First Synthesis of 5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol by Pd-Catalyzed Arylation

Article abstract of DOI:10.1080/00397910902730861

5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol was synthesized by a Pd-catalyzed arylation, which proceeds efficiently with 2 equivalents of benzylated clioquinol and 1 equivalent of oxazolo[4,5-b]pyridine. The product was smoothly debenzylated b

Full text of DOI:10.1080/00397910902730861

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First Synthesis of 5-Chloro-7-
[1,3]oxazolo[4,5-b]pyridin-2-
ylquinolin-8-ol by Pd-Catalyzed
Arylation
Uthai Sakee a & Ronald Grigg b
a Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Department of Chemistry, Faculty of
Science, Mahasarakham University, Mahasarakham,
Thailand
b Molecular Innovation, Diversity, and Automated
Synthesis (MIDAS) Centre, School of Chemistry,
University of Leeds, Leeds, United Kingdom
Published online: 03 Aug 2009.
To cite this article: Uthai Sakee & Ronald Grigg (2009): First Synthesis of 5-Chloro-7-
[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol by Pd-Catalyzed Arylation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:17, 3031-3037
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Synthetic Communications1, 39: 3031–3037, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730861
First Synthesis of 5-Chloro-7-
[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol
by Pd-Catalyzed Arylation
Uthai Sakee1 and Ronald Grigg2
1Center of Excellence for Innovation in Chemistry (PERCH-CIC),
Department of Chemistry, Faculty of Science, Mahasarakham University,
Mahasarakham, Thailand
2Molecular Innovation, Diversity, and Automated Synthesis (MIDAS)
Centre, School of Chemistry, University of Leeds, Leeds, United Kingdom
Abstract: 5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol was synthesized
by a Pd-catalyzed arylation, which proceeds efficiently with 2 equivalents of
benzylated clioquinol and 1 equivalent of oxazolo[4,5-b]pyridine. The product
was smoothly debenzylated by boron trichloride in dichloromethane.
Keywords: Arylation, clioquinol, oxazolopyridine, palladium, synthesis
In the search for biologically active compounds as potential drug
candidates, the efficient synthesis of both libraries and individual hetero-
cyclic small molecules is of major importance to the pharmaceutical
industry. Benzoxazoles[1] and their derivatives[2] are key components of
natural products, pharmaceuticals, and their synthetic intermediates.[3]
For example, they find application in drug discovery as melatonin
receptor agonists,[4] cyclooxygenase (COX) inhibitors,[5] anticancer
agents,[6] and 5-HT3 receptor antagonists.[7]
Received October 2, 2008.
Address correspondence to Uthai Sakee, Center of Excellence for Innovation
in Chemistry (PERCH-CIC), Department of Chemistry, Faculty of Science,
Mahasarakham University, Mahasarakham 44150, Thailand. E-mail: uthai.s@
msu.ac.th
3031

3032
U. Sakee and R. Grigg
Interestingly, the oxazolopyridine moiety is far less common in the
literature, although it might offer some advantages from a medicinal
chemistry point of view. The pyridine fragment may provide better water
solubility by offering an additional site for protonation or it might
enhance intermolecular interactions with a target protein by formation
of an additional hydrogen bond.
Clioquinol 1, a derivative of 8-hydroxyquinoline, is a monoprotic
bidentate metal chelator of copper, zinc, and iron. It was first prepared
in Germany in the early part of the past century and has been widely used
for many years as an antimicrobial agent for the treatment of diarrhea
and skin infections. More recently, because it binds copper and zinc,
metals essential for the activity of the enzyme superoxide dismutase-1
(SOD1), it has been featured as a potential treatment for Alzheimer’s
disease.[8] In the 1970s, it was linked to an outbeak of subacute
myelo-optic neuropathy in Japan and was banned in many countries.[9]
Approaches involving arylation of oxazolo[4,5-b]pyridine 3 by
palladium (pd)–catalyzed coupling have been successfully developed[10]
and used to explore the arylation of oxazolo[4,5-b]pyridine 3 with
benzylated clioquinol 2.
Clioquinol 1 was smoothly benzylated in dimethylformamide (DMF)
with benzyl chloride (BnCl) in the presence of K2CO3 to provide a good
yield of O-benzyl clioquinol 2 (Scheme 1).[11] Oxazolo[4,5-b]pyridine 3
was prepared by the known procedure.[12] Initial attempts to effect the
Pd-catalyzed arylation of 3 with 2 under conditions for literature-related
processes were unsuccessful (Table 1, entries 1–6). Variation of the Pd
source was then examined. The compounds Pd2(dba)3=PPh3 in refluxing
acetone worked but gave a poor yield of arylation product 4 (Table 1,
entry 7). Further optimization, using CH3CN as the solvent, afforded 4
in 35% yield while changing the ligand to tri-2-furylphosphine (TFP)
decreased the yield to 30% (Table 1, entry 8). The effect of ligand
indicated that steric factors appeared to be some of the essential
control elements. Tri-2-furylphosphine was found to be as efficient as
Scheme 1. Benzylation of clioquinol 1.

Pd-Catalyzed Arylation
3033
Table 1. Arylation of oxazolo[4,5-b]pyridine (3) with 8-(benzyloxy)-5-
chloro-7-iodoquinoline (2) by Pd catalysta
Entry
Solvent
Catalyst=ligand
Yield (%)b
c
1
2
3
4
5
6
7
8
9
10
Acetone
Acetone
Acetone
CH3CN
DMF
Acetone
CH3CN
CH3CN
CH3CN
CH3CN
Pd(OAc)2=PPh3
Pd(OAc)2=PPh3
Pd(PPh3)4
Pd(OAc)2=PPh3
Pd(OAc)2=PPh3
Pd2(dba)3=PPh3
Pd2(dba)3=PPh3
Pd2(dba)3=TFP
Pd2(dba)3=PPh3
Pd2(dba)3=PPh3
—
—
—
—
—
5
35
30
70d
40e
aConditions: 2 (2 mol equiv), 3 (1 mol equiv), 5 mol% Pd, 20 mol% ligand, and
Cs2CO3 (2 mol equiv).
bIsolated yield.
cReaction run at room temperature; no product was detected.
d10 mol% Pd, 40 mol% PPh3.
e10 mol% Pd, 20 mol% PPh3.
the marginally larger PPh3. An excess of O-benzyl clioquinol 2 together
with increased amount of catalyst (10 mol%) and ligand (40 mol%) gave
a 75% yield of 4 (Table 1, entry 9). A 4:1 molar ratio of Pd2(dba)3=PPh3
was important for maintaining catalytic efficiency, because lowering the
amount of triphenyl phosphine from 40 to 20 mol% decreased the yield
(Table 1, entry 10).
The O-benzyl group of 4 was easily cleaved with boron trichloride
in dichloromethane (DCM) at ꢀ78 to 0ꢁC (BCl3=CH2Cl2) to provide
5-chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol 5 (Scheme 2).
In conclusion, the first synthesis of 5-chloro-7-[1,3]oxazolo[4,5-b]
pyridin-2-ylquinolin-8-ol 5 by Pd-catalyzed arylation is reported. The
arylation proceeds efficiently with 2 equivalents of o-benzyl clioquinol
2 and 1 equivalent of oxazolo[4,5-b]pyridine 3 using Pd2(dba)3 and
PPh3 as catalyst and ligand, respectively, to provide the arylated product,
which was readily debenzylated by BCl3 at ꢀ78 to 0ꢁC.

3034
U. Sakee and R. Grigg
Scheme 2. Debenzylation of compound 4.
EXPERIMENTAL
All reagents were commercially available and used without purification.
Flash-column chromatography was performed using silica gel 60 (230–
400 mesh). Melting points were determined on a Kofler hot-stage
apparatus. Microanalyses were obtained using a Carlo Erba Elemental
Analyzer model 1106. Accurate molecular masses were recorded on a
micro-TOF machine. Infrared (IR) spectra were recorded using a
Perkin-Elmer Fourier transform (FT)–IR spectrometer. Nuclear mag-
netic resonance (NMR) spectra were determined at 500 MHz (1H) and
at 75 Mz (13C) on Bruker spectrometers. Chemical shift values are quoted
in parts per million (ppm) downfield from tetramethylsilane (TMS), and
coupling constants are in hertz. Chemical shift multiplicities are reported
as s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m,
multiplet; br, broad; br s, broad singlet; app. t, apparent triplet. Oxazo-
lo[4,5-b]pyridine 3 was prepared according to the literature method.[12]
8-(Benzyloxy)-5-chloro-7-iodoquinoline (2)
Clioquinol 1 (5.0 g, 16.37 mmol) was dissolved in DMF (17 mL) and
K2CO3(4.52 g, 32.74 mmol), and benzyl chloride (2.28 g, 18.0 mmol)
added. The resulting mixture was stirred and heated under reflux for
2.5 h, cooled, poured into water, and extracted with CH2Cl2 (2 ꢂ 20 mL).
The organic layer was separated and washed with water (3 ꢂ 50 mL),
dried (Na2SO4), and evaporated. Crystallization of the residue from ethyl
acetate yielded the product (5.50 g, 13.91 mmol, 85%), which crystallized
as yellow needles from ethyl acetate, mp 105–106ꢁC. IR (solid): 3063,
3033, 2967, 2941, 2884, 1949, 1810, 1733, 1598, 1572, 1482, 1448, 1390,
1350, 1273, 1207, 1133, 1081, 1037, 960, 941, 908, 867, 843, 810, 790,
760, 723, 695, 665, 614, 603, 556, 483 cmꢀ1. 1H NMR (500 MHz, CDCl3):
d ¼ 9.0 (1H, dd, J ¼ 4.27 and 1.71, ArH), 8.5 (1H, dd, J ¼ 8.55 and

Pd-Catalyzed Arylation
3035
1.71, ArH), 7.9 (1H, s, ArH), 7.6 (2H, d, J ¼ 7.3, 2 ꢂ ArH), 7.5 (1H, dd,
J ¼ 8.55 and 4.27, ArH), 7.4 (1H, t, J ¼ 7.3, ArH), 7.2–7.3 (2H, m, ArH),
5.4 (2H, s, CH2Ph). 13C NMR (75 MHz, CDCl3): d ¼ 150.8, 137.4, 135.5,
133.9, 129.2, 128.8, 128.6, 127.9, 127.0, 122.7, 91.2, 76.9. MS (ESþ): m=z
(%) ¼ 396 (35Cl MHþ, 100), 398 (37Cl MHþ, 30). Anal. calcd. for
C16H11IClNO: C, 48.57; H, 2.80; Cl, 8.96; I, 32.08; N, 3.54. Found: C,
48.50; H, 2.75; Cl, 8.85; I, 31.90; N, 3.54%.
8-(Benzyloxy)-5-chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinoline (4)
A suspension of oxazolo[4,5-b]pyridine (3) (0.060 g, 0.500 mmol),
8-(benzyloxy)-5-chloro-7-iodoquinoline 2 (0.395 g, 1.000 mmol), Cs2CO3
(0.325 g, 1.000 mmol), Pd2(dba)3 (0.088 g, 0.100 mmol), and PPh3
(0.508 g, 0.400 mmol) in CH3CN (5 mL) was stirred and heated under
reflux for 24 h. The mixture was then cooled, diluted with DCM
(30 mL), and washed with sat. NH4Cl (30 mL) and then sat. brine
(50 mL). The aqueous layer was separated and extracted with DCM
(2 ꢂ 50 mL). The combined organic layer was dried (Na2SO4) and
filtered, and the filtrate evaporated under reduced pressure. The residue
was purified by flash-column chromatography, eluting with 1:1 v=v ethyl
acetate–hexane, to afford the product (0.271 g, 0.700 mmol, 70%) as
colorless needles from ethyl acetate, mp 137–138ꢁC. IR (solid) 3061,
3027, 2950, 2890, 1608, 1588, 1559, 1542, 1493, 1443, 1405, 1357, 1262,
1175, 1133, 1080, 1041, 963, 937, 907, 846, 782, 742, 725, 694, 669, 601,
578 cmꢀ1
.
1H NMR (500 MHz, CDCl3): d ¼ 9.1 (1H, dd, J ¼ 4.1 and
1.5, ArH), 8.62–8.65 (2H, m, ArH), 8.5 (1H, s, ArH), 7.77 (1H, dd,
J ¼ 8.3 and 1.35, ArH), 7.66 (2H, dd, J ¼ 8.3 and 4.1, ArH), 7.3–7.6
(2H, m, ArH and ArH), 7.3–7.6 (4H, m, ArH), 5.6 (2H, s, CH2Ph).
13C NMR (75 MHz, CDCl3): d ¼ 163.9, 156.0, 155.0, 151.1, 147.5,
144.6, 143.6, 137.4, 133.8, 129.9, 129.1, 128.7, 128.6, 127.3, 127.1,
124.0, 120.9, 120.0, 118.8, 78.58. MS (ESþ): m=z (%) ¼ 388 (35Cl MHþ,
100), 390 (37Cl MHþ, 30). HRMS m=z 388.0839 (calcd. for
C22H15ClN3O2, 388.0847). Anal. calcd. for C22H14ClN3O2 ꢃ 0.25 H2O:
C, 67.35; H, 3.73; Cl, 9.04; N, 10.71. Found: C, 67.65; H, 3.50; Cl,
9.20; N, 10.65%.
5-Chloro-7-[1,3]oxazolo[4,5-b]pyridin-2-ylquinolin-8-ol (5)
Boron trichloride (1 M in DCM, 1.000 mL, 1.000 mmol) was added to a
stirred solution of compound 4 (0.080 g, 0.206 mmol) in dry CH2Cl2
(4 mL) under N2 via a syringe at ꢀ78ꢁC over 5 min. The mixture was

3036
U. Sakee and R. Grigg
stirred at 0ꢁC for 1 h, diluted with DCM (5 mL), and quenched with ice
water (20 mL). The organic layer was separated, dried (Na2SO4), and
filtered, and the filtrate evaporated. Crystallization of the residue from
5% MeOH=DCM afforded the product 5 (0.056 g, 0.188 mmol, 91%) as
orange-red needles, mp 168–170ꢁC. IR (solid) 3307, 3005, 1629, 1599,
1552, 1503, 1448, 1369, 1267, 1138, 1089, 803, 761, 705, 589, 490 cmꢀ1
.
1H NMR (500 MHz, DMSO-d6): d ¼ 9.6 (1 H, d, J ¼ 8.5, ArH), 9.2
(1H, d, J ¼ 8.5, ArH), 8.7 (1H, d, J ¼ 4.7, ArH), 8.5 (1H, s, ArH), 8.3
(1H, dd, J ¼ 8.5 and 4.7, ArH), 8.2 (1H, d, J ¼ 8.1, ArH), 7.6 (1H, dd,
J ¼ 8.1 and 4.7, ArH). 13C NMR (75 MHz, DMSO-d6): d ¼ 166.9, 163.0,
153.1, 152.3, 147.8, 146.8, 142.0, 136.9, 132.4, 129.9, 126.7, 125.9, 125.7,
123.1, 122.5. MS (ESþ): m=z (%) ¼ 298 (35Cl MHþ, 100), 300 (37Cl
MHþ, 30). HRMS m=z 298.0380 (calcd. for C15H9ClN3O2, 298.0378).
ACKNOWLEDGMENTS
We thank the European Union for a Marie Curie fellowship (MIF1-
CT-2005-514549), PERCH-CIC, Faculty of Science, Mahasarakham
University, for the research fellowship, and Leeds University for support.
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