Supporting Information carboxylic acids with Aryl bromides ... · S1 Supporting Information Ligand-free Pd-catalysed decarboxylative arylation of Imidazo[1,2-a]pyridine-3-carboxylic

S1

Supporting Information

Ligand-free Pd-catalysed decarboxylative arylation of Imidazo[1,2-a]pyridine-3-carboxylic acids with Aryl bromides†

Uttam B. Karalea,b, Saradhi Kalaria, Jala Shivakumarc, Vitthal B. Makanea,b, Dattatraya A. Babara,b, Ritesh P. Thakared, Bathini Nagendra Babuc, Sidharth Choprad, Haridas B. Rodea,b*

a Department of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India

bAcademy of Scientific and Innovative Research (AcSIR), New Delhi, IndiacDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and

Research, Balanagar, Hyderabad - 500 037, IndiadMicobiology Division, Central Drug Research Institute, Lucknow - 226 031, India

CORRESPONDING AUTHOR’S E-MAIL [email protected]

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

S2

Table of Contents

Materials and Methods S3

Bromides used in the study S4

Chlorides used in the study S5

Synthesis of starting materials S61H and 13C NMR spectra of the compounds S10

Antibacterial assay S68

References S68

S3

Materials and Methods1H and 13C NMR spectra were recorded on a Bruker Avance 300 or 400 or 500 spectrometer

and are referred to the residual solvent signal: dimethylsulfoxide-d6(2.50) for 1H and (39.52)

for 13C; CDCl3: (7.26) for 1H and (77.16) for 13C. Chemical shifts (δ) are given in ppm and

coupling constants (J) were measured in Hz. The following abbreviations are used; s-singlet,

d-doublet, dd-doublet of doublet, t-triplet, td-triplet of doublet, dt-doublet of triplet, q-

quartet, qd-quartet of doublet, qn-quintet, br-broad. ESI- and HR ESI-MS were recorded

using Finnigan MAT 1020B and Thermo Scientific Q Exactive hybrid quadrupole-Orbitrap

mass; values are given in m/z. Column chromatography was carried out using silica gel (60–

120 mesh) packed in glass columns. Analytical TLC was carried out on Macherey-Nagel 60

F245aluminium-backed silica gel plates. Melting point of compound was measured on Stuart

melting point apparatus SMP3. Anhydrous solvents and chemical materials were purchased

from commercial sources.

S4

Bromides used in the study

Br Br2b

Br

O

Br

O

Br

N

BrH

O

O

Br

NO2

Br

CF3

BrBr

2d 2e

2h

Br

OO

2i 2j

2l

2k

Br

O

Br2m 2n

2q

2o 2pBr

F

CN

Br

F

F

O

O

OH

2g

2fBr2c

O

Br

CN

2a

Br

S

Br

N

2r

2y2x

Br

N

Br

N

N

2v

2t2s

Br

O

O

O

N

Br Br

NHHN

2u

2w

Br

S5

Chlorides used in the study

Cl Br

Cl

O

Cl

NO2

Cl

CF3

ClCl

2d' 2h'

2i' 2j'

Cl

O

2n'

OH

2g'Cl2c'

Cl

CN

2a' 2b'

2m'

S6

Synthesis of starting materials

N

NH2R1

R2

R3R4

R1 R2 R3 R4

CH3

CH3

CH3

Cl

N

N

OO

R3

R1R2

R41. DMF acetal, 50 °C

2. ethyl 2-bromoacetate,NaHCO3, DMF,50 °C

No.

1b1/1b2/1b

N

N

OHO

R3

R1R2

R4LiOH, H2O/EtOH,reflux

ester synthesisreaction time (h)

stage1

stage2

ester hydrolysisreaction time (h)

1c1/1c2/1c

1d1/1d2/1d

1f1/1f2/1f

1b1, 1c1,1d1, 1f1

1b2, 1c2,1d2, 1f2

1b, 1c,1d, 1f

4 12

24 12

12

12

7 15 24

8 12 72

H H

H H H

H H H

H

H H H

N

NH2R1

R2

R3

R1 R2 R3

CH3

CF3

N

N

OO

R3

R1R2

ethyl 2-chloroacetoacetate,DME, reflux 3 days

No.

1e1/1e2/1e

N

N

OHO

R3

R1R2

LiOH, H2O/EtOH,reflux

esterhydrolysis

r eactionti me(h)

1g1/1g2/1g

1h1/1h2/1h

1e1, 1g1, 1h1 1e2, 1g2, 1h2 1e, 1g, 1h

Cl

24

48

36

H H

H H

H H

Imidazo[1,2-a]pyridine-3-carboxylic acids 1b-1h were synthesized using reporting procedure or modification thereof.1 Below is the brief description of their preparation and analysis.

S7

Synthesis of 1b, 1c, 1d, 1f

6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (1b)

5-Methylpyridin-2-amine 1b1 (5g, 46.23 mmol) and N,N-dimethyl formamide dimethyl acetal (30 mL) were stirred at 50 °C for 4 hrs. Upon completion, reaction mixture was evaporated on rotary evaporator and dried. The dried residue, ethyl 2-bromoacetate (11.50 g, 69.29 mmol) and NaHCO3 (5.8 gm, 69.04 mmol) in DMF (30 mL) were stirred at 50 °C. The progress of reaction was monitored by TLC. After 15 hrs the reaction mixture was added in water (200 mL) and extracted with ethyl acetate (2x150 mL). The combined organic phase was separated, washed with water (100 mL), brine (100 mL) and dried with sodium sulphate. The organic solvent was evaporated on rotary evaporator and crude material obtained was purified using silica gel column chromatography with 20% ethyl acetate in hexane. 1b2 was obtained as green liquid (5g, 53% yield). 1H NMR (400 MHz, CDCl3): δ 9.11 (S, 1H), 8.25 (s, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.27 (dd, J = 9.1, 1.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 160.6, 147.1, 140.8, 130.5, 125.4, 124.2, 116.8, 115.4, 60.3, 18.3, 14.4; HRMS (ESI-MS):Calc. for C11H13N2O2 [(M+H)+]: 205.0972, Found: 205.0976.

1b2(2g, 9.8 mmol) was dissolved in ethanol (24 mL) and 20 mL of LiOH (1 N aq. solution, 19.6 mmol) was added drop wise. The resulting reaction mixture was refluxed for 12 hrs. Ethanol was then removed on rotary evaporator and resulting mixture was cooled at ice bath temperature. The 4N HCl was added drop wise till the PH of reaction mixture became ≈ 4. The precipitated solid was filtered off and dried to furnish 1b2 as white solid (1.2 gm, 91 % yield). mp= 188-190°C; 1H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H), 8.18 (s, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.40 (dd, J = 9.1, 1.7 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 161.4, 146.8, 140.8, 130.7, 125.0, 124.1, 116.8, 115.6, 17.9; HRMS (ESI-MS):Calc. for C9H9N2O2 [(M+H)+]: 177.0659, Found: 177.0667.

In an analogous way 1c, 1d, 1f were synthesized.

1c22: Obtained 6.19 g (65%) 1c2 as white solid from 5.0g of 1c1. mp= 72-74°C; 1H NMR (400 MHz, CDCl3): δ 9.15-9.09 (m, 1H), 8.24-8.17 (m, 1H), 7.46 (s, 1H), 6.84 (d, J = 6.8 Hz, 1H), 4.42-4.33 (m, 2H), 2.43 (s, 3H), 1.40-1.32 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 160.6, 148.8, 141.4, 138.7, 126.6, 116.6, 116.3, 115.3, 60.2, 21.3, 14.4; HRMS (ESI-MS):Calc. for C11H13N2O2 [(M+H)+]: 205.09715, Found: 205.09837.

1c2: Obtained 0.64 g (74%) 1c as white solid from 1.0g of 1c2. mp= 189-192°C; 1H NMR (400 MHz, DMSO-d6): δ 9.16 (d, J = 7.0 Hz, 1H), 8.13 (s, 1H), 7.55 (s, 1H), 7.04 (dd, J = 7.0, 1.5 Hz, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 161.4, 148.1, 140.9, 138.6, 126.6, 116.8, 115.9, 115.6, 20.7; HRMS (ESI-MS):Calc. for C9H9N2O2 [(M+H)+]: 177.0659, Found: 177.0667.

1d2: Obtained 3.25 g (34%) 1d2 as red solid from 5.0g of 1d1. mp= 72-74°C;1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 7.19-7.15 (m, 1H), 6.91 (t, J = 7.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,

S8

CDCl3): δ 160.8, 148.7, 140.8, 127.7, 126.5, 125.5, 116.3, 114.3, 60.5, 17.0, 14.6; HRMS (ESI-MS):Calc. for C11H13N2O2 [(M+H)+]: 205.0972, Found: 205.0977.

1d: Obtained 0.65 g (49%) 1d as violet solid from 1.5 g of 1d2. mp= 184-185°C; 1H NMR (400 MHz, DMSO-d6): δ 9.20 (d, J = 7.0 Hz, 1H), 8.44 (s, 1H), 7.54 (d, J = 7.1 Hz, 1H), 7.27 (t, J = 7.0 Hz, 1H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 160.8, 144.9, 135.5, 129.9, 125.8, 125.5, 117.0, 116.4, 16.5; HRMS (ESI-MS):Calc. for C9H9N2O2 [(M+H)+]: 177.06585, Found: 177.06720.

1f21c: Obtained 5.5 g (63%) 1f2 as yellow semisolid from 5.0g of 1f1. 1H NMR (400 MHz, CDCl3) δ 9.39 (dd, J = 2.0, 0.8 Hz, 1H), 8.29 (s, 1H), 7.68 (dd, J = 9.5, 0.8 Hz, 1H), 7.39 (dd, J = 9.5, 2.0 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 160.5, 146.8, 141.9, 129.0, 125.9, 122.9, 118.2, 116.4, 60.9, 14.6; HRMS (ESI-MS):Calc. for C10H10ClN2O2 [(M+H)+]: 225.0425, Found: 225.0428.

1f1c: Obtained 0.72 g (54%) 1f as violet solid from 1.5 g of 1f2. mp= 206°C; 1H NMR (400 MHz, DMSO-d6): δ 9.31 (dd, J = 2.0, 0.6 Hz, 1H), 8.27 (s, 1H), 7.84 (dd, J = 9.5, 0.6 Hz, 1H), 7.62 (dd, J = 9.5, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):160.1, 140.2, 127.4, 126.8, 124.0, 120.3, 117.8, 117.2; HRMS (ESI-MS):Calc. for C8H6ClN2O2 [(M+H)+]: 197.01123, Found: 197.01253.

Synthesis of 1e, 1g, 1h

Ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) and 2-Amino-4-picoline (10.0 g, 91.5 mmol)were dissolved in 95 mL of 1,2-dimethoxyethane (DME) and heated for 48 hrs at reflux. The reaction mixture was cooled and solid (2-amino-4-picoline hydrochloride salt) was collected and washed with hexane. The filtrate was concentrated in vacuo and resulting residue was dissolved in dichloromethane (200 mL) and washed with 5% acetic acid solution (2x 50 mL) and brine. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo. Crude product was purified by silica gel with 22% ethyl acetate in hexane to furnish 7.0 g (34%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate (1e2)1a as a yellowish solid. mp= 66°C;1H NMR (500 MHz, CDCl3): δ 9.12 (d, J = 7.1 Hz, 1H), 7.35 (s, 1H), 6.76 (dd, J = 7.1, 1.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H), 2.40 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 161.4, 152.6, 147.2, 139.1, 127.1, 116.1, 115.3, 112.1, 60.2, 21.3, 16.5, 14.5; HRMS (ESI-MS):Calc. for C12H15N2O2 [(M+H)+]: 219.11280, Found: 219.11397.

1e2 (4.0 g, 18.34 mmol) was dissolved in of 55 mL ethanol and 37 mL of 1 N LiOH solution (36.58 mmol) was added. The reaction mixture was refluxed for 48 hrs. Once complete, ethanol was removed on rotary evaporator and resulting mixture was cooled at ice bath temperature. The 4N HCl was added drop wise till the pH of reaction mixture became ≈ 4. The precipitated solid was filtered off and dried under vacuum to furnish 1e1a as white solid (2.6 gm, 78 % yield). mp= 216-218°C; 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J = 7.1 Hz, 1H), 7.79 (s, 1H), 7.45 (dd, J = 7.1, 1.5 Hz, 1H), 2.71 (s, 3H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 160.9, 146.4, 141.9, 140.0, 128.4, 120.1, 113.3, 110.8, 21.0, 12.3; HRMS (ESI-MS):Calc. for C10H11N2O2 [(M+H)+]: 191.08150, Found: 191.08264.

S9

In an analogous way 1g and 1h were synthesized.

1g21c: Obtained 4.0 g (43%) 1g2 as yellow solid from 10.0 g of 1g1. mp= 102-104°C;1H NMR (500 MHz, CDCl3): δ 9.40 (dd, J = 2.0, 0.7 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.35 (dd, J = 9.3, 2.0 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 161.3, 153.3, 145.2, 128.9, 126.1, 122.1, 117.0, 113.2, 60.7, 16.7, 14.6; HRMS (ESI-MS):Calc. for C11H12ClN2O2 [(M+H)+]: 239.05818, Found: 239.05941.

1g1c: Obtained 1.5g (68%) 1g as white solid from 1.0 g of 1g2. mp= 158-160°C; 1H NMR (400 MHz, DMSO-d6): δ 9.31 (dd, J = 2.1, 0.6 Hz, 1H), 7.71 (dd, J = 9.5, 0.6 Hz, 1H), 7.59 (dd, J = 9.5, 2.1 Hz, 1H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 151.7, 144.2, 128.7, 125.4, 120.8, 117.0, 113.1, 15.9; HRMS (ESI-MS):Calc. for C9H8ClN2O2 [(M+H)+]: 211.02688, Found: 211.02825.

1h2: Obtained 0.72 g (45%) 1h2 as yellow solid from 1.0 g of 1h1. mp= 88-90°C;1H NMR (500 MHz, CDCl3): δ 9.51 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.78 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H), 13C NMR (100 MHz, DMSO-d6): δ 161.3, 153.7, 142.5, 131.1, 125.7, 125.6, 122.2 (q, J= 272.2 Hz), 113.5, 112.0, 60.8, 16.9, 14.4; HRMS (ESI-MS):Calc. for C12H12F3N2O2 [(M+H)+]: 273.08454, Found: 273.08563.

1h: Obtained 0.29 g (52%) 1h as pale yellow solid from 0.62 g of 1h2. mp= 171-173°C;1H NMR (400 MHz, DMSO-d6): δ 9.49 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 7.1 Hz, 1H), 2.65 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 162.0, 152.1, 141.3, 131.7, 126.3 (X2), 119.2 (q, J= 272.1 Hz), 112.5, 16.1; HRMS (ESI-MS):Calc. for C10H8F3N2O2 [(M+H)+]: 245.05324, Found: 245.05448.

S10

1H and 13C NMR spectra of the compounds

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.13

3.44

2.14

1.01

1.13

1.00

1.01

1.371.391.40

2.372.38

4.354.374.394.40

7.237.237.257.257.617.64

8.22

9.08

N

N

OO

1H NMR spectrum of 1b2

102030405060708090100110120130140150160f1 (ppm)

14.4

18.3

60.3

115.4

116.8

124.2

125.4

130.5

140.8

147.1

160.6

N

N

OO

13C NMR spectrum of 1b2

S11

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.22

1.06

1.03

0.97

1.00

2.37

7.397.397.417.41

7.677.69

8.18

9.07

N

N

OOH

1H NMR spectrum of 1b

2030405060708090100110120130140150160170180f1 (ppm)

17.9

115.6

116.8

124.1

125.0

130.7

140.8

146.8

161.4

N

N

OOH

13C NMR spectrum of 1b

S12

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.12

3.20

2.08

1.04

0.96

0.93

1.00

1.341.40

2.43

4.334.42

6.836.84

7.46

8.178.24

9.089.119.139.16

N

N

OO

1H NMR spectrum of 1c2

0102030405060708090100110120130140150160f1 (ppm)

14.4

21.3

60.2

115.3

116.3

116.6

126.6

138.7

141.4

148.8

160.6

N

N

OO

13C NMR spectrum of 1c2

S13

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.27

1.06

0.96

0.90

1.00

2.42

7.037.05

7.55

8.13

9.159.17

N

N

OOH

1H NMR spectrum of 1c

0102030405060708090100110120130140150160170f1 (ppm)

20.7

115.6

115.9

116.8

126.6

138.6

140.9

148.1

161.4

N

N

OOH

13C NMR spectrum of 1c

S14

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.08

3.00

2.00

1.00

0.92

0.88

0.94

1.381.391.41

2.63

4.364.384.394.41

6.896.916.937.137.20

8.25

9.129.14

N

N

OO

1H NMR spectrum of 1d2

102030405060708090100110120130140150160170f1 (ppm)

14.6

17.0

60.5

114.3

116.3

125.5

126.5

127.7

140.8

148.7

160.8

N

N

OO

13C NMR spectrum of 1d2

S15

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.14

1.07

1.03

0.93

1.00

2.59

7.257.277.28

7.537.55

8.44

9.199.21

N

N

OOH

1H NMR spectrum of 1d

0102030405060708090100110120130140150160170f1 (ppm)

16.5

116.4

117.0

125.5

125.8

129.9

135.5

144.9

160.8

N

N

OOH

13C NMR spectrum of 1d

S16

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.5f1 (ppm)

4.34

2.44

1.19

1.27

1.08

1.00

1.42

4.404.424.444.45

7.377.387.407.407.677.69

8.29

9.399.399.399.39

10.69

N

N

OO

Cl

1H NMR spectrum of 1f2

0102030405060708090100110120130140150160170f1 (ppm)

14.6

60.9

116.4

118.2

122.9

125.9

129.0

141.9

146.8

160.5

N

N

OO

Cl

13C NMR spectrum of 1f2

S17

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.001.06

0.88

0.90

7.607.617.637.637.837.85

8.27

9.319.319.319.31

N

N

OOH

Cl

1H NMR spectrum of 1f

-100102030405060708090100110120130140150160170f1 (ppm)

117.2

117.8

120.3

124.0

126.8

127.4

140.2

160.1

N

N

OOH

Cl

13C NMR spectrum of 1f

S18

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.14

3.22

3.14

2.08

1.04

0.96

1.00

1.40

2.40

2.66

4.374.39

6.766.766.776.77

7.35

9.119.13

N

N

OO

1H NMR spectrum of 1e2

102030405060708090100110120130140150160f1 (ppm)

14.5

16.5

21.3

60.2

112.1

115.3

116.1

127.1

139.1

147.2

152.6

161.4

N

N

OO

13C NMR spectrum of 1e2

S19

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.173.00

1.07

1.03

1.06

2.552.71

7.437.447.457.46

7.79

9.329.34

N

N

OOH

1H NMR spectrum of 1e

0102030405060708090100110120130140150160170f1 (ppm)

12.3

21.0

110.8

113.3

120.1

128.4

140.0

141.9

146.4

160.9

N

N

OOH

13C NMR spectrum of 1e

S20

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.09

2.98

2.00

0.941.00

0.80

1.431.441.46

2.71

4.424.434.454.46

7.347.347.367.367.557.57

9.409.409.409.40

N

N

OO

Cl

1H NMR spectrum of 1g2

0102030405060708090100110120130140150160f1 (ppm)

14.6

16.7

60.7

113.2

117.0

122.1

126.1

128.9

145.2

153.3

161.3

N

N

OO

Cl

13C NMR spectrum of 1g2

S21

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.47

1.111.19

1.00

2.59

7.587.587.607.617.697.707.727.72

9.319.319.319.31

N

N

OOH

Cl

1H NMR spectrum of 1g

0102030405060708090100110120130140150160f1 (ppm)

15.9

113.1

117.0

120.8

125.4

128.7

144.2

151.7

161.9

N

N

OOH

Cl

13C NMR spectrum of 1g

S22

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.33

3.16

2.12

1.08

1.11

1.00

1.431.451.46

2.78

4.424.444.464.47

7.027.047.06

7.697.72

9.509.52

N

N

OO

F

F

F

1H NMR spectrum of 1h2

0102030405060708090100110120130140150160f1 (ppm)

14.4

16.9

60.8

112.0

113.5

118.6

124.0

125.7

131.1

142.5

153.7

161.3

N

N

OO

F

F

F

13C NMR spectrum of 1h2

S23

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.22

1.05

1.01

1.00

2.65

7.247.267.28

7.937.95

9.499.50

N

N

OOH

F

F

F

1H NMR spectrum of 1h

0102030405060708090100110120130140150160170f1 (ppm)

16.1

112.5

113.6

117.4

121.0

124.6

131.7

141.3

152.1

162.0

N

N

OOH

F

F

F

13C NMR spectrum of 1h

S24

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.05

1.12

3.113.00

1.02

6.916.91

7.257.31

7.687.747.78

8.368.38

N

N

N

1H NMR spectrum of 3a

0102030405060708090100110120130140150f1 (ppm)

111.4

113.6

118.6

123.3

125.4

133.2

134.1

134.3

147.2

N

N

N

13C NMR spectrum of 3a

S25

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.18

1.02

1.012.032.051.90

1.00

2.44

6.776.806.83

7.167.34

7.647.69

8.318.32

N

N


0102030405060708090100110120130140150f1 (ppm)

21.47

112.54

118.35

123.51

124.18

125.90

126.47

128.17

138.32

146.11

N

N


S26

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

1.01

1.01

1.024.021.070.94

1.00

6.77

7.16

7.387.487.52

7.67

8.298.31

N

N


05101520253035404550556065707580859095105115125135145f1 (ppm)

112.5

118.1

123.3

125.6

128.1

132.4

146.0

N

N


S27

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.14

1.00

2.011.00

2.000.881.00

0.94

3.88

7.037.087.157.20

7.457.507.637.658.248.248.25

8.26

N

N

O


0102030405060708090100110120130140150160f1 (ppm)

55.55

112.52

114.84

118.30

121.68

124.10

129.82

132.08

145.90

159.77

N

N

O


S28

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

6.00

1.132.11

1.04

2.010.981.02

1.00

3.03

6.746.756.766.766.776.776.816.87

7.12

7.38

7.607.637.658.268.278.28

N

N

N


404550556065707580859095105115125135145155f1 (ppm)

40.5

112.3

112.8

116.7

118.1

123.6

123.8

126.3

129.4

131.4

145.6

150.5

N

N

N


S29

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.13

1.010.980.982.03

1.03

1.030.90

1.00

3.87

6.826.936.997.077.097.117.147.23

7.44

7.667.697.70

8.368.38

N

N

O


0102030405060708090100110120130140150160f1 (ppm)

55.5

112.7

113.7

113.9

118.4

123.7

130.5

130.7

132.7

146.3

160.4

N

N

O


S30

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.05

1.17

1.991.051.001.002.13

1.061.06

1.03

6.85

7.24

7.517.647.747.81

8.018.428.43

N

N


05101520253035404550556065707580859095105115125135145f1 (ppm)

113.0

118.3

123.5

126.6

126.9

132.5

133.0

133.7

146.1

N

N


S31

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

1.00

1.07

1.062.181.911.020.930.972.10

6.676.686.707.197.237.397.437.507.567.69

7.79

N

N


0102030405060708090100110120130140150f1 (ppm)

112.3

118.1

123.7

124.4

125.7

126.4

128.8

129.7

133.8

145.9

N

N


S32

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.00

3.68

3.042.95

1.00

6.866.886.90

7.217.29

7.677.737.76

8.358.37

N

N

F

FF

1H NMR spectrum of 3i

0102030405060708090100110120130140150f1 (ppm)

113.14

118.68

123.02

123.28

124.48

124.97

126.42

127.97

146.85

147.42

N

N

F

FF

13C NMR spectrum of 3i

S33

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.14

0.99

1.32

3.081.03

2.01

1.00

2.66

6.866.886.897.217.28

7.65

8.09

8.408.41

N

N

O

1H NMR spectrum of 3j

0102030405060708090100110120130140150160170180190200f1 (ppm)

26.6

113.1

118.4

123.4

129.3

133.7

133.9

136.1

146.8

197.1

N

N

O

13C NMR spectrum of 3j

S34

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.03

0.99

2.83

2.051.020.91

1.96

1.00

3.97

6.88

7.227.29

7.647.68

7.808.15

8.398.41

N

N

OO

1H NMR spectrum of 3k

-100102030405060708090100110120130140150160170f1 (ppm)

52.4

113.2

118.6

123.5

125.0

127.4

129.4

130.7

146.7

166.7

N

N

OO

13C NMR spectrum of 3k

S35

2.63.03.43.84.24.65.05.45.86.26.67.07.47.88.2f1 (ppm)

3.23

1.06

1.09

1.031.100.961.132.07

1.00

3.56

6.746.776.80

7.207.24

7.487.577.627.668.098.108.118.11

N

N

O

O

1H NMR spectrum of 3l

35404550556065707580859095105115125135145155165f1 (ppm)

52.4

112.4

117.9

124.0

124.7

129.1

129.4

131.2

131.3

133.0

145.6

167.2

N

N

O

O

13C NMR spectrum of 3l

S36

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

1.03

3.262.070.981.061.001.00

1.00

1.02

6.88

7.227.30

7.697.79

8.108.348.36

10.11

N

N

O

H

1H NMR spectrum of 3m

0102030405060708090100110120130140150160170180190f1 (ppm)

113.3

118.5

123.2

124.5

125.0

128.4

129.7

130.3

146.6

191.9

N

N

O

H

13C NMR spectrum of 3m

S37

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.03

1.05

0.942.081.00

1.961.07

6.94

7.277.347.737.757.76

7.868.368.41

N

N

N+ OO-

1H NMR spectrum of 3n

0102030405060708090100110120130140150f1 (ppm)

113.8

118.9

123.4

123.8

124.9

134.7

136.0

147.0

147.4

N

N

N+ OO-

13C NMR spectrum of 3n

S38

4.24.44.64.85.05.25.45.65.86.06.26.46.66.87.07.27.47.67.88.08.28.48.68.8f1 (ppm)

1.05

1.06

2.09

1.04

1.08

1.00

1.10

7.00

7.337.38

7.657.73

7.86

8.068.11

8.268.278.28

8.618.62

N

N

F

N

1H NMR spectrum of 3o

0102030405060708090100110120130140150160170f1 (ppm)

113.2

113.8

117.4

120.5

125.3

132.7

133.6

135.3

145.9

160.0

163.4

N

N

F

N

13C NMR spectrum of 3o

S39

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

1.042.01

0.78

1.00

1.89

1.00

6.846.987.087.217.267.457.66

7.947.95

N

N

F

F

1H NMR spectrum of 3p

0102030405060708090100110120130140150160170f1 (ppm)

105.0

118.3

119.3

124.2

124.7

132.4

134.0

146.5

159.1

161.5

162.1

164.6

N

N

F

F

13C NMR spectrum of 3p

S40

3.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.093.05

1.191.08

1.64

1.061.001.14

1.04

1.06

3.964.02

6.846.94

7.237.297.617.707.71

7.927.93

9.68

N

N

O

O

O

H

1H NMR spectrum of 3q

0102030405060708090100110120130140150160170180190f1 (ppm)

56.4

56.6

109.6

113.1

113.4

118.3

123.3

126.7

134.9

146.2

150.2

154.4

189.9

N

N

O

O

O

H

13C NMR spectrum of 3q

S41

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.08

1.47

1.060.991.000.951.011.031.111.05

1.00

6.90

7.24

7.637.78

8.178.188.338.33

9.139.13

N

N

N

1H NMR spectrum of 3r

0102030405060708090100110120130140150f1 (ppm)

113.3

118.6

122.6

123.1

127.6

133.8

133.9

146.8

147.5

149.9

N

N

N

13C NMR spectrum of 3r

S42

3.43.84.24.65.05.45.86.26.67.07.47.88.28.69.09.4f1 (ppm)

1.04

1.661.00

3.050.880.97

1.01

1.00

0.99

6.78

7.257.307.387.39

7.737.827.858.128.14

8.508.52

9.38

N

N

N

1H NMR spectrum of 3s

0102030405060708090100110120130140150160f1 (ppm)

112.9

118.0

122.1

124.9

127.3

133.0

134.2

134.8

144.1

146.2

153.3

N

N

N

13C NMR spectrum of 3s

S43

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

0.98

1.00

1.123.101.061.040.92

0.99

0.90

6.78

7.227.287.367.50

7.71

7.858.218.228.55

N

N

NH

1H NMR spectrum of 3t

05101520253035404550556065707580859095105115125135145f1 (ppm)

102.2

111.7

112.2

118.0

120.6

121.0

122.3

125.2

132.7

136.4

145.9

N

N

NH

13C NMR spectrum of 3t

S44

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

0.891.03

1.052.001.051.040.940.96

1.00

0.89

6.606.666.78

7.157.227.307.387.53

7.718.368.38

9.27

N

N

NH

1H NMR spectrum of 3u

0102030405060708090100110120130140150f1 (ppm)

102.7

112.1

112.4

117.9

120.9

123.7

125.7

131.7

135.9

145.6

N

N

NH

13C NMR spectrum of 3u

S45

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.01

1.00

1.07

2.08

1.05

1.05

1.00

3.94

6.716.72

7.00

7.297.35

7.70

8.02

8.848.86

N

N

O

O

O

1H NMR spectrum of 3v

0102030405060708090100110120130140150160f1 (ppm)

52.1

107.4

114.0

116.7

118.3

125.8

125.9

134.5

143.2

146.9

149.0

159.1

N

N

O

O

O

13C NMR spectrum of 3v

S46

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.13

1.281.000.970.99

1.271.11

1.00

6.87

7.287.29

7.677.697.77

8.398.41

N

N

S

1H NMR spectrum of 3w

05101520253035404550556065707580859095105115125135145f1 (ppm)

112.9

118.0

123.8

124.5

125.9

133.5

146.2

N

N

S

13C NMR spectrum of 3w

S47

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.07

1.19

1.030.991.081.030.96

1.08

0.950.90

6.93

7.277.33

7.75

8.048.25

8.57

8.898.898.908.91

N

N

N

N

1H NMR spectrum of 3x

0102030405060708090100110120130140150f1 (ppm)

113.5

118.6

123.5

125.3

130.1

130.8

134.2

142.5

143.5

145.2

145.9

N

N

N

N

13C NMR spectrum of 3x

S48

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.19

1.301.03

1.041.001.261.04

0.991.00

6.86

7.217.45

7.707.75

8.27

8.648.658.668.668.848.84

N

N

N

1H NMR spectrum of 3y

0102030405060708090100110120130140150f1 (ppm)

113.2

118.4

122.3

123.0

124.0

133.4

135.2

146.7

148.9

149.3

N

N

N

13C NMR spectrum of 3y

S49

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.14

1.00

1.092.201.052.01

1.00

2.34

7.107.117.137.13

7.597.657.73

8.13

N

N

N


0102030405060708090100110120130140150f1 (ppm)

18.5

111.1

117.9

118.7

120.8

123.3

127.7

133.1

134.0

134.3

146.2

N

N

N


S50

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.11

0.98

1.931.010.891.03

0.980.921.00

0.93

2.34

7.127.147.607.787.90

8.158.178.198.32

9.12

N

N

N


0102030405060708090100110120130140150f1 (ppm)

18.5

117.9

120.7

122.3

123.0

123.1

127.6

133.6

134.1

145.9

147.5

150.0

N

N

N


S51

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

3.11

0.99

0.940.761.171.000.970.981.00

0.96

2.43

6.696.70

7.457.697.707.817.837.897.908.078.22

10.10

N

N

O

H


0102030405060708090100110120130140150160170180190f1 (ppm)

21.4

115.8

116.9

122.5

128.2

130.2

133.2

135.9

147.2

191.9

N

N

O

H


S52

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.16

3.00

1.011.04

0.991.01

0.98

1.02

2.43

3.92

6.656.666.796.806.816.81

7.297.297.44

7.92

8.698.70

N

N

O

O

O


0102030405060708090100110120130140150160f1 (ppm)

21.4

52.1

106.9

116.1

116.6

120.0

125.1

134.2

137.1

143.0

147.3

149.2

159.1

N

N

O

O

O


S53

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.28

1.00

2.14

1.041.04

0.98

1.010.99

2.41

6.686.69

7.387.477.667.83

8.148.16

8.618.81

N

N

N


0102030405060708090100110120130140150f1 (ppm)

20.4

114.9

115.8

120.9

121.3

123.0

132.0

134.1

135.2

146.2

147.8

148.1

N

N

N


S54

6.46.56.66.76.86.97.07.17.27.37.47.57.67.77.87.98.08.18.28.38.48.5f1 (ppm)

1.04

1.03

2.07

1.06

0.98

2.10

1.09

1.00

1.00

6.76

7.027.04

7.50

7.59

7.657.67

7.80

7.85

7.937.967.988.02

8.308.32

N

N


05101520253035404550556065707580859095105115125135145f1 (ppm)

17.2

112.9

121.4

126.0

126.6

127.0

128.1

132.3

132.9

133.7

146.7

N

N


S55

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.173.06

0.99

0.97

2.07

1.97

1.00

2.412.48

6.626.64

7.35

7.55

7.78

8.018.02

N

N

N


0102030405060708090100110120130140150f1 (ppm)

14.3

21.4

111.0

115.3

115.9

118.8

122.1

129.3

133.0

134.7

136.3

142.4

145.9

N

N

N


S56

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.35

1.132.172.171.031.11

1.00

2.44

7.147.167.167.34

7.617.637.67

8.318.32

N

N

Cl


0102030405060708090100110120130140150f1 (ppm)

21.5

118.3

118.6

121.1

121.4

125.7

126.1

126.5

128.2

138.9

144.3

N

N

Cl


S57

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.09

1.12

1.071.07

1.051.00

1.00

0.930.94

7.237.287.697.71

7.93

8.27

8.57

8.908.92

N

N

Cl

N

N

1H NMR spectrum of 4i

05101520253035404550556065707580859095105115125135145f1 (ppm)

119.1

121.4

122.0

125.1

130.0

135.0

142.8

143.5

145.4

145.5

146.0

N

N

Cl

N

N

13C NMR spectrum of 4i

S58

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

2.061.000.851.020.85

0.86

7.187.247.297.307.477.487.49

7.77

8.408.41

N

N

Cl

S

1H NMR spectrum of 4j

0102030405060708090100110120130140150f1 (ppm)

118.6

119.8

121.5

121.8

126.0

126.7

134.6

144.7

N

N

Cl

S

13C NMR spectrum of 4j

S59

2.63.03.43.84.24.65.05.45.86.26.67.07.47.88.28.6f1 (ppm)

3.08

1.00

1.203.10

3.271.040.97

7.157.157.177.18

7.527.557.897.968.02

8.168.16

N

N

Cl

1H NMR spectrum of 4k

05101520253035404550556065707580859095105115125135145f1 (ppm)

14.0

117.4

120.7

125.8

127.0

133.1

133.7

142.2

142.8

N

N

Cl

13C NMR spectrum of 4k

S60

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.09

0.97

0.961.013.011.030.881.021.00

2.44

6.68

7.307.327.427.507.577.637.977.998.02

N

N

F

F

F

1H NMR spectrum of 4l

05101520253035404550556065707580859095105115125135145f1 (ppm)

14.2

110.1

119.9

122.1

122.6

124.9

125.8

126.6

127.2

129.9

132.2

140.2

143.7

N

N

F

F

F

13C NMR spectrum of 4l

S61

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

3.14

0.97

0.96

0.971.011.93

0.98

0.99

1.00

2.40

6.75

7.147.15

7.547.68

8.15

8.478.48

9.38

N

N

N

F

F

F

1H NMR spectrum of 4m

0102030405060708090100110120130140150160f1 (ppm)

14.2

110.6

117.7

119.4

122.9

125.1

127.4

134.0

140.6

144.2

144.3

153.4

N

N

N

F

F

F

13C NMR spectrum of 4m

S62

3.03.43.84.24.65.05.45.86.26.67.07.47.88.2f1 (ppm)

0.89

2.00

1.892.34

7.127.137.137.147.39

7.647.677.687.71

S

N


0102030405060708090100110120130140150f1 (ppm)

110.7

119.0

125.2

126.2

128.7

132.9

138.8

142.2

S

N


S63

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

2.48

2.71

7.507.527.687.70

N

S

N


0102030405060708090100110120130140150160170f1 (ppm)

16.5

19.3

111.1

118.7

129.6

132.6

137.3

148.9

165.0

N

S

N


S64

5.35.45.55.65.75.85.96.06.16.26.36.46.56.66.76.86.97.07.17.27.37.47.57.67.77.8f1 (ppm)

1.00

1.461.152.111.38

2.191.162.13

2.08

1.00

6.95

7.217.257.267.277.307.317.347.377.407.437.467.477.50

7.727.76

N

N


05101520253035404550556065707580859095105115125135145f1 (ppm)

105.8

110.6

110.9

118.9

121.3

127.9

132.1

137.1

138.1

138.5

139.8

N

N


S65

3.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

2.00

1.044.062.01

2.112.18

1.03

7.287.347.417.467.537.587.597.627.717.757.807.847.957.99

N

N

1H NMR spectrum of 5c'

35404550556065707580859095100105110115120125130135140145150f1 (ppm)

109.3

111.4

117.4

119.5

119.9

121.7

123.5

124.8

127.6

130.0

132.8

137.1

139.1

140.3

N

N

13C NMR spectrum of 5c'

S66

5.55.75.96.16.36.56.76.97.17.37.57.77.9f1 (ppm)

0.95

1.16

1.27

1.08

1.07

2.02

2.00

7.187.18

7.257.307.337.38

7.537.567.617.657.717.74

7.937.97

O

N


50556065707580859095100105110115120125130135140145150155160f1 (ppm)

104.5

111.6

111.6

118.9

121.6

125.2

128.8

132.7

134.6

153.7

155.4

O

N


S67

3.54.04.55.05.56.06.57.07.58.0f1 (ppm)

1.10

2.33

5.162.132.00

7.297.347.407.497.587.647.687.727.787.83

O

N

N

1H NMR spectrum of 5d'

0102030405060708090100110120130140150f1 (ppm)

111.8

112.3

112.3

118.5

124.0

127.4

130.5

133.2

137.4

149.1

154.5

O

N

N

13C NMR spectrum of 5d'

S68

Antibacterial assay

The screening panel consist of E. coli ATCC 25922, S. aureus ATCC 29213, P. aeruginosa ATCC 27853, K. pneumoniae BAA-1705 and A. baumannii BAA-1605. The bacterial strains were procured from ATCC (ATCC, Manassas, VA, USA) and Mueller Hinton broth II (MHB II) (Becton Dickinson) was used to propagate the bacteria. The compounds were serially diluted utilizing 2-fold dilutions and bacteria were subsequently added to a final count of 104-105 cfu/ml. The 96-well plates were incubated at 37°C for 24 hrs and the antimicrobial activity was determined by visual inspection. The MIC of the active compounds was determined and was defined as the lowest concentration of the compound that inhibited visible growth after 24 hrs.

References

1. (a)G. C. Moraski, L. D. Markley, P. A. Hipskind, H. Boshoff, S. Cho, S. G. Franzblau and M. J. Miller, Acs Med Chem Lett, 2011, 2, 466-470; (b) F. Hongli, L. Xin, L. Xinsheng and C. Jintao, PCT Chin Appl, CN 103965190 A, 2014; (c)S. Kang, R. Y. Kim, M. J. Seo, S. Lee, Y. M. Kim, M. Seo, J. J. Seo, Y. Ko, I. Choi, J. Jang, J. Nam, S. Park, H. Kang, H. J. Kim, J. Kim, S. Ahn, K. Pethe, K. Nam, Z. No and J. Kim, J Med Chem, 2014, 57, 5293-5305.

2. F. Liang, M. Gibney, V. Yeh, X. Li, V. Molteni, D. Shaw, A. M. Berman, S. Lewis, J. Loren and V. Furminger, PCT Int Appl, WO 2013033620 A1, 2013.

Documents

Supporting Information carboxylic acids with Aryl bromides ... · S1 Supporting Information Ligand-free Pd-catalysed decarboxylative arylation of Imidazo[1,2-a]pyridine-3-carboxylic