A new versatile synthesis of 4-substituted diaminopyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.089

A new convenient method for the synthesis of substituted 2,6-diacetamido pyridines has been developed. It starts from 4-hydroxypyridine and comprises the introduction of the amino groups by the Chichibabin reaction. After several protection and deprotection steps 2,6-diacetamido-4-hydroxy pyridine is obtained, which is regarded as a key compound for the synthesis of various substituted 2,6-diacetamido pyridines. It is shown that the free hydroxy group is susceptible for nucleophilic substitution. This provides an easy access to the introduction of different functional groups at 4-position of 2,6-diacetamido pyridine. The advantages over other procedures described in the literature are discussed.

Full text of DOI:10.1016/j.tetlet.2012.02.089

Tetrahedron Letters 53 (2012) 2236–2238
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Tetrahedron Letters
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A new versatile synthesis of 4-substituted diaminopyridine derivatives
Sumela Banerjee a, Brigitte Voit a, Gert Heinrich a,b, Frank Böhme a,
⇑
a Leibniz Institute of Polymer Research Dresden, Hohe Straße 6, Dresden, Germany
b Technische Universität Dresden, Institut für Werkstoffwissenschaft, D-01069 Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A new convenient method for the synthesis of substituted 2,6-diacetamido pyridines has been developed.
It starts from 4-hydroxypyridine and comprises the introduction of the amino groups by the Chichibabin
reaction. After several protection and deprotection steps 2,6-diacetamido-4-hydroxy pyridine is
obtained, which is regarded as a key compound for the synthesis of various substituted 2,6-diacetamido
pyridines. It is shown that the free hydroxy group is susceptible for nucleophilic substitution. This pro-
vides an easy access to the introduction of different functional groups at 4-position of 2,6-diacetamido
pyridine. The advantages over other procedures described in the literature are discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 January 2012
Revised 13 February 2012
Accepted 17 February 2012
Available online 24 February 2012
Keywords:
Substituted diaminopyridine
Chichibabin reaction
Nucleophilic substitution
Heterocyclic compounds
Pyridine derivatives are an essential class of azaheterocycles
found in many natural products, active pharmaceuticals, and
functional materials. Beside its well known applications in the
pharmaceutical industry, nowadays substituted pyridines espe-
cially 2,6-diaminopyridine are widely used as key compounds for
the preparation of different supramolecular assemblies. A very
important one is 4-hydroxy-2,6-diaminopyridine which can be
used to make versatile building blocks in supramolecular networks
by incorporating long chains at 4-position having different end
groups.1–6 Consequently, it is not surprising that many successful
synthesis routes toward 4-substituted-2,6-diaminopyridine have
been developed.
The most popular of them involves the Curtius rearrangement
which was reported by Markees and Kidder in 1956.7 Later on, in
2001 Arienzo and Kilburn described a procedure which utilizes
the Hofmann rearrangement.8 Both procedures start from chelida-
mic acid or esters thereof and aim at introducing desired substitu-
ents on the oxygen in 4-position first. After this the amino groups
are introduced by the Curtius or the Hoffmann rearrangement as
depicted in a very simplified manner in Scheme 1.
comprises the introduction of the amino groups first followed by
the introduction of the substituent in the last step. In the proce-
dure described by Arienzo and Kilburn,8 the primary substituent
(R2 = benzyl ether) is removed by hydrogenolysis so that the
deprotected OH group in 4-position is available for further conver-
sions with various substituents. This is an essential advantage
compared to the procedure of Markees and Kidder,7 however, still
demands several steps to achieve the targeted products.
We are interested in using substituted 2,6-diacetamidopyri-
dines as building blocks for polymers with self-healing character-
istics. Therefore, we looked for a more effective synthetic route
for this important component. This study describes a procedure
which starts form 4-hydroxy-2,6-diaminopyridine which is easily
available by conversion of 4-hydroxy pyridine with sodium amide
according to Chichibabin. The amination of pyridine derivatives
with sodium amide was reported first by Chichibabin and Seide
in 1914.9 Since then, it has been recognized as one of the most
important and influential developments in pyridine chemistry. In
1955, Bojarska-Dahlig and Nantka-Namirski reported the Chichi-
babin reaction on 4-hydroxy pyridine to achieve 4-hydroxy-2,6-
diaminopyridine.10 Since then no attempt was reported on this
specific reaction.
We synthesized 4-hydroxy-2,6-diaminopyridine (3) by conver-
sion of 4-hydroxy pyridine (1) with sodium amide (Scheme 2)
slightly modified according to the procedure described by
Bojarska-Dahlig and Nantka-Namirski.10 Liquid paraffin was used
as solvent instead of paraffin wax, which makes the solvent handling
more easy. The reaction mixture was heated stepwise from 180 to
230 °C up to 250 °C under nitrogen atmosphere. The evolution of
hydrogen and ammonia gas indicated the beginning of the reaction.
Here, a subsequent color change from orange to brown to black was
Disadvantage of these approaches is the early introduction of
the substituent R2. This may complicate further steps, especially
if the substituent contains other reactive or functional groups. Fur-
thermore, if the preparation of differently substituted 2,6-diamino-
pyridine derivatives is intended, the whole procedure has to be
repeated each time again from the beginning which is very time
consuming. Much more advantageous is an approach which
⇑
Corresponding author.
E-mail address: Boehme@ipfdd.de (F. Böhme).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.089

S. Banerjee et al. / Tetrahedron Letters 53 (2012) 2236–2238
2237
OR2
N
OH
N
OR2
Curtius
Hoffmann
H2N
NH2
R1OOC
COOR1
R1OOC
N
COOR1
Scheme 1. Conventional preparation of substituted diamino pyridines.
OH
OH
OH
1. NaNH2 Liq. paraffin
NaHCO3
250 °C,12 h
2. conc. HNO3, 70%
hot water,88%
N+
H
NH2
N
H2N
H2N
N
NH2
-
NO3
2
3
1
Scheme 2. Chichibabin reaction of 4-hydroxy pyridine followed by neutralization.11,12
observed. After 12 h heating, diamino substitution was obtained
with more than 70% yield.11
hydrochloride.15 Generally, it was found that higher acidity
containing functional groups are preferentially tert-butoxy
carboxylated.15 The high selectivity during Boc-protection of com-
pound 3 can be explained by the strong electron withdrawing effect
of the three nitrogen atoms resulting in an increased acidity of the
OH group.
In the next step, compound 4 was reacted with acetyl chloride
in the presence of triethylamine in dichloromethane to obtain acet-
amide 5 in 89% yields.16 Finally, deprotection of 5 using TFA in
DCM followed by neutralization gave compound 6 almost quanti-
tatively (Scheme 3).17
Compound 6 with a free OH group and two protected amino
groups is the key compound for the synthesis of various
substituted diacetamidopyridines. Substitution can easily be per-
formed by conversion of the alkali salt of 6 with alkyl halides.
The following two examples demonstrate the synthesis of substi-
tuted diacetamidopyridines with additional protected amino and
thiol groups, respectively (see Scheme 4).
2,6-Diamino-4-hydroxypyridine was isolated from the post
reaction mixture as its nitrate salt (2) which is sparingly water
soluble. Isolation of the free amine (3) was carried out by treating
the nitrate salt with sodium bicarbonate. The brown solid obtained
was crystallized from water and in this step the yield was about
88%. Finally, the structure of 3 was confirmed by 1H and 13C
NMR spectroscopy.12
In order to introduce active substituents in 4-position, protec-
tion of the amino groups was required. For this reason, compound
3 was converted with di-tert-butyl dicarbonate (Boc-protection)
in THF with a slight heat up to 50 °C. Surprisingly, this reaction
provided the hydroxyl protected compound 4 with more than
86% yield.13 In the case of 4-amino phenol, high selectivity was
observed with respect to the carboxylation of the amino groups,
while in the presence of NaOH the oxygen was converted
preferably.14 The same applies to the conversion of 4-amino phenol
O
O
OH
O
N
O
O
O
TFA , DCM
(BOC)2O
AcCl
O
O
O
O
Et3N, DCM, 89%
3
NaHCO3 , 90 %
THF, 86%
N
H
N
N
H
H2N
NH2
N
H
N
N
H
4
5
6
Scheme 3. Synthesis of 2,6- diacetamido-4-hydroxy pyridine as its TFA salt.13,16,17
R
O
K2CO3, DMF
7a/8a:
7b/8b:
R =
R =
S
C
O
CH3
R
6
+
Cl
H
N
110°C, 18 hr, 70-76%
O
O
C
O
7
O
N
H
N
N
H
8
Scheme 4. Conversion of 2,6-diacetamido-4-hydroxy pyridine with functional alkyl halides.20,21

2238
S. Banerjee et al. / Tetrahedron Letters 53 (2012) 2236–2238
compound 4 (6.1 g, 86.32%) as a yellow oil. 1H NMR (500 MHz, DMSO-d6):
For the preparation of 8a and 8b, S-(6-chlorohexyl) ethanethio-
d = 5.54 (s, 4H), 5.43 (s, 2H), 1.47 ppm (s, 9H); 13C NMR (125 MHz, DMSO-d6):
d = 160.1, 159.8, 150.5, 87.6, 83.0, 27.2 ppm.
ate (7a) and tert-butyl 6-chlorohexylcarbamate (7b) were synthe-
sized according to the literature.18,19 The conversions of 6 with
7a and 7b, respectively, were carried out for 18 h with a strong
heating up to 110 °C in the presence of an excess of K2CO3 using
DMF as solvent. After purification, solid products were obtained
in both cases with more than 70% yields.20,21 Compounds 8a and
8b can be regarded as potential building blocks for supramolecular
assemblies which after deprotection of the thiol and amino groups,
respectively, are available for surface modifications, polymer anal-
ogous reactions etc.
14. Houlihan, F.; Bouchard, F.; Frechet, J. M. J.; Willson, C. G. Can. J. Chem. 1985, 63,
153.
15. Saito, Y.; Ouchi, H.; Takahata, H. Tetrahedron 2006, 62, 11599–11607.
16. tert-Butyl (2,6-diacetamidopyridine-4-yl) carbonate (5): To a solution of 4 (6.3 g,
27.91 mmol) in 80 mL of CH2Cl2, triethyl amine (7.79 mL) and acetyl chloride
(3.97 mL, 55.92 mmol) were added sequentially at room temperature. The
reaction mixture was stirred at room temperature for 1 h under nitrogen
atmosphere. The crude was directly purified by column chromatography
(EtOAc/hexanes = 1/1) using silica gel without any workup to give 5 (7.72 g,
89.24%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6): d = 10.23 (s, 2H),
7.59 (s, 2H), 2.11 (s, 6H), 1.50 ppm (s, 9H); 13C NMR (125 MHz, DMSO-d6):
d = 169.6, 159.6, 151.5, 149.7, 101.5, 84.2, 27.1, 24.0 ppm.
The advantage of the procedure described here is its versatility.
With the preparation of compound 6, a key compound is provided
which serves as a starting material for various reactive or nonreac-
tive substituted 2,6-diacetamidopyridines for various applications.
This is an essential advantage compared to the procedures which
start form chelidamic acid where the substituents are introduced
prior to the amino groups.
17. 2,6-Diacetamido-4-hydroxy pyridine (6): To
a stirred solution of 5 (5.0 g,
16.16 mmol) in 40 mL of CH2Cl2, trifluoroacetic acid was added slowly at
0 °C. The reaction mixture was stirred for 3 h at room temperature under
drying condition. The excess of solvent was removed under reduced pressure.
The crude product was neutralized with a saturated NaHCO3 solution. The
whole aqueous part was evaporated and the solid obtained was stirred in
70 mL of methanol for 1 h. The solution was filtered and the filtrate was dried
over Na2SO4 and concentrated to give compound 6 (3.05 g, 90.23%) as an off
white solid. 1H NMR (500 MHz, DMSO-d6): d = 10.48 (s, 1H), 9.78 (s, 2H), 7.24
(s, 2H), 2.07 ppm (s, 6H); 13C NMR (125 MHz, DMSO-d6): d = 169.1, 166.5,
151.2, 96.7, 24.0 ppm.
Acknowledgment
18. (a) Zheng, T. C.; Burkart, M.; Richardson, D. E. Tetrahedron Lett. 1999, 40, 603–
606
The authors wish to thank the Deutsche Forschungsgemeins-
chaft (DFG) for the proposal grant in the Priority Program
(Schwerpunktprogramm, SPP 1568) ‘Design and Generic Principles
of Self-Healing Materials’.
(b) S-(6-Chlorohexyl) ethanethioate (7a): A mixture of 1-chloro-6-iodohexane
(5.0 g, 20.24 mmol), 10 mL of acetone, and potassium thioacetate (2.31 g,
20.24 mmol) was stirred at room temperature for 20 h under nitrogen
atmosphere. The excess of acetone was removed and the crude product was
diluted with water and extracted three times with CH2Cl2. The combined
organic layers were dried over Na2SO4 and concentrated to give 7a (3.74 g, 95%
yield) as a white solid. 1H NMR (500 MHz, CDCl3): d = 3.46 (t, J = 6.6 Hz, 2H),
2.80 (t, J = 7.4 Hz, 2H), 2.25 (s, 3H), 1.70 (m, 2H), 1,52 (m, 2H), 1.40–1.30 ppm
(m, 4H); 13C NMR (125 MHz, CDCl3): d = 195.8, 44.9, 32.4, 30.6, 29.3, 28.9, 28.0,
26.3 ppm.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.089. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
19. (a) Hallett, A. J.; Christian, P.; Jones, J. E.; Pope, S. J. A. Chem. Commun. 2009,
4278–4280
(b) tert-Butyl 6-chlorohexylcarbamate (7b): To
a stirred solution of 6-
aminohexan-1-ol (3.0 g, 25.59 mmol) in 4 mL of chloroform thionyl chloride
was added (1.98 mL, 25.59 mmol) at 0 °C. The reaction mixture was stirred for
3 h under dry conditions. The excess of solvent was removed by distillation.
The crude product was triturated with ether. After this a brown solid was
obtained which was identified as hydrochloride of 6-chlorohexan-1-amine (9)
(4.08 g, 93% yield). 1H NMR (500 MHz, DMSO-d6): d = 8.21 (s, 3H), 3.47 (t,
J = 6.5 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.77–1.70 (m, 4H), 1.46-1.36 ppm (m,
4H); 13C NMR (125 MHz, DMSO-d6): d = 45.2, 38.5, 31.8, 26.7, 25.8, 25.0 ppm.
To a solution of 9 (0.5 g, 2.96 mmol) in 5 mL of THF and 3 mL of methanol,
triethylamine (0.41 mL, 2.96 mmol) and di-tert-butyl dicarbonate (0.63 g,
2.96 mmol) were added at room temperature. The reaction mixture was
carried out at 40 °C for 3 h under dry conditions. After the mixture was cooled
to room temperature, the excess of THF and methanol was removed under
reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and
washed with water and brine. The organic phase was dried over Na2SO4 and
concentrated to give compound 7b (0.663 g, 83.33%) as light yellow oil. 1H
NMR (500 MHz, CDCl3): d = 4.44 (br, 1H), 3.46 (t, J=6.7 Hz, 2H), 3,05 (m, 2H),
1.70 (m, 2H), 1.45-1.35 (m, 4H), 1.37 (s, 9H), 1.30–1.25 (m, 2H); 13C NMR
(125 MHz, CDCl3): d = 155.3, 77.2, 59.6, 45.2, 31.9, 28.2, 25.9, 25.4 ppm
References and notes
1. Fullam, S.; Rao, S. N.; Fitzmaurice, D. J. Phys. Chem. 2000, 104, 6164–6173.
2. Salameh, A. S.; Ghadder, T.; Isied, S. S. J. Phys. Org. Chem. 1999, 12, 247–254.
3. Moraczewski, A. L.; Banaszynski, L. A.; From, A. M.; White, C. E.; Smith, B. D. J.
Org. Chem. 1998, 63, 7258–7262.
4. Deetz, M. J.; Jonas, M.; Malerich, J. P.; Smith, B. D. Supramol. Chem. 2002, 14,
487–489.
5. Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010–4011.
6. Feibush, B.; Figueroa, A.; Charles, R.; Onan, K. D.; Feibush, P.; Karger, B. L. J. Am.
Chem. Soc. 1986, 108, 3310–3318.
7. Markees, D. G.; Kidder, G. W. J. Am. Chem. Soc. 1956, 78, 4130–4135.
8. Arienzo, R.; Kilburn, J. D. Tetrahedron 2002, 58, 711–719.
9. Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc. 1914, 46, 1212.
10. Bojarska-Dahlig, H.; Nantka-Namirski, P. Rocz. Chem. (Pol. J. Chem.) 1955, 29,
1007–1017.
11. Nitrate salt of 4-hydroxy-2,6-diaminopyridine (2):
A mixture of 1 (10.0 g,
20. S-6-(2,6-Diacetamidopyridine-4-yloxy)hexyl ethanethioate (8a): To
a stirred
105.1 mmol), sodium amide (16.4 g, 420.6 mmol), and liquid paraffin (52 mL)
was heated stepwise from 180 to 250 °C under nitrogen atmosphere for 12 h.
Subsequent color change from orange to brown to black was observed. The
mixture was cooled in an ice bath. Water (100 mL) was added carefully to
quench the excess of sodium amide and it was stirred for 10 min. The paraffin
layer was separated and washed by water. The combined aqueous solutions
were acidified with concd HNO3. The black precipitate obtained was filtered off
and dried. Finally it was crystallized from hot water to give 2 as a deep brown
solid (13.72 g, 70% yield). 1H NMR (500 MHz, DMSO-d6): d = 11.34 (br, 1H),
11.22 (s, 1H), 6.84 (br, 4H), 5.40 ppm (s, 2H); 13C NMR (125 MHz, DMSO-d6):
d = 170.8, 153.2, 83.6 ppm.
solution of 6 (2.0 g, 9.56 mmol) in 15 mL of DMF, K2CO3 (5.29 g, 38.27 mmol)
and 7a (2.23 g, 11.47 mmol) were added at room temperature. The reaction
mixture was heated at 110 °C for 24 h under nitrogen atmosphere. After being
cooled to room temperature, the reaction mixture was diluted with 150 mL of
water and extracted thrice with EtOAc. The combined organic layers were
dried over Na2SO4, concentrated, and purified by column chromatography
(MeOH/EtOAc = 1/20) using silica gel to give 8a (2.66 g, 76% yield) as an off
white solid. 1H NMR (500 MHz, DMSO-d6): d = 9.92 (s, 2H), 7.36 (s, 2H), 3.97 (t,
J = 6.1 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.08 (s, 6H), 1.70 (m, 2H),
1.52 (m, 2H), 1.41–1.35 ppm (m, 4H), 13C NMR (125 MHz, DMSO-d6): d = 195.2,
169.3, 167.3, 151.4, 95.3, 67.5, 30.5, 28.9, 28.2, 28.1, 27.7, 24.8, 24.0 ppm.
12. 4-Hydroxy-2,6-diaminopyridine (3): To a solution of 2 (8.0 g, 42.06 mmol) in
100 mL of hot water, sodium bicarbonate (3.5 g) was added with slow stirring.
After cooling to room temperature, the precipitate was filtered off and washed
with a small amount of cold water. The substance was crystallized from water
to give 3 as brown crystals (5.4 g, 88% yield). 1H NMR (500 MHz, DMSO-d6):
d = 9.28 (br, 1H), 5.15 (s, 2H), 5.08 ppm (s, 4H); 13C NMR (125 MHz, DMSO-d6):
d = 166.8, 159.3, 84.0 ppm.
13. tert-Butyl (2,6-diaminopyridine-4-yl) carbonate (4): To a solution of 3 (4.0 g,
31.96 mmol) in 10 mL of THF and 10 mL of methanol, di-tert-butyl dicarbonate
(13.95 g, 63.92 mmol) was added at room temperature. The reaction mixture
was heated at 50 °C for 3 h. After the mixture was cooled to room temperature,
the excess of THF and methanol was removed under reduced pressure. The
residue was dissolved in ethyl acetate (100 mL) and washed with water and
brine. The organic phase was dried over Na2SO4 and concentrated to give
21. tert-Butyl (6-((2,6-diacetamidopyridine-4-yl)oxy)hexyl)carbamate (8b): To
a
stirred solution of (1.0 g, 3.10 mmol) in 15 mL of DMF, K2CO3 (1.71 g,
6
12.42 mmol) and 7b (0.8 g, 3.41 mmol) were added at room temperature. The
reaction mixture was heated at 110 °C for 24 h under nitrogen atmosphere.
After being cooled to room temperature, the reaction mixture was diluted with
150 mL of water and extracted thrice with EtOAc. The combined organic layers
were dried over Na2SO4, concentrated, and purified by column
chromatography (MeOH/EtOAc = 1/20) using silica gel to give 8b (0.89 g, 71%
yield) as an off white solid. 1H NMR (500 MHz, DMSO-d6): d = 9.91 (s, 2H), 7.36
(s, 2H), 6.71 (s, 1H), 3.97 (t, J = 6.3 Hz, 2H), 2.90 (m, 2H), 2.09 (s, 6H), 1.70 (m,
2H), 1.45-1.37 (m, 4H), 1.37 (s, 9H), 1.30 ppm (m, 2H), 13C NMR (125 MHz,
DMSO-d6): d = 169.3, 167.3, 151.4, 95.3, 67.5, 29.2, 28.3, 28.2, 25.9, 25.0,
24.0 ppm.