the first solvent-free synthesis of privileged - and ... · the first solvent-free synthesis of...

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Supporting information for

The first solvent-free synthesis of privileged - and -lactams via the

Castagnoli-Cushman reaction

Anastasia Lepikhina, Dmitry Dar’in, Olga Bakulina and Mikhail Krasavin*

Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof,

198504 Russian Federation

* Corresponding Author; phone: + 7 931 3617872, fax: +7 812 428 6939.

E-mail: [email protected]

Table of Contents

1. General Information............................................................................................................ S2

2. Experimental procedures and analytical data..................................................................... S2

3. Crystallographic data for compounds 7a, 7i and 8a........................................................ S13

4. References………………………..................................................................................... S14

5. Copies of 1H and 13C NMR spectra of compounds 6, 7, 8 and 9………………….......... S15

Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2016

mailto:[email protected]

S2

1. General Information

NMR spectra were recorded on a Bruker Avance III 400 spectrometer (1H: 400.13 MHz; 13С: 100.61

MHz; chemical shifts are reported as parts per million (δ, ppm); the residual solvent peaks were used

as internal standards: 7.28 and 2.50 ppm for 1H in CDCl3 and DMSO-d6 respectively, 40.01 and 77.02

ppm for 13C in DMSO-d6 and CDCl3 respectively; multiplicities are abbreviated as follows: s = singlet,

d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants, J, are reported in

Hz. Mass spectra were recorded on a Bruker micrOTOF spectrometer (ESI ionization). Melting points

were determined in open capillary tubes on Stuart SMP30 Melting Point Apparatus.

2. Experimental procedures and analytical data

Table S1. Screening of temperature regimens for the solvent-free reaction N-benzylidene aniline with succinic (2) and glutaric (3) anhydrides.a

Temperature Yield (n = 2)

Conversion of imine

Yield (n = 1)

Conversion of imine

90 °C < 20% ~40% < 20% ~50%

110 °C 24% ~50% 22% ~60%

130 °C 42% 98% 36% 100%

150 °C 65% 100% 48% 100%

170 °C 66% 100% 50% 100% aThe data represent NMR yield of the product (trans+cis).

Sample preparation: Anhydride 2 or 3 (20 mg) and N-(benzylidene)aniline (1 equiv.) were grounded

together and placed in a glass test tube with a screw cap, placed in a pre-heated bath and kept at

corresponding temperature for 24 hours. After cooling to ambient temperature the reaction mixture

was dissolved in CDCl3 (with addition of a few drops of DMSO-d6) and transferred into NMR test-

tube. n-Tetradecane was added as internal standard (0.4–0.7 equiv.). The intensity of 2-CH protons of

6a or 7a was determined relative to intensity of CH3 protons signals in n-tetradecane (integrated from

0.92 to 0.80 ppm equal 6). The NMR yield of 6a or 7a was calculated from equation:

�� = � × �(��)

0.1136 × 0.88× 100%

n(st) – amount of added n-tetradecane (mmol)

The factor of 0.9 was determined from 1H NMR integration experiments of solutions containing

known concentrations of 6a or 7a and n-tetradecane to reflect the difference in relaxation times of 2-

CH protons in 6a or 6a and the protons of terminal methyl groups in n-tetradecane.

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Preparation of Castagnoli-Cushman lactams 6, 7, 8 and 9.

General procedure (scale ‒ 2 mmol for 2, 1.75 mmol for 3 and 1 mmol for 4,5). The corresponding

cyclic anhydride (1 equiv.) and imine 1 (1 equiv.) were grounded together and placed in a glass test

tube with a screw cap, placed in a pre-heated bath (150 °C or 170 °C) and kept at this temperature for

indicated period of time.

Method A (this was used, unless otherwise stated). After cooling to ambient temperature 10% aqueous

KHCO3 (8 mL) was added and mixture was stirred vigorously for 10–16 hours. Filtration through a

pad of Celite afforded clear aqueous solution which was acidified with conc. HCl to pH ~ 2 and stirred

for 1‒2 h in ice bath. The crystalline precipitate was collected and dried in air to yield product as

diastereomeric mixture (dr varies from 10:1 to 3:1) with purity not less than 95%. Recrystallization

from aqueous ethanol was used for additional purification and isolation of pure trans-isomer in some

cases.

Method B. After cooling to ambient temperature reaction mixture was dissolved in a minimum

amount of boiling ethanol and water was gradually added to the stirred hot solution till opacity

appears. After cooling in ice bath the crystals formed was filtered and dried in air.

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trans/cis-5-Oxo-1,2-diphenylpyrrolidine-3-carboxylic acid (6a). Yield 280 mg (50%), dr 7:1;

crystallization from aqueous ethanol afforded dr 10:1; Beige solid; 1H NMR (400

MHz, DMSO-d6) δ for trans-isomer:[1] 12.89 (br.s, 1H, COOH), 7.41 (d, J = 8.0

Hz, 2H), 7.35 – 7.21 (m, 7H), 7.05 (t, J = 7.4 Hz, 1H), 5.58 (d, J = 5.3 Hz, 1H, 2-

H), 3.10 (ddd, J = 9.5, 6.6, 5.3 Hz, 1H, 3-H), 2.97 (dd, J = 17.0, 9.5 Hz, 1H, 4-H),

2.76 (dd, J = 17.0, 6.6 Hz, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-

isomer: 174.0, 172.3, 140.8, 138.1, 129.2, 128.9, 128.3, 127.2, 125.3, 123.2, 65.2,

46.2, 34.6. HRMS (ESI), m/z calcd for C17H15NO3 [M+Na]+ 304.0944, found 304.0943.

trans/cis-2-(4-Methoxyphenyl)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid (6b). Yield 306 mg

(50%), dr 5:1; crystallization from aqueous ethanol afforded dr 7:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.80 (br.s, 1H, COOH),

7.39 (d, J = 7.8 Hz, 2H, o-Ph), 7.29 – 7.20 (m, 4H, 2',6'-H and m-Ph), 7.05 (t, J

= 7.4 Hz, 1H, p-Ph), 6.84 (d, J = 8.7 Hz, 2H, 3',5'-H), 5.50 (d, J = 5.5 Hz, 1H, 2-

H), ), 3.69 (s, 3H, OCH3), 3.08 (ddd, J = 9.4, 6.9, 5.5 Hz, 1H, 3-H), 2.95 (dd, J =

16.9, 9.4 Hz, 1H, 4-H), 2.74 (dd, J = 16.9, 6.9 Hz, 1H, 4-H). 13C NMR (101

MHz, DMSO-d6) δ for trans-isomer: 174.1, 172.2, 159.2, 138.2, 132.5, 128.9, 128.5, 125.3, 123.4,

114.5, 64.8, 55.5, 46.4, 34.6. HRMS (ESI), m/z calcd for C18H17NO4 [M+Na]+ 334.1050, found

334.1056.

trans/cis-2-(4-Fluorophenyl)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid (6c). Crystallization

from aqueous ethanol afforded 234 mg (40%), dr 7:1; Beige solid; 1H NMR (400

MHz, DMSO-d6) δ for trans-isomer:[1] 12.85 (br.s, 1H, COOH), 7.41 – 7.35 (m, 4H,

2',6'-H and o-Ph), 7.25 (t, J = 7.6 Hz, 2H, m-Ph), 7.12 (t, J = 8.8 Hz, 2H, 3',5'-H),

7.06 (t, J = 7.4 Hz, 1H, p-Ph), 5.59 (d, J = 5.8 Hz, 1H, 2-H), 3.12 (ddd, J = 9.5, 7.2,

5.7 Hz, 1H, 3-H), 2.96 (dd, J = 17.0, 9.5 Hz, 1H, 4-H), 2.76 (dd, J = 17.0, 7.2 Hz,

1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 173.9, 172.2, 162.0 (d, J = 243.8 Hz),

138.0, 136.9 (d, J = 3.0 Hz), 129.5 (d, J = 8.4 Hz), 128.9, 125.4, 123.5, 115.9 (d, J = 21.5 Hz), 64.5,

46.2, 34.5. HRMS (ESI), m/z calcd for C17H14FNO3 [M+Na]+ 322.0850, found 322.0849.

trans-5-Oxo-1-phenyl-2-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (6d). Yield

239 mg (35%), dr 9:1; crystallization from aqueous ethanol afforded pure trans-

isomer; Beige solid; Mp 169−170 °C (EtOH-H2O); 1H NMR (400 MHz,

DMSO-d6) δ 12.92 (br.s, 1H, COOH), 7.74 (s, 1H, 2'-H), 7.65 (d, J = 7.6 Hz,

1H, 4'-H), 7.58 (d, J = 7.9 Hz, 1H, 6'-H), 7.52 (t, J = 7.7 Hz, 1H, 5'-H), 7.40 (d,

J = 7.8 Hz, 2H, o-Ph), 7.25 (t, J = 7.8 Hz, 2H, m-Ph), 7.06 (t, J = 7.6 Hz, 1H, p-

Ph), 5.73 (d, J = 6.2 Hz, 1H, 2-H), 3.21 (ddd, J = 9.5, 7.5, 6.2 Hz, 1H, 3-H),

2.97 (dd, J = 17.0, 9.5 Hz, 1H, 4-H), 2.80 (dd, J = 17.0, 7.5 Hz, 1H, 4-H). 13C NMR (101 MHz, DMSO-

d6) δ 173.7, 172.3, 142.2, 137.8, 131.6, 130.1, 129.7 (q, J = 31.7 Hz), 125.6, 125.1 (q, J = 3.7 Hz), 124.5

(q, J = 272.4 Hz), 124.4 (q, J = 4.1 Hz), 123.6, 64.5, 45.9, 34.5. HRMS (ESI), m/z calcd for

C18H14F3NO3 [M+H]+ 350.0999, found 350.1002.

NO

CO2H

CF31'

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trans/cis-1-(4-Methoxyphenyl)-5-oxo-2-(p-tolyl)pyrrolidine-3-carboxylic acid (6e). Crystallization

from aqueous ethanol afforded 220 mg (35%), dr 9:1; additional crystallization

afforded dr 16:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (br.s, 1H,

COOH), 7.26 (d, J = 9.0 Hz, 2H, 2'',6''-H), 7.19 (d, J = 8.1 Hz, 2H, 2',6'-H), 7.09

(d, J = 8.0 Hz, 2H, 3',5'-H), 6.80 (d, J = 9.0 Hz, 2H, 3'',5''-H), 5.42 (d, J = 5.6

Hz, 1H, 2-H), 3.67 (s, 3H, OCH3), 3.06 (ddd, J = 9.5, 7.0, 5.6 Hz, 1H, 3-H), 2.92

(dd, J = 16.9, 9.5 Hz, 1H, 4-H), 2.72 (dd, J = 16.9, 7.0 Hz, 1H, 4-H), 2.23 (s, 3H,

4'-CH3). 13C NMR (101 MHz, DMSO) δ 174.1, 172.0, 156.8, 137.8, 137.5,

131.1, 129.7, 127.3, 125.2, 114.1, 65.5, 55.5, 46.3, 34.5, 21.1. HRMS (ESI), m/z calcd for C19H19NO4

[M+Na]+ 348.1206, found 348.1215.

trans/cis-1-(4-Chlorophenyl)-5-oxo-2-(p-tolyl)pyrrolidine-3-carboxylic acid (6f). Crystallization


MHz, DMSO) δ for trans-isomer: 12.87 (br.s, 1H, COOH), 7.43 (d, J = 8.9 Hz,

2H, 2'',6''-H), 7.30 (d, J = 8.9 Hz, 2H, 3'',5''-H), 7.20 (d, J = 8.1 Hz, 2H, 2',6'-H),

7.10 (d, J = 8.1 Hz, 2H, 3',5'-H), 5.52 (d, J = 5.5 Hz, 1H, 2-H), 3.08 (ddd, J = 9.4,

6.9, 5.5 Hz, 1H, 3-H), 2.95 (dd, J = 17.0, 9.4 Hz, 1H, 4-H), 2.76 (dd, J = 17.0, 6.9

Hz, 1H, 4-H), 2.23 (s, 3H, CH3). 13C NMR (101 MHz, DMSO-d6) δ for trans-

isomer: 173.9, 172.4, 137.6, 137.4, 137.1, 129.8, 129.2, 128.8, 127.1, 124.8, 64.9,

46.2, 34.6, 21.1. HRMS (ESI), m/z calcd for C18H16ClNO3 [M+Na]+ 352.0711, found 352.0716.

trans/cis-1,2-Bis(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (6g). Crystallization from

aqueous ethanol afforded 220 mg (36%), dr 7:1; Beige solid; 1H NMR (400 MHz,

DMSO-d6) δ for trans-isomer: 12.86 (br.s, 1H, COOH), 7.41 – 7.37 (m, 4H, 2',6'-

H and 2'',6''-H), 7.15 – 7.06 (m, 4H, 3',5'-H and 3'',5''-H), 5.55 (d, J = 6.1 Hz, 1H,

2-H), 3.16 – 3.10 (m, 1H, 3-H), 2.94 (dd, J = 17.0, 9.5 Hz, 1H, 4-H), 2.76 (dd, J =

17.0, 7.6 Hz, 1H, 4-H).13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 173.8,

172.2, 162.0 (d, J = 250.9 Hz), 159.6 (d, J = 249.0 Hz), 136.70 (d, J = 3.0 Hz),

134.26 (d, J = 2.7 Hz), 129.65 (d, J = 8.4 Hz), 125.78 (d, J = 8.3 Hz), 115.91 (d, J

= 21.6 Hz), 115.65 (d, J = 22.4 Hz), 64.7, 46.2, 34.5. HRMS (ESI), m/z calcd for C17H13F2NO3 [M+Na]+

340.0756, found 340.0743.

trans-2-(4-Chlorophenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylic

acid (6h). Method A: crystallization from aqueous ethanol afforded 209 mg (28%),

dr 10:1. Method B: yield 373 mg (50%), pure trans-isomer; Beige solid; Mp

210−211 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 12.87 (br.s, 1H,

COOH), 7.39 – 7.34 (m, 4H, ArH'), 6.93 (d, J = 2.4 Hz, 1H, 2''-H), 6.78 (dd, J = 8.7,

2.4 Hz, 1H, 6''-H), 6.71 (d, J = 8.7 Hz, 1H, 5''-H), 5.47 (d, J = 5.7 Hz, 1H, 2-H),

4.19 – 4.14 (m, 4H, OCH2CH2O), 3.07 (ddd, J = 9.5, 7.1, 5.7 Hz, 1H, 3-H), 2.90

(dd, J = 17.0, 9.5 Hz, 1H, 4-H), 2.72 (dd, J = 17.0, 7.1 Hz, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ

173.8, 172.1, 143.3, 141.3, 139.9, 132.8, 131.3, 129.4, 129.1, 117.0, 116.7, 113.0, 64.7, 64.5, 64.3, 46.0,

34.3. HRMS (ESI), m/z calcd for C19H16ClNO5 [M+H]+ 374.0790, found 374.0795.

NO

CO2H

F

F

1'

1''

S6

trans/cis-2-(4-(Methoxycarbonyl)phenyl)-5-oxo-1-(p-tolyl)pyrrolidine-3-carboxylic acid (6i).

Method A: crystallization from aqueous ethanol afforded 261 mg (37%), dr

10:1. Method B: yield 380 mg (54%), dr 11:1; Beige solid; 1H NMR (400 MHz,

DMSO-d6) δ for trans-isomer: 12.91 (br.s, 1H, COOH), 7.87 (d, J = 8.3 Hz, 1H,

3',5'-H), 7.48 (d, J = 8.3 Hz, 1H, 2',6'-H), 7.27 (d, J = 8.4 Hz, 1H, 2'',6''-H), 7.04

(d, J = 8.4 Hz, 1H, 3'',5''-H), 5.62 (d, J = 5.7 Hz, 1H, 2-H), 3.81 (s, 3H,

CO2CH3), 3.13 (ddd, J = 9.6, 7.1, 5.7 Hz, 1H, 3-H), 2.94 (dd, J = 17.0, 9.6 Hz,

1H, 4-H), 2.77 (dd, J = 17.0, 7.1 Hz, 1H, 4-H), 2.18 (s, 3H, CH3). 13C NMR (101 MHz, DMSO-d6) δ for

trans-isomer: 173.7, 172.1, 166.3, 146.3, 135.4, 134.7, 130.0, 129.6, 129.4, 127.8, 123.3, 64.9, 52.6,

45.8, 34.4, 20.8. HRMS (ESI), m/z calcd for C20H19NO5 [M+Na]+ 376.1155, found 376.1139.

trans/cis-2-(2-Chlorophenyl)-5-oxo-1-(p-tolyl)pyrrolidine-3-carboxylic acid (6j). Crystallization


MHz, DMSO-d6) δ for trans-isomer: 13.00 (br.s, 1H, COOH), 7.46 – 7.43 (m, 1H,

6'-H), 7.32 – 7.27 (m, 5H, 3',4',5'-H and 2'',6''-H), 7.08 (d, J = 8.4 Hz, 2H, 3'',5''-H),

5.86 (d, J = 4.0 Hz, 1H, 2-H), 3.16 – 3.07 (m, 1H, 3-H), 2.98 (dd, J = 17.2, 9.6 Hz,

1H, 4-H), 2.74 (dd, J = 17.2, 4.9 Hz, 1H, 4-H), 2.20 (s, 3H, CH3). 13C NMR (101

MHz, DMSO-d6) δ for trans-isomer: 174.0, 172.3, 137.2, 135.5, 134.7, 132.5,

130.5, 130.5, 130.1, 129.6, 128.2, 122.4, 62.6, 44.4, 34.6, 20.8. HRMS (ESI), m/z

calcd for C18H16ClNO3 [M+H]+ 330.0891, found 330.0894.

trans/cis-1,2-Bis(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid (6k). Crystallization from

aqueous ethanol afforded 237 mg (37%), dr 10:1; Beige solid; 1H NMR (400

MHz, DMSO-d6) δ for trans-isomer: 12.76 (br.s, 1H, COOH), 7.25 (d, J = 9.0

Hz, 2H, 2'',6''-H), 7.23 (d, J = 8.7 Hz, 2H, 2',6'-H), 6.84 (d, J = 8.7 Hz, 2H,

3',5'-H), 6.80 (d, J = 9.0 Hz, 2H, 3'',5''-H), 5.40 (d, J = 5.8 Hz, 1H, 2-H), 3.69

(s, 3H, 4'-CH3), 3.67 (s, 3H, 4''-CH3), 3.08 (ddd, J = 9.5, 7.2, 5.8 Hz, 1H, 3-H),

2.92 (dd, J = 16.9, 9.5 Hz, 1H, 4-H), 2.72 (dd, J = 16.9, 7.2 Hz, 1H, 4-H). 13C

NMR (101 MHz, DMSO-d6) δ for trans-isomer: 174.1, 171.9, 159.2, 156.9,

132.6, 131.0, 128.7, 125.4, 114.4, 114.1, 65.3, 55.5, 55.4, 46.4, 34.5. HRMS (ESI), m/z calcd for

C19H19NO5 [M+Na]+ 364.1155, found 364.1155

trans/cis-5-Oxo-2-(thiophen-3-yl)-1-(p-tolyl)pyrrolidine-3-carboxylic acid (6l). Method A:

crystallization from aqueous ethanol afforded 209 mg (35%), dr 6:1. Method B:

yield 377 mg (63%) dr 7:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for

trans-isomer: 12.82 (br.s, 1H, COOH), 7.45 (dd, J = 4.9, 3.0 Hz, 1H, 4'-H), 7.42

(dd, J = 3.0, 1.3 Hz, 1H, 2'-H), 7.27 (d, J = 8.5 Hz, 2H, 2'',6''-H), 7.09 – 7.05 (m,

3H, 5'-H and 3'',5''-H), 5.61 (d, J = 5.0 Hz, 1H, 2-H), 3.14 (ddd, J = 9.5, 6.3, 5.0 Hz,

1H, 3-H), 2.97 (dd, J = 17.0, 9.5 Hz, 1H, 4-H), 2.71 (dd, J = 17.0, 6.3 Hz, 1H, 4-H),

2.21 (s, 3H, CH3). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 174.1,

171.8, 141.9, 135.6, 134.7, 129.4, 127.5, 126.5, 123.8, 123.5, 61.4, 45.3, 34.6, 20.9. HRMS (ESI), m/z

calcd for C16H15NO3SNa [M+Na]+ 324.0665, found 324.0670.

NO

CO2H

OMe

OMe

1'

1''

S7

trans-6-Oxo-1,2-diphenylpiperidine-3-carboxylic acid (7a). Yield 400 mg (67%), dr 6:1;

crystallization from aqueous ethanol afforded pure trans-isomer; Colorless solid; Mp

258–259 °C (EtOH-H2O) (lit[1] Mp 200 °C); 1H NMR (400 MHz, DMSO-d6) δ 12.56

(br.s, 1H, COOH), 7.33 – 7.30 (m, 4H, ArH), 7.28 – 7.21 (m, 3H, ArH), 7.19 – 7.10

(m, 3H, ArH), 5.37 (d, J = 4.4 Hz, 1H, 2-H), 3.00 (dt, J = 5.8, 4.5 Hz, 1H, 3-H), 2.67

(ddd, J = 18.0, 6.8, 5.6 Hz, 1H, 5-H), 2.56 – 2.48 (m, 1H, 5-H), 2.16 – 2.06 (m, 1H, 4-

H), 2.03 – 1.94 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ 173.8, 169.1, 143.0, 141.0, 128.85,

128.80, 127.87, 127.85, 127.5, 126.6, 65.8, 46.8, 30.4, 20.3. HRMS (ESI), m/z calcd for C18H17NO3

[M+Na]+ 318.1101, found 318.1097.

trans-2-(4-Methoxyphenyl)-6-oxo-1-phenylpiperidine-3-carboxylic acid (7b). Yield 373 mg (65%),

dr 7:1; crystallization from aqueous ethanol afforded pure trans-isomer;

Colorless solid; Mp 224−225 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ

12.49 (br.s, 1H, COOH), 7.27 – 7.20 (m, 4H, 2',6'-H and m-Ph), 7.17 – 7.10 (m,

3H, o-Ph and p-Ph), 6.87 (d, J = 8.5 Hz, 2H, 3',5'-H), 5.30 (d, J = 4.7 Hz, 1H, 2-

H), 3.73 (s, 3H, OCH3), 2.96 (dt, J = 6.2, 4.5 Hz, 1H, 3-H), 2.67 (ddd, J = 17.9,

7.0, 5.6 Hz, 1H, 5-H), 2.55 – 2.46 (m, 1H, 5-H), 2.14 – 2.05 (m, 1H, 4-H), 2.04 – 1.96 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ 173.8, 169.1, 159.1, 143.1, 132.9, 128.8, 128.7, 127.9, 126.6,

114.4, 65.4, 55.6, 47.0, 30.5, 20.4. HRMS (ESI), m/z calcd for C19H19NO4 [M+Na]+ 348.1206, found

348.1199.

trans/cis-2-(4-Fluorophenyl)-6-oxo-1-phenylpiperidine-3-carboxylic acid (7c). Yield 390 mg

(72%), dr 8:1; crystallization from aqueous ethanol afforded dr 13:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.53 (br.s, 1H, COOH), 7.37

– 7.34 (m, 2H, 2',6'-H), 7.27 – 7.23 (m, 2H, m-Ph), 7.18 – 7.07 (m, 5H, 3',5'-H, o-

Ph and p-Ph), 5.36 (d, J = 5.0 Hz, 1H, 2-H), 3.00 (dt, J = 6.4, 4.6 Hz, 1H, 3-H),

2.68 (dt, J = 17.9, 6.4 Hz, 1H, 5-H), 2.55 – 2.46 (m, 1H, 5-H), 2.17 – 2.08 (m, 1H,

4-H), 2.05 – 1.96 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 173.7, 169.0,

161.9 (d, J = 243.9 Hz), 142.8, 137.0 (d, J = 3.1 Hz), 129.7 (d, J = 8.3 Hz), 128.8, 128.0, 126.7, 115.5

(d, J = 21.5 Hz), 65.2, 47.0, 30.6, 20.7. HRMS (ESI), m/z calcd for C18H16FNO3 [M+Na]+ 336.1006,

found 336.1009.

trans/cis-6-Oxo-1-phenyl-2-(3-(trifluoromethyl)phenyl)piperidine-3-carboxylic acid (7d). Yield

417 mg (66%), dr 6:1; crystallization from aqueous ethanol afforded dr 10:1;

Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.55 (br.s, 1H,

COOH), 7.68 – 7.63 (m, 2H, Ar'H), 7.58 – 7.52 (m, 2H, Ar'H), 7.25 (t, J = 7.8

Hz, 2H, m-Ph), 7.15 (d, J = 7.6 Hz, 2H, o-Ph), 7.12 (t, J = 7.6 Hz, 1H, p-Ph),

5.48 (d, J = 5.3 Hz, 1H, 2-H), 3.09 (dt, J = 6.6, 4.7 Hz, 1H, 3-H), 2.73 (dt, J =

17.9, 6.6 Hz, 1H, 5-H), 2.56 – 2.48 (m, 1H, 5-H), 2.19 – 2.10 (m, 1H, 4-H), 2.05 – 1.94 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 173.8, 169.1, 142.4, 142.2, 132.1, 129.9, 129.5 (q,

J = 31.6 Hz), 129.0, 128.1, 126.9, 124.7 (q, J = 3.8 Hz), 124.6 (q, J = 3.8 Hz), 124.5 (q, J = 272.4 Hz),

65.1, 46.6, 30.5, 20.8. HRMS (ESI), m/z calcd for C19H16F3NO3 [M+Na]+ 386.0974, found 386.0967.

NO

CO2H

S8

trans/cis-1-(4-Methoxyphenyl)-6-oxo-2-p-tolylpiperidine-3-carboxylic acid (7e). Yield 413 mg

(70%) dr 6.5:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer:

12.48 (br.s, 1H, COOH), 7.19 (d, J = 8.3 Hz, 2H, Ar'H), 7.13 (d, J = 8.3 Hz, 2H,

Ar'H), 7.05 (d, J = 8.9 Hz, 2H, Ar''H), 6.80 (d, J = 8.9 Hz, 2H, Ar''H), 5.26 (d, J =

4.3 Hz, 1H, 2-H), 3.70 (s, 3H, OCH3), 2.93 (dt, J = 6.0, 4.3 Hz, 1H, 3-H), 2.62

(ddd, J = 18.0, 6.8, 5.4 Hz, 1H, 5-H), 2.54 – 2.44 (m, 1H, 5-H), 2.27 (s, 3H, 4'-

CH3), 2.13 – 2.04 (m, 1H, 4-H), 2.02 – 1.93 (m, 1H, 4-H). 13C NMR (101 MHz,

DMSO-d6) δ for trans-isomer: 173.8, 169.1, 157.9, 138.1, 137.0, 135.9, 129.4, 128.9, 127.4, 114.3,

65.9, 55.7, 46.9, 30.4, 20.9, 20.3. HRMS (ESI), m/z calcd for C20H21NO4 [M+Na]+ 362.1363, found

362.1356.

trans/cis-1-(4-Chlorophenyl)-6-oxo-2-p-tolylpiperidine-3-carboxylic acid (7f). Yield 383 mg (64%)

dr 7:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer:12.49 (br.s,

1H, COOH), 7.29 (d, J = 8.7 Hz, 2H, 3'',5''-H), 7.19 (d, J = 8.0 Hz, 2H, Ar'H), 7.17

(d, J = 8.7 Hz, 2H, 2'',6''-H), 7.13 (d, J = 8.0 Hz, 2H, Ar'H), 5.30 (d, J = 4.7 Hz,

1H, 2-H), 2.97 (dt, J = 6.1, 4.6 Hz, 1H, 3-H), 2.66 (ddd, J = 18.0, 6.9, 5.7 Hz, 1H,

5-H), 2.55 – 2.45 (m, 1H, 5-H), 2.26 (s, 3H, 4'-CH3), 2.14 – 2.05 (m, 1H, 4-H),

2.04 – 1.94 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer:

173.7, 169.2, 141.8, 137.7, 137.2, 131.1, 129.6, 129.5, 128.8, 127.5, 65.5, 46.9, 30.5, 20.9, 20.5.

HRMS (ESI), m/z calcd for C19H18ClNO3 [M+Na]+ 366.0867, found 366.0867.

trans-2-(3,4-Dimethoxyphenyl)-6-oxo-1-(4-(trifluoromethyl)phenyl)piperidine-3-carboxylic acid

(7g). Crystallization from aqueous ethanol afforded 378 mg (51%) dr 8:1; pure

trans-isomer was obtained after crystallization from aqueous ethanol; Beige

solid; Mp 194−195 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 12.53

(br.s, 1H, COOH), 7.63 (d, J = 8.5 Hz, 2H, 3'',5''-H), 7.43 (d, J = 8.5 Hz, 2H,

2'',6''-H), 6.90 (d, J = 2.2 Hz, 1H, 2'-H), 6.88 (d, J = 8.3 Hz, 1H, 5'-H), 6.83 (dd,

J = 8.3, 2.2 Hz, 1H, 6'-H), 5.36 (d, J = 4.7 Hz, 1H, 2-H), 3.75 (s, 3H, OCH3),

3.73 (s, 3H, OCH3), 3.06 (dt, J = 6.2, 4.5 Hz, 1H, 3-H), 2.70 (ddd, J = 18.1, 6.9, 5.6 Hz, 1H, 5-H), 2.56

– 2.47 (m, 1H, 5-H), 2.17 – 2.07 (m, 1H, 4-H), 2.06 – 1.97 (m, 1H, 4-H). 13C NMR (101 MHz,

DMSO-d6) δ 173.8, 169.4, 149.7, 149.1, 146.6, 133.0, 128.5, 127.1 (q, J = 32.0 Hz), 125.9 (q, J = 3.7

Hz), 124.5 (q, J = 272.0 Hz), 119.9, 112.8, 112.1, 65.1, 56.4, 56.3, 46.8, 30.5, 20.5. HRMS (ESI), m/z

calcd for C21H20F3NO5 [M+Na]+ 446.1186, found 446.1197.

trans-2-(4-(Methoxycarbonyl)phenyl)-6-oxo-1-p-tolylpiperidine-3-carboxylic acid (7h). Yield

465 mg (74%), dr 6:1; pure trans-isomer was obtained after crystallization from

aqueous ethanol; Beige solid; Mp 230−231 °C (EtOH-H2O); 1H NMR (400

MHz, DMSO-d6) δ 12.57 (br.s, 1H, COOH), 7.90 (d, J = 8.2 Hz, 2H, 3',5'-H),

7.48 (d, J = 8.2 Hz, 2H, 2',6'-H), 7.05 (s, 4H, Ar''H), 5.41 (d, J = 4.6 Hz, 1H, 2-

H), 3.85 (s, 3H, CO2CH3), 3.01 (dt, J = 6.2, 4.5 Hz, 1H, 3-H), 2.67 (ddd, J =

17.9, 6.8, 5.6 Hz, 1H, 5-H), 2.55 – 2.46 (m, 1H, 5-H), 2.21 (s, 3H, 4''-CH3),

2.17 – 2.07 (m, 1H, 4-H), 2.03 – 1.93 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ 173.5, 169.1,

166.4, 146.4, 140.2, 136.1, 129.7, 129.5, 129.4, 128.1, 127.7, 65.7, 52.4, 46.7, 30.5, 20.8, 20.5. HRMS

(ESI), m/z calcd for C21H21NO5 [M+Na]+ 390.1312, found 390.1311.

S9

trans-2-(2-Chlorophenyl)-6-oxo-1-p-tolylpiperidine-3-carboxylic acid (7i). Yield 486 mg (80%), dr

7:1; pure trans-isomer was obtained after crystallization from aqueous ethanol;

Beige solid; Mp 264−265 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 12.73

(br.s, 1H, COOH), 7.58 (dd, J = 7.8, 1.7 Hz, 1H, Ar'H), 7.44 – 7.39 (m, 1H, Ar'H),

7.37 (dd, J = 8.0, 1.5 Hz, 1H, Ar'H), 7.33 – 7.26 (m, 1H, Ar'H), 7.10 – 7.03 (m, 4H,

Ar''H), 5.75 (d, J = 3.4 Hz, 1H, 2-H), 3.00 (dt, J = 4.5, 3.7 Hz, 1H, 3-H), 2.67 (ddd, J

= 18.2, 6.8, 3.9 Hz, 1H, 5-H), 2.56 – 2.45 (m, 1H, 5-H), 2.23 (s, 3H, 4''-CH3), 2.17 –

2.08 (m, 1H, 4-H), 2.01 – 1.90 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ 173.5, 169.1, 140.4,

137.7, 136.3, 132.1, 130.3, 129.81, 129.80, 129.5, 127.7, 127.4, 63.1, 43.8, 30.0, 20.9, 19.7. HRMS

(ESI), m/z calcd for C19H18ClNO3 [M+Na]+ 366.0867, found 366.0869.

trans/cis-6-Oxo-2-(thiophen-3-yl)-1-p-tolylpiperidine-3-carboxylic acid (7j). Yield 353 mg (64%),

dr 4:1; crystallization from aqueous ethanol afforded dr 8:1; Beige solid; 1H NMR

(400 MHz, DMSO-d6) δ for trans-isomer: 12.52 (br.s, 1H, COOH), 7.45 (dd, J =

5.0, 3.0 Hz, 1H, 4'-H), 7.35 (ddd, J = 3.0, 1.4, 0.8 Hz, 1H, 2'-H), 7.10 – 7.05 (m,

5H, 5'-H and Ar''H), 5.40 (d, J = 4.1 Hz, 1H, 2-H), 3.85 (s, 3H, CO2CH3), 3.03 (dt,

J = 5.5, 4.3 Hz, 1H, 3-H), 2.59 (ddd, J = 17.9, 7.2, 4.9 Hz, 1H, 5-H), 2.53 – 2.42

(m, 1H, 5-H), 2.25 (s, 3H, 4''-CH3), 2.16 – 2.06 (m, 1H, 4-H), 2.05 – 1.94 (m, 1H,

4-H). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 173.7, 168.7, 142.6,

140.6, 135.9, 129.3, 127.5, 127.1, 127.0, 123.2, 62.2, 46.0, 30.2, 20.9, 20.4. HRMS (ESI), m/z calcd

for C17H17NO3S [M+Na]+ 338.0821, found 338.0828.

trans/cis-1,2-Bis(4-methoxyphenyl)-6-oxopiperidine-3-carboxylic acid (7k). Yield 444 mg (72%),

dr 6:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.43

(br.s, 1H, COOH), 7.21 (d, J = 8.6 Hz, 2H, 2',6'-H), 7.04 (d, J = 8.9 Hz, 2H,

Ar''H), 6.87 (d, J = 8.6 Hz, 2H, 3',5'-H), 6.80 (d, J = 8.9 Hz, 2H, Ar''H), 5.23 (d, J

= 4.6 Hz, 1H, 2-H), 3.74 (s, 3H, 4'-OCH3), 3.70 (s, 3H, 4''-OCH3), 2.93 (dt, J =

6.1, 4.5 Hz, 1H, 3-H), 2.62 (ddd, J = 17.9, 6.9, 5.5 Hz, 1H, 5-H), 2.53 – 2.43 (m,

1H, 5-H), 2.12 – 2.04 (m, 1H, 4-H), 2.03 – 1.94 (m, 1H, 4-H). 13C NMR (101

MHz, DMSO-d6) δ for trans-isomer: 173.8, 169.1, 159.1, 157.9, 135.9, 133.0, 128.9, 128.7, 114.4,

114.3, 65.6, 55.7, 55.6, 47.0, 30.5, 20.5. HRMS (ESI), m/z calcd for C20H21NO5 [M-H]- 354.1336,

found 354.1345.

trans-1-(3-(Methoxycarbonyl)phenyl)-2-(4-nitrophenyl)-6-oxopiperidine-3-carboxylic acid (7l).

Yield 387 mg (56%), dr 6:1; pure trans-isomer was obtained after crystallization

from aqueous ethanol; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ 12.64 (br.s,

1H, COOH), 8.13 (d, J = 8.8 Hz, 2H, 3',5'-H), 7.83 (t, J = 2.0 Hz, 1H, 2''-H), 7.73

(dt, J = 7.5, 1.5 Hz, 1H, 6''-H), 7.67 (d, J = 8.8 Hz, 2H, 2',6'-H), 7.46 (ddd, J =

8.0, 2.2, 1.5 Hz, 1H, 4''-H). 7.40 (t, J = 7.9 Hz, 1H, 5''-H), 5.58 (d, J = 5.1 Hz, 1H,

2-H), 3.84 (s, 3H, CO2CH3), 3.10 (ddd, J = 6.8, 5.1, 4.1 Hz, 1H, 3-H), 2.76 (dt, J = 17.9, 6.5 Hz, 1H, 5-

H), 2.58 – 2.47 (m, 1H, 5-H), 2.24 – 2.14 (m, 1H, 4-H), 2.08 – 1.98 (m, 1H, 4-H). 13C NMR (101

MHz, DMSO-d6) δ 173.3, 169.3, 166.1, 148.2, 147.6, 142.8, 132.7, 130.9, 129.4, 129.3, 128.8, 127.6,

123.9, 65.2, 52.5, 46.6, 30.6, 20.8. HRMS (ESI), m/z calcd for C20H18N2O7 [M-H]- 397.1030, found

397.1045.

NO

CO2H

3'

1''

Me

S

5'

S10

trans-1-(3,5-Bis(trifluoromethyl)phenyl)-2-(2,4-dimethoxyphenyl)-6-oxopiperidine-3-carboxylic

acid (7m). Method B: yield 502 mg (59%); Beige solid; Mp 234−235 °C

(EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 12.81 (br.s, 1H, COOH), 7.79

(s, 1H, 4''-H), 7.76 (s, 2H, 2'',6''-H), 7.19 (d, J = 8.3 Hz, 1H, 6'-H), 6.47 (dd, J =

8.3, 2.2 Hz, 1H, 5'-H), 6.45 (d, J = 2.2 Hz, 1H, 3'-H), 5.55 (d, J = 6.4 Hz, 1H,

2-H), 3.71 (s, 6H, 2'-OCH3 and 4'-OCH3), 3.12 (ddd, J = 7.9, 6.4, 4.1 Hz, 1H),

2.70 (ddd, J = 17.9, 7.9, 6.6 Hz, 1H), 2.58 – 2.51 (m, 1H, 5-H) 2.23 – 2.13 (m, 1H, 4-H), 2.11 – 2.04

(m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ 173.9, 169.9, 161.1, 157.9, 144.5, 130.86 (q, J = 33.2

Hz), 129.9, 128.9 (q, J = 4.8 Hz), 123.4 (q, J = 272.7 Hz), 120.2 – 119.8 (m), 119.3, 105.7, 99.3, 61.0,

56.0, 55.7, 45.0, 31.0, 22.0. HRMS (ESI), m/z calcd for C22H19FNO5 [M+H]+ 492.1240, found

492.1252.

trans/cis-2-(4-Chlorophenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-oxopiperidine-3-carboxylic

acid (7n). Yield 601 mg (89%), dr 5:1; Beige solid; 1H NMR (400 MHz, DMSO-

d6) δ for trans-isomer: 12.51 (br.s, 1H, COOH), 7.40 – 7.32 (m, 4H, ArH'), 6.71 (d,

J = 8.6 Hz, 1H, 5''-H), 6.65 (d, J = 2.3 Hz, 1H, 2''-H), 6.60 (dd, J = 8.5, 2.3 Hz, 1H,

6''-H), 5.28 (d, J = 4.5 Hz, 1H, 2-H), 4.18 (s, 4H, OCH2CH2O), 2.94 (dt, J = 5.6,

4.5 Hz, 1H, 3-H), 2.69 – 2.57 (m, 1H, 5-H), 2.54 – 2.41 (m, 1H, 5-H), 2.16 – 2.01

(m, 1H, 4-H), 2.01 – 1.86 (m, 1H, 4-H). 13C NMR (101 MHz, DMSO-d6) δ for

trans-isomer: 173.6, 169.1, 143.4, 142.4, 140.1, 136.1, 132.6, 129.5, 128.8, 120.7, 116.9, 116.9, 65.4,

64.5, 64.5, 46.6, 30.3, 20.2. HRMS (ESI), m/z calcd for C20H18ClNO5 [M+Na]+ 410.0766, found

410.0762.

trans/cis-1,2-Bis(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid (7o). Yield 419 mg (73%), dr

6:1; Beige solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.49 (br.s,

1H, COOH), 7.35 (dd, J = 8.8, 5.3 Hz, 2H), 7.16 (dd, J = 9.0, 5.1 Hz, 2H), 7.10 (t,

J = 8.8 Hz, 2H), 7.05 (t, J = 8.9 Hz, 2H), 5.31 (d, J = 5.3 Hz, 1H, 2-H), 3.00 (ddd,

J = 6.9, 5.3, 4.2 Hz, 1H, 3-H), 2.69 (dt, J = 17.8, 6.6 Hz, 1H, 5-H), 2.55 – 2.45 (m,

1H, 5-H), 2.17 – 2.08 (m, 1H, 4-H), 2.07 – 1.98 (m, 1H, 4-H). 13C NMR (101

MHz, DMSO-d6) δ for trans-isomer: 173.6, 169.2, 162.5 (d, J = 128.2 Hz), 160.1

(d, J = 127.6 Hz), 138.9 (d, J = 3.1 Hz), 136.8 (d, J = 3.0 Hz), 130.1 (d, J = 8.6 Hz), 129.9 (d, J = 8.3

Hz), 115.7 (d, J = 0.8 Hz), 115.5 (d, J = 2.0 Hz), 65.4, 47.0, 30.6, 20.9. HRMS (ESI), m/z calcd for

C18H15F2NO3 [M-H]- 330.0936, found 330.0948.

trans-4,4-Dimethyl-6-oxo-1,2-diphenylpiperidine-3-carboxylic acid (8a). Yield 222 mg (69%), dr

4:1; pure trans-isomer was obtained after crystallization from aqueous ethanol;

Colorless solid; Mp 287−288 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ

12.41 (br.s, 1H, COOH), 7.27 – 7.08 (m, 7H, ArH), 7.06 – 7.00 (m, 3H, ArH), 5.10

(d, J = 11.0 Hz, 1H, 2-H), 2.99 (d, J = 11.0 Hz, 1H, 3-H), 2.82 (d, J = 16.5 Hz, 1H,

5-H), 2.27 (d, J = 16.5 Hz, 1H, 5-H), 1.27 (s, 3H, 4-CH3), 1.09 (s, 3H, 4-CH3). 13C NMR (101 MHz, DMSO-d6) δ 172.5, 168.9, 141.2, 140.1, 128.74, 128.73,

128.72, 128.5, 128.0, 126.7, 64.6, 58.2, 47.5, 33.1, 28.8, 21.3. HRMS (ESI), m/z calcd for C20H21NO3

[M+H]+ 324.1594, found 324.1612.

S11

trans/cis-1-(4-Chlorophenyl)-4,4-dimethyl-6-oxo-2-(p-tolyl)piperidine-3-carboxylic acid (8b).

Yield 133 mg (36%), dr 5:1; crystallization from aqueous ethanol afforded dr

7:1; Colorless solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.37

(br.s, 1H, COOH), 7.22 (d, J = 8.7 Hz, 2H, 2'',6''-H), 7.11 (d, J = 8.0 Hz, 2H,

2',6'-H), 7.07 (d, J = 8.7 Hz, 2H, 3'',5''-H), 6.99 (d, J = 8.0 Hz, 2H, 3',5'-H), 5.06

(d, J = 11.0 Hz, 1H, 2-H), 2.96 (d, J = 11.0 Hz, 1H, 3-H), 2.81 (d, J = 16.5 Hz,

1H, 5-H), 2.26 (d, J = 16.5 Hz, 1H, 5-H), 2.18 (s, 3H, 4'-CH3), 1.24 (s, 3H, 4-

CH3), 1.07 (s, 3H, 4-CH3); signals of cis-isomer: 5.52 (d, J = 5.6 Hz, 1H, 2-H),

3.04 (d, J = 17.1 Hz, 1H, 5-H), 2.16 (s, 3H, 4'-CH3), 1.32 (s, 3H, 4-CH3), 1.03 (s, 3H, 4-CH3). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 172.4, 169.1, 140.2, 137.2, 136.8, 130.9, 130.5,

129.2, 128.7, 128.6, 64.0, 58.1, 47.4, 33.0, 28.7, 21.3, 21.1. HRMS (ESI), m/z calcd for C21H22ClNO3

[M+H]+ 394.1180, found 394.1196.

trans/cis-1,2-Bis(4-fluorophenyl)-4,4-dimethyl-6-oxopiperidine-3-carboxylic acid (8c). Yield

208 mg (58%), dr 4:1; Colorless solid; 1H NMR (400 MHz, DMSO-d6) δ for

trans-isomer: 12.42 (br.s, 1H, COOH), 7.32 – 7.21 (m, 2H, ArH), 7.10 – 6.94 (m,

6H, ArH), 5.10 (d, J = 11.1 Hz, 1H, 2-H), 3.02 (d, J = 11.1 Hz, 1H, 3-H), 2.82 (d,

J = 16.6 Hz, 1H, 5-H), 2.27 (d, J = 16.6 Hz, 1H, 5-H), 1.26 (s, 3H, 4-CH3), 1.09

(s, 3H, 4-CH3); signals of cis-isomer: 5.58 (d, J = 5.7 Hz, 1H, 2-H), 3.06 (d, J =

17.0 Hz, 1H, 5-H), 2.86 (dd, J = 5.7, 1.6 Hz, 1H, 3-H), 2.16 (dd, J = 17.0, 1.6 Hz,

1H, 5-H), 1.33 (s, 3H, 4-CH3), 1.04 (s, 3H, 4-CH3). 13C NMR (101 MHz, DMSO-

d6) δ for trans-isomer: 172.4, 169.1, 161.8 (d, J = 243.9 Hz), 160.5 (d, J = 243.2 Hz), 137.3 (d, J = 2.9

Hz), 136.1 (d, J = 3.0 Hz), 131.0 (d, J = 8.3 Hz), 130.7 (d, J = 8.6 Hz), 115.6 (d, J = 16.9 Hz), 115.4

(d, J = 15.8 Hz), 63.8, 57.9, 47.4, 33.0, 28.7, 21.4; signals of cis-isomer: 173.0, 170.6, 162.5 (d, J =

243.5 Hz), 161.44 (d, J = 243.2 Hz), 137.5 (d, J = 2.9 Hz), 134.6 (d, J = 3.2 Hz), 130.1 (d, J = 8.6 Hz),

114.9 (d, J = 21.3 Hz), 61.0, 56.3, 42.5, 32.2, 28.2, 27.7. HRMS (ESI), m/z calcd for C20H19F2NO3

[M+Na]+ 382.1225, found 382.1227.

trans-2-(4-Chlorophenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,4-dimethyl-6-oxopiperidine-

3-carboxylic acid (8d). Yield 207 mg (50%), dr 7:1; pure trans-isomer was

obtained after crystallization from aqueous ethanol; Colorless solid; Mp

295−296 °C (EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 12.45 (br.s, 1H,

COOH), 7.30 – 7.22 (m, 4H, ArH'), 6.65 (d, J = 9.0 Hz, 1H, 5''-H), 6.52 – 6.46

(m, 2H, 2''-H and 6''-H), 5.01 (d, J = 11.0 Hz, 1H, 2-H), 4.17 – 4.10 (m, 4H,

OCH2CH2O), 2.92 (d, J = 11.0 Hz, 1H, 3-H), 2.77 (d, J = 16.5 Hz, 1H, 5-H), 2.24

(d, J = 16.5 Hz, 1H, 5-H), 1.22 (s, 3H, 4-CH3), 1.06 (s, 3H, 4-CH3). 13C NMR

(101 MHz, DMSO-d6) δ 172.3, 169.1, 143.2, 142.1, 139.4, 134.2, 132.5, 130.6, 128.6, 121.3, 117.6,

116.9, 64.3, 64.0, 58.1, 47.4, 33.1, 28.7, 21.3. HRMS (ESI), m/z calcd for C22H22ClNO5 [M+Na]+

438.1079, found 438.1064.

S12

trans-8-(4-Methoxyphenyl)-9-oxo-7-(p-tolyl)-8-azaspiro[4.5]decane-6-carboxylic acid (9a). Yield

219 mg (63%), dr 4:1; pure trans-isomer was obtained after crystallization from

aqueous ethanol; Colorless solid; Mp >300 °C (EtOH-H2O); 1H NMR (400

MHz, DMSO-d6) δ 12.45 (br.s, 1H, COOH), 7.08 (d, J = 8.0 Hz, 2H, 2',6'-H),

6.99 (d, J = 8.0 Hz, 2H, 3',5'-H), 6.87 (d, J = 8.9 Hz, 2H, 2'',6''-H), 6.71 (d, J =

8.9 Hz, 2H, 3'',5''-H), 4.96 (d, J = 10.8 Hz, 1H, 7-H), 3.65 (s, 3H, OCH3), 3.11 (d,

J = 10.8 Hz, 1H, 6-H), 2.74 (d, J = 16.5 Hz, 1H, 10-H), 2.40 (d, J = 16.5 Hz, 1H,

10-H), 2.34 – 2.25 (m, 1H), 2.19 (s, 3H, 4'-CH3), 1.81 – 1.60 (m, 4H), 1.59 –

1.38 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.9, 169.2, 157.6, 137.4, 137.0, 134.0, 129.7,

129.2, 128.5, 114.0, 65.4, 57.0, 55.5, 46.3, 43.8, 37.4, 30.1, 24.9, 24.7, 21.1. HRMS (ESI), m/z calcd

for C24H27NO4 [M+K]+ 432.1572, found 432.1579.

trans/cis-7-(2-Chlorophenyl)-9-oxo-8-(p-tolyl)-8-azaspiro[4.5]decane-6-carboxylic acid (9b). Yield

238 mg (60%) dr 3:1; Colorless solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-

isomer: 12.07 (br.s, 1H, COOH), 7.47 – 7.37 (m, 1H, 6'-H), 7.29 – 7.15 (m, 3H,

ArH'), 6.99 (d, J = 8.3 Hz, 2H, 2'',6''-H), 6.89 (d, J = 8.3 Hz, 2H, 3'',5''-H), 5.52 (d,

J = 10.0 Hz, 1H, 7-H), 3.34 (d, J = 10.0 Hz, 1H, 6-H), 2.69 (d, J = 16.5 Hz, 1H,

10-H), 2.48 (d, J = 16.5 Hz, 1H, 10-H), 2.42 – 2.31 (m, 1H), 2.20 (s, 3H, 4''-CH3),

1.85 – 1.46 (m, 7H); signals of cis-isomer: 5.85 (d, J = 5.8 Hz, 1H, 7-H), 3.20 (d, J

= 17.0 Hz, 1H, 10-H), 3.04 (dd, J = 5.8, 1.9 Hz, 1H, 6-H), 2.18 (s, 3H, 4''-CH3). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 172.4, 169.0, 138.7, 137.3,

136.2, 131.5, 130.3, 129.8, 129.2, 129.1, 128.0, 127.52, 127.48, 55.2, 46.6, 44.4, 37.9, 31.1, 25.0, 24.6,

20.8. HRMS (ESI), m/z calcd for C23H24ClNO3 [M+H]+ 398.1517, found 398.1522.

trans/cis-9-Oxo-7-(thiophen-3-yl)-8-(p-tolyl)-8-azaspiro[4.5]decane-6-carboxylic acid (9c). Yield

110 mg (30%) dr 2:1; Colorless solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-

isomer: 12.17 (br.s, 1H, COOH), 7.32 (dd, J = 5.0, 2.9 Hz, 1H, 4'-H), 7.10 (dd, J =

2.9, 1.0 Hz, 1H, 2'-H), 7.04 – 6.95 (m, 3H, 5'-H and 2'',6''-H), 6.85 (d, J = 8.2 Hz,

2H, 3'',5''-H), 5.17 (d, J = 10.3 Hz, 1H, 7-H), 3.20 (d, J = 10.3 Hz, 1H, 6-H), 2.67

(d, J = 16.5 Hz, 1H, 10-H), 2.42 (d, J = 16.5 Hz, 1H, 10-H), 2.31 – 2.22 (m, 1H),

2.22 (s, 3H, 4''-CH3), 1.85 – 1.44 (m, 7H); signals of cis-isomer: 5.54 (d, J = 5.6

Hz, 1H, 7-H), 3.01 (d, J = 17.0 Hz, 1H, 10-H), 2.90 (dd, J = 5.8, 1.6 Hz, 1H, 6-H),

2.19 (s, 3H, 4''-CH3). 13C NMR (101 MHz, DMSO-d6) δ for trans-isomer: 172.8,

168.7, 141.7, 139.0, 135.9, 129.2, 128.3, 127.4, 126.4, 124.3, 61.1, 56.5, 46.6, 44.0, 37.7, 30.6, 25.0,

24.6, 20.9; signals of cis-isomer: 173.1, 169.9, 140.0, 139.2, 135.3, 128.9, 128.5, 128.1, 125.1, 124.4,

59.0, 55.4, 43.3, 41.4, 38.0, 37.5, 23.9, 23.8, 20.9. HRMS (ESI), m/z calcd for C21H23NO3S [M+Na]+

392.1291, found 392.1294.

S13

trans/cis-9-Oxo-7,8-diphenyl-8-azaspiro[4.5]decane-6-carboxylic acid (9d). Yield 286 mg (82%),

dr 5:1; Colorless solid; 1H NMR (400 MHz, DMSO-d6) δ for trans-isomer: 12.20

(br.s, 1H, COOH), 7.24 – 7.09 (m, 7H, ArH), 7.06 (t, J = 7.5 Hz, 1H, p-Ph), 6.99

(d, J = 7.5 Hz, 2H, o-Ph), 5.12 (d, J = 10.5 Hz, 1H, 7-H), 3.18 (d, J = 10.5 Hz, 1H,

6-H), 2.76 (d, J = 16.5 Hz, 1H, 10-H), 2.47 (d, J = 16.5 Hz, 1H, 10-H), 2.40 – 2.29

(m, 1H), 1.87 – 1.45 (m, 7H); signals of cis-isomer: 5.49 (d, J = 5.7 Hz, 1H, 7-H),

3.13 (d, J = 17.0 Hz, 1H, 10-H), 2.94 (dd, J = 5.7, 1.5 Hz, 1H, 6-H). 13C NMR (101

MHz, DMSO-d6) δ for trans-isomer: 172.7, 169.0, 141.6, 140.4, 128.7, 128.66,

128.65, 128. 6, 127.9, 126.6, 65.7, 57.2, 46.7, 44.1, 37.7, 30.5, 25.0, 24.6; signals of cis-isomer: 172.8,

170.4, 141.8, 138.6, 128.9, 128.3, 128.3, 127.9, 127.4, 126.0, 63.0, 55.9, 43.5, 41.2, 38.1, 37.4), 24.0,

23.8. HRMS (ESI), m/z calcd for C22H23NO3 [M+Na]+ 372.1570, found 372.1564.

3. Crystallographic data for compounds 7a, 7i and 8a

X-ray Single Crystal analyses were performed on Agilent Technologies Xcalibur Eos and Agilent

Technologies (Oxford Diffraction) «Supernova» diffractometers. Using Olex2 [2], structures were

solved with the Superflip [3] structure solution program using Charge Flipping and refined with the

ShelXL [4] refinement package using Least Squares minimisation. CCDC 1470615, 1470616,

1470618 contain the supplementary crystallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.

7a 7i 8a

S14

Table S2. Crystal data and structure refinement for 7a, 7i and 8a

Identification code 7a 7i 8a Empirical formula C18H17NO3 C19H18ClNO3 C20H21NO3

Formula weight 295.32 343.79 323.38

Temperature/K 100(2) 100(2) 100(2)

Crystal system monoclinic monoclinic monoclinic

Space group P21/c P21/c P21/c a/Å 9.2973(3) 10.15491(19) 6.1741(3)

b/Å 9.6961(3) 11.7971(2) 22.3708(7)

c/Å 17.2808(6) 14.1333(3) 12.6253(4)

β/° 110.402(3) 97.8247(17) 103.267(4)

Volume/Å3 1460.10(9) 1677.37(5) 1697.25(11)

Z 4 4 4

ρcalcg/cm3 1.343 1.361 1.266

μ/mm-1 0.744 0.244 0.085

F(000) 624.0 720.0 688.0

Crystal size/mm3 0.1 × 0.1 × 0.1 0.3 × 0.3 × 0.25 0.25 × 0.25 × 0.15

Radiation CuKα (λ = 1.54184) MoKα (λ = 0.71073) MoKα (λ = 0.71073)

2Θ range for data collection/°

10.15 to 149.95 5.322 to 55 6.392 to 54.998

Index ranges -11 ≤ h ≤ 11, -11 ≤ k ≤ 12, -

20 ≤ l ≤ 21 -13 ≤ h ≤ 13, -15 ≤ k ≤ 15, -

18 ≤ l ≤ 18 -3 ≤ h ≤ 8, -26 ≤ k ≤ 29, -16

≤ l ≤ 13

Reflections collected 9351 28349 7371

Independent reflections 2995 [Rint = 0.0406, Rsigma =

0.0362] 3845 [Rint = 0.0327, Rsigma =

0.0168] 3881 [Rint = 0.0197, Rsigma =

0.0362]

Data/restraints/parameters 2995/0/199 3845/0/219 3881/0/219

Goodness-of-fit on F2 1.034 1.028 1.031

Final R indexes [I>=2σ (I)] R1 = 0.0431, wR2 = 0.1103 R1 = 0.0322, wR2 = 0.0811 R1 = 0.0436, wR2 = 0.0941

Final R indexes [all data] R1 = 0.0511, wR2 = 0.1185 R1 = 0.0361, wR2 = 0.0840 R1 = 0.0583, wR2 = 0.1009

Largest diff. peak/hole / e Å-

3 0.55/-0.25 0.38/-0.31 0.34/-0.20

CCDC 1470616 1470618 1470615

4. References:

1. Tabcheh, M.; Baroudi, M.; Elomar, F.; Elzant, A.; Elkhatib, M.; Rolland, V. Asian J.

Chem., 2006, 18(3), 1771–1782.

2. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. J. Appl. Cryst.,

2009, 42, 339–341.

3. Palatinus, L.; Chapuis, G. J. Appl. Cryst., 2007, 40, 786–790; Palatinus, L.; van der Lee, A. J.

Appl. Cryst., 2008, 41, 975–984; Palatinus, L.; Prathapa, S. J.; van Smaalen, S. J. Appl. Cryst.,

2012, 45, 575–580.

4. Sheldrick, G.M. Acta Cryst., 2015, C71, 3–8.

S15

1H and 13C NMR spectra of compound 6a

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

0.11

1.01

1.03

1.02

1.00

0.10

1.11

7.49

2.00

0.94

2.73

2.75

2.77

2.79

2.94

2.96

2.98

3.00

3.08

3.09

3.09

3.10

3.11

3.11

3.12

3.13

5.57

5.58

5.72

5.75

7.03

7.05

7.07

7.21

7.23

7.25

7.27

7.28

7.30

7.32

7.32

7.34

7.40

7.42

12.87

0102030405060708090100110120130140150160170180190

34.56

46.17

65.21

123.23

125.29

127.20

128.26

128.91

129.16

138.15

140.77

172.32

174.04

S16

1H and 13C NMR spectra of compound 6b

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.03

1.04

1.09

3.31

1.00

0.14

2.21

1.19

0.28

4.25

1.93

0.22

0.99

2.71

2.73

2.75

2.77

2.92

2.94

2.96

2.98

3.05

3.07

3.07

3.08

3.08

3.09

3.09

3.11

3.69

5.49

5.51

6.83

6.85

7.03

7.05

7.07

7.23

7.23

7.25

7.26

7.27

7.38

7.40

12.80

0102030405060708090100110120130140150160170180

34.6446.3855.45

64.83

114.50

123.44

125.28

128.51

128.87

132.51

138.16

159.19172.19

174.09

S17

1H and 13C NMR spectra of compound 6c

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.12

1.12

1.11

1.10

0.14

1.25

2.36

2.44

4.37

1.03

2.73

2.75

2.78

2.79

2.92

2.95

2.97

2.99

3.09

3.11

3.11

3.12

3.13

3.13

3.14

3.15

5.58

5.60

5.77

5.79

7.04

7.06

7.08

7.09

7.12

7.14

7.23

7.25

7.27

7.37

7.38

7.39

7.40

7.40

12.85

0102030405060708090100110120130140150160170180

34.55

46.16

64.46

115.80

116.01

123.50

125.40

128.91

129.45

129.53

136.88

136.91

137.97

160.78

163.20

172.20

173.88

S18

1H and 13C NMR spectra of compound 6d

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.03

1.02

1.05

1.00

1.05

2.04

2.00

1.07

1.06

1.01

1.00

0.94

2.77

2.78

2.81

2.83

2.93

2.96

2.98

3.00

3.18

3.19

3.20

3.20

3.21

3.22

3.22

3.23

5.72

5.74

7.04

7.06

7.07

7.23

7.25

7.27

7.39

7.41

7.50

7.52

7.54

7.57

7.59

7.64

7.66

7.74

12.92

0102030405060708090100110120130140150160170180190

34.52

45.95

64.47

120.96

123.15

123.58

124.35

124.39

124.43

124.47

125.03

125.07

125.11

125.14

125.55

125.86

127.46

128.96

129.24

129.53

129.84

130.15

131.57

137.80

142.24

172.29

173.66

S19

1H and 13C NMR spectra of compound 6e

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

2.99

1.01

1.00

0.98

2.99

1.00

0.06

1.99

2.09

1.91

1.93

0.93

2.23

2.69

2.71

2.73

2.75

2.89

2.91

2.95

3.67

5.41

5.42

5.58

5.60

6.79

6.81

7.08

7.10

7.18

7.20

7.25

7.27

12.80

0102030405060708090100110120130140150160170180190

21.08

34.46

46.27

55.55

65.48

114.11

125.22

127.27

129.68

131.07

137.46

137.85

156.85

172.00

174.11

S20

1H and 13C NMR spectra of compound 6f

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

3.05

1.00

1.04

1.03

0.98

2.15

1.98

2.07

1.94

0.92

2.23

2.73

2.74

2.77

2.79

2.92

2.94

2.96

2.98

3.05

3.06

3.07

3.07

3.08

3.09

3.09

3.10

5.51

5.53

5.69

5.71

7.09

7.11

7.19

7.21

7.29

7.31

7.42

7.45

12.87

0102030405060708090100110120130140150160170180190

21.08

34.57

46.24

64.90

124.78

127.15

128.83

129.18

129.78

137.07

137.42

137.61

172.40

173.93

S21

1H and 13C NMR spectra of compound 6g

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.5

0.75

0.31

1.04

0.99

0.23

1.06

0.58

0.23

1.00

0.21

4.29

0.39

3.71

0.37

1.14

1.05

1.06

1.08

2.73

2.75

2.78

2.79

2.91

2.93

2.95

2.97

3.10

3.12

3.14

3.16

3.44

3.46

3.81

3.83

3.86

3.88

5.54

5.56

5.74

5.76

7.07

7.09

7.10

7.11

7.12

7.15

7.26

7.28

7.28

7.30

7.37

7.38

7.39

7.40

7.40

7.50

7.50

7.52

7.53

12.85

0102030405060708090100110120130140150160170180190

34.47

46.20

64.67

115.53

115.76

115.80

116.01

125.74

125.82

129.61

129.69

134.27

136.68

136.71

158.35

160.75

160.82

163.25

172.21

173.79

S22

1H and 13C NMR spectra of compound 6h

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.09

1.04

1.01

3.97

1.00

0.98

1.00

1.01

3.91

0.97

2.69

2.70

2.73

2.75

2.87

2.89

2.91

2.93

3.04

3.06

3.06

3.07

3.08

3.09

4.17

5.46

5.48

6.70

6.72

6.77

6.78

6.79

6.80

6.93

6.94

7.34

7.35

7.36

7.37

7.38

7.39

12.86

0102030405060708090100110120130140150160170180190

34.35

45.96

64.35

64.48

64.73

113.01

116.75

117.01

129.11

129.36

131.31

132.81

139.92

141.27

143.26

172.08

173.80

S23

1H and 13C NMR spectra of compound 6i

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

2.95

1.00

1.06

0.96

2.97

1.00

0.11

1.97

1.85

0.30

1.85

1.91

0.89

2.18

2.74

2.76

2.78

2.80

2.91

2.94

2.98

3.12

3.81

5.61

5.63

5.79

5.81

7.03

7.05

7.26

7.28

7.36

7.37

7.38

7.47

7.49

7.84

7.86

7.88

12.91

0102030405060708090100110120130140150160170180190

20.83

34.43

45.80

52.57

64.91

123.35

127.83

129.43

129.61

129.96

134.68

135.42

146.28

166.30

172.15

173.74

S24

1H and 13C NMR spectra of compound 6j

1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

3.21

1.14

1.03

1.02

1.00

0.08

2.17

5.19

1.07

0.84

2.20

2.71

2.73

2.76

2.77

2.94

2.97

2.99

3.01

5.86

5.87

6.13

6.15

7.07

7.09

7.27

7.28

7.29

7.29

7.30

7.44

7.45

7.46

13.02

0102030405060708090100110120130140150160170180190

20.84

34.57

44.36

62.64

122.45

122.83

128.17

129.62

130.11

130.47

132.46

134.72

135.48

137.24

S25

1H and 13C NMR spectra of compound 6k

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

1.07

1.01

1.03

6.64

1.00

0.13

4.47

0.27

3.99

0.28

0.92

2.69

2.71

2.73

2.75

2.76

2.89

2.91

2.93

2.95

3.05

3.06

3.07

3.07

3.08

3.09

3.09

3.10

3.67

3.69

5.39

5.41

5.57

5.60

6.78

6.79

6.80

6.81

6.81

6.82

6.83

6.83

6.85

7.12

7.15

7.22

7.23

7.24

7.26

7.26

7.27

7.36

7.38

12.76

0102030405060708090100110120130140150160170180190

34.51

46.37

55.45

55.55

65.26

114.10

114.18

114.44

124.74

125.40

128.66

131.04

132.62

156.88

159.19

171.93

174.13

S26

1H and 13C NMR spectra of compound 6l

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

3.39

1.03

1.06

0.98

0.14

1.00

0.14

0.14

3.28

2.00

2.54

1.01

2.21

2.70

2.73

2.74

2.93

2.96

3.00

3.13

3.76

3.78

3.79

3.80

3.81

3.83

5.60

5.61

5.75

5.77

6.95

6.96

6.96

7.06

7.07

7.08

7.26

7.28

7.37

7.39

7.40

7.41

7.42

7.43

7.44

7.45

7.45

7.46

12.82

0102030405060708090100110120130140150160170180190

20.89

34.59

45.28

61.40

122.74

123.47

123.79

126.52

127.55

129.38

129.45

134.67

135.64

141.93

171.76

174.11

S27


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

0.92

0.90

0.92

0.90

0.90

2.66

2.63

3.55

0.82

1.95

1.96

1.98

2.00

2.01

2.02

2.03

2.07

2.09

2.10

2.12

2.14

2.15

2.48

2.54

2.56

2.62

2.64

2.64

2.65

2.67

2.68

2.69

2.70

2.98

2.99

3.00

3.00

3.01

3.02

5.37

5.38

7.11

7.13

7.14

7.16

7.18

7.22

7.23

7.25

7.27

7.32

7.33

12.56

0102030405060708090100110120130140150160170180190

20.32

30.42

46.85

65.85

126.64

127.52

127.85

127.87

128.80

128.85

140.99

143.06

169.11

173.75

NO

CO2H

NO

CO2H

S28


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

0.92

0.91

1.64

0.92

0.91

2.73

0.91

1.80

2.69

3.61

0.77

2.01

2.01

2.08

2.09

2.11

2.50

2.51

2.51

2.52

2.53

2.53

2.55

2.61

2.62

2.63

2.64

2.67

2.94

2.95

2.95

2.96

2.97

3.73

5.29

5.31

6.86

6.88

7.11

7.13

7.14

7.16

7.21

7.23

7.25

7.27

12.49

0102030405060708090100110120130140150160170180190

20.45

30.49

47.04

55.61

65.36

114.44

126.59

127.91

128.71

128.77

132.86

143.08

159.13

169.06

173.82

S29


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

1.36

1.30

2.49

1.40

1.29

0.10

0.10

1.28

6.68

2.80

2.61

1.24

2.00

2.01

2.02

2.03

2.10

2.11

2.13

2.15

2.49

2.49

2.49

2.50

2.50

2.50

2.51

2.51

2.52

2.53

2.53

2.53

2.55

2.55

2.64

2.66

2.67

2.70

2.98

2.99

2.99

3.00

3.01

3.02

5.35

5.37

7.07

7.10

7.11

7.12

7.13

7.14

7.15

7.16

7.23

7.25

7.27

7.34

7.35

7.36

7.37

12.53

0102030405060708090100110120130140150160170180190

20.67

30.57

46.96

65.23

115.43

115.65

126.70

128.01

128.83

129.70

129.78

137.04

137.07

142.83

160.67

163.10

169.05

173.66

S30


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.30

1.14

2.51

1.26

1.12

0.12

0.11

1.11

3.48

2.40

2.24

2.55

1.07

2.02

2.03

2.12

2.14

2.16

2.49

2.50

2.50

2.51

2.51

2.52

2.54

2.69

2.71

2.72

2.75

3.08

3.09

3.10

3.10

3.55

3.57

3.58

3.59

3.61

5.43

5.45

5.47

5.49

7.10

7.12

7.14

7.14

7.16

7.23

7.25

7.27

7.48

7.52

7.54

7.55

7.57

7.60

7.63

7.65

7.67

12.55

0102030405060708090100110120130140150160170180

21.01

30.69

65.42

131.93

131.94

142.37

142.56

169.16

173.52

S31

1H and 13C NMR spectra of compound 7e

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

1.13

1.05

3.37

1.98

1.20

1.01

0.15

3.41

0.13

1.00

2.24

2.01

2.40

2.05

1.05

1.96

1.97

1.98

1.99

2.00

2.06

2.07

2.09

2.27

2.46

2.46

2.49

2.53

2.58

2.60

2.61

2.63

2.64

2.91

2.92

2.93

2.95

3.70

5.18

5.19

5.26

5.27

6.79

6.81

7.04

7.06

7.12

7.14

7.18

7.20

12.48

0102030405060708090100110120130140150160170180190

20.25

20.95

30.35

46.91

55.72

65.87

114.28

127.42

128.90

129.44

135.95

137.02

138.13

157.95

169.14

173.82

S32

1H and 13C NMR spectra of compound 7f

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.12

1.04

3.35

2.21

1.14

1.00

0.14

1.00

2.49

4.13

2.24

0.92

1.95

1.96

1.97

1.99

2.00

2.02

2.03

2.04

2.06

2.08

2.09

2.11

2.13

2.14

2.26

2.46

2.48

2.50

2.50

2.51

2.51

2.52

2.52

2.54

5.24

5.26

5.30

5.31

7.12

7.12

7.14

7.16

7.17

7.18

7.18

7.20

7.28

7.31

12.49

0102030405060708090100110120130140150160170180190

20.50

20.95

30.48

46.95

65.52

127.46

128.82

129.51

129.65

131.09

137.20

137.67

141.83

169.23

173.73

S33

1H and 13C NMR spectra of compound 7g

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

2.10

5.34

1.05

1.28

2.83

2.77

1.00

0.98

1.86

1.91

1.87

0.92

2.03

2.04

2.04

2.09

2.11

2.13

2.49

2.54

2.54

2.54

2.66

2.67

2.68

2.69

2.72

2.72

3.04

3.05

3.05

3.06

3.06

3.08

3.73

3.75

5.36

5.37

6.81

6.82

6.83

6.84

6.87

6.89

6.89

6.90

7.42

7.44

7.62

7.64

12.53

0102030405060708090100110120130140150160170180190

20.54

30.52

46.83

56.26

56.40

65.14

112.11

112.82

119.96

125.80

125.84

125.88

125.91

126.67

126.98

127.30

127.62

128.50

132.98

146.61

149.06

149.72

169.42

173.79

S34

1H and 13C NMR spectra of compound 7h

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.06

1.02

3.05

1.95

1.09

1.13

2.93

1.00

4.00

1.91

2.01

0.78

1.97

1.99

2.00

2.10

2.11

2.13

2.15

2.21

2.46

2.48

2.50

2.51

2.51

2.53

2.55

2.63

2.65

2.66

2.69

2.99

3.00

3.02

3.03

3.85

5.40

5.42

7.05

7.47

7.49

7.89

7.91

12.57

0102030405060708090100110120130140150160170180190

20.53

20.84

30.46

46.66

52.37

65.72

127.71

128.08

129.42

129.54

129.70

136.07

140.24

146.42

166.38

169.07

173.53

S35

1H and 13C NMR spectra of compound 7i

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.02

1.02

2.98

1.88

1.02

1.00

0.99

3.92

1.00

1.95

1.01

0.82

1.94

1.95

1.96

1.96

1.97

1.98

1.99

2.00

2.11

2.13

2.14

2.16

2.23

2.46

2.48

2.48

2.50

2.51

2.51

2.52

2.53

2.55

2.63

2.64

2.65

2.66

2.68

2.69

2.70

2.71

2.99

3.00

3.01

3.02

5.75

5.75

7.04

7.05

7.07

7.09

7.28

7.30

7.31

7.32

7.36

7.38

7.39

7.41

7.43

12.73

0102030405060708090100110120130140150160170180190

19.71

20.86

29.97

43.82

63.11

127.43

127.73

129.52

129.80

129.81

130.34

132.05

136.30

137.66

140.36

169.13

173.46

S36

1H and 13C NMR spectra of compound 7j

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.21

1.02

3.33

0.84

1.09

1.04

0.13

0.99

5.07

0.94

1.04

0.95

1.99

2.01

2.01

2.02

2.09

2.10

2.12

2.25

2.47

2.48

2.49

2.50

2.55

2.56

2.57

2.58

2.61

3.02

3.03

3.04

3.05

5.33

5.34

5.39

5.40

7.05

7.05

7.07

7.08

7.09

7.09

7.34

7.35

7.44

7.45

7.45

7.46

12.52

0102030405060708090100110120130140150160170180190

20.41

20.88

30.22

46.03

62.22

123.19

127.01

127.06

127.53

129.33

135.92

140.56

142.63

168.75

173.72

S37

1H and 13C NMR spectra of compound 7k

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

2.18

0.55

1.13

1.04

3.47

3.58

0.18

1.00

2.31

2.39

0.32

2.00

0.35

2.01

0.91

1.98

1.99

2.00

2.01

2.02

2.06

2.08

2.09

2.11

2.44

2.46

2.48

2.48

2.59

2.60

2.62

2.63

2.65

2.91

2.92

2.93

2.95

3.70

3.74

5.16

5.17

5.22

5.23

6.79

6.81

6.86

6.88

7.03

7.05

7.20

7.22

12.43

0102030405060708090100110120130140150160170180190

20.46

30.45

47.05

55.62

55.72

65.60

114.27

114.43

128.73

128.96

132.99

135.89

157.94

159.12

169.11

173.85

S38

1H and 13C NMR spectra of compound 7l

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

1.09

1.04

0.72

1.11

1.13

2.98

1.00

1.08

0.97

1.98

1.01

0.95

2.00

0.90

2.02

2.03

2.04

2.05

2.16

2.18

2.19

2.21

2.54

2.56

2.58

2.72

2.73

2.75

2.76

2.78

3.08

3.09

3.09

3.10

3.11

3.12

3.84

5.57

5.58

7.38

7.40

7.42

7.45

7.45

7.45

7.45

7.47

7.47

7.47

7.47

7.66

7.68

7.72

7.74

7.83

8.12

8.14

8.15

12.64

0102030405060708090100110120130140150160170180190

20.84

30.58

46.56

52.50

65.17

123.90

127.64

128.86

129.34

129.42

130.89

132.75

142.78

147.63

148.17

166.13

169.34

173.34

S39

1H and 13C NMR spectra of compound 7m

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.0

2.10

5.34

1.05

1.28

2.83

2.77

1.00

0.98

1.86

1.91

1.87

0.92

2.03

2.04

2.04

2.09

2.11

2.13

2.49

2.54

2.54

2.54

2.66

2.67

2.68

2.69

2.72

2.72

3.04

3.05

3.05

3.06

3.06

3.08

3.73

3.75

5.36

5.37

6.81

6.82

6.83

6.84

6.87

6.89

6.89

6.90

7.42

7.44

7.62

7.64

12.53

0102030405060708090100110120130140150160170180190

20.54

30.52

46.83

56.26

56.40

65.14

112.11

112.82

119.96

125.80

125.84

125.88

125.91

126.67

126.98

127.30

127.62

128.50

132.98

146.61

149.06

149.72

169.42

173.79

S40

1H and 13C NMR spectra of compound 7n

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

1.32

1.08

0.98

1.40

1.14

4.91

0.12

1.00

1.18

0.98

1.18

0.35

4.20

0.91

1.92

1.93

1.95

1.97

2.06

2.08

2.09

2.11

2.42

2.44

2.44

2.46

2.47

2.49

2.49

2.59

2.60

2.62

2.63

2.64

2.66

2.93

2.94

2.95

2.96

4.18

5.20

5.22

5.28

5.29

6.59

6.60

6.61

6.62

6.65

6.66

6.70

6.72

7.33

7.35

7.36

7.38

12.51

0102030405060708090100110120130140150160170180190

20.24

30.32

46.65

64.49

64.52

65.44

116.89

116.94

120.75

128.83

129.54

132.58

136.06

140.08

142.41

143.40

169.08

173.60

S41

1H and 13C NMR spectra of compound 7o

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

1.11

1.02

1.96

1.18

1.14

0.14

1.00

4.26

2.15

1.98

0.95

2.03

2.03

2.04

2.05

2.05

2.10

2.12

2.14

2.15

2.48

2.48

2.50

2.50

2.51

2.51

2.52

2.52

2.54

2.65

2.67

2.68

2.69

2.71

2.98

2.99

2.99

3.00

3.00

3.01

3.01

3.02

5.26

5.28

5.30

5.32

7.03

7.05

7.07

7.07

7.10

7.12

7.15

7.16

7.17

7.18

7.33

7.35

7.36

7.37

12.49

0102030405060708090100110120130140150160170180190

20.92

30.62

47.01

65.38

115.45

115.47

115.68

115.68

129.82

129.90

130.01

130.09

136.81

136.84

138.90

138.93

159.44

160.71

161.86

163.13

169.23

173.65

S42


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

2.98

2.96

0.98

1.02

0.98

1.00

3.09

7.30

0.96

1.09

1.27

2.25

2.29

2.80

2.85

2.98

3.00

5.08

5.11

5.56

5.57

7.00

7.02

7.04

7.06

7.09

7.10

7.11

7.12

7.13

7.13

7.14

7.15

7.16

7.17

7.18

7.19

7.20

7.22

12.41

0102030405060708090100110120130140150160170180190

21.33

28.76

33.11

47.50

58.18

64.57

126.69

128.03

128.50

128.72

128.73

128.74

140.13

141.25

168.95

172.48

S43


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

0.43

3.06

2.96

0.41

3.42

1.00

1.13

1.00

0.16

1.00

0.14

0.27

1.96

4.21

2.46

1.10

1.03

1.07

1.24

1.32

2.16

2.18

2.24

2.28

2.79

2.83

2.95

2.97

3.02

3.06

5.05

5.08

5.52

5.53

6.98

7.00

7.06

7.08

7.10

7.12

7.21

7.23

12.37

0102030405060708090100110120130140150160170180190

21.09

21.35

28.72

33.03

47.41

58.15

63.99

128.65

128.72

129.22

130.55

130.94

136.84

137.23

140.16

169.06

172.40

S44


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

3.09

10.00

9.78

3.03

1.05

3.30

3.25

1.02

4.29

3.24

1.00

23.49

10.57

3.91

1.04

1.09

1.26

1.33

2.14

2.14

2.18

2.18

2.25

2.29

2.80

2.84

2.85

2.86

2.87

2.87

3.01

3.04

3.08

5.08

5.11

5.58

5.59

6.95

6.97

6.99

7.00

7.01

7.02

7.03

7.04

7.04

7.05

7.06

7.07

7.07

7.08

7.24

7.25

7.26

7.27

7.27

7.28

7.29

7.29

7.30

12.42

0102030405060708090100110120130140150160170180190

21.39

27.66

28.15

28.71

32.25

33.04

42.46

47.39

56.34

57.90

61.04

63.80

114.81

115.02

115.28

115.44

115.49

115.66

130.10

130.18

130.68

130.77

130.92

131.00

134.56

134.59

136.10

136.13

137.29

137.32

137.52

137.55

161.24

163.78

169.11

170.58

172.36

173.03

S45


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.513.013.5

3.04

3.00

1.01

1.00

1.01

3.96

1.00

2.00

1.04

4.08

0.92

1.06

1.22

2.22

2.26

2.75

2.79

2.90

2.93

4.10

4.12

4.14

4.15

4.17

4.18

5.00

5.03

6.48

6.48

6.50

6.50

6.63

6.66

7.25

7.25

7.27

7.28

7.29

12.45

0102030405060708090100110120130140150160170180190

21.30

28.70

33.09

47.43

58.15

63.97

64.32

116.95

117.65

121.31

128.60

130.64

132.54

134.17

139.38

142.12

143.19

169.12

172.33

S46


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

3.06

4.12

3.03

1.06

1.00

1.00

1.01

3.13

1.00

2.03

2.01

2.00

2.05

0.84

1.45

1.46

1.47

1.48

1.49

1.51

1.52

1.54

1.64

1.66

1.67

1.68

1.69

2.19

2.38

2.42

2.72

2.76

3.10

3.13

3.65

4.95

4.98

6.70

6.72

6.86

6.88

6.98

7.00

7.07

7.09

12.45

0102030405060708090100110120130140150160170180190

21.10

24.66

24.88

30.15

37.43

43.85

46.35

55.48

57.00

65.40

113.98

128.50

129.18

129.67

134.04

137.02

137.42

157.63

169.20

172.92

S47


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

3.47

3.70

1.92

0.65

3.00

1.35

0.87

1.11

0.39

0.32

1.03

1.00

0.25

1.96

2.86

0.44

3.18

1.14

1.23

1.46

1.48

1.50

1.52

1.53

1.55

1.55

1.56

1.56

1.57

1.59

1.61

1.62

1.64

1.68

1.69

1.70

1.71

1.71

1.72

1.73

1.74

1.76

1.78

1.79

1.80

1.81

1.82

1.82

1.83

1.83

1.85

2.18

2.20

2.30

2.31

2.33

2.35

2.36

2.37

2.38

2.40

2.46

2.50

2.67

2.71

3.03

3.03

3.04

3.05

3.18

3.22

3.33

3.36

5.51

5.53

5.85

5.86

6.88

6.90

6.98

7.00

7.01

7.04

7.06

7.10

7.11

7.11

7.12

7.16

7.18

7.18

7.18

7.20

7.20

7.22

7.23

7.24

7.26

7.40

7.41

7.42

7.44

0102030405060708090100110120130140150160170180190

20.80

24.60

24.98

31.06

37.92

44.44

46.57

55.16

127.48

127.52

127.96

129.05

129.24

129.77

130.31

131.50

133.32

136.17

137.28

138.73

169.00

172.39

S48


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

3.48

6.90

1.19

2.96

1.41

1.02

1.02

0.42

0.46

1.03

1.00

0.40

1.98

0.39

4.50

0.98

0.78

0.94

1.05

1.48

1.49

1.51

1.52

1.54

1.55

1.56

1.57

1.66

1.67

1.68

1.70

1.71

1.79

1.81

1.82

1.84

2.19

2.22

2.24

2.25

2.28

2.28

2.40

2.44

2.65

2.69

2.99

3.03

3.18

3.21

5.16

5.19

5.53

5.55

6.84

6.86

6.99

7.00

7.00

7.02

7.03

7.03

7.04

7.04

7.10

7.10

7.10

7.11

7.31

7.32

7.33

7.33

12.17

0102030405060708090100110120130140150160170180190

20.89

24.59

24.89

30.59

37.70

43.98

46.57

56.50

61.10

124.26

126.37

127.44

128.30

129.25

135.91

139.05

141.70

168.75

172.78

S49


0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.512.513.5

8.45

1.23

1.00

1.05

0.25

0.45

1.17

1.00

0.19

2.13

1.15

7.96

0.37

0.84

1.50

1.51

1.52

1.57

1.58

1.69

1.69

1.70

1.71

1.72

1.73

1.81

1.84

2.31

2.32

2.33

2.34

2.35

2.36

2.45

2.49

2.74

2.78

2.93

2.94

2.95

3.11

3.15

3.17

3.20

5.10

5.13

5.48

5.50

6.98

7.00

7.04

7.06

7.08

7.10

7.12

7.12

7.13

7.14

7.15

7.15

7.17

7.18

7.19

7.20

7.21

7.22

7.23

7.26

7.28

12.20

0102030405060708090100110120130140150160170180190

23.85

23.97

24.63

24.96

30.54

37.42

37.68

38.09

41.25

43.47

44.13

46.68

55.90

57.25

63.02

65.70

126.04

126.63

127.40

127.92

127.95

128.26

128.33

128.49

128.56

128.66

128.93

138.64

140.41

141.58

141.81

169.01

170.42

172.65

172.77

the first solvent-free synthesis of privileged - and ... · the first solvent-free synthesis of...

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