR spectra of the crude reaction mixture instead. The following treatment with acetic acid in boiling methanol led to the conversion of 5aa into indoline 2aa (m/z 269, M + Na), which was isolated in 57% yield (entry 2) as a yellowish-orange crystalline solid with properties identical to those reported in the literature.⁴⁴ Next, we attempted to increase the loading of KCN, which had a significant positive effect – although not dramatic (entry 3). Nearly the same efficiency was achieved in a test in which the second stage of the reaction was carried out at room temperature for 12 h (entry 4). The best results were obtained in the experiment involving the initial treatment of chalcone 1aa with KCN in methanol in the presence of water (entry 5), which improves the solubility of cyanide. It is important to mention, that ideal homogenization of the reaction mixture seems to be crucial for achieving good yields of 2aa. Indeed, KCN reagent did not dissolve in the mixtures when the test reactions were carried out in THF or acetone even in the presence of additional water. In these cases, product 2aa did not form at all (Table 1, entries 6–9). The reaction in polar aprotic solvents, such as DMSO and DMF, was also tested. It was found that the outcome of these reactions also improves in the presence of water, but the overall performance in these solvents remains relatively poor (entries 10–13).

Table 1 Optimization of the reaction condition towards formation of product 2aa

#	KCN, mg	Solvent, 1.5 mL	H2O, mg	Yield of 2aa^a, %
a NMR yields are reported.b All reagents were mixed in one pot and the reaction was carried out at reflux for 1 h.c The second stage of the reaction was carried out at RT for 12 h.d KCN is insoluble in this reaction mixture.
1	65	MeOH	0	0^b
2	40	MeOH	0	57
3	65	MeOH	0	65
4	40	MeOH	0	62^c
5	40	MeOH	200	78
6	40	THF	0	0^d
7	40	THF	200	0^d
8	40	Acetone	0	0^d
9	40	Acetone	200	0^d
10	40	DMSO	0	24
11	40	DMSO	200	50
12	40	DMF	0	0^d
13	40	DMF	200	44

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With optimized conditions in hand we decided to evaluate the scope of the reaction of various chalcones and with respect to the nature of substituent R¹ (originated from an aldehyde precursor). To this end, a series of chalcones 1 were prepared from o-nitroacetophenones 6 and aldehydes 7. These chalcones were subjected to the reaction with KCN under the optimized reaction conditions. The results are presented in Scheme 3. The preparative reaction of chalcone 1aa proceeded uneventfully affording product 1aa in 76% isolated yield (entry 1). Reactions of chalcones 1ab–1ae, derived from benzaldehydes 7b–e bearing alkyl substituents also proceeded smoothly to yield the corresponding indolines 2ab–2ae in good yields (Scheme 3, entries 2–5). Next, the tolerance to substitution with halogenes was tested. We were pleased to find that the corresponding products 2af–2aj formed in good to high yields (entries 6–10). The reactivity of chalcones 1ak and 2ak derived from electron-rich benzaldehydes 7k,l was also examined (entries 11 and 12). These materials also reacted smoothly, although isolation of product 2al bearing NMe₂ substituent proved to be more challenging due to the partial decomposition, which reduced the overall efficiency of the process (entry 12). The same problem was encountered in the attempt to employ pyridine carboxaldehyde derivatives 1am–1ao. The corresponding indolines 2am–2ao formed smoothly, but were isolated in moderate yields (entries 13–15). Reaction of piperonal derivative 1ap was accompanied by a notable decomposition of the target product 2ap, which was isolated in quite marginal yield (entry 16). Such decomposition became much greater issue in the experiments involving chalcones 1aq and 1ar, derived from thiophene-2-carbaldehyde and hydrocinnamic aldehyde, respectively. The corresponding products 2aq and 2ar were not isolated (entries 17 and 18). Finally, the reaction of chalcone 1ba, derived from 1-(4,5-dimethoxy-2-nitrophenyl)ethan-1-one (6b) and benzaldehyde (7a), was also tested. The corresponding product 2ba was isolated in 51% yield (Scheme 3, entry 19), thus confirming the possibility for the installation of additional substituents onto the aromatic ring of the indoline. Formation of the (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitrile moiety was unambiguously confirmed by single crystal X-ray diffraction of compound 2ad (CCDC #1992506, Fig. 2).

Scheme 3 Preparation of (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles via featured cyanide-induced cyclization of chalcones.

Fig. 2 ORTEP drawing of crystal structure of compound 2ad (CCDC #1992506) showing 50% probability thermal ellipsoids and atom numbering scheme.

The putative mechanistic rationale proposed for the featured transformation is shown in Scheme 4. It is assumed that the reaction begins with the Michael-type addition of the CN-anion across the conjugate C=C bond of chalcone 1 to afford enolate 8. This enolate triggers a 5-exo-trig cyclization involving the ortho-nitro group in the substrate molecule. Mechanistically related to the Baeyer–Drewson reaction, this step affords cyclic nitronate 9, which should exist in equilibrium with tautomeric cyclic enolate form 10. Subsequent elimination of water would afford 3-oxo-3H-indole N-oxide 11, which should quickly transform into the thermodynamically more stable 1-hydroxy-2-methyleneindolin-3-one form 5. It should be pointed out, that this intermediate was detected in MS and ¹H NMR spectra of the crude reaction mixture involving chalcone 1aa (R = Ph). Evidently, the formation of this structure is responsible for the intense color of the reaction mixtures. Finally, upon acidification with acetic acid, emerald-green 5 is reduced into orange-red product 2. Although the precise mechanism of this reduction was not elucidated, we believe it could involve the methanol used as a solvent. Since the product 2 is an enamine, it should exist in tautomeric equilibrium between E and Z forms. Only E-tautomers were observed, suggesting that they are thermodynamically much more favored. This stereochemical outcome could be easily rationalized taking into account greater steric hindrance provided by aryl substituent as compared to nitrile functional group.

Scheme 4 Proposed mechanistic rationale.

In order to avoid utilization of highly toxic KCN reagent, other cyanide ion sources were also tested, such as Me₃SiCN and K₄[Fe(CN)₆]. In both cases, however, formation of the (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitrile products was not detected. Evidently, the reaction requires a high concentration of nucleophile, which cannot be achieved in the presence of reagents, slowly releasing free cyanide.

Conclusion

In conclusion, an unusual cascade cyclization triggered by the conjugate addition of the cyanide anion to ortho-nitrosubstituted chalcones was unexpectedly discovered. This novel transformation involves an intramolecular 5-exo-trig attack of an enolate on the electrophilic nitro-group, which is mechanistically related to the Baeyer–Drewson reaction. A series of (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles was efficiently, obtained in good to excellent yield.

Experimental part

General information. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance-III spectrometer (400 or 100 MHz, respectively) equipped with a BBO probe in CDCl₃ or DMSO-d₆ using TMS as an internal standard. High-resolution mass spectra were registered with a Bruker Maxis spectrometer (electrospray ionization, in MeCN solution, using HCO₂Na–HCO₂H for calibration). Melting points were measured with a Stuart smp30 apparatus. Unless specified otherwise, all reactions were performed in 5 mL round-bottomed flasks equipped with reflux condensers. The reaction progress and purity of isolated compounds were controlled by TLC on Silufol UV-254 plates, with hexanes/EtOAc mixtures used as eluents. 1-(4,5-Dimethoxy-2-nitrophenyl)ethan-1-one was prepared according to the known procedure⁴⁵ and had physical and spectral properties identical to those reported in literature. (E)-1-(2-Nitrophenyl)-5-phenylpent-2-en-1-one was obtained according to the known procedure and was identical to the material described in literature.⁴⁶ All other reagents and solvents were purchased from commercial vendors and used as received.

Preparation of chalcones

(E)-1-(2-Nitrophenyl)-3-phenylprop-2-en-1-one (1aa). This compound was prepared according to the known procedure⁴⁶ employing benzaldehyde (1a) (825 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.214 g (4.80 mmol, 96%), colorless solid, mp 124.1–126.0 °C, lit.⁴⁷ 130 °C, R_f 0.40 (EtOAc/Hex, 1 : 4). ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 7.3 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.50 (dd, J = 7.7, 4.2 Hz, 3H), 7.39 (d, J = 6.5 Hz, 3H), 7.24 (d, J = 15.9 Hz, 1H), 7.01 (d, J = 16.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 193.2, 146.9, 146.5, 136.5, 134.2, 134.1, 131.2, 130.7, 129.2 (2C), 129.0, 128.7 (2C), 126.4, 124.7; FTIR (KBr, cm⁻¹): 3741, 3298, 3092, 1647, 1531, 1340, 1277, 1107; HRMS (ES TOF) calc'd for C₁₅H₁₁NNaO₃ (M + Na)⁺ 276.0631, found 276.0634 (1.0 ppm).

(E)-1-(2-Nitrophenyl)-3-(o-tolyl)prop-2-en-1-one (1ab). This compound was prepared according to the known procedure⁴⁶ employing 2-methylbenzaldehyde (7b) (600 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.255 g (4.70 mmol, 94%), light yellow crystals, mp 95.0–96.2 °C. R_f 0.53 (EtOAc/Hex, 1 : 2); ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 7.7 Hz, 1H), 7.82–7.72 (m, 1H), 7.71–7.63 (m, 1H), 7.61–7.56 (m, 2H), 7.54 (dd, J = 7.5, 1.0 Hz, 1H), 7.33–7.14 (m, 3H), 6.91 (d, J = 16.1 Hz, 1H), 2.30 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.9, 147.0, 143.8, 138.2, 136.5, 134.1, 133.0, 131.0, 130.9, 130.8, 129.0, 127.1, 126.8, 126.6, 124.6, 19.7; FTIR (KBr, cm⁻¹): 2931, 2363, 1673, 1561, 1525, 1363, 1327, 1218, 1030; HRMS (ES TOF) calc'd for C₁₆H₁₃NNaO₃ (M + Na)⁺ 290.0788, found 290.0783 (1.6 ppm).

(E)-1-(2-Nitrophenyl)-3-(p-tolyl)prop-2-en-1-one (1ac). This compound was prepared according to the known procedure⁴⁶ employing 4-methylbenzaldehyde (7c) (600 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.295 g (4.85 mmol, 97%), colorless solid, mp 130.8–131.6 °C (EtOH), lit.⁴⁷ mp 134–135 °C, R_f 0.28 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.24–7.16 (m, 3H), 6.97 (d, J = 16.2 Hz, 1H), 2.37 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.2, 146.9, 146.7, 141.9, 136.6, 134.1, 131.3, 130.6, 129.9 (2C), 129.0, 128.7 (2C), 125.5, 124.7, 21.7; FTIR (KBr, cm⁻¹): 3067, 1668, 1591, 1524, 1364, 1320, 1230, 1210, 1029; HRMS (ES TOF) calc'd for C₁₆H₁₃N₁NaO₃ (M + Na)⁺ 290.0788, found 290.0790 (0.8 ppm).

3-(2-Fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1af). This compound was prepared according to the known procedure⁴⁶ employing 2-fluorobenzaldehyde (7f) (620 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.246 g (4.60 mmol, 92%), colorless crystals, mp 97.3–97.9 °C, R_f 0.46 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.1 Hz, 1H), 7.77 (dd, J = 7.4, 6.8 Hz, 1H), 7.72–7.62 (m, 1H), 7.59–7.47 (m, 2H), 7.41–7.33 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.13–7.00 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 193.0, 161.5 (d, J = 254.6 Hz), 146.8, 138.5 (d, J = 3.3 Hz), 136.2, 134.2, 132.7 (d, J = 8.9 Hz), 130.8, 129.1 (d, J = 2.5 Hz), 128.9, 128.3 (d, J = 5.9 Hz), 124.72 (d, J = 3.8 Hz), 124.68, 122.2 (d, J = 11.5 Hz), 116.3 (d, J = 21.7 Hz); FTIR (KBr, cm⁻¹): 3289, 3065, 1651, 1603, 1531, 1340, 1290, 1215; HRMS (ES TOF) calc'd for C₁₅H₁₀FNNaO₃ (M + Na)⁺ 294.0537, found 294.0538 (0.4 ppm).

3-(4-Fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ag). This compound was prepared according to the known procedure⁴⁶ employing 4-fluorobenzaldehyde (7g) (620 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.233 g (4.55 mmol, 91%), colorless solid, mp 99.1–100.5 °C, R_f 0.46 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 8.2 Hz, 1H), 7.82–7.72 (m, 1H), 7.70–7.60 (m, 1H), 7.55–7.44 (m, 3H), 7.21 (d, J = 16.3 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 6.92 (d, J = 16.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 192.8, 164.4 (d, J = 252.8 Hz), 146.8, 145.0, 136.4, 134.2, 130.8, 130.7 (d, J = 8.7 Hz, 2C), 130.3 (d, J = 3.2 Hz), 128.9, 126.1 (d, J = 2.2 Hz), 124.7, 116.3 (d, J = 22.0 Hz, 2C); FTIR (KBr, cm⁻¹): 3302, 3052, 1651, 1522, 1353, 1286, 1232, 1112; HRMS (ES TOF) calc'd for C₁₅H₁₀FNNaO₃ (M + Na)⁺ 294.0537, found 294.0538 (0.4 ppm).

(E)-3-(3-Chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ah). This compound was prepared according to the known procedure⁴⁶ employing 3-chlorobenzaldehyde (7h) (700 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.291 g (4.50 mmol, 90%), light-yellow solid, mp 122.0–124.1 °C (EtOH), R_f 0.27 (EtOAc/Hex, 1 : 4), 0.52 (EtOAc/Hex, 1 : 2); ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 8.0 Hz, 1H), 7.82–7.73 (m, 1H), 7.71–7.62 (m, 1H), 7.50 (dd, J = 7.5, 1.0 Hz, 1H), 7.46 (s, 1H), 7.34 (tt, J = 15.2, 7.4 Hz, 3H), 7.18 (d, J = 16.3 Hz, 1H), 6.98 (d, J = 16.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 192.7, 146.8, 144.4, 136.2, 135.9, 135.1, 134.3, 130.93, 130.89, 130.4, 128.9, 128.4, 127.5, 126.7, 124.7; FTIR (KBr, cm⁻¹): 3050, 1647, 1514, 1340, 1284, 1254, 1205, 1099; HRMS (ES TOF) calc'd for C₁₅H₁₀Cl₁N₁Na₁O₃ (M + Na)⁺ 310.0241, found 310.0246 (−1.5 ppm).

(E)-3-(4-Chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ai). This compound was prepared according to the known procedure⁴⁶ employing 4-chlorobenzaldehyde (7i) (700 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.409 g (4.90 mmol, 98%), white solid, mp 120.4–121.4 °C, lit.⁴⁸ mp 123–124 °C. R_f 0.35 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.28–8.14 (m, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.70–7.63 (m, 1H), 7.50 (dd, J = 7.6, 1.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 16.3 Hz, 1H), 6.96 (d, J = 16.3 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 192.7, 146.8, 144.7, 137.1, 136.3, 134.3, 132.6, 130.8, 129.8 (2C), 129.4 (2C), 128.9, 126.7, 124.7; FTIR (KBr, cm⁻¹): 3258, 3056, 2868, 1906, 1638, 1527, 1343; HRMS (ES TOF) calc'd for C₁₅H₁₀ClNNaO₃ (M + Na)⁺ 310.0241, found 310.0246 (1.5 ppm).

(E)-3-(4-Bromophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1aj). This compound was prepared according to the known procedure⁴⁶ employing 4-bromobenzaldehyde (7j) (920 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.572 g (4.75 mmol, 95%), colorless solid, mp 130.4–132.1 °C (EtOH), lit.⁴⁹ mp 145–147 °C, R_f 0.25 (EtOAc/hexanes 1 : 4); ¹H NMR (400 MHz, DMSO) δ 8.21 (d, J = 8.0 Hz, 1H), 7.91 (t, J = 7.3 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.76–7.68 (m, 3H), 7.62 (d, J = 8.3 Hz, 2H), 7.44–7.27 (m, 2H); ¹³C NMR (101 MHz, DMSO) δ 192.2, 146.7, 144.6, 135.3, 134.5, 133.3, 132.0 (2C), 131.5, 130.8 (2C), 129.1, 126.4, 124.6, 124.6; FTIR (KBr, cm⁻¹): 3255, 3061, 1638, 1584, 1527, 1487, 1347, 1307, 1290; HRMS (ES TOF) calc'd for C₁₅H₁₀BrNNaO₃ (M + Na)⁺ 353.9736, found 353.9739 (0.9 ppm).

(E)-3-(4-Methoxyphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ak). This compound was prepared according to the known procedure⁴⁶ employing anisaldehyde (7k) (680 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.316 g (4.65 mmol, 93%), white solid, mp 97.0–97.5 °C, lit.⁵⁰ mp 101–103 °C, R_f 0.13 (EtOAc/Hex, 1 : 4), 0.56 (EtOAc/Hex, 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 8.2 Hz, 1H), 7.79–7.71 (m, 1H), 7.69–7.60 (m, 1H), 7.50 (dd, J = 7.5, 1.1 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 16.2 Hz, 1H), 6.94–6.82 (m, 3H), 3.83 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.1, 162.2, 146.9, 146.5, 136.7, 134.1, 130.6 (2C), 130.5, 129.0, 126.8, 124.7, 124.1, 114.6 (2C), 55.6; FTIR (KBr, cm⁻¹): 3288, 2939, 1654, 1521, 1347, 1251, 1172, 1026; HRMS (ES TOF) calc'd for C₁₆H₁₃NNaO₄ (M + Na)⁺ 306.0737, found 306.0730 (2.3 ppm).

3-(4-(Dimethylamino)phenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1al). This compound was prepared according to the known procedure⁴⁶ employing 4-(dimethylamino)benzaldehyde (7l) (745 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.391 g (4.70 mmol, 94%), orange solid, 101.4–102.6 °C, lit.⁵¹ mp 157 °C. R_f 0.27 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.1 Hz, 1H), 7.63–7.54 (m, 1H), 7.53–7.43 (m, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 16.0 Hz, 1H), 6.80 (d, J = 16.0 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 3.00 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 192.9, 152.4, 148.0, 146.9, 137.0, 133.8, 130.7, 130.2, 129.0, 124.5, 121.5, 120.8, 111.8 (2C), 40.1 (2C); FTIR (KBr, cm⁻¹): 3096, 3029, 2900, 2820, 1598, 1522, 1433, 1348, 1299, 1237, 1179, 1112; HRMS (ES TOF) calc'd for C₁₇H₁₆N₂NaO₃ (M + Na)⁺ 319.1053, found 319.1053 (0.1 ppm).

(E)-1-(4,5-Dimethoxy-2-nitrophenyl)-3-phenylprop-2-en-1-one (1ba). This compound was prepared according to the known procedure⁵² employing benzaldehyde (1a) (825 mg, 5.00 mmol) and 1-(4,5-dimethoxy-2-nitrophenyl)ethan-1-one⁴⁵ (1.126 g, 5.00 mmol). The titled compound was obtained as colorless solid, mp 113.4–116.3 °C (benzene), lit.⁵² mp 159–160 °C (EtOH), R_f 0.28 (EtOAc/Hex, 1 : 2). Yield 1.330 g (4.25 mmol, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.52–7.44 (m, 2H), 7.42–7.32 (m, 3H), 7.20 (d, J = 16.2 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.85 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.1, 153.9, 149.7, 145.4, 139.4, 134.1, 131.0, 130.8, 129.1 (2C), 128.6 (2C), 126.7, 110.0, 107.1, 56.8, 56.7; FTIR (KBr, cm⁻¹): 3036, 2977, 1650, 1571, 1514, 1445, 1337, 1287, 1217, 1122; HRMS (ES TOF) calc'd for C₁₇H₁₅NNaO₅ (M + Na)⁺ 336.0842, found 336.0849 (1.9 ppm).

(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(2-nitrophenyl)prop-2-en-1-one (1ap). This compound was prepared according to known procedure,⁵³ employing piperonal (7p) (1.50 g, 10.00 mmol) and 2′-nitroacetophenone (6a) (1.65 g, 10.00 mmol). The title compound was obtained as colorless solid, mp 129.2–130.9 °C, lit.⁵³ mp 126–128 °C, R_f 0.55 (EtOAc/Hex, 1 : 2). Yield 2.525 g (8.5 mmol, 85%). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.1 Hz, 1H), 7.69–7.61 (m, 1H), 7.49 (dd, J = 7.5, 0.9 Hz, 1H), 7.16 (d, J = 16.1 Hz, 1H), 7.03 (d, J = 1.2 Hz, 1H), 6.95 (dd, J = 8.0, 1.2 Hz, 1H), 6.87–6.75 (m, 2H), 6.01 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 192.9, 150.5, 148.6, 146.9, 146.4, 136.6, 134.1, 130.6, 128.9, 128.5, 125.7, 124.7, 124.4, 108.8, 106.8, 101.9; FTIR (film, NaCl, cm⁻¹): 3262, 3101, 3014, 2913, 1645, 1524, 1498, 1447, 1337, 1243, 1106; HRMS (ES TOF) calc'd for C₁₆H₁₁NNaO₅ (M + Na)⁺ 320.0529, found 320.0527 (0.7 ppm).

(E)-1-(2-Nitrophenyl)-3-(pyridin-2-yl)prop-2-en-1-one (1am). This compound was prepared via modified literature protocol⁴⁸ (typical procedure A): a 15 mL Erlenmeyer flask equipped with magnetic stirring bar was charged with picolinaldehyde (7m) (535 mg, 5.00 mmol), 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol) and EtOH (3 mL). The stirred reaction mixture was cooled in the ice bath, and a solution of KOH (56 mg, 1.00 mmol) in water (300 μL) was added upon stirring maintaining the reaction temperature below +10 °C. After consumption of the starting acetophenone (TLC, EtOAc : Hex 1 : 4) the reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (4 × 15 mL). Combined organic extracts were washed consecutively with water (3 × 15 mL) and brine (15 mL). After concentration in vacuo the crude product was recrystallized from EtOH to afford the titled compound as colorless solid, mp 101.2–103.5 °C (EtOH), lit.⁴⁸ mp 102–105 (isopropanol), R_f 0.40 (EtOAc/Hex, 1 : 1). Yield 1.143 g (0.45 mmol, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.81–7.69 (m, 2H), 7.69–7.61 (m, 1H), 7.55–7.46 (m, 2H), 7.41 (d, J = 16.1 Hz, 1H), 7.33–7.22 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 193.1, 152.7, 150.3, 146.7, 144.6, 137.0, 136.4, 134.3, 130.9, 129.7, 128.9, 124.8, 124.7, 124.5; FTIR (KBr, cm⁻¹): 3074, 1752, 1661, 1528, 1431, 1337, 1277, 1247; HRMS (ES TOF) calc'd for C₁₄H₁₀N₂NaO₃ (M + Na)⁺ 277.0584, found 277.0593 (3.4 ppm).

3-(4-Ethylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ad). This compound was prepared according to the typical procedure A employing 4-ethylbenzaldehyde (7d) (670 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). The crude product was purified by preparative column chromatography eluting with EtOAc/Hex, 1 : 4. Yield 1.306 g (4.65 mmol, 93%), pale brown oil, R_f 0.51 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 8.2 Hz, 1H), 7.75 (td, J = 7.5, 0.9 Hz, 1H), 7.67–7.61 (m, 1H), 7.49 (dd, J = 7.5, 1.2 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.26–7.17 (m, 3H), 6.97 (d, J = 16.3 Hz, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.1, 148.1, 146.8, 146.7, 136.4, 134.1, 131.5, 130.6, 128.9, 128.8 (2C), 128.6 (2C), 125.4, 124.6, 28.9, 15.3; FTIR (KBr, cm⁻¹): 3035, 2970, 2873, 1652, 1596, 1531, 1350, 1210; HRMS (ES TOF) calc'd for C₁₇H₁₅NNaO₃ (M + Na)⁺ 304.0944, found 304.0948 (1.1 ppm).

(E)-3-(4-Isopropylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ae). This compound was prepared according to the typical procedure A employing 4-isopropylbenzaldehyde (7e) (740 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). The crude product was purified by preparative column chromatography eluting with EtOAc/Hex, 1 : 4. Yield 1.292 g (4.4 mmol, 88%), yellow oil, R_f 0.38 (EtOAc/Hex, 1 : 4); ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 8.2 Hz, 1H), 7.75 (td, J = 7.5, 0.9 Hz, 1H), 7.67–7.61 (m, 1H), 7.50 (dd, J = 7.5, 1.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.24 (dd, J = 12.1, 3.8 Hz, 3H), 6.99 (d, J = 16.3 Hz, 1H), 2.92 (septet, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 193.1, 152.7, 146.8, 146.6, 136.4, 134.1, 131.6, 130.6, 128.9, 128.8 (2C), 127.2 (2C), 125.4, 124.6, 34.2, 23.7 (2C); FTIR (KBr, cm⁻¹): 2958, 1742, 1653, 1591, 151, 1360, 1300, 1280, 1244, 1201, 1109; HRMS (ES TOF) calc'd for C₁₈H₁₇N₁Na₁O₃ (M + Na)⁺ 318.1101, found 318.1101 (0.1 ppm).

(E)-1-(2-Nitrophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (1an). This compound was prepared according to typical procedure A employing nicotinaldehyde (7n) (535 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.092 g (4.30 mmol, 86%), colorless solid, mp 88.3–89.8 °C (EtOH), R_f 0.25 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J = 1.4 Hz, 1H), 8.60 (dd, J = 4.7, 1.2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.82–7.72 (m, 1H), 7.72–7.58 (m, 1H), 7.55–7.42 (m, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 7.24 (d, J = 16.4 Hz, 1H), 7.04 (d, J = 16.4 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 192.4, 151.7, 150.3, 146.7, 142.1, 136.1, 134.5, 134.4, 131.0, 129.9, 128.9, 128.1, 124.8, 124.0; FTIR (KBr, cm⁻¹): 3308, 3034, 1661, 1581, 1524, 1350, 1256, 1102; HRMS (ES TOF) calc'd for C₁₄H₁₀N₂NaO₃ (M + Na)⁺ 277.0584, found 277.0585 (−0.6 ppm).

(E)-1-(2-Nitrophenyl)-3-(pyridin-4-yl)prop-2-en-1-one (1ao). This compound was prepared according to typical procedure A employing isonicotinaldehyde (7o) (535 mg, 5.00 mmol), 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1041.4 mg (4.1 mmol, 82%), colorless crystals, mp 140.0–141.6 °C (EtOH), R_f 0.22 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J = 5.1 Hz, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 5.0 Hz, 2H), 7.13 (q, J = 16.3 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 192.3, 150.8 (2C), 146.7, 142.4, 141.2, 135.9, 134.5, 131.1, 130.1, 128.8, 124.7, 122.1 (2C); FTIR (KBr, cm⁻¹): 3308, 3060, 1661, 1598, 1524, 1413, 1343, 1286, 1109; HRMS (ES TOF) calc'd for C₁₄H₁₀N₂NaO₃ (M + Na)⁺ 277.0584, found 277.0576 (2.8 ppm).

(E)-1-(2-Nitrophenyl)-3-(thiophen-2-yl)prop-2-en-1-one (1aq). This compound was prepared according to the typical procedure A employing thiophene-2-carbaldehyde (7q) (560 mg, 5 mmol) and 2′-nitroacetophenone (6a) (825 mg, 5.00 mmol). The title compound was obtained as colorless solid, mp 95.0–96.2 °C, lit.⁵⁴ mp 94–95 °C, R_f 0.35 (EtOAc/Hex, 1 : 4). Yield 1.062 g (4.1 mmol, 82%). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.54–7.33 (m, 3H), 7.29–7.17 (m, 1H), 7.12–6.99 (m, 1H), 6.78 (d, J = 15.9 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 192.4, 146.7, 139.3, 138.8, 136.3, 134.1, 132.5, 130.7, 130.2, 128.8, 128.5, 124.8, 124.7; FTIR (KBr, cm⁻¹): 3107, 2859, 1651, 1604, 1521, 1420, 1343, 1280, 1253, 1193; HRMS (ES TOF) calc'd for C₁₃H₉N₁Na₁O₃S₁ (M + Na)⁺ 282.0195, found 282.0195 (0.0 ppm).

Synthesis of (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles

(E)-2-(3-Oxoindolin-2-ylidene)-2-phenylacetonitrile (2aa). Typical procedure B: reaction vessel was charged with (E)-1-(2-nitrophenyl)-3-phenylprop-2-en-1-one (1aa) (253 mg, 1.00 mmol), KCN (80 mg, 1.23 mmol), water (400 mg), and methanol (3 mL). The mixture was stirred at reflux for 15 min monitoring the reaction by TLC. When the starting chalcon was consumed, the emerald-green mixture was cooled down to room temperature and acetic acid (40 mg, 0.66 mmol) was added slowly (Caution! This process is very exothermic and toxic HCN may evolve, use well-ventilated fume hood. Residual materials containing free cyanides should be quenched with KOH and FeCl₃ aqueous solutions). The refluxing was continued for additional 15 min. Then, the mixture was diluted with water (10 mL), treated with saturated aqueous solution of sodium bicarbonate (5 mL), and extracted with ethyl acetate (4 × 20 mL). Crude product was purified by preparative column chromatography eluting with a mixture EtOAc/hexanes, gradient 1 : 2–1 : 1. Additional purification can be performed by recrystallization from ethanol. The titled compound was obtained as red crystals, mp 233.1–235.9 °C (EtOH), lit.⁴⁴ mp 236–237 °C, R_f 0.32 (EtOAc/hexanes 1 : 2), R_f 0.65 (EtOAc/hexanes 1 : 1). Yield 187 mg (0.76 mmol, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 7.70–7.43 (m, 7H), 7.09 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 152.5, 142.5, 137.5, 132.1, 129.3 (2C), 129.1, 128.8 (2C), 124.9, 121.5, 119.5, 118.0, 112.7, 88.8; FTIR (KBr, cm⁻¹): 3308, 3060, 2222, 1708, 1601, 1470, 1447, 1391, 1340, 1213; HRMS (ES TOF) calc'd for C₁₆H₁₀N₂NaO (M + Na)⁺ 269.0685, found 269.0692 (−2.3 ppm).

(E)-2-(3-Oxoindolin-2-ylidene)-2-(o-tolyl)acetonitrile (2ab). This compound was prepared according to the typical procedure B employing (E)-1-(2-nitrophenyl)-3-(o-tolyl)prop-2-en-1-one (1ab) (267 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 2. Yield 203 mg (0.78 mmol, 78%), red crystals, mp 201.8–203.5 °C (EtOH), R_f 0.29 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 11.2, 4.1 Hz, 1H), 7.44–7.28 (m, 4H), 7.08–6.87 (m, 2H), 2.31 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.0, 152.5, 143.9, 137.6, 136.9, 131.0, 130.8, 130.0, 129.5, 126.8, 124.9, 121.3, 119.6, 117.6, 112.4, 87.7, 19.3; FTIR (KBr, cm⁻¹): 3336, 2215, 1708, 1598, 1377, 1330, 1220, 1139, 1082, 965; HRMS (ES TOF) calc'd for C₁₇H₁₂N₂NaO (M + Na)⁺ 283.0842, found 283.0840 (0.5 ppm).

(E)-2-(3-Oxoindolin-2-ylidene)-2-(p-tolyl)acetonitrile (2ac). This compound was prepared according to the typical procedure B employing (E)-1-(2-nitrophenyl)-3-(p-tolyl)prop-2-en-1-one (1ac) (267 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 3. Yield 164 mg (0.63 mmol, 63%), orange crystals, mp 231–234 °C (EtOH), lit.⁴⁴ mp 236–240 °C, R_f 0.46 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 16.7, 7.8 Hz, 3H), 7.38 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (101 MHz, DMSO) δ 184.2, 152.5, 142.2, 139.0, 137.4, 129.9 (2C), 129.2, 128.8 (2C), 124.9, 121.4, 119.5, 118.0, 112.7, 89.2, 20.9; FTIR (KBr, cm⁻¹): 3296, 2208, 1705, 1591, 1471, 1307, 1243, 811; HRMS (ES TOF) calc'd for C₁₇H₁₂N₂NaO⁺ (M + Na)⁺ 283.0842, found 283.0844 (0.8 ppm).

(E)-2-(4-Ethylphenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ad). This compound was prepared according to the typical procedure B employing (E)-3-(4-ethylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ad) (281 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 3. Yield 170 mg (0.62 mmol, 62%), red crystals, mp 223.2–225.7 °C (EtOH), R_f 0.56 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.60–7.50 (m, 3H), 7.41 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 2.68 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 152.5, 145.2, 142.1, 137.4, 129.4, 128.9 (2C), 128.8 (2C), 124.9, 121.4, 119.5, 118.0, 112.7, 89.2, 28.0, 15.4; FTIR (KBr, cm⁻¹): 3429, 2933, 2255, 2134, 1665, 1585, 1461, 1370, 1243, 1022, 998, 828; HRMS (ES TOF) calc'd for C₁₈H₁₄N₂NaO (M + Na)⁺ 297.0998, found 297.0997 (0.4 ppm).

(E)-2-(4-Isopropylphenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ae). This compound was prepared according to the typical procedure B employing (E)-3-(4-isopropylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ae) (295 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, gradient 1 : 3–1 : 2. Yield 184 mg (0.64 mmol, 64%), red crystals, mp 223.0–226.6 °C (EtOH), lit.⁴⁴ mp 228–230 °C, R_f 0.47 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 7.5 Hz, 3H), 7.44 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 2.96 (septet, J = 6.7 Hz, 1H), 1.24 (d, J = 6.7 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 152.5, 149.7, 142.1, 137.4, 129.6, 128.9 (2C), 127.4 (2C), 124.9, 121.4, 119.5, 118.0, 112.8, 89.2, 33.4, 23.7 (2C); FTIR (KBr, cm⁻¹): 3349, 2959, 2872, 2208, 1708, 1591, 1524, 1464, 1333, 1210; HRMS (ES TOF) calc'd for C₁₉H₁₆N₂NaO (M + Na)⁺ 311.1155, found 311.1155 (0.0 ppm).

(E)-2-(2-Fluorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2af). This compound was prepared according to the typical procedure B employing (E)-3-(2-fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1af) (271 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 2. Yield 216 mg (0.82 mmol, 82%), red crystals, mp 211.1–212.6 °C (EtOH), lit.⁴⁴ mp 215–216 °C, R_f 0.26 (EtOAc/hexanes 1 : 2), R_f 0.63 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 7.70–7.50 (m, 4H), 7.47–7.33 (m, 2H), 7.12–6.96 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 183.9, 159.4 (d, J = 249.6 Hz), 152.3, 144.2, 137.8, 131.8 (d, J = 8.5 Hz), 131.5 (d, J = 1.8 Hz), 125.4 (d, J = 3.4 Hz), 125.1, 121.6, 119.43 (d, J = 14.7 Hz), 119.40, 117.3, 116.7 (d, J = 20.8 Hz), 112.4, 81.9; FTIR (KBr, cm⁻¹): 3296, 3047, 2222, 1718, 1598, 1454, 1340, 1306; HRMS (ES TOF) calc'd for C₁₆H₉FN₂NaO (M + Na)⁺ 287.0591, found 287.0597 (1.9 ppm).

(E)-2-(4-Fluorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ag). This compound was prepared according to the typical procedure B employing (E)-3-(4-fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ag) (271 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 3. Yield 192 mg (0.73 mmol, 73%), orange crystals, mp 281.1–282.8 °C (EtOH), lit.⁴⁴ mp 282–284 °C, R_f 0.54 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 7.78–7.62 (m, 3H), 7.58 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 8.4 Hz, 2H), 7.08 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 162.1 (d, J = 247.8 Hz), 152.5, 142.7, 137.5, 131.3 (d, J = 8.7 Hz, 2C), 128.5 (d, J = 3.1 Hz), 124.9, 121.5, 119.5, 118.0, 116.4 (d, J = 22.0 Hz, 2C), 112.7, 87.8; FTIR (KBr, cm⁻¹): 3302, 2222, 1715, 1608, 1511, 1468, 1330, 1240, 1213, 1103, 965, 844; HRMS (ES TOF) calc'd for C₁₆H₉FN₂NaO (M + Na)⁺ 287.0591, found 287.0590 (0.5 ppm).

(E)-2-(3-Chlorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ah). This compound was prepared according to the typical procedure B employing (E)-3-(3-chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ah) (287 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 3. Yield 185 mg (0.66 mmol, 66%), orange solid, mp 267–269 °C (EtOH), R_f 0.57 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.66 (d, J = 7.5 Hz, 2H), 7.64–7.51 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) 184.2, 152.4, 143.2, 137.6, 134.2, 133.9, 131.2, 129.0, 128.5, 127.6, 125.0, 121.7, 119.4, 117.7, 112.7, 87.0; FTIR (KBr, cm⁻¹): 3289, 2215, 1709, 1458, 1243, 1096, 1016; HRMS (ES TOF) calc'd for C₁₆H₉ClN₂NaO⁺ (M + Na)⁺ 303.0296, found 303.0293 (1.0 ppm).

(E)-2-(4-Chlorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ai). This compound was prepared according to the typical procedure B employing (E)-3-(4-chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ai) (287 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, gradient 1 : 2–1 : 1. Yield 160 mg (0.57 mmol, 57%), orange crystals, mp 285.9–287.8 °C (EtOH), R_f 0.22 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.74–7.51 (m, 6H), 7.13–6.94 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 152.4, 142.9, 137.6, 133.7, 131.0, 130.7 (2C), 129.4 (2C), 125.0, 121.6, 119.5, 117.8, 112.7, 87.5; FTIR (KBr, cm⁻¹): 3282, 2222, 1715, 1601, 1468, 1407, 1336, 1250, 1096, 1015, 841; HRMS (ES TOF) calc'd for C₁₆H₉ClN₂NaO (M + Na)⁺ 303.0296, found 303.0297 (0.5 ppm).

(E)-2-(4-Bromophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2aj). This compound was prepared according to the typical procedure employing (E)-3-(4-bromophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1aj) (331 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, gradient 1 : 4–1 : 2. Yield 297 mg (0.92 mmol, 92%), red crystals, mp 278.8–282.5 °C (EtOH), R_f 0.66 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 8.1 Hz, 3H), 7.07 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.2, 152.4, 142.9, 137.6, 132.3 (2C), 131.4, 130.9 (2C), 125.0, 122.4, 121.6, 119.4, 117.7, 112.7, 87.5; FTIR (KBr, cm⁻¹): 3282, 3060, 2215, 1712, 1602, 1487, 1464, 1407, 1333, 1243; HRMS (ES TOF) calc'd for C₁₆H₉BrN₂NaO (M + Na)⁺ 346.9790, found 346.9790 (0.2 ppm).

(E)-2-(4-Methoxyphenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ak). This compound was prepared according to the typical procedure B employing (E)-3-(4-methoxyphenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ak) (283 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 2–1 : 1. Yield 199 mg (0.72 mmol, 72%), red crystals, mp 250.1–251.1 °C (EtOH), lit.⁴⁴ mp 245–247 °C, R_f 0.23 (EtOAc/hexanes 1 : 2), R_f 0.43 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 7.60 (td, J = 15.9, 7.6 Hz, 4H), 7.11 (dd, J = 14.9, 8.4 Hz, 3H), 7.01 (t, J = 7.4 Hz, 1H), 3.84 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.1, 159.8, 152.4, 141.6, 137.3, 130.4 (2C), 124.8, 124.1, 121.3, 119.6, 118.0, 114.8 (2C), 112.7, 89.4, 55.5; FTIR (KBr, cm⁻¹): 3289, 3060, 2208, 1705, 1594, 1300, 1246, 1176; HRMS (ES TOF) calc'd for C₁₇H₁₂N₂NaO₂ (M + Na)⁺ 299.0791, found 299.0794 (1.0 ppm).

(E)-2-(4-(Dimethylamino)phenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2al). This compound was prepared according to the typical procedure B employing (E)-3-(4-(dimethylamino)phenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1al) (296 mg, 1.00 mmol). Reaction time was extended to 3 h at the first stage, and to 1 h at the second stage. Eluent for chromatographic purification: EtOAc/hexanes, 1 : 1. Yield 135 mg (0.47 mmol, 47%), violet crystals, mp 234.8–237.6 °C (EtOH), lit.⁴⁴ mp 220–225 °C, R_f 0.20 (EtOAc/hexanes 1 : 2), R_f 0.69 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 9.7 Hz, 3H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 3.01 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 183.7, 152.2, 150.5, 139.7, 136.8, 130.0 (2C), 124.5, 121.0, 119.8, 118.6, 118.0, 112.8, 112.3 (2C), 91.4, 39.8 (2C); FTIR (KBr, cm⁻¹): 3315, 2899, 2798, 2201, 1698, 1608, 1521, 1364, 1323, 1199; HRMS (ES TOF) calc'd for C₁₈H₁₅N₃NaO (M + Na)⁺ 312.1107, found 312.1110 (−0.8 ppm).

(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-2-yl)acetonitrile (2am). This compound was prepared according to the typical procedure B employing (E)-1-(2-nitrophenyl)-3-(pyridin-2-yl)prop-2-en-1-one (1am) (254 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc/hexanes, 1 : 2. Yield 151 mg (0.61 mmol, 61%), purple crystals, mp 202.6–204.9 °C (EtOH), R_f 0.36 (EtOAc/hexanes 1 : 2); ¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 8.76 (d, J = 3.9 Hz, 1H), 8.00 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72–7.54 (m, 2H), 7.49–7.28 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 185.2, 152.4, 151.8, 149.2, 143.2, 138.0, 137.6, 125.0, 122.6, 122.5, 122.2, 119.1, 116.6, 113.5, 85.0; FTIR (KBr, cm⁻¹): 3228, 3121, 2214, 1708, 1591, 1464, 1434, 1343, 1236; HRMS (ES TOF) calc'd for C₁₅H₉N₃NaO (M + Na)⁺ 270.0638, found 270.0640 (0.9 ppm).

(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-3-yl)acetonitrile (2an). This compound was prepared according to the typical procedure B employing (E)-1-(2-nitrophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (1an) (254 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc. Yield 138 mg (0.56 mmol, 56%), light-brown crystals, mp 208.1–211.1 °C (EtOH), R_f 0.34 (EtOAc); ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.66 (d, J = 3.9 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.63–7.54 (m, 2H), 7.21–6.93 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.1, 152.4, 149.6, 149.4, 143.5, 137.7, 136.4, 128.6, 125.1, 124.2, 121.7, 119.4, 117.6, 112.7, 85.2; FTIR (KBr, cm⁻¹): 3557, 2215, 1712, 1622, 1591, 1541, 1467, 1417, 1387, 1337, 1219, 1190, 1136; HRMS (ES TOF) calc'd for C₁₅H₉N₃NaO (M + Na)⁺ 270.0638, found 270.0635 (1.0 ppm).

(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-4-yl)acetonitrile (2ao). This compound was prepared according to the typical procedure B employing (E)-1-(2-nitrophenyl)-3-(pyridin-4-yl)prop-2-en-1-one (1ao) (254 mg, 1.00 mmol). Eluent for chromatographic purification: EtOAc – EtOH/EtOAc, 1 : 3. Yield 131 mg (0.53 mmol, 53%), red crystals, mp 266.3–268.4 °C (EtOH), R_f 0.17 (EtOAc), 0.65 (EtOH/EtOAc 1 : 3); ¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.74 (d, J = 5.7 Hz, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 7.1 Hz, 3H), 7.10 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.3, 152.3, 150.5 (2C), 143.8, 140.1, 137.8, 125.2, 122.9 (2C), 122.1, 119.3, 117.2, 112.8, 85.3; FTIR (KBr, cm⁻¹): 2993, 2221, 1742, 1718, 1598, 1557, 1517, 1373, 1250, 1206; HRMS (ES TOF) calc'd for C₁₅H₉N₃NaO (M + Na)⁺ 270.0638, found 270.0630 (2.7 ppm).

(E)-2-(Benzo[d][1,3]dioxol-5-yl)-2-(3-oxoindolin-2-ylidene)acetonitrile (2ap). This compound was prepared according to the typical procedure B employing (E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(2-nitrophenyl)prop-2-en-1-one (1ap) (297 mg, 1.00 mmol). The title compound was obtained as red solid, mp 247.9–248.7 °C. R_f 0.62 (EtOAc/Hex, 1 : 2). Yield 133 mg (0.46 mmol, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.23–7.07 (m, 4H), 7.01 (t, J = 7.4 Hz, 1H), 6.14 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 184.1, 152.4, 148.1, 148.0, 141.9, 137.4, 125.7, 124.8, 123.6, 121.4, 119.6, 118.0, 112.7, 109.2, 108.9, 101.9, 89.2; FTIR (film, NaCl, cm⁻¹): 3316, 2926, 2208, 1712, 1595, 1481, 1350, 1247, 1206, 1046; HRMS (ES TOF) calc'd for C₁₇H₁₀N₂NaO₃ (M + Na)⁺ 313.0584, found 313.0586 (0.8 ppm).

(E)-2-(5,6-Dimethoxy-3-oxoindolin-2-ylidene)-2-phenylacetonitrile (2ba). This compound was prepared according to the typical procedure B employing (E)-1-(4,5-dimethoxy-2-nitrophenyl)-3-phenylprop-2-en-1-one (1ba) (313 mg, 1.00 mmol). Reaction time was extended to 1 h at the first stage of the reaction. Eluent for chromatographic purification: EtOAc/hexanes, 1 : 1. Yield 156 mg (0.51 mmol, 51%), purple crystals, mp 205.2–207.6 °C (EtOH), R_f 0.47 (EtOAc/hexanes 1 : 1); ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (s, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.47 (t, J = 7.1 Hz, 1H), 7.07 (s, 1H), 6.62 (s, 1H), 3.85 (s, 3H), 3.75 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 181.9, 157.8, 150.2, 144.9, 143.9, 132.3, 129.3 (2C), 129.0, 128.8 (2C), 118.0, 110.4, 105.8, 95.9, 88.5, 56.1, 55.9; FTIR (KBr, cm⁻¹): 3282, 3000, 2839, 2215, 1682, 1598, 1491, 1441, 1323, 1203, 1172; HRMS (ES TOF) calc'd for C₁₈H₁₄N₂NaO₃ (M + Na)⁺ 329.0897, found 329.0901 (1.3 ppm).

It should be pointed out, that preparation of basic compounds, containing dimethylamine functionality (2al) or pyridine ring (2am–2ao) requires twice more acetic acid (80 mg) at the second stage of the procedure. It is also worth mentioning that these compounds slowly decompose in solutions of ethyl acetate or acetone, but perfectly shelf-stable in crystalline form.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Russian Science Foundation (grant #19-73-00091).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Spectral data. CCDC 1992506. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ra03520c

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