Safe and Efficient Ritter Reactions in Flow

Abstract

Efficient mixing, temperature control and small environmental exposures allow reactions carried out in microfluidic de­vices to perform superior to their batch-type counterparts in conventional flasks. The Ritter reaction has been optimised for flow conditions leading to short reaction times and higher yields and also is more feasible with regards to safety, productivity and tolerance towards substrate functionalities.

Key words

amide - carbocation - microreactor - Ritter Reaction - safety

References and Notes

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11

The micromixing device ‘Comet X-01’, available from Techno Applications Co., Ltd, 34-16-204, Hon, Denenchofu, Oota, Tokyo 145-0072, Japan, was used.

12

Syringe A was loaded with 85% H₂SO₄ (5 mL). Syringe B was loaded with alcohol (6 mmol) and nitrile (6 mmol), diluted with acetic acid to 5 mL. The PTFE micromixer and the attached PTFE tubing (2 m, 0.5 mm inner diameter) were inserted into the heating bath and the temperature was adjusted to 45 ˚C (85 ˚C for secondary alcohols). The flow rate was set at 0.1 mL/min (reaction time: 3 min). The crude product was quenched by dropping into excess of ice-2 M NaOH. After the reaction, the tube was flushed with EtOAc and the crude mixture was washed with aq 2 M NaOH (80 mL) and EtOAc (3 × 100 mL). The organic layers were combined, dried over MgSO₄ and the solvent was removed under reduced pressure.
Selected Spectroscopic Data: 3,3′-Oxybis[N-(tert-butyl)propanamide] (13): ^¹H NMR (500 MHz, CDCl₃): δ = 1.31 (s, 18 H, Me), 2.34 (t, 4 H, J = 6.0 Hz, CH₂), 3.66 (t, 4 H, J = 6.0 Hz, CH₂), 5.85 (s, 2 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 28.8, 37.8, 51.0, 67.1, 170.2. EI-MS: m/z (%) = 272 [M⁺](3), 257 (48), 242 (6), 229 (3), 217 (49), 207 (7), 200(100), 183 (18). HRMS: m/z [M + H]⁺ calcd for C₁₄H₂₉N₂O₃: 273.2173; found: 273.2177. IR (neat): 3549, 3460, 3330, 3067, 2979, 2927, 2897, 1664, 1639, 1547, 1455, 1361, 1227, 1109 cm^-¹.
N-(tert-Butyl)-2-(2-iodophenyl)acetamide (14): ^¹H NMR (500 MHz, CDCl₃): δ = 1.31 (s, 9 H, Me), 3.61 (s, 2 H, CH₂), 5.22 (s, 1 H, NH), 6.98 (m, 1 H, ArH), 7.34 (m, 2 H, ArH), 7.86 (d, 1 H, J = 7.7 Hz, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 28.7, 49.6, 51.4, 101.0, 128.8, 128.9, 130.8, 138.8, 139.8, 168.6. EI-MS: m/z (%) = 318 [M⁺](4), 302 (13), 281 (4), 262 (28), 244 (100), 232 (6). HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₇INO: 318.0349; found: 318.0349. IR (neat): 3378, 3276, 2972, 2960, 1643, 1552, 1466, 1448, 1417, 1360, 1341, 1288, 1259, 1155, 1014 cm^-¹.