[4,4′-Bipyridine]-1,1′-diium tricyanomethanide as a nanostructured molten salt and its catalytic application in the synthesis of tetrahydrobenzo[b]pyrans, amido and aminoalkyl naphthol derivatives

Article abstract of DOI:10.1016/j.molliq.2016.07.132

An efficient process for the synthesis of tetrahydrobenzo[b]pyrans derivatives was attained via the reaction of dimedone, various aldehydes and malononnitrile using [4,4′-Bipyridine]-1,1′-diium tricyanomethanide {[4,4′-BPyH][C(CN)₃]₂

Full text of DOI:10.1016/j.molliq.2016.07.132

[4,4ꢀ-Bipyridine]-1,1ꢀ-diium tricyanomethanide as a nanostructured molten
salt and its catalytic application in the synthesis of tetrahydrobenzo[b]pyrans,
amido and aminoalkyl naphthol derivatives
Mohammad Ali Zolfigol, Meysam Yarie, Saeed Baghery
PII:
DOI:
Reference:
S0167-7322(16)30734-6
doi: 10.1016/j.molliq.2016.07.132
MOLLIQ 6146
To appear in:
Journal of Molecular Liquids
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Accepted date:
24 March 2016
28 July 2016
Please cite this article as: Mohammad Ali Zolfigol, Meysam Yarie, Saeed Bagh-
ery, [4,4ꢀ-Bipyridine]-1,1ꢀ-diium tricyanomethanide as a nanostructured molten salt
and its catalytic application in the synthesis of tetrahydrobenzo[b]pyrans, amido
and aminoalkyl naphthol derivatives, Journal of Molecular Liquids (2016),
doi:
10.1016/j.molliq.2016.07.132
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ACCEPTED MANUSCRIPT
[4,4'-Bipyridine]-1,1'-diium tricyanomethanide as a nanostructured molten
salt and its catalytic application in the synthesis of tetrahydrobenzo[b]pyrans,
amido and aminoalkyl naphthol derivatives
Mohammad Ali Zolfigol,* Meysam Yarie, Saeed Baghery
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
Abstract: An efficient process for the synthesis of tetrahydrobenzo[b]pyrans derivatives was attained via
the reaction of dimedone, various aldehydes and malononnitrile using [4,4'-Bipyridine]-1,1'-diium
tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a green mild nano structure molten salt catalyst under
solvent-free conditions at room temperature. To further investigation on catalytic properties of {[4,4'-
BPyH][C(CN)3]2}, it was used in the synthesis of amido and aminoalkyl naphthol derivatives under
solvent-free conditions at 75 oC. {[4,4'-BPyH][C(CN)3]2} has advantages such as cleaner reaction profile,
benign characters, cost effectiveness, reusability of the catalysts and being in agreement with the green
chemistry protocols.
Keywords: Bifunctional nano structure molten salt; [4,4'-Bipyridine]-1,1'-diium tricyanomethanide;
Tetrahydrobenzo[b]pyrans; Amidoalkyl naphthol; Aminoalkyl naphthol; Solvent-free conditions.
*Corresponding Author: Fax: +988138257407
E-mail: zolfi@basu.ac.ir and mzolfigol@yahoo.com (M.A. Zolfigol).
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1.
Introduction
It is generally acknowledged that there is an increasing significance for more accessible eco-
friendly approaches in the chemical and heterocyclic synthesis and pharmaceutical industries. This
advanced improvement called ‘green chemistry’ or ‘ecological technology’ needs a model alteration
taken from customary ideas of procedure efficiency, that focuses chiefly on yield of product, to one that
assigns economic value, removing waste and avoiding the usage of dangerous and toxic materials [1].
Room-temperature molten salts (RTMSs), named as room-temperature ionic liquids, (RTILs), which are
immiscible or only partially miscible with water, are promising to be replacements of usual organic
solvents. Molten salts (MSs) have significant potentials such as electrolyte substances. The molten salts,
recently termed ionic liquids, have drawn much consideration in numerous scientific fields [2]. Molten
salts or ionic liquids are usually liquid electrolytes combined of ions. More recently, the melting point
pattern has been introduced to make identification of molten salts (very corrosive medium, high-melting
and highly viscous) and ionic liquids (relatively low viscosity and liquid below 100 °C) [3] possible.
Molten salts have noteworthy potentials such as electrolyte substances. Scientists have performed
experiments to change solid salts into liquids using appropriate substances and also efforts have been
made to polymerize molten salts into solid films. Numerous investigations have been done to improve a
superb ion-conductive matrix, among which polymerization of molten salts is a promising process to
create highly ion-conductive polymer films [4, 5]. Besides the polarization procedure applied, molecular
dynamics simulations of molten salts in which polarization effects are included have exposed that the
mobility of liquids increases [6, 7]. Furthermore, other uses of molten salt are in methane reforming and
methanol steam reforming [8, 9].
Multicomponent reactions (MCRs) demonstrate a very efficient and economic approach to build
up complex structures in a single synthetic process from very simple reactants, most of the time in a one-
pot reaction [10]. Such reactions display methodological ease, high selectivity and high atom economy
because of the formation of carbon-carbon and carbon-heteroatom bonds in a single step [11]. MCRs are
usually very high yielding being a one-pot process and are basically fully different from two-component
reactions [12]. One such MCRs is the one-pot three-component tandem Knoevenagel-Michael
cyclocondensation synthesis of tetrahydrobenzo[b]pyran derivatives that is one of the significant types of
organic compounds. Tetrahydrobenzo[b]pyran derivatives are significant compounds that have full-
fledged remarkable consideration in past years owing to their varied range of biological activities [13] for
example diuretic, anticancer, anti-anaphylactic activities and anticoagulant [14]. Correspondingly,
tetrahydrobenzo[b]pyrans are applied as cognitive enhancers for the treatment of neurodegenerative
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illness, for instance Alzheimer’s, Huntington’s, Parkinson’s illnesses and Down’s syndrome in addition to
the treatment of myoclonus and schizophrenia [15]. Owing to the significance of
tetrahydrobenzo[b]pyrans, various methodologies have been reported for its synthesis in past years [16].
Other significant types of organic compounds are the 1-(amino or amidoalkyl)-2-naphthol
derivatives, called Betti bases [17]. Recently, attention to the chemistry of the Betti base [18] has
increased because of their attractive catalytic [19] and biological [20] properties. These compounds can
be transformed into derivatives having hypotensive, antibacterial and bradycardiac activities [21]. There
are various processes described for the synthesis of 1-(amino or amidoalkyl)-2-naphthols containing
saccharin sulfonic acid (SASA) [22], nano-S (S8-NP) [23], [Msim]Cl or [Dsim]Cl or [Msim]AlCl4 [24],
{[HMIM]C(CN)3} [25], {[1,4-DHPyrazine][C(NO2)3]2} [26], un-catalyzed in water [27] and sulfanilic
acid-functionalized silica-coated magnetite nanoparticles [28].
Following our previous studies linked to the design, synthesis, applications and knowledge-based
development of novel solid acids and inorganic acidic salts [29], novel nano structured, green and benign
ionic liquids, molten salts and organo-catalysts for organic functional group transformations and as a
section of our continuous work to the development of environmentally benign synthetic procedures for
MCRs to synthesize various biologically significant heterocyclic compounds [30], herein we wish to
report the synthesis of an efficient and reusable bifunctional nano structure molten salt catalyst, namely
[4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} (Scheme 1) [31] and its
application for the highly effective synthesis of tetrahydrobenzo[b]pyrans and amido or aminoalkyl
naphthol derivatives under solvent-free conditions (Scheme 2).
>Scheme 1<
>Scheme 2<
2.
Experimental
The materials were purchased from Merck, Fluka and Sigma-Aldrich and were used without any
additional purification. All reactions were monitored by thin layer chromatography (TLC) on gel F254
plates. Spectrometer (1H NMR 400 MHz and 13C NMR 100) in pure deuterated DMSO with
tetramethylsilane (TMS) as the internal standard. Characteristics of the synthesized catalyst were
1
determined by IR, H NMR, 13C NMR, mass, X-ray diffraction patterns (XRD), scanning electron
microscopy (SEM) and transmission electron microscopy (TEM), thermo gravimetric (TG) and derivative
thermal gravimetric (DTG) analysis. X-ray diffraction (XRD) patterns of all catalysts were performed on
a APD 2000, Ital structure with Cu K_ radiation (k = 0.1542 nm) operating at 50 kV and 20 mA in a 2 h
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range of 10–70° with step size 0.01° and time step 1.0 s to assess the crystallinity of the catalyst. Fourier
transform-infrared spectra of the samples were recorded on a Perkin–Elmer FT-IR spectrometer 17259
using KBr disks. Thermo gravimetric analyses using a Perkin–Elmer TGA were performed on catalysts.
The weight loss about 152 oC was identified. The SEM analyses were done with a TESCAN/MIRA with
a maximum acceleration voltage of the primary electrons between 10 and 15 kV. Transmission electron
microscope, TEM measurements were carried out on a Philips CM10 analyzer. Operating at 120 kV.
General procedure for the synthesis of bifunctional nano strcture molten salt catalyst: [4,4'-
bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2}
The NMS {[4,4'-BPyH][C(CN)3]2} as a green catalyst was synthesized according to our
previously reported procedure [31]. A pale yellow solid was prepared in high purity and then the physical
data of this identified NMS was found to be identical with the reported procedure (Scheme 1).
[4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2}
o
Pale yellow solid; M.p: >300 C; Yield: 97% (1.641 g); Spectral data: IR (KBr): υmax = 3411,
1
3070, 3025, 2927, 2169, 2082, 1662, 1486, 1218 cm-1; H NMR (400 MHz, DMSO-d6): δppm = 6.92 (d,
4H, J = 0.8 Hz, ArH), 7.12 (d, 4H, J = 0.8 Hz, ArH), 7.63 (s, 2H, —NH); 13C NMR (100 MHz, DMSO-
d6): δppm 50.1, 109.8, 121.7, 151.0, 167.3; MS: m/z = 338 [M]+.
General procedure for the tandem Knoevenagel-Michael cyclocondensation reaction synthesis of
tetrahydrobenzo[b]pyran derivatives
{[4,4'-BPyH][C(CN)3]2} (1 mol%; 0.0034 g) as a green mild catalyst was added to a mixture of
aromatic aldehydes (1 mmol), malononitrile (0.066 g, 1 mmol) and dimedone (0.140 g, 1 mmol) in a
round bottom flask, and the consequent mixture was first stirred magnetically under solvent-free
condition at room temperature. After completion of the reaction, as known by TLC n-hexane/ethyl acetate
(5:2), ethyl acetate (10 mL) was added to the reaction mixture, stirred and refluxed for 5 min, and then
was washed with water (10 mL) and decanted to separate catalyst from the reaction mixture (the reaction
mixture was soluble in hot ethyl acetate and NMS catalyst was soluble in water). The solvent of organic
layer was evaporated and the crude product was purified via recrystallization from ethanol/water (10:1).
In this investigation, bifunctional NMS catalyst was recycled and reused for four experimental errors with
negligible losing of its catalytic activity.
General procedure for the synthesis of amido or aminoalkyl naphthol derivatives
{[4,4'-BPyH][C(CN)3]2} (1 mol%; 0.0034 g) as a green mild catalyst was added to a mixture of
aromatic aldehydes (1 mmol), β-naphthol (0.144 g, 1 mmol) and amide or amine derivatives (1 mmol) in
a round bottom flask, and the subsequent mixture was first stirred magnetically under solvent-free
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o
condition at 75 C. After completion of the reaction, as identified by TLC n-hexane/ethyl acetate (5:3),
ethyl acetate (10 mL) was added to a reaction mixture, stirred and refluxed for 5 min, and then was
washed with water (10 mL) and decanted to separate catalyst from the reaction mixture (the reaction
mixture was soluble in hot ethyl acetate and NMS catalyst was soluble in water). The solvent of organic
layer was evaporated and the crude product was purified by recrystallization from ethanol/water (10:1). In
this study, bifunctional NMS catalyst were recycled and reused for five experimental errors with a minor
loss of its catalytic activity.
Spectral data analysis for compounds
2-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(Table 3, entry 8)
White solid; M.p: 188-190 oC; Yield: 96%; IR (KBr): υmax = 3358, 3181, 2900, 2190, 1673, 1637,
1
1507, 1366, 1216 cm-1; H NMR (400 MHz, DMSO-d6): δppm = 0.95 (s, 3H—CH3), 1.04 (s, 3H,—CH3),
2.13 (d, 2H, J = 8.0 Hz, —CH2), 2.27 (d, 2H, J = 8.0 Hz, —CH2), 4.20 (s, 1H,—CH aliphatic), 7.11 (s,
2H, —NH2), 7.16 (d, 2H, J = 6.0 Hz, ArH), 7.20 (d, 2H, J = 6.0 Hz, ArH); 13C NMR (100 MHz, DMSO-
d6): δppm = 26.8, 28.3, 31.8, 34.8, 49.9, 58.0, 112.6, 114.9, 115.1, 119.6, 129.0, 129.1, 158.3, 158.4, 159.7,
162.1, 162.5, 195.7.
2-Amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(Table 3, entry 14)
White solid; M.p: 205-207 oC; Yield: 92%; IR (KBr): υmax = 3319, 3183, 2962, 2169, 1682, 1655,
1367, 1215 cm-1; 1H NMR (400 MHz, DMSO-d6): δppm = 0.95 (s, 3H—CH3), 1.04 (s, 3H,—CH3), 2.13 (d,
2H, J = 8.0 Hz, —CH2), 2.27 (d, 2H, J = 8.0 Hz, —CH2), 3.36 (s, 2H, —NH2), 4.18 (s, 1H,—CH
aliphatic), 7.13 (d, 2H, J = 8.4 Hz, ArH), 7.50 (d, 2H, J = 8.4 Hz, ArH); 13C NMR (100 MHz, DMSO-d6):
δppm = 18.5, 26.8, 28.3, 31.8, 35.1, 49.9, 55.9, 57.6, 112.2, 119.5, 119.6, 129.5, 131.2, 144.1, 158.3, 158.4,
162.6, 195.7.
4,4'-(1,4-Phenylene)bis(2-amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile) (Table 3, entry 15)
White solid; M.p: 269-271 oC; Yield: 85%; IR (KBr): υmax = 3452, 3331, 3187, 2962, 2198, 1683,
1
1665, 1364, 1212 cm-1; H NMR (400 MHz, DMSO-d6): δppm = 0.99 (s, 6H—CH3), 1.04 (s, 6H,—CH3),
2.19 (d, 4H, J = 8.0 Hz, —CH2), 2.26 (d, 4H, J = 8.0 Hz, —CH2), 2.51 (s, 4H, —NH2), 4.14 (s, 2H,—CH
aliphatic), 7.04 (s, 4H, ArH); 13C NMR (100 MHz, DMSO-d6): δppm = 27.2, 28.2, 31.8, 34.9, 49.9, 58.3,
112.7, 112.8, 119.7, 126.9, 142.8, 158.4, 158.5, 162.7, 195.8.
2-Amino-4-(3-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(Table 3, entry 17)
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White solid; M.p: 230-232 oC; Yield: 94%; IR (KBr): υmax = 3321, 3184, 2965, 2191, 1682, 1659,
1372, 1213 cm-1; 1H NMR (400 MHz, DMSO-d6): δppm = 0.96 (s, 3H—CH3), 1.04 (s, 3H,—CH3), 2.15 (d,
2H, J = 8.0 Hz, —CH2), 2.28 (d, 2H, J = 8.4 Hz, —CH2), 2.53 (s, 2H, —NH2), 4.22 (s, 1H,—CH
aliphatic), 7.13 (d, 1H, J = 7.6 Hz, ArH), 7.17 (s, 1H, ArH), 7.27 (d, 1H, J = 8.0 Hz, ArH), 7.36 (t, 1H, J
= 7.6 Hz, ArH); 13C NMR (100 MHz, DMSO-d6): δppm = 26.8, 28.2, 31.8, 35.3, 49.9, 57.6, 112.0, 119.4,
125.9, 126.6, 127.0, 130.3, 132.9, 147.2, 158.4, 158.5, 162.8, 195.7.
3.
Results and discussion
Application of [4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a
bifunctional nano structure molten salt catalyst in the synthesis of tandem Knoevenagel-Michael
cyclocondensation synthesis of tetrahydrobenzo[b]pyran derivatives.
Firstly, to optimize the reaction conditions, the condensation reaction of 4-chlorobenzaldehyde,
malononitrile and dimedone was chosen as a typical model and various amounts of bifunctional nano
structure molten salt catalyst at range of 25–100 °C were tested under solvent-free conditions (Table 1).
As revealed in Table 1, the best results were attained when the reaction was achieved in the presence of 1
mol% of bifunctional nano structure molten salt at room temperature (Table 1, entries 5 and 9). No
improvement was identified in the yield of reaction via increasing the amount of the nano molten salt
catalyst and the temperature. Table 1 clearly displays that in the absence of nano molten salt catalyst,
reaction progressed slowly and the product was obtained with low yield (Table 1, entries 1 and 2).
>Table 1<
To compare the effect of the solution with solvent-free conditions, a mixture of 4-
chlorobenzaldehyde, malononitrile and dimedone was selected as classic reaction, by 1 mol% of
bifunctional nano structure molten salt as a catalyst in numerous solvents for instance H2O, CH3CN,
C2H5OH, CH2Cl2, CH3CO2Et, n-hexane and toluene was studied at room temperature. As it can be
detected in Table 2, solvent-free condition was the best one in this reaction. Consequently, solvent-free
condition was selected for running condensation reactions.
>Table 2<
After optimization of the reaction conditions, to consider the efficacy and the scope of the
presented procedure, various of tetrahydrobenzo[b]pyran derivatives were prepared by the one-pot three-
component tandem Knoevenagel-Michael cyclocondensation reaction between aromatic aldehydes,
malononitrile and dimedone in the presence of a catalytic amount of [4,4'-bipyridine]-1,1'-diium
tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a novel bifunctional nano structure molten salt catalyst at
6

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room temperature under solvent-free reaction conditions. The results are presented in Table 3. The effect
of substituents on the aromatic ring displayed was estimated strong in terms of yields under same reaction
conditions. All aromatic aldehydes including electron-releasing substituents and electron-withdrawing
substituents on their aromatic ring provided the desired products in high to excellent yields in short
reaction times. The reaction times of aromatic aldehydes possessing electron withdrawing groups were
rather faster than electron donating groups.
>Table 3<
A plausible mechanism for the creation of the tetrahydrobenzo[b]pyran (4) is well-defined in
Scheme 3 [16a]. Firstly, {[4,4'-BPyH][C(CN)3]2} as a nano molten salt (NMS) catalyst activates the
carbonyl group of the aromatic aldehyde to provide intermediate (8) and malononitrile (2) tautomerized to
(9). The tandem Knoevenagel condensation of intermediate (8) and (9) was happened to form the
arylidene malononitrile (11). Subsequently, dimedone (3) tautomerized to (10) tolerates nucleophilic
attack to (11) and affords the Michael adduct (12). The Michael adduct (12) tautomerizes using NMS
catalyst to make intermediate (13) which cyclizes to provide compound (14) and which then tautomerized
to afford the completely aromatized tetrahydrobenzo[b]pyran (4).
>Scheme 3<
Furthermore, reusability of the {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst was
approved via condensation of 4-chlorobenzaldehyde, malononitrile and dimedone as a model. At the end
of the reaction, ethyl acetate was added to the reaction mixture and heated to extract product from
remained substances. This solution was washed with water to separate bifunctional NMS catalyst from
other materials (the product is soluble in hot ethyl acetate and bifunctional NMS catalyst is soluble in
water). The aqueous layer was decanted, separated and used for additional reaction after eliminating
water. It is identified that the catalytic activity of the catalyst was restored within the limits of the
experimental errors for four continuous runs (Table 4). The deactivation of the bifunctional NMS catalyst
is low. The reaction was scaled up to 10 mmol of 4-chlorobenzaldehyde, malononitrile and dimedone by
10 mol% of {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst at room temperature. The yield of
the reaction was 94% after 7 min and 78% after 12 min the fourth run.
>Table 4<
Application of [4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2}
as a bifunctional nano structure molten salt catalyst in the synthesis of amido or aminoalkyl
naphthol derivatives.
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After the synthesis of {[4,4'-BPyH][C(CN)3]2} as a bifunctional nano structure molten
salt catalyst, to optimize the reaction conditions, we approved the effect of the NMS catalyst in
the synthesis of amino or amidoalkyl naphthols (Scheme 2). For this purpose, as a typical
reaction, the condensation between acetamide, 4-chlorobenzaldehyde and β-naphthol was studied
using different amounts of the catalyst at range of 25–125 °C under solvent-free conditions
(Table 5). As Table 5 displays, the best results were attained when the reaction was achieved in
o
the presence of 1 mol% of NMS catalyst at 75 C (Table 5, entry 7). Increasing the reaction
temperature and catalyst loading did not improve the rate of the reaction (Table 5, entries 9-13).
In the absence of catalyst a low yield of the products was attained after 120 min (Table 5, entries
1 and 2).
>Table 5<
To compare the result of the solution with that of solvent-free conditions, a mixture of acetamide,
4-chlorobenzaldehyde and β-naphthol as a model reaction, using 1 mol% of NMS catalyst in numerous
solvents such as H2O, C2H5OH, CH3CN, CH3CO2Et, CH2Cl2, n-Hexane and toluene was investigated
under reflux conditions. Also, reaction was performed under solvent-free condition at 75 oC. As it can be
seen in Table 6, solvent-free condition was the best one in this reaction.
>Table 6<
With the purpose of approving this main process, we decided to synthesize several amido or
aminoalkyl naphthol derivatives from three-component condensation reaction of numerous aromatic
aldehyde, β-naphthol and several amine or amide under solvent-free conditions at 75 oC in the presence of
a catalytic amount of {[4,4'-BPyH][C(CN)3]2} as a NMS catalyst. The results are presented in Table 7.
The effect of substituents on the aromatic ring exhibitions was estimated strong in terms of yields under
these reaction conditions. All aromatic aldehydes bearing electron-withdrawing and electron-releasing
substituents on their aromatic ring provided the related products in high to excellent yields in short
reaction time. The reaction time of aromatic aldehydes having electron-withdrawing groups was rather
faster than that of electron donating groups.
>Table 7<
In Scheme 4, we have proposed a probable mechanism for the synthesis of amido or aminoalkyl
naphthol derivatives using {[4,4'-BPyH][C(CN)3]2} as a NMS catalyst. The reaction of aromatic
aldehydes with β-naphthol in the presence of NMS catalyst is plausible to produce ortho-quinone
methides (o-QMs). The prepared o-QMs, reacted with amide or amine derivatives to provide amido or
aminoalkyl naphthols. A practical explanation for this result can be identified by studying the
8

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nucleophilic addition of amide or amine to o-QMs intermediate and eventually the desired product was
attained after aromatization [25, 26].
>Scheme 4<
Furthermore, recyclability and reusability of the {[4,4'-BPyH][C(CN)3]2} as a NMS catalyst was
approved from the condensation between acetamide, 4-chlorobenzaldehyde and β-naphthol. After the
completion of the reaction, ethyl acetate was added to the reaction mixture and heated to extract the
product. This solution was washed with water to separate catalyst from other materials (the product is
soluble in hot ethyl acetate and NMS catalyst is soluble in water). The aqueous layer was decanted,
separated and used for alternative reaction after removing of water. It has been proved that the catalytic
activity of the catalyst was changed within the limits of the experimental errors for five continuous runs.
The deactivation of the NMS catalyst is low. The reaction was scaled up to 10 mmol of acetamide, 4-
o
chlorobenzaldehyde and β-naphthol using 10 mol% of NMS catalyst at 75 C. The yield of the reaction
was 93% after 20 min and 91% after the fifth run. The results are summarized in Fig. 1.
>Fig. 1<
4.
Conclusion
In summary, an environmentally friendly, green, mild and efficient bifunctional nano structure
molten salt catalyst namely [4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} was
used and investigated in the synthesis of tandem Knoevenagel-Michael cyclocondensation synthesis of
tetrahydrobenzo[b]pyran derivatives by three-component condensation reaction of various aldehydes,
malononitrile and dimedone under solvent-free conditions at room temperature. In another study catalytic
properties of {[4,4'-BPyH][C(CN)3]2}, it was applied in the synthesis of amido and aminoalkyl naphthol
derivatives under solvent-free conditions at 75 oC. Other works offered that the NMS basicity and acidity
displays a significant role to play in the dual-catalyzed reactions. Different noteworthy advantages of this
study are reasonably ease of product isolation, cleaner reaction profile, short reaction time, high yield,
recyclability of the NMS catalyst and accordance with the green chemistry disciplines. More study for
systematic and knowledge-based development of nano molten salt is going on in our research group.
Acknowledgement
We thank Bu-Ali Sina University, Iran National Science Foundation (INSF) (The Grant
of Allameh Tabataba'i's Award, Grant Number BN093) and National Elites Foundation for
financial support to our research group.
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Zolfigol, F. Derakhshan-Panah, M. Shiri, H.G. Kruger, M. Mokhlesi, Synthesis of
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M.A. Zolfigol, M. Yarie, S. Baghery, Application of {[4,4′-BPyH][C(CN)3]2} as a bifunctional
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solvent-free and benign conditions, Synlett, In press, Corrected proof (2016) DOI: 10.1055/s-
0035-1561345.
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Scheme, Table and Figure section:
Scheme 1. The synthesis of [4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a bifunctional nano
structure molten salt catalyst.
15

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Scheme 2. The synthesis of tetrahydrobenzo[b]pyrans and amido or aminoalkyl naphthol derivatives in the presence of [4,4'-
bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a green bifunctional nano structure molten salt catalyst.
Table 1. Result of amount of the catalyst and temperature on the condensation reaction among 4-chlorobenzaldehyde,
malononitrile and dimedone under solvent-free conditions.a
Entry
Catalyst amount (mol%)
Reaction temperature (oC)
Reaction time (min)
Yieldb (%)
1
2
—
—
0.5
0.5
1
r.t.
100
r.t.
120
120
60
60
7
33
33
81
81
94
94
94
94
94
94
89
89
3
4
100
r.t.
5
6
1
50
7
7
1
75
7
8
1
100
r.t.
7
9
2
7
10
11
12
2
100
r.t.
7
5
10
10
10
r.t.
Reaction conditions: a4-Chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), dimedone (1 mmol); bIsolate yield.
Table 2. The effect of numerous solvents on the reaction between 4-chlorobenzaldehyde, malononitrile and dimedone catalyzed
by {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS (1 mol%) at room temperature.a
Entry
Solvent
Reaction time (min)
Yieldb (%)
1
2
3
4
5
6
Solvent-free
H2O
7
7
94
93
91
93
89
83
CH3CN
7
C2H5OH
CH2Cl2
7
15
20
CH3CO2Et
16

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7
5
n-Hexane
30
30
77
77
Toluene
Reaction conditions: a4-Chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), dimedone (1 mmol); bIsolate yield.
Table 3. The tandem Knoevenagel-Michael cyclocondensation reaction synthesis of tetrahydrobenzo[b]pyran derivatives using
[4,4'-bipyridine]-1,1'-diium tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst.a
Entry
1
Aldehyde
Time (min)
7
Yieldb (%)
M.p (oC) [Lit.]Ref. (Color)
94
210-212 [208-210]16a (White solid)
2
3
10
8
90
91
227-229 [229-230]16a (White solid)
180-182 [175-177]16p (White solid)
4
5
7
95
87
226-228 [225-228]16n (White solid)
219-221 [214-216]16a (White solid)
18
6
11
92
211-213 [202-204]16a (White solid)
7
8
15
5
88
96
212-214 [218-219]16a (White solid)
188-190 [178-180]16a (White solid)
9
10
90
195-197 [208-212]16a (White solid)
17

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10
11
10
15
91
89
120-122 [183-186]16a (White solid)
179-181 [158-160]16p (White solid)
12
13
14
10
9
90
91
92
215-217 [216-217]16a (White solid)
157-159 [150-152]16a (White solid)
205-207 [207-208]16a (White solid)
8
15
16
17
14
85
90
269-271 (White solid)
206-208 [212-213]16a (Orange solid)
17
18
9
94
92
230-232 [235-237]16p (White solid)
235-237 [215-217]16p (White solid)
10
a
Reaction conditions: Aromatic aldehyde (1 mmol), malononitrile (1 mmol), dimedone (1 mmol), {[4,4'-BPyH][C(CN)3]2} as a
NMS catalyst (1 mol%), solvent-free, r.t.; bIsolate yield.
18

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Scheme 3. The proposed mechanism for the tandem Knoevenagel-Michael cyclocondensation synthesis of
tetrahydrobenzo[b]pyran derivatives using {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst.
Table 4. Reusability of {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst on the synthesis of 2-amino-4-(4-chlorophenyl)-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile.a
Experimental errors
Time (min)
Isolated yieldsb
1
2
3
4
7
8
94
93
85
78
11
12
Reaction conditions: a4-Chlorobenzaldehyde (10 mmol), malononitrile (10 mmol), dimedone (10 mmol), {[4,4'-
BPyH][C(CN)3]2} as a NMS catalyst (10 mol%), Solvent-free, r.t.; bIsolate yield.
19

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Table 5. Result of amount of the catalyst and temperature on the condensation reaction between acetamide, 4-
chlorobenzaldehyde and β-naphthol under solvent-free conditions.a
Entry
Catalyst amount (mol%)
Reaction temperature (oC)
Reaction time (min)
Yieldb (%)
1
2
—
—
0.5
0.5
1
r.t.
100
r.t.
120
120
120
60
5
7
3
23
25
51
78
93
93
93
51
93
51
93
4
100
r.t.
5
60
6
1
50
60
7
1
75
20
8
1
100
125
r.t.
20
9
1
20
10
11
12
13
2
60
2
100
r.t.
20
5
60
5
100
20
Reaction conditions: a4-Chlorobenzaldehyde (1 mmol), β-naphthol (1 mmol), acetamide (1 mmol); bIsolate yield.
Table 6. Reaction of acetamide, 4-chlorobenzaldehyde and β-naphthol catalyzed using {[4,4'-BPyH][C(CN)3]2} as a bifunctional
NMS (1 mol%) in various solvents under reflux conditions. Reaction was done under solvent-free condition at 75 oC .a
Entry
Solvent
Reaction time (min)
Yieldb (%)
1
2
3
4
5
6
7
5
Solvent-free
H2O
20
60
45
60
60
60
60
60
93
18
78
35
71
29
15
21
CH3CN
C2H5OH
CH2Cl2
CH3CO2Et
n-Hexane
Toluene
Reaction conditions: a4-Chlorobenzaldehyde (1 mmol), β-naphthol (1 mmol), acetamide (1 mmol); bIsolate yield.
20

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Table 7. The synthesis of amino or amidolalkyl naphthol derivatives in the presence of [4,4'-bipyridine]-1,1'-diium
tricyanomethanide {[4,4'-BPyH][C(CN)3]2} as a bifunctional NMS catalyst.a
Entry
1
Aldehyde
R’
Time (min)
15
Yieldb (%)
95
M.p (oC)[Lit.]Ref. (Color)
243-245 [248-250]25 (Yellow
solid)
COMe
248-250 [253-255]25 (White
solid)
2
3
4
COPh
CONH2
2-Pyridyl
20
25
15
93
92
95
195-197 [200-202]25
(Yellow solid)
181-183 [189-191]26 (Cream
solid)
281-283 [290-292]26 (Brown
solid)
5
6
4-Pyridyl
COMe
10
20
25
30
20
96
93
90
88
93
95
254-256 [258-260]25 (White
solid)
201-203 [205-207]25 (White
solid)
7
COPh
171-173 [161-163]25 (White
solid)
8
CONH2
2-Pyridyl
4-Pyridyl
201-203 [209-2211]26 (Cream
solid)
9
217-219 [218-220]26 (Cream
solid)
10
15
21

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274-276 [280-282]25 (White
solid)
11
12
COMe
COPh
25
30
91
88
264-266 [271-273]25 (Cream
solid)
203-205 [206-208]25 (Cream
solid)
13
14
CONH2
35
25
87
91
163-165 [172-174]26 (Cream
solid)
2-Pyridyl
253-255 [263-265]26 (Cream
solid)
15
16
4-Pyridyl
CONH2
20
35
93
85
181-183 [177-179]25 (White
solid)
Reaction conditions: aAromatic aldehyde (1 mmol), β-naphthol (1 mmol), amine or amide derivatives (1 mmol), {[4,4'-
BPyH][C(CN)3]2} as a NMS catalyst (1 mol%), solvent-free, 75 oC; bIsolate yield.
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ACCEPTED MANUSCRIPT
Scheme 4. Suggested mechanism for the synthesis of amido or aminoalkyl naphthol derivatives using {[4,4'-BPyH][C(CN)3]2} as
a NMS catalyst.
Fig. 1. Reusability of the NMS catalyst in 20 minutes in the synthesis of corresponded amidoalkyl naphthol.
23

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Highlights

An efficient method for the synthesis of tetrahydrobenzo[b]pyrans and amino(amido)alkyl
naphthols were described.


{[4,4'-BPyH][C(CN)3]2} as an efficient nano molten salt (NMS) catalyst was applied.
The major advantages of the described method are low catalytic amount, easy recovery and
reusability of the catalyst.
25