Ligand-free Pd-catalysed decarboxylative arylation of imidazo[1,2-: A] pyridine-3-carboxylic acids with aryl bromides

Article abstract of DOI:10.1039/c6ra12166g

A facile ligand-free method for Pd(OAc)₂ catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids with hetero(aryl) bromides has been developed. This method is applicable to a variety of (hetero)aryl bromides as coupling partners. Electron withdrawing and donating groups on imidazo[1,2-a]pyridine-3-carboxylic acids are well tolerated. It represents the first general protocol for ligand-free Pd(OAc)₂ catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids with (hetero)aryl halides. A few of the compounds synthesized using this protocol showed antibacterial activity against Staphylococcus aureus.

Full text of DOI:10.1039/c6ra12166g

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Ligand-free Pd-catalysed decarboxylative arylation of Imidazo[1,2-
a]pyridine-3-carboxylic acids with Aryl bromides†
Uttam B. Karalea,b, Saradhi Kalaria, Jala Shivakumarc, Vitthal B. Makanea,b, Dattatraya A. Babara,b
Ritesh P. Thakared, Bathini Nagendra Babuc, Sidharth Choprad, Haridas B. Rodea,b
Received 00th January 20xx,
Accepted 00th January 20xx
,
*
DOI: 10.1039/x0xx00000x
A facile ligand-free method for Pd(OAc)2 catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids
with hetero(aryl) bromides has been developed. This method is applicable to variety of (hetero)aryl bromides as coupling
partner. Electron withdrawing and donating groups on imidazo[1,2-a]pyridine-3-carboxylic acids are well tolerated. It
represent the first general protocol for ligand-free Pd(OAc)2 catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-
3-carboxylic acids with (hetero)aryl halides. Few of the compounds synthesized using this protocol showed antibacterial
www.rsc.org/
activity
against
Staphylococcus
aureus.
albeit with generation of two regioisomers in few cases.8 The
direct arylation of imidazo[1,2-a]pyridines has also been
reported.9 These methods make use of aryl bromides or
tosylate or mesylate. However, they have either limited
substrate scope with respect to substituents on imidazo[1,2-
Introduction
The imidazopyridines have attracted much attention due to
their unique biological properties in recent time.1 Imidazo[1,2-
a]pyridine, in particular, is an important scaffold and has
shown various biological activities including antiviral,
9b, 9e
9d
a]pyridines core9a,
or limited to C-2 substituted9c,
imidazo[1,2-a]pyridines.
analgesic,
anthelmintic,
antifungal,
antibacterial,
The decarboxylative arylation reaction makes use of carboxylic
acids and aryl halides. In general, aromatic acids are stable
solids, thereby easy to handle, making such strategy an
important synthetic method.10 Only two methods have been
reported for the decarboxylative arylation of imidazo[1,2-
a]pyridine-3-carboxylic acid till date. First method uses
Pd(0)bis(carbene) complex, prepared from NHC ligand
precursor and palladium precursor11, and has limited substrate
scope.12 The second method uses aryl chloride with 5 mol%
Pd(OAc)2 and S-Phos as ligand in DMA/H2O medium.10 This
method requires phosphine ligand and many a times it
become difficult to separate such ligands from the product,
jeopardizing its applicability. Hence, a ligand-free catalytic
approach becomes the method of choice in such scenario.
Ligandless catalytic process are the most economical and
efficient ones and hence are widely used in industries.13
Hence, there is a need for a ligandless facile synthesis of C-3
antiprotozoal, anxiolytic etc.2 A preclinical candidate Q203 has
been developed for its antimycobacterial potential and has
shown significant activity against the multidrug resistant
strains of Mycobacterium tuberculosis.3 The marketed drugs
zolpidem, necopidem, olprinone, saripidem, alpidem contain
imidazo[1,2-a]pyridine scaffold.4 As a result modifications of
imidazo[1,2-a]pyridine have been a focus of drug discovery
research. Chemically diverse set of compounds can be
obtained in one step within a reasonably short duration of
time using palladium catalyzed cross-coupling reactions. The
modification of imidazo[1,2-a]pyridines using Suzuki-type
cross-coupling5 and Stille cross-coupling6 have been reported.
However, these reactions showed limited substrate scope, and
commercial availability of heteroaromatic boronic acids or
stannanes limits its applicability. Further, the strategy for
regioselective palladium-catalyzed arylation of imidazo[1,2-
a]pyridine with aryl/heteroaryl bromide has been described
and depends on triphenyl phosphine as ligand or Pd(PPh3)4.2c, 7
Recently palladium catalyzed oxidative cross-coupling reaction
to obtain 3-aryl imidazo[1,2-a]pyridine has been demonstrated
substituted imidazo[1,2-a]pyridines. Herein, we report
a
method for synthesis of C-3 aryl/heteroaryl imidazo[1,2-
a]pyridines from aryl/heteroaryl bromides and imidazo[1,2-
a]pyridine-3-carboxylic acids with palladium acetate in the
absence of ligand. This facile protocol offers good tolerability
towards various aryl/heteroaryl bromides and also applicable
to various imidazo[1,2-a]pyridine-3-carboxylic acids. Till date
there is no report on ligand-free palladium (II) catalyzed
a.Department of Natural Product Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India
b.Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
c. Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Balanagar, Hyderabad - 500 037, India
decarboxylative arylation of
carboxylic acid with aryl halides.
imidazo[1,2-a] pyridine-3-
d.
Micobiology Division, Central Drug Research Institute, Lucknow - 226 031, India
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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involving ligand free Pd(OAc)2 as catalyst and aryl bromide as
coupling partner.14 Further reduction in Pd(OAc)2 (1 mol%) did
not result in completion of the reaction in 24 hrs. Next, we
turned our attention to the stoichiometry of reactants wherein
1a (from 1.2 to 1.6 equivalent) was employed with 2a (1
equivalent), Pd(OAc)2 (2 mol%), KOAc (2 equivalents) in DMA
(entry 9 to 13). The 1.4 equivalent of 1a resulted in high yield,
85%, of 3a. The use of 1.5 and 1.6 equivalent of 1a furnished
eventually similar yields of 3a although with traces of
decarboxylative homodimerization (3a'). Furthermore, neither
additives such as TBAB and TBAI (entry 14 and 15) nor the use
of NMP or DMF as solvents (entry 16 and 17) showed any
improvement in the yield of 3a. This led to the identification of
optimized reaction condition as illustrated in table 1, entry 11.
The substrate scope and generality of decarboxylative
arylation was investigated under optimized condition and
results are summarized in table 2. The electron deficient aryl
bromides reacted with 1a to produce coupled products in
Results and Discussion
For initial optimization of reaction conditions, the
decarboxylative arylation between imidazo[1,2-a]pyridine-3-
carboxylic acid (1a) with 4-bromobenzonitrile (2a) in the
presence of catalytic amount of Pd(OAc)2 at 160 °C in DMA
solvent was selected as a model reaction. The results are
summarized in table 1.
Table 1. Optimization of Pd(OAc)2 catalysed decarboxylative arylationa,b
moderate to good yield (3i
-
3p). High reactivity was observed
2k 2n 2p
for most of the electron deficient aryl bromides (2i
-
,
-
Entry
1
2c
1a(equiv.)
1.2
Base (equiv.)
Ag2CO3 (2)
Ag2CO3 (1)
AgOAc (2)
KOAc (2)
Cu(OAc)2 (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
Pd(OAc)2 (equiv.)
0.10
3a(%)b
42
17
50
62
25
84
71
67
71
80
85
84
83
80
75
60
77
table 2, supporting information) with exception of 3-
bromobenzaldehyde (2m) which took 24 hrs to complete the
reaction. The ortho substituted aryl bromides furnished 3l in
68% yield. The longer reaction time in this case may be
attributed to the steric hindrance caused by ortho-substituent.
1.2
0.10
3
1.2
0.10
4
1.2
0.10
The
trisubstituted
2-bromo-4,6-dimethoxybenzaldehyde
5
1.2
0.10
successfully furnished 3q in modest yield. Furthermore,
electron rich aryl bromides successfully furnished 3b-3h in
moderate to high yields. In general, the electron rich aryl
bromides required longer reaction time compared to electron
deficient aryl bromides. 2e reacted sluggishly with 1a (5 days
reaction time) resulting in complex reaction mixture allowing
to isolate 3e in 20%. The reaction of bromo naphthalenes with
6
1.2
0.05
7
8c
1.2
0.02
1.2
0.01
9
1.2
0.02
10
11
12d
13d
14e
15f
16g
17h
1.3
0.02
1.4
0.02
1.5
0.02
1a produced 3g, 3h in high yield (91% and 95% respectively).
1.6
0.02
The reaction tolerated variety of electron withdrawing and
donating groups as shown in table 2.
1.4
0.02
1.4
0.02
The scope of the decarboxylative arylation was extended to
aryl chlorides and is shown in table 2 (condition l). Compound
3a, 3j and 3n were obtained in 44%, 58% and 85% respectively.
In this protocol when 4-chloroanisole, 2-chloronaphthalene, 1-
chloronaphthalene, and 4-chlorobezotrifluoride were treated
1.4
0.02
1.4
0.02
aReaction conditions: 1a
, 2a (0.1g, 1 equivalent), base, Pd(OAc)2 in 7 mL DMA at
160 °C for 24 hrs under N2 atmosphere. bisolated yields. cstarting material 1a was
present after 24 hrs of reaction time. dtraces of decarboxylative
homodimerization product 3a' observed. e0.5 equivalent of TBAB was used. 0.5
f
with 1a, the decarboxylative arylated products 3d, 3g, 3h and
equivalent of TBAI was used. gNMP was used as solvent. hDMF was used as
solvent.
3i were obtained in lower yields along with the
protodecarboxylation of 1a. The protodecarboxylation was the
only product isolated when 1a was treated with
chlorobenzene or 3-chlorobenzaldehyde or 4-chlorotoluene,
indicating limitation for some of the aryl chlorides in this
protocol.
The screening of various bases with 10 mol% Pd(OAc)2 resulted
in low to moderate yield of 3a (entry 1 to 5). Of note the use of
Ag2CO3 as base resulted in byproducts formation along with 3a
whilst the use of AgOAc slightly suppressed the byproduct
formation. Furthermore, use of KOAc (2 equivalent) produced
3a in moderate yields with negligible amounts of byproducts.
We were pleased to observe that the catalyst loading could be
reduced to 5 to 2 mol% with high yields of 3a along with
complete suppression of byproducts (entry 6, 7). This is in
agreement with the observation that the low catalytic loading
reduces colloid formation of Pd(0) species and hence increases
the efficiency of reaction as observed in Heck reaction
Further, the scope of reaction was studied with respect to
heteroaryl bromides (table 3). The decarboxylative arylation
between 1a with bromides of quinoline, isoquinoline, indole,
furan, thiophene, quinoxaline, and pyridine successfully
furnished diverse molecules (table 3, 3r-3y). These hybrid-
chemotypes are important as they contain various
heterocycles which are known to be the privileged scaffolds in
drug discovery.15 The heteroatom in these privileged motifs
often take part in various interactions with biological
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shown in supplementary information. bisolated yield. cfor 14 hrs. dfor 5 hrs. efor 20 hrs.
targets/proteins.16 The coupling of 3-bromoquinoline, 5-
i
j
ffor 5 days. gfor 24 hrs. hfor 3.5 hrs. for18 hrs. for 8 hrs. kfor 12 hrs. laryl chlorides (1
bromoisoquinoline and 4-bromo indole with 1a resulted 3r, 3s
equivalent) were used instead of aryl bromides with 1a (1.4 equivalents), KOAc (2
equivalents),
2 mol% Pd(OAc)2 in DMA at 160 °C under N2 atmosphere.
and 3t in high yields whereas 5-bromo indole gave 3u in 50%
yield. Presence of electron withdrawing groups like ester on
furan (3v) was tolerated. The 2-bromothiophene and 6-
Upon having successfully studied scope of the method with
respect to various aryl/heteroaryl bromides, we next turned
our attention to study the scope of method with respect to
various imidazo[1,2-a]pyridine-3-carboxylic acids. The results
of this study is summarized in table 4. Various imidazo[1,2-
bromoquinoxaline could produce 3w, 3x respectively in
moderate yield. The 3-bromopyridine successfully coupled
with 1a to produce 3y. The protocol tolerated free NH group in
indole substrate (3t, 3u).
a]pyridine-3-carboxylic acids 1b-1i were synthesized according
to the reported method or modifications therof.17 Details of
Table 2. Scope of aryl bromidesa,b
Table 3. Scope of heteroaryl bromidea,b
aReaction conditions: 1a (1.4 equivalents), 2r-2y (1 equivalent), KOAc (2 equivalents), 2
mol% Pd(OAc)2 in DMA at 160 °C under N2 atmosphere. Heteroaryl bromide structures
are shown in supplementary information. bisolated yield. cfor 3 hrs. dfor 12 hrs. efor 5
hrs.
ffor
36
hrs.
gfor
13
hrs.
hfor
4
hrs.
their synthesis has been described in the supporting
information. Imidazo[1,2-a]pyridine-3-carboxylic acids with
methyl substituent at various positions underwent
decarboxylative arylation with good yields (4a, 4c, 4f and 4g).
In addition, electron withdrawing groups like chloro,
trifluoromethyl on imidazo[1,2-a]pyridine-3-carboxylic acid
were well tolerated in the reaction
(4h, 4k and 4l).
Furthermore, we were pleased to find that the reaction is
applicable to substituted imidazo[1,2-a]pyridine-3-carboxylic
acids with various heteroaryl bromides producing 4b
4i 4j and 4m in various yields.
, 4d, 4e,
,
aReaction conditions: 1a (1.4 equivalents), 2b-2q (1 equivalent), KOAc (2 equivalents), 2
mol% Pd(OAc)2 in DMA at 160 °C under N2 atmosphere. Aryl bromide structures are
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Table 4. Scope of substituted imidazo[1,2-a]pyridine-3-carboxylic acids with
hetero(aryl) bromidea,b
Scheme 1. Scope of various heterocyclic acids with aryl bromides
The scope of the ligand-free Pd-catalysed decarboxylative
arylation reaction was further extended to different
heterocyclic acids as shown in scheme 1. The 2-
thiophenecarboxylic acid, 2,4-disubstituted thiazole-5-
carboxylic acid underwent decarboxylative arylation with 2a
and produced 5a (21%) and 5b (59%) respectively. Further, N-
substituted indole 2-carboxylic acid produced 2-arylated N-
substituted indole 5c (43%) with minor amount of 3-arylated
N-substituted indole 5c' (7%). When benzofuran-2-carboxylic
acid was used in the protocol, the expected 2-arylated
benzofuran 5d was obtained in 34% yield along with 12% 2,3-
diarylated benzofuran 5d'
.
The previous study on decarboxylative arylation of 1a with aryl
chloride in the presence of palladium acetate, S-Phos are
reported by Wu et al and proposed via Pd(0) species.10 The
generation of Pd(0) species was proposed through
decarboxylative homocoupling of 1a, although formation of
homodimer 3a' in the presence of aryl chloride was not
observed. To understand the decarboxylative arylation
process, we submitted 1a under standard condition without
aryl bromide and isolated 74% homodimer 3a', while in the
absence of aryl chloride, Wu et al isolated homodimer 3a' in
98%10 yield. Additionally, we observed 3a' only in the cases
where excess (1.5 equivalent and more; entry 12 and 13 in
table 1) of 1a with 2a (1 equivalent) was used indicating the
formation of 3a' may be a consequence of excess amount of
1a. Based on these observations a plausible mechanism for
decarboxylative arylation is proposed and is shown in scheme
2.
aReaction conditions: 1b-1i (1.4 equivalents), aryl/heteroaryl bromide (1 equivalent),
KOAc (2 equivalents), 2 mol % Pd(OAc)2 in DMA at 160 °C under N2 atmosphere. aryl
and heteroaryl bromide structures are shown in supplementary information. bisolated
yield. cfor 12 hrs. dfor 4 hrs. efor 18 hrs. ffor 2 days. gfor 6 hrs
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more potent and drug like compounds. Further, generation of
new heteroaryl-hetero(aryl) motif will find importance in drug
discovery.
Pd(OAc)2
ref 13b, 16
Ar1Br
Experimental
Ar1 Ar2
Pd(0)
In a typical procedure, the mixture of
2 (0.1g, 1 equivalent), 1
I
or heterocyclic acids [2-thiophenecarboxylic acid/2,4-
disubstituted thiazole-5-carboxylic acid/N-substituted indole 2-
carboxylic acid/ benzofuran-2-carboxylic acid] (1.4 equivalent),
Pd(OAc)2 (2 mol%), KOAc (2 equivalent) in 7 mL DMA were
stirred at 160 °C. The progress of reaction was monitored
through TLC. Upon completion of the reaction, the mixture
was diluted with 200 mL of water and extracted with ethyl
acetate (2x70 mL). The ethyl acetate layer was washed with
water (200 mL), brine (100 mL) and dried with sodium sulfate.
The organic solvent evaporated under vacuum and residue
was purified by column chromatography to afford pure 3-aryl
II Ar1 Pd Br
Ar1 Pd Ar2
IV
III
Ar1 Pd Br
KO
HO
Ar2
CO2, KBr
KOAc
Ar2
O
O
Scheme 2. Plausible mechanism of decarboxylative arylation
imidazo[1,2-a]pyridines 3 or 4.
The catalytic cycle begins with formation of Pd(0) species I in
the reaction. Formation of Pd(0) species from Pd(OAc)2
catalysed Heck reaction in ligand-free condition at high
4-(Imidazo[1,2-a]pyridin-3-yl)benzonitrile (3a).12 Yellow solid.
1
Yield: 102 mg (85%). mp= 177°C; H NMR (400 MHz, CDCl3): δ
14
temperature has been reported by de Vries et al.13b, The
8.37 (dt, J = 7.0, 1.1 Hz, 1H), 7.82-7.78 (m, 3H), 7.74-7.68 (m,
3H), 7.31-7.25 (m, 1H), 6.91 (td, J = 6.9, 1.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 147.2, 134.3, 134.1, 133.2 (x2), 127.8 (x2),
125.4, 124.1, 123.3, 118.8, 118.6, 113.6, 111.4; HRMS (ESI-
MS): Calc. for C14H10N3 [(M+H)+]: 220.0869, Found: 220.0891.
3-(p-Tolyl)imidazo[1,2-a]pyridine (3b).12 Yellow solid. Yield:
110 mg (90%). mp= 78-80°C; 1H NMR (500 MHz, CDCl3): δ 8.31
(d, J = 7.0 Hz, 1H), 7.69-7.64 (m, 2H), 7.45 (d, J = 8.1 Hz, 2H),
7.33 (d, J = 8.1 Hz, 1H), 7.21-7.16 (m, 1H), 6.80 (td, J = 6.8, 1.1
Hz, 1H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 146.0,
138.3, 132.4, 128.2, 126.4, 125.9, 124.2, 123.5, 118.4, 112.5,
21.5; HRMS (ESI-MS):Calc. for C14H13N2 [(M+H)+]: 209.1073,
Found: 209.1062.
Pd(0) initially is in soluble palladium cluster form13b which
further can form insoluble palladium black. Hence such
ligandless systems work well with low catalyst loading so as to
avoid the insoluble palladium black formation due to
aggregation.9b,
13b, 18
We observed that the yield of arylated
product decreased in case of 10 mol% Pd(OAc)2 as compared
to 5 mol% Pd(OAc)2 (entry 4 and 6, table 1) which probably is
due to the formation of palladium black. The next step in
plausible mechanism is the oxidative addition of aryl bromide
to
I resulting in intermediate II. This palladium (II) complex
coordinates with carboxylate and forms intermediate III which
upon decarboxylation collapses in intermediate IV. Finally,
reductive elimination converts Pd(II) to Pd(0) with release of 3-
aryl imidazo[1,2-a]pyridine.
3-phenylimidazo[1,2-a]pyridine (3c).12 Brown liquid. Yield: 115
1
mg (92%) H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.0 Hz, 1H),
Finally compounds were screened on bacteria panel consisting
of E. coli, S. aureus, P. aeruginosa, K. pneumoniae and A.
baumannii. The MIC of active compounds was determined and
was defined as the lowest concentration of a compound that
7.67 (s, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.57-7.45 (m, 4H), 7.38 (t, J
= 7.5 Hz, 1H), 71.6 (t, J = 7.5 Hz, 1H), 6.77 (t, J = 6.7 Hz, 1H); 13
C
NMR (100 MHz, CDCl3): δ 146.0, 132.4, 129.2, 128.1, 127.9,
125.6, 124.2, 123.3, 118.1, 112.5; HRMS (ESI-MS): Calc. for
C13H10N2Na [(M+Na)+]: 217.0736, Found: 217.0729.
inhibited visible growth of bacteria after 24 hrs. Compound 3i
,
4l, 4f and 3h showed MIC of 50, 50, 25 and 50 µM against S.
3-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3d).9b Brown
solid. Yield: 75 mg (63%). mp= 116°C; 1H NMR (500 MHz,
CDCl3): δ 8.25 (dt, J = 7.0, 1.1 Hz, 1H), 7.66 (d, J = 10.0 Hz, 1H),
7.63 (s, 1H), 7.50-7.45 (m, 2H), 7.20-7.15 (m, 1H), 7.08-7.03
(m, 2H), 6.78 (td, J = 6.8, 1.1 Hz, 1H), 3.88 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 159.8, 145.9, 132.1, 129.8, 125.7, 124.1, 123.4,
121.7, 118.3, 114.8, 112.5, 55.6; HRMS (ESI-MS):Calc. for
C14H13N2O [(M+H)+]: 225.1022, Found: 225.1013.
aureus respectively. Modifications of 4f are in progress to
obtain more potent analogues and the results pertaining to
this will be published in due course.
Conclusion
In summary, we have successfully developed a facile ligand-
free palladium catalysed decarboxylative arylation reaction of
imidazo[1,2-a]pyridine-3-carboxylic acids with various aryl and
heteroaryl bromides. This method provides a broad substrate
scope and excellent functional group tolerance. The protocol is
applied to generate heteroaryl-hetero(aryl) motifs and few of
these motifs showed antibacterial activity against S. aureus.
The efforts are underway to modify these motifs to obtain
4-(Imidazo[1,2-a]pyridin-3-yl)-N,N-dimethylaniline
(3e).9b
Yellow solid. Yield: 23 mg (20%). mp= 128°C; 1H NMR (500
MHz, CDCl3): δ 8.27 (dt, J = 7.0, 1.1 Hz, 1H), 7.64 (d, J = 10.0 Hz,
1H), 7.60 (s, 1H), 7.44-7.38 (m, 2H), 7.17-7.12 (m, 1H), 6.87-
6.81 (m, 2H), 6.76 (td, J = 6.8, 1.1 Hz, 1H), 3.03 (s, 6H); 13C NMR
(125 MHz, CDCl3): δ 150.5, 145.6, 131.4, 129.4, 126.3, 123.8,
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123.6, 118.1, 116.7, 112.8, 112.3, 40.5; HRMS (ESI-MS):Calc. 1H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.2, 145.6,
for C15H15N3Na [(M+Na)+]: 260.1158, Found: 260.1171.
133.0, 132.7, 132.2, 131.3, 131.2, 129.4, 129.1, 124.7, 124.1,
3-(3-Methoxyphenyl)imidazo[1,2-a]pyridine (3f).9e White 124.0, 117.9, 112.4, 52.4; HRMS (ESI-MS):Calc. for C15H13N2O2
solid. Yield: 95 mg (79%). mp= 110°C; 1H NMR (500 MHz, [(M+H)+]: 253.0972, Found: 253.0983.
CDCl3): δ 8.37 (dt, J = 7.0, 1.1 Hz, 1H), 7.70 (s, 1H), 7.68 (dt, J = 3-(Imidazo[1,2-a]pyridin-3-yl)benzaldehyde (3m).9b Yellow
9.1, 1.1 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.23-7.18 (m, 1H), 7.17- solid. Yield: 100 mg (83%). mp= 76°C; 1H NMR (500 MHz,
7.14 (m, 1H), 7.11-7.07 (m, 1H), 6.99-6.93 (m, 1H ), 6.82 (td, J = CDCl3): δ 10.11 (s, 1H), 8.35 (dt, J = 7.0, 1.1 Hz, 1H), 8.10 (t, J =
6.9, 1.1 Hz, 1H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 1.6 Hz, 1H), 7.93 (dt, J = 7.6, 1.4 Hz, 1H), 7.85 (dt, J = 7.6, 1.4
160.4, 146.3, 132.7, 130.7, 130.5, 125.8, 124.4, 123.7, 120.4, Hz, 1H), 7.79 (s, 1H), 7.75-7.69 (m, 2H), 7.30-7.22 (m, 1H), 6.88
118.4, 113.9, 113.7, 112.7, 55.5; HRMS (ESI-MS):Calc. for (td, J = 7.0, 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 191.9,
C14H13N2O [(M+H)+]: 225.1022, Found: 225.1032.
146.6, 137.4, 133.8, 133.2, 130.6, 130.2, 129.7, 128.4, 125.0,
3-(Naphthalen-2-yl)imidazo[1,2-a]pyridine (3g).9e Brown 124.5, 123.2, 118.5, 113.3; HRMS (ESI-MS):Calc. for C14H11N2O
1
liquid. Yield: 108 mg (91%). H NMR (500 MHz, CDCl3): δ 8.43 [(M+H)+]: 223.0866, Found: 223.0878.
(d, J = 6.9 Hz, 1H), 8.01 (s, 1H), 8.97 (d, J = 8.4 Hz, 1H), 7.92- 3-(4-Nitrophenyl)imidazo[1,2-a]pyridine (3n).9b Yellow solid.
1
7.88 (m, 2H), 7.81 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.64 (d, J = Yield: 95 mg (80%). mp= 185°C; H NMR (500 MHz, CDCl3): δ
9.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 6.85 (t, J 8.42 (d, J = 7.0 Hz, 1H), 8.40-8.36 (m, 2H), 7.86 (s, 1H), 7.78-
= 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 146.1, 133.7, 133.0, 7.75 (m, 2H),7.74 (d, J = 9.1 Hz, 1H), 7.34-7.27 (m, 1H), 6.94
132.5, 129.2, 128.1, 128.0, 126.9 (overlapped), 126.7, 126.6, (td, J = 7.0, 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 147.4,
125.9, 125.8, 123.5, 118.3, 113.0; HRMS (ESI-MS):Calc. for 147.0, 136.0, 134.7, 127.7, 125.6, 124.9, 123.8, 123.4, 118.9,
C17H13N2 [(M+H)+]: 245.1073, Found: 245.1085.
113.8; HRMS (ESI-MS):Calc. for C13H10N3O2 [(M+H)+]: 240.0768,
3-(Naphthalen-1-yl)imidazo[1,2-a]pyridine (3h).9e Yellow Found: 240.0776.
semisolid. Yield: 100 mg (84%). 1H NMR (400 MHz, CDCl3): δ 2-Fluoro-5-(imidazo[1,2-a]pyridin-3-yl)benzonitrile
(3o).19
1
8.02-7.94 (m, 2H), 7.79 (s, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.70 (d, Brown solid. Yield: 50 mg (42%). mp= 217-219°C; H NMR (500
J = 6.9 Hz, 1H), 7.61-7.56 (m, 2H), 7.56-7.48 (m, 2H), 7.46-7.38 MHz, DMSO-d6): δ 8.61 (dt, J = 7.0, 1.1 Hz, 1H), 8.27 (dd, J =
(m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.68 (t, J = 6.8 Hz, 1H); 13C NMR 6.1, 2.3 Hz, 1H), 8.11-8.06 (m, 1H), 7.86 (s, 1H), 7.73-7.65 (m,
(100 MHz, CDCl3): δ 145.9, 134.0, 133.8, 132.1, 129.7, 129.2, 2H), 7.38-7.33 (m, 1H), 7.00 (td, J = 7.0, 1.1 Hz, 1H); 13C NMR
128.8, 127.0, 126.4, 126.3, 125.7, 125.2, 124.4, 124.1, 123.7, (100 MHz, DMSO-d6): δ 161.7 (d, J = 256.4 Hz), 145.9, 135.3 (d,
118.1, 112.3; HRMS (ESI-MS):Calc. for C17H12N2Na [(M+Na)+]: J = 8.5 Hz), 133.6, 132.7, 126.7 (d, J = 3.2 Hz), 125.3, 124.4,
267.0893, Found: 267.0909.
122.4, 120.5, 117.6 (d, J = 19.8 Hz), 117.5, 113.8, 113.2; HRMS
(3i).9b (ESI-MS):Calc. for C14H9FN3 [(M+H)+]: 238.0775, Found:
3-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridine
Yellow solid. Yield: 100 mg (85%). mp= 152°C; 1H NMR (500 238.0774.
MHz, CDCl3): δ 8.36 (dt, J = 7.0, 1.1 Hz, 1H), 7.81-7.74 (m, 3H), 3-(2,4-Difluorophenyl)imidazo[1,2-a]pyridine (3p). White
7.74- 7.67 (m, 3H), 7.29-7.21 (m, 1H), 6.88 (td, J = 7.0, 1.1 Hz, solid. Yield: 75 mg (63%). mp= 95°C; 1H NMR (500 MHz, CDCl3):
1H); 13C NMR (125 MHz, CDCl3): δ 146.8, 133.7, 133.1, 130.2, δ 7.94 (dt, J = 7.0, 1.1 Hz, 1H), 7.73-7.66 (m, 2H), 7.52-7.45 (m,
129.9, 128.0, 126.4, 124.5, 123.3, 118.7, 113.2; HRMS (ESI- 1H), 7.26-7.21 (m, 1H), 7.08-6.98 (m, 2H), 6.84 (td, J = 7.0, 1.1
MS):Calc. for C14H10F3N2 [(M+H)+]: 263.0791, Found: 263.0821. Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 163.4 (dd, J = 251.4, 11.7
1-(4-(Imidazo[1,2-a]pyridin-3-yl)phenyl)ethanone
(3j).9b Hz), 160.3 (dd, J = 251.5, 11.7 Hz), 146.5, 134.0, 132.4(AB q, J =
Yellow solid. Yield: 95 mg (80%). mp= 164°C; 1H NMR (400 4.7 Hz), 124.7, 124.2 (d, J =3.7 Hz), 119.3, 118.3, 113.5 (dd, J
MHz, CDCl3): δ 8.40 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), =15.2, 3.3 Hz), 112.7, 112.4 (dd, J = 21.6, 3.4 Hz), 105.0 (t, J
7.80 (s, 1H), 7.75-7.65 (m, 3H), 7.28-7.21 (m, 1H), 6.88 (t, J = =25.6
Hz);
HRMS
(ESI-MS):Calc.
for
C13H9F2N2
6.8 Hz, 1H), 2.66 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 197.1, [(M+H)+]:231.0728, Found: 231.0734.
146.8, 136.1, 133.9, 133.7, 129.3, 127.2, 124.8, 124.7, 123.4, 6-(Imidazo[1,2-a]pyridin-3-yl)-2,3dimethoxybenzaldehyde
1
118.4, 113.1, 26.6; HRMS (ESI-MS):Calc. for C15H13N2O (3q). Yellow semisolid. Yield: 60 mg (52%). H NMR (400 MHz,
[(M+H)+]: 237.1022, Found: 237.1032.
CDCl3) δ: 9.68 (s, 1H), 7.93 (dt, J = 6.8, 1.0 Hz, 1H), 7.72 (dt, J =
Methyl 4-(imidazo[1,2-a]pyridin-3-yl)benzoate (3k).9b Yellow 9.1, 1.0 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.29-7.23 (m, 1H),
solid. Yield: 60 mg (51%); mp= 145°C; 1H NMR (400 MHz, 6.93 (s, 1H), 6.84 (dt, J = 6.8, 1.0 Hz, 1H), 4.02 (s, 3H), 3.96 (s,
CDCl3): δ 8.40 (dt, J = 7.0, 1.1 Hz, 1H), 8.21-8.15 (m, 2H), 7.80 3H); 13C NMR (125 MHz, CDCl3) δ: 189.9, 154.4, 150.2, 146.2,
(s, 1H), 7.71 (dt, J = 9.1, 1.0 Hz, 1H), 7.68-7.64 (m, 2H), 7.29- 134.9, 128.8, 126.7, 125.1, 123.3, 120.5, 118.3, 113.4, 113.1,
7.22 (m, 1H), 6.88 (td, J = 7.0, 1.1 Hz, 1H), 3.97 (s, 3H); 13C NMR 109.6, 56.6, 56.4; HRMS (ESI-MS):Calc. for C16H15N2O3
(100 MHz, CDCl3): δ 166.7, 146.7, 133.9, 133.7, 130.7, 129.4, [(M+H)+]: 283.1077, Found: 283.1095.
127.4, 125.0, 123.5, 118.6, 113.2, 52.4; HRMS (ESI-MS):Calc. 3-(Imidazo[1,2-a]pyridin-3-yl)quinoline (3r).9b Brown solid.
1
for C15H13N2O2 [(M+H)+]: 253.0972, Found: 253.0985.
Yield: 90 mg (76%). mp= 140°C; H NMR (500 MHz, CDCl3): δ
Methyl 2-(imidazo[1,2-a]pyridin-3-yl)benzoate (3l).9b Yellow 9.13 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 6.9 Hz, 1H), 8.33 (d, J = 2.1
semisolid. Yield: 80 mg (68%). 1H NMR (500 MHz, CDCl3): δ Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.87 (s,
8.10 (dd, J = 8.0, 1.1 Hz, 1H), 7.76-7.70 (m, 2H), 7.66 (td, J = 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.64 (t, J =
7.6, 1.4 Hz, 1H), 7.62 (s, 1H), 7.57 (td, J = 7.6, 1.4 Hz, 1H), 7.48 7.2 Hz, 1H), 7.31-7.24 (m, 1H), 6.90 (t, J = 6.8 Hz, 1H); 13C NMR
(dd, J = 7.6, 1.4 Hz, 1H), 7.24-7.20 (m, 1H), 6.77 (t, d, J = 6.8 Hz, (125 MHz, CDCl3): δ 149.9, 147.5, 146.8, 133.9, 133.8, 130.1,
6 | J. Name., 2012, 00, 1-3
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129.5, 127.9 (x2), 127.6, 125.0, 123.1, 122.8, 122.6, 118.6, 3-(Pyridin-3-yl)imidazo[1,2-a]pyridine (3y).9b Brown semisolid.
113.2; HRMS (ESI-MS):Calc. for C16H11N3Na [(M+Na)+]: Yield: 60 mg (49%). 1H NMR (400 MHz, CDCl3): δ 8.84 (d, J = 2.2
268.0845, Found: 268.0858.
Hz, 1H), 8.65 (dd, J = 1.6, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.90-
5-(Imidazo[1,2-a]pyridin-3-yl)isoquinoline (3s). Brown solid. 7.84 (m, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.45 (dd, J =
1
Yield: 85 mg (73%). mp= 133°C; H NMR (500 MHz, CDCl3) δ 4.9, 3.0 Hz, 1H), 7.28-7.22 (m, 1H), 6.88 (td, J = 6.8, 1.0 Hz, 1H);
9.38 (d, J = 1.2 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 8.2 13C NMR (125 MHz, CDCl3): δ 149.3, 148.9, 146.7, 135.2, 133.4,
Hz, 1H), 7.86 (dd, J = 7.1, 1.2 Hz, 1H), 7.82 (s, 1H), 7.80-7.73 (m, 125.7, 125.0, 124.0, 123.0, 122.3, 118.5, 113.2; HRMS (ESI-
3H), 7.39 (d, J = 6.0 Hz, 1H), 7.30-7.25 (m, 1H), 6.78 (td, J = 6.8, MS):Calc. for C12H9N3Na [(M+Na)+]: 218.0689, Found:
1.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 153.3, 146.2, 144.1, 218.0684.
134.8, 134.2, 133.0, 129.1, 127.3, 125.7, 124.9, 123.8, 122.1, 4-(6-methylimidazo[1,2-a]pyridin-3-yl)benzonitrile
118.3, 118.0, 112.9; HRMS (ESI-MS):Calc. for C16H12N3 White solid. Yield: 100 mg (78%). mp= 152-154°C; 1H NMR (400
[(M+H)+]: 246.1026, Found: 246.1034.
MHz, CDCl3): δ 8.13 (s, 1H), 7.82-7.76 (m, 2H), 7.73 (s, 1H),
(4a).
3-(1H-Indol-4-yl)imidazo[1,2-a]pyridine (3t). Brown solid. 7.71-7.65 (m, 2H), 7.60 (d, J = 15.8 Hz, 1H), 7.12 (dd, J = 9.2, 1.6
Yield: 60 mg (50%). mp= 198-200°C; 1H NMR (500 MHz, CDCl3): Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 146.2,
δ 8.55 (bs, 1H), 8.22 (dt, J = 7.0, 1.1 Hz, 1H), 7.85 (s, 1H), 7.72 134.3, 134.0, 133.1 (x2), 128.5, 127.7 (x2), 123.7, 123.3, 120.8,
(dt, J = 9.1, 1.0 Hz, 1H), 7.50 (dt, J = 7.5, 1.0 Hz, 1H),7.36-7.30 118.7, 117.9, 111.7, 18.5; HRMS (ESI-MS):Calc. for C15H12N3
(m, 2H), 7.29 (t, J = 2.8 Hz, 1H), 7.24-7.19 (m, 1H), 6.77 (td, J = [(M+H)+]: 234.1026, Found: 234.1033.
6.8, 1.1 Hz, 1H), 6.43-6.39 (m, 1H); 13C NMR (100 MHz, CDCl3): 3-(6-Methylimidazo[1,2-a]pyridin-3-yl)quinoline (4b). Brown
δ 145.9, 136.4, 132.7, 126.8, 125.2, 124.8, 124.4, 122.3, 121.0, solid. Yield: 120 mg (96%). mp= 138-140°C; 1H NMR (500 MHz,
120.6, 118.0, 112.2, 111.7, 102.2; HRMS (ESI-MS):Calc. for CDCl3): δ 9.12 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.18
C15H11N3Na [(M+Na)+]: 256.0845, Found: 256.0867.
(d, J = 8.4 Hz, 1H), 8.15(s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.81 (s,
3-(1H-Indol-5-yl)imidazo[1,2-a]pyridine (3u). Brown semisolid. 1H), 7.80-7.76 (m, 1H), 7.69-7.60 (m, 2H), 7.13 (dd, J = 9.2, 1.4
1
Yield: 60 mg (50%). H NMR (500 MHz, CDCl3): δ 9.27 (bs, 1H), Hz, 1H), 2.34 (d, J = 0.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
8.36 (d, J = 7.0, Hz, 1H), 7.83 (s, 1H), 7.71(s, 1H), 7.67 (d, J = 9.1 150.0, 147.5, 145.9, 134.1, 133.6, 130.1, 129.6, 128.3, 128.0,
Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.15 127.9, 127.6, 123.1, 123.0, 122.3, 120.7, 117.9, 18.5; HRMS
(m, 1H), 6.78 (td, J = 6.8, 0.9 Hz, 1H), 6.66-6.60 (m, 1H); 13C (ESI-MS):Calc. for C17H14N3 [(M+H)+]: 260.1182, Found:
NMR (125 MHz, CDCl3): δ 145.6, 135.9, 131.7, 128.6, 127.3, 260.1194.
125.7, 124.1, 123.7, 122.6, 120.9, 120.3, 117.9, 112.4, 112.1, 3-(7-Methylimidazo[1,2-a]pyridin-3-yl)benzaldehyde
(4c).
102.7; HRMS (ESI-MS):Calc. for C15H12N3 [(M+H)+]: 234.1026, Yellow solid. Yield: 110 mgs (85%). mp= 80-82°C; H NMR (500
Found: 234.1056. MHz, CDCl3): δ 10.10 (s, 1H), 8.23 (d, J = 7.0 Hz, 1H), 8.07 (s,
Methyl 5-(imidazo[1,2-a]pyridin-3-yl)furan-2-carboxylate 1H), 7.89 (dt, J = 7.6, 1.2 Hz, 1H), 7.82 (dt, J = 7.7, 1.9, 1.2 Hz,
1
(3v).20 Yellow solid. Yield: 34 mg (40%). mp= 133-135°C; 1H 1H), 7.70 (s, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 6.69 (dd, J
NMR (500 MHz, CDCl3): δ 8.85 (dt, J = 7.0, 1.1 Hz, 1H), 8.02 (s, = 7.0, 1.5 Hz, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
1H), 7.72 (dt, J = 9.1, 1.0 Hz, 1H), 7.35-7.19 (m, 2H), 7.00 (td, J 191.9, 147.2, 137.3, 135.9, 133.6, 133.2, 130.9, 130.2, 129.4,
= 6.9, 1.0 Hz, 1H), 6.72 (d, J = 3.6, 1.0 Hz, 1H), 3.94 (s, 3H); 13
NMR (125 MHz, CDCl3): δ 159.1, 149.0, 146.9, 143.2, 134.5, for C15H13N2O [(M+H)+]: 237.1022, Found: 237.1033.
125.9, 125.8, 119.9, 118.3, 116.7, 114.0, 107.4, 52.1; HRMS Methyl 5-(7-methylimidazo[1,2-a]pyridin-3-yl)furan-2-
(ESI-MS):Calc. for C13H10N2NaO3 [(M+Na)+]: 265.0584, Found: carboxylate (4d). Yellow solid. Yield: 23 mg (18%). mp= 124°C;
C
128.2, 123.9, 122.5, 116.9, 115.8, 21.4; HRMS (ESI-MS):Calc.
265.0607.
1H NMR (500 MHz, CDCl3): δ 8.69 (d, J = 7.1 Hz, 1H), 7.92 (s,
3-(Thiophen-2-yl)imidazo[1,2-a]pyridine (3w).21 Yellow oil. 1H), 7.44 (s, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.80 (dd, J = 7.1, 1.6
Yield: 92 mg (75%). H NMR (400 MHz, CDCl3): δ 8.40 (d, J = Hz, 1H), 6.65 (d, J = 3.6, Hz, 1H), 3.93 (s, 3H), 2.43 (s, 3H); 13C
1
4.9, Hz, 1H), 7.77 (s, 1H); 7.68(d, J = 9.1 Hz, 1H), 7.44 (dd, J = NMR (125 MHz, CDCl3): δ 159.1, 149.2, 147.3, 143.0, 137.1,
5.2, 1.2 Hz, 1H), 7.29 (dd, J = 3.6, 1.1 Hz, 1H), 7.25-7.22 (m, 134.2, 125.1, 120.0, 116.6, 116.1, 106.9, 52.1, 21.4; HRMS (ESI-
1H), 7.22-7.18 (m, 1H), 6.87 (t, J = 6.8, 1.1 Hz, 1H); 13C NMR MS):Calc. for C14H13N2O3 [(M+H)+]: 257.0921, Found: 257.0937.
(100 MHz, CDCl3): δ 146.2, 133.5, 129.9, 127.8, 125.9 (x2), 7-Methyl-3-(pyridin-3-yl)imidazo[1,2-a]pyridine (4e). Yellow
124.5, 123.8, 119.2, 118.0, 112.9; HRMS (ESI-MS):Calc. for semisolid. Yield: 55 mg (42%). 1H NMR (500 MHz, CDCl3): δ
C11H9N2S [(M+H)+]: 201.0481, Found: 201.0476.
8.81 (s, 1H), 8.61 (d, J = 4.8, 1.5 Hz, 1H), 8.15 (d, J = 7.0 Hz, 1H),
6-(Imidazo[1,2-a]pyridin-3-yl)quinoxaline (3x). Yellow solid. 7.86-7.81 (m, 1H), 7.66 (s, 1H), 7.47-7.38 (m, 2H), 6.68 (d, J =
Yield: 62 mg (50%). mp= 143-145°C; 1H NMR (400 MHz, CDCl3): 7.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 148.1,
δ 8.91 (d, J = 1.8, Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 147.8, 146.2, 135.2, 134.1, 132.0, 124.9, 123.0, 121.3, 120.9,
7.0 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.03 115.8, 114.9, 20.4; HRMS (ESI-MS):Calc. for C13H11N3Na
(dd, J = 8.7, 2.0 Hz, 1H), 7.93 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), [(M+Na)+]: 232.0845, Found: 232.0835.
7.33-7.27 (m, 1H), 6.93 (td, J = 6.8, 1.1 Hz, 1H); 13C NMR (100 8-Methyl-3-(naphthalen-2-yl)imidazo[1,2-a]pyridine
(4f).
MHz, CDCl3): δ 147.0, 145.9, 145.2, 143.5, 142.5, 134.2, 131.3, Yellow solid. Yield: 61 mg (49%). mp= 106°C. 1H NMR (400
130.8, 130.1, 126.5, 125.3, 124.5, 123.5, 118.6, 113.5; HRMS MHz, CDCl3): δ 8.31 (d, J = 6.9 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J =
(ESI-MS):Calc. for C15H11N4 [(M+H)+]: 247.0978, Found: 8.5 Hz, 1H), 7.92-7.85 (m, 2H), 7.80 (s, 1H), 7.66 (d, J = 8.5 Hz,
247.0991.
1H), 7.59-7.50 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 6.76 (t, J = 6.8
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Hz, 1H), 2.68 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 146.7, 5-(2-Methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-
1
133.7, 132.9, 132.3, 129.1, 128.1, 127.9, 127.0, 126.8 (x2), yl)isoquinoline (4m). Yellowish liquid. Yield: 118 mg (75%). H
126.6, 126.3, 126.0, 123.4, 121.4, 112.9, 17.2; HRMS (ESI- NMR (500 MHz, CDCl3): δ 9.38 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H),
MS):Calc. for C18H15N2[(M+H)+]: 259.123, Found: 259.1237
8.15 (d, J = 8.0 Hz, 1H), 7.82-7.75 (m, 2H), 7.67 (d, J = 6.9 Hz,
4-(2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)benzonitrile (4g). 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.15 (d, J = 5.8 Hz, 1H), 6.75 (t, J =
White solid. Yield: 114 mg (84%). mp= 169-171°C; 1H NMR (400 7.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.4,
MHz, CDCl3): δ 8.01 (d, J = 7.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.60- 144.3, 144.2, 140.6, 134.9, 130.0, 129.6, 129.2, 127.4, 126.8,
7.55 (m, 2H), 7.35 (s, 1H), 6.63 (dd, J = 7.0, 1.6 Hz, 1H), 2.48 (s, 125.1, 123.0, 123.1 (q, J = 272.1 Hz, CF3), 122.9, 119.4, 117.7,
3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 145.9, 142.4, 110.6, 14.2; HRMS (ESI-MS):Calc. for C18H12F3N3Na [(M+Na)+]:
136.3, 135.6, 134.7, 133.0, 129.3, 122.1, 119.3, 118.8, 115.9, 350.0876, Found: 350.0911.
115.3, 111.0, 21.4, 14.3; HRMS (ESI-MS):Calc. for C16H14N3 4-(Thiophen-2-yl)benzonitrile (5a).22 Yellow solid. Yield: 44 mg
[(M+H)+]:248.1182, Found: 248.1209.
(21%). mp= 79-81°C; 1H NMR (400 MHz, CDCl3): δ 7.71-7.68 (m,
6-Chloro-3-(p-tolyl)imidazo[1,2-a]pyridine
(4h).
Brown 2H), 7.67-7.64(m, 2H), 7.43-7.39 (m, 2H), 7.13 (dd, J = 5.1, 3.7
semisolid. Yield: 45 mg (32%). 1H NMR (500 MHz, CDCl3): δ Hz, 1H); 13C NMR (100 MHz, CDCl3): 142.2, 138.8, 132.9 (x2),
8.83 (dd, J = 1.9, 0.7 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 9.2 Hz, 128.7, 127.0, 126.2 (x2), 125.2, 119.0, 110.7; HRMS (ESI-
1H), 7.42 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.15 (dd, J MS):Calc. for C11H7NNaS [(M+Na)+]: 208.0191, Found:
= 9.5, 1.9 Hz, 1H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 208.0194.
144.3, 138.9, 134.5, 133.0, 130.2, 128.2, 126.5, 126.1, 125.7, 4-(2,4-dimethylthiazol-5-yl)benzonitrile (5b).23 Yellow solid.
1
121.4, 121.1, 118.6, 118.3, 21.5; HRMS (ESI-MS):Calc. for Yield: 70 mg (59%). mp= 69-70°C; H NMR (400 MHz, CDCl3):
C14H12ClN2 [(M+H)+]: 243.0684, Found: 243.0704.
7.69 (d, J = 8.5, Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 2.71 (s, 3H),
6-(6-Chloroimidazo[1,2-a]pyridin-3-yl)quinoxaline (4i). Yellow 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): 165.0, 148.9, 137.3,
solid. Yield: 75 mg (55%). mp= 222°C; 1H NMR (500 MHz, 132.6 (x2), 129.6 (x2), 118.7, 111.1, 19.3, 16.5; HRMS (ESI-
CDCl3): δ 9.92 (d, J = 1.7 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.57 MS):Calc. for C12H11N2S [(M+H)+]: 215.0637, Found: 215.0645.
(d, J = 1.3 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 8.7 Hz, 4-(1-phenyl-1H-indol-2-yl)benzonitrile (5c).24 Yellow solid.
1H), 7.99 (dd, J = 8.7, 1.9 Hz, 1H), 7.93 (s, 1H), 7.70 (d, J = 9.5 Yield: 70 mg (43%). mp= 184-186°C; 1H NMR (400 MHz, CDCl3):
Hz, 1H), 7.28-7.23 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 146.0, 7.76-7.72 (m, 1H), 7.57-7.53 (m, 2H), 7.50-7.47 (m, 2H), 7.43-
145.5, 145.4, 143.5, 142.8, 135.0, 131.1, 130.7, 130.0, 127.0, 7.46 (m, 1H), 7.37-7.40 (m, 2H), 7.31-7.34 (m, 1H), 7.27-7.30
126.6, 125.1, 122.0, 121.4, 119.1; HRMS (ESI-MS):Calc. for (m, 2H), 7.27-7.26 (m, 1H), 7.21-7.25 (m, 1H), 6.95 (S, 1H); 13C
C15H10ClN4 [(M+H)+]: 281.0589, Found: 281.0603.
NMR (100 MHz, CDCl3):139.8, 138.5, 138.1, 137.1, 132.1 (x2),
6-Chloro-3-(thiophen-2-yl)imidazo[1,2-a]pyridine (4j). Green 129.7 (x2), 129.0 (x2), 128.0 (x2), 127.9, 123.6, 121.3, 121.1,
semisolid. Yield: 88 mg (62%). 1H NMR (400 MHz, CDCl3): δ 118.9, 110.9, 110.6, 105.8; HRMS (ESI-MS):Calc. for C21H14N2Na
8.40 (dd, J = 2.0, 0.8 Hz, 1H), 7.77 (s, 1H), 7.63 (dd, J = 9.5, 0.8 [(M+Na)+]: 317.1049, Found: 317.1059.
Hz, 1H), 7.48 (dd, J = 5.2, 1.1 Hz, 1H), 7.30 (dd, J = 3.6, 1.1 Hz, 4-(1-phenyl-1H-indol-3-yl)benzonitrile (5c').25 Yellow solid.
1
1H), 7.24-7.18 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 144.7, Yield: 12 mg (7%). mp= 105-107°C; H NMR (400 MHz, CDCl3):
134.6, 129.2, 128.1, 126.7, 126.6, 126.0, 121.8, 121.5, 119.8, 7.99-7.95 (m, 1H), 7.84-7.80 (m, 2H), 7.75-7.71 (m, 2H), 7.62-
118.6; HRMS (ESI-MS):Calc. for C11H7ClN2NaS [(M+Na)+]: 7.59 (m, 2H), 7.58-7.53 (m, 4H), 7.46-7.41 (m, 1H), 7.34-7.28
256.9911, Found: 256.9927.
(m, 2H); 13C NMR (100 MHz, CDCl3): 140.3, 139.1, 137.1, 132.8
6-Chloro-2-methyl-3-(naphthalen-2-yl)imidazo[1,2-a]pyridine (x2), 130.0 (x2), 127.6 (x2), 127.4, 126.9, 126.5, 124.8 (x2),
(4k). Brown semisolid. Yield: 100 mg (70%). 1H NMR (400 MHz, 123.5, 121.7, 119.9, 119.5, 117.4, 111.4, 109.3; HRMS (ESI-
CDCl3): δ 8.16 (d, J = 1.3 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.96- MS):Calc. for C21H14N2Na [(M+Na)+]: 317.1049, Found:
7.89 (m, 3H), 7.62-7.56 (m, 3H), 7.53 (dd, J = 8.5, 1.7 Hz, 1H), 317.1043.
7.16 (dd, J = 9.5, 2.0 Hz, 1H); 2.53 (s, 3H); 13C NMR (100 MHz, 4-(benzofuran-2-yl)benzonitrile (5d).26 Yellow solid. Yield: 82
CDCl3): δ 142.8, 142.2, 133.7, 133.1, 129.3, 129.0, 128.2, 128.0, mg (34%). mp= 121-125°C; 1H NMR (400 MHz, CDCl3):7.97-7.93
127.0 (X2), 126.7, 126.1, 125.8, 122.3, 121.1, 120.7, 117.4, (m, 2H), 7.74-7.71 (m, 2H), 7.65-7.61 (m, 1H), 7.56-7.53 (m,
14.0; HRMS (ESI-MS):Calc. for C18H14ClN2 [(M+H)+]: 293.084, 1H), 7.38-7.33 (m, 1H), 7.30-7.25 (m, 1H), 7.18 (d, J = 0.8 Hz,
Found: 293.0843.
1H); 13C NMR (100 MHz, CDCl3): 155.4, 153.7, 134.6, 132.7 (x2),
2-Methyl-3-(naphthalen-1-yl)-8-(trifluoromethyl)imidazo[1,2- 128.8, 125.7, 125.2 (x2), 123.6, 121.6, 118.9, 111.6 (x2), 104.5;
a]pyridine (4l). Yellow solid. Yield: 120 mg (95%). mp= 95- HRMS (ESI-MS):Calc. for C15H9NNaO [(M+Na)+]: 242.0576,
98°C. 1H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 8.2 Hz, 1H), 7.98 Found: 242.0586.
d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.63 (t, J = 7.2 Hz, 4,4'-(benzofuran-2,3-diyl)dibenzonitrile (5d').26 Yellow solid.
1H), 7.57-7.50 (m, 3H), 7.42 (t, J = 7.1 Hz, 1H), 7.31 (d, J = 8.4 Yield: 43 mg (12%). mp= 165-167°C; 1H NMR (400 MHz, CDCl3):
Hz, 1H), 6.68 (t, J = 7.0 Hz, 1H), 2.44 (s, 3H); 13C NMR (125 MHz, 7.83-7.78 (m, 2H), 7.72-7.68 (m, 2H), 7.64-7.58 (m, 5H), 7.49-
CDCl3): δ 143.7, 140.2, 134.1, 132.2, 130.1, 129.9, 128.9, 127.2, 7.40 (m, 2H), 7.34-7.29 (m, 1H); 13C NMR (100 MHz, CDCl3):
127.1, 126.6, 125.8, 125.7, 124.9, 123.2 (q, J = 272.1 Hz, CF3), 154.5, 149.1, 137.4, 134.3, 133.2 (x2), 132.6 (x2), 130.5 (x2),
122.6, 122.5, 120.9, 110.1, 14.2; HRMS (ESI-MS):Calc. for 129.1, 127.4 (x2), 126.5, 124.0, 120.1, 118.7, 118. 6, 118.5,
C19H14F3N2 [(M+H)+]: 327.1104, Found: 327.1139.
112.3 (x2), 111.8; HRMS (ESI-MS):Calc. for C22H12N2NaO
[(M+Na)+]: 343.0842, Found: 343.0868.
8 | J. Name., 2012, 00, 1-3
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Acknowledgements
This research was financially supported by Council of Scientific
and Industrial Research of India through CSC0108 project and
Open Source Drug Discovery Programme (HCP0001).
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A facile ligand-free method for Pd(OAc)2 catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids
with hetero(aryl) bromides has been developed. This method is applicable to variety of (hetero)aryl bromides as coupling
partner. Electron withdrawing and donating groups on imidazo[1,2-a]pyridine-3-carboxylic acids are well tolerated. It
represent the first general protocol for ligand-free Pd(OAc)2 catalysed decarboxylative arylation of imidazo[1,2-a]pyridine-
3-carboxylic acids with (hetero)aryl bromides. Few of the compounds generated using this protocol showed antibacterial
activity against Staphylococcus aureus.