Unravelling 2-aminoquinazolin-4(3: H)-one as an organocatalyst for the chemoselective reduction of nitroarenes

Article abstract of DOI:10.1039/c7nj03333h

A novel, mild and transition metal-free, 2-aminoquinazolin-4(3H)-one-assisted reduction of nitroarenes employing hydrazine hydrate as reducing agent and potassium carbonate as a base is reported. For the first time, the activation of hydrazine hydrate with an organocatalyst has been explored for reduction reactions. Also for the first time, 2-aminoquinazolin-4(3H)-one and its derivatives have been investigated as hydrogen bonding organocatalysts for the reduction of nitroarenes to anilines. Sensitive functional groups such as sulfonamide, carboxyl, amide and halides were well tolerated in this green methodology with scalability and high chemoselectivity.

Full text of DOI:10.1039/c7nj03333h

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The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C7NJ03333H
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ARTICLE
Unravelling 2-aminoquinazolin-4(3H)-one as an organocatalyst for
the chemoselective reduction of nitroarenes
Received 00th January 20xx,
Accepted 00th January 20xx
Maheshwar S. Thakur,a,b Onkar S. Nayal,a,b Rohit Rana,a,b Manoranjan Kumar,a,b Sushila Sharma,a,b
Neeraj Kumarc and Sushil K. Maurya*a,b
DOI: 10.1039/x0xx00000x
A novel, mild and transition metal free, 2-aminoquinazolin-4(3H)-one assisted reduction of nitroarenes employing
hydrazine hydrate as reducing agent and potassium carbonate as a base is reported. Activation of hydrazine hydrate with
organocatalyst was first time explored for the reduction reactions. 2-Aminoquinazolin-4(3H)-one and its derivatives were
first time investigated as hydrogen bonding organocatalyst for the reduction of nitroarenes to anilines. Sensitive functional
groups such as sulphonamide, carboxyl, amide and aryl halides were well tolerated in this green methodology with
www.rsc.org/
scalability
and
high
chemoselectivity.
bond interaction properties of 2-aminoquinazolin-4(3H)-ones
with various organic molecules (Fig. 1b and 1c) and used as H-
bond organocatalyst in Michael addition reactions.5a Similarly,
Kobayashi et al. described benzothiadiazine catalyzed
epoxidation of α,β-unsaturated amides for the synthesis of
chiral 2-oxiranecarboxamides through H-B interactions.5b
Moreover, Takemoto group also reported the enantioselective
hydrazination of β-keto esters facilitated by H-B donor sites of
2-aminoquinazolin-4-one.5c
Above reports splashed that 2-aminoquinazolin-4(3H)-one
have hydrogen bond donor (D) as well as acceptor (A) sites
along with Lewis basic site those are capable of interacting
with the diverse class of molecules (Fig 2). These ADDA or
DADA hydrogen bonding sites enforce us to explore its
potential as an organocatalyst in transfer hydrogenation
reactions (Fig. 2).
Introduction
Hydrogen bond donor and acceptor molecules have emerged
as powerful tool in sustainable organic synthesis, which led to
selective organocatalysis enabling new approaches.1 Distinct
hydrogen bond donor motifs associated with complementary
functional or structural frameworks offer promising interfaces
with other molecules.2 Therefore, these are known to catalyze
an array of various cross-coupling reactions with high
chemoselectivity and broad substrate scope.3 Thioureas,4a,4b
squaramides,4c,4d,4e
2-aminobenzimidazoles,4f,4g
2-
aminopyridinium salts4h and silanediols4i,4j type motifs have
been introduced to date as hydrogen bond (H-B) catalyst. So,
numerous endeavors were ongoing towards the design and
synthesis of new H-B organocatalyst. In this frame, inspired
from selective hydrogen bond mechanism of guanine with
cytosine in DNA (Fig. 1a),5a Suez et al. in 2011 disclosed the H-
Fig. 2 Various catalytic sites on 2-aminoquinazolin-4(3H)-one
Fig. 1 (a) H-Bond interactions between guanine and cytosine in DNA.5a (b)
Hypothetical interactions of guanine with nitrobenzene.5a (c) Hypothetical
interactions of 2-aminoquinazolin-4(3H)-one with nitrobenzene.
Moreover, we have been working for the development of
approaches for the reduction of nitroarenes and recently
reported a reduction reaction of nitroarenes using vasicine, a
quinazoline alkaloid, as an organocatalyst.[6a] However, this
reaction required prolonged reaction time, high catalyst
loading and elevated temperature. Therefore to overcome
these limitations, we continue our studies further and
envisioned to investigate the application of selected
quinazolin-4(3H)-one molecules, synthesized earlier,[6b] as an
organocatalyst in the reduction of nitroarenes to anilines (Fig.
a. Natural Product Chemistry & Process Development Division, CSIR -Institute of
Himalayan Bioresource Technology Palampur, Himachal Pradesh 176061, India.
b. Academy of Scientific and Innovative Research, Anusandhan Bhawan, 2 Rafi
Marg, New Delhi-110001, India.
c. Deceased on 28th March 2016.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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3). Anilines are present in a broad range of natural products, increasing the quantity from 6 to 8 equivalents (Table 1,
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DOI: 10.1039/C7NJ03333H
pharmaceuticals, dyes, agrochemicals and photographic entries 6, 13 and 14). 6 Equivalents of hydrazine hydrate was
materials.7 Owing to their immense importance, numerous found optimum for this reaction (Table 1, entries 14).
metal catalyzed methodologies have been reported for the
reduction of nitroarenes using variety of reducing agents such
Table 1 Optimization of reaction conditions
as sodium borohydride,8 hydrosilane,9 hydrazine derivatives10
and formates.11 However, most of these methods demands
harsh reaction conditions, non-ecofriendly solvents, utilized
relatively expensive and toxic metal catalyst.12
Reducing
Entry Catalyst
Additive Solvent Yieldb
source
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
N2H4.H2O
HCOOH
PhSiH3
PMHS
N2H4.H2O
N2H4.H2O
N2H4.H2O
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
L2
L2
-
-
-
-
-
-
16
34
27
19
13
78
21
22
24
N.R.
N.R.
N.R.
80c
60d
51
K2CO3
Na2CO3
KCl
NaCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Fig. 3 Variety of quinazolin-4(3H)-one derivative synthesized6b
.
Therefore, development of sustainable and greener method
for the reduction of nitroarenes to anilines is highly desirable.
Accordingly, few transition metal free reports are
demonstrated to date using 9,10-dihydroanthracene,13a (2-
pyridyl)phenylmethanol,13b graphene oxide,13e fullerenes,13d
1,4-dihydropyridines,13c mesoporous carbon13f and glucose13g
as catalyst. Herein, we report pristine 2-aminoquinazolin-
4(3H)-one catalyzed reduction of aromatic nitro compounds
utilizing hydrazine hydrate as reducing agent in methanol.
Notably, hydrazine hydrate is stable, safe and convenient to
handle as compared to its anhydrous form.10a Moreover, the
by-product of hydrazine hydrate is non-toxic N2 gas which makes it
a suitable and safe reducing agent.10a Also, this protocol employed
methanol as a non-toxic and easily available solvent.12a
aReaction conditions: 4-Iodonitrobenzene (0.1mmol), catalyst (10 mol%),
reducing agent (6 equiv.), additive (1 equiv.), solvent (2 mL) at 100 oC for 5h.
bIsolated yield. c8 equiv. hydrazine hydrate. d4 equiv. hydrazine hydrate.
In the absence of catalyst, 51% of the desired product was
observed (Table 1, entry 15). Comparative observation in the
yield are shown by NMR titration in figure 4 and figure 5.
Results and discussion
For the optimization of reaction conditions, 4-
iodonitrobenzene (1a) was chosen as model substrate. Initially,
various quinazolin-4(3H)-one derivatives (Fig. 3) were screened
for the reduction of 1a in the presence of 4 equivalents of
hydrazine hydrate in methanol. It was observed that L2
afforded relatively higher yield than L1, L3, L4 and L5 (Table 1,
entries 1-5). It might be due to less steric hindrance and
effective H-bond interactions in case of L2. To enhance the
yield, various additives such as K2CO3, Na2CO3, NaCl, KCl were
tested (Table 1, entries 6-9). Among them, K2CO3 showed a
significant increase in the yield of the desired product (Table 1,
entries 6). In addition, investigations were extended for the
activity of different reducing agents and only hydrazine
hydrate afforded the optimum yield of desired product (Table
1, entries 6 and 10-12). Moreover, significant variations in the
yield of desired product were monitored with changing the
quantity of hydrazine hydrate. Decrease in yield was observed
when quantity of reducing agent was decreased from 6 to 4
equivalents while slight increase in yield was observed on
Fig. 4 Reaction observation by NMR in the presence of catalyst
Subsequently, the effect of solvent was checked and it was
observed that reaction proceeded efficiently in protic solvents
and highest yield was found in methanol (SI Table 1, entries 8
and 20-25). However, no reaction was observed in polar
aprotic solvents and non-polar solvents (SI Table 1, entries 22-
25). Also, variation in yield was observed with temperature
and at 100 oC highest yield of desired product was observed (SI
Table 1, entries 8, 26 and 27).
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nitrobenzonitrile, hydration of nitrile group along with the
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DOI: 10.1039/C7NJ03333H
reduction of nitro group was observed (Table 2, entries 2i and
2k). To overcome this hydration, reduction of nitrile
substituted nitroarenes was conducted in the absence of base
and good yield was obtained (Table 2, entries 2j and 2l).
Reduction of 1,3-dinitrobenzene in methanol afforded mixture
of
3,3’-diaminoazobenzene,
3-nitroaniline
and
1,3-
diaminobenzene while reduction in water gave regioselectively
3-nitroaniline (Table 2, 2m). Hence, reductions of dinitroarenes
were carried out in water (Table 2, 2m-2o). 1,4-Dinitrobenzene
was selectively reduced to 4-nitroaniline (2n) in good yield
while 3,5-dinitrobenzamide afforded
a
regioselectively
reduced product, 3-amino-5-nitrobenzamide (2o) in
a
Fig.5 Reaction observation by NMR in the absence of catalyst
moderate yield (Table 2, 2n and 2o). Electron rich nitroarenes
such as 3-phenylnitrobenzene and 4-methoxynitrobenzene
were reduced successfully to afford corresponding anilines in
moderate yield (Table 2, 2q and 2r). However, reduction of 3-
nitroaniline afforded 3,3’-diaminoazobenzene (2p) instead of
desired 1,3-diaminobenzene (Table 2, 2p). Developed method
was further explored for the reduction of polycyclic
nitroarenes. Reduction of 1-nitronaphthalene and 2-
nitrofluorene afforded corresponding amines in moderate
yield (Table 2, 2s and 2t), while heterocyclic nitroarenes such
as 5-nitroisoquinoline and 5-nitroindole were converted to
their corresponding amines in a good yield without affecting
the heterocyclic ring (Table 2, 2u and 2v).
After the optimization of reaction conditions, the feasibility of
the developed method (Table 1, entry 6) was assessed for the
reduction of nitroarenes and hetero-nitroarenes. First, halogen
substituted nitroarenes were reduced to corresponding
haloanilines in good yield (Table 2, 2a-2d). Previously,
dehalogenated products of halonitroarenes were reported
using different approaches such as catalytic hydrogenation,
Pd(OAc)2/PMHS and S8/mild.[14]
Table 2 Substrate scope
Encouraged by these results, we subsequently carried out the
reduction of 1,3-dinitrobenzene in gram scale to demonstrate
the utility of this method. The reaction of 1 gram of 1,3-
dinitrobenzene in water afforded 83% of regioselectively
reduced product i.e. 3-nitroaniline (Scheme 1).
Scheme 1 Gram scale reaction of 1,3-dinitrobenzene
To understand the reaction mechanism, numbers of control
experiments were conducted (Scheme 2). First, the reduction
pathway was investigated. It was well established that nitro
reduction follows radical pathway, direct pathway or
condensation pathway.[8] Therefore, to rule out the
involvement of radical pathway, model reaction was carried
out in the presence of TEMPO (Scheme 2A). As expected, no
appreciable change in the yield of the product (1b) was
observed, indicating the absence of radical pathway. No
product was observed when the reaction was carried out with
azobenzene under method A (Scheme 2B). Even its partially
reduced product i.e. hydrazobenzene was not found in GC-MS
analysis. However, 65% of desired product was obtained with
nitrosobenzene (Scheme 2C). These experiments revealed that
reaction followed the direct pathway rather than the
condensation pathway.
aReaction conditions: nitroarene (0.5 mmol), 2-aminoquinazolin-4(3H)-one
(L2, 10 mol%), N2H4.2H2O (6 equiv.), K2CO3 (1 equiv.), CH3OH (3 mL) at 100 oC.
bReaction carried out in the absence of base. cReaction carried out in water.
Next, the reductions of nitroarenes having electron
withdrawing functional groups were investigated (Table 2, 2f-
2o). Electron withdrawing functional groups such as amides,
sulphonamide, carboxyl and nitro were well tolerated and
quite high yield was observed with optimized conditions (Table
2, 2f-2h and 2m-2o). However, in the reduction of m- and p-
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elongation of N2H4 (SI Figure 3).[16] Also new peaks at 2017,
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2032, 2158 and 2181 cm-1 might be due to polarization of C=O,
DOI: 10.1039/C7NJ03333H
C=N and C-N bonds of L2 because of hydrogen bond
interactions (SI Figure 3).[17]
Scheme 2 Control experiments performed for the mechanism of reaction.
After the successful finding of reaction pathway, the role of
hydrazine hydrate for the reduction of nitro group was
investigated. In literature, hydrazine hydrate was outlined to
dissociates into hydrogen ions, nitrogen gas and ammonia in
the presence of metal salts.[15a] Therefore, to ascertain the role
of ammonia in reaction,[15b] reduction of 1a was attempted
with aqueous ammonia (Scheme 2D) and gaseous ammonia
i.e. by means of heating urea (Scheme 2E), but the reduced
product was not observed in both cases. These experiments
indicated that hydrogen ions and electrons from hydrazine
actually participated in the reduction process. [15]
Fig. 6 Plausible mechanism of the reaction.
Moreover, to support the IR observation, we performed UV-
Vis and Fluorescence spectroscopy experiment of the reaction
of L2 with hydrazine hydrate. In the UV-Vis spectroscopy, 2-
aminoquinazolin-4(3H)-one (L2) showed absorption at 260 nm
and 315 nm in methanol. However, addition of hydrazine
hydrate resulted in the very low intensity band at 260 nm and
decrease in the intensity of band at 315 nm was observed (SI,
Figure 4). Moreover, in fluorescence experiment, excitation at
315 nm, it exhibited a blue emission at 400 nm. Further, the
addition of hydrazine hydrate resulted in quenching of
emission spectrum (SI, Figure 5). Thus, absorption and
emission results suggested that the hydrazine hydrate attack
at the nucleophilic carbonyl center and distorts the
conjugation in molecules.
On the basis of results of above experiments, it was discovered
that reduction reaction followed the direct pathway and the
catalytic role of L2 catalyst could be attributed to the transfer
of hydrogen ions and electrons from hydrazine hydrate for this
pathway. Taking into account the above discussion, the
plausible mechanism was depicted in figure 6.
Table 3. Data comparing yield of reaction with catalyst L2, Thiourea and Guanidine
Catalyst
Yield
L2
34%a
Thiourea
8%b
Guanidine
12% b
aReaction conditions: 4-iodonitrobenzene (0.1 mmol), N2H4.H2O (6 equiv.),
catalyst (10 mol%), methanol (2 mL), isolated yield. bNMR yield
Next, we sought to investigate the facet of organocatalyst in
the reduction of nitroarenes. Since L2 have proton acceptor as
well as proton donor sites and hydrazine is proton rich
molecule, therefore the possibility of hydrogen bond
interaction between L2 and hydrazine could not be ignored. To
compare the extent of H-B interaction, parallel reactions were
performed with other catalyst (Table 3). However 34%, 8% and
12% yield was observed using catalyst L2, thiourea and
guanidine respectively. Further, infrared spectroscopy was
performed to find hydrogen bond interactions between L2 and
hydrazine.
The infrared spectra of hot aqueous solution of L2 (SI Figure 1)
and hydrazine hydrate (SI Figure 2) were compared with IR
spectra of the reaction of N2H4.H2O with L2 (SI Figure 3) in
water. Blue shift was observed for N-N stretching frequency
from 1080 to 1089 cm-1 indicating the decrease in N-N bond
length of hydrazine while red shift is observed for N-H bending
frequency from 1612 to 1606 cm-1 signifying N-H bond
Conclusions
Herein, guanine type bicyclic moiety i.e. 2-aminoquinazolin-
4(3H)-one is first time reported as hydrogen bond
donor/accepter organocatalyst which facilitates the reduction
of nitroarenes by interacting with hydrazine. This transition
metal free methodology avoids the implementation of
hazardous reagents, high pressure, flammable hydrogen gas
and harsh reaction conditions. Additionally, moderate reaction
time, relatively less expensive reagents, good to high yields
and broad functional group tolerance are other noticeable
features of this important organic transformation. Further
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5
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Experimental
Hydrazine hydrate (3 mmol) was added to the mixture of
nitroarene (0.5 mmol), K2CO3 (0.5 mmol) and 2-
aminoquinazolin-4(3H)-one (10 mol%) in solvent (H2O/CH3OH
according to reactant) 3 mL at 100 °C for 2-12 h. However, in
case of methanol as a solvent, it was also added to the vessel
during the progress of reaction before it become dry. After
completion of the reaction (as monitored by TLC and GC-MS),
reaction vessel was kept at room temeperature and product
was extracted with ethyl acetate (3 x 5 mL). Combined organic
layer was washed with brine and distilled water (3 x 5 mL),
dried on anhydrous sodium sulphate and solvent was
evaporated under vaccum. Crude product was analyzed
directly using GC-MS and product was isolated from crude by
column chromatography.
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Conflicts of interest
Authors declare no conflict of interest.
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Acknowledgements
The authors are grateful to the Director, CSIR-IHBT for financial
support (MLP0066). M.S.T., M. K. and S.S. are thankful to UGC
and R. R. is thankful to CSIR, New Delhi, India for their
Fellowships. IHBT communication no. for this publication is
4150.
Notes and references
1
2
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ARTICLE
Journal Name
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DOI: 10.1039/C7NJ03333H
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New Journal of Chemistry
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DOI: 10.1039/C7NJ03333H
Unravelling 2-aminoquinazolin-4(3H)-one as an organocatalyst for the
chemoselective reduction of nitroarenes
Maheshwar S. Thakur, Onkar S. Nayal, Manoranjan Kumar, Sushila Sharma, Neeraj Kumar and Sushil K.
Maurya*
O
Organocatalysis
NH
K2CO3
Transition metal free
N
NH2
Methodology
N2H4. 2H2O
H
NO2
NH2
NH2
2H+
N
O
N
H
CH3OH
R
N
R
NH2
2e-
NH2 K2CO3
R = -CONH2, -COOH, -NO2,
-OCH3, -SO2NH2,- Ph
H
H2O
N2
N
H
Products
Reactants
Abstract
A novel, mild and transition metal free, 2-aminoquinazolin-4(3H)-one assisted reduction of nitroarenes
employing hydrazine hydrate as reducing agent and potassium carbonate as a base is reported.
Activation of hydrazine hydrate with organocatalyst was first time explored for the reduction reactions.
To the best of our knowledge, 2-aminoquinazolin-4(3H)-one and its derivatives were first time
investigated as hydrogen bonding organocatalyst for the reduction of nitroarenes to anilines. Sensitive
functional groups such as sulphonamide, carboxyl, amide and aryl halides were well tolerated in this
green methodology with scalability and high chemoselectivity.

New Journal of Chemistry
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DOI: 10.1039/C7NJ03333H