Cooperative Catalysis-Enabled Asymmetric Î±-Arylation of Aldehydes

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Cooperative Catalysis-Enabled Asymmetric #-Arylation of Aldehydes Using 2-Indolylmethanols as Arylation Reagents Meng-Meng Xu, Hai-Qing Wang, Yu-Jia Mao, Guang-Jian Mei, Shu-Liang Wang, and Feng Shi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00228 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

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The Journal of Organic Chemistry

Cooperative Catalysis-Enabled Asymmetric α-Arylation of Aldehydes Using 2-Indolylmethanols as Arylation Reagents Meng-Meng Xu, Hai-Qing Wang, Yu-Jia Mao, Guang-Jian Mei, Shu-Liang Wang and Feng Shi*

School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China E-mail: [email protected]

Abstract: A catalytic aymmetric α-arylation of aldehydes using 2-indolylmethanols as arylation reagents has been established. This reaction was enabled by a cooperative catalytic system consisting of a gold complex, a Brønsted acid and a chiral amine, which have a synergistic effect in the reaction process. By using this strategy, a series of α-arylation products of aldehydes were generated in overall acceptable yields and good enantioselectivities (up to 69%, 91:9 er). The control experiments demonstrated that the addition of PPh3AuCl as a gold complex was helpful to improve the yield, and trifluoroacetic acid as a Brønsted acid played a crucial role in the reaction by promoting the generation of carbocation and chiral enamine intermediates, which are two key intermediates of the aymmetric α-arylation reaction. In addition, the enantioselectivity of the reaction was mainly controlled by the chiral amine catalyst via forming a chiral enamine intermediate. This reaction has not only provided a useful protocol for catalytic aymmetric α-arylation of aldehydes, but also enriched the research contents of 2-indolymethanol-involved reactions and asymmetric cooperative catalysis.

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Introduction

Catalytic asymmetric α-functionalization of aldehydes is a powerful method for generating a new carbon-carbon bond and constructing a chiral center.1-3 So, rapid developments have been achieved in this research area (Scheme 1). However, most of the transformations are focused on the catalytic asymmetric α-alkylation2 and α-allylation3 of aldehydes (eq. 1), and this class of reactions have been well-established.2-3 In sharp contrast, catalytic asymmetric α-arylation of aldehydes is underdeveloped (eq. 2), which has scarcely been reported in the literature.4 Nevertheless, this transformation will create a chiral benzylic center with the simultaneous formation of a new C-C bond, which is very useful in the synthesis of natural products and pharmaceuticals.5-6

Scheme 1. Profile of catalytic asymmetric α-functionalization of aldehydes

Survey of the literature only revealed very limited examples of catalytic asymmetric α-arylation of aldehydes (Scheme 2).4 For instance, the MacMillan group established a chiral amine-copper co-catalyzed asymmetric α-arylation of aldehydes by using diaryliodonium salts as arylation reagents (eq. 3).4a In addition, the MacMillan group4b and the Nicolaou group4c have independently devised an intramolecular Friedel-Crafts type enantioselective α-arylation of aldehydes in the presence of a chiral amine catalyst and an oxidant (eq. 4). In spite of previous


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elegant approaches, the catalytic asymmetric α-arylations of aldehydes are rather limited. This is because there are some challenges imbedded in such transformation. The first one is to find suitable electrophilic arylation reagents; the second one is to control the enantioselectivity of the arylation process; the last but not the least is to avoid the racemization of the enolizable α-carbonyl benzylic stereogenic centers. So, it has become an urgent task to develop new strategies and arylation reagents for catalytic asymmetric α-arylations of aldehydes.

Scheme 2. Limited examples and challenges of catalytic asymmetric α-arylation of aldehydes

In order to fulfill this task, we consider to employ 2-indolymethanols7-9 as arylation reagents because we have discovered that the C3-position of 2-indolymethanols exhibits an unusual electrophilicity10 in the presence of a Brønsted acid,11 which can be attacked by nucleophiles (Nu) to perform indole-Nu couplings. On the other hand, cooperative catalysis has proven to be a robust method for controlling the enantioselectivity of the reactions and for establishing new transformations, which can hardly occur in mono-catalytic system.12-13 So, based on the unique property of 2-indolymethanols and the advantages of cooperative catalysis, we design a cooperative catalysis-enabled asymmetric α-arylation of aldehydes using 2-indolylmethanols as arylation reagents (Scheme 3). In this design, chiral amine14-15 and Brønsted acid (BH) will be



used as a cooperative catalytic system to catalyze the reaction. In the presence of BH, 2-indolylmethanols would transform into a delocalized carbocation I via dehydration. Simultaneously, under the co-catalysis of chiral amine and BH, aldehydes would transform into a chiral enamine intermediate II. Then, the enamine intermediate II would perform an enantioselective nucleophilic attack on the delocalized carbocation I, thus generating a transient intermediate III, which could rapidly isomerize into the final α-arylation product via hydrolysis. In the reaction process, BH would play multiple roles such as promoting the formation of intermediates I and II, activating intermediate I via the formation of ion-pairing and hydrogen-bonding interactions. In addition, the generated α-arylation products belong to a class of chiral indole derivatives, which might find their application in pharmaceuticals because chiral indole framework constitutes the core structures of many natural alkaloids and bioactive compounds.16

Scheme 3. Design of the catalytic asymmetric α-arylation of aldehydes using 2-indolylmethanols as arylation reagents

Results and Discussion


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Based on this design, initially, the reaction of 2-indolymethanol 1a with n-butyl aldehyde 2a was employed as a model reaction to testify our hypothesis in the presence of chiral secondary amines 4 and Brønsted acids (Table 1). However, screening of commonly used Brønsted acids (entries 1–5) revealed that only trifluoroacetic acid (TFA) could co-catalyze the designed α-arylation reaction in the presence of chiral amine 4a (entry 5), which afforded α-arylation product 3aa in 37% yield and 81:19 er. In spite of the low yield and moderate enantioselectivity, this preliminary result demonstrated that our design on the catalytic asymmetric α-arylation of aldehydes was feasible. Then, we screened a series of chiral secondary amines 4 and found that catalyst 4h could deliver the reaction in the highest enantioselectivity of 85:15 er and with an improved yield of 45%. In our previous investigations on 2-indolymethanol-involved reaction, we found the addition of some transition metals such as palladium complexes could stabilize the delocalized cation generated from 2-indolymethanols, which was beneficial for the yield and the enantioselectivity.10d So, in order to further improve the yield and the enantioselectivity of the α-arylation reaction of aldehydes, we added some transition metals to the reaction system (entries 13–18) and found that the addition of a gold complex (PPh3AuCl) could greatly improve the yield to 80% with a retained enantioselectivity of 85:15 er (entry 18). In addition, several other gold complexes were evaluated (entries 19–21), which found that none of them was better than PPh3AuCl in terms of the yield (entries 19–21 vs entry 18). Thus, the multiple cooperative catalytic system of chiral amine 4h, Brønsted acid TFA and gold complex PPh3AuCl (entry 18) was set as the most suitable catalytic system for further condition optimization. Table 1. Screening of catalysts for asymmetric α-arylation of aldehydesa



a

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entry

4

BH

metal

yield (%)b

erc

1

4a

AcOH

-

trace

-

2

4a

TsOH

-

trace

-

3

4a

CF3SO3H

-

trace

-

4

4a

PhCOOH

-

trace

-

5

4a

TFA

-

37

81:19

6

4b

TFA

-

48

78:22

7

4c

TFA

-

18

64:36

8

4d

TFA

-

30

71:29

9

4e

TFA

-

44

79:21

10

4f

TFA

-

25

79:21

11

4g

TFA

-

34

75:25

12

4h

TFA

-

45

85:15

13

4h

TFA

Pd(dba)2

39

85:15

14

4h

TFA

Pd(PPh3)4

31

78:22

15

4h

TFA

[IrcodCl]2

33

76:24

16

4h

TFA

PPh3RhCl

45

77:23

17

4h

TFA

PPh3RuCl

37

72:28

18

4h

TFA

PPh3AuCl

80

85:15

19

4h

TFA

Ph3PAuBr

63

85:15

20

4h

TFA

IPrAuCl

70

84:16

21

4h

TFA

Ph3PAuNTf2

66

85:15

Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale and catalyzed by 20 mol% 4, 20

mol% BH, and 5 mol% metal in MeCN (1 mL) at 50 oC for 7 h, and the molar ratio of 1a:2a was 1:4. bIsolated yield. cThe er value was determined by HPLC.

Subsequently, a series of representative solvents were screened (Table 2, entries 1–6), which disclosed that acetonitrile was still better than other solvents with regard to the enantioselective control (entry 1 vs entries 2–6). Next, some additives were added to the reaction system in order to


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improve the enantioselectivity. However, the addition of molecular sieves (MS) could not benefit the reaction (entries 7–9). In the literature, the addition of some amount of hexafluoroisopropanol (HFIP) was helpful to the α-allylation of aldehydes.3g So, we added a small amount of HFIP to the reaction system, which could enhance the enantioselectivity of the reaction to 89:11 er although the yield was decreased to some extent (entry 10). Then, we investigated the effect of temperature on the reaction (entries 10–13), which found that lowering the reaction temperature was detrimental to the yield (entries 11–12 vs entry 10), while elevating the reaction temperature would sharply decrease the enantioselectivity (entry 13 vs 10). Thus, 50 oC was still selected as the optimal reaction temperature (entry 10). The subsequent modulation of reagents ratio (entries 14–16) revealed that suitably decreasing the amount of aldehyde 2a could enhance the yield of product 3aa to 75% with a maintained enantioselectivity of 89:11 er (entry 14 vs 10). Finally, suitably diluting the reaction concentration could further improve the enantioselectivity to a good level of 91:9 er although the yield was decreased to a moderate level of 60% (entry 17). Nevertheless, this condition was chosen as the relatively optimal reaction condition in terms of the enantioselective control. Table 2. Further optimization of reaction conditionsa

entry

yield (%)b

erc

50

80

85:15

50

trace

-

50

70

63:37

50

72

84:16

1:4

50

trace

-

1:4

50

83

56:44

solvent

additive

1a:2a

1

MeCN

-

1:4

2

EtOAc

-

1:4

3

CHCl3

-

1:4

4

acetone

-

1:4

5

1,4-dioxane

-

6

toluene

-

T (℃)



7

MeCN

3 Å MS

1:4

50

trace

-

8

MeCN

4 Å MS

1:4

50

trace

-

9

MeCN

5 Å MS

1:4

50

71

81:19

10

MeCN

HFIP

1:4

50

60

89:11

11

MeCN

HFIP

1:4

0

trace

-

12

MeCN

HFIP

1:4

30

55

89:11

13

MeCN

HFIP

1:4

70

72

76:24

14

MeCN

HFIP

1:2

50

75

89:11

15

MeCN

HFIP

2:1

50

67

86:14

16

MeCN

HFIP

1:1

50

62

86:14

d

MeCN

HFIP

1:2

50

60

91:9

17 a

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Unless otherwise indicated, the reaction was carried out at the 0.1 mmol scale and catalyzed by 20 mol% 4h, 20

mol% TFA, and 5 mol% PPh3AuCl in a solvent (1 mL) at T oC for 7 h, and the amount of additives was 100 mg (for MS) or 0.1 mL (for HFIP). bIsolated yield. cThe er value was determined by HPLC. dUsing 2 mL MeCN and 0.2 mL HFIP.

After establishing the optimal reaction conditions, we performed the study on the substrate scope of this catalytic asymmetric α-arylation of aldehydes using 2-indolymethanols as arylation reagents. As shown in Table 3, in overall, this α-arylation reaction could be applicable to a variety of 2-indolymethanols 1 and aldehydes 2 in acceptable yields and moderate to good enantioselectivities. In detail, this reaction was amenable to a series of aldehydes 2 bearing different R2 substituents (H, Me, Et, n-Bu, Ph), which afforded chiral α-arylation products 3 in generally good enantioselectivities (entries 1–5). In addition, a wide range of 2-indolymethanols 1 bearing various R1/Ar groups could be utilized as arylation reagents to react with aldehydes 2a-2b, offering chiral α-arylation products 3 with structural diversity (entries 6–15). Obviously, either electron-donating or electron-withdrawing substituents at C5 or C6-position of the indole ring could serve as suitable R1 groups of 2-indolymethanols 1 (entries 6–9 and 11–13). Besides, the Ar group of 2-indolymethanols 1 could be altered (entries 10 and 14–15). Table 3. Substrate scope of catalytic asymmetric α-arylation of aldehydesa


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entry

3

R1/Ar (1)

R2 (2)

yield (%)b

erc

1

3aa

H/Ph (1a)

Me (2a)

60

91:9

2

3ab

H/Ph (1a)

H (2b)

63

86:14

d

3ac

H/Ph (1a)

Et (2c)

43

84:16

d

3ad

H/Ph (1a)

n-Bu (2d)

40

85:15

d

5

3ae

H/Ph (1a)

Ph (2e)

40

88:12

6

3ba

5-Br/Ph (1b)

Me (2a)

43

86:14

d

3ca

5-Cl/Ph (1c)

Me (2a)

57

86:14

d

3da

5-MeO (1d)

Me (2a)

48

89:11

d

3

4

7

8 9

3ea

6-Br/Ph (1e)

Me (2a)

44

86:14

d

10

3fa

H/p-ClC6H4 (1f)

Me (2a)

48

82:18

11

3db

5-MeO/Ph (1d)

H (2b)

53

78:22

d

12

3eb

6-Br/Ph (1e)

H (2b)

62

82:18

13

3gb

6-MeO/Ph (1g)

H (2b)

69

86:14

d

3hb

H/m-MeOC6H4 (1h)

H (2b)

64

80:20

d

3ib

H/p-MeOC6H4 (1i)

H (2b)

58

85:15

14

15 a

Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in MeCN (2mL) and HFIP (0.2 mL) at

50 oC for 7 h, and the molar ratio of 1:2 was 1:2. bIsolated yield. cThe er value was determined by HPLC. dUsing 1 mL MeCN and 0.1 mL HFIP.

The structures of all products 3 were unambiguously assigned by 1H and 13C NMR, IR, and HR MS. Furthermore, the structure of product 3aa was confirmed by X-ray single crystal analysis (see the Supporting Information for details).17 In order to gain some insights into the role of PPh3AuCl and TFA, we performed some control experiments (Table 4). First, we carried out the reaction of 1a with 2a under the two optimal reaction conditions in the presence of PPh3AuCl (entries 1 and 3) or in the absence of PPh3AuCl (entries 2 and 4). In two cases, the addition of Au (I) to the reaction system could greatly improve the yield with a slightly enhanced enantioselectivity (entry 1 vs 2; entry 3 vs 4). This result indicated that the addition of PPh3AuCl was helpful to control the reactivity, but it was



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not a decisive factor to accomplish the reaction. Second, we performed the same reaction in the absence of TFA (entry 5). However, in this case, no reaction (N.R.) occurred, which demonstrated that TFA played a crucial role in controlling the reactivity. Table 4. Control experiments to investigate the role of Au (I) and TFAa

a

entry

Ph3PAuCl

TFA

MeCN (mL)

HFIP (mL)

yield (%)b

erc

1

5 mmol%

20 mmol%

2

0.2

60

91:9

2

-

20 mmol%

2

0.2

40

89:11

3

5 mmol%

20 mmol%

1

0.1

75

89:11

4

-

20 mmol%

1

0.1

46

86:14

5

5 mmol%

-

2

0.2

N.R.

o

Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in MeCN and HFIP at 50 C for 7 h,

and the molar ratio of 1a:2a was 1:2. bIsolated yield. cThe er value was determined by HPLC.

Furthermore, to demonstrate the role of the N-H group in the indole moiety, N-methyl protected 2-indolylmethanol 1j was employed as a substrate under the standard reaction conditions (Scheme 4). In this case, no reaction occurred, which implied that the N-H group of 2-indolylmethanols played an important role in controlling the reactivity by forming a hydrogen bond with the TFA anion.

Scheme 4. Control experiment to demonstrate the role of N-H group


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Based on the control experiments, we suggested a possible reaction pathway and activation mode of the catalyst to the substrates (Scheme 5). Initially, 2-indolylmethanols 1 were possibly activated by Au (I) via the interaction between the carbon-carbon double bond of the indole ring and the gold complex, which promoted the formation of the delocalized carbocation I via dehydration with the aid of TFA. In this process, Au (I) and TFA imposed a cooperative catalysis on the formation of the intermediate I. At the same time, aldehydes 2 transformed into the chiral enamine intermediate II in the presence of chiral amine catalyst 4h and TFA. Then, a nucleophilic attack of the enamine intermediate II to the delocalized carbocation I occurred in an enantioselective mode due to the cooperative action of chiral enamine catalysis and Brønsted acid catalysis. In detail, the TFA anion generated a hydrogen-bonding and ion-pairing interaction with the carbocation intermediate I, which facilitated the enantioselective attack of the chiral enamine intermediate II to give rise a transient intermediate III. Subsequently, this intermediate III rapidly isomerized into intermediate IV due to the force of rearomatization of the indole ring. Finally, intermediate IV transformed into the final α-arylation products 3 via hydrolysis. So, in the whole process, the multiple catalytic system of chiral amine 4h, TFA and Au (I) realized a cooperative catalysis on the asymmetric α-arylation of aldehydes. In addition, the presence of Au (I) has a beneficial effect on forming the delocalized carbocation I, which resulted in the increased yields (Table 4, entries 1 and 3). But the addition of Au (I) was not a necessity for performing the reaction. On the contrary, the addition of Brønsted acid (TFA) was a necessity for carrying out the reaction because the key intermediates I and II could not be generated in the absence of a Brønsted acid. This is the reason why no reaction occurred in the absence of TFA in the control experiment (Table 4, entry 5).



Scheme 5. Proposed reaction pathway and activation mode

Finally, to show the utility of this catalytic asymmetric α-arylation of aldehydes, a one mmol scale reaction of 2-indolymethanol 1a with aldehyde 2a was performed under the standard reaction conditions (Scheme 6, eq. 5). Compared to the small-scale reaction (Table 3, entry 1), this reaction afforded product 3aa in a moderate yield of 55% and a nearly retained enantioselectivity of 89:11er, which indicated that this asymmetric α-arylation reaction could be scaled up. In addition, a preliminary derivation was carried out by the reduction of the aldehyde group of compound 3aa into an alcohol functionality, which generated compound 5 in a high yield of 80% and with a nearly maintained enantioselectivity (eq. 6).

Scheme 6. One mmol scale synthesis and preliminary derivation


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In summary, we have established a catalytic aymmetric α-arylation of aldehydes using 2-indolylmethanols as arylation reagents. This reaction was enabled by a cooperative catalytic system consisting of a gold complex, a Brønsted acid and a chiral amine, which have a synergistic effect in the reaction process. By using this strategy, a series of α-arylation products of aldehydes were generated in generally acceptable yields and good enantioselectivities (up to 69%, 91:9 er). The control experiments demonstrated that the addition of PPh3AuCl as a gold complex was helpful to improve the yield, and trifluoroacetic acid as a Brønsted acid played a crucial role in the reaction by promoting the generation of carbocation and chiral enamine intermediates, which are two key intermediates of the aymmetric α-arylation reaction. In addition, the enantioselectivity of the reaction was mainly controlled by the chiral amine catalyst via forming a chiral enamine intermediate. This reaction has not only provided a useful protocol for catalytic aymmetric α-arylation of aldehydes, but also enriched the research contents of 2-indolymethanol-involved reactions and asymmetric cooperative catalysis.

Experimental Section

1

H and

13

C NMR spectra were measured respectively at 400 and 100 MHz, respectively. The

solvent used for NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by a HRMS/MS instrument. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for the determination of enantiomeric ratios by chiral HPLC were Chiralpak AD-H and OD-H columns. Optical rotation values were measured with instruments operating at λ = 589 nm, corresponding to the sodium D line at the temperatures indicated. The X-ray source used for the single crystal X-ray diffraction analysis of compound 3aa was CuKα (λ = 1.54178), and the



Page 14 of 27

thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were distilled before use. All starting materials commercially available were used directly,and 2-indolylmethanol 1 was prepared according to the literature method.18

General procedure for the synthesis of products 3 Under argon atmosphere, to the mixture of 2-indolylmethanol 1 (0.1 mmol) and Ph3PAuCl (0.005 mmol) in a dried Shrek tube, was added the solution of chiral amine catalyst 4h (0.02 mmol) in acetonitrile (1 mL). Then, aldehyde 2 (0.2 mmol) was added to the reaction mixture. Subsequently, acetonitrile (1 mL), HFIP (0.2 mL) and TFA (0.02 mmol) were sequentially added to the reaction mixture, which was stirred at 50 oC for 7 hours. After stopping the reaction, the reaction mixture was purified through preparative thin layer chromatography to afford pure products 3.

2-(2-benzhydryl-1H-indol-3-yl)butanal

(3aa):

Flash

column

chromatography

eluent,

petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 60% (21.2 mg); white solid; m.p. 111-112 oC; [α]D20 = -31.2 (c 0.49, acetone); 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.73 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.39 – 7.26 (m, 7H), 7.20 – 7.12 (m, 5H), 7.11 – 7.05 (m, 1H), 5.80 (s, 1H), 3.61 (dd, J = 9.0, 5.8 Hz, 1H), 2.26 – 2.11 (m, 1H), 1.94 – 1.75 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 141.8, 141.5, 138.2, 135.4, 129.0, 128.9, 128.8, 127.7, 127.2, 127.1, 121.9, 119.9, 119.1, 111.1, 106.6, 52.2, 48.4, 21.1, 12.1; IR (KBr): 3325, 2529, 1652, 1017, 538 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H22NO 352.1706, Found 352.1686; Enantiomeric ratio: 91:9, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 80/ 20, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 4.187 min (major), tR = 5.050 (minor).


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2-(2-benzhydryl-1H-indol-3-yl)propanal (3ab): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 63% (21.4 mg); white solid; m.p. 108-109 oC; [α]D20 = -25.6 (c 0.51, acetone); 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 7.77 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.38 – 7.27 (m, 7H), 7.21 – 7.15 (m, 5H), 7.14 – 7.08 (m, 1H), 5.82 (s, 1H), 3.80 (q, J = 7.0 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 141.7, 141.5, 137.4, 135.4, 129.0, 128.9, 127.5, 127.2, 121.9, 120.0, 118.9, 111.1, 108.3, 48.5, 44.5, 13.4; IR (KBr): 3389, 2930, 1721, 1450, 744, 699 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C24H20NO 338.1550, Found 338.1541; Enantiomeric ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 3.977 min (major), tR = 4.530 (minor). 2-(2-benzhydryl-1H-indol-3-yl)pentanal (3ac): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 43% (15.8 mg); yellow solid; m.p. 112-113 oC; [α]D20 = -33.6 (c 0.35, acetone); 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.72 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.36 – 7.26 (m, 8H), 7.18 – 7.12 (m, 5H), 7.11 – 7.06 (m, 1H), 5.78 (s, 1H), 3.70 (dd, J = 9.0, 5.7 Hz, 1H), 2.17 – 2.03 (m, 1H), 1.84 – 1.72 (m, 1H), 1.25 – 1.09 (m, 4H), 0.78 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 141.5, 138.0, 135.4, 129.0, 128.9, 128.8, 127.8, 127.2, 127.1, 121.8, 119.9, 119.1, 111.0, 106.8, 50.2, 48.5, 30.0, 20.7, 13.9; IR (KBr): 3395, 3024, 1710, 1450, 748, 700 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C26H24NO 366.1863, Found 366.1846; Enantiomeric ratio: 84:16, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 3.620 min (major), tR = 4.067 (minor).



2-(2-benzhydryl-1H-indol-3-yl)heptanal (3ad): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 40% (15.9 mg); yellow solid; m.p. 121-122 oC; [α]D20 = -39.9 (c 0.36, acetone); 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.74 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41 – 7.26 (m, 7H), 7.21 – 7.12 (m, 5H), 7.09 (t, J = 7.5 Hz, 1H), 5.80 (s, 1H), 3.70 (dd, J = 9.1, 5.6 Hz, 1H), 2.19 – 2.05 (m, 1H), 1.88 – 1.74 (m, 1H), 1.22 – 1.03 (m, 6H), 0.79 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.7, 141.8, 141.5, 138.1, 135.4, 129.0, 128.9, 128.8, 127.7, 127.2, 127.1, 121.8, 119.9, 119.2, 111.1, 106.8, 50.5, 48.4, 31.7, 27.9, 27.2, 22.4, 14.0; IR (KBr): 3395, 2925, 1711, 1448, 744, 700 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C28H28NO 394.2176, Found 394.2158; Enantiomeric ratio: 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 3.520 min (major), tR = 3.960 (minor). 2-(2-benzhydryl-1H-indol-3-yl)-3-phenylpropanal (3ae): Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; Reaction time = 7 h; yield: 40% (16.6 mg); yellow solid; m.p. 131-132 oC; [α]D20 = -25.9 (c 0.41, acetone); 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.29 – 7.26 (m, 3H), 7.26 – 7.24 (m, 3H), 7.22 – 7.17 (m, 4H), 7.16 – 7.13 (m, 1H), 7.12 – 7.10 (m, 1H), 7.07 – 7.03 (m, 2H), 6.93 – 6.89 (m, 2H), 6.77 – 6.73 (m, 2H), 5.18 (s, 1H), 3.84 (dd, J = 9.7, 4.9 Hz, 1H), 3.51 (dd, J = 13.5, 4.9 Hz, 1H), 3.04 (dd, J = 13.5, 9.7 Hz, 1H);

13

C NMR (100 MHz, CDCl3) δ 200.0, 141.9, 141.1, 140.2, 138.7,

135.3, 129.2, 129.0, 128.8, 128.7, 128.6, 128.2, 127.4, 127.1, 127.0, 126.0, 121.8, 120.1, 118.9, 111.2, 105.5, 53.1, 48.2, 34.0; IR (KBr): 3389, 3919, 1712, 1493, 1451, 1278, 744, 699 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H24NO 414.1863, Found 414.1850; Enantiomeric


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ratio: 88:12, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 3.847 min (major), tR = 6.117 (minor). 2-(2-benzhydryl-5-bromo-1H-indol-3-yl)butanal (3ba): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 43% (18.6 mg); red solid; m.p. 101-102 oC; [α]D20 = -22.3 (c 0.35, acetone); 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.35 – 7.28 (m, 7H), 7.24 – 7.21 (m, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.14 – 7.10 (m, 3H), 5.77 (s, 1H), 3.61 – 3.52 (m, 1H), 2.22 – 2.09 (m, 1H), 1.86 – 1.75 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.2, 141.5, 141.2, 139.5, 134.0, 129.4, 129.0, 128.9, 128.7, 127.4, 127.3, 124.8, 121.6, 113.3, 112.5, 106.4, 52.0, 48.5, 21.2, 12.1; IR (KBr): 3402, 2920, 1712, 1462, 1277, 796, 699 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H21BrNO 430.0812, Found 430.0818; Enantiomeric ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 6.087 min (major), tR = 7.373 (minor). 2-(2-benzhydryl-5-chloro-1H-indol-3-yl)butanal (3ca): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 57% (22.1 mg); yellow solid; m.p. 108-109 oC; [α]D20 = -29.1 (c 0.44, acetone); 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.78 (s, 1H), 7.44 (s, 1H), 7.36 – 7.28 (m, 6H), 7.18 – 7.08 (m, 6H), 5.77 (s, 1H), 3.56 (dd, J = 8.9, 5.9 Hz, 1H), 2.21 – 2.08 (m, 1H), 1.87 – 1.74 (m, 1H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.2, 141.5, 141.2, 139.7, 133.7, 129.0, 128.9, 128.8, 128.7, 127.4, 127.3, 125.7, 122.2, 118.6, 112.1, 106.4, 52.0, 48.5, 21.1, 12.1; IR (KBr): 3351, 2917, 1713, 1451, 1294, 798, 700 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H21ClNO 386.1317, Found 386.1308; Enantiomeric



ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 5.910 min (major), tR = 7.073 (minor). 2-(2-benzhydryl-5-methoxy-1H-indol-3-yl)butanal (3da): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 48% (18.4 mg); white solid; m.p. 99-100 oC; [α]D20 = -20.9 (c 0.38, acetone); 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.62 (s, 1H), 7.37 – 7.27 (m, 6H), 7.19 – 7.12 (m, 5H), 6.90 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.7, 2.4 Hz, 1H), 5.77 (s, 1H), 3.82 (s, 3H), 3.58 (dd, J = 9.0, 5.8 Hz, 1H), 2.25 – 2.07 (m, 1H), 1.90 – 1.76 (m, 1H), 0.82 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.6, 154.2, 141.9, 141.5, 139.0, 130.5, 129.0, 128.9, 128.9, 128.8, 128.1, 127.2, 127.1, 111.9, 111.8, 106.1, 101.0, 55.9, 52.2, 48.5, 20.9, 12.1; IR (KBr): 3351, 2931, 1713, 1484, 1217, 1030, 700 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C26H24NO2 382.1812, Found 382.1810; Enantiomeric ratio: 89:11, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 6.120 min (major), tR = 7.913 (minor). 2-(2-benzhydryl-6-bromo-1H-indol-3-yl)butanal (3ea): Flash column chromatography eluent, petroleum ether/dichloromethane = 4/1; Reaction time = 7 h; yield: 44% (19.0 mg); yellow solid; m.p. 111-112 oC; [α]D20 = -19.6 (c 0.28, acetone); 1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 0.9 Hz, 1H), 7.74 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.37 – 7.27 (m, 7H), 7.20 – 7.09 (m, 5H), 5.77 (s, 1H), 3.58 (dd, J = 8.9, 5.9 Hz, 1H), 2.21 – 2.07 (m, 1H), 1.86 – 1.72 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.3, 141.5, 141.2, 138.9, 136.2, 129.0, 128.9, 128.7, 127.3, 127.2, 126.6, 123.2, 120.4, 115.4, 114.1, 106.8, 52.0, 48.4, 21.1, 12.0; IR (KBr): 3430, 2819, 1721, 1454, 810, 699 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H21BrNO 430.0812, Found 430.0815; Enantiomeric ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/


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isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 6.027 min (major), tR = 7.710 (minor). 2-(2-(bis(4-chlorophenyl)methyl)-1H-indol-3-yl)butanal

(3fa):

Flash

column

chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 48% (20.2 mg); yellow solid; m.p. 121-122 oC; [α]D20 = -19.6 (c 0.28, acetone); 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.65 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.34 – 7.28 (m, 5H), 7.21 – 7.15 (m, 1H), 7.13 – 7.03 (m, 5H), 5.73 (s, 1H), 3.59 (dd, J = 9.0, 5.9 Hz, 1H), 2.25 – 2.09 (m, 1H), 1.90 – 1.74 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.2, 139.9, 139.6, 136.8, 135.6, 133.4, 133.3, 130.2, 130.0, 129.2, 129.1, 127.6, 122.3, 120.2, 119.2, 111.2, 107.1, 52.2, 47.1, 21.3, 12.2; IR (KBr): 2963, 1714, 1500, 1090, 1014, 827, 745 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H20Cl2NO 420.0927, Found 420.0911; Enantiomeric ratio: 82:18, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 5.670 min (major), tR = 6.640 (minor). 2-(2-benzhydryl-5-methoxy-1H-indol-3-yl)propanal (3db): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 53% (19.6 mg); white solid; m.p. 95-96 oC; [α]D20 = -15.3 (c 0.31, acetone); 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.62 (s, 1H), 7.36 – 7.28 (m, 6H), 7.19 – 7.13 (m, 5H), 6.87 (d, J = 2.4 Hz, 1H), 6.81 (m, 1H), 5.78 (s, 1H), 3.82 (s, 3H), 3.75 (q, J = 7.0 Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.2, 154.2, 141.7, 141.5, 138.2, 130.4, 128.9, 128.8, 127.9, 127.2, 111.9, 111.8, 107.9, 100.8, 55.9, 48.6, 44.4, 13.1; IR (KBr): 3375, 2931, 1708, 1488, 1217, 1030, 700 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H22NO2 368.1656, Found 368.1638; Enantiomeric ratio:



78:22, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 6.980 min (major), tR = 8.063 (minor). 2-(2-benzhydryl-6-bromo-1H-indol-3-yl)propanal (3eb): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 62% (25.9 mg); yellow solid; m.p. 101-102 oC; [α]D20 = -15.9 (c 0.32, acetone); 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.69 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.37 – 7.27 (m, 7H), 7.20 – 7.11 (m, 5H), 5.77 (s, 1H), 3.75 (q, J = 7.0 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.9, 141.4, 141.1, 138.0, 136.1, 129.0, 128.9, 128.8, 127.3, 126.3, 123.3, 120.1, 115.4, 114.1, 108.6, 48.5, 44.3, 13.4; IR (KBr): 3061, 2809, 1721, 1446, 1202, 810, 697 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C24H19BrNO 416.0655, Found 416.0652; Enantiomeric ratio: 82:18, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 3.960 min (major), tR = 4.597 (minor). 2-(2-benzhydryl-6-methoxy-1H-indol-3-yl)propanal (3gb): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 69% (25.5 mg); yellow solid; m.p. 108-109 oC; [α]D20 = -20.1 (c 0.48, acetone); 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 7.61 (s, 1H), 7.37 – 7.27 (m, 7H), 7.19 – 7.14 (m, 4H), 6.79 – 6.74 (m, 2H), 5.76 (s, 1H), 3.80 (s, 3H), 3.75 (q, J = 7.0 Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.3, 156.3, 141.9, 141.7, 136.2, 136.0, 128.9, 128.8, 127.1, 121.7, 119.6, 109.8, 108.2, 94.8, 55.7, 48.5, 44.5, 13.5; IR (KBr): 3368, 2928, 1720, 1626, 1455, 1039, 807, 699 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C25H22NO2 368.1656, Found 368.1648; Enantiomeric ratio: 86:14, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 4.523 min (major), tR = 5.323 (minor).


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2-(2-(bis(3-methoxyphenyl)methyl)-1H-indol-3-yl)propanal

(3hb):

Flash

column

chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 64% (25.5 mg); white solid; m.p. 103-104 oC; [α]D20 = -28.3 (c 0.44, acetone); 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.75 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.25 – 7.21 (m, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.81 (m, 2H), 6.77 – 6.68 (m, 4H), 5.72 (s, 1H), 3.82 – 3.70 (m, 8H), 1.40 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 159.9, 143.2, 142.9, 137.0, 135.3, 129.9, 129.8, 127.5, 121.8, 121.2, 121.2, 119.9, 118.9, 115.1, 112.1, 112.0, 111.1, 108.3, 55.2, 48.5, 44.4, 13.4; IR (KBr): 3360, 2935, 1715, 1597, 1487, 1257, 746, 698 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C26H24NO3 398.1761, Found 398.1758; Enantiomeric ratio: 80:20, determined by HPLC (Daicel Chiralpak OD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 4.847 min (minor), tR = 5.360 (major). 2-(2-(bis(4-methoxyphenyl)methyl)-1H-indol-3-yl)propanal

(3ib):

Flash

column

chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 7 h; yield: 58% (23.2 mg); white solid; m.p. 103-104 oC; [α]D20 = -26.8 (c 0.32, acetone); 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 7.83 – 7.76 (m, 1H), 7.70 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 5.5 Hz, 1H), 7.18 – 7.12 (m, 1H), 7.08 – 7.04 (m, 4H), 6.86 (m, 4H), 5.70 (s, 1H), 3.83 – 3.72 (m, 8H), 1.39 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 158.5, 138.1, 135.2, 134.1, 133.8, 132.2, 129.9, 129.8, 127.6, 121.7, 119.9, 118.8, 114.1, 113.4, 111.1, 107.9, 55.3, 46.9, 44.4, 13.4; IR (KBr): 3354, 2931, 1721, 1508, 1249, 1031, 830, 744 cm-1; HRMS (ESI-TOF) m/z: [M - H]Calcd for C26H24NO3 398.1761, Found 398.1762; Enantiomeric ratio: 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70/ 30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR =5.700 min (major), tR = 9.753 (minor).



Procedure for the synthesis of product 5 To the solution of 3aa (0.1 mmol) in MeOH (1 mL) was added NaBH4 (0.6 mmol). Then, the reaction mixture was stirred at 25 oC for 1 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography to afford pure product 5. 2-(2-benzhydryl-1H-indol-3-yl)butan-1-ol (5): Flash column chromatography eluent, petroleum ether/dichloromethane = 5/1; Reaction time = 2 h; yield: 80% (28.4 mg); white solid; m.p. 118-119 oC; [α]D20 = -31.8 (c 0.66, acetone); 1H NMR (400 MHz, CDCl3) ) δ 7.67 (s, 1H), 7.65 (s, 1H), 7.35 – 7.27 (m, 6H), 7.26 – 7.23 (m, 1H), 7.19 – 7.11 (m, 5H), 7.10 – 7.03 (m, 1H), 5.87 (s, 1H), 3.91 (dd, J = 10.5, 9.0 Hz, 1H), 3.82 (dd, J = 10.5, 5.8 Hz, 1H), 3.11 – 2.96 (m, 1H), 1.95 – 1.73 (m, 2H), 0.71 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.3, 142.1, 138.0, 135.9, 128.9, 128.8, 128.6, 127.1, 127.0, 126.9, 121.4, 120.0, 119.3, 111.4, 111.1, 66.1, 48.1, 42.5, 23.8, 12.5; IR (KBr): 3307, 2956, 1493, 1449, 1029, 746, 698 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C25H24NO 354.1863, Found 354.1839; Enantiomeric ratio: 88:12, determined by HPLC (Daicel Chiralpak OD-H, hexane/ isopropanol = 90/ 10, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 5.860 min (major), tR = 6.787 (minor).

Acknowledgements

We are grateful for financial support from National Natural Science Foundation of China (21772069), Natural Science Foundation of Jiangsu Province (BK20160003), and Six Kinds of Talents Project of Jiangsu Province (SWYY-025).

Supporting Information


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Characterization data (including 1H and 13C NMR spectra) of products 3 and 5, HPLC spectra of products 3 and 5, single crystal data of product 3aa. This material is available free of charge via the Internet at http://pubs.acs.org.

References and Footnotes

(1) For some reviews: (a) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748. (b) Vesely, J.; Rios, R. ChemCatChem 2012, 4, 942. (2) For some examples on enantioselective α-alkylation of aldehydes: (a) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc. 1997, 119, 4080. (b) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem. Int. Ed. 2009, 48, 1313. (c) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 9286. (d) Stiller, J.; Marques-Lopez, E.; Herrera, R. P.; Frohlich, R.; Strohmann, C.; Christmann, M. Org. Lett. 2011, 13, 70. (e) Gómez-Bengoa, E.; Landa, A.; Lizarraga, A.; Mielgo, A.; Oiarbide, M.; Palomo, C. Chem. Sci. 2011, 2, 353; (f) Jiménez, J.; Landa, A.; Lizarraga, A.; Maestro, M.; Mielgo, A.; Oiarbide, M.; Velilla, I.; Palomo, C. J. Org. Chem., 2012, 77, 747 (g) Capdevila, M. G.; Emer, E.; Benfatti, F.; Gualandi, A.; Wilson, C. M.; Cozzi, P. G. Asian J. Org. Chem. 2012, 1, 38. (h) Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassani, C.; Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 6120. For a recent review: (i) Hodgson, D. M.; Charlton, A. Tetrahedron 2014, 70, 2207. (3) For some examples on enantioselective α-allylation of aldehydes: (a) Capdevila, M. G.; Benfatti, F.; Zoli, L.; Stenta, M.; Cozzi, P. G. Chem. - Eur. J. 2010, 16, 11237. (b) Usui, I.; Schmidt, S.; Breit, B. Org. Lett. 2009, 11, 1453. (c) Jiang, G.; List, B. Angew. Chem. Int. Ed. 2011, 50, 9471. (d) Yoshida, M.; Terumine, T.; Masaki, E.; Hara, S. J. Org. Chem. 2013, 78, 10853. (e) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065.



(f) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem. Int. Ed. 2014, 53, 6776. (g) Mo, X.; Hall, D. G. J. Am. Chem. Soc. 2016, 138, 10762. (h) Wright, T. B.; Evans, P. A. J. Am. Chem. Soc., 2016, 138, 15303. (4) For limited examples on enantioselective α-arylation of aldehydes: (a) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260. (b) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11640. (c) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Brase, S. J. Am. Chem. Soc. 2009, 131, 2086. (d) Volla, C. M. R.; Fava, E.; Atodiresei, I.; Rueping, M. Chem Comm. 2015, 51, 15788. (e) Aleman, J.; Cabrera, S.; Maerten, E.; Overgaard, J.; Jøergensen, K. A. Angew. Chem. Int. Ed. 2007, 46, 5520. (f) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk K. N.; MacMillan, D. W. C. J. Am. Chem. Soc., 2010, 132, 6001. (g) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X. Angew. Chem. Int. Ed. 2012, 51, 1059. (5) For some reviews on catalytic asymmetric α-arylation of carbonyl compounds: (a) Burtoloso, A. C. B. Synlett, 2009, 320. (b) Mazet, C. Synlett, 2012, 23, 1999. (6) For some examples on catalytic asymmetric α-arylation of carbonyl compounds: (a) Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918. (b) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050. (c) Bogle, K. M.; Hirst, D. J.; Dixon, D. J. Org. Lett. 2007, 9, 4901. (d) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195. (e) Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302. (f) Huang, Z.; Liu, Z.; Zhou, J. R. J. Am. Chem. Soc. 2011, 133, 15882. (7) For related reviews: (a) Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol. Chem. 2010, 8, 1259. (b) Chen, L.; Yin, X.-P.; Wang, C.-H.; Zhou, J. Org. Biomol. Chem. 2014, 12, 6033. (c)


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Wang, L.; Chen, Y.-Y.; Xiao, J. Asian J. Org. Chem. 2014, 3, 1036. (d) Zhu, S.; Xu, B.; Wang, L.; Xiao, J. Chin. J. Org. Chem. 2016, 36, 1229. (e) Mei, G.-J.; Shi, F. J. Org. Chem. 2017, 82, 7695. (8) For some recent examples on 3-indolylmethanol-involved reactions: (a) Song, J.; Guo, C.; Adele, A.; Yin, H.; Gong, L.-Z. Chem. - Eur. J. 2013, 19, 3319. (b) Xu, B.; Shi, L.-L.; Zhang, Y.-Z.; Wu, Z.-J.; Fu, L.-N.; Luo, C.-Q.; Zhang, L.-X.; Peng, Y.-G.; Guo, Q.-X. Chem. Sci. 2014, 5, 1988. (c) Guo, Z.-L.; Xue, J.-H.; Fu, L.-N.; Zhang, S.-E.; Guo, Q.-X. Org. Lett. 2014, 16, 6472. (d) Wen, H.; Wang, L.; Xu, L.; Hao, Z.; Shao, C.-L.; Wang, C.-Y.; Xiao, J. Adv. Synth. Catal. 2015, 357, 4023. (e) Xiao, J.; Wen, H.; Wang, L.; Xu, L.; Hao, Z.; Shao, C.-L.; Wang, C.-Y. Green Chem. 2016, 18, 1032. (9) For some recent examples on 2-indolylmethanol-involved reactions: (a) Yin, Q.; Wang, S.-G.; You, S.-L. Org. Lett. 2013, 15, 2688. (b) Qi, S.; Liu, C.-Y.; Ding, J.-Y.; Han, F.-S. Chem. Commun. 2014, 50, 8605. (c) Zhang, H.-H.; Wang, Y.-M.; Xie, Y.-W.; Zhu, Z.-Q.; Shi, F.; Tu, S.-J. J. Org. Chem. 2014, 79, 7141. (d) Zhong, X.; Li, Y.; Zhang, J.; Zhang, W.-X.; Wang, S.-X.; Han, F.-S. Chem. Commun. 2014, 50, 11181. (e) Bera, K.; Schneider, C. Chem. - Eur. J. 2016, 22, 7074. (f) Bera, K.; Schneider, C. Org. Lett. 2016, 18, 5660. (10) (a) Sun, X.-X.; Zhang, H.-H.; Li, G.-H.; He, Y.-Y.; Shi, F. Chem. - Eur. J. 2016, 22, 17526. (b) Zhu, Z.-Q.; Shen, Y.; Sun, X.-X.; Tao, J.-Y.; Liu, J.-X.; Shi, F. Adv. Synth. Catal. 2016, 358, 3797. (c) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Angew. Chem. Int. Ed. 2017, 56, 116. (d) Zhu, Z.-Q. Shen, Y.; Liu, J.-X.; Tao, J.-Y.; Shi, F. Org. Lett. 2017, 19, 1542. (11) For some reviews: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008, 35, 4097. (c) Terada, M. Synthesis 2010, 1929. (d) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156. (e) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.



2014, 114, 9047. (f) Wu, H.; He, Y.-P.; Shi, F. Synthesis, 2015, 47, 1990. (g) Akiyama, Takahiko; Mori, K. Chem. Rev. 2015, 115, 9277. (12) For some reviews: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999. (c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (d) Xing, D.; Hu, W. Tetrahedron Lett. 2014, 55, 777. (e) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (f) Yang, Z.-P.; Zhang, W.; You, S.-L. J. Org. Chem. 2014, 79, 7785. For a book chapter: (g) Long, C.; Liu, Y.-L.; Zhou, J. in: multicatalyst system in asymmetric catalysis, Ed.: Zhou, J., John Wiley & Sons, Inc., Hoboken, New Jersey, 2015; Vol. 4, p 291. (13) For some recent examples on cooperative asymmetric catalysis: (a) Jiang, G.-X.; List, B. Angew. Chem., Int. Ed. 2011, 50, 9471. (b) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren, B.-Y.; Lv, F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am. Chem. Soc. 2011, 133, 8428. (c) Qiu, H.; Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle, M. P.; Hu, W.-H. Nat. Chem. 2012, 4, 733. (d) Han, Z.-Y.; Chen, D.-F.; Wang, Y.-Y.; Guo, R.; Wang, P.-S.; Wang, C.; Gong, L.-Z. J. Am. Chem. Soc. 2012, 134, 6532. (e) Wang, P.-S.; Lin, H.-C.; Zhai, Y.-J.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem. Int. Ed. 2014, 53, 12218. (f) Tao, Z.-L.; Li, X.-H.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137, 4054. (g) Tao, Z.-L.; Adele, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem. Int. Ed. 2016, 55, 4322. (14) For some reviews on chiral aminocatalysis: (a) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res. 2012, 45, 1491. (b) Donslund, B. S.; Johansen, T. K.; Poulsen, P. H.; Halskov, K. S;. Jøgensen, K. A. Angew. Chem. Int. Ed. 2015, 54, 13860. (c) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986.


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(15) For some recent examples on chiral amine-catalyzed asymmetric reactions of aldehydes: (a) Filippini, G.; Silvi, M.; Melchiorre, P. Angew. Chem. Int. Ed. 2017, 56, 4447. (b) Silvi, M.; Verrier, C.; Rey, Y. P.; Buzzetti, L.; Melchiorre, P. Nat. Chem. 2017, 9, 868. (c) Xiao, B.-X.; Yan, R.-J.; Gao, X.-Y.; Du, W.; Chen, Y.-C. Org. Lett. 2017, 19, 4652. (d) Ran, G.-Y.; Gong, M.; Yue, J.-F.; Yang, X.-X.; Zhou, S.-L.; Du, W.; Chen, Y.-C. Org. Lett. 2017, 19, 1874. (e) Næsborg, L.; Tur, F.; Meazza, M.; Blom, J.; Halskov, K. S.; Jørgensen, K. A. Chem. - Eur. J. 2017, 23, 268. (f) Leth, L. A.; Glaus, F.; Meazza, M.; Fu, L.; Thøgersen, M. K; Bitsch, E. A.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2016, 55, 15272. (16) (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, 1996. (b) Rahman, A. Indole Alkaloids; Harwood Academic: Amsterdam, 1988. (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (d) Ryan, K. S.; Drennan, C. L. Chem. Biol. 2009, 16, 351. (e) Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 17, 1630. (17) CCDC 1819210 for 3aa, see the Supporting Information for details. (18) He, Y.-Y.; Sun, X.-X.; Li, G.-H.; Mei, G.-J.; Shi, F. J. Org. Chem. 2017, 82, 2462.


Cooperative Catalysis-Enabled Asymmetric Î±-Arylation of Aldehydes

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