Improved Synthesis of 3-Azaspiro[5,5]undecane-2,4-dione
505
to dry heat a solid powder mixture on a large scale. Furthermore, the process requires the
installation of scrubbers to handle the copious quantities of carbon dioxide and ammonia
gases evolved. This present note reports a new and simple process for the preparation of 2
which is suitable for industrial scale (Scheme 1).
Earlier, Chirac et al. prepared related cyclic imides by heating cyclic carboxylic an-
hydrides or corresponding dicarboxylic acids with formamide at 170–180◦C for 5–6 h.6
N-methyl-2-pyrrolidone (NMP) was used as additional solvent for substrates which had
poor solubility in formamide. In these reactions, formic acid is formed as by-product. A sim-
ilar method is also reported for the preparation of certain substituted 2,6-dioxopiperidines.7
In the present work, although 1 is not soluble in formamide, no additional solvent is required
as the initial suspension liquefied after heating. Further heating at 150–160◦C was sufficient
to complete the reaction in about 4 h as monitored by HPLC; formic acid and water are
formed as the by-products. Pouring the hot reaction mixture into water (40 mL) gives 2 as
a precipitate which is washed with water and dried to give 2 in high yields (>95%) and
in very high purity (99.5% HPLC). The process is environmentally friendly as there is no
evolution of gases during the process.
Experimental Section
All raw materials were obtained from commercial suppliers and were used as received.
Melting points were determined on a Polmon MP-96 digital melting point apparatus and
1
are uncorrected. H NMR and 13C NMR spectra were obtained on a Bruker-300 spec-
trometer using DMSO-d6 as the solvent with TMS as the internal standard. Mass spectra
were measured with a Thermo Scientific LCQ Fleet spectrometer. Monitoring of the reac-
tion and the purity of the compound was analyzed using HPLC in Hypersil gold RP-18,
150 × 4.6 mm, 5 μm column with mobile phase as water: acetonitrile: trifluroacetic acid
(15:85:0.01%).
3-Azaspiro-[5,5]-undecane-2, 4-dione 2. To a 100 ml three-neck flask equipped with a
thermometer, mechanical stirrer and a reflux condenser was added 1,1-cyclohexanediacetic
acid (1, 10.0 g, 50 mmol) and formamide (4.5 g, 100 mmol). The initial suspension, on
heating, became a clear colorless solution and was further heated and stirred at 150–160◦C
for 4 h. The hot clear reaction mixture was poured cautiously into water (40 ml). The
colorless precipitate obtained was collected, washed with water (10 ml) and dried under
vacuum to give 8.80 g (97% yield) of 2 as a colorless solid (99.9% purity by HPLC),
1
mp. 168–169◦C, lit5 169–170◦C. H NMR (300 MHz, DMSO-d6): δ 10.67 (br s, 1H),
2.42 (s, 4H), 1.30–1.41 (m, 10H); 13C NMR (75 MHz, DMSO-d6): δ 172.72, 42.50, 35.29,
32.45, 25.36, 20.97. (M + H)+: Calculated Mass for C10H15NO2 :182.23, Found (ESI-MS):
182.21.
References
1. M. Ferrari, M. Ghezzi and P. Belotti, US Patent 6846950, 2005; Chem. Abstr., 140, 271196 (2004).
2. K. Nagarajan, G. R. Preshad and M. Arulselvan, PCT Int. Appl. WO 2010023694, 2010; Chem.
Abstr., 152, 311897 (2010).