Formation

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Copper-Catalyzed Ring Expansion of Cyclopropyl Ketones/ Formation of N-acyliminium/ Hetero-[4+2]-Cycloaddition: A Route to Substituted Pentacyclic Isoindolin-1-one Jian Li, Shuhua Bai, Yang Li, Zhengbing Wang, Xiaoyu Huo, and Li Liu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01120 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018

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The Journal of Organic Chemistry

Copper-Catalyzed Ring Expansion of Cyclopropyl Ketones /Formation of N-acyliminium/ Hetero-[4+2]-Cycloaddition: A Route to Substituted Pentacyclic Isoindolin-1-one Jian Li,*, † Shuhua Bai,† Yang Li,† Zhengbing Wang,† Xiaoyu Huo,† Li Liu‡ †

School of Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou, 213164, China

‡

School of Petrochemical Engineering, Changzhou University, Changzhou, 213164, China Supporting Information Placeholder O R2

OTf CHO R1 CN

[

O

I R

R2

N

1

R3

Cu(OAc)2 10 mol% R o

R

DCE, 110 C O

rapid reaction

up to 83% yield

simple catalyst

readily available precursors

]

ABSTRACT: A Cu-catalyzed three-component cascade cyclization among 2-formylbenzonitrile, cyclopropyl ketones and diaryliodonium salts for construction of fused isoindolin-1-one compounds is achieved. Pentacyclic isoindolinone derivatives could be obtained in moderate to good yields. The proposed mechanism involved ring expansion of cyclopropyl ketones / formation of Nacyliminium / hetero- [4+2]-cycloaddition process.

The isoindolin-1-one structural motif forms the core of many natural products and pharmaceuticals exhibiting important biological activities.1 In particular, ring-fused isoindolin-1-one represents an important class of alkaloids2 and bioactive compounds due to their various medicinal properties (Figure 1), such as PARO-1 inhibitor,3 non-nucleoside HIVreverse transcriptase inhibitors,4 anti-Parkinson5 and vasodilators.6 In view of the structural diversity and the broad range of biological activities, extensive efforts toward those coveted structures synthesis have been made in the past decades.7 However, available methods generally require multistep reactions and are often unsatisfactory both in yield and generality. Thus, it is highly desirable to develop more efficient and convenient methods for the synthesis of polycyclic isoindolin-1ones. Recently, we developed a tandem annulation synthesizing poly-substituted isoindolin-1-ones from diaryliodonium salts and 2-formylbenzonitrile.8 According Gaunt’s proposal, the process involved a Cu(III)-aryl species, which possesses a d8 configuration and is more electrophilic compared to other d8 species,9 and the species can activate nitriles to give an Narylnitrilium intermediate by copper catalyzed. When orthosubstituted group of benzonitrile was aldehyde, an interesting reaction happened by the activated of copper catalyst, the proposed mechanism involved an intermediate N-aryl nitrilium cation, which was highly reactive species and can easily undergo coupling reaction forming new C-C bonds simultaneously.10 Two other examples of our group demonstrate this

reaction strategy and 2,3-disubstituted isoindolin-1-ones were synthesized.11 Figure 1. Examples of biologically active polycyclic isoindolinones. O

OMe O

OMe O MeO

MeO

N

N

N

MeO OMe

O

O

O

OMe O

O

MeO N HO O O O Chilenine (natural compound)

O

O

O Lennoxamine (alkaloid)

Nuevamine (alkaloid)

Isonuevamine (alkaloid)

N

O N

O MeO NH MeO

HO OMe Br CRR-228 (PARO-1 inhibitor)

Non-nucleoside HIV-1 reverse transcriptase inhibitor

Taliscanine (anti-Parkinson)

On the other hand, cyclopropanes have attracted much attention as versatile building blocks in organic synthesis due to their remarkable reactivity through ring opening reactions.12 In the case of the compounds having double bonds, such as C=O, the η2–coordination between transition metal and ketone could enhance the ring opening reaction become a very powerful method to construct cyclic compounds.13 In one of them, dihy-

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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

drofurans can be prepared from cyclopropyl ketones via [1,3]transposition under Lewis acid or transition metal-catalyzed.14 Scheme 1. Synthetic strategies of pentacyclic isoindolines. O

R

O

R

Lewis acid H H

H H

H H

O

H H

N

[4+2]

OTf CHO

O

R

R

O

O

I N

CN

Page 2 of 7

cyclopropyl ketones 2 is catalyzed by copper salt; (ii) 2formylbenzonitrile 1 is trigged by diaryliodonium salts 3 to afford N-aryl nitrilium cation in the presence of copper catalyst; (iii) the catalytic sequence is terminated by N-aryl nitrilium cation via hetero-[4+2]-cycloaddition reaction, affording fused isoindolin-1-ones in moderate to good yields. The developed methodology provides straightforward access to pentacyclic isoindolin-1-ones derivatives from readily available 2-formylbenzonitrile, cyclopropyl ketones and diaryliodonium salts in a one-pot reaction. Table 2. Scope of reaction with various 2formylbenzonitrile 1 and diaryliodonium salts 3 a

Inspired by the above study, we wondered if the formation of N-aryl nitrilium cation and the ring-enlargement of cyclopropyl ketones could happen in one pot. To verify this idea, we decided to investigate the cascade reaction with 2formylbenzonitrile, cyclopropyl ketones and diaryliodonium salts. The proposed sequential transformation involves a three step catalysis (Scheme 1), where (i) ring-opening reaction of Table 1. Optimization of the reaction conditions a

O

OTf CHO R1

I

O

R3

+ R2

+

Cu(OAc)2 10mol% DCE, 110oC

CN

O

2a

1

3

4 O

O

OTf

OTf

Cl

Cl

N

I

N

I

Cl O

3b

O

4b, 52% O

3a 4a, 57% OTf

O I

O +

Cl

1a

2a

Cl

4a

3a

Me

I

Cl

N

Br

O

Me

Br

3d

catalyst

solvent

1

--

DCE

temperature (o C) 110

2

CuBr2

DCE

110

O 4d, 65%

Br

O

3c

OTf

O

N

F

yield (%) --

O I

Me

Me

O 3f

Me

OTf

F

I

4c, 55%

entry

Me

O

OTf

N

catalyst solvent

+

CN

N

I

OTf CHO

R2

N

R1

4f, 63%

N

O OTf N

8

4e, 68%

3

CuBr

DCE

110

33

4

Cu(OTf)2

DCE

110

31

5

Cu2O

DCE

110

DCE

110

4

7

CuCl

DCE

110

14

8

Cu(OAc)2

DCE

110

51

9

[Cu(CH3CN)4]PF6

DCE

110

17

4g, 69% O

MeO N

CHO

N

Br

Br

Cl CN

CuI

O 3g

15

6

MeO

O MeO

OMe

I

O

3e

CHO

O

1b

4h, 65%

O 4i, 72%

1c

Br CHO

Br

CN

Cl

O N

Br

CN

10

b

Cu(OAc)2

DCE

110

55

c

Cu(OAc)2

DCE

110

57

11

11

Cu(OAc)2

CH3CN

110

--

12

Cu(OAc)2

1,4-dioxane

110

--

13

Cu(OAc)2

Toluene

110

27

14

Cu(OAc)2

THF

110

--

15

Cu(OAc)2

DMF

110

--

16

Cu(OAc)2

DCE

r.t

--

17

Cu(OAc)2

DCE

80

19

18

Cu(OAc)2

DCE

130

43

d

Cu(OAc)2

DCE

110

42

20 e

Cu(OAc)2

DCE

110

11

f

Cu(OAc)2

DCE

110

--

19 21 a

Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.36 mmol) and catalyst (10 mol %) in DCE (2.0 mL), 110 °C, 12 hours. b 2 hours. c 30 mins. d Catalyst (5 mol %). e Catalyst (1 mol %).f Diphenyliodonium bromide was used instead of 3a.

O 1d

4j, 83%

a

Reaction condition: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.36 mmol) and Cu(OAc)2 (10 mol %) in DCE (2.0 mL), 110 °C, 30 mins.

Initially, an investigation of the reaction conditions was conducted by using 2-formylbenzonitrile 1a, 1cyclopropylethanone 2a and bis(4-chlorophenyl)iodonium triflate 3a as starting materials. No target compound was observed in dichloromethane (DCM) in the absence of catalyst at 110 oC for 12 hours. Generally, under Lewis acid and transition-metal catalysis, chelation to the acyl groups would act to weaken the cyclopropane bond leading to ring opening.15 Therefore, we chose 10 mol% of CuBr2 as the catalyst, DCE as the solvent, we were pleased to isolate 4a in 8% yield after 12 hours (Table 1, entry 1). Further investigation showed that anhydrous Cu(OAc)2 was a better catalyst than CuBr, Cu(OTf)2, Cu2O, CuI and [Cu(CH3CN)4]PF6, which 4a in 51% yield (Table 1, entries 3-9). Remarkably, shorten the time to 30 minutes, the reaction furnished 4a in 57% yield (Table 1, entry 11). DCE seemed to be the optimal solvent for the threecomponent cascade cyclization as it performed in other sol-


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The Journal of Organic Chemistry vents gave the corresponding product 4a in lower yields (entries 11-15), even in some solvent (CH3CN, 1,4-dioxane, THF, DMF), no desired isoindolin-1-one compound was isolated. Lowering the reaction temperature from 110 oC to 80 oC or room temperature, the product outcome was affected to lower yields dramatically. In contrast, when the reaction was performed at higher temperature (130 oC), the yield of 4a decreased to 43% after the same time. Reduction the loadings of Cu(OAc)2 (5 mol% and 1mol%) resulted in significantly decreased yields (entries 19-20). Interestingly, the iodonium salts with Br anion did not afford corresponding product (entry 21). With the optimized conditions in hand, the generality of this cascade reaction was then examined. As summarized in Table 2, the reaction with a series of diaryliodonium salts 3 reacted smoothly with 2-formylbenzonitrile 1a and 1cyclopropylethanone 2a to generate the expected fused ring derivatives in moderate yields with excellent chemoselectivity. The reaction works well with the symmetric (3a-e) and unsymmetric (3f, 3g) diaryliodonium salts. As can be seen from Table 2, the reactivity of the salts can be increased by installation of an electron-donating group, such as methyl, methoxy at the para-position, and the salt with a halogen group became sluggish (4a, 4c and 4f). Even the metasubstrate 3e can produced the target compound 4e in 68% yield smoothly. Of note is that reactions with unsymmetrical Table 3. Scope of cyclopropyl ketones a O OTf

O

CHO

I

+

+ R4

CN

Cu(OAc)2 10mol%

N

X

DCE,110 oC

X

X

R4

O 3

2

1a

diaryliodonium reagents are more suitable for this transformation compared with symmetric substrates. This is likely due to the nontransferable aryl ring is mesitylene the so-called “anti-ortho”effect,16 which governs chemo-selectivity. To our delight, a variety of 2-formylbenzonitrile 1 containing various electronic natures at 4- and 5-positions afforded 4 in moderate to good yields. When the substituent group of 4position was Br, the yield of 4i was up to 83%. The structure of 4i was confirmed by X-ray crystallographic analysis. The successful reaction of ring-enlargement / cycloaddition with 1-cyclopropylethanone prompted us to investigate its reaction with arylcarbonylcyclopropane, the substrate scope of the reaction was examined (Table 3). To our delight, various arylcarbonylcyclopropane 2 bearing either electron-donating groups (e.g., methyl and ethyl) or electron-withdrawing groups (e.g., ethyl formate and trifluoromethyl) on the phenyl rings were all smoothly transformed under the standard conditions to give the desired products 4aa-4ah in moderate to good yields. The results indicated that electron-donating substrates (2c, 2e) are more suitable for this reaction than the electronwithdrawing substrates (2h, 2i). The steric hindrance effect 17 of cyclopropyl ketones 2 was not observed in the reaction of cyclopropyl(o-tolyl)methanone 2d with other substrates, which generated 4ac in 68% yield. Meanwhile, the structures of 4ab and 4af were confirmed by X-ray crystallographic diffraction, the steric structure of the products obtained from the aryl cyclopropyl ketones are difference from alkyl cyclopropyl ketones, which may be due to steric hindrance effects. Scheme 2. Experiments for mechanistic understanding.

4 O

O O

N

N

Br

Br

I

O +

O

O

O

Me

4aa, 53%

Br

O N

2c

F

6 (0.3 mmol)

4aa', 71%

N

Me

O

2e

O Me

2d

Et 4ad, 81%

4ac, 68%

O O

O

N

N

Br

Et

F O

2e

Et

O

F

4ad', 81%

F 4ae, 51%

O

O O

N

N

Br

Br O

CO2Et

O

O

2h

Br

CO2Et

4af, 83%

4ag, 59%

Br 2g

O O

N

CF3 2i

Br O CF3

4ah, 63%

a

O 5 (0.6 mmol)

4b, 61% yield

Br

Br Et

2f

N

DCE,110 oC

O

N

O

Cu(OAc)2 10 mol%

O

O O

O +

OH

O 2b

O 4c, 49% yield

3c (0.36 mmol) O

Me N

Br

DCE,110 oC

4ab, 79%

O O

Br

1a (0.3 mmol) 5(0.6 mmol)

N

Cu(OAc)2 10 mol%

+

CN 2b

O

OTf CHO

Reaction condition: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.36 mmol) and catalyst (10 mol %) in DCE (2.0 mL), 110 °C, 30 mins.

To gain insight into the mechanism of this cascade reaction, several control experiments were performed (Scheme 2). First, 2 equiv. of 5-methyl-2,3-dihydrofuran 5 was used instead of 1cyclopropylethanone 2a, 49% yield of 4c was obtained under the standard condition, which suggested that the ringenlargement of 1-cyclopropylethanone might take place via the catalyst activation. Next, treatment of 5-methyl-2,3dihydrofuran 5 with 3-hydroxy-2-phenylisoindolin-1-one 6, 18 which was used as the N-acyliminium ion precursor, 61% yield of 4b was successfully assembled under the promotion of Cu(OAc)2. This demonstrates that the mechanism of this one-pot reaction involved the formation of N-acyliminium ion and hetero-[4+2]-cycloaddition process. Based on the above control experimental results, we proposed the mechanism shown in Figure 2. Initially, the 2formylbenzonitrile 1 is subjected to a reaction with diaryliodonium salts 3 to provide N-aryl nitrilium cation A in the presence of copper catalyst,19 followed by an intramolecular cyclization reaction to produce intermediate B. On the other hand, ring-enlargement of cyclopropyl ketones 2 occurs catalyzed by the copper salts to give dihydrofuran derivatives C



simultaneously.20 Then, the hetero-[4+2] cycloaddition take place between the intermediate B and dihydrofuran C to generate intermediate F. Finally, the deprotonation of the intermediate F affords the final product isoindolinone 4. Figure 2. Proposed reaction mechanism OTf

H

O

I

O

O H

N

3 N

I

N 1

B

R

A

O C O Cu R Cu(OTf)2

O

O

O -H+

N

N

+

Friedel-Crafts reaction

O

N

2

H O 4

R

O

R

E

R

R O D

Compound (4a). white solid (55.6 mg, 57%). Mp: 166-168 °C. H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.8 Hz, 1H),7.95 (d, J = 7.5 Hz, 1H), 7.65 (dt, J = 7.4, 1.2 Hz, 1H), 7.57-7.51 (m, 3H), 7.31 (dd, J = 8.8, 2.5 Hz, 1H), 5.03 (d, J = 3.1 Hz, 1H), 3.83-3.75 (m, 1H), 3.48-3.41 (m, 1H), 2.82 (dt, J = 9.5, 3.0 Hz, 1H), 1.79 (s, 3H), 1.58-1.51 (m, 1H), 1.21-1.14 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.7, 143.0, 133.2, 132.7, 132.5, 130.0, 128.9, 128.5, 127.8, 124.5, 121.7, 120.8, 80.0, 65.3, 57.9, 46.7, 29.7, 28.6, 24.2. HRMS (ESI) calcd for C19H17ClNO2 ([M+H]+): 326.0942 found 326.0937. 1

Compound (4b). white solid ( 45.4 mg, 52%). Mp: 149-152 °C. 1 H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 8.3, 1.5 Hz, 1H), 7.97-7.95 (m, 1H), 7.66 -7.63 (m, 1H), 7.58-7.51 (m, 3H), 7.36 (dt, J = 8.4, 2.0 Hz, 1H), 7.20 (dt, J = 7.5, 1.2 Hz, 1H), 5.05 (d, J = 3.0 Hz, 1H), 3.82-3.74 (m, 1H), 3.49-3.38 (m, 1H), 2.82 (dt, J = 9.5, 3.0 Hz, 1H), 1.81 (s, 3H), 1.58-1.51 (m, 1H), 1.20-1.14 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.7, 143.3, 134.7, 133.0, 132.4, 130.5, 128.8, 128.4, 127.8, 124.9, 124.4, 121.6, 119.5, 80.2, 65.1, 58.0, 47.0, 28.8, 24.3. HRMS (ESI) calcd for C19H18NO2 ([M+H]+): 292.1332 found 292.1327.

In conclusion, we have developed a copper-catalyzed cascade reaction of 2-formylbenzonitrile, cyclopropyl ketones and diaryliodonium salts via ring expansion of cyclopropyl ketones / formation of N-acyliminium / hetero-[4+2]cycloaddition process. The developed methodology afforded an approach for the construction of biologically important pentacyclic isoindolin-1-one skeleton. Further research to explore the possibility for synthesis of complicated fused isoindolinones is ongoing in our laboratory.

Compound (4c). white solid (60.8 mg, 55%). Mp: 116-117 °C. 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.68-7.62 (m, 2H), 7.54 (t, J = 8.7 Hz, 2H), 7.44 (dd, J = 8.9, 2.4 Hz, 1H), 5.04 (d, J = 3.1 Hz, 1H), 3.82-3.75 (m, 1H), 3.48-3.40 (m , 1H), 2.82 (dt, J = 9.5, 3.0 Hz, 1H), 1.79 (s, 3H), 1.62-1.51 (m, 1H), 1.27-1.14 (m, 1H). 13 C{1H}NMR (125 MHz, CDCl3) δ 166.7, 143.1, 133.7, 132.6, 131.4, 130.7, 128.9, 124.4, 121.7, 121.1, 117.7, 79.9, 65.3, 57.8, 46.7, 28.6, 24.2. HRMS (ESI) calcd for C19H17BrNO2 ([M+H]+): 370.0437 found 370.0435.

EXPERIMENTAL SECTION

Compound (4d). white solid (59.4 mg, 65%). Mp: 84-86 °C. 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.1 Hz, 1H), 7.56-7.52 (m, 2H), 7.38 (s, 1H), 7.20-7.17 (m, 1H), 5.02 (d, J = 2.8 Hz, 1H), 3.77 (dd, J = 15.0, 8.5 Hz, 1H), 3.46-3.40 (m, 1H), 2.81 (dt, J = 9.5, 3.0 Hz, 1H), 2.36 (s, 3H), 1.80 (s, 3H), 1.58-1.54 (m, 1H), 1.25-1.20 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.5, 143.2, 134.5, 133.1, 132.3, 132.2, 130.3, 129.2, 128.7, 128.0, 124.3, 121.6, 119.3, 80.2, 65.1, 58.0, 47.1, 29.7, 28.7, 24.3, 21.1. HRMS (ESI) calcd for C20H20NO2 ([M+H]+): 306.1489 found 306.1494.

General Information. All reactions were carried out under an air atmosphere condition. Various reagents were purchased from Aldrich, Acros or Alfa. 2-Formylbenzonitrile 1, arylcarbonylcyclopropane 2 and diaryliodonium salts 3 were prepared according literature. Flash column chromatography was performed using silica gel (200-300 mesh). NMR spectra were recorded in CDCl3 on Bruker NMR-400 (400 MHz) and NMR-500 (500 MHz) with TMS as an internal reference. HRMS were performed on Agilent 6540 Q-TOF mass spectrometer (ESI). X-ray crystallographic data were collected using a SMART APEX II X-ray diffractometer. Melting points were determined on a SGW X-4B melting point apparatus.

General Procedure for preparation of compound 4. A solution of 2-formylbenzonitrile 1 (0.3 mmol), cyclopropyl ketones 2 (0.6 mmol), diaryliodonium salt 3 (0.36 mmol), Cu(OAc)2 (0.03 mmol, 5.5 mg, 10 mol%) in DCE (2 mL) was stirred at 110 ºC for 30 mins. After completion of the reaction (observed on TLC), the solvent was evaporated and the residues was purified by silica-gel column chromatography (Ethyl acetate / Petroleum ether = 1/4 - 1/2) to afford the pure product 4. The obtained product was analyzed by 1H NMR, 13C NMR and HRMS.

Page 4 of 7

Compound (4e). white solid (62.2 mg, 68%). Mp: 154-159 °C. 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.57-7.52 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 3.0 Hz, 1H), 3.80-3.77 (m, 1H), 3.45-3.49 (m, 1H), 2.85-2.80 (m, 1H), 2.42 (s, 3H), 1.81 (s, 3H), 1.58-1.55 (m, 1H), 1.22-1.20 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.7, 143.3, 138.4, 134.7, 133.1, 132.3, 128.8, 127.6, 125.9, 124.4, 121.6, 119.8, 80.1, 65.0, 58.2, 47.1, 28.8, 24.4, 21.5. HRMS (ESI) calcd for C20H20NO2 ([M+H]+): 306.1489 found 306.1493. Compound (4f). white solid (58.4 mg, 63%). Mp: 117-121 °C. 1 H NMR (400 MHz, CDCl3) δ 8.48 (q, J = 5.2 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.58-7.53 (m, 2H), 7.27-7.25 (m, 1H), 7.07 (dt, J = 8.2, 2.8 Hz, 1H), 5.05 (d,


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The Journal of Organic Chemistry J = 2.9 Hz, 1H), 3.79 (q, J = 6.8 Hz, 1H), 3.46-3.43 (m, 1H), 2.83 (dt, J = 9.5, 3.0 Hz, 1H), 1.80 (s, 3H), 1.58-1.55 (m, 1H), 1.21-1.14 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.6, 159.7 (d, J = 246.2 Hz), 143.0, 132.8 (d, J = 6.4 Hz), 132.7, 130.8, 128.9, 124.4, 121.6, 121.2 (d, J = 7.8 Hz), 115.4 (d, J = 22.3Hz), 114.2, 114.0, 80.1, 65.3, 57.9, 46.8, 28.6, 24.2. 19F NMR (282 MHz, CDCl3) δ -116.7. HRMS (ESI) calcd for C19H17FNO2 ([M+H]+): 310.1238 found 310.1233. Compound (4g). white solid ( 66.5 mg, 69%). Mp: 190-193 °C. 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.65-7.61 (m, 1H), 7.56-7.51 (m, 2H), 7.09 (d, J = 2.9 Hz, 1H), 6.94 (dd, J =9.0 2.9 Hz, 1H), 5.02 (d, J = 3.0 Hz, 1H), 3.85 (s, 3H), 3.81-3.76 (m, 1H), 3.48-3.42 (m, 1H), 2.83 (dd, J = 9.5, 3.1 Hz, 1H), 1.81 (s, 1H), 1.61-1.52 (m, 3H), 1.23-1.18 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.4, 156.7, 143.1, 133.2, 132.1, 132.0, 128.7, 124.2, 121.6, 120.8, 114.5, 112.2, 80.3, 65.2, 57.9, 55.5, 47.1, 28.7, 24.3. HRMS (ESI) calcd for C20H20NO3 ([M+H]+): 322.1438 found 322.1432. Compound (4h). white solid (77.8 mg, 65%). Mp: 165-167 °C. 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.67-7.68 (m, 1H), 7.45 (dd, J = 8.8, 1.6 Hz, 1H), 7.08-7.05 (m, 1H), 6.99 (br, 1H), 4.98 (d, J = 1.5 Hz, 1H), 3.94 (s, 3H), 3.81 (q, J = 8.4 Hz, 1H), 3.49-3.44 (m, 1H), 2.77 (dt, J = 9.4, 3.0 Hz, 1H), 1.79 (s, 3H), 1.64-1.57 (m, 1H), 1.27-1.24 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.6, 163.7, 145.4, 137.9, 132.5, 131.4, 1307, 125.9, 125.1, 121.0, 117.4, 115.5, 106.4, 80.0, 65.3, 57.5, 55.8, 46.8, 28.6, 24.2. HRMS (ESI) calcd for C20H19BrNO3 ([M+H]+): 400.0543 found 400.0538. Compound (4i). white solid (87.0 mg, 72%). Mp: 249-251 °C. 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.70-7.69 (m, 1H), 7.54-7.53 (m, 2H), 7.47 (dd, J = 8.8, 2.2 Hz, 1H), 5.03 (d, J = 2.8 Hz, 1H), 3.82 (q, J = 8.5 Hz, 1H), 3.50-3.44 (m, 1H), 2.79 (dt, J = 9.5, 3.0 Hz, 1H), 1.79 (s, 3H), 1.68-1.63 (m, 1H), 1.19-1.15 (m, 1H). 13 C{1H} NMR (125 MHz, CDCl3) δ 165.6, 144.6, 139.1, 133.4, 132.7, 131.5, 131.1, 130.8, 129.7, 125.7, 122.2, 121.1, 118.0, 79.9, 65.3, 57.5, 46.6, 28.6, 24.2. HRMS (ESI) calcd for C19H16BrClNO2 ([M+H]+): 404.0047 found 404.0042. Compound (4j). white solid (111.0 mg, 83%). Mp: 251-254 °C. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71-7.69 (m, 3H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 5.03 (d, J = 3.2 Hz, 1H), 3.85-3.79 (m, 1H), 3.503.44 (m, 1H), 2.79 (dt, J = 9.4, 3.0 Hz, 1H), 1.79 (s, 3H), 1.681.63 (m, 1H), 1.22-1.15 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.6, 144.7, 133.3, 132.6, 132.4, 131.5, 131.4, 130.7, 127.3, 125.8, 125.0, 120.9, 117.9, 79.8, 65.1, 57.3, 46.5, 28.5, 24.0. HRMS (ESI) calcd for C19H16Br2NO2 ([M+H]+): 447.9542 found 447.9537. Compound (4aa). white solid (68.5 mg, 53%). Mp: 194196 °C. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.67-7.57 (m, 3H), 7.45 (dd, J = 8.8, 2.8 Hz, 1H), 7.32-7.24 (m, 5H), 7.20 (d, J = 2.2 Hz, 1H), 4.63 (d, J = 11.6 Hz, 1H), 4.35-4.31 (m, 2H), 2.65 (dd, J = 11.4, 6.7 Hz, 1H), 2.57-2.51 (m, 1H), 2.31-2.23 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 165.4, 144.6, 143.6, 133.2, 133.1, 132.9, 132.6, 132.3, 131.5, 128.9, 128.4, 127.2, 125.3, 124.7,

122.6, 121.9, 117.6, 85.5, 65.5, 58.4, 50.9, 27.8. HRMS (ESI) calcd for C24H19BrNO2 ([M+H]+): 432.0594 found 432.0600. Compound (4aa’). white solid (79.0 mg, 71%). Mp: 218219°C. 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 9.1, 5.2 Hz, 1H), 8.04-8.03 (m, 1H), 7.67-7.59 (m, 3H), 7.32-7.27 (m, 2H), 7.25-7.23 (m, 3H), 7.08-7.03 (m, 1H), 6.78 (dd, J = 9.2, 3.0 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.4 Hz, 2H), 2.68-2.64 (m, 1H), 2.57-2.54 (m, 1H), 2.32-2.22 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.4, 159.4 (d, J = 243.0 Hz), 144.9, 143.7, 133.1 (d, J = 7.5 Hz),130.2, 129.0,128.4, 127.3,125.4, 124.7, 122.6, 122.1 (d, J = 8.2 Hz), 116.9 (d, J = 22.6 Hz), 115.8 (d, J = 22.6 Hz), 85.7, 65.6, 58.6, 50.9, 27.9. 19F NMR (376 MHz, CDCl3) δ -116.4. HRMS (ESI) calcd for C24H19FNO2 ([M+H]+): 372.1394 found 372.1389. Compound (4ab). white solid (105.4 mg, 79%). Mp: 189192 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 7.1 Hz, 1H), 7.67-7.57 (m, 3H), 7.44 (dd, J = 8.8, 2.3 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 13.2, 8.3 Hz, 4H), 4.62 (d, J = 11.6 Hz, 1H), 4.31 (dd, J = 9.3, 5.4 Hz, 2H), 2.62 (dd, J = 11.5, 6.7 Hz, 1H), 2.54-2.51 (m, 1H), 2.32 (s, 3H), 2.28-2.20 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 143.7, 141.7, 137.0, 133.3, 133.2, 133.1, 132.7, 132.4, 131.6, 129.2, 129.0, 125.4,124.8, 122.7, 122.0, 117.7, 85.5, 65.5, 58.5, 50.9, 27.9, 21.0. HRMS (ESI) calcd for C25H21BrNO2 ([M+H]+): 446.0750 found 446.0748. Compound (4ac). white solid (90.8 mg, 68%). Mp: 246248 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.677.59 (m, 3H), 7.49 (dd, J = 8.8, 2.3 Hz, 1H), 7.32-7.78 (m, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.14 (d, J =2.2 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 4.67 (d, J = 11.6 Hz, 1H), 4.46-4.41 (m, 1H), 4.37-4.31 (m, 1H), 2.64-2.60 (m, 1H), 2.58-2.53 (m, 1H), 2.23-2.19 (m, 1H), 1.67 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 143.8, 142.1, 133.7, 133.5, 132.5, 132.4, 131.6, 129.1, 127.9, 125.8, 125.6, 124.9, 122.8, 122.8, 122.0, 117.8, 85.5, 65.3, 57.8, 47.7, 27.9, 20.2. HRMS (ESI) calcd for C25H21BrNO2 ([M+H]+): 446.0750 found 446.0745. Compound (4ad). white solid (111.5 mg, 81%). Mp: 187189 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.63-7.58 (m, 3H), 7.45 (dd, J = 8.8, 2.3 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 12.6, 8.5 Hz, 4H), 4.63 (d, J =11.6 Hz, 1H), 4.33-4.30 (m, 2H), 2.65-2.59 (m, 3H), 2.54-2.51 (m, 1H), 2.29-2.28 (m, 1H), 1.22 (t, J =7.6 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 143.7, 143.3, 131.9, 133.3, 133.2, 132.7, 131.6, 129.0, 127.9, 125.4, 124.8, 122.7, 122.0, 117.8, 85.5, 65.5, 58.5, 50.9, 28.4, 27.9, 15.3. HRMS (ESI) calcd for C26H23BrNO2 ([M+H]+): 460.0907 found 460.0902. Compound (4ad’). white solid (94.5 mg, 79%). Mp: 173-175 1 °C. H NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 9.0, 5.2 Hz, 1H), 8.04-8.02 (m, 1H), 7.67-7.56 (m, 3H), 7.17-7.11 (m, 4H), 7.07-7.02 (m, 1H), 6.80 (dd, J = 9.3, 3.0 Hz, 1H), 4.64 (d, J =11.5 Hz, 1H), 4.31 (dd, J = 9.3, 5.4 Hz, 2H), 2.67-2.59 (m, 3H), 2.57-2.50 (m, 1H), 2.33-2.28 (m, 1H), 1.31 (t, J =7.6 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.4, 159.4 (d, J = 242.9 Hz), 143.7, 143.3, 142.0, 133.2 (d, J = 7.0 Hz), 132.8, 132.2, 130.9, 128.9, 127.8, 125.3, 124.7, 122.1 (d, J = 7.8 Hz), 116.8 (d, J = 22.6 Hz), 115.7 (d, J = 22.6 Hz),85.7, 65.5, 58.7,



50.9, 28.4, 28.0, 15.4. 19F NMR (376 MHz, CDCl3) δ -116.4. HRMS (ESI) calcd for C26H23FNO2 ([M+H]+): 400.1707 found 400.1722. Compound (4ae). white solid (87.5 mg, 65%). Mp: 174-178°C. 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 7.0 Hz, 1H), 7.67-7.57 (m, 3H), 7.45 (dd, J = 8.8, 2.3 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (d, J = 2.2 Hz, 1H), 6.99 (t, J = 8.6 Hz, 2H), 4.63 (d, J = 11.6 Hz, 1H), 4.32 (dd, J = 9.5, 5.2 Hz, 2H), 2.62-2.54 (m, 2H), 2.27-2.20 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 162.2 (d, J = 244.9 Hz), 143.6, 140.6, 133.3, 132.7 (d, J = 21.2 Hz), 132.5, 131.7, 129.2, 127.2 (d, J = 8.0 Hz), 124.8, 122.7, 122.1, 117.7, 115.4 (d, J = 21.3 Hz), 85.3, 65.6, 58.4, 51.1, 27.8. 19F NMR (376 MHz, CDCl3) δ -115.1. HRMS (ESI) calcd for C24H18BrFNO2 ([M+H]+): 450.0499 found 450.0494. Compound (4af). white solid (126.4 mg, 83%). Mp: 263266 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.48-7.42 (m, 3H), 7.17-7.12 (m, 3H), 4.62 (d, J = 11.6 Hz, 1H), 4.344.30 (m, 2H), 2.61-2.54 (m, 2H), 2.29-2.19 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.5, 144.0, 143.5, 133.2, 131.8, 131.6, 129.1, 127.3, 124.9, 122.7, 122.1, 121.4, 117.8, 85.3, 65.7, 58.3, 50.9, 27.9. HRMS (ESI) calcd for C24H18Br2NO2 ([M+H]+): 509.9699 found 509.9692. Compound (4ag). white solid (89.0 mg, 59%). Mp: 221224 °C. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H),7.657.59 (m, 3H), 7.47 (dd, J = 8.8, 2.2 Hz, 1H ), 7.33 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 2.2 Hz, 1H), 4.65 (d, J = 11.6 Hz, 1H), 4.39-4.33 (m, 4H), 2.67-2.55 (m, 2H), 2.26-2.22 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 165.5, 149.8, 143.5, 133.2, 132.6, 132.5, 132.4, 131.9, 129.8, 129.7, 129.2, 125.5, 124.9, 122.7, 122.1, 117.8, 85.6, 65.7, 61.0, 58.3, 50.9, 27.9, 14.3. HRMS (ESI) calcd for C27H23BrNO4 ([M+H]+): 504.0805 found 504.0799. Compound (4ah). white solid (94.3 mg, 63%). Mp: 230232 °C. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.66-7.60 (m, 3H), 7.58-7.56 (m, 2H), 7.48 (dd, J = 8.8, 2.3 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 2.2 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.35 (dd, J =9.5, 5.1 Hz, 2H), 2.65-2.56 (m, 2H), 2.26-2.23 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.6, 149.2, 143.5, 133.3, 133.2, 132.7, 132.4, 132.1, 129.3, 125.9, 125.6, 124.9, 122.8, 122.3, 117.9, 85.5, 65.9, 58.4, 51.3, 28.0. 19F NMR (376 MHz, CDCl3) δ -62.5. HRMS (ESI) calcd for C25H18BrF3NO2 ([M+H]+): 500.0468 found 500.0473.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications webs site at DOI:. Copies of the 1H and 13C NMR spectra for all new products and crystal data. Single-crystal X-ray data for 4h (CCDC no. 1834908), 4ab (CCDC no. 1834909), 4af (CCDC no. 1834907).

Accession Codes

Page 6 of 7

CCDC 1834907-1834909 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID

Jian Li: 0000-0001-6713-1302 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful to National Natural Science Foundation of China (21402013), the Natural Science Foundation of Jiangsu Province (BK20140259), Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110) and Advanced Catalysis and Green Manufacturing Collaborative Innovation Center.

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Formation

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