Direct Arylation of Adenine by Fluoro-and Chloronitrobenzenes: Effect of Microwaves

Article abstract of DOI:10.1080/00397911.2013.831902

Direct arylation of adenine with fluoro-and chloronitrobenzenes leads to mixtures of N9 and N7 substituted adenines. After separation by column chromatography, the individual isomers can be efficiently hydrogenated on Pd to give the corresponding aminophenyladenines. A significant enhancement of the reaction rate by microwave irradiation was observed. This two-step procedure was found to be a feasible route to otherwise hardly available 7- aminophenyladenines. Correlation between calculated shielding constants and experimental values of chemical shifts in ¹³C and ¹⁵N NMR was used for assignment of the site of substitution. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.831902

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Direct Arylation of Adenine by Fluoro-
and Chloronitrobenzenes: Effect of
Microwaves
Lubomír Váňa a , Lukáš Vrzal b , Hana Dvořáková b , Michal Himl a &
Igor Linhart a
a Department of Organic Chemistry , Institute of Chemical
Technology, Prague , Prague , Czech Republic
b Central Laboratories , Institute of Chemical Technology, Prague ,
Prague , Czech Republic
Published online: 20 Feb 2014.
To cite this article: Lubomír Váňa , Lukáš Vrzal , Hana Dvořáková , Michal Himl & Igor Linhart (2014)
Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:6, 788-799, DOI: 10.1080/00397911.2013.831902
To link to this article: http://dx.doi.org/10.1080/00397911.2013.831902
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Synthetic Communications1, 44: 788–799, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.831902
DIRECT ARYLATION OF ADENINE BY FLUORO- AND
CHLORONITROBENZENES: EFFECT OF MICROWAVES
1
2
2
´
´
ˇ
´
ꢀ
ˇ´
´
Lubomır Vana, Lukas Vrzal, Hana Dvorakova,
Michal Himl,1 and Igor Linhart1
1Department of Organic Chemistry, Institute of Chemical Technology,
Prague, Prague, Czech Republic
2Central Laboratories, Institute of Chemical Technology, Prague, Prague,
Czech Republic
GRAPHICAL ABSTRACT
Abstract Direct arylation of adenine with fluoro- and chloronitrobenzenes leads to mixtures
of N9 and N7 substituted adenines. After separation by column chromatography, the indi-
vidual isomers can be efficiently hydrogenated on Pd to give the corresponding aminophe-
nyladenines. A significant enhancement of the reaction rate by microwave irradiation was
observed. This two-step procedure was found to be a feasible route to otherwise hardly
available 7-aminophenyladenines. Correlation between calculated shielding constants and
experimental values of chemical shifts in 13C and 15N NMR was used for assignment of
the site of substitution.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Chemoselectivity; microwave chemistry; N-arylation; purines
Received June 26, 2013.
Address correspondence to Igor Linhart, Department of Organic Chemistry, Institute of Chemical
´
Technology, Prague, Technicka 1905, Prague, CZ-16628, Czech Republic. E-mail: linharti@vscht.cz
788

ARYLATION OF ADENINE BY HALONITROBENZENES
789
INTRODUCTION
Substituted purines continue to attract attention as biologically active
compounds, molecular tools, and probes for investigating biological systems.[1–4]
Because of their similarity to adenosine, many 9-substituted adenines interact with
adenosine receptors, showing important biological activity including antiviral and
cytostatic effects.[5–7] Although 7-substituted adenines are not so readily available,
some of them were also shown to have significant activity against viruses.[8] Position
9 of adenine appears to be the most reactive one in the reactions with various
electrophiles, although these reactions are generally not completely regioselective
so that mixtures of isomers are formed.[9–14] In connection with our research on
DNA adducts we studied previously copper-mediated N-arylation of adenine by
arylboronic acids, which gave mixtures of 9- and 3-arylated adenines and was found
to be a feasible route to the latter ones.[15] Direct arylation of adenine (1) with several
halo-nitrobenzenes was studied by Zare et al.[16,17] Reactions gave moderate to good
yields of 9-substituted adenines if accomplished in dimethylsulfoxide (DMSO) at
150 ꢀC in the presence of Cs2CO3 of K2CO3 and silica gel as a solid support, but
rather long reaction times were needed.[16] The same reaction was performed also
in ionic liquids in the presence of ZnO[17] as well as in dimethylformamide (DMF)
in the presence of KF=Al2O3.[18] In these latter cases a significant rate-enhancing
effect of microwaves was reported. However, 9-substituted adenines were always
the only isomers identified.
Many reactions can be accelerated by microwave irradiation, some of them in
a spectacular way. It is, however, not clear whether the effect of microwave in
these reactions is purely thermal (i.e., caused by a very efficient heating in the whole
volume) or if some nonthermal microwave-specific effects exist.[19,20] Arylation
reactions performed in heterogeneous systems containing polar solvents are likely
to be enhanced by both thermal and nonthermal effects of microwaves. In fact,
nonthermal effects cannot be easily separated from the thermal ones, because both
of them may arise from similar interactions between microwave fields and the
material.[19] In many cases where acceleration of a reaction was shown, reaction
temperature and time profile were not measured with sufficient accuracy. Very often,
what is referred to as reaction temperature is not actually measured directly in the
reaction mixture but is the temperature of the heating medium, mainly oil bath. This
was also the case of hitherto reported arylations of adenine.[16–18] Therefore, we decided
to perform a comparative study of adenine arylation by fluoro- and chloronitro-
benzenes with the aim to characterize expected minor product(s) of the reaction and
to assess the effect of microwaves on the reaction rate and regioselectivity under the
conditions of controlled reaction temperature and, if possible, to distinguish between
purely thermal and microwave-specific effects.
RESULTS AND DISCUSSION
Reaction of adenine (1) with 2- and 4-fluoronitrobenzene (2a and 2b) under the
conditions described by Khalafi-Nezhad et al.[16] proceeded quickly so that it was
complete within minutes. Under these conditions, differences between classical and
microwave-assisted reactions were within the range of experimental uncertainty
and possible effect of microwaves was not measurable (Table 1). In both cases

´ ˇ
L. VANA ET AL.
790
Table 1. Arylation of adenine (1) by halonitrobenzenes (2) at 150 ꢀC with and without MW irradiation;
analytical yields (mean ꢁ SE; n ¼ 3) as determined by HPLC-UV
Yield of aryladenine (%)
Reaction time
(min)
Product ratio
3/4
Halo-nitrobenzene
MW
3
4
3 þ 4
2-Fluoro-2a
2-Fluoro-2a
2-Fluoro-2a
2-Fluoro-2a
4-Fluoro-2b
4-Fluoro-2b
4-Fluoro-2b
4-Fluoro-2b
2-Chloro-2c
2-Chloro-2c
2-Chloro-2c
2-Chloro-2c
4-Chloro-2d
4-Chloro-2d
4-Chloro-2d
4-Chloro-2d
5
5
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
40.7 ꢁ 2.6
42.0 ꢁ 2.3
41.2 ꢁ 3.6
42.6 ꢁ 1.2
65.4 ꢁ 2.9
67.5 ꢁ 2.0
65.3 ꢁ 3.0
58.5 ꢁ 3.0
13.9 ꢁ 2.6
20.4 ꢁ 1.8
28.3 ꢁ 4.4
44.0 ꢁ 3.1
38.2 ꢁ 4.4
50.9 ꢁ 2.1
61.2 ꢁ 3.8
71.5 ꢁ 3.5
37.5 ꢁ 3.0
41.8 ꢁ 3.4
29.6 ꢁ 2.2
24.9 ꢁ 1.1
29.0 ꢁ 2.0
30.2 ꢁ 0.6
17.6 ꢁ 0.8
16.9 ꢁ 1.2
2.2 ꢁ 0.6
3.8 ꢁ 0.3
4.5 ꢁ 0.7
6.4 ꢁ 0.5
3.5 ꢁ 0.3
4.8 ꢁ 0.5
5.3 ꢁ 0.5
6.3 ꢁ 0.3
78.2
83.8
70.8
67.5
94.4
97.7
82.9
75.4
16.1
24.2
32.8
50.4
41.7
55.7
66.5
77.8
52=48
50=50
58=42
63=37
70=30
69=31
79=21
78=22
86=14
84=16
86=14
87=13
92=8
25
25
5
5
25
25
25
25
50
50
25
25
50
50
91=9
92=8
92=8
corresponding 9-nitrophenyladenine (3) was the main product slightly predomi-
nating over a new isomer, which was isolated and identified by NMR and mass
spectrometry as 7-(2-nitrophenyl)- and 7-(4-nitrophenyl)adenine (4a and 4b) for
reactions with 2a and 2b, respectively. The site of substitution was confirmed by
correlation of calculated shielding constants with experimental chemical shift values
for 13C and 15N nuclei (vide infra).
Arylations with fluoroarenes bearing strongly electron-withdrawing substi-
tuents generally proceed much faster than those with chloro- and bromoarenes.[21,22]
Therefore, the effect of microwaves on the reactions of 1 with 2- and 4-chloronitro-
benzenes (2c and 2d) should become more apparent compared to that obtained with
fluoronitrobenzenes 2a and 2b. To obtain identical or closely similar temperature
profiles irrespective of whether the reaction was heated in an oil bath or in a micro-
wave oven, we first measured the temperature profile after immersion of the reaction
flask into the oil bath, which was preheated to 150 ꢀC. After 5 min, a steady-state
temperature of 142 ꢀC in the reaction mixture was achieved. Then, the same tempera-
ture profile was programmed in the microwave oven (Fig. 1).
Reactions were performed in triplicates, and the yields were determined
analytically by high-performance liquid chromatography (HPLC) with a photodiode
array (PDA) detection. Peaks were identified by a preliminary or simultaneous
analysis using electrospray ionization–mass spectrometry (ESI-MS) detection in ser-
ies with PDA and confirmed by comparison with authentic samples of 3a, 3b, 4a, and
4b. A typical chromatogram is shown in the Fig. 2. Isolated products were used as
analytical standards for calibration of the ultraviolet (UV) responses. As shown in
Table 1, the yields of both 9- and 7-arylated products were significantly greater in
the microwave-assisted experiments. Prolongation of the reaction time over 50 min
did not lead to any significant increase in product yields. The greatest total yields
3 þ 4 were obtained with fluoronitrobenzenes 2a and 2b after 5 min of heating. Ortho

ARYLATION OF ADENINE BY HALONITROBENZENES
791
Figure 1. Temperature profile determined after immersing the reaction flask into the oil bath preheated to
150 ꢀC and programmed in the microwave reactor.
isomer 2a was somewhat less reactive and gave approximately 1:1 mixture of 3a and
4a. Prolonged heating (25 min) led to a significant decrease in the yield of N7-isomer
4a while the yield of N9-isomer remained almost unchanged. Compared to 2a para
isomer 2b gave a significantly greater yield of N9-isomer 3b but not of 4b so that the
product ratio 3:4 increased to 3:1 (Table 1).
These trends can be explained by formation of diarylated adenines, which were
detected as minor products by HPLC-MS at m=z 272 (Fig. 2). The yield of N7-
isomers, unlike that of the N9-isomers, decreased with reaction time, indicating their
greater reactivity in the subsequent arylation.
Figure 2. Typical chromatogram of the reaction mixture from the reaction of adenine (1) with 4-
fluornitrobenzene (2b). (a) UV trace taken in the range of 250–260 nm; (b) MS trace, SIM at m=z 257
for detecting the 3 and 4 isomers; (c) MS trace, SIM at m=z 378 for detecting dinitrophenyladenines
(DNFA). The intensity ranges for traces b and c (in ion counts) differ by nearly two orders of magnitude.

´ ˇ
L. VANA ET AL.
792
Compared to fluoronitrobenzenes, chloronitrobenzenes 2c and 2d gave much
lower total yields and showed a different regioselectivity. Corresponding N9-isomers
3a and 3b, respectively, were the predominant products. Microwave irradiation had
a modest but significant effect, increasing the total yield, whereas it had no effect
upon product ratio.
Direct arylation by fluoronitroarenes appears to be a suitable synthetic route
toward 7-aryladenines, which are otherwise hardly available. It has been reported
that adenine reacts with electrophiles predominantly at positions N9, minor sites
of attack being N3 and N1 positions.[7–14] The attack at N1 results in Dewar
rearrangement, affording products of substitution at the exocyclic amino group
N6.[23] The method described here leads to a mixture of N7 and N9 isomers, which
can be efficiently separated by column chromatography on silica gel and further used
for preparation of corresponding aminoaryladenines. The latter compounds were
obtained smoothly in good yields by palladium-catalyzed hydrogenation of
nitrophenyladenines 3a, 3b, 4a, and 4b (Scheme 1). Formation of the N7 isomers
was unexpected as this position has shown minor or no reactivity in hitherto known
reactions of adenine with various electrophiles.[7–14]
Observed significant acceleration of the reaction by microwave irradiation
cannot be attributed to purely nonthermal microwave-specific effects because in
heterogeneous mixtures temperature inhomogeneity may easily occur. It is likely
that polar water molecules at the surface of silica gel are selectively heated by
microwaves.[19,20] Therefore, even if temperatures measured macroscopically in the
reaction mixtures are equal, in the case of microwave irradiation the temperature
at the actual site of reaction, which is most likely the interface between silica gel
and DMSO, can be higher.
1
For structural assignment, a complete set of H, 13C, and 15N NMR chemical
shifts of the studied isomers were determined experimentally in solution by
combination of 1H, 13C-APT, 1H-13C HMQC (heteronuclear multiple quantum
1
1
correlation), H-13C HMBC (heteronuclear multiple bond correlation), and H-15N
HMBC. 15N chemical shifts were extracted from 1H-15N HMBC experiments. These
Scheme 1. Arylation of adenine with halonitrobenzenes followed by nitro group reduction.

ARYLATION OF ADENINE BY HALONITROBENZENES
793
experiments allowed us to exclude substitution at N1, N3 as well as at the exocyclic
N6 position. However, they did not allow us to distinguish between N7 and N9 sub-
stituted isomers because aryl substituents lack a hydrogen at ipso position, which
would otherwise make possible the assignment by heterocorrelated 1H-13C 2D
NMR experiments (HMBC). Preliminary assignment of positional isomers was
therefore based on the assumption that N9-substituted products should predomi-
nate. To prove or disprove this assumption, correlation between calculated shielding
constant and experimental 13C and 15N NMR chemical shifts was performed for
nitroaryladenines 3a, 3b, 4a, and 4b.
Conformational analysis found two pairs of minima on the potential energy
hypersurface pertaining to two pairs of enanatiomeric rotamers for 2-nitrophenyla-
denines 3a and 4a, and only one pair of minima pertaining to the most populated
pair of enantiomers for 4-nitrophenyladenines 3b and 4b (Figs. 3 and 4).
Dihedral angles C4-N9-Cipso-Cortho of the most populated conformers of 3a were
55ꢀ and 135 ꢀ and that of 3b was ꢂ31ꢀ. Similarly, dihedral angles C5-N7-Cipso-Cortho
were ꢂ126 ꢀ and 72ꢀ for 4a and 42ꢀ for 4b. The shielding constants (13C and 15N) were
then calculated for the most populated conformers using Becke-6-Lee-Parr (B3LYP)
hybrid functional implemented in Gaussian03 package[24] with or without solvent
effects (DMSO). Correlation between calculated shielding constants and experimental
values of 13C and 15N chemical shifts in simulated solvent (DMSO) are shown on
Figs. 5 and 6 for 2-nitrophenyl- and 4-nitrophenyladenines, respectively. Very good
Figure 3. The optimized structures of 9-(2-nitrophenyl)adenine (3a) and 7-(2-nitrophenyl)adenine (4a).
Two enantiomeric pairs of conformers at local minima of energy were found for each regioisomer. (Figure
is provided in color online.)

´ ˇ
L. VANA ET AL.
794
Figure 4. The optimized structure of 9-(4-nitrophenyl)adenine (3b) and 7-(4-nitrophenyl)adenine (4b).
For each regioisomer, only one enantiomeric pair of conformers at local energy minimum was found.
(Figure is provided in color online.)
correlation was obtained in all cases (R2 > 0.989). These results confirmed our
preliminary structural assignment of all positional isomers.
In conclusion, direct arylation of adenine with fluoro- and chloronitroarenes
followed by nitro group reduction is a feasible synthetic route to both 7- and
9-aminoaryladenines. A significant rate-enhancing effect of microwave irradiation
was observed in controlled experiments at the same reaction temperature. This effect
can be attributed to thermal inhomogeneity of the reaction mixtures rather than to
a purely nonthermal effect of microwaves.
EXPERIMENTAL
Adenine (purity > 99.5%) and DMSO, extra dry on molecular sieves, were
purchased from Acros Organics (Belgium). Silica gel 60, particle size 63–200 mm,
was from Fluka. All other chemicals were of analytical or synthetic grade and were
used as received. Microwave activation experiments were performed in a Synthewave
402 reactor from Prolabo (France) working at 2.47 GHz with a maximum output of
300 W containing a cylindrical quartz reactor rotating around a static glass paddle.
The reactor was operated in programmed temperature mode, the temperature of the
reaction mixture being measured by an infrared sensor. Merck silica-gel 60 F254
plates were used for thin-layer chromatography (TLC) analyses. HPLC analyses
were performed on a Janeiro LC system (Thermo Fisher Scientific), consisting of
two Rheos 2200 pumps, CTC PAL autosampler, a photodiode-array detector
PDA, and an LXQ linear trap mass spectrometer with electrospray ionization
(ESI). Capillary temperature was set to 300 ꢀC; capillary voltage was 4.2 kV.
Nitrogen was used as drying gas; helium was used as collision gas. Samples were
injected on a BDS Hypersil C18 column 15 ꢃ 2.1 mm, 5 mm particle size. The mobile
phase consisted of acetonitril and aqueous formic acid. Formic acid concentration
was kept constant at 0.15%, and acetonitrile concentration increased linearly starting
from 8.5% to 58% within 15 min and further to 73.5% in an additional 5 min. The
flow rate was 200 mL=min. NMR spectra were measured on a Bruker 600 Avance
(600 MHz for 1H) or a Varian Mercury 300 (300 MHz for 1H) spectrometer.

ARYLATION OF ADENINE BY HALONITROBENZENES
795
Figure 5. Correlation between calculated isotropic part of shielding tensor ,calc and experimental chemical
shift dexp of 3a and 4a. (Figure is provided in color online.)
High-resolution mass spectra were measured on an LTQ Orbitrap Velos instrument
(Thermo Fisher Scientific) using electrospray ionization.
Arylation of Adenine, General Procedure 1: Conventional Heating
A mixture of adenine (1.351 g, 10 mmol), halonitrobenzene 2 (2.60 g,
16.5 mmol), dry potassium carbonate (1.382 g, 10 mmol), and silica gel (3.5 g) in
10 mL DMSO was placed into a 25-mL, three-necked flask equipped with magnetic
stirrer and a thermometer. The flask was immersed into an oil bath, which was
preheated to 150 ꢀC, and the reaction temperature was registered in 1-min intervals

´ ˇ
L. VANA ET AL.
796
Figure 6. Correlation of calculated isotropic part of shielding tensor ,calc and experimental chemical shift
dexp of 3b and 4b. (Figure is provided in color online.)
until it reached steady state. Samples (100mL) were taken after 25 and 50min, diluted
4000 times with aqueous methanol (1:1), and analyzed by HPLC-UV-ESI-MS.
Arylation of Adenine, General Procedure 2: Microwave Irradiation
A mixture of adenine (1.351 g, 10 mmol), chloronitrobenzene 2c or 2d (2.60 g,
16.5 mmol), dry potassium carbonate (1.382 g, 10 mmol), and silica gel (3.5 g) in
10 mL DMSO was placed into a cylindrical quartz vessel, which was then placed
into the microwave reactor. Reaction temperature was programmed to simulate
the temperature profile obtained during conventional heating experiments. Because it
was not possible to take samples without interrupting the irradiation, separate

ARYLATION OF ADENINE BY HALONITROBENZENES
797
experiments were used for each time point. Hence the reaction was stopped after 10,
25, or 50 min, and diluted samples of the reaction mixture were then analyzed by
HPLC-UV-ESI-MS.
9-(2-Nitrophenyl)adenine (3a)[17]. Compound 3a was obtained as the main
product by reaction of 1 with 2a (general procedure 1).
7-(2-Nitrophenyl)adenine (4a). Compound 4a was obtained as a by-product
of 3a. The yield was 303 mg (12%). Rf ¼ 0.30 (10:1 chloroform–methanol). 1H NMR
(DMSO-d6): d ¼ 6.29 (br s, 2H, NH2), 7.81 (d, J ¼ 8 Hz, 1H, 60-H), 7.88 (t, J ¼ 8 Hz,
1H, 40-H), 7.97 (t, J ¼ 8 Hz, 1H, 50-H), 8.31 (s, 1H, 2-H), 8.35 (d, J ¼ 8 Hz, 1H, 30-H),
8.50 (s, 1H, 8-H) ppm.
7-(4-Nitrophenyl)adenine (4b). Compound 4b was obtained as a by-product
1
of 3b. The yield was 203 mg (8%). Rf ¼ 0.25 (8:1 chloroform–methanol). H NMR
(DMSO-d6): d ¼ 6.52 (br s, 2H, NH2), 7.82 (d, J ¼ 8.4 Hz, 2H, 20-H), 8.35 (s, 1H,
2-H), 8.46 (d, J ¼ 8.4 Hz, 2H, 30-H), 8.66 (s, 1H, 8-H) ppm. 13C NMR (DMSO-d6):
d ¼ 110.3 (C5), 125.7 (C30), 126.6 (C20), 140.9 (C10), 146.6 (C8), 147.3 (C40), 151.8
(C6), 153.6 (C2), 161.2 (C4) ppm.
9-(4-Nitrophenyl)adenine (3b)[26]. Compound 3b was obtained as the main
product by reaction of 1 with 2b (general procedure 1).
Preparation of Aminophenyladenines: General Procedure 3
The catalyst, 10% palladium on charcoal (31 mg, 15 mol % Pd), was activated
by heating for 1 h to 90 ꢀC in the stream of argon. The reaction flask was than cooled
to ambient temperature; nitrophenyladenine 3a, 4a, 3b, or 4b (50 mg, 1.95 mmol)
solution in 20 mL of absolute methanol was added, and the reaction mixture
was evacuated and filled with argon repeatedly to remove oxygen. A gentle stream
of hydrogen was introduced, and the reaction mixture was heated to 30 ꢀC for
20 h. The catalyst was filtered off and washed carefully with methanol. The washes
were added to the filtrate, and methanol was then evaporated in a vacuum to yield
pure products.
9-(2-Aminophenyl)adenine (5a). White powder, mp 243–244 ꢀC, obtained
from 3a, yield 39 mg, 89%. 1H NMR (DMSO-d6): d ¼ 5.08 (br s, 2H, ArNH2),
6.68 (t, J ¼ 7.5 Hz, 1H, 50-H), 6.91 (d, J ¼ 8.1 Hz, 1H, 30-H), 7.10 (d, J ¼ 7.8 Hz,
1H, 60-H), 7.20 (t, J ¼ 7.7 Hz, 1H, 40-H), 7.32 (br s, 2H, NH2), 8.12 (s, 1H, 2-H),
13
8.15 (s, 1H, 8-H) ppm. C NMR: d ¼ 116.7 (C50), 116.8 (C30), 119.2 (C5), 120.2
(C10), 128.7 (C60), 130.1 (C40), 141.6 (C8), 145.0 (C20), 150.6 (C4), 153.2 (C2),
156.7 (C6) ppm. HRMS (ESI): calcd. for C11H10N7 227.1040; found 227.1040.
7-(2-Aminophenyl)adenine (6a). White powder, mp > 260 ꢀC, obtained
1
from 4a, yield 36 mg, 82%. H NMR (DMSO-d6): d ¼ 5.40 (br s, 2H, Ar-NH2),
5.88 (br s, 2H, NH2), 6.70 (t, J ¼ 7.5 Hz, 1H, 50-H), 6.94 (d, J ¼ 8.2 Hz, 1H, 30-H),
7.14 (d, J ¼ 7.8 Hz, 1H, 60-H), 7.27 (t, J ¼ 7.7 Hz, 1H, 40-H), 8.27 (s, 1H, 2-H),
13
8.29 (s, 1H, 8-H) ppm. C NMR d ¼ 112.5 (C5), 116.6 (C30), 116.9 (C50), 120.3
(C10), 129.3 (C60), 131.3 (C40), 145.6 (C20), 146.4 (C8), 151.9 (C6), 152.9 (C2),
160.0 (C4) ppm. HRMS (ESI): calcd. for C11H10N7 227.1040; found 227.1040

´ ˇ
L. VANA ET AL.
798
9-(4-Aminophenyl)adenine (5b). White powder, mp > 260 ꢀC, obtained
from 3b, yield 35 mg, 80%. 1H NMR (DMSO-d6): d ¼ 6.73 (d, J ¼ 8.7 Hz, 2H,
13
30-H), 7.40 (d, J ¼ 8.7 Hz, 2H, 20-H), 7.41 (br s, 2H, NH2), 8.19 (s, 1H, 2-H), 8.37
(s, 1H, 8-H) ppm. C NMR (DMSO-d6): d ¼ 114.4 (C30), 119.5 (C5), 124.0 (C10),
125.1 (C20), 140.7 (C8), 148.8 (C40), 149.7 (C4), 152.8 (C2), 156.3 (C6) ppm. HRMS
(ESI): calcd. for C11H10N7 227.1040; found 227.1041.
7-(4-Aminophenyl)adenine (6b). White powder, mp > 260 ꢀC, obtained
1
from 4b, yield 40 mg, 91%. H NMR (DMSO-d6): d ¼ 5.59 (br s, 2H, Ar-NH2),
5.93 (br s, 2H, NH2), 6.72 (d, J ¼ 8.6 Hz, 2H, 30-H), 7.21 (d, J ¼ 8.6 Hz, 2H, 20-H),
8.27 (s, 1H, 2-H), 8.32 (s, 1H, 8-H) ppm. 13C NMR (DMSO-d6): d ¼ 111.7 (C5),
114.3 (C30), 123.6 (C10), 127.5 (C20), 146.2 (C8), 150.4 (C40), 151.7 (C6), 152.9
(C2), 159.7 (C4) ppm. HRMS (ESI): calcd. for C11H10N7 227.1040; found 227.1040
SUPPORTING INFORMATION
1
Full experimental detail, H and 13C NMR spectra, and HPLC traces can be
found via the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENT
Financial support of this work by grant No. 20=2013 (specific university
research) from the Ministry of Education, Youth and Sports of the Czech republic
is gratefully acknowledged.
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