Electronic Supplementary Material (ESI) for Organic & … · 2019. 3. 25. · S3 Method B: To a...

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2019

Supporting Information

Autocatalyzed three-component cyclization of polyfluoroalkyl-3-oxo esters, methyl ketones and alkyl amines: novel approach to 3-alkylamino-5-hydroxy-5-polyfluoroalkylcyclohex-2-en-1-onesMarina V. Goryaeva,a Svetlana O. Kushch,a Olga G. Khudina,a Yanina V. Burgart,a Yulia S.

Kudyakova,a Marina A. Ezhikova,a Mikhail I. Kodess,a Pavel A. Slepukhin,a Lilya Sh.

Sadretdinova,a Nataliya P. Evstigneeva,b Nataliya A. Gerasimovab and Victor I. Saloutin*a

aPostovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, S. Kovalevskoy St. 22, 620990 Ekaterinburg, Russia. E-mail: [email protected]

bUral Research Institute for Dermatology, Venereology and Immunopathology, Scherbakova St. 8, 620076 Ekaterinburg, Russia.

Table of contents

1. General Remarks …………….……………………………………………………………S2

2. General procedures………………………………………….………………………….….S3

6. Characterization data of all new compounds………………………………………………S3

7. Antifungal activity assay…………………………………………………………………..S24

8. Antibacterial activity assay………………………………………………………………...S24

7. X-ray Analysis…………………………………………………………………………......S25

8. References………………………………………………………………………………….S28

9. Copies of 1H, 13C, 19F NMR spectra for all compounds …………………………………..S29

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2019

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General Remarks

Melting points were measured in the open capillaries with a Stuart SMP3 melting-point

apparatus. The IR spectra were recorded with a diffuse reflectance attachment (DRA) on a

Perkin-Elmer Spectrum One FT-IR spectrometer and with the attenuated total reflectance (ATR)

accessory on a Nicolet 6700 FT-IR spectrometer in the range 400 - 4000 cm–1. The 1H, 19F and 13C NMR spectra were registered on a Bruker DRX-400, an AVANCE 500 and an AVANCE

NEO 600 spectrometers using Me4Si (1H) and C6F6 (19F) as internal standards. The 13C chemical

shifts were calibrated using the solvent signal DMSO-d6 (δC 39.5 ppm) or CDCl3 (δC 77.0 ppm).

A signal in 1H NMR spectra at δ 3.30–3.33 ppm corresponds to water in DMSO-d6.1 The

complete assignment of 1H and 13C signals was based on 2D 1H-13C HSQC and HMBC

experiments for heterocycles 4aae, 4aah, 4aba, 8, 9b; on 2D 1H-13C HSQC data for compound

4abi. The high-resolution mass spectra (HRMS) were recorded on a Bruker maXis impact mass

spectrometer (ESI). Optical rotation values were measured with a Perkin Elmer M 341

polarimeter. All optical rotations were obtained at room temperature. High-performance liquid

chromatography (HPLC) for was performed on a Knauer SmartLine 1000 instrument (for

compounds 6a, 6c, 6d) and an Agilent 1100 instrument with a diode array detector (for

compound 6b). The column chromatography was performed on Merck silica gel 60 (0.063–0.200

mm).

Ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (1c), ethyl 4,4,5,5-tetrafluoro-3-oxopentanoate

(1d), ethyl 4,4,5,5,6,6,6-heptafluoro-3-oxohexanoate (1e) were obtained according to the

literature procedure.2 Ethyl 4,4,4-trifluoro-3-oxobutanoate (1a), ethyl 4,4-difluoro-3-

oxobutanoate (1b), acetone (2a), 2-butanone (2b), 2-hexanone (2c), cyclohexylamine (3a),

cyclopropylamine (3b), octylamine (3c), dodecylamine (3d), N,N′-dimethylethylenediamine

(3e), benzylamine(3f), 4-fluorobenzylamine (g), 3,4-dimethoxybenzylamine (h), furfurylamine

(3i), pyrrolidine (3j), piperidine (3k), morpholine (3l), L-proline (3m) are commercially

available (purchased from Alfa Aesar, Acros Organics, and Sigma–Aldrich).

General procedures for the synthesis of compounds 4.

Method A: To a solution of the corresponding 3-oxo ester 1 (3 mmol) and methyl ketone 2 (3

mmol) in absolute ethanol (15 mL) was added the zeolite catalyst (molecular sieves 3Å (1000

mg)). Then amine 3 (3 mmol) was added and the reaction mixture was stirred for 2–3 days at

room temperature (25 °C). After the reaction was complete (TLC monitoring), the reaction

mixture was filtered to separate zeolite catalyst. After evaporation of the solvent from filtrate, the

residue was washed with diethyl ether and crystallized from the proper solvent (acetonitrile,

acetone, hexane, ethanol, benzene).

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Method B: To a mixture of the corresponding aldol 6 (3 mmol) and zeolite catalyst (molecular

sieves 3Å (1000 mg)) in absolute ethanol (15 mL) was added amine 3 (3 mmol). The reaction

mixture was stirred for 2–3 days at room temperature. After the reaction was complete (TLC

monitoring), the reaction mixture was filtered to separate zeolite catalyst. After evaporation of

the solvent from filtrate, the residue was washed with diethyl ether and crystallized from the

proper solvent (acetonitrile, acetone, hexane, ethanol, benzene).

General procedure for the synthesis of compounds 5.

A mixture of the corresponding aldol 6 (3 mmol) and amine 3 (3 mmol) in 95% ethanol (15 mL)

was stirred for 2–3 days at room temperature(25 °C). After the reaction was complete (TLC

monitoring), the solvent was evaporated and the residue was washed with hexane and

crystallized from acetonitrile.

General procedure for the synthesis of compounds 6.

To a solution of 3-oxo ester 1 (10 mmol) and methyl ketone 2 (50 mmol) in toluene (50 mL) was

added L-proline (1 mmol). The reaction mixture was kept under cooling (0 °С) for 3–5 days.

After the reaction was complete (TLC monitoring), the solvent was evaporated and the residue

was purified by column chromatography (eluent chloroform).

General procedures for the synthesis of compounds 9.

Method C: A mixture of the corresponding cyclohexenone 4 (1.5 mmol) and p-toluensulfonic

acid monohydrate (1.5 mmol) in toluene (100 mL) was heated with azeotropic distillation system

for removal of water for 3–4 days. After the reaction was complete (TLC monitoring), the hot

solution was filtered and the filtrate was concentrated with a rotary evaporator. The residue was

purified by column chromatography (eluent chloroform/diethyl ether = 1:1).

Method D: A mixture of cyclohexenone 4 (1.5 mmol) and 20% aq. sulfuric acid (30mL) was

heated for 3–4 days. After the reaction was complete (TLC monitoring), the reaction mixture

was cooled, poured into water (100 mL) and neutralized to pH 7 with sodium hydrogen

carbonate. The mixture was extracted with chloroform (3 x 50 mL). The solvent was evaporated,

and the residue was purified by column chromatography (eluent chloroform/diethyl ether = 1:1).

3-(Cyclohexylamino)-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aaa)

HN

O

HOF3C

Isolated by crystallization (acetonitrile); Chemical Formula: C13H18F3NO2; White powder; M.P.

234–236°С; Yield (method A) 616 mg (74%). 1H NMR (500 MHz, DMSO-d6): = 1.10–1.23

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(m, 3 H, H cyclohexyl), 1.26–1.35 (m, 2 H, H cyclohexyl), 1.54–1.59 (m, 1 H, H cyclohexyl),

1.66–1.72 (m, 2 H, H cyclohexyl), 1.83–1.86 (m, 2 H, H cyclohexyl), 2.25 (dd, J = 16.3, 1.9 Hz,

1 H, H-6B), 2.46 (d, J = 16.3 Hz, 1 H, H-6A), 2.50 (d, J = 16.3 Hz, 1 H, H-4B), 2.68 (d, J =

16.3, 1 H, H-4A), 3.20 (m, 1 H, NCH), 4.93 (s, 1 H, H-2), 6.21 (s, 1 H, OH), 7.07 (d, J = 7.2 Hz,

1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 24.13, 24.17, 25.14, 31.42 and 31.71 (5*C

cyclohexyl), 33.46 (C-4), 40.83 (C-6), 50.68 (NCH), 72.24 (q, J = 28.0 Hz, C-5), 93.33 (C-2),

125.79 (q, J = 285.7 Hz, CF3), 158.09 (C-3), 188.94 (C-1) ppm. 19F NMR (470 MHz, DMSO-

d6): = 80.36 (s, CF3) ppm. DRA: ν = 3274 (O–H, N–H), 3082, 2937, 2858 (C–H), 1581, 1525,

1455 (C=O, C=C), 1174–1102 (C–F) cm-1. HRMS (ESI): calcd. for С13H19F3NO2 [M + H]+

278.1367; found 278.1362.

3-(Cyclopropylamino)-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aab)

HN

O

HOF3C


217–219°C; Yield (method A) 367 mg (52%). 1H NMR (500 MHz, DMSO-d6): = 0.41–0.48

(m, 2 H, H cyclopropyl), 0.69–0.76 (m, 2 H, H cyclopropyl), 2.27 (dd, J = 16.2, 1.8 Hz, 1 H, H-

6B), 2.35-2.41 (m, 2 H, H-4B and NCH), 2.47 (d, J = 16.2 Hz, 1 H, H-6A), 2.68 (d, J = 16.4 Hz,

1 H, H-4A), 5.20 (s, 1 H, H-2), 6.23 (s, 1 H, OH), 7.42 (br. s, 1 H, NH) ppm. 13C NMR (126

MHz, DMSO-d6): = 6.08 and 6.34 (2*CH2), 24.03 (NCH), 32.89 (C-4), 40.99 (C-6), 72.37 (q,

J = 28.2 Hz, C-5), 95.20 (C-2), 125.78 (q, J = 285.7 Hz, CF3), 160.41 (C-3), 189.31 (C-1) ppm. 19F NMR (470 MHz, DMSO-d6): = 80.32 (s, CF3) ppm. DRA: ν = 3318, 3227 (O–H, N–H),

3060, 2970, 2828 (C–H), 1602, 1573, 1506 (C=O, C=C), 1162–1100 (C–F) cm-1. HRMS (ESI):

calcd. for С10H13F3NO2 [M + H]+ 236.0893; found 236.0895.

5-Hydroxy-3-(octylamino)-5-(trifluoromethyl)cyclohex-2-en-1-one (4aac)

HN

C8H17

O

HOF3C

Isolated by crystallization (acetonitrile); Chemical Formula: C15H24F3NO2, White powder; M.P:

150–151 °C, Yield (method A) 627 mg (68%); 1H NMR (500 MHz, DMSO-d6): = 0.86 (t, J =

6.9 Hz, 3 H, CH3), 1.23–1.34 (m, 10 H, 5 CH2), 1.51 (qw, J = 7.2 Hz, 2 H, CH2), 2.26 (dd, J =

16.2, 2.0 Hz, 1 H, H-6B), 2.46 (d, J = 16.3 Hz, 1 H, H-6A), 2.49 (d, J = 16.3 Hz, 1 H, H-4B,

overlapped with DMSO signal), 2.70 (d, J = 16.3 Hz, 1 H, H-4A), 2.98 (td, J = 6.9, 5.4 Hz, 2 H,

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NCH2), 4.87 (s, 1 H, H-2), 6.22 (s, 1 H, OH), 7.19 (t, J = 5.4 Hz, 1 H, NH) ppm. 13C NMR (126

MHz, DMSO-d6): = 13.92 (CH3), 22.07, 26.52, 27.65, 28.63, 28.70 and 31.22 (6*CH2), 33.31

(C-4), 40.90 (C-6), 42.30 (NCH2), 72.31 (q, J = 28.1 Hz, C-5), 93.30 (C-2), 125.83 (q, J = 286.0

Hz, CF3), 159.37 (C-3), 188.99 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.36 (s, CF3)

ppm. DRA: ν = 3227 (N–H, O–H), 3060, 2954, 2920, 2856 (C–H), 1594, 1552, 1520 (C=O,

C=C), 1166–1103 (C–F) cm-1. HRMS (ESI): calcd. for С15H25F3NO2 [M + H]+ 308.1832; found

308.1830.

5-Hydroxy-3-(dodecylamino)-5-(trifluoromethyl)cyclohex-2-en-1-one (4aad)

HN

C12H25

O

HOF3C

Isolated by crystallization (acetonitrile); Chemical Formula: C19H32F3NO2; White powder; M.P:

135–137 °C; Yield (method A) 687 mg (63%). 1H NMR (500 MHz, DMSO-d6): = 0.86 (t, J =

6.9 Hz, 3 H, CH3), 1.21–1.32 (m, 20 H, 10 CH2), 1.50 (qw, J = 7.1 Hz, 2 H, CH2), 2.26 (dd, J =

16.2, 2.0 Hz, 1 H, H-6B), 2.45 (d, J = 16.2 Hz, 1 H, H-6A), 2.49 (d, J = 16.2 Hz, 1 H, H-4B,

overlapped with DMSO signal), 2.70 (d, J = 16.2 Hz, 1 H, H-4A), 2.97 (td, J = 6.9, 5.2 Hz, 2 H,

NCH2), 4.87 (s, 1 H, H-2), 6.22 (s, 1 H, OH), 7.18 (t, J = 5.2 Hz, 1 H, NH) ppm. 13C NMR (126

MHz, DMSO-d6): = 13.92 (CH3), 22.07, 26.51, 27.64, 28.69, 28.73, 28.98, 29.00, 29.03 and

31.27 (9*CH2), 33.31 (C-4), 40.90 (C-6), 42.28 (NCH2), 72.30 (q, J = 28.1 Hz, C-5), 93.30 (C-

2), 125.82 (q, J = 285.7 Hz, CF3), 159.34 (C-3), 188.97 (C-1) ppm. 19F NMR (376 MHz, DMSO-

d6): = 80.37 (s, CF3) ppm. DRA: ν = 3341, 3240 (N–H, O–H), 3083, 2919, 2853 (C–H), 1593,

1559, 1514 (C=O, C=C), 1174–1100 (C–F) cm-1. HRMS (ESI): calcd. for С19H33F3NO2 [M +

H]+ 364.2458; found 364.2458.

3-{[2-(Dimethylamino)ethyl]amino}-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aae)

HN

O

HOF3C N(Me)2

Isolated by crystallization (acetonitrile); Chemical Formula: C11H17F3N2O2; White powder; M.P:

186–188 °C; Yield (method A) 471 mg (59%). 1H NMR (500 MHz, DMSO-d6): = 2.16 (s, 6 H,

N(CH3)2), 2.26 (dd, J = 16.2, 2.0 Hz, 1 H, H-6B), 2.40 (t, J = 6.5 Hz, 2 H, H-3'), 2.47 (d, J = 16.2

Hz, 1 H, H-6A), 2.53 (dd, J = 16.2, 2.0 Hz, 1 H, H-4B), 2.70 (d, J = 16.2 Hz, 1 H, H-4A), 3.08

(br. q, J = 6.0 Hz, 2 H, H-2'), 4.91 (s, 1 H, H-2), 6.23 (s, 1 H, OH), 7.10 (t, J = 5.3 Hz, 1 H, NH)

ppm. 13C NMR (126 MHz, DMSO-d6): = 33.32 (C-4), 40.43 (C-2'), 40.93 (C-6), 45.14

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(N(CH3)2), 56.67 (C-3'), 72.33 (q, J = 28.0 Hz, C-5), 93.47 (C-2), 125.82 (q, J = 285.9 Hz, CF3),

159.37 (C-3), 189.09 (C-1) ppm. 19F NMR (470 MHz, DMSO-d6): = 80.38 (s, CF3) ppm.

DRA: ν = 3253 (N–H, O–H), 3097, 2992, 2970, 2874, 2838 (C–H), 1609, 1555 (C=O, C=C),

1178–1099 (C–F) cm-1. HRMS (ESI): calcd. for С11H18F3N2O2 [M + H]+ 267.1315; found

267.1316.

3-(Benzylamino)-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aaf)

HN

O

HOF3C


194–195 °C; Yield (method A) 488 mg (57%). 1H NMR (400 MHz, DMSO-d6): = 2.25 (dd, J

= 16.3, 1.9 Hz, 1 H, H-6B), 2.46 (d, J = 16.3 Hz, 1 H, H-6A), 2.57 (dd, J = 16.4, 1.9 Hz, 1 H, H-

4B), 2.80 (d, J = 16.4 Hz, 1 H, H-4A), 4.27 (d, J = 5.8 Hz, 2 H, NCH2), 4.90 (s, 1 H, H-2), 6.26

(s, 1 H, OH), 7.25–7.37 (m, 5 H, Ph), 7.74 (t, J = 5.8 Hz, 1 H, NH) ppm. 13C NMR (126 MHz,

DMSO-d6): = 33.33 (C-4), 40.90 (C-6), 45.79 (NCH2), 72.34 (q, J = 28.1 Hz, C-5), 94.31 (C-

2), 125.80 (q, J = 285.6 Hz, CF3), 127.06 (Cp), 127.26 (Co), 128.39 (Cm), 137.69 (Ci), 159.37 (C-

3), 189.30 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.39 (s, CF3) ppm. DRA: ν = 3372,

3233 (N–H, O–H), 3076, 2919, 2869 (C–H), 1590, 1575, 1526 (C=O, C=C), 1099–1170 (C–F)

cm-1. HRMS (ESI): calcd. for С14H15F3NO2 [M + H]+ 286.1049; found 286.1049.

3-[(4-Fluorobenzyl)amino]-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aag)

O

HO

F3C

HN

F

Isolated by crystallization (ethanol); Chemical Formula: C14H13F4NO2; White powder; M.P:

182–184 °С; Yield (method A) 482 mg (53%); Yield (method B) 809 mg (89%). 1H NMR (500

MHz, DMSO-d6): = 2.26 (dd, J = 16.2, 1.9 Hz, 1 H, H-6B), 2.47 (d, J = 16.2 Hz, 1 H, H-6A),

2.56 (dd, J = 16.4, 1.9 Hz, 1 H, H-4B), 2.80 (d, J = 16.4 Hz, 1 H, H-4A), 4.25 (d, J = 5.8 Hz, 2

H, NCH2), 4.90 (s, 1 H, H-2), 6.27 (s, 1 H, OH), 7.18 (t, J = 8.9 Hz, 2 H, Hm), 7.35 (dd, J = 8.5,

5.7 Hz, 2 H, Ho), 7.73 (t, J = 5.8 Hz, 1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 33.33

(C-4), 40.91 (C-6), 45.00 (NCH2), 72.35 (q, J = 28.1 Hz, C-5), 94.37 (C-2), 115.14 (d, J = 21.7

Hz, Cm), 125.81 (q, J = 285.7 Hz, CF3), 129.25 (d, J = 7.9 Hz, Co), 133.90 (d, J = 2.5 Hz, Ci),

159.28 (C-3), 161.32 (d, J = 242.5 Hz, Cp), 189.39 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6):

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= 46.83 (tt, J = 8.9, 5.7 Hz, 1 F, CF), 80.37 (s, 3 F, CF3) ppm. DRA: ν = 3321 (N–H, O–H),

3089, 2984, 2798 (C–H), 1598, 1574, 1532, 1512 (C=O, C=C), 1186–1104 (C–F) cm-1. HRMS

(ESI): calcd. for C14H14F4NO2 [M + H]+ 304.0955; found 304.0958.

3-[(3,4-Dimethoxybenzyl)amino]-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aah)

O

HO

F3C

HN

OMe

OMe

Isolated by crystallization (hexane); Chemical Formula: C16H18F3NO4; White powder; M.P: 164–

165 °С; Yield (method A) 425 mg (41%); Yield (method B) 870 mg (84%). 1H NMR (500 MHz,

DMSO-d6): = 2.26 (d, J = 16.2 Hz, 1 H, H-6B), 2.46 (d, J = 16.2 Hz, 1 H, H-6A), 2.56 (d, J =

16.2 Hz, 1 H, H-4B), 2.78 (d, J = 16.2 Hz, 1 H, H-4A), 3.73 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3),

4.17 (d, J = 5.2 Hz, 2 H, NCH2), 4.91 (s, 1 H, H-2), 6.25 (s, 1 H, OH), 6.83 (dd, J = 8.1 Hz, 1 H,

H-6'), 6.90–6.92 (m, 2 H, H-2' and H-5'), 7.64 (t, J = 5.2 Hz, 1 H, NH) ppm. 13C NMR (126

MHz, DMSO-d6): = 33.34 (C-4), 40.91 (C-6), 45.65 (NCH2), 55.43 (OCH3), 55.54 (OCH3),

72.36 (q, J = 28.1 Hz, C-5), 94.29 (C-2), 111.31 (C-2'), 111.75 (C-5'), 119.46 (C-6'), 125.83 (q, J

= 285.9 Hz, CF3), 129.90 (C-1'), 147.95 (C-4'), 148.75 (C-3'), 159.28 (C-3), 189.25 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.43 (CF3) ppm. DRA: ν = 3617, 3368, 3190 (N–H, O–

H), 3016, 2970, 2840 (C-H), 1594, 1569, 1519 (C=O, C=C), 1174–1101 (C–F); HRMS (ESI):


3-[(Furan-2-ylmethyl)amino]-5-hydroxy-5-(trifluoromethyl)cyclohex-2-en-1-one (4aai)

O

HO

F3C

HN

O

Isolated by crystallization (dichloromethane); Chemical Formula: C12H12F3NO3; White powder;

M.P: 179–180 °С; Yield (method A) 421 mg (51%); Yield (method B) 718 mg (87%). 1H NMR

(400 MHz, DMSO-d6): = 2.26 (dd, J = 16.2, 1.8 Hz, 1 H, H-6B), 2.47 (d, J = 16.2 Hz, 1 H, H-

6A, overlapped with DMSO signal), 2.51 (d, J = 16.4 Hz, 1 H, H-4B, overlapped with DMSO

signal), 2.73 (d, J = 16.4 Hz, 1 H, H-4A), 4.24 (d, J = 5.4 Hz, 2 H, NCH2), 5.05 (s, 1 H, H-2),

6.25 (s, 1 H, OH), 6.37 (br. d, J = 3.2 Hz, 1 H, H-3'), 6.42 (dd, J = 3.2, 1.9 Hz, 1 H, H-4'), 7.60–

7.63 (m, 2 H, H-5' and NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 33.22 (C-4), 39.5 (NCH2,

overlapped with DMSO signal), 40.93 (C-6), 72.34 (q, J = 28.1 Hz, C-5), 94.29 (C-2), 108.00

(C-3'), 110.48 (C4'), 125.79 (q, J = 285.5 Hz, CF3), 142.57 (C-5'), 150.64 (C-2'), 159.11 (C-3),

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189.56 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.39 (s, CF3) ppm. DRA: ν = 3390,

3224 (N–H, O–H), 3066, 2929, 2860 (C–H), 1639, 1616, 1524 (C=O, C=C), 1099–1165 (C–F)


5-Hydroxy-3-(pyrrolidin-1-yl)-5-(trifluoromethyl)cyclohex-2-en-1-one (4aaj)

N

O

HOF3C

Isolated by crystallization (acetonitrile); Chemical Formula: C11H14F3NO2; Yelow powder; M.P.

238–240 °C; Yield (method A) 538 mg (72%). 1H NMR (400 MHz, DMSO-d6): = 1.81–1.96

(m, 4 H, CH2), 2.25 (dd, J = 16.0, 1.8 Hz, 1 H, H-6A), 2.43 (d, J = 16.0 Hz, 1 H, H-6B), 2.67

(dd, J = 16.8, 1.8 Hz, 1 H, H-4A), 2.85 (d, J = 16.8 Hz, 1 H, H-4B), 3.09–3.24 (m, 2 H, NCH2),

3.46 (m, 2 H, NCH2), 4.85 (s, 1 H, H-2), 6.21 (s, 1 H, OH) ppm. 13C NMR (126 MHz, DMSO-

d6): = 24.28 and 24.87 (2*CH2), 32.39 (C-4), 40.29 (C-6), 47.58 and 47.98 (NCH2), 72.42 (q, J

= 28.0 Hz, C-5), 95.78 (C-2), 125.81 (q, J = 285.7 Hz, CF3), 157.79 (C-3), 188.10 (C-1) ppm. 19F

NMR (376 MHz, DMSO-d6): = 80.39 (s, CF3) ppm. DRA: ν = 3117, 3233 (N–H, O–H), 2935,

2904, 2873 (C–H), 1596, 1555 (C=O, C=C), 1188–1102 (C–F) cm-1. HRMS (ESI): calcd. for

С11H15F3NO2 [M + H]+ 250.1045; found 250.1049.

5-Hydroxy-3-(piperidin-1-yl)-5-(trifluoromethyl)cyclohex-2-en-1-one (4aak)

N

O

HOF3C

Isolated by crystallization (hexane); Chemical Formula: C12H16F3NO2; White powder; M.P. 187–

189 °С, Yield (method A) 419 mg (53%). 1H NMR (600 MHz, DMSO-d6): = 1.47–1.63 (m, 6

H, CH2), 2.26 (dd, J = 16.0, 1.5 Hz, 1 H, H-6B), 2.46 (d, J = 16.0 Hz, 1 H, H-6A), 2.67 (dd, J =

16.5, 1.5 Hz, 1 H, H-4B), 2.72 (d, J = 16.5 Hz, 1 H, H-4A), 3.29–3.37 (m, 2 H, NCH2,

overlapped with H2O signal), 5.16 (s, 1 H, H-2), 6.20 (s, 1 H, OH) ppm. 13C NMR (151 MHz,

DMSO-d6): = 23.74 and 25.12 (3*CH2), 31.68 (C-4), 40.02 (C-6), 47.26 (2*NCH2), 72.47 (q, J

= 28.0 Hz, C-5), 96.93 (C-2), 125.88 (q, J = 285.9 Hz, CF3), 158.80 (C-3), 189.60 (C-1) ppm. 19F

NMR (376 MHz, DMSO-d6): = 80.41 (s, CF3) ppm. DRA: ν = 3141 (N–H, O–H), 2951, 2928,

2861 (C–H), 1580, 1550 (C=O, C=C), 1181–1103 (C–F); HRMS (ESI): calcd. for С12H17F3NO2

[M + H]+ 264,1206; found 264.1208.

3-(Cyclohexylamino)-5-hydroxy-2-methyl-5-(trifluoromethyl)cyclohex-2-en-1-one (4aba)

S9

HN

O

HOF3C

Me

Isolated by crystallization (hexane); Chemical Formula: C14H20F3NO2; White powder; M.P: 223–

225°С; Yield (method A) 551 mg (63%). 1H NMR (500 MHz, DMSO-d6): = 1.07 (m, 1 H, H

cyclohexyl), 1.25–1.41 (m, 4 H, H cyclohexyl), 1.57–1.62 (m, 1 H, H cyclohexyl), 1.60 (s, 3 H,

CH3), 1.68–1.77 (m, 3 H, H cyclohexyl), 1.82–1.84 (m, 1 H, H cyclohexyl), 2.30 (dd, J = 16.1,

1.9 Hz, 1 H, H-6B, overlapped with DMSO signal), 2.48 (d, J= 16.1 Hz, 1 H, H-6A), 2.69 and

2.76 (AB system, J = 16.6 Hz, 2 H, H-4), 3.28-3.36 (m, 1 H, NCH, overlapped with H2O signal),

5.94 (d, J = 9.0 Hz, 1 H, NH), 6.14 (s, 1 H, OH) ppm. 13C NMR (126 MHz, DMSO-d6): = 8.23

(CH3), 24.74, 24.78 and 24.96 (3*CH2), 30.09 (C-4), 33.62 and 33.56 (2*CH2), 40.14 (C-6),

51.55 (NCH), 71.63 (q, J = 27.8 Hz, C-5), 101.03 (C-2), 125.89 (q, J = 286.2 Hz, CF3), 155.12

(C-3), 186.90 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.34 (s, CF3) ppm. DRA: ν =

3203 (O–H, N–H), 2937, 2845 (C–H), 1554 (C=O, C=C), 1176–1084 (C–F) cm-1. HRMS (ESI):


3-(Cyclopropylamino)-5-hydroxy-2-methyl-5-(trifluoromethyl)cyclohex-2-en-1-one (4abb)

HN

O

HOF3C

Me

Isolated by crystallization (acetonitrile); Chemical Formula: C11H14NO2F3; White powder; M.P.

203–205 °C; Yield (method A) 359 mg (48%); Yield (method B) 725 mg (97%). 1H NMR (500

MHz, DMSO-d6): = 0.63 (br. s, 2 H, H cyclopropyl), 0.71 (br. s, 2 H, H cyclopropyl), 1.56 (s, 3

H, CH3), 2.31 (d, J = 16.1 Hz, 1 H, H-6B), 2.49 (d, J = 16.1 Hz, 1 H, H-6A, overlapped with

DMSO signal), 2.62 (br.s, 1 H, NCH), 2.86 (d, J = 16.6 Hz, 1 H, H-4B), 3.03 (d, J = 16.6 Hz, 1

H, H-4A), 6.17 (s, 1 H, OH), 6.66 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): =

7.39 and 7.61 (2*CH2), 8.08 (CH3), 24.69 (NCH), 30.92 (C-4), 40.36 (C-6), 71.63 (q, J = 27.8

Hz, C-5), 101.77 (C-2), 125.91 (q, J = 285.6 Hz, CF3), 157.72 (C-3), 187.38 (C-1) ppm. 19F

NMR (470 MHz, DMSO-d6): = 80.21 (s, CF3) ppm. DRA: ν = 3325, 3306, 3105 (O–H, N–H),

2962, 2915 (C–H), 1585, 1538 (C=O, C=C), 1169–1075 (C–F) cm-1. HRMS (ESI): calcd. for

С11H15F3NO2 [M + H]+ 250.1049; found 250.1050.

5-Hydroxy-2-methyl-3-(octylamino)-5-(trifluoromethyl)cyclohex-2-en-1-one (4abc)

S10

HN

C8H17

O

HOF3C

Me



MHz, DMSO-d6): = 0.86 (t, J = 7.0 Hz, 3 H, CH3), 1.23–1.30 (m, 10 H, 5 CH2), 1.50 (qw, J =

7.2 Hz, 2 H, CH2), 1.59 (s, 3 H, C2-CH3), 2.30 (dd, J = 16.0, 1.6 Hz, 1 H, H-6B), 2.47 (d, J =

16.0 Hz, 1 H, H-6A), 2.68 and 2.72 (AB system, J = 16.8 Hz, 2 H, H-4), 3.16 (td, J = 7.2, 6.2

Hz, 2 H, NCH2), 6.14 (s, 1 H, OH), 6.42 (t, J = 6.2 Hz, 1 H, NH) ppm. 13C NMR (126 MHz,

DMSO-d6): = 8.11 (C2-CH3), 13.92 (CH3), 22.07, 26.16, 28.61 and 28.67 (4*CH2), 29.95 (C-

4), 30.30 and 31.23 (2*CH2), 40.20 (C-6), 42.61 (NCH2), 71.62 (q, J = 27.9 Hz, C-5), 101.02 (C-

2), 125.90 (q, J = 285.9 Hz, CF3), 156.36 (C-3), 186.69 (C-1) ppm. 19F NMR (376 MHz, DMSO-

d6): = 80.23 (s, CF3) ppm. DRA: ν = 3333 (N–H, O–H), 3064, 2927, 2851 (C–H), 1608, 1528

(C=O, C=C), 1181–1114 (C–F) cm-1. HRMS (ESI): calcd. for С16H27F3NO2 [M + H]+ 322.1988;

found 322.1985.

3-{[2-(Dimethylamino)ethyl]amino}-5-hydroxy-2-methyl-5-(trifluoromethyl)-cyclohex-2-en-1-one (4abe)

HN

O

HOF3C

Me

N(Me)2

Isolated by crystallization (acetonitrile); Chemical Formula: C12H19F3N2O2, White powder; M.P:

172–174 °C; Yield (method A) 538 mg (64%). 1H NMR (500 MHz, DMSO-d6): = 1.58 (s, 3 H,

C2-CH3), 2.20 (s, 6 H, N(CH3)2), 2.31 (dd, J = 16.0, 1.8 Hz, 1 H, H-6B), 2.42 (br. t, J = 6.4 Hz, 2

H, H-3'), 2.48 (d, J = 16.0 Hz, 1 H, H-6A, overlapped with DMSO signal), 2.69 (d, J = 16.7 Hz,

1 H, H-4B), 2.79 (d, J = 16.7 Hz, 1 H, H-4A), 3.29 (q, J = 6.3 Hz, 2 H, H-2'), 6.17 (s, 1 H, OH),

6.22 (br. t, J = 6.2 Hz, 1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 7.83 (C2-CH3),

30.07 (C-4), 40.21 (C-6), 40.31 (C-2'), 45.10 (N(CH3)2), 58.79 (C-3'), 71.56 (q, J = 27.9 Hz, C-

5), 101.17 (C-2), 125.88 (q, J = 285.4 Hz, CF3), 156.16 (C-3), 186.80 (C-1) ppm. 19F NMR (376

MHz, DMSO-d6): = 80.21 (s, CF3) ppm. DRA: ν = 3321, 3219 (N–H, O–H), 2970, 2962, 2879,

2845 (C–H), 1581, 1551 (C=O, C=C), 1182–1079 (C–F) cm-1. HRMS (ESI): calcd. for

С12H20F3N2O2 [M + H]+ 281.1471; found 281.1471.

3-(Benzylamino)-5-hydroxy-2-methyl-5-(trifluoromethyl)cyclohex-2-en-1-one (4abf)

S11

HN

O

HOF3C

Me



MHz, DMSO-d6): = 1.68 (s, 3 H, CH3), 2.32 (dd, J = 16.1, 1.6 Hz, 1 H, H-6B), 2.48 (d, J =

16.1 Hz, 1 H, H-6A, overlapped with DMSO signal), 2.54 (d, J = 16.9 Hz, 1 H, H-4B), 2.66 (d, J

= 16.9 Hz, 1 H, H-4A), 4.46 (d, J = 6.5 Hz, 2 H, NCH2), 6.16 (s, 1 H, OH), 7.09 (t, J = 6.5 Hz, 1

H, NH), 7.24–7.29 (m, 3 H, Ho and Hp), 7.34–7.37 (m, 2 H, Hm) ppm. 13C NMR (126 MHz,

DMSO-d6): = 8.18 (CH3), 30.18 (C-4), 40.27 (C-6), 45.67 (NCH2), 71.55 (q, J = 27.9 Hz, C-5),

101.84 (C-2), 125.78 (q, J = 286.4 Hz, CF3), 126.49 (Co), 126.91 (Cp), 128.50 (Cm), 139.71 (Ci),

156.41 (C-3), 187.15 (C-1) ppm. 19F NMR (470 MHz, DMSO-d6): = 80.19 (s, CF3) ppm.

DRA: ν = 3354 (N–H, O–H), 3085, 2876 (C–H), 1607, 1534 (C=O, C=C), 1130–1087 (C–F) cm-

1. HRMS (ESI): calcd. for С15H17F3NO2 [M + H]+ 300.1203; found 300.1206.

3-[(4-Fluorobenzyl)amino]-5-hydroxy-2-methyl-5-(trifluoromethyl)cyclohex-2-en-1-one (4abg)

O

HO

F3C

HN

Me

F

Isolated by crystallization (ethanol); Chemical Formula: C15H15F4NO2; White powder; M.P:


MHz, DMSO-d6): = 1.67 (s, 3 H, CH3), 2.32 (dd, J = 16.0, 1.6 Hz, 1 H, H-6B), 2.48 (d, J =

16.0 Hz, 1 H, H-6A), 2.55 (d, J = 16.9 Hz, 1 H, H-4B), 2.64 (d, J = 16.9 Hz, 1 H, H-4A), 4.44 (d,

J = 6.4 Hz, 2 H, NCH2), 6.16 (s, 1 H, OH), 7.07 (t, J = 6.4 Hz ,1 H, NH), 7.19 (t, J = 8.9 Hz, 2 H,

Hm), 7.32 (dd, J = 8.5, 5.6 Hz, 2 H, Ho) ppm. 13C NMR (126 MHz, DMSO-d6): = 8.18 (CH3),

30.19 (C-4), 40.20 (C-6), 44.97 (NCH2), 71.56 (q, J = 27.8 Hz, C-5), 101.96 (C-2), 115.24 (d, J

= 21.3 Hz, Cm), 125.78 (q, J = 285.7 Hz, CF3), 128.54 (d, J = 8.1 Hz, Co), 135.89 (d, J = 3.0 Hz,

Ci), 156.26 (C-3), 161.21 (d, J = 242.5 Hz, Cp), 187.24 (C-1) ppm. 19F NMR (376 MHz, DMSO-

d6): = 46.56 (tt, J = 8.9, 5.6 Hz, 1 F, CF), 80.23 (s, 3 F, CF3) ppm. DRA: ν = 3339 (N–H, O–

H), 3084, 2878, 2679 (C–H), 1605, 1526 (C=O, C=C), 1199–1087 (C–F) cm-1. HRMS (ESI):


3-[(Furan-2-ylmethyl)amino]-5-hydroxy-2-methyl-5-(trifluoromethyl)cyclohex-2-en-1-one

(4abi)

S12

O

HO

F3C

HN

O

Me

Isolated by crystallization (dichloromethane); Chemical Formula: C13H14F3NO3; White powder;

M.P: 192–193 °С; Yield (method A) 269 mg (31%); Yield (method B) 738 mg (85%). 1H NMR

(500 MHz, DMSO-d6): = 1.61 (s, 3 H, CH3), 2.34 (d, J = 16.1 Hz, 1 H, H-6B), 2.55 (d, J =

16.1 Hz, 1 H, H-6A, overlapped with DMSO signal), 2.70 (d, J = 16.8 Hz, 1 H, H-4B), 2.81 (d, J

= 16.8 Hz, 1 H, H-4A), 4.37–4.47 (m, 2 H, NCH2), 6.18 (s, 1 H, OH), 6.26 (br. d, J = 2.7 Hz, 1

H, H-3'), 6.42 (br.t, J = 2.4 Hz, 1 H, H-4'), 6.93 (t, J = 6.2 Hz, 1 H, NH), 7.61 (br.s, 1 H, H-5')

ppm. 13C NMR (126 MHz, DMSO-d6): = 8.11 (CH3), 30.02 (C-4), 39.5 (NCH2, overlapped

with DMSO signal), 40.30 (C-6), 71.59 (q, J = 27.9 Hz, C-5), 102.14 (C-2), 106.94 (C-3'),

110.54 (C-4'), 125.84 (q, J = 286.1 Hz, CF3), 142.42 (C-5'), 152.55 (C-2'), 156.03 (C-3), 187.42

(C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.24 (s, CF3) ppm. ATR: ν = 3290, 3205 (N–

H, O–H), 1607, 1524 (C=O, C=C), 1086–1176 (C–F); HRMS (ESI): calcd. for С13H15F3NO3 [M

+ H]+ 290.0999; found 290.1001.

5-Hydroxy-2-methyl-3-(pyrrolidin-1-yl)-5-(trifluoromethyl)cyclohex-2-enone (4abj)

N

O

HOF3C

Me



(m, 2 H, CH2), 1.83 (s, 3 H, CH3), 1.83–1.90 (m, 2 H, CH2), 2.32 (dd, J = 16.0, 1.7 Hz, 1 H, H-

6B), 2.48 (d, J = 16.0 Hz, 1 H, H-6A), 2.79 and 2.82 (AB system, J = 17.3 Hz, 2 H, H-4), 3.46–

3.50 (m, 2 H, NCH2), 3.53–3.58 (m, 2 H, NCH2), 6.11 (s, 1 H, OH) ppm. 13C NMR (126 MHz,

DMSO-d6): = 12.00 (CH3), 25.04 (2*CH2), 34.03 (C-4), 40.39 (C-6), 50.92 (2*NCH2), 70.94

(q, J = 27.9 Hz, C-5), 102.96 (C-2), 125.83 (q, J = 285.7 Hz, CF3), 156.75 (C-3), 189.16 (C-1)

ppm. 19F NMR (470 MHz, DMSO-d6): = 80.34 (s, CF3) ppm. DRA: ν = 3208 (N–H, O–H),

2981, 2880, 2873 (C–H), 1581, 1535, 1516 (C=O, C=C), 1153–1094 (C–F) cm-1. for

С12H17F3NO2 [M + H]+ 264.1206; found 264.1205.

3-{[2-(Dimethylamino)ethyl]amino}-5-hydroxy-2-propyl-5-(trifluoromethyl)-cyclohex-2-en-1-one (4ace)

S13

HN

O

HOF3C

Pr

N(Me)2

Isolated by crystallization (acetonitrile); Chemical Formula: C14H23F3N2O2, White powder; M.P.:


7.4 Hz, 3 H, CH3), 1.23 (sxt, J = 7.4, 2 H, CH2), 2.09–2.18 (m, 2 H, CH2), 2.18 (s, 6 H, 2

N(CH3)2), 2.30 (dd, J = 16.0, 1.8 Hz, 1 H, H-6B), 2.38 (t, J = 6.7 Hz, 2 H, H-3'), 2.47 (d, J = 16.0

Hz, 1 H, H-6A), 2.68 (dd, J = 16.8, 1.8 Hz, 1 H, H-4B), 2.78 (d, J = 16.8 Hz, 1 H, H-4A), 3.26

(q, J = 6.4 Hz, 2 H, H-2'), 6.14 (s, 1 H, OH), 6.26 (t, J = 6.0 Hz, 1 H, NH) ppm. 13C NMR (126

MHz, DMSO-d6): = 13.97 (CH3), 20.70 and 23.82 (2*CH2), 30.04 (C-4), 40.28 (C-6 and C-2'),

44.32 (N(CH3)2), 57.96 (C-3'), 71.56 (q, J = 28.1 Hz, C-5), 107.05 (C-2), 125.88 (q, J = 285.8

Hz, CF3), 155.58 (C-3), 187.23 (C-1) ppm.19F NMR (376 MHz, DMSO-d6): = 80.22 (s, CF3)

ppm. DRA: ν = 3341, 3159 (N–H, O–H), 2960, 2872, 2829 (C–H), 1598, 1544 (C=O, C=C),

1186–1121 (C–F) cm-1. HRMS (ESI): calcd. for С14H24F3N2O2 [M + H]+ 309.1784; found

309.1785.

5-Hydroxy-2-propyl-3-(pyrrolidin-1-yl)-5-(trifluoromethyl)cyclohex-2-en-1-one (4acj)

N

O

HOF3C

Pr

Isolated by crystallization (acetonitrile); Chemical Formula: C14H20F3NO2, White powder; M.P.:


7.3 Hz, 3 H, CH3 propyl), 1.12–1.40 (m, 2 H, CH2 propyl), 1.74–1.91 (m, 4 H, CH2), 2.26 (m, 1

H, CH propyl), 2.32 (d, J = 16.0, 1 H, H-6B), 2.40–2.48 (m, 2 H, CH propyl and H-6A,

overlapped with DMSO signal), 2.80 and 2.82 (AB system, J = 17.3 Hz, 2 H, H-4), 3.42–3.54

(m, 4 H, NCH2), 6.09 (s, 1 H, OH) ppm. 13C NMR (151 MHz, DMSO-d6): = 14.04 (CH3),

23.31 (CH2 propyl), 25.07 (2*CH2), 26.55 (CH2 propyl), 34.29 (C-4), 40.55 (C-6), 50.82

(2*NCH2), 70.90 (q, J = 27.9 Hz, C-5), 108.54 (C-2), 125.85 (q, J = 285.6 Hz, CF3), 155.69 (C-

3), 189.37 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 80.34 (s, CF3) ppm. DRA: ν = 3165

(N–H, O–H), 2962, 2932, 2874 (C–H), 1591, 1519 (C=O, C=C), 1158–1106 (C–F) cm-1. HRMS

(ESI): calcd. for С14H21F3NO2 [M + H]+ 292.1519; found 292.1522.

3-(Cyclohexylamino)-5-hydroxy-5-(difluoromethyl)cyclohex-2-en-1-one (4baa)

S14

HN

O

HOHF2C

Isolated by crystallization (acetonitrile); Chemical Formula: C13H19F2NO2, White powder; M.P:


MHz, DMSO-d6): = 1.10–1.24 (m, 3 H, H cyclohexyl), 1.25-1.36 (m, 2 H, H cyclohexyl),

1.54–1.60 (m, 1 H, H cyclohexyl), 1.65–1.72 (m, 2 H, H cyclohexyl), 1.83–1.86 (m, 2 H, H

cyclohexyl), 2.12 (dd, J = 16.4, 1.6 Hz, 1 H, H-6B), 2.30 (d, J = 16.4 Hz, 1 H, H-6A), 2.34 (d, J

= 16.5 Hz, 1 H, H-4B), 2.54 (d, J = 16.5, 1 H, H-4A), 3.18 (m, 1 H, NCH), 4.89 (s, 1 H, H-2),

5.47 (s, 1 H, OH), 5.79 (t, J = 55.8 Hz, 1 H, CF2H), 7.00 (d, J = 7.0 Hz, 1 H, NH) ppm. 13C

NMR (126 MHz, DMSO-d6): = 24.24, 24.29, 25.21, 31.52, and 31.79 (5*CH2), 33.70 (C-4),

41.49 (C-6), 50.68 (NCH), 71.62 (t, C-5, J = 20.6 Hz), 93.66 (C-2), 116.78 (t, J = 246.1 Hz,

CF2H), 158.82 (C-3), 190.19 (C-1) ppm. 19F NMR (470 MHz, DMSO-d6): = 29.68 and 31.07

(AB system, 2JFF = 275.7 Hz, 2JFH = 55.8 Hz, CF2H) ppm. DRA: ν = 3223 (N–H, O–H), 3062,

2933, 2857 (C–H), 1581, 1547, 1452 (C=O, C=C), 1028–1121 (C–F) cm-1. HRMS (ESI): calcd.

for С13H20F2NO2 [M + H]+ 260.1460; found 260.1457.

5-Hydroxy-3-(pyrrolidin-1-yl)-5-(1,1-difluoromethyl)cyclohex-2-enone (4baj)

N

O

HOF2HC

Isolated by crystallization (acetonitrile); Chemical Formula: C11H15F2NO2; Yelow powder; M.P.


(m, 4 H, CH2), 2.12 (dd, J = 16.1, 1.8 Hz, 1 H, H-6B), 2.29 (d, J = 16.1 Hz, 1 H, H-6A), 2.54

(dd, J = 16.9, 1.8 Hz, 1 H, H-4B), 2.67 (d, J = 16.9 Hz, 1 H, H-4A), 3.09–3.22 (m, 2 H, NCH2),

3.44 (m, 2 H, NCH2), 4.81 (s, 1 H, H-2), 5.50 (s, 1 H, OH), 5.82 (t, J = 55.9 Hz, 1 H, CF2H)

ppm. 13C NMR (126 MHz, DMSO-d6): = 24.29 and 24.88 (2*CH2), 32.59 (t, J = 3.3 Hz, C-4),

40.74 (C-6), 47.54 and 47.85 (2*NCH2), 71.77 (t, J = 20.6 Hz, C-5), 96.16 (C-2), 116.82 (t, J =

246.5 Hz, CF2H), 158.45 (C-3), 189.36 (C-1) ppm. 19F NMR (470 MHz, DMSO-d6): = 30.22

and 30.92 (AB system, 2JFF = 275.0 Hz, 2JFH = 55.9 Hz, CF2H) ppm. DRA: ν = 3110, 3233 (N–

H, O–H), 2987, 2949, 2873 (C–H), 1592, 1547, 1526 (C=O, C=C), 1124–1030 (C–F) cm-1.

HRMS (ESI): calcd. for С11H16F2NO2 [M + H]+ 232.1137; found 232.1144.

3-{[2-(Dimethylamino)ethyl]amino}-5-hydroxy-5-(pentafluoroethyl)cyclohex-2-en-1-one (4cae)

S15

HN

O

HOC2F5 N(Me)2

Isolated by crystallization (acetonitrile); Chemical Formula: C12H17F5N2O2; White powder; M.P.:

223–224 °C with decomposition; Yield (method A) 446 mg (47%). 1H NMR (600 MHz, DMSO-

d6): = 2.18 (s, 6 H, N(CH3)2), 2.33 (d, J = 16.2 Hz, 1 H, H-6B), 2.42 (t, J = 6.5 Hz, 2 H, H-3'),

2.50 (d, J = 16.2 Hz, 1 H, H-6A), 2.62 (d, J = 16.3 Hz, 1 H, H-4B), 2.73 (d, J = 16.3 Hz, 1 H, H-

4A), 3.08 (br. q, J = 6.0 Hz, 2 H, H-2'), 4.92 (s, 1 H, H-2), 6.35 (s, 1 H, OH), 7.14 (br t, J = 5.2

Hz, 1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 33.45 (C-4), 40.38 (C-2'), 40.98 (C-6),

45.07 (N(CH3)2), 56.60 (C-3'), 73.46 (q, J = 22.6 Hz, C-5), 93.40 (C-2), 114.23 (tq, J = 261.6,

34.1 Hz, CF2), 119.22 (qt, J = 288.3, 36.6 Hz, CF3), 159.37 (C-3), 188.83 (C-1) ppm.19F NMR

(376 MHz, DMSO-d6): = 38.36 and 39.02 (AB system, J = 273.10 Hz, 2 F, CF2,), 85.17 (s, 3 F,

CF3) ppm. DRA: ν = 3248 (N–H, O–H), 3090, 2992, 2880 (C–H), 1610, 1555 (C=O, C=C),

1173–1068 (C–F) cm-1. HRMS (ESI): calcd. for C12H18F5N2O2 [M + H]+ 317.1283; found

317.1286.

5-Hydroxy-5-(pentafluoroethyl)-3-(pyrrolidin-1-yl)cyclohex-2-en-1-one (4caj)

N

O

HOC2F5



MHz, DMSO-d6): = 1.82–1.95 (m, 4 H, CH2), 2.32 (br. d, J = 16.2 Hz, 1 H, H-6B), 2.47 (d, J =

16.2 Hz, 1 H, H-6A), 2.73 (d, J = 16.7, 1.7 Hz, 1 H, H-4B), 2.89 (d, J = 16.7 Hz, 1 H, H-4A),

3.10-3.25 (m, 2 H, NCH2), 3.45–3.48 (m, 2 H, NCH2), 4.87 (s, 1 H, H-2), 6.34 (s, 1 H, OH) ppm. 13C NMR (126 MHz, DMSO-d6): = 24.23 and 24.81 (2*CH2), 32.41 (C-4), 40.47 (C-6), 47.50

and 48.02 (2*NCH2), 73.54 (t, J =22.8 Hz, C-5), 95.70 (C-2), 114.23 (tq, J = 261.3, 33.8 Hz,

CF2), 119.19 (qt, J = 288.2, 36.6 Hz, CF3), 157.70 (C-3), 187.84 (C-1) ppm. 19F NMR (470

MHz, DMSO-d6): = 38.06 (d, J = 272.7 Hz, 1 F, CFB), 39.41 (d, J = 272.7 Hz, 1 F, CFA), 85.27

(s, 3 F, CF3) ppm. DRA: ν = 3115 (N–H, O–H), 2978, 2877 (C–H), 1557 (C=O, C=C), 1211–

1103 (C–F) cm-1. HRMS (ESI): calcd. for С12H15F5NO2 [M + H]+ 300.1018; found 300.1019.

3-(Cyclohexylamino)-5-hydroxy-5-(1,1,2,2-tetrafluoroethyl)cyclohex-2-en-1-one (4daa)

S16

HN

O

HOH(F2C)2



(m, 5 H, H cyclohexyl), 1.55–1.60 (m, 1 H, H cyclohexyl), 1.65–1.73 (m, 2 H, H cyclohexyl)

1.83–1.87 (m, 2 H, H cyclohexyl), 2.26 (d, J = 16.3 Hz, 1 H, H-6B), 2.41(d, J = 16.3 Hz, 1 H, H-

6A), 2.51 (d, J = 16.4 Hz, 1 H, H-4B, overlapped with DMSO signal), 2.64 (d, J = 16.4, 1 H, H-

4A), 3.19 (m, 1 H, NCH), 4.92 (s, 1 H, H-2), 6.17 (s, 1 H, OH), 6.55 (tt, J = 52.1, 6.2 Hz, 1 H,

(CF2)2H), 7.09 (d, J = 7.3 Hz, 1 H, NH) ppm. 13C NMR (126 MHz, DMSO-d6): = 24.21, 24.25,

25.20, 31.45 and 31.78 (5*CH2), 33.50(C-4), 40.92 (C-6), 50.73 (NCH), 72.92 (t, J = 23.4 Hz, C-

5), 93.41 (C-2), 109.23 (tt, J = 248.3, 30.9 Hz, CF2H), 116.07 (tt, J = 256.4, 23.6 Hz, CF2),

158.42 (C-3), 189.27 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 25.87 and 26.69 (AB

system, both ddm, 2JFF = 301.0 Hz, 2JFH = 52.1 Hz, 2 F, HCF2), 32.15 and 33.18 (AB system,

both dm, J = 262.8 Hz, 2 F, CF2) ppm. DRA: ν = 3284 (N–H, O–H), 3077, 2946, 2861 (C–H),

1585, 1538, 1452 (C=O, C=C), 1135–1074 (C–F) cm-1. HRMS (ESI): calcd. for С14H20F4NO2

[M + H]+ 310.1424; found 310.1425.

5-Hydroxy-3-(pyrrolidin-1-yl)-5-(1,1,2,2-tetrafluoroethyl)cyclohex-2-enone (4daj)

N

O

HOH(F2C)2



(m, 4 H, CH2), 2.27 (br. d, J = 16.2 Hz, 1 H, H-6B), 2.38 (d, J = 16.2 Hz, 1 H, H-6A), 2.69 (br.

d, J = 17.0, 1.4 Hz, 1 H, H-4B), 2.80 (d, J = 17.0 Hz, 1 H, H-4A), 3.10–3.24 (m, 2 H, NCH2),

3.45 (m, 2 H, NCH2), 4.85 (s, 1 H, H-2), 6.16 (s, 1 H, OH), 6.60 (tt, J = 51.9, 6.3 Hz, 1 H,

(CF2)2H) ppm. 13C NMR (126 MHz, DMSO-d6): = 24.28 and 24.86 (2*CH2), 32.32 (q, J = 3.1

Hz, C-4), 40.46 (C-6), 47.54 and 47.98 (2*NCH2), 73.05 (t, J = 23.7 Hz, C-5), 95.89 (C-2),

109.21 (tt, J = 248.7, 30.7 Hz, CF2H), 116.06 (tt, J = 257.2, 22.9 Hz, CF2), 158.01 (C-3), 188.48

(C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 25.72 (ddt, 1 F, HCFB, J = 300.9, 51.9, 7.8 Hz),

27.20 (ddt, 1 F, HCFA, J = 300.6, 51.9, 7.2 Hz), 32.81 (br. q, J = 7.5 Hz 2 F, CF2) ppm. DRA: ν

= 3228 (N–H, O–H), 3020, 2988, 2958, 2881 (C–H), 1586, 1558 (C=O, C=C), 1118–1065 (C–F)


S17

5-Hydroxy-5-(heptafluoropropyl)-3-(pyrrolidin-1-yl)cyclohex-2-en-1-one (4eaj)

N

O

HOC3F7


212 °C with decomposition; Yield (method A) 220 mg (21%). 1H NMR (600 MHz, DMSO-d6):

= 1.80–1.94 (m, 4 H, CH2), 2.34 (d, J = 16.0 Hz, 1 H, H-6B), 2.49 (d, J = 16.0 Hz, 1 H, H-6A,

overlapped with DMSO signal), 2.76 (d, J = 16.7 Hz, 1 H, H-4B), 2.92 (d, J = 16.7 Hz, 1 H, H-

4A), 3.10–3.25 (m, 2 H, NCH2), 3.43–3.49 (m, 2 H, NCH2), 4.87 (s, 1 H, H-2), 6.41 (s, 1 H, OH)

ppm. 13C NMR (151 MHz, DMSO-d6): = 24.27 and 24.86 (2*CH2), 32.46 (C-4), 40.53 (C-6),

47.53 and 48.06 (2*NCH2), 74.66 (q, J = 23.2 Hz, C-5), 95.71 (C-2), 110.04 (tm, J = 267.8 Hz,

CF2), 115.65 (tt, J = 261.8, 28.6 Hz, CF2), 117.53 (qt, J = 288.1, 33.9 Hz, CF3), 157.70 C-3),

187.80 (C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 39.47 and 39.78 (AB system, 2JFF =

289.9 Hz, 2 F, CF2), 41.65 and 42.54 (AB system, 2JFF = 278.8 Hz, 2 F, CF2), 82.52 (t, J = 10.3

Hz, 3 F, CF3) ppm. DRA: ν = 3094 (N–H, O–H), 2996, 2874 (C–H), 1594, 1558 (C=O, C=C),

1205–1100 (C–F) cm-1. HRMS (ESI): calcd. for С12H15F7NO2 [M + H]+ 350.2520; found

350.2523.

Cyclohexanaminium 3-hydroxy-5-oxo-3-(trifluoromethyl)hexanoate (5a)

F3COH

O-

O

Me

O

NH312

3

45

6

Chemical Formula: C13H22F3NO4; White powder; M.P. 124–126°C; Yield 620 mg (66%). 1H

NMR (500 MHz, DMSO-d6): = 1.18–1.29 (m, 5 H, H cyclohexyl), 1.57 (m, 1 H, H

cyclohexyl), 1.66–1.92 (m, 4 H, H cyclohexyl), 2.11 (d, J = 16.0 Hz, 1 H, H-2B), 2.17 (s, 3 H,

H-6), 2.34 (d, J = 16.0 Hz, 1 H, H-2A), 2.37 ( d, J = 13.0 Hz, 1 H, H-4B), 2.72 (d, J = 13.0 Hz, 1

H, H-4A), 2.92 (m, 4 H, NCH2), 7.98 (br. s, 3 H, NH3+), 10.63 (br. s, 1 H, OH), ppm. 19F NMR

(376 MHz, DMSO-d6): = 81.96 (s, CF3) ppm. DRA: ν = 3252 (O–H, N–H), 3005, 2937, 2859

(C–H), 2582, 2526 (NH3+), 1703, 1658 (C=O), 1177–1156 (C–F) cm-1. HRMS (ESI): calcd. for

С13H23F3NO4 [M + H]+ 314.1574; found 314.1576.

Cyclohexanaminium 3-hydroxy-5-oxo-3-(trifluoromethyl)heptanoate (5b)

S18

F3COH

O-

O

Et

O

NH3

Chemical Formula: C14H24F3NO4; White powder; M.P. 156–158°C; Yield 766 mg (78%). 1H

NMR (500 MHz, DMSO-d6): = 0.88 (t, J = 7.2 Hz, 3 H, H-7), 1.03–1.12 (m, 1 H, H

cyclohexyl), 1.19–1.29 (m, 4 H, H cyclohexyl), 1.56–1.60 (m, 1 H, H cyclohexyl), 1.68–1.73 (m,

2 H, H cyclohexyl), 1.85–1.91 (m, 2 H, H cyclohexyl), 2.11 (d, J = 16.0 Hz, 1 H, H-2B), 2.34 (d,

J = 13.1 Hz, 1 H, H-4B), 2.41 (dq, J = 16.0, 1.2 Hz, 1 H, H-2A), 2.56 (q, J = 7.2 Hz, 2 H, H-6),

2.73 (d, J = 13.1 Hz, 1 H, H-4A), 2.96 (m, 1 H, NCH), 8.01 (br s, 3 H, NH3+), 10.44 (br s, 1 H,

OH) ppm. 13C NMR (126 MHz, DMSO-d6): = 7.36 (C-7), 23.78, 24.59 and 30.47 (3*CH2),

36.60 (C-2), 37.67 (C-6), 46.65 (C-4), 49.13 (NCH), 72.13 (q, J =27.2 Hz, C-3), 126.42 (q, J =

287.9 Hz, CF3), 173.34 (C-1), 207.93 (C-5) ppm. 19F NMR (470 MHz, DMSO-d6): = 81.88 (s,

CF3) ppm. DRA: ν = 3235 (O–H, N–H), 3036, 2977, 2859 (C–H), 1702, 1659 (C=O), 1175–

1128 (C–F) cm-1. HRMS (ESI): calcd. for С14H21F3NO2 [M-H2O + H]+ 292.1519; found

292.1520.

Piperidinium 3-hydroxy-5-oxo-3-(trifluoromethyl)hexanoate (5c)

F3COH

O-

O

Me

O

H2N

Chemical Formula: C12H20F3NO4; White powder; M.P. 108–109 °C; Yield 736 mg (82%). 1H

NMR (500 MHz, DMSO-d6): = 1.50–1.68 (m, 6 H, CH2), 2.14 (d, J = 17.0 Hz, 1 H, H-2B),

2.17 (s, 3 H, H-6), 2.38 (d, J = 17.0 Hz, 1 H H-2A), 2.385 (d, J = 13.0 Hz, 1 H, H-4B), 2.73 (d, J

= 13.0 Hz, 1 H, H-4A), 2.97 (m, 4 H, NCH2), 8.4–11.0 (3 H, NH2+ and OH), ppm. 13C NMR

(126 MHz, DMSO-d6): = 21.76 and 22.24 (2*CH2), 32.33 (C-6), 36.67 (C-2), 43.49 (2*NCH2),

47.75 (C-4), 72.10 (q, J = 27.3 Hz, C-3), 126.34 (q, J = 287.8 Hz, CF3), 173.30 (C-1), 205.59 (C-

5) ppm. 19F NMR (470 MHz, DMSO-d6): = 81.95 (s, CF3) ppm. DRA: ν = 2960, 2930, 2864

(C–H), 2531, 2457 (NH2+), 1710, 1636 (C=O), 1192–1112 (C–F) cm-1. HRMS (ESI): calcd. for

С12H21F3NO4 [M + H]+ 300.1417; found 300.1419.

Ethyl 3-hydroxy-5-oxo-3-(trifluoromethyl)hexanoate (6a)

OEtF3C

OHO

O

Me

S19

Chemical Formula: C9H13F3O4; Yellow oil, 2059 mg (85%). Spectral data correspond to the

previously reported3 [α]D = +0.59 (c = 1.0, CH2Cl2). HPLC: 3.8% ee, Chiralcel ODH-3, hexane :

iPrOH = 100:1, flow rate = 1.0 mL/min, T = 24 °C, UV = 220 nm, tR = 11.25 min (major), tR =

13.52 min (minor).

Ethyl 3-hydroxy-5-oxo-3-(difluoromethyl)hexanoate (6b)

OEtHF2C

OHO

O

Me

Chemical Formula: C9H14F2O4; Yellow oil, 1390 mg (62%). [α]D = +3.09 (c = 1.0, CH2Cl2). 1H

NMR (500 MHz, CDCl3): = 1.28 (t, J = 7.1 Hz, 3 H, CH3), 2.26 (s, 3 H, H-6), 2.68 and 2.70

(AB system, J = 15.4 Hz, 2 H, CH2), 2.90 (s, 2 H, CH2), 4.17 (q, J = 7.1 Hz, 2 H, OCH2), 4.96 (s,

1 H, OH), 5.86 (t, J = 56.0 Hz, 1 H, CF2H) ppm. 13C NMR (126 MHz, CDCl3): = 13.98 (CH3),

31.92 (C-6), 38.00 (t, J = 2.9 Hz, C-2), 44.06 (t, J = 2.2 Hz, C-4), 61.13 (OCH2), 72.88 (t, J

=22.0 Hz, C-3), 115.86 (t, J = 248.5 Hz, CF2H), 170.60 (C-1), 208.65 (C-5) ppm. 19F NMR (470

MHz, CDCl3): = 29.84 and 30.15 (AB system, 2JFF = 281.5 Hz, 2JFH = 56.0 Hz, CF2H) ppm.

ATR: ν = 3449 (OH, NH), 2986, 2938, 2911 (C-H), 1728, 1709 (C=O), 1068-1029 (C-F) cm-1.

HRMS (ESI): calcd. for С9H15F2O4 [M + H]+ 225.0931; found 225.0933. HPLC: 10.8% ee,

Kromasil 5-Cellucoat, MeOH : H2O = 40:60, flow rate = 0.5 mL/min, T = 24 °C, UV = 220 nm,

tR = 25.41 min (major), tR = 27.22 min (minor).

Ethyl 3-hydroxy-5-oxo-3-(pentafluoroethyl)hexanoate (6c)

OEtC2F5

OHO

O

MeChemical Formula: C10H13F5O4; Yellow oil, 1717 mg (67%). [α]D = - 1.48 (c = 1.0, CH2Cl2). 1H

NMR (500 MHz, CDCl3): = 1.28 (t, J = 7.1 Hz, 3 H, CH3), 2.29 (s, 3 H, H-6), 2.83 (d, J = 15.5

Hz, 1 H, CH), 2.88 (dd, J = 15.5, 1.5 Hz, 1 H, CH), 3.02 (d, J = 16.4 Hz, 1 H, CH), 3.11 (d, J =

16.4, 1.5 Hz, 1 H, CH), 4.18 (q, J = 7.1 Hz, 2 H, OCH2), 5.96 (br s, 1 H, OH) ppm. 13C NMR

(126 MHz, CDCl3): = 13.82 (CH3), 32.00 (C-6), 37.49 (C-2), 43.00 (C-4), 61.30 (OCH2), 75.03

(t, J = 23.8 Hz, C-3), 114.21 (tq, J = 262.3, 35.0 Hz, CF2), 119.02 (qt, J = 287.9, 36.0 Hz, CF3),

170.44 (C-1), 208.61 (C-5) ppm. 19F NMR (470 MHz, CDCl3): = 39.04 and 39.77 (AB system,

J = 279.7 Hz, 2 F, CF2), 83.75 (s, 3 F, CF3) ppm. ATR: ν = 3366 (OH, NH), 2988, 2944, 2909

(C-H), 1731, 1713 (C=O), 1216-1146 (C-F) cm-1. HRMS (ESI): calcd. for С10H14F5O4 [M + H]+

S20

293.2072; found 293.2073. HPLC: 13.6% ee, Chirapak AD, hexane : iPrOH = 100:1, flow rate =

1.0 mL/min, T = 24 °C, UV = 220 nm, tR = 8.85 min (minor), tR = 10.27 min (major).

Ethyl 3-hydroxy-5-oxo-3-(trifluoromethyl)heptanoate (6d)

OEtF3C

OHO

O

Et

Chemical Formula: C9H15F3O4; Yellow oil; Yield 2396 mg (82%). [α]D = -2.88 (c = 1.0,

CH2Cl2). 1H NMR (500 MHz, CDCl3): = 1.07 (t, J = 7.2 Hz, 3 H, H-7), 1.28 (t, J = 7.2 Hz, 3

H, CH3), 2.53–2.65 (m, 2 H, H-6), 2.76 and 2.84 (AB system, J = 15.3 Hz, 2 H, CH2), 2.93 and

2.98 (AB system, J = 16.1 Hz, 2 H, CH2), 4.18 (q, J = 7.2 Hz, 2 H, OCH2), 5.82 (s, 1 H, OH)

ppm. 13C NMR (126 MHz, CDCl3): = 7.15 (С-7), 13.96 (CH3), 37.44 (C-2), 38.27 (C-6), 42.05

(C-4), 61.37 (OCH2), 73.85 (q, J =29.1 Hz, C-3), 125.03 (q, J = 286.1 Hz, CF3), 170.37 (C-1),

210.97 (C-5) ppm. 19F NMR (470 MHz, CDCl3): = 79.54 (s, CF3) ppm. ATR: ν = 3382 (O–H),

2985, 29448 (C–H), 1731, 1716 (C=O), 1173–1107 (C–F) cm-1. HRMS (ESI): calcd. for

С10H16F3O4 [M + H]+ 257.0996; found 257.0995. HPLC: 21.8% ee, Chiralcel ODH-3, hexane :

iPrOH = 50:1, flow rate = 1.0 mL/min, T = 24 °C, UV = 230 nm, tR = 6.58 min (minor), tR =

7.47 min (major).

Diethyl 3,7-dihydroxy-5-oxo-3,7-bis(trifluoromethyl)nonanedioate (7).

OCF3 CF3

OHOEt

O

EtO

O

OH

To a solution of ester 1a (10 mmol) and methyl ketone 3a (30 mmol) in toluene (15 mL) was

added L-proline (0.1 mmol) and the reaction mixture was kept under reflux for 2 days. After the

reaction was complete (TLC monitoring), the solvent was evaporated and the residue was

purified by column chromatography (eluent chloroform). The first fraction contains the product

6a, and the second fraction - the product 7.

Chemical Formula: C15H20F6O7; Brown oil, 1449 mg (34%). Mixture of two diastereomers, ratio

~ 1:1. 1H NMR (500 MHz, CDCl3): = 1.29 (t, J = 7.1 Hz, 6 H, CH3), 2.75 and 2.76 (both d, J =

15.9 Hz, 2 H, 2*CH), 2.87 (d, J = 15.9 Hz, 1 H, CH), 2.92 (d, J = 15.9 Hz, 1 H, CH), 2.96 and

3.00 (both d, J = 16.0 Hz, 2 H, 2*CH), 3.13 and 3.14 (both d, J = 16.0 Hz, 2 H, 2*CH), 4.17-

4.23 (m, 4 H, OCH2), 5.56 (br.s, 2 H, OH) ppm. 13C NMR (126 MHz, CDCl3): = 13.94 (CH3),

36.30 and 36.50 (C-2, 8), 45.66 and 45.76 (C-4, 6), 61.64 (OCH2), 73.57 (q, J = 29.2 Hz, C-3, 7),

124.84 and 124.86 (both q, J = 286.0 Hz, CF3), 170.77 and 170.83 (C-1, 9), 207.34, 206.73 (C-5)

ppm. 19F NMR (470 MHz, CDCl3): = 79.58 and 79.59 (both s, CF3) ppm. ATR: ν = 3441, 3290

S21

(O–H), 2990 (C–H), 1714 (C=O), 1174–1122 (C–F). HRMS (ESI): calcd. for С15H21F6O7 [M +

H]+ 427.1185; found 427.1186.

Pyrrolidinium 5-Hydroxy-2-propyl-5-(trifluoromethyl)cyclohex-1-one-3-olate (8)

O

OPr

HO

F3C - H2N

To a solution of the corresponding 3-oxo ester 1a (3 mmol) and 2-hexanone 2c (3 mmol) in 95%

ethanol (15 mL) was added pyrrolidine 3c (3 mmol) and the reaction mixture was stirred for 2–3

days at room temperature (25 °C). After the reaction was complete (TLC monitoring), the solvent

was evaporated and the residue was washed with diethyl ether and crystallized from acetonitrile.

Chemical Formula: C14H22F3NO3; White powder; M.P. 169–170 °C; Yield (method A) 278 mg

(30%). 1H NMR (500 MHz, DMSO-d6): = 0.78 (t, J = 7.3 Hz, 3 H, CH3 propyl), 1.24 (sxt, 2 H,

CH2 propyl), 1.75–1.82 (m, 4 H, 2*CH2), 2.07 (m, 2 H, CH2 propyl), 2.24 (d, J = 16.3 Hz, 2 H,

H-4B, H-6B), 2.45 (d, J = 16.3 Hz, 2 H, H-4A, H-6A), 2.96–3.04 (m, 4 H, NCH2), 5.01–6.96

(NH2 + H2O) ppm. 13C NMR (126 MHz, DMSO-d6): = 14.37 (CH3), 21.94 (CH2 propyl),

24.03 (CH2), 24.64 (CH2 propyl), 39.59 (C-4, 6), 45.09 (NCH2), 71.76 (q, J = 27.4 Hz, C-5),

110.21 (C-2), 126.32 (q, J = 285.2 Hz, CF3), 182.28 (C-1, 3) ppm. 19F NMR (470 MHz, DMSO-

d6): = 80.25 (s, CF3) ppm. DRA: ν = 3119 (NH), 2958, 2749 (C–H), 2583, 2462 (NH2+), 1605,

1575 (C=O), 1174–1092 (C–F) cm-1. HRMS (ESI): calcd. for С14H21F3NO3 [M - H]+ 308.1468;

found 308.1463.

3-(Propylamino)-5-(trifluoromethyl)phenol (9a)

HN

Pr

OH

F3C

Chemical Formula: C10H12F3NO; White powder; M.P. 65–66 °С; Yield (method C) 207 mg

(63%). 1H NMR (400 MHz, CDCl3): = 0.99 (t, J = 7.4 Hz, 3 H, CH3), 1.65 (sxt, J = 7.4 Hz, 2

H, CH2), 3.08 (t, J = 7.3 Hz, 2 H, NCH2), 4.88 (br. s, 2 H, NH and OH), 6.34 (br. t, J = 2.3 Hz, 1

H, H-2), 6.45 (br. t, J = 2.3 Hz, 1 H, H-6), 6.49 (br. t, J = 2.3 Hz, 1 H, H-4) ppm. 19F NMR (376

MHz, CDCl3): = 98.57 (s, CF3) ppm. DRA: ν = 3396, 3340 (O–H, N–H), 3074, 2966, 2879

(C–H), 1615, 1597 (C=C), 1180–1104 (C–F) cm-1. HRMS (ESI): calcd. for С10H13F3NO [M +

H]+ 220.0944; found 220.0947.

3-(Octylamino)-5-(trifluoromethyl)phenol (9b)

S22

HN

C8H17

OH

F3C

Chemical Formula: C15H22F3NO; Brown oil; Yield (method C) 321 mg (74%). 1H NMR (500

MHz, CDCl3): = 0.88 (t, J = 7.0 Hz, 3 H, CH3), 1.24–1.40 (m, 10 H, 5 CH2), 1.61 (qw, J = 7.5

Hz, 2 H, CH2), 3.09 (t, J = 7.2 Hz, 2 H, NCH2), 4.63 (br. s, 2 H, NH and OH), 6.28 (br. s, 1 H,

H-2), 6.42 (br. s, 1 H, H-6), 6.45 (br. s, 1 H, H-4) ppm. 13C NMR (126 MHz, CDCl3): = 14.05

(CH3), 22.62, 27.01, 29.02, 29.19, 29.29 and 31.77 (6*CH2), 44.47 (NCH2), 100.89 (q, J = 3.6

Hz, C-6), 102.72 (C-2), 103.05 (q, J = 3.9 Hz, C-4), 123.90 (q, J = 272.5 Hz, CF3), 132.66 (q, J

= 32.0 Hz, C-5), 149.15 (C-3), 156.92 (C-1) ppm. 19F NMR (470 MHz, CDCl3): = 98.61 (s,

CF3) ppm. ATR: ν = 3412, 3348 (O–H, N–H), 2956, 2929, 2857 (C–H), 1621, 1605 (C=C),

1172–1127 (C–F) cm-1. HRMS (ESI): calcd. for С15H23F3NO [M + H]+ 290.1726; found

290.1727.

3-(Dodecylamino)-5-(trifluoromethyl)phenol (9c)

HN

C12H25

OH

F3C

Chemical Formula: C19H30F3NO; White powder; M.P. 59–61 °С; Yield (method D) 357 mg

(69%). 1H NMR (400 MHz, DMSO-d6): = 0.85 (t, J = 6.7 Hz, 3 H, CH3), 1.21–1.37 (m, 18 H,

9 CH2), 1.51 (qw, J = 7.1 Hz, 2 H, CH2), 2.95 (br. q, J = 6.3 Hz, 2 H, NCH2), 5.94 (t, J = 5.7 Hz,

1 H, NH), 6.15-6.18 (m, 2 H, H arom), 6.28 (s, 1 H, H arom.), 9.53 (s, 1 H, OH) ppm. 13C NMR

(151 MHz, DMSO-d6): = 13.91 (CH3), 22.07, 26.58, 28.44, 28.69, 28.82, 28.99, 29.01, 29.04

and 31.28 (10*CH2), 42.59 (NCH2), 98.77 (q, J = 4.0 Hz C-4/6), 99.69 (q, J = 4.0 Hz, C-6/4),

101.13 (C-2), 124.47 (q, J = 272.1 Hz, CF3), 130.39 (q, J = 3.7 Hz, C-5), 150.78 (C-3), 158.63

(C-1) ppm. 19F NMR (376 MHz, DMSO-d6): = 100.96 (s, CF3) ppm. DRA: ν = 3292 (O–H, N–

H), 3090, 2918, 2853 (C–H), 1609 (C=C), 1181–1127(C–F) cm-1. HRMS (ESI): calcd. for

С19H31F3NO [M + H]+ 346.4502; found 346.4504.

3-(Cyclohexylamino)-5-(trifluoromethyl)phenol (9d)

HN

OH

F3C

S23

Chemical Formula: C13H16F3NO; White powder; M.P. 93–94 °С; Yield (method C) 296 mg

(76%). 1H NMR (500 MHz, CDCl3): = 1.11–1.41 (m, 5 H, H cyclohexyl), 1.65–1.79 (m, 3 H,

H cyclohexyl), 2.00–2.05 (m, 2 H, H cyclohexyl), 3.22 (tt, J = 10.1, 3.8 Hz, 1 H, NCH), 3.5–5.2

(2 H, OH and NH), 6.18 (t, J = 2.2 Hz, 1 H, H-2), 6.33 (br. t, J = 2.2 Hz, 1 H, H-6), 6.38 (br. t, J

= 2.2 Hz, 1 H, H-4) ppm. 13C NMR (126 MHz, CDCl3): = 24.86, 25.75 and 33.18 (C

cyclohexyl), 51.61 (NCH), 100.49 (q, J = 3.8 Hz, C-6), 102.04 (C-2), 102.94 (q, J = 3.9 Hz, C-

4), 123.99 (q, J = 272.6 Hz, CF3), 132.61 (q, J = 31.9 Hz, C-5), 149.08 (C-3), 156.80 (C-1) ppm. 19F NMR (470 MHz, CDCl3): = 98.59 (s, CF3) ppm. ATR: ν = 3270 (O–H, N–H), 3081, 2933,

2858 (C–H), 1582, 1575, 1536 (C=C), 1179–1114 (C–F) cm-1. HRMS (ESI): calcd. for

С13H17F3NO [M + H]+ 260.1257; found 260.1257.

3-(Benzylamino)-5-(trifluoromethyl)phenol (9e)

HN

OH

F3C

Chemical Formula: C14H12F3NO; Brown oil; Yield (method C) 261 mg (65%). 1H NMR (500

MHz, CDCl3): = 4.31 (s, 2 H, NCH2), 4.23 and 5.02 (each br.s, 1 H, NH and OH), 6.19 (br. t, J

= 2.2 Hz, 1 H, H-2), 6.39 (br. s, 1 H, H-6), 6.46 (br. s, 1 H, H-4), 7.27–7.37 (m, 5 H, C6H5) ppm. 13C NMR (126 MHz, CDCl3): = 48.06 (NCH2), 101.33 (q, J = 3.5 Hz, C-6), 102.01 (C-2),

102.75 (q, J = 3.9 Hz, C-4), 123.92 (q, J = 273.4 Hz, CF3), 127.44 (Co), 125.54 (Cp), 128.78

(Cm), 123.61 (q, J = 32.1 Hz, C-5), 138.36 (Ci), 149.78 (C-3), 156.82 (C-1) ppm. 19F NMR (470

MHz, CDCl3): = 98.60 (s, CF3) ppm. ATR: ν = 3419 (O–H, N–H), 3065, 3032, 2859 (C–H),

1622, 1606 (C=C), 1179–1114 (C–F) cm-1. HRMS (ESI): calcd. for С14H13F3NO [M + H]+

268.0945; found 268.0944.

3-(Pyrrolidin-1-yl)-5-(trifluoromethyl)phenol (9f)

N

OH

F3C

Chemical Formula: C11H12F3NO; Beige powder; M.P. 143–145 °С; Yield (method C) 232 mg

(67%). 1H NMR (500 MHz, CDCl3): = 1.97-2.04 (m, 4 H, CH2), 3.23–3.30 (m, 4 H, NCH2),

4.95 (br. s, 1 H, OH), 6.14 (br. t, J = 2.2 Hz, 1 H, H-2), 6.34–6.36 (m, 2 H, H-4 and H-6) ppm. 13C NMR (126 MHz, CDCl3): = 25.40 (CH2), 47.69 (NCH2), 99.19 (q, J = 3.8 Hz, C-6), 101.05

(C-2), 101.42 (q, J = 4.0 Hz, C-4), 124.20 (q, J = 272.5 Hz, CF3), 132.36 (q, J = 31.7 Hz, C-5),

S24

149.27 (C-3), 156.54 (C-1) ppm. 19F NMR (470 MHz, CDCl3): = 98.78 (s, CF3) ppm. DRA: ν

= 3163 (O–H, N–H), 3075, 2962, 2885 (C–H), 1623 (C=C), 1168-1117 (C-F) cm-1. HRMS

(ESI): calcd. for С11H13F3NO [M + H]+ 232.0941; found 232.0944.

Antifungal activity assay. The following fungal strains were used: Trichophyton rubrum (RCPF F-1408), Trichophyton mentagrophytes var. gypseum (RCPF F-1425), Trichophyton tonsurans (RCPF F-1458), Trichophiton violaceum (RCPF F-1393/658), Trichophyton mentagrophytes var. interdigitale (RCPF F-1229), Epidermophyton floccosum (RCPF F-1174), Microsporum canis (RCPF F-1403), Candida albicans (RCPF Y -401/NCTC 885-653). The fungal strains were obtained from Russian Collection of Patogenic Fungi (RCPF), Kashkin Research Institute of Medical Mycology (St. Peterburg, Russia). Fungi were cultivated at 27 °C on Sabouraud Dextrose Agar (SDA) and MIC was determined by using Sabouraud Dextrose Broth (SDB). The test and standard compounds were dissolved in dimethylsulfoxide (DMSO, 1/10) and applied in different concentrations (1000–0.19 μg/mL). Dimethylsulfoxide was used as a negative control and antifungal drug Terbinafine as a positive control. The broth dilution test was performed in test tubes. The inoculum suspension, which gave the final concentration of 1 x 108 CFU/mL, was prepared. A growth control tube and sterility control tube were used in each test. After 14 days incubation at 27 °C, MIC was determined visually as the lowest concentration that inhibited the growth, evidenced by the absence of turbidity.

Antibacterial activity assay. Assays were performed using reference strain Neisseria gonorrhoeae NCTC 12700 from the National Collection of Type Cultures (NCTC, UK). Microorganisms were identified with an accuracy of 99.9% using a VITEK MS MALDI-TOF Plus analyzer (BioMerieux, France) by flight mass spectrometry of samples embedded in a matrix of bacterial proteins. The inocolum of N. gonorrhoeae was prepared from an overnight culture using a DensiCHEK™ Plus densitometer (BioMerieux, France), the optical density of the inoculums was 0.5 MacFarland standard, which corresponds to 1 x 108 CFU/mL. The inocolum dose of N. gonorrhoeae was 5.0 x 105 CFU/mL. The plates were incubated at 37 C at a CO2 concentration of 5.0% in a wet chamber of a MCO-15AC CO2 incubator (Sanyo, Japan). The results were visually assessed within 24 h using a Leica MZ 16 stereomicroscope equipped with a DFC 420 digital camera and the Image Manager IM 50 software (Leica Microsystems, Germany).

The criteria for interpretation of the results were as follows: the concentrations of the tested compound in the well, in which growth retardation of N. gonorrhoeae colonies was observed, corresponds to the MIC of the tested compound against this strain.

The antibacterial activity of 3-aminophenols against N. gonorrhoeae was evaluated by the serial two-fold agar dilution method (gold standard).4 The agar-based nutrient medium Complegon supplemented with a 1% growth additive (Russia, registration certificate number FSR 2007/00163) was used as the culture medium. The liquid state of the medium was maintained by heating (52 C) in a WB-4 MS water bath (BioSan, Latvia). Serial two-fold agar dilutions were prepared in sterile 24-well flat-bottomed plates (Sarstedt, Germany). For each compound, at least 12 dilutions were prepared; the final concentration range was 250.0 - 0.122 g/mL. The stock solution of the tested compounds (10 mg/mL) was prepared in DMSO; the working solution (5 mg/mL) and a series of two-fold dilutions were prepared in sterile distilled water for injection. Nine parts of the agar-based culture medium and one part of a ten-fold diluted solution of 3-aminophenol were aseptically added to plate wells and then thoroughly mixed using a TS-100 thermoshaker (BioSan, Latvia). The DMSO and water content of the culture medium was 2.5 - 0.012%, which had no effect on the growth properties of N. gonorrhoeae. Each series of experiments included two control experiments: the control of the growth of the culture inoculum (К+) and the control of the purity of the culture medium (К–).41

Spectinomycin (Sigma-Aldrich, USA; 102K05447V) was used as the reference.

S25

X-ray Analysis

The XRD analyses were accomplished on a “Xcalibur 3” diffractometer on standard procedure

(graphite monochromator, ω-scans with 1o step). Empirical absorption correction was applied.

Using Olex2,5 the structure was solved with the ShelXS structure solution program using Direct

Methods and refined with the ShelXL6 refinement package using Least Squares minimization.

All non-hydrogen atoms were refined in the anisotropic approximation; H-atoms of the OH- and

NH-groups were localized from the electron density peaks and refined independently, H-atoms at

the C-H bonds were refined in the “rider” model with dependent displacement parameters.

Results of the refinement are summarized in the Table S2. CCDC – 1887247 (for 4aae) and –

1887248 (for 8) contain the supplementary crystallographic data for this paper. These data can be

obtained free of charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif

Fig. S1 ORTEP drawing of compound 4aae showing thermal ellipsoids at the 50% probability level.

According to XRD data, the compound 4aae is crystallized in the centrosymmetric space

group. General geometry of the molecule is shown on the Fig. S1. The N(1) atom has a typical

sp3-hybridized non-planar configuration and deviated from the plane C(9)C(10)C(11) on 0.489

Å. N(2) atom is placed in the anti-periplanar configuration toward N(1) and has a conjugated

with O(2)=C(3)-C(4)=C(5) moiety planar configuration. As a result, the N(2)-C(5) bond (length

1.333(3) Å) much lesser than N(2)-C(8) bond (length 1.448(3) Å). The cyclohexenyl moiety has

a configuration “sofa”. The atoms C(2)C(3)C(4)C(5)C(6) are deviated from its least-squared

plane less than 0.05 Å, C(1) atom is deviated from its plane on the distance 0.643 Å with

(pseudo) axial placed OH-group. The crystal packing is ordered by intermolecular H-bonds

(Table S1). The H-bonds O(1)H…N(1) form the centrosymmetric intermolecular dimers of the

molecules and N(2)H…O(2) H-bonds form a layers of the molecules, oriented along 0a axis.

S26

Fig. S2 ORTEP drawing of compound 8. The disordering of the alkyl substituent is omitted for clarity.

According to XRD data, the compound 8 is crystallized in the centrosymmetric space group of

the monoclinic system. General geometry of the molecule is shown on the Fig. S2. The alkyl

substituent C3H7 demonstrates the strong disordering of the atomic positions and restraints for its

anisotropic displacement parameters and interatomic distances were applied. The cyclohexenyl

moiety has a configuration “sofa”. The atoms C(6)C(7)C(8)C(9)C(11) are deviated from its

least-squared plane less than 0.03 Å, C(10) atom is deviated from its plane on the distance 0.627

Å with (pseudo) axial placed OH-group. The bond C(6)-C(7) and C(7)-C(8) lengths are near in

the magnitude and show strong delocalization of the charge in the carbanion. The measured C=O

bonds lengths (1.255–1.275 Å) also indicate the participation of the carbonyl groups in the

delocalization of the anionic charge. The asymmetry in the bond distances of the symmetrical

anion may be explained by asymmetry of the intermolecular surrounding. Both H-atoms in the

NH2+ group of the pyrrolydinic cation are bonded with anionic parts by intermolecular H-bonds

(Table S1). These H-bonds form layer of the molecules along 0a axis. Additional

centrosymmetric H-bonds O(1)H…O(2) form dimers from these layers providing mean motif of

the crystal packing.

S27

Table S1 Hydrogen bonds with H..A < r(A) + 2.000 Å and <DHA > 110o.

D-H d(D-H) d(H..A) <DHA d(D..A) A4aaeO1-H17 0.95(4) 1.83(4) 170(2) 2.772(3) N1 [-x, -y+1, -z+2]N2-H2 0.93(3) 1.89(3) 171(2) 2.817(3) O2 [x+1, y, z]8N1-H1N 0.94(4) 1.85(4) 172(2) 2.784(4) O2 [ x-1, y, z-1]N1-H2N 1.04(3) 1.69(3) 153(3) 2.656(4) O3 [ x, y, z-1]O1-H1 0.89(4) 1.83(4) 166(3) 2.694(4) O2 [ -x, -y+1, -z]

Table S2 Crystal data and structure refinement.

4aae 8Empirical formula C11H17F3N2O2 C14H22F3NO3Formula weight 266.27 309.33Wavelength, Å 0.71073 (MoKα) 0.71073 (MoKα)T, K 145(2) 295(2)Crystal system Triclinic MonoclinicSpace group P-1 P21/ca, Å 7.0958(6) 9.1257(9)b, Å 8.4262(7) 21.064(2)c, Å 11.3160(8) 8.9372(10)α, o 87.424(6) 90β, o 82.903(6) 117.891(14)γ, o 75.668(7) 90Volume, Å3 650.44(9) 1518.4(3)Z 2 4Dcalk, g/cm3 1.360 1.353μ, mm-1 0.122 0.118F(000) 280 656Θ range for data collection

3.63 < Θ < 30.80o 3.85 < Θ < 30.93o

Reflections collected 5313 9806Independent reflections

3488 (Rint = 0.0399)

4151 (Rint = 0.0360)

Goodness-of-fit on F2 1.002 1.003R1 [I>2σ(I)] 0.0646 0.0666wR2 [I>2σ(I)] 0.1552 0.1804R1 (all data) 0.1146 0.1277wR2 (all data) 0.2089 0.2429Δρē, ēÅ-3 0.341/-0.322 0.399/-0.210

S28

References 1. G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M. Stoltz,

J. E. Bercaw, K. I. Goldberg, Organometallics, 2010, 29, 2176. 2. (a) A. L. Henne, M. S. Newman, L. L. Quill, R. A. Staniforth, J. Am. Chem. Soc., 1947,

69, 1819; (b) M. Hauptschein, R. A. Braun, J. Am. Chem. Soc., 1955, 77, 4930.3. C. G. Kokotos, J. Org. Chem. 2012, 77, 1131.4. Clinical and laboratory standards institute. Performance standards for antimicrobial

susceptibility testing; twenty-fourth informational supplement; CLSI document M100-S24, Wayne, USA, 2014, р. 226.

5. O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, J. Appl. Cryst., 2009, 42, 339.

6. G.M. Sheldrick, Acta Cryst., 2008, A64, 112.

S29

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 ppm

1.11

1.13

1.16

1.18

1.21

1.22

1.23

1.27

1.28

1.29

1.30

1.31

1.32

1.33

1.33

1.35

1.56

1.57

1.58

1.59

1.67

1.69

1.70

1.71

1.84

1.86

2.23

2.23

2.26

2.26

2.44

2.47

2.49

2.50

2.50

2.50

2.51

2.66

2.70

3.19

3.19

3.20

3.21

3.21

3.32

4.93

6.21

7.06

7.08

5.2

1.0

2.1

2.1

1.0

1.4

1.0

1.0

1.0

1.0

1.0

O

HO

F3C

HN

Fig. S4 1H NMR (500 MHz, DMSO-d6) spectrum of 4aaa.

406080100120140160180 ppm

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.09

40.84

50.67

71.90

72.12

72.35

72.57

93.33

122.39

124.66

126.93

129.20

158.09

188.94

Fig. S5 13C NMR (126 MHz, DMSO-d6) spectrum of 4aaa.

S30

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

80.36

Fig. S6 19F NMR (470 MHz, DMSO-d6) spectrum of 4aaa.

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 ppm

0.44

0.44

0.45

0.71

0.73

2.25

2.25

2.28

2.28

2.36

2.38

2.41

2.45

2.48

2.49

2.50

2.50

2.50

2.51

2.66

2.69

3.32

5.20

6.23

7.42

2.0

2.1

1.0

2.0

1.1

1.0

1.0

1.0

1.0

O

HOF3C

HN

Fig. S7 1H NMR (500 MHz, DMSO-d6) spectrum of 4aab.

S31

180 160 140 120 100 80 60 40 20 ppm

6.08

6.34

24.02

32.89

39.04

39.20

39.37

39.46

39.54

39.63

39.71

39.80

39.87

39.96

40.04

40.13

40.99

72.03

72.26

72.48

72.70

95.19

122.38

124.65

126.92

129.19

160.41

189.31

Fig. S8 13C NMR (126 MHz, DMSO-d6) spectrum of 4aab.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.32

Fig. S9 19F NMR (470 MHz, DMSO-d6) spectrum of 4aab.

S32

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 ppm

0.86

0.86

0.88

1.26

1.27

1.28

1.30

1.31

1.33

1.48

1.49

1.51

1.52

2.24

2.24

2.27

2.28

2.44

2.47

2.50

2.50

2.50

2.51

2.51

2.69

2.72

2.95

2.97

2.98

2.99

3.34

3.34

4.88

6.22

7.18

7.19

7.20

3.1

10.4

2.1

1.0

1.4

1.0

2.0

1.0

1.0

1.0

O

HO

F3C

HN

C8H17

Fig. S10 1H NMR (500 MHz, DMSO-d6) spectrum of 4aac.

20406080100120140160180 ppm

28.63

28.70

31.22

33.31

39.00

39.16

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.90

42.30

71.97

72.20

72.42

72.64

93.29

124.69

126.96

159.37

188.99

Fig. S11 13C NMR (126 MHz, DMSO-d6) spectrum of 4aac.

S33

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.36

Fig. S12 19F NMR (376 MHz, DMSO-d6) spectrum of 4aac.

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 ppm

0.84

0.86

0.87

1.24

1.27

1.30

1.47

1.49

1.50

1.52

1.53

2.24

2.24

2.27

2.28

2.44

2.47

2.50

2.50

2.50

2.51

2.51

2.68

2.72

2.95

2.97

2.98

2.99

3.33

4.87

6.22

7.17

7.18

7.19

3.2

19.8

2.1

1.0

1.4

1.1

2.1

1.0

1.0

0.9

O

HO

F3C

HN

C12H25

Fig. S13 1H NMR (500 MHz, DMSO-d6) spectrum of 4aad.

S34

180 160 140 120 100 80 60 40 20 ppm

28.98

28.99

29.03

31.28

33.30

39.00

39.16

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.90

42.15

42.29

71.97

72.19

72.41

72.64

93.29

124.68

126.96

159.34

188.97

Fig. S14 13C NMR (126 MHz, DMSO-d6) spectrum of 4aad.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.37

Fig. S15 19F NMR (376 MHz, DMSO-d6) spectrum of 4aad.

S35

2.02.53.03.54.04.55.05.56.06.57.0 ppm

2.24

2.27

2.28

2.39

2.40

2.41

2.45

2.48

2.50

2.50

2.51

2.54

2.68

2.72

3.06

3.07

3.08

3.09

3.34

4.91

6.23

7.10

6.0

1.0

2.0

1.0

0.6

1.0

1.9

1.0

1.0

0.9

O

HO

F3C

HN

N(Me)2

Fig. S16 1H NMR (500 MHz, DMSO-d6) spectrum of 4aae.

406080100120140160180 ppm

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.43

40.92

45.14

56.67

71.99

72.21

72.44

72.66

93.47

95.38

122.41

124.68

126.95

129.22

159.37

189.09

Fig. S17 13C NMR (126 MHz, DMSO-d6) spectrum of 4aae.

S36

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.38

Fig. S18 19F NMR (470 MHz, DMSO-d6) spectrum of 4aae.

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 ppm

-0.00

2.23

2.23

2.27

2.27

2.44

2.49

2.49

2.50

2.50

2.50

2.51

2.54

2.58

2.78

2.82

3.33

4.26

4.27

4.90

6.26

7.25

7.26

7.28

7.28

7.29

7.30

7.32

7.32

7.33

7.34

7.35

7.37

7.72

1.0

0.8

1.0

1.1

2.0

1.0

1.0

5.1

1.0

O

HOF3C

HN

Fig. S191H NMR (400 MHz, DMSO-d6) spectrum of 4aaf.

S37

406080100120140160180 ppm

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.90

45.79

72.01

72.23

72.45

72.68

94.32

124.67

126.94

127.05

127.26

128.39

129.21

137.69

159.38

189.30

Fig. S20 13C NMR (126 MHz, DMSO-d6) spectrum of 4aaf.

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.39

Fig. S21 19F NMR (376 MHz, DMSO-d6) spectrum of 4aaf.

S38

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 ppm

2.24

2.24

2.27

2.28

2.45

2.48

2.50

2.50

2.51

2.54

2.57

2.78

2.82

3.35

4.25

4.26

4.90

6.27

7.16

7.18

7.19

7.34

7.35

7.35

7.37

7.72

7.73

7.74

1.0

1.0

1.0

1.0

2.1

1.0

1.0

2.0

2.0

1.0

O

HOF3C

HN

F

Fig. S22 1H NMR (500 MHz, DMSO-d6) spectrum of 4aag.

406080100120140160180 ppm

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.09

40.91

45.00

72.01

72.24

72.46

72.68

94.37

115.05

115.22

122.40

124.67

126.94

129.22

129.28

133.89

133.91

159.28

160.35

162.28

189.39

Fig. S23 13C NMR (126 MHz, DMSO-d6) spectrum of 4aag.

S39

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

46.79

46.81

46.82

46.83

46.85

46.86

46.87

80.37

1.0

3.1

Fig. S24 19F NMR (376 MHz, DMSO-d6) spectrum of 4aag.

8 7 6 5 4 3 2 1 ppm

2.24

2.27

2.45

2.48

2.50

2.54

2.58

2.76

2.79

3.33

3.73

3.74

4.17

4.18

4.91

6.25

6.82

6.84

6.90

6.91

6.92

7.64

1.0

1.1

1.0

1.0

6.0

2.0

1.0

1.0

1.0

2.0

1.0

O

HOF3C

HN

OMe

OMe

Fig. S25 1H NMR (500 MHz, DMSO-d6) spectrum of 4aah.

S40

406080100120140160180 ppm

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.91

45.65

55.43

55.54

72.03

72.25

72.47

72.70

94.30

111.31

111.76

119.46

124.69

126.96

129.90

147.95

148.75

159.28

189.25

Fig. S26 13C NMR (126 MHz, DMSO-d6) spectrum of 4aah.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.43

Fig. S27 19F NMR (376 MHz, DMSO-d6) spectrum of 4aah.

S41

8 7 6 5 4 3 2 1 ppm

0.00

2.24

2.28

2.45

2.50

2.50

2.51

2.53

2.71

2.75

3.33

4.23

4.25

5.05

6.25

6.36

6.37

6.41

6.41

6.42

6.42

7.62

1.0

0.7

0.7

1.1

2.0

1.0

1.0

2.0

1.9

O

HOF3C

HN

O

Fig. S28 1H NMR (400 MHz, DMSO-d6) spectrum of 4aai.

406080100120140160180 ppm

39.16

39.33

39.50

39.59

39.67

39.75

39.83

39.92

40.00

40.09

40.92

72.01

72.23

72.45

72.68

94.29

108.00

110.48

122.38

124.65

126.92

129.19

142.57

150.64

159.11

189.56

Fig. S29 13C NMR (126 MHz, DMSO-d6) spectrum of 4aai.

S42

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.39

Fig. S30 19F NMR (376 MHz, DMSO-d6) spectrum of 4aai.

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 ppm

1.83

1.86

1.87

1.92

2.22

2.23

2.26

2.27

2.41

2.45

2.50

2.50

2.50

2.65

2.65

2.69

2.69

2.83

2.87

3.14

3.20

3.33

3.46

4.85

6.21

4.0

1.0

1.0

1.0

1.0

2.0

2.0

1.0

1.0

O

HOF3C

N

Fig. S31 1H NMR (400 MHz, DMSO-d6) spectrum of 4aaj.

S43

406080100120140160180 ppm

39.17

39.33

39.43

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.28

47.58

47.98

72.08

72.30

72.53

72.75

95.78

122.42

124.69

126.96

129.23

157.79

188.10

Fig. S32 13C NMR (126 MHz, DMSO-d6) spectrum of 4aaj.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.39

Fig. S33 19F NMR (376 MHz, DMSO-d6) spectrum of 4aaj.

S44

6 5 4 3 2 1 0 ppm

1.50

1.51

1.52

1.53

1.54

1.55

1.56

1.57

1.59

1.60

1.61

1.62

1.63

2.24

2.24

2.27

2.45

2.47

2.50

2.50

2.50

2.66

2.66

2.68

2.69

2.71

2.73

3.30

3.31

3.33

3.33

3.34

3.35

3.36

3.37

3.37

5.16

6.20

5.9

1.0

1.0

2.0

4.8

1.0

0.9

N

O

HOF3C

Fig. S34 1H NMR (600 MHz, DMSO-d6) spectrum of 4aak.

406080100120140160180 ppm

25.13

31.68

39.09

39.22

39.36

39.50

39.64

39.78

39.92

40.02

47.27

72.19

72.38

72.56

72.75

96.93

123.04

124.93

126.83

128.72

158.80

189.60

Fig. S35 13C NMR (151 MHz, DMSO-d6) spectrum of 4aak.

S45

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.41

Fig. S36 19F NMR (376 MHz, DMSO-d6) spectrum of 4aak.

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.09

1.11

1.24

1.26

1.26

1.27

1.28

1.29

1.30

1.31

1.33

1.35

1.38

1.40

1.57

1.60

1.70

1.72

1.73

1.76

1.82

1.84

2.28

2.31

2.46

2.50

2.50

2.50

2.51

2.67

2.70

2.74

2.78

3.33

5.93

5.95

6.14

1.0

4.3

4.0

4.1

1.0

0.6

2.0

0.5

0.2

0.9

1.0

HN

O

HOF3C

CH3

Fig. S37 1H NMR (500 MHz, DMSO-d6) spectrum of 4aba.

S46

20406080100120140160180 ppm

24.96

30.09

33.57

33.62

39.00

39.17

39.33

39.43

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.14

51.55

71.52

71.74

101.03

127.03

155.12

186.90

Fig. S38 13C NMR (126 MHz, DMSO-d6) spectrum of 4aba.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.34

Fig. S39 19F NMR (376 MHz, DMSO-d6) spectrum of 4aba.

S47

7 6 5 4 3 2 1 ppm

-0.00

0.63

0.72

1.56

2.30

2.33

2.47

2.50

2.61

2.84

2.88

3.01

3.04

3.33

6.17

6.66

3.9

2.9

1.0

0.7

1.0

2.0

0.9

1.0

O

HOF3C

HN

CH3

Fig. S40 1H NMR (500 MHz, DMSO-d6) spectrum of 4abb.

180 160 140 120 100 80 60 40 20 ppm

7.39

7.61

8.07

24.69

30.91

39.00

39.17

39.33

39.50

39.67

39.76

39.83

39.92

40.00

40.36

71.52

71.74

101.77

124.77

127.04

157.72

187.38

Fig. S41 13C NMR (126 MHz, DMSO-d6) spectrum of 4abb.

S48

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.21

Fig. S42 19F NMR (470 MHz, DMSO-d6) spectrum of 4abb.

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 ppm

0.00

0.85

0.86

0.88

1.26

1.27

1.28

1.49

1.50

1.51

1.59

2.28

2.29

2.32

2.32

2.46

2.49

2.50

2.50

2.50

2.51

2.51

2.65

2.69

2.71

2.75

3.14

3.16

3.17

3.19

3.34

6.14

6.41

6.43

6.44

3.0

10.4

2.1

3.0

1.0

1.1

2.0

2.0

1.0

1.0

O

HOF3C

HN

C8H17

CH3

Fig. S43 1H NMR (500 MHz, DMSO-d6) spectrum of 4abc.

S49

20406080100120140160180 ppm

29.94

30.30

31.23

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.10

40.20

42.61

71.28

71.51

71.73

71.95

95.39

101.02

124.76

127.03

156.36

186.69

Fig. S44 13C NMR (126 MHz, DMSO-d6) spectrum of 4abc.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.23

Fig. S45 19F NMR (376 MHz, DMSO-d6) spectrum of 4abc.

S50

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.58

2.20

2.29

2.30

2.32

2.33

2.43

2.44

2.47

2.50

2.50

2.51

2.51

2.68

2.72

2.78

2.81

3.27

3.28

3.29

3.31

3.35

6.17

6.21

6.22

2.9

5.9

1.1

1.9

0.6

2.0

2.5

1.9

O

OH

CF3

NH

N(CH3)2CH3

Fig. S46 1H NMR (500 MHz, DMSO-d6) spectrum of 4abe.

180 160 140 120 100 80 60 40 20 ppm

7.83

30.07

39.00

39.17

39.33

39.50

39.60

39.67

39.76

39.84

39.93

40.00

40.09

40.21

40.31

45.10

58.79

71.22

71.45

71.67

101.17

124.70

126.98

156.16

186.80

Fig. S47 13C NMR (126 MHz, DMSO-d6) spectrum of 4abe.

S51

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.21

Fig. S48 19F NMR (376 MHz, DMSO-d6) spectrum of 4abe.

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 ppm

1.68

2.30

2.34

2.46

2.50

2.50

2.50

2.52

2.56

2.64

2.68

4.45

4.47

6.16

7.08

7.09

7.11

7.24

7.26

7.27

7.29

7.34

7.36

7.37

2.9

1.0

0.6

1.3

1.0

1.9

0.9

1.0

2.9

1.9

O

HOF3C

HN

CH3

Figure S49 1H NMR (500 MHz, DMSO-d6) spectrum of 4abf.

S52

180 160 140 120 100 80 60 40 20 ppm

8.19

30.18

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.27

45.67

71.21

71.44

71.66

71.88

101.84

124.65

126.49

126.91

128.50

139.71

156.41

187.15

Fig. S50 13C NMR (126 MHz, DMSO-d6) spectrum of 4abf.

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.19

Fig. S51 19F NMR (470 MHz, DMSO-d6) spectrum of 4abf.

S53

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 ppm

1.67

2.30

2.33

2.46

2.49

2.50

2.50

2.51

2.51

2.52

2.57

2.62

2.66

3.33

4.43

4.44

6.16

7.05

7.07

7.09

7.16

7.19

7.21

7.30

7.32

7.33

2.9

1.0

0.6

2.1

1.9

0.9

1.0

2.0

2.0

O

HOF3C

HN

CH3

F

Fig. S52 1H NMR (400 MHz, DMSO-d6) spectrum of 4abg.

20406080100120140160180 ppm

8.18

30.19

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.29

44.97

71.23

71.45

71.67

71.89

101.96

115.16

115.33

124.64

126.92

128.50

128.57

129.19

135.88

135.90

156.26

160.24

162.16

187.24

Fig. S53 13C NMR (126 MHz, DMSO-d6) spectrum of 4abg.

S54

4550556065707580 ppm

46.52

46.54

46.55

46.56

46.58

46.59

46.60

80.23

1.0

3.0

Fig. S54 19F NMR (376 MHz, DMSO-d6) spectrum of 4abg.

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 ppm

1.62

2.32

2.36

2.50

2.53

2.64

2.69

2.72

2.79

2.83

3.35

4.38

4.39

4.41

4.42

4.44

4.46

4.47

6.18

6.26

6.42

6.93

7.61

2.9

1.0

0.7

1.0

1.0

2.0

1.0

0.9

0.9

1.0

0.8

O

HOF3C

HN

O

Me

Fig. S55 1H NMR (500 MHz, DMSO-d6) spectrum of 4abi.

S55

20406080100120140160180 ppm

8.11

30.02

39.00

39.17

39.34

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.09

40.31

71.26

71.48

71.70

71.92

102.14

106.94

110.54

124.70

126.98

129.25

142.42

152.55

156.03

187.42

Fig. S56 13C NMR (126 MHz, DMSO-d6) spectrum of 4abi.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.24

Fig. S57 19F NMR (376 MHz, DMSO-d6) spectrum of 4abi.

S56

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

-0.00

1.71

1.74

1.75

1.75

1.76

1.77

1.79

1.83

1.85

1.86

1.87

1.90

2.31

2.31

2.34

2.34

2.46

2.49

2.50

2.50

2.50

2.51

2.76

2.80

2.81

2.84

3.33

3.46

3.47

3.48

3.49

3.49

3.50

3.53

3.55

3.56

3.58

6.11

2.1

5.0

1.0

1.2

2.0

4.0

1.0

O

HOF3C

N

CH3

Fig. S581 1H NMR (500 MHz, DMSO-d6) spectrum of 4abj.

20406080100120140160180 ppm

25.04

34.03

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.09

40.39

50.92

70.61

70.83

71.05

71.27

102.96

122.42

124.69

126.96

129.23

156.75

189.16

Fig. S59 13C NMR (126 MHz, DMSO-d6) spectrum of 4abj.

S57

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.34

Fig. S60 19F NMR (470 MHz, DMSO-d6) spectrum of 4abj.

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 ppm

-0.00

0.81

0.83

0.85

1.20

1.22

1.24

1.26

2.07

2.11

2.13

2.15

2.18

2.28

2.32

2.36

2.38

2.40

2.45

2.50

2.50

2.50

2.66

2.70

2.76

2.80

3.23

3.25

3.26

3.28

3.32

6.14

6.26

3.2

2.9

8.0

4.1

2.2

2.2

1.0

1.0

HN

O

HOF3C N(CH3)2

CH3

Fig. S61 1H NMR (500 MHz, DMSO-d6) spectrum of 4ace.

S58

20406080100120140160180 ppm

13.97

20.70

23.82

30.04

39.08

39.22

39.36

39.50

39.64

39.78

39.92

40.04

40.28

44.32

57.96

71.28

71.47

71.65

71.84

95.39

107.05

124.94

126.83

128.72

155.58

187.23

Fig. S62 13C NMR (151 MHz, DMSO-d6) spectrum of 4ace.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.22

Fig. S63 19F NMR (376 MHz, DMSO-d6) spectrum of 4ace.

S59

6 5 4 3 2 1 0 ppm

0.00

0.81

0.83

0.85

1.15

1.17

1.19

1.24

1.35

1.37

1.78

1.83

1.87

2.22

2.23

2.26

2.27

2.28

2.30

2.34

2.40

2.42

2.43

2.45

2.46

2.50

2.50

2.51

2.76

2.81

2.86

3.32

3.45

3.46

3.49

3.50

6.09

3.1

2.4

4.1

2.1

2.3

2.0

4.1

0.9

N

O

HOF3C

CH3

Fig. S64 1H NMR (400 MHz, DMSO-d6) spectrum of 4acj.

406080100120140160180 ppm

25.07

26.55

34.29

39.08

39.22

39.36

39.50

39.64

39.78

39.92

40.04

40.55

50.82

70.80

70.99

108.55

124.90

126.80

155.70

189.37

Fig. S65 13C NMR (151 MHz, DMSO-d6) spectrum of 4acj.

S60

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.34

Fig. S66 19F NMR (376 MHz, DMSO-d6) spectrum of 4acj.

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 ppm

1.26

1.27

1.29

1.29

1.30

1.31

1.31

1.32

1.32

1.34

1.35

1.56

1.58

1.59

1.67

1.69

1.71

1.83

1.86

2.07

2.10

2.13

2.29

2.32

2.36

2.50

2.50

2.51

2.53

2.56

3.17

3.18

3.19

3.34

4.89

5.47

5.68

5.79

5.91

6.99

7.00

3.2

2.1

1.0

2.1

2.1

1.0

2.0

1.0

1.0

1.0

1.0

1.0

1.0

O

HOHF2C

HN

Fig. S67 1H NMR (500 MHz, DMSO-d6) spectrum of 4baa.

S61

406080100120140160180 ppm

33.70

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.93

40.00

40.09

41.49

50.68

71.46

71.62

71.79

93.66

114.83

116.78

118.74

158.82

190.19

Fig. S68 13C NMR (126 MHz, DMSO-d6) spectrum of 4baa.

30 25 20 15 10 5 0 ppm

-0.00

29.27

29.39

29.86

29.98

30.78

30.89

31.36

31.48

1.0

1.0

Fig. S69 19F NMR (470 MHz, DMSO-d6) spectrum of 4baa.

S62

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

-0.00

1.84

1.85

1.86

1.87

1.91

1.92

2.10

2.10

2.13

2.13

2.27

2.31

2.49

2.50

2.50

2.50

2.51

2.52

2.53

2.56

2.56

2.65

2.69

3.11

3.13

3.18

3.19

3.33

3.44

4.81

5.50

5.71

5.82

5.94

4.0

1.0

1.0

1.0

1.0

2.0

1.9

1.0

1.0

1.0

O

HOHF2C

N

Fig. S70 1H NMR (500 MHz, DMSO-d6) spectrum of 4baj.

406080100120140160180 ppm

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.74

47.54

47.85

71.61

71.77

71.94

96.16

114.86

116.82

118.78

158.45

189.36

Fig. S71 13C NMR (126 MHz, DMSO-d6) spectrum of 4baj.

S63

30 25 20 15 10 5 ppm

-0.00

29.77

29.88

30.35

30.47

30.68

30.80

31.26

31.38

1.0

1.0

Fig. S72 19F NMR (470 MHz, DMSO-d6) spectrum of 4baj.

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 ppm

-0.00

1.84

1.85

1.86

1.87

1.89

1.91

1.92

1.93

2.30

2.33

2.45

2.49

2.49

2.50

2.50

2.50

2.51

2.72

2.75

2.88

2.91

3.13

3.14

3.21

3.22

3.32

3.46

4.87

6.34

4.1

1.0

1.0

1.0

1.0

2.0

2.0

1.0

1.0

N

O

HOC2F5

Fig. S73 1H NMR (500 MHz, DMSO-d6) spectrum of 4caj.

S64

406080100120140160180 ppm

39.17

39.33

39.43

39.50

39.59

39.67

39.76

39.83

39.93

40.00

40.09

40.47

47.50

48.02

73.36

73.55

73.73

95.36

95.70

112.02

112.29

113.83

114.10

114.37

114.63

115.76

115.91

116.17

116.45

117.75

118.05

118.34

120.05

120.34

120.63

122.63

157.70

187.84

Fig. S74 13C NMR (126 MHz, DMSO-d6) spectrum of 4caj.

90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

37.77

38.35

39.12

39.70

85.27

1.0

1.0

2.9

Fig. S75 19F NMR (470 MHz, DMSO-d6) spectrum of 4caj.

S65

7 6 5 4 3 2 1 ppm

-0.00

1.24

2.18

2.32

2.35

2.41

2.42

2.43

2.49

2.50

2.50

2.50

2.52

2.60

2.63

2.72

2.75

3.07

3.08

3.09

3.10

3.33

4.92

6.35

7.14

6.0

1.0

2.0

0.6

0.5

1.0

1.0

2.0

1.0

1.0

1.0

HN

O

HO

F2C N(CH3)2

F3C

Fig. S276 1H NMR (600 MHz, DMSO-d6) spectrum of 4cae.

406080100120140160180 ppm

39.22

39.36

39.50

39.64

39.78

39.92

40.04

40.38

40.98

45.08

56.60

73.31

73.46

73.61

93.40

112.39

112.61

114.12

114.34

115.84

116.07

118.02

118.26

118.51

119.93

120.17

120.41

122.08

159.38

188.83

Fig. S77 13C NMR (151 MHz, DMSO-d6) spectrum of 4cae.

S66

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

37.83

38.56

38.82

39.54

85.17

2.0

3.0

Fig. S78 19F NMR (376 MHz, DMSO-d6) spectrum of 4cae.

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 ppm

1.10

1.13

1.16

1.18

1.21

1.23

1.26

1.27

1.30

1.32

1.56

1.59

1.68

1.69

1.70

1.83

1.86

2.25

2.29

2.39

2.43

2.50

2.50

2.53

2.62

2.66

3.18

3.19

3.20

3.33

4.92

6.17

6.41

6.42

6.44

6.54

6.55

6.57

6.67

6.68

6.70

7.08

5.5

1.1

2.1

2.1

1.1

1.1

0.6

1.1

1.2

1.0

0.9

1.1

1.0

O

HOH(F2C)2

HN

Fig. S79 1H NMR (400 MHz, DMSO-d6) spectrum of 4daa.

S67

406080100120140160180 ppm

39.17

39.34

39.43

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.10

40.92

50.73

72.73

72.92

73.10

93.41

95.39

107.01

107.26

107.50

108.98

109.23

109.47

110.96

111.20

111.45

113.85

114.02

114.22

115.88

116.07

116.26

117.93

118.12

118.30

158.42

189.27

Fig. S80 13C NMR (126 MHz, DMSO-d6) spectrum of 4daa.

35 30 25 20 15 10 5 0 ppm

-0.00

25.25

25.39

26.05

26.19

26.38

26.39

26.52

26.53

27.18

27.31

31.69

32.39

32.94

33.64

2.0

2.0

Fig. S81 19F NMR (376 MHz, DMSO-d6) spectrum of 4daa.

S68

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 ppm

1.24

1.84

1.86

1.87

1.89

1.91

1.92

1.93

2.07

2.25

2.29

2.36

2.39

2.50

2.50

2.50

2.67

2.71

2.78

2.81

3.12

3.14

3.20

3.21

3.33

3.45

4.85

6.16

6.48

6.49

6.51

6.58

6.60

6.61

6.69

6.70

6.71

4.0

1.0

1.0

1.0

1.0

2.0

2.0

1.0

1.0

1.0

O

HOH(F2C)2

N

Fig. S82 1H NMR (500 MHz, DMSO-d6) spectrum of 4daj.

406080100120140160180 ppm

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

40.46

47.54

47.98

72.86

73.05

73.24

95.89

106.99

107.24

107.48

108.97

109.21

109.46

110.94

111.19

111.43

113.83

114.02

114.20

115.88

116.06

116.24

117.93

118.11

118.29

158.01

188.48

Fig. S83 13C NMR (126 MHz, DMSO-d6) spectrum of 4daj.

S69

35 30 25 20 15 10 5 0 ppm

-0.00

25.96

25.98

26.00

26.07

26.09

26.11

26.83

26.84

26.93

26.95

32.79

32.80

32.82

32.83

1.0

1.0

2.0

Fig. S84 19F NMR (470 MHz, DMSO-d6) spectrum of 4daj.

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 ppm

-0.00

1.84

1.85

1.86

1.87

1.89

1.91

1.91

1.92

1.93

2.33

2.36

2.48

2.50

2.50

2.50

2.50

2.75

2.77

2.90

2.93

3.13

3.14

3.21

3.22

3.32

3.46

3.46

4.87

6.41

4.6

1.0

0.9

1.0

1.0

2.2

2.2

1.1

1.0

N

O

HOC3F7

Fig. S85 1H NMR (600 MHz, DMSO-d6) spectrum of 4eaj.

S70

406080100120140160180 ppm

32.46

39.08

39.22

39.36

39.50

39.64

39.78

39.92

40.04

40.53

47.54

48.06

74.50

74.66

74.81

95.71

109.92

110.17

113.90

115.45

115.64

115.83

116.35

116.58

117.38

118.26

118.49

157.70

187.80

Fig. S86 13C NMR (151 MHz, DMSO-d6) spectrum of 4eaj.

404550556065707580 ppm

41.13

41.14

41.15

41.17

41.87

41.88

41.89

41.91

42.29

42.30

42.31

42.33

43.03

43.04

43.06

43.07

82.49

82.52

82.54

2.1

1.0

0.9

3.0

Fig. S87 19F NMR (376 MHz, DMSO-d6) spectrum of 4eaj.

S71

7 6 5 4 3 2 1 ppm

-0.00

0.76

0.78

0.79

1.20

1.22

1.23

1.25

1.77

1.77

1.78

1.79

1.80

2.05

2.07

2.08

2.21

2.25

2.42

2.45

2.50

2.50

2.51

2.99

3.00

3.02

2.9

2.0

3.7

1.9

1.9

1.9

3.7

4.0

O

O

HO

F3C -

H2NCH3

Fig. S88 1H NMR (500 MHz, DMSO-d6) spectrum of 8.

20406080100120140160180 ppm

14.37

21.94

24.03

24.64

39.00

39.16

39.33

39.50

39.67

39.76

39.83

39.92

40.00

40.09

45.10

71.44

71.66

71.87

72.09

110.21

125.18

127.45

129.73

182.28

Fig. S89 13C NMR (126 MHz, DMSO-d6) spectrum of 8.

S72

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

80.25

Fig. S90 19F NMR (470 MHz, DMSO-d6) spectrum of 8.

11 10 9 8 7 6 5 4 3 2 1 ppm

1.29

1.56

1.59

1.70

1.88

2.09

2.11

2.13

2.17

2.23

2.27

2.32

2.36

2.39

2.44

2.50

2.50

2.51

2.66

2.70

2.74

2.92

3.35

4.93

7.98

10.63

1.1

5.0

1.2

2.4

2.3

1.0

2.8

2.0

1.0

1.1

2.9

0.5

CF3

OHO-

O

H3C

O +H3N

Fig. S91 1H NMR (500 MHz, DMSO-d6) spectrum of 5a (impurity of 4aaa is about 13%).

S73

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

80.38

81.96

13.7

86.2

Figure S92 19F NMR (470 MHz, DMSO-d6) spectrum of 5a (impurity of 4aaa is about 13%).

11 10 9 8 7 6 5 4 3 2 1 ppm

1.26

1.28

1.56

1.59

1.70

1.71

1.87

1.88

2.09

2.12

2.33

2.35

2.39

2.42

2.50

2.50

2.51

2.54

2.55

2.57

2.58

2.72

2.74

2.90

2.91

2.92

8.01

2.8

1.1

4.0

1.0

2.0

2.0

1.0

2.1

1.8

1.0

1.0

2.9

1.0

HOF3C

O

O

O-NH3

+

H3C

Fig. S93 1H NMR (500 MHz, DMSO-d6) spectrum of 5b.

S74

200 180 160 140 120 100 80 60 40 20 ppm

30.47

36.59

37.66

39.00

39.17

39.33

39.50

39.59

39.67

39.76

39.83

39.92

40.00

40.09

46.65

49.13

71.80

72.01

72.23

72.45

125.28

127.56

173.34

207.93

Fig. S94 13C NMR (126 MHz, DMSO-d6) spectrum of 5b.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

0.00

81.88

Fig. S95 19F NMR (470 MHz, DMSO-d6) spectrum of 5b.

S75

12 11 10 9 8 7 6 5 4 3 2 1 ppm

1.24

1.54

1.55

1.64

2.05

2.13

2.17

2.30

2.37

2.40

2.50

2.73

2.75

2.83

2.97

9.04

6.0

3.8

2.0

1.0

4.0

3.0

HOF3C

OO

CH3

O-

+H2N

Figure S96 1H NMR (500 MHz, DMSO-d6) spectrum of 5c.

406080100120140160180200 ppm

39.00

39.17

39.34

39.50

39.67

39.76

39.84

39.93

40.00

40.09

43.49

47.75

71.77

71.99

72.20

72.42

122.91

125.20

127.48

129.77

173.30

205.59

Fig. S97 13C NMR (126 MHz, DMSO-d6) spectrum of 5c.

S76

85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

81.95

Fig. S98 19F NMR (470 MHz, DMSO-d6) spectrum of 5c.

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

-0.00

1.27

1.28

1.29

2.26

2.66

2.69

2.69

2.72

2.90

4.15

4.17

4.18

4.20

4.96

5.75

5.86

5.98

3.1

2.9

2.0

2.0

2.0

0.9

1.0

OHF2C

OHO

O

CH3

CH3

Fig. S99 1H NMR (500 MHz, CDCl3) spectrum of 6b.

S77

406080100120140160180200 ppm

13.98

31.92

37.98

38.00

38.03

44.05

44.06

44.08

61.13

72.71

72.88

73.06

76.75

77.00

77.26

113.89

115.86

117.84

170.60

208.65

Fig. S100 13C NMR (126 MHz, CDCl3) spectrum of 6b.

30 25 20 15 10 5 0 ppm

29.30

29.42

29.90

29.97

30.02

30.09

30.57

30.69

Fig. S101 19F NMR (470 MHz, CDCl3) spectrum of 6b.

S78

6 5 4 3 2 1 0 ppm

-0.00

1.26

1.28

1.29

1.29

2.26

2.29

2.82

2.85

2.86

2.87

2.90

2.90

3.01

3.04

3.09

3.12

4.16

4.17

4.18

4.20

5.96

3.0

3.0

2.0

2.0

2.0

0.9

O

C2F5 O

OH

O

H3C CH3

Fig. S102 1H NMR (500 MHz, CDCl3) spectrum of 6c.

406080100120140160180200 ppm

13.82

32.00

37.49

43.00

61.30

74.84

75.03

75.22

76.75

77.00

77.25

111.98

112.26

113.79

114.07

114.35

114.63

115.59

115.88

116.16

116.43

117.59

117.88

118.17

119.88

120.17

120.45

122.46

170.44

208.61

Fig. S 103 13C NMR (126 MHz, CDCl3) spectrum of 6c.

S79

3540455055606570758085 ppm

38.64

39.24

39.58

40.18

83.75

1.0

1.0

2.9

Fig. S104 19F NMR (470 MHz, CDCl3) spectrum of 6c.

6 5 4 3 2 1 0 ppm

-0.00

1.05

1.07

1.08

1.27

1.28

1.30

2.56

2.57

2.58

2.58

2.59

2.60

2.61

2.61

2.75

2.78

2.83

2.86

2.91

2.95

2.97

3.01

4.16

4.17

4.19

4.20

5.82

3.0

3.1

2.0

2.1

2.1

2.0

0.9

O

CF3 O

OH

OH3C

CH3

Fig. S105 1H NMR (500 MHz, CDCl3) spectrum of 6d.

S80

20406080100120140160180200 ppm

7.15

13.96

37.45

38.27

42.05

61.37

73.50

73.73

73.96

74.19

76.74

77.00

77.25

121.62

123.89

126.17

128.44

170.37

210.97

Fig. S106 13C NMR (126 MHz, CDCl3) spectrum of 6d.

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

79.54

Fig. S1073 19F NMR (470 MHz, CDCl3) spectrum of 6d.

S81

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

-0.00

1.27

1.29

1.30

2.74

2.75

2.77

2.78

2.86

2.89

2.91

2.94

2.95

2.98

3.01

3.11

3.12

3.14

3.15

4.18

4.18

4.19

4.20

4.21

4.21

4.22

5.55

6.4

2.0

4.0

2.0

4.0

1.8

OCF3 CF3

OHO

O

O

O

OHCH3H3C

Fig. S108 1H NMR (500 MHz, CDCl3) spectrum of 7.

20406080100120140160180200 ppm

13.94

36.30

36.50

45.66

45.76

61.64

73.22

73.45

73.69

73.92

76.75

77.00

77.25

123.72

123.74

126.00

126.01

170.78

170.84

207.35

207.73

Fig. S109 13C NMR (126 MHz, CDCl3) spectrum of 7.

S82

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm

-0.00

79.58

79.59

Fig. S110 19F NMR (470 MHz, CDCl3) spectrum of 7.

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 ppm

-0.00

0.97

0.99

1.01

1.63

1.64

1.66

1.68

3.06

3.08

3.10

6.34

6.45

6.49

7.26

3.0

2.2

2.0

1.9

1.0

1.9

NH

HO

CF3

CH3

Fig. S111 1H NMR (500 MHz, CDCl3) spectrum of 10a.

S83

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

98.57

Fig. S112 19F NMR (470 MHz, CDCl3) spectrum of 10a.

7 6 5 4 3 2 1 ppm

-0.00

0.87

0.88

0.90

1.27

1.28

1.29

1.30

1.34

1.36

1.37

1.58

1.60

1.61

1.63

1.64

3.07

3.09

3.10

6.28

6.42

6.45

7.26

3.1

10.7

2.1

2.0

1.9

1.0

2.0

NH

C8H17HO

CF3

Fig. S113 1H NMR (500 MHz, CDCl3) spectrum of 10b.

S84

2030405060708090100110120130140150160 ppm

14.06

22.62

27.01

29.02

29.19

29.29

31.77

44.47

76.75

77.00

77.26

101.88

101.90

102.72

103.04

103.07

120.65

122.82

124.98

127.15

132.28

132.54

132.79

133.04

149.15

156.92

Fig. S114 13C NMR (126 MHz, CDCl3) spectrum of 10b.

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

98.61

Fig. S115 19F NMR (470 MHz, CDCl3) spectrum of 10b.

S85

9 8 7 6 5 4 3 2 1 ppm

-0.00

0.84

0.85

0.87

1.24

1.33

1.49

1.51

1.53

2.50

2.92

2.94

2.96

2.97

3.33

5.93

5.94

5.95

6.17

6.28

9.53

3.0

18.4

2.0

2.0

1.0

3.0

1.0

NH

C12H25

OH

F3C

Fig. S116 1H NMR (400 MHz, DMSO-d6) spectrum of 10c.

2030405060708090100110120130140150160 ppm

26.58

28.43

28.69

28.82

28.99

29.01

29.04

31.27

39.08

39.22

39.36

39.50

39.64

39.78

39.92

40.04

42.59

98.75

98.78

99.68

99.71

101.13

121.77

123.57

125.38

127.18

130.09

130.30

130.50

130.70

150.78

158.63

Fig. S117 13C NMR (151 MHz, DMSO-d6) spectrum of 10c.

S86

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

100.96

Fig. S118 19F NMR (376 MHz, DMSO-d6) spectrum of 10c.

7 6 5 4 3 2 1 ppm

1.12

1.14

1.14

1.16

1.18

1.19

1.21

1.23

1.23

1.24

1.26

1.32

1.33

1.34

1.36

1.38

1.38

1.39

1.41

1.63

1.64

1.65

1.66

1.67

1.68

1.74

1.75

1.75

1.77

1.77

1.78

2.01

2.02

2.03

2.04

2.04

3.20

3.21

3.22

3.23

3.24

6.17

6.18

6.18

6.33

6.38

7.26

3.2

2.1

1.1

2.1

2.0

1.0

1.9

1.0

1.0

1.0

HO

CF3

NH

Fig. S119 1H NMR (500 MHz, CDCl3) spectrum of 10d.

S87

30405060708090100110120130140150160 ppm

24.86

25.75

33.18

51.61

76.75

77.00

77.25

100.44

100.47

100.50

100.53

102.04

102.89

102.92

102.95

102.98

120.74

122.91

125.07

127.24

132.23

132.48

132.74

132.99

149.08

156.80

Fig. S120 13C NMR (126 MHz, CDCl3) spectrum of 10d.

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

98.59

Fig. S121 19F NMR (470 MHz, CDCl3) spectrum of 10d.

S88

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 ppm

-0.00

1.72

4.23

4.31

5.02

6.19

6.39

6.46

7.25

7.28

7.28

7.29

7.30

7.30

7.31

7.33

2.9

1.0

1.0

2.0

5.0

HO

CF3

NH

Fig. S122 1H NMR (500 MHz, CDCl3) spectrum of 10e.

5060708090100110120130140150160 ppm

48.06

76.75

77.00

77.26

101.28

101.31

101.34

101.37

102.01

102.70

102.73

102.76

102.79

122.83

125.00

127.44

127.54

128.78

132.48

132.73

138.36

149.78

156.82

Fig. S123 13C NMR (126 MHz, CDCl3) spectrum of 10e.

S89

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

98.60

Fig. S124 19F NMR (470 MHz, CDCl3) spectrum of 10e.

6 5 4 3 2 1 0 ppm

-0.00

1.98

1.99

2.00

2.01

2.01

2.02

2.03

3.25

3.27

3.28

4.95

6.14

6.34

6.36

4.0

4.0

0.9

1.0

1.9

HO

CF3

N

Fig. S125 1H NMR (500 MHz, CDCl3) spectrum of 10f.

S90

30405060708090100110120130140150160 ppm

25.40

47.69

76.75

77.00

77.25

99.15

99.18

99.21

99.24

101.04

101.38

101.41

101.44

101.47

120.95

123.11

125.28

127.45

131.99

132.24

132.49

132.74

149.27

156.53

Fig. S1264 13C NMR (126 MHz, CDCl3) spectrum of 10f.

100 90 80 70 60 50 40 30 20 10 ppm

-0.00

98.78

Fig. S127 19F NMR (470 MHz, CDCl3) spectrum of 10f.

Electronic Supplementary Material (ESI) for Organic & … · 2019. 3. 25. · S3 Method B: To a...

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