2,6-Diamination of substituted pyridines via heterogeneous Chichibabin reaction

Article abstract of DOI:10.1016/j.tetlet.2015.12.013

A series of ring substituted pyridines were selected for the sodium amide initiated heterogeneous Chichibabin amination to obtain 2,6-diaminopyridine derivatives which are important synthons for the preparation of PNP pincer ligands. The substrates were treated with an excess of sodium amide in neat mineral oil as solvent under an argon atmosphere. The reaction required temperatures of up to 215°C under vigorous stirring with an overall reaction time of 3-5 h. In the case of methyl, tert-butyl, phenyl, pyridinyl, and hydroxyl substituted pyridines the desired products were obtained in good to excellent yields (63-96%). Thus, the Chichibabin reaction provides an inexpensive and economic alternative to methodologies starting from halopyridines or pyridine N-oxides provided that the substituents are inert under the harsh reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.12.013

Accepted Manuscript
2,6-Diamination of Substituted Pyridines via Heterogeneous Chichibabin Re-
action
Matthias Mastalir, Ernst Pittenauer, Günter Allmaier, Karl Kirchner
PII:
S0040-4039(15)30428-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.013
TETL 47060
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2015
27 November 2015
2 December 2015
Please cite this article as: Mastalir, M., Pittenauer, E., Allmaier, G., Kirchner, K., 2,6-Diamination of Substituted
Pyridines via Heterogeneous Chichibabin Reaction, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.12.013
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1
2,6-Diamination of Substituted Pyridines via Heterogeneous
Chichibabin Reaction
Matthias Mastalir,a Ernst Pittenauer,b Günter Allmaier,b Karl Kirchner*,a
a
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163,
1060 Vienna, Austria
b Institute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9,
A-1060 Vienna, AUSTRIA
Abstract
A series of ring substituted pyridines was selected for the sodium amide initiated heterogeneous
Chihibabin amination to obtain 2,6-diaminopyridine derivatives which are important synthons for the
preparation of PNP pincer ligands. The substrates were treated with an excess of sodium amide in
neat mineral oil as solvent under an argon atmosphere. The reaction required temperatures of up to
215oC under vigorous stirring with an overall reaction time of 3-5 h. In the case of methyl, tert-butyl,
phenyl, pyridinyl, and hydroxyl substituted pyridines the desired products were obtained in good to
excellent yields (63-96%). Thus, the Chichibabin reaction provides an inexpensive and economic
alternative to methodologies starting from halo pyridines or pyridine N-oxides provided that the
substituents are inert under the harsh reaction conditions.
Keywords: Amination, 2,6-diaminopyridines, heterocycles, Chichibabin reaction
________________
* Corresponding author. Tel.: +43 1 58801 163611; Fax.: +43 1 58801 16299; E-mail:
kkirch@mail.tuwien.ac.at (Karl Kirchner)

2
1. Introduction
Ring-substituted 2,6-diaminopyridines are an important class of heterocycles which are useful building
blocks for macrocycles, polymers, agrochemicals, dyes, and pharmacologically potent
molecules.1,2,3,4,5,6 Furthermore 2,6-diaminopyridines are valuable scaffolds for the design of tridentate
ligands in coordination and organometallic chemistry. We are particularly interested in using ring-
substituted 2,6-diaminopyridines as building blocks for new tridentate PNP ligands, so called pincer
ligands, which are typically obtained according to Scheme 1.7
Scheme 1 Synthesis of PNP pincer ligands based on the 2,6-diaminopyridine scaffold
Since 2,6-diaminopyridine is the only commercially available and convenient precursor, we sought a
new efficient general synthetic route to obtain ring substituted 2,6-diaminoyridines. For this purpose,
we selected the sodium amide initiated amination of pyridine, known as the Chichibabin reaction.8 A
DFT calculated mechanism of the Chichibabin reaction was recently reported.9 This method is very
useful for the preparation of 2-aminopyridine and parent 2,6-diaminopyridine by the reaction of
pyridine with sodium amide under heterogeneous conditions, but was hardly applied to ring-
substituted pyridines. A rare example of a 2,6-diamination under Chichibabin conditions was reported
recently by Kempe and co-workers who prepared 4-methylpyridine-2,6-diamine from 4-metylpyridine
albeit in only 22% yield.10 It has to be emphasized that the Chichibabin reaction provides an
inexpensive and economic alternative to methodologies starting from halo pyridines via nucleophilic
substitutions catalysed by copper, copper salts or proline,11,12,13,14 and Buchwald-Hartwig
aminations,15,16,17,18,19 or pyridine N-oxides.20 Moreover, this reaction allows the synthesis of
unsymmetrically alkylated diaminopyridines which are otherwise difficult to prepare.21
2,6-Diamino-4-methylpyridin
2. Results and discussion
A series of substituted pyridines were treated with an excess (3-6-equivs) of sodium amide in mineral
oil (white oil, liquid paraffin) as solvent under an argon atmosphere. It has to be noted that Bojarska-
Dahlig reported the use of Vaseline as solvent,22 while Banerjee recently significantly improved and
optimized the heterogeneous Chichibabin reaction by using mineral oil as reaction medium.23 Running
the reactions in neat N,N-dimethylaniline improved the solubility of the reactants and increased the
reaction rates, but due the toxicity of this solvent as well as its high polarity, workup to obtain pure
products turned out to be difficult and was thus not further used. Additives (10%) such as n-
dodecylamine, and n-tributylamine showed no appreciable effects as reaction rates and yields are

3
concerned. Moreover, it is important to mention that with the solvents N,N-dimethylaniline, decalin, or
tetralin the required high temperatures are not obtained resulting in lower yields.9,24 Accordingly, neat
mineral oil was used as reaction medium throughout where reaction temperatures of 215oC were
easily reached. An overview of all substrates tested is given in Scheme 2. However, only in the case of
methyl, tert-butyl, phenyl, pyridinyl, and hydroxyl substituted pyridines the desired products were
obtained (Table 1). The reaction mixture was typically heated stepwise from 120 up to 215oC under
vigorous stirring with an overall reaction time of 3-5 h. Higher temperatures and/or longer
Scheme 2 Overview of ring-substituted pyridines tested in the heterogeneous Chichibabin reaction
reaction times did not result in higher yields rather than partial decomposition of the products. A color
change from orange to brown to black was observed in all reactions. The evolution of hydrogen gas
indicated the beginning of the reaction at about 120oC due to the formation 2-aminopyridines. At about
o
180oC the second amination step was initiated which, after 3h additional heating at 215 C, led to
formation of the 2,6-diaminopyridines (1-9) and 6-aminopyridine-2(1H)-one (10) (Table 1). It has to be
noted that 1 was also obtained with 4-methylpyridine-2-amine (Table 1, entry 2). All these compounds
were obtained in good to excellent isolated yields. 4-Hydroxy-pyridine-2,6-diamine (9) was first
isolated from the reaction mixture as its nitrate salt 8 (Table 1, entry 9) which is sparingly water
soluble. Isolation of free 9 was carried out by treating the nitrate salt with potassium hydroxide and
was obtained in 96% isolated yield. Arienzo25 and Kilburn26 described an alternative procedure to
obtain 9 via a Hofmann or Curtius rearrangement using chelidamic acid as precursor. Bojarska-Dahlig
and Banerjee also used the Chichibabin reaction for the synthesis of 9 utilizing a slightly different
procedure.2,5 Compound 10 was prepared recently via deamination of 2,6-diaminopyridine in
concentrated hydrochloric acid with 83 % isolated yield.27 This emphasizes the advantage of the

4
Chichibabin reaction reported here in comparison to alternative procedures for the synthesis of 9 and
10.
For the Chichibabin reaction, the optimal pKa range of pyridines is believed to be in the range
of 5-8 and it was postulated that outside this range no reaction takes place. However, also 2-
hydroxypyridine/2-pyridinone and 4-hydroxypyridine/4-pyridinone with pKa values of 11.7/1.3 and
11.1/3.1, respectively, reacted readily with sodium amide to yield 8 and 10 (Table 1, entries 9 and 10).
All compounds were fully characterized by their melting points, HRMS, 1H and 13C{1H} NMR
spectroscopy (see supporting information).
Finally, under the standard reaction conditions all other substrates used (Scheme 2) did not
afford the desired 2,6-diaminopyridines. For instance, pyridines featuring -COOH, -CONH2 and -
CON(CH3)2 substituents in the 3- and 4-position were decarboxylated yielding parent 2,6-
diaminopyridine. For comparison, McGill and co-workers reported the conversion of nicotinic acid to 6-
amino-nicotinic acid at lower temperature (122°-145° C) and 360 psi albeit in low yields (26 %).28
Likewise, all other 3- and -4-substituted pyridines did not react at all or underwent elimination and
polymerization reactions yielding intractable material which could not be characterized. Moreover,
while pyridines with methyl and tert-butyl substituents (Table 1, entries 1-5) reacted cleanly to afford
2,6-diaminopyridines, 4-ethylpyridine and 4-benzylpyridine formed 4-vinylpyridine and intractable
polymeric materials, respectively. Accordingly, for these type of 2,6-diamonopyridines different
methodologies have to be used.29
3. Conclusion
A series of substituted pyridines was selected for the sodium amide initiated heterogeneous
Chihibabin amination to obtain 2,6-diaminopyridine derivatives. The substrates were treated with an
excess of sodium amide in neat mineral oil as solvent under an argon atmosphere. The reaction
required temperatures of up to 215oC under vigorous stirring with an overall reaction time of 3-5 h. In
the case of methyl, tert-butyl, phenyl, pyridinyl, and hydroxyl substituted pyridines the desired products
were obtained in good to excellent yields. All other 3- and -4-substituted pyridines featuring, for
instance COOH, -CONH2 and -CON(CH3)2, -NH2, -NMe2, -SH, benzyl, and ethyl substituents,
underwent uncontrolled elimination and polymerization reactions to yield intractable materials. The
Chichibabin reaction provides an inexpensive and atom economic alternative to methodologies
starting from halo pyridines or pyridine N-oxides provided that the substituents are inert under the
harsh reaction conditions.
Acknowledgments
Financial support by the Austrian Science Fund (FWF) (Project No. P24202-N17) is gratefully
acknowledged.
Supplementary data
Supplementary data (detailed experimental procedures and NMR data for all compounds) associated
with this article can be found, in the online version, at http://xxxxxxxxxxxxxxxxx

5
Table 1. Synthesis of 2,6-diaminopyridines and 6-aminopyridine-2(1H)-one
Entry
1
Reactant
Product
Yield [%]
66
2
3
4
5
6
76
84
83
85
83
7
8
73
63
9
77
83
10

6
TOC
2,6-Diamination of Substituted Pyridines via Heterogeneous Chichibabin
Reaction
A series of methyl, tert-butyl, phenyl, pyridinyl, and hydroxyl substituted 2,6-diaminopyridines is
prepared via the heterogeneous Chichibabin amination in neat mineral oil at temperatures up to 215oC
with an overall reaction time of 3-5 h.

7
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