Choline hydroxide: An efficient and biodegradable catalyst for the synthesis of 2-amino-3-nitro-4H-chromene derivatives in an aqueous medium

Article abstract of DOI:10.1080/10426507.2018.1469489

An expedient, eco-friendly and efficient procedure for the synthesis of novel 2-amino-3-nitro-4H-chromene derivatives has been developed through the reaction of various 2-hydroxybenzaldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine in the presence of the basic ionic liquid catalyst (choline hydroxide (ChOH)) at room temperature an aqueous medium. The advantageous of this method is a biodegradable and recyclable catalyst, mild, environmentally friendly and high products yields (83-96%) in short reaction times.

Full text of DOI:10.1080/10426507.2018.1469489

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Choline Hydroxide: An efficient and biodegradable
catalyst for the synthesis of 2-amino-3-nitro-4H-
chromene derivatives in an aqueous medium
Suresh Kumar Krishnammagari, Kwon Taek Lim, Byung Gwon Cho & Yeon
Tae Jeong
To cite this article: Suresh Kumar Krishnammagari, Kwon Taek Lim, Byung Gwon Cho & Yeon
Tae Jeong (2018): Choline Hydroxide: An efficient and biodegradable catalyst for the synthesis of
2-amino-3-nitro-4H-chromene derivatives in an aqueous medium, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2018.1469489
To link to this article: https://doi.org/10.1080/10426507.2018.1469489
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Choline Hydroxide: An efficient and biodegradable catalyst for the synthesis of 2-amino-
3-nitro-4H-chromene derivatives in an aqueous medium
Suresh Kumar Krishnammagari, Kwon Taek Lim, Byung Gwon Cho, Yeon Tae Jeong*
Department of Image Science and Engineering, Pukyong National University, Busan 608-
737, Republic of Korea
Corresponding author Tel.: +82-51-629-6411; fax: +82-51-629-6408;
E-mail: ytjeong@pknu.ac.kr
A shortened title of the article (running head): Synthesis of 2-amino-3-nitro-4H-
chromene derivatives
Abstract
An expedient, eco-friendly and efficient procedure for the synthesis of novel 2-amino-3-nitro-
4H-chromene derivatives has been developed through the reaction of various 2-
hydroxybenzaldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine in the presence of
the basic ionic liquid catalyst (choline hydroxide (ChOH)) at room temperature an aqueous
medium. The advantageous of this method is a biodegradable and recyclable catalyst, mild,
environmentally friendly and high products yields (83-96%) in short reaction times.
Keywords: Choline hydroxide, Green chemistry, 2-amino-3-nitro-4H-chromene derivatives,
Aqueous medium.

Introduction
An economic and eco-friendly method for the synthesis of bioactive synthetic organic
compounds remains as the primary objective in the current research endeavors. The
introduction of new methods for the efficient assembling of functionalized intermediates
obtained from simple precursors has become necessary due to the ever-increasing complexity
of the organic target molecules. An appealing strategy to realize this end is the development of
novel tandem reactions, where sequential transformations are performed without isolation or
purification of intermediates in a single-step.1 An especially critical aspect of research is
finding and utilizing a single catalyst that promotes in tandem more than one chemical
transformation in a selective manner.2
Oxygen heterocycles and their derivatives have attracted significant interest owing to
their wide range of bioactivities in medicine, bio-organic, and pharmacy. Also, these
molecules serve as an important ligands in various catalysts.3 Among them, 2H-chromene and
4H-chromene, found in many naturally occurring compounds,4 play pivotal role in
pharmaceutical properties such as antioxidant, antileishmanial, antibacterial, antifungal,
hypotensive, anticoagulant, antiviral, diuretic, antiallergenic, and antitumor activities.5 In
addition, 2-Amino-4H-chromene derivatives are widely employed as pigments, cosmetics,6
laser dyes,7 optical brighteners,8 and potential biodegradable agrochemicals.9 Fused
chromenes were also used as anticancer,10 antiviral,11 anti-inflammatory,12 and pesticidal
compounds.13 Additionally, due to their photosensitive properties they are also used as
fluorescent compounds in laser technology and in monitoring of biomolecules.14 The
structures of a few biologically active 2-amino-4H-chromenes possessing anticancer activities
are depicted in Fig 1.
Insert Figure 1 Here
Due to such important biological properties of 2-amino-4H-chromenes, it remains as

an important challenging task to develop an easy and efficient method for their synthesis. An
extensive survey of the literature revealed that various methods have been developed for the
preparation of chromene derivatives.15 Majority of the reports revealed that the chromene
derivatives are synthesized via multicomponent reaction between aldehyde/2-
hydroxybenzaldehydes (or isatin) and various deferent active methylene compounds such as
barbituric acid, dimedone, cyclohexane-1,3-dione, malononitrile, and alkyl cyanoacetate.
Generally synthesis of the chromene derivatives is promoted by bases. Rao et al.16 have
developed a base (DBU) that promoted the formation of two component 2-amino-3-nitro-4H-
chromene derivatives without any active methylene compounds. This method shows varying
degrees of limitations as well as successes. Prolonged reaction times, requirement of excess
reagent or catalyst and relatively low yields based on this shows the need alternative milder
and environmentally sustainable procedures for the synthesis of 2-amino-3-nitro-4H-
chromene derivatives.
In recent years, major development has taken place in green chemistry using water
and ionic liquids as an environmentally benign reaction media in place of traditional organic
reaction media.17 In this context, Choline hydroxide (ChOH) is an environmentally benign,
easy to prepare base, which displays strong basicity. The activity of ChOH has been explored
by various groups in organic synthesis due to its economical, easily available, recyclable,
inexpensiveness and water compatibility. Recently, it has been used for the thiolysis of
epoxides, and synthesis of α-hydroxyphosphonates, biscoumarins, pyrans, pyrimidines and
other heterocyclic derivatives.18
To the best of our knowledge there are no reports on the synthesis of 2-amino-3-nitro-
4H-chromene derivatives promoted by ChOH. As part of our ongoing research interest in the
development of efficient, inexpensive, new methodologies.19 We developed an eco-friendly
method for synthesis of 2-amino-3-nitro-4H-chromene derivatives by the reaction of

substituted 2-hydroxybenzaldehyde and (E)-N-methyl-1-(methylthio)-2-nitroethenamine in
presence of ChOH as catalyst in water at room temperature (Scheme 1).
Scheme 1: Synthesis of 2-amino-3-nitro-4H-chromene derivatives
Result and discussion
To start with, a model reaction was performed with 2-hydroxybenzaldehyde 1a (1.0
mmol), and (E)-N-methyl-1-(methylthio)-2-nitroethenamine 2 (1.0 mmol) in the presence of
various catalysts. To find out the influence of the catalyst, the two-component reaction was
first carried out in water without a catalyst, which resulted in no reaction progress, even after
o
70 h at room temperature and 30 h at 80 C (Table 1, entry 1). After that we attempted the
reaction in the presence of organo-base catalysts. DABCO was able to catalyze the reaction in
aqueous media (Table 1, entry 2) to afford the product 3a with 62% yield. The use of DMAP,
triethylamine, trimethylamine, piperidine and imidazole gave similar results (Table 1, entries
3 to 6). Under aqueous conditions, even pyridine exhibited some catalytic effect, albeit much
slower (Table 1, entry 7). After that we investigated with different inorganic bases, such as
K2CO3, CaCO3, Cs2CO3 and LiOH.H2O which gave the desired product in the range 60% to
40% yields (Table 1, entry 9-12). Later we turned towards surfactants such as sodium dodecyl
sulfate (SDS) and cetyltrimethylammonium bromide (CTAB) (entries 13,14) these surfactant
catalyst afforded the products with yields 60 % and 72 % after 24 h. Hence, there was no
synthetic advantage in using surfactants for this chemical transformation. The bases were
equally efficient in providing the desired product 3a in good yield and a short reaction time,
however, these basic catalysts are not reusable.
In order to overcome these problems, we turned our attention toward recyclable ILs.
It is interesting to note that ChOH (10 mol%) act as remarkable catalysts in aqueous media

giving the best results in terms of yield and reaction rate (Table 1, entry 17). The higher
yield of the product was obtained with ChOH because it acts as a homogeneous catalyst in an
aqueous medium which helps to improve the solubility of the reactants through hydrogen
bonding and hence increases the rate of the reaction. With ChOH as our optimal catalyst, we
then systematically evaluated the solvent effect of this reaction using the reaction of 2-
hydroxybenzaldehyde 1a (1.0 mmol), and (E)-N-methyl-1-(methylthio)-2-nitroethenamine 2
(1.0 mmol) as a model. The above reaction was carried out in conventional organic solvents
such as DCM, CH3CN, ethanol, THF and water. Water as a solvent provided the best yields
compared to DCM, CH3CN ethanol and THF (Table 1, entries 17 to 21). To determine the
optimum catalyst ChOH loading, model reaction addition of 5 mol% ChOH afforded the
product in low yield (Table 1, entry 22), an increase in the amount of ChOH to 10 mol% gave
the desired product 3a in 95% yield; further increase in the amount of catalyst 15 mol% did
not increase the product yield. The results are summarized in Table 1.
Insert Table 1 Here
After the initial assessment of the optimum reaction conditions, we investigated the
scope of the reaction by condensing (E)-N-methyl-1-(methylthio)-2-nitroethenamine 2 with
various commercially available and also prepared substituted 2-hydroxybenzaldehydes having
different electronically activating or deactivating substituent’s to form a series of 2-amino-3-
nitro-4H-chromene derivatives (Table 2). As illustrated in Table 2, 2-hydroxybenzaldehydes
1a-x having either an electron-donating or electron-withdrawing group on the aromatic ring
gave the corresponding 4H-chromene in good yields (Table 2, entries 3a–x). Obviously, the
electron-rich 2-hydroxybenzaldehydes provided the desired products in slightly higher yields
than the electron-poor 2-hydroxybenzaldehydes along with the shorter reaction time. Among
them
2-hydroxybenzaldehydes
3a–3w
which
were
examined,
3-methoxy-2-
hydroxybenzaldehyde and 3-ethoxy-2-hydroxybenzaldehyde gave the most desirable results,

providing 4H-chromenes with high yield (Table 2, entry 3e and 3i). This can be attributed to
the increased nucleophilicity of the hydroxy moiety in the 2-hydroxybenzaldehydes due to
electron-donating substituents. It was observed that 2-hydroxybenzaldehydes having methyl,
ethyl and t-butyl moiety (Table 2, entry 3f-3h and 3p) on the ring were equally compatible
with the catalytic system and were easily introduced to the 4H-chromene skeleton with
excellent yields. Electron-withdrawing groups such as chloro, bromo, and nitro on the 2-
hydroxybenzaldehydes, also smoothly furnished the desired products in good yield (Table 2,
entries 3b-3d and 3i-3o). 2-Hydroxybenzaldehydes with fused ring systems were also found
to be active under the set of reaction conditions and resulted in adequate yield (entry 3k, Table
2).
In the literature report by using base catalyst, condensation reaction of (E)-N-methyl-
1-(methylthio)-2-nitroethenamine with 4-alkoxy-2-hydroxybenzaldehyde did not take place.16
The same substrates (4-methoxy-2-hydroxybenzaldehyde and 4-ethoxy-2-hydroxy-aldehyde)
reacted under the optimized conditions (ChOH, 10 mol%) and given good yields (Table 2,
entries 3u and 3v). The reaction of benzyloxy substituted at the 4th-position of 2-
hydroxybenzaldehydes also gave the corresponding 4H-chromenes 3q, 3r, 3s, 3t in 90%, 88%,
87% and 89% yield respectively under the optimized reaction conditions (Table 2, entries 3q,
3r, 3s and 3t). It is noteworthy that, any substituted 2-hydroxybenzaldehyde smoothly
furnished the desired products under the optimized conditions
Insert Table 2 Here
To further demonstrate the practicality and efficiency of the developed reaction
sequence, a scale-up reaction was performed. Gram-scale synthesis of N-methyl-4-
(methylthio)-3-nitro-4H-chromen-2-amine (3a, 3.92 g) could be achieved under the optimized
reaction conditions in 95% yield from 2-hydroxybenzaldehyde as the starting material
(Scheme 2). This gram scale reaction yield was relatively similar to the submillimolar scale

reaction. It concludes that the present methodology is a practical and scalable synthetic entry
to synthesize highly functionalized the 2-amino-3-nitro-4H-chromene derivative.
Scheme 2: Gram-scale Synthesis of 4H-chromene derivative 3a
1
13
The syntheses of all the 4H-chromene derivatives were confirmed using H and C
1
NMR spectroscopy. In the H NMR spectra, the –NH– proton signals appeared as a broad
singlet in the region of 10.46–10.05 ppm. The Ar–CH proton signals also appeared as a
singlet in the region of 6.13–5.39 ppm. N-methyl protons appeared as a doublet in the region
of 3.32–3.21 ppm, and also a sharp signal for S-methyl protons appeared as a singlet in the
region of 1.96–1.81 ppm, confirming product formation;16 the remaining proton signals were
13
observed in the expected regions. In the C NMR spectra, the Ar–CH carbon signals were
observed in the region of 41.28–37.66 ppm, confirming the formation of 4H-chromenes. A
detailed description of the spectral data for all compounds (3a–3w) is provided in the
experimental section.
Experimental
Material and methods
Chemicals were purchased from Aldrich and Alfa Aesar Chemical Companies and
used without further purification. NMR spectra were recorded in parts per million (ppm) in
CDCl3 or DMSO-d6 on a Jeol JNM ECP 600 or Jeol JNM ECP 400 NMR instrument using
TMS as internal standard. Standard abbreviations were used to denote signal multiplicities (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet and brs = broad singnal) and the
coupling constants are given in hertz (Hz). Mass spectra were recorded on a Jeol JMS-700
mass spectrometer. All melting points were determined using open capillaries on an

Electrothermal-9100 (Japan) instrument and are uncorrected. The Supplemental Materials
contains sample 1H and 13C NMR spectra of products 3b-3x (Figure S 1 – S 40)
Procedure for the preparation of ChOH18b
ChOH was synthesized according to a literature procedure. Choline chloride (7 mmol)
was dissolved in methanol (15 mL), KOH (7 mmol) was added slowly at room temperature,
and the mixture was heated at reflux for overnight. After mixture cooling to room temperature,
the reaction mixture was filtered to remove solid KCl, concentrated to remove methanol until
the weight of the residue remained constant, and used without further purification. ChOH was
characterized using a mass spectrum, it is provided in the Supporting information. The
massspectra showed good agreement with the reported results. The mass spectrum clearly
showed the exact molecular weight of the ChOH.18b MS (FAB, m/z): [M+H]+ calcd for
C5H15NO2, 122.11; found 122.09.
Synthesis of N-Methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3a)
The ChOH 10 mol% in water (3 mL) was added to a mixture of 2-
hydroxybenzaldehyde (1a, 1.0 mmol) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine (2,
1.0 mmol) (1 mmol) in a 10 mL reaction flask equipped with a magnetic stirrer. The resulting
mixture was stirred for the appropriate time at room temperature. After completion of the
reaction (confirmed by TLC, hexanes: EtOAc 1:1), the solid product was filtered and washed
with water. The obtained crude product was recrystallized from ethanol to yield the pure
product. The same method was adopted for the synthesis of all the targeted products 3a-x.
Spectral characterization
N-Methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3a): Yellow solid; Yield: 95%,
m.p. 154–155 °C (152–153 °C)16 ; 1H NMR (600 MHz, CDCl3) δ 10.29 (brs, 1H), 7.43 (dd, J
= 7.6, 1.6 Hz, 1H), 7.30 (td, J = 7.8, 1.7 Hz, 1H), 7.25 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (dd, J =

13
8.1, 1.0 Hz, 1H), 5.50 (s, 1H), 3.23 (d, J = 5.2 Hz, 3H), 1.88 (s, 3H); C NMR (151 MHz,
CDCl3) δ 160.15, 148.99, 129.31, 128.87, 126.32, 122.59, 115.88, 105.98, 40.52 (Ar-CH),
28.13, 12.50; HRMS (ESI, m/z): calcd for C11H12N2O3S (M+H+) 252.0569, found: 252.0574.
6-Chloro-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3b): Yellow solid;
Yield: 88%, m.p. 187–189 °C (185–187 °C)16; 1H NMR (600 MHz, CDCl3) δ 10.23 (brs, 1H),
7.41 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 8.8, 2.5 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 5.43 (s, 1H),
3.22 (d, J = 5.2 Hz, 3H), 1.89 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 159.79, 147.43, 131.45,
129.03, 128.95, 124.39, 117.30, 105.32, 40.34 (Ar-CH), 28.19, 12.57; HRMS (ESI, m/z):
calcd for C11H11ClN2O3S (M+H+) 286.0179, found: 286.0175.
6-Bromo-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3c): Yellow solid;
Yield: 90%, m.p. 156–158 °C (154–157 °C)16; 1H NMR (600 MHz, CDCl3) δ 10.23 (brs, 1H),
7.57 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 8.7, 2.3 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.44 (s, 1H),
3.22 (d, J = 5.2 Hz, 3H), 1.90 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 159.76, 147.99, 131.94,
131.92, 124.85, 118.87, 117.62, 105.40, 40.27 (Ar-CH), 28.17, 12.63; HRMS (ESI, m/z):
calcd for C11H11BrN2O3S (M+H+) 329.9674, found: 329.9680.
N-Methyl-4-(methylthio)-3,6-dinitro-4H-chromen-2-amine (3d): Yellow solid; Yield:
1
85%, m.p. 189–191 °C; H NMR (600 MHz, CDCl3) δ 10.16 (brs, 1H), 8.36 (d, J = 2.6 Hz,
1H), 8.20 (dd, J = 9.0, 2.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 5.54 (s, 1H), 3.26 (d, J = 5.2 Hz,
13
3H), 1.96 (s, 3H); C NMR (151 MHz, CDCl3) δ 159.15, 152.47, 145.62, 125.30, 124.70,
124.39, 117.13, 105.02, 40.38 (Ar-CH), 28.35, 13.04; HRMS (ESI, m/z): calcd for
C11H11N3O5S (M+H+) 297.0419, found: 297.0415.
8-Methoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3e): Yellow solid;
Yield: 96%, m.p. 146–148 °C (144–146 °C)16; 1H NMR (600 MHz, CDCl3) δ 10.22 (brs, 1H),
7.17 (t, J = 8.0 Hz, 1H), 6.98 (dd, J = 7.9, 1.1 Hz, 1H), 6.86 (dd, J = 8.2, 1.3 Hz, 1H), 5.49 (s,
13
1H), 3.91 (s, 3H), 3.25 (d, J = 5.2 Hz, 3H), 1.89 (s, 3H); C NMR (151 MHz, CDCl3) δ

159.84, 147.25, 138.33, 125.88, 123.44, 119.91, 110.65, 105.66, 55.97, 40.39 (Ar-CH), 27.95,
12.26; HRMS (ESI, m/z): calcd for C12H14N2O4S (M+H+) 282.0674, found: 282.0680.
N,6-Dimethyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3f): Yellow solid; Yield:
1
94%, m.p. 154-157 ºC (154–157 °C)16; H NMR (600 MHz, CDCl3) δ 10.32 (br s, 1H), 7.21
(s, 1H), 7.10 (br d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.44 (s, 1H), 3.22 (d, J = 5.2 Hz,
3H), 2.36 (s, 3H), 1.82 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.10, 146.98, 136.06,
129.52, 129.26, 121.95, 115.45, 105.93, 40.47 (Ar-CH), 28.08, 20.81, 12.23; HRMS (ESI,
m/z): calcd for C12H14N2O3S (M+H+) 266.0725, found: 266.0719.
6-Ethyl-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3g): Yellow solid;
1
Yield: 93%, m.p. 163–166 ºC (163–166 °C)16; H NMR (600 MHz, CDCl3) δ 10.31 (s, 1H),
7.22 (br s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.48 (s, 1H), 3.22 (d, J =
13
5.1 Hz, 3H), 2.66 (q, J = 7.5 Hz, 2H), 1.87 (s, 3H), 1.2 (t, J = 7.5 Hz, 3H); C NMR (151
MHz, CDCl3) δ 160.10, 147.01, 142.32, 128.2, 128.01, 121.90, 115.50, 105.80, 40.51 (Ar-
CH), 28.10, 27.92, 15.53, 12.30; HRMS (ESI, m/z): calcd for C13H16N2O3S (M+H+) 280.0882,
found: 280.0888.
6-Tert-butyl-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3h): Yellow solid;
Yield: 93%, m.p. mp 166-170 ºC (166–170 °C)16; 1H NMR (600 MHz, CDCl3) δ 10.30 (s, 1H),
7.38 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.50 (s,
13
1H), 3.22 (d, J = 5.4 Hz, 3H), 1.88 (s, 3H), 1.32 (s, 9H); C NMR (151 MHz, CDCl3) δ
160.21, 149.30, 146.72, 125.80, 125.71, 121.52, 115.20, 106.11, 40.70 (Ar-CH), 34.51, 31.30,
27.92, 12.50; HRMS (ESI, m/z): calcd for C15H20N2O3S (M+H+) 308.1195, found: 308.1191.
8-Ethoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3i): Yellow solid;
Yield: 95%, m.p. 163–165°C; 1H NMR (600 MHz, CDCl3) δ 10.20 (s, 1H), 7.14 (t, J = 8.0 Hz,
1H), 6.95 (d, J = 7.1 Hz, 1H), 6.84 (dd, J = 8.1, 0.9 Hz, 1H), 5.47 (s, 1H), 4.10 (q, 7.0 Hz, 2H),
3.25 (d, J = 5.2 Hz, 3H), 1.88 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ

160.08, 146.84, 138.69, 126.06, 123.64, 119.98, 111.89, 105.91, 64.66, 40.63 (Ar-CH), 28.05,
14.90, 12.48; HRMS (ESI, m/z): calcd for C13H16N2O4S (M+H+) : 296.0831, found: 296.0838.
N7,N7-Diethyl-N2-methyl-4-(methylthio)-3-nitro-4H-chromene-2,7-diamine
(3j):
1
Yellow solid; Yield: 90%, m.p. 140–143°C; H NMR (600 MHz, CDCl3) δ 10.41 (brs, 1H),
7.19 (d, J = 8.7 Hz, 1H), 6.54 (dd, J = 8.7, 2.6 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 5.40 (s, 1H),
13
3.35 (q, J = 7.5 Hz, 4H), 3.22 (d, J = 5.2 Hz, 3H), 1.86 (s, 3H), 1.17 (t, J = 7.1 Hz, 6H); C
NMR (151 MHz, CDCl3) δ 160.38, 154.67, 150.24, 129.60, 110.00, 106.88, 106.25, 97.24,
45.59, 44.48, 40.37, 28.08, 12.52; HRMS (ESI, m/z): calcd for C15H21N3O3S (M+H+)
323.1304, found: 323.1309.
N-Methyl-1-(methylthio)-2-nitro-1H-benzo[f]chromen-3-amine (3k): Yellow solid;
Yield: 91%, m.p. 195–197°C; 1H NMR (600 MHz, CDCl3) δ 10.26 (brs, 1H), 8.23 (d, J = 8.4
Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.3 Hz,
1H), 7.53 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.13 (s, 1H), 3.28 (d, J =
13
5.2 Hz, 3H), 1.81 (s, 3H); C NMR (151 MHz, CDCl3) δ 159.93, 146.82, 131.74, 130.13,
129.76, 128.82, 127.71, 126.15, 123.75, 115.44, 114.60, 106.39, 37.66 (Ar-CH), 28.18, 12.03;
HRMS (ESI, m/z): calcd for C15H14N2O3S (M+H+) 302.0725, found: 302.0720.
6,8-Dichloro-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3l): Yellow
solid; Yield: 83%, m.p. 206–208°C; 1H NMR (600 MHz, CDCl3) δ 10.07 (brs, 1H), 7.37 (d, J
= 2.4 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 5.44 (s, 1H), 3.28 (d, J = 5.2 Hz, 3H), 1.94 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 159.36, 143.57, 131.25, 129.29, 127.24, 125.99, 122.47,
105.08, 40.55 (Ar-CH), 28.44, 12.88; HRMS (ESI, m/z): calcd for C11H10Cl2N2O3S (M+H+)
319.9789, found: 319.9795.
8-Bromo-6-chloro-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine
(3m):
Yellow solid; Yield: 85%, m.p. 209–211°C; 1H NMR (600 MHz, CDCl3) δ 10.05 (s, 1H), 7.52
(d, J = 2.4 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 5.45 (s, 1H), 3.30 (d, J = 5.3 Hz, 3H), 1.95 (s,

3H); 13C NMR (151 MHz, CDCl3) δ 159.57, 144.67, 132.14, 131.65, 127.98, 125.98, 110.74,
105.20, 40.73 (Ar-CH), 28.63, 12.98; HRMS (ESI, m/z): calcd for C11H10BrClN2O3S (M+H+)
363.9284, found: 363.9279.
6,8-Dibromo-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3n): Yellow
solid; Yield: 86%, m.p. 196–198°C; 1H NMR (600 MHz, CDCl3) δ 10.06 (brs, 1H), 7.66 (d, J
= 1.0 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 5.44 (s, 1H), 3.30 (d, J = 5.2 Hz, 3H), 1.94 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 159.53, 145.14, 134.82, 130.93, 126.37, 118.78, 111.02,
105.24, 40.59 (Ar-CH), 28.64, 12.98; HRMS (ESI, m/z): calcd for C11H10Br2N2O3S (M+H+)
407.8779, found: 407.8786.
6-Bromo-8-methoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine
(3o):
1
Yellow solid; Yield: 91%, m.p. 193–195°C; H NMR (600 MHz, CDCl3) δ 10.15 (brs, 1H),
7.11 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 5.39 (s, 1H), 3.90 (s, 3H), 3.23 (d, J = 5.2
Hz, 3H), 1.89 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 159.64, 148.07, 137.68, 125.12, 122.67,
118.40, 114.39, 105.29, 56.50, 40.32 (Ar-CH), 28.20, 12.51; HRMS (ESI, m/z): calcd for
C12H13BrN2O4S (M+H+) 359.9779, found: 359.9774.
6,8-Di-tert-butyl-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3p): Yellow
solid; Yield: 93%, m.p. 173–175°C; 1H NMR (600 MHz, CDCl3) δ 10.46 (brs, 1H), 7.30 (d, J
= 2.4 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 5.49 (s, 1H), 3.32 (d, J = 5.3 Hz, 3H), 1.88 (s, 3H),
13
1.47 (s, 9H), 1.32 (s, 9H); C NMR (151 MHz, CDCl3) δ 160.29, 148.61, 145.87, 136.29,
124.25, 123.82, 122.34, 106.12, 41.28 (Ar-CH), 34.97, 34.83, 31.46, 30.05, 29.34, 12.75;
HRMS (ESI, m/z): calcd for C19H28N2O3S (M+H+) 364.1821, found: 364.1827.
7-(Benzyloxy)-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3q): Yellow
solid; Yield: 90%, m.p. 144–146°C (144 °C)16; 1H NMR (600 MHz, CDCl3) δ 10.32 (brs, 1H),
7.44 – 7.39 (m, 4H), 7.37 – 7.34 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.89 (dd, J = 8.6, 2.5 Hz,
1H), 6.73 (d, J = 2.5 Hz, 1H), 5.45 (s, 1H), 5.08 (s, 2H), 3.21 (d, J = 5.2 Hz, 3H), 1.86 (s, 3H);

13C NMR (151 MHz, CDCl3) δ 160.08, 159.06, 149.57, 136.20, 130.03, 128.86, 128.45,
127.63, 114.59, 113.67, 106.35, 101.96, 70.58, 40.23 (Ar-CH), 28.16, 12.38; HRMS (ESI,
m/z): calcd for C18H18N2O4S (M+H+) 358.0987, found: 358.0994.
7-(4-Nitrobenzyloxy)-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine
(3r):
1
Yellow solid; Yield: 87%, m.p. 193–195°C; H NMR (600 MHz, CDCl3) δ 10.29 (brs, 1H),
8.27 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.6 Hz, 1H), 6.89 (dd, J = 8.6,
2.5 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 5.46 (s, 1H), 5.19 (s, 2H), 3.22 (d, J = 5.2 Hz, 3H), 1.88
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.01, 158.41, 149.65, 147.95, 143.60, 130.30,
127.77, 124.11, 115.56, 113.39, 106.30, 102.21, 69.24, 40.22 (Ar-CH), 28.15, 12.52; HRMS
(ESI, m/z): calcd for C18H17N3O6S (M+H+) 403.0838, found: 403.0833.
7-(4-Fluorobenzyloxy)-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3s):
1
Yellow solid; Yield: 87%, m.p. 167–169°C; H NMR (600 MHz, CDCl3) δ 10.31 (brs, 1H),
7.42 – 7.38 (m, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.11 – 7.07 (m, 2H), 6.88 (dd, J = 8.6, 2.5 Hz,
1H), 6.71 (d, J = 2.5 Hz, 1H), 5.45 (s, 1H), 5.03 (s, 2H), 3.21 (d, J = 5.2 Hz, 3H), 1.86 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 162.78 (d, J = 246.9 Hz), 160.06, 158.87, 149.58, 131.96 (d, J
= 3.3 Hz), 130.08, 129.54 (d, J = 8.4 Hz), 115.81 (d, J = 21.7 Hz), 114.78, 113.58, 106.32,
101.98, 69.92, 40.21 (Ar-CH), 28.15, 12.39; HRMS (ESI, m/z): calcd for C18H17FN2O4S
(M+H+) 376.0893, found: 376.0899.
7-((Naphthalen-1-yl)methoxy)-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine
1
(3t): Yellow solid; Yield: 90%, m.p. 198–200°C; H NMR (600 MHz, CDCl3) δ 10.30 (brs,
1H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 – 7.83 (m, 2H), 7.62 – 7.52 (m, 3H), 7.49 (dd, J = 8.2, 6.7
Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 8.3, 2.5 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H),
5.51 (s, 2H), 5.47 (s, 1H), 3.21 (d, J = 5.1 Hz, 3H), 1.90 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 160.12, 159.17, 149.65, 135.14, 133.97, 131.58, 130.09, 129.53, 128.98, 126.86, 126.77,
126.21, 125.46, 123.61, 114.90, 113.72, 106.42, 102.14, 69.32, 40.31 (Ar-CH), 28.14, 12.52;

HRMS (ESI, m/z): calcd for C22H20N2O4S (M+H+) 408.1144, found: 408.1139.
7-Methoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3u): Yellow solid;
Yield: 90%, m.p. 142–144°C; 1H NMR (600 MHz, CDCl3) δ 10.32 (brs, 1H), 7.33 (d, J = 8.6
Hz, 1H), 6.82 (dd, J = 8.6, 2.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 5.45 (s, 1H), 3.83 (s, 3H),
3.22 (d, J = 5.2 Hz, 3H), 1.86 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.11, 159.95, 149.63,
130.00, 114.27, 112.98, 106.41, 100.94, 55.82, 40.22 (Ar-CH), 28.15, 12.34; HRMS (ESI,
m/z): calcd for C12H14N2O4S (M+H+) 282.0674, found: 282.0680.
7-Ethoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3v): Yellow solid;
Yield: 89%, m.p. 142–144°C; 1H NMR (600 MHz, CDCl3) δ 10.32 (brs, 1H), 7.32 (d, J = 8.6
Hz, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 5.44 (s, 1H), 4.26 – 3.87 (m,
13
2H), 3.21 (d, J = 5.2 Hz, 3H), 1.85 (s, 3H) 1.46 (t, J = 7.0 Hz, 3H); C NMR (151 MHz,
CDCl3) δ 160.06, 159.90, 149.58, 129.95, 114.22, 112.93, 106.36, 100.89, 64.64, 40.61 (Ar-
CH), 28.03, 14.88, 12.46; HRMS (ESI, m/z): calcd for C13H16N2O4S (M+H+) 296.0831, found:
296.0836.
7-Butoxy-N-methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine (3w): Yellow solid;
Yield: 89%, m.p. 124–126°C; 1H NMR (600 MHz, CDCl3) δ 10.32 (brs, 1H), 7.31 (d, J = 8.6
Hz, 1H), 6.80 (dd, J = 8.6, 2.5 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.45 (s, 1H), 3.97 (t, J = 6.5
Hz, 2H), 3.22 (d, J = 5.2 Hz, 3H), 1.85 (s, 3H), 1.80–1.75 (m, 2H), 1.53 – 1.47 (m, 2H), 0.98
13
(t, J = 7.4 Hz, 3H); C NMR (151 MHz, CDCl3) δ 160.15, 159.53, 149.60, 129.90, 113.96,
113.46, 106.45, 101.39, 68.34, 40.25 (Ar-CH), 31.26, 28.13, 19.33, 13.96, 12.34; HRMS (ESI,
m/z): calcd for C15H20N2O4S (M+H+) 324.1144, found: 324.1150.
N-methyl-4-(methylthio)-3-nitro-7-(octyloxy)-4H-chromen-2-amine (3x): Yellow solid;
Yield: 88%, m.p. 119–120°C; 1H NMR (600 MHz, CDCl3) δ 10.32 (brs, 1H), 7.31 (d, J = 8.7
Hz, 1H), 6.80 (dd, J = 8.6, 2.5 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.45 (s, 1H), 3.95 (t, J = 6.5
Hz, 2H), 3.21 (d, J = 5.2 Hz, 3H), 1.85 (s, 3H), 1.81-1.76 (m, 2H), 1.49 – 1.41 (m, 2H), 1.39 –

1.23 (m, 8H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 160.15, 159.53, 149.60,
129.90, 113.96, 113.46, 106.45, 101.39, 68.66, 40.25 (Ar-CH), 31.94, 29.45, 29.36, 29.22,
28.13, 26.13, 22.80, 14.25, 12.34; HRMS (ESI, m/z): calcd for C19H28N2O4S (M+H+) 380.177,
found: 380.177.
Recycling of choline hydroxide
Choline hydroxide (10 mol %) was added to a stirred solution of 2-
hydroxybenzaldehyde (1a, 1.0 mmol) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine (2,
1.0 mmol) (1 mmol) in water (3 mL). The reaction was stirred at r.t. After completion of the
reaction (confirmed by TLC, hexanes: EtOAc 1:1), the solid product was filtered. Filtrate
choline hydroxide was washed with dry diethyl ether (2X2 mL). Fresh 2-
hydroxybenzaldehyde (1a, 1.0 mmol) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine (2,
1.0 mmol) were added to the IL phase for the second run of the reaction. The third run was
performed as described for the second run.
Conclusion
In conclusion, we have demonstrated an efficient and eco-friendly protocol for the
synthesis of N-Methyl-4-(methylthio)-3-nitro-4H-chromen-2-amine derivatives in an aqueous
medium through the choline hydroxide ionic liquid catalyzed reaction of 2-
hydroxybenzaldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine. This new
method is endowed with advantages such as low cost, use of non-toxic catalyst, green reaction
medium, easy work-up process, environmentally benign reaction conditions and good yields.
The procedure provides access to compounds that are useful in heterocyclic synthesis.

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Supporting Information
Experimental detail, 1H and 13C NMR spectra have been provided in supporting information.
Fig.1. Selected examples of pharmaceutically active 2-amino-4H-chromene derivatives
Table 1: Effect of various catalysts on the synthesis of compound 3a at room temperature.a
Entry
Catalyst
mol %
-
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Time (h)
70 (30d)
16
Yield (%)b
Nre
c
1
2
3
4
5
6
7
8
9
10
-
DABCO
20
20
30
20
20
20
20
20
20
62
DMAP
24
58
Triethylamine
Trimethylamine
Piperidine
Pyridine
24
60
17
55
19
70
17
Traces
80
Imidazole
K2CO3
15
16
79d
CaCO3
24
60d

11
12
13
14
15
16
17
18
19
20
21
22
23
Cs2CO3
LiOH.H2O
SDSf
10
20
20
20
10
40
10
10
10
10
10
5
H2O
24
40
24
24
6
72d
52 (60)d
59
H2O
H2O
CTABg
ChCl:Urea
ChCl
H2O
72
-
Nre
Traces
95
H2O
H2O
CH2Cl2
CH3CN
Ethanol
THF
H2O
H2O
4
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
5
5
40
6
50
6
57
6
71
5
85
15
5
92
aReaction conditions: 2-hydroxybenzaldehyde (1, 1 mmol), (E)-N-methyl-1-(methylthio)-2-
nitroethenamine (2, 1 mmol), solvent (3 mL), R.T.
bYield of the isolated product.
cNo catalyst.
dReaction at 80 oC.
eNo reaction.
fSodium dodecyl sulfate (SDS).
gCetyltrimethylammonium bromide (CTAB).

Table 2: Synthesis of 2-amino-3-nitro-4H-chromenes (3a–x) from different substituted 2-
hydroxybenzaldehyde (1a–x) and (E)-N-methyl-1-(methylthio)-2-nitroethenamine 2.a
aReaction conditions: 2-hydroxybenzaldehyde (1, 1 mmol), (E)-N-methyl-1-(methylthio)-2-
b
nitroethenamine (2, 1 mmol), ChOH (10mol%) H2O (3 mL), R.T; Yield of the isolated
product.