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Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate† Lianpeng Zhang, Ping Lu* and Yanguang Wang*
Received 18th June 2015, Accepted 25th June 2015
The copper-mediated cyanation of indoles with DMF as a single surrogate has been realized. This
DOI: 10.1039/c5ob01244a
aldehydes were demonstrated to be the key intermediates in the cascade process of cyanation of indoles and electron-rich arenes.
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approach could be applied for the cyanation of some electron-rich arenes and aryl aldehydes as well. Aryl
Introduction Aryl nitriles are an important class of compounds in medicinal science. For example, therapeutic estrogen receptor ligand A shows activity in treatment of diseases associated with the estrogen receptor such as depressive disorders, anxiety disorders, and Alzheimer’s disease (Scheme 1).1 Taranabant is a cannabinoid receptor type 1 inverse agonist investigated as a potential treatment for obesity, and contains a cyano group on its phenyl ring.2 Moreover, the cyano group on aryl nitriles could be transferred into various functional groups, such as carboxylic acids, amides, amidines, amines, imidazoles, tri-
Scheme 1 nitriles.
Structures of representative drugs prepared from aryl
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China. E-mail: [email protected], [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c5ob01244a
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azoles, and tetrazoles. Therefore, aryl nitriles are important intermediates both in organic synthesis and in the pharmaceutical industry. For instance, nortopsentins A–D, exhibiting antiviral, antimicrobial, anti-inflammatory, and anticancer activities,3 were synthesized from 3-cyanoindoles. Forasartan, a nonpeptide angiotensin II receptor antagonist clinically used for the treatment of hypertension,4 was prepared from 2-bromobenzonitrile. Among the aryl nitriles, 3-cyanoindoles have attracted much more attention due to their importance. The published strategies for the preparation of 3-cyanoindoles include the construction of the indole ring and the functionalization of indoles. The former one is seldom utilized because specified substrates are required in those cases (Scheme 2A).5 Classical approaches for the functionalization of indoles include the electrophilic aromatic substitution of indoles (Scheme 2B)6–8 and the functional transformations of 3-substituted indoles (Scheme 2C).9–11 The modern approach to 3-cyanoindoles is the metal-mediated direct cyanation of indoles, which has emerged as a powerful tool because of easily available starting materials and mild reaction conditions.12 In this blooming field, the palladium-catalyzed C3-cyanation of indoles is of particular importance (Scheme 2D).13 However, the large affinity of the cyanide anion to the palladium center inevitably results in the overloading of cyanide anions on palladium and directly inhibits the catalyst activity.14 Three strategies could be applied to avoid this drawback. Those are selecting suitable ligands, releasing or forming “CN” during the reaction process,15 and changing the metal. Replacing palladium with zinc,16 ferrous,17 and copper18 is of economic value no matter what kind of mechanism is followed. It has been disclosed that “CN” for the copper-catalyzed C3-cyanation of indole could be generated from benzyl cyanide,19 DMF/NH4I,20 or TMEDA/(NH4)2CO3 21 (Scheme 2E). In our ongoing research towards the development of the copper-mediated cyanation of
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Scheme 2
Published methods for preparation of 3-cyanoindoles.
aryl halides using DMF as a single source,22 we recently found that this approach could be applied to the cyanation of indoles and some other electron-rich arenes. Herein, we report our results on this subject.
Results and discussion Our initial attempt was launched with the cyanation of indole (1a). To our delight, when the mixture of 1a, CuI, HOAc, and TBHP in DMF (in 1 : 1.2 : 8 : 2 ratio) was stirred in air at 120 °C for 48 h, 3-cyanoindole (2a) was isolated in 64% yield (Table 1, entry 1). By changing the Cu(I) source to others, such as CuBr, CuCl, and Cu2O, decreased yields were observed (Table 1, entries 2–4). The Cu(II) sources, such as CuBr2, Cu(OAc)2, CuSO4, Cu(NO3)2·3H2O, CuCl2·2H2O, CuO, and Cu(OTf )2, gave poor yields (Table 1, entries 5–11). Some of them did not afford the expected product. 2a could only be detected in traces by TLC when copper powder was used (Table 1, entry 12). Decreasing the amount of CuI led to a decrease in the yield of 2a, while increasing the amount of CuI to 1.5 equivalents did not improve the yield (Table 1, entries 1, 13 and 14). However, 3-formylindole instead of obtaining 2a was obtained in 78% yield when 0.3 equivalents of CuI were used. The optimal amount of HOAc was determined to be 4 equivalents to the amount of 1a (Table 1, entries 1 and 15–17). In the absence of HOAc, 2a was isolated in 45% yield (Table 1, entry 18). The optimal TBHP was determined to be 2 equivalents (Table 1, entries, 16, 19 and 20). Without TBHP, 2a was
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Paper Table 1
Screening of the reaction conditionsa
Entry
[Cu] (equiv.)
HOAc (equiv.)
TBHP (equiv.)
Temp (°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
CuI (1.2) CuBr (1.2) CuCl (1.2) Cu2O (1.2) CuBr2 (1.2) Cu(OAc)2 (1.2) CuSO4 (1.2) Cu(NO3)2·3H2O (1.2) CuCl2·2H2O (1.2) CuO (1.2) Cu(OTf)2 (1.2) Cu (1.2) CuI (1.0) CuI (1.5) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2)
8 8 8 8 8 8 8 8 8 8 8 8 8 8 12 4 2 — 4 4 4 4 4 4
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 1 — 2 2 2
120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 110 130 120
64 35 25 40 Trace 41 Trace 39 Trace Trace Trace Trace 45 64 60 68 48 45 62 47 41 46 51 Tracec
a Reaction conditions: 1a (0.5 mmol), [Cu] source, HOAc, TBHP, DMF (3.0 mL), air, 48 h. b Yield of the isolated product after column chromatography on silica gel. c Dry N2 atmosphere.
obtained in 41% yield (Table 1, entry 21). The optimal reaction temperature was determined to be 120 °C (Table 1, entries 16, 22 and 23). When the reaction was carried out in nitrogen, traces of 2a were detected by TLC (Table 1, entry 24). With the optimized reaction conditions in hand, we tested the substrate diversity of this reaction (Table 2). Lots of functional groups were compatible and tolerated the reaction conditions. When the NH of indoles was protected with methyl, ethyl, allyl, phenyl, 4-methoxyphenyl, and benzyl, 2b–g were obtained at 130 °C in 55–80% yields. The oxidation of the C–H bond in either N–CH3 or allylic/benzylic was not observed. Cyanation exclusively occurred on the 3-position of indoles without the contaminant derived from the cyanation on the 2-position of indoles or on the phenyl ring of 1-(4-methoxyphenyl)-1H-indole. tert-Butyl indole-1-carboxylate afforded 2a in 73% yield. In this case, the tert-butyl group was removed. Whereas, the cyanation of 1-tosyl-1H-indole did not occur, implying that the decreased electron density of the substrate influenced the reactivity. 2-Substituted indoles such as 2-phenylindole and 2-(4-fluorophenyl)indole were also examined and the desired products 2h and 2i were isolated in 86% and 66% yields, respectively. 5-Substituted indoles provided 2j–l in relatively lower yields. With phenyl blocked on the 2-position of indoles, 2m was prepared in 80% yield. When NH of
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Table 2
Organic & Biomolecular Chemistry Copper-mediated cyanation of indoles and arenesa
Scheme 3
a
Reaction conditions: 1 (0.5 mmol), CuI (0.6 mmol), HOAc (2.0 mmol), TBHP (1.0 mmol), DMF (3 mL), air, 48 h. b 120 °C. c 130 °C. d 140 °C.
indoles was protected by the ethyl group, 2n and 2o were produced in 65% and 30% yields, respectively. Instead of indoles, 9H-carbazole and 1-ethyl-1H-pyrrolo[2,3-b]pyridine could also work as the substrate to furnish the corresponding cyanation products 2p and 2q in 38% and 60% yields, respectively. Under the standard reaction conditions, some electron-rich carbocyclic arenes, such as 1,3,5-trimethoxybenzene, 1,3-dimethoxybenzene, and 3,4,5-trimethoxytoluene could also be cyanated to give 2r, 2s, and 2t in 80%, 51%, and 35% yields, respectively. However, without any electron-donating group on the arenes, naphthalene, anthracene, and pyrene did not afford any desired products. Moreover, benzothiophene and benzofuran also didn’t work for this transformation, and the starting materials were recovered after the reaction. This protocol could be scaled up and of practical usage in the preparation of therapeutic estrogen receptor ligand A (Scheme 3). Thus, 1.489 g of 2f was prepared in 75% yield by using this protocol. After a sequential bromination, demethylation, and amination, therapeutic estrogen receptor ligand A was successfully afforded in 35% total yield. In order to have a deep insight into the reaction mechanism, we tracked the reaction with carbon-13 labeled on carbo-
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Preparation of therapeutic estrogen receptor ligand A.
nyl carbon of DMF. 3-Cyanoindole (2a) was obtained without the appearance of carbon-13 (Scheme 4). To our surprise, when 3-formylindole (3a-13C), the carbonyl carbon labelled with carbon-13, was used as a substrate, 2a-13C was obtained. Moreover, the results of the screening of the reaction conditions (Table 2, entries 18 and 21) indicated that the carbon of “CN” in 3-cyanoindole could not come from HOAc or TBHP. Based on these experiments, it could be concluded that carbon of “CN” came from the methyl of DMF. Without any other choices, nitrogen of “CN” came from DMF. Thus, both carbon and nitrogen of “CN” in the final product came from a single DMF. It is also noticeable that 3-formylindole (3a) was isolated in 72% yield when N,N-dimethylacetamide (DMA) was used instead of DMF. Furthermore, 2a could also be prepared from 3-(N,N-dimethylamino)methylindole (4). The reaction profile using 1a under the standard reaction conditions is shown in Fig. S1 (see the ESI†). As the reaction
Scheme 4
Mechanistic study.
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progressed, 1a was completely consumed in the initial 5 h and transferred into 3a as the key intermediate. A steady increment of 2a was observed after the reaction was carried out from 10 h to 40 h. On the basis of these results, we proposed a possible mechanism for this cascade transformation (Scheme 5). In the presence of Cu(I) and an oxidant, DMF is oxidized into electrondeficient iminium species.20 Then, electrophilic aromatic substitution on electron-rich indole (1a) occurs to form intermediate A. Further copper-catalyzed oxidation, followed by hydrolysis, forms 3-formylindole (3a) as the key intermediate.13c Subsequently, 3a condenses with dimethylamine which is decomposed from DMF23 to generate iminium intermediate C. A sequential demethylation, oxidation, and demethylation through intermediates D and E furnish 2a. Effective transformation from 4 to 2a is indicative of the formation of intermediate C. Since 3-formylindole (3a) is the key intermediate for the formation of 2a from 1a, we were encouraged to develop a preparation of aryl nitriles from aldehydes using DMF as a single surrogate. After screening the reaction conditions by using the cyanation of 3a as the model reaction (see the ESI, Table S1†), the best result was obtained when the mixture of 3a (0.5 mmol), Cu(NO3)2·3H2O (1.0 equiv.), HOAc (8 equiv.) and TBHP (2 equiv.) in DMF (3.0 mL) was stirred under an air atmosphere, at 130 °C for 48 h. With the optimized reaction conditions, we tested the diversity of aryl aldehydes 3 (Table 3). Without the protecting group on N–H of indoles, 2u–2x were obtained in yields ranging from 52% to 75%. By blocking the 2-position of indoles with the aryl group, 2h and 2i were isolated in yields of 85% and 75%, respectively. 1-Methylindole-3-carbaldehyde gave 2b in 82% yield. Furthermore, a variety of aryl aldehydes were converted into the corresponding aryl nitriles 2y, 2z and 2A–G via this reaction. It should be indicated that 2y, 2z and 2A could not be
Scheme 5
Postulated mechanism.
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Paper Table 3
Copper-mediated cyanation of aryl aldehydesa
a
Reaction conditions: 3 (0.5 mmol), Cu(NO3)2·3H2O (0.5 mmol), HOAc (4.0 mmol), TBHP (1.0 mmol), DMF (3.0 mL), air, 130 °C, 48 h.
directly cyanated from the corresponding arenes using the aforementioned standard reaction conditions established for cyanation of indoles. As an exception, 5-methoxy-2-methylisoindoline-1,3-dione (5a) was obtained when 3-methoxybenzaldehyde was subjected to this reaction under the standard reaction conditions (Scheme 6). Similarly, 5b, 5c, and 5d were isolated. During the preparation of this manuscript, Ge reported a direct carbonylation from benzamide to isoindoline-1,3-dione using the
Scheme 6
Preparation of 5a–d.
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methyl of DMF as the carbonyl source in the presence of Cu(acac)2, NiBr2, and O2.24
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Conclusions In conclusion, we developed a copper-mediated cyanation reaction of indoles using DMF as a single surrogate of “CN”. This protocol could be scaled up and of practical usage in the preparation of therapeutic estrogen receptor ligand A. A variety of electron-rich arenes and aryl aldehydes could also be converted into the corresponding aryl nitriles by this approach. Based on the isotope labelling and the controlled experiments, aryl aldehydes were believed to be the key intermediates for the cyanation of arenes. Moreover, isoindoline-1,3-diones were eventually obtained in which C–H activation and subsequent carbonylation were observed although the mechanism is unclear at this stage.
Experimental General methods and materials Unless stated otherwise, reactions were conducted in flamedried glassware. Commercially available reagents and solvents were used as received. 300–400 mesh silica gel was used for flash column chromatography. Visualization on TLC was achieved by the use of UV light (254 nm). 400 MHz and 100 MHz were used to record 1H NMR and 13C NMR spectra, respectively. Chemical shifts (δ) were reported in parts per million referring to either the internal standard of TMS or the residue of the deuterated solvents. The splitting pattern was described as follows: s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet. Coupling constants were reported in Hz. The high-resolution mass spectrum (HRMS) was recorded on a GCT premier instrument. Typical procedure for Cu-mediated cyanation of arenes An oven-dried 25 mL eggplant-shaped bottle equipped with a magnetic stir bar was charged with CuI (0.6 mmol), arene (0.5 mmol), HOAc (2.0 mmol), t-BuOOH (1.0 mmol, 70% aq.) and DMF (3.0 mL). The mixture was stirred under air at 120–140 °C (oil bath temperature) for about 48 hours (checked by TLC). After the arene was completely consumed, the reaction mixture was cooled to room temperature, quenched with 10 mL of water, and extracted with DCM (3 × 10 mL). The organic layer was washed with saturated salt water and concentrated under reduced pressure. The residue was purified by column chromatography to afford the pure product. Typical procedure for Cu-mediated cyanation of aromatic aldehydes An oven-dried 25 mL eggplant-shaped bottle equipped with a magnetic stir bar was charged with Cu(NO3)2·3H2O (0.5 mmol, 1.0 equiv.), aromatic aldehyde (0.5 mmol), HOAc (4.0 mmol), t-BuOOH (1.0 mmol, 70% aq.) and DMF (3.0 mL). The mixture was stirred under air at 130–140 °C (oil bath temperature) for
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about 48 hours (checked by TLC). After the aromatic aldehyde was completely consumed, the reaction mixture was cooled to room temperature, quenched with 10 mL of water, and extracted with DCM (3 × 10 mL). The organic layer was washed with saturated salt water and then concentrated under reduced pressure. The residue was purified through a silica gel column to afford the pure product. 1H-Indole-3-carbonitrile (2a).19a Yellow solid, m.p. 178–180 °C. 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.35 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.31 (td, J = 7.2 Hz, 1.2 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 135.2, 132.2, 127.3, 124.7, 122.7, 120.0, 116.2, 112.4, 87.8. 1-Methyl-1H-indole-3-carbonitrile (2b).19a White solid, m.p. 53–55 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.2, 135.8, 127.9, 124.0, 122.3, 119.9, 116.2, 110.6, 85.5, 33.8. 1-Ethyl-1H-indole-3-carbonitrile (2c). Brown solid, m.p. 88–90 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 4.10 (q, J = 7.3 Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 135.3, 134.2, 128.2, 123.9, 122.3, 120.1, 116.3, 110.7, 85.6, 42.1, 15.4. 1-Allyl-1H-indole-3-carbonitrile (2d). Brown oil, 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 7.2, 1.0 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.36–7.23 (m, 2H), 5.97 (ddd, J = 22.5, 10.6, 5.5 Hz, 1H), 5.28 (d, J = 10.4 Hz, 1H), 5.14 (dd, J = 17.0, 0.6 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 135.6, 135.0, 131.9, 128.1, 124.1, 122.4, 120.1, 119.2, 116.1, 111.0, 86.1, 49.7. 1-Phenyl-1H-indole-3-carbonitrile (2e).20b White solid, m.p. 116–118 °C. 1H NMR (400 MHz, CDCl3) δ 7.85–7.83 (m, 1H), 7.81 (s, 1H), 7.58 (t, J = 8.0 Hz, 2H), 7.53–7.47 (m, 4H), 7.37–7.34 (m, 2H).13C NMR (100 MHz, CDCl3) δ 138.2, 136.0, 135.0, 130.4, 128.7, 128.3, 125.3, 124.9, 123.2, 120.4, 115.9, 111.9, 88.5. 1-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (2f ). White solid, m.p. 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (s, 1H), 7.44–7.40 (m, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.34–7.30 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H).13C NMR (100 MHz, CDCl3) δ 159.8, 136.3, 135.3, 130.9, 128.2, 128.0, 126.7, 124.7, 122.9, 120.2, 115.4, 111.8, 87.7, 56.0. 1-Benzyl-1H-indole-3-carbonitrile (2g). Yellow solid, m.p. 70–72 °C. 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (m, 1H), 7.40 (s, 1H), 7.26–7.08 (m, 6H), 6.98 (dd, J = 7.2, 1.8 Hz, 2H), 5.14 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 135.7, 135.5, 135.3, 129.2, 128.5, 128.1, 127.3, 124.2, 122.4, 112.0, 116.1, 111.1, 86.2, 51.0. 2-Phenyl-1H-indole-3-carbonitrile (2h). White solid, m.p. 245–247 °C. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.72–7.63 (m, 3H), 7.62–7.56 (m, 2H), 7.35 (dd, J = 8.1, 1.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.1 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 145.7, 136.5, 130.9, 130.3, 130.3, 129.2, 127.9, 124.9, 123.0, 119.3, 118.0, 113.6, 82.3.
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2-(4-Fluorophenyl)-1H-indole-3-carbonitrile (2i). White solid, m.p. 239–241 °C. 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.11–8.00 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.9 Hz, 2H), 7.36 (td, J = 7.2, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 162.8 (d, JC–F = 247.0 Hz), 143.8, 135.5, 129.4 (d, JC–F = 8.0 Hz), 128.2, 125.9 (d, JC–F = 3.0 Hz), 123.9, 122.1, 118.3, 116.9, 116.4 (d, JC–F = 21.0 Hz), 112.6, 81.4. 5-Methoxy-1-methyl-1H-indole-3-carbonitrile (2j).19a Yellow solid, m.p. 103–105 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.13 (s, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.9, 2.4 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 156.2, 135.7, 131.3, 128.9, 116.5, 114.8, 111.5, 101.0, 85.0, 56.0, 34.0. 1-Methyl-5-nitro-1H-indole-3-carbonitrile (2k).19a Yellow 1 solid, m.p. 159–160 °C. H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.24 (dd, J = 9.1, 1.8 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 3.97 (s, 3H). 13C NMR (100 MHz, DMSO) δ 143.6, 142.5, 139.7, 127.1, 119.4, 116.1, 115.6, 113.5, 86.7, 34.9. 5-Chloro-1-methyl-1H-indole-3-carbonitrile (2l). Yellow solid, m.p. 97–99 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.31–7.24 (m, 2H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.8, 134.7, 128.9, 128.5, 124.6, 119.5, 111.8, 85.4, 34.2. HRMS: Calcd for C10H7ClN2 [M]+, 190.0298; found, 190.0296. 5-Methoxy-1-methyl-2-phenyl-1H-indole-3-carbonitrile (2m). Canary yellow solid, m.p. 253–255 °C. 1H NMR (400 MHz, DMSO) δ 7.81–7.47 (m, 6H), 7.15 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 9.0, 2.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H). 13C NMR (100 MHz, DMSO) δ 156.7, 148.5, 132.5, 130.8, 130.7, 129.9, 129.4, 128.5, 117.6, 114.9, 113.7, 100.7, 84.4, 56.4, 32.8. 1-Ethyl-2-phenyl-1H-indole-3-carbonitrile (2n).19a Yellow 1 solid, m.p. 108–110 °C. H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.0 Hz, 1H), 7.62–7.52 (m, 5H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (td, J = 7.2, 1.2 Hz, 1H), 7.32 (td, J = 8.0, 1.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.1, 135.9, 130.2, 130.0, 129.4, 128.2, 124.1, 122.6, 120.0, 116.9, 111.1, 86.3, 39.9, 15.6. 1-Ethyl-2-methyl-1H-indole-3-carbonitrile (2o). Brown solid, m.p. 89–91 °C. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.30–7.22 (m, 2H), 4.16 (q, J = 7.3 Hz, 2H), 2.58 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 145.2, 135.5, 127.5, 123.2, 122.1, 119.4, 117.0, 110.1, 85.2, 39.0, 15.2, 12.0. 9H-Carbazole-3-carbonitrile (2p). White solid, m.p. 180–181 °C. 1H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.85 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H).13C NMR (100 MHz, DMSO) δ 142.6, 141.2, 129.5, 127.9, 126.5, 123.6, 122.5, 121.9, 121.5, 120.8, 113.0, 112.5, 101.1. 1-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2q). Yellow solid, m.p. 72–74 °C. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.80 (s, 1H), 7.28 (t, J = 4.0 Hz, 1H), 4.43 (q, J = 7.3 Hz, 2H), 1.55 (t, J = 7.3 Hz,
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3H). 13C NMR (100 MHz, CDCl3) δ 146.6, 145.4, 134.8, 128.7, 120.6, 118.4, 115.5, 84.6, 40.8, 15.8. HRMS: Calcd for C10H9N3 [M]+, 171.0796; found, 171.0794. 2,4,6-Trimethoxybenzonitrile (2r).20a White solid, m.p. 139–140 °C. 1H NMR (400 MHz, CDCl3) δ 6.07 (s, 2H), 3.88 (s, 6H), 3.86 (s, 3H).13C NMR (100 MHz, CDCl3) δ 165.7, 164.1, 114.9, 90.7, 84.4, 56.4, 56.0. 2,4-Dimethoxybenzonitrile (2s).20a White solid, m.p. 93–94 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6, 1H), 6.46 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.0, 163.2, 135.2, 117.3, 106.1, 98.8, 94.3, 56.3, 56.0. 2,3,4-Trimethoxy-6-methylbenzonitrile (2t). Colorless oil, 1 H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 4.03 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 2.46 (s, 3H).13C NMR (100 MHz, CDCl3) δ 157.5, 156.1, 139.9, 139.3, 116.2, 109.0, 100.2, 62.1, 61.5, 56.5, 30.0. HRMS: Calcd for C11H13NO3 [M]+, 207.0895; found, 207.0896. 5-Methoxy-1H-indole-3-carbonitrile (2u).19a White solid, m.p. 154–156 °C. 1H NMR (400 MHz, CDCl3) δ 12.10 (s, 1H), 8.20 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.9, 2.4 Hz, 1H), 3.85 (s, 3H).13C NMR (100 MHz, DMSO) δ 156.2, 135.3, 131.0, 128.5, 117.6, 114.8, 100.7, 84.9, 56.4. 1H-Indole-3,5-dicarbonitrile (2v). Yellow solid, m.p. 257–259 °C. 1H NMR (400 MHz, DMSO) δ 12.73 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 138.3, 138.0, 127.3, 127.2, 125.0, 120.6, 116.1, 115.3, 105.1, 86.4. 5-Chloro-1H-indole-3-carbonitrile (2w). White solid, m.p. 165–167 °C. 1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.36 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 137.1, 134.7, 128.8, 127.5, 124.6, 118.7, 116.7, 115.6, 85.1. 4-Chloro-1H-indole-3-carbonitrile (2x). Yellow solid, m.p. 223–225 °C. 1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 8.41 (s, 1H), 7.62–7.47 (m, 1H), 7.38–7.10 (m, 2H). 13C NMR (100 MHz, DMSO) δ 137.6, 137.4, 125.3, 125.2, 124.5, 122.8, 117.2, 113.2, 84.6. Benzo[b]thiophene-3-carbonitrile (2y). White solid, m.p. 72–74 °C. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.59–7.46 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 138.8, 137.9, 137.6, 126.5, 126.3, 123.2, 122.9, 114.7, 107.4. 2,3-Dihydrobenzofuran-5-carbonitrile (2z). White solid, m.p. 68–70 °C. 1H NMR (400 MHz, CDCl3) δ 7.46–7.44 (m, 2H), 6.82 (d, J = 8.2 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.25 (t, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 164.1, 133.9, 129.2, 128.9, 119.9, 110.6, 103.9, 72.4, 29.3. Benzo[d][1,3]dioxole-5-carbonitrile (2A). White solid, m.p. 91–93 °C. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.06 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 151.8, 148.3, 128.5, 119.2, 111.7, 109.4, 105.2, 102.5. 3,4,5-Trimethoxybenzonitrile (2B). White solid, m.p. 92–94 °C. 1H NMR (400 MHz, CDCl3) δ 6.79 (s, 2H), 3.83
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(s, 3H), 3.81 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 153.8, 142.6, 119.3, 109.7, 107.0, 61.3, 56.7. 4-Methoxybenzonitrile (2C).15b White solid, m.p. 57–58 °C. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H).13C NMR (100 MHz, CDCl3) δ 163.2, 134.3, 119.5, 115.1, 104.3, 55.9. 4-Chlorobenzonitrile (2D).20a White solid, m.p. 90–91 °C. 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 139.9, 133.7, 130.1, 118.3, 111.2. 4-Nitrobenzonitrile (2E).20a Yellow solid, m.p. 140–141 °C. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 133.8, 128.7, 124.6, 118.7, 117.1. 1-Naphthonitrile (2F).15b White solid, m.p. 55–56 °C. 1 H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.4, 7.0 Hz, 1H), 7.62 (dd, J = 8.4, 7.0 Hz, 1H), 7.52 (dd, J = 8.4, 7.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 133.6, 133.3, 133.0, 132.7, 129.0, 128.9, 127.9, 125.5, 125.3, 118.1, 110.5. Pyrene-1-carbonitrile (2G). White solid, m.p. 152–154 °C. 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 7.6 Hz, 2H), 8.17 (dd, J = 13.1, 5.9 Hz, 3H), 8.07 (t, J = 7.6 Hz, 2H), 8.00 (d, J = 9.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 134.4, 133.1, 131.0, 130.72, 130.69, 129.8, 127.3, 127.24, 127.21, 127.1, 124.6, 124.14, 124.12, 123.7, 119.1, 105.8. 2-(Dimethylamino)-1-(4-hydroxyphenyl)-1H-indole-3-carbonitrile. Yellow solid, m.p. 223–225 °C. 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 2.89 (s, 6H). 5-Methoxy-2-methylisoindoline-1,3-dione (5a). White solid, m.p. 155–157 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.3, 2.3 Hz, 1H), 3.91 (s, 3H), 3.14 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.7, 168.6, 164.9, 135.1, 125.2, 124.4, 119.8, 108.4, 56.4, 24.3. 5-Ethoxy-2-methylisoindoline-1,3-dione (5b). White solid, m.p. 109–111 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.15 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 168.7, 164.3, 135.1, 125.2, 124.2, 120.3, 108.8, 64.8, 24.3, 14.9. 5-Isopropoxy-2-methylisoindoline-1,3-dione (5c). White solid, m.p. 93–95 °C 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.09 (dd, J = 8.3, 2.2 Hz, 1H), 4.67 (dt, J = 12.1, 6.0 Hz, 1H), 3.14 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 168.7, 163.4, 135.1, 125.2, 123.9, 121.3, 109.5, 71.3, 24.2, 22.1. HRMS: Calcd for C12H13NO3 [M]+, 219.0895; found, 219.0893. 5-(Benzyloxy)-2-methylisoindoline-1,3-dione (5d). White solid, m.p. 123–125 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 1H), 7.45–7.38 (m, 6H), 7.22 (dd, J = 8.3, 2.3 Hz, 1H), 5.18 (s, 2H), 3.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.63, 168.60, 164.0, 135.8, 135.1, 129.1, 128.8, 127.9, 125.3,
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124.7, 120.7, 109.3, 24.3. HRMS: Calcd for C16H13NO3 [M]+, 267.0895; found, 267.0897.
Acknowledgements The authors thank the National Natural Science Foundation of China (no. 21472173, 21272203) for financial support.
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14 S. Erhardt, V. V. Grushin, A. H. Kilpatrick, S. A. Macgregor, W. J. Marshall and D. C. Roe, J. Am. Chem. Soc., 2008, 130, 4828. 15 (a) X. Ren, J. Chen, F. Chen and J. Cheng, Chem. Commun., 2011, 47, 6725; (b) Q. Wen, J. Jin, B. Hu, P. Lu and Y. Wang, RSC Adv., 2012, 2, 6167; (c) J. Kim, H. J. Kim and S. Chang, Angew. Chem., Int. Ed., 2012, 51, 11948. 16 Y. Nagase, T. Sugiyama, S. Nomiyamaa, K. Yonekura and T. Tsuchimoto, Adv. Synth. Catal., 2014, 356, 347. 17 (a) Z. Shu, W. Ji, X. Wang, Y. Zhou, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2014, 53, 2186; (b) G. Zhang, G. Lv, C. Pan, J. Cheng and F. Chen, Synlett, 2011, 2991. 18 Q. Wen, J. Jin, Y. Mei, P. Lu and Y. Wang, Eur. J. Org. Chem., 2013, 4032. 19 (a) L. Zhang, Q. Wen, J. Jin, C. Wang, P. Lu and Y. Wang, Tetrahedron, 2013, 69, 4236; (b) O. Y. Yuen, P. Y. Choy,
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Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate† Lianpeng Zhang, Ping Lu* and Yanguang Wang*
Received 18th June 2015, Accepted 25th June 2015
The copper-mediated cyanation of indoles with DMF as a single surrogate has been realized. This
DOI: 10.1039/c5ob01244a
aldehydes were demonstrated to be the key intermediates in the cascade process of cyanation of indoles and electron-rich arenes.
www.rsc.org/obc
approach could be applied for the cyanation of some electron-rich arenes and aryl aldehydes as well. Aryl
Introduction Aryl nitriles are an important class of compounds in medicinal science. For example, therapeutic estrogen receptor ligand A shows activity in treatment of diseases associated with the estrogen receptor such as depressive disorders, anxiety disorders, and Alzheimer’s disease (Scheme 1).1 Taranabant is a cannabinoid receptor type 1 inverse agonist investigated as a potential treatment for obesity, and contains a cyano group on its phenyl ring.2 Moreover, the cyano group on aryl nitriles could be transferred into various functional groups, such as carboxylic acids, amides, amidines, amines, imidazoles, tri-
Scheme 1 nitriles.
Structures of representative drugs prepared from aryl
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China. E-mail: [email protected], [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c5ob01244a
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azoles, and tetrazoles. Therefore, aryl nitriles are important intermediates both in organic synthesis and in the pharmaceutical industry. For instance, nortopsentins A–D, exhibiting antiviral, antimicrobial, anti-inflammatory, and anticancer activities,3 were synthesized from 3-cyanoindoles. Forasartan, a nonpeptide angiotensin II receptor antagonist clinically used for the treatment of hypertension,4 was prepared from 2-bromobenzonitrile. Among the aryl nitriles, 3-cyanoindoles have attracted much more attention due to their importance. The published strategies for the preparation of 3-cyanoindoles include the construction of the indole ring and the functionalization of indoles. The former one is seldom utilized because specified substrates are required in those cases (Scheme 2A).5 Classical approaches for the functionalization of indoles include the electrophilic aromatic substitution of indoles (Scheme 2B)6–8 and the functional transformations of 3-substituted indoles (Scheme 2C).9–11 The modern approach to 3-cyanoindoles is the metal-mediated direct cyanation of indoles, which has emerged as a powerful tool because of easily available starting materials and mild reaction conditions.12 In this blooming field, the palladium-catalyzed C3-cyanation of indoles is of particular importance (Scheme 2D).13 However, the large affinity of the cyanide anion to the palladium center inevitably results in the overloading of cyanide anions on palladium and directly inhibits the catalyst activity.14 Three strategies could be applied to avoid this drawback. Those are selecting suitable ligands, releasing or forming “CN” during the reaction process,15 and changing the metal. Replacing palladium with zinc,16 ferrous,17 and copper18 is of economic value no matter what kind of mechanism is followed. It has been disclosed that “CN” for the copper-catalyzed C3-cyanation of indole could be generated from benzyl cyanide,19 DMF/NH4I,20 or TMEDA/(NH4)2CO3 21 (Scheme 2E). In our ongoing research towards the development of the copper-mediated cyanation of
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Scheme 2
Published methods for preparation of 3-cyanoindoles.
aryl halides using DMF as a single source,22 we recently found that this approach could be applied to the cyanation of indoles and some other electron-rich arenes. Herein, we report our results on this subject.
Results and discussion Our initial attempt was launched with the cyanation of indole (1a). To our delight, when the mixture of 1a, CuI, HOAc, and TBHP in DMF (in 1 : 1.2 : 8 : 2 ratio) was stirred in air at 120 °C for 48 h, 3-cyanoindole (2a) was isolated in 64% yield (Table 1, entry 1). By changing the Cu(I) source to others, such as CuBr, CuCl, and Cu2O, decreased yields were observed (Table 1, entries 2–4). The Cu(II) sources, such as CuBr2, Cu(OAc)2, CuSO4, Cu(NO3)2·3H2O, CuCl2·2H2O, CuO, and Cu(OTf )2, gave poor yields (Table 1, entries 5–11). Some of them did not afford the expected product. 2a could only be detected in traces by TLC when copper powder was used (Table 1, entry 12). Decreasing the amount of CuI led to a decrease in the yield of 2a, while increasing the amount of CuI to 1.5 equivalents did not improve the yield (Table 1, entries 1, 13 and 14). However, 3-formylindole instead of obtaining 2a was obtained in 78% yield when 0.3 equivalents of CuI were used. The optimal amount of HOAc was determined to be 4 equivalents to the amount of 1a (Table 1, entries 1 and 15–17). In the absence of HOAc, 2a was isolated in 45% yield (Table 1, entry 18). The optimal TBHP was determined to be 2 equivalents (Table 1, entries, 16, 19 and 20). Without TBHP, 2a was
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Paper Table 1
Screening of the reaction conditionsa
Entry
[Cu] (equiv.)
HOAc (equiv.)
TBHP (equiv.)
Temp (°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
CuI (1.2) CuBr (1.2) CuCl (1.2) Cu2O (1.2) CuBr2 (1.2) Cu(OAc)2 (1.2) CuSO4 (1.2) Cu(NO3)2·3H2O (1.2) CuCl2·2H2O (1.2) CuO (1.2) Cu(OTf)2 (1.2) Cu (1.2) CuI (1.0) CuI (1.5) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2) CuI (1.2)
8 8 8 8 8 8 8 8 8 8 8 8 8 8 12 4 2 — 4 4 4 4 4 4
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 1 — 2 2 2
120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 110 130 120
64 35 25 40 Trace 41 Trace 39 Trace Trace Trace Trace 45 64 60 68 48 45 62 47 41 46 51 Tracec
a Reaction conditions: 1a (0.5 mmol), [Cu] source, HOAc, TBHP, DMF (3.0 mL), air, 48 h. b Yield of the isolated product after column chromatography on silica gel. c Dry N2 atmosphere.
obtained in 41% yield (Table 1, entry 21). The optimal reaction temperature was determined to be 120 °C (Table 1, entries 16, 22 and 23). When the reaction was carried out in nitrogen, traces of 2a were detected by TLC (Table 1, entry 24). With the optimized reaction conditions in hand, we tested the substrate diversity of this reaction (Table 2). Lots of functional groups were compatible and tolerated the reaction conditions. When the NH of indoles was protected with methyl, ethyl, allyl, phenyl, 4-methoxyphenyl, and benzyl, 2b–g were obtained at 130 °C in 55–80% yields. The oxidation of the C–H bond in either N–CH3 or allylic/benzylic was not observed. Cyanation exclusively occurred on the 3-position of indoles without the contaminant derived from the cyanation on the 2-position of indoles or on the phenyl ring of 1-(4-methoxyphenyl)-1H-indole. tert-Butyl indole-1-carboxylate afforded 2a in 73% yield. In this case, the tert-butyl group was removed. Whereas, the cyanation of 1-tosyl-1H-indole did not occur, implying that the decreased electron density of the substrate influenced the reactivity. 2-Substituted indoles such as 2-phenylindole and 2-(4-fluorophenyl)indole were also examined and the desired products 2h and 2i were isolated in 86% and 66% yields, respectively. 5-Substituted indoles provided 2j–l in relatively lower yields. With phenyl blocked on the 2-position of indoles, 2m was prepared in 80% yield. When NH of
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Table 2
Organic & Biomolecular Chemistry Copper-mediated cyanation of indoles and arenesa
Scheme 3
a
Reaction conditions: 1 (0.5 mmol), CuI (0.6 mmol), HOAc (2.0 mmol), TBHP (1.0 mmol), DMF (3 mL), air, 48 h. b 120 °C. c 130 °C. d 140 °C.
indoles was protected by the ethyl group, 2n and 2o were produced in 65% and 30% yields, respectively. Instead of indoles, 9H-carbazole and 1-ethyl-1H-pyrrolo[2,3-b]pyridine could also work as the substrate to furnish the corresponding cyanation products 2p and 2q in 38% and 60% yields, respectively. Under the standard reaction conditions, some electron-rich carbocyclic arenes, such as 1,3,5-trimethoxybenzene, 1,3-dimethoxybenzene, and 3,4,5-trimethoxytoluene could also be cyanated to give 2r, 2s, and 2t in 80%, 51%, and 35% yields, respectively. However, without any electron-donating group on the arenes, naphthalene, anthracene, and pyrene did not afford any desired products. Moreover, benzothiophene and benzofuran also didn’t work for this transformation, and the starting materials were recovered after the reaction. This protocol could be scaled up and of practical usage in the preparation of therapeutic estrogen receptor ligand A (Scheme 3). Thus, 1.489 g of 2f was prepared in 75% yield by using this protocol. After a sequential bromination, demethylation, and amination, therapeutic estrogen receptor ligand A was successfully afforded in 35% total yield. In order to have a deep insight into the reaction mechanism, we tracked the reaction with carbon-13 labeled on carbo-
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Preparation of therapeutic estrogen receptor ligand A.
nyl carbon of DMF. 3-Cyanoindole (2a) was obtained without the appearance of carbon-13 (Scheme 4). To our surprise, when 3-formylindole (3a-13C), the carbonyl carbon labelled with carbon-13, was used as a substrate, 2a-13C was obtained. Moreover, the results of the screening of the reaction conditions (Table 2, entries 18 and 21) indicated that the carbon of “CN” in 3-cyanoindole could not come from HOAc or TBHP. Based on these experiments, it could be concluded that carbon of “CN” came from the methyl of DMF. Without any other choices, nitrogen of “CN” came from DMF. Thus, both carbon and nitrogen of “CN” in the final product came from a single DMF. It is also noticeable that 3-formylindole (3a) was isolated in 72% yield when N,N-dimethylacetamide (DMA) was used instead of DMF. Furthermore, 2a could also be prepared from 3-(N,N-dimethylamino)methylindole (4). The reaction profile using 1a under the standard reaction conditions is shown in Fig. S1 (see the ESI†). As the reaction
Scheme 4
Mechanistic study.
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progressed, 1a was completely consumed in the initial 5 h and transferred into 3a as the key intermediate. A steady increment of 2a was observed after the reaction was carried out from 10 h to 40 h. On the basis of these results, we proposed a possible mechanism for this cascade transformation (Scheme 5). In the presence of Cu(I) and an oxidant, DMF is oxidized into electrondeficient iminium species.20 Then, electrophilic aromatic substitution on electron-rich indole (1a) occurs to form intermediate A. Further copper-catalyzed oxidation, followed by hydrolysis, forms 3-formylindole (3a) as the key intermediate.13c Subsequently, 3a condenses with dimethylamine which is decomposed from DMF23 to generate iminium intermediate C. A sequential demethylation, oxidation, and demethylation through intermediates D and E furnish 2a. Effective transformation from 4 to 2a is indicative of the formation of intermediate C. Since 3-formylindole (3a) is the key intermediate for the formation of 2a from 1a, we were encouraged to develop a preparation of aryl nitriles from aldehydes using DMF as a single surrogate. After screening the reaction conditions by using the cyanation of 3a as the model reaction (see the ESI, Table S1†), the best result was obtained when the mixture of 3a (0.5 mmol), Cu(NO3)2·3H2O (1.0 equiv.), HOAc (8 equiv.) and TBHP (2 equiv.) in DMF (3.0 mL) was stirred under an air atmosphere, at 130 °C for 48 h. With the optimized reaction conditions, we tested the diversity of aryl aldehydes 3 (Table 3). Without the protecting group on N–H of indoles, 2u–2x were obtained in yields ranging from 52% to 75%. By blocking the 2-position of indoles with the aryl group, 2h and 2i were isolated in yields of 85% and 75%, respectively. 1-Methylindole-3-carbaldehyde gave 2b in 82% yield. Furthermore, a variety of aryl aldehydes were converted into the corresponding aryl nitriles 2y, 2z and 2A–G via this reaction. It should be indicated that 2y, 2z and 2A could not be
Scheme 5
Postulated mechanism.
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Copper-mediated cyanation of aryl aldehydesa
a
Reaction conditions: 3 (0.5 mmol), Cu(NO3)2·3H2O (0.5 mmol), HOAc (4.0 mmol), TBHP (1.0 mmol), DMF (3.0 mL), air, 130 °C, 48 h.
directly cyanated from the corresponding arenes using the aforementioned standard reaction conditions established for cyanation of indoles. As an exception, 5-methoxy-2-methylisoindoline-1,3-dione (5a) was obtained when 3-methoxybenzaldehyde was subjected to this reaction under the standard reaction conditions (Scheme 6). Similarly, 5b, 5c, and 5d were isolated. During the preparation of this manuscript, Ge reported a direct carbonylation from benzamide to isoindoline-1,3-dione using the
Scheme 6
Preparation of 5a–d.
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methyl of DMF as the carbonyl source in the presence of Cu(acac)2, NiBr2, and O2.24
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Conclusions In conclusion, we developed a copper-mediated cyanation reaction of indoles using DMF as a single surrogate of “CN”. This protocol could be scaled up and of practical usage in the preparation of therapeutic estrogen receptor ligand A. A variety of electron-rich arenes and aryl aldehydes could also be converted into the corresponding aryl nitriles by this approach. Based on the isotope labelling and the controlled experiments, aryl aldehydes were believed to be the key intermediates for the cyanation of arenes. Moreover, isoindoline-1,3-diones were eventually obtained in which C–H activation and subsequent carbonylation were observed although the mechanism is unclear at this stage.
Experimental General methods and materials Unless stated otherwise, reactions were conducted in flamedried glassware. Commercially available reagents and solvents were used as received. 300–400 mesh silica gel was used for flash column chromatography. Visualization on TLC was achieved by the use of UV light (254 nm). 400 MHz and 100 MHz were used to record 1H NMR and 13C NMR spectra, respectively. Chemical shifts (δ) were reported in parts per million referring to either the internal standard of TMS or the residue of the deuterated solvents. The splitting pattern was described as follows: s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet. Coupling constants were reported in Hz. The high-resolution mass spectrum (HRMS) was recorded on a GCT premier instrument. Typical procedure for Cu-mediated cyanation of arenes An oven-dried 25 mL eggplant-shaped bottle equipped with a magnetic stir bar was charged with CuI (0.6 mmol), arene (0.5 mmol), HOAc (2.0 mmol), t-BuOOH (1.0 mmol, 70% aq.) and DMF (3.0 mL). The mixture was stirred under air at 120–140 °C (oil bath temperature) for about 48 hours (checked by TLC). After the arene was completely consumed, the reaction mixture was cooled to room temperature, quenched with 10 mL of water, and extracted with DCM (3 × 10 mL). The organic layer was washed with saturated salt water and concentrated under reduced pressure. The residue was purified by column chromatography to afford the pure product. Typical procedure for Cu-mediated cyanation of aromatic aldehydes An oven-dried 25 mL eggplant-shaped bottle equipped with a magnetic stir bar was charged with Cu(NO3)2·3H2O (0.5 mmol, 1.0 equiv.), aromatic aldehyde (0.5 mmol), HOAc (4.0 mmol), t-BuOOH (1.0 mmol, 70% aq.) and DMF (3.0 mL). The mixture was stirred under air at 130–140 °C (oil bath temperature) for
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Organic & Biomolecular Chemistry
about 48 hours (checked by TLC). After the aromatic aldehyde was completely consumed, the reaction mixture was cooled to room temperature, quenched with 10 mL of water, and extracted with DCM (3 × 10 mL). The organic layer was washed with saturated salt water and then concentrated under reduced pressure. The residue was purified through a silica gel column to afford the pure product. 1H-Indole-3-carbonitrile (2a).19a Yellow solid, m.p. 178–180 °C. 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.35 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.31 (td, J = 7.2 Hz, 1.2 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 135.2, 132.2, 127.3, 124.7, 122.7, 120.0, 116.2, 112.4, 87.8. 1-Methyl-1H-indole-3-carbonitrile (2b).19a White solid, m.p. 53–55 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.2, 135.8, 127.9, 124.0, 122.3, 119.9, 116.2, 110.6, 85.5, 33.8. 1-Ethyl-1H-indole-3-carbonitrile (2c). Brown solid, m.p. 88–90 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 4.10 (q, J = 7.3 Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 135.3, 134.2, 128.2, 123.9, 122.3, 120.1, 116.3, 110.7, 85.6, 42.1, 15.4. 1-Allyl-1H-indole-3-carbonitrile (2d). Brown oil, 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 7.2, 1.0 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.36–7.23 (m, 2H), 5.97 (ddd, J = 22.5, 10.6, 5.5 Hz, 1H), 5.28 (d, J = 10.4 Hz, 1H), 5.14 (dd, J = 17.0, 0.6 Hz, 1H), 4.75 (d, J = 5.5 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 135.6, 135.0, 131.9, 128.1, 124.1, 122.4, 120.1, 119.2, 116.1, 111.0, 86.1, 49.7. 1-Phenyl-1H-indole-3-carbonitrile (2e).20b White solid, m.p. 116–118 °C. 1H NMR (400 MHz, CDCl3) δ 7.85–7.83 (m, 1H), 7.81 (s, 1H), 7.58 (t, J = 8.0 Hz, 2H), 7.53–7.47 (m, 4H), 7.37–7.34 (m, 2H).13C NMR (100 MHz, CDCl3) δ 138.2, 136.0, 135.0, 130.4, 128.7, 128.3, 125.3, 124.9, 123.2, 120.4, 115.9, 111.9, 88.5. 1-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (2f ). White solid, m.p. 126–128 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (s, 1H), 7.44–7.40 (m, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.34–7.30 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H).13C NMR (100 MHz, CDCl3) δ 159.8, 136.3, 135.3, 130.9, 128.2, 128.0, 126.7, 124.7, 122.9, 120.2, 115.4, 111.8, 87.7, 56.0. 1-Benzyl-1H-indole-3-carbonitrile (2g). Yellow solid, m.p. 70–72 °C. 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (m, 1H), 7.40 (s, 1H), 7.26–7.08 (m, 6H), 6.98 (dd, J = 7.2, 1.8 Hz, 2H), 5.14 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 135.7, 135.5, 135.3, 129.2, 128.5, 128.1, 127.3, 124.2, 122.4, 112.0, 116.1, 111.1, 86.2, 51.0. 2-Phenyl-1H-indole-3-carbonitrile (2h). White solid, m.p. 245–247 °C. 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.72–7.63 (m, 3H), 7.62–7.56 (m, 2H), 7.35 (dd, J = 8.1, 1.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.1 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 145.7, 136.5, 130.9, 130.3, 130.3, 129.2, 127.9, 124.9, 123.0, 119.3, 118.0, 113.6, 82.3.
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2-(4-Fluorophenyl)-1H-indole-3-carbonitrile (2i). White solid, m.p. 239–241 °C. 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.11–8.00 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.9 Hz, 2H), 7.36 (td, J = 7.2, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 162.8 (d, JC–F = 247.0 Hz), 143.8, 135.5, 129.4 (d, JC–F = 8.0 Hz), 128.2, 125.9 (d, JC–F = 3.0 Hz), 123.9, 122.1, 118.3, 116.9, 116.4 (d, JC–F = 21.0 Hz), 112.6, 81.4. 5-Methoxy-1-methyl-1H-indole-3-carbonitrile (2j).19a Yellow solid, m.p. 103–105 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.13 (s, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.9, 2.4 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 156.2, 135.7, 131.3, 128.9, 116.5, 114.8, 111.5, 101.0, 85.0, 56.0, 34.0. 1-Methyl-5-nitro-1H-indole-3-carbonitrile (2k).19a Yellow 1 solid, m.p. 159–160 °C. H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.24 (dd, J = 9.1, 1.8 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 3.97 (s, 3H). 13C NMR (100 MHz, DMSO) δ 143.6, 142.5, 139.7, 127.1, 119.4, 116.1, 115.6, 113.5, 86.7, 34.9. 5-Chloro-1-methyl-1H-indole-3-carbonitrile (2l). Yellow solid, m.p. 97–99 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.31–7.24 (m, 2H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.8, 134.7, 128.9, 128.5, 124.6, 119.5, 111.8, 85.4, 34.2. HRMS: Calcd for C10H7ClN2 [M]+, 190.0298; found, 190.0296. 5-Methoxy-1-methyl-2-phenyl-1H-indole-3-carbonitrile (2m). Canary yellow solid, m.p. 253–255 °C. 1H NMR (400 MHz, DMSO) δ 7.81–7.47 (m, 6H), 7.15 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 9.0, 2.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H). 13C NMR (100 MHz, DMSO) δ 156.7, 148.5, 132.5, 130.8, 130.7, 129.9, 129.4, 128.5, 117.6, 114.9, 113.7, 100.7, 84.4, 56.4, 32.8. 1-Ethyl-2-phenyl-1H-indole-3-carbonitrile (2n).19a Yellow 1 solid, m.p. 108–110 °C. H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.0 Hz, 1H), 7.62–7.52 (m, 5H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (td, J = 7.2, 1.2 Hz, 1H), 7.32 (td, J = 8.0, 1.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148.1, 135.9, 130.2, 130.0, 129.4, 128.2, 124.1, 122.6, 120.0, 116.9, 111.1, 86.3, 39.9, 15.6. 1-Ethyl-2-methyl-1H-indole-3-carbonitrile (2o). Brown solid, m.p. 89–91 °C. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.30–7.22 (m, 2H), 4.16 (q, J = 7.3 Hz, 2H), 2.58 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 145.2, 135.5, 127.5, 123.2, 122.1, 119.4, 117.0, 110.1, 85.2, 39.0, 15.2, 12.0. 9H-Carbazole-3-carbonitrile (2p). White solid, m.p. 180–181 °C. 1H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.85 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H).13C NMR (100 MHz, DMSO) δ 142.6, 141.2, 129.5, 127.9, 126.5, 123.6, 122.5, 121.9, 121.5, 120.8, 113.0, 112.5, 101.1. 1-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2q). Yellow solid, m.p. 72–74 °C. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.80 (s, 1H), 7.28 (t, J = 4.0 Hz, 1H), 4.43 (q, J = 7.3 Hz, 2H), 1.55 (t, J = 7.3 Hz,
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3H). 13C NMR (100 MHz, CDCl3) δ 146.6, 145.4, 134.8, 128.7, 120.6, 118.4, 115.5, 84.6, 40.8, 15.8. HRMS: Calcd for C10H9N3 [M]+, 171.0796; found, 171.0794. 2,4,6-Trimethoxybenzonitrile (2r).20a White solid, m.p. 139–140 °C. 1H NMR (400 MHz, CDCl3) δ 6.07 (s, 2H), 3.88 (s, 6H), 3.86 (s, 3H).13C NMR (100 MHz, CDCl3) δ 165.7, 164.1, 114.9, 90.7, 84.4, 56.4, 56.0. 2,4-Dimethoxybenzonitrile (2s).20a White solid, m.p. 93–94 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6, 1H), 6.46 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.0, 163.2, 135.2, 117.3, 106.1, 98.8, 94.3, 56.3, 56.0. 2,3,4-Trimethoxy-6-methylbenzonitrile (2t). Colorless oil, 1 H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 4.03 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 2.46 (s, 3H).13C NMR (100 MHz, CDCl3) δ 157.5, 156.1, 139.9, 139.3, 116.2, 109.0, 100.2, 62.1, 61.5, 56.5, 30.0. HRMS: Calcd for C11H13NO3 [M]+, 207.0895; found, 207.0896. 5-Methoxy-1H-indole-3-carbonitrile (2u).19a White solid, m.p. 154–156 °C. 1H NMR (400 MHz, CDCl3) δ 12.10 (s, 1H), 8.20 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.9, 2.4 Hz, 1H), 3.85 (s, 3H).13C NMR (100 MHz, DMSO) δ 156.2, 135.3, 131.0, 128.5, 117.6, 114.8, 100.7, 84.9, 56.4. 1H-Indole-3,5-dicarbonitrile (2v). Yellow solid, m.p. 257–259 °C. 1H NMR (400 MHz, DMSO) δ 12.73 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 138.3, 138.0, 127.3, 127.2, 125.0, 120.6, 116.1, 115.3, 105.1, 86.4. 5-Chloro-1H-indole-3-carbonitrile (2w). White solid, m.p. 165–167 °C. 1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.36 (s, 1H), 7.70 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 137.1, 134.7, 128.8, 127.5, 124.6, 118.7, 116.7, 115.6, 85.1. 4-Chloro-1H-indole-3-carbonitrile (2x). Yellow solid, m.p. 223–225 °C. 1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 8.41 (s, 1H), 7.62–7.47 (m, 1H), 7.38–7.10 (m, 2H). 13C NMR (100 MHz, DMSO) δ 137.6, 137.4, 125.3, 125.2, 124.5, 122.8, 117.2, 113.2, 84.6. Benzo[b]thiophene-3-carbonitrile (2y). White solid, m.p. 72–74 °C. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.59–7.46 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 138.8, 137.9, 137.6, 126.5, 126.3, 123.2, 122.9, 114.7, 107.4. 2,3-Dihydrobenzofuran-5-carbonitrile (2z). White solid, m.p. 68–70 °C. 1H NMR (400 MHz, CDCl3) δ 7.46–7.44 (m, 2H), 6.82 (d, J = 8.2 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.25 (t, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 164.1, 133.9, 129.2, 128.9, 119.9, 110.6, 103.9, 72.4, 29.3. Benzo[d][1,3]dioxole-5-carbonitrile (2A). White solid, m.p. 91–93 °C. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.06 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 151.8, 148.3, 128.5, 119.2, 111.7, 109.4, 105.2, 102.5. 3,4,5-Trimethoxybenzonitrile (2B). White solid, m.p. 92–94 °C. 1H NMR (400 MHz, CDCl3) δ 6.79 (s, 2H), 3.83
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(s, 3H), 3.81 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 153.8, 142.6, 119.3, 109.7, 107.0, 61.3, 56.7. 4-Methoxybenzonitrile (2C).15b White solid, m.p. 57–58 °C. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H).13C NMR (100 MHz, CDCl3) δ 163.2, 134.3, 119.5, 115.1, 104.3, 55.9. 4-Chlorobenzonitrile (2D).20a White solid, m.p. 90–91 °C. 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H).13C NMR (100 MHz, CDCl3) δ 139.9, 133.7, 130.1, 118.3, 111.2. 4-Nitrobenzonitrile (2E).20a Yellow solid, m.p. 140–141 °C. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 133.8, 128.7, 124.6, 118.7, 117.1. 1-Naphthonitrile (2F).15b White solid, m.p. 55–56 °C. 1 H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.4, 7.0 Hz, 1H), 7.62 (dd, J = 8.4, 7.0 Hz, 1H), 7.52 (dd, J = 8.4, 7.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 133.6, 133.3, 133.0, 132.7, 129.0, 128.9, 127.9, 125.5, 125.3, 118.1, 110.5. Pyrene-1-carbonitrile (2G). White solid, m.p. 152–154 °C. 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 7.6 Hz, 2H), 8.17 (dd, J = 13.1, 5.9 Hz, 3H), 8.07 (t, J = 7.6 Hz, 2H), 8.00 (d, J = 9.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 134.4, 133.1, 131.0, 130.72, 130.69, 129.8, 127.3, 127.24, 127.21, 127.1, 124.6, 124.14, 124.12, 123.7, 119.1, 105.8. 2-(Dimethylamino)-1-(4-hydroxyphenyl)-1H-indole-3-carbonitrile. Yellow solid, m.p. 223–225 °C. 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 2.89 (s, 6H). 5-Methoxy-2-methylisoindoline-1,3-dione (5a). White solid, m.p. 155–157 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.3, 2.3 Hz, 1H), 3.91 (s, 3H), 3.14 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.7, 168.6, 164.9, 135.1, 125.2, 124.4, 119.8, 108.4, 56.4, 24.3. 5-Ethoxy-2-methylisoindoline-1,3-dione (5b). White solid, m.p. 109–111 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.3, 2.3 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.15 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 168.7, 164.3, 135.1, 125.2, 124.2, 120.3, 108.8, 64.8, 24.3, 14.9. 5-Isopropoxy-2-methylisoindoline-1,3-dione (5c). White solid, m.p. 93–95 °C 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.09 (dd, J = 8.3, 2.2 Hz, 1H), 4.67 (dt, J = 12.1, 6.0 Hz, 1H), 3.14 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 168.7, 163.4, 135.1, 125.2, 123.9, 121.3, 109.5, 71.3, 24.2, 22.1. HRMS: Calcd for C12H13NO3 [M]+, 219.0895; found, 219.0893. 5-(Benzyloxy)-2-methylisoindoline-1,3-dione (5d). White solid, m.p. 123–125 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 1H), 7.45–7.38 (m, 6H), 7.22 (dd, J = 8.3, 2.3 Hz, 1H), 5.18 (s, 2H), 3.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.63, 168.60, 164.0, 135.8, 135.1, 129.1, 128.8, 127.9, 125.3,
8328 | Org. Biomol. Chem., 2015, 13, 8322–8329
Organic & Biomolecular Chemistry
124.7, 120.7, 109.3, 24.3. HRMS: Calcd for C16H13NO3 [M]+, 267.0895; found, 267.0897.
Acknowledgements The authors thank the National Natural Science Foundation of China (no. 21472173, 21272203) for financial support.
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