Selectfluor-promoted regioselective chlorination/bromination of 2-aminopyridines and 2-aminodiazines using LiCl/LiBr

Article abstract of DOI:10.1039/c9ob00972h

Using LiCl as a chlorine source, the chlorination of 2-aminopyridines or 2-aminodiazines in the presence of Selectfluor and DMF is established under mild conditions. This method gives chlorinated pyridines or diazines in good to high yields with high regioselectivities. Also, this method is extended to the bromination of 2-aminopyridines or 2-aminodiazines by using LiBr. The regioselectivity of the chlorination reaction is strongly dependent upon the substituent pattern in either the 2-aminopyridines or 2-aminodiazines. The synthesis of Buparlisib from chlorinated pyridines was explored. A study of the mechanism revealed that this chlorination occurs via either a pyridine or diazine radical process.

Full text of DOI:10.1039/c9ob00972h

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DOI: 10.1039/C9OB00972H
ARTICLE
Selectfluor-promoted regioselective
chlorination/bromination of 2-aminopyridines and 2-
aminodiazines using LiCl/LiBr
Received 00th January 20xx,
Accepted 00th January 20xx
Jiao Hu,a,§ Gang Zhou,a,§ Yawei Tiana and Xiaoming Zhaoa,*
DOI: 10.1039/x0xx00000x
Using LiCl as a chlorine source, a chlorination of 2-amiopyridines or 2-aminodiazines in the
presence of Selectfluor and DMF is established under mild conditions. This method gives
chlorinated pyridines or diazines in good to high yields with high regioselectivities. Also, this
method is extended to a bromination of 2-aminopyridines or 2-aminodiazines by using LiBr. The
regioselectivity of the chlorination reactions is strongly depended upon the substituent pattern in
either 2-amiopyridines or 2-aminopyrizations. The synthesis of Buparlisib from chlorinated
pyridines was explored. The mechanic study firstly revealed that this chlorination undergoes
either pyridine or diazine radical process as well.
chlorination on the pyridine and diazines remains a challenge.
In this paper, we reported a regioselective chlorination of
pyridine, pyrimidine and pyrizanes with LiCl under mild
Introduction
Chlorinated pyridines and diazines are of greatly importance
to pharmaceutical industry.1 For example, there are
representative drugs containing either chlorinated pyridine or
pyrimidine or pyrizane moiety including Avatrombopag,2
Tiochorim,3 Forchlorfenuron,4 and Amiloride5 (Figure 1).
Therefore, new methods for the chlorination of pyridines, and
diazines have been attracting synthetic chemists. The
conventional methods for the synthesis of chlorinated
pyridines and diazines include (1) direct chlorination with Cl2
or chlorinated agent such as N-chlorosuccinimide (NCS),
SO2Cl2, HCl, POCl3;6 (2) Sandmeyer reaction;7 and (3)
transition-metal catalyzed C-H chlorination.8 There are some
drawbacks in above-mentioned methods such as low
regioselectivities6 and poor stabilities under strong acid
conditions.7 In addition to that, pyridines and diazines can
serve as an auxiliary group in transition-metal-catalyzed C-H
activation and halogenation.8
Interestingly, the application of lithium chloride (LiCl) as
chlorine source in the synthesis of chlorinated pyridines,
pyrimidines and pyrizanes is unexplored yet at present.
Chlorinated 2-aminopyridines are key intermediates in
pharmaceutical industry.9 It is noteworthy that the chlorine
substituent pattern on the pyridine ring has a great influence on the
bioactivity of chlorinated pyridines.2,4,10 In fact, selective
conditions.
O
OH
N
N
NH2
N
H
N
N
S
S
O
O
Cl
N
N
N
O
Cl
NH2
OH
OH
SCH3
Tioclorim
Avatrombopag
Cl
O
NH
O
N
Cl
H2N
N
N
N
NH2
H
N
H
N
H
Cl
NH2
Forchlorfenuron
Amiloride
Figure 1. Four drugs with chlorinated 2-amionpyridine
Results and discussion
In our previous works on the fluorination of pyridines and
diazines (eq-1 in Scheme 1),11 we found that 2-aminopyridines
are treated with Selectfluor to form a 2-aminopyridine
radical.11 The chlorination of 2-aminopyridines and 2-
aminodiazines was respectively described by Baran6a and
Yang6c (eq-2 in Scheme 1). We envision that this 2-
aminopyridine radical may react with chlorine sources to give a
chlorination product (eq-3 in Scheme 1). To test the
hypothesis, we examined a reaction of 2-aminopyridines 1 with
various chlorine sources 2 such as sodium chloride (NaCl), lithium
chloride (LiCl) and cupper chloride (CuCl) in the presence of
oxidizing agents 3 including Selectfluor, K3CrO4 and K2S2O8.12 After
a. School of Chemical Technology and Engineering, Tongji University, 1239 Siping
Road, 200092 Shanghai, P.R. China. E-mail: xmzhao08@tongji.edu.cn ; §J.H. and
G. Z. contributed equally.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available:
See DOI: 10.1039/x0xx00000x
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Journal Name
screening the reaction conditions (see SI), we found that a (e.g., Me, Cl, Ph, 2-MeOC6H4, 3-MeOC6H4, and 3-ClC6H4) specifically
chlorination of 4-cyano-2-aminopyridne 1a (1.0 eq) with LiCl 2a (1.0 gave 5-brominated 2-aminopyrizanes 6e-6j in modVeireawtAertictloe Ohnilginhe
DOI: 10.1039/C9OB00972H
eq) in the presence of Selectfluor 3a (1.0 eq) and DMF (2 mL) yields (Table 2). For pyrimidine substrates, 2-aminopyrimidines 5k-
occurred at room temperature and it gave a 70% yield of 4a along 5l bearing a 4-substituted group (e.g., 4-CNC6H4 and 4-MeC6H4)
with a trace 3-Cl-4-cyano-2-aminopyridine 4a’ (Table 1). There are selectively produced 6k-6l in moderate to good yields; no
two peaks at 8.17 and 6.86 ppm on the 1H NMR spectra of 4a, bromination on benzene ring were observed (Table 2).
which are distributed to a 3-hydrogen and a 6-hydrogen on the
pyridine ring; and these are in consistent with that of 5-Cl-4-cyano- Table 1 Chlorination of 2-aminopyridines or 2-amiondiazines 1 by
2-aminopyridine;9 we thus deduced that the chlorination reaction using LiCl in the presence of Selectfluor.a,b
NH2
NH2
takes place at 5-position. Interestingly, 4a is a key intermediate for
NH2
3a
Selectfluor
DMF, 15 o
N
X
Y
Cl
N
X
Y
the synthesis of a drug regulators of T-type calcium channel, which
LiCl
N
+
+
FG
FG
FG
has important physiological and pathological significance.13
C
Y
2a
Cl
1
Previous work
4'
4
Cl
N
NH2
NH2
2BF4
N
NH2
Cl
F
NH2
NH2
NH2
N
N
N
FH
eq-1
NH2
Cl
G
N
G
G
N
N
N
CHCl3, H2O, 15 o
C
up to 94%
CN
CF3
Cl
N
Cl
Cl
Cl
4c
NH2
4a
, 70%
4a 4a'
MeO2C
CO2Me
Cl
4b
, 70%
4b/4b' > 10/1
NCS
or
N
N
H
4d
, 70%
, 60%
/
> 10/1
N
H
eq-2
G
NH2
NH2
Cl
NO2
NH2
Ph
N
NH2
Cl
S
OMe
N
N
O
N
up to 81%
O
N
N
N
N
N
This work
NH2
Cl
Cl
N
Cl
Cl
4g
2BF4
Cl
N
NH2
4e
, 60%
4e 4e'
/
4f
4h
, 75%
, 80%
F
, 55%
> 10/1
N
N
eq-3
G
G
NH2
N
NH2
N
F
NH2
N
LiCl
NH2
N
Cl
N
N
N
Cl
Cl
F
Scheme 1 Selective halogenations of 2-amionpyridines in the
presence of Selectfluor.
N
Cl
Cl
Cl
NC
Cl
4i
, 70%
4j
, 70%
4k
4l
, 80%
, 80%
The scope of 2-aminopyridines or 2-aminodiazines 1 was tested
under the optimized conditions. For pyridine derivatives, the
substrates 1a-1d with either electron-rich (e.g., 3-Me) or electron-
poor substituent (e.g., 4-CN, 4-CF3 and 3-Cl) on the pyridine ring
gave the corresponding 4a9-4d in moderate to good yields with high
regioselectivities (Table 1). 2-Aminopyridines with a substituent at
3-position only gave 5-chlorinated products (4c and 4d) and no
other chlorinated products were observed. For pyrizane derivatives,
2-aminopyrizane 1e afforded 4e in a 60% yield with 4e/4e’ > 10/1.
The pyrizanes 1g-1i with a substituent (e.g., Cl, Ph, 4-NO2C6H4 and
4-FC6H4) at 3-position selectively produced 4g-4i in good to high
yields; no chlorination on benzene ring were observed. For
pyrimidines, 2-aminopyrimidines 1j-1l with a substituent (e.g., 4-
CNC6H4, 3-FC6H4 and 2,4-di-ClC6H4) at 6-position specifically gave
rise to 4j-4l in moderate to high yields (Table 1). More interestingly,
both 3-methylpyridine 1m and 2-methylaniline 1n were examined
and no chlorinated products 4m and 4n were observed (Table 1).
These outcomes suggest that both amino and pyridine ring are
crucial for this chlorination.
NH2
N
Cl
4m
Cl
, 0%
4n
, 0%
a
Reaction conditions: 2-aminopyridine 1 (0.10 mmol), Selectfluor 3a (0.10
mmol), LiCl 2a (0.10 mmol) and DMF (2 mL) at 15 °C for 24h. b Isolated yield.
Table 2 Bromination of 2-aminopyridines and 2-aminodiazines
substrates 4 by using LiBr in the presence of Selectfluor.a,b
We also took advantage of the same strategy as this chlorination
to conduct a bromination by using salt bromide. After examining a
range of salt bromides as the bromine source under the similar
conditions (see: SI), we found the bromination of 2-aminopyridine
5a (1.0 eq) with NaBr14 (1.0 eq) occurred in the presence of
Selectfluor 3a (1.0 eq) and DMF (2 mL) at 30 °C and it selectively
gave 5-bromo-2-aminopyridine 6a in a 75% yield; however, no 3-
bromo-2-aminopyridine 6a’ were observed. The other pyridines 5b-
5d containing a 3-substituted group (e.g., 4-MeC6H4, 3-MeOC6H4
and 3-ClC6H4) regioselectively provided 6b-6d in moderate to good
yields; no bromination on benzene rings were observed (Table 2).
For pyrizane substrates, 2-aminopyrizanes 5e-5j with a 3-substitent
2 | J. Name., 2012, 00, 1-3
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ARTICLE
intermediate B;14 the latter isomerizes to form C VaienwdArtDic.le OnTlhinee
chlorine radical E is formed by the reaction of LiCl 2a with A,15
DOI: 10.1039/C9OB009a72nHd
NH2
NH2
3a
N
X
Y
Selectfluor
N
X
Y
LiBr
+
FG
FG
DMF, 30 o
C
then the reaction between E and D occurs to form F. The
aromatization of F thus proceeds to produce 4. The regioselectivity
of 4a, 4b and 4e probably is explained by the steric demand of
amino and substituent, which decreases the formation of 3-
chlorinated products. The bromination of 5 with LiBr 6a in the
presence of 3a proceeds by means of a similar path way to the
chlorination to give the corresponding 7 shown in Scheme 3.
6a
5
Br
7
NH2
N
NH2
NH2
Br
NH2
OMe
N
Cl
N
N
Br
Br
7d
Br
7a
, 75%
,
65%
7b,
7c
, 70%
70%
NH2
Cl
N
NH2
2BF4
NH2
NH2
NH2
Cl
N
N
N
R
Cl
N
N
3a
F
N
N
N
F
N
N
N
N
OMe
NH2
B
A
Br
Br
Br
7g
Br
-H
N
N
R
LiCl
2a
, 60%
7h
, 80%
7e
7f
,
, 80%
75%
NH2
NH
NH
-F
1
NH2
NH2
N
NH2
R
R
Cl
N
N
N
N
N
Cl
N
OMe
E
N
N
C
D
NH
NH2
Br
, 70%
Br
Br
Br
aromatization
N
NC
N
R
7l
R
7i,
70%
7k
, 60%
7j
, 60%
Cl
4
Cl
F
a Reaction conditions: 5 (0.1 mmol), Selectfluor 3a (0.1 mmol), LiBr 6a
(0.1 mmol) and DMF (2 mL) at 30 °C for 24 h. b Isolated yield.
Scheme 3 Possible mechanism for the chlorination.
O
3a
Selectfluor
3.54 g
10 mmol
NH2
N
NH2
N
Conclusions
We developed
N
NH2
ref 13a
N
eq-1
+
LiCl
2a
425 mg
10 mmol
a chlorination of 2-aminopyridines and 2-
DMF, 15 o
C
N
F3C
F3C
CF3
aminodiazines with LiCl in the presence of Selectfluor in DMF under
the mild conditions, which gave 5-chloro-2-aminopyridines and
diazines in good to high yields with high regioselsctivities. This
method is efficiently extended their bromination by using LiBr as a
bromine source. Both chlorination and bromination allow use of a
range of 2-aminopyridine and 2-aminodiazine substrates, tolerates
various functionalized groups, and afford new way to chlorinated or
brominated pyridines and diazines.
Cl
1b
1.6 g
10 mmol
N
N
4b
1.27 g
65 %
O
Buparlisib (BKM120)
3a
Selectfluor
NH2
N
NH2
O
2.7 g
7.7 mmol
ref 13b
N
N
+
N
LiCl
eq-2
CF3
H
N
DMF, 15 o
C
2a
331 mg
7.7 mmol
NC
NC
Cl
Cl
1a
4a
916 mg
7.7 mmol
8
806 mg
68 %
F
F
Conflicts of interest
There are no conflicts to declare.
Scheme 2 Large-scale synthesis of 4 and its application for the
synthesis of Buparlisib.
The large-scale synthesis of chlorinated pyridine 4 generated by
this method was demonstrated in Scheme 2. The chlorination of 4-
trifluoromethyl-2-aminopyridine 1b (1.6 g, 10 mmol) with LiCl 2a
(425 mg, 10 mmol) in the presence of 3a (3.54 g, 10 mmol) was
performed in DMF at 15 °C and it produced 4b (1.27 g, 65%) with
4b/4b’ > 20/1. Significantly, 4b will be transferred into Buparlisib13;
and 4a was also synthesized by a large-scale and converted into the
bioactive compound 8 according to a previous method (Scheme
2).13
Acknowledgements
The authors are grateful to the Chinese National Science Foundation
(NSF) (grant number 21272175) and the Fundamental Research
Funds for the Central Universities for financial support of this
research.
A controlled experiment was performed under the identical
conditions as shown in Table 1, namely, a reaction of 3-methyl-2-
aminopyridine 1c (0.10 mmol), LiCl 2a (0.10 mmol) and Selectfluor
3a (0.10 mmol) in the presence of 2,2,6,6-tetramethylpiperidine-N-
oxyl radical (TEMPO, 0.40 mmol) was carried out and no chlorinated
products 4c were observed.
Notes and references
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1667-1672. (b) A. Deleon, N. C. Patel and M. L. Crismon, Clin Ther,
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4 | J. Name., 2012, 00, 1-3
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