Efficient tandem synthesis of a variety of pyran-annulated heterocycles, 3,4-disubstituted isoxazol-5(4H)-ones, and α,β-unsaturated nitriles catalyzed by potassium hydrogen phthalate in water

Article abstract of DOI:10.1007/s11164-014-1863-7

A variety of 4H-chromenes, benzochromenes, 4,5-dihydropyrano[3,2-c]chromenes, 4H-pyran-3-carboxylates, and 3,4-disubstituted isoxazol-5(4H)-ones have been synthesized in high yields by using potassium hydrogen phthalate (KHP) as an inexpensive, commercially available catalyst. It was found that the three-component tandem reaction enabled synthesis of pyran-annulated heterocycles in water at 50 °C. 3,4-Disubstituted isoxazol-5(4H)-ones were synthesized by use of 10 mol% KHP in water at room temperature. Also, treatment of methylene-containing compounds (malononitrile or ethyl cyanoacetate) with aromatic aldehydes in the presence of 5 mol% KHP resulted in α,β-unsaturated nitriles. The procedure is an easily performed, straightforward method for synthesis of a variety of pyran-annulated compounds, isoxazol-5(4H)-one-containing heterocycles, and Knoevenagel adducts. The reaction is safe, uses mild conditions, and is environmentally benign. Other notable advantages are reuse of the catalyst, no use of hazardous organic solvents, and ease of work-up.

Full text of DOI:10.1007/s11164-014-1863-7

Res Chem Intermed
DOI 10.1007/s11164-014-1863-7
Efficient tandem synthesis of a variety of pyran-
annulated heterocycles, 3,4-disubstituted isoxazol-
5(4H)-ones, and a,b-unsaturated nitriles catalyzed
by potassium hydrogen phthalate in water
•
Hamzeh Kiyani Fatemeh Ghorbani
Received: 23 August 2014 / Accepted: 29 October 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A variety of 4H-chromenes, benzochromenes, 4,5-dihydropyrano[3,2-
c]chromenes, 4H-pyran-3-carboxylates, and 3,4-disubstituted isoxazol-5(4H)-ones
have been synthesized in high yields by using potassium hydrogen phthalate (KHP)
as an inexpensive, commercially available catalyst. It was found that the three-
component tandem reaction enabled synthesis of pyran-annulated heterocycles in
water at 50 °C. 3,4-Disubstituted isoxazol-5(4H)-ones were synthesized by use of
10 mol% KHP in water at room temperature. Also, treatment of methylene-con-
taining compounds (malononitrile or ethyl cyanoacetate) with aromatic aldehydes in
the presence of 5 mol% KHP resulted in a,b-unsaturated nitriles. The procedure is
an easily performed, straightforward method for synthesis of a variety of pyran-
annulated compounds, isoxazol-5(4H)-one-containing heterocycles, and Knoeve-
nagel adducts. The reaction is safe, uses mild conditions, and is environmentally
benign. Other notable advantages are reuse of the catalyst, no use of hazardous
organic solvents, and ease of work-up.
Keywords Three-component reaction Á 4H-Chromenes Á 4H-Pyrans Á Isoxazol-
5(4H)-ones Á Potassium hydrogen phthalate Á Cyano compounds
Introduction
In recent years, multicomponent reactions (MCRs) have become essential, efficient,
bond-forming methods for expedient synthesis of a wide range of active organic
compounds and natural products without separation and purification of intermediates.
The MCRs, which are important classes of chemical transformations, have recently
attracted much attention owing to their high efficacy, shorter reaction times, mild
H. Kiyani (&) Á F. Ghorbani
School of Chemistry, Damghan University, 36715-364 Damghan, Iran
e-mail: hkiyani@du.ac.ir
123

H. Kiyani, F. Ghorbani
conditions, simplicity, and environmental friendliness [1–3]. These effective and
attractive processes also eliminate waste production and costly purification processes.
They are also simple strategies for synthesis of heterocyclic structures in a single
vessel from three or more components with high atom and structural economy [4–7].
Implementation of MCRs in water as reaction medium is one of the most suitable
methods, and is significant in the context of green chemistry [8–12].
Pyran-annulated frameworks, for example 4H-chromene or 4H-pyran-containing
heterocyclic rings are important structures with potent biological and pharmaceu-
tical activity. Over the past few years, both these six-membered oxygen-containing
heterocycles and their derivatives have attracted much attention, owing to their wide
range of biological activity, for example spasmolytic, diuretic, anticoagulant, anti-
anaphylactic [13], antimicrobial [14], antifungal [15], antibacterial [16], antioxidant
[17], antileishmanial [18], antitumor [19], local anesthetic [20], antihistaminic [21],
and antiallergenic [22] activity and because of their use for treatment of
Alzheimer’s disease [23] and schizophrenia [24]. Moreover, several chromenes
are widely used as pigments [25], cosmetics [26], and laser dyes [27]. Some
diversely functionalized 4H-chromenes with strong biological activity are shown in
Fig. 1. Compound MX58151 (A) might have potential for treatment of drug-
resistant cancers [28, 29]. Chromene pyrazole derivative B is an inhibitor of human
Chk1 kinase [30]. Compound EPC2407 (C) is currently in phase I/II clinical trials as
vascular anticancer drug and apoptosis inducer for treatment of patients with
advanced solid tumors [31]. Benzochromene LY290181 (D) is an inhibitor of
diabetes-induced vascular dysfunction [26, 32–35]. 2-Amino-5-oxo-5,6,7,8-tetra-
hydro-4H-chromenes (E) act as antibacterial agents [36]. HA14-1 (F) is an
antagonist for antiapoptotic Bcl-2 proteins which can effectively induce apoptosis of
human acute myeloid leukemia cells [37]. Compounds G and H have a benzopyran
core and are non-peptidic insulin-regulated aminopeptidases (IRAP) that can
enhance memory in two memory models [38]. Chromene I and structurally similar
OCH3
OCH3
OH
OCH3
Br
NO2
Br
OH
H3CO
CN
CN
CN
CN
HN
N
NH2
O
H3C
N
CH3
O
NH2
O
NH2
H2N
O
NH2
NH2
D LY290181
A MX58151
B an inhibitor of
C EPC2407
an anticancer agent
an inhibitor of diabet
human Chk1
an anticancer agent
H3CO
O
N
EtO2C CN
O
Ar
O
N
CN
Br
CO2Et
CO2Et
NH
CN
CO2Et
NH2
NH2
O
NH2
HO
O
NH2
O
HO
O
O
I UCPH-101, an inhibitor
F HA 14-1
Bcl-2 inhibitor
G HFI-419
an IRAP inhibitor
H HFI-435
an IRAP inhibitor
E antibacterial
of EAAT1
activity
Fig. 1 Representative examples of biologically active 4H-chromene-containing compounds
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
compounds act as selective inhibitors of excitatory amino acid transporter 1
(EAAT1) [39].
Taking into consideration these characteristics of derivatives of highly
functionalized 4H-chromenes and 4H-pyrans, much attention has been focused on
the development of ecologically benign methods for synthesis of such useful
heterocyclic structures by multicomponent cyclization of a variety of aldehydes, C–
H enolizable molecules, and methylene-containing compounds.
Several synthetic methods have been widely applied for synthesis of pyran-based
heterocyclic compounds, using many homogeneous or heterogeneous organic,
inorganic, and nanomaterial catalysts, for example hexamethylenetetramine (HMT)
[40], heteropolyacid [41], diammonium hydrogen phosphate [42], DBU [43],
piperidine [44–47], tetrabutylammonium bromide (TBAB) [48], ionic liquids [49],
morpholine [50], 4-(dimethylamino)pyridine (DMAP) [51], urea [52], 3-hydroxy-
propanaminium acetate (HPAA) [53], N-propylpiperazine sodium n-propionate
(SBPPSP) [54], silica gel [55], sulfonic acid-functionalized silica [56], 2-hydrox-
yethanaminium acetate [57], a-Fe2O3 [58], cellulose-SO3H [59], potassium sodium
tartrate (KNaC4H4O6.4H2O) [60], meglumine [61], I2/K2CO3 [62], cetyltrimethyl-
ammonium bromide (CTABr) [63], nano-sized MgO [64], nano-structured
Na2CaP2O7 [65], NaHCO3 [66], Na2CO3 [67], triazine-functionalized ordered
mesoporous organosilica [68], potassium phosphate tribasic trihydrate [69], Mg/Al
hydrotalcite [70], Amberlyst A21 [71], DABCO [72], CeO2/CaO nanocomposite
oxide [73], triton B [74], tetrabutylammonium chloride (TBAC) [75], nano-eggshell
powder [76], basic alumina [77], [bmim]OH [78, 79], LiBr [80], glycine [81], silica
nanoparticles [82], ionic liquid choline chloride-urea [83], borax [84], natural
clinoptilolite (CP) zeolite [85], SBA-DABCO [86], imidazole [87], tungstic acid-
functionalized SBA-15 [88], multi-walled carbon nanotube-supported Fe3O4
nanoparticles [89], CoFe2O4 nanoparticles [90], tendon hydrolysate (TH) [91],
aminosilane-modified Fe3O4 nanoparticles (MNPs-NH2) [92], starch solution [93],
ammonium acetate [94], aminopropylated SiO2 [95], surfactant-modified bentonite
(CTMAB-bentonite) [96], and amino-functionalized MCM-41 [97].
Functionalized isoxazoles have long been regarded as ‘‘privileged substructures’’
in pharmaceutical chemistry and have been widely used as frameworks for drug
development, salient targets in bioorganic research, and building blocks in synthetic
organic chemistry [98–100]. Many isoxazole-containing heterocycles have diverse
biological activity, including antimicrobial, fungicidal, anticonvulsant, HDAC
inhibitory, protein-tyrosine phosphatase 1B (PTP1B) inhibitory, analgesic, antiox-
idant, anti-apoptotic, anti-obesity, COX-2 inhibitory, nematicidal, anti-nociceptive,
anti-inflammatory, antiviral, anti-tubercular, herbicidal, protein kinase C (PKC)
inhibitory, and antineoplastic [101–107] activity. The isoxazole nucleus is also
found in inhibitory agents [108], sulfisoxazoles [109], antibiotics [110, 111], and
anti-androgens [112, 113]. Isoxazoles are, thus, very attractive synthetic targets for
investigation of efficient and green synthetic methods.
3,4-Disubstituted isoxazol-5(4H)-ones have been prepared by one-pot, three-
component reaction (3CR) of b-oxoesters, hydroxylamine hydrochloride, and aryl
aldehydes in the presence of organic bases [114–122] and nanomaterials [123].
Catalyst-free grinding or heating has also been reported [124]. More recently, we
123

H. Kiyani, F. Ghorbani
have used sodium ascorbate [125], sodium citrate [126], sodium saccharin [127],
sodium tetraborate [128], sodium azide [129], boric acid [130], and potassium
phthalimide (PPI) [131] as catalysts for synthesis of isoxazol-5(4H)-ones.
Since the discovery of the Knoevenagel condensation reaction [132], it has been
shown to be a convenient method for synthesis of numerous chemical compounds
including substituted olefins, coumarin derivatives [133], hetero Diels–Alder
products [134], cosmetics [135], perfumes [136], pharmaceutical chemicals [137],
and materials for organic solar cells [138, 139]. The Knoevenagel condensation of
aldehydes with active methylene compounds gives rise to the corresponding alkene
derivatives. This condensation can be easily conducted in the presence of a variety
of catalysts including Lewis acids [140], zeolites [141], amine-functionalized
materials [142–144], ionic liquids [145, 146], and nanomaterials [147, 148], each of
which gives variable yields of the Knoevenagel adducts. In addition, solid bases
[149, 150] and organic bases, for example piperidine, pyridine, urea, DABCO, and
guanidine [151–153], have been used for Knoevenagel condensations.
Although the procedures listed above have their own merits, some require use of
a hazardous amine-based catalyst; others use such organic solvents as DMSO and
harsh reaction conditions. Some of the methods involve complex steps, furnish low
yields, and require tedious work-up procedures, expensive catalysts, and special
apparatus (ultrasound or microwaves). Therefore, development of efficient, simple,
mild, and eco-friendly procedures for preparation of densely functionalized 4H-
chromenes, 4H-pyrans, isoxazol-5(4H)-ones, and Knoevenagel products is of
substantial interest. Water is one of the best solvents for many organic
transformations because of its intrinsic features such as safety, nontoxicity, and
nonflammability. It is also inexpensive, environmentally benign, and more readily
available than organic solvents. Isolation of products from an aqueous environment
is usually easy. The rate and chemoselectivity of many chemical reactions have also
been improved by use of aqueous media [154–156].
Development of solid-phase, inexpensive, green, and commercially available
catalysts is an interesting topic in organic synthesis which is attracting much
attention [157, 158]. Potassium hydrogen phthalate (KHP), a traditionally used
primary solid standard for volumetric titrations [159] and the reference pH standards
[160], can be used as a surface modifier [161], as a crystal analyzer for long-wave
X-ray spectrometry, and as substrate for the growth of highly oriented films of
conjugated polymers [162, 163]. Our literature survey revealed there is no report on
use of KHP as a catalyst in the synthesis of 4H-chromenes, 4H-pyrans, isoxazol-
5(4H)-ones, and a,b-unsaturated nitriles. To the best of our knowledge, this is the
first report of the use of KHP for synthesis of these structures (Schemes 1, 2).
Experimental
General
Unless otherwise specified, all chemicals were purchased from commercial sources
and were used without further purification, with the exception of liquid aldehydes,
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Ar
OH
O
O
Z
O-K+
KHP, 25 mol%
H2O, 50 oC
HO2C
NC
Z
+
+
Ar
H
NH2
O
Z = CN, CO2Et
2
3
4, 6-7, 9, 12-13, 15
KHP
OH
OH
OH
HO
OH
OH
OH
OH
=
O
O
OH
O
O
O
O
1
5a
5b
8
10
11
14
Scheme 1 KHP-catalyzed 3CRs leading to a variety of chromene-3-carbonitriles and 4H-pyran-3-
carboxylates at 50 °C in water
Ar
H
O
2
Z
O
O
Ar
Z
KHP, 10 mol%
H2O, RT
+
N
O
O
O
16
18a-t
14: Z = H
17: Z = Cl
Scheme 2 One-pot, 3CR of hydroxylamine hydrochloride (16), aryl aldehydes (2), and b-ketoesters (14,
17) for preparation of 3,4-disubstituted isoxazol-5(4H)-ones (18a-t) in the presence of KHP at room
temperature (RT)
which were distilled before use. The products were characterized by comparison of
their physical data with those of known samples or from their spectral data. Melting
points were measured on a Buchi 510 melting point apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded at ambient temperature on Bruker
Avance DRX 500 and 400-MHz instruments with DMSO-d6 as solvent. FT-IR
spectra were recorded on a Perkin–Elmer RXI spectrometer. The progress of
reactions was monitored by thin-layer chromatography (TLC) on Merck pre-coated
silica gel 60 F254 aluminum sheets, visualized by use of UV light.
General procedure for synthesis of chromene derivatives (4a–n) 4H-chromene-
3-carbonitriles (4a–j) benzochromenes (6a–h and 7a–l), 4,5-dihydropyrano[3,2-
c]chromenes (9a–n), 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromenes (12a–r,
13a–e), and ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3-carboxylates
(15a–g)
A mixture of aromatic aldehyde 2 (1 mmol), C–H enolizable compounds 1, 5, 8, 10,
11, or 14 (1 mmol), malononitrile or ethyl cyanoacetate 3 (1 mmol), and KHP
(25 mol%) in distilled water (5 mL) was heated at 50 °C. The progress of the
reaction was monitored by TLC analysis. After completion of the reaction, the
123

H. Kiyani, F. Ghorbani
reaction mixture was cooled to room temperature and solid which precipitated was
filtered, washed with cold distilled water (4 mL), and air-dried to obtain the pure
products. If necessary, the solid products can be recrystallized from suitable solvent.
After removal of water from the filtered solution, the catalyst was recovered and
then used for subsequent reaction. The identity of the known products was
confirmed by comparison of their spectroscopic data and physical properties with
those available in recent papers [164–166]. Spectral data for 4b, 6e, and 7e were:
2-Amino-7-hydroxy-4-(4-nitrophenyl)-4H-chromene-3-carbonitrile (4b)
1H NMR (400 MHz, DMSO-d6): d = 9.83 (s, 1H), 8.22 (d, J = 8.8 Hz, 2H), 7.44
(d, J = 8.8 Hz, 2H), 7.02 (s, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 8.4,
2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 4.87 (s, 1H); 13C NMR (100 MHz, DMSO-
d6): d = 161.3, 158.1, 154.4,147.0, 130.5, 129.2, 125.5, 121.3, 118.6, 113.3, 112.8,
102.9, 79.5, 55.6.
2-Amino-4-(p-tolyl)-4H-benzo[h]chromene-3-carbonitrile (6e)
1H NMR (400 MHz, DMSO-d6): d = 8.03 (d, J = 8.0 Hz, 1H), 7.67 (d,
J = 8.0 Hz, 1H), 7.33–7.42 (m, 3H, ArH), 7.15–7.25 (m, 4H), 7.08 (d,
J = 8.0 Hz, 1H), 6.90 (s, 2H), 4.56 (s, 1H), 2.25 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d = 161.0, 145.3, 141.5, 133.6, 132.8, 130.4, 128.7, 127.5, 126.1,
125.7, 124.2, 123.9, 122.8, 122.1, 120.4, 119.6, 56.0, 43.8, 31.5.
3-Amino-1-(4-bromophenyl)-1H-benzo[f]chromene-2-carbonitrile (7e)
1H NMR (400 MHz, DMSO-d6): d = 7.84 (d, J = 8.5 Hz, 2H), 7.61-7.64 (m, 1H),
7.39–7.44 (m, 4H), 7.28 (d, J = 6.3 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 5.24 (s, 1H),
4.64 (s, 2H); 13C NMR (100 MHz, DMSO-d6): d = 160.2, 147.3, 145.6, 132.1,
131.3, 130.5, 130.2, 129.7, 128.9127.7, 125.5, 124.0, 120.9, 120.2, 117.3, 115.5,
57.7, 37.9.
General procedure for preparation of 3,4-disubstituted isoxazol-5(4H)-ones
(18a–t)
Equimolar quantities of aryl aldehyde 2 (1 mmol), hydroxylamine hydrochloride 16
(0.07 g, 1 mmol), b-ketoesters 14 or 17 (0.130 g, 1 mmol), 10 mol% KHP, and
distilled water (5 mL) were mixed at room temperature. After completion of the
reaction, the solid product was isolated by simple filtration and washed with water
(4 mL). The filtrate was evaporated to remove the water and leave the catalyst. The
same catalyst was used for synthesis of further derivatives. If necessary, further
purification was performed by recrystallization from hot ethanol to give the desired
compounds in high yields. The identities of known products were confirmed by
comparison of their spectroscopic data and physical properties with those available
in recent papers [114–116, 120–131].
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Spectral data for 3-(chloromethyl)-4-(4-(diethylamino)-2-hydroxybenzylidene)
isoxazol-5(4H)-one (18t)
1H NMR (400 MHz, DMSO-d6): d = 11.08 (s, 1H), 9.14 (d, J = 9.6 Hz, 1H), 8.07
(s, 1H), 6.52 (dd, J = 2.0, 9.6 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 3.50 (q, J = 6.8,
7.2 Hz, 4H), 1.17 (t, J = 6.8, 7.2 Hz, 6H); 13C NMR (100 MHz, DMSO-d6):
d = 170.9, 164.2, 162.2, 156.4, 143.1, 136.1, 111.9, 106.9, 101.2, 95.8, 45.2, 36.4,
13.1.
General procedure for preparation of a,b-unsaturated nitriles (19a–w)
A mixture of aryl aldehyde 2 (1 mmol), malononitrile or ethyl cyanoacetate 3
(1 mmol), and 5 mol% KHP in distilled water (5 mL) was stirred at room
temperature. After completion of the reaction, the solid product was isolated by
simple filtration and washed with water (4 mL). The filtrate was evaporated to
remove water and leave the catalyst. The same catalyst was used for subsequent
reactions. The identities of known products were confirmed by comparison of their
spectroscopic data and physical properties with those available in recent papers
[144, 146, 150, 153]. Spectral data for 19a and 19n were:
2-Benzylidenemalononitrile (19a)
1H NMR (400 MHz, CDCl3): d = 7.93 (d, J = 7.6 Hz, 2H), 7.80 (s, 1H), 7.63 (t,
J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d = 160.0, 134.6, 131.0, 130.7, 129.8, 113.7, 82.9.
Ethyl 2-cyano-3-(4-nitrophenyl)acrylate (19n)
1H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 8.6 Hz, 2H), 8.32 (s, 1H), 8.15 (d,
J = 8.6 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 161.4, 151.6, 149.8, 136.9, 131.6, 124.2, 114.5, 107.6,
63.2, 14.1.
Results and discussion
Initially, the best reaction conditions were investigated by using the reaction
between equimolar quantities (1 mmol) of resorcinol (1), 4-methylbenzaldehyde
(2e), and malononitrile (3a) as model reaction. The results are listed in Table 1.
It was observed that in the absence of the catalyst, reaction of resorcinol (1) with
4-methylbenzaldehyde (2e) and malononitrile (3a) led to only trace amounts of
2-amino-7-hydroxy-4-(p-tolyl)-4H-chromene-3-carbonitrile (4e) after 10 h at room
temperature (RT) and 50 °C (entries 1 and 2). When the reaction was performed
using 2.5 mol% KHP in water, product formation was observed after 4 h at 50 °C
(entry 3), demonstrating the effectiveness of the catalyst in the reaction. When the
reaction was conducted in the presence of 5 mol% KHP, the yield improved slightly
123

H. Kiyani, F. Ghorbani
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
123

H. Kiyani, F. Ghorbani
(entry 4). Increasing the amount of catalyst from 5 to 10 mol% and 15 mol% did not
result in significant improvement in the yields and reaction times at the same
temperature (entries 5 and 6). Treating the starting materials with 20 mol% catalyst
in water led to 70 % yield of expected product (4e) after 3.5 h at 50 °C (entry 7).
These results encouraged us to investigate use of a larger quantity of catalyst.
Performing the reaction with 25 mol% KHP in water led to the formation of 4e in
92 % yield after 3 h at 50 °C (entry 8). A larger amount of catalyst (30 mol%)
neither increased the yield nor shortened the reaction time (entry 9). The product
was obtained in 60 % yield when the substrates and 25 mol% KHP were stirred at
RT (entry 10). It was also observed that higher reaction temperatures led to lower
yields (entries 11 and 12). Solvent effects are also screened. Performing the reaction
in MeCN, 1,4-dioxane, CH2Cl2, EtOAc, or CHCl3 led to a trace amount of product
(4e) (entries 13–17). EtOH and a 1:1 (v/v) mixture of EtOH and H2O also afforded
lower yields of the desired product (4e) under similar conditions (entries 18 and 19).
Hence, use of 25 mol% catalyst and heating at 50 °C in water were selected as the
best conditions for this reaction.
Using these optimized reaction conditions the scope of the reaction was
investigated by use of a variety of aryl and heteroaryl aldehydes (2a–j), and
2-amino-4-aryl-7-hydroxy-4H-chromene-3-carbonitriles (4a–j) were isolated in
high yields by use of this simple 3CR (Scheme 3). The results are summarized in
Table 2.
These results indicated that this KHP-catalyzed 3CR worked well for a wide
variety of heteroaryl aldehydes and substituted benzaldehydes with numerous
functional groups including electron-deficient (for example –NO2 and –Cl) and
electron-rich (for example –CH3, –OCH3, –OH, and –N(CH3)2) substituents. In all
cases, the reaction proceeded smoothly and the expected products (4a–j) were
obtained with high purity. If further purification was required, they could be
recrystallized from ethanol. The electronic nature of the functional groups on the
phenyl ring at the C-4 position has no significant effect on the yield of desired
products; however the reaction times are affected. Substrates with electron-deficient
functional groups (entries 2–4) reacted rapidly whereas electron-rich substituents
(entries 5-8) decreased the reactivity, so longer reaction time was required. The
reaction also proceeded smoothly with electron-rich aromatic heterocyclic alde-
hydes, for example furan-2-carbaldehyde (2i) and thiophene-2-carbaldehyde (2j),
Ar
Ar
O
H
O
HO
2a-j
+
CN
KHP, 25 mol%
H2O, 50 oC
CN
NH2
HO
CN
OH
3a
4a-j
1
Scheme 3 One-pot, three-component tandem cyclocondensation for preparation of 2-amino-4-aryl-7-
hydroxy-4H-chromene-3-carbonitriles (4a–j) in the presence of KHP at 50 °C
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 2 Scope of the synthesis of 2-amino-4-aryl-7-hydroxy-4H-chromene derivatives (4a–j) catalyzed
by KHPa
Entry Aldehyde
Product
Time
(h)
Yield
(%)b
Mp (°C)
Found
Lit. [Ref.]
230-232 [78]
1
2.75
93
228-230
H
C
O
N
C
2a
2b
H
O
O
N
NH
2 4a
N
C
O2
2
2.5
84
210-211
210-212 [70]
188-190 [70]
O2
H
O
N
C
H
H
O
O
NH
2 4b
3
4
N
N
O2
2.5
2.5
94
95
204-206
162-164
O2
H
C
O
N
C
2c
O
O
C
NH
2 4c
l
C
l
162-163 [78],
159-161 [70]
H
N
C
C
O
2d
2e
H
H
O
O
C
NH2
4d
5
3
92
186-188
183-186 [64],
180-182 [70]
H
H
H
C
3
3
C
O
N
C
O
O
NH
2 4e
123

H. Kiyani, F. Ghorbani
Table 2 continued
6
7
8
3
92
95
97
110-112
252-254
188-190
112-113 [51] 110-
112 [64], 112-114
[70]
H
H
3
OC
OC
3
H
C
N
C
O
2f
H
H
O
O
NH
2 4f
3.2
252-254 [48],
248-250 [70]
H
H
O
O
H
C
N
C
O
2g
O
O
NH
2 4g
H
3C
H
H
3C
H
C
3.25
189-191 [165]
C
3
3
N
C
N
H
O
N
C
2h
H
O
O
NH
2 4h
9
2.5
2.5
92
97
191-193
205-206
190-192 [48] 208-
210 [64]
O
O
H
O
C
N
C
2i
2j
H
O
O
NH
2 4i
10
205-206 [165]
S
S
H
O
C
N
C
H
O
O
NH
2 4j
a Reaction conditions: substrates 1 mmol; water (5 mL); KHP (25 mol%); stirred at 50 °C
b Yields refer to those of pure isolated products.
a
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (25 mol%); stirred at 50 °C
Yields refer to those of pure isolated products
b
and high yields were obtained (entries 9 and 10). According to the results listed in
Table 2, because of steric crowding between the two hydroxyl groups in resorcinol,
reaction occurs at the C-4 position.
Inspired by these results, the optimized reaction conditions were also applied to
3CR of aryl and heteroaryl aldehydes (2) with cyano-containing compounds (3a, b),
and naphthols (a-naphthol (5) and b-naphthol (6)) at 50 °C (Scheme 4).
When aryl aldehydes, malononitrile (3a) or ethyl cyanoacetate (3b), and
1-naphthol (5) were treated with 25 mol% KHP in water at 50 °C, the 2-amino-4-
aryl-4H-benzo[h]chromenes (6a–h) were obtained in high yields (Table 3, entries
1–8). On replacing 1-naphthol (5) with 2-naphthol (6), the reaction was successful
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Ar
Ar
H
O
2
Ar
O
Z
KHP, 25 mol%
H2O, 50 oC
Z
OH
or
Z
+
or
NH2
O
CN
NH2
OH
3a: Z = CN
5a
5b
3b: Z = CO2Et
7a-l
6a-h
Scheme 4 One-pot, 3CRs for preparation of 2-amino-4-aryl-4H-benzo[h]chromenes (6a–h) and
3-amino-1-aryl-1H-benzo[f]chromenes (7a–l) in the presence of KHP at 50 °C
and 3-amino-1-aryl-1H-benzo[f]chromene derivatives (7a–l) were also isolated in
high yields (Table 3, entries 9–20).
Reaction with compounds with a variety of functional groups on the phenyl ring
proceeded smoothly to give high yields of the products. On the basis of the yields of
the reaction, we concluded that the electronic nature of the substituent had no effect
on reaction yield. However, when aromatic aldehydes with electron-deficient groups
were used as substrates, the reaction time was shorter, because the reaction
proceeded faster than with aromatic aldehydes with electron-rich groups. It was
found that this reaction involving less reactive ethyl cyanoacetate (3b) gave the
corresponding products in lower yield and required longer reaction time than
malononitrile (3a) (Table 3, entries 8 and 18–20); this may be because the cyanide
group stabilized the reaction intermediates better than the ester group.
Among the different attempts to extend the generality of the procedure, the aryl
aldehydes (2) reacted with active methylene-containing compounds (3a, b) and
4-hydroxycoumarin (8), as an activated C–H enolizable substrate in the presence of
25 mol% KHP to give the corresponding 2-amino-5-oxo-4-aryl-4,5-dihydropyr-
ano[3,2-c]chromenes (9a–n) in high yields (Scheme 5).
Representative results are listed in Table 4. Under the optimized reaction
conditions, a wide variety of substituted benzaldehydes, including those containing
electron-deficient (for example, –NO2 and –Cl; entries 2–4, 10, 12 and 13) and
electron-rich (for example, –OCH3, –CH3, –N(CH3)2, –OH; entries 5–7, 9 and 14)
functional groups, and a p-excessive heterocyclic aldehyde (entry 8) were
investigated. The 3CR was almost equally facile with aryl aldehydes; as expected,
reaction of substituted benzaldehydes bearing electron-deficient groups occurred in
higher yields and with shorter reaction times than for the electron-rich counterparts.
In other attempts, the optimized reaction conditions were also applied to
synthesis of 4H-chromene and 4H-pyran derivatives. Use of KHP as catalyst was
investigated for preparation of 4H-chromene and 4H-pyran heterocycles from
aldehydes (2), active nitrile-containing compounds (3a, b), and three enolizable 1,3-
dicarbonyl compounds, 5,5-dimethylcyclohexane-1,3-dione (dimedone) (10), 1,3-
cyclohexanedione (11), and ethyl acetoacetate (14) (Scheme 6).
A wide range of aryl aldehydes with electron-donating and electron-withdrawing
functional groups and p-excessive heterocyclic aldehydes (i.e., furan-2-carbalde-
hyde and thiophene-2-carbaldehyde), were used in these 3CRs, affording the
corresponding 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene derivatives (12a–r,
13a–e). The products were obtained in high yields, as summarized in Table 5.
123

H. Kiyani, F. Ghorbani
Table 3 Scope of the synthesis of 2-amino-4-aryl-4H-benzo[h]chromenes (6a–h) and 3-amino-1-aryl-
1H-benzo[f]chromenes (7a–l) catalyzed by KHPa
Entry Aldehyde
Product
Time (h) Yield
(%)b
Mp (°C)
Lit. [Ref.]
Found
1
4.5
90
91
207-208
210-211 [66]
N
C
H
C
O
2a
2b
NH2
O
N
6a
N
C
O2
2
4
240-242
242-243 [66]
O2
N
C
H
O
NH2
O
6b
6c
3
4
O2
N
N
O2
4
4
91
92
210-212
231-233
210-212 [67]
230-233 [85]
N
C
H
C
O
2c
NH2
O
l
C
l
C
N
C
H
C
O
2d
2e
2f
NH2
O
C
6d
6e
6f
5
6
H
H
H
4.75
4.75
94
93
198-200
187-189
202-204 [75]
C
3
3
N
C
C
O
NH2
O
H
H
188-189 [66]
OC
OC
3
3
N
C
H
C
O
NH2
O
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 3 continued
Entry Aldehyde
Product
Time (h) Yield
(%)b
Mp (°C)
Lit. [Ref.]
Found
7
H
O
H
O
4.5
95
246-247
247-249 [62]
N
C
H
C
O
2g
NH2
O
6g
8
N
O2
N
O2
4.5
92
199-201
198-200 [74]
CO2Et
CHO
2c
NH2
O
O
6h
9
4.75
4.2
91
90
272-274
181-183
273-275 [67]
182-183 [66]
N
C
H
C
O
2a
NH
2 7a
N
O2
10
N
O2
N
C
CHO
2b
NH
2 7b
O
11
12
O2
N
N
O2
4.2
4.5
88
94
189-191
200-201
189-190 [75]
203-205 [67]
N
C
CHO
2c
NH
2 7c
O
l
C
Cl
N
C
CHO
Br
2d
2k
NH
2 7d
O
Br
13
4.2
93
242-243
242-243 [164]
N
C
CHO
NH
2 7e
O
123

H. Kiyani, F. Ghorbani
Table 3 continued
Entry Aldehyde
Product
Time (h) Yield
(%)b
Mp (°C)
Found
Lit. [Ref.]
14
15
H
4.75
89
256-257
256-257 [164]
C
CH3
3
N
C
CHO
2e
NH
O
2 7f
OCH3
CHO
H
OC
4.75
90
185-186
185-186 [164]
3
N
C
2f
NH
O
2 7g
16
17
OH
O
4.5
92
245-247
243-245
245-245 [164]
244-245 [75]
OH
N
C
CHO
2g
NH
2 7h
H
3C
H
C
H
3C
H
5
95
C
3
3
N
N
N
C
CHO
2h
NH
O
2 7i
18
19
6
5
89
90
167-168
189-191
166-168 [74]
188-190 [74]
Et
CO2
NH2
CHO
2a
O
O
O
7j
7k
7l
N
O2
N
O2
Et
CO2
NH2
CHO
2c
20
Cl
Cl
5
90
202-205
202-204 [74]
CO2Et
NH2
CHO
2l
a
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (25 mol%); stirred at 50 °C
Yields refer to those of pure isolated products
b
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Ar
H
O
O
O
2
Ar
O
KHP, 25 mol%
H2O, 50 oC
O
Z
+
Z
OH
CN
O
NH2
3a: Z = CN
3b: Z = CO2Et
8
9a-n
Scheme 5 Tandem cyclocondensation for synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-
c]chromenes (9a–n) in the presence of KHP at 50 °C
The results obtained showed that the electronic nature of the substituent on the
aromatic moiety had little effect on yield. In addition, sterically hindered aldehydes,
for example 2,4-dichlorobenzaldehyde (2n) and 2-nitrobenzaldehyde (2p), also
reacted with malononitrile (3a) and dimedone (10) to give the corresponding
products (12l and 12n) in high yields (entries 12 and 14), although the reactions
proceeded rather slowly. Hence, steric factors had no remarkable effect on the rate
and yield of this 3CR. In all cases, the reaction was clean, and no chromatographic
separation was necessary, because no impurities were observed. It was found that
the rate of reaction of ethyl cyanoacetate (3b) with cyclic 1,3-dicarbonyl
compounds (10 and 11) was slower than that of malononitrile (3a), possibly
because of the lower reactivity of the cyanoacetates. When ethyl acetoacetate (14)
was used as enolizable substrate, the reaction proceeded efficiently, and ethyl
6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate
g) were formed in high yields (Table 5, entries 24–30).
derivatives
(15a–
After successful synthesis of chromenes and 4H-pyran derivatives (described
above), we decided to investigate other 3CR to the synthesis of 3,4-disubstituted
isoxazol-5(4H)-ones (Scheme 2). As usual, the optimum reaction conditions were
studied. Therefore, we investigated three-component synthesis of 4-(4-hydroxyb-
enzylidene)-3-methylisoxazol-5(4H)-one (18d) as a model to find the best reaction
conditions. Table 6 shows the results of these studies. The best reaction conditions
were: 10 mol% KHP, reaction time 30 min, water as solvent, and RT (bold values in
Table 6).
After finding the best conditions, the scope of the procedure was studied by
reaction of different substituted aryl/heteroaryl aldehydes with ethyl acetoacetate
(14) and hydroxylamine hydrochloride (16) in the presence of 10 mol% KHP in
water at RT (entries 1–13). When ethyl 4-chloroacetoacetate (17) was used instead
of ethyl acetoacetate (14) the 3CR proceeded furnishing another type of 3,4-
disubstituted isoxazol-5(4H)-one derivative (entries 15–23). The results for this
3CR are presented in Table 7. The reactions are clean and afford 3,4-disubstituted
isoxazol-5(4H)-ones (18a–t) in excellent yields (88–97 %) in reaction times ranging
time from 30 to 120 min.
It was found that substituted benzaldehydes with electron-rich functional groups
afforded the corresponding products. In addition, reaction with p-excessive
heterocyclic aldehydes also proceeded smoothly with high yields in short reaction
times (entries 6–7, 12, and 18). Sterically hindered aryl aldehydes (2q and 2r) also
123

H. Kiyani, F. Ghorbani
Table 4 Scope of the synthesis of 2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromenes (9a–
n) catalyzed by KHPa
Entry Aldehyde
Product
Time Yield
(h)
Mp (°C)
(%)b
Found
Lit. [Ref.]
257-258 [49]
1
3.5
93
260-262
O
O
O
CHO
2a
N
C
O
NH2
NO2
9a
NO2
2
3
90
258-260
259-260 [49],
O
O
CHO
2b
CN
O
O
NH2
9b
9c
3
4
O2N
N
3
3
88
95
259-260
265-266
258-260 [49], 259-
260 [166]
O2
O
O
O
CHO
2c
CN
NH2
l
264-266 [49], 265-
266 [166]
C
l
C
O
O
CHO
CN
2d
2e
O
O
NH2
9d
9e
H
C
5
H
C
5
91
257-259
258-260 [49], 257-
259 [166]
3
3
CHO
N
C
NH2
6
7
4
4
89
95
235-236
259-261
235-237 [49]
OCH3
CHO
OC
H
3
O
O
O
O
CN
NH2
2f
O
O
9f
OH
O
H
260-261 [49], 259-
261 [166]
CHO
CN
2g
NH2
9g
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 4 continued
Entry Aldehyde
Product
Time Yield
(h)
(%)b
Mp (°C)
Found
Lit. [Ref.]
8
2.75
93
252-254
252-253 [43]
O
O
O
CHO
O
2i
CN
NH2
O
9h
OH
9
H
4
8
96
81
252-254
252-255
253-254 [40], 252-
254 [166]
O
H3CO
H3CO
O
O
CHO
2m
CN
O
NH2
9i
Cl
10
253-255 [49], 253-
255 [166]
C
l
O
O
Cl
Cl
CN
O
O
CHO
2n
O
O
NH2
9j
11
12
4
3
81
92
209-210
231-232
187-189 [51]
242-244 [51]
CHO
2a
CO2Et
NH2
9k
NO2
NO2
O
O
CHO
2b
CO2Et
NH2
O
9l
13
14
Cl
l
3
5
89
83
192-193
196-197
193-194 [51]
C
O
O
O
O
CHO
CO2Et
2d
O
O
NH2
9m
CH3
195-197 [166]
C
H
3
CHO
CO2Et
NH2
2e
9n
a
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (25 mol%); stirred at 50 °C
Yields refer to those of pure isolated products
b
123

H. Kiyani, F. Ghorbani
Ar
O
O
Z
O
NH2
O
Ar
O
O
O
O
O
O
10
or
12a-r
Z
O
KHP, 25 mol%
H2O, 50 o
14
O
NC
Z
+
+
H
or
Ar
C
KHP, 25 mol%
H2O, 50 o
3a: Z = CN
H2N
Ar
O
O
3b: Z = CO2Et
C
Z
3
Z = CN, 15a-g
NH2
O
13a-e
11
Scheme 6 One-pot, 3CRs for preparation of 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene derivatives
(12a–r, 13a–e) and ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3-carboxylate derivatives (15a–
g) in the presence of KHP at 50 °C
afforded the desired products (entries 10 and 20). Interestingly, when 4-hydroxy-3-
nitrobezaldehyde (2s), which contains both electron-accepting (–NO2) and electron-
donating (–OH) functional groups, was used, the corresponding product (18k) was
obtained in a shorter reaction time and with higher yield (entry 11). Accordingly, it
is concluded that this reaction is affected by electron-donor functional groups and
their position on the phenyl ring. Attempts to react aromatic aldehydes bearing
electron-deficient groups and p-deficient heterocyclic aldehydes were unsuccessful,
even after 12 h under the optimized reaction conditions.
Although the exact mechanism of these transformations is not completely clear,
on the basis of our previous work [164–166] a feasible reaction mechanism for
formation of the final chromene and pyran products (4, 6, 7, 9, 12, 13, and 15) is
proposed in Scheme 7. Dissociation of KHP in water gave the potassium cation
(K?) and the hydrogen phthalate anion (HP-). Hydrogen phthalate reacts reversibly
with water to furnish hydronium (H3O?) and phthalate anions (P2-). Removal of the
acidic hydrogen from active methylene nitriles (3a, b) by P2- leads to generation of
arylidenenitrile anions A. The arylidene nitrile intermediates F (Knoevenagel
adducts) are then formed by Knoevenagel condensation of activated aldehydes
B with intermediate arylidenenitrile anions A. The intermediates F then participate
in Michael-type addition with the enolizable compounds, giving rise to in-situ
formation of intermediates G (Michael adducts), which subsequently undergo
intramolecular nucleophilic cyclization (Thorpe–Ziegler type reaction) and tauto-
merization to afford the desired pyran-based heterocyclic compounds.
To validate the suggested mechanism, we synthesized 4b in two steps under
similar conditions (Scheme 8). In the first step, the Knoevenagel condensation
product 19b was prepared. Measurement of the melting point of solid 19b and
comparison with that of the known compound (prepared in accordance with
Ref. [153]), confirmed formation of the arylidene malononitrile intermediate 19b in
this step. Also, the FT-IR spectrum of intermediate 19b contained a nitrile peak at
2,220 cm-1, suggesting formation of a malononitrile. Reaction of intermediate 19b
with resorcinol (1) gave product 4b, similar to the one-pot reaction. Additional
evidence was obtained by TLC analysis of the model reaction. TLC analysis 7 min
after initiation of the reaction showed that the spots of 3-methylbenzaldehyde and
malononitrile had disappeared and a new spot had appeared. The new spot is that of
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 5 Scope of the synthesis of 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene derivatives (12a–r,
13a–e) and ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3-carboxylate derivatives (15a–g) cata-
lyzed by KHPa
Entry Aldehyde
Product
Time (h)
3.25
Yield
Mp (°C)
Lit. [Ref.]
(mol%)b
Found
1
95
94
222-224
223-224 [78]
230-232 [80]
O
H
C
O
N
C
2a
O
N
NH
2 12a
N
C
O2
O2
2
3
183-185
179-180 [78]
180-181 [80]
O
H
O
N
C
2b
O
NH
2 12b
N
3
4
N
O2
3
93
96
209-210
210-212
208-209 [78]
O2
O
CHO
C
N
2c
O
C
NH
2 12c
l
3.2
208-209 [78]
215-215 [80]
l
C
O
N
C
CHO
2d
2e
O
C
NH
2 12d
2 12e
2 12f
2 12g
H
5
6
7
3.75
3.75
3.75
91
91
92
216-218
198-199
220-223
217-218 [78]
224-225 [80]
H
C
3
3
O
O
O
CN
NH
CHO
O
OCH3
198-200 [78]
202-203 [80]
OCH3
CHO
N
C
2f
O
O
NH
H
204-205 [78]
220-222 [80]
OH
N
C
CHO
2g
O
NH
123

H. Kiyani, F. Ghorbani
Table 5 continued
Entry Aldehyde
Product
Time (h)
Yield
(mol%)
Mp (°C)
Lit. [Ref.]
b
Found
H3C
8
H3C CH3
N
CH3
4
97
209-210
201-202 [78]
N
O
O
O
O
CHO
CN
2h
NH
2 12h
2 12i
2 12j
9
3.25
3.2
94
95
225-227
217-220
225-226 [80]
216-218 [80]
O
O
S
CHO
CN
NH
2i
O
O
10
S
CHO
CN
NH
2j
OH
OH
11
12
13
3.75
4.25
3.5
94
90
93
240-242
192-194
226-227
239-242 [165]
192-193 [78]
224-226 [36]
H3CO
H3CO
O
CHO
CN
NH
2m
O
2 12k
Cl
Cl
Cl
CN
Cl
CHO
O
2n
O
NH
2 12l
HO
HO
O
C
HO
CN
NH
2o
O
O
O
2 12m
14
15
3
93
88
220-222
155-157
223-224 [78]
157-158 [80]
NO2
CN
NO2
CHO
O
O
2p
NH2
12n
5.5
t
C
HO
CO2E
2a
NH2
12o
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 5 continued
Entry Aldehyde
Product
Time (h)
4
Yield
(mol%)
Mp (°C)
Lit. [Ref.]
b
Found
NO2
16
17
O2N
90
153-155
154-156 [51]
O
t
t
CO2E
CHO
2c
NH2
O
12p
12q
Cl
4
92
147-149
156-157
154-155 [80]
139-142 [51]
Cl
O
CO2E
NH2
CHO
2d
O
N
18
H3C CH3
N
H
5.75
94
156-157 [165]
H3C
C
3
O
CHO
t
CO2E
2h
NH2
O
12r
19
20
21
22
23
Cl
O
3.3
3.25
3
90
93
94
94
93
165-167
222-224
218-220
225-226
223-225
163-165 [51]
221-222 [83]
Cl
O
O
O
O
t
t
CO2E
CHO
2d
NH2
13a
13b
NO2
NO2
CO2E
NH2
CHO
2b
O
Cl
228-229 [80]
203-205 [83]
Cl
CN
NH
CHO
2d
O
2 13c
CH3
4
224-226 [80]
220-221 [83]
CH3
CN
NH
CHO
2e
O
2 13d
H3C CH3
N
H3C
O
4.25
223-224 [83]
CH3
N
CHO
CN
NH
2h
O
2 13e
123

H. Kiyani, F. Ghorbani
Table 5 continued
Entry Aldehyde
Product
Time (h)
5
Yield
(mol%)
Mp (°C)
Lit. [Ref.]
b
Found
24
88
192-194
195-196 [36]
CHO
EtO2C
N
C
2a
O
NH
2 15a
NO2
N
O2
25
4
93
180-182
176-178 [82]
180-183 [36]
CHO
EtO2C
N
C
2b
O
NH
2 15b
N
26
27
O2N
O2
4
4
91
89
172-173
172-173
171-173 [82]
172-174 [36]
CHO
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
N
C
2c
O
NH
2 15c
Cl
Cl
N
C
CHO
2d
2e
O
NH
2 15d
2 15e
2 15f
2 15g
H
28
29
30
C
4.5
4.5
4.5
90
92
92
178-181
141-143
174-177
177-179 [79]
CH3
3
N
C
CHO
O
NH
OCH3
136-138 [81]
142-144 [36]
OCH3
CHO
N
C
2f
O
O
NH
H
175-177 [79]
OH
N
C
CHO
2g
O
NH
a
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (25 mol%); stirred at 50 °C
Yields refer to those of pure isolated products
b
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 6 Optimization of the catalytic three-component synthesis of 4-(4-hydroxybenzylidene)-3-
methylisoxazol-5(4H)-one (18d)
O
O
H
H
C
3
KHP
H
O
C
H
3
+
.
NH2OH HCl
+
H
O
Solvent (5 mL), Temp.
O
N
O
O
O
2g
Entry Solvent
14
16
18d
Amounts of catalyst (mol%) Time (min) Temp. (°C) Isolated yield (%)
1
H2O
None
5
30
30
RT
RT
RT
RT
RT
50
10
82
96
97
94
88
40
35
40
35
40
Trace
35
45
60
40
2
H2O
3
H2O
H2O
10
15
20
10
10
10
10
10
10
10
10
10
30
4
30
5
H2O
30
6
H2O
40
7
H2O
40
75
8
H2O
50
100
RT
RT
RT
RT
RT
RT
RT
RT
9
EtOH
CH3CN
100
120
120
300
150
120
80
10
11
12
13
14
15
16
1,4-dioxane
THF
Hexane
Acetone
H2O/EtOH (1:1) 10
No solvent 10
120
Reaction conditions: 1 mmol of all substrates and catalyst stirred at different temperatures
The optimum conditions are shown in bold
the condensation product 19b, which is evidence in support of the suggested
pathway.
Another pathway could be proposed for this reaction (Scheme 9). Under the
optimum reaction conditions, the reaction between resorcinol (1) and 4-nitrobenz-
aldehyde (2b) was investigated. Increasing the reaction time to 3 h did not lead
exclusively to formation of 4b. It can be concluded that the reaction proceeds via the
mechanism suggested in Scheme 7.
Encouraged by the results above and the importance of a,b-unsaturated nitriles as
valuable intermediates in the preparation of fine chemicals, we decided to perform
the Knoevenagel reaction with wide ranges of aryl aldehydes and cyano-containing
compounds (3a, b) (Scheme 10). In this reaction, a,b-unsaturated nitriles (19a–
w) were obtained in excellent yields and short reaction times.
In this case, condensation of benzaldehyde (2a) with malononitrile (3a) was
chosen as model reaction to find the best reaction conditions. It was found that the
maximum product yield was obtained after 5 min when the reaction was conducted
in the presence of 5 mol% KHP at room temperature (Table 8, entry 1). On the basis
of these optimum reaction conditions, a variety of aryl aldehydes were reacted with
123

H. Kiyani, F. Ghorbani
Table 7 Scope of the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones (18a–t)a
Entry Aldehyde
Product
Time Yield
(min) (%)b
Mp (°C)
Found
Reportedc
141-143
1
60
90
140-142
CHO
H
C
3
2a
N
O
O
18a
2
45
95
135-137
135-136
H3C
CHO
H
H
3C
H
C
3
2e
N
O
O
18b
3
4
45
30
95
96
175-177
213-215
174-176
214-216
H3CO
CHO
3CO
H
C
3
2f
N
O
O
18c
H
O
H
O
CHO
CHO
H
C
3
2g
N
O
O
18d
H3C
H
H
3C
5
35
95
227-229
227-228
N
N
H
C
3
H3C
3C
2h
N
O
O
18e
6
7
8
9
120
30
88
96
97
93
239-241
146-147
213-215
201-203
238-241
146-147
214-215
202-203
H
C
3
CHO
CHO
O
O
2i
N
O
O
O
18f
H
C
3
S
S
2j
N
O
O
18g
30
CHO
HO
H
O
H
C
3
H3CO
H
3CO
N
O
2m
18h
35
CHO
H
C
3
H
2o
H
O
O
N
O
O
18i
H
O
H
O
10
11
40
40
91
88
198-200
268-269
198-201
267-268
CHO
H
C
3
2q
N
O
O
18j
O2N
N
O2
HO
CHO
H
O
H
C
3
2s
N
O
O
18k
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 7 continued
Entry Aldehyde
Product
Time Yield
(min) (%)b
Mp (°C)
Reportedc
Found
S
S
12
13
30
95
146-148
146-147
CHO
H
C
3
2t
N
O
O
18l
O
O
O
100
90
243-244
242-244
CHO
H
C
3
O
N
O
O
2u
O
18m
14
15
60
40
91
94
118-123
175-178
183-186
175-177
H
C
O
H
C
l
2C
2a
N
O
18n
H3CO
CHO
H
3CO
H
2C
l
C
2f
N
O
O
18o
16
17
35
45
95
94
184-186
178-180
183-186
179-180
H
O
H
H
O
C
O
H
l
C
2C
2g
N
O
O
18p
H3C
H
H
3C
N
CHO
N
H
l
C
2C
H3C
3C
2h
N
O
O
18q
18
19
20
45
35
60
96
97
90
145-147
141-143
205-207
146-148
142-145
-
H l
C 2C
H
C
O
S
S
2j
N
O
O
18r
CHO
HO
H
O
H
l
C
2C
H3CO
H
3CO
N
O
O
2m
18s
OH
CHO
H
O
N
N
H
C
l
2C
2r
N
O
O
18t
a
b
c
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (10 mol%); stirred at RT
Yields refer to those of pure isolated products
Melting points are listed in Refs. [114–116, 120–131]
123

H. Kiyani, F. Ghorbani
P2- + H3O+
K+HP- + H2O
O O
O O
-O
O-
HO
HP-
O-
O
P2-
H
H
Ar
2
NC
Z
HP-
NC
H
Ar
Z
NC
P2-
O
+
NC
Z
H
Z
H
+
Ar
Ar
OH
OH2
3a,b
B
A
D
C
P2-
O
OH
K+
O
K+HP-
HP-
- P2-
CN
Ar
+
Enolization
Z
Michael
addition
F
Knoevenagel
adducts
1, 5, 8, 10, 11 and 14
E
Ar
Z
Ar
Ar
Z
Thorpe-Ziegler
type reaction
H
C
H
Z
Tautomerization
K+HP-
+
C
O-attack
O
NH2
O
NH
O
N
G
4, 6, 7, 9, 12, 13 and 15
H
Michael adducts
Scheme 7 Proposed mechanism for formation of final products 4, 6, 7, 9, 12, 13, and 15
NO2
O
HO
OH
NC
H
CN
KHP, H2O
+
1
NC
CN
O2N
O2N
CN
2b
3a
19b
NH2
O
HO
4b
Scheme 8 The synthesis of 4b from 2b and 3a in two steps under the optimum condition reactions
OH
O
O
NC
CN
KHP, H2O
3a
H
+
4b
OH
O2N
OH
NO2
1
2b
20
Scheme 9 Synthesis of 4b from 1 and 2b in two steps under the optimum condition reactions
malononitrile (3a) in the presence of KHP in water (Table 8). Both electron-rich
and electron-deficient substituted benzaldehydes reacted well and gave excellent
product yields in short reaction times. Substituted benzaldehydes bearing electron-
rich substituents needed more time than their electron-deficient counterparts (entries
1–8 and 10–12), however. Furan-2-carbaldehyde as electron-rich heterocyclic
123

Efficient tandem synthesis of a variety of pyran-annulated heterocycles
Table 8 KHP-catalyzed Knoevenagel condensation of a variety of aryl aldehydes with active methy-
lene-containing compounds (3a, b) for synthesis of a,b-unsaturated nitriles (19a–w) in water at RTa
Entry Aldehyde
Product
Time Yield
(min) (%)b
Mp (°C)
Lit. [Ref.]
Found
84-85
CHO
H
1
5
98
83-84 [153]
CN
CN
2a
19a
C
HO
H
5
95
159-161
161-162 [153]
2
CN
CN
O2N
O2N
2b
2c
O2N
O2N
19b
19c
3
4
CHO
H
6
5
93
94
102-104
163-164
103-104 [144]
164-165 [153]
CN
CN
CHO
H
CN
CN
Cl
2d
Cl
19d
H
5
6
CHO
6
6
95
97
129-131
112-113
133-134 [153]
113-115 [144]
CN
CN
H3C
2e
H3C
19e
CHO
H
CN
CN
H3CO
2f
H3CO
19f
H
C
HO
7
8
7
7
99
99
188-189
178-180
188-189 [150]
179-180 [150]
CN
HO
H3C
2g
CN
HO
19g
CHO
H
CN
CN
N
CH3
H3C
2h
N
CH3
19h
H
9
C
HO
10
12
94
95
68-70
69-70 [153]
O
CN
CN
2i
O
18i
H3CO
HO
CHO
H
10
135-136
135-136 [150]
H
3CO
CN
CN
2m
HO
19j
H
11
Cl
C
l
10
92
154-156
154-155
CHO
CN
CN
Cl
Cl
2n
19k
123

H. Kiyani, F. Ghorbani
Table 8 continued
Entry Aldehyde
Product
Time Yield
(min) (%)b
Mp (°C)
Lit. [Ref.]
Found
95-96
12
13
14
CHO
Cl
Cl
H
15
10
10
92
91
93
92-93 [144]
48-49 [153]
173-174 [153]
CN
CN
2t
19l
CHO
H
47-48
CN
2t
t
CO2E
19m
CHO
H
170-172
CN
O2N
O2N
2b
2c
E
t
CO2
O2N
19n
H
15
CHO
10
92
129-130
127.6-128.3
[146]
CN
O2N
t
CO2E
19o
CHO
H
16
17
18
10
12
12
93
93
93
92-93
89-90
80-81
89-90 [153]
90-92 [153]
CN
Cl
2d
t
CO2E
Cl
19p
CHO
H
CN
CN
H3C
2e
H3C
19q
CHO
H
81.8-82.3
[146]
CN
H3CO
2f
t
CO2E
H3CO
19r
CHO
CHO
H
19
20
15
15
94
96
169-170
123-125
169-170 [150]
CN
HO
H3C
2g
t
CO2E
HO
19s
H
124.8-125.2
[146]
CN
N
CH3
H3C
CO2Et
2h
N
CH3
19t
H3CO
HO
CHO
H
21
15
93
110-111
109.8-110.2
[146]
CN
H3CO
2m
CO2Et
HO
19u
Cl
C
l
H
22
23
12
18
92
90
84-85
50-52
83.8-84.5
[146]
CHO
CN
CN
Cl
Cl
Cl
2n
19v
C
l
H
52-53 [144]
CHO
CN
CO2Et
2t
19w
a
Reaction conditions: substrates 1 mmol; water (5 mL); KHP (5 mol%); stirred at RT
Yields refer to those of pure isolated products
b
123