The organocatalytic highly enantioselective Knoevenagel condensation: applications in the synthesis of various chiral amide derivatives

Article abstract of DOI:10.1007/s13738-019-01670-x

Abstract: In this work, efficient organocatalysts were designed, synthesized and successfully applied to the Knoevenagel condensation. In this reaction, different α-branched aldehydes were treated with various malonate compounds to give the desired produc

Full text of DOI:10.1007/s13738-019-01670-x

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01670-x
ORIGINAL PAPER
The organocatalytic highly enantioselective Knoevenagel
condensation: applications in the synthesis of various chiral amide
derivatives
Veeramanoharan Ashokkumar1 · Ayyanar Siva1 · Balakrishnan Sankar1
Received: 11 December 2018 / Accepted: 5 April 2019
© Iranian Chemical Society 2019
Abstract
In this work, efcient organocatalysts were designed, synthesized and successfully applied to the Knoevenagel condensation.
In this reaction, diferent α-branched aldehydes were treated with various malonate compounds to give the desired products
up to 97% yield and excellent e.r up to 99.68:0.32 under the mild reaction conditions. Moreover, the Knoevenagel product
was converted into diferent chiral amide derivatives in higher enantioselectivity.
Graphical abstract
We have designed and synthesized efcient chiral organocatalysts and successfully applied to the Knoevenagel condensa-
tion reaction. In this reaction, the diferent α-branched aldehydes were treated with various malonate derivatives to give
enantiomerically enriched Knoevenagel products with higher chemical yield (up to 97%) and excellent e.r up to 99.68 0.32
via dynamic kinetic resolution. Further the Knoevenagel adduct was converted into enantiomerically enriched valuable
γ-alkyl-substituted amides without loss in enantiomeric ratio.
organocatalysts
COOR2
COOR2
R3
N
COOR2
COOR2
(10 mol %)
R1
CHO
C
O
R4
R1
Ph
TEA/EtOH, r.t.
16 examples
5 examples
R
O
N
O
O
O
O
N
N
O
R
N
2Br
OMe
MeO
R = H (10a)
R = allyl (10b)
Organocatalysts
Keywords Organocatalysts · Enantioselectivity · Knoevenagel condensation · Dynamic kinetic resolution · Chiral amide
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01670-x) contains
The Knoevenagel condensation is a powerful, general, and
supplementary material, which is available to authorized users.
frequently used reaction for the construction of C–C bonds
[1–5], and archetype of modern organocatalysis [6–10].
The reaction has been successfully utilized for the syn-
thesis of diferent kinds of organic compounds including
coumarin derivatives [11], cosmetics [12], perfumes [13]
and pharmaceutical chemicals [14]. Various catalysts,
* Veeramanoharan Ashokkumar
veeraashok86@gmail.com
* Ayyanar Siva
drasiva@gmail.com; siva.chem@mkuniversity.org
Extended author information available on the last page of the article
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Scheme 1 Asymmetric Kno-
evenagel condensation reaction
via dynamic kinetic resolution
COOR2
COOR2
organocatalysts
(10 mol %)
COOR2
COOR2
COOR2
COOR2
CHO
TEA/EtOH, r.t.
R1
R1
4
R1
2
1
3
R2 = CH3, C2H5, iPr, nBu, nPr, Bnz
R1 = H, 4-OCH3, 4-CH3, 4-Cl, 4-Br, 4-F, 3-F, 2-F,c-C6H11
such as Lewis acids [15], zeolites [16], calcite [17], ionic
liquids [18, 19], surfactants [20], ammonium salts [21,
22], aminoacids [23–25], dimethylaminopyridine [26],
potassium fuoride mixture, synthetic phosphates [27–29],
urea-derived catalysts [30, 31] and organocatalyst [32, 33],
have been employed to catalyse this kind of reactions in
recent decades. First, in 2011, List’s group reported an
example of asymmetric Knoevenagel condensation of
racemic-branched aldehydes to give the corresponding
enantiomerically enriched products in dynamic kinetic
resolution (DKR) using cinchona catalysts [34–37].
The dynamic kinetic resolution (DKR) is one of the
most signifcant approaches to prepare optically active
compounds [38–43]. In spite of their potential utility, some
of these methods are limited by low yields, longer reac-
tion times, harsh conditions, and the use of toxic solvents.
Thus, there is an increasing interest in the development of
new catalysts under mild reaction conditions with cleaner
reaction profles, good yields, less catalyst loading, and
simple experimental procedures. The synthesis of chiral
amides has received wide attention given its presence as
the most common structural motifs in modern pharma-
ceuticals and biologically active compounds [44–48]. In
this connection, here we have explored an asymmetric
Knoevenagel condensation reaction that proceeds through
dynamic kinetic resolution (DKR) of α-branched alde-
hydes with malonate compounds, catalysed by cinchona-
derived organocatalysts under mild reaction conditions
(Scheme 1). Further, the desired γ-substituted chiral amide
derivatives can be obtained from the Knoevenagel prod-
uct, by reacting with diferent amine compounds in higher
chemical yield and excellent enantiomeric ratio. Herein,
we present a new method to obtain γ-alkyl-substituted chi-
ral amides in an asymmetric fashion using Knoevenagel
products obtained.
3-fluorobenzaldehyde, 2-fluorobenzaldehyde, diethyl-
malonate, dimethyl malonate, and diisopropyl malonate,
N-bromosuccinimide were obtained from Sigma-Aldrich,
acetic acid and ZnCl2 were purchased from Merck, and all
the solvents were obtained from Laboratory Grade.
The 1H and 13C NMR spectra were recorded on a Bruker
(Avance) 300 and 400 MHz NMR instrument using TMS
as an internal standard and CDCl3 as a solvent. Standard
Bruker software was used throughout. Chemical shifts are
given in parts per million (δ-scale), and the coupling con-
stants are given in Hertz. Silica gel-G plates (Merck) were
used for TLC analysis with a mixture of n-hexane and ethyl
acetate as an eluent. Column chromatography was carried
out in silica gel (60–120 mesh) using n-hexane and ethyl
acetate as an eluent. High-resolution mass spectroscopic
(HRMS) data were obtained using Bruker Apex IV RTMS.
The HPLC was recorded in SHIMADZU LC-6AD with Chi-
ral Column (Chiralcel OD-H), using HPLC grade n-hexane
and isopropanol as solvents.
Experimental procedure
Preparation of compound 7
About 1 g (7.3 mmol) of pentaerythritol was dissolved in
1:1 ratio of ethanol and acetic acid at 80 °C under constant
stirring. Then, 1.64 mL (14.7 mmol) of p-tolualdehyde was
added and followed by the addition of anhydrous ZnCl2 in
a catalytic amount. Then, the mixture was allowed to refux
for about 12 h. After completion of the reaction, the reaction
mixture was extracted with ethyl acetate and the solvent was
removed under vacuum. The crude reaction mass was puri-
fed by column chromatography using pet. ether and ethyl
acetate as an eluent, and isolated yield of 7 is 2 g, 80% yield.
1H NMR (300 MHz, CDCl3) δH 2.19 (s, 6H), 3.74 (s, 8H),
5.99 (s, 2H), 7.11 (d, J=6.0 Hz, 4H), 7.38 (d, J=6.1 Hz,
4H); 13C NMR (75 MHz, CDCl3) δC 21.33, 31.90, 68.67,
109.34, 127.33, 128.86, 134.31, 137.58.
Experimental section
Materials and methods
Preparation of compound 8
All the chemicals and reagents used in this work were of
analytical grade. Mesitylene, allylbromide, (+)-quinine,
and benzoyl peroxide were obtained from Alfa Aesar, ben-
zaldehyde, 4-methylbenzaldehyde, 4-fuorobenzaldehyde,
Compound 7 (1 g, 2.9 mmol), NBS (1.1 g 6.1 mmol) and the
catalytic amount of benzoyl peroxide and benzene (15 ml)
were taken in a 100-ml RB fask. The reaction mixture was
refuxed for about 6 h at 70 °C. The reaction was monitored
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Journal of the Iranian Chemical Society
2+
by TLC, after completion of reaction, and the reaction mix-
ture was poured into 10% sodium bicarbonate solution,
extracted with ethyl acetate, washed with brine and dried
over sodium sulphate. The product was concentrated and
purifed by column chromatography using pet. ether and
ethyl acetate as an eluent. The isolated yield of 8 is 1.05 g,
157.34. HRMS (ESI+) m/z calculated for C69H78N4O8
2Br−Na(M+Na+) 1247.4067, found 1247.4064.
General procedure for the catalytic enantioselective
Knoevenagel condensation reaction
1
72% yield. H NMR (300 MHz, CDCl3) δH 3.74 (s, 8H),
The catalyst 10a/10b (0.01 mmol) and aldehyde 1
(0.1 mmol) were dissolved in ethanol (2.0 mL). The reac-
tion mixture was stirred for about 10 min, and then malonate
2 (1.0 mmol) and triethylamine (0.2 mmol) were added at
room temperature. After vigorous stirring for about 48–72 h,
the reaction mixture was poured into water (3 mL) and
extracted with ethyl acetate (3×15 mL). The organic frac-
tion was dried over anhydrous MgSO4 and concentrated
under reduced pressure. The crude product was purifed by
column chromatography to aford 3a–p as desired products.
4.56 (s, 4H), 5.98 (s, 2H), 7.32 (d, J = 6.2 Hz, 4H), 7.46
(d, J=6.0 Hz, 4H); 13C NMR (75 MHz, CDCl3) δC 31.87,
33.33, 68.53, 109.32, 127.71, 128.89, 137.13.
Synthesis of quinine (containing free C9‑OH)‑based chiral
organocatalyst (10a)
A mixture of compound 8 (0.5 g, 1 mmol) and quinine with
free C9-OH 9a (0.68 g, 2.1 mmol) was dissolved in 15 ml
of EtOH/DMF/ACN (30:50:20 ratio), and the whole reac-
tion mixture was refuxed overnight. The of-white solid
was fltered of, washed with diethyl ether and dried, to get
Characterization of Knoevenagel products
1
pure white organocatalyst (10a) (2.12 g, 92% yield). H
(R)‑diethyl 2‑(2‑phenylpropylidene)malonate (3a)
NMR (400 MHz, CDCl3) δH 1.23 (m, 2H), 1.47 (m, 8H),
2.60 (m, 2H), 3.37–3.46 (m, 8H), 3.73 (s, 8H), 3.81 (s,
6H), 3.86 (m, 2H), 4.50 (s, 4H), 5.03–5.17 (m, 6H), 5.41
(d, J = 8.2 Hz, 2H), 5.70 (m, 2H), 5.98 (s, 2H), 7.19 (d,
J=9.3 Hz, 4H), 7.37–7.39 (m, 6H), 7.52 (d, J=9.2 Hz, 4H),
7.85 (d, J=8.4 Hz, 2H), 8.65 (d, J=8.4 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δC 23.81, 26.19, 28.24, 31.97, 38.85,
52.81, 55.82, 59.34, 63.81, 65.23, 79.95, 101.3, 109.34,
117.69, 122.03, 122.62, 126.13, 127.39, 128.60, 128.95,
129.61, 130.67, 134.31, 137.55, 142.81, 147.18, 148.21,
1
Colourless oil, Yield: 92%, e.r: 97.58:2.48. H NMR
(300 MHz, CDCl3) δH 1.27 (t, J = 7.2 Hz, 3H), 1.34 (t,
J = 7.2 Hz, 3H), 1.44 (d, J = 5.8 Hz, 3H), 3.88 (m, 1H),
4.21 (q, J=6.3, Hz, 2H), 4.34 (q, J=6.3 Hz, 2H), 6.98 (d,
J = 6.4 Hz, 1H), 7.24–7.34 (m, 5H); 13C NMR (75 MHz,
CDCl3) δc 14.14, 14.24, 20.15, 39.48, 61.39, 126.94, 127.17,
128.84, 142.49, 151.85, 164.02. HRMS (ESI+) m/z calcu-
lated for C16H20O4Na(M+Na+) 299.1254, found 299.1256.
The enantiomeric excess was determined by HPLC, Chi-
ralcel (OD-H), 254 nm, hexane/IPA 97:3, flow rate:
1 mL min−1, retention time: 14.19 min (major), 19.97 min
(minor).
2+
157.36. HRMS (ESI+) m/z calculated for C61H70N4O8
2Br−Na(M+Na+) 1167.3441, found 1167.3445.
Synthesis of allylated quinine‑based chiral organocatalyst
(10b)
(R)‑diethyl 2‑(2‑(4‑methoxyphenyl)propylidene)malonate
(3b)
A mixture of compound 8 (0.5 g, 1 mmol) and allylated
quinine 9b (0.77 g, 2.1 mmol) was dissolved in 15 ml of
EtOH/DMF/ACN (30:50:20 ratio), and the whole reaction
mixture was refuxed overnight. The of-white solid was fl-
tered of, washed with diethyl ether and dried, to get pure
1
Colourless oil, Yield: 95%, e.r: 98.32:1.68. H NMR
(300 MHz, CDCl3) δH 1.27 (t, J = 7.1 Hz, 3H), 1.32 (t,
J=6.9 Hz, 3H), 1.42 (d, J=6.7 Hz, 3H), 3.51–3.49 (m, 1H),
3.80 (s, 1H), 4.22 (q, J=7.0 Hz, 2H), 4.33 (q, J=6.7 Hz,
2H), 6.86 (d, J=8.0 Hz, 2H), 6.93 (d, J=6.4 Hz, 1H), 7.15
(d, J=7.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δC 14.11,
14.21, 20.21, 29.74, 38.73, 55.34, 61.38, 114.14, 126.14,
128.15, 152.07, 165.83. HRMS (ESI+) m/z calculated for
C17H22O5Na(M + Na+) 329.1359, found 329.1356. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 11.24 min (major), 16.57 min (minor).
1
white organocatalyst (10b) (3.0 g, 90% yield). H NMR
(400 MHz, CDCl3) δH 1.23 (m, 2H), 1.47 (m, 8H), 2.60
(m, 2H), 3.37–3.46 (m, 8H), 3.73 (s, 8H), 3.81 (s, 6H),
4.06 (m, 6H), 4.50 (s, 4H), 5.03–5.17 (m, 6H), 5.31–5.43
(m, 4H), 5.70 (m, 2H), 5.98 (s, 2H), 6.07 (m, 2H), 7.19
(d, J=9.3 Hz, 4H), 7.37–7.39 (m, 6H), 7.52 (d, J=9.2 Hz,
4H), 7.85 (d, J=8.4 Hz, 2H), 8.65 (d, J=8.4 Hz, 2H); 13
C
NMR (125 MHz, CDCl3) δC 24.10, 25.23, 28.27, 31.92,
38.94, 52.57, 55.81, 59.30, 65.33, 72.09, 101.38, 109.25,
117.66, 121.22, 122.01, 122.36, 126.14, 127.32, 128.60,
128.85, 129.51, 130.85, 137.55, 142.89, 147.15, 148.27,
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Journal of the Iranian Chemical Society
(R)‑diethyl 2‑(2‑(p‑tolyl)propylidene)malonate (3c)
J=7.1 Hz, 3H), 1.44 (d, J=6.0 Hz, 3H), 3.88–3.91 (m, 1H),
4.23 (q, J=6.9, Hz, 2H), 4.33 (q, J=6.9 Hz, 2H), 6.90–6.95
(m, 2H), 6.95–6.97 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H),
7.25–7.30 (m, 1H); 13C NMR (75 MHz, CDCl3) δc 14.10,
14.16, 20.11, 39.21, 61.52, 61.84, 113.78, 113.96, 114.04,
114.21, 122.82, 122.86, 127.32, 130.23, 144.96, 145.00,
150.81, 162.05, 163.94, 164.05, 165.38. HRMS (ESI+)
m/z calculated for C16H19O4F1Na(M + Na+) 317.1160,
found 317.1157. The enantiomeric excess was determined
by HPLC, Chiralcel (OD-H), 254 nm, hexane/IPA 97:3,
fow rate: 1 mL min−1, retention time: 16.17 min (major),
24.15 min (minor).
1
Colourless oil, Yield: 96%, e.r: 98.41:1.59. H NMR
(300 MHz, CDCl3) δH 1.26 (t, J = 7.1 Hz, 3H), 1.39 (t,
J = 7.1 Hz, 3H), 1.45 (d, J = 7.8 Hz, 3H), 2.32 (s, 3H),
3.83–3.87 (m, 1H), 4.21 (q, J = 6.9 Hz, 2H), 4.35 (q,
J=6.9 Hz, 2H), 6.96 (d, J=6.7 Hz, 1H), 7.12–7.16 (m, 4H);
13C NMR (75 MHz, CDCl3) δC 14.11, 14.23, 20.24, 21.04,
39.18, 61.37, 61.39, 126.58, 127.02, 129.44, 136.59, 139.41,
152.01, 164.10, 165.57. HRMS (ESI+) m/z calculated for
C17H22O4Na(M + Na+) 313.1410, found 313.1408. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 12.71 min (major), 21.94 min (minor).
(R)‑diethyl 2‑(2‑(3‑fuorophenyl)propylidene)malonate (3g)
1
Colourless oil, Yield: 90%, e.r: 94.89:5.11. H NMR
(R)‑diethyl 2‑(2‑(4‑bromophenyl)propylidene)malonate
(3d)
(300 MHz, CDCl3) δH 1.27 (t, J = 7.1 Hz, 3H), 1.34 (t,
J = 7.1 Hz, 3H), 1.46 (d, J = 6.3 Hz, 3H), 3.88–3.91 (m,
1H), 4.21 (q, J = 6.9 Hz, 2H), 4.33 (q, J = 6.9 Hz, 2H),
6.91–6.98 (m, 3H), 7.06 (d, J = 7.9, 1H), 7.26–7.30 (m,
1H); 13C NMR (75 MHz, CDCl3) δc 14.10, 14.17, 20.10,
39.18, 61.51, 113.79, 113.94, 114.05, 114.21, 122.85,
122.88, 127.27, 130.19, 130.27, 144.95, 145.00, 150.83,
163.93, 165.35, 190.26. HRMS (ESI+) m/z calculated for
C16H19O4F1Na(M + Na+) 317.1160, found 317.1162. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 10.98 min (major), 20.20 min (minor).
1
Colourless oil, Yield: 85%, e.r: 95.54:4.46. H NMR
(300 MHz, CDCl3) δ 1.30 (t, J=5.9 Hz, 3H), 1.36–1.32 (m,
3H), 1.44 (d, J=6.4 Hz, 3H), 3.88–3.84 (m, 1H), 4.22 (q,
J=6.8, Hz, 2H), 4.32 (q, J=6.8 Hz, 2H), 6.91 (d, J=8.9 Hz,
1H), 7.13 (d, J=6.6 Hz, 2H), 7.43 (d, J=6.6 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) δc 14.02, 14.16, 20.06, 38.95, 61.75,
119.94, 127.65, 128.83, 133.31, 141.36, 150.90, 168.08.
HRMS (ESI+) m/z calculated for C16H19O4Br1Na(M+Na+)
377.0359, found 377.0357. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 17.41 min
(major), 29.65 min (minor).
(R)‑diethyl 2‑(2‑(2‑fuorophenyl)propylidene)malonate (3h)
1
Colourless oil, Yield: 87%, e.r: 91.89:8.11. H NMR
(300 MHz, CDCl3) δH 1.25–1.33 (m, 6H), 1.46 (d,
J=6.2 Hz, 3H), 4.14–4.19 (m, 1H), 4.22 (q, J=6.9 Hz, 2H),
4.35 (q, J=7.0 Hz, 2H), 7.00–7.05 (m, 2H), 7.07–7.12 (m,
2H), 7.19–7.25 (m, 2H); 13C NMR (75 MHz, CDCl3) δC
14.07, 14.09, 20.12, 33.78, 61.38, 61.43, 115.64, 115.84,
124.41, 124.43, 127.69, 128.23, 128.43, 128.48, 129.47,
129.84, 150.29, 150.63, 159.60, 161.55, 164.04, 165.24.
HRMS (ESI+) m/z calculated for C16H19O4F1Na(M+Na+)
317.1159, found 317.1157. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 18.79 min
(major), 25.67 min (minor).
(R)‑diethyl 2‑(2‑(4‑chlorophenyl)propylidene)malonate (3e)
1
Colourless oil, Yield: 87%, e.r: 97.45:2.55. H NMR
(300 MHz, CDCl3) δ 1.28 (t, J=6.6 Hz, 3H), 1.37–1.32 (m,
3H), 1.42 (d, J=5.8 Hz, 3H), 3.88–3.84 (m, 1H), 4.22 (q,
J=6.7, Hz, 2H), 4.33 (q, J=6.7 Hz, 2H), 6.91 (d, J=7.1 Hz,
1H), 7.19 (d, J=8.1 Hz, 2H), 7.35 (d, J=6.4 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) δc 14.06, 14.16, 20.15, 38.85,
52.15, 61.48, 61.79, 119.52, 127.15, 127.33, 128.37, 128.47,
128.87, 132.74, 140.88, 151.05, 163.92, 165.38, 168.03.
HRMS (ESI+) m/z calculated for C16H19O4Cl1Na(M+Na+)
333.0864, found 333.0866. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 14.51 min
(major), 21.74 min (minor).
(R)‑dimethyl 2‑(2‑phenylpropylidene)malonate (3i)
1
Colourless oil, Yield: 93%, e.r: 97.00:3.00. H NMR
(300 MHz, CDCl3) δH 1.44 (d, J = 6.4 Hz, 3H), 3.73 (s,
3H), 3.86 (s, 3H), 3.87–3.89 (m, 1H), 7.03 (d, J=9.4 Hz,
1H), 7.21–7.24 (m, 3H), 7.30–7.33 (m, 2H); 13C NMR
(75 MHz, CDCl3) δC 20.24, 39.65, 52.34, 126.04, 127.0,
127.12, 128.78, 142.26, 152.76, 164.42, 165.82. HRMS
(R)‑diethyl 2‑(2‑(4‑fuorophenyl)propylidene)malonate (3f)
1
Colourless oil, Yield: 92%, e.r: 97.06:2. 94. H NMR
(300 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.34 (t,
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Journal of the Iranian Chemical Society
(ESI+) m/z calculated for C14H16O4Na(M+Na+) 271.0941,
found 271.0942. The enantiomeric excess was determined
by HPLC, Chiralcel (OD-H), 254 nm, hexane/IPA 97:3,
fow rate: 1 mL min−1, retention time: 9.73 min (major),
17.65 min (minor).
(R)‑dibutyl 2‑(2‑phenylpropylidene)malonate (3m)
1
Colourless oil, Yield: 97%, e.r: 98.94:1.06. H NMR
(300 MHz, CDCl3) δH 0.91 (t, J = 6.1 Hz, 3H), 0.94 (t,
J = 6.2 Hz, 3H), 1.36–1.44 (m, 4H), 1.45 (d, J = 6.0 Hz,
3H), 1.56–1.66 (m, 2H), 1.64–1.70 (m, 2H), 3.86–3.89
(m, 1H), 4.16 (t, J=5.7 Hz, 2H), 4.26 (t, J=5.4 Hz, 2H),
6.98 (d, J=7.3 Hz, 1H), 7.22–7.26 (m, 3H), 7.31–7.34 (m,
2H); 13C NMR (75 MHz, CDCl3) δC 13.67, 19.09, 20.27,
30.59, 39.56, 65.29, 126.92, 126.96, 127.13, 128.75, 142.42,
151.67, 164.15, 165.72. HRMS (ESI+) m/z calculated for
C20H28O4Na(M + Na+) 355.1880, found 355.1882. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 11.32 min (major), 19.64 min (minor).
(R)‑dimethyl 2‑(2‑(p‑tolyl)propylidene)malonate (3j)
1
Colourless oil, Yield: 95%, e.r: 99.11:0. 89. H NMR
(300 MHz, CDCl3) δH 1.43 (d, J = 6.4 Hz, 3H), 2.32 (s,
3H), 3.76 (s, 3H), 3.86 (s, 3H), 4.10–4.15 (m, 1H), 7.02 (d,
J=9.4 Hz, 1H), 7.14 (s, 4H); 13C NMR (75 MHz, CDCl3) δC
20.23, 21.00, 39.26, 52.37, 126.96, 129.46, 136.62, 139.29,
153.09, 164.47, 165.89. HRMS (ESI+) m/z calculated for
C15H18O4Na(M + Na+) 285.1097, found 285.1095. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 8.71 min (major), 15.94 min (minor).
(R)‑dipropyl 2‑(2‑phenylpropylidene)malonate (3n)
1
Colourless oil, Yield: 95%, e.r: 98.42:1.58. H NMR
(300 MHz, CDCl3) δH 0.93 (t, J = 6.1 Hz, 3H), 0.97
(t, J = 6.0 Hz, 3H), 1.45 (d, J = 4.3 Hz, 3H), 1.60–1.70
(m, 2H), 1.71–1.77 (m, 2H), 3.87–3.90 (m, 1H), 4.12 (t,
J=5.3 Hz, 2H), 4.23 (t, J=5.2 Hz, 2H), 6.99 (d, J=5.9 Hz,
1H), 7.21–7.26 (m, 3H), 7.31–7.34 (m, 2H); 13C NMR
(75 MHz, CDCl3) δC 10.33, 10.43, 20.26, 21.94, 22.00,
39.55, 66.94, 67.01, 126.94, 127.09, 127.15, 128.81, 142.44,
151.73, 164.19, 165.74. HRMS (ESI+) m/z calculated for
C18H24O4Na(M + Na+) 327.1567, found 327.1563. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 20.10 min (major), 35.64 min (minor).
(R)‑diisopropyl 2‑(2‑phenylpropylidene)malonate (3k)
1
Colourless oil, Yield: 95%, e.r: 98.58:1.42. H NMR
(300 MHz, CDCl3) δH 1.28–1.24 (m, 6H), 1.33 (dd, J=6.1,
4.1 Hz, 6H), 1.45 (d, J= 6.7 Hz, 3H), 3.86–3.89 (m, 1H),
5.07 (p, J = 6.2 Hz, 1H), 5.22 (p, J = 6.2 Hz, 1H), 6.92
(d, J = 9.9 Hz, 1H), 7.28- 7.23 (m, 3H), 7.38–7.33 (m,
2H); 13C NMR (75 MHz, CDCl3) δC 20.28, 21.71, 39.47,
60.38, 68.95, 126.86, 127.12, 127.57, 128.70, 142.57,
150.81, 163.59, 165.17. HRMS (ESI+) m/z calculated for
C18H24O4Na(M + Na+) 327.1567, found 327.1569. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 13.11 min (major), 22.65 min (minor).
(R)‑dibutyl 2‑(2‑phenylpropylidene)malonate (3o)
1
Colourless oil, Yield: 85%, e.r: 93.04:6.96. H NMR
(300 MHz, CDCl3) δH 1.40 (d, J=5.6 Hz, 3H), 3.82–3.86 (m,
1H), 5.18 (q, J=5.4 Hz, 2H), 5.27 (q, J=5.2 Hz, 2H), 7.06
(d, J=6.0 Hz, 1H), 7.14–7.30 (m, 15H); 13C NMR (75 MHz,
CDCl3) δC 20.31, 39.65, 67.01, 67.28, 126.01, 126.22,
127.00, 127.13, 128.18, 128.29, 128.42, 128.55, 128.66,
128.77, 135.34, 135.47, 142.23, 153.15, 163.90, 165.29.
HRMS (ESI+) m/z calculated for C26H24O4Na(M + Na+)
423.1567, found 423.1561. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 25.51 min
(major), 39.41 min (minor).
(R)‑diisopropyl 2‑(2‑(p‑tolyl)propylidene)malonate (3l)
1
Colourless oil, Yield: 96%, e.r: 99.69:0.31. H NMR
(300 MHz, CDCl3) δH 1.26–1.24 (m, 6H), 1.33 (dd, J=6.1,
3.0 Hz, 6H), 1.43 (d, J = 6.7 Hz, 3H), 2.32 (s, 3H), 4.12
(q, J = 7.1 Hz, 1H), 5.06 (p, J = 6.2 Hz, 1H), 5.22 (p,
J = 6.2 Hz, 1H), 6.91 (d, J = 9.3 Hz, 1H), 7.17- 7.12 (m,
4H); 13C NMR (75 MHz, CDCl3) δC 20.22, 20.90, 21.13,
29.12, 39.11, 68.90, 127.05, 127.37, 129.49, 136.47, 139.57,
151.07, 163.62, 165.24. HRMS (ESI+) m/z calculated for
C19H26O4Na(M + Na+) 341.1723, found 341.1721. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 12.45 min (major), 27.34 min (minor).
(R)‑diethyl 2‑(2‑cyclohexylbutylidene)malonate (3p)
1
Colourless oil, Yield: 89%, e.r: 95.56:4.44. H NMR
300 MHz, CDCl3) δH 0.85–0.91 (m, 2H), 0.99 (d,
J = 6.7 Hz, 3H), 1.09–1.21 (m, 4H), 1.24–1.30 (m, 6H),
1.60–1.74 (m, 5H), 2.26–2.28 (m, 1H), 4.19 (dd, J = 7.1,
1 3

Journal of the Iranian Chemical Society
7.2 Hz, 2H), 4.25 (dd, J = 7.1, 7.2 Hz, 2H), 6.79 (d,
J = 11.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δC 14.1,
14.2, 17.0, 26.3, 26.4, 30.4, 30.9, 40.3, 42.8, 53.5, 61.1,
61.2, 127.6, 153.5, 164.1, 165.9. HRMS (ESI+) m/z
calculated for C16H26O4Na(M + Na+) 305.1723, found
355.1725. The enantiomeric excess was determined by
HPLC, Chiralcel (OD-H), 254 nm, hexane/IPA 97:3,
fow rate: 1 mL min−1, retention time: 19.21 min (major),
28.16 min (minor).
(R)‑4‑phenylpentanoic acid (13a)
A mixture of compound 12a (50 mg, 0.242 mmol) and
LiOH(11.5 mg, 0.484 mmol, 2 equiv.) was stirred in THF/
water (2:1) for 2 h, then we got lithium salt of acid, it was
neutralized by dil HCl, and then the residue was purifed
by column chromatography (hexane/ethyl acetate = 7:3).
1
Colourless oil, Yield: 87%, e.r: 96.38:3.62. H NMR
(300 MHz, CDCl3) δ 1.28 (t, J = 4.8 Hz, 3H), 1.85–2.00
(m, 2H), 2.17–2.30 (m, 2H), 2.68–2.78 (m, 1H), 7.14–7.24
(m, 3H), 7.30 (t, J = 6.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δc 22.18, 32.20, 32.92, 39.32, 126.32, 127.01,
128.58, 146.04, 179.83. HRMS (ESI+) m/z calculated for
C11H14O2Na(M + Na+) 201.0886, found 201.0881. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 10.93 min (major), 24.10 min (minor).
Characterization of applications of Knoevenagel
product
(R)‑diethyl‑2‑(2‑phenylpropyl)malonate (11a)
A mixture of compound 3a (100 mg, 0.362 mmol) and
Pd(OH)2/C (10 mg) in ethyl acetate was stirred for 2 h at
room temperature under H2 (1 atm). The mixture was fl-
tered on Celite, the fltrate was evaporated, and the resi-
due was purifed by column chromatography (hexane/ethyl
acetate=8:2). Colourless oil, Yield: 92%, e.r: 98.53:1.47. 1H
NMR (300 MHz, CDCl3) δ 1.21 (t, J=5.8 Hz, 3H), 1.26 (t,
J=7.1 Hz, 3H), 1.28 (d, J=5.8 Hz, 3H), 2.13–2.25 (m, 2H),
2.70–2.75 (m, 1H), 3.16–3.19 (m, 1H), 4.06–4.12 (m, 2H),
4.13–4.22 (m, 2H), 7.16–7.31(m, 5H); 13C NMR (75 MHz,
CDCl3) δc 14.02, 14.13, 22.43, 36.95, 37.84, 61.31, 61.34,
126.48, 127.15, 128.56, 145.42, 169.49, 169.56. HRMS
(ESI+) m/z calculated for C16H22O4Na(M+Na+) 301.1410,
found 301.1405. The enantiomeric excess was determined
by HPLC, Chiralcel (OD-H), 254 nm, hexane/IPA 97:3,
fow rate: 1 mL min−1, retention time: 8.76 min (major),
21.85 min (minor).
General procedure for the synthesis of chiral amide
derivatives
A solution of EDCI (0.673 mmol) and HOBt (0.673 mmol)
in CH2Cl2 (3 mL) was added dropwise to a stirred sus-
pension of acid 13a (0.561 mmol) and diferent types of
amine (0.616 mmol) in CH2Cl2 (3 mL) at 0 °C under argon
atmosphere, which were stirred for 12 h. The reaction was
monitored by TLC; after the completion of the reaction, the
mixture was added with EtOAc (20 ml) and the organic solu-
tion was washed with H2O (10 mL) and brine (10 mL), dried
(Na2SO4), and concentrated in vacuo. Purifcation of the
residue by column chromatography (silica gel, PE–EtOAc.
4:1) aforded pure amide derivatives.
(R)‑N,4‑diphenylpentanamide (15aa)
(R)‑ethyl‑4‑phenylpentanoate (12a)
White solid, Yield: 92%, e.r: 98.82:1.18. 1H NMR
(300 MHz, CDCl3) δH 1.16 (d, J=6.2 Hz, 3H), 1.90–1.93
(m, 2H), 1.96 (t, J=8.6 Hz, 2H), 2.48–2.55 (m, 1H), 7.18
(t, J=5.8 Hz, 1H), 7.32 (d, J=6.2 Hz, 2H), 7.38–7.45 (m,
5H), 7.56 (d, J = 6.4 Hz, 2H), 7.98 (brS, 1H); 13C NMR
(75 MHz, CDCl3) δC 20.44, 32.07, 33.27, 37.85, 109.00,
126.02, 128.19, 128.85, 147.19, 150.22, 155.61, 179.85.
HRMS (ESI+) m/z calculated for C17H19NONa(M + Na+)
276.1359, found 276.1355. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 11.13 min
(major), 28.81 min (minor).
A mixture of compound 11a (60 mg, 0.216 mmol),
LiCl (19.4 mg, 0.432 mmol, 2 equiv.) and H2O (8 μL,
0.432 mmol, 2 equiv.) in dry DMSO was stirred for 20 h
at 160 °C. After completion of the reaction the residue
was purified by column chromatography (hexane/ethyl
1
acetate = 8:2). Yellow oil, Yield: 90%, e.r: 98.36:1.64. H
NMR (300 MHz, CDCl3) δ 1.22 (t, J = 5.8 Hz, 3H), 1.27
(d, J=6.2 Hz, 3H), 1.87–1.97 (m, 2H), 2.13–2.17 (m, 2H),
2.59–2.68 (m, 1H), 3.98–4.04 (m, 2H), 7.10–7.25 (m, 5H);
13C NMR (75 MHz, CDCl3) δc 14.24, 22.18, 32.63, 33.22,
39.47, 60.23, 126.22, 127.07, 128.49, 146.34, 173.74.
HRMS (ESI+) m/z calculated for C13H18O2Na(M + Na+)
229.1199, found 229.1193. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 12.75 min
(major), 27.84 min (minor).
(R)‑4‑phenyl‑N‑(pyridin‑4‑yl)pentanamide (15ab)
White solid, Yield: 93%, e.r: 98.49:1.51. 1H NMR
(300 MHz, DCl3) δH 1.16 (d, J=6.2 Hz, 3H), 1.83–1.90 (m,
2H), 2.04 (t, J=7.7 Hz, 2H), 2.48–2.55 (m, 1H), 7.17–7.29
1 3

Journal of the Iranian Chemical Society
(m, 5H), 8.41 (d, J=6.5 Hz, 2H), 8.56 (d, J=6.5 Hz, 2H),
8.98 (brS, 1H); 13C NMR (75 MHz, CDCl3) δC 20.42, 32.07,
33.27, 37.85, 109.00, 126.02, 128.19, 128.84, 147.13,
150.22, 155.61, 179.85. HRMS (ESI+) m/z calculated for
C16H18N2ONa(M + Na+) 277.1311, found 277.1307. The
enantiomeric excess was determined by HPLC, Chiralcel
(OD-H), 254 nm, hexane/IPA 97:3, fow rate: 1 mL min−1,
retention time: 9.98 min (major), 23.20 min (minor).
CH3
O
O
O
O
H3C
CH3
7
O
H
6
a
b
Br
O
O
O
O
Br
OH
OH
8
HO
HO
N
OR1
5
R1 = H (9a)
1 = allyl (9b)
c
MeO
R
N
9
N
R1O
O
O
O
(R)‑N‑butyl‑4‑phenylpentanamide (15ac)
N
N
OR1
N
O
10
Yellow oil, Yield: 89%, e.r: 96.74:3.26. 1H NMR (300 MHz,
CDCl3) δH 0.88 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.2 Hz,
3H), 1.29–1.37 (m, 2H), 1.43–1.50 (m, 2H), 1.882–1.89
(m, 2H), 2.04 (t, J=6.8 Hz, 2H), 2.51–2.54 (m, 1H), 3.02
R1 = H (10a)
1 = allyl (10b)
2Br
OMe
MeO
R
Scheme 2 Synthesis of chiral cinchona-derived organocatalysts (10a
and 10b). Reagents and conditions: (a) ZnCl2, CH3COOH, ethanol.
(b) NBS, BPO, benzene, refux. (c) EtOH/DMF/ACN (30:50:20),
overnight refux
(t, J=5.7 Hz, 2H), 7.16–7.28 (m, 5H), 7.76 (brS, 1H); 13
C
NMR (75 MHz, CDCl3) δC 13.82, 19.80, 20.48, 32.42,
33.64, 37.82, 38.96, 126.03, 128.14, 128.82, 147.19, 172.63.
HRMS (ESI+) m/z calculated for C15H23NONa(M + Na+)
256.1672, found 256.1668. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 7.09 min
(major), 19.26 min (minor).
IPA 97:3, fow rate: 1 mL min−1, retention time: 12.07 min
(major), 17.18 min (minor).
Results and discussion
(R)‑1‑morpholino‑4‑phenylpentan‑1‑one (15ad)
The compound 7 was obtained from the reaction between
p-tolualdehyde and pentaerythritol, and then it was bromi-
nated with NBS in the presence of benzene to aford the
bromo compound 8 in 75% yield. The cinchona-based chiral
organocatalysts were synthesized from the reaction of bromo
compound 8 with quinine free C9-OH (9a) and O-allyl qui-
nine (9b) [49–52], respectively, as depicted in scheme 2.
In the initial step of optimization, the catalyst screening
was done for enhancing chemical yield and e.r. In 2011,
List et al. [32] reported the Knoevenagel condensation of
racemic-branched aldehydes using primary amine catalysts
derived from cinchona alkaloids (9c) to deliver adducts
with reasonable yield and e.r. albeit with the addition of
60 mol% of benzene −1,3,5 tricarboxylic acid as additive
and with much higher equivalents of diethyl malonate (50
equvi.) and longer reaction times (up to 168 h) (Table 1,
entry 1). Subsequently, Gao and co-workers [33] designed
a phenylalanine–urea-catalysed Knoevenagel condensation
in a water medium, where they obtained good yields, but
poor selectivity using a higher loading (20 mol%) of catalyst
(9d) (Table 1, entry 2). In 2016, Lu group [35] demonstrated
the same methodology using chiral tertiary diamine catalyst
(9e) ofering moderate yields and e.r. for the Knoevenagel
adducts under heating conditions (60 °C) and longer reaction
times (up to 168 h) (Table 1, entry 3).
1
Colourless oil, Yield: 90%, e.r: 97.66:2.34. H NMR
(300 MHz, CDCl3) δH 1.16 (d, J=6.2 Hz, 3H), 1.79–1.88
(m, 2H), 2.04 (t, J = 7.4 Hz, 2H), 2.48–2.59 (m, 1H),
3.40–3.46 (m, 4H), 3.69–3.81 (m, 4H), 7.15–7.28 (m, 5H);
13C NMR (75 MHz, CDCl3) δC 20.47, 31.43, 32.74, 37.83,
48.02, 66.22, 126.01, 128.11, 128.87, 147.13, 172.56.
HRMS (ESI+) m/z calculated for C15H21NO2Na(M+Na+)
270.1464, found 270.1460. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
IPA 97:3, fow rate: 1 mL min−1, retention time: 15.78 min
(major), 24.87 min (minor).
(R)‑4‑phenyl‑1‑(pyrrolidin‑1‑yl)pentan‑1‑one (15ae)
1
Colourless oil, Yield: 91%, e.r: 97.87:2.13. H NMR
(300 MHz, CDCl3) δH 1.16 (d, J=6.2 Hz, 3H), 1.80–1.85
(m, 4H), 1.87–1.94 (m, 2H), 2.04 (t, J = 7.4 Hz, 2H),
2.52–2.61 (m, 1H), 39.09 (t, J=9.6 Hz, 4H), 7.19–7.29 (m,
5H); 13C NMR (75 MHz, CDCl3) δC 20.44, 25.46, 41.47,
32.75, 37.89, 49.02, 126.04, 128.20, 128.91, 147.13, 176.12.
HRMS (ESI+) m/z calculated for C15H21NONa(M + Na+)
254.1515, found 254.1510. The enantiomeric excess was
determined by HPLC, Chiralcel (OD-H), 254 nm, hexane/
1 3

Journal of the Iranian Chemical Society
Table 1 Catalyst screening for the asymmetric Knoevenagel condensation
COOEt
COOEt
COOEt
COOEt
(10 mol %)
CHO
COOEt
COOEt
organocatalysts
Ethanol, r.t.
TEA
1a
2a
3a
4a
R1
OMe
H
N
O
N
N
N
O
2HCl
N
HN
O
NH2
N
R1
9d
Previously reported catalysts
R1 = CH2-tBu
9c
9e
Entry
Catalysts
Time (h)
168
72
168
48
3a/4aa ratio
Yield (%)b
E.rcAbs.Conf.d
1
2
3
4
5
9c
60:40
62:38
97:3
90:10
96:4
91
82
75
83
92
95.5:4.5
9d
21.26:78.74
86.5:13.5
92.06:7.93
97.58:2.42
9e
10a
10b
48
Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), various catalysts (10 mol%), TEA (0.2 mmol) and ethanol (2 mL) at room temperature con-
dition in 48 h
aDetermined by GC–MS analysis
bYield of isolated product
cDetermined by HPLC analysis chiral column (Chiralcel OD-H) with hexane-IPA as an eluent
dAbsolute confguration was determined by comparison of the HPLC retention time using known literature data [32–37]
To overcome the issues with prolonged reaction time,
higher catalyst loading and heating conditions, we care-
fully designed multi-active-site-containing organocatalyst
derived from cinchona alkaloid using pentaerythritol as a
linker. These catalysts yielded the desired adducts with
much higher yields and e.r. under mild reaction condition
(rt), low catalyst loading (10 mol%) and comparatively
lesser reaction time (48 h) (Table 1, entries 4 and 5).
Further, the optimization was focused on the choice of
suitable solvents for Knoevenagel condensation reaction.
The observed results of Table 2 show that ethanol is the best
reaction medium, in which 3a/4 ratio is up to 96:4 along
with higher chemical yields and e.r (Table 2, entry 7). The
polarity of solvents drastically afected the chemical yield
and e.r of Knoevenagel condensation product. The highly
polar aprotic solvents gave good 3a/4 ratio and yields, but
moderate e.r was obtained (Table 2, entries 1–3). Some
other polar aprotic solvents gave lower chemical yields and
good e.r (Table 2, entries 4–6). Further, no reaction was
observed in the presence of nonpolar solvents (Table 2,
entries 8–10). These nonpolar solvents have low dielectric
constants (<5) and are not good solvents for charging spe-
cies such as anions and cations. Henceforth, we have chosen
ethanol as a suitable solvent for further investigations of
asymmetric Knoevenagel condensation reaction.
Furthermore, we carried out the optimization of the base for
the asymmetric Knoevenagel condensation reaction of hydrat-
ropaldehyde (1a) with diethylmalonate (2a) in the presence of
organocatalyst 10b under identical reaction conditions. From
the results, we observed that triethylamine as a more efective
base than other inorganic and organic bases, such as K2CO3,
Cs2CO3, KtOBu, NaOH, KOH and DIEA, pyridine, piperidine,
morpholine (Table 3, entries 1–10).
The results obtained from Table 4 show that temperature
and catalyst loading afect the chemical yields and e.r of
1 3

Journal of the Iranian Chemical Society
Table 2 Optimization of solvents for asymmetric Knoevenagel condensation
COOEt
COOEt
COOEt
COOEt
10b
CHO
COOEt
COOEt
(10 mol %)
TEA,Solvents,
r.t.
1a
2a
3a
4a
Entry
Solvents
3a/4aa ratio
Yield (%)b
e.rc Abs.Conf.d
1
2
3
4
5
6
7
8
9
10
DMF
DMSO
Acetonitrile
THF
DCM
80:20
75:25
70:30
66:34
69:31
62:38
96:4
74
70
65
62
57
52
92
–
84.96:15.64
79.48:20.52
87.18:12.82
86.33:13.67
91.02:8.98
89.67:10.33
97.58:2.42
–
CHCl3
Ethanol
o-Xylene
Toluene
Cyclohexane
n.re
n.re
–
–
–
–
n.re
Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), 10b (10 mol%), TEA (0.2 mmol) and solvents (2 mL) at room temperature in 48 h
aDetermined by GC–MS analysis
bYield of isolated product
cDetermined by HPLC analysis chiral column (Chiralcel OD-H) with hexane–IPA as an eluent
dAbsolute confguration was determined by comparison of the HPLC retention time using known literature data [32–37]
eNo reaction
the desired product and that 10 mol% of the catalyst gave a
higher chemical yield and excellent e.r when compared to
others. This may be due to the catalyst poison taking place in
this reaction irrespective of the organocatalysts. Further, the
temperature condition of the reaction strongly afected the
product yields and e.r. From the observed results of Table 4,
a higher chemical yield and e.r were obtained at room tem-
perature, when compared to other temperature conditions,
i.e. 60 °C, 0 °C and −10 °C (Table 4, entries 1–12). Sum-
ming up these experimental results, the optimized reaction
conditions are: ethanol selected as a solvent triethylamine
(TEA) as a base, concentration of catalyst as 10 mol% and
the room temperature condition suitable for asymmetric
Knoevenagel condensation reaction.
Various substituted α-branched aromatic/aliphatic aldehydes
were treated with diferent malonate compounds. When
using both electron-donating and electron-withdrawing
substrates, the desired products were obtained in very good
yield and e.r (Table 5, entries 1–14). The 2-phenyl propa-
nal was treated with diethyl malonate to give the desired
Knoevenagel product with higher yield and e.r (Table 5,
entry 1). The yield and e.r obtained were slightly higher,
and no by-product was observed in the case of electron-
donating substituted aromatic aldehyde used in the reaction
(Table 5, entries 2 and 3). The halo-substituted aldehydes
also gave the higher yield and e.r (entries 4 and 5). In addi-
tion to that, para-substituted aromatic aldehydes showed a
slightly higher chemical yield and e.r when compared to
ortho- and meta-substituted benzaldehydes (Table 5, entries
6–8). When the reaction was carried out in the presence of
The scopes of the catalysts are measured by diferent
substrates under optimized reaction conditions in Table 5.
1 3

Journal of the Iranian Chemical Society
Table 3 Optimization of bases for asymmetric Knoevenagel condensation
COOEt
COOEt
COOEt
COOEt
10b
CHO
COOEt
COOEt
(10 mol %)
Bases, EtOH
r.t.
1a
2a
3a
4a
Entry
Bases
3a/4aa
Yield (%)b
E.rc Abs.Conf.d
1
2
3
4
5
6
7
8
9
10
K2CO3
Cs2CO3
KtOBu
NaOH
KOH
TEA
70:30
62:38
n.re
75
64
–
–
–
92
90
80
78
84
86.33:13.67
83.72:16.28
–
–
–
97.58:2.48
95.54:4.46
91.02:8.98
90.22:9.78
87.18:12.82
n.re
n.re
96:4
92:8
80:20
83:17
85:15
DIEA
Pyridine
Piperidine
Morpholine
Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), 10b (10 mol%), various bases (0.2 mmol) and ethanol (2 mL) at room temperature in 48 h
aDetermined by GC–MS analysis
bYield of isolated product
cDetermined by HPLC analysis chiral column (Chiralcel OD-H) with hexane–IPA as an eluent
dAbsolute confguration was determined by comparison of the HPLC retention time using known literature data [32–37]
eNo reaction
dimethyl malonate, we achieved very good yields and e.r
(Table 5, entries 9 and 10). Among these malonate com-
pounds, we found that the steric efect of these compounds
could create benefcial infuence on the enantiomeric excess
when using diisopropyl malonate, dibutyl malonate, dipropyl
malonate and dibenzyl malonate (Table 5, entries 11–15).
Aliphatic aldehydes are found to be suitable substrates for
enantioselective Knoevenagel condensation (Table 5, entry
16).
between R4N+ of the catalyst and anion of polarized alde-
hyde (Fig. 1a), (2) similar interaction happened between the
enolate of the diethylmalonate and anion of polarized alde-
hydes with R4N+ of the catalyst (Fig. 1c) and (3) at that same
time, the intermolecular hydrogen bonding between the free
C9 –OH of the organocatalyst with anion of polarized alde-
hyde and carbonyl group of diethylmalonate (Fig. 1b). We
strongly believed that the above three possible electrostatic
processes are responsible for deciding the chemical yield and
e.r. [53–56]. The intermolecular hydrogen bonding prevents
the perfect ion-pair interaction between the catalyst and sub-
strates. Therefore, the higher yield and e.r were achieved in
the presence of allyl protected catalysts 10b compared to
free C9 (OH) catalysts 10a (Fig. 1c).
From the observed results, the higher chemical yield and
e.r for C9(O)-protected catalyst 10b (Table 1) are due to
the presence of efective ion-pair interaction between the
R4N+ of the catalyst and the enolate anion of the diethyl-
malonate and anion of polarized aldehyde. In general, irre-
spective of free C9 OH (10a) or C9 (O)-protected catalyst
(10b), there should be three factors which can infuence the
chemical yield and e.r: (1) an efective ion-pair interaction
In addition to observed results, allyl protected catalyst
10b was more efcient than the free C9 –OH-containing cat-
alyst 10a since the allyl protected catalyst has more binding
1 3

Journal of the Iranian Chemical Society
Table 4 Optimization of temperature and catalyst loading for asymmetric Knoevenagel condensation
COOEt
COOEt
COOEt
10b
COOEt
COOEt
CHO
COOEt
TEA, Ethanol,
temperature
2a
3a
1a
4a
Entry
Temperature (°C)
Mol% of catalyst
3a/4aa
Yield (%)b
E.rc Abs.Conf.d
1
2
3
4
5
6
7
8
60
60
60
30
30
30
0
0
0
5
10
20
5
10
20
5
10
20
5
10
20
63:37
80:20
57:43
70:30
96:4
67
82
52
75
92
57
–
–
–
–
–
85.71:14:29
91.88:8.12
76.61:23.39
89.34:10.66
97.58:2.48
79.04:20.96
–
–
–
–
–
–
60:40
Trace
Trace
Trace
n.re
9
10
11
12
−10
−10
−10
n.re
n.re
–
Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), 10b (various mol%), TEA (0.2 mmol) and ethanol (2 mL) at diferent temperature condi-
tions for 36 h
aDetermined by GC–MS analysis
bYield of isolated product
cDetermined by HPLC analysis chiral column (Chiralcel OD-H) with hexane-IPA as an eluent
dAbsolute confguration was determined by comparison of the HPLC retention time using known literature data [32–37]
eNo reaction
with the substrate. In the case of 10a as a catalyst, hydrogen
bonding between the enolate anion of the diethyl malonate
and anion of a polarized aldehyde with the C9–OH of the
catalyst prevented the perfect ion-pair interaction between
the catalyst and anion of the substrates; hence, we got a
slightly lower yield as well as the e.r (Fig. 2a, b) [57–63].
Based on these results, we proposed plausible transition
state for the formation of the catalytic highly enantioselec-
tive asymmetric Knoevenagel condensation reaction (Fig. 3).
The phenyl group of aldehyde has a π–π stacking interaction
with one of the quinoline moiety of the alkaloid moiety of
the catalyst. The results also suggested that apart from the
ionic interaction between the catalyst and substrates, there
is π-π stacking interaction between the quinoline part of the
respective C9(O)-protected catalyst with an aryl group of the
aldehyde which can be strongly infuenced the binding of the
two species as a results we found very good yield as well as
enantiomeric excess. In addition to that this in turn shows to
facilitate efective ion-pair interaction and thus afected in
parallel increasing of yield and e.r than corresponding cata-
lyst containing free C9 –OH. In addition to that, Cinchona
alkaloid catalysts 10a and 10b have C2-symmetric type of
catalysts. Hence, the two cinchona units (free C9 –OH and
C9 (O) protected) should present at the end of the pentae-
rythritol linker due to steric hindrance of the quinoline moi-
ety of the cinchona alkaloids.23g Further, the pentaerythri-
tol-based chiral catalysts (10a and 10b) can strongly bind
with the anion of polarized aldehyde and anion of malonate
derivatives simultaneously, and hence we found higher yield
and e.r at lower concentration of organocatalysts, base and
lesser reaction time (Tables 1, 2, 3, 4, 5).
1 3

Journal of the Iranian Chemical Society
Table 5 Substrate variations in Knoevenagel condensation
COOR2
COOR2
COOR2
COOR2
COOR2
CHO
10b (10 mol %)
COOR2
R1
Ethanol, r.t.
TEA
R1
R1
2
1
3
4
Entry
R1
H
4-OMe
4-CH3
4-Br
4-Cl
4-F
3-F
2-F
H
4-CH3
H
R2
Product
3/4a
Yield (%)b
E.rc Abs.Conf.d
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
iPr
iPr
nBu
nPr
Bnz
Et
3a
3b
3c
3d
3e
3f
96:4
100:0
100:0
93:7
94:6
97:3
95:5
94:6
96:4
98:2
97:3
99:1
96:4
98:2
90:10
92:8
92
95
96
85
87
92
90
87
93
95
95
96
97
95
85
89
97.58:2.48
98.32:1.68
98.41:1.59
95.54:4.46
97.45:2.55
97.06:2. 94
94.89:5.11
91.89:8. 11
97.00:3.00
99.11:0. 89
98.58:1.42
99.69:0.31
98.94:1.06
98.42:1.58
93.04:6.96
95.56:4.44
3 g
3 h
3i
9
10
11
12
13
14
15
16
3j
3 k
3 l
3 m
3n
3o
3p
4-CH3
H
H
H
c-C6H11
Reaction conditions: 1 (0.1 mmol), 2 (1.0 mmol), catalyst 10b (10 mol%), TEA (0.2 mmol) and ethanol (2 mL) at room temperature condition in
48–72 h
aDetermined by GC–MS analysis
cYield of isolated product
dDetermined by HPLC analysis chiral column (Chiralcel OD-H) with hexane–IPA as an eluent
eAbsolute confguration was determined by comparison of the HPLC retention time using known literature data [32–37]
Spacer
EtO
N
Spacer
OH
N
OEt
OEt
O
N
Spacer
O
O
H
O
H
O
O
H
OH
H
EtO
O
H
O
H
H
H
O
N
N
O
N
O
O
a
b
c
Ion -pair formed between R4N+
Hydrogen bonding between
Ion-pair formed between R4N+ of catalyst
with anion of polarized aldehyde and
enolate anion of diethylmalonate due
to electrostatic attraction
diethylmalonate, anion of polarized
aldehyde and free -OH present in C9
position of catalyst
of catalyst with anion of polarized
aldehyde due to electrostatic attraction
Fig. 1 Formation of various molecular assemblies during Knoevenagel condensation using free C9 –OH and allyl protected organocatalysts (10a
and 10b)
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Journal of the Iranian Chemical Society
N
N
O
N
N
O
H
OEt
H
OEt
OEt
MeO
O
O
O
MeO
O
O
OEt
O
H
H
O
OEt
O
OEt
OEt
OEt
O
O
Ion-pair formed between R4N+ of catalyst 10a
with anion of the diethyl malonate and anion of polarized
aldehyde due to electrostatic attraction
Hydrogen bond between the C9 free -OH present in the
catalyst 10a with enolate anion of the diethyl malonate and
anion of polarized aldehyde
a
b
Fig. 2 Plausible transition state for the formation of various intermediates/molecular assemblies during the enantioselective Knoevenagel con-
densation reaction using free C9 –OH catalyst (10a)
To expose the usefulness of Knoevenagel products, com-
pound 3a was converted into diferent γ-alkyl-substituted
chiral amides using various amines such as aniline, 4-amino-
pyridine, n-butylamine, morpholine and pyrrolidine. Inter-
estingly, the optical purity of the amides obtained was very
high consistent with the Knoevenagel adduct used.
Conclusions
We have designed two diferent types of novel chiral organo-
catalysts from cinchona alkaloids for enantioselective Kno-
evenagel condensation reaction. The racemic α-branched
aldehydes can be converted into the corresponding enan-
tiomerically enriched products with higher chemical yield
(up to 97%) and an excellent enantiomeric ratio (up to
99.68:0.32) via dynamic kinetic resolution. Further the
Knoevenagel adduct 3a was converted into enantiomerically
Applications of Knoevenagel product
See Scheme 3.
1 3

Journal of the Iranian Chemical Society
O
O
N
N
N
O
N
O
OEt
MeO
MeO
O
OEt
EtO
H
H
O
O
O
OEt
O
OEt
OEt
O
OEt
OEt
O
O
Formation of π−π interaction between the quinoline part of the
Ion-pair formed between R4N+ of catalyst
10b with enolate anion of the diethyl malonate and anion
of polarized aldehyde due to electrostatic attraction
catalyst with aromatic ring of the substrate (aldehyde)
a
b
Fig. 3 The plausible transition state for highly enantioselective Knoevenagel condensation reaction catalysed by cinchona-derived C9 –allyl pro-
tected catalyst (10b)
enriched valuable γ-alkyl-substituted amides without loss
in enantioselectivity. We believed that this study greatly
expands the potential of this approach, through the addition
of α-branched aldehydes to various malonate derivatives,
towards the preparation of synthetic and pharmaceutically
valuable Knoevenagel products and therein chiral γ-alkyl-
substituted amides.
1 3

Journal of the Iranian Chemical Society
1 3

Journal of the Iranian Chemical Society
Acknowledgements V.A. acknowledges the financial support of
CSIR-HRDG, New Delhi, India, CSIR File No. 09/201/0417/2016-
EMR-I, for providing SRF (Senior Research Fellowship) and also
Department of Science and Technology, Extramural Research Pro-
ject EMR/2015/000969, CSIR, EMR, New Delhi, India (Grant No.
01(2901)17/EMR-II, and also we thank DST-PURSE, UPE program,
for providing instrumental facilities.
30. M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 39,
1279 (2000)
31. C.J. Wang, X.Q. Dong, Z.H. Zhang, Z.Y. Xue, H.L. Teng, J. Am.
Chem. Soc. 130, 8606 (2008)
32. A. Lee, A. Michrowska, S.S. Mosse, B. List, Angew. Chem. Int. Ed.
50, 1707 (2011)
33. W.J. Le, H.F. Lu, J.T. Zhou, H.L. Cheng, Y.H. Gao, Tetrahedron
Lett. 54, 5370 (2013)
Compliance with ethical standards
34. S. Sakshi, S. Baldev, Bioorg. Med. Chem. Lett. 22, 5388 (2012)
35. X. Gu, Y. Tang, X. Zhang, Z. Luob, H. Lu, New J. Chem. 40, 6580
(2016)
Conflict of interest The authors declare no confict of interest.
36. T. Murase, Y. Nishijima, M. Fujita, J. Am. Chem. Soc. 134, 162
(2012)
37. J.J. Han, Y.F. Xu, Y.P. Su, X.G. She, X.F. Pan, Catal. Commun. 9,
2077 (2008)
References
38. H. Pellissier, Adv. Synth. Catal. 353, 659 (2011)
39. K. Horiguchi, E. Yamamoto, K. Saito, M. Yamanaka, T. Akiyama,
Chem. Eur. J. 22, 8078 (2016)
1. E. Knoevenagel, Chem. Dtsch. Ber. Ges. 27, 2345 (1894)
2. L.F. Tietze, U. Beifuss, B.M. Trost, Comprehensive Organic Syn-
thesis, vol. 2 (Pergamon, Oxford, 1991), p. 341
3. G. Jones, Organic Reactions, vol. 5 (Wiley, New York, 1967), p. 204
4. F. Freeman, Chem. Rev. 80, 329 (1980)
40. H.Z. You, E. Rideau, M. Sidera, S.P. Fletcher, Nature 517, 351
(2015)
41. S.K. Nimmagadda, S.C. Mallojjala, L. Woztas, S.E. Wheeler, J.C.
Antilla, Angew. Chem. Int. Ed. 56, 2454 (2017)
5. L.F. Tietze, Chem. Rev. 96, 115 (1996)
42. L. Rasu, J.M. John, E. Stephenson, R. Endean, S. Kalapugama, R.
Clement, S.H. Bergens, J. Am. Chem. Soc. 139, 3065 (2017)
43. A.E. Cotman, D. Cahard, B. Mohar, Angew. Chem. Int. Ed. 128,
5380 (2016)
6. T. Kanzian, S. Lakhdar, H. Mayr, Angew. Chem. Int. Ed. 49, 9526
(2010)
7. B. List, Angew. Chem. Int. Ed. 49, 1730 (2010)
8. B. List, J.W. Yang, Science 313, 1584 (2006)
9. D.W.C. MacMillan, Nature 455, 304 (2008)
10. B. List, Chem. Commun. 8, 819 (2006)
44. B.L. Bray, Nat. Rev. Drug Discov. 2, 587 (2003)
45. V.R. Pattabiraman, J.W. Bode, Nature 480, 471 (2011)
46. E. Valeur, M. Bradley, Chem. Soc. Rev. 38, 606 (2009)
47. C. Gunanathan, Y.B. David, D. Milstein, Science 317, 790 (2007)
48. A.K. Schoonen, M.A. Fernandez-Ibanez, M. Fananas-Mastral, J.F.
Teicherta, B.L. Feringa, Org. Biomol. Chem. 12, 36 (2014)
49. M.R. Fernandez, X. Yan, J.F. Collados, P.B. White, S.R. Harutyun-
yan, J. Am. Chem. Soc. 139, 14224 (2017)
11. R.S. Pottorf, N.K. Chadha, M. Katkevics, Tetrahedron Lett. 44, 175
(2003)
12. N. Yu, J.M. Aramini, M.W. Germann, Z. Huang, Tetrahedron Lett.
41, 6993 (2000)
13. S. Balalaie, A.M. Sheikh, M. Bararjanian, Catal. Commun. 8, 1724
(2007)
50. C.E. Song, Cinchona Alkaloids in Synthesis and Catalysis, Ligands,
Immobilization and Organocatalysis, vol. 359 (Wiley-VCH, Wein-
heim, 2009)
14. F. Bigi, L. Chesini, R. Maggi, G. Sartori, J. Org. Chem. 64, 1033
(1999)
15. D. Prajapati, K.C. Lekhok, J.S. Sandhu, A.C. Ghosh, J. Chem. Soc.
Perkin Trans. 1, 959 (1996)
51. A. Jesin Beneto, J. Sivamani, V. Ashokkumar, R. Balasaravanan, K.
Duraimurugan, A. Siva, New J. Chem. 39, 3098 (2015)
52. J. Sivamani, V. Ashokkumar, V. Sadhasivam, K. Duraimurugan, A.
Siva, RSC Adv. 4, 60293 (2014)
16. T.I. Reddy, R.S. Varma, Tetrahedron Lett. 38, 1721 (1997)
17. S. Wada, H. Suzuki, Tetrahedron Lett. 44, 399 (2003)
18. J.S. Yadav, B.V.S. Reddy, A.K. Basak, A.V. Narsaiah, Tetrahedron
Lett. 44, 1047 (2003)
53. V. Ashokkumar, R. Balasaravanan, V. Sadhasivam, S. Mehtob Jeno-
far, A. Siva, J. Mol. Catal. A. Chem. 409, 127 (2015)
54. E.J. Corey, F. Xu, M.C. Noe, J. Am. Chem. Soc. 119, 12414 (1997)
55. E.J. Corey, M.C. Noe, F. Xu, Tetrahedron Lett. 39, 5347 (1998)
56. E.J. Corey, Y. Bo, J.B. Peterson, J. Am. Chem. Soc. 120, 13000
(1998)
19. B.C. Ranu, R. Jana, Eur. J. Org. Chem. 2006, 3767 (2006)
20. Z.J. Ren, W.G. Cao, W.Q. Tong, X.P. Jing, Synth. Commun. 32,
1947 (2002)
21. S. Wang, Z. Ren, W. Cao, W. Tong, Synth. Commun. 31, 673 (2001)
22. S. Balalaie, M. Bararjanian, Synth. Commun. 36, 2549 (2006)
23. L.F. Tietze, U. Beifuss, The Knoevenagel reaction, in Comprehen-
sive organic synthesis, vol. 2, ed. by B.M. Trost, I. Fleming (Perga-
mon Press, Oxford, 1991), p. 341
57. V. Ashokkumar, A. Siva, Org. Biomol. Chem. 13, 10216 (2015)
58. H.G. Park, B.S. Jeong, M.S. Yoo, M.K. Park, H. Huh, S.S. Jew,
Tetrahedron Lett. 42, 4645 (2001)
59. N. Mase, T. Ohno, N. Hoshikawa, K. Ohishi, H. Morimoto, H. Yoda,
K. Takabe, Tetrahedron Lett. 44, 4073 (2003)
24. K. Sakthivel, W. Notz, T. Bui, C.F. Barbas III, J. Am. Chem. Soc.
123, 5260 (2001)
60. K. Maruoka, T. Ooi, Chem. Rev. 103, 3013 (2003)
61. A. Siva, E. Murugan, J. Mol. Catal. A Chem. 241, 101 (2005)
62. E. Murugan, A. Siva, Synthesis 12, 2022 (2005)
63. J. Sivamani, K. Duraimurugan, A. Jesin Benito, P. Subha, R. Bala-
saravanan, A. Siva, Synlett. 25, 1685 (2014)
25. H. Groger, J. Wilken, Angew. Chem. Int. Ed. 40, 529 (2001)
26. A.V. Narsaiah, A.K. Basak, B. Visali, K. Nagaiah, Synth. Commun.
34, 2893 (2004)
27. S. Sebti, A. Smahi, A. Solhy, Tetrahedron Lett. 43, 1813 (2002)
28. S. Sebti, R. Nazih, R. Tahir, A. Saber, Synth. Commun. 31, 993
(2001)
29. D. Fildes, V. Caignaert, D. Villemin, P.A. Jafres, Green Chem. 3,
52 (2001)
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Journal of the Iranian Chemical Society
Afliations
Veeramanoharan Ashokkumar1 · Ayyanar Siva1 · Balakrishnan Sankar1
1
Supramolecular and Organometallic Chemistry Lab, School
of Chemistry, Madurai Kamaraj University, Madurai,
Tamil Nadu 625 021, India
1 3