PAPER
A Practical Synthesis of tert-Alkylamines via the Ritter Reaction with Chloroacetonitrile
1711
1H NMR (200 MHz, CDCl3): = 2.0 2.4 (6 H, m), 2.7 2.9 (2 H,
m), 3.55 (2 H, s), 4.00 (2 H, s), 6.75 (1 H, s), 7.1 7.4 (10 H, m).
N-Benzyl-4-amino-4-phenylpiperidine (3e)
Mp 60-61 °C; TLC (CHCl3/MeOH/25% aq NH3, 6:1:1, bottom lay-
er); Rf 0.78.
13C NMR (50 MHz, CDCl3) = 35.43, 43.01, 49.39, 56.68, 63.06,
124.97, 127.0, 128.36, 129.08, 138.12, 144.82, 164.41.
1H NMR (200 MHz, CDCl3): = 1.48 (2 H, br s), 1.70 (2 H, d,
J = 13 Hz) 2.1 2.3 (2 H, m), 2.4 2.6 (2 H, m), 2.70 (2 H, dt, J = 14,
2 Hz), 3.56 (2 H, s), 7.2 7.4 (8 H, m), 7.45 7.6 (2 H, m).
13C NMR (50 MHz, CDCl3): = 37.72, 49.78, 52.02, 63.14, 124.92,
126.41, 126.94, 128.14, 129.10, 138.54.
N-Chloroacetyldiphenylglycine (2f)
Mp 213 214 °C (dec.); TLC (CHCl3/MeOH/H2O, 7: 2: 1 bottom
layer); Rf 0.15.
1
IR (nujol): = 3340, 1710, 1640 cm .
Diphenylglycine (3f)
Mp 245 247 °C (dec.); TLC (EtOAc/H2O/BuOH/AcOH, 1:1:1:1);
Rf 0.74.
1H NMR (200 MHz, D2O): = 7.4 7.6 (m).
13C NMR (50 MHz, D2O): = 71.83, 130.28, 131.81, 132.53,
138.30, 174.11.
1H NMR (200 MHz, DMSO-d6): = 4.26 (2 H, s), 7.1 7.4 (10 H,
m).
13C NMR (50 MHz, DMSO-d6) = 42.90, 69.91, 127.53, 127.91,
128.32, 140.45, 165.58, 171.89.
tert-Alkylamines 3a-f; General Procedure
A solution of amide 2 (5 mmol) and thiourea (0.46 g, 6 mmol) in a
mixture of EtOH (10 mL) and AcOH (2 mL) was refluxed for 10 h.
The workup procedure for individual amines was as follows.
N-Aminoiminomethylthioacetyl-1,3,3,5,5-pentamethylcyclo-
hexanamine Hydrochloride (4)
A solution of amide 2a (0.245 g, 1 mmol) and thiourea (0.092 g, 1.2
mmol) in EtOH (2 mL) was refluxed for 10 min. EtOH was evapo-
rated and the residue treated with MeCN (10 mL). The precipitate
formed was collected by filtration and dried in vacuo to give 4
(0.120 g, 37%); mp 209 211 °C; TLC (CHCl3/MeOH/25% aq NH3,
6:1:1, bottom layer); Rf 0.25.
To isolate amines 3a e, H2O (50 mL) was added to the reaction
mixture and the resulting precipitate was filtered. The filtrate was
made alkaline with aq 20% NaOH. The product was extracted with
hexane (3 × 30 mL), the combined extracts were washed with brine
(30 mL) and dried (NaOH). The solution of amine in hexane was fil-
tered through a Celite pad, and a solution of 1.6 M HCl in Et2O (6
mL) was added. The solvent and the excess of HCl were removed
in vacuo. The residue was treated with Et2O, filtered and dried
(NaOH). Amine 3e was isolated as a free base after evaporation of
hexane.
1
IR (nujol): = 3200, 3070, 1660 cm .
1H NMR (200 MHz, DMSO-d6): = 0.86 (6 H, s), 1.05 (6 H, s),
1.20 (3 H, s), 0.8 1.31 (4 H, m), 2.18 (2 H, d, J = 14 Hz), 3.93 (2
H, s), 7.86 (1 H, s), 8.34 (4 H, br s).
To isolate amino acid 3f, the mixture was evaporated, and H2O (20
mL) was added to the residue. The resulting mixture was acidified
to pH ~1 and filtered. The filtrate was neutralized to pH 6 7 with
20% aq NaOH solution. The resulting precipitate was collected on
a filter, washed with H2O (1 mL) and dried in vacuo over NaOH.
13C NMR (50 MHz, DMSO-d6): = 28.23, 29.95, 31.18, 34.62,
35.92, 46.48, 51.37, 54.64, 167.42, 170.36.
Acknowledgement
1,3,3,5,5-Pentamethylcyclohexanamine Hydrochloride (3a)
Mp 235 237 °C; TLC (CH3Cl/MeOH/25% aq NH3, 6:1:1, bottom
layer); Rf 0.50.
1H NMR (200 MHz, CDCl3): = 1.02 (6 H, s), 1.07 (6 H, s), 1.23
(1 H, d, J = 14 Hz), 1.30 (1 H, d, J = 14 Hz), 1.64 (3 H, s), 1.66 (2
H, d, J = 14 Hz), 1.76 (2 H, d, J = 14 Hz), 8.25 (3 H, br s).
We acknowledge I. Dipans for recording IR spectra and E. Sarule
for obtaining microanalyses. We also wish to thank Dr. A. Klapars
for valuable comments during the preparation of the manuscript.
References
13C NMR (50 MHz, CDCl3): = 28.19, 30.72, 32.41, 36.05, 48.43,
51.19, 57.53.
(1) (a) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4045.
(b) Ritter, J. J; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048.
(c) Krimen, I.; Cota, D. J. Organic Reactions 1969, 17, 213.
(d) Bishop, R. In Comprehensive Organic Transformations;
Trost, B. M., Ed.; Pergamon: Oxford 1991; Vol. 6, Chapter
1.9, pp 261 300.
(2) Bishop, R.; Burgess, G. Tetrahedron Lett. 1987, 28, 1585.
(3) Ichikawa Y. Chem. Lett. 1990, 1347.
(4) Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R.; Danysz,
W.; Parsons, C. G.; Quack, G. Eur. J. Med. Chem., in press.
(5) (a) Masaki, M.; Kitahara, T.; Kurita, H.; Ohta, M. J. Am.
Chem. Soc. 1968, 90, 4508.
3-Ethylheptane-3-amine Hydrochloride (3b)
Mp >280 °C; TLC (CHCl3/MeOH/25% aq NH3, 6:1:1, bottom lay-
er); Rf 0.64.
1H NMR (200 MHz, CDCl3): = 1.01 (9 H, t, J = 7.5 Hz), 1.73 (6
H, d, J = 7.5 Hz), 8.3 (3 H, br s).
13C NMR (50 MHz, CDCl3): = 7.45, 28.03, 60.62.
Adamantane-1-amine Hydrochloride (3c)
Mp >300 °C; TLC (CHCl3/MeOH/25% aq NH3, 6:1:1, bottom lay-
er); Rf 0.50.
1H NMR (200 MHz, CDCl3): = 1.68 (6 H, s), 2.03 (6 H, s), 2.14
(3 H, s), 8.3 (3 H, br s).
(b) Fontana, A.; Scoffone, E. Gazz. Chim. Ital. 1968, 98, 1261.
(c) Steglich, W.; Batz, H. Angew. Chem.Int. Ed. Engl. 1971,
10, 75.
13C NMR (50 MHz, CDCl3): = 28.87, 35.30, 40.49, 52.87.
(d) Allmendinger, T.; Rihs, G.; Wetter, H. Helv. Chim. Acta
1988, 71, 395.
1,1-Dimethyl-2-phenylethylamine Hydrochloride (3d)
Mp 196 200 °C; TLC (CHCl3/MeOH/25% aq NH3, 6:1:1, bottom
layer); Rf 0.68.
1H NMR (200 MHz, CDCl3): = 1.46 (6 H, s), 3.09 (2 H, s), 7.1
7.4 (5 H, m), 8.5 (3 H, br s).
13C NMR (50 MHz, CDCl3): = 25.07, 46.23, 55.77, 127.24,
128.44, 130.61, 134.68.
(6) Alcohol 1a in the Ritter reaction with HCN gave 85% of
corresponding formamide, however, under the same
conditions with MeCN the yield of acetamide was only 3%
(Jirgensons, A.; Kauss, V., unpublished results).
(7) Christol, H.; Laurent, A.; Mousseron, M. Bull. Soc. Chim. Fr.
1961, 2319.
(8) Giardina, G. A. M., Grugni M., Rigolio R., Vassallo M.,
Erhard K., Farina C. Biorg. Med. Chem. Lett. 1996, 6, 2307.
Synthesis 2000, No. 12, 1709–1712 ISSN 0039-7881 © Thieme Stuttgart · New York