One-pot three-component reaction: Synthesis of substituted β-cyanocarbonyls in aqueous media

Article abstract of DOI:10.1016/j.crci.2012.01.004

An environmentally friendly and simple method for the synthesis of alkyl nitriles or β-cyanocarbonyls via a one-pot three-component reaction of Meldrum's acid, aldehydes and sodium cyanide in water, without using any catalyst or activation at room temperature is reported.

Full text of DOI:10.1016/j.crci.2012.01.004

C. R. Chimie 15 (2012) 273–277
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Preliminary communication/Communication
One-pot three-component reaction: Synthesis of substituted
-cyanocarbonyls in aqueous media
b
*
Ebrahim Soleimani , Mohammad Mehdi Khodaei, Afsaneh Taheri Kal Koshvandi
Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran
A B S T R A C T
A R T I C L E I N F O
Article history:
An environmentally friendly and simple method for the synthesis of alkyl nitriles or
Received 25 August 2011
Accepted after revision 6 January 2012
Available online 10 February 2012
b
-cyanocarbonyls via a one-pot three-component reaction of Meldrum’s acid, aldehydes
and sodium cyanide in water, without using any catalyst or activation at room
temperature is reported.
ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Alkyl nitrile
Multi-component reactions
Water
b-Cyanocarbonyls
Sodium cyanide
Meldrum’s acid
1. Introduction
topic for academic research that also satisfies the practical
interest of applied science [2,3].
Organic reactions in aqueous media have attracted
much attention recently not only because water is the
most abundant, environmentally benign, and cheapest
solvent but also because unique selectivity and reactivity
can be expected from this solvent [1].
Multicomponent reactions (MCR) are very efficient
synthetic methods. The strategy offers significant advan-
tages over classical stepwise approaches allowing the
formation of several bonds and the construction of complex
molecular architectures from simple precursors in a single
synthetic operation without the need for isolation of
intermediates [2]. MCRs, particularly those performed in
aqueous media, have become increasingly useful tools for
the synthesis of chemically and biologically important
compounds because of their environmentally friendly atom
economy and green characteristics [3]. Furthermore, the
discovery of novel MCRs can be considered an interesting
The organic nitriles are of much importance in organic
synthesis as these are versatile intermediates in the
synthesis of amines, carboxylic acids, esters and ketones
which are useful raw materials for pharmaceuticals,
agrochemicals and dyes [4]. The cyano moiety is also
present in numerous bioactive molecules [5]. The classical
method for the synthesis of alkyl cyanide involves
nucleophilic substitution of an alkyl halide with metal
cyanides [4a].
Furthermore, the introduction of nitrile into organic
compounds can be achieved using different routes
including: the direct conversion of aldehydes [6], oxime
ethers [7], thioamides [8], carboxylic acid and their esters
[9], dehydration of aldoximes [10] and amides [11] with
various reagents, oxidation of amines [12], and reduction
of primary aliphatic nitro compounds [13], enzymatic
methods [14] and application of organoborane/diazoace-
tonitrile [15]. Unfortunately, most of the reported methods
suffer from serious drawbacks such as the difficulty of
available reagents, low yields, drastic reaction conditions
and tedious work-up procedures. Thus, the development of
a convenient and efficient methodology for the synthesis of
* Corresponding author.
E-mail address: e_soleimanirazi@yahoo.com (E. Soleimani).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2012.01.004

274
E. Soleimani et al. / C. R. Chimie 15 (2012) 273–277
Me
O
Me
O
Me
O
Me
O
CHO
H2O
O
ONa
+
R
NaCN
+
r.t
O
O
CN
R
3
4
1
2
Scheme 1. Synthesis of
b-cyanocarbonyls.
Table 1
two equivalents of Meldrum’s acid with aldehyde is a
competing reaction; the product of this reaction was
separated as a by-product in high temperature [18].
With the optimal conditions in hand, the range of the
substrates was checked. The Knoevenagel condensation
and Michael addition reaction were carried out using a
series of different aldehydes with Meldrum’s acid and
sodium cyanide. The results are summarized in Table 1.
The structures of the products were established by
different spectroscopic methods (for details see Experi-
mental section). In all cases, excellent yields were
obtained, whatever the nature of the substituent present
on the aldehyde (electron-donating or electron-withdraw-
ing). This confirms the reliability of the synthetic method.
For the scope and limitation of the method, we
investigated the reaction of 2-naphthyl carbaldehyde with
Meldrum’s acid and sodium cyanide under the above
conditions led to the formation of the corresponding alkyl
nitriles in 99% yields (Scheme 2).
Reaction of Meldrum’s acid and aldehyde with sodium cyanide in water at
room temperature.
Entry
R1
Product
Yield (%)a
1
2
3
4
5
6
7
8
H
4a
4b
4c
4d
4e
4f
99
98
98
99
99
99
98
98
4-Cl
4-OH
4-NO2
4-OMe
4-Me
3-OH
3-NO2
4g
4h
a
Isolated yield.
b-cyanocarbonyl compounds is an interesting target for
investigation.
One of the best methods for the introduction of a
cyanide group involves the Michael addition of cyanide
anion to an
a,b-unsaturated carbonyl derivatives in the
presence of strong bases or Lewis acid catalysts [16]. As
part of our ongoing research aimed at developing synthesis
of alkyl nitriles [17], herein we report a one-pot, three-
component reaction of Meldrum’s acid 1, an aldehyde 2
and sodium cyanide 3, for the preparation of alkyl nitrile or
Mechanistically, it is conceivable that the reaction
involves the initial formation of activated alkene or
a,b-
unsaturated carbonyl 5 through a Knoevenagel conden-
sation reaction of Meldrum’s acid and aldehyde. After-
wards the intermediate 5 undergoes Michael addition
b-cyanocarbonyl 4 without using any catalyst at room
reaction with cyanide to afford b-cyanocarbonyls 4
temperature in water (Scheme 1).
(mechanism A). Another mechanism possible for this
reaction involves the initial formation of cyanohydrin 6
through a cyanohydrin formation of sodium cyanide with
aldehyde. Afterwards nucleophilic substitution of the
2. Results and discussion
We compared the reaction rate in different solvents by
measuring the isolated yield using identical amounts of
cyanohdrin 6 with sodium cyanide affords to b-cyano-
carbonyls 4 (mechanism B) (Scheme 3). To clarify the
proposed mechanisms, first, the Michael acceptor 5 was
synthesized from condensation of Meldrum’s acid and
benzaldehyde, subsequently reaction of 5 with sodium
reactants for
a fixed reaction time of 6 h at room
temperature. The desired product was obtained in protic
solvents such as water, ethanol, and methanol but water
can afford the product in good yield even better than
ethanol and methanol. The desired product was scarcely
obtained in dichloromethane, benzene, and toluene. We
also studied the reaction at different temperatures. The
reaction rate decreased as the reaction temperature was
raised. Because at high temperature reaction aldol-Michael
cyanide afforded corresponding
b-cyanocarbonyl 4. Also
for further clarification, cyanohdrin 6 was synthesized
from reaction aldehyde with sodium cyanide in water;
subsequently cyanohdrin 6 did not undergo reaction with
Meldrum’s acid under the reaction conditions. Therefore
mechanism A is reasonable.
CHO
Me
O
Me
O
CN ONa
H2O
r.t
O
+
+
NaCN
Me
O
O
O
O
Me
4i
Scheme 2. Synthesis of alkyl nitrile derivative.

E. Soleimani et al. / C. R. Chimie 15 (2012) 273–277
275
Me
Me
O
CHO
O
+
NaCN
+
O
O
3
1
2
Cyanohydrin formation
Mechanism B
Knoevenagel condensation
Mechanism A
Me
Me
O
OH
O
O
CN
O
6
5
Me
O
Me
O
Me
O
Me
O
O
O
NaCN
Michael addition
O
ONa
S
N Reaction
CN
4
Scheme 3. Proposal mechanisms.
3. Conclusion
temperature. After completion of the reaction as indicated
by TLC, the solvent was evaporated, and the residue was
washed with ether and recrystallized in ether/n-hexane
(50/50) to give the pure product 4a. White powder (0.28 g,
yield 99%). Mp 218 8C. IR (KBr) (nmax /cmÀ1): 3183, 2272,
1720. MS, (m/z): 232 (M+-NaCN). 1H NMR (200 MHz,
DMSO-d6): dH (ppm) 1.44 (6H, s, CH3-C-CH3), 5.09 (1H, s,
CH-CN), 7.16–7.35 (5H, m, H-Ar). 13C NMR (50 MHz,
In conclusion, the efficient synthesis of alkyl nitrile in
water, without employing catalyst has been described. The
three-component reaction involving Meldrum’s acid, an
aromatic aldehyde and sodium cyanide afforded the
desired products with excellent yields. A wide range of
aromatic aldehydes were tested, bearing either electron-
donating or electron-withdrawing substituent’s, suggest-
ing that this method can be used to synthesize a large
variety of compounds. It has therefore been demonstrated
that using water as the solvent is ideally suited for the
synthesis of alkyl nitriles.
DMSO-d6): dC (ppm) 26.2 (CH3-C-CH3), 32.4 (CH-CN), 71.7
(C=CC-ONa), 100.4 (CH3-C-CH3), 121.7, 126.8, 127.2, 128.4,
139.2 (C-Ar and CN), 164.6 (C=CO). Anal. Calcd for
C14H12NNaO4: C, 59.79; H, 4.30; N, 4.98. Found: C,
59.83; H, 4.27; N, 5.11.
4.3. 2-(4-chlorophenyl)-2-(sodium-2,2-dimethyl-4-oxo-4H-
4. Experimental
1,3-dioxin-5-yl-6-oxide) acetonitrile (4b)
4.1. Materials and techniques
Yellow powder (0.29 g, yield 98%). Mp 197 8C. IR (KBr)
(n
max /cmÀ1): 3182, 2271, 1725. MS, (m/z): 266 (M+-NaCN).
Melting points were taken on an Electrothermal 9100
apparatus and left uncorrected. IR spectra were obtained on
a Shimadzu IR-470 spectrometer. 1H and 13C NMR spectra
were recorded on a Bruker DRX-200 Avance spectrometer at
200 and 50 MHz. NMR spectra were obtained on solutions in
DMSO using tetramethylsilane as internal standard. All of
the chemicals were purchased from Fluka, Merck and
Aldrich and used without purification.
1H NMR (200 MHz, DMSO-d6):
CH3), 5.07 (1H, s, CH-CN), 7.30–7.32 (4H, m, H-Ar). 13C
NMR (50 MHz, DMSO-d6): C (ppm) 26.1 (CH3-C-CH3), 31.9
dH (ppm) 1.42 (6H, s, CH3-C-
d
(CH-CN), 71.8 (C=C-ONa), 100.7 (CH3-C-CH3), 121.3, 128.4,
129.1, 131.5, 138.2 (C-Ar and CN), 164.7 (C=O). Anal. Calcd
for C14H12ClNO4: C, 57.25; H, 4.12; Cl, 12.07; N. Found: C,
57.33; H, 4.17; N, 12.11.
4.4. 2-(sodium-2,2-dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-
4.2. Typical procedure: preparation of 2-(sodium 2,2-
dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-oxide)-2-
phenylacetonitrile (4a)
oxide)-2-(4-hydroxyphenyl) acetonitrile (4c)
Red powder (0.29 g, yield 98%). Mp 193 8C. IR (KBr)
(n
max /cmÀ1): 3184, 2273, 1727. MS, (m/z): 248 (M+-NaCN).
A solution of Meldrum’s acid (0.14 g, 1 mmol), benzal-
dehyde (0.11 g, 1 mmol) and sodium cyanide (0.05 g,
1 mmol) in H2O (10 mL) was stirred for 6 h at room
1H NMR (200 MHz, DMSO-d6):
dH (ppm) 1.49 (6H, s, CH3-C-
CH3), 3.47 (OH exchanged with water of DMSO-d6), 5.02
(1H, s, CH-CN), 6.70 (2H, d, 3JHH = 8.4 Hz, H-Ar), 7.20 (2H, d,

276
E. Soleimani et al. / C. R. Chimie 15 (2012) 273–277
3JHH = 8.4 Hz, H-Ar). 13C NMR (50 MHz, DMSO-d6): dC
(ppm) 26.3 (CH3-C-CH3), 31.6 (CH-CN), 71.7 (C=C-ONa),
100.1 (CH3-C-CH3), 115.1, 122.1, 128.3, 129.7, 156.2 (C-Ar
and CN), 164.4 (C=O). Anal. Calcd for C14H12NNaO5: C,
56.57; H, 4.07; N, 4.71. Found: C, 56.62; H, 4.17; N, 4.79.
4.9. 2-(sodium-2,2-dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-
oxide)-2-(3-nitrophenyl) acetonitrile (4h)
Cream powder (0.32 g, yield 98%). Mp 185 8C. IR (KBr)
(n
max /cmÀ1): 3183, 2271, 1729. MS, (m/z): 248 (M+-NaCN).
1H NMR (200 MHz, DMSO-d6):
CH3), 5.23 (1H, s, CH-CN), 7.50–8.13 (4H, m, H-Ar). 13C
NMR (50 MHz, DMSO-d6): C (ppm) 26.1 (CH3-C-CH3), 32.4
dH (ppm) 1.43 (6H, s, CH3-C-
4.5. 2-(sodium-2,2-dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-
oxide)-2-(4-nitrophenyl) acetonitrile (4d)
d
(CH-CN), 71.50 (C=CC-ONa), 100.8 (CH3-C-CH3), 120.8,
121.7, 122.1, 130.1, 134.0, 141.5, 147.5 (C-Ar and CN),
164.7 (C=CO). Anal. Calcd for C14H11N2NaO6: C, 51.54; H,
3.40; N, 8.59. Found: C, 51.44; H, 3.38; N, 8.51.
Brown powder (0.32 g, yield 99%). Mp 178 8C. IR (KBr)
(
nmax /cmÀ1): 3187, 2270, 1726. MS, (m/z): 248 (M+-
NaCN). 1H NMR (200 MHz, DMSO-d6):
dH (ppm) 1.48 (6H,
s, CH3-C-CH3), 5.29 (1H, s, CH-CN), 7.63 (2H, d,
3
3JHH = 8.5 Hz, H-Ar), 8.22 (2H, d, JHH = 8.5 Hz, H-Ar). 13C
4.10. 2-(sodium-2,2-dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-
NMR (50 MHz, DMSO-d6): dC (ppm) 26.2 (CH3-C-CH3),
31.8 (CH-CN), 71.10 (C=C-ONa), 100.1 (CH3-C-CH3), 123.0,
123.7, 128.4, 130.4, 147.5 (C-Ar and CN), 164.4 (C=O).
Anal. Calcd for C14H11N2NaO6: C, 51.54; H, 3.40; N, 8.59.
Found: C, 51.60; H, 3.38; N, 8.60.
oxide)-2-(naphthalen-3-yl) acetonitrile (4i)
Cream powder (0.33 g, yield 98%). Mp 188 8C. IR (KBr)
(n
max /cmÀ1): 3184, 2270, 1726. MS, (m/z): 304 (M+-NaCN).
1H NMR (200 MHz, DMSO-d6):
CH3), 5.32 (1H, s, CH-CN), 7.50–7.91 (7H, m, H-Ar). 13C
NMR (50 MHz, DMSO-d6): C (ppm) 26.2 (CH3-C-CH3), 32.6
dH (ppm) 1.50 (6H, s, CH3-C-
4.6. 2-(sodium-2,2-dimethyl-4-oxo-4H-1,3-dioxin-5-yl-6-
d
oxide)-2-(4-methoxyphenyl) acetonitrile (4e)
(CH-CN), 71.80 (C=CC-ONa), 100.5 (CH3-C-CH3), 120.6,
125.1, 126.0, 126.1, 126.6, 127.8, 128.0, 128.1, 132.2, 133.0,
136.9 (C-Ar and CN), 164.6 (C=CO). Anal. Calcd for
C18H14NNaO4: C, 65.26; H, 4.26; N, 4.23. Found: C,
65.34; H, 4.22; N, 4.32.
Cream powder (0.31 g, yield 99%). Mp 195 8C. IR (KBr)
(n
max /cmÀ1): 3183, 2277, 1730. MS, (m/z): 262 (M+-NaCN).
1H NMR (200 MHz, DMSO-d6):
d
H (ppm) 1.40 (6H, s, CH3-C-
CH3), 3.67 (3H, s, OCH3), 5.10 (1H, s, CH-CN), 7.80 (2H, d,
3JHH = 8.0 Hz, H-Ar), 7.22 (2H, d, JHH = 8.0 Hz, H-Ar). 13C
NMR (50 MHz, DMSO-d6): dC (ppm) 26.3 (CH3-C-CH3), 31.6
3
Acknowledgements
(CH-CN), 55.5 (OCH3), 71.7 (C=C-ONa), 100.2 (CH3-C-CH3),
113.8, 122.0, 128.4, 131.4, 158.2 (C-Ar and CN), 164.4
(C=CO). Anal. Calcd for C15H14NNaO5: C, 57.88; H, 4.53; N,
4.50. Found: C, 57.78; H, 4.59; N, 4.42.
We gratefully acknowledge financial support from the
Research Council of Razi University.
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max /cmÀ1): 3183, 2271, 1726. MS, (m/z): 248 (M+-NaCN).
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dH (ppm) 1.36 (6H, s, CH3-C-
CH3), 3.67 (OH exchanged with water of DMSO-d6), 4.91
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Calcd for C14H12NNaO5: C, 56.57; H, 4.07; N, 4.71. Found: C,
56.64; H, 4.27; N, 4.73.

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