Access to 2-pyridinylamide and imidazopyridine from 2-fluoropyridine and amidine hydrochloride

Article abstract of DOI:10.1039/d0ob01904f

Under catalyst-free conditions, an efficient method to synthesize 2-pyridinylamides has been developed, and the protocol uses inexpensive and readily available 2-fluoropyridine and amidine derivatives as the starting materials. Simultaneously, the copper-catalysed approach to imidazopyridine derivatives has been established with high chemoselectivity and regiospecificity. The results suggest that the nitrogen-heterocycles containing iodide substituents can also be compatible for the reaction via the cascade Ullmann-type coupling, and the nucleophilic substitution reaction provides the target products in a one-pot manner.

Full text of DOI:10.1039/d0ob01904f

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Li, S. Huang, J.
Li, J. Li, X. Ji, J. Liu, L. Chen, S. Peng and K. Zhang, Org. Biomol. Chem., 2020, DOI:
10.1039/D0OB01904F.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Page 1 of 9
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01904F
Journal Name
ARTICLE
Access to 2-Pyridinylamide and Imidazopyridine from 2-
Fluoropyridine and Amidine Hydrochloride
Received 00th January
20xx,
Accepted 00th January
20xx
Yibiao Li,*a Shuo Huang,a Jiaming Li,a Jian Li,a Xiaoliang Ji,a Jiashen Liu,a Lu Chen,a Shiyong
Penga and Kun Zhang*a
Under catalyst-free conditions, an efficient method to synthesize 2-pyridinylamides has been developed, and the protocol
uses inexpensive and readily available 2-fluoropyridine and amidine derivatives as the starting materials. Simultaneously,
the Copper-catalysed approach to imidazopyridine derivatives has been established with high chemoselectivity and
regiospecificity. The results suggest that the nitrogen-heterocycles containing iodide substituents can also be compatible
for the reaction via the cascade Ullmann-type coupling, and the nucleophilic substitution reaction provides the target
products in a one-pot manner.
DOI: 10.1039/x0xx00000x
www.rsc.org/
developed, amines with a strongly electron-withdrawing group or a
larger steric hindrance are not suitable to synthesize amide
compounds. We also used Pd-catalysed halogenated aromatics and
isonitriles in the coupling reaction to prepare amide compounds.13
Recently, the metal-free catalysed synthesis of pyridyl pyridones14
and 2-aminopyridines15 through the hydroxylation and arylation
reaction of 2-fluoropyridines was reported by our group. With an
increased interest in the potential reactivity of 2-halopyridines, we
aimed to develop more 2-halopyridine selective functionalization
reactions under metal-free catalysed conditions. Herein, we
Introduction
Amide derivatives are important building blocks found in large
number of natural products because of their recognized biological
and therapeutic activities. The development of simple and efficient
protocols to synthesize amides is an important task in organic
synthesis. Amides are the core structure of many drugs such as
lidocaine,1 roflumilast2 and atorvastatin.3 Amide bonds are also
essential for biological structure because amide bonds are the basis
for amino acids to form proteins.4 The simplest and cheapest
method to prepare amides is probably the direct condensation of
carboxylic acids and amines. However, it is well known that this
amidation process requires severe harsh conditions to prevent the
formation of low-activity carboxylate-ammonium salts.5 Therefore,
the more efficient method to synthesize amides is based on the
nucleophilic substitution of amines with activated carboxylic acid
derivatives such as acid chlorides and carboxylic anhydrides
disclose
a controlled nucleophilic substitution and selective
amination of amidine hydrochloride with 2-fluoropyridine to
synthesize amides and imidazopyridine derivatives.
Scheme 1. Major pathways to synthesize amides
Reported work:
O
R1
R1
N
R2 CO
(a)
+
R2
N
H
6
amine
surrogate
carboxylic acid
surrogate
(Scheme 1a). Although this strategy has successfully synthesized
O
amides, the activation of carboxylic acids often requires additional
synthetic steps, and the use of some toxic reagents and the
byproducts are stoichiometrically generated. In contrast, when
carboxylic acid becomes an ester or equivalent, the carboxylic
group becomes more electrophilic and will certainly stimulate the
amidation reaction. Under certain catalytic conditions, alcohols,7
aldehydes,8 ketones,9 nitriles,10 and thioacids11 can be used as
equivalents of unactivated esters to participate in the synthesis of
amides. The preparation of amides via the combination of
halogenated aromatics, amines, and CO in the metal-transition
catalysis is an effective synthesis strategy (Scheme 1b).12
Unfortunately, although many synthetic methods have been
X
(b)
(c)
R
and CO
N
R
Pd cat.
N
H
+
Ar
or
N R
Ar
C
X = Cl, Br, F
This work:
H
N
NH
F
R
Cs2CO3
·HCl
+
N
R
NH2
Transition-Metal-Free
N
O
Results and discussion
For optimize the reaction conditions, 2-fluoro-3-iodopyridine 1a,
acetamidine hydrochloride 2a and H2O (3.0 equiv.) were selected as
the model system. First, dimethyl sulfoxide (DMSO) was selected as
t
the solvent, and BuOLi was selected as the base to optimize the
a
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020
China, E-mail: Leeyib268@126.com; kzhang@gdut.edu.cn
†Electronic Supplementary Information (ESI) available: General experimental
information, and NMR spectra. See DOI: 10.1039/x0xx00000x
reaction conditions. After 18 hours of reaction at 90 °C, we found
that this reaction can give the designed product 3a in 12% yield
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 9
ARTICLE
Journal Name
(Table 1, entry 1). Next, we screened the base and found that CsF aReaction conditions: 2-fluoro-3-iodopyridine 1a Vi(e1w.0Articmle mOnolinl)e,
DOI: 10.1039/D0OB01904F
and KF exhibited no apparent promotion effect (Table 1, entries 2- acetamidine hydrochloride (1.3 mmol), base (3.0 mmol), H2O (3.0
c
3). However, moderate yields were obtained when NaOH or tBuONa mmol) in solvent (3 mL) for 18 h; bIsolated Yield; acetamidine
d
were used (Table 1, entries 4-5). In the presence of H2O, strong hydrochloride (1.0 mmol) was used; N2 and anhydrous condition.
t
base such as NaOH or BuONa provides more active -OH groups for e12 h.
nucleophilic substitution and hydrolysis of 2-Pyridinylamide 3a and
give 2-aminopyridine derivatives.15 Next, we further screened the
weak base and found that K2CO3 exhibited a better effect (Table 1,
entry 6). Surprisingly, when Cs2CO3 was used, the yield can be
significantly improved to 93% (Table 1, entry 7). The solvent
screening shows that DMSO is the optimal solvent (Table 1, entries
8-10); when NMP, DMF and MeCN were used as the solvent, a
lower yield was detected. We found that when the temperature
was increased or decreased, the yield of this reaction decreased
(Table 1, entries 11-12). By decreasing the amount of acetamidine
hydrochloride and Cs2CO3, the yield was reduced to 87%, 85% and
37%, respectively (Table 1, entries 13-15). Under N2 and anhydrous
condition, the yield of the nucleophilic substitution reaction is
significantly affected (Table 1, entry 16) possibly because the
progress of the nucleophilic substitution and hydrolysis reaction is
hindered. Furthermore, shorten the reaction time, the yield of the
amidation reaction is slightly affected (Table 1, entry 17).
With the optimal conditions in hand (Table 1, entry 6), the
substrates for this amidation with high chemoselectivity were
developed. The results suggest that when the iodine groups were
embedded into the pyridine ring, the amidation can be smoothly
completed with a high yield of the target product (Scheme 2, 3a-3f).
It is remarkable that iodopyridine was reserved in this
transformation, since further functionalization of the product can
be made to C-I bond. It was also mechanistically interesting, since it
is well-known that the C(sp2)-I bond is notably susceptible in a
transition metal catalyzed cross coupling reaction. This reaction is
also tolerant to other substituent groups such as cyclopropyl,
cyclobutyl, -F, -Cl, -Br, -CF3, -OMe and -Me groups. Among these
amide products, the structure of N-(5-bromopyridin-2-yl)acetamide
3m was confirmed by crystal X-ray diffraction analysis (CCDC
2023439). More importantly, when the fluorine, chlorine, bromine
and iodine substituents are embedded into pyridine, the reaction
takes priority at the 2-position fluorine to give designed product in
good yields, while the halogen atoms at other positions are fully
compatible (Scheme 2, 3n-3r). When 2-fluoropyrazine was used as
the raw material for the amination reaction, the reaction could also
smoothly proceed and gave N-(pyrazin-2-yl)acetamide 3s in 92%
yield.
Table 1. Optimization of the Reaction Conditionsa
I
I
NH
O
Base, H2O
·HCl
NH2
+
N
N
H
Me
N
F
2a
1a
3a
Entry
Solve
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
Base (mmol)
tBuOLi (3)
CsF (3)
T/oC
90
90
90
90
90
90
90
90
90
90
80
100
90
90
90
90
100
yield/%b
12
Scheme 2. Synthesis of amide derivativesa
R1
1
2
R1
NH
R2
NH
O
air
R1
Cs2CO3
·HCl
+
<5
R2 NH2
F
N
R2
N
N
N
N
DMSO, H2O
H
H
2
1
3
3
KF (3)
<5
, R1 = 4-Me, 80%
, R1 = 3-F, 89 %
, R1 = 6-F, 88%
, R1 = 5-Cl, 74%
, R1 = 6-Cl, 69%
, R1 = 6-Br, 81 %
Me
3g
, R2 = Me, 93%
3a
3h
3i
4
NaOH (3)
tBuONa (3)
K2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (3)
Cs2CO3 (3)
37
I
, R2 = Et, 81 %
O
3b
3c
3d
3e
3f
O
, R2 = Cyclopropyl, 61%
, R2 = tBu, 87%
, R2 = Cyclobutyl, 68%
R1
3j
R2
5
47
N
N
N
N
Me
H
3k
3l
H
6
85
, R2 = -CH2OCH3, 69%
F
Cl
Br
7
93
O
Br
N
O
O
N
N
Me
N
H
N
H
N
Me
8
81
H
3m
3n,
, 93%
91%
3o
, 83%
9
DMF
63
Me
I
N
F3C
Cl
Cl
Br
O
O
O
O
10
11
12
13c
14
15
16d
17e
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
79
N
H
N
Me
N
H
N
Me
N
H
N
Me
N
H
N
87
3p
, 69%
3q
, 92%
3s
3r
, 92%
, 73%
aReaction conditions: 2-fluoropyridine (1.0 mmol), acetamidine
hydrochloride (1.3 mmol), Cs2CO3 (3.0 mmol), H2O (3.0 mmol) in
DMSO (3 ml) at 90 °C for 18 h under open air; b Isolated yields.
90
87
85
37
Imidazopyridine is the core structure of nitrogen-containing
heterocyclic compounds.16 Because of its unique biological activity,
such as antibacterial,17 anticancer,18 and anti-virus characteristics,19
it has been widely applied in biology, pesticide and medicinal
chemistry. The two-fold amination of amidine with 2,3-
<5
82
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 9
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
bReaction conditions b: 2-fluoropyridine 1 (1.0 mmol), amidine
dihalopyridines is an alternative strategy to synthesize
imidazopyridines. However, the reported Cu-catalysed double
amination of 2,3-dihalopyridine required the difficult-to-access
ortho-halopyridine iodides.20 In fact, the most of two-fold amination
methods gave low regioselectivity and yields, which greatly
diminished the practical application and academic value of this
amination process. Here, we adopt two methods to achieve the
regioselective synthesis of imidazo[4,5-b]pyridine products starting
from amidine hydrochloride, which constituted a general and highly
regiospecific method to synthesize the structurally diverse 2-
substituted 3H-imidazo[4,5-b]pyridine and 2-substituted 1H-
imidazo[4,5-b]pyridine (Scheme 3). First, the tandem base-
promoted nucleophilic substitution and Cu-catalysed intermolecular
amination gave the 2-substituted 3H-imidazo[4,5-b]pyridine
products (Scheme 4a). In this case, when the Cs2CO3-promoted
nucleophilic substitution reaction is complete, the CuI catalyst was
added and completed the subsequent amination reaction. The
View Article Online
DOI: 10.1039/D0OB01904F
hydrochloride (1.3 mmol), CuI (10 mol%), and Cs2CO3 (3.0 mmol) in
DMSO (3 mL) at 90 °C for 18 h; b Isolated yield.
This methodology was also applicable to the preparation of
1,2-disubstituted imidazo[4,5-b]pyridines in
a
three-
component reaction. As shown in Scheme 4, ortho-
fluoropyridines with different substituents such as –Me, -Cl, -Br
and -I groups were well tolerated. The -Br or I group embedded
into the ortho-fluoropyridines did not significantly affect the
reaction yields and produced the desired products in 38-75%
yields. Importantly, this method provides a concise entry to
iodide substituents polycyclic pyrimidines by using 2-fluoro-3-
iodopyridines as a suitable substrate, which was not easily
accessed in the copper catalyst amination system.
Scheme 4. Cu-catalysed Domino Synthesis of Imidazo[4,5-
reaction conditions enabled the two-fold amination to proceed with b]pyridines via Ullmann-Type Coupling Reaction
electron-donating and electron-withdrawing groups to produce the
design product in moderate to good yield. As shown in Scheme 3,
R
I
NH
I
CuI, Cs2CO3
DMSO, 90oC
ortho-fluoropyridines with different substituents such as -Me, -tBu, -
Br and -Cl groups were well tolerated (Scheme 3, 4a-4h). With 2-
iminopiperidine hydrochloride as the substrates, the amination
reaction gave the highest yield (4i, 92%). Correspondingly, when CuI
was directly added to the reaction system as a catalyst in a one-pot
manner, the double amination of 2-fluoro-3-iodopyridine gave 2-
substituted 1H-imidazo[4,5-b]pyridine products 5a and 5b in
moderate yields.
N
HCl

R
+
6
NH2
Me
N
N
N
1
F
R1
Cl
Me
2
N
Me
Br
I
N
I
Br
Br
N
N
N
N
Me
N
Cl
Br
N
N
N
Me
Me
Me
Me
N
N
N
N
N
N
N
6a
, 75%
c
6c
6b
, 43%
, 41%
6d
, 38%
Scheme 3. Synthesis of imidazo[4,5-b]pyridine derivative
aReaction conditions: halopyridine (2.2 mmol), acetamidine
hydrochloride (1.0 mmol), Cs2CO3 (3.0 mmol), CuI (10 mol%) in
(a) Synthesis of 3H-imidazo[4,5-b]pyridine derivativea,b
I
N
(1) Cs2CO3, 90 oC, 18 h
(2) CuI, 10h
NH
R1
R2
c
DMSO (3 mL) at 110 °C for 24 h; bIsolated yield; 3,5-dibromo-2-
HCl
+
R2 NH2
N
H
N
N
F
fluoropyridine was used as the substrate.
1
2
4
N
N
N
N
tBu
Et
Me
To further verify the reaction mechanism and expand the
N
H
N
N
N
H
N
N
H
N
N
H
practicability of this reaction, we chose
a few acetamidine
4a
4b
, 81%
, 78%
4c
, 85%
derivatives with electron withdrawing group for the amination with
2-fluoropyridine to synthesize amidine derivatives [Eq. (1)]. The
reaction successfully obtained 2,2,2-trifluoro-N-(3-iodopyridin-2-
yl)acetimidamide (7a, 43%), which can be used to prepare 2-
pyridinylamides through hydrolysis. Due to the influence of the
strong electron-withdrawing group (CF3), 2,2,2-trifluoro-N-(3-
iodopyridin-2-yl)acetimidamide 7a is not prone to hydrolysis
reaction to give the amide products under current reaction
conditions.
4e
, 87%
Br
Me
N
N
N
N
Me
Cl
Me
Me
N
N
H
N
H
N
N
N
N
H
N
4f
, 57%
4g
, 55 %
4h, 61%
4i, 92%
(b) Synthesis of 1H-imidazo[4,5-b]pyridine derivative a,b
I
H
N
NH
HCl
NH2
CuI, Cs2CO3
DMSO, 18h
tBu
+
5a,
5b
48%
tBu
N
F
N
N
HCl
I
H
I
I
NH
NH
CF3
Cs2CO3 (3.0 mmol)
N
NH
·HCl
CuI, Cs2CO3
DMSO, 18h
+
N
Eq. (1)
+
DMSO (2 mL), H2O (3.0 mmol),
, 83%
F3C
NH2
N
N
H
N
90 oC, 18 h
N
F
N
F
N
1.3 mmol
1 mmol
7a, 43%
aReaction conditions a: 2-fluoropyridine 1 (1.0 mmol), amidine
hydrochloride 2 (1.3 mmol), Cs2CO3 (3.0 mmol) in DMSO (3 mL)
at 90 °C for 18 h; then, CuI (10 mol%) was added and reacted
at 90 °C for 10 h; b Isolated yield.
The obtained N-(3-iodopyridin-2-yl)acetamides are highly attractive
as intermediates to prepare more functionalized alkynylpyridines.
N-(3-iodopyridin-2-yl)acetamide 3a was further functionalized into
useful moieties such as N-(3-((trimethylsilyl)ethynyl)pyridin-2-
yl)acetamide 8a in 85% yield by the palladium-catalysed
Sonogashira coupling reaction (Scheme 5). Next, The Pd-catalyzed
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 9
ARTICLE
Journal Name
coupling of N-(3-iodopyridin-2-yl)pivalamide 3d with phenylboronic
acid gave N-(3-phenylpyridin-2-yl)pivalamide 8b in 65% yield
(Scheme 5).
convenient option to synthesize amide and imidazo[4,5-b]pyridines,
View Article Online
which are important intermediates for mediDciOnIa:l1s0y.1n0t3h9e/sDe0sO. B01904F
TMS
Experimental section
Materials and methods
I
PdCl2(PPh3)2 (5 mol%)
CuI, (10 mol%)
O
O

TMS
8a
, 85%
N
N
H
CH3CN (1mL), Et3N (1mL)
60 oC, 12 h
N
N
N
H
Me
tBu
3a
, 1 mmol
1.5 mmol
Unless otherwise noted, all commercial materials and solvents were
used without further purification and all the reactions were carried
out in a Schlenk tube equipped with magnetic stir bar. 1H NMR
spectra were recorded in CDCl3 at 400 MHz (500 MHz or 600 MHz)
and 13C NMR NMR spectra were recorded in CDCl3 at 100 MHz (125
MHz or 150 MHz) respectively, 1H and 13C NMR NMR were
referenced to CDCl3 at δ 7.26 (DMSO-d6 at δ 2.50) and 77.0 (DMSO-
d6 at δ 39.52) respectively. GC–MS was obtained using electron
ionization (Agilent Technologies 7890A/5975C). HRMS spectra were
acquired using an Agilent 6210 ESI/TOF mass spectrometer and
MAT 95XP (Double-focusing Magnetic Sector Analyzer), Thermo (EI,
70eV). TLC was performed using commercially prepared 100-400
mesh silica gel plates (GF254), and visualization was effected at 254
nm. All the other chemicals were purchased from Aldrich
Chemicals. Commercial reagents were used without further
purification.
I
Pd(PPh3)4 (10 mol%)
Cs2CO3 (1.2 mmol)
O
Ph

O
PhB(OH)2
8b
, 65%
tBu
N
N
H
THF (2 mL), H2O (0.2 mL)
N2 (1 atm), 60 oC, 12 h
N
H
3d
, 0.6 mmol 1.0 mmol
Scheme 5. Transformations of iodopyridine
The plausible reaction mechanism for this amination reaction is
as follows (Scheme 6): first, acetamidine hydrochloride 2 reacts
21
with Cs2CO3 to produce acetamidine A, which reacts with 2-
fluoropyridine 1 via nucleophilic substitution under the assistance
of Cs2CO3 to yield N-(3-iodopyridin-2-yl)acetimidamide B. Then,
with the aid of water, Cs2CO3 provides hydroxy groups for the
nucleophilic attack of N-(3-iodopyridin-2-yl)acetimidamide B to
yield C. Intermediate C may be converted into amide 3 and release
NH3. In addition, the copper-catalysed Ullmann-type coupling of 2-
fluoro-3-iodopyridine with acetamidine
A
provides N-(2-
fluoropyridin-3-yl)acetimidamide D. Intermediate D experiences a
nucleophilic substitution with the assistance of Cs2CO3 to yield 1H-
imidazo[4,5-b]pyridine product 5. Next, 1H-imidazo[4,5-b]pyridine
General methods for the synthesis of N-(3-iodopyridin-2-
yl)acetamide 3a: A 25 mL Schlenk tube was charged with 2-fluoro-
3-iodopyridine 1a (1.0 mmol, 223 mg), acetamidine hydrochloride
2a (1.3 mmol, 123 mg), Cs2CO3 (3.0 mmol, 978 mg), DMSO (3 mL),
H2O (3.0 mmol, 48 mg) and a magnetic stirring bar. The Schlenk
tube was then immersed in an oil bath at 90 oC stirring for 18h.
After the reaction finished, the mixture was diluted with ethyl
acetate and passed through Celite. After evaporation of the solvent
the residue was adsorbed on silica gel and the crude product was
purified by column chromatography using petroleum/ethyl acetate
= 1:1 as eluent.
product
5 reacts with excess 2-fluoro-3-iodopyridine in the
nucleophilic substitution process to give product 6 instead of
participating in an Ullmann-type coupling reaction. Similarly, with
the copper catalyst, the imine group of amidine intermediate B
coupling with C-I bond gives 3H-imidazo[4,5-b]pyridine product 4.
Scheme 6. Possible mechanism to synthesize amides and imidazo
[4,5-b] pyridine
N
Me
N
N
General methods for the synthesis of 3H-imidazo[4,5-b]pyridine
4a: A 25 mL Schlenk tube was charged with 2-fluoro-3-iodopyridine
1a (1.0 mmol, 223 mg), acetamidine hydrochloride 2a (1.3 mmol,
123 mg), Cs2CO3 (3.0 mmol, 978 mg), DMSO (3 mL) and a magnetic
stirring bar. The Schlenk tube was then immersed in an oil bath at
90 oC stirring for 18 h, the CuI (10 mol%, 19 mg) was add and
reaction at 90 °C stirring for 10 h again. After the reaction finished,
the mixture was diluted with ethyl acetate and passed through
Celite. After evaporation of the solvent the residue was adsorbed
on silica gel and the crude product was purified by column
chromatography using petroleum/ethyl acetate = 1:1 as eluent.
4
H
I
[Cu]
I
NH
I
NH
NH2
NH
OH
H2
Cs2CO3
Me
•HCl
Cs2CO3
NH2
OH
+
Me
NH2
Me
CsCl + H2CO3
O
N
N
H
Me
N
N
H
F
N
2-
2
A
CsF + CO3
1
B
C
[Cu]
Me
NH3
H
N
N
H
N
I
1,
Cs2CO3
I
Cs2CO3
O
N
N
Me
NH
F
Me
N
2-
2-
N
N
CsF + CO3
CsF + CO3
N
N
H
Me
N
D
5
3
6
Conclusions
In conclusion, we reported a transition-metal-free method to
synthesize 2-pyridinylamide derivatives from 2-fluoropyridine and
amidine derivatives. The Cu-catalysed approach to produce
imidazo[4,5-b]pyridine derivatives has been established with high
chemoselectivity in good yield. The reaction uses inexpensive and
relatively safe amidine hydrochloride as the ammonium source to
produce amides and imidazo[4,5-b]pyridines with high
chemoselectivity and regiospecificity. This method provides a
General methods for the synthesis of 1H-imidazo[4,5-b]pyridine
5a: A 25 mL Schlenk tube was charged with 2-fluoro-3-iodopyridine
1a (1.0 mmol, 223 mg), pivalimidamide hydrochloride 2a (1.3 mmol,
177 mg), CuI (10 mol%, 19 mg), Cs2CO3 (3.0 mmol, 978 mg), DMSO
(3 mL) and a magnetic stirring bar. The Schlenk tube was then
immersed in an oil bath at 90 C stirring for 18h. After the reaction
finished, the mixture was diluted with ethyl acetate and passed
through Celite. After evaporation of the solvent the residue was
o
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 9
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
adsorbed on silica gel and the crude product was purified by 147.5, 146.1, 118.3, 95.3, 38.9, 28.7; ESI-HRMS m/z [M+H]+calcd for
View Article Online
DOI: 10.1039/D0OB01904F
column chromatography using petroleum/ethyl acetate = 1:1 as C10H14IN2O 305.0145, found 305.0137.
eluent.
N-(3-iodopyridin-2-yl)cyclobutanecarboxamide (3e): Yellow liquid,
(205.4 mg, 68% yield); Rf = 0.35 (petroleum ether/ethyl acetate =
3:1); 1H NMR (600 MHz, CDCl3) δ 9.3 (s, 1H), 8.20 (t, J = 5.4 Hz, 1H),
8.12 (d, J = 7.8 Hz, 1H), 6.60 – 6.58 (m, 1H), 3.23 – 3.16 (m, 1H), 2.52
– 2.45 (m, 2H), 2.24 (t, J = 10.2 Hz, 2H), 2.03 – 1.90 (m, 2H); 13C NMR
(150 MHz, DMSO) δ 165.8, 160.9, 147.3, 146.0, 118.4, 94.6, 41.4,
26.2 (2C), 25.2, 17.9; ESI-HRMS m/z [M+H]+calcd for C10H12IN2O
302.9989, found 302.9981.
N-(3-iodopyridin-2-yl)-2-methoxyacetamide (3f): Yellow liquid,
(201 mg, 69% yield); Rf = 0.22 (petroleum ether/ethyl acetate = 2:1);
1H NMR (600 MHz, CDCl3) δ 8.97 (s, 1H), 8.47 (s, 1H), 8.11 (d, J = 7.2
Hz, 1H), 6.86 – 6.84 (m, 1H), 4.11 (s, 2H), 3.56 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 167.8, 150.3, 148.5, 148.1, 121.8, 86.1, 72.6,
59.8; ESI-HRMS m/z [M+H]+calcd for C8H10IN2O2 292.9781, found
292.9775.
N-(4-methylpyridin-2-yl)acetamide (3g)23: Yellow liquid, (120.1 mg,
80% yield); Rf = 0.56 (petroleum ether/ethyl acetate = 2:1); 1H NMR
(500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.14 (dd, J = 5.0, 0.5 Hz, 1H),
7.91 (s, 1H), 6.91 (dq, J = 2.0, 1.5, 1.0 Hz, 1H), 2.29 (s, 3H), 2.07 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 169.2, 152.2, 148.7, 147.5,
120.2, 113.7, 23.9, 21.0; ESI-HRMS m/z [M+H]+calcd for C8H11N2O
151.0866, found 151.0861.
General methods for the synthesis of imidazo[4,5-b]pyridine 6a: A
25 mL Schlenk tube was charged with 2-fluoro-3-iodopyridine 1a
(2.2 mmol, 491 mg), acetamidine hydrochloride 2a (1.0 mmol, 94
mg), CuI (10 mol%, 19 mg), Cs2CO3 (3.0 mmol, 978 mg), DMSO (3
mL) and a magnetic stirring bar. The Schlenk tube was then
immersed in an oil bath at 110 oC stirring for 24h. After the reaction
finished, the mixture was diluted with ethyl acetate and passed
through Celite. After evaporation of the solvent the residue was
adsorbed on silica gel and the crude product was purified by
column chromatography using petroleum/ethyl acetate = 1:1 as
eluent.
Gram-scale synthesis of N-(3-iodopyridin-2-yl)acetamide 3a: A 50
mL Schlenk tube was charged with 2-fluoro-3-iodopyridine 1a (4.48
mmol, 1 g), acetamidine hydrochloride 2a (6.0 mmol, 1.5 equiv.,
0.64 g), Cs2CO3 (13.5 mmol, 3.0 equiv., 4.4 g), DMSO (15 mL), H2O
(13.5 mmol, 0.24 g) and a magnetic stirring bar. The Schlenk tube
o
was then immersed in an oil bath at 90 C stirring for 36 h under
open air. After the reaction finished, the mixture was diluted with
ethyl acetate and passed through Celite. After evaporation of the
solvent the residue was adsorbed on silica gel and the crude
product was purified by column chromatography using
petroleum/ethyl acetate = 3:1 as eluent, affording the N-(3-
iodopyridin-2-yl)acetamide 3a (0.97 g, 83 %) as a yellow liquid.
N-(3-fluoropyridin-2-yl)acetimidamide (3h): Yellow liquid, (137.1
1
mg, 89% yield); Rf = 0.24 (petroleum ether/ethyl acetate = 3:1); H
NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.23 (d, J = 4.8 Hz, 1H ),
7.73(dd, J = 9.6, 7.8 Hz, 1H ), 7.33 – 7.29 (m, 1H), 2.07 (d, J = 1.8 Hz,
3H); 13C NMR (150 MHz, DMSO-d6) δ 168.5, 152.2 (d, J = 259.1 Hz),
143.9 (d, J = 5.1 Hz), 140.2 (d, J = 12.8 Hz), 124.7 (d, J = 18.3 Hz),
122.78 (d, J = 3.6 Hz), 22.9; ESI-HRMS m/z [M+H]+calcd for
C7H8FN2O 155.0615, found 155.0608.
N-(6-fluoropyridin-2-yl)acetamide (3i): Yellow solid, (135.5 mg,
88% yield); mp. 119-121 oC; Rf = 0.24 (petroleum ether/ethyl
acetate = 3:1); 1H NMR (600 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.14 (dd,
J = 7.8, 2.4 Hz, 1H), 7.09 (dd, J = 16.2, 7.8 Hz, 1H), 5.98 (dd, J = 7.2,
1.8 Hz, 1H) , 1.24 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 169.5,
161.3 (d, J = 236.5 Hz), 150.5 (d, J = 14.9 Hz), 143.9 (d, J = 8.0 Hz),
110.2 (d, J = 4.1 Hz), 103.3 (d, J = 35.6 Hz), 23.9; ESI-HRMS m/z
[M+H]+calcd for C7H8FN2O 155.0615, found 155.0611.
N-(5-chloropyridin-2-yl)acetamide (3j)24: White solid, (125.8 mg,
74% yield); mp. 172-174 oC; Rf = 0.22 (petroleum ether/ethyl
acetate = 3:1); 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.33 (t,
J = 2.9 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.85 (ddd, J = 9.0, 4.0, 2.3 Hz,
1H), 2.09 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 169.44, 150.8,
146.3, 137.8, 124.8, 114.4, 23.9; ESI-HRMS m/z [M+H]+calcd for
C7H8ClN2O 171.0320, found 171.0314.
N-(6-chloropyridin-2-yl)acetamide (3k)25： White solid, (117.3 mg,
69% yield); mp. 150-152 oC; Rf = 0.22 (petroleum ether/ethyl
acetate = 3:1); 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.04 (d,
J = 8.0 Hz, 1H), 7.81 – 7.62 (m, 1H), 7.16 – 7.11 (m, 1H), 2.08 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 169.6, 152.2, 148.0, 141.7, 118.9,
111.9, 23.9; ESI-HRMS m/z [M+H]+calcd for C7H8ClN2O 171.0320,
found 171.0314.
N-(3-iodopyridin-2-yl)acetamide (3a): Yellow liquid, (243.7 mg, 93%
yield); Rf = 0.34 (petroleum ether/ethyl acetate = 3:1); 1H NMR (500
MHz, DMSO-d6) δ 10.12 (s, 1H), 8.42 (dd, J = 5.0, 2.0 Hz, 1H), 8.29
(dd, J = 7.5, 1.5 Hz, 1H), 7.05 (dd, J = 7.5, 4.5 Hz, 1H), 2.01 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 168.5, 152.5, 148.3, 148.1, 123.3,
94.0, 23.0; ESI-HRMS m/z [M+H]+calcd for C7H8IN2O 262.9676,
found 262.9670.
N-(3-iodopyridin-2-yl)propionamide (3b): Yellow solid, (223.6 mg,
81% yield); mp. 94-96 oC; Rf = 0.24 (petroleum ether/ethyl acetate =
3:1); 1H NMR (600 MHz, Acetone-d6) δ 9.01 (s, 1H), 8.40 (dd, J = 4.8,
1.8 Hz, 1H), 8.28 (dd, J = 7.8, 1.2 Hz, 1H), 7.00 (dd, J = 7.8, 4.8 Hz,
1H), 2.49 (q, J = 7.8, 15.6 Hz, 2H), 1.17 (t, J = 7.8 , 7.2 Hz, 3H); 13C
NMR (150 MHz, Acetone-d6) δ 172.9, 153.4, 149.2, 148.9, 123.3,
91.7, 29.9, 9.6; ESI-HRMS m/z [M+H]+calcd for C8H10IN2O 276.9832,
found 276.9825.
N-(3-iodopyridin-2-yl)cyclopropanecarboxamide
(3c):
Yellow
liquid, (175.7 mg, 61% yield); Rf = 0.35 (petroleum ether/ethyl
acetate = 3:1); 1H NMR (600 MHz, CDCl3) δ 9.62 (s, 1H), 8.15 (dd, J =
4.8, 1.8 Hz, 1H), 8.06 (dd, J = 7.8, 1.8 Hz, 1H), 6.52 (dd, J = 7.8, 4.8
Hz, 1H), 1.38-1.33 (m, 1H), 1.26 – 1.23 (m, 2H), 0.88 – 0.84 (dt, J =
7.2, 3.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 165.4, 160.7, 147.1,
145.8, 117.8, 94.7, 17.0, 8.9 (2C); ESI-HRMS m/z [M+H]+calcd for
C9H10IN2O 288.9832, found 288.9824.
N-(3-iodopyridin-2-yl)pivalamide (3d)22: Yellow liquid, (264.5 mg,
87% yield); Rf = 0.26 (petroleum ether/ethyl acetate = 3:1); 1H NMR
(500 MHz, CDCl3) δ 12.79 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.13 (m
1H), 1.39 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.0, 161.3,
N-(6-bromopyridin-2-yl)acetamide (3l)26: White solid, (194.7 mg,
91% yield); mp. 155-157 oC; Rf = 0.24 (petroleum ether/ethyl
acetate = 3:1); 1H NMR (600 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.07 (d,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 9
ARTICLE
Journal Name
J = 8.4 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 2.08 MHz, DMSO-d6) δ 153.6, 151.9, 142.6 131.8, 122.6, 117.2, 15.0; ESI-
View Article Online
(s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 169.5, 152.3, 141.3, 138.7, HRMS m/z [M+H]+calcd for C7H8N3 134.0713D, fOoIu: 1n0d.1103349/.0D700O7B.01904F
122.7, 112.1, 23.9; ESI-HRMS m/z [M+H]+calcd for C7H8BrN2O 2-ethyl-3H-imidazo[4,5-b]pyridine (4b)30: Yellow liquid, (114.7 mg,
214.9815, found 214.9808.
78% yield); Rf = 0.22 (petroleum ether/ethyl acetate = 1:1); 1H NMR
N-(5-bromopyridin-2-yl)acetamide (3m)27: White solid, (162.6 mg, (500 MHz, CDCl3) δ 8.32 (d, J = 4.8 Hz, 1H), 8.02 (dd, J = 7.9, 1.1 Hz,
76% yield); mp. 169-171 oC; Rf = 0.24 (petroleum ether/ethyl 1H), 7.23 (dd, J = 7.9, 4.9 Hz, 1H), 3.49 (s, 1H), 3.08 (q, J = 7.6 Hz,
1
acetate = 3:1); H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.41 2H), 1.54 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9,
(dd, J = 2.4, 0.6 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.97 (dd, J = 9.0, 3.0 150.0, 142.0, 134.8, 125.7, 117.8, 23.1, 12.0; ESI-HRMS m/z
Hz, 1H), 2.09 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 169.4, 151.1, [M+H]+calcd for C8H10N3 148.0869, found 148.0868.
148.4, 140.5, 115.0, 113.2, 23.9; ESI-HRMS m/z [M+H]+calcd for 2-cyclopropyl-3H-imidazo[4,5-b]pyridine (4c): White solid, (135.2
C7H8BrN2O 214.9815, found 214.9809.
mg, 85% yield); mp. 173-175 oC; Rf = 0.21 (petroleum ether/ethyl
N-(3-chloro-5-fluoropyridin-2-yl)acetamide (3n): White solid, acetate = 1:1); 1H NMR (500 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.19 (d,
(172.0 mg, 91% yield); mp. 86-88 oC; Rf = 0.32 (petroleum J = 5.0 Hz, 1H), 7.79 (dd, J = 8.0, 1.5 Hz, 1H), 7.09 (dd, J = 8.0, 5.0 Hz,
ether/ethyl acetate = 3:1); 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 2.29 – 2.13 (m, 1H), 2.16 – 2.10 (m, 2H), 1.09 – 1.06 (m, 2H);
1H), 8.44 (t, J = 2.4 Hz, 1H), 8.13 (dd, J = 8.0, 2.8 Hz, 1H), 2.05 (s, 13C NMR (100 MHz, CDCl3) δ 159.9, 149.6, 141.21, 135.6, 125.6,
3H); 13C NMR (100 MHz, DMSO-d6) δ 168.6, 156.7 (d, J = 257.95 Hz), 117.7, 10.6, 9.6; ESI-HRMS m/z [M+H]+calcd for C9H10N3 160.0869,
144.9 (d, J = 2.93 Hz), 134.7 (d, J = 23.9 Hz), 127.2 (d, J = 5.5 Hz), found 160.0867.
126.2 (d, J = 22.5 Hz), 22.7; ESI-HRMS m/z [M+H]+calcd for 2-tert-butyl-3H-imidazo[4,5-b]pyridine (4d): White solid, (152.3
C7H7FClN2O 189.0225, found 189.0218.
mg, 87% yield); mp. 155-157 oC; Rf = 0.20 (petroleum ether/ethyl
N-(5-bromo-4-methylpyridin-2-yl)acetamide (3o)23: Brown solid, acetate = 1:1); 1H NMR (600 MHz, CDCl3) δ 13.86 (s, 1H), 8.36 (t, J =
(189.2 mg, 83% yield); mp. 150-152 oC; Rf = 0.36 (petroleum 4.8 Hz, 1H), 8.09 (d, J = 6.6 Hz, 1H), 7.25 (dd, J = 3.6, 8.4 Hz, 1H),
ether/ethyl acetate = 3:1); 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1.61 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 165.06, 149.47, 142.04,
1H), 8.32 (s, 1H), 8.06 (s, 1H), 2.31 (s, 3H), 2.08 (s, 3H); 13C NMR 136.05, 127.45, 117.86, 34.09, 29.50; ESI-HRMS m/z [M+H]+calcd
(100 MHz, DMSO-d6) δ 169.2, 151.4, 148.6, 147.9, 116.0, 115.1, for C10H14N3 176.1182, found 176.1180.
23.9, 22.2; ESI-HRMS m/z [M+H]+calcd for C8H10BrN2O 228.9971, 2,6-dimethyl-3H-imidazo[4,5-b]pyridine (4e): Brown solid, (83.8
found 228.9965.
mg, 57% yield); mp. 213-215 oC; Rf = 0.22 (petroleum ether/ethyl
N-(3-iodo-5-methylpyridin-2-yl)acetamide (3p): Yellow liquid, acetate = 1:1); 1H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.07 (s,
(190.4 mg, 69% yield); Rf = 0.30 (petroleum ether/ethyl acetate = 1H), 7.64 (s, 1H), 2.49 (s, 3H), 2.36 (s, 3H); 13C NMR (125 MHz,
1
3:1); H NMR (600 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.24 (dd, J = 1.2, DMSO-d6) δ 153.5, 148.1, 142.7, 135.5, 127.5, 126.3, 18.8, 15.7; ESI-
2.4 Hz, 1H), 8.13 (dd, J = 0.6, 1.8 Hz, 1H), 2.23 (s, 3H), 2.00 (s, 3H); HRMS m/z [M+H]+calcd for C8H10N3 148.0869, found 148.0867.
13C NMR (150 MHz, DMSO-d6) δ 168.7, 150.1, 148.2, 133.1, 93.9, 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine(4f)29: Brown solid,
40.4, 23.0, 16.7; ESI-HRMS m/z [M+H]+calcd for C8H10IN2O (116.1 mg, 55% yield); Rf = 0.21 (petroleum ether/ethyl acetate =
1
276.9832, found 276.9824.
1:1); H NMR (500 MHz, DMSO) δ 12.90 (s, 1H), 8.30 (d, J = 2.0 Hz,
N-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetamide (3q): Yellow 1H), 8.11 (d, J = 2.0 Hz, 1H), 2.51 (d, J = 5.3 Hz, 3H); 13C NMR (125
liquid, (219.0 mg, 92% yield); Rf = 0.46 (petroleum ether/ethyl MHz, DMSO) δ 155.9, 143.3, 112.6, 15.56.( Three carbon signals of
acetate = 3:1); 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.75 (s, 13C NMR are missing).
1H), 8.42 (s, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine (4g)31: Yellow
168.7, 151.9, 143.6 (d, J = 4.4 Hz), 136.1 (d, J = 2.4 Hz), 125.4, 123.8 liquid, (159.2 mg, 92% yield); Rf = 0.24 (petroleum ether/ethyl
1
(d, J = 74.44 Hz), 123.3 (d, J = 33.43 Hz), 121.5, 23.2; ESI-HRMS m/z acetate = 1:1); H NMR (600 MHz, DMSO-d6) δ 7.35 (dd, J = 4.8, 1.2
[M+H]+calcd for C8H7F3ClN2O 239.0194, found 239.0191.
Hz, 1H ), 7.02 (dd, J = 8.4, 1.8 Hz, 1H), 6.32 (dd, J = 7.8, 4.8 Hz, 1H),
N-(3-bromo-5-chloropyridin-2-yl)cyclopropanecarboxamide (3r)26: 3.24 (t, J =6.0 Hz, 2H), 2.09 (t, J =6.0 Hz, 2H), 1.17 – 1.12 (m, 2H),
Yellow liquid, (200.0 mg, 73% yield); Rf
=
0.26 (petroleum 1.07 – 1.02 (m, 2H); 13C NMR (150 MHz, DMSO-d6) δ 153.4, 147.6,
1
ether/ethyl acetate = 3:1); H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 142.1, 134.5, 125.4, 117.9, 41.2, 25.2, 21.7, 20.0; ESI-HRMS m/z
2.4 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 1.44 – 1.39 (m, 1H), 1.22 – 1.19 [M+H]+calcd for C10H12N3 174.1026, found 174.1016.
(m, 2H), 0.90 – 0.86 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 165.7, 2-tert-butyl-1H-imidazo[4,5-b]pyridine (5a): White solid, (84 mg,
157.9, 143.3, 140.3, 123.3 , 117.7, 17.2, 9.0.
48% yield); mp. 247-249 oC; Rf = 0.34 (petroleum ether/ethyl
N-(pyrazin-2-yl)acetamide (3s)28: White solid, (126.1 mg, 92% acetate = 1:1); 1H NMR (600 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.24 (s,
yield); Rf = 0.26 (petroleum ether/ethyl acetate = 1:1); 1H NMR (400 1H), 7.88 (s, 1H), 7.13 (dd, J = 7.8, 3.2 Hz, 1H), 1.39 (s, 9H); 13C NMR
MHz, DMSO) δ 10.71 (s, 1H), 9.30 (s, 1H), 8.33 (d, J = 14.4 Hz, 2H), (150 MHz, DMSO-d6) δ 163.8, 149.4, 142.7, 134.4, 125.7, 117.2,
2.13 (s, 3H); 13C NMR (100 MHz, DMSO) δ 169.5, 148.8, 142.5 , 33.5, 28.9 (3C); ESI-HRMS m/z [M+H]+calcd for C10H12N3 176.1182,
139.4, 136.2, 23.6; ESI-HRMS m/z [M+H]+calcd for C6H8N3O found 176.1174.
138.0662, found 138.0666.
6,7,8,9-tetrahydroimidazo[1,2-a:4,5-b']dipyridine (5b): Yellow
2-methyl-3H-imidazo[4,5-b]pyridine (4a)29: Yellow solid, (107.7mg, solid, (143.6 mg, 83% yield); mp. 95-97 oC; Rf = 0.32 (petroleum
81% yield); Rf = 0.23 (petroleum ether/ethyl acetate = 1:1); 1H NMR ether/ethyl acetate = 1:1); 1H NMR (600 MHz, CDCl3) δ 8.15 (dd, J =
(500 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.22 (dd, J = 5.5 Hz, 1H), 7.85 4.8, 1.8 Hz, 1H), 7.78 (dd, J = 8.4, 1.8 Hz, 1H), 7.04 (dd, J = 8.4, 4.8
(s, 1H), 7.14 (dd, J = 7.5, 4.5 Hz, 1H), 2.52 (s, 3H); 13C NMR (125 Hz, 1H), 4.08 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 2.00 – 1.97
(m, 2H), 1.92 – 1.87 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 153.1,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 7 of 9
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
147.5, 142.5, 134.8, 125.9, 118.0, 41.3, 25.5, 21.2, 20.34; ESI-HRMS
m/z [M+H]+calcd for C10H12N3 174.1026, found 174.1023.
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/D0OB01904F
1-(3-iodopyridin-2-yl)-2-methyl-1H-imidazo[4,5-b]pyridine
(6a):
Yellow liquid, 252 mg, 75% yield); Rf = 0.26 (petroleum ether/ethyl
1
acetate = 1:1); H NMR (400 MHz, DMSO-d6) δ 8.73 (dd, J = 4.4, 1.6
Acknowledgements
Hz, 1H), 8.65 (dd, J = 8.0, 1.6 Hz, 1H), 8.43 (d, J = 3.6 Hz, 1H), 7.52 –
7.46 (m, 2H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H), 2.41 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 155.0, 153.4, 149.8, 149.6, 149.5, 144.3,
127.1, 126.8, 118.5, 118.2, 95.2, 14.2; ESI-HRMS m/z [M+H]+calcd
for C12H10IN4 336.9945, found 336.9934.
1-(3-iodo-5-methylpyridin-2-yl)-2,6-dimethyl-1H-imidazo[4,5-
b]pyridine (6b): White solid, (149 mg, 41% yield); mp. 152-154 C;
Rf = 0.24 (petroleum ether/ethyl acetate = 1:1); H NMR (600 MHz,
The authors thank the Foundation of the Department of Education
of Guangdong Province (2019KZDXM052, 2017KZDXM085 and
2018KZDXM070), Science Foundation for Young Teachers of Wuyi
University (2019td06), Natural Science Foundation of Guangdong
Province (No. 2018A030310680), Innovation Project of Guang Dong
Graduate Education (2020SFKC065) and Chemical Industry
Collaborative Innovation Center of Yueshan Town 2017(368) for
financial support.
o
1
DMSO-d6) δ 8.55 (dd, J = 1.8, 0.6 Hz, 1H), 8.49 (dd, J = 1.8, 0.6 Hz,
1H), 8.26 (d, J = 2.4, 0.6 Hz, 1H), 7.27 (dd, J = 1.8, 0.6 Hz, 1H), 2.41
(s, 3H), 2.36 (d, J = 2.4 Hz, 6H); 13C NMR (150 MHz, DMSO-d6) δ
153.3, 152.8, 150.0, 149.3, 147.2, 144.9, 136.9, 127.5, 127.2, 118.2,
94.6, 18.0, 17.0, 14.1; ESI-HRMS m/z [M+H]+calcd for C14H14IN4
365.0258, found 365.0254.
1-(3-bromo-5-chloropyridin-2-yl)-6-chloro-2-dimethyl-1H-
imidazo[4,5-b]pyridine (6c): White solid, (153 mg, 43% yield); mp.
177-179 oC; Rf = 0.20 (petroleum ether/ethyl acetate = 1:1); 1H NMR
(500 MHz, DMSO-d6) δ 8.82 (t, J = 2.5 Hz, 2H), 8.45 (d, J = 2.5 Hz,
1H), 8.01 (d, J = 2.5 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 155.3, 153.5, 147.9, 144.4, 143.0, 142.8, 133.1, 127.6, 125.3,
119.6, 118.9, 14.1; ESI-HRMS m/z [M+H]+calcd for C12H8BrCl2N4
356.9304, found 356.9304.
6-bromo-1-(3,5-dibromopyridin-2-yl)-2-methyl-1H-imidazo[4,5-
b]pyridine (6d): Yellow liquid, (168.7 mg, 38% yield); Rf = 0.24
(petroleum ether/ethyl acetate = 1:1); 1H NMR (500 MHz, DMSO-d6)
δ 8.90 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz,
1H), 8.12 (d, J = 2.0 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 155.1, 153.7, 150.1, 145.4, 145.0, 144.7, 128.2, 122.1, 121.6,
119.9, 113.6, 14.1; ESI-HRMS m/z [M+H]+calcd for C12H8Br3N4
444.8294, found 444.8301.
Notes and references
1
(1) (a) D. Ye, C. Gu, A. Ewing, ACS Chem. Neurosci. 2018, 9,
2941–2947. (b) P. Berton, K. R. Di Bona, D. Yancey, S. A. A. Rizvil,
M. Gray, G. Gurau, J. L. Shamshina, J. F. Rasco, R. D. Rogers, ACS
Med. Chem. Lett. 2017, 8, 498–503.
2
(a) C. D. Savi, R. J. Cox, D. J. Warner, A. R. Cook, M. R. Dickinson,
A. McDonough, L. C. Morrill, B. Parker, G. Andrews, S. S. Young,
P. S. Gilmour, R. Riley, M. S. Dearman, J. Med. Chem. 2014, 57,
4661–4676. (b) W. Albrecht, A. Unger, S. M. Bauer, S. A. Laufer,
J. Med. Chem. 2017, 60, 5290–5305.
3
T. Zarganes-Tzitzikas, C. G. Neochoritis, A. Dömling, ACS Med.
Chem. Lett. 2019, 10, 389–392. (b) H. M. Colhoun, D. J.
Betteridge, P. N. Durrington, G. A. Hitman, H. A. W. Neil, S. J.
Livingstone, M. J. Thomason, M. I. Mackness, V. Charlton-
Menys, J. H. Fuller, The Lancet, 2004, 364, 685-696.
4
5
(a) Y. Zhang, S. M. Muthana, D. Farnsworth, O. K. Ludek,
Adams, J. J. Barchi, J. C. Gildersleeve, J. Am. Chem. Soc. 2012,
134, 6316−6325. (b) F. Nisic, M. Andreini, A. Bernardi, Eur. J.
Org. Chem. 2009, 2009, 5744−5751.
(a) J. Cossy, C. Pale-Grosdemange, Tetrahedron Lett, 1989, 30,
2771−2774. (b) H. Charville, D. A. Jackson, G. Hodges, A.
Whiting, M. R. Wilson, Eur. J. Org. Chem. 2011, 2011,
5981−5990.
2,2,2-trifluoro-N-(3-iodopyridin-2-yl)acetimidamide (7a): Yellow
liquid, (135.5 mg, 43% yield); Rf = 0.85 (petroleum ether/ethyl
acetate = 1:1); 1H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 8.30 (dd, J
= 4.8, 1.6 Hz, 1H), 8.21 (dd, J = 7.8, 1.7 Hz, 1H), 6.77 (dd, J = 7.8, 4.8
Hz, 1H), 6.02 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 159.6, 148.4 (q, J
= 35.5 Hz, 1C), 148.2, 146.0, 120.8, 118.0 (q, J = 276.8 Hz, 1C), 95.3.
ESI-HRMS m/z [M+H]+calcd for C7H6F3IN3 315.9553, found 315.9552.
N-(3-((trimethylsilyl)ethynyl)pyridin-2-yl)acetamide (8a)32: Yellow
liquid, (197.2 mg, 85% yield); Rf = 0.48 (petroleum ether/ethyl
6
7
(a) R. M. de Figueiredo, J. S. Suppo, J. M. Campagne, Chem. Rev.
2016, 116, 12029–12122. (b) C. Bednared, I. Wehl, N. Jung, U.
Schepers, S. Brӓse, Chem. Rev. 2020, 120, 4301–4354.
(a) N. Ambreen, T. Wirth, Eur. J. Org. Chem. 2014, 2014,
7590−7593. (b) S. Kegnæs, J. Mielby, U. V. Mentzel, T. Jensen, P.
Fristrup, A. iisager, Chem. Commun., 2012, 48, 2427−2429. (c) C.
Chen, S. H. Hong, Org. Biomol. Chem., 2011, 9, 20−26.
(a) S. Muthaiah, S. C. Ghosh, J. E. Jee, C. Chen, J. Zhang, S. H.
Hong, J. Org. Chem. 2010, 75, 3002−3006. (b) Y. Tamaru, Y.
Yamada, Z. Yoshida, Synthesis, 1983, 1983, 474−476.
8
9
1
acetate = 5:1); H NMR (500 MHz, CDCl3) δ 8.31 (dd, J =5.0, 2.0 Hz,
1H), 8.15(s, 1H), 7.71 (dd, J = 7.5, 1.5 Hz, 1H), 6.97 (dd, J = 7.5, 4.5
Hz, 1H), 0.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 152.1, 147.8,
140.7, 118.5, 104.6, 98.5, 25.1, -0.09 (3C); ESI-HRMS m/z [M+H]+
calcd for C12H17SiON2 233.1105, found 233.1097.
(a) W. Ding, Q. Song, Org. Chem. Front., 2015, 2, 765−770. (b) Y.
Liu, H. Sun, Z. Huang, C. Ma, A. Lin, H. Yao, J. Xu, S. Xu, J. Org.
Chem. 2018, 83, 14307–14313.
10 R. S. Ramón, N. Marion, S. P.Nolan, Chem. Eur. J. 2009, 15,
8695−8697.
N-(3-phenylpyridin-2-yl)pivalamide (8b): Yellow liquid, (99.1 mg,
65% yield); Rf = 0.50 (petroleum ether/ethyl acetate = 1:1); 1H NMR
(500 MHz, CDCl3) δ 8.47 (s, 1H), 7.74 (S, 1H), 7.65 (d, J = 7.6 Hz, 1H),
7.45 (t, J = 8.0 Hz, 2H), 7.40-7.37 (m, 3H), 7.24-7.20 (m, 1H), 1.11 (s,
9H); 13C NMR (125 MHz, CDCl3) 175.7, 148.3, 147.4, 139.0, 137.5,
130.8, 128.8 (2C), 128.4 (2C), 128.0, 120.9, 39.6, 27.2 (3C). ESI-
HRMS m/z [M+H]+calcd for C16H19N2O 255.1492, found 255.1490.
11 D. Crich, K. Sana, S. Guo, Org. Lett. 2007, 9, 4423−4426.
12 (a) J. B. Peng, F. P. Wu, X. F. Wu, Chem. Rev. 2019, 119, 2090–
2127. (b) H. Matsubara, T. Kawamoto, T. Fukuyama, I. Ryu, Acc.
Chem. Res. 2018, 51, 2023–2035. (c) Z. Yin, J. X. Xu, X. F. Wu,
ACS Catal. 2020, 10, 6510–6531. (d) L. Zeng, H. Li, S. Tang, X.
Gao, Y. Deng, G. Zheng, C. W. Pao, J. L. Chen, J. F. Lee, A. Lei,
ACS Catal. 2018, 8, 5448–5453. (e) K. Orito, M.Miyazawa, T.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
Nakamura, A. Horibata, H. Ushito, H. Nagasaki, M. Yuguchi, S. 30 W. Miltz, J. Velcicky, J. Dawson, A. Littlewood-Evans, M. Ludwig,
View Article Online
Yamashita, T. Yamazaki, M. Tokada, J. Org. Chem. 2006, 71,
5951–5958. (f) Y. Bai, D. C. Davis, M. Dai, J. Org. Chem. 2017, 82,
2319–2328.
K. Seuwen, R. Feifel, B. Oberhauser, A. Meyer, D. Gabriel, M.
DOI: 10.1039/D0OB01904F
Nash, P. Loetscher, Bioorgan Med Chem, 2017, 25, 4512-4525.
31 C. Salomé, M. Schmitt, J. Bourguignon, Tetrahedron Lett, 2009,
50, 3798-3800.
32 H. Konno, T. Sato, Y. Saito, I. Skamoto, K. Akaji, Bioorgan Med
Chem Lett., 2015, 25, 5127-5132.
13 H. Jiang, B. liu, Y. Li, A. Wang, H. Huang, Org. Lett. 2011, 13,
1028–1031.
14 C. Liao, J. Li, J. X. Chen, J. Lu, Q. Liu, L. Chen, Y. Huang, Y. Li, Org.
Biomol. Chem., 2020, 18, 1185-1193.
15 Y. Li, S. Huang, C. Liao, Y. Shao, Y. Li, Org. Biomol. Chem., 2018,
16, 7564-7567.
16 (a) F. Dinness, D. P. Fairlie, Angew. Chem. Int. Ed., 2012, 51,
8012-8016; (b) S. Fang, X. Niu, B. Yang, Y. Li, X. Si, L. Feng, C. Ma,
ACS Comb. Sci. 2014, 16, 328–332; (c) J. Kato, Y. Ito, R. Liuin, H.
Aoyama, T. Yokomatsu, Org. Lett., 2013, 15, 14, 3794–3797.
17 (a) K. Yamawaki, T. Nomura, T. Yasukata, N. Tanimoto, K. Uotani,
H. Miwa, Y. Yamano, K. Takedab, Y. Nishitani, Bioorg Med
Chem., 2008, 16, 1632-1647. (b) H. Ertepinar, Y. Gök, Ö. Geban,
S. Özden, Eur. J. Med. Chem., 1995, 30, 171-175.
18 (a) V. Bavetsias, S. Crumpler, C. Sun, S. Avery, B. Atrash, A.
Faisal, A. S. Moore, M. Kosmopoulou, N. Brown, P. W.
Sheldrake, K. Bush, A. Henley, G. Box, M. Valenti, A. H. Brandon,
F. I. Raynaud, P. Workman, S. A. Eccles, R. Bayliss, S.
Linardopoulos, J. Blagg, J. Med. Chem. 2012, 55, 8721-8734. (b)
N. M. Ghanem, F. Farouk, R. F. George, S. E. Abbas, O. M. El-
Badry, Bioorg Chem., 2018, 80, 565-576; (e) C. Temple, J. D.
Rose, R. N. Comber, G. A. Render, J. Med. Chem. 1987, 30, 1746-
1751.
19 (a) Xing, Y.; Zuo, J.; Krogstad P.; Jung, M. E, J. Med. Chem. 2018,
61, 1688-1703; (b) Cristalli, G.; Vittori, S.; Eleuteri, A.; Volpini,
R.; Camaioni, E.; Lupidi, G.; Mahmood, N.; Bevilacqua, F.; Palu,
G, J. Med. Chem., 1995, 38, 4019-4025.
20 (a) T. Ishida, T. Suzuki, S. Hirashima, K. Mizutani, A. Yoshida, I.
Ando, S. Ikeda, T.Adachi, H. Hashimoto, Bioorg. Med. Chem.
Lett. 2006, 16, 1859–1863. (b) D. S. Surry, S. L. Buchwald,
Angew. Chem. Int. Ed. 2008, 47, 6338–6361. (c) G. Evindar, R. A.
Batey, Org. Lett. 2003, 5, 133–136. (d) Z. Li, H. Sun, H. Jiang, H.
Liu, Org. Lett. 2008, 10, 3263–3266. (e) S. Murru, B. K. Patel, J.
Le Bras,J. Muzart, J. Org. Chem. 2009, 74, 2217–2220; (f) X. Lv,
W. Bao, J. Org. Chem. 2009, 74, 5618–5621.
21 (a) X. Deng, H. McAllister, N. S. Mani, J. Org. Chem. 2009, 74,
5742–5745. (b) D. Zhao, J. Hu, N. Wu, X. Huang, X. Qin, J. Lan, J.
You, Org. Lett, 2011, 13, 6516-6519. (c) M. Cortes-Salva, C.
Garvin, J. C. Antilla, J. Org. Chem., 2011, 76, 1456-1459. (d) X.
Deng, N. S. Mani, Eur. J. Org. Chem. 2010, 2010, 680–686.
22 C. Pillard, C. E. Bassène, F. Suzenet, G. Guillaumet, Synthesis
2008, 13, 2049-2054.
23 K. Chen, C. Risatti, J. Simpson, M. Soumeillant, M. Soltani, M.
Bultman, B. Zheng, B. Mudryk, J. C. Tripp, T. E. La Cruz, Y. Hsiao,
D. A. Conlon, M. D. Eastgate, Org. Process Res. Dev. 2017, 21,
1110–1121.
24 A. A. Chudinov, R. S. Dovbnya, E. A. Krasnokutskaya, V. D.
Ogorodnikov, I. L. Filimonova, Russ. Chem. Bull., 2016, 65,
2312–2314.
25 J. Zhang, F. Zhu, G. Tian, X. Jiang, J. Shen, Org. Process Res. Dev.
2020, 24, 1175–1179.
26 C. Yang. X. Zhang, Y. Wang, Y. Yang, X. Liu, M. Deng, Y. Jia, Y.
Ling, L. Meng, Y. Zhou, ACS Med. Chem. Lett. 2017, 8, 875–880.
27 H. Staats, F. Eggers, O. Haß, F. Fahrenkrug, J. Matthey. U.
Lüning, A. Lützen, Eur. J. Org. Chem. 2009, 28, 4777-4792.
28 D. Balakrishna, V. Suryadevara, R. Dandela, A. Vegendla, V. B. R.
Mandava, P. Manojit, Curr Green Chem, 2014, 1, 73-79.
29 S. Caron, B. P. Jones, L. Wei, Synthesis 2012, 44, 3049-3054.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 9
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01904F
X
X
H
19 examples,
up to 93% yields
NH
F
N
R
Cs2CO3
DMSO, 90 o
·HCl
+
R
R
R
NH2
C
O
N
N
N
Transition-Metal-Free
N
X
H
N
or
or
N
N
Cu cat.
X = I, Br
R
R
R
R
R
R
N
H
N
N
N
N
2 examples,
up to 83% yields
8 examples,
up to 92% yields
4 examples,
up to 75% yields
An efficient method to synthesize 2-pyridinylamides and Imidazopyridine has been developed,
and the protocol uses inexpensive and readily available 2-fluoropyridine and amidine derivatives
as the starting materials.