Synthesis and orthogonal functionalization of oxazolo[5′,4′:4,5]pyrano[2,3-b]pyridine by intra- and intermolecular Pd-catalyzed direct C-H bond heteroarylation

Article abstract of DOI:10.1039/c6ob00227g

The construction and subsequent orthogonal functionalization of a hitherto unknown oxazolo[5′,4′:4,5]pyrano[2,3-b]pyridine are reported. A palladium-catalyzed direct C-H bond functionalization methodology was used to build the tricyclic scaffold as well as to achieve the subsequent C-H bond functionalization at the C-2 position of the oxazole unit with various (hetero)aryl iodides. Remarkably, selective C-H construction and functionalization procedures preserve the chorine atom on the pyridine moiety offering a late-stage substitution site to progress drug design.

Full text of DOI:10.1039/c6ob00227g

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Synthesis
and
Orthogonal
Functionalization
by Intra-
of
and
Oxazolo[5’,4’:4,5]pyrano[2,3-b]pyridine
Received 00th January 20xx,
Accepted 00th January 20xx
Intermolecular Pd-Catalyzed Direct C−H Bond Heteroarylation
Laure Théveau,a Cédric Schneider,a Olivier Querolle,b Lieven Meerpoel,b Vincent Levacher a and
DOI: 10.1039/x0xx00000x
Christophe Hoarau*a
www.rsc.org/
The construction and subsequent orthogonal functionalization of a hitherto unknown oxazolo[5’,4’:4,5]pyrano[2,3-
b]pyridine is reported. Palladium-catalyzed direct C−H bond functionalization methodology was used to build the tricyclic
scaffold as well as to achieve the subsequent C−H bond functionalization at the C-2 position of the oxazole unit with various
(hetero)aryl iodides. Remarkably, selective C−H construction and functionalization procedures preserve the chorine atom on
the pyridine moiety offering a late-stage substitution site to progress in the drug design.
oxazole- and pyridine-based tricyclic heterocycles IV was
Introduction
undertaken (Figure 1).
A:
B:
R2
R2
O
Transition metal-catalyzed C−Η functionalization is a step
and atom economic synthetic strategy for carbon-carbon and
carbon-heteroatom bonds formation which is remarkably useful
for the rapid construction and decoration of highly
functionalized molecules.1 Today, this synthetic tool is actively
incorporated into the synthesis of complex natural products,
pharmaceuticals, agrochemicals or materials.2 Notably several
indole-containing polycyclic compounds with strong biological
activities have been prepared through palladium-catalyzed
R2
O
O
N
R
N
N
N
O
O
X
O
Y
N
N
R1
R1
N
R1
X=O; Y=CH
X=CH2; Y=N
(IV)
(I)
(II)
(III)
Fig. 1 (A) Reported tricyclic bis-azole(one)-pyridine(piperidine) compounds possessing
direct intramolecular C
direct intramolecular functionalization of
−H/C−
X couplings.3 By contrast, the
bond
biological activity. (B) Our targeted oxazolo[5’,4’:4,5]pyrano[2,3-b]pyridine analogue
C−H
The innovative two-phases construction and subsequent
methodology remains sparsely exploited to design various
heteroaryl-based polycyclic nitrogen-containing heterocycles.4
Oxazole and pyridine moieties are encountered in many
biologically active natural products or naturally-occurring
heterocyclic molecules, and are often used in the design of
drugs.5-8 In particular, tricyclic heteroatom- or
n-alkyl-bridged
bis-azole(one)-pyridine(piperidine) structures have been
claimed in several patents to have potential biological activity
to treat heart failure (
and vascular diseases (III) (Figure 1).9 On our ongoing
research objective to develop palladium-catalyzed direct C
functionalization methodologies of 1,3-diazoles
applications to medicinal and material chemistry programs,10
functionalization
]pyridine is depicted in figure 2. The neat construction of
the etheryl-bridged oxazolopyridine involved a nucleophilic
aromatic substitution SNAr between the readily available 3-
bromo-2,5-dichloropyridine ( ) and 4-hydroxymethyloxazole
), followed by an intramolecular direct C H pyridinylation of
the oxazole ring (Figure 2-A). This new polycyclic heteroaryl
ether was then studied in the challenging and selective
intermolecular palladium-catalyzed direct bond
of
the
oxazolo[5’,4’:4,5]pyrano[2,3-
b
1
2
3
(
4
−
1
I), psychotic disorders (II) or autoimmune
C−H
(hetero)arylation at the C-2 with various (hetero)aryl iodides,
while preserving the chorine atom at the C-8 position. Finally,
the chlorinated frameworks obtained were engaged as
electrophiles in late-stage standard cross-couplings reactions
(figure 2-B).
−
H
for
a
quick construction and orthogonal functionalization of original
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Journal Name
DMAc to achieve the selective CMD-based direct C−H
arylation of non-activated oxazole at the C-5 position.13
Table 1. Optimization of reaction parameters
Entrya
[Pd] source
Solvent
Base
Yieldb (%) Ratio 1:6
Fig. 2. (A) Retrosynthetic pathway for the construction of the platform 1. (B)
Subsequent orthogonal functionalization of the platform 1
1c
2
Pd(OAc)2/PCy3•HBF4 1,4-Dioxane
Pd(OAc)2/PCy3•HBF4 1,4-Dioxane
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
nBu4OAc
KOAc
10
7,
8:2
8:2
8:2
8:2
8:2
8:2
8:2
8:2
8:2
9:1
100
Results and discussion
3c
4
Pd(OAc)2/PCy3•HBF4
Pd(OAc)2/PCy3•HBF4
Pd(OAc)2/PCy3•HBF4
PdCl2(PPh3)2
DMF
DMF
13,
20,
38,
45
The synthesis of the etheryl-bridged oxazolopyridine
2, as the
key-intermediate
towards
the
synthesis of
5
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
oxazolopyranopyridine
1, was firstly investigated. The first
6
step consisted in the formation of the 4-methylhydroxyoxazole
which was obtained by the reduction of the readily available
ethyl oxazole-4-carboxylate was
(Scheme 1).11 The alcohol
4
7
PdCl2(PPh3)2
36
5
4
8
PdCl2(PPh3)2
62
then deprotonated by treatment with NaH in DMF and the
corresponding alcoolate was engaged with the commercially
9
PdCl2(dppf)•CH2Cl2
PdCl2(dppf)•CH2Cl2
PdCl2(dppf)•CH2Cl2
KOAc
65
10d
11e
KOAc
75
available 3-bromo-2,5-dichloropyridine
selective SNAr at the C-2 position of the pyridine moiety gave
the expected etheryl-bridged oxazolopyridine in 45% yield
(Scheme 1).12 This latter has been then used as building block
for the cyclization which proceed through selective
H heteroarylation (Table
3 at 40 °C. The
KOAc
80, 72f
2
aReaction conditions: 2 (0.2 mmol), [Pd] (5 mol%), ligand (10 mol%), base (2.0
equiv), anhydrous solvent (1.5 mL). bYield based on isolated product after flash
chromatography. cPivOH (30 mol%). dDMAc (2 mL). eDMAc (4 mL). fCarried out on
2.76 mmol of 2
a
intramolecular Pd-catalyzed direct C5
1).
−
After a screening of palladium sources and bases, the best
result was obtained using Pd(dppf)•CH2Cl2 (5 mol%) and
KOAc, base frequently used to promote the direct 5-arylation
of azoles (Table 1, entries 5-9).14 In contrast to the result
reported recently by Bellina and coworker, a low efficiency
was observed with nBu4NOAc.15 It is noteworthy that the
reaction was completed in only 1 hour at 110 °C and we
observed that the decrease of the temperature affect
dramatically the efficiency of the reaction.16 We noticed also
the formation of a dimer
6 resulting of a homocoupling product
2
with a ratio 8:2 respectively. At this stage, the major
Scheme 1. Synthesis of the etheryl-bridged oxazolopyridine 2
challenge to improve the yield was to circumvent this side
homocoupling reaction revealing thus the good reactivity of
oxazole unit in base-assisted palladium-catalyzed direct C−H
arylation with halides. In order to overcome this intermolecular
side product, we found that lowering the concentration from
Inspired by our previous studies on the selective concerted
metallation-deprotonation (CMD)-based direct C
of alkyl-oxa(thia)-4-carboxylate with halides at the C-5
position,10e we initiated our investigation by
set of
−H arylation
a
0.13 to 0.05
M was crucial (Table 1, entries 9-11).
experiments using the Pd(OAc)2 / PCy3•HBF4 combination as
catalyst, with K2CO3 as base and pivalic acid as additive in 1,4-
dioxane or DMF (Table 1, Entries 1-4). Although a first
promising result was obtained in DMF (Table 1, entry 4), we
found that the use of DMAc as solvent dramatically improved
the yields (Table 1, Entry 5). This observation is in perfect
accordance with previous reports that employ specifically
Interestingly, the optimized protocol was also easily scaled up
from 0.2 to 2.76 mmol without a tremendous decrease of yield
(Table 1 entries 11). Finally, the structure
1 and 6 were
confirmed by single crystal X-ray structure determination
(Figure 3).17
2 | J. Name., 2012, 00, 1-3
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due to the degradation of the starting materials (1). To
circumvent this drawback, we decided to decrease the
temperature. Moreover, based on the recent work of Walsh and
coworkers, we examined the efficiency of the van Leeuwen’s
Nixantphos as ligand (Table 2, Entries 6-7).18 Surprisingly, the
nature of the base (tBuONa, tBuOLi and tBuOK) as well as the
ligand had crucial impact on the yield in THF at 60°C.16 The
essay dropped to 71% yield when the temperature was reduced
to room temperature (Entry 8). We then screened several
solvents at rt and obtained 87% yield when the reaction was
Fig. 3. X-ray single crystal structure of 1 and 6. Only one molecule from each unit cell is
shown and hydrogens are omitted for clarity
conducted in DME with t
BuONa as base (Entries 8-9).16 Under
With the compound
chemo-selective direct C
various (hetero)aryl iodides indirectly used as competitive
coupling partners to the chlorinated pyridinic moiety (Table
2). Regarding the highly acidic C H bond at the C-2 position
1
in hands, a further challenging and
these conditions, the reaction time to completion required 12
hours and only (hetero)aryl iodide partners work (Entries 10-
11). Thus, the optimized conditions for the direct
chemoselective arylation are Pd(OAc)2 (5 mol%), NiXantphos
−
H arylation was achieved with
1
−
(10 mol%) with tBuONa in DME at room temperature.
of the oxazolic moiety, we naturally employed our previously
reported conditions for the palladium-catalyzed Cs2CO3-
assisted direct C2−
H arylation of activated oxazole.10 We were
pleased to observe that by using the Pd(OAc)2 / CyJohnPhos
combination with 4-iodotoluene and Cs2CO3 in 1,4-dioxane,
the expected product 7a was obtained in fair 32% yield (Table
2, entry 1). Switching solvent to DMAc led to the formation of
the arylated product 7a in 57% yield (Table 2, entry 2).
Table 2. Pd-catalyzed intermolecular direct C−H arylation under various reaction
conditions
Entry
Ligand
Solvent
Base
T (°C) t (h) Yield (%)a
1
2
Cy-JohnPhos 1,4-dioxane Cs2CO3
110
110
110
110
110
60
5
2
32
57
64
40
10
18
82
71
87
n.r.
42
Cy-JohnPhos
Cy-JohnPhos
Cy-JohnPhos
Cy-JohnPhos
Cy-JohnPhos
NiXantPhos
NiXantPhos
NiXantPhos
NiXantPhos
NiXantPhos
DMAc
DMAc
DMAc
DMAc
THF
Cs2CO3
CsOAc
3
3
4
KOAc
3
5
t-BuOLi
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
2
6
2
7
THF
60
2
8
THF
r.t.
12
12
12
12
9
DME
DME
DME
r.t.
10c
11C
r.t.
100
aYield based on isolated product after flash chromatography. bWith 0.2
equivalent of CuBr. cWith 1.3 equivalents 4-bromotoluene.
Scheme 2. Scope of the intermolecular direct C−H arylation with various (hetero)aryl
iodides
Because the role of base is crucial to the metalation-
deprotonation process (Table 2, entries 2-5), a screening was
achieved and the best result in DMAc at 110 °C was obtained
using CsOAc as base. However, we never exceeded 64% yields
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Me
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
NiXantPhos (10 mol%)
NaOtBu, DME, r.t., 12 h
O
XPhos (10 mol%)
K3PO4, 1,4-dioxane
H2O, 110 °C, 2 h
N
Cl
Me
OMe
N
O
Me
81%
Route A
I
(HO)2B
7a: 87%
H
O
MeO
O
O
N
Cl
N
Route A: 71% yield overall
Route B: 67% yield overall
N
O
N
1
9
H
OMe
MeO
Me
Route B
O
N
89%
(HO)2B
I
Pd(OAc)2 (5 mol%)
XPhos (10 mol%)
K3PO4, 1,4-dioxane
H2O, 110 °C, 2 h
Pd(OAc)2 (5 mol%)
NiXantPhos (10 mol%)
NaOtBu, DME, r.t., 12 h
N
O
8b 75%
Scheme 4. Chemoselective orthogonal functionalization by C−H arylation / Suzuki-Miyaura coupling of 1
With the optimized conditions in hands, the establishment Having defined reasonable generality for the intermolecular
of the scope of the direct C H arylation at the C-2 position was direct C H (hetero)arylation of oxazolo[5’,4’:4,5]pyrano[2,3-
undertaken with a broad panel of (hetero)aryl iodides. Chemo- ]pyridine methodology for the synthesis of C-2
selective direct C H arylations of were successfully achieved (hetero)arylated product , we sought to investigate the
with aryl iodides bearing electron-withdrawing as well as combination of both the C H (hetero)arylation and standard
electron-donating substituents affording desired 2-arylated cross-coupling reaction in order to design innovative, modular
−
−
b
1
−
1
7
−
oxazolopyranopyridines 7b-7i in fair to excellent yields (50-
and short route for the synthesis of the bis-arylated polycyclic
9
87%). Importantly, these conditions proved to be compatible
(Scheme 4). For this purpose, we next turn our attention to the
with the presence of important functional groups on the chemoselective orthogonal functionalization of the 3-chloro-
aromatic moiety such as ester (85%), cyano (76%) and chloro pyridine moiety
via Suzuki-Miyaura reaction.19 After
(82%). Moreover, the steric hindrance on aryl iodides has no
screening of several parameters (solvent, base, ligand),16 cross-
influence on the success of the direct C H arylation. More coupling reactions with aryl boronic acids bearing electron-
challenging, we then examined a series of heteroaromatic donating and -withdrawing groups could be selectively
coupling partners with . The reactions proceeded well with achieved in good yields (72-75%), using XPhos as ligand and
heteroaryl iodides such as 3- and 4-iodopyridines, 3- K3PO4 as base in 1,4-dioxane/H2O mixture at 110 °C (Scheme
1
−
1
iodothiophene and 2-iodobenzofuran to afford products 7j
in 53-92% yields.
-
7m 3).
As application herein, we decided to take advantage of
selective direct arylation methodologies of C2 H and C8-Cl
bonds in order to orthogonally functionalize both positions,
enabling the synthesis of decorated compound . The 2,8-bis-
arylated product could be selectively, rapidly and efficiently
prepared in two routes, A and B, involving the two-step
sequential combination of direct C2 H bond arylation with aryl
iodides followed by Suzuki-Miyaura reaction respectively or
ice versa (Scheme 4). Finally, whatever the sequence, similar
−
Pd(OAc)2 (5 mol%)
R1
H
H
N
XPhos (10 mol%)
(Het)Ar-B(OH)2 (1,3 equiv)
K3PO4 (2 equiv)
1,4-dioxane/H2O (3/1)
3 h, 110 °C
O
O
9
N
Cl
9
N
O
N
O
−
1
8a-c
H
H
H
N
v
MeO
NC
O
O
O
overall yields were obtained (67-71%).
N
N
N
O
N
O
N
O
Conclusion
8a: 74%
8b: 75%
8c: 72%
Scheme 3. Suzuki-Miyaura coupling at the chlorine moiety of compound 1
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In summary, we have reported an efficient construction and at room temperature and
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a
solution of 2,5-dichloro-4-
subsequent orthogonal functionalization of a new tricyclic bromopyridine ( 3.13 g, 13.8 mmol, 1.2 equiv) in anhydrous
heteroaryl ether through an intra- and intermolecular DMF ( 9 mL) was added. The reaction mixture was heated
palladium-catalyzed direct bond (hetero)arylation. overnight at 40 °C. The mixture was then quenched with
1
C−H
Remarkably, the intermolecular heteroarylation is functional saturated NH4Cl aqueous solution and extracted with CH2Cl2
group tolerant, step-economical, and proceeds at room (3x30 mL). The organic phase was dried over MgSO4 and the
temperature in moderate to good yield with a large scope of solvents were removed under reduced pressure. The crude
heteroaryles iodides
construction and functionalization, tolerate the presence of a (EtOAc/PE 1:9) to afford 4-(((3-bromo-5-chloropyridin-2-
chlorine atom on the pyridine moiety which was subsequently yl)oxy)methyl)oxazole (1.65 g, 5.69 mmol) in 50% yield as a
used to create
new disconnection through palladium- beige solid. mp 75-76 °C (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3)
catalyzed Suzuki-Miyaura coupling, enabling thus an opening δ 8.06 (d, 1H, J = 2.3 Hz), 7.89 (s, 1H), 7.82 (d, 1H, J = 2.3 Hz),
. Moreover, both coupling reactions, product was purified by flash column chromatography
2
a
of the chemical space.
7.76 (d, 1H, J = 1.0 Hz), 5.38 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
157.9 (C), 151.4 (CH), 143.7 (CH), 141.4 (CH), 137.4 (CH), 136.2
(C), 124.5 (C), 107.4 (C), 61.3 (CH2); IR (neat) νmax 3047, 2922,
1580, 1514, 1440, 1050 cm-1; MS (ESI) m/z 288 [M+H+, 79Br],
290 [M+H+, 81Br]; HMRS (ESI-TOF): calc. for C9H7N2O2ClBr:
288.9379; found: 288.9370.
Experimental
General experimental procedures
Commercially available reagents were used throughout
without further purification. Reactions were routinely carried
out under an N2 atmosphere using oven or flame-dried
glassware. Melting points were determined on a hot stage
8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 1.
sealed pressure tube with stir bar was charged with 4-(((3-
Bromo-5-chloropyridin-2-yl)oxy)methyl)oxazole (60 mg, 0.2
mmol, 1 equiv.), PdCl2(dppf) CH2Cl2 (9 mg, 0.01 mmol, 5 mol
A
2
1
melting point apparatus and are uncorrected. H, 19F and 13C
•
NMR spectra were recorded using
a 300 spectrometer
%) and KOAc (40 mg, 0.4 mmol, 2 equiv). The tube was
evacuated and back-filled with argon (this was repeated three
additional times). Degassed anhydrous DMAc (4 mL) was
added and the reaction mixture was allowed to stir at 110 °C
for 1 h. The reaction mixture was filtered through a plug of
celite (washed with CH2Cl2) and the solvents were removed
under reduced pressure. The crude product was purified by
flash column chromatography (EtOAc/PE 3:7) to afford 8-
operating at 300 MHz (1H frequency, corresponding 13C and
19F frequencies are 75 and 282 MHz). The chemical shifts are
calibrated to residual proton and carbon resonance of CDCl3
(1H 7.26 and 13C 77.16 ppm) or DMSO (1H 2.52 and 13C 39.5
ppm). In the 13C NMR spectra, signals corresponding to C, CH,
CH2, or CH3 groups are assigned from DEPT. The obtained
signal multiplicities were distinguished with the common
abbreviations s (singlet), d (doublet), t (triplet), q (quartet), bs
(broad singlet), hep (heptet), sex (sextet) and the
combinations thereof. IR spectra were recorded on a FT-IR
intrument. Low resolution mass spectra analyses were
performed with spectrometer in chemical ionisation. High
Resolution Mass spectra (HRMS) were performed under ESI
conditions with a micro Q-TOF detector. All reactions were
monitored by thin-layer chromatography with silica gel 60
F254 pre-coated aluminium plates (0.25 mm). Flash
chromatography was performed with the indicated solvents
using silica gel 60 (35-70 µm mesh).
chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1 (33 mg,
0.159 mmol) in 80% yield as a white solid. mp 178-179 °C
(CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J = 2.7
Hz), 7.95 (s, 1H), 7.56 (d, 1H, J = 2.7 Hz), 5.68 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 157.8 (C), 152.5 (CH), 145.7 (CH), 140.8 (C),
130.8 (C), 127.9 (CH), 125.5 (C), 110.8 (C), 67.2 (CH2); IR (neat)
νmax 3053, 2950, 1558, 1488, 1477, 1426, 1239, 1075 cm-1; MS
(ESI) m/z 209 [M+H+]; HMRS (ESI-TOF): calc. for C9H6N2O2Cl:
209.0118; found: 209.0117.
5,14-dichloro-9,18-
dihydrodioxazolo[5',4':4,5;5'',4'':10,11][1,7]dioxacyclododeci
no[2,3-b:8,9-b']dipyridine 6. mp 264-265 °C (CH2Cl2/PE); 1H
NMR (300 MHz, CDCl3) δ 8.19 (d, 2H, J = 2.6 Hz), 7.92 (s, 2H),
7.73 (d, 2H, J = 2.6 Hz), 5.26 (s, 4H); 13C NMR (75 MHz, CDCl3) δ
159.0 (2xC), 150.4 (2xCH), 146.8 (2xCH), 144.8 (2xC), 138.5
(2xCH), 132.8 (2xC), 124.8 (2xC), 112.9 (2xC), 61.1 (2xCH2); IR
(neat) νmax 3133, 3059, 2918, 1567, 1503, 1450, 1429, 1301,
1234, 1083, 1031, 986 cm-1; MS (ESI) m/z 417 [M+H+]; HMRS
(ESI-TOF): calc. for C18H11N4O4Cl2: 417.0157; found: 417.0152.
4-(((3-bromo-5-chloropyridin-2-yl)oxy)methyl)oxazole 2. To a
solution of ethyl oxazole-4-carboxylate (5 g, 35 mmol, 1
equiv.) in THF (0.3 M), NaBH4 (1.8 equiv.) and H2O (1.8 equiv.)
were added. The mixture was then stirred overnight at reflux.
The mixture was quenched with saturated NH4Cl aqueous
solution and then extracted
3 times with CH2Cl2. The
combined organic layers were quickly washed with saturated
aqueous NaCl solution, dried over MgSO4 and concentrated in
vacuo. The crude product
purification as colorless oil (2.3 g, 67%). Thus, to a solution of
the 4-oxazolemethanol (1.139 g, 11.50 mmol) in anhydrous
4 was then used without further
General procedure for the C-2 heteroarylation
4
A flame-dried tube filled with argon was charged with
DMF (30 mL) was added imidazole (78 mg, 1.15 mmol, 0.1
equiv) and NaH 60% in oil (598 mg, 14.95 mmol, 1.3 equiv) at
0 °C respectively. The mixture was then stirred during 30 min
heteroaryl iodides (0.26 mmol, 1.3 equiv), 8-chloro-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1 (42 mg, 0.2 mmol,
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DOI: 10.1039/C6OB00227G
ARTICLE
1.0 equiv), NiXantphos (11 mg, 0.02 mmol, 10 mol%), Pd(OAc)2 mmol) in 82% yield as
Journal Name
a
white solid. mp 225-226 °C
(2 mg, 0.01 mmol, 5 mol%), tBuONa (49 mg, 0.5 mmol, 2.5 (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H, J = 8.4
equiv). The tube was sealed, evacuated and back-filled with Hz), 7.97 (d, 1H, J = 2.5 Hz), 7.59 (d, 1H, J = 2.5 Hz), 7.47 (d, 2H,
argon (this was repeated three additional times). Freshly J = 8.4 Hz), 5.70 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 162.9 (C),
degassed and anhydrous DME (1 mL) was added and the 157.7 (C), 145.3 (CH), 140.6 (C), 137.6 (C), 133.0 (C), 129.5
reaction mixture was stirred at room temperature for 12 (2xCH), 127.9 (2xCH), 127.4 (CH), 125.5 (C), 125.0 (C), 110.9
hours. Then, the reaction mixture was filtered through a plug (C), 67.2 (CH2); IR (neat) νmax 3059, 2972, 1552, 1477, 1433,
of celite (washed with CH2Cl2) and the solvents were removed 1251, 1090, 887 cm-1; MS (ESI) m/z 319 [M+H+]; HMRS (ESI-
under reduced pressure. The crude product was then purified TOF): calc. for C15H9N2O2Cl2: 319.0041; found: 319.0044.
by flash column chromatography
tert-butyl
4-(8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridin-2-yl)benzoate 7d. Compound 7d was prepared from
8-chloro-2-(p-tolyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7a.
Compound 7a was prepared from 4-iodotoluene (57 mg, 0.26
tert-butyl 4-iodobenzoate (61 mg, 0.26 mmol) and 8-chloro-
4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1
(42 mg, 0.2
. The
mmol)
and
(42 mg, 0.2 mmol, 1.0 equiv) according to the
. The crude product was purified by flash
8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-
mmol, 1.0 equiv) according to the general procedure
A
b]pyridine
1
crude product was purified by flash column chromatography
(EtOAc/PE 2:8) to afford tert-butyl 4-(8-chloro-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine-2-yl)benzoate 7d (65
mg, 0.169 mmol) in 85% yield as a yellow solid. mp 150-151 °C
general procedure
A
column chromatography (EtOAc/PE 3:7) to afford 8-chloro-2-
(p-tolyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7a (52 mg,
0.174 mmol) in 87% yield as a beige solid. mp 185-186 °C
(CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 7.97 (d, 1H, J = 2.5
Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.61 (d, 1H, J = 2.5 Hz), 7.30 (d, 2H,
J = 8.0 Hz), 5.72 (s, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 164.1 (C), 157.7 (C), 144.8 (CH), 142.0 (C), 140.0 (C), 132.8
(C), 129.9 (2xCH), 127.1 (CH), 126.7 (2xCH), 125.4 (C), 123.8
(C), 111.2 (C), 67.3 (CH2), 21.7 CH3); IR (neat) νmax 3046, 1610,
1555, 1488, 1432, 1352, 1238, 1197, 1010 cm-1; MS (ES) m/z
299 [M+H+]; HMRS (ESI-TOF): calc. for C16H12N2O2Cl: 299.0587;
found: 299.0592.
1
(CH2Cl2/PE); H NMR (300 MHz, CDCl3) δ 8.10 (s, 4H), 8.00 (d,
1H, J = 2.5 Hz), 7.64 (d, 1H, J = 2.5 Hz), 5.72 (s, 2H), 1.62 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 164.8 (C), 162.9 (C), 157.7 (C),
145.3 (CH), 140.9 (C), 134.2 (C), 133.1 (C), 130.1 (2xCH), 129.6
(C), 127.5 (CH), 126.3 (2xCH), 125.5 (C), 110.8 (C), 81.8 (C),
67.1 (CH2), 28.2 (3xCH3); IR (neat) νmax 2979, 2938, 1708, 1428,
1290, 1243, 1161, 1107 cm-1; MS (ESI) m/z 385 [M+H+]; HMRS
(ESI-TOF): calc. for C20H18N2O4Cl: 385.0955; found: 385.0948.
4-(8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridin-2-
yl)benzonitrile 7e. Compound 7e was prepared from 4-
iodobenzonitrile (60 mg, 0.26 mmol) and 8-chloro-4H-
8-chloro-2-(4-methoxyphenyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7b
was prepared from 4-iodoanisole (61 mg, 0.26 mmol) and 8-
chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg,
0.2 mmol, 1.0 equiv) according to the general procedure
. Compound 7b
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1.0 equiv) according to the general procedure
product was purified by flash column chromatography
(CH2Cl2/EtOAc 97:3) to afford 4-(8-chloro-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine-2-yl)benzonitrile 7e
1
(42 mg, 0.2 mmol,
A
. The crude
1
A
.
The crude product was purified by flash column
chromatography (EtOAc/PE 3:7) to afford 8-chloro-2-(4-
methoxyphenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7b
(43 mg, 0.137 mmol) in 69% yield as a beige solid. mp 215-216
°C (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.00 (d, 2H, J = 8.9
Hz), 7.96 (d, 1H, J = 2.5 Hz), 7.59 (d, 1H, J = 2.5 Hz), 7.00 (d, 2H,
J = 8.9 Hz), 5.71 (s, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 164.0 (C), 162.2 (C), 157.6 (C), 144.7 (CH), 139.7 (C), 132.9
(C), 128.5 (2xCH), 126.9 (CH), 125.4 (C), 119.2 (C), 114.6
(2xCH), 111.3 (C), 67.3 (CH2), 55.6 (CH3); IR (neat) νmax 3066,
2999, 2938, 1609, 1488, 1434, 1240, 1197, 1034 cm-1; MS (ESI)
m/z 315 [M+H+]; HMRS (ESI-TOF): calc. for C16H12N2O3Cl:
315.0536; found: 315.0536.
(45 mg, 0.145 mmol) in 73% yield as a yellow solid. mp 266-
267 °C (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.16 (d, 2H, J =
8.4 Hz), 8.01 (d, 1H, J = 2.5 Hz), 7.78 (d, 2H, J = 8.4Hz), 7.63 (d,
1H, J = 2.5 Hz), 5.72 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 161.7
(C), 157.9 (C), 145.9 (CH), 141.6 (C), 133.4 (C), 132.9(2xCH),
130.2 (C), 127.8 (CH), 127.0 (2xCH), 125.7 (C), 118.2 (C), 114.5
(C), 110.6 (C), 67.0 (CH2); IR (neat) νmax 3069, 2227, 1551,
1464, 1428, 1243 cm-1; MS (ESI) m/z 310 [M+H+]; HMRS (ESI-
TOF): calc. for C16H9N3O2Cl: 310.0383; found: 310.0372.
8-chloro-2-(4-(trifluoromethyl)phenyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7f. Compound 7f was
prepared from 4-iodobenzotrifluoride (71 mg, 0.26 mmol) and
8-chloro-2-(4-chlorophenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridine 7c. Compound 7c was prepared from 1-chloro-4-
iodobenzene (62 mg, 0.26 mmol) and 8-chloro-4H-
8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1 (42 mg,
0.2 mmol, 1.0 equiv) according to the general procedure
A
.
The crude product was purified by flash column
chromatography (EtOAc/PE 2:8) to afford 8-chloro-2-(4-
(trifluoromethyl)phenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridine 7f (61 mg, 0.173 mmol) in 87% yield as a yellow
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1
(42 mg, 0.2 mmol,
. The crude
1.0 equiv) according to the general procedure
A
product was purified by flash column chromatography
(EtOAc/PE 15:85) to afford 8-chloro-2-(4-chlorophenyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7c (52 mg, 0.163
1
solid. mp 180-181 °C (CH2Cl2/PE); H NMR (300 MHz, CDCl3) δ
8.17 (d, 2H, J = 8.2 Hz), 8.00 (d, 1H, J = 2.6 Hz), 7.75 (d, 2H, J =
6 | J. Name., 2012, 00, 1-3
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ARTICLE
8.2 Hz), 7.64 (d, 1H, J = 2.6 Hz), 5.72 (s, 2H); 13C NMR (75 MHz, oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7i (34 mg, 0.114 mmol)
1
CDCl3) δ 162.2 (C), 157.7 (C), 145.5 (CH), 141.1 (C), 133.0 (C), in 57% yield as a yellow solid. mp 137-139 °C (CH2Cl2/PE); H
132.3 (C, J = 33 Hz), 129.5 (C), 127.5 (CH), 126.8 (2xCH), 126.1 NMR (300 MHz, CDCl3) δ 8.03 (dd, 1H, J = 1.6 and 9.0 Hz), 7.97
(2xCH, J = 3.3 Hz), 125.5 (C), 123.7 (C, J = 275 Hz), 110.6 (C), (d, 1H, J = 2.5 Hz), 7.58 (d, 1H, J = 2.5 Hz), 7.41-7.32 (m, 3H),
67.0 (CH2); 19F NMR (282 MHz, CDCl3) δ -62.9; IR (neat) νmax 5.74 (s, 2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.2 (C),
3065, 1619, 1555, 1468, 1435, 1320, 1167, 1108 cm-1; MS (ESI) 157.8 (C), 144.9 (CH), 139.8 (C), 138.0 (C), 132.7 (C), 132.0
m/z 354 [M+H+]; HMRS (ESI-TOF): calc. for C16H9N2O2ClF3: (CH), 130.9 (CH), 129.0 (CH), 127.3 (CH), 126.3 (CH), 125.5 (C),
353.0304; found: 353.0308.
125.4 (C), 111.2 (C), 67.4 (CH2), 22.3 (CH3); IR (neat) νmax 3073,
2924, 1673, 1601, 1550, 1454, 1429, 1238, 1200, 1048 cm-1;
MS (ESI) m/z 299 [M+H+]; HMRS (ESI-TOF): calc. for
8-chloro-2-(3-methoxyphenyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7g. Compound 7g was C16H12N2O2Cl: 299.0587; found: 299.0582.
prepared from 3-iodoanisole (61 mg, 32 L, 0.26 mmol) and 8-
chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 8-chloro-2-(pyridin-3-yl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
0.2 mmol, 1.0 equiv) according to the general procedure b]pyridine 7j. Compound 7j was prepared from 3-iodopyridine
The crude product was purified by flash column (54 mg, 0.26 mmol) and 8-chloro-4H-
chromatography (EtOAc/PE 4:6) to afford 8-chloro-2-(3- oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol,
methoxyphenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7g 1.0 equiv) according to the general procedure . The crude
µ
1
A
.
1
A
(33 mg, 0.105 mmol) in 53% yield as a yellow solid. mp 199- product was purified by flash column chromatography
200 °C (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H, J = (EtOAc/PE 7:3) to afford 8-chloro-2-(pyridin-3-yl)-4H-
2.5 Hz), 7.65 (d, 1H, J = 7.7 Hz), 7.61 (d, 1H, J = 2.5 Hz), 7.57- oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7j (30 mg, 0.105 mmol)
1
7.56 (m, 1H), 7.40 (t, 1H, J = 8.1 Hz), 7.05 (dd, 1H, J = 2.5 and in 53% yield as a yellow solid. mp 235-236 °C (CH2Cl2/PE); H
8.1 Hz), 5.71 (s, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ NMR (300 MHz, CDCl3) δ 9.30 (bs, 1H), 7.74 (d, 1H, J = 3.7 Hz),
163.8 (C), 160.1 (C), 157.7 (C), 145.1 (CH), 140.4 (C), 132.9 (C), 8.32 (t, 1H, J = 1.8 and 8.0 Hz), 8.01 (d, 1H, J = 2.5 Hz), 7.64 (d,
130.3 (CH), 127.7 (C), 127.3 (CH), 125.5 (C), 119.1 (CH), 117.9 1H, J = 2.5 Hz), 7.45 (dd, 1H, J = 4.9 and 8.0 Hz), 5.73 (s, 2H);
(CH), 111.2 (CH), 111.1 (C), 67.2 (CH2), 55.6 (CH3); IR (neat) 13C NMR (75 MHz, CDCl3) δ 161.4 (C), 157.8 (C), 151.9 (CH),
νmax 3066, 2999, 2923, 1599, 1469, 1432, 1224, 1030 cm-1; MS 147.9 (CH), 145.6 (CH), 141.1 (C), 133.7 (CH), 133.0 (C), 127.7
(ESI) m/z 315 [M+H+]; HMRS (ESI-TOF): calc. for C16H12N2O3Cl: (CH), 125.6 (C), 123.9 (CH), 122.9 (C), 110.7 (C), 67.1 (CH2); IR
315.0536; found: 315.0538.
(neat) νmax 3068, 2922, 1553, 1464, 1427, 1243, 1004 cm-1; MS
(ESI) m/z 286 [M+H+]; HMRS (ESI-TOF): calc. for C14H9N3O2Cl:
286.0383; found: 286.0387.
2-(3,5-bis(trifluoromethyl)phenyl)-8-chloro-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7h. Compound 7h
was prepared from 1-iodo-3,5-trifluoromethylbenzene (84 mg, 8-chloro-2-(pyridin-4-yl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
47 L, 0.26 mmol) and 8-chloro-4H- b]pyridine 7k. Compound 7k was prepared from 4-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol, iodopyridine (54 mg, 50 µL, 0.26 mmol) and 8-chloro-4H-
1.0 equiv) according to the general procedure . The crude oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol,
product was purified by flash column chromatography (CH2Cl2) 1.0 equiv) according to the general procedure . The crude
to afford 2-(3,5-bis(trifluoromethyl)phenyl)-8-chloro-4H- product was purified by flash column chromatography
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7h (65 mg, 0.155 (EtOAc/PE 8:2) to afford 8-chloro-2-(pyridin-4-yl)-4H-
mmol) in 77% yield as beige solid. mp 187-188 °C oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7k (33 mg, 0.116
µ
1
A
1
A
a
1
(CH2Cl2/PE); H NMR (300 MHz, CDCl3) δ 8.50 (bs, 2H), 8.04 (d, mmol) in 58% yield as a yellow solid. mp 197-198 °C
1H, J = 2.5 Hz), 7.99 (bs, 1H), 7.72 (d, 1H, J = 2.5 Hz), 5.74 (s, (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.79 (d, 2H, J = 6.0
2H); 13C NMR (75 MHz, CDCl3) δ 160.7 (C), 157.9 (C), 146.1 Hz), 8.03 (d, 1H, J = 2.5 Hz), 7.89 (d, 2H, J = 6.0 Hz), 7.66 (d, 1H,
(CH), 141.8 (C), 133.4 (C, J = 34 Hz), 133.2 (C), 132.5 (C, J = 34 J = 2.5 Hz), 5.73 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 161.3 (C),
Hz), 128.4 (C), 128.0 (CH), 126.4 (2xCH, J = 3.7 Hz), 125.7 (C), 157.9 (C), 150.9 (2xCH), 146.0 (CH), 141.7 (C), 133.4 (C), 133.2
126.6 (C, J = 271 Hz), 124.4 (CH, J = 3.7 Hz), 119.3 (C, J = 271 (C), 127.9 (CH), 125.7 (C), 120.0 (2xCH), 110.5 (C), 67.0 (CH2);
Hz), 110.4 (C), 66.9 (CH2); 19F NMR (282 MHz, CDCl3) δ 63.1; IR IR (neat) νmax 3065, 1619, 1555, 1468, 1435, 1238, 1010 cm-1;
(neat) νmax 3086, 3059, 2923, 1470, 1436, 1374, 1301, 1272, MS (ESI) m/z 286 [M+H+]; HMRS (ESI-TOF): calc. for
1125 cm-1; MS (ESI) m/z 421 [M+H+]. HMRS (ESI-TOF): calc. for C14H9N3O2Cl: 286.0383; found: 286.0378.
C17H8N2O2ClF6: 421.0178; found: 421.0173.
8-chloro-2-(thiophen-3-yl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
8-chloro-2-(o-tolyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridine 7i. Compound 7i was prepared from 2-iodotoluene iodothiophene19 (55 mg, 27 µL, 0.26 mmol) and 8-chloro-4H-
(57 mg, 34 L, 0.26 mmol) and 8-chloro-4H- oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol,
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol, 1.0 equiv) according to the general procedure . The crude
1.0 equiv) according to the general procedure . The crude product was purified by flash column chromatography
product was purified by flash column chromatography (EtOAc/PE 3:7) to afford 8-chloro-2-(thiophen-3-yl)-4H-
(EtOAc/PE 2:8) to afford 8-chloro-2-(o-tolyl)-4H- oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7l (50 mg, 0.172 mmol)
b]pyridine 7l. Compound 7l was prepared from 2-
µ
1
1
A
A
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Journal Name
1
in 86% yield as a yellow solid. mp 190-191 °C (CH2Cl2/PE); H 7.47-7.42 (m, 2H), 7.39-7.34 (m, 1H), 5.68 (s, 2H); 13C NMR (75
NMR (300 MHz, CDCl3) δ 8.02 (dd, 1H, J = 1.2 and 3.0 Hz), 7.96 MHz, CDCl3) δ 158.9 (C), 152.0 (CH), 145.6 (CH), 141.6 (C),
(d, 1H, J = 2.5 Hz), 7.62 (dd, 1H, J = 1.2 and 5.1 Hz), 7.58 (d, 1H, 136.9 (C), 131.5 (C), 129.9 (C), 129.1 (2xCH), 127.9 (CH), 126.6
J = 2.5 Hz), 7.43 (dd, 1H, J = 3.0 and 5.1 Hz), 5.69 (s, 2H); 13C (3xCH), 109.7 (C), 67.0 (CH2); IR (neat) νmax 3091, 2926, 1647,
NMR (75 MHz, CDCl3) δ 160.6 (C), 157.7 (C), 144.9 (CH), 139.7 1601, 1439 cm-1; MS (ESI) m/z 251 [M+H+]; HMRS (ESI-TOF):
(C), 132.6 (C), 128.5 (C), 127.4 (CH), 127.1 (CH), 126.9 (CH), calc. for C15H11N2O2: 251.0821; found: 251.0815.
125.9 (CH), 125.4 (C), 111.1 (C), 67.2 (CH2); IR (neat) νmax 3080,
2925, 1481, 1584, 1432, 1246, 1036, 869 cm-1; MS (ESI) m/z 8-(4-methoxyphenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
291 [M+H+]; HMRS (ESI-TOF): calc. for C13H8N2O2SCl: 290.9995; b]pyridine 8b. Compound 8b was prepared from 4-
found: 290.9989.
methoxyphenylboronic acid (40 mg, 0.26 mmol, 1.3 equiv) and
8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg,
0.2 mmol, 1.0 equiv) according to the general procedure
1
8-chloro-2-(benzofuran-2-yl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
B.
b]pyridine 7m. Compound 7m was prepared from 2- The crude product was purified by flash column
iodobenzofuran20 (64 mg, 0.26 mmol) and 8-chloro-4H- chromatography
(EtOAc/PE 1:1) to afford 8-(4-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine (42 mg, 0.2 mmol, methoxyphenyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 8b
1.0 equiv) according to the general procedure . The crude (42 mg, 0.150 mmol) in 75% yield as a beige solid. mp 201-202
1
A
product was purified by flash column chromatography °C (CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.94 (s,
(EtOAc/PE 3:7) to afford 8-chloro-2-(benzofuran-2-yl)-4H- 1H), 7.74 (s, 1H), 7.46 (d, 2H, J = 8.3 Hz), 6.98 (d, 2H, J = 8.3
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7m (60 mg, 0.185 Hz), 5.68 (s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.6
mmol) in 93% yield as a yellow solid. mp 227-229 °C (C), 158.5 (C), 152.0 (CH), 145.2 (CH), 141.8 (C), 131.3 (C),
(CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J = 2.5 129.9 (C), 129.4 (C), 127.8 (2xCH), 126.3 (CH), 114.6 (2xCH),
Hz), 7.68 (d, 1H, J = 7.8 Hz), 7.64 (d, 1H, J = 2.5 Hz), 7.59 (d, 1H, 109.6 (C), 66.9 (CH2), 55.5 (CH3); IR (neat) νmax 3142, 2926,
J = 8.3 Hz), 7.45 (s, 1H), 7.41 (dd, 1H, J = 1.0 and 7.4 Hz), 7.32 1557, 1481, 1463, 1438, 1251, 1236, 1198, 1016, 1006 cm-1;
(t, 1H, , J = 7.4 Hz), 5.72 (s, 2H); 13C NMR (75 MHz, CDCl3) δ MS (ESI) m/z 281 [M+H+]; HMRS (ESI-TOF): calc. for
157.7 (C), 156.1 (C), 155.6 (C), 145.6 (CH), 142.9 (C), 140.8 (C), C16H13N2O3: 281.0926; found: 281.0919.
132.9 (C), 127.6 (CH), 127.5 (C), 127.1 (CH), 125.6 (C), 124.1
(CH), 122.3 (CH), 112.0 (CH), 110.6 (C), 109.1 (CH), 67.0 (CH2); 8-(4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridin-8-yl)benzonitrile
IR (neat) νmax: 3053, 2923, 1622, 1549, 1468, 1429, 1246, 1002 8c. Compound 8c was prepared from 4-cyanophenylboronic
cm-1; MS (ESI) m/z 325 [M+H+]; HMRS (ESI-TOF): calc. for acid
(39
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1.0 equiv) according to the general procedure
product was purified by flash column chromatography
(EtOAc/CH2Cl2 2:8) to afford 8-(4H-
mg,
0.26
mmol)
and
(42 mg, 0.2 mmol,
. The crude
8-chloro-4H-
C17H10N2O3Cl: 325.0380; found: 325.0382.
1
B
General procedure for the Suzuki-Miyaura cros-coupling
A flame-dried tube filled with argon was charged with boronic
oxazolo[5',4':4,5]pyrano[2,3-b]pyridin-8-yl)benzonitrile 8c (35
acid
(0.26
mmol,
1.3
equiv),
8-chloro-4H-
mg, 0.140 mmol) in 68% yield as a beige solid. mp 241-242 °C
1
(CH2Cl2/PE); H NMR (300 MHz, CDCl3) δ 8.30 (d, 1H, J = 2.3
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
1
(42 mg, 0.2 mmol,
1.0 equiv), XPhos (10 mg, 0.02 mmol, 10 mol%), Pd(OAc)2 (3
mg, 0.01 mmol, 5 mol%), K3PO4 (85 mg, 0.4 mmol, 2.0 equiv).
The tube was sealed, evacuated and back-filled with argon
(this was repeated three additional times). Freshly degassed
1,4-dioxane (600 µL) as well as H2O (200 µL) were added and
the reaction mixture was stirred at 110 °C for 4 hours. Then,
the reaction mixture was filtered through a plug of celite
(washed with CH2Cl2) and the solvents were removed under
reduced pressure. The crude product was then purified by
flash column chromatography.
Hz), 7.98 (s, 1H),7.80 (d, 1H, J = 2.3 Hz), 7.75 (d, 2H, J = 8.4 Hz),
7.66 (d, 2H, J = 8.4 Hz), 5.74 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
159. 8 (C), 152.4 (CH), 145.8 (CH), 141.5 (C), 141.2 (C), 133.0
(2xCH), 130.3 (C), 129.6 (C), 127.3 (2xCH), 126.5 (CH), 118.6
(C), 111.7 (C), 110.1 (C), 67.3 (CH2); IR (neat) νmax 3053, 2925,
2223, 1607, 1575, 1489, 1445, 1063 cm-1; MS (ESI) m/z 276
[M+H+]; HMRS (ESI-TOF): calc. for C16H10N3O2: 276.0773;
found: 276.0771.
8-(4-methoxyphenyl)-2-(p-tolyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridine 9.
8-phenyl-4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
8a.
Route A, procedure (7a → 9): A flame-dried tube filled with
argon was charged with 4-methoxyphenyl boronic acid (46
mg, 0.304 mmol, 1.3 equiv), 8-chloro-2-(p-tolyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 7a (70 mg, 0.234
mmol, 1.0 equiv), XPhos (12 mg, 0.023 mmol, 10 mol%),
Pd(OAc)2 (3 mg, 0.012 mmol, 5 mol%), K3PO4 (105 mg, 0.492
mmol, 2.0 equiv). The tube was sealed, evacuated and back-
filled with argon (this was repeated three additional times).
Freshly degassed 1,4-dioxane (600 µL) as well as H2O (200 µL)
were added and the reaction mixture was stirred at 110 °C for
Compound 8a was prepared from phenylboronic acid (32 mg,
0.26 mmol) and 8-chloro-4H-oxazolo[5',4':4,5]pyrano[2,3-
b]pyridine
1
(42 mg, 0.2 mmol, 1.0 equiv) according to the
. The crude product was purified by flash
general procedure
B
column chromatography (EtOAc/PE 4:5) to afford 8-phenyl-
4H-oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 8a (35 mg, 0.140
mmol) in 70% yield as a beige solid. mp 144-146 °C
(CH2Cl2/PE); 1H NMR (300 MHz, CDCl3) δ 8.26 (d, 1H, J = 2.4
Hz), 7.93 (s, 1H), 7.77 (d, 1H, J = 2.4 Hz), 7.54-7.51 (m, 2H),
8 | J. Name., 2012, 00, 1-3
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2
3
(a) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011, 40,
4 hours. Then, the reaction mixture was filtered through a
plug of celite (washed with CH2Cl2) and the solvents were
removed under reduced pressure. The crude product was
purified by flash column chromatography (EtOAc/PE 4:6) to
1976; (b) L. McMurray, F. O'Hara and M. J. Gaunt, Chem. Soc. Rev.,
2011, 40, 1885; (c) J. Yamaguchi, A. D. Yamaguchi and K. Itami,
Angew. Chem. Int. Ed., 2012, 51, 8960; (d) L. G. Mercier and M.
Leclerc, Acc. Chem. Res., 2013, 46, 1597; (e) J. Wencel-Delord and
afford
8-(4-methoxyphenyl)-2-(p-tolyl)-4H-
F. Glorius, Nat. Chem., 2013, 5, 369.
(a) A. P. Kozikowski, D. Ma, J. Brewer, S. Sun, E. Costa, E. Romeo
and A. Guidotti, J. Med. Chem., 1993, 36, 2908; (b) E. Desarbre and
J.-Y. Mérour, Heterocycles, 1995, 41, 1987; (c) B. Malapel-Andrieu
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oxazolo[5',4':4,5]pyrano[2,3-b]pyridine
9 (70 mg, 0.174 mmol)
in 81% yield as a yellow solid.
Route B, procedure (8b → 9): A flame-dried tube filled with
argon was charged with heteroaryl iodides (51 mg, 0.232
Calogeropoulou, M.-T. The and D. Sugden, J. Med. Chem., 2000, 43
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1050; (e) S. Routier, J.-Y. Mérour, N. Dias, A. Lansiaux, C. Bailly,
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(a) D. E. Ames and D. Bull, Tetrahedron, 1982, 38, 383-387; (b) Y.-
mmol,
1.3
equiv),
8-(4-methoxyphenyl)-4H-
oxazolo[5',4':4,5]pyrano[2,3-b]pyridine 8b (50 mg, 0.178
mmol, 1.0 equiv), NiXantphos (10 mg, 0.018 mmol, 10 mol%),
Pd(OAc)2 (2 mg, 0.009 mmol, 5 mol%), NaOtBu (39 mg, 0.5
mmol, 2.5 equiv). The tube was sealed, evacuated and back-
filled with argon (this was repeated three additional times).
Freshly degassed and anhydrous DME (900 µL) was added and
the reaction mixture was stirred at room temperature for 12
hours. Then, the reaction mixture was filtered through a plug
of celite (washed with CH2Cl2) and the solvents were removed
under reduced pressure. The crude product was purified by
flash column chromatography (EtOAc/PE 4:6) to afford 8-(4-
methoxyphenyl)-2-(p-tolyl)-4H-oxazolo[5',4':4,5]pyrano[2,3-
4
M. Zhang, T. Razler and P. F. Jackson, Tetrahedron Lett., 2002, 43
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8235; (c) E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino and
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M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Synthesis,
2008, 136; (f) K. Beydoun and H. Doucet, Eur. J. Org. Chem., 2012,
6745.
Oxazole moiety found in many natural products: (a) Z. Jin, Z. Li and
R. Huang Z. Nat. Prod. Rep., 2002, 19 454; (b) Z. Jin, Nat. Prod.
Rep., 2003, 20, 584; (c) Z. Jin, Nat. Prod. Rep., 2013, 30, 869.
Oxazole moiety present in many drugs: (a) I. J. Turchi and M. J. S.
Dewar, Chem. Rev. 1975, 75, 389; (b) A. M. Azman and R. J.
Mullins, In Heterocyclic Chemistry in Drug Discovery, ed Jie Jack
Li, Wiley, 2013, 231. Antibiotics: (c) N. R. Stokes, N. Baker, J. M.
Bennett, P. K. Chauhan, I. Collins, D. T. Davies, M. Gavade, D.
Kumar, P. Lancett, R. Macdonald, L. MacLeod, A. Mahajan, J. P.
Mitchell, N. Nayal, Y. Nandan Nayal, G. R. W. Pitt, M. Singh, A.
Yadav, A. Srivastava, L. G. Czaplewski and D. J. Haydon, Bioorg.
Med. Chem. Lett. 2014, 24, 353; Anti-inflammatory: (d) K. Seth, S.
K. Garg, R. Kumar, P. Purohit, V. S. Meena,; R. Goyal, U. C.
5
6
b]pyridine
9 (59 mg, 0.159 mmol) in 89% yield as a yellow
1
solid. mp 207-209 °C (CH2Cl2/PE); H NMR (300 MHz, CDCl3) δ
8.21 (d, 1H, J = 2.4 Hz), 7.97 (d, 2H, J = 8.2 Hz), 7.78 (d, 1H, J =
2.4 Hz), 7.51 (d, 2H, J = 8.7 Hz), 7.29 (d, 2H, J = 8.2 Hz), 7.00 (d,
2H, J = 8.7 Hz), 5.72 (s, 2H), 3.86 (s, 3H), 2.42 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.6 (C), 159.6 (C), 158.4 (C), 144.5 (CH),
141.6 (C), 141.0 (C), 132.0 (C), 131.2 (C), 129.8 (2xCH), 129.6
(C), 127.8 (2xCH), 126.5 (2xCH), 125.7 (CH), 124.1 (C), 114.6
(2xCH), 110.0 (C), 67.1 (CH2), 55.5 (CH3), 21.7 (CH3); IR (neat)
νmax 3039, 2932, 1609, 1489, 1467, 1439, 1203, 1244 cm-1; MS
(ESI) m/z 371 [M+H+]; HMRS (ESI-TOF): calc. for C23H19N2O3:
371.1398; found: 371.1385.
Banerjee and A. K. Chakraborti, ACS Med. Chem. Lett. 2014, 5, 512;
Antiproliferative: (e) M. J. Choi, E. S. No, D. A. Thorat, J. W. Jang,
H. Yang, J. Lee, H. Choo, S. J. Kim, C. S. Lee, S. Y. Ko, J. Lee, G.
Nam and A. N. Pae, J. Med. Chem. 2013, 56, 9008.
Pyridine moiety found in many natural products (a) J. P. Michael
Nat. Chem., 2005, 22, 627. (b) A. E. Goetz and N. K. Garg, Nat.
7
8
Chem., 2013, 5, 54.
(a) Twelve therapeutics containing a pyridine moiety in the top 200
pharmaceutical products by U.S. retail sales in 2012:
http://www.pharmacytimes.com/publications/issue/2013/July2013/T
op-200-Drugs-of-2012; (b) Qiao, J. X. In Heterocyclic Chemistry in
Drug Discovery, Li J. J., Ed.; Wiley; Hoboken, NJ, 2013, 398. (c) M.
Acknowledgements
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-
0029). We also gratefully acknowledge Janssen R&D for
finacial support and the CRIHAN for software optimization and
kind technical support.
Baumann and I. R. Baxendale, Beilstein J. Org. Chem., 2013, 9,
2265.
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DOI: 10.1039/C6OB00227G
ARTICLE
Journal Name
Schneider, D. Masi, S. Couve-Bonnaire, X. Pannecoucke and C.
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10 | J. Name., 2012, 00, 1-3
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