Nitroalkenes as surrogates for cyanomethylium species in a one-pot synthesis of non-symmetric diarylacetonitriles

Abstract

Nitroalkenes were used as synthetic equivalents of the cyanomethylium cation in a modular, one-pot synthesis of 2-(3-indolyl)acetonitriles and 2,2-diarylacetonitriles involving electrophilic functionalization of aromatic and heteroaromatic C–H bond.

---

Introduction

Development of synthetic approaches to alkaloid-mimics embedding the indolyl moiety is one of the central themes of contemporary organic and medicinal chemistry.¹ We have recently reported on promising anti-tumor activity of 2-aryl-2-(3-indolyl)acetohydroxamic acids 3, which were isolated as intermediates in the ANRORC reaction of indoles producing 2-quinolones 4 (Scheme 1).² Hydroxamic acids 3 demonstrated significant activity against glioma, melanoma, esophageal, and many other cancer lines intrinsically resistant to apoptosis induction and poorly responsive to treatment with traditional proapoptotic drugs.³ Our on-going SAR studies of analogs of 3 required an expeditious access to small libraries of nitriles 5. Initially, we tested the possibility to access 5 via the phosphorus trichloride-assisted reduction of hydroxamic acid 3 (R = H, Ar¹ = 2-naphthyl, Ar² = Ph, Scheme 1).³ However, this method proved impractical for rapid assembly of compound series, as it required isolation and purification of intermediate hydroxamic acids 3. The traditional multi-step approach involving electrophilic alkylation or formylation and subsequent nucleophilic substitution with cyanides⁴ was also ruled out due to its length and high toxicity of reagents. Herein we report a convenient, one-pot synthesis of indolyl acetonitriles and diarylacetonitriles proceeding via electrophilic C–H functionalization of electron-rich (het)arenes with nitrostyrenes.

Scheme 1

Results and discussion

A straightforward route to nitriles 5 was envisioned via electrophilic alkylation of indoles 1 with nitroalkenes 2 followed by reductive conversion of primary nitroalkanes 6 into aldoximes 7,⁵ and their subsequent dehydration (Scheme 2). The shortcoming of this approach is its sensitivity to sterics at 2-position of indole,^1a which would make the first step very sluggish and thus unsuitable for functionalization of 2-arylindoles 1.⁶ Should this problem be addressed, the subsequent conversion of primary nitroalkanes into nitriles is unlikely to pose a problem, as both stepwise and one-pot^7–10 protocols are well documented. Reducing agents employed in such transformations include isocyanides and isocyanates,⁷ low-valent sulphur derivatives,⁸ or organometallic complexes⁹ including transition metal-based photo-redox systems.¹⁰ Accordingly, a one-pot transformation of indoles 1 directly into nitriles 5 would require a catalyst that is: (a) fully compatible with a sensitive indole moiety; (b) inert in the subsequent steps.

Scheme 2

Alternatively, there must be the possibility for efficient deactivation of the catalyst by reagents utilized in the reduction step. Based on the above reasoning, weak acids were probed as catalysts for the alkylation step (Table 1). Among other carboxylic acids considered for this role, we found formic acid to be the most suitable since it can be destroyed tracelessly upon heating with a dehydrating agent. This newly designed reaction cascade would provide the desired direct approach to 3-indolyl acetonitriles, in which nitroalkene 2 would serve as a synthetic equivalent of the uncommon electrophilic cyanomethylium synthon 9.

Table 1 Optimization of organic acid catalyst for the alkylation step^a

#	Acid cat.	Acid : 1a	Time, h (T, °C)	Yield, %
a NMR yields of nitroalkane 6aa.b The reaction was performed in molten mixture of neat starting materials.
1	None	0^b	1 (130) + 24 (RT)	24
2	CH3CO2H	2 : 1	4 (110)	0
3	CH3CO2H	4 : 1	4 (110)	0
4	ClCH2CO2H	2 : 1	2 (110)	0
5	ClCH2CO2H	2 : 1	2 (130)	26
6	CF3CO2H	2 : 1	1 (60)	18
7	CF3CO2H	2 : 1	1(85)	62
8	CF3CO2H	2 : 1	1 (100)	24
9	HCO2H	2 : 1	1 (85)	80
10	HCO2H	2 : 1	1 (95)	68

---

To evaluate this idea we performed the reaction between 2-phenylindole (1a) and 2-nitrostyrene (2a). The alkylation step proceeded as expected at 85 °C affording the corresponding nitroalkane 6aa within 1 h. Upon addition of phosphorus trichloride in the next step, 6aa was cleanly converted into nitrile 5aa, which was obtained as a sole product in good yield (Table 2, entry 1). The same indole 1a afforded the corresponding acetonitrile 5ad in reaction with 2-bromophenylnitroalkene 2d (entry 2). Taking into account that a bulky lipophilic substituent at C-2 of the indole unit was essential for attaining the desired biological activity, we tested 2-(2-naphthyl)indole (1b) against a series of nitrostyrenes (2a–g). The reaction appeared to be very general and tolerated various aromatic substituents, including halogenated (entries 4–6) aryls, as well as arenes bearing strong electron-withdrawing (entry 7) or strong electron-donating functionalities (entries 8–9). The reaction was also very tolerant to the size of the substituent at C-2 of indole. Thus, indoles bearing p-tolyl (1c), 2,4-(1d) or 3,4-dimethoxyphenyl (1e) groups, as well as tetrahydronaphthalen-2-yl moiety (1f) gave useful preparative yields of the corresponding acetonitriles in the reaction with nitrostyrene 2a (entries 10–13). Reaction of N-methylated indole 1g also successfully afforded respective product 5gb (entry 14).

Table 2 One-pot synthesis of indolylacetonitriles in reaction of indoles with nitroalkenes

#	1	2	R^1	Ar^1	Ar^2	5	Yield, %^a
a Isolated yields of purified nitrile products.b 5,6,7,8-Tetrahydronaphthalene-2-yl.
1	1a	2a	H	Ph	Ph	5aa	77
2	1a	2d	H	Ph	2-BrC6H4	5ad	71
3	1b	2a	H	2-Naphthyl	Ph	5ba	73
4	1b	2b	H	2-Naphthyl	2-FC6H4	5bb	74
5	1b	2c	H	2-Naphthyl	3-FC6H4	5bc	71
6	1b	2d	H	2-Naphthyl	2-BrC6H4	5bd	68
7	1b	2e	H	2-Naphthyl	4-NO2C6H4	5be	62
8	1b	2f	H	2-Naphthyl	4-MeOC6H4	5bf	69
9	1b	2g	H	2-Naphthyl	4-EtOC6H4	5bg	63
10	1c	2a	H	4-MeC6H4	Ph	5ca	76
11	1d	2a	H	2,4-(MeO)2C6H3	Ph	5da	59
12	1e	2a	H	3,4-(MeO)2C6H3	Ph	5ea	61
13	1f	2a	H	2-C10H11^b	Ph	5fa	72
14	1g	2b	Me	2-Naphthyl	2-FC6H4	5gb	62

---

We also explored the possibility to adapt the methodology described above to other electron-rich aromatic substrates. Initial attempts to carry out the reaction between anisole (10a) and 2-nitrostyrene (2a) in the presence of formic acid proved unsuccessful and returned intact starting materials. It was reasoned that a stronger acid might be required to enable this transformation. Indeed, the same reaction proceeded much more readily in the presence of 20 mol% sulphuric acid. Subsequent treatment of the crude reaction mixture with phosphorus trichloride in pyridine provided the desired diarylacetonitrile 11a in good yield (Scheme 3). Analogously, the reaction of 1,2-dimethoxybenzene (10b) produced cleanly nitrile 11b. We also demonstrated that this method is suitable for installation of acetonitrile moiety into more elaborated substrates, such as benzo-crown ethers, 15-crown-5 (10c) and 18-crown-6 (10d). Both macrocyclic products were easily recovered from the reaction mixtures by extraction and additionally purified by column chromatography to obtain analytically pure samples.

Scheme 3

Conclusions

We have developed a novel one-pot transformation allowing for easy installation of the acetonitrile functionality in aromatic or heteroaromatic substrates via electrophilic aromatic alkylation with nitroalkenes and subsequent reductive dehydration. Employment of formic acid as a promoter helped circumvent the adverse steric factors in the first step of the reaction, while nitroalkene conveniently served as a synthetic surrogate for cyanomethylium acceptor. This method offers an atom-economic, metal-free, one-pot route to 2,2-diaryl- and 2-(indol-3-yl)-2-aryl-substituted acetonitriles from readily available aromatic and heteroaromatic starting materials.

Experimental part

¹H and ¹³C NMR spectra were recorded on a Bruker Avance-III spectrometer (400 or 100 MHz, respectively) equipped with BBO probe in CDCl₃ using TMS as internal standard. High-resolution mass spectra were registered with Bruker Maxis spectrometer (electrospray ionization, in MeCN, using HCO₂Na–HCO₂H for calibration). Melting points were measured with Stuart smp30 apparatus. All reactions were performed in oven-dried drum vials open to the atmosphere, employing overhead stirring. The reaction progress and purity of isolated compounds were monitored by TLC eluted with EtOAc. Flash column chromatography was performed on Silica gel (32–63 μm, 60 Å). All reagents and solvents were purchased from commercial vendors and used as received.

General procedure A (applied for indoles)

To a molten mixture of arene (1.0 mmol) and nitrostyrene (1.0 mmol) heated to 85 °C, was added concentrated formic acid (75 μL, 2.0 mmol). The mixture was vigorously stirred for 1 h, then cooled down and diluted with pyridine (8.2 mL). Phosphorous trichloride was added in one portion (0.95 mL, 1.50 g, 10.9 mmol), and the mixture was stirred at 60 °C for 4 h, then poured into a mixture of concentrated hydrochloric acid (5 mL, 36%) and crushed ice (∼20 g). The resulting emulsion was extracted with dichloromethane (3 × 25 mL). Combined organic phases were concentrated in vacuum, and the residual oil was purified by preparative column chromatography on silica gel.

2-Phenyl-2-(2-phenyl-1H-indol-3-yl)acetonitrile (5aa). Yield 237 mg (0.77 mmol, 77%), off-white crystalline solid, R_f 0.46 (hexane/EtOAc 4 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.42–7.31 (m, 9H), 7.28–7.20 (m, 3H), 7.16–7.12 (m, 1H), 7.03–6.98 (m, 1H), 5.52 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 137.0, 136.1, 135.5, 131.6, 129.4 (2C), 129.1 (2C), 128.6 (2C), 128.0, 127.3 (2C), 126.8, 123.2, 120.8, 120.0, 119.7, 111.3, 106.1, 77.2, 33.5; FT IR (NaCl, cm⁻¹): 3338, 3070, 3029, 2376, 2349, 1691, 1659, 1498, 1449, 1207, 1072; HRMS (ES TOF): calc'd for C₂₂H₁₆N₂Na⁺ (M + Na) 331.1206, found 331.1207 (0.3 ppm).

2-(2-Bromophenyl)-2-(2-phenyl-1H-indol-3-yl)acetonitrile (5ad). Yield 275 mg (0.71 mmol, 71%), colorless crystals, mp 148–149 °C (benzene), R_f 0.30 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 7.8, 1.6 Hz, 1H), 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.50–7.40 (m, 4H), 7.37–7.34 (m, 2H), 7.32–7.25 (m, 2H), 7.23–7.16 (m, 2H), 5.72 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 137.2, 135.9, 134.9, 133.6, 131.5, 130.0, 129.9, 129.2 (2C), 128.9, 128.3 (2C), 128.0, 127.3, 123.7, 123.0, 120.9, 119.7, 118.7, 111.4, 104.6, 34.5; FT IR (NaCl, cm⁻¹): 3347, 2363, 2332, 2249, 1458, 1435, 1026, 907, 764, 743; HRMS (ES TOF): calc'd for C₂₂H₁₅⁷⁹BrN₂Na⁺ (M + Na) 409.0311, found 409.0319 (2.0 ppm).

2-(2-(Naphthalen-2-yl)-1H-indol-3-yl)-2-phenylacetonitrile (5ba):³. Yield 261 mg (0.73 mmol, 73%), mp 146–147 °C (toluene); ¹H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.11–8.04 (m, 2H), 8.02–7.92 (m, 2H), 7.70 (dd, J = 8.5, 1.8 Hz, 1H), 7.62–7.55 (m, 2H), 7.47 (dd, J = 15.0, 8.1 Hz, 2H), 7.42–7.36 (m, 4H), 7.36–7.28 (m, 1H), 7.19 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.05 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 6.08 (s, 1H).

2-(2-Fluorophenyl)-2-(2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5bb). Yield 278 mg (0.74 mmol, 74%), colorless crystals, mp 186–187 °C (benzene), R_f 0.27 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 7.82–7.68 (m, 4H), 7.64 (d, J = 8.0 Hz, 1H), 7.49–7.38 (m, 4H), 7.31 (d, J = 8.1 Hz, 1H), 7.22–7.12 (m, 2H), 7.06 (t, J = 7.3 Hz, 1H), 7.02–6.90 (m, 2H), 5.70 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 171.2, 160.2 (d, ¹J_CF = 249.3 Hz), 136.9, 136.1, 133.3 (d, J = 15.2 Hz), 130.3, 130.2, 129.4 (d, J = 8.2 Hz), 129.1 (d, J = 2.7 Hz), 128.8, 128.3, 128.0 (d, J = 3.3 Hz), 127.1, 127.0 (2C), 126.1, 125.8, 124.6 (d, J = 3.7 Hz), 123.1, 120.9, 119.7, 118.8, 116.1, 115.9, 111.5, 104.8, 28.2; FT IR (NaCl, cm⁻¹): 3451, 2357, 2332, 1485, 1454, 1219, 860, 827, 762, 743; HRMS (ES TOF): calc'd for C₂₆H₁₇FN₂Na⁺ (M + Na) 399.1268, found 399.1276 (2.0 ppm).

2-(3-Fluorophenyl)-2-(2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5bc). Yield 267 mg (0.71 mmol, 71%), colorless crystals, mp 92–93 °C (benzene), R_f 0.33 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.00–7.94 (m, 2H), 7.93–7.85 (m, 2H), 7.62–7.54 (m, 3H), 7.48 (dd, J = 12.3, 8.1 Hz, 2H), 7.42 (d, J = 1.1 Hz, 1H), 7.38–7.33 (m, 1H), 7.31–7.26 (m, 3H), 7.18–7.12 (m, 1H), 5.65 (s, 1H); ¹³C NMR (101 MHz, CDCl3) δ 160.1 (d, J = 247.3 Hz), 137.6, 137.2, 136.3, 135.1, 133.4 (d, J = 10.8 Hz), 130.3, 129.5, 128.6, 128.4, 128.3, 128.1, 128.0, 127.5, 127.3, 126.6, 125.7, 125.5, 123.5, 121.1, 119.8, 119.1, 111.5, 105.9, 77.2, 33.3; FT IR (NaCl, cm⁻¹): 3333, 3055, 2922, 2851, 1595, 1574, 1474, 1454, 1425, 1342, 1263, 1242, 895, 860, 820, 739, 721, 700; HRMS (ES TOF): calc'd for C₂₆H₁₇FN₂Na⁺ (M + Na) 399.1268, found 399.1276 (2.0 ppm).

2-(2-Bromophenyl)-2-(2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5be). Yield 297 mg (0.68 mmol, 68%), light brown crystals, mp 205–206 °C (benzene); ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.84–7.78 (m, 1H), 7.76–7.72 (m, 2H), 7.69 (s, 1H), 7.63 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 (dd, J = 7.9, 1.2 Hz, 1H), 7.50–7.45 (m, 2H), 7.43–7.38 (m, 2H), 7.25–7.20 (m, 2H), 7.16–7.11 (m, 2H), 5.76 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 137.1, 136.0, 135.1, 133.6, 133.3, 133.1, 130.1, 130.0, 129.2, 128.7, 128.3, 128.0, 127.9, 127.7, 127.4, 126.98, 126.96, 125.3, 123.7, 123.1, 121.0, 119.8, 118.6, 111.3, 105.1, 34.6; FT IR (NaCl, cm⁻¹): 3345, 2361, 1497, 1350, 1026, 957, 897, 814, 756, 736, 708; HRMS (ES TOF): calc'd for C₂₆H₁₇⁷⁹BrN₂Na⁺ (M + Na) 459.0467, found 459.0469 (0.4 ppm).

2-(2-(Naphthalen-2-yl)-1H-indol-3-yl)-2-(4-nitrophenyl)acetonitrile (5be). Yield 250 mg (0.62 mmol, 62%), light-brown crystals, mp 98–99 °C (benzene), R_f 0.26 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.07–8.02 (m, 2H), 7.89–7.83 (m, 2H), 7.83–7.74 (m, 2H), 7.50–7.44 (m, 5H), 7.37 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.63 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 147.7, 142.7, 137.5, 136.3, 133.4, 133.4, 129.6, 128.3 (2C), 128.3, 128.1 (2C), 127.4 (2C), 126.3, 125.6, 124.3 (2C), 123.7, 121.3, 119.4, 118.6, 111.7, 105.3, 33.6, 29.8; FT IR (NaCl, cm⁻¹): 3383, 2920, 2853, 1599, 1518, 1454, 1342, 1242, 1109, 1015, 905, 854, 822, 743, 727, 708; HRMS (ES TOF): calc'd for C₂₆H₁₇N₃NaO₂⁺ (M + Na) 426.1213, found 426.1211 (0.5 ppm).

2-(4-Methoxyphenyl)-2-(2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5bf). Yield 268 mg (0.69 mmol, 69%), light brown crystalline solid, mp 198–199 °C (benzene), R_f 0.24 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.96 (d, J = 8.9 Hz, 2H), 7.93–7.82 (m, 2H), 7.60 (dd, J = 8.4, 1.8 Hz, 1H), 7.58–7.51 (m, 3H), 7.45 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.29–7.23 (m, 1H), 7.16–7.10 (m, 1H), 6.90–6.83 (m, 2H), 5.63 (s, 1H), 3.79 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 159.3, 136.8, 136.3, 133.5, 133.3, 129.3, 128.9, 128.5 (2C), 128.3, 128.0, 127.9, 127.6, 127.2, 127.1, 126.9, 125.8, 123.3, 120.9, 120.1, 120.0, 114.5 (2C), 111.3, 106.9, 55.5, 32.9; FT IR (NaCl, cm⁻¹): 3345, 2363, 1508, 1439, 1248, 1179, 1024, 826, 741; HRMS (ES TOF): calc'd for C₂₇H₂₀N₂NaO⁺ (M + Na) 411.1468, found 411.1476 (1.9 ppm).

2-(4-Ethoxyphenyl)-2-(2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5bg). Yield 253 mg (0.63 mmol, 63%), light-grey crystalline solid, mp 149–150 °C (benzene), R_f 0.28 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 7.98–7.80 (m, 4H), 7.62–7.51 (m, 4H), 7.44 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 8.9 Hz, 2H), 7.30–7.21 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 5.63 (s, 1H), 4.00 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 158.7, 136.8, 136.3, 133.4, 133.2, 129.3, 128.9, 128.5, 128.3 (2C), 128.0, 127.9, 127.4, 127.12, 127.07, 126.9, 125.8, 123.2, 120.9, 120.1, 120.0, 115.0 (2C), 111.3, 106.9, 63.6, 32.9, 14.9; FT IR (NaCl, cm⁻¹): 3335, 2922, 2237, 1740, 1607, 1508, 1445, 1389, 1346, 1302, 1254, 1236, 1177, 1113, 1043, 957, 903, 816, 758, 739, 704; HRMS (ES TOF): calc'd for C₂₈H₂₂N₂NaO⁺ (M + Na) 425.1624, found 425.1631 (1.6 ppm).

2-Phenyl-2-(2-(p-tolyl)-1H-indol-3-yl)acetonitrile (5ca). Yield 245 mg (0.76 mmol, 76%), light brown crystalline solid, mp 84–85 °C (benzene), R_f 0.35 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.46–7.37 (m, 5H), 7.37–7.27 (m, 5H), 7.26–7.20 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 5.62 (s, 1H), 2.43 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 139.1, 137.2, 136.0, 135.6, 130.1 (2C), 129.0 (2C), 128.6, 128.4, 127.9 (2C), 127.3 (2C), 126.8, 123.0, 120.7, 119.84, 119.78, 111.3, 105.7, 33.5, 21.4; FT IR (NaCl, cm⁻¹): 3345, 2243, 1504, 1493, 1450, 1342, 1314, 1263, 1244, 820, 739, 718; HRMS (ES TOF): calc'd for C₂₃H₁₈N₂Na⁺ (M + Na) 345.1362, found 345.1363 (0.3 ppm).

2-(2-(2,4-Dimethoxyphenyl)-1H-indol-3-yl)-2-phenylacetonitrile (5da). Yield 217 mg (0.59 mmol, 59%), light-brown crystals, mp 75–76 °C (benzene), R_f 0.15 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 7.45–7.39 (m, 4H), 7.34–7.27 (m, 3H), 7.24–7.19 (m, 1H), 7.09–7.05 (m, 1H), 6.99–6.92 (m, 3H), 5.54 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 153.9, 151.3, 136.1, 135.7, 133.5, 128.9 (2C), 127.8, 127.4 (2C), 126.4, 122.9, 120.8, 120.5, 119.9, 119.8, 116.4, 115.6, 113.1, 111.2, 107.3, 56.3, 55.9, 33.9; FT IR (NaCl, cm⁻¹): 3364, 2926, 1493, 1460, 1437, 1277, 1215, 1179, 1042, 1020, 808, 768, 735, 719; HRMS (ES TOF): calc'd for C₂₄H₂₀N₂NaO₂⁺ (M + Na) 391.1417, found 391.1419 (0.5 ppm).

2-(2-(3,4-Dimethoxyphenyl)-1H-indol-3-yl)-2-phenylacetonitrile (5ea). Yield 244 mg (0.61 mmol, 61%), light brown crystals, mp 222–223 °C (benzene), R_f 0.15 (hexane/EtOAc 1 : 1); NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44–7.39 (m, 3H), 7.37–7.28 (m, 3H), 7.24–7.20 (m, 1H), 7.14–7.02 (m, 2H), 6.98–6.92 (m, 2H), 5.61 (s, 1H), 3.93 (s, 3H), 3.81 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 149.8, 149.6, 137.1, 135.9, 135.7, 129.1 (2C), 128, 127.3 (2C), 127, 124.1, 123, 121.1, 120.8, 119.8, 119.7, 111.8, 111.6, 111.2, 105.6, 56.2, 56.1, 33.5; FT IR (NaCl, cm⁻¹): 3374, 2359, 1510, 1250, 1217, 1177, 1140, 1020, 748; HRMS (ES TOF): calc'd for C₂₄H₂₀N₂NaO₂+ (M + Na) 391.1417, found 391.1416 (0.3 ppm).

2-Phenyl-2-(2-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5fa). Yield 261 mg (0.72 mmol, 72%), yellowish oil, R_f 0.43 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.54–7.43 (m, 4H), 7.43–7.40 (m, J = 7.9, 1.3 Hz, 1H), 7.40–7.25 (m, 5H), 7.23 (d, J = 7.6 Hz, 1H), 7.17–7.10 (m, 1H), 5.68 (s, 1H), 2.93–2.82 (m, 4H), 1.95–1.83 (m, 4H); ¹³C NMR (101 MHz, CDCl₃) δ 138.5, 138.41, 137.39, 136.0, 135.7, 130.2, 129.1, 129.0 (2C), 128.6, 128.5, 127.9, 127.3 (2C), 126.8, 125.6, 122.9, 120.7, 119.9, 119.8, 111.2, 105.7, 33.5, 29.6, 29.4, 23.1; FT IR (NaCl, cm⁻¹): 3397, 2930, 2241, 1493, 1456, 1435, 1310, 1263, 1246, 914, 831, 735, 719; HRMS (ES TOF): calc'd for C₂₆H₂₂N₂Na⁺ (M + Na) 385.1675, found 385.1684 (2.3 ppm).

2-(2-Fluorophenyl)-2-(1-methyl-2-(naphthalen-2-yl)-1H-indol-3-yl)acetonitrile (5gb). Yield 242 mg (0.62 mmol, 62%), colorless crystals, mp 65–66 °C (benzene), R_f 0.47 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 8.4 Hz, 1H), 7.92–7.79 (m, 3H), 7.71 (d, J = 8.0 Hz, 1H), 7.62–7.54 (m, 3H), 7.45–7.39 (m, 2H), 7.32 (dd, J = 11.2, 4.1 Hz, 1H), 7.25 (ddd, J = 8.7, 7.5, 1.7 Hz, 1H), 7.19 (dd, J = 11.1, 4.0 Hz, 1H), 7.09 (ddd, J = 7.6, 0.8 Hz, 1H), 6.97 (dd, J = 9.8, 8.8 Hz, 1H), 5.53 (s, 1H), 3.64 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 160.1 (d, J = 249.4 Hz), 139.6, 137.4, 133.3 (d, J = 21.0 Hz), 130.4, 130.1, 129.4, 128.7, 128.4, 128.0, 127.8, 127.7, 127.3, 125.9, 124.4 (d, J = 3.6 Hz), 123.5, 123.4, 122.6, 120.6, 119.5, 119.0, 116.1, 115.8, 110.0, 105.5, 31.2, 29.9; FT IR (NaCl, cm⁻¹): 2920, 2851, 1742, 1478, 1456, 1364, 1231, 907, 862, 824, 814, 739; HRMS (ES TOF): calc'd for C₂₇H₂₀FN₂⁺ (M + H) 391.1605, found 391.1612 (1.8 ppm).

General procedure B (applied for electron-reach arenes)

To a molten mixture of arene (1.0 mmol) and nitrostyrene (1.0 mmol) heated to 85 °C, was added concentrated sulfuric acid (10 μL, 20 mg, 0.2 mmol). The mixture was vigorously stirred for 1 h, then cooled down and diluted with pyridine (8.2 mL). Phosphorous trichloride was added in one portion (0.95 mL, 1.50 g, 10.9 mmol), and the mixture was stirred at 60 °C for 4 h, then poured into a mixture of concentrated hydrochloric acid (5 mL, 36%) and crushed ice (∼20 g). The resulting emulsion was extracted with dichloromethane (3 × 25 mL). Combined organic phases were concentrated in vacuum, and the residual oil was purified by preparative column chromatography on silica gel.

2-(4-Methoxyphenyl)-2-phenylacetonitrile (11a)¹¹. Yield 143 mg (0.64 mmol, 64%), colorless crystals, mp 134–136 °C (EtOH), R_f 0.78 (hexane/EtOAc 3 : 1); ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.34 (m, 5H), 7.24 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.09 (s, 1H), 3.79 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 159.6, 136.4, 129.3 (2C), 129.0 (2C), 128.3, 128.1, 127.8 (2C), 120.0, 114.7 (2C), 55.5, 41.9; HRMS (ES TOF): calc'd for C₁₅H₁₃NNaO⁺ (M + Na) 246.0889, found 246.0894 (2.0 ppm).

2-(3,4-Dimethoxyphenyl)-2-phenylacetonitrile (11b). Yield 154 mg (0.61 mmol, 61%), light-orange oil, R_f 0.55 (hexane/EtOAc 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.26 (m, 5H), 6.88 (d, J = 1.8 Hz, 1H), 6.81–6.79 (m, 2H), 5.52 (s, 1H), 3.77 (s, 3H), 3.71 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.9, 150.4, 135.6, 129.0 (2C), 128.0, 127.7 (2C), 125.5, 120.0, 115.2, 114.1, 112.2, 56.2, 55.8, 36.4; IR (NaCl, cm⁻¹): 2940, 2832, 2255, 1736, 1592, 1503, 1449, 1283, 1238, 1050; HRMS (ES TOF): calc'd for C₁₆H₁₅NNaO₂⁺ (M + Na) 276.0995, found 276.1003 (2.9 ppm).

2-(2,3,5,6,8,9,11,12-Octahydrobenzo[b][1,4,7,10,13]pentaoxacyclopentadecin-15-yl)-2-phenylacetonitrile (11c). Yield 241 mg (0.63 mmol, 63%), yellow oil, R_f 0.75 (EtOAc/EtOH 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.28 (m, 5H), 6.88–6.78 (m, 3H), 5.06 (s, 1H), 4.12–4.06 (m, 4H), 3.90–3.85 (m, 4H), 3.73 (s, 8H), ¹³C NMR (101 MHz, CDCl₃) δ 149.6, 149.2, 136.1, 129.2 (C), 128.7, 128.2, 127.7 (2C), 120.8, 119.9, 114.1, 113.5, 71.14, 71.13, 70.54, 70.52, 69.53, 69.50, 69.2, 69.1, 42.1; FT IR (NaCl, cm⁻¹): 3554, 2932, 2874, 2227, 1735, 1593, 1515, 1450, 1431, 1347, 1269, 1243, 1137, 1043, 972, 933; HRMS (ES TOF): calc'd for C₂₂H₂₅NNaO₅⁺ (M + Na) 406.1625, found 406.1634 (2.2 ppm).

2-(2,3,5,6,8,9,11,12,14,15-Decahydrobenzo[b][1,4,7,10,13, 16]hexaoxacyclooctadecin-18-yl)-2-phenylacetonitrile (11d). Yield 260 mg (0.61 mmol, 61%), yellow oil, R_f 0.48 (EtOAc/EtOH 1 : 1); ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.29 (m, 5H), 6.89–6.79 (m, 3H), 5.06 (s, 1H), 4.17–4.09 (m, 4H), 3.95–3.87 (m, 4H), 3.79–3.66 (m, 12H); ¹³C NMR (101 MHz, CDCl₃) δ 149.5, 149.1, 136.2, 129.2 (2C), 128.7, 128.3, 127.8 (2C), 120.8, 119.9, 114.2, 113.7, 70.98, 70.97, 70.89, 70.85, 69.6, 69.4, 69.33, 69.28, 69.2, 69.0, 42.2; IR (NaCl, cm⁻¹): 3607, 2926, 2877, 2215, 1771, 1597, 1503, 1440, 1265, 1247, 1122, 1059; HRMS (ES TOF): calc'd for C₂₄H₂₉NNaO₆⁺ (M + Na) 450.1887, found 450.1896 (2.0 ppm).

Acknowledgements

Financial support for this work was provided by Russian Science Foundation (grant #14-23-00068).

Notes and references

1. See for reviews: (a) S. Lancianesi, A. Palmeri and M. Petrini, Chem. Rev., 2014, 114, 7108; (b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (c) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003; (d) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489.
2. (a) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem. Commun., 2013, 49, 9305; (b) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, A. S. Bijieva and M. Rubin, Org. Biomol. Chem., 2014, 12, 9786; (c) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, J. P. Matheny and M. Rubin, RSC Adv., 2015, 5, 8647.
3. A. V. Aksenov, A. N. Smirnov, I. V. Magedov, M. R. Reisenauer, N. A. Aksenov, I. V. Aksenova, A. L. Pendleton, G. Nguyen, R. K. Johnston, M. Rubin, A. De Carvalho, R. Kiss, V. Mathieu, F. Lefranc, J. Correa, D. A. Cavazos, A. J. Brenner, B. A. Bryan, S. Rogelj, A. Kornienko and L. Frolova, J. Med. Chem., 2015, 58, 2206.
4. See, for example: (a) M. Arisawa, Y. Kasaya, T. Obata, T. Sasaki, T. Nakamura, T. Araki, K. Yamamoto, A. Sasaki, A. Yamano, M. Ito, H. Abe, Y. Ito and S. Shuto, J. Med. Chem., 2012, 55, 8152; (b) M. Arisawa, Y. Kasaya, T. Obata, T. Sasaki, M. Ito, H. Abe, Y. Ito, A. Yamano and S. Shuto, ACS Med. Chem. Lett., 2011, 2, 353; (c) T. Tsuchimoto and M. Kanbara, Org. Lett., 2011, 13, 912.
5. (a) J. von Braun and W. Sobecki, Ber. Dtsch. Chem. Ges., 1911, 44, 2526; (b) J. von Braun and E. Danziger, Ber. Dtsch. Chem. Ges., 1913, 46, 103; (c) M. Bartra, P. Romea, F. Urpí and J. Vilarasa, Tetrahedron, 1990, 46, 587; (d) D. Edmont and D. M. Williams, Tetrahedron Lett., 2000, 41, 8581; (e) C. C. Hughes and D. Trauner, Angew. Chem., Int. Ed., 2002, 41, 4556; (f) D. H. R. Barton, I. Fernandez, C. S. Richard and S. Z. Zard, Tetrahedron, 1987, 43, 551; (g) D. Albanese, D. Landini, M. Peno and G. Pozzi, Synth. Commun., 1990, 20, 965; (h) D. Albanese, D. Landini and M. Penseo, Synthesis, 1990, 333; (i) K. Johnson and E. F. Degering, J. Am. Chem. Soc., 1939, 61, 3194; (j) J. E. McMurry and J. Melton, J. Org. Chem., 1973, 38, 4367; (k) Y. Akita, M. Inaba, H. Uchida and A. Ohta, Synthesis, 1977, 792.
6. See, for example: (a) K. S. Babu, V. R. S. Rao, P. Sunitha, S. S. Babu and J. M. Rao, Synth. Commun., 2008, 38, 1784; (b) V. P. Kumar, R. Sridhar, B. Srinivas, M. Narender and K. R. Rao, Can. J. Chem., 2008, 86, 907; (c) P. M. Habib, V. Kavala, C.-W. Kuo and C.-F. Yao, Tetrahedron Lett., 2008, 49, 7005; (d) P. M. Habib, V. Kavala, C.-W. Kuo, M. J. Raihan and C.-F. Yao, Tetrahedron, 2010, 66, 7050; (e) Y. Gu, J. Barrault and F. Jerome, Adv. Synth. Catal., 2008, 350, 2007; (f) M. Bandini, P. Melchiorre, A. Melloni and A. Umani-Ronchi, Synthesis, 2002, 1110; (g) C.-W. Kuo, C.-C. Wang, H.-L. Fang, D. Rama Raju, V. Kavala, P. M. Habib and C.-F. Yao, Molecules, 2009, 14, 3952.
7. L. El Kaim and A. Gacon, Tetrahedron Lett., 1997, 38, 3391.
8. (a) B. Temelli and C. Unaleroglu, Synthesis, 2014, 46, 1407; (b) S. C. Tsay, P. Gani and J. R. Hwu, J. Chem. Soc., Perkin Trans. 1, 1991, 1493.
9. R. G. de Noronha, C. C. Romao and A. C. Fernandes, J. Org. Chem., 2009, 74, 6960.
10. S. Cai, S. Zhang, Y. Zhao and D. Z. Wang, Org. Lett., 2013, 15, 2660.
11. G. Chen, Z. Wang, J. Wu and K. Ding, Org. Lett., 2008, 10, 4573.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. See DOI: 10.1039/c5ra20953f

---