Preparation of benzimidazole N-oxides by a two-step continuous flow process

Article abstract of DOI:10.1007/s10593-017-1992-1

A continuous flow process for the synthesis of nitrobenzimidazole N-oxides from 2,6-dinitrochlorobenzene and amines or amino acids is reported. The process, performed in a two-step sequence, is faster than previously reported batch processes and avoids so

Full text of DOI:10.1007/s10593-017-1992-1

DOI 10.1007/s10593-017-1992-1
Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
Preparation of benzimidazole N-oxides
by a two-step continuous flow process
Fabrizio Politano1,2, Elba I. Buján2, Nicholas E. Leadbeater1*
1 Department of Chemistry, University of Connecticut,
55 North Eagleville Road, Storrs, Connecticut 06269-3060, USA
e-mail: nicholas.leadbeater@uconn.edu
2 Instituto de Investigaciones en Físico Química de Córdoba (INFIQC)-CONICET,
Departamento de Química Orgánica, Facultad de Ciencias Químicas,
Universidad Nacional de Córdoba, Ciudad Universitaria,
X5000HUA Córdoba, Argentina; e-mail: fpolitano@fcq.unc.edu.ar
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(11), 952–957
Submitted October 7, 2016
Accepted November 21, 2016
A continuous flow process for the synthesis of nitrobenzimidazole N-oxides from 2,6-dinitrochlorobenzene and amines or amino acids is
reported. The process, performed in a two-step sequence, is faster than previously reported batch processes and avoids some of the isola-
tion and purification steps.
Keywords: benzimidazoles, N-oxides, cyclization, flow chemistry, green chemistry, nucleophilic aromatic substitution.
The majority of bioactive compounds are heterocyclic
molecules. Nitrogen-containing heterocyclic compounds
are considered particularly privileged structures in drug
development since they can increase binding efficiency and
solubility and can facilitate the formation of salts. These
properties are important in terms of oral absorption and
bioavailability of the drug.1,2
Compounds derived from benzimidazoles and
benzimidazole N-oxides exhibit a wide range of biological
properties. They play roles in agrochemistry3 as well as in
human4–8 and veterinary9 medicine. This wide number of
applications has fueled the study of different synthetic
methods for the preparation of benzimidazole N-oxides,
which cannot be obtained by direct oxidation of
benzimidazoles. Thermal and photochemical cyclizations
of 2-nitroaniline derivatives having electron-withdrawing
substituents at the α-carbon next to the amino group are
known to give benzimidazole N-oxides,10 but the reaction
fails in some cases.11 Therefore, the development of new
synthetic methods to obtain a variety of benzimidazole
N-oxide derivatives is of interest.
synthetic methods. To this end, continuous flow processing
is becoming very useful for the development of medicinal
chemistry.13 Reactions can often be streamlined, multiple
steps can be linked together, and reactions that were
challenging in batch are now available for chemists to use.
There is also better control of heating and mixing, allowing
for reactions to be performed under very precise and
reproducible conditions. While the synthesis of hetero-
cycles, including benzimidazole derivatives, has been
reported using flow processing,14,15 to our knowledge, there
are no reports of synthesis of benzimidazole N-oxides deri-
vatives using this technology. We present our results here.
A series of nitrobenzimidazole N-oxides 1 has been
previously prepared by means of the cyclization of
N-substituted 2,6-dinitroanilines 2 (Scheme 1a). The
method involves heating compound 2 at reflux with sodium
hydroxide in a 1,4-dioxane–water 6:4 mixture as the
solvent.16–18 The disadvantage of this methodology is the
need to synthesize compounds 2 as they are not com-
mercially available. These starting materials were prepared
by an SNAr reaction of 2,6-dinitrochlorobenzene (3) and
amine using DMF as solvent (Scheme 1b).16–18
With increasing legislation and environmental aware-
ness, chemists are under pressure to find cleaner, greener,
and more sustainable ways of making their target
compounds.12 By adopting new technology, it is often
possible to open up avenues for the development of new
Our objective was to improve this method according to
the principles of green chemistry.19 The choice of solvent is
the key to this.20–23 Solvents such as 1,4-dioxane or DMF
are hazardous and their substitution is required. To this
0009-3122/16/52(11)-0952©2016 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
Scheme 1
We turned our attention next to the second step of the
process, the base-mediated cyclization of N-substituted
2,6-dinitroanilines to the corresponding benzimidazole
N-oxides. In microwave-heated batch trials employing a
water–dioxane 1:1 solvent mixture, we found that sodium
hydroxide can be used as the base. However, along with the
desired benzimidazole N-oxide we observed formation of
2,6-dinitrophenol, the result of a substitution reaction. By
keeping the sodium hydroxide concentration lower than
0.2 M we were able to limit the formation of this by-
product.25,26 Moving to ethanol as a solvent, we observed a
number of new by-products. We believed that this was due
to the formation of sodium ethoxide which triggered the
undesired side reactions. For this reason, we decided to
transition to a milder base, selecting potassium carbonate.27
We performed the reaction in batch using compound 2a as
a test substrate, adding a 0.3 M aqueous solution of K2CO3
to an ethanol solution of compound 2a. Heating at 95°C for
20 min gave the desired benzimidazole N-oxide 1a in
quantitative conversion.
In transitioning to flow, we wanted to be able to take the
product stream from the first reaction (conversion of
compound 3 to compound 2), introduce an aqueous
solution of base, and then pass the mixture through a
second 10 ml capacity coil. To achieve this, we needed to
shorten the residence time for the second step from the
20 min we used in batch to around 10–11 min. We decided
to perform a trial reaction. We prepared an ethanol solution
of compound 2a at the concentration it would come out of
coil 1 and a 0.3 M aqueous solution of K2CO3. Pumping
the solution of compound 2a at a flow rate of 0.4 ml/min
and the solution of base at flow rate of 0.5 ml/min through
a 10 ml capacity coil (0.9 ml/min combined flow rate, 11.1 min
residence time) at 120°C, gave a quantitative conversion to
compound 1a (Scheme 3).
(a) Preparation of benzimidazole N-oxides
R
HN
NO2
H
N
O2N
NO2
NaOH
Dioxane
H2O,
R
N
O
1
2
(b) Preparation of N-substituted 2,6-dinitroaniline precursors
R
Cl
HN
O2N
NO2
O2N
NO2
R
NH2
+
DMF
3
2
end, we attempted to perform the SNAr reaction of com-
pound 3 and a range of different amines and α-amino acids.
Reactions were initially run in batch using microwave
heating as a tool.24 When performing reactions involving
simple amines, we selected ethanol as the solvent, while in
the case of α-amino acids a water–ethanol 1:1 mixture was
used. We were successful in preparing a representative
number of N-substituted 2,6-dinitroanilines. Reactions
were performed at 95°C for 10 min employing a 1:2
stoichiometric ratio of compound 3 to amine (in order to
neutralize the HCl liberated in the SNAr reaction).
In planning to translate this methodology to continuous
flow processing, we had to ensure that the reaction mixture
remained homogeneous throughout. When working at
elevated temperatures, use of a back pressure regulator
allows for solvents and reaction mixtures to be heated well
above their boiling points. However, if the product
precipitates out of solution, blockage of the back pressure
regulator or the exit tube can be a potential problem. While
specialized equipment is available for processing slurries,
when using most commercially available apparatus issues
of heterogeneity can be a hurdle that needs to be overcome.
In an attempt to find optimal conditions for the first step
of the process in flow, we selected the reaction of
compound 3 with n-butylamine. Using a 0.15 M solution of
compound 3 in ethanol and a 0.3 M solution of
n-butylamine in ethanol and pumping each at a flow rate of
0.5 ml/min through a 10 ml capacity coil (1 ml/min
combined flow rate; 10 min residence time) at 95°C gave a
71% conversion to compound 2a. By increasing the
residence time to 25 min (0.2 ml/min on each pump) and
the temperature to 120°C we were able to obtain 100%
conversion to compound 2a (Scheme 2).
Scheme 3
With operating conditions for both steps of the reaction
in hand, we moved to concatenating the two steps. The
progress of the reaction could be clearly seen. There is a
marked color change from yellow to red, attributed to the
formation of a Meisenheimer complex (Fig. 1).26 Turning
our attention to product purification, we again wanted to
take an approach with the tenets of green chemistry in
mind. We developed a purification strategy that did not
require chromatography. Instead, using only ethyl acetate
as solvent, we obtained the pure product by aqueous–
organic phase extraction. Working on the 0.25 mmol scale,
we obtained a quantitative conversion of compound 3 and
an 72% isolated yield of compound 1a.
Scheme 2
We next moved to probe the substrate scope of the
methodology. Embarking on this endeavor, we discovered
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Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
a solubility problem when the outlet stream of the first
reactor was mixed with the aqueous stream of base. We
remedied this with the addition of an organic cosolvent to
the base solution. We needed to choose a suitable solvent
that would allow us to keep the organic components of the
reaction in solution but at the same time assure the
solubility of the mineral base. We decided to use
2-propanol as the cosolvent, an 11:2 volume ratio of water–
2-propanol being optimal and allowing us to maintain a
base concentration of 0.3 M. With this improvement, we
prepared a series of six benzimidazole N-oxides (Table 1,
entries 1–6). The flow configuration used is shown in
Figure 2. Good to excellent yields of the N-oxide products
1 were obtained in each case. In the case of ethanolamine
and ethylene diamine (Table 1, entries 5 and 6), rather than
the expected 2-substituted nitrobenzimidazole, 7-nitro-1H-
benzimidazole 3-oxide 1e was formed. This product
implies the loss of CH2OH and CH2NH2 for the reaction
with ethanolamine and ethylene diamine, respectively.
The reaction was also performed with two amino acids –
β-alanine and γ-aminobutyric acid. To ensure complete
solubility for the initial SNAr reaction, we dissolved the
amino acids in water along with two equivalents of
NaHCO3 in order to neutralize the carboxylic acid group
and the HCl liberated in the reaction. With this
modification we were able to obtain good yields of N-oxide
products 1f,g (Table 1, entries 7 and 8). The expected
substituted nitrobenzimidazole N-oxide 1g was obtained
Figure 1. The conversion of compound 3 to
compound 1a using a two-step flow process.
Figure 2. The flow configuration used for the preparation of nitrobenzimidazole N-oxides 1 in flow.
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Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
Table 1. Preparation of nitrobenzimidazole N-oxides 1a–g in flow*
when using γ-aminobutyric acid but in the case of β-alanine,
decarboxylation occurred upon cyclization yielding
compound 1f.
Where available, we compared product yields reported
in the literature with those obtained using our greener
continuous flow procedure. Our methodology resulted in
similar yields, higher in three cases (Table 1, entries 5, 6,
and 8), but with a great improvement from the perspective
of sustainability due to the use of greener solvents, as well
as the avoidance of chromatographic separation in the
purification step. In addition, our flow approach is faster as
compared with the previously reported methods and does
not require the isolation and purification of the
N-substituted aniline intermediate.
Entry
1
Amine
Product
Yield,** %
72, 72***
(75)16
We did attempt to perform the reaction in one step, but
adding a high concentration of base to the reaction mixture
of compound 3 and the amine resulted in the formation of
2,6-dinitrophenol as the principal product. At a low
concentration of base, the SNAr product 2 is the principal
product with little to none of the desired compound 1 being
formed.
In summary, we have developed a continuous flow
process for the synthesis of nitrobenzimidazole N-oxides
from 2,6-dinitrochlorobenzene and amines or amino acids.
The process, performed in a two-step sequence, is faster
than previously reported batch processes and avoids some
of the isolation and purification steps.
2
3
4
5
6
7
8
59 (63)17
53
69
Experimental
1H and 13C NMR spectra were performed at 298 K on
Bruker Advance (300 and 75 MHz, respectively) or Bruker
Advance III (400 and 101 MHz, respectively) spectrometers in
DMSO-d6 and referenced to residual non-deuterated
DMSO (2.50 and 39.5 ppm, respectively) in the deuterated
solvent. Mass spectra were recorded using an Agilent
Technologies 5975 mass spectrometer. High-resolution mass
spectra were obtained using a JEOL AccuTOF-DART SVP
100 instrument in positive direct analysis in real time
(DART) ionization method, using PEG as internal
standard. Reactions were monitored by 1H NMR and/or by
TLC on silica gel plates (60 Å porosity, 250 μm thickness).
TLC analyses were performed using hexane–EtOAc and
Et2O as the eluent, visualizing the compounds with UV
light.
76 (42)18
90 (42)18
65 (69)18
80 (63)18
Flow configuration. Reactions were performed using a
Vapourtec E series flow unit. The two reactor coils used
were made of PFA and had an internal volume of 10 ml.
PEEK Y-mixers (Y-connector, 0.02-in. through-hole) were
purchased from Upchurch Scientific. The configuration
shown in Figure 2 was assembled using the aforementioned
equipment.
Preparation of 7-nitro-2-propyl-1H-benzimidazole
3-oxide (1a) (General method). To a glass vial was added
2-chloro-1,3-dinitrobenzene (3) (49.6 mg, 0.246 mmol,
1 equiv) and anhydrous EtOH to a total volume of 2.5 ml
(0.1 M). To another vial was added n-butylamine (36.0 mg,
0.05 ml, 0.500 mmol, 2 equiv) and made up to 2.5 ml with
anhydrous EtOH. A third vial was filled with 0.3 M K2CO3
solution in water–2-propanol, 11:2. With these solutions
* Reactions performed on the 0.25 mmol scale.
** Literature yield in brackets over two steps in batch.
*** Reaction performed on the 1.0 mmol scale.
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Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
prepared, the continuous flow process was initiated. The
1.34 (3H, t, J = 7.3, CH3). 13C NMR spectrum (101 MHz),
δ, ppm: 156.3; 137.8; 135.0; 131.2; 121.2; 118.1; 115.3;
19.2; 11.2. Mass spectrum, m/z: 208 [M+H]+.
pumps assigned for substrate and amine were primed and
flushed with anhydrous EtOH and the pump for the second
step was primed and flushed with deionized water. The
flow system was equipped with two 10-ml capacity coils in
series (coil 1 and coil 2). Three pumps were employed
(pump A, B, and C). The outlets of pumps A and B were
joined to a Y-piece and the outlet of the Y-piece attached to
the "reagent in'' port of the first reactor coil. The "reagent
out" port of the first reactor coil and the outlet of pump C
were attached to a Y-piece and the outlet of the Y-piece
attached to the "reagent in" port of the second reactor coil.
The ''reagent out'' port of the second reactor coil was
directly interfaced with a back pressure regulator after
which there was a short length of tubing leading to a
collection vessel. The flow system was primed using the
equipment manufacturer's suggested start-up sequence. The
entire system was flushed with EtOH for 5 min at a flow
rate of 0.5 ml/min on each pump. The reactor coils were set
at 120°C and the back regulator pressure set at 5 bar. Then,
the substrate 3 and amine solutions were loaded into the
reactor coil at a flow rate of 0.2 ml/min. Once these solu-
tions were completely loaded, both pumps were set to pump
anhydrous EtOH. After 5 min, pump C (pumping the aqueous
base) was started at a flow rate of 0.5 ml/min. Once the
product mixture was completely out of the system (observed
clearly by the change from red to a colorless solution), all
pumps were stopped. The resulting reaction mixture was
transferred from the collection flask to a separatory funnel.
An extraction with ~15 ml of ethyl acetate was
performed, in order to eliminate the all non-acidic products.
The aqueous layer was acidified using 2 M aqueous HCl,
until pH between 2 and 5 was reached. A color change
from red to yellow in the solution was observed at this point.
The aqueous layer was extracted with EtOAc (3×15 ml). The
combined organic layers were washed with brine (~30 ml)
and dried with Na2SO4. The solvent was removed under
reduced pressure by rotary evaporation affording the pure
benzimidazole N-oxide 1a (39.0 mg, 72%) as a clear
yellow solid. 1H NMR spectrum (300 MHz), δ, ppm
(J, Hz): 7.95 (1H, d, J = 7.1, H-4); 7.72 (1H, d, J = 7.4, H-6);
7.29 (1H, t, J = 8.0, H-5); 2.85–2.78 (2H, m, CH2); 1.83–
1.65 (2H, m, CH2); 0.93 (3H, t, J = 7.4, CH3). 13C NMR
spectrum (101 MHz), δ, ppm: 155.2 (C-2); 137.8 (C-7);
135.1 (C-7a); 131.3 (C-3a); 121.2 (C-5); 118.2 (C-6); 115.5
(C-4); 27.5 (CH2CH2CH3); 20.2 (CH2CH2CH3); 13.8
(CH2CH2CH3). Mass spectrum, m/z: 222 [M+H]+.
7-Nitro-2-phenyl-1H-benzimidazole 3-oxide (1c). To a
glass vial was added 2-chloro-1,3-dinitrobenzene (3) (49.4 mg,
0.245 mmol, 1 equiv) and anhydrous EtOH to a total
volume of 2.5 ml (0.1 M). To another vial was added
benzylamine (50.0 mg, 0.051 ml, 0.470 mmol, 2 equiv) and
made up to 2.5 ml with anhydrous EtOH. A third vial was
filled with 0.3 M K2CO3 in water–2-propanol, 11:2. The
general method was followed for the flow processing step.
The resulting product mixture was transferred from the
collection flask to a separatory funnel. An extraction with
~15 ml of ethyl acetate was performed, in order to
eliminate the all non-acidic products. The aqueous layer
was acidified using 2 M aqueous HCl, until pH between 2
and 5 was reached. A color change from red to yellow in
the solution was observed at this point, along with
formation of a precipitate. The precipitate was isolated by
vacuum filtration, and washed with cold water, affording
the pure benzimidazole 3-oxide 1c (32.9 mg, 53%) as a
1
clear yellow solid. H NMR (400 MHz), δ, ppm (J, Hz):
12.61 (1H, s, NH); 8.31 (2H, dd, J = 6.6, J = 3.0, H Ar);
8.11 (1H, d, J = 7.7, H Ar); 8.01 (1H, d, J = 7.8, H Ar);
7.69–7.56 (3H, m, H Ar); 7.49 (1H, t, J = 8.0, H-5).
13C NMR spectrum (101 MHz), δ, ppm: 150.7; 138.6; 136.7;
131.8; 131.4; 129.3; 129.2; 128.2; 122.6; 119.7; 116.7.
Mass spectrum, m/z: 256 [M+H]+. Found, m/z: 256.0697
[M+H]+. C13H10N3O3. Calculated, m/z: 256.0722.
2-Heptyl-7-nitro-1H-benzimidazole 3-oxide (1d). To a
glass vial was added 2-chloro-1,3-dinitrobenzene (3) (50 mg,
0.247 mmol, 1 equiv) and anhydrous EtOH to a total
volume of 2.5 ml (0.1 M). To another vial was added
octylamine (64 mg, 0.082 ml, 0.496 mmol, 2 equiv) and
made up to 2.5 ml with anhydrous EtOH. A third vial was
filled with 0.3 M K2CO3 in water–2-propanol, 11:2. The
general method was followed for the flow processing step
and the purification protocol used for compound 1c was
followed, affording the pure benzimidazole 3-oxide 1d
1
(47 mg, 69%) as a clear yellow solid. H NMR spectrum
(400 MHz), δ, ppm (J, Hz): 12.11 (1H, s, NH); 8.01 (1H, d,
J = 8.0, H-4); 7.88 (1H, d, J = 7.9, H-6); 7.40 (1H, t, J = 8.0,
H-5); 2.92 (2H, t, J = 7.7, CH2); 1.79 (2H, quint, J = 7.5,
CH2); 1.45–1.13 (8H, m, 4CH2); 0.86 (3H, t, J = 6.7, CH3).
13C NMR spectrum (101 MHz), δ, ppm: 155.4; 137.8;
134.9; 131.2; 121.2; 118.2; 115.3; 31.1; 28.6; 28.3; 26.6;
25.5; 22.0; 13.9. Mass spectrum, m/z: 278 [M+H]+. Found,
m/z: 278.1495 [M+H]+. C14H19N3O3. Calculated, m/z: 278.1505.
7-Nitro-1H-benzimidazole 3-oxide (1e). To a glass vial
was added 2-chloro-1,3-dinitrobenzene (3) (50.0 mg,
0.247 mmol, 1 equiv) and anhydrous EtOH to a total
volume of 2.5 ml (0.1 M). To another vial was added
ethylenediamine (29.7 mg, 0.033 ml, 0.490 mmol, 2 equiv)
and made up to 2.5 ml with anhydrous EtOH. A third vial
was filled with 0.3 M K2CO3 in water–2-propanol, 11:2.
The general method was followed, affording the pure
benzimidazole 3-oxide 1e (40.0 mg, 90%) as a clear yellow
solid. 1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 12.45
(1H, s, NH); 8.71 (1H, s, H-2); 8.08 (1H, d, J = 7.9, H-4);
2-Ethyl-7-nitro-1H-benzimidazole 3-oxide (1b). To a
glass vial was added 2-chloro-1,3-dinitrobenzene (3) (49.9 mg,
0.247 mmol, 1 equiv) and anhydrous EtOH to a total
volume of 2.5 ml (0.1 M). To another vial was added
n-propylamine (28.8 mg, 0.04 ml, 0.490 mmol, 2 equiv)
and made up to 2.5 ml with anhydrous EtOH. A third vial
was filled with 0.3 M K2CO3 in water–2-propanol, 11:2.
The general method was followed, affording the pure
benzimidazole 3-oxide 1b (30.2 mg, 59%) as a clear yellow
solid. 1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 12.15
(1H, s, NH); 8.00 (1H, d, J = 7.9, H-4); 7.87 (1H, d, J = 7.9,
H-6); 7.40 (1H, t, J = 8.0, H-5); 2.95 (2H, q, J = 7.4, CH2);
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Chemistry of Heterocyclic Compounds 2016, 52(11), 952–957
2. Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Discov. 2007,
7.98 (1H, d, J = 8.0, H-6); 7.49 (1H, t, J = 8.0, H-5).
13C NMR spectrum (75 MHz), δ, ppm: 143.0; 137.1; 132.4;
131.0; 122.2; 118.7; 116.2. Mass spectrum, m/z: 180 [M+H]+.
2-Methyl-7-nitro-1H-benzimidazole 3-oxide (1f). To a
glass vial was added 2-chloro-1,3-dinitrobenzene (3) (50 mg,
0.247 mmol, 1 equiv) and anhydrous EtOH to a total
volume of 2.5 ml (0.1 M). To another vial was added
β-alanine (22 mg, 0.247 mmol, 1 equiv), NaHCO3 (42 mg,
0.500 mmol, 2 equiv) and made up to 2.5 ml with water–
anhydrous EtOH, 1:1. A third vial was filled with 0.3 M
K2CO3 in water–2-propanol, 11:2. The representative
procedure was followed, affording the pure benzimidazole
6, 881.
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1
N-oxide 1f (31 mg, 65%) as a clear yellow solid. H NMR
spectrum (300 MHz), δ, ppm (J, Hz): 12.16 (1H, s, NH);
8.01 (1H, d, J = 8.0, H-4); 7.88 (1H, d, J = 7.3, H-6); 7.41
(1H, t, J = 8.0, H-5); 2.59 (3H, s, CH3). 13C NMR spectrum
(101 MHz), δ, ppm: 152.3; 137.5; 135.1; 131.2; 121.0;
118.1; 115.5; 13.4. Mass spectrum, m/z: 194 [M+H]+.
12. Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437.
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3-(7-Nitro-3-oxido-1H-benzimidazol-2-yl)propionic acid
(1g). To a glass vial was added 2-chloro-1,3-dinitrobenzene
(3) (50 mg, 0.247 mmol, 1 equiv) and anhydrous EtOH to a
total volume of 2.5 ml (0.1 M). To another vial was added
γ-aminobutyric acid (26 mg, 0.252 mmol, 1 equiv),
NaHCO3 (42 mg, 0.5 mmol, 2 equiv) and made up to
2.5 ml with water–anhydrous EtOH, 1:1. A third vial was
filled with 0.3 M K2CO3 in water–2-propanol, 11:2. The
general method was followed, affording the pure
benzimidazole N-oxide 1g (50 mg, 80%) as a clear yellow
solid. 1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 12.30
(1H, s, NH); 8.01 (1H, d, J = 8.0, H-4); 7.89 (1H, d, J = 7.9,
H-6); 7.41 (1H, t, J = 8.0, H-5); 3.15 (2H, t, J = 7.2, CH2);
2.85 (2H, t, J = 7.2, CH2). 13C NMR spectrum (101 MHz),
δ, ppm: 173.3; 154.3; 137.9; 135.1; 131.1; 121.5; 118.3;
115.5; 30.2; 21.1. Mass spectrum, m/z: 252 [M+H]+.
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Fabrizio Politano is thankful to Consejo Nacional de
Investigaciones Científicas
y
Técnicas (CONICET),
Argentina, for a PhD fellowship and to Bec.Ar – Fulbright
Commission, for an exchange fellowship.
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