Enantioselective synthesis of α-perfluoroalkylated ... · MeOH 6 100 85 >99 CF3CH(OH)CF3 6 98 71...

Enantioselective synthesis of α-perfluoroalkylated prolines, their 6,7-

membered homologues and derivatives

Natalia G. Voznesenskaia,[a] Olga I. Shmatova,[a] Victor N. Khrustalev,[b] and Valentine G. Nenajdenko*[a]

[a] Prof. Dr. V.G. Nenajdenko, N.G. Voznesenskaia, Dr. O.I. Smatova, Department of Chemistry, Lomonosov Moscow State University,

Leninskiye Gory, 1-3, Moscow, 119991, Russia

[b] Prof. Dr. V.N. Khrustalev, Peoples’ Friendship University of Russia, Miklukho-Maklay Street, 6, 117198 Moscow, Russia

Contents

General method 2

Reaction optimization 2

Synthesis 6

NMR spectra 26

References 114

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2018

General method

1D NMR (1H, 19F, and 13C) spectra were obtained with Bruker AV-400, and Agilent 400-MR spectrometers. Chemical shifts for 1H NMR

spectroscopic data were referenced to internal tetramethylsilane (δ = 0.0 ppm); chemical shifts for 13C NMR spectroscopic data were

referenced to CDCl3 (δ = 77.0 ppm); chemical shifts for 19F NMR spectroscopic data were referenced to PhCF3 (δ = –63.90 ppm).

Enantiomeric excess (ee) were determined by HPLC («Stayer» by Akvilon). TLC was carried out on precoated silica plates (Silufol UV-

254), which were visualized with UV light and/or staining with ninhydrine solution or aqueous Ce(SO4)2 solution with phosphomolybdic

and sulfuric acids. Flash chromatography was carried out using MP Silica 60 (320–630 mesh) with the solvents indicated. Starting cyclic

imines were synthesized according to the following procedure1. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R)-(-)-2-

9dimethylamino)cyclohexyl)thiourea (Takemoto catalyst) was purchased from abcr.

Reaction optimization

The model reactions in several protic (i-PrOH, MeOH), polar aprotic (CH2Cl2, C2H4Cl2, Et2O, DMF, DMSO, CH3CN, THF) and nonpolar

(benzene, xylene, toluene, hexane) solvents were investigated. It was found out that the reaction in protic solvents resulted in racemic 3a and

proceeded more rapidly (4 days for i-PrOH and 1 day for MeOH). Low conversion (10-12% accordingly 19F NMR monitoring) after two

months was observed in DMF, DMSO, THF and Et2O. Others solvents (CH2Cl2, C2H4Cl2, CH3CN, benzene, xylene, toluene, hexane)

demonstrated up to 99% ee, however the reaction in C2H4Cl2 proceeded in reasonable time (4 days) to give after hydrolysis of 2a amide 3a

in the highest yield (88%).

Table 1. Solvent optimization

NCF3

TMSCN 1,5eq/MeOHTakemoto cat 5mol%,

solvent NH

CF3

CN

NH

CF3

NH2

OLiOH, H2OH2O2 50%

Solvent 1st step time 1st step yield 2st step [α]D20 ee, %

reaction,

days

(19F NMR

spectra), %

yield, %

i-PrOH 5 98 81 0 0

MeOH 1 100 82 0 0

Benzene 18 97 68 -81.0 >99

Xylene 12 95 86 -81.4 >99

Toluene 6 95 74 -69.0 95

Hexene 10 95 87 -81.2 >99

C2H4Cl2 4 98 88 -82.2 >99

CH2Cl2 7 94 82 -50.6 -

CHCl3 6 97 68 -81.2 >99

CH3CN 48 92 69 -50.8 -

Et2O 8 4 - - -

THF 4 4 - - -

DMF 5 7 - - -

DMSO 30 80 - - -

Also to finding an optimal reaction condition different addictive (CF3CH(OH)CF3, CF3CH2OH, i-PrOH) for producing HCN were

investigated. However use of addictive other than methanol lead to decrease of reaction enantioselectivity.

Table 2. Additives optimization

NCF3

TMSCN 1,5eq/xTakemoto cat 5 mol%,

C2H4Cl2rt

NH

CF3

CN

NH

CF3

NH2

OLiOH, H2OH2O250%

x 1st step time

reaction, days

1st step yield (19F

NMR spectra),

2st step

yield, %

ee, %

- 14 16 - -

MeOH 6 100 85 >99

CF3CH(OH)CF3 6 98 71 84

CF3CH2OH 6 96 68 86

i-PrOH 9 95 57 82

After finding the optimal conditions for obtaining pure enantiomer 2-trifluoromethyl-pyrrolidyne carboxyamide (3a) (99% ee) those were

applied for others imines b-e. The reaction was very sensitive to the ring size and substituent at α-position of starting imine.

Pentafluoroethyl-substituted imines (1b, 1d) reacted very slowly (about two months) with low enantioselectivity (42 % ee for 1b and 11% ee

for 1d). The most difficult situation was observed in the case of 6-membered imine 1d bearing pentafluoroethyl group. We believe that these

results can be explained by much higher steric bulkiness of C2F5 group over CF3 moiety as well as significant difference in geometry of

starting imines. In cases of hydrocyanation of trifluoromethylated imines 1c and 1e reasonably high enantioselectivity was achieved - 79 and

80% ee correspondingly.

Table 3. Influence of substituent and ring size on reaction enantioselectivity

NRF

TMSCN 1,5eq/MeOHTakemoto cat 5 mol%,

C2H4Cl2rt

NH

RF

CN

NH

RF

NH2

OLiOH, H2OH2O250%

n n n

n R 1st step

time

reaction,

days

1st step

yield (19F

NMR

spectra)

2st step

yield, %

ee, %

1 CF3 4 100 88 >99

1 C2F5 10 74 64 42

2 CF3 12 92 67 79

2 C2F5 24 92 78 11

3 CF3 18 100 87 80

To improve enantioselectivity of the reaction with imines 1c and 1e hydrocyanation under decreased temperature was studied. . Imines with

pentafluoroethyl substituents (1b, 1d) were not used for temperature optimization due to long reaction time. The enantiomeric excess for

amide 3c obtained from imine 1c reached 90% ee at -20°C. In the case of amide 3e the improvement of enantioselectivity was lower than

expected (from 80% ee to 83% ee at 0°C and 81% ee at -20°C).

Table 4. Temperature optimization for imines 1c and 1e

NRF

TMSCN 1,5eq/MeOHTakemoto cat 5 mol%,

C2H4Cl2tC

NH

RF

CN

NH

RF

NH2

OLiOH, H2OH2O250%

n n n

n RF

t°C 1st step time

reaction, days

1st step yield (19F

NMR spectra)

2st step

yield, %ee, %

0 13 70 65 812 CF3

-20 9 96 93 90

0 4 100 90 803 CF3

-20 4 95 85 83

Increasing the amount of Takemoto catalyst (15 mol %) resolved this problem and enantioselectivity of Strecker reaction was improved

significantly to provide 95-96% ee for both imines 1c and 1e. Using 20% of catalyst the reaction with 1b also gave appropriate 90% ee for

amide 3b in 85% isolated yield (Table 5).

Table 5. Optimal condition for enantioselective Strecker reaction with cyclic imines 1a-e

NRF

TMSCN 1,5eq/MeOHTakemoto cat x mol%,

C2H4Cl2tC

NH

RF

CN

NH

RF

NH2

OLiOH, H2OH2O250%

n n n

Imine n RfCat,

mol% T, °C

1st step reac-tion

time, days

Yield of 3, (%) ee, %

1a 1 CF3 5 rt 4 82 991b 1 C2F5 20 rt 90 85 901c 2 CF3 15 -20 6 97 961d 2 C2F5 5 rt 90 89 111e 3 CF3 15 0 6 98 95

Synthesis

Procedure for synthesis of cyclic nitriles 2a-e

A. For racemic products

In a screw-capped vial cyclic imine (1mmol) and TMSCN (1.5 mmol, 0.215mL) was added. Reaction mixture was dissolved by MeOH

(about 5mL) as solvent and stay for a night. After reaction complete, the solvent was carefully removed under vacuum (volatile product) and

crude products were let into the next transformation without purification.

B. For asymmetric products

In a screw-capped vial cyclic imine (1mmol) was dissolved in dichloroethane (2mL). To the solution cat Takemoto (0.05mmol for 1a, 0.15

mmol for 1c,e, 0.2mmol for 1b), TMSCN (1.5 mmol, 0.215mL), MeOH (1.5 mmol, 0.05mL) were added. Reaction was monitoring by 19F

spectra. After reaction complete, the solvent was carefully removed under vacuum (volatile product) and the residue was purified by silica

gel chromatography (CH2Cl2).

(R)-2-(trifluoromethyl)pyrrolidine-2-carbonitrile (2a), According to NMR 19F - 100 %, after evaporation – 97%, colorless NH

CF3

CN

volatile liquid, 1H NMR (400 MHz, CDCl3): 1.87-2.04 (2H, m), 2.24-2.36 (2H, m), 2.53 (1H, bs, NH), 3.13-3.16 (2H, m). 13C NMR (100

MHz, CDCl3): 24.0, 33.0 (CH2-Cq), 46.3 (CH2-N), 62.1 (q, JCF = 33.1 Hz, C-CF3), 117.7 (CN), 123.3 (q, JCF = 281.2 Hz, CF3). 19F NMR

(280 MHz, CDCl3): -79.1 (3F, s, CF3). IR(KBr): 3465 (bs), 3273 (bs), 1309, 1189, 1057, 953 cm-1. HRMS (ESI): calcd. for C6H8F3N2

[M+H]+ 165.0640, found 165.0636.

Optical rotation [α]20D = +12.0 (c = 0.5, MeOH).

2-(Pentafluoroethyl)pyrrolidine-2-carbonitrile (2b), According to NMR 19F - 100 %, after evaporation – 99%, , colorless NH

C2F5

CN

volatile liquid, 1H NMR (400 MHz, CDCl3): 1.98-2.10 (2H, m), 2.26 (1H, bs, NH), 2.36-2.45 (2H, m, CH2), 3.24-3.27 (2H, m). 13C NMR

(100 MHz, CDCl3): 23.9, 33.4 (CH2-Cq), 46.3 (CH2-N), 61.7 (t, JCF = 26.5 Hz, C-CF2), 112.2 (tq, JCF = 260.6 Hz, JCF = 36.1 Hz, CF2),

117.7 (CN), 118.9 (qt, JCF = 287.9 Hz, JCF = 35.8 Hz, CF3). 19F NMR (280 MHz, CDCl3): -79.1 (3F, s, CF3), -119.8 (1F, d, JFF = 271.3 Hz,

CF2), -123.8 (1F, d, JFF = 271.3 Hz, CF2). IR(KBr): 3361 (bs), 2237, 1346, 1209, 1169, 1111, 1049, 742 cm-1. HRMS (ESI): calcd. for

C7H8F5N2 [M+H]+ 215.0608, found 215.0606.


2-(trifluoromethyl)piperidine-2-carbonitrile (2c), According to NMR 19F - 100 %, after evaporation –73 %, colorless volatile NH CF3

CN

liquid, 1H NMR (400 MHz, CDCl3): 1.47-1.54 (1H, m), 1.64-1.82 (3H, m), 1.89-1.91 (1H, m), 2.00-2.03 (1H, m), 2.15 (1H, bs, NH), 2.92-

2.97 (1H, m, N-CH2), 3.12-3.14 (1H, m, N-CH2). 13C NMR (100 MHz, CDCl3): 20.1, 23.8, 28.3 (CH2-Cq), 42.6 (CH2-N), 60.7 (q, JCF =

30.2 Hz, C-CF3), 115.3 (CN), 122.8 (q, JCF = 282.0 Hz, CF3). 19F NMR (280 MHz, CDCl3): -80.2 (3F, s, CF3). IR(KBr): 3334 (bs), 1311,

1203, 1194, 1176, 1128 cm-1. HRMS (ESI): calcd. for C7H9F3N2 [M+H]+ 179.0796, found 179.0801.

Optical rotation [α]20D = +40.8 (c = 0.5, CH2Cl2).

2-(Perfluoroethyl)piperidine-2-carbonitrile (2d), According to NMR 19F - 100 %, after evaporation – 63 %, colorless volatile NH

C2F5

CN


2.99 (1H, m, N-CH2), 3.11-3.14 (1H, m, N-CH2). 13C NMR (100 MHz, CDCl3): 20.3, 23.8, 28.2 (CH2-Cq), 42.7 (CH2-N), 61.1 (t, JCF =

23.4 Hz, C-CF2), 112.2 (tq, JCF = 262.1 Hz, JCF = 36.5 Hz, CF2), 114.8 (CN), 118.7 (qt, JCF = 287.9 Hz, JCF = 35.4 Hz, CF3). 19F NMR (280

MHz, CDCl3): -78.2 (3F, s, CF3), -121.9 (1F, d, JFF = 278.3 Hz, CF2), -122.8 (1F, d, JFF = 278.3 Hz, CF2). IR(KBr): 3461 (bs), 3257 (bs),

1338, 1310, 1216, 1058 cm-1. HRMS (ESI): calcd. for C8H10F5N2 [M+H]+ 229.0764, found 229.0762.

2-(trifluoromethyl)azepane-2-carbonitrile (2e), According to NMR 19F - 100 %, after evaporation –95 %, colorless volatile NH CF3

CN


3.03 (2H, m, N-CH2). 13C NMR (100 MHz, CDCl3): 22.4, 28.5, 30.6, 32.3 (CH2-Cq), 43.5 (CH2-N), 62.5 (q, JCF = 28.8 Hz, C-CF3), 117.3

(CN), 123.4 (q, JCF = 284.9 Hz, CF3). 19F NMR (280 MHz, CDCl3): -79.2 (3F, s, CF3). IR(KBr): 3356 (bs), 1269, 1194, 1180, 1119 cm-1.

HRMS (ESI): calcd. for C7H11F3N [M – CN]+ 166.0844, found 166.0846.


Procedure for synthesis of amides 3a-e

To a solution of aminonitile 2 (1mmol) in MeOH (3mL) LiOH*H2O (0.21 g, 3.5 mmol), H2O (1 mL), H2O2 30% (0.5 mL) were added and

mixture was stirred at rt for 1.5-2 hours. After that, water was added and solution was extracted with EtOAc. Organic lay was dried on

Na2SO4 and concentrated under reduced pressure to obtain crude amide, which was purified by silica gel chromatography (EtOac/Hex =

2/1).

(R)-2-(trifluoromethyl)pyrrolidine-2-carboxamide (3a), 88 %, 99 % ee, white solid, mp 108-110ºC 1H NMR (400 MHz, NH

CF3

CONH2

CDCl3): 1.71-1.87 (2H, m), 2.18-2.22 (2H, m), 3.04-3.07 (2H, m), 6.83 (1H, bs, NH2CO), 7.31 (1H, bs, NH2CO). 13C NMR (100 MHz,

CDCl3): 25.3, 32.2 (CH2-Cq), 47.5 (CH2-N), 70.7 (q, JCF = 26.2 Hz, C-CF3), 125.9 (q, JCF = 283.4 Hz, CF3), 173.0 (CONH2). 19F NMR

(280 MHz, DMSO): -74.1 (3F, s, CF3). IR(KBr): 1703, 1171 cm-1. HRMS (ESI): calcd. for C6H9F3N2O [M+H]+ 183.0740, found

183.0747.

Optical rotation [α]20D = -88.2 (c = 0.5, MeOH).

HPLC condition: Chiral column Chiracel OJ (250×4.6 mm), heptane/i-PrOH = 9/1, flow rate = 1 mL/min, wavelength = 206 nm. tr minor =

8.983 min (0.455), tr major = 10.122 min (99.545)

2-(pentafluoroethyl)prolinamide (3b), 85 %, 90 % ee, white solid, mp 41-43ºC 1H NMR (400 MHz, CDCl3): 1.68-1.91 (2H, NH

C2F5

CONH2

m), 2.23-2.38 (2H, m, CH2-Cq), 2.62 (1H, bs, NH), 3.03-3.05 (2H, m, CH2-N), 6.77 (1H, bs, NH2CO), 7.14 (1H, bs, NH2CO). 13C NMR

(100 MHz, CDCl3): 25.1, 32.6 (CH2-Cq), 47.8 (CH2-N), 70.7 (t, JCF = 21.6 Hz, C-CF2), 114.7 (tq, JCF = 262.4 Hz, JCF = 35.8 Hz, CF2),

119.0 (qt, JCF = 287.9 Hz, JCF = 36.5 Hz, CF3), 172.7 (d, JCF = 4.8 Hz, CONH2). 19F NMR (280 MHz, CDCl3): -79.4 (3F, s, CF3), -115.6 (1F, d, JFF = 276.8 Hz, CF2), -120.8 (1F, d, JFF = 276.8 Hz, CF2). IR(KBr): 1691,

1213 cm-1. HRMS (ESI): calcd. for C7H9F5N2O [M+H]+ 233.0708, found 233.0714.

Optical rotation [α]20D = -33.2 (c = 1, MeOH).

HPLC condition: Chiral column CHIRALPAK AS-H (250×4.6 mm), heptane/i-PrOH = 9/1, flow rate = 1 mL/min, wavelength = 206 nm. tr

minor = 8.338 min (4.858), tr major = 10.085 min (95.142)

2-(trifluoromethyl)piperidine-2-carboxamide (3c), 97 %, 96% ee, white solid, mp 128-130ºC 1H NMR (400 MHz, CDCl3): NH

CF3

CONH2

1.24-1.60 (4H, m), 1.74-1.82 (2H, m), 2.40-2.44 (1H, m), 2.68-2.75 (1H, m, CH2-Cq), 3.02-3.05 (1H, m, CH2-Cq), 6.05 (1H, bs, CONH2),

7.18 (1H, bs, CONH2). 13C NMR (100 MHz, CDCl3): 20.3, 25.3, 26.3 (CH2-Cq), 42.4 (CH2-N), 64.7 (q, JCF = 24.7 Hz, C-CF3), 124.7 (q,

JCF = 284.2 Hz, CF3), 169.6 (CONH2). 19F NMR (280 MHz, CDCl3): -76.8 (3F, s, CF3). IR(KBr): 3396 (NH), 3307 (NH), 3217 (NH),

1697 (CO), 1674 (CO), 1184 cm-1. HRMS (ESI): calcd. for C7H11F3N2O [M+H]+ 197.0896, found 197.0892.


HPLC condition: Chiral column CHIRALPAK AS-H (250×4.6 mm), heptane/i-PrOH = 9/1, flow rate = 1 mL/min, wavelength = 206 nm. tr

minor = 10.937 min (2.241), tr major = 12.628 min (97.759)

2-(Perfluoroethyl)piperidine-2-carboxamide (3d), 89 %, 11 % ee, white solid, mp 72-74ºC 1H NMR (400 MHz, CDCl3): NH

C2F5

CONH2

1.22-1.64 (4H, m), 1.78-1.81 (1H, m, CH2-Cq), 2.39-2.43 (1H, m, CH2-Cq), 2.68-2.76 (1H, m, CH2-NH), 2.98-3.02 (1H, m, CH2-NH), 6.69

(1H, bs, CONH2), 7.15 (1H, bs, CONH2). 13C NMR (100 MHz, CDCl3): 20.4, 25.2, 26.2 (CH2-Cq), 42.4 (CH2-N), 65.2 (t, JCF = 20.1 Hz,

C-CF2), 114.0 (tq, JCF = 262.4 Hz, JCF = 36.5 Hz, CF2), 119.1 (qt, JCF = 287.9 Hz, JCF = 36.7 Hz, CF3), 169.6 (CONH2). 19F NMR (280

MHz, CDCl3): -78.8 (3F, s, CF3), -121.6 (1F, d, JFF = 278.8 Hz, CF2), -122.5 (1F, d, JFF = 278.8 Hz, CF2). IR(KBr): 1693, 1678, 1119,

1099, 1059 cm-1. HRMS (ESI): calcd. for C8H11F5N2O [M+H]+ 247.0864, found 247.0870.

HPLC condition: Chiral column CHIRALPAK AS-H (250×4.6 mm), heptane/i-PrOH = 9/1, flow rate = 1 mL/min, wavelength = 206 nm.

tr minor = 7.128 min (44.367), tr major = 7.852 min (55.633)

2-(Trifluoromethyl)azepane-2-carboxamide (3e), 99 %, 96 % ee, white solid, mp 72-73ºC 1H NMR (400 MHz, DMSO): 1.13-NH CONH2

CF3

1.40 (3H, m), 1.69-1.71 (3H, m), 1.79-1.85 (1H, m), 2.27-2.33 (1H, m), 2.82-2.92 (2H, m, CH2-N), 7.02 (1H, bs, NH2CO), 7.62 (1H, bs,

NH2CO). 13C NMR (100 MHz, DMSO): 22.7, 29.6, 30.3, 33.0 (CH2-Cq), 43.7 (CH2-N), 68.1 (q, JCF = 24.0 Hz, C-CF3), 126.4 (q, JCF =

288.2 Hz, CF3), 173.5 (CONH2). 19F NMR (280 MHz, DMSO): -75.1 (3F, s, CF3). IR(KBr): 3421 (NH), 3361 (NH), 3250 (bs, NH), 3192

(bs, NH), 1693 (CO), 1171 cm-1. HRMS (ESI): calcd. for C8H13F3N2O [M+H]+ 211.1053, found 211.1053.


HPLC condition: Chiral column 3-AmyCoat (150×4.6 mm), heptane/i-PrOH = 98/2, flow rate = 1 mL/min, wavelength = 206 nm. tr minor =

14.712 min (2.002), tr major = 17.863 min (97.998)

Procedure for synthesis of aminoacids 4a-e

Amide 2 (1 mmol) was dissolved in HBr (HI) (4 mL) and was heated to reflux. Reaction was monitoring by NMR 19F spectra. After

reaction complete solution concentrated under reduced pressure. Residue was recrystallized with methanol and concentrated to obtain salt of

aminoacid.

2-(trifluoromethyl)pyrrolidine-2-carboxylic acid hydrobromide (4a) 99 %, white solid, degradation over 200°C. 1H NMR (400

NH

CF3

COOH

HBr

MHz, D2O): 1.82-2.08 (2H, m), 2.27-2.39 (2H, m), 2.92-2.98 (1H, m), 3.25-3.31 (1H, m). 13C NMR (100 MHz, D2O): 25.9, 32.1, 47.4

(CH2-N), 71.9 (q, JCF = 25.0 Hz, C-CF3), 126.5 (q, JCF = 281.6 Hz, CF3), 175.3 (COOH). 19F NMR (280 MHz, D2O): -73.1 (3F, s, CF3).

IR(KBr): 3389 cm-1 (OH), 2970 cm-1(NH+), 1712 cm-1 (CO), 1200 cm-1 (CF), 1185 cm-1(CF). HRMS (ESI): calcd. for C6H9F3NO2 [M+H]+

184.0585, found 184.0576.


2-(perfluoroethyl)pyrrolidine-2-carboxylic acid hydrobromide (4b), 98 %, white solid, degradation over 200°C. 1H NMR (400 NH

C2F5

COOH

HBr

MHz, D2O): 1.7-1.99 (2H, m), 2.32-2.50 (2H, m), 3.27-3.37 (2H, m). 13C NMR (100 MHz, D2O): 22.0, 30.3, 47.4, 72.2 (t, JCF = 29.4 Hz,

C-CF3), 111.6 (tq, JCF = 262.1 Hz, JCF = 39.1 Hz, CF2), 117.5 (qt, JCF = 286.4 Hz, JCF = 35.4 Hz, CF3), 166.1 (COOH). 19F NMR (280

MHz, D2O): -80.97 (s, CF3), -117.78 (q, JCF = 285.4 Hz, CF2). IR(KBr): 2870 cm-1 (OH), 2750 cm-1 (NH+), 1760 cm-1 (CO), 1220 cm-1

(CF), 1110 cm-1 (CF). HRMS (ESI): calcd. for C7H9F5NO2 [M+H]+ 234.0548 found 234.0548.


2-(trifluoromethyl)piperidine-2-carboxylic acid hydrobromide (4c), 98 %, brown solid, 255-257°C. 1H NMR (400 MHz, NH CF3

COOH

HBr

D2O): 1.20-1.31 (1H, m), 1.43-1.53 (1H, m), 1.67-1.77 (3H, m), 2.32 (1H, d, J = 14.5 Hz), 3.09 (1H, dt, JH,H = 13.0 Hz, JH,H = 3.1 Hz),

3.28 (1H, d, J = 12.8 Hz). 13C NMR (100 MHz, D2O): 17.7, 20.1, 42.9, 66.0 (q, JCF = 28.4 Hz, C-CF3), 121.9 (q, JCF = 284.9 Hz, CF3),

164.5 (COOH). 19F NMR (280 MHz, D2O): -75.8 (s, CF3). IR(KBr): 3096 cm-1 (OH), 2830 cm-1 (NH+), 1751 cm-1 (CO), 1215 cm-1 (CF),

1146 cm-1 (CF). HRMS (ESI): calcd. for C7H11F5NO2 [M+H]+ 198.0737 found 198.0737.

Optical rotation [α]20D = +5.9 (c = 1, MeOH).

2-(trifluoromethyl)azepane-2-carboxylic acid hydrobromide (4e), 99 %, brown oil. 1H NMR (400 MHz, D2O): 1.18-1.38

NH CF3

COOHHBr

(2H, m), 1.44-1.79 (4H, m), 2.01-2.08 (1H, m), 2.26-2.32 (1H, m), 3.14-3.26 (2H, m). 13C NMR (100 MHz, D2O): 21.6, 25.6, 26.4, 27.7,

45.5, 70.2 (q, JCF = 23.9 Hz, C-CF3), 122.6 (q, JCF = 285.3 Hz, CF3), 166.2 (COOH). 19F NMR (280 MHz, D2O): -73.6 (s, CF3). IR(KBr):

3097 cm-1 (OH), 2834 cm-1 (NH+), 1747 cm-1 (CO), 1251 cm-1 (CF), 1186 cm-1 (CF). HRMS (ESI): calcd. for C8H13F3NO2 [M+H]+

212.0893 found 212.0900.


Procedure for synthesis of diamines 5a-e

To a stirred solution of cyclic nitrile 2a-c,e (2 mmol) in MeOH (5 mL) NH3 aq (3 mL), Ni-Ra were added and reaction was vacuumed and

carried out in H2 atmosphere. Mixture was stirred during two days after that, filtered over celite, rinsed by water and concentrated to half

volume. Residue extracted with Et2O, organic lay dried over Na2SO4 and concentrated under reduced pressure to obtain pure product.

(2-(Trifluoromethyl)pyrrolidin-2-yl)methanamine (5a), 90 %, yellowish oil. 1H NMR (400 MHz, CDCl3): 1.54-1.73 (5H, m), NH

CF3

NH2

1.80-1.96 (2H, m), 2.63 (1H, dd, J1 = 0.8 Hz, J2 = 13.3 Hz), 2.89-3.04 (3H, m). 13C NMR (100 MHz, CDCl3): 25.9, 30.0, 44.9 (CH2-Cq),

47.3 (CH2-N), 67.2 (q, JCF = 24.7 Hz, C-CF3), 128.3 (q, JCF = 284.5 Hz, CF3). 19F NMR (280 MHz, CDCl3): -78.2 (3F, s, CF3). IR(KBr):

3299 (bs, NH), 3414 (bs, NH),1167 (C-F), 1151 (C-F) cm-1. HRMS (ESI): calcd. for C6H11F3N2 [M+H]+ 169.0947, found 169.0954.


1-[2-(Pentafluoroethyl)pyrrolidin-2-yl]methanamine (5b), 78 %, colorless oil. 1H NMR (400 MHz, CDCl3): 1.56-1.81 (6H, NH

C2F5

NH2

m), 1.96-2.04 (1H, m), 2.57 (1H, d, J = 13.5 Hz, CH2-NH2), 2.84-2.91 (2H, m including 2.86, d, J = 13.5 Hz, CH2-NH2), 2.95-3.00 (1H, m). 13C NMR (100 MHz, CDCl3): 25.6, 30.2, 45.2, 47.1, 67.6 (t, JCF = 19.2 Hz, C-C2F5), 116.9 (tq, J1 = 257.3 Hz, J2 = 35.0 Hz, CF2), 119.5

(qt, J1 = 287.5 Hz, J2 = 37.2 Hz, CF3). 19F NMR (280 MHz, CDCl3): -119.6 (2F, CF2), -79.2 (3F, s, CF3). IR(ATR, ZnSe): 3322 (bs), 2960,

1336, 1191, 1159, 1043, 736 cm-1. HRMS (ESI): calcd. for C7H12F5N2 [M+H]+ 219.0915, found 219.0925.


(2-(Trifluoromethyl)piperidin-2-yl)methanamine (5c), 82 %, colorless oil. 1H NMR (400 MHz, CDCl3): 1.39-1.62 (9H, m), NH

CF3

NH2

2.63-2.66 (1H, m, CH2-NH), 2.70 (2H, s, CH2-NH2), 2.79-2.80 (1H, m, CH2-NH). 13C NMR (100 MHz, CDCl3): 19.5, 24.5, 25.4 (CH2-

Cq), 40.7 (CH2-N), 42.8 (CH2-N), 58.0 (q, JCF = 22.8 Hz, C-CF3), 128.1 (q, JCF = 288.6 Hz, CF3). 19F NMR (280 MHz, CDCl3): -75.8 (3F,

s, CF3). IR(KBr): 3305 (bs, NH), 1156 (C-F), 1130 (C-F) cm-1. HRMS (ESI): calcd. for C7H13F3N2 [M+H]+ 183.1104, found 187.1108.

Optical rotation [α]20D = -0.8 (c = 1, CH2Cl2).

1-[2-(Trifluoromethyl)azepan-2-yl]methanamine (5e), 79 %, colorless oil. 1H NMR (400 MHz, CDCl3): 1.23-1.47 (5H, m), NH

CF3NH2

1.59-1.76 (5H, m), 2.57-2.61 (1H, m), 2.76-2.82 (3H, m). 13C NMR (100 MHz, CDCl3): 22.6, 30.5, 30.9, 33.6, 43.1, 46.3, 61.5 (q, JCF =

22.1 Hz, C-CF3), 128.9 (q, JCF = 290.4 Hz, CF3). 19F NMR (280 MHz, CDCl3): -76.9 (3F, s, CF3). IR(neat): 3350 (bs), 1160 cm-1. HRMS

(ESI): calcd. for C8H16F3N2 [M+H]+ 197.1260, found 197.1262.

Optical rotation [α]20D = -6.4 (c = 0.5, CH2Cl2).

Procedure for synthesis of Boc-protected diamines 6a-e

To a solution of diamines 4 (1 mmol) in CH2Cl2 Boc2O (1.1 mmol) and Et3N (1.5 mmol) were added. Mixture was stirred over night. After

that, reaction was concentrated under reduced pressure and purified with silica gel chromatography (CH2Cl2/MeOH = 100/1).

tert-butyl ((2-(trifluoromethyl)pyrrolidin-2-yl)methyl)carbamate (6a), 99 %, 98% ee, white solid, mp 90-92°C. 1H NMR NH

CF3

NHBoc

(400 MHz, CDCl3): 1.43 (9H, s), 1.68-1.80 (2H, m), 1.84-1.90 (1H, m), 1.95-1.99 (1H, m), 2.10 (1H, bs, NH), 2.96-3.05 (2H, m), 3.28-

3.40 (2H, m), 4.97 (1H, bs, NH). 13C NMR (100 MHz, CDCl3): 25.7, 28.2, 29.9, 43.6, 47.2, 66.9 (q, JCF = 24.7 Hz, C-CF3), 79.8, 127.9 (q,

JCF = 284.5 Hz), 156.7. 19F NMR (280 MHz, CDCl3): -78.0 (s, CF3). IR(KBr): 3230 (bs), 2987, 1698, 1554, 1369, 1282, 1164, 946 cm-1.

HRMS (ESI): calcd. for C11H20F3N2O2 [M+H]+ 269.1472, found 219269.1473.


HPLC condition: Chiral column CHIRALCEL OD (250×4.6 mm), heptane/i-PrOH = 99.5/0.5, flow rate = 1 mL/min, wavelength = 206 nm.

tr minor = 20.008 min (0.7716), tr major = 17.075 min (99.228).

tert-butyl ((2-(perfluoroethyl)pyrrolidin-2-yl)methyl)carbamate (6b), 99 %, 97% ee, colorless liquid. 1H NMR (400 MHz, NH

C2F5

NHBoc

CDCl3): 1.42 (9H, s), 1.71-1.87 (3H, m), 2.07-2.13 (2H, m), 2.93-3.09 (2H, m), 3.26-3.40 (2H, m), 5.00 (1H, bs, NH). 13C NMR (100

MHz, CDCl3): 25.6, 28.2, 30.0, 43.8, 47.3, 67.5 (t, JCF = 19.9 Hz, C-CF2), 79.8, 116.5 (tq, J1 = 222.2 Hz, J2 = 35.0 Hz, CF2), 119.5 (qt, J1

= 287.5 Hz, J2 = 37.0 Hz, CF3). 156.8. 19F NMR (280 MHz, CDCl3): -120.5 (2F, s, CF2), -78.9 (3F, s, CF3). IR(KBr): 3282, 2979, 1698,

1558, 1371, 1172, 950, 728 cm-1. HRMS (ESI): calcd. for C12H20F5N2O2 [M+H]+ 319.1440, found 319.1440.


HPLC condition: Chiral column 3-AmyCoat (150×4.6 mm), heptane/i-PrOH = 98/, flow rate = 1 mL/min, wavelength = 206 nm. tr minor =

4.832 min (1.404), tr major = 5.173 min (98.596).

tert-butyl ((2-(trifluoromethyl)piperidin-2-yl)methyl)carbamate (6c), 99%, 95% ee, colorless oil. 1H NMR (400 MHz, CDCl3):

NH

CF3

BocHN

1.39 (9H, s), 1.44-1.72 (7H, m), 2.78-2.87 (2H, m), 3.10 (1H, dd, J1 = 4.3 Hz, J2 = 14.5 Hz), 3.53-3.59 (1H, m), 4.88 (1H, bs, NH). 13C NMR

(100 MHz, CDCl3): 19.4, 24.5, 25.3, 28.2, 40.8, 41.1, 58.0 (q, JCF = 23.6 Hz, C-CF3), 79.5, 127.7 (q, JCF = 287.5 Hz), 156.0. 19F NMR

(280 MHz, CDCl3): -77.2 (s, CF3). IR(KBr): 33230 (bs), 2952, 1716, 1544, 1265, 1172, 744, 651 cm-1. HRMS (ESI): calcd. for

C12H22F3N2O2 [M+H]+ 283.1628, found 283.1628.


HPLC condition: Chiral column 3-AmyCoat (150×4.6 mm), heptane/i-PrOH = 98/2, flow rate = 1 mL/min, wavelength = 206 nm. tr minor

=12.522 min (2.383), tr major = 14.905 min (97.617).

tert-butyl ((2-(trifluoromethyl)azepan-2-yl)methyl)carbamate (6e), 99%, >99% ee, white solid, mp 82-84°C. 1H NMR (400 NH

CF3

NHBoc

MHz, CDCl3): 1.29-1.34 (2H, m), 1.40 (9H, s), 1.55-1.81 (7H, m), 2.77-2.87 (2H, m), 3.16-3.21 (1H, m), 3.30-3.36 (1H, m), 4.82 (1H, bs,

NH). 13C NMR (100 MHz, CDCl3): 22.7, 28.2, 30.5, 30.9, 33.6, 43.4, 44.2, 61.7 (q, JCF = 22.2 Hz, C-CF3), 79.6, 128.4 (q, JCF = 289.0 Hz),

156.2. 19F NMR (280 MHz, CDCl3): -77.9 (s, CF3). IR(KBr): 3268 (bs), 2953, 1687, 1367, 1255, 1162, 1058, 781 cm-1. HRMS (ESI):

calcd. for C12H22F3N2O2 [M+H]+ 297.1785, found 297.1785.

Optical rotation [α]20D = -1.4 (c = 1, CH2Cl2).

HPLC condition: Chiral column Kromasil-3-AmyCoat (150x4.6 мм), heptane/i-PrOH = 95.5/0.5, flow rate = 1 mL/min, wavelength = 206

nm. tr minor = 12.238 min (0.148), tr major = 8.512 min (99.852)

NMR spectra

12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

2.032.002.00 1.00

1.87

1.89

1.91

1.92

1.94

1.96

1.98

1.99

2.01

2.02

2.04

2.26

2.27

2.29

2.31

2.31

2.32

2.34

2.36

2.53

3.133.

143.

15

7.27

NH

F

F

FN

1H NMR (400 MHz, CDCl3) for compound 2a

3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9Chemical Shift (ppm)

2.032.002.00 1.00

3.16

3.15

3.14

3.13

2.53

2.36

2.34

2.32

2.31

2.31

2.29

2.27

2.26

2.24

2.04

2.02

2.01

1.99

1.98

1.96

1.94

1.92

1.91

1.89

1.87

NH

F

F

FN

1H NMR (400 MHz, CDCl3) for compound 2a aliphatic region

192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

127.

4912

4.69

121.

8911

9.10

117.

73

77.3

277

.00

76.6

8

62.6

0 62.2

861

.96

61.6

4

46.3

4

33.0

4

24.0

3

NH

F

F

FN

13C NMR (100 MHz, CDCl3) for compound 2a

200 180 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260 -280 -300Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-79.

12

NH

F

F

FN

19F NMR (280 MHz, CDCl3) for compound 2a

12 11 10 9 8 7 6 5 4 3 2 1 0 -1Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

2.012.002.00

1.98

2.002.

022.06

2.08

2.10

2.41

2.45

3.24

3.25

3.27

7.27

NH

F

F

NF

F

F

1H NMR (400 MHz, CDCl3) for compound 2b

NH

F

F

NF

F

F

3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9Chemical Shift (ppm)

2.012.002.00 1.00

1.98

2.002.

022.

032.

052.

062.

082.

10

2.26

2.36

2.37

2.39

2.41

2.43

2.45

3.24

3.25

3.27

1H NMR (400 MHz, CDCl3) for compound 2b aliphatic region

230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

23.8

9

33.4

3

46.3

3

61.3

961.6

661

.92

76.6

877

.00

77.3

2

109.

7511

1.98

112.

3411

4.57

116.

9211

7.27

117.

6812

0.13

120.

49

130 125 120 115 110 105Chemical Shift (ppm)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12N

orm

aliz

ed In

tens

ity

109.

0310

9.39

109.

75

111.

6211

1.98

112.

34

114.

5711

4.92

116.

9211

7.27

117.

68

119.

7812

0.13

120.

49

NH

F

F

NF

F

F

13C NMR (100 MHz, CDCl3) for compound 2b

24 16 8 0 -8 -16 -24 -32 -40 -48 -56 -64 -72 -80 -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

3.00 1.95

-124

.15

-123

.43

-119

.99

-119

.27

-79.

12

NH

F

F

NF

F

F

19F NMR (280 MHz, CDCl3) for compound 2b


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

3.071.031.00

1.47

1.48

1.51

1.64

1.68

1.71

1.89

2.00

2.15

2.92

2.94

3.12

3.14

7.27

NH

F

F

F

N

1H NMR (400 MHz, CDCl3) for compound 2c

3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4Chemical Shift (ppm)

3.07 1.031.03 1.021.00 0.99 0.96

1.47

1.48

1.49

1.51

1.54

1.64

1.68

1.71

1.76

1.78

1.79

1.82

1.89

1.91

2.00

2.032.

15

2.92

2.94

2.97

3.12

3.14

NH

F

F

F

N

1H NMR (400 MHz, CDCl3) for compound 2c aliphatic region

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

20.0

823

.78

28.3

3

42.6

1

60.5

760

.88

76.6

877

.00

77.3

2

115.

3311

8.60

121.

4112

4.21

127.

02

NH

F

F

F

N

13C NMR (100 MHz, CDCl3) for compound 2c


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-80.

17

NH

F

F

F

N

19F NMR (280 MHz, CDCl3) for compound 2c

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00N

orm

aliz

ed In

tens

ity

2.051.921.00

1.43

1.45

1.46

1.50

1.51

1.52

1.65

1.67

1.68

1.71

1.84

1.85

1.88

1.99

2.10

2.14

2.93

2.96

2.99

3.12

3.15

7.27

NH

NF

F

F

F

F

1H NMR (400 MHz, CDCl3) for compound 2d


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

2.042.01 1.021.00 1.000.97 0.91

1.42

1.43

1.45

1.46

1.47

1.50

1.50

1.53

1.54

1.63

1.64

1.64

1.65

1.67

1.68

1.68

1.71

1.72

1.74

1.75

1.81

1.82

1.84

1.85

1.88

1.92

1.99

2.03

2.10

2.14

2.14

2.33

2.93

2.96

2.99

3.113.

123.

14

NH

NF

F

F

F

F

1H NMR (400 MHz, CDCl3) for compound 2d aliphatic region


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

20.2

723

.75

28.2

4

42.6

6

60.8

561.0

861

.31

76.6

877

.00

77.3

2

109.

4010

9.76

112.

0111

2.37

114.

6111

4.78

117.

1311

9.99

120.

3512

2.85

NH

NF

F

F

F

F

128 126 124 122 120 118 116 114 112 110 108 106 104Chemical Shift (ppm)

0.05

0.10

0.15

0.20

0.25

Nor

mal

ized

Inte

nsity

109.

4010

9.76

111.

6511

2.01

112.

3711

2.73

114.

27114.

6111

4.78

114.

97

116.

78117.

1311

7.48

119.

6411

9.99

120.

35

122.

85

13C NMR (100 MHz, CDCl3) for compound 2d

-75 -80 -85 -90 -95 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

3.00 1.98

-123

.08

-122

.59

-122

.12

-121

.63

-78.

24

NH

NF

F

F

F

F

19F NMR (280 MHz, CDCl3) for compound 2d

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00N

orm

aliz

ed In

tens

ity

6.323.002.00

1.56

1.57

1.58

1.58

1.59

1.60

1.61

1.65

1.67

1.67

1.68

1.76

1.88

1.90

1.92

2.11

2.12

2.13

2.14

2.16

2.16

2.282.

942.

952.97

2.98

7.27

NH

NF

F

F

1H NMR (400 MHz, CDCl3) for compound 2e

NH

NF

F

F


4.002.022.00 1.09 1.070.99

1.59

1.611.

641.

65

1.71

1.73

1.741.

761.

77

1.861.87

2.09

2.13

2.14

2.19

2.25

2.91

2.95

2.96

2.97

3.01

1H NMR (400 MHz, CDCl3) for compound 2e aliphatic region

192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00N

orm

aliz

ed In

tens

ity

22.7

4

28.8

230

.98

32.6

643.8

5

62.7

363

.01

76.6

877

.00

77.3

2

117.

65

122.

32125.

15

NH

NF

F

F

13C NMR (100 MHz, CDCl3) for compound 2e

NH

NF

F

F


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-79.

20

19F NMR (280 MHz, CDCl3) for compound 2e


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

2.02 2.012.001.030.97

1.71

1.73

1.74

1.761.

851.

861.

872.

182.

202.

22

3.04

3.05

3.07

6.83

7.27

7.31

NH

FF

F

NH2

O


3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0In

tens

ity

2.02 2.012.00

1.71

1.731.

741.

761.

78

1.85

1.86

1.87

2.18

2.20

2.22

3.04

3.05

3.07

NH

FF

F

NH2

O


210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

25.3

4

32.2

1

47.5

2

70.2

770.5

370

.79

71.0

576

.68

77.0

077

.32

121.

6812

4.50

127.

3213

0.14

173.

02

NH

FF

F

NH2

O


30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-74.

04

NHF F

F

O

NH2



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0In

tens

ity

2.022.00 1.971.000.990.99

0.08

1.68

1.70

1.71

1.731.821.

841.

851.

861.

912.

232.

252.

262.

272.

332.

352.

362.

382.

622.

663.

033.

05

6.77

7.14

7.27

NH

F

F

F

F F

NH2O



2.022.00 1.971.00

1.68

1.70

1.71

1.73

1.75

1.771.79

1.81

1.821.

841.

851.

86

1.91

2.23

2.25

2.26

2.27

2.31

2.33

2.35

2.36

2.38

2.62

2.66

3.03

3.05

NH

F

F

F

F F

NH2O



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

25.1

1

32.6

2

47.8

2

70.4

770

.68

70.9

076

.68

77.0

077

.32

111.

8711

2.23

114.

4911

4.84

117.

0511

7.22

117.

4111

7.58

120.

0812

0.44

123.

30

172.

69

NH

F

F

F

F F

NH2O

123 122 121 120 119 118 117 116 115 114 113 112 111 110 109Chemical Shift (ppm)

109.

94

111.

5811

1.87

112.

2311

2.60

114.

4911

4.84

117.

0511

7.22

117.

4111

7.58

117.

95120.

0812

0.44

120.

81

123.

30



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

3.14 2.00

-121

.21

-120

.48

-115

.95

-115

.22

-79.

42

NH

F

F

F

F F

NH2O


11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

3.962.051.031.02 1.011.00 0.97

1.24

1.26

1.29

1.31

1.32

1.35

1.46

1.49

1.53

1.54

1.56

1.57

1.59

1.60

1.74

1.79

1.82

2.40

2.43

2.44

2.68

2.72

2.75

3.02

3.05

6.05

7.18

7.27

NH F

F

F

O

NH2



3.962.051.011.00 0.97

1.24

1.26

1.27

1.29

1.30

1.31

1.32

1.34

1.35

1.37

1.38

1.391.

431.

451.

461.

471.

491.

521.

531.

531.

541.

561.

571.

591.

60

1.74

1.79

1.82

2.40

2.40

2.43

2.44

2.68

2.72

2.75

3.02

3.05

NH F

F

F

O

NH2



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

20.3

425.3

026

.28

42.4

4

64.5

664.8

265

.06

65.3

2

76.6

877

.00

77.3

2

120.

4712

3.30

126.

1412

8.97

169.

62NH F

F

F

O

NH2


NH F

F

F

O

NH2


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-76.

82


11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

4.141.07 1.061.031.021.01 1.00

0.04

0.05

0.07

0.08

0.11

0.12

1.22

1.24

1.28

1.29

1.32

1.33

1.35

1.52

1.53

1.56

1.57

1.60

1.61

1.78

1.81

2.39

2.43

2.68

2.72

2.75

2.99

3.02

6.697.15

7.27NH

F

F

F

F

FNH2 O

1H NMR (400 MHz, CDCl3) for compound 3d


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

4.141.07 1.061.031.00

1.22

1.24

1.25

1.28

1.29

1.31

1.32

1.33

1.35

1.361.

391.

421.

421.

451.

461.

461.

491.

501.

521.

531.

551.

561.

571.

581.

601.

611.

64

1.78

1.78

1.791.

81

2.39

2.43

2.68

2.69

2.72

2.75

2.76

2.982.

99

3.02

NH

F

F

F

F

FNH2 O

1H NMR (400 MHz, CDCl3) for compound 3d aliphatic region


-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

20.0

3

24.8

325

.77

42.0

2

64.5

764

.77

64.9

7

76.2

876

.60

76.9

2

110.

7711

3.0311

3.38

113.

74

116.

7411

7.11

117.

4711

9.97

120.

33

169.

17

NH

F

F

F

F

FNH2 O

13C NMR (100 MHz, CDCl3) for compound 3d


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nor

mal

ized

Inte

nsity

3.00 2.02

-122

.14

-121

.98

-78.

82

NH

F

F

F

F

FNH2 O

19F NMR (280 MHz, CDCl3) for compound 3d


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

3.033.022.00 1.051.000.94

-0.0

10.

000.

040.

04

1.121.13

1.15

1.16

1.181.19

1.29

1.31

1.34

1.36

1.40

1.69

1.71

1.82

1.85

2.272.30

2.31

2.33

2.82

2.86

2.88

2.92

7.02

7.27

7.62

NH

F

F

F

NH2

O


3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1.0Chemical Shift (ppm)

3.033.022.00 1.05 0.99

1.121.13

1.15

1.16

1.181.19

1.21

1.22

1.26

1.29

1.30

1.31

1.33

1.34

1.36

1.40

1.40

1.69

1.71

1.791.

811.

821.

85

2.272.30

2.31

2.33

2.82

2.86

2.88

2.912.

92

NH

F

F

F

NH2

O



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

22.7

0

29.5

630

.30

32.9

8

43.7

0

67.7

968

.02

68.2

668

.50

76.6

877

.00

77.3

2

122.

1012

4.96

127.

8213

0.69

173.

47

NH

F

F

F

NH2

O



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-75.

13

NH

F

F

F

NH2

O



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

2.032.011.011.00

1.84

1.851.87

2.01

2.02

2.29

2.30

2.32

2.34

2.36

2.922.

942.

963.

253.27

3.28

3.30

3.31

4.65

4.68

NH

F

F F

OH

O

1H NMR (400 MHz, D2O) for compound 4a

3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7Chemical Shift (ppm)

2.032.011.011.00

1.82

1.841.851.

871.

89

1.98

1.99

2.01

2.02

2.04

2.05

2.08

2.272.

292.

302.

322.

342.

362.

372.

39

2.92

2.94

2.95

2.962.

962.

983.25

3.27

3.28

3.30

3.31

NH

F

F F

OH

O

1H NMR (400 MHz, D2O) for compound 4a aliphatic region


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

25.9

4

32.1

4

47.3

9

71.5

671

.81

72.0

672

.31

122.

3012

5.1012

7.90

130.

70

175.

26

NH

F

F F

OH

O

13C NMR (100 MHz, D2O) for compound 4a

NH

F

F F

OH

O


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-73.

13

19F NMR (280 MHz, D2O) for compound 4a


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

2.032.002.00

1.74

1.801.82

1.931.

951.

962.

342.352.

372.

452.

47

2.50

3.27

3.293.

303.

323.

343.

373.

373.

39

4.72

NH

F

F

F

F F

OH

O

BrH

1H NMR (400 MHz, D2O) for compound 4b

3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6Chemical Shift (ppm)

2.032.002.00

1.74

1.76

1.78

1.80

1.82

1.84

1.861.

921.

931.

951.

961.

981.

99

2.32

2.34

2.35

2.37

2.40

2.44

2.45

2.46

2.47

2.49

2.49

2.503.27

3.29

3.30

3.32

3.34

3.37

3.37

3.39

NH

F

F

F

F F

OH

O

BrH

1H NMR (400 MHz, D2O) for compound 4b aliphatic region

130 128 126 124 122 120 118 116 114 112 110 108 106 104 102Chemical Shift (ppm)

108.

81109.

17111.

4011

1.78

112.

16

113.

6211

3.99

114.

39

115.

6911

6.05

116.

40118.

5511

8.90

119.

25

121.

75


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

21.9

9

30.2

6

47.3

9

72.0

172

.21

72.4

5

108.

5110

9.17

111.

4011

1.78

114.

39116.

0511

8.90

119.

2512

1.75

166.

10

NH

F

F

F

F F

OH

O

BrH

13C NMR (100 MHz, D2O) for compound 4b

NH

F

F

F

F F

OH

O

BrH

-8 -16 -24 -32 -40 -48 -56 -64 -72 -80 -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-119

.11

-118

.35

-117

.22

-116

.46

-80.

97

19F NMR (280 MHz, D2O) for compound 4b


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

3.001.00 1.00 1.00

1.20

1.241.

271.

461.

501.

671.

711.

741.

771.

78

2.30

2.34

3.06

3.09

3.10

3.27

3.30

4.73

NH F

F

F

OH

OBrH

1H NMR (400 MHz, D2O) for compound 4c

3.5 3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2 1.1Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25In

tens

ity

3.00 1.011.00 1.001.00 1.00

1.20

1.24

1.27

1.31

1.43

1.461.50

1.53

1.67

1.71

1.74

1.77

1.78

2.30

2.34

3.06

3.06

3.09

3.10

3.12

3.13

3.27

3.30

NH F

F

F

OH

OBrH

1H NMR (400 MHz, D2O) for compound 4c aliphatic region


-0.05

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

17.6

620

.11

24.3

1

42.9

6

65.5

765

.85

66.1

366

.42

117.

6512

0.48

123.

3212

6.15

164.

50

NH F

F

F

OH

OBrH

13C NMR (100 MHz, D2O) for compound 4c


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-75.

79

NH F

F

F

OH

OBrH

19F NMR (280 MHz, D2O) for compound 4c

11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

4.05 2.082.00 1.01

1.19

1.251.35

1.45

1.46

1.57

1.602.

012.

042.

052.

082.

262.

282.

302.

32

3.15

3.18

3.18

3.20

3.22

3.25

4.74

NH

O

OH

F

F F

BrH

1H NMR (400 MHz, D2O) for compound 4e

3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4 1.3 1.2Chemical Shift (ppm)

4.05 2.082.00 1.011.00

1.18

1.19

1.21

1.22

1.25

1.30

1.31

1.321.

331.

341.

351.

361.

371.

38

1.44

1.45

1.46

1.46

1.47

1.48

1.541.

541.

571.

581.

591.60

1.611.

741.75

1.77

1.79

2.01

2.04

2.05

2.08

2.26

2.28

2.30

2.32

3.143.

153.

183.

203.

223.

233.

253.

26

NH

O

OH

F

F F

BrH

1H NMR (400 MHz, D2O) for compound 4e aliphatic region

200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

21.6

5

25.6

326

.39

27.6

6

45.5

1

70.0

970

.33

118.

3412

1.18

124.

0112

6.85

166.

24NH

O

OH

F

F F

BrH

13C NMR (100 MHz, D2O) for compound 4e


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

-73.

64

NH

O

OH

F

F F

BrH

19F NMR (280 MHz, D2O) for compound 4e


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0In

tens

ity

4.993.00 2.021.00

1.36

1.541.

611.

641.

651.

701.

711.

901.

911.

931.

94

1.96

2.61

2.65

2.89

2.93

2.95

3.00

3.01

3.03

3.04

7.27

NH

F

F

F

NH2



4.993.00 2.021.00

1.36

1.54

1.581.60

1.61

1.64

1.65

1.681.

701.

711.

73

1.80

1.811.83

1.84

1.86

1.87

1.90

1.91

1.93

1.94

1.96

2.61

2.62

2.65

2.65

2.89

2.91

2.93

2.94

2.95

2.99

3.00

3.01

3.03

3.04

NH

F

F

F

NH2



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

25.8

7

30.0

0

44.8

947

.27

67.0

867

.33

76.6

877

.00

77.3

2

124.

0112

6.85

129.

6713

2.51

NHF F

F

NH2


200 180 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260 -280 -300Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-78.

18

NHF F

F

NH2


NH

F

F

F

F F

NH2


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

6.011.99 1.011.00

1.56

1.59

1.61

1.63

1.65

1.75

1.76

1.78

1.79

1.81

2.01

2.04

2.55

2.59

2.84

2.88

2.89

2.97

2.99

3.007.27


3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5 1.4Chemical Shift (ppm)

6.011.99 1.011.01 1.00

1.56

1.581.

591.

611.

631.

651.

671.

691.

711.72

1.74

1.75

1.76

1.78

1.79

1.81

1.96

1.982.

002.

012.

04

2.55

2.59

2.84

2.88

2.89

2.912.95

2.97

2.99

3.00

NH

F

F

F

F F

NH2



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

25.6

2

30.2

0

45.1

947

.10

67.3

867.5

767

.76

76.6

877

.00

77.3

2

114.

5411

5.22

116.

7511

7.10

118.

07

120.

9312

1.30

123.

79

132 130 128 126 124 122 120 118 116 114 112 110 108Chemical Shift (ppm)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12

Inte

nsity

114.

1911

4.54

115.

22

116.

7511

7.10

117.

7011

8.07

118.

44

119.

3111

9.6612

0.56

120.

9312

1.30

123.

79

NH

F

F

F

F F

NH2


NH

F

F

F

F F

NH2


0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

3.08 2.00

-119

.59

-79.

20



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

9.011.93

1.39

1.40

1.44

1.57

1.59

1.60

1.622.632.

642.

662.

702.

792.

80

7.27

NH F

F

F

NH2


NH F

F

F

NH2


9.011.93 1.011.00

1.39

1.40

1.44

1.551.

571.

591.

601.

622.632.

642.

66

2.70

2.79

2.80



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

19.5

1

24.5

225

.41

40.6

642

.81

57.6

257

.86

58.0

858

.30

76.6

877

.00

77.3

2

123.

7912

6.66

129.

5213

2.39

NH

F

F

F

NH2



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Nor

mal

ized

Inte

nsity

-75.

82

NH

F

F

F

NH2



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0In

tens

ity

5.16 5.033.00

1.23

1.261.

281.

411.

601.

631.

691.

721.

76

2.57

2.61

2.76

2.80

2.82

7.27

NH

F

FF

NH2


NH

F

FF

NH2


5.025.003.00 1.00

1.23

1.261.

281.

30

1.34

1.36

1.39

1.41

1.44

1.47

1.59

1.60

1.61

1.63

1.66

1.68

1.69

1.72

1.73

1.76

2.57

2.61

2.76

2.78

2.79

2.80

2.82



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

22.5

7

30.5

433

.57

43.0

646

.29

61.4

561

.67

76.6

877

.00

77.3

2

124.

6212

7.51

130.

3913

3.28

NH

F

FF

NH2



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-76.

87

NH

F

FF

NH2



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

9.022.012.00 2.001.01 1.01

1.43

1.73

1.74

1.78

1.87

1.95

1.982.

102.

983.00

3.033.

053.31

3.33

3.34

3.36

4.97

7.27

NH

F

F

F

NH

OO

CH3

CH3CH3


5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)

9.022.012.00 2.001.01 1.01 1.001.00

1.43

1.68

1.70

1.71

1.73

1.74

1.75

1.86

1.87

1.89

1.95

1.961.98

1.99

2.10

2.96

2.983.

003.05

3.283.

293.

313.

333.

343.

363.

383.

40

4.97

NH

F

F

F

NH

OO

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d 25.7

128

.24

29.9

0

43.5

947

.25

66.6

266

.86

67.1

167

.34

76.6

877

.00

77.3

279

.84

123.

5312

6.36

129.

1913

2.02

156.

73

NH

F

F

F

NH

OO

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-78.

04

NH

F

F

F

NH

OO

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

9.023.002.012.00 1.990.96

1.42

1.741.

761.

772.10

2.132.

952.97

3.043.

053.

073.

273.29

3.31

3.34

3.36

5.00

7.27

NH

F

F

F

F F

NH

OO

CH3

CH3CH3


5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5Chemical Shift (ppm)

9.023.002.012.00 1.990.96

1.42

1.71

1.74

1.76

1.77

1.81

1.84

1.85

1.87

2.07

2.10

2.13

2.93

2.952.

973.

043.

053.

073.

09

3.263.27

3.29

3.31

3.34

3.36

3.38

3.40

5.00

NH

F

F

F

F F

NH

OO

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

25.5

928

.20

30.0

4

43.8

447

.26

67.2

767

.46

67.6

6

76.6

877

.00

77.3

279

.85

114.

0811

6.29

116.

6311

8.08

118.

4411

8.85

119.

2012

0.57

120.

9412

1.30

123.

80156.

77

126 125 124 123 122 121 120 119 118 117 116 115 114 113 112 111Chemical Shift (ppm)

114.

0811

4.42

115.

22

115.

9411

6.29

116.

6311

6.97

117.

7111

8.08

118.

4411

8.85

119.

20

120.

5712

0.94

121.

30

123.

80

NH

F

F

F

F F

NH

OO

CH3

CH3CH3



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

3.01 2.00

-120

.46

-78.

86

NH

F

F

F

F F

NH

OO

CH3

CH3CH3



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0In

tens

ity

9.032.011.001.00 0.97

1.39

1.46

1.47

1.611.

681.

70

2.80

2.812.83

2.84

2.853.093.11

3.12

3.53

3.55

3.574.88

7.27

NH F

F

F

NH

O

O

CH3

CH3CH3



9.037.032.011.001.00 0.97

1.39

1.44

1.45

1.46

1.47

1.49

1.51

1.53

1.571.

591.

651.68

1.70

1.72

2.78

2.802.812.

832.

842.

852.

87

3.08

3.093.

113.

12

3.533.55

3.57

3.59

4.88

NH F

F

F

NH

O

O

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

Chloroform-d

19.4

2

24.5

125

.34

28.1

7

40.7

741

.13

57.6

457

.87

58.1

158

.33

76.6

877

.00

77.3

279

.52

123.

39126.

2612

9.11

131.

98156.

02

NH F

F

F

NH

O

O

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

-77.

17

NH F

F

F

NH

O

O

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00In

tens

ity

9.052.001.020.99

1.291.

321.

341.

401.

621.

711.

751.

781.

81

2.772.

802.

823.

183.20

3.21

3.30

3.32

3.34

3.364.82

7.27

NH

F

FF

NH

O

O

CH3

CH3CH3


NH

F

FF

NH

O

O

CH3

CH3CH3


9.057.03 2.002.001.020.99 0.96

1.29

1.32

1.34

1.40

1.551.57

1.61

1.62

1.65

1.67

1.71

1.75

1.78

1.79

1.81

2.77

2.80

2.82

2.87

3.163.

183.

203.

213.

303.

323.

343.

36

4.82



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

nsity

Chloroform-d

22.7

1

28.1

830

.50

33.6

0

43.4

344

.25

61.3

861

.60

61.8

262

.04

76.6

877

.00

77.3

279

.57

124.

10126.

9712

9.85

132.

72

156.

22

NH

F

FF

NH

O

O

CH3

CH3CH3



0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Inte

nsity

-77.

93

NH

F

FF

NH

O

O

CH3

CH3CH3


References

(1) a) A. V. Gulevich, N., E. Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G. Nenajdenko, Synlett, 2009, 3, 0403 b) E. N.

Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G. Nenajdenko, Synthesis, 2010, 1, 0120.

Enantioselective synthesis of α-perfluoroalkylated ... · MeOH 6 100 85 >99 CF3CH(OH)CF3 6 98 71...

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Transcript of Enantioselective synthesis of α-perfluoroalkylated ... · MeOH 6 100 85 >99 CF3CH(OH)CF3 6 98 71...