Metal-free synthesis of aminomethylated imidazoheterocycles: dual role of tert-butyl hydroperoxide as both an oxidant and a methylene source

Article abstract of DOI:10.1039/C8OB02432D

A novel and efficient aminomethylation approach has been developed for the regioselective functionalization of imidazoheterocycles under metal-free conditions. A wide range of imidazoheterocycles and 2/4-aminoazaheterocycles successfully provided corresponding aminomethylated imidazoheterocycles in moderate to excellent (33-80%) yields. The isotopic labelling study suggested that TBHP played a dual role as both an oxidant and a methylene source in this transformation. The developed protocol follows a radical pathway which is supported by radical trapping experiments.

Full text of DOI:10.1039/C8OB02432D

Organic &
Biomolecular Chemistry
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PAPER
Metal-free synthesis of aminomethylated
imidazoheterocycles: dual role of tert-butyl
hydroperoxide as both an oxidant and a
methylene source†
Cite this: Org. Biomol. Chem., 2018,
6, 8620
1
Om P. S. Patel, Nitesh Kumar Nandwana, Ajay Kumar Sah and Anil Kumar
*
A novel and efficient aminomethylation approach has been developed for the regioselective functionali-
zation of imidazoheterocycles under metal-free conditions. A wide range of imidazoheterocycles and
2/4-aminoazaheterocycles successfully provided corresponding aminomethylated imidazoheterocycles
in moderate to excellent (33–80%) yields. The isotopic labelling study suggested that TBHP played a dual
role as both an oxidant and a methylene source in this transformation. The developed protocol follows a
radical pathway which is supported by radical trapping experiments.
Received 29th September 2018,
Accepted 24th October 2018
DOI: 10.1039/c8ob02432d
rsc.li/obc
On the other hand, imidazoheterocycles are privileged
Introduction
nitrogen heterocycles as these compounds display a broad
8
Transition-metal free construction of C–N and C–C bonds via range of biological and photophysical properties. It has been
cross-dehydrogenative coupling (CDC) reactions represents an observed that the nature of the substituents at the C-2 or C-3
ideal strategy in the perspective of green and sustainable positions of imidazoheterocycles significantly influences their
1
chemistry. These reactions generally demonstrate step- and biological activities. Amidomethylated and aminomethylated
atom-efficiency and eliminate the use of pre-functionalized linkers on imidazo[1,2-a]pyridine are found in a number of
2
substrates for C–H bond functionalization. The oxidative commercially available drugs such as necopidem, saripidem,
3
9
functionalization of sp C–H bonds remains a challenge due to GSK812397 and bioactive lead compounds (Fig. 1). Therefore,
the poor acidity and high bond dissociation energy and is substantial efforts have been devoted to the synthesis and
3
therefore of special interest. Recently, remarkable progress functionalization of the imidazoheterocycles substituted at the
has been realized toward the radical initiated domino C-3 position of the core ring.
approach for the selective functionalization of C–H bonds.
9
a,10
Regioselective aminomethyl-
ation of imidazoheterocycles may generate diversely substi-
4
Organic peroxides are most commonly used as hydrogen tuted imidazoheterocycles for medicinal chemistry appli-
acceptors for the functionalization and synthesis of a diverse cation. However, a careful literature survey revealed that the
range of N-heterocyclic compounds via radical addition/cycli- aminomethylated strategy on imidazoheterocycles is rarely
5
zation reactions. In recent years, peroxides have been explored and limited to only morpholine as an amine coupling
1
1
exploited as one carbon source for the methylation of C–H, partner.
N–H, OH and S–H bonds. In addition, peroxides have also
6
Owing to the valuable applications of organic peroxides in
been used as one carbon source for decarboxylative methyl- organic synthesis, our previous results on the use of dimethyl
7
12
13
ation and the methylation–cyclization strategy. Most of these sulfoxide (DMSO), and dimethylacetamide (DMA) as the
reactions rely on transition metal-catalysis to produce the carbon synthon and our efforts towards synthesis and
14
methyl radical species from organic peroxides. However, utiliz- functionalisation of N-heteroaromatics, we herein report a
ation of organic peroxides as a methylene synthon for the
aminomethylation reaction has not been reported so far in the
literature.
Department of Chemistry, Birla Institute of Technology and Science Pilani,
Pilani Campus, 333031 Rajasthan, India. E-mail: anilkumar@pilani.bits-pilani.ac.in
†
Electronic supplementary information (ESI) available: Experimental details and
1
13
characterization of all compounds, copies of H and C NMR, ESI-HRMS
spectra for compounds. See DOI: 10.1039/c8ob02432d
Fig. 1 Representative examples of bioactive imidazo[1,2-a]pyridines.
8620 | Org. Biomol. Chem., 2018, 16, 8620–8628
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(
(
CP), dicumyl peroxide (DCP) and tert-butyl peroxybenzoate
TBPB) were used under identical reaction conditions. The
desired product 3aa was obtained in 51%, 70%, 9% and 62%
yields by using DTPB, CP, DCP and TBPB, respectively
Scheme 1 Aminomethylation
aminoazaheterocycles.
of
imidazoheterocycles
with
(
Table 1, entries 2–5). Acetophenone was also isolated in 75%
yield from the reaction of 1a and 2a in the presence of CP.
Moreover, the use of the TBHP/TBAI oxidative system afforded
the desired product (3aa) in 72% yield (Table 1, entry 6).
Decreasing the reaction temperature to 100 °C resulted in
reduced yield (33%) of 3aa and 1a was recovered in 59% yield
regioselective aminomethylation of imidazoheterocycles with
aminoazaheterocycles using TBHP as a mild and eco-friendly
oxidant as well as a carbon synthon (Scheme 1). The developed
3
2
(
Table 1, entry 7). The screening of different solvents viz H O/
2
strategy involves sp and sp C–H bond functionalization
SLS, 1,4-dioxane, chlorobenzene and DMF revealed that DMSO
was the best choice for the present reaction (Table 1, entries 1
vs. 8–12). Lower yields of 3aa were obtained in 1,4-dioxane,
chlorobenzene and toluene, whereas the reaction did not
under metal-free conditions.
Results and discussion
2
proceed in H O/SLS. The use of DMF as the solvent resulted in
We began our investigation by choosing 2-phenylimidazo[1,2-a] ring opening of 1a via oxidative cleavage of C–C and C–N
pyridine (1a) and 2-aminopyridine (2a) as model substrates. The bonds followed by oxygenation to afford the N-(pyridin-2-yl)
1
5
results for the optimization of the reaction conditions are given benzamide in 85% yield after 24 h along with a trace amount
in Table 1. The initial reaction of 1a and 2a was performed in of desired product 3aa (Table 1, entry 12). Further increasing
DMSO using TBHP (70% aqueous solution; 3 equiv.) as an exter- the concentration of TBHP to 4 equiv. under optimal reaction
nal oxidant at 120 °C. Pleasingly, the desired product conditions resulted in no significant enhancement in the yield
N-((2-phenylimidazo[1,2-a]pyridin-3yl)methyl)pyridin-2-amine of 3aa (Table 1, entry 13). In the absence of TBHP as an exter-
(
3aa) was obtained in 75% yield after 12 h (Table 1, entry 1). nal oxidant, we could not observe the desired product 3aa.
1
2
The molecular structure of 3aa was unambiguously assigned However, we have isolated 3,3′-bisimidazopyridinylmethane
by 1D, 2D-NMR spectroscopy and ESI-HRMS analysis (ESI†).
(4a) in 32% yield in 24 h under optimal reaction conditions
In light of the above results, various organic peroxides (Table 1, entry 14).
namely di-tert-butyl peroxide (DTBP), cumene hydroperoxide
After establishing the optimal reaction conditions (Table 1,
entry 1), we turned our attention to explore the substrate scope
of imidazo[1,2-a]pyridines having various substitutions for the
regioselective aminomethylation with 2-aminopyridine (2a)
a
Table 1 Optimization of the reaction conditions
(
Table 2). Imidazo[1,2-a]pyridines having electron donating
groups (p-Me, p-OMe) on the C-2 phenyl ring (1b and 1c)
reacted smoothly with 2a and afforded respective products 3ba
and 3ca in 77 and 80% yields, respectively. The substrate with
electron withdrawing groups (p-Cl, p-Br, p-NO
and m-NO ) on the C-2 phenyl ring of imidazo[1,2-a]pyridines
1d–i) also delivered corresponding products (3da–ia) in mod-
erate to good yields (56–73%). Furthermore, substrates having
the methyl substituent (7-Me and 6-Me) on the pyridine ring
of imidazo[1,2-a]pyridine (1j and 1k) furnished the desired
products 3ja and 3ka in 70 and 78% yields, respectively.
Interestingly, imidazo[1,2-a]pyridine having the fluoro substi-
tuent on the pyridine ring (1l) also afforded desired product
2 3
, p-CN, p-CF
b
Temp.
(°C)
Time
(h)
Yield
(%)
2
Entry
Peroxide
Solvent
(
1
2
3
4
5
6
7
8
9
TBHP
DTBP
CP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
100
120
120
120
120
120
120
120
12
18
12
15
15
12
24
24
24
24
24
24
12
24
75
51
70
c
DCP
9
TBPB
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
62
72
33
d
e
2
H O/SLS
NR
25
33
1,4-Dioxane
Chlorobenzene
Toluene
DMF
DMSO
DMSO
3la in 58% yield. The imidazo[1,2-a]pyridines with the bromo
10
11
12
13
14
group on the pyridine ring and chloro or bromo groups on the
C-2 phenyl ring also afforded corresponding products 3ma
and 3na in 59 and 55%, yields, respectively. Similarly, imidazo
17
f
Trace
74
g
TBHP
h
—
—
[1,2-a]pyridine with the methyl group at the C-6 position and
a
Reaction conditions: 1a (0.8 mmol), 2a (1.0 mmol), peroxide the nitro group on the C-2 phenyl ring (1o) gave the respective
b
(
2.4 mmol), DMSO (5 mL), 120 °C, 12–24 h. Isolated yield.
Acetophenone was isolated in 75% yield. 20 mol% TBAI was used.
a was recovered in 59%. N-(Pyridine-2-yl)benzamide (5a) was iso-
product 3oa in 74% yield. It is worth mentioning that halogens
c
d
1
6
e
f
(F, Cl and Br), –NO
, −CN and pharmaceutically active –CF
1
2
3
g
h
lated in 85% yield. 4 equivalent TBHP was used. Bis(2-phenylimi- groups were well tolerated under optimized reaction con-
dazo[1,2-a]pyridine-3-yl)methane (4a) was obtained in 32% yield; NR =
no reaction; DTBP = di-tert-butyl peroxide; CP = cumene hydroperox-
ide; DCP = dicumyl peroxide; TBPB = tert-butyl peroxybenzoate; SLS =
ditions and may serve as crucial substituents for post-
functionalization reactions. Imidazo[1,2-a]pyridine with C-2
sodium lauryl sulfate.
thiophene-yl (1p) yielded corresponding product 3pa in 54%
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a,b
a,b
Table 2 Substrate scope of imidazoheterocycles
Table 3 Substrate scope of 2/4-aminoazaheterocycles
a
Reaction conditions: 1 (0.8 mmol), 2 (1.0 mmol), TBHP (2.4 mmol),
b
c
DMSO (5 mL), 120 °C, 12 h. Isolated yields. Reaction time 17 h.
d
Reaction time 20 h.
ducts 3ag and 3bg were obtained by the reaction of 4-amino-
pyridine (2g) with 1a and 1b along with the recovery of reac-
tants. We were unable to isolate the desired product from the
reaction of 3-aminopyridine (2h) with 1a due to multiple side
product formation. Finally, the reaction of 2-aminopyrimidine
(2i) and 2-aminopyrazine (2j) with 1a under optimized reaction
conditions resulted in corresponding products 3ai and 3aj in
a
Reaction conditions: 1 (0.8 mmol), 2a (1.0 mmol), TBHP (2.4 mmol),
b
c
DMSO (5 mL), 120 °C, 12 h. Isolated yields. 24 h.
49% and 51% yields, respectively.
To check the practical utility of the present approach, the
yield. Pleasingly, the substrate having the tert-butyl group at gram-scale experiment was performed with 1a (1.5 g) and 2a
the C-2 position (1q) smoothly delivered the respective product (0.870 g) under the standard reaction conditions. To our
3
qa in 60% yield under similar reaction conditions. However, delight, the desired product 3aa was formed in 64% yield in
the reaction of imidazo[1,2-a]pyridine bearing –CF
substi- 20 h (Scheme 2).
tution at the C-2 position (1r) failed to afford the desired
To understand the reaction pathway, we performed a series
product 3ra. It might be due to the deactivation of the C-3 of control experiments (Scheme 3). The reaction of 1a and 2a
position due to the strong electron withdrawing nature of the in the presence of TBHP in DMSO-d as a solvent resulted in
CF
group. Notably, unsubstituted imidazo[1,2-a]pyridine at the formation of 3aa in 68% yield (Scheme 3; eqn (i)). This
3
6
–
3
the C-2 position (1s) afforded the desired product 3sa in 33% indicated that TBHP acts as a methylene source in this reac-
yield along with the recovery of 1s in 58% yield, which also tion and not DMSO. The radical trapping study with different
confirms the C-3 regioselectivity of the present reaction. The radical scavengers such as 2,2,6,6-tetramethylpiperidine-1-oxyl
low yield in the case of 3sa might be due to the poor stabiliz- (TEMPO), 1,1-diphenylethylene (DPE), and 2,4-di-tertbutyl-
ation of the radical intermediate generated in the reaction. 4-methylphenol (BHT) was performed to shed light on the kind
2
-(4-Methoxyphenyl)imidazo[1,2-a]pyrimidine
(1t)
and of mechanism involved. The use of TEMPO resulted in com-
6
-phenylimidazo[2,1-b]thiazole (1u) also reacted smoothly plete inhibition of 3aa formation in the reaction. The methyl
under standard reaction conditions to afford corresponding adduct of TEMPO (7a) was observed in the ESI-HRMS analysis
products 3ta and 3ua in 61% and 53% yields, respectively.
(m/z 172.1697) indicating the generation of the methyl radical
Next, we evaluated the compatibility of various 2-aminopyri- in the reaction mixture (Scheme 3; eqn (ii)). The addition of
dines and related aminoazaheterocycles under the optimized DPE in the reaction of 1a and 2a resulted in reduced yield
reaction conditions (Table 3). To our delight, different
2
-aminopyridines with chloro, bromo and methyl substituents
(
2b–e) reacted smoothly with 1a to afford corresponding pro-
ducts 3ab–ae in moderate to good (43–61%) yields. Similarly,
the reaction of 2-amino-4-methylpyridine (2d) and 2-amino-
5
-methylpyridine (2e) with 1o having the nitro group on the
C-2 phenyl ring gave corresponding products 3od and 3of in
6
5% and 70% yields, respectively. Low yields (35–38%) of pro- Scheme 2 Gram scale application.
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Scheme 4 Proposed mechanism.
Based on preliminary mechanistic studies, ESI-HRMS ana-
6
b,c,h,17
lysis and relevant literature studies,
a possible mecha-
nism is depicted in Scheme 4. Initially, TBHP undergoes
homolytic fission to produce a tert-butoxy radical which then
produces the methyl radical species via β-methyl elimination.
The radical species i.e. tert-butoxy/tert-butylperoxy/hydroxy
abstracted the hydrogen atom from 2-aminopyridine to give
aminyl radical intermediate A which may get stabilized with
the pyridine ring. The formation of aminyl radical intermedi-
ate A was supported by radical trapping experiments with BHT
and DPE (see the ESI†). Intermediate A reacted with the in situ
Scheme 3 Control experiments.
(
(
20%) of 3aa along with the formation of 4a in 25% yield generated methyl radical to form intermediate 2a′.
Scheme 3; eqn (iii)) which is due to homocoupling of 1a with Furthermore, hydrogen atom abstraction from intermediate
the methylene synthon in situ produced by DMSO under 2a′ resulted in the formation of radical C. Radical addition of
1
2
aerobic oxidative conditions. Similarly, addition of BHT in C to 1a generated radical intermediate E which upon hydrogen
the reaction of 1a and 2a also led to reduction in the yield atom abstraction in the presence of the tert-butoxy/tert-butyl-
(
41%) of 3aa (Scheme 3; eqn (iv)). The aminomethylated BHT peroxy radical afforded the desired product 3aa.
adduct (8a) and aminated BHT adduct (9a) were also observed
in the ESI-HRMS analysis of the reaction mixture. However, in
the case of BHT and DPE, the methyl adducts (10a and 11a)
were not observed in the ESI-HRMS analysis. Possibly BHT and
Conclusions
DPE failed to capture the reactive methyl radical which sub- In summary, a highly efficient metal-free method has been
sequently reacted with 2a to produce 3aa in 41% and 20% developed for the synthesis of aminomethylated imidazo-
yields, respectively. TEMPO exhibited better reactivity than heterocycles that involves intermolecular cross-dehydrogenative
BHT and DPE, captured the reactive methyl radical and there- coupling and uses TBHP as a methylene source as well as a
fore completely inhibited the formation of 3aa. These experi- hydrogen acceptor. The developed protocol follows a radical
ments strongly supported that the reaction involved a substan- pathway which is supported by the radical trapping experi-
tial amount of radical-mediated pathway. To identify possible ments and isotopic labelling study. A series of aminomethyl-
intermediates of the present reaction, 3-methyl-2-phenylimi- ated imidazoheterocycles was synthesized in good to high
dazo[1,2-a]pyridine (1a′) was allowed to react with 2a under the yields under very simple and practical reaction conditions.
optimum reaction conditions. Only traces of 3aa were observed Tolerance of various functional groups as well as secondary
on TLC along with the formation of imidazopyridine-3-carbal- amine derived products may give an excellent opportunity for
dehyde (6a) and N-(pyridine-2-yl)benzamide (5a) in 18% and post-functionalization in medicinal chemistry application.
3
9% yields, respectively (Scheme 3; eqn (v)). These results indi-
cate that 1a′ may not be the intermediate for this transform-
ation. On the other hand, 3aa was obtained in 70% yield from
the reaction of N-methylpyridin-2-amine (2a′) with 1a under
the standard reaction conditions (Scheme 3; eqn (vi)) which
Experimental section
General information
strongly supports the hypothesis that the reaction proceeds via Melting points were determined in open capillary tubes on
methylation of 2-aminopyridine to generate 2a′ as an inter- EZ-Melt automated melting point apparatus and are uncor-
1
13
mediate which subsequently underwent a radical addition rected. All the compounds were fully characterized by H, C,
reaction with 1a to afford 3aa.
and IR and further confirmed by ESI-HRMS analysis.
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Reactions were monitored by using thin layer chromatography (100 MHz, CDCl
3
) δ = 158.3, 148.1, 145.2, 144.7, 137.5, 134.2,
1
13
(TLC) on 0.2 mm silica gel F254 plates (Merck). H and
C
128.7 (2 × CH), 128.5 (2 × CH), 128.0, 124.8, 124.4, 117.5,
NMR spectra were recorded on 400 MHz and 100 MHz instru- 117.1, 113.7, 112.4, 108.4, 35.7 ppm; HRMS (ESI) calcd for
+
+
ments, respectively, with CDCl
3
and DMSO-d
6
as the solvent
C
19
H
17
N
4
[M + H] 301.1448, found 301.1449.
using TMS as an internal standard. Peak multiplicities of
H-NMR signals were designated as s (singlet), br s (broad amine (3ba). Off-white solid; 77% yield; mp = 121–122 °C;
N-((2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-
1
singlet), d (doublet), dd (doublet of doublet), t (triplet), FT-IR (neat): 3270, 1610, 1517, 1477, 1380, 1343, 1265, 970,
q (quartet), m (multiplet), etc. Chemical shifts (δ) and coupling 758 cm− ; H NMR (400 MHz, CDCl ): δ = 8.19–8.17 (m, 2H),
1 1
3
constants (J) are reported in parts per million (ppm) relative to 7.69–7.64 (m, 3H), 7.43 (t, J = 7.8 Hz, 1H), 7.27–7.22 (m, 3H,
the residual signal of TMS in deuterated solvents and hertz, overlapped with residual signal), 6.81 (t, J = 6.8 Hz, 1H), 6.66
respectively. ESI-HRMS were recorded using Q-TOF LC/MS. IR (t, J = 6.0 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 4.7 Hz,
1
3
3
spectra were recorded using an FT-IR spectrophotometer, and 2H), 4.65 (s, 1H), 2.39 (s, 3H) ppm; C NMR (100 MHz, CDCl )
−
1
values are reported in cm . Column chromatography was per- δ = 158.1, 147.9, 145.2, 144.8, 138.0, 137.7, 131.2, 129.6 (2 ×
formed over silica gel (60–120 mesh) using EtOAc–n-hexane as CH), 128.4 (2 × CH), 124.9, 124.4, 117.5, 116.8, 113.7,
+
an eluent. Imidazoheterocycles were prepared from corres- 112.5, 108.4, 35.7, 21.4 ppm; HRMS (ESI) calcd for C20
H
19
N
4
+
ponding methyl ketones and 2-aminopyridines/2-aminopyri- [M + H] 315.1604, found 315.1595.
1
8
midines/2-aminothiazoles following the reported procedure.
N-((2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)
All the chemicals were obtained from the commercial suppli- pyridin-2-amine (3ca). Off-white solid; 80% yield; mp =
ers and used without further purification.
160–162 °C; FT-IR (neat): 3232, 1597, 1481, 1242, 1172, 1026,
Experimental procedure for the preparation of 3aa. To a 840, cm− ; H NMR (400 MHz, CDCl ): δ = 8.15 (dd, J = 5.2,
1 1
3
stirred solution of 2-phenylimidazo[1,2-a]pyridine 1a 2 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.58
(
(
0.8 mmol) in DMSO (5 mL) were added 2-aminopyridine 2a (d, J = 9 Hz, 1H), 7.44–7.40 (m, 1H), 7.16 (t, J = 7.1 Hz, 1H),
1 mmol) and t-BuOOH (70% aqueous solution) (2.4 mmol) at 6.93 (d, J = 8.7 Hz, 2H), 6.74 (t, J = 6.6 Hz, 1H), 6.66–6.62 (m,
room temperature and the reaction mixture was stirred at 1H), 6.48 (d, J = 8.3 Hz, 1H), 4.96 (d, J = 4.7 Hz, 2H), 4.80 (t, J =
1
3
1
3
20 °C for 12 h. After completion of the reaction, observed by 4.8 Hz, 1H), 3.82 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ =
TLC, the mixture was allowed to attain room temperature. The 159.6, 158.2, 148.1, 145.1, 144.5, 137.5, 129.6 (2 × CH), 126.6,
reaction mixture was poured into 20 mL of water and extracted 124.7, 124.3, 117.3, 116.3, 114.2 (2 × CH), 113.6, 112.3, 108.4,
+
+
with EtOAc (3 × 15 mL). The combined organic layer was dried 55.4, 35.7 ppm; HRMS (ESI) calcd for C20
over Na SO and evaporated under vacuum. The resulting 331.1553, found 331.1551.
19 4
H N O [M + H]
2
4
crude solid was purified by column chromatography (silica gel
N-((2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)
6
0–120 mesh) using EtOAc–n-hexane (4.0 : 6.0, v/v) as an eluent pyridin-2-amine (3da). Off-white solid; 69% yield; mp =
to afford 3aa in 75% yield as the amorphous white solid.
157–159 °C; FT-IR (neat): 3240, 1597, 1481, 1419, 1357, 1280,
Procedure for radical trapping experiments. To a stirred 979, 833, 732 cm− ; H NMR (400 MHz, CDCl
1
1
): δ = 8.18 (d, J =
3
solution of 2-phenylimidazo[1,2-a]pyridine 1a (0.8 mmol) in 4.3 Hz, 1H), 8.15 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H),
DMSO (5 mL) were added 2-aminopyridine 2a (1 mmol), 7.62 (d, J = 9.1 Hz, 1H), 7.47–7.42 (m, 1H), 7.39 (d, J = 8.4 Hz,
t-BuOOH (70% aqueous solution) (2.4 mmol) and TEMPO/ 2H), 7.22 (t, J = 7.7 Hz, 1H), 6.80 (t, J = 6.6 Hz, 1H), 6.69–6.66
BHT/DPE (5 equiv.) at room temperature and the reaction (m, 1H), 6.48 (d, J = 8.3 Hz, 1H), 4.99 (d, J = 4.9 Hz, 2H), 4.66
1
3
mixture was stirred at 120 °C for 12 h. The reaction mixture (t, J = 4.8 Hz, 1H) ppm; C NMR (100 MHz, CDCl ) δ = 158.1,
3
was allowed to attain room temperature and poured into 148.1, 145.2, 143.5, 137.6, 134.0, 132.6, 129.6 (2 × CH), 129.0
2
0 mL of water and extracted with EtOAc (3 × 15 mL). The com- (2 × CH), 125.2, 124.4, 117.6, 117.2, 113.9, 112.7, 108.5,
+
+
bined organic layer was dried over Na SO and evaporated 35.6 ppm; HRMS (ESI) calcd for C H ClN
4
[M + H]
2
4
19 16
under vacuum. The resulting crude solid was purified over 335.1058, found 335.1054.
silica gel (60–120 mesh) column chromatography by using N-((2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)
EtOAc–n-hexane (4.0 : 6.0, v/v) to afford 3aa in 0, 41% and 20% pyridin-2-amine (3ea). Off-white solid; 62% yield; mp =
yields in the case of TEMPO, BHT and DPE, respectively. The 167–169 °C; FT-IR (neat): 3240, 1597, 1504, 1481, 1357, 1280,
same reaction mixtures were directly analysed by ESI-HRMS 979, 825, 771, 725 cm−
1
;
1
H NMR (400 MHz, CDCl
analysis to observe the corresponding intermediates and 8.18–8.16 (m, 1H), 8.13 (dt, J = 6.9, 1.2 Hz, 1H), 7.63–7.58 (m,
adducts of radical scavengers such as TEMPO, BHT and DPE. 3H), 7.53–7.49 (m, 2H), 7.47–7.42 (m, 1H), 7.23–7.18 (m, 1H),
N-((2-Phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine 6.79 (td, J = 6.8, 1.2 Hz, 1H), 6.69–6.65 (m, 1H), 6.50 (dt, J =
3
): δ =
1
9
(3aa). Off-white solid; 75% yield; mp = 177–178 °C (lit.,
8.3, 1.0 Hz, 1H), 4.96 (d, J = 4.8 Hz, 2H), 4.78 (t, J = 4.8 Hz, 1H)
1
3
1
7
2
78–179 °C); FT-IR (neat): 3240, 1597, 1481, 1350, 1249, 979, ppm; C NMR (100 MHz, CDCl
3
) δ 158.1, 148.1, 145.2, 143.4,
): δ = 8.16–8.13 (m, 137.6, 133.0, 131.9 (2 × CH), 129.8 (2 × CH), 125.2, 124.4,
H), 7.75 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.42–7.39 122.2, 117.5, 117.3, 113.8, 112.7, 108.5, 35.6 ppm; HRMS (ESI)
56, 702 cm− ; H NMR (400 MHz, CDCl
1
1
3
+
+
(m, 3H), 7.35 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.75 (t, calcd for C19
H
16BrN
4
[M + H] 379.0553, found 379.0549.
J = 6.8 Hz, 1H), 6.63 (t, J = 5.9 Hz, 1H), 6.45 (d, J = 8.3 Hz, 1H),
N-((2-(4-Nitrophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
1
3
5
.00 (d, J = 4.7 Hz, 2H), 4.75 (br s, 1H) ppm; C NMR 2-amine (3fa). Yellow solid; 71% yield; mp = 196–198 °C; FT-IR
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neat): 3232, 1597, 1512, 1334, 1111, 979, 858, 732 cm− ; H 144.3, 137.6, 136.0, 134.2, 128.7 (2 × CH), 128.5 (2 × CH),
1 1
(
NMR (400 MHz, CDCl ): δ = 8.23 (d, J = 8.7 Hz, 2H), 8.20–8.17 127.9, 123.7, 116.4, 115.9, 115.2, 113.6, 108.4, 35.7, 21.5 ppm;
3
+
+
(
m, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 9.1 Hz, 1H), HRMS (ESI) calcd for C20
H
19
N
4
[M + H] 315.1604, found
7
.49–7.45 (m, 1H), 7.28–7.23 (m, 1H, overlapped with the 315.1598.
residual signal), 6.83 (t, J = 6.7 Hz, 1H), 6.71–6.68 (m, 1H), 6.53
N-((6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
(
1
d, J = 8.3 Hz, 1H), 5.03 (d, J = 4.9 Hz, 2H), 4.79 (d, J = 4.4 Hz, 2-amine (3ka). Off-white solid; 78% yield; mp = 209–211 °C;
1
3
−1 1
3
H) ppm; C NMR (100 MHz, CDCl ) δ = 157.9, 148.1, 147.2, FT-IR (neat): 3240, 1597, 1473, 1388, 1242, 771, 702 cm ; H
1
45.5, 142.0, 140.6, 137.7, 128.8 (2 × CH), 125.8, 124.6, 124.0 NMR (400 MHz, CDCl ): δ = 8.19–8.17 (m, 1H), 7.93 (s, 1H),
3
(
(
3
2 × CH), 118.9, 117.8, 114.1, 113.1, 108.7, 35.5 ppm; HRMS 7.76–7.74 (m, 2H), 7.54 (d, J = 9.2 Hz, 1H), 7.45–7.40 (m, 3H),
+
+
ESI) calcd for C19
46.1318.
4
H
16
N
5
O
2
[M + H] 346.1299, found 7.36–7.32 (m, 1H), 7.06 (dd, J = 9.2, 1.4 Hz, 1H), 6.68–6.65 (m,
1H), 6.48 (d, J = 8.3 Hz, 1H), 4.95 (d, J = 4.8 Hz, 2H), 4.69 (t, J =
1
3
-((3-((Pyridin-2-ylamino)methyl)imidazo[1,2-a]pyridin-2-yl) 5.0 Hz, 1H), 2.29 (s, 3H) ppm; C NMR (100 MHz, CDCl
benzonitrile (3ga). Off-white solid; 63% yield; mp 158.3, 148.1, 144.5, 144.3, 137.6, 134.2, 128.7 (2 × CH), 128.4
34–136 °C; FT-IR (neat): 3263, 2229, 1604, 1504, 1481, 1280, (2 × CH), 128.1, 127.9, 122.2, 122.0, 116.9, 116.6, 113.7, 108.4,
3
) δ =
=
1
9
2
1
5
79, 732 cm− ; H NMR (400 MHz, CDCl
H), 7.83 (d, J = 8.3 Hz, 2H), 7.61–7.57 (m, 3H), 7.47–7.43 (m, 315.1604, found 315.1619.
H), 7.24–7.20 (m, 1H), 6.80 (t, J = 6.8 Hz, 1H), 6.68 (t, J = N-((6-Fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
.2 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 4.96 (s, 3H, overlapped 2-amine (3la). Off-white solid; 58% yield; mp = 187–189 °C;
1
1
): δ = 8.17–8.12 (m, 35.9, 18.5 ppm; HRMS (ESI) calcd for C20
H
N
+
[M + H]
+
3
19
4
1
3
with the NH signal); C NMR (100 MHz, CDCl
1
3
) δ = 157.9, FT-IR (neat): 3248, 3008, 1604, 1489, 1334, 1219, 848, 763,
48.1, 145.3, 142.2, 138.6, 137.6, 132.4 (2 × CH), 128.6 (2 × 702 cm− ; H NMR (400 MHz, CDCl ): δ = 8.19 (dd, J = 4.4,
1
1
3
CH), 125.7, 124.5, 118.9, 118.5, 117.6, 114.0, 113.0, 111.2, 2.4 Hz, 1H), 8.16 (dd, J = 5.1, 1.8 Hz, 1H), 7.72–7.70 (m, 2H),
+
+
1
3
08.7, 35.4; HRMS (ESI) calcd for C20
26.1400, found 326.1399.
H
16
N
5
[M + H]
7.56 (dd, J = 9.8, 5.1 Hz, 1H), 7.43–7.39 (m, 3H), 7.36–7.32 (m,
1H), 7.11–7.06 (m, 1H), 6.65 (dd, J = 6.8, 5.5 Hz, 1H), 6.48 (d,
N-((2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl) J = 8.3 Hz, 1H), 4.98 (d, J = 5.2 Hz, 2H), 4.83 (t, J = 4.8 Hz, 1H)
1
3
methyl)pyridin-2-amine (3ha). White solid; 56% yield; mp = ppm; C NMR (100 MHz, CDCl
3
) δ = 158.14, 153.3 (JC–F
=
1
1
75–177 °C; FT-IR (neat): 3240, 1597, 1481, 1319, 1242, 1165, 235 Hz), 148.0, 145.86, 145.84, 142.7, 137.6, 133.8, 128.8 (2 ×
064, 910, 732 cm− ; H NMR (400 MHz, CDCl
1
1
): δ = 8.15–8.14 CH), 128.3 (2 × CH), 128.1, 118.9 (JC–F = 2.0 Hz), 117.8 (JC–F
=
3
(
7
6
m, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 9.0 Hz), 116.8 (JC–F = 25 Hz), 113.8, 111.7, 111.3, 108.6,
.55–7.51 (m, 3H), 7.46–7.42 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 35.5 ppm; HRMS (ESI) calcd for C H FN [M + H] 319.1354,
19 16 4
+
+
.72–6.64 (m, 2H), 6.59 (d, J = 8.3 Hz, 1H), 5.26 (br s, 1H), 4.92 found 319.1350.
1
3
(d, J = 4.6 Hz, 2H) ppm; C NMR (100 MHz, CDCl
3
) δ = 158.2,
N-((6-Bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)
1
48.0, 145.1, 142.6, 137.5, 137.4, 129.6 (q, JC–F = 32 Hz), 128.2 methyl)pyridin-2-amine (3ma). Off-white solid; 59% yield; mp
(
1
2 × CH), 125.5 (q, JC–F = 4 Hz), 125.4, 124.4, 122.9 (JC–F = 270 Hz), = 177–179 °C; FT-IR (neat): 3232, 1597, 1411, 1327, 1280, 1095,
18.0, 117.4, 113.7, 112.8, 108.7, 35.4 ppm; HRMS (ESI) calcd for 771, 732, 671 cm− ; H NMR (400 MHz, CDCl
1 1
): δ = 8.40 (d, J =
1.0 Hz, 1H), 8.19 (dd, J = 5.1, 1.0 Hz, 1H), 7.67–7.63 (m, 2H),
3
+
C H F N [M + H] 369.1322, found 369.1324.
20 16 3 4
N-((2-(3-Nitrophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin- 7.48–7.44 (m, 2H), 7.38–7.35 (m, 2H), 7.26–7.23 (m, 1H, over-
-amine (3ia). White solid; 73% yield; mp = 135–137 °C; FT-IR lapped with the residual signal), 6.70–6.67 (m, 1H), 6.53 (d, J =
neat): 3302, 3248, 3086, 1604, 1504, 1473, 1342, 1280, 1149, 8.4 Hz, 1H), 4.93 (d, J = 4.9 Hz, 2H), 4.88 (t, J = 4.9 Hz, 1H)
2
(
072, 987, 709 cm− ; H NMR (400 MHz, CDCl
1
1
13
1
1
3 3
): δ = 8.63 (t, J = ppm; C NMR (100 MHz, CDCl ) δ = 158.0, 148.1, 144.0,
.8 Hz, 1H), 8.19–8.13 (m, 3H), 8.07 (d, J = 7.8 Hz, 1H), 7.59 (d, 143.5, 137.6, 134.3, 132.1, 129.5 (2 × CH), 129.0 (2 × CH),
J = 9 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.47–7.43 (m, 1H), 128.6, 124.9, 118.08, 118.03, 114.1, 108.7, 107.4, 35.5 ppm;
+
+
7
6
.24–7.20 (m, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.69–6.66 (m, 1H), HRMS (ESI) calcd for C19
.54 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 4.5 Hz, 2H), 4.97 (br s, 1H) 413.0154.
4
H15BrClN [M + H] 413.0163, found
1
3
ppm; C NMR (100 MHz, CDCl ) δ = 157.9, 148.6, 148.0,
1
1
N-((6-Bromo-2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)
45.3, 141.9, 137.6, 135.9, 134.1, 129.6, 125.6, 124.6, 123.1, methyl)pyridin-2-amine (3na). White solid; 55% yield; mp =
22.6, 118.2, 117.6, 114.0, 113.0, 108.8, 35.4 ppm; HRMS (ESI) 183–185 °C; FT-IR (neat): 3248, 1597, 1481, 1411, 1327, 1273,
3
+
+
−1 1
calcd for C H N O [M + H] 346.1299, found 346.1292.
1080, 833, 771, 545 cm ; H NMR (400 MHz, DMSO-d ): δ =
6
1
9
16
5
2
N-((7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin- 8.85 (s, 1H), 8.03 (d, J = 5.1 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H),
-amine (3ja). Off-white solid; 70% yield; mp = 189–191 °C; 7.67 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 9.4 Hz, 1H), 7.44–7.38 (m,
2
−
1
FT-IR (neat): 3240, 1597, 1481, 1350, 1080, 771, 702 cm
;
2H), 6.57 (t, J = 6.2 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.89 (s,
1
13
3 3
H NMR (400 MHz, CDCl ): δ = 8.17–8.15 (m, 1H), 7.98 (d, J = 2H), ppm; C NMR (100 MHz, CDCl ) δ = 157.9, 147.9, 144.1,
7
7
.0 Hz, 1H), 7.73 (d, J = 6.9 Hz, 2H), 7.45–7.37 (m, 3H), 143.6, 137.7, 132.6, 132.0 (2 × CH), 129.8 (2 × CH), 128.6,
.35–7.27 (m, 2H, overlapped with the residual signal), 125.0, 122.6, 118.1, 114.1, 108.8, 107.4, 35.5 ppm; HRMS (ESI)
+
+
6.67–6.63 (m, 1H), 6.58 (dd, J = 7.0, 1.8 Hz, 1H), 6.51 (d, J = 8.4 Hz, calcd for C19
H
15Br
2
N
4
[M + H] 456.9658, found 456.9640.
1
H), 4.95 (s, 3H, overlapped with the N–H signal), 2.38 (s, 3H)
N-((6-Methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)
1
3
ppm; C NMR (100 MHz, CDCl ) δ = 158.2, 147.9, 145.6, pyridin-2-amine (3oa). Yellow solid; 74% yield; mp
=
3
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2
1
8
7
6
4
06–208 °C; FT-IR (neat): 3248, 1597, 1512, 1481, 1334, 1265,
N-((6-Phenylimidazo[2,1-b]thiazol-5-yl)methyl)pyridin-2-amine
−
1 1
111, 979, 856, 771, 709 cm ; H NMR (400 MHz, CDCl ): δ = (3ua). White solid; 53% yield; mp = 123–125 °C; FT-IR (neat):
3
−
1 1
.19–8.17 (m, 1H), 8.16–8.13 (m, 2H), 7.97 (d, J = 7.0 Hz, 1H), 3271, 3008, 1604, 1489, 1334, 1141, 918, 763, 702 cm
.88–7.84 (m, 2H), 7.50–7.45 (m, 1H), 7.33–7.32 (m, 1H), NMR (400 MHz, CDCl ): δ = 8.15–8.13 (m, 1H), 7.71–7.68 (m,
.71–6.68 (m, 1H), 6.62–6.58 (m, 2H), 5.06 (t, J = 4.6 Hz, 1H), 2H), 7.58 (d, J = 4.5 Hz, 1H), 7.43–7.38 (m, 3H), 7.34–7.29 (m,
; H
3
1
3
.94 (d, J = 4.8 Hz, 2H), 2.40 (s, 3H) ppm; C NMR (100 MHz, 1H), 6.76 (d, J = 4.5 Hz, 1H), 6.65–6.62 (m, 1H), 6.40 (d, J =
) δ = 158.0, 148.1, 146.9, 145.8, 141.4, 140.6, 137.6, 137.0, 8.4 Hz, 1H), 4.93 (d, J = 5.4 Hz, 2H), 4.74 (t, J = 4.7 Hz, 1H)
CDCl
3
1
3
1
1
C
28.5 (2 × CH), 123.9 (2 × CH), 123.6, 118.4, 116.0, 115.8, ppm; C NMR (100 MHz, CDCl ) δ = 158.1, 149.2, 147.9,
13.9, 108.8, 35.4, 21.5 ppm; HRMS (ESI) calcd for 145.3, 137.6, 134.3, 128.7 (2 × CH), 127.7 (2 × CH), 127.5,
3
+
+
20
H
18
N
5
O
2
[M + H] 360.1455, found 360.1439.
119.7, 118.5, 113.7, 112.2, 108.4, 36.3 ppm; HRMS (ESI) calcd
+
+
N-((2-(Thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin- for C H N S [M + H] 307.1012, found 307.1006.
1
7
15 4
2-amine (3pa). Off-white solid; 54% yield; mp = 149–151 °C;
5-Chloro-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
FT-IR (neat): 3224, 3055, 1597, 1388, 1280, 1149, 771, 725, 2-amine (3ab). Off-white solid; 54% yield; mp = 158–160 °C;
1 1
6
7
1
6
1
86 cm− ; H NMR (400 MHz, CDCl ): δ = 8.21–8.18 (m, 2H), FT-IR (neat): 3242, 1597, 1470, 1413, 1328, 1281, 979, 842,
3
.59 (d, J = 9.1 Hz, 1H), 7.45–7.41 (m, 2H), 7.35 (dd, J = 5.1, 731cm−1
.2 Hz, 1H), 7.21–7.16 (m, 1H), 7.09 (dd, J = 5.0, 3.7 Hz, 1H), 1.8 Hz, 1H), 8.09 (dd, J = 6.9 Hz, 1H), 7.81 (dd, J = 8.0 Hz, 2H),
.78 (t, J = 6.7 Hz, 1H), 6.67–6.64 (m, 1H), 6.48 (d, J = 8.4 Hz, 7.59–7.56 (m, 3H), 7.47–7.43 (m, 1H), 7.20–7.16 (m, 1H), 6.74
H), 5.10 (d, J = 4.4 Hz, 2H), 4.76 (br s, 1H) ppm; C NMR (t, J = 6.8 Hz, 1H), 6.68–6.65 (m, 1H), 6.56 (d, J = 8.3 Hz, 1H),
100 MHz, CDCl
;
1
H NMR (400 MHz, CDCl
): δ = 8.16 (dd, J = 5.2,
3
1
3
1
3
(
3
) δ 158.1, 147.9, 145.1, 138.9, 137.6, 137.0, 5.07 (t, J = 5.0 Hz, 1H), 4.95 (d, J = 4.6 Hz, 2H) ppm; C NMR
1
1
3
28.0, 127.9, 125.27, 125.21, 124.5, 117.3, 116.7, 113.7, 112.6, (100 MHz, CDCl ) δ = 156.5, 146.4, 145.2, 144.7, 137.4, 134.0,
3
+
+
08.7, 35.3 ppm; HRMS (ESI) calcd for C17
07.1012, found 307.1014.
H
15
N
4
S [M + H]
128.8 (2 × CH), 128.4 (2 × CH), 128.1, 125.0, 124.3, 120.7,
117.5, 116.9, 112.6, 109.4, 35.7 ppm; HRMS (ESI) calcd for
+
+
N-((2-(tert-Butyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2- C H ClN [M + H] 335.1058, found 335.1061.
1
9
16
4
amine (3qa). White solid; 60% yield; mp = 195–197 °C; FT-IR
(
5-Bromo-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
neat): 3209, 2962, 1589, 1427, 1319, 1273, 779, 732 cm− ; H 2-amine (3ac). Off-white solid; 52% yield; mp = 220–222 °C;
1
1
NMR (400 MHz, CDCl ): δ = 8.16–8.14 (m, 1H), 8.01 (d, J = FT-IR (neat): 3263, 1589, 1496, 1465, 1357, 1273, 987, 925, 817,
3
1
6
7
1
4
1
1
C
.8 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.43–7.39 (m, 1H), 748, 702 cm−1
; H NMR (400 MHz, CDCl ): δ = 8.20 (d, J =
3
.14–7.10 (m, 1H), 6.71 (td, J = 6.8, 1.2 Hz, 1H), 6.65–6.62 (m, 2.1 Hz, 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 7.1 Hz, 2H),
H), 6.43 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 4.8 Hz, 2H), 4.33 (t, J = 7.63 (d, J = 9.0 Hz, 1H), 7.49 (dd, J = 8.8, 2.5 Hz, 1H), 7.42 (t, J =
.8 Hz, 1H), 1.48 (s, 9H) ppm; C NMR (100 MHz, CDCl ) δ = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.23–7.19 (m, 1H) 6.80 (t,
3
1
3
58.1, 153.7, 148.1, 143.7, 137.4, 123.9, 123.6, 117.2, 115.4, J = 6.8 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 5.0 Hz, 2H),
1
3
13.5, 112.0, 108.4, 36.0, 33.4, 31.2 ppm; HRMS (ESI) calcd for 4.70 (t, J = 5.0 Hz, 1H) ppm; C NMR (100 MHz, CDCl ) δ =
3
+
+
17
H
21
N
4
[M + H] 281.1761, found 281.1761.
156.7, 148.7, 145.2, 144.8, 139.9, 134.0, 128.8 (2 × CH), 128.5
N-((6-Chloroimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine (2 × CH), 128.1, 125.1, 124.3, 117.6, 116.8, 112.6, 110.0, 108.1,
+
+
(
1
3sa). Brownish semi-solid; 33% yield; FT-IR (neat): 3248, 3079, 35.6 ppm; HRMS (ESI) calcd for C H BrN
[M + H]
1
9
16
4
597, 1481, 1288, 1072, 771, 732, 694 cm−1
;
1
H NMR 379.0553, found 379.0549.
4-Methyl-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-
(400 MHz, CDCl
3
): δ = 8.34 (d, J = 1.2 Hz, 1H), 8.15–8.13 (m,
1
1
H), 7.54 (s, 1H), 7.49 (dd, J = 9.5, 0.9 Hz, 1H), 7.43–7.39 (m, 2-amine (3ad). Off-white solid; 61% yield; mp = 190–192 °C;
H), 7.10 (dd, J = 9.6, 2.0 Hz, 1H), 6.65–6.62 (m, 1H), 6.46 (dt, FT-IR (neat): 3278, 1612, 1519, 1481, 1396, 1342, 1257, 1172,
J = 8.4, 1.0 Hz, 1H), 4.91 (t, J = 5.8 Hz, 1H), 4.85 (d, J = 5.0 Hz, 979, 756 cm− ; H NMR (400 MHz, CDCl
1
1
): δ = 8.15 (d, J = 6.9
3
1
3
2
1
1
2
H) ppm; C NMR (100 MHz, DMSO-d ) δ = 157.6, 146.9, Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.77–7.57 (m, 2H), 7.62 (d, J =
6
43.4, 136.4, 133.0, 124.6, 122.8, 122.4, 119.5, 117.2, 112.4, 9.0 Hz, 1H), 7.45–7.41 (m, 2H), 7.37–7.33 (m, 1H), 7.21–7.17
+
+
08.1, 34.2 ppm; HRMS (ESI) calcd for C13
59.0745, found 259.0744.
H
12ClN
4
[M + H]
(m, 1H), 6.76 (t, J = 6.7 Hz, 1H), 6.49 (d, J = 5.1 Hz, 1H), 6.24 (s,
1H), 4.98 (d, J = 4.8 Hz, 2H), 4.72 (br s, 1H), 2.20 (s, 3H) ppm;
C NMR (100 MHz, CDCl ) δ = 158.4, 148.7, 147.6, 145.2,
3
1
3
N-((2-(4-Methoxyphenyl)imidazo[1,2-a]pyrimidin-3-yl)methyl)
pyridin-2-amine (3ta). Off-white solid; 61% yield; mp = 144.7, 134.2, 128.7 (2 × CH), 128.5 (2 × CH), 128.0, 124.9,
1
1
8
4
55–157 °C; FT-IR (neat): 3255, 1705, 1604, 1504, 1481, 1342, 124.5, 117.5, 117.2, 115.4, 112.4, 108.5, 35.7, 21.2 ppm; HRMS
−1
1
+
+
249, 1180, 1026, 840, 763 cm ; H NMR (400 MHz, CDCl
.52 (d, J = 6.0 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.09 (d, J =
.4 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 6.89 pyridin-2-amine (3ae). Off-white solid; 43% yield; mp =
3
): δ = (ESI) calcd for C20
19 4
H N [M + H] 315.1604, found 315.1596.
6-Methyl-N-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)
(
6
d, J = 8.5 Hz, 2H), 6.76–6.73 (m, 1H), 6.63 (t, J = 5.9 Hz, 1H), 148–150 °C; FT-IR (neat): 3271, 2924, 1597, 1458, 1257, 1172,
.52 (d, J = 8.3 Hz, 1H), 5.96 (br s, 1H), 4.94 (s, 2H), 3.81 (s, 3H) 779, 732 cm−
1
; H NMR (400 MHz, CDCl ): δ = 8.25 (d, J =
1
3
1
3
ppm; C NMR (100 MHz, CDCl ) δ = 159.8, 157.9, 149.7, 148.0, 6.9 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.45
3
1
(
46.9, 145.5, 138.1, 132.3, 129.8 (2 × CH), 125.7, 115.2, 114.2 (t, J = 7.5 Hz, 2H), 7.38–7.32 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H),
2 × CH), 113.5, 108.9, 108.5, 55.4, 35.2 ppm; HRMS (ESI) calcd 6.79 (t, J = 6.8 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 6.26 (d, J = 8.2
+
+
for C H N O [M + H] 332.1506, found 332.1510.
Hz, 1H), 4.99 (d, J = 5.1 Hz, 2H), 4.53 (br s, 1H), 2.42 (s, 3H)
19
18 5
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1
3
) δ = 157.8, 157.1, 145.2, 802, 732 cm−1
1
ppm; C NMR (100 MHz, CDCl
3
;
H NMR (400 MHz, CDCl
3
): δ = 8.19 (d, J =
1
1
44.8, 138.0, 134.3, 128.8 (2 × CH), 128.6 (2 × CH), 128.0, 6.6 Hz, 3H), 7.79 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H),
24.9, 124.7, 117.6, 117.4, 113.0, 112.4, 104.6, 35.9, 24.5 ppm; 7.46 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.22 (t, J =
+
+
HRMS (ESI) calcd for C20
H
19
N
4
[M + H] 315.1604, found 7.4 Hz, 1H), 6.80 (t, J = 6.7 Hz, 1H), 6.56 (t, J = 4.8 Hz, 1H), 5.82
1
3
3
15.1604.
-Methyl-N-((6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridin- (100 MHz, CDCl
-yl)methyl)pyridin-2-amine (3od). Yellow solid; 65% yield; 134.0, 128.7 (2 × CH), 128.5 (2 × CH), 128.0, 124.9, 124.3,
(t, J = 5.2 Hz, 1H), 5.09 (d, J = 5.2 Hz, 2H) ppm; C NMR
4
3
) δ = 162.0, 158.0 (2 × CH), 145.1, 144.8,
3
mp = 220–222 °C; FT-IR (neat): 3248, 1604, 1512, 1481, 1342, 117.5, 116.7, 112.4, 111.3, 35.3 ppm; HRMS (ESI) calcd for
−1
1
+
+
1
172, 856, 702 cm ; H NMR (400 MHz, CDCl
3
): δ = 8.25 (d,
C
18
H
16
N
5
[M + H] 302.1400, found 302.1398.
J = 8.4 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H),
N-((2-Phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrazin-2-amine
7
6
2
1
.38 (s, 1H), 6.67 (d, J = 7.0 Hz, 1H), 6.55 (d, J = 5.3 Hz, 1H), (3aj). Off-white solid; 51% yield; mp = 153–155 °C; FT-IR
.32 (s, 1H), 4.98 (d, J = 4.8 Hz, 2H), 4.59 (t, J = 5.2 Hz, 1H), (neat): 3217, 3070, 1589, 1504, 1537, 1273, 1141, 1072, 995,
1
3
−1 1
.42 (s, 3H), 2.25 (s, 3H) ppm; C NMR (100 MHz, CDCl
3 3
) δ = 748 cm ; H NMR (400 MHz, CDCl ): δ = 8.07–8.04 (m, 2H),
58.2, 148.8, 147.7, 147.1, 145.9, 141.6, 140.8, 137.0, 128.6 (2 × 7.99 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.58 (d, J =
CH), 124.0 (2 × CH), 123.7, 118.4, 116.1, 115.8, 115.7, 108.8, 8.8 Hz, 1H), 7.38–7.31 (m, 3H), 7.19 (t, J = 7.3 Hz, 1H), 6.78 (t,
+
3
20 5 2
5.6, 21.5, 21.2 ppm; HRMS (ESI) calcd for C21H N O [M + J = 6.4 Hz, 1H), 5.28 (t, J = 5.0 Hz, 1H), 4.99 (d, J = 5.0 Hz, 2H)
+
13
H] 374.1612, found 374.1609.
-Methyl-N-((6-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridin- 144.8, 141.8, 133.7, 133.4, 133.3, 128.8 (2 × CH), 128.3 (2 ×
-yl)methyl)pyridin-2-amine (3of). Yellow solid; 70% yield; CH), 128.1, 125.2, 124.2, 117.5, 116.5, 112.7, 34.8 ppm;
ppm;
C NMR (100 MHz, CDCl3) δ = 154.4, 145.2,
5
3
+
+
mp = 225–227 °C; FT-IR (neat): 3271, 1604, 1504, 1334, 1257, HRMS (ESI) calcd for C H N [M + H] 302.1400, found
1
8
16 5
−1 1
1
172, 856, 709 cm ; H NMR (400 MHz, CDCl
3
): δ = 8.06 (d, 302.1395.
Bis(2-phenylimidazo[1,2-a]pyridin-3-yl)methane (4a). White
J = 8.5 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.78 (d, J =
1
2
1
8
.5 Hz, 2H), 7.30–7.24 (m, 2H), 6.54 (d, J = 7.9 Hz, 2H), 5.11 (t, solid; 32% yield; mp = 214–216 °C (lit., 216–218 °C); H NMR
3
J = 5.1 Hz, 1H), 4.85 (d, J = 5.0 Hz, 2H), 2.35 (s, 3H), 2.21 (s, (400 MHz, CDCl ): δ = 7.78 (d, J = 7.8 Hz, 4H), 7.54–7.49 (m,
1
3
3
1
H) ppm; C NMR (100 MHz, CDCl
45.7, 141.1, 140.5, 138.7, 136.9, 128.3 (2 × CH), 123.7 (2 × 7.4 Hz, 2H), 6.47 (t, J = 6.7 Hz, 2H), 4.99 (s, 2H) ppm; C NMR
) δ = 145.0, 144.1, 134.3, 129.0 (2 × CH), 128.9
(2 × CH), 128.3, 124.5, 123.9, 117.5, 114.3, 112.4, 19.8 ppm;
3
) δ = 156.3, 147.5, 146.8, 6H), 7.44–7.40 (m, 2H), 7.33 (d, J = 6.8 Hz, 2H), 7.05 (t, J =
1
3
CH), 123.6, 122.7, 118.6, 115.8, 115.6, 108.4, 35.6, 21.4, (100 MHz, CDCl
7.5 ppm; HRMS (ESI) calcd for C21
74.1612, found 374.1610.
3
+
+
1
3
H
20
N
5
O
2
[M + H]
+
+
HRMS (ESI) calcd for C H N [M + H] 401.1761, found
2
7
21 4
N-((2-Phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-4-amine 401.1756.
3ag). White solid; 35% yield; mp = 166–168 °C; FT-IR (neat): N-(Pyridin-2-yl)benzamide (5a). White solid; 85% yield;
(
240, 3024, 2862, 1597, 1481, 1388, 1180, 756, 702 cm− ; H mp = 83–85 °C (lit.,
): δ = 8.18 (d, J = 4.1 Hz, 2H), 7.78 (d, J = δ = 9.22 (br s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.12–8.11 (m, 1H),
.6 Hz, 2H), 7.64 (d, J = 9.1 Hz, 1H), 7.45–7.41 (m, 3H), 7.36 (t, 7.93–7.90 (m, 2H), 7.75–7.70 (m, 1H), 7.55–7.51 (m, 1H),
J = 7.3 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.79 (t, J = 6.8 Hz, 1H), 7.47–7.43 (m, 2H), 7.01 (dd, J = 7.1, 5.0 Hz, 1H) ppm;
1
1
15b
82–84 °C); H NMR (400 MHz, CDCl ):
3
1
3
NMR (400 MHz, CDCl
7
3
1
3
6
5
1
.66 (t, J = 5.8 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.02 (d, J =
C NMR (100 MHz, CDCl
3
) δ = 166.1, 151.8, 147.8, 138.5,
1
3
Hz, 2H), 4.59 (s, 1H) ppm; C NMR (100 MHz, CDCl
58.2, 148.1, 145.3, 144.8, 137.6, 134.2, 128.8 (2 × CH), 128.6 HRMS (ESI) calcd for C H N O [M + H] 199.0866, found
3
) δ = 134.4, 132.2, 128.8 (2 × CH), 127.4 (2 × CH), 119.9, 114.4 ppm;
+
+
1
2
11 2
(
3
2 × CH), 128.1, 124.9, 124.5, 117.6, 117.1, 113.8, 112.5, 108.4, 199.0861.
+
+
5.7 ppm; HRMS (ESI) calcd for C19
H
17
N
4
[M + H] 301.1448,
2-Phenylimidazo[1,2-a]pyridine-3-carbaldehyde (6a). White
1
5b
1
found 301.1452.
N-((2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-4-amine NMR (400 MHz, CDCl
solid; 18% yield; mp = 129–131 °C (lit.,
128–130 °C); H
3
): δ = 10.06 (s, 1H), 9.65 (dt, J = 6.9,
(
2
3bg). Yellow semi-solid; 38% yield; FT-IR (neat): 3248, 3022, 1.2 Hz, 1H), 7.83–7.78 (m, 3H), 7.59–7.49 (m, 4H), 7.11 (td, J =
−
1
1
13
861, 1597, 1478, 1380, 1181, 756, 702 cm
): δ = 8.19 (d, J = 6.8 Hz, 2H), 7.69–7–63 (m, 158.4, 147.8, 132.5, 130.4, 129.9 (2 × CH), 129.9, 128.99 (2 ×
H), 7.43 (t, J = 7.2 Hz, 1H), 7.27–7.25 (m, 2H, overlapped with CH), 128.93, 120.9, 117.5, 115.3 ppm; HRMS (ESI) calcd for
;
H NMR 6.8, 1.3 Hz, 1H) ppm; C NMR (100 MHz, CDCl ): δ = 179.6,
3
(400 MHz, CDCl
3
3
+
+
the residual signal), 7.21 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 6.8 Hz, C H N O [M + H] 223.0866, found 223.0862.
1
4
11 2
1
4
H), 6.66 (t, J = 6.2 Hz, 1H), 6.44 (d, J = 8.3 Hz, 1H), 5.02 (d, J =
.4 Hz, 2H), 4.63 (br s, 1H), 2.39 (s, 3H) ppm; C NMR 75% yield; mp = 155–157 °C (lit., 157 °C); H NMR (400 MHz,
3-Methyl-2-phenylimidazo[1,2-a]pyridine (1a′). White solid;
13
20
1
(100 MHz, CDCl ) δ = 158.2, 147.9, 145.1, 144.7, 137.9, 137.6, CDCl ): δ = 7.86 (dt, J = 6.9, 1.2 Hz, 1H), 7.80–7.77 (m, 2H),
3 3
1
1
31.1, 129.5 (2 × CH), 128.4 (2 × CH), 124.9, 124.4, 117.4, 7.62 (dt, J = 9.0, 1.1 Hz, 1H), 7.47–7.43 (m, 2H), 7.35–7.31 (m,
16.8, 113.6, 112.4, 108.4, 35.7, 21.4 ppm; HRMS (ESI) calcd 1H), 7.16–7.12 (m, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H), 2.60 (s,
+
+
13
for C H N [M + H] 315.1604, found 315.1606.
3H) ppm; C NMR (100 MHz, CDCl ) δ = 144.4, 142.5, 135.0,
3
2
0
19
4
N-((2-Phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2- 128.5 (2
× CH), 128.4 (2 × CH), 127.4, 123.5, 122.9,
+
amine (3ai). White solid; 49% yield; mp = 109–111 °C; FT-IR 117.5, 115.9, 112.0, 9.7 ppm; HRMS (ESI) calcd for C14
13 2
H N
+
(
neat): 3224, 3062, 1589, 1527, 1450, 1419, 1357, 1265, 1180, [M + H] 209.1073, found 209.1075
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C. Yan and Z.-Q. Liu, Org. Lett., 2014, 16, 5670–5673;
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Conflicts of interest
The authors declare no competing financial interest.
(
e) G. Rong, D. Liu, L. Lu, H. Yan, Y. Zheng, J. Chen and
J. Mao, Tetrahedron, 2014, 70, 5033–5037; (f) F. L. Tan,
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Acknowledgements
3602–3610.
Financial support by the DST-FIST [SR/FST/CSI-270/2015] for
the HRMS facility and central analytical lab BITS Pilani for
NMR studies is acknowledged. O. P. S. Patel is thankful to
SERB-New Delhi for national post-doctorate fellowship (File
No. PDF/2017/001910) to carry out the research
work. N. K. N. is thankful to CSIR, New Delhi, India for SRF.
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8628 | Org. Biomol. Chem., 2018, 16, 8620–8628
This journal is © The Royal Society of Chemistry 2018