Michael addition of malononitrile to indenones: Synthesis and characterization of 2-(1-oxo-2,3-dihydro-1H-inden-2-yl) (aryl)(methyl)malononitrile derivatives

Article abstract of DOI:10.1080/00397911.2017.1312450

Indanones 3 were prepared from the reaction of indanone (1) with corresponding benzaldehyde derivatives 2, as described in the literature. Then, indenones 3 were subjected to KOtBu-catalyzed Michael addition with malononitrile to give a mixture of diaster

Full text of DOI:10.1080/00397911.2017.1312450

Synthetic Communications
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Michael Addition of Malononitrile to Indenones:
Synthesis and Characterization of 2-(1-oxo-2,3-
dihydro-1H-inden-2-yl) (Aryl)(Methyl)malononitrile
Derivatives
Betül Şahin, Meliha Burcu Gürdere & Mustafa Ceylan
To cite this article: Betül Şahin, Meliha Burcu Gürdere & Mustafa Ceylan (2017): Michael
Addition of Malononitrile to Indenones: Synthesis and Characterization of 2-(1-oxo-2,3-
dihydro-1H-inden-2-yl) (Aryl)(Methyl)malononitrile Derivatives, Synthetic Communications, DOI:
10.1080/00397911.2017.1312450
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1312450
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Date: 14 April 2017, At: 08:19

Michael Addition of Malononitrile to Indenones: Synthesis and Characterization of
2-(1-oxo-2,3-dihydro-1H-inden-2-yl) (Aryl)(Methyl)malononitrile Derivatives
Betül Şahin1, Meliha Burcu Gürdere1, Mustafa Ceylan1
1Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University,
Tokat, Turkey
Corresponding author: Mustafa Ceylan E-mail: mustafac.ceylan@gop.edu.tr
Abstract
Indanones 3 were prepared from the reaction of indanone (1) with corresponding
benzaldehyde derivatives 2, as described in the literature. Then, indenones 3 were
subjected to KOtBu-catalyzed Michael addition with malononitrile to give a mixture of
diastereomers 5 with a low conversion and no diastereoselection. Employment of phase
transfer catalyst such as benzyltriethylammonium chloride or N-Benzylcinchonidinium
chloride had a positive effect on both conversion and diastereoselection. The structure of
diastereomers 5 was determined by spectroscopic methods (NMR, IR).
Graphical Abstract
KEYWORDS: Indenones, Malononitrile, Michael addition, Phase transfer catalyst
1

INTRODUCTION
The Michael addition of active methylene compounds to
-unsaturated carbonyl
compounds is a general route to construct for carbon-carbon bond.[1–7] An active
methylene compounds, malononitrile, has been widely used as Michael donor, since it
serves as an equivalent of 1,3-diketone and offers an access to preparation carboxylic
acids,[8] esters,[9] amines,[10–12] polyfunctional aromatics, pyridines, pyridones,
pyridazines and pyrazoles.[13–17]
For Michael addition of malononitrile to
-unsaturated carbonyl compounds, a variety
of catalysts, including acids, bases and organocatalysts have been used.[18–23]
In this paper, we report KOtBu-catalyzed Michael addition of malononitrile to indenones
3 in the presence of benzyltriethylammonium chloride (TEBAC) as a phase transfer
catalyst to furnish addition products as a mixture of diastereomers in a ratio of 3:1.
RESULTS AND DISCUSSION
The starting compounds, 2-benzylidene-2,3-dihydro-1H-inden-1-one derivatives 3a-k,
were synthesized from the addition of benzaldehyde derivatives to 1-indanone in the
presence of NaOH in EtOH for 6 hours at room temperature (Scheme 1).[30–33] The
products were purified by means of crystallization and their structures were determined
by spectroscopic methods (NMR, IR and Elemental Analysis) and compared with the
reported data.[32–39]
2

After preparation and characterization of the starting materials, we focused on
optimization of reaction conditions for the Michael addition of malononitrile (4) to
indenones 3. For this purpose, addition of malononitrile (4) to indenone 3a was chosen as
the model reaction (Scheme 2). The results were given in Table 1. The reaction of 3a (1
equiv.) with 4 (1.2 equiv.) and KOtBu (20 % mmol) was performed in CH2Cl2 (5 ml) for
24 hours at room temperature. The reaction resulted in the formation of a mixture of
diastereomer (5a and 5a’) in a ratio of 1:1 with 20 % conversion (Table 1, entry 1). When
the reaction was conducted in the presence of benzyltriethylammonium chloride
(TEBAC) (act as a Brønsted acid) (10 % mmol) diastereoselectivity and conversion
increased up to 3:1 and 100%, respectively, (Table 1, entry 2). Replacement of TEBAC
with N-Benzylcinchonidinium chloride did not affect outcome of the reaction (Table 1,
entry 3). For this reason, we continued our work with TEBAC.
The structure of isolated compounds 5a and 5a’ were determined on the basis of spectral
data. In the 1H-NMR spectrum of compound 5a, the proton HC(4) resonates as a doublet
at 7.75 ppm (J = 4.8 Hz), and the proton HC(3) resonates as a doublet of doublet at 4.27
(J = 12.0, 4.8 Hz), and the proton HC(2) resonates as a doublet of doublet of doublet at
3.37 (J = 12.0, 7.6, 4.8 Hz), These coupling constants indicate that the protons HC(4) and
HC(3) are cis and the HC(3) and HC(2) are trans.
In the 1H-NMR spectrum of compound 5a’, the proton HC(4) resonates as a doublet at
7.55 ppm (J = 11.2 Hz), and the proton HC(3) resonates as a doublet of doublet at 4.61 (J
= 11.2, 4.8 Hz). These coupling constants indicate that the protons HC(4) and HC(3) are
3

trans to each other. Furthermore, all these results show that the compounds 5a and 5a’
are diastereomers. Summary, the reaction of malononitrile (4) with the inonones (3) can
gives 4 possible stereoisomer having SS, RR, RS and SR configurations. From the NMR
studies, we assume that the a-isomer has SS or RR configurations and a'-isomer has RS
or SR configurations.
After these results, we continued the reactions with others indenones (3b-k) using
TEBAC (10 % mmol) and KOtBu (20 % mmol) (Scheme 3). The results were presented
in Table 2.
The products were separated by crystallization, thin layer- and column chromatography
and/or HPLC. The diastereomers 5a-k and 5a’, 5b’, 5e’, 5f’, 5i’ and 5j’ were isolated as
pure products. Despite all our efforts, the other diastereomers 5c’, 5d’, 5g’, 5h’ and 5k’
could not be isolated as pure products.
The reaction mechanism can be illustrated as shown below. We assume that the
benzyltriethylammonium chloride interacts with oxygen atom of carbonyl group to form
the enolate form I. Then, malononitrile anion (iminium ion), formed by acting of KOtBu,
interacts with I and formed the transition state II. In the transition state II, the formation
of C-C bond takes place rather one side of the transition state II. Removing of the
benzyltriethylammonium ion from III give the malononitrile adducts.
4

Addition, we assume that, the m-substituents on phenyl ring increase the energy of the
transition state II due to the steric effect and reduce product yield.
CONCLUSION
In summary, KOtBu-catalyzed addition of malononitrile to indenones 3 in the presence of
TEBAC gave addition products with acceptable yields. These products may find
synthetic utility for the preparation valuable intermediates in organic chemistry.
EXPERIMENTAL
All the reagents and solvents for synthesis were purchased from Sigma-Aldrich and
Fluka. Thin layer chromatography was carried out on Merck silica F254 0.255-mm plates,
and spots were visualized by UV fluorescence at 254 nm. Classic column
chromatography was performed using Merck 60 (70-230 mesh) silica gel. Melting points
were measured on Electrothermal 9100 apparatus. IR spectrums (KBr disc) were
recorded on a Jasco FT/IR-430 spectrometer. 1H- and 13C-NMR spectrum was recorded
on a Bruker Avance DPX-400 instrument. As internal 0.00) for standards served TMS
(1H NMR and CDCl3 (77.0) for 13C NMR spectroscopy J values are given in Hz.
Elemental analyses were obtained from a LECO CHNS 932 Elemental Analyzer.
5

General Procedure For The Synthesis Of 2-(Benziliden)-2,3-Dihidro-1H-Inden-1-One
(Chalcone Analogues) Derivatives (3a-K)
The chalcone analogues, 2-(benziliden)-2,3-dihidro-1H-inden-1-one derivatives, (3a-k)
were synthesized by previously published methods.[30–33]
General Procedure For The Addition Of Malononitrile To Chalcone Analogues (3a-
K): Synthesis Of 5a-K And 5a’-5k’
The mixture of chalcone analogue 3 (0.5 g, 1 mmol) and malononitrile (4) (0.16 g, 1.2
mmol) was dissolved in 5 ml of CH2Cl2. To this solution was added
benzyltriethylammonium chloride (10% mmol) and KOt-Bu (20%mmol) and the mixture
was stirred for 6 hours at room temperature. Reaction mixture was diluted with CH2Cl2
(50 ml) and added solution of 5% HCl. Organic layer was washed with H2O and dried
with Na2SO4. The solvent was removwed. The crude product was submitted to
crystallization (using different solvent mixture: 2:1 ether: ethanol; CH2Cl2: hexane),
and/or colon chromatography (silica gel), and/or thin layer chromatography (silica gel)
and/or HPLC for separation of isomers.
2-((R)-(2-Bromophenyl)((S)-1-Oxo-2,3-Dihydro-1H-Inden-2-Yl)Methyl)Malononitrile.
(5a)
White cyrstals, Yield: 40%. mp: 145-148°C. IR (KBr, cm-1): 3064, 2900, 2254, 1697,
1602, 1565, 1475, 1463, 1434, 1274, 1211, 1186, 1076, 997, 925, 796, 763, 736, 665,
615. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.6 Hz, 1H), 7.76-7.73 (m, 2H), 7.65 (t,
J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz,
6

1H), 7.34 (t, J = 8.0 Hz, 1H), 5.75 (d, J = 4.8 Hz, 1H), 4.27 (dd, J = 12.0, 4.8 Hz, 1H),
3.37 (ddd, J = 12.6, 7.6, 4.8 Hz,1H), 3.13 (dd, J = 17.2, 7.6 Hz, 1H), 2.64 (dd, J = 17.2,
4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 205.8, 152.2, 135.9, 135.8, 135.5, 133.9,
130.6, 128.7, 128.3, 128.2, 126.3, 125.9, 124.4, 111.9, 111.3, 47.2, 43.8, 32.5, 26.5. Anal.
calc. for C19H13BrN2O: C, 62.48; H, 3.59; N, 7.67. Found: C, 62.36; H, 3.47; N, 7.63.
2-((S)-(2-Bromophenyl)((S)-1-Oxo-2,3-Dihydro-1H-Inden-2-Yl)Methyl)Malononitrile.
(5a’)
White cyrstals, Yield: 15%. mp: 196-199°C. IR (KBr, cm-1): 3079, 3064, 2942, 2252,
1698, 1604, 1473, 1434, 1294,1280, 1205, 1024, 759, 750, 715, 651, 578. 1H NMR (400
MHz, CDCl3): δ 7.77 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.6 Hz,
1H), 7.38 (t, J = 7.6 Hz, 2H), 7.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.15
(t, J = 8.0 Hz, 1H), 5.55 (d, J = 11.2 Hz, 1H), 4.61 (dd, J = 11.2, 4.8 Hz, 1H), 3.51-3.41
(m, 2H), 2.81 (dd, J = 16.0, 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 206.6, 153.0,
136.4, 135.7, 133.9, 133.6, 130.5, 128.7, 128.1, 127.9, 126.6, 126.4, 124.0, 112.5, 111.6,
47.0, 45.5, 30.1, 26.0. Anal. calc. for C19H13BrN2O: C, 62.48; H, 3.59; N, 7.67. Found: C,
62.36; H, 3.48; N, 7.56.
ACKNOWLEDGEMENT
The authors are indebted to the Gaziosmanpasa University, Scientific Research Projects
Commission (Project No: BAP2014/73) for financial supports.
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Table1. Optimization studies
Entry Compound Catalyst Time(h) Conv.% Product
ratio
5a:5a’
-
24
6
20
1:1
3:1
3:1
1
2
3
3a
3a
3a
A
B
100
100
6
A = Benzyltriethylammonium chloride =
B = N-Benzylcinhoninium chloride =
11

Table 2. Synthesized diastereomers 5a-k and 5a’-k’
Entry
X
Comp. Yield% Comp.
Yield%
15a)
1
2-Br
40a)
5a
5b
5c
5d
5e
5f
5a’
5b’
5c’
5d’
5e’
5f’
2
3-Br
43a)
67a)
60a)
65a)
56a)
62a)
45a)
64a)
63a)
71a)
17a)
3
4-Br
17b)
23b)
25a)
4
3-Cl
5
4-Cl
6
3-OCH3
4-OCH3
2-CH3
3-CH3
2,5-diOCH3
2-Cl,5-NO2
21a)
7
21b)
19b)
23a)
5g
5h
5i
5g’
5h’
5i’
8
9
10
11
22a)
5j
5j’
16b)
5k
5k’
a) Isolated yield;
b) Calculated yield from 1H-NMR spectrum of mixture of isomers
12

Scheme 1. Synthesis of indenones (3a-k)
13

Scheme 2. Determination of the optimum reaction conditions
14

Scheme 3. Michael Additof of Malanonitrile to Indenones
15