Preparative-scale synthesis of amino coumarins through new sequential nitration and reduction protocol

Article abstract of DOI:10.1016/j.tetlet.2017.09.040

In contrast to the conventional deleterious approach for nitration (for example HNO₃/H₂SO₄) and for reduction (for example Zn/HCl), we hypothesized that sensitive heterocycles such as coumarins could not withstand with those hard conditions. Hence, while studying this reaction sequence to prepare amino coumarins (which is our ongoing project to synthesize antitubercular coumarin agents), we came across mild and greener reagent for nitration using calcium nitrate (Ca(NO₃)₂·4H₂O; lime nitrate), and reduction using D-glucose. These two mild, chemoselective, high yielding methods are discussed herein.

Full text of DOI:10.1016/j.tetlet.2017.09.040

Accepted Manuscript
Preparative-scale synthesis of amino coumarins through new sequential nitra-
tion and reduction protocol
Hemchandra K. Chaudhari, Akshata Pahelkar, Balaram S. Takale
PII:
S0040-4039(17)31167-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.040
TETL 49310
Reference:
Tetrahedron Letters
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11 September 2017
15 September 2017
Please cite this article as: Chaudhari, H.K., Pahelkar, A., Takale, B.S., Preparative-scale synthesis of amino
coumarins through new sequential nitration and reduction protocol, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.09.040
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Tetrahedron Letters
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Preparative-scale synthesis of amino coumarins through new sequential nitration and
reduction protocol
Hemchandra K. Chaudharia, ∗ Akshata Pahelkara and Balaram S. Takaleb
a Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400 019, Maharashtra, India
b Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
In contrast to the conventional deleterious approach for nitration (for example HNO3/H2SO4)
and for reduction (for example Zn/HCl), we hypothesized that sensitive heterocycles such as
coumarins could not withstand with those hard conditions. Hence, while studying this reaction
sequence to prepare amino coumarins (which is our ongoing project to synthesize antitubercular
coumarin agents), we came across mild and greener reagent for nitration using calcium nitrate
(Ca(NO3)2.4H2O; lime nitrate), and reduction using D-glucose. These two mild, chemoselective,
high yielding methods are discussed herein.
Received in revised form
Accepted
Available online
Keywords:
Amines
2009 Elsevier Ltd. All rights reserved.
Coumarins
Nitration
Pharmaceuticals
Reduction
Nitration and reduction are important reactions in organic
synthesis and it is obvious that most common way to do nitration
and reduction would be to use cheap commercial available
nitrating reagent HNO3/H2SO4 and Zn/HCl, respectively. But
how frequently is that possible when it comes to heterocyclic
compounds as starting materials? The answer is rare, because
these harder conditions would lead to either decomposition of
starting materials or other side reactions if applied on
heterocycles. At least we have failed to prepare aminocoumarins
by using these conventional approaches vide infra (Scheme 1). In
used as the hydrogen source for catalytic transfer hydrogenation.
However, most of these conditions require tedious work up, toxic
and/expensive transition metals which create serious
environmental issues18, 19
.
1. Conventional Nitration/Reduction
Nitration
Conc. HNO3 O N
Conc. H2SO4
O30% yield
OH
O
OH
OH
O
2
O2N
O
O
O
55%
45%
this context, chemistry plays a vital role and a variety of mild
methods were developed and found in the literature1,
Reduction
Zn/HCl (poor yield)
OH
2
.
For
example, noteworthy in the case of nitration is the use of acetyl
nitrate (AcONO2)3, triflyl nitrate (TfONO2)4, Cr(NO3)3.2N2O45,
Bi(NO3)3/montmorillonite KSF6, NaNO3/wet SiO27, PEG-bound
metal nitrate8, Cu(NO3)2/clay, Fe(NO3)3·9H2O/ionic liquid9, and
VO(NO3)310. It should be mentioned here that these methods are
although mild and selective, there application on heterocyclic
compound is very rare11. To test the compatibility and reactivity
of coumarin with conventional nitration conditions
(HNO3/H2SO4), we reacted hydroxycoumarin with the former
and found that poor yield (30%) of mixed regioisomer 6- and 7-
nitro coumarin was obtained in the ratio 55:45, respectively. In
the other reaction step, which is reduction of nitro group, Zn/HCl
is widely used reaction (we could not get good yield), but more
convenient and mild methods such as transition metal catalyst
along with H212, toxic hydrazine hydrate13, silanes14, sodium
hydrosulphite15, formates16 and decaborane17 as hydrogen sources
H2N
O
O
2. This work
Nitration/Reduction
Nitration
Reduction
D-Glucose
OH
OH
OH
O
Ca(NO3)2•4H2O
O2N
H2N
CH3COOH
O
O
O
O
O
Scheme 1. Conventional versus current protocol of nitration and
reduction.
In short, the synthesis of aminocoumarines which are very
important synthons in pharmaceuticals20, 21 could not be achieved
efficiently using traditional methods in high selectivity and yield.
This led us to develop new, mild and efficient method to
synthesize biologically important synthons based on
aminocoumarins using calcium nitrate and D-glucose for
have been developed. Additionally, isopropanol or formic acid is
———
∗ Corresponding author. Tel.: +91-22-3361-1111; fax: +91-22-3361-1020; e-mail: hk.chaudhari@ictmumbai.edu.in

2
nitration and reduction, respectively. Both Calcium nitrate and D-
glucose are relatively greener as well as mild and regioselective
reagents, and hence impose a great advantage to be used in
organic synthesis22.
Table 2. Nitration of coumarin derivatives using
Ca(NO3)2·4H2Oa
As a starting point, we focused on optimization for nitration of
hydroxycoumarin. Accordingly, 6.2 mmol (1.0 g) of 1 was
treated with 6.2 mmol of Ca(NO3)2·4H2O (1.5 g) in water as
Entry Reactant 1
Product 2
Yieldb(%)
of 2
o
solvent at 100 C, however no expected product was detected
1
90
82
90
85
83
89
82
80
(entry 1). Acidic solvent such as H2SO4 could not give the
desired product (entry 2), instead the decomposition of starting
materials was occurred, however use of relatively weak acid like
acetic acid was surprising and led to the formation of the desired
product in 65% yield (entry 3). While using acetic acid, we found
that complete conversion of 1 was obtained but the yield was
O
2
3
4
5
6
7
8
O2N
OC2H5
OC2H5
O
O
O
o
CH3
poor, hence we reduced reaction temperature to 80 C (entry 4)
and 60 oC (entry 5), remarkably we could achieve high chemical
yield of the desired product at 60 oC. In fact, lowering the
temperature down to 0 oC has negative effect on the reaction and
gave very trace amount of the product. Excess use of
Ca(NO3)2·4H2O did not significantly improve the yield further
(entry 6), hence we applied these optimized conditions (entry 5)
on other coumarin derivatives and results are summarized in
Table 2.
O2N
HO
O
O
CH3
O
O
O
O2N
HO
OH
Table 1. Optimization for nitration of hydroxycoumarin (1a)a
OH
OH
Ca(NO3)2•4H2O
O2N
Solvent,
T
oC,1 h
O
O
O
O
1a
2a
Entry
Solvent
Water
T (°C)
100
100
100
80
Yieldb (%) of 2a
1
2
3
4
5
6
7
No reaction
Sulphuric acid
Acetic acid
Acetic acid
Acetic acid
Acetic acid
No reaction
aReaction conditions: 1 (6.2 mmol), Ca(NO3)2·4H2O (6.2 mmol), acetic acid
65
(5 mL) stirred at 60 oC for 1 h.
62
bIsolated yield.
60
90
60
91c
65d
After synthesizing nitrocoumarins in high yields using new
mild method, we subjected them under newly developed
reduction reaction using D-glucose. Although reduction using D-
glucose in alkaline media was reported by Galbrait et al.,24 its
wide scope was not studied on heterocycles such as coumarins.
Hence it had promoted us to use D-glucose for reduction of
coumarins. Initially, 4-hydroxy-6-nitrocoumarin was heated at
Acetic anhydride
60
aReaction conditions: 1a (6.2 mmol), Ca(NO3)2·4H2O (6.2 mmol), solvent (5
mL) stirred at mentioned temperature for 1 h.
bIsolated yield.
cTwo equiv. of Ca(NO3)2·4H2O was used.
dReaction time was 2 h.
o
120 C with 1 equivalents of D-glucose and 1 equivalents of
KOH in dimethyl sulfoxide (DMSO) as solvent. We could obtain
45% yield of the desired amine in 24 h (entry 1). It seemed to us
that recovery of the product from DMSO was not easy hence we
tried to input water as additional solvent and found that DMSO:
water (1:1) led to slight improvement in the yield (entry 2).
Changing the quantity of D-glucose and KOH to 2 equiv and 4
equiv, respectively led to the maximum yield of 65% (entry 3). In
fact, we were surprised to see that reaction works well only in
water as a solvent (80%, entry 4). Ethanol as a solvent reached
chemical yield to 75% (entry 5). Mixed solvent system of
ethanol: water (1:9) gave excellent yield of the desired product
(entry 6). Changing the reducing source to other carbohydrate
such as fructose (entry 7), maltose (entry 8), sucrose (entry 9) did
not result in any further improvement in the yield. Use of
previously reported transfer hydrogenating quinazoline alkaloid,
vascicine was found give satisfactory yield of the desired product
but led to difficulty in purifying desired product due to leftover
organic impurities from the reducing source (entry 10)25. We
found that the absence of reducing source but only in the
Most of these coumarin derivatives were underwent nitration
in high chemical yields (Table 2). Noteworthy to mention is entry
2 and 3 in which ester group was tolerated and no acid catalyzed
hydrolysis was observed which would have been difficult to
avoid using harsh HNO3/H2SO4 conditions. Also, acid
functionality was well tolerated and found to give good chemical
yields of the desired products (entry 4 and 5). Chloro group was
sufficiently stable in our condition and gave 82% of the desired
product (entry 7). One of the interesting examples here is entry 8
where nitration of starting material already bearing basic amine
moiety was performed and found to give good yield of the
desired product.
It will be early to predict actual mechanism by which
coumarin undergo nitration, but it is quite reasonable that
Ca(NO3)2 in the presence of acetic acid led to the formation of
some amount of nitric acid and/ CH3COONO2 which helps in
nitration23.

3
presence of KOH, reaction failed to give the desired product
(entry 11).
4
62
85
80
80
70
45
Table 3. Reduction of nitrocoumarin derivatives using hydrogen
source and basea
5
6
Entry Hydrogen
source (equiv)
Base
Solvent (ratio)
Yieldb (%) of
7
(equiv)
3a
1
D-glucose (1)
D-Glucose (1)
D-Glucose (2)
D-Glucose (2)
D-Glucose (2)
D-Glucose (2)
Fructose (2)
Maltose (2)
Sucrose (2)
Vasicine
KOH (1)
KOH (1)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
none
DMSO
45
8
2
H2O: DMSO (1:1)
H2O: DMSO (1:1)
H2O
58
3
65
4
80
9d
5
EtOH
75
6
H2O: EtOH (9:1)
H2O: EtOH (9:1)
H2O: EtOH (9:1)
H2O: EtOH (9:1)
H2O: EtOH (9:1)
H2O: EtOH (9:1)
92
aReaction conditions: Nitrocoumarin 2 (1 mmol), D-glucose (2 equiv), KOH
(4 equiv), Solvent (4 mL) stirred at 110 oC.
7
40
8
45
bIsolated yield.
9
no reaction
80
cGram scale (8 mmol) reaction; dReduction was performed using conventional
(Zn/HCl) method.
10c
11
none
KOH (4)
no reaction
aReaction conditions: Nitrocoumarin (1 mmol), Hydrogen source (2 mmol)
Base (4 mmol) and Solvent (4 mL).
Excited by mild reactivity conditions that Ca(NO3)2·4H2O
and D-glucose could offer, we were curious to see if these
systems have wide applicability. Accordingly, other heterocycle
such as benzimidazole 4 was subjected to optimized conditions
of nitration/reduction and compared with traditional methods. As
expected, acceptable chemical yield of the desired products 5 and
6 was obtained in current optimized condition, while traditional
reaction conditions could not give good results.
bIsolated yield.
cReduction using literature reported conditions.
With the optimized conditions in hand, we subjected a variety of
previously synthesized nitrocoumarins for reduction, and results
are summarized in Table 4. Most of the coumarins were reduced
in high chemical yield with excellent chemoselectivity (entry 1-
8). To prepare the aminocoumarins in gram scale for our
subsequent project of coumarin based antitubercular agents, we
tested suitability of this protocol for large scale reduction of 2a,
we could obtain satisfactory yield of the desired product 3a
(entry 1, yield in parentheses). Substrates bearing multiple
reducible functional groups such as ester derivatives (entry 2 and
3), and acid derivatives (entry 4 and 5) were reduced in excellent
chemoselectivity. Sterically demanding substrate such as 2h
could give good yield of the desired product (entry 8). However,
this substrate failed to give satisfactory yield of the desired
product (entry 9) using conventional reduction strategy (Zn/HCl)
Scheme 2. Extension of designed nitration/reduction strategy to
imidazole.
Our understanding towards the mechanism of reduction is based
on the previous facts that D-glucose undergoes degradation in hot
alkaline media to produce series of carboxylates along with the
hydrogen23, 26. We believe that this hydrogen is responsible for
reduction of nitrocoumarins (Scheme 3).
Table 4. Reduction of Nitrocoumarin derivatives using D-glucosea
Entry Reactant 2
Product 3
Yieldb
(%) of 3
92 (84) c
1
Scheme 3. Plausible pathway for reduction using D-glucose.
2
3
62
In conclusion, we have demonstrated a new reaction strategy for
high scale synthesis of aminocoumarins which are important
synthons in pharmaceuticals. Nitration is achieved using calcium
62
nitrate,
while
reduction
is
performed
using
D-glucose. Both are mild, relatively greener, and cheap,
commercially available reagents. There unique selectivity could

4
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Preparative-scale synthesis of amino
coumarins through new sequential nitration
and reduction protocol
Hemchandra K. Chaudharia,* Akshata Pahelkara and Balaram S. Takaleb

6
Tetrahedron
Preparative-scale synthesis of amino
coumarins through new sequential
nitration and reduction protocol
Hemchandra K. Chaudharia, ∗ Akshata Pahelkara
and Balaram S. Takaleb
a Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Matunga (E), Mumbai 400 019, Maharashtra, India
b Department of Chemistry and Biochemistry, University of California, Santa
Barbara 93106, USA
A new reaction strategy for high scale synthesis of
aminocoumarins which are important synthons in
pharmaceuticals. Nitration is achieved using
calcium nitrate, while reduction is performed using
D-glucose. Both are mild, relatively greener, and
cheap, commercially available reagents. There
unique selectivity could prove synthetically useful
for nitration and or reduction of various
heterocycles.
———