Study of an efficient conversion of 1,3-dimethyl-5-(Arylazo)-6-Amino-Uracils to 1,3-dimethyl-8-(Aryl)-Azapurin-2,6-Diones

Article abstract of DOI:10.1016/j.molstruc.2017.08.087

6-Aminouracils have extensively been used as precursors for synthesizing numerous uracil derivatives of biological and pharmaceutical significance. This study describes an application of 1,3-dimethyl-5-(arylazo)-6-aminouracils (Uazo: Uazo1-Uazo4, precursors) for an efficient synthesis of a series of 8-substituted-azapurins (AP), namely 1,3-dimethyl-8-(aryl)-azapurin-2,6-diones (aryl = p-HC₆H₄ (AP1), -MeC₆H₄ (AP2), –ClC₆H₄ (AP3), and –SO₂NH₂C₆H₄ (AP4)) following an oxidation method in the presence of copper (II) nitrate and in alkaline medium. The obtained compounds were isolated in good yields as crystalline air-stable products and have been fully characterized in the solution by UV–vis and NMR spectroscopy, as well as in the solid state by FT-IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction (for AP2 and AP4). UV–vis study evidences that the conversion of the 6-aminouracil precursors occurs via an intermediate, Cu(II)-complex and a plausible mechanism for the formation of AP1-AP4 has been proposed. Unlike AP2 the crystal structure of AP4 reveals the formation of interdigitated 1D H-bonded chains that has been topologically classified within the 2C1 type. The ¹H NMR spectra of the products have proton signals that completely devoid of hydrazone (–NH–) and imine (=NH) signals of their parent Uazo derivatives, thus confirming their full conversion and a stability of the AP1-AP4 in solution. The excitation and emission spectra of AP1-AP4 were also recorded in solution, revealing electronic transitions between similar vibrational energy levels of S₀ (singlet ground state) and S₁ (singlet first excited state).

Full text of DOI:10.1016/j.molstruc.2017.08.087

Accepted Manuscript
Study of an efficient conversion of 1,3-dimethyl-5-(Arylazo)-6-Amino-Uracils to 1,3-
dimethyl-8-(Aryl)-Azapurin-2,6-Diones
Diptanu Debnath, Atanu Purkayastha, Alexander Kirillov, Rakesh Ganguly, Tarun
Kumar Misra
PII:
S0022-2860(17)31167-5
10.1016/j.molstruc.2017.08.087
MOLSTR 24225
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 May 2017
Revised Date: 25 August 2017
Accepted Date: 26 August 2017
Please cite this article as: D. Debnath, A. Purkayastha, A. Kirillov, R. Ganguly, T.K. Misra, Study of an
efficient conversion of 1,3-dimethyl-5-(Arylazo)-6-Amino-Uracils to 1,3-dimethyl-8-(Aryl)-Azapurin-2,6-
Diones, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.08.087.
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ACCEPTED MANUSCRIPT
Study of an Efficient Conversion of 1,3-Dimethyl-5-(Arylazo)-6-Amino-
Uracils to 1,3-Dimethyl-8-(Aryl)-Azapurin-2,6-Diones
Diptanu Debnath, Atanu Purkayastha, Alexander Kirillov, Rakesh Ganguly and Tarun Kumar
Misra
1,3-Dimethyl-5-(arylazo)-6-amino-uracils are converted to 1,3-dimethyl-8-(aryl)-azapurin-2,6-
dione under modified alkaline copper(II)-oxidation method.

ACCEPTED MANUSCRIPT
Study of an Efficient Conversion of 1,3-Dimethyl-5-(Arylazo)-6-Amino-
Uracils to 1,3-Dimethyl-8-(Aryl)-Azapurin-2,6-Diones
Diptanu Debnatha, Atanu Purkayasthaa, Alexander Kirillovb*, Rakesh Gangulyc* and Tarun
Kumar Misraa*
aDepartment of Chemistry, National Institute of Technology, Agartala 799046, Tripura, India
bInstituto Superior Técnico, University of Lisbon, Lisbon 1049001, Portugal
cDivision of Chemistry & Biological Chemistry, Nanyang Technology University, Singapore
639798
*Corresponding Authors: E-mail: atkmisra70@yahoo.com; bkirillov@tecnico.ulisboa.pt;
crganguly@ntu.edu.sg; Tel.: +91-381-2346630; Fax: +91-381-2346360.
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Abstract
6-Aminouracils have extensively been used as precursors for synthesizing numerous uracil
derivatives of biological and pharmaceutical significance. This study describes an application of
1,3-dimethyl-5-(arylazo)-6-aminouracils (Uazo: Uazo1-Uazo4, precursors) for an efficient
synthesis of a series of 8-substituted-azapurins (AP), namely 1,3-dimethyl-8-(aryl)-azapurin-2,6-
diones (aryl = p-HC6H4 (AP1), -MeC6H4 (AP2), -ClC6H4 (AP3), and -SO2NH2C6H4 (AP4))
following an oxidation method in the presence of copper(II) nitrate and in alkaline medium. The
obtained compounds were isolated in good yields as crystalline air-stable products and have been
fully characterized in the solution by UV-vis and NMR spectroscopy, as well as in the solid state
by FT-IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction (for AP2 and
AP4). UV-vis study evidences that the conversion of the 6-aminouracil precursors occurs via an
intermediate, Cu(II)-complex and a plausible mechanism for the formation of AP1-AP4 has been
proposed. Unlike AP2 the crystal structure of AP4 reveals the formation of interdigitated 1D H-
bonded chains that has been topologically classified within the 2C1 type. The 1H NMR spectra of
the products have proton signals that completely devoid of hydrazone (–NH–) and imine (=NH)
signals of their parent Uazo derivatives, thus confirming their full conversion and a stability of
the AP1-AP4 in solution. The excitation and emission spectra of AP1-AP4 were also recorded in
solution, revealing electronic transitions between similar vibrational energy levels of S0 (singlet
ground state) and S1 (singlet first excited state).
Keywords: Organic synthesis, Aminouracils, Azapurins, Spectroscopic characterization, Crystal
structures.
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1. Introduction
Purine (adenine and guanine) and pyrimidine (cytosine, thymine, and uracil) bases are the
two different important hydrolysis products of nucleic acids. These bases have widely been
studied from diverse perspectives, particularly their interactions with metals and chemical
modification [1-16], aiming at understanding in their vivo functioning and tuning
pharmacological behavior. Chemical modification of natural nucleobases (i.e., purines and
pyrimidine bases) in search of new drugs for effective antiviral and antitumour therapy has
extensively been explored [4-16]. In particular, the modification in purines (see Scheme 1(A))
has generally been accomplished at its imidazole ring, resulting in the substitution of CH by N in
position 8 of the purine ring and forming 8-azapurines [6-8] (see Scheme 1(B)). Such a
conversion of purines to 8-azapurines leads to an effective decrease of the electron density at this
position [17] and thus can significantly influence their chemical and biological properties [18],
including their recognized activity as anti-tumour drugs [18a]. Moreover, 8-azapurine family
includes 8-azaadenines (6-amino-8-azapurine), 8-azaguanines (2-amino-8-azapurin-6-one), 8-
azainosine (9-β-D-ribofuranosyl-8-azapurin-6-one), 8-azahypoxanthines (8-aza-purin-6-one),
and 8-azaxanthines (8-azapurin-2,6-dione, Scheme 1C), which differ from each other by the
presence of amino and/or hydroxyl substituents in the positions 2 and 6 [9,19].
(Scheme 1)
The present work deals with the derivatives of 1,3-dimethyl-8-azapurin-2,6-dione (Scheme
1D). The synthesis of 8-azapurine derivatives generally starts with the starting materials based on
either pyrimidine or 1,2,3-triazole derivatives. The first of 8-azapurines, 1,3-dimethyl-8-
azapurin-2,6-dione (Scheme 1D), was made by Traube [20] via cyclization of the corresponding
4,5-diaminopyrimidine with nitrous acid. Later on, the Traube synthesis has proved to be
compatible with many kinds of groups in the starting pyrimidine moiety for synthesizing 8-
azapurines [21-24]. The mobile hydrogen atom at the 8-position in 1,3-dimethyl-8-azapurin-2,6-
dione (Scheme 1D) can, theoretically, be attached to any one of the three triazole-nitrogen atoms,
giving the possibility to synthesize different N-substituted derivatives. A notable deficiency of
the Traube synthesis concerns its inability to produce 7- or 8- substituted 8-azapurines starting
from aminopyrimidine derivatives [25, 26] and such difficulty could be overcome using triazole
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derivatives [27]. It is noteworthy to mention that the bond arrangement in 8-azapurine (Scheme
1B) might suggest instability.
Nevertheless, the 6-aminouracils are extensively used as precursors for synthesizing
numerous uracil derivatives of biological and pharmaceutical importance [28-30]. For example,
Sulfadimethoxine [30], a sulphanilamide or sulfa-drug, is prepared from 6-aminouracil and is
used to inhibit the uracil-DNA glycosylase [31] and the dihydropyrimidine dehydrogenase
enzymes [32]. Our laboratory has been engaged in synthesizing 5-(arylazo)-6-aminouracils and
exploring their chemistry [33]. From literature it is found that there are several effective methods
[34, 35] converting 2-amino-azo compounds to 2-substituted v-triazole derivatives; these are
heating, chromic acid oxidation, lead tetraacetate oxidation, oxidation with alkaline copper
sulfate, and oxidation with copper sulfate in pyridine-water. In particular, Islam and Nagamatsu
[36] demonstrated the synthesis of some derivatives of 1,3-dimethyl-8-(aryl)azapurin-2,6-diones
via the oxidation with copper sulfate in pyridine-water medium.
Inspired by these results and following our general interest in this area of synthetic organic
chemistry, we report in the present study an efficient conversion of a series of 1,3-dimethyl-5-
(arylazo)-6-aminouracils (Uazo1-Uazo4) to 1,3-dimethyl-8-(aryl)azapurin-2,6-diones (AP1-
AP4), by applying a procedure for the oxidation with alkaline copper nitrate in DMF-water
mixture. As a base, NaHCO3 was used. The present report thus includes the synthesis, full
characterization, and detailed spectroscopic studies of the AP1-AP4 products, crystal structures
of AP2 and AP4, as well as a topological analysis of the identified 1D H-bonded network in the
crystal packing pattern of AP4. The sulfonamide derivative, in particular, can potentially
constitute a promising pharmaceutically active agent, as the sulfonamide (-SO2NH2) group is an
integral part of various sulfa-drugs [37-39]. In addition, the molecules containing sulfonamide
functionality can exhibit interesting solid state properties [40-44].
2. Experimental
2.1. Materials and instruments
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All chemicals were commercially available (reagent grade) and were used without any
further purification. All solvents were of A. R. grade. 1,3-Dimethyl-6-aminouracil and 1,3-
dimethyl-5-(arylazo)-6-aminouracil were prepared following reported procedures [33].
Melting points were determined on a Labtech Digital melting point apparatus with a heating
rate of 2 °C/min and not corrected. IR spectra were recorded on a Perkin Elmer FT-IR
1
spectrophotometer (model RX-1) in the region 4000–400 cm-1 (KBr pellets). The H NMR and
13C NMR spectra in DMSO-D6 were recorded on a JEOL DELTA2 spectrometer at 500 MHz
and 125 MHz, respectively. The electronic spectra were recorded on a Shimadzu UV-vis-1800
spectrophotometer. Excitation and emission spectra of all the compounds were recorded on a
Perkin Elmer LS 55 Fluorescence Spectrometer. Excitation and emission slits were set to 10 and
2.5 nm. Elemental analyses were made on a Perkin Elmer 2400 series-II analyzer and the
obtained results are in good agreement with the calculated values.
2.2. Synthesis of 1,3-dimethyl-8-(aryl)-azapurin-2,6-dione derivatives (AP1-AP4)
General procedure. The compounds AP1-AP4 were synthesized via an alkaline copper
sulfate method [34] with some modifications. Typically, 1,3-dimethyl-5-(phenylazo)-6-
aminouracil (Uazo1, 103.6 mg, 0.4 mmol) was dissolved in DMF, followed by the addition of an
o
aqueous solution of NaHCO3 (33.6 mg, 0.4 mmol). The obtained mixture was heated at 70 C
with continuous stirring over 20 minutes. Then, to this warm mixture a DMF solution of
Cu(NO3)2·3H2O (48.4 mg, 0.2 mmol) was added slowly with continuous stirring for further 1 h
at the same temperature. An intense yellow powder of the product started to precipitate in the
course of cooling the reaction mixture down to room temperature. The product was filtered off,
washed with water, and dried in vacuum. X-ray quality single crystals can be obtained by re-
dissolving the product in DMF-water (3:1 v/v) mixture, followed by slow evaporation for two
weeks. Single crystals of AP2 and AP4 were analyzed for molecular structure of the products.
Physical and spectral data of the obtained products are given as follows.
1,3-dimethyl-8-(phenyl)-azapurin-2,6-dione (AP1)
Yellow square-plate crystals (yield: 53%) with a melting point of 265±1 °C. FT-IR (KBr
pellet, υ/cm-1): 2817 (bw, Ar-H), 1726, 1676 (s, >C=O), 1606, 1592 (bs, >C=N-), 1493 (sw, -C-
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C), 1384, 1351, 1295 (s, -N-C), 1061 (s, -N-N), 990, 961, 764, 744, 692, and 652 (other bands).
1H NMR (DMSO-D6, δ/ppm): 8.08–8.06 (d, 2H, Ar-H), 7.64–7.49 (m, 3H, Ar-H), 3.49 (s, 3H,
N(3)-CH3), and 3.28 (s, 3H, N(1)-CH3). 13C NMR (125 MHz, DMSO-D6, δ/ppm): 155.91
(>C=O), 155.77 (>C=O), 150.74 (>C=N), 150.06 (>C=N), 138.54 (Ar-C), 131.40 (Ar-C), 129.91
(Ar-C), 129.04 (Ar-C), 126.68 (Ar-C), 118.89 (Ar-C), 30.80 (N-CH3), 28.17 (N-CH3). Anal.
Calcd. for C12H11N5O2: C, 56.03; H, 4.31; N, 27.22, Found: C, 56.12; H, 4.26; N, 27.02.
1,3-dimethyl-8-(p-Me-phenyl)-azapurin-2,6-dione (AP2)
Yellow square-plate crystals (yield: 58%) with a melting point of 271±1 °C. FT-IR (KBr
pellet, υ/cm-1): 2822 (bw, Ar-H), 1726, 1677 (s, >C=O), 1595 (bs, >C=N-), 1508 (sw, -C-C),
1
1384, 1353, 1297 (s, -N-C), 1054 (s, -N-N), 989, 977, 775, and 747(other bands). H NMR
(DMSO-D6, δ/ppm): 7.95-7.39 (dd, 4H, Ar-H), 3.47 (s, 3H, N(3)-CH3), 3.27 (s, 3H, N(1)-CH3),
and 2.37 (s, 3H, Ar-CH3). 13C NMR (125 MHz, DMSO-D6, δ/ppm): 155.95 (>C=O), 155.81
(>C=O), 150.79 (>C=N), 150.01 (>C=N), 138.90 (Ar-C), 136.45 (Ar-C), 130.28 (Ar-C), 126.39
(Ar-C), 125.67 (Ar-C), 118.84 (Ar-C), 30.81 (N-CH3), 28.18 (N-CH3), and 20.58 (Ar-CH3).
Anal. Calcd. for C13H13N5O2: C, 57.56; H, 4.83; N, 25.82, Found: C, 57.51; H, 4.52; N, 25.89.
1,3-dimethyl-8-(p-Cl-phenyl)-azapurin-2,6-dione (AP3)
Yellow square-plate crystals (yield: 61%) with a melting point of 261±1 °C. FT-IR (KBr
pellet, υ/cm-1): 2830 (bw, Ar-H), 1717, 1683 (s, >C=O), 1608 (bs, >C=N-), 1493 (sw, -C-C),
1
1384, 1351, 1292 (s, -N-C), 1091, 1054 (s, -N-N), 965, 776, and 744 (other bands). H NMR
(DMSO-D6, δ/ppm): 8.10-7.67 (dd, 4H, Ar-H), 3.49 (s, 3H, N(3)-CH3) and 3.28 (s, 3H, N(1)-
CH3). 13C NMR (125 MHz, DMSO-D6, δ/ppm): 155.68 (>C=O), 150.70 (>C=N), 150.16
(>C=N), 137.29 (Ar-C), 133.32 (Ar-C), 129.90 (Ar-C), 127.01 (Ar-C), 120.59 (Ar-C), 30.79 (N-
CH3), 28.18 (N-CH3). Anal. Calcd. for C12H10ClN5O2: C, 49.41; H, 3.46; N, 24.01, Found: C,
50.01; H, 3.59; N, 23.92.
1,3-dimethyl-8-(p-SO2NH2-phenyl)-azapurin-2,6-dione (AP4)
Yellow square-plate crystals (yield: 55%) with a melting point of 248±1 °C. FT-IR (KBr
pellet, υ/cm-1): 2924 (bw, Ar-H), 1725, 1669 (s, >C=O), 1609, 1590 (bs, >C=N-), 1494 (sw, -C-
C), 1384, 1351, 1299 (s, -N-C), 1161 (s, >S=O),1096, 1055 (s, -N-N), 958, 856, 775, 744, 647,
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1
and 551 (other bands); H NMR (DMSO-D6, δ/ppm): 8.27–8.02 (dd, 4H, Ar-H), 7.52 (s, -
SO2NH2), 3.49 (s, 3H, N(3)-CH3) and 3.28 (s, 3H, N(1)-CH3). 13C NMR (125 MHz, DMSO-D6,
δ/ppm): 155.52 (>C=O), 150.54 (>C=N), 150.15 (>C=N), 143.77 (Ar-C), 140.18 (Ar-C), 127.43
(Ar-C), 119.06 (Ar-C), 30.65 (N-CH3), 28.02 (N-CH3). Anal. Calcd. for C12H12N6O4S: C, 42.85;
H, 3.60; N, 24.99, Found: C, 43.03; H, 3.55; N, 25.09.
2.3. Single crystal X-ray structure and refinement details for AP2 and AP4
The intensity data were collected on a Bruker Kappa APEXII diffractometer equipped with a
CCD area detector, employing MoKα radiation (λ = 0.71073 Å) and using graphite
monochromator with ω scan. Crystal cell refinement and data reduction were carried out using
Bruker SAINT-software package whereas absorption effects in the compound were corrected by
using the Multi-Scan method (SADABS) [45]. The structural solution and refinement were
carried out using the SHELXL-2014/7 suite of programs [46]. The structures were solved by
employing direct methods or Patterson maps to locate the heavy atoms, followed by difference
maps for the light, non-hydrogen atoms. All non-hydrogen atoms were refined with anisotropic
thermal parameters. A summary of the crystallographic data collection and structure parameters
for AP2 and AP4 is given in Table 1.
(Table 1)
2.4. Topological analysis
The H-bonded network in the structure of AP4 was analyzed from the topological viewpoint
by following the concept of the simplified underlying net [47,48]. Such a net was generated by
contracting the molecular units to centroids, maintaining their connectivity via hydrogen bonds.
Only strong D−HꢀꢀꢀA hydrogen bonds were considered, wherein the HꢀꢀꢀA <2.50 Å, DꢀꢀꢀA <3.50
Å, and (D−HꢀꢀꢀA) >120°; D and A stand for donor and acceptor atoms [47].
3. Results and discussion
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3.1. Synthesis and structure
The new derivatives of 8-azapurin-2,6-dione (i.e. 8-azaxanthines, Scheme 1C), 1,3-dimethyl-
8-(aryl)-azapurin-2,6-diones (AP1-AP4), were synthesized by following an oxidation procedure
in the presence of copper ions and in alkaline medium. The reaction mixture containing 1,3-
dimethyl-5-(arylazo)-6-aminouracils (abbreviated as Uazo1-Uazo4), NaHCO3 and
Cu(NO3)2·3H2O in DMF-water was treated at 70 °C with stirring for 1 h (see reaction in Scheme
2). The reactions were monitored by UV-vis spectroscopy as shown in Figure 1 (representative
spectra for AP2). The Uazo compounds exist in anionic form of hydrazone in DMF; there is an
H-bond between (λmax= 369 nm for Uazo2-, Figure 1a) of Uazo- and +HDMF [33a,e]. There is no
remarkable band shifting occurs in the presence of base (NaHCO3), also confirming an anionic
form of hydrazone (λmax= 369 nm for Uazo2-, Figure 1b) [33a] in DMF. Upon addition of Cu(II)
nitrate into the reaction mixture at heating condition, the absorption maximum (λmax for Uazo2-)
shifts from 369 nm to 390 nm and a new weak band appears at 470 nm, indicating the formation
of Cu(II)-complex with the Uazo2 (t = 0-5 min, Figure 1c) [49]. On further prolonging the
heating, a new band is being developed at 315 nm; its intensity increases progressively with
time. Simultaneously, the intensity at 390 nm decreases. The reaction is completed within 1 h.
These data indicate that a new type of compounds has formed from Uazo substrates, specifically
from Uazo Cu(II)-complexes, because the new band with a maximum at 315 nm is neither
matched with the Uazo2 nor its copper(II) complex [49]. The products are the derivatives of 1,3-
dimethyl-8-(aryl)-azapurin-2,6-diones. Based on the UV-vis data a mechanism of their formation
is proposed and depicted in Scheme 3. The crystalline products (AP1-AP4) precipitated from the
reaction mixture upon slow evaporation, and were then filtered off. The structures and
spectroscopic properties of the compounds were established by studying them in the solid state
(FT-IR and single crystal X-ray diffraction) and in solution (UV–vis and NMR spectroscopy).
(Scheme 2 and 3, Figure 1)
3.2. IR spectroscopic characterization
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The IR data for all the compounds (AP1-AP4) are given in the experimental section. A
representative IR spectrum for AP3 along with its parent Uazo substrate, Uazo3 is shown in
Figure 2 and rests are given in Figures S1-S3 (Supporting material). The IR spectra of AP1-AP4
exhibit two sharp intense peaks at 1717 cm-1 and 1683 cm-1 (for AP3, Figure 2A) due to the
carbonyl groups (2C=O) and (6C=O), respectively, in the uracil ring (see Scheme 2 for
numbering). The peak positions are found red-shifted significantly in comparison with the parent
Uazo compounds [33a] (Figure 2B). Another almost indistinguishable pair of sharp peaks at
1608 cm-1 and 1594 cm-1 is assigned to the ν(-C=N-) stretching frequencies; these peaks, as
expected, are absent in the Uazo substrates (Figure 2B). The peaks at 1384 cm-1 and 1351 cm-1
belong to (-N-N-) group. In comparison with the spectrum of Uazo3 (Figure 2B) it is evident that
the product is devoid of the –N=N– stretching frequency, supporting the formation of AP3 from
Uazo3. The IR study thus reveals that the products synthesized from Uazo compounds are
devoid from the stretching frequencies of the azo-functionality and contain the –C=N- functions,
thus providing an additional support toward the formation of 1,3-dimethyl-8-(aryl)-azapurin-2,6-
diones (AP1-AP4).
(Figure 2)
3.3. Crystal structures of AP2 and AP4 and topological analysis of AP4
The crystal structures of 1,3-dimethyl-8-(p-Me/SO2NH2-phenyl)-azapurin-2,6-dione
(AP2/AP4) were solved to establish their solid state structures. Ellipsoid plots of AP2 and AP4
with atom labeling scheme are given in Figure 3 and 4, respectively. The bonding parameters
about the triazole ring of the structures are listed in Table 2 and detail are given in Table S1, as
supplementary material. The crystal of AP2 consist twin molecular units (Figure 3) whereas AP4
is single (Figure 4). In comparison with bond length data of the uracil moiety of Uazo4 [33e],
these are shortened in AP4 as well as in AP2. The v-triazole ring is formed in the products under
reaction condition by linking –NH2 group at 6-position of the uracil moiety with one of the azo-
nitrogen, resulting –N-N- bond (Scheme 3). The newly formed –N-N- bond distance is found
equivalent in molecule B of AP2 (N(1)B-N(2)B) and AP4 (N(1)-N(2)) (see Table 2) and in
molecule A of AP2 the distance is lengthened by 0.01 Å (N(1)A-N(2)A). As expected, in
comparison with Uazo4 [33e], the N(1)-N(3) bond length increases by 0.014 Å and the C(7)-
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N(3) bond distance decreases by 0.042 Å in AP4. Some anomaly is observed over the C(7)-C(8)
(decreases by 0.042 Å) and C(8)-N(2) (increases by 0.014 Å) bond lengths. The N(1)-C(6) bond
length in AP4 remains similar to that of Uazo4. However, the C(7)-C(8) bond length is
essentially identical to the -C-C- bond length of its phenyl ring, indicating the existence of a ring
current within neighboring bonds. The increase of C(8)-N(2) bond length might be the cause of
the formation of triazole ring via the N(2)-N(1) bonding (1.355 Å). The bond length data within
the –N(1)-N(3)-C(7)-C(8)-N(2)-N(1)– ring thus suggest that Uazo4 converts to AP4 via the
formation of a triazole ring, having a ring current within the –N(3)-C(7)-C(8)-N(2)– bonds.
Similar phenomenon about bond distances is observed in the molecular structure of A and B of
AP2 (Table 2). Nevertheless, the bond length values of uracil and triazole rings are essentially
identical to those in 1,3-dimethyl-8-azaxanthine monohydrate [17]. The bond angles about
triazole ring, especially C(7)-N(3)-N(1), N(3)-N(1)-N(2), and C(8)-N(2)-N(1) in AP4 and
similar in the molecular structure of A and B of AP2 are also concomitant to those in 1,3-
dimethyl-8-azaxanthine monohydrate [17]. The molecules of AP2 and AP4 are almost planar
wherein three rings (uracil, triazole, and phenyl) are projected on a plane.
(Figure 3 and 4, Table 2)
In contrast to the molecular structures of AP2, the molecular structure of AP4 exhibits H-
bonded networks, mainly due to its potential H-bond acceptors and donors present in
sulfonamide group. The H-bonding parameters for AP4 are listed in Table 3. The structure of
AP4 is composed of the discrete 0D organic molecular units (Figure 4) that are assembled by
two conventional N−H…O hydrogen bonds [N(6)-H(6B)...O(4) 3.122(4) Å; N(6)-H(6A)...O(2)
2.991(5) Å] to give a 1D H-bonded chain (Figure 5A). From the Figure 5A it is clearly seen that
the sulfonamide groups of the molecular units are mainly involved in H-bonding interactions
among themselves and act as ‘self-molecular glue’. Of the two –NH groups of the sulfonamide
group of a molecular unit, one acts as a single ‘two-centered’ and other one as a double ‘three-
centered’ H-bond donor. Molecular units form self-assembled dimeric motifs in antiparallel
fashion through two symmetrically related H-bonds involving uracil-O(4) and one –NH of the
sulfonamide group. From the topological viewpoint, the resulting 1D H-bonded chains can be
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classified as a uninodal 2-connected net with the 2C1 topology [47]. Interestingly, the adjacent
chains are interdigitated to give a grid-like packing pattern along the c axis (Figure 5B).
(Table 3, Figure 5)
3.4. NMR spectroscopic characterization
The formation of AP1- AP4 from Uazo substrates could also be confirmed by a comparative
1
analysis of their H NMR spectra in DMSO-D6 with those of the parent Uazo compounds [33a,
e]. The chemical shifts of different types of protons and carbons in the NMR spectra of the
products are given in the experimental section. From comparison of the 1H NMR spectra of AP4
and Uazo4 (see Figure 6), it is quite apparent that the spectrum of AP4 (Figure 6A) is completely
devoid of signals corresponding to hydrazone (–NH-) and imine (=NH) moieties (these are
present in the parent Uazo4 compound (Figure 6B) [33e]). The as-synthesized compounds AP1-
AP3 contain only the –N-CH3, and Ar-H protons (see Figures S4, S6, S8) and including these
AP4 has additional –NH2 protons of –SO2NH2 moiety. The protons of two –N-CH3 groups
appear as singlet at 3.28 and 3.49 ppm. The –SO2NH2 protons exhibit a singlet at 7.52 ppm at the
spectrum of AP4 (Figure 6A). The four aromatic protons show a doublet-doublet signal in the
8.02-8.27 ppm range. In comparison with the parent Uazo compounds, all the protons in AP1-
AP4 appear up-fielded, which may be the reason for the formation of a triazole ring. Thus, the
NMR-study supports the formation of AP1-AP4 products from their corresponding Uazos and its
stability in solution. The 13C NMR spectrum of AP4 (a representative case) displays
characteristic carbon signals at 155.52 ppm for two >C=O (uracil) and at 150.54 and 150.15 ppm
for >C=N (triazole ring) functionalities. The peaks in the 143.77–119.06 ppm region (143.77,
140.18, 127.43, and 119.06 ppm) are due to aromatic carbon atoms. The signals at 30.65 and
28.02 ppm are assigned to the carbon signals of the N-CH3 groups (uracil). However, peak
values are quite different than that of Uazo4 [33e].
(Figure 6)
3.5. Absorption, excitation and emission behavior
11

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The UV-vis, excitation and emission data for AP1- AP4 were recorded in DMSO and DMF
solution and are listed in Table 4. The absorption spectra of AP1- AP4 are very different from
those of their parent compounds, Uazo1-Uazo4. Figure 7A shows a representative example for
AP1 and Uazo1. The absorption maximum of AP1 (λmax, 313 nm in DMSO) is quite sharp and
blue-shifted than that of Uazo1 (λmax, 366 nm) in DMSO. Moreover, absorption maxima of all
the products lie in the 311–322 nm range along with a weak broad peak centered at 386-392 nm
in DMSO and DMF solvents. The former peak is attributed to π→π* transitions whereas the later
peak corresponds to n→π* transitions. Resembling the absorption electronic transitions, the
compounds also exhibit two excitation peaks in the corresponding emission spectra. These are
307 and 338 nm for AP2 upon emission at 410 nm in DMSO. On the other hand, each
compound, upon excitation at 330 nm, exhibits two emission peaks. For example, for AP2 these
are 381 and 403 nm in DMSO (Figure 7B). Both excitation and emission spectra seem to follow
mirror image rule and are symmetric in nature. The symmetric nature of these spectra result from
the same electronic transitions are being involved in both excitation and emission and the similar
vibrational energy levels of S0 (singlet ground state) and S1 (singlet first excited state).
(Table 4, Figure 7)
4. Conclusions
The difficulty in the synthesis of stable 8-substituted 8-azapurin derivatives could potentially
be overcome by following the oxidation of 5-(arylazo)-6-aminouracil precursors using an
alkaline copper sulfate/nitrate method. In the present work, we explored such a method by
converting a series of four 1,3-dimethyl-5-(arylazo)-6-aminouracil substrates to novel 1,3-
dimethyl-8-(aryl)-azapurin-2,6-dione derivatives AP1- AP4. The reactions proceed efficiently, in
DMF-water medium, and result in good product yields and purity. The obtained products were
fully characterized in solution and solid state by standard methods, revealing also the stability of
the compounds in solution. Single crystals of 1,3-dimethyl-8-(p-Me/SO2NH2-phenyl)azapurin-
2,6-dione (AP2/AP4) were also isolated and characterized by X-ray diffraction. An interesting
feature of the crystal structure of AP4 concerns the formation of 1D H-bonded chains that were
topologically classified within the 2C1 type.
12

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Given the presence of bioactive uracil and triazole moieties along with other functional
groups in the structures of AP1- AP4, the obtained compounds may show promising biological
or pharmacological properties, with a particular interest toward modelling new pharmaceutical
agents. For the purposes, the molecule containing a bioactive sulphonamide group (AP4) can be
particularly attractive. Further research toward the exploration of biological and/or
pharmacological behaviour of these derivatives as well as the synthesis of an extended library of
such organic compounds will be pursued.
Acknowledgements
The authors are thankful to Department of Chemistry, NIT Agartala, India for providing
financial support and research facilities. We thank SAIF IIT Madras, for single crystal X-ray
diffraction data for AP4. D.D. and A.P. greatly acknowledge NIT, Agartala for financial support.
AMK acknowledges the FCT, Portugal (UID/QUI/00100/2013).
Appendix A. Supplementary material
CCDC number 1545458 and 1545459 contain the supplementary crystallographic data for
the products, AP2 and AP4, respectively. This data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
Supplementary data includes IR spectra (Figures S1–S3), NMR spectra (Figures S4–S10) of
AP1–AP4 and bond lengths and angles for AP2 and AP4 (Table S1).
13

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Legends to Scheme, Figures and Tables
Schemes
Scheme 1. Molecular structures of purine derivatives (A-D).
Scheme 2. A general reaction scheme for the synthesis of 1,3-dimethyl-8-(aryl)azapurin-2,6-
diones (AP1-AP4).
Scheme 3. Plausible mechanistic paths for the conversion of 1,3-dimethyl-5-(arylazo)-6-
aminouracils (Uazo1–Uazo4) to 1,3-dimethyl-8-(aryl)-azapurin-2,6-diones (AP1–
AP4).
Figures
Figure 1. UV-vis spectra of intermediate products (a, b) and of the reaction mixture in the
course of the formation of the AP2 product (c) with 5 min time-intervals for 1h.
Figure 2. IR spectra of (A) 1,3-dimethyl-8-(p-Cl-phenyl)-azapurin-2,6-dione (AP3) and (B) 1,3-
dimethyl-5-(p-Cl-phenylazo)-6-aminouracil (Uazo3).
Figure 3. Molecular view of AP2 with atom labelling scheme and 40% probability thermal
ellipsoids.
Figure 4. Molecular view of AP4 with atom labelling scheme and 40% probability thermal
ellipsoids.
Figure 5. Structural fragments of AP4. (A) 1D H-bonded chain (H-bonds are shown as dashed
lines. (B) Topological representation of an underlying 1D H-bonded network showing a
packing arrangement of uninodal 2-connected chains with the 2C1 topology. Further
details: (A): color codes: C (pale green), O (red), N (blue), S (yellow), H (gray); (B)
centroids of 2-connected molecular nodes (pale green balls), view along the c axis.
Figure 6. 1H NMR spectra of: (A) the as-synthesized AP4 product and (B) the Uazo4 precursor.
Figure 7. (A) UV-vis spectra of Uazo1 and AP1 in DMSO. (B) Excitation and emission spectra
of (a) AP1, (b) AP2, (c) AP3, and (d) AP4.
17

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Tables
Table 1. Crystallographic data and structure refinement of AP2 and AP4
Table 2. Selected bond lengths (Å) and angles (º) of compound AP2 and AP4 in and around
triazole ring.
Table 3. Hydrogen bonding parameters for AP4 [Å and (°)].
Table 4. UV-vis, excitation and emission data of AP1-AP4
18

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Table 1. Crystallographic data and structure refinement of AP2 and AP4
Empirical formula
C13H13N5O2(AP2)
271.28
C12H12N6O4S (AP4)
Formula weight
336.34
296(2)
Temperature/K
293(2)
Crystal system
Triclinic
P-1
Monoclinic
P21/c
Space group
a/Å
7.1521(14)
12.613(3)
14.782(3)
88.151(6)
84.146(6)
74.766(6)
1279.9(4)
4
12.6717(6)
8.9385(4)
13.2445(7)
90
b/Å
c/Å
α/°
β/°
113.366(3)
90
γ/°
Volume/Å3
Z
ρcalcMg/m3
ꢀ/mm-1
1377.12(12)
4
1.408
1.622
0.100
0.269
F(000)
568.0
696
Crystal size/mm3
0.320 × 0.120 × 0.040
5.94 to 52.94
0.350 x 0.300 x 0.250
2.828 to 24.998
2θ range for data collection/°
-8 ≤ h ≤ 8, -15 ≤ k ≤ 15, -18 ≤ -15<=h<=15, -10<=k<=10, -
Index ranges
l ≤ 18
31252
15<=l<=15
26166
Reflections collected
Independent reflections
5215 [Rint = 0.1214, Rsigma
0.0729]
=
2413 [R(int) = 0.0713]
Data/restraints/parameters
Goodness-of-fit on F2
5215/0/367
1.085
2413 / 3 / 216
1.055
Final R indexes [I ≥ 2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å-3
R1 = 0.0972, wR2 = 0.2560
R1 = 0.1573, wR2 = 0.3153
0.43/-0.30
R1 = 0.0459, wR2 = 0.0977
R1 = 0.0826, wR2 = 0.1186
0.326 and -0.302

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Table 2. Selected bond lengths (Å) and angles (º) of compound AP2 and AP4 in and around
triazole ring.
Compound AP2
Compound AP4
Molecule A
Bonds
Molecule B
Bonds
Bond
length
(Å)
Bond
length
(Å)
Bonds
Bond
length (Å)
N(1)-N(2)
N(1)-N(3)
C(7)-N(3)
C(7)-C(8)
C(8)-N(2)
C(6)-N(1)
C(8)-N(4)
C(7)-C(10)
C(1)-C(6)
C(5)-C(6)
1.355(3)
1.324(3)
1.337(4)
1.376(4)
1.327(4)
1.422(4)
1.367(4)
1.436(4)
1.383(4)
1.388(4)
C(1)A-C(2)A
1.379(6) C(1)B-C(2)B
1.428(6) C(2)B-C(3)B
1.370(5) C(1)B-N(5)B
1.325(5) C(1)B-N(1)B
1.361(4) N(1)B-N(2)B
1.330(5) N(2)B-N(3)B
1.348(5) C(2)B-N(3)B
1.416(5) C(7)B-N(2)B
1.382(6) C(7)B-C(8)B
1.377(6) C(7)B-C(13)B
1.381(6)
1.421(6)
1.377(5)
1.325(5)
1.354(5)
1.324(5)
1.348(5)
1.438(5)
1.366(6)
1.378(6)
Bond
C(2)A-C(3)A
C(1)A-N(5)A
C(1)A-N(1)A
N(1)A-N(2)A
N(2)A-N(3)A
C(2)A-N(3)A
C(7)A-N(2)A
C(7)A-C(8)A
C(7)A-C(13)A
Bonds
Bond
angles
(º)
Bonds
Bonds
Bond
angles
(º)
angles (º)
N(3)-N(1)-C(6) 121.9(2)
N(2)-N(1)-C(6) 121.8(2)
C(8)-N(2)-N(1) 101.6(2)
N(1)-N(3)-C(7) 102.6(2)
N(3)-N(1)-N(2) 116.4(2)
N(3)-C(7)-C(10) 128.2(3)
C(8)-C(7)-C(10) 122.5(3)
N(2)-C(8)-N(4) 127.2(3)
N(2)-C(8)-C(7) 110.3(3)
N(4)-C(8)-C(7) 122.5(3)
N(1)A-C(1)A-N(5)A
N(5)A-C(1)A-C(2)A
N(3)A-C(2)A-C(3)A
C(13)A-C(7)A-C(8)A
C(8)A-C(7)A-N(2)A
N(1)A-C(1)A-C(2)A
N(3)A-C(2)A-C(1)A
C(1)A-C(2)A-C(3)A
C(13)A-C(7)A-N(2)A
C(1)A-N(1)A-N(2)A
N(3)A-N(2)A-C(7)A
N(2)A-N(3)A-C(2)A
N(3)A-N(2)A-N(1)A
N(1)A-N(2)A-C(7)A
125.5(4) N(1)B-C(1)B-N(5)B
122.9(4) N(5)B-C(1)B-C(2)B
129.7(4) N(3)B-C(2)B-C(3)B
120.8(4) C(8)B-C(7)B-C(13)B
119.5(4) C(13)B-C(7)B-N(2)B
111.6(4) N(1)B-C(1)B-C(2)B
108.4(4) N(3)B-C(2)B-C(1)B
121.9(4) C(1)B-C(2)B-C(3)B
119.7(4) C(8)B-C(7)B-N(2)B
100.8(3) C(1)B-N(1)B-N(2)B
122.4(3) N(3)B-N(2)B-C(7)B
102.4(3) N(2)B-N(3)B-C(2)B
116.8(3) N(3)B-N(2)B-N(1)B
120.8(3) N(1)B-N(2)B-C(7)B
127.0(4)
121.7(4)
130.1(4)
120.1(4)
120.2(4)
111.2(4)
107.9(4)
122.0(4)
119.7(4)
101.4(3)
121.3(3)
103.1(3)
116.4(3)
122.4(3)
C(1)-C(6)-C(5)
121.4(3)
C(1)-C(6)-N(1) 119.8(3)
C(5)-C(6)-N(1) 118.8(3)
N(3)-C(7)-C(8) 109.2(3)

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Table 3. Hydrogen bonding parameters for AP4 [Å and (°)].
D-H...A
d(D-H)
0.812(18)
0.812(18)
0.819(17)
0.93
d(H...A)
2.58(4)
2.50(3)
2.180(18)
2.58
d(D...A)
3.146(4)
3.122(4)
2.991(5)
3.302(4)
3.153(4)
3.017(4)
3.209(4)
3.542(4)
<(DHA)
128(3)
135(4)
171(3)
134.3
N(6)-H(6B)...O(1)#5
N(6)-H(6B)...O(4)#6
N(6)-H(6A)...O(2)#7
C(1)-H(1)...O(2)#1
C(4)-H(4)...O(3)#2
C(5)-H(5)...O(3)#2
C(12)-H(12A)...O(1)#3
C(12)-H(12C)...N(3)#4
0.93
2.63
116.4
0.93
2.36
127.8
0.96
2.44
136.7
0.96
2.59
171.4
Symmetry transformations used to generate equivalent atoms:
#1 -x+1,-y+1,-z ; #2 x,y+1,z ; #3 x+1,-y+1/2,z+1/2 ; #4 -x+2,-y,-z; #5 -x+1,y+1/2,-z-1/2; #6 -
x+2,-y+1,-z; #7 -x+1,-y+2,-z
Table 4. UV-vis, excitation and emission data of AP1-AP4
Compd.
UV-Vis
Excitation and Emission
DMF
DMSO
λmax, nm
313, 386
318, 388
317, 390
322, 392
DMF
λex, nm λem, nm
DMSO
λex, nm
λmax, nm
311, 386
315, 388
316, 390
320, 392
λem, nm
376, 405
381, 403
379, 400
380, 405
304, 334
306, 338
307, 338
308, 344
376, 404 304, 334
381, 403 307, 338
379, 404 306, 338
379, 405 307, 343
AP1
AP2
AP3
AP4

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Figure 1
Figure 1. UV-vis spectra of intermediate products (a, b) and of the reaction mixture in the
course of the formation of the AP2 product (c) with 5 min time-intervals for 1h.

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Figure 2
Figure 2. IR spectra of (A) 1,3-dimethyl-8-(p-Cl-phenyl)-azapurin-2,6-dione (AP3) and (B) 1,3-
dimethyl-5-(p-Cl-phenylazo)-6-aminouracil (Uazo3).

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Figure 3
Figure 3. Molecular view of AP2 with atom labelling scheme and 40% probability thermal
ellipsoids.

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Figure 4
Figure 4. Molecular view of AP4 with atom labelling scheme and 40% probability thermal
ellipsoids.

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Figure 5
A
B
Figure 5. Structural fragments of AP4. (A) 1D H-bonded chain (H-bonds are shown as dashed
lines. (B) Topological representation of an underlying 1D H-bonded network showing a packing
arrangement of uninodal 2-connected chains with the 2C1 topology. Further details: (A): color
codes: C (pale green), O (red), N (blue), S (yellow), H (gray); (B) centroids of 2-connected
molecular nodes (pale green balls), view along the c axis.

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Figure 6
Figure 6. 1H NMR spectra of: (A) the as-synthesized AP4 product and (B) the Uazo4 precursor.

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Figure 7
Figure 7. (A) UV-vis spectra of Uazo1 and AP1 in DMSO. (B) Excitation and emission spectra
of (a) AP1, (b) AP2, (c) AP3, (d) AP4.