Enantioselective A3-Coupling Reaction Employing Chiral CuI

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Enantioselective A3-Coupling Reaction Employing Chiral CuIiPrpyboxdiPh/N-Boc-(L)-Proline Complex under Cooperative Catalysis: Application in the Synthesis of (Indol-2-yl)methanamines Sivasankaran Dhanasekaran, Vinod Kumar Kannaujiya, Rayhan Gafur Biswas, and Vinod K. Singh J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03225 • Publication Date (Web): 21 Feb 2019 Downloaded from http://pubs.acs.org on February 22, 2019

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The Journal of Organic Chemistry

Enantioselective A3-Coupling Reaction Employing Chiral CuIi PrpyboxdiPh/N-Boc-(L)-Proline Complex under Cooperative Catalysis: Application in the Synthesis of (Indol-2-yl)methanamines Sivasankaran Dhanasekaran,‡ a Vinod. K. Kannaujiya,‡ a Rayhan G. Biswas,‡ and Vinod K. Singh †* ‡

Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, MP – 462 066, India † Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP – 208 016, India

Graphical Abstract Ph O H 2N

Ph Z

X

N H

O Ph

N N

N

Ph

4e

Z NH

-

[Cu(CH3CN)4]PF6 4e (10 mol %) N-Boc-(L)-Proline (20 mol %)

R

DCE, rt, 4 Å MS

O

up to 94%

H Y

X

N H

R

Z

1. p-Ts-Cl (1.2 equiv.) pyridine, CH2Cl2, rt, 3-4 h 2. K2CO3 (4.0 equiv.) CH3CN, 40 °C, 4-6 h

Y

Propargylamine, 6-8 up to 98% ee

up to 88%

NH X

N Ts Y

(Indol-2-yl)methamines, 10 up to 95% ee

* Cooperative catalysis * Ambient conditions * Operationly simple * Gram Scale synthesis * Functionaly diversed substrates

Abstract An efficient route to enantioenriched propargylamines via three-component alkynylation reaction using cooperative catalysis with CuI-iPrpyboxdiPh complex and N-Boc-(L)-proline have been accomplished. A variety of functionalized amines, aldehydes and 2-ethynyl anilines were reacted smoothly at ambient temperature to furnish a wide range of propargylamines in high yields (up to 94%) and excellent enantioselectivities (up to 98% ee). Synthetic utility of the methodology has been demonstrated by transforming the products into various synthetically useful intermediates. Finally, propargylamines were transformed into biologically important (indol-2-yl)methanamines over two steps in good yields (up to 88%) with excellent level of enantioselectivities (up to 95%).

Introduction Enantioenriched (indol-2-yl)methanamines are important structural motifs found in many natural products and pharmaceuticals.1 In particular, substituted (indol-2-yl)methanamines are useful advanced intermediates in the synthesis of a variety of drugs2 which have prominent biological properties such as inhibition of HIV protease,3 5HT2B receptor antagonists,4 antiviral,5 antimalarial,6 and anticancer activities,7 making them attractive synthetic targets. For instance, calindol 1a,8 a synthetic (indol-2-yl)methanamine, is a well known calcium sensing receptor. Chiral (indol-2yl)methanamine sulfonamide 1b,9 acts as an endothelial differentiation gene 1 receptor antagonist for treatment of cancer (Figure 1). Tetrahydro-β -carbolines (THβCs) and pyrazino[1,2-a]indoles are two important classes of compounds which contains (indol-2-yl)methanamines as their basic unit. These classes of compounds also exist widely in alkaloids and synthetic pharmaceuticals and show broad spectra of biological activities.10-12

1

ACS Paragon Plus Environment

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SO2C6H4Cl

Page 2 of 33

OH

HN

R

H HN

N Et 1b

Me N H calindol, 1a calcium sensing receptor agonists

Me

N R

O N H

OH

H Me N

O

NH

H EtO2C

O

O tetalafil, 2b erectile disfunction

harmicine, 2a

pyrazino[1,2-a]indole, 3a

H

N

N

H

NH

vinoxine, 1c

Me N

O

N H

MeO2C

endothelial differentiation gene 1 receptor antagonists

N

N

N N

amalicine, 2c α1-adrenergic antagonist receptor

3b agricultural fungicide

Figure 1: Selected (indol-2-yl)methanamine containing bioactive molecules. Substituted (indol-2-yl)methanamines have drawn significant attention of the synthetic organic chemists due to their potential synthetic value and biological properties. Few elegant diastereoselective and enantioselective approaches have been documented in the literature.13-21 For instance, diastereoselective approaches includes resolution of hydroxyurea,13 diastereoselective addition of 2-lithiated indoles to either SAMP-hydrazones14 or (R)-N-tert-butylsulfinyl aldimines.15 On the other hand, enantioselective synthesis involves Sonogashira-type cyclization of palladium mediated chiral propargylamines with 2-iodoanilines,16,17 dilithiated N-Boc-o-toluidine addition to chiral α-amino acid derivatives.18 Catalytic enantioselective process includes chiral phosphoric acid catalyzed Friedel-Craft reaction, followed by oxidation of 4,7-dihydroindoles with N-tosyl aldimines,19 and multi-component copper catalyzed propargylation/cyclization cascade using N-tosyl 2-ethynylanilines, aldehyde and secondary amines.20,21 The majority of work in this area have certain limitations such as use of stoichiometric amount of chiral auxiliary14,15 or chiral reagent,16,17 harsh condition,18 costly reagent,19 limited substrate scope for example use of only secondary amines.20,21 To overcome all these issues, development of novel and efficient synthetic method to access (indol-2yl)methanamine is highly desirable. 1. Our previous report

i

O Ar

R

Ar1 NH2

Prpybox-diPh (5.5 mol %), CuPF6(CH3CN)4 (5 mol %), CHCl3, 0 °C to rt up to 99%

HN

Ar1

Ph Ph

Ar

O

O

N N

N

Ph Ph

R up to 96% ee Org. Lett. 2006, 8, 2405.

2. Current work HN H 2N R 1 NH R

O Ar

Cooperative Catalysis Chiral CuI-box

Ar

Propargylation N H 6-8

5

R1

R

Base Cyclization

HN R1 N R

Ar

10

I

Scheme 1: Propargylation via chiral Cu -box complex followed by base mediated cyclization for the synthesis of (indol-2-yl)methanamines. 2


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Chiral propargylamines can serve as a key intermediate for the synthesis of bioactive molecules like (indol-2-yl)methanamines.21 In 2002 Li and co-workers developed the first catalytic enantioselective alkynylation of in situ generated aldimines with terminal alkynes catalyzed by Cu(I)Pybox to synthesis enantioenriched propargylamines22a and later, in 2006 our group reported the chiral Cu(I)-iPr-diPh-pybox catalyzed one-pot three-component reaction for the enantioselective synthesis of propargylamines using commercially available starting materials (Scheme 1).22b This protocol was operationally simple, and furnished a wide range of propargylamines in high yields and excellent enantioselectivies (up to 99% ee). Inspired by our previous results, here, we have proposed a practical approach for the synthesis of (indol-2-yl)methanamines using a chiral CuI-box (4) catalyzed three-component alkynylation (A3-coupling)/cyclization sequence using readily available starting materials.

Results and Discussion Initially, the model reaction was carried out via three-component alkynylation and cyclization process using 0.2 mmol of benzaldehyde, 0.2 mmol p-anisidine and 0.24 mmol 2-ethynylaniline with 10 mol % CuI- complex of ligand 4a in dichloromethane at room temperature under inert atmosphere (Table 1, entry 1). Unfortunately, the reaction did not proceed even after 2 days and similar results were observed when CuI-complexes of other bisoxazolidines (box) ligands 4b-c were screened (Table 1, entries 2-3). Since pybox ligands were found to be efficient for the enantioselective alkynylation reaction,22 it was worthwhile to utilize these ligands for our alkynylation/cyclization cascade. Towards this, the reaction was conducted with CuI-pybox (4d) in dichloromethane at room temperature. Delightfully, the propargylamine 6a was obtained in 33% yield with 55% enantioselectivity (Table 1, entry 4). However, we did not observe the expected cyclized indole derivative 10 even after 3 days. Table 1: Screening of catalyst and acid additive. R1 R1 H O

O

O N

N

N

N

H

R R R = i-Pr, R1 = Me, 4a R = t-Bu, R1 = H, 4b

H

O

N N

R1 R1

N R

R = i-Pr, R1 = H, 4d R = i-Pr, R1 = Ph, 4e R = Ph, R1 = Ph, 4f R = i-Bu, R1 = Ph, 4g R = t-Bu, R1 = Ph, 4h

4c

O

PMP NH

[(CuOTf)2-benzene] 4 (10 mol %) acid additive (20 mol %) CH2Cl2, rt, 4 Å MS, 29 h

Ph

up to 76%

5a

Entry Ligand

O

R1 R1 R

H2N PMP NH2

O H

Additive

HN PMP

* Ph N H

NH2 ee, 6a to 88% up

Ph 10

Reaction time (hours) Yield (%)b ee (%)c

1

4a

-

48

NR

ND

2

4b

-

48

NR

ND

3

4c

-

48

NR

ND

4

4d

-

36

33

55

5

4e

-

36

35

75

6

4f

-

36

31

67

7

4g

-

36

28

72

3



Page 4 of 33

8

4h

-

36

30

69

9 10

4e 4e 4e 4e

TFA N-Boc-(L)-t-leucine

28 30

68 71

55 77

N-Boc-(L)-proline N-Boc-(D)-proline

29 29

76 75

88

11 12

−53d

a

Unless otherwise noted all the reactions were performed with 0.2 mmol of each benzaldehyde and p-anisidine and 0.24 mmol of 2-ethynyl aniline (ratio 1:1:1.2) in 2 mL in CH2Cl2. bIsolated yields. cDetermined by chiral HPLC analysis using chiral column ID. dOpposite enantiomer. NR = No Reaction. ND = Not Determined.

Importantly, the propargylamine 6a could serve as an advanced intermediate for the synthesis of indole derivative 10.21 Various pybox ligands 4e-h were screened for the three component alkynylations, CuI-4e was found to be the best to afford the propargylamine 6a in 35% yield with 75% enantiselectivity (Table 1, entries 5-8). However, the aforementioned results were unsatisfactory. In order to improve the yield and enantioselectivity further, it was thought to implement Lewis acid/Brønsted acid cooperative approach in the catalytic system. Inspired by literature reports,23,24 a variety of acid additives along with CuI-4e complex were screened for the alkynylation reaction. Interestingly, the product formation was increased dramatically when N-Boc-(L)-proline was used as an acid additive and the propargylamine 6a was obtained in 76% yield with enhanced enantioselectivity from 75% to 88% ee (Table 1, entry 11). Surprisingly, when N-Boc-(D)-proline was used as an acid additive the opposite enantiomer ent-6a was observed in 75% yield, albeit with lower enantioselectivity (Table 1, entry 12). To gain some insights into the role of Cu-4e complex and N-Boc-(L)-proline, a series of experiments were carried out and the results are summarized in Table 2. To determine the influence of N-Boc-(L)-proline on the enantioselectivity, the reaction was carried out with copper complex of racemic pybox, i.e, CuI-(±)4e in combination with either N-Boc-(L)-proline or N-Boc-(D)-proline as an acid additive for the A3 coupling, the propargylamines were obtained in good yields and moderate enantioselectivities in 60% ee (Table 2, entries 1-2). Similar results were also observed, when the copper complexes of CuI-4i and CuI-P(o-tolyl)3 were used along with N-Boc-(L)-proline (Table 2, entries 3-4). These results clearly indicate that N-Boc-(L)-proline itself can induce the chirality in A3 coupling with moderate level of enantioselectivity. Next, we turned our attention to find out the role of CuI-4e on the enantioinduction in cooperative catalysis, the background reaction was carried out utilizing CuI-4e complex with N-Boc-(D/L)-proline as an acid additive. The propargylamine 6a was obtained in 78% yield with moderate enantioselectivity in 62% ee (Table 2, entry 5). These background results clearly indicate that the combination of CuI-4e complex and N-Boc-(L)-proline are essential to achieve high level of asymmetric induction. Table 2: Control experiment for the cooperative catalysis

H2N PMP

NH2

O Ph

5a

[(CuOTf)2-benzene] 4 (10 mol %) acid additive (20 mol %) CH2Cl2, rt, 4 Å MS, reaction time (h) up to 78%

PMP NH * Ph

NH2 6a up to 76% ee

O

Ph Ph

N H

O

N

H

Ph Ph

N 4i

H

H

Reaction Time (h) Yield (%)b ee (%)c

Entry

Catalyst

Acid Additive

1

(±)-4e

N-Boc-(L)-proline

30

70

59

2

(±)-4e

N-Boc-(D)-proline

32

73

−60d 4


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3

4i

N-Boc-(L)-proline

33

75

62

4

P(o-tolyl)3

N-Boc-(L)-proline

36

65

76

5

4e

N-Boc-(D/L)-proline

29

78

62

e

a

Unless otherwise noted all the reactions were performed with 0.2 mmol of each benzaldehyde and p-anisidine and 0.24 mmol of 2-ethynyl aniline (ratio 1:1:1.2) in 2 mL CH2Cl2. bIsolated yields. cDetermined by chiral HPLC analysis using chiral column ID. dOpposite enantiomer . e20 mol% P(o-tolyl)3 was used.

After determination of the best ligand 4e with N-Boc-(L)-proline for the alkynylation reaction, different metal salts were examined, [Cu(CH3CN)4]PF6 was found to be superior in terms of yield and enantioselectivity (Table 3, entry 3). Various solvents were tested to improve the yield and enantioselectivity furthermore, 1,2-Dichloroethane (DCE) was found to be the best to furnish the product in 90% yield with 92% enantiselectivity (Table 3, entry 7). Lowering the reaction temperature has adverse effect on the rate of the reaction as well as in the enantioselectivity (Table 3, entry 12). On decreasing and increasing the catalyst loading in the A3 coupling, a negative effect on the reaction rate and enantioselectivities were observed (Table 3, entries 13-14). After extensive optimization, we found that 10 mol % Cu(CH3CN)4PF6-4e with 20 mol % of N-Boc-(L)-proline in DCE were optimal for this transformation. Table 3: Screening of metal salts and solvents.a

NH2 5a

metal salt-4e (10 mol %) N-Boc-(L)-Proline (20 mol %) H2N PMP solvent, rt, 4 Å MS, 29 h H up to 90% O Ph

PMP NH Ph Ph O Ph NH2

Solvent Yield (%)b ee (%)c

1

[(CuOTf)2-toluene]

CH2Cl2

79

86

2

[Cu(CH3CN)4]BF4 CH2Cl2

64

89

3

[Cu(CH3CN)4]PF6

CH2Cl2

82

90

4

Cu(OTf)2

CH2Cl2

60

84

5

AgOTf

CH2Cl2

NR

ND

6

[Cu(CH3CN)4]PF6

CHCl3

71

88

7

[Cu(CH3CN)4]PF6

DCE

90

92

8

[Cu(CH3CN)4]PF6

Et2O

78

80

9

[Cu(CH3CN)4]PF6

THF

44

72

10

[Cu(CH3CN)4]PF6

EtOAc

57

89

11

[Cu(CH3CN)4]PF6

toluene

68

75

d

[Cu(CH3CN)4]PF6

DCE

70

85

e

[Cu(CH3CN)4]PF6

DCE

80

92

f

[Cu(CH3CN)4]PF6

DCE

86

90

14

Ph

4e

Metal Salt

13

N

6a up to 92% ee

Entry

12

O Ph

N N

a

Unless otherwise noted all the reactions were performed with 0.2 mmol of each benzaldehyde and p-anisidine and 0.24 mmol of 2-ethynyl aniline (ratio 1:1:1.2) in 2 mL solvent. bIsolated yields. cDetermined by chiral HPLC analysis using chiral column ID. dReaction was carried out at 0°C. eReaction was carried out with 5 mol % of catalyst. fReaction was carried out with 20 mol % of catalyst. NR = No Reaction. ND = Not Determined. 5



Page 6 of 33

Having optimized conditions in hand, the substrate scope for our catalytic system was explored. First, a wide range of aromatic amines were utilized under optimized conditions which afforded the products 6a-s in synthetically viable yields (up to 94%) with excellent enantioselectivities (up to 96% ee) as shown in scheme 2. Aromatic amines having both electron donating and electron withdrawing group at para-position individually reacted smoothly and furnished the products 6a-j with good yields (up to 85%) and excellent enantioselectivities (up to 92%). Evidently, position of the substituent in the aromatic amine has significant effect on the product formation, while para-substituted anilines reacted faster as compared to ortho- and meta- substituted anilines. Unfortunately, ortho-substituted aniline did not respond to our protocol and we did not observe product 6k even after 48 hours, this might be due to sluggish formation of aldimine from sterically hindered ortho-anisidine. R

NH R NH2 [Cu(CH3CN)4]PF6 4e (10 mol %) Ph N-Boc-(L)-Proline (20 mol %) DCE, rt, 4 Å MS O NH2 up to 94% Ph H propargylamine, 6a-s up to 96% ee -

NH2 5a

Ph O

NH2 6a-j

R1 = OMe, 29 h, 90%, 92% ee, 6a R1 = SMe, 30 h, 71%, 86% ee, 6b R1 = t-Bu, 31 h, 80%, 84% ee, 6c NH R1 = Me, 31 h, 75%, 88% ee, 6d Ph R1 = H, 31 h, 70%, 73% ee, 6e R1 = CF3, 50 h, 59%, 73% ee, 6f R1 = CN, 60 h, 54%, 6% ee, 6g R1 = I, 36 h, 76%, 86% ee, 6h R1 = Br, 34 h, 79%, 91% ee, 6i R1 = F, 33 h, 84%, 92% ee, 6j

N

Ph

N

Ph

4e

R

R1

O Ph

N

NH Ph

NH2

6k-s

R = 2-OMe-C6H4, 48 h, NR, ND, 6k R = 3-OMe-C6H4, 33 h, 82%, 89% ee, 6l R = 3-F-C6H4, 40 h, 73%, 94% ee, 6m R = 3-CF3-C6H4, 40 h, 66%, 87% ee, 6n R = 3,4-di-OMe-C6H3, 28 h, 82%, 94% ee, 6o R = 3,4,5-tri-OMeC6H2, 28 h, 94%, 96% ee, 6p R = 3,4-di-Me-C6H3, 30 h, 89%, 92% ee, 6q R = 3,5-di-Me-C6H3, 30 h, 85%, 93% ee, 6r R = Bn, 40 h, 67%, 82% ee, 6s

Scheme 2: Scope of the reaction with various aromatic amines. Notably, di- and tri- substituted anilines also reacted well and furnished the products 6o-r in high yields up to 94% and excellent enantioselectivities up to 96%. It is noteworthy to mention that electronic factor has a pivotal role in the A3 coupling, aromatic amine bearing electron withdrawing groups (CF3, CN, F) took longer time for completion of the reaction as compared to amines having electron donating groups (6f, 6g, 6m and 6n vs 6o and 6p). Interestingly, aliphatic amine such as benzyl amine also responded smoothly to our protocol and yielded the product 6s in moderate yield (in 67%) and good enantioselectivity (in 82% ee). Electron rich aromatic amines such as paramethoxyphenyl (PMP) and 3,4,5-trimethoxyphenyl amines (TMP) were chosen wisely as these could be cleaved oxidatively to access unprotected amines, which can be useful for various transformations.25 Next, a wide range of aromatic aldehydes were investigated in three-component alkynylation reactions by choosing PMP-NH2 and TMP-NH2 as amine partners. A variety of propargylamines 7a-y were obtained in synthetically useful yields (up to 92%) with excellent enantioselectivities (up to 98% ee) as shown in Scheme 3. Among all para-substituted benzaldehydes, 4-tert-butyl benzaldehyde furnished the corresponding product 7h in highest level of enantioselectivity (98% ee). Notably,

6


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electron withdrawing aldehydes like 4-CN- and 4-CF3- benzaldehydes also furnished the products 7km in synthetically useful yields with albeit lower enantioselectivities (up to 86% ee). O

[Cu(CH3CN)4]PF6 4e (10 mol %) N-Boc-(L)-Proline (20 mol %)

H

up to 94%

R NH2

5a

NH2

R HN

R

X NH2

X

7a-l

R = PMP, X = F, 33 h, 76%, 81% ee, 7a R = TMP, X = F, 30 h, 84%, 88% ee, 7b R = TMP, X = Cl, 30 h, 76%, 89% ee, 7c R = TMP, X = Br, 31 h, 82%, 83% ee, 7d R = TMP, X = I, 31 h, 85%, 91% ee, 7e R = TMP, X = Me, 30 h, 78%, 89% ee, 7f R = PMP, X = t-Bu, 30 h, 88%, 90% ee, 7g R = TMP, X = t-Bu, 29 h, 92%, 98% ee, 7h R = PMP, X = Ph, 30 h, 84%, 87% ee, 7i R = TMP, X = Ph, 29 h, 74%, 95% ee, 7j R = PMP, X = CN, 33 h, 74%, 72% ee, 7k R = TMP, X = CN, 33 h, 94%, 86% ee, 7l R = TMP, X = CF3, 31 h, 74%, 82% ee, 7m

X

propargylamine, 7a-y up to 98% ee

R = 4-OMe-C6H4- (PMP) R = 3,4,5-tri-OMe-C6H2 (TMP) HN

R

DCE, rt, 4 Å MS

X NH2

HN H

NH2

7n-t

HN

R

NH2 7u-x HN

R = TMP, X = OMe, 36 h, 86%, 91% ee, 7n R = PMP, X = Me, 32 h, 84%, 92% ee, 7o R = TMP, X = Me, 30 h, 79%, 97% ee, 7p R = TMP, X = Br, 36 h, 72%, 94% ee, 7q R = PMP, X = F, 32 h, 87%, 89% ee, 7r R = TMP, X = F, 31 h, 90%, 96% ee, 7s R = TMP, X = NO2, 48 h, 49%, 91% ee, 7t

R = TMP, X = 3-F, 30 h, 91%, 93% ee, 7u R = PMP, X = 2,3-di-Me, 36 h, 90%, 93% ee, 7v X R = TMP, X = 2,3-di-Me, 36 h, 79%, 94% ee, 7w R = TMP, X = 2,4-di-Cl, 36 h, 80%, 95% ee, 7x

R

R = TMP, 36 h, 85%, 90% ee, 7y NH2

7y

Scheme 3: Scope of the reaction with series of aromatic aldehydes. A variety of ortho-substituted benzaldehydes were subjected to A3 coupling under the optimized conditions. Most of them proceeded well and the products 7n-t were obtained with up to 90% yields and up to 96% enantioselectivities. It was observed that the ortho-subtituted benzaldehydes were superior over para-substituted benzaldehydes in terms of optical yield (7p, 7q and 7s vs 7f, 7d and 7b), it might be due to a favorable steric effect at the ortho-position. Furthermore, we extended our catalytic system to di- and tri-substituted benzaldehydes all of them reacted smoothly and yielded the products 7u-x in high yields (up to 90%) with excellent enantioselectivities (up to 95%). It is noteworthy to mention that aliphatic aldehyde such as pivalaldehyde also responded well to our protocol and afforded the product 7y in 85% yield with 90% enantioselectivity. Later, the three-component reactions were carried out with differently substituted 2-ethynyl anilines with substituted benzaldehydes under the optimized conditions. Rewardingly, an array of Nsubstituted 2-ethynyl anilines were furnished the products 8a-f in synthetically viable yields (up to 87%) with excellent enantioselectivities (up to 96% ee) as shown in scheme 4. Sterically less hindered N-substituted 2-ethynylanilines (N-Acetyl- and N-Ethyl- 2-ethynylanilines) afforded the products in high enantioselectivities as compared to more bulky N-Tosyl-2-ethynyl aniline (8b, 8d and 8e vs 8a and 8c). Moreover, a variety of 2-ethynyl anilines bearing diverse substituent on the aromatic ring also proceeded well and yielded the products 8e-i in good yields (up to 87%) with high level of enantioselectivities (up to 95% ee) as shown in Scheme 4. In order to show the practical efficacy of the methodology, an A3 coupling reaction was carried out in large scale (4.0 mmol) under the optimized conditions and afforded the product 6a in 80% yield with 87% enantioselectivity.

7



O H Y

R1

[Cu(CH3CN)4]PF6 4e (10 mol %) N-Boc-(L)-Proline (20 mol %) DCE, rt, 4 Å MS

X

NH 5b-j

HN

HN

PMP

8a-b

NH R

R = Ts, 33 h, 87%, 79% ee, 8a R = Ac, 31 h, 79%, 90% ee, 8b

X NH2 propargylamine, 8a-k up to 96% ee

TMP

HN

F NH R

NH

Y

up to 87% R1 NH2 = R1 4-OMe-C6H4 (PMP) R1 = 3,4,5-tri-OMe-C6H2- (TMP)

R

Page 8 of 33

Y

TMP

F NH2

8c-f

R = Ts, 30 h, 87%, 72% ee, 8c R = Ac, 28 h, 79%, 96% ee, 8d R = Et, 28 h, 78%, 94% ee, 8e R = Bn, 30 h, 70%, 91% ee, 8f

8g-k Y = 4 CH3, 29 h, 82%, 92% ee, 8g Y = 5-Cl, 30 h, 70%, 92% ee, 8h Y = 4 Br, 31 h, 87%, 95% ee, 8i Y = 4 COOMe, 36 h, 84%, 94% ee, 8j Y = 4-CN, 36 h, 73%, 95% ee, 8k

Scheme 4: Scope of the reaction with variety of 2-ethynyl anilines. To illustrate the synthetic utility of our methodology, we converted the propargylamines into synthetically useful intermediates by exploiting the reactivity of alkyne moiety through hydrogenation using Lindlar catalyst. The compounds 8a and 8b were converted into corresponding olefins 9a-b in high yields (up to 93%) with slight erosion in the enantiopurities (Scheme 5). MeO NH

OMe

MeO p-Ts-Cl (1.2 equiv) , pyridine, CH2Cl2 rt, 4 h 90% yield

NH2

NH

Lindlar Cat. (10 mol %) HN H2 (1 atm), EtOAc, rt, 8 h Ph up to 93%

NHR

92% ee, 6a PMP NH N Ts

PMP K2CO3 (4.0 equiv.) CH3CN, 40 °C R = Ts, 92% ee, 8a

92% ee, 10a R

NHR R = Ts, 93%, 85% ee, 9a R = Ac, 91%, 90% ee, 9b

R = Ts, 92% ee, 8a R = Ac, 90% ee, 8b

90% yield

NH

K2CO3 (4.0 equiv.) CH3CN, 40 °C

NH R

NH

X

R NH

1. p-Ts-Cl (1.2 equiv), pyridine, CH2Cl2, 2. K2CO3 (4.0 equiv.) CH3CN, 40 °C

NH2

N Ts X

up to 88%

6-7

compound decomposed

R = H, 92% ee, 6a

10a-g up to 95% ee

R = PMP, X = H, 92% ee, 6a R = TMP, X = H, 96% ee, 6p R = PMP, X = 4-t-Bu,90% ee, 7g R = PMP, X = 4-Ph, 87% ee, 7i R = PMP, X = 2-Me, 92% ee, 7o R = PMP, X = 2-F, 89% ee, 7r R = PMP, X = 2,3-Dimethyl, 93% ee, 7v

R = PMP, X = H, 88%, 92% ee, 10a R = TMP, X = H, 83%, 95% ee, 10b R = PMP, X = 4-t-Bu, 81%, 90% ee, 10c R = PMP, X = 4-Ph, 70%, 87% ee, 10d R = PMP, X = 2-Me, 82%, 92% ee, 10e R = PMP, X = 2-F, 86%, 89% ee,10f R = PMP, X = 2,3-Dimethyl, 84%, 92% ee, 10g

Scheme 5: Synthetic utility of propargylamines and synthesis of (indol-2-yl)methanamines.

8


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Having synthesized a wide range of propargylamines, we turned our attention towards the synthesis of biologically active (indol-2-yl)methamines 10 which was our target molecule. Towards this, compound 8a was treated with potassium carbonate in acetonitrile at 40 ºC, which afforded the expected indole moiety 10a (CCDC 1872513) in 90% yield without loss of enantiopurity.21 Unfortunately, when the propargylamine 6a was treated under the similar condition, a complex mixture was observed and the starting material was decomposed. Moreover, we converted the functionally diverse propargylamines (6 and 7) into corresponding indole derivatives 10a-g via tosylation followed by base mediated 5-endo-dig cyclization. Substituted (indol-2-yl)methanamines 10a-g were furnished with up to 88% yields over two steps with retention of enantioselectivities (Scheme 5). The X-ray crystal structure analysis of compound 10a confirmed the absolute stereochemistry to be (R). The absolute stereochemistry of the other products within the series and the propargylamines 6-8 were determined by analogy. To rationalize the absolute stereochemistry, we propose a plausible transition state, based on our experimental results.22b,24 It is hypothesized that 2ethynyl aniline reacts with chiral CuI-4e complex and forms copper-acetylide and simultaneously aldimine was activated by N-Boc-(L)-proline through hydrogen bonding. Later, the chiral copper acetylide approaches the activated imine from the Si-face, as the Re-face was hindered by the chiral N-Boc-(L)-proline and it afforded the desired propargylamines as (R)-isomer (Figure 2). O

H

O H O

Ph Ph (S)

N

N CuI

O N

Ph Ph (S)

(S)

O

N O

N

R

HN

HN

(R)

NH2

NH2

H H

R (R)

H

H 2N Si-face approach to imine R HN Ts N

(R)

H

(R)

N HN Ts

H R

10a CCDC 1872513

Figure 2: Plausible Transition State.

Conclusion We have reported a highly efficient CuI-iPrpyboxdiPh-complex/N-Boc-(L)-proline cooperative catalytic system for the enantioselective synthesis of propargylamines in high yields up to 94% with excellent enantioselectivities up to 98% using readily available starting materials. Salient features of this reaction are (i) functionally diverse amines, aldehydes and 2-ethynyl anilines were utilized, (ii) reaction proceeds well at ambient temperature, (iii) operationally simple and mild condition. The products were transformed into useful intermediates and the methodology has been successfully exploited in the synthesis of indole derivatives over two steps with retention of enantioselectivity.

9



Page 10 of 33

Experimental Section Materials and Methods All reactions were carried out in oven dried glassware with magnetic stirring. All solvents were purified and dried according to standard methods prior to use. 1H NMR spectra were recorded on 400 MHz or 500 MHz in CDCl3 and DMSO-d6. 13C{1H}NMR spectra were recorded on 100 or 125 MHz in CDCl3 and DMSO-d6 using TMS or residual solvent signals as internal standard. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, coupling constant (s) in Hz, integration). Data for 13 C{1H}NMR are reported in terms of chemical shift (δ, ppm). High resolution mass spectra (HRMS) were obtained by the ESI (Q-TOF) ionization sources. IR spectra were measured with FT/IR Vector 22 spectrometer. Optical rotations were measured on a commercial automatic polarimeter and reported as follows: [α]DT (c = g/100 mL, solvent). Routine monitoring of reactions were performed using precoated silica gel TLC plates from E-Merck. All the chromatographic separations were carried out by using silica gel (Acme’s, 100-200 mesh). Melting points were recorded by using a melting point apparatus and are uncorrected. The enantioselectivity was determined by chiral HPLC analysis using chiralpak IA, IC, ID and chiralcel-ODH, with a 254 UV-detector by using iso-propanol and n-hexane as eluent at 25 °C. Starting materials such as aldehyde and amines are commercially available. All the Box (4ac) and Pr-pybox (4d) ligands are commercially available. N-Boc-prolines are commercially available. All pyboxdiPh (4e-h) ligands are synthesized according to the literature known procedures.22b,26 i

General Procedure and characterization data for the synthesis of 2,6-bis(5,5-diphenyl-4,5dihydrooxazol-2-yl)pyridine (4i): 22,26 2-amino-1,1-diphenylethan-1-ol (4ia) was synthesized according to reported procedure.27 General Procedure for Synthesis of N2,N6-bis(2-hydroxy-2,2-diphenylethyl)pyridine-2,6dicarboxamide (4ib): To a stirred solution of 2-amino-1,1-diphenylethan-1-ol (1.86 g, 8.2 mmol) and Et3N (3.0mL, 22 mmol) in CH2Cl2 (30 mL) was added drop wise a solution of dipicolinyl chloride (812 mg, 4 mmol) in 5 mL of CH2Cl2 at 0 °C, and the mixture was stirred for 12 h (0 °C to rt). Upon completion of the reaction (monitored by TLC), the mixture was diluted with CH2Cl2 (40 mL) and washed with aqueous sat. NaHCO3, water, and brine. The combined organic layer was dried over Na2SO4, and the solvent was evaporated in vacuum. Purification by column chromatography over silica gel gave pure amidoalcohol as white solid. N2,N6-bis(2-hydroxy-2,2-diphenylethyl)pyridine-2,6-dicarboxamide (4ib): White solid, 2.0 g, 90% yield. Rf = 0.2 (80% EtOAc in hexanes).1H NMR (400 MHz, Chloroform-d + DMSO-d6) δ 8.39 (t, J = 5.9 Hz, 2H), 8.19 (d, J = 7.7 Hz, 2H), 7.89 (t, J = 7.8 Hz, 1H), 7.48 – 7.46 (m, 7H), 7.27 – 7.24 (m, 9H), 7.16 (t, J = 7.3 Hz, 4H), 5.09 (s, 2H), 4.19 (d, J = 6.0 Hz, 4H). 13C{1H}NMR (100 MHz, CDCl3 + DMSO-d6) δ 163.7, 148.4, 145.2, 138.9, 128.3, 127.2, 126.3, 124.9, 78.3, 49.1. IR (film) νmax 3388, 2920, 2851, 1732, 1663, 1538, 1453, 1363, 1304, 1251, 1156, 1076, 997, 854, 744, 646 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C35H32N3O4 [M+H]+: 558.2398; Found: 558.2395. MP: 230−232 °C General procedure for cyclization of amido alcohols (4ib) to 2,6-bis(5,5-diphenyl-4,5dihydrooxazol-2-yl)pyridine (4i).26 Methanesulfonic acid (1.3 mL, 20 mmol) was added drop wise to a solution of amidoalcohol (1.4 g, 2.5 mmol) in CH2Cl2 (60 mL) at 0 °C over a period of approximately 10 min. and the reaction mixture was stirred for 30 min. at the same temperature. Later 10


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


the reaction mixture was warmed slowly to rt and stirred for another 10 h. Upon completion of the reaction (monitored by TLC), the mixture was diluted with CH2Cl2 (60 mL) and washed with aqueous sat. NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo to afford product as pale yellow solid, which was purified by column chromatography. 2,6-bis(5,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine (4i): Pale yellow solid, 1.1 g, 85% yield. Rf = 0.25 (80% EtOAc in hexanes) 1H NMR (500 MHz, Chloroform-d) δ 9.2 (d, J = 11.4 Hz, 2H), 8.3 (d, J = 7.8 Hz, 2H), 8.1 (t, J = 7.7 Hz, 1H), 7.6 (d, J = 11.3 Hz, 2H), 7.5 – 7.2 (m, 16H), 7.2 – 7.0 (m, 4H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 161.1, 148.9, 140.2, 139.4, 137.2, 129.6, 129.2, 128.5, 128.0, 127.5, 127.4, 127.4, 125.6, 119.2. IR (film) νmax 3382, 3053, 1692, 1638, 1596, 1482, 1442, 1352, 1265, 1211, 1140, 1073, 998, 880, 766, 702 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C35H28N3O2 [M+H]+: 522.2179; Found: 522.2176. MP: 222−224 °C General procedure and characterization data for the synthesis of 2-ethynylanilines (5):28 2-Ethynylanilines were prepared using literature known methods.28b In an oven-dried, 2-neck, RB flask were placed PdCl2(PPh3)2 (161 mg, 0.23 mmol), CuI (44 mg, 0.23 mmol) and THF (25 ml). To this suspension were added 2-iodoaniline (2.5 mg, 11.41 mmol) and triethylamine (3.2 mL, 22.82 mmol). The reaction mixture was deoxygenated by bubbling with argon for 15 min. Trimethylsilylacetylene (2.1 mL, 14.82 mmol) was then added and the reaction mixture was stirred at rt for overnight. After complete consumption of the 2-iodoaniline (monitored by TLC), the reaction mixture was filtered through celite and the solvent removed by rotary evaporation. The crude product was dissolved in methanol (30 mL), K2CO3 (1.64 g, 17.11 mmol) was added and then the suspension stirred at rt for 4-6 h. After removal of the methanol by rotary evaporation, the residue was dissolved in water (15 ml), and the product extracted with diethyl ether (3×15 ml). The combined organic layer were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified via column chromatography on silica gel (10% EA/Hex). A similar procedure was used to prepare the other 2-ethynylanilines from 1.0 g of corresponding 2-iodoanilines. 2-Ethynylaniline (5a):28a Yellow viscous liquid, 1.13 g, 85% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.38 (dt, J = 7.6, 2.0 Hz, 1H), 7.18 (td, J = 7.7, 1.6 Hz, 1H), 6.82 – 6.55 (m, 2H), 4.28 (bs, 2H), 3.43 (s, 1H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.7, 132.7, 130.2, 117.8, 114.4, 106.6, 82.7, 80.8. IR (film) νmax 3473, 3382, 3287, 3069, 3021, 2925, 2090, 1615, 1487, 1456, 1363, 1158, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C8H8N [M+H]+: 118.0636; Found: 118.0651. 2-Ethynyl-4-methylaniline (5b):28b Orange Solid, 467 mg, 83% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.18 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.3, 2.0 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 4.14 (bs, 2H), 13 1 3.39 (s, 1H), 2.24 (s, 3H). C{ H}NMR (125 MHz, Chloroform-d) δ 146.2, 132.7, 131.0, 127.1, 114.5,

106.7, 82.2, 80.8, 20.2. IR (film) νmax 3462, 3367, 3292, 3021, 2925, 2867, 2101, 1620, 1503, 1299, 1257 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C9H10N [M+H]+: 132.0808; Found: 132.0809. MP: 36−37 °C 5-Chloro-2-ethynylaniline (5c):28b Orange Solid, 436 mg, 73% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.22 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 4.30 (bs, 2H), 3.39 (s, 1H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 149.4, 135.8, 133.6, 118.0, 114.0, 105.1, 83.2, 79.7. IR (film) νmax 3473, 3377, 3292, 2361, 2101, 1612, 1562, 1490, 1426, 1262, 1092, cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C8H7ClN [M+H]+: 152.0262; Found: 152.0254. MP: 58−59 °C 11



Page 12 of 33

4-Bromo-2-ethynylaniline (5d):28d Pale yellow solid, 546 mg, 83% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.6, 2.4 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 4.24 (bs, 2H), 3.40 (s, 1H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 147.5, 134.7, 133.0, 115.8, 108.7, 108.4, 83.6, 79.2. IR (film) νmax 3420, 3319, 3292, 3058, 2930, 1615, 1485, 1402, 1251, 1150 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C8H7BrN [M+H]+: 195.9756; Found: 195.9736. MP: 65−66 °C Methyl 4-amino-3-ethynylbenzoate (5e):28b Pale yellow solid, 486 mg, 77% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.80 (dd, J = 8.6, 2.0 Hz, 1H), 6.67 (dd, J = 8.6, 1.5 Hz, 1H), 4.78 (bs, 2H), 3.85 (s, 3H), 3.42 (s, 1H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 166.5, 152.3, 134.9, 131.8, 119.0, 113.3, 105.7, 83.1, 79.5, 51.8. IR (film) νmax 3478, 3372, 3281, 2957, 2361, 2090, 1700, 1620, 1503, 1437, 1299, 1259 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C10H10NO2 [M+H]+: 176.0706; Found: 176.0698. MP: 109−110 °C 4-Amino-3-ethynylbenzonitrile (5f):28b Pale yellow solid, 413 mg, 71% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.56 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.6, 2.0 Hz, 1H), 6.70 (dd, J = 8.6, 1.4 Hz, 1H), 4.91 (bs, 2H), 3.47 (s, 1H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.0, 136.9, 133.6, 119.4, 114.1, 106.7, 99.5, 84.3, 78.3. IR (film) νmax 3468, 3367, 3281, 2367, 2223, 1633, 1617, 1503, 1318, 898 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C9H7N2 [M+H]+: 143.0604; Found: 143.0601. MP: 105−106 °C N-benzyl-2-ethynylaniline (5g):28b Brown viscous liquid, 543 g, 81% yield 1H NMR (400 MHz, Chloroform-d) δ 7.38 (d, J = 6.3 Hz, 5H), 7.31 (dd, J = 6.0, 2.6 Hz, 1H), 7.22 – 7.15 (m, 1H), 6.65 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 5.11 (s, 1H), 4.44 (d, J = 5.7 Hz, 2H), 3.42 (s, 1H). 13 C{1H}NMR (100 MHz, Chloroform-d) δ 149.4, 139.0, 132.7, 130.4, 128.7, 127.3, 127.2, 116.5, 109.9, 106.3, 83.1, 80.8, 47.7. IR (film) νmax 3414, 3292, 3063, 2925, 2851, 2090, 1596, 1572, 1506, 1450, 744 cm-1 HRMS (ESI-TOF) m/z: Exact mass calcd for C15H14N [M+H]+: 208.1121; Found: 208.1102. General procedure and characterization data of N-(2-ethynylphenyl)acetamide (5h):29 N-(2-Ethynylphenyl)acetamide (5h) was synthesized according to the literature procedure.29 To a mixture of 2-ethynylaniline (500 mg, 4.3 mmol), triethylamine (0.9 mL, 6.4 mmol), DMAP (52.5 mg, 0.43 mmol) were taken in dry dichloromethane (8 mL), then acetyl chloride was added ( 460 µL, 6.46 mmol) drop wise to the reaction mixture at 0 °C and the mixture was warmed to rt slowly and stirred for overnight. The reaction was quenched by water, extracted with ethyl acetate twice. The organic layer were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified via column chromatography on silica gel (10% EA/Hex). N-(2-Ethynylphenyl)acetamide (5h):29 Orange solid. 591 mg, 87% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.42 (d, J = 8.4 Hz, 1H), 7.93 (bs, 1H), 7.48 (dd, J = 7.8, 1.6 Hz, 1H), 7.38 (ddd, J = 8.7, 7.5, 1.5 Hz, 1H), 7.09 – 7.02 (m, 1H), 3.53 (s, 1H), 2.25 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 168.3, 139.6, 132.2, 130.2, 123.3, 119.3, 110.5, 84.3, 79.3, 24.9. IR (film) νmax 3281, 2361, 1665, 1572, 1525, 1437, 1368, 1294, 1254, 1012, 760 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C10H10NO [M+H]+: 160.0757; Found: 160.0737. M P: 80−82 °C. General procedure and characterization methylbenzenesulfonamide (5i):21a

data

of

N-(2-ethynylphenyl)-4-

12


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N-(2-Ethynylphenyl)-4-methylbenzenesulfonamide (5i) was synthesized according to the literature procedure.21a To a mixture of 2-ethynylaniline (500 mg, 4.3 mmol), pyridine (0.77 mL, 9.5 mmol), DMAP (52.5 mg, 0.43 mmol) were taken in dry dichloromethane (8 mL), then ptoluenesulphonyl chloride (p-Ts-Cl) was added (991 mg, 5.19 mmol) portion wise to the reaction mixture at 0 °C and the mixture was warmed to rt slowly and stirred for overnight. The reaction was quenched by water, extracted with ethyl acetate (10 mL x 2). The combined organic layer were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified via column chromatography on silica gel (10% EA/Hex). N-(2-Ethynylphenyl)-4-methylbenzenesulfonamide (5i):21a White solid, 0.80 g, 69% yield. 1H NMR (500 MHz, Chloroform-d) δ 7.72 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 8.3, 1.0 Hz, 1H), 7.35 (dd, J = 7.8, 1.5 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 3.40 (s, 1H), 2.38 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 144.1, 138.5, 135.9, 132.5, 130.2, 129.7, 127.3, 124.2, 119.3, 112.7, 84.4, 84.4, 78.6, 21.6. IR (film) νmax 3281, 3063, 1599, 1578, 1490, 1448, 1397, 1341, 1280, 1089, 914 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C15H14NO2S [M+H]+: 272.0740; Found: 272.0718. M P: 57−59 °C. General procedure and characterization data of N-ethyl-2-ethynylaniline (5j):30a N-Ethyl-2-ethynylaniline (5i) was synthesized according to the literature known modified procedure.30b N-Acetyl-2-iodoaniline (2.0 g, 7.66 mmol) was dissolved in dry THF and cooled to 0 °C. NaBH4 (551 mg, 30.64 mmol) was added portion wise over 10 minutes to the mixture and stirred for 30 minutes and then BF3.OEt2 (4.7 mL, 38.30 mmol) was added and continued the starring at 0 °C. After 1 hour the mixture was slowly warmed to rt and stirred for one day. Upon completion of the reaction, the mixture was quenched by the addition of ice water and solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with aqueous sat. NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated in vacuum. The crude material was converted into the title compound using literature known procedure.28b N-ethyl-2-ethynylaniline (5j): Brown viscous liquid, 572 mg, 53% yield 1H NMR (400 MHz, Chloroform-d) δ 7.33 (d, J = 6.0 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.60 (d, J = 8.2 Hz, 2H), 4.53 (bs, 1H), 3.41 (s, 1H), 3.22 (dd, J = 7.2, 5.3 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 149.6, 132.7, 130.4, 116.0, 109.5, 106.0, 82.7, 80.9, 38.0, 14.7. IR (film) νmax 3409, 3292, 3079, 2973, 2867, 2095, 1604, 1575, 1509, 1456, 1320, 1283, 1164, 750 cm-1. HRMS (ESITOF) m/z: Exact mass calcd for C10H12N [M+H]+: 146.0964; Found: 146.0940. General procedure and characterization data for the synthesis of proprgylamine 6a–8k: The solution of [Cu(CH3CN)4]PF6 (7.45 mg, 0.02 mmol) and iPr-Pybox-diPh (4e) (14.54 mg, 0.024 mmol) in 2 mL DCE stirred at rt for 30 min and then aniline (0.2 mmol), aldehyde (0.2 mmol) and 50 mg of 4 Å molecular sieves (MS), were added to the reaction mixture and stirred for another one hour. Later N-Boc-(L)-Proline (8.6 mg, 0.04 mmol) and 2-ethynylaniline (0.24) were added and the reaction mixture was stirred at rt. Upon completion of the reaction (monitored by TLC, 28-36 h) the mixture was purified by column chromatography using silica gel with EtOAc/Hexane as eluent. (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-methoxyaniline (6a): Yellow viscous liquid, 59 mg, 90% yield. Rf = 0.35 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 7.4 Hz, 2H), 7.50 – 7.43 (m, 2H), 7.42 – 7.36 (m, 1H), 7.31 – 7.26 (m, 1H), 7.15 – 7.08 (m, 1H), 6.84 (q, J = 9.1 Hz, 4H), 6.72 – 6.63 (m, 2H), 5.55 (s, 1H), 3.96 (s, 3H), 3.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.1, 148.1, 140.7, 139.7, 132.0, 129.7, 128.8, 128.2, 127.4, 117.7, 13



Page 14 of 33

116.3, 114.8, 114.2, 107.4, 94.1, 82.1, 55.7, 52.1. IR (film) νmax 2925, 2856, 2186, 1615, 1511, 1243, 1034, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H21N2O [M+H]+: 329.1648; Found: 329.1647. [α]D25 = +106.4 (CHCl3, c = 0.93 for 92% ee). HPLC (Chiralpak ID, n-hexane/ isopropanol = 80/20, 1.0 mL/min, 254 nm): tR = 15.41 min (minor), 20.87 min (major) (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-(methylthio)aniline (6b): Yellow viscous liquid, 49 mg, 71% yield. Rf = 0.35 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.71 (dd, J = 7.4, 1.7 Hz, 2H), 7.45 (dd, J = 8.4, 6.7 Hz, 2H), 7.42 – 7.36 (m, 1H), 7.29 – 7.24 (m, 3H), 7.15 – 7.09 (m, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.71 – 6.62 (m, 2H), 5.59 (s, 1H), 4.18 (s, 1H), 4.00 (s, 2H), 2.46 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 145.2, 139.3, 132.1, 130.7, 129.8, 128.9, 128.3, 127.4, 126.3, 117.7, 115.1, 114.2, 107.2, 93.5, 82.1, 51.1, 18.6. IR (film) νmax 3468, 3367, 3026, 2920, 2367, 2207, 1604, 1493, 1315, 1185, 970, 816, 744 cm-1. HRMS (ESITOF) m/z: Exact mass calcd for C22H21N2S [M+H]+: 345.1420; Found: 345.1401. [α]D25 = +115.4 (CHCl3, c = 1.03 for 86% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 9.42 min (minor), 12.07 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-(tert-butyl)aniline (6c): Pale yellow viscous liquid, 56 mg, 80% yield. Rf = 0.39 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.74 – 7.67 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.39 – 7.34 (m, 1H), 7.29 – 7.23 (m, 3H), 7.10 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 6.68 – 6.59 (m, 2H), 5.58 (s, 1H), 4.05 (s, 1H), 3.93 (s, 2H), 1.31 (s, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 144.3, 141.7, 139.8, 132.1, 129.7, 128.8, 128.1, 127.4, 126.0, 117.7, 114.3, 114.2, 107.4, 94.1, 81.9, 51.4, 34.0, 31.6. IR (film) νmax 3478, 3377, 2950, 2208, 1615, 1453, 1307, 1263, 824, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H27N2 [M+H]+: 355.2169; Found: 355.2145. [α]D25 = +100.8 (CHCl3, c = 0.80 for 84% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 0.5 mL/min, 254 nm): tR = 11.82 min (minor), 12.62 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-methylaniline (6d): Yellow viscous liquid, 46.5 mg, 75% yield. Rf = 0.41 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 (dd, J = 7.4, 1.6 Hz, 2H), 7.45 (dd, J = 8.4, 6.8 Hz, 2H), 7.42 – 7.36 (m, 1H), 7.32 – 7.25 (m, 1H), 7.12 (td, J = 7.8, 1.6 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.72 – 6.63 (m, 2H), 5.59 (s, 1H), 3.99 (s, 3H), 2.30 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 144.4, 139.7, 132.1, 129.7, 129.7, 128.8, 128.2, 128.1, 127.4, 117.7, 114.7, 114.2, 107.4, 94.0, 81.9, 51.4, 20.5. IR (film) νmax 3473, 3372, 3037, 2920, 2861, 2218, 1601, 1433, 1312, 1262, 1021, 824, 747 cm1 . HRMS (ESI-TOF) m/z: Exact mass calcd for C22H21N2 [M+H]+: 313.1699; Found: 313.1715. [α]D25 = +112.0 (CHCl3, c = 1.9 for 88% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 14.29 min (minor), 17.59 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)aniline (6e): Colorless viscous liquid, 42 mg, 70% yield. Rf = 0.42 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 7.4 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.42 – 7.35 (m, 1H), 7.29 – 7.23 (m, 3H), 7.11 (td, J = 7.8, 1.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 3H), 6.71 – 6.61 (m, 2H), 5.63 (s, 1H), 4.03 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 146.6, 139.5, 132.1, 129.7, 129.3, 128.9, 128.2, 127.4, 118.9, 117.7, 114.5, 114.2, 107.3, 93.8, 82.0, 51.1. IR (film) νmax 3380, 3051, 2918, 2184, 1596, 1498, 1311, 744 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C21H19N2 [M+H]+: 299.1543; Found: 299.1555. [α]D25 = +89.6 (CHCl3, c = 1.23 for 73% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 12.63 min (minor), 15.70 min (major).

14


Page 15 of 33 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)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-(trifluoromethyl)aniline (6f): Yellow 1 viscous liquid, 43 mg, 59% yield. Rf = 0.36 (30% EtOAc in hexanes). H NMR (500 MHz, Chloroform-d) δ 7.76 – 7.64 (m, 2H), 7.50 – 7.42 (m, 3H), 7.43 – 7.35 (m, 1H), 7.28 (s, 2H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.73 – 6.61 (m, 2H), 5.62 (d, J = 6.8 Hz, 1H), 4.51 (d, J = 7.2 Hz, 1H), 4.01 (s, 2H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.9, 148.1, 138.8, 132.2, 130.0, 129.0, 128.5, 127.3, 126.6 (q, J = 3.6 Hz), 117.8, 114.3, 113.4, 107.0, 92.8, 82.4, 50.5. IR (film) νmax 3377, 3037, 2930, 2180, 1615, 1493, 1328, 1163, 1063, 829, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H18F3N2 [M+H]+: 367.1417; Found: 367.1435. [α]D25 = +31.67 (CHCl3, c = 0.2 for 73% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 90/10, 1.0 mL/min, 254 nm): tR = 8.03 min (minor), 8.77 min (major). (R)-4-((3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)amino)benzonitrile (6g): yellow viscous liquid, 35 mg, 54% yield. Rf = 0.41 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroformd) δ 7.71 (dd, J = 6.9, 1.4 Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.40 – 7.39 (m, 2H), 7.35 – 7.32 (m, 1H), 7.26 – 7.23 (m, 2H), 7.21 – 7.18 (m, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 8.8 Hz, 2H), 5.09 (d, J = 5.2 Hz, 1H).13C{1H}NMR (125 MHz, Chloroform-d) δ 148.6, 138.4, 134.9, 133.9, 129.5, 129.4, 129.3, 126.3, 124.3, 122.2, 121.4, 120.4, 119.7, 113.3, 109.6, 102.8, 101.7, 68.7. IR (film) νmax 3345, 3058, 2920, 2851, 2218, 1896, 1604, 1517, 1453, 1328, 1177, 1081, 1015, 884, 742.cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H18N3 [M+H]+: 324.1495; Found: 324.1468. [α]D25 = -19.57 (CHCl3, c = 0.47 for 6% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 95/05, 1.0 mL/min, 254 nm): tR = 21.32 min (minor), 23.91 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-iodoaniline (6h): Yellow viscous liquid, 65 mg, 76% yield. Rf = 0.38 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.75 – 7.65 (m, 2H), 7.53 – 7.48 (m, 2H), 7.48 – 7.43 (m, 2H), 7.42 – 7.37 (m, 1H), 7.30 – 7.26 (m, 1H), 7.14 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.72 – 6.65 (m, 2H), 6.64 – 6.57 (m, 2H), 5.56 (s, 1H), 4.22 (s, 1H), 4.02 (s, 2H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 146.1, 139.1, 137.8, 132.2, 129.9, 128.9, 128.4, 127.3, 117.8, 116.5, 114.3, 107.1, 93.1, 82.3, 79.8, 50.8. IR (film) νmax 3382, 2920, 2856, 2180, 1612, 1594, 1487, 1312, 1312, 1182, 1055, 816, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C21H16IN2 [M-H]−: 423.0353; Found: 423.0327. [α]D25 = +101.1 (CHCl3, c = 2.03 for 86% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 12.60 min (minor), 16.28 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-bromoaniline (6i): Yellow viscous liquid, 59 mg, 79% yield. Rf = 0.37 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 – 7.65 (m, 2H), 7.48 – 7.42 (m, 2H), 7.42 – 7.36 (m, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.29 – 7.26 (m, 1H), 7.13 (td, J = 7.8, 1.5 Hz, 1H), 6.76 – 6.63 (m, 4H), 5.56 (d, J = 7.1 Hz, 1H), 4.21 (s, 1H), 4.01 (s, 2H). 13 C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 145.5, 139.1, 132.2, 132.0, 129.9, 128.9, 128.4, 127.3, 117.8, 116.0, 114.3, 110.6, 107.1, 93.2, 82.3, 50.9. IR (film) νmax 3372, 2930, 2186, 1607, 1490, 1310, 1071, 811, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C21H18BrN2, [M+H]+: 377.0648; Found: 377.0644. [α]D25 = +124.6 (CHCl3, c = 1.0 for 91% ee). HPLC (Chiralpak ID, nhexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 12.03 min (minor), 16.42 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-4-fluoroaniline (6j): Yellow viscous liquid, 53 mg, 84% yield. Rf = 0.34 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.71 (d, J = 7.5 Hz, 2H), 7.45 (dd, J = 8.2, 6.6 Hz, 2H), 7.42 – 7.37 (m, 1H), 7.28 – 7.24 (m, 1H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 6.96 (dd, J = 9.7, 7.7 Hz, 2H), 6.83 – 6.74 (m, 2H), 6.70 – 6.64 (m, 2H), 5.55 (s, 1H), 4.00 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 156.6 (d, J = 236.9 Hz), 148.1, 142.9 (d, 15



Page 16 of 33

J = 2.2 Hz), 139.3, 132.1, 129.8, 128.9, 128.3, 127.4, 117.8, 115.8 (d, J = 11.3 Hz), 115.6 (d, J = 3.6 Hz), 114.2, 107.2, 93.6, 82.2, 51.7. IR (film) νmax 3473, 3382, 2930, 2180, 1615, 1503, 1453, 1312, 1219, 821, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C21H18FN2 [M+H]+: 317.1449; Found: 317.1440. [α]D25 = +85.25 (CHCl3, c = 1.2 for 92% ee). HPLC (Chiralpak ID, n-hexane/ isopropanol = 70/30, 1.0 mL/min, 254 nm): tR = 12.81 min (minor), 15.36 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3-methoxyaniline (6l): Yellow viscous liquid, 54 mg, 82% yield. Rf = 0.34 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.72 (dd, J = 7.3, 1.7 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H), 7.30 – 7.28 (m, 1H), 7.19 – 7.09 (m, 2H), 6.70 – 6.64 (m, 2H), 6.45 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 6.42 – 6.39 (m, 2H), 5.60 (s, 1H), 4.05 (s, 3H), 3.80 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.7, 148.2, 148.0, 139.5, 132.1, 130.0, 129.7, 128.9, 128.2, 127.4, 117.7, 114.2, 107.3, 107.3, 104.2, 100.4, 93.7, 82.0, 55.2, 51.0. IR (film) νmax 2975, 2806, 2116, 1625, 1531, 1456, 1223, 1104, 770 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H21N2O [M+H]+: 329.1648; Found: 329.1650. [α]D25 = +117.7 (CHCl3, c = 0.57 for 89% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 90/10, 1.0 mL/min, 254 nm): tR = 33.79 min (minor), 39.35 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3-fluoroaniline (6m): colourless viscous liquid, 46 mg, 73% yield. Rf = 0.47 (10% EtOAc in hexanes. 1H NMR (500 MHz, Chloroformd) δ 7.71 (d, J = 7.2 Hz, 2H), 7.47 (dd, J = 8.4, 6.7 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.21 – 7.10 (m, 2H), 6.72 – 6.66 (m, 2H), 6.61 – 6.50 (m, 3H), 5.58 (d, J = 6.8 Hz, 1H), 4.31 (d, J = 7.3 Hz, 1H), 4.05 (s, 2H).13C{1H}NMR (125 MHz, Chloroform-d) δ 163.9 (d, J = 243.5 Hz), 148.3 (d, J = 10.5 Hz), 139.1, 132.2, 130.4 (d, J = 10.0 Hz), 129.9, 129.0, 128.4, 127.3, 117.8, 114.3, 110.1 (d, J = 2.4 Hz), 107.2, 105.3 (d, J = 21.5 Hz), 101.2 (d, J = 25.4 Hz), 93.2, 82.3, 50.9. IR (film) νmax 3382, 3069, 2925, 2856, 2212, 1617, 1588, 1493, 1453, 1312, 1150, 1002, 835, 747.cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C21H18FN2 [M+H]+: 317.1449; Found: 317.1442. [α]D25 = +133.84 (CHCl3, c = 0.13 for 94% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 7.83 min (minor), 8.96 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3-(trifluoromethyl)aniline (6n): yellow 1 viscous liquid, 48 mg, 66% yield. Rf = 0.48 (10% EtOAc in hexanes. H NMR (500 MHz, Chloroform-d) δ 7.71 (dd, J = 7.2, 1.8 Hz, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.43 – 7.39 (m, 1H), 7.36 – 7.31 (m, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.15 – 7.11 (m, 1H), 7.07 (dd, J = 6.6, 1.3 Hz, 2H), 6.99 – 6.95 (m, 1H), 6.72 – 6.65 (m, 2H), 5.63 (d, J = 7.1 Hz, 1H), 4.37 (d, J = 7.5 Hz, 1H), 4.02 (s, 2H).13C{1H}NMR (125 MHz, Chloroform-d) δ 148.1, 146.7, 138.9, 132.2, 129.9, 129.7, 129.0, 128.5, 127.4, 125.3, 123.1, 117.8, 117.2, 115.16 (q, J = 3.9 Hz), 114.3, 110.6, 107.0, 92.8, 82.4, 50.7. IR (film) νmax 3382, 3031, 2930, 2856, 2212, 1615, 1493, 1453, 1339, 1164, 1121, 1066, 884, 752.cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H18F3N2 [M+H]+: 367.1417; Found: 367.1400. [α]D25 = +97.02 (CHCl3, c = 0.47 for 87% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 95/05, 1.0 mL/min, 254 nm): tR = 7.24 min (major), 8.02 min (minor). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3,4-dimethoxyaniline (6o): Yellow viscous liquid, 58 mg, 82% yield. Rf = 0.31 (20% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.77 – 7.66 (m, 2H), 7.45 (dd, J = 8.2, 6.7 Hz, 2H), 7.41 – 7.38 (m, 1H), 7.29 – 7.27 (m, 1H), 7.12 (td, J = 7.7, 1.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.70 – 6.62 (m, 2H), 6.46 (d, J = 2.6 Hz, 1H), 6.42 (dd, J = 8.5, 2.6 Hz, 1H), 5.55 (s, 1H), 3.85 (d, J = 1.0 Hz, 6H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 149.8, 148.1, 142.6, 141.3, 139.6, 132.0, 129.7, 128.8, 128.2, 127.4, 117.7, 114.2, 112.8, 107.3, 105.9, 100.7, 94.0, 82.2, 56.6, 55.8, 52.0. IR (film) νmax 3468, 3361, 2925, 1615, 1511, 1453, 1235, 1137, 16


Page 17 of 33 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


1028, 758, 699 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C23H23N2O2 [M+H]+: 359.1754; Found: 359.1775. [α]D25 = +36.4 (CHCl3, c = 0.80 for 94% ee). HPLC (Chiralpak IB, n-hexane/ isopropanol = 80/20, 1.0 mL/min, 254 nm): tR = 25.76 min (major), 30.76 min (minor). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3,4,5-trimethoxyaniline (6p): Colourless viscous liquid, 72.5 mg, 94% yield. Rf = 0.33 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.76 – 7.69 (m, 2H), 7.49 – 7.43 (m, 2H), 7.42 – 7.36 (m, 1H), 7.31 – 7.25 (m, 1H), 7.12 (td, J = 7.8, 1.6 Hz, 1H), 6.73 – 6.57 (m, 2H), 6.09 (s, 2H), 5.57 (s, 1H), 4.39 – 3.90 (m, 3H), 3.82 (d, J = 8.6 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.8, 148.2, 143.3, 139.5, 132.0, 131.0, 129.8, 128.9, 128.3, 127.4, 117.7, 114.2, 107.2, 93.7, 92.3, 82.4, 61.1, 56.0, 51.6. IR (film) νmax 3451, 3372, 2946, 2595, 2295, 1896, 1610, 1319, 1116, 960, 885, 840 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H25N2O3 [M+H]+: 389.1860; Found: 389.1866. [α]D25 = +109.8 (CHCl3, c = 1.2 for 96% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 18.40 min (minor), 20.86 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3,4-dimethylaniline (6q): Yellow viscous liquid, 58 mg, 89% yield. Rf = 0.45 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.77 – 7.71 (m, 2H), 7.47 (td, J = 7.8, 7.4, 1.6 Hz, 2H), 7.41 (dd, J = 7.3, 1.6 Hz, 1H), 7.35 – 7.27 (m, 1H), 7.14 (dd, J = 8.6, 6.9 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.76 – 6.57 (m, 4H), 5.61 (s, 1H), 4.01 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 148.2, 144.8, 139.8, 137.3, 132.1, 130.3, 129.7, 128.8, 128.1, 127.4, 126.9, 117.7, 116.4, 114.2, 112.0, 107.5, 94.2, 81.9, 51.4, 20.1, 18.9. IR (film) νmax 3372, 2925, 2196, 1615, 1496, 1450, 1318, 1265, 805, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C23H23N2 [M+H]+: 327.1856; Found: 327.1881. [α]D25 = +129.8 (CHCl3, c = 0.7 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 9.02 min (minor), 9.97 min (major). (R)-N-(3-(2-Aminophenyl)-1-phenylprop-2-yn-1-yl)-3,5-dimethylaniline (6r): Yellow viscous liquid, 55 mg, 85% yield. Rf = 0.45 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.74 (dd, J = 7.3, 1.8 Hz, 2H), 7.49 – 7.38 (m, 3H), 7.33 – 7.26 (m, 1H), 7.13 (ddd, J = 8.9, 7.5, 1.6 Hz, 1H), 6.72 – 6.63 (m, 2H), 6.51 (d, J = 6.9 Hz, 3H), 5.62 (s, 1H), 4.04 (s, 3H), 2.31 (s, 6H). 13 C{1H}NMR (125 MHz, Chloroform-d) δ 148.2, 146.8, 139.7, 138.9, 132.1, 129.7, 128.8, 128.2, 127.4, 120.9, 117.6, 114.2, 112.4, 107.4, 94.0, 81.9, 51.0, 21.6. IR (film) νmax 3392, 2885, 2186, 1625, 1499, 1437, 1323, 1165, 888, 791 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C23H23N2 [M+H]+: 327.1856; Found: 327.1864. [α]D25 = +102.8 (CHCl3, c = 0.97 for 93% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 6.80 min (minor), 8.01 min (major). (R)-2-(3-(Benzylamino)-3-phenylprop-1-yn-1-yl)aniline (6s): Yellow viscous liquid, 42 mg, 67% yield. Rf = 0.42 (10% EtOAc in hexanes. 1H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 7.4 Hz, 2H), 7.46 – 7.43 (m, 2H), 7.42 (s, 1H), 7.41 – 7.34 (m, 5H), 7.34 – 7.30 (m, 1H), 7.17 (td, J = 7.8, 1.6 Hz, 1H), 6.76 – 6.72 (m, 2H), 4.91 (s, 1H), 4.22 (s, 2H), 4.08 – 4.01 (m, 2H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 147.9, 140.5, 139.7, 132.3, 129.6, 128.6, 128.5, 128.4, 127.8, 127.6, 127.1, 117.9, 114.3, 107.8, 94.7, 82.4, 53.9, 51.2. IR (film) νmax 3058, 2968, 2930, 1670, 1580, 1493, 1450, 1262, 1177, 962, 736. cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H21N2 [M+H]+: 313.1699; Found: 313.1702. [α]D25 = -209.75 (CHCl3, c = 1.2 for 82% ee). HPLC (Chiralpak ID, nhexane/ iso-propanol = 95/05, 1.0 mL/min, 254 nm): tR = 9.85 min (major), 11.30 min (minor). (R)-N-(3-(2-Aminophenyl)-1-(4-fluorophenyl)prop-2-yn-1-yl)-4-methoxyaniline (7a): Yellow viscous liquid, 53 mg, 76% yield. Rf = 0.31 (10% EtOAc in hexanes). 1H NMR (500 MHz, 17



Page 18 of 33

Chloroform-d) δ 7.76 – 7.65 (m, 2H), 7.32 – 7.23 (m, 1H), 7.17 – 7.06 (m, 3H), 6.88 – 6.76 (m, 4H), 6.72 – 6.58 (m, 2H), 5.51 (s, 1H), 3.93 (s, 3H), 3.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 162.5 (d, J = 246.6 Hz), 153.3, 148.1, 140.5, 135.5 (d, J = 3.3 Hz), 132.0, 129.8, 129.1 (d, J = 8.2 Hz), 117.7, 116.4, 115.6 (d, J = 21.7 Hz), 114.8, 114.2, 107.2, 93.8, 82.3, 55.7, 51.5. IR (film) νmax 3386, 3366, 2953, 2195, 1681, 1511, 1458, 1309, 1344, 1267, 1137, 1052, 912, 778 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C22H20FN2O [M+H]+: 347.1554; Found: 347.1533. [α]D25 = +99.8 (CHCl3, c = 1.0 for 81% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 11.31 min (minor), 15.14 min. (major). (R)-N-(3-(2-Aminophenyl)-1-(4-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7b): Colourless viscous liquid, 68 mg, 84% yield. Rf = 0.31 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.69 (dd, J = 8.6, 5.3 Hz, 2H), 7.33 – 7.24 (m, 1H), 7.17 – 7.09 (m, 3H), 6.74 – 6.62 (m, 2H), 6.08 (s, 2H), 5.54 (s, 1H), 4.05 (s, 3H), 3.81 (d, J = 9.3 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 162.6 (d, J = 246.9 Hz), 153.9, 148.2, 143.1, 135.2 (d, J = 3.2 Hz), 132.0, 131.2, 129.9, 129.1 (d, J = 8.2 Hz), 117.7, 115.7 (d, J = 21.7 Hz), 114.3, 107.0, 93.4, 92.4, 82.6, 61.1, 56.0, 50.9. IR (film) νmax 3486, 3322, 3052, 2859, 2203, 1657, 1615, 1432, 1260, 1157, 1060, 875, 727 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24FN2O3 [M+H]+: 407.1765; Found: 407.1774. [α]D25 = +78.8 (CHCl3, c = 1.17 for 88% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 27.78 min (minor), 40.45 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-chlorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7c): 1 Yellow viscous liquid, 64 mg, 76% yield. Rf = 0.35 (30% EtOAc in hexanes). H NMR (500 MHz, Chloroform-d) δ 7.66 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.31 – 7.24 (m, 1H), 7.13 (ddd, J = 8.5, 7.5, 1.6 Hz, 1H), 6.74 – 6.63 (m, 2H), 6.06 (s, 2H), 5.54 (s, 1H), 3.98 (d, J = 79.6 Hz, 3H), 3.81 (d, J = 7.4 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.0, 138.0, 134.1, 132.0, 131.2, 130.0, 129.0, 128.7, 117.7, 114.3, 106.9, 93.1, 92.4, 82.7, 61.1, 56.0, 51.0. IR (film) νmax 3372, 3052, 2930, 2828, 1607, 1509, 1453, 1263, 1129, 1012, 804, 739 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24ClN2O3 [M+H]+: 423.1470; Found: 423.1440. [α]D25 = +98.8 (CHCl3, c = 1.23 for 89% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 60/40, 1.0 mL/min, 254 nm): tR = 12.75 min (minor), 18.65 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-bromophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7d): 1 Yellow viscous liquid, 76 mg, 82% yield. Rf = 0.37 (30% EtOAc in hexanes). H NMR (500 MHz, Chloroform-d) δ 7.66 – 7.50 (m, 4H), 7.32 – 7.23 (m, 1H), 7.13 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.79 – 6.55 (m, 2H), 6.06 (s, 2H), 5.52 (s, 1H), 4.06 (s, 3H), 3.81 (d, J = 7.4 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.0, 138.6, 132.0, 132.0, 131.2, 130.0, 129.1, 122.2, 117.7, 114.3, 106.9, 93.0, 92.4, 82.7, 61.1, 56.0, 51.0. IR (film) νmax 3376, 3092, 2952, 2810, 1687, 1609, 1462, 1217, 1177, 1032, 855, 723 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24BrN2O3 [M+H]+: 467.0965; Found: 467.0954. [α]D25 = +70.88 (CHCl3, c = 1.5 for 83% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 60/40, 1.0 mL/min, 254 nm): tR = 13.86 min (minor), 20.45 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-iodophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7e): White solid, 82 mg, 85% yield. Rf = 0.36 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.77 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.16 – 7.08 (m, 1H), 6.74 – 6.61 (m, 2H), 6.06 (s, 2H), 5.51 (s, 1H), 4.07 (s, 3H), 3.81 (d, J = 6.6 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.0, 139.3, 137.9, 132.0, 131.2, 130.0, 129.3, 117.7, 114.3, 106.9, 93.9, 93.0, 92.3, 82.7, 61.1, 56.0, 51.1. IR (film) 1 νmax 3377, 3053, 2930, 2856, 2168, 1612, 1456, 1312, 1235, 1132, 1007, 744 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24IN2O3 [M+H]+: 515.0826; Found: 515.0807. MP: 102−103 °C. [α]D25 = +47.6 (CHCl3, c = 1.46 18


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for 91% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 23.60 min (minor), 32.72 min (major). (R)-N-(3-(2-Aminophenyl)-1-(p-tolyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7f): Colourless viscous liquid, 66 mg, 78% yield. Rf = 0.38 (30% EtOAc in hexanes 1H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 8.1 Hz, 2H), 7.26 – 7.21 (m, 3H), 7.09 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.68 – 6.58 (m, 2H), 6.07 (s, 2H), 5.49 (s, 1H), 3.80 (d, J = 13.1 Hz, 9H), 2.38 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.8, 148.2, 143.4, 138.1, 136.5, 132.0, 131.0, 129.7, 129.5, 127.3, 117.7, 114.2, 107.3, 93.9, 92.2, 82.1, 61.1, 56.0, 51.3, 21.2. IR (film) 1 νmax, 3340, 3058, 2930, 2856, 2181, 1609, 1509, 1453, 1323, 1124, 1012, 808, 739 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H27N2O3 [M+H]+: 403.2016; Found: 403.1991. [α]D25 = +85.1 (CHCl3, c = 1.13 for 89% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 11.61 min (minor), 14.66 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-(tert-butyl)phenyl)prop-2-yn-1-yl)-4-methoxyaniline (7g): Colourless viscous liquid, 68 mg, 88% yield. Rf = 0.44 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.71 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 7.7, 1.6 Hz, 1H), 7.14 (td, J = 7.7, 1.6 Hz, 1H), 6.88 (q, J = 9.1 Hz, 4H), 6.71 (td, J = 7.6, 1.2 Hz, 1H), 6.66 (dd, J = 8.1, 1.2 Hz, 1H), 5.56 (s, 1H), 3.98 (s, 2H), 3.82 (s, 3H), 1.43 (s, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.1, 151.2, 148.2, 140.9, 136.7, 132.1, 129.6, 127.3, 125.8, 117.7, 116.3, 114.8, 114.2, 107.5, 94.4, 81.9, 55.8, 51.8, 34.7, 31.0. IR (film) νmax 3468, 2957, 2920, 2851, 2186, 1620, 1511, 1456, 1241, 1034, 824, 753 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd C26H29N2O [M+H]+: 385.2274; Found: 385.2269. [α]D25 = +94.8 (CHCl3, c = 5.88 for 90% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 11.02 min (minor), 13.50 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-(tert-butyl)phenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7h): Colourless viscous liquid, 82 mg, 92% yield. Rf = 0.38 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.64 – 7.58 (m, 2H), 7.47 – 7.41 (m, 2H), 7.25 (dd, J = 7.5, 1.5 Hz, 1H), 7.12 – 7.05 (m, 1H), 6.71 – 6.54 (m, 2H), 6.08 (s, 2H), 5.51 (s, 1H), 1.35 (s, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.8, 151.4, 148.1, 143.4, 136.4, 132.0, 131.0, 129.7, 127.2, 125.8, 117.7, 114.2, 107.3, 93.9, 92.2, 82.1, 61.1, 56.0, 51.2, 34.6, 31.4. IR (film) 1 νmax 3468, 3372, 2962, 2867, 2180, 1607, 1409, 1312, 1127, 1010, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C28H33N2O3 [M+H]+: 445.2486; Found: 445.2506. [α]D25 = + 40.5 (CHCl3, c = 2.57 for 98% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 13.61 min (major), 16.08 min (minor). (R)-N-(1-([1,1'-Biphenyl]-4-yl)-3-(2-aminophenyl)prop-2-yn-1-yl)-4-methoxyaniline (7i): Colourless viscous liquid, 68 mg, 84% yield. Rf = 0.42 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.85 – 7.79 (m, 2H), 7.72 – 7.65 (m, 4H), 7.52 (dd, J = 8.5, 7.0 Hz, 2H), 7.46 – 7.41 (m, 1H), 7.34 (dd, J = 7.7, 1.6 Hz, 1H), 7.18 – 7.13 (m, 1H), 6.91 – 6.84 (m, 4H), 6.71 (td, J = 7.5, 1.1 Hz, 1H), 6.67 (dd, J = 8.1, 1.1 Hz, 1H), 5.61 (s, 1H), 4.00 (d, J = 22.1 Hz, 2H), 3.81 (s, 3H). 13 C{1H}NMR (125 MHz, Chloroform-d) δ 153.2, 148.2, 141.1, 140.7, 140.7, 138.8, 132.1, 129.8, 128.9, 127.9, 127.6, 127.6, 127.5, 127.2, 117.7, 116.4, 114.9, 114.8, 114.3, 107.4, 94.1, 82.2, 55.8, 51.9. IR (film) νmax 3377, 2920, 2851, 2200, 1617, 1511, 1450, 1312, 1241, 1036, 824, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd C28H25N2O [M+H]+: 405.1961; Found: 405.1963. [α]D25 = +50.2 (CHCl3, c = 1.56 for 87% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 21.10 min (minor), 37.79 min (major). (R)-N-(1-([1,1'-Biphenyl]-4-yl)-3-(2-aminophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7j): Yellow solid, 80 mg, 74% yield. Rf = 0.38 (30% EtOAc in hexanes). 1H NMR (500 MHz, 19



Page 20 of 33

Chloroform-d) δ 7.77 (d, J = 8.2 Hz, 2H), 7.69 – 7.59 (m, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.40 – 7.34 (m, 1H), 7.28 (dd, J = 7.7, 1.6 Hz, 1H), 7.11 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 6.74 – 6.56 (m, 2H), 6.10 (s, 2H), 5.59 (s, 1H), 4.08 (s, 3H), 3.81 (d, J = 10.6 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.3, 141.3, 140.5, 138.5, 132.0, 131.1, 129.8, 128.9, 127.9, 127.6, 127.5, 127.1, 117.7, 114.3, 107.2, 93.6, 92.3, 82.4, 61.1, 56.0, 51.3. IR (film) 1 νmax 3462, 3367, 2930, 2856, 2180, 1615, 1506, 1456, 1315, 1238, 1129, 1010, 739 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C30H29N2O3 [M+H]+: 465.2173; Found: 465.2162. MP: 98−100 °C. [α]D25 = +56.6 (CHCl3, c = 1.23 for 95% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 32.22 min (minor), 53.49 min (major). (R)-4-(3-(2-Aminophenyl)-1-((4-methoxyphenyl)amino)prop-2-yn-1-yl)benzonitrile (7k): Yellow solid, 52 mg, 74% yield. Rf = 0.46 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.84 (d, J = 8.1 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.30 – 7.23 (m, 1H), 7.13 (td, J = 7.8, 1.6 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 6.71 – 6.62 (m, 2H), 5.58 (s, 1H), 3.97 (s, 3H), 3.78 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.5, 148.2, 145.1, 140.0, 132.6, 132.1, 130.1, 128.1, 118.7, 117.8, 116.5, 114.8, 114.3, 112.0, 106.7, 92.6, 83.2, 55.7, 51.9. IR (film) νmax 3468, 3372, 2925, 2228, 1615, 1504, 1409, 1312, 1243, 1034, 824, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C23H20N3O [M+H]+: 354.1601; Found: 354.1613. MP: 93−94 °C [α]D25 = +48.33 (CHCl3, c = 1.2 for 72% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 20.73 min (minor), 38.03 min (major). (R)-4-(3-(2-Aminophenyl)-1-((3,4,5-trimethoxyphenyl)amino)prop-2-yn-1-yl)benzonitrile (7l): Colourless viscous liquid, 78 mg, 94% yield. Rf = 0.31 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.84 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.14 (ddd, J = 8.8, 7.5, 1.6 Hz, 1H), 6.78 – 6.58 (m, 2H), 6.03 (s, 2H), 5.62 (s, 1H), 4.06 (s, 3H), 3.80 (d, J = 2.1 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 144.9, 142.7, 132.7, 132.1, 131.4, 130.2, 128.1, 118.6, 117.8, 114.4, 112.1, 106.5, 92.5, 92.2, 83.4, 61.1, 56.0, 51.3. IR (film) νmax 3468, 3361, 3058, 2929, 2851, 2234, 2180, 1615, 1452, 1360, 1129, 1009, 825, 742 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H24N3O3 [M+H]+: 414.1812; Found: 414.1796. [α]D25 = +41.9 (CHCl3, c = 2.46 for 86% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 26.71 min (minor), 32.95 min (major). (R)-N-(3-(2-Aminophenyl)-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7m): White solid, 67 mg, 74% yield. Rf = 0.31 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.83 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.28 – 7.23 (m, 1H), 7.11 (ddd, J = 8.7, 7.5, 1.6 Hz, 1H), 6.71 – 6.59 (m, 2H), 6.03 (s, 2H), 5.60 (s, 1H), 4.07 (s, 3H), 3.79 (d, J = 5.0 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.5, 142.9, 132.0, 131.3, 130.1, 127.7, 125.8 (q, J = 3.8 Hz), 125.1, 117.8, 114.3, 106.7, 92.7, 92.4, 83.0, 61.1, 56.0, 51.3. IR (film) 1 νmax 3473, 3362, 3058, 2936, 2853, 2112, 1613, 1553, 1447, 1321, 1126, 1007, 803, 736 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H24F3N2O3 [M+H]+: 457.1734; Found: 457.1713. MP: 111−112 °C. [α]D25 = +51.2 (CHCl3, c = 0.6 for 82% ee). HPLC (Chiralpak ID, n-hexane/ isopropanol = 70/30, 1.0 mL/min, 254 nm): tR = 20.62 min (minor), 25.18 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2-methoxyphenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7n): Yellow viscous liquid, 72 mg, 86% yield. Rf = 0.33 (30% EtOAc in hexanes). 1H NMR (400 MHz, Chloroform-d) δ 7.69 (dd, J = 7.5, 1.7 Hz, 1H), 7.34 (td, J = 7.9, 1.7 Hz, 1H), 7.22 (dd, J = 7.9, 1.6 Hz, 1H), 7.05 (dtd, J = 21.1, 7.6, 1.3 Hz, 2H), 6.98 – 6.92 (m, 1H), 6.67 – 6.58 (m, 2H), 6.09 (s, 2H), 5.82 (s, 1H), 4.47 – 3.96 (m, 3H), 3.91 (s, 3H), 3.82 (s, 6H), 3.77 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 156.6, 153.8, 148.2, 143.5, 131.9, 130.9, 129.6, 129.6, 128.6, 127.9, 121.1, 117.6, 20


Page 21 of 33 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


114.1, 111.1, 107.5, 94.3, 92.3, 80.9, 61.1, 56.0, 55.7, 46.2. IR (film) 1 νmax 3468, 3372, 3053, 2925, 2856, 2218, 1607, 1466, 1233, 1132, 1007, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H27N2O4 [M+H]+: 419.1965; Found: 419.1975. [α]D25 = + 4.8 (CHCl3, c = 1.2 for 91% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 31.74 min (minor), 34.33 min (major). (S)-N-(3-(2-aminophenyl)-1-(o-tolyl)prop-2-yn-1-yl)-4-methoxyaniline (7o): Yellow viscous liquid, 58 mg, 84% yield. Rf = 0.42 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.95 – 7.88 (m, 1H), 7.37 – 7.30 (m, 4H), 7.15 (td, J = 7.7, 1.6 Hz, 1H), 6.94 – 6.82 (m, 4H), 6.71 (td, J = 7.5, 1.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.68 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 3.83 (s, 3H), 2.57 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.1, 148.2, 141.0, 137.5, 136.4, 132.1, 130.9, 129.7, 128.3, 127.4, 126.5, 117.7, 116.0, 114.9, 114.3, 107.6, 94.1, 82.0, 55.8, 49.5, 19.0. IR (film) νmax 3473, 3372, 2925, 2851, 2207, 1651, 1511, 1456, 1243, 1036, 821, 750 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C23H23N2O [M+H]+: 343.1805; Found: 343.1808. [α]D25 = +121.6 (CHCl3, c = 4.9 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 11.35 min (minor), 21.37 min (major). (S)-N-(3-(2-aminophenyl)-1-(o-tolyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7p): Yellow viscous liquid, 63 mg, 79% yield. Rf = 0.38 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.83 (dd, J = 5.4, 3.6 Hz, 1H), 7.30 – 7.23 (m, 4H), 7.12 – 7.05 (m, 1H), 6.71 – 6.55 (m, 2H), 6.06 (s, 2H), 5.62 (s, 1H), 4.03 (s, 3H), 3.82 (s, 6H), 3.79 (s, 3H), 2.50 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 143.5, 137.2, 136.2, 132.0, 130.9, 129.7, 128.4, 127.5, 126.6, 117.7, 114.2, 107.3, 93.6, 91.9, 82.2, 61.1, 56.0, 48.9, 19.0. IR (film) 1 νmax 3458, 3361, 3058, 2996, 2844, 2212, 1615, 1456, 1410, 1310, 1298, 1129, 1007, 809, 796 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H27N2O3 [M+H]+: 403.2016; Found: 403.2035. [α]D25 = +94.9 (CHCl3, c = 1.8 for 97% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 10.81 min (minor), 14.71 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2-bromophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7q): 1 Yellow viscous liquid, 67 mg, 72% yield. Rf = 0.34 (30% EtOAc in hexanes). H NMR (500 MHz, Chloroform-d) δ 7.83 (dd, J = 7.8, 1.7 Hz, 1H), 7.62 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 (td, J = 7.5, 1.3 Hz, 1H), 7.23 (ddd, J = 10.9, 7.8, 1.7 Hz, 2H), 7.12 – 7.08 (m, 1H), 6.69 – 6.59 (m, 2H), 5.99 (s, 2H), 5.84 (s, 1H), 4.12 (s, 3H), 3.79 (s, 6H), 3.76 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.8, 148.2, 142.9, 138.8, 133.3, 132.0, 131.0, 129.9, 129.8, 129.1, 128.2, 123.4, 117.7, 114.3, 106.9, 92.8, 92.0, 82.4, 61.1, 56.0, 51.5. IR (film) 1 νmax 3468, 3367, 3058, 2926, ,2856, 2218, 1612, 1503, 1456, 1312, 1135, 1007, 744 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H23BrN2O3Na [M+Na]+: 489.0784; Found: 489.0780. [α]D25 = +64.5 (CHCl3, c = 0.4 for 94% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 21.26 min (minor), 23.39 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-4-methoxyaniline (7r): Colourless viscous liquid, 60 mg, 87% yield. Rf = 0.34 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.75 (td, J = 7.6, 1.7 Hz, 1H), 7.36 (tdd, J = 7.5, 5.2, 1.8 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.22 (td, J = 7.6, 1.1 Hz, 1H), 7.18 – 7.10 (m, 2H), 6.87 – 6.81 (m, 4H), 6.70 – 6.65 (m, 2H), 5.78 (s, 1H), 4.04 (s, 3H), 3.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.4 (d, J = 248.0 Hz), 153.4, 148.2, 140.3, 132.1, 129.9 (d, J = 8.4 Hz), 129.8, 128.9 (d, J = 3.6 Hz), 127.2 (d, J = 13.2 Hz), 124.6 (d, J = 3.6 Hz), 117.7, 116.6, 115.9 (d, J = 21.4 Hz), 114.8, 114.2, 107.2, 93.2, 81.7, 55.7, 46.6 (d, J = 3.9 Hz). IR (film) νmax 3404, 2925, 2856, 2207, 1617, 1511, 1458, 1235, 1034, 821, 755 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd C22H20FN2O [M+H]+: 347.1554; Found: 347.1568.

21



Page 22 of 33

[α]D25 = +65.3 (CHCl3, c = 1.8 for 89% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 14.89 min (minor), 19.01 min (major). (R)-N-(3-(2-Aminophenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7s): White solid, 74 mg, 90% yield. Rf = 0.30 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 (td, J = 7.6, 1.8 Hz, 1H), 7.36 (s, 1H), 7.25 – 7.18 (m, 2H), 7.15 – 7.06 (m, 2H), 6.71 – 6.55 (m, 2H), 6.06 (s, 2H), 5.78 (s, 1H), 4.11 (s, 3H), 3.79 (d, J = 17.9 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.3 (d, J = 248.1 Hz), 153.8, 148.2, 142.9, 132.0, 131.2, 130.1 (d, J = 8.3 Hz), 129.9, 129.0 (d, J = 3.3 Hz), 127.0 (d, J = 13.3 Hz), 124.7 (d, J = 3.6 Hz), 117.7, 115.9 (d, J = 21.5 Hz), 114.3, 107.0, 92.8, 92.2, 81.9, 61.1, 56.0, 45.7 (d, J = 4.1 Hz). IR (film) νmax 3468, 3367, 3053, 2930, ,2834, 2212, 1605, 1412, 1315, 1132, 1007, 808, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24FN2O3 [M+H]+: 407.1765; Found: 407.1744. MP: 108-109 °C [α]D25 = +91.6 (CHCl3, c = 0.93 for 96% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 21.31min (major) 23.52 min (minor). (S)-N-(3-(2-Aminophenyl)-1-(2-nitrophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7t): Yellow solid, 49 mg, 49% yield. Rf = 0.30 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.02 (dd, J = 7.9, 1.4 Hz, 1H), 7.93 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (td, J = 7.6, 1.4 Hz, 1H), 7.51 (td, J = 7.8, 1.4 Hz, 1H), 7.22 (dd, J = 8.1, 1.6 Hz, 1H), 7.15 – 7.06 (m, 1H), 6.68 – 6.53 (m, 2H), 6.25 (s, 1H), 5.98 (s, 2H), 4.05 (s, 3H), 3.77 (d, J = 7.8 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.8, 148.2, 142.6, 134.3, 133.4, 132.1, 131.6, 130.1, 129.5, 129.2, 125.1, 117.7, 114.3, 106.5, 92.7, 92.7, 91.5, 83.1, 61.0, 56.0, 55.9, 48.5. IR (film) 1 νmax 3468, 3372, 2925, ,2851, 2218, 1612, 1506, 1453, 1312, 1127, 1023, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H22N3O5 [M−H]-: 432.1554; Found: 432.1537. MP: 130−132 °C. [α]D25 = +50.5 (CHCl3, c = 0.2 for 91% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 60/40, 1.0 mL/min, 254 nm): tR = 21.37 min (major), 30.13 min (minor). (R)-N-(3-(2-Aminophenyl)-1-(3-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7u): Yellow viscous liquid, 76 mg, 91% yield. Rf = 0.33 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.52 – 7.46 (m, 1H), 7.45 – 7.35 (m, 2H), 7.28 – 7.22 (m, 1H), 7.13 – 7.02 (m, 2H), 6.70 – 6.61 (m, 2H), 6.04 (s, 2H), 5.54 (s, 1H), 4.05 (s, 3H), 3.79 (s, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 163.1 (d, J = 246.9 Hz), 153.9, 148.2, 143.0, 142.1 (d, J = 6.8 Hz), 132.0, 131.2, 130.4 (d, J = 8.2 Hz), 130.0, 122.9 (d, J = 2.9 Hz), 117.7, 115.2 (d, J = 21.2 Hz), 114.5, 114.3 (d, J = 2.3 Hz), 106.9, 93.0, 92.4, 82.7, 61.1, 56.0, 51.1 (d, J = 1.9 Hz). IR (film) 1 νmax 3458, 3372, 3058, 2936, ,2844, 2180, 1605, 1503, 1442, 1312, 1129, 1004, 739 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H24FN2O3 [M+H]+: 407.1765; Found: 407.1754. [α]D25 = +79.8 (CHCl3, c = 1.4 for 93% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 13.36 min (minor), 18.10 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2,3-dimethylphenyl)prop-2-yn-1-yl)-4-methoxyaniline (7v): 1 Colourless viscous liquid, 64 mg, 90% yield. Rf = 0.40 (10% EtOAc in hexanes). H NMR (500 MHz, Chloroform-d) δ 7.79 (t, J = 4.6 Hz, 1H), 7.31 (dd, J = 7.7, 1.6 Hz, 1H), 7.25 (d, J = 5.1 Hz, 2H), 7.14 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.92 – 6.84 (m, 4H), 6.73 – 6.65 (m, 2H), 5.72 (s, 1H), 3.99 (d, J = 20.9 Hz, 2H), 3.82 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.0, 148.2, 141.0, 137.6, 137.4, 135.0, 132.1, 130.1, 129.6, 125.9, 125.4, 117.7, 115.9, 114.9, 114.2, 107.6, 94.5, 81.9, 55.8, 49.8, 20.7, 14.9. IR (film) νmax 3372, 2920, 2851, 2361, 1617, 1511, 1456, 1310, 1238, 1034, 821, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd C24H25N2O [M+H]+: 357.1961; Found: 357.1964. [α]D25 = +134.7 (CHCl3, c = 3.18 for 93% ee). HPLC 22


Page 23 of 33 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


(Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 11.98 min (minor), 23.87 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2,3-dimethylphenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7w): Yellow viscous liquid, 70 mg, 79% yield. Rf = 0.38 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.71 (d, J = 3.7 Hz, 1H), 7.25 (dd, J = 7.7, 1.6 Hz, 1H), 7.19 (d, J = 5.5 Hz, 2H), 7.11 – 7.06 (m, 1H), 6.69 – 6.57 (m, 2H), 6.08 (s, 2H), 5.67 (s, 1H), 4.03 (s, 3H), 3.81 (d, J = 16.8 Hz, 9H), 2.36 (d, J = 15.1 Hz, 6H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.1, 143.5, 137.6, 137.0, 134.8, 132.0, 130.9, 130.1, 129.7, 126.0, 125.5, 117.6, 114.2, 107.4, 94.0, 91.9, 82.2, 61.1, 56.0, 49.3, 20.7, 14.9. IR (film) 1 νmax 3372, 2900, 2854, 2212, 1604, 1495, 1315, 1235, 1129, 1004, 747 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C26H29N2O3 [M+H]+: 417.2173; Found: 417.2190. [α]D25 = +77.88 (CHCl3, c = 0.9 for 94% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 14.02 min (minor), 18.79 min (major). (S)-N-(3-(2-Aminophenyl)-1-(2,4-dichlorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (7x): Yellow viscous liquid, 73 mg, 80% yield. Rf = 0.31 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.76 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.27 (ddd, J = 41.2, 8.1, 1.8 Hz, 2H), 7.11 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.69 – 6.60 (m, 2H), 5.97 (s, 2H), 5.81 (s, 1H), 4.08 (s, 3H), 3.78 (d, J = 12.7 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.2, 142.7, 136.0, 134.7, 133.8, 132.1, 131.2, 130.1, 129.8, 129.8, 127.9, 117.8, 114.3, 106.7, 92.2, 92.0, 82.5, 61.1, 56.0, 48.6. IR (film) 1 νmax 3462, 3325, 3055, 2926, 2854, 2210, 1612, 1517, 1466, 1323, 1128, 1006, 741 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H23Cl2N2O3 [M+H]+: 457.1080; Found: 457.1072. [α]D25 = +90.8 (CHCl3, c = 1.26 for 95% ee). HPLC (Chiralpak IB, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 14.97 min (major), 18.12 min (minor). (R)-N-(1-(2-aminophenyl)-4,4-dimethylpent-1-yn-3-yl)-3,4,5-trimethoxyaniline (7y): yellow solid, 62 mg, 85% yield. Rf = 0.40 (10% EtOAc in hexanes. 1H NMR (500 MHz, Chloroform-d) δ 7.22 (dd, J = 7.6, 1.6 Hz, 1H), 7.11 – 7.05 (m, 1H), 6.67 – 6.61 (m, 2H), 6.07 (s, 2H), 4.06 (s, 1H), 3.87 (s, 6H), 3.81 (s, 3H), 1.21 (s, 9H).13C{1H}NMR (125 MHz, Chloroform-d) δ 153.9, 148.0, 144.2, 131.9, 130.8, 129.4, 117.6, 114.1, 107.7, 94.4, 92.2, 80.9, 61.1, 61.1, 57.5, 56.0, 35.0, 26.6. IR (film) νmax 3468, 3367, 2957, 2872, 2207, 1609, 15096, 1456, 1408, 1312, 1238, 1127, 1004, 803, 747.cm1 . HRMS (ESI-TOF) m/z: Exact mass calcd for C22H29N2O3 [M+H]+: 369.2173; Found: 369.2154. MP: 78−80 °C [α]D25 = +66.58 (CHCl3, c = 1.23 for 90% ee). HPLC (Chiralpak ID, n-hexane/ isopropanol = 80/20, 1.0 mL/min, 254 nm): tR = 11.51 min (major), 13.42 min (minor). (R)-N-(2-(3-((4-Methoxyphenyl)amino)-3-phenylprop-1-yn-1-yl)phenyl)-4methylbenzenesulfonamide (8a): Yellow solid, 87 mg, 87% yield. Rf = 0.28 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.67 – 7.61 (m, 2H), 7.59 (dd, J = 8.2, 1.1 Hz, 1H), 7.51 – 7.46 (m, 4H), 7.45 – 7.40 (m, 1H), 7.31 – 7.24 (m, 2H), 7.14 – 7.07 (m, 2H), 7.05 (s, 1H), 7.01 (td, J = 7.6, 1.1 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 6.83 – 6.78 (m, 2H), 5.46 (s, 1H), 3.80 (s, 3H), 2.34 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.3, 143.8, 140.2, 139.0, 138.0, 136.0, 132.1, 129.6, 129.5, 129.0, 128.4, 127.2, 124.1, 119.5, 115.9, 115.1, 113.6, 96.0, 79.8, 55.7, 51.8, 21.5. IR (film) νmax 3323, 3058, 2946, 2269, 1609, 1514, 1400, 1336, 1241, 1129, 1034, 816, 758 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C29H27N2O3S [M+H]+: 483.1737; Found: 483.1723. MP: 123−125 °C. [α]D25 = +3.51 (CHCl3, c = 1.5 for 79% ee). HPLC (Chiralpak IC, n-hexane/ isopropanol = 80/20, 1.0 mL/min, 254 nm): tR = 20.44 min (major), 21.95 min (minor). (R)-N-(2-(3-((4-Methoxyphenyl)amino)-3-phenylprop-1-yn-1-yl)phenyl)acetamide (8b): Yellow solid, 68 mg, 79% yield. Rf = 0.30 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 23



Page 24 of 33

8.36 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 7.2, 1.7 Hz, 2H), 7.67 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.41 (dd, J = 7.7, 1.9 Hz, 2H), 7.33 (td, J = 7.9, 1.5 Hz, 1H), 7.04 (td, J = 7.6, 1.2 Hz, 1H), 6.89 – 6.80 (m, 4H), 5.53 (s, 1H), 3.78 (s, 3H), 1.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 168.5, 153.3, 139.3, 139.3, 131.6, 129.7, 129.0, 128.5, 127.3, 123.2, 119.3, 115.7, 115.0, 111.2, 96.1, 80.5, 55.7, 51.6, 24.3. IR (film) νmax 3382, 3063, 2920, 2851, 2361, 1694, 1517, 1445, 1304, 1235, 1034, 821, 760 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd C24H23N2O2 [M+H]+: 371.1754; Found: 371.1763. MP: 86−88 °C [α]D25 = +134.29 (CHCl3, c = 3.56 for 90% ee). HPLC (Chiralpak IC, nhexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 22.04 min (minor), 26.22 min (major). (S)-N-(2-(3-(2-Fluorophenyl)-3-((3,4,5-trimethoxyphenyl)amino)prop-1-yn-1-yl)phenyl)-4methylbenzenesulfonamide, (8c): Colourless viscous liquid, 97 mg, 87% yield. Rf = 0.35 (30% EtOAc in hexanes) 1H NMR (500 MHz, Chloroform-d) δ 7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.59 (dd, J = 8.7, 1.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.42 (dddd, J = 8.3, 7.3, 5.3, 1.8 Hz, 1H), 7.28 – 7.25 (m, 2H), 7.25 – 7.20 (m, 1H), 7.14 (s, 1H), 7.09 (d, J = 7.6 Hz, 2H), 7.01 (td, J = 7.6, 1.1 Hz, 1H), 6.06 (s, 2H), 5.71 (s, 1H), 3.84 (s, 6H), 3.80 (s, 3H), 2.34 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.2 (d, J = 247.6 Hz), 154.0, 143.9, 142.4, 138.1, 135.9, 132.0, 131.4, 130.4 (d, J = 8.3 Hz), 129.9, 129.5, 128.7 (d, J = 3.5 Hz), 127.2, 126.5 (d, J = 13.1 Hz), 124.9 (d, J = 3.5 Hz), 124.2, 119.5, 116.2 (d, J = 21.4 Hz), 113.3, 94.9, 92.0, 79.4, 61.1, 56.0, 45.6 (d, J = 3.9 Hz), 21.5. IR (film) νmax 3381, 2924, 2851, 2261, 1605, 1511, 1451, 1401, 1339, 1234, 1157, 1004, 766, 673 cm-1. HRMS (ESITOF) m/z: Exact mass calcd for C31H28FN2O5S [M−H]−: 559.1697; Found: 559.1694. [α]D25 = −37.6 (CHCl3, c = 1.9 for 72% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 41.46 min (major), 47.30 min (minor). (S)-N-(2-(3-(2-Fluorophenyl)-3-((3,4,5-trimethoxyphenyl)amino)prop-1-yn-1-yl)phenyl) acetamide (8d): Colourless viscous liquid, 71 mg, 79% yield. Rf = 0.38(30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.71 (td, J = 7.6, 1.8 Hz, 1H), 7.39 (td, J = 7.7, 1.8 Hz, 2H), 7.33 (ddd, J = 8.6, 7.5, 1.6 Hz, 1H), 7.25 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (ddd, J = 10.5, 8.2, 1.2 Hz, 1H), 7.03 (td, J = 7.6, 1.2 Hz, 1H), 6.08 (s, 2H), 5.78 (s, 1H), 4.34 (s, 1H), 3.80 (d, J = 17.8 Hz, 9H), 1.94 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 168.4, 160.2 (d, J = 247.6 Hz), 154.0, 142.5, 139.4, 131.5, 131.3, 130.4 (d, J = 8.3 Hz), 130.0, 128.8 (d, J = 3.3 Hz), 126.6 (d, J = 13.1 Hz), 124.9 (d, J = 3.6 Hz), 123.2, 119.3, 116.1 (d, J = 21.3 Hz), 110.9, 94.8, 91.8, 80.2, 61.0, 56.0, 45.5 (d, J = 3.9 Hz), 24.3 IR (film) νmax 3377, 2930, 2851, 2261, 1694, 1601, 1571, 1453, 1304, 1235, 1120, 1007, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C26H26FN2O4 [M+H]+: 449.1871; Found: 449.1856. [α]D25 = +50.2 (CHCl3, c = 2.84 for 96% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 22.16 min (major), 44.90 min (minor). (S)-N-(3-(2-(Ethylamino)phenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (8e): Yellow viscous liquid, 76 mg, 78% yield. Rf = 0.30 (30% EtOAc in hexanes). Yellow oil, 76 mg, 78% yield. Rf = 0.30 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.74 (td, J = 7.6, 1.8 Hz, 1H), 7.40 – 7.32 (m, 1H), 7.28 – 7.08 (m, 4H), 6.66 – 6.44 (m, 2H), 6.06 (s, 2H), 5.78 (s, 1H), 4.53 – 4.00 (m, 2H), 3.79 (d, J = 18.0 Hz, 9H), 3.09 (qd, J = 7.2, 2.5 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). 13 C{1H}NMR (125 MHz, Chloroform-d) δ 160.3 (d, J = 247.9 Hz), 153.9, 149.3, 142.8, 131.9, 131.1, 130.2, 130.1 (d, J = 8.3 Hz), 129.0 (d, J = 3.5 Hz), 127.1 (d, J = 13.3 Hz), 124.7 (d, J = 3.6 Hz), 115.9 (d, J = 21.4 Hz), 115.9, 109.4, 106.3, 93.1, 92.0, 82.0, 61.0, 55.9, 45.5 (d, J = 4.0 Hz), 37.9, 14.5. IR (film) νmax 3377, 2930, 2851, 2261, 1694, 1601, 1571, 1453, 1304, 1235, 1120, 1007, 752 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C26H28FN2O3 [M+H]+: 435.2078; Found: 435.2069. [α]D25 = +85.7 (CHCl3, c = 1.2 for 94% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 13.11 min (minor), 21.59 min (major). 24


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(S)-N-(3-(2-(Benzylamino)phenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (8f): Yellow viscous liquid, 69 mg, 70% yield. Rf = 0.32 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.72 (td, J = 7.6, 1.8 Hz, 1H), 7.36 – 7.26 (m, 7H), 7.20 – 7.07 (m, 3H), 6.63 (td, J = 7.4, 1.1 Hz, 1H), 6.57 – 6.50 (m, 1H), 6.08 (d, J = 1.5 Hz, 2H), 5.81 (s, 1H), 4.34 (s, 2H), 3.81 (d, J = 1.3 Hz, 6H), 3.75 (d, J = 1.6 Hz, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.2 (d, J = 248.0 Hz), 153.9, 149.0, 142.8, 139.0, 132.0, 131.1, 130.2, 130.1 (d, J = 8.3 Hz), 128.9 (d, J = 3.4 Hz), 128.6, 127.1, 127.0, 127.0 (d, J = 13.1 Hz), 124.7 (d, J = 3.6 Hz), 116.4, 115.9 (d, J = 21.4 Hz), 110.0, 106.7, 93.5, 92.1, 81.9, 61.0, 55.9, 47.5, 45.6 (d, J = 4.0 Hz). IR (film) νmax 3398, 2925, 2851, 2260, 1604, 1509, 1413, 1323, 1235, 1127, 1010, 736 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C31H30FN2O3 [M+H]+: 497.2235; Found: 497.2219. [α]D25 = +70.2 (CHCl3, c = 1.36 for 91% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 17.00 min (minor), 18.82 min (major). (S)-N-(3-(2-Amino-5-methylphenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (8g): Yellow solid, 69 mg, 82% yield. Rf = 0.31 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.76 (td, J = 7.6, 1.8 Hz, 1H), 7.37 (m, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (ddd, J = 10.4, 8.2, 1.2 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.94 (dd, J = 8.2, 2.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.08 (s, 2H), 5.79 (s, 1H), 3.83 (s, 6H), 3.79 (s, 3H), 2.21 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 13C NMR (126 MHz, Chloroform-d) δ 160.2 (d, J = 248.0 Hz), 153.8, 145.8, 142.9, 132.1, 131.1, 130.7, 130.0 (d, J = 8.2 Hz), 129.0 (d, J = 3.3 Hz), 127.0 (d, J = 12.0 Hz), 124.7 (d, J = 3.5 Hz), 115.9 (d, J = 21.6 Hz), 114.5, 107.0, 82.1, 61.1, 56.0, 45.6 (d, J = 4.1 Hz), 20.2. IR (film) νmax 3372, 2920, 2223, 1607, 1508, 1453, 1233, 1127, 1010, 760 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H26FN2O3 [M+H]+: 421.1922; Found: 421.1901. MP: 112−114 °C. [α]D25 = +11.0 (CHCl3, c = 0.7 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 28.50 min (major), 33.09 min (minor). (S)-N-(3-(2-Amino-4-chlorophenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (8h): Yellow solid, 62 mg, 70% yield. Rf = 0.29 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 1.8 Hz, 1H), 7.41 – 7.33 (m, 1H), 7.24 (dd, J = 7.6, 1.2 Hz, 1H), 7.16 (dd, J = 8.3, 3.0 Hz, 2H), 6.72 – 6.54 (m, 2H), 6.07 (s, 2H), 5.79 (s, 1H), 4.18 (s, 3H), 3.82 (s, 6H), 3.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.2 (d, J = 248.1 Hz), 153.9, 149.1, 142.8, 135.5, 132.9, 131.2, 130.2 (d, J = 8.3 Hz), 128.9 (d, J = 3.3 Hz), 126.7 (d, J = 13.2 Hz), 124.7 (d, J = 3.6 Hz), 117.8, 115.9 (d, J = 21.4 Hz), 114.0, 105.4, 93.6, 92.3, 80.9, 61.1, 56.0, 45.7 (d, J = 4.0 Hz). IR (film) νmax 3367, 2936, 2223, 1615, 1514, 1456, 1238, 1120, 1004, 758 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H22ClFN2O3 [M+H]+: 441.1364; Found: 441.1376. MP: 110−112 °C [α]D25 = +50.1 (CHCl3, c = 1.46 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 17.41 min (major), 19.01 min (minor). (S)-N-(3-(2-Amino-5-bromophenyl)-1-(2-fluorophenyl)prop-2-yn-1-yl)-3,4,5-trimethoxyaniline (8i): Yellow solid, 84.2 mg, 87% yield. Rf = 0.29 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.76 – 7.69 (m, 1H), 7.38 (ddd, J = 7.4, 2.6, 1.4 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.24 (td, J = 7.5, 1.2 Hz, 1H), 7.19 (dd, J = 8.6, 2.4 Hz, 1H), 7.15 (ddd, J = 10.4, 8.3, 1.2 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.07 (s, 2H), 5.79 (s, 1H), 4.12 (d, J = 10.0 Hz, 3H), 3.83 (s, 6H), 3.80 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.2 (d, J = 248.2 Hz), 153.9, 147.3, 142.8, 134.1, 132.7, 131.3, 130.2 (d, J = 8.3 Hz), 128.9 (d, J = 3.4 Hz), 126.6 (d, J = 13.3 Hz), 124.8 (d, J = 3.6 Hz), 115.9 (d, J = 21.4 Hz), 115.7, 108.8, 108.6, 93.9, 92.3, 80.5, 61.1, 56.0, 45.7 (d, J = 4.1 Hz). IR (film) νmax 3361, 2930, 2260, 1609, 1511, 1410, 1310, 1235, 1132, 1004, 760 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H23BrFN2O3 [M+H]+: 485.0871; Found: 485.0839. MP: 124−126 °C 25



Page 26 of 33

[α]D25 = +65.0 (CHCl3, c = 1.58 for 95% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 22.92 min (major), 27.33 min (minor). Methyl (S)-4-Amino-3-(3-(2-fluorophenyl)-3-((3,4,5-trimethoxyphenyl)amino)prop-1-yn-1yl)benzoate (8j): Yellow solid, 78 mg, 84% yield. Rf = 0.28 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.97 (d, J = 2.0 Hz, 1H), 7.82 – 7.71 (m, 2H), 7.38 (dt, J = 6.3, 1.8 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.18 – 7.12 (m, 1H), 6.62 (dd, J = 8.6, 1.0 Hz, 1H), 6.08 (s, 2H), 5.80 (s, 1H), 4.54 (s, 2H), 4.16 (s, 1H), 3.85 (d, J = 1.1 Hz, 3H), 3.83 (d, J = 1.3 Hz, 6H), 3.79 (d, J = 0.7 Hz, 3H). 13 C{1H}NMR (125 MHz, Chloroform-d) δ 166.5, 160.2 (d, J = 248.1 Hz), 153.9, 151.9, 142.8, 134.3, 131.6, 131.2, 130.2 (d, J = 8.2 Hz), 129.0 (d, J = 3.3 Hz), 126.6 (d, J = 13.3 Hz), 124.8 (d, J = 3.5 Hz), 119.1, 119.1, 115.9 (d, J = 21.4 Hz), 113.2, 106.1, 93.3, 92.3, 80.8, 61.1, 56.0, 51.7, 45.7 (d, J = 4.0 Hz). IR (film) νmax 3368, 2946, 2845, 2101, 1700, 1617, 1500, 1458, 1293, 1134, 1007, 766 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C26H26FN2O5 [M+H]+: 465.1820; Found: 465.1798. MP: 140−142 °C [α]D25 = +66.9 (CHCl3, c = 1.94 for 94% ee). HPLC (Chiralpak ID, n-hexane/ isopropanol = 70/30, 1.0 mL/min, 254 nm): tR = 32.78 min (major), 44.83 min (minor). (S)-4-Amino-3-(3-(2-fluorophenyl)-3-((3,4,5-trimethoxyphenyl)amino)prop-1-yn-1yl)benzonitrile (8k): Yellow solid, 63 mg, 73% yield. Rf = 0.30 (30% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.71 (td, J = 7.6, 1.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.33 (dd, J = 8.5, 2.0 Hz, 1H), 7.25 (td, J = 7.5, 1.2 Hz, 1H), 7.16 (ddd, J = 10.4, 8.2, 1.2 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.07 (s, 2H), 5.79 (s, 1H), 4.63 (s, 2H), 4.28 – 4.00 (m, 1H), 3.83 (s, 6H), 3.79 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) 160.3 (d, J = 248.2 Hz), 153.9, 151.5, 142.7, 136.2, 133.4, 131.3, 130.4 (d, J = 8.4 Hz), 128.9 (d, J = 3.2 Hz), 126.2 (d, J = 13.3 Hz), 124.8 (d, J = 3.6 Hz), 119.3, 116.0 (d, J = 21.3 Hz), 113.9, 107.1, 99.7, 94.5, 92.7, 92.3, 79.5, 61.1, 56.0, 45.7 (d, J = 4.0 Hz). IR (film) νmax 3366, 3053, 2990, 2223, 1615, 1508, 1416, 1235, 1129, 1007, 736 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C25H23FN3O3 [M+H]+: 432.1718; Found: 432.1716. MP: 108−110 °C. [α]D25 = +145.7 (CHCl3, c = 1.5 for 95% ee). HPLC (Chiralpak ID, nhexane/ iso-propanol = 70/30, 1.0 mL/min, 254 nm): tR = 12.32 min (minor), 18.32 min (major). General procedure and characterization data for synthesis of compound 9a-b: A solution of propargyl amine (8a or 8b) (0.2 mmol) in EtOAc (2.0 mL) was degassed with nitrogen gas. Then the (Lindlar catalyst) Pd/CaCO3 (5% w/w) was added to the reaction mixture. The mixture was purged with hydrogen gas for 10 min and kept continue stirring under Hydrogen atmosphere for 8 h at rt. Upon completion of reaction (monitored by TLC) the crude product was purified by column chromatography using EtOAc/Hexane as eluent to offered the product 9a or 9b up to 93% yield. (S,Z)-N-(2-(3-((4-Methoxyphenyl)amino)-3-phenylprop-1-en-1-yl)phenyl)-4methylbenzenesulfonamide (9a): Yellow solid, 90 mg, 93% yield. Rf = 0.28 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 6.7 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.37 – 7.27 (m, 6H), 7.19 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 6.9 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 8.5 Hz, 2H), 6.12 (d, J = 11.2 Hz, 1H), 5.98 – 5.88 (m, 1H), 4.97 (d, J = 9.5 Hz, 1H), 3.74 (s, 3H), 2.40 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.9, 143.7, 141.8, 140.1, 137.1, 136.7, 134.6, 129.8, 129.6, 128.9, 128.8, 127.6, 127.1, 126.7, 126.0, 125.3, 122.9, 116.0, 114.8, 56.7, 55.7, 21.6. IR (film) νmax 3367, 3053, 2920, 2297, 2058, 1599, 1511, 1400, 1333, 1238, 1161, 1036, 920, 816, 706 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C29H29N2O3S [M+H]+: 485.1893; Found: 485.1870. MP: 78−80 °C. [α]D25 = +30.4 (CHCl3, c = 0.5 for 85% ee). HPLC (Chiralpak IC, nhexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 23.23 min (major), 35.84 min (minor). 26


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(S,Z)-N-(2-(3-((4-Methoxyphenyl)amino)-3-phenylprop-1-en-1-yl)phenyl)acetamide (9b): Yellow viscous liquid, 68 mg, 91% yield. Rf = 0.28 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J = 7.8 Hz, 1H), 7.47 – 7.29 (m, 7H), 7.23 – 7.10 (m, 2H), 6.75 – 6.65 (m, 2H), 6.60 – 6.53 (m, 1H), 6.47 – 6.44 (m, 1H), 6.04 (td, J = 10.3, 8.9, 2.3 Hz, 1H), 5.06 (dd, J = 9.9, 3.1 Hz, 1H), 3.73 (s, 3H), 1.91 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 168.5, 152.7, 141.8, 140.4, 136.5, 135.6, 129.2, 128.9, 128.6, 127.7, 126.9, 126.4, 124.2, 121.9, 121.9, 115.8, 114.7, 77.4, 77.1, 76.9, 56.6, 55.7, 55.6, 24.3. IR (film) νmax 3329, 2925, 2308, 1954, 1673, 1580, 1440, 1368, 1299, 1121, 1034, 824, 705 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C24H25N2O2 [M+H]+: 373.1911; Found: 373.1921. [α]D25 = +54.2 (CHCl3, c = 3.04 for 90% ee). HPLC (Chiralpak ADH, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 8.92 min (minor), 9.79 min (major). General procedure and characterization data for synthesis of compound 10a-g: To a mixture of propargylamines 6-7 (1.0 equiv.), pyridine (2.2 equiv.), DMAP (0.1 equiv.) were taken in dry dichloromethane (4 mL), then p-toluenesulphonyl chloride was added (1.2 equiv.) portion wise to the reaction mixture at 0 °C and the mixture was warmed to rt slowly and stirred for 34 h. After the completion of reaction monitored by TLC, the reaction mixture was diluted with dichloromethane and washed with 4 M hydrochloric acid, saturated Na2CO3 solution. The organic layer was washed with brine twice and dried over Na2SO4 and concentrated in vacuum. The residue was dissolved in dry acetonitrile, K2CO3 (4.0 equiv.) was added to the mixture and stirred at 40 °C for 4-6 h. After the completion of the reaction (monitored by TLC) the solvent was evaporated and the crude product was dissolved in dichloromethane (10 mL) and washed with water (5 ml x 2). The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography using silica gel with EtOAc/Hexane as eluent. (R)-4-Methoxy-N-(phenyl(1-tosyl-1H-indol-2-yl)methyl)aniline (10a): White crystalline solid, 85 mg, 88% yield. Rf = 0.32 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.22 (d, J = 8.4 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.39 – 7.35 (m, 2H), 7.36 – 7.29 (m, 4H), 7.25 (td, J = 7.6, 1.0 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.72 (s, 1H), 6.70 (d, J = 2.8 Hz, 2H), 6.47 (d, J = 9.0 Hz, 2H), 6.30 (s, 1H), 3.93 (s, 1H), 3.75 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.3, 144.6, 142.4, 141.1, 140.9, 137.7, 136.1, 129.6, 129.1, 128.7, 128.2, 127.8, 126.7, 124.6, 123.5, 121.0, 114.8, 114.7, 114.6, 111.3, 57.0, 55.7, 21.5. IR (film) νmax 3409, 3063, 2920, 2835, 2196, 1601, 1506, 1450, 1371, 1246, 1172, 1039, 813, 742 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C29H27N2O3S [M+H]+: 483.1737; Found: 483.1745. MP: 138−140 °C. [α]D25 = −36.3 (CHCl3, c = 2.5 for 92% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 8.78 min (major), 10.92 min (minor). (R)-3,4,5-Trimethoxy-N-(phenyl(1-tosyl-1H-indol-2-yl)methyl)aniline (10b): White crystalline solid, 90 mg, 83% yield. Rf = 0.38 (20% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.18 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.40 – 7.29 (m, 8H), 7.27 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 6.44 (s, 1H), 5.87 (s, 2H), 4.11 (s, 1H), 3.78 (s, 3H), 3.73 (s, 6H), 2.31 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 153.8, 144.6, 143.4, 142.2, 140.7, 137.6, 135.9, 130.5, 129.5, 129.0, 128.7, 128.1, 127.8, 126.6, 124.7, 123.6, 121.0, 114.8, 111.4, 91.2, 61.1, 61.0, 56.3, 55.9, 21.5. IR (film) νmax 3436, 2920, 2856, 1609, 1453, 1368, 1235, 1120, 1089, 1012, 811, 736, 702, 577 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C31H31N2O5S [M+H]+: 543.1948; Found: 543.1951. MP: 180−182 °C. [α]D25 = −2.0 (CHCl3, c = 0.2 for 95% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 40.41 min (minor), 43.29 min (major).

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(R)-N-((4-(tert-Butyl)phenyl)(1-tosyl-1H-indol-2-yl)methyl)-4-methoxyaniline (10c): White solid, 88 mg, 81% yield. Rf = 0.38 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.20 (dd, J = 8.6, 4.6 Hz, 1H), 7.52 – 7.43 (m, 1H), 7.41 – 7.28 (m, 7H), 7.25 (s, 1H), 7.08 – 7.02 (m, 2H), 6.78 (s, 1H), 6.74 – 6.66 (m, 2H), 6.51 – 6.44 (m, 2H), 6.29 (s, 1H), 3.93 (s, 1H), 3.74 (d, J = 1.5 Hz, 3H), 2.34 (s, 3H), 1.36 (d, J = 3.7 Hz, 9H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.2, 150.8, 144.4, 142.7, 141.0, 138.0, 137.7, 136.1, 129.5, 129.2, 128.0, 126.7, 125.5, 124.4, 123.5, 120.9, 114.8, 114.7, 114.5, 111.0, 77.3, 77.0, 76.8, 56.7, 55.7, 34.6, 31.4, 21.6. IR (film) νmax 3430, 2968, 2095, 1644, 1511, 1450, 1371, 1241, 1174, 1086, 1036, 813, 670, 577 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C33H34N2O3S [M+H]+: 539.2363; Found: 539.2348. MP: 128−130 °C. [α]D25 = −42.5 (CHCl3, c = 1.6 for 90% ee). HPLC (Chiralpak IC, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 7.48 min (major), 11.02 min (minor). (R)-N-([1,1'-Biphenyl]-4-yl(1-tosyl-1H-indol-2-yl)methyl)-4-methoxyaniline (10d): White solid, 78 mg, 70% yield. Rf = 0.36 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.24 (d, J = 8.4 Hz, 1H), 7.61 – 7.58 (m, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.48 (t, J = 7.8 Hz, 3H), 7.43 – 7.38 (m, 5H), 7.35 (dd, J = 8.6, 7.3 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.77 (s, 1H), 6.73 (d, J = 8.9 Hz, 2H), 6.51 (d, J = 8.9 Hz, 2H), 6.34 (s, 1H), 3.75 (s, 3H), 2.29 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.4, 144.5, 142.3, 140.9, 140.8, 140.6, 140.0, 137.9, 136.2, 129.5, 129.1, 128.8, 128.7, 127.4, 127.3, 127.0, 126.6, 124.6, 123.5, 121.0, 114.8, 114.7, 114.6, 111.2, 56.7, 55.7, 21.5. IR (film) νmax 3441, 2925, 2851, 1644, 1511, 1453, 1363, 1241, 1169, 1039, 813, 742, 670, 577 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C35H29N2O3S [M−H]−: 557.1893; Found: 557.1877. MP: 89−91 °C. [α]D25 = −29.00 (CHCl3, c = 0.6 for 87% ee). HPLC (Chiralpak ID, nhexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 20.24 min (major), 31.23 min (minor). (R)-4-Methoxy-N-(o-tolyl(1-tosyl-1H-indol-2-yl)methyl)aniline (10e): Yellow viscous liquid, 82 mg, 82% yield. Rf = 0.38 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.26 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.38 – 7.34 (m, 1H), 7.30 – 7.21 (m, 4H), 7.06 (d, J = 8.2 Hz, 2H), 7.02 – 6.94 (m, 2H), 6.75 – 6.67 (m, 3H), 6.48 – 6.43 (m, 3H), 3.75 (s, 3H), 2.48 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.2, 144.5, 142.0, 141.0, 139.2, 137.8, 137.2, 136.2, 130.8, 129.5, 129.0, 127.7, 126.8, 126.7, 126.1, 124.5, 123.4, 120.9, 114.8, 114.7, 114.0, 111.5, 55.7, 53.4, 21.5, 19.1. IR (film) νmax 3680, 2973, 2925, 2356, 1599, 1511, 1453, 1368, 1235, 1174, 1089, 954, 816, 744, 675 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C30H29N2O3S [M+H]+: 497.1893; Found: 497.1872. [α]D25 = −5.5 (CHCl3, c = 0.43 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 9.80 min (minor), 12.24 min (major). (R)-N-((2-Fluorophenyl)(1-tosyl-1H-indol-2-yl)methyl)-4-methoxyaniline (10f): White solid, 86 mg, 86% yield. Rf = 0.33 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.26 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.37 – 7.29 (m, 3H), 7.25 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 9.8 Hz, 1H), 7.10 – 7.06 (m, 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.57 (s, 1H), 6.54 (s, 1H), 6.46 (d, J = 8.9 Hz, 2H), 3.74 (s, 3H), 2.37 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 160.6 (d, J = 248.3 Hz), 152.5, 144.8, 141.0, 140.6, 137.9, 136.0, 129.7, 129.5 (d, J = 8.2 Hz), 128.9, 128.8 (d, J = 3.6 Hz), 128.3 (d, J = 13.7 Hz), 126.8, 124.8, 124.3 (d, J = 3.6 Hz), 123.6, 121.0, 115.7 (d, J = 21.5 Hz), 115.0, 114.7, 114.7, 112.0, 55.7, 50.7 (d, J = 3.9 Hz), 21.6. IR (film) νmax 3436, 2920, 2851, 2090, 1644, 1511, 1450, 1368, 1233, 1172, 1089, 1036, 816, 750, 670 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C29H26FN2O3S [M+H]+: 501.1643; Found: 501.1636. MP: 160−162 °C. [α]D25 = −29.7 (CHCl3, c = 0.44 for 89% ee). HPLC (Chiralpak IC, nhexane/ iso-propanol = 80/20, 1.0 mL/min, 254 nm): tR = 8.69 min (major), 14.72 min (minor). 28


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(R)-N-((2,3-Dimethylphenyl)(1-tosyl-1H-indol-2-yl)methyl)-4-methoxyaniline (10g): White solid, 86 mg, 84% yield. Rf = 0.38 (10% EtOAc in hexanes). 1H NMR (500 MHz, Chloroform-d) δ 8.27 (dd, J = 8.4, 0.9 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.46 – 7.42 (m, 2H), 7.37 (d, J = 1.3 Hz, 1H), 7.29 (dd, J = 7.6, 1.0 Hz, 1H), 7.15 (dd, J = 7.5, 1.4 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.86 (dd, J = 7.8, 1.4 Hz, 1H), 6.75 (s, 1H), 6.72 (d, J = 5.3 Hz, 2H), 6.54 (s, 1H), 6.47 (d, J = 8.9 Hz, 2H), 3.76 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H). 13C{1H}NMR (125 MHz, Chloroform-d) δ 152.1, 144.5, 142.5, 141.0, 139.2, 137.8, 137.3, 136.2, 135.6, 129.5, 129.5, 129.0, 126.8, 125.5, 124.8, 124.4, 123.4, 120.9, 114.8, 114.7, 114.0, 111.4, 55.7, 55.7, 53.6, 21.6, 20.8, 14.8. IR (film) νmax 3471, 2925, 2851, 1599, 1511, 1450, 1368, 1238, 1172, 1089, 816, 744, 670, 580 cm-1. HRMS (ESI-TOF) m/z: Exact mass calcd for C31H31N2O3S [M+H]+: 511.2050; Found: 511.2035. MP: 86−88 °C. [α]D25 = −51.9 (CHCl3, c = 1.6 for 92% ee). HPLC (Chiralpak ID, n-hexane/ iso-propanol = 90/10, 0.50 mL/min, 254 nm): tR = 31.43 min (minor), 32.87 min (major).

Associated Content AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Author Contributions Both the authors contributed equally

a

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT Financial support through the J. C. Bose fellowship and SERB research project are gratefully acknowledged. S.D. thanks to IISERB for Institute postdoctoral fellowship, V. K. K. thanks to IISERB for Project fellowship, R. G. B. thanks to IISERB for SRF fellowship. Facilities from the Department of Chemistry, IISER Bhopal are gratefully acknowledged.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Crystallographic data for compounds 10a. 1 H, 13C{1H}NMR spectra for all compounds and HPLC chromatograms

References and Notes: (1) (a) Bosch, J.; Bennasar, M.-L. A General Method for the Synthesis of Bridged Indole Alkaloids. Addition of Carbon Nucleophiles to N-Alkylpyridinium Salts. Synlett, 1995, 587. (b) Saxton, J. E. Recent Progress in the Chemistry of the Monoterpenoid Indole Alkaloids. Nat. Prod. Rep. 1997, 14, 559. (c) Leonard, J. Recent Progress in the Chemistry of Monoterpenoid Indole Alkaloids Derived from Secologanin. Nat. Prod. Rep. 1999, 16, 319. (d) Lobo, A. M.; Prabhakar, S. Recent Developments in the Synthesis of Biologically Active Indole Alkaloids. J. Heterocycl. Chem. 2002, 39, 429. (e) Takayama, H. Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa. Chem. Pharm. Bull. 2004, 52, 916. (f) Takayama, H.; Kitajima, M.; Kogure, N. Chemistry of Indole Alkaloids Related to the Corynanthe-Type from 29



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Enantioselective A3-Coupling Reaction Employing Chiral CuI

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