Stereoselective one-pot synthesis of polycyanosubstituted piperidines

Article abstract of DOI:10.1007/s00706-018-2187-x

Abstract: An effective and facile multicomponent method for the synthesis of polysubstituted piperidines is described. The Michael–Mannich type cascade of benzylidenemalononitriles with aromatic aldehydes and ammonium acetate or aqueous ammonia provides c

Full text of DOI:10.1007/s00706-018-2187-x

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ORIGINAL PAPER
Stereoselective one-pot synthesis of polycyanosubstituted piperidines
Anatoly N. Vereshchagin1 Kirill A. Karpenko1 Michail N. Elinson1 Sergey V. Gorbunov1
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Alexandra M. Gordeeva1 Pavel I. Proshin1 Alexander S. Goloveshkin2 Mikhail P. Egorov1
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Received: 22 January 2018 / Accepted: 14 March 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
An effective and facile multicomponent method for the synthesis of polysubstituted piperidines is described. The Michael–
Mannich type cascade of benzylidenemalononitriles with aromatic aldehydes and ammonium acetate or aqueous ammonia
provides convenient access to the stereoselective synthesis of 3,3,5,5-tetracyano-2,4,6-triarylpiperidines in good to
excellent yields in one-pot manner. Ammonium acetate or aqueous ammonia plays a role both as a catalyst and as a
nitrogen source. It is established that the reaction proceeds via sequence of equilibriums and a competitive mechanisms are
implemented.
Graphical abstract
Keywords Multicomponent reaction Á Polysubstituted piperidines Á Aromatic aldehydes Á Benzylidenemalononitriles Á
Stereoselectivity
Introduction
significant time of process decrease and labor expenses as
well as costs for raw materials, which is particularly
important in large-scale drugs and natural products syn-
theses [7–10]. The second one is eco-friendly type of
processes characterized by reducing the amount of waste,
because it does not require isolation of intermediate prod-
ucts and their purification. Such dynamic development of
multicomponent strategy allows to obtain a wide range of
structures for modern organic [11–16], medicinal [17–21],
applied [22, 23], and combinatorial [24–28] chemistry.
The piperidine nucleus is a well-known heterocyclic
component in a variety of natural compounds [29–31]. The
most important out of them are morphine, codeine, coniine,
lobeline, piperidine, sedamine, etc. Compounds bearing the
piperidine moiety possess anti-hypertensive, anticonvul-
sant, antimicrobial, antimycobacterial, antihistamine, anti-
inflammatory, antimalarial, and anti-HIV activities
[32–35]. The studies showed that some 3-spiroindole-2,4-
In recent decades, the growing number of studies in the
field of multicomponent processes is connected with the
fact that methodology of multicomponent ‘one-pot’ reac-
tions has serious advantages in comparison to an ordinary
multi-step synthesis [1–6]. The first advantage is a
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-018-2187-x) contains
supplementary material, which is available to authorized
users.
& Anatoly N. Vereshchagin
vereshchagin@ioc.ac.ru
1
N. D. Zelinsky Institute of Organic Chemistry, Russian
Academy of Sciences, Moscow, Russian Federation
2
A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow, Russian Federation
123

A. N. Vereshchagin et al.
Fig. 1 Pharmacological activity of products containing piperidine moety
diarylpiperidine-6-ones (Fig. 1) are noted with an inherent
anti-cancer activity [36]. These compounds inhibit the
protein binding between MDM2, produced by cancer cells,
and p53 protein (the so-called ‘‘guardian of the genome’’)
which is responsible for the normal functioning of cells.
5-Nitro-4,6-diaryl-2-piperidones act as inhibitors of farne-
syltransferase (FTase) and induce a regression of cattle
brain tumor without any toxicity [37]. Also, piperidines
have been identified as antiviral [38] and herbicidal [39]
agents. For instance, N-methyl-2,4,6-triphenylpiperidine
(Fig. 1) demonstrates an efficiency against the smallpox
virus [38].
reaction. However, to date the multicomponent reactions
are rather limited for the construction of structurally and
stereochemically diverse polysubstituted piperidine
derivatives. These methods have a number of drawbacks
such as necessity for rigorous conditions (extra dry sol-
vents, inert atmosphere and are limited to utilization of
expensive reagents [43]).
Recently Wang et al. proposed a new multicomponent
approach to the synthesis of polysubstituted piperidines
(Scheme 2) [44–47]. In particular, formamide [44] or
ammonium acetate [45–47] was used as nitrogen source for
the piperidine cycle construction. Therefore, the multi-
component synthesis of nitro-substituted piperidines from
nitrostyrene, aromatic aldehydes, C–H acid (malonic ester,
cyanoacetic ester, Meldrum’s acid), and ammonium acetate
or formamide was implemented. Although these multi-
component processes provide a wide variation of aryl
substituents, they significantly suffer from moderate yields
(no more 75%) and long reaction times. Furthermore,
Guareschi’s imides synthesis via condensation of
ketones, ethyl cyanoacetate, and ammonia should be con-
sidered as the first multicomponent synthesis of substituted
piperidine (Scheme 1) [40]. Another prominent multi-
component reaction for the preparation of piperidines is
Robinson’s [41] tropinone synthesis, which was modified
¨ ¨
by Schopf [42] and known as the Robinson–Schopf
Scheme 1
123

Stereoselective one-pot synthesis of polycyanosubstituted piperidines
Scheme 2
column chromatography is required for purification of the
desired products.
analogous procedures resulted in piperidine 4a in 70 and
63% product yields, respectively (entries 8, 9). However,
when we tried to synthesized 2,4,6-tris(4-methylphe-
nyl)piperidine-3,3,5,5-tetracarbonitrile (4b) at the same
conditions, completely different results were obtained
(Table 1, entries 10–22). Heating of (4-methylbenzyli-
dene)malononitrile (1b), p-tolualdehyde (2b), and ammo-
nium acetate at 65 °C in methanol for 4 h resulted in the
formation of 4b in trace amount (entry 10). Arguably, the
cause for such a low performance is a result of 2b poor
solubility in alcohol. However, an increase in the solvent
amount did not lead to any improvement in the process
(entry 11). Next, we surveyed a numbers of bases for
optimization of 4b synthesis and found that the presence of
base almost has no effect on yield (entries 12–18).
Adapting the aqueous ammonia as a ‘‘nitrogen source’’
drastically changed the outcome. When two equivalents of
(4-methylbenzylidene)malononitrile, p-tolualdehyde, and
aqueous ammonia were mixed in methanol for 6 h, a 77%
yield of 4b was obtained, wherein full conversion of 1b
was achieved (entry 19). The optimal amount of ammonia
was also 1.5 equiv. (entries 19–21). Temperature increase
led to reducing yield of 4b up to 62% (entry 22). The
optimal conditions found (entry 19) were also effective for
the synthesis of 4a (entry 23).
As a part of our continuous interest directed toward the
development of new methodologies using alkyliden-
malononitriles as essential building blocks for the synthesis
of different type of cyclic (cyclopropanes [48–51], cyclo-
hexanes [52]) and heterocyclic (pyrrolines [53], pyrrolidi-
nones [54], spiropyrimidines [55], spiropyrazolones [56])
systems, we report now effective multicomponent
approach to polysubstituted piperidines from benzylidene-
malononitriles, aromatic aldehydes and ammonium acetate
or aqueous ammonia without catalyst under mild
conditions.
Results and discussion
In the present study, we report our research on multicom-
ponent synthesis of 2,4,6-triarylpiperidine-3,3,5,5-te-
tracarbonitriles. In order to find optimal conditions
multicomponent transformations of benzylidenemalononi-
trile (1a) with benzaldehyde (2a) and ammonium acetate
(3a) or aqueous ammonia (3b, 25% by weight in water,
labeled as NH4OH) were selected as model reactions
(Table 1, entries 1–9, 23). There ammonium acetate was
applied as ‘‘nitrogen source’’. Triethylamine was used as a
base, because of its better catalytic activity for sequential
With these reaction conditions identified, benzylidene-
malononitriles 1a–1i, aromatic aldehydes 2a–2j (both with
electron-withdrawing and electron-donating substituents),
and ammonium acetate or aqueous ammonia were trans-
formed into corresponding 2,4,6-triarylpiperidine-3,3,5,5-
tetracarbonitriles 4a–4j (Table 2).
Michael
addition/aza-Mannich
cascade
between
nitrostyrenes, Meldrum’s acid, malonate, and ammonium
acetate [49]. Surprisingly, it was found that the presence of
a base did not affect the yield of 4a (Table 1, entries 1–3).
An increase in the temperature led to reduced reaction time
and increased yield of 4a (entry 4). The optimal amount of
ammonium acetate was found to be 1.5 equivalent to
benzaldehyde (entry 7). For instance, decrease up to 1
equiv. negatively affected the piperidine 4a yield from 86
to 59% (entry 6). Heating at 78 or 40 °C in ethanol,
As it is shown from Table 2, transformations of ben-
zylidenemalononitriles 1b, 1c containing weak electron-
donating methyl group were proceeded in the presence of
more reactive aqueous ammonia as a nitrogen source
(Table 2, entries 2, 3). Nevertheless, olefin 1d containing
strong electron-donating methoxy group did not react even
123

A. N. Vereshchagin et al.
Table 1 Optimization of reaction conditions in the synthesis of 4a and 4b
Entry
R
X, equiv.
Solvent
Base, mmol
T/°C
Time/h
Product
Yield/%a
1
H
Ac, 3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
Et3N, 1.5
rt
2
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4a
76
2
H
Ac, 3
Et3N, 0.3
rt
75
3
H
Ac, 3
–
rt
2.5
0.5
0.5
0.5
0.5
0.5
1
76
4
H
Ac, 3
–
65
65
65
65
78
40
65
65
65
65
65
65
65
65
82
rt
86
5
H
Ac, 2
–
86
6
H
Ac, 1
–
59
7
H
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
Ac, 1.5
H, 1.5
H, 3
–
86
8
H
–
70
9
H
EtOH
–
63
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
MeOH
MeOHb
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
–
4
Trace
Trace
(15)c
(17)c
(10)c
(15)c
(10)c
Trace
Trace
77
–
4
Et3N, 1.5
4
Et3N, 3.0
4
Et3N, 3.0
12
12
4
Piperidine, 3.0
NaOH, 3.0
NaOH, 3.0
12
4
NaOH, 3.0
–
–
–
–
–
6
rt
6
64
H, 1
rt
6
52
H, 1.5
H, 1.5
40
rt
4
62
2
82
Reaction conditions: benzylidenemalononitrile 1 (6 mmol), benzaldehyde 2 (3 mmol), and ammonium acetate or aqueous ammonia were stirred
at selected conditions in 5 cm3 of solvent until complete conversion of 1 was achieved (indicated by TLC)
aIsolated yields
b20 cm3 of MeOH was used
1
cAccording to H NMR data. There was a low conversion of 1b
after 48 h stirring at rt or 6 h refluxing (entries 4, 5).
Apparently, this is due to the fact that (4-methoxylbenz-
ylidene)malononitrile (1d) has a low electrophilicity and
hardly reacts with nucleophiles under catalyst-free condi-
tions [57]. The olefins 1e–1j which contain electron-with-
drawing groups in aromatic ring are more electrophilic than
1b, 1c and reacted in the presence of ammonium acetate to
form corresponding piperidines 4e–4j (entries 6–10,
11–13). Moreover, reaction of highly electrophilic (4-
nitrobenzylidene)malononitrile (1i) with 4-nitrobenzalde-
hyde (2i) and ammonium acetate at the same conditions
resulted in oligomerization of the product (entry 11).
Piperidine 4i was obtained under milder conditions. 1i full
conversion and formation of 4i in 70% yield were achieved
at rt within 8 h stirring (entry 12).
The new multicomponent reaction allows to obtain
tetracyanopiperidines 4 in moderate to excellent yields in
one step from cheap and available starting materials. It
123

Stereoselective one-pot synthesis of polycyanosubstituted piperidines
Table 2 Multicomponent synthesis of piperidines 4
Entry
Alkene
Aldehyde
Ar
X
T/°C
Time/h
Product
Yield/%a
1
1a
1b
1c
1d
1d
1e
1f
2a
2b
2c
2d
2d
2e
2f
Ph
Ac
H
65
rt
0.5
6
4a
4b
4c
4d
4d
4e
4f
86
2
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-MeOC6H4
2-FC6H4
3-FC6H4
4-FC6H4
3-BrC6H4
3-BrC6H4
4-NO2C6H4
4-NO2C6H4
3-Py
77
3
H
rt
6
69
4
H
rt
48
6
Not detected
5
H
65
65
65
65
65
rt
Not detected
6
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
0.5
0.5
0.5
0.5
36
0.5
8
72
7
78
8
1g
1h
1h
1i
2g
2h
2h
2i
4g
4h
4h
4i
82
9
96
10
11
12
13
92
65
rt
Not detected
1i
2i
4i
70
94
1j
2j
65
0.5
4j
Reaction conditions: benzylidenemalononitrile 1 (6 mmol), benzaldehyde 2 (3 mmol), and ammonium acetate or aqueous ammonia (4.5 mmol)
were stirred at selected conditions in 5 cm3 of methanol until complete conversion of 1 was achieved (indicated by TLC)
aIsolated yields
should be noted that products were isolated by simple fil-
tration of the reaction mixture. The synthesis of 4a, 4b had
been reported earlier [58]. However, the method of its
preparation has significant disadvantages. Firstly, 4a, 4b
were obtained from commercially unavailable 1-aryl-N,N-
bis(arylmethylene)methanediamine by reaction with
malononitrile and ammonium acetate in a boiling ethanol
in moderate yields (53% for 4a and 60% for 4b). Secondly,
purification of 4a, 4b was proceeded via recrystallization
from THF/methanol. Moreover, no any information about
stereochemistry of the piperidines 4a, 4b is contained in
the paper [58].
In NMR spectra of 4a–4c, 4e–4j, only a single set of
signals were identified assuming stereoselective formation
of individual diastereoisomers. The X-ray crystal diffrac-
tion data indicated that the phenyl substituents are located
in equatorial position of the piperidine ring (Fig. 2).
Fig. 2 The general view of 4a in crystal. Atoms are represented by
thermal displacement ellipsoids (p = 50%)
To evaluate the synthetic potential of the procedure, we
proposed that the multicomponent transformation of ben-
zylidenemalononitrile (1a, 2 equiv.), p-tolualdehyde (2b, 1
equiv.), and ammonium acetate (3a, 1.5 equiv.) in dry
methanol has been carried out (Scheme 3).
Surprisingly, it was found that the main product was 2,4,6-
triphenylpiperidine-3,3,5,5-tetracarbonitrile (4a) and minor
product was the expected 2-(4-methylphenyl)-4,6-diphe-
nylpiperidine-3,3,5,5-tetracarbonitrile (5) in ratio 2:1 (by
A complete conversion of starting materials was
observed with two products obtained in the reaction.
123

A. N. Vereshchagin et al.
Scheme 3
NMR). In case of water ammonia (3b, 1.5 equiv.) as a
nitrogen source for the same reaction (stirring at rt for 6 h
in methanol) afforded a similar mixture of 4a and 5 in ratio
3:1. The chemical shifts difference of the donor- and
acceptor-substituted piperidines is enough for structure
Next, the Schiff base was afforded from the intermediate
C and aromatic aldehyde I, finally by intramolecular
nucleophilic addition of intermediate arylimine J to form
the piperidine 4.
The retro-Knoevenagel reactions are known and appli-
cable in organic synthesis [60, 61]. In favor of pathway 2
stands the fact that the ratio between products 4a and 5
changed when water ammonia was used as a nitrogen
source for the assembling of benzylidenemalononitrile (1a)
and p-tolualdehyde (2b) into piperidine cycle. Excess of
the water caused a faster retro-Knoevenagel reaction and
formation of aldehyde I and subsequently of product 4a.
The study of benzylidenemalononitrile behavior in
methanolic ammonia can serve as an additional evidence of
pathway 2 (Table 3).
1
elucidation. The characteristic signals of H NMR spectra
of the piperidines 4a, 4b, 4i, and 5 are represented in
Fig. 3. For example, the NH proton of 4a was registered on
4.83 ppm (Fig. 3a). Chemical shifts of NH and 4-CH
protons of piperidines were confirmed by 2D NMR (see
supplementary materials). The same proton signal of 4b
shifted into strong field on 4.64 ppm (Fig. 3b). In the case
of strong acceptor like nitro-group NH proton noticeable
shifted in downfield and was registered on 5.35 ppm
(Fig. 3c). We postulate the formation of the piperidine 5
based on NMR data.
We have found that piperidines 4 can be obtained
directly from benzylidenemalononitriles 1 by aqueous
ammonia action in moderate yields. This domino trans-
formation considers the realization of both reaction path-
ways (Scheme 4).
The NH signal of 5 slightly shifted into strong field in
comparison with the same signal of the 4a (Fig. 3d;
4.75 ppm for 5, 4.83 ppm for 4a). Apparently, this is due to
the fact that NH group of new compound is surrounded by
more donor substituents than the same NH in 4a; however,
in the same time it is surrounded by less acceptor sub-
stituents than the same NH in 4b. We suppose that this is a
middle option between 4a and 4b that corresponds to the
structure 5. Moreover, only one CH3 signal on 2.36 ppm
was registered in the 1H NMR spectra of the mixture of 4a
and 5.
Conclusion
The new one-pot assembling of benzylidenmalononitriles,
aromatic aldehydes, and ammonium acetate or aqueous
ammonia as nitrogen source leads to the stereoselective
formation of 3,3,5,5-tetracyano-2,4,6-triarylpiperidines in
69–96% yields. It is established that the reaction proceeds
via sequence of equilibriums and competitive mechanisms
are implemented. The process smoothly proceeds with
olefins and aromatic aldehydes bearing both electron-do-
nating and electron-withdrawing groups. Ammonium
acetate or aqueous ammonia plays a role both as a catalyst
and as a nitrogen source. Products were purified by simple
filtration and column chromatography was avoided
entirely.
Taking into consideration the data obtained and results
on domino reactions of benzylidenecyanoacetates with
methanolic ammonia into functionalized 2-piperidones
[59], we envisaged the following sequence of equilibriums
to explain the formation of 4 and 5 (Scheme 4). We believe
that parallel pathways should exist. The benzylidene-
malononitriles 1 undergo Michael attack by one molecule
of ammonia to result in the formation of the
2-[amino(aryl)methyl]malononitrile
A which then is
deprotonated by ammonia to form anion B. The derived
anion triggers a second Michael addition at the b-position
of another molecule of 1 to form the anion C (pathway 1).
Further condensation of C with aldehyde 2 and cyclization
affords the product 5 (when Ar1 = Ar2, product 5 is equal
to 4). Another competing pathway deals with imine E for-
mation followed by retro-Knoevenagel with the formation
of aldehyde I and anion of malononitrile H (pathway 2).
Experimental
All melting points were measured with a Gallenkamp
1
melting point apparatus. H and 13C NMR were recorded
with a Bruker AM300 at ambient temperature in DMSO-d6
123

Stereoselective one-pot synthesis of polycyanosubstituted piperidines
Fig. 3 Characteristic proton signals of: a, 4a; b, 4b; c, 4i; d, mixture of 4a and 5
123

A. N. Vereshchagin et al.
Scheme 4
Table 3 Direct synthesis of piperidines 4 from benzylidenemalononitriles 1 by aqueous ammonia action
Entry
Alkene
Ar
Product
Yield/%a
1
2
3
4
5
6
1a
1b
1e
1f
Ph
4a
4b
4e
4f
41
35
37
37
42
44
4-MeC6H4
3-FC6H4
4-FC6H4
3-BrC6H4
3-Py
1g
1i
4g
4i
Reaction conditions: benzylidenemalononitrile 1 (3 mmol), ammonia (in water, 25% by weight, 3 mmol) in 5 cm3 of methanol were stirred at rt
for 16 h
aIsolated yields
solutions. Chemical shifts values are given in d scale rel-
ative to Me4Si. IR spectra were recorded with a Bruker
ALPHA-T FT-IR spectrometer in KBr pellets. Mass
spectra (EI = 70 eV) were recorded with a Finningan MAT
INCOS 50 spectrometer. Thin-layer chromatography
(TLC) was performed using silica gel GF254 precoated
plates (0.20 mm thickness). Visualization on TLC was
achieved by UV light (254 nm). Benzaldehydes 2 were
obtained from commercial sources and used without fur-
ther purification. Benzylidenemalononitriles
1
were
obtained from benzaldehydes 2 and malononitrile by
Knoevenagel condensation using sodium acetate as a cat-
alyst [62, 63].
123

Stereoselective one-pot synthesis of polycyanosubstituted piperidines
1362, 1279, 1135, 779 cm-1; MS: m/z (%) = [M?] (29),
364 (16), 289 (49), 263 (46), 220 (49), 199 (100), 185 (50),
130 (99), 89 (51); 1H NMR (300.13 MHz, DMSO-d6):
d = 2.40 (s, 9H, 3 CH3), 4.73 (s, 3H, 2 CH ? NH), 4.90 (s,
1H, CH), 7.27–7.79 (m, 12H, Ar) ppm; 13C NMR
(75.47 MHz, DMSO-d6): d = 20.8 (2C), 21.1, 44.8, 49.1,
66.2 (2C), 112.1 (2C), 112.9 (2C), 125.6, 126.0, 128.3,
128.7, 129.5, 130.0, 130.5, 131.3, 132.5, 135.0, 137.6,
138.8 ppm.
General procedure for multicomponent synthesis
of 2,4,6-triarylpiperidine-3,3,5,5-
tetracarbonitriles 4
To a stirred solution of benzylidenemalononitrile 1
(6 mmol) and aromatic aldehyde 2 (3 mmol) in 5 cm3 of
methanol, 0.35 g ammonium acetate (3a, 4.5 mmol) or
aqueous ammonia (3b, 25% by weight, 4.5 mmol) was
added. The resultant mixture was stirred at the temperature
and time indicated in Table 2. The reaction was completed
as indicated by TLC. The reaction mixture was cooled to
- 10 °C for 1 h. The precipitate solid was filtered and
dried to afford pure product 4.
2,4,6-Tris(2-fluorophenyl)piperidine-3,3,5,5-tetracarboni-
trile (4e, C27H16F3N5) White solid; yield 1.01 g (72%);
ꢀ
m.p.: 175–176 °C; IR: m = 3333, 2968, 1617, 1589, 1494,
1461, 1378, 1283, 1241, 813 cm-1; MS: m/z (%) = [M?]
(1), 230 (86), 201 (7), 183 (21), 172 (44), 145 (47), 124 (24),
1
123 (100), 122 (75); H NMR (300.13 MHz, DMSO-d6):
General procedure for multicomponent synthesis
of 2,4,6-triarylpiperidine-3,3,5,5-
tetracarbonitriles 4 directly
d = 4.81 (s, 1H, CH), 5.56 (s, 1H, NH), 5.61 (s, 2H, CH),
7.28–7.59 (m, 9H, Ar), 8.01 (t, J = 7.3 Hz, 2H, Ar), 8.29 (t,
J = 7.3 Hz, 1H, Ar) ppm; 13C NMR (75.47 MHz, DMSO-
d6): d = 43.5, 57.4 (2C), 58.1 (2C), 112.0 (2C), 112.1 (2C),
from benzylidenemalononitriles 1
To a stirred methanolic solution of benzylidenemalononi-
trile 1 (3 mmol in 5 cm3 of MeOH) aqueous ammonia (3b,
25% by weight, 3 mmol) was added. The resultant mixture
was stirred at the room temperature for 16 h. The reaction
mixture was cooled to - 10 °C for 1 h. The precipitate
solid was filtered and dried to afford pure product 4.
115.1 (d, J4
= 4.4 Hz, 2C), 115.7 (d, J4
= 4.4 Hz),
C-F
C-F
116.1 (d, J3 = 8.8 Hz, 2C), 116.3 (d, J3
= 7.7 Hz),
C-F
C-F
127.7 (d, J3C-F = 21.0 Hz, 2C), 129.1 (d, J2C-F = 28.9 Hz),
129.2 (d, J2C-F = 26.5 Hz, 2C), 129.3 (d, J2C-F = 24.8 Hz),
131.1 (d, J2 = 8.9 Hz, 2C), 131.8 (d, J2
= 7.7 Hz),
C-F
C-F
159.3 (d, J1 = 247.7 Hz, 2C), 159.5 (d, J1
C-F
C-
= 245.5 Hz) ppm.
2,4,6-Triphenylpiperidine-3,3,5,5-tetracarbonitrile
(4a)
F
White solid; yield 1.07 g (86%); m.p.: 191–192 °C (lit.
m.p.: 178–179 °C [58]). Single crystals of C27H19N5 were
grown from methanol. A suitable crystal was selected and
placed on a Bruker Apex II CCD diffractometer. The
crystal was kept at 120 K during data collection. Using
Olex2 [64], the structure was solved with the XS [65]
structure solution program using Direct Methods and
refined with the XL [65] refinement package using least
squares minimization.
2,4,6-Tris(3-fluorophenyl)piperidine-3,3,5,5-tetracarboni-
trile (4f, C27H16F3N5) White solid; yield 1.09 g (78%);
ꢀ
m.p.: 177–178 °C; IR: m = 3335, 3077, 1616, 1594, 1491,
1455, 1276, 1243, 1162, 1152 cm-1; MS: m/z (%) = [M?]
(1), 231 (16), 230 (100), 201 (7), 172 (48), 145 (34), 123
1
(68), 122 (42), 96 (11); H NMR (300.13 MHz, DMSO-
d6): d = 4.85 (s, 2H, CH), 5.06 (s, 1H, NH), 5.12 (s, 1H,
CH), 7.38 (t, J = 8.3 Hz, 2H, Ar), 7.52–7.60 (m, 7H, Ar),
7.68 (d, J = 9.6 Hz), 8.77 (t, J = 5.3 Hz, 2H, Ar) ppm; 13
C
Crystal data for 4a (C27H19N5, M = 413.47 g/mol):
monoclinic, space group P21/c (no. 14), a = 11.482(2)
NMR (75.47 MHz, DMSO-d6): d = 44.3, 48.1 (2C), 65.3
(2C), 111.7 (2C), 112.4 (2C), 114.2 (J2
= 21.8 Hz),
= 23.2 Hz),
= 3.3 Hz),
C-F
˚
˚
˚
A, b = 15.755(3) A, c = 12.458(3) A, b = 03.71(3)°, V =
115.3 (d, J2
= 23.2 Hz), 116.7 (d, J2
C-F
C-F
3
-1
,
˚
2189.4(8) A , Z = 4, T = 296.15 K, l(CuKa) = 0.604 mm
116.8 (d, J2 = 21.0 Hz), 117.9 (d, J4
C-F
C-F
Dcalc = 1.254 g/cm3; 12423 reflections measured
(7.926° B 2H B 135.282°), 3847 unique (Rint = 0.0483,
Rsigma = 0.0437) which were used in all calculations. The
final R1 was 0.0411 (I [ 2r(I)) and wR2 was 0.1014 (all
data). Obtained crystal structure was deposited in CCDC
(CCDC 1563837).
118.2 (d, J4 = 3.3 Hz), 130.6 (d, J3 = 7.7 Hz), 131.6
C-F
C-F
(d, J3
= 7.7 Hz), 134.6 (d, J3
= 7.7 Hz), 139.4 (d,
C-F
C-F
J3
= 7.7 Hz), 161.9 (d, J1
= 244.4 Hz), 162.0 (J1
C-F
C-F C-
= 243.3 Hz) ppm.
F
2,4,6-Tris(4-fluorophenyl)piperidine-3,3,5,5-tetracarboni-
trile (4g, C27H16F3N5) White solid; yield 1.15 g (82%);
2,4,6-Tris(4-methylphenyl)piperidine-3,3,5,5-tetracarboni-
trile (4b) White solid; yield 1.05 g (77%); m.p.:
161–162 °C (lit. m.p.: 159–160 °C [58]).
ꢀ
m.p.: 187–188 °C; IR: m = 3569, 3338, 2255, 2232, 1608,
1512, 1431, 1239, 1162, 842 cm-1; MS: m/z (%) = [M?-
CN] (0.2), 414 (0.3), 295 (99), 231 (27), 230 (99), 183 (33),
173 (21), 172 (100), 145 (49), 123 (98), 122 (72); 1H NMR
(300.13 MHz, DMSO-d6): d = 4.80 (s, 2H, CH), 4.91 (s,
1H, NH), 5.08 (s, 1H, CH), 7.39 (t, J = 8.7 Hz, 4H, Ar),
2,4,6-Tris(3-methylphenyl)piperidine-3,3,5,5-tetracarboni-
trile (4c, C30H25N5) White solid; yield 0.94 g (69%); m.p.:
ꢀ
136–137 °C; IR: m = 3333, 2923, 2840, 1609, 1491, 1459,
123

A. N. Vereshchagin et al.
Acknowledgements This work was supported by the Russian Science
Foundation (RSF Grant 17-73-20260).
7.53 (t, J = 8.7 Hz, 2H, Ar), 7.75–7.82 (m, 4H, Ar),
7.94–8.12 (m, 2H, Ar) ppm; 13C NMR (75.47 MHz,
DMSO-d6): d = 44.8, 47.9 (2C), 65.2 (2C), 111.8 (2C),
112.6 (2C), 115.7 (d, J2 = 21.7 Hz, 4C), 116.9 (d, J2
C-F
C-
References
= 21.9 Hz, 2C), 128.7 (d, J4 = 3.2 Hz, 2C), 130.5 (d,
F
C-F
J3 = 8.6 Hz, 4C), 131.1 (d, J4 = 2.9 Hz), 131.4 (d,
C-F
C-F
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C-F
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C-F
2,4,6-Tris(3-bromophenyl)piperidine-3,3,5,5-tetracarboni-
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112.3 (2C), 121.6 (2C), 122.5 (2C), 127.8 (2C), 127.9 (2C),
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150 (30), 141 (47), 126 (62), 114 (21), 99 (18); H NMR
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