Synthesis of 4-substituted 3,5-dicyano-2,6-piperidinediones using lithium nitride as a convenient source of ammonia

Article abstract of DOI:10.3987/COM-08-11584

A simple and efficient one-pot synthesis of 4-substituted-3,5-dicyano-2,6-piperidinediones was achieved in good yields via the three-component reaction of aldehyde or ketone, ethyl cyanoacetate, lithium nitride (Li₃N) as a convenient source of ammonia in MeOH.

Full text of DOI:10.3987/COM-08-11584

HETEROCYCLES, Vol. 78, No. 4, 2009
977
HETEROCYCLES, Vol. 78, No. 4, 2009, pp. 977 - 982. © The Japan Institute of Heterocyclic Chemistry
Received, 20th October, 2008, Accepted, 27th November, 2008, Published online, 3rd December, 2008
DOI: 10.3987/COM-08-11584
SYNTHESIS OF 4-SUBSTITUTED 3,5-DICYANO-2,6-PIPERIDINE-
DIONES USING LITHIUM NITRIDE AS A CONVENIENT SOURCE OF
AMMONIA
Liqiang Wu, * Chunguang Yang, Liming Yang, and Lijuan Yang
School of Pharmacy, Xinxiang Medical College, Xinxiang, Henan 453003, P. R.
China. E-mail: wliq1974@sohu.com
Abstract
–
A
simple
and
efficient
one-pot
synthesis
of
4-substituted-3,5-dicyano-2,6-piperidinediones was achieved in good yields via
the three-component reaction of aldehyde or ketone, ethyl cyanoacetate, lithium
nitride (Li3N) as a convenient source of ammonia in MeOH.
INTRODUCTION
4-Substituted-3,5-dicyano-2,6-piperidinediones exhibit a large range of biological activities such as
anticonvulsant, sedative and analgesic activities.1 They are also useful synthetic intermediates for
various pharmaceuticals and active compounds.2 There are two strategies for synthesis of
4-substituted-3,5-dicyano-2,6-piperidinediones: (1) They are synthetized by Guareschi-Thorpe reaction in
following manner: The one-pot, three-component condensation of an aldehyde or ketone with ethyl
cyanoacetate and ammonia in alcohol. 2-3 The reaction requires at least 48 hours to proceed to completion,
and more typically between 48-168 hours for completion. in addition, current environmental regulations
make it impractical to produce gaseous NH3 in ethanol on a large scale. (2) The other approaches for the
preparation of 4-substituted-3,5-dicyano-2,6-piperidinediones using aldehyde or ketone, substituted
α-cyanoacetamide, ethyl cyanoacetate in an ethanolic solution of sodium ethoxide at room temperature
have also been reported. 1 Substituted α-cyanoacetamide as the starting materia of the route is not easy to
obtain. We now report a simple and efficient route to 4-substituted-3,5-dicyano-2,6-piperidinediones
using Li3N as a convenient source of ammonia.
RESULTS AND DISCUSSION
A range of 4-substituted-3,5-dicyano-2,6-piperidinediones was synthesized from a combination of
aldehyde or ketone (1), ethyl cyanoacetate (2) and Li3N (3) in a 1: 2: 2 ratio in an MeOH solution (Table
1). The reaction was completed 12-16 hours at room temperature and the crude product was isolated by
precipitation upon addition of hydrochloric acid to the mixture, the separated soild was filtered off and

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HETEROCYCLES, Vol. 78, No. 4, 2009
crystallized form the appropriate solvent.
Table 1 Synthesis of 4-substituted-3,5-dicyano-2,6-piperidinedionesa
NC
O
O
R2
R1
MeOH
rt
12-16 h
NH
O
+ Li N
NC
CO2Et
3
+
R2
R1
NC
4
2
3
1
Entry
Aldehyde or Ketone
Product 4
Time (h) Yield
(%)b
NC
O
NH
O
4a
12
12
79
NC
NC
O
O
NH
O
4b
4c
81
76
O
NC
NC
NC
O
NH
O
16
O
NC
O
NH
O
4d
4e
4f
14
14
14
12
12
12
16
82
83
76
84
74
78
75
NC
NC
O
O
NH
O
NC
NC
O
O
O
NH
O
O
NC
NC
O
O
NH
CHO
4g
4h
4i
NC
NC
O
O
F
NH
F
CHO
NC
NC
O
O
MeO
NH
MeO
CHO
NC
O
NC
NC
O
O
C
NH
O
4j
aAldehyde or ketone: ethyl cyanoacetate: Li3N =1: 2: 2; reactions executed in a sealed vessel at room temperature.
bIsolated yield

HETEROCYCLES, Vol. 78, No. 4, 2009
979
In recent study, we have discoverd that Li3N as electrode material4 and catalyst in synthesis of cBN5 in
chemistry industry can releases ammonia upon treatment with MeOH along with the corresponding
lithium methoxide. Thus, this reagent can serve a dual role as it releases ammonia in situ while generating
lithium methoxide with the potential to act as a catalyst (see Figure 1).
NH3
Li3N + MeOH
+ LiOMe
3
NC
H2N
EtO
NC
H2N
EtO
NC
NC
NC
LiOMe
O
LiOMe
NH3
O-
OH
H2N
H2N
O
EtO
O
2
a
R1
R2
R1
R1
OH
R2
O
NC
NC
NC
NC
R2
LiOMe
LiOMe
1
EtO
O
O
EtO
O
EtO
O
EtO
O
2
b
O
NC
R1
O
NC
R1
NC
R1
OEt
LiOMe
OEt
NH2
MeOH
H
-
＋
b
a
NH
R2
NHLi
R2
R2
NC
NC
NC
O
O
O
4
Figure 1. The mechanism of reaction using Li3N as a source of ammonia
In order to determine the efficiency of Li3N as a source of ammonia, the same reactions were carried out
with ammonia, NH4Ac and other commercially nitrides (Mg3N2, Zn3N2, AlN)employed in related
condensations. The results summarized in Table 2 revealed that these systems gave lower yields of the
desired product or no desired product. The results also emphasized the importance of using lithium
methoxide (entry 3), which could improve yield.
Table 2 Synthesis of 4,4-dimethyl-3,5-dicyano-2,6-piperidinediones using different source of ammoniaa
Entry
Source of Ammonia
2 equiv NH3
Solvent
H2O
Yield (%)b
1
2
3
4
5
6
7
6
24
58
0
2 equiv NH3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2 equiv NH3+6 equiv LiOMe
2 equiv NH4Ac
1 equiv Mg3N2
31
0
1 equiv Zn3N2
2 equiv AlN
0
aAcetone: ethyl cyanoacetate=1: 2, reactions executed in a sealed vessel at room temperature for 12 h.
bIsolated yield

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HETEROCYCLES, Vol. 78, No. 4, 2009
In summary, we first developed a simple and efficient methodology to synthesise a range of
4-substituted-3,5-dicyano-2,6-piperidinediones using Li3N as a convenient source of ammonia. We
believe that this methodology will be a valuable addition to the existing methods in the field of
4-substituted-3,5-dicyano-2,6-piperidinediones.
EXPERIMENTAL
NMR spectra were determined on FT-NMR Avance 400 spectrometer, coupling constants (J) were
measured in Hz; Elemental analysis were recorded on a PEA-1110 elemental analyzer. Melting points
were determined on a Mel-Temp capillary tube apparatus and were uncorrected; Commercially available
reagents were used throughout without further purification unless otherwise stated.
General Procedure for the Preparation of 4. To a stirred solution of aldehyde or ketone (10 mmol) and
ethyl cyanoacetate (2.26 g, 20 mmol) in MeOH (5 mL) at 8 oC in a 10 mL, lithium nitride (0.7 g, 20
mmol) was added in a single portion. The reaction mixture was sealed immediately and stirred at rt for
12-16 h. The mixture was then acidified by hydrochloric acid (15mL in 50 mL water) and the separated
soild was filtered off and crystallized form MeOH to give 4 as a white soild.
4,4-Dimethyl-3,5-dicyano-2,6-piperidinedione (4a) : mp 215-217oC (lit.,2b mp 214-216oC); IR (KBr) ν:
1
3211 (NH), 2242 (CN), 1723, 1698 (C=O) cm-1; H NMR (DMSO-d6, 400 MHz) δ: 12.02 (s, 1 H, NH),
4.42 (s, 2 H, CH), 1.28 (t, J=7.5 Hz, 6 H, CH3); Anal. Calcd for C9H9N3O2: C, 56.54; H, 4.74; N, 21.98.
Found: C, 56.49; H, 4.70; N, 21.89.
4-Ethyl-4-methyl-3,5-dicyano-2,6-piperidinedione (4b) : mp 188-190oC (lit.,2b mp 191-193oC); IR
(KBr) ν: 3240 (NH), 2225 (CN), 1743, 1702 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz) δ: 11.92 (s, 1 H,
NH), 4.51 (s, 2 H, CH), 1.28-1.23 (m, 2H, CH2), 1.16 (t, J=7.3 Hz, 3H, CH3), 0.96-0.92 (m, 3H, CH3);
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.44; H, 5.45; N, 20.39.
4-Methyl-4-(4-methylpent-3-enyl)-3,5-dicyano-2,6-piperidinedione (4c) : mp 192-193oC; IR (KBr) ν:
1
3235 (NH), 2240 (CN), 1730, 1698 (C=O) cm-1; H NMR (DMSO-d6, 400 MHz) δ: 12.08 (s, 1 H, NH),
5.12 (m, 1 H, CH=), 4.43 (s, 2 H, CH), 2.10-2.06 (m, 2H, CH2),1.29-1.25 (m, 2H, CH2), 1.20 (t, J=7.2 Hz,
3H, CH3), 0.92-0.89 (m, 3H, CH3); Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N, 16.20. Found: C,
64.70; H, 6.75; N, 16.35.
6, 10-Dicyano-8-azaspiro[4,5]decane-7,9-dione (4d) : mp 162-163oC (lit.,1 mp 166 oC); IR (KBr) ν:
1
3212 (NH), 2243 (CN), 1745, 1708 (C=O) cm-1. H NMR (DMSO-d6, 400 MHz) δ: 11.94 (s, 1 H, NH),
4.63 (s, 2 H, CH), 1.75-1.69(m, 8H, CH2); Anal. Calcd for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34.
Found: C, 60.84; H, 5.15; N, 19.41.
1, 5-Dicyano-3-azaspiro[5,5]undecane-2,4-dione (4e) : mp 196-198oC (lit.,1 mp 200 oC); IR (KBr) ν:
1
3201(NH), 2239(CN), 1732, 1712 (C=O) cm-1. H NMR (DMSO-d6, 400 MHz) δ: 12.02 (s, 1 H, NH),

HETEROCYCLES, Vol. 78, No. 4, 2009
981
4.53 (s, 2 H, CH), 1.69-1.43(m, 10H, CH2); Anal. Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17.
Found: C, 62.41; H, 5.60; N, 19.21.
7,11-Dicyano 3-Oxa-9-azaspiro[5.5]undecane-8,10-dione (4f) : mp 196-198oC. IR (KBr) ν: 3234 (NH),
2219 (CN), 1734, 1705 (C=O) 1185 (C-O) cm-1; 1H NMR (DMSO-d6, 400 MHz) δ: 12.10 (s, 1 H, NH),
4.92 (s, 2 H, CH), 3.72-3.66 (m, 4 H, OCH2),1.72-1.68 (m, 4H, CH2); Anal. Calcd for C11H11N3O3: C,
56.65; H, 4.76; N, 18.02. Found: C, 56.45; H, 4.68; N, 18.15.
4-Phenyl-3,5-dicyano-2,6-piperidinedione (4g) : mp 248-249oC (lit.,1 mp 255oC); IR (KBr) ν: 3305
1
(NH), 2260 (CN), 1712, 1692 (C=O) cm-1; H NMR (DMSO-d6, 400 MHz) δ: 12.02 (s, 1 H, NH),
7.45-7.32 (m, 5 H, ArH), 4.96-4.87 (m, 2 H, CH), 4.40-4.32 (m, 1 H, CH); Anal. Calcd for C13H9N3O2: C,
52.79; H, 5.64; N, 22.39. Found: C, 52.65; H, 5.58; N, 22.35.
4-(4-Fluorophenyl)-3,5-dicyano-2,6-piperidinedione (4h) : mp 245-247oC (lit.,1 mp 255oC); IR (KBr)
ν: 3315 (NH), 2274 (CN), 1726, 1702 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz) δ: 12.08 (s, 1 H, NH),
7.20-6.92(m, 4 H, ArH), 4.73-4.69 (m, 2 H, CH), 4.34-4.28 (m, 1 H, CH); Anal. Calcd for C13H8FN3O2:
C, 60.70; H, 3.13; N, 16.33. Found: C, 60.45; H, 3.15; N, 16.20.
4-(4-Methoxyphenyl)-3,5-dicyano-2,6-piperidinedione (4i) : mp 317-318oC (lit.,1 mp 325oC); IR (KBr)
ν: 3294 (NH), 2256 (CN), 1736, 1698 (C=O), 1282, 1088 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz) δ:
12.02 (s, 1 H, NH), 7.40-6.95(m, 4 H, ArH), 4.82-4.76 (m, 2 H, CH), 4.22-4.16 (m, 1 H, CH), 3.74 (s, 3 H,
CH3); Anal. Calcd for C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 62.22; H, 4.15; N, 15.52.
4-Methyl-4-phenyl-3,5-dicyano-2,6-piperidinedione (4j) : mp 290-291oC; IR (KBr) ν: 3304 (NH),
2238 (CN), 1746, 1706 (C=O) cm-1; 1H NMR (DMSO-d6, 400 MHz) δ: 12.15 (s, 1 H, NH), 7.44-7.20(m,
5 H, ArH), 4.82 (s, 2 H, CH), 1.46 (s, 3 H, CH3); Anal. Calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59.
Found: C, 66.20; H, 4.27; N, 16.40.
ACKNOWLEDGEMENTS
We are pleased to acknowledge the financial support from Xinxiang Medical College (No.
04GXLP05).
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