DOI:
10.1039/C5RA20953F
(Paper)
RSC Adv., 2015,
5, 106492-106497
Nitroalkenes as surrogates for cyanomethylium species in a one-pot synthesis of non-symmetric diarylacetonitriles†
Received
9th October 2015
, Accepted 30th November 2015
First published on 2nd December 2015
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-pot7–10 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 stepa
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 |
R1 |
Ar1 |
Ar2 |
5 |
Yield, %a |
Isolated yields of purified nitrile products. 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-C10H11b |
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, Rf 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), Rf 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), Rf 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, 1JCF = 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), Rf 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), Rf 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), Rf 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), Rf 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), Rf 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), Rf 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), Rf 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, Rf 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), Rf 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), Rf 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, Rf 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, Rf 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, Rf 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
- See for reviews:
(a) S. Lancianesi, A. Palmeri and M. Petrini, Chem. Rev., 2014, 114, 7108 CrossRef CAS PubMed;
(b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748 CrossRef CAS PubMed;
(c) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003 CrossRef CAS;
(d) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489 CrossRef CAS PubMed.
-
(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 RSC;
(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 RSC;
(c) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, J. P. Matheny and M. Rubin, RSC Adv., 2015, 5, 8647 RSC.
- 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 CrossRef CAS PubMed.
- 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 CrossRef CAS PubMed;
(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 CrossRef CAS PubMed;
(c) T. Tsuchimoto and M. Kanbara, Org. Lett., 2011, 13, 912 CrossRef CAS PubMed.
-
(a) J. von Braun and W. Sobecki, Ber. Dtsch. Chem. Ges., 1911, 44, 2526 CrossRef;
(b) J. von Braun and E. Danziger, Ber. Dtsch. Chem. Ges., 1913, 46, 103 CrossRef;
(c) M. Bartra, P. Romea, F. Urpí and J. Vilarasa, Tetrahedron, 1990, 46, 587 CrossRef CAS;
(d) D. Edmont and D. M. Williams, Tetrahedron Lett., 2000, 41, 8581 CrossRef CAS;
(e) C. C. Hughes and D. Trauner, Angew. Chem., Int. Ed., 2002, 41, 4556 CrossRef CAS;
(f) D. H. R. Barton, I. Fernandez, C. S. Richard and S. Z. Zard, Tetrahedron, 1987, 43, 551 CrossRef CAS;
(g) D. Albanese, D. Landini, M. Peno and G. Pozzi, Synth. Commun., 1990, 20, 965 CrossRef CAS;
(h) D. Albanese, D. Landini and M. Penseo, Synthesis, 1990, 333 CrossRef CAS;
(i) K. Johnson and E. F. Degering, J. Am. Chem. Soc., 1939, 61, 3194 CrossRef CAS;
(j) J. E. McMurry and J. Melton, J. Org. Chem., 1973, 38, 4367 CrossRef CAS;
(k) Y. Akita, M. Inaba, H. Uchida and A. Ohta, Synthesis, 1977, 792 CrossRef CAS.
- 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 CrossRef CAS;
(b) V. P. Kumar, R. Sridhar, B. Srinivas, M. Narender and K. R. Rao, Can. J. Chem., 2008, 86, 907 CrossRef CAS;
(c) P. M. Habib, V. Kavala, C.-W. Kuo and C.-F. Yao, Tetrahedron Lett., 2008, 49, 7005 CrossRef CAS;
(d) P. M. Habib, V. Kavala, C.-W. Kuo, M. J. Raihan and C.-F. Yao, Tetrahedron, 2010, 66, 7050 CrossRef CAS;
(e) Y. Gu, J. Barrault and F. Jerome, Adv. Synth. Catal., 2008, 350, 2007 CrossRef CAS;
(f) M. Bandini, P. Melchiorre, A. Melloni and A. Umani-Ronchi, Synthesis, 2002, 1110 CrossRef CAS;
(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 CrossRef CAS PubMed.
- L. El Kaim and A. Gacon, Tetrahedron Lett., 1997, 38, 3391 CrossRef CAS.
-
(a) B. Temelli and C. Unaleroglu, Synthesis, 2014, 46, 1407 CrossRef;
(b) S. C. Tsay, P. Gani and J. R. Hwu, J. Chem. Soc., Perkin Trans. 1, 1991, 1493 RSC.
- R. G. de Noronha, C. C. Romao and A. C. Fernandes, J. Org. Chem., 2009, 74, 6960 CrossRef CAS PubMed.
- S. Cai, S. Zhang, Y. Zhao and D. Z. Wang, Org. Lett., 2013, 15, 2660 CrossRef CAS PubMed.
- G. Chen, Z. Wang, J. Wu and K. Ding, Org. Lett., 2008, 10, 4573 CrossRef CAS PubMed.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, physico-chemical and spectral data. See DOI: 10.1039/c5ra20953f |
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