dione Derivatives - ACS Publications - American Chemical Society

Subscriber access provided by EKU Libraries

Note

Reductant-Free Aerobic Hydroxylation of Isoquinoline-1,3(2H,4H)-dione Derivatives YUANYONG YANG, YINGXIAN LI, CHENG CHENG, GUO YANG, SHUIYING WAN, Jiquan Zhang, YUANHU MAO, YONGLONG ZHAO, LIN ZHANG, CHUN LI, and Lei Tang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02977 • Publication Date (Web): 15 Jan 2019 Downloaded from http://pubs.acs.org on January 15, 2019

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 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 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.

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 17 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

Reductant-Free Aerobic Hydroxylation of Isoquinoline-1,3(2H,4H)-dione Derivatives Yuanyong Yang, *,# Yingxian Li, # Cheng Cheng, Guo Yang, Shuiying Wan, Jiquan Zhang, Yuanhu Mao, Yonglong Zhao, Lin Zhang, Chun Li and Lei Tang * State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China. *Corresponding

authors: E-mail addresses: [email protected]; [email protected] #These authors made equal contribution to this work.

R2

R2 OH O

R

N O

Cs2CO3 (5 mmol%), Air

R1

MeCN, 25 °C

O R

Transition Metal and Reductant Free !

N

R1

26 examples 82%-95% yield

O

Abstract: Base catalyzed efficient hydroxylation of isoquinoline-1,3(2H,4H)-diones with air under transition metal and reductant-free condition was established. This methodology is essentially mild and compatible with broad range of substrate, including aryl, heteroaryl and alkyl groups. And the product could be simply transformed into hydroxylated tetrahydroisoquinoline core structure through reductive process. Isoquinolinedione (trivially known as homophthalimide) is an important structural motif that prevalent in variety of bioactive compounds and natural products.1 Several representative bioactive isoquinolinedione containing molecules are listed in figure 1. For instance, compound 1 is a hepatitis C virus NS5B polymerase inhibitor,1g 2 is a selective tyrosyl DNA phosphodiesterase II inhibitor which will enhance the efficacy of clinically important Top2-targeting anticancer drugs,1a 3 is a potent caspase-3 inhibitor and 4 has dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities.1b,1h To date, the developments of new bioactive compounds depend heavily on organic synthetic chemistry. Thus, the introduction of new functional groups into such a structural motif would offer more opportunities to discover new intriguing bioactive molecules.

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

Page 2 of 17

O

O N HO

NH

Br

1 O OMe

N H

O

O O S N H

O

N H

2

O

H N

O

O Ph

N

NH

O

OH O

O 3

4

Figure 1. Bioactive compounds bearing isoquinolinedione In the past decade, considerable advances were achieved in the synthesis of functionalized isoquinolinediones. Using radical initiated addition-cyclization of activated alkenes, groups like alkyl,2 sulfonyl,3 fluoroalkyl,4 nitro,5 bromo6 and phenylthio7 groups were successfully incorporated into the framework of isoquinolinediones. Recently, 4-hydroxyisoquinolinediones were synthesized from the addition of N-alkylbenzamides to ketoesters, Friedel–Crafts reaction of indoles with isoquinoline-1,3,4-triones, autooxidation-rearrangement reaction of isoquinolinone derivatives, 1,3-dipolar cycloaddition reaction and oxidation reactions with benzoyl peroxide.8 Although there are methods to synthesize 4-hydroxy-isoquinoline-1,3(2H,4H)-diones, limitations like harsh reaction conditions, costly reagents, poor efficiency and stoichio metric amount of external of oxidant still persist. Thus, exploiting more convenient and environmental benign procedure towards 4-hydroxyisoquinolinedione derivatives is still challenging tasks for chemists. Previous W ork: R

R OH O N

Bn

R OH O

NaOH (cat), Air N

Excess P(OEt)3

O

Bn

O

6 R = iPr, 97% yield

O

NaOH (cat) N

Air

Bn

O

5

BnHN R

O

O O

6 7 R = Et, 36% yield, 25% yield R = Bn, 33% yield, 11% yield

This W ork: R

R OH O N

Bn

O

Base, Air Reductant free

N

O

O

5

6

Bn

Scheme 1. Hydroxylation of isoquinolinediones with air On the other hand, air, as the greenest and abundant oxidant, found wide application in the hydroxylation of carbonyl compounds.9 However, transitional metal or reductant as triethyl phosphite is generally required to reduce the peroxy intermediates to push the reaction forward.9a In 1997, Heaney’s group reported their hydroxylation of isoquinolinediones with air under basic conditions (scheme 1).10 In the absence of reductant, hydroxylation occurred reluctantly even under prolonged


Page 3 of 17 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


reaction time along with rearranged product. As a continuous investigation on the hydroxylation of carbonyl compounds with air,11 we wish to report our results on the hydroxylation of isoquinolinediones. Based on our previous investigation on the hydroxylation of 2-oxindole with air,11 2-benzyl-4-phenylisoquinoline-1,3(2H,4H)-dione was used as model substrate for the hydroxylation reaction under phase-transfer conditions and the results are summarized in Table 1. Table 1. Reaction Condition for the Hydroxylation 2-Benzyl-4-Phenylisoquinoline-1, 3(2H, 4H)-dione with Air. Ph

Ph OH O N

Bn

Ph CONHBn

O

Base, TBAB, Air Solvent, 25 °C

N

O

O

5a

6a

of

O Bn O 7a

Entry

Base

Solvent

Time (h)

Yield(%)a,b

Ratio (6:7)c

1

/

Toluene

24

20:1

5

Cs2CO3

DCM

5

85

>20:1

6

Cs2CO3

CHCl3

5

72

>20:1

7

Cs2CO3

MeCN

2

93

>20:1

8d

Cs2CO3

MeCN

3

92

>20:1

9d

K2CO3

MeCN

4

83

>20:1

10 d

NaOH

MeCN

2

35

5:5

11 d

KOH

MeCN

2

56

6:4

12 d

tBuOK

MeCN

2

80

9:1

a

Reactions were run on a 0.2 mmol scale with 5 mol% TBAB and 5 mol% of base in 500 μl solvent, 25 ℃, under air. b Yield was based on the isolated product of 6. c The ratio was determined by TLC analysis. d Reaction was conducted in the absence of TBAB. Initially, 5% tetrabutyl ammonium bromide (TBAB) was employed as a catalyst and toluene as a solvent, 2-benzyl-4-phenylisoquinoline-1,3(2H,4H)-dione 5a failed to give any product in the absence of base or in the presence of organic base Et3N (Table 1, Entries 1-2). Then, inorganic base Cs2CO3 was used and delivered the hydroxylation product 6a in 70% yield after 24 hours. Moreover, the rearranged product 7a was not detected under this reaction condition (Table 1, Entry 3). As different solvent have different stabilizing effect on the ion pair intermediate formed between the substrate and phase-transfer catalyst, the solvent effect on the reaction



Page 4 of 17

yield was screened. Gratifyingly, the efficiency could be improved drastically with common polar solvents like THF, DCM, CHCl3 and MeCN. With MeCN as a reaction solvent, 93% yield and excellent selectivity was achieved within 2 hours (Table 1, Entries 4-7). In light of certain solubilizing ability of MeCN to inorganic base, we envision this reaction could be achieved without the addition of TBAB. To test our hypothesis, one reaction in the absence of PTC was conducted. We were pleased to found the reaction proceed smoothly and finished within 3 hours with comparable yield and selectivity (Table 1, Entry 8). Encouraged by this inspiring result, we carry on investigating the base effect on this PTC free hydroxylation reaction. Weaker base K2CO3 give slightly lower yield although maintained the selectivity (Table 1, Entry 9). Stronger base like NaOH and KOH give poor selectivity result in poor yield, mainly due to the rearrangement of 6a to 7a under this strong basic condition (Table 1, Entries 10-11), as stronger base tend to deprotonate the hydroxy group which induced the intramolecular rearrangement. To test this, strong base tBuOK was used and the reaction finished within 2 hours and 80% yield was obtained along with some rearranged product (Table 1, Entry 12). Therefore, 5% Cs2CO3 in MeCN was established as the optimal condition for this hydroxylation and the generality of this reaction was tested. Table 2. Substrate Scope for the Hydroxylation of a 2-Benzyl-4-Phenylisoquinoline-1, 3(2H, 4H)-dione Derivatives with Air. Ar

Ar OH O N

R1

R

O

Cs2CO3, Air MeCN, 25 °C

N

R1

O 5

O 6


R

Page 5 of 17 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


O N

N

O OH

6b 85% yield

O

O N

Ph

N

Me

Me MeO

6c 94% yield

6d 90% yield

N

O N

Bn

O OH

O OH

O OH

Cl 6e 92% yield

OMe 6f 87% yield

Cl 6g 90% yield

Bn

N

O OH Cl

Cl

O N

Bn

O OH

Bn

O Bn

O OH

6m 86% yield

6j 91% yield O Bn N O OH

6n 93% yield

Cl 6h 91% yield O

O N

N

Bn

N

Bn

O OH

O OH

OMe

F 6i 82% yield

N

O

O OH

Cl

F

O OH

O Bn

Me

N

O OH

O OH

6a 92% yield

MeO

O

O

O Bn

Ac

CN 6k 90% yield

6l 89% yield

O

O N

Bn

O OH

S 6o 94% yield

N

Bn

O OH

HN 6p 95% yield

a

Reactions were run on a 0.2 mmol scale with 5 mol% of Cs2CO3 in 500 μl MeCN, 25 ℃, under air for 3 h. Initially, the substitution group on nitrogen of isoquinolinedione was studied for the steric effect on the hydroxylation reaction. The reaction was found to be amenable to steric groups like methyl, benzyl and phenyl, providing the hydroxylation product with excellent yield (Table 2, Entries 6a-6c). Further, we assessed the influence of a methoxy group at the R1 position and again the product was delivered in excellent yield (Table 2, Entries 6d-6e). Finally, the steric and electronic effect of 4-aryl substitution group was studied. As anticipated, this method demonstrates its utilization by tolerating a wide range of functional groups. Electron-donating and electron-withdrawing groups ortho-, meta- or para- on the aromatic ring are all well tolerated, good to excellent yield was achieved (Table 2, Entries 6f-6m). Moreover, replacement of simple aryl to streic hindered 2-naphthyl or electron rich heteroaryl are all prove to be fruitful and excellent yield was obtained (Table 2, Entries 6n-6p). Table 3. Substrate Scope for the Hydroxylation 2-Benzyl-4-Alkylisoquinoline-1, 3(2H, 4H)-dione Derivatives with Air.a


of


R

R OH O N

N

MeCN, 25 °C

Bn

O

5

6

F

HO

O 6q 91% yield

N

N

N

Bn

Bn

O

O 6s 90% yield

6r 93% yield

O

O

Bn

O

Me

HO

HO O

Bn

Bn

Br

Cl

O N

O

Cs2CO3, Air

O

HO

Page 6 of 17

6t 95% yield

MeO OMe

Cl HO

HO N

O N

Bn

O 6u 88% yield

HO

HO

O

Bn

O 6v 94% yield

O

O N

Bn

O 6w 87% yield

N

Bn

O 6x 91% yield

HO

HO

O

O N O 6y 86% yield

Bn

N

Bn

O 6z 87% yield

a

Reactions were run on a 0.2 mmol scale with 5 mol% of Cs2CO3 in 500 μl MeCN, 25 ℃, under air for 3 h.

After achieving the hydroxylation of 4-aryl isoquinoline-1,3(2H,4H)-diones, we move our attention to 4-alkyl isoquinoline-1,3(2H,4H)-diones. As the enolate of 4-alkyl isoquinoline-1,3(2H,4H)-diones is less conjugate than the 4-aryl isoquinoline-1,3(2H,4H)-diones, presumably, 4-alkyl isoquinoline-1,3(2H,4H)-diones should be less reactive. Then, 2,4-dibenzylisoquinoline-1,3(2H,4H)-dione 5q was used to react under standard reaction condition. Gratifyingly, 5q was conveniently transformed to 6q in 91% yield (Table 3, Entry 6q). Without further optimization, the established reaction condition was applied to 4-benzyl isoquinoline-1,3(2H,4H)-diones with different substitution groups on the benzyl ring. The results shows both electron-donating and electron-withdrawing groups were compatible with this hydroxylation reaction, very good yields were achieved (Table 3, Entries 6r-6x). Moreover, liner butyl or steric hindered isobutyl groups were also reactive under standard reaction condition to deliver the hydroxylation products in high yields (Table 3, Entries 6y, 6z).


Page 7 of 17 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


OH O

O N

Cs2CO3 (5% mmol), Air

(a)

6a 90% yield, 0.926 g

HO

HO

O

1. BH3, THF, Reflux 2. HCl

Me

O 6c

N

OMe

O Bn

HCl Me

(b)

8c 82% yield

N Br H OH 5% mol, K2CO3

N

N

Bn

O

O 5a 3 mmol, 0.98 g

N

N

MeCN, 25 °C

Bn

OH O

Toluene, 25 °C, 48 h

N

(c) Bn

O 6q 92% yield, 15% ee

O 5q

Scheme 2. Reduction of 6c with BH3 To demonstrate the practical utilization of this protocol, a gram scale reaction was conducted under optimized reaction condition and the hydroxylated product 6a was isolated in 90% yield, as shown in Scheme 2a. Moreover, hydroxylation product 6c was reduced with borane to deliver 8c in 82% yield after acid work up, Scheme 2b. Compound 8c is a norepinephrine potentiator and the hydroxyl group is essential for the high selectivity.12 Besides, a chiral version of this reaction was attempted using quinine derived phase-transfer catalyst, however, only 15% ee was obtained as shown in Scheme 2c.

HO

HO O N

Bn

O

TEMPO, 2 equiv Standard condition

O

N

Bn

Standard condition

O

6a 85% yield

O

BHT, 2 equiv

5a

N

Bn

O 6a 80% yield

Scheme 3. Control experiments To gain mechanistic insight into the hydroxylation reaction, control experiments were conducted, Scheme 3. The addition of 2 equivalents of 2,2,6,6-tetramethylpiperidinooxy (TEMPO) under standard conditions didn’t inhibited the reaction and 85% of hydroxylated product was isolated. Besides, the addition of 2,6-di-tert-butyl-4-methylphenol (BHT) also didn’t alter the reaction pathway. These experimental results ruled out radical intermediates were involved in this transformation. However, this reaction could be totally suppressed when the air was replaced with nitrogen. Based on these control experiments and former reports,10 the plausible mechanism



Page 8 of 17

was outlined in scheme 4. Compound 5 was deprotonated with base to give enolate 9, which reacts with oxygen in the air and further protonation to get organic hydroperoxide 10. Then, the hydroperoxide 10 react with enolate 9 to give the final product 6. O

O

O N

R

N

Base O

R1 5

R 5

N

O2

9

N

9 O

O R1

O

R

9

R1 O HO 10

R O

R1 OH 6

Scheme 4. Proposed pathway for this oxidation reaction In conclusion, an efficient transition metal and reductant-free base catalyzed hydroxylation of isoquinoline-1,3(2H,4H)-diones with air was established. This mild reaction condition compatible with a broad array of substrates and provides an alternate route for the synthesis of hydroxylated isoquinoline-1,3(2H,4H)-diones. Moreover, the product could be conveniently transformed to hydroxylated tetrahydroisoquinoline core structure through simple reductive process.

Experiment Section 1. General information. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) spectra were recorded on INOVA 400 MHz spectrometer (400 MHz and 100 MHz). Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CDCl3:  7.26). Chemical shifts for carbon are reported in parts per million downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3:  77.0). Data are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz). All high resolution mass spectra were obtained on a Waters G2-XSQTof mass spectrometer. Melting points were determined on a Tektronix X-4 melting point apparatus. Analytical TLC was performed using EM separations percolated silica gel 0.2 mm layer UV 254 fluorescent sheets. 2. Starting Materials. All solvents and inorganic reagents were from commercial sources and used without purification unless otherwise noted. isoquinoline-1,3(2H,4H)-diones were prepared following the literature procedures.13 3. General Procedure for Synthesis of 6a-6z Isoquinoline-1,3(2H,4H)-dione (0.2 mmol, 1.0 equiv.) was dissolved in 500μl of MeCN and the temperature was maintained at 25 ℃. After five minutes, Cs2CO3 (3.3 mg, 0.05 equiv.) was added and reacted for 3 hours. After the complete consumption of 5 by TLC, the reaction solution was placed under a reduced pressure to remove solvent at 45 ℃ . The crude reaction mixture was purified by flash column chromatography (hexane/ethyl acetate = 30:1 to 5:1) to yield the desired product.


Page 9 of 17 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. Reduction of 6c to bioactive compound 8c. To a round bottom flask with 6c (133 mg, 0.5 mmol) dissolved in 2 mL of THF was added 2 mL of 1M BH3−THF complex at 0 °C. The mixture was stirred at 0 °C for 4 h and was heated to reflux for 10 h, followed by addition of 2 mL of 1M HCl. The mixture was heated to reflux for 1 h to quench the reaction. The mixture was extracted with CHCl3 (5 mL × 5), and the solvent was removed under a rotary evaporator. The residue was purified by silica gel chromatography (DCM/MeOH = 100:1 to 20:1) to yield the desired product 8c (113 mg, 82% yield) as a hydrochloride salt. 2-benzyl-4-hydroxy-4-phenylisoquinoline-1,3(2H,4H)-dione(6a): White solid, 63 mg, 92% yield, mp: 144.2-145.3 ℃; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 0.9 Hz, 1H), 7.53 (dd, J = 5.2, 2.7 Hz, 1H), 7.24 – 7.21 (m, 3H), 7.20 (s, 2H), 7.20 (s, 2H), 7.19 (s, 1H), 7.13 (d, J = 1.4 Hz, 2H), 7.11 (d, J = 1.9 Hz, 1H), 5.11 (q, J = 14.1 Hz, 2H), 4.54 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.7, 163.9, 142.2, 140.1, 136.0, 134.6, 128.8, 128.7, 128.5, 128.5, 128.5, 128.4, 127.6, 126.2, 125.0, 124.6, 76.0, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H18NO3 344.1287, found 344.1283. 4-hydroxy-2,4-diphenylisoquinoline-1,3(2H,4H)-dione (6b): White solid, 56 mg, 85% yield, mp: 58.5-59.6 ℃ ; 1H NMR (500 MHz, CDCl3) δ 8.27 (dd, J = 7.9, 0.7 Hz, 1H), 7.75 (dd, J = 7.0, 1.3 Hz, 1H), 7.59 (dd, J = 1.5, 0.8 Hz, 1H), 7.50 – 7.41 (m, 4H), 7.34 – 7.32 (m, 3H), 7.32 – 7.30 (m, 2H), 7.31 (s, 1H), 7.04 (s, 1H), 4.60 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 175.8, 164.1, 142.2, 140.0, 134.8, 134.5, 129.4, 129.0, 128.9, 128.9, 128.7, 128.7, 128.0, 126.3, 125.1, 124.8, 76.5; HRMS (ESI-TOF) m/z [M+H]+ calculated for C21H16NO3 330.1130, found 330.1124. 4-hydroxy-2-methyl-4-phenylnaphthalene-1,3(2H,4H)-dione (6c): White solid, 55 mg, 94% yield, mp: 105.9-106.7 ℃; 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.28 (s, 1H), 7.27 (d, J = 5.6 Hz, 2H), 7.22 (d, J = 2.2 Hz, 2H), 7.20 (d, J = 1.5 Hz, 1H), 4.57 (s, 1H), 3.34 (s, 3H); 13C{1H} NMR (126 MHz, CDCl ) δ 176.0, 164.3, 142.5, 140.3, 134.5, 128.8, 128.7, 3 128.5, 128.3, 126.3, 124.9, 124.4, 75.8, 27.8; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C16H13NO3Na 290.0793, found 290.0796. 4-hydroxy-7-methoxy-2-methyl-4-phenylisoquinoline-1,3(2H,4H)-dione (6d): White solid, 54 mg, 90% yield, mp: 144.6-145.7 ℃; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.28 (t, J = 4.6 Hz, 3H), 7.23 (d, J = 2.5 Hz, 2H), 7.21 (d, J = 1.7 Hz, 1H), 4.47 (s, 1H), 3.91 (s, 3H), 3.35 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.2, 164.3, 159.8, 142.7, 132.7, 128.8, 128.4, 127.8, 125.5, 124.9, 122.4, 110.8, 75.6, 55.7, 27.9; HRMS (ESI-TOF) m/z [M+H]+ calculated for C17H16NO4 298.1079, found 298.1084. 4-(3,4-dichlorophenyl)-4-hydroxy-7-methoxy-2-methylisoquinoline-1,3(2H,4H)-di one(6e): White solid, 67 mg, 92% yield; mp: 149.5-150.6 ℃; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 2.7 Hz, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 4.50 (s, 1H), 3.91 (s, 3H), 3.35 (s, 3H); 13C{1H} NMR (101 MHz, CDCl ) δ 175.3, 163.9, 160.1, 142.9, 133.1, 132.9, 131.6, 3



130.6, 127.8, 127.3, 125.4, 124.5, 122.7, 111.1, 74.8, 55.7, 28.1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C17H14Cl2NO4 366.0300, found 366.0283. 2-benzyl-4-hydroxy-4-(4-methoxyphenyl)isoquinoline-1,3(2H,4H)-dione (6f): White solid, 65 mg, 87 %yield, mp: 38.5-39.2 ℃ ; 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.54 – 7.49 (m, 1H), 7.20 (d, J = 3.7 Hz, 2H), 7.19 – 7.18 (m, 1H), 7.19 – 7.18 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 5.10 (dd, J = 31.5, 14.1 Hz, 2H), 4.55 (s, 1H), 3.73 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.8, 163.9, 159.6, 140.2, 136.0, 134.5, 134.4, 128.7, 128.5, 128.4, 128.3, 127.5, 126.5, 126.1, 124.6, 113.9, 75.7, 55.3, 44.3; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C23H19NO4Na 396.1212, found 396.1197. 2-benzyl-4-(4-chlorophenyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione (6g): White solid, 68 mg, 90% yield, mp: 76.5-77.8 ℃ ; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.43 – 7.27 (m, 2H), 7.26 (s, 2H), 7.26 – 7.23 (m, 3H), 7.18 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 5.21 – 5.10 (m, 2H), 4.58 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.3, 163.7, 140.8, 139.6, 135.8, 134.7, 134.6, 134.5, 129.2, 129.0, 128.8, 128.6, 128.6, 128.4, 127.7, 126.5, 126.1, 75.6, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H17ClNO3 378.0897, found 378.0890. 2-benzyl-4-(3,4-dichlorophenyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione (6h): Off white paste, 75 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 2.7 Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 7.20 – 7.19 (m, 2H), 7.18 (s, 1H), 7.13 (s, 2H), 7.11 (d, J = 2.0 Hz, 1H), 5.10 (dd, J = 32.1, 14.1 Hz, 2H), 4.45 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.8, 163.5, 142.3, 139.1, 135.6, 134.9, 133.1, 132.9, 130.5, 129.2, 128.8, 128.7, 128.5, 127.9, 127.2, 126.0, 124.3, 75.1, 44.5; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H16Cl2NO3 412.0507, found 412.0497. 2-benzyl-4-(3-chloro-4-fluorophenyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6i ): White solid, 65 mg, 82% yield, mp: 41-42.5 ℃; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 32.1 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.26 – 7.24 (m, 2H), 7.21 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 5.17 (t, J = 9.3 Hz, 2H), 4.60 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.9, 163.5, 157.9 (d, J = 251.1 Hz), 139.3, δ139.2 (d, J = 3.6 Hz), 135.6, 134.8, 129.2, 128.7, 128.7, 128. 4, 127.8, 127.7, 126.1, 125.0 (d, J = 7.6 Hz), 124.3, 121.5 (d, J = 17.8 Hz),116.6 (d, J = 21.5 Hz), 75.1, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H16ClFNO3 396.0803, found 396.0793. 2-benzyl-4-hydroxy-4-(3-methoxyphenyl)isoquinoline-1,3(2H,4H)-dione (6j): Off white solid, 68 mg, 91% yield, mp: 90.5-91.3 ℃; 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 2.6 Hz, 4H), 7.29 (d, J = 2.6 Hz, 1H), 7.25 – 7.22 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 5.18 (q, J = 14.0 Hz, 2H), 4.59 (s, 1H), 3.70 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 163.9, 159.8, 143.7, 140.0, 136.0, 134.5, 129.7, 128.8, 128.6, 128.4, 128.4, 127.6, 126.1, 124.5, 117.2, 113.9, 110.7,


Page 10 of 17

Page 11 of 17 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


75.8, 55.1, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H20NO4 374.1392, found 374.1390. 3-(2-benzyl-4-hydroxy-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)benzonitrile( 6k): White solid, 66 mg, 90% yield, mp: 69-71 ℃; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 7.9, 0.9 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.63 (dd, J = 7.8, 0.8 Hz, 1H), 7.58 (dd, J = 10.8, 4.3 Hz, 1H), 7.53 – 7.50 (m, 1H), 7.50 – 7.48 (m, 1H), 7.42 (s, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.27 (s, 1H), 7.23 (dd, J = 5.6, 2.6 Hz, 4H), 7.21 – 7.19 (m, 1H), 5.12 (q, J = 13.9 Hz, 2H), 4.56 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.6, 163.4, 143.7, 139.0, 135.5, 134.9, 132.0, 129.5, 129.4, 128.8, 128.8, 128.7, 128.5, 127.9, 126.1, 124.3, 118.1, 112.9, 75.3, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H17N2O3 369.1239, found 369.1235. 4-(3-acetylphenyl)-2-benzyl-4-hydroxyisoquinoline-1,3(2H,4H)-dione (6l): White solid, 69 mg, 89% yield, mp: 90.5-91.3 ℃ ; 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 7.7 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.79 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.56 – 7.53 (m, 1H), 7.53 (dd, J = 6.2, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.23 (dd, J = 6.4, 4.8 Hz, 2H), 7.21 (s, 1H), 7.21 – 7.17 (m, 2H), 7.15 (d, J = 3.4 Hz, 1H), 5.12 (s, 2H), 4.67 (s, 1H), 2.43 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 197.3, 175.1, 163.7, 142.8, 139.7, 137.5, 135.8, 134.7, 129.4, 129.1, 129.0, 128.7, 128.6, 128.4, 128.2, 127.7, 126.1, 124.8, 124.4, 75.7, 44.3, 26.5; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H20NO4 386.1392, found 386.1383. 2-benzyl-4-(2-fluorophenyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione (6m): Yellow solid, 62 mg,86% yield, mp: 119.4-120.5 ℃; 1H NMR (500 MHz, CDCl3) δ 8.23 (dd, J = 7.9, 0.8 Hz, 1H), 7.71 (td, J = 8.0, 1.7 Hz, 1H), 7.58 (td, J = 7.7, 1.3 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.39 (s, 1H), 7.32 – 7.26 (m, 2H), 7.25 (d, J = 5.6 Hz, 1H), 7.23 (dd, J = 6.3, 2.2 Hz, 1H), 7.23 – 7.16 (m, 2H), 6.86 (dd, J = 11.6, 8.2 Hz, 1H), 5.20 (dd, J = 35.1, 14.0 Hz, 2H), 4.16 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 174.2, 163.6, 159.0 (d, J = 247.2 Hz), 138.7, 136.2, 134.2, 130.56 (d, J = 8.6 Hz), 130.11 (d, J = 12.0 Hz), 129.00, 128.66, 128.44, 128.37, 127.53, 127.05, 126.54 (d, J = 2.8 Hz), 124.57 (d, J = 3.6 Hz), 124.40 (d, J = 1.8 Hz), 116.09 (d, J = 21.8 Hz), 72.97, 44.23; HRMS (ESI-TOF) m/z [M+H]+ calculated for C22H17FNO3 362.1192, found 362.1179. 2-benzyl-4-hydroxy-4-(naphthalen-2-yl)isoquinoline-1,3(2H,4H)-dione (6n): White solid,73mg, 93% yield, mp: 107.5-108.8 ℃ ; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 7.9, 0.8 Hz, 1H), 7.75 (d, J = 4.1 Hz, 1H), 7.74 (d, J = 2.9 Hz, 1H), 7.73 (d, J = 0.8 Hz, 1H), 7.70 – 7.68 (m, 1H), 7.68 – 7.67 (m, 1H), 7.66 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.54 (s, 1H), 7.46 – 7.43 (m, 2H), 7.28 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 7.15 (d, J = 3.5 Hz, 2H), 7.13 (s, 1H), 5.14 (q, J = 14.0 Hz, 2H), 4.60 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.6, 163.9, 140.1, 139.7, 135.9, 134.6, 132.9, 132.8, 128.8, 128.7, 128.7, 128.5, 128.4, 128.4, 127.6, 127.4, 126.7, 126.5, 126.2, 124.5, 124.2, 122.3, 76.1, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C26H20NO3 394.1443, found 394.1440. 4-(benzo[b]thiophen-5-yl)-2-benzyl-4-hydroxyisoquinoline-1,3(2H,4H)-dione (6o):



Off white solid,75 mg, 94% yield,mp: 47.9-48.6 ℃; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 5.4 Hz, 1H), 7.22 (d, J = 6.9 Hz, 2H), 7.17 (s, 1H), 7.15 (s, 2H), 7.13 – 7.11 (m, 1H), 5.24 – 5.06 (m, 2H), 4.62 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.7, 163.9, 140.3, 139.8, 139.6, 138.8, 135.9, 134.6, 128.8, 128.6, 128.5, 128.3, 127.6, 127.5, 126.2, 124.5, 124.0, 122.8, 121.0, 120.1, 76.0, 44.4; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C24H17NO3SNa 422.0827, found 422.0823. 2-benzyl-4-hydroxy-4-(1H-indol-5-yl)isoquinoline-1,3(2H,4H)-dione (6p): White solid,73 mg, 95% yield, mp: 78.4-79.3 ℃; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 1.3 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.68 (dd, J = 7.4, 1.3 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.53 (dd, J = 7.7, 1.0 Hz, 1H), 7.31 (d, J = 1.7 Hz, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 7.02 (dd, J = 8.7, 1.9 Hz, 2H), 6.40 (t, J = 2.2 Hz, 1H), 5.12 (d, J = 23.0 Hz, 2H), 4.56 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.3, 164.2, 140.9, 136.1, 135.4, 134.4, 134.1, 128.6, 128.5, 128.3, 128.3, 127.7, 127.5, 126.3, 125.2, 124.7, 119.1, 117.6, 111.3, 103.2, 76.4, 44.4; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H19N2O3 383.1396, found 383.1387. 2,4-dibenzyl-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6q): Colorless paste, 65 mg, 91% yield; 1H NMR (1 MHz, CDCl3) δ 8.00 – 7.91 (m, 1H), 7.62 – 7.54 (m, 2H), 7.42 – 7.31 (m, 3H), 7.26 – 7.15 (m, 3H), 7.11 – 7.03 (m, 1H), 6.98 – 6.90 (m, 2H), 6.42 – 6.34 (m, 2H), 5.02 – 4.92 (m, 1H), 4.91 – 4.80 (m, 1H), 3.78 (s, 0H), 3.11 – 3.03 (m, 1H), 3.01 – 2.93 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.0, 163.3, 139.7, 136.2, 134.0, 133.0, 129.9, 129.4, 128.5, 128.5, 128.2, 128.0, 127.7, 127.4, 125.3, 124.7, 75.7, 53.7, 44.0; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H20NO3 358.1443, found 358.1441. 2-benzyl-4-(4-fluorobenzyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6r): Colorless paste, 70 mg, 93% yield; 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 0.7 Hz, 1H), 7.62 – 7.50 (m, 2H), 7.43 – 7.32 (m, 3H), 7.27 – 7.18 (m, 3H), 6.57 (t, J = 8.7 Hz, 2H), 6.34 – 6.23 (m, 2H), 5.00 (d, J = 13.7 Hz, 1H), 4.85 (d, J = 13.7 Hz, 1H), 3.00 (d, J = 13.1 Hz, 1H), 2.91 (d, J = 13.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.8, 163.3, 162.0 (d, J = 246.4 Hz), 139.6, 136.2, 134.0, 131.4 (d, J = 8.1 Hz), 129.5, 128.7 (d, J = 3.3 Hz), 128.6, 128.5, 128.3, 127.8, 125.3, 124.5, 114.8 (d, J = 21.4 Hz), 75.4, 52.6, 44.0; HRMS (ESI-TOF) m/z [M+ Na]+ calculated for C23H18FNO3Na 398.1168, found 398.1172. 2-benzyl-4-(4-chlorobenzyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6s): Colorless paste, 71 mg, 90% yield; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.8 Hz, 1H), 7.63 – 7.47 (m, 3H), 7.37 (m, 5H), 7.27 – 7.10 (m, 5H), 6.86 (d, J = 8.1 Hz, 2H), 6.27 (d, J = 8.2 Hz, 2H), 5.02 (d, J = 13.8 Hz, 1H), 4.87 (d, J = 13.7 Hz, 1H), 3.75 (s, 1H), 2.99 (d, J = 13.0 Hz, 1H), 2.90 (d, J = 13.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.7, 163.4, 139.6, 136.2, 134.1, 133.4, 131.4, 131.2, 129.5, 128.7, 128.5, 128.4, 128.1, 127.9, 125.3, 124.4, 75.3, 52.7, 44.0; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H19ClNO3 392.1053, found 392.1048. 2-benzyl-4-(4-bromobenzyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6t): Colorless paste, 83 mg, 95% yield; 1H NMR (400 MHz, CDCl3) δ 8.07 – 7.98 (m, 1H),


Page 12 of 17

Page 13 of 17 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


7.62 – 7.49 (m, 2H), 7.44 – 7.32 (m, 3H), 7.28 – 7.20 (m, 3H), 7.03 – 6.97 (m, 2H), 6.24 – 6.15 (m, 2H), 5.02 (d, J = 13.7 Hz, 1H), 4.86 (d, J = 13.7 Hz, 1H), 2.96 (d, J = 13.1 Hz, 1H), 2.88 (d, J = 13.1 Hz, 1H);13C{1H} NMR (101 MHz, CDCl3) δ 175.7, 163.5, 139.6, 136.2, 134.1, 131.8, 131.6, 131.0, 129.5, 128.7, 128.5, 128.4, 127.9, 125.3, 124.4, 121.5, 75.2, 52.7, 44.0; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H19BrNO3 436.0548, found 436.0553. 2-benzyl-4-hydroxy-4-(4-methylbenzyl)isoquinoline-1,3(2H,4H)-dione(6u): Colorless paste, 65 mg, 88% yield; 1H NMR (400 MHz, CDCl3) δ 7.97 (dt, J = 7.8, 1.0 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.40 (ddd, J = 7.9, 5.4, 3.2 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.26 – 7.18 (m, 3H), 6.74 (d, J = 7.7 Hz, 2H), 6.32 – 6.22 (m, 2H), 4.97 (d, J = 13.8 Hz, 1H), 4.85 (d, J = 13.8 Hz, 1H), 3.03 (d, J = 13.0 Hz, 1H), 2.93 (d, J = 13.0 Hz, 1H), 2.17 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.9, 163.4, 139.9, 137.0, 136.3, 134.0, 129.8, 129.3, 128.7, 128.5, 128.4, 128.4, 128.2, 127.7, 125.2, 124.6, 75.7, 53.3, 44.0, 21.1; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H22NO3 372.1600, found 372.1598. 2-benzyl-4-hydroxy-4-(4-methoxybenzyl)isoquinoline-1,3(2H,4H)-dione(6v): Colorless paste, 73 mg, 94% yield; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 7.0, 1.5 Hz, 2H), 7.43 – 7.31 (m, 3H), 7.28 – 7.16 (m, 4H), 6.44 (d, J = 8.6 Hz, 2H), 6.27 (d, J = 8.6 Hz, 2H), 4.98 (d, J = 13.8 Hz, 1H), 4.86 (d, J = 13.8 Hz, 1H), 3.63 (s, 3H), 3.00 (d, J = 13.1 Hz, 1H), 2.90 (d, J = 13.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.0, 163.4, 158.8, 139.9, 136.3, 133.9, 130.9, 129.4, 128.8, 128.4, 128.2, 127.7, 125.3, 124.9, 124.6, 113.3, 75.7, 55.1, 52.8, 44.0; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H22NO4 388.1549, found 388.1545. 2-benzyl-4-(2-chlorobenzyl)-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6w): Colorless paste, 68 mg, 87% yield; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.47 – 7.30 (m, 4H), 7.24 – 7.13 (m, 5H), 7.08 (td, J = 7.7, 1.5 Hz, 1H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.67 (dd, J = 7.6, 1.2 Hz, 1H), 5.06 – 4.94 (m, 2H), 3.91 (s, 1H), 3.26 (d, J = 13.4 Hz, 1H), 3.16 (d, J = 13.4 Hz, 1H);13C{1H} NMR (101 MHz, CDCl3) δ 175. 9, 163.3, 139.4, 136.3, 135.3, 133.9, 132.6, 131.2, 129.28, 128.99, 128.96, 128.6, 128.43, 128.39, 127.6, 126.3, 125.4, 124.5, 75.2, 49.1, 44.7; HRMS (ESI-TOF) m/z [M+H]+ calculated for C23H19ClNO3 392.1053, found 392.1034. 2-benzyl-4-hydroxy-4-(2-methoxybenzyl)isoquinoline-1,3(2H,4H)-dione(6x): Colorless paste, 71 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.39 – 7.29 (m, 4H), 7.23 – 7.10 (m, 5H), 6.65 (t, J = 7.7 Hz, 2H), 6.54 (dd, J = 7.3, 1.4 Hz, 1H), 5.01 – 4.87 (m, 2H), 3.98 (s, 1H), 3.47 (s, 3H), 3.11 (q, J = 13.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.2, 163.4, 157.48, 140.1, 136.4, 133.4, 132.2, 129.1, 129.0, 128.4, 128.1, 128.0, 127.5, 125.3, 124.5, 121.6, 120.1, 109.8, 75.7, 55.0, 47.0, 44.3; HRMS (ESI-TOF) m/z [M+H]+ calculated for C24H22NO4 388.1549, found 388.1548. 2-benzyl-4-butyl-4-hydroxyisoquinoline-1,3(2H,4H)-dione(6y): Colorless paste, 56 mg, 86% yield; 1H NMR (400 MHz, CDCl3) δ 8.10 – 8.06 (m, 1H), 7.64 – 7.56 (m, 2H), 7.44 – 7.35 (m, 3H), 7.26 – 7.17 (m, 3H), 5.13 (d, J = 13.9 Hz, 1H), 5.04 (d, J = 13.9 Hz, 1H), 1.82 – 1.59 (m, 2H), 1.00 – 0.92 (m, 2H), 0.84 – 0.65



(m, 2H), 0.60 (dd, J = 8.8, 5.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.1, 164.1, 141.1, 136.6, 134.2, 129.1, 128.7, 128.6, 128.4, 127.9, 125.0, 124.2, 75.2, 47.3, 44.1, 25.4, 22.4, 13.8; HRMS (ESI-TOF) m/z [M+H]+ calculated for C20H22NO3 324.1600, found 324.1604. 2-benzyl-4-hydroxy-4-isobutylisoquinoline-1,3(2H,4H)-dione (6z): Colorless oil, 56 mg, 87% yield; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.4 Hz, 2H), 7.22 (s, 2H), 7.20 – 7.14 (m, 1H), 5.07 (d, J = 3.1 Hz, 2H), 3.63 (s, 1H), 1.69 (s, 1H), 1.59 (s, 1H), 1.34 (s, 1H), 0.61 (d, J = 6.6 Hz, 3H), 0.53 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 177.2, 164.0, 141.3, 136.4, 134.0, 129.0, 128.7, 128.5, 128.3, 127.7, 125.2, 124.0, 75.4, 55.5, 44.2, 24.0, 23.9, 23.7; HRMS (ESI-TOF) m/z [M+Na]+ calculated for C20H21NO3Na 346.1419, found 346.1404. 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol(8c): White solid, 113 mg, 82% yield, mp: 125.8-126.7 ℃ ; 1H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.36 (s, 2H), 7.34 (s, 1H), 7.33 – 7.26 (m, 3H), 7.24 (s, 1H), 7.19 (d, J = 7.3 Hz, 1H), 4.52 (s, 1H), 4.52 (s, 1H), 4.50 (s, 1H), 3.79 (d, J = 12.7 Hz, 1H), 3.57 (d, J = 12.8 Hz, 1H), 2.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 144.0, 138.4, 129.4, 128.6, 128.5, 128.0, 126.8, 126.4, 72.7, 63.1, 54.8, 43.3; HRMS (ESI-TOF) m/z [M+H]+ calculated for C16H18NO [M+H]+ 240.1388, found 240.1388. ASSOCIATED CONTENT Supporting Information 1H and 13C NMR spectra of compounds. ACKNOWLEDGMENT Financial support from the National Natural Science Foundation of China (81660348, 81703356, 21502030, 21562010), Office of Science & Technology of Guiyang ([20151001]06, JZ[2015]2001), Guizhou Provincial Engineering Laboratory for Chemical Drug R&D, Guizhou High-School Engineering Research Center for Medicinal Chemistry (KY2014-219) were greatly appreciated. REFERENCES 1. (a) Kankanala, J.; Marchand, C.; Abdelmalak, M.; Aihara, H.; Pommier, Y.; Wang, Z. Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2). J. Med. Chem. 2016, 59, 2734−2746. (b) Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. T.; Parniak, M. A.; Wang, Z. Design, Synthesis, Biochemical, and Antiviral Evaluations of C6 Benzyl and C6 Biarylmethyl Substituted 2-Hydroxylisoquinoline-1,3-diones: Dual Inhibition against HIV Reverse Transcriptase-Associated RNase H and Polymerase with Antiviral Activities. J. Med. Chem. 2015, 58, 651−664. (c) Chen, Y.-L.; Tang, J.; Kesler, M. J.; Sham, Y. Y.; Vince, R.; Geraghty, R. J.; Wang, Z. The Design, Synthesis and Biological Evaluations of C-6 or C-7 Substituted 2-Hydroxyisoquinoline-1,3-diones as Inhibitors of Hepatitis C Virus. Bioorg. Med. Chem. 2012, 20, 467−479. (d) Billamboz, M.; Bailly, F.; Lion, C.; Touati, N.; Vezin, H.; Calmels, C.; Andréola,


Page 14 of 17

Page 15 of 17 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


M.; Christ, F.; Debyser, Z.; Cotelle, P. Magnesium Chelating 2-Hydroxyisoquinoline-1,3(2H,4H)-diones, as Inhibitors of HIV-1 Integrase and/or the HIV-1 Reverse Transcriptase Ribonuclease H Domain: Discovery of a Novel Selective Inhibitor of the Ribonuclease H Function. J. Med. Chem. 2011, 54, 1812−1824. (e) Tsou, H.; Otteng, M.; Tran, T.; Floyd, M. B.; Reich, M. J.; Birnberg, G.; Kutterer, K.; Kaloustian, S. A.; Ravi, M.; Nilakantan, R.; Grillo, M.; McGinnis, J. P.; Rabindran, S. K. 4-(Phenylaminomethylene)isoquinoline1,3(2H,4H)-diones as Potent and Selective Inhibitors of the Cyclin-Dependent Kinase 4 (CDK4). J. Med. Chem. 2008, 51, 3507−3525. (f) Lu, X. -Y.; Chen, Y. -D.; Sun, N. -Y.; Jiang, Y. -J.; You, Q. -D. Molecular-Docking-Guided 3D-QSAR Studies of Substituted Isoquinoline-1,3-(2H,4H)-diones as Cyclin-Dependent Kinase 4 (CDK4) Inhibitors. J. Mol. Model. 2010, 16, 163−173. (g) Ontoria, J. M.; Rydberg, E. H.; Marco, S. D.; Tomei, L.; Attenni, B.; Malancona, S.; Hernando, J. I. M.; Gennari, N.; Koch, U.; Narjes, F.; Rowley, M.; Summa, V.; Carroll, S. S.; Olsen, D. B.; Francesco, R. D.; Altamura, S.; Migliaccio, G.; Carfì, A. Identification and Biological Evaluation of a Series of 1H-Benzo[de]isoquinoline1,3(2H)-diones as Hepatitis C Virus NS5B Polymerase Inhibitors. J. Med. Chem. 2009, 52, 5217−5227. (h) Chen, Yi.-H.; Zhang, Y.-H.; Zhang, H.-J.; Liu, D.-Z.; Gu, M.; Li, J.-Y.; Wu, F.; Zhu, X.-Z.; Li, J.; Nan, F.-J. Design, Synthesis, and Biological Evaluation of Isoquinoline-1,3,4-trione Derivatives as Potent Caspase-3 Inhibitors. J. Med. Chem. 2006, 49, 1613−1623. (i) Singh, S. B.; Malamas, M. S.; Hohman, T. C.; Nilakantan, R.; Carper, D. A.; Kitchen, D. Molecular Modeling of the Aldose Reductase-Inhibitor Complex Based on the X-ray Crystal Structure and Studies with Single-Site-Directed Mutants. J. Med. Chem. 2000, 43, 1062−1070. 2. (a) Pan, C.; Chen, C.; Yu, J.-T. Oxidative Decarbonylative Coupling of Aliphatic Aldehydes with Methacryloyl Benzamides to Generate Isoquinoline-1,3(2H,4H)-diones. Org. Biomol. Chem. 2017, 15, 1096−1099. (b) Li, Z.-Z.; Yu, J.; Wang, L.-N.; Chen, S.-L.; Sheng, R.-L.; Tang, S. Cascade Radical Cyclization/Cross-Coupling of Halobenzamides by Synergistic Cu/Fe Catalysis: An Access to 7-tert-alkylated Isoquinolinediones. Tetrahedron, 2018, 74, 6558−6568. 3. (a) Liu, X.; Cong, T.; Liu, P.; Su, P. Visible Light-promoted Synthesis of 4-(sulfonylmethyl)isoquinoline-1,3(2H,4H)-diones via a Tandem Radical Cyclization and Sulfonylation Reaction. Org. Biomol. Chem. 2016, 14, 9416−9422. (b) Xia, X.-F.; Zhu, S.-L.; Wang, D.; Liang, Y.-M. Sulfide and Sulfonyl Chloride as Sulfonylating Precursors for the Synthesis of Sulfone-Containing Isoquinolinonediones. Adv. Synth. Catal. 2017, 359, 859−865. 4. (a) Lu, M.; Liu, Z.; Zhang, J.; Tian, Y.; Qin, H.; Huang, M.; Hua, S.; Cai, S. Synthesis of Oxindoles Through Trifluoromethylation of N-Aryl Acrylamides by Photoredox Catalysis. Org. Biomol. Chem. 2018, 16, 6564−6568. (b) Kong, W.; Casimiro, M.; Fuentes, N.; Merino, E.; Nevado, C. Metal-Free Aryltrifluoromethylation of Activated Alkenes. Angew. Chem., Int. Ed. 2013, 52, 13086−13090. (c) Zhang, T.; Guo, X.; Shi, Y.; He, C.; Duan, C. Dye-incorporated



Coordination Polymers for Direct Photocatalytic Trifluoromethylation of Aromatics at Metabolically Susceptible Positions. Nat. Commun. 2018, 9, 4024. 5. Li, X.; Zhuang, S.; Fang, X.; Liu, P.; Sun, P. Addition of Nitrogen Dioxide to Carbon–Carbon Double Bond Followed by a Cyclization to Construct Nitromethylated Isoquinolinediones. Org. Biomol. Chem. 2017, 15, 1821−1827. 6. Huang, S.; Niu, P.; Su, Y.; Hua, D.; Huo, C. Tandem Radical Cyclization of N-Methacryloyl Benzamides with CBr4 to Construct Brominated Isoquinolinediones. Org. Biomol. Chem. 2018, 16, 7748−7752. 7. Yuan, Y.-O.; Kumar, P. S.; Zhang, C.-N.; Yang, M.-H.; Guo, S.-R. Aerobic Thiyl Radical Addition/Cyclization of N-Methacryloyl Benzamides for the Synthesis of Isoquinoline-1,3(2H,4H)-dione Derivatives. Org. Biomol. Chem. 2017, 15, 7330−7338. 8. (a) Kobayashi, K.; Honda, Y. An Efficient One-Pot Synthesis of 4-Hydroxyisoquinoline-1,3(2H,4H)-diones from N-Alkylbenzamides and α-Keto Esters. Heterocycles, 2017, 94, 1099−1106. (b) Srivastava, A.; Yadav, A.; Samanta, S. Biopolymeric Alginic Acid: an Efficient Recyclable Green Catalyst for the Friedel–Crafts Reaction of Indoles with Isoquinoline-1,3,4-triones in Water. Tetrahedron Lett. 2015, 56, 6003−6007. (c) Blanco, M. M.; Shmidt, M. S.; Perillo, I. A. Autooxidation and Rearrangement Reactions of Isoquinolinone Derivatives. Arkivoc 2009, xii, 106−118. (d) Jegham, N.; Bahi, A.; Guesmi, N. E.; Kacem, Y.; Hassine, B. B. Regio- and Stereoselective Synthesis of New Spiro-Isoxazolidines via 1,3-Dipolar Cycloaddition. Arab. J. Chem. 2017, 10, s3889−s3894. (e) Semple, J. E.; Rydzewski, R. M.; Gardner, G. An Efficient Synthetic Route to Ethyl 2-Aryl-4-hydroxy-1,3(2H,4H)-dioxoisoquinoline-4carboxylates. J. Org. Chem. 1996, 61, 7967−7972. 9. (a) Chaudhari, M. B.; Sutar, Y.; Malpathak, S.; Hazra, A.; Gnanaprakasam, B. Transition-Metal-Free C–H Hydroxylation of Carbonyl Compounds. Org. Lett., 2017, 19, 3628−3631. (b) Sim, S-B. D.; Wang, M.; Zhao, Y. Phase-Transfer-Catalyzed Enantioselective α-Hydroxylation of Acyclic and Cyclic Ketones with Oxygen. ACS Catal. 2015, 5, 3609−3612. (c) Liang, Y.-F.; Jiao, N. Highly Efficient C–H Hydroxylation of Carbonyl Compounds with Oxygen under Mild Conditions. Angew. Chem., Int. Ed. 2014, 53, 548−552. (d) Chuang, G. J.; Wang, W.; Lee, E.; Ritter, T. A Dinuclear Palladium Catalyst for α-Hydroxylation of Carbonyls with O2. J. Am. Chem. Soc. 2011, 133, 1760−1762. 10. (a) Heaney, H.; Taha, M. O.; Slawin, A. M. Z. The Oxidation of Homophthalimide Derivatives by Dioxygen in Alkaline Media and Cleavage-Cyclisation Reactions. Tetrahedron Lett. 1997, 38, 3051−3054. (b) Heaney, H.; Taha, M. O. The Oxidation of 3-Alkylhomophthalimide Derivatives by Dioxygen in Alkaline Media and Bischler-Napieralski Reactions of Cleavage-Cyclisation Products. Arkivoc 2000, iii, 343−359. 11. (a) Yang, Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C.-H. Pentanidium–Catalyzed Enantioselective α-Hydroxylation of Oxindoles Using Molecular Oxygen. Org. Lett. 2012, 14, 4762−4765. (b) Zhou, S.; Zhang, L.; Li, C.; Mao, Y.; Wang, J.; Zhao, P.; Tang, L.; Yang, Y. Pentanidium Catalyzed


Page 16 of 17

Page 17 of 17 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


Enantioselective Hydroperoxidation of 2-Oxindole using Molecular Oxygen. Catal. Commun. 2016, 82, 29−31. 12. Kihara, M.; Kashimoto, M.; Kobayashi, S.; Ishida, Y.; Moritoki, H.; Taira, Z. Resolution, Absolute Stereochemistry, and Enantioselectivity of 2-Methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol. J. Med. Chem. 1990, 33, 2283−2286. 13. (a) Yang, Y.; Li, Y.; Cheng, C.; Yang, G.; Zhang, J.; Zhang, Y.; Zhao, Y.; Zhang, L.; Li, C.; Tang, L. Synthesis of 4-Aryl Isoquinolinedione Derivatives by a Palladium-Catalyzed Coupling Reaction of Aryl Halides with Isoquinoline-1,3(2H,4H)-diones. J. Org. Chem. 2018, 83, 3348−3353. (b) Jangir, R.; Argade, N. P. Total Synthesis of Tetrahydroisoquinoline-Based Bioactive Natural Products Laudanosine, Romneine, Glaucine, Dicentrine, and Their Unnatural Analogues Isolaudanosine and Isoromneine. Synthesis 2017, 49, 1655−1663. (c) Jangir, R.; Argade, N. P. A Facile Synthesis of Oxyavicine. RSC Advances, 2012, 2, 7087−7090.


dione Derivatives - ACS Publications - American Chemical Society

Recommend Documents