Synthetic Access to Secondary Propargylamines via a Copper

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Synthetic Access to Secondary Propargylamines via CopperCatalyzed Oxidative Deamination-Alkynylation Cascade Huiqiong Li, Huangdi Feng, Jingxian Zhang, Erik V. Van der Eycken, and Liliang Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01431 • Publication Date (Web): 26 Jul 2019 Downloaded from pubs.acs.org on July 27, 2019

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The Journal of Organic Chemistry

Synthetic Access to Secondary Propargylamines via Copper-Catalyzed Oxidative Deamination-Alkynylation Cascade Huiqiong Li,† Huangdi Feng,*† Jingxian Zhang † Erik V. Van der Eycken‡,§ and Liliang Huang† †College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, 201620, China ‡Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, Leuven 3001, Belgium §Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russia. *E-mail: [email protected];

Graphical Abstract H 2N H 2N

+

R1 Homo Deamination R1

(i)

(ii)

TBHP R3

NH

R3

Cross Deamination R1

Cu

R1

R1

25 examples

R2

NH

R2

+

NH2 NH2

R3

R1 9 examples

Abstract A novel and selective cascade reaction of primary amines and alkynes for the synthesis of the corresponding secondary propargylamines is described. This protocol proceeds with a CuBr2/TBHP system through a process of oxidative deamination of primary amines to imine and alkynylation, featuring a wide scope of substrates with good functional-group tolerance and operational-simplicity. Additionally, the use of two different primary amines could also work smoothly using this protocol.

Introduction Propargylamines are robust substrates widely valued for the generation of diverse heterocycles in organic synthesis.1 A number of these compounds also exhibit intrinsic biological activities in the treatment of neurodegenerative diseases.2 Owing to their apparent importance, significant efforts have been done for the synthesis of propargylamines. In particular, the transition metal-catalyzed three-component coupling of an amine, an aldehyde, and a terminal alkyne, known as the A3coupling, is now broadly employed for the synthesis of propargylamines (Scheme 1, eq 1).3 Also, a decarboxylative A3-coupling process has been developed as an alternative approach for accessing 1

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

propargylamines.4

In

addition,

transition

metal-catalyzed

Page 2 of 19

tandem

hydroamination

of

alkynes/alkynylation has been firmly established by Li, Hammond, Dyson, Blecherta, Larsen and others, leading to the construction of functionalized propargylamines (Scheme 1, eq 2).5 At the same time, tertiary amines have emerged as direct precursors that can undergo oxidative crossdehydrogenative coupling (CDC) with alkynes to produce a series of tertiary propargylamines (Scheme 1, eq 3).6,7 However, the lower reactivity of primary amines mostly makes the reported strategies not ideally suitable for the yielding of secondary propargylamines which have revealed a broader range of transformations than tertiary propargylamines.8 Therefore, the exploration of a new and efficient protocol for the synthesis of secondary propargylamines is still highly desirable. R R

R

2 NH

+

O R

R1 2 NH

R R

1

transition metal

R4

+

3

R +

R

R3

1

R3

R NH2 R

NH2

R3

R4

(1) R3 R1 N R2

or R3

Cu, Fe, Zn

R4

+

R1 N R2

3

Cu, Zn, etc

2N

R1

3

R1 N R2

R3 Me R1 N R2

R4

oxidants

(3) R3

R1 R

+

3

Cu, oxidant

R1

N

or Homo-

NH2 R

R1

NH

R3

R

1

R3

(2)

NH

R3 Cross-

R

(4)

(this work)

Scheme 1. Representative routes to propargylamines: (1) Transition metal-catalyzed A3-coupling, (2) Cross-dehydrogenative coupling, (3) Tandem hydroamination/alkynylation; (4) Present work: deamination/alkynylation cascade. It has been well established that oxidative deamination of amines can be performed to form imines in the presence of metal catalysts.9 For example, the copper/oxidant dual system was successfully applied for the reaction of a primary amine.10 In pursuit of expanding our knowledge about A3coupling reactions,11 we speculated that the imines resulting from direct oxidation of primary amines, could be trapped by alkynes in the presence of a copper catalyst (Scheme 1, eq 4). To the best of our knowledge this is the first report of an efficient synthesis of secondary propargylamines from primary amines and alkynes, through a catalytic oxidative deamination/alkynylation cascade process. This strategy poses significant challenges, not just because of the propensity of overoxidation of the imine to the nitrile,12 but also because of the rapid homocoupling of alkynes under

2


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oxidative conditions13 Moreover, another impediment is the competing over-oxidation of the final propargylamines.

Results and Discussion An optimization campaign ascertained suitable reaction conditions opting for a model reaction of benzylamine 1a and phenylacetylene 2a in the presence of CuBr2. Employing 12.5 mol% Cu with 1.25 equiv tert-butyl hydroperoxide (70% TBHP) in toluene, a 70% yield of propargylamine 3a was obtained after 3 h at 100 °C (Table 1, entry 1). The importance of water for the yield was pronounced when TBHP-decane was introduced instead of aqueous 70% TBHP (entry 2). Using H2O2, no desired product was observed (entry 3). Different copper catalysts such as CuCl2, Cu(OTf)2, CuI and CuBr as well as various catalyst loadings showed lower catalytic efficacy, giving 3a in 18−58% yields (entries 4−9). Switching the solvent to DCE, CH3CN or omitting it, resulted in lower yields (entries 10−12). Further, tuning the reaction parameters such as ratio of substrates, temperature and time had a positive effect on the yield (entries 13−16). A 79% yield of product was observed when 2.5 equiv of phenylacetylene 2a was applied at 110 oC for 4 h (entry 16). Table 1. Oxidative Deaminative Reaction with Alkynes NH2

+

1a (0.8 mmol)

Ph

12.5 mol% CuBr2 70% TBHP (12.5 equiv)

HN

toluene (1 mL), 100 oC, 3 h 2a (0.8 mmol)

3a

standard conditions

entry

deviation from the “standard conditions”

yielda (%)

1

none

70

2

TBHP-decane instead of 70% TBHP

53

3

H2O2 instead of 70% TBHP

NDb

4

CuCl2 instead of CuBr2

46

5

Cu(OTf)2 instead of CuBr2

18

6

CuI instead of CuBr2

51

7

CuBr instead of CuBr2

58

8

8 mol% of CuBr2

56

9

20 mol% of CuBr2

39

10

DCE instead of toluene

55

11

CH3CN instead of toluene

28

12

omit toluene

64

13

1a (1.0 mmol)

69

14

2a (1.0 mmol)

74

15

2a (1.0 mmol), reaction time prolonged to 4 h

76

16

2a (1.0 mmol), temperature increased to 110 °C, 4 h

79

aIsolated

yields.

bND

= not detected

3



Page 4 of 19

With the optimized reaction conditions in hand, a series of propargylamines 3 were generated from their corresponding amines and alkynes (Table 2). Firstly, a range of benzylamines was examined demonstrating that both electron-donating and electron-withdrawing substrates could react with 2a smoothly to deliver the corresponding products (3a−3e, 3g−3j) in good to excellent yields. Surprisingly, meta-substituted benzylamines provided lower yields (3c and 3e) than ortho-and parasubstituted ones (3b and 3d) together with the corresponding aldehydes as byproducts (monitored by GC-MS). However, when the 3,4-dimethoxybenzylamine was used, no desired product (3f) was obtained. Remarkably, for aliphatic primary amines involving cyclohexylmethanamine, n-butylamine and phenethylamine, only cyclohexylmethanamine could be successfully converted into the desired product (3k). This might be owing to the fact that most aliphatic amines are more difficult converted into the corresponding imine as compared to benzylamine employing the standard conditions.14 It is also worth noting that a secondary amine tolerates the reaction conditions, giving the tertiary propargylamine 3n. The result suggests that the final secondary propargylamine is potential to further transformation. Furthermore, the scope of alkynes was evaluated using benzylamine 1a. To our delight, all the target products (3aa−3an) were obtained with very good yields when reacted with different phenylacetylenes. However, it turned out that the reaction efficiency was susceptible to electronic effects. In general, phenylacetylenes containing electron-donating groups including methyl, methoxy, ethyl, butyl, amyl and t-butyl afforded higher yields (3aa−3ag) than those with electron-withdrawing groups, including Cl, F, CF3 (3ah−3an). No product (3ao) was obtained with ethynylcyclopropane. Table 2. Applicable Amines and Alkynes to Homo-Deaminative Couplinga. R1

R2

+

NH2

CuBr2(12.5 mol%),TBHP(1.25 equiv) toluene,110 oC, 4 h

2

1

R1 HN

R2

R1

3

Amines OMe

HN

HN

HN

HN

HN

MeO

3a, 79% yield

3b, 87% yield

OMe

3c, 63% yield

Cl

3d, 81% yield

Cl

HN

F

Br

HN

OMe

3e, 57% yield HN

HN

HN Cl

MeO MeO

Br

Cl

4


F

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3f, 0% yield

3g, 59% yield

HN

3h, 70% yield

3i, 61% yield

3j, 72% yield

N

HN HN

3k, 57% yield

3l, 0% yield

3m, 0% yield

3n, 66% yield

Alkynes HN

HN

HN

HN OMe

3aa, 88% yield

3ab, 82% yield

3ac, 90% yield

HN

HN

3ae, 87% yield HN

3ad, 79% yield

HN

HN

tBu

nBu

Et

Cl

nAm

3af, 86% yield

3ag, 86% yield

HN

3ah, 73% yield

HN

HN F

F

F3C

F

3ai, 73% yield HN

3aj, 78%yield

3ak, 71% yield

HN

3al, 51% yield

HN CF3

CF3

3am, 84% yield

3an, 67% yield

3ao, 0% yield

aReaction

scale: 0.8 mmol of amine 1, 1.0 mmol of alkyne 2, 12.5 mmol% of CuBr2, 1.25 equiv of 70% TBHP, 1 mL toluene. Reported yields are isolated yields. It is well-known that the cross-deamination of two different amines is more difficult. In order to further demonstrate the synthetic practicality of our protocol, a three-component tandem reaction of a benzylamine, an amine and a phenylacetylene was tested under slightly improved conditions. The initial study started using benzylamine 1a and n-butylamine under the standard conditions, but only

39% yield of the corresponding products 4a was isolated. An increased yield to 48% was obtained when 2.0 equiv. TBHP was introduced. (Table 3). Subsequently, different amines 1’ were evaluated, and moderate yields of the desired products (4b−4e) were obtained, because the homo-deamination of benzylamine 1a could not be fully avoided, giving 3a as a main isolated byproduct. Notably, when two different benzylamines were employed in the reaction, the desired product 4b was isolated

5



Page 6 of 19

in 56% yield. Furthermore, various benzylamines 1 and phenylacetylenes 2 with common functional groups could also be applied, resulting in the formation of the corresponding propargylamines (4f−4i) in moderate yields. Table 3. Applicable Amines and Alkynes to Cross-Deaminative Couplinga. NH2

R1

CuBr2(15 mol%), TBHP(2.0 equiv)

3

+

1

R2

R + NH 1'

2

toluene,110 oC, 4 h

R4

OMe

HN

4a, 48% yield HN

R1

O

N

N

HN

4b, 50% yield

4c, 49% yield

HN

R4

4

OMe

OMe

HN

R3 R2 N

4d, 30% yield

HN

4e, 39% yield HN OMe

CF3

F

4f, 41% yield

4g, 40% yield

4h, 46% yield

aReaction

scale: 0.5 mmol of benzylamine 1, 0.3 mmol of amine 2, 1 mL toluene. Reported yields are isolated yields.

1’,

4i, 43% yield

1.0 mmol of phenylacetylenes

A plausible mechanism is depicted in Scheme 2. Key intermediate methanimine A2 is generated with the regeneration of the copper catalyst via CuBr2/TBHP initiated dehydrogenative oxidation of primary amine 1 through the intermediate A1.15 Subsequently, the imine A3 could be produced through two pathways:8 1) partial hydrolysis of intermediate A2 resulting in the corresponding aldehyde, followed by a condensation reaction with another molecule of amine 1 or 1’, 2) direct deaminative reaction of A2 with another molecule of amine 1 or 1’. Meanwhile, the copper acetylide B2 is in situ formed from an alkyne 2 and a copper catalyst through the intermediate B1, followed by the reaction with the imine intermediate A3, leading to the desired homo-deamination product 3 or cross-deamination product 4.

6


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CuII B1

R1 1

R3

NH2

CuII B2

CuII R1 A1

TBHP

R3 R3

HN

2

CuII

R

R1

R2

HN

3

3 or 4 R

1

R

2

N

A3

NH

A2

NH2 2 R1 R 1'

Scheme 2. Mechanistic Hypothesis.

Conclusion In summary, we have developed a novel protocol to generate a diverse array of secondary propargyl amines starting from two amines and an alkyne. The reaction proceeds via a copper-catalyzed aerobic deamination/alkynylation cascade, in which the [Cu]-acetylide is postulated to capture the imine intermediate. This homo- or cross-deaminative coupling reaction complements disconnections in traditional synthetic routes to secondary propargyl amines.

Experimental Sections General information. Unless otherwise noted, all commercial reagents were used directly as purchased. All work-up and purification procedures were carried out with reagent-grade solvents that had not been pre-dried under ambient atmosphere. Thin-layer chromatography (TLC) was performed and visualization of the compounds was accomplished with UV light (254 nm) or iodine. Flash column chromatography was performed on silica gel (200–300 mesh). All 1H and 13C NMR spectra were recorded on a Bruker Avance III instrument (400 MHz and 100 MHz, respectively). Chemical shifts (δ) are reported in ppm relative to the tetramethylsilane (TMS) signal or residual protio solvent signal. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, coupling constant (s) in Hz, integration). Data for

13C

NMR is reported in terms of chemical shift (δ, ppm). High

resolution mass spectra were obtained on a Waters GC-TOFMS mass spectrometer with an electron impact ionization (EI) probe. General Procedure for the synthesis of secondary propargylamines 3. Amines 1 (0.8 mmol), CuBr2 (11.16 mg, 12.5 mol%), 70% TBHP (64 mg, 0.5 mmol) and toluene (1 mL) were charged

7



into a 10 mL tube along with a magnetic stir bar. The mixture was stirred in oil bath at 110 oC for 4-5 min, then alkynes 2 (1.0 mmol) were added into the reaction system, and the resulting mixture was stirred at 110 oC for another 4 h until amines 1 were completely consumed, monitoring with TLC. Subsequently, the mixture was cooled to room temperature), and purified by running column chromatography on silica gel using petroleum ether/ethyl acetate (v/v, 30:1) as eluent to afford the desired products 3. General Procedure for the synthesis of secondary propargylamines 4. Benzylamine 1 (0.5 mmol), another amines (0.3 mmol), CuBr2 (10 mg, 15 mol%), 70% TBHP (77 mg, 0.6 mmol) and toluene (1 mL) were charged into a 10 mL tube along with a magnetic stir bar. The mixture was stirred in oil bath at 110 ℃ for 4-5 min, phenylacetylenes 2 (1.0 mmol) was then added into the reaction system. After that, the reaction was performed again and refluxed at 110 oC for 4 h. Subsequently, the mixture was cooled to room temperature, and purified by running column chromatography on silica gel using petroleum ether/ethyl acetate (v/v, 30:1-20:1) as eluent to afford the desired products 4. N-benzyl-1, 3-diphenylprop-2-yn-1-amine (3a)16. yellow oil; 94.1 mg; 79% yield. 1H NMR (400 MHz, CDCl3) δ 7.62–7.60 (m, 2H), 7.50–7.47 (m, 2H), 7.44–7.27 (m, 10H), 7.27–7.21 (m, 1H), 4.80 (s, 1H), 4.09–3.86 (m, 2H), 1.77 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.4, 139.9, 131.8, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 127.1, 123.2, 89.3, 85.8, 77.4, 53.7, 51.2. N-(2-methylbenzyl)-3-phenyl-1-(o-tolyl)prop-2-yn-1-amine (3b). yellow oil; 113.2 mg; 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.82–7.67 (m, 1H), 7.57–7.43 (m, 2H), 7.41–7.26 (m, 4H), 7.24–7.18 (m, 2H), 7.18–7.15 (m, 4H), 4.93 (s, 1H), 4.07 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 12.6 Hz, 1H), 2.38 (d, J = 7.0 Hz, 6H), 1.53 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.3, 137.8, 137.0, 136.4, 131.8, 130.7, 130.4, 129.3, 128.4, 128.2, 127.8, 127.5, 127.3, 126.1, 125.9, 123.4, 89.6, 85.7, 51.5, 49.5, 19.0, 18.9. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1828. N-(3-methylbenzyl)-3-phenyl-1-(m-tolyl)prop-2-yn-1-amine (3c). milk white oil; 82.0 mg; 63% yield. 1H NMR (400 MHz, CDCl3) δ 7.57–7.55 (m, 2H), 7.46 (s, 2H), 7.40–7.35 (m, 3H), 7.34–7.25 (m, 4H), 7.18–7.12 (m, 2H), 4.85 (s, 1H), 4.10–3.93 (m, 2H), 3.04 (s, 1H), 2.41 (d, J = 9.5 Hz, 6H). 13C{1H}

NMR (100 MHz, CDCl3) δ 139.6, 138.9, 138.3, 138.1, 131.8, 129.4, 128.8, 128.5, 128.5,

128.4, 128.3, 128.3, 128.1, 125.7, 124.9, 123.2, 88.8, 86.1, 53.7, 51.0, 21.5, 21.4. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1829. 8


Page 8 of 19

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N-(4-methylbenzyl)-3-phenyl-1-(p-tolyl)prop-2-yn-1-amine (3d). milk white oil; 105.0 mg; 81% yield. 1H NMR (400 MHz, CDCl3) δ 7.59–7.51 (m, 4H), 7.40–7.35 (m, 5H), 7.26–7.21 (m, 4H), 4.83 (s, 1H), 4.06–3.97 (m, 2H), 2.42 (d, J = 5.0 Hz, 6H), 1.95 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 137.5, 137.4, 136.8, 136.6, 131.8, 129.2, 129.1, 128.4, 128.3, 128.1, 127.6, 123.3, 89.6, 85.5, 53.3, 50.8, 21.1, 21.1. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1830. N-(3-methoxybenzyl)-1-(3-methoxyphenyl)-3-phenylprop-2-yn-1-amine (3e). milk white oil; 81.4 mg; 57% yield. 1H NMR (400 MHz, CDCl3) δ 7.58–7.52 (m, 2H), 7.41–7.29 (m, 5H), 7.29– 7.24 (m, 2H), 7.09–7.02 (m, 2H), 6.94–6.84 (m, 2H), 4.86 (s, 1H), 4.08–4.00 (m, 2H), 3.88 (d, J = 7.8 Hz, 6H), 2.15 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.8, 141.8, 141.3, 131.8, 129.5, 129.4, 128.3, 128.2, 123.1, 120.8, 120.1, 113.9, 113.4, 112.7, 89.1, 85.8, 55.3, 55.2, 53.6, 51.1. HRMS (EI) m/z calcd for C24H23NO2 [M]+ 357.1729, found 357.1728. N-(2-chlorobenzyl)-1-(2-chlorophenyl)-3-phenylprop-2-yn-1-amine (3g). yellow oil; 86.6 mg; 59% yield. 1H NMR (400 MHz, CDCl3) δ 7.86–7.83 (m, 1H), 7.50–7.47 (m, 3H), 7.38–7.30 (m, 6H), 7.25–7.18 (m, 3H), 5.22 (s, 1H), 4.14 (d, J = 13.5 Hz, 1H), 4.05 (d, J = 13.5 Hz, 1H), 2.04 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 137.6, 137.0, 134.1, 133.4, 131.8, 131.8, 130.7, 129.8, 129.5, 129.2, 128.6, 128.3, 127.7, 127.2, 126.9, 123.0, 88.2, 85.7, 51.3, 49.2. HRMS (EI) m/z calcd for C22H17Cl2N [M]+ 365.0738, found 365.0730. N-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-phenylprop-2-yn-1-amine (3h). yellow soild; 102.3 mg; 70% yield; MP: 64.1–67.2 oC. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.49– 7.46 (m, 2H), 7.35–7.30 (m, 7H), 7.30–7.26 (m, 2H), 4.73 (s, 1H), 3.93 (d, J = 9.8 Hz, 2H), 1.74 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.8, 138.2, 133.6, 132.9, 131.8, 129.8, 129.1, 128.7, 128.6, 128.5, 128.4, 122.9, 88.5, 86.3, 53.0, 50.4. HRMS (EI) m/z calcd for C22H17Cl2N [M]+ 365.0738, found 365.0726. N-(4-bromobenzyl)-1-(4-bromophenyl)-3-phenylprop-2-yn-1-amine (3i). white soild; 110.4 mg; 61% yield; MP: 86.8–87.6 oC. 1H NMR (400 MHz, CDCl3) δ 7.58–7.39 (m, 8H), 7.35–7.32 (m, 3H), 7.29–7.22 (m, 2H), 4.72 (s, 1H), 3.92 (d, J = 10.8 Hz, 2H), 1.78 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.2, 138.6, 131.8, 131.6, 131.6, 130.2, 129.4, 128.5, 128.4, 122.8, 121.8, 121.0, 88.3, 86.4, 53.0, 50.4. HRMS (EI) m/z calcd for C22H17Br2N [M]+ 452.9728, found 452.9729. N-(4-fluorobenzyl)-1-(4-fluorophenyl)-3-phenylprop-2-yn-1-amine (3j). colorless oil; 96.0 mg; 72% yield. 1H NMR (400 MHz, CDCl3) δ 7.60–7.55 (m, 2H), 7.54–7.44 (m, 2H), 7.39–7.30 (m, 9



5H), 7.09–6.98 (m, 4H), 4.75 (s, 1H), 4.02–3.87 (m, 2H), 1.77 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.6, 163.3, 161.0 (d, J C, F = 30.9 HZ), 136.1 (d, J C, F = 2.5 HZ), 135.5 (d, J C, F = 2.7 HZ), 131.8, 130.0 (d, J C, F = 7.8 HZ), 129.3 (d, J C, F =8.1 HZ), 128.4, 123.0, 115.4 (d, J C, F = 5.7 HZ), 115.2 (d, J

C, F

= 5.5 HZ), 88.8, 86.1, 52.9, 50.4. HRMS (EI) m/z calcd for C22H17F2N [M]+

333.1329, found 333.1327. 1-cyclohexyl-N-(cyclohexylmethyl)-3-phenylprop-2-yn-1-amine (3k). yellow oil; 70.2 mg; 57% yield. 1H NMR (400 MHz, CDCl3) δ 7.44–7.41 (m, 2H), 7.32–7.27 (m, 3H), 3.36 (d, J = 5.7 Hz, 1H), 2.75–2.70 (m, 1H), 2.51–2.46 (m, 1H), 1.78–1.56 (m, 8H), 1.55–1.39 (m, 3H), 1.33–1.15 (m, 10H), 0.99–0.88 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 131.9, 128.8, 128.4, 122.0, 56.4, 52.7, 40.3, 35.1, 31.2, 30.4, 30.1, 27.9, 26.1, 26.0, 25.8, 25.6, 25.5. HRMS (EI) m/z calcd for C22H31N [M]+ 309.2457, found 309.2450. N-benzyl-N-methyl-1, 3-diphenylprop-2-yn-1-amine (3n)17. yellow oil; 82.1 mg; 66% yield. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 2H), 7.58–7.56 (m, 2H), 7.42 (d, J = 7.2 Hz, 2H), 7.39–7.22 (m, 9H), 4.92 (s, 1H), 3.73 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 13.1 Hz, 1H), 2.24 (s, 3H). 13C{1H}

NMR (100 MHz, CDCl3) δ 139.4, 139.1, 132.0, 129.1, 128.4, 128.4, 128.3, 128.2, 127.6,

127.2, 123.4, 88.8, 84.8, 77.4, 59.7, 59.0, 38.1. N-benzyl-1-phenyl-3-(m-tolyl)prop-2-yn-1-amine (3aa)18. colorless oil; 109.5 mg; 88% yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.37–7.26 (m, 7H), 7.26–7.21 (m, 1H), 7.20–7.14 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.04–3.89 (m, 2H), 2.31 (s, 3H), 1.79 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.6, 140.0, 138.1, 132.5, 129.2, 129.0, 128.6, 128.6, 128.6, 128.3, 127.9, 127.8, 127.2, 123.1,89.1, 86.5, 53.8, 51.3, 21.3. N-benzyl-1-phenyl-3-(p-tolyl)prop-2-yn-1-amine (3ab). colorless oil; 102.5 mg; 82% yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.3 Hz, 2H), 7.43–7.37 (m, 3H), 7.37–7.19 (m, 7H), 7.10 (d, J = 7.9 Hz, 2H), 4.78 (s, 1H), 4.03–3.92 (m, 2H), 2.32 (s, 3H), 1.77 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.6, 140.0, 138.3, 131.7, 129.1, 128.6, 128.5, 127.8, 127.1, 120.2, 88.6, 85.9, , 53.8, 51.2, 21.5. HRMS (EI) m/z calcd for C23H21N [M]+ 311.1674, found 311.1673. N-benzyl-3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-amine (3ac)18. colorless oil; 117.8 mg; 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.43–7.37 (m, 4H), 7.36–7.21 (m, 6H), 6.86–6.78 (m, 2H), 4.78 (s, 1H), 4.03–3.91 (m, 2H), 3.76 (s, 3H), 2.21 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 140.6, 139.9, 133.2, 128.6, 128.5, 128.5, 127.8, 127.7, 127.1, 115.4, 10


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114.0, 87.8, 85.7, 55.3, 53.8, 51.2. N-benzyl-3-(4-ethylphenyl)-1-phenylprop-2-yn-1-amine (3ad). yellow oil; 102.8 mg; 79% yield. 1H

NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 2H), 7.44–7.19 (m, 10H), 7.13 (d, J = 8.1 Hz,

2H), 4.78 (s, 1H), 4.05–3.89 (m, 2H), 2.64–2.59 (m, 2H), 1.80 (s, 1H), 1.23–1.19 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 140.6, 140.0, 131.9, 128.6, 128.6, 128.6, 128.0, 127.8, 127.2, 120.5, 88.7, 86.1, 53.8, 51.3, 29.0, 15.6. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1829. N-benzyl-3-(4-butylphenyl)-1-phenylprop-2-yn-1-amine (3ae). yellow oil; 122.9 mg; 87% yield. 1H

NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.7 Hz, 2H), 7.41–7.38 (m, 4H), 7.37–7.19 (m, 6H), 7.11

(d, J = 7.9 Hz, 2H), 4.78 (s, 1H), 4.08–3.89 (m, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.77 (s, 1H), 1.64– 1.48 (m, 2H), 1.37–1.28 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.4, 140.7, 140.1, 131.8, 128.6, 128.6, 128.6, 128.5, 127.8, 127.2, 120.5, 88.7, 86.1, 53.8, 51.3, 35.7, 33.5, 22.4, 14.1. HRMS (EI) m/z calcd for C26H27N [M]+ 353.2143, found 353.2143. N-benzyl-3-(4-(tert-butyl)phenyl)-1-phenylprop-2-yn-1-amine (3af). yellow oil; 121.5 mg; 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 7.4 Hz, 2H), 7.37–7.18 (m, 8H), 4.79 (s, 1H), 4.07–3.91 (m, 2H), 1.77 (s, 1H), 1.30 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.5, 140.6, 140.1, 131.6, 128.6, 128.5, 127.8, 127.2, 125.4, 120.3, 88.7, 86.0, 53.8, 51.3, 34.8, 31.3. HRMS (EI) m/z calcd for C26H27N [M]+ 353.2143, found 353.2145. N-benzyl-3-(4-pentylphenyl)-1-phenylprop-2-yn-1-amine (3ag). yellow oil; 125.8 mg; 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.41–7.38 (m, 4H), 7.36–7.21 (m, 6H), 7.12 (d, J = 8.0 Hz, 2H), 4.78 (s, 1H), 4.08–3.89 (m, 2H), 2.68–2.47 (m, 2H), 1.77 (s, 1H), 1.68–1.47 (m, 2H), 1.36–1.21 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 143.4, 140.6, 140.0, 131.8, 128.6, 128.6, 128.5, 127.8, 127.2, 120.5, 88.7, 86.1, 53.8, 51.3, 36.0, 31.5, 31.1, 22.7, 14.2. HRMS (EI) m/z calcd for C27H29N [M]+ 367.2300, found 367.2303. N-benzyl-3-(4-chlorophenyl)-1-phenylprop-2-yn-1-amine (3ah). colorless oil; 97.1 mg; 73% yield. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.4 Hz, 2H), 7.42–7.21 (m, 12H), 4.78 (s, 1H), 4.03–3.88 (m, 2H), 1.84 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.2, 139.8, 134.3, 133.1, 128.7, 128.7, 128.6, 128.5, 128.0, 127.7, 127.2, 121.7, 90.4, 84.7, 53.7, 51.3. HRMS (EI) m/z calcd for C22H18ClN [M]+ 331.1128, found 331.1124. N-benzyl-3-(2-fluorophenyl)-1-phenylprop-2-yn-1-amine (3ai). Colorless oil; 92.5 mg; 73% 11



Page 12 of 19

yield. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.50–7.24 (m, 10H), 7.11–7.06 (m, 2H), 4.83 (s, 1H), 4.08–3.95 (m, 2H), 1.80 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 161.8, 139.8 (d, J C, F = 21.4 HZ), 133.6, 129.9 (d, J C, F = 7.9 HZ), 128.6, 128.5, 128.5, 127.9, 127.7, 127.1, 123.9 (d, J C, F = 37.1 HZ), 115.5 (d, J C, F = 20.8 HZ), 111.8 (d, J C, F = 16.7 HZ), 94.6 (d, J C, F = 3.0 HZ), 79.3, 53.8, 51.1. HRMS (EI) m/z calcd for C22H18FN [M]+ 315.1423, found 315.1422. N-benzyl-3-(3-fluorophenyl)-1-phenylprop-2-yn-1-amine (3aj). yellow oil; 98.2 mg; 78% yield. 1H


(d, J = 8.8 Hz, 1H), 7.03–6.95 (m, 1H), 4.78 (s, 1H), 4.05–3.86 (m, 2H), 1.79 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.7, 161.2, 140.0 (d, J

C, F

= 35.5 HZ), 130.0 (d, J

C, F

= 8.5 HZ), 128.7,

128.6, 128.5, 128.0, 127.8, 127.7, 127.2, 125.1 (d, J C, F = 9.5 HZ), 118.7 (d, J C, F = 22.6 HZ), 115.6 (d, J C, F = 21.0 HZ), 90.5, 84.6 (d, J C, F = 3.3 HZ), 53.7, 51.3. HRMS (EI) m/z calcd for C22H18FN [M]+ 315.1423, found 315.1421. N-benzyl-3-(4-fluorophenyl)-1-phenylprop-2-yn-1-amine (3ak). yellow oil; 89.5 mg; 71% yield. 1H


(t, J = 8.5 Hz, 2H), 4.78 (s, 1H), 4.04–3.86 (m, 2H), 1.86 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.7, 161.3, 140.1 (d, J

C, F

= 50.3 HZ), 133.6 (d, J

C, F

= 8.2 HZ), 128.6, 128.5, 128.4, 127.8,

127.7, 127.2, 119.3 (d, J C, F = 3.5 HZ), 115.6 (d, J C, F = 21.9 HZ), 89.0, 84.7, 53.7, 51.2. HRMS (EI) m/z calcd for C22H18FN [M]+ 315.1423, found 315.1420. N-benzyl-1-phenyl-3-(2-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3al). yellow oil; 74.5 mg; 51% yield. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 1H), 7.64–7.59 (m, 3H), 7.48 (t, J = 7.4 Hz, 1H), 7.43–7.25 (m, 9H), 4.84 (s, 1H), 4.11–3.96 (m, 2H), 1.79 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.0, 139.9, 134.3, 131.4, 128.5, 128.5, 128.0, 127.9, 127.7, 127.1, 126.5, 125.9 (q, J C, F = 15.1 HZ), 125.1, 122.4, 121.5 (dd, J C, F = 6.0 HZ), 95.4, 81.8, 53.8, 51.1. HRMS (EI) m/z calcd for C23H18F3N [M]+ 365.1391, found 365.1390. N-benzyl-1-phenyl-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3am). yellow oil; 122.1 mg; 84% yield. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.63–7.58 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H), 7.42–7.34 (m, 6H), 7.33–7.29 (m, 2H), 7.28–7.23 (m, 1H), 4.80 (s, 1H), 4.05–3.92 (m, 2H), 1.82 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.1, 139.8, 135.0, 131.0 (d, J C, F = 32.4 HZ), 128.9, 128.7, 128.6, 128.5, 128.0, 127.7, 127.3, 125.2, 124.8 (q, J C, F =10.9 HZ), 124.2, 122.5, 91.2, 84.3, 53.7, 51.3. HRMS (EI) m/z calcd for C23H18F3N [M]+ 365.1391, found 365.1393. 12


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N-benzyl-1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3an). colorless oil; 98.1 mg; 67% yield. 1H NMR (400 MHz, CDCl3) δ 7.63–7.53 (m, 6H), 7.41–7.31 (m, 7H), 7.30–7.24 (m, 1H), 4.81 (s, 1H), 4.08–3.88 (m, 2H), 1.81 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.0, 139.7, 132.1, 130.2 (d, J

C, F

= 32.8 HZ), 128.7, 128.6, 128.5, 128.0, 127.7, 127.3, 127.0, 125.4-

125.2 (m), 122.7, 92.0, 84.5, 53.7, 51.3. HRMS (EI) m/z calcd for C23H18F3N [M]+ 365.1391, found 365.1391. N-(1,3-diphenylprop-2-yn-1-yl)butan-1-amine (4a)19. yellow oil; 38.2 mg; 48% yield. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 2H), 7.48–7.45 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.34– 7.28 (m, 4H), 4.80 (s, 1H), 2.93–2.79 (m, 1H), 2.79–2.64 (m, 1H), 1.61 (s, 1H), 1.57–1.46 (m, 2H), 1.41–1.35 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.7, 131.7, 128.5, 128.2, 128.1, 127.7, 127.6, 123.3, 89.7, 85.3, 54.8, 47.0, 32.1, 20.5, 14.0. N-(3, 4-dimethoxybenzyl)-1, 3-diphenylprop-2-yn-1-amine (4b). yellow oil; 53.6 mg; 50% yield. 1H

NMR (400 MHz, CDCl3) δ 7.70–7.61 (m, 2H), 7.54 (d, J = 3.4 Hz, 2H), 7.46–7.31 (m, 6H),

6.96–7.01 (m, 2H), 6.85–6.88 (m, 1H), 4.83 (d, J = 3.4 Hz, 1H), 3.98 (s, 2H), 3.90–3.94 (m, 6H), 1.78 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 148.3, 140.5, 132.5, 131.7, 128.5, 128.3, 128.2, 127.7, 127.6, 123.2, 120.6, 111.8, 111.3, 89.3, 85.7, 56.0, 55.9, 53.6, 51.0. HRMS (EI) m/z calcd for C24H23NO2 [M]+ 357.1729, found 357.1728. N-(3-methoxyphenethyl)-1, 3-diphenylprop-2-yn-1-amine (4c). yellow oil; 50.1 mg; 49% yield. 1H

NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz, 2H), 7.49–7.42 (m, 2H), 7.36 (t, J = 7.3 Hz, 2H),

7.31–7.27 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.79–6.67 (m, 2H), 4.83 (s, 1H), 3.76 (s, 3H), 3.16–3.09 (m, 1H), 3.04–2.98 (m, 1H), 2.90–2.77 (m, 2H), 1.58 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 141.5, 140.4, 131.7, 129.4, 128.5, 128.3, 128.1, 127.7, 127.6, 123.1, 121.2, 114.4, 111.6, 89.3, 85.4, 55.1, 54.6, 48.2, 36.3. HRMS (EI) m/z calcd for C24H23NO [M]+ 341.1780, found 341.1778. 1-(1, 3-diphenylprop-2-yn-1-yl)pyrrolidine (4d)17. yellow oil; 23.0 mg; 30% yield. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 1.5 Hz, 2H), 7.38–7.31 (m, 6H), 4.88 (s, 1H), 2.69 (s, 4H), 1.80 (s, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.2, 131.8, 128.4, 128.3, 128.1, 128.0, 127.7, 123.2, 87.0, 86.8, 59.1, 50.2, 23.5. 4-(1, 3-diphenylprop-2-yn-1-yl)morpholine (4e)17. yellow oil; 32.3 mg; 39% yield. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.54–7.48 (m, 2H), 7.39–7.29 (m, 6H), 4.79 (s, 1H), 3.79– 13



Page 14 of 19

3.66 (m, 4H), 2.63 (d, J = 4.0 Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 137.9, 131.8, 128.6, 128.3, 128.3, 128.2, 127.8, 123.0, 88.5, 85.1, 67.2, 62.1, 49.9. N-(1-(4-fluorophenyl)-3-phenylprop-2-yn-1-yl)butan-1-amine (4f)19. yellow oil; 35.2 mg; 41% yield. 1H NMR (400 MHz, CDCl3) δ 7.62–7.52 (m, 2H), 7.47–7.45 (m, 2H), 7.41–7.27 (m, 4H), 7.05 (t, J = 8.7 Hz, 1H), 4.79 (d, J = 8.0 Hz, 1H), 2.90–2.78 (m, 1H), 2.76–2.65 (m, 1H), 1.58–1.45 (m, 3H), 1.38 (t, J = 11.1 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.3 (d, J C, F = 244.3 HZ), 136.5 (d, J C, F = 3.0 HZ), 131.7, 129.2 (d, J C, F = 8.1 HZ), 128.3, 127.6, 123.1, 115.2 (d, J C, F = 21.3 HZ), 89.3, 85.5, 54.0, 47.0, 32.1, 20.5, 14.0. N-(3-phenyl-1-(o-tolyl)prop-2-yn-1-yl)butan-1-amine (4g). yellow oil; 33.3 mg; 40% yield. 1H NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 1H), 7.48–7.42 (m, 2H), 7.32–7.27 (m, 3H), 7.24–7.14 (m, 3H), 4.90 (s, 1H), 2.99–2.87 (m, 1H), 2.79–2.66 (m, 1H), 2.47 (s, 3H), 1.54–1.50 (m, 3H), 1.42– 1.34 (m, 2H), 0.92 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.7, 136.1, 131.7, 130.7, 128.2, 128.0, 127.6, 127.2, 126.1, 123.4, 89.8, 84.9, 52.0, 47.6, 32.2, 20.6, 19.0, 14.0. HRMS (EI) m/z calcd for C20H23N [M]+ 277.1830, found 277.1829. N-(1-phenyl-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)butan-1-amine (4h). yellow oil; 46.2 mg; 46% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 3H), 7.44 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H), 2.88–2.82 (m, 1H), 2.75–2.68 (m, 1H), 1.58 (s, 1H), 1.56–1.48 (m, 2H), 1.42–1.35 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 134.8 (d, J C, F = 0.8 HZ), C, F

= 32.5 HZ), 128.8, 128.6, 128.5, 128.5, 127.8, 127.5, 124.7 (dd, J

C, F

130.9 (d, J

= 7.1 HZ), 124.2, 91.4,

83.7, 54.7, 47.1, 32.1, 20.5, 14.0. HRMS (EI) m/z calcd for C20H20F3N [M]+ 331.1548, found 331.1551. N-(3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-yl)butan-1-amine (4i). yellow oil; 37.8 mg, 43% yield. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 2H), 7.40–7.36 (m, 3H), 7.33–7.27(m, 2H), 6.84 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.78 (s, 1H), 3.80 (s, 3H), 2.87–2.81 (m, 1H), 2.74–2.67 (m, 1H), 1.54–1.49 (m, 3H), 1.43–1.34 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.5, 140.9, 133.1, 128.5, 128.4, 128.4, 127.6, 113.9, 88.1, 85.1, 55.3, 54.8, 47.1, 32.1, 20.5, 14.0. HRMS (EI) m/z calcd for C20H23NO [M]+ 293.1780, found 293.1776.

Associated Content 14


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR spectra for compounds 3a−3e, 3g−3k, 3n, 3aa−3an, 4a-4i (PDF)

Author Information Corresponding Authors *E-mail: [email protected].

ORCID Huangdi Feng: 0000-0002-5500-8283 Notes The authors declare no competing financial interest.

Acknowledgements The authors would like to thank Hua Wei for assistance. This research was supported by the Innovation Research Projects of Shanghai University of Engineering Science (201810856017, cs1704006, A1-0601-19-01017), and the Opening Project of Shanghai Key Laboratory of Chemical Biology for financial support. We also acknowledge the support of the RUDN University Program 5-100.

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Synthetic Access to Secondary Propargylamines via a Copper

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