Copper-Catalyzed Radical Cascade Cyclization To Access 3

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Copper-Catalyzed Radical Cascade Cyclization to Access 3-Sulfonated Indenones with AIE Phenomenon Kai Sun, Xiao-Lan Chen, Shi-Jun Li, Dong-Hui Wei, Xiao-Ceng Liu, Yin-Li Zhang, Yan Liu, Lu-Lu Fan, Ling-Bo Qu, Bing Yu, Kai Li, Yuan-Qiang Sun, and Yufen Zhao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02175 • Publication Date (Web): 01 Nov 2018 Downloaded from http://pubs.acs.org on November 1, 2018

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The Journal of Organic Chemistry

Copper-Catalyzed Radical Cascade Cyclization to Access 3Sulfonated Indenones with AIE Phenomenon Kai Sun,a Xiao-Lan Chen,a,b* Shi-Jun Li,a Dong-Hui Wei,a Xiao-Ceng Liu,a Yin-Li Zhang, a

Yan Liu,a,c Lu-Lu Fan,a Ling-Bo Qu,a Bing Yu,a,* Kai Li,a,* Yuan-Qiang Sun,a,* and Yu-

Fen Zhaoa,b.

a

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China.

b The

c

Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China.

College of biological and pharmaceutical engineering, Xinyang Agriculture & Forestry University, Xinyang,

464000, China

E-mail: [email protected]; [email protected]; [email protected]; [email protected].

R1 +

R2 CN

O R3 S NHNH2 O

CuI (20 mol%) TBHP (4 equiv.) CH3CN/H2O 60 °C, 8 h

R3 O S O

R2 = H ,CH3, F, Cl, Br; R1, R3 = aryl efficient method to 3-sulfoned indenones novel AIEgens

R1

R2

DFT calculation

O

Cell imaging AIE Phenomenon

successfully used in live cell imaging

ABSTRACT: An efficient copper-catalyzed radical cascade cyclization strategy was developed, by which a wide variety of 3-sulfonyl substituted indenones were prepared in one-pot via reaction of 2-alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild reaction conditions. Much more importantly, the 3-sulfonyl indenones, synthesized through our newly developed copper-catalyzed radical cascade cyclization strategy, were found to own typical aggregation-induced emission (AIE) properties, showing orange to red emission with large stokes shift (more than 135 nm). In ACS Paragon Plus Environment

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addition, such newly found AIEgens could be successfully used in live cell imaging, exhibiting excellent biocompatibility and application potential.

Introduction AIE phenomenon was first reported by Tang et al in 2001.1 Most of the traditional luminogens exhibit weak luminescence in solid or aggregated state due to the notorious aggregation-caused quenching (ACQ) effect.2 On contrast, AIEgens shows excellent luminescene properties in solid or aggregated state, which have been widely used in the development of biosensors, organic light-emitting diodes, stimuli-responsive materials, and so on.3 To date, numbers of classic AIEgens have been developed including tetraphenylethene

(TPE),

tetraphenylpyrazine

(TPP),

hexaphenylsilole

(HPS),

salicylaldehyde hydrazine, salicyladazine (SA) 2,5-bis(4-alkoxycarbonylphenyl)-1,4diaryl-1,4-dihydropyrrolo[3,2-b]pyrrole (AAPP).4 Nevertheless, the number and type of the core structure of AIEgens are still very limited. The development of new AIEgens with a facile synthesis process and excellent luminescence properties remains challenging and in great need. Cascade reaction, also known as “tandem” reaction, has emerged as one of the most promising and powerful synthetic strategies in organic chemistry.5 The distinguished merits of cascade reaction include high atom economy and great reduction of work and time required to carry them out.6 Among the diverse cascade methodologies, strategies using free-radical cascade reactions are highly valuable because they enable to synthesize complex and usually poly molecular skeletons in only few synthetic steps.7 Despite the

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promising achievement that has been made in the recent past few years, the development of specific free-radical cascade reactions with high regioselectivity or stereoselectivity is still highly expected. Indenones are privileged structural motifs that exist in natural products and many synthetic compounds with various biologically activities.8 For example, Euplectin, a naturally occurring product with an indenone moiety, exhibits a strong anti-tumor activity.9 Some indenones are also important alcoholic fermentation activators.10 Meanwhile, indenones have frequently been employed as starting materials in preparation of a great number of biologically and photochemically important molecules, such as estrogen receptor,11 C-nor-D-homo steroids,12 gibberellins,13 substituted naphthalenes,14 and photochromic indenones15 etc. The preparation of indenones has thus triggered great interest among synthetic chemists in past decades. The two classical synthetic strategies for indenones involve intramolecular Friedel-Crafts acylation16 and Grignard reagentinitiated reactions17. However, the classical methods require harsh reaction conditions, and thus suffer from practical inconvenience. In 1989, Heck et al first reported the synthesis of 2,3-diphenyl-1-indenone from o-iodobenzaldehyde and diphenylacetylene (Scheme 1a),18 and since then the palladium- or rhodium-catalyzed annulation reactions of orthobifunctionalized arenes with alkynes have been extensively explored (Scheme 1b).19 In recent years, Rh-catalyzed annulations of aryl aldehydes, nitriles, or amides with alkynes towards indenone derivatives have appeared (Scheme 1c).20 Nevertheless, the high cost of the precious metal catalysts (Rh, Pd, etc.), and the poor regioselectivity when



unsymmetrical alkynes were employed as reactant, might limit their synthetic application.19f Very recently, Lei’s group provided a powerful radical cascade cyclization method for construction of 2-sulfonated indenones from ynones and sulfinic acids (Scheme 1d).21 Similar radical cascade synthesis methods have also successively been adopted to synthesize several other 2-substituted indenones, including 2-phophsphoryl, cycloalkyl, and phenylthioindenones.22 It is especially worth mentioning here that, even though significant progress has been made in the construction of various 2-functionalized indenones, however, only two types of 3-substituted indenones, 3-phosphorylindenones and 3-alkylindenones can be seen synthesized by the group of Tu.23 Scheme 1e shows Tu’s synthetic method towards 3-phosphorylindenones, and however, up to two stoichiometric amounts of sliver salt were necessarily required for this cascade cyclization.23a The similar drawback also can be seen in another recent method developed by Tu’s group towards 3alkylindenones.23b It is well known that sulfonyl-containing molecules are widely found in marketed drugs and valuable synthetic intermediates. The introduction of sulfonyl groups into the aromatic compounds has gained considerable attention over recent years.24 As part of our continuing interest in the development of novel synthetic methodologies to synthesize various aromatic sulfones,25 herein we present a novel and efficient CuIcatalyzed radical cascade cyclization to access a large variety of 3-sulfonyl indenones, by reacting various 2-alkynylbenzonitriles with different sulfonyl hydrazides in one-pot under mild reaction conditions (Scheme 1g). While submitting this manuscript, Tu et al published a Cu(OTf)2-catalyzed procedure for 3-sulfonyl indenones construction (Scheme 1f).26 They


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used a much more expensive a copper (II) salt, Cu(OTf)2 as the catalyst. In contrast, we used CuI, a much cheaper and easily available copper (I) salt, as our catalyst. In the mechanism they proposed, the role of Cu(II) salt is only to facilitate to generate sulfonyl radicals that triggered the following cyclization process. However, in our reaction pathway, we pointed out in this paper that Cu(I) salt participated and took an indispensable role for the whole radical cyclization. In particular, a DFT calculation was further carried out to Previous works: O

Ph H

(a)

NaOAc

Ph

Ph

+

Ph

DMF, 120 °C

I

O

FG1

(b) FG2

R2

R1

R1

Pd or Rh

+

R1 +

R2

R2

O

O poor regioselectivity

FG1/FG2 = CN/I; CHO/halo; CN/B(OH)2; etc. R1, R2 = aryl, alkyl.

O

FG

(c)

+

R

1

R

Rh Cat.

2

R1

H

R2

FG = CN, CHO, C(O)NH2 etc. R1, R2 = aryl, alkyl.

O

(d) R1

Ar

+ R

2

SO2H

Pt (+) | Pt (-) undivided cell constant current TBAI, LiClO4 CH3CN/H2O

ynones

Ar R

3

1

2 1

O 2-sulfonated indenones

R2 O P 3 R

Ar

(e)

R1

+ CN

O H P R2 R3

AgNO3 (2 equiv.)

R1

CH3CN, H2O, 80 °C

R3 O S O

R1 +

R2 CN

O R3 S NHNH2 O

Ar O

Just Publised Cu(OTf)2 Catalyzed Radical Cyclization:

(f)

O S R2 O

Cu(OTf)2, TBHP CH3CN/H2O 80 °C, 4 h

R1

R2 O

This work: CuI Catalyzed Radical Cyclization: R1

(g)

+

R2 CN

O R3 S NHNH2 O

R2 = H ,CH3, F, Cl, Br; R1, R3 = aryl

CuI (20 mol%) TBHP (4 equiv.) CH3CN/H2O 60 °C, 8 h

R3 O S O 3

R2

2 1

R1

O

AIE Phenomenon

Scheme 1. Comparision with previous works highlight the essential role of CuI in the radical cascade cyclization. Much more importantly, our newly synthesized 3-sulfonyl substituted indenones were found to own



typical aggregation-induced emission (AIE) properties. These compounds show orange to red emission with large stokes shift (more than 135 nm). In addition, such novel AIEgens can be successfully used in live cell imaging, which exhibited excellent biocompatibility.

Results and Discussion We initiated our study by establishing optimal experimental conditions using the model reaction of 2-(phenylethynyl)benzonitrile 1a with TsNHNH2 2a (Table 1). It is pleased that, when the reaction was performed using 10 mol% CuI and 2 equiv. of TBHP in CH3CN/H2O (v/v = 3/1), the desired product 3a was obtained in 40% yield (entry 1). However, the yields were not improved by using other copper catalysts, such as CuBr, CuCl, Cu2O, and CuSO4 (entries 2-5). Subsequently, several other commonly used catalysts were tested as shown in entries 6-11. The results showed that FeSO4 and FeCl3 did not exhibit better reactivity than CuI (entries 6 and 7), and I2, TBAI, NH4I as well as KI gave no product as well (entries 8-11). It is pleased to see that, the yield of 3a increased to 48% along with the increase of the amount of CuI from 10 mol% to 20 mol% (entry 12) and then ceased to increase as the amount of CuI continued to increase up to 30 mol% (entry 13). After that, several other oxidants, such as DTBP, BPO, and K2S2O8 were investigated, and unfortunately, no satisfied results were observed (entries 14-16). To our delight, when the amount of TBHP was increased to 4 equiv., a satisfied yield of 3a was obtained (72%, entry 18), and afterwards, a slight decrease was observed when 5 equiv. of TBHP was employed (entry 19). Furthermore, several different solvent systems were tested as shown in entries 20-25, however, no improved yields were obtained. Investigation on


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Table 1. Optimization of reaction conditions[a] Ts

Ph +

catalyst, oxidant

TsNHNH2

1a

Ph

solvent (v/v = 3/1) Temp., time

CN

3a

2a

O

Entry

Catalyst (mol%)

Oxidant

Solvent

Yield[b] %

1

CuI (10)

TBHP (2)

CH3CN/H2O

40

2

CuBr (10)

TBHP (2)

CH3CN/H2O

38

3

CuCl (10)

TBHP (2)

CH3CN/H2O

35

4

Cu2O (10)

TBHP (2)

CH3CN/H2O

27

5

CuSO4 (10)

TBHP (2)

CH3CN/H2O

29

6

FeSO4 (10)

TBHP (2)

CH3CN/H2O

23

7

FeCl3 (10)

TBHP (2)

CH3CN/H2O

29

8

I2 (10)

TBHP (2)

CH3CN/H2O

ND[c]

9

TBAI (10)

TBHP (2)

CH3CN/H2O

ND[c]

10

NH4I (10)

TBHP (2)

CH3CN/H2O

ND[c]

11

KI (10)

TBHP (2)

CH3CN/H2O

ND[c]

12

CuI (20)

TBHP (2)

CH3CN/H2O

48

13

CuI (30)

TBHP (2)

CH3CN/H2O

47

14

CuI (20)

DTBP (2)

CH3CN/H2O

ND[c]

15

CuI (20)

BPO (2)

CH3CN/H2O

35

16

CuI (20)

K2S2O8 (2)

CH3CN/H2O

40

17

CuI (20)

TBHP (3)

CH3CN/H2O

59

18

CuI (20)

TBHP (4)

CH3CN/H2O

72

19

CuI (20)

TBHP (5)

CH3CN/H2O

70

20

CuI (20)

TBHP (4)

DMSO/H2O

Trace[c]

21

CuI (20)

TBHP (4)

DMF/H2O

Trace[c]

22

CuI (20)

TBHP (4)

EtOH/H2O

Trace[c]

23

CuI (20)

TBHP (4)

THF/H2O

Trace[c]

24

CuI (20)

TBHP (4)

DCE/H2O

35

25

CuI (20)

TBHP (4)

Acetone/H2O

57

26[d]

CuI (20)

TBHP (4)

CH3CN/H2O

29

27[e]

CuI (20)

TBHP (4)

CH3CN/H2O

67

28[f]

CuI (20)

TBHP (4)

CH3CN/H2O

54

29[g]

CuI (20)

TBHP (4)

CH3CN/H2O

71

30

--

TBHP (2)

CH3CN/H2O

ND[c]

31

CuI (20)

--

CH3CN/H2O

ND[c]

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10-20 mol%), oxidant (2-5 equiv.), solvent (2 mL) at 60 °C for 8 h. TBHP = tert-butyl hydroperoxide (70% aqueous solution), TBAI = tetrabutylammonium iodide, DTBP = Di-tert-butyl peroxide, BPO = benzoyl peroxide, DCE = 1,2dichloroethane, ND = Not detected. [b] Isolated yields. [c] Detected by TLC. [d] At 40 ºC. [e] At 80 °C. [f] For 4 h. [g] For 12 h.

[a]



temperature as well as time on the reaction were also performed, and the results showed that 60 °C and 8 h were still the best choices (entries 26-29). Further tests indicated that the reaction did not occur in the absence of either CuI or TBHP (entries 30 and 31). After intensive experimentation, the optimized reaction conditions were established as follows: 1a (0.2 mmol), 2a (0.4 mmol), CuI (20 mol%) and TBHP (4 equiv.) were mixed in CH3CN/H2O (v/v = 3/1) solution at 60 ºC for 8 h. With the optimized reaction conditions established, we next explored the substrate scope by examining various 2-alkynylbenzonitriles 1 and sulfonyl hydrazides 2, and the results were illustrated in Scheme 2. As it can be seen, various 2-(phenylethynyl)benzonitriles reacted smoothly with TsNHNH2 under the optimized conditions, regioselectively giving the resulting 3-sulfonted indenones 3a-i in moderate to good yields (52-78%). Among them, 2-(phenylethynyl)benzonitriles with electron-donating groups (-Me, -Et, -OMe) attached to phenyl ring in R1 moieties, resulted in relatively high yields (3b-f, 70-78%), whereas electron-withdrawing groups (-F, -Cl, -Br) in R1 gave slightly low yields (3g-i, 5265%). It was observed that a substrate with a sterically hindered R1 group (pyrenyl group) was also suitable for this transformation, although the corresponding product 3j was obtained in relatively low yield. Furthermore, 2-(phenylethynyl)benzonitriles with different R2 groups were employed to react with TsNHNH2, yielding the desired products 3k-n in good yields (65-77%). Electronic effects were also observed in those cases. 2(phenylethynyl)benzonitriles with electron-withdrawing groups (6-Cl, 6-Br, 7-F) rendered higher yields (3l-n, 73-77%), compared to those with electron-donating groups (6-Me, 3k).


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Finally, 2-(phenylethynyl)benzonitrile 1a was employed to react with various sulfonyl hydrazides bearing different R3 groups under the optimized reaction conditions, giving the corresponding products 3o-x in moderate to good yields. R3 O S O

R1 R2

CuI (20 mol%) TBHP (4 equiv.)

O R3 S NHNH2 O

+ CN 1

3

Me R

1

R =

O

3a, 72%

3b, 76%

4 5

3

2 1

6 7

Et 3c, 73%

3e, 77%

3d, 70%

F

Cl

3g, 52%

3f, 78% Ts

Me

Me

OMe

R2

O

2

Ts 1

R1

R2

CH3CN/H2O 60 oC, 8 h

Br

3h, 58%

3i, 65%

R2 = 6-CH3

R2 = 6-Cl

R2 = 6-Br

R2 = 7-F

3k, 65%

3l, 74%

3m, 73%

3n, 77%

3j, 34%

O R3 O S O

O

Me

Me

3

R =

t

OMe 3o, 63%

3p, 65%

Cl

F

3t, 58%

3u, 63%

3r, 74%

3q, 67%

Br

3v, 68%

3s, 75%

CF3

I 3w, 70%

Bu

3x, 45%

Reaction conditions: 2-(arylethynyl)benzonitriles 1 (0.2 mmol), sulfonyl hydrazides 2 (0.4 mmol), CuI (20 mol%), TBHP (4 equiv.), CH3CN/H2O (v/v = 3/1) as solvent (2 mL), 60 oC, 8 h. Isolated yields were provided.

Scheme 2. Substrate scope for the synthesis of 3-sulfonated indenones We then carried out several control experiments to explore the reaction mechanism (Scheme 3). When TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl) and BHT (2,6di-tert-butyl-4-methylphenol), two widely used radical scavengers, were added into the reaction system, respectively, no desired product 3a was observed in each case, suggesting that the reaction might proceed via a radical process (Scheme 3a-b). It is worth reminding that when the control reaction was performed with BHT under optimized reaction condition ACS Paragon Plus Environment


Page 10 of 36

(Scheme 3b), products 9 has been successfully separated and identified, indicating that tosyl radical (Ts·) was produced in the reaction process (for details see Fig S1).27 It was reported that TBAI together with TBHP can effectively assist the generation of sulfonyl radicals from sulfonyl hydrazides.28 Thus we carried out a control experiment using TBAI together with TBHP as tosyl radical promoter (Scheme 3c). The result showed that compound 9 was also generated in the reaction process (Figure S2). Finally, an isotopic labeling experiment with H218O was conducted (Scheme 3d), affording

18O-lableled

3a

(Figure S3). That meant the carbonyl oxygen in 3a was originated from H2O instead of O2 in the air. It was experienced here that, in every control experiment (Scheme 3a-d), after catalyst CuI or the tosyl radical promoter (TBAI/TBHP) was added to the reaction solution, the formation of bubbles in the solution was always observed. Ph

Ts TEMPO (3 equiv.)

(a)

+

TsNHNH2

Ph

Standard conditions

CN

O

1a

2a

3a (0%)

Ph +

(b)

TsNHNH2

CN

Ph +

TsNHNH2

CN 1a

+

TsNHNH2

CN

OH

Ts

t

Ph O

Ts

16

O

2a

Ph

+

Ph 18

Bu

Ts 9 (Yield: 18%)

Ts

CuI (20 mol%) TBHP (4 equiv.) CH3CN/H218O 60 oC, 8 h

t

Bu

+

3a (0%)

2a

Ph

1a

CH3CN/H2O 60 oC, 8 h

Bu

Ts 9 (Yield: 22%)

3a (0%)

TBAI (20 mol%) BHT (3 equiv.) TBHP (4 equiv.)

t

Bu

+

Ph

Standard conditions

2a

(d)

t

O

1a

(c)

OH

Ts BHT (3 equiv.)

O

Yield: 70 %

Scheme 3. Control experiments The mechanism is proposed based upon our experimental outcomes and literature reports, as shown in Scheme 4. Initially, TBHP reacts with CuI to produce tert-butoxyl ACS Paragon Plus Environment

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radical (t-BuO·) and tert-butylperoxy radical (t- BuOO·).29 Then, successive H-abstraction of sulfonyl hydrazide 2 by the resultant radicals yields sulfonyldiazene radical 4, which subsequently releases molecular N2, affording sulfonyl radical 5.24b Then, a cascade cyclization is triggered by sulfonyl radical 5. Initially, sulfonyl 5 regioselectively adds to the C-C triple bond of 2-alkynylbenzonitriles 1, giving radical 6, which immediately undergoes an intramolecular cyclization, rendering the iminyl radical 7. Afterwards, the coupling of radical 7 with Cu(OH)I yields the intermediate 8, which subsequently abstracts a hydrogen atom from t-BuOOH to give imine 10. Finally, imine 10 undergoes in situ hydrolysis to yield the target products 3. Again, it can be seen from scheme 4 that iodide anion (I-) from CuI can react with t-BuOOH to generate tert-butoxyl radical (t-BuO·) which is capable of reacting with sulfonyl hydrazide 2 to give tosyl radical. However, it was observed from entry 7 of Table 1 that there was in fact no target product 3a obtained without participation of CuI, even with the presence of tosyl radical 5 generated by reacting sulfonyl hydrazide 2 with radical promoter (TBAI/TBHP), making it clear that the copper ion is indispensable for the following tosyl radical-initiated cascade cyclization reaction.



t-BuOOH

t-BuO

Cu+

Cu2+

O R S NHNH2 O 2

t-BuOOH

+ OH

t-BuO

I

t-BuOOH + OH R O S O

Ar

t-BuOO

or t-BuO t-BuOOH or t-BuOH

O R S N N O 4

N2

O R S O 5

+ OH

1/2 I2

t-BuOO +H2O

t-BuOOH + OH

t-BuOO +H2O

Page 12 of 36

Ar + CN 1

N 6

Cyclization

R O S O Ar O 3

R O S O H 2O

Ar 10

NH

R O S O TBHP

I

Ar

CuI(OH)(t-BuOO) 8

CuII

R O S O Ar

OH

N CuIII I OH

N 7

Scheme 4. Proposed mechanism In order to explore the possible reaction pathways, we have systematically studied and compared non-Cu-catalyzed pathway with Cu-catalyzed pathway by performing DFT calculations (Figure 1), which have been widely used in the mechanisms of organometallic reactions.30 As shown in Figure 1, both of two reaction pathways share the same structural transformation from 1a to intermediate 14. Firstly, the radical 11 would like to attack on the C-C triple bond of 1a to form the C–S bond via transition state TS1, and then the intramolecular cyclization leads to the radical 13 via transition state TS2. The energy barriers are 8.9 and 9.9 kcal/mol via TS1 and TS2, respectively. For the non-Cu-catalyzed pathway, the radical 13 reacts with t-BuOOH to form the intermediate 14 via transition state TS3, and the energy barrier is only 1.1 kcal/mol. Alternatively, the Cu(II) coordinates with radical 13 to form a stable intermediate 15, which could easily obtained via transition state TS3'. It should be mentioned that the energy barrier via TS3' is 1.9 kcal/mol without the zero point vibrational correction, but this process would become a barrierless process and the difference between TS3' and 15 would be negative (-3.4 kcal/mol) with zero point ACS Paragon Plus Environment

Page 13 of 36

vibrational correction. For the non-Cu-catalyzed pathway, the energy barrier of the reverse reaction is 27.2 kcal/mol, showing the process would be reversible. However, with the assistance of copper, the reverse energy barrier would be up to 54.5 kcal/mol. Therefore, the 14 only can be irreversibly generated with the presence of Cu salt, which plays an important role to promote the reaction and stabilize the radical intermediate. All the DFT calculated results are in an agreement with the experimental observations. O Ph S O TS3

Ph

TBHP 14 O Ph S 11 O

Ph O S O

Ph

Ph

TS1 1a

CN

12

Non-Cu-catalyzed pathway

Ph O S O TS2

Ph

N

13

NH

I CuII OH

N

Ph O S O

Ph O S O TS3'

Ph N CuIII I 15 OH

Ph

TBHP 14

NH

Cu-catalyzed pathway

Non-Cu-catalyzed pathway: -----Cu-catalyzed pathway: ------

TS2 15.6 TS2

TS1

8.9 TS1

TS3

5.7 12

0.0 1a

reversible

-0.4

0.7

13

TS3

-11.6 14+ t-BuOO

TS3'

irreversible

Relative Gibbs free energies (kcal/mol)

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


-26.4 15

-29.8 TS3'

S

O

C

N

-38.9

H

14+ CuI(OH)(t-BuOO)

Reaction Coordinate

Figure 1. The energy profile for different reaction pathways (energy: kcal/mol)



The new 3-sulfonyl indenones synthesized through our newly developed coppercatalyzed radical cascade cyclization strategy were serendipitously found to possess typical aggregation-induced emission (AIE) properties. As shown in Figure 2A, 3a showed very weak fluorescence in water/EtOH mixtures with water fraction (fw) lower than 80%. When fw was above 80%, intense orange fluorescence could be clearly observed. Water normally is a poor solvent for most organic molecules, which thus should promote the aggregation of 3a. The intense fluorescence of 3a in the solutions with high fw might be originated from its aggregation, i.e., AIE fluorescence. A direct evidence for the aggregation of 3a was obtained from dynamic light scattering (DLS) measurements. Particles of around 700 nm could be detected in the 99% water/EtOH solution, while no particles was observed in the pure EtOH solution (Figure 2B). Analogous results can be found in Table S2, which means that 3-sulfonyl indenone core structure is a new AIE system.

Figure 2. A) Fluorescence spectra of 50 μmol/L 3a in EtOH/water mixtures with diﬀerent water fractions (fw). Inset: Fluorescence photos of 3a in EtOH/water mixtures (fw = 0 and 99 vol%), taken under the illumination of a UV lamp. B) Fluorescence intensity of 3a at 577 nm as a function of fw. Inset: DLS result of 2 in water.


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To further understand the origination of AIE character of 3a, its crystal structure was investigated. 3a exist in a typical propeller-like stucture in crystal state (Figure 3).31 The dihedral angle between the conjugate rigid planes are 57.03o and 89.35o, respectively. This structure feature could effectively weaken the π-π stacking interaction between neighbouring molecules to avoid fluorescence quenching. As shown in Figure 3, the minimum distance between the adjacent conjugate planes was as high as 4.08 Å, suggesting that the π-π stacking interaction can be ignored.32 Meanwhile, the C-C single bond between the conjugate planes make them rotatable in dissolved state, which effective release the energy of 3a in excited state. Thus, the excited states of dissolved state often decay or relax back to the ground state via non-radiative channels, resulting in weak fluorescence.

Figure 3. X-ray crystallography of 3a The AIE character of 3-sulfonyl indenones endow them with intense fluorescence in aqueous solution, which make them suitable for the application in cell imaging. The biological application of compound 3a was then assessed in HeLa cells. Hela cells were incubated with compound 3a (10 μM) for 15 min and intense fluorescence in red channel was noted (Figure 4). The low toxic of compound 3a was also supported by CCK-8 assay. (Figure S4).



20 μM

20 μM

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20 μM

Figure 4. Fluorescence images of HeLa cells stained with 10 μmol/L 3a. From left to right are fluorescence image, bright field image, and overlay image.

Conclusion In conclusion, we report a novel and efficient radical cascade cyclization strategy, by which a wide variety of 3-sulfonated indenones were prepared in one-pot via reaction of 2alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild reaction conditions. The cascade reaction is constituted by the selective addition of sulfonyl radical to the C-C triple bond of 2-alkynylbenzonitriles, intramolecular cyclization and in situ hydrolysis. Copper catalyst is essential both for the formation of sulfonyl radicals in the radical initiation steps and for the smooth progress of the radical cascade cyclization reaction. The mechanism was further supported by DFT calculation. Great advantages of this strategy include catalytic amount of copper, experimental simplicity and efficiency, mild reaction conditions and easy work-up. More importantly, the 3-sulfonyl indenones, synthesized through our newly developed copper-catalyzed radical cascade cyclization strategy, were found to own typical aggregation-induced emission (AIE) properties, showing orange to red emission with large stokes shift (more then 135 nm). In addition, such novel AIEgens could be successfully used in live cell imaging, exhibiting excellent ACS Paragon Plus Environment

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biocompatibility and application potential. Further studies on the applications of this synthetic strategy as well as 3-sulfonated indenones as a new type of AIE fluorescent material are underway in our laboratory.

Experimental Section General Information 1H, 13C

and 19F NMR spectra were recorded with a Bruker Avance 400 or 600 MHz

spectrometer. 13C NMR spectra being recorded with broad band proton decoupled. Proton chemical shifts δ were given in ppm using tetramethyl silane as internal standard. All NMR spectra were recorded in CDCl3 at room temperature (20 ± 3 °C). High resolution mass spectra (HRMS) were taken with a 3000-mass spectrometer, using Waters Q-Tof MS/MS system using the ESI technique. For column chromatography, 200-300 mesh silica gel was used as the stationary phase. Fluorescence spectra were recorded with Hitachi F-4600 spectrophotometer. The bioimaging of Hela cells was measured on the Leica TCS SP8 confocal microscopy system in College of Public Health, Zhengzhou University. The synthesis of 2-arynylbenzonitrile ： A mixture of 2-bromobenzonitrile or 2iodobenzonitrile (1.0 equiv., 10 mmol), alkynes (1.2 equiv., 12.0 mmol), Pd(PPh3)2Cl2 (0.02 equiv., 0.2 mmol) and CuI (0.01 equiv., 0.1 mmol) in Et3N (40 mL) was stirred at 60 ºC under N2 atmosphere for 2 h. After completion of the reaction as indicated by TLC, the reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and brine (1 × 10 mL), and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure



and purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to afford the desired product.

The synthesis of aryl sulfonyl hydrazides：The hydrazine hydrate (40% in water) (23 mmol) was added into the solution of aryl sulfonyl chloride (10 mmol) in THF (50 mL) at 0 ºC. Subsequently, the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation, and the residue was extracted with dichloromethane. The organic layer was washed with water, and brine, and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the residue was purified on silica gel flash chromatography to give products. Typical procedure of the CuI-catalyzed radical cascade cyclization: To a 25 mL reaction tube, 2-(phenylethynyl) benzonitrile (0.2 mmol), sulfonyl hydrazide (0.4 mmol), CuI (20 mol%), CH3CN (1.5 mL), H2O (0.5 mL) and TBHP (0.8 mmol) were added. The mixture was stirred at 60 ºC for 8 h. After cooling, the solvent was evaporated under vacuum, and the residue was quenched with water (5 mL), extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1) to give the desired product. 2-phenyl-3-tosyl-1H-inden-1-one (3a) 51 mg, 72%; Yellow solid, mp 136-138 °C; 1H NMR (400 MHz, CDCl3, δ) 7.98 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.3,


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151.3, 145.2, 141.22, 139.9, 136.8, 135.0, 130.4, 129.6, 129.5, 128.8, 127.9, 127.8, 127.6, 124.4, 123.9, 21.6; HRMS Calcd for C22H17O3S [M + H]+: m/z 361.0898, Found: 361.0896. 2-(p-tolyl)-3-tosyl-1H-inden-1-one (3b) 56 mg, 76%; Red solid, mp 133-135 °C; 1H NMR (400 MHz, CDCl3, δ) 7.93 (d, J = 7.6 Hz, 1H), 7.65-7.52 (m, 3H), 7.50-7.46 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.20-7.18 (m, 4H), 7.15 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.5, 150.5, 145.2, 141.3, 140.2, 139.8, 137.0, 135.0, 130.5, 129.6, 129.3, 128.8, 128.4, 127.8, 124.9, 124.3, 123.7, 21.6, 21.5; HRMS Calcd for C23H19O3S [M + H]+: m/z 375.1055, Found: 375.1052 2-(m-tolyl)-3-tosyl-1H-inden-1-one (3c) 54 mg, 73%; Yellow solid, mp 140-143 °C; 1H NMR (400 MHz, CDCl3, δ) 7.97 (d, J = 7.6 Hz, 1H), 7.61-7.52 (m, 3H) , 7.49 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.26-7.15 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.2Hz, 2H), 6.97 (s, 1H), 2.33 (s, 3H), 2.32 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3, δ) 194.4, 151.2, 145.2, 141.2, 140.0, 137.1,

136.8, 135.0, 130.8, 130.2, 129.56, 129.51, 128.8, 127.9, 127.8, 127.6, 127.4, 124.4, 123.9, 21.6, 21.3; HRMS Calcd for C23H19O3S [M + H]+: m/z 375.1055, Found: 375.1056 2-(o-tolyl)-3-tosyl-1H-inden-1-one (3d) 52 mg, 70%; Yellow solid. mp 137-140 °C; 1H NMR (400 MHz, CDCl3, δ) 8.04 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.52-7.55 (m, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.32-7.35 (m, 1H), 7.29-7.25 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.12-7.08 (m, 3H), 7.02-7.00 (m, 1H), 2.36 (s, 3H), 1.87 (s, 3H) ; 13C{1H} NMR (100 MHz, CDCl3, δ)193.9, 152.8, 145.3, 141.1, ACS Paragon Plus Environment


141.0, 136.8, 136.4, 134.9, 130.1, 129.7, 129.6, 129.5, 129.3, 129.0, 128.1, 125.2, 124.5, 123.9, 21.6, 20.2; HRMS Calcd for C23H19O3S [M + H]+: m/z 375.1055, Found: 375.1055 2-(4-ethylphenyl)-3-tosyl-1H-inden-1-one (3e) 60 mg, 77%; Red solid, mp 144-146 °C; 1H NMR (400 MHz, CDCl3, δ) 7.95 (d, J = 7.6 Hz, 1H), 7.56-7.54 (m, 3H), 7.49 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21-7.11 (m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.5, 150.6, 146.1, 145.1, 141.3, 140.0, 136.9, 135.0, 130.6, 129.5, 129.3, 128.8, 127.9, 127.2, 125.0, 124.3, 123.8, 28.8, 21.6, 15.4; HRMS Calcd for C24H21O3S [M + H]+: m/z 389.1211, Found: 389.1208 2-(4-methoxyphenyl)-3-tosyl-1H-inden-1-one (3f) 61 mg, 78%; Red solid, mp 131-132 °C; 1H NMR (400 MHz, CDCl3, δ) 7.93 (d, J = 7.6 Hz, 1H), 7.58-7.54 (m, 3H), 7.50-7.46 (m, 1H), 7.32-7.26 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.7, 161.0, 149.5, 145.1, 141.5, 139.8, 137.1, 135.0, 132.5, 129.6, 129.2, 128.7, 127.7, 124.3, 123.6, 119.9, 113.2, 55.3, 21.6; HRMS Calcd for C23H19O4S [M + H]+: m/z 391.1004, Found:391.1001 2-(4-fluorophenyl)-3-tosyl-1H-inden-1-one (3g) 39 mg, 52%; Red soild, mp 127-129 °C; 1H NMR (400 MHz, CDCl3, δ) 7.96 (d, J = 7.6 Hz, 1H), 7.57-7.54 (m, 3H), 7.50 (t, J = 7.6 Hz, 1H), 7.33-7.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.08-7.03 (m, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.1, 163.5 (d, 1JC-F = 249.2 Hz), 151.3, 145.5, 141.0, 138.8, 136.8, 135.1, 132.7 (d, 3JC-F = 8.4 Hz), 129.7, 129.6, ACS Paragon Plus Environment

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128.7, 127.8, 124.5, 123.9, 123.7 (d, 4JC-F = 3.5 Hz), 114.9 (d, 2JC-F= 22.0 Hz) , 21.6; 19F NMR (376 MHz, CDCl3, δ) -110.4; HRMS Calcd for C22H16FO3S [M + H]+: m/z 379.0804, Found: 379.0801

2-(4-chlorophenyl)-3-tosyl-1H-inden-1-one (3h) 45 mg, 58%, Red solid, mp 130-131 °C; 1H NMR (400 MHz, CDCl3, δ) 7.95 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 3H), 7.52-7.49 (m, 1H), 7.35-7.30 (m, 3H), 7.23-7.17 (m, 4H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.9, 151.6, 145.6, 140.9, 138.5, 136.7, 135.9, 135.1, 131.9, 129.8, 129.7, 128.7, 127.9, 126.2, 124.5, 124.0, 21.6; HRMS Calcd for C22H16ClO3S [M + H]+: m/z 395.0509, Found: 395.0507

2-(4-bromophenyl)-3-tosyl-1H-inden-1-one (3i) 57 mg, 65%; Red solid. mp 132-133 °C; 1H NMR (400 MHz, CDCl3, δ) 7.95 (d, J = 7.2 Hz, 1H), 7.58-7.55 (m, 3H), 7.55-7.48 (m, 3H), 7.35-7.31 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.16-7.12 (m, 2H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.8, 151.6, 145.6, 140.9, 138.5, 136.6, 135.1, 132.1, 130.9, 129.8, 129.7, 128.7, 127.9, 126.7, 124.5, 124.3, 124.0, 21.7; HRMS Calcd for C22H16BrO3S [M + H]+: m/z 439.0004, Found:439.0000 2-(pyren-1-yl)-3-tosyl-1H-inden-1-one (3j) 33 mg, 34%; Brown solid. mp 183-184 °C; 1H NMR (400 MHz, CDCl3, δ) 8.22 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.2 Hz, 2H), 8.12-8.07 (m, 2H), 8.05-8.00 (m, 2H), 7.89 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.63-7.59 (m, 1H), 7.47-7.40 (m, 2H), 7.16 (d, J = 8.4Hz, 2H), 6.31(d, J = 8.4Hz, 2H), 1.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.4, 154.8, 144.7, 141.1, 138.8, 135.1, 131.9, 131.0, 130.7, 129.8, 129.5, ACS Paragon Plus Environment


129.0, 128.5, 128.2, 128.0, 127.8, 127.7, 127.1, 126.1, 125.7, 125.5, 124.8, 124.6, 124.28, 124.2, 124.1, 124.0, 123.1, 20.6; HRMS Calcd for C32H21O3S [M + H]+: m/z 485.1211, Found: 485.1205 6-methyl-2-phenyl-3-tosyl-1H-inden-1-one (3k) 48 mg, 65%; Yellow solid. mp 165-167 °C; 1H NMR (400 MHz, CDCl3, δ) 7.83 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41-7.33 (m, 4H), 7.29-7.23 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.6, 153.1, 151.5, 145.1, 140.0, 139.3, 138.4, 136.9, 135.0, 130.4, 129.6, 129.3, 129.1, 128.0, 127.8, 127.6, 125.4, 123.7, 21.6, 21.2; HRMS Calcd for C23H19O3S [M + H]+: m/z 375.1055, Found: 375.1054 6-chloro-2-phenyl-3-tosyl-1H-inden-1-one (3l) 58 mg, 74%; Yellow solid. mp 158-160 °C; 1H NMR (400 MHz, CDCl3, δ) 7.93 (d, J = 8.0 Hz, 1H), 7.51-7.45 (m, 4H), 7.43-7.33 (m, 3H), 7.25-7.23 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.1, 151.2, 145.5, 139.8, 139.2, 136.5, 135.9, 134.2, 130.47, 130.40, 129.74, 129.70, 127.9, 127.7, 127. 4, 124.9, 124.8, 21.6; HRMS Calcd for C22H16ClO3S [M + H]+: m/z 395.0509, Found: 395.0504 6-bromo-2-phenyl-3-tosyl-1H-inden-1-one (3m) 67 mg, 73%; Yellow solid. mp 163-165 °C; 1H NMR (400 MHz, CDCl3, δ) 7.87 (d, J = 7.6 Hz, 1H), 7.66-7.63 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.41-7.33 (m, 3H), 7.25-7.23 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.1, 151.3, 145.5, 139.8, 139.6, 137.3, 136.6, 130.4, 129.75, 129.70, 127.8, 127.7, 127.6, 127. ACS Paragon Plus Environment

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4, 125.2, 123.7, 21.6; HRMS Calcd for C22H15BrO3SNa [M + Na]+: m/z 460.9823, Found: 460.9819 7-fluoro-2-phenyl-3-tosyl-1H-inden-1-one (3n) 58 mg, 77%; Yellow solid. mp 156-158 °C; 1H NMR (400 MHz, CDCl3, δ) 7.83 (d, J = 7.6 Hz, 1H), 7.53-7.47 (m, 3H), 7.39 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 8.4 Hz, 2H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 190.1 (d, 3JC-F = 1.4 Hz), 158.4 (d, 1JC-F = 265.2 Hz), 150.5 (d, 4JC-F = 4.3 Hz), 145.4, 142.7 (d, 3JC-F = 3.3 Hz), 140.7, 137.6 (d, 3JC-F = 8.6 Hz), 136.6, 130.5, 129.74, 129.71, 127.8, 127.6, 127.4, 120.3 (d, 4JC-F = 2.3 Hz), 118.8 (d, 2JC-F = 20.9 Hz), 114.4 (d, 2JC-F = 13.1 Hz), 21.6; 19F NMR (376 MHz, CDCl3, δ) -110.3; HRMS Calcd for C22H16FO3S [M + H]+: m/z 379.0804, Found: 379.0804 2-phenyl-3-(phenylsulfonyl)-1H-inden-1-one (3o) 44 mg, 63%; Yellow solid. mp 130-132 °C; 1H NMR (400 MHz, CDCl3, δ) 8.00 (d, J = 7.6 Hz, 1H), 7.65 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.54-7.48 (m, 2H), 7.40-7.31 (m, 6H), 7.26-7.23 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.1, 151.0, 141.1, 140.3, 139.8, 135.1, 134.0, 130.4, 129.65, 129.60, 128.9, 128.7, 127.79, 127.75, 127.70, 124.5, 123.9; HRMS Calcd for C21H15O3S [M + H]+: m/z 347.0742, Found:347.0740 2-phenyl-3-(m-tolylsulfonyl)-1H-inden-1-one (3p) 47 mg, Yellow solid. mp 133-135 °C; 1H NMR (400 MHz, CDCl3, δ) 8.01 (d, J = 6.8 Hz,



1H), 7.56-7.46 (m, 3H), 7.36-7.22 (m, 9H), 2.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 194.2, 151.4, 141.2, 140.1, 139.5, 139.2, 135.1, 134.8, 130.4, 129.5, 128.8, 128.7, 128.3, 127.8, 127.6, 124.9, 124.4, 124.0, 21.1; HRMS Calcd for C22H17O3S [M + H]+: m/z 361.0898, Found: 361.0855 2-phenyl-3-(o-tolylsulfonyl)-1H-inden-1-one (3q) 48 mg, 67%; Yellow solid. mp 132-134 °C; 1H NMR (400 MHz, CDCl3, δ) 7.91 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.50-7.46 (m, 1H), 7.34-7.24 (m, 3H), 7.22-7.15 (m, 4H), 7.06 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H) ; 13C{1H} NMR (100 MHz, CDCl3, δ) 194.2, 150.7, 141.3, 139.0, 138.0, 137.3, 135.1, 133.8, 132.2, 130.2, 129.6, 129.5, 128.5, 127.5, 127.3, 125.9, 124.4, 124.1, 20.1; HRMS Calcd for C22H17O3S [M + H]+: m/z 361.0898, Found: 361.0897 3-((4-methoxyphenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3r) 56 mg, 74%; Yellow solid. mp 136-138 °C; 1H NMR (400 MHz, CDCl3, δ) 7.99 (d, J = 7.6 Hz, 1H), 7.58-7.55 (m, 3H), 7.51 (t, J = 7.6 Hz, 1H), 7.42-7.30 (m, 4H), 7.25-7.23 (m, 2H), 6.79-6.77 (m, 2H), 3.79 (s, 3H) ; 13C{1H} NMR (100 MHz, CDCl3, δ) 194.3, 164.0, 151.7, 141.2, 139.5, 135.0, 131.2, 130.4, 130.2, 129.5, 129.4, 128.8, 127.9, 127.6, 124.3, 123.9, 114.2, 55.6; HRMS Calcd for C22H17O4S [M + H]+: m/z 377.0848, Found: 377.0844 3-((4-(tert-butyl)phenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3s) 60 mg, 75%; Red solid. mp 165-168 °C; 1H NMR (400 MHz, CDCl3, δ) 8.01 (d, J = 7.6 Hz, 1H), 7.66-7.58 (m, 3H), 7.54-7.49 (m, 1H), 7.37-7.29 (m, 6H), 7.23-7.20 (m, 2H), 1.26


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(s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3, δ) 194.3, 158.0, 151.4, 141.2, 139.7, 136.5, 135.0, 130.4, 129.5, 129.4, 128.79, 127.88, 127.83, 127.6, 125.9, 124.4, 124.0, 35.2, 30.9; HRMS Calcd for C25H23O3S [M + H]+: m/z 403.1368, Found: 403.1366 3-((4-fluorophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3t) 42 mg, 58%; Yellow solid. mp 135-137 °C; 1H NMR (400 MHz, CDCl3, δ) 8.01 (d, J = 7.6 Hz, 1H), 7.65-7.59 (m, 3H), 7.55-7.51 (m, 1H), 7.43-7.33 (m, 4H), 7.23-7.21 (m, 2H), 7.006.95 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.9, 165.8 (d, 1JC-F = 256.2 Hz), 151.1, 141.0, 140.1, 135.7 (d, 4JC-F = 2.9 Hz), 135.1, 130.8 (d, 3JC-F = 9.6 Hz), 130.4, 129.74, 129.72, 128.6, 127.79, 127.70, 124.6, 123.9, 116.2 (d, 2JC-F = 22.7 Hz); 19F NMR (376 MHz, CDCl3, δ) -102.2; HRMS Calcd for C21H14FO3S [M + H]+: m/z 365.0648, Found: 365.0646 3-((4-chlorophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3u) 48 mg, 63%; Yellow solid. mp 136-139 °C; 1H NMR (400 MHz, CDCl3, δ) 7.99 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.40 (m, 1H), 7.37-7.32 (m, 3H), 7.29-7.25 (m, 2H), 7.23-7.21 (m, 2H) ; 13C{1H} NMR (100 MHz, CDCl3, δ) 193.9, 150.8, 140.9, 140.8, 140.3, 138.1, 135.2, 130.4, 129.79, 129.76, 129.27, 129.24, 128.65, 127.8, 127.6, 124.6, 123.9; HRMS Calcd for C21H14ClO3S [M + H]+: m/z 381.0352, Found: 381.0350 3-((4-bromophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3v) 57 mg, 68%; Yellow solid. mp 140-141 °C; 1H NMR (400 MHz, CDCl3, δ) 7.98 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.48-7.40 (m, 5H), 7.37-7.32 (m,



3H), 7.22-7.20 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.9, 150.8, 140.9, 140.3, 138.6, 135.2, 132.2, 130.4, 129.79, 129.77, 129.5, 129.2, 128.6, 127.8, 127.6, 124.6, 123.9; HRMS Calcd for C21H14BrO3S [M + H]+: m/z 424.9847, Found: 424.9845 3-((4-iodophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3w) 66 mg, 70%; Red solid. mp 143-145 °C; 1H NMR (400 MHz, CDCl3, δ) 7.98 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.45-7.41 (m, 1H), 7.38-7.30 (m, 5H), 7.22-7.20 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3, δ) 193.9, 150.8, 140.9, 140.3, 139.3, 138.2, 135.2, 130.4, 129.7, 129.0, 128.6, 127.8, 127.6, 124.6, 123.9, 102.3; HRMS Calcd for C21H14IO3S [M + H]+: m/z 472.9708, Found: 472.9705 2-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-inden-1-one (3x) 37 mg, 43%; Yellow solid. mp 162-166 °C; 1H NMR (400 MHz, CDCl3, δ) 8.02 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.56-7.52 (m, 3H), 7.42-7.30 (m, 4H), 7.19 (d, J = 7.2 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3, δ) 193.6, 150.5, 143.1, 140.9, 140.7, 135.4 (q, 2JC-F = 33.1 Hz ), 135.2, 130.4, 129.88, 129.86, 128.6, 128.4, 127.8, 127.5, 125.9 (q, 3JC-F = 3.7 Hz), 124.8, 124.0, 122.9 (q, 1JC-F = 273.3 Hz) ; 19F NMR (376 MHz, CDCl3, δ) -63.3; HRMS Calcd for C22H14F3O3S [M + H]+: m/z 415.0616, Found: 415.0599 2,6-di-tert-butyl-4-(tosylmethyl)phenol (9) White solid, mp 131-133 °C; 1H NMR (400 MHz, CDCl3, δ) 7.46 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.8 (s, 2 H), 5.3 (s, 1 H), 4.2 (s, 2 H), 2.4 (s, 3 H), 1.3 (s,18 H). 13C{1H} NMR (101 MHz, CDCl3, δ) 154.2, 144.3, 135.9, 134.8, 129.3, 128.9, 127.6, 118.9, 63.2, ACS Paragon Plus Environment

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34.1, 30.0, 21.5.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxx 1H, 13C, 19F

NMR spectra and HRMS date for all products, The density functional theory

(DFT) data, primary mechanistic studies of the reactions (PDF) X-ray data for 3a (CIF) Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We acknowledge financial support from National Natural Science Foundation of China (Nos. 21501010, 21708035), the 2017 Science and Technology Innovation Team in Henan Province (No. 22120001), Major scientific and technological projects in Henan Province (No. 181100310500), China Postdoctoral Science Foundation (No. 2017M620302), and the Key Laboratory for Chemical Biology of Fujian Province (Xiamen University) (No. 2017002)

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Copper-Catalyzed Radical Cascade Cyclization To Access 3

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