Phenyliodine(III) Diacetate-Mediated 1,2-ipso-Migration in Mannich Bases of Imidazo[1,2-a]pyridines: Preparation of N-Acetoxymethyl/Alkoxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines

Article abstract of DOI:10.1021/acs.joc.0c00674

Phenyliodine(III) diacetate-mediated 1,2-ipso-migration of an imidazo[1,2-a]pyridine ring via the formation of an aziridine intermediate in Mannich bases derived from imidazo[1,2-a]pyridines, 2-pyridylamines or arylamines, and formaldehyde is reported. The imidazo[1,2-a]pyridines bearing different substituents showed excellent migratory aptitude and resulted in corresponding N-acetoxymethyl-, N-alkoxymethyl-, and N-hydroxymethyl-N-arylimidazo[1,2-a]pyridine-3-amine derivatives in moderate to excellent (42 examples; 35-93%) yields. Radical trapping experiments confirmed the involvement of a non-radical intermediate. The developed protocol is amenable for a scale-up reaction, and synthetic utility of N-acetoxymethyl products was demonstrated by transforming them to corresponding N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines.

Full text of DOI:10.1021/acs.joc.0c00674

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Article
PIDA-Mediated 1,2-ipso-Migration in Mannich Bases of
Imidazo[1,2-a]pyridines: Preparation of N-Acetoxymethyl/
Alkoxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines
Om P. S. Patel, Sonam Jaspal, Vikki N Shinde, Nitesh Kumar Nandwana, Krishnan Rangan, and Anil Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00674 • Publication Date (Web): 15 May 2020
Downloaded from pubs.acs.org on May 15, 2020
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PIDA-Mediated 1,2-ipso-Migration in Mannich Bases of
Imidazo[1,2-a]pyridines:
Preparation
of
N-Acetoxymethyl/
Alkoxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines
9
Om P. S. Patel,†,§,¶ Sonam Jaspal,†,§ Vikki N. Shinde,† Nitesh K. Nandwana,† Krishnan Rangan,‡
and Anil Kumar†,*
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†Department of Chemistry, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan,
333031, India
‡Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus,
Telangana, 500078, India
E-mail: anilkumar@pilani.bits-pilani.ac.in
Table of content
OR
R1
OAc/OH
R1
R1
N
HN
N
R1
N
N
Synthetic utility
ROH, 50 C
Toluene, 50 C
N
N
N
R2
R2
N
R2
R1 = HetAr; OAc
R1 = HetAr/Ar
N
R2
N
4 examples
92-96% yields
>95% purity w/o
column purification
R1 = HetAr; OAc (16 examples)
21 examples
35-92% yields
N
R1 = Ar; OH
(5 examples)
42-93% yields
PhI(OAc)2
C to N shift of imidazo[1,2-a]pyridine
H
N
Nucleophile-assisted acetoxylation/alkoxylation
Useful synthetic application to access sec-amines
Simple, mild and metal-free protocol
R1
R2
N
N
ABSTRACT: A PIDA-mediated 1,2-ipso-migration of imidazo[1,2-a]pyridine ring via the
formation of aziridine intermediate in the Mannich bases derived from imidazo[1,2-a]pyridines,
2-pyridylamines or arylamines and formaldehyde is reported. The imidazo[1,2-a]pyridines
bearing different substituents showed excellent migratory aptitude and resulted corresponding N-
acetoxymethyl-, N-alkoxymethyl- and N-hydroxymethyl-N-arylimidazo[1,2-a]pyridine-3-amine
derivatives in moderate to excellent (42 examples; 35-93%) yields. Radical trapping experiments
confirmed the involvement of non-radical intermediate. The developed protocol is amenable for
a scale-up reaction and synthetic utility of N-acetoxymethyl products was demonstrated by
transforming them to the corresponding N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines.
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INTRODUCTION
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The intramolecular ipso-migration of arenes or heteroarenes via C-C bond cleavage is an
interesting area of research in synthetic organic chemistry.1 The intramolecular migration
generally proceeds through the formation of 3, 4, 5 or 6-member spirocyclic intermediate or
transition state followed by functionalization.1a Carbon to carbon migration of arenes and
heteroarenes has been explored in great detail,2 but migration from carbon to nitrogen of arene or
heteroarene ring is rarely explored and limited only to triflic amides.3 In this perspective, Shi and
Nevado groups successively reported [1,4]-arene migration from C to N through radical
intermediates via single electron transfer (SET) reaction (Scheme 1a).3-4 Very recently, Bi group
reported a [1,4]-arene migration from C to N followed by trifluoromethylation and/ or
sulfonylation (Scheme 1b).5 Both these approaches involve formation of 5-membered spirocyclic
intermediate and subsequent functionalization.
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On the other hand, hypervalent iodine(III) reagents have been considered as effective reagent for
oxidative rearrangements due to their electrophilicity and good leaving group tendency as well as
their environmentally-friendly behaviour.6 These reagents have been successfully employed for
the oxidative rearrangement of arene ring through ring expansion, ring contraction, or arene or
heteroarene migration.6d However, oxidative migration reactions to heteroatoms other than the
amidic nitrogen have remained under-explored. The Zhu and Antonchick group independently
reported unprecedented oxidative demethylenation of N-benzyl-2-aminopyridines and N-benzyl-
2-aminoquinolines to give coressponding pyrido[1,2-a]benzimidazoles and quinolino[1,2-
a]benzimidazoles (Scheme 1c).7 These reactions are reported to proceed through a rearranged N-
(alkoxymethyl)-N-arylpyridin-2-amine intermediate that is generated via hypervalent iodine(III)-
mediated ipso-1,2-arene migration from C to N atom. However, Zhu group failed to isolate the
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N-(alkoxymethyl)-N-arylpyridin-2-amine intermediate in hexafluoroisopropanol (HFIP). Murai
group reported phenyliodine(III) diacetate (PIDA)-mediated oxidative rearrangement of primary
and secondary amines via 1,2-C to N migration of amines (Scheme 1d).8
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Scheme 1. Oxidative Rearrangement of Arene/Heteroarene from C to N
2015
2017
, 56, 10521)
a) Arene migration from C to N (J. Am. Chem. Soc.
, 137, 14586 & Angew. Chem. Int. Ed.
Tf
Ag catalyst, PhI(OTFA)2,
K2CO3, PhCl:DCE, 120 C
Tf
N
Ar
N
NTf
H
Y
Ar
Ar
or
SET oxidation
Nu addition
Y
Ir Photocatalyst, K2HPO4, rt
R
Oxidative 1,4-ipso-migration
2019
Y = OTFA, H, Br,
R1
b) Het(arene) migration from C to N (ACS Catal.
, 9, 4203)
ROSO
Ag3PO4, K2S2O8,
DMSO, 70-80 C
TMSN3/ RSO2Na
N3
OSOR
HO
Ar
Ar
HO Ar
or
N
O
HN
Ring opening
Oxidative 1,4-ipso-migration
R = CF3, alkyl, aryl
HO Ar
Hypervalent iodine(III)-mediated migration from C to N
2013,
2014
, 53,
(c) Synthesis of pyrido-/quinolino[1,2-a]benzimidazole (Org. Lett.,
15, 3476; Angew. Chem. Int. Ed.
8163)
OR
PhI(OPiv)2 or
PhI(OAc)2
N
N
N
ROH
N
N
N
HFIP
Cyclization
N
N
H
2018,
2019
, 21, 3023)
d) Rearrangement of primary and secondary amines (Org. Lett.,
20, 2333 & Org. Lett.,
i) PhI(OAc)2
R
N
H
R
ii) NaBH3CN or NaBH4
R'
N
R''
R''
R'
CF3CH2OH or CH3OH
Oxidative 1,2-ipso-migration
This Work
e)
:
R2
PhI(OAc)2 (1.5 equiv)
Toluene or ROH, 50 C
N
N
OAc or ROH
N
H
N
OAc/OR/OH
N
N
R2
N
N
Nu ring opening
Aromatization
N
Oxidative 1,2-ipso-migration
R2
R1
R1
Aziridine intermediate
R1
R2 = HetAr and Ar
R1 = Ar, HetAr, Alkyl
42 examples
yields up to 93%
On the other hand, N-arylimidazo[1,2-a]pyridine-3-amines have attracted significant interest in
medicinal chemistry due to their potential anticancer, antimalarial, anti-inflammatory,
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antifibrosis and HIV-1 reverse transcriptase inhibitor activities.9 Owing to their interesting
biological properties and our interest towards synthesis and functionalization of imidazo[1,2-
a]pyridines,10 herein, we report PIDA-mediated [1,2]-ipso-migration of heteroaryl ring in
Mannich bases derived from imidazo[1,2-a]pyridines, 2-pyridylamines or arylamines and
formaldehyde to give the corresponding N-acetoxymethyl/N-alkoxymethyl-N-aryl-imidazo[1,2-
a]pyridine-3-amines under mild and simple reaction conditions.
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RESULTS AND DISCUSSION
Our studies commenced with the reaction of Mannich base i.e. N-((2-phenylimidazo[1,2-
a]pyridin-3-yl)methyl)pyridin-2-amine (1a) using iodobenzene diacetate as an oxidant in EtOAc
at 50 °C. We expected that intramolecular amination would yield a 6-membered cyclic product
i.e. 5-(pyridin-2-yl)-5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinoline (2). However, ((2-
phenylimidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4a) was obtained in 75%
yield within 3 h (Scheme 2). The molecular structure of 4a was established by the 1H, 13C NMR,
and HRMS spectroscopic data and was further confirmed unambiguously by a single-crystal X-
ray diffraction analysis (CCDC No. 1957417, Supporting Information).
Scheme 2. Intial Design and Observed Reaction of 1a with PIDA.
Py
HN
OAc
Py
Py
N
N
PhI(OAc)2
N
N
N
N
Py =
Ph
X
EtOAc, 50 C
N
N
N
1a
2
4a
; 75%
"Initial design"
"Observed product"
In order to find optimum conditions for this rearrangement reaction, the reaction of 1a with
PIDA was performed in different solvents such as 1,2-dicholoroethane (DCE), toluene, THF,
1,4-dioxane, DMSO, DMF, DMA, H2O and MeOH. When the reaction was performed in DCE
and toluene, yield of 4a increased to 82% and 90%, respectively (Table 1, entries 1 vs 2 and 3).
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While in other solvents (THF, 1,4-Dioxane, DMSO, DMF and DMA) yield of 4a decresed
significantly (Table 1, entries 4-8). The use of environmentally benign solvent such as water with
or without phase-transfer-catalyst (SLS) did not improve the yield of 4a (Table 1, entries 9-10).
On the other hand, N-(methoxymethyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine
(6aa) was obtained in 90% yield with traces of 4a when methanol was used as solvent (Table 1,
entry 11). The decreasing amount of PIDA (1.2 equiv.) showed a detrimental effect on the yield
of 4a (Table 1, entry 12). The use of [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser's reagent),
bis(trifluoroacetoxy)iodo)benzene (PIFA) and organo-catalytic conditions11 did not produce the
desired product 4a (entry 13-15).
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Table 1. Optimization of Reaction Conditions for 4a.a
OAc
H
Py
N
N
Py
N
Oxidant
N
N
Py =
Ph
Ph
Solvent, 50 C, 3 h
N
N
3a
4a
entry
oxidant
solvent
EtOAc
% yield 4ab
1
PhI(OAc)2
75
2
3
4
5
6
7
8
9
10c
11
12e
13
14
15g
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
HTIB
1,2-DCE
Toluene
THF
1,4-Dioxane
DMSO
DMF
82
90
37
48
39
70
29
7
DMA
H2O
H2O
MeOH
Toluene
Toluene
Toluene
Toluene
16
<5d
83
f
-
-
f
PhI(OCOCF3)2
PhI + m-CPBA
Traces
b
aReaction conditions: 3a (0.5 mmol), oxidant (1.5 equiv.), solvent (5 mL), 50 °C, 3 h. Isolated
c
d
yield. SLS (20 mol %) was used. N-methoxymethyl product 6aa was obtained in 90% yield.
e1.2 equiv. of PIDA was used. fNo reaction. gPhI (20 mol %) with m-CPBA (3 equiv.) and AcOH
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(5 equiv.) was used. SLS = Sodium lauryl sulfate; DMSO = dimethyl sulfoxide; DMF = N,N-
dimethyl formamide; DMA = N,N-dimethyl acetamide; THF = tetrahydrofuran; m-CPBA =
meta-chloroperbenzoic acid.
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8
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With the optimized conditions in hand (Table 1, entry 3), the scope and generality of the
methodology was investigated systematically (Scheme 3). In the beginning, Mannich bases of
imidazo[1,2-a]pyridine with various substituents (-Me, -OMe, -F, -Cl, -Br, -CN and CF3) on C-2
aryl ring were reacted and corresponding N-acetoxymethyl products (4a-i) were obtained in good
to excellent (45-93%) yields. Mannich bases with the electron-donating groups at the para-
position on C-2 aryl ring provided better yields than those with electron-withdrawing groups on
C-2 aryl ring (compare 4a and 4b-c vs 4d-h, Scheme 3).
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Scheme 3. Substrate Scope for Preparation of N-Acetoxymethyl Derivatives 4.a,b
HetAr
OAc
ArHet
NH
N
PhI(OAc)2 (1.5 eq.)
N
N
N
R1
R1
R
Py =
R
N
N
Toluene, 50 C, 3 h
N
3a-3p
4a-4p
OAc
OAc
OAc
OAc
OAc
OAc
Py
N
Py
N
Py
N
Py
Py
N
N
N
N
N
N
Cl
Me
OMe
F
N
N
N
N
N
4a,
4b,
4e,
80%
90%
91%
Py
4c,
4d,
93%
81%
OAc
OAc
Py
OAc
OAc
Py
Py
Py
N
N
N
N
OMe
N
N
N
S
N
N
N
CF3
CN
Br
N
N
N
N
N
4g,
77%
4f,
83%
4h,
69%
4i,
Cl
45%
4j,
84%
N
N
OAc
OAc
OAc
OAc
Ph
OAc
Ph
OAc
Py
Me
Py
Py
N
Py
N
N
N
N
N
N
N
Me
Cl
N
N
N
N
Ph
Ph
Me
Ph
N
N
N
N
N
N
4m,
82%
4k,
4l,
4n,
4o,
4p,
42%
88%
85%
89%
87%
b
aReaction conditions: 3 (0.5 mmol), PIDA (1.5 equiv.), toluene (5 mL), 50 °C, 3 h. Isolated
yields.
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Similarly, Mannich base with thiophene ring at the C-2 position afforded the desired N-
acetoxymethyl product 4j in 84% yield. Mannich bases decorated with substituents (-Me and –
Cl) at different positions on imidazo[1,2-a]pyridine nucleus and 2-aminopyridine ring delivered
the corresponding acetoxylated products (4k-o) in high (82-89%) yield under the identical
reaction conditions. Interestingly, the tert-butyl group at C-2 position of Mannich base also
afforded the desired product 4p in 42% yield. However, in the case of N-methyl-1-(2-
phenylimidazo[1,2-a]pyridin-3-yl)methanamine 3q (Mannich base derived from methylamine
and 2-phenylimidazo[1,2-a]pyridine), we could not isolate the desired product 4q due to the
formation of complex reaction mixture (Scheme S2; SI).
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During the reaction condition optimization studies it was observed that the use of methanol as
solvent resulted N-methoxymethyl product 6aa in 90% yield along with a trace amount (>5%) of
N-acetoxymethyl product 4a (Table 1, entry 11). It might be due to the relatively high
nucleophilicity of methoxy group as compared to the acetate group, which facilitated the ring
opening of aziridine intermediate better than the acetate group resulting in formation of N-
1
13
methoxymethyl product. The structure of 6aa was established by the H, C NMR, and HRMS
spectroscopic data and was further confirmed unambiguously by a single-crystal X-ray
diffraction analysis (CCDC No. 1913162, See SI).
We thus took up a systematic study to evaluate substrate scope for the formation of N-
alkoxymethyl products by employing different alcohols 5 as solvent with 3a (Scheme 4).
Different alcohols such as methanol, ethanol, 2-triflurorethanol, HFIP and cyclopentanol
smoothly reacted with 3a and delivered the desired N-alkoxymethyl products 6aa-6ae in 56-90%
yields. A long-chain alcohol i.e. lauryl alcohol also reacted and gave the desired product 6ai in
35% yield; while phenol could not afford the respective product 6af, most likely due to the weak
nucleophilicity of phenol.12 Propargyl alcohol (5g) and allyl alcohol (5h) also reacted well and
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furnished the respective products 6ag and 6ah in 76% and 53% yields, respectively. This
transformation is interesting from the view-point of medicinal chemistry as it further opens scope
of post-modification.
Scheme 4. Substrate Scope for Alkoxylated Derivativesa,b
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OR
HetAr
NH
HetAr
N
N
Py =
N
PhI(OAc)2 (1.5 eq.)
50 C, 3 h
R1
N
Ar
R1
Ar
R OH
N
N
6
5a-i
3
OCH2CF3
O
OMe
OCH(CF3)2
OCH2CH3
Py
N
Py
N
Py
N
Py
Py
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
6ac,
78%
6ae,
6ad,
Py
56%
84%
6aa,
6ab,
90%
79%
( )10
O
OPh
OMe
O
O
Py
Py
Py
Py
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Me
Ph
Ph
N
N
N
N
35%
N
6ai,
6ag,
6af,
76%
6ah
, 53%
0%
6ba
, 92%
OMe
OCH(CF3)2
OMe
OCH2CH3
Py
Py
N
Py
Py
N
N
N
N
OMe
N
N
N
F
Me
Me
N
N
N
N
Cl
6ia,
49%
6bb,
80%
6bd
6da
, 78%
, 81%
N
N
N
N
OMe
OCH(CF3)2
Me
OMe
OMe
Me
Py
N
N
N
N
Cl
N
N
N
Ph
Ph
Ph
Ph
N
N
N
N
6na,
6oa,
87%
89%
6nd,
83%
6ma
, 74%
aReaction conditions: 3 (0.5 mmol), PIDA (1.5 equiv.), ROH (5 mL), 50 °C for 3 h. Isolated
b
yields.
The Mannich bases bearing methyl (3b), methoxy (3i) and fluoro (3d) groups on the C-2 aryl
ring, chloro (3l) group on imidazo[1,2-a]pyridine nucleus also reacted smoothly with different
alcohols (MeOH, EtOH and HFIP) in the presence of PIDA to give the corresponding N-
alkoxymethyl products (6ba-6ma) in good to excellent (49-92%) yields. Similarly, Mannich
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bases with methyl (3n) and chloro (3o) groups on the 2-aminopyridine ring also participated well
in the reaction and gave corresponding N-alkoxylmethyl products (6na-6oa) in 83-89% yields.
As in case of toluene, reaction of 3q in MeOH also resulted in an unseperable mixture and we
could not isolate the desired N-methoxymethyl product 6qa (Scheme S2; SI).
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Next, the scope of the reaction for Mannich bases derived from imidazo[1,2-a]pyridines and
anilines (7) was studied (Scheme 5). Interestingly, reaction of different Mannich bases with
substituted N-aryl rings (7a-d) with PIDA in toluene afforded (aryl(2-aryllimidazo[1,2-a]pyridin-
3-yl)amino)methanols (8a-d) 71-78% yields. It is believed that N-hydoxymethyl products (8) are
generated by hydrolysis of N-acetoxymethyl products. Results from these reactions indicated that
the pyridyl ring has no specific role in the 1,2-Ipso-migration of imidazo[1,2-a]pyridine core in
Mannich bases, however it might have stabilized N-acetoxymethyl derivatives. On the other
hand, reaction of 7a-d with PIDA in methanol produced the corresponding N-methoxymethyl
derivatives (9a-d) in moderate to excellent yields (56-81%). Structure of 8 and 9 was confirmed
13
by NMR (1H, C) and HRMS analysis (see SI). Further, structure of 8a was also elucidated by
single-crystal X-ray diffraction analysis (CCDC 1986133; See SI). Compound 8a is crystallized
in monoclinic P21/c space group with two molecules per asymmetric unit. It forms
intermolecular hydrogen bonding dimeric structure through the alcohol O1-H as donor and N2 as
acceptor with H---A bond length of 1.99 Å and D-H-A bond angle of 176.1° (Fig S4, SI). It is
worth mentioning that the reaction of N-((1-tosyl-1H-indol-3-yl)methyl)aniline with PIDA in
toluene resulted 1-tosyl-1H-indole-3-carbaldehyde instead of the desired rearranged product
(Scheme S1, SI). The formation of 3-formylindole derivative can be explained via PIDA
mediated oxidation of secondary amine to imine followed by hydrolysis.13
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Scheme 5. Substrate Scope for Mannich Bases Derived from Arylamines.a,b
5
6
7
8
OMe
Ar'
OH
Ar
Ar
ArHN
N
N
PhI(OAc)2 (1.5 eq.)
Toluene, 50 oC, 3h
PhI(OAc)2 (1.5 eq.)
MeOH, 50 oC, 3 h
N
N
N
Ar'
Ar'
9
N
N
N
10
11
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9
7
8
Me
Me
Cl
OH
OH
OH
OH
N
N
N
N
N
N
N
N
OMe
N
N
N
N
8c,
78%
8b,
72%
8a
, 75%
8d,
71%
Me
Me
Cl
OMe
OMe
OMe
OMe
N
N
N
N
N
N
N
N
OMe
N
N
N
N
9c,
9a
73%
, 81%
9b,
77%
9d,
56%
aReaction conditions: 7 (0.5 mmol), PIDA (1.5 equiv.), MeOH (5 mL) or toluene (5 mL), 50 °C
for 3 h. bIsolated yields.
Furthermore, to evaluate the potentiality of the developed methodology for the large-scale
synthesis of N-acetoxymethyl and N-alkoxymethyl compounds, we performed gram-scale
reaction of 3a (1.5 g) under standard reaction conditions in toluene and MeOH (Scheme 6). To
our expectation, the desired products 4a and 6aa were obtained in 84% and 82% yields,
respectively, without significant change in the efficacy of the reaction.
Scheme 6. Gram Scale Experiment
N
N
N
OMe
Ph
OAc
Ph
NH
Ph
N
N
PhI(OAc)2
(1.5 equiv.)
PhI(OAc)2
(1.5 equiv.)
N
N
N
MeOH, 50 C,
3 h
N
Toluene, 50 C,
3 h
N
N
4a
, 84%
3a,
1.5 g
6aa
, 82%
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To demonstrate the synthetic utility of the developed protocol, N-acetoxymethyl derivatives (4a-
c and 4n) were stirred with NaHCO3 for 2 h in MeOH to obtain corresponding 3-(pyridin-2-
yl)aminoimidazo[1,2-a]pyridines (10a-c and 10n) (Scheme 7). The products 10 were obtained in
excellent yields (92-96%) and high purity (>95%, HPLC) without using column chromatography
(See; SI). The 3-arylaminoimidazo[1,2-a]pyridines are generally prepared by the Groebke-
Blackburn-Bienaymé reaction which require isocyanides as one of the substrate.14 The developed
method provides a simple and straightforward synthetic strategy for the preparation of bioactive
3-arylaminoimidazo[1,2-a]pyridines.9a, 9c
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Scheme 7. Synthetic Utility: Removal of N-Acetoxymethyl from 4.
N
NH
N
OAc
Me/H
Me/H
NaHCO3 (9 equiv.)
MeOH (5 mL),
N
N
N
R
R
rt , 2 h
N
N
"No column purification"
10
4
N
N
N
N
Me
NH
NH
NH
NH
N
N
N
N
Ph
Me
OMe
Ph
N
N
N
N
, 96%
10a
, 95%
10b
, 93%
10n
10c
, 92%
To gain an insight into the mechanism for the oxidative 1,2-migration followed by
functionalization, a set of control experiments were performed (Scheme 8). First, to confirm the
role of PIDA, we performed the reaction of 1a in toluene and methanol in the absence of PIDA.
The reaction did not produce the corresponding products 4a and 6aa, justifying the essential role
of PIDA in the reaction (Scheme 8a). Second, reaction of 3a under standard reaction conditions
in the presence of different radical scavengers including 2,2,6,6-tetramethylpiperidine-1-oxy
(TEMPO), 1,2-diphenylethylene (DPE) and butylated hydroxytoluene (BHT) resulted 4a in 86%,
88% and 89% yields, respectively (Scheme 8b). Similarly, product 6aa was also formed in 84%
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yield from the reaction of 3a with PIDA in methanol in the presence of TEMPO (Scheme 8c).
The results from radical scavengers experiments ruled out the involvement of the radical
pathway which is in stark contrast to what is observed by Murai in the PIDA-mediated direct
1,2-C-to-N migration of amines.8 Based on these results and effect of substituents on C-2 aryl
ring on the yields of products, we believe that the reaction involves a non-radical, ionic
mechanism.
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Scheme 8. Control Experiments
N
OAc/OMe
N
Toluene/MeOH
N
N
a)
Ph
N
N
50 C, 3 h
H
N
N
3a
4a
, 0%;
Ph
6aa
, 0%
N
N
OAc
Ph
PhI(OAc)2 (1.5 equiv.)
N
N
b)
Toluene, 50 C, 3 h
Radical scavenger (3 equiv.)
N
N
N
H
N
4a
% Yield
Ph
TEMPO
DPE
86
88
89
3a
BHT
N
OMe
Ph
N
PhI(OAc)2 (1.5 equiv.)
N
N
c)
N
H
N
MeOH, 50 C, 3 h
TEMPO (3 equiv.)
N
N
3a
Ph
6aa
, 84%
Based on the control experiments and literature reports,7, 15 a plausible mechanistic pathway is
depicted in Scheme 9. It is believed that initially, the reaction of 3 with PIDA gives the iodinated
intermediate A with the removal of acetic acid. The intermediate A is further converted into a
Wheland-type aziridine intermediate B via nucleophilic ipso-attack of imidazo[1,2-a]pyridinyl
group and subsequent removal of iodobenzene and acetate group . The intermediate B is then
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attacked by acetate/alkoxy nucleophile at methylene carbon initially and triggers aziridine ring
opening to form [1,2]-ipso-migrated N-acetoxylmethyl or N-alkoxymethyl product 4a/6aa.
Scheme 9. Proposed Reaction Mechanism
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AcO
N
Ph
N
I
N
N
OAc/OMe
Ph
N
N
OAc
I
H
OAc
or
MeOH
N
N
Ph
OAc
-PhI
N
N
N
N
Ph
Ph
Ph
-AcOH
N
-OAc
N
N
N
4a/6aa
3a
A
B
CONCLUSIONS
In summary, this report delineates a novel protocol for the preparation of N-acetoxymethyl-, N-
alkoxymethyl- and N-hydroxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines in moderate to
excellent yields through PIDA-mediated [1,2]-ipso-migration in Mannich bases derived from
imidazo[1,2-a]pyridines, 2-aminopyridines/arylamines and formaldehyde. The reaction is
believed to proceed through [1,2]-ipso-heteroaryl migration via the formation of a Wheland-type
aziridine intermediate followed by nucleophile-assisted ring opening reaction. The protocol is
amenable for a scale-up reaction and the N-acetoxymethyl products 4 were easily transformed to
the corresponding 2-aryl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines (10) by treating with
NaHCO3 in methanol. Given the high pharmaceutical importance of 3-arylaminoimidazo[1,2-
a]pyridine derivatives, the newly developed methodology will be useful for the synthesis of
variety of 3-arylaminoimidazo[1,2-a]pyridines under metal-free and mild reaction conditions.
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EXPERIMENTAL SECTION
5
6
7
1. General information
8
9
Melting points were determined in open capillary tubes on EZ-Melt automated melting point
apparatus and are uncorrected. All the compounds were fully characterized by 1 H, 13C, and IR
and further confirmed by ESI-HRMS analysis. Reactions were monitored by using thin-layer
chromatography (TLC) on 0.2 mm silica gel F254 plates (Merck). 1H and 13C NMR spectra were
recorded on 400 MHz and 100 MHz instruments, respectively, with CDCl3 as the solvent using
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1
TMS as an internal standard. Peak multiplicities of H-NMR signals were designated as s
(singlet), d (doublet), dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet), t
(triplet), q (quartet), m (multiplet), etc. Chemical shifts (δ) and coupling constants (J) are
reported in parts per million (ppm) relative to the residual signal of TMS in deuterated solvents
and hertz, respectively. ESI-HRMS were recorded using Q-TOF LC/MS. IR spectra were
recorded using an FT-IR spectrophotometer, and values are reported in cm−1. Column
chromatography was performed over silica gel (60-120 mesh) using EtOAc–n-hexane as an
eluent. All the chemicals were obtained from the commercial suppliers and used without further
purification. The Mannich bases of imidazo[1,2-a]pyridines (3 and 7) were prepared either by
the reaction of 2-arylimidazo[1,2-a]pyridines (5.33 mmol) and 2-aminopyridines in TBHP10a or
by reductive amination of 2-aryllimidazo[1,2-a]pyridine-3-carbaldehyde (5.33 mmol) with
arylamines.16
2. Experimental Procedure
2.1 Experimental procedure for the preparation of N-acetoxymethyl or N-hydroxymethyl
products (4 and 8).
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To a solution of 3 or 7 (0.5 mmol; 1 equiv.) in toluene (5 mL) was added PhI(OAc)2 (1.5 equiv.)
at room temperature and the reaction mixture was stirred at 50 °C for 3 h. After completion of
the reaction, observed by TLC, the mixture was allowed to attain room temperature. The reaction
mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The
resulting crude solid was purified by column chromatography (silica gel 60-120 mesh) using
EtOAc-n-hexane as an eluent to afford 4 or 8.
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2.2 Experimental procedure for the preparation of N-alkoxymethyl products (6 and 9).
To a solution of 3 or 7 (0.5 mmol; 1 equiv.) in alcohol (5 mL) was added PhI(OAc)2 (1.5 equiv.)
at room temperature and the reaction mixture was stirred at 50 °C for 3 h. After completion of
the reaction, alcohol was evaporated under vacuum. The resulting crude solid was purified by
column chromatography (silica gel 60-120 mesh) using EtOAc-n-hexane as an eluent to afford 6
or 9.
2.3 Experimental procedure for the preparation of 3-(pyridin-2-yl)aminoimidazo[1,2-
a]pyridines (10).
To a solution of 4 (0.14 mmol; 1 equiv.) in MeOH (5 mL) was added NaHCO3 (9 equiv.) and the
reaction mixture was stirred for 2 h at room temperature. After completion of the reaction,
methanol was evaporated under vacuum. The obtained reaction mixture was extracted with water
(20 mL) and EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4
and evaporated under vacuum. The resulting crude solid was washed with diethyl ether to get the
pure off-white solid 10.
3. Characterization data of new substrates and final products.
N-((2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine (3d): White solid; 1.1
g, 65% yield; The eluent used was ethyl acetate/petroleum ether (6:4 v/v); mp = 178-180 °C; 1H
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NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.67 – 7.64 (m,
2H), 7.55 (d, J = 9.0 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.18-7.14 (m, 1H), 7.06 – 7.01 (m, 2H), 6.73
(t, J = 6.5 Hz, 1H), 6.64 (dd, J = 6.5, 5.5 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 5.01 (t, J = 5.0 Hz,
13
1H), 4.91 (d, J = 4.8 Hz, 2H) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 162.5 (d, JC-F = 246
10
11
12
13
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Hz), 158.1, 147.9, 144.9, 143.4, 137.4, 130.0 (d, JC-F = 3 Hz), 129.9 (d, JC-F = 8 Hz), 124.9,
124.2, 117.2, 116.7, 115.6 (d, JC-F = 22 Hz), 113.6, 112.4, 108.4, 35.4 ppm; HRMS (ESI) calcd
for C19H16FN4 [M + H]+ 319.1354, found 319.1351.
+
N-((2-(3-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine (3i): Off-white
solid; 1.28 g, 73% yield; The eluent used was ethyl acetate/petroleum ether (65:35, v/v); mp =
154-156 °C; 1H NMR (400 MHz, CDCl3): δ 8.19 – 8.17 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.46 –
7.42 (m, 1H), 7.38 (s, 1H), 7.34 – 7.33 (m, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.94 – 6.90 (m, 1H),
6.80 (t, J = 6.8 Hz, 1H), 6.68 – 6.65 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 4.4 Hz, 2H),
4.83 (s, 1H), 3.83 (s, 3H); C{1H} NMR (100 MHz, CDCl3) 159.9, 158.1, 148.0, 145.0, 144.4,
13
137.4, 135.4, 129.6, 124.8, 124.4, 120.8, 117.4, 117.2, 114.2, 113.6, 113.4, 112.4, 108.3, 55.3,
35.6; HRMS (ESI) calcd for C20H19N4O+ [M + H]+ 331.1553, found 331.1548.
N-((6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyridin-2-amine (3m): White solid;
1.05 g, 59% yield; The eluent used was ethyl acetate/petroleum ether (6:4 v/v); mp = 160-162 °C
(lit.,17 172.2−173.4 °C); 1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 1.3 Hz, 1H), 8.11 (dd, J =
5.1, 1.1 Hz, 1H), 7.67 – 7.65 (m, 2H), 7.46 (dd, J = 9.5, 0.8 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.37-
7.30 (m, 3H), 7.08 (dd, J = 9.5, 2.0 Hz, 1H), 6.65 – 6.62 (m, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.21
(t, J = 5.1 Hz, 1H), 4.90 (d, J = 4.9 Hz, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.1,
147.8, 145.1, 143.2, 137.4, 133.4, 128.6, 128.17, 128.10, 126.1, 122.5, 120.5, 117.9, 117.4,
113.6, 108.5, 35.4 ppm; HRMS (ESI) calcd for C19H16ClN4 [M + H]+ 335.1058, found
+
335.1056.
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((2-Phenylimidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4a): White solid; 161
mg, 90% yield; The eluent used was ethyl acetate/petroleum ether (1:3 v/v); mp = 195-196 °C;
7
8
9
1
FT-IR (neat): 3741, 3093, 1728, 1504, 1350, 1049, 979, 840, 686 cm-1; H NMR (400 MHz,
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CDCl3): δ = 8.42 – 8.40 (m, 1H), 7.94 – 7.91 (m, 2H), 7.85 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 9.0
Hz, 1H), 7.48 – 7.43 (m, 1H), 7.40 – 7.36 (m, 2H), 7.33 – 7.25 (m, 2H), 6.91 (ddd, J = 7.3, 5.0,
0.9 Hz, 1H), 6.79 (td, J = 6.7, 1.2 Hz, 1H), 6.42 (d, J = 10.3 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H),
5.69 (d, J = 10.2 Hz, 1H), 1.89 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 170.6, 155.5,
148.6, 143.2, 139.7, 138.8, 132.7, 128.6, 128.2, 126.8, 125.6, 122.5, 119.7, 118.0, 116.8, 112.5,
+
107.9, 74.2, 20.9 ppm; HRMS (ESI) calcd for C21H19N4O2 [M + H]+ 359.1503, found
359.1503.
(Pyridin-2-yl(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)amino)methyl acetate (4b). White solid; 169
mg, 91% yield; The eluent used was ethyl acetate/petroleum ether (1:3 v/v); mp = 195-196 °C;
1
FT-IR (neat): 3723, 3070, 1732, 1590, 1468, 1352, 1228, 923, 769, 691 cm-1; H NMR (400
MHz, CDCl3): δ = 8.40 – 8.38 (m, 1H), 7.83 – 7.79 (m, 3H), 7.67 (dt, J = 9.0, 1.1 Hz, 1H), 7.45
– 7.40 (m, 1H), 7.27 – 7.23 (m, 1H, overlapped with CDCl3 residual signal), 7.17 (d, J = 8.0 Hz,
2H), 6.90-6.87 (m, 1H), 6.76 (td, J = 6.7, 1.1 Hz, 1H), 6.42 (d, J = 10.2 Hz, 1H), 6.23 (d, J = 8.4
13
Hz, 1H), 5.64 (d, J = 10.2 Hz, 1H), 2.33 (s, 3H), 1.90 (s, 3H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ = 170.6, 155.5, 148.6, 143.1, 139.7, 138.7, 138.1, 129.8, 129.4, 126.7, 125.4, 122.5,
+
119.4, 117.9, 116.8, 112.3, 108.0, 74.4, 21.2, 20.9 ppm; HRMS (ESI) calcd for C22H21N4O2 [M
+ H]+ 373.1659, found 373.1651.
((2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4c):
White solid; 180 mg, 93% yield; The eluent used was ethyl acetate/petroleum ether (3:7, v/v); mp
= 167-169 °C; FT-IR (neat): 3726, 3086, 1728, 1589, 1473, 1350, 1234, 933, 779, 694 cm-1; 1H
NMR (400 MHz, CDCl3): δ = 8.41 – 8.39 (m, 1H), 7.87 – 7.83 (m, 2H), 7.82 (dt, J = 6.8, 1.2 Hz,
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1H), 7.66 (dt, J = 9.0, 1.1 Hz, 1H), 7.45 – 7.41 (m, 1H), 7.27 – 7.22 (m, 1H, overlapped with
CDCl3 residual signal), 6.92 – 6.87 (m, 3H), 6.76 (td, J = 6.7, 1.1 Hz, 1H), 6.41 (d, J = 10.2 Hz,
1H), 6.24 (d, J = 8.4 Hz, 1H), 5.67 (d, J = 10.2 Hz, 1H), 3.81 (s, 3H), 1.91 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 170.7, 159.7, 155.5, 148.6, 143.1, 139.6, 138.8, 128.1, 125.4,
125.3, 122.4, 118.8, 117.8, 116.8, 114.1, 112.3, 108.0, 74.3, 55.2, 21.0 ppm; HRMS (ESI) calcd
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+
for C22H21N4O3 [M + H]+ 389.1608, found 389.1598.
((2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4d): White
solid; 152 mg, 81% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
1
177-179 °C; FT-IR (neat): 3749, 3113, 1735, 1589, 1392, 1273, 937, 840, 744 cm-1; H NMR
(400 MHz, CDCl3): δ = 8.41 (d, J = 4.6 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.84 (d, J = 6.8 Hz, 1H),
7.69 (d, J = 9.1 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.31 – 7.27 (m, 1H), 7.07 (t, J = 8.7 Hz, 2H), 6.92
(dd, J = 6.8, 5.2 Hz, 1H), 6.81 (t, J = 6.6 Hz, 1H), 6.37 (d, J = 10.2 Hz, 1H), 6.26 (d, J = 8.4 Hz,
13
1H), 5.72 (d, J = 10.2 Hz, 1H), 1.91 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 170.6,
162.7 (d, JC-F = 246 Hz), 155.4, 148.7, 143.1, 138.9, 138.8, 128.9 (d, JC-F = 3.0 Hz), 128.7 (d, JC-F
= 8.0 Hz), 125.7, 122.5, 119.4, 118.0, 117.0, 115.6 (d, JC-F = 22 Hz), 112.6, 107.8, 74.1, 20.9
+
ppm; HRMS (ESI) calcd for C21H18FN4O2 [M + H]+ 377.1408, found 377.1420.
((2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4e): White
solid; 166 mg, 80% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
1
164-166 °C; FT-IR (neat): 3745, 3016, 1735, 1589, 1496, 1350, 1273, 987, 760, 709 cm-1; H
NMR (400 MHz, CDCl3): δ 8.44 (d, J = 4.0 Hz, 1H), 7.92 – 7.89 (m, 3H), 7.65 (d, J = 9.6 Hz,
1H), 7.53 – 7.48 (m, 1H), 7.41 – 7.32 (m, 3H), 7.25 (dd, J = 9.6, 2.0 Hz, 1H), 6.96 (dd, J = 7.2,
4.8 Hz, 1H), 6.43 (d, J = 10.4 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 5.67 (d, J = 10.4 Hz, 1H), 1.94
13
(s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 170.6, 155.2, 148.8, 141.5, 140.8, 139.0, 132.3,
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128.8, 128.6, 127.0, 126.9, 121.0, 120.6, 120.3, 118.5, 117.2, 107.9, 74.1, 20.9; HRMS (ESI)
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+
calcd for C21H18ClN4O2 [M + H]+ 393.1113, found 393.1115.
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((2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4f): White
solid; 181 mg, 83% yield; The eluent used was ethyl acetate/petroleum ether (1:4, v/v); mp =
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174-176 °C; FT-IR (neat): 3741, 2978, 1735, 1589, 1473, 1350, 1141, 933, 779, 609 cm-1; H
NMR (400 MHz, CDCl3): δ = 8.40 – 8.38 (m, 1H), 7.83 – 7.78 (m, 3H), 7.67 (d, J = 9.1 Hz, 1H),
7.50 – 7.42 (m, 3H), 7.30 – 7.27 (m, 1H), 6.91 (dd, J = 6.9, 5.2 Hz, 1H), 6.79 (td, J = 6.8, 0.8 Hz,
1H), 6.34 (d, J = 10.3 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 1.90 (s, 3H)
ppm; C{1H} NMR (100 MHz, CDCl3) δ = 170.6, 155.3, 148.7, 143.2, 138.8, 138.6, 131.8,
13
131.7, 128.4, 125.8, 122.5, 122.4, 119.8, 118.1, 117.0, 112.7, 107.8, 74.1, 20.9 ppm; HRMS
+
(ESI) calcd for C21H18BrN4O2 [M + H]+ 437.0608, found 437.0593.
((2-(4-Cyanophenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl
acetate
(4g):
Colorless semi-solid; 147.5 mg, 77% yield; The eluent used was ethyl acetate/petroleum ether
(1:3, v/v); FT-IR (neat): 3749, 2954, 2242, 1736, 1589, 1485, 1349, 1248, 970, 759, 701 cm-1; 1H
NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 6.8
Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.49 – 7.45 (m, 1H), 7.34 – 7.29 (m,
1H), 6.93 (dd, J = 7.3, 5.0 Hz, 1H), 6.83 (t, J = 6.8 Hz, 1H), 6.32 (d, J = 10.4 Hz, 1H), 6.25 (d, J
= 8.3 Hz, 1H), 5.72 (d, J = 10.4 Hz, 1H), 1.89 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
= 170.5, 155.0, 148.8, 143.4, 139.0, 137.5, 137.3, 132.5, 132.4, 127.2, 126.4, 122.6, 121.0,
+
118.8, 118.3, 117.3, 113.1, 111.4, 107.8, 74.0, 20.9 ppm; HRMS (ESI) calcd for C22H18N5O2
[M + H]+ 384.1455, found 384.1443.
(Pyridin-2-yl(2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)amino)methyl
acetate
(4h): White solid; 147 mg, 69% yield; The eluent used was ethyl acetate/petroleum ether (1:3,
v/v); mp = 144-146 °C; FT-IR (neat): 3749, 3047, 1732, 1573, 1435, 1276, 948, 767, 701 cm-1;
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1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.84 (d, J =
6.9 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.30 (t, J
= 7.8 Hz, 1H), 6.92 (t, J = 6.0 Hz, 1H), 6.82 (t, J = 6.8 Hz, 1H), 6.33 (d, J = 10.4 Hz, 1H), 6.26
13
(d, J = 8.4 Hz, 1H), 5.72 (d, J = 10.3 Hz, 1H), 1.88 (s, 3H) ppm; C{1H} NMR (100 MHz,
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CDCl3) δ = 170.6, 155.2, 148.8, 143.3, 138.9, 138.2, 136.3, 129.9 (q, JC-F = 32 Hz), 127.0, 126.1,
125.6 (q, JC-F = 3.0 Hz), 124.1 (q, JC-F = 270 Hz), 122.6, 120.6, 118.3, 117.1, 112.9, 107.8, 74.0,
20.9 ppm; HRMS (ESI) calcd for C22H18F3N4O2 [M + H]+ 427.1376, found 427.1359.
+
((2-(3-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4i): White
solid; 87 mg, 45% yield; The eluent used was ethyl acetate/petroleum ether (3:7, v/v); mp = 97-
99 °C; 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.72 (d,
J = 9.2 Hz, 1H), 7.52 – 7.46 (m, 3H), 7.32 – 7.27 (m, 2H), 6.94 – 6.87 (m, 2H), 6.82 (t, J = 6.8
Hz, 1H), 6.42 (d, J = 10.0 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.72 (d, J = 10.4 Hz, 1H), 3.77 (s,
3H), 1.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 159.8, 155.6, 148.6, 143.1, 139.6,
138.8, 134.0, 129.7, 125.6, 122.5, 119.9, 119.2, 118.1, 116.9, 114.9, 112.6, 111.6, 108.0, 74.2,
55.2, 20.9; HRMS (ESI) calcd for C22H21N4O3 [M + H]+ 389.1608, found 389.1598.
+
(Pyridin-2-yl(2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)amino)methyl acetate (4j): White
solid; 153 mg, 84% yield; The eluent used was ethyl acetate/petroleum ether (3:7, v/v); mp =
116-118 °C; FT-IR (neat): 3774, 3016, 1743, 1589, 1473, 1357, 1273, 933, 732 cm-1; H NMR
1
(400 MHz, CDCl3): δ 8.41 (m, 1H), 7.88 (dt, J = 6.8, 1.2 Hz, 1H), 7.69 (dt, J = 9.1, 1.1 Hz, 1H),
7.48 (dd, J = 3.6, 1.1 Hz, 1H), 7.43 (ddd, J = 9.2, 7.2, 1.9 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.05 (dd,
J = 5.1, 3.7 Hz, 1H), 6.90 (ddd, J = 7.6, 5.2, 1.2 Hz, 1H), 6.81 (td, J = 6.8, 1.1 Hz, 1H), 6.55 (d, J
= 10.3 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 2.99 (s, unassigned
impurity), 1.99 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 170.6, 155.2, 148.5, 143.3, 138.7,
13
136.0, 135.4, 127.8, 126.1, 125.8, 124.9, 122.6, 118.6, 117.8, 117.0, 112.6, 108.0, 74.2, 42.7
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(unassigned impurity), 21.1. ppm; HRMS (ESI) calcd for C19H17N4O2S+ [M + H]+ 365.1067,
found 365.1058.
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((6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4k): White
solid; 164 mg, 88% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
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169-171 °C; FT-IR (neat): 3734, 3047, 1735, 1589, 1473, 1342, 1219, 933, 786, 725 cm-1; H
NMR (400 MHz, CDCl3): δ 8.43 (dd, J = 5.0, 1.0 Hz, 1H), 7.92 – 7.90 (m, 2H), 7.63 – 7.59 (m,
2H), 7.46 (m, 1H), 7.40 – 7.34 (m, 2H), 7.35 – 7.26 (m, 1H), 7.14 (dd, J = 9.1, 1.8 Hz, 1H), 6.98
– 6.88 (m, 1H), 6.36 (d, J = 10.2 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H),
2.29 (s, 3H), 1.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 155.6, 148.6, 142.3, 139.6,
138.8, 132.9, 128.8, 128.6, 128.1, 126.8, 122.4, 120.1, 117.4, 116.8, 108.0, 74.1, 20.9, 18.3 ppm;
+
HRMS (ESI) calcd for C22H21N4O2 [M + H]+ 373.1659, found 373.1649.
((7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4l): White
solid; 158 mg, 85% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
1
163-165 °C; FT-IR (neat): 3741, 3078, 1728, 1589, 1473, 1350, 1211, 933, 779, 694 cm-1; H
NMR (400 MHz, CDCl3): δ = 8.41 (dd, J = 5.0, 1.8 Hz, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.72 (d, J
= 6.9 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.90 (dd, J
= 7.3, 5.0 Hz, 1H), 6.62 (dd, J = 7.0, 1.6 Hz, 1H), 6.42 (d, J = 10.2 Hz, 1H), 6.26 (d, J = 8.4 Hz,
1H), 5.67 (d, J = 10.2 Hz, 1H), 2.43 (s, 3H), 1.90 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ = 170.7, 155.6, 148.5, 143.6, 139.3, 138.7, 136.6, 132.8, 128.6, 128.1, 126.7, 121.8, 119.2,
116.8, 116.4, 115.1, 108.0, 74.3, 21.4, 21.0 ppm; HRMS (ESI) calcd for C22H21N4O2 [M + H]+
+
373.1659, found 373.1645.
((6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4m): White
solid; 161 mg, 82% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
170-172 °C; FT-IR (neat): 3742, 3011, 1733, 1470, 1352, 1210, 943, 730, 689 cm-1; H NMR
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(400 MHz, CDCl3): δ = 8.41 (d, J = 4.0 Hz, 1H), 7.89 – 7.86 (m, 3H), 7.62 (d, J = 9.5 Hz, 1H),
7.48 (t, J = 8.2 Hz, 1H), 7.38 – 7.29 (m, 3H), 7.23 (dd, J = 9.5, 2.0 Hz, 1H), 6.93 (t, J = 6.1 Hz,
1H), 6.40 (d, J = 10.4 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 10.3 Hz, 1H), 1.91 (s, 3H)
13
ppm; C{1H} NMR (100 MHz, CDCl3) δ = 170.6, 155.1, 148.7, 141.5, 140.7, 138.9, 132.3,
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128.7, 128.5, 127.0, 126.8, 121.0, 120.5, 120.2, 118.4, 117.2, 107.8, 74.1, 20.9 ppm; HRMS
(ESI) calcd for C21H18ClN4O2 [M + H]+ 393.1113, found 393.1110.
+
((4-Methylpyridin-2-yl)(2-phenylimidazo[1,2-a]pyridin-3-yl)amino)methyl acetate (4n): White
solid; 165.5 mg, 89% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
156-158 °C; FT-IR (neat): 3896, 2985, 1743, 1481, 1357, 1234, 918, 694 cm-1; H NMR (400
1
MHz, CDCl3): δ = 8.25 (d, J = 5.1 Hz, 1H), 7.92 – 7.90 (m, 2H), 7.82 (dt, J = 6.8, 1.2 Hz, 1H),
7.69 (d, J = 9.0 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.31 – 7.24 (m, 2H, overlapped with CDCl3
residual signal), 6.77 (td, J = 6.8, 0.8 Hz, 1H), 6.72 (d, J = 5.0 Hz, 1H), 6.37 (d, J = 10.2 Hz,
1H), 6.06 (s, 1H), 5.66 (d, J = 10.3 Hz, 1H), 2.10 (s, 3H), 1.86 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ = 170.6, 155.7, 150.2, 148.2, 143.2, 139.6, 132.7, 128.6, 128.2, 126.8, 125.6,
122.6, 119.9, 118.4, 118.0, 112.5, 108.1, 74.4, 21.2, 20.9 ppm; HRMS (ESI) calcd for
C22H21N4O2 [M + H]+ 373.1659, found 373.1670.
+
((5-Chloropyridin-2-yl)(2-phenylimidazo[1,2-a]pyridin-3-yl)amino)methyl acetate (4o): White
solid; 170.5 mg, 87% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp =
156-158 °C; FT-IR (neat): 3734, 3001, 1735, 1473, 1357, 1211, 933, 732, 686 cm-1; H NMR
1
(400 MHz, CDCl3): δ = 8.32 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.81 (d, J = 6.8 Hz,
1H), 7.69 (d, J = 9.1 Hz, 1H), 7.41 – 7.27 (m, 5H), 6.80 (t, J = 6.8 Hz, 1H), 6.33 (d, J = 10.3 Hz,
1H), 6.21 (d, J = 8.8 Hz, 1H), 5.63 (d, J = 10.3 Hz, 1H), 1.88 (s, 3H) ppm; C{1H} NMR (100
13
MHz, CDCl3) δ = 170.5, 153.9, 147.1, 143.2, 139.7, 138.5, 132.5, 128.7, 128.4, 126.8, 125.8,
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+
124.4, 122.4, 119.3, 118.1, 112.7, 108.9, 74.3, 20.9 ppm; HRMS (ESI) calcd for C21H18ClN4O2
[M + H]+ 393.1113, found 393.1100.
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((2-(tert-Butyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)amino)methyl acetate (4p): White solid;
71 mg, 42% yield; The eluent used was ethyl acetate/petroleum ether (4:6, v/v); mp = 126-128
°C; 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.64 (d, J
= 9.2 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 7.2, 5.0 Hz, 1H), 6.73
(t, J = 6.8 Hz, 1H), 6.63 (d, J = 10.0 Hz, 1H), 6.04 (d, J = 8.4 Hz, 1H), 5.52 (d, J = 10.4 Hz, 1H),
2.06 (s, 3H), 1.41 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 155.9, 150.0, 148.3, 142.3,
138.3, 125.0, 122.6, 119.0, 117.6, 116.4, 111.8, 108.1, 76.0, 33.3, 30.0, 21.2; HRMS (ESI) calcd
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+
for C19H23N4O2 [M + H]+ 339.1816, found 339.1425.
N-(Methoxymethyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6aa): White solid;
148.5 mg, 90% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v); mp = 116-
1
117 °C; FT-IR (neat): 3074, 2916, 1631, 1589, 1473, 1346, 1242, 1141, 941, 771, 694 cm-1; H
NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 3.2 Hz, 1H), 7.97 – 7.94 (m, 3H), 7.68 (d, J = 9.1 Hz,
1H), 7.44 – 7.37 (m, 3H), 7.33 – 7.25 (m, 2H), 6.85 (dd, J = 6.7, 5.3 Hz, 1H), 6.78 (t, J = 6.6 Hz,
1H), 6.22 (d, J = 8.4 Hz, 1H), 5.94 (d, J = 9.5 Hz, 1H), 4.72 (d, J = 9.5 Hz, 1H), 3.36 (s, 3H)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ = 156.2, 148.6, 143.1, 138.7, 138.5, 133.0, 128.7,
128.1, 126.6, 125.4, 123.2, 121.1, 117.7, 116.1, 112.3, 107.8, 82.0, 56.6 ppm; HRMS (ESI) calcd
for C20H19N4O+ [M + H]+ 331.1553, found 331.1554.
N-(Ethoxymethyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ab): White solid;
136 mg, 79% yield; The eluent used was ethyl acetate/petroleum ether (32:68, v/v); mp = 120-
122 °C; FT-IR (neat): 3062, 2978, 1967, 1635, 1589, 1427, 1350, 1234, 1141, 918, 732, 686 cm-
1; 1H NMR (400 MHz, CDCl3): δ = 8.36 – 8.34 (m, 1H), 7.94 – 7.91 (m, 3H), 7.66 (d, J = 9.1 Hz,
1H), 7.41 – 7.34 (m, 3H), 7.31 – 7.22 (m, 2H, overlapped with CDCl3 residual signal), 6.82 (dd,
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J = 6.6, 5.1 Hz, 1H), 6.75 (td, J = 6.7, 1.2 Hz, 1H), 6.20 (d, J = 8.6 Hz, 1H), 5.98 (d, J = 10.0 Hz,
1H), 4.78 (d, J = 9.9 Hz, 1H), 3.63 – 3.55 (m, 1H), 3.55 – 3.45 (m, 1H), 1.08 (t, J = 7.0 Hz, 3H)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ = 156.4, 148.5, 143.1, 138.7, 138.5, 133.0, 128.6,
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128.0, 126.7, 125.4, 123.3, 121.1, 117.7, 116.0, 112.1, 107.7, 80.0, 64.8, 15.2 ppm; HRMS (ESI)
calcd for C21H21N4O+ [M + H]+ 345.1710, found 345.1715.
2-Phenyl-N-(pyridin-2-yl)-N-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridin-3-amine
(6ac): Colorless viscous oil; 132 mg, 78% yield; The eluent used was ethyl acetate/petroleum
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ether (35:65, v/v); FT-IR (neat): 3060, 2952, 1633, 1590, 1470, 1229, 1113, 923, 789 cm-1; H
NMR (400 MHz, CDCl3): δ = 8.29 – 8.27 (m, 1H), 7.81 (d, J = 7.0 Hz, 3H), 7.59 (d, J = 9.1 Hz,
1H), 7.35 – 7.26 (m, 3H), 7.23 – 7.15 (m, 2H), 6.78 (dd, J = 7.0, 5.2 Hz, 1H), 6.69 (t, J = 6.8 Hz,
1H), 6.11 (d, J = 8.4 Hz, 1H), 5.97 (d, J = 10.1 Hz, 1H), 4.94 (d, J = 10.1 Hz, 1H), 4.05 (q, J =
13
8.8 Hz, 2H) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 155.8, 148.4, 143.2, 139.1, 138.8,
132.8, 128.7, 128.2, 126.7, 125.7, 123.9 (q, JC-F = 278 Hz), 122.9, 120.3, 117.8, 116.7, 112.5,
107.9, 81.7, 67.4 (q, JC-F = 34 Hz) ppm; HRMS (ESI) calcd for C21H18F3N4O+ [M + H]+
339.1427, found 339.1425.
N-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)methyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-
a]pyridin-3-amine (6ad): White solid; 196 mg, 84% yield; The eluent used was ethyl
acetate/petroleum ether (35:65, v/v); mp = 151-153 °C; FT-IR (neat): 3062, 2954, 1635, 1593,
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1473, 1350, 1226, 1103, 933, 779, 702 cm-1; H NMR (400 MHz, CDCl3): δ = 8.41 – 8.39 (m,
1H), 7.91 – 7.88 (m, 3H), 7.70 (d, J = 9.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.42 – 7.27 (m, 4H), 6.96-
6.92 (m, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H), 6.23-6.20 (m, 2H), 5.55 (sept, J = 6.1 Hz, 1H), 5.16
13
(d, J = 10.8 Hz, 1H) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 155.1, 148.1, 143.3, 139.1,
139.0, 132.6, 128.8, 128.3, 126.6, 125.9, 122.94, 122.93, 121.8 (q, JC-F = 282 Hz), 119.8, 117.8,
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117.1, 112.7, 108.1, 83.9, 75.8 (p, JC-F = 32 Hz) ppm; HRMS (ESI) calcd for C22H17F6N4O+ [M +
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H]+ 467.1301, found 467.1294.
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(6ae):
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Colorless semi-solid; 107.5 mg, 56% yield; The eluent used was ethyl acetate/petroleum ether
(3:7, v/v); FT-IR (neat): 3076, 2910, 1633, 1580, 1471, 1342, 1232, 1121, 939, 770, 697 cm-1; 1H
NMR (400 MHz, CDCl3): δ = 8.33 (dd, J = 5.0, 1.8 Hz, 1H), 7.96 – 7.93 (m, 3H), 7.65 (dt, J =
9.0, 1.2 Hz, 1H), 7.41 – 7.34 (m, 3H), 7.30-7.21 (m, 2H, overlapped with CDCl3 residual signal),
6.80 (dd, J = 7.2, 5.0 Hz, 1H), 6.73 (td, J = 6.8, 0.9 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 5.99 (d, J
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= 9.8 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.07-4.03 (m, 1H), 1.65 – 1.41 (m, 8H) ppm; C{1H}
NMR (100 MHz, CDCl3) δ = 156.4, 148.5, 143.1, 138.7, 138.4, 133.1, 128.6, 128.0, 126.7,
125.4, 123.6, 121.2, 117.6, 115.9, 111.9, 107.7, 79.7, 78.2, 32.6, 32.3, 23.5, 23.4 ppm; HRMS
(ESI) calcd for C24H25N4O+ [M + H]+ 385.2023, found 385.2012.
2-Phenyl-N-((prop-2-yn-1-yloxy)methyl)-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ag):
White solid; 134.5 mg, 76% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v);
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mp = 105-107 °C; FT-IR (neat): 3147, 2939, 1631, 1585, 1473, 1242, 995, 775, 694 cm-1; H
NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 4.0 Hz, 1H), 7.96 – 7.91 (m, 3H), 7.70 (d, J = 8.9 Hz,
1H), 7.44 – 7.35 (m, 3H), 7.32 – 7.27 (m, 2H), 6.86 – 6.83 (m, 1H), 6.78 (t, J = 6.6 Hz, 1H), 6.24
(d, J = 8.4 Hz, 1H), 6.05 (d, J = 10.0 Hz, 1H), 4.89 (d, J = 10.0 Hz, 1H), 4.33 – 4.23 (m, 2H),
2.30 (t, J = 2.4 Hz, 1H), ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.0, 148.5, 142.9, 138.6,
128.7, 128.2, 126.7, 125.93, 125.90, 123.4, 120.8, 117.5, 116.4, 112.5, 107.8, 79.8, 79.3, 74.4,
56.5 ppm; HRMS (ESI) calcd for C22H19N4O+ [M + H]+ 355.1553, found 355.1556.
N-((Allyloxy)methyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ah): White
solid; 94 mg, 53% yield; The eluent used was ethyl acetate/petroleum ether (1:3, v/v); mp = 65-
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67 °C; FT-IR (neat): 3140, 2930, 1639, 1581, 1463, 1232, 991, 773, 697 cm-1; H NMR (400
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MHz, CDCl3): δ = 8.38 (s, 1H), 7.95 (d, J = 3.4 Hz, 3H), 7.69 (d, J = 9.1 Hz, 1H), 7.44 – 7.25 (m,
4H, overlapped with CDCl3 residual signal), 6.86 – 6.75 (m, 2H), 6.23 (d, J = 8.5 Hz, 1H), 6.02
(d, J = 9.9 Hz, 1H), 5.85 – 5.76 (m, 1H), 5.17 – 5.07 (m, 2H), 4.83 (d, J = 9.9 Hz, 1H), 4.09 (s,
2H), ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.3, 148.5, 143.1, 138.8, 138.5, 134.3, 133.0,
128.7, 128.0, 126.7, 125.4, 123.3, 121.0, 117.7, 116.8, 116.1, 112.2, 107.8, 79.7, 70.0 ppm;
HRMS (ESI) calcd for C22H21N4O+ [M + H]+ 357.1710, found 357.1725.
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N-((Dodecyloxy)methyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ai): Yellow
oil; 85 mg, 35% yield; The eluent used was ethyl acetate/petroleum ether (2:4, v/v); FT-IR (neat):
3240, 1597, 1481, 1350, 1249, 979, 756, 702 cm-1; 1H NMR (400 MHz, CDCl3): δ = 8.35 – 8.33
(m, 1H), 7.94 – 7.91 (m, 3H), 7.66 (dt, J = 9.0, 1.2 Hz, 1H), 7.42 – 7.34 (m, 3H), 7.31 – 7.22 (m,
2H, overlapped with CDCl3 residual signal), 6.83 – 6.80 (m, 1H), 6.74 (td, J = 6.7, 1.1 Hz, 1H),
6.22 (d, J = 8.6 Hz, 1H), 5.95 (d, J = 9.8 Hz, 1H), 4.77 (d, J = 9.8 Hz, 1H), 3.54-3.48 (m, 1H),
3.42-3.47 (m, 1H), 1.61 – 1.52 (m, 2H), 1.44 (t, J = 6.5 Hz, 2H), 1.25 (br s, 16H), 0.88-0.85 (m,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.4, 148.5, 143.1, 138.7, 138.4, 133.0, 128.6,
128.0, 126.7, 125.4, 123.4, 121.2, 117.6, 116.0, 112.1, 107.7, 80.3, 69.4, 31.9, 29.7, 29.66, 29.63,
29.61, 29.5, 29.4, 29.38, 29.35, 26.0, 22.6, 14.1 ppm; HRMS (ESI) calcd for C31H41N4O+ [M +
H]+ 485.3275, found 485.3243.
N-(Methoxymethyl)-N-(pyridin-2-yl)-2-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (6ba): White
solid; 158 mg, 92% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v); mp =
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126-128 °C; FT-IR (neat): 3078, 2924, 1586, 1473, 1350, 1273, 941, 779 cm-1; H NMR (400
MHz, CDCl3): δ = 8.36 – 8.34 (m, 1H), 7.92 (dt, J = 6.8, 1.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H),
7.66 (d, J = 9.0, 1H), 7.39 (m, 1H), 7.26 – 7.22 (m, 1H, overlapped with CDCl3 residual signal),
7.17 (d, J = 8.0 Hz, 2H), 6.83 – 6.80 (m, 1H), 6.75 (td, J = 6.8, 1.2 Hz, 1H), 6.19 (d, J = 8.4 Hz,
1H), 5.91 (d, J = 9.6 Hz, 1H), 4.69 (d, J = 9.6 Hz, 1H), 3.34 (s, 3H), 2.33 (s, 3H) ppm; 13C{1H}
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NMR (100 MHz, CDCl3): δ = 156.2, 148.5, 142.9, 138.6, 138.5, 138.0, 130.0, 129.4, 126.5,
125.5, 123.2, 120.8, 117.5, 116.1, 112.3, 107.8, 81.9, 56.6, 21.3 ppm; HRMS (ESI) calcd for
C21H21N4O+ [M + H]+ 345.1710, found 345.1711.
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N-(Ethoxymethyl)-N-(pyridin-2-yl)-2-(p-tolyl)imidazo[1,2-a]pyridin-3-amine (6bb): White solid;
143 mg, 80% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v); mp = 150-
152 °C; FT-IR (neat): 3075, 2933, 1581, 1478, 1352, 1279, 931, 789 cm-1; 1H NMR (400 MHz,
CDCl3): δ = 8.35 – 8.33 (m, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.68 (d, J =
9.0 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.27-7.22 (m, 1H, overlapped with CDCl3 residual signal), 7.17
(d, J = 7.9 Hz, 2H), 6.82-6.79 (m, 1H), 6.75 (td, J = 6.8, 1.1 Hz, 1H), 6.20 (d, J = 8.6 Hz, 1H),
5.98 (d, J = 9.9 Hz, 1H), 4.76 (d, J = 9.9 Hz, 1H), 3.63 – 3.55 (m, 1H), 3.53 – 3.45 (m, 1H), 2.33
(s, 3H), 1.08 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.3, 148.5, 142.9,
138.5, 138.4, 138.0, 129.9, 129.4, 126.5, 125.5, 123.3, 120.8, 117.5, 116.0, 112.2, 107.7, 80.0,
64.7, 21.3, 15.2 ppm; HRMS (ESI) calcd for C22H23N4O+ [M + H]+ 359.1866, found 359.1878.
N-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)methyl)-N-(pyridin-2-yl)-2-(p-tolyl)imidazo[1,2-
a]pyridin-3-amine (6bd): White solid; 194 mg, 81% yield; The eluent used was ethyl
acetate/petroleum ether (35:65, v/v); mp = 154-156 °C; FT-IR (neat): 3086, 1643, 1589, 1473,
1350, 1219, 941, 732, 686 cm-1; 1H NMR (400 MHz, CDCl3): δ = 8.38 – 8.36 (m, 1H), 7.85 (d, J
= 6.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.28 –
7.24 (m, 1H, overlapped with CDCl3 residual signal), 7.18 (d, J = 7.8 Hz, 2H), 6.92 – 6.89 (m,
1H), 6.77 (td, J = 6.8, 1.2 Hz, 1H), 6.20-6.17 (m, 2H), 5.52 (sept, J = 6.1 Hz, 1H), 5.12 (d, J =
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10.7 Hz, 1H), 2.34 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 155.1, 148.0, 143.3,
139.2, 139.0, 138.3, 129.8, 129.5, 126.5, 125.8, 122.87, 122.86, 121.8 (q, JC-F = 281 Hz), 119.4,
117.7, 117.0, 112.5, 108.2, 83.9, 75.8 (p, JC-F = 32 Hz), 21.3 ppm; HRMS (ESI) calcd for
C23H19F6N4O+ [M + H]+ 481.1458, found 481.1438.
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N-(Methoxymethyl)-2-(3-methoxyphenyl)-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ia):
Off-white solid; 88 mg, 49% yield; The eluent used was ethyl acetate/petroleum ether (4:6, v/v);
mp = 136-138 °C; 1H NMR (400 MHz, CDCl3): δ 8.38 (dd, J = 4.8, 2.0 Hz, 1H), 7.97 (d, J = 6.8
Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.56 – 7.51 (m, 2H), 7.45 – 7.41 (m, 1H), 7.31 – 7.26 (m, 2H,
overlapped with CDCl3 residual signal), 6.89 – 6.84 (m, 2H), 6.79 (t, J = 6.8 Hz, 1H), 6.23 (d, J
= 8.4 Hz, 1H), 5.94 (d, J = 9.6 Hz, 1H), 4.75 (d, J = 9.6 Hz, 1H), 3.78 (s, 3H), 3.38 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 156.3, 148.6, 143.0, 138.6, 138.5, 134.3, 129.7,
125.5, 123.2, 121.3, 119.1, 117.8, 116.2, 114.7, 112.4, 111.4, 107.8, 82.0, 56.6, 55.2; HRMS
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(ESI) calcd for C21H21N4O2 [M + H]+ 361.1659, found 361.1648.
2-(4-Fluorophenyl)-N-(methoxymethyl)-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6da):
White solid; 136 mg, 78% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v);
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mp = 168-170 °C; FT-IR (neat): 3086, 1589, 1473, 1396, 1234, 933, 779, 694 cm-1; H NMR
(400 MHz, CDCl3): δ = 8.34 (d, J = 4.0 Hz, 1H), 7.92 – 7.88 (m, 3H), 7.64 (d, J = 9.0 Hz, 1H),
7.39 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H, overlapped with CDCl3 residual signal), 7.04 (t,
J = 8.6 Hz, 2H), 6.82 (t, J = 5.4 Hz, 1H), 6.75 (t, J = 6.7 Hz, 1H), 6.19 (d, J = 8.4 Hz, 1H), 5.84
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(d, J = 9.5 Hz, 1H), 4.73 (d, J = 9.5 Hz, 1H), 3.34 (s, 3H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ = 162.6 (d, JC-F, 246 Hz), 156.1, 148.6, 143.1, 138.5, 138.0, 129.2 (d, JC-F, 3 Hz),
128.5 (d, JC-F, 8 Hz), 125.6, 123.2, 120.8, 117.6, 116.3, 115.6 (d, JC-F, 22 Hz), 112.4, 107.7, 81.8,
56.6 ppm; HRMS (ESI) calcd for C20H18FN4O+ [M + H]+ 349.1459, found 349.1475.
6-Chloro-N-(methoxymethyl)-2-phenyl-N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine (6ma):
White solid; 135 mg, 74% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v);
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mp = 180-182 °C; FT-IR (neat): 3034, 1632, 1470, 1351, 1232, 981, 789, 689 cm-1; H NMR
(400 MHz, CDCl3): δ = 8.37 – 8.35 (m, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.90 (d, J = 7.2 Hz, 2H),
7.60 (d, J = 9.5 Hz, 1H), 7.45-7.41 (m, 1H), 7.38 – 7.34 (m, 2H), 7.32 – 7.28 (m, 1H), 7.20 (dd, J
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= 9.5, 1.9 Hz, 1H), 6.86 (dd, J = 6.8, 5.1, 1H), 6.22 (d, J = 8.7 Hz, 1H), 5.89 (d, J = 9.5 Hz, 1H),
4.67 (d, J = 9.5 Hz, 1H), 3.37 (s, 3H), ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 155.9, 148.7,
141.4, 139.7, 138.7, 132.5, 128.8, 128.4, 126.9, 126.6, 121.6, 121.2, 120.8, 118.1, 116.5, 107.6,
81.8, 56.5 ppm; HRMS (ESI) calcd for C20H18ClN4O+ [M + H]+ 365.1164, found 365.1173.
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N-(Methoxymethyl)-N-(4-methylpyridin-2-yl)-2-phenylimidazo[1,2-a]pyridin-3-amine
(6na):
White solid; 153 mg, 89% yield; The eluent used was ethyl acetate/petroleum ether (35:65, v/v);
mp = 162-164 °C; FT-IR (neat): 3039, 1635, 1473, 1357, 1242, 987, 779, 686 cm-1; H NMR
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(400 MHz, CDCl3): δ = 8.20 (d, J = 5.1 Hz, 1H), 7.95 – 7.90 (m, 3H), 7.69 (dt, J = 9.0, 1.1 Hz,
1H), 7.38 – 7.34 (m, 2H), 7.31 – 7.23 (m, 2H, overlapped with CDCl3 residual signal), 6.76 (td, J
= 6.8, 1.0 Hz, 1H), 6.66 (d, J = 5.1 Hz, 1H), 6.03 (s, 1H), 5.89 (d, J = 9.6 Hz, 1H), 4.66 (d, J =
9.6 Hz, 1H), 3.31 (s, 3H), 2.09 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.4, 149.8,
148.2, 142.9, 138.3, 132.8, 128.7, 128.1, 126.6, 125.7, 123.3, 121.3, 117.7, 117.5, 112.4, 108.0,
+
82.1, 56.5, 21.2 ppm; HRMS (ESI) calcd for C21H21N4O2 [M + H]+ 345.1710, found 345.1736.
N-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)methyl)-N-(4-methylpyridin-2-yl)-2
phenylimidazo[1,2-a]pyridin-3-amine (6nd): White solid; 199 mg, 83% yield; The eluent used
was ethyl acetate/petroleum ether (3:7, v/v); mp = 163-164 °C; FT-IR (neat): 3047, 1612, 1357,
1226, 945, 736, 682 cm-1; 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 5.2 Hz, 1H), 7.90 – 7.86
(m, 3H), 7.68 (d, J = 9.0 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.33 – 7.26 (m, 2H, overlapped with
CDCl3 residual signal), 6.78 (t, J = 6.7 Hz, 1H), 6.75 (d, J = 5.1 Hz, 1H), 6.18 (d, J = 10.8 Hz,
1H), 6.01 (s, 1H), 5.57 (sept, J = 6.0 Hz, 1H), 5.10 (d, J = 10.8 Hz, 1H), 2.10 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 155.3, 150.5, 147.7, 143.3, 139.0, 132.7, 128.8, 128.3,
126.6, 125.9, 123.03, 123.01, 121.9 (q, JC-F = 281 Hz), 120.0, 118.6, 117.7, 112.6, 108.3, 84.0,
75.8 (p, JC-F = 32 Hz), 21.2 ppm; HRMS (ESI) calcd for C23H19F6N4O+ [M + H]+ 481.1458,
found 481.1475.
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