Organocatalysis in synthesis: L-proline as an enantioselective catalyst in the synthesis of pyrans and thiopyrans

Article abstract of DOI:10.3390/molecules17044300

The multicomponent reaction (MCR) of aromatic aldehydes 1 and malononitrile (2) with active methylenes 5a-h in the presence of L-proline produced pyrans and thiopyrans 6a-h stereospecifically and in good yields. Moreover a novel MCR of ethyl propiolate (8) with 1 and 2 in the presence of L-proline to afford (R)-polysubstituted pyran is also reported. X-ray structures, e.e. and optical activity of the synthesized compounds indicated that L-proline as a catalyst is responsible for the observed enantioselectivity in the studied reactions.

Full text of DOI:10.3390/molecules17044300

Molecules 2012, 17, 4300-4312; doi:10.3390/molecules17044300
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Organocatalysis in Synthesis: L-Proline as an Enantioselective
Catalyst in the Synthesis of Pyrans and Thiopyrans
Noha M. Hilmy Elnagdi * and Noura Saad Al-Hokbany
Women Students-Medical Studies & Sciences Sections, Chemistry Department, College of Science,
King Saud University, Riyadh, KSA, P.O. Box 22452, Riyadh 11495, Saudi Arabia
* Author to whom correspondence should be addressed; E-Mail: elnagdinoha@yahoo.com;
Tel.: +966-50-043-2102; Fax: +966-1-477-2245.
Received: 26 January 2012; in revised form: 19 March 2012 / Accepted: 20 March 2012 /
Published: 10 April 2012
Abstract: The multicomponent reaction (MCR) of aromatic aldehydes 1 and malononitrile
(2) with active methylenes 5a–h in the presence of L-proline produced pyrans and
thiopyrans 6a–h stereospecifically and in good yields. Moreover a novel MCR of ethyl
propiolate (8) with 1 and 2 in the presence of L-proline to afford (R)-polysubstituted pyran
is also reported. X-ray structures, e.e. and optical activity of the synthesized compounds
indicated that L-proline as a catalyst is responsible for the observed enantioselectivity in
the studied reactions.
Keywords: L-proline; pyran; assymetric synthesis; enantioselectivity; ethyl propiolate;
optical activity
1. Introduction
Polyfunctionally substituted pyrans are no doubt an important class of heterocycles due to their
great biological and pharmacological importance [1–6]. The addition of active methylene reagents to
arylidenemalononitrile in the presence of homogeneous basic catalysts has been extensively used in the
past for the synthesis of these compounds [7–12]. Interest in these reactions has recently been
revived [13,14] with the aim of developing green laboratory reaction conditions [15,16], such as
replacing homogeneous catalysis with heterogeneous ones [17–20], to synthesize enantiomerically
pure pyrans for which diverse biological applications were noticed [21–23] and patented [24–26].
Many of these new approaches use multicomponent reactions and either an organocatalyst [27,28] or

Molecules 2012, 17
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sometimes metal or nanoparticulated catalysts [29–31]. Although in plenty of these reactions a chiral
center is being created only a few published works have discussed the exact stereochemistry of the
synthesized compounds.
Since L-proline is a readily obtainable naturally occurring amino acid and is easy to obtain in high
enantiomeric purity it has been reported as an eco-friendly catalyst for the synthesis of several
heterocycles [32–37]. Recently Muramulla et al. reported the use of modularly designed
organocatalysts (MDO) of L-proline in dichloromethane as a solvent for the synthesis of chiral
pyranopyrazoles in moderate e.e. [38]. Gou et al. have also reacted aromatic aldehydes, malononitrile,
and dimedone, in the presence of D,L-proline as a catalyst in the absence of solvent to obtain
2-amino-3-cyano-4-aryl-7,7-dimethyl-5,6,7,8-tetrahydrobenzo[b]pyran [27].
It seemed thus of value to see if the use of L-proline as a catalyst in the reaction of active methylene
ketones with ,β-unsaturated nitriles in MCRs can be used to induce enantioselectivity of the
synthesized pyrans. In this article the syntheses of pyrans, condensed pyrans and thiopyrans are
reported. Moreover a novel pyran was prepared via the MCR of ethyl propiolate (8) with aldehydes
and malononitrile in the presence of L-proline as a catalyst.
2. Results and Discussion
First in an attempt to synthesize the chiral pyranopyrazoles 4, we have reacted benzaldehyde (1),
malononitrile (2) and pyrazolon-5-one (3) with 10% mol L-proline as the only catalyst. In contrast to
Muramulla et al’s. findings that for the same reaction using L-proline alone as a catalyst under the
reported reaction conditions no product was obtained, in our case after the reaction mixture was refluxed
in ethanol for 4 h, the pyranopyrazole 4 was isolated in 81% yield (Scheme 1). To initially test if
L-proline has induced any enantioselectivity in this reaction, compound 4 was tested for optical activity
and found to be optically active with a specific rotation of +247.02 ([]D, 25 °C, c = 1, DMF).
Scheme 1. Synthesis of 6-amino-3,4-dimethyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (4).
NC
NH2
O
Ph
O
O
*
CN
L-proline (10% mol)
EtOH, reflux 4 h
+
+
NH
Ph
H
H3C
CN
N
N
H3C
N
H
2
1
3
4
81% yield
Next reacting benzaldehyde (1), malononitrile (2) and 3-oxo-3-phenylpropanenitrile (5g) in the
presence of 10% L-proline as a catalyst afforded 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile
(6g) in 83% yield and 70% e.e. (Scheme 2).

Molecules 2012, 17
Scheme 2. Synthesis of 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g).
4302
Ph
NC
Ph
CN
O
O
CN
*
L-proline (10% mol)
+
+
CN
EtOH
reflux 4 h
CN
Ph
Ph
H
O
NH2
5g
2
1
6g
ee = 70%
The 4H-pyran 6g was found to have 70% e.e. Confirmation that the 4H-pyran 6g indeed displayed
an enantiomeric excess was obtained by performing 1H-NMR experiments with 6g in the presence of a
chiral shift reagent (europium tris[3-heptafluoropropylhydroxymethylene]-(+)-camphorate). After
making successive additions of this chiral shift reagent to a CDCl3 solution of 6g, the 4H-proton at δH
4.7 ppm appeared to resolve into two components (most obviously after the addition of 6 mg of the
1
chiral shift reagent), and by calculation of the area under the chosen peak from the H-NMR that
showed the maximum separation of the two components, 6g was found to be in 70% e.e. However at
this stage, we cannot judge the predominance of the R or S enantiomers for this compound.
The above reported results encouraged us to prepare a series of polysubstituted 4H-pyrans. Pyrans
6a–h were all synthesized by the addition of benzaldehyde (1) and malononitrile (2) to active
methylenes 5a–h using L-proline (10% mol) as a catalyst in a MCR to afford chiral pyrans 6a–h
(Scheme 3). Active methylenes used are listed in Table 1. Structures and yields of the products 6a–h,
as well as the reaction conditions are listed in Table 2.
Scheme 3. Synthesis of enantioselective pyrans, benzopyrans, and thiopyrans 6a–h in a
multicomponent reaction using L-proline as a catalyst.
Ph
O
R2
CN
*
CN
CN
L-proline (10% mol)
+
+
5 a-h
Ph
H
EtOH / reflux 4 h
or by grinding at r.t
R1
X
NH2
1
2
6 a-h
Table 1. Compounds 5a–h.
5a
5b
5c
5d
CH3COCH2COOEt
CH3COCH2COCH3
5e
5f
EtCOOCH2COPh
PhCH2COOCH2COCH3
NCCH2CSNH2
5g
5h
PhCOCH2CN
O
O
O
O

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4303
Table 2. Compounds 6a–h and their yields.
Compound a
X
O
O
S
R1
R2
Yield (%)
6a
CH3
CH3
NH2
COOEt
COCH3
CN
72
60
92
90
6b
6c
O
6d *
O
6e
O
O
O
O
Ph
COOEt
87
6f
CH3
Ph
COOCH2Ph 65
6g
CN
83
78
6h *
O
a Compounds were characterized by their spectral data (IR, 13C-NMR, 1H-NMR). * These compounds
could be prepared without a solvent at r.t. using grinding for 5 min. Compounds 6a, b, c, e, f, g
were prepared using EtOH as a solvent and refluxing for 4 h.
Specific rotation measurements for some selected synthesized compounds revealed that these
compounds are optically active, which supports the assumption that L-proline when used as a catalyst
brings about enantioselectivity in such reactions. The specific rotation of some selected compounds is
listed in Table 3.
Table 3. Specific rotation for some of the synthesized compounds.
Entry
6a
Specific rotation []D 25 °C, c = 1, DMF
+318.20
+198.81
+198.20
+247.02
+272.0
6e
6h
4
13
Structures proposed of the products 6a, b, d, e, h were well documented by X-ray crystallography
1
as shown in Figures 1–6 [39]. It is worth mentioning that the H-NMR of the compound 6a has
revealed the formation of two products in 2:1 ratio that could be separated by column chromatography.
The first product could be shown by X-ray crystal structure (Figure 1) to be the 4H-pyran derivative
(S)-ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (6a), while the other product
with molecular formula C22H22N2O4 and m/z = 378.2 is believed to be diethyl 5,5-dicyano-4,6-dimethyl-
2-phenylcyclohexa-3,6-diene-1,3-dicarboxylate (7) as was proven by its spectroscopic data (Scheme 4).

Molecules 2012, 17
Figure 1. X-ray crystal structure of (S)-ethyl 5-cyano-2,6-dimethyl-4-phenyl-4H-pyran-3-
4304
carboxylate (6a).
Figure 2. X-ray crystal structure of (R)-5-acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-
carbonitrile (6b).
Figure 3. X-ray crystal structure of (S)-2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile(6d).

Molecules 2012, 17
Figure 4. X-ray crystal structure of (S)-ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-
4305
carboxylate (6e).
Figure 5. X-ray crystal structure of (R)-2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6h).
Figure 6. X-ray crystal structure of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-
carboxylate 13.

Molecules 2012, 17
4306
Scheme 4. Synthesis of the two products 6a and 7 in a 2:1 ratio.
Ph
Ph
EtOOC
COOEt
O
EtOOC
H3C
CN
COOEt
CN
*
L-proline 10%
+
+
+
CH2
Ph
H
EtOH / reflux
CN
COCH3
H3C
CH3
O
NH2
6
a
NC
CN
1
5a
2
7
66%
33%
In addition a novel synthesis of pyran 13 could be achieved by mixing benzaldehyde (1), and
malononitrile (2) with ethyl propiolate (8) in ethanol and 10% L-proline as a catalyst. It is believed that
initially L-proline (9) adds to ethyl propiolate (8) affording the enamine ester 10, while benzaldehyde
(1) condenses with malononitrile (2) affording 2-benzylidenemalononitrile (11). This was followed by
the addition of the electron rich β-carbon in the enamine ester to the electron poor π system in the
benzylidine-malononitrile 11, affording an adduct. This adduct 12 is then hydrolyzed by H2O and
cyclizes into 13 (Scheme 5). Compound 13 was also tested for optical activity and found to be
optically active with a specific rotation of +272.0 ([]D 25 °C, c = 1, DMF). The structure of 13 has
been confirmed with certainty via X-ray crystal structure determination (Figure 6).
As shown in the X-ray structures (Figures 1–6), we have obtained the R-enantiomer in the case of
compounds 9a, h, and 14, and the S-enantiomer in the cases of 9a, d, and e, but both enantiomers exist
of course in the original product as a mixture.
Scheme 5. Synthesis of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate (13).
CO2Et
+
COOH
N
COOH
CO2Et
N
H
8
9
10
O
CN
CN
CN
L-proline
+
CN
Ph
H
Ph
2
1
11
Ph
COOH
EtOOC
CN
N
H2O
O
NH2
-
EtO2C
CN
CN
COOH
N
H
13
Ph
12

Molecules 2012, 17
4307
3. Experimental
3.1. General
1
The H-NMR and 13C-NMR spectra were determined by using a Bruker DPX instrument at
400 MHz for 1H-NMR and 100 MHz for 13C-NMR. The chemical shifts are reported in ppm downfield
1
to TMS ( = 0) or DMSO-D6 ( = 2.5) for H-NMR and relative to the central CDCl3 resonance
( = 77.0) or DMSO-D6 ( = 40.0) for 13C-NMR. The coupling constants J are given in Hz. Mass spectra
were measured using a high resolution GC-MS (DFS) Thermo spectrometer with EI (70 EV). Column
chromatography was performed using Acme’s silica gel (particle size 0.063–0.200 mm). IR spectra were
recorded using KBr disks on a Perkin-Elmer System 2000 FT-IR spectrophotometer. Microanalyses
were performed on a LECO CHNS-932 Elemental Analyzer. Optical rotations were measured on an
Autopol IV (Rudolph Instruments) automatic polarimeter at 25 °C in DMF at concentration 1 mol. X-ray
crystal structures were determined using a Single Crystal X-ray Crystallography-Rigaku Rapid II system
and all the X-ray samples were prepared by recrystallization from hot ethanol. All melting points were
recorded on a Griffin melting point apparatus and are reported uncorrected.
3.2. General Experimental Procedure for the Synthesis of Pyrans 6a–h and Compound 7
A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol) and 10% mol L-proline was
stirred at r.t. for 2 min. then active methylenes 5a–h (0.01 mol) were added. The mixture was refluxed
in ethanol (10 mL) for 4–6 h followed by TLC. The crude compounds formed were recrystallized from
ethanol and further purified using column chromatography using 2:1 petroleum ether/ethyl acetate as
an eluent.
Ethyl-5-cyano-2,6-dimethyL-4-phenyl-4H-pyran-3-carboxylate (6a). White crystalline solid, Mp
1
189–190 C; yield 72%, H-NMR [DMSO-d6], : ppm = 7.31 (t, 1H, Ar), 7.23 (m, 1H, Ar), 7.15 (d,
J = 7.6 Hz, 1H, Ar), 6.94 (s, 2H, NH2), 4.29 (s, 1H), 3.94 (m, 2H, CH2), 2.30 (s, 3H, CH3), 1.03 (t, 3H,
CH3); 13C-NMR: : ppm = 166 (O=C), 158.8 (C), 156.6 (C), 144.8 (CH), 128.5 (2C), 127.0 (2C),
126.9 (2C), 119.5 (CN), 107.0 (C), 60.0 (CH2), 58.8 (C), 19.6 (CH3), 17.0 (CH3); MS: m/z % 284.1
(M+100); Anal. calcd for C16H16N2O3 (284.30): C, 67.59; H, 5.67; N, 9.85; O, 16.882. Found:
C, 67.63; H, 5.66; N, 9.71%.
5-Acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile (6b). White crystalline solid, Mp
185–186 C; yield 72%, 1H-NMR [DMSO-d6]  7.34 (m, 2H, Ar), 7.23 (m, 1H, Ar), 7.18 (m, 2H, Ar),
6.87 (s, 2H, NH2), 4.46 (s, 1H), 2.25 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C-NMR: [DMSO-d6],
: ppm = 198 (O=C), 158.2 (C), 154.8 (C), 144.5 (CH), 128.7 (2C), 127.1 (2C), 126.9 (2C),
119.8 (CN), 114.9 (C), 57.7 (C), 29.8 (CH3), 18.4 (CH3); MS: m/z % 254.1 (M+100); Anal. calcd for
C15H14N2O2 (254.1): C, 70.85; H, 5.55; N, 11.02; O, 12.58. Found: C, 71.40; H, 5.34; N, 10.98;
O, 12.28%.
2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile (6c). Yellow crystalline solid, Mp 192–193 C;
1
yield 92%, H-NMR [DMSO-d6], : ppm = 7.35 (m, 2H, Ar), 7.26 (m, 3H, Ar), 6.93 (s, 4H, 2NH2),
4.26 (s, 1H); 13C-NMR: [DMSO-d6], : ppm = 151.2 (2C), 143.5 (C), 128.7 (2C), 127.1 (C),

Molecules 2012, 17
4308
126.6 (2C), 118.8 (2C, CN), 71.9 (2C), 43.3 (C); MS: m/z % 254.1 (M+100); Anal. calcd for C13H10N4S
(255.31): C, 61.15; H, 4.34; N, 21.94; S, 12.55. Found: C, 61.14; H, 4.02; N, 21.50; S, 12.51%.
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6d). Faint yellow
1
crystalline solid, Mp 228–230 C; yield 90%, H-NMR [DMSO-d6], : ppm = 7.30 (m, 2H, Ar), 7.18
(m, 3H, Ar), 7.02 (s, 2H, NH2), 4.20 (s, 1H), 2.62 (m, 2H, CH2), 2.25 (m, 2H, CH2), 1.91 (m, 2H,
13
CH2); C-NMR: [DMSO-d6], : ppm = 197.6 (C=O), 174.2 (C), 163.8 (C), 144.9 (C), 128.2 (2CH),
127.3 (2CH), 126.5 (CH), 119.4 (CN), 113.6 (C), 58.7 (C), 38.4 (CH2), 36.3 (C), 35.4 (CH2), 32.4 (C),
25.5 (2CH3); MS: m/z % 294.1 (M+100); Anal. calcd for C18H18N2O2 (294.3): C, 73.45; H, 6.16;
N, 9.52; O, 10.87. Found: C, 73.67; H, 6.25; N, 9.34; O, 10.70%.
Ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-carboxylate (6e). Yellow crystalline solid, Mp
191–192 C; yield 87%, 1H-NMR [DMSO-d6],  7.45 (m, 5H, Ar), 7.36 (m, 2H, Ar), 7.26 (m, 3H, Ar),
7.04 (s, 2H, NH2), 4.26 (s, 1H), 3.75 (q, 2H, CH2), 0.73 (t, 3H, CH3); 13C-NMR: [DMSO-d6],
: ppm = 156.5 (C=O), 159.1 (C), 154.2 (C), 144.1 (C), 133.1 (C), 129.9 (CH), 128.6 (2CH),
128.4 (2CH), 128.0 (2CH), 127.3 (2CH), 127.1 (CH), 119.7 (CN), 108.9 (C), 60.19 (CH2), 56.9 (C),
40.1 (CH), 13.2 (CH3); MS: m/z % 346.1 (M+100); Anal. calcd for C21H18N2O3 (346.3): C, 72.82;
H, 5.24; N, 8.09; O, 13.86. Found: C, 72.90; H, 5.28; N, 8.06; O, 13.76%.
Benzyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (6f). White crystalline solid,
Mp 199–200 C; yield 65%, 1H-NMR [DMSO-d6],  7.26 (m, 6H, Ar), 7.13 (m, 2H, Ar), 7.08 (m, 2H,
13
Ar), 6.95 (s, 2H, NH2), 5.02 (q, 2H, CH2), 4.34 (s, 1H), 2.34 (s, 3H, CH3); C-NMR: [DMSO-d6],
: ppm = 156.3 (C=O), 158.3 (C), 157.4 (C), 144.8 (C), 135.7 (C), 128.5 (2CH), 128.2 (2CH),
127.8 (CH), 127.5 (2CH), 127.1 (2CH), 126.8 (CH), 119.7 (CN), 106.8 (C), 65.7 (CH2), 57.3 (C),
18.3 (CH3); MS: m/z % 346.2 (M+100); Anal. calcd for C21H18N2O3 (346.3): C, 72.82; H, 5.24;
N, 8.09; O, 13.86. Found: C, 72.75; H, 5.13; N, 8.09; O, 14.03%.
2-Amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g). Yellow crystalline solid, Mp 162–163 C;
yield 83%, 1H-NMR [DMSO-d6],  7.80 (m, 2H, Ar), 7.57 (m, 3H, Ar), 7.45 (m, 2H, Ar), 7.37 (m, 2H,
Ar), 7.32 (s, 2H, NH2), 3.44 (s, 1H); 13C-NMR: [DMSO-d6], : ppm = 158.5 (C), 157.6 (C), 142.2 (C),
131.7 (C), 130.0 (CH), 128.9 (2CH), 128.7 (2CH), 127.9 (CH), 127.8 (2CH), 127.7 (2CH),
118.9 (CN), 117.3 (CN), 55.6 (C); MS: m/z % 299.6 (M+100); Anal. calcd for C19H13N3O (299.3):
C, 76.24; H, 4.38; N, 14.04; O, 5.35. Found: C, 76.84; H, 4.42; N, 14.01; O, 4.69%.
2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6h). Yellow crystalline solid,
Mp 172–173 C; yield 78%, 1H-NMR [DMSO-d6], : ppm = 7.30 (m, 2H, Ar), 7.18 (m, 3H, Ar), 7.02
(s, 2H, NH2), 4.20 (s, 1H), 2.62 (m, 2H, CH2), 2.25 (m, 2H, CH2), 1.91 (m, 2H, CH2); 13C-NMR:
[DMSO-d6], : ppm = 198.8 (C=O), 174.4 (C), 164.4 (C), 144.8 (C), 128.3 (2CH), 127.1 (2CH),
126.5 (CH), 119.7 (CN), 113.8 (C), 58.2 (C), 36.3 (C), 35.4 (CH2), 26.4 (CH2), 19.8 (CH2); MS: m/z %
266.1 (M+100); Anal. calcd for C16H14N2O2 (266.2): C, 72.16; H, 5.30; N, 10.52; O, 12.02. Found:
C, 72.04; H, 5.54; N, 10.41; O, 11.98%.

Molecules 2012, 17
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Diethyl 5,5-dicyano-4,6-dimethyL-2-phenylcyclohexa-3,6-diene-1,3-dicarboxylate (7). Pale yellow
1
crystalline solid, Mp 210 C; yield 25%, H-NMR [DMSO-d6], : ppm = 7.60–7.42 (m, 5H, Ar), 7,
7.02 (s, 2H, NH2), 3.95 (s, 1H), 3.93 (m, 4H, 2CH2), 2.5 (S, 3H, CH3), 2.31 (S, 3H, CH3), 1.04 (m, 6H,
2CH3); 13C-NMR: [DMSO-d6], : ppm = 167.5 (2C=O), 137 (C), 136 (C), 129 (2C), 128 (C), 127 (C),
125 (C), 123 (2C), 117 (C), 116 (C), 61 (2C), 45 (C), 30 (C), 25 (2C), 15 (2C); MS: m/z % 378.4
(M+100); Anal. calcd for C22H22N2O4 (378.16): C, 69.83; H, 5.86; N, 7.40; O, 16.91. Found: C, 71.2;
H, 5.80; N, 7.5; O, 16.31%.
3.3. Experimental Procedure for the Synthesis of 4
A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol) and 10% mol L-proline, then
pyrazolon-5-one (3, 0.01 mol) was added. The mixture was refluxed in ethanol (15 mL) for 4 h and
followed by TLC. The crude compound formed was recrystallized from ethanol and further purified
using column chromatography using ethyl acetate as eluent.
6-Amino-3,4-dimethyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4). Yellow crystalline
1
solid, Mp 225–226 C; yield 81%, H-NMR [DMSO-d6],  12.1 (s, 1H, NH); 7.30 (m, 2H, Ar), 7.26
(m, 2H, Ar), 7.18 (d, J = 7.2 Hz, 1H, Ar), 6.78 (s, 2H, NH2), 1.79 (s, 3H, CH3), 1.76 (t, 3H, CH3);
13C-NMR: [DMSO-d6], : ppm = 159.9, 153.9, 147.3, 134.9, 128.0, 126.3, 126.0, 119.9, 116.3, 63.6,
30.1, 24.6, 13.6; MS: m/z % 266.1 (M+100); Anal. calcd for C15H14N4O (266.3): C, 67.65; H, 5.30;
N, 21.04; O, 6.01. Found: C, 67.66; H, 5.01; N, 20.98, O, 6.33%.
3.4. Experimental Procedure for the Synthesis of 13
A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol), ethyl propiolate (8, 0.01 mol),
pyrazolon-5-one (3, 0.01 mol) and L-proline (9, 10% mol) was added together. The mixture was
refluxed in ethanol (15 mL) for 4 h, followed by TLC. The crude compound formed was recrystallized
from ethanol and further purified using column chromatography using ethyl acetate as eluent.
Ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate (13). White crystalline solid, Mp 227–230 C;
yield 65%, 1H-NMR [DMSO-d6],  7.71 (s, 1H), 7.32 (m, 2H, Ar), 7.24 (m, 1H, Ar), 7.22 (m, 2H, Ar),
13
7.02 (s, 2H, NH2), 4.23 (s, 2H, NH2), 4.01 (m, 2H, CH2), 1.07 (t, 3H, CH3); C-NMR: [DMSO-d6],
: ppm = 164.5 (CH-pyran), 164.1 (C=O), 158.6 (C), 133.3 (CH), 130.5 (2CH), 128.4 (CH),
126.5 (CH), 119.6 (CN), 11.3 (C), 61.7 (CH2), 57.3 (C), 30.7 (CH), 14.1 (CH3); MS: m/z % 270.1
(M+100); Anal. calcd for C15H14N2O3 (270.28): C, 66.66; H, 5.22; N, 10.36; O, 17.76. Found:
C, 66.73; H, 5.34; N, 10.35, O, 17.64%.
4. Conclusions
L-Proline could be used as a catalyst in the reaction of active methylene ketones with
,β-unsaturated nitriles in a multicomponent reaction that leads to creation of a chiral center,
and bringing about enantioselectivity for the preparation of the produced pyrans and thiopyrans in
good yields.

Molecules 2012, 17
4310
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding the work through the research group project NO. (RGP-VPP-041).
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© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).