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Jan 9, 2018 - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College,. Huazhong ...
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Cite This: J. Org. Chem. 2018, 83, 1525−1531

Silver-Mediated Cyanomethylation of Cinnamamides by Direct C(sp3)−H Functionalization of Acetonitrile Kongchao Wang,†,§ Xia Chen,†,§ Ming Yuan,‡ Meng Yao,† Hucheng Zhu,† Yongbo Xue,† Zengwei Luo,*,† and Yonghui Zhang*,† †

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ‡ School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China S Supporting Information *

ABSTRACT: An efficient, silver-induced tandem radical addition/ cyclization for the synthesis of 3,4-dihydroquinolinones is presented, which exhibits a good functional group tolerance. The reaction is easy to operate and amenable to a multigram-scale synthesis. Additionally, this work illustrates the formation of a key skeleton for the synthesis of biologically interesting 3,4-dihydroquinolinone alkaloids.

N

itriles,1 especially for acetonitrile, are major feedstocks for the chemical industry and are widely found in diverse areas of sciences. Moreover, the cyano group2 can be converted into many useful functional groups, it is of great importance for direct transformations of these compounds via C−H functionalization. A radical reaction is one of the most powerful tools in organic synthesis, especially for the construction of heterocycles. Recently, the synthesis of substituted oxindoles through the radical 5-exo-trig pathway3 to access 3,3disubstituted oxindoles has attracted special attention.4 You2b and Zhu2c used DTBP as an initiator for arylalkylation of activated alkenes with Cu+ or Fe2+ as a catalyst, respectively. Both Li5 and Pan2g used diazonium salts as a promoter for cyanomethyl oxindoles. Zhao and Tang2d developed a cascade cyanomethylation of alkenes using cheap Mn(OAc)2. Compared to the former five-membered ring, the synthesis for the six-membered ring through the 6-endo-trig pathway has been less extensively studied.6 3,4-Dihydroquinolineone derivatives are a highly valuable class of heterocyclic compounds with remarkable biological activities.7 In view of their importance, some approaches to 3,4-dihydroquinolinones,2a,8 reactions of activated alkenes with simple reagents, have been developed including carboxylic acid,8a−c,f toluene,8d aldehyde,8f etc. Liu’s group2a had documented the oxidative dicarbonation of N-aryl acrylamides to construct cyano substituted oxindoles through a cascade Pd-catalyzed C(sp2)−H and C(sp3)−H activation (Scheme 1a), and it was demonstrated that AgF was indispensable to the reaction. In the report, only one example was illustrated for cyano-containing dihydroquinolinone. Mai and his colleagues reported the silver-catalyzed radical decarboxylative cyclization of N-arylcinnamamides to afford 3,4-disubstituted dihydroquinolinones (Scheme 1b). Then a tandem addition and cyclization of N-arylcinnamamides with toluene or Togni’s reagent was established for the alkylated product by Duan and Wang,8d,e respectively (Scheme 1c). In © 2018 American Chemical Society

Scheme 1. Difunctionalization of Activated Alkenes

spite of their significance in this field, most of them suffered from a low efficiency and limited substrate scope. Thus, the direct and efficient synthesis of 3,4-dihydroquinolinones is still highly desired. Herein, we report an efficient Ag(I)-induced tandem radical addition/cyclization for the synthesis of cyanomethylated 3,4-dihydroquinolinones with a good functional group tolerance (Scheme 1d). Received: October 11, 2017 Published: January 9, 2018 1525

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

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The Journal of Organic Chemistry

Scheme 2. Cyanomethylation of N-Arylcinnamamidesa,b,c

Primarily, N-methyl-N-arylcinnamamide 1a was chosen as a model substrate to investigate the reaction conditions (Table 1). Inspired by the functionalization of an active methylene Table 1. Optimization of Typical Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9 10c 11 12 13 14d 15e 16f

oxidant (equiv) AgOAc (2.0) AgOAc (4.0) AgOAc (5.0) AgOAc (4.0) AgOAc (4.0) Ag2CO3 (4.0) Ag2O (4.0) AgF (4.0) AgOTf (4.0)

CuCl (0.1)/DTBP (3.0) FeCl3 (0.1)/DTBP (3.0) AgOAc (4.0) AgOAc (4.0) AgOAc (0.1)

T (°C)

yieldb (%)

ratiog

120 120 120 130 140 130 130 130 130 130 130 130 130 130 130 130

39 51 50 79 76 43 22 40 trace 0 0 46 37 32 65 trace

4.8:1 4.9:1 5.2:1 5.2:1 5.2:1 4.7:1 4.2:1 4.5:1

4.6:1 3.9:1 4.9:1 5.0:1

a

Conditions: 1a (0.2 mmol) and CH3CN (2.0 mL) in a Schlenk tube for 36 h, under N2. bYield of isolated products. cKOAc (4.0 equiv). d Under air. e2.0 mL of CH3CN with 1% water. fAdditive Mg(NO3)2· 6H2O (0.4 mmol). gRatio = trans/cis

compound using silver salts,2a,9 compound 1a was treated with AgOAc (2.0 equiv) in CH3CN (2.0 mL) at 120 °C. The desired product 2a was achieved in 39% yield with separable diastereoisomers (Table 1, entry 1). It was found that the yield can be increased to 79% with AgOAc (4.0 equiv) at 130 °C with a moderate diastereoselectivity through carefully modulating the reaction temperature and dosage of AgOAc (entries 2−5). Subsequently, other silver salts failed to afford better yields and diastereoselectivity, like Ag2CO3, Ag2O, AgF, and AgOTf (entries 6−9). It was inferred that the alkaline substance might matter most in the reaction from the different performance between AgOTf and AgOAc in this reaction. Thus, an acetate salt, KOAc, was added, but no product was obtained (entry 10). Then AgOAc was found necessary for the full consumption of the substrate (entry 11). Further examination of other transition metals and peroxide did not result in a significant improvement (entries 12 and 13). Besides, air and water were found detrimental to the reaction (entries 14 and 15). Furthermore, we found that the catalytic amount of silver did not work in this reaction (entry 16). Finally, under the optimization process, the reaction was most productive with complete conversion of 1a to 3,4-dihydronquinolinone providing 2a in 79% yield with a ratio of 5.2:1 (trans/cis) at 130 °C within 36 h (entry 4). With a set of optimized conditions in hand, the substrate scope of the cyanomethylation of N-arylcinnamamides with AgOAc was investigated. All cinnamamide derivatives were subjected to the optimal conditions in Scheme 2. In general, this method exhibited a good functional group compatibility.

a

Reaction conditions: 1 (0.2 mmol), AgOAc (0.8 mmol), and CH3CN (2.0 mL) in a Schlenk tube at 130 °C under a nitrogen atmosphere for 36 h. bIsolated yield. cRatio = trans/cis.

Lots of functional groups were tolerated, such as methoxyl, methyl, halogen, cyanide, nitro, and trifluoromethyl. Electrondonating or electron-withdrawing groups on aniline at the para position did not affect the efficiency of the reaction, affording the desired products in moderate to excellent yields (2a−2i), and it was worth noting that electron-withdrawing groups gave better results. Substituents at the ortho, meta, and para positions on the other aromatic ring of the substrate were well-tolerated, and the corresponding products were obtained in moderate yields (2j−2s). The reaction still proceeded well when the Nmethyl group was changed to N-phenyl (2t). To our surprise, when the substituent on the N atom was hydrogen or an electron-withdrawing group (Ts), the corresponding products were also obtained (2u−2v), which cannot be easily obtained in the usual radical addition/cyclization process.8d,10 Besides, the heterocyclic substrate can also get the target product in a 1526

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

Note

The Journal of Organic Chemistry

and a parallel experiment (kH/kD = 2.47) (Scheme 4, experiment 3), which implied that the rate-determining step involves the C−H cleavage of acetonitrile. Thus, based on the experimental data and literatures,11 a plausible mechanism for this addition/cyclization procedure is proposed in Scheme 5. Two pathways may be involved in the

moderate yield (2w), but it is unfortunate that no reaction occurred when acetonitrile was replaced with propionitrile (2x). It was worthy to note that the diastereoselectivity may mainly originate from steric effect. To demonstrate the practical potential, the reaction of 1a was carried out on the 2.0 g scale. The reactions proceeded smoothly to deliver the product in 80% yield with a ratio of 4.8:1 (trans/cis) (Scheme 3).

Scheme 5. Plausible Reaction Mechanism Scheme 3. Gram-Scale Reactions

reaction. First, a cyanomethyl radical is generated from the intermediate A, and then the radical adds to the double bond of 1a to provide intermediate B. At the same time, B might also be generated through the addition of A to the alkene, followed by a silver-induced formation of an alkyl radical step. Subsequently, intermediate C will be generated from radical B through intramolecular homolytic aromatic substitution. Finally, the desired product 2a is accomplished via oxidation of intermediate C. In summary, an efficient and practical approach for the synthesis of cyano-containing 3,4-dihydroquinolin-2(1H)-ones has been developed through AgOAc-mediated radical cyanomethylation. The reaction conditions employed in the protocol exhibited a wide range of functional group compatibility. Since the cyano group can be transformed into many useful functional groups, the convenient and efficient methodology for the synthesis of functionalized 3,4-dihydroquinolin-2(1H)ones might be beneficial for the medicinal chemistry of 3,4dihydroquinolinones compounds.

To gain insight into the mechanistic pathway, a series of experiments were carried out (Scheme 4). First, radical Scheme 4. Preliminary Mechanistic Study

■

EXPERIMENTAL SECTION

General Information. 1H NMR and 13C NMR spectra were measured on a 400 MHz Bruker unit (400 MHz for 1H NMR, 100 MHz for 13C NMR) using CDCl3 as the solvent at room temperature. Chemical shifts (δ) are given in parts per million relative to the solvent peak, and coupling constants (J) are given in hertz. Melting points were obtained using an X-5 microscopic melting point apparatus (BeijingTech, China). High-resolution electrospray ionization mass spectra were carried out in the positive ion mode on a Thermo Fisher LC-LTQ-Orbitrap XL spectrometer. All of the reactions performed under a nitrogen atmosphere were conducted using standard Schlenk techniques. Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. Silica gel (200−300 mesh size) was used for column chromatography. TLC analysis of the reaction mixtures was performed using silica gel plates. General Experimental Procedure for the Synthesis of Cyanomethylated 3,4-Dihydroquinolin-2(1H)-ones. To a Schlenk tube were added N-methyl-N-arylcinnamamide 1 (0.2 mmol), AgOAc (0.8 mmol), and CH3CN (2.0 mL). The reaction was stirred at 130 °C under nitrogen for 36 h. After completion of the reaction, the reaction mixture was evaporated, and the gained residue was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and filtered; then the solvent was removed by rotary evaporation. The obtained crude product was purified by silica column chromatography (PE/EtOAc 5:1) to give desired product 2. 2-(1-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2a): 43.6 mg, 79% yield (trans/cis = 5.2:1), yellow solid. trans-2a: 1H NMR (400 MHz, CDCl3) δ 7.40−7.34 (m, 2H), 7.32 (dt, J = 9.8, 4.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 1.8 Hz,

trapping experiments were carried out with the increasing dosage of radical scavengers, and the reactions were slowly quenched. When enough of the radical scavenger was added (4.0 equiv), the reaction was completely suppressed, which indicated that the reactions involve a radical process (Scheme 4, experiment 1). Furthermore, kinetic isotope effect (KIE) experiments were conducted. Evident KIE was observed in an intermolecular competition reaction of a mixed solvent, CH3CN/CD3CN (kH/kD = 2.7) (Scheme 4, experiment 2), 1527

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

Note

The Journal of Organic Chemistry 1H), 7.19 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 4.19 (d, J = 13.2 Hz, 1H), 3.41 (s, 3H), 3.00 (dt, J = 13.2, 4.8 Hz, 1H), 2.87 (dd, J = 16.5, 4.3 Hz, 1H), 2.18 (dd, J = 16.5, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.1, 139.5, 138.4, 129.5, 129.0, 128.3, 128.3, 128.3, 128.2, 123.5, 117.7, 114.9, 45.8, 43.8, 30.4, 17.4; HRMS m/z (ESI+) calcd for C18H16N2ONa [M + Na]+ 299.1155, found 299.1153. cis-2a: 1H NMR (400 MHz, CDCl3) δ 7.30−7.25 (m, 1H), 7.23− 7.20 (m, 1H), 7.18 (d, J = 3.4 Hz, 2H), 7.17−7.14 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.03−6.98 (m, 3H), 4.31 (d, J = 6.4 Hz, 1H), 3.41 (s, 3H), 3.32−3.21 (m, 1H), 3.00 (dd, J = 17.4, 4.4 Hz, 1H), 2.10 (dd, J = 17.4, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4, 155.2, 139.4, 137.3, 129.3, 129.0, 128.6, 128.2, 128.0, 127.9, 124.0, 115.7, 45.4, 42.4, 30.2, 16.5; HRMS m/z (ESI+) calcd for C18H16N2ONa [M + Na]+ 299.1155, found 299.1154. 2-(6-Methoxy-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2b): 41.0 mg, 67% yield (trans/cis = 4.9:1), yellow solid. trans-2b: mp 178.6−180.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.43−7.38 (m, 2H), 7.38−7.32 (m, 1H), 7.24 (t, J = 4.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.23 (dd, J = 2.8, 1.1 Hz, 1H), 4.20 (d, J = 12.9 Hz, 1H), 3.64 (s, 3H), 3.42 (s, 3H), 3.01 (dd, J = 12.9, 4.9 Hz, 1H), 2.90 (dd, J = 16.4, 4.4 Hz, 1H), 2.22 (dd, J = 16.4, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 155.7, 138.3, 133.1, 129.8, 129.5, 129.0, 128.2, 117.7, 115.8, 115.0, 112.3, 55.5, 45.9, 43.7, 30.5, 17.4; HRMS m/z (ESI + ) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1258. cis-2b: mp 134.1−135.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.24− 7.20 (m, 2H), 7.18 (d, J = 4.3 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.80 (dd, J = 8.9, 2.9 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 6.3 Hz, 1H), 3.69 (s, 3H), 3.38 (s, 3H), 3.29−3.18 (m, 1H), 2.99 (dd, J = 17.4, 4.3 Hz, 1H), 2.08 (dd, J = 17.4, 11.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.8, 156.0, 137.1, 133.0, 129.5, 129.3, 128.0, 127.9, 118.9, 116.8, 114.2, 113.8, 55.6, 45.7, 42.4, 30.3, 16.5; HRMS m/z (ESI+) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1258. 2-(1,6-Dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2c): 41.2 mg, 71% yield (trans/cis = 2.2:1), yellow solid. trans-2c: mp 158.4−160.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.40−7.34 (m, 2H), 7.31 (ddd, J = 7.4, 3.6, 1.4 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.17 (s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.42 (s, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.38 (s, 3H), 2.97 (dt, J = 12.7, 4.9 Hz, 1H), 2.84 (dd, J = 16.5, 4.6 Hz, 1H), 2.18 (dd, J = 16.5, 5.3 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.9, 138.6, 137.1, 133.2, 129.5, 129.0, 128.7, 128.1, 127.9, 117.7, 114.8, 45.8, 43.9, 30.4, 20.7, 17.4; HRMS m/z (ESI + ) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1306. cis-2c: mp 116.3−117.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 6.5 Hz, 1H), 7.24 (s, 2H), 7.14 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 2H), 7.05−6.99 (m, 2H), 4.33 (d, J = 6.3 Hz, 1H), 3.46 (s, 3H), 3.37−3.26 (m, 1H), 3.06 (dd, J = 17.4, 4.3 Hz, 1H), 2.28 (s, 3H), 2.15 (dd, J = 17.3, 11.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.2, 137.5, 137.0, 133.7, 129.6, 129.3, 129.1, 128.0, 128.0, 127.9, 118.9, 115.6, 45.4, 42.5, 30.2, 20.6, 16.5; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1308. 2-(6-Bromo-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2d): 53.8 mg, 76% yield (trans/cis = 3.5:1), yellow solid. trans-2d: mp 162.4−164.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.25 (d, J = 4.5 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.77 (s, 1H), 4.23 (d, J = 13.4 Hz, 1H), 3.45 (s, 3H), 3.04 (dt, J = 13.1, 4.5 Hz, 1H), 2.96 (dd, J = 16.4, 4.0 Hz, 1H), 2.21 (dd, J = 16.4, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.7, 138.6, 137.4, 131.3, 131.0, 130.4, 129.8, 128.9, 128.6, 117.4, 116.5, 116.5, 45.6, 43.5, 30.5, 17.3; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0251. cis-2d: mp 101.9−103.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.32−7.30 (m, 1H), 7.30−7.25 (m, 2H), 7.05 (dd, J = 7.5, 1.9 Hz, 2H), 6.99 (d, J = 8.7 Hz, 1H), 4.34 (d, J = 6.4 Hz, 1H), 3.46 (s, 3H), 3.31 (dt, J = 10.9, 5.4 Hz,

1H), 3.05 (dd, J = 17.4, 4.4 Hz, 1H), 2.15 (dd, J = 17.4, 11.1 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.0, 138.6, 136.6, 131.8, 131.5, 130.1, 129.5, 128.3, 127.8, 118.6, 117.3, 116.6, 45.1, 42.2, 30.3, 16.4; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0259. 3-(Cyanomethyl)-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (2e): 51.8 mg, 86% yield (trans/cis = 4.2:1), yellow solid. trans-2e: mp 193.6−195.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.49−7.42 (m, 2H), 7.26 (s, 1H), 7.25 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.92 (s, 1H), 4.26 (d, J = 13.9 Hz, 1H), 3.50 (s, 3H), 3.11−3.05 (m, 1H), 3.02 (dd, J = 16.4, 3.6 Hz, 1H), 2.22 (dd, J = 16.4, 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.9, 143.1, 136.6, 132.7, 131.9, 130.0, 129.7, 129.0, 128.9, 118.5, 117.2, 115.4, 106.8, 45.4, 43.1, 30.6, 17.2; HRMS m/z (ESI+) calcd for C19H15N3ONa [M + Na]+ 324.1107, found 324.1106. cis-2e: mp 165.9−167.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.5, 1.5 Hz, 1H), 7.48 (s, 1H), 7.24 (d, J = 3.6 Hz, 3H), 7.14 (d, J = 8.5 Hz, 1H), 7.04−6.93 (m, 2H), 4.37 (d, J = 6.5 Hz, 1H), 3.45 (s, 3H), 3.36−3.22 (m, 1H), 3.00 (dd, J = 17.4, 4.4 Hz, 1H), 2.13 (dd, J = 17.3, 10.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.3, 143.1, 136.1, 132.8, 132.7, 129.7, 129.0, 128.6, 127.6, 118.2, 118.1, 116.2, 107.3, 45.1, 42.0, 30.3, 16.4; HRMS m/z (ESI+) calcd for C19H15N3ONa [M + Na]+ 324.1107, found 324.1109. 2-(1-Methyl-6-nitro-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin3-yl)acetonitrile (2f): 53.2 mg, 83% yield (trans/cis = 3.9:1), yellow solid. trans-2f: mp 161.4−162.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.9 Hz, 1H), 7.56 (s, 1H), 7.54−7.48 (m, 2H), 7.48−7.42 (m, 1H), 7.29 (d, J = 7.4 Hz, 2H), 7.18 (d, J = 8.9 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 3.54 (s, 3H), 3.10 (dt, J = 14.0, 4.4 Hz, 1H), 3.02 (dd, J = 16.5, 3.6 Hz, 1H), 2.23 (dd, J = 16.5, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.0, 144.7, 143.3, 136.5, 130.1, 129.5, 129.1, 128.9, 124.4, 123.8, 117.1, 115.1, 45.5, 43.3, 30.9, 17.2; HRMS m/z (ESI+) calcd for C18H15N3O3Na [M + Na]+ 344.1006, found 344.1005. cis-2f: mp 137.3−138.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 9.0, 2.5 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 5.1, 1.6 Hz, 3H), 7.16 (d, J = 9.0 Hz, 1H), 6.99 (dd, J = 7.0, 2.1 Hz, 2H), 4.43 (d, J = 6.5 Hz, 1H), 3.47 (s, 3H), 3.31 (m, 1H), 2.98 (dd, J = 17.4, 4.6 Hz, 1H), 2.13 (dd, J = 17.4, 10.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4, 160.6, 144.7, 143.4, 136.0, 129.7, 128.8, 128.7, 127.6, 124.7, 124.5, 118.1, 115.9, 114.0, 45.3, 42.0, 30.6, 16.4; HRMS m/z (ESI+) calcd for C18H15N3O3Na [M + Na]+ 344.1006, found 344.1001. 2-(1-Methyl-2-oxo-4-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2g): 53.6 mg, 78% yield (trans/cis = 3.0:1), yellow solid. trans-2g: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.45−7.40 (m, 1H), 7.27 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 6.91 (s, 1H), 4.28 (d, J = 13.6 Hz, 1H), 3.50 (s, 3H), 3.08 (dt, J = 13.5, 4.6 Hz, 1H), 2.98 (dd, J = 16.5, 3.9 Hz, 1H), 2.22 (dd, J = 16.5, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.0, 142.3, 137.2, 129.8, 129.0, 128.9, 128.7, 125.7, 125.7, 125.6, 125.3, 117.3, 115.0, 45.6, 43.5, 30.6, 17.3; HRMS m/z (ESI+) calcd for C19H15F3N2ONa [M + Na]+ 367.1029, found 367.1028. cis-2g: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.30 (d, J = 6.6 Hz, 3H), 7.21 (d, J = 8.5 Hz, 1H), 7.13− 7.00 (m, 2H), 4.44 (d, J = 6.4 Hz, 1H), 3.51 (s, 3H), 3.41−3.30 (m, 1H), 3.06 (dd, J = 17.4, 4.4 Hz, 1H), 2.18 (dd, J = 17.4, 11.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.4, 142.3, 136.4, 129.6, 128.6, 128.4, 127.8, 126.1, 125.9, 125.9, 125.8, 118.4, 115.8, 45.3, 42.2, 30.3, 16.4; HRMS m/z (ESI+) calcd for C19H15F3N2ONa [M + Na]+ 367.1029, found 367.1026. 2-(8-Methoxy-1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2h): 37.9 mg, 62% yield, yellow solid; mp 151.7− 153.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 7.1 Hz, 2H), 7.30 (d, J = 7.1 Hz, 1H), 7.14 (d, J = 7.0 Hz, 2H), 6.91 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.11 (d, J = 12.5 Hz, 1H), 3.82 (s, 3H), 3.40 (s, 3H), 3.01−2.91 (m, 1H), 2.70 (dd, J = 16.4, 4.4 Hz, 1H), 2.20 (dd, J = 16.5, 5.8 Hz, 1H); 13C NMR (100 1528

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

Note

The Journal of Organic Chemistry MHz, CDCl3) δ 169.5, 149.7, 138.1, 132.8, 129.4, 129.4, 129.1, 128.1, 124.9, 120.2, 117.8, 112.2, 55.9, 46.4, 43.9, 35.3, 17.1; HRMS m/z (ESI+) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1254. 2-(3-Oxo-1-phenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin2-yl)acetonitrile (2i): 41.7 mg, 69% yield (trans/cis = 2.6:1), yellow solid. trans-2i: 1H NMR (400 MHz, CDCl3) δ 7.37 (t, J = 7.2 Hz, 2H), 7.32 (dd, J = 8.4, 6.1 Hz, 1H), 7.21 (d, J = 6.1 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 4.25−4.18 (m, 1H), 4.15 (d, J = 13.3 Hz, 1H), 3.67−3.57 (m, 1H), 3.02 (dt, J = 13.2, 4.8 Hz, 1H), 2.89 (dd, J = 16.5, 4.3 Hz, 1H), 2.84−2.71 (m, 2H), 2.20 (dd, J = 16.5, 5.3 Hz, 1H), 2.02−1.91 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.2, 138.8, 135.0, 129.4, 129.0, 128.7, 128.1, 127.6, 126.4, 125.4, 123.0, 117.7, 45.8, 43.5, 41.7, 27.3, 21.4, 17.4; HRMS m/ z (ESI+) calcd for C20H18N2ONa [M + Na]+ 325.1311, found 325.1311. cis-2i: 1H NMR (400 MHz, CDCl3) δ 7.23−7.19 (m, 1H), 7.19− 7.13 (m, 2H), 7.05−7.00 (m, 3H), 6.98 (d, J = 7.4 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 4.35−4.21 (m, 2H), 3.52−3.37 (m, 1H), 3.33−3.21 (m, 1H), 3.00 (dd, J = 17.4, 4.4 Hz, 1H), 2.91−2.72 (m, 2H), 2.08 (dd, J = 17.4, 11.1 Hz, 1H), 2.02−1.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 137.6, 134.8, 129.3, 128.8, 127.9, 127.9, 127.5, 126.9, 126.1, 123.6, 118.9, 45.4, 42.2, 41.3, 27.2, 21.5, 16.4; HRMS m/z (ESI+) calcd for C20H18N2ONa [M + Na]+ 325.1311, found 325.1308. 2-(4-(4-Bromophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2j): 53.1 mg, 75% yield (trans/cis = 4.4:1), yellow solid. trans-2j: mp 159.2−161.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.18 (d, J = 12.5 Hz, 1H), 3.40 (s, 3H), 2.94 (ddd, J = 19.1, 12.8, 4.5 Hz, 2H), 2.29−2.06 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.7, 139.4, 137.5, 132.7, 130.7, 128.6, 128.2, 127.5, 123.6, 122.2, 117.4, 115.1, 45.3, 43.6, 30.5, 17.3; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0252. cis-2j: mp 144.9−146.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 4.35 (d, J = 6.4 Hz, 1H), 3.47 (s, 3H), 3.38−3.30 (m, 1H), 3.09 (dd, J = 17.4, 4.3 Hz, 1H), 2.16 (dd, J = 17.4, 11.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.1, 139.3, 136.3, 132.5, 129.6, 128.9, 128.9, 127.6, 124.1, 122.1, 118.6, 115.8, 44.8, 42.2, 30.2, 16.4; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0258. 2-(1-Methyl-2-oxo-4-(p-tolyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2k): 46.9 mg, 81% yield (trans/cis = 6.8:1), yellow solid. trans-2k: mp 128.8−130.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.08−7.03 (m, 1H), 6.96 (td, J = 7.6, 0.9 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 4.20 (d, J = 13.2 Hz, 1H), 3.46 (s, 3H), 3.13−2.98 (m, 1H), 2.92 (dd, J = 16.4, 4.2 Hz, 1H), 2.39 (s, 3H), 2.25 (dd, J = 16.4, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.2, 139.5, 137.9, 135.2, 130.2, 128.9, 128.5, 128.3, 128.2, 123.4, 117.7, 114.8, 45.4, 43.8, 30.4, 21.2, 17.3; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1306. cis-2k: mp 107.6−109.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.37− 7.29 (m, 1H), 7.22 (dd, J = 7.5, 1.5 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.09−7.03 (m, 3H), 6.95 (d, J = 8.1 Hz, 2H), 4.34 (d, J = 6.3 Hz, 1H), 3.47 (s, 3H), 3.37−3.25 (m, 1H), 3.06 (dd, J = 17.4, 4.4 Hz, 1H), 2.27 (s, 3H), 2.25−2.10 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.5, 139.4, 137.8, 134.2, 130.0, 128.9, 128.5, 128.5, 127.7, 124.0, 118.9, 115.7, 45.0, 42.4, 30.2, 21.0, 16.4; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1304. 2-(4-(4-Methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2l): 40.4 mg, 66% yield (trans/cis = 4.7:1), yellow solid. trans-2l: 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.1 Hz, 1H), 6.98 (t, J = 7.7 Hz, 3H), 6.71 (d, J = 7.6 Hz, 1H), 4.21 (d, J = 13.1 Hz, 1H), 3.85 (s, 3H), 3.47 (s, 3H), 3.05−2.98 (m, 1H), 2.96 (dd, J = 16.2, 4.1 Hz, 1H), 2.26

(dd, J = 16.2, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.2, 159.3, 139.4, 130.1, 128.7, 128.3, 128.2, 123.4, 117.8, 114.9, 114.9, 55.4, 45.0, 43.8, 30.4, 17.3; HRMS m/z (ESI + ) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1258. cis-2l: 1H NMR (400 MHz, CDCl3) δ 7.40−7.33 (m, 1H), 7.24 (d, J = 6.5 Hz, 1H), 7.16−7.05 (m, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 6.3 Hz, 1H), 3.77 (s, 3H), 3.49 (s, 3H), 3.39−3.25 (m, 1H), 3.08 (dd, J = 17.4, 4.3 Hz, 1H), 2.21 (dd, J = 17.4, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.5, 159.2, 139.3, 129.2, 129.0, 128.9, 128.5, 128.5, 124.0, 119.0, 115.7, 114.7, 55.3, 44.6, 42.5, 30.2, 16.4; HRMS m/z (ESI+) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1253. 2-(1-Methyl-2-oxo-4-(4-trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2m): 39.9 mg, 58% yield (trans/cis = 5.4:1), yellow solid. trans-2m: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 8.0, 7.2 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 4.30 (d, J = 12.6 Hz, 1H), 3.41 (s, 3H), 3.02 (dt, J = 12.5, 4.8 Hz, 1H), 2.92 (dd, J = 16.5, 4.5 Hz, 1H), 2.15 (dd, J = 16.5, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.5, 142.8, 139.4, 129.4, 128.8, 128.2, 127.0, 126.5, 126.5, 123.7, 117.2, 115.2, 45.6, 43.6, 30.5, 17.4; HRMS m/z (ESI+) calcd for C19H15F3N2ONa [M + Na]+ 367.1029, found 367.1027. cis-2m: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.34−7.27 (m, 1H), 7.14 (dd, J = 4.8, 3.3 Hz, 3H), 7.08 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.39 (d, J = 6.4 Hz, 1H), 3.42 (s, 3H), 3.39−3.23 (m, 1H), 3.04 (dd, J = 17.5, 4.4 Hz, 1H), 2.07 (dd, J = 17.5, 11.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.0, 141.4, 139.4, 129.1, 129.0, 128.4, 127.2, 126.4, 126.3, 126.3, 124.2, 118.5, 115.9, 45.1, 42.2, 30.2, 16.4; HRMS m/z (ESI+) calcd for C19H15F3N2ONa [M + Na]+ 367.1029, found 367.1026. 4-(3-(Cyanomethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin4-yl)benzonitrile (2n): 42.3 mg, 72% yield (trans/cis = 6.0:1), yellow solid. trans-2n: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.95 (td, J = 7.6, 0.8 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 4.30 (d, J = 12.1 Hz, 1H), 3.40 (s, 3H), 3.01 (dt, J = 12.0, 4.9 Hz, 1H), 2.90 (dd, J = 16.6, 4.9 Hz, 1H), 2.18 (dd, J = 16.6, 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.2, 144.2, 139.4, 133.2, 129.8, 129.0, 128.1, 126.4, 123.8, 118.3, 117.1, 115.3, 112.4, 45.9, 43.5, 30.5, 17.5; HRMS m/z (ESI+) calcd for C19H15N3ONa [M + Na]+ 324.1107, found 324.1104. cis-2n: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.9 Hz, 3H), 7.15 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 4.46 (d, J = 6.3 Hz, 1H), 3.48 (s, 3H), 3.44−3.35 (m, 1H), 3.11 (dd, J = 17.5, 4.2 Hz, 1H), 2.11 (dd, J = 17.6, 11.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.7, 142.7, 139.4, 133.1, 129.3, 129.0, 128.8, 126.7, 124.3, 118.4, 118.2, 116.0, 112.2, 45.2, 42.1, 30.2, 16.5; HRMS m/z (ESI+) calcd for C19H15N3ONa [M + Na]+ 324.1107, found 324.1105. 2-(4-(2-Bromophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2o): 54.5 mg, 77% yield (trans/cis = 8.2:1), yellow solid. trans-2o: mp 183.5−185.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H), 7.38−7.30 (m, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 16.0, 8.2 Hz, 2H), 6.69 (d, J = 7.6 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 3.47 (s, 3H), 3.39−3.27 (m, 1H), 2.76 (dd, J = 16.7, 5.5 Hz, 1H), 2.53 (dd, J = 16.7, 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.8, 139.5, 137.6, 134.0, 129.6, 128.6, 128.5, 128.3, 126.2, 125.7, 123.8, 117.5, 115.1, 45.3, 43.0, 30.4, 17.6; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0253. cis-2o: mp 172.7−174.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.38−7.27 (m, 2H), 7.13 (td, J = 7.6, 1.3 Hz, 1H), 7.08 (dd, J = 10.7, 4.7 Hz, 2H), 7.06−7.00 (m, 1H), 6.85 (dd, J = 7.7, 1.7 Hz, 1H), 5.13 (d, J = 7.0 Hz, 1H), 3.49 (s, 3H), 3.47−3.35 (m, 1H), 2.87 (dd, J = 17.1, 6.4 Hz, 1H), 2.41 (dd, J = 17.1, 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.4, 139.1, 137.7, 133.8, 129.5, 128.9, 128.9, 128.8, 128.2, 127.8, 124.7, 124.0, 118.7, 115.9, 43.2, 42.6, 1529

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

Note

The Journal of Organic Chemistry 30.2, 16.0; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0257. 2-(1-Methyl-2-oxo-4-(o-tolyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2p): 40.6 mg, 70% yield (trans/cis = 10:1), yellow solid; mp 154.6−156.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 6.9 Hz, 2H), 7.28−7.23 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 7.05−6.99 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.56 (d, J = 13.4 Hz, 1H), 3.49 (s, 3H), 3.17 (dd, J = 13.3, 4.6 Hz, 1H), 2.98 (dd, J = 16.5, 4.1 Hz, 1H), 2.41 (s, 3H), 2.37 (dd, J = 16.5, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 139.6, 138.1, 136.2, 131.5, 128.2, 128.2, 127.8, 127.8, 127.3, 127.2, 123.6, 118.0, 114.9, 43.0, 41.0, 30.5, 19.8, 17.1; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1306. 2-(4-(3-Methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2q): 40.4 mg, 66% yield (trans/cis = 4.6:1), yellow solid. trans-2q: mp 159.3−160.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.32−7.21 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.84 (dd, J = 8.2, 2.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 13.2 Hz, 1H), 3.75 (s, 3H), 3.40 (s, 3H), 2.98 (dt, J = 13.2, 4.8 Hz, 1H), 2.88 (dd, J = 16.4, 4.2 Hz, 1H), 2.21 (dd, J = 16.4, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.0, 160.4, 140.0, 139.4, 130.6, 128.3, 128.1, 123.5, 121.2, 117.7, 114.9, 114.8, 113.3, 55.3, 45.8, 43.7, 30.4, 17.3; HRMS m/z (ESI+) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1258. cis-2q: mp 118.8−119.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.36− 7.29 (m, 1H), 7.23−7.14 (m, 2H), 7.12−7.01 (m, 2H), 6.75 (dd, J = 8.2, 2.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 6.61−6.57 (m, 1H), 4.32 (d, J = 6.4 Hz, 1H), 3.71 (s, 3H), 3.45 (s, 3H), 3.36−3.25 (m, 1H), 3.06 (dd, J = 17.4, 4.4 Hz, 1H), 2.18 (dd, J = 17.4, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4, 160.1, 139.4, 138.8, 130.3, 129.0, 128.6, 128.1, 124.0, 120.1, 118.9, 115.8, 113.9, 113.1, 55.1, 45.4, 42.4, 30.2, 16.5; HRMS m/z (ESI+) calcd for C19H18N2O2Na [M + Na]+ 329.1260, found 329.1255. 2-(1-Methyl-2-oxo-4-(m-tolyl)-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2r): 42.3 mg, 73% yield (trans/cis = 2.9:1), yellow solid. trans-2r: mp 164.6−166.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (td, J = 7.6, 3.2 Hz, 2H), 7.11 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 9.4 Hz, 3H), 6.90 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.13 (d, J = 13.3 Hz, 1H), 3.40 (s, 3H), 2.99 (dt, J = 13.3, 4.8 Hz, 1H), 2.86 (dd, J = 16.4, 4.2 Hz, 1H), 2.30 (s, 3H), 2.19 (dd, J = 16.4, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.2, 139.5, 139.2, 138.3, 129.7, 129.3, 128.9, 128.4, 128.4, 128.3, 126.0, 123.4, 117.8, 114.8, 45.7, 43.7, 30.4, 21.5, 17.4; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1302. cis-2r: mp 94.7−96.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.30−7.24 (m, 1H), 7.18−7.14 (m, 1H), 7.07 (dd, J = 14.1, 7.5 Hz, 2H), 6.99 (dd, J = 11.9, 7.6 Hz, 2H), 6.83−6.75 (m, 2H), 4.26 (d, J = 6.4 Hz, 1H), 3.41 (s, 3H), 3.29−3.21 (m, 1H), 2.99 (dd, J = 17.3, 4.4 Hz, 1H), 2.21 (s, 3H), 2.11 (dd, J = 17.4, 11.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4, 139.4, 138.9, 137.2, 129.2, 128.9, 128.8, 128.7, 128.5, 128.4, 124.8, 124.0, 118.9, 115.7, 45.4, 42.4, 30.1, 21.6, 16.5; HRMS m/z (ESI+) calcd for C19H18N2ONa [M + Na]+ 313.1311, found 313.1306. 2-(4-(3-Bromophenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2s): 43.2 mg, 61% yield (trans/cis = 2.6:1), yellow solid. trans-2s: mp 146.3−148.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.33 (dd, J = 13.5, 7.7 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.25 (d, J = 12.8 Hz, 1H), 3.47 (s, 3H), 3.04 (dt, J = 12.6, 4.8 Hz, 1H), 2.98 (dd, J = 16.4, 4.4 Hz, 1H), 2.27 (dd, J = 16.3, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 141.0, 139.4, 131.7, 131.5, 131.1, 128.7, 128.2, 127.9, 127.3, 123.7, 123.6, 117.4, 115.1, 45.5, 43.6, 30.5, 17.4; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0258. cis-2s: mp 112.8−114.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 12.5, 4.6 Hz, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.13−7.05 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 4.27 (d, J = 6.3

Hz, 1H), 3.41 (s, 3H), 3.33−3.21 (m, 1H), 3.02 (dd, J = 17.4, 4.4 Hz, 1H), 2.19−2.04 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.0, 139.5, 139.4, 131.3, 131.0, 130.8, 129.0, 128.9, 127.5, 126.6, 124.2, 123.4, 118.6, 115.9, 45.0, 42.3, 30.2, 16.5; HRMS m/z (ESI+) calcd for C18H15BrN2ONa [M + Na]+ 377.0260, found 377.0255. 2-(2-Oxo-1,4-diphenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2t): 41.2 mg, 61% yield (trans/cis = 3.4:1), yellow solid. trans-2t: mp 171.4−173.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.2 Hz, 3H), 7.36−7.30 (m, 1H), 7.29− 7.24 (m, 2H), 7.23−7.16 (m, 2H), 7.02 (t, J = 7.7 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.37 (d, J = 12.7 Hz, 1H), 3.23 (dt, J = 12.7, 5.0 Hz, 1H), 2.86 (dd, J = 16.5, 4.5 Hz, 1H), 2.28 (dd, J = 16.5, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.9, 140.5, 138.5, 138.0, 130.0, 129.6, 129.0, 128.9, 128.6, 128.5, 128.3, 128.1, 127.6, 123.7, 117.5, 117.3, 46.2, 44.2, 17.2; HRMS m/z (ESI+) calcd for C23H18N2ONa [M + Na]+ 361.1311, found 361.1303. cis-2t: mp 148.9−150.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.36−7.26 (m, 2H), 7.24 (d, J = 5.5 Hz, 2H), 7.23−7.19 (m, 3H), 7.18−7.14 (m, 1H), 7.08−7.02 (m, 1H), 6.99−6.94 (m, 1H), 6.46 (d, J = 8.1 Hz, 1H), 4.44 (d, J = 6.5 Hz, 1H), 3.51 (ddd, J = 11.0, 6.4, 4.3 Hz, 1H), 3.03 (dd, J = 17.5, 4.3 Hz, 1H), 2.16 (dd, J = 17.5, 11.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4, 140.3, 138.1, 137.5, 130.1, 129.4, 129.1, 128.8, 128.6, 128.3, 128.1, 128.0, 127.7, 124.2, 118.8, 118.0, 45.6, 42.7, 16.3; HRMS m/z (ESI+) calcd for C23H18N2ONa [M + Na]+ 361.1311, found 361.1306. 2-(2-Oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetonitrile (2u): 21.5 mg, 41% yield (trans/cis = 2.1:1), yellow solid. trans-2u: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 7.0 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 4.25 (d, J = 13.1 Hz, 1H), 3.03 (dt, J = 13.1, 4.7 Hz, 1H), 2.92 (dd, J = 16.5, 4.3 Hz, 1H), 2.21 (dd, J = 16.5, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.2, 137.8, 135.2, 128.7, 128.1, 127.8, 127.6, 127.4, 125.3, 122.9, 116.6, 114.7, 45.5, 42.7, 15.8; HRMS m/z (ESI+) calcd for C17H14N2ONa [M + Na]+ 285.0998, found 285.0996. cis-2u: 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.22 (d, J = 6.3 Hz, 1H), 7.19 (t, J = 3.9 Hz, 3H), 7.14 (d, J = 7.4 Hz, 3H), 6.96 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 4.37 (d, J = 6.7 Hz, 1H), 3.33 (ddd, J = 11.0, 6.6, 4.4 Hz, 1H), 3.01 (dd, J = 17.4, 4.3 Hz, 1H), 2.07 (dd, J = 17.4, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 137.7, 135.9, 129.4, 129.2, 128.6, 128.1, 127.9, 126.5, 124.3, 118.6, 116.1, 45.8, 42.0, 15.7; HRMS m/z (ESI+) calcd for C17H14N2ONa [M + Na]+ 285.0998, found 285.0997. 2-(3-Oxo-1-phenyl-4-tosyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetonitrile (2v): 24.1 mg, 29% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.35−7.27 (m, 3H), 7.18 (dd, J = 10.4, 5.9 Hz, 4H), 7.12−7.07 (m, 2H), 6.98 (d, J = 7.8 Hz, 2H), 3.92 (d, J = 10.4 Hz, 1H), 3.89−3.79 (m, 1H), 3.10 (dd, J = 17.0, 7.4 Hz, 1H), 2.84 (dd, J = 17.0, 3.3 Hz, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 139.1, 137.6, 137.4, 133.6, 129.5, 129.0, 128.7, 128.2, 128.1, 127.5, 124.7, 120.1, 118.6, 57.0, 44.1, 23.4, 21.0; HRMS m/z (ESI+) calcd for C24H20N2O3SNa [M + Na]+ 439.1087, found 439.1082. 2-(1-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-1,8-naphthyridin3-yl)acetonitrile (2w): 32.1 mg, 58% yield (trans/cis = 3.8:1), yellow solid. trans-2w: 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 4.4 Hz, 1H), 7.44 (dq, J = 14.4, 7.1 Hz, 3H), 7.28 (d, J = 9.5 Hz, 2H), 6.98 (d, J = 7.5 Hz, 1H), 6.90 (dd, J = 7.5, 4.9 Hz, 1H), 4.26 (d, J = 13.8 Hz, 1H), 3.58 (s, 3H), 3.13−3.07 (m, 1H), 3.03 (dd, J = 16.3, 4.0 Hz, 1H), 2.25 (dd, J = 16.4, 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.4, 151.2, 147.0, 137.5, 136.3, 129.7, 128.9, 128.6, 123.4, 118.9, 117.4, 44.8, 43.6, 28.9, 17.1; HRMS m/z (ESI+) calcd for C17H15N3ONa [M + Na]+ 300.1107, found 300.1103. cis-2w: 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 3.4 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.31−7.26 (m, 3H), 7.12−7.05 (m, 2H), 7.00 (dd, J = 7.4, 5.0 Hz, 1H), 4.38 (d, J = 6.6 Hz, 1H), 3.59 (s, 3H), 3.40− 1530

DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531

Note

The Journal of Organic Chemistry 3.32 (m, 1H), 3.12 (dd, J = 17.4, 4.3 Hz, 1H), 2.16 (dd, J = 17.4, 11.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.0, 151.3, 147.5, 137.0, 136.8, 129.5, 128.4, 127.7, 123.1, 119.2, 118.6, 44.1, 42.2, 28.7, 16.3; HRMS m/z (ESI+) calcd for C17H15N3ONa [M + Na]+ 300.1107, found 300.1104.

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(7) (a) Patel, M.; McHugh, R. J., Jr; Cordova, B. C.; Klabe, R. M.; Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Bioorg. Med. Chem. Lett. 2001, 11, 1943−1945. (b) Ma, S.-S.; Mei, W.-L.; Guo, Z.K.; Liu, S.-B.; Zhao, Y.-X.; Yang, D.-L.; Zeng, Y.-B.; Jiang, B.; Dai, H.F. Org. Lett. 2013, 15, 1492−1495. (c) Uchida, R.; Imasato, R.; Yamaguchi, Y.; Masuma, R.; Shiomi, K.; Tomoda, H.; Omura, S. J. Antibiot. 2006, 59, 646−651. (8) (a) Mai, W. P.; Wang, J. T.; Yang, L. R.; Yuan, J. W.; Xiao, Y. M.; Mao, P.; Qu, L. B. Org. Lett. 2014, 16, 204−207. (b) Mai, W.-P.; Sun, G.-C.; Wang, J.-T.; Song, G.; Mao, P.; Yang, L.-R.; Yuan, J.-W.; Xiao, Y.-M.; Qu, L.-B. J. Org. Chem. 2014, 79, 8094−8102. (c) Yang, H.; Guo, L.-N.; Duan, X.-H. RSC Adv. 2014, 4, 52986−52990. (d) Zhou, S.-L.; Guo, L.-N.; Wang, S.; Duan, X.-H. Chem. Commun. 2014, 50, 3589−3591. (e) Wang, Q.; Han, G.; Liu, Y.; Wang, Q. Adv. Synth. Catal. 2015, 357, 2464−2468. (f) Mai, W.-P.; Wang, J.-T.; Xiao, Y.-M.; Mao, P.; Lu, K. Tetrahedron 2015, 71, 8041−8051. (9) Liu, J.; Liu, Z.; Liao, P.; Zhang, L.; Tu, T.; Bi, X. Angew. Chem., Int. Ed. 2015, 54, 10618−10622. (10) (a) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 3638−3641. (b) Dai, Q.; Yu, J.; Jiang, Y.; Guo, S.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 3865−3867. (c) Xia, D.; Li, Y.; Miao, T.; Li, P.; Wang, L. Chem. Commun. 2016, 52, 11559−11562. (11) (a) Chen, Y.-R.; Duan, W.-L. J. Am. Chem. Soc. 2013, 135, 16754−16757. (b) Unoh, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, 12975−12979. (c) Li, Y.-M.; Sun, M.; Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52, 3972− 3976.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02585. Mechanistic studies and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Yongbo Xue: 0000-0001-9133-6439 Yonghui Zhang: 0000-0002-7222-2142 Author Contributions §

K.W. and X.C. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is financially supported by the National Natural Science Foundation of China (nos. 81102334, 31370372, and 31170323), the Program for New Century Excellent Talents in University, State Education Ministry of China (NCET-20080224), and the Fundamental Research Funds for the Central Universities (2017KFYXJJ152).

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DOI: 10.1021/acs.joc.7b02585 J. Org. Chem. 2018, 83, 1525−1531