Transition-metal-free access to 2-aminopyridine derivatives from 2-fluoropyridine and acetamidine hydrochloride

Article abstract of DOI:10.1039/c8ob02129e

Under catalyst-free conditions, an efficient method for the synthesis of 2-aminopyridine derivatives through the nucleophilic substitution and hydrolysis of 2-fluoropyridine and acetamidine hydrochloride has been developed. This amination uses inexpensive acetamidine hydrochloride as the ammonia source and has the advantages of a high yield, high chemoselectivity and wide substrate adaptability. The results suggest that other N-heterocycles containing fluorine substituents can also complete the reaction via these reaction conditions and yield the target products.

Full text of DOI:10.1039/c8ob02129e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Transition-metal-free access to 2-aminopyridine derivatives from
2-fluoropyridine and acetamidine hydrochloride
Yibiao Li*a, Shuo Huanga, Chunshu Liaoa, Yan Shaoa and Lu Chena
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Under catalyst-free conditions, an efficient method for the conditions and providing 2-aminopyridines in good yields. [6] In
synthesis of 2-aminopyridine derivatives through the nucleophilic addition, this reaction has low chemoselectivity and substrate
substitution and hydrolysis of 2-fluoropyridine and acetamidine adaptability. 2-Aminopyridine can also be obtained from the
[7]
hydrochloride has been developed. This amination uses hydrolysis and Hofmann degradation of 2-cyanopyridine.
inexpensive acetamidine hydrochloride as the ammonia source However, this method requires the use of a large amount of
and has the advantages of a high yield, high chemoselectivity and oxidants and toxic bromine and is therefore not suitable for
wide substrate adaptability. The results suggest that other N- large-scale production because of the difficulty in controlling
heterocycles containing fluorine substituents can also complete the reactivity. 2-Aminopyridine can be obtained from the
the reaction via these reaction conditions and yield the target Pd/H2-catalysed reduction of 2-nitropyridine[8]
.
The
products.
preparation of 2-aminopyridine through the Chichibabin
reaction of pyridine compounds and sodium amide has very
high atom economy. [9] However, the substrate of this reaction
has very narrow applicability. In addition, the reaction suffers
from many side reactions and strict reaction conditions.
Although many methods for the synthesis of 2-aminopyridine
exist, the continuous development of synthetic methods for 2-
aminopyridine that have mild and controllable conditions and
high chemoselectivity is extremely important.
The formation of C−N bonds consꢀtutes one of the most
important transformations in organic synthesis, primarily due
to the large proportion of medicinally relevant structures,
dyes, and materials that contain amines.[1] 2-Aminopyridine
derivatives have attracted much attention because of their
wide application in heterocyclic synthesis. 2-Aminopyridine is a
ubiquitous structural element in the synthesis of natural
products, pharmaceutical and medicinal compounds, and fine
[2]
chemicals such as luminescent materials.
Therefore, the
development of a highly chemoselective method for the
synthesis of 2-aminopyridine derivatives has both research
significance and application value. Among the many methods
for the synthesis of 2-aminopyridine, the copper-catalysed
amination of 2-halogenopyridine is the most commonly used
method, which has advantages such as high yield and mild
[3]
reaction conditions.
The Pd-catalysed amination of 2-
bromopyridine and (Me3Si)2NHLi results in an 88% yield of the
[4]
product 2-aminopyridine.
2-Aminopyridine can also be
prepared from the ammonolysis of 2-fluoro-pyridine and
ammonia. However, high pressure and a sealed reaction vessel
are required for the use of ammonia at high temperature. [5]
Singarama and co-worker reported that lithium amides
promote the amination of 2-fluoropyridine under mild
Scheme 1 Synthesis of 2-aminopyridine
One important characteristic of more environmentally
benign synthesis is to avoid the use of expensive transition
metals and to use water as the surrogate solvent. While
investigating the synthesis of haloimidazoles through the
copper-catalysed reaction of 1,1-dibromoalkenes and
amidines,10 we found that in the synthesis of amidine
compounds, small amounts of aniline by-products can be
obtained from the copper-catalysed reaction of iodobenzene
and acetamidine hydrochloride. Fu et al. also reported the
preparation of primary aromatic amine derivatives from the
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen,
Guangdong Province 529090, China, E-mail: leeyib268@126.com
†Electronic Supplementary Informaꢀon (ESI) available: General Experimental
information, experimental procedure for product synthesis, full characterization
data, 1H and 13C NMR spectra of all products. See DOI: 10.1039/x0xx00000x
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copper-catalysed coupling and hydrolysis of iodobenzene and
acetamidine hydrochloride; the results showed that catalysts
and ligands are crucial to the reaction.[11] In the preparation of
benzofuran, benzothiophene, thienopyridine and other
heterocycles through cyclization from the oxygen and sulfur
nucleophilic substitution of the C-F bond in 2-
fluorophenylacetylene derivatives, we found that the reactivity
of nucleophilic substitution on halogen atoms follows the
descending order of F>Br>Cl>I.[12] In particular, the C-F bond
close to the C-C triple bond is highly reactive and prone to
nucleophilic substitution. In the present paper, we found that
the C-F bond in the 2-position of pyridine also has high
reactivity and chemoselectivity in nucleophilic substitution.
Herein, we report an efficient transition-metal-free method for
the synthesis of 2-aminopyridine derivatives with high yields
from 2-fluoropyridine and acetamidine hydrochloride by using
water as the mixing solvent.
Entry
1
Base
Solvent
DMSO
DMF
Yield[b](%)
23
13
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K3PO4
tBuOLi
tBuONa
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
2
3
DMAC
NMP
16
0
4
5
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
glycerol
H2O
0
25
6
7
44
63
8
9
76
79
88
69
10
11
12[c]
13[d]
14[e]
15[f]
16[g]
17
18
91
95
82
79
24
At first, 2-fluoro-3-iodopyridine and acetamidine
hydrochloride were chosen as the model substrates to
optimize the reaction conditions. In lieu of transition metals as
catalysts, Cs2CO3 was chosen as the base, and dimethyl
sulfoxide (DMSO) was chosen as the solvent. After reacting for
24 hours at 120 °C, we found that this reaction can proceed to
give a 23% yield of the target product (Table 1, entry 1). We
found through the solvent screening that DMSO is the optimal
solvent (Table 1, entries 2-5), whereas when toluene was used
as the solvent, no target product was detected. Next, we
further screened the base and found that carbonates and
K3PO4 exhibited no apparent promotion effect (Table 1, entries
<5
aReaction conditions: 2-fluoro-3-iodopyridine (1.0 mmol),
acetamidine hydrochloride (1.2 mmol), base (2.5 mmol), H2O
(0.5 mL) in solvent (2.5 mL) at 120 °C for 24 h; bYields of
isolated products; cReaction was carried out at 120 °C for 12 h;
dReaction was carried out at 120 °C for 36 h; eReaction was
carried out at 130 °C for 24 h; fPentanimidamide hydrochloride
g
was used instead of acetamidine hydrochloride; carboxamide
hydrochloride was used instead of acetamidine hydrochloride.
By using the best conditions screened for the transition
metal-free synthesis of 2-aminopyridine derivatives from 2-
fluoropyridine derivatives and acetamidine hydrochloride
(Table 1, entry 14), the development of substrates for this
amination with high chemoselectivity was performed. The
results suggest that when the pyridine ring has electron-
withdrawing groups, the amination can be completed
smoothly with a high yield of the target product. This reaction
is tolerant to substituent groups such as iodine, bromine,
chlorine, trifluoromethyl, nitro, and methyl. When fluorine is
at the 2-position of pyridine, this fluorine atom has high
reactivity, thus leading to high yields of the target products.
The co-existing iodine substituents are not affected (Scheme 2,
3a-3b). When the fluorine and chlorine or bromine
substituents are at the 2-position and 6-position, the reaction
takes priority at the fluorine to give 6-chloropyridin-2-amine
and 6-bromopyridin-2-amine in a high yield (Scheme 2, 3e and
3f). Interestingly, when fluorine substituents are present at
different locations on the pyridine ring, the reaction takes
priority on the fluorine at the 2-position to give 2-
aminopyridine, while the fluorine atoms at other positions are
t
6-8). However, moderate yields were obtained when BuOLi
and sodium tert-butoxide were used (Table 1, entries 9-10).
Surprisingly, when inexpensive NaOH was used, the yield can
be significantly improved to 88%. When the reaction time was
shortened to 12 hours, the yield decreased to 69%. However,
when the reaction time was extended to 36 hours, the yield
improved slightly to 91% (Table 1, entries 12-13). Lastly, we
found that when the temperature was 130 °C, the reaction
yield can reach 95% (Table 1, entry 14). This is likely because
the amination requires nucleophilic substitution and
hydrolysis; low temperature is unfavourable for the hydrolysis
of amidine intermediates, thus resulting in the incomplete
hydrolysis
of
the
intermediate
N-(3-iodopyridin-2-
yl)acetamidine in the reaction. Lastly, we tested the
ammonolysis by replacing acetamidine hydrochloride with
pentanimidamide hydrochloride and cyclobutane carboxamide
hydrochloride. The results suggest that acetamidine
hydrochloride exhibited the best ammonolysis effect (Table 1,
entries 15-16). It was found that the presence of glycerol or
H2O as solvent does not facilitate the reaction (Table 1 entries
17-18).
not affected (Scheme 2, 3h-3j). It can be seen from the
Table 1. Optimization of the Reaction Conditionsa
substrate development that steric hindrance has little impact
on this amination reaction, while the electronegativity of the
pyridine substituent is the most important influencing factor.
When the pyridine ring is joined by the strong electron-
withdrawing nitro group, the reaction can proceed at low
temperature and result in excellent yields (Scheme 2, 3o-3r). In
addition, when the pyridine ring is combined with electron-
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donating groups such as a methyl group, the reaction can be NaOH promoted the degradation of DMF. The amination then
completed, resulting in moderate yields of the target products proceeded, and a high yield of N,N'-dimethylaminopyridine 4a
(Scheme 2, 3s-
3t). It is worth noting that when pyrimidine was was obtained [Eq. (1)].[13]
used as the raw material for the amination, the reaction can
also proceed smoothly, and the sole target product 3u was
obtained. Lastly, 2-fluoropyrazine was used as the raw
material for the amination reaction under standard reaction
conditions; a 52% yield of the target product pyrazin-2-amine
3v was obtained. Unfortunately, the reaction with 2-
fluoropyridine failed in the reactions under the standard
reaction conditions. Increasing the reaction temperature can
slightly increase the yield. When use 2,6-difluoropyridine as
the substrate, only afforded a complex mixture and no product
was detected. In addition, when using normal pyridine (C5H5N)
as the substrate, the reaction does not work.
To further verify the reaction mechanism and expand the
practicability of this reaction, we chose a few pyridine
derivatives with multiple substituents that have high steric
hindrance for the amination with acetamidine hydrochloride
to synthesize amidine substituent derivatives [Eq. (2)]. We
successfully obtained N-(3,5-dichloro-4,6-difluoropyridin-2-yl)
acetamidine (5a, 87%), which can be used to prepare 2-
aminopyridine derivatives through hydrolysis. More
importantly, amidine derivatives are important intermediates
for medicinal and organic synthesis.[14] Interestingly, under a
H2O (5 equiv) condition, 2,3,5,6-tetrafluoropyridine reaction
with acetamidine hydrochloride gave the N-(3,5,6-
trifluoropyridin-2-yl)acetamide product 6a in 75% yield [Eq.
(3)].
Scheme
2
Transition-metal-free synthesis of pyridin-2-amine
derivativesa
The plausible reaction mechanism for this amination
[11, 14a]
reaction is as follows (Scheme 3):
hydrochloride
which reacts with 2-fluoropyridine
substitution under the assistance of NaOH to yield N-(pyridin-
2-yl)acetamidine intermediate . Then, in the presence of
water, NaOH provides -OH groups for the nucleophilic attack
of intermediate to yield . Intermediate may be conversion
into amide according to the revelation of [Eq. (3)]. Finally,
the hydrolysis of amide under interaction with water yields
acetamidine
2
first reacts with NaOH to yield acetamidine
A,
1
via nucleophilic
B
B
C
C
D
D
the target product 2-aminopyridine derivatives
acetate.
3 and sodium
Scheme 3 Possible mechanism for the synthesis of pyridin-2-
amines.
NH
NH
HCl
NH2
+
+
H2O
+
NaCl
NaOH
NH2
A
2
NH
NH
+
R
+
H2O
R
NaOH
NaF
+
NH2
N
N
N
F
H
A
B
1
aReaction conditions: 2-fluoropyridine (1.0 mmol), acetamid
ine hydrochloride (1.2 mmol), NaOH (2.5 mmol), H2O (0.5 mL)
OH-
H2O
R
NH2
OH
NaOH
R
R
N
N
H
N
N
O
N
NH2
b
in DMSO (2.5 mL) at 130 °C for 24 h; Yields of isolated
H
CH3COONa
NH3
C
D
3
products. c2-chloro-3-iodopyridine was used as substrate.
In conclusion, we reported an efficient and transition-metal-
free method for the synthesis of 2-aminopyridine derivatives
Interestingly, when we investigated the amination, we
found that when dimethylformamide (DMF) was used as the
raw material and acetamidine hydrochloride was not added,
from
2-fluoropyridine
derivatives
and
acetamidine
hydrochloride. The reaction uses inexpensive and more safe
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7
8
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,
We thank the National Natural Science Foundation of China
(21302146), the Foundation of the Department of Education of
Guangdong Province (2016KTSCX144, 2017KZDXM085) and
Science Foundation for Young Teachers of Wuyi University
(2015td01) and Chemical Industry Collaborative Innovation
Center of Yueshan Town 2017(368) for financial support.
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