HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 4, 2009, pp. 977-982
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-piperidinediones Using Lithium Nitride as a Convenient Source of Ammonia

Li qiang Wu,* Chunguang Yang, Liming Yang, and Lijuan Yang

College of Pharmacy, Xinxiang Medical University, East of JinSui Road, XinXiang City, Henan Province, 453003, China

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 crystallized form the appropriate solvent.

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).

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.

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: 3211 (NH), 2242 (CN), 1723, 1698 (C=O) cm-1; 1H 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: 3235 (NH), 2240 (CN), 1730, 1698 (C=O) cm-1; 1H 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: 3212 (NH), 2243 (CN), 1745, 1708 (C=O) cm-1. 1H 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: 3201(NH), 2239(CN), 1732, 1712 (C=O) cm-1. 1H NMR (DMSO-d6, 400 MHz) δ: 12.02 (s, 1 H, NH), 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 (NH), 2260 (CN), 1712, 1692 (C=O) cm-1; 1H 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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