Stereoselective multicomponent synthesis of (2RS,6SR)-2,6-diaryl-3,3,5,5-tetracyanopiperidines

Article abstract of DOI:10.1007/s11172-018-2252-y

Multicomponent reaction between alkylidenemalononitriles, formaldehyde, and ammonium acetate upon reflux in alcohols gives stereoselectively 2,6-diaryl-3,3,5,5-tetracyanopiperidines in 65—92% yields. In this process, ammonium acetate acts as both a cataly

Full text of DOI:10.1007/s11172-018-2252-y

Russian Chemical Bulletin, International Edition, Vol. 67, No. 8, pp. 1534—1537, August, 2018
1534
Stereoselective multicomponent synthesis
of (2RS,6SR)-2,6-diaryl-3,3,5,5-tetracyanopiperidines
A. N. Vereshchagin, K. A. Karpenko, M. N. Elinson, S. V. Gorbunov, Yu. E. Anisina, and M. P. Egorov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6390. Е-mail: vereshchagin@ioc.ac.ru
Multicomponent reaction between alkylidenemalononitriles, formaldehyde, and ammo-
nium acetate upon reflux in alcohols gives stereoselectively 2,6-diaryl-3,3,5,5-tetracyanopiper-
idines in 65—92% yields. In this process, ammonium acetate acts as both a catalyst and a source
of nitrogen for the piperidine ring.
Key words: substituted piperidines, multicomponent reactions, stereoselectivity, alkylidene-
malononitriles.
A piperidine ring is a structural unit of a huge number
gen.9—11 As a continuation of our research on the use of
alkylidenemalononitriles as synthons in the synthesis of
various cyclic (cyclopropanes,12—14 cyclohexanes15) and
heterocyclic (pyrrolines,16 spiropyrimidines,17 spiropyr-
azolones,18 spirooxazolones,19 chromenes,20,21 pyrano-
pyridines,22 pyranoquinolines,23 etc.) compounds, in the
present work we report a multicomponent synthesis of
2,6-diaryl-3,3,5,5-tetracyanopiperidines from benzylidene-
malononitriles, formaldehyde, and ammonium acetate as
a source of nitrogen (Scheme 1, Table 1).
of natural and synthetic biologically active compounds,
many of which are widely used in medicine. About a third
of all known alkaloids contain a piperidine ring in their
structure. Approximately every tenth medicine has a pip-
eridine fragment in the molecule.1 Among pharmaceutical
drugs, substituted 4-phenylpiperidine and 4,6-diphenyl-
piperidine derivatives, resembling a pharmacophore frag-
ment of morphine, are of great importance. A number of
valuable medicines with various physiological properties
have been obtained on their basis, for example, analgesics,2
neuroleptics,3 antidepressants,4 antiallergic drugs,5 and
many others.
Scheme 1
At present, many strategies are known for constructing
six-membered heterocycles with one nitrogen atom as the
only hetero atom, and the overwhelming majority of them
is a sequence of classical two-component reactions. This
approach has a number of significant disadvantages. In
a two-component paradigm, even relatively small and not
too complex molecules often have to be synthesized using
complex multi-step synthesis, which leads to great labor
costs and small overall yields, resulting in high cost of final
products. This problem becomes especially pressing if
several stereocenters are present in the target molecule,
which must have a strictly defined configuration. Multi-
component synthesis has already become an instrument
of classical organic synthesis.6 The success of a multicom-
ponent approach in assembling a piperidine ring was
demonstrated as far back as in 1917 when a three-compo-
nent assembly of tropinone, a key compound in the syn-
thesis of atropine, was accomplished. Later, the synthesis
of tropinone was improved.8 At present, this reaction is
known as the Robinson—Schöpf reaction. Recently,
a multicomponent synthesis of substituted piperidines was
carried out using ammonium acetate as a source of nitro-
1, 2
a
Ar
Ph
1, 2
Ar
d
e
f
3-BrC6H4
3-NO2C6H4
3-PyC6H4
b
4-MeC6H4
4-EtC6H4
c
Reagents and conditions: MeOH, 65 С, 2 h.
The reaction was carried out upon reflux in methanol
under conditions optimal for obtaining 2,4,6-triaryl-
3,3,5,5-tetracyanopiperidines from benzylidenemalono-
nitriles, aromatic aldehydes, and ammonium acetate
without any additives.24 It was found that the yields of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1534—1537, August, 2018.
1066-5285/18/6708-1534 © 2018 Springer Science+Business Media, Inc.

Tetracyanopiperidines
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1535
Table 1. Multicomponent synthesis of (2RS,6SR)-2,6-diaryl-3,3,5,5-tetracyanopiperidines 2a—f
from benzylidenemalononitriles 1a—f, formaldehyde, and ammonium acetateа
Entry
Olefin 1
Ar
Source of CH2O
Piperidine 2
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1с
1d
1e
1f
Ph
Formalin
Paraformaldehyde
Formalin
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
2a
2a
2b
2b
2c
2d
2e
2f
54
83
52
74
77
72
65
92
Ph
4-MeC6H4
4-MeC6H4
4-EtC6H4
3-BrC6H4
3-NO2C6H4
3-PyC6H4
a
Conditions: benzylidenemalononitrile 1 (6 mmol), formaldehyde (3 mmol), and ammonium
acetate (6 mmol) was refluxed in methanol (10 mL) for 2 h.
b Of isolated product 2.
piperidines 2 were considerably higher when paraformal-
dehyde was used as a source of formaldehyde, rather than
formalin (37% aqueous formaldehyde, see Table 1, en-
tries 1 and 2). Piperidines 2 crystallized upon reaction
completion and can be separated by common filtration.
Compounds 2a and 2b were described earlier, however,
they were obtained by the reaction of commercially
unavailable highly reactive propane-1,1,3,3-tetracarbo-
nitrile and 1-aryl-N,N-bis[(1Е)-arylmethylidene]methane-
diamines.25 The stereochemistry of compounds 2a,b was
not specified.
idine (2c) (Fig. 1). It is obvious that the bulky aromatic
substituents are placed in the equatorial positions of the
piperidine ring. A similar equatorial arrangement of aryl
substituents was observed for 2,6-triaryl-3,3,5,5-tetra-
cyanopiperidines 2 obtained from aromatic aldehydes,
malononitrile, formaldehyde, and ammonium acetate,
which was confirmed by X-ray diffraction study.26
A plausible mechanism of this multicomponent reac-
tion is given in Scheme 2. Ammonia, being both a source
of nitrogen and a base, undergoes aza-Michael addition
to benzylidenemalononitrile 1. Further nucleophilic ad-
dition of anion А to formaldehyde and repeated aza-
Michael reaction with a second molecule of olefin 1 leads
to anion В. The subsequent intramolecular cyclization
under conditions of the least steric hindrance results in
(2RS,6SR)-2,6-diaryl-3,3,5,5-tetracyanopiperidine 2.
Synthetic potential of this reaction can be extended by
using primary amines as a source of nitrogen for the pi-
peridine ring, similarly to the synthesis of 1-alkyl-4,6-
The formation of 2,6-diarylsubstituted (rather than
2,4-disubstituted) piperidines was confirmed by NMR
spectroscopy. All the 1Н and 13С spectra of compounds 2
exhibit one set of aromatic signals, indicating symmetric
2,6-arrangement of aromatic substituents. For example,
one set of signals is observed for both the aliphatic ethyl
1
protons and the aromatic protons in the Н NMR spec-
trum of 2,6-bis(4-ethyl)phenyl-3,3,5,5-tetracyanopiper-
8.01
3.01
1.03
1.02
3.97
6.00
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0

Fig. 1. 1Н NMR spectrum of compound 2c.

1536
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Vereshchagin et al.
Scheme 2
[M – C14H8N4 – H]+ (81), 78 [M – C15H10N5 + H]+ (65).
Found (%): C, 74.73; H, 4.49; N, 20.76. C21H15N5. Calculated (%):
C, 74.76; H, 4.48; N, 20.76.
diaryl-5-nitrо-2-piperidones from 3-aryl-4-nitrоbutan-
oates, an aromatic aldehyde, and a primary amine.27
In conclusion, we accomplished a multicomponent
reaction between benzylidenemalononitriles, substituted both
with electron-donating and electron-withdrawing sub-
stituents at the aromatic ring, formaldehyde, and ammo-
nium acetate to form (2RS,6SR)-2,6-diaryl-3,3,5,5-tetra-
cyanopiperidines in 65—92% yield. The reaction is easily
handled, reaction products are isolated by common filtration.
(2RS,6SR)-2,6-Bis(4-methylphenyl)-3,3,5,5-tetracyanopiper-
idine (2b). The yield was 0.81 g (74%), a white powder, m.p.
1
217—218 С (Ref. 25: m.p. 155—156 С (decomp.)). H NMR
(DMSO-d6, 300.13 МHz), : 2.36 (s, 3 H, CH3); 3.46, 3.96
(both d, 1 H each, CH2, J = 14.3 Hz); 4.36 (s, 1 H, NH); 4.55
(s, 2 H, 2 CH); 7.30, 7.52 (both d, 4 H each, Ar, J = 7.3 Hz).
13C NMR (DMSO-d6, 75.47 МHz), : 20.8 (s, 2 C, CH3); 35.6
(s, 1 C, CH2); 37.6 (s, 2 C(CN)2); 64.7 (s, 2 C(NH)); 112.4
(s, 2 CN); 113.9 (s, 2 CN); 127.9 (s, 4 C, Ar); 128.9 (s, 4 C, Ar);
132.6 (s, 2 C, Ar); 139.2 (s, 2 C, Ar). IR (KBr), /cm–1: 3378,
2974, 2253, 1516, 1431, 1246. MS (EI, 70 eV), m/z (Irel (%)): 365
[M]+ (25), 287 [M – 3 CN]+ (56), 222 [M – C7H2N4 – H]+
(100), 168 [M – C12H11N3]+ (39), 182 [M – C13H13N3]+ (37),
119 [M – C15H10N4]+ (79), 118 [M – C15H10N4 – H]+ (45).
Found (%): C, 75.58; H, 5.25; N, 19.12. C23H19N5. Calculated (%):
C, 75.59; H, 5.24; N, 19.16.
Experimental
1Н and 13C NMR spectra were recorded on a Bruker AM-300
spectrometer (300.13 and 75.47 МHz), respectively). Mass spectra
were recorded on a Finnigan MAT INCOS 50 mass-spectrometer.
IR spectra were recorded on a Specord M82 Fourier-transform
spectrometer in KBr pellets, using Soft Spectra software. Melting
points were measured on a Gallenkamp hot stage. Olefins 1 were
obtained by the Knoevenagel condensation from aromatic alde-
hydes and malononitrile, using sodium acetate as a catalyst.28
Multicomponent synthesis of (2RS,6SR)-2,6-diaryl-3,3,5,5-
tetracyanopiperidines (general procedure). A mixture of benzyl-
idenemalononitrile 1 (6 mmol), paraformaldehyde (84 mg,
3 mmol) and ammonium acetate (462 mg, 6 mmol) was refluxed
in methanol (10 mL) for 2 h. Then, the reaction mixture was kept
at –10 С for 30 min (for more complete crystallization of the
product), the precipitate was collected by filtration and dried to
obtained pure piperidine 2.
(2RS,6SR)-2,6-Diphenyl-3,3,5,5-tetracyanopiperidine (2a).
The yield was 1.71 g (63%), a white powder, m.p. 216—217 С
(Ref. 25: m.p. 204—205 С). 1H NMR (DMSO-d6, 300.13 МHz),
: 3.52, 4.02 (both d, 1 H each, CH2, J = 13.9 Hz); 4.55 (s, 1 H,
NH); 4.62 (s, 2 H, 2 CH); 7.45—7.71 (m, 10 H, Ar). 13C NMR
(DMSO-d6, 75.47 МHz), : 35.7 (s, CH2); 37.5 (s, 2 C(CN)2);
64.8 (s, 2 C(NH)); 112.3 (s, 2 CN); 113.8 (s, 2 CN); 128.0 (s, 4 C,
Ar); 128.4 (s, 4 C, Ar); 129.7 (s, 2 C, Ar); 135.4 (s, 2 C, Ar). IR
(KBr), /cm–1: 3387, 3063, 2979, 2253, 1461, 1424, 1130. MS
(EI, 70 eV), m/z (Irel (%)): 337 [M]+ (22), 259 [M – 3 CN]+
(100), 194 [M – C7H2N4 – H]+ (49), 154 [M – C11H9N3]+ (20),
117 [M – C14H13N – CN]+ (36), 105 [M – C14H8N4]+ (91), 104
(2RS,6SR)-2,6-Bis(4-ethylphenyl)-3,3,5,5-tetracyanopiper-
idine (2c). The yield was 0.91 g (77%), a white powder, m.p.
210—211 С. 1H NMR (DMSO-d6, 300.13 МHz), : 1.22 (t, 6 H,
2 CH3, J = 7.3 Hz); 2.67 (q, 4 H, 2 CH2, J = 7.3 Hz); 3.48, 3.99
(both d, 1 H each, CH2, J = 13.9 Hz); 4.43 (s, 1 H, NH); 4.56
(s, 2 H, 2 CH); 7.36 (d, 4 H, Ar); 7.56 (d, 4 H, Ar, J = 7.3 Hz).
13C NMR (DMSO-d6, 75.47 МHz), : 15.3 (s, 2 C, CH3); 27.8
(s, 2 C, CH2); 35.6 (s, 1 C, CH2); 37.5 (s, 2 C(CN)2); 64.7
(s, 2 C(NH)); 112.4 (s,2 CN); 113.9 (s, 2 CN); 127.7 (s, 4 C, Ar);
128.0 (s, 4 C, Ar); 132.8 (s, 2 C, Ar); 145.3 (s, 2 C, Ar). IR (KBr),
/cm–1: 3371, 2974, 2253, 1515, 1434, 1131. MS (EI, 70 eV), m/z
(Irel (%)): 393 [M]+ (19), 315 [M – 3 CN]+ (39), 250 [M –
– C7H2N4 – H]+ (97), 221 [M – C7H2N4 – H – Et]+ (31), 182
[M – C13H13N3]+ (37), 167 [M – C13H13N3 – Me]+ (46), 133
[M – C16H12N4]+ (100), 91 [M – C17H14N5 – Me + H]+ (30),
77 [M – C17H14N5 – Et + H]+ (16). Found (%): C, 76.28; H, 5.91;
N, 17.80. C25H23N5. Calculated (%): C, 76.31; H, 5.89; N, 17.80.
(2RS,6SR)-2,6-Bis(3-bromophenyl)-3,3,5,5-tetracyanopiper-
idine (2d). The yield was 1.06 g (72%), a white powder, m.p.
223—224 С. 1H NMR (DMSO-d6, 300.13 МHz), : 3.45, 4.04
(both d, 1 H each, CH2, J = 13.2 Hz); 4.64 (s, 2 H, 2 CH); 4.78
(s, 1 H, NH); 7.49 (dd, 2 H, Ar, J1 = 8.8 Hz, J2 = 7.7 Hz); 7.61,
7.71 (both d, 2 H each, Ar, J = 7.7 Hz); 7.84 (s, 2 H, Ar). 13C NMR

Tetracyanopiperidines
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1537
(DMSO-d6, 75.47 МHz), : 35.3 (s, 1 C, CH2); 37.2 (s, 2 C,
C(CN)2); 63.8 (s, 2 C, C(NH)); 112.1 (s, 2 CN); 113.4 (s, 2 CN);
121.6 (s, 2 C, Ar); 127.5 (s, 2 C, Ar); 130.6 (s, 4 C, Ar); 132.7 (s, 2 C,
Ar); 137.5 (s, 2 C, Ar). IR (KBr), /cm–1: 3330, 2983, 2948,
2255, 1570, 1476, 1437, 1263, 660. MS (EI, 70 eV), m/z (Irel (%)):
495 [M]+ (6), 417 [M – 3 CN]+ (39), 352 [M – C7H2N4 + H]+ (26),
349 [M – C7H2N4 – H]+ (8), 234 [M – 4 CN – 2 Br + H]+ (30),
232 [M – 4 CN – 2 Br – H]+ (29), 185 [M – 2 C6H4Br + H]+
(100), 183 [M – 2 C6H4Br – H]+ (86), 153 [M – C11H8BrN3 –
–Br]+ (30). Found (%): C, 50.92; H, 2.67; Br, 32.26, N, 14.12.
C21H13Br2N5. Calculated (%): C, 50.94; H, 2.65; Br, 32.25; N, 14.14.
(2RS,6SR)-2,6-Bis(3-nitrоphenyl)-3,3,5,5-tetracyanopiper-
idine (2e). The yield was 0.83 g (65%), a white powder, m.p.
226—227 С. 1H NMR (DMSO-d6, 300.13 МHz), : 3.54, 4.16
(both d, 1 H each, CH2, J = 13.9 Hz); 4.92 (s, 2 H, 2 CH); 5.10
(s, 1 H, NH); 7.89 (t, 2 H, Ar, J = 8.1 Hz); 8.14, 8.41 (both d,
2 H each, Ar, J = 8.1 Hz); 8.55 (s, 2 H, Ar). 13C NMR (DMSO-d6,
75.47 МHz), : 35.1 (s, 1 C, CH2); 37.1 (s, 2 C, C(CN)2); 63.7
(s, 2 C, C(NH)); 112.0 (s, 2 CN); 113.3 (s, 2 CN); 122.8 (s, 2 C,
Ar); 124.9 (s, 2 C, Ar); 130.4 (s, 2 C, Ar); 135.2 (s, 2 C, Ar); 136.9
(s, 2 C, Ar); 147.6 (s, 2 C, Ar). IR (KBr), /cm–1: 3315, 3079,
2835, 2256, 1528, 1484, 1441, 1351. MS (EI, 70 eV), m/z
(Irel (%)): 349 [M – 3CN]+ (10), 284 [M – C7H2N4 – H]+ (100),
238 [M – C7H2N4 – H – NO2]+ (11), 199 [M – C11H8N4O2] (52),
153 (74), 150 [M – C14H7N5O2]+ (73), 149 [M – C14H7N5O2 –
– H]+ (27), 126 [M – C11H8N4O2 – CN – NO2 – H] (38).
Found (%): C, 58.98; H, 3.08; N, 22.92. C21H13N7O4. Calculat-
ed (%): C, 59.02, H, 3.07, N, 22.94.
(2RS,6SR)-2,6-Di(3-pyridyl)-3,3,5,5-tetracyanopiperidine (2f).
The yield was 0.93 g (92%), a white powder, m.p 197—198 С.
1H NMR (DMSO-d6, 300.13 МHz), : 3.54 (d, 1 H, CH2,
J = 14.7 Hz); 4.09 (d, 1H, CH2, J = 13.9 Hz); 4.75 (s, 2 H, 2 CH);
4.90 (s, 1 H, NH); 7.58 (dd, 2 H, Ar, J1 = 4.3 Hz, J2 = 5.1 Hz);
8.10 (d, 2 H, Ar, J = 8.1 Hz); 8.71 (d, 2 H, Ar, J = 4.4 Hz); 8.82
(s, 2 H, Ar). 13C NMR (DMSO-d6, 75.47 МHz), : 34.9 (s, 1 C,
CH2); 37.3 (s, 2 C, C(CN)2); 62.6 (s, 2 C, C(NH)); 112.1
(s, 2 CN); 113.4 (s, 2 CN); 123.6 (s, 2 C, Ar); 130.9 (s, 2 C, Ar);
135.9 (s, 2 C, Ar); 149.1 (s, 2 C, Ar); 151.1 (s, 2 C, Ar). IR (KBr),
/cm–1: 3332, 2968, 2253, 1578, 1482, 1453, 1432, 1342, 1359.
MS (EI, 70 eV), m/z (Irel (%)): 339 [M]+ (8), 261 [M – 3 CN]+ (90),
196 [M – C7H2N4 – H]+ (100), 155 [M – C10H8N4]+ (33), 128
[M – C10H8N4 – CN – H]+ (43), 105 [M – C10H8N4 – 2 CN +
+ H]+ (64), 78 [Py]+ (46). Found (%): C, 67.22; H, 3.87;
N, 28.88. C19H13N7. Calculated (%): C, 67.25; H, 3.86; N, 28.89.
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This work was financially supported by the Russian
Science Foundation (Project No. 17-73-20260).
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Received April 6, 2018;
in revised form June 18, 2018;
accepted June 19, 2018