Charting the Chemical Reactivity Space of 2,3-Substituted Furo[2,3-b]pyridines Synthesized via the Heterocyclization of Pyridine-N-oxide Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01329

A concise strategy for the synthesis of 2,3-substituted furo[2,3-b]pyridines is described. Mild, metal-free conditions were successfully applied to produce a range of 2-(alkyl or aryl)-3-ethylcarboxylate-furo[2,3-b]pyridines in yields of 50-91%. Then, the chemical reactivity of this heterocyclic framework was explored to develop straightforward methods for its functionalization. The pyridine moiety reactivity was successfully explored by C-H amination and borylation reactions, although C-H fluorination and radical C-H arylation processes were not as efficient. In addition, while the furopyridine core proved stable under basic conditions, the ring-opening reaction of the furan moiety with hydrazine generated a valuable new pyridine-dihydropyrazolone scaffold.

Full text of DOI:10.1021/acs.joc.6b01329

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Article
Charting the chemical reactivity space of 2,3-substituted furo[2,3-b]pyridines
synthesized via the heterocyclization of pyridine-N-oxide derivatives
Fernando Fumagalli, and Flavio da Silva Emery
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01329 • Publication Date (Web): 26 Jul 2016
Downloaded from http://pubs.acs.org on July 29, 2016
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Charting the chemical reactivity space of 2,3-substituted furo[2,3-
b]pyridines synthesized via the heterocyclization of pyridine-N-oxide
derivatives
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Fernando Fumagalli and Flavio da Silva Emery*,∆
Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão
Preto, University of São Paulo, 14040ꢀ903 Ribeirão PretoꢀSP, Brazil
∆ ISHC member
*
flavioemery@fcfrp.usp.br, flavioemery@qhetem.com
GRAPHICAL ABSTRACT
ABSTRACT: A concise strategy for the synthesis of 2,3ꢀsubstituted furo[2,3ꢀb]pyridines is
described. Mild, metalꢀfree conditions were successfully applied to produce a range of 2ꢀ
(alkyl or aryl)ꢀ3ꢀethylcarboxylateꢀfuro[2,3ꢀb]pyridines in yields of 50ꢀ91%. Then, the
chemical reactivity of this heterocyclic framework was explored to develop straightforward
methods for its functionalization. The pyridine moiety reactivity was successfully explored by
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C–H amination and borylation reactions, although C–H fluorination and radical C–H arylation
processes were not as efficient. In addition, while the furopyridine core proved stable under
basic conditions, the ringꢀopening reaction of the furan moiety with hydrazine generated a
valuable new pyridineꢀdihydropyrazolone scaffold.
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INTRODUCTION
The furo[2,3ꢀb]pyridine core has recently received extensive attention from the medicinal
chemistry community as a useful pharmacophore for the development of several drug
candidates in different therapeutic areas (Figure 1).1 This heterocyclic core can be found in
the structure of 1, a highly active type 1 cannabinoid receptor (CB1R) modulator, active in the
treatment of foodꢀborne diseases.2 It is also found in compound 2, a protein kinase inhibitor
and candidate for cancer treatment.3 Pharmacological studies of compound 3 and its
derivatives, designed from the structure of the antiviral Nesbuvir, have demonstrated their
high activity against the hepatitis C virus by the inhibition of nonstructural protein 5B
(NS5B).4
Figure 1. Representative examples of biologically
active furo[2,3ꢀb]pyridine derivatives.
Despite their importance, synthetic methodologies for furopyridines remain limited.5 There
are two main strategies for the synthesis of this heterocyclic fragment, differing by the
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heterocyclic starting material, whether furan or pyridine.6 To the best of our knowledge, when
pyridine substrates are used, only three methods to obtain furo[2,3ꢀb]pyridine 2,3ꢀsubstituted
compounds (Scheme 1) have been described in the literature. Eastman et al.4 explored the
Sonogashira coupling, producing 2ꢀhydroxyꢀ3ꢀalkyneꢀsubstituted pyridines that underwent
palladiumꢀcatalyzed cyclization to afford the furan ring (eq 1). Cailly et al.7 used nucleophilic
aromatic substitution to synthesize a 3ꢀaminoꢀfuro[2,3ꢀb]pyridineꢀ2ꢀcarboxylate (eq 2), and
Cartwright et al.8 reported furopyridine core construction by the annelation of perfluorinated
pyridines using 1,3ꢀdicarbonyl derivatives (eq 3).
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Scheme 1. Synthetic strategies for 2,3-
substituted furo[2,3-b]pyridine derivatives
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In addition to the lack of synthetic strategies for this heteroaromatic core, descriptions of its
reactivity, especially of the pyridine ring, are limited.1,9 For example, the pyridine ring of
furo[2,3ꢀb]pyridines was found to be reactive to electrophiles and nucleophiles when oxidized
to the Nꢀoxide derivative: cyanation and acetoxylation typically occur at Cꢀ6, whereas
chlorination proceeds at Cꢀ4.10,11 Therefore, the chemical reactivity of the pyridine moiety
remains synthetically underexplored, as is the development of more efficient strategies for
generating the furopyridine core.
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In this work, we describe a facile and concise strategy for the synthesis of 2,3ꢀsubstituted
furo[2,3ꢀb]pyridines from pyridineꢀNꢀoxide derivatives (eq 4). Under mild, metalꢀfree
conditions, we synthesized ten examples by the reaction of the pyridineꢀNꢀoxides with acyl
chlorides or anhydrides in yields up to 91%. In addition, considering the recent advances in
the C–H activation of electronꢀdeficient rings,12 we explored the reactivity of this
heteroaromatic core through C–H amination,13 radical C–H arylation,14 and C–H
fluorination15 reactions, as well as in a C–H borylation/Suzuki coupling reaction sequence.16
Finally, the reactivity of the furan moiety in the presence of nucleophiles was evaluated, as
well as its stability under basic conditions.
RESULTS AND DISCUSSION
Development of synthetic strategy for 2,3-substituted furo[2,3-b]pyridines
While attempting to produce 2ꢀacetoxypyridine 6 from the reaction of Nꢀoxide 5a with acetic
anhydride (Scheme 2), the fully characterized furo[2,3ꢀb]pyridines 7aa and 7ab were instead
observed in low conversion and yield. This unexpected result spurred us to study the reaction,
both to improve the yield and selectivity of 7aa and possibly develop a more efficient,
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alternative synthesis of reaction intermediates used to obtain antiviral compound 3 (Figure
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Scheme 2. Synthesis of furo[2,3-b]pyridine derivatives from pyridine 4a.
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A plausible mechanism for the formation of these furopyridines, supported by the
optimization study, is presented in Scheme 3. In both cases, the Nꢀacetoxypyridine derivative
is formed (A), which is subsequently deprotonated at the benzylic position to form an enolate
(B). For 7aa, the enolate reacts with another equivalent of anhydride to afford an ethyl
acetoacetate derivative (C), whereas for 7ab, the enolate reacts with a second Nꢀ
acetoxypyridine derivative (F). In the next step, the hydrogen alpha to the carbonyl group is
deprotonated and heterocyclization occurs (D and G). Finally, furopyridines 7aa and 7ab are
formed after deprotonation and reꢀaromatization processes (E and H).
Scheme 3. Proposed reaction mechanism for the synthesis of 7aa and 7ab.
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Table 1. Optimization of reaction conditions for the synthesis of 2,3-substituted furo[2,3-
b]pyridines
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Entry Solvent
Acyl Source
DMAP
Base
(1.2 equiv)
Temp
Yield [%]a
(ratio
7aa/7ab)
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Ac2O
Ac2O
ꢀ
ꢀ
12 (1:1)
20 (1:1)
45 (8:2)
10 (1:0)
75 (1:0)
83 (1:0)
60 (1:0)
80 (1:0)
78 (1:0)
70 (1:0)
60 (1:0)
70 (1:0)
06 (1:0)
50 (1:0)
05 (1:0)
1
2
120°C
ꢀ
tBuONa
DBU
DBU
ꢀ
120°C
Ac2O
ꢀ
3
120°C
Ac2O
ꢀ
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
Ac2O
2 equiv
2 equiv
4 equiv
6 equiv
2 equiv
1 equiv
0.1 equiv
2 equiv
4 equiv
6 equiv
2 equiv
5
Ac2O
DBU
DBU
DBU
DBU
DBU
DBU
DBUb
DBU
DBU
DBU
6
Ac2O (4 equiv)
Ac2O (6 equiv)
Ac2O (6 equiv)
Ac2O (6 equiv)
Ac2O (6 equiv)
Ac2O (6 equiv)
CH3COCl (4 equiv)
CH3COCl (6 equiv)
CH3COCl (6 equiv)
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aYield of isolated product after overnight reaction.bReaction carried out with 0.1 equiv of DBU.
Considering the assistance by acetate for heterocyclization, according to the mechanism
proposed, we initially studied the influence of an additional source of base in the reaction
(Table 1, Entries 2 and 3). The acetate formed under the original conditions was not a
sufficiently strong base to efficiently perform the reaction. To our delight, DBU proved to be
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a good choice (Table 1, Entry 3), improving the yield (45%) and selectivity for 7aa over 7ab
(8:2). Selectivity for 7aa was improved at lower temperature in the presence of DBU, albeit in
low yield (Table 1, Entry 4). The addition of DMAP increased the electrophilicity of the
acetylating reagent, resulting in higher heterocyclization yields (Table 1, Entries 5 and 6).
This suggests that the initial acetylation step is rateꢀlimiting, because heterocyclization was
poor even when using a large excess of acetic anhydride. Interestingly, the use of acetyl
chloride as the acetylating reagent reduced the yield when compared to Ac2O, even in the
presence of DMAP (Table 1, Entries 6 to 15). It was found that, when acetic anhydride is used
in excess (6 equiv), just 2 equiv DMAP are necessary to selectively produce furopyridine 7aa
in good yield (Table 1, Entry 9), although for acyl chlorides, 6 equiv DMAP are required
(Table 1, Entry 14). In addition, the use of catalytic amounts of DBU and DMAP (Table 1,
Entries 11 and 12) did not reduce the yields to a great extent. Based on these results, we
determined that the heterocylization of pyridineꢀNꢀoxides with acyl anhydrides or chlorides
proceeded optimally in the presence of DBU and DMAP, using DCM as solvent (Table 1,
Entries 9 and 14, respectively). These conditions were applied while evaluating the scope of
reaction, as described below.
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After optimizing the reaction and understanding the probable mechanism, we evaluated the
substrate scope. First, the starting substrates were synthesized (Scheme 4). Halogenated
compounds 4b and 4c were obtained from their respective commercially available acids.
PyridineꢀNꢀoxide derivatives 5a–c were synthesized in yields comparable to those reported in
the literature.17–19
Scheme 4. Synthesis of pyridine-N-oxide derivatives
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Using the optimized methods for anhydrides and acyl chlorides, ten new 2ꢀ(alkyl or aryl)ꢀ3ꢀ
ethylcarboxylateꢀfuro[2,3ꢀb]pyridine compounds were obtained in good to excellent yields
(Scheme 5). The 2ꢀalkylꢀsubstituted furopyridines were obtained in better yields compared to
arylꢀsubstituted ones. The use of trifluoroacetic anhydride, chloroformates, or cyclic
anhydrides did not afford the desired furo[2,3ꢀb]pyridines. According to these results, we
established that our methodology could be applied successfully with both alkyl and aryl
anhydrides or acyl chlorides, as well as substituted pyridines, and thus produce a diverse
library of furo[2,3ꢀb]pyridines.
Scheme 5. Scope of reaction for the synthesis of 2,3-substituted furo[2,3-b]pyridines
Reaction conditions: PyridineꢀNꢀoxide (1.0 equiv), acyl
source (6 equiv), DBU (1.2 equiv), DMAP (6 equiva or 2
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a
equivb), DCM, room temperature, overnight. Reaction
b
performed with acyl chlorides. Reaction performed with
anhydrides.
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Chemical reactivity of the pyridine moiety of the furo[2,3-b]pyridine core
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We explored the chemical tractability of the furopyridine core, in order to understand the
reactivity of the electronꢀpoor ring and provide strategies for chemical library development.
Although there have recently been advances in the C–H activation of electronꢀdeficient
rings,12 this subject remains a challenge for synthetic chemists, considering the large amount
of heteroaryl substrates necessary to carry out the reaction.20 Herein, we applied some of the
most efficient reported strategies for these cases to substrate 7aa.
Preliminary studies involving C–H fluorination15 and radical C–H arylation with
aryldiazonium salts14 were unsuccessful, furnishing the desired products in low yields
(Scheme 6), with substitutions in Cꢀ6 and Cꢀ4, respectively. In both cases, the isolated
products reflect typically observed pyridine reactivity, with
α and γ substitution for
fluorination and arylation, respectively.14,15 These results illustrates the challenge mentioned
before. The direct fluorination of electronꢀpoor heteroarenes is an incipient chemistry field,
with just few successful examples and some limitations reported.15,21 Same reactivity is
described for the radical arylation of πꢀdeficient heterocycles, which in some case are known
to have low yields, with better results when large excess of the heterocyclic ring are used.22
Scheme 6. C–H fluorination and radical C–H arylation of furo[2,3-b]pyridine
core
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Although limited results were observed for these previous showed reactions, with slightly
lower yields compared to similar systems in the literature, the findings were enough
stimulation in challenging us to find efficient ways to decorate the furo[2,3ꢀb]pyridine.
Recently, the Hartwig group reported the efficient iridiumꢀcatalyzed C−H borylation of
azaindoles, yielding unstable boronic esters that were used in Suzuki crossꢀcoupling
reactions.16 In our studies, Hartwig’s C–H borylation method was efficient in converting the
starting material, furnishing a product which proved to be unstable during purification by
column chromatography. Monitoring the reaction by GCꢀMS, the siteꢀselective process
yielded 78% of boronate furopyridine 10a, which was directly used as a substrate in the
Suzuki coupling reaction in a tandem procedure (Scheme 7), using optimal known conditions
for these type of substrates.23 Although the isolated yield for arylation was poor (10b, 25%),
the structure elucidation confirmed the
βꢀfunctionalization, following the same reactivity
pattern as described previously for azaindoles, and suggesting the crossꢀcoupling as the
limiting step. The recovering of 40% of 7aa, after Suzuki coupling reaction, indicates that a
protodeboronation is a probable sideꢀreaction.24 Nevertheless, the borylated compound 10a
also can be useful for other derivatives reactions.16
Scheme 7. C–H borylation/arylation and C–H amination of furo[2,3-b]pyridine core
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aYield determined by GCꢀMS, bYield of isolated product
These findings encourage us to expand the functionalization studies. Recently, C–H amination
of pyridine Nꢀoxides has been described as a usefulmethod for the selective functionalization
of the pyridines’ αꢀpositions. This reaction is carried out using a phosphonium salt and a
nucleophilic amine to furnish the aminated product. Compared to furo[2,3ꢀb]pyridines, the Nꢀ
oxides derivatives are known to be more reactive toward nucleophiles and electrophiles, using
classical methodologies that limit structure diversification. Therefore, we subjected
furopyridine Nꢀoxide derivative 11 to C–H amination under the same conditions used for
pyridines (Table 2, entry 1). However, in contrast to the reported pyridine substrates,13
mixture of two regioisomers, 12a and 12b, was obtained in low yield, with higher selectivity
for ꢀamination instead of specificity for the ꢀposition (2:1). This unexpected siteꢀselectivity
a
β
α
stimulated a wider study of this reaction (Table 2). We found that, by reacting 11 with
PyBroP and pyrrolidine under optimized conditions (Table 2, Entry 8), amination products
12a and 12b could be obtained in 97% yield (Scheme 7).
Table 2. Optimization of reaction conditions for direct amination of 11
Entry Additive Pyrrolidine Solvent Temp
Yield [%]a
(ratio 12a/12b)
1
PyBropb
3 equiv
DCM
rt
34 (2:1)
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2
PyBOPc
PyBOP
DCPe
3 equiv
ꢀ
DCM
DCM
rt
rt
23 (2:1)
ꢀd
3
4
5
3 equiv
3 equiv
6 equiv
6 equiv
6 equiv
3 equiv
6 equiv
DCM
rt
ꢀd
10
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PyBOP
PyBOP
PyBOP
PyBrop
PyBOP
PyBOP
of
MeCN
MeCN
DCM
rt
30 (1:1)
87 (1:2)
54 (1:1)
97 (1:1)
53 (1:2)
80 (1:2)
6
rt
7
rt
8
MeCN
MeCN
MeCN
rt
9
70°C
70°C
10
aYield
isolated
product
after
overnight
reaction.
bBromotripyrrolidinophosphonium
hexafluorophosphate.
c(Benzotriazolꢀ1ꢀ
yloxy)tripyrrolidinophosphonium hexafluorophosphate. dNo conversion was
observed. eDiethyl chlorophosphate.
Varying the phosphonium salt between PyBOP and PyBrop did not change the reactivity
when DCM was used as solvent (Table 2, Entries 1 and 2). However, when the solvent was
changed to MeCN, regioisomers 12a/12b were produced equally in low yield (Table 2, Entry
5). To evaluate the importance of the pyrrolidine source, we investigated whether the
pyrrolidine present in the phosphonium salt was sufficient to drive the reaction; however, no
conversion of 11 was observed (Table 2, Entry 3). The use of diethyl chlorophosphate (DCP)
did not afford any aminated product (Table 2, Entry 4). Higher yields were obtained using a
larger excess of pyrrolidine in MeCN (Table 2, Entries 6–8 and 10), especially for the
phosphonium complex with PyBrop (97%; Table 2, Entry 8). Although preliminary, the
results suggest that temperature seems to have little effect on the yield or selectivity (Table 2,
Entries 5, 6 and 9). On the other hand, changes in both the solvent polarity and phosphonium
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salt affect both the yield and regioselectivity. Higher selectivity for 12a was only seen in
DCM, whereas 12b was predominant only for MeCN as solvent.
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9
Our observed preliminary results for the C–H amination reactions contradict the previously
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reported preference for the
greater influence of charge effects on directing the reaction to the
furopyridines, ꢀamination is also observed, which can be explained by the charge
stabilization on nitrogen due to the resonance contribution by the furan ring (Scheme 8,
α
ꢀamination of pyridines,13 which we suspect is related to the
αꢀposition. However, for
β
Pathway A). These findings represent a novel approach to
can be largely influenced by the fused furan ring.
βꢀamination of pyridines, which
Scheme 8. Proposed reaction mechanism for the formation of 12a.
Chemical reactivity of the furan moiety of furo[2,3-b]pyridine core
It is well known that furo[2,3ꢀb]pyridines substituted by electronꢀwithdrawing groups undergo
ringꢀopening reactions when treated with strong bases or nucleophiles,9 which can be a useful
strategy for producing pyridines substituted by carbocycles or heterocycles.25 To evaluate the
stability and reactivity of the compounds synthesized herein, we studied the reactions of
compound 7d with lithium hydroxide and hydrazine (Scheme 9).
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Scheme 9. Chemical reactivity of furo[2,3-b]pyridine with nucleophilic species
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In the first case, the furan ring is stable under the basic conditions, and ester hydrolysis is the
prevailing process, furnishing acid derivative 13 (72%). However, a ringꢀopening process is
observed upon reacting 7d with hydrazine. This reaction is suggested to occur through a
mechanism involving hydrazide formation (Scheme 9), followed by conjugate addition and
ringꢀopening of the resulting tricyclic furan intermediate, affording 2ꢀhydroxypyridinyl
pyrazolone 14. 2D NMR spectroscopy (Supporting Information) was useful in proving the
structure of 14. The HMBC experiment for 14 revealed a correlation between the γꢀpyridine
and methylene hydrogens and the carbon of the dihydropyrazolone directly bonded to position
3 of the pyridine ring (Scheme 9).
CONCLUSION
In summary, we have reported a versatile and efficient synthesis of a small library of 2ꢀ(alkyl
or aryl)ꢀ3ꢀethylcarboxylateꢀfuro[2,3ꢀb]pyridines in good to excellent yields. In addition, the
chemical reactivities of the pyridine and furan moieties of this heteroaromatic core were
evaluated. Although some types of C–H activation were unsuccessful, C–H amination and C–
H borylation proved to be good strategies to decorate this core. Although the scope of these
reactions needs to be further investigated, some relevant findings, as βꢀamination of pyridine
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moiety is unprecedented in the literature. The furan moiety in this heterocyclic scaffold is
stable under basic conditions, but is very reactive toward hydrazine, furnishing a
dihydropyrazolone ring system. The strategies described in this work involve an
underexplored heterocycle in organic and medicinal chemistry; however, they may be applied
to generate a library of fragments that could be useful in several research areas, including as
valuable building blocks with potentially interesting molecular properties and activities for
medicinal chemistry.
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EXPERIMENTAL SECTION
General Remarks. Commercially available reagents and solvents were used without further
purification. Melting points were determined in open capillary tubes using an electronic
apparatus. Yields refer to isolated and purified products, unless otherwise noted. Reactions
were monitored by thin layer chromatography (TLC) and visualized under UV light at 254
1
and 365 nm. Column chromatography was performed using silica gel 60 (70–230 mesh). H
and 13C NMR spectra were recorded at 300, 400 or 500 MHz and 75, 101 or 126 MHz,
respectively. Chemical shifts were referenced to the deuterated solvent (i.e., for CDCl3, δ =
7.26 and 77.16; for DMSOꢀd6, δ = 2.50 and 39.52, for 1H and 13C NMR, respectively) and are
reported in parts per million (ppm, δ). Coupling constants (J) are stated in Hz using the
splitting abbreviations: s, singlet; d, doublet; t, triplet; quin, quintet; hept, heptet; m, multiplet;
br, broad. Highꢀresolution mass spectra (HRMS) were measured by a TOF (Time of Flight)
spectrometer, using electrospray ionization (ESI). Gas chromatography (GC) analyses were
performed on a GC system coupled to a massꢀselective detector with electron impact
ionization (EI). Infrared (IR) spectra were measured in KBr, and wavelengths are reported in
cm−1.
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General procedure for the synthesis of ethyl pyridinylacetate substrates 4b and 4c: To a
solution of the respective 2ꢀ(pyridinꢀ3ꢀyl)acetic acid (4 mmol) in ethanol (30 mL) under
nitrogen atmosphere was added concentrated H2SO4 (200 ꢁL). The mixture was stirred at
100°C for 24 h. After cooling, the reaction mixture was concentrated to dryness and the
residue was taken up in chloroform, washed with water, dried over MgSO4, and concentrated
under reduced pressure. The crude material was purified by column chromatography on silica
gel with hexane/ethyl acetate (8:2) to afford the desired product.
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Ethyl 2-(5-bromopyridin-3-yl)acetate (4b): 923 mg (95%); pale yellow oil; H NMR (400
MHz, DMSOꢀd6) δ 8.61 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H),
4.10 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSOꢀ
d6) δ 170.3, 149.0, 148.6, 139.7, 132.5, 119.7, 60.6, 36.5, 14.0; HRMS (+ESI) m/z: [M + H]+
+
Calcd for C9H11BrNO2 243.9968; Found 243.9987.
1
Ethyl 2-(6-chloropyridin-3-yl)acetate (4c): 716 mg (90%); yellow oil; H NMR (300 MHz,
CDCl3) δ 8.26 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.2, 2.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H),
4.13 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
170.3, 150.3, 150.1, 139.8, 128.8, 124.1, 61.4, 37.6, 14.1; HRMS (+ESI) m/z: [M + H]+ Calcd
+
for C9H11ClNO2 200.0473; Found 200.0475.
General procedure for the synthesis of pyridine-N-oxide derivatives: A solution of mꢀ
CPBA (4.5 mmol) in CH3Cl (10 mL) was added dropwise to a solution of pyridine substrate
(3 mmol) in CH3Cl (10 mL) with stirring at room temperature. After overnight reaction, the
solvent was removed under reduced pressure and the residue was taken up in 2 M Na2CO3
solution and extracted with chloroform (3 × 20 mL). The organic layer was dried with MgSO4
and the solvent removed under reduced pressure to give the desired product.
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3-(2-Ethoxy-2-oxoethyl)pyridine 1-oxide (5a): 494 mg (91%); white solid; mp 90–92°C;
5
6
NMR data according to the literature.19
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8
9
3-Bromo-5-(2-ethoxy-2-oxoethyl)pyridine 1-oxide (5b): 699 mg (90%); pale yellow solid;
mp 57–59°C; 1H NMR (400 MHz, DMSOꢀd6) δ 8.49 (t, J = 1.6 Hz, 1H), 8.24 (t, J = 1.2 Hz,
1H), 7.57 (t, J = 1.3 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, DMSOꢀd6) δ 169.7, 138.8, 138.3, 134.6, 129.7, 119.2, 60.8, 36.2, 14.0;
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+
HRMS (+ESI) m/z: [M + H]+ Calcd for C9H11BrNO3 259.9917; Found 259.9924.
2-Chloro-5-(2-ethoxy-2-oxoethyl)pyridine 1-oxide (5c): 322 mg (50%); pale yellow solid; mp
1
85–87°C; H NMR (400 MHz, DMSOꢀd6) δ 8.44 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.4 Hz,
1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 1.19 (t, J = 7.1 Hz,
13
3H); C NMR (101 MHz, DMSOꢀd6) δ 169.8, 140.8, 138.6, 132.4, 127.5, 126.6, 60.7, 36.1,
+
13.9; HRMS (+ESI) m/z: [M + H]+ Calcd for C9H11ClNO3 216.0422; Found 216.0437.
Ethyl 2-(6-(2-ethoxyfuro[2,3-b]pyridin-3-yl)pyridin-3-yl)acetate (7ab): 5a (362 mg, 2 mmol)
in acetic anhydride (20 mL) was stirred at 100°C for 24 h. After cooling, the reaction mixture
was concentrated to dryness and the residue was taken up in chloroform, washed with water,
dried over MgSO4, and the solvent removed under reduced pressure. The crude material was
purified by column chromatography on silica gel with hexane/ethyl acetate (8:2) to afford the
1
desired product 7ab (39 mg, 0.12 mmol, 6%) as a yellow solid, mp 62–64°C. H NMR (500
MHz, DMSOꢀd6) δ 9.04 (s, 1H), 8.53 (dd, J = 8.0, 1.4 Hz, 1H), 8.48 (dd, J = 4.5, 1.4 Hz, 1H),
8.23 (d, J = 9.4 Hz, 1H), 7.58 (dd, J = 8.0, 4.5 Hz, 1H), 7.54 (dd, J = 9.4, 1.4 Hz, 1H), 4.36 (q,
J = 7.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H);
13C NMR (126 MHz, DMSOꢀd6) δ 170.8, 164.2, 142.2, 140.9, 138.6, 133.2, 129.5, 123.8,
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121.6, 120.5, 119.1, 118.3, 91.8, 60.5, 59.1, 36.5, 14.5, 14.0; IR (KBr) ν 2982, 2930, 1738,
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1682, 1577, 1517, 1476, 1442, 1378, 1335, 1286, 1262, 1218, 1159, 1043, 840, 800, 769, 749,
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9
+
711; HRMS (+ESI) m/z: [M + H]+ Calcd for C18H19N2O4 327.1339; Found 327.1364.
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General procedure for the synthesis of 2,3-substituted furo[2,3-b]pyridines: DCM (3
mL) was added to a vial containing the pyridineꢀNꢀoxide substrate (0.5 mmol), DMAP (6
equiv [when acyl chlorides were used] or 2 equiv [when anhydrides were used]), and DBU
(1.2 equiv). Then, the acyl source (6 equiv) was added and the mixture was stirred at room
temperature overnight. The reaction mixture was concentrated to dryness and the residue was
taken up in chloroform, washed with water, dried over MgSO4, and the solvent removed
under reduced pressure. The crude material was purified by column chromatography on silica
gel with hexane/ethyl acetate (9:1) to afford the desired product.
Ethyl 2-methylfuro[2,3-b]pyridine-3-carboxylate (7aa): 80 mg (78%); white solid; mp 88–
90°C; 1H NMR (400 MHz, DMSOꢀd6) δ 8.30 (dd, J = 4.9, 1.7 Hz, 1H), 8.22 (dd, J = 7.7, 1.7
Hz, 1H), 7.43 (dd, J = 7.7, 4.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.36 (t, J = 7.1
13
Hz, 3H); C NMR (101 MHz, DMSOꢀd6) δ 163.1, 162.8, 159.8, 144.0, 130.6, 120.7, 117.8,
107.7, 60.4, 14.1, 14.0; IR (KBr) ν 3062, 2999, 2982, 2938, 2913, 2876, 2100, 1950, 1917,
1890, 1713, 1597, 1475, 1450, 1413, 1385, 1368, 1329, 1282, 1232, 1167, 1083, 1043, 1000,
+
929, 862, 826, 802, 784, 764; HRMS (+ESI) m/z: [M + H]+ Calcd for C11H12NO3 206.0812;
Found 206.0828.
Ethyl 5-bromo-2-methylfuro[2,3-b]pyridine-3-carboxylate (7b): 108 mg (76%); white solid;
mp 108–109°C; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.1 Hz,
13
1H), 4.42 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
CDCl3) δ 164.8, 163.3, 159.1, 144.8, 133.2, 120.6, 116.4, 108.4, 60.9, 14.6, 14.5; IR (KBr) ν
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3068, 2978, 2968, 2876, 2666, 2598, 2551, 1862, 1716, 1594, 1474, 1445, 1416, 1364, 1330,
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1325, 1274, 1237, 1155, 1092, 1010, 944, 897, 830, 760, 707; HRMS (+ESI) m/z: [M + H]+
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9
+
Calcd for C11H11BrNO3 283.9917; Found 283.9931.
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Ethyl 6-chloro-2-methylfuro[2,3-b]pyridine-3-carboxylate (7c): 109 mg (91%); white solid;
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mp 108–110°C; H NMR (400 MHz, DMSOꢀd6) δ 8.23 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1
Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
DMSOꢀd6) δ 163.6, 162.4, 158.4, 144.3, 133.3, 120.9, 117.1, 107.9, 60.6, 14.09, 14.00; IR
(KBr) ν 3087, 2987, 2912, 2876, 2550, 1959, 1825, 1721, 1582, 1480, 1439, 1387, 1370,
1310, 1238, 1193, 1116, 1082, 1000, 932, 906, 851, 827, 757, 718; HRMS (+ESI) m/z: [M +
+
H]+ Calcd for C11H11ClNO3 240.0422; Found 240.0426.
Ethyl 2-ethylfuro[2,3-b]pyridine-3-carboxylate (7d): 75 mg (68%); white solid; mp 50–51°C;
1H NMR (400 MHz, DMSOꢀd6) δ 8.33 (dd, J = 4.9, 1.7 Hz, 1H), 8.27 (dd, J = 7.7, 1.7 Hz,
1H), 7.46 (dd, J = 7.7, 4.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.21 (q, J = 7.6 Hz, 2H), 1.37 (t,
13
J = 7.1 Hz, 3H), 1.30 (t, J = 7.6 Hz, 3H); C NMR (101 MHz, DMSOꢀd6) δ 167.3, 162.7,
159.9, 144.1, 130.8, 120.8, 117.9, 107.0, 60.4, 20.9, 14.0, 11.7; IR (KBr) ν 3101, 3068, 3026,
2987, 2943, 2913, 1967, 1917, 1868, 1717, 1591, 1483, 1406, 1377, 1356, 1333, 1267, 1227,
1163, 1112, 1084, 1044, 987, 871, 806, 761; HRMS (+ESI) m/z: [M + H]+ Calcd for
+
C12H14NO3 220.0968; Found 220.0978.
1
Ethyl 2-propylfuro[2,3-b]pyridine-3-carboxylate (7e): 76 mg (65%); yellow oil; H NMR
(400 MHz, DMSOꢀd6) δ 8.32 (dd, J = 4.8, 1.7 Hz, 1H), 8.26 (dd, J = 7.7, 1.7 Hz, 1H), 7.45
(dd, J = 7.7, 4.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.16 (t, J = 7.4 Hz, 2H), 1.81–1.71 (dt, J =
7.4, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, DMSOꢀd6) δ
166.2, 162.7, 159.9, 144.1, 130.8, 120.8, 117.8, 107.7, 60.4, 29.1, 20.7, 14.0, 13.5; IR (KBr) ν
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6
+
1049, 892, 806, 784, 766; HRMS (+ESI) m/z: [M + H]+ Calcd for C13H16NO3 234.1125;
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Found 234.1137.
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Ethyl 2-isopropylfuro[2,3-b]pyridine-3-carboxylate (7f): 99 mg (83%); pale yellow solid; mp
39–41°C; 1H NMR (400 MHz, DMSOꢀd6) δ 8.32 (dd, J = 4.9, 1.7 Hz, 1H), 8.26 (dd, J = 7.7,
1.7 Hz, 1H), 7.45 (dd, J = 7.7, 4.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.96 (hept, J = 6.9 Hz,
13
1H). 1.37 (t, J = 7.1 Hz, 3H), 1.34 (s, 3H), 1.33 (s, 3H); C NMR (101 MHz, DMSOꢀd6) δ
170.1, 162.6, 159.8, 144.1, 130.9, 120.8, 117.8, 106.0, 60.4, 26.9, 20.1, 14.0; IR (KBr) ν
3086, 3058, 3026, 2980, 2940, 2930, 2879, 1966, 1864, 1722, 1586, 1471, 1412, 1376, 1327,
1276, 1259, 1233, 1179, 1151, 1128, 1056, 942, 873, 810, 767; HRMS (+ESI) m/z: [M + H]+
+
Calcd for C13H16NO3 234.1125; Found 234.1120.
1
Ethyl 2-isobutylfuro[2,3-b]pyridine-3-carboxylate (7g): 105 mg (85%); pale yellow oil; H
NMR (400 MHz, DMSOꢀd6) δ 8.32 (dd, J = 4.8, 1.7 Hz, 1H), 8.27 (dd, J = 7.7, 1.7 Hz, 1H),
7.45 (dd, J = 7.7, 4.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.08 (d, J = 7.2 Hz, 2H), 2.15 (hept, J
= 6.8 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz,
DMSOꢀd6) δ 165.5, 162.7, 159.9, 144.2, 130.8, 120.8, 117.7, 108.3, 60.4, 27.8, 22.1, 14.0; IR
(KBr) ν 3068, 2960, 2933, 2872, 1717, 1589, 1411, 1386, 1269, 1243, 1209, 1163, 1105,
+
1052, 888, 803, 783, 766; HRMS (+ESI) m/z: [M + H]+ Calcd for C14H18NO3 248.1281;
Found 248.1273.
Ethyl 2-phenylfuro[2,3-b]pyridine-3-carboxylate (7h): 80 mg (60%); white solid; mp 46–
1
48°C; H NMR (300 MHz, DMSOꢀd6) δ 8.47–8.32 (m, 2H), 8.10–7.94 (m, 2H), 7.66–7.35
(m, 4H), 4.34 (q, J = 7.1 Hz, 2H), 3.35 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
DMSOꢀd6) δ 162.3, 159.9, 159.2, 145.2, 131.9, 131.1, 129.5, 128.3, 128.1, 121.1, 118.9,
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1607, 1587, 1567, 1474, 1447, 1404, 1372, 1284, 1256, 1226, 1177, 1091, 1086, 1053, 870,
7
8
9
+
813, 791, 779, 761, 701; HRMS (+ESI) m/z: [M + H]+ Calcd for C16H14NO3 268.0968;
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Found 268.0989.
Ethyl 2-(p-tolyl)furo[2,3-b]pyridine-3-carboxylate (7i): 87 mg (62%); white solid; mp 64–
66°C; 1H NMR (400 MHz, DMSOꢀd6) δ 8.39 (dd, J = 4.8, 1.7 Hz, 1H), 8.36 (dd, J = 7.8, 1.7
Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 7.8, 4.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H),
4.34 (q, J = 7.1 Hz, 2H), 2.40 (s, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSOꢀ
d6) δ 164.5, 161.9, 161.4, 147.1, 143.2, 133.8, 131.4, 131.0, 127.4, 123.1, 121.1, 109.3, 62.8,
23.2, 16.0; IR (KBr) ν 3091, 3034, 2982, 2905, 2857, 1920, 1719, 1603, 1583, 1553, 1506,
1472, 1407, 1369, 1317, 1285, 1259, 1218, 1192, 1089, 1053, 915, 874, 732, 802, 797, 764;
HRMS (+ESI) m/z: [M + H]+ Calcd for C17H16NO3 282.1125; Found 282.1152.
+
Ethyl 2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (7j): 71 mg (50%); white solid;
1
mp 80–82°C; H NMR (400 MHz, DMSOꢀd6) δ 8.41 (dd, J = 4.8, 1.7 Hz, 1H), 8.38 (dd, J =
7.8, 1.7 Hz, 1H), 8.16–8.08 (m, 2H), 7.51 (dd, J = 7.8, 4.8 Hz, 1H), 7.46–7.38 (m, 2H), 4.34
(q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSOꢀd6) δ 163.4 (164.7–
162.25; d, J = 249.9 Hz), 162.3, 159.8, 158.2, 145.2, 132.1 (132.2–132.1; d, J = 9.0 Hz),
131.9, 124.7 (124.7–124.6; d, J = 3.2 Hz), 121.1, 118.8, 115.4 (115.5–115.3; d, J = 22.0 Hz),
107.7, 60.8, 13.9; IR (KBr) ν 3084, 2982, 1723, 1610, 1573, 1505, 1473, 1407, 1376, 1289,
1260, 1235, 1159, 1082, 1052, 834, 800, 766; HRMS (+ESI) m/z: [M + H]+ Calcd for
+
C16H13FNO3 286.0874; Found 286.0884.
Ethyl 6-fluoro-2-methylfuro[2,3-b]pyridine-3-carboxylate (8): To an ovenꢀdried vial was
added 7aa (51 mg, 0.25 mmol, 1.0 equiv) and MeCN (3.0 mL). While the solution was
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stirring rapidly, AgF2 (109.5 mg, 0.75 mmol, 3.00 equiv) was added at once. The vial was
sealed and stirred at 60°C for 18 h. After cooling, the reaction was poured into a separatory
funnel containing saturated aqueous NaHCO3 (20 mL) and extracted with CH3Cl (30 mL).
The organic layer was washed once with brine (20 mL), dried over MgSO4, and the solvent
removed under reduced pressure. The crude material was purified by column chromatography
on silica gel with hexane/ethyl acetate (9:1) to afford the desired product 8 as a white solid (8
mg, 0.4 mmol, 15%); mp 79–81°C. 1H NMR (300 MHz, CDCl3) δ 8.31 (t, J = 7.95, 1H), 6.95
(dd, J = 8.3, 1.1 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.79 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 163.4, 162.9 (162.9–163.0, d, J = 4.2 Hz), 160.3 (158.7–161.9, d, J
= 242.9 Hz), 157.3, 134.9 (134.9–135.0, d, J = 8.7 Hz), 116.0 (115.9–116.0, d, J = 3.9 Hz),
108.7, 105.7 (105.5–105.9, d, J = 36.3 Hz), 60.7, 29.7, 14.3; IR (KBr) ν 3093, 2988, 2963,
2929, 2880, 1953, 1705, 1604, 1469, 1394, 1326, 1235, 1164, 1104, 1087, 1029, 1006, 974,
10
11
12
13
14
15
16
17
18
19
20
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40
41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
864, 834, 757; HRMS (+ESI) m/z: [M + H]+ Calcd for C11H11FNO3 224.0717; Found
224.0710.
Ethyl 2-methyl-4-(4-nitrophenyl)furo[2,3-b]pyridine-3-carboxylate (9): To an ovenꢀdried
vial was added 7aa (82 mg, 0.4 mmol, 1.0 equiv) and acetone (2.0 mL). While the solution
was stirring, a solution of ferrocene (37 mg, 0.2 mmol, 0.5 equiv) in acetone (1.0 mL) was
added dropwise during 30 min. The vial was sealed and stirred at room temperature for 18 h.
The reaction mixture was concentrated to dryness and the residue was taken up in chloroform,
washed with water, dried over MgSO4, and the solvent removed under reduced pressure. The
crude material was purified by column chromatography on silica gel with hexane/ethyl acetate
(8:2) to afford the desired product 9 as a yellow solid (10 mg, 0.03 mmol, 8%); mp 121–
1
123°C; H NMR (300 MHz, DMSOꢀd6) δ 8.42 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 8.8 Hz, 2H),
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7.72 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 5.1 Hz, 1H), 3.77 (q, J = 7.1 Hz, 2H), 2.73 (s, 3H), 0.75
(t, J = 7.1 Hz, 4H). 13C NMR (75 MHz, DMSOꢀd6) δ 162.4, 162.4, 160.4, 147.3, 145.1, 144.1,
141.9, 129.7, 123.2, 121.6, 114.8, 108.9, 60.3, 13.8, 13.2; IR (KBr) ν 3109, 3075, 2961,
2927, 2853, 1591, 1515, 1411, 1348, 1272, 1211, 1104, 1078, 1021, 938, 870, 852, 832, 805,
10
11
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52
53
54
55
56
57
58
59
60
+
756; HRMS (+ESI) m/z: [M + H]+ Calcd for C17H15N2O5 327.0975; Found 327.0980.
Ethyl 2-methyl-5-(4-nitrophenyl)furo[2,3-b]pyridine-3-carboxylate (10b): Furo[2,3ꢀ
b]pyridine 7aa (102.5 mg, 0.5 mmol, 1 equiv), bis(pinacolato)diboron (B2pin2, 127 mg, 1
equiv), [Ir(COD)OMe]2 (6.6 mg, 0.01 mmol, 2.0 mol%), 1,10ꢀphenanthroline (3.6 mg, 0.02
mmol, 4.0 mol%), and dioxane (2.0 mL) were stirred at 100°C for 48 h. After cooling, the
reaction mixture was concentrated to dryness and to the residue was added 4ꢀ
nitrophenyltriflate 4ꢀnitroꢀaryltriflate (synthesized according to the literature,26 135 mg, 0.5
mmol),
Pd(OAc)2
(5
mg,
0.02
mmol,4
mol%),
CyJohnPhos
(2ꢀ
(dicyclohexylphosphino)biphenyl ,14 mg, 0.04 mmol, 8 mol%), and LiOH (29 mg, 1.2 mmol,
2.4 equiv). In sequence to the closed vial under nitrogen atmosphere was added 3 mL of
THF/H2O (1:4). The reaction mixture was stirred at room temperature for 24 h. The reaction
mixture was concentrated to dryness and the residue was taken up in chloroform, washed with
water, dried over MgSO4, and the solvent removed under reduced pressure. The crude
material was purified by column chromatography on silica gel with hexane/ethyl acetate (8:2)
to afford the desired product 10b as a pale yellow solid (41 mg, 0.125 mmol, 25%); mp 149–
151°C; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.35
(d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.86 (s, 3H), 1.46 (t, J
= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.6, 163.5, 160.9, 147.6, 144.8, 143.2, 132.1,
129.6, 128.4, 124.5, 119.3, 108.9, 61.0, 14.7, 14.5; IR (KBr) ν 3119, 2987, 2965, 2920, 2851,
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1711, 1604, 1502, 1468, 1421, 1395, 1349, 1316, 1264, 1215, 1159, 1089, 1033, 947, 917,
5
6
+
854, 803, 763, 699; HRMS (+ESI) m/z: [M + H]+ Calcd for C17H15N2O5 327.0975; Found
7
8
9
327.0975.
10
11
12
13
14
15
16
17
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19
20
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59
60
3-(Ethoxycarbonyl)-2-methylfuro[2,3-b]pyridine 7-oxide (11): The reaction was conducted
via the general procedure for pyridineꢀNꢀoxides. The desired product was obtained after 48 h
of reaction and purification by column chromatography on silica gel with DCM/MeOH
(9.5:0.5), as a white solid (544 mg, 82%); mp 132–134°C; 1H NMR (400 MHz, DMSOꢀd6) δ
8.30 (dd, J = 6.4, 0.9 Hz, 1H), 7.76 (dd, J = 7.9, 0.9 Hz, 1H), 7.38 (dd, J = 7.9, 6.4 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 2.78 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSOꢀ
d6) δ 163.6, 162.1, 150.3, 135.3, 122.7, 121.8, 119.5, 109.1, 60.8, 14.0, 13.9; IR (KBr) ν 3426,
3128, 2994, 1952, 1881, 1809, 1717, 1655, 1611, 1481, 1454, 1385, 1332, 1272, 1253, 1211,
1161, 1120, 1102, 1065, 1009, 965, 873, 816, 799, 727; HRMS (+ESI) m/z: [M + H]+ Calcd
+
for C11H12NO4 222.0761; Found 222.0754.
Procedure for the C–H amination of 11: Acetonitrile (3 mL) was added to a closed vial
containing 11 (66 mg, 0.3 mmol, 1.0 equiv), Bromotripyrrolidinophosphonium
hexafluorophosphate (PyBrop, 182 mg, 0.39 mmol, 1.3 equiv), and diisopropylethylamine
(DIPEA, 156 ꢁL, 0.9 mmol, 3 equiv). Then, pyrrolidine (150 ꢁL, 1.8 mmol, 6 equiv) was
added and the mixture was stirred at 70°C for 18 h. The mixture reaction was concentrated to
dryness and the residue was taken up in chloroform, washed with water, dried over MgSO4,
and the solvent removed under reduced pressure. The crude material was purified by column
chromatography on silica gel with hexane/ethyl acetate (8:2) to afford the desired product.
Ethyl 2-methyl-5-(pyrrolidin-1-yl)furo[2,3-b]pyridine-3-carboxylate (12a): 38 mg (47%);
pale orange solid; mp 86–88°C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.7 Hz, 1H), 7.39
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(d, J = 2.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.38–3.32 (m, 4H), 2.75 (s, 3H), 2.13–1.97 (m,
4H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 163.4, 153.9, 142.7,
129.2, 119.0, 112.2, 108.2, 60.4, 48.5, 25.5, 14.8, 14.5; IR (KBr) ν 3096, 3071, 2971, 2925,
2869, 1944, 1706, 1622, 1576, 1510, 1482, 1416, 1398, 1341, 1304, 1241, 1193, 1168, 1131,
10
11
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56
57
58
59
60
+
1077, 1021, 922, 808, 760, 670; HRMS (+ESI) m/z: [M + H]+ Calcd for C15H19N2O3
275.1390; Found 275.1372.
Ethyl 2-methyl-6-(pyrrolidin-1-yl)furo[2,3-b]pyridine-3-carboxylate (12b): 41 mg (50%);
pale yellow solid, mp 81–83°C; 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1H), 6.34
(d, J = 8.5 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.51–3.46 (m, 4H), 2.69 (s, 3H), 2.06–1.95 (m,
4H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.6, 160.7, 158.0, 154.9, 131.9,
108.7, 106.2, 104.0, 60.2, 47.1, 25.6, 14.5, 14.1; IR (KBr) ν 3083, 3053, 2928, 2852, 1698,
1600, 1593, 1503, 1420, 1396, 1369, 1341, 1263, 1157, 1090, 1032, 985, 936, 884, 844, 805,
750; HRMS (+ESI) m/z: [M + H]+ Calcd for C15H19N2O3 275.1390; Found 275.1383.
+
2-Ethylfuro[2,3-b]pyridine-3-carboxylic acid (13): THF:H2O (3 mL, 1:1) was added to a
closed vial containing 7d (87.6 mg, 0.4 mmol, 1.0 equiv) and LiOH (14.4 mg, 0.6 mmol, 1.5
equiv). The reaction was stirred at room temperature for 18 h. The reaction mixture was
concentrated to dryness and the crude material was purified by column chromatography on
silica gel with hexane/MeOH/AcOH (9.8:1.5;0.5) to afford the desired product 13 (55 mg,
72%) as a white solid, mp 174–176°C; 1H NMR (300 MHz, DMSOꢀd6) δ 13.20 (s, 1H), 8.29
(dd, J = 4.9, 1.7 Hz, 1H), 8.25 (dd, J = 7.7, 1.7 Hz, 1H), 7.40 (dd, J = 7.7, 4.9 Hz, 1H), 3.19
13
(q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); C NMR (75 MHz, DMSOꢀd6) δ 167.0, 164.4,
160.0, 143.9, 130.8, 120.6, 118.4, 107.7, 20.9, 11.9; IR (KBr) ν 3428, 2962, 2925, 2853,
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1710, 1599, 1481, 1414, 1261, 1174, 1088, 1030, 809, 753; HRMS (ꢀESI) m/z: [M ꢀ H]ꢀ Calcd
5
6
−
for C10H8NO3 190.0510; Found 190.0495.
7
8
9
5-Ethyl-4-(2-hydroxypyridin-3-yl)-1,2-dihydro-3H-pyrazol-3-one (14): To a solution of 7d
(220 mg, 1 mmol, 1 equiv) in EtOH:THF (3 mL, 1:1) was added hydrazine hydrate (50–60%,
1 mL, ~18 equiv), and the reaction was stirred at room temperature overnight. The reaction
mixture was concentrated to dryness and the crude material was washed with water (5 mL),
THF (10 mL), and CHCl3 (10 mL) to afford the desired product 14 (164 mg, 80%) as a white
solid, mp 236–238°C; 1H NMR (300 MHz, DMSOꢀd6) δ 11.59 (s, 1H), 7.55 (dd, J = 7.2, 1.9
Hz, 1H), 7.41 (dd, J = 6.3, 1.9 Hz, 1H), 6.49 (t, J = 6.74 Hz, 1H), 2.65 (q, J = 7.5 Hz, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.13 (t, J = 7.5 Hz, 3H); C NMR (75 MHz, DMSOꢀd6) δ 162.6, 158.9, 144.0, 137.5, 131.9,
124.4, 108.1, 97.9, 19.5, 12.6; IR (KBr) ν 3277, 3191, 3118, 2982, 2931, 1638, 1518, 1440,
1327, 1256, 1228, 1165, 1074, 1009, 915, 872, 775; HRMS (+ESI) m/z: [M + H]+ Calcd for
+
C10H12N3O2 206.0924; Found 206.0919.
ACKNOWLEDGMENTS
The authors thank the Coordination for the Improvement of Higher Education Personnel
(CAPES) and São Paulo Research Foundation (grants 2014/50265ꢀ3 and 2015/06588ꢀ5, São
Paulo Research Foundation (FAPESP)), for grants and scholarships.
Supporting Information:
Copies of 1H and 13C NMR spectra for all new compounds.
REFERENCES
1. Sirakanyan, S. N.; Hovakimyan, A. A.; Noravyan, A. S., S. Russ. Chem. Rev. 2015, 84,
441ꢀ454.
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7
8
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2. Debenham, J. S.; MadsenꢀDuggan, C. B.; Toupence, R. B.; Walsh, T. F.; Wang, J.; Tong,
X.; Kumar, S.; Lao, J.; Fong, T. M.; Xiao, J. C.; Huang, C. R. R. C.; Shen, C.ꢀP.; Feng, Y.;
Marsh, D. J.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Goulet, M. T. Bioorg. Med.
Chem. Lett. 2010, 20, 1448ꢀ1452.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Wu, Z.; Robinson, R. G.; Fu, S.; Barnett, S. F.; DefeoꢀJones, D.; Jones, R. E.; Kral, A. M.;
Huber, H. E.; Kohl, N. E.; Hartman, G. D.; Bilodeau, M. T. Bioorg. Med. Chem. Lett. 2008,
18, 2211ꢀ2214.
4. Eastman, K. J.; Parcella, K. E.; Kadow, J. F. Novel Compounds for the Treatment of
Hepatitis C. US Patent 2014/0275154 A1, September, 18, 2014.
5. Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409ꢀ
2412.
6. JasselinꢀHinschberger, A.; Comoy, C.; Chartoire, A.; Fort, Y. Eur. J. Org. Chem. 2015,
2015, 2321ꢀ2331.
7. Cailly, T.; Lemaître, S.; Fabis, F.; Rault, S. Synthesis 2007, 2007, 3247ꢀ3251.
8. Cartwright, M. W.; Parks, E. L.; Pattison, G.; Slater, R.; Sandford, G.; Wilson, I.; Yufit, D.
S.; Howard, J. A. K.; Christopher, J. A.; Miller, D. D. Tetrahedron 2010, 66, 3222ꢀ3227.
9. Shiotani, S. Heterocycles 1997, 45, 975ꢀ1011.
10. Yamaguchi, S.; Awajima, K.; Hirai, Y.; Yokoyama, H.; Shiotani, S. J. Heterocyclic
Chem. 1998, 35, 1249ꢀ1255.
11. Shiotani, S.; Taniguchi, K. J. Heterocyclic Chem. 1997, 34, 925ꢀ929.
12. (a) Yan, G.; Borah, A. J.; Yang, M. Adv. Synth. Catal. 2014, 356, 2375ꢀ2394. (b)
Stephens, D. E.; Larionov, O. V. Tetrahedron 2015, 71, 8683ꢀ8716.
13. Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254ꢀ5257.
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2
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5
6
7
8
9
14. (a) Abramovitch, R. A.; Saha, J. G. Tetrahedron 1965, 21, 3297ꢀ3303. (b) Verbelen, B.;
Boodts, S.; Hofkens, J.; Boens, N.; Dehaen, W. Angew. Chem. Int. Edit. 2015, 54, 4612ꢀ4616.
15. Fier, P. S.; Hartwig, J. F. Science 2013, 342, 956ꢀ960.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16. Larsen, M. A.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4287ꢀ4299.
17. Bremner, D. H.; Dunn, A. D.; Wilson, K. A.; Sturrock, K. R.; Wishart, G. Synthesis 1997,
1997, 949ꢀ952.
18. Alonso, J. A.; Andrés, M.; Bravo, M.; Buil, M. A.; Calbet, M.; Castro, J.; Eastwood, P.
R.; Eichhorn, P.; Esteve, C.; Gómez, E.; González, J.; Mir, M.; Petit, S.; Roberts, R. S.; Vidal,
B.; Vidal, L.; Vilaseca, P.; Zanuy, M. Bioorg. Med. Chem. Lett. 2014, 24, 5118ꢀ5122.
19. Silva Junior, P. E.; Rezende, L. C. D.; Gimenes, J. P.; Maltarollo, V. G.; Dale, J.; Trossini,
G. H. G.; Emery, F. S.; Ganesan, A. RSC Adv. 2016, 6, 22777ꢀ22780.
20. (a) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254ꢀ9256. (b)
Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett. 2009, 11, 2679ꢀ2682. (c) Ye, M.;
Gao, G.ꢀL.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2011, 133, 6964ꢀ6967. (d) Ye, M.; Gao, G.ꢀL.;
Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2011, 133,
19090ꢀ19093. (e) Gao, G.ꢀL.; Xia, W.; Jain, P.; Yu, J.ꢀQ. Org. Lett. 2016, 18, 744ꢀ747.
21. Fier, P. S.; Hartwig, J. F., J. Am. Chem. Soc. 2014, 136, 10139ꢀ10147.
22. (a) Zoller, J.; Fabry, D. C.; Rueping, M., ACS Cat. 2015, 5 , 3900ꢀ3904. (b) Fürst, M. C.
D.; Bock, L. R.; Heinrich, M. R. J. Org. Chem. 2016, 81 , 5752ꢀ5758.
23 Ishikawa, S.; Manabe, K., Chem. Comm. 2006, 24, 2589ꢀ2591.
24. (a) Matteson, D. S. J. Organomet. Chem. 1999, 581, 51ꢀ65. (b) Alessi, M.; Larkin, A. L.;
Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588ꢀ
1594. (c) Lennox, A. J. J.; LloydꢀJones, G. C., Chem. Soc. Rev. 2014, 43, 412ꢀ443.
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25. Stroganova, T. A.; Vasilin, V. K.; Shestakova, P. S.; Red'kin, V. M.; Krapivin, G. D. J.
Heterocyclic Chem. 2015, 52, 227ꢀ234.
7
8
9
26. Goossen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P. Chem–Eur. J. 2009, 15, 9336ꢀ
9349.
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ACS Paragon Plus Environment