A new one-pot solvent-free synthesis of pyridinyl tosylates via diazotization of aminopyridines

Article abstract of DOI:10.1016/j.tetlet.2010.10.163

A new, convenient, one-pot method for the synthesis of pyridinyl tosylates is developed. The procedure involves sequential diazotization/tosylation of aminopyridines with sodium nitrite and p-toluenesulfonic acid under solvent-free conditions in a water p

Full text of DOI:10.1016/j.tetlet.2010.10.163

Tetrahedron Letters 52 (2011) 85–87
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Tetrahedron Letters
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A new one-pot solvent-free synthesis of pyridinyl tosylates via diazotization of
aminopyridines
Alexey N. Tretyakov a, Elena A. Krasnokutskaya a, Dmitry A. Gorlushko a, Vladimir D. Ogorodnikov b,
Victor D. Filimonov a,
⇑
a Department of Organic Chemistry, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia
b Institute of Petroleum Chemistry, Siberian Division, Russian Academy of Sciences, 634021 Tomsk, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, convenient, one-pot method for the synthesis of pyridinyl tosylates is developed. The procedure
involves sequential diazotization/tosylation of aminopyridines with sodium nitrite and p-toluenesulfonic
acid under solvent-free conditions in a water paste at room temperature.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 May 2010
Revised 18 October 2010
Accepted 29 October 2010
Available online 4 November 2010
The good leaving ability of tosylate makes aryl and heteroaryl
tosylates an important class of compounds with high versatility
in organic synthesis. For example, they are useful for carbon–car-
bon or carbon–heteroatom bond formation.1 Magnesium deriva-
tives of pyridinyl tosylates serve as convenient precursors for the
generation of 3,4-difunctionalized pyridynes,2 and the tosylate
group in some quinolinyl tosylates can be replaced by iodide.3 Aryl
and heteroaryl tosylates are prepared in organic solvents by tosy-
lation of the corresponding hydroxy derivatives with p-toluenesul-
fonyl chloride.1,2,4,5
Recently, we reported p-toluenesulfonic acid (PTSA) as a mild
and efficient reagent for the diazotization/iodination of aromatic
amines in solvents or water paste,6,7 and for the preparation of
exceptionally stable arenediazonium tosylates.8 When trying to
apply our diazotization/iodination protocol6–8 to 2-aminopyridine
(1), pyridin-2-yl tosylate (1a) was isolated as the major product
instead of the expected 2-iodopyridine. The reason for these
differences between aromatic amines and aminopyridines is the
well-known instability of pyridine diazonium salts compared to
arenediazonium salts.9 To the best of our knowledge no precedent
for the direct conversion of aminopyridines into pyridinyl tosylates
has been reported. This new tosyloxy-dediazotization reaction
represents a simple, environmentally friendly alternative approach
To demonstrate the scope of this new transformation we chose
to study aminopyridines 1–11 and found that the diazotization/
tosylation reaction was general, affording the corresponding pyrid-
inyl tosylates 1a–11a in moderate isolated yields (Scheme 1 and
Table 1).10
Typically, an aminopyridine (2 mmol), PTSA monohydrate
(6 mmol), and water (0.5 mL, 30 mmol) were ground in a mortar
for 3–5 min to give
a homogeneous mixture. Next, NaNO2
(4 mmol) was added and grinding was continued for another
5 min. The so formed slurry was left for 1–12 h with grinding every
15–20 min. Formation of the intermediate diazonium salts was
verified by a positive color test with 2-naphthol and reaction com-
pletion was indicated by a negative test with 2-naphthol. Pure
products 1a–10a were isolated simply by sequential washing of
the reaction mixture with aqueous sodium carbonate and water.
It was found that the product yields depended on the molar
ratio of reagents; a substrate/NaNO2/PTSA ratio of 1:2:3 was
optimal. PTSA plays a dual role in the conversion. On one hand, it
provides an acidic medium which is necessary for generation of
the diazotizing reagent with NaNO2. On the other hand, it partici-
pates in the replacement of the diazonium groups resulting in
pyridinyl tosylates. This is why at least 2 equiv of PTSA were
to pyridinyl tosylates. Furthermore, as
a rule, the starting
aminopyridines are cheaper and more readily available than the
corresponding hydroxypyridines used in traditional syntheses of
pyridinyl tosylates.2,4,5 Herein, we report a new route to pyridinyl
tosylates from aminopyridines and sodium nitrite/PTSA under mild
reaction conditions.
R
R
p-TsOH, NaNO2
NH2
OTs
water paste, rt
N
N
1-11
1a-11a
⇑
Corresponding author. Tel./fax: +7 3822 563 637.
E-mail address: filimonov@tpu.ru (V.D. Filimonov).
Scheme 1. One-pot transformation of aminopyridines 1–11 in pyridinyl tosylates
1a–11a.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.163

86
A. N. Tretyakov et al. / Tetrahedron Letters 52 (2011) 85–87
Table 1
hydroxypyridines were detected as side products. This contributed
to an overall decrease of products 1a–10a yields despite full con-
version of the starting compounds. Fortunately, hydroxypyridine
impurities were easily removed by washing the reaction mixtures
with aqueous sodium carbonate. Products 1a–10a, after simple
aqueous washing, had high GS–MS and NMR purity and did not
need any additional purification. It should be noted that conven-
tional tosylation of hydroxypyridines with p-toluenesulfonyl
chloride provides known pyridinyl tosylates 1a–3a in low to mod-
erate 55%, 75%, and 20% yields, respectively,4 and in 42% yield for
compound 3a in another example.5
The yield of 2,6-ditosyloxypyridine 11a was lower due to tar
formation during the diazotization. Attempts at selective tosyl-
oxy-dediazotization of only one amino group were not successful
leading to a mixture of starting diamine 11 and pyridinyl tosylate
11a being obtained.
Syntheses of pyridinyl tosylates 1a–11a by diazotization of aminopyridines 1–11 in a
water paste at room temperature (substrate/NaNO2/PTSA, 1:2:3)
Entry
1
Product
Time (h)
3.5
Isolated yield (%)
52
N
OTs
OTs
1a
2a
2
3
1.0
1.0
50
80
N
OTs
N
3a
Br
In general, we did not observe any clear correlation between
reaction time or electronic and steric effects of substituents on
the pyridine ring and the product yields. This situation is rather
common for the diazotization–dediazotization reactions of aro-
matic amines in which substituents may often produce opposite
effects at different stages of the reaction mechanism.11 However,
aminopyridines bearing strong electron-withdrawing groups such
as nitro (e.g., in 2-amino-5-nitropyridine and 3-amino-2-nitropyr-
idine) could not be diazotizated with NaNO2 in water paste. Thus,
the diazotization/tosylation presented is general for aminopyri-
dines bearing moderate electron-donating and withdrawing
substituents.
In summary, we have described a new method for the direct
transformation of aminopyridines into the corresponding pyridinyl
tosylates by diazotization of aminopyridines with sodium nitrite
and PTSA in a water paste at room temperature. The advantages of
this approach are operating simplicity and an aqueous reaction
medium. The yields of the pyridinyl tosylates were comparable with
those obtained using classic procedures (tosylation of hydroxypyri-
dines with p-toluenesulfonyl chloride in organic solvents).
4
5
6
7
2.5
4.5
1.5
1.0
79
69
66
55
N
OTs
4a
I
N
OTs
5a
Br
Br
N
OTs
6a
CH3
N
OTs
7a
CH3
8
9
1.0
55
47
N
OTs
N
8a
12
H3C
OTs
Acknowledgments
9a
CH3
The work was supported by the Russian Foundation for Basic
Research (project no. 09-03-99019). The authors are grateful to
Dr. Nick Moskalev for constructive criticism and useful remarks.
I
10
11
10
75
20
N
OTs
10a
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 doi:10.1016/
j.tetlet.2010.10.163.
2.0
TsO
N
OTs
11a
needed for the conversion to occur. We found that either increas-
ing or decreasing the optimal 1:3 substrate to PTSA molar ratio
led to a decrease in the product yields. For example, the use of
either 1:1 or 1:5 ratios of 2 to PTSA led to a lower yield of
pyridin-3-yl tosylate (2a). The amount of water present in the reac-
tion mixture was very important for successful diazotization/tosy-
lation. Diazotization of aminopyridines 1–11 in aqueous solutions
in the presence of PTSA led predominantely to the corresponding
hydroxypyridines, whereas pyridinyl tosylates 1a–11a were
formed only in trace quantities. In the absence of water, diazotiza-
tion of aminopyridines 1–11 and formation of products 1a–11a
did not occur at all. An increase to 0.1–0.15 mL (5–8 mmol) of
water was not enough to provide full conversion of the aminopyri-
dines. Use of 0.5 mL (30 mmol) of water per 2 mmol of substrate
led to predominant formation of the corresponding pyridinyl
tosylates. However, even when using the given conditions,
References and notes
1. (a) Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531; (b) Tang, Z.-Y.;
Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058; (c) Zim, D.; Lando, V. R.; Dupont, J.;
Monteiro, A. L. Org. Lett. 2001, 3, 3049; (d) Huang, X.; Anderson, K. W.; Zim, D.;
Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653; (e) Tang,
Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron Lett. 2006, 47, 2427; (f) Limmert, M. E.;
Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364; (g) Furstner, A.; Leitner, A.;
Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856; (h) Ogata, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 13848; (i) Pschierer, J.; Plenio, H. Eur. J.
Org. Chem. 2010, 2934.
2. Lin, W.; Chen, L.; Knochel, P. Tetrahedron 2007, 63, 2787.
3. Meshram, H. M.; Madhavi, A. V.; Eeshwaraiah, B.; Reddy, P. N.; Nageswar, Y.;
Rao, V. D.; Yadav, J. S. J. Mol. Catal. A 2007, 272, 57.
4. Cavallito, C. J.; Haskell, T. H. J. Am. Chem. Soc. 1944, 66, 1927.
5. Del Giudice, M. R.; Settimj, G.; Delfini, M. Tetrahedron 1984, 40, 4067.
6. Krasnokutskaya, E. A.; Filimonov, V. D.; Knochel, P.; Semenischeva, N. I.
Synthesis 2007, 81.
7. Gorluschko, D. A.; Filimonov, V. D.; Krasnokutskaya, E. A.; Semenischeva, N. I.;
Go, B. S.; Hwang, H. Y.; Cha, E. H.; Chi, K.-W. Tetrahedron Lett. 2008, 49, 1080.

A. N. Tretyakov et al. / Tetrahedron Letters 52 (2011) 85–87
87
8. Filimonov, V. D.; Trusova, M. E.; Krasnokutskaya, E. A.; Postnikov, P. S.; Lee, Y.
M.; Hwang, H. Y.; Kim, H.; Chi, K.-W. Org. Lett. 2008, 10, 3961.
9. Butler, R. N. Chem. Rev. 1974, 75, 241.
10. 3,5-Dibromopyridin-2-yl 4-methylbenzenesulfonate (6a). Yield 66%, mp 98–
99 °C. 1H NMR (300 MHz, CDCl3): d 2.5 (s, 3H), 7.4 (d, J = 7.5, 2H), 7.9 (d,
J = 7.8, 2H), 8.1 (s, 1H), 8.2 (s, 1H). 13C NMR (75 MHz, CDCl3): d 21.8, 112.1,
118.0, 128.9, 129.8, 133.7, 145.3, 145.8, 147.3, 153.2. MS m/z: 407 (1, M+), 343
(45), 262 (2), 124 (5), 194 (4), 155 (38), 121 (5), 91 (100), 77 (3), 65 (21), 51 (3),
39 (4). Anal. Calcd for C12H9Br2NO3S: C, 35.41; H, 2.23; Br, 39.26; N, 3.44.
Found: C, 35.04; H, 2.34; Br, 39.52; N, 3.38.
A typical experimental procedure is as follows: A mixture of an aminopyridine
(2 mmol), PTSA (1.14 g, 6 mmol), and H2O (0.5 mL, 30 mmol) was ground for 3–
5 min in an agate mortar until a homogeneous paste formed. Next, NaNO2
(0.28 g, 4 mmol) was added and the mixture was ground for 5 min and then
left in the open air for 1–4.5 h with grinding every 15–20 min. With longer
reaction times, partial drying of the H2O pastes occurred, so to compensate,
0.1–0.2 mL of H2O was added. The crude pastes were treated with 20 mL of 3%
aqueous Na2CO3, and the solid products 2a–11a were filtered, washed with
H2O, and dried. Compound 11a was additionally purified by recrystallization
from hexane. Liquid product 1a was extracted with CH2Cl2 (3 Â 15 mL), the
extract dried over Na2SO4, and the solvent evaporated in vacuum.
CAUTION! Although arenediazonium tosylate salts are stable in the dry
state,8 the operation needs to be conducted carefully. Diazonium salts may
decompose violently upon heating.
Pyridin-2,6-diyl bis(4-methylbenzenesulfonate) (11a). Yield 20%, mp 81–82 °C
(hexane). 1H NMR (300 MHz, CDCl3): d 2.5 (s, 6H), 7.0 (d, J = 7.8 Hz, 2H), 7.3 (d,
J = 8.1 Hz, 4H), 7.8 (m, 5H). 13C NMR (75 MHz, CDCl3): d 21.7, 114.2, 128.7,
129.8, 133.1, 143.4, 145.6, 154.8. MS m/z: 355 (6, M+ÀSO2), 327 (2), 291 (3),
274 (2), 263 (2), 200 (25), 184 (3), 165 (2), 155 (59), 139 (5), 129 (1), 107 (2), 91
(100), 77 (2), 65 (16), 39 (5). Anal. Calcd for C19H17NO6S2: C, 54.40; H, 4.08; N,
3.34. Found: C, 54.60; H, 3.97; N, 3.50.
11. Zollinger, H. Diazo Chemistry I: Aromatic and Heteroaromatic Compounds; VCH:
Weinheim, 1994.