Flow Chemistry Synthesis of Zolpidem, Alpidem and other GABA A · Flow Chemistry Synthesis of...

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Supporting information

Flow Chemistry Synthesis of Zolpidem, Alpidem and other GABAA

Agonists and their Biological Evaluation through the use of In-line

Frontal Affinity Chromatography

Synthesis S2

General S2

Synthesis of unsaturated ketone intermediates 3-5 S2

Synthesis of imidazo[1,2-a]pyridine intermediates 6-14 S3

Synthesis of amides 1, 2, 15-25 S7

Synthesis of carboxylic acids 26-34 S12

References S14

Electronic Supplementary Material (ESI) for Chemical ScienceThis journal is © The Royal Society of Chemistry 2013

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Synthesis

General

All solvents were distilled prior to use and stored under argon. Commercially available starting

materials were bought from Sigma-Aldrich and Alfa Aesar; IRA-743 resin was purchased from Sigma-

Aldrich, and QP-SA and QP-BZA resins from Johnson Matthey. All flow reactions were performed on

a FlowsynTM (Uniqsis) equipped with Automatic Loop Filling (ALFTM, Uniqsis) and a FC203B fraction

collector (Gilson). 1H and 13C NMR spectra were recorded either on a Bruker Avance DPX-400 or a DRX-500

spectrometer with residual solvent as the internal reference (CHCl3 in CDCl3 or CH3OH in CD3OD).

LC/MS analysis was performed on an Agilent HP 1100 chromatograph (Luna Max RP column)

attached to an HPLC/MSD mass spectrometer. Elution was carried out using a reverse-phase

gradient of MeCN/water with the water containing 0.1% formic acid. For HRMS an LCT Premier

Micromass spectrometer was used.

Synthesis of unsaturated ketone intermediates 3-5

In this first step the acid catalysed condensation between ethyl glyoxylate and acetophenone

derivatives leads to unsaturated ketone intermediates (3-5) which need to be produced on large

scale and repetitively, it is therefore important that a scalable and automated route can be used for

this synthetic step.

OEtO

O120 °C

0.1 mL/min

TolueneQP-SA QP-BZA

R1

O

OEtO

O

R1100 psi

R1 = H, 3R1 = CH3, 4R1 = Cl, 5

1.5 equiv.

A mixture of 10 mmol of acetophenone derivative, 15 mmol of ethyl glyoxylate (50% in toluene) in

toluene (total volume 10 mL) was injected through a reactor packed with 2 g of polymer supported

sulfonic acid resin (QP-SA, 6 mmol) and heated at 120 °C, with a residence time of 25 minutes (0.1

mL/min). The exiting stream was passed through a column of QP-BZA (3 g, around 10 mmol), a

supported benzyl amine that scavenges the excess of glyoxylate in the reaction stream. The

combination of these two heterogeneous reagents affords a process that is free of downstream

purification. The product is collected and transferred to the next step.

(E)-Ethyl 4-phenyl-4-oxo-2-butenoate 3: Yellow oil, isolated yield = 76%. In

agreement with the structural data reported in literature.[1]

Rt = 4.44 min. HRMS (ESI): m/z: calcd for C12H13O3 [M+H+]: 205.0865; found

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205.0872. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.00 (d, 3J H-H = 7.5 Hz, 2×CH), 7.90 (d, 3J H-H = 15.5 Hz,

CH), 7.60 (d, 3J H-H = 7.5 Hz, CH), 7.49 (app. t, 3J H-H = 7.5 Hz, 3J H-H = 7.5 Hz, 2×CH), 6.87 (d, 3J H-H = 15.5

Hz, CH), 4.29 (q, 3J H-H = 7.1 Hz, CH2), 1.35 (t, 3J H-H = 7.1 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm)

189.5 (Cketone), 165.5 (Cester), 136.6 (C), 136.4 (CH), 133.8 (C), 132.6 (CH), 128.9 (4 CH), 61.4 (CH2),

14.2 (CH3).

(E)-Ethyl 4-(4-methyl-phenyl)-4-oxo-2-butenoate 4: Yellow oil, isolated yield =

85%. In agreement with the structural data as reported in literature.[1,2]


219.1014. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.88 (d, 3J H-H = 8.2 Hz, CH), 7.87 (d, 3J H-H = 15.3 Hz,

CH), 7.24 (d, 3J H-H = 8.2 Hz, 2×CH), 6.83 (d, 3J H-H = 15.3 Hz, CH), 4.27 (q, 3J H-H = 7.3 Hz, CH2), 2.40 (s,

CH3), 1.32 (t, 3J H-H = 7.3 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 189.0 (Cketone), 172.2 (Cester),

144.9 (C), 136.6 (C), 134.4 (2×CH), 132.2 (2×CH), 129.4 (CH), 129.2 (CH), 61.3 (CH2), 21.7 (CH3), 15.2

(CH3).

(E)-Ethyl 4-(4-chloro-phenyl)-4-oxo-2-butenoate 5: Yellow oil, isolated yield =

82%. In agreement with the structural data as reported in literature.[2]


219.0479. 1H NMR (CDCl3, 400 MHz): 7.92 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 7.84 (d, 3J H-H = 15.6

Hz, CH), 7.48 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 6.87 (d, 3J H-H = 15.6 Hz, CH), 4.29 (q, 3J H-H = 7.2

Hz, CH2), 1.32 (t, 3J H-H = 7.2 Hz, CH3).13C NMR (CDCl3, 100 MHz): 188.2 (Cketone), 165.4 (Cester), 140.5

(C), 135.8 (CH), 135.0 (C), 133.0 (CH), 130.2 (2×CH), 129.2 (2×CH), 61.5 (CH2), 14.1 (CH3).

Synthesis of imidazo[1,2-a]pyridine intermediates 6-14 O

EtO

O R1

NR3

NH2

cat. HBF4.Et2O

1.5 equiv.

R2

Uniqsis ALF

120 °C14 mL

0.1 mL/minMeCN

MgSO4

50 °C

NR3

NH2

Biotage

R2

QP-SA

N

N

R3R1

OOEt

R2

3-5

0.1 mL/minMeCN loop A

loop B

100 psi

NH3 in MeOH

6-14 5-30 %

The dispensing of different unsaturated ketones and aminopyridines into the reactors is done

automatically to prepare a diverse collection of compounds. The use of flow process also

accommodates safely superheating the solvent under pressure. Indeed, using conventional heating

conditions the reaction typically takes 24 hours to progress whereas in the superheated equivalent

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only 4 hours are required. Similar results can be achieved by using microwave reactors, although

scaling up these microwave reactions is not always easy.

Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of unsaturated

ketone (3-5) and a solution of 1.5 equivalents of a commercially available aminopyridine with a

catalytic amount of HBF4.Et2O in acetonitrile were used to fill sample loop A and B (1 mL loop each).

Both delivery pumps were operated at a flow rate of 0.1 mL/min and the mixture was injected then

mixed at a standard T-connector and passed through a column packed with magnesium sulfate to

promote ketimine formation. The reaction stream was then progressed into a 14 mL CFC

(Continuous Flow Coil) reactor at 120 °C leading to 5-exo cyclization. For the preparation of

analogues 6-9 and 11-13, this process was best catalysed by acid. The reaction mixture was then

eluted through a column packed with 1 g of QP-SA to capture the excess aminopyridine. The

aminopyridine reagent can be easily recovered later by injecting ammonia in methanol to displace it

from the column.

Ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 6: N.B. The solution of 2-

aminopyridine was prepared in DMF instead of acetonitrile. Yellow solid, isolated

yield = 18% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl

acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement with the structural data

reported in literature.[3]

Rt = 4.42 min. HRMS (ESI): m/z: calcd for C17H17N2O2 [M+H+]: 281.1285; found 281.1281. 1H NMR

(CDCl3, 400 MHz): δ (ppm) 8.12 (d, 3J H-H = 8.0 Hz, CH), 7.84 (d, 3J H-H = 8.0 Hz, 2×CH), 7.66 (d, 3J H-H =

8.0 Hz, CH), 7.48 (t, 3J H-H = 8.0 Hz, 2×CH), 7.39 (m, CH), 7.23 (m, 2×CH), 6.87 (t, 3J H-H = 8.0 Hz, CH),

4.22 (q, 3J H-H = 7.2 Hz, CH2), 4.05 (s, CH2), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ

(ppm) 169.4 (Cester), 145.0 (C), 144.7 (C), 134.1 (C), 128.6 (2×2×CH), 128.0 (CH), 124.5 (CH), 127.8

(CH), 117.7 (CH), 113.0 (C), 112.4 (CH), 61.7 (CH2), 30.9 (CH2), 14.2 (CH3).

Ethyl 2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 7: N.B. The solution

of 5-methyl-2-aminopyridine was prepared in DMF instead of acetonitrile. Yellow

solid, isolated yield = 12% after chromatography (Biotage SP1, 12g cartridge,

eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In agreement

with the structural data reported in literature.[4]



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9.2 Hz, CH), 7.46 (m, 2×CH), 7.37 (m, CH), 7.06 (dd, 3J H-H = 9.2 Hz, 4J H-H = 1.2 Hz, CH), 4.22 (q, 3J H-H =

7.2 Hz, CH2), 4.01 (s, CH2), 2.35 (s, CH3), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ

(ppm) 169.6 (Cester), 144.4 (C), 144.1 (C), 134.3 (C), 128.6 (2×2×CH), 127.8 (CH), 127.7 (CH), 122.1 (C),

121.4 (CH), 116.9 (CH), 112.7 (C), 61.6 (CH2), 30.9 (CH2), 18.5 (CH3), 14.2 (CH3).

Ethyl 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate 8: Yellow solid,

isolated yield = 8% after chromatography (Biotage SP1, 12g cartridge, eluent:

hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In

agreement with the structural data reported in literature.[4]

Rt = 4.38 min. HRMS (ESI): m/z: calcd for C17H16ClN2O2 [M+H+]: 315.0895; found 315.0890. 1H NMR


9.5 Hz, CH), 7.47 (m, 2×CH), 7.40 (m, CH), 7.18 (dd, 3J H-H = 9.5 Hz, 4J H-H = 2.1 Hz, CH), 4.23 (q, 3J H-H =

7.2 Hz, CH2), 4.01 (s, CH2), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 169.1

(Cester), 145.6 (C), 144.3 (C), 133.6 (C), 128.7 (2×CH), 128.6 (2×CH), 128.2 (CH), 125.9 (CH), 123.4 (CH),

121.8 (C), 117.9 (CH), 113.7 (C), 108.4 (C), 61.9 (CH2), 14.2 (CH3).

Ethyl 2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 9: Yellow solid, isolated yield =

14% after chromatography (Biotage SP1, 12g cartridge, eluent: hexane:ethyl

acetate 1:9 gradually changed to 4:6 over 8 column volumes).


(CDCl3, 400 MHz): δ (ppm) 8.13 (d, 3J H-H = 6.4 Hz, CH), 7.71 (m, 3×CH), 7.26 (m, 3×CH), 6.89 (t, 3J H-H =

6.2 Hz, CH), 4.21 (q, 3J H-H = 7.2 Hz, CH2), 4.03 (s, CH2), 2.40 (s, CH3), 1.27 (t, 3J H-H = 7.2 Hz, CH3). 13C

NMR (CDCl3, 100 MHz): δ (ppm) 169.4 (Cester), 144.7 (C), 144.1 (C), 138.0 (C), 130.6 (C), 129.4 (2×CH),

128.6 (2×CH), 125.0 (CH), 123.8 (CH), 117.3 (CH), 112.8 (C), 112.7 (CH), 61.7 (CH2), 30.8 (CH2), 21.3

(CH3), 14.2 (CH3).

Ethyl 2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 10: Yellow solid,


hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes). In

agreement with the structural data reported in literature.[3-5]


(CDCl3, 400 MHz): δ (ppm) 7.88 (s, m, CH), 7.70 (d, 3J H-H = 7.9 Hz, 2×CH), 7.58 (d, 3J H-H = 8.8 Hz, CH),

7.27 (d, 3J H-H = 7.9 Hz, 2×CH), 7.06 (d, 3J H-H = 8.8 Hz, CH), 4.22 (q, 3J H-H = 7.2 Hz, CH2), 4.00 (s , CH2),

2.40 (s, CH3), 2.36 (s, CH3), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR (CDCl3, 100 MHz): 169.6 (Cester),

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144.0 (C), 137.7 (C), 131.1 (C), 129.3 (2×CH), 128.4 (2×CH), 127.8 (CH), 122.1 (C), 121.4 (CH), 120.6

(C), 116.8 (C), 112.4 (C), 61.6 (CH2), 30.9 (CH2), 21.3 (CH3), 18.5 (CH3), 14.2 (CH3).

Ethyl 2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 11: Yellow solid,


hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes).


(CDCl3, 400 MHz): δ (ppm) 8.18 (d, 4J H-H = 2 Hz, CH), 7.70 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 7.59

(d, 3J H-H = 9.6 Hz, CH), 7.28 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 7.18 (dd, 3J H-H = 9.6 Hz, 4J H-H = 2

Hz, CH), 4.25 (q, 3J H-H = 7.2 Hz, CH2), 4.01 (s , CH2), 2.42 (s, CH3), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR

(CDCl3, 100 MHz): 169.2 (Cester), 145.7 (C), 143.4 (C), 138.2 (C), 130.6 (C), 129.4 (2×CH), 128.4 (2×CH),

126.8 (CH), 121.7 (CH), 120.6 (C), 117.8 (CH), 113.4 (C), 61.8 (CH2), 30.8 (CH2), 21.4 (CH3), 14.2 (CH3).

Ethyl 2-(8-bromo-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetate 12:

Orange solid, isolated yield = 5% after chromatography (Biotage SP1, 12g

cartridge, eluent: hexane:ethyl acetate 5:95 gradually changed to 30:70 over 15

column volumes).

Rt = 4.55 min. HRMS (ESI): m/z: calcd for C19H20BrN2O2 [M+H+]: 387.0708; found 387.0708. 1H NMR


1.2 Hz, CH), 7.27 (d, 3J H-H = 8.0 Hz, 2×CH), 4.21 (q, 3J H-H = 7.1 Hz, CH2), 3.98 (s, CH2), 2.40 (s, CH3),

2.36 (s, CH3), 2.40 (t, 3J H-H = 7.1 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 169.3 (Cester), 145.2 (C),

137.9 (C), 130.8 (C), 129.9 (CH), 129.3 (2×CH), 128.8 (2×CH), 122.3 (C), 121.8 (C), 120.9 (CH), 114.3

(C), 111.0 (C), 61.7 (CH2), 31.1 (CH2), 21.3 (CH3), 18.3 (CH3), 14.2 (CH3).

Ethyl 2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)acetate 13:

Yellow solid, isolated yield = 15% after chromatography (Biotage SP1, 12g

cartridge, eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8

column volumes).


(CDCl3, 400 MHz): δ (ppm) 7.88 (s, CH), 7.75 (d, 3J H-H = 7.1 Hz, 2×CH), 7.51 (d, 3J H-H = 9.1 Hz, CH),

7.40 (d, 3J H-H = 8.3 Hz, 2×CH), 7.05 (d, 3J H-H = 9.1 Hz, CH), 4.20 (q, 3J H-H = 7.1 Hz, CH2), 3.95 (s , CH2),

2.34 (s, CH3), 1.26 (t, 3J H-H = 7.1 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 169.3 (Cester), 144.2 (C),

143.2 (C), 133.8 (C), 132.8 (C), 129.7× (2 CH), 128.8 (2×CH), 128.0 (CH), 122.3 (C), 121.4 (CH), 116.9

(CH), 112.8 (C), 61.7 (CH2), 30.8 (CH2), 18.4 (CH3), 14.2 (CH3).

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Ethyl 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate 14, in

agreement with the structural data reported in literature:[3,4] Yellow solid,

isolated yield = 18% after chromatography (Biotage SP1, 12g cartridge,

eluent: hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes).

Rt = 4.82 min. HRMS (ESI): m/z: calcd for C17H15Cl2N2O2 [M+H+]: 349.0496; found 349.0511. 1H NMR

(CDCl3, 400 MHz): δ (ppm) 8.20 (d, 3J H-H = 2 Hz, CH), 7.76 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 7.58

(d, 3J H-H = 9.6 Hz, CH), 7.45 (dd, 3J H-H = 6.8 Hz, 4J H-H = 2 Hz, 2×CH), 7.20 (dd, 3J H-H = 9.6 Hz, 4J H-H = 2

Hz, CH), 4.24 (q, 3J H-H = 7.2 Hz, CH2), 3.99 (s , CH2), 1.28 (t, 3J H-H = 7.2 Hz, CH3). 13C NMR (CDCl3, 100

MHz) δ (ppm) 168.9 (Cester), 144.6 (C), 143.5 (C), 134.3 (C), 132.1 (C), 129.8 (2×CH), 129.0 (2×CH),

126.1 (CH), 121.8 (CH), 120.9 (C), 118.0 (CH), 113.7 (C), 61.9 (CH2), 30.8 (CH3), 14.1 (CH3).

Synthesis of amides 1, 2, 15-25

HN(R4)2 (5 equiv.) DIPEA (10 equiv.) Me2AlCl (4 equiv.)

DCM0.05 mL/min

40 °C14 mL

IRA-743N

N

R2R1

OR4

R3

Uniqsis Fraction Collector

40 psi

Uniqsis ALF

loop A

loop B

N

N

R2R1

OOEt

R3

6-14

DCM0.05 mL/min

1, 2, 15-25

R4 = NMe2, 1, 15-22 26-99%

R4 = NPr2, 2, 23-25 33-93% Reaction to convert the esters directly to the corresponding amides using aluminium chloride salts

has already been achieved in flow using microfluidic devices.[6] The authors mentioned that the

reaction can be accelerated upon heating whereas in batch sub-zero temperatures are typically

utilized. However, in our hands, degradation was observed at high temperatures; consequently the

reaction was carried out at 40 °C with a residence time of 280 min. Finally, as long as anhydrous

conditions are maintained, a library of corresponding amides can be prepared in an automated

fashion.

Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of ester intermediate

(6-14, 0.3 mmol) and a solution containing 10 equivalents of DIPEA, 4 equivalents of dimethyl

aluminium chloride (1 M in hexane) and 5 equivalents of amine were respectively filled in sample

loop A (1 mL) and sample loop B (1 mL); when the amine was dimethylamine (2 M in THF), the

mixture was cooled at 0 °C prior to injection. Both delivery pumps were running at 0.05 mL/min and

the mixture was injected then mixed at a standard T-connector and passed through a 14 mL CFC

reactor heated at 40 °C. The exiting mixture was passed through a column packed with 0.5 g of IRA-

743 (polyol resin) and a plug of silica gel to conveniently remove the aluminium salts and the excess

of base. Final compounds 1, 2, 15-25 were collected using a Uniqsis fraction collector, evaporated

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and analyzed. For each reaction, a 10 µL aliquot of the reaction mixture was also automatically

collected and transferred into a 2 mL LC-MS vial containing PBS. These samples were then used to

run automated FAC experiments.

N,N- dimethyl-2- (6-methyl-2-p-tolylimidazo [1,2-a] pyridin-3-yl) acetamide

(zolpidem) 1: White solid, isolated yield = 90%. In agreement with the

structural data as reported in literature.[3, 5, 7]

Rt = 3.94 min. HRMS (ESI): m/z: calcd for C19H22N3O [M+H+]: 308.1752; found 308.1763. 1H NMR

(CDCl3, 400 MHz): 7.99 (d, 4J H-H = 1.7 Hz, CH),.7.53 (d, 3J H-H = 7.4 Hz, 2×CH), 7.51 (d, 3J H-H = 9.2 Hz,

CH), 7.25 (d, 3J H-H = 7.4 Hz, 2×CH), 7.03 (dd, 3J H-H = 9.2 Hz, 4J H-H = 1.7 Hz, CH), 4.07 (s, CH2), 2.94 (s,

CH3), 2.87 (s, CH3), 2.39 (s, CH3), 2.33 (s, CH3). 13C NMR (CDCl3, 100 MHz): 168.3 (Camide), 144.1 (C),

143.7 (C), 137.5 (C), 131.8 (C), 129.4 (2×CH), 128.5 (2×CH), 127.6 (CH), 122.3 (CH), 121.8 (C), 116.6

(CH), 113.7 (C), 37.6 (CH3), 35.9 (CH3), 30.3 (CH2), 21.3 (CH3), 18.5 (CH3).

2-(6-chloro-2- (4-chlorophenyl) imidazo[1,2-a] pyridin-3-yl) -N,N-dipropyl

acetamide (alpidem) 2: White solid, isolated yield = 36 %. In agreement with

the structural data reported in literature.[4]

Rt = 4.84 min. HRMS (ESI): m/z: calcd for C21H24Cl2N3O [M+H+]: 404.1298; found 404.1296. 1H NMR

(CDCl3, 400 MHz): 8.26 (s, CH), 7.58 (d, 3JH-H = 8.4 Hz, 2×CH), 7.56 (d, 3JH-H = 9.6 Hz, CH), 7.43 (d, 3JH-H

= 8.4 Hz, 2×CH), 7.17 (d, 3JH-H = 9.6 Hz, CH), 4.06 (s, CH2), 3.31 (t, 3JH-H = 7.4 Hz, CH2), 3.14 (t, 3JH-H =

7.4 Hz, CH2), 1.54 (m, 2×CH2), 0.87 (t, 3JH-H = 7.4 Hz, CH3), 0.78 (q, 3JH-H = 7.4 Hz, CH3). 13C NMR

(CDCl3, 100 MHz): 167.2 (Camide), 143.6 (C), 140.1 (C), 134.2 (C), 132.7 (C), 129.9 (2×CH), 129.0

(2×CH), 126.1 (CH), 122.7 (CH), 120.7 (C), 117.8 (CH), 115.6 (C), 50.1 (CH2), 37.6 (CH2), 30.1 (CH2),

22.2 (CH2), 20.1 (CH2), 11.3 (CH3), 11.0 (CH3).

N,N-dimethyl-2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetamide 15: Yellow solid,

isolated yield = 60%

Rt = 3.48 min. HRMS (ESI): m/z: calcd for C17H18N3O [M+H+]: 280.1450; found


2×CH), 7.63 (d, 3J H-H = 7.4 Hz, CH), 7.45 (t, 3J H-H = 7.4 Hz, 2×CH), 7.38 (d, 3J H-H = 7.4 Hz, CH), 7.21 (d, 3J

H-H = 6.8 Hz, CH), 6.83 (d, 3J H-H = 6.8 Hz, CH), 4.14 (s, CH2), 2.93 (s, CH3), 2.86 (s, CH3). 13C NMR

(CDCl3, 100 MHz): δ (ppm) 168.2 (Camide), 145.2 (C), 144.1 (C), 134.7 (C), 128.7 (2×2×CH), 127.9 (CH),

124.8 (CH), 124.4 (CH), 117.4 (CH), 114.1 (C), 112.2 (CH), 37.5 (CH3), 35.9 (CH3), 30.3 (CH2).

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N,N-dimethyl-2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetamide 16:

Yellow solid, isolated yield = 42%.


294.1605. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.00 (s, CH), 7.65 (d, 3J H-H = 7.0 Hz, 2×CH), 7.53 (d, 3J H-H

= 9.1 Hz, CH), 7.44 (m, 2×CH), 7.36 (d, 3J H-H = 7.0 Hz, CH), 7.04 (d, 3J H-H = 9.1 Hz, CH), 4.09 (s, CH2),

2.94 (s, CH3), 2.87 (s, CH3), 2.34 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 168.3 (Camide), 144.3 (C),

143.9 (C), 134.9 (C), 128.7 (2×CH), 128.6 (2×CH), 127.7 (CH), 127.6 (CH), 122.3 (CH), 121.8 (C), 116.8

(CH), 113.8 (C), 37.5 (CH3), 35.9 (CH3), 30.3 (CH2), 18.5 (CH3).

2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide 17:

Yellow solid, isolated yield = 99%

Rt = 3.77 min. HRMS (ESI): m/z: calcd for C17H17ClN3O [M+H+]: 314.1055; found

314.1045. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.25 (s, CH), 7.63 (d, 3J H-H = 7.0 Hz, 2×CH), 7.55 (d, 3J H-H

= 9.5 Hz, CH), 7.45 (m, 2×CH), 7.38 (d, 3J H-H = 7.0 Hz, CH), 7.15 (d, 3J H-H = 9.5 Hz, CH), 4.08 (s, CH2),

2.96 (s, CH3), 2.93 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 167.8 (Camide), 145.1 (C), 134.3 (C),

128.7 (2×CH), 128.6 (2×CH), 128.1 (CH), 125.8 (CH), 122.6 (CH), 120.4 (C), 118.7 (C), 117.7 (CH), 115.1

(C), 37.5 (CH3), 35.9 (CH3), 29.9 (CH2).

N,N-dimethyl-2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide 18: Yellow solid,

isolated yield = 62%.


294.1587. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.21 (d, 3J H-H = 7.0 Hz, CH), 7.60 (d, 3J H-H = 7.0 Hz, CH),

7.54 (d, 3J H-H = 8.0 Hz, 2×CH), 7.24 (d, 3J H-H = 8.0 Hz, 2×CH), 7.16 (t, 3J H-H = 7.0 Hz, CH), 6.78 (t, 3J H-H =

7.0 Hz, CH), 4.09 (s, CH2), 2.90 (s, CH3), 2.84 (s, CH3), 2.34 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ

(ppm) 168.3 (Camide), 145.1 (C), 144.1 (C), 137.6 (C), 131.7 (C), 129.4 (2×CH), 128.5 (2×CH), 124.7 (CH),

124.3 (CH), 117.3 (CH), 113.8 (C), 112.1 (CH), 37.5 (CH3), 35.8 (CH3), 30.3 (CH2), 21.3 (CH3).

2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide 19:

White solid, isolated yield = 87%.

Rt = 4.01 min. HRMS (ESI): m/z: calcd for C18H19ClN3O [M+H+]: 328.1211;

found 328.1196. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.25 (d, 4J H-H = 1.9 Hz, CH), 7.55 (d, 3J H-H = 9.5

Hz, CH), 7.53 (d, 3J H-H = 8.3 Hz, 2×CH), 7.26 (d, 3J H-H = 8.3 Hz, 2×CH), 7.13 (dd, 3J H-H = 9.5 Hz, 4J H-H =

1.9 Hz, CH), 4.10 (s, CH2), 2.96 (s, CH3), 2.92 (s, CH3), 2.40 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ

NN

NN

OONNMMee22

1166

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OONNMMee22

1188

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NN

OONNMMee22

1199

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OONNMMee22

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1177


S10

(ppm) 167.9 (Camide), 145.2 (C), 143.5 (C), 137.9 (C), 131.3 (C), 129.4 (2×CH), 128.5 (2×CH), 127.6 (CH),

122.6 (CH), 122.3 (C), 117.6 (CH), 114.8 (C), 37.6 (CH3), 35.9 (CH3), 30.3 (CH2), 14.2 (CH3).

2-(8-bromo -6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)

-N,N-dimethylacetamide 20: Yellow solid, isolated yield = 26%.

Rt = 4.09 min. HRMS (ESI): m/z: calcd for C19H21BrN3O [M+H+]: 386.0868; found


2×CH), 7.33 (d, 4J H-H = 1.4 Hz, CH), 7.24 (d, 3J H-H = 8.0 Hz, 2×CH), 4.07 (s, CH2), 2.94 (s, CH3), 2.86 (s,

CH3), 2.40 (s, CH3), 2.34 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 168.1 (Camide), 137.8 (2×C),

133.7 (C), 131.4 (C), 129.8 (CH), 129.3 (2×CH), 128.8 (2×CH), 122.0 (CH), 121.9 (C), 115.6 (C), 110.7

(C), 37.6 (CH3), 35.9 (CH3), 30.6 (CH2), 21.3 (CH3), 18.2 (CH3).

2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl

acetamide 21: Yellow solid, isolated yield = 59%.

Rt = 4.03 min. HRMS (ESI): m/z: calcd for C18H19ClN3O [M+H+]: 328.1211;

found 328.1209. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.90 (s, CH), 7.58 (d, 3J H-H = 6.6 Hz, 2×CH), 7.49

(d, 3J H-H = 9.2 Hz, CH), 7.40 (d, 3J H-H = 6.6 Hz, 2×CH), 7.02 (d, 3J H-H = 9.2 Hz, CH), 4.01 (s, CH2), 2.94 (s,

CH3), 2.91 (s, CH3), 2.31 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 168.1 (Camide), 144.3 (C), 142.7

(C), 133.6 (C), 133.4 (C), 129.8 (2×CH), 128.7 (2×CH), 127.8 (CH), 122.1 (CH), 122.0 (C), 116.7 (CH),

114.1 (C), 37.5 (CH3), 35.9 (CH3), 30.1 (CH2), 18.5 (CH3).

2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl

acetamide 22: White solid, isolated yield = 60%.

Rt = 4.14 min. HRMS (ESI): m/z: calcd for C17H16Cl2N3O [M+H+]: 348.0687;

found 348.0670. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.20 (d, 4J H-H = 2 Hz, CH), 7.58 (d, 3J H-H = 6.8 Hz,

2×CH), 7.56 (d, 3J H-H = 9.6 Hz, CH), 7.43 (d, 3J H-H = 6.8 Hz, 2×CH), 7.17 (dd, 3J H-H = 9.6 Hz, 4J H-H = 2 Hz,

CH), 4.05 (s, CH2), 2.99 (s, 2 CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 167.6 (Camide), 144.0 (C), 143.6

(C), 134.2 (C), 132.7 (C), 129.9 (2×CH), 129.0 (2×CH), 126.1 (CH), 122.5 (CH), 120.6 (C), 117.8 (CH),

115.2 (C), 37.6 (CH3), 36.0 (CH3), 29.8 (CH2).

2-(2-phenylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide 23: Yellow solid,

isolated yield = 93 %. In agreement with the structural data as reported in

literature.[5]

Rt = 4.30 min. HRMS (ESI): m/z: calcd for C21H26N3O [M+H+]: 336.2076; found 336.2087. 1H NMR

(CDCl3, 400 MHz): 8.30 (dt, 3JH-H = 7.0 Hz, 4JH-H = 1.1 Hz, CH), 7.65 (dt, 3JH-H = 7.0 Hz, 4JH-H = 1.1 Hz,

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OONNMMee22

2200

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NN

NN

OONNMMee22

2211

CCll

NN

NN

OONNMMee22

2222

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OONNPPrr22

2233


S11

2×CH), 7.59 (dt, 3JH-H = 9.0 Hz, 4JH-H = 1.1 Hz, CH), 7.44 (m, 2×CH), 7.35 (m, CH), 7.16 (ddd, 3JH-H = 7.0

Hz, 3JH-H = 9.0 Hz, 4JH-H = 1.1 Hz, CH), 6.78 (td, 3JH-H = 7.0 Hz, 4JH-H = 1.1 Hz, CH), 4.11 (s , CH2), 3.22 (t, 3J H-H = 7.8 Hz, CH2), 3.00 (t, 3J H-H = 7.8 Hz, CH2), 1.47 (m, CH2), 1.36 (m, CH2), 0.79 (t, 3J H-H = 7.4 Hz,

CH3), 0.60 (q, 3J H-H = 7.4 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 167.7 (Camide), 145.1 (C), 143.8

(C), 134.6 (C), 128.7 (2×2×CH), 127.9 (CH), 125.0 (CH), 124.4 (CH), 117.3 (CH), 114.6 (C), 112.1 (CH),

49.8 (CH2), 47.9 (CH2), 30.6 (CH2), 22.1 (CH2), 20.9 (CH2), 11.3 (CH3), 10.8 (CH3).

N,N-dipropyl-2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide 24: Yellow solid,

isolated yield = 33 %.


350.2221. 1H NMR (CDCl3, 400 MHz): 8.26 (d, 3JH-H = 7.0 Hz, CH), 7.58 (d, 3JH-H =

7.0 Hz, CH), 7.54 (d, 3JH-H = 6.4 Hz, 2×CH), 7.25 (d, 3JH-H = 6.4 Hz, 2×CH), 7.35 (m, CH), 7.15 (t, 3JH-H =

7.0 Hz, CH), 6.78 (t, 3JH-H = 7.0 Hz, CH), 4.10 (s, CH2), 3.22 (t, 3J H-H = 7.8 Hz, CH2), 3.00 (t, 3J H-H = 7.8

Hz, CH2), 2.37 (s, CH3), 1.47 (m, CH2), 1.35 (m, CH2), 0.79 (t, 3J H-H = 7.4 Hz, CH3), 0.60 (q, 3J H-H = 7.4

Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ (ppm) 167.8 (Camide), 145.1 (C), 143.8 (C), 134.7 (C), 131.7 (C),

129.4 (2×CH), 128.6 (2×CH), 124.9 (CH), 124.3 (CH), 117.2 (CH), 114.3 (C), 113.1 (CH), 49.8 (CH2),

47.9 (CH2), 30.6 (CH2), 22.1 (CH2), 21.2 (CH3), 20.9 (CH2), 11.3 (CH3), 10.8 (CH3).

2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide 25:

Orange solid, isolated yield = 45 %.


364.2365. 1H NMR (CDCl3, 400 MHz): 8.04 (s, CH), 7.53 (d, 3JH-H = 8.0 Hz, 2×CH), 7.49 (d, 3JH-H = 9.2

Hz, CH), 7.24 (d, 3JH-H = 8.0 Hz, 2×CH), 7.01 (d, 3JH-H = 9.2 Hz, CH), 4.08 (s, CH2), 3.17 (t, 3J H-H = 7.8 Hz,

CH2), 3.03 (t, 3J H-H = 7.8 Hz, CH2), 2.38 (s, CH3), 2.34 (s, CH3), 1.56 (m, 2×CH2), 0.87 (m, 2×CH3). 13C

NMR (CDCl3, 100 MHz): δ (ppm) 168.0 (Camide), 144.2 (C), 143.7 (C), 137.5 (C), 131.9 (C), 129.3 (2 CH),

128.5 (2 CH), 124.4 (CH), 122.4 (CH), 121.6 (C), 116.6 (CH), 114.1 (C), 49.8 (CH2), 47.9 (CH2), 30.7

(CH2), 22.5 (CH2), 21.6 (CH3), 21.2 (CH2), 11.6 (CH3), 11.2 (CH3).

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2255

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2244


S12

Synthesis of carboxylic acids 26-34

90 °C14 mL

N

N

R3R1

OOH

R2

Uniqsis Fraction Collector

100 psi

Uniqsis ALF

loop A

loop B

N

N

R3R1

OOEt

R2

6-1426-34 10-70 %

NaOH 2M (4 equiv.)

EtOH

combined flow rate

of 0.5 mL/min

Using an autosampler with Automatic Loop Filling (ALF™, Uniqsis), 1 equivalent of ester intermediate

(6-14) (0.3 mmol) and a solution of 2 M sodium hydroxide in ethanol were respectively filled in

sample loops A and B (1 mL loop each). Both delivery pumps were running at a combined flow rate

of 0.5 mL/min using 4 equivalents of base relative to the ester intermediate (residence time of 30

min) The mixture was injected then mixed at a standard T-connector and passed through a 14 mL

CFC reactor heated at 90 °C. Final compounds 26-34 were collected using a Uniqsis fraction collector,

precipitated with a solution of 1 M HCl and analyzed. For each reaction, a 10 µL aliquot of the

reaction mixture was also automatically collected and transferred into a 2 mL LC-MS vial containing

PBS. Moderate yields obtained through this process are due to the solubility of the final products in

aqueous media, even at low pH.

2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 26: Yellow solid, isolated yield =

60 %.

Rt = 3.38 min. HRMS (ESI): m/z: calcd for C15H13N2O2 [M+H+]: 253.0977; found

253.0986. 1H NMR (CD3OD, 400 MHz): δ (ppm) 8.84 (d, 3J H-H = 7.0 Hz, CH), 8.05 (m, CH), 7.96 (d, 3J H-H

= 9.0 Hz, CH), 7.73 (m, 2×CH), 7.68-7.56 (m, 4×CH), 4.27 (s, CH2). 13C NMR (CD3OD, 100 MHz): δ

(ppm) 171.4 (Cacid), 141.1 (C), 135.5 (C), 135.1 (CH), 132.0 (CH), 130.8 (2×CH), 129.8 (2×CH), 128.4

(CH), 127.6 (C), 118.9 (C), 118.6 (CH), 113.0 (CH), 29.8 (CH2).

2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 27: Yellow solid,

isolated yield = 20%.


267.1136. 1H NMR (CD3OD, 500 MHz): δ (ppm) 8.64 (s, CH), 7.87 (m, 2×CH), 7.67 (m, 2×CH), 7.62 (m,

3×CH), 4.23 (s, CH2), 2.54 (s, CH3). 13C NMR (CD3OD, 120 MHz): δ (ppm) 171.5 (Cacid), 139.8 (C), 137.7

(CH), 135.4 (C), 131.9 (CH), 130.7 (2×CH), 129.7 (2×CH), 129.6 (CH), 127.5 (C), 126.1 (CH), 118.6 (C),

112.2 (C), 29.8 (CH2), 18.1 (CH3).

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2266

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OOOOHH

2277


S13

2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 28: Yellow solid,


Rt = 3.41 min. HRMS (ESI): m/z: calcd for C15H12ClN2O2 [M+H+]: 287.0587; found

287.0577. 1H NMR (CD3OD, 500 MHz): δ (ppm) 8.61 (s, CH), 7.84 (m, CH), 7.72-7.60 (m, 2×CH), 7.51-

7.33 (m, 3×CH), 6.63 (m, CH), 4.12 (s, CH2). 13C NMR (CD3OD, 120 MHz): δ (ppm) 171.2 (Cacid), 157.2

(C), 142.3 (C), 138.9 (CH), 131.9 (C), 128.5 (2×CH), 128.2 (2×CH), 127.8 (C), 123.2 (CH), 121.4 (C),

115.6 (CH), 110.8 (CH), 29.3 (CH2).

2-(2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 29: Yellow solid, isolated yield =

35 %.


267.1134. 1H NMR (CD3OD, 400 MHz): δ (ppm) 8.65 (d, 3J H-H = 7.0 Hz, CH), 7.84 (m, 2×CH), 7.59 (d, 3J

H-H = 6.9 Hz, 2×CH), 7.40 (m, 2×CH), 7.27 (m, CH), 4.15 (s, CH2), 2.38 (s, CH3). 13C NMR (CD3OD, 100

MHz): δ (ppm) 172.4 (Cacid), 142.2 (C), 141.7 (C), 137.6 (C), 132.7 (CH), 131.1 (2×CH), 129.6 (2×CH),

127.7 (CH), 126.6 (C), 118.3 (C), 117.2 (CH), 113.9 (CH), 30.6 (CH2), 21.5 (CH3).

2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 30: Yellow solid,

isolated yield = 70%. In agreement with the structural data reported in

literature.[5, 7]


(CD3OD, 400 MHz): δ (ppm) 8.61 (s, CH), 7.88 (d, 3J H-H = 9.1 Hz, CH), 7.83 (d, 3J H-H = 9.1 Hz, CH), 7.58

(d, 3J H-H = 8.0 Hz, 2×CH), 7.45 (d, 3J H-H = 8.0 Hz, 2×CH), 4.22 (s, CH2), 2.53 (s, CH3), 2.45 (s, CH3). 13C

NMR (CD3OD, 100 MHz): δ (ppm) 170.2 (Cacid), 141.2 (C), 138.4 (C), 136.1 (CH), 134.2 (C), 130.0

(2×CH), 128.2 (2×CH), 128.1 (C), 124.6 (CH), 123.4 (C), 116.8 (C), 110.8 (CH), 28.5 (CH2), 20.0 (CH3),

16.7 (CH3).

2-(6-chloro-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 31: Yellow solid,


Rt = 3.88 min. HRMS (ESI): m/z: calcd for C16H14ClN2O2 [M+H+]: 301.0744;

found 301.0742. 1H NMR (CD3OD, 400 MHz): δ (ppm) 8.91 (s, CH), 7.82 (m, 2×CH), 7.57 (d, 3J H-H = 6.4

Hz, CH), 7.41 (d, 3J H-H = 6.4 Hz, 2×CH), 7.27 (m, CH), 4.19 (s, CH2), 2.43 (s, CH3). 13C NMR (CD3OD, 100

MHz): δ (ppm) 170.4 (Cacid), 140.5 (C), 139.6 (C), 137.8 (C), 131.8 (CH), 129.7 (2×CH), 128.2 (2×CH),

128.6 (CH), 124.6 (CH), 123.8 (C), 117.0 (C), 113.4 (C), 28.8 (CH2), 19.9 (CH3).

NN

NN

OOOOHH

2299

NN

NN

OOOOHH

3300

NN

NN

OOOOHH

3311

CCll

NN

NN

OOOOHH

2288

CCll


S14

2-(8-bromo-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetic acid 32: Yellow

solid, isolated yield = 10 %.

Rt = 4.00 min. HRMS (ESI): m/z: calcd for C17H16BrN2O2 [M+H+]: 359.0395;

found 359.0399. 1H NMR (CD3OD, 500 MHz): δ (ppm) 8.34 (s, CH), 7.80 (m, CH),

7.58 (d, 3J H-H = 8.0 Hz, 2×CH), 7.35 (d, 3J H-H = 8.0 Hz, 2×CH), 4.07 (s, CH2), 2.45 (s, CH3), 2.41 (s, CH3). 13C NMR (CD3OD, 125 MHz): δ (ppm) 172.4 (Cacid), 140.7 (C), 135.1 (CH), 130.6 (2×CH), 130.1 (2×CH),

128.7 (C), 126.4 (C), 124.1 (CH), 118.8 (C), 108.3 (C), 30.8 (CH2), 21.4 (CH3), 17.9 (CH3).

2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)acetic acid 33:

Yellow solid, isolated yield = 62 %.

Rt = 4.01 min. HRMS (ESI): m/z: calcd for C16H14ClN2O2 [M+H+]: 301.0744;

found 301.0750. 1H NMR (CD3OD, 400 MHz): δ (ppm) 8.54 (s, CH), 7.98 (d, 3J H-H = 8.4 Hz, CH), 7.70

(d, 3J H-H = 8.4 Hz, 2×CH), 7.62 (d, 3J H-H = 8.4 Hz, 2×CH), 7.47 (d, 3J H-H = 8.4 Hz, CH), 4.18 (s, CH2), 2.51

(s, CH3). 13C NMR (CD3OD, 100 MHz): δ (ppm) 170.4 (Cacid), 139.3 (C), 136.2 (C), 135.6 (C), 131.0 (CH),

129.9 (2×CH), 129.3 (2×CH), 128.4 (CH), 127.4 (C), 124.2 (C), 117.3 (C), 111.5 (CH), 28.8 (CH2), 16.8

(CH3).

2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetic acid 34:

Yellow solid, isolated yield = 41 %.

Rt = 4.00 min. HRMS (ESI): m/z: calcd for C15H11Cl2N2O2 [M+H+]: 321.0198;

found 321.0204. 1H NMR (CD3OD, 400 MHz): δ (ppm) 9.06 (s, CH), 7.99 (m, 2×CH), 7.73-7.45 (m,

4×CH), 4.26 (s, CH2). 13C NMR (CD3OD, 100 MHz): δ (ppm) 169.8 (Cacid), 138.7 (C), 136.8 (C), 134.5 (C),

134.0 (CH), 130.0 (2×CH), 129.6 (2×CH), 125.3 (CH), 125.2 (C), 125.1 (C), 118.3 (C), 112.8 (CH), 28.6

(CH2).

References

[1] S.S. Bhella, M. Elango, M.P.S. Mohar, Tetrahedron 2009, 65, 240-246

[2] H.-H. Lu, X.-F. Wang, C.-J. Yao, J.-M. Zhang, H. Wu, W.-J Xiao, Chem. Commun. 2009, 4251-

4253

[3] N. Chernyak, V. Gevorgyan, Angew. Chem. Int. Ed. 2010, 49, 2743-2746

[4] G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G. Genchi, E. Sanna, F. Tuveri, E. Cagetti, G.

Biggio, G. Liso, J. Med. Chem. 1997, 40, 3109-3118

[5] Y. Sumalatha, T.R. Reddy, P.P. Reddy, B. Satyanarayana, Arkivoc 2009, 315-320

[6] T. Gustafsson, F. Pontén, P. H. Seeberger, Chem. Commun. 2008, 1100-1102

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S15

[7] J.-P. Kaplan, P. George, US 4,382,938 1983


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