Organocatalyzed domino reactions: diversity oriented synthesis of pyran-annulated scaffolds using in situ-developed benzylidenemalononitriles

Article abstract of DOI:10.1007/s11164-016-2772-8

Molecular diversity for the synthesis of pyran annulated heterocyclic scaffolds has been achieved from the multicomponent reaction of aldehyde, malonitrile and a third participant such as dimedone, barbituric acid and 3-methyl-1H-pyrazol-5(4H)-one. The re

Full text of DOI:10.1007/s11164-016-2772-8

Res Chem Intermed
DOI 10.1007/s11164-016-2772-8
Organocatalyzed domino reactions: diversity oriented
synthesis of pyran-annulated scaffolds using in situ-
developed benzylidenemalononitriles
Abdul Ahad1 Maqdoom Farooqui1
•
Received: 31 July 2016 / Accepted: 8 October 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Molecular diversity for the synthesis of pyran annulated heterocyclic
scaffolds has been achieved from the multicomponent reaction of aldehyde,
malonitrile and a third participant such as dimedone, barbituric acid and 3-methyl-
1H-pyrazol-5(4H)-one. The reactions completed successfully using in situ-devel-
oped benzylidenemalononitriles via Knoevenagel reaction catalyzed by aspartic
acid as a new efficient organo-catalyst in aqueous ethanol as a green medium at
ambient conditions.
Keywords Multicomponent reactions Á Pyran annulated heterocyclic scaffolds Á
Aqueous ethanol Á Aspartic acid
Introduction
Pyran annulated molecules are the core fragment of many natural products [1].
These potentially active scaffolds have a broad spectrum of physiological activities
[2, 3]. The ‘‘privileged’’ motif containing structures exhibits activities like diuretic
[4], anticancer [5], anticoagulant [6], anticonvulsant [7], antimicrobial [8], anti-HIV
[9], antimalarial [10], anti-tumour [11] antihyperglycemic and antidyslipidemic
[12]. Also, many of them are used in Huntington’s and Alzheimer’s, Parkinson
disease [13] and many more [14, 15]. Moreover, different substituted 4H-pyran
derivatives have played increasing roles in synthetic approaches to promising
molecules in the field of agrochemicals [16], medicinals [17, 18], and the cosmetics
industries [19]. Some of the naturally occurring and synthetic pyran annulated
&
Maqdoom Farooqui
maqdoomf789@gmail.com
1
Post Graduate and Research Center, Dr. Rafiq Zakaria Campus, Maulana Azad College,
Rouza Baugh, Aurangabad, M.S, India
123

A. Ahad, M. Farooqui
EtOOC
COOEt
CN
C6H4OMe-p
CN
O
O
OH
F3C
N
Br
O
N
O
3
NH2
O
1
NH2
HO
OH
p-F C6H4
2
Antitumor
Anticancer
Anticancer & Bci-2 inhibitor
NH2
OH
OH
NH2
CN
O
CN
Ar
O2N
O
HO
O
O
NO2
OH
Antihepatitis B virus
Fig. 1 Some pyran-containing pharmaceutical drug scaffolds
O
5
4
6
Anti-rheumatic
Anticancer
molecules are shown in Fig. 1 1–6, which shows a diverse and wide range of
pharmaceutical potentials [20–27].
Such a numerous application of pyran annulated heterocyclic compounds in
medicinal chemistry have produced substantial interest among synthetic chemists
during the last few years to develop efficient and convenient synthetic protocols for
these privileged scaffolds. Consequently, so many methods and strategies are already
reported, which includes use of ultrasonic irradiation [28], microwaves [29] and a
variety of catalysts and reagents such as DBU [30], heteropolyacids [31], diammo-
nium hydrogen phosphate [32], DMAP [33], basic ionic liquids [34], ZnO-b-Zeolite
[35], tetrabutylammonium bromide [36], iodine [37], nano MgO [38], phenylboronic
acid [39], b-cyclodextrin [40], alum [41], Zn[(L)proline] [42], Amberlyst A21 [43],
aminopro-pylated-SiO2 [44], magnetic nanocatalyst [45], (S)-proline [46], Amberlite
IRA-40 (OH) [47] and urea [48]. However some of these methods suffer from
limitations such as elevated temperatures, use of strong corrosive acids, unsatisfactory
yields, long reaction time, high catalytic loading and use of hazardous solvents and, in
some cases, the need to use ultrasonic or microwave irradiation. However, some of the
heterogeneous catalysts and nano-particles promoted methods that provide better
results, but they are not only costly, their preparation requires tiresome methods and
results in low yields. Thus, the development of a new, convenient and readily available
procedure that avoids many of these problems is extremely desirable.
Aspartic acid is an amino acid broadly used in different sectors such as the
pharmaceutical, agriculture, cosmetics industries, and they are used as nutrition
supplements in the food and beverage industries [49–52]. Aspartic acid is safe,
readily available, nontoxic and of low cost. Our literature search at this stage
revealed that there are no reports on the synthesis of 2-amino-3-cyano-4H-pyrans,
1H-Pyrano[2,3-d] pyrimidine-2,4(3H,5H)-diones and 1,4-dihydropyrano [2,3-c]
pyrazoles catalyzed by aspartic acid as an efficient organo-catalyst in an aqueous
ethanol medium. As part of our investigations aimed at developing newer
123

Organocatalyzed domino reactions: diversity oriented…
O
H3C
O
O
H3C
3
O
HN
NH
H3C
N
7
O
N
H
O
5
Aspartic Acid
R.T
O
1
CN
CN
O
R
R
H
2
R
O
H3C
HN
CN
EtOH:H2O
HN
CN
O
N
H
O
NH2
N
NH2
6a-f
8a-h
O
R
O
CN
H3C
H3C
NH2
4a-h
Scheme 1 Diversity oriented synthesis of pyrans using aspartic acid as a catalyst
convenient, efficient and environmentally friendly methodologies for some diverse
heterocyclic scaffolds [53–56], and following our interest in organo-catalysis
herein, we wish to report an efficient and simple protocol for the diversity oriented
synthesis of 2-amino-3-cyano-4H-pyrans, 1H-pyrano [2,3-d] pyrimidine-2, 4
(3H,5H)-diones and 1,4-dihydropyrano[2,3-c] pyrazoles (Scheme 1).
Experimental
All the chemicals were obtained from commercial sources and used without further
purification. To monitor progress of the reaction by TLC, silica gel-coated aluminum
sheets (Merck made) were used. Melting points were determined in an open glass
capillary tube and are uncorrected. The NMR spectra were recorded on a Bruker
Advance DPX-250. Mass spectra were recorded on a Waters Mass spectrometer.
General procedure for the synthesis of 2-amino-3-cyano-4H-pyrans(4a–4h),
1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones (6a–6f) and 1,4-dihydropyrano
[2,3-c]pyrazoles (8a–8h)
A 25 mL round bottom flask was charged with aldehyde 1 (1 mmol), malononitrile 2
(1.1 mmol) and aspartic acid (20 mol%) in 4 mL EtOH: H2O (1:1), the reaction mixture
123

A. Ahad, M. Farooqui
was then stirred vigorously at room temperature for about 10 min. After that, the third
reactant, dimedone3/barbituricacid5/3-methyl-1H-pyrazol-5(4H)-one7(1 mmol)was
added to the reaction mixture, and stirring was continued for an appropriate time at
ambient temperature as mentioned in respective tables in the text. On completion of the
reaction (as monitored by TLC), water(5 mL) was added and stirring was continued
until a solid mass precipitated out that was filtered off and washed with water to obtain a
crudeproduct.Thedriedcrudeproductwassuccessivelywashedbyamixtureofhexane:
ethyl acetate (80:20) and then dried, to obtained the desired pure product.
Selected spectral data
2-amino-7, 7-dimethyl-5-oxo-4-phenyl-5, 6, 7, 8-tetrahydro-4H-chromene-3-
carbonitrile (4a) M P. 230–232 °C; 1H NMR (400 MHz, DMSO) d (ppm):
7.24–7.27 (m, 2H), 7.15–7.18 (m, 3H), 6.82 (brs, 2H), 4.20 (s, 1H), 2.52 (2H, s)
2.44–2.54 (d, 2H), 2.25 (d, 1H), 2.09 (d, 1H), 1.07 (s, 3H), 0.98 (s, 3H); 13C NMR
(100 MHz, DMSO) d (ppm): 195.6, 162.4, 158.4, 144.7, 128.3, 127.1, 126.5, 119.7,
112.6, 58.31, 49.9, 35.5, 31.7, 28.3, 26.7.; Mass (m/z) = 295.1 [M ? 1].
2-amino-4-(4-methoxyphenyl)-7, 7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chro-
mene-3-carbonitrile (4f) M P. 201–203 °C; 1H NMR (400 MHz, DMSO) d (ppm):
7.04–7.07 (d, 2H), 6.83 (s, 2H), 6.79–6.82 (d, 2H), 4.14 (s, 1H), 3.72 (s, 3H), 2.22 (d,
1H), 2.08 (d, 1H), 1.08 (s, 3H), 0.97 (s, 3H).; 13C NMR (100 MHz, DMSO) d (ppm):
196.1, 162.5, 158.8, 158.3, 137.2, 128.6, 120.2, 114.0; Mass (m/z) = 323.2 [M - 1].
7-Amino-5-(4-chlorophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrim
1
idine-6-carbonitrile (6b) M P. 232–234 °C; H NMR (400 MHz, DMSO-d6) d
(ppm): 11.12 (s, 1H), 7.35(d, 2H), 7.25 (d, 2H), 7.19 (s, 2H) 4.25 (s, 1H); 13C NMR
(100 MHz, DMSO) d (ppm): 162.9,158.0, 152.8, 149.8, 143.4, 131.6, 129.6, 128.5,
119.4, 88.3, 58.6, 35.5. Mass (m/z) = 315.1 [M - 1].
6-amino-4-(4-methoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (8b) M P. 172–174 °C; 1H NMR (400 MHz, DMSO) d (ppm): 12.00
(s, 1H), 7.07 (d, 2H), 6.83(d, 2H), 6.71 (s, 2H), 4.51 (s, 1H), 3.74 (s, 3H), 1.79 (s,
3H); 13C NMR (100 MHz, DMSO) d (ppm): 160.6, 157.8, 154.7, 136.3, 135.3,
128.3, 120.7, 113.5, 97.6, 57.6, 54.8, 35.5, 9.7; Mass (m/z) = 283.2 [M ? 1].
6-amino-4-(4-chlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitrile (8e) M P. 170–172 °C; 1H NMR (400 MHz, DMSO): d (ppm): 12.06 (s,
1H), 7.34 (d, 2H), 7.19 (d, 2H), 6.82 (s, 2H), 4.59(s, 1H), 1.80 (s, 3H); 13C NMR
(100 MHz, DMSO) d (ppm): 160.8, 154.6, 143.2, 135.4, 131.3, 129.1, 128.2, 120.5,
96.9, 56.8, 35.7, 9.7; Mass (m/z) m/z = 287.1 [M ? 1].
Results and discussion
Herein, we wish to report a convenient and facile access to some highly substituted
2-amino-3-cyano-4H-pyrans, 1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and
1,4-dihydropyrano[2,3-c]pyrazoles via one-pot three component reaction of
123

Organocatalyzed domino reactions: diversity oriented…
aldehydes, malonitrile and dimedone/barbaturic acid/3-methyl-1H-pyrazol-5(4H)-
one in aqueous ethanol medium promoted by aspartic acid. Preliminary observations
were mainly conducted on a number of trial reactions of dimedone (1 mmol),
anisaldehyde (1 mmol) and malonitrile (1.1 mmol) in the presence of different
catalysts in ethanol at room temperature for the synthesis of 2-amino-3-cyano-4H-
pyrans. The catalyst-free reaction gave a mixture of products that included some
amounts of the desired product (Table 1, entry 1). Sodium azide, sodium saccharin,
and alanine afforded the desired product in moderate yield (Table 1, entry 2–4). The
reaction furnished the product in 80 % yield within 1 h (Table 1, entry 5) when
aspartic acid as a catalyst was used. Aspartic acid is an amino acid with two
carboxylic groups in its structure whereas alanine has one, and the presence of two
carboxylic groups may be relevant to the unique role of aspartic acid for maximum
yield than does alanine. The yield and the rate of the aspartic acid-catalyzed reaction
were quite better when ethanol was used as a solvent (Table 1, entry 5). This shows
that the aspartic acid exhibited a good catalytic activity for the synthesis of 2-amino-
3-cyano-4H-pyrans.
Table 1 Optimization of the reaction conditions for the synthesis of 2-amino-3-cyano-4H-pyrans
OCH3
O
O
Catalyst, Solvent
R.T
CHO
CN
CN
CN
H3C
H3C
H3C
H3C
O
MeO
O
NH2
3
4f
2
1
Entry
Catalyst (20 mol%)
Solvent
Time (h)
Yield (%)a
1
None
EtOH
10
9
8
6
1
3
3
2
2
4
3
3
1
1
1
20
38
52
50
80
40
25
60
55
45
65
70
96
89
94
2
Sodium azide
Sodium saccharin
Alanine
EtOH
3
EtOH
4
EtOH
5
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid
Aspartic acid (10 %)
Aspartic acid (25 %)
EtOH
6
MeOH
7
Dioxane
Acetonitrile
DCM
8
9
10
11
12
13
14
15
a
Toulene
H2O
ACN:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
Isolated yields
123

A. Ahad, M. Farooqui
Next, we studied the effects of other solvent systems on the model reaction;, we
used different solvents, such as MeOH, dioxane, acetonitrile, DCM, toulene, water,
ACN: water (1:1) and EtOH: Water (1:1) in presence of a catalytic amount
(20 mol%) of aspartic acid at room temperature. Water alone as a reaction medium
provided considerably better yield (Table 1, entry 11), but the product was obtained
as a sticky solid material. As can been seen in (Table 1, entry 13), the aspartic acid
catalyzed reaction in ethanol: Water (1:1, v/v) led to higher yields in shorter
reaction times than the others. As a consequence, ethanol: Water (1:1, v/v) was
nominated as the suitable solvent. Recently, we have reported an organo-catalyzed
synthesis of isoxazoles in aqueous ethanol medium at room temperature [55]. In
pursuance of making the methodology economical and green, water: ethanol (1:1,
v/v) was found to be an ideal medium. Moreover, we tried to optimize the reaction
by varying the amount of aspartic acid. When 20, 10 and 25 mol% of aspartic acid
were used, the yields were 96, 89 and 94 %, respectively (Table 1, entry 13–15).
Therefore, 20 mol% of aspartic acid was found to be an optimal amount for the
reaction completion. To explore the effectiveness and generality of the protocol, the
present observations were extended to different aromatic aldehydes having electron
releasing/withdrawing substituents such as methoxy, nitro, hydroxyl, methyl,
halogens and so on (Table 2, entry 1–8). All the reactions smoothly resulted in the
formation of corresponding 2-amino-3-cyano-4H-pyrans in greater yields
(90–96 %). The pure products were isolated without chromatographic purification
just by washing with water and then a mixture of hexane: Ethyl acetate, as on
completion of the reaction most of the products come out as solid precipitate in the
reaction vessel. All the products are quite stable in aqueous media (Scheme 2).
Encouraged by these results and to illustrate the applicability of our procedure,
we endeavored to continue the aspartic acid catalyzed protocol to find out whether
the protocol could explore similar results in the case of other multicomponent
reactions, which involved an in situ formed benzylidene malononitrile intermediate.
Here we used barbaturic acid as an active methylene compound instead of dimedone
along with anisaldehyde and malonitrile as the model substrates (Scheme 3).
Table 2 Multicomponent condensation of aromatic aldehydes, dimedone, and malononitrile
Entry
R
Product
Time (h)
Yield (%)a
M. p. (°C)
Observed
Literature
1
2
3
4
5
6
7
8
a
C6H5
4a
4b
4c
4d
4e
4f
1
93
95
92
94
95
96
94
95
230–232
212–214
216–218
200–202
217–220
201–203
218–220
200–202
224–226 [48]
215–217 [29]
204–206 [48]
201–203 [44]
208–210 [34]
199–201 [29]
223–225 [44]
193–195 [34]
4-Cl–C6H4
3-NO2–C6H4
2-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
4-OH–C6H4
4-(Br)–C6H4
1.5
2
1.5
1
1
4g
4h
1.5
1.5
Isolated yields
123

Organocatalyzed domino reactions: diversity oriented…
R
O
CHO
O
Aspartic acid
(20mo%)
CN
NH2
CN
CN
H3C
H3C
H3C
H3C
EtOH: H2O, R.T
O
O
R
1
3
2
4a-h
Scheme 2 The efficient synthesis of 2-amino-3-cyano-4H-pyrans
R
O
O
Aspartic acid(20mo%)
CHO
1
CN
CN
CN
2
HN
HN
EtOH: H2O, R.T
R
O
N
H
O
NH2
O
N
H
O
5
6a-f
Scheme 3 The efficient synthesis of 1H-Pyrano [2, 3-d] pyrimidine-2, 4(3H, 5H)-diones
The C–H activated barbituric acid underwent reaction very smoothly with
malonitrile and anisaldehyde under the similar optimized reaction conditions. The
desired products 1H-Pyrano [2, 3-d] pyrimidine-2, 4(3H, 5H)-diones (Table 3,
entries 1–6) with other aldehydes were equally formed in maximum yields
(80–90 %) within the limited time period. As it can be seen from Table 3, the
electronic nature of the groups on benzaldehyde has an insignificant effect on the
conversion.
After developing a general and common procedure for the synthesis of 2-amino-
3-cyano-4H-pyrans, as well as 1H-Pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones, we
focused our interest towards another significant pyran-annulated heterocycle,
namely pyrano [3,2-c] pyrazoles (Scheme 4), since the molecules belonging to this
scaffold hold a position of eminence owing to their human chk1 inhibitor activity
Table 3 Synthesis of pyrano [2, 3-d] pyrimidinones
Entry
R
Product
Time (h)
Yield (%)a
M.p. (oC)
Observed
Literature
1
2
3
4
5
6
a
C6H5
6a
6b
6c
6d
6e
6f
2
90
92
90
93
94
92
218–220
232–234
270–272
225–226
276–278
228–230
223–224 [42]
236–238 [48]
271–273 [41]
225–226 [42]
280–281 [42]
222–234 [41]
4-Cl–C6H4
3-NO2–C6H4
4-Me–C6H4
4-MeO–C6H4
4-(Br)–C6H4
2.5
2.5
1.5
1.5
2
Isolated yields
123

A. Ahad, M. Farooqui
R
CHO
1
O
H3C
HN
CN
Aspartic acid (20mol%)
EtOH:H2O, R.T
CN
CN
NH
R
H3C
N
N
O
NH2
8a-h
2
7
Scheme 4 The efficient synthesis of pyrano [3, 2- c] pyrazoles
[57, 58]. Here also the synthesis of 1, 4-dihydropyrano [2, 3-c] pyrazoles was
accomplished successfully by a one-pot model reaction of anisaldehyde, malonon-
itrile and 3-methyl-1H-pyrazol-5(4H)-one in the presence of 20 mol% aspartic acid
in ethanol: water at room temperature conditions.
This success led us to apply these conditions to other aldehydes; to our delight,
all the aldehydes afforded the corresponding pyrano pyrazoles in excellent yields
(Table 4, entries 1–8). All the products (4a–h), (6a–6f), (8a–8h) are known
compounds, and their structures were confirmed by comparison of their physical and
spectral data with those reported previously [29, 34, 40–44], [48]. From all these
observations, we have found that aspartic acid is a versatile organocatalyst for
multicomponent reactions using in situ-developed benzylidene malononitrile with
various C–H-activated compounds.
To rationalize the synthesis of various pyran annulated heterocyclic scaffolds, a
possible mechanism of the reaction among aldehyde, malonitrile and dimedone
catalyzed by aspartic acid is explained in Scheme 5 based on previous reports of an
amino acid (glycine) catalyzed protocol for the synthesis of 2-amino-4H-chromenes
[59]. The knoevenagel intermediate benzylidine malonitrile A was formed in situ by
the reaction of aldehyde and malonitrile in the presence of aspartic acid. This
knoevenagel intermediate A reacts with an in situ formed carbanion of the C–H
activated dimedone by a Michael addition reaction to give rise to intermediate
Table 4 Synthesis of dihydropyrano pyrazoles
Entry
R
Product
Time (h)
Yield (%)a
M. p. (°C)
Observed
Literature
1
2
3
4
5
6
7
8
a
H
8a
8b
8c
8d
8e
8f
6
5
7
5
5
6
7
6
88
90
87
84
90
85
88
91
242–244
172–174
220–222
192–194
170–172
202–204
244–246
208–210
244–246 [40]
174–175 [43]
218–220 [40]
194–196 [48]
175–176 [43]
206–208 [40]
240–242 [40]
206–208 [40]
4-OCH3
4-OH
3-NO2
4-Cl
4-Br
2-Cl
8g
8h
4-Me
Isolated yields
123

Organocatalyzed domino reactions: diversity oriented…
(a)
COOH
H3N COO
COOH
H3N COOH
O
CN
CN
CN
CN
H
H
O
H
H
H
Knoevenagel
condensation
CN
CN
OH
H
H
CN
CN
A
Benzylidenemalononitriles
Intermediate
(b)
COOH
H3N COO
O
O
H
Michael Adition
CN
O
C N
O
H+
O
O
Ring Clousure
H
CN
CN
NH
O
NH2
O
B
Scheme 5 Proposed mechanism for the aspartic acid catalyzed synthesis of 2-Amino-4 H-benzo
[b] pyrans
B. The intermediate B after ring closure affords the desired 2-amino-3-cyano-4H-
pyrans.
Conclusion
In conclusion, we have described, for the first time, aspartic acid catalyzed an
alternative and facile protocol for easy access to functionalized pyran-annulated
heterocycles via multicomponent domino Knoevenagel-cyclocondensation of
123

A. Ahad, M. Farooqui
substituted aldehydes, malononitrile, and C–H-activated compounds in aqueous
ethanol at room temperature. Simple procedures, easy workup, maximum products
yields, mild reaction conditions, the avoidance of toxic reagents and organic
solvents are significant advantages of the present protocol compared to the reported
ones.
Acknowledgments Laboratory facilities and financial assistance from the Postgraduate and Research
Centre, Dr. Rafiq Zakaria Campus, Maulana Azad College is gratefully acknowledged. We are also
grateful to SAIF Punjab University and YB Chavhan College of Pharmacy, Aurangabad, for providing
analytical facilities.
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