New facile, eco-friendly and rapid synthesis of trisubstituted alkenes using bismuth nitrate as lewis acid

Article abstract of DOI:10.2174/1570178613666160109005421

Background: For the synthesis of tri and tetra-substituted alkenes, Knoevenagel condensations have previously been performed in solvents like dichloromethane, DMF, toluene, acetonitrile, DMSO etc. These conditions suffer from certain limitations like long

Full text of DOI:10.2174/1570178613666160109005421

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Letters in Organic Chemistry, 2016, 13, 231-235
231
New Facile, Eco-Friendly and Rapid Synthesis of Trisubstituted Alkenes
Using Bismuth Nitrate as Lewis Acid
Munira T. Muhammada, Khalid M. Khana,*, Muhammad Tahab,c, Tariq Khana, Shafqat Hussaina,d,
Muhammad I. Fakhria, Shahnaz Perveene and Wolfgang Voelterf
aH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,
b
University of Karachi, Karachi-75270, Pakistan; Atta-ur-Rahman Institute for Natural Product Dis-
covery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Se-
c
langor D. E. Malaysia; Faculty of Applied Science Universiti Teknologi MARA, 40450 Shah Alam,
d
Malaysia Department of Chemistry, Karakoram International University, Gilgit-15100, Gilgit-
e
Baltistan, Pakistan; PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui,
Karachi-75280, Pakistan; fInterfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-
Str. 4, D-72076 Tübingen, Germany
Received July 22, 2015: Revised November 26, 2015: Accepted December 14, 2015
Abstract: Background: For the synthesis of tri and tetra-substituted alkenes, Knoevenagel condensations have previously
been performed in solvents like dichloromethane, DMF, toluene, acetonitrile, DMSO etc. These conditions suffer from
certain limitations like long reaction times are required in DMSO or harsh heating conditions are necessary using DMF as
a solvent decreasing the yields to below 50%. Tedious work up is required after long reaction times or/and high tempera-
tures, if the reaction is performed in toluene.
Methods: In a typical reaction, 1 mmol of aromatic aldehyde with 1.1 mmol of malanonitrile in the presence of bismuth
nitrate (3 mmol%) was refluxed in water (10 ml) for 25-30 min. After completion of the reaction (TLC analysis), excess
bismuth nitrate was filtered for next use and the filtrate was kept at room temperature over night for crystallization. Crys-
tals were filtered, washed with water and dried. In a separate reaction the catalyst was re-used for the one of the same re-
actions and found satisfactory results.
Results: In order to generalize our newly developed methodology, we selected a variety of aldehydes to synthesize differ-
ent trisubstituted alkenes and found that this method can also be applied on aromatic aldehydes. For comparison purposes,
the reaction was carried out in ethanol in parallel to water and found that water is the best solvent for this reaction.
Conclusion: In summary, we have discovered a facile and rapid method for Knoevenagel condensations using bismuth ni-
trate as Lewis acid. The advantages of bismuth nitrate as a catalyst are: easy to remove from the reaction mixture by sim-
ple filtration, recyclable, requires water as solvent, is eco-friendly and afforded high yields (90-97%).
Keywords: Bismuth nitrate, eco-friendly, knoevenagel, trisubstituted alkenes.
1. INTRODUCTION
condensed with aldehydes, yield trisubstituted alkenes serv-
ing as important intermediates in many reactions [4-9]. For
the synthesis of such trisubstituted alkenes, Knoevenagel
condensations have previously been performed in solvents
like dichloromethane, DMF, toluene, acetonitrile, DMSO
etc. [10, 11]. These conditions suffer from certain limitations
like long reaction times are required in DMSO [12, 13] or
harsh heating conditions are necessary using DMF as a
solvent decreasing the yields to below 50%. Tedious work
up is required after long reaction times or/and high
temperatures, if the reaction is performed in toluene. Also,
under solvent-free conditions using microwave irradiation
only 50-75% yield in 15-180 minutes have been achieved
[14, 15]. Additionally, catalysts like morphine, pyridine,
piperidine, piperazine, I2, PPh3, in the presence of Pd, Cu (I)
mediated, Tf2NH Catalysed, alkali metal hydroxides (KOH,
NaOH), basic zeolites (Cs, lanthanum-impregnated
mesoporous) MCM-41, alkali-exchanged zeolites or biocata-
Knoevenagel condensation is a well-established method
for carbon-carbon bond formation: Compounds containing
active methylene groups are condensed either with aldehydes
or ketones to trisubstituted and tetrasubstituted alkenes, re-
spectively [1]. Alkenes are present in numerous naturally
occurring compounds such as ꢀ-carotene, ꢁ-carotene, vita-
min A, macrocycles, polycycles, terpenes, etc. It is also re-
ported that compounds containing longer conjugated unsatu-
rated carbon chains have redox activity in the living system
and may serve as anticancer agents [2, 3]. Compounds con-
taining active methylene moieties like malononitrile, when
*Address correspondence to this author at the H. E. J. Research Institute of
Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi-75270, Pakistan; Tel: 0092-21-34824910;
Fax: 0092-21-34819018-9; E-mails: khalid.khan@iccs.edu, and
hassaan2@super.net.pk
1875-6255/16 $58.00+.00
© 2016 Bentham Science Publishers

232 Letters in Organic Chemistry, 2016, Vol. 13, No. 3
Muhammad et al.
lysts like lipase were also used but found inappropriate [16-
18]. The major problems using these catalysts are not to be
active in all solvents, to require tedious work up, and some-
times suffer from poor yields. High costs, poor yields along
with troublesome isolation procedures are the disadvantages
of applying biocatalysts. These limitations clearly indicate
that a Knoevenagel condensation under conventional condi-
tions is a limited approach for the synthesis of trisubstituted
alkenes [19].
In continuation of our work on bismuth-containing Lewis
acids as catalyst and other catalysts for Knoevenagel con-
densations [19-21], we herein want to report an improved,
facile, expeditious and high yielding method for the synthe-
Table 1. Synthesized Trisubstituted Alkene 1-12.
H
CN
R
CN
H2O
EtOH
Comp. No.
1
R
Yield (%)
Time (min)
Yield (%)
Time (min)
Cl
94
90
30
92
34
Cl
Cl
2
28
82
32
Cl
3
4
95
88
24
26
90
80
27
25
O2N
NO2
5
6
89
89
25
30
84
85
30
34
Cl
O2N
7
8
9
93
95
94
24
20
24
88
82
82
22
20
28
H3C
HO
O
10
11
89
89
30
24
80
80
35
30
N
Br
12
95
30
85
34
OEt
OH

New Facile, Eco-Friendly and Rapid Synthesis
Letters in Organic Chemistry, 2016, Vol. 13, No. 3
233
The reaction between malononitrile and aldehydes was
explored by using different bases which abstract the acidic
proton from malononitrile, however, in the newly developed
method, Bi(NO3)3 acts as a Lewis acid and activates the al-
dehydic carbon. As water (Pka 15.7) as well as ethanol (Pka
15.9) are basic enough to de-protonate malononitrile, and
due to the presence of Bi(NO3)3, the aldehydic carbon be-
comes more electrophillic. Thus, the attack of the anion of
malononitrile results in the formation of an alkoxide bonded
to bismuth nitrate. As soon as this oxygen atom abstracts a
proton from the solvent, Bi(NO3)3 departs and forms an al-
cohol. Elimination of a water molecule from the alcohol and
formation of a trisubstituted alkene takes place. Almost all
aromatic aldehydes, either having electron- withdrawing or -
donating groups are activated nearly to the same extent with
Bi(NO3)3, and the reaction times (below 40 min) for all reac-
tions were nearly the same (Fig. 1). Some experiments were
also carried out in dichloromethane and acetonitrile, but
found to be ineffective.
H
O
CN
H2O, 25 min
R
NC
NC
CN
CN
+
Bi(NO3)3.5H2O
R
H
CN
Scheme 1.
O
H
EtOH, 40 min
Bi(NO3)3.5H2O
CN
R
+
R
H
CN
Scheme 2.
sis of trisubstituted alkenes using bismuth nitrate in water or
ethanol (Schemes 1 and 2, Table 1).
2. RESULTS AND DISCUSSION
During a total synthesis of a bioactive natural product,
we found that bismuth nitrate can catalyze Knoevenagel
condensations, and to the best of our knowledge, bismuth
nitrate is used for the first time for this condensation.
3. CONCLUSION
In summary, we have discovered a facile and rapid
method for Knoevenagel condensations using bismuth nitrate
as Lewis acid. The advantages of bismuth nitrate as a cata-
lyst are: easy to remove from the reaction mixture by simple
filtration, recyclable, requires water as solvent, is eco-
friendly, and afforded high yields (90-97%).
In order to generalize our newly developed methodology,
we selected a variety of aldehydes to synthesize different
trisubstituted alkenes and found that this method can be ap-
plied also on aromatic aldehydes. For comparison purposes,
the reaction was carried out in ethanol in parallel to water
and found that water is the best solvent for this reaction
(Scheme 1 and 2).
4. EXPERIMENTAL
In a typical reaction, 1 mmol of aromatic aldehyde with
1.1 mmol of malanonitrile in the presence of bismuth nitrate
(3 mmol%) was refluxed in water (10 ml) for 25-30 min.
After completion of the reaction (TLC analysis), excess bis-
muth nitrate was filtered for next use and the filtrate was
kept at room temperature over night for crystallization. Crys-
tals were filtered, washed with water and dried. In a separate
reaction the catalyst was re-used for the one of the same re-
actions and found satisfactory results.
4.1. General Procedure for the Synthesis of Compounds
1-12
In a round-bottomed flask corresponding aldehydes (1
mmol) and a catalytic amount (3 mol%) of Bi(NO3)3 in wa-
ter/ethanol (10 mL) were stirred for 2 minutes at room tem-
perature, and then malononitrile (1.1 mmol) was added. The
reaction mixture was refluxed for 20 minutes. After comple-
tion of the reaction (TLC analysis), Bi(NO3) 3 was filtered
O
BiNO3
R
NO3
O3N
Bi
H
NO3
NO3
O
O
Bi
NO3
NO3
H
H
H
H
H
O
NO3
NO3
R
NC
CN
O3N
Bi
H
CN
CN
O
CN
H
CN
R
Fig. (1). Plausible mechanism of BiNO3 catalyzed Knoevenagel condensation.

234 Letters in Organic Chemistry, 2016, Vol. 13, No. 3
Muhammad et al.
for the next use and the filtrate was kept at room temperature
over night for crystallization. Crystals were filtered, washed
with water, dried, and were re-crystallized from hot ethanol.
All aldehydes and other starting materials were used as re-
ceived from the supplier. Nuclear magnetic resonance spec-
tra were recorded on Bruker 300 MHz and 500 MHz spec-
trometers and mass spectra were recorded at JEOL JMS-
HX110 mass spectrometer using FABMS-H. Thin layer
chromatography was carried out on aluminum plates pre-
coated with silica gel (Kieselgel 60, E. Merck, Darmstadt,
Germany). UV light at 254 and 365 nm was used for chro-
matograms visualization.
130.3 (C-6), 129.8 (C-5), 127. 9 (C-4), 134.2 (C-2), 129.6
(C-1), 113.4 (C-2’’), 112.3 (C-1ꢃꢃ).
4.1.6. 2-(3-Nitrobenzylidene)malononitrile (6)
Yield: 89%; M.p. 133°C, UV ꢀmax (MeOH) nm (log ꢁ): 268
(5.83); IR (KBr) ꢂmax cm-1: 3746, 3049, 1577, 1348, 1210;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.76 (s, 1H, H-8), 8.71 (s,
1H, H-6), 8.49 (dd, 1H, J = 9.9 Hz, 6.3 Hz, H-4), 8.33 (d,
1H, J = 7.8 Hz, H-2) 7.91 (t, 1H, J = 15.9 Hz, H-3); MS: m/z
13
199 (85%), 153 (100%), 126 (50%), 75 (15%); C- NMR;
(75 MHz, DMSO-d6) ꢀ 159.2 (C-1ꢃ), 135.8 (C-2), 131.1 (C-
2), 127.9 (C-5), 124.8 (C-6), 148.0 (C-3), 132.4 (C-4), 113.6
(C-2’’), 112.5 (C-1ꢃꢃ), 84.9 (C-1).
4.1.1. 2-(2, 4-Dichlorobenzylidene)malononitrile (1)
4.1.7. 2-Benzylidenemalononitrile (7)
Yield: 94%; M.p. 149°C; UV ꢀmax (MeOH) nm (log ꢁ): 310
(13.02); IR (KBr) ꢂmax cm-1: 3746, 3044, 1738, 1376, 1264;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.62 (s, 1H, H-8), 8.045
(d, 1H, J = 8.4 Hz, H-2), 7.92 (d, 1H, J = 1.8 Hz, H-3), 7.72
(dd, 1H, J = 6.6, 10.5 Hz, H-5); MS: m/z 223 (100%), 195
(20%), 187(100%), 124 (10%), 83 (60%); 13C-NMR; (75
MHz, DMSO-d6) ꢀ 156.7 (C-1), 130.9 (C-3), 130.0 (C-5),
128.3 (C-6), 138.6 (C-2), 135.5 (C-4), 113.3 (C-1ꢃ), 112.2
(C-2’), 87.1 (C-1ꢃꢃ).
Yield: 93%; M.p. 80°C, UV ꢀmax (MeOH) nm (log ꢁ): 344
(5.92); IR (KBr) ꢂmax cm-1: 3747, 2219, 1549, 1346, 1211;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.53 (s, 1H, H-8), 7. 95
(d, 2H, J=7.2 Hz, H-5, 6), 7.96 (m, 3H, H-2, 3, 4); MS: m/z
154 (100%), 123 (70%), 103 (50%), 44 (70%); 13C-NMR;
(75 MHz, DMSO-d6) ꢀ 161.5 (C-1’), 134.3 (C-4), 131.2 (C-
1), 130.4 (C-6, C-2), 129.5 (C-3, C-5), 114.1 (C-1’), 113.1
(C-2’), 81.6 (C-2”).
4.1.2. 2-(2, 6-Dichlorobenzylidene)malononitrile (2)
4.1.8. 2-[(5-Methyl-2-furyl)methylene]malononitrile (8)
Yield: 90%; M.p. 94°C; UV ꢀmax (MeOH) nm (log ꢁ): 287
(37.36); IR (KBr) ꢂmax cm-1: 3746, 3076, 2236, 1796, 1325;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.62 (s, 1H, H-8), 7.70
(d, 2H, J = 1.8 Hz, H-4, 5), 7.62 (m, 1H, H-3); MS: m/z 223
(100%), 195 (20%), 187 (100%), 124 (10%), 83 (60%); 13C-
NMR; (75 MHz, DMSO-d6) ꢀ 159.5 (C-1), 133.4 (C-2, C-6),
129.1 (C-4), 128.9 (C-5, C-3), 112.0 (C-3ꢃ), 111.0 (C-4ꢃ),
93.0 (C-2ꢃ).
Yield: 95%; M.p. 98°C, UV ꢀmax (MeOH) nm (log ꢁ): 358
1
(8.93); IR (KBr) ꢂmax cm-1: 3747, 3129, 2217, 1545; H-
NMR; (300 MHz, DMSO-d6) ꢀ 8.13 (s, 1H, H-6), 7.39 (d,
1H, J = 3.6 Hz, H-3), 6.61 (d, 1H, J = 3.6 Hz, H-4), 2.44 (s,
3H, H-10); MS: m/z 158 (100%), 131 (60%), 103 (25%), 53
(15%); 13C-NMR; (75 MHz, DMSO-d6) ꢀ 162.1 (C-4), 147.0
(C-1), 143.4 (C-1ꢃ), 128.0 (C-2), 114.9 (C-3ꢃ), 113.6 (C-4ꢃ),
112.2 (C-3), 72.1 (C-2ꢃ), 14.0 (C-1ꢃꢃ).
4.1.3. 2-(4-Nitrobenzylidene) malononitrile (3)
4.1.9. 2-(4-Hydroxybenzylidene)malononitrile (9)
Yield: 95%; M.p. 135°C; UV ꢀmax (MeOH) nm (log ꢁ): 307
(3.14); IR (KBr) ꢂmax cm-1: 3745, 3084, 2226, 1595, 1151;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.83 (s, 1H, H-8), ꢀ 8. 43
(d, 2H, J = 9.0 Hz, H-5, 6), 8.14 (d, 2H, J = 9.0 Hz, H-2, 3);
MS: m/z 199 (100%), 169 (40%), 153 (90%), 126 (90%),
114 (50%); 13C-NMR; (75 MHz, DMSO-d6) ꢀ 159.2 (C-1ꢃ),
149.6 (C-1), 136.6 (C-4), 131.4 (C-5, C-3), 124.3 (C-2- C-6),
113.5 (C-3ꢃ), 112.4 (C-4ꢃ), 85.9 (C-2ꢃ).
Yield: 94%; M.p. 185°C, UV ꢀmax (MeOH) nm (log ꢁ): 354
(6.392); IR (KBr) ꢂmax cm-1: 3746, 3351, 1610, 1322, 1172;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.290 (s, 1H, H-8), ꢀ
7.894 (d, 2H, J = 8.7 Hz , H-5, 6), 6.971 (d, 2H, J = 8.7 Hz,
H-2, 3); MS: m/z 170 (100%), 142 (80%), 115 (60%), 91
(25%), 63 (15%); 13C-NMR; (75 MHz, DMSO-d6) ꢀ 163.8
(C-1ꢃ), 160.4 (C-4), 133.8 (C-2, C-6), 122.7 (C-1), 116.6 (C-
3, C-5), 115.0 (C-3ꢃ), 114.1 (C-4ꢃ), 75.0 (C-2ꢃ).
4.1.4. 2-(2-Nitrobenzylidene)malononitrile (4)
4.1.10. 2-(1H-Indol-3-ylmethylene)malononitrile (10)
Yield: 88%; M.p. 130°C, UV ꢀmax (MeOH) nm (log ꢁ): 254
(5.82); IR (KBr) ꢂmax cm-1: 3735, 3047, 1567, 1346, 1211;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.96 (s, 1H, H-8), 8.34
(d, 2H, J = 0.8 Hz, H-2, 3), 8.00 (m, 2H, H-4, 5); MS: 199
m/z 199 (90%), 144 (50%), 126 (90%), 114 (85%), 92
(100%), 75 (50%); 13C-NMR; (75 MHz, DMSO-d6) ꢀ 161.3
(C-1ꢃ), 135.0 (C-2), 133.3 (C-5), 130.4 (C-4), 127.1 (C-1),
125.4 (C-6), 113.0 (C-3ꢃ), 111.7 (C-4ꢃ), 87.0 (C-2ꢃ).
Yield: 89%; M.p. 220°C, UV ꢀmax (MeOH) nm (log ꢁ): 287
1
(9.26); IR (KBr) ꢂmax cm-1: 3722, 2234, 1610, 1358; H-
NMR; (300 MHz, DMSO-d6) ꢀ 8.69 (s, 1H,H-10), 8.52 (s,
1H, H-2), 8.04 (dd, 1H, J = 17.4, 4.2 Hz, H-6), 7.58 (dd, 1H,
J = 8.4 Hz, 4.5 Hz, H-9),7.32 (m, 2H, H-7, 8); MS: m/z 193
(100%), 166 (65%), 139 (25%), 88 (10%); 13C-NMR; (75
MHz, DMSO-d6) ꢀ 160.4 (C-1ꢃ), 139.4 (C-1), 129.3 (C-6),
120.9 (C-5), 123.6 (C-3), 121.3 (C-4), 114.8 (C-3ꢃ), 113.4
(C-4ꢃ), 112.5 (C-2), 90.0 (C-2ꢃ).
4.1.5. 2-(2-Chlorobenzylidene)malononitrile (5)
4.1.11. 2-(2-Bromobenzylidene)malononitrile (11)
Yield: 89%; M.p. 90°C, UV ꢀmax (MeOH) nm (log ꢁ): 287
(5.61); IR (KBr) ꢂmax cm-1: 3745, 3049, 1635, 1358, 1210;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 8.669 (s, 1H, H-8), 8.034
Yield:89%; M.p. 92°C, UV ꢀmax (MeOH) nm (log ꢁ): 298
(10.44); IR (KBr) ꢂmax cm-1: 3741, 2229, 1645, 1322, 1348,
1
(d, 1H, J = 7.5 Hz), 7.713 (m, 1H); MS: m/z 188 (90%), 134
1241; H-NMR; (300 MHz, DMSO-d6) ꢀ 8.59 (s, 1H, H-8),
13
(50%), 114 (90%), 102 (85%), 90 (100%), 65(50%);
C-
7.98 (dd, 1H, J = 9Hz, 6Hz, H-6), 7.87 (dd, 1H, J = 9Hz , 6.6
Hz, H-3), 7.64 (m, 2H, H-4, 5); MS: m/z 233 (100%), 153
NMR; (75 MHz, DMSO-d6) ꢀ 157.9 (C-1ꢃ), 134.8 (C-3),

New Facile, Eco-Friendly and Rapid Synthesis
Letters in Organic Chemistry, 2016, Vol. 13, No. 3
235
(100%), 126 (85%), 99 (65%), 75 (70%);13C-NMR; (75
MHz, DMSO-d6) ꢀ 157.3 (C-1ꢃ), 135.1 (C-2), 132.3 (C-6),
129.4 (C-4), 128.2 (C-5), 126.1 (C-3), 123.2 (C-1), 114.2 (C-
3ꢃ), 115.4 (C-4ꢃ), 80.2 (C-2ꢃ).
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4.1.12. 2-(3-Ethoxy-4-hydroxybenzylidene)malononitrile (12)
Yield: 95%; M.p. 134°C, UV ꢀmax (MeOH) nm (log ꢁ): 295
(7.44); IR (KBr) ꢂmax cm-1: 3747, 2219, 1555, 1346, 1348;
1H-NMR; (300 MHz, DMSO-d6) ꢀ 10.70 (s, 1H, OH), 8. 24
(s, 1H, H-11), 7.61 (s, 1H, H-6), 7.48 (d, 1H, J = 6.9 Hz, H-
4) , 6.98 (d, 1H, J = 8.4, H-3), 4.07 (q, 2H, J = 6.9, H-8),
1.37 (t,3H, J = 13.8 Hz, H-9); MS: m/z 214(40 %), 193 (
55%), 154 (35%), 132 (20%); 13C-NMR; (75 MHz, DMSO-
d6) ꢀ 162.1 (C-1ꢃ), 149.3 (C-3), 148.1 (C-4), 128.7 (C-1),
123.3 (C-6), 117.2 (C-5), 114.1 (C-2), 114.1 (C-3ꢃ), 115.2
(C-4ꢃ), 81.3 (C-2ꢃ).
[9]
[10]
[11]
[12]
CONFLICT OF INTEREST
[13]
[14]
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
The authors are thankful to Higher Education Commis-
sion (HEC) Pakistan for financial support to Project No. 20-
2073 under National Research Program for Universities and
DAAD (Deutscher Akademischer Austauschdienst), Bonn,
(Germany) for granting a fellowship to Prof. Dr. Khalid M.
Khan.
[15]
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