Pseudo six-component stereoselective synthesis of 2,4,6-triaryl-3,3,5,5-tetracyanopiperidines

Article abstract of DOI:10.1016/j.mencom.2018.07.014

The Kn?venagel–Michael–Mannich cascade reaction of aromatic aldehyde (3 equiv.), malononitrile (2 equiv.) and ammonium acetate or aqueous ammonia provides convenient stereoselective access to cis,cis-2,4,6-triaryl-3,3,5,5-tetracyanopiperidines in 62–94% y

Full text of DOI:10.1016/j.mencom.2018.07.014

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 384–386
Pseudo six-component stereoselective synthesis
of 2,4,6-triaryl-3,3,5,5-tetracyanopiperidines
a
a
a
Anatoly N. Vereshchagin,* Kirill A. Karpenko, Michail N. Elinson,
a
b
a
Evgeniya O. Dorofeeva, Alexander S. Goloveshkin and Mikhail P. Egorov
a
b
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: vereshchagin@ioc.ac.ru
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
1
19991 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2018.07.014
The Knövenagel–Michael–Mannich cascade reaction of
aromatic aldehyde (3 equiv.), malononitrile (2 equiv.) and
ammonium acetate or aqueous ammonia provides convenient
stereoselective access to cis,cis-2,4,6-triaryl-3,3,5,5-tetra-
cyanopiperidines in 62–94% yields. Six new bonds form as
a result of the domino process, ammonium acetate serving
as a nitrogen source.
Ar
NC
NC
Ar
CN
CN
Ar
CN
CN
3
Ar
O + 2
+ NH OAc
4
MeOH
5 °C, 2 h
N
H
6
7 examples
2–94%
6
In recent decades, the number of multicomponent studies
permanently boosts since the methodology of multicomponent
As a part of our continuous interest in the development of new
methodologies using malononitrile as essential building block
1
1–13
‘
one-pot’ reactions has serious advantages in comparison to
for the synthesis of different type of cyclic (cyclopropanes,
14
15
16
an ordinary multi-step synthesis, such as minimization of the
environmental loading, access to complicated molecules without
isolation of intermediates, and decrease in labour expenses as
well as costs for raw materials.1 The dynamic development of
multicomponent strategy allows one to obtain a wide range
cyclohexanes ) and heterocyclic (pyrrolines, spiropyrimidines,
17,18
19
20
chromenes,
chromenopyridines, pyranoquinolines, poly-
2
1
heterocycles ) systems, we report herein a new effective multi-
component approach to polycyano-substituted piperidines from
aromatic aldehydes, malononitrile and ammonium acetate without
catalyst (Scheme 1, Table 1).
,2
of structures for modern organic,3 medicinal and applied
,4
5
6
chemistry.
At the optimization stage, benzaldehyde 1a was selected as
the model reactant (see Table 1). Initially, we tested the catalytic
efficacy of different bases (entries 1–5). When triethylamine and
piperidine were used as the bases, product 2a was obtained in 78
and 65% yields, respectively (entries 1, 3). Aprotic acetonitrile
as a solvent (entry 2) as well as inorganic bases (entries 4, 5)
were ineffective for the synthesis of 2a. We have found that the
absence of a base catalyst did not affect the yield of 2a (entry 6).
The temperature played an important role in the Knoevenagel–
Michael–Mannich cascade. Lowering it from 65 to 25°C caused
drop in the yield up to 15% (entry 7). The yield was not improved
The piperidine nucleus is a well-known heterocyclic compo-
nent in a variety of natural compounds. Compounds bearing the
7
piperidine moiety possess a lot of biological actions, for example,
anticonvulsant, antimicrobial, antihistamine, anti-inflammatory,
antimalarial, anti-HIV, and anticancer activities.8
Recently Wang et al. proposed a new multicomponent approach
to the synthesis of polysubstituted piperidines,10 when ammonium
acetate was used as nitrogen source for the piperidine cycle
assembling from nitrostyrene, aromatic aldehydes, and C–H acids.
Although these processes enable a wide variation of aryl substi-
tuents, they significantly suffer from moderate yields (no more
,9
7
5%) and long reaction times. Furthermore, column chromato-
Table 1 Multicomponent transformation of benzaldehyde 1a, malono-
nitrile and ammonium acetate into substituted piperidine 2a.a
graphy was required for purification of the desired products.
Entry Base (50 mol%)
Solvent
T/°C t/h Yield of 2a (%)
Ar
NC
NC
CN
CN
Ar
1
2
3
4
5
6
7
8
9
0
Et3N
MeOH
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
65
81
65
65
65
65
25
78
65
65
1
1
1
1
1
1
1
1
2
4
78b
15c
65b
CN
CN
3
ArCHO +
a–g
2
+ NH OAc
4
Et3N
MeOH, 65 °C,
reflux, 2 h
Ar
N
H
Piperidine
1
K CO3
not detected
2
2
a–g
NaOH
not detected
78b
15c
72b
85b
a Ar = Ph, 85%
e Ar = 3-BrC6H4, 94%
Ar = 3-Py, 92%
g Ar = 4-Py, 62%
–
–
–
–
–
b Ar = 4-MeC6H4, 72%
c Ar = 2-FC6H4, 70%
d Ar = 4-FC6H4, 83%
f
MeOH
MeOH
Scheme 1 Reagents and conditions: ArCHO 1 (9 mmol), CH (CN)2
6 mmol) and NH OAc (6 mmol), MeOH (5 ml), reflux, 2 h; for 2b aqueous
ammonia (25 wt%, 6 mmol) was used as nitrogen source, 25°C, reaction
time was 6 h.
84b
2
1
(
4
a
Benzaldehyde 1a (9 mmol), malononitrile (6 mmol) and ammonium acetate
(6 mmol) were stirred in solvent (5 ml). b Isolated yield. NMR data.
c
©
2018 Mendeleev Communications. Published by ELSEVIER B.V.
–
384 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2018, 28, 384–386
when ethanol possessing higher boiling point was used (entry 8).
Optimal duration of the process in refluxing methanol was 2 h
NH3
CN
CN
CN
CN
CN
(
from NH4OAc)
1
Ar
OH–
+
–
NH4
(entries 9, 10).
CN
Under optimal conditions thus found (see Table 1, entry 9),
3
A
the similar reactions between various aromatic aldehydes 1a–g
both with electron-withdrawing and electron-donating substi-
Ar
Ar
NC
(
CH2(CN)2, OH–
H2O
1, NH3
CN
CN
NC
CN
NC
tuents), malononitrile and ammonium acetate were carried out
to prepare the corresponding 2,4,6-triaryl-3,3,5,5-tetracyano-
–
CN CN
Ar
NH2
†
piperidines 2a–g in 62–94% yields (see Scheme 1). However,
B
C
when we tried to synthesized tri-p-tolyl analogue 2b from p-tolu-
aldehyde 1b under the same conditions, completely different
results were obtained: (4-methylbenzylidene)malononitrile 3b
was isolated in 92% yield. It is known that olefins containing
electron-donating groups have a low electrophilicity and hardly
react with nucleophiles in the absence of catalyst.22 Therefore, on
moving to aqueous ammonia as a nitrogen source, the desired
product 2b was obtained in 72% yield (~20°C, 6 h, MeOH) with
full consumption of intermediate olefin 3b.
Ar
Ar
NC
NC
Ar
NC
NC
Ar
CN
CN
Ar
CN
, OH–
1
NH4
–
H2O
CN
Ar
– NH3
N
N
H
2
D
Scheme 2
Thus, the new multicomponent reaction provides tetracyano-
piperidines 2a–g in moderate to excellent yields in one step from
cheap and available starting materials. Note that products were
isolated by simple filtration of the reaction mixture. The synthesis
of compounds 2a,b had been reported earlier,23 however, that
method had significant disadvantages. First, they were produced
from commercially unavailable 1-aryl-N,N-bis(arylmethylene)
methanediamines by reaction with malononitrile and ammonium
acetate in boiling ethanol in moderate yields (53% for 2a and
The NH OAc-catalyzed Knoevenagel condensation of malono-
4
nitrile with aromatic aldehyde results in benzylidenemalononitrile
3, which then undergoes the Michael attack by the second molecule
of malononitrile to give 1,1,3,3-tetracyanopropane anion B. Species
B exists in alcohol solution in the equilibrium with the molecule
of benzylidenemalononitrile 3 and the anion of malononitrile
2
4
A. The Mannich reaction of aldehyde 1, ammonia (formed
in situ from NH OAc) and B leads to tetracyanoamine C. Next,
4
Schiff base D is formed from intermediate C and the second
molecule of aldehyde 1. Finally, cyclization of intermediate D
affords sterically less hindered cyclic amine 2 as cis,cis-isomer.
In conclusion, the new pseudo-six-component reaction has been
developed, which allows one to obtain 2,4,6-triaryl-3,3,5,5-tetra-
cyanopiperidines in high yields as single diastereomers in one
step from cheap and available starting materials. Six new bonds
form as a result of the Knoevenagel–Michael addition–Mannich
cascade. The process smoothly occurs with aromatic aldehydes
bearing both electron-donating and electron-withdrawing groups.
Ammonium acetate or aqueous ammonia serve both as catalysts
and as nitrogen sources. Products were purified by simple filtration,
no column chromatography was needed.
6
0% for 2b). Second, purification of 2a,b by recrystallization
from THF–methanol was needed. Moreover, no data on stereo-
chemistry of piperidines 2a,b was given.23
In the NMR spectra of compounds 2a–g only a single set of
signals was observed assuming formation of individual diastereo-
isomers. The X-ray diffraction data of single crystal of compound
2
f indicated that the aryl substituents are located in equatorial
‡
positions of the piperidine ring (Figure 1).
Taking into consideration the data obtained and results on
domino reaction of nitrostyrenes, malonate, aromatic aldehydes
10
and ammonium acetate giving substituted piperidin-2-ones, the
mechanism for the current transformation is proposed (Scheme 2).
This work was supported by the Russian Science Foundation
(
grant no. 17-73-20260). The authors are grateful to the Center
C(1S)
C(23)
C(22)
C(21)
for Molecular Composition Studies of A. N. Nesmeyanov Institute
of Organoelement Compounds, Russian Academy of Sciences.
O(1S)
N(8)
C(24)
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2018.07.014.
C(20)
C(7)
N(4)
C(8)
N(5)
N(1)
C(9)
C(16)
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Received: 2nd March 2018; Com. 18/5497
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