Synthesis of β-cyanopropan-1-one derivates by domino reaction

Article abstract of DOI:10.1039/c4gc00386a

Domino nucleophilic addition was used for four-component Al ₂O₃-catalyzed environmentally friendly synthesis of polysubstituted β-cyanopropan-1-one. Domino nucleophilic addition involves removal of the cyano group linked to active methylene by the action of KF, and direct addition to enones. The reaction's capability for nucleophilic attack is F^- > CN^- in DMF. The use of low-toxicity reagents hints that the reaction is more environmentally friendly than traditional approaches. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00386a

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Synthesis of β-cyanopropan-1-one derivates by
domino reaction†
Cite this: Green Chem., 2014, 16,
3454
Hong-Ru Dong,a Wang-Jun Dong,a Rong-Shan Li,a Yi-Ming Hu,b
Received 4th March 2014,
Accepted 26th May 2014
Heng-Shan Dong*a and Zhi-Xiang Xie*a
DOI: 10.1039/c4gc00386a
www.rsc.org/greenchem
Domino nucleophilic addition was used for four-component acetone cyanohydrin as the cyanide source)2 or a transition
Al2O3-catalyzed environmentally friendly synthesis of polysubsti- metal cyanide in the presence of Lewis acid catalysts such
tuted β-cyanopropan-1-one. Domino nucleophilic addition as Gd,3 Al complexes4 and SnCl2.5 Recently, hydrocyanation
involves removal of the cyano group linked to active methylene by of efficient conjugate chalcones and related enones with a
the action of KF, and direct addition to enones. The reaction’s TMSCN (TMSCN is costly and easily decomposes) under
capability for nucleophilic attack is F− > CN− in DMF. The use solvent- and additive-free microwave conditions was reported
of low-toxicity reagents hints that the reaction is more environ- by Iida et al.6 There are other efficient methods for the syn-
mentally friendly than traditional approaches.
thesis of β-cyanoketones. For example, β-cyanoadducts can be
prepared by reacting α,β-unsaturated ketones with acetone
cyanohydrin in the presence of TBAF or Na2CO3.7 Reaction of
α,β-enones with KCN also yields Michael adducts.8
Cascade reactions and multicomponent domino reactions are
being increasingly applied to the construction of natural and
designed molecules. Such processes, in which ideally a single
event triggers the conversion of a starting material to a
product which then becomes a substrate for the next reaction
until termination leads to a stable final product, are highly
desirable not only due to their elegance, but also because of
their efficiency and economy in terms of reagent consumption
and purification. Often, these multistep, one-pot procedures
are accompanied by dramatic increases in molecular complex-
ity and impressive selectivity. The discovery of a new molecular
diversity from Nature and the demand for more efficient and
environmentally benign chemical processes dictates and
invites the further development of such synthetic strategies
and tactics as we move into a new age of chemical synthesis.1
Conjugate hydrocyanation of α,β-unsaturated carbonyl com-
pounds is of great interest because the resulting β-cyano-
adducts are easily converted to other products under various
conditions. A powerful method for cyano introduction in the
β-position is the hydrocyanation reaction of conjugated α,β-un-
saturated ketones with HCN (HCN, potassium and acetic acid,
Here we report a new method for the synthesis of β-cyano-
ketones. A series of 1,4-adducts was obtained by the reactions
of chalcones (E)-3-aryl-1-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)-
prop-2-en-1-ones with malononitrile in the presence of
KF–Al2O3 and N,N-dimethylformamide (DMF). Fluoride salts
are useful as potential bases in a variety of synthetic reactions,9
but their low solubility in ordinary solvents limits their appli-
cation in organic synthesis. Inorganic solid supports are
increasingly used as catalysts for many years because of higher
selectivity, milder reaction conditions and easier work-up.10 In
particular, KF-coated alumina is a versatile solid-supported
reagent for Knoevenagel,11 Henry,12 Darzens,13 Witting,14
alkylation,15 elimination,16 and many other reactions.17 We
found that KF–Al2O3 is an efficient catalyst for reactions
between α,β-unsaturated ketones and malononitrile for
β-cyanoketone synthesis.
When (E)-1,3-diarylprop-2-en-1-ones 1 (1 equiv.), malono-
nitrile (1.2 equiv.), and KF–Al2O3 (2 equiv.) were heated at
90–100 °C for 1–4 h in DMF (Table 1), the desired 2,4-diaryl-
butyronitriles 2 were obtained in good yield. The 1H-1,2,3-tria-
zole derivative is a heterocyclic compound with wide biological
activity and applications in many fields.17 Our interest in the
1H-1,2,3-triazole heterocyclic ring18 prompted us to synthesize
some new 2-[1-aryl-3-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)-3-
oxopropyl]malononitriles, but we obtained a new series of
2-aryl-4-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)butyronitriles 5 by
the reactions of compounds 4 (1 equiv.) and malononitrile
(1.2 equiv.) in the presence of KF–Al2O3 (2 equiv.) at 90–100 °C
aCollege of Chemistry and Chemical Engineering, State Key Laboratory of Applied
Organic Chemistry, Institute of Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, P. R. China. E-mail: donghengshan@lzu.edu.cn, xiezx@lzu.edu.cn;
Fax: (+86) 0931-8912582
bThe School of Nuclear Science and Technology, Lanzhou University, Lanzhou,
Gansu 730000, P. R. China
†Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C NMR spectra of products. See DOI:
10.1039/c4gc00386a
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Table 1 Cyano Michael addition catalyzed by Al2O3
Table 2 Cyano-Michael addition catalyzed by KF–Al2O3
R1
R2
Product
Time (h)
Yielda (%)
Ar1
Ar2
Product
Time (h)
Yielda (%)
H
H
H
H
H
H
CH3
CH3
CH3
H
CH3
3,4-diCH3
4-Cl
3-Cl
4-CH3O
4-Cl
4-CH3O
4-(CH3)2N
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
2
3
1
1.5
1
2
1
4
63
72
75
55
72
69
66
62
57
C6H5
C6H5
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
6
8
6
8
6
8
6
8
6
7
6
6
6
6
6
8
6
6
92
62
86
63
90
70
90
74
79
65
89
74
92
79
95
77
95
64
C6H5
4-CH3C6H4
4-ClC6H4
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
4-C2H5OC6H4
4-ClC6H4
C6H5
a Isolated yield.
5f
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4g
5g
4h
5h
4i
for 6–8 h (Table 2). The nitrogen heterocyclic ring (Pyridine N,
pyrrole N, imidazole or triazole N etc.) was shown in the follow-
ing drug molecule structures. If the reaction of these mole-
cules and active methylene cyano compounds and (KF/Al2O3)
was similar to the 1,2,3-triazole heterocyclic ring, the hetero-
cyclic ring was not to interfere in this reaction.
5i
a Isolated yield.
Scheme 1 Mechanism postulated for KF–Al2O3-catalyzed conjugate
addition.
The targets were synthesized according to the procedure in
Table 2. From the results we hypothesized that KF might be
crucial for removal of the cyano group from malononitrile. To
confirm our hypothesis, we reacted 4f (1 equiv.), malononitrile were obtained (Table 3). Al2O3 has sufficient Lewis acidity to
activate the carbonyl group in chalcones and generate an
(1.2 equiv.) and KF (2 equiv.) in DMF at 100 °C for 8 h and
obtained 5f in 35% yield without alumina. Based on our electrophilic substrate (Michael acceptor) (Scheme 1). Malono-
results, we propose
Scheme 1.
a
possible reaction mechanism in nitrile was attacked by the highly nucleophilic F− ion to give a
negatively charged CN− ion. Finally, the activated chalcone was
To investigate the reaction mechanism, we reacted 4 attacked by CN− as a Lewis base or a nucleophile (Michael
(1 equiv.), malononitrile (1.2 equiv.) and Al2O3 (2 equiv.) under donor) during addition. The cyano group in malononitrile can
be removed by the action of KF–Al2O3 and the cyano group
the same conditions. Instead of the targets 5, 2-[1-aryl-3-(1-
aryl-5-methyl-1H-1,2,3-triazol-4-yl)-3-oxopropyl]malononitriles 6 linked to the other active methylene can also be removed in a
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respectively, but CH3CN and CH2vCH–CN did not give any
yield. The yield of compound 5g is a function of the 5g and
KF/Al2O3 ratio (Table 4). Highly toxic HCN and metal cyanides
are replaced by low-toxicity malononitrile, 2-phenyl acetonitrile
or ethyl cyanoacetate. The capability of nucleophilic substitution
reaction was PhCH2CN + F− = PhCH2F + CN− > NCCH2CN + F− =
NCCH2F + CN− > EtOOCCH2CN + F− = EtOOCCH2F + CN−.
Table 3 Carbon Michael addition catalyzed by Al2O3
Ar1
Ar2
Product
Time (h)
Yielda (%)
Conclusions
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
4-C2H5OC6H4
C6H5
6a
6b
6c
6d
6e
6f
6g
6h
6i
7
7
6
6
6
6
6
6
6
72
62
73
72
62
79
70
78
77
In conclusion, a novel tandem nucleophilic addition was used
for four-component KF–Al2O3-catalyzed environmentally
friendly synthesis of polysubstituted β-cyanopropan-1-one. The
tandem nucleophilic addition involves removal of the cyano
group linked to active methylene by the action of KF, and then
direct addition to enones. The reaction uses reagents of low
toxicity and is thus more environmentally friendly than some
traditional approaches.
4-CH3C6H4
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-CH3C6H4
4-ClC6H4
4-ClC6H4
a Isolated yield.
one-pot tandem reaction. The cyano group linked to active
methylene removed by KF action is then directly added to
Acknowledgements
enones (X = Ph, isolate, identified by NMR; PhCH2CN + F−
=
PhCH2F + CN−). The reaction capability for nucleophilic attack
is F− > CN− in DMF (CN− > Cl− > I−, F− is not reported), in aprotic
solvents, PhCH2CN + F− = PhCH2F + CN−; but reaction capa-
bility for nucleophilic attack is CN− > F− in H2O (CN− > I− > Cl−),
in protic solvent, PhCH2F + CN− = PhCH2CN + F−.19
Reaction of 4f (1 equiv.), KF–Al2O3 (2 equiv.) and ethyl
cyanoacetate or 2-phenyl acetonitrile (1.2 equiv.) under the
same conditions (Scheme 2) gave 5f in yields of 25% and 87%,
We gratefully acknowledge financial support from Lanzhou
University SKLAOC.
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