NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles

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NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles Yongjia Shi, Qian Gao, and Senmiao Xu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02308 • Publication Date (Web): 25 Oct 2018 Downloaded from http://pubs.acs.org on October 26, 2018

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The Journal of Organic Chemistry

NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles Yongjia Shi,† Qian Gao,† and Senmiao Xu*,†,‡ †State

Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis,

Suzhou Research Institute , Lanzhou Institute of Chemical Physics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lanzhou 73000, China. ‡Key

Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal

University, Hangzhou 311121, P. R. China Supporting Information Placeholder

O

O

R'' L, CuCl, NaOtBu

R

[

N CO2R'

PhMe2Si-Bpin MeOH, rt

R''

L:

SiMe2Ph

R

N CO2R'

16 examples 85-92% ee

iPr N

N

PF6iPr HO

]

ABSTRACT: We report an asymmetric dearomative silylation reaction of 3-acylindoles using a chiral NHC-copper(I) complex as catalyst to afford a range of cyclic -aminosilanes with high regio- and enantioselectivity. Initial mechanistic studies revealed that the observed high diastereoselectivity was attributed to the facile epimerization of the 3-acyl group. We also demonstrated that the product could be used as a versatile precursor for the synthesis of functionalized indolines in high enantiomeric purity.

Organosilane compounds are of importance in synthetic chemistry because carbon-silicon bonds can further participate in a variety of chemical derivatizations.1 In addition, they also find applications in medicinal chemistry.2 Among these,

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chiral -aminosilanes have received considerable attention because they have shown significant bioactivities and served as the key constituents of peptidomimetics.2,3 Although many advances have been made in the synthesis of racemic chiral -aminosilanes,4,5 only a few methods have been documented on their asymmetric synthesis. Early examples rely on diastereoselective synthesis such as the reverse aza-Brook rearrangement6 and addition of silyllithium reagents to chiral aldimines3,7, which usually suffered from harsh reaction conditions. On the other hand, elegant copper-catalyzed asymmetric transformations provide mild and convenient routes to access these structures with wide functional group compatibility. Examples include silyl addition to the aldimines,8 addition of Grignard reagents to aromatic silyl ketimines,9 hydroamination and aminoboration of vinyl silanes.10 Despite these advances, new catalytic methods are still needed to access versatile and highly functionalized chiral -aminosilanes.6 Catalytic dearomative silylation of N-heteroarenes has recently gained growing interest because it offers a straightforward method to synthesizing a diverse range of azacyclic compounds.11 The first example of this field was the reduction of pyridine by heterogeneous catalysis in 1960s, which produced a series of N-silylated di- and tetrahydropyridines.12 A number of homogeneous systems have been developed to control chemo- and regioselectivity of the dearomative silylation in the last two decades.11e,13,14 These reactions usually occurred with the formation of the stable Si-N bonds and the valuable silyl groups were sacrificed in most cases through the hydrolysis of the Si-N bonds. Only a few examples have focused on silylative reduction pertaining to the more useful C-Si bond forming reactions.13j,13k,14a,14b Furthermore, the enantioselective dearomative silylation remains elusive. In view of the increasing interest in chiral organosilanes, it is appealing to develop catalytic asymmetric dearomative silylation starting from readily available N-heteroarenes. In this communication, we disclose the first example of regio- and stereoselective dearomative silylation of 3-acylindoles with Sugimone’s silylation reagent PhMe2Si-Bpin15 by way of the silylcopper species.8,16 A range of cyclic chiral -aminosilanes are obtained with high regio- and enantioselectivity. Recently, we developed a QuinoxP*/copper(I)-catalyzed asymmetric dearomative borylation of 3-substituted indoles. As a continuous effort in this area, we embarked on developing asymmetric dearomative silylation of 3-substituted indoles.17 However, the use of phosphine ligand was not successful probably due to the competitive decomposition of the silylation reagent PhMe2Si-Bpin.16q We envisioned this issue would probably be circumvented by applying ligands having more -donating ability capable of facilitating silylation reaction. Another issue that caused low efficiency was substrate itself. A relatively strong electron-withdrawing group is necessary to make the reaction happen in a


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reasonable extent. To this end, we chose N-heterocyclic carbenes (NHCs) as ligands and 3-acetylindole 1a as the pilot substrate. Our intial studies using (S,S)-1,2-diphenylethylenediamine ((S,S)-DPEN) derived NHCs resulted in silylated product in poor yields with low enantioselectivities. We then turned our attention to N-aryl-N‘-alkoxy-NHC.18 Preliminary results showed that the reaction of 1a with PhMe2Si-Bpin in the presence of (S)-valinol derived ligand L1 (10 mol %), CuCl (10 mol %), NaOtBu (20 mol %), and MeOH (2.0 equiv) in THF at room temperature for 24 hours afforded trans-2-silylindoline 2a as the single diastereomer in 82% isolated yield albeit with moderate ee value (55%). Tuning the 2,6-substituents of the phenyl ring of L had significant influence on chiral induction. For exmaple, L3 bearing the 2,6-diisopropylphenyl group enhanced ee to 73% (Table 1, entry 3) while inferior enantioselectivity was observed with L2 containing the 2,6-diethylphenyl group (Table 1, entry 3, 44% ee). The enantioselectivity was also sensitive to the substitutent at the stereogenic center of the chiral ligand. Some of them decreased the ee of 2a (Table 1, entris 4 and 5). To our pleasure, using L6 and L7 significantly elevated enantioselectivity compared to L1 (Table 1, entries 6 and 7, 81% and 79% ee, respectively). Incorporation of larger N-aryl substituent (L8) led to further improvement of enantioselectivity (Table 1, entry 8, 90% yield, 89% ee). Solvent effects were observed when the reaction was carried out in CH3CN, the corresponding product 2a was obtained in 91% yield with an excellent ee value (Table 1, entry 11, 91% ee). As a comparison, the nearly racemic product was obtained in low yield using methylated ligand L9 (Table 1, entry 12), indicating the importance of the free hydroxyl group in controlling both reactivity and enantioselectivity.19 TABLE 1. Optimization of Reaction Conditions.a O

N COOMe

CuCl (10 mol %) NHC (10 mol %) NaOtBu (20 mol %) PhMe2SiBpin MeOH THF, r.t. 24 h

1a

O SiMe2Ph N COOMe 2a

entry

ligand

yield (%)b

ee (%)c

1

L1

82

55

2

L2

82

44

3

L3

80

73

4

L4

26

37

5

L5

17

28

6

L6

68

81

7

L7

61

79

8

L8

90

89

9d

L8

45

87

10e

L8

19

88

11f

L8

91

91



12

L9

Page 4 of 23

22

5

aUnless

otherwise noted, all the reactions were carried out with 1a (0.2 mmol), PhMe2Si-Bpin (0.3 mmol), MeOH (0.4 mmol), L (0.02 mol), CuCl (0.02 mmol), and NaOtBu (0.04 mmol), in THF (1 mL) at 25 ˚C for 24 h. bThe yield refers to isolated 2a. cThe enantiomeric excess was determined by HPLC on a chiral AD-H column. dDioxane as the solvent. eToluene as the solvent. fCH3CN as the solvent. Et

Me N

PF6Me HO

Me

iPr N

N

Et

Me

N Me

Me

L3

N

N iPr

N Me

N

N

PF6HO

N PF6HO L6

iPr

iPr

L7

Ph

PF6HO

L5

L4 Me

PF6HO

iPr

N PF6HO

N

iPr

Me N

Me

N

PF6HO L2

L1 Me

Me

N

iPr

N PF6HO

N

N

PF6iPr MeO

L8

L9

With optimized conditions identified, we then turned our attention to the substrate scope of this reaction as illustrated in Table 2. Most of substrates were compatible with this transformation in CH3CN and the corresponding products were isolated as single diastereomers. Substrates bearing a substituent at the 4- or 7-position gave rise to the corresponding product in moderate yield with good enantioselectivity (2b and 2n). Good to excellent ee values were observed for most of 5- or 6-substituted indoles (2c, 2e, 2f, and 2k). Reactions of some substrates were carried out in THF (condition B) due to poor yield in CH3CN, affording products with enantioselectivities ranging from 85% to 92% (2d, 2g, 2h, 2i, 2j, and 2m ). To evaluate the effect of the 5-membered ring substituent on enantioselectivity, we also performed dearomative silylation with indoles bearing a Cbz group at the nitrogen atom or a propionyl group at the 3-position. These provided products in moderate yields with good ee values (Table 2. 2o and 2p). The absolute configuration of 2g was determined to be 2R, 3R by X-ray diffraction analysis.20 The other products were tentatively assigned by analogy. Table 2. Reaction Generality of Copper-Catalyzed Dearomative Silylation Reactions.a


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The Journal of Organic Chemistry O

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

R

1

2

O

O

F

O

Me

MeO SiMe2Ph N COOMe

SiMe2Ph N COOMe

SiMe2Ph N COOMe 2a: condition A 91%, 91% ee

2b: condition A 89%, 88% ee

O

2d: condition B 76%, 91% ee O

O

Cl

I

Br

SiMe2Ph N COOMe

SiMe2Ph N COOMe

2e: condition A 83%, 89% ee

SiMe2Ph N COOMe

2c: condition A 62%, 91% ee

O

F

R''

SiMe2Ph N CO2R'

R

PhMe2Si-Bpin MeOH Condition A or B

N CO2R'

O

O

CuCl (10 mol %) L8 (10 mol %) NaOtBu (20 mol %)

R''

2f: condition A 91%, 92% ee

O

SiMe2Ph N COOMe

SiMe2Ph N COOMe 2g: condition B 85%, 85% ee

2h: condition B 55%, 85% ee

O

O

O

NC SiMe2Ph N MeO COOMe

2j: condition B 59%, 92% ee

2i: condition B 89%,90% ee O

2k: condition A 78%, 92% ee

O SiMe2Ph

N COOMe

Br

SiMe2Ph N Cl COOMe

SiMe2Ph N F COOMe

2m: condition B 74%, 90% ee

aCondition

Me

SiMe2Ph

N COOMe

N CO2Bn

2o: condition A 70%, 86% ee

2n: condition A 74%, 87% ee

2l: condition A 69%, 88% ee O

O SiMe2Ph

SiMe2Ph N COOMe

Et

SiMe2Ph N COOMe 2p: condition A 52%, 87% ee

A: CH3CN as the solvent; condition B: THF as the solvent.

To further demonstrate the synthetic utility of this method, we conducted several transformations of 2a as depicted in Figure 1. Deprotonation of 2a with LDA followed by addition of allyl bromide furnished 2,3,3-trisubstituted chiral indoline 3 in 65% yield with 89% ee. Addition of MeMgBr to the acetyl of 2a afforded 4 in 96% yield with 88% ee. Reaction of 2a with an ylide reagent afforded alkene derivative 5 in 86% yield with 89% ee. In addition, treatment of 2a with glycol followed by nBu4NF (TBAF) provided desilylated ketal 6 in 78% overall yield with 88% ee. We were also interested in converting C-Si bond into other functionalities such as hydroxyl group. However, Tamao-Fleming oxidation of 3 under various reaction conditions led to exclusive protodesilylation product.21 The electron withdrawing inductive effect of the adjacent nitrogen would probably result in more polarized C-Si bond compared to the carbonaceous analogy, which would make desilylation more likely to happen prior to 1,2-migration. O Me SiMe2Ph N CO2Me 5, 86%, 89% ee O

O Me

N CO2Me 6, 78%, 88% ee

Ph3P+MeBrKOtBu THF, rt-60 C 12 h

(CH2OH)2 TsOH, toluene 110 C, 12 h then TBAF, THF rt, 12 h

LDA, allyl bromide O

THF, -78 C, 12 h Me

SiMe2Ph N CO2Me 2a, 89% ee

Me

SiMe2Ph N CO2Me 3, 65%, 89% ee HO Me Me

MeMgBr THF, 0 C, 2 h

Figure 1. Transformations of 2a.


SiMe2Ph N CO2Me 4, 96%, 88% ee


Page 6 of 23

We were interested in why the diastereochemistry of the isolated products differed from previously studied systemthat

gave rise to the kinetic cis-product.22 To gain insight into the diastereoselectivity of the current reaction

during the reaction course, we performed the reaction of 1a in d8-THF at room temperature. As shown in Figure 1, the reaction is completed within 24 hours. Acetyl methyl groups of both the substrate and the products were used as diagnostic peaks (Figure 2). At the beginning (15 min), the reaction gave almost cis-2a (Figure 2, b). However, as the reaction proceeded, cis-2a gradually converted to thermodynamically more stable trans-2a (Figure 2, c-g) probably via an enolization/protonation process. Therefore, the observed single diastereomer was attributed to a facile epimerization of the C3 position of the cis-product due to the significant acidity of the C3-H. O

N COOMe 1a

CuCl (10 mol%) NHC (10 mol%) NaOtBu (20 mol %) PhMe2Si-Bpin MeOH Solvent, r.t. 24 h

O SiMe2Ph N COOMe 2a

O SiMe2Ph N COOMe cis-2a

Figure 2. Reaction monitoring of 1a in d8-THF by 1H NMR.

On the basis of the above observations, we proposed a plausible mechanism as shown in Figure 3. Reaction of in-situ generated copper alkoxide LCuOR A with borylsilane would provide silylcopper intermediate B.16b Coordination of B with the C2-C3 -bond followed by 1,4-addition would provide the O-bound copper enolate D.16i In accord with the aforementioned 1H NMR results, the protonation would occur preferentially from the side opposite the silyl group due to the steric repulsion, giving the mixture of cis-2a (major) and 2a (minor). The active species A would regenerate simultaneously in this step. Product cis-2a would undergo facile epimerization during the reaction course, ultimately leading to thermodynamically more stable 2a as a single isolated diastereoisomer.


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The Journal of Organic Chemistry MeOC

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

MeOC

N CO Me 2

B-OtBu

Si

LCu-Si

N CO Me B-Si 2

1a

B MeOC

2a (minor)

LCu-Si N CO Me 2 C

+

epimerization

LCu-OR MeOC

A

Si N CO Me 2

cis-2a (major)

disf avored Me

MeOH

Si L: L8 B-Si: pinB-SiMe2Ph

O-CuL

N f avored MeO2C MeOH D

Figure 3. Plausible reaction mechanism.

To explain origin of enantioselectivity of this reaction, two plausible transition states (TS-R and TS-S) leading to chiral enloates ((R)-enolate and (S)-enolate) was proposed as shown in Figure 4. Fused benzo ring of substrate 1a would lie close to the moiety of aminoalcohol of L8 to avoid steric repulsion with bulky 2,6-iPr2C6H3. A secondary interaction, hydrogen bond between OH of the catalyst and acetyl group of substrate 1a would probably stabilize TS-R. There is no such interaction in TS-S. Therefore the energy barrier for TS-R would probably be lower than TS-S, giving R product as the major. Hydrogen bonding Me

OCuL

PhMe2Si

N MeO2C (R)-enolate

N HN O Cu Si

N

O vs N CO2Me

TS-R (favored)

Si = SiMe2Ph

O

N HO

Me

OCuL

PhMe2Si

Cu Si N CO2Me TS-S

N MeO2C (S)-enolate

Figure 4. Propsed origin of enantioselectivity.

In summary, we have developed a regio- and enantioselective copper-catalyzed asymmetric dearomative silylation of 3-acyl indoles. The reaction adds a silicon nucleophile regioselectively at the 2-position of indoles, affording chiral, cyclic -aminosilanes with good to excellent enantioselectivities. Facile epimerization of the C3-position was responsible for the isolation of products as single diastereomers. The product is a versatile precusor for a range of chiral indolines. Further applications of these products are currently underway in our laboratory.

EXPERIMENT SECTION 1. General Information. All oxygen- and moisture-sensitive manipulations were carried out under an inert atmosphere using standard Schlenk techniques or glovebox. THF, toluene, CH3CN, and 1,4-dioxane were purified by passing through a neutral alumina column under argon. All other chemicals and solvents were purchased and used as received.



Page 8 of 23

Preparation of 3-acylindoles 1 (5 mmol scale) and NHC ligands L1-L8 (30 mmol scale) were according to the literature procedures.18,23 Characterization data for 3-acylindoles 1a and 1g,23 L1, L3-L518 were consistent with literature reported. 1H

NMR,

13C{1H}

NMR and

19F

NMR spectra were recorded on Zhongke-Niujin 400 NMR spectrometer at ambient

temperature. 13C shifts were obtained with 1H decoupling. Chemical shifts and coupling constants are listed in ppm and Hz, respectively. HPLC data were collected on a Shimadzu LC-20AT spectrometer. Optical Rotation was recorded on a Perkin Elmer 341 polarimeter. Melting points were determined on an Electrothermal IA9000 Series Digital Melting Point Apparatus. High-resolution mass spectroscopy data were obtained on Agilent 6530 TOF LC/MS spectrometer. X-ray crystallography was measured on Burker Smart APEX II. 2. Characterization Data for 3-acyl-1H-indole carboxylate 1. Methyl 3-acetyl-4-fluoro-1H-indole-1-carboxylate (1b): 0.92 g, 78% yield, yellow solid, mp = 122.0 – 122.9 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.03 – 6.98 (m, 1H), 4.08 (s, 3H), 2.58 (s, 3H); 13C{1H} NMR (100 MHz, Acetone-d6) δ 191.7, 156.9 (d, J = 251.4 Hz), 151.5, 139.1 (d, J = 9.7 Hz), 133.6, 127.5 (d, J = 7.7 Hz), 121.8 (d, J = 5.8 Hz), 115.7 (d, J = 21.1 Hz), 112.0 (d, J = 3.9 Hz), 111.2 (d, J = 21.0 Hz), 55.2, 28.8 (d, J = 4.4 Hz). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H11FNO3 236.0717; found 236.0722. Methyl 3-acetyl-5-methyl-1H-indole-1-carboxylate (1c): 0.93 g, 80% yield, white solid, mp = 124.0 – 124.2 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.10 (s, 3H), 2.56 (s, 3H), 2.48 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 151.0, 134.4, 133.7, 132.0, 127.3, 127.0, 122.5, 121.0, 114.4, 54.4, 27.7, 21.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H13NNaO3 254.0788; found 254.0789. Methyl 3-acetyl-5-methoxyl-1H-indole-1-carboxylate (1d): 1.1 g, 87% yield, white solid, 135.5 – 136.2 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.02 (d, J = 9.6 Hz, 1H), 7.88 (s, 1H), 7.00 (d, J = 9.2 Hz, 1H), 4.10 (s, 3H), 3.90 (s, 3H), 2.56 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 157.3, 150.8, 132.2, 129.9, 128.1, 120.9, 115.5, 115.1, 104.4, 55.6, 54.4, 27.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14NO4 248.0917; found 248.0916. Methyl 3-acetyl-5-fluoro-1H-indole-1-carboxylate (1e): 0.94 g, 80% yield, yellow solid, 143.5 – 144.1 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.13 – 8.05 (m, 2H), 7.15 – 7.10 (m, 1H), 4.12 (s, 3H), 2.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 160.4 (d, J = 240.7 Hz), 150.7, 132.9, 131.8, 130.4, 128.2 (d, J = 11.4 Hz), 120.9 (d, J = 3.8 Hz), 115.9 (d, J = 9.2 Hz), 113.70 (d, J = 25.1 Hz), 108.6 (d, J = 25.1 Hz), 54.6, 27.5. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C12H10FNNaO3 258.0537; found 258.0541.


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Methyl 3-acetyl-5-chloro-1H-indole-1-carboxylate (1f): 0.97 g, 77% yield, White solid, mp = 141.3 – 144.2 ˚C 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H), 2.56 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 193.4, 150.6, 133.8, 132.7, 130.6, 128.3, 126.0, 122.4, 120.5, 115.8, 54.7, 27.6. HRMS

(ESI-TOF) m/z: [M+H]+calcd for C12H11ClNO3 252.0422; found 252.0421. Methyl 3-acetyl-5-iodo-1H-indole-1-carboxylate (1h): 1.45 g, 85% yield, white solid, 184.4 – 184.7 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.19 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, DMSO) δ 194.1, 150.3, 134.4, 133.7, 130.2, 130.1, 129.0, 118.9, 117.0, 89.4, 55.0, 27.7. HRMS (ESI-TOF) m/z: [M+Na]+calcd for C12H10INNaO3 365.9598; found 365.9603. Methyl 3-acetyl-5-cyano-1H-indole-1-carboxylate (1i): 0.97 g, 80% yield, white solid, mp = 214.1 – 214.7 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.35 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 4.16 (s, 3H), 2.59 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 193.1, 150.3, 137.2, 133.2, 128.9, 127.8, 127.3, 120.7, 119.1, 115.8, 108.3, 55.0, 27.6.

HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H11N2O3 243.0764; found 243.0761. Methyl 3-acetyl-6-methoxyl-1H-indole-1-carboxylate (1j): 1.05 g, 85% yield, white solid, mp = 147.5 – 148.6. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.72 (s, 1H), 7.00 – 6.98 (m, 1H), 4.10 (s, 3H), 3.89 (s, 3H), 2.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8, 158.6, 151.0, 136.7, 130.7, 123.2, 121.4, 120.8, 113.4, 99.1, 55.6, 54.4, 27.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H14NO4 248.0917; found 248.0915. Methyl 3-acetyl-6-fluoro-1H-indole-1-carboxylate (1k): 0.85 g, 72% yield, white solid, mp = 151.2 – 151.9 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.34 – 8.30 (m, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.14 – 7.09 (m, 1H), 4.12 (s, 3H), 2.56 (s, 3H);

13C{1H}

NMR (100 MHz, DMSO-d6) δ 194.0, 160.4 (d, J = 238.9 Hz), 150.3, 135.2 (d, J = 12.3 Hz), 134.0,

123.3, 123.2, 119.8, 112.5 (d, J = 23.4 Hz), 101.8 (d, J = 27.9 Hz), 54.9, 27.6. HRMS (ESI-TOF) m/z: [M+H]+calcd for C12H11FNO3 236.0717; found 236.0715. Methyl 3-acetyl-6-cholro-1H-indole-1-carboxylate (1l): 0.94 g, 75% yield, yellow solid, mp = 173.2 - 174.0 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.35 (d, J = 6.8 Hz, 1H), 4.13 (s, 3H), 2.56 (s, 3H); 13C{1H}


(ESI-TOF) m/z: [M+Na]+ calcd for C12H10ClNNaO3 274.0241; found 274.0243. Methyl 3-acetyl-6-bromo-1H-indole-1-carboxylate (1m): 1.08 g, 73% yield, white solid, mp = 180.0 – 180.4 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.24 (d, J=8.8 Hz 1H), 8.21(s, 1H), 7.49 (d, J = 8.8Hz, 1H), 4.13 (s, 3H), 2.56 (s, 3H);



13C{1H}

Page 10 of 23


(ESI-TOF) m/z: [M+Na]+calcd for C12H10BrNNaO3 317.9716; found 317.9719. Methyl 3-acetyl-7-methyl-1H-indole-1-carboxylate (1n): 1.0 g, 87% yield, white solid, mp = 122.9 – 123.8 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.28 - 8.22 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 2.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 150.7, 135.0, 134.4, 129.1, 128.5, 125.0, 124.9, 120.9, 120.3, 54.5, 27.7, 22.0. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C13H13NNaO3 254.0788; found 254.0791. Benzyl 3-acetyl-1H-indole-1-carboxylate (1o): 1.1 g, 78% yield, white solid, mp = 115.3 – 116.1 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.36 (m, 1H), 8.25 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.52 – 7.35 (m, 7H), 5.51 (s, 2H), 2.56 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 193.7, 150.3, 135.5, 134.3, 131.8, 129.0, 128.8, 128.7, 127.2, 125.7, 124.6, 122.7, 121.2, 114.9, 69.6, 27.7. HRMS (ESI) m/z: [M+Na]+ calcd for C18H15NNaO3 316.0944; found 316.0940. Methyl 3-propionyl-1H-indole-1-carboxylate (1p): 0.93 g, 80% yield, white solid, mp = 95.2 – 96.3 ˚C.1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 6.4 Hz, 1H), 8.26 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 4.11 (s, 3H), 2.94 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 196.8, 150.7, 135.3, 130.9, 127.2, 125.4, 124.3, 122.5,

120.3, 114.6, 54.2, 32.8, 8.2. HRMS (ESI-TOF) m/z: [M+Na]+calcd for C13H13NNaO3 254.0788; found 254.0789. 3. Characterization Data for L (S)-1-(2,6-Diethylphenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate(V) (L2): 5.96 g, 46% yield, pale white solid, mp = 130.9 – 131.9 ˚C,

= +22.58 (c 0.70,

CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.22 – 7.16 (m, 2H), 4.29 – 4.11 (m, 4H), 3.99 – 3.92 (m, 1H), 3.73 – 3.62 (m, 2H), 3.14 (s, 1H), 2.65 – 2.54 (m, 4H), 1.99 – 1.91 (m, 1H), 1.27 – 1.21 (m, 6H), 1.05 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.6, 141.8, 141.4, 131.4, 130.6, 127.3, 127.1, 66.8, 58.8, 51.6, 45.4, 27.0, 23.7, 23.7, 19.6, 18.7, 14.9, 14.8;

19F

NMR (376 MHz, CDCl3) δ -72.6 (d, JPF = 711.8 Hz). HRMS (ESI-TOF)

m/z: [M-PF6-]+ calcd for C18H29N2O 289.2274; found 289.2279. (S)-1-(2,6-Diisopropylphenyl)-3-(2-hydroxy-1-phenylethyl)-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate(V) (L6): 2.95 g, 20% yield, pale white solid, mp = 134.1 – 134.7 ˚C.

= +15.30 (c 0.34,

CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.46 – 7.40 (m, 4H), 7.38 – 7.33 (m, 2H), 7.23 (d, J = 7.6 Hz, 2H), 5.11 – 5.05 (m, 1H), 4.21 – 4.12 (m, 4H), 4.11 – 4.04 (m, 2H), 3.40 (s, 1H), 2.96 – 2.85 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.25 (d, J =


Page 11 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.2 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 157.9, 146.6, 132.9, 131.1,

129.7, 129.6, 129.5, 127.7, 124.8, 63.7, 60.8, 52.9, 47.1, 28.5, 24.7, 24.5, 23.9, 23.7. 19F NMR (376 MHz, CDCl3) δ -72.7 (d, JPF = 712.1 Hz); HRMS (ESI-TOF) m/z: [M-PF6-]+ calcd for C23H31N2O 351.2431; found 351.2430. 3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-1-mesityl-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate(V) (L7): 3.08 g, 22% yield, white solid, , mp = 183.4 – 184.3 ˚C,

= -38.49 (c 1.02, CHCl3).1H

NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.41 – 7.28 (m, 4H), 6.93 (s, 2H), 5.25 (d, J = 5.6 Hz, 1H), 4.99 – 4.95 (m, 1H), 4.21 – 4.08 (m, 4H), 3.49 (s, 1H), 3.31 (dd, J = 17.2, 6.4 Hz, 1H), 3.00 (dd, J = 16.8, 5.2 Hz, 1H), 2.28 (s, 9H);

13C{1H}

NMR (100

MHz, DMSO) δ 159.4, 141.5, 139.2, 136.2, 135.5, 131.3, 129.3, 129.3, 127.3, 125.5, 125.4, 70.6, 64.5, 50.4, 48.7, 39.3, 20.5, 17.1; 19F NMR (376 MHz, DMSO) δ -70.2 (d, JPF = 710.3 Hz); HRMS (ESI-TOF) m/z: [M-PF6-]+ calcd for C21H25N2O 321.1961; found 321.1962. 1-(2,6-Diisopropylphenyl)-3-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate(V) (L8): 6.12 g, 40% yield, white solid, mp = 178.7 – 180.7 ˚C,

= -66.11 (c 0.82, CHCl3). 1H

NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.35 – 7.26 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 5.17 (d, J = 4.8 Hz, 1H), 4.98 (s, 1H), 4.47 – 4.39 (m, 2H), 4.32 – 4.20 (m, 2H), 3.47 (s, 1H), 3.23 (dd, J = 16.8, 5.6 Hz, 1H), 3.05 – 2.93 (m, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H);

13C{1H}

NMR (100

MHz, CDCl3) δ 158.2, 147.1, 146.5, 141.3, 136.0, 131.1, 130.0, 129.8, 127.8, 125.9, 124.8, 124.7, 124.6, 70.8, 65.5, 53.3, 49.7, 39.7, 28.4, 28.3, 24.9, 24.6, 23.8, 23.5.

19F

NMR (376 MHz, CDCl3) δ -73.0 (d, JPF = 712.1 Hz); HRMS (ESI-TOF) m/z:

[M-PF6-]+calcd for C24H31N2O 363.2431; found 363.2424. 4.

Preparation

and

Characterization

Data

for

1-(2,6-diisopropylphenyl)-3-((1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate(V) (L9). The preparation of Ligand L9 was adapted from literature procedures.24 To a 25-mL flask charged with L8 (101.7 mg, 0.20 mmol), HBF4 (35 μL, 40 wt%, 0.20 mmol ), and CH2Cl2 (5 mL) was added trimethylsilyldiazomethane (0.8 mL, 2 M in hexanes, 1.6 mmol) at 0 ˚C. The resulting mixture was allowed to stir at room temperature for 2 h. Water (10 mL) was added to the reaction system and the mixture was extracted with CH2Cl2 3 times (3 x 20 mL). The combined organic phase was dried over Na2SO4. After removal of the solvent, the residue was dissolved in MeOH/H2O (4: 1, 25 mL) and KPF6 (40 mg, 0.22 mmol) was added at room temperature. The resulting mixture was



Page 12 of 23

allowed to stir at room temperature for additional 1.5 h. After removal of volatiles, the residue was extracted with CH2Cl2 3 times (3 x 20 mL). After removal of the solvent, the residue was purified by column chromatography on silica gel using acetone/CH2Cl2 (1: 20) as the eluent to afford L9 as yellow solid (80 mg, 84% yield, mp = 135.3 – 136.7 ˚C).

=

-3.37 (c 0.52, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.41 (apparent s, 6H), 7.23 (d, J = 7.6 Hz, 2H), 5.10 (d, J = 4.4 Hz, 1H), 4.20 – 4.05 (m, 6H), 3.82 (d, J = 8.8 Hz, 1H), 3.42 (s, 3H), 2.88 – 2.92 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H) 1.25 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H);

13C{1H}

NMR (100 MHz, CDCl3) δ 157.8, 146.7, 146.5, 133.1, 131.1, 129.8, 126.6,

129.5, 127.9, 124.9, 124.8, 70.5, 61.7, 58.9, 53.1, 47.6, 28.6, 28.5, 24.7, 24.5, 24.0, 23.9. 19F NMR (376 MHz, CDCl3) δ -72.5 (d, JPF = 712.5 Hz); HRMS (ESI-TOF) m/z: [M-PF6-]+ calcd for C25H33N2O 377.2588; found 377.2587. 5. General Procedure and Characterization Data for 2-silylindolines 2. Method A: In a nitrogen-filled glovebox, to a flame-dried 25-mL Schlenk tube charged with CuCl (2.0 mg, 0.02 mmol), NaOtBu (4.0 mg, 0.04 mmol) and L8 (10.2 mg, 0.02 mmol) was added CH3CN (0.5 mL). The resulting mixture was allowed to stir at room temperature for 2 h. PhMe2Si-Bpin (0.30 mmol 71 μL) was then introduced and the reaction was allowed to stir at room temperature for 30 min. followed by addition of indole 1 (43.4 mg, 0.20 mmol), CH3CN (0.5 mL) and MeOH (16.2 μL, 0.4 mmol) at room temperature. The resulting mixture was continued to stir for 24-48 hours. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (20:1) as the eluent to affording corresponding chiral -aminosilane 2. Method B: In a nitrogen-filled glovebox, to a flame-dried 25-mL Schlenk tube charged with CuCl (2.0 mg, 0.02 mmol), NaOtBu (4.0 mg, 0.04 mmol) and L8 (10.2 mg, 0.02 mmol) was added THF (0.5 mL). The resulting mixture was allowed to stir at room temperature for 2 h. PhMe2Si-Bpin (0.30 mmol 71 μL) was then introduced and the reaction was allowed to stir at room temperature for 30 min. followed by addition of indole 1 (43.4 mg, 0.20 mmol), THF (0.5 mL) and MeOH (16.2 μL, 0.4 mmol) at room temperature. The resulting mixture was continued to stir for 24-48 hours. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (20: 1) as the eluent to affording corresponding chiral -aminosilane 2. (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)indoline-1-carboxylate (2a) (Method A): 64.2 mg, 91% yield, 91% ee, colorless solid, mp = 75.9 – 76.1 ˚C,

= +32.63 (c 0.44, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H),

7.42 – 7.40 (m, 2H), 7.35 – 7.29 (m, 3H), 7.23 – 7.21 (m, 1H), 7.13 (d, J = 6.0 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 4.61 (s, 1H),


Page 13 of 23 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


3.78 (s, 1H), 3.60 (s, 3H), 2.03 (s, 3H), 0.31 (s, 3H), 0.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.8, 153.2, 142.7, 135.4, 133.7, 129.5, 128.9, 127.8, 124.7, 123.0, 116.1, 56.2, 52.2, 26.3, -4.4, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H23NNaO3Si 376.1339; found 376.1341. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95: 5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 8.11 (major), 9.80 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-4-fluoroindoline-1-carboxylate (2b) (Method A): 66.1 mg, 89% yield, 88% ee, colorless oil,

= +17.16 (c 0.58, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.42 – 7.41 (m, 2H),

7.36 – 7.30 (m, 3H), 7.21 – 7.19 (m, 1H), 6.66 (t, J = 8.8 Hz, 1H), 4.63 (d, J = 2.0 Hz, 1H), 3.89 (s, 1H), 3.60 (s, 3H), 2.05 (s, 3H), 0.32 (s, 3H), 0.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.1, 158.6 (d, J= 244.4 Hz), 152.8, 145.0, 134.9, 133.6, 132.9, 130.6 (d, J = 7.3 Hz), 129.5, 127.7, 111.8, 109.6 (d, J = 20.3 Hz), 53.4, 52.1, 27.1, 27.0, -4.7, -6.0. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22FNNaO3Si 394.1245; found 394.1246. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 7.8 (major), 8.5 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-methylindoline-1-carboxylate Compound (2c) (Method A): 45.6 mg, 62% yield, 91% ee, white solid, mp = 73.2 – 74.0 ˚C,

= +14.63 (c 0.67, MeOH). 1H NMR (400 MHz, CDCl3)

δ 7.72 (s, 1H), 7.42 – 7.41 (m, 2H), 7.36 – 7.30 (m, 3H), 7.04 – 7.03 (m, 1H), 6.93 (s, 1H), 4.56 (s, 1H), 3.74 (s, 1H), 3.55 (s, 3H), 2.28 (s, 3H), 2.02 (s, 3H), 0.29 (s, 3H), 0.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.1, 153.2, 140.4, 135.6, 133.8, 132.6, 129.5, 128.9, 127.8, 125.3, 115.9, 56.3, 52.4, 52.0, 26.4, 20.9, -4.3, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H25NNaO3Si 390.1496; found 390.1496. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 11.66 (major), 17.06 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-methoxylindoline-1-carboxylate (2d) (Method B): 58.3 mg, 76% yield, 91% ee, white solid, mp = 87.6 – 88.9 ˚C,

= +17.83 (c 1.37, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.76 (s,

1H), 7.42 – 7.41 (m, 2H), 7.36 – 7.32 (m, 3H), 6.79 - 6.77 (m, 1H), 6.70 (s, 1H), 4.56 (s, 1H), 3.76 (s, 3H), 3.73(s, 1H), 3.56 (s, 3H), 2.03 (s, 3H), 0.28 (s, 3H), 0.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.9, 155.8, 153.1, 136.5, 135.4, 133.7, 130.2, 129.5, 127.8, 116.7, 113.6, 111.0, 56.4, 55.6, 52.5, 52.0, 26.3, -4.5, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H25NNaO4Si 406.1445; found 406.1444. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 17.56 (major), 21.07 (minor).



Page 14 of 23

(2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-fluoroindoline-1-carboxylate (2e) (Method A): 61.7 mg, 83% yield, 89% ee, colorless oil,

= +15.88 (c 0.38, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.41 – 7.39 (m, 2H),

7.36 – 7.30 (m, 3H), 6.94 – 6.91 (m, 1H), 6.83 (s, 1H), 4.61 (s, 1H), 3.73 (s, 1H), 3.59 (s, 3H), 2.04 (s, 3H), 0.31 (s, 3H), 0.23 (s, 3H);

13C

NMR (100 MHz, CDCl3) δ 204.2, 158.7 (d, J = 240.8 Hz), 153.1 (d, J = 5.4 Hz), 139.0, 135.1, 133.7, 129.7, 127.9,

116.9 (d, J = 6.0 Hz), 115.4 (d, J = 23.1 Hz), 112.1 (d, J = 24.4 Hz), 56.0, 52.6, 52.2, 26.5, -4.5, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22FNNaO3Si 394.1245; found 394.1242. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 9.31 (major), 10.06 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-chloroindoline-1-carboxylate (2f) (Method A): 70.5 mg, 91% yield, 92% ee, white solid, mp = 83.7 – 84.3 ˚C,

= -10.92 (c 1.37, MeOH ). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H),

7.41 – 7.37 (m, 2H), 7.35 – 7.30 (m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 7.09 (s, 1H), 4.60 (d, J = 2.0 Hz, 1H), 3.74 (s, 1H), 3.59 (s, 3H), 2.04 (s, 3H), 0.31 (s, 3H), 0.23 (s, 3H);

13C

NMR (100 MHz, CDCl3) δ 204.0, 153.0, 141.5, 135.1, 133.7, 130.7, 129.7,

128.9, 127.9, 127.8, 124.8, 117.0, 55.9, 52.7, 52.3, 26.5, -4.4, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22ClNO3Si 410.0950; found, 410.0954. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95: 5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 10.92 (major), 12.12 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-bromoindoline-1-carboxylate (2g) (Method B): 73.3 mg, 85% yield, 85% ee, colorless oil,

= -11.22 (c 0.41, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.40 – 7.37 (m, 2H), 7.35 –

7.30 (m, 4H), 7.23 (s, 1H), 4.59 (d, J = 2.8 Hz, 1H), 3.74 (s, 1H), 3.61 (s, 3H), 2.03 (s, 3H), 0.32 (s, 3H), 0.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0, 153.1, 142.0, 135.1, 133.8, 131.9, 129.7, 128.0, 127.7, 117.5, 115.2, 55.8, 52.7, 52.4, 26.6, -4.4, -5.8. HRMS (ESI) m/z: [M+Na]+ calcd for C20H22BrNO3Si 456.0424; found 456.0427. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 13.9 (major), 17.2 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-iodoindoline-1-carboxylate (2h) (Method B): 52.7 mg, 55% yield, 85% ee, white solid, mp = 83.3 – 84.3 ˚C,

= -14.98 (c 0.51, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H),

7.52 (d, J = 6.8 Hz, 1H), 7.40 – 7.38 (m, 3H), 7.36 – 7.31 (m, 3H), 4.57 (s, 1H), 3.73 (s, 1H), 3.59 (s, 3H), 2.03 (s, 3H), 0.32 (s,


Page 15 of 23 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


3H), 0.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.1, 153.0, 142.6, 137.8, 135.1, 133.7, 133.5, 131.5, 129.7, 127.9, 118.1, 85.3, 55.8, 52.6, 52.3, 26.6, -4.3, -5.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22INNaO3Si 502.0306; found 502.0305. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 14.27 (major), 20.97 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-5-cyanoindoline-1-carboxylate (2i) (Method B): 67.4 mg, 89% yield, 90% ee, white solid, mp = 76.0 – 77.3 ˚C,

= -10.61 (c 0.47, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H),

7.52 (d, J = 8.4 Hz, 1H), 7.38 – 7.37 (m, 4H), 7.33 – 7.29 (m, 2H), 4.65 (s, 1H), 3.79 (s, 1H), 3.67 (s, 3H), 2.06 (s, 3H), 0.35 (s, 3H), 0.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 203.1, 152.7, 146.3, 134.5, 133.7, 133.6, 129.9, 129.8, 128.3, 127.9, 118.8, 116.1, 105.6, 55.2, 52.8, 52.6, 26.7, -4.6, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H22N2NaO3Si 401.1292; found 401.1287. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 17.43 (major), 29.06 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-6-methoxylindoline-1-carboxylate (2j) (Method B): 45.3 mg, 59% yield, 92% ee, colorless oil,

= +18.61 (c 0.83, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.43 – 7.41 (m,

2H), 7.37 – 7.33 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.61 (s, 1H), 3.81 (s, 3H), 3.71 (s, 1H), 3.55 (s, 3H), 2.03 (s, 3H), 0.28 (s, 3H), 0.23 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 205.4, 160.7, 153.2, 144.1, 135.6, 133.8, 129.6,

127.9, 125.1, 120.8, 109.6, 101.8, 58.4, 55.5, 53.1, 52.1, 26.2, -4.4, -5.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H25NNaO4Si 406.1445; found 406.1438. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 9.53 (major), 12.80 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-6-fluoroindoline-1-carboxylate (2k) (Method A): 57.9 mg, 78% yield, 92% ee, white solid, mp = 56.4 – 57.3 ˚C,


7.41 – 7.39 (m, 2H), 7.36 – 7.30 (m, 3H), 7.04 (s, 1H), 6.65 – 6.61 (m, 1H), 4.62 (d, J = 2.8 Hz, 1H), 3.73 (s, 1H), 3.59 (s, 3H), 2.03 (s, 3H), 0.31 (s, 3H), 0.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.6, 163.3 (d, J = 243.0 Hz), 152.9 (d, J = 2.3 Hz), 144.2, 135.1, 133.7, 129.6, 127.8, 125.3 (d, J = 9.0 Hz), 124.3, 109.5 (d, J = 23.1 Hz), 104.3 (d, J = 28.3 Hz), 55.4, 53.1, 52.2, 26.3, -4.6, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22FNNaO3Si 394.1245; found 394.1249. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 6.73 (major), 8.50 (minor).



Page 16 of 23

(2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-6-chloroindoline-1-carboxylate (2l) (Method A): 53.4 mg, 69% yield, 88% ee, white solid, mp = 102.6 – 104.0 ˚C,

= +10.95 (c 2.00, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.89 (s,

1H), 7.41 – 7.39 (m, 2H), 7.37 – 7.30 (m, 3H), 7.02 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 4.61 (d, J = 2.4 Hz, 1H), 3.73 (s, 1H), 3.58 (s, 3H), 2.02 (s, 3H), 0.31 (s, 3H), 0.24 (s, 3H).

13C{1H}

NMR (100 MHz, CDCl3) δ 204.2, 152.9, 143.8, 135.0, 134.6, 133.7,

129.6, 127.8, 125.4, 122.9, 116.4, 55.6, 52.8, 52.3, 26.4, -4.5, -5.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22ClNNaO3Si 410.0950; found 410.0950. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 7.16 (major), 8.23 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-4-bromoindoline-1-carboxylate (2m) (Method B): 64.0 mg, 74% yield, 90% ee, colorless oil,

= +12.92 (c 0.29, MeOH). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.41 – 7.39 (m,

2H), 7.37 – 7.32 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 4.60 (s, 1H), 3.72 (s, 1H), 3.59 (s, 3H), 2.02 (s, 3H), 0.31 (s, 3H), 0.24 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 204.2, 153.0, 144.0 135.1, 133.7, 129.7, 127.9, 125.9, 125.8,

122.7, 119.4, 55.8, 52.9, 52.4, 26.4, -4.4, -5.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C20H22BrNNaO3Si 456.0424; found 456.0426. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IF column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 10.71 (major), 11.60 (minor). (2R,3R)-Methyl 3-acetyl-2-(dimethyl(phenyl)silyl)-7-methylindoline-1-carboxylate Compound (2n) (Method A): 54.4 mg, 74% yield, 87% ee, colorless oil,

= -26.36 (c 0.37, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.37 (m, 2H),

7.32 – 7.27 (m, 3H), 7.02 – 6.91 (m, 3H), 4.72 (s, 1H), 3.76 (s, 3H), 3.57 (s, 1H), 2.25 (s, 3H), 2.08 (s, 3H), 0.30 (s, 3H), 0.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.2, 155.4, 142.0, 135.1, 133.7, 132.3, 131.1, 129.5, 129.2, 127.7, 125.0, 122.1, 56.6, 55.3, 52.9, 26.3, 19.8, -5.0, -6.2. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H25NNaO3Si 390.1496; found 390.1497. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak AD-H column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 13.12 (minor), 19.00 (major). (2R,3R)-Benzyl 3-acetyl-2-(dimethyl(phenyl)silyl)-indoline-1-carboxylate (2o) (Method A): 60.1 mg, 70% yield, 86% ee, colorless oil,

= -6.37 (c 0.33, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.37 – 7.25 (m, 11H), 7.11 (d,

J = 6.8 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 4.81 (s, 1H), 4.64 (d, J = 2.4 Hz, 1H), 3.75 (s, 1H), 2.00 (s, 3H), 0.24 (s, 3H), 0.17 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.9, 152.8, 142.2, 136.0, 135.4, 133.8, 129.6, 129.0, 128.5,


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128.2, 127.8, 124.8, 123.5, 123.2, 116.5, 67.2, 56.3, 52.5, 26.3, -4.0, -5.6. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C26H27NNaO3Si 452.1652; found 452.1654. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IB column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 6.53 (minor), 7.42 (major). (2R,3R)-Methyl 3-propionyl-2-(dimethyl(phenyl)silyl)-indoline-1-carboxylate (2p) (Method A): 38.2 mg, 52% yield, 87% ee, white solid, mp = 88.2 – 88.8 ˚C,


7.41 – 7.40 (m, 2H), 7.35 – 7.31 (m, 3H), 7.24 – 7.20 (m, 1H), 7.12 – 7.11 (m, 1H), 6.93 (t, J = 7.2 Hz, 1H), 4.61 (s, 1H), 3.79 (s, 1H), 3.60 (s, 3H), 2.46 (s, 1H), 2.24 (s, 1H), 0.92 (t, J = 6.8 Hz, 3H), 0.31 (s, 3H), 0.21 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 207.8, 153.3, 142.6, 135.6, 133.8, 129.5, 128.9, 127.8, 124.7, 123.0, 116.2, 55.5, 52.5, 52.2, 32.3, 7.6, -4.3, -5.7. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H25NNaO3Si 390.1496; found 390.1499. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IA column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 6.99 (major), 7.93 (minor). 6. Preparation of (2R,3S)-methyl 3-acetyl-3-allyl-2-(dimethyl(phenyl)silyl)indoline-1-carboxylate (3). To a flame-dried 50-mL flask charged with 2-silylindoline 2a (71 mg, 0.2 mmol) and THF (1 mL) was added LDA (0.15 mL, 2M in heptane/ethylbenzene, 0.3 mmol, 1.5 equiv) at -78 °C dropwisely. The resulting mixture was allowed at same temperature for 30 min. The allyl bromide (26 μL, 0.3 mmol, 1.5 equiv) was then added slowly at -78 °C. The reaction mixuture was then allowed to warm to room temerature and continued to stir at same temperature for 12 h. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (30: 1). as the eluent to afford C3 allylated 2-silylindoline 3 as colorless oil (51.6 mg, 65% yield). 89% ee,

= +39.52 (c 0.20,

MeOH). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.0 Hz, 1H), 7.32 – 7.23 (m, 7H), 7.02 (t, J = 7.2 Hz, 1H), 5.47 – 5.38 (m, 1H), 5.03 - 4.94 (m, 2H), 4.23 (s, 1H), 3.66 (s, 3H), 2.64 – 2.59 (m, 1H), 2.51 – 2.45 (m, 1H), 1.82 (s, 3H), 0.29 (s, 3H), 0.16 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3) δ 207.6, 153.6, 142.0, 137.4, 134.5, 133.3, 132.3, 129.1, 128.3, 127.5, 125.1, 122.9,

119.1, 116.5, 64.8, 59.7, 52.4, 44.1, 28.9, -2.4, -3.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H27NNaO3Si

416.1652,

found 416.1649. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IA column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 15.08 (minor), 15.83 (major). 7. Preparation of (2R,3R)-methyl 2-(dimethyl(phenyl)silyl)-3-(2-hydroxypropan-2-yl)indoline-1-carboxylate (4). To a flame-dried 50-mL flask charged with 2-silylindoline 2a (71mg, 0.2 mmol) and THF (1 mL) was added MeMgBr



Page 18 of 23

(0.15 mL, 2M in THF, 0.3 mmol, 1.5 equiv) at 0 °C dropwisely. The resulting mixture was allowed at same temperature for 2 h. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (20: 1). as the eluent to afford C3-( 2-hydroxypropan-2-yl) 2-silylindoline 4 as colorless oil (70.9 mg, 96% yield). 88% ee, = +55.68 (c 0.23, MeOH). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.45 – 7.43 (m, 2H), 7.33 – 7.31 (m, 3H), 7.23 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 4.15 (s, 1H), 3.83 (s, 1H), 3.51 (s, 3H), 2.97 (s, 1H), 1.01 (s, 6H), 0.21 (s, 3H), 0.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.1, 143.3, 135.9, 133.9, 131.7, 129.4, 128.4, 127.7, 125.8, 122.6, 115.7, 73.1, 53.7, 53.3, 51.9, 25.8, -5.0, -6.0. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C21H27NNaO3Si 392.1652; found 392.1660. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IA column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 9.92 (minor), 11.75 (major). 8. Preparation of (2R,3S)-methyl 2-(dimethyl(phenyl)silyl)-3-(prop-1-en-2-yl)indoline-1-carboxylate (5). To a flame-dried 50-mL flask charged with Ph3P+CH3Br- and THF (1 mL) was added KOtBu (0.15 mL, 2 M in THF, 0.3 mmol) at room temperature. The resulting mixture was allowed at same temperature for 30 min. The 2-silylindoline 2a (71 mg, 0.2 mmol) was then added The resulting mixture was allowed to stir at 60 ˚C for 12 h. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (30: 1). as the eluent to afford 2-silyllindoline 5 as colorless oil (60.4 mg, 86% yield). 89% ee,

= +31.47 (c 0.48, MeOH). 1H NMR (400 MHz, CDCl3)

δ 7.80 (s, 1H), 7.46 (d, J = 6.4 Hz, 2H), 7.33 – 7.32 (m, 3H), 7.20 - 7.17 (m, 1H), 6.99 – 6.91 (m, 2H), 4.57 (s, 1H), 4.43 (s, 1H), 4.01 (s, 1H), 3.69 (s, 1H), 3.53 (s, 3H), 1.46 (s, 3H), 0.29 (s, 3H), 0.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.5, 147.1, 142.6, 136.1, 133.9, 132.1 129.3, 127.9, 127.7, 124.8, 123.0, 122.9, 115.6, 110.7, 55.6, 52.0, 50.4, 18.4, -4.5, -5.7. HRMS (ESI) m/z: [M+H]+calcd for C21H26NO2Si

352.1727, found 352.1726. The enantiopurity was determined by HPLC analysis

(Daicel Chiralpak IA column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 4.27 (minor), 4.64 (major). 9. Preparation of (S)-methyl 3-(2-methyl-1,3-dioxolan-2-yl)indoline-1-carboxylate (6). To a 25-mL flask charged with 2-silylindoline 2a (105.9 mg, 0.3 mmol), (CH2OH)2 (34 μL, 0.6, 2.0 equiv) and toluene (3.0 mL) was added TsOH (10.7 mg, 0.09 mmol) at room temperature. The resulting mixture was allowed at 110℃ for 12 h. After removal of the solvent, the residue (ketal) was used for the next step without further purification. Then to a 25-mL flask charged with crude ketal was added nBuNF (3.0 mL, 1 M in THF, 3.0 mmol) at room temperature. The resulting mixture was allowed at


Page 19 of 23 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


temperature for 12 h. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE/EtOAc (20: 1). as the eluent to afford 6 as colorless oil (61.6 mg, 78% yield). 89% ee,

= +125.15 (c 0.60,

MeOH). 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.03 – 3.82 (m, 9H), 3.55 (t, J = 7.6 Hz, 1H), 1.20 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.3, 130.1, 128.3, 126.1, 122.5, 114.5, 110.9, 65.0, 64.8, 52.4, 50.0, 47.6, 20.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H18NO4 264.1230; found 264.1232. The enantiopurity was determined by HPLC analysis (Daicel Chiralpak IE column, Hexane/iPrOH = 95:5, flow rate = 1.0 mL/min., wavelength = 254 nm, tR = 13.48 (minor), 16.90 (major).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H

and 13C{1H}, 19F NMR, and HPLC spectra and crystallographic data (PDF)

Crystallographic of 2g (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes Any additional relevant notes should be placed here.

ACKNOWLEDGMENT We thank the 1000-Youth Talents Plan, a Start-up Grant from Lanzhou Institute of Chemical Physics, National Natural Science Foundation of China (21573262) and Natural Science Foundation of Jiangsu Province (BK20161259, BK20170422) for generous financial support.

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NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles

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