Choline chloride based eutectic solvent for the efficient synthesis of 2-amino-4H-chromen-4-yl phosphonate derivatives via multicomponent reaction under mild conditions

Article abstract of DOI:10.1080/10426507.2017.1417296

Synthesis of 2-amino-4H-chromen-4-ylphosphonate derivatives has been accomplished by the one-pot three-component reaction of salicylaldehyde, malononitrile/ethylcyanoacetate and dialkyl phosphites in the presence of reusable deep eutectic solvent (DES) under mild conditions. The advantages of this method are mild reaction conditions, simple work-up procedure, use of DES as a green solvent and an economical protocol for the preparation of important biologically active phosphorus-containing compounds.

Full text of DOI:10.1080/10426507.2017.1417296

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Choline chloride based eutectic solvent for the
efficient synthesis of 2-amino-4H-chromen-4-yl
phosphonate derivatives via multicomponent
reaction under mild conditions
Suresh Kumar Krishnammagari, Byung Gwon Cho & Yeon Tae Jeong
To cite this article: Suresh Kumar Krishnammagari, Byung Gwon Cho & Yeon Tae Jeong (2017):
Choline chloride based eutectic solvent for the efficient synthesis of 2-amino-4H-chromen-4-yl
phosphonate derivatives via multicomponent reaction under mild conditions, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1417296
To link to this article: https://doi.org/10.1080/10426507.2017.1417296
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Date: 18 December 2017, At: 18:06

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Choline chloride based eutectic solvent for the efficient synthesis of 2-amino-4H-chromen-
4-yl phosphonate derivatives via multicomponent reaction under mild conditions
Suresh Kumar Krishnammagari, 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): Chromenylphosphonates
Abstract
Synthesis of 2-amino-4H-chromen-4-ylphosphonate derivatives has been accomplished by the
one-pot three-component reaction of salicylaldehyde, malononitrile / ethylcyanoacetate and
dialkyl phosphites in the presence of reusable deep eutectic solvent (DES) under mild conditions.
The advantages of this method are mild reaction conditions, simple work-up procedure, use of
DES as a green solvent and an economical protocol for the preparation of important biologically
active phosphorus-containing compounds.
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Graphical Abstract
Keywords: Multicomponent reaction; 2-amino-4H-chromen-4-ylphosphonate derivatives; deep
eutectic solvent; one-pot synthesis; green chemistry
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Introduction
Development of operationally simple and eco-friendly routes for the synthesis of organic
and medicinal compounds having important biological properties are the most significant
objectives in synthetic chemistry.1 In this context, accomplishment of various transformations in
a single operation is highly compatible with the goals of green chemistry. One-pot condensation
reactions in which three or more component combine to form a new targeted product without
isolation of any intermediate are known as multi-component reactions (MCRs).2 They are highly
attractive in terms of their ability to construct two or more C–C, C–heteroatom (C–P, C–O, C–N
and C–S) bonds in a single step. MCRs with their inherent advantages such as short reaction
times, high atom-economy and simple purification processes,3 provide a unique way for
optimizing chemical reactions. MCRs are involved in the recently introduced concept of
fragment based drug-design4,5 and diversity-oriented synthesis of heterocyclic entities with high
selectivity.6
Phosphonates are an important class of organophosphorus compounds (OPCs). They
have been the focus of research in organic chemistry because of their wide range of applications
in material chemistry,7 catalysis,8 and medicinal chemistry.9 There are various types of
phosphonates, such as α-amino- and α-hydroxy-phosphonates and β- phosphonomalononitriles.
All of these phosphonates are produced via P-C bond formation.10 Phosphonates and their
derivatives show diverse pharmacological activities, in addition to acting as enzyme inhibitors
and metabolic probes,11 peptide mimetics,12 antibiotics and pharmacological agents.13 Owing to
the broad importance of these phosphorus compounds the researchers have focused their
attention on them.14 In this context, Michaelis-Arbuzov,15 Pudovik,16 and phospha-Michael
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addition14 are the most important reactions for the synthesis of OPCs. Amongst these, the
phospha-Michael addition represents one of the most adaptable and powerful tools for C-P bond
formation. 2-Amino-4H-chromen-4-ylphosphonates are formed through Knoevenagel
condensation, Pinner cyclisation, and phospha-Michael reactions in a one-pot method. In
addition, these compounds are analogues of 2-amino-4H-chromenes, and fused chromenes
possess anti-tumour/cancer17 and antiviral18 activity and are used in biodegradable
agrochemicals.19 Some of the biologically active 2-amino-4H-chromenes shown in Figure 1.20,21
Recently synthesis of 2-amino-4H-chromen-4-ylphosphonates has attracted much
attention.22-34 Methods have been reported on the one-pot synthesis of 2-amino-4H-chromen-4-
ylphosphonates
promoted
by DMAP,22
imidazole,23
SBA-IM/SO3H,24
LiOH,25
tetramethylguanidine,26 silica supported 2-hydroxyethylammonium acetate (HEAA),27
diethylamine,28 ethylenediamine diacetate,29 I2,30 K3PO4,31 poly(ethylene glycol) (PEG),32 β-
cyclodextrin,33 and InCl3.34 However, most of these procedures are limited in scope because they
suffer from relatively low product yields and require catalysts. Therefore the development of
alternative solvents which are environmentally benign, cheap, inexpensive, easily preparable,
and non-toxic is highly desirable.
The demand for “greener” solvents has lead to the emergence of Deep Eutectic Solvents
(DES). DES are a sub-category of ionic liquids (ILs), first introduced in 2003 by Abbott and
coworkers.35 A notable feature of DES is their melting points, which are typically lower than the
freezing points of their individual components. Thus, the majority of the DES stays in liquid
form at room temperature. In general, the important components of DES include a hydrogen
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bond acceptor (HBA) (e.g. quaternary ammonium or phosphonium salts) and hydrogen bond
donor (HBD) (e.g. organic acids, amides, amino acids, polyols and sugars), that are bonded
chemically via hydrogen bonds.36,37 In addition, other attractive properties have been associated
with DES, such as their lack of flammability, low volatility, thermal and chemical stability,
tenability, wide polarity, negligible vapor pressure, high solvability, and affordability.38 Although
they are classified in several categories (according to the chemical nature of the HBA and HBD),
the most frequently encountered DESs are prepared using the quaternary ammonium salt (ChCl),
because of its biodegradability and low cost.39 Another important point is a known component of
vitamin B complex, its use for DES preparations has led to the anticipation of safe and
sustainable mixtures. These interesting features of DESs have made them green solvents, which
are increasingly popular for use in electrochemistry, material chemistry and organic synthesis.40
Result and discussion
In continuation of our ongoing research towards development of multicomponent
reactions in novel and green reaction media,41 we describe herein the dual role (as catalyst and
solvent) of deep eutectic solvent based on urea and choline chloride for convenient synthesis of
2-amino-4H-chromen-4-ylphosphonates via the domino reaction of salicylaldehydes,
malononitrile / ethylcyanoacetate and dialkyl phosphite (Scheme 1).
Deep eutectic solvent were prepared by a previously reported method40c. Choline
chloride (1 mol) was allowed to react with urea, acids (oxalic acid, Mandelic acid) and inorganic
salts (ZnCl2, FeCl3, SnCl2) at 80-100 °C. The resulting DES was used directly in reactions
without further purification. This method produced no byproducts; therefore there was no loss
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during isolation of the solvent.
After preparation of DES, to optimize the reaction conditions, a model reaction
involving salicylaldehyde (1 mmol), malononitrile (1 mmol) and diethyl phosphite (1 mmol) was
carried out using different DES and the results are given in Table 1. The initial experiment was
performed in the presence of DES (urea–ChCl) at room temperature for 5 h; no product was
formed (entry 1). After that we increased the temperature to 40 °C; trace amounts of the product
was observed. Next, the reaction was performed at higher temperatures (60 °C and 80 °C). The
yield was higher at 80 °C than at 60°C. Hence, 80 °C was selected as the optimized reaction
temperature. The corresponding product 4a was formed as the only product and was isolated in
92 % yield (Table 1, entry 4).
To test the suitability of other DESs, the model reaction under optimized conditions was
carried out in different DESs, such as oxalic acid–ChCl (Table 1, entry 5), glycerol–ChCl (Table
1, entry 6), mandelic acid–ChCl (Table 1, entry 7), ZnCl2–ChCl (Table 1, entry 8), FeCl3–ChCl
(Table 1, entry 9), and SnCl2–ChCl (Table 1, entry 10) at 80 °C for 2 h. The results presented in
Table 1 demonstrate low activity of the other DESs. To test the model reaction with non choline
based DES like fructose : urea at 80 °C for 5h, we obtained KC (Table 1, entry 9). Also model
reaction performed at 80 °C for 5h in presence of choline chloride only trace amounts of the
product were observed (Table 1, entry 9). Finally performing the model reaction at the same
reaction conditions (80 °C) with ZnCl2 and urea as solvent did not result in the formation of the
product.
Under the optimized conditions, the reaction of salicylaldehyde with malononitrile and
diethyl phosphite was then carried out. It furnished the product 2-amino-3-cyano-4H-chromen-4-
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yl phosphonate (4a) in 92 % yield within 2 h (Table 2, entry 2). In order to establish the
generality of this newly developed protocol, additional reactions of various substituted
salicylaldehydes (1) with malononitrile (2) and dialkyl phosphites (3) such as methyl, ethyl, n-
butyl phosphites were carried out in DES under optimized reaction conditions. The results are
summarized in Table 2. Reactions of salicylaldehydes (1) having both electron-withdrawing and
electron-donating groups such as chloro, bromo, nitro, methyl, tert-butyl, methoxy, ethoxy,
hydroxy and benzyloxy groups at 80 °C for 2-3 h produced the corresponding chromeneyl
phosphonates in 85-93 % yields (Table 2). With 2-naphthaldehyde, products 4z, and 4ax were
also produced in 91 % and 90 % yield, respectively (Table 2, entries 26 and 27). The same
reaction, when carried out with ethylcyanoacetate, resulted in the formation of the corresponding
ethyl 2-amino-4-(diethoxyphosphoryl)-4H-chromene-3-carboxylate in good yields (Table 2). In
these reactions the substituents of the salicylaldehyde do not have significant effect on the
product yields. However, when we replaced malononitrile with ethylcyanoacetate there was a
slight decrease in the product yields due to electronic factors. All the isolated products were fully
1
13
characterized on the basis of analytical data and detailed spectral studies including H and C
NMR as well as HRMS.
This reaction protocol was also successfully applied for the synthesis of bis-
chromenylphosphonates for the first time. The synthesis of diethyl 7-((4-(ethoxyphosphono)-2-
amino-3-cyano-4H-chromen-7-yl)methyl)-2-amino-3-cyano-4H-chromen-4-yl-4-phospho-nate
(4au) from the multi-component reaction between 5,5'-methylene-bis-salicylaldehyde,
malononitrile and diethyl phosphite was achieved following this protocol in 85 % yield (Scheme
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2).
Although the detailed mechanism and the role of DES in the present work have not been
confirmed yet, a possible mechanism is proposed in a manner similar to that described in the IL
catalyzed reactions.42 We assume that choline chloride and hydrogen-bonding donors of urea in
DES are the main reason for the high catalytic activity.42d,42e DES activates the aldehyde
functionality of salicylaldehyde (1) through hydrogen bonding to start the nucleophilic addition
of malononitrile / ethylcyanoacetate (2), to provide a nucleophilic urea via capturing a proton of
2 (malononitrile / ethylcyanoacetate) to form corresponding carbanions. Activation of the starting
aldehyde by hydrogen bonding increases the electrophilicity of the aldehyde and assists the
formation of Knoevenagel condensations product (5) with malononitrile (Scheme 3). The
resulting Knoevenagel condensation products undergo intramolecular Pinner reaction to form
iminocoumarine (6). In the next step, imino-coumarin 6 takes part into a phospha-Michael
addition reaction with diethylphosphite (3) giving rise to the desired functionalized amino-4H-
chromen-4-yl phosphonate derivatives 4.
The reusability of DES was further investigated using the reaction between
salicylaldehydes (5 mmol), malononitrile (5 mmol) and diethyl phosphite (5 mmol) in DES (5
mL) under the optimized conditions (Table 3, entry 2). After completion of the reaction, water
(15 mL) was added to the reaction medium to dissolve the DES. The chromeneyl phosphonate
product was separated by simple filtration, washed with water, and purified by recrystallization
from ethanol. The filtrate was evaporated under vacuum and recovered DES was used for the
next cycle. Applying this procedure, DES could be reused up to four times without any
1
significant loss of the initial catalytic activity (Table 3). We recorded H NMR spectra of fresh
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DES and recovered DES. It confirms that recovered DES was not decomposed after the reaction
(see in SI).
Experimental
Material and methods
Chemicals were purchased from Aldrich and Alfa Aesar Chemical Companies and used
without further purification. NMR spectra were recorded in CDCl3 or DMSO-d6 with 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 signal) and the coupling constants are given in Hertz (Hz).
Mass spectra were recorded with a Jeol JMS-700 mass spectrometer. All melting points were
determined using open capillaries on an Electrothermal-9100 (Japan) instrument and are
1
13
31
uncorrected. The Supplemental Materials contains sample H, C and P NMR spectra for the
products 4 (Figure S 1 – S 139).
Synthesis of diethyl 2-amino-3-cyano-4H-chromen-4-yl-4-phosphonate (4b)
A mixture of DES (1 mL), salicylaldehyde (1 mmol), malnonitrile (1 mmol), and diethyl
phosphite (1 mmol) was stirred at 80 °C. Stirring was continued at 80 °C until reaction was
complete. The reaction mixture was diluted with water (5 mL), whereupon the desired product
was separated as a solid, that was isolated by filtration. Further purification was done by
recrystallization from ethanol. The resulting compounds were characterized by melting point and
1H and 13C NMR spectra, which corresponded to those reported in the literature. Compounds 4a-
4au were also synthesized by adopting this procedure.
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Ethyl 4-(ethoxyphosphono)-2-amino-4H-chromene-3-carboxylate (4d)
Viscous liquid; yield: 90 %; 1H NMR (600 MHz, CDCl3): δ = 7.35 – 7.33 (m, 1H), 7.22
– 7.19 (m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.45 (brs, 2H), 4.38 (d, J =
19.5 Hz, 1H), 4.26 – 4.14 (m, 2H), 4.04 – 3.97 (m, 2H), 3.90 – 3.71 (m, 2H), 1.30 (t, J = 7.1 Hz,
3H), 1.23 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ = 168.7,
161.9, 150.8, 129.6, 128.4, 124.6, 119.9, 116.0, 70.8, 62.8 (d, 2JPC = 7.6 Hz), 62.5 (d, 2JPC = 7.4
1
3
3
31
Hz), 59.8, 35.1 (d, JPC = 145.5 Hz), 16.5 (d, JPC = 6.1 Hz), 16.4 (d, JPC = 5.7 Hz), 14.7; P
NMR (243 MHz, CDCl3): δ = 24.4; HRMS (ESI, m/z): Calcd. for C16H22NO6P (M+H+) 355.1185,
Found: 355.1180.
Ethyl 4-(ethoxyphosphono)-2-amino-6-chloro-4H-chromene-3-carboxylate (4h)
1
Viscous liquid; yield: 87 %; H NMR (600 MHz, CDCl3): δ = 7.31 (d, J = 8.3 Hz, 1H),
7.19 – 7.15 (m, 1H), 6.99– 6.88 (m, 1H), 6.46 (brs, 2H), 4.35 – 3.81 (m, 7H), 1.29 (t, J = 7.2 Hz,
3H), 1.23 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 6.5 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ = 168.5,
161.8, 149.4, 129.5, 129.3, 128.4, 121.9, 117.3, 70.5, 62.9 (d, 2JPC = 7.4 Hz), 62.7 (d, 2JPC = 7.3
Hz), 59.9, 35.1 (d, 1JPC = 146.0 Hz), 16.5 (t, 3JPC = 5.8 Hz) 14.7; 31P NMR (243 MHz, CDCl3): δ
= 23.6; HRMS (ESI, m/z): Calcd. for C16H21ClNO6P (M+H+) 389.0795, Found: 389.0792.
Ethyl 4-(ethoxyphosphono)-2-amino-6-nitro-4H-chromene-3-carboxylate (4l)
Solid; yield: 85 %; mp 145-148 °C; 1H NMR (600 MHz, CDCl3): δ = 8.25 (t, J = 2.6 Hz,
1H), 8.19 – 8.14 (m, 1H), 7.13 (d, J = 9.0 Hz, 1H), 5.01 (brs, 2H), 4.33 (d, J = 19.9 Hz, 1H), 4.22
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13
– 3.80 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 6.3 Hz, 3H); C
NMR (151 MHz, CDCl3): δ = 175.8, 168.5, 161.7, 149.4, 129.4, 129.3, 128.4, 121.9, 117.3, 62.9
2
2
1
31
(d, JPC = 7.6 Hz), 62.7 (d, JPC = 7.4 Hz), 59.9, 35.0 (d, JPC = 146.0 Hz), 16.5, 16.4, 14.6; P
NMR (243 MHz, CDCl3): δ = 24.5; HRMS (ESI, m/z): Calcd. for C16H21N2O8P (M+H+)
400.1036, Found: 400.1031.
Ethyl 4-(ethoxyphosphono)-2-amino-6-bromo-4H-chromene-3-carboxylate (4p)
Solid; yield: 88 %; mp 125-127 °C; 1H NMR (600 MHz, CDCl3): δ = 7.46 (d, J = 1.7 Hz,
1H), 7.32 (dd, J = 8.6, 2.0 Hz, 1H), 6.86 (d, J = 8.6, 1H), 6.39 (brs, 2H), 4.33 (d, J = 19.9 Hz,
1H), 4.26 – 4.12 (m, 2H), 4.05 – 3.98 (m, 2H), 3.96 – 3.82 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.24
13
(t, J = 7.0 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 168.4, 161.6,
2
2
149.9, 132.2, 131.3, 122.5, 117.7, 116.9, 70.4, 62.9 (d, JPC = 7.7 Hz), 62.7 (d, JPC = 7.2 Hz),
1
3
31
60.0, 35.0 (d, JPC = 146.2 Hz), 16.5 (t, JPC = 6.1 Hz), 14.7; P NMR (243 MHz, CDCl3): δ =
23.6; HRMS (ESI, m/z): Calcd. for C16H22NO6P (M+H+) 355.1185, Found: 355.1181.
Diethyl 2-amino-3-cyano-8-methoxy-4H-chromen-4-yl-4-phosphonate (4t)
Solid; yield 93 %; mp 168-171 °C; 1H NMR (600 MHz, CDCl3): δ = 7.08 (t, J = 8.0 Hz,
1H), 6.94 – 6.92 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.93 (brs, 2H), 4.16 – 4.10 (m, 2H), 4.04 –
3.85 (m, 6H), 1.35 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ =
161.9, 147.7, 139.5, 124.9, 121.1, 119.6, 117.7, 111.6, 63.4 (d, 2JPC = 7.3 Hz), 63.1 (d, 2JPC = 7.2
1
3
3
31
Hz), 56.1, 51.7, 35.6 (d, JPC = 148.7 Hz), 16.5 (d, JPC = 5.7 Hz), 16.5 (d, JPC = 5.2 Hz); P
NMR (243 MHz, CDCl3): δ = 22.3; HRMS (ESI, m/z): Calcd. for C15H19N2O5P (M+H+)
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338.1032, Found: 338.1029.
Dibutyl 2-amino-3-cyano-8-methoxy-4H-chromen-4-yl-4-phosphonate (4u)
Solid; yield: 92 %; mp 174-176 °C; 1H NMR (600 MHz, CDCl3): δ = 7.06– 7.03 (m, 1H),
6.91 – 6.86 (m, 1H), 6.83 (d, J = 7.5 Hz, 1H), 5.14 (brs, 2H), 4.10 – 3.81 (m, 8H), 1.48 – 1.15 (m,
8H), 0.89 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ = 161.9,
2
2
147.6, 139.5, 124.8, 121.0, 119.6, 117.8, 111.5, 67.0 (d, JPC = 7.7 Hz), 66.7 (d, JPC = 7.6 Hz),
56.1, 51.4, 35.6 (d, 1JPC = 148.3 Hz), 32.6 (d, 3JPC = 5.4 Hz), 32.5 (d, 3JPC = 6.2 Hz), 18.8, 13.7;
31P NMR (243 MHz, CDCl3): δ = 22.4; HRMS (ESI, m/z): Calcd. for C19H27N2O5P (M+H+)
394.1658, Found: 394.1654.
Ethyl 4-(ethoxyphosphono)-2-amino-8-methoxy-4H-chromene-3-carboxylate (4v)
Solid; yield: 89 %; mp 144-146 °C; 1H NMR (600 MHz, CDCl3): δ = 6.95 (t, J = 7.9 Hz,
1H), 6.86 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.22 (brs, 2H), 4.32 (d, J = 19.5 Hz, 1H),
4.18 – 3.82 (m, 9H), 1.24 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H);
13C NMR (151 MHz, CDCl3): δ = 168.6, 162.0, 146.7, 140.5, 124.2, 121.1, 121.0, 112.5, 70.5,
62.8 (d, 2JPC = 7.4 Hz), 62.4 (d, 2JPC = 7.3 Hz), 59.9, 35.2 (d, 1JPC = 145.5 Hz), 16.5 (d, 3JPC = 5.8
3
Hz), 16.4 (d, JPC = 5.4 Hz), 14.8; 31P NMR (243 MHz, CDCl3): δ = 24.7; HRMS (ESI, m/z):
Calcd. for C22H33N2O4P (M+H+) 385.1290, Found: 385.1287.
Diethyl 2-amino-3-cyano-8-ethoxy-4H-chromen-4-yl-4-phosphonate (4w)
Solid; yield: 93 %; mp 181-183 °C; 1H NMR (600 MHz, CDCl3): δ = 7.04 (t, J = 8.0 Hz,
12
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1H), 6.90 (dd, J = 6.4, 1.4 Hz, 1H), 6.83 (dt, J = 8.2, 1.6 Hz, 1H), 5.06 (brs, 2H), 4.14 – 3.91 (m,
6H), 3.87 (d, J = 17.8 Hz, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1
Hz, 3H); 13C NMR (151 MHz, CDCl3): δ = 162.0, 147.0, 139.7, 124.8, 121.0, 119.7, 117.8, 112.9,
64.8, 63.3 (d, 2JPC = 7.6 Hz), 63.1 (d, 2JPC = 7.4 Hz), 51.8, 35.7 (d, 1JPC = 148.6 Hz), 16.5 (d, 3JPC
3
31
= 5.8 Hz), 16.5 (d, JPC = 5.4 Hz), 14.8; P NMR (243 MHz, CDCl3): δ = 22.3; HRMS (ESI,
m/z): Calcd. for C16H21N2O5P (M+H+) 352.1188, Found: 352.1185.
Dibutyl 2-amino-3-cyano-8-ethoxy-4H-chromen-4-yl-4-phosphonate (4x)
Solid; yield: 91 %; mp 175-177 °C14; 1H NMR (600 MHz, CDCl3): δ = 7.02 (t, J = 8.0
Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.09 (brs, 2H), 4.07 – 3.80 (m, 7H),
1.69 – 1.64 (m, 2H), 1.50 – 1.45 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.38 – 1.16 (m, 4H), 0.89 (t, J
13
= 7.4 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 162.0, 147.0, 139.7,
124.7, 121.0, 119.7, 117.8, 112.8, 66.9 (d, 2JPC = 7.7 Hz), 66.7 (d, 2JPC = 7.4 Hz), 64.8, 51.6, 35.6
31
(d, 1JPC = 148.9 Hz), 32.6 (t, 3JPC = 5.3 Hz), 18.8, 14.8, 13.7; P NMR (243 MHz, CDCl3): δ =
22.4; HRMS (ESI, m/z): Calcd. for C20H29N2O5P (M+H+) 408.1814, Found: 408.1811.
Ethyl 4-(ethoxyphosphono)-2-amino-8-ethoxy-4H-chromene-3-carboxylate (4y)
Solid; yield: 90 %; mp 139-141 °C; 1H NMR (600 MHz, CDCl3): δ = 6.96 (t, J = 7.9 Hz,
1H), 6.88 – 6.86 (m, 1H), 6.77 – 6.76 (m, 1H), 4.33 (d, J = 19.5 Hz, 1H), 4.21 – 4.08 (m, 2H),
4.05 – 3.93 (m, 4H), 3.86 – 3.70 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.18
13
(t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 168.6, 161.9,
2
2
146.6, 140.4, 124.1, 121.0, 120.9, 112.4, 70.4, 64.7, 62.7 (d, JPC = 7.4 Hz), 62.4 (d, JPC = 7.3
13
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Hz), 59.6, 35.1 (d, 1JPC = 145.5 Hz), 16.4 (d, 3JPC = 5.8 Hz), 16.3 (d, 3JPC = 5.4 Hz), 14.7, 14.5;
31P NMR (243 MHz, CDCl3): δ = 24.4; HRMS (ESI, m/z): Calcd. for C18H26NO7P (M+H+)
399.1447, Found: 399.1445.
Diethyl 3-amino-2-cyano-1H-benzo[f]chromen-1-yl-1-phosphonate (4z)
Solid, yield: 91 %; mp 218-220 °C; 1H NMR (600 MHz, CDCl3): δ = 8.05 (d, J = 8.5 Hz,
1H), 7.84 – 7.75 (m, 2H), 7.59 (dd, J = 7.9, 6.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 8.9
Hz, 1H), 5.11 (brs, 2H), 4.54 (d, J = 16.1 Hz, 1H), 4.05 – 3.74 (m, 4H), 0.86 (t, J = 7.4 Hz, 3H),
13
0.82 (t, J = 7.4 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 162.7, 148.6, 131.4, 130.7, 129.9,
2
2
128.4, 127.1, 125.5, 124.2, 119.6, 116.7, 111.2, 63.3 (d, JPC = 7.6 Hz), 63.0 (d, JPC = 7.4 Hz),
1
3
3
31
51.8, 35.7 (d, JPC = 148.6 Hz), 16.5 (d, JPC = 5.8 Hz), 16.4 (d, JPC = 5.4 Hz); P NMR (243
MHz, CDCl3): δ = 22.5; HRMS (ESI, m/z): Calcd. for C18H19N2O4P (M+H+) 358.1082, Found:
358.1078.
Dibutyl 3-amino-2-cyano-1H-benzo[f]chromen-1-yl-1-phosphonate (4aa)
Solid; yield: 90 %; mp 158-160 °C; 1H NMR (600 MHz, CDCl3): δ = 8.05 (d, J = 8.5 Hz,
1H), 7.82 – 7.77 (m, 2H), 7.60 – 7.57 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 4.91 (brs, 2H), 4.54 (d, J
= 16.2 Hz, 1H), 4.02 – 3.72 (m, 4H), 1.54 – 1.44 (m, 4H), 1.30 – 1.14 (m, 4H), 0.86 – 0.82 (m,
13
6H); C NMR (151 MHz, CDCl3): δ = 162.7, 148.6, 131.4, 130.6, 129.9, 128.4, 127.1, 125.5,
2
2
1
124.2, 119.6, 116.7, 111.2, 66.8 (d, JPC = 8.1 Hz), 66.6 (d, JPC = 7.9 Hz), 63.3, 32.9 (d, JPC =
3
3
144.8 Hz), 32.7 (d, JPC = 5.8 Hz), 32.5 (d, JPC = 5.9 Hz), 18.7, 13.6; 31P NMR (243 MHz,
CDCl3): δ = 22.8; HRMS (ESI, m/z): Calcd. for C22H27N2O4P (M+H+) 414.1708, Found:
14
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414.1703.
Ethyl 1-(ethoxyphosphono)-3-amino-1H-benzo[f]chromene-2-carboxylate (4ab)
Solid; yield: 88 %; mp 142-144 °C; 1H NMR (600 MHz, CDCl3): δ = 8.19 (d, J = 8.5 Hz,
1H), 7.78 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.4
Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.59 (brs, 2H), 5.09 (d, J = 18.0 Hz, 1H), 4.30 – 4.21 (m, 2H),
3.97 – 3.76 (m, 4H), 1.35 (t, J = 7.1 Hz, 3H), 1.11 – 1.06 (m, 6H); 13C NMR (151 MHz, CDCl3):
δ = 168.6, 162.3, 149.0, 131.1, 131.0, 129.1, 128.2, 126.7, 125.0, 124.4, 116.7, 113.8, 71.3, 62.7
(d, 2JPC = 7.7 Hz), 62.4 (d, 2JPC = 7.3 Hz), 59.8, 31.7 (d, 1JPC = 147.0 Hz), 16.4 (d, 3JPC = 2.2 Hz),
31
16.4 (d, 3JPC = 2.4 Hz), 14.7; P NMR (243 MHz, CDCl3): δ = 24.5; HRMS (ESI, m/z): Calcd.
for C20H24NO6P (M+Na+) 428.1239, Found: 428.1237.
Diethyl 2-amino-6,8-dichloro-3-cyano-4H-chromen-4-yl-4-phosphonate (4ac)
1
Solid; yield: 90 %; mp 168-170 °C; H NMR (600 MHz, CDCl3) δ 7.33 (t, J = 2.3 Hz,
1H), 7.23 (t, J = 2.4 Hz, 1H), 5.08 (brs, 2H), 4.17 – 4.03 (m, 4H), 3.84 (d, J = 18.6 Hz, 1H), 1.35
13
(t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 161.5, 144.8,
2
2
130.0, 129.6, 127.8, 122.8, 120.1, 118.7, 63.7 (d, JPC = 7.5 Hz), 63.5 (d, JPC = 7.3 Hz), 51.6,
35.8 (d, 1JPC = 149.1 Hz), 16.6, 16.5; 31P NMR (243 MHz, CDCl3): δ = 21.0; HRMS (ESI, m/z):
Calcd. for C14H15Cl2N2O4P (M+H+) 376.0146, Found: 376.0146.
Dibutyl 2-amino-6,8-dichloro-3-cyano-4H-chromen-4-yl-4-phosphonate (4ad)
Solid; yield: 89 %; mp 115-118 °C; 1H NMR (600 MHz, CDCl3): δ = 7.32 (d, J = 1.8 Hz,
15
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1H), 7.22 (d, J = 1.7 Hz, 1H), 5.02 (s, 2H), 4.07 – 3.95 (m, 4H), 3.83 (d, J = 18.6 Hz, 1H), 1.68 –
13
1.52 (m, 4H), 1.42 – 1.27 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); C NMR
(151 MHz, CDCl3): δ = 161.3, 144.7, 129.9, 129.5, 127.9, 122.8, 120.1, 118.6, 67.2 (d, 2JPC = 7.8
Hz), 67.1 (d, 2JPC = 7.7 Hz), 51.8, 35.8 (d, 1JPC = 149.1 Hz), 32.6 (d, 3JPC = 5.5 Hz), 18.8, 13.7;
31P NMR (243 MHz, CDCl3): δ = 21.0; HRMS (ESI, m/z): Calcd. for C18H23Cl2N2O4P (M+H+)
432.0772, Found: 432.0769.
Ethyl 4-(ethoxyphosphono)-2-amino-6,8-dichloro-4H-chromene-3-carboxylate (4ae)
Solid; yield: 87 %; mp 144-146°C; 1H NMR (600 MHz, CDCl3): δ = 7.60 (d, J = 2.2 Hz,
1H), 7.42 (d, J = 2.2 Hz, 1H), 5.70 (brs, 2H), 4.46 – 3.85 (m, 7H), 1.32 (t, J = 7.1 Hz, 3H), 1.26
13
(t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 168.4, 161.6,
2
2
149.9, 132.2, 131.3, 122.5, 117.7, 116.9, 70.4, 62.9 (d, JPC = 7.7 Hz), 62.7 (d, JPC = 7.2 Hz),
1
3
31
60.0, 35.0 (d, JPC = 146.2 Hz), 16.5 (t, JPC = 6.1 Hz), 14.7; P NMR (243 MHz, CDCl3): δ =
23.6; HRMS (ESI, m/z): Calcd. for C16H20Cl2NO6P (M+H+) 423.0405, Found: 423.0401.
Diethyl 2-amino-8-bromo-6-chloro-3-cyano-4H-chromen-4-yl-4-phosphonate (4af)
Solid; yield: 91 %; mp 200-203 °C; 1H NMR (600 MHz, CDCl3): δ = 7.47 (t, J = 2.3 Hz,
1H), 7.25 (t, J = 2.3 Hz, 1H), 5.20 (brs, 2H), 4.20 – 3.95 (m, 4H), 3.83 (d, J = 18.6 Hz, 1H), 1.33
13
(t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 161.6, 145.8,
2
2
132.4, 130.3, 128.6, 120.0, 118.7, 111.2, 63.7 (d, JPC = 7.7 Hz), 63.5 (d, JPC = 7.5 Hz), 51.7,
36.0 (d, 1JPC = 149.2 Hz), 16.5, 16.4; 31P NMR (243 MHz, CDCl3): δ = 21.0; HRMS (ESI, m/z):
Calcd. for C14H15BrClN2O4P (M+H+) 419.9641, Found: 419.9637.
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Dibutyl 2-amino-8-bromo-6-chloro-3-cyano-4H-chromen-4-yl-4-phosphonate (4ag)
Solid; yield: 89 %; mp 142-144 °C; 1H NMR (600 MHz, CDCl3): δ = 7.48 (t, J = 2.3 Hz,
1H), 7.27 (t, J = 2.6 Hz, 1H), 4.93 (brs, 2H), 4.09 – 3.93 (m, 4H), 3.83 (d, J = 18.6 Hz, 1H), 1.69
– 1.64 (m, 2H), 1.56 – 1.27 (m, 6H), 0.93 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR
(151 MHz, CDCl3): δ = 161.5, 145.8, 132.3, 130.2, 128.6, 120.0, 118.7, 111.1, 67.2 (d, 2JPC = 7.8
Hz), 67.1 (d, 2JPC = 7.7 Hz), 51.6, 35.9 (d, 1JPC = 149.3 Hz), 32.6 (d, 3JPC = 5.9 Hz), 18.7, 13.7;
31P NMR (243 MHz, CDCl3): δ = 21.1; HRMS (ESI, m/z): Calcd. for C18H23BrClN2O4P (M+H+)
476.0267, Found: 476.0262.
Ethyl 4-(ethoxyphosphono)-2-amino-8-bromo-6-chloro-4H-chromene-3-carboxyla-te
(4ah)
Solid; yield: 88 %; mp 141-143 °C; 1H NMR (600 MHz, CDCl3): δ = 7.43 (d, 1.2 Hz,
1H), 7.26 (d, J = 1.2 Hz, 1H), 6.39 (brs, 2H), 4.32 (d, J = 20.0 Hz, 1H), 4.28 – 4.12 (m, 2H), 4.08
– 3.99 (m, 2H), 3.97 – 3.83 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 1.14 (t, J =
13
7.7 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 168.2, 161.3, 146.6, 131.6, 129.7, 128.6, 123.4,
110.6, 70.7, 63.0 (d, 2JPC = 7.6 Hz), 62.9 (d, 2JPC = 7.2 Hz), 60.1, 35.6 (d, 1JPC = 146.4 Hz), 16.5
3
(d, 3JPC = 5.9 Hz), 16.4 (d, JPC = 5.6 Hz), 14.6; 31P NMR (243 MHz, CDCl3): δ = 22.9; HRMS
(ESI, m/z): Calcd. for C16H20BrClNO6P (M+H+) 466.9900, Found: 466.9895.
Diethyl 2-amino-6,8-dibromo-3-cyano-4H-chromen-4-yl-4-phosphonate (4ai)
Solid; yield: 90 %; mp 190-192 °C; 1H NMR (600 MHz, CDCl3): δ = 7.63 (t, J = 1.8 Hz,
17
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1H), 7.41 (t, J = 2.3 Hz, 1H), 5.13 (brs, 2H), 4.20 – 4.01 (m, 4H), 3.84 (d, J = 18.6 Hz, 1H), 1.34
13
(t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 161.5, 146.3,
2
2
135.2, 131.5, 120.4, 118.7, 117.5, 111.5, 63.7 (d, JPC = 7.5 Hz), 63.5 (d, JPC = 7.3 Hz), 52.0,
35.9 (d, 1JPC = 149.1 Hz), 16.6, 16.5; 31P NMR (243 MHz, CDCl3): δ = 21.0; HRMS (ESI, m/z):
Calcd. for C14H15Br2N2O4P (M+H+) 463.9136, Found: 463.9132.
Dibutyl 2-amino-6,8-dibromo-3-cyano-4H-chromen-4-yl-4-phosphonate (4aj)
Solid; yield: 89 %; mp 151-153 °C; 1H NMR (600 MHz, CDCl3): δ = 7.62 (t, J = 2.2 Hz,
1H), 7.41 (t, J = 2.4 Hz, 1H), 4.97 (brs, 2H), 4.07 – 3.93 (m, 4H), 3.83 (d, J = 18.6 Hz, 1H), 1.70
– 1.51 (m, 4H), 1.41 – 1.27 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR
(151 MHz, CDCl3): δ = 161.4, 146.2, 135.1, 131.4, 120.5, 118.6, 117.4, 111.4, 67.2 (d, 2JPC = 7.7
2
1
31
Hz), 67.1 (d, JPC = 7.6 Hz), 51.8, 35.8 (d, JPC = 149.3 Hz), 32.6, 32.5, 18.7, 13.7; P NMR
(243 MHz, CDCl3): δ = 21.8; HRMS (ESI, m/z): Calcd. for C18H23Br2N2O4P (M+H+) 519.9762,
Found: 519.9758.
Ethyl 4-(ethoxyphosphono)-2-amino-6,8-dibromo-4H-chromene-3-carboxylate (4ak)
Solid; yield; 86 %; mp 146-148 °C; 1H NMR (600 MHz, CDCl3): δ = 7.58 (d, J = 2.1 Hz,
1H), 7.41 (d, J = 2.4 Hz, 1H), 6.26 (brs, 2H), 4.33 (d, J = 20.0 Hz, 1H), 4.26 – 3.85 (m, 6H), 1.30
(t, J = 7.1 Hz, 3H), 1.25 (t, J = 6.4 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz,
CDCl3): δ = 168.1, 161.2, 146.5, 131.6, 129.7, 128.5, 127.4, 123.3, 110.5, 63.0 (d, 2JPC = 7.6 Hz),
62.8 (d, 2JPC = 7.2 Hz), 60.1, 35.6 (d, 1JPC = 146.4 Hz), 16.5 (d, 3JPC = 5.9 Hz), 16.4 (d, 3JPC = 5.6
Hz), 14.6; 31P NMR (243 MHz, CDCl3): δ = 22.9; HRMS (ESI, m/z): Calcd. for C16H20Br2NO6P
18
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(M+H+) 510.9395, Found: 510.9390.
Diethyl 2-amino-6-bromo-3-cyano-8-methoxy-4H-chromen-4-yl-4-phosphonate (4al)
Solid; yield: 92 %; mp 173-174 °C; 1H NMR (600 MHz, CDCl3): δ = 7.05 (s, 1H), 6.96
(s, 1H), 5.06 (brs, 2H), 4.13 – 4.04 (m, 4H), 3.85 (s, 3H), 3.81 (d, J = 18.4 Hz, 1H), 1.34 (t, J =
13
6.5 Hz, 3H), 1.25 (t, J = 6.4 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 162.0, 148.3, 138.8,
123.4, 119.5, 119.4, 117.0, 115.0, 63.5 (d, 2JPC = 7.4 Hz), 63.4 (d, 2JPC = 7.1 Hz), 56.4, 50.6, 35.4
(d, 1JPC = 149.3 Hz), 16.5 (dd, 3JPC = 5.0, 3.2 Hz); 31P NMR (243 MHz, CDCl3): δ = 21.7; HRMS
(ESI, m/z): Calcd. for C15H18BrN2O5P (M+H+) 416.0137, Found: 416.0136.
Dibutyl 2-amino-6-bromo-3-cyano-8-methoxy-4H-chromen-4-yl-4-phosphonate (4am)
Solid; yield: 90 %; mp 175-177 °C; 1H NMR (600 MHz, CDCl3): δ = 7.05 (d, J = 2.1 Hz,
1H), 6.96 (d, J = 1.9 Hz, 1H), 4.90 (brs, 2H), 4.06 – 3.79 (m, 8H), 1.68 – 1.23 (m, 8H), 0.92 (t, J
13
= 7.4 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H); C NMR (151 MHz, CDCl3): δ = 162.0, 148.3, 138.8,
123.5, 123.4, 119.4, 117.0, 115.0, 67.2 (d, 2JPC = 7.8 Hz), 67.1 (d, 2JPC = 7.7 Hz), 56.4 51.8, 35.8
(d, 1JPC = 149.1 Hz), 32.6 (d, 3JPC = 5.5 Hz), 18.8, 13.7; 31P NMR (243 MHz, CDCl3): δ = 21.6;
HRMS (ESI, m/z): Calcd. for C C19H26BrN2O5P (M+H+) 472.0763, Found: 472.0759.
Ethyl
late (4an)
4-(ethoxyphosphono)-2-amino-6-bromo-8-methoxy-4H-chromene-3-carboxy-
Solid; yield: 87 %; mp 137-140 °C; 1H NMR (600 MHz, CDCl3): δ = 7.08 (s, 1H), 6.95
(s, 1H), 6.46 (brs, 2H), 4.32 (d, J = 19.8 Hz, 1H), 4.28 – 3.90 (m, 6H), 3.85 (s, 3H), 1.31 (t, J =
7.0 Hz, 3H), 1.25 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 6.9 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ =
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168.5, 161.6, 148.1, 139.5, 123.7, 123.0, 116.5, 114.5, 70.5, 62.8 (d, 2JPC = 7.4 Hz), 62.7 (d, 2JPC
= 7.1 Hz), 59.9, 56.4, 35.1 (d, 1JPC = 146.4 Hz), 16.6 (d, 3JPC = 5.7 Hz), 16.5 (d, 3JPC = 5.7 Hz),
14.6; 31P NMR (243 MHz, CDCl3): δ = 23.5; HRMS (ESI, m/z): Calcd. for C17H23BrNO7P
(M+Na+) 486.0293, Found: 486.0287.
Diethyl 6,8-di-tert-butyl-2-amino-3-cyano-4H-chromen-4-yl-4-phosphonate (4ao)
Solid; yield: 93 %; mp 190-192 °C; 1H NMR (600 MHz, CDCl3): δ = 7.26 (t, J = 2.3 Hz,
1H), 7.18 (t, J = 2.3 Hz, 1H), 4.78 (brs, 2H), 4.11 (p, J = 7.1 Hz, 2H), 4.00 – 3.89 (m, 2H), 3.87
(d, J = 17.8 Hz, 1H), 1.39 (s, 9H), 1.34 (t, J = 7.1 Hz, 4H), 1.30 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H);
13C NMR (151 MHz, CDCl3): δ = 161.8, 147.1, 146.8, 136.7, 124.8, 123.7, 119.6, 116.5, 63.3 (d,
2
1
2JPC = 7.3 Hz), 62.8 (d, JPC = 7.3 Hz), 52.1, 36.3 (d, JPC = 148.7 Hz), 35.1, 34.7, 31.5, 30.4,
3
3
31
16.6 (d, JPC = 5.8 Hz), 16.5 (d, JPC = 5.6 Hz); P NMR (243 MHz, CDCl3): δ = 22.6; HRMS
(ESI, m/z): Calcd. for C22H33N2O4P (M+H+) 420.2178, Found: 420.2175.
Dibutyl 6,8-di-tert-butyl-2-amino-3-cyano-4H-chromen-4-yl-4-phosphonate (4ap)
Solid; yield: 91 %; mp 145-147 °C; 1H NMR (600 MHz, CDCl3): δ = 7.26 (d, J = 2.2 Hz,
1H), 7.18 (d, J = 2.3 Hz, 1H), 4.72 (brs, 2H), 4.12 – 3.78 (m, 5H), 1.68 – 1.14 (m, 26H), 0.91 (t,
J = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 2H); 13C NMR (151 MHz, CDCl3): δ = 161.6, 147.1, 146.7,
136.6, 124.8, 123.6, 119.5, 116.5, 66.8 (d, 2JPC = 7.7 Hz), 66.5 (d, 2JPC = 7.7 Hz), 36.2 (d, 1JPC
=
148.6 Hz), 35.0, 34.7, 32.7 (d, 3JPC = 5.8 Hz), 32.6 (d, 3JPC = 5.7 Hz), 31.5, 30.4, 18.8, 13.7; 31P
NMR (243 MHz, CDCl3): δ = 22.8; HRMS (ESI, m/z): Calcd. for C26H41N2O4P (M+H+)
476.2804, Found: 476.2801.
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Ethyl
4-(ethoxyphosphono)-6,8-di-tert-butyl-2-amino-4H-chromene-3-carboxylate
(4aq)
Solid; yield: 90 %; mp 214-216 °C; 1H NMR (600 MHz, CDCl3): δ = 7.23 (d, J = 1.9 Hz,
1H), 7.21 (d, J = 1.7 Hz, 1H), 6.34 (brs, 2H), 4.37 (d, J = 19.5, 1H), 4.29 – 4.12 (m, 2H), 4.02 (m,
2H), 3.91 – 3.67 (m, 2H), 1.40 (s, 9H), 1.31 (m, 12H), 1.24 (t, J = 7.0 Hz, 4H), 1.10 (t, J = 7.0
Hz, 3H); 13C NMR (151 MHz, CDCl3): δ = 165.4, 161.7, 147.5, 146.5, 140.5, 136.1, 124.8,
122.9, 119.8, 62.6 (d, 2JPC = 7.4 Hz), 62.3 (d, 2JPC = 7.2 Hz), 59.8, 35.8 (d, 1JPC = 145.3 Hz), 35.0,
3
3
34.7, 31.6, 30.4, 16.6 (d, JPC = 6.0 Hz), 16.5 (d, JPC = 5.7 Hz), 14.7; 31P NMR (243 MHz,
CDCl3): δ = 24.6; HRMS (ESI, m/z): Calcd. for C24H38NO6P (M+H+) 467.2437, Found:
467.2435.
Ethyl 4-(ethoxyphosphono)-2-amino-7-hydroxy-4H-chromene-3-carboxylate (4ar)
Solid; yield: 87 %; mp 160-161 °C; 1H NMR (600 MHz, CDCl3): δ = 8.88 (brs, 1H),
7.04 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 4.32 (d, J = 17.6 Hz, 1H), 4.26 –
13
3.83 (m, 6H), 1.33 – 1.27 (m, 6H), 1.18 (t, J = 7.0 Hz, 3H); C NMR (151 MHz, CDCl3): δ =
167.6, 161.9, 157.2, 150.8, 129.2, 111.2, 109.3, 102.3, 68.5, 61.6 (d, 2JPC = 7.3 Hz), 61.3 (d, 2JPC
= 7.2 Hz), 58.5, 33.3 (d, 1JPC = 145.1 Hz), 15.9, 15.8 (d, 3JPC = 2.5 Hz) 14.1; 31P NMR (243 MHz,
CDCl3): δ = 23.6; HRMS (ESI, m/z): Calcd. for C16H22NO7P (M+H+) 371.1134, Found:
371.1130.
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Ethyl 4-(ethoxyphosphono)-2-amino-7-(benzyloxy)-4H-chromene-3-carboxylate (4as)
Solid; yield: 90 %; mp 133-136 °C; 1H NMR (600 MHz, CDCl3): δ = 7.42–7.32 (m, 5H),
7.25 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 6.36 (brs, 2H), 5.04 (s, 2H), 4.33
(d, J = 18.2 Hz, 1H), 4.27 – 4.13 (m, 2H), 4.06 – 3.98 (m, 2H), 3.90 – 3.71 (m, 2H), 1.32 (t, J =
7.0 Hz, 3H), 1.25 (t, J = 6.9 Hz, 3H), 1.11 (t, J = 6.7 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ =
168.8, 161.7, 159.0, 151.4, 136.6, 130.1, 128.7, 128.2, 127.6, 111.9, 111.5, 102.8, 71.3, 70.3,
62.8 (d, 2JPC = 7.4 Hz), 62.4 (d, 2JCP = 7.1 Hz), 59.8, 34.4 (d, 1JPC = 146.1 Hz), 16.5 (t, 3JPC = 5.7
31
Hz), 14.7; P NMR (243 MHz, CDCl3): δ = 24.7; HRMS (ESI, m/z): Calcd. for C23H28NO7P
(M+Na+) 484.1501, Found: 484.1495.
Ethyl
4-(ethoxyphosphono)-7-(4-fluorobenzyloxy)-2-amino-4H-chromene-3-
carboxylate (4at)
Solid; yield: 90 %; mp 112-115 °C; 1H NMR (600 MHz, CDCl3): δ = 7.40 – 7.38 (m,
2H), 7.26 (d, J = 8.5 Hz, 1H), 7.09 – 7.05 (m, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.60 (s, 1H), 6.34
(brs, 2H), 5.00 (s, 2H), 4.33 (d, J = 18.3 Hz, 1H), 4.25– 4.10 (m, 2H), 4.04 – 4.01 (m, 2H), 3.88
13
– 3.72 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H); C
1
NMR (151 MHz, CDCl3): δ = 168.8, 162.7 (d, JCF = 246.5 Hz), 161.7, 158.8, 151.5, 132.4,
4
3
2
130.2 (d, JCF = 3.9 Hz), 129.5 (d, JCF = 8.3 Hz), 115.7 (d, JCF = 21.6 Hz), 111.4, 102.8, 71.3,
69.7, 62.8 (d, 2JPC = 7.3 Hz), 62.4 (d, 2JPC = 7.0 Hz), 59.8, 34.9, 33.9, 34.4 (d, 1JPC = 146.0 Hz),
16.5 (t, 3JPC = 5.6 Hz), 14.7; 31P NMR (243 MHz, , CDCl3): δ = 24.7; HRMS (ESI, m/z): Calcd.
for C23H27FNO7P (M+H+) 479.1509, Found: 479.1504.
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Diethyl
7-((4-(ethoxyphosphono)-2-amino-3-cyano-4H-chromen-7-yl)methyl)-2-
amino-3-cyano-4H-chromen-4-yl-4-phosphonate (4au)
Solid; yield: 85 %; mp 198-200 °C; 1H NMR (600 MHz, DMSO-d6): δ = 7.10 (d, J = 8.3
Hz, 2H), 7.08 – 6.98 (m, 4H), 6.90 (s, 4H), 3.96 – 3.76 (m, 11H), 1.12-1.07 (m, 12H); 13C NMR
(151 MHz, DMSO-d6): δ = 161.9, 147.7, 139.5, 124.9, 121.1, 119.6, 117.7, 111.6, 63.4 (d, 2JPC
=
2
1
3
7.3 Hz), 63.1 (d, JPC = 7.2 Hz), 51.8, 46.4, 35.6 (d, JPC = 148.7 Hz), 16.5 (d, JPC = 5.7 Hz),
16.4 (d, 3JPC = 5.2 Hz); 31P NMR (243 MHz, DMSO-d6): δ = 22.1; HRMS (ESI, m/z): Calcd. for
C29H34N4O8P2 (M+H+) 628.1852, Found: 628.1857.
Conclusion
We have developed an efficient, simple, and green protocol for the synthesis of 2-amino-
4H-chromen-4-ylphosphonates in deep eutectic solvent based on urea and choline chloride. In
this reaction medium, product separation is convenient and DES is reusable. Green solvent
applicability to various substrates under mild reaction condition is the merit of this novel
protocol.
Acknowledgement
This work was supported by a Research Grant of Pukyoung National University (2017).
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References
1. Anatas, P.; Williams, T. Green Chemistry, Frontiers in Benign Chemical Synthesis and
Procedures, Oxford Science Publications: Oxford, 1998.
2. (a) Zhu, J.; Wang, Q.; Wang, M. Multicomponent Reactions in Organic Synthesis, Wiley-
VCH, 2014; (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 10, 1471-1499.
3. (a) Shingate, B. B. Organic Chem. Curr. Res., 2012, 1, e107. (b) A. Domling, Chem. Rev.
2006, 106, 17-89.
4. Erlanson, D. A.; McDowell, R. S.; O’Brien, T. J. Med. Chem., 2004, 47, 3463-3482.
5. (a) Ali, K.; Shaghayegh S. K.; Hossein N.; Abdolhamid B. Tetrahedron 2016, 72, 6536-6542;
(b) Hajduk, P. J.; Greer, J. Nat. Rev. Drug Discovery 2007, 6, 211-219. (c) Kalla, R. M. N.;
Choi, J. -S.; Yoo, J. -W.; Byeon, S. J.; Heo, M. S.; Kim, I. Eur. J. Med. Chem. 2014, 76, 61-
66.
6. Morteza, S. Chem. Rev. 2012, 112, 3508-3549; (b) Amol, B. A.; Jeong, Y. T. Tetrahedron
Lett. 2013, 54, 1302-1306.
7. (a) Onouchi, H.; Miyagawa, T.; Furuko, A.; Maeda, K.; Yashima, E. J. Am. Chem. Soc. 2005,
127, 2960−2965; (b) Queffelec, C.; Petit, M.; Janvier, P.; Knight, D. A.; Bujoli, B. Chem.
Rev. 2012, 112, 3777-3807.
8. (a) Chelucci, G.; Orru, G.; Pinna, G. A. Tetrahedron 2003, 59, 9471-9515. (b) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338−6361; (c) Guo, Y.; Fu, H.; Chen, H.;
Li, X. Catal. Commun. 2008, 9, 1842-1845; (d) Li, Y.; Lu, L.-Q.; Das, S.; Pisiewicz, S.;
Junge, K.; Beller, M. J. Am. Chem. Soc. 2012, 134, 18325-18329.
9. (a) Dang, Q.; Liu, Y.; Cashion, D. K.; Kasibhatla, S. R.; Jiang, T.; Taplin, F.; Jacintho, J. D.;
24
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Li, H.; Sun, Z.; Fan, Y.; DaRe, J.; Tian, F.; Li, W.; Gibson, T.; Lemus, R.; Van Poelje, P. D.;
Potter, S. C.; Erion, M. D. J. Med. Chem. 2011, 54, 153-165. (b) Chen, X.; Kopecky, D. J.;
Mihalic, J.; Jeffries, S.; Min, X.; Heath, J.; Deignan, J.; Lai, S.; Fu, Z.; Guimaraes, C.; Shen,
S.; Li, S.; Johnstone, S.; Thibault, S.; Xu, H.; Cardozo, M.; Shen, W.; Walker, N.; Kayser, F.;
Wang, Z. J. Med. Chem. 2012, 55, 3837-3851.
10. (a) Enders, D.; Saint-Dizier, A.; Lannou, M. I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29−49;
(b) Corbridge, D. E. C. Phosphorus, an Outline of Chemistry, Biochemistry and Uses, 5th
ed., Elsevier, Amsterdam, 1995.
11. Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652-
1661.
12. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193-215.
13. Atherton, F. R.; Hassal, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29-46.
14. Enders, D.; Dizier, A. S.; Lannou, M. I.; Lenzen, A. Eur. J. Org. Chem. 2006, 1, 29-49.
15. (a) Michaelis, A.; Kaehne, R. Ber. Dtsch. Chem. Ges. 1898, 31, 1048-1055.
16. Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81-96.
17. Ough, M.; Lewis, A.; Bey, E. A.; Gao, J.; Ritchie, J. M.; Bornmann, W.; Boothman, D. A.;
Oberley, L. W.; Cullen, J. J. Cancer Biology & Therapy, 2005, 4, 95-102.
18. Hiramoto, K.; Nasuhara, A.; Michiloshi, K.; Kato, T.; Kikugawa, K.; Mutation Research
1997, 395, 47-56.
19. Hafez, E. A. A.; Elangdi, M. H.; Elgamey, A. G. A.; El-Taweel, F. M. A. A. Heterocycles
1987, 26, 903-907.
20. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S. K.;
25
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Belyakov, P. A.; Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591-601.
21. Moafi, L.; Ahadi, S.; Bazgir, A. Tetrahedron Lett. 2010, 51, 6270-6274.
22. Kour, P. ; Kumar, A.; Rai, V. K. C. R. Chimie 2017, 20, 140-145.
23. Darvish, F.; Abdollahzade, A.; Saravani, D. Res Chem Intermed. 2017, 43, 1487-1494.
24. Nasab, M. J.; Kiasat, A. R. Microporous and Mesoporous Materials 2016, 223, 10-17.
25. Dai, P.; Zha, G.; Lai, X.; Lie, W.; Gan, Q.; Shen, Y. RSC Adv. 2014, 4, 63420-63424.
26. Kalla, R. M. N.; Byeon, S. J.; Heo, M. S.; Kim, I. Tetrahedron 2013, 69, 10544-10551.
27. Sobhani, S.; Honarmand, M. Catalysis Lett. 2013, 143, 476-485.
28. Kulakarni, M. A.; Pandurangi, V. R.; Desai, U. V.; Wasgaonkar, P. P. C. R. Chimie 2012, 15,
745-752.
29. Kolla, S. R.; Lee, Y. R. Tetrahedron 2012, 68, 226-237.
30. Rajasekhar, M.; Rao, K. U. M.; Sundar, C. S.; Reddy, N. B.; Nayak, S. K.; Reddy, C. S.
Chemical & Pharmaceutical Bulletin 2012, 60, 854-858.
31. Gaikwad, D. S.; Undale, K. A.; Shaikh, T. S.; Pore, D. M.; C. R. Chimie 2011, 14, 865-868.
32. Das, B.; Balasubramanyam, P.; Reddy, G. C.; Salvanna, N. Helv. Chim. Acta 2011, 94, 1347-
1350.
33. Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett. 2010, 51,
3649-3653.
34. Jayashree, P.; Shanthi, G.; Perumal, P. T. Synlett 2009, 6, 917-920.
35. Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V.; Chem. Commun.
2003, 70-71.
36. Smith, E. L.; Abbott, A. P.; Ryder, K. S. Chem. Rev. 2014, 114, 11060–11082.
26
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
37. (a) Mbous, Y. P.; Hayyan1, M.; Wong, W. F.; Looi, C. Y.; Hashim, M. A. Scientific Reports
2017, 7, 41257; (c) Smith, E. L.; Abbott, A. P.; Ryder, K. S. Chem. Rev. 2014, 114, 11060-
11082; (d) Zhang, Q.; Vigier, K. D. O.; Royer, S.; Jerome, F. Chem. Soc. Rev. 2012, 41,
7108–7146; (e) Zhang, Z.-H.; Zhang, X.-N.; Mo, L.-P.; Li, Y.-X.; Ma, F.-P. Green Chem.
2012, 14, 1502-1506.
38. Wang, P.; Ma, F.-P.; Zhang, Z.-H.; J. Mol. Liq. 2014, 198, 259-262; (b) Tang, B.; Row, K. H.
Monatsh. Chem. - Chem. Mon. 2013, 144, 1427–1454.
39. (a) Park, T.-J.; Lee, S. H. Green Chem. 2017, 19, 910–913; (b) Kim, S. H.; Park, S.; Yu, H.;
Kim, J. H.; Kim, H. J.; Yang, Y.-H.; Kim, Y. H.; Kim, K. J.; Kan E.; Lee, S. H. J. Mol. Catal.
B: Enzym. 2016, 128, 65-72.
40. (a) Zhang, M.; Liua, Y. H.; Shang, Z. R.; Hu, H. C.; Zhang, Z. H. Catal. Commun. 2017,
88, 39–44; (b) (f) Azizi, N.; Haghayegh, M. S. ChemistrySelect 2017, 2, 8870-8873; (c)
Alonso, D. A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I. M.; Ramon, D. J. Eur. J.
Org. Chem. 2016, 612–632; (d) Liu, P.; Hao, J. -W.; Mo L. -P.; Zhang, Z. -H. RSC Adv. 2015,
5, 48675–48704; (e) X.-T. Li, Y.-H. Liu, X. Liu, Z.-H. Zhang, RSC Adv. 2015, 5, 25625-
25633. (f) García-Álvarez, J.; Hevia, E.; Capriati, V. Eur. J. Org. Chem. 2015, 6779-6799;
(g) García-Álvarez, J. Eur. J. Inorg. Chem. 2015, 5147–5157; (h) Hu, H. C.; Liu, Y. H.; Li,
B. L.; Cui, Z. S.; Zhang, Z. H. RSC Adv. 2015, 5, 7720–7728.
41. (a) Jadhav, A. M.; Krishnammagari, S. K.; Kim, J. T.; Jeong Y. T. Tetrahedron 2017, 73,
5163–5169; (b) Reddy, M. V.; Kim Lien, N. T.; Reddy, G. C. S.; Lim, K. T.; Jeong, Y. T.
Green Chem. 2016, 18, 4228–4239.
42. (a) Azizi, N.; Ahooie, T. S.; Hashemi, M. M. J. Mol. Liq. 2017, 246, 221–224; (b) Lohar, T.;
27
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Kumbhar, A.; Barge, M.; Salunkhe, R. J. Mol. Liq. 2016, 224, 1102–1108; (c) Khandelwal,
S.; Tailor, Y. K.; Kumar, M. J. Mol. Liq. 2016, 215, 345–386; (d) Azizi, N.; Dezfooli, S.;
Hashemi, M. M. J. Mol. Liq. 2014, 194, 62–67; (e) Azizi, N.; Dezfooli, S.; Khajeh M.;
Hashemi, M. M. J. Mol. Liq. 2013, 186, 76–80.
Figure 1 Structures of some biologically active 2-amino-4H-chromenes.
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Scheme 1 Preparation of 2-amino-4H-chromen-4-yl phosphonate derivatives.
Scheme 2 Synthesis of bis-chromenylphosphonates
Scheme 3 Possible mechanism for the formation of chromenylphosphonates 4.
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