Knoevenagel condensation shadowed by michael addition & o-alkylation of resorcinol, malononitrile and benzadehyde to form pyrrolidine, piperidine and morpholine substituted benzopyran derivatives in Dry K2CO3

Article abstract of DOI:10.14233/ajchem.2019.21901

A condensation reaction of resorcinol, malononitrile and benzaldehyde in presence of sodium carbonate at room temperature on vigorous stirring gives 2-amino-7-hydroxy-4-phenyl-4H-1-benzopyran-3-carbonitrile which on alkylation in presence of dry potassium

Full text of DOI:10.14233/ajchem.2019.21901

Asian Journal of Chemistry; Vol. 31, No. 7 (2019), 1470-1472
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21901
Knoevenagel Condensation Shadowed by Michael Addition & O-Alkylation of
Resorcinol, Malononitrile and Benzadehyde to form Pyrrolidine, Piperidine
and Morpholine Substituted Benzopyran Derivatives in Dry K2CO3
1,
1,*,
2,
AVIDHA KULSHRESTHA , JAYA PANDEY
and DEEPA PANHEKAR
1Amity School of Applied Sciences, Amity University, Uttar Pradesh, Lucknow Campus, Lucknow-226010, India
2Department of Chemistry, Dr. Ambedkar College, Deeksha Bhoomi, Nagpur-440010, India
*Corresponding author: E-mail: jpandey@lko.amity.edu
Received: 28 December 2018;
Accepted: 12 February 2019;
Published online: 21 May 2019;
AJC-19398
A condensation reaction of resorcinol, malononitrile and benzaldehyde in presence of sodium carbonate at room temperature on vigorous
stirring gives 2-amino-7-hydroxy-4-phenyl-4H-1-benzopyran-3-carbonitrile which on alkylation in presence of dry potassium carbonate
in dry acetone at 70-80 ºC with 1,2-chloroethyl pyrrolidine, 1,2-chloroethyl piperidine, 1,2-chloroethyl morpholine gives corresponding
novel compounds.
Keywords: Knoevenagel condensation, Michael addition, 1,2-Chloroethyl pyrrolidine, Piperidine, Morpholine.
In the same multi-component reaction second turn of the
reaction undergone by Michael addition, in which benzyldine
propanedinitrile reacts with 1,3-resorcinol and to form [(2,4-
dihydroxyphenyl)(phenyl)methyl]propane dinitrile which on
cyclization and bond shifting formed 2-amino-7-hydroxy-4-
phenyl-4H-1-benzopyran-3-carbonitrile [10]. Michael addition
is appropriate to the larger class of conjugated addition and
the most useful method for C-C bond formation. The Michael
addition is thermodynamically controlled; the reaction donors
are active methylene′s such as malonates and nitroalkanes, and
the acceptors are activated olefins such as α,β-unsaturated
carbonyl compounds [11,12]. The second step reaction under-
gone O-alkylation in which 1,2-chloroethylpyrrolidine,1,2-
chloroethylpiperidine or 1,2-chloroethylmorpholine act as
alkylating agent and -OH part of substrate alkylate and given
ether as product. The alkyl group may be transferred as an alkyl
carbocation, a free radical, carbanion or a carbine or their equi-
valents [13,14]. When the alkylating agent is an alkyl halide,
the conversion is known asWilliamson ether synthesis.Alcohols
are also considered as good alkylating agents in the presence
of suitable acid/base catalysts [15].
INTRODUCTION
It is well known that one pot multicomponent reactions
are always better than multi-step synthesis, as they require
minimal workup and desired product can be obtained in one
pot often in quantitative yields [1,2]. Water is easily available
solvent, use of water as solvent in the organic synthesis give
rise to green chemistry. It is less pollutant, non-hazardous,
non-combustible solvent these properties of water promote it
in organic synthesis [3,4]. We report pyridine, piperidine and
morpholine substituted 2-aminobenzopyran moiety which is
very active and possess many biological activities. Formation
of this moiety undergone Knoevenagel condensation, in which
malononitrile (an active methylene compound) react with
benzaldehyde in presence of tracing amount of methanol and
aqueous solution of sodium carbonate and formed benzylidine
propane dinitrile on loss of a water molecule. A Knoevenagel
condensation is a nucleophilic addition of an active hydrogen
compounds to a carbonyl group followed by dehydration
reaction in which a molecule of water is eliminated [5,6].Active
hydrogen compounds viz. diethyl malonate, meldrum′s acid,
ethylacetoacetate, malonic acid, cyanoacetic acid, malono-
nitrile, etc. [7-9].
The interest in benzopyrans and their derivatives increased
since many years because these compounds are components
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Vol. 31, No. 7 (2019)
Knoevenagel Condensation Shadowed by Michael Addition & O-Alkylation of Some Compounds 1471
of many naturally occurring products and have also been sub-
jected to structural modifications for potential medicinal prop-
erties. 2-Amino-7-hydroxy-4-phenyl-4H-1-benzopyran-3-
carbonitrile (1a) had reported as in vitro cytotoxic activity on
a human breast tumor cell line (MCF7, IC508 nM) [16,17].
2-Amino-4-phenyl-7-[2-(morpholin-1-yl)ethoxy]-4H-
1-benzopyran-3-carbonitrile (1d):A mixture of 2-amino-3-
cyano-7-hydroxy-4-phenyl-4H-chromene (1a) (0.264 g, 1
mmol), 1-(2-chloroethyl)morpholine·HCl (0.279 g, 1.5 mmol)
dry K2CO3 (0.276 g, 2 mmol) dissolved in 25 mL dry acetone
in 50 mL round bottom flask and then refluxed the solution
for 8 h at 60-70 ºC. Cooled the solution at room temperature
and workup with ethyl acetate and water, evaporate the solvent
with rotatory evaporator and collect the yellow crystalline
compound. Monitored the compound by TLC with methanol
and dichloromethane (DCM) (4:6)
EXPERIMENTAL
Laboratory grade chemicals and solvents were purchased
from Sigma Aldrich and Merck and used without any further
purification. The reactions were monitored by TLC using
Merck′s silica gel 60F254 aluminium sheets. Infrared spectra
were recorded neat on Agilent cary 630 spectrophotometer.
High resolution mass spectra were recorded on Agilent 6520
(Q-TOF). NMR spectra were recorded on a BrukerAvance 400
(FT NMR) DPX300MHz NMR spectrometer.
Synthesis of 2-amino-7-hydroxy-4-phenyl-4H-1-benzo-
pyran-3-carbonitrile (1a):A mixture of benzadehyde, malono-
nitrile and resorcinol in 2:2:2 dissolved in 1 mL methanol in
round bottom flask. A 20 mL solution of 10 % Na2CO3 was
added in round bottom flask and the resulting suspension kept
on vigorous stirring for 10 h at 25 ºC. After the completion of
reaction filter the solution and residue washed with water then
cold methanol and dried in oven at 100 ºC (Scheme-I).
2-Amino-4-phenyl-7-[2-(pyrrolidin-1-yl)ethoxy]-4H-1-
benzopyran-3-carbonitrile (1b): A mixture of 2-amino-3-
cyano-7-hydroxy-4-phenyl-4H-chromene (1a) (0.264 g, 1
mmol), 1-(2-chloroethyl)pyrolidine·HCl (0.255 g, 1.5 mmol)
dry K2CO3 (0.276 g 2 mmol) dissolved in 25 mL dry acetone
in 50 mL round bottom flask and refluxed the solution for 8 h
at 60-70 ºC. Cooled the solution at room temperature and work-
up with ethyl acetate and water, evaporate the solvent with rotatory
evaporator and collected the yellow crystalline compound.
Monitored the compound by TLC with methanol and chloro-
form (5:5).
2-Amino-4-phenyl-7-[2-(piperidin-1-yl)ethoxy]-4H-1-
benzopyran-3-carbonitrile (1c): A mixture of 2-amino-3-
cyano-7-hydroxy-4-phenyl-4H-chromene (1a) (0.264g, 1
mmol), 1-(2-chloroethyl)piperidine·HCl (0.276 g, 1.5 mmol)
dry K2CO3 (0.276 g, 2 mmol) dissolved in 25 mL dry acetone
in 50 mL round bottom flask and refluxed the solution for 8 h
at 60-70 ºC. Cooled the solution at room temperature and work-
up with ethyl acetate and water, evaporate the solvent with
rotatory evaporator and collected the bright pink crystalline
compound. Monitored the compound by TLC with methanol
and dichloromethane (DCM) (4:6)
Spectral data of selected compounds
2-Amino-7-hydroxy-4-phenyl-4H-1-benzopyran-3-
carbonitrile (1a): Yield 85 %; white amorphous solid, m.p.
230-235 ºC; IR (KBr, νmax, cm-1): 3495 (R-OH), 3332(R-NH2),
2193 (R-CN),1652 (C=CN vinyl nitrile), 1588-1406 (C-C
arom.); 1H NMR (400 MHz, DMSO δ ppm): 9.76 (s, Ar-OH
), 7.36-7.33 (t, J = 12 Hz), 7.26-7.20 (q, J = 8 Hz) 6.90-6.84
(t, J = 12 Hz) 6.55-6.52 (dd, J = 4 Hz), 6.478-6.472 (d, J =
2.4 Hz), 4.66 (s). 13C NMR (100.60 MHz, DMSO δ ppm):
160.23-160.20, 156.98, 148.82, 146.31, 129.88, 127.33, 126.62,
113.75, 112.34, (C-C arom.),120.60 (CN), 102.14 (C=C vinylic),
56.28 (C-O). HRMS-EI (m/z) calcd. for C16H12N2O2: 264.2786,
found 264.2886. Elemental analysis % calcd. (found): C 72.72
(72.69), H 4.58 (4.60), N 10.60 (10.60).
2-Amino-4-phenyl-7-[2-(pyrrolidin-1-yl)ethoxy]-4H-1-
benzopyran-3-carbonitrile ( 1b): Yield 75 %; brown color
solid, m.p. 265-272 ºC; IR (KBr, νmax, cm-1): 3334 (R-NH2),
2188 (R-CN),1649 (-C=CN), 1579-1400 (C-C arom.),1336 (-
C-OR, OR = ethoxypyrrolidine); 1H NMR (300 MHz, CDCl3
δ ppm): 7.24-7.23 (t, J = 1.2 Hz), 7.21-7.20 (d, J = 1.5 Hz),
7.18 (s), 7.15-7.14 (t, J = 1.35), 7.13-7.12 (t, J = 5.4), 7.105-
7.100 (d, J = 1.5 Hz), 6.76 (s), 6.73 (s), 6.54-6.53 (d, J = 2.4
Hz), 6.519-6.510 (d, J = 2.7 Hz), 6.47-6.46 (d, J = 2.7 Hz),
4.18 (s), 4.56 (s), 4.00-3.96 (t, J = 11.7 Hz), 2.83-2.79 (t, J =
11.7 Hz), 2.57-2.53 (t, J = 12.9 Hz),1.96 (s), 1.89 (s), 1.77-
1.68 (m, J = 7.5 Hz). 13C NMR (75.49 MHz, CDCl3, δ ppm):
159.50, 158.67, 149.31, 145.06, 130.34, 129.31, 128.90, 128.02,
127.29, 120.26, 115.16, 112.25, 102.13, 77.65, 77.23, 67.29,
60.67, 59.29, 54.96, 54.72, 40.61, 23.60, 1.16. HRMS-EI (m/z)
calcd. for C16H12N2O3: 361.43692; ESI-SCAN-MS: + 362.18.
Elemental analysis % calcd. (found): C 73.11 (73.15), H 6.41
(6.45), N 8.16 (8.16).
2-Amino-4-phenyl-7-[2-(piperidin-1-yl)ethoxy]-4H-1-
benzopyran-3-carbonitrile (1c):Yield 70 %; bright pink color
R1
R1
R
R
Dry acetone/anhy. K2CO3
CN
R2
CN
+
8 h reflux at 70-80 °C
R2
Cl
O
O
NH2
HO
O
NH2
Where R= H,Br, OCH3, OH R1= H,OH,OCH3 R2 = Pyrrolidine, Piperidine, Morpholine
Scheme-I

1472 Kulshrestha et al.
Asian J. Chem.
solid, m.p. 275-280 ºC; IR (KBr, νmax, cm-1): 3350 (R-NH2), 2240
compounds reacted with pyrrlidine, piperidine and morpholine
substituted alkyl halide, in presence of dry. K2CO3 and dry
acetone as medium to form novel benzopyran derivatives.
Simple reaction conditions and easy available catalyst made it
favourable for synthesis in high yields.
(R-CN), 1639 (C=CN vinyl nitrile), 1589-1450 (C-C arom.),
1
1302 (C-OR, OR = ethoxypiperidine); H NMR (300 MHz,
CDCl3 δ ppm): 7.26-7.24 (t, J = 3 Hz), 7.214-7.209 (d = 1.5),
7.189 (s), 7.15-7.14 (d, J = 3 Hz), 6.77 (s), 6.75 (s), 6.547-
6.539 (d, J = 2.4 Hz), 6.519-6.510 (d, J = 2.7 Hz), 6.472-6.462
(d, J = 2.7 Hz), 4.819 (s), 4.565 (s), 4.009-3.966 (t, J = 6.9
Hz), 2.98 (s) 2.833-2.794 (t, J = 5.7 Hz), 2.576-2.533 (q, J =
6.45 Hz), 1.96 (s), 1.89 (s). 13C NMR (75.49 MHz, CDCl3, δ
ppm): 157.31, 155.55, 155.20, 131.06, 129.33, 129.10, 119.99,
115.16, 114.25, 104.25, 77.44, 77.23, 62.88, 61.86, 57.88, 55.09,
42.22, 34.55, 31.96. HRMS-EI (m/z) calcd. for C23H25N3O2:
375.4635; ESI-SCAN-MS: +376.09. Elemental analysis %
calcd. (found): C 71.79 (71.83), H 6.43 (6.44), N 11.16 (11.19).
2-Amino-4-phenyl-7-[2-(morpholin-1-yl)ethoxy]-4H-
1-benzopyran-3-carbonitrile (1d):Yield 68 %; yellow color
solid; m.p. 275-280 ºC; IR (KBr, νmax, cm-1): 3335 (R-NH2),
2198 (R-CN), 1644 (C=CN vinyl nitrile), 1599-1442 (C-C arom.),
1335 (C-OR, OR = ethoxymorpholine); 1H NMR (300 MHz,
CDCl3 δ ppm): 7.255-7.241 (t, J = 4.2 Hz), 7.112-7.090 (d, J
= 6.6 Hz), 7.009 (s), 6.990-6.987 (d, J = 0.9 Hz), 6.88 (s),
6.76 (s), 6.455-6.454 (d, J = 0.3 Hz), 6.424-6.420 (d, J = 1.2
Hz), 4.908 (s), 4.670 (s), 4.098-4.086 ( t, J = 3.6 Hz), 2.992
(s), 2.883-2.862 (t, J = 6.3 Hz), 2.588-2.537 (q, J = 7.65 Hz),
2.003 (s), 1.962 (s), 1.884 (s). 13C NMR (75.49 MHz, CDCl3, δ
ppm): 159.66, 156.31, 153.55, 152.20, 135.96, 129.33, 129.10,
120.99, 115.16, 114.85, 104.25, 77.98, 77.23, 65.88, 61.86,
57.88, 55.70, 42.22, 39.33, 35.65, 31.22. HRMS-EI (m/z) calcd.
for C22H23N3O3: 377.43632; ESI-SCAN-MS: +377.47509.
Elemental analysis % calcd. (found): C 70.01 (70.83), H 6.14
(6.22), N 11.13 (11.15).
ACKNOWLEDGEMENTS
The authors are thankful for financial support from DST
(Grant registration # CS-176/2013) and UPCST (Grant regis-
tration # CST/ D 6547/2017) andAmity University, Uttar Pradesh,
Lucknow Campus, India for providing the research facilities.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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In the present work, a multi component reaction in which
active methylene compounds (malononitrile) reacted with
carbonyl compounds (benzaldehyde and substituted benzalde-
hyde) in presence of tracing amount of methanol and weak basic
medium (aq. Na2CO3) and formed benzylidine propanedi-
nitrile. The benzylidinepropanedinitrile reacted with resorcinol
and formed [(2,4-dihydroxyphenyl)(phenyl)methyl]propane-
dinitrile which on cyclization given 7-hydroxy-2-imino-4-phenyl-
3,4-dihydro-2H-1-benzopyran-3-carbonitrile by hydrogen
shift it converted into 2-amino-7-hydroxy-4-phenyl-4H-1-
benzopyran-3-carbonitrile. In the second step, above formed
https://doi.org/10.24820/ark.5550190.p010.040.