Synthesis of (E)-diethyl 6,6′-(diazene-1,2-diyl)bis(5-cyano-2-methyl- 4-phenylnicotinates), a new type of 2,2′-azopyridine dyes

Article abstract of DOI:10.1016/j.tetlet.2010.09.095

An unexpected, but simple method for the efficient synthesis of new 2.2′-azopyridine dyes, such as (E)-diethyl 6,6′-(diazene-1,2-diyl) bis(5-cyano-2-methyl-4-phenylnicotinates) (2, 4, 6, 8, 10, and 12), based on the treatment of ethyl 6-amino-5-cyano-2-methyl-4-arylnicotinates (1, 3, 5, 7, 9, and 11) with NBS/benzoyl peroxide, is described. The X-ray diffraction analysis and the UV-vis absorption spectra of dye 2 are reported and discussed.

Full text of DOI:10.1016/j.tetlet.2010.09.095

Tetrahedron Letters 51 (2010) 6278–6281
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (E)-diethyl 6,60-(diazene-1,2-diyl)bis(5-cyano-2-methyl-
4-phenylnicotinates), a new type of 2,20-azopyridine dyes
Daniel Botelho da Silva a,b, Abdelouahid Samadi a, Lourdes Infantes c, María do Carmo Carreiras b,
José Marco-Contelles a,
⇑
a Laboratorio de Radicales Libres y Química Computacional, IQOG (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain
b iMed.UL, Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Forças Armadas, 1600-083 Lisbon, Portugal
c Instituto de Química-Física ‘Rocasolano’, C/Serrano, 119, 28006-Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
An unexpected, but simple method for the efficient synthesis of new 2.20-azopyridine dyes, such as (E)-
diethyl 6,60-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates) (2, 4, 6, 8, 10, and 12), based
on the treatment of ethyl 6-amino-5-cyano-2-methyl-4-arylnicotinates (1, 3, 5, 7, 9, and 11) with NBS/
benzoyl peroxide, is described. The X-ray diffraction analysis and the UV–vis absorption spectra of dye
2 are reported and discussed.
Article history:
Received 22 July 2010
Revised 15 September 2010
Accepted 20 September 2010
Available online 15 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2.20-Azopyridine
Dyes
(E)-Diethyl 6,60-(diazene-1,2-diyl)bis(5-
cyano-2-methyl-4-phenylnicotinates)
Ethyl 6-amino-5-cyano-2-methyl-4-
arylnicotinates
NBS
Oxidation
Aromatic azo molecules have been traditionally used in dye and
food industries.1 Current synthetic methods for the synthesis of
azo compounds include either the oxidation of anilines, using per-
manganate,2 lead tetraacetate,2 or N-chloroacetanilide,3 and the
reduction of nitro aromatic derivatives by stoichiometric amounts
of metals.4 Symmetric aromatic azo compounds have been synthe-
sized by coupling aryl diazonium salts, prepared from anilines and
the toxic nitrous acid,5 with electron-rich substituted aromatic
derivatives.6 As a typical example, 2,20-azopyridine has been pre-
pared by oxidation of 2-aminopyridine with aqueous sodium
hypochlorite in 30% yield.7 In spite of this, no satisfactory method-
ologies in terms of experimental conditions and environmental
consequences are available. On the other hand, and from the per-
spective of green chemistry, new, more friendly and sustainable
chemical processes are mandatory. In this context, it has been
recently reported that gold nanoparticles on TiO2 (Au/TiO2) cata-
lyze the aerobic oxidation of aromatic anilines to aromatic azo
compounds in high yields and mild reaction conditions.8 Regarding
the possible applications, azobenzene derivatives have been used
for several switching processes in which chirality is critical9 and
for the stabilization of the helical structures.10 Similarly, the photo-
chemical E/Z isomerization of azobenzene derivatives has been
exploited extensively to modulate the conformational and biolog-
ical properties of folded peptides and helical polymers.11 In biol-
ogy, the introduction of azobenzene photo-switches has led to
the development of photocontrolled ion channels and enzymes.12
Congo red, for instance, the sodium salt of benzidinediazo-bis-1-
naphthylamine-4-sulfonic acid, due to its strong affinity for fibril-
lar amyloid proteins, is a paradigmatic marker used to examine
in vitro tissue sections for amyloid deposits.13 Finally, 2,20-azopyri-
dines are known to form a variety of dinuclear complexes showing
unusual electronic and structural features.14
In this Letter we report a new, simple, and efficient method for
the synthesis of 2,20-azopyridines from 2-aminopyridines, which
has been particularly useful for the synthesis of (E)-diethyl 6,60-
(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates). The
method is based on the unexpected reactivity of ethyl 6-amino-
5-cyano-2-methyl-4-arylnicotinates with N-bromosuccinimide
(NBS), in the presence of benzoyl peroxide.
In the course of a project in progress in our laboratory for the
synthesis of new multipotent drugs for the treatment of Alzhei-
mer0s disease,15 and when trying to prepare the bromomethyl
derivative of ethyl 6-amino-5-cyano-2-methyl-4-phenylnicotinate
(1),16a by typical free radical bromination conditions (NBS, benzoyl
peroxide), instead of the expected molecule, a new compound (2)
⇑
Corresponding author. Tel.: +34 91 5622900; fax: +34 91 5644853.
E-mail address: iqoc21@iqog.csic.es (J. Marco-Contelles).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.095

D. B. da Silva et al. / Tetrahedron Letters 51 (2010) 6278–6281
6279
NBS, (PhCO)2O2
CH3CN, reflux,
18-50 h
Ar
N
Ar
CN
N
N
EtO2C
CN
CO2Et
EtO2C
N
N
NC
Ar
NH2
1
3
5
7
2
4
6
Ar= C6H5
(79%)
(68%)
(74%)
Ar= p-ClC6H4
Ar= o-MeC6H4
Ar= 4'-pyridyl
8 (40%)
Scheme 1. Synthesis of (E)-diethyl 6,60-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates) 2, 4, 6, and 8.
Figure 1. X-ray molecular structure of the compound 2 showing the atomic numbering scheme. Ellipsoids are drawn at the 50% probability level for non-H atoms, and the H
atoms are denoted as spheres of 0.1 Å radius.
We have also measured the UV–vis absorption spectra of the azo
4.0
derivative 2 in acetone, at different concentrations (6.3 ꢀ 10ꢁ4
M–1.09 ꢀ 10ꢁ4 M). The absorption spectra of 2,20-azopyridine 2
0.7
3.5
6.30E-4 M
0.6
shows two bands, the first at 330 nm (strong) (emax = 10,613
4.22E-4 M
2.82E-4 M
1.88E-4 M
1,56E-4 M
1,30E-4 M
1.09E-4 M
Mꢁ1 cmꢁ1) and the second (weak) with a maximum intensity at
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0.5
0.4
0.3
0.2
0.1
0.0
470 nm (e
max = 986 Mꢁ1 cmꢁ1) (Fig. 2). UV–vis spectroscopic studies
were carried out also in other solvents.20 These spectra show bands
at 330 nm and at 470 nm with similar molar extinction coefficients
(e
max) at 470 nm.
This result was completely unexpected, as neither the bromo-
methyl derivative of compound 1 or brominated aromatic mole-
cules were detected or isolated. Instead, the 2,20-azopyridine 2
was formed in good yield, possibly by oxidation of the 2-aminopyr-
idine to the corresponding diazonium salt, followed by the reaction
with 1 equiv of the starting material, but we cannot exclude a free
radical mechanism2 involving a secondary aminyl radical (RNHÅ)
followed by dimerization and oxidation to give the azo derivative.
To check the generality of this reaction, a number of related pre-
cursors (3,16a 5,16b and 716c) have been synthesized and submitted
to the same experimental conditions, to give the azo compounds 4,
6, and 8, respectively, in moderate to good yields (Scheme 1). The
reaction was also possible in ethyl 6-amino-5-cyano-2-methyl-4-
(2-thienyl)nicotinate (9),19,16c but in this case, the resulting sym-
metric azo compound (10) (Scheme 2) was monobrominated at
the thiophene ring at C-50.17a,b This is also in good agreement with
the known tendency of thiophenes to undergo free radical substi-
tutions reactions at C-2.21 Next, and in order to simplify the struc-
ture of the precursor, we submitted compound 11,15 bearing no
aryl ring at C-4, to the same experimental conditions. We isolated
the expected azo compound 12 in 46% yield (Scheme 3).17a Next,
but as expected, due to the aromatic free available positions, the
reaction of the commercially available 2-amino-6-methylpyridine
(13) with NBS/benzoyl peroxide gave a complex reaction mixture
formed by polybrominated derivatives, where we were able to
400
450
500
550
600
650
300
400
500
600
700
800
Wavelength (nm)
Figure 2. UV–vis absorption spectra of 2,20-azopyridine 2 in acetone at different
concentrations.
(Scheme 1) was obtained in 79% yield, and isolated as a strong red
colored dye solid (‘MarcoRed’) whose structure was established by
inspection of its spectroscopic and analytical data.17a Final confir-
mation of this structure was obtained by X-ray diffraction analysis
(Fig. 1).
Molecules of compound 2 crystallize with an inversion center at
the middle point of the N@N azo bond. Therefore, the crystal shows
a half independent molecule. Primary distances and angles are nor-
mal compared with those in similar moieties contained in the
Cambridge Structural Database.18 The phenyl ring and the carbox-
ylate group are twisted 60° and 52° with respect to the pyridine
ring (Fig. 1).19

6280
D. B. da Silva et al. / Tetrahedron Letters 51 (2010) 6278–6281
Br
S
NBS, (PhCO)2O2
S
CN
N
CH3CN, reflux,
72.5 h
EtO2C
CN
N
CO2Et
EtO2C
N
N
N
NH2
NC
S
Br
9
10
(56%)
Scheme 2. Synthesis of (E)-diethyl 6,60-(diazene-1,2-diyl)bis(4-(5-bromothiophen-2-yl)-5-cyano-2-methylnicotinate) (10).
compounds, using NBS in the presence of benzoyl peroxide. The
NBS, (PhCO)2O2
CH3CN, reflux,
3-26 h
Y
N
present exploratory experiments suggest that the method is
general for a wide structural diversity of substrates, but point out
also that special requirements in the type and functionalization
of the precursors are mandatory. These conditions seem to be
particularly suitable for ethyl 6-amino-4-aryl-5-cyano-2-methyl-
nicotinates, a large number of useful and easily available mole-
cules,25 that have afforded a new type of 2,20-azopyridines, such
as (E)-diethyl 6,60-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phe-
nylnicotinates). These are new dyes of wide potential application
in different areas of interest, such as catalysis, biology, and new
materials. These issues are being currently investigated in our
laboratory and will be reported in due course.
X
Y
N
Y
X
N
N
N
NH2
X
11
12
X= CO2Et, Y= CN
(46%)
13 X, Y= H
14 X, Y= Br (8%)
Scheme 3. Synthesis of (E)-diethyl 6,60-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-
phenylnicotinates) 12 and 14.
R
NC
Cl
CN
CN
NH2
Acknowledgments
N
NH2
O
Daniel da Silva thanks the Fundação para a Ciência e Tecnologia
do Ministério da Ciência, Tecnologia e Ensino Superior of Portugal
for his grant belonging to project PTDC/SAU-NEU/64151/2006. A.S.
thanks the CSIC for a I3P post-doctoral contract. J.M.C. thanks also
the MICINN (SAF2006-08764-C02-01; SAF2009-07271), Comuni-
dad de Madrid (S/SAL-0275-2006), and the Instituto de Salud Car-
los III [Retic RENEVAS (RD06/0026/1002)] for support.
15
R= H
21
16 R= Ph
Figure 3. Structure of compounds 15, 16 and 21.
NC
CN
NC
CN
NH2
NBS, (PhCO)2O2
CH3CN, reflux, 1.5 h
N
N
Me
Supplementary data
N
N
N
Me
N
Me
N
N
Supplementary data (general methods and synthesis of com-
pounds 2, 4, 5, 6, 8, 10, 12, 14, 18, and 20; and UV–vis analyzes
of compound 2) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.09.095.
NC
CN
17
18
(60%)
Scheme 4. Synthesis of (E)-3,30-(diazene-1,2-diyl)bis(1-methyl-1H-pyrazole-4,5-
dicarbonitrile) (18).
References and notes
NC
CN
Me
N
NC
CN
NH2
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N
N
N
N
N
N
Me
N
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CN
19
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reactivity on related compounds 1522 and 1623 (Fig. 3), but surpris-
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precursors, the readily available pyrazoles 1724 and 1924 were sub-
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compounds 18 (Scheme 4) and 20 (Scheme 5), in 60% and 54%
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nitrile 21 (Fig. 3) did not react under the usual conditions.
To sum up, a new, mild, and simple synthetic method has been
found to transform 2-aminopyridines into the corresponding azo

D. B. da Silva et al. / Tetrahedron Letters 51 (2010) 6278–6281
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