CAL-B accelerated novel synthetic protocols for 3,3’-arylidenebis-4-hydroxycoumarins and dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates

Article abstract of DOI:10.1007/s11164-021-04535-2

Green protocols for the syntheses of 3,3′-arylidenebis-4-hydroxycoumarins and dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates have been first time developed using biocatalyst, CAL-B (lipase). These are carried at room temperature under st

Full text of DOI:10.1007/s11164-021-04535-2

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04535-2
CAL‑B accelerated novel synthetic protocols
for 3,3’‑arylidenebis‑4‑hydroxycoumarins and dimethyl
((substituted phenyl) (phenylamino)methyl) phosphonates
Anusaya S. Chavan1 · Arun S. Kharat2 · Manisha R. Bhosle1 ·
Sambhaji T. Dhumal1 · Ramrao A. Mane1
Received: 2 March 2021 / Accepted: 5 July 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
Green protocols for the syntheses of 3,3′-arylidenebis-4-hydroxycoumarins and
dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates have been frst
time developed using biocatalyst, CAL-B (lipase). These are carried at room tem-
perature under stirring and are convenient and cost efective. The developed proto-
cols are environmentally acceptable and are giving better to excellent yields of the
titled products.
Graphic abstract
Keywords CAL-B · Lipase · Biocatalysts · 3,3-Arylidenebis-4-hydroxycoumarins ·
Dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates ·
Multicomponent condensation
* Ramrao A. Mane
manera2011@gmail.com
1
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad 431004, India
2
Laboratory of Applied Microbiology, School of Life Sciences, Jawaharlal Nehru University,
New Delhi 110067, India
Vol.:(0123456789)
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A. S. Chavan et al.
Introduction
Coumarins and α‐amino phosphonates are gaining more importance as some of
their derivatives have shown promising bioactivities. Coumarins are found nat-
urally in various plants and are members of a class of heterocyclic compounds
[1]. They are extensively employed as food and cosmetic additives [2], dye lasers
[3–5] and gain stabilizing medium. They are found to possess anticoagulant, anti-
biotic, antitumor, anti-HIV, antihypertensive, analgesic, anti-infammatory and
anti-arrhythmia activities and are explored as precursor molecules in pharma-
ceutical industries [6–13]. Biscoumarins are vital organic compounds and have
received considerable attention because of their broad spectrum of biological and
interesting potential therapeutic activities. They often possess interesting phar-
macological properties and act as antitumor, antibacterial [3–8], anticancer [9],
urease and α-glucosidase inhibitory [10, 11], antifungal [12], and antiprolifera-
tive [13] agents. Dicoumarol and taxolin combination enhances synergistic inhi-
bition of cell division of sea urchin embryos. These two compounds can be used
in combination in order to reduce the high toxicity of taxol.
The distinctive nature of bioactive organophosphorus compounds has estab-
lished their wide applicability in agricultural, medicinal, and industrial areas.
α-Aminophosphonates are structural analogs of natural amino acids. They are
considered as an important class of compounds with diverse and interesting bio-
logical activities [14–19]. Organophosphorus chemistry has provided valuable
materials with potential biological activities of medicinal importance, and such
products act as enzyme inhibitors [14], and are found to have HIV protease [15],
antibiotic [16], herbicidal, fungicidal, insecticidal [17], plant growth regulating
[18], antithrombotic [19], peptidases and proteases properties [20].
In view of these applications, several synthetic protocols have been reported
to synthesize these compounds. Biscoumarins usually synthesized by carrying
separately one-pot condensation of 4-hydroxycoumarins and aryl aldehydes in the
presence of one of the catalysts viz. glacial acetic acid [21], acetic acid anhy-
dride [22, 23], iodine [24], silica-supported sodium hydrogen sulfate and indion
190 resin in toluene [25], ionic liquids [26], silica-supported preyssler nanopar-
ticles [27], tetrabutyl ammonium bromide (TBAB) [28], microwave irradiation
with silica-gel support [21, 29, 30], dodecyl benzene sulfonic acid (DBSA)MW
[31], phospho sulfonic acid [32], CuO–CeO2 nanocomposite [33], starch-sulfuric
acid [34], LTNPs [35], MgO-NPs [36], BiVO4-NPs [37], SiO2-OSO3H NPs [38],
P4VPy-CuO [39], magnetic nanoparticle catalyst TrBr/[Fe3O4@SiO2@(CH2)3-
ImSO3H]Cl [40], IL@CNTs [41], Hnmp/ZnCl3 [42], [Dabco-H][AcO] [43],
[TMG][Ac] [44], RHA-SO3H [45], KF-montmorillonite [46], and PS-Zn-anthra
complex [47], and Mn(pbdo)2Cl2/MCM-41 [48].
Mostly practiced synthetic route for obtaining α‐amino organophosphonates
involves one-pot condensation of anilines, aryl aldehydes and di/trimethylphos-
phite. Eforts are also found to be directed to accelerate this condensation using
various catalysts viz. lanthanide trifate, scandium tris(dodecyl sulfate) [49],
samarium diiodide along with 4-Å molecular sieves [50], heterogenous catalysts
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CAL‑B accelerated novel synthetic protocols for…
such as InCl3 [51], TaCl5-SiO2 [52] (bromodimethyl) sulfonium bromide [53],
LiClO4 [54], montmorillonite KSF [55], ZrCl4 [56], TiO2 [57], alumina‐sup-
ported reagents [58], ionic liquids [59], H3PW12O40 [60], Amberlite‐IR120 [61],
and oxalic acid [62]. Recently, a synthesis of α‐amino phosphonates from ferro-
cene‐1‐carboxaldehyde, anilines and diethyl phosphite under neat condition, cata-
lyzed by KHSO4, has been reported [63].
The above referred synthetic protocols are having one or other kind of drawbacks.
These are not cost efective and need non-readily available and non-biodegradable
heterogeneous/homogeneous catalysts. It is also reviewed that a little attention
is found to be paid on the use of biocatalysts, particularly immobilized lipases to
accelerate the above condensations leading to the titled compounds. Biocatalysts/
enzymes are functional proteins and now a days they are used as safer and economic
catalysts for carrying organic transformations leading to biodynamic compounds.
Our group has explored the use of active Baker’s yeast as a whole cell source of
biocatalysts for carrying various cyclocondensations leading to biodynamic hetero-
cycles [64–72].
Recently some of the lipases are also found to be used as catalyst for carrying
cost efectively value-added organic transformations [73–79].
Lipases are employed for variety of reaction viz. esterifcations [73], transes-
terifcations [74], hydrolyses [75], Bayer-Villiger oxidations [76–78], and amida-
tions [79]. Biocatalytical promiscuity of lipases has also been reported. Lipases are
well explored as biocatalysts and do catalyze hydrolysis of water soluble carboxylic
esters, particularly triglycerides and phospholipids. Among lipases Candida Antar-
tica Lipase B has been used as a biocatalyst in its pure form is as a immobilized
CAL-B form to accelerate various organic reactions and biotransformations. Open
and closed structures of this lipase have been thoroughly established by Benjamine
et. al [80]. CAL-B is structurally similar to several other lipases and has a fexible
lid. It is made up of 317 amino acids and is a member of α/β hydrolase-fold family.
It consists of Serine, Hisdine, and Asparic/Glutamic catalytical triad and has sec-
ondary alcoholic binding pocket. Usually these active sites viz. Serine, Histidine,
Asparic/Glutamic amino acid residues participate to display catalytic behavior to
accelerate the rates of organic/ biotranformations [81]
Considering the dire need of establishing more convenient, cost-efective and
eco-friendly synthetic protocols for the titled compounds, and signifcance of lipases
as biocatalysts, here frst time we have made an attempt to develop such synthetic
protocols by carrying separately the above condensations in the presence of immo-
bilized lipase, CAL-B, for obtaining the titled products 3,3’-arylidenebis-4-hydrox-
ycoumarins and dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates
conveniently and cost efectively.
Experimental
All the chemicals used were of laboratory grade. Lipase B Candida Antarctica
immobilized on immobead 150 recombinant from yeast is procured from Sigma
Alrich. Melting points of all the synthesized compounds were determined in open
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A. S. Chavan et al.
1
capillary tubes and are uncorrected. H NMR spectra were recorded with a Bruker
Avance 300 spectrometer operating at 400 MHz using DMSO-d6 solvent and tetra-
methylsilane (TMS) as the internal standard and chemical shift in δ ppm.13C NMR
spectra were recorded on Bruker Avance 75 MHz on Jeol. The purity of each com-
pound was checked by TLC using silica-gel, 60F254 aluminum sheets as adsorbent
and visualization was accomplished by iodine/ultraviolet light.
Synthesis of 3,3’‑(Phenylmethylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3a)
Lipase, CAL-B (100 mg) was added to the reaction fask, containing ethanol
(15 ml). Then, a mixture of benzaldehyde (1 gm/9.4 mmol) (1a) and 4-hydroxy cou-
marin (3.1 gm/18.8 mmol) (2) was added to the fask, and the whole reaction mass
was stirred at rt. The progress of reaction was monitored by TLC using ethyl acetate:
pet ether (2:8) as eluent. After stirring for 9 h, then ethyl acetate (3×10 ml) was
added to the reaction mass and then stirred at room temperature for 10 min. and then
fltered through Whatman paper. The solid residue remained on flter paper was fur-
ther washed with 10 ml ethyl acetate. The obtained solid residue, CAL-B was dried
and reused as a biocatalyst. Then, ethyl acetate and ethanol were removed from the
collected fltrate under vacuum, and obtained crude residue remained was then crys-
tallized using ethanol.
Similarly other derivatives of the series are prepared. The melting points and the
isolated yields of the derivatives are recorded in Table 3. Melting points and spectral
data of the 3,3′-arylidenebis-4-hydroxycoumarins (3a–l) are in good agreement with
those reported in the literature [2, 15].
The scan copies of spectra of 3a are submitted herewith as a representative of the
series (3a–l).
Synthesis of Dimethyl (phenyl(phenylamino)methyl)phosphonate (6a)
Benzaldehyde (0.5 gm/4.7 mmol) (1a) and aniline (0.438 gm/4.7 mmol) (4) were
dissolved in acetonitrile (7 ml), and then solution was stirred for few minutes. Then,
trimethylphosphite (0.585 gm/4.7 mmol) (5) and CAL-B, lipase (50 mg) were added
to the solution and then reaction mixture was stirred at room temperature. Progress
of reaction was monitored by TLC. After 40 min, water (10 ml) and ethyl acetate
(30 ml) were added into the reaction mass and it was then stirred for 15 min and
fltered. The residue recovered, CAL-B was dried and reused. The ethyl acetate
layer was separated from fltrates and washed with water, and dried over anhy-
drous Na2SO4. The solvent ethyl acetate was removed under reduced pressure and
obtained diethyl (phenyl(phenylamino)methyl) phosphonates (6a). The obtained
crude products were then crystalized using ethanol. Similarly other derivatives of
the series were prepared (6a–k). Melting points and isolated yields of the deriva-
tives are recorded in Table 4. The identity of the products was confrmed by 1H and
13C NMR, and HRMS, The spectral data in good agreement in those reported in the
literature [82, 83].
Scan copies of spectra of 6b are provided as a representative of the series (6a–k).
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CAL‑B accelerated novel synthetic protocols for…
Spectral data of compounds (3a‑l)
3’‑(Phenylmethylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3a)
1H NMR (DMSO-d6, 300 MHz, δ ppm): 6.34 (s, 1H, –CH), 7.09–7.89 (m, 13H,
Ar–H), 12.52 (s, 2H, 2OH).13C NMR (DMSO-d6, 75 MHz, δ ppm): 35.97, 91.01,
104.17, 115.80, 115.98, 116.35, 117.81, 123.19, 123.79, 123.90, 125.61, 126.71,
128.09, 128.54, 129.25, 131.95, 132.67, 132.82, 139.76, 152.20, 153.52, 161.88,
164.87, 165.17, 165.63. HRMS (ESI+): (M + H)+ calculated 413.1025, observed
413.1028.
3’‑((4‑Methoxyphenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3b)
1H NMR (DMSO-d6, 300 MHz, δ ppm): 3.84 (s, 3H, OCH3), 6.24 (s, 1H, –CH),
7.02–7.18 (m, 8H, Ar–H), 7.34–7.76 (m, 4H, Ar–H), 12.22 (s, 2H, 2OH).13C
NMR (DMSO-d6, 75 MHz, δ ppm): 35.77, 56.98, 91.11, 104.23, 115.84, 115.58,
116.21, 117.68, 123.08, 123.56, 123.87, 125.48, 126.64, 128.01, 128.34, 129.15,
131.65, 132.57, 132.76, 139.45, 152.19, 153.34, 161.56, 164.45, 165.07, 165.52.
HRMS (ESI+): (M + H)+ calculated 443.1131, observed 443.1029.
3’‑(Tolylmethylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3c)
1H NMR (CDCl3, 300 MHz, δ ppm): 2.33 (s, 3H, CH3), 6.06 (s, 1H,
–CH), 7.08–8.05 (m, 12H, Ar–H), 11.30–11.49 (d, 2H, 2OH).13C NMR (CDCl3,
75 MHz, δ ppm): 21.17, 36.08, 104.29, 105.96, 116.82, 124.58, 125.04, 126.57,
129.53, 132.25, 132.98, 136.67, 152.71, 164.75, 165.89, 167.04, 169.51. HRMS
(ESI+): (M + H)+ calculated 427.1181, observed 427.1172.
3’‑((4‑Hydroxyphenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3d)
1H NMR (DMSO-d6, 300 MHz, δ ppm): 4.98 (s, 1H, OH), 6.25 (s, 1H, –CH),
6.96–7.24 (m, 8H, Ar–H), 7.27–7.66 (m, 4H, Ar–H), 12.32 (s, 2H, 2OH).13C
NMR (DMSO-d6, 75 MHz, δ ppm): 35.54, 91.32, 105.87, 115.65, 116.01, 116.37,
117.58, 121.47, 123.21, 123.87, 124.76, 126.65, 128.78, 128.92, 129.47, 131.49,
132.02, 132.94, 138.19, 152.45,153.69, 161.08, 164.56, 165.69, 165.40. HRMS
(ESI+): (M + H)+ calculated 429.0974, observed 429.0832.
3’‑((3‑Bromophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3e)
1H NMR (DMSO-d6, 300 MHz, δ ppm): 6.44 (s, 1H, –CH), 7.18–7.42 (m, 8H,
Ar–H), 7.55–8.06 (m, 4H, Ar–H), 12.67 (s, 2H, 2OH).13C NMR (DMSO-d6,
75 MHz, δ ppm):36.02, 90.98, 104.64, 115.36, 115.57, 116.39, 117.65, 123.56,
123.83, 123.34, 125.46, 126.59, 127.54, 128.21, 129.49, 131.43, 132.78, 132.28,
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A. S. Chavan et al.
139.54, 152.76, 153.21, 161.78, 164.23, 165.27, 165.57. HRMS (ESI+): (M + H)+
calculated 491.0130, observed 491.0028.
3’‑((4‑Fluorophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3f)
1H NMR (CDCl3, 300 MHz, δ ppm): 6.05 (s, 1H, –CH), 6.98–8.07 (m, 12H, Ar–H),
11.32–11.52 (d, 2H, 2OH).13C NMR (CDCl3, 75 MHz, δ ppm): 35.87, 104.14,
105.68, 115.59, 115.81, 116.58, 116.85, 117.06, 124.60, 125.15, 128.32, 128.40,
131.02, 131.05, 133.17, 152.49, 152.73, 160.69, 163.14, 164.80, 166.08, 167.02,
169.40. HRMS (ESI+): (M+H)+ calculated 431.0931, observed 431.0924.
3’‑((4‑Trifuromethylphenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3 g)
1H NMR (DMSO-d6, 300 MHz, δ ppm):6.19 (s, 1H, –CH), 7.03–7.22 (m, 8H,
Ar–H), 7.33–7.66 (m, 4H, Ar–H), 12.25 (s, 2H, 2OH).13C NMR (DMSO-d6,
75 MHz, δ ppm): 35.95, 91.09, 104.51, 115.46, 115.87, 116.89, 117.03, 123.36,
123.62, 123.89, 124.67, 126.56, 128.87, 128.87, 129.32, 130.76, 132.45, 132.76,
139.32, 152.48, 153.92, 161.23, 164.74, 166.37, 168.89. HRMS (ESI+): (M+H)+
calculated 481.0899, observed 481.0835.
3’‑((4‑Trifuromethoxyphenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3 h)
1H NMR (DMSO-d6, 300 MHz, δ ppm):6.21 (s, 1H, –CH), 7.02–7.17 (m, 8H,
Ar–H), 7.31–7.77 (m, 4H, Ar–H), 12.24 (s, 2H, 2OH).13C NMR (DMSO-d6,
75 MHz, δ ppm): 35.95, 91.76, 104.56, 115.43, 115.84, 116.65, 117.65, 123.20,
123.78, 123.87, 125.65, 126.52, 128.23, 128.34, 129.76, 131.65, 132.45, 132.79,
139.98, 152.56, 153.46, 161.72, 164.81, 165.63, 166.89. HRMS (ESI+): (M+H)+
calculated 497.0848, observed 497.0876.
3’‑((4‑Dimethylaminophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3i)
1H NMR (DMSO-d6, 300 MHz, δ ppm):3.09 (s, 6H, CH3), 6.42 (s, 1H, –CH),
7.01–7.28 (m, 8H, Ar–H), 7.33–7.76 (m, 4H, Ar–H), 12.42 (s, 2H, 2OH).13C NMR
(DMSO-d6, 75 MHz, δ ppm): 35.89, 50.23, 90.97, 105.52, 115.67, 116.21, 116.67,
117.38, 121.57, 123.50, 123.81, 125.42, 126.68, 128.39, 128.64, 129.78, 130.37,
132.49, 132.75, 139.59, 152.17, 153.72, 161.81, 163.78, 165.76, 167.41. HRMS
(ESI+): (M+H)+calculated 456.1447, observed 456.1356.
1
3’‑((4‑Nitrophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3j) H
NMR
(CDCl3, 300 MHz, δ ppm):6.12 (s, 1H, –CH), 7.26–8.20 (m, 12H, Ar–H), 11.35–
11.56 (d, 2H, 2OH).13C NMR (CDCl3, 75 MHz, δ ppm): 36.72, 103.47, 104.96,
116.43, 116.92, 116.99, 124.05, 124.69, 125.34, 125.40,127.76, 133.54, 143.55,
147.09, 152.52, 152.77, 165.01, 166.60, 167.17, 169.28. HRMS (ESI+): (M+H)+
calculated 458.0876, observed 458.0882.
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CAL‑B accelerated novel synthetic protocols for…
1
3’‑((4‑Chlorophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3 k) H NMR
(DMSO-d6, 300 MHz, δ ppm):6.34 (s, 1H, –CH), 7.29–7.45 (m, 8H, Ar–H), 7.54–7.99
(m, 4H, Ar–H), 12.57 (s, 2H, 2OH).13C NMR (DMSO-d6, 75 MHz, δ ppm):35.87,
91.56, 112.43, 115.53, 115.86, 116.71, 117.63, 123.58, 123.17, 123.49, 125.18, 126.53,
128.27, 128.83, 129.54, 131.76, 132.38, 132.76, 139.42, 152.45, 153.76, 161.98, 164.56,
165.37, 166.37. HRMS (ESI+): (M+H)+ calculated 447.0635, observed 447.0658.
1
3’‑((2‑Bromophenyl)methylene)bis(4‑hydroxy‑2H‑chromen‑2‑one) (3 l) H NMR
(DMSO-d6, 300 MHz, δ ppm): 6.44 (s, 1H, –CH), 7.21–7.45 (m, 8H, Ar–H), 7.52–8.06
(m, 4H, Ar–H), 12.67 (s, 2H, 2OH).13C NMR (DMSO-d6, 75 MHz, δ ppm): 35.92,
91.12, 104.43, 114.64, 115.79, 115.96, 116.91, 122.97, 123.45, 123.68, 124.89, 125.65,
128.76, 128.23, 129.45, 130.65, 131.32, 132.58, 139.71, 152.42, 153.64, 161.86, 164.09,
165.18, 165.45. HRMS (ESI+): (M+H)+ calculated 491.0130, observed 491.0028.
Spectral data of compounds (6a–k)
Dimethyl ((4‑methoxyphenyl)(phenylamino)methyl)phosphonate (6b)
1H NMR (CDCl3, 400 MHz, δ ppm):3.50 (s, 3H, –OCH3), 3.74 (s, 3H, –OCH3), 3.77
(s, 3H, –OCH3), 4.72 (s, 1H, –CH), 4.79 (s, 1H, –NH), 6.58–7.40 (m, 9H, Ar–H).13C
NMR (CDCl3, 100 MHz, δ ppm): 53.93, 54.00, 54.45, 55.97, 114.12, 114.39, 114.41,
118.72, 127.54, 127.57, 129.09, 129.14, 129.37, 146.24, 146.39, 159.62. HRMS
(ESI+): (M+H)+ calculated 322.1208, observed 322.1205.
Dimethyl (phenyl(phenylamino)methyl)phosphonate (6a)
1H NMR (CDCl3, 400 MHz, δ ppm): 3.46 (s, 3H, –OCH3), 3.75 (s, 3H, –OCH3),
4.67–4.71 (d, 1H, –CH), 4.78 (s, 1H, –NH), 6.59–7.49 (m, 10H, Ar–H).13C NMR
(CDCl3, 100 MHz, δ ppm): 54.05, 55.14, 56.64, 114.09, 118.76, 127.98, 128.03,
128.29, 128.92, 129.40, 133.19, 135.78, 135.80, 146.21, 146.36. HRMS (ESI+):
(M+H)+ calculated, 292.1102, observed, 292.1068.
Dimethyl (4‑tolyl)(phenylamino)methyl)phosphonate (6c)
1H NMR (CDCl3, 400 MHz, δ ppm):2.65 (s, 3H, –CH3), 3.53 (s, 3H, –OCH3), 3.78
(s, 3H, –OCH3), 4.77 (s, 1H, –CH), 4.84 (s, 1H, –NH), 6.46–7.71 (m, 9H, Ar–H).13C
NMR (CDCl3, 100 MHz, δ ppm): 23.59, 54.08, 55.32, 56.62, 115.62, 118.76, 127.87,
128.52, 128.86, 128.92, 128.97, 129.42, 130.18, 135.67, 146.38, 146.84. HRMS
(ESI+): (M+H)+ calculated, 306.1259, observed, 306.1168.
Dimethyl (4‑hydroxyphenyl)(phenylamino)methyl)phosphonate (6d)
1H NMR (CDCl3, 400 MHz, δ ppm): 3.44 (s, 3H, –OCH3), 3.73 (s, 3H, –OCH3),
4.79–4.86 (d, 1H, –CH), 4.91 (s, 1H, –NH), 5.46 (s, 1H, OH), 6.61–7.52 (m, 9H,
Ar–H).13C NMR (CDCl3, 100 MHz, δ ppm): 53.97, 54.34, 56.74, 114.67, 118.59,
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A. S. Chavan et al.
127.24, 128.74, 128.78, 129.32, 129.69, 130.53, 133.67, 135.39, 135.47, 146.98.
HRMS (ESI+): (M+H)+ calculated, 308.1051, observed, 308.0682.
Dimethyl (3‑Bromophenyl)(phenylamino)methyl)phosphonate (6e)
1H NMR (CDCl3, 400 MHz, δ ppm):3.43 (s, 3H, –OCH3), 3.78 (s, 3H, –OCH3),
4.77–4.83 (d, 1H, –CH), 4.87 (s, 1H, –NH), 6.67–7.72 (m, 9H, Ar–H).13C NMR
(CDCl3, 100 MHz, δ ppm): 53.89, 54.23, 56.16, 114.67, 118.24, 127.82, 128.59,
128.12, 128.87, 128.36, 128.58,128.69, 135.86, 135.59, 146.79. HRMS (ESI+):
(M+H)+ calculated, 370.0207, observed, 370.0158.
Dimethyl (4‑Flurophenyl)(phenylamino)methyl)phosphonate (6f)
1H NMR (CDCl3, 400 MHz, δ ppm):3.28 (s, 3H, –OCH3), 3.46 (s, 3H, –OCH3),
4.38–4.73 (d, 1H, –CH), 4.86 (s, 1H, –NH), 6.98–7.53 (m, 9H, Ar–H).13C NMR
(CDCl3, 100 MHz, δ ppm): 54.01, 55.39, 56.57, 115.37, 118.68, 127.38, 128.72,
128.49, 128.42, 128.58, 130.27, 135.46, 135.72, 146.35, 146.64. HRMS (ESI+):
(M+H)+ calculated, 310.1008, observed, 310.1068.
Dimethyl ((phenylamino)(4‑(trifuoromethyl)phenyl)methyl)phosphonate (6g)
1H NMR (CDCl3, 400 MHz, δ ppm):3.55 (s, 3H, –OCH3), 3.77 (s, 3H, OCH3),
4.83 (s, 1H, –CH), 4.89 (s, 1H, –NH), 6.55–6.75 (m, 5H, Ar–H), 7.10–7.62 (m, 4H,
Ar–H).13C NMR (CDCl3, 100 MHz, δ ppm): 53.96, 54.96, 56.45, 114.04, 119.20,
120.13, 122.84, 125.88, 125.91, 128.33, 129.53, 130.61, 130.96, 140.27, 145.80,
145.94. HRMS (ESI+): (M+H)+ calculated, 360.0976, observed, 360.0976.
Dimethyl ((phenylamino)(4‑(trifuoromethoxy)phenyl)methyl)phosphonate (6h)
1H NMR (CDCl3, 400 MHz, δ ppm): 3.53 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
4.78 (s, 1H, –CH), 4.83 (s, 1H, –NH), 6.56–7.26 (m, 5H, Ar–H), 7.49–7.52 (d, 4H,
Ar–H).13C NMR (CDCl3,100 MHz, δ ppm):53.93, 54.51, 56.02, 114.03, 119.09,
119.34, 121.33, 121.90, 129.33, 129.39, 129.51, 134.61, 134.64, 145.90, 146.04,
149.17. HRMS (ESI+): (M+H)+ calculated 376.0925, observed 376.0921.
Dimethyl ((4‑(dimethylamino)phenyl)(phenylamino)methyl)phosphonate (6i)
1H NMR (CDCl3, 400 MHz, δ ppm): 3.46 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
4.77–4.83 (d, 1H, –CH), 6.59–7.49 (m, 10H, Ar–H).13C NMR (CDCl3, 100 MHz,
δ ppm): 43.69, 54.02, 55.37, 56.76, 114.13, 118.47, 127.78, 128.43, 128.57, 128.73,
128.85, 129.29, 133.45, 135.76, 146.27, 146.69. HRMS (ESI+): (M+H)+ calcu-
lated, 335.1524, observed, 335.1481.
1
Dimethyl (4‑nitrophenyl)(phenylamino)methyl)phosphonate (6j) H NMR (CDCl3,
400 MHz, δ ppm): 3.48 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 4.69 (s, 1H, –CH),
4.86 (s, 1H, –NH), 6.98–7.76 (m, 9H, Ar–H).13C NMR (CDCl3, 100 MHz, δ ppm):
1 3

CAL‑B accelerated novel synthetic protocols for…
53.72, 54.21, 56.73, 114.64, 118.86, 127.46, 128.38, 128.57, 128.38, 128.48, 129.51,
130.53, 135.49, 146.54, 146.38. HRMS (ESI+): (M+H)+ calculated, 337.0925,
observed, 337.0798.
1
Dimethyl (4‑chlorophenyl)(phenylamino)methyl)phosphonate (6k) H NMR
(CDCl3, 400 MHz, δ ppm): 3.52 (s, 3H, –OCH3), 3.69 (s, 3H, –OCH3), 4.71 (s, 1H,
–CH), 4.82 (s, 1H, –NH), 6.75–7.89 (m, 9H, Ar–H).13C NMR (CDCl3, 100 MHz,
δ ppm): 53.99, 54.08, 56.64, 114.53, 118.65, 127.81, 128.49, 128.85, 128.97,
129.13, 129.67, 130.82, 135.58, 146.79, 146.93. HRMS (ESI+): (M+H)+ calculated,
326.0713, observed, 326.0687.
Results and discussion
In view to optimize reaction conditions, we separately carried the condensa-
tions of a) benzaldehyde (1a) (1 gm/9.4 mmol), and 4-hydroxy coumarin (2) (3.1
gm/18.8 mmol), and b) benzaldehyde (1a), (0.5 gm/4.7 mmol), aniline (4) (0.438
gm/4.7 mmol), and trimethyl phosphite (5) (0.584 gm/4.7 mmol) as model reactions
in the presence of CAL-B for obtaining 3,3′-((phenyl)methylene)bis(4-hydroxy-2H-
chromen-2-one) (3a) and dimethyl (phenyl(phenylamino)methyl)phosphonate (6a),
Table 1 Efect of diferent reaction conditions on the isolated yields of 3,3’-((phenyl)methylene)bis(4-
hydroxy-2H-chromen-2-one) (3a)a
Entry
Solvent
Temp (°C)
Lipase(mg)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
MeOH
MeCN
DCM
DMF
1,4-Dioxane
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
40
100
100
100
100
100
100
100
0
25
50
75
100
100
100
100
9
9
9
9
9
9
9
82
64
56
59
67
78
88
Trace
66
77
80
88
91
88
90
Even after 36
9
9
9
9
9
9
9
9
10
11
12
13
14
15
45
50
After optimization, by varrying solvents, reaction temperature and amount of catalyst the best one were
chosen for conducting the condensations are represented in bold form
aReaction conditions: Benzaldehyde (9.4 mmol) (1a), 4-hydroxy coumarin (18.8 mmol) (2) in solvent
(15 ml)
1 3

A. S. Chavan et al.
Table 2 Efect of diferent reaction conditions on the isolated yields of dimethyl (phenyl(phenylamino)
methyl)phosphonate (6a)a
Entry
Solvent
Temp (°C)
Lipase(mg)
Time (min)
Yield (%)
1
Neat condition
EtOH
MeOH
MeCN
DCM
DMF
H2O
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
40
50
50
50
50
50
50
50
0
25
50
75
50
50
50
35
35
35
35
35
35
35
120
35
35
35
35
35
35
82
79
74
89
56
59
68
Trace
89
89
90
89
90
89
2
3
4
5
6
7
8
9
10
11
12
13
14
45
50
After optimization, by varrying solvents, reaction temperature and amount of catalyst the best one were
chosen for conducting the condensations are represented in bold form
aReaction conditions: Benzaldehyde (4.7 mmol), aniline (4.7 mmol), trimethyl phosphite (4.7 mmol), in
solvents (7 ml)
respectively, by varying the amounts of CAL-B, reaction temperature and solvents
and the observed results are incorporated in Tables 1 and 2.
It was observed (Table 1) that a model reaction when carried using benzaldehyde
(1a) (1 gm/9.4 mmol), and 4-hydroxy coumarin (2) (3.1 gm/18.8 mmol), in ethanol
(15 ml) in the presence of CAL-B (100 mg) at room temperature gave 90% yield
within 9 h and hence considered these reaction conditions as optimal conditions
for conducting the condensation. It was also noted (Table 2) that the other multi-
component reaction when performed using benzaldehyde (1a), (500 mg/4.7 mmol),
aniline (4) (0.438 gm/4.7 mmol), and trimethyl phosphite (5) (0.585 gm/4.7 mmol)
in acetonitrile (7 ml) in the presence of CAL-B at room temperature gave dime-
thyl (phenyl(phenylamino)methyl)phosphonate (6a) with 89% yield within 35 min.
These reaction conditions are chosen as optimal conditions for this kind of con-
densation reaction for getting 6a–k. It was also observed that the CAL-B retained
its potential catalytic activity even after its frst use and found to be reusable. The
details of its isolation and reuse have been incorporated in experimental procedure.
With these inspiring observations, we carried the synthesis of substituted
3,3’-arylidenebis-4-hydroxycoumarins (3a-l) (Scheme 1) and dimethyl ((substituted
phenyl) (phenylamino)methyl) phosphonates (6a-k) (Scheme 2) using the above-
optimized conditions and obtained better to excellent yields of the titled products.
1 3

CAL‑B accelerated novel synthetic protocols for…
Scheme 1 Synthesis of substituted 3,3′-arylidenebis-4-hydroxycoumarins (3a-l)
Scheme 2 Synthesis of dimethyl ((substituted phenyl) (phenylamino)methyl) phosphonates (6a-k)
Table 3 Physical data of
Entry
Compound
R
Yield(%)b
M.P. (°C)c
substituted 3,3’-arylidenebis-4-
hydroxycoumarins (3a-l)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3 g
3 h
3i
H
88
90
87
88
79
89
90
86
87
88
88
88
276–277
234–235
266–268
255–257
225–228
215–218
227–229
265–267
243–244
237–239
289–290
239–241
4-OMe
4-Me
4-OH
3-Br
4-F
4-CF3
4-OCF3
4-NMe2
4-NO2
4-Cl
9
10
11
12
3j
3 k
3 l
2-Br
aReaction conditions: Substituted benzaldehydes (9.4 mmol) (1a-l),
4-hydroxy coumarin (18.8 mmol) (2), Lipase (100 mg) in ethanol
(10 ml) at room temperature for 9 h
bIsolated yields
cMelting points are in good agreement with those reported in the lit-
erature [2, 15]
1 3

A. S. Chavan et al.
Table 4 Physical data of
dimethyl ((substituted phenyl)
(phenylamino)methyl)
Entry
Compound
R
Yieldb (%)
M.P. (°C)c
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
89
92
87
78
83
91
93
88
86
78
92
89–91
130–132
59–61
93–95
63–65
134–136
110–112
80–82
123–125
112–114
58–60
phosphonates (6a-k)a
4-OCH3
4-CH3
4-OH
3-Br
4-F
4-CF3
4-OCF3
4-NMe2
4-NO2
4-Cl
9
10
11
6j
6k
aReaction conditions: Substituted benzaldehyde (4.7 mmol), Aniline
(4.7 mmol), trimethyl phosphite (4.7 mmol), Lipase (50 mg) in ace-
tonitrile (7 ml),stirred at room temperature for 35 min
bIsolated yield
cMelting points are in good agreement with those reported in the lit-
erature [82, 83]
Physical data are summarized in Tables 3 and 4. All the synthesized compounds are
known/reported and their physical constants and spectral data are in good agreement
with those reported in the literature [2, 15, 82, 83].
It seems from the results recorded in Tables 1 and 2 that the condensations under
reference are not found to be run satisfactorily in the absence of CAL-B, lipase and
it is also observed that in the presence of lipase both the type of condensation are
found to undergo rapidly, yielding reaction products at rt with better to excellent
yields. Therefore, it is confrmed that lipase is displaying its catalytic role in both the
condensations through the active amino acid residues. The plausible mechanism of
these two types of condensations leading to titled products 3,3′-arylidenebis-4-hy-
droxycoumarins and dimethyl ((substituted phenyl) (phenylamino)methyl) phospho-
nates in presence of CAL-B has been depicted in Schemes 3 and 4.
Efcient recovery and reusability of the catalyst are the valuable advantages in
modern catalysis research and green chemistry. In this respect, the recovery and
reusability of CAL-B were investigated for the model reactions. Consequently, the
model reactions were performed. After completion of reaction, ethyl acetate was
added in the reaction mixture and CAL-B was easily separated from the product by
simple fltration. The obtained solid residue, CAL-B was washed with ethyl acetate
and reused for next three consecutive cycles for the synthesis of 3a. As shown in the
recyclability graph of catalytic efciency of CAL-B, the isolated yields were almost
similar until the third recycling (Fig. 1). Only a slight decrease in the yield of the
desired product 3a, was noticed.
1 3

CAL‑B accelerated novel synthetic protocols for…
Scheme 3 Plausible mechanism for the synthesis of 3,3’-(Phenylmethylene)bis(4-hydroxy-2H-chromen-
2-one) (3a)
Conclusion
First time an environmentally accepted, versatile, and efcient CAL-B catalyzed syn-
thetic protocols have been developed for obtaining high yields of the 3,3′-arylidene
bis-4-hydroxycoumarins and diethyl(phenyl (phenylamino)methyl) phosphonates.
Catalyst lipase, CAL-B used here is biodegradable and cost-efective. These con-
densations leading to the title products, 3,3′-arylidene bis-4-hydroxycoumarins and
diethyl(phenyl (phenylamino)methyl) phosphonates occur at room temperature in
ethanol and in acetonitrile, respectively. Thus, we have opened up a new possibility
for the synthesis of various heterocycles derivatives using CAL-B as catalyst. The
protocols have nontedious workup in conducting and isolation of the products.
1 3

A. S. Chavan et al.
Scheme 4 Plausible mechanism for the synthesis of Dimethyl (phenyl(phenylamino)methyl)phosphonate
6a)
92
91
91
90
92
90
88
86
84
82
80
78
76
88
86
86
82
Naꢀve
RUN I
RUN II
RUN III
Yield (%) 3a
Catalyst recovery
Fig. 1 Recycle and recovery of CAL-Band its efect on yield of (3a)
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04535-2.
Acknowledgements The authors are thankful to Late Professor D. B. Ingle for his invaluable discussions
and guidance. The authors are also thankful to SAIF, Central Drug Research Institute (CDRI), Lucknow
for spectral analysis.
1 3

CAL‑B accelerated novel synthetic protocols for…
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