S1
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
S2
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]
Rt = 4.60 min. HRMS (ESI): m/z: calcd for C13H15O3 [M+H+]: 219.1021; found
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]
Rt = 4.96 min. HRMS (ESI): m/z: calcd for C13H15O3 [M+H+]: 239.0475; found
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]
Rt = 4.66 min. HRMS (ESI): m/z: calcd for C18H19N2O2 [M+H+]: 295.1441; found 295.1427. 1H NMR
(CDCl3, 400 MHz): δ (ppm) 7.88 (d, 4J H-H = 1.2 Hz, CH), 7.82 (d, 3J H-H = 8.5 Hz, 2×CH), 7.56 (d, 3J H-H =
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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
(CDCl3, 400 MHz): δ (ppm) 8.18 (d, 4J H-H = 2.1 Hz, CH), 7.79 (d, 3J H-H = 8.0 Hz, 2×CH), 7.60 (d, 3J H-H =
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).
Rt = 4.23 min. HRMS (ESI): m/z: calcd for C18H19N2O2 [M+H+]: 295.1441; found 295.1427. 1H NMR
(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,
isolated yield = 30% 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.[3-5]
Rt = 4.78 min. HRMS (ESI): m/z: calcd for C19H21N2O2 [M+H+]: 308.1525; found 308.1536. 1H NMR
(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,
isolated yield = 10% after chromatography (Biotage SP1, 12g cartridge, eluent:
hexane:ethyl acetate 1:9 gradually changed to 4:6 over 8 column volumes).
Rt = 4.50 min. HRMS (ESI): m/z: calcd for C18H18ClN2O2 [M+H+]: 329.1074; found 329.1057. 1H NMR
(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
(CDCl3, 400 MHz): δ (ppm) 7.86 (d, 4J H-H = 1.2 Hz, CH), 7.71 (d, 3J H-H = 8.0 Hz, 2×CH), 7.36 (d, 4J H-H =
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).
Rt = 4.27 min. HRMS (ESI): m/z: calcd for C18H18ClN2O2 [M+H+]: 329.1043; found 329.1057. 1H NMR
(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
280.1440. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.26 (d, 3J H-H = 6.8 Hz, CH), 7.67 (d, 3J H-H = 7.4 Hz,
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%.
Rt = 3.82 min. HRMS (ESI): m/z: calcd for C18H20N3O [M+H+]: 294.1606; found
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%.
Rt = 3.91 min. HRMS (ESI): m/z: calcd for C18H20N3O [M+H+]: 294.1601; found
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
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(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
386.0858. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.03 (d, 4J H-H = 1.4 Hz, CH), 7.54 (d, 3J H-H = 8.0 Hz,
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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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 %.
Rt = 4.40 min. HRMS (ESI): m/z: calcd for C22H28N3O [M+H+]: 350.2227; found
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 %.
Rt = 4.40 min. HRMS (ESI): m/z: calcd for C23H30N3O [M+H+]: 364.2383; found
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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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%.
Rt = 3.48 min. HRMS (ESI): m/z: calcd for C16H15N2O2 [M+H+]: 267.1134; found
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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2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetic acid 28: Yellow solid,
isolated yield = 57 %.
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 %.
Rt = 4.32 min. HRMS (ESI): m/z: calcd for C16H15N2O2 [M+H+]: 267.1134; found
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]
Rt = 3.87 min. HRMS (ESI): m/z: calcd for C17H17N2O2 [M+H+]: 281.1290; found 281.1294. 1H NMR
(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,
isolated yield = 15 %.
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).
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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
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Electronic Supplementary Material (ESI) for Chemical ScienceThis journal is © The Royal Society of Chemistry 2013
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[7] J.-P. Kaplan, P. George, US 4,382,938 1983
Electronic Supplementary Material (ESI) for Chemical ScienceThis journal is © The Royal Society of Chemistry 2013
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