Non-catalytic solvent-free synthesis of 5,6,7,8-tetrahydro-4H-chromenes from aldehydes, dimedone and malononitrlie at ambient temperature

Article abstract of DOI:10.1016/j.mencom.2015.05.008

Non-catalytic solvent-free assembling of aldehydes, dimedone and malononitrile at ambient temperature affords substituted 5,6,7,8-tetrahydro-4H-chromenes in 88-98% yields.

Full text of DOI:10.1016/j.mencom.2015.05.008

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 185–187
Non-catalytic solvent-free synthesis of 5,6,7,8-tetrahydro-4H-chromenes
from aldehydes, dimedone and malononitrlie at ambient temperature
Michail N. Elinson,*a Fedor V. Ryzhkov,a Tatiana A. Zaimovskayab and Mikhail P. Egorova
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: + 7 499 135 5328; e-mail elinson@ioc.ac.ru
b A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow,
Russian Federation.
DOI: 10.1016/j.mencom.2015.05.008
Non-catalytic solvent-free assembling of aldehydes, dimedone and malononitrile at ambient temperature affords substituted
5,6,7,8-tetrahydro-4H-chromenes in 88–98% yields.
O
Ar
Multicomponent reactions (MCRs) became the efficient strategy
in the sustainable and diversity oriented synthesis of hetero-
cycles.1–3 The application of high-throughput screening in bio-
medical studies has sufficiently increased the demand for sub-
stances to test for new drug-like molecules.4,5 In recent years, the
synthesis of small-molecule heterocyclic libraries has emerged
as a valuable tool in the search for novel lead structures.6
Me Me
CN
CN
CN
Grinding
O
ArCHO
Me
O
NH2
O
Me
1a–i
2a–i
a Ar = Ph
d Ar = 4-MeOC6H4
e Ar = 3-BrC6H4
g Ar = 4-ClC6H4
h Ar = 4-O2NC6H4
i Ar = 2,6-Cl2C6H3
b Ar = 4-MeC6H4
c Ar = 4-EtC6H4
Among the heterocycles, functionally substituted 4H-chromenes
f
Ar = 4-BrC6H4
have received considerable attention due to their spasmolytic,
diuretic, anti-coagulant, anti-cancer and anti-anaphylactic acti-
vities.7–9 Chromene fragment constitutes the structural unit of a
series of natural products.10,11 The current interest to 4H-chro-
menes bearing nitrile functionality and especially to 2-amino-
4-aryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles
arises from their potential application to the treatment of human
neurodegenerative disorders, including Alzheimer’s disease,
amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s
disease, AIDS associated dementia and Down’s syndrome.12
The known multicomponent procedures for the synthesis of
2-amino-4-aryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbo-
nitriles employ the assembling of aromatic aldehydes, cyclic
1,3-diketones and malononitrile. Piperidine,13 piperidine/ammo-
nium acetate system14 or triethylamine15 used as catalysts provide
70–85% yields of the products. The second set of methods offers
the catalysis with alkyl ammonium salts in water,16,17 (S)-proline
in water or water–ethanol mixtures,18 potassium phthalimide-
N-oxyl19 or nanozeolite clinoptilolite 1,20 as well as non-catalytic
process in glycerol as a solvent.21 Although these MCRs afford
the products in higher (75–95%) yields, they significantly suffer
from prolonged reaction times and high reaction temperatures
(up to 90°C). Electrochemical22 and electrocatalytic23 methods
to initiate this process are also known. The solid state technique
in the presence of sodium bromide under microwave irradia-
tion24 was performed at 70–85°C in a special reactor, and
further recrystallization of crude reaction mixture from ethanol
was required.24 Two-step solvent-free protocol comprises the
Knoevenagel condensation of aldehyde with malononitrile (150°C,
1 h) followed by the reaction of the adduct with dimedone
(100–150°C, 1 h).25
Scheme 1
solvent-free cascade and multicomponent reactions of aldehydes
and C–H acids.27 Recently we have also revealed some non-
catalytic multicomponent transformations of carbonyl com-
pounds and C–H acids.28 Taking into consideration the above
results we have developed a convenient fast and efficient solvent-
free multicomponent transformation of aromatic aldehydes 1a–i,
malononitrile and dimedone into substituted 5,6,7,8-tetrahydro-
4H-chromenes 2a–i (Scheme 1, Tables 1, 2).†
Sodium acetate, an inexpensive, non-toxic and readily available
substance, was used as mild base catalyst for aldol condensation
of aromatic aldehydes and acid anhydrides (Perkin reaction)29 and
Table 1 Solvent-free multicomponent transformation of aldehyde 1a, malono-
nitrile and dimedone into 5,6,7,8-tetrahydro-4H-chromene 2a.a
Isolated yield of
chromene 2a (%)
Entry
Base (mol%)
Time/min
1
2
3
4
5
6
7
8
AcONa (10)
AcONa (5)
AcONa (2)
KF (10)
KF (5)
KF (2)
—
—
15
15
15
15
15
15
15
10
74
79
85
77
82
88
96
92
aAldehyde 1a (3 mmol), malononitrile (3 mmol), dimedone (3 mmol) and
sodium acetate or potassium fluoride (0.3 mmol), or without catalyst were
grinded with the pestle in mortar at room temperature for 10 to 15 min.
Obviously, any new, facile and highly efficient synthetic
multicomponent approach to the 5,6,7,8-tetrahydro-4H-chro-
mene-3-carbonitrile system is an object of considerable interest.
Moreover, taking into consideration the basic principles of ‘green
chemistry’especiallybothsolvent-freeandnon-catalyticprocedures
are particularly welcome.26 We have already found a series of
†
General (typical) procedure. Aldehyde 1 (3 mmol), malononitrile
(3 mmol, 0.20 g) and dimedone (3 mmol, 0.42 g) were grinded with a
pestle in a mortar at ambient temperature for 15 min. After the reaction
was finished, the material was dried in air to afford practically pure
substituted 5,6,7,8-tetrahydro-4H-chromene 2. For characteristics of
products 2a–i, see Online Supplementary Materials.
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 185 –

Mendeleev Commun., 2015, 25, 185–187
Mechano-chemical
activation
CN
CN
ArCHO
1
O
Ar
CN
Ar
CN
CN
CN
CN
O
Me
O
NH2
Me Me
Me
O
Ar
O
2
CN
OH
O
Ar
O
O
Me
NH
One-pot
multicomponent
process
CN
CN
Me
H2O
3
O
Ar
CN
Me
Me
O
Me
O
Ar
O
Ar
O
N
Me
CN
CN
CN
CN
Me
Me
O
OH
Me
Me
Scheme 2
for Knoevenagel condensation of carbonyl compounds.30 Earlier
we used sodium acetate to catalyze multicomponent cyclization
of aldehydes, malononitrile and acetone into cis-4-dicyano-
methylidene-2,6-diarylcyclohexane-1,1-dicarbonitrile.31 Thus,
initially the reaction between aldehyde 1a, malononitrile and
dimedone was carried out under solvent-free base catalytic con-
ditions with sodium acetate (Table 1, entries 1–3).
Surprisingly we have found that yields of 5,6,7,8-tetrahydro-
4H-chromene 2a increased from 74 to 85% with lowering quantity
of sodium acetate from 10 to 2 mol%. The same tendency has
been observed for potassium fluoride (Table 1, entries 4–6):
increasing the yields of 2a from 77 up to 88% with the same
decreasing quantity of potassium fluoride. The best results were
achieved without any catalyst, when product 2a was obtained
in 92 and 96% yields in 10 and 15 min reaction time period,
respectively. Under optimum non-catalytic solvent-free condi-
tions thus found (ambient temperature grinding, 15 min reaction
time), substituted 5,6,7,8-tetrahydro-4H-chromenes 2a–i were
obtained in excellent 88–98% yields (Table 2). The final crude
materials were the practically pure products.
Taking into consideration the above results, the data on non-
catalytic multicomponent transformation of carbonyl compounds
and C–H acids28 as well as solvent-free cascade and multicom-
ponent reactions of aldehydes and C–H acids27 the following
mechanism for the non-catalytic solvent-free transformation of
aldehydes 1a–i, malononitrile and dimedone into substituted
5,6,7,8-tetrahydro-4H-chromenes 2a–i was suggested (Scheme 2).
At the first step, the formation of malononitrile anion occurs
as the result of mechano-chemical activation by grinding in the
mortar. Then Knoevenagel condensation of malononitrile anion
with aldehyde 1 occurs with elimination of hydroxide anion and
formation of the corresponding arylidenemalononitrile 3.32 The
subsequent hydroxide-promoted Michael addition of cyclic
1,3-diketone to electron deficient Knoevenagel adduct 3 fol-
lowed by intramolecular cyclization leads to the corresponding
5,6,7,8-tetrahydro-4H-chromene 2 with regeneration of malono-
nitrile anion at the last step, which continues the catalytic process
by the interaction with the next molecule of aldehyde 1 (see
Scheme 2). Thus, the generation of even single malononitrile
anion is theoretically sufficient for total conversion of equimolar
quantities of aldehyde, malononitrile and cyclic 1,3-diketone into
the corresponding 5,6,7,8-tetrahydro-4H-chromene system under
conditions studied.
In conclusion, simple grinding as mechanochemical activa-
tion can induce assembling of aromatic aldehydes, dimedone
and malononitrile into chromenes in the absence of solvent and
catalyst at ambient temperature. The developed efficient non-
catalytic solvent-free approach to the 5,6,7,8-tetrahydro-4H-
chromene system is beneficial from the viewpoint of diversity-
oriented large-scale processes and represents a new example
of the ecologically benign synthetic concept for not only non-
catalytic but also solvent-free ‘domino’ reactions strategy at
ambient temperature. Our findings bring us a step closer to the
notion of ‘ideal synthesis’.26
Table 2 Solvent-free multicomponent transformation of aldehydes 1a–i,
malononitrile and dimedone into 5,6,7,8-tetrahydro-4H-chromenes 2a–i.a
Starting
aldehyde
Obtained
chromene
Isolated
yield (%)
Entry
Time/min
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1c
1c
1d
1e
1f
1g
1h
1h
1h
1i
15
15
15
10
5
15
15
15
15
15
10
5
2a
2b
2c
2c
2c
2d
2e
2f
2g
2h
2h
2h
2i
96
93
95
83
79
88
90
95
97
98
85
83
93
This work was supported by the Russian Foundation for Basic
Research (project no. 13-03-00096a).
15
Online Supplementary Materials
aAldehydes 1a–i (3 mmol), malononitrile (3 mmol), dimedone (3 mmol)
were grinded with a pestle in a mortar at ambient temperature for 5 to 15 min.
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.05.008.
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Mendeleev Commun., 2015, 25, 185–187
22 L. Fotouhi, M. M. Heravi, A. Fatehi and K. Bakhtiari, Tetrahedron Lett.,
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Received: 22nd October 2014; Com. 14/4490
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