Construction of 3,4-Dihydroisoquinolinones and Indanones via DTBP

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Construction of 3,4-Dihydroisoquinolinones and Indanones via DTBPPromoted Oxidative Coupling of N-Allylbenzamides with Aromatic Aldehydes Zhong-Qi Xu, Chao Wang, Lin Li, Lili Duan, and Yue-Ming Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01242 • Publication Date (Web): 14 Aug 2018 Downloaded from http://pubs.acs.org on August 14, 2018

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The Journal of Organic Chemistry

Construction of 3,4-Dihydroisoquinolinones and Indanones via DTBP-Promoted Oxidative Coupling of N-Allylbenzamides with Aromatic Aldehydes Zhong-Qi Xu, Chao Wang, Lin Li, Lili Duan* and Yue-Ming Li* State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People’s Republic of China. ABSTRACT: A metal-free oxidative tandem coupling of N-allylbenzamide with aryl aldehydes was realized. This method allowed the 1,2-difunctionalization of the C=C double bond in N-allylbenzamides through simultaneous formation of two C(sp2)-C(sp3) bonds. In the presence of DTBP, 4-substituted 3,4-dihydroisoquinolin-1(2H)-ones were obtained in satisfactory isolated yields. 3-Substituted indanones could also be formed by varying the structures of the starting materials. O

O O R

N

DTBP, Toluene O H

+

N

R1

R2

+ R1 R3

R = aryl

120 °C, 24 h R3

R2

R3

O R1 = 4-F, 4-Cl, 4-Br, 4-CN

O

O R1

N R2

N R2

R = alkyl

R3 O

INTRODUCTION Nitrogen-containing heterocycles are prevalent skeletons in natural products, pharmaceuticals and agrochemicals. Among these structures, dihydroisoquinolones have drawn considerable attention due to their fascinating biological activities such as anti-tumor or anti-inflammatory activities and their widespread application in cancer diagnosis.1 For these reasons, strenuous

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efforts have been made toward the synthesis of dihydroisoquinolones from easily accessible starting materials. Among the variety of methods developed, activation and functionalization of C-H bonds have proved to be a straightforward route to dihydroisoquinolones.2 Typical examples included the free radical cyclization of N-allyl benzamides and other C=C double bonds.3 Recently, oxidative acylation of alkenes involving dehydrogenative cross-coupling between olefinic C(sp2)-H bond and C(sp2)-H bond of aldehydes attracted considerable attention as a straightforward approach to novel ketone structures.4 Especially worthy of mentioning is the construction of isoquinolinone skeletons via oxidative cross-coupling of N-allylbenzamides with aromatic aldehydes without the use of halides, pseudo halides and/or organometallic reagents.5 For example, Wang et al. disclosed the radical cyclization of N-allylbenzamide in the presence of an oxidant,6 and the desired dihydroisoquinolones were obtained in good yields (Scheme 1a). Lei et al. reported a copper-catalyzed oxidative coupling of alkenes with aldehydes leading to the formation of α, β-unsaturated ketones.7 Simultaneous formation of two C(sp2)-C(sp3) bonds via oxidative coupling of an alkene with an aldehyde C(sp2)-H bond followed by coupling with another aryl C(sp2)-H bond was also reported.8 For example, 1,2-difunctionalization of the C=C double bonds of N-aryl acrylamides using TBHP as an oxidant produced 3-(2-oxoethyl)indolin-2-ones in good yields (Scheme 1b).9 Scheme 1. Construction of Heterocycle via Radical Cyclization


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(a) Wang's work O

O OMe +

N H

HO

O S

N

TBHP

OMe

Ar S O

Ar O

(b) Li's work R2 N

O

R1

O +

H

H

TBHP

R2 N

R1

O

R4 R3

R3

R4

O

(c) This work O R

O R2 N +

O DTBP, Toluene

H R3

120 °C, 24 h

N

R2

O R1

R1 R = aryl

N R2 R = alkyl

O

R3 O

R3

In addition, the synthesis of indanones also attracted considerable attention due to the abundance of cyclic ketones in natural products and pharmaceuticals, as well as the utility of such ketones as important building blocks in organic synthesis and drug discovery.10 It is our purpose to develop new method for the construction of structurally diversified heterocycles. Herein, we wish to report a free radical reaction between N-allylbenzamide and aldehydes using di-tert-butyl peroxide (DTBP) as an oxidant under metal-free conditions. RESULTS AND DISCUSSION Han et al. showed in the presence of an oxidant such as DTBP, aliphatic secondary alcohols like isopropanol could be oxidized to the corresponding free radical intermediates which subsequently reacted with N-allyl benzamides to produce the desired isoquinolinones (Scheme 2).11 Scheme 2. Hydroxyalkylation-Initiated Radical Cyclization of N‑ ‑Allylbenzamide



O

O N

R3

H R2

R1

+ HO

R5 R4

DTBP, 120 °C N2, 24 h

N R1

R2 R4

R3

OH R5

We anticipated that in the presence of a suitable oxidant, C(sp2)-H bond of aldehydes could be oxidized to generate the corresponding free radicals, and the resulted radicals could undergo a variety of reactions to give the cyclization products.9 To test this assumption, reaction between N-allyl-N-methylbenzamide (1a) and benzaldehyde (2a) was carried out as a model (Table 1).12 Several regular oxidants were tested, and DTBP was found to be the most effective oxidant for the reaction. The reaction media were also screened. Toluene was found to be the most suitable solvent, and the product 3aa was obtained in 65% yield. Reactions in 1,4-dioxane, DMF, THF, DCE or MeCN/H2O were not successful, and the desired 3aa was obtained in low yields (Table 1, entries 1-6). To our delight, 80% yield of 3aa was achieved when the amount of DTBP was increased to 4.0 equiv (Table 1, entry 7). Further increasing the amount of DTBP did not increase the yield of the product (entry 7). Low isolated yield was obtained when benzyl alcohol13 was used in replacement of 2a, and no product was detected when benzylamine14 was used in replacement of 2a. Finally, 53% and 81% yields were achieved respectively when changing the amount of 2a from 3.0 equiv to 2.0 equiv and 4.0 equiv, revealing that 3.0 equiv of 2a was good enough for the reaction (entries 9-10). Table 1. Optimization of Reaction Conditionsa O

O O N H 1a

+

Ph

Oxidant, Solvent H

2a

N

120 °C, 24 h 3aa

Ph O


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entry

DTBP (equiv)

solvent

isolated yield (%)

1

3.0

MeCN

49

2

3.0

1,4-Dioxane

34

3

3.0

MeCN/H2O

27

4

3.0

DCE

52

5

3.0

THF

21

6

3.0

Toluene

65

7

4.0

Toluene

80

8

5.0

Toluene

77

9

4.0

Toluene

53b

10

4.0

Toluene

81c

11

4.0

Toluene

15d

11

4.0

Toluene

NDef

a

Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol, 3.0 equiv), oxidant = DTBP (di-tert-butyl

peroxide), solvent (3.0 mL), reaction temperature = 120 °C, reaction time = 24 h, under argon atmosphere. Isolated yield based on N-allyl-N-methylbenzamide. b2.0 equiv of 2a was used. c

4.0 equiv of 2a was used. d3.0 equiv of BnOH was used in replacement of 2a. e3.0 equiv of

BnNH2 was used in replacement of 2a. fND= not detected. With the optimized conditions in hand, the synthetic viability of the reactions was studied via reaction of benzaldehyde with a variety of N-allyl-N-methylbenzamides. As shown in Table 2, the cyclization reaction tolerated a wide range of N-allyl-N-methylbenzamides, and the expected products (3aa-3na) were obtained in up to 89% isolated yields. In particular,



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N-allyl-N-methylbenzamide derivatives bearing electron-withdrawing groups such as F-, Cl-, Br- or CN- (1b to 1d) could also be cyclized, although the desired products 3ba-3ea were obtained in slightly lower isolated yields (24%-53%). Surprisingly, 3-substituted indanone derivatives 4ba-4ea were obtained when these substrates were subjected to the reactions. Reactions of substrates bearing bulky groups on benzene rings also proceeded readily, and the expected products 3ga and 3ha were obtained in good isolated yields. It was noteworthy that the reaction of di-substituted substrate 1l also gave the expected product 3la in good yield. In the case of alkoxy substituted substrates, the reaction took place smoothly, affording products 3ia and 3ja in moderate yields. Substrate 1m bearing substituent at meta-position of the carboxyl group was also tested, and the products were obtained in moderate yield with almost no regioselectivity (3ma, 43%; 3ma', 34%). Table 2. Scope of Reaction of N-Allyl-N-Methylbenzamides with Benzaldehydea O N R1 1

H

DTBP (4.0 equiv) toluene, Ar

O +

H

2a

Ph

O

O N

R1

N

+

120 °C, 24 h

R1

3

Ph

4

O

O

entry

substrate 1 (R1)

product (isolated yields)

3:4b

1

H (1a)

3aa (80%)

-

2

4-F (1b)

3ba (53%) + 4ba (19%)

2.8:1 (1.5:1)b

3

4-Cl (1c)

3ca (51%) + 4ca (17%)

3.0:1 (1.4:1)b

4

4-Br (1d)

3da (53%) + 4da (18%)

2.9:1 (1.4:1)b

5

4-CN (1e)

3ea +4ea (40%, inseparable)

(1.5:1)b

6

4-Me (1f)

3fa (82%)

-


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7

4-nBu (1g)

3ga (82%)

-

8

4-tBu (1h)

3ha (89%)

-

9

4-MeO (1i)

3ia (79%)

-

10

4-EtO (1j)

3ja (75%)

-

11

4-Ph (1k)

3ka (63%)

-

12

3,5-DiMe (1l)

3la (84%)

-

13

3-Me (1m)

O

O N

Ph O 3ma (43%)

14

-

N

2-Naphthyl (1n)

Ph O 3ma' (34%)

O

-

N

Ph 3na (68%)

a

O

Reaction conditions: N-allyl-N-methylbenzamide 1 (0.5mmol), aldehyde 2a (1.5 mmol),

DTBP (2.0 mmol), 120 °C, 24 h, under argon atmosphere. Isolated yield based on 1. bBased on crude 1H NMR analysis of the reaction mixtures. After studying the scope of N-allyl-N-methylbenzamides, different aldehydes were subjected to the reactions. The results are summarized in Table 3. Benzaldehydes bearing 2-substituents were suitable substrates in the transformations, and the desired products 3ai and 3ak were isolated in 46% and 41% yields, respectively. Reactions of benzaldehydes bearing 4-F, -Br or -Cl groups produced the desired products 3ab-3ad in moderate yields. 3-Methoxybenzaldehyde could react with 1a smoothly, generating the corresponding 3ah in 74% yield. When 4-methoxybenzaldehyde was subjected to the same reaction, the product was obtained in 64% isolated yield. Further, reaction of benzaldehyde bearing electron withdrawing group 4-trifluoromethylbenzaldehyde gave product in 59% yield (Table 3, entry 9). Reactions of substituted benzamide 1c with different substituted benzaldehydes were



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further studied. It was noteworthy that the proportion of indanone product could increase slightly when electron-donating group was presented on benzene ring (Table 3, entry 14). Table 3. Reaction of Substituted Benzaldehydes with 1aa O Me N + H

Ar

H 2

1

O


O

N

Me

120 °C, 24 h 3

Ar O

entry

1

Ar

products

3:4b

1

1a

4-FC6H4

3ab (71%)

-

2

1a

4-ClC6H4

3ac (72%)

-

3

1a

4-BrC6H4

3ad (69%)

-

4

1a

4-MeC6H4

3ae (76%)

-

5

1a

3-4-DiMeC6H3

3af (80%)

-

6

1a

4-MeOC6H4

3ag (64%)

-

7

1a

3-MeOC6H4

3ah (74%)

-

8

1a

2-MeOC6H4

3ai (46%)

-

9

1a

4-CF3C6H4

3aj (59%)

-

10

1a

2-CF3OC6H4

3ak (41%)

-

11

1a

4-biphenyl

3al (57%)

-

12

1c

4-ClC6H4

3cc (39%) + 4cc (19%)

2.1:1 (1.4:1)b

13

1c

4-MeC6H4

3ce (35%) +4ce (31%)

1.1:1 (1: 1)b

14

1c

4-MeOC6H4

3cg (36%) +4cg (25%)

1.4:1(1.2:1)b

a

Reaction conditions: N-allyl-N-methylbenzamide 1 (0.5 mmol), aldehyde 2 (1.5 mmol),

DTBP (2.0 mmol), 120 °C, 24 h, under argon atmosphere. Isolated yield based on 1. bBased


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on crude 1H NMR analysis of the reaction mixtures. To further expand the scope of the substrates 1 and to confirm that the five-membered ring can be achieved separately, reactions of 1a, 1o, 1p, 1q with 2-naphthaldehyde were carried out, and indanone derivatives 4am, 4om, 4pm, 4qm were obtained in acceptable yields (Table 4). The structures of 3am and 4am were further confirmed by X-ray diffraction analysis.12 Benzaldehyde is not suitable for this reaction, possibly due to the lower reactivity of benzaldehyde than that of 2-naphthaldehyde. Table 4. Synthesis of Indanone Derivativesa O

O R1

O N


N

R1

+ H 120 °C, 24h

O

1 2m

4

O 1

1a, R = Ph

O N

N O

O 3am (53%)

4am (28%)

O 1

1o, R1 = tBu 1p, R1 = cyclopropyl 1q, R1 = nC5H11-

a

N O 4

R

4om, R1 = tBu 39% 4pm, R1 = cyclopropyl 35% 4qm, R1 = nC5H11 38%

Reaction conditions: N-allyl-N-methylbenzamide 1 (0.5 mmol), 2-Naphthaldehyde 2m (1.5

mmol), DTBP (2.0 mmol), 120 °C, 24 h, under argon atmosphere. Isolated yield based on 1. Finally, the effect of substituents on nitrogen atom of substrate 1 was studied (Table 5). Several alkyl and aryl substituents bulkier than methyl were used to examine the effect of steric hindrance on the course of the reactions. The substrate bearing an N-ethyl group could react very well with 2a, giving the corresponding product in 85% yield (3ra). However, slightly lower yields were found when the substituents on the nitrogen atom become bulkier,



and the products 3sa, 3ta were obtained in 75% and 68% yields, respectively. It was noteworthy that methoxyl and phenyl substituents were also tolerated in this reaction, and the corresponding products 3ua and 3va were obtained in moderate isolated yields. Table 5. Reaction Scope of 1 Bearing Different Substituents on Nitrogen Atomsa O 2

N

R + Ph

H

2a

O


O H

N

R2

120 °C， 24 h 3

1

Ph O

entry

R2

product

isolated yield (%)

1

Et

3ra

85

2

iPr

3sa

75

3

Cy

3ta

68

4

MeO

3ua

60

5

Ph

3va

61

a

Reaction conditions: N-allylbenzamide 1 (0.5 mmol), aldehyde 2a (1.5 mmol), DTBP (2.0

mmol), 120 °C, 24 h, under argon atmosphere. Isolated yield based on 1. To understand the mechanism of the reactions, excess amount (2.0 equiv) of well-known radical-trapping agents such as TEMPO or BHT (2,6-di-tert-butyl-4-methyl-phenol) was added to reaction mixture of the model reaction. Although free radical captures were not observed, complete inhibition of the reactions was observed, suggesting a radical process of the reactions. DFT calculations were carried out to study the transition states of the free radical cyclization step (Scheme 3). The cyclization might happen from either cis- or trans- direction, and the


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cis- or trans- intermediates could be formed via cis- or trans-transition states (cis-TS or trans-TS) (Scheme 3). DFT calculations were carried out to get the activation energies for all these four types of transition states. The transition states were identified by the presence of only one imaginary frequency. Carefully examining the structures of the transition states indicated that transition state cis-TS-1 was preferable due to low activation energy. From this transition state, intermediate B was produced and compound 3 could be formed as the final cyclization product. Scheme 3. Proposed Transition States for the Free Radical Cyclization Reactions O

O NH

NH O

O O O

O NH

NH

NH H

H

O

O

TS-1

O

O NH

H

B

O

A

H

NH

H

O

H O

cis-TS-1

trans-TS-1

O

O

O H NH

NH

H

A

NH

H

C O

O TS-2


O


O

Page 12 of 39

O H NH

H NH

H

H

O

O

cis-TS-2

trans-TS-2

Based on our observations and the reported results,7-9,15

a plausible reaction pathway is

proposed in Scheme 4. Firstly, thermo-homolysis of DTBP produced tert-butoxyl radical A, which could abstract hydrogen from benzaldehyde 2 to afford an aryl acyl radical B. Addition of the radical intermediate B to the double bond of alkene 1 afforded the alkyl radical intermediate C, and intramolecular radical cyclization of C produced radical intermediate D.16 Final product 3 was formed by the action of DTBP as proposed by Han et al.11 Similarly, products 4 were formed when aliphatic substrates 1 were subjected to the same reaction. DFT calculations results also suggested that the formation of isoquinolinones was preferable due to low activation energies of the reaction pathway.12 Scheme 4. Possible Pathways of the Reactions

O A

tBuOH

tBuO

O O O

H

R3

O

R3

2

B

O

O O

N

N

B

N

3 DH

C

1

R3

O

O

O

R

O R

O

R

N N

N

B

1

R3

4 O

O C' R3

D'

R3

CONCLUSION


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In summary, a metal-free oxidative tandem coupling of activated alkenes with carbonyl C(sp2)-H bonds and aryl C(sp2)-H bonds was established using a DTBP oxidation process. This tandem radical reaction provided a simple access to dihydroisoquinolone derivatives and indanone derivatives from easily available N-allylbenzamide substrates. Application of this transformation in organic synthesis is underway. EXPERIMENTAL SECTION General Experimental Information. All reactions were carried out with commercially available reagents in oven-dried apparatus. Thin layer chromatography (TLC) was performed on silica gel GF254. Column chromatography was performed employing 200-300 mesh silica gel unless otherwise noted. Melting points were measured on a digital melting-point apparatus without correction of the thermometer. 1H and 13C NMR spectra were recorded at 298 K using deuterated chloroform as solvent and TMS as internal reference. Infrared spectra were reported in wave number (cm-1). HRMS analyses were carried out with Varian FTICR-MS 7.0T. Unless otherwise indicated, starting materials and reagents used in the study were purchased and were used as received without further purification. General Procedure for the Radical Cyclization of N-Allylamide with Aldehydes. A 35 mL Schlenk-type tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with N-allyl-N-methylbenzamide (1a, 0.5 mmol, 87.6 mg). The reaction tube was then vacuumed and charged with Ar. DTBP (4.0 equiv, 292.4 mg), benzaldehyde (2a, 1.5 mmol, 159.2 mg) and toluene (3.0 mL) was added with the Ar streaming. The reaction tube was then sealed and placed in an oil bath at 120 °C. After the reaction mixture was stirred for 24 hours, it was allowed to cool to ambient temperature. The solvent was



Page 14 of 39

removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate: petroleum ether= 1: 10, v/v) to afford the desired product 3aa. 4-(2-Oxo-2-phenylethyl)-2-methyl-3,4-dihydroisoquinol-in-1(2H)-one (3aa). Compound 3aa was isolated as colorless oil (112 mg, 80% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.36 (q, J = 7.5 Hz, 3H), 7.27 (t, J = 7.1 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 3.80 (dd, J = 12.8, 4.2 Hz, 1H), 3.65-3.56 (m, 1H), 3.42-3.28 (m, 2H), 3.08 (dd, J = 17.6, 4.4 Hz, 1H), 3.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 198.0, 164.6, 141.4, 136.5, 133.6, 132.0, 128.8, 128.4, 128.1, 127.5, 126.6, 51.9, 41.9, 35.5, 33.3. IR (KBr): υ =3062, 2924, 1684, 1495, 754, 693 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H17NaNO2, 302.1152; found: 302.1161. 6-Fluoro-4-(2-oxo-2-phenylethyl)-2-methyl-3,4-dihydro-isoquinolin-1(2H)-one

(3ba).

Compound 3ba was isolated as yellow oil (79.2 mg, 53% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 8.6, 5.8 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.04 (td, J = 8.6, 2.5 Hz, 1H), 6.96 (dd, J = 8.9, 2.5 Hz, 1H), 3.90 (dd, J = 12.8, 4.2 Hz, 1H), 3.73-3.67 (m, 1H), 3.52-3.38 (m, 2H), 3.19 (dd, J = 17.7, 4.4 Hz, 1H), 3.11 (s, 3H). CDCl3): δ =-107.0ppm;

19

F NMR (376 MHz,

13

C NMR (101 MHz, CDCl3) δ 197.6, δ 164.49 (d, J = 252.4 Hz),

163.9, 144.18 (d, J = 8.4 Hz), 136.4, 133.7, 131.29 (d, J = 9.3 Hz), 128.44 (d, J = 74.7 Hz), 128.35, 125.1, 114.72 (d, J = 21.7 Hz), 113.42 (d, J = 22.1 Hz), 52.0, 41.6, 35.5, 33.2. IR (KBr): υ =3063, 2921, 1653, 1494, 752, 690 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H16FNaNO2, 320.1057; found: 320.1062.


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4-Fluoro-N-methyl-N-((3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)benzamide

(4ba).

Compound 4ba was isolated as yellow oil (27.8 mg, 19% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.2 Hz, 2H), 7.79 (dd, J = 9.2, 2.7 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.26-7.22 (m, 1H), 7.13 (td, J = 8.3, 2.8 Hz, 1H), 3.89 (dd, J = 12.8, 4.2 Hz, 1H), 3.75-3.67 (m, 1H), 3.49-3.38 (m, 2H), 3.20-3.10 (m, 4H). 19F NMR (376 MHz, CDCl3): δ = -113.9 ppm;

13

C

NMR (101 MHz, CDCl3) δ 197.8, 162.56 (d, J = 265.1 Hz), 163.3, 137.06 (d, J = 3.1 Hz), 136.4, 133.7, 128.8, 128.52 (d, J = 7.6 Hz),128.1, 119.10 (d, J = 22.0 Hz), 115.2, 115.0, 52.1, 42.0, 35.6, 32.6. IR (KBr): υ =3062, 2925, 1652, 1484, 751, 691 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H16FNaNO2, 320.1057; found: 320.1060. 6-Chloro-4-(2-oxo-2-phenylethyl)-2-methyl-3,4-dihydro-isoquinolin-1(2H)-one

(3ca).

Compound 3ca was isolated as yellow oil (80.0 mg, 51% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.21-7.16 (m, 1H), 3.81 (dd, J = 12.9, 4.2 Hz, 1H), 3.65-3.57 (m, 1H), 3.43-3.31 (m, 2H), 3.09 (dd, J = 17.7, 4.2 Hz, 1H), 3.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.5, 163.8, 143.1, 138.0, 136.3, 133.7, 130.1, 128.8, 128.1, 127.8, 127.2, 126.6, 51.8, 41.6, 35.5, 33.1. IR (KBr): υ =3060, 2974, 1675, 1447, 745, 690 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H16ClNaNO2, 336.0762; found: 336.0763. 6-Chloro-4-(2-(4-chlorophenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3cc). Compound 3cc was isolated as yellow oil (67.9 mg, 39% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J



Page 16 of 39

= 8.3 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 3.82 (dd, J = 12.9, 3.9 Hz, 1H), 3.63 – 3.56 (m, 1H), 3.39 – 3.30 (m, 2H), 3.11 – 3.05 (m, 1H), 3.03 (s, 3H).13C NMR (101 MHz, CDCl3) δ 196.3, 163.8, 142.9, 140.2, 138.1, 134.6, 130.2, 129.5, 129.1, 127.9, 127.2, 126.7, 51.8, 41.7, 35.5, 33.0. IR (KBr): υ =3061, 2924, 1685, 1399, 730, 691 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H15Cl2NaNO2, 370.0372; found: 370.0375. 6-Chloro-2-methyl-4-(2-oxo-2-(p-tolyl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ce).

Compound 3ce was isolated as yellow oil (57.4 mg, 35% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.21 – 7.17 (m, 3H), 3.79 (dd, J = 12.8, 4.0 Hz, 1H), 3.63 – 3.55 (m, 1H), 3.41 – 3.29 (m, 2H), 3.09 – 3.00 (m, 4H), 2.34(s, 3H).

13

C

NMR (101 MHz, CDCl3) δ 197.1, 163.8, 144.7, 143.2, 138.0, 133.9, 130.1, 129.5, 128.2, 127.8, 127.3, 126.6, 51.8, 41.5, 35.5, 33.1, 21.7. IR (KBr): υ =3054, 2922, 1657, 814, 693cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H19ClNO2, 328.1099; found: 328.1102. 6-Chloro-4-(2-(4-methoxyphenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-o ne (3cg). Compound 3cg was isolated as yellow oil (61.8 mg, 36% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.26 (dd, J = 8.3, 1.9 Hz, 1H), 7.22 – 7.14 (m, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.84 – 3.75 (m, 4H), 3.64 – 3.56 (m, 1H), 3.38 – 3.28 (m, 2H), 3.06 – 2.99 (m, 4H).13C NMR (101 MHz, CDCl3) δ 196.0, 163.9, 143.3, 138.0, 130.4, 130.1, 129.5, 127.8, 127.3, 126.6, 113.9, 55.6, 51.8, 41.2, 35.5, 33.2. IR (KBr): υ =3061, 2933, 1654,


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730, 693 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C19H18ClNaNO3, 366.0867; found: 366.0870. 4-Chloro-N-methyl-N-((3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)benzamide

(4ca).

Compound 4ca was isolated as yellow oil (26.6 mg, 17% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.31 (dd, J = 8.1, 2.3 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 3.80 (dd, J = 12.8, 4.2 Hz, 1H), 3.66-3.59 (m, 1H), 3.40-3.31 (m, 2H), 3.08 (dd, J = 17.7, 4.7 Hz, 1H), 3.03 (s, 3H).13C NMR (101 MHz, CDCl3) δ 197.6, 163.4, 139.7, 136.4, 133.7, 133.6, 132.0, 130.3, 128.8, 128.4, 128.2, 128.0, 52.0, 41.8, 35.6, 32.7. IR (KBr): υ =3064, 2974, 1684, 1448, 735, 690 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H16ClNaNO2, 336.0762; found: 336.0765. 4-Chloro-N-((6-chloro-3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)-N-methylbenzamide (4cc). Compound 4cc was isolated as yellow oil (33.1 mg, 19% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 8.1, 2.2 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 3.81 (dd, J = 12.9, 4.2 Hz, 1H), 3.65 – 3.59 (m, 1H), 3.36 – 3.27 (m, 2H), 3.09 – 3.01 (m, 4H).13C NMR (101 MHz, CDCl3) δ 196.4, 163.3, 140.2, 139.4, 134.7, 133.7, 132.0, 130.3, 129.5, 129.1, 128.5, 128.2, 52.0, 41.8, 35.6, 32.7. IR (KBr): υ =3064, 2924, 1685, 1400, 820, 731cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C18H15Cl2NaNO2, 370.0372; found: 370.0376. 4-Chloro-N-methyl-N-((6-methyl-3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)benzamide (4ce). Compound 4ce was isolated as yellow oil (50.8mg, 31% yield) after flash



Page 18 of 39

chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 7.8 Hz, 3H), 7.12 (d, J = 8.1 Hz, 1H), 3.80 (dd, J = 12.8, 3.6 Hz, 2H), 3.66 – 3.58 (m, 2H), 3.38 – 3.27 (m, 3H), 3.10 – 3.00 (m, 3H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.3, 144.7, 139.8, 134.0, 133.6, 132.0, 130.3, 129.5, 128.4, 128.2, 52.0, 41.6, 35.6, 32.8, 21.7. IR (KBr): υ =3029, 2922, 1655, 1440, 810, 734cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H19ClNO2, 328.1099; found: 328.1102. 4-Chloro-N-((6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)-N-methylbenzamide (4cg). Compound 4cg was isolated as yellow oil (42.9 mg, 25% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.3 Hz, 1H), 7.91 – 7.87 (m, 2H), 7.39 (dd, J = 8.1, 2.3 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.96 – 6.88 (m, 2H), 3.91 – 3.83 (m, 4H), 3.72 – 3.65 (m, 1H), 3.44 – 3.31 (m, 2H), 3.12 – 3.04 (m, 4H).13C NMR (101 MHz, CDCl3) δ 196.1, 163.9, 163.4, 139.8, 133.6, 132.0, 130.4, 130.3, 129.5, 128.4, 128.2, 113.9, 55.6, 52.0, 41.4, 35.6, 32.9. IR (KBr): υ =3296, 2931, 1655, 830, 732 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for: C19H18ClNaNO3, 366.0867; found: 366.0869. 6-Bromo-4-(2-oxo-2-phenylethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3da).

Compound 3da was isolated as yellow oil (91.3 mg, 53% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.00-7.91 (m, 3H), 7.59 (t, J = 7.4 Hz, 1H), 7.52-7.44 (m, 3H), 7.42 (d, J = 1.6 Hz, 1H), 3.88 (dd, J = 12.9, 4.2 Hz, 1H), 3.72-3.63 (m, 1H), 3.52-3.37 (m, 2H), 3.16 (dd, J = 17.7, 4.1 Hz, 1H), 3.10 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.5, 163.9, 143.3, 136.3, 133.7, 130.8, 130.3, 129.6, 128.8, 128.1,


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127.7, 126.7, 51.8, 41.6, 35.5, 33.0. IR (KBr): υ =3059, 1684, 754, 741, 690 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H17BrNO2, 358.0437; found: 358.0441. 4-Bromo-N-methyl-N-((3-oxo-2,3-dihydro-1H-inden-1-yl)methyl)benzamide

(4da).

Compound 4da was isolated as yellow oil (31.8 mg, 18% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.54 (dd, J = 8.1, 2.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.15 (d, J = 8.1 Hz, 1H), 3.88 (dd, J = 12.9, 4.2 Hz, 1H), 3.72-3.65 (m, 1H), 3.48-3.39 (m, 2H), 3.16 (dd, J = 17.7, 4.7 Hz, 1H), 3.11 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.6, 163.2, 140.2, 136.4, 134.9, 133.7, 131.4, 130.5, 128.8, 128.5, 128.1, 121.5, 51.9, 41.7, 35.6, 32.8. IR (KBr): υ =3062, 2975, 1683, 756, 730, 690 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H17BrNO2, 358.0437; found: 358.0440. 4-(2-Oxo-2-phenylethyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (3ea) /4-cyano-N-methyl-N-((3-oxo-2,3-dihydro-1H-inden-1-yl)methyl) benzamide (4ea). Compound 3ea/4ea was isolated as yellow oil (60.8 mg, 40% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.7 Hz, 0.39H), 8.14 (d, J = 8.0 Hz, 0.58H), 7.88-7.82 (m, 2H), 7.63 (dd, J = 7.9, 1.8 Hz, 0.53H), 7.58 (dd, J = 8.0, 1.5 Hz, 0,71H), 7.56-7.50 (m, 1.58H), 7.44-7.37 (m, 2H), 7.34 (d, J = 7.9 Hz, 0.51H), 3.85 (dd, J = 13.0, 4.2 Hz, 1H), 3.78-3.68 (m, 1H), 3.45-3.33 (m, 2H), 3.19-3.11 (m, 1H), 3.07 (d, J = 3.4 Hz, 3H).

13

C NMR (101 MHz, CDCl3) δ 197.0, 162.8,

162.5, 146.2, 142.3, 136.2, 135.0, 133.9, 132.4, 132.4, 131.1, 130.6, 129.2, 128.9, 128.1, 127.9, 118.1, 115.4, 111.8, 51.8, 51.7, 41.6, 41.5, 35.7, 35.6, 33.2, 32.8. IR (KBr): υ = 3061,



Page 20 of 39

2229, 1684, 1492, 750, 689 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H17N2O2, 305.1285; found: 305.1283. 4-(2-Oxo-2-phenylethyl)-2,6-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

(3fa).

Compound 3fa was isolated as yellow oil (120.2 mg, 82% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.0 Hz, 1H), 7.39 (t, J = 7.3 Hz, 2H), 7.20-7.18 (m, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.96 (s, 1H), 3.79 (dd, J = 12.9, 3.1 Hz, 1H), 3.61-3.53 (m, 1H), 3.44-3.29 (m, 2H), 3.05 (m, 4H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 198.2, 164.8, 142.6, 141.4, 136.6, 133.6, 132.8, 128.8, 128.5, 128.3, 128.1, 127.1, 126.5, 126.1, 52.0, 41.9, 35.4, 33.3, 21.6. IR (KBr): υ =3059, 2923, 1683, 751, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1489. 4-(2-Oxo-2-phenylethyl)-6-butyl-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ga):

Compound 3ga was isolated as yellow oil (137.5 mg, 82% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 1H), 7.86-7.81 (m, 2H), 7.53-7.47 (m, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.10 (dd, J = 8.0, 1.5 Hz, 1H), 6.96-6.94 (m, 1H), 3.81 (dd, J = 12.7, 4.2 Hz, 1H), 3.62-3.54 (m, 1H), 3.42-3.29 (m, 2H), 3.08 (dd, J = 17.5, 4.3 Hz, 1H), 3.02 (s, 3H), 2.53 (t, J = 7.89, 7.73 Hz, 2H), 1.54-1.45 (m, 2H), 1.25 (dq, J = 14.5, 7.3 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 198.2, 164.8, 147.6, 141.4, 136.6, 133.5, 128.7, 128.5, 128.1, 127.7, 126.5, 126.3, 52.0, 42.0, 35.7, 35.4, 33.5, 33.3, 22.4, 14.0. IR (KBr): υ = 2956, 1651, 1448, 846, 753, 692 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C22H26NO2, 336.1958; found: 336.1961.


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4-(2-Oxo-2-phenylethyl)-6-(tert-butyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3ha). Compound 3ha was isolated as a white solid (149.2 mg, 89% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 104-106°C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.29 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H), 3.81 (dd, J = 12.8, 4.1 Hz, 1H), 3.61-3.55 (m, 1H), 3.42-3.29 (m, 2H), 3.07 (dd, J = 17.3, 4.4 Hz, 1H), 3.01 (s, 3H), 1.20 (s, 9H).13C NMR (101 MHz, CDCl3) δ 198.3, 164.7, 155.6, 141.1, 136.6, 133.5, 128.7, 128.2, 128.1, 126.1, 124.6, 123.5, 52.1, 42.0, 35.4, 35.0, 33.9, 31.1. IR (KBr): υ= 2968, 1689, 802, 757, 706 cm-1. HRMS (ESI)m/z: [M+H]+ calcd for: C22H26NO2, 336.1958; found: 336.1965. 4-(2-Oxo-2-phenylethyl)-6-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ia).

Compound 3ia was isolated as yellow oil (122.1 mg, 79% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 6.78 (dd, J = 8.7, 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 3.78 (dd, J = 12.8, 4.1 Hz, 1H), 3.74 (s, 3H), 3.61-3.53 (m, 1H), 3.45-3.26 (m, 1H), 3.07 (dd, J = 17.5, 4.2 Hz, 1H), 3.00 (s, 3H).13C NMR (101 MHz, CDCl3) δ 197.0, 163.6, 161.4, 142.5, 135.5, 132.5, 129.5, 127.7, 127.0, 120.5, 111.9, 110.5, 54.4, 50.9, 40.8, 34.3, 32.6. IR(KBr): υ= 2959, 1683, 1447, 750, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO3, 310.1438; found: 310.1439. 4-(2-Oxo-2-phenylethyl)-6-ethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ja).

Compound 3ja was isolated as yellow solid(121.1 mg, 75% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 119-121°C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J



Page 22 of 39

= 8.6 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 6.76 (dd, J = 8.6, 2.3 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 3.96 (q, J = 6.9 Hz, 2H), 3.77 (dd, J = 12.7, 4.0 Hz, 1H), 3.58-3.50 (m, 1H), 3.43-3.25 (m, 2H), 3.07 (dd, J = 17.5, 4.2 Hz, 1H), 2.99 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.0, 163.6, 160.8, 142.4, 135.5, 132.5, 129.5, 127.7, 127.0, 120.4, 112.3, 110.9, 62.6, 51.0, 40.8, 34.3, 32.6, 13.7. IR (KBr): υ= 3064, 2980, 1677, 700, 687 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C20H22NO3, 324.1594; found: 324.1593. 4-(2-Oxo-2-phenylethyl)-6-phenyl-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ka).

Compound 3ka was isolated as yellow solid (119.1 mg, 63% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 60-62°C. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.54-7.44 (m, 4H), 7.40-7.31 (m, 5H), 7.31-7.24 (m, 1H), 3.83 (dd, J = 12.8, 4.1 Hz, 1H), 3.71-3.64 (m, 1H), 3.47-3.32 (m, 2H), 3.13 (dd, J = 17.6, 4.2 Hz, 1H), 3.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 196.9, 163.4, 143.7, 140.9, 138.9, 135.5, 132.5, 128.0, 127.8, 127.7, 127.0, 126.5, 126.1, 125.1, 124.2, 50.9, 40.9, 34.4, 32.5. IR (KBr): υ= 3030, 2959, 1683, 1492, 758, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C24H22NO2, 356.1645; found: 356.1641. 2,5,7-Trimethyl-4-(2-oxo-2-phenylethyl)-3,4-dihydroisoquinolin-1(2H)-one

(3la).

Compound 3la was isolated as yellow solid (129.1 mg, 84% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 88-91°C. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.8 Hz, 2H), 7.72 (s, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.04 (s, 1H), 3.76-3.61 (m, 2H), 3.44 (dd, J = 18.4, 11.3 Hz, 1H), 3.31 (d, J = 12.8 Hz, 1H), 2.96 (s, 3H), 2.74 (d, J = 17.8 Hz, 1H), 2.25 (s, 3H), 2.19 (s, 3H).13C NMR (101 MHz,


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CDCl3) δ 198.3, 165.1, 136.8, 136.5, 134.7, 133.7, 133.6, 128.8, 128.1, 126.8, 51.2, 39.4, 35.5, 29.7, 21.0, 18.3. IR (KBr): υ= 3064, 2923, 1680, 1449, 767, 695 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C20H22NO2, 308.1645; found: 308.1648. 4-(2-Oxo-2-phenylethyl)-2,5-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

(3ma).

Compound 3ma was isolated as yellow oil (63.3 mg, 43% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.0 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.27-7.17 (m, 2H), 3.74 (t, J = 14.5 Hz, 2H), 3.48 (dd, J = 17.8, 10.6 Hz, 1H), 3.34 (d, J = 12.6 Hz, 1H), 2.99 (s, 3H), 2.77 (d, J = 17.9 Hz, 1H), 2.24 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 197.1, 163.9,

138.6, 135.4, 132.8, 132.8, 132.6, 128.0, 127.7, 127.0, 126.1, 125.4, 50.0, 38.3, 34.5, 28.9, 17.4. IR (KBr): υ =3063, 2923, 1683, 1448, 756, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1493. 4-(2-Oxo-2-phenylethyl)-2,7-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

(3ma’).

Compound 3ma’ was isolated as yellow oil (49.8 mg, 34% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 3H), 7.49 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.20-7.13 (m, 1H), 7.06 (t, J = 5.9 Hz,1H), 3.77 (dd, J = 12.7, 3.7 Hz, 1H), 3.60-3.53 (m, 1H), 3.42-3.28 (m, 2H), 3.11-2.96 (m, 4H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.1, 163.7, 137.4, 136.2, 135.5, 132.5, 131.7, 127.7, 127.4, 127.3, 127.0, 126.1, 125.4, 51.0, 40.9, 34.5, 31.9, 20.0. IR(KBr): υ=3059, 2923, 1684, 1448, 752, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1494.



1-(2-Oxo-2-phenylethyl)-3-methyl-2,3-dihydrobenzo[f]isoquinolin-4(1H)-one

Page 24 of 39

(3na).

Compound 3na was isolated as yellow solid (111.9 mg, 68% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 107-110°C. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.84-7.80 (m, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.54-7.45 (m, 3H), 7.37 (t, J = 7.7 Hz, 2H), 4.34 (d, J = 10.8 Hz, 1H), 3.91 (dd, J = 12.9, 3.6 Hz, 1H), 3.69-3.55 (m, 1H), 3.46 (d, J = 13.0 Hz, 1H), 3.06 (s, 3H), 2.95 (d, J = 18.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.1, 163.9, 137.7, 135.4, 134.3, 132.6, 128.0, 128.0, 127.7, 127.1, 126.6, 126.5, 126.1, 125.3, 123.4, 122.5, 50.2, 38.9, 34.5, 28.0. IR (KBr): υ= 3060, 2924, 1681, 1491, 765, 689 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C22H20NO2, 330.1489; found: 330.1486. 4-(2-(4-Fluorophenyl)-2-oxoethyl)-2-methyl-3,4-dihydroiso quinolin-1(2H)-one (3ab). Compound 3ab was isolated as yellow oil (105.5 mg, 71 % yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 1H), 7.86 (dd, J = 8.7, 5.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.04 (t, J = 8.5 Hz, 2H), 3.82 (dd, J = 12.8, 4.1 Hz, 1H), 3.64-3.57 (m, 1H), 3.39-3.30 (m, 2H), 3.11-3.01 (m, 4H). 19F NMR (376 MHz, CDCl3) δ -104.2; 13C NMR (101 MHz, CDCl3) δ 196.4, δ 165.96 (d, J = 255.7 Hz), 141.2, 132.97 (d, J = 3.0 Hz), 130.76 (d, J = 9.3 Hz), 128.7, 128.4, 127.6, 126.6, 115.88 (d, J = 22.1 Hz), 51.9, 41.8, 35.5, 33.3. IR (KBr): υ =3068, 2925, 1683, 837, 754, 699 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H17FNO2, 298.1238; found: 298.1239. 4-(2-(4-Chlorophenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ac).

Compound 3ac was isolated as yellow oil (112.9 mg, 72% yield) after flash chromatography


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(EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.39-7.31 (m, 3H), 7.28 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 3.81 (dd, J = 12.8, 4.1 Hz, 1H), 3.65-3.57 (m, 1H), 3.39-3.28 (m, 2H), 3.12-3.00 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 196.8, 164.6, 141.2, 140.1, 134.8, 132.1, 129.5, 129.1, 128.7, 128.5, 127.6, 126.6, 51.9, 41.9, 35.5, 33.2. IR(KBr): υ= 2924, 1685, 821, 758, 698 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H17ClNO2, 314.0942; found: 314.0942. 4-(2-(4-Bromophenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ad).

Compound 3ad was isolated as yellow oil (123.6 mg, 69% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), 3.81 (dd, J = 12.8, 4.1 Hz, 1H), 3.65-3.57 (m, 1H), 3.37-3.28 (m, 2H), 3.10-3.01 (m, 4H).13C NMR (101MHz, CDCl3) δ 197.0, 164.5, 141.1, 135.2, 132.1, 132.1, 129.6, 128.8, 128.7, 128.5, 127.6, 126.6, 51.9, 41.9, 35.5, 33.2. IR(KBr): υ= 3063, 1684, 817, 757, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H17BrNO2, 358.0437; found: 358.0440. 4-(2-Oxo-2-(p-tolyl)ethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3ae). Compound 3ae was isolated as yellow solid (111.5 mg, 76% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 114-116°C. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.22-7.13 (m, 3H), 3.81 (dd, J = 12.8, 4.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.42-3.30 (m, 2H), 3.10-3.00 (m, 4H), 2.33 (s, 3H).13C NMR (101MHz, CDCl3) δ 197.7, 164.6, 144.5, 141.5, 134.1, 132.0, 129.4, 128.7, 128.4, 128.2, 127.5, 126.6, 51.9, 41.7, 35.5, 33.4, 21.7. IR (KBr):



υ= 3074, 1679, 1455, 848, 757, 699 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1493. 4-(2-(3,4-Dimethylphenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3af). Compound 3af was isolated as yellow oil (123.0 mg, 80% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.21-7.09 (m, 2H), 3.79 (dd, J = 12.8, 4.2 Hz, 1H), 3.67-3.57 (m, 1H), 3.41-3.30 (m, 2H), 3.09-2.98 (m, 4H), 2.22 (d, J = 4.1 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 197.9, 164.6, 143.3, 141.6, 137.2, 134.5, 132.0, 130.0, 129.2, 128.7, 128.4, 127.4, 126.6, 125.8, 51.9, 41.7, 35.5, 33.4, 20.1, 19.8. IR (KBr): υ =3026, 1650, 820, 753, 699 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C20H22NO2, 308.1645; found: 308.1646. 4-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3ag). Compound 3ag was isolated as yellow oil (98.9 mg, 64% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.30-7.22 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 3.80-3.72 (m, 4H), 3.61-3.54 (m, 1H), 3.35-3.25 (m, 2H), 3.05-2.96 (m, 4H).13C NMR (101MHz, CDCl3) δ 196.5, 164.6, 163.8, 141.5, 132.0, 130.4, 129.6, 128.7, 128.3, 127.4, 126.6, 113.8, 55.5, 51.9, 41.4, 35.5, 33.4. IR (KBr): υ =3065, 2934, 1649, 833, 754, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO3, 310.1438; found: 310.1438. 4-(2-(3-Methoxyphenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3ah). Compound 3ah was isolated as yellow oil (114.3 mg, 74% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 1H),


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7.36 (dt, J = 13.2, 7.6 Hz, 3H), 7.31-7.22 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.02 (dd, J = 8.1, 2.4 Hz, 1H), 3.78 (dd, J = 12.9, 4.2 Hz, 1H), 3.74 (s, 3H), 3.63-3.56 (m, 1H), 3.39-3.29 (m, 2H), 3.06 (dd, J = 17.7, 4.4 Hz, 1H), 3.02 (s, 3H).13C NMR (101 MHz, CDCl3) δ 164.6, 159.9, 141.4, 141.3, 137.8, 132.1, 129.8, 128.7, 128.4, 127.5, 126.6, 120.7, 120.1, 112.2, 55.5, 51.9, 42.0, 35.5, 33.3. IR (KBr): υ =3069, 1683, 1487, 789, 752, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO3, 310.1438; found: 310.1441. 4-(2-(2-Methoxyphenyl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

(3ai).

Compound 3ai was isolated as yellow oil (71.1 mg, 46% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 7.7, 1.5 Hz, 1H), 7.64 (dd, J = 7.7, 1.8 Hz, 1H), 7.44-7.33 (m, 2H), 7.31-7.25 (m, 1H), 7.15 (dd, J = 7.5, 1.2 Hz, 1H), 6.94 (td, J = 7.6, 1.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.80-3.74 (m, 4H), 3.63-3.57 (m, 1H), 3.41-3.32 (m, 2H), 3.13 (dd, J = 17.8, 4.9 Hz, 1H), 3.05 (s, 3H).13C NMR (101 MHz, CDCl3) δ 200.3, 164.6, 158.7, 141.7, 134.0, 131.9, 130.3, 128.9, 128.2, 127.8, 127.2, 126.6, 120.7, 111.6, 55.5, 52.0, 46.8, 35.4, 33.5. IR (KBr): υ= 2926, 1652, 1485, 756, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO3, 310.1438; found: 310.1440. 4-(2-Oxo-2-(4-(trifluoromethyl)phenyl)ethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-on e (3aj). Compound 3aj was isolated as yellow oil (102.4 mg, 59% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 6.9 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 3.83 (dd, J = 12.8, 3.9 Hz, 1H), 3.65-3.60 (m, 1H), 3.43-3.31 (m, 2H), 3.13 (dd, J = 17.8, 4.4 Hz, 1H), 3.03 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -63.2.;

13

C NMR (101 MHz, CDCl3) δ 197.0, 164.5, 141.0, 139.1, 134.58 (q, J =



33.2 Hz),132.1, 128.7, 128.5, 128.4, 127.6, 126.6, 126.24 (q, J = 272.8 Hz), 125.80 (q, J = 3.4 Hz), 51.9, 42.2, 35.5, 33.2. IR(KBr): υ= 3069, 2933, 1692, 833, 737, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H17F3NO2, 348.1206; found: 348.1203. 2-Methyl-4-(2-oxo-2-(2(trifluoromethoxy)phenyl)ethyl)-3,4-dihydroisoquinolin-1(2H)-o ne (3ak). Compound 3ak was isolated as yellow oil (74.5 mg, 41% yield) after flash chromatography (EtOAc/Petroleum ether 20% v/v). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.31-7.25 (m, 2H), 7.24-7.18 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H), 3.79 (dd, J = 12.7, 3.6 Hz, 1H), 3.63-3.55 (m, 1H), 3.38-3.23 (m, 2H), 3.10 (dd, J = 18.1, 4.7 Hz, 1H), 3.04 (s, 3H).13C NMR (101 MHz, CDCl3) δ 198.7, 164.5, 146.4, 140.9, 133.3, 132.5, 132.0, 129.9, 128.7, 128.4, 127.5, 127.3, 126.5, 121.6, 52.0, 46.1, 35.4, 33.2. IR (KBr): υ =2927, 1698, 1493, 763, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H17F3NO3, 364.1155; found: 364.1155. 4-(2-([1,1'-Biphenyl]-4-yl)-2-oxoethyl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3al). Compound 3al was isolated as yellow solid (101.2 mg, 57% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 66-68°C. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 24.0, 7.6 Hz, 4H), 7.41-7.27 (m, 5H), 7.17 (d, J = 6.9 Hz, 1H), 3.81 (dd, J = 13.3, 2.8 Hz, 1H), 3.67-3.60 (m, 1H), 3.39 (dt, J = 18.4, 10.0 Hz, 2H), 3.11 (dd, J = 17.4, 3.5 Hz, 1H), 3.04 (s, 3H).13C NMR (101 MHz, CDCl3) δ 196.5, 163.5, 145.1, 140.3, 138.5, 134.1, 131.0, 127.9, 127.7, 127.6, 127.4, 127.3, 126.4, 126.3, 126.2, 125.5, 50.8, 40.8, 34.5, 32.3. IR (KBr): υ =2960, 1678, 1479, 800, 762, 696 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C24H22NO2, 356.1645; found: 356.1647.


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2-Methyl-4-(2-(naphthalen-2-yl)-2-oxoethyl)-3,4-dihydroisoquinolin-1(2H)-one

(3am).

Compound 3am was isolated as colorless solid (87.2 mg, 53% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 158-160°C. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.93 (dd, J = 8.6, 1.6 Hz, 1H), 7.87-7.76 (m, 3H), 7.50 (dt, J = 21.5, 6.9 Hz, 2H), 7.37 (td, J = 7.4, 1.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.22-7.17 (m, 1H), 3.84 (dd, J = 12.8, 4.1 Hz, 1H), 3.72-3.66 (m, 1H), 3.54 (dd, J = 17.4, 9.3 Hz, 1H), 3.38 (dd, J = 12.8, 2.5 Hz, 1H), 3.20 (dd, J = 17.4, 4.2 Hz, 1H), 3.04 (s, 3H).13C NMR (101 MHz, CDCl3) δ 197.9, 164.6, 141.5, 135.8, 133.9, 132.4, 132.1, 130.0, 129.6, 128.8, 128.7, 128.5, 127.8, 127.5, 127.0, 126.6, 123.6, 52.0, 42.0, 35.6, 33.5. IR (KBr): υ =3056, 2909, 1655, 826, 767, 700 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C22H20NO2, 330.1489; found: 330.1491. N-Methyl-N-((3-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)methyl)benzamide (4am). Compound 4am was isolated as yellow solid (46.1 mg, 28% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v), m.p. 126-128oC. 1H NMR (400 MHz, CDCl3) δ 8.56-8.42 (m, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 6.1 Hz, 1H), 7.62 (s, 2H), 7.34 (s, 5H), 4.52-4.36 (m, 2H), 3.25-3.12 (m, 2H), 2.87 (d, J = 38.2 Hz, 1H), 2.76 (s, 3H).13C NMR (101 MHz, CDCl3) δ 205.3, 172.5, 146.6, 137.0, 136.1, 134.8, 129.8, 129.6, 129.2, 129.2, 128.5, 127.5, 126.9, 125.4, 119.4, 100.0, 54.5, 42.1, 40.2, 37.2. IR (KBr): υ =3056, 2961, 1703, 818, 699 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C22H20NO2, 330.1489; found: 330.1488. N-Methyl-N-((3-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)methyl)pivalamide (4om). Compound 4om was isolated as colorless oil (60.2 mg, 39% yield) after purified



through preparative thin layer chromatography silica gel plate (EtOAc/Petroleum ether 30% v/v). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 7.4 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.62-7.58 (m, 2H), 4.42-4.29 (m, 2H), 3.00 (s, 3H), 2.89-2.78 (m, 2H), 2.65 (d, J = 18.7 Hz, 1H), 1.25 (s, 9H).13C NMR (101 MHz, CDCl3) δ 205.7, 178.5, 157.2, 136.9, 134.6, 130.3, 129.4, 129.2, 129.0, 127.5, 125.7, 119.3, 57.2, 41.7, 39.6, 39.1, 36.9, 28.1. IR (KBr): υ =3057, 2969, 1706, 819, 753, 695 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C20H24NO2, 310.1802; found: 310.1804. N-Methyl-N-((3-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)methyl)cyclopropan ecarboxamide (4pm). Compound 4pm was isolated as colorless oil (51 mg, 35% yield) after purified through preparative thin layer chromatography silica gel plate (EtOAc/Petroleum ether 30% v/v). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.70-7.65 (m, 2H), 4.41-4.31 (m, 2H), 3.10-2.99 (m, 4H), 2.93 (dd, J = 18.8, 6.2 Hz, 1H), 2.75 (d, J = 18.7 Hz, 1H), 1.77-1.70 (m, 1H), 1.12-1.01 (m, 2H), 0.84 (d, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 205.6, 174.5, 156.9, 136.9, 134.7, 130.3, 129.4, 129.2, 129.0, 127.4, 125.5, 119.3, 55.6, 42.1, 38.2, 37.4, 11.6, 7.8, 7.7. IR (KBr): υ =2962, 1682, 1488, 802, 758, 701 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1491. N-Methyl-N-((3-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)methyl)hexanamide (4qm). Compound 4qm was isolated as colorless oil (61.4 mg, 38% yield) after purified through preparative thin layer chromatography silica gel plate (EtOAc/Petroleum ether 30% v/v). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 7.3 Hz, 1H), 7.93-7.85 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.64-7.57 (m, 2H), 4.37-4.26 (m, 2H), 3.01-2.86 (m,


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2H), 2.84 (s, 3H), 2.67 (d, J = 18.7 Hz, 1H), 2.27 (t, J = 7.6 Hz, 2H), 1.67-1.60 (m, 2H), 1.32-1.24 (m, 2H), 1.24-1.16 (m, 2H), 0.86 (t, J = 5.5 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 205.6, 174.3, 157.0, 136.9, 134.7, 130.3, 129.4, 129.2, 129.0, 127.5, 125.6, 119.3, 55.3, 42.1, 38.1, 37.3, 33.9, 31.7, 24.7, 22.5, 14.0. IR (KBr): υ =2928, 1702, 1460, 820, 788, 753 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C21H26NO2, 324.1958; found: 324.1962. 4-(2-Oxo-2-phenylethyl)-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one

(3ra). Compound

3ra was isolated as yellow oil (124.6 mg, 85% yield) after flash chromatography (EtOAc/Petroleum ether 5% v/v). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.36-7.28 (m, 3H), 7.24 (t, J = 7.1 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 3.74 (dd, J = 12.8, 4.0 Hz, 1H), 3.62-3.47 (m, 2H), 3.45-3.27 (m, 3H), 3.03 (dd, J = 17.7, 4.2 Hz, 1H), 1.01 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.9, 163.8, 141.4, 136.5, 133.5, 132.0, 129.0, 128.7, 128.4, 128.0, 127.4, 126.5, 49.1, 42.0, 41.6, 33.2, 12.6. IR (KBr): υ =3063, 2972, 1684, 1481, 754, 692 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C19H20NO2, 294.1489; found: 294.1486. 4-(2-Oxo-2-phenylethyl)-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one

(3sa).

Compound 3sa was isolated as yellow oil (115.4 mg, 75% yield) after flash chromatography (EtOAc/Petroleum ether 5% v/v). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 8.3 Hz, 3H), 7.28 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 5.01 (hept, J = 6.7 Hz, 1H), 3.66-3.58 (m, 1H), 3.49 (qd, J = 13.0, 3.0 Hz, 2H), 3.35 (dd, J = 18.1, 9.6 Hz, 1H), 3.01 (dd, J = 18.1, 3.9 Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 198.0, 163.6, 141.2, 136.5, 133.5, 132.0, 129.4, 128.8, 128.7, 127.9, 127.5, 126.4, 43.4, 42.3, 41.2, 32.8, 19.8,



Page 32 of 39

19.2. IR (KBr): υ =3062, 2972, 1684, 1480, 754, 691 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C20H22NO2, 308.1645; found: 308.1644. 2-Cyclohexyl-4-(2-oxo-2-phenylethyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ta).

Compound 3ta was isolated as yellow oil (118.1 mg, 68% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 6.9 Hz, 1H), 7.33 (q, J = 7.2 Hz, 3H), 7.26 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 4.57 (t, J = 10.1 Hz, 1H), 3.62-3.46 (m, 3H), 3.32 (dd, J = 18.0, 9.4 Hz, 1H), 2.99 (dd, J = 18.1, 3.7 Hz, 1H), 1.73-1.50 (m, 4H), 1.43 (d, J = 10.9 Hz, 1H), 1.35-1.24 (m, 3H), 1.16 (t, J = 11.7 Hz, 1H), 1.00-0.88 (m, 1H).13C NMR (101 MHz, CDCl3) δ 198.1, 163.5, 141.2, 136.5, 133.5, 131.9, 129.5, 128.7, 128.7, 127.9, 127.4, 126.4, 51.6, 43.6, 41.2, 33.0, 30.0, 29.8, 25.6, 25.5, 25.4. IR (KBr): υ =3062, 2928, 1684, 1478, 754, 697 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C23H26NO2, 348.1958; found: 348.1954. 4-(2-Oxo-2-phenylethyl)-2-methoxy-3,4-dihydroisoquinolin-1(2H)-one

(3ua).

Compound 3ua was isolated as yellow oil (88.6 mg, 60% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.7 Hz, 1H), 7.90-7.83 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.43-7.36 (m, 3H), 7.34-7.28 (m, 1H), 7.18 (d, J = 6.8 Hz, 1H), 4.03 (dt, J = 11.8, 3.1 Hz, 1H), 3.84-3.77 (m, 1H), 3.73 (s, 3H), 3.67 (dt, J = 12.0, 2.5 Hz, 1H), 3.51 (ddd, J = 17.7, 9.4, 2.5 Hz, 1H), 3.12 (dt, J = 17.7, 3.1 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 196.6, 161.8, 139.7, 135.4, 132.6, 131.7, 127.8, 127.6, 127.1, 127.0, 126.6, 125.8, 60.5, 50.6, 41.1, 33.5. IR (KBr): υ =3063, 2930, 1677, 1448, 753, 693 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C18H18NO3, 296.1281; found: 296.1287.


Page 33 of 39 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


4-(2-Oxo-2-phenylethyl)-2-phenyl-3,4-dihydroiso quinolin-1(2H)-one (3va). Compound 3va was isolated as yellow oil (104.1 mg, 61% yield) after flash chromatography (EtOAc/Petroleum ether 10% v/v). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.35-7.26 (m, 3H), 7.27-7.18 (m, 5H), 7.10 (t, J = 6.6 Hz, 1H), 4.18 (dd, J = 12.4, 3.4 Hz, 1H), 3.79-3.68 (m, 2H), 3.48 (dd, J = 17.7, 8.7 Hz, 1H), 3.20 (dd, J = 17.7, 4.2 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 197.8, 164.0, 143.0, 141.7, 136.5, 133.6, 132.6, 129.1, 129.1, 128.8, 128.1, 127.7, 126.7, 126.4, 125.4, 53.3, 41.8, 33.7. IR (KBr): υ =3061, 1682, 754, 723, 692 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for: C23H20NO2, 342.1489; found: 342.1493. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxx. Optimization of reaction conditions, copies of NMR spectra, and X-ray diffraction data for compounds, computational results for transition states (PDF) Crystallographic data for compounds 3am and 4am (CIF) AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected] ORCID Yue-Ming Li: 0000-0003-2632-9253



Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS We acknowledge financial support from the National Natural Science Foundation of China (NSFC 21672106, NSFC 21272121) and Tianjin Municipal Commission of Science and Technology (15JCZDJC33300). Y.M.L. acknowledges the support from “The Fundamental Research Funds for the Central Universities (63171337)”. REFERENCES (1)

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Construction of 3,4-Dihydroisoquinolinones and Indanones via DTBP

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