One-Pot Synthesis of Naphtho[1′,2′:4,5]imidazo[1,2-a]pyridin-5-yl(aryl)methanones through Sequential Sonogashira Coupling/Alkyne–Carbonyl Metathesis

Article abstract of DOI:10.1002/ejoc.201700496

An efficient one-pot route for the construction of naphtho[1′,2′:4,5]imidazo[1,2-a]pyridin-5-yl(aryl)methanones and 5-phenylnaphtho[1′,2′:4,5]imidazo[1,2-a]pyridines by sequential Sonogashira coupling reaction followed by trifluoroacetic acid promoted alk

Full text of DOI:10.1002/ejoc.201700496

A Journal of
Accepted Article
Title: One pot synthesis of naphtho [1',2':4,5] imidazo[1,2-a]pyridin-5-
yl(aryl)methanones via a sequential Sonogashira coupling/
alkyne-carbonyl metathesis
Authors: Mirza Feroz Baig, siddiq pasha shaik, namballa hari Krishna,
neeraj Kumar Chouhan, Abdullah Alarifi, and Ahmed Kamal
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700496
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
One pot synthesis of naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
yl(aryl)methanones via a sequential Sonogashira
coupling/alkyne-carbonyl metathesis
Mirza Feroz Baig,a,b Siddiq Pasha Shaik,a,b Namballa Hari Krishna,a,c Neeraj Kumar Chouhan,a,c
Abdullah Alarifi,d and Ahmed Kamal*a,c,d
Abstract:
Particularly, intramolecular ACM version is attractive as it
generates a variety of complex carbonyl and heterocycles from
simple starting materials. Generally, these reactions are
catalyzesd by Lewis acids, strong Brønsted acids or transition-
metal catalysts.16
An
naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(aryl)methanones and 5-
phenylnaphtho[1',2':4,5]imidazo[1,2-a]pyridines via sequential
Sonogashira coupling followed by TFA promoted alkyne-carbonyl
efficient
one-pot
route
for
the
construction
of
a
metathesis
(ACM)
has
been
developed.
2-(2-
bromophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde
underwent
preferentially ACM pathway with phenyl acetylenes. While
intramolecular hydroarylation was the common pathway in the
absence of carbonyl moiety at C-3 position under similar conditions.
This protocol is compatible towards a wide variety of functional
groups and delivered corresponding naphtho[1',2':4,5]imidazo[1,2-
a]pyridines in good to excellent yields.
Figure1.Medicinally interesting imidazo[1,2-a] pyridine benzimidazole-fused
heterocycles.
Introduction
As part of our research interest in developing one pot operations
for the synthesis of bio-active scaffolds,17 we wish to synthesise
Fused nitrogen heterocycles constitute an important class of
polycyclic heterocycles which are ubiquitous structural skeletons
in numerous natural products with interesting biological
properties and pharmacologically active compounds. Among
them, Imidazo[1,2-a]pyridines, particularly their fused variants
are predominantly attractive because of their intriguing structural
features, extensive applications in material science1-3 and far-
reaching pharmaceutical applications,4,5 where they exhibit a
plenty of biological activities such as antifungal A,6 anticancer
B,7 and antimalarial C8 (Figure 1), anticonvulsant, antiviral,
antimicrobial, anti-inflammatory, and antibacterial. Despite their
biological properties, not many synthetic approaches have
reported in the literature9. Considering the importance of these
fused heterocyclic motifs and limited synthetic approaches,
development of efficient methodologies for the synthesis of
these fused heterocycles is highly desirable. On the other hand,
one pot domino reactions have emerged as powerful tools for
the construction of fused heterocycles from relatively simple
building blocks through atom and step economic transformations
by forming multiple bonds in single operation, which enable the
generation of huge libraries of scaffolds for high-throughput
screening which is a key requisite for drug discovery process.
Alkyne-carbonyl metathesis (ACM)10-14 represents a valuable
tool for the synthesis of substituted α, β-unsaturated carbonyl
compounds via a [2+2] cycloaddition and cycloreversion process
between C−O double bond and C−C triple bond in atom
economical manner which is a viable alternative for the
traditional aldol and Wittig reactions for the construction of C-C
naphtho[1',2':4,5]imidazo[1,2-a]pyridines
with
distinctive
substitutions by employing intramolecular ACM on imidazo[1,2-
a]pyridine substituted with formyl and alkyne functionalities at
appropriate position, which was generated in-situ from
imidazo[1,2-a]pyridine bearing formyl and bromo group through
Sonogashira cross-coupling in one pot operation. While our
studies are under way, Kim and co-workers reported a TFA
promoted deformylative intramolecular hydroarylation on formyl
and alkyne substituted indolizines as shown in Scheme 1 along
with traces of intramolecular ACM product.18Interestingly, during
our study, we were pleased to observe that intramolecular ACM
was the major pathway resulting in generation of only
naphtho[1',2':4,5]imidazo[1,2-a]pyridine (5) with an acyl
substituent at the C5 position exclusively, these interesting
results prompted us to scrutinize the method in detail, and the
findings are presented here.
Scheme1. TFA promoted reactions of indolizines and
imidazo[1,2-a]pyridines with and without C3 formyl group.
double bonds.15
aMedicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of
Chemical Technology (IICT), Hyderabad-500007, India
E-mail:ahmedkamal@iict.res.in
bAcademy of Scientific and Innovative Research, New Delhi, 110 025, India
cDepartment of Medicinal Chemistry, National Institute of Pharmaceutical
Education & Research (NIPER), Hyderabad-500037, India
dCatalytic Chemistry Research Chair, Chemistry Department, College of
Science, King Saud University, Riyadh 11451, Saudi Arabia
1
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
aromatic alkyne increased the rate of reaction and provided the
corresponding products (7b, 7c, 7d, 7h, 7i & 7l as shown in
Scheme 3, 7n, 7o, 7p, 7q, 7s, 7t, 7u, 7v, & 7w as shown in
Scheme 4) in excellent yield. However, aromatic alkynes bearing
the inductively electron withdrawing (e.g., 4-F & 2, 4-Di-F) and
electron deficient (4-formyl) substituents are relatively less
reactive and comparably lesser yields of the products were
observed (7e & 7f, Scheme 3), which clearly demonstrates the
influence of electronic nature on the rate and efficiency of the
reaction. Furthermore, 2-ethynyl-6-methoxynaphthalene also
reacted smoothly with various imidazo[1,2-a]pyridines to afford
the expected products (7l: 83%, 7z: 68%, & 7aa: 74%) in good
yield. In addition, heteroaryl alkyne such as thienyl acetylene
was also well compatible with the optimized conditions and gave
the corresponding product in 78% yield. Even aliphatic acetylene
such as 3-ethynylcyclohex-1-ene also furnished the
corresponding product however the yield is comparably less
than the aromatic acetylenes. Subsequently, the substrate
scope of this reaction was extended to imidazo[1,2-a]pyridine
moiety, it is noteworthy to observed that the electron density on
the imidazo[1,2-a]pyridine is not affect the efficiency of this
reaction (Scheme 4).
Our study commenced with the preparation of required starting
materials for which relatively
a straightforward synthetic
approach was followed. Initially pyridin-2-amines are condensed
with 2-bromo-1-(2-bromophenyl)ethanone (2), which were
obtained from the corresponding 1-(2-bromophenyl)ethanone (1)
to produce 2-(2-bromophenyl)imidazo[1,2-a]pyridine (4) under
refluxing condition in presence of base. Compound 4 was
subsequently subjected to Vilsmeier-Haack formylation to
generate the required 2-(2-bromophenyl)imidazo[1,2-a]pyridine-
3-carbaldehyde (5) in good yields.
Scheme 2. Synthesis of 2-(2-bromophenyl)imidazo [1,2-a]pyridine-3-
carbaldehyde 5a-c
Table 1. Optimization of reaction conditions for one-pot
synthesis of 7aa
Reagents and conditions: (a) NBS, p-TSA, CH3CN, 80 oC, 8 h, 85%; (b)
EtOH, reflux, 8 h, 85-94%; and (c) POCl3, DMF, CHCl3, 0 oC to rt, 10 h, 80-
89%.
Enty
Catalyst
(5 mol %)
Base/
Acid
Temp(oC) 7a(%)b
/Time(h)
After having the required starting materials in hand, the optimal
conditions for one-pot Sonogashira cross-coupling/ACM
Solvet
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DIPA/
THF
In(OTf)3
(5 mol %)
rt/16
nr
operation were explored via
a
sequential exposure to
Sonogashira conditions by changing the Pd catalyst as well as
base followed by different acidic conditions and the results are
summarized in Table 1. When 2-(2-bromophenyl)imidazo[1,2-
a]pyridine-3-carbaldehyde (5) was treated with phenyl acetylene
in presence of Pd(PPh3)4 followed by different Lewis acids such
as In(OTf)3,Bi(OTf)3 no required product was observed even in
trace amounts. Usage of Yb(OTf)3 resulted in formation of 1-
(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)ethanone (7) in 14%
yield (table 1, entry 3) and the structure was unambiguously
confirmed by its spectroscopic data. It was found that increasing
the temperature to refluxing conditions led to improvement in the
yield (table 1, entry 4). Comparably better yields were obtained
when the reaction was carried out in presence of TFA, and the
Et3N/
THF
Bi(OTf)3
(5 mol %)
rt/16
nr
3
Et3N/
THF
Yb(OTf)3
(5 mol %)
rt/16
14
27
35
43
52
84
57
35
41
4
Et3N/
THF
Yb(OTf)3
(5 mol %)
80/10
rt/12
5
Et3N/
THF
TFA
TFA
TFA
TFA
TFA
TFA
TFA
6
Et3N/
THF
80/12
rt/16
7
Pd(PPh3)2
Cl2
Et3N/
THF
o
yields were increased with increasing the temperature to 80 C
8
Pd(PPh3)2
Cl2
Et3N/
THF
80/10
80/12
90/12
80/16
(table 1, entries 5 & 6). Switching the palladium source from
Pd(PPh3)4 to Pd(PPh3)2Cl2 has significantly improved the yield of
the product, however in none of the conditions intramolecular
hydroarylation product was observed. Moreover, decrease in the
yield was observed with more polar solvent like DMF.
9
Pd(PPh3)2
Cl2
DIPA/
THF
10
11
Pd(PPh3)2
Cl2
Et3N/
DMF
PdCl2
Et3N/
THF
With the optimized conditions established, the generality and
scope of this protocol was explored. As depicted in schemes 3 &
4, the reaction demonstrated wide substrate scope with respect
to the aromatic terminal alkyne as well as imidazo[1,2-a]pyridine
moiety. Electron rich (e.g., 3-OMe, 4-OMe) as well as electron-
neutral (e.g., 3-Me, 4-Me, 4-Et, 2,4,5-Tri-Me) substituents on the
aThe reactions were run with 5a (0.16 mmol), alkynes (1.2 equiv),
pd catalyst (5 mol %), CuI (5 mol %) and base (3 equiv) in solvent
(4 mL) at 80 oC, after 4 h acid (0.5 mL) was added and heated for 6
more hours. bIsolated yield (%).
2
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
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In light of these encouraging results, we expected that 2-(2-
bromophenyl)imidazo[1,2-a]pyridine without formyl group could
undergo intramolecular hydroarylation, thus cyclization of 2-(2-
bromophenyl)imidazo[1,2-a]pyridine with 4-methoxy phenyl
acetylene under the conditions mentioned above resulted in
Finally to know whether the differential reactivity is due to
substrate structure (indolizine and imidazopyridine) or due to the
reaction conditions (two steps and one-pot), few controlled
experiments were conducted. Accordingly
a reaction was
performed by isolating the product obtained after Sonogashira
coupling i.e with compound 8 (equation ii, Scheme 6), which
resulted in ACM product in 86% yields. This concludes that the
differential reactivity is not due to the reactions conditions but
due to the difference in substrate i.e imidazo [1,2-a]pyridine
(Scheme 6).
hydroarylated
product
i.e.,
naphtho[1',2':4,5]imidazo[1,2-
a]pyridine with an aryl substituent at C6 position. This is similar
to Kim’s intramolecular hydroarylated product on indolizine with
carboxylate and alkyne group (Scheme 5). Then to elaborate the
substrate scope; a variety of alkyne partners were treated with
2-(2-bromophenyl)imidazo[1,2-a]pyridine which delivered the
Scheme 5. Synthesis of 8 from 4a,b
corresponding C6 arylated
naphtho[1',2':4,5]imidazo[1,2-
a]pyridines (8a, 8b & 8c) in good yields.
Scheme 3. Substrate Scope of phenyl acetylenesa,b
On bases of the related reports and based on our observations,
the reasons behind the differential reactivity of indolizines and
imidazo[1,2-a]pyridine moieties both bearing formyl and alkyne
groups under similar catalysis could be explained by their
electronic nature. It is seemed that the deformylative
intramolecular hydroarylation on indolizines is due to the fact
that the C3 site in indolizine is too electron rich to attack the
neighbouring alkyne moiety that ultimately forms an indolizinium
salt which after by subsequent extrusion of formyl group retains
aromaticity. In contrast, the C3-site of imidazo[1,2-a]pyridine is
not sufficiently nucleophilic to attack the alkyne moiety, which
might be due to the presence of electronegative nitrogen atom at
the C2-position in imidazo[1,2-a]pyridine (scheme 5). Instead, it
is assumed that intramolecular [2+2] cycloaddition pathway is
enabled resulting in oxetene (F) via a vinylic cation intermediate
with hydroxyl group (E) due to attack of alkyne onto more
aThe reactions were run with: 5 (0.16 mmol), alkynes (1.2 equiv), (Ph3P)2PdCl2
(5 mol %), CuI (5 mol %) and Et3N (3 equiv) in THF (4 mL) at 80 oC, after 4 h
TFA (0.5 mL) was added and heated for 6 more hours. bIsolated yield (%).
Scheme 4. Substrate Scope of imidazo[1,2-a]pyridinesa,b
Scheme 6. Control Experiments
aThe reactions were run with: 5 (0.16 mmol), alkynes (1.2 equiv), (Ph3P)2PdCl2
(5 mol %), CuI (5 mol %) and Et3N (3 equiv) in THF (4 mL) at 80 oC, after 4 h
TFA (0.5 mL) was added and heated for 6 more hours. bIsolated yield (%).
3
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
as a Brown solid, 2.64 g, 91%; Rf = 0.3 (20% ethyl acetate in hexanes).
Melting point: 131–132 oC.1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H),
8.17 – 8.14 (m, 1H), 8.14 – 8.12 (m, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H),
7.63 (d, J = 9.1 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.17 (td, J = 7.6, 1.5 Hz,
2H), 6.78 (td, J = 6.7, 1.0 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 144.5,
143.2, 134.4, 133.7, 131.7, 128.9, 127.6, 125.8, 124.8, 121.5, 117.6,
112.5, 112.1.HRMS (ESI)calcd for C13H9BrN2 [M+H]+273.00080, found
273.00219.
nucleophilic, protonated carbonyl carbon before C3-site attacks
onto the alkyne group. This after subsequent cycloreversion
delivers the desired product (7). However, in the absence of
formyl group i.e. with 2-(2-bromophenyl)imidazo[1,2-a]pyridine
(4) intramolecular hydroarylation is the predominant pathway,
resulting
in
generation
of
C-6
aryl
substituted
naphtho[1',2':4,5]imidazo[1,2-a]pyridine (8).
Scheme 7. Proposed Mechanism for formation of 6 and 7
2-(2-Bromophenyl)-6-methylimidazo[1,2-a]pyridine (4b): Yellow solid,
2.74 g, 88%. Rf = 0.4 (20% ethyl acetate in hexanes).Melting point: 145–
147 oC; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.13 (dd, J = 7.8, 1.7
Hz, 1H), 7.94 (s, 1H), 7.66 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (d, J = 9.2 Hz,
1H), 7.40 (tt, J = 5.5, 2.7 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.04 (dd, J = 9.2,
1.6 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 143.6, 142.8,
134.5, 133.7, 131.6, 128.8, 128.2, 127.6, 123.4, 122.2, 121.5, 116.9,
111.8, 18.2; HRMS (ESI) calcd for C14H12BrN2 [M]+ 287.01822, found
287.01784.
2-(2-Bromophenyl)-6-chloroimidazo[1,2-a]pyridine (4c): Brown solid,
2.7 g, 81%. Rf = 0.3 (25% ethyl acetate in hexanes).Melting point: 135–
137 oC 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 22.1 Hz, 1H), 7.99 (d, J
= 6.8 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.52 – 7.44 (m, 1H), 7.35 – 7.26
(m, 1H), 7.19 (ddd, J = 23.0, 13.5, 6.4 Hz, 1H), 7.12 – 7.01 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 134.9, 133.8, 131.7, 129.8, 129.3, 127.7,
126.4, 123.6, 117.9, 112.3. HRMS (ESI) calcd for C13H8BrClN2
[M+H]+306.96412, found 306.96322.
Conclusions
In summary, an efficient one-pot method for the synthesis of
naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(aryl)methanones via
a sequential Sonogashira coupling followed by TFA promoted
alkyne-carbonyl metathesis was achieved. Noteworthy is the
imidazo[1,2-a]pyridines propensity to deliver alkyne-carbonyl
metathesis (ACM) product in contrast to the indolizines which
induce hydroarylation under the similar conditions. Additionally,
2-(2-Bromophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (5a): To a
stirred solution of 4a(2 g, 6.7 mmol) in DMF (2 mL) at 0 °C was drop wise
added POCl3 ( 2.5 mL, 16.1 mmol ) in CHCl3 (18 mL). After being stirred
at rt for 12 h, the reaction mixture was quenched with iced water and
neutralized with aq. 2N NaOH solution at 0 °C. The solid was filtered and
dried to furnish 5a as a pale brown solid, 1.8 g, 84%. Rf= 0.6 (20% ethyl
acetate in hexanes). Melting point: 139.3–140.0 °C. 1H NMR (400 MHz,
CDCl3) δ 9.76 (s, 1H), 9.60 (dt, J = 6.8, 1.1 Hz, 1H), 7.84 (dt, J = 9.0, 1.0
Hz, 1H), 7.74 (dd, J = 8.0, 1.1 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.59 – 7.55
(m, 1H), 7.49 – 7.43 (m, 1H), 7.37 (qd, J = 3.9, 2.0 Hz, 1H), 7.18 (td, J =
6.9, 1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 179.4, 156.9, 147.6,
133.4, 133.4, 132.5, 131, 130.3, 128.6, 127.4, 123.4, 121.1, 117.7, 115.6.
HRMS (ESI) calcd for C14H9BrN2O [M]+ 300.99754, found 300.99710.
facile
formation
of
C-6
aryl
from
substituted
imidazo[1,2-
naphtho[1',2':4,5]imidazo[1,2-a]pyridines
a]pyridine without a formyl group at the C3 position via
hydroarylation under the similar conditions was achieved.
Further decoration of this skeleton by varying the substitution
pattern and biological evaluation of the synthesized compounds
are underway.
Experimental Section
2-(2-Bromophenyl)-6-methylimidazo[1,2-a]pyridine-3-carbaldehyde
(5b): Brown solid, 1.9 g, 89%; Rf = 0.7 (20% ethyl acetate in hexanes).
Melting point: 141–142 °C.1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H),
9.42 (s, 1H), 7.78 – 7.69 (m, 2H), 7.60 – 7.53 (m, 1H), 7.47 – 7.42 (m,
2H), 7.36 (td, J = 7.9, 1.4 Hz, 1H), 2.46 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 179.2, 156.8, 146.5, 133.6, 133.3, 133.1, 132.5, 130.9, 127.4,
126.6, 125.9, 123.4, 120.9, 116.9, 18.4.HRMS(ESI)calcd for
C15H11BrN2O [M+1]+ 315.01332, found 315.01275.
General: Starting materials, reagents, and solvents were purchased as
reagent grade and used without further purification. 1H and 13C NMR
spectra were recorded on a 300, 400 and 500 MHz spectrometer at
25 °C. Chemical shifts values are given in ppm and calibrated relative to
the residual signal of the TMS solvent. The peak patterns are defined as
follows: s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; m,
multiplet; dd, doublet of doublets, and td, triplet of doublets. The coupling
constants J, are reported in Hertz (Hz). Column chromatography was
performed over silica gel (60− 120 mesh or 100−200 mesh) using a
mixture of n-hexane and ethyl acetate (EtOAc) as the eluent. TLC plates
(Silica gel GF254) were visualized by exposure to ultraviolet light. High
resolution mass spectrometry (HRMS) was obtained on a QTOF micro
spectrometer. Melting points were determined with a melting point
apparatus without corrections. Organic solutions were concentrated by
rotary evaporation below 45 °C in vacuum.
2-(2-Bromophenyl)-6-chloroimidazo[1,2-a]pyridine-3-carbaldehyde
(5c) Yellow solid, 1.8 g, 85%. Rf
= 0.4 (20% ethyl acetate in
hexanes).Melting point: 148–149 C1H NMR (500 MHz, CDCl3) δ 9.78 –
9.64 (m, 1H), 8.43 (d, J = 26.3 Hz, 1H), 8.27 – 8.13 (m, 1H), 7.81 – 7.71
(m, 1H), 7.60 – 7.51 (m, 2H), 7.49 – 7.43 (m, 1H), 7.38 (td, J = 7.8, 1.8
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 179.5, 159.1, 156.9, 146.6, 145.8,
138.2, 133.4, 133.1, 132.4, 131.4, 127.5, 123.9, 121.2, 117.9; HRMS
(ESI) calcd for C14H8BrClN2O [M+H]+ 334.95884, found 334.95813.
o
Synthetic Procedures:
Naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(phenyl)methanone (7a):
To a flask charged with 5a (80 mg, 0.26 mmol), (Ph3P)2PdCl2 (9.3 mg,
0.05 equiv), CuI (2.5 mg, 0.05 equiv) and ethynylbenzene (27 mg, 1.5
equiv) in THF (4 mL) was added Et3N (0.11 mL, 3.0 equiv) at rt. It was
then after stirred at 80 °C for 2 h. Next, TFA (0.5 mL) was added and the
resulting solution stirred at 80 oC for 6 h. After concentration of the
reactionmixture, purification by column chromatography on silica gel to
give 7a as a pale yellow solid, 63 mg, 74%; Rf = 0.4 (30% ethyl acetate in
2-(2-Bromophenyl)imidazo[1,2-a]pyridine (4a): A mixture of 2-bromo-
2’-bromoacetophenone (3 g, 10.81 mmol) and 2-aminopyridine (10.81
mmol) in ethanol (30mL) was heated at 70 oC for 8 h. After completion of
reaction (monitored by TLC), the mixture was cooled and solvent was
evaporated under reduced pressure. To this mixture, aqueous solution of
NaHCO3 was added to quench the reaction, and then extracted with ethyl
acetate and dried over anhydrous Na2SO4. The crude compound was
purified using silica gel (60-120 mesh) column chromatography to give 4a
4
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
hexanes).Melting point: 204–205.0 °C1H NMR (400 MHz, CDCl3) δ 8.92
(d, J = 8.1 Hz, 1H), 8.49 (d, J = 6.5 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.12
(s, 1H), 7.91 (d, J = 7.5 Hz, 3H), 7.74 (t, J = 7.4 Hz, 1H), 7.62 (q, J = 6.7
Hz, 2H), 7.50 (q, J = 7.8 Hz, 3H), 6.98 (t, J = 6.5 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ 197.7, 148.8, 144.1, 143.3, 139.30, 136.4, 130.82, 130.7,
130.1, 129.3, 127.1, 127, 126.9, 124.8, 123.3, 122.8, 119, 114.1, 113.3,
111.9, 29.7; HRMS (ESI) calcd for C22H14ON2 [M+H]+ 323.11728, found
323.11789.
hexanes).Melting point: 212–213 °C. 1H NMR (400 MHz, CDCl3) δ 10.06
(s, 1H), 9.67 (d, J = 6.8 Hz, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.80 – 7.76 (m,
3H), 7.74 (d, J = 2.0 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.55 (ddd, J = 7.7, 5.5,
1.7 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.18 (td, J = 6.9, 1.1 Hz, 1H).13
C
NMR (100 MHz, CDCl3) δ 191.4, 179.9, 156.1, 147.8, 135.6, 134.5,
133.3, 132, 131.1, 130.2, 129.6, 129.5, 129.4, 129, 128.6, 122.7, 121,
117.6, 115.6, 92.2, 91.9. HRMS(ESI)calcd for C23H14O2N2
[M+H]+351.11169, found 351.11280.
(4-Methoxyphenyl)(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
yl)methanone (7b): Yellow solid, 78.5 mg, 84%; Rf = 0.5 (30% ethyl
acetate in hexanes).Melting point: 197–198 °C.1H NMR (300 MHz,
CDCl3) δ 8.93 (d, J = 8.1 Hz, 1H), 8.52 (d, J = 6.6 Hz, 1H), 8.21 (d, J =
8.4 Hz, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H),
7.61 (d, J = 7.6 Hz, 1H), 7.57 – 7.48 (m, 2H), 7.01 (t, J = 5.9 Hz, 1H),
6.96 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H).13C NMR (125 MHz, CDCl3) δ 196.3,
163.8, 148.6, 142.9, 132.8, 131.6, 131.3, 130, 128.8, 127, 126.9, 124.8,
123.3, 122.8, 118.2, 113.8, 112.6, 112, 55.6. HRMS (ESI)calcd for
C23H16O2N2 [M+H]+353.12831, found 353.12845.
(4-Ethylphenyl)(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5
yl)methanone (7h): Green solid, 79 mg, 84%; Rf = 0.4 (30% ethyl
acetate in hexanes).Melting point:191–192 °C. 1H NMR (400 MHz,
CDCl3) δ 8.92 (d, J = 8.1 Hz, 1H), 8.48 (d, J = 6.6 Hz, 1H), 8.29 (d, J =
8.4 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.1 Hz,
2H), 7.73 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.54 – 7.44 (m, 1H),
7.30 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 6.7 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H),
1.29 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 197.2, 150.2,
148.7, 143.2, 136.6, 130.8, 130.1, 128.9, 128.1, 127, 126, 126.9, 124.8,
123.3, 122.7, 118.1, 113.3, 111.9, 29.1, 15.2.HRMS (ESI)calcd for
C24H19ON2 [M+H]+351.14895, found 351.14919.
Naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(m-tolyl)methanone (7c):
Yellow solid, 71 mg, 80%; Rf
=
0.4 (30% ethyl acetate in
Naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(2,4,5-
hexanes).Melting point: 169–171 °C. 1H NMR (500 MHz, CDCl3) δ 8.93
(d, J = 8.1 Hz, 1H), 8.50 (d, J = 6.7 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.11
(s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.75 (t, J = 7.2 Hz, 2H), 7.67 – 7.59 (m,
2H), 7.55 – 7.51 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H),
7.01 (t, J = 6.7 Hz, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
180,156.4, 147.8, 137.9, 134.4, 133.1, 132.1, 130.9, 129.9, 129.4, 128.6,
128.2, 123.6, 122.5, 121.1, 117.6, 115.34, 9.16, 87.9, 21.2.HRMS (ESI)
calcd for C23H16ON2 [M+H]+337.13150, found 337.13354.
trimethylphenyl)methanone (7i): Yellow solid, 80.6 mg, 83%; Rf = 0.3
(20% ethyl acetate in hexanes).Melting point: 208–209 °C. 1H NMR (400
MHz, CDCl3) δ 8.93 (d, J = 7.5 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.48 (d,
J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.80 – 7.72 (m,
1H), 7.71 – 7.64 (m, 1H), 7.52 (ddd, J = 9.0, 6.8, 1.1 Hz, 1H), 7.21 (s, 1H),
7.12 (s, 1H), 6.98 (dd, J = 9.7, 3.8 Hz, 1H), 2.42 (s, 3H), 2.32 (s, 3H),
2.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 199.5, 149.1, 143.8, 140.3,
137.6, 135.9, 133.7, 132.9, 131.8, 131.3, 130.1, 129.1, 127.5, 127.1, 127,
125, 123.3, 122.8, 118.1, 115.3, 112, 20.2, 19.81, 19.2.HRMS (ESI)calcd
for C25H20ON2 [M+H]+365.16502, found 365.16484.
Naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(p-tolyl)methanone (7d):
Brown solid, 74 mg, 83%; Rf = 0.4 (30% ethyl acetate in hexanes).
Melting point:198–199 °C.1H NMR (500 MHz, CDCl3) δ 8.93 (d, J = 8.1
Hz, 1H), 8.50 (d, J = 6.8 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H),
7.92 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.5 Hz, 1H),
7.60 (t, J = 7.4 Hz, 1H), 7.52 (t, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.00 (t, J =
6.7 Hz, 1H), 2.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 197.7, 148.8,
144.1, 143.3, 139.30, 136.4, 130.82, 130.7, 130.1, 129.3, 127.1, 127,
126.9, 124.8, 123.3, 122.8, 119, 114.1, 113.3, 111.9, 29.7.HRMS
(ESI)calcd for C23H16ON2 [M+H]+337.13324, found 337.13354.
Naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(thiophen-3-
yl)methanone (7j):Brown solid, 68 mg, 78%. Rf = 0.4 (30% ethyl acetate
in hexanes).Melting point:210–211 °C. 1H NMR (400 MHz, CDCl3) δ 8.91
(d, J = 8.0 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.21
(s, 1H), 7.90 (d, J = 10.5 Hz, 2H), 7.74 (t, J = 7.3 Hz, 1H), 7.68 (d, J = 4.1
Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 6.7 Hz, 1H), 7.44 – 7.39 (m,
1H), 7.00 (s, 1H). 13C NMR (75 MHz, CDCl3+DMSO) δ 195.3, 153.6,
148.1, 147.7, 140.3, 135.6, 134.3, 134.3, 133.1, 131.7, 131.3, 130.9,
127.9, 127.6, 122.3, 118.9, 116.9.HRMS (ESI)calcd for C20H12ON2S
[M+H]+329.07402, found 329.07431.
(2,4-Difluorophenyl)(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
yl)methanone (7e): Yellow solid, 62.2 mg, 65%; Rf = 0.3 (30% ethyl
acetate in hexanes).Melting point: 175–176 °C.1H NMR (400 MHz,
CDCl3) δ 8.93 (d, J = 7.8 Hz, 1H), 8.66 (d, J = 8.3 Hz, 1H), 8.50 (d, J =
6.3 Hz, 1H), 8.16 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.78 (dd, J = 15.1, 7.6
Hz, 2H), 7.73 – 7 .66 (m, 1H), 7.59 – 7.51 (m, 1H), 7.04 (dd, J = 11.8, 6.5
Hz, 2H), 6.91 (t, J = 8.6 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 192.5,
162.63 (d, J = 248.856 Hz), 162.71 (d, J = 248.856) 149.3, 144.4 (d, J =
20.89 Hz), 114.3 (d, J = 19.98 Hz), 129.7, 129.5, 129.3, 127.7, 127.3,
126.9, 126.5, 124.9, 123.5, 122.7, 118.2, 115.3, 112.3, 105.3, 105.,
104.8. HRMS (ESI) calcd for C22H12ON2F2 [M+H]+ 359.09883, found
359.09905.
Cyclohex-1-en-1-yl(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
yl)methanone (7k): Pale yellow solid, 57 mg, 65%.Rf = 0.5 (30% ethyl
acetate in hexanes).Melting point: 181–183 °C. 1H NMR (400 MHz,
CDCl3) δ 8.87 (d, J = 7.8 Hz, 1H), 8.55 (d, J = 6.5 Hz, 1H), 8.08 (d, J =
8.4 Hz, 1H), 7.74 – 7.68 (m, 1H), 7.68 – 7.58 (m, 2H), 7.49 (dd, J = 16.5,
7.7 Hz, 2H), 7.01 (t, J = 6.7 Hz, 1H), 6.63 (s, 1H), 2.59 (s, 2H), 2.20 (s,
2H), 1.84 – 1.77 (m, 2H), 1.74 – 1.66 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ 199.1, 146.9, 141.1, 132.1, 130.1, 129.1, 128.6, 127.2, 126.9,
126.6, 124.7, 123.4, 122.6, 117.8, 117.5, 112.2, 111, 26.4, 23.6, 22.1,
21.7.HRMS (ESI)calcd for C22H18ON2 [M+H]+327.14831, found
327.14919.
(4-Fluorophenyl)(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
yl)methanone (7f): Yellow solid, 61.5 mg, 68%; Rf = 0.4 (30% ethyl
acetate in hexanes).Melting point: 194–195 °C.1H NMR (300 MHz,
CDCl3+DMSO) δ 8.93 (s, 1H), 8.61 (d, J = 6.3 Hz, 1H), 8.22 (d, J = 8.3
Hz, 1H), 8.15 (s, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.97 – 7.88 (m, 2H), 7.78
(s, 1H), 7.63 (t, J = 7.7 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.14 – 7.09 (m,
2H).13C NMR (75 MHz, CDCl3+DMSO) δ 200, 172.2, 165.1 (d, J = 254.7
Hz) 139.7, 138.1, 137.9, 136.7, 135.6, 134.8, 132.5 (d, J = 9.4 Hz) 132.3,
131.5, 126.8 (d, J = 7.2 Hz) 121, 120.8, 120.5, 119.3, 118.6.HRMS
(ESI)calcd for C22H13ON2F [M+H]+ 341.10840, found 341.10847.
(6-Methoxynaphthalen-2-yl)(naphtho[1',2':4,5]imidazo[1,2-a]pyridin-
5-yl)methanone (7l): Brown solid, 88.8 mg, 83%. Rf = 0.3 (20% ethyl
acetate in hexanes). Melting point: 222–223 °C. 1H NMR (400 MHz,
CDCl3) δ 8.94 (d, J = 8.1 Hz, 1H), 8.48 (d, J = 6.7 Hz, 1H), 8.30 (d, J =
8.4 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.92 (d, J
= 9.2 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 16.0, 8.2 Hz, 2H),
7.59 (t, J = 7.4 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.19 (s, 1H), 7.19 – 7.14 (m,
1H), 6.97 (t, J = 6.6 Hz, 1H), 3.96 (s, 3H). 13C NMR (75 MHz,
CDCl3+DMSO) δ 201.9, 164.7, 153.5, 1532, 147.8, 142.1, 138.9, 137.3,
136, 135.4, 134.8, 133.9, 132.4, 132, 131.6, 131, 130.2, 128, 127.7,
124.5, 122.6, 118.5, 116.8, 110.6, 60.2.HRMS (ESI)calcd for C27H19O2N2
[M+H]+403.14284, found 403.14410.
4-(Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5-carbonyl)benzaldehyde
(7g): Yellow solid, 60.3 mg, 65%; Rf = 0.5 (30% ethyl acetate in
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
(9-Methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(3-
yl)(phenyl)methanone (7m): Yellow solid, 63.7 mg, 75%. Rf = 0.4 (20%
ethyl acetate in hexanes).Melting point: 218–219 °C.1H NMR (500 MHz,
CDCl3) δ 8.92 – 8.88 (m, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.09
(s, 1H), 7.91 (dd, J = 8.2, 1.2 Hz, 2H), 7.81 (d, J = 9.3 Hz, 1H), 7.76 –
7.71 (m, 1H), 7.66 – 7.59 (m, 2H), 7.50 (dd, J = 10.8, 4.8 Hz, 2H), 7.37
(dd, J = 9.3, 1.5 Hz, 1H), 2.42 (s, 3H).13C NMR (100 MHz, CDCl3) δ
197.5, 148, 143.4, 139.2, 133, 132.3, 130.5, 130, 129.9, 128.5, 127,
126.9, 126.9, 123.3, 122.5, 122.4, 121.9, 117.4, 114.1, 18.3.HRMS
(ESI)calcd for C23H16ON2[M+H]+ 337.13340, found 337.13354.
methoxyphenyl)methanone (7s): Yellow solid, 74.3 mg, 81%; Rf = 0.4
(20% ethyl acetate in hexanes). Melting point: 188–191 °C. 1H NMR (500
MHz, CDCl3) δ 8.87 (d, J = 8.2 Hz, 1H), 8.53 – 8.50 (m, 1H), 8.31 (d, J =
8.4 Hz, 1H), 8.05 (s, 1H), 7.84 (dd, J = 9.6, 0.7 Hz, 1H), 7.77 – 7.72 (m,
1H), 7.63 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.46
(dd, J = 9.6, 2.0 Hz, 1H), 7.39 – 7.36 (m, 2H), 7.21 – 7.17 (m, 1H), 3.87
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 197.1, 159.9, 146.9, 144.3, 143.6,
140.2, 138.6, 131.3, 130.2, 130.1, 129.5, 127.4, 127.4, 126.9, 123.5,
123.3, 122.8, 122.6, 120.2, 119.8, 118.5, 114.3, 113.3,
55.6.HRMS(ESI)calcd for C23H15ClN2O2 [M+H]+ 387.08908, found
387.08948.
(9-Methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(m-
tolyl)methanone (7n): Brown solid, 73.5 mg, 83%. Rf = 0.4 (20% ethyl
acetate in hexanes).Melting point: 174–176 °C.1H NMR (400 MHz,
CDCl3) δ 8.93 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 9.4 Hz, 2H), 8.08 (s, 1H),
7.89 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 18.4, 7.7
Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.38 (dd, J = 15.8, 8.1 Hz, 2H), 2.45 (s,
3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.6, 147.2, 139.1,
138.5, 134, 132.9, 132.2, 132.1, 132.1, 130.9, 130.8, 130.1, 128.6, 128.5,
128.4, 127.9, 127.3, 127.2, 126.8, 126.3, 123.5, 122.5, 122.3, 117, 113.5,
21.4, 18.3. HRMS(ESI)calcd for C24H18ON2 [M+H]+ 351.14809, found
351.14919.
9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(4-
methoxyphenyl)methanone (7t): Yellow solid, 77.5 mg, 84%; Rf = 0.4
(20% ethyl acetate in hexanes).Melting point: 196–198 °C.1H NMR (500
MHz, CDCl3) δ 8.88 (d, J = 8.1 Hz, 1H), 8.52 (s, 1H), 8.20 (d, J = 8.4 Hz,
1H), 8.01 (d, J = 10.1 Hz, 1H), 7.91 – 7.88 (m, 2H), 7.85 (d, J = 9.6 Hz,
1H), 7.74 (t, J = 7.4 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.45 (dd, J = 9.6, 1.7
Hz, 1H), 6.98 – 6.94 (m, 2H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
196.1, 163.9, 146.7, 145.8, 143.2, 137.9, 132.9, 132.1, 131.4, 130, 129.9,
127.3, 127.1, 126.9, 123.3, 122.7, 120, 118.5, 113.9, 112.2, 55.6.HRMS
(ESI) calcd for C23H15O2N2Cl [M+H]+387.08915, found 387.08948.
(9-Methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(p-
tolyl)methanone (7o): Yellow solid, 70 mg, 81%. Rf = 0.4 (20% ethyl
acetate in hexanes).Melting point: 231–232 °C.1H NMR (400 MHz,
CDCl3) δ 8.89 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H),
8.06 (s, 1H), 7.80 (t, J = 8.6 Hz, 3H), 7.72 (t, J = 7.4 Hz, 1H), 7.59 (t, J =
7.5 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 2.46 (s,
3H), 2.40 (s, 3H).13C NMR (100 MHz, CDCl3) δ 197.2, 147.9, 143.9,
143.2, 136.5, 132.1, 130.7, 130.3, 130, 129.2, 126.9, 126.8, 123.2, 122.5,
122.4, 121.8, 117.3, 113.6, 21.8, 18.2. HRMS (ESI)calcd for C24H19ON2
[M+H]+ 351.14884, found 351.14919.
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(3,4,5-
trimethylphenyl)methanone (7u): Pale yellow solid, 78.7 mg, 83%; Rf
= 0.3 (30% ethyl acetate in hexanes). Melting point: 185–188 °C. 1H
NMR (400 MHz, CDCl3) δ 8.89 (d, J = 8.2 1H), 8.65 (d, J = 8.4 Hz, 1H),
8.49 (d, J = 1.2 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 9.7 Hz, 1H), 7.80 –
7.74 (m, 1H), 7.69 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.46 (dd, J = 9.6, 2.0
Hz, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 2.43 (s, 3H), 2.33 (s, 3H), 2.18 (s,
3H).13C NMR (125 MHz, CDCl3) δ 199.3, 147.1, 144, 140.6, 137.2, 136.1,
133.7, 132.9, 132.4, 131.9, 130.2, 130.1, 127.7, 127.4, 127.1, 126.9,
123.3, 122.9, 122.7, 120.1, 118.5, 114.7, 20.3, 19.8, 19.2.
HRMS(ESI)calcd for C25H19ON2Cl [M+H]+ 399.12596, found 399.12587.
(3-Methoxyphenyl)(9-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-
5-yl)methanone (7p): Pale yellow solid, 71.5 mg, 84%. Rf = 0.3 (30%
ethyl acetate in hexanes).Melting point: 161–163 °C.1H NMR (500 MHz,
CDCl3) δ 8.89 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.26 (s, 1H),
8.09 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.64 – 7.59
(m, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.41 – 7.34 (m, 3H), 7.18 (ddd, J = 7.6,
2.5, 1.6 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H).13C NMR (125 MHz, CDCl3) δ
197.2, 174.2, 159.8, 147.9, 143.1, 140.6, 132.4, 130, 129.9, 129.4, 127,
126.9, 126.8, 126.8, 123.5, 123.3, 122.4, 122, 119.6, 117, 114.4, 114.1,
55.6, 18.2.HRMS (ESI)calcd for C24H18O2N2 [M+H]+367.14214, found
367.14410.
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(4-
ethylphenyl)methanone (7v): Green solid, 74.8 mg, 82%Rf= 0.4 (30%
1
ethyl acetate in hexanes). Melting point: 236.1–237.0 °C. H NMR (400
MHz, CDCl3) δ 8.87 (dd, J = 8.2, 0.7 Hz, 1H), 8.51 (dd, J = 1.9, 0.8 Hz,
1H), 8.28 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.86 – 7.82 (m, 3H), 7.77 –
7.71 (m, 1H), 7.62 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.47 – 7.43 (m, 1H),
7.32 (d, J = 8.3 Hz, 2H), 2.76 (q, J = 7.6 Hz, 2H), 1.33 – 1.28 (m, 3H).13
C
NMR (100 MHz, CDCl3) δ 197, 150.4, 146.7, 143.4, 136.4, 131.6, 130.8,
130, 128.1, 127.3, 127.2, 126.9, 123.2, 122.8, 122.7, 120, 118.5, 112.9,
29.1, 15.2.HRMS(ESI) calcd for C24H17ClN2O [M+H]+ 385.11149, found
385.11022.
(4-Methoxyphenyl)(9-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-
5-yl)methanone (7q): Brown solid, 69.8 mg, 82%. Rf = 0.4 (30% ethyl
acetate in hexanes).Melting point: 219–220 °C.1H NMR (500 MHz,
CDCl3) δ 8.90 (d, J = 8.1 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H),
8.07 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.72 (t, J =
7.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.96 (d, J =
8.8 Hz, 2H), 3.90 (s, 3H), 2.43 (s, 3H).13C NMR (125 MHz, CDCl3) δ
196.3, 163.7, 147.7, 142.9, 132.9, 132.1, 131.7, 130.8, 130.7, 129.9,
126.9, 126.9, 126.7, 123.2, 122.6, 122.4, 121.8, 117.4, 113.8, 112.9,
55.6, 18.3.HRMS (ESI) calcd for C24H18O2N2 [M+H]+367.14214, found
367.14410.
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(m-
tolyl)methanone (7w): Yellow solid, 71.5 mg, 81%. Rf = 0.4 (30% ethyl
acetate in hexanes).Melting point: 186–188 °C. 1H NMR (300 MHz,
CDCl3) δ 8.87 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H),
8.03 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.75 (t, J = 7.2 Hz, 2H), 7.63 (dd, J
= 11.7, 7.3 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 2.42
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 197.6, 146.8, 143.6, 138.9, 138.5,
134.1, 131.5, 130.8, 130.1, 128.4, 127.9, 127.4, 127.3, 126.9, 123.3,
122.8, 122.6, 120.1, 118.5, 113.2, 21.4.HRMS(ESI) calcd for
C23H15ClN2O [M+H]+ 371.09549, found 371.09457.
(9-Chloronaphtho[1',2’:4,5]imidazo[1,2-a]pyridin-5
yl)(Phenyl)methanone (7r):Green solid, 61 mg, 72%; Rf = 0.4 (30%
ethyl acetate in hexanes).Melting point: 156–157 °C.1H NMR (400 MHz,
CDCl3) δ 8.53 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J =
7.4 Hz, 3H), 7.77 (s, 1H), 7.64 (d, J = 5.2 Hz, 2H), 7.55 – 7.46 (m, 3H),
5.30 (s, 1H).13C NMR (125 MHz, CDCl3) δ 197.3, 146.9, 143.8, 138.8,
133.3, 131.3, 130.5, 130.1, 128.6, 127.4, 127.4, 127, 126.9, 123.3, 122.8,
122.6, 120.1, 118.6, 113.3.HRMS (ESI)calcd for C22H13ON2Cl [M+H]+
357.07864, found 357.07892.
(9-Methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(thiophen-3-
yl)methanone (7x): Brown solid, 65 mg, 75%; Rf = 0.4 (30% ethyl
acetate in hexanes).Melting point: 240–241 °C.1H NMR (400 MHz,
CDCl3) δ 8.88 (d, J = 7.7 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H),
8.18 (s, 1H), 7.93 (dd, J = 2.9, 1.2 Hz, 1H), 7.83 (d, J = 9.3 Hz, 1H), 7.76
– 7.71 (m, 1H), 7.69 (dd, J = 5.1, 1.2 Hz, 1H), 7.62 (ddd, J = 8.4, 7.0, 1.3
Hz, 1H), 7.42 (dd, J = 5.1, 2.9 Hz, 1H), 7.36 (dd, J = 9.3, 1.6 Hz, 1H),
2.43 (S, 3H).13C NMR (100 MHz, CDCl3) δ 190.7, 147.7, 143.6, 134.9,
132.5, 130.9, 129.6, 128.6, 127.2, 127, 126.7, 126.5, 123.3, 122.4, 122.1,
6
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10.1002/ejoc.201700496
European Journal of Organic Chemistry
FULL PAPER
117.3, 113.2, 18.3.HRMS (ESI) calcd for C21H14ON2S [M+H]+343.08815,
found 343.08996.
6-(6-methoxynaphthalen-2-yl)naphtho[1',2':4,5]imidazo[1,2-
a]pyridine (8b): Brown solid, 95 mg, 86%; Rf = 0.3 (40% ethyl acetate in
hexanes).Melting point: 179–181 °C.1H NMR (500 MHz, CDCl3) δ 8.91 (d,
J = 8.1 Hz, 1H), 8.00 (d, J = 4.7 Hz, 2H), 7.92 (dd, J = 13.6, 7.7 Hz, 2H),
7.85 (dd, J = 16.9, 8.9 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.66 – 7.60 (m,
3H), 7.33 (dd, J = 8.4, 7.4 Hz, 1H), 7.27 (d, J = 10.4 Hz, 2H), 6.54 (t, J =
6.8 Hz, 1H), 4.00 (s, 3H);13C NMR (100 MHz, CDCl3) δ 158.4, 147.9,
141.8, 134.2, 133.4, 131.6, 129.7, 128.9, 128.2, 128.1, 127.8, 127.4,
126.7, 126.4, 126.1, 124, 123.1, 122.6, 119.8, 117.9, 110.7, 105.9,
55.5.HRMS(ESI) calcd for C26H18N2O [M+H]+ 375.14755, found
375.14919.
(6-Methoxynaphthalen-2-yl)(9-methylnaphtho[1',2':4,5]imidazo[1,2-
a]pyridin-5-yl)methanone (7y): Yellow solid, 87.2 mg, 83%; Rf = 0.3
(30% ethyl acetate in hexanes).Melting point: 213–214 °C.1H NMR (400
MHz, CDCl3) δ 8.91 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.22 (d,
J = 9.1 Hz, 2H), 8.11 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.84 – 7.78 (m,
2H), 7.75 – 7.69 (m, 2H), 7.60 – 7.54 (m, 1H), 7.32 (d, J = 9.1 Hz, 1H),
7.20 – 7.13 (m, 2H), 3.94 (s, 3H), 2.36 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 197.2, 179.3, 160, 146.9, 137.5, 134.2, 133, 132.7, 131.3,
130.9, 130.2, 127.7, 127.4, 127.3, 126.9, 126.4, 126.2, 123.6, 122.6,
119.8, 116.9, 113.2, 105.9, 55.5, 18.3. HRMS(ESI) calcd for C28H20O2N2
[M+H]+ 417.15853, found 417.15975.
6-(4-Ethylphenyl)naphtho[1',2':4,5]imidazo[1,2-a]pyridine (8c): Yellow
solid, 79 mg, 84%; Rf = 0.4 (40% ethyl acetate in hexanes). Melting point:
187–189 °C.1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 8.1 Hz, 1H), 8.27
(s, 1H), 8.17 – 8.12 (m, 2H), 7.66 (dd, J = 8.6, 6.0 Hz, 3H), 7.56 (s, 1H),
7.40 (d, J = 7.8 Hz, 2H), 7.18 (tdd, J = 7.6, 4.9, 2.5 Hz, 2H), 6.80 (t, J =
6.7 Hz, 1H), 2.82 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H).13C NMR
(125 MHz, CDCl3) δ 144.4, 142.9, 134.2, 133.7, 131.7, 129.3, 129.1,
128.4, 128.2, 127.6, 126.5, 125.8, 125.2, 121.6, 117.5, 112.7, 112.1,
28.7, 15.6.HRMS(ESI)calcd for C23H18N2 [M+H]+ 323.15486, found
323.15428.
Cyclohex-1-en-1-yl(9-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridin-
5-yl)methanone (7z): Brown solid, 58.8 mg, 68%; Rf = 0.5 (20% ethyl
acetate in hexanes).Melting point: 163–165 °C.1H NMR (500 MHz,
CDCl3) δ 8.78 (d, J = 8.0 Hz, 1H), 8.23 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H),
7.85 (s, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.52 (t, J =
7.5 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.55 (s, 1H), 2.52 (s, 2H), 2.36 (s,
3H), 2.14 (s, 2H), 1.76 – 1.71 (m, 2H), 1.66 – 1.60 (m, 2H).13C NMR (100
MHz, CDCl3) δ 199.1, 146.9, 146.7, 141.4, 141.1, 132.2, 132.1, 132,
131.8, 129.9, 128.6, 128.5, 127, 126.7, 126.6, 126.5, 123.3, 122.4, 122.3,
122, 117.1, 111.2, 29.7, 26.4, 23.6, 22.1, 21.7, 18.3.HRMS (ESI) calcd
for C23H20ON2 [M+H]+341.16370, found 341.16484.
Acknowledgements
The authors thank CSIR, UGC and NIPER-H, for the award of
fellowships. We also thank funding received from the project
entitled ‘Affordable Cancer Therapeutics (ACT)’ under XIIth five
year plan and extend our appreciation to the International
Scientific Partnership Program ISPP at King Saud University for
funding this research work through ISPP#0054.
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(thiophen-3-
yl)methanone (7aa): Green solid, 64 mg, 74%; Rf = 0.3 (30% ethyl
acetate in hexanes). Melting point: 172–174 °C. 1H NMR (300 MHz,
CDCl3+DMSO) δ 13.76 (s, 1H), 13.52 (d, J = 8.1 Hz, 1H), 13.18 (s, 1H),
13.03 (d, J = 8.4 Hz, 1H), 12.68 (d, J = 1.8 Hz, 1H), 12.52 (d, J = 9.7 Hz,
1H), 12.41 (dd, J = 16.0, 6.2 Hz, 2H), 12.33 (d, J = 7.2 Hz, 1H), 12.23 –
12.16 (m, 2H).13C NMR (75 MHz, DMSO) δ 189.9, 146.5, 142.6, 137.1,
130.3, 129.1, 127.9, 127.7, 127, 126.3, 125.5, 123, 122.8, 117.9,
115.3.HRMS(ESI)calcd for C20H11ClN2OS[M+H]+ 363.03493, found
363.03534.
Keywords: Heterocycles • Imidazopyridine • Alkyne-Carbonyl
Metathesis • TFA • Synthetic methodologies
(9-Chloronaphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl)(6-
References:
methoxynaphthalen-2-yl)methanone (7ab): Brown solid, 77.5 mg,
80%; Rf = 0.3 (30% ethyl acetate in hexanes).Melting point: 141–143 °C.
1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 8.3 Hz, 1H), 8.51 (s, 1H), 8.30
(d, J = 8.2 Hz, 1H), 8.23 (s, 1H), 8.10 – 8.05 (m, 1H), 7.85 (t, J = 8.6 Hz,
2H), 7.75 (dd, J = 19.7, 8.1 Hz, 2H), 7.67 – 7.57 (m, 1H), 7.46 (d, J = 9.7
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C
NMR (125 MHz, CDCl3) δ 197.1, 160.1, 146.6, 143.1, 142.9, 137.5, 134,
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a flask charged with 4a (100 mg, 0.37 mmol), (Ph3P)2PdCl2 (12.8 mg,
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European Journal of Organic Chemistry
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8
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Graphical abstract:
2-(2-Bromophenyl)imidazo[1,2-a]pyridine with and without a C-3 aldehyde was studied for alkyne-carbonyl metathesis (ACM) vs
hydroarylation. 2-(2-bromophenyl)imidazo[1,2-a]pyridine with a C-3 aldehyde underwent preferentially ACM pathway with phenyl
acetylenes. While intramolecular hydroarylation was the common pathway in the absence of carbonyl moiety at C-3 position.
Mirza Feroz Baig,a,b Siddiq Pasha Shaik,a,b Namballa Hari Krishna,a,c Neeraj Kumar Chouhan,a,c Abdullah Alarifi,d and Ahmed
Kamal*a,c,d
One pot synthesis of naphtho[1',2':4,5]imidazo[1,2-a]pyridin-5-yl(aryl)methanone via a sequential Sonogashira
coupling/alkyne-carbonyl metathesis
9
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