Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines

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Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines Mu-Wang Chen, Qin Yang, Zhihong Deng, Yirong Zhou, Qiuping Ding, and Yiyuan Peng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00873 • Publication Date (Web): 08 Jun 2018 Downloaded from http://pubs.acs.org on June 8, 2018

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The Journal of Organic Chemistry

Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines Mu-Wang Chen,a Qin Yang,a,b Zhihong Deng,a Yirong Zhou,a Qiuping Dinga,b and Yiyuan Penga,b* a

Key Laboratory of Small Functional Organic Molecule, Ministry of Education and College of Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.

b

Jiangxi’s Key Laboratory of Green Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022, China *E-mail: [email protected], [email protected].

ABSTRACT

Highly chemoselective catalytic transfer hydrogenation of fluorinated alkynyl ketimines has been achieved by employing chiral phosphoric acid as catalyst with benzothiazoline as hydride source, providing the corresponding chiral fluorinated propargylamines in good yields and excellent enantioselectivities. In addition, iodocyclization of fluorinated propargylamine affords chiral 3-iodo-2-(trifluoromethyl)-1,2dihydroquinoline, which can be easily converted to 2-(trifluoromethyl)- 1,2-dihydroquinoline derivatives with the selective COX-2 inhibitory activity.

Chiral fluorinated amine compounds are important building blocks for the preparation of pharmaceuticals, agrochemicals and biologically active natural products (Figure 1).1 DPC 961, the second generation nonnucleoside reverse transcriptase inhibitor, exhibits increasing effectiveness against K103N containing human immunodeficiency virus.2a Compound II acts as neutral endopeptidase inhibitor,2b and Odanacatib, also called MK-0822, is a selective inhibitor of cathepsin K for the treatment of osteroporosis.2c Given the importance of chiral fluorinated amines, the development of efficient synthetic methods for preparation of this class of compounds is significant for medicine chemistry.

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Figure 1. Some bioactive chiral amines bearing trifluoromethyl. In the past decades, chemists have made tireless efforts to develop two major strategies for the preparation of chiral fluorinated amines.3-4 One method involves the chiral auxiliary or organocatalysts to induce the nucleophilic addition of trifluoromethyl group to the imines.3 For example, in 2009, Shibata reported the enantioselective trifluoromethylation of imine with Me3SiCF3 by employing Cinchona alkaloids as chiral catalysts.3h The other process is the asymmetric transformation of fluorinated block,4 such as nucleophilic additions to fluorinated imines,5 isomerization of fluorinated imines,6 ring opening reaction of active trifluomethylated epoxides7 and kinetic resolution of racemic trifluoromethyl amines.8 Noteworthy, asymmetric hydrogenation of fluorinated imines/enamides is regarded as one of the most straightforward and atom-economic methods toward the synthesis of chiral trifluoromethylated amines.9-12 Although great advance has been achieved in asymmetric hydrogenation of simple fluorinated imines utilizing Pd,9 Ir,10a Rh, 10b

Ru11 and organocatalysts,12 there are few reports for the synthesis of chiral fluorinated propargylamines

by the asymmetric hydrogenation method due to difficulties in the chemoselectivity between C=N and C≡C bonds, including reduction of imine, partial reduction of the triple bond, and complete reduction of the triple bond. Therefore, the precisely controlled chemoselective reduction is a challenge. For example, for asymmetric reduction of β,γ-alkynyl-α-imino esters to afford the trans-alkenyl-α-imino esters, both partial reduction of C≡C bond and C=N reduction is observed (Scheme 1, eq. 1).13 Very recently, Zhou’s group reported an efficient approach for the synthesis of chiral fluorinated propargylamines through ruthenium/CPA relay catalytic chemoselective asymmetric hydrogenation of fluorinated alkynyl ketimines with a high hydrogen pressure of 1000 psi (Scheme 1, eq. 2).14 Consequently, the development of a general and simple method for synthesis of chiral fluorinated propargylamines is still highly desirable. Herein, we reported a chemoselective asymmetric transfer hydrogenation of C=N of fluorinated alkynyl ketimines for the synthesis of chiral fluorinated propargylamines with excellent enantioselectivities. Scheme 1. Selective Reduction of C=N of Alkynyl Ketimines


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We began our exploration with 4-methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-ylidene)aniline (1a) as the model substrate and excess amount of benzothiazoline 4a in dichloromethane in the presence of catalytic amount of chiral phosphoric acid 3a15 under similar conditions to Akiyama’s reaction12b,16 (Table 1). Pleasingly, the reaction proceeded smoothly, and moderate yield as well as enantioselectivity was obtained (entry 1). Then, the solvent effects were examined (entries 1-5). Among the various solvents, dichloromethane was the best choice, giving the desired product in 39% ee and 66% conversion. Subsequently, different benzothiazolines 4b-d were investigated (entries 6-8), the results showed that 4a was the best hydride source. To further improve the activity, a series of chiral phosphoric acids were evaluated (entries 9-13). The best result was achieved with H8-binol derived chiral phosphoric acid 3f bearing 3,5bis(trifluoromethyl)phenyl, providing the product in 96% ee and full conversion (entry 13). To our delight, no loss in conversion and enantioselectivity was observed with the decreased loading of benzothiazoline 4a (1.5 equiv. vs 2.0 equiv., entry 14). Finally, decreasing the amount of solvent dichloromethane from 3.0 mL to 1.5 mL resulted in a slight improvement in the enantioselectivity from 95% to 98% (entry 15). In addition, a series of other hydrogen sources were tested under chiral phosphoric acid 3f/ dichloromethane /40 oC condictions. Unfortunately, no conversion was observed using Hantzsch ester instead of benzothiazoline as hydrogen source and the yield was low (18% yield & 32% ee) when dihydrophenanthridine was used as hydrogen source. Therefore, the optimal reaction condition was established as: phosphoric acid 3f (10 mol %), benzothiazoline 4a (1.5 equiv.), dichloromethane and 40 oC. Table 1. Optimization of the Reaction Conditions a

Entry

Solvent

CPA3

4

Yieldb (%)


Eec (%)


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1

CH2Cl2

3a

4a

66

39

2

THF

3a

4a

95

96

14d

CH2Cl2

3f

4a

>95

95

15e

CH2Cl2

3f

4a

>95

98

a Conditions: 1a (0.10 mmol), CPA 3 (10 mol %), 4 (2.0 equiv.), solvent (3.0 mL), 48 h, 40 oC. b Determined by 1H NMR spectroscopy. c Determined by chiral HPLC analysis. d 4a (1.5 equiv.). e CH2Cl2 (1.5 mL).

After establishing the optimal condition, our attention was turned to investigate the scope of various substituted fluorinated alkynyl ketimines, and the results were summarized in Table 2. Gratifyingly, N-arylsubstituted substrates with either electron-donating or electron-withdrawing substituent on the aromatic ring could be smoothly converted to the corresponding products in high yields and excellent enantioslectivities (entries 1-6). Next, the R group with different aryl, alkyl, alkenyl and alkynyl substituent was also examined in this reaction and the target products were obtained in high yields with excellent enantioselectivies (entries 7-13). The electronic and steric properties of R had a marginal effect on the reactivity and ee values (entries 7-10). Subsequently, difluoroalkyl and perfluoroalkyl-substituted substrates were also evaluated, giving the desired difluoroalkyl amine and pentafluoroalkyl amine in 82% yield with 92% ee and 34% yield with 93% ee, respectively (entries 14-15). However, the activity of the reaction was very low for heptafluoroalkyl imine which may be due to steric hindrance.


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Table 2. Substrate Scope of Fluorinated Alkynyl Ketimines a

Entry

Ar

Rf

R

Yieldb (%)

Eec (%)

1

4-MeOC6H4

CF3

C6H5

98

98

2

4-MeC6H4

CF3

C6H5

92

98

3

4-ClC6H4

CF3

C6H5

91

98

4

4-CF3C6H4

CF3

C6H5

92

98

5

C6H5

CF3

C6H5

93

98

6

3-MeOC6H4

CF3

C6H5

92

98

7

4-MeOC6H4

CF3

4-MeC6H4

88

98

8

4-MeOC6H4

CF3

4-MeOC6H4

87

98

9

4-MeOC6H4

CF3

4-FC6H4

98

98

10

4-MeOC6H4

CF3

2-FC6H4

99

97

11

4-MeOC6H4

CF3

Cyclohexene

84

97

12

4-MeOC6H4

CF3

C4H9

96

97

13

4-MeOC6H4

CF3

C6H5C≡C

91

98

14

4-MeOC6H4

CF2H

C6H5

82

92

15

4-MeOC6H4

CF2CF3

C6H5

34

93

a Conditions: 1 (0.2 mmol), CPA 3f (10 mol %), 4a (1.5 equiv.), CH2Cl2 (3.0 mL), 40 oC, 48 h. b Isolated yields. c Determined by chiral HPLC analysis.

To demonstrate the utility of this method, a short synthesis of the chiral 2-(trifluoromethyl)-1,2dihydroquinoline was also conducted (Scheme 2). 1,2-Dihydroquinolines are common structural motifs present in bioactive compounds and natural products, such as 2-trifluoromethyl-1,2-dihydro-quinoline derivatives, which have selective COX-2 inhibitory activity.17 The product 5a was obtained by Borch methylation of 2a with formaldehyde. Next, 5a was treated with iodine in the presence of sodium bicarbonate in acetonitrile, iodocyclized product 6a was obtained in 90% yield.18 Subsequently, 2-trifluoromethyl-1,2-dihydroquinoline 7a could be obtained by Suzuki coupling of 6a with (4-methoxyphenyl)boronic acid in 94% yield and 97% ee. Significantly, the enantioselectivities of these products remained excellent. In



addition, the alkynyl group of the chiral propargylamines was readily converted into the corresponding alkyl and alkenyl group by controlling the reduction of C≡C bond. 14 Meanwhile, chiral primary amine 8a could be obtained by removing the p-methoxyphenyl group through oxidative cleavage of the hydrogenated product 2, and the optical purity still remained (Scheme 2).9c, 14 Scheme 2. Transformations of Chiral Trifluoromethylated Propargylamine

Notably, an enantioreversal phenomenon was observed in asymmetric reduction of fluorinated alkynyl ketimine 1a (Scheme 3) using the same (S)-CPA 3f between our catalytic system and Zhou’s system ((S)CPA3f/phenanthridine/Ru[(p-cymene)I2]2/H2).14 The discrepancy is possibly attributed to the different hydrogen source, dihydrophenanthridine versus benzothiazoline. For the course of 1,2-hydride transfer process, interaction among chiral phosphoric acid, substrate and hydrogen source may be different due to steric hindrance of benzothiazole substituent.19 The different facial attack leads to enantioreversal. Based on the above experimental results and putative mechanism on acid-catalyzed transfer hydrogenation, a plausible hydride transfer pathway was outlined in Scheme 4. Scheme 3. Enantioreversal in Asymmetric Reduction of Fluorinated Alkynyl Ketimines 1a


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Scheme 4. The Proposed Transition State Model for Asymmetric Transfer Hydrogenation of the Fluorinated Alkynyl Ketimines 1a

S

N H

R H F3 C Ph

F3C

(S)-CPA O O P O O

Ph H

This work: Re-face attack

H

N H

vs

H N PMP 1a

N PMP 1 O O P O O (S)-CPA

Zhou's work: Si-face attack

In summary, we have successfully developed an efficient and convenient method for the synthesis of chiral fluorinated propargylamines through chiral phosphoric acid-catalyzed asymmetric precise reduction of C=N bond of the fluorinated alkynyl ketimines with up to 98% ee. Carbon-carbon triple bond remain intact due to mild reaction condition. Moreover, the synthetic applicability of the developed method was demonstrated in synthesis of chiral biologically active 2-(trifluoromethyl)-1,2-dihydroquinoline. Further extension of this methodology to asymmetric synthesis is currently ongoing in our laboratory.

EXPERIMENTAL SECTION Commercially available reagents were used without further purification. Solvents were treated prior to use according to the standard methods. 1H NMR,

13

C NMR and

19

F NMR spectra were recorded at room

temperature in CDCl3 on 400 MHz instrument with tetramethylsilane (TMS) as internal standard. Enantiomeric excess was determined by HPLC analysis, using chiral column described below in detail. Optical rotations were measured by polarimeter. Flash column chromatography was performed on silica gel (200-300 mesh). Typical Procedure for Asymmetric Transfer Hydrogenation of Fluorinated Alkynyl Ketimines: In a dry, nitrogen flushed Schlenk tube, ﬂuorinated alkynyl ketimines 1 (0.20 mmol), (S)-CPA 3f (15.6 mg, 0.02 mmol) and 2-(4-nitrophenyl)-2,3-dihydrobenzothiazole (77.5 mg, 0.30 mmol) were dissolved in dichloromethane (DCM, 3.0 mL) was stirred at 40 oC for 48 h, the reaction mixture was directly purified by column chromatography on silica gel using hexanes/dichloromethane = 1/1 to give the product 2. (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (2a): 61 mg, 98% yield, yellow oil, Rf = 0.67 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -213.26 (c 0.61, CHCl3) [lit.14: [α]20D = -231.28 (c 1.16, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.42-7.42 (m, 2H), 7.30-7.28 (m, 3H), 6.83-6.75 (m, 4H), 4.75 (q, J = 6.2 Hz, 1H), 3.77 (d, J = 9.1 Hz, 1H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.2, 138.9, 132.0, 129.2, 128.4, 123.8 (q, J = 280.0 Hz), 121.5, 116.9, 114.9, 86.3, 80.9 (q, J = 2.0 Hz),



55.6, 52.2 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.6; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 11.0 min, t2 = 11.8 min (maj). (R)-(-)-4-Methyl-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (2b): 53 mg, 92% yield, pale yellow oil, Rf = 0.71 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -218.66 (c 0.53, CHCl3) [lit.14: [α]20D = -210.11 (c 0.82, CHCl3) for 93% ee]; 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.31-7.29 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 4.84 (q, J = 6.2 Hz, 1H), 3.88 (brs, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.7, 132.0, 130.0, 129.7, 129.2, 128.4, 123.8 (q, J = 280.0 Hz), 121.4, 114.9, 86.1, 80.7 (q, J = 2.0 Hz), 51.2 (q, J = 34.0 Hz), 20.5;

19

F NMR (376 MHz, CDCl3) δ -75.7; HPLC (AD-H, elute:

Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 7.5 min, t2 = 8.4 min (maj). (R)-(-)-4-Chloro-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (2c): 56 mg, 91% yield, pale yellow oil, Rf = 0.77 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -206.24 (c 0.56, CHCl3) [lit.14: [α]20D = -233.58 (c 1.14, CHCl3) for 93% ee]; 1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 2H), 7.33-7.30 (m, 3H), 7.20-7.18 (m, 2H), 6.69 (d, J = 8.8 Hz, 2H), 4.84 (q, J = 6.1 Hz, 1H), 4.03 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.6, 132.0, 129.4 (d), 128.4, 125.1, 123.6 (q, J = 280.0 Hz), 121.2, 115.7, 86.5, 80.0 (q, J = 2.0 Hz), 50.7 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.6; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 10.0 min, t2 = 11.5 min (maj). (R)-(-)-N-(1,1,1-Trifluoro-4-phenylbut-3-yn-2-yl)-4-(trifluoromethyl)aniline (2d): 63 mg, 92% yield, pale yellow oil, Rf = 0.85 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -163.16 (c 0.63, CHCl3) [lit.14: [α]20D = -174.60 (c 1.30, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 4H), 7.40-7.31 (m, 3H), 6.80 (d, J = 8.6 Hz, 2H), 4.97 (q, J = 6.0 Hz, 1H), 4.36 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.6, 132.0, 129.4, 128.5, 126.8 (q, J = 4.0 Hz), 123.6 (q, J = 280.0 Hz), 123.2 (t, J = 269.0 Hz), 121.5 (q, J = 34.0 Hz), 121.0, 113.5, 86.7, 79.5 (q, J = 2.0 Hz), 49.8 (q, J = 35.0 Hz); 19F NMR (376 MHz, CDCl3) δ 61.4, -75.6; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 10.0 min, t2 = 11.3 min (maj). (R)-(-)-N-(1,1,1-Trifluoro-4-phenylbut-3-yn-2-yl)aniline (2e): 51 mg, 93% yield, pale yellow oil, Rf = 0.76 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -181.95 (c 0.51, CHCl3) [lit.14: [α]20D = -188.85 (c 1.06, CHCl3) for 94% ee]; 1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.32-7.25 (m, 5H), 6.90-6.86 (m, 1H), 6.80-6.77 (m, 2H), 4.90 (q, J = 6.1 Hz, 1H), 4.03 (brs, 1H);

13

C NMR (100 MHz, CDCl3) δ 145.0, 132.0,

129.5, 129.2, 128.4 , 123.8 (d, J = 280.0 Hz), 121.4, 120.2, 114.5, 86.2, 80.5 (q, J = 2.0 Hz), 50.6 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.7; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 7.9 min, t2 = 9.2 min (maj). (R)-(-)-3-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (2f): 57 mg, 92% yield, pale yellow oil,


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Rf = 0.57 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -160.52 (c 0.57, CHCl3) [lit.14: [α]20D = -188.83 (c 1.12, CHCl3) for 92% ee]; 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 7.5, 1.2 Hz, 2H), 7.33-7.30 (m, 3H), 7.15 (t, J = 8.1 Hz, 1H), 6.45-6.33 (m, 3H), 4.90 (q, J = 6.1 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.78 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 160.9, 146.4, 132.0, 130.3, 129.2, 128.4, 123.7 (q, J = 280.0 Hz), 121.3,

107.1, 105.3, 100.8, 86.2, 80.4 (q, J = 2.0 Hz), 55.2, 50.5 (d, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ 75.7; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 11.8 min, t2 = 16.2 min (maj). (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-4-p-tolylbut-3-yn-2-yl)aniline (2g): 55 mg, 88% yield, pale yellow solid, Rf = 0.30 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -232.59 (c 0.46, CHCl3) [lit.14: [α]20D = 288.76 (c 0.90, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.84-6.76 (m, 4H), 4.73 (q, J = 6.2 Hz, 1H), 3.75 (s, 4H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.1, 139.4, 139.0, 131.9, 129.1, 123.8 (q, J = 280 Hz), 118.4, 116.9, 114.9, 86.5, 80.2 (t, J = 2.0 Hz), 55.7, 52.1 (d, J = 34.0 Hz), 21.5; 19F NMR (376 MHz, CDCl3) δ -75.7; HPLC (AS-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 8.5 min, t2 = 9.5 min (maj). (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-yn-2-yl)aniline (2h): 58 mg, 87% yield, pale yellow oil, Rf = 0.24 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -196.19 (c 0.58, CHCl3) [lit.14: [α]20D = -239.65 (c 1.20, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.7 Hz, 2H), 6.836.75 (m, 6H), 4.73 (q, J = 6.1 Hz, 1H), 3.79 (s, 4H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 154.1, 139.0, 133.5, 123.9 (q, J = 280.0 Hz), 116.8, 114.9, 114.0, 113.5, 86.3, 79.5 (q, J = 2.0 Hz), 55.7, 55.3, 52.2 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.7; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 19.5 min, t2 = 20.5 min (maj). (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-4-(4-fluorophenyl)but-3-yn-2-yl)aniline (2i): 63 mg, 98% yield, pale yellow oil, Rf = 0.37 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -219.03 (c 0.63, CHCl3) [lit.14: [α]20D = -204.91 (c 1.26, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.00 (t, J = 8.8 Hz, 2H), 6.85-6.76 (m, 4H), 4.74 (q, J = 6.2 Hz, 1H), 3.76 (s, 3H), 3.74 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 163.0 (d, J = 249.0 Hz), 154.2, 138.8, 134.0 (d, J = 9.0 Hz), 123.7 (q, J = 280.0 Hz), 117.5 (d, J = 4.0 Hz), 116.9, 115.7 (d, J = 22.0 Hz), 114.9, 85.2, 80.6 (t, J = 2.0 Hz), 55.6, 52.2 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.7, -109.4; HPLC (AS-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 11.4 min, t2 = 17.2 min (maj). (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-4-(2-fluorophenyl)but-3-yn-2-yl)aniline (2j): 64 mg, 99% yield, pale yellow oil, Rf = 0.34 (hexanes/dichloromethane = 1/1), 97% ee, [α]20D = -241.23 (c 0.64, CHCl3) [lit.14: [α]20D = -230.49 (c 1.18, CHCl3) for 94% ee]; 1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 1H), 7.34-7.32 (m, 1H),



7.12-7.05 (m, 2H), 6.87-6.79 (m, 4H), 4.80 (q, J = 5.4 Hz, 1H), 3.80 (d, J = 9.6, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4 (d, J = 251.0 Hz), 154.6, 139.0, 134.1 (d, J = 1.0 Hz), 131.3 (d, J = 8.0 Hz), 124.0 (q, J = 280.0 Hz), 124.3 (d, J = 4.0 Hz), 117.4, 115.9 (d, J = 21.0 Hz), 115.2, 110.4 (d, J = 16.0 Hz), 86.3 (q, J = 3.0 Hz), 80.2, 55.9, 52.6 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.6, -109.4; HPLC (AS-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 10.8 min, t2 = 13.8 min (maj). (R)-(-)-N-(4-Cyclohexenyl-1,1,1-trifluorobut-3-yn-2-yl)-4-methoxyaniline (2k): 52 mg, 84% yield, pale yellow oil, Rf = 0.46 (hexanes/dichloromethane = 1/1), 97% ee, [α]20D = -191.34 (c 0.52, CHCl3) [lit.14: [α]20D = -200.40 (c 1.22, CHCl3) for 94% ee]; 1H NMR (400 MHz, CDCl3) δ 6.82-6.71 (m, 2H), 6.74-6.71 (m, 2H), 6.16-6.14 (m, 1H), 4.65-4.61 (q, J = 6.2 Hz, 1H), 3.76 (s, 3H), 3.65 (d, J = 9.3 Hz, 1H), 2.09-2.06 (m, 4H), 1.62-1.55 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 154.0, 139.1, 137.1, 123.8 (q, J = 280.0 Hz), 119.6, 116.7, 114.8, 88.1, 78.1 (q, J = 2.0 Hz), 55.7, 52.0 (d, J = 34.0 Hz), 28.7, 25.6, 22.1, 21.3; 19F NMR (376 MHz, CDCl3) δ -75.9; HPLC (OD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 o

C, t1 = 6.9 min (maj), t2 = 7.7 min. (R)-(-)-4-Methoxy-N-(1,1,1-trifluorooct-3-yn-2-yl)aniline (2l): 55 mg, 96% yield, pale yellow oil, Rf =

0.36 (hexanes/dichloromethane = 1/1), 97% ee, [α]20D = -112.90 (c 0.55, CHCl3) [lit.14: [α]20D = -131.87 (c 1.12, CHCl3) for 95% ee]; 1H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 8.9 Hz, 2H), 4.43-4.41 (m, 1H), 3.67 (s, 3H), 2.13-2.09 (m, 2H), 1.41-1.27 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 154.0, 139.1, 123.9 (q, J = 280.0 Hz), 116.7, 114.8, 87.4, 72.1 (d, J = 2.0 Hz), 55.6, 51.6 (q, J = 33.0 Hz), 30.3, 21.8, 18.3, 13.5;

19

F NMR (376 MHz, CDCl3) δ -76.2; HPLC (AD-H, elute:

Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 6.7 min (maj), t2 = 8.5 min. (R)-(-)-4-Methoxy-N-(1,1,1-trifluoro-6-phenylhexa-3,5-diyn-2-yl)aniline (2m): 60 mg, 91% yield, pale yellow oil, Rf = 0.44 (hexanes/dichloromethane = 1/1), 98% ee, [α]20D = -329.98 (c 0.56, CHCl3) [lit.14: [α]20D = -334.82 (c 1.24, CHCl3) for 94% ee]; 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.35-7.31 (m, 3H), 6.86-6.84 (m, 2H), 6.78-6.76 (m, 2H), 4.67 (d, J = 5.8 Hz, 1H), 3.78 (s, 3H), 3.75(brs, 1H); 13C NMR (100 MHz, CDCl3) δ 154.5, 138.3, 132.7, 129.8, 128.5, 123.3 (q, J = 280.0 Hz), 120.8, 117.1, 114.9, 79.1, 74.0 (d, J = 1.8 Hz), 72.7, 71.0, 55.6, 52.4 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -75.2; HPLC (AD-H, elute: Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 14.1 min (maj), t2 = 17.0 min. (R)-N-(1,1-Difluoro-4-phenylbut-3-yn-2-yl)-4-methoxyaniline (2n) 20a: 47 mg, 82% yield, pale yellow oil, Rf = 0.20 (hexanes/dichloromethane = 1/1), 92% ee, [α]20D = -203.60 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42-7.40 (m, 2H), 7.30-7.27 (m, 3H), 6.84-6.77 (m, 4H), 6.10-5.81 (td, J = 2.9 Hz, 1H), 4.60-4.53


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(m, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 139.2, 132.0, 128.8, 128.3, 121.9, 116.9, 114.9, 114.0 (t, J = 246.0 Hz ), 86.1, 82.4 (t, J = 5.0 Hz), 55.7, 51.3 (t, J = 24.0 Hz); 19F NMR (376 MHz, CDCl3) δ -124.2 (d, J = 278.5 Hz, 1F); -126.6 (d, J = 278.5 Hz, 1F); HPLC (AD-H, elute: Hexanes/i-PrOH = 97/3, detector: 254 nm, flow rate: 0.7 mL/min), 30 oC, t1 = 23.6 min, t2 = 24.8 min (maj). (R)-(-)-4-Methoxyphenyl-(1-pentafluoroethyl-3-phenyl-prop-2-ynyl)-amine (2o): 24 mg, 34% yield, pale yellow oil, Rf = 0.30 (petroleum ether/ethyl acetate = 30/1), 93% ee, [α]20D = -217.90 (c 0.24, CHCl3) [lit.14: [α]20D = -227.45 (c 1.42, CHCl3) for 98% ee]; 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 2H), 7.37-7.32 (m, 3H), 6.88-6.80 (m, 4H), 4.86 (t, J = 11.3, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 138.2, 131.4, 128.6, 127.8, 121.0, 116.8, 115.7 (q, J = 286.0 Hz ), 114.4, 111.9, 86.8, 79.8, 55.1, 50.5 (t, J = 25.0 Hz);

19

F NMR (376 MHz, CDCl3) δ -80.7 (s, 3F); -120.1 (d, 1F), -123.2 (d, 1F); HPLC (OD-H, elute:

Hexanes/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 7.3 min (maj), t2 = 9.9 min. Typical Procedure for synthesis of 2-(trifluoromethyl)-1,2-dihydroquinoline: To a mixture of (R)-2a (228.0 mg, 0.75 mmol), HOAc (0.5 mL), HCHO (37-40%) (730 mg, 11.2 mmol), NaBH3CN (212.0 mg, 3.375 mmol) and CH3CN (5.0 mL) in 25 mL round-bottomed flask, the mixture was stirred at room time over night. The mixture was diluted with 30 mL of EtOAc, washed with 25 mL of saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to get the crude product. The crude product was chromatographed on a silica gel column using 30:1 hexanes /EtOAc as eluent to afford the analytically pure product 5a in 168 mg. 20b (R)-4-Methoxy-N-methyl-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline (5a): 168 mg, 70% yield, pale yellow oil, Rf = 0.76 (hexanes/ethyl acetate = 30/1), 97% ee, [α]20D = -240.17 (c 1.08, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.48 (m, 2H), 7.36-7.34 (m, 3H), 7.00-6.90 (m, 2H), 6.89-6.87 (m, 2H), 5.99 (q, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.3, 144.2, 132.0, 129.1, 128.4, 124.2 (q, J = 282.0 Hz), 121.7, 118.5, 114.6, 88.8, 78.3 (d, J = 2.0 Hz), 58.6 (q, J = 33.0 Hz), 55.6, 33.7; 19F NMR (376 MHz, CDCl3) δ -73.1; HPLC (OJ-H, elute: Hexanes/i-PrOH = 97/3, detector: 254 nm, flow rate: 0.7 mL/min), 30 oC, t1 = 15.7 min, t2 = 16.8 min (maj); IR (KBr) ν 2955, 2233m 1511, 1249, 1135, 1037, 757, 691; HRMS (ESI, positive) m/z Calculated for C18H17F3NO [M+H]+ 320.1257, found 320.1257. To a mixture of (R)-5a (168.0 mg, 0.526 mmol), NaHCO3 (88.5 mg, 1.052 mmol), I2 (267.0 mg, 1.052 mmol) and CH3CN (6 mL) in 25 mL round-bottomed flask, the mixture was stirred at 80 oC over night. The mixture was diluted with 30 mL of EtOAc, and washed with saturated aqueous solution of Na2S2O3 (30 mL). The organic layer was separated and the aqueous layer was extracted with fresh EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using 30:1 hexanes



/EtOAc as eluentunless otherwise stated to get pure 6a in 211 mg. 18 (+)-3-Iodo-6-methoxy-1-methyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydroquinoline (6a): 212 mg, 90% yield, pale yellow oil, Rf = 0.80 (hexanes/ethyl acetate = 30/1), [α]20D = +84.94 (c 1.98, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 1H), 7.42-7.40 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.04-7.02 (m, 1H), 6.82-6.80 (m, 1H), 6.64-6.61 (m, 1H), 6.23 (t, J = 2.9 Hz, 1H), 4.83 (q, J = 2.7 Hz, 1H), 3.58 (s, 3H), 3.14 (s, 3H);13C NMR (100 MHz, CDCl3) δ 151.8, 148.4, 141.7, 137.2, 128.6, 128.5, 128.2, 126.4 (q, J = 292.0 Hz), 124.1, 115.1 114.2, 112.5, 78.6, 71.6 (q, J = 28.0 Hz), 55.6, 39.5; 19F NMR (376 MHz, CDCl3) δ -71.7; IR (KBr) ν 2952, 1617, 1499, 1225, 1142, 1033, 760, 610; HRMS (ESI, positive) m/z Calculated for C18H16F3INO [M+H]+ 446.0223, found 446.0224. In a dry, nitrogen flushed Schlenk tube, 6a (44.5 mg, 0.1 mmol), (4-methoxyphenyl)boronic acid (24.3 mg, 0.16 mmol), PdCl2(PPh3)2 (3.5 mg, 0.005 mmol) and K2CO3 (27.6 mg, 0.2 mmol) in 3.0 mL of DMF/H2 O (v/v = 4:1), the reaction mixture was stirred under 100 oC for 20 h. The mixture was cooled to room temperature and diluted with 25 mL of EtOAc, washed with 25 mL of H2 O and 25 mL of saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to get the crude product. The crude product was chromatographed on a silica gel column using 30:1 hexanes /EtOAc as eluent to afford the analytically pure product 7a in 40 mg. 18 (+)-6-methoxy-3-(4-methoxyphenyl)-1-methyl-4-phenyl-2-(trifluoromethyl)-1,2-dihydroquinoline (7a): 40 mg, 94% yield, pale yellow oil, Rf = 0.40 (hexanes/ethyl acetate = 30/1), 97% ee, [α]20D = +71.74 (c 0.40, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23-7.03 (m, 7H), 6.81-6.78 (m, 1H), 6.66-6.63 (m, 3H), 6.49 (d, J = 2.9 Hz, 1H), 4.67 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 3.61 (s, 3H), 3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 151.8, 138.3, 137.6, 137.4, 132.0, 130.7, 128.1, 127.0, 126.3 (q, J = 295.0 Hz), 125.1, 125.0, 114.0, 113.9, 113.3, 111.7, 66.2 (q, J = 27.0 Hz), 55.6, 55.1, 39.4;

19

F NMR (376 MHz, CDCl3) δ -71.6; HPLC

(AD-H, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 5.0 min (maj), t2 = 10.2 min; IR (KBr) ν 2936, 1606, 1511, 1290, 1119, 1054, 840, 707; HRMS (ESI, positive) m/z Calculated for C25H23F3NO2 [M+H]+ 426.1675, found 426.1674. Typical Procedure for Deprotection of Fluorinated Propargylamines (R)-2a: To a solution of cerium ammonium nitrate (CAN, 5.0 eq) in acetonitrile/water (10 mL, 1:1) at 0 oC was added a solution of (R)-2a (91.0 mg, 0.30 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 0 oC for 1 h and quenched with saturated aqueous sodium hydrogen sulfite (2 mL). The reaction mixture was exacted with ethyl acetate. The resulting solution was washed brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified on silica gel to give the corresponding amine (R)-(+)-8a.14 (R)-(+)-1,1,1-Trifluoro-4-phenylbut-3-yn-2-amine (8a): 20 mg, 34% yield, pale yellow oil, Rf = 0.25


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(petroleum ether/ethyl acetate = 5/1), 97% ee, [α]20D = +18.50 (c 0.20, CHCl3) [lit.14: [α]20D = +28.63 (c 0.66, CHCl3) for 94% ee]; 1H NMR (400 MHz, CDCl3) δ 7.47-7.32 (m, 5H), 4.29 (q, J = 6.1 Hz, 1H), 1.82 (brs, 2H);13C NMR (100 MHz, CDCl3) δ 131.4, 128.5, 127.8, 123.6 (q, J = 279.0 Hz), 121.1, 84.8, 83.0, 47.3 (q, J = 34.0 Hz); 19F NMR (376 MHz, CDCl3) δ -78.2; HPLC (OD-H, elute: Hexanes/i-PrOH = 80/20, detector: 230 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 8.4 min, t2 = 15.5 min (maj).

ASSOCIATED CONTENT Supporting information NMR spectra of products, and HPLC for racemic and chiral products of all compounds. This material is available free of charge via the internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding author *E-mail: [email protected], [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We Financial support from the National Natural Science Foundation of China (Nos: 21502188, 21362014) and the Open Project Program of Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University (No. KLFS-KF-201705) is acknowledged.

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prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org. Lett. 2000, 2, 3119. (b) Molteni, M.; Volonterio, A.; Fossati, G.; Lazzari, P.; Zanda, M. Conjugated additions of amines and β-amino alcohols to trifluorocrotonic acid derivatives: synthesis of ψ[NHCH(CF3)]-retro-thiorphan. Tetrahedron Lett. 2007, 48, 589. (c) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Léger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741. (3) For reviews, see: (a) Dilman, A. D.; Levin, V. V. Nucleophilic trifluoromethylation of C=N bonds. Eur. J. Org. Chem. 2011, 831. (b) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 2013, 52, 8214. (c) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond. Chem. Rev. 2015, 115, 683. (d) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 2015, 115, 826. (e) Liu, J.; Hu, J. Synthesis of fluorinated chiral amines using Ntert-butylsulfinyl imines. Future Med. Chem. 2009, 1, 875. For selective examples, see: (f) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Stereoselective nucleophilic trifluoromethylation of N-(tertbutylsulfinyl)imines by using trimethyl(trifluoromethyl)silane. Angew. Chem. Int. Ed. 2001, 40, 589. (g) Liu, Z.-J; Liu, J.-T. Asymmetric synthesis of either diastereomer of trifluoromethylated allylic amines by the selective reduction of trifluoromethyl α,β-unsaturated N-tert-butanesulfinyl ketoimines. Chem. Commun. 2008, 5233. (h) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N. Catalytic enantioselective trifluoromethylation of azomethine imines with trimethyl(trifluoromethyl)silane. Angew. Chem. Int. Ed. 2009, 48, 6324. (i) Bernardi, L.; Indrigo, E.; Pollicino, S.; Ricci, A. Organocatalytic trifluoromethylation of imines using phase-transfer catalysis with phenoxides. A general platform for catalytic additions of organosilanes to imines. Chem. Commun. 2012, 48, 1428. (4) (a) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates. Chem. Rev. 2011, 111, 455. (b) Cahard, D.; Bizet, V. The influence of fluorine in asymmetric catalysis. Chem. Soc. Rev. 2014, 43, 135. (5) For selected examples see:. (a) Jiang, B.; Si, Y.-G. Highly enantioselective construction of a chiral tertiary carbon center by alkynylation of a cyclic N-acyl ketimine: an efficient preparation of HIV therapeutics. Angew. Chem. Int. Ed. 2004, 43, 216. (b) Huang, G.; Yin, Z.; Zhang, X. Construction of optically active quaternary propargyl amines by highly enantioselective Zinc/BINOL-catalyzed


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Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines

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