Zn(L-proline)2 as an efficient and reusable catalyst for the multi-component synthesis of pyran-annulated heterocyclic compounds

Article abstract of DOI:10.1002/aoc.4807

We have developed a simple, straightforward and highly efficient multi-component one-pot synthesis of 2-amino-3-cyano-4H-pyrans and pyran-annulated heterocyclic compounds. Zn(L-proline)₂ has been utilized as a mild and efficient Lewis acid cata

Full text of DOI:10.1002/aoc.4807

Received: 5 October 2018
DOI: 10.1002/aoc.4807
Revised: 22 December 2018
Accepted: 27 December 2018
F U L L P A P E R
Zn(L‐proline)2 as an efficient and reusable catalyst for the
multi‐component synthesis of pyran‐annulated heterocyclic
compounds
Daryoush Tahmassebi
| John E. Blevins | Shori S. Gerardot
Department of Chemistry, Purdue
We have developed a simple, straightforward and highly efficient multi‐
University Fort Wayne, 2101 E. Coliseum
Blvd, Fort Wayne, IN 46805, USA
component one‐pot synthesis of 2‐amino‐3‐cyano‐4H‐pyrans and pyran‐
annulated heterocyclic compounds. Zn(L‐proline)2 has been utilized as a mild
and efficient Lewis acid catalyst for the three‐component reaction of aromatic
aldehydes, malononitrile and enolizable C‐H acids or activated phenols to
synthesize pyran‐annulated scaffolds. 3‐Methyl‐1‐phenyl‐2‐pyrazolin‐5‐one,
4‐hydroxycoumarine, dimedone, 4‐hydroxy‐6‐methyl‐2‐pyrone, resorcinol,
1‐naphthol and 2‐naphthol were used as activated C‐H acids. The products
were isolated in high yields via vacuum filtration and without using any chro-
matography. The Zn(L‐proline)2 was recovered and reused in another reaction
(three times) without significant loss of activity.
Correspondence
Daryoush Tahmassebi, Department of
Chemistry, Purdue University Fort
Wayne, 2101 E. Coliseum Blvd, Fort
Wayne, IN 46805, USA.
Email: tahmassd@pfw.edu
KEYWORDS
aldehydes, malononitrile, multi‐component reaction, recyclable catalyst, Zn(L‐proline)2
1 | INTRODUCTION
L‐proline has been used extensively as a catalyst for
enantioselective reactions such as aldol condensation.[8]
Multi‐component reactions (MCRs) play an important
role in organic and medicinal chemistry. Normally the
MCR strategy affords a high degree of atom economy,
the simplicity of a one‐pot procedure, possible structural
variations, and significantly lower time and effort for
the synthesis. These features make MCRs very attractive
in combinatorial chemistry[1] and also useful in a green
chemistry approach. The MCRs can be used to synthesize
complex molecules in a single procedural step, as well as
avoiding complicated purification processes and saving
both reagents and solvents.[2] Nevertheless, continued
efforts are being made to explore new MCR strategies
for organic reactions. MCR methodology has been exten-
sively used for the synthesis of heterocyclic compounds
such as 4H‐chromene,[3] 2H‐chromen‐2‐one,[4] 7,8‐
dihydro‐4H‐chromen‐5(6H)‐one,[5] pyrano[3,2‐c]pyran‐
5(4H)‐one,[6] and 1,4‐dihydropyrano[2,3‐c]pyrazole[7]
using different catalysts and reaction conditions.
The catalytic role of proline was related to the formation
of an enamine with the nucleophile, which resembles the
class I aldolases.[9] The complexes of various amino acids
and Zn (II) have been reported by Darbre,[10] and were
also successfully used to catalyze the aldol condensation
in water with a high degree of enantioselectivity. The
location of the secondary amine and the carboxylate func-
tional groups make the proline the most prominent
amino acid for coordination with Zn. Coordination of
Zn (II) by chiral ligands such as L‐proline makes the Zn
complexes a moderately soft Lewis acid. Recently, Zn(L‐
proline)2 complex emerged as a powerful catalyst for var-
ious transformations, such as aldol and nitro aldol con-
densation, Hantzsch condensation, and some other
reactions including heterocyclic synthesis.[11] Zn(L‐pro-
line)2 (1) complex can be prepared easily from Zn (II)
salts and the amino acid in a basic alcoholic solvent.[10a]
The Zn(L‐proline)2 (1) and other amino acid complexes
Appl Organometal Chem. 2019;e4807.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4807

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TAHMASSEBI ET AL.
are water soluble and stable under different reaction con-
ditions. The water solubility of these complexes plays an
important role in their function as a homogenous catalyst
in mixed organic solvents and water as it ensures enough
solubility of both reagents that are involved in the reac-
tion as well as the catalyst at the same time. It has been
shown that at least 5% water content is necessary to dis-
solve the Zn(L‐proline)2 complex.[10b] This complex is
almost insoluble in any other solvent, which makes the
recovery of the catalyst very simple, and the recovered
catalyst can be used again numerous times without loss
of activity.
2 | EXPERIMENTAL
2.1 | General
Commercially available materials were used without fur-
ther purification. Melting points were determined on an
Electrothermal 9100 apparatus and were uncorrected.
Infrared spectra were recorded on a Nicolet iS5 or iS550
Fourier transform‐infrared (FT‐IR) spectrophotometer
1
using ATR. H and 13C‐NMR spectra were recorded on
a Varian Mercury 5 spectrometer (200 and 50 MHz for
1H and 13C, respectively) using DMSO‐d6 or CDCl3 as
the solvent, and TMS as an internal standard. Thin‐layer
chromatography was performed on EMD silica gel
60 F254 plates using hexane:EtOAc; 4:1 as the eluent.
All compounds in this work were known and previously
reported. The isolated products were fully characterized
on the basis of analytical data and detailed spectral stud-
Pyran‐annulated scaffolds such as pyranopyrazoles,
pyranopyranes, pyranochromenes and benzopyranes are
known to possess many biological and pharmacological
properties. For example, dihydropyrano[2,3‐c] pyrazoles
have been used as antibacterial,[12] anticancer,[13] anti‐
inflammatory,[14]
hypnotic[15]
and
molluscicidal
1
ies, including FT‐IR, H‐NMR and 13C‐NMR spectra. All
agents,[16] as well as an insecticide.[17] Normally, they
have been prepared by condensation of an aromatic alde-
hyde, malononitrile and an active C‐H compound such as
pyrazolin‐5‐one, 4‐hydroxycoumarine, dimedone, 4‐
hydroxy‐pyran‐2‐one or activated phenols in basic or
acidic conditions. A literature survey shows that several
modified methods have been reported using homogenous
or heterogeneous basic or acidic catalysts, such as
urea,[18] potassium phthalimide,[19] KHP,[20] DMBA,[21]
SBA‐15,[22] DMAP,[23] heteropolyacids,[24] ammonium
acetate,[25] ionic liquids,[26] TBAB,[4e,27] DBU,[3d] I2/
K2CO3,[28] Et3N,[29] diammonium hydrogen phos-
phate,[30] rare earth perfluorooctanates [Yb (PFO)3],[31]
compounds had physical and spectroscopic data identical
to the literature values.
Zn(L‐proline)2 (1) and other Zn‐amino acid complexes
were prepared according to the previously reported
method (Scheme 1).[10a] To a solution of L‐proline (2
mmol) in MeOH (10 mL), 0.3 mL of Et3N was added, and
the reaction mixture was stirred for 10 min. The zinc ace-
tate (1 mmol) was added, and the mixture was stirred for
a further 45 min until a white precipitate was formed and
collected by filtration, rinsed with diethyl ether and dried
in a vacuum oven for 10 hr. The complex (1) was charac-
terized by FT‐IR and 1H‐NMR using D2O as the solvent.
NbCl5,[32]
(L)‐proline,[33]
(L)‐proline/melamine,[34]
aliquat 336,[35] CTACl,[3a] CTABr,[36] TEBACl,[37] γ‐
alumina,[3b] hydroxyapatatite,[38] BF3 on silica,[39]
MgO,[40] gold and gold nanoparticles,[41] ZrO nanoparti-
cles,[42] ZnO nanoparticles,[43] CuO nanoparticles,[44]
TiO2 nanoparticles,[45] iron ore,[46] magnetic nano‐
catalyst including γ‐Fe2O3,[47] sulfonic acid‐Fe3‐xTixO4,[48]
chitosan,[49] phenylboronic acid[50] and per‐6‐amino‐β‐
cyclodextrine.[51] However, most of those methods are
not very practical as they suffer from disadvantages,
including relying on multi‐step syntheses, using toxic sol-
vents or catalysts containing transition metals, expensive
catalysts, tedious work‐up procedure, long reaction time,
harsh reaction conditions and low yield.
2.2 | General procedure for the synthesis
of pyran‐annulated heterocyclic scaffolds
The aromatic aldehyde (2) (1 mmol), malononitrile (3) (1
mmol) and Zn(L‐proline)2 (1) (0.2 mmol) were added to a
SCHEME 2 Three‐component reaction of benzaldehyde (2a),
malononitrile (3) and 6‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐ one (4)
SCHEME 1 Synthesis of Zn(L‐proline)2
(1) from zinc (II) acetate and L‐proline

TAHMASSEBI ET AL.
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10‐mL round‐bottom flask containing 5 mL aqueous etha-
nol (2:3) as the solvent, and then an active C‐H acid such as
3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one (4) (1 mmol) was
added to the mixture and stirred under reflux for 3 hr. After
completion of the reaction [determined by thin‐layer chro-
matography (TLC) using hexane:ethyl acetate, 4:1 as elu-
ent], the mixture was left to settle. The solid was collected
by vacuum filtration and washed with aqueous ethanol.
6‐Amino‐4‐aryl‐1,4‐dihydro‐3‐methyl‐1‐
phenylpyrano[2,3‐c]pyrazole‐5‐carbonitrile (6) derivatives
were isolated and recrystallized with ethanol and charac-
1
terized by their melting point, FT‐IR, H‐NMR and 13C‐
NMR spectra, and compared with the data reported in
the literature.
To recover the catalyst (1), the filtrate was evaporated
under reduced pressure, and the remaining solid was
TABLE 1 Optimization of the three‐component reaction of benzaldehyde (2a), malononitrile (3) and 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one
(4) under various conditions (Scheme 2)a
Entry
Catalyst
Catalyst (mol%)
Solvent
Temperature
Time (hr)
Yielda (%)
1
–
–
EtOH
R.T.b
8
8
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
trace
trace
72
2
–
–
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
R.T.
3
(NH4)2HPO4
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
EtOH (aq.)c
4
p‐TsOH
DABCOd
EtOH
35
5
EtOH
78
6
DBUe
EtOH
72
7
TBAFf
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
H2O
39
8
TBAClg
TBABrh
41
9
35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
34
25
26
27
ZnCl2
55
Zn(L‐proline)2
Zn(L‐alanine)2
Zn(L‐glycine)2
Zn(L‐lysine)2
Zn(L‐cysteine)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
Zn(L‐proline)2
51
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
R.T.
30
35
42
25
89
55
MeOH
45
AcOH
trace
51
CH2Cl2
THF
58
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
EtOH (aq.)
85
10
20
20
30
40
89
91
60
Reflux
Reflux
90
89
aIsolated yield of 6a.
bRoom temperature.
c40% water.
d1,4‐Diazabicyclo[2.2.2]octane.
e1,8‐Diazabicyclo[5.4.0]undec‐7‐ene.
fTetrabutylammonium fluoride.
gTetrabutylammonium chloride.
hTetrabutylammonium bromide.

4 of 11
TAHMASSEBI ET AL.
washed with diethyl ether and dried at 70°C under vac-
uum for 1 hr; it was then reused in another reaction with-
out significant loss of catalytic activity.
Spectral data of some representative products are
given in the Supporting Information.
effective catalyst was found to be Zn(L‐proline)2, which
resulted in the highest yield (89%) when it was used in
aqueous ethanol (40% water) at the reflux condition
(entry 16). When water was used as the solvent, the prod-
uct yield was only 55% (entry 17). Also performing the
3CR in EtOH (aq.) in the presence of Zn(L‐proline)2 at
room temperature resulted in only a 51% yield (entry
11). These results showed that the aqueous ethanol with
40% water content and at reflux is the most suitable con-
dition for the 3CR. Then the effect of catalyst loading on
the completion of the reaction was studied. As can be
seen in Table 1, adding 20 mol% catalyst resulted in the
highest yield of the product (entry 24). Increasing the cat-
alyst load beyond 20 mol% did not improve the efficiency
of the reaction and resulted in almost the same yield
(entries 26 and 27). Therefore, we decided that using 20
mol% of Zn(L‐proline)2 in refluxing EtOH (aq.)
would be the optimum condition for the 3CR of benzalde-
hyde (2a), malononitrile (3) and 3‐methyl‐1‐phenyl‐2‐
pyrazolin‐5‐one (4).
3 | RESULTS AND DISCUSSION
In continuation of our interest in developing environ-
mentally benign methodologies for organic reactions, we
report herein the application of Zn(L‐proline)2 (1) as a
catalyst in different MCRs to synthesize various types of
heterocyclic compounds, such as pyranopyrazoles,
pyranopyranes, pyranochromenes and benzopyranes.
In our first effort to utilize Zn(L‐proline)2 in a MCR,
we investigate its catalytic properties in a three‐
component reaction (3CR) between an aromatic aldehyde
(2), malononitrile (3) and 3‐methyl‐1‐phenyl‐2‐pyrazolin‐
5‐one (4) (1:1:1 molar ratio; Scheme 2).
To find the optimum conditions, we carried out a sys-
tematic study considering different variables that can
affect the reaction time and yield, such as the type of cat-
alyst and/or the solvent, the reaction time and the
amount of catalyst that has been used in the reaction.
The results are summarized in Table 1. We discovered
that only a trace amount of the desired 6‐amino‐1,4‐
dihydro‐3‐methyl‐1,4‐diphenylpyrano[2,3‐c]pyrazole‐5‐
carbonitrile was obtained when no catalyst was used
(entries 1 and 2). We have tested both basic and acidic
catalysts for the above reaction. As shown in Table 1,
using basic catalysts such as DBU, DABCO or TBAF
resulted in lower yield of the product (entries 5–7).
Brønsted or Lewis acid catalysts such as p‐TsOH, ZnCl2
or other Zn‐amino acid complexes such as alanine, gly-
cine, lysine and cysteine all resulted in lower yields of
the product (entries 3, 10, 12, 13, 14 and 15). The most
Inspired by the results obtained from our optimiza-
tion reaction and to develop the scope of the reaction,
we carried out similar 3CR between 3‐methyl‐1‐phenyl‐
2‐pyrazolin‐5‐one (4), malononitrile (3) and different aro-
matic and heterocyclic aldehydes (2) in the presence of
20 mol% Zn(L‐proline)2 (1) in EtOH (aq.) (40% water)
under reflux conditions for 3 hr. The progress of the reac-
tion was monitored by TLC. At the end of the reaction,
products were isolated by vacuum filtration and washed
with aqueous ethanol followed by recrystallization from
ethanol. The catalyst was recovered after evaporating
the filtrate, washed with diethyl ether and dried in the
vacuum oven at 70°C for 1 hr. The recovered catalyst
was used in another catalytic cycle. It was observed
that the catalyst could be used at least three times
without significant loss of catalytic activity (Figure 1).
When butyraldehyde was used as an aliphatic aldehyde,
FIGURE 1 Reusability of Zn(L‐
proline)2 for the synthesis of 6‐amino‐1,4‐
dihydropyrano[2,3‐c]pyrazole‐5‐
carbonitrile (6a)

TAHMASSEBI ET AL.
5 of 11
no considerable amount of product was isolated, which is
consistent with the reports from literature.[52]
carbonitrile. The reactions were completed with high
yields. We were able to use the same optimal conditions
as a general condition for the reactions, and collect the
products with simple vacuum filtration. Once again, no
difference was found between electron‐withdrawing and
electron‐donating substituents on the aromatic aldehydes
in terms of the yield of the product. The results have been
summarized in Table 3.
Subsequently, dimedone (9) was used as the
enolizable C‐H acid in the 3CR to synthesize derivatives
of 2‐amino‐5,6,7,8‐tetrahydro‐7,7‐dimethyl‐5‐oxo‐4‐phe-
nyl‐4H‐chromene‐3‐carbonitrile (10) in high yield using
different aromatic or heterocyclic aldehydes (2) and
malononitrile (3) under the same optimal conditions. Dif-
ferent substituents with different electronic effects have
shown no significant difference in these reactions. The
results have been summarized in Table 4.
Different types of aromatic aldehydes with electron‐
withdrawing or electron‐donating substituents as well as
heterocyclic aldehydes and cinnamaldehyde have been
used in the one‐pot 3CR, and they all proceeded smoothly
with no significant difference between different substitu-
ents. It is noteworthy that the attempt to use ethyl
cyanoacetate in the above reaction was unsuccessful.
We believe that this could be attributed to the fact that
the cyanide group is better able to stabilize the reaction
intermediate compared with the ester group. The results
have been summarized in Table 2.
The scope of the present protocol was further investi-
gated with other C‐H activated acidic compounds. The
one‐pot 3CR of 4‐hydroxycoumarine (7), malononitrile
(3) and various aromatic or heterocyclic aldehydes (2)
was performed in EtOH (aq.) in the presence of 20
mol% Zn(L‐proline)2 (1) as the catalyst under reflux con-
ditions for 3 hr to form derivatives of 2‐amino‐4,5‐
dihydro‐5‐oxo‐4‐phenylpyrano[3,2‐c]chromene‐3‐
Next, 4‐hydroxy‐6‐methyl‐2‐pyrone (11) was used as
an enolizable active C‐H acid, and reacted with different
aromatic or heterocyclic aldehydes (2) and malononitrile
(3) under the same optimal reaction conditions. The
derivatives of 2‐amino‐4,5‐dihydro‐7‐methyl‐5‐oxo‐4‐
TABLE 2 Three‐component reaction of an aromatic aldehyde (2),
malononitrile (3) and 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one (4) in
TABLE 3 Three‐component reaction of an aromatic aldehyde (2),
malononitrile (3) and 4‐hydroxycoumarine (7) in the presence of
a
the presence of 20 mol% Zn(L‐proline)2
a
20 mol% Zn(L‐proline)2
Yield Mp (obs.) Mp (lit.)
Entry Ar
Product (%)b (°C)
(°C)
Yield Mp (obs.) Mp (lit.)
1
2
3
4
5
6
C6H5
6a
6b
6c
6d
6e
6f
91
85
82
90
90
93
170–172
171–173
143–144
188–190
197–198
174–176
170–171[53]
175–176[53]
145–146[53]
190–191[53]
195–196[53]
175–176[53]
Entry Ar
Product (%)b
(°C)
(°C)
4‐Cl‐C6H4
1
C6H5
8a
8b
8c
8d
8e
88
85
89
90
92
92
90
88
94
89
88
85
83
92
255–256 256–258[3d]
258–260 260–262[3d]
271–272 273–274[58]
260–262 261–262[58]
253–255 256–258[3d]
256–258 258–259[3d]
242–244 242–243[3d]
250–251 252–254[3d]
255–257 253–255[3d]
243–245 248–250[3d]
262–263 266–267[3d]
251–253 252–253[59]
225–227 228–229[60]
183–186 182–185[52a]
2‐Cl‐C6H4
2
4‐Cl‐C6H4
3‐NO2‐C6H4
4‐NO2‐C6H4
3
2‐Cl‐C6H4
4
3‐NO2‐C6H4
4‐NO2‐C6H4
3,4‐OCH2O
‐C6H3
5
7
3‐Cl‐C6H4
4‐OH‐C6H4
4‐Br‐C6H4
4‐Me‐C6H4
6g
6 h
6i
90
88
89
93
82
92
90
88
91
155–157
210–212
181–183
169–170
176–178
184–185
225–228
172–174
138–140
158–160[53]
210–212[53]
182[54]
6
2,4‐Cl2‐C6H3 8f
8
7
3‐Cl‐C6H4
4‐Br‐C6H4
4‐Me‐C6H4
8g
8i
8j
9
8
10
11
12
13
14
15
6j
177–178[53]
171–172[53]
185–186[53]
233–235[55]
168–169[56]
140–142[57]
9
4‐MeO‐C6H4 6k
2,4‐Cl2‐C6H3 6l
10
11
12
13
14
4‐MeO‐C6H4 8k
4‐OH‐C6H4
2‐Furyl
8l
2‐Furyl
6m
6n
6o
8m
8n
8o
2‐Thienyl
PhCH=CH‐
2‐Thienyl
PhCH=CH‐
aReaction conditions: 2:3:4 (1:1:1 molar ratio) in ethanol/water (3:2, 5 mL,
aReaction conditions: 2:3:7 (1:1:1 molar ratio) in ethanol/water (3:2, 5 mL,
reflux, 3 hr).
reflux, 3 hr).
bIsolated yield.
bIsolated yield.

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TAHMASSEBI ET AL.
TABLE 4 Three‐component reaction of an aromatic aldehyde (2), malononitrile (3) and dimedone (9) in the presence of 20 mol% Zn(L‐
a
proline)2
Entry
Ar
Product
Yield (%)b
Mp (obs.) (°C)
Mp (lit.) (°C)
1
C6H5
10a
10b
10c
10d
10e
10f
85
89
88
90
94
94
88
87
89
92
94
79
87
230–231
210–211
195–197
212–213
178–180
210–211
190–191
203–205
216–218
201–203
229–230
221–223
184–185
233–234[5e]
214–215[5e]
200–202[5e]
214–215[5e]
180–181[5e]
214–215[61]
192–195[30b]
207–209[30b]
218–219[5e]
200–202[5e]
226–228[62]
220–222[56]
182–184[52c]
2
4‐Cl‐C6H4
2‐Cl‐C6H4
3‐NO2‐C6H4
4‐NO2‐C6H4
3,4‐OCH2O‐C6H3
2,4‐Cl2‐C6H3
4‐Br‐C6H4
4‐Me‐C6H4
4‐MeO‐C6H4
2‐Furyl
3
4
5
6
7
10g
10i
8
9
10j
10
11
12
13
10k
10l
2‐Thienyl
10m
10n
PhCH=CH‐
aReaction conditions: 2:3:9 (1:1:1 molar ratio) in ethanol/water (3:2, 5 mL, reflux, 3 hr).
bIsolated yield.
TABLE 5 Three‐component reaction of an aromatic aldehyde (2), malononitrile (3) and 4‐hydroxy‐6‐methyl‐2‐pyrone (11) in the presence
a
of 20 mol% Zn(L‐proline)2
Entry
Ar
Product
Yield (%)b
Mp (obs.) (°C)
Mp (lit.) (°C)
1
C6H5
12a
12b
12c
12d
12e
12f
12g
12h
12i
86
90
88
92
90
89
94
88
91
92
86
85
218–219
265–267
255–256
230–232
230–231
232–233
208–209
215–217
225–226
195–197
220–223
238–240
221–223[3d]
270–271[63]
255–257[63]
231–232[63]
234–235[63]
235–237[40a]
210–212[3d]
218–220[64]
228–230[64]
200–201[3d]
223–224[6e]
242–244[6e]
2
2‐Cl‐C6H4
3‐Cl‐C6H4
4‐Cl‐C6H4
2,4‐Cl2‐C6H3
3‐NO2‐C6H4
4‐NO2‐C6H4
4‐Br‐C6H4
4‐Me‐C6H4
4‐MeO‐C6H4
2‐Furyl
3
4
5
6
7
8
9
10
11
12
12j
12k
12l
2‐Thienyl
aReaction conditions: 2:3:11 (1:1:1 molar ratio) in ethanol/water (3:2, 5 mL, reflux, 3 hr).
bIsolated yield.

TAHMASSEBI ET AL.
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SCHEME 3 Three‐component reaction
of aromatic aldehydes (2a), malononitrile
(3) and resorcinol (13), or 1‐naphthol (15)
or 2‐naphthol (17) in the presence of
20 mol% Zn(L‐proline)2 (1)
TABLE 6 Three‐component reaction of an aromatic aldehyde (2), malononitrile (3) and resorcinol (13), or 1‐naphthol (15) or 2‐naphthol
(17) in the presence of 20 mol% Zn(L‐proline)2 (Scheme 3)a
Entry
Ar
Product
Yield (%)b
Mp (obs.) (°C)
Mp (lit.) (°C)
1
C6H5
14a
14b
14c
14d
14e
14f
89
90
91
94
89
88
86
90
88
89
88
92
89
91
92
90
88
85
90
94
90
88
89
230–231
208–209
94–95
232–234[65]
210–212[66]
95–96[26a]
2
4‐Cl‐C6H4
2‐Cl‐C6H4
3‐NO2‐C6H4
4‐Me‐C6H4
2‐Furyl
3
4
170–172
180–181
188–190
202–203
215–218
231–232
235–237
211–212
235–236
167–168
186–197
231–233
277–279
210–212
270–271
188–189
184–185
238–240
223–224
255–257
169–170[67]
184–186[67]
189–191[67]
204–205[67]
218–219[3d]
232–234[3d]
239–241[3d]
214–216[3d]
237–238[3d]
168–169[68]
188–190[69]
237–238[68]
278–279[65]
209–210[70]
270–271[70]
190–191[70]
187–188[70]
239–241[71]
225–226[72]
258–260[73]
5
6
7
2‐Thienyl
C6H5
14g
16a
16b
16c
16d
16e
16f
6
7
4‐Cl‐C6H4
4‐Br‐C6H4
3‐NO2‐C6H4
4‐NO2‐C6H4
2‐Furyl
8
9
10
11
12
13
14
15
16
17
19
20
21
22
2‐Thienyl
PhCH=CH‐
C6H5
16g
16h
18a
18b
18c
18d
18e
18f
4‐Cl‐C6H4
2‐Cl‐C6H4
4‐MeO‐C6H4
4‐NO2‐C6H4
3‐NO2‐C6H4
2‐Furyl
18g
18h
2‐Thienyl
aReaction conditions: 2:3:13 or 2:3:15 or 2:3:17 (1:1:1 molar ratio) in ethanol/water (3:2, 5 mL, reflux, 3 hr).
bIsolated yield.

8 of 11
TAHMASSEBI ET AL.
SCHEME 4 Two‐step reaction for the
synthesis of 6‐amino‐1,4‐dihydro‐3‐
methyl‐1,4‐diphenylpyrano[2,3‐c]
pyrazole‐5‐ carbonitrile (6a) with or
without the Zn(L‐proline)2 (1) catalyst and
the isolated yield for each reaction
phenylpyrano[4,3‐b]pyran‐3‐carbonitrile (12) have been
isolated in high yield and characterized. The results have
been summarized in Table 5.
respectively, in high yield. The results have been summa-
rized in Table 6.
Although the mechanism of the reaction has not been
studied in detail, we believe that the reaction starts with a
Knoevenagel condensation between an aldehyde and
malononitrile to form a benzylidenemalononitrile inter-
mediate followed by a domino Michael cyclization reaction
with an enolizable active C‐H acid such as 3‐methyl‐1‐phe-
nyl‐2‐pyrazolin‐5‐one (4). We believe that Zn(L‐proline)2
(1) has a catalytic role in both steps of this domino
Knoevenagel–Michael cyclization reaction. To evaluate
the catalytic effect of (1) on the mentioned 3CR, we carried
out two test reactions with and without the catalyst
In addition to enolizable C‐H acids, we have
utilized activated phenols such as resorcinol (13), 1‐
naphthol (15) and 2‐naphthol (17) in the 3CR with aro-
matic or heterocyclic aldehydes (2) and malononitrile
(3) under the same optimal reaction conditions in the pres-
ence of Zn(L‐proline)2 (1) as the catalyst (Scheme 3). We
were able to isolate 2‐amino‐7‐hydroxy‐4‐phenyl‐4H‐
chromene‐3‐carbonitrile (14), 2‐amino‐4‐phenyl‐4H‐
benzo[h]chromene‐3‐carbonitrile (16) and 3‐amino‐1‐phe-
nyl‐1H‐benzo[f]chromene‐2‐carbonitrile (18) derivatives,
SCHEME 5 Proposed mechanism for
the three‐component reaction

TAHMASSEBI ET AL.
9 of 11
(Scheme 4). First the Knoevenagel condensation between
benzaldehyde (2a) and malononitrile (3) was performed
under two different conditions. The reaction produces only
32% alkene (5) when no catalyst was used vs. 96% yield in
the presence of the catalyst. Also, the catalyst has improved
the reaction yield between the alkene (5) and 3‐methyl‐1‐
phenyl‐2‐pyrazolin‐5‐one (4) under the same reaction con-
ditions from 25% in the absence of the catalyst to 88% in the
presence of the catalyst. Therefore, we can conclude that
Zn(L‐proline)2 has some catalytic role in almost all steps
of the reaction, and our proposed mechanism shows the
involvement of the catalyst in this 3CR.
Our proposed mechanism has been presented in
Schemes 5. We believe that the first step of the reaction
could be catalyzed by formation of an imine between
the aldehyde and proline residue of the catalyst, which
activates the carbonyl group followed by the
nucleophilic addition of malononitrile onto the imine
intermediate (Scheme 5). In the next step the Michael
addition of an active C‐H acid compound to the
benzylidenemalononitrile intermediate (5) followed by
cyclization and tautomerization will result in the desired
product (Scheme 5).
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Daryoush Tahmassebi
5621
https://orcid.org/0000-0001-8191-

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How to cite this article: Tahmassebi D, Blevins
JE, Gerardot SS. Zn(L‐proline)2 as an efficient and
reusable catalyst for the multi‐component synthesis
of pyran‐annulated heterocyclic compounds. Appl
Organometal Chem. 2019;e4807. https://doi.org/
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