Organocatalyzed biomimetic selective reduction of c=c double bonds of chalcones

Article abstract of DOI:10.14233/ajchem.2018.21480

In this article, we reported a biomimetic approach for chemoselective reduction of C=C double bonds in chalcones under metal and acid free conditions, that relies on olefin activation by hydrogen bond formation. The process requires only catalytic amount of ephedrine as hydrogen bond donor and utilizes Hantzsch esters for transfer hydrogenation.

Full text of DOI:10.14233/ajchem.2018.21480

Asian Journal of Chemistry; Vol. 30, No. 10 (2018), 2322-2324
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21480
Organocatalyzed Biomimetic Selective Reduction of C=C Double Bonds of Chalcones
2
VISHWA DEEPAK TRIPATHI1,* and ANAND MOHAN JHA
1Department of Chemistry, M.K. College, Darbhanga-846 003, India
2Department of Chemistry, K.S.R. College, Sarairanjan, Samastipur-848 127, India
*Corresponding author: E-mail: vishwadeepak66@gmail.com
Received: 26 May 2018;
Accepted: 13 June 2018;
Published online: 31 August 2018;
AJC-19066
In this article, we reported a biomimetic approach for chemoselective reduction of C=C double bonds in chalcones under metal and acid
free conditions, that relies on olefin activation by hydrogen bond formation. The process requires only catalytic amount of ephedrine as
hydrogen bond donor and utilizes Hantzsch esters for transfer hydrogenation.
Keywords: Biomimetic, Reduction, Hydrogenation, Hantzsch ester, Chalcones.
activities. They are one of the key precursors in the synthesis
of many biologically important heterocycles such as benzo-
thiazepine [22], pyrazolines [23], 1,4-diketones [24] and
flavones [25]. Selective hydrogenation of C=C bonds of α,β-
unsaturated carbonyl compounds (chalcones) is an important
organic transformation in the synthesis of many drugs mole-
cules such as pioglitazone, rosiglitazone, troglitazone, etc.
The natural product enzyme cofactors NAD(P) and NAD(P)H
have been a stimulus for the investigation of use of Hantzsch
ester as attractive biomimetic reducing agents [26-30]. Recently,
an increasing interest has been focused over the application
of Hantzsch esters as reducing agents [31-35]. The role of small
organic molecules as catalyst in organic synthesis is one of
the most attractive research area for chemists during last several
years. The observation encouraged us to investigate an organo-
catalytic reduction of chalcones by catalytic amount of ephedrine
as hydrogen bond donor. We reasoned that activation of chalcone
1 by H-bonding would enable hydrogen transfer from dihydro-
pyrimidine (3) to generate a reduced chalcone 2 in a similar
fashion reported by Menche et al. [36,37] in reductive amination
(Scheme-I).
INTRODUCTION
Reduction of carbon-carbon double bonds in compounds
such as carbonyls, imines, and olefins are of great importance
in chemistry, biology and as well as from the industrial pers-
pective. Reduction of double bond-containing such compounds
and various other α,β-unsaturated systems via hydrogenation
often involves the use of metal catalysts [1,2] or stoichiometric
amount of metal hydrides [3,4]. Several metal free catalytic
hydrogenations of olefins have also been reported in area of
green catalysis [5-9]. The resulting products are important frame-
works in medicinal chemistry and have direct applications to
drug discovery process.
The reduction of carbon-carbon double bonds of α,β-
unsaturated systems is very important synthetic transformation
but this particular step is a tricky one because (a) both 1,2- and
1,4-reductions readily occur simultaneously (b) low selectivity
for either of the two pathways and (c) functional groups which
are sensitive to metal hydrogenation conditions such as ester,
nitro and nitrile groups are usually not tolerated. Thus, it is of
great importance to develop a mild, catalytic, one-pot, chemo-
selective and green methodology for this reaction.
EXPERIMENTAL
Chalcones are well reported for their wide range of biolo-
gical activities, including antimalarial [10], anticancer [11,12],
antituberculosis [13], cardiovascular [14], antileishmanial [15],
antimitotic [16], antihyperglycemic [17], nitric oxide inhibition
[18,19], anti-inflammatory [20], tyrosinase inhibition [21]
Unless otherwise specified all the reagents were purchased
from Sigma-Aldrich and were used without further any purifi-
cation. The common organic solvents were used was of LR
grade and purchased from Ranchem. Organic solutions were
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Vol. 30, No. 10 (2018)
Organocatalyzed Biomimetic Selective Reduction of C=C Double Bonds of Chalcones 2323
H
H
CH2O
O
O
ROOC
COOR
COOR
ROOC
PTSA
RO
+
OR
O
O
N
MeOH
N
H
O
O
H 3b
NH4OAc
R = Me, 3a, 93%
R = Et, 3b, 94%
R = tBu, 3c, 88%
R1
R2
4
Organocatalyst
(0.2 eq.)
R1
R2
2
1
Scheme-I: Ephedrine catalyzed transfer hydrogenation of α,β-unsaturated
Scheme-II: Synthesis of reducing agent
carbonyl compounds
TABLE-1
concentrated under reduced pressure on a Büchi rotary
evaporator. Chromatographic purification of products was
accomplished using flash chromatography on 60-100 mesh
silica gel. Reactions were monitored by thin-layer chromato-
graphy (TLC) on 0.25 mm silica gel plates visualized under
UV light, iodine or KMnO4 staining. 1H and 13C NMR spectra
were recorded on a Brucker DRX -300 Spectrometer. Chemical
shifts (δ) are given in ppm relative to TMS, coupling constants
(J) in Hz. Mass spectra (ESI MS) were obtained by Micromass
Quattro II instrument.
Synthetic procedure for synthesis of Hantzsch esters:
All the three derivatives were synthesized via well known multi-
component Hantzsch reaction. Alkyl acetoacetate, formal-
dehyde and ammonium acetate were mixed in ethanol in
eqimolar ratio and stirred at room temperature in 50 mL ethanol
for 4 h. White precipitate formed was filtered off and recrysta-
llized in ethanol to get the pure product.
Synthetic procedure for reduction of C=C in chalcones:
Chalcone derivative (1 mol eq.) and Hantzsch ester (1.1 mol
eq.) was dissolved in 20 mL toluene and stirred at room tempe-
rature followed by slow addition of organocatalyst ephedrin
(20 mol %). Resulting mixture was stirred at room temperature
upto disappearance of chalcone spot on TLC.After completion
solvent was removed in rotavapor and residue was purified
using silica coloumn chromatography and ethyl acetate: hexane
as mobile phase. Reduced chalcone isolated were further charac-
terized by 1H and 13C NMR spectroscopy.
1,3-Diphenylpropan-1-one (1): Light yellow oil; ESI
MS (m/z) = 211.26 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ
= 7.94 (d, J = 8Hz, 2H), 7.62-7.55 (m, 3H), 7.40-7.27 (m,
5H), 2.88 (t, J = 8Hz, 2H), 2.71 (t, J = 8 Hz, 2H). 13C NMR
(75 MHz, DMSO-d6) δ = 200.1, 141.3, 140.2, 133.5, 128.8,
128.2, 127.9, 127.7, 126.4, 125.9, 43.9, 30.6.
ORGANOCATALYZED REDUCTION OF
C=C BOND OF CHALCONE 1a
Entrya
Time (h)
Yield (%)b
Organocatalyst (4)
None
4 (mol %)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
10
5
72
48
48
48
36
36
36
36
< 5
45
53
58
84
95
87
79
Pyrolidine (4a)
Morpholine (4b)
Cinconidine (4c)
Thiourea (4d)
Ephedrine (4e)
Ephedrine (4e)
Ephedrine (4e)
aReaction conditions: All reactions were performed using chalcone 1a
(1 mmol), Hantzsch ester 3b (1.1 mmol) in toluene at 60 °C using
organocatalyst 4 under N2 atomosphere.
bIsolated yield after column chromatography.
was observed. Ephedrine was proved to be the best organo-
catalyst for this reaction showing the fastest reaction rate and
best yields of saturated ketone (entry 6, Table-1). However,
thiourea was also showing promising catalytic activity.
Further exploration of ephedrine and thiourea catalyzed
transfer hydrogenation concentrated on the solvent employed
(Table-2). Best results were obtained in non-polar solvents
such as toluene, benzene at elevated temperature with ephedrine
as organocatalyst. Performing the reaction at lower temperature
(30 ºC instead of 60 ºC) resulted in lower yield and longer
reaction time. Surprisingly in more polar media, the reaction
was sluggish and yields were considerably diminished (entry
6 and 7, Table-3).
The general applicability of this procedure was also studied.
Various sterically, electronically, and functionally diverse
chalcones were reduced smoothly in excellent yields. Ethyl
Hantzsch ester was taken as reducing agent and ephedrine as
catalyst. Other reducible functional groups present in chalcones
RESULTS AND DISCUSSION
TABLE-2
We synthesized Hantzsch esters 3 (reducing agent) via
one-pot coupling of formaldehyde, acetoacetate ester and
ammonium acetate in the presence of catalytic amount of
p-toluene sulphonic acid (Scheme-II). Methyl, ethyl and t-butyl
Hantzsch esters were prepared. Among the three Hantzsch
esters synthesized, ethyl Hantzsch ester (3b) was found to be
the best for transfer hydrogenation. Hence, further experiments
were carried out using 3b as reducing agent.
Initial experiments focused on the examination of various
organocatalysts for this transformation (Table-1). We used
several organocatalyst (5-20 mol %) to catalyze the reduction
of chalcone 1a. In each instance, the reaction was carried out
with 1.1 equivalents of Hantzsch esters 3b in toluene for several
hours. In the absence of organocatalyst, little hydrogen transfer
SOLVENT EFFECT ON
ORGANOCATALYSED HYDROGENATIONa
Thiourea (4d)
Time (h) Yield (%)b Time (h) Yield (%)b
Ephedrine (4e)
Entry Solvent
1
2
3
4
5
6
7
Toluene
Benzene
CH2Cl2
CHCl3
MeCN
MeOH
EtOH
36
36
48
48
48
48
48
85
84
72
71
78
65
68
36
36
48
48
48
48
48
95
94
81
82
78
65
66
aReaction conditions: All reactions were performed using chalcone 1a
(1 mmol), Hantzsch ester 3b (1.1 mmol) using organocatalyst 4 under
N2 atomosphere.
bIsolated yield after column chromatography.

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C6H5
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C=C of chalcones.
In summary, a new acid and metal free efficient organo-
catalytic, biomimetic and selective hydrogenation of C=C bonds
of chalcones using Hantzsch esters as reducingagent is developed.
The C=C bond is selectively reduced in excellent yields without
affecting the other reducible functional groups present in chal-
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conditions render it an attractive approach to saturated chalcones.
ACKNOWLEDGEMENTS
One of the authors, Vishwa Deepak Tripathi is thankful
to CSIR-New Delhi for financial support in the form of a Junior
Research Fellowship.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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