Glucose as an Eco-Friendly Reductant in a One-Pot Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1002/ejoc.202000970

Carbohydrates such as glucose are an abundant renewable resource that can be employed in synthetic processes as a source of carbon and/or hydrogen to yield products of high economical and biological impact. Herein, we report a versatile and environmentally friendly protocol for the one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones, a privileged scaffold in medicinal chemistry, based on the use of glucose as an eco-friendly reductant in alkaline aqueous medium. This method can be viewed as a blueprint for the development of further one-pot sequences involving glucose as a reductant.

Full text of DOI:10.1002/ejoc.202000970

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Glucose as an eco-friendly reductant in a one-pot synthesis of
2,3-dihydroquinazolin-4(1H)-ones
Authors: Thiago dos Santos, Caroline Grundke, Tobias Lucas, Luca
Großmann, Giuliano Cesar Clososki, and Till Opatz
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000970
Link to VoR: https://doi.org/10.1002/ejoc.202000970
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000970
COMMUNICATION
Glucose as an eco-friendly reductant in a one-pot synthesis of
2
,3-dihydroquinazolin-4(1H)-ones
Thiago dos Santos, [a,b] Caroline Grundke, Tobias Lucas, Luca Großmann, Giuliano Cesar
[a]
[a]
[a]
[b]
[a]
Clososki,* Till Opatz*
[
[
a]
b]
Msc. T. D. Santos, Msc. C. Grundke, Msc. T. Lucas, Msc. L. Großmann, Prof. Dr. T. Opatz
Department of Chemistry
Johannes Gutenberg University
55128 Mainz, Germany.
E-mail: opatz@uni-mainz.de
Prof. Dr. G. C. Clososki
Department of Biomolecular Sciences
Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo
Avenida do Café s/n, 14040-900 Ribeirão Preto - SP, Brazil.
E-mail: gclososki@fcfrp.usp.br
Supporting information for this article is given via a link at the end of the document.
Abstract: Carbohydrates such as glucose are an abundant
renewable resource that can be employed in synthetic processes as
a source of carbon and/or hydrogen to yield products of high
economical and biological impact. Herein, we report a versatile and
environmentally friendly protocol for the one-pot synthesis of 2,3-
dihydroquinazolin-4(1H)-ones, a privileged scaffold in medicinal
chemistry, based on the use of glucose as an eco-friendly reductant
in alkaline aqueous medium. This method can be viewed as a
blueprint for the development of further one-pot sequences involving
glucose as a reductant.
Considering the wide variety of pharmaceuticals and
other bioactive molecules bearing the 2,3-
dihydroquinazolin-4(1H)-one motif (illustrated in Figure
),[13–16] the development of protocols for its synthesis is
1
relevant for the area of drug discovery.
One-pot reaction cascades are known to provide
considerable economical and ecological advantages over
[17]
stepwise transformations. They not only consume less solvent
and sometimes also lower quantities of reagents and, most
importantly, reduce the number of individual isolation and
purification operations. Thus, we aimed at developing a one-pot
reaction involving D-glucose as an eco-friendly reductant.
Dihydroquinazolinones have been obtained from various
precursors for the central bicyclic ring system including 2-
aminobenzamides,[ isatoic anhydride,[19] o-halobenzonitriles,[20]
Carbohydrates have found application as building blocks to
construct larger saccharidic structures or as scaffolds in
combinatorial chemistry.[1-3] Moreover, they have been employed
18]
as abundant renewable carbon sources in the preparation of N-
heterocycles[4,5] or as hydrogen sources in mild end eco-friendly
2-nitrobenzamide[21], and 2-aminobenzonitrile[22].
[6–8]
reduction processes.
In particular, D-glucose is an extremely
abundant natural product which can be easily obtained from
lignocellulosic biomass (e.g. wood) via enzymatic treatment or
acid hydrolysis.[9,10] Its reductive properties have even been
employed in the generation of hydrogen in alkaline medium.[11,12]
The reductive properties of D-glucose directly reflect its nature
as
a
reduced form of CO
2
produced in the course of
photosynthetic water splitting.
Scheme 1. Synthetic protocols to furnish 2,3-dihydroquinazolin-4(1H)-ones
from 2-nitrobenzonitrile.
Figure 1. Examples of drugs and bioactive molecules containing the 2,3-
dihydroquinazolin-4(1H)-one scaffold.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000970
COMMUNICATION
In a recent report, Liu and co-workers have employed 2-
nitrobenzonitrile as a precursor to 2,3-dihydroquinazolin-4(1H)-
entry 6 as the established optimum set of conditions, 2-
aminobenzamide was isolated in 92% yield.
ones in
a combined reduction/hydration/cyclocondensation
Table 2. Optimization of the reaction conditions for the synthesis of 2-phenyl-
sequence. However, they had to employ an excess of diboronic
acid and copper as a catalyst in a water/methanol mixture
,3-dihydroquinazolin-4(1H)-one[a]
2
(
Scheme 1).[23] The intermediate formation of 2,3-
dihydroquinazolin-4(1H)-ones from 2-nitrobenzonitrile had also
been observed by Kumar and co-workers in the reaction of the
latter substrates with phenylglycine in the presence of FeCl
3
and
Entr
y
Solvent
(H O)
Temp.
[°C]
Benzaldehyde
Time
Yield [%][b]
K
2
CO
3
.[24] Based on the natural abundance and mild reducing
2
2
3
4
properties of D-glucose, we envisioned the establishment of an
eco-friendly transition-metal free alternative one-pot protocol for
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from 2-
nitrobenzonitrile in alkaline aqueous solution.
1
2
3
4
5
6
7
8
2 mL
2 mL
100
100
120
120
120
120
120
120
120
120
1.0 equiv.
2.0 equiv.
1.2 equiv.
1.2 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
1.5 equiv.
16 h 35 **
16 h 18 17
55
54
63
72
75
78[c]
72
76
77
74
2 mL
16 h 13
6
1 mL
16 h 17 (trace)
1 mL
16 h
7
**
Table 1. Synthesis of 2-aminobenzamide under various conditions[a]
0.8 mL
0.6 mL
0.8 mL
0.8 mL
0.8 mL
16 h
5
**
16 h 14 **
24 h
16 h
16 h
** **
** **
** **
9[d]
1 [
0
e]
Entry
α-D-glucose
2 equiv.
1.5 equiv.
2 equiv.
2 equiv.
1 equiv.
2 equiv.
2 equiv.
2 equiv.
None
Solvent
0.8 mL
0.8 mL
0.8 mL
0.8 mL
4 mL
Base amount
4 equiv.
3 equiv.
2 equiv.
2 equiv.
2 equiv.
2 equiv.
4 equiv.
4 equiv.
2 equiv.
Yield [%][b]
79
1
2
[a] 0.2 mmol equiv. of 2-nitrobenzonitrile, air as atmosphere, α-D-glucose (2
equiv.) and K
stated. [b] Determined by H-NMR using dimethyl sulfone as a standard. [c]
Isolated yield: 75% (white solid). ** Not detected by 1H-NMR. [d] α-D-glucose
(1.5 equiv.) and K
employed.
2
CO
3
(2 equiv.) apply for all the reactions unless otherwise
87
1
3
91
4[c]
90
2 3 2 3
CO (3 equiv.) were employed. [e] K CO (4 equiv.) was
5
74
6
4 mL
94[d]
7
4 mL
95
Knowing that two equivalents of glucose in water with two
equivalents of potassium carbonate satisfactorily led to the
conversion of 2-nitrobenzamide into anthranilamide, we then
questioned the possibility of using benzaldehyde to afford the
imine formation and subsequent 6-endo-trig-cyclization
furnishing the desired the 2,3-dihydroquinazolin-4(1H)-one in a
one-pot fashion. Gratifyingly, with one equivalent of
benzaldehyde at 100 °C for 16 hours (entry 1, Table 2), 2-
phenyl-2,3-dihydroquinazolin-4(1H)-one (4) was obtained in 55%
yield along with 2-aminobenzamide (2). Increasing the amount
of aldehyde favored the conversion of 2 into the imine 3 (entry 2)
while setting the temperature to 120 °C with a slight excess of
benzaldehyde positively influenced the produced amount of 4
8[e]
4 mL
None
None[f]
9
4 mL
[a] The time of 3 h, temperature of 100 °C, air as atmosphere and 0.2 mmol of
2-nitrobenzonitrile apply for all the reactions unless otherwise stated. [b]
Dimethyl sulfone was employed as NMR standard for quantification. [c] Argon
as atmosphere. [d] Isolated yield: 92%. [e] The temperature of 50 °C favored
the formation of 2-nitrobenzamide (86% yield, NMR quantification after
extraction with AcOEt 3·10 mL). [f] Only 2-nitrobenzamide was observed.
Under avoidance of strong bases such as potassium
hydroxide or sodium hydroxide which were regularly applied in
reductions with glucose,[6,12,25] an environmentally benign and
inexpensive base, potassium carbonate,[26] was chosen in
conjunction with an aqueous glucose solution (Table 1). Initially,
by setting the temperature to 100 °C and the solvent volume to
(
entry 3). Keeping this temperature but reducing the amount of
solvent led to a substantial increase in yield (entry 4, 72%). This
change in conditions was then repeated with 1.5 equivalents of
benzaldehyde (entries 5, 6 and 7) with 0.8 mL of water being the
optimal observed amount of solvent. Working with a higher
amount of the base (entry 10), 1.5 equivalents of glucose with 3
equivalents of potassium carbonate (entry 9) or prolonging the
reaction time to 24 hours (entry 8) did not increase the yield. By
adopting entry 6 as the optimized set of conditions, 4 was
isolated as white solid in 75% yield.
0
.8 mL with 0.8 mmol (4 equiv.) of the base, both the conversion
of the nitroarene into the aniline and the hydration of the cyano
group were observed in the formation of 2-aminobenzamide
(
2
entry 1, 79%). When the reaction was monitored by HPLC-MS,
-nitrobenzamide and 2-aminobenzonitrile were not observed.
Based on the detection of 2-nitrobenzamide at lower
temperature, it can be assumed that the nitrile hydration is the
first reaction in the sequence. Reducing the excess of potassium
carbonate and varying the amount of glucose (entries 2 and 3)
produced a higher yield while running the reaction in air instead
of inert atmosphere did not change the outcome (entries 3 and
With the establishment of
a one-pot protocol for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones with glucose in
alkaline water, the reaction scope was investigated, and the
results are summarized in Table 3. Considering electron rich
aldehydes, mono-substituted benzaldehydes bearing electron
donating groups such as methyl and methoxy in para position
afforded 2,3-dihydroquinazolin-4(1H)-ones in good yields (6b,
7% and 6e, 75%). Disubstituted benzaldehydes with similar
electronic characteristics as for 6k and 6l, were also tolerated
and the former one was produced in the highest isolated yield
4
). Interestingly, by working with more diluted solutions, a higher
yield was obtained (entries 6 and 7) unless the amount of
glucose was changed (entry 5). When the reaction was run at
7
5
0 °C for three hours or in the absence of glucose, only the
hydration of the cyano group of 2-nitrobenzonitrile was observed
entries 8 and 9, respectively). From the reaction described in
(
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000970
COMMUNICATION
(
6
90%). With three substituents as verified in for the synthesis of
r, the obtained yield was lower. For halogenated
benzaldehydes, the yield ranged from low to moderate
23−65%). Acetophenone did not react with 2-aminobenzamide
from the strong electron withdrawing effect of the ortho-nitro
group.
The subsequent nitro reduction to the amine may take two
different pathways according to the Haber mechanism,[28] one
with a hydroxylamine intermediate and the other one involving
(
under the stablished conditions to furnish 6s as a limitation.
Extending the scope with heterocyclic aldehydes, the product
derived from 2-thiophenecarboxaldehyde (6h) was isolated in
heterodimerization to azoxy and azo compounds which are
usually formed under high alkaline conditions.[
25,29]
However, no
5
9% yield while furfural (6u) and 2-pyridinecarboxaldehyde (6t)
azoxy and azo species were observed by Opolonick in the
reduction of nitrobenzene to aniline using glucose in water with
potassium carbonate.[30] The synthesis of azoxy compounds can
be straightforwardly accomplished by adding glucose to an
aqueous solution of NaOH and the nitro compound, while the
did not produce any noticeable yield. The developed protocol
was however suitable for a model aliphatic aldehyde, pentanal,
with a moderate yield of 56% (6j) and cyclic aliphatic ketones as
for cyclohexanone (6i, 79%) and cyclopentanone (6n, 61%).
addition of
a
second equivalent of glucose reduces the
Table 3. Substrate scope[a]
[25,31]
generated azoxy compound to the azo species.
To mainly
obtain the hydroxylamine while avoiding further reduction to the
corresponding amine, glucose can be employed as the
[32]
reductant in an enzymatic process with a nitroreductase or in
a fermentation with baker’s yeast.[33] Considering the possible
competing reactions for the synthesis of 2,3-dihydroquinazolin-
4
(1H)-ones, it is worth mentioning the amide hydrolysis to the
carboxylic acid even with potassium carbonate as verified via
HPLC-MS and base-induced reactions[34] of the aldehyde
component.
In summary, the established environmentally friendly one-pot
protocol promoting nitrile hydration, nitro-reduction, imine
formation and cyclization with glucose in alkaline water (scheme
2
2
) represents a new, valuable method for the rapid synthesis of
,3-dihydroquinazolin-4(1H)-ones and can be viewed as a
blueprint for the development of further one-pot sequences
involving glucose as a reductant. Glucose is an important
renewable resource accessible from lignocellulosic biomass
through well-established technology while water serves as the
solvent and potassium carbonate (“potash”, available from plant
ashes) as the base. It should be noted that no competition of the
aldehyde glucose with the externally added carbonyl compound
in the cyclization step was encountered and that aldehyde-
derived dihydroquinazolinones can be easily oxidized under eco-
friendly conditions[35] to the corresponding quinazolinones, which
find even wider application in medicinal chemistry.[
36]
[a] Isolated yields. [b] 0.2 mmol scale. [c] 0.5 mmol scale.
From a mechanistic point of view, it is well established that
glucose under hot alkaline conditions produces reduction
equivalents (“H ”), and the hydroxide anion plays an essential
role in its decomposition into carboxylates such as formate,
lactate and glycolate.[11] It was possible to detect formate in the
Scheme 2. Proposed mechanistic pathway for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones from 2-nitrobenzonitrile.
2
2
mixture in a standard reaction performed in D O (Table 1 –
optimized conditions, see the SI). Tu and co-workers have Acknowledgements
proven the suitability of potassium carbonate to promote the
hydration of diverse nitriles and proposed it to deprotonate water
in the generation of this ionic species.[27] Thus, it is plausible to
expect that hydroxide anion can act on glucose decomposition
and nitrile hydration at the same time leading to 2-
amizobenzamide as observed in this study at temperatures
equal to or above 100 °C. The facile hydration of 2-
nitrobenzonitrile into 2-nitrobenzamide observed at 50 °C profits
NMR spectroscopy and mass spectrometry related contributions
are greatly acknowledged from Dr. Johannes C. Liermann
(Mainz) and Dr. Christopher Kampf (Mainz) as well as financial
support (CAPES-PRINT - 88887.368237/2019-00, CNPq n.
140137/2018-1, and FAPESP n. 2018/14150-8), and the
chemistry-based fruitful discussions and general support from
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000970
COMMUNICATION
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4
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents
Sugar Reduction
The synthesis of 2,3-dihydroquinazolin-4(1H)-ones in a one-pot cascade manner (nitrile hydration, nitro-reduction, imine formation,
and cyclocondensation) is reported. Glucose, a renewable resource, can be easily obtained from abundant lignocellulosic biomass
and was employed as a mild reductant in alkaline aqueous medium with 2-nitrobenzonitrile.
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