Synthesis of N-(5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetamides using the Ritter reaction Kirill V. Nikitin* and Nonna P. Andryukhova Department of Chemistry, M. V. Lomonosov Moscow State University, 119899 Moscow, Russian Federation. Fax: +7 095 939 0798; e-mail: newscientist@mtu-net.ru DOI: 10.1070/MC2000v010n01ABEH001197 Aromatic tert-alkylamines and N-(5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetamides were successfully prepared using the Ritter reaction under mild dilute conditions. Aliphatic tertiary alkyl amines are extensively used in con- structing biologically active molecules. 1 The Ritter reaction 2 with hydrogen cyanide in acidic media followed by hydrolysis of the resulting amide is a useful and practical way to obtain alkylamines 3 from more readily available alcohols. Nevertheless, the synthesis of tert-alkylamines under classical Ritter conditions (acetic acid, sulfuric acid, 50 °C) is restricted due to competitive elimination and requires the use of milder conditions. 4 More- over, the use of highly toxic alkali metal cyanides in an acidic medium requires careful handling. We used the Ritter reaction with acetonitrile under dilute con- ditions followed by amide methylation and hydrolysis 5 (Scheme 1) for the synthesis of tert-alkylamines which cannot be prepared under classical Ritter conditions. We also applied the dilute con- ditions to the synthesis of previously unknown N-[1-(tert-butyl)- 3,4-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl]acetamides ex- pected to be potent herbicides. 6 The key factors affecting the amide yield are the initial alcohol concentration and the acidity. The greater is the excess of acetonitrile, the higher is the amide yield provided that the initial quantity of sulfuric acid is low and constant (Table 1). Under classical conditions, the reaction of 2-(3-chlorophenyl)- propan-2-ol 1a (R 1 =R 2 = Me, R 3 = 3-ClC 6 H 4 ) with acetonitrile does not lead to 2-(3-chlorophenyl)-2-acetamidopropane 2a at all (Table 1, run 1); the products were substituted indans and chain styrene dimers easily formed from 1a under acidic con- ditions. 7 The dilution of the initial reaction mixture with MeCN in the absence of AcOH drastically enhanced the formation of 2a (run 2), and it became predominant at a 0.2 mol dm –3 initial concentration of 1a. If the concentration of 1a was 0.1 mol dm –3 or lower (runs 4 and 5), 2a became the only product in the form of sulfate 4a, which can be easily isolated by filtration. Examples of the preparation of N-alkylamides 2 from alcohols 1 are summarised in Table 2. Under dilute conditions (0.1 M solutions of starting alcohols), N-tert-alkylamides 2a–c,e were prepared in high yields (runs 1–3 and 5), but primary alkylamides (runs 6 and 7) could not be obtained. We found that phenyl- acetonitrile (run 2) can be employed as a nitrogen nucleophile under dilute conditions. Unfortunately, 2-phenyl-2-acetamidopropane 2d (run 4) was not obtained preparatively even under dilute conditions because of elimination and irreversible formation of -methylstyrene dimers. 7 The difference may be accounted for a lower electro- philic activity of the carbocation formed from 2d. The reaction under dilute conditions appeared to be indis- pensable for the preparation of potentially biologically active N-(5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetamides 5 (Scheme 2). The syntheses of previously unavailable compounds 5 in high yields are summarised in Table 3. R 1 R 3 R 2 OH R 1 R 3 R 2 NHCOR 4 R 1 R 3 R 2 NH 2 R 4 CN, i, Me 2 SO 4 ii, H 2 O, NaOH H 2 SO 4 1 2 3 Scheme 1 a Ritter conditions: 1a (5 mmol), acetic acid (2 ml), sulfuric acid (1 ml), MeCN (10 mmol, 0.5 ml), 60 °C. Dilute conditions: 1a (5 mmol), sulfuric acid (15 mmol), MeCN (according to Table 1), 20–25 °C. b 3-Chloro- -methyl- styrene dimers are formed. c Procedure: to a solution of 1a (0.85 g, 5 mmol) in acetonitrile (50 ml, 1 mol) sulfuric acid (1.47 g, 15 mmol) was added, and the reaction mixture was stirred for 2 h at ambient temperature. Salt 4a (0.94 g, yield 61%) was filtered off as a solid; 6 water (10 ml) was added, and the mixture was extracted with ethyl acetate; 2a (0.64 g, 61%) was isolated. The acetonitrile filtrate was neutralised with triethylamine (3 g, 30 mmol), concentrated and extracted with ethyl acetate; additional amide 2a (0.20 g, yield 19%) was isolated as a solid: mp 114 °C, 1 H NMR (CDCl 3 ) d: 1.63 (s, 6H), 1.94 (s, 3H), 5.98 (br. s, 1H), 7.1–7 .4 (m, 4H). Table 1 Reaction of 1a with MeCN under Ritter (run 1) and dilute con- ditions. a Run Initial concentration of 1a/ mol dm –3 Yield of 4a (%) Total yield of 2a (%) 1 1.25 — 0 b 2 0.625 19 20 3 0.42 33 38 4 0.2 50 60 5 c 0.1 61 80 Table 2 Preparation of amides 2 from alcohol 1 under dilute conditions (Scheme 1). Run R 1 R 2 R 3 R 4 Time/h Product Yield (%) 1 3-ClC 6 H 4 Me Me Me 24 2a 86 2 3-ClC 6 H 4 Me Me PhCH 2 96 2b 60 3 3,5-Cl 2 C 6 H 3 Me Me Me 24 2c 84 4 Ph Me Me Me 24 2d 6 5 Me Me Me Me 24 2e 68 6 Me H H Me 24 — 0 7 H H H Me 24 — 0 N O OH R 1 R 2 R 3 N O NHCOMe R 1 R 2 R 3 MeCN, H 2 SO 4 Scheme 2 5 a To a solution of 1-(tert-butyl)-5-hydroxy-3,4-dimethyl-1,5-dihydro-2H- pyrrol-2-one (0.376 g, 2 mmol) in MeCN (25 ml) sulfuric acid (0.6 g, 6 mmol) was added, the mixture was stirred at room temperature for 24 h, triethylamine (2 ml) was added, the mixture was evaporated, extracted with ethyl acetate, washed with water and aqueous NaHCO 3 and dried. N-[1-(tert- Butyl)-3,4-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl]acetamide (0.41 g, 91%) was isolated as a solid: mp 169 °C; 1 H NMR (CDCl 3 ) d: 1.38 (s, 9H), 1.64 (s, 3H), 1.79 (s, 3H), 2.02 (s, 3H), 5.89 (d, 1H, 9.5 Hz), 6.35 (d, 1H, 9.5 Hz, exchangeable); IR (KBr, n/cm –1 ): 1223, 1256, 1375, 1526, 1665, 3294; MS, m/z: 225 (M + 1). b , -Dimethyl-3,5-dichlorobenzyl. Table 3 Preparation of 5 from corresponding 5-hydroxy-1,5-dihydro-2H- pyrrol-2-ones (MeCN, 0.1 M solution of the starting compound, 0.3 M H 2 SO 4 , 24 h, ambient temperature). Run R 1 R 2 R 3 Yield of 5 (%) 1 Bu t Me Me 91 a 2 PhCH 2 R 2 +R 3 = –CH=CH–CH=CH– 88 3 DDB b Me Me 98 4 DDB 2-FC 6 H 4 Me 93 5 DDB Ph Me 95 – 31 – Mendeleev Commun., 2000, 10(1), 31–32