Silver-Mediated Cyanomethylation of Cinnamamides by Direct C(sp3

Subscriber access provided by READING UNIV

Note

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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02585 • Publication Date (Web): 09 Jan 2018 Downloaded from http://pubs.acs.org on January 10, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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

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

Nitriles,1 especially for acetonitrile, are major feedstocks for the chemical industry and widely found in diverse areas of sciences. Moreover, the cyano group2 can be converted into many useful functional groups, it is of great meanings for direct transformations of these compounds via C–H functionalization. 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 radical 5-exo-trig pathway3 to access 3,3-disubstituted oxindoles have attracted special attention.4 You2b and Zhu,2c respectively, used DTBP as an initiator for arylalkylation of activated alkene with Cu+ or Fe2+ as catalysts. Both Li5 and Pan2g used diazonium salts as a promoter for cyanomethyl oxindoles. Zhao and Tang2d developed 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,8f toluene,8d and aldehyde,8f etc. Liu group2a had documented 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 1, a). 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

Scheme 1 Difunctionalization of activated alkenes colleagues reported the silver-catalyzed radical decarboxylative cyclization of N- arylcinnamamides to afford 3,4disubstituted dihydroquinolinones (Scheme 1, b). Then a tandem addition and cyclization of N-arylcinnamamides with

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Table 1 Optimization of Typical Reaction Conditions.a

Page 2 of 8

Scheme 2 Cyanomethylation of N-arylcinnamamides.a,b,c

Oxidant CN

CH3CN , N2 , 36 h N

O

N

1a

O

2a

Entry

Oxidant (equiv)

T (oC)

Yieldb (%)

Ratio f

1

AgOAc (2.0)

120

39

4.8: 1

2

AgOAc (4.0)

120

51

4.9: 1

3

AgOAc (5.0)

120

50

5.2: 1

4

AgOAc (4.0)

130

79

5.2: 1

5

AgOAc (4.0)

140

76

5.2: 1

6

Ag2CO3 (4.0)

130

43

4.7: 1

7

Ag2O (4.0)

130

22

4.2: 1

8

AgF (4.0)

130

40

4.5: 1

9

AgOTf (4.0)

130

trace

/

10c

/

130

0

/

11

/

130

0

/

CuCl(0.1)

130

46

4.6: 1

12

CN N

FeCl3 (0.1) /DTBP

O

CN

37

2e: 86% (4.2:1)

N

O

2d: 76% (3.5:1)

CN N

CN

O

2g: 78% (3.0:1)

2f: 83% (3.9:1)

CN

O

F3C

Br

N

O

O 2h: 62% O

N O

CN

CN

CN

N

N

O

O

3.9: 1

CN N

2k: 81% (6.8:1)

2j: 75% (4.4:1) CN

2i: 69% (2.6:1)

O

2l: 66% (4.7:1)

Br CN

CN CN N

AgOAc (4.0)

Br

2c: 71% (2.2:1)

O

CN

130

e

AgOAc (4.0)

130

16f

AgOAc (0.1)

130

15

N

CN N

(3.0) 14d

O

O2N

O

CF3

130

CN

2b: 67% (4.9:1)

NC N

CN N

2a: 79% (5.2:1)

/DTBP(3.0) 13

O

32

N

4.9: 1

N

65

5.0: 1

2m: 58% (5.4:1)

trace

/

O

N

O

O

O

2n: 72% (6:1)

2o: 77% (8.2:1)

O

2p: 70% (10:1)

Br

a

Conditions: 1a (0.2 mmol), CH3CN (2.0 mL) in a Schlenk tube, 36 h, under N2. bYield of isolated products. cKOAc (4.0 equiv.). d under air. e 2.0 ml CH3CN with 1% water. fAdditive Mg(NO3)2.6H2O (0.4 mmol). fratio = trans: cis

toluene or togni’s reagent was established for the alkylated product by Duan and Wang,8d,8e respectively (Scheme 1, c). In spite of their significance in this field, most of them suffered from 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 good functional group tolerance (Scheme 1, d). Primarily, N-methyl-N-arylcinnamamide 1a was chosen as a model substrate to investigate reaction conditions (Table 1). Inspired by the functionalization of active methylene compound using silver salts,2a,9 compound 1a was treated with AgOAc (2.0 equiv) in CH3CN (2.0 mL) at 120 oC. 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 oC with moderate diastereoselectivity through careful modulating the reaction temperature and dosage of AgOAc (entry 2~5). Subsequently, other silver salts failed to afford better yield and diastereoselectivity, like Ag2CO3, Ag2O, AgF and AgOTf (entry 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

CN N

O

CN N

2q: 66% (4.6:1)

O

O

2u:41% (2.1:1)

O

2s:61% (2.6:1)

CN

CN N H

N

2r: 73% (2.9:1)

N O Ts 2v:29%

CN

CN

N O Ph 2t:61% (3.4:1)

CN

CN N

N

O

2w:58% (3.8:1)

N

O

2x:trace

a

Reaction conditions: 1 (0.2 mmol), AgOAc (0.8 mmol), CH3CN (2.0 mL) in a Schlenk tube at 130 oC under nitrogen atmosphere for 36 h. b Isolated yield. c ratio = trans: cis.

transition metals and peroxide, didn’t result in significant improvement (entry 12~13). Besides, air and water were found detrimental to the reaction (entry 14~15). Furthermore, we found that the catalytic amount of silver didn’t work in this reaction (entry 16). Finally, under the optimization process, the reaction was most productive with complete conversion 1a to 3,4-dihydronquinolinone providing 2a in 79% yield with a ratio of 5.2: 1 (trans: cis) at 130 oC 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 good functional group compatibility. 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


Page 3 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry (2a~2i). And it was worth to note 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 N-methyl 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 can’t be easily obtained in the usual radical addition/cyclization process.8d,10 Besides, heterocyclic substrate can also get target product in 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 2.0gram scale. The reactions proceeded smoothly to deliver the product in 80% yield with a ratio of 4.8: 1 (trans: cis) (Scheme 3).

Radical trap experiment

Standard conditions CN

trap reagent N

N

O

(1)

O

2a

1a

Yield Reagent TEMPO BHT

1 36% 14%

Equiv. 2 12% 5%

4 0 0

Scheme 3 Gram-scale reactions

To gain insight into the mechanistic pathway, a series of experiments were carried out (Scheme 4). Firstly, radical trapping experiments were carried out, as the increasing dosage of radical scavengers, the reactions were slowly quenched. When radical scavenger was added enough (4.0 equiv.), the reaction was completely suppressed, which indicated that the reactions involve a radical process (Scheme 4, (1)). Furthermore, kinetic isotope effect (KIE) experiments were conducted. Evident KIE was observed in an intermolecular competition reaction of a mixed sovlent CH3CN/CD3CN (kH/kD = 2.7) (Scheme 4, (2)) and a parallel experiment (kH/kD = 2.47) (Scheme 4, (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 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 groups 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-dihydroquinolin2(1H)-ones might be beneficial for the medicinal chemistry of 3,4-dihydroquinolinones compounds.

Scheme 4 Preliminary Mechanistic study

Scheme 5 Plausible Reaction Mechanism

EXPERIMENTAL SECTION General information. 1H NMR and 13C NMR spectra were measured on a 400 MHz Bruker (400 MHz for 1H NMR, 100MHz 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 LCLTQ-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 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 oC 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. 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-3yl)acetonitrile (2a). (43.6 mg, 79% yield, trans: cis = 5.2:1) as a 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, 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2b) (41.0 mg, 67% yield, trans: cis = 4.9:1) as a yellow solid. trans-2b: mp: 178.6-180.5 oC; 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 oC; 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-tetrahydroquinolin3-yl)acetonitrile (2c) (41.2 mg, 71% yield, trans: cis = 2.2:1) as a yellow solid. trans-2c: mp: 158.4-160.2 oC; 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 oC; 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2d) (53.8 mg, 76% yield, trans: cis = 3.5:1) as a yellow solid. trans-2d: mp: 162.4-164.1 oC; 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 oC; 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). 13C 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-1,2,3,4tetrahydroquinoline-6-carbonitrile (2e) (51.8 mg, 86% yield, trans: cis = 4.2:1) as a yellow solid. trans-2e: mp: 193.6-195.3 oC; 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 oC; 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2f) (53.2 mg, 83% yield, trans: cis = 3.9:1) as a yellow solid. trans-2f: mp: 161.4-162.9 oC; 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


Page 4 of 8

Page 5 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry 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 oC; 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)-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2g) (53.6 mg, 78% yield, trans: cis = 3.0:1) as a 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). 13C 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2h) (37.9 mg, 62% yield) as a yellow solid. 2h: mp: 151.7-153.4 oC; 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 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[3,2,1ij]quinolin-2-yl)acetonitrile (2i) (41.7 mg, 69% yield, trans: cis = 2.6:1) as a 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-1,2,3,4tetrahydroquinolin-3-yl) acetonitrile (2j) (53.1 mg, 75% yield, trans: cis = 4.4:1) as a yellow solid. trans-2j: mp: 159.2-161.1 oC; 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 oC; 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-3yl) acetonitrile (2k) (46.9 mg, 81% yield, trans: cis = 6.8:1) as a yellow solid trans-2k: mp: 128.8-130.3 oC; 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 oC; 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2l) (40.4 mg, 66% yield, trans: cis = 4.7:1) as a 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)-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2m) (39.9 mg, 58% yield, trans: cis = 5.4:1) as a 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-1,2,3,4tetrahydroquinolin-4-yl)benzonitrile (2n) (42.3 mg, 72% yield, trans: cis = 6.0:1) as a 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2o) (54.5 mg, 77% yield, trans: cis = 8.2:1) as a yellow solid. trans-2o: mp: 183.5-185.4 oC; 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 oC; 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). 13C 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, 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-3yl) acetonitrile (2p) (40.6 mg, 70% yield, trans: cis = 10:1) as a yellow solid. 2p: mp: 154.6-156.1 oC; 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2q) (40.4 mg, 66% yield, trans: cis = 4.6:1) as a yellow solid. trans-2q: mp: 159.3-160.7 oC; 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 oC; 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-tetrahydroquinolin3-yl)acetonitrile (2r) (42.3 mg, 73% yield, trans: cis = 2.9:1) as a yellow solid. trans-2r: mp: 164.6-166.3 oC; 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.


Page 6 of 8

Page 7 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry cis-2r: mp: 94.7-96.3 oC; 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-1,2,3,4tetrahydroquinolin-3-yl)acetonitrile (2s) (43.2 mg, 61% yield, trans: cis = 2.6:1) as a yellow solid. trans-2s: mp: 146.3-148.1 oC; 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 oC; 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-3yl)acetonitrile (2t) (41.2 mg, 61% yield, trans: cis = 3.4:1) as a yellow solid. trans-2t: mp: 171.4-173.1 oC; 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 oC; 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) as a 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). 13 C 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-2yl) acetonitrile (2v)(24.1 mg, 29% yield) as a yellow solid 2v: 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-1,8naphthyridin-3-yl)acetonitrile (2w) (32.1 mg, 58% yield, trans: cis = 3.8:1) as a 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), 3.40–3.32 (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.

ASSOCIATED CONTENT Supporting Information Spectroscopic data including NMR, spectra. The materials are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (Z.L.). *E-mail: [email protected] (Y.Z.).

Author Contributions §

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

Notes The authors declare no competing financial interest.



ACKNOWLEDGMENT This work is financially supported by the National Natural Science Foundation of China (No. 81102334, 31370372, 31170323), the Program for New Century Excellent Talents in University, State Education Ministry of China (NCET-2008-0224) and the Fundamental Research Funds for the Central Universities (2017KFYXJJ152).

REFERENCES (1) (a)Rappoport, Z. The Chemistry of the Cyano Group; Wiley: London, 1970; (b)Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53, 79027917; (c)F. Fleming, F. Nat. Prod. Rep. 1999, 16, 597-606; (d)Coates, G. W.; Hustad, P. D.; Reinartz, S. Angew. Chem., Int. Ed. 2002, 41, 2236-2257;(e)López, R.; Palomo, C. Angew. Chem., Int. Ed. 2015, 54, 13170-13184. (2) (a)Wu, T.; Mu, X.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 12578-12581; (b)Li, J.; Wang, Z.; Wu, N.; Gao, G.; You, J. Chem. Commun. 2014, 50, 15049-15051; (c)Pan, C.; Zhang, H.; Zhu, C. Org. Biomol. Chem. 2015, 13, 361-364; (d)Li, X.; Xu, J.; Gao, Y.; Fang, H.; Tang, G.; Zhao, Y. J. Org. Chem. 2015, 80, 2621-2626; (e)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, 1606-1612; (f)Li, Z.; Xiao, Y.; Liu, Z.-Q. Chem. Commun. 2015, 51, 9969-9971; (g)Ni, Z.; Huang, X.; Wang, J.; Pan, Y. RSC Adv. 2016, 6, 522-526. (3) (a)Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 2469-2473; (b)Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135, 4640-4643. (4) (a)Song, R.-J.; Liu, Y.; Xie, Y.-X.; Li, J.-H. Synthesis 2015, 47, 1195-1209; (b)Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J. Synthesis 2015, 47, 604-629. (5) Zhang, J.-L.; Liu, Y.; Song, R.-J.; Jiang, G.-F.; Li, J.-H. Synlett 2014, 25, 1031-1035. (6) (a)Pan, C.; Zhang, H.; Han, J.; Cheng, Y.; Zhu, C. Chem. Commun. 2015, 51, 3786-3788; (b)Zhao, W.; Xie, P.; Zhang, M.; Niu, B.; Bian, Z.; Pittman, C.; Zhou, A. Org. Biomol. Chem. 2014, 12, 7690-7693; (c)Li, L.; Deng, M.; Zheng, S.C.; Xiong, Y.-P.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16, 504507; (d)Kong, W.; Casimiro, M.; Fuentes, N.; Merino, E.; Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 13086-13090. (7) (a)Patel, M.; McHugh Jr, R. J.; 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, 80418051. (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.


Page 8 of 8

Silver-Mediated Cyanomethylation of Cinnamamides by Direct C(sp3

Recommend Documents