Asymmetric Palladium-Catalyzed CâH Functionalization Cascade for

Subscriber access provided by Nottingham Trent University

Article

Asymmetric Palladium-Catalyzed C#H Functionalization Cascade for Synthesis of Chiral 3,4-Dihydroisoquinolones Manman Sun, Haijian Wu, Xiangyu Xia, Weida Chen, Zhiming Wang, and Jianguo Yang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01372 • Publication Date (Web): 02 Sep 2019 Downloaded from pubs.acs.org on September 2, 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 46 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

Asymmetric Palladium-Catalyzed C‒H Functionalization Cascade for Synthesis of Chiral 3,4-Dihydroisoquinolones Manman Sun, Haijian Wu, Xiangyu Xia, Weida Chen, Zhiming Wang, and Jianguo Yang* Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. China. E-mail: [email protected]

Graphical Abstract O

O R1

N H

SO2R

Z

+

Pd(II)/PyrOx oxidant air

R1

N

SO2R

F3C

Z

N

N

PyrOx

36 examples up to 83% yield up to 96% ee

Z = Aryl, Alkyl, EWG

O

ABSTRACT A palladium-catalyzed C‒H functionalization/intramolecular asymmetric allylation cascade of N-sulfonyl benzamides with 1,3-dienes has been developed. In the presence of a chiral pyridine-oxazoline ligand, this protocol enables the synthesis of chiral 3,4-dihydroisoquinolones in yields of up to 83% with enantioselectivities of up to 96%, using environmentally friendly air as the terminal oxidant.

INTRODUCTION Chiral isoquinolines and their derivatives constitute an important class of heterocycles and play a significant role in pharmaceuticals and materials.1 Among them, chiral 3,4-dihydroisoquinolone frameworks are ubiquitous in various bioactive natural products and medicinal compounds.2 For example, isoquinolone alkaloids such as (+)-narciclasine (I), (‒)-gusanlung D (II), and (+)-pancratistatin (III) have shown potent antitumor and antiviral activities (Figure 1),3 and molecule

IV

is

an

effective

5-HT2C

agonists

(Figure

1).4

Moreover,

chiral

3,4-dihydroisoquinolones are also widely employed as valuable precursors in the asymmetric total

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

synthesis

of

natural

3,4-dihydroisoquinolones

alkaloids.2

tetrahydroisoquinoline are

constructed

Page 2 of 46

through

Traditionally,

intramolecular

chiral

Bischler‒Napieralski,

Pomeranz‒Fritsch‒Bobbitt, Friedel‒Crafts, or Heck reactions from their corresponding chiral amine substrates.5 The major drawbacks of these classic approaches, however, are multistep procedures and relatively high costs of starting materials or reagents. In this context, the development of asymmetric methods to achieve chiral 3,4-dihydroisoquinolones turns out to be a challenging and meaningful task. Surprisingly, in sharp contrast to their well-developed racemic versions,6 asymmetric synthetic strategies for chiral 3,4-dihydroisoquinolone construction are relatively rare.7,8 Very recently, rhodium-catalyzed C‒H functionalization with chiral cyclopentadienyl ligands has developed to be a robust process for enantioselective synthesis of 3,4-dihydroisoquinolones (Scheme 1 A).7c,d Despite this impressive progress, methods for preparation of functionalized chiral 3,4-dihydroisoquinolones from more readily available starting materials and reagents using cascade strategy remain in urgent demand. OH

OH OH O

OH

O O

HO N H

NH

O OH

OH

O

OH (-)-gusanlung D (II)

R

OH NH

O

O

(+)-narciclasine (I)

O

N NH

O

(+)-pancratistatin (III)

H O

5-HT2C receptor agonists (IV)

Figure 1. Examples of bioactive molecules with a chiral 3,4-dihydroisoquinolone core. In the past decade, palladium-catalyzed C‒H functionalization of arenes has dramatically improved the efficiency and step-economy of the carbon-carbon bond and carbon-heteroatom bond formations,9 especially the cascade cyclization based on benzamide derivatives.10 Despite these advances, palladium-catalyzed C‒H functionalization cascade cyclization of benzamides with alkenes to prepare 3,4-dihydroisoquinolones is still challenging, mainly due to the


Page 3 of 46 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


competitive β-hydride elimination followed by intramolecular aza-Wacker-type cyclization or Michael addition leading to the formation of undesired products.10a,11 The only successful example is palladium-catalyzed heteroannulation of N-alkoxyl benzamides with 1,3-dienes.12 However, the yields are relatively low and the reaction scope is unexplored (Scheme 1 B). Inspired by aromatic C‒H

functionalizations

assisted

by

an

N-sulfonylcarboxamide

group9b,10,11a

and

palladium-catalyzed asymmetric cyclization reactions for the synthesis of six-membered nitrogen-containing frameworks,13 we envisaged that a carefully chosen catalytic system would promote a palladium-catalyzed C‒H functionalization/intramolecular asymmetric allylation sequence between N-sulfonyl benzamides and 1,3-dienes, leading to functionalized chiral 3,4-dihydroisoquinolones. As part of ongoing study on the development of heterocyclic compound formations based on transition-metal-catalyzed approaches,14 herein we report an asymmetric palladium-catalyzed C‒H functionalization cascade for the regio- and stereoselective synthesis of functionalized chiral 3,4-dihydroisoquinolones (Scheme 1 C). Scheme 1. Transition-metal-catalyzed C‒H functionalizations for synthesis of chiral 3,4-dihydroisoquinolones A) Asymmetric rhodium-catalyzed C-H functionalization cyclization of N-alkoxyl benzamides with alkenes O O OR Rh(III)/Cp* 3 NH N R + R1 R1 H with internal oxidant R2 R3 12-94%ee R2 B) Palladium-catalyzed C-H functionalization cyclization of N-alkoxyl benzamides with 1,3-dienes O R1

O N H

OR +

Z

Pd(II) oxidant

R1

NOR

Z Z = Ph or CO2Et, 9 examples, 3-64% yields C) This work: Asymmetric palladium-catalyzed C-H functionalization cyclization of N-sulfonyl benzamides with 1,3-dienes O O SO2R SO2R Pd(II)/PyrOx N N Z + R1 R1 H oxidant Z Z = Aryl, Alkyl, EWG, 36 examples, up to 83% yield, up to 96% ee



RESULTS AND DISCUSSION To optimize reaction conditions, we selected N-((4-nitrophenyl)sulfonyl)benzamide (1a) and (E)-buta-1,3-dien-1-ylbenzene (2a) as model substrates (Table 1). Inspired by asymmetric C‒H functionalizations in which oxygen or air serves as terminal oxidant,10a,15 we initially performed the reaction in air in the presence of Pd(TFA)2 (10 mol%) and Cu(OAc)2 (30 mol%). Screening of various chiral ligands showed that substituting the pyridine-oxazoline-type ligand with an electron-withdrawing group gave higher yield and enantioselectivity of chiral product 3aa (entries 1‒5). Since yields of 52‒68% exceeded the amount of Cu(OAc)2, we conclude that air was the terminal oxidant. Exclusion copper oxidant resulted in a sharply decreased yield (entry 6), suggesting that a reoxidant was needed in addition to air. Under oxygen atmosphere, the yield did not increase (entry 7). Considering the N‒H bond in sulfonamide requires base-mediated deprotonation to coordinate with Pd-catalyst,16 and a base can activate aromatic C‒H bonds,17,15b we added catalytic amount of base to the reaction. To our delight, adding Et3N to the reaction substantially increased both yield and enantioselectivity (entry 8). Screening of other bases identified bulkier DIPEA as the best (entries 9‒12). Then other oxidants were examined, and 2,6-DMBQ gave the highes enantioselectivity (entries 13‒16). Reducing the temperature to 80 oC slightly decreased yield, but increased enantioselectivity (entry 17). Further reducing the temperature to 70 oC gave even higher enantioselectivity, but sharply reduced yield (entry 18). Subsequently, other chiral pyridine-oxazoline-type ligands substituted with electron-withdrawing groups were screened. Less bulky i-Pr or Ph group in oxazoline sharply diminished enantioselectivity (entries 19 and 20). CN or NO2 group in pyridine gave lower enantioselectivity than CF3 group (entries 21 and 22). Using other Pd-catalysts and solvents did not improve yield or


Page 4 of 46

Page 5 of 46 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


enantioselectivity (see Supporting Information). Eventually, scaling up the reaction to one gram gave 3aa in slightly lower yield with maintained enantioselectivity (entry 23). Hence, the optimal reaction conditions are those shown in entry 17 of Table 1. Table 1. Optimization of reaction conditionsa

O O O S N H

Pd(TFA)2 (10 mol%) ligand (12 mol%) additive (20 mol%)

+

2a, 2.0 eq

Me Me

PPh2 PPh2

COOH

N

oxidant (30 mol%) PhCF3, air temp., 48 h

NO2 1a, 1.0 eq

O

Ph 3aa

O

O P N O

O

L2

L4

L3

1

1

R

O

N N

R2

N

S

NHBoc L1

Ns

2

L5: R = CF3, R = t-Bu L6: R1 = CF3, R2 = i-Pr L7: R1 = CF3, R2 = Ph L8: R1 = CN, R2 = t-Bu L9: R1 = NO2, R2 = t-Bu

entry

ligand

additive

oxidant

temp. (oC)

yield(%)b

ee(%)c

1 2 3 4 5 6 7d 8 9 10 11 12 13 14 15 16 17 18 19 20 21

L1 L2 L3 L4 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L6 L7 L8

Et3N DIPEAe DABCOf DBUg pyridine DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 2,6-DMBQh 2,5-DMBQi BQ Ag2CO3 2,6-DMBQ 2,6-DMBQ 2,6-DMBQ 2,6-DMBQ 2,6-DMBQ

90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 80 70 80 80 80

16 52 55 61 68 18 63 86 87 89 90 90 85 61 79 57 83 41 73 80 65

0 0 0 37 54 52 54 77 80 74 73 55 84 82 80 78 88 90 58 61 86



22 23j

L9 L5

DIPEA DIPEA

2,6-DMBQ 2.6-DMBQ

Page 6 of 46

80 80

73 77

85 88

a

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Pd(TFA)2 (0.01 mmol), ligand (0.012 mmol), additive (0.02 mmol) and oxidant (0.03 mmol) in PhCF3 (0.2 ml) for 48 h under air. b Isolated yield. c Determined by HPLC. d Under oxygen atmosphere. e DIPEA = N-ethyl-N-isopropylpropan-2-amine. f DABCO = g h 1,4-diazabicyclo[2.2.2]octane. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. 2,6-DMBQ = i j 2,6-dimethoxy-1,4-benzoquinone. 2,5-DMBQ = 2,5-dimethyl-1,4-benzoquinone. 3.0 mmol scale.

With the optimized reaction conditions in hand, we firstly investigated the substrate scope of N-((4-nitrophenyl)sulfonyl)

benzamides.

As

shown

in

scheme

2,

benzamides

with

electron-donating groups functioned smoothly in the annulation reactions, affording the desired chiral 3,4-dihydroisoquinolones 3ba‒3ha in good yields with good enantioselectivities. X-ray crystallographic analysis of 3ca allowed the absolute configuration of the stereogenic center to be assigned as S.18 The meta-substituted benzamide containing two possible C‒H functionalization sites gave only one regioisomer 3fa. Benzamides with electron-withdrawing substituents afforded 3ia‒3na in relatively low yields with moderate ee values. This may be due to the poor solubility of these amides. Introducing a methoxy group into fluoro-substituted benzamide increased both yield and ee value of 3oa. Then

we

turned

our

attention

to

variations

of

the

1,3-dienes.

Para-substituted

(E)-buta-1,3-dien-1-ylbenzenes on phenyl ring with electron-donating and -withdrawing groups were well tolerated, giving products 3ab‒3af in moderate to good yields and ee values. Meta-substituted (E)-buta-1,3-dien-1-ylbenzene also reacted well, generating 3ag in 66% yield with 83% ee. Excitingly, ortho-substituted (E)-buta-1,3-dien-1-ylbenzenes gave higher ee values up to 96%. We suspect that steric hindrance at the 2-position were beneficial to the enantioselectivity of 3ah‒3an. In contrast, electron-deficient 1,3-diene only obtained 3ao in moderate yield with moderate enantioselectivity. Gratifyingly, aliphatic diene also afforded 3ap


Page 7 of 46 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


with good enantioselectivity, and only the E-product was obtained even though the penta-2,4-dien-1-ylbenzene substrate was a mixture of Z/E-isomers (Z/E = 51/49). The result suggested that there should be an isomerization of the π-allylpalladium intermediate, and the subsequent reductive elimination gave only the E-product. 1,3-Butadiene could also undergo the asymmetric cascade reaction when equivalent amount of 2,6-DMBQ was used and the reaction was carried out in a sealed tube, although the enantioselectivity of 3aq was low. Eventually, some N-substituted benzamides were also tested, generating 3pa‒3sa with good enantioselectivities, although the yield of 3pa was low. The “CF3SO2 group” resulted in reduced yield and enantioselectivity in the formation of 3ta. Moreover, heterocyclic arylamide was also compatible with the reaction. 3ua were obtained in moderate yield with moderate enantioselectivity.



Page 8 of 46

Scheme 2. Scope of asymmetric palladium-catalyzed C-H functionalization cascadesa Pd(TFA)2 (10 mol%)

O SO2R N + H

R1

Z 2

1 O

O

Ns

SO2R

N

R1

Z 3 O

O N

R1

L5 (12 mol%) DIPEA (20 mol%) 2,6-DMBQ (30 mol%) PhCF3, air 80 oC, 48 h

N

Ns

N

R2

Ns

Ph 3ba (R1 = 4-Me): 80%, 84% ee 3ca (R1 = 4-Et): 76%, 86% ee 3da (R1 = 4-t-Bu): 81%, 87% ee 3ea (R1 = 4-OMe): 62%, 86% ee 3fa (R1 = 3-Me): 80%, 82% ee 3ga (R1 = 2-Me): 72%, 80% ee 3ha (R1 = 2,4-Me): 74%, 82% ee 3ia (R1 = 4-F): 43%, 62% ee 3ja (R1 = 4-Cl): 46%, 73% ee 3ka (R1 = 4-Br): 33%, 78% ee 3la (R1 = 4-NO2): 52%, 67% eeb 3ma (R1 = 4-COOMe): 46%, 76% ee 3na (R1 = 4-CF3): 42%, 85% ee 3oa (R1 = 3-F-4-OMe): 54%, 82% ee

2

3ab (R = 4-Me): 82%, 85% ee 3ac (R2 = 4-OMe): 69%, 84% ee 3ad (R2 = 4-F): 79%, 76% ee 3ae (R2 = 4-Cl): 73%, 85% ee 3af (R2 = 4-Br): 59%, 83% ee 3ag (R2 = 3-Br): 66%, 83% ee

R2 3ah (R = Me): 80%, 92% ee 3ai (R2 = OMe): 64%, 90% ee 3aj (R2 = OCF3): 78%, 90% ee 3ak (R2 = F): 77%, 92% ee 3al (R2 = Cl): 78%, 89% ee 3am (R2 = Br): 68%, 96% ee 3an (R2 = 2-Br-5-OMe): 62%, 96% ee 2

O N

Ns COOEt

3ao: 56%, 75% ee

O

O N

Ns

N

Ns

Ph 3ap: 64%, 90% ee (formed from mixture of Z/E-dienes) O OO S N

crystal structure of 3ca (recrystallization, > 99% ee)

O OO S N

O OO S N Ph

Ph

3pa: 32%, 80% ee

3qa: 55%, 83% ee

O2N O OO S N

O

3ta: 45%, 77% ee

Ns N

Ph

N

Ph

Ph

CF3

Ph 3ra: 77%, 86% ee

O OO S CF3 N

3sa: 70%, 81% ee a Reaction

3aq: 63%, 21% eec

3ua: 78%, 65% ee

conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd(TFA)2 (0.01 mmol), L5 (0.012 mmol), DIPEA (0.02 mmol)

and 2,6-DMBQ (0.03 mmol) in PhCF3 (0.2 ml) at 80 oC for 48 h under air. b The reaction was carried out at 100 oC. c 2,6-DMBQ

(0.1 mmol) was used and the reaction was carried out in a sealed tube.

To demonstrate the synthetic utility of this protocol, we conducted some further transformations using the recrystallized products (Scheme 3). The N-protecting group in 3aa was smoothly


Page 9 of 46 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


removed by p-MePhSH, giving the product 4 with maintained enantioselectivity.19 Taking advantage of the carbon-carbon double bond left over from the 1,3-diene, the compound 4 was further converted to tricyclic chiral heterocycle 5. The carbonyl group and the carbon-carbon double bond were feasibly reduced, giving products 6 and 7 in excellent yields without racemization. Scheme 3. Further synthetic transformations O

O N

(1)

Ns

NH

p-MePhSH Ph

3aa, 97% ee (recrystallization)

K2CO3 DMF, rt

Ph 4, 91%, 97% ee LiAlH4 AlCl3

(2)

O OO S N Ph 3ra, 96% ee (recrystallization)

1) Allyl bromide NaH, DMF

OO S N

THF/Et2O CF3

2) Grubbs II CH2Cl2

O N 5, 73%, 95% ee

CF3 Ph

6, 95%, 97% ee Pd/C H2 THF/EtOH

O OO S N

CF3

Ph 7, 96%, 98% ee

According to all above results and previous studies,20 a plausible mechanism is presented in Scheme 4. First, chiral PyrOx ligand coordinates with Pd(TFA)2 to generate the chiral Pd(II)-catalyst I. Then deprotonation of the N‒H bond and metallation of the sp2 C‒H bond generate a five-membered palladacycle II which subsequently undergoes migratory insertion of the 1,3-diene 2a, leading to the π-allyl palladium complex III. Finally, back attack of the nitrogen nucleophile to the π-allyl palladium moiety affords chiral product 3aa, with regeneration of the palladium(0) species IV which can be oxidized to Pd(II)-catalyst I to participate the next catalytic cycle.



Page 10 of 46

Scheme 4. Plausible mechanism Pd(TFA)2 O N H

2 DIPEA +

2,6-DMBQ + H2O

L5 Ns

1/2 O2

.

2,6-DMBQ 2H + 2 DIPEA

O N

1a

TFA

.

2 HTFA DIPEA

N Pd

CF3

2,6-DMBQ + 2 HTFA DIPEA

.

TFA

I O

O N Ns N O

N

CF3

N Pd

Pd

IV

O II O

Ph

CF3

N

N N Ns Pd N

CF3 Ph

O N

Ns Ph

2a

3aa

III

CONCLUSIONS In summary, we have developed a palladium-catalyzed C‒H functionalization/intramolecular asymmetric allylation cascade of N-sulfonyl benzamides with 1,3-dienes using a chiral PyrOx as the ligand and environmentally friendly air as the terminal oxidant. A series of chiral 3,4-dihydroisoquinolones were obtained in yields of up to 83% with enantioselectivities of up to 96%. The obtained chiral products were readily converted to interesting heterocycles via simple modifications with maintained enantioselectivities. It will be a good development of asymmetric transition-metal-catalyzed C‒H functionalization cascades.

EXPERIMENTAL SECTION General Information. 1H NMR and 13C NMR spectra were recorded on Bruker Avance 400, and tetramethylsilane (TMS) or CDCl3 (7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR) or DMSO-d6 (2.50 ppm for 1H NMR, 39.5 ppm for

13C

NMR) was used as a reference. Data for 1H were

reported as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, br = broad singlet), coupling constants (Hz), and


Page 11 of 46 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


integration. Data for

13C

NMR were reported as ppm. Optical rotations were determined on

SGW-1. High resolution mass spectra analyses were performed on Waters SYNAPT G2-Si mass spectrometer. HPLC analyses were carried out on a Shimadzu LC20AR instrument. Melting points were determined using a X-4 digital micro melting point apparatus. X-ray structural analysis was conducted on the Gemini A Ultra instrument. Thin-layer chromatography (TLC) was performed and visualization of the compounds was accomplished with UV light (254 nm). Flash column chromatography was performed on silica gel (200–300 mesh). Known compounds 1a and 1b,21a 1e‒1g,21a 1i‒1k,21a 1n,21b 1p,21c 1q,21d 1r and 1s,21e 1t,21f 2a‒2e,22a 2f,22b 2g,22c 2h and 2i,22b 2k,22d 2l,22a 2m,22e 2o,22f 2p,22g L4,23a L5,23b L6 and L7,23c,d L8 and L923e were prepared according to the known literatures and their analysis data was identical with the reported data. Tetrahydrofuran (THF), and diethyl ether were distilled from sodium/benzophenone prior to use. Other purchased reagents and solvents were used without further purification. Procedure for Preparation of Substituted N-sulfonyl benzamides 1. To a suspension solution of corresponding acid (6 mmol) in CH2Cl2 (80 ml) was added DMF (11 mg, 0.15 mmol,) at 0 oC. Oxalyl chloride (1.08 ml, 12 mmol) was subsequently added dropwise by syringe. The reaction was allowed to warm to room temperature gradually and stirred for another 3 h. Then, the reaction mixture was evaporated to afford acid chloride which was used without any further purification. To a round-bottom flask under N2 was added 4-nitrobenzenesulfonamide (1.01 g, 5 mmol), DMAP (61 mg, 0.5 mmol), Et3N (1.7 mL, 12.5 mmol), and EtOAc (10 mL). The above-mentioned acid chloride was then added at 0 oC over 15 minutes. The mixture was stirred for 1 hour at 55 °C under N2, cooled to room temperature and quenched with HCl (1N, 20 mL). The resulting mixture was then extracted with EtOAc (20 mL ×3). The combined organic layer was dried over



Page 12 of 46

anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the pure product 1. Componds 1c, 1d, 1l and 1m were synthesized from purchased acid chlorides. Componds 1h, 1o and 1u were synthesized from corresponding acids. 4-Ethyl-N-((4-nitrophenyl)sulfonyl)benzamide (1c): White solid; 1.44 g; 86% yield; mp = 167–168 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br, 1H), 8.53–8.42 (m, 2H), 8.34–8.25 (m, 2H), 7.89– 7.79 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.0, 150.7, 150.6, 145.2, 129.8, 129.2, 129.0, 128.5, 124.9, 28.6, 15.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C15H14N2O5SNa) 357.0521, found 357.0523. 4-(Tert-butyl)-N-((4-nitrophenyl)sulfonyl)benzamide (1d): White solid; 1.48 g; 82% yield; mp = 210–211 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (br, 1H), 8.55–8.43 (m, 2H), 8.35–8.25 (m, 2H), 7.92–7.82 (m, 2H), 7.61–7.49 (m, 2H), 1.28 (s, 9H); 13C{1H} NMR

(100 MHz, DMSO-d6)

δ 165.9, 157.2, 150.7, 145.2, 129.8, 129.0, 128.8, 126.0, 124.9, 35.3, 31.2; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C17H18N2O5SNa) 385.0834, found 385.0834. 2,4-Dimethyl-N-((4-nitrophenyl)sulfonyl)benzamide (1h): White solid; 1.39 g; 83% yield; mp = 157–158 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.78 (br, 1H), 8.55–8.43 (m, 2H), 8.32–8.22 (m, 2H), 7.43 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 2.30 (s, 3H), 2.20 (s, 3H); 13C{1H}

NMR (100 MHz, DMSO-d6) δ 168.0, 150.7, 145.2, 142.1, 137.5, 132.2, 130.0, 129.7,

129.0, 126.7, 125.0, 21.3, 20.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C15H14N2O5SNa) 357.0521, found 357.0523. 4-Nitro-N-((4-nitrophenyl)sulfonyl)benzamide (1l): White solid; 1.26 g; 72% yield; mp = 222–223 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.50–8.42 (m, 2H), 8.34–8.29 (m, 2H), 8.29–8.23 (m, 2H),


Page 13 of 46 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


8.14–8.08 (m, 2H);

13C{1H}

NMR (100 MHz, DMSO-d6) δ 165.3, 150.7, 150.5, 145.5, 137.8,

130.6, 129.9, 124.9, 124.1; HRMS (ESI-TOF) m/z calcd for [M - H]- (C13H8N3O7S) 350.0083, found 350.0086. Methyl 4-(((4-nitrophenyl)sulfonyl)carbamoyl)benzoate (1m): White solid; 1.42 g; 78% yield; mp = 207–208 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.50–8.44 (m, 2H), 8.30–8.24 (m, 2H), 8.08– 8.03 (m, 2H), 8.02–7.97 (m, 2H), 3.88 (s, 3H);

13C{1H}

NMR (100 MHz, DMSO-d6) δ 165.9,

165.8, 150.7, 145.1, 135.8, 133.9, 129.9, 129.7, 129.4, 125.0, 53.0; HRMS (ESI-TOF) m/z calcd for [M - H]- (C15H11N2O7S) 363.0287, found 363.0288. 3-Fluoro-4-methoxy-N-((4-nitrophenyl)sulfonyl)benzamide (1o): White solid; 1.43 g; 81% yield; mp = 173–174 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.48–8.44 (m, 2H), 8.27–8.23 (m, 2H), 7.80– 7.74 (m, 2H), 7.31–7.27 (m, 1H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.6 (d, J = 2.3 Hz), 152.0 (d, J = 10.4 Hz), 151.2 (d, J = 243.8 Hz), 150.7, 145.2, 129.8, 126.9 (d, J = 3.4 Hz), 124.9, 123.8 (d, J = 5.8 Hz), 116.4 (d, J = 19.8 Hz), 113.9 (d, J = 1.0 Hz), 56.9; HRMS (ESI-TOF) m/z calcd for [M - H]- (C14H10N2O6SF) 353.0244, found 353.0235. 1-Methyl-N-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxamide (1u): Yellow solid; 1.40 g; 78% yield; mp = 198–199 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.32 (br, 1H), 8.51–8.44 (m, 2H), 8.41 (s, 1H), 8.32–8.26 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 3.88 (s, 3H);

13C{1H}

NMR (100 MHz, DMSO-d6) δ 162.1,

150.5, 146.0, 137.4, 136.5, 129.6, 126.9, 124.9, 123.4, 122.5, 121.2, 111.3, 106.6, 33.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C16H13N3O5SNa) 382.0474, found 382.0478. Procedure for Preparation of dienes 2. To a solution of sodium hydroxide (1.2 g, 30 mmol) in a mixture of ethanol (16 mL) and water (48 mL) was added aldehyde (30 mmol). The mixture was



Page 14 of 46

stirred at 0 oC for 10 minute. Then 40 percent acetaldehyde (6.6 g, 60 mmol) was added dropwise to the mixture over 3 h at the same temperature. Stirring was continued for 8 h at room temperature. The resulting solution was extracted with DCM, the combined organic layer was washed with water and brine three times, and dried with anhydrous Na2SO4. The solution was concentrated and purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 15:1) to give the pure α,β-unsaturated aldehydes. To a suspension of methyltriphenylphosphonium bromide (4.3 g, 12 mmol) in THF (50 mL) at 0 °C was added dropwise n-butyllithium (4.8mL, 2.5 M in Hexane, 12 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min until all phosphonium bromide dissolved. Then a solution of substituted α,β-unsaturated aldehyde (10 mmol) in THF (5 mL) was added dropwise. After stirring 1 hour, the mixture was warmed to room temperature and stirred for additional 2 hours. Then the mixture was quenched with saturated solution of NH4Cl (50 mL), extracted with Et2O (3 ×50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/ether, 40:1) to give the desired product 2. (E)-1-(Buta-1,3-dien-1-yl)-2-(trifluoromethoxy)benzene (2j): Colorless oil; 1.82 g; 85% yield; 1H NMR (400 MHz, CDCl3) δ 7.64–7.60 (m, 1H), 7.27–7.20 (m, 3H), 6.86–6.77 (m, 2H), 6.60–6.51 (m, 1H), 5.39 (dd, J = 16.9, 1.5 Hz, 1H), 5.25 (dd, J = 10.0, 1.5 Hz, 1H);

13C{1H}

NMR (100

MHz, CDCl3) δ 146.4 (d, J = 1.8 Hz), 137.1, 132.2, 130.5, 128.5, 126.9, 126.5, 125.2, 121.4 (d, J = 1.2 Hz), 120.6 (q, J = 255.9 Hz), 119.0; HRMS (EI) m/z calcd for [M]+ (C11H9OF3) 214.0605, found 214.0609. (E)-1-Bromo-2-(buta-1,3-dien-1-yl)-4-methoxybenzene (2n): Yellow oil; 1.53 g; 64% yield; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 6.89 (d, J = 15.4 Hz,


Page 15 of 46 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


1H), 6.75–6.67 (m, 2H), 6.57 (dt, J = 16.8, 10.1 Hz, 1H), 5.40 (d, J = 16.7 Hz, 1H), 5.26 (d, J = 9.8 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.9, 137.5, 136.9, 133.6, 132.2, 131.4, 119.0, 115.2, 114.8, 111.5, 55.5; HRMS (EI) m/z calcd for [M]+ (C11H11OBr) 237.9993, found 237.9992. General Procedure for Preparation of Chiral 3,4-Dihydroisoquinolones 3. An 10 ml oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, substrate 1 (0.1 mmol), Pd(TFA)2 (3.3 mg, 0.01 mmol, 10 mol%), L5 (3.3 mg, 0.012 mmol, 12 mol%), 2,6-DMBQ (5.0 mg, 0.03 mmol, 30 mol%), DIPEA (2.5 mg, 0.02 mmol, 20 mol%) and PhCF3 (0.2 ml). After stirred at 80 ºC for 10 minutes under air, diene 2 (0.2 mmol, 2.0 eq) was added to the mixture via syringe, and stirred at 80 ºC for 48 h. The residue was cooled to room temperature and purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1 or 3:1) to give the pure product 3. (S,E)-2-((4-Nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3aa): Light yellow solid; 36 mg; 83% yield; 88% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 15.8 min (major) and tR = 40.0 min (minor)]; mp = 198–199 ºC; [α]D20 = +78.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.24 (m, 4H), 7.99 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31–7.20 (m, 6H), 6.71 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.1 Hz, 1H), 5.71–5.66 (m, 1H), 3.73 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 150.5, 144.7, 136.8, 135.2, 134.6, 134.4, 130.8, 129.1, 128.8, 128.7, 128.4, 127.8, 127.2, 126.6, 125.3, 123.7, 58.0, 34.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa) 457.0834, found 457.0836.



(S,E)-6-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one

Page 16 of 46

(3ba):

Light yellow solid; 35.8 mg; 80% yield; 84% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.9 min (major) and tR = 50.7 min (minor)]; mp = 180–181 ºC; [α]D20 = +210.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.23 (m, 4H), 7.86 (d, J = 8.0 Hz, 1H), 7.31–7.27 (m, 3H), 7.22–7.20 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.70 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.1 Hz, 1H), 5.68– 5.64 (m, 1H), 3.68 (dd, J = 16.2, 5.9 Hz, 1H), 3.03 (dd, J = 16.3, 2.0 Hz, 1H), 2.37 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 163.0, 150.4, 145.6, 144.8, 136.8, 135.2, 134.5, 130.8, 129.2,

129.0, 128.8, 128.8, 128.7, 126.6, 125.4, 124.5, 123.7, 58.1, 34.9, 21.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0991. (S,E)-6-Ethyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ca): Light yellow solid; 35.1 mg; 76% yield; 86% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.6 min (major) and tR = 49.5 min (minor)]; mp = 137–139 ºC; [α]D20 = +117.1 (c = 0.9, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28–8.23 (m, 4H), 7.89 (d, J = 8.1 Hz, 1H), 7.33–7.17 (m, 6H), 7.04 (s, 1H), 6.71 (d, J = 15.7 Hz, 1H), 6.02 (dd, J = 15.7, 8.1 Hz, 1H), 5.69–5.65 (m, 1H), 3.70 (dd, J = 16.2, 5.9 Hz, 1H), 3.05 (dd, J = 16.3, 2.0 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 151.7, 150.4, 144.8, 136.9, 135.2, 134.5, 130.8, 129.3, 128.8, 128.7, 127.8, 127.6, 126.6, 125.5, 124.7, 123.7, 58.1, 34.9, 29.0, 14.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C25H22N2O5SNa) 485.1147, found 485.1147. (S,E)-6-(Tert-butyl)-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3da): Light yellow solid; 39.7 mg; 81% yield; 87% ee; [determined by HPLC analysis Daicel Chirapak


Page 17 of 46 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


IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 15.3 min (major) and tR = 47.9 min (minor)]; mp = 110–112 ºC; [α]D20 = +147.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.23 (m, 4H), 7.90 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.32–7.22 (m, 5H), 7.20 (s, 1H), 6.73 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 15.7, 8.2 Hz, 1H), 5.69–5.65 (m, 1H), 3.72 (dd, J = 16.2, 5.9 Hz, 1H), 3.07 (dd, J = 16.4, 2.0 Hz, 1H), 1.31 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 158.6, 150.4, 144.8, 136.6, 135.3, 134.5, 130.8, 129.0, 128.8, 128.7, 126.6, 125.6, 125.2, 125.2, 124.4, 123.6, 58.2, 35.3, 35.1, 31.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C27H26N2O5SNa) 513.1460, found 513.1461. (S,E)-6-Methoxy-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one

(3ea):

Light yellow solid; 28.8 mg; 62% yield; 86% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 22.9 min (major) and tR = 63.4 min (minor)]; mp = 69–70 ºC; [α]D20 = +109.56 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28–8.22 (m, 4H), 7.93 (d, J = 8.7 Hz, 1H), 7.32–7.27 (m, 3H), 7.22–7.20 (m, 2H), 6.85–6.82 (m, 1H), 6.70 (d, J = 19.3 Hz, 1H), 6.68 (s, 1H), 6.02 (dd, J = 15.8, 8.2 Hz, 1H), 5.67– 5.63 (m, 1H), 3.84 (s, 3H), 3.69 (dd, J = 16.3, 5.9 Hz, 1H), 3.03 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 164.4, 162.6, 150.4, 144.9, 139.3, 135.2, 134.5, 131.5, 130.8,

128.8, 128.7, 126.6, 125.4, 123.6, 119.7, 113.6, 113.2, 58.0, 55.6, 35.2; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O6SNa) 487.0940 found 487.0944. (S,E)-7-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3fa): Light yellow solid; 35.8 mg; 80% yield; 82% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.8 min (major) and tR = 55.3 min (minor)]; mp = 180–181 ºC; [α]D20 = +160.75 (c = 0.8, CH2Cl2); 1H NMR (400 MHz, CDCl3)



Page 18 of 46

δ 8.29–8.23(m, 4H), 7.78 (s, 1H), 7.34–7.27 (m, 4H), 7.22–7.20 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.7, 8.1 Hz, 1H), 5.68–5.64 (m, 1H), 3.67 (dd, J = 16.2, 5.9 Hz, 1H), 3.06 (dd, J = 16.3, 1.9 Hz, 1H), 2.33 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ

163.2, 150.4, 144.7, 137.8, 135.3, 135.2, 134.5, 133.8, 130.8, 129.3, 128.8, 128.7, 128.3, 126.9, 126.6, 125.4, 123.7, 58.1, 34.4, 21.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0991. (S,E)-8-Methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one

(3ga):

Light yellow solid; 32.2 mg; 72% yield; 80% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 12.2 min (major) and tR = 31.2 min (minor)]; mp = 147–148 ºC; [α]D20 = +174.03 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30–8.25 (m, 4H), 7.35 (t, J = 7.6 Hz, 1H), 7.31–7.23 (m, 5H), 7.14 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 15.7 Hz, 1H), 6.02 (dd, J = 15.8, 7.8 Hz, 1H), 5.64–5.60 (m, 1H), 3.66 (dd, J = 16.0, 5.8 Hz, 1H), 3.07 (dd, J = 16.0, 2.1 Hz, 1H), 2.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 150.3, 145.2, 142.9, 137.8, 135.4, 134.5, 133.3, 131.7, 130.5, 128.7, 128.6, 126.6, 126.5, 125.4, 125.3, 123.7, 57.4, 35.8, 22.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0994. (S,E)-6,8-Dimethyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ha): Light yellow solid; 34.2 mg; 74% yield; 82% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 13.7 min (major) and tR = 36.1 min (minor)]; mp = 194–195 ºC; [α]D20 = +54.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.24 (m, 4H), 7.35–7.24 (m, 5H), 6.94 (s, 1H), 6.86 (s, 1H), 6.72 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 15.8, 7.8 Hz, 1H), 5.62–5.69 (m, 1H), 3.62 (dd, J = 15.9, 5.8 Hz, 1H), 3.00 (dd,


Page 19 of 46 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


J = 16.0, 2.2 Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 150.3, 145.3, 144.2, 142.9, 137.9, 135.5, 134.4, 132.6, 130.4, 128.7, 128.5, 127.2, 126.6, 125.5, 123.7, 122.7, 57.4, 35.8, 22.6, 21.5; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C25H22N2O5SNa) 485.1147, found 485.1146. (S,E)-6-Fluoro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ia): Light yellow solid; 19.4 mg; 43% yield; 62% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 14.2 min (major) and tR = 36.5 min (minor)]; mp = 174–175 ºC; [α]D20 = +107.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.24 (m, 4H), 8.01 (dd, J = 8.8, 5.6 Hz, 1H), 7.32–7.27 (m, 3H), 7.23–7.20 (m, 2H), 7.04 (td, J = 8.5, 2.5 Hz, 1H), 6.94 (dd, J = 8.5, 2.4 Hz, 1H), 6.70 (d, J = 15.7 Hz, 1H), 5.99 (dd, J = 15.7, 8.0 Hz, 1H), 5.70–5.67 (m, 1H), 3.72 (dd, J = 17.0, 5.3 Hz, 1H), 3.09 (dd, J = 16.5, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 166.22 (d, J = 256.1 Hz), 162.0, 150.5, 144.5, 140.0 (d, J =

9.4 Hz), 135.0, 134.8, 132.2 (d, J = 10.0 Hz), 130.9, 128.8, 128.8, 126.6, 124.9, 123.7, 123.5 (d, J = 2.7 Hz), 115.5 (d, J = 22.1 Hz), 115.4 (d, J = 22.2 Hz), 57.9, 34.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SFNa) 475.0740, found 475.0746. (S,E)-6-Chloro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3ja): Light yellow solid; 21.5 mg; 46% yield; 73% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 14.9 min (major) and tR = 34.8 min (minor)]; mp = 220–222 ºC; [α]D20 = +244.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.24 (m, 4H), 7.92 (d, J = 8.4 Hz, 1H), 7.35–7.20 (m, 7H), 6.69 (d, J = 15.7 Hz, 1H), 5.97 (dd, J = 15.7, 8.0 Hz, 1H), 5.70–5.67 (m, 1H), 3.70 (dd, J = 16.4, 5.9 Hz, 1H), 3.08 (dd, J = 16.8, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 150.5, 144.4, 140.9, 138.5, 134.9, 134.9,



Page 20 of 46

130.9, 130.7, 128.9, 128.4, 128.4, 126.6, 125.6, 124.8, 123.7, 57.9, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SClNa) 491.0444, found 491.0444. (S,E)-6-Bromo-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one

(3ka):

Light yellow solid; 16.9 mg; 33% yield; 78% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 16.0 min (major) and tR = 35.9 min (minor)]; mp = 201–202 ºC; [α]D20 = +208.5 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28–8.24 (m, 4H), 7.84 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4z, 1H), 7.42 (s, 1H), 7.32– 7.26 (m, 3H), 7.23–7.20 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.97 (dd, J = 15.7, 8.0 Hz, 1H), 5.70– 5.66 (m, 1H), 3.71 (dd, J = 16.4, 5.9 Hz, 1H), 3.07 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 150.5, 144.4, 138.6, 134.9, 131.4, 131.4, 130.9, 130.7, 129.6, 128.9, 126.6, 126.1, 124.8, 123.7, 57.9, 34.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9941. (S,E)-6-Nitro-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3la): Light yellow solid; 24.9 mg; 52% yield; 67% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 30.1 min (major) and tR = 49.1 min (minor)]; mp = 204–205 ºC; [α]D20 = +69.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.31–8.26 (m, 4H), 8.22–8.16 (m, 2H), 8.12 (s, 1H), 7.32–7.26 (m, 3H), 7.20–7.17 (m, 2H), 6.67 (d, J = 15.6 Hz, 1H), 5.94 (dd, J = 15.7, 7.6 Hz, 1H), 5.78–5.75 (m, 1H), 3.79 (dd, J = 16.5, 5.9 Hz, 1H), 3.27 (dd, J = 16.5, 2.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 151.0, 150.7, 143.9, 138.5, 135.3, 134.6, 132.2, 131.0, 130.7, 129.0, 128.9, 126.6, 124.2, 123.8, 123.5, 122.7, 57.7, 34.9; HRMS (ESI-TOF) m/z calcd for [M - H]- (C23H16N3O7S) 478.0709, found 478.0705. (S,E)-Methyl


Page 21 of 46 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


2-((4-nitrophenyl)sulfonyl)-1-oxo-3-styryl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

(3ma):

Light yellow solid; 22.6 mg; 46% yield; 76% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 28.2 min (major) and tR = 60.0 min (minor)]; mp = 193–194 ºC; [α]D20 = +172.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.33–8.23 (m, 4H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.30– 7.26 (m, 3H), 7.20–7.18 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.96 (dd, J = 15.7, 7.9 Hz, 1H), 5.75– 5.68 (m, 1H), 3.93 (s, 3H), 3.74 (dd, J = 16.4, 5.8 Hz, 1H), 3.19 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 165.8, 162.2, 150.6, 144.3, 136.9, 135.1, 134.9, 134.8, 130.9,

130.7, 129.6, 129.3, 128.8, 128.7, 126.6, 124.8, 123.7, 57.9, 52.7, 34.8; HRMS (ESI-TOF) m/z calcd for [M - H]- (C25H19N2O7S) 491.0926, found 491.0925. (S,E)-2-((4-Nitrophenyl)sulfonyl)-3-styryl-6-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (3na): Light yellow solid; 21.1 mg; 42% yield; 85% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 9.0 min (major) and tR = 17.4 min (minor)]; mp = 214–215 ºC; [α]D20 = +34.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30–8.25 (m, 4H), 8.12 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 7.32–7.28 (m, 3H), 7.23–7.19 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.96 (dd, J = 15.7, 7.9 Hz, 1H), 5.75–5.72 (m, 1H), 3.76 (dd, J = 16.4, 5.9 Hz, 1H), 3.19 (dd, J = 16.5, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 150.6, 144.2, 137.6, 135.7 (q, J = 32.7 Hz), 135.1, 134.8, 130.9, 130.2, 129.8, 128.9, 128.8, 126.6, 125.4 (q, J = 3.7 Hz), 124.7 (q, J = 3.6 Hz), 124.6, 123.7, 123.2 (q, J = 271.3 Hz), 57.8, 34.8; HRMS (ESI-TOF) m/z calcd for [M - H]- (C24H16N2O5SF3) 501.0732, found 501.0738. (S,E)-7-Fluoro-6-methoxy-2-((4-nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one



Page 22 of 46

(3oa): Light yellow solid; 26.0 mg; 54% yield; 82% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.9 min (major) and tR = 45.4 min (minor)]; mp = 175–176 ºC; [α]D20 = +100.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.28–8.23 (m, 4H), 7.67 (d, J = 11.2 Hz, 1H), 7.32–7.28 (m, 3H), 7.24–7.21 (m, 2H), 6.74–6.69 (m, 2H), 6.01 (dd, J = 15.7, 8.2 Hz, 1H), 5.68–5.64 (m, 1H), 3.93 (s, 3H), 3.69 (dd, J = 16.5, 6.0, 1H), 3.02 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 152.8, 151.6 (d, J = 257.6 Hz), 150.5, 144.6, 135.0, 134.7, 134.5 (d, J = 3.5 Hz), 130.9, 128.9, 128.8 (d, J = 4.0 Hz), 126.6, 125.0, 123.7, 119.7 (d, J = 6.5 Hz), 116.3 (d, J = 40 Hz), 112.0 (d, J = 1.2 Hz), 58.1, 56.4, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H19N2O6FSNa) 505.0846, found 505.0854. (S,E)-3-(4-Methylstyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ab):

Light yellow solid; 36.7 mg; 82% yield; 85% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 16.1 min (major) and tR = 46.1 min (minor)]; mp = 189–190 ºC; [α]D20 = +103.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.23 (m, 4H), 7.98 (d, J = 7.8Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.12–7.07 (m, 4H), 6.68 (d, J = 15.7 Hz, 1H), 5.94 (dd, J = 15.7, 8.2 Hz, 1H), 5.69–5.64 (m, 1H), 3.72 (dd, J = 16.3, 5.9 Hz, 1H), 3.09 (dd, J = 16.3, 2.0 Hz, 1H), 2.32 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 162.9, 150.4, 144.7, 138.8, 136.9, 134.6, 134.4,

132.3, 130.9, 129.5, 129.1, 128.4, 127.8, 127.2, 126.5, 124.1, 123.7, 58.2, 34.9, 21.3; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0993. (S,E)-3-(4-Methoxystyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ac):

Light yellow solid; 32.1 mg; 69% yield; 84% ee; [determined by HPLC analysis Daicel Chirapak


Page 23 of 46 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


IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 25.7 min (major) and tR = 59.1 min (minor)]; mp = 141–142 ºC; [α]D20 = +178.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.22 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.16–7.14 (m, 2H), 6.82–6.80 (m, 2H), 6.67 (d, J = 15.7 Hz, 1H), 5.85 (dd, J = 15.7, 8.3 Hz, 1H), 5.67–5.63 (m, 1H), 3.80 (s, 3H), 3.72 (dd, J = 16.3, 5.8 Hz, 1H), 3.08 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 160.0, 150.4, 144.7, 136.9, 134.3, 134.2, 130.8, 129.1, 128.4, 127.9, 127.8, 127.2, 123.6, 122.8, 114.2, 58.3, 55.3, 35.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O6SNa) 487.0940, found 487.0943. (S,E)-3-(4-Fluorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ad):

Light yellow solid; 35.7 mg; 79% yield; 76% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.9 min (major) and tR = 39.7 min (minor)]; mp = 163–164 ºC; [α]D20 = +76.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.27–8.26 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25–7.18 (m, 3H), 7.00–6.94 (m, 2H), 6.69 (d, J = 15.7 Hz, 1H), 5.94 (dd, J = 15.8, 8.1 Hz, 1H), 5.69–5.65 (m, 1H), 3.72 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 162.8 (d, J = 247.3 Hz), 150.5, 144.7, 136.7, 134.4, 133.4, 131.3 (d, J = 3.4 Hz), 130.8, 129.1, 128.4, 128.3 (d, J = 8.0 Hz), 127.9, 127.1, 125.0 (d, J = 2.3 Hz), 123.7, 115.8 (d, J = 21.6 Hz), 57.9, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SFNa) 475.0740, found 475.0743. (S,E)-3-(4-Chlorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ae):

Light yellow solid; 34.2 mg; 73% yield; 85% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 18.8 min (major) and tR =



Page 24 of 46

37.2 min (minor)]; mp = 170–171 ºC; [α]D20 = +115.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.29–8.25 (m, 4H), 7.98 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.26–7.23 (m, 3H), 7.17–7.13 (m, 2H), 6.68 (d, J = 15.7 Hz, 1H), 6.01 (dd, J = 15.8, 8.0 Hz, 1H), 5.69–5.65 (m, 1H), 3.71 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.5, 134.4, 133.6, 133.3, 130.8, 129.1, 129.0, 128.4, 127.9, 127.8, 127.1, 126.0, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SClNa) 491.0444, found 491.0443. (S,E)-3-(4-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3af):

Light yellow solid; 30.3 mg; 59% yield; 83% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.9 min (major) and tR = 38.9 min (minor)]; mp = 174–175 ºC; [α]D20 = +64.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30–8.25 (m, 4H), 7.98 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.41–7.35 (m, 3H), 7.24 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 15.7 Hz, 1H), 6.02 (dd, J = 15.7, 7.9 Hz, 1H), 5.69–5.65 (m, 1H), 3.71 (dd, J = 16.3, 6.0 Hz, 1H), 3.09 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.5, 134.4, 133.6, 133.3, 130.8,

129.1, 129.0, 128.4, 127.9, 127.8, 127.1, 126.0, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9937. (S,E)-3-(3-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ag):

Light yellow solid; 33.8 mg; 66% yield; 83% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.1 min (major) and tR = 36.4 min (minor)]; mp = 96–97 ºC; [α]D20 = +32.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.30–8.25 (m, 4H), 7.99 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.39–7.35 (m, 3H), 7.24 (d,


Page 25 of 46 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


J = 7.6 Hz, 1H), 7.17–7.11 (m, 2H), 6.63 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 15.8, 7.8 Hz, 1H), 5.69–5.66 (m, 1H), 3.71 (dd, J = 16.3, 6.0 Hz, 1H), 3.10 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 137.3, 136.5, 134.5, 133.0, 131.5, 130.8, 130.3, 129.3, 129.2, 128.4, 128.0, 127.1, 127.0, 125.4, 123.8, 122.9, 57.7, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9945. (S,E)-3-(2-Methylstyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ah):

Light yellow solid; 35.8 mg; 80% yield; 92% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 15.8 min (major) and tR = 33.0 min (minor)]; mp = 134–135 ºC; [α]D20 = +48.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.31–8.27 (m, 4H), 7.98 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 15.1 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.24–7.06 (m, 4H), 6.94 (d, J = 15.6 Hz, 1H), 5.90 (dd, J = 15.6, 7.6 Hz, 1H), 5.72–5.69 (m, 1H), 3.72 (dd, J = 16.3, 5.8 Hz, 1H), 3.12 (dd, J = 16.3, 2.0 Hz, 1H), 2.22 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 163.0,150.5,144.8, 136.8, 135.9, 134.4,

134.4, 132.4, 130.7, 130.5, 129.0, 128.5, 128.4, 127.8, 127.3, 126.7, 126.2, 125.5, 123.7, 58.0, 34.9, 19.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0999. (S,E)-3-(2-Methoxystyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ai):

Light yellow solid; 29.6 mg; 64% yield; 90% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.8 min (major) and tR = 54.8 min (minor)]; mp = 126–127 ºC; [α]D20 = +167.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.33–8.31 (m, 2H), 8.24–8.22 (m, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.26–7.22 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 15.8 Hz, 1H),



Page 26 of 46

6.86 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 5.95 (dd, J = 15.8, 8.5 Hz, 1H), 5.71–5.67 (m, 1H), 3.80 (s, 3H), 3.73 (dd, J = 16.0, 5.6 Hz, 1H), 3.10 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 156.8, 150.4, 144.7, 137.1, 134.3, 131.0, 129.8, 129.1, 128.4, 127.7, 127.2, 126.8, 125.5, 124.2, 123.6, 120.7, 110.9, 58.6, 55.5, 35.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O6SNa) 487.0940, found 487.0944. (S,E)-2-((4-Nitrophenyl)sulfonyl)-3-(2-(trifluoromethoxy)styryl)-3,4-dihydroisoquinolin-1(2H)-on e (3aj): Light yellow solid; 40.4 mg; 78% yield; 90% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 10.3 min (major) and tR = 19.7 min (minor)]; mp = 76–77 ºC; [α]D20 = +55.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.31–8.26 (m, 4H), 7.98 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31–7.16 (m, 5H), 6.89 (d, J = 15.8 Hz, 1H), 6.08 (dd, J = 15.9, 7.6 Hz, 1H), 5.75–5.70 (m, 1H), 3.73 (dd, J = 16.3, 5.8 Hz, 1H), 3.12 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.6, 134.4, 130.8, 129.7, 129.1, 128.7, 128.6, 128.3, 127.9, 127.4, 127.2, 127.1, 127.0, 123.7, 121.5, 120.4 (q, J = 257.0 Hz), 57.7, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H17N2O6F3SNa) 541.0657, found 541.0665. (S,E)-3-(2-Fluorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ak):

Light yellow solid; 34.8 mg; 77% yield; 92% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.4 min (major) and tR = 35.9 min (minor)]; mp = 180–181 ºC; [α]D20 = +86.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.32–8.26 (m, 4H), 7.99 (d, J = 7.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26–7.15 (m, 3H), 7.05–7.00 (m, 2H), 6.81 (d, J = 15.9 Hz, 1H), 6.08 (dd, J = 15.9, 7.9 Hz, 1H), 5.72–5.68 (m, 1H), 3.73 (dd, J = 16.3, 5.9 Hz, 1H), 3.12 (dd, J = 16.4, 1.9 Hz, 1H); 13C{1H}


Page 27 of 46 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


NMR (100 MHz, CDCl3) δ 162.9, 160.3 (d, J = 248.7 Hz), 150.5, 144.6, 136.7, 134.4, 130.8, 130.0 (d, J = 8.4 Hz), 129.1, 128.3, 128.2 (d, J = 5.2 Hz), 127.9, 127.7 (d, J = 3.4 Hz), 127.2 (d, J = 3.2 Hz), 127.2, 124.3 (d, J = 3.5 Hz), 123.7, 123.1 (d, J = 12.0 Hz), 116.0 (d, J = 21,7 Hz), 58.0, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SFNa) 475.0740, found 475.0746. (S,E)-3-(2-Chlorostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3al):

Light yellow solid; 36.5 mg; 78% yield; 89% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.9 min (major) and tR = 35.2 min (minor)]; mp = 153–154 ºC; [α]D20 = +61.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.34–8.25 (m, 4H), 7.99 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.38–7.33 (m, 2H), 7.26–7.07 (m, 5H), 5.97 (dd, J = 15.7, 8.0 Hz, 1H), 5.75–5.72 (m, 1H), 3.74 (dd, J = 16.3, 5.8 Hz, 1H), 3.13 (dd, J = 16.4, 2.1 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 162.9, 150.5, 144.6,

136.8, 134.4, 133.5, 133.3, 130.9, 130.9, 129.9, 129.6, 129.1, 128.4, 128.2, 127.9, 127.2, 127.0, 126.9, 123.7, 57.8, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SClNa) 491.0444, found 491.0453. (S,E)-3-(2-Bromostyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3am):

Light yellow solid; 34.9 mg; 68% yield; 96% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 17.8 min (major) and tR = 35.8 min (minor)]; mp = 240–241 ºC; [α]D20 = +76.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 9.0 Hz, 2H), 8.27 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.56–7.52 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.26–7.09 (m, 4H), 7.05 (d, J = 15.6 Hz, 1H), 5.93 (dd, J = 15.6, 8.0 Hz, 1H), 5.75–5.72 (m, 1H), 3.74 (dd, J = 16.3, 5.8 Hz, 1H), 3.13 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 162.8, 150.5, 144.6, 136.7, 135.3, 134.4, 133.5, 133.1, 130.9,



129.9, 129.2, 128.4, 128.3, 127.9, 127.6, 127.2, 127.1, 123.8, 123.7, 57.7, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H17N2O5SBrNa) 534.9939, found 534.9945. (S,E)-3-(2-Bromo-5-methoxystyryl)-2-((4-nitrophenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one (3an): Light yellow solid; 33.6 mg; 62% yield; 96% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.6 min (major) and tR = 41.5 min (minor)]; mp = 152–153 ºC; [α]D20 = +75.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.35–8.27 (m, 4H), 7.99 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.43–7.41 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 15.6 Hz, 1H), 6.71–6.68 (m, 2H), 5.90 (dd, J = 15.6, 7.9 Hz, 1H), 5.75–5.70 (m, 1H), 3.77–3.72 (m, 4H), 3.12 (dd, J = 16.4, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 158.9, 150.5, 144.5, 136.7, 136.0, 134.4, 133.7, 133.5, 131.0, 129.2, 128.4, 128.4, 127.9, 127.2, 123.7, 115.1, 114.4, 113.1, 57.6, 55.6, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H19N2O6SBrNa) 565.0045, found 565.0051. (S,E)-Ethyl

3-(2-((4-nitrophenyl)sulfonyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)acrylate

(3ao): White solid; 24.1 mg; 56% yield; 75% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 20.5 min (major) and tR = 29.8 min (minor)]; mp = 168–169 ºC; [α]D20 = +80.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.38–8.28 (m, 4H), 7.96 (dd, J = 7.9, 1.3 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 15.6, 6.1 Hz, 1H), 5.93 (dd, J = 15.6, 1.5 Hz, 1H), 5.70–5.66 (m, 1H), 4.19–4.06 (m, 2H), 3.66 (dd, J = 16.4, 6.2 Hz, 1H), 3.10 (dd, J = 16.5, 2.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 165.2, 162.6,

150.7, 144.2, 143.3, 135.9, 134.6, 130.8, 129.2, 128.3, 128.1, 127.0, 124.8, 123.9, 61.0, 56.0, 33.6,


Page 28 of 46

Page 29 of 46 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


14.1; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C20H18N2O7SNa) 453.0732, found 453.0733. (S,E)-2-((4-Nitrophenyl)sulfonyl)-3-(3-phenylprop-1-en-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (3ap): Light yellow solid; 28.7 mg; 64% yield; 90% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 19.2 min (major) and tR = 49.8 min (minor)]; mp = 176–177 ºC; [α]D20 = +246.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.15–8.08 (m, 4H), 7.95 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.29–7.23 (m, 4H), 6.97 (d, J = 6.4 Hz, 2H), 5.88–5.80 (m, 1H), 5.56–5.53 (m, 1H), 5.45 (dd, J = 15.1, 7.2 Hz, 1H), 3.63 (dd, J = 16.2, 5.7 Hz, 1H), 3.29 (dd, J = 15.0, 6.8 Hz, 1H), 3.16 (dd, J = 15.0, 7.6 Hz, 1H), 3.02 (dd, J = 16.0, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.3, 144.5, 139.0, 137.0, 134.3, 134.1, 130.7, 129.0, 128.7, 128.4, 128.3, 127.7, 127.7, 127.3, 126.5, 123.6, 57.2, 38.5, 34.8; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20N2O5SNa) 471.0991, found 471.0996. (S)-2-((4-Nitrophenyl)sulfonyl)-3-vinyl-3,4-dihydroisoquinolin-1(2H)-one (3aq): Light yellow solid; 22.6 mg; 63% yield; 21% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 80/20, 254 nm UV detector, 1.0 mL/min, tR = 36.6 min (major) and tR = 41.5 min (minor)]; mp = 169–170 ºC; [α]D20 = +20.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.41–8.28 (m, 4H), 7.94 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 5.79–5.70 (m, 1H), 5.55–5.51 (m, 1H), 5.28 (d, J = 17.0 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 3.62 (dd, J = 16.2, 5.9 Hz, 1H), 3.04 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 150.5, 144.7, 136.7, 134.8, 134.3, 130.7, 128.9, 128.2, 127.7, 127.3, 123.7, 119.1, 57.8, 34.4; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C17H14N2O5SNa) 381.0521, found 381.0519.



Page 30 of 46

(S,E)-3-Styryl-2-tosyl-3,4-dihydroisoquinolin-1(2H)-one (3pa): White solid; 12.9 mg; 32% yield; 80% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 70/30, 254 nm UV detector, 1.0 mL/min, tR = 20.7 min (major) and tR = 31.0 min (minor)]; mp = 112–113 ºC; [α]D20 = +72.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.01–8.98 (m, 3H), 7.47 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.26–7.17 (m, 8H), 6.63 (d, J = 15.9 Hz, 1H), 6.01 (dd, J = 15.7, 7.4 Hz, 1H), 5.71–5.67 (m, 1H), 3.66 (dd, J = 16.2, 5.9 Hz, 1H), 3.05 (dd, J = 16.3, 1.9 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 144.7, 136.8, 136.2, 135.7, 133.8, 133.8, 129.4, 129.2, 129.0, 128.6, 128.2, 128.2, 127.9, 127.6, 126.6, 126.2, 57.4, 34.9, 21.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H21NO3SNa) 426.1140, found 426.1140. (S,E)-2-(Naphthalen-2-ylsulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3qa): Yellow solid; 28.5 mg; 65% yield; 83% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 70/30, 254 nm UV detector, 1.0 mL/min, tR = 19.3 min (major) and tR = 28.9 min (minor)]; mp = 160–161 ºC; [α]D20 = +33.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 9.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.53–7.47 (m, 2H), 7.32–7.19 (m, 7H), 6.74 (d, J = 15.8 Hz, 1H), 6.04 (dd, J = 15.7, 7.8 Hz, 1H), 5.79–5.75 (m, 1H), 3.73 (dd, J = 16.2, 5.8 Hz, 1H), 3.09 (d, J = 16.2 Hz, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 162.8, 136.8, 136.0, 135.6, 135.3,

134.1, 133.9, 131.8, 131.5, 129.7, 129.2, 129.0, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 127.6, 127.3, 126.7, 126.1, 124.1, 57.7, 34.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C27H21NO3SNa) 462.1140, found 462.1141. (S,E)-3-Styryl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one

(3ra):

White solid; 35.2 mg; 77% yield; 86% ee; [determined by HPLC analysis Daicel Chirapak IC,


Page 31 of 46 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


n-hexane/i-PrOH = 70/30, 254 nm UV detector, 1.0 mL/min, tR = 7.8 min (major) and tR = 12.1 min (minor)]; mp = 237–238 ºC; [α]D20 = +48.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.29–7.16 (m, 6H), 6.64 (d, J = 15.8 Hz, 1H), 6.01 (dd, J = 15.8, 7.8 Hz, 1H), 5.71–5.67 (m, 1H), 3.71 (dd, J = 16.3, 5.9 Hz, 1H), 3.09 (dd, J = 16.3, 2.0 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 162.9, 142.6, 136.8, 135.3, 135.1 (q, J = 32.9 Hz), 134.3,

134.2, 130.1, 129.1, 128.7, 128.5, 128.3, 127.8, 127.4, 126.6, 125.7 (q, J = 3.7 Hz), 125.5, 123.1 (q, J = 268.5 Hz), 57.8, 34.9; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H18NO3SF3Na) 480.0857, found 480.0859. (S,E)-2-((2-Nitrophenyl)sulfonyl)-3-styryl-3,4-dihydroisoquinolin-1(2H)-one (3sa): Light yellow solid; 30.4 mg; 70% yield; 81% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 80/20, 254 nm UV detector, 1.0 mL/min, tR = 14.7 min (minor) and tR = 16.0 min (major), the absolute configuration of the stereogenic center was determined by the product of removing the N-protecting group, which was consistent with 4]; mp = 188–189 ºC; [α]D20 = +5.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.85–7.75 (m, 3H), 7.51 (t, J = 7.5 Hz, 1H), 7.35–7.18 (m, 7H), 6.77 (d, J = 15.8 Hz, 1H), 6.22 (dd, J = 15.8, 6.6 Hz, 1H), 5.53–5.49 (m, 1H), 3.95 (dd, J = 16.3, 6.0 Hz, 1H), 3.10 (d, J = 16.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 148.2, 137.2, 135.8, 135.5, 134.7, 134.2, 133.5, 132.8, 132.1, 128.8, 128.5, 128.3, 128.1, 127.6, 127.5, 126.8, 126.3, 124.5, 57.7, 33.6; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C23H18N2O5SNa) 457.0834, found 457.0836. (S,E)-3-styryl-2-((trifluoromethyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one (3ta): Light yellow solid; 17.1 mg; 45% yield; 77% ee; [determined by HPLC analysis Daicel Chirapak IB,



n-hexane/i-PrOH = 90/10, 254 nm UV detector, 1.0 mL/min, tR = 8.1 min (minor) and tR = 8.5 min (major)]; mp = 155–156 ºC; [α]D20 = +33 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.30–7.21 (m, 6H), 6.67 (d, J = 15.8 Hz, 1H), 6.07 (dd, J = 15.7, 7.9 Hz, 1H), 5.54–5.37 (m, 1H), 3.71 (dd, J = 16.4, 5.7 Hz, 1H), 3.11 (dd, J = 16.5, 2.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 137.0, 135.3, 135.1, 134.9, 129.8, 128.7, 128.6, 128.6, 128.1, 126.8, 126.7, 124.1, 119.4 (q, J = 322.8 Hz), 59.9, 34.7; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C18H14NO3SF3Na) 404.0544, found 404.0546. (S,E)-5-methyl-2-((4-nitrophenyl)sulfonyl)-3-styryl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-o ne (3ua): Yellow solid; 38.0 mg; 78% yield; 65% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 25.2 min (major) and tR = 81.4 min (minor)]; mp = 222–223 ºC; [α]D20 = –14.4 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ 8.38–8.31 (m, 4H), 7.79 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.33– 7.16 (m, 7H), 6.58 (d, J = 15.8 Hz, 1H), 6.39 (dd, J = 15.9, 6.4 Hz, 1H), 5.83–5.80 (m, 1H), 3.82 (dd, J = 17.6, 6.6 Hz, 1H), 3.77 (s, 3H), 3.50 (dd, J = 17.6, 1.5 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO) δ 160.8, 150.5, 147.2, 145.6, 138.3, 135.7, 132.5, 130.5, 129.1, 128.6, 128.0, 127.0, 125.0, 124.5, 123.2, 122.8, 120.0, 111.4, 103.2, 58.2, 30.6, 28.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C26H21N3O5SNa) 510.1100, found 510.1101. Procedure for Scale-up Synthesis of Compound 3aa. An 25 ml oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, substrate 1a (918 mg, 3 mmol), Pd(TFA)2 (99.7 mg, 0.3 mmol, 10 mol%), L5 (97.9 mg, 0.36 mmol, 12 mol%), 2,6-DMBQ (151.2 mg, 0.9 mmol, 30 mol%), DIPEA (77.4 mg, 0.6 mmol, 20 mol%) and PhCF3 (6.0 ml). After stirred at 80 ºC for 10 minutes under air, diene 2a (780 mg, 6 mmol, 2.0 eq) was


Page 32 of 46

Page 33 of 46 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


added to the mixture via syringe over 1 h, and stirred at 80 ºC for 48 h. The residue was cooled to room temperature and purified by column chromatography on silica gel (PE/EA = 5:1) to give the pure product 3aa (1002.5 mg; 77% yield, 84% ee). Procedure for Removal of N-protecting Group of Product 3aa. A round bottom flask was charged with a stir bar, compound 3aa ( 43.4 mg, 0.1 mmol), K2CO3 (27.6 mg, 0.2 mmol) and DMF (2 ml). Then p-MePhSH (18.6 mg, 0.15 mmol) was added to the above solution. After stirred at ambient temperature overnight, the mixture was diluted with water, and the combined aqueous phases were extracted three times with ethyl acetate. The organic layers were combined, dried over Na2SO4, and concentrated to yield the crude product, which was further purified by silica gel chromatography (petroleum ether/ethyl acetate = 2:1) to provide the desired product 4. (S,E)-3-Styryl-3,4-dihydroisoquinolin-1(2H)-one (4): White solid; 22.6 mg; 91% yield; 97% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 12.3 min (minor) and tR = 15.7 min (major)]; mp = 164–165 ºC; [α]D20 = +102.0 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.39–7.25 (m, 6H), 7.22 (d, J = 7.5 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.23 (dd, J = 15.8, 7.4 Hz, 1H), 5.97 (s, 1H), 4.47–4.41 (m, 1H), 3.15 (dd, J = 15.6, 5.0 Hz, 1H), 3.05 (dd, J = 15.7, 9.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 137.4, 135.9, 132.6, 132.5, 128.7, 128.4, 128.3, 128.2, 128.0, 127.5, 127.3, 126.6, 54.0, 35.0; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C17H15NONa) 272.1051, found 272.1053. Procedure for Synthesis of Tricyclic Chiral Heterocycle 5. A suspension of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.24 mmol) in DMF (1 ml) at 0 °C, under nitrogen, was treated dropwise over 15 min with a solution of 4 (24.9 mg, 0.1 mmol) in DMF (1 ml), stirred at



0 °C for an additional 20 min, treated with allyl bromide (18 mg, 0.15 mmol) at 0 °C, allowed to warm to room temperature, and stirred overnight. The reaction mixture was partitioned between water and methylene chloride. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1) to afford the product. An oven-dried Schlenk tube under an N2 atmosphere was charged with above product, Grubbs II catalyst (17 mg, 0.02 mmol). Methylene chloride (2 ml) was added under an N2 atmosphere. Then the mixture was refluxed for 4 h. After removed the solvent, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 2:1) to afford the product 5. (S)-10,10a-Dihydropyrrolo[1,2-b]isoquinolin-5(3H)-one (5): White solid; 13.5 mg; 73% yield; 95% ee; [determined by HPLC analysis Daicel Chirapak IC, n-hexane/i-PrOH = 50/50, 254 nm UV detector, 1.0 mL/min, tR = 14.0 min (minor) and tR = 14.9 min (major)]; mp = 96–97 ºC; [α]D20 = –223.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 6.05–6.02 (m, 1H), 5.91–5.89 (m, 1H), 4.80–4.73 (m, 1H), 4.66–4.59 (m, 1H), 4.33–4.27 (m, 1H), 3.04 (dd, J = 15.0, 3.9 Hz, 1H), 2.94–2.86 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 162.6, 137.1, 131.7, 130.4, 129.1,

127.8, 127.4, 127.3, 127.3, 62.8, 52.2, 34.4; HRMS (ESI-TOF) m/z calcd for [M + H]+ (C12H12NO) 186.0919, found 186.0925. Procedure for Reduction of Carbonyl Group of Product 3ra. An oven-dried Schlenk tube under an N2 atmosphere was charged with LiAlH4 (38 mg, 1 mmol) and AlCl3 (160.2 mg, 1.2 mmol), mixed solvents anhydrous THF (0.2 ml) and anhydrous Et2O (0.6 ml) were added at 0 oC and the mixture was stirred at 0 oC for 30 minutes. Substrate 3ra (45.7 mg, 0.1 mmol) was


Page 34 of 46

Page 35 of 46 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


dissolved in anhydrous THF (0.4 ml), and added to the above mixture by syringe. After the reaction was stirred at 0 oC for 12 h, the sat. aq. NH4Cl was added. The aqueous layer was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1) to afford the desired product 6. (S,E)-3-Styryl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline (6): White solid; 42.1 mg; 95% yield; 97% ee; [determined by HPLC analysis Daicel Chirapak IA, n-hexane/i-PrOH = 90/10, 254 nm UV detector, 1.0 mL/min, tR = 10.2 min (major) and tR = 11.0 min (minor)]; mp = 140–141 ºC; [α]D20 = –9.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.24–7.15 (m, 5H), 7.11–7.04 (m, 4H), 6.44 (d, J = 16.0 Hz, 1H), 5.81 (dd, J = 15.9, 6.9 Hz, 1H), 5.05–5.01 (m, 1H), 4.77 (d, J = 15.8 Hz, 1H), 4.30 (d, J = 15.8 Hz, 1H), 3.21 (dd, J = 16.1, 5.9 Hz, 1H), 2.86 (dd, J = 16.2, 2.4 Hz, 1H); 13C{1H}

NMR (100 MHz, CDCl3) δ 143.0, 135.8, 134.2 (q, J = 32.8 Hz), 133.6, 131.7, 131.0,

129.2, 128.5, 128.1, 128.0, 127.3, 126.6, 126.4, 126.1 (q, J = 3.5 Hz), 126.1, 125.2, 123.2 (q, J = 271.3 Hz), 54.0, 44.0, 34.1; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20NO2SF3Na) 466.1065, found 466.1065. Procedure for Reduction of Carbon-carbon Double Bond of Product 3ra. An oven-dried Schlenk tube was charged with substrate 3ra (45.7 mg, 0.1 mmol), 5% Pd/C (10 mg, 0.005 mmol). Anhydrous THF (1.0 ml) and anhydrous EtOH (1.0 ml) were added under a H2 atmosphere. The mixture was stirred at room temperature for 3 h, then filtrated with silica gel and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1) to afford the desired product 7. (R)-3-Phenethyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroisoquinolin-1(2H)-one


(7):


White solid; 44.1 mg; 96% yield; 98% ee; [determined by HPLC analysis Daicel Chirapak IA, n-hexane/i-PrOH = 90/10, 254 nm UV detector, 1.0 mL/min, tR = 14.4 min (minor) and tR = 25.7 min (major)]; mp = 73–74 ºC; [α]D20 = +19.8 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.29–7.26 (m, 2H), 7.21–.16 (m, 2H), 7.12 (d, J = 7.0 Hz, 2H), 5.04– 4.98 (m, 1H), 3.38 (dd, J = 16.3, 5.5 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.12–2.00 (m, 1H), 1.94–1.84 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 143.0, 140.2, 136.7, 135.1 (q, J = 33.0 Hz), 134.1, 129.5, 129.0, 128.6, 128.3, 128.3, 127.7, 127.7, 126.3, 125.9 (q, J = 3.5 Hz), 123.1 (q, J = 271.5 Hz), 55.9, 35.1, 32.7, 32.5; HRMS (ESI-TOF) m/z calcd for [M + Na]+ (C24H20NO3SF3Na) 482.1014, found 482.1020.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR (1H, 13C) spectra, HPLC analytic results (PDF) X-ray crystallographic data for compound 3ca (CIF)

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. ORCID Zhiming Wang: 0000-0002-6583-3826 Jianguo Yang: 0000-0003-4268-7384 Notes The authors declare no competing financial interest.


Page 36 of 46

Page 37 of 46 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


ACKNOWLEDGEMENTS This work was supported by Natural Science foundation of Zhejiang Province (No. LY18B020002), PhD Start-up Grant, Nurturing Project (2018PY049) from Taizhou University. REFERENCES (1) (a) Zhan, G.; Zhou, J.; Liu, R.; Liu, T.; Guo, G.; Wang, J.; Xiang, M.; Xue, Y.; Luo, Z.; Zhang, Y.; Yao, G. Galanthamine, Plicamine, and Secoplicamine Alkaloids from Zephyranthes candida and Their Anti-acetylcholinesterase and Antiinflammatory Activities. J. Nat. Prod. 2016, 79, 760. (b) Dubost, E.; Dumas, N.; Fossey, C.; Magnelli, R.; Butt-Gueulle, S.; Ballandonne, C.; Caignard, D. H.; Dulin, F.; Santos, J. S. d.-O.; Millet, P.; Charnay, Y.; Rault, S.; Cailly, T.; Fabis, F. Synthesis and Structure-Affinity Relationships of Selective HighAffinity 5-HT4 Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers. J. Med. Chem. 2012, 55, 9693. (c) Chrzanowska, M.; Rozwadowska, M. D. Asymmetric Synthesis of Isoquinoline Alkaloids. Chem. Rev. 2004, 104, 3341. (d) Su, Y.-J.; Huang, H.-L.; Li, C.-L.; Chien, C.-H.; Tao, Y.-T.; Chou, P.-T.; Datta, S.; Liu, R.-S. Highly Efficient Red Electrophosphorescent Devices Based on Iridium Isoquinoline Complexes: Remarkable External Quantum Efficiency Over a Wide Range of Current. Adv. Mater. 2003, 15, 884. (e) Rozwadowska, M. D. Recent Progress in the Enantioselective Synthesis of Isoquinoline Alkaloids. Heterocycles 1994, 39, 903. (2) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004-2015. Chem. Rev. 2016, 116, 12369. (3) (a) Griffin, C.; Karnik, A.; McNulty, J.; Pandey, S. Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts. Mol. Cancer Ther.



Page 38 of 46

2011, 10, 57. (b) Jin, Z. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 2005, 22, 111. (c) Zhang, J.-S.; Men-Olivier, L. L.; Massiot, G. Isoquinoline Alkaloids from Acangelisia Gusanlung. Phytochemistry 1995, 39, 439. (4) Zhao, G.; Kwon, C.; Bisaha, S. N.; Stein, P. D.; Rossi, K. A.; Cao, X.; Ung, T.; Wu, G.; Hung, C.-P.; Malmstrom, S. E.; Zhang, G.; Qu, Q.; Gan, J.; Keim, W. J.; Cullen, M. J.; Rohrbach, K. W.; Devenny, J.; Pelleymounter, M. A.; Miller, K. J.; Robl, J. A. Synthesis and SAR of Potent and Selective Tetrahydropyrazinoisoquinolinone 5-HT2C Receptor Agonists. Bioorg. Med. Chem. Lett. 2013, 23, 3914. (5) (a) Vshyvenko, S.; W’Giorgis, Z.; Weber, A.; Neverova, N.; Hedberg, B.; Hudlicky, T. Synthesis and Biological Activity of 10-Aza-narciclasine. Adv. Synth. Catal. 2015, 357, 83. (b) Mengozzi, L.; Gualandi, A.; Cozzi, P. G. A Highly Enantioselective Acyl-Mannich Reaction of Isoquinolines

with

Aldehydes

promoted

by

Proline

Derivatives:

an

Approach

to

13-AlkylTetrahydroprotoberberine Alkaloids. Chem. Sci. 2014, 5, 3915. (c) Sun, Z.; Zhou, M.; Li, X.; Meng, X.; Peng, F.; Zhang, H.; Shao, Z. Catalytic Asymmetric Assembly of Octahydroindolones:

Divergent

Synthesis

of

Lycorine-type

Amaryllidaceae

Alkaloids

(+)-a-Lycorane and (+)-Lycorine. Chem. Eur. J. 2014, 20, 6112. (d) Cagide-Fagín, F.; Nieto-García, O.; Lago-Santomé, H.; Alonso, R. Enantioselective Synthesis of Protected Nitrocyclohexitols with Five Stereocenters. Total Synthesis of (+)-Pancratistatin. J. Org. Chem. 2012, 77, 11377. (e) Grajewska, A.; Rozwadowska, M. D. Diastereoselective Pomeranz–Fritsch– Bobbitt Synthesis of (S)-(–)-O-Methylbharatamine Using (S)-N-tert-Butanesulfinimine as a Substrate. Tetrahedron: Asymmetry 2007, 18, 2910. (6) For recent selected examples, see: (a) Trifonova, E. A.; Ankudinov, N. M.; Kozlov, M. V.;


Page 39 of 46 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


Sharipov, M. Y.; Nelyubina, Y. V.; Perekalin, D. S. Rhodium(III) Complex with a Bulky Cyclopentadienyl Ligand as a Catalyst for Regioselective Synthesis of Dihydroisoquinolones via C–H Activation of Arylhydroxamic Acids. Chem. Eur. J. 2018, 24, 16570. (b) Yu, X.; Chen, K.; Wang, Q.; Zhang, W.; Zhu, J. Co(III)-Catalyzed N-Chloroamide-Directed C–H Activation for 3,4Dihydroisoquinolone Synthesis. Org. Chem. Front. 2018, 5, 994. (c) Mondal, A.; Kundu, P.; Jash, M.;

Chowdhury,

C.

Palladium-Catalysed

Stereoselective

Synthesis

of

4-(Diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones: Expedient Access to 4-Substituted Isoquinolin-1(2H)-ones and Isoquinolines. Org. Biomol. Chem. 2018, 16, 963. (d) Vijayan, A.; Jumaila, C. U.; Radhakrishnan, K. V. Rhodium(III)-Catalyzed C–H Activation of O-Acetyl Ketoximes/N-Methoxybenzamides toward the Synthesis of Isoquinoline/Isoquinolone-Fused Bicycles. Asian J. Org. Chem. 2017, 6, 1561. (e) Hyster, T. K.; Dalton, D. M.; Rovis, T. Ligand Design for Rh(III)-Catalyzed C–H Activation: an Unsymmetrical Cyclopentadienyl Group Enables a Regioselective Synthesis of Dihydroisoquinolones. Chem. Sci. 2015, 6, 254. (f) Cui, S.; Zhang, Y.; Wu, Q. Rh(III)-Catalyzed C–H Activation/Cycloaddition of Benzamides and Methylenecyclopropanes: Divergence in Ring Formation. Chem. Sci. 2013, 4, 3421. (g) Guimond, N.; Gorelsky, S. I.; Fagnou, K. Rhodium(III)-Catalyzed Heterocycle Synthesis Using an Internal Oxidant: Improved Reactivity and Mechanistic Studies. J. Am. Chem. Soc. 2011, 133, 6449. (h) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. Rh(III)-Catalyzed Directed C–H Olefination Using an Oxidizing Directing Group: Mild, Efficient, and Versatile. J. Am. Chem. Soc. 2011, 133, 2350. (7) (a) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T. Biotinylated Rh(III) Complexes in Engineered Streptavidin for Accelerated Asymmetric C–H Activation. Science, 2012, 338, 500.



Page 40 of 46

(b) Ye, B.; Cramer, N. Chiral Cyclopentadienyl Ligands as Stereocontrolling Element in Asymmetric C–H Functionalization. Science, 2012, 338, 504. (c) Trifonova, E. A.; Ankudinov, N. M.; Mikhaylov, A. A.; Chusov, D. A.; Nelyubina, Y. V.; Perekalin, D. S. A Planar-Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones. Angew. Chem. Int. Ed. 2018, 57, 7714. (d) Jia, Z.-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick, A. P.; Waldmann, H. General Enantioselective C–H Activation with Efficiently Tunable Cyclopentadienyl Ligands. Angew. Chem. Int. Ed. 2017, 56, 2429. (e) Huang, K. -L.; Guo, C.; Cheng, L.-J.; Xie, L.-G.; Zhou, Q.-L.; Xu, X.-H.; Zhu, S.-F. Enantioselective Palladium-Catalyzed Ring-Opening Reaction of Azabenzonorbornadienes

with

Methyl

2-Iodobenzoate:

An

Efficient

Access

to

cis-Dihydrobenzo[c]phenanthridinones. Adv. Synth. Catal. 2013, 355, 2833. (8) During this manuscript was prepared, Han and Gong group reported a “Pd(II)-Catalyzed Asymmetric Oxidative Annulation of N-Alkoxyheteroaryl Amides and 1,3-Dienes”, see: (a) Zhang, T.; Shen, H.-C.; Xu, J.-C.; Fan, T.; Han, Z.-Y.; Gong, L.-Z. Org. Lett. 2019, 21, 2048. Cramer group reported a “Chiral Cyclopentadienyl Cobalt(III) Complexes Enable Highly Enantioselective 3d-Metal-Catalyzed C–H Functionalizations”, see: (b) Ozols, K.; Jang, Y.-S.; Cramer, N. J. Am. Chem. Soc. 2019, 141, 5675. (9) For some reviews, see: (a) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G. Transition-Metal-Catalyzed C–H Alkylation Using Alkenes. Chem. Rev. 2017, 117, 9333. (b) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition Metal-Catalyzed C–H Bond Functionalizations by the Use of Diverse Directing Groups. Org. Chem. Front. 2015, 2, 1107. (c) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Recent Advances in Directed C–H


Page 41 of 46 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


Functionalizations Using Monodentate Nitrogen-Based Directing Groups. Org. Chem. Front. 2014, 1, 843. (10) For recent selected examples, see: (a) Youn, S. W.; Ko, T. Y.; Kim, Y. H.; Kim, Y. A. Pd(II)/Cu(II)-Catalyzed

Regio-

and

Stereoselective

Synthesis

of

(E)-3-

Arylmethyleneisoindolin-1-ones Using Air as the Terminal Oxidant. Org. Lett. 2018, 20, 7869. (b) Zhang, W.; Chen, P.; Liu, G. Enantioselective Palladium(II)-Catalyzed Intramolecular Aminoarylation of Alkenes by Dual N–H and Aryl C–H Bond Cleavage. Angew. Chem. Int. Ed. 2017, 56, 5336. (c) Watt, M. S.; Booker-Milburn, K. I. Palladium(II) Catalyzed C–H Functionalization Cascades for the Diastereoselective Synthesis of Polyheterocycles. Org. Lett. 2016, 18, 5716. (d) Xia, X.-F.; Wang, Y.-Q.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M. Palladium-Catalyzed C–H Activation and Intermolecular Annulation with Allenes. Chem. Eur. J. 2014, 20, 5087. (e) Pimparkar, S.; Jeganmohan, M. Palladium-Catalyzed Cyclization of Benzamides with Arynes: Application to the Synthesis of Phenaglydon and N-Methylcrinasiadine. Chem. Commun. 2014, 50, 12116. (f) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. One-Pot Formation of C–C and C–N Bonds through Palladium-Catalyzed Dual C–H Activation: Synthesis of Phenanthridinones. Angew. Chem., Int. Ed. 2011, 50, 1380. (11) (a) Zhu, C.; Falck, J. R. N-Acylsulfonamide Assisted Tandem C–H Olefination/Annulation: Synthesis of Isoindolinones. Org. Lett. 2011, 13, 1214. (b) Li, D.-D.; Yuan, T.-T.; Wang, G.-W. Synthesis of Isoindolinones via Palladium-Catalyzed C–H activation of N-Methoxybenzamides. Chem. Commun. 2011, 47, 12789. (12) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. New Heteroannulation Reactions of N-Alkoxybenzamides by Pd(II) Catalyzed C–H Activation. Org.



Lett. 2011, 13, 5326. (13) For recent selected examples, see: (a) Wang, P.-S.; Shen, M.-L.; Wang, T.-C.; Lin, H.-C.; Gong, L.-Z. Access to Chiral Hydropyrimidines through Palladium-Catalyzed Asymmetric Allylic C–H Amination. Angew. Chem. Int. Ed. 2017, 56, 16032. (b) Mei, G.-J.; Li, D.; Zhou, G.-X.; Shi, Q.; Cao, Z; Shi, F. a Catalytic Asymmetric Construction of A Tetrahydroquinoline-based Spirooxindole Framework via a Diastereo- and Enantioselective Decarboxylative [4 + 2] Cycloaddition. Chem. Commun. 2017, 53, 10030. (c) Mei, G.-J.; Bian, C.-Y.; Li, G.-H.; Xu, S.-L.; Zheng, W.-Q.; Shi, F. Catalytic Asymmetric Construction of the Tryptanthrin Skeleton via an Enantioselective Decarboxylative [4 + 2] Cyclization. Org. Lett. 2017, 19, 3219. (d) Lu, Y.-N.; Lan, J.-P.; Mao, Y.-J.; Wang, Y.-X.; Mei, G.-J.; Shi, F. Catalytic Asymmetric de Novo Construction of Dihydroquinazolinone Scaffolds via Enantioselective Decarboxylative [4 + 2] Cycloadditions. Chem. Commun. 2018, 54, 13527. (e) Jin, J.-H.; Wang, H.; Yang, Z.-T.; Yang, W.-L.; Tang, W.; Deng, W.-P. Asymmetric Synthesis of 3,4-Dihydroquinolin-2-ones via a Stereoselective Palladium-Catalyzed Decarboxylative [4 + 2] Cycloaddition. Org. Lett. 2018, 20, 104. (14) (a) Yang, J.; Mo, H.; Wu, H.; Cao, D.; Pan, C.; Wang, Z. An Elimination/Heck Coupling/Allylation Cascade Reaction: Synthesis of 2,3-Dihydrobenzofurans from Allenoate Adducts. Chem. Commun. 2018, 54, 1213. (b) Yang, J.; Mo, H.; Jin, X.; Cao, D.; Wu, H.; Chen, D.; Wang, Z. Vinylogous Elimination/Heck Coupling/Allylation Domino Reactions: Access to 2-Substituted 2,3-Dihydrobenzofurans and Indolines. J. Org. Chem. 2018, 83, 2592. (c) Cao, D.; Ying, A.; Mo, H.; Chen, D.; Chen, G.; Wang, Z.; Yang, J. [4 + 2] Annulation of 3-Nitroindoles with Alkylidene Malononitriles: Entry to Substituted Carbazol-4-amine Derivatives. J. Org.


Page 42 of 46

Page 43 of 46 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


Chem. 2018, 83, 12568. (15) (a) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters. J. Am. Chem. Soc. 2015, 137, 15668. (b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C–H Olefination of Diphenylacetic Acids. J. Am. Chem. Soc. 2010, 132, 460. (c) He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Pd(II)/tBu-quinolineoxazoline: An Air-Stable and Modular Chiral Catalyst System for Enantioselective Oxidative Cascade Cyclization. Org. Lett. 2009, 11, 5626. (16) Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q. Enantioselective ortho-C–H Cross-Coupling of Diarylmethylamines with Organoborons. Angew. Chem. Int. Ed. 2015, 54, 11143. (17) (a) Nishimura, T.; Ebe, Y.; Hayashi, T. Iridium-Catalyzed [3 + 2] Annulation of Cyclic N-Sulfonyl Ketimines with 1,3-Dienes via C–H Activation. J. Am. Chem. Soc. 2013, 135, 2092. (b) Zhou, B.; Chen, H.; Wang, C. Mn-Catalyzed Aromatic C–H Alkenylation with Terminal Alkynes. J. Am. Chem. Soc. 2013, 135, 1264. (18) The X-ray crystallographic structure for 3c has been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1909117. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc. cam.ac.uk/data_request/cif. (19) Nayak, S.; Ghosh, N.; Prabagar, B.; Sahoo, A. K. p-TsOH Promoted Au(I)-Catalyzed Consecutive

Endo

Cyclization

of

Yne-Tethered

Ynamide:

Access

to

Benzofused

Dihydroisoquinolones. Org. Lett. 2015, 17, 5662. (20) (a) Chen, S.-S.; Wu, M.-S.; Han, Z.-Y. Palladium-Catalyzed Cascade sp2 C–H



Functionalization/Intramolecular Asymmetric Allylation: From Aryl Ureas and 1,3-Dienes to Chiral Indolines. Angew. Chem. Int. Ed. 2017, 56, 6641. (b) Bai, L.; Wang, Y.; Ge, Y.; Liu, J.; Luan, X. Diastereoselective Synthesis of Dibenzo[b,d]azepines by Pd(II)-Catalyzed [5 + 2] Annulation of o-Arylanilines with Dienes. Org. Lett. 2017, 19, 1734. (c) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Distinct Reactivity of Pd(OTs)2: The Intermolecular Pd(II)-Catalyzed 1,2-Carboamination of Dienes. J. Am. Chem. Soc. 2008, 130, 10066. (d) Son, J.-Y.; Kim, H.; Jeon, W. H.; Baek, Y.; Seo, B.; Um, K.; Lee, K.; Lee, P. H. Synthesis of Dihydrophosphaisocoumarins through a Palladium-Catalyzed Oxidative Cyclization of Arylphosphonic Acid Monoethyl Esters with 1,3-Dienes. Adv. Synth. Catal. 2017, 359, 3194. (e) Sun, Y.; Zhang, G. Palladium-Catalyzed Formal [4+2] Cycloaddition of Benzoic and Acrylic Acids with 1,3-Dienes via C-H Bond Activation: Efficient Access to 3,4-Dihydroisocoumarin and 5,6-Dihydrocoumalins. Chin. J. Chem. 2018, 36, 708. (21) (a) Yang, L.; Li, S.; Cai, L.; Ding, Y.; Fu, L.; Cai, Z.; Ji, H.; Li, G. Palladium-Catalyzed C–H Trifluoroethoxylation of N-Sulfonylbenzamides. Org. Lett. 2017, 19, 2746. (b) Belfrage, A. K.; Abdurakhmanov, E.; Åkerblom, E,; Brandt, P.; Oshalim, A.; Gising, J.; Skogh, A.; Neyts, J.; Danielson, U. H.; Sandström, A. Discovery of Pyrazinone Based Compounds That Potently Inhibit the Drug-resistant Enzyme Variant R155K of the Hepatitis C Virus NS3 Protease. Bioorg. Med. Chem. 2016, 24, 2603. (c) Péron, F.; Fossey, C.; Cailly, T.; Fabis, F. N-Tosylcarboxamide as a Transformable Directing Group for Pd-Catalyzed C–H Ortho-Arylation. Org. Lett. 2012, 14, 1827. (d) Fang, Y.; Gu, Z.-Y.; Wang, S.-Y.; Yang, J.-M.; Ji, S.-J. Co-Catalyzed Synthesis of N-Sulfonylcarboxamides from Carboxylic Acids and Sulfonyl Azides. J. Org. Chem. 2018, 83, 9364. (e) Sturino, C. F.; Labelle, M. A Convenient Method for the Preparation of


Page 44 of 46

Page 45 of 46 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


Acylsulfonamide Libraries. Tetrahedron Lett. 1998, 39, 5891. (f) Yagupolskii, L. M.; Shelyazhenko, S. V.; Maletina, I. I.; Petrik, V. N.; Rusanov, E. B.; Chernega, A. N. The Aza Curtius Rearrangement. Eur. J. Org. Chem. 2001, 1225. (22) (a) Qiao, C.; Chen, A.; Gao, B.; Liu, Y.; Huang, H. Palladium-Catalyzed Cascade Double C−N Bond Activation: A New Strategy for Aminomethylation of 1,3-Dienes with Aminals. Chin. J. Chem. 2018, 36, 929. (b) Mundal, D. A.; Lutz, K. E.; Thomson, R. J. Stereoselective Synthesis of Dienes from N-Allylhydrazones. Org. Lett. 2009, 11, 465. (c) Quinn, M, P.; Yao, M.-L.; Yong, L.; Kabalka, G. W. Synthesis 2011, 23, 3815. (d) Takimoto, M.; Mori, M. Cross-Coupling Reaction of Oxo-π-allylnickel Complex Generated from 1,3-Diene under an Atmosphere of Carbon Dioxide. J. Am. Chem. Soc. 2001, 123, 2895. (e) Maity, S.; Zheng, N. A Visible-Light-Mediated Oxidative C−N Bond Formation/Aromatization Cascade: Photocatalytic Preparation of N-Arylindoles. Angew. Chem. Int. Ed. 2012, 51, 9562. (f) Rodriguez, J.; Waegell, B. An Efficient One-Pot Preparation of 2,4-Pentadienoic Esters from α,β-Unsaturated Aldehydes. Synthesis 1988, 7, 534. (g) Timsina, Y. N.; Biswas, S.; RajanBabu, T. V. Chemoselective Reactions of (E)-1,3-Dienes. Cobalt-Mediated Isomerization to (Z)-1,3-Dienes and Reactions with Ethylene. J. Am. Chem. Soc. 2018, 140, 2700. (23) (a) Kondo, H.; Yu, F.; Yamaguchi, J.; Liu, G.; Itami, K. Branch-selective Allylic C–H Carboxylation of Terminal Alkenes by Pd/sox Catalyst. Org. Lett. 2014, 16, 4212. (b) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a Redox-Relay Strategy. Science 2012, 338, 1455. (c) Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to 5- 6- and 7-Membered β-substituted Cyclic Enones: Enantioselective



Construction of All-Carbon Quaternary Stereocenters. J. Am. Chem. Soc. 2011, 133, 6902. (d) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters. J. Am. Chem. Soc. 2015, 137, 15668. (e) Zhang, C.; Tutkowski, B.; DeLuca, R. J.; Joyce, L. A.; Wiest, O.; Sigman, M. S. Palladium-Catalyzed Enantioselective Heck Alkenylation of Trisubstituted Allylic Alkenols: A Redox-Relay Strategy to Construct Vicinal Stereocenters. Chem. Sci. 2017, 8, 2277.


Page 46 of 46

Asymmetric Palladium-Catalyzed CâH Functionalization Cascade for

Recommend Documents

Asymmetric Palladium-Catalyzed CâH Functionalization Cascade for