A new synthesis of pyridinyl trifluoromethanesulfonates via one-pot diazotization of aminopyridines in the presence of trifluoromethanesulfonic acid

Article abstract of DOI:10.1016/j.tetlet.2014.05.052

The first method for the direct one-pot transformation of aminopyridines into pyridinyl trifluoromethanesulfonates is developed. The procedure involves diazotization of aminopyridines with sodium nitrite in a DMSO paste in the presence of trifluoromethanesulfonic acid.

Full text of DOI:10.1016/j.tetlet.2014.05.052

Tetrahedron Letters 55 (2014) 3771–3773
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Tetrahedron Letters
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A new synthesis of pyridinyl trifluoromethanesulfonates
via one-pot diazotization of aminopyridines in the presence
of trifluoromethanesulfonic acid
⇑
⇑
Elena A. Krasnokutskaya , Assiya Zh. Kassanova, Makpal T. Estaeva, Victor D. Filimonov
Department of Biotechnology and Organic Chemistry, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The first method for the direct one-pot transformation of aminopyridines into pyridinyl trifluorome-
thanesulfonates is developed. The procedure involves diazotization of aminopyridines with sodium
nitrite in a DMSO paste in the presence of trifluoromethanesulfonic acid.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 5 March 2014
Revised 22 April 2014
Accepted 7 May 2014
Available online 21 May 2014
Keywords:
Aminopyridines
Diazotization
Trifluoromethanesulfonic acid
Pyridinyl trifluoromethanesulfonates contain a triflate as a good
leaving group and hence represent compounds of significant value
for organic synthesis. For example, substitution of the triflate
group can give valuable pyridine derivatives such as bipyridines,1a
pyridinylpiperazines,1b highly functionalized indolizines,1c b-carb-
olines,1d arylpyridines,1e and pyridyl guanidines,1f iodopyridines,
quinolines, isoquinolines,2a–d pyrrolo-[2,3 b]pyridines,2e and pyrid-
inyl biosensors.2f
Currently, the esterification of hydroxypyridine with trifluoro-
methanesulfonic acid anhydride and harmful and toxic trifluorome-
thane sulfonylchloride1–4 or trifluoromethanesulfonic acid amides5
in the presence of the base in organic solvents are the only methods
for the synthesis of pyridinyl trifluoromethanesulfonates. In general,
these methods provide good yields of pyridinyl trifluoromethane-
sulfonates, but the high cost of reagents, inert atmosphere in some
cases, and low temperature (down to À78 °C) make the target
products fairly expensive to prepare.
The goal of this work was to develop a one-pot synthesis of
pyridinyl trifluoromethanesulfonates from aminopyridines which
are often more accessible and cheaper starting materials in com-
parison with pyridinols. The background for this approach is given
in our previous work.6 We have shown that diazotization of amino-
pyridines with sodium nitrite in the presence of p-TsOH in water
paste led to the corresponding pyridinyl tosylates in one step.6
This differentiated significantly the aminopyridines from other
aromatic amines that form stable arenediazonium tosylates7 after
diazotization in the presence of p-TsOH. The reason for these dif-
ferences between aromatic amines and aminopyridines6,7 is the
well-known instability of pyridine diazonium salts compared to
arenediazonium salts.8
Initially, the approach described in our previous work6 was uti-
lized. p-TsOH was replaced by TfOH (Method A) in the water paste
with no desirable effect. It was found that the addition of sodium
nitrite to aminopyridines 1a–k in aqueous paste with 3 equiv of
TfOH at ambient temperature led to a rapid release of nitrogen oxi-
des and incomplete conversion of the initial aminopyridine. The
major products were the corresponding hydroxypyridines and
starting aminopyridines 1, although the desired pyridinyl trifluo-
romethanesulfonates 2a–k were identified in the reaction mixture.
The lower selectivity of diazotization–triflation relative to diazoti-
zation–tosylation6 probably is a reflection of the lower nucleophi-
licity of TfOH. A more detailed search for suitable conditions was
conducted for the synthesis of pyridinyl trifluoromethanesulfo-
nates via diazotization of 2-amino-5-bromopyridine 1a (Table 1)
in the presence of TfOH.
Diazotization of aminopyridine 1a by grinding with NaNO2 and
TfOH under solvent-free conditions (Method B) almost eliminated
the side hydroxypyridine formation, however, full conversion of
starting substrate 1a took a long time (36 h). Using n-BuONO as
the diazotizing agent instead of NaNO2 (Method C) did not give a
satisfactory result. Tar formation, a low yield of the desired triflate
2a, incomplete conversion of the starting amine, and large
amounts of the 5-bromo-N-butylpyridin-2-amine side product
(Table 1) were observed. Apparently, this side product is formed
⇑
Corresponding authors. Tel./fax: +7 3822 563 637.
E-mail addresses: eak@tpu.ru (E.A. Krasnokutskaya), filimonov@tpu.ru (V.D.
Filimonov).
http://dx.doi.org/10.1016/j.tetlet.2014.05.052
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3772
E. A. Krasnokutskaya et al. / Tetrahedron Letters 55 (2014) 3771–3773
by the alkylation of initial aminopyridine 1a with n-BuOTf or pro-
tonated n-BuONO, which can appear in the presence of TfOH. A
similar side product 5-bromo-N-(tert-butyl)pyridin-2-amine was
formed by diazotization of 1a in tert-butanol (Method D, Table 1);
the alkylation process in this case was probably due to t-BuOH.
Using ethanol instead of t-butanol (Method E) led to the formation
of significant quantities of the side product, 5-bromo-2-ethoxy-
pyridine (Table 1). Diazotization in acetonitrile (Method F, Table 1),
both using NaNO2 and n-BuONO, ensured the formation of N-(5-
bromopyridin-2-yl)acetamide as a side product, probably, via the
reactions shown in Scheme 1.
The formation of N-(5-bromopyridin-2-yl)acetamide as a side
product in the diazotization–iodination of 1a in acetonitrile in
the presence of p-TsOH has been also observed previously.9
A relatively high yield of the target product 2a was obtained by
diazotization with n-BuONO in DMSO solution (Method G, Table 1).
Previously, DMSO has been successfully used for the diazotization–
halogenation of aromatic amines, 2-amino-5-nitropyridine, and
amino-derivatives of quinoline, isoquinoline, and anthraquinone.10
However, even in those cases complete conversion of amine 1a was
not achieved. Furthermore, 5-bromopyridin-2-ol appeared as a
side product due to the presence of residual water in DMSO. In
addition, there were problems with preparative separation of
highly soluble pyridines from DMSO solution. To reduce the
amounts of DMSO and water we performed the diazotization by
grinding aminopyridine 1a, NaNO2, and TfOH in DMSO and allow-
ing the slurried mixture to stand for 5.5 h without further grinding
(Method H). This method showed the optimal selectivity and effi-
ciency with the GC yield of 2a being more than 90% (Table 1), a pre-
parative yield of 70% was obtained (Table 2). The optimal approach
H was used to obtain a series of pyridinyl trifluoromethanesulfo-
nates 2a–k11 (Table 2). It is important to mention that Method H
in all cases ensures complete conversion of initial aminopyridines
1a–k, and gives no side pyridinols. In general, the yields of pyridyl
triflates 2a, 2c, 2g, 2h, and 2i were comparable, and for compounds
2b and 2d they were higher than obtained using traditional
hydroxypyridine esterification.1–5 Moreover, Method H allowed
Table 2
The synthesis of pyridinyl trifluoromethanesulfonates 2a–l using Method H
Table 1
Substrate
Product
Time (h)
Isolated
yield (%)
The diazotization of 2-amino-5-bromopyridine 1a via Methods A–H
Br
Br
Br
[NO+]
Br
Br
+
5.5
2.5
6.5
70
89
78
TfOH, 20 o
C
N
2a
OTf
N
X
N
NH2
N
NH2
NH2
N
OTf
OTf
2a
2b
1a
1b
1a
Cl
Cl
Methoda Solvent Source
of [NO+]
The reaction mass composition (GC) (%)
N
N
Br
I
I
2a
1a
N
X
N
NH2
N
OTf
2c
1c
Br
Br
Br
Br
Br
Br
Br
O2N
O2N
Water
paste
A
B
C
D
E
F
NaNO2
NaNO2
21
93
35
34
18
30
83
52
0
2.5
7.0
86
65
N
OH
OH
N
NH2
N
OTf
2d
27
1d
None
N
NH2
N
OTf
N
2e
4
1e
n-
BuONO
None
30
54
60
13
10
6.5
90
N
N
N
NH-n-Bu
NH-t-Bu
20
N
NH2
N
OTf
2f
1f
t-
BuOH
n-
BuONO
6.0
4.0
5.0
80
70
75
12
N
NH2
N
OTf
2g
1g
NH2
OTf
n-
BuONO
EtOH
OEt
22
N
N
N
N
1h
1i
2h
NH2
Cl
OTf
Cl
n-
BuONO
MeCN
DMSO
N
N
NHAc
35
2i
n-
BuONO
NH2
OTf
G
H
OH
7
6.0
18
60
56
DMSO
paste
NaNO2
93 Not detected
Not
detected
N
N
1j
2j
Br
Br
Br
Br
Mole ratio of 1a: [NO+]: TfOH and the reaction time: 1:2:3, 5 h (Method A); 1:2:3,
36 h (Method B); 1:2:3, 4 h (Method C); 1:2:3, 4 h (Method D); 1:2.5:3, 4 h (Method
E); 1:2:3, 4 h (Method F); 1:2.5:3, 4 h (Method G); 1:2.5:3, 5.5 h (Method H).
a
N
NH2
N
OTf
2k
1k
2a
TfO-
Br
Br
[NO+]
1a
+
-N2
TfOH
N
TfO-
N2
N
Br
MeCN
N
NHAc
Scheme 1. Plausible reaction pathways for the diazotization of 1a in acetonitrile.

E. A. Krasnokutskaya et al. / Tetrahedron Letters 55 (2014) 3771–3773
3773
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R
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NaNO2/TfOH
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TfO
N
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H2N
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Scheme 2. Diazotization of diaminopyridines 1l,m in the presence of TfOH.
the synthesis of novel 5-iodopyridin-2-yl trifluoromethanesulfo-
nate 2c, pyridin-4-yl trifluoromethanesulfonate 2j, and 3,5-dib-
romopyridin-2-yl trifluoromethanesulfonate 2k.
Thus, unlike a number of well-established methods, the proce-
dure presented in this Letter can be broadly applied to the synthe-
sis of 2-, 3-, and 4-pyridine triflates in one step starting from
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Also we tried to apply Method H on pyridine-2,6-diamine 1l
and 3,5-diiodopyridine-2,6-diamine 1m with 6 equiv of TfOH, but
the results were ambiguous. In both cases the diazotization reac-
tions occurred much more slowly than for monoaminopyridines
1a–k (up to 30–38 h), and with incomplete conversion of the dia-
minopyridines 1l,m. At the same time, the reaction mixtures con-
tained products of substitution only of both amine groups to
triflates 2l,m (GC–MS data) (Scheme 2).
In the case of the diazotization of 1m we were able to isolate
product 2m in 35% preparative yield. Compound 2m represents a
rare example of a pyridine with two triflate groups and possesses
interesting synthetic potential because it has four active sites. As
far as we know, only one pyridine with two triflate substituents
was described before.12
In summary, an efficient and economic method for the synthe-
sis of pyridinyl trifluoromethanesulfonates via one-pot diaz-
otization of aminopyridines with sodium nitrite in the presence
of trifluoromethanesulfonic acid in DMSO paste has been pre-
sented for the first time. It differs from the known methods in
the use of easily available reagents, and employs mild conditions
and a simple synthetic procedure.
6. Tretyakov, A. N.; Krasnokutskaya, E. A.; Gorlushko, D. A.; Ogorodnikov, W. D.;
Filimonov, V. D. Tetrahedron Lett. 2011, 52, 82.
7. Filimonov, V. D.; Trusova, M. E.; Postnikov, P. S.; Krasnokutskaya, E. A.; Lee, Y.
M.; Hwang, H. Y.; Kim, H.; Chi, K.-W. Org. Lett. 2008, 10, 3961.
Acknowledgments
8. Butler, R. N. Chem. Rev. 1975, 75, 241.
9. Krasnokutskaya, E. A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P.
Synthesis 2007, 81.
10. Baik, W.; Luan, W.; Lee, H. J.; Yoon, Ch. H.; Koo, S.; Kim, B. H. Can. J. Chem. 2005,
83, 213.
11. A typical experimental procedure is as follows: Trifluoromethanesulfonic acid,
DMSO, and NaNO2 were used without further purification and drying. All
The financial support from the Russian Foundation for Basic
Research (Project No. 14-03-00743) is gratefully acknowledged.
E.A.K. acknowledges the Scientific Programme «Nauka» (N 3.133
3.2014), V.F. acknowledges the Scientific Programme «Nauka»
(N 3.1344.2014). The authors are grateful to Dr. Nick Moskalev
for constructive criticism and useful remarks and Patricia Schnei-
der (postgraduate student at JF University, Grenoble) for the signif-
icant experimental assistance during the summer practice in TPU.
operations were performed in air using normal wet.
A mixture of an
aminopyridine 1 (2 mmol) and NaNO2 (5 mmol) was ground with a pestle in
an agate mortar until a homogeneous mixture formed. The mixture was
added to solution of TfOH (6 mmol, 0.54 mL) and DMSO (1.3 mmol, 0.1 mL)
cooled to 5 °C, and ground once again. The resulting homogenous paste was
left in open to air for 2.5–18 h (Table 2) at room temperature during which
gradual evolution of N2 took place. The crude paste was suspended in H2O
(40 mL), stirred, and treated with 25% aqueous Na2CO3 (4 mL) until pH = 10,
and then extracted with CH2Cl2 (3 Â 15 mL). The combined organic phase
was washed with H2O (2 Â 15 mL), dried over anhydrous Na2SO4, and the
solvent evaporated in vacuum. The products 2a–k,m were purified by silica
gel flash chromatography, eluent CH2Cl2.
Supplementary data
Supplementary data (the synthetic procedure and spectral and
analytical data for all compounds are provided) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.05.052.
5-Bromopyridin-2-yl trifluoromethanesulfonate (2a).3g Yield 70%, oil. 1H NMR
(300 MHz, CDCl3) d: 7.1 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.6 Hz, 2.4 Hz, 1H),
8.5 (d, J = 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) d: 116.8, 118.5 (q,
J = 300 Hz), 120.5, 143.6, 149.7, 154.5. MS (EI): m/z 307 (15) [
81Br, M]+,
References and notes
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