La(OTf)3-catalysed one-pot synthesis of pyrazole tethered imidazo[1,2-: A] azine derivatives and evaluation of their light emitting properties

Article abstract of DOI:10.1039/c9nj05426j

A facile and efficient protocol has been unfolded towards the diversity-oriented synthesis of highly fluorescent pyrazole C-3(5) tethered imidazo[1,2-a]azines via an La(OTf)₃ catalysed one-pot multicomponent assembly of pyrazole carbaldehydes, 2-aminoazines and isonitriles. This present protocol offers several advantages such as multiple bond formation in a single step, low catalyst loading, short reaction time, appreciable atom economy, good functional group tolerance, scalability and easy to perform reaction conditions. The optical properties of pyrazolyl imidazo[1,2-a]azines were also studied, and they exhibited an excellent fluorescence quantum yield (Φ_F up to 83%).

Full text of DOI:10.1039/c9nj05426j

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La(OTf)3-catalysed one-pot synthesis of pyrazole
tethered imidazo[1,2-a]azine derivatives and
evaluation of their light emitting properties†
Cite this:DOI: 10.1039/c9nj05426j
a
b
a
Shubham Sharma,
Avijit Kumar Paul
and Virender Singh
*
A facile and efficient protocol has been unfolded towards the diversity-oriented synthesis of highly
fluorescent pyrazole C-3(5) tethered imidazo[1,2-a]azines via an La(OTf)3 catalysed one-pot multicomponent
assembly of pyrazole carbaldehydes, 2-aminoazines and isonitriles. This present protocol offers several
advantages such as multiple bond formation in a single step, low catalyst loading, short reaction time,
appreciable atom economy, good functional group tolerance, scalability and easy to perform reaction
conditions. The optical properties of pyrazolyl imidazo[1,2-a]azines were also studied, and they exhibited
an excellent fluorescence quantum yield (FF up to 83%).
Received 30th October 2019,
Accepted 23rd November 2019
DOI: 10.1039/c9nj05426j
rsc.li/njc
Introduction
Synthetic organic chemistry offers an endless scope in pharma-
ceutical, material and agriculture industries. The advancement
of effortless synthetic tools for biologically significant hetero-
cyclic frameworks remains an on-going excitement in organic
synthesis.1 Among heterocycles, pyrazole derivatives have delivered
a vast spectrum of commercial drugs and biologically active
molecules to treat various life-challenging diseases.2 Pyrazole
derivatives display a wide array of pharmacological activities
such as analgesic,3 antibacterial,4 anticancer,5 antiviral,6 anti-
inflammatory,7 antioxidant, antimicrobial,8 ACE-inhibitory
activity,9 anticonvulsant,10 and antidepressant,11 along with a
deep history of applications in material chemistry12 and agro-
Fig. 1 Few drug molecules based on pyrazole and imidazo[1,2-a]pyridine
scaffolds.
chemical field.13 Importantly, many drugs have been delivered (anti-ulcer agent), Saripidem and Necopidem (sedative drug),
by this scaffold such as Celecoxib,14 Sildenafil,15 and Fomepizole Olprinone (PDE3 inhibitor) and GSK812397 (anti-HIV) contain
to name a few (Fig. 1).16 Owing to their enormous applications, the imidazo[1,2-a]pyridine moiety23 (Fig. 1).
it is highly desired to develop pyrazole-based new molecular
architectures.
In addition, it is noteworthy to mention that imidazo[1,2-
a]azines have also been extensively used in the area of molecular
Similarly, imidazo[1,2-a]pyridine is another privileged scaffold recognition and optoelectronic industry and as bio-imaging
that has received considerable attention in organic and medicinal probes owing to their excellent luminescence properties.24 There-
chemistry. This framework is also known to display a large fore, it was envisaged to associate these two pharmacophores, i.e.,
spectrum of pharmacological activities such as antimicrobial,17 pyrazole and imidazo[1,2-a]azine to develop a molecular hybrid
anticancer,18 anti-inflammatory,19 antiviral,20 antioxidant,21 and with optical properties. In order to develop the designed prototype,
anti-Alzheimer’s.22 Importantly, several existing drugs, such as it was considered worthwhile to explore the multicomponent
Zolpidem (hypnotic drug), Alpidem (anxiolytic drug), Zolimidine approaches as they have received considerable attention from
organic chemists and emerged as a powerful tool for yielding
complex and novel molecular architectures.25 Multicomponent
reactions provide distinct and highly functionalized compounds
in a single operation via the creation of multiple bonds without
isolating the intermediate or changing the reaction conditions.
Owing to the growing number of publications in this field,
a Department of Chemistry, Dr B R Ambedkar National Institute of Technology (NIT)
Jalandhar, 144011, Punjab, India. E-mail: singhv@nitj.ac.in
b Department of Chemistry, National Institute of Technology (NIT) Kurukshetra,
136119, Haryana, India
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj05426j
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with more than 2000 patent applications (since the innovation methyl alcohols furnished the corresponding desired pyrazole
of Zolpidem in 1998), the scientific community has accepted the carbaldehydes 15a, 16a, 17a–b, 18a, 19a, 20a and 21a–b in very
Groebke–Blackburn–Bienayme (GBB) reaction26 as the potential good yields (Scheme 1).
tool for the synthesis of imidazo[1,2-a]pyridine derivatives. Our
In order to achieve the synthesis of targeted pyrazole-tethered
group has also summarised the synthetic advancement and imidazopyridines via the GBB multicomponent approach, 5-(4-
medicinal potential of imidazo[1,2-a]pyridine derivatives.27 chlorophenyl)-1-phenyl-1H-pyrazole-3-carbaldehyde (17a), 2-amino-
The analysis of literature disclosed that various procedures have pyridine (A) and tert-butyl isocyanide (X) were selected as the model
been adopted for the construction of imidazo[1,2-a]pyridine precursors (Table 1). As water is reported to display an amazing
derivatives, but the GBB reaction remains one of the most reactivity profile in many organic transformations, it was envisaged
preferred approaches towards the synthesis of this molecular to initiate the present study from an aqueous medium under
framework.28 Therefore, it was planned to explore this multi- catalyst-free conditions at 100 1C, but the starting material
component strategy for the preparation of pyrazole-tethered remained intact for 16 h (Table 1, entry 1). The addition of
imidazo[1,2-a]azine scaffolds. In addition, it was noted that Sc(OTf)3 and I2 as catalysts under aqueous conditions also failed to
La(OTf)3 was used for the first time for the GBB multicomponent furnish the anticipated product, which revealed that the solubility
reaction towards the one-pot construction of pyrazolylimidazo[1,2-a]- of reactants was a limiting factor (Table 1, entries 2 and 3).
azine derivatives.
Similarly, when the reaction was performed in toluene under
catalyst-free conditions, the formation of the targeted product was
noted in traces only and the model substrate was not consumed
completely even after 20 h (Table 1, entry 4). Further, we conducted
experiments using toluene as a solvent with different types
of Lewis acids (I2, Cu(OTf)2, La(OTf)3 and Sc(OTf)3) as catalysts
(10 mol%) for the desired transformation (Table 1, entries 5–8).
Interestingly, it was noted that all the Lewis acids afforded a highly
fluorescent product in 1–24 h; however, La(OTf)3 was found as the
most efficient catalyst and required only 1 h to furnish a clean and
complete reaction (Table 1, entry 7). The GBB product was isolated
in 80% yield after a short silica gel column chromatographic
purification and the structure of 17aAX was confirmed via spectro-
scopic analyses. Further, we focused on screening different solvent
Results and discussion
The study commenced with the synthesis of 1H-pyrazole-3(5)-
carbaldehydes, which was achieved via alterations in the previously
reported procedure (Scheme 1).29 Initially, the condensation of
various 1,3-diketoesters 1–4 with suitable hydrazines a–b was
achieved in the presence of TFA (cat.), which resulted in a mixture
of pyrazole C-3(5) esters 1a, 2a, 3a–b, 4a, 5a, 6a, and 7a–b.
However, at this stage, the separation of these pyrazole esters
was not feasible due to less difference in their retention factor.
Next, the reduction in both the regioisomers was achieved with
LiAlH4 in dry THF to afford the corresponding pyrazole alcohols
8a, 9a, 10a–b, 11a, 12a, 13a, and 14a–b. Delightedly, these
regioisomers were easily separated at this alcohol stage via
column chromatography, and the regioisomers 8a, 9a, 10a–b
and 11a were obtained as the major products in 65–78% yield,
while 12a, 13a and 14a–b were afforded in minor amounts
(15–21%). Thereafter, an MnO2-mediated oxidation of pyrazole
Table 1 Optimization of reaction conditionsa
Entry Catalyst (10 mol%) Solventb Temp. (1C) Time (h) Yieldc (%)
1d
2d
3d
4
5
6
7
8
9
10
11
12
13
14
15e
16 f
—
Sc(OTf)3
I2
—
I2
Cu(OTf)2
La(OTf)3
Sc(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
I2
H2O
H2O
H2O
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
MeOH
DMF
DMSO
DMF
100
100
100
16
16
16
20
24
5
NR
NR
NR
Traces
70
51
80
61
60
62
65
63
59
Traces
75
71
1
3
80
120
160
120
120
80
12
12
12
24
24
10
2
I2
I2
DMSO
EtOH
Toluene 120
Toluene 120
La(OTf)3
La(OTf)3
0.5
a
All the reactions were optimized with 0.07 mmol (1 equiv.) of 17a,
0.07 mmol (1.05 equiv.) of A, 0.09 mmol (1.1 equiv.) of X and 10 mol%
b
of catalyst in 2 mL of solvent. The reactions were examined in dry
c
solvents (except entries 1–3 and 14). The yield of purified product.
d
f
e
Starting material remained intact. 5 mol% of catalyst was utilised.
20 mol% of catalyst was utilised.
Scheme 1 Synthesis of diversely substituted pyrazole C-3(5) carbaldehydes.
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systems to upsurge the efficiency of the reaction. Notably, when
toluene was replaced by MeOH, DMF or DMSO, the reaction took a
longer time (12 h) and the desired compound was yielded in lower
quantities (60–65%, entries 9–11). The use of iodine as a catalyst in
DMF and DMSO also afforded 17aAX but in 59–63% yield (Table 1,
entries 12 and 13). However, I2 in ethanol failed to yield the
anticipated product (Table 1, entry 14). The optimisation studies
affirmed that La(OTf)3 in dry toluene was the best catalytic system
to furnish the desired product.
We further analysed the catalyst (La(OTf)3) loading and it
was noticed that when either 5 or 20 mol% of La(OTf)3 was
used; the yield of the GBB product was declined (Table 1,
entries 15 and 16). Finally, the optimisation studies (Table 1)
led to the conclusion that 10 mol% of La(OTf)3 used as a
catalyst in dry toluene under heating were the most suitable
conditions for our current study (Table 1, entry 7).
Having optimized conditions in hand, the generality of the
present approach was investigated by using diversely substituted
pyrazole aldehydes, substituted 2-aminopyridines and isonitriles
towards the synthesis of a desired framework, as depicted in
Schemes 2–5. Initially, the reaction was analyzed with pyrazole
C-3 carbaldehydes 16a, 17a–b, 2-aminopyridine A–J and isocyanides
X–Y to furnish the targeted product (Scheme 2). It is noteworthy
to mention that all the reactants responded positively to afford
the desired imidazo[1,2-a]pyridine analogues 16aGY, 17aAX–IX,
17bAX, 17bCX, 17bDX, 17bGX–JX, 17bGY, 17bHY and 17bJY in
16–81% yield, as illustrated in Scheme 2. The N-aryl as well as
N-alkyl pyrazole C-3 carbaldehydes 16a and 17a–b reacted with
equal ease. Similarly, tert-butylisocyanide and ethyl isocyano-
acetate (X–Y) furnished the products smoothly with no marked
difference in the reactivity. The electron donating as well as
electron withdrawing substituents in 2-aminopyridine (A–J)
were also well-tolerated towards the GBB reaction with N-aryl/
methyl pyrazole C-3 carbaldehydes and isocyanides to deliver the
desired product in good yield. However, 2-amino 3,5-dichloro-
pyridine (H) afforded the corresponding MCR products 17aHX,
17bHX and 17bHY in relatively low yields (16–49%), which may
be possible due to the steric hindrance offered by the two chloro
substituents.
Scheme 2 One-pot synthesis of pyrazole C-3-tethered imidazo[1,2-a]-
pyridine derivatives.
The versatility of this multicomponent reaction was further
enhanced by varying the 2-aminoazine component with 2-amino-
pyrazine (K) and 2-aminothiazole (L) for the synthesis of pyrazole
C-3-substituted imidazo[1,2-a]pyrazine 17aKX and imidazo[2,1-
b]thiazole derivative 17bLX. Both of these 2-aminoazines (K–L)
reacted similar to 2-aminopyridines (A–J) and afforded the
desired products in 58–66% yield in 1–1.5 h (Scheme 3).
After the successful synthesis of pyrazole C-3-tethered imidazo-
[1,2-a]azines, we further studied the reaction of pyrazole-5-carb-
aldehydes 21a–b with 2-aminopyridines (G and D) and tert-butyl-
isocyanide (X), as shown in Scheme 4.
Scheme 3 Synthesis of pyrazole C-3-substituted imidazo[1,2-a]pyrazine
and imidazo[2,1-b]thiazole derivative.
Surprisingly, pyrazole-5-carbaldehyde 21a–b was found to be
less reactive as compared to pyrazole-3-carbaldehydes and required
a longer time (2.5–3 h) to deliver the anticipated products 21aDX A,D and tert-butylisocyanide (X) under standard reaction condi-
and 21bGX in moderate yield (37–54%). tions, as depicted in Scheme 5. It was found that 22–23a delivered
Next, the scope of the strategy was investigated with the reaction the anticipated imidazo[1,2-a]pyridines 22aDX, 23aAX in good to
of 4-iodo-pyrazole-3-carbaldehyde 22–23a with 2-aminopyridines excellent yields (53–86%).
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Fig. 2 A probable mechanism for the synthesis of pyrazolylimidazo[1,2-a]-
pyridine derivative.
Scheme 4 La(OTf)3 catalysed synthesis of pyrazole C-5-tethered imi-
dazo[1,2-a]pyridines.
2-aminopyridine (A) resulted in the formation of the Schiff base
25aA, which further participated in the nonconcerted [4+1]
cycloaddition with tert-butylisocyanide (X) to generate another
intermediate 27aAX. A subsequent 1,3-proton shift may result in
the construction of pyrazole-substituted imidazo[1,2-a]pyridine
derivative 17aAX.
Photophysical studies
Recently, Balakirev et al.33 reported that imidazo[1,2-a]pyridine
derivatives are promising candidates as luminescent probes,
which can be utilized in the field of biomedical research and
clinical diagnostics.34 Moreover, these types of molecules may
also be developed as chemosensors.35 Our group also recently
synthesized some b-carboline-based fluorophores.36 Therefore,
it was considered worthwhile to evaluate the light-emitting
properties of these pyrazolylimidazo[1,2-a]azines so that they
may find application in materials science. The compound
17bGX was chosen as the model fluorophore for the present
study, and initially, different organic solvents (CHCl3, EtOAc,
ethanol and THF) were screened to obtain maximum emission
(Fig. 3). The solvent-based studies demonstrated that the synthe-
sized product 17bGX exhibited appreciable fluorescence emission
in all the solvents; however, the maximum fluorescence intensity
was obtained in CHCl3, as the solvent (Fig. 3).
Scheme 5 Synthesis of 4-iodo-pyrazole30 C-3 tethered imidazo[1,2-
a]pyridine derivatives.
To further demonstrate the scope of this protocol, it was
planned to remove the tert-butyl group because the free amine
group can be further explored in coupling reactions, annulation
reactions, Pictet–Spengler condensation31 and in the fabrication
of biologically relevant heterocyclic frameworks. Hence, the
dealkylation of 17aDX was studied by using 40% HBF4 (aq.) at
120 1C in dry toluene. Gratifyingly, we successfully achieved the
dealkylation of 17aDX to afford 24aDX within 30 min in
excellent yield (92%) (Scheme 6).
To further demonstrate the applicability of this methodology,
we also executed a scaled-up reaction of 17a (1.5 g) with 2-amino-
pyridine (A) and tert-butylisocyanide (X) under the catalysis of
La(OTf)3 in toluene for the synthesis of 17aAX. As expected, the
Groebke–Blackburn–Bienayme reaction was completed in 1.5 h
under optimized conditions and delivered the product 17aAX
(1.82 g) in 78% yield after a short silica gel chromatography
(60–120 mesh).
On the basis of the above results, chloroform was selected as
the solvent of choice for the photophysical analysis of pyrazolyl-
imidazo[1,2-a]azine derivatives. A series of quantitative experiments
were conducted to evaluate various photophysical parameters of
imidazo[1,2-a]azines, including excitation, absorption, emission,
On the basis of current observations and previous findings,32
a probable mechanistic route has been outlined in Fig. 2
considering 17a, A and X as model substrates. It is anticipated
that the condensation of pyrazole C-3 carbaldehyde 17a and
Scheme 6 HBF4-Mediated dealkylation of GBB product.
Fig. 3 Screening of solvent.
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molar extinction coefficient, brightness, Stokes shift and fluores-
cence quantum yield. For the UV-vis and fluorescence measure-
ments of the samples, a stock solution of each derivative
(1.0 mM) was prepared and diluted to a final concentration of
2.0 mM using CHCl3 as a solvent. The quantum yield of com-
pounds under study (FS) was calculated relative to quinine sulfate
(FR = 0.546 in 0.1 M H2SO4 at 350 nm excitation) as a standard
compound.37
The quantum yield (QY) was calculated by using the equation
as mentioned below:
Fig. 4 Fluorescence emission spectra of pyrazole-tethered imidazo[1,2-
a]pyridine derivatives derived from 2-aminopyridines containing electron
donating substituents.
2
IS AR ZS
FS ¼ FR
ꢀ
ꢀ
ꢀ
2
IR AS ZR
R – references, S – sample.
The photophysical data of synthesized compounds are sum-
marised in Tables 2 and 3, and their graphical data is displayed in
Table 2 Photophysical data of pyrazole-tethered imidazo[1,2-a]pyridine
derivatives derived from 2-aminopyridines containing electron donating
substituents
UV-visa Fluorescencea e (molar
extinction
coeff.)
Stokes
Brightnessb shift
c
lEx (nm) lEm (nm)
FF
17aAX 324.30
443.21
431.69
440.17
445.20
430.06
435.32
435.93
442.64
435.68
37 500
23 000
35 000
36 000
20 500
19 500
87 000
17 000
31 500
16 087
5244
11 410
5868
5207
10 140
4611
119
116
123
118
102
118
193
129
106
0.43
0.23
0.33
0.16
0.25
0.52
0.05
0.40
0.23
Fig. 5 Emission spectra of pyrazolylimidazo[1,2-a]pyridine derivatives
derived from 2-aminopyridines containing halogens (F, Cl and Br) as the
electron withdrawing substituents.
17aBX 315.21
17aCX 317.12
17aDX 327.45
17aEX 328.02
17bAX 317.30
17bCX 242.22
313.72
Fig. S57 and S58 (ESI†). The fluorescence intensities (emission
spectra) of these fluorophores are represented in Fig. 4 and 5.
It is noteworthy to mention that the fluorescence spectra of
some pyrazolyl-imidazo[1,2-a]pyridine fluorophores 17aHX, 17bCX,
17bGX, 17bHX were recorded at two excitation wavelengths
to investigate the luminescence quantum yield. It was found
that these fluorophores exhibited better fluorescence quantum
yield at longer wavelengths as compared to that at shorter
wavelengths (Tables 2 and 3). Therefore, we investigated the
photophysical studies of the remaining compounds at longer
wavelengths only (excitation region lEx = 313–453 nm) and the
emission range was observed to be from 430 to 521 nm. To our
delight, all the compounds gave good to excellent luminescent
quantum yield (FF = 5–83%). These compounds exhibited
Stokes shift, molar extinction coefficient and brightness in the
6749
7245
17bDX 329.16
a
b
Measured at 2 mM concentration in CHCl3. Brightness = e ꢀ FF.
c
Quantum yields (FF) were determined with reference to quinine
sulfate (0.1 M aq. H2SO4 excited at 350 nm).
Table 3 Photophysical data of pyrazolylimidazo[1,2-a]pyridine derivatives
derived from 2-aminopyridines containing halogens (F, Cl and Br) as the
electron withdrawing substituents
UV-visa Fluorescencea
e (molar
Stokes
extinction co.) Brightnessb shift FF
c
lEx (nm) lEm (nm)
16aGY 332
460.4
17aFX 330.30 456.06
17aHX 240.63 460.10
329.18 457.84
17 500
36 500
80 000
20 500
20 500
12 500
84 500
18 000
64 000
11 000
20 000
23 500
8000
13 125
19 491
3840
8815
615
9125
6929
11 700
7040
9130
1080
1739
6280
11 842
1556
1470
128
126
220
128
114
68
208
127
212
128
130
131
128
129
120
140
0.75
0.53
0.05
0.43
0.03
0.07
0.08
0.65
0.11
0.83
0.05
0.07
0.78
0.58
0.05
0.14
range of 68–140 nm, 8000–37 500 and 615–19 491 Mꢁ1 cmꢁ1
respectively (Tables 2 and 3).
,
17aIX 329.73 443.70
17aKX 453.33 521.37
17bGX 240.11 448.31
328.86 455.38
A comparative structure analysis of 17aAX and 17bAX
revealed that when phenyl ring (R2 = Ph) was situated at the
N-1 position of the pyrazole ring, a low fluorescent quantum
yield was obtained (FF = 43%) as compared to methyl (R2 = Me)
substitution (FF = 52%) at the same position (Table 2). Similarly,
pyrazolylimidazo[1,2-a]pyridine derivatives 17aDX and 17bDX
derived from 2-amino, 5-methylpyridine (D) containing methyl
substituent displayed a low quantum yield (FF = 16–23%) in
comparison to other similar analogues 17aBX, 17aCX, 17aEX and
17bCX, bearing a methyl group at other positions (FF = 23–40%)
(Table 2). Overall, a wide range of molar extinction coefficient and
17bHX 242.9
454.87
458.38
330
17bIX 322.53 452.85
17bJX 328.92 459.21
17bLX 328.02 456.91
17bGY 330.08 459.15
21bGX 345.06 465.84
20 500
30 500
10 500
23aAX 320
460.4
a
b
Measured at 2 mM concentration in CHCl3. Brightness = e ꢀ FF.
c
Quantum yields (FF) were determined with reference to quinine
sulfate (0.1 M aq. H2SO4, excited at 350 nm).
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brightness was observed (17 000–37 500 and 5207–16 087 Mꢁ1 cmꢁ1
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,
Melting points were determined on a Precision Digital melting
respectively) in case of pyrazolylimidazo[1,2-a]pyridine derivatives point apparatus with open capillary tubes. IR spectra were
1
bearing methyl substituents (Table 2). Surprisingly, bromide recorded on an Agilent FTIR spectrophotometer. H-NMR and
substitution (R3 = Br) in imidazo[1,2-a]pyridine ring 17aIX, 13C-NMR spectra were recorded either on an Avance III Bruker
17bJX and 17bIX drastically decreased the quantum yield or JEOL JNM-ECS spectrometer at operating frequencies of
(3–7%), as depicted in Table 3. Moreover, imidazo[1,2-a]pyridine 200/400/500 MHz (1H) and/or 100/125 MHz (13C), as indicated
derivatives bearing fluorine and chlorine substituents 16aGY, in the individual spectrum using TMS as an internal standard.
17bGY, 17aFX, 17aHX, 17bGX, 17bHX and 21bGX afforded good The room temperature varied between 25 1C to 35 1C. The
to excellent quantum yields (5–83%) with an emission wave- multiplicities in the 1H-NMR spectra are presented as s for
length lEm = 455–465 nm (Table 3).
singlet, d for doublet, dd for doublet of doublet, t for triplet and
Thereafter, the photophysical properties of pyrazolyl C-3 imidazo- m for multiplet.
[1,2-a]pyridine 17aAX, imidazo[1,2-a]pyrazine 17aKX and imidazo-
[1,2-a]thiazole 17bLX were compared. The imidazo[1,2-a]pyrazine
Experimental section
17aKX derivative displayed a low quantum yield (17aKX; FF = 7%),
General procedure for the synthesis of compounds (16aGY,
but a significant bathochromic shift in excitation (453 nm) 17aAX–IX, 17bAX, 17bCX, 17bDX, 17bGX–JX, 17bGY, 17bHY,
and emission wavelengths (521 nm) was observed. However, 17bJY, 17aKX, 17bLX, 21aDX, 21bGX, 22aDX and 23aAX) as
imidazo[1,2-a]thiazole derivative 17bLX exhibited an excellent exemplified for N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-
fluorescence quantum yield (FF = 78%) with a slight redshift in 1H-pyrazol-3-yl)imidazo[1,2-a]pyridin-3-amine (17aAX). To a stirred
the emission wavelength (lEm = 456 nm). Notably, the emission solution of pyrazole C-3 carbaldehyde 17a (0.20 g, 0.70 mmol),
maxima of pyrazole C-5-tethered imidazo[1,2-a]pyridine (21bGX; 2-aminopyridine (A) (0.07 g, 0.74 mmol) and tert-butylisocyanide
lEm = 465 nm) shifted towards a longer wavelength as compared (X) (0.087 mL, 0.84 mmol) in anhydrous toluene; La(OTf)3 (0.041 g,
to that of C-3-tethered imidazo[1,2-a]pyridine (17bGX; lEm 0.14 mmol) was added. The reaction flask was heated under
=
455 nm) with 120 nm Stokes shift and exhibited 5% quantum stirring at 120 1C for 1 h. After the completion of the reaction,
yield. Overall, the synthesized imidazo[1,2-a]azine derivatives dis- as monitored by TLC, the reaction mixture was cooled to room
played excellent optical properties, as depicted in Tables 2 and 3. temperature, followed by the addition of water and the product
Further studies of the most fluorescent pyrazolylimidazo[1,2-a]- was extracted with ethyl acetate (3 ꢀ 25 mL). The organic layer was
azines as analytical sensors are underway in our laboratory.
washed with brine and dried over anhydrous sodium sulfate,
which was further concentrated under a reduced pressure to
afford a crude product 17aAX, which was purified by silica gel
(60–120 mesh) column chromatography using hexane and ethyl
acetate (70 : 30, v/v) as an eluent to obtain an analytically pure
product 17aAX in 80% yield (0.25 g from 0.20 g; Rf = 0.19,
(hexane/EtOAc, 70 : 30, v/v)) as a white solid.
Ethyl-2-((6-chloro-2-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-
3-yl)imidazo[1,2-a]pyridin-3-yl)amino)acetate (16aGY). Yield:
69% (0.19 g from 0.20 g) as a yellow solid; m.p. 135–137 1C;
Rf = 0.31 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) =
1748 (CO2Et), 3288 (NH); 1H NMR (500 MHz, CDCl3): d = 1.22 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3), 3.96 (d, J = 5.9 Hz, 2 H, NCH2),
4.18 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.82 (t, J = 6.0 Hz, 1 H,
NH), 7.02 (t, J = 8.7 Hz, 2 H, ArH), 7.08–7.12 (m, 2 H, ArH),
7.24–7.27 (m, 2 H, ArH), 7.31–7.38 (m, 5 H, ArH), 7.50 (d, J = 9.4 Hz,
1 H, ArH), 8.27 (s, 1 H, ArH) ppm; 13C NMR (125 MHz, CDCl3):
d = 14.2, 49.4, 61.3, 106.7, 115.8 (d, J = 21.2 Hz), 117.9, 120.6, 120.9,
125.1, 125.3, 126.7 (d, J = 3.6 Hz), 127.3, 127.5, 129.0, 130.4, 130.7
(d, J = 8.8 Hz), 140.0, 143.0, 147.6, 162.8 (d, J = 247.5 Hz), 171.2
ppm; HRMS (ESI) m/z: calcd for C26H21ClFN5O2 [M + H+]: 490.1446,
found: 490.1421.
Conclusions
In summary, a straightforward and operationally simple strategy
has been disclosed for the one-pot syntheses of diversely sub-
stituted imidazo[1,2-a]azines. In addition, La(OTf)3 was explored
for the first time for the GBB reaction towards the synthesis of
highly fluorescent pyrazole-tethered imidazo[1,2-a]pyridine,
imidazo[1,2-a]pyrazine and imidazo[2,1-b]thiazole derivatives. In
brief, this study has numerous advantages such as one-pot
procedure, formation of C–C and C–N bonds in a single operation,
short reaction time, high atom economy, wide functional group
tolerance, operational simplicity and simple purification procedure.
Moreover, the pyrazole-tethered imidazo[1,2-a]azine derivatives
turned out to be the promising fluorophores with excellent
quantum yields (up to 83%).
Experimental
General information
All chemicals and reagents were purchased from Sigma Aldrich,
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-
Acros, Avera Synthesis, Spectrochem Pvt. Ltd and used without imidazo[1,2-a]pyridin-3-amine (17aAX). Yield: 80% (0.25 g from
further purification. Commercially available anhydrous solvents 0.20 g) as a white solid; m.p. 148–150 1C; Rf = 0.19 (hexane/
(THF, DMF, DMSO, toluene, MeOH, EtOH and CH2Cl2 Spectro- EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3333 (NH); 1H NMR
chem) were used in the reactions. Thin-layer chromatography (400 MHz, CDCl3): d = 1.25 (s, 9 H, C(CH3)3), 4.42 (s, 1 H, NH),
(TLC) was performed using pre-coated aluminium plates pur- 6.73–6.77 (m, 1 H, ArH), 7.09–7.12 (m, 1 H, ArH), 7.13
chased from E. Merck (silica gel 60 PF254, 0.25 mm). Column (s, 1 H, ArH), 7.21–7.25 (m, 2 H, ArH), 7.28–7.41 (m, 7 H, ArH),
chromatography was performed using a 60–120 mesh silica gel. 7.54 (d, J = 9.1 Hz 1 H, ArH), 8.27–8.29 (m, 1 H, ArH) ppm;
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13C NMR (100 MHz, CDCl3): d = 30.4, 57.2, 107.2, 111.3, 117.4,
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-
123.7, 124.1, 125.2, 126.2, 127.6, 128.9, 129.1, 130.1, 131.3, 134.4, 6-fluoroimidazo[1,2-a]pyridin-3-amine (17aFX). Yield: 65%
140.2, 142.3, 142.4, 148.9 ppm; HRMS (ESI) m/z: calcd for (0.211 g from 0.20 g) as off white solid; m.p. 197–199 1C; Rf =
C26H24ClN5 [M + H+]: 442.1798, found: 442.1795.
0.27 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3338
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)- (NH); 1H NMR (500 MHz, CDCl3): d = 1.24 (s, 9 H, C(CH3)3), 4.39
8-methylimidazo[1,2-a]pyridin-3-amine (17aBX). Yield: 56% (s, 1 H, NH), 7.01–7.06 (m, 1 H, ArH), 7.10 (s, 1 H, ArH),
(0.18 g from 0.20 g) as a yellow solid; m.p. 144–146 1C; Rf = 7.21–7.23 (m, 2 H, ArH), 7.28–7.41 (m, 7 H, ArH), 7.51
0.63 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3338 (dd, J1 = 9.8 Hz, J2 = 5.1 Hz, 1 H, ArH), 8.20 (s, 1 H ArH) ppm;
(NH); 1H NMR (400 MHz, CDCl3): d = 1.22 (s, 9 H, C(CH3)3), 2.64 13C NMR (100 MHz, CDCl3): d = 30.4, 57.3, 107.1, 110.6
(s, 3 H, ArCH3), 4.39 (s, 1 H, NH), 6.67 (t, J = 6.8 Hz, 1 H, ArH), (d, J = 42 Hz), 115.8 (d, J = 26 Hz), 117.8 (d, J = 9.1 Hz), 125.2,
6.89–6.92 (m, 1 H, ArH), 7.15 (s, 1 H, ArH), 7.22–7.25 (m, 2 H, 127.7, 128.9, 129.1, 129.2, 130.1, 133.1, 134.5, 139.9, 140.0
ArH), 7.28–7.41 (m, 7 H, ArH), 8.15 (d, J = 6.8 Hz, 1 H, ArH) ppm; (d, J = 25 Hz), 148.6 ppm; HRMS (ESI) m/z: calcd for C26H23ClFN5
13C NMR (100 MHz, CDCl3): d = 16.8, 30.4, 57.0, 107.4, 111.3, [M + H+]: 460.1704, found: 460.1735.
122.0, 122.5, 125.2, 126.5, 127.0, 127.6, 128.8, 129.1, 129.2,
N-(tert-butyl)-6-chloro-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-
130.1, 131.0, 134.3, 140.2, 142.3, 142.6, 149.0 ppm; HRMS 3-yl)imidazo[1,2-a]pyridin-3-amine (17aGX). Yield: 72% (0.24 g
(ESI) m/z: calcd for C27H26ClN5 [M + H+]: 456.1955, found: from 0.20 g) as a yellow solid; m.p. 184–186 1C; Rf = 0.60
456.1957.
(hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3312 (NH);
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)- 1H NMR (500 MHz, CDCl3): d = 1.24 (s, 9 H, C(CH3)3), 4.39
7-methylimidazo[1,2-a]pyridin-3-amine (17aCX). Yield: 53% (s, 1 H, NH), 7.07 (dd, J = 9.5 Hz, 1.9 Hz, 1 H, ArH) 7.11 (s, 1 H,
(0.17 g from 0.20 g) as a dull white solid; m.p. 164–166 1C; ArH), 7.22 (d, J = 8.5 Hz, 2 H, ArH), 7.29–7.41 (m, 7 H, ArH), 7.48
Rf = 0.31 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax (cmꢁ1) = (d, J = 9.6 Hz, 1 H, ArH), 8.30 (s 1 H, ArH) ppm; 13C NMR
3318 (NH); 1H NMR (400 MHz, CDCl3): d = 1.23 (s, 9 H, C(CH3)3), (100 MHz, CDCl3): d = 30.4, 57.3, 107.2, 117.7, 119.9, 121.9,
2.38 (s, 3 H, ArCH3), 4.37 (s, 1 H, NH), 6.58 (dd, J1 = 7.1 Hz, 125.1, 125.2, 126.7, 127.8, 128.9, 129.0, 129.2, 130.1, 132.5,
J2 = 1.5 Hz, 1 H, ArH), 7.11 (s, 1 H, ArH), 7.21–7.24 (m, 2 H, ArH), 134.5, 140.1, 140.5, 142.6, 148.4 ppm; HRMS (ESI) m/z: calcd
7.28–7.38 (m, 8 H, ArH), 8.15 (d, J = 7.0 Hz, 1 H, ArH); 13C NMR for C26H23Cl2N5 [M + H+]: 476.1409, found: 476.1428.
(100 MHz, CDCl3): d = 21.4, 30.3, 57.0, 107.2, 114.0, 115.7, 123.3,
N-(tert-butyl)-6,8-dichloro-2-(5-(4-chlorophenyl)-1-phenyl-1H-
125.2, 125.7, 127.6, 128.8, 129.0, 129.1, 129.2, 130.1, 130.8, pyrazol-3-yl)imidazo[1,2-a]pyridin-3-amine (17aHX). Yield: 49%
134.3, 134.6, 140.2, 142.3, 142.7, 148.9; HRMS (ESI) m/z: calcd (0.175 g from 0.20 g) as a white solid; m.p. 194–196 1C; Rf = 0.88
for C27H26ClN5 [M + H+]: 456.1955, found: 456.1977.
(hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3355 (NH);
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)- 1H NMR (500 MHz, CDCl3): d = 1.23 (s, 9 H, C(CH3)3), 4.47
6-methylimidazo[1,2-a]pyridin-3-amine (17aDX). Yield: 81% (s, 1 H, NH), 7.20–7.23 (m, 4 H, ArH), 7.28–7.32 (m, 4 H, ArH),
(0.26 g from 0.20 g) as an off white solid; m.p. 192–194 1C; 7.35–7.41 (m, 3 H, ArH), 8.26 (d, J = 1.8 Hz, 1 H, ArH) ppm; 13
C
Rf = 0.17 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = NMR (100 MHz, CDCl3): d = 30.4, 57.5, 107.7, 118.9, 120.9, 123.2,
3310 (NH); 1H NMR (500 MHz, CDCl3): d = 1.24 (s, 9 H, C(CH3)3), 123.7, 125.2, 127.8, 128.1, 128.8, 128.9, 129.2, 130.1, 133.3,
2.33 (d, J = 0.5 Hz, 3 H, ArCH3), 4.39 (s, 1 H, NH), 6.96 (dd, J1 = 134.5, 137.8, 140.1, 142.5, 148.1 ppm; HRMS (ESI) m/z: calcd
9.2 Hz, J2 = 1.0 Hz, 1 H, ArH), 7.11 (s, 1 H, ArH), 7.21–7.23 for C26H22Cl3N5 [M + H+]: 510.1019, found: 510.1023.
(m, 2 H, ArH), 7.28–7.30 (m, 2 H, ArH), 7.31–7.36 (m, 3 H, ArH),
8-Bromo-N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-
7.37–7.40 (m, 2 H, ArH), 7.43–7.47 (m, 1 H, ArH), 8.05 (s, 1 H, 3-yl)imidazo[1,2-a]pyridin-3-amine (17aIX). Yield: 56% (0.205 g from
ArH) ppm; 13C NMR (100 MHz, CDCl3): d = 18.6, 30.4, 57.2, 0.20 g) as an off white solid; m.p. 176–178 1C; Rf = 0.73 (hexane/
107.1, 116.7, 120.9, 121.7, 125.2, 125.9, 127.0, 127.6, 128.9, 129.1, EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3344 (NH); 1H NMR
129.2, 130.1, 131.2, 134.4, 140.2, 141.5, 142.4, 149.0 ppm; HRMS (500 MHz, CDCl3): d = 1.22 (s, 9 H, C(CH3)3), 4.48 (s, 1 H, NH),
(ESI) m/z: calcd for C27H26ClN5 [M + H+]: 456.1955, found: 6.64 (t, J = 7.1 Hz, 1 H, ArH), 7.22–7.24 (m, 3 H, ArH), 7.29–7.40
456.1941.
(m, 8 H, ArH), 8.27 (d, J = 6.7 Hz, 1 H, ArH) ppm; 13C NMR
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)- (100 MHz, CDCl3): d = 30.4, 57.3, 107.9, 111.3, 114.5, 123.5,
5-methylimidazo[1,2-a]pyridin-3-amine (17aEX). Yield: 53% 125.2, 126.0, 127.6, 127.7, 128.9, 129.1, 129.1, 130.1, 132.4,
(0.17 g from 0.20 g) as a red solid; m.p. 149–151 1C; Rf = 0.36 134.4, 139.8, 140.2, 142.3, 148.5 ppm; HRMS (ESI) m/z: calcd
(hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3303 (NH); for C26H23BrClN5 [M + H+]: 520.0903, found: 520.0884.
1H NMR (500 MHz, CDCl3): d = 1.10 (s, 9 H, C(CH3)3), 3.00
6-Bromo-N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-
(s, 3 H, ArCH3), 4.24 (s, 1 H, NH), 6.49 (d, J = 6.7 Hz, 1 H, ArH), 3-yl)imidazo[1,2-a]pyridin-3-amine (17aJX). Yield: 50% (0.185 g from
7.05–7.08 (m, 1 H, ArH), 7.15 (s, 1 H, ArH), 7.28 (s, 1 H, ArH), 0.20 g) as a yellow solid; m.p. 204–206 1C; Rf = 0.48 (hexane/EtOAc,
7.32 (t, J = 7.5 Hz, 2 H, ArH), 7.36–7.47 (m, 7 H, ArH) ppm; 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3310 (NH); 1H NMR (500 MHz,
13C NMR (125 MHz, CDCl3): d = 20.4, 29.6, 57.2, 107.3, 114.0, CDCl3): d = 1.24 (s, 9 H, C(CH3)3), 4.39 (s, 1 H, NH), 7.11 (s, 1 H,
115.6, 124.2, 125.4, 127.7, 128.0, 128.9, 129.1, 129.2, 130.0, ArH), 7.16 (dd, J1 = 9.5 Hz, J2 = 1.9 Hz, 1 H, ArH), 7.20–7.23
133.4, 134.3, 137.5, 140.2, 142.6, 143.5, 149.0 ppm; HRMS (m, 2 H, ArH), 7.29–7.44 (m, 8 H, ArH), 8.40 (s, 1 H, ArH) ppm;
(ESI) m/z: calcd for C27H26ClN5 [M + H+]: 456.1955, found: 13C NMR (100 MHz, CDCl3): d = 30.4, 57.3, 106.4, 107.2, 118.1,
456.1959.
124.2, 125.2, 126.5, 127.1, 127.8, 128.9, 129.0, 129.2, 130.1,
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132.3, 134.5, 140.1, 140.2, 140.6, 142.6, 148.4 ppm; HRMS (ESI) m/z: 8.24 (s, 1 H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d = 30.4,
calcd for C26H23BrClN5 [M + H+]: 520.0903, found: 520.0941.
37.9, 57.5, 105.8, 118.7, 120.8, 123.2, 123.5, 127.7, 129.1, 130.1,
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)- 133.8, 134.8, 137.7, 143.1, 146.2; HRMS (ESI) m/z: calcd for
imidazo[1,2-a]pyridin-3-amine (17bAX). Yield: 51% (0.175 g C21H20Cl3N5 [M + H+]: 448.0862, found: 448.0853.
from 0.20 g) as a yellow solid; m.p. 140–142 1C; Rf = 0.21
8-Bromo-N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-
(hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax (cmꢁ1) = 3306 (NH); 3-yl)imidazo[1,2-a]pyridin-3-amine (17bIX). Yield: 81% (0.34 g from
1H NMR (500 MHz, CDCl3): d = 1.20 (s, 9 H, C(CH3)3), 3.92 0.20 g) as an off white solid; m.p. 208–210 1C; Rf = 0.38 (hexane/
(s, 3 H, NCH3), 6.77 (t, J = 6.7 Hz, 1 H, ArH), 6.92 (s, 1 H, ArH), EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3328 (NH); 1H NMR
7.12–7.15 (m, 1 H, ArH), 7.42–7.46 (m, 4 H, ArH), 7.65 (400 MHz, CDCl3): d = 1.21 (s, 9 H, C(CH3)3), 3.92 (s, 3 H, NCH3),
(d, J = 9.0 Hz, 1 H, ArH), 8.28 (d, J = 6.8 Hz, 1 H, ArH) ppm; 4.30 (s, 1 H, NH), 6.86 (s, 1 H, ArH), 7.04 (d, J = 9.0 Hz, 1 H, ArH),
13C NMR (100 MHz, CDCl3): d = 30.3, 37.8, 57.3, 106.4, 111.8, 7.43–7.46 (m, 5 H, ArH), 8.28 (s, 1 H, ArH) ppm; 13C NMR
116.9, 124.0, 124.5, 125.7, 129.1, 130.1, 130.7, 134.7, 141.8, (100 MHz, CDCl3): d = 30.3, 37.8, 57.3, 105.8, 111.2, 111.4, 123.4,
143.1, 146.0 ppm; HRMS (ESI) m/z: calcd for C21H22ClN5 125.8, 127.3, 129.1, 129.2, 130.0, 132.9, 134.6, 139.7, 142.9,
[M + H+]: 380.1642, found: 380.1635.
146.6 ppm; HRMS (ESI) m/z: calcd for C21H21BrClN5 [M + H+]:
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)- 458.0747, found: 458.0742.
7-methylimidazo[1,2-a]pyridin-3-amine (17bCX). Yield: 69%
6-Bromo-N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-
(0.248 g from 0.20 g) as a white solid; m.p. 198–200 1C; Rf = 3-yl)imidazo[1,2-a]pyridin-3-amine (17bJX). Yield: 41% (0.17 g from
0.16 (hexane/EtOAc, 30 : 70, v/v); IR (neat): nmax (cmꢁ1) = 3326 0.20 g) as a pale yellow solid; m.p. 178–180 1C; Rf = 0.21 (hexane/
(NH); 1H NMR (400 MHz, CDCl3): d = 1.19 (s, 9 H, C(CH3)3), EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3321 (NH); 1H NMR
2.36 (s, 3 H, ArCH3), 3.91 (s, 3 H, NCH3), 4.26 (s, 1 H, NH), 6.56 (400 MHz, CDCl3): d = 1.20 (s, 9 H, C(CH3)3), 3.92 (s, 3 H, NCH3),
(d, J = 7.0 Hz, 1 H, ArH), 6.86 (d, J = 0.6 Hz, 1 H, ArH), 7.25 4.29 (s, 1 H, NH), 6.86 (s, 1 H, ArH), 7.13 (dd, J1 = 9.4 Hz, J2 = 1.9
(s, 1 H, ArH), 7.41–7.45 (m, 4 H, ArH), 8.12 (d, J = 7.0 Hz, 1 H, Hz, 1 H, ArH), 7.38–7.46 (m, 5 H, ArH), 8.38 (s, 1 H, ArH) ppm;
ArH) ppm; 13C NMR (100 MHz, CDCl3): d = 21.4, 30.4, 37.8, 57.0, 13C NMR (100 MHz, CDCl3): d = 30.4, 37.9, 57.3, 105.1, 106.2,
87.3, 105.0, 113.9, 115.7, 123.2, 125.2, 129.1, 129.4, 130.1, 131.4, 118.0, 124.1, 126.1, 126.9, 129.1, 129.2, 130.1, 132.9, 134.7,
134.3, 134.6, 142.7, 147.1 ppm; HRMS (ESI) m/z: calcd for 140.5, 143.1, 146.6 ppm; HRMS (ESI) m/z: calcd for C21H21BrClN5
C22H24ClN5 [M + H+]: 394.1798, found: 394.1781.
[M + H+]: 458.0747, found: 458.0767.
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)-
Ethyl-2-((6-chloro-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-
6-methylimidazo[1,2-a]pyridin-3-amine (17bDX). Yield: 54% 3-yl)imidazo[1,2-a]pyridin-3-yl)amino)acetate (17bGY). Yield:
(0.195 g from 0.20 g) as an off white solid; m.p. 168–170 1C; 67% (0.27 g from 0.20 g) as a yellow solid; m.p. 97–99 1C;
Rf = 0.15 (hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax (cmꢁ1) = Rf = 0.15 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) =
1
3324 (NH); 1H NMR (400 MHz, CDCl3): d = 1.21 (s, 9 H, C(CH3)3), 1750 (CO2Et), 3256 (NH); H NMR (400 MHz, CDCl3): d = 1.28
2.32 (s, 3 H, ArCH3), 3.91 (s, 3 H, NCH3), 4.29 (s, 1 H, NH), 6.87 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 3.93 (s, 4 H, NCH3 and NCHH),
(s, 1 H, ArH), 6.93 (d, J = 8.8 Hz, 1 H, ArH), 7.41–7.43 (m, 5 H, 3.94 (s, 1 H, NCHH), 4.24 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.73
ArH), 8.03 (s, 1 H, ArH) ppm; 13C NMR (125 MHz, CDCl3): (t, J = 6.1 Hz, 1 H, NH), 6.90 (s, 1 H, ArH), 7.09 (dd, J1 = 9.6 Hz,
d = 18.5, 30.3, 37.8, 57.1, 104.9, 116.6, 120.7, 121.5, 125.4, 126.7, J2 = 1.8 Hz, 1 H, ArH), 7.40–7.50 (m, 5 H, ArH), 8.26 (s, 1 H, ArH)
129.1, 129.3, 130.0, 131.7, 134.5, 141.3, 142.9, 147.1 ppm; HRMS ppm; 13C NMR (100 MHz, CDCl3): d = 14.3, 38.0, 49.3, 61.3,
(ESI) m/z: calcd for C22H24ClN5 [M + H+]: 394.1798, found: 104.7, 117.8, 120.4, 120.8, 125.1, 126.8, 129.0, 129.2, 130.0,
394.1801.
N-(tert-butyl)-6-chloro-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol- calcd for C21H19Cl2N5O2 [M + H+]: 444.0994, found: 444.0985.
3-yl)imidazo[1,2-a]pyridin-3-amine (17bGX). Yield: 80% (0.302 g Ethyl-2-((6,8-dichloro-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-
130.7, 134.8, 139.9, 143.5, 145.9, 171.3 ppm; HRMS (ESI) m/z:
from 0.20 g) as a dull white solid; m.p. 180–182 1C; Rf = 0.11 3-yl)imidazo[1,2-a]pyridin-3-yl)amino)acetate (17bHY). Yield: 16%
(hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax (cmꢁ1) = 3319 (NH); (0.07 g from 0.20 g) as a yellow solid; m.p. 162–164 1C; Rf = 0.64
1H NMR (400 MHz, CDCl3): d = 1.21 (s, 9 H, C(CH3)3), 3.92 (s, 3 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 1744 (CO2Et),
H, NCH3), 4.30 (s, 1 H, NH), 6.86 (s, 1 H, ArH), 7.04 (d, J = 9.2 Hz, 3240 (NH); 1H NMR (500 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H,
1 H, ArH), 7.41–7.46 (m, 5 H, ArH), 8.28 (s, 1 H, ArH) ppm; 13
C
CO2CH2CH3), 3.93 (s, 5 H, NCH3 and NCH2), 4.22 (q, J = 7.2 Hz,
NMR (125 MHz, CDCl3): d = 30.4, 37.9, 57.3, 106.0, 117.7, 119.7, 2 H, CO2CH2CH3), 4.84 (s, 1 H, NH), 6.98 (s, 1 H, ArH),
121.8, 124.9, 126.2, 129.1, 130.0, 133.0, 134.7, 140.4, 143.1, 146.5 7.19 (d, J = 1.5 Hz, 1 H, ArH), 7.39–7.45 (m, 4 H, ArH), 8.21
ppm; HRMS (ESI) m/z: calcd for C21H21Cl2N5 [M + H+]: 414.1252, (s, 1 H, ArH) ppm; 13C NMR (125 MHz, CDCl3): d = 14.3, 38.0,
found: 414.1256.
49.2, 61.4, 106.3, 119.4, 119.7, 123.4, 123.6, 128.3, 129.0, 129.2,
N-(tert-butyl)-6,8-dichloro-2-(5-(4-chlorophenyl)-1-methyl-1H- 130.0, 131.4, 134.8, 137.1, 143.3, 145.7, 171.2 ppm; HRMS
pyrazol-3-yl)imidazo[1,2-a]pyridin-3-amine (17bHX). Yield: 45% (ESI) m/z: calcd for C21H18Cl3N5O2 [M + H+]: 478.0604, found:
(0.183 g from 0.20 g) as a dull white solid; m.p. 201–203 1C; 478.0623.
Rf = 0.82 (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) =
Ethyl-2-((6-bromo-2-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-
3309 (NH); 1H NMR (500 MHz, CDCl3): d = 1.20 (s, 9 H, C(CH3)3), 3-yl)imidazo[1,2-a]pyridin-3-yl)amino)acetate (17bJY). Yield: 61%
3.92 (s, 3 H, ArCH3), 4.41 (s, 1 H, NH), 6.97 (s, 1 H, ArH), (0.27 g from 0.20 g) as a yellow solid; m.p. 130–132 1C; Rf = 0.20
7.18 (d, J = 1.8 Hz, 1 H, ArH), 7.42–7.47 (m, 4 H, ArH), (hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 1747 (CO2Et),
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3306 (NH); 1H NMR (500 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, 1H NMR (400 MHz, CDCl3): d = 1.10 (s, 9 H, C(CH3)3), 2.35
CO2CH2CH3), 3.91 (s, 3 H, NCH3), 3.93 (s, 2 H, NCH2), 4.22 (s, 3 H, ArCH3), 3.94 (s, 1 H, NH), 6.99–7.01 (m, 1 H, ArH), 7.16–
(q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.74 (s, 1 H, NH), 6.89 (s, 1 H, 7.18 (m, 1 H, ArH), 7.24–7.25 (m, 2 H, ArH), 7.27–7.38 (m, 6 H,
ArH), 7.18 (d, J = 9.4 Hz, 1 H, ArH), 7.39–7.46 (m, 5 H, ArH), 8.35 ArH), 7.51–7.53 (m, 1 H, ArH), 8.08 (s, 1 H, ArH) ppm; 13C NMR
(s, 1 H, ArH) ppm; 13C NMR (125 MHz, CDCl3): d = 14.4, 38.1, 49.4, (100 MHz, CDCl3): d = 18.6, 30.0, 56.3, 64.7, 117.4, 121.1,
61.5, 104.9, 107.2, 118.0, 123.2, 126.7, 127.5, 129.0, 129.3, 130.1, 121.4, 124.9, 125.4, 126.3, 127.2, 127.9, 128.3, 128.6, 129.0,
130.2, 134.9, 140.0, 143.6, 145.7, 171.4 ppm; HRMS (ESI) m/z: calcd 129.2, 131.8, 131.9, 135.3, 138.0, 139.8, 141.3, 143.8, 150.0;
for C21H19BrClN5O2 [M + H+]: 488.0489, found: 488.0496.
HRMS (ESI) m/z: calcd for C27H25ClIN5 [M + H+]: 582.0921,
N-(tert-butyl)-2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)- found: 582.0919.
imidazo[1,2-a]pyrazin-3-amine (17aKX). Yield: 58% (0.045 g
2-(5-(3-Bromophenyl)-4-iodo-1-phenyl-1H-pyrazol-3-yl)-N-(tert-
from 0.050 g) as a light pink solid; m.p. 147–148 1C; Rf = 0.12 butyl)imidazo[1,2-a]pyridin-3-amine (23aAX). Yield: 53% (0.101 g
(hexane/EtOAc, 50 : 50, v/v); IR (neat): nmax (cmꢁ1) = 3323 (NH); from 0.14 g) as a white solid; m.p. 164–166 1C; Rf = 0.12 (hexane/
1
1H NMR (500 MHz, CDCl3): d = 1.25 (s, 9 H, C(CH3)3), 4.59 EtOAc, 70: 30, v/v); IR (neat): nmax (cmꢁ1) = 3352 (NH); H NMR
(s, 1 H, NH), 7.15 (s, 1 H, ArH), 7.22 (d, J = 8.3 Hz, 2 H, ArH), (400 MHz, CDCl3): d = 1.10 (s, 9 H, C(CH3)3), 3.97 (s, 1 H, NH),
7.29–7.40 (m, 7 H, ArH), 7.81 (d, J = 4.5 Hz, 1 H, ArH), 8.17 6.76–6.80 (m, 1 H, ArH), 7.12–7.16 (m, 1 H, ArH), 7.20–7.25
(d, J = 4.1 Hz, 1 H, ArH), 8.98 (s, 1 H, ArH) ppm; 13C NMR (m, 3 H, ArH), 7.27–7.35 (m, 4 H, ArH), 7.50–7.54 (m, 2 H, ArH),
(125 MHz, CDCl3): d = 30.5, 57.7, 107.2, 116.9, 125.2, 127.8, 7.60 (d, J = 9.1 Hz, 1 H, ArH), 8.31 (d, J = 6.8 Hz, 1 H, ArH) ppm;
127.9, 128.7, 128.8, 129.0, 129.2, 130.1, 133.8, 134.6, 137.5, 13C NMR (100 MHz, CDCl3): d = 30.1, 56.4, 64.8, 111.5, 118.0,
140.0, 142.7, 143.4, 148.0 ppm; HRMS (ESI) m/z: calcd for 123.9, 124.0, 124.9, 128.0, 129.0, 129.3, 130.2, 132.1, 132.2, 132.3,
C25H23ClN6 [M + H+]: 443.1751, found: 443.1778.
N-(tert-butyl)-6-(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)- C26H23BrIN5 [M + H+]: 612.026, found: 612.029.
133.4, 139.6, 142.2, 143.4, 149.9 ppm; HRMS (ESI) m/z: calcd for
imidazo[2,1-b]thiazol-5-amine (17bLX). Yield: 66% (0.23 g from
Typical procedure for the synthesis of 2-(5-(4-chlorophenyl)-
0.20 g) as a light pink solid; m.p. 155–157 1C; Rf = 0.22 (hexane/ 1-phenyl-1H-pyrazol-3-yl)-6-methylimidazo[1,2-a]pyridin-3-amine
EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3298 (NH); 1H NMR (24aDX). To a stirred solution of compound 17aDX (0.10 g,
(500 MHz, CDCl3): d = 1.21 (s, 9 H, C(CH3)3), 3.88 (s, 3 H, NCH3), 0.22 mmol) in dry toluene (6 mL), 40% aqueous HBF4 (0.015 mL,
4.43(s, 1 H, NH), 6.70 (d, J = 4.5 Hz, 1 H, ArH), 6.73 (s, 1 H, ArH), 0.24 mmol) was added dropwise at room temperature and reaction
7.39–7.44 (m, 5 H, ArH) ppm; 13C NMR (125 MHz, CDCl3): d = was heated at 120 1C for 30 min. On completion of reaction, solid
30.2, 37.7, 56.3, 104.1, 111.3, 118.3, 127.9, 129.1, 129.3, 130.0, product was precipitated out. The solid product was filtered under
132.1, 134.5, 142.8, 145.3, 147.1 ppm; HRMS (ESI) m/z: calcd for vacuum and washed with aqueous solution of sodium bicarbonate.
C19H20ClN5S [M + H+]: 386.1206, found: 386.1234.
The desired product was dried in air and finally triturated with
N-(tert-butyl)-2-(1,3-diphenyl-1H-pyrazol-5-yl)-6-methylimidazo- hexane to obtain a pure product 24aDX in 92% yield (0.08 g;
[1,2-a]pyridin-3-amine (21aDX). Yield: 54% (0.115 g from 0.20 g) Rf = 0.48 (hexane/EtOAc, 70 : 30, v/v)).
as a yellow solid; m.p. 148–150 1C; Rf = 0.21 (hexane/EtOAc, 50 :50,
2-(5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-6-methylimid-
v/v); IR (neat): nmax (cmꢁ1) = 3323 (NH); 1H NMR (500 MHz, azo[1,2-a]pyridin-3-amine (24aDX). Yield: 92% (0.08 g from 0.1 g)
CDCl3): d = 0.80 (s, 9 H, C(CH3)3), 2.32 (s, 3 H, ArCH3), 7.05–7.11 as a dull yellow solid; m.p. 180–182 1C; Rf = 0.48 (hexane/EtOAc,
(m, 2 H, ArH), 7.32–7.53 (m, 9 H, ArH), 7.88–7.89 (m, 3 H, ArH) 70: 30, v/v); IR (neat): nmax (cmꢁ1) = 3313 (NH); 1H NMR
ppm; 13C NMR (125 MHz, CDCl3): d = 18.5, 29.5, 55.7, 106.8, 116.9, (400 MHz, CDCl3 and DMSO-d6): d = 2.38 (s, 3 H, ArCH3), 5.70
121.3, 121.5, 123.9, 124.9, 127.2, 127.8, 128.2, 128.9, 129.6, 131.7, (s, 2 H, NH2), 7.01–7.04 (m, 1 H, ArH), 7.09–7.13 (m, 2 H, ArH),
133.8, 139.9, 140.6, 141.9, 151.7 ppm; HRMS (ESI) m/z: calcd for 7.19–7.23 (m, 4 H, ArH), 7.29–7.32 (m, 3 H, ArH), 7.40 (d, J = 9.2 Hz,
C27H27N5 [M + H+]: 422.2344, found: 422.2375.
1 H, ArH), 7.61–7.64 (m, 1 H, ArH), 8.27 (s, 1 H, ArH) ppm; 13C
N-(tert-butyl)-6-chloro-2-(3-(4-chlorophenyl)-1-methyl-1H-pyrazol- NMR (125 MHz, DMSO-d6): d = 17.7, 105.5, 108.4, 108.5, 111.4,
5-yl)imidazo[1,2-a]pyridin-3-amine (21bGX). Yield: 37% (0.140 g 121.7, 125.5, 125.6, 128.1, 128.5, 128.8, 128.9, 129.3, 130.2, 133.7,
from 0.20 g) as a dull white solid; m.p. 158–160 1C; Rf = 0.14 134.1, 139.0, 141.4, 143.2 ppm; HRMS (ESI) m/z: calcd for
(hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3300 (NH); C23H18ClN5 [M + H+]: 400.1329, found: 400.1423.
1H NMR (400 MHz, CDCl3): d = 1.04 (s, 9 H, C(CH3)3), 3.06
(s, 1 H, NH), 4.11 (s, 3 H, NCH3), 6.69 (s, 1 H, ArH), 7.13–7.16
Conflicts of interest
(m, 1 H, ArH), 7.34–7.38 (m, 2 H, ArH), 7.48 (d, J = 9.5 Hz, 1 H,
ArH), 7.74–7.77 (m, 2 H, ArH), 8.26 (s, 1 H, ArH) ppm; 13C NMR
There are no conflicts to declare.
(100 MHz, CDCl3): d = 30.2, 38.3, 56.3, 103.6, 118.2, 120.6, 121.6,
126.2, 126.4, 126.8, 128.9, 132.1, 133.4, 138.0, 140.6, 149.3 ppm;
HRMS (ESI) m/z: calcd for C21H21Cl2N5 [M + H+]: 414.1252,
found: 414.1244.
Acknowledgements
N-(tert-butyl)-2-(5-(4-chlorophenyl)-4-iodo-1-phenyl-1H-pyrazol- S. S. gratefully acknowledges the Ministry of Human Resource
3-yl)-6-methylimidazo[1,2-a]pyridin-3-amine (22aDX). Yield: 86% Development and Council of Scientific & Industrial Research,
(0.245 g from 0.20 g) as a dull white solid; m.p. 170–172 1C; Rf = 0.30 New Delhi, India for Junior Research Fellowships. V. S. is highly
(hexane/EtOAc, 70 : 30, v/v); IR (neat): nmax (cmꢁ1) = 3313 (NH); grateful to the Department of Science and Technology, Science
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spectroscopic data.
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