Synthesis of Cyano-Containing Phenanthridine Derivatives via

Mar 31, 2017 - Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst-, Base-, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanid...
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Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst‑, Base‑, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanides Weihong Song, Peipei Yan, Dan Shen, Zhangtao Chen, Xiaofei Zeng,* and Guofu Zhong* College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China S Supporting Information *

ABSTRACT: An efficient catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN has been developed under mild conditions. This strategy provides an elusive and rapid access to a wide range of cyano-containing phenanthridine derivatives in good yields via a one-pot alkylation/cyclization radical-cascade process. The mild reaction conditions together with no need of any catalyst, base, or oxidant make this protocol environmentally benign and practical.

P

cyano group.15 In keeping with our continuing interest in the development of new methods to obtain important organic compounds, we hypothesized that the cyanoalkylarylation of isocyanides with AIBN leading to cyano-containing phenanthridines via a radical addition/cyclization/C−C bond formation cascade reaction might be possible. Herein, a novel, simple, cost-effective, practical, and “green” protocol for the construction of phenanthridine derivatives under catalyst-, base-, and oxidant-free conditions was disclosed. The presented methodology provides a highly attractive and complementary approach to a diverse range of cyano-containing phenanthridines in moderate to high yields with excellent functional group tolerance. Our studies build on the report of Nanni et al.15c In an initial study, 2-isocyanobiphenyl (1a) and AIBN (2a) were chosen as model substrates for the radical cyanoalkylarylation reaction, and various catalysts and bases were tested in solvents at different temperatures (Table 1). When the reaction was carried out in the presence of DABCO as base and copper salts as catalyst, the desired product could be formed in high yields (85−88%, entries 1−3). Consequently, a lower amount of the product (62%) was observed in the absence of base (entry 4). We then tested the reaction under metal-free conditions. To our delight, the cyanoalkylarylation of 1a actually could proceed smoothly without any metal catalysts. A comparative and high yield (86%) of desired product 3a was afforded by performing the reaction of 2-isocyanobiphenyl (1a) and AIBN (2a) in toluene at 100 °C with only the addition of 2 equiv of DABCO (entry 6). Further attempts to improve the yield by screening of other bases, including DBU, K2CO3, and K3PO4 (entries 6−8), failed. It was found that the metal catalyst did not affect this transformation, and base additive also did not make sense for promotion of the radical process. When the reaction was

henanthridines are an important class of structural motifs that widely exist in many bioactive natural products and biologically relevant compounds.1 Thus far, considerable efforts have been directed toward the development of efficient methods for their synthesis.2 In particular, transition-metalcatalyzed or -mediated radical-cascade reactions have emerged as a powerful synthetic method for bond activation and construction processes to achieve the phenanthridine key fragment.3 A series of radical precursors, such as halides,4 ethers,5 alkanes,6 boronic acids,7 aldehydes,8 alcohols,9 and fluoroalkylation reagents,10 were introduced to react with the isocyanides for phenanthridine preparations. Recently, several groups have reported C(sp3)−H bond functionalization and cyclization to produce phenanthridine derivatives under transition-metal-free conditions.11 However, these approaches always suffered from one or more limitations including limited functional group tolerance, poor substrate scope, and the use of external oxidants or base additives, which may limit their practical application in synthetic chemistry. Therefore, although considerable advances in this field have been achieved, the development of more efficient, practical, and especially operationally simple and environmental benign strategies for phenanthridine preparation is still of great significance and a challenging and worthwhile endeavor. The incorporation of cyano or cyano-containing moieties into molecules, leading to various organic functional groups of diverse skeletons, is a significant topic of interest for organic chemists.12 Moreover, nitriles are widely used as important building blocks in many pharmaceuticals, fine chemicals, agrochemicals, and materials.13 Transition-metal-catalyzed cyanation of arenes and heteroarenes is undoubtedly considered as one of the most effective strategies to introduce nitrile moieties into organic molecules.14 Recently, the discovered novel approach through radical processes by utilizing azobis(isobutyronitrile) (AIBN) as a radical initiator presents an alternative methodology for introduction of the © 2017 American Chemical Society

Received: February 13, 2017 Published: March 31, 2017 4444

DOI: 10.1021/acs.joc.7b00343 J. Org. Chem. 2017, 82, 4444−4448

Note

The Journal of Organic Chemistry Table 1. Reaction Condition Optimizationa

Table 2. Exploration of Substrate Scopea

entry

catalyst

base

solvent

temp (°C)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

CuCl CuSO4 CuBr CuCl

DABCO DABCO DABCO

toluene toluene toluene toluene toluene toluene toluene toluene benzene THF DCE EtOAc toluene toluene toluene

100 100 100 100 100 100 100 100 100 100 100 100 80 60 r.t.

88 85 86 62 71 65 60 86 78 57 86 65 90 51 0

DBU K2CO3 K3PO4

a

Reactions were performed with 1a (0.4 mmol), 2a (0.8 mmol), catalyst (0.04 mmol), and base (0.8 mmol) in solvent (4 mL) at the indicated temperature for 24 h. bYields of isolated products.

conducted under metal- and base-free conditions, a high yield was also achieved (86%, entry 9). Next, we examined the reaction in other solvents, such as benzene, THF, DCE, and DMF. Unfortunately, no improvement of the yield was found (entries 10−13). Decreasing the reaction temperature to 80 °C resulted in an increase in yield (90%, entry 14); further decreasing the reaction temperature to 60 °C and rt led to a lower yield (51%) or even no reaction (entries 15 and 16). Finally, the product 3a could be obtained in 90% yield when the reaction of isocyanide 1a was conducted with 2.0 equiv of AIBN in toluene at 80 °C for 14 h. With the optimal reaction conditions in hand, we turned our attention to the scope with respect to the substrates. As shown in Table 2, AIBN (2a) could react with a variety of 2isocyanobiphenyls (1) to afford the expected product in good to excellent chemical yields (54−94%). The substituents at different positions of the cyclized phenyl ring of the biphenyl isocyanides did not interfere with the reaction efficiency. In case of meta-substituted aryl isocyanides 2g, 2h, and 2k, the cyclization slightly preferred to take place at the more crowed position of the phenanthridines, and a mixture of regioisomers was provided with a ratio of 1:1.2−1:1.8 (3g/3g′, 3h/3h′, and 3k/3k′). When isocyanides having disubstituents on the cyclized phenyl ring (2l and 2m) were employed, slightly diminished yields were obtained. Additionally, the isocyanide bearing a pyridine instead of benzene ring underwent the cyanoalkylarylation reaction smoothly, providing 3n in good yields. A further substrate scope study was performed to investigate the substitution effect on the aromatic ring with the isocyano group, giving the corresponding products in moderate to high yield (3p−s). A substrate containing two methylsubstituted group on the aromatic phenyl ring with an isocyano group also worked well, and phenanthridine 3o was produced in 65% yield. Moreover, we also investigated the performance of the AIBN analogue in the cyanoalkylarylation reaction (Scheme 1). To

a

Reaction conditions: 1 (0.4 mmol), 2a (0.8 mmol) in toluene (4 mL) at 80 °C for 24 h. bYields of isolated products based on 1.

Scheme 1. Reaction of Isocyanide with 2b

our delight, the azo compound (2b) bearing an α-functionalized, more sterically hindered tertiary alkyl group was also compatible with the optimal conditions, leading to 6-tertalkylated phenanthridine 3t in moderate yield. On the basis of experimental results and previous related reports,11 a possible mechanism for this transformation is depicted in Scheme 2. First, thermal decomposition of AIBN would result in the generation of radical A with the release of one molecule of nitrogen. Then the addition of radical A to isocyanobiphenyl (1a) occurred and afforded the radical intermediate B, which further underwent an intramolecular radical substitution to give the intermediate C. Finally, hydrogen radical abstraction from intermediate C by initially generated radical A would lead to the formation of the desired cyanoalkylarylated phenanthridines 3a and isobutyronitrile.

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CONCLUSION In conclusion, we have developed a novel catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN via a radical-cascade process for the synthesis of cyano4445

DOI: 10.1021/acs.joc.7b00343 J. Org. Chem. 2017, 82, 4444−4448

Note

The Journal of Organic Chemistry

2-(8-Chlorophenanthridin-6-yl)-2-methylpropionitrile (3c): colorless solid; yield 74%; mp 153.9−155.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 8.9 Hz, 1H), 8.52−8.49 (m, 1H), 8.14 (dd, J = 8.1, 1.1 Hz, 1H), 7.82 (dd, J = 8.9, 2.0 Hz, 1H), 7.77−7.68 (m, 2H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.2, 142.5, 133.4, 132.4, 131.2, 130.6, 129.2, 128.1, 125.7, 124.8, 124.6, 124.0, 123.4, 121.8, 37.8, 28.0; HRMS m/z (ESI) calcd for C17H13Cl N2 (M + H)+ 281.0840, found 281.0840. 6-(2-Cyanopropan-2-yl)phenanthridine-8-carbonitrile (3d): white solid; yield 81%; mp 177.0−179.0 °C; 1H NMR (500 MHz, CDCl3) δ 9.10 (d, J = 1.2 Hz, 1H), 8.78 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 8.1, 0.9 Hz, 1H), 8.04 (dd, J = 8.6, 1.5 Hz, 1H), 7.86−7.81 (m, 1H), 7.78−7.75 (m, 1H), 2.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.7, 143.4, 136.6, 131.8, 131.4, 130.8, 130.7, 128.6, 124.51, 124.3, 122.7, 122.6, 122.4, 118.3, 110.9, 37.8, 28.0; HRMS m/z (ESI) calcd for C18H13N3 (M + H)+ 272.1182, found 272.1188. 2-Methyl-2-(8-methylphenanthridin-6-yl)propionitrile (3e): white solid; yield 76%; mp 137.6−139.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.60−8.50 (m, 3H), 8.11 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 12.7, 8.2 Hz, 3H), 2.66 (s, 3H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.9, 142.3, 137.3, 132.2, 131.8, 130.4, 128.4, 127.6, 125.9, 125.1, 124.1, 123.3, 123.0, 121.7, 37.7, 28.1, 22.1; HRMS m/z (ESI) calcd for C18H16N2 (M + H)+ 261.1386, found 261.1366. 2-(8-tert-Butylphenanthridin-6-yl)-2-methylpropanenitrile (3f): white solid; yield 90%; mp 82.8−85.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 1.7 Hz, 1H), 8.53 (d, J = 8.7 Hz, 1H), 8.43 (dd, J = 8.0, 0.9 Hz, 1H), 8.03 (dd, J = 8.0, 1.1 Hz, 1H), 7.85 (dd, J = 8.7, 1.8 Hz, 1H), 7.62−7.55 (m, 2H), 1.98 (s, 6H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.5, 150.3, 142.5, 131.7, 130.4, 128.8, 128.4, 127.9, 127.5, 125.0, 124.0, 122.8, 122.5, 121.8, 37.7, 35.4, 31.4, 28.1; HRMS m/z (ESI) calcd for C21H22N2 (M + H)+ 303.1856, found 303.1854. 2-(7-Fluorophenanthridin-6-yl)-2-methylpropanenitrile (3g): white solid; yield 34%; mp 140.2−142.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.82 (dd, J = 9.2, 5.5 Hz, 1H), 8.43 (dd, J = 8.2, 1.1 Hz, 1H), 8.29 (dd, J = 10.2, 2.6 Hz, 1H), 8.14 (dd, J = 8.1, 0.9 Hz, 1H), 7.77 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.70 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.50 (ddd, J = 9.3, 7.8, 2.6 Hz, 1H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 163.4 (d, JC−F = 252.5 Hz), 155.8, 142.8, 136.6 (d, JC−F = 9.3 Hz), 130.6, 129.5, 129.3 (d, JC−F = 9.3 Hz), 127.8, 124.9, 123.6, 122.1, 120.1, 116.3 (d, JC−F = 23.8 Hz), 108.3 (d, JC−F = 21.9 Hz), 37.8, 28.0; HRMS m/z (ESI) calcd for C17H13FN2 (M + H)+ 265.1136, found 265.1137. 2-(9-Fluorophenanthridin-6-yl)-2-methylpropanenitrile (3g′): white solid; yield 41%; mp 151.3−152.7 °C; 1H NMR (500 MHz, CDCl3) δ 8.43 (t, J = 11.1 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.76 (td, J = 8.1, 5.2 Hz, 1H), 7.71−7.60 (m, 2H), 7.39 (dd, J = 12.9, 7.9 Hz, 1H), 1.96 (d, J = 0.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 158.5 (d, JC−F = 252.5 Hz), 153.9, 142.3, 136.4 (d, JC−F = 3.9 Hz), 131.4 (d, JC−F = 10.2 Hz), 130.5, 129.5, 128.2, 125.6, 124.4, 122.3, 119.1 (d, JC−F = 3.8 Hz), 114.7 (d, JC−F = 25.9 Hz), 112.3, 40.7, 28.2; HRMS m/z (ESI) calcd for C17H13FN2 (M + H)+ 265.1136, found 265.1133. 2-(9-Methoxyphenanthridin-6-yl)-2-methylpropionitrile (3h): white solid; yield 91%; mp 104.3−105.9 °C; 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J = 9.2 Hz, 1H), 8.3−8.32 (m, 1H), 7.98 (dd, J = 8.1, 1.0 Hz, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.61−7.58 (m, 1H), 7.52 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.23 (dd, J = 9.2, 2.6 Hz, 1H), 3.91 (s, 3H), 1.93 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 160.9, 155.9, 143.0, 136.2, 130.4, 128.9, 128.2, 127.1, 125.1, 123.8, 122.0, 117.8, 117.6, 114.2, 41.2, 28.1, 23.4; HRMS m/z (ESI) calcd for C18H16N2O (M + H)+ 277.1335, found 277.1336. 2-(7-Methoxyphenanthridin-6-yl)-2-methylpropionitrile (3h′): white solid; yield 91%; mp 144.0−145.6 °C; 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 8.9 Hz, 1H), 8.52−8.49 (m, 1H), 8.14 (dd, J = 8.1, 1.1 Hz, 1H), 7.82 (dd, J = 8.9, 2.0 Hz, 1H), 7.77−7.68 (m, 2H), 4.09 (s, 3H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 156.6, 155.8, 142.4, 136.2, 131.2, 130.0, 128.9, 127.4, 125.7, 123.3, 122.4, 115.9, 115.0, 108.8, 54.7, 41.6, 29.1; HRMS m/z (ESI) calcd for C18H16N2O (M + H)+ 277.1335, found 277.1333.

Scheme 2. Proposed Reaction Mechanism

containing phenanthridines. Such a protocol, which exhibits a broad substrate scope and good functional group compatibility as well as good chemical yield production under mild conditions, provides a simple, convenient, efficient, costeffective, and practical approach for preparing highly valuable phenanthridine derivatives.

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EXPERIMENTAL SECTION

General Information. The products were isolated by column chromatography on silica gel (200−300 mesh) using petroleum ether (60−90 °C) and ethyl acetate. Melting points were determined on an X-5 Data microscopic melting point apparatus. 1H and 13C NMR spectra were recorded on a Bruker Advance 500 spectrometer at ambient temperature with CDCl3 as solvent unless otherwise noted and tetramethylsilane (TMS) as the internal standard. 1H NMR data were reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double−doublet, m = multiplet and br = broad), coupling constant (J values, Hz). 13C NMR data were reported in terms of chemical shift (δ ppm). High-resolution mass spectrometry (HRMS) was recorded on QTOF perimer for ESI +. Analytical thin-layer chromatography (TLC) was performed on Merk precoated TLC (silica gel 60 F254) plates. General Procedure for the Reaction of AIBN with Isocyanide. To a round-bottom flask containing a solution of 1a (71.63 mg, 0.40 mmol, 1.0 equiv) in 4 mL of toluene was added AIBN (131.37 mg, 0.80 mmol, 1.0 equiv). The resulting solution was stirred under 80 °C until the limited reactant was consumed (monitored by TLC). The reaction mixture was diluted with DCM (10 mL) and washed with brine (10 mL) and H2O (10 mL). The organic layer was dried on MgSO4, and solvents were removed under reduced pressure. The residue was purified by column chromatography (EtOAc/PE = 1:10−1:4) to provide pure 3a. 2-Methyl-2-phenanthridin-6-yl-propionitrile (3a): 15c colorless solid; yield 71.63 mg (90%); mp 95.5−97.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.79 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 8.3 Hz, 1H), 8.59−8.54 (m, 1H), 8.14 (dd, J = 8.1, 1.1 Hz, 1H), 7.88 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.83−7.62 (m, 3H), 2.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 156.3, 146.6, 142.6, 133.9, 130.5, 130.4, 128.9, 127.7, 127.2, 126.4, 125.0, 124.0, 123.1, 121.9, 37.8, 28.1; HRMS m/z (ESI) calcd for C17H14N2 (M + H)+ 247.1230, found 247.1230. 2-(8-Fluoro-phenanthridin-6-yl)-2-methyl-propionitrile (3b): white solid; yield 71%; mp 126.7−128.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.63 (dd, J = 9.1, 5.5 Hz, 1H), 8.43 (dd, J = 8.0, 1.3 Hz, 1H), 8.34 (dd, J = 10.4, 2.5 Hz, 1H), 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.68− 7.61 (m, 2H), 7.56 (ddd, J = 9.2, 7.8, 2.5 Hz, 1H), 1.97 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 160.9 (d, JC−F = 247.5 Hz), 155.4, 142.3, 130.6 (d, JC−F = 3.8 Hz), 128.8, 128.1, 125.7 (d, JC−F = 8.6 Hz), 124.6, 124.3, 124.2, 123.5, 121.7, 119.8 (d, JC−F = 23.7 Hz), 111.3 (d, JC−F = 22.7 Hz), 37.8, 27.9; HRMS m/z (ESI) calcd for C17H13FN2 (M + H)+ 265.1136, found 265.1136. 4446

DOI: 10.1021/acs.joc.7b00343 J. Org. Chem. 2017, 82, 4444−4448

Note

The Journal of Organic Chemistry

2-(2-Fluorophenanthridin-6-yl)-2-methylpropanenitrile (3q): white solid; yield 77%; mp 142.6−143.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 8.3 Hz, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.23−8.06 (m, 2H), 7.93−7.84 (m, 1H), 7.85−7.75 (m, 1H), 7.51−7.44 (m, 1H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 161.7 (d, JC−F = 322.5 Hz), 155.6, 139.4, 133.4 (d, JC−F = 3.6 Hz), 132.7(d, JC−F = 13.2 Hz), 130.5, 127.9, 126.5, 125.4, 125.3, 124.8, 123.3, 117.7 (d, JC−F = 25.4 Hz), 106.7 (d, JC−F = 42.3 Hz), 37.7, 28.0; HRMS m/z (ESI) calcd for C17H13FN2 (M + H)+ 265.1136, found 265.1131. 2-(2-Chlorophenanthridin-6-yl)-2-methylpropanenitrile (3r): white solid; yield 58%; mp 148.0−150.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.89 (dd, J = 11.3, 4.0 Hz, 1H), 7.84−7.78 (m, 1H), 7.68 (dd, J = 8.7, 2.2 Hz, 1H), 2.05 (s, 6H); 13 C NMR (125 MHz, CDCl3) δ 156.6, 141.0, 133.6, 132.9, 131.9, 130.8, 129.4, 127.9, 126.5, 125.1, 124.8, 123.3, 123.2, 121.6, 37.8, 28.0; HRMS m/z (ESI) calcd for C17H13ClN2 (M + H)+ 281.0840, found 281.0841. 2-(2-Phenylphenanthridin-6-yl)-2-methylpropanenitrile (3s): white solid; yield 78%; mp 210.0−212.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.80 (t, J = 9.0 Hz, 2H), 8.74 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 8.4, 1.9 Hz, 1H), 7.88 (dd, J = 11.4, 3.9 Hz, 1H), 7.79 (ddd, J = 7.3, 5.1, 1.8 Hz, 3H), 7.54 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 2.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 156.2, 141.9, 140.8, 140.5, 133.9, 130.8, 130.5, 129.0, 128.2, 127.8, 127.6, 127.3, 126.5, 124.9, 124.1, 123.3, 121.3, 120.2, 37.8, 28.0; HRMS m/z (ESI) calcd for C23H18N2 (M + H)+ 323.1543, found 323.1545. 1-(Phenanthridin-6-yl)cyclohexanecarbonitrile (3t): white solid, yield 58%; mp 131.5−133.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.0, 0.9 Hz, 1H), 7.81−7.75 (m, 1H), 7.70−7.64 (m, 2H), 7.64−7.59 (m, 1H), 2.15 (td, J = 13.5, 4.0 Hz, 2H), 2.07−1.70 (m, 6H), 1.37−1.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 156.7, 142.7, 133.9, 130.4, 130.3, 128.7, 127.5, 127.0, 126.3, 123.9, 123.3, 123.1, 123.0, 121.9, 44.6, 35.9, 25.3, 23.2; 1HRMS m/z (ESI) calcd for C20H18N2 (M + H)+ 287.1543, found 287.1540.

2-(10-Chlorophenanthridin-6-yl)-2-methylpropionitrile (3i): white solid; yield 81%; mp 150.5−152.0 °C; 1H NMR (400 MHz, CDCl3) δ 9.77 (dd, J = 8.6, 0.8 Hz, 1H), 8.78 (dd, J = 8.4, 1.0 Hz, 1H), 8.16 (dd, J = 8.1, 1.3 Hz, 1H), 7.96 (dd, J = 7.7, 1.0 Hz, 1H), 7.80−7.76 (m, 1H), 7.71−7.65 (m, 2H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.9, 143.6, 134.4, 132.3, 131.1, 130.6, 129.2, 127.14, 126.9, 126.4, 125.7, 125.6, 124.8, 123.1, 37.9, 28.3; HRMS m/z (ESI) calcd for C17H13ClN2 (M + H)+ 281.0840, found 281.0844. 2-(10-Methoxyphenanthridin-6-yl)-2-methylpropionitrile (3j): white solid; yield 68%; mp 122.8−125.0 °C; 1H NMR (500 MHz, CDCl3) δ 9.50 (dd, J = 8.5, 1.1 Hz, 1H), 8.42 (dd, J = 8.4, 0.8 Hz, 1H), 8.14 (dd, J = 8.0, 1.3 Hz, 1H), 7.74−7.70 (m, 2H), 7.66 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.15 (s, 3H), 2.06 (s, 6H); 13 C NMR (125 MHz, CDCl3) δ 158.9, 155.8, 143.1, 130.2, 128.1, 127.9, 127.5, 127.3, 125.2, 124.5, 123.8, 121.4, 118.7, 111.6, 55.9, 28.2, 23.4; HRMS m/z (ESI) calcd for C18H16N2O (M + H)+ 277.1335, found 277.1340. 2-([1,3]Dioxolo[4,5-j]phenanthridin-6-yl)-2-methylpropanenitrile (3k) and 2-([1,3]Dioxolo[4,5-i]phenanthridin-4-yl)-2-methylpropanenitrile (3k′): white solid; yield 54%; mp 200.9−203.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.43−8.39 (m, 1H), 8.36 (dd, J = 8.1, 1.3 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.13- 8.09 (m, 2H), 8.04 (dt, J = 5.5, 3.1 Hz, 1H), 7.99 (s, 1H), 7.71−7.65 (m, 1H), 7.65−7.60 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 6.28 (s, 1H), 6.19 (s, 2H), 2.03 (s, 6H), 2.02 (s, 4H); 13C NMR (125 MHz, CDCl3) δ 154.9, 153.8, 150.7, 148.0, 146.7, 142.5, 141.4, 131.9, 130.5, 130.4, 129.2, 128.2, 128.1 132.3, 124.9, 124.3, 124.2, 123.7, 121.8, 121.7, 121.4, 119.7, 117.0, 113.2, 110.7, 103.9, 102.2, 101.1, 100.80, 40.1, 39.4, 27.9, 27.7; HRMS m/z (ESI) calcd for C18H14N2O2 (M + H)+ 291.1128, found 291.1129. 2-(7,10-Dichlorophenanthridin-6-yl)-2-methylpropanenitrile (3l): white solid; yield 58%; mp 154.0−156.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.07 (dd, J = 8.1, 1.0 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.1, 1.2 Hz, 1H), 7.71−7.67 (m, 1H), 2.10 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 154.8, 142.0, 137.8, 136.1, 132.3, 131.2, 130.1, 129.9, 128.6, 124.9, 122.1, 122.0, 121.5, 121.4, 40.7, 30.2; HRMS m/z (ESI) calcd for C17H12Cl2N2 (M + H)+ 315.0450, found 315.0457. 2-(10-Methoxy-7-methylphenanthridin-6-yl)-2-methylpropanenitrile (3m): white solid; yield 77%; mp 110.0−112.0 °C; 1H NMR (500 MHz, CDCl3) δ 9.37 (dd, J = 8.6, 1.0 Hz, 1H), 7.99 (dd, J = 8.1, 1.3 Hz, 1H), 7.65 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.56 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.45 (dd, J = 8.2, 0.6 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.09 (s, 3H), 2.98 (s, 3H), 1.97 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 156.5, 156.1, 141.9, 131.2, 128.6, 128.0, 127.0, 126.9, 125.8, 125.6, 125.4, 123.1, 121.5, 111.1, 55.9, 30.3, 25.9, 23.4; HRMS m/z (ESI) calcd for C19H18N2O (M + H)+ 291.1492, found 291.1486. 2-(Benzo[c][2,7]naphthyridin-5-yl)-2-methylpropanenitrile (3n): white solid; yield 66%; mp 140.3−142.2 °C; 1H NMR (500 MHz, CDCl3) δ 10.18 (s, 1H), 8.96 (d, J = 5.7 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.17 (dd, J = 8.2, 0.9 Hz, 1H), 7.90− 7.80 (m, 1H), 7.78−7.68 (m, 1H), 2.09 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 156.3, 149.83, 148.4, 143.8, 138.9, 131.1, 130.7, 128.3, 124.4, 122.7, 122.4, 121.9, 118.4, 116.1, 37.9, 28.1; HRMS m/z (ESI) calcd for C16H13N3 (M + H)+ 248.1182, found 248.1181. 2-(2,4-Dimethylphenanthridin-6-yl)-2-methylpropanenitrile (3o): white solid; yield 65%; mp 133.3−135.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 7.85−7.79 (m, 1H), 7.73 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.43 (s, 1H), 2.80 (s, 3H), 2.58 (s, 3H), 2.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 153.7, 139.5, 138.1, 137.1, 134.0, 131.3, 130.3, 126.8, 126.2, 125.1, 123.8, 123.3, 122.9, 119.3, 38.1, 28.1, 22.0, 17.0; HRMS m/z (ESI) calcd for C19H18N2 (M + H)+ 275.1543, found 275.1546. 2-Methyl-2-(2-methylphenanthridin-6-yl)-propionitrile (3p): white solid; yield 94%; mp 118.2−120.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.87−7.82 (m, 1H), 7.77−7.72 (m, 1H), 7.56 (d, J = 8.3 Hz, 1H), 2.63 (s, 3H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.2, 141.0, 137.6, 133.7, 130.5, 130.2, 130.2, 127.0, 126.3, 125.1, 123.8, 123.2, 123.1, 121.5, 37.7, 28.1, 22.1; HRMS m/z (ESI) calcd for C18H16N2 (M + H)+ 261.1386, found 261.1388.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00343.

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Experimental procedures, full spectroscopic data for compounds 3, and 1H and 13C NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected] ORCID

Xiaofei Zeng: 0000-0003-4222-1365 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

We gratefully acknowledge the Natural Science Foundation of China (Nos. 21373073 and 21672048), the Young National Natural Science Foundation of China (No. 21302033), the PCSIRT (IRT 1231), the Public Welfare Project of Zhejiang Province (2016C33088), and Hangzhou Normal University for financial support. X.Z. acknowledges a Xihu Scholar award from Hangzhou City, and G.Z. acknowledges a Qianjiang Scholar from Zhejiang Province in China. 4447

DOI: 10.1021/acs.joc.7b00343 J. Org. Chem. 2017, 82, 4444−4448

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The Journal of Organic Chemistry

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B.; Hu, J.-B. Org. Lett. 2016, 18, 5912. (d) Noel-Duchesneau, L.; Lagadic, E.; Morlet-Savary, F.; Lohier, J.-F.; Chataigner, I.; Breugst, M.; Lalevee, J.; Gaumont, A.-C.; Lakhdar, S. Org. Lett. 2016, 18, 5900. (e) Zhou, Y.-H.; Wu, C.-P.; Dong, X.-L.; Qu, J.-P. J. Org. Chem. 2016, 81, 5202. (f) Wang, J.; Li, J.; Huang, J.-B.; Zhu, Q. J. Org. Chem. 2016, 81, 3017. (12) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience Publishers: New York, 1970. (b) Fatiadi, A. J. Preparation and Synthetic Application of Cyano Compounds; Patai, S., Rappaport, Z., Eds.; Wiley: New York, 1983. (c) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd ed.; Wiley-VCH: New York, 1988. (d) Larock, R. C. Comprehensive Organic Transformations; VCH: New York, 1989. (e) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563. (13) (a) Schore, N. E. Comprehensive Organic Synthesis; Pergamon Press: New York, 1991. (b) Bishop, R. Comprehensive Organic Synthesis; Pergamon Press: New York, 1991. (c) Nakanishi, T.; Suzuki, M. J. Nat. Prod. 1998, 61, 1263. (d) Read, M. L.; Gundersen, L. L. J. Org. Chem. 2013, 78, 1311. (e) Harayama, T.; Akiyama, T.; Kawano, K. Chem. Pharm. Bull. 1996, 44, 1634. (f) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985. (14) (a) Leow, D.; Li, G.; Mei, M.-T.; Yu, J.-Q. Nature 2012, 486, 518. (b) Li, J.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 3635. (c) Shu, Z. B.; Ji, W. Z.; Wang, X.; Zhou, Y. J.; Zhang, Y.; Wang, J. B. Angew. Chem. 2014, 126, 2218. (d) Gong, T.-J.; Xiao, B.; Cheng, W.M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630. (e) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.Q. J. Am. Chem. Soc. 2013, 135, 7567. (f) Yang, Y.-F.; Cheng, G.-J.; Liu, P.; Leow, D.; Sun, T.-Y.; Chen, P.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344. (15) (a) Xia, J. H.; Matyjaszewski, K. Macromolecules 1997, 30, 7692. (b) Hammond, G. S.; Sen, J. N.; Boozer, C. E. J. Am. Chem. Soc. 1955, 77, 3244. (c) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A. Tetrahedron 1995, 51, 9045. (d) Spaccini, R.; Pastori, N.; Clerici, A.; Punta, C.; Porta, O. J. Am. Chem. Soc. 2008, 130, 18018. (e) Li, L.; Shu, X.; Zhu, J. Polymer 2012, 53, 5010. (f) Wan, W.-M.; Pickett, P. D.; Savin, D. A.; McCormick, C. L. Polym. Chem. 2014, 5, 819. (g) Wei, W.; Wen, J. W.; Yang, D. S.; Guo, M. Y.; Tian, L. J.; You, J. M.; Wang, H. RSC Adv. 2014, 4, 48535. (h) Zhou, D.; Li, Z. H.; Li, J.; Li, S. H.; Wang, M. W.; Luo, X. L.; Ding, G. L.; Sheng, R. L.; Fu, M. J.; Tang, S. Eur. J. Org. Chem. 2015, 2015, 1606.

REFERENCES

(1) (a) Viladomat, F.; Bastida, J.; Tribo, G.; Codina, C.; Rubiralta, M. Phytochemistry 1990, 29, 1307. (b) Fang, S.-D.; Wang, L.-K.; Hecht, S. M. J. Org. Chem. 1993, 58, 5025. (c) Nakanishi, T.; Suzuki, M. J. Nat. Prod. 1998, 61, 1263. (d) Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kabasawa, T. J. Nat. Prod. 1999, 62, 864. (e) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985. (f) Nakanishi, T.; Masuda, A.; Suwa, M.; Akiyama, Y.; Hoshino-Abe, N.; Suzuki, M. Bioorg. Med. Chem. Lett. 2000, 10, 2321. (g) Ishikawa, T. Med. Res. Rev. 2001, 21, 61. (h) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119. (i) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6, 263. (2) For selected examples on the synthesis of phenanthridines, see: (a) Intrieri, D.; Mariani, M.; Caselli, A.; Ragaini, F.; Gallo, E. Chem. Eur. J. 2012, 18, 10487. (b) Wang, W.-Y.; Feng, X.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. J. Org. Chem. 2013, 78, 6025. (c) Read, M. L.; Gundersen, L.-L. J. Org. Chem. 2013, 78, 1311. (d) Xiao, T.; Li, L.; Lin, G.; Wang, Q.; Zhang, P.; Mao, Z.; Zhou, L. Green Chem. 2014, 16, 2418. (e) Gu, L.; Jin, C.; Liu, J.; Ding, H.; Fan, B. Chem. Commun. 2014, 50, 4643. (3) For selected examples, see: (a) Xia, Z.-H.; Huang, J.-B.; He, Y.M.; Zhao, J.-J.; Lei, J.; Zhu, Q. Org. Lett. 2014, 16, 2546. (b) Sun, X.; Yu, S. Org. Lett. 2014, 16, 2938. (c) Zhang, B.; Daniliuc, C. G.; Studer, A. Org. Lett. 2014, 16, 250. (d) Zhu, Z.-Q.; Wang, T.-T.; Bai, P.; Huang, Z.-Z. Org. Biomol. Chem. 2014, 12, 5839. (e) Pan, C.-D.; Han, J.; Zhang, H.-L.; Zhu, C.-J. J. Org. Chem. 2014, 79, 5374. (f) Li, C.-X.; Tu, D.-S.; Yao, R.; Yan, H.; Lu, C.-S. Org. Lett. 2016, 18, 4928. (g) Jin, Y.-H.; Jiang, M.; Wang, H.; Fu, H. Sci. Rep. 2016, 6, 20068. (h) Mao, H.; Gao, M.-C.; Liu, B.-X.; Xu, B. Org. Chem. Front. 2016, 3, 516. (4) (a) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S. Angew. Chem., Int. Ed. 2013, 52, 13289. (b) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 3990. (c) Gu, J.-W.; Zhang, Xi. Org. Lett. 2015, 17, 5384. (d) Zhang, Z.; Tang, X.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401. (e) Wang, B.; Dai, Y.; Tong, W.; Gong, H. Org. Biomol. Chem. 2015, 13, 11418. (5) (a) Cao, J.; Zhu, T.; Wang, S.; Gu, Z.; Wang, X.; Ji, S. Chem. Commun. 2014, 50, 6439. (b) Wang, L.; Sha, W. X.; Dai, Q.; Feng, X. M.; Wu, W. T.; Peng, H. B.; Chen, B.; Cheng, J. Org. Lett. 2014, 16, 2088. (c) Anton-Torrecillas, C.; Felipe-Blanco, D.; Gonzalez-Gomez, J. C. Org. Biomol. Chem. 2016, 14, 10620. (d) Xu, Y.-L.; Chen, Y.-Y.; Li, W.; Xie, Q.; Shao, L.-M. J. Org. Chem. 2016, 81, 8426. (6) (a) Sha, W.; Yu, J.; Jiang, Y.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 9179. (b) Li, Z.; Fan, F.; Yang, J.; Liu, Z. Q. Org. Lett. 2014, 16, 3396. (c) Xu, Z.-B.; Yan, C.-X.; Liu, Z.-Q. Org. Lett. 2014, 16, 5670. (d) Fang, H.; Zhao, J.; Ni, S.; Mei, H.; Han, J.; Pan, Y. J. Org. Chem. 2015, 80, 3151. (e) Rong, J.; Deng, L.; Tan, P.; Ni, C.; Gu, Y.; Hu, J. Angew. Chem., Int. Ed. 2016, 55, 2743. (f) Zhou, H.; Deng, X.-Z.; Zhang, A.-H.; Tan, X. Org. Biomol. Chem. 2016, 14, 10407. (7) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem., Int. Ed. 2012, 51, 11363. (8) (a) Leifert, D.; Daniliuc, C. G.; Studer, A. Org. Lett. 2013, 15, 6286. (b) Liu, J.; Fan, C.; Yin, H.; Qin, C.; Zhang, G.; Zhang, X.; Yi, H.; Lei, A. Chem. Commun. 2014, 50, 2145. (c) Li, X.; Fang, M.; Hu, P.; Hong, G.; Tang, Y.; Xu, X. Adv. Synth. Catal. 2014, 356, 2103. (9) (a) Nie, Z.-Y.; Ding, Q.-P.; Peng, Y.-Y. Tetrahedron 2016, 72, 8350. (b) Xu, Z.-B.; Hang, Z.-J.; Liu, Z.-Q. Org. Lett. 2016, 18, 4470. (10) (a) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846. (b) Cheng, Y.; Jiang, H.; Zhang, Y.; Yu, S. Org. Lett. 2013, 15, 5520. (c) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2013, 52, 10792. (d) Sakamoto, R.; Kashiwagi, H.; Selvakumar, S.; Moteki, S. A.; Maruoka, K. J. Org. Biomol. Chem. 2016, 14, 6417. (e) Wan, W.; Ma, G.-B.; Li, J.-L.; Chen, Y.-R.; Hu, Q.Y.; Li, M.-J.; Jiang, H.-Z.; Deng, H.-M.; Hao, J. Chem. Commun. 2016, 52, 1598. (f) Tang, X.-Y.; Song, S.; Liu, C.-B.; Zhu, R.; Zhang, B. RSC Adv. 2015, 5, 76363. (g) Rong, J.; Deng, L.; Tan, P.; Ni, C.-F.; Gu, Y.C.; Hu, J.-B. Angew. Chem., Int. Ed. 2016, 55, 2743. (11) (a) Lu, S.; Gong, Y.; Zhou, D. J. Org. Chem. 2015, 80, 9336. (b) Zhang, M.; Sheng, W.; Ji, P.; Liu, Y.; Guo, C. RSC Adv. 2015, 5, 56438. (c) Xiao, P.; Rong, J.; Ni, C.-F.; Guo, J.-K.; Li, X.-J.; Chen, D.4448

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