Highly Efficient Ruthenium-Catalyzed Oxime to Amide Rearrangement Nathan A. Owston,a Alexandra J. Parkerb and Jonathan M. J. Williamsa a Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK Process Research and Development, AstraZeneca, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, UK
b
General Methods: Reactions which required the use of anhydrous, inert atmosphere techniques were carried out under an atmosphere of nitrogen. In all cases, solvents were distilled and degassed prior to use, apparatus was oven dried or flame dried under vacuum and purged with inert gas by three cycles of removal under vacuum and replacement with inert gas where appropriate. Toluene was stored in sealed Young’s ampoules and dispensed using standard Schlenk techniques. TLC using polythene or glass backed plates precoated with Macherey-Nagel Sil G/UV254nm neutral silica were used to monitor reactions where appropriate. Visualisation of these plates was by 254nm UV light and/or KMnO4 or 2,4-DNP dips followed by gentle warming. TLC data quoted for specific compounds indicate the most suitable method of visualisation. Organic layers were routinely dried with anhydrous MgSO4 or Na2SO4 and evaporated using a Büchi rotary evaporator. Where necessary, further drying was facilitated by high vacuum. Flash column chromatography was carried out using Davisil LC 60Å silica gel (35-70 micron) purchased from Fluorochem. NMR spectra were run in CDCl3, d6-benzene or d6-DMSO on a Bruker Avance 300 (300 MHz) instrument and recorded at the following frequencies: proton (1H – 300 MHz), carbon (13C – 75.4/ MHz). Chemical shifts are reported relative to the residual solvent peak where possible or alternatively to SiMe4 ( = 0.00 ppm) as internal standard. Coupling constants (J) are given in Hz and multiplicities denoted as singlet (s), doublet (d), triplet (t), quartet (q), pentet (pent), septet (sep), unresolved multiplet (m) or broad (br.). General assignments are classified as (Ph) phenyl, (Ar) aromatic, (C) quaternary carbon, (CH) methyne carbon, (CH2) methylene carbon and (CH3) methyl carbon. Protons that possess chemical but not magnetic equivalence (AA’BB’ systems) as in the case of 1,4-disubstituted aromatics are reported as multiplets or doublets, depending on their appearance in spectra. Melting points were carried out on a Gallenkamp MF-370 hot stage melting point apparatus and are uncorrected.
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Unless preparative details are provided, all reagents were commercially available and purchased from either Acros Organics, Sigma-Aldrich, Alfa Aesar, Avocado, Fluka, Lancaster, Maybridge or Strem chemical companies. Oximes were purified by recrystallization from a suitable solvent prior to use.
Experimental Methods: Preparation of carbonyl(dihydrido)tris(triphenylphosphine)ruthenium (II); Ru(PPh3)3(CO)H2
PcPh3 Ph3Pd H Ru a OC Hb PcPh3 To a nitrogen purged, 3-necked round bottomed flask charged with triphenylphosphine (6.28 g, 23.9 mmol) was added degassed anhydrous methanol (200 cm3). The mixture was heated at reflux for 10 minutes, forming a solution. In quick succession, ruthenium trichloride hydrate (1.04 g, 4.0 mmol) in methanol (40 cm3), aqueous formaldehyde (37% w/w) (40 cm3) and potassium hydroxide (1.20 g, 21.4 mmol) in methanol (40 cm3) were added. The resulting solution was heated for 30 minutes at reflux and then cooled in an ice bath with stirring for a further 30 minutes. The grey precipitate was collected by vacuum filtration and washed with absolute ethanol (50 cm3), water (50 cm3), absolute ethanol (50 cm3) and finally hexane (50 cm3). The crude product was dissolved in toluene and filtered through a column of neutral alumina and washed through thoroughly with toluene. The toluene solution was concentrated in vacuo to approximately 20 cm3 and layered with anhydrous methanol producing a precipitate which was collected by vacuum filtration as a white solid (Ru(PPh3)3(CO)H2). Yield 2.50 g, (68%). 1H NMR (300MHz, C6D6, 25 °C); I = -6.53 (1H, ddt, Ru-Ha, JPc-Ha = 30.5 Hz, JPd-Ha = 15.3 Hz, JHa-Hb = 6.1 Hz), 8.29 (1H, ddt, Ru-Hb, JPd-Hb = 74.5 Hz, JPc-Hb = 28.1 Hz, JHa-Hb = 6.1 Hz). 31P{1H}: I = 58.2 (d, JPc-Pd = 16.8 Hz, 46.1 (t, JPd-Pc = 16.8 Hz). IR (nujol mull, cm-1): 1960 (MCO).
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Preparation of (Z)-benzaldehyde oxime1: (E)-benzaldehyde oxime5 (3.0 g, 24.8 mmol) was added portionwise to an excess of ice-cold concentrated hydrochloric acid with vigorous stirring (exothermic). The mixture was further cooled to 5°C and the precipitate filtered. The solid product was slowly added to a stirred solution of aqueous sodium bicarbonate and the resulting slurry filtered again to yield the crude product. This was recrystallized from dichloromethane-hexane to yield (Z)-benzaldehyde oxime (1.77 g, 59%). m.p. 130132 °C ; Rf = 0.27 (8:2 petroleum ether (b.p. 40-60 °C):diethyl ether, det: UV); Preparation of para-methoxybenzaldehyde oxime: To a solution of para-anisaldehyde (5.60 g, 5 cm3, 0.034 mol) in methanol (20 cm3) was added pyridine (10 cm3) followed by hydroxylamine hydrochloride (3.57 g, 0.051 mol, 1.5 eqv) and the mixture stirred for 24 h at ambient temperature. Solvents were removed in vacuo and the residual oil taken up in diethyl ether, washed with water (2 x 15 cm3), dried with anhydrous magnesium sulfate, filtered and solvent removed in vacuo. The crude product was purified by column chromatography using petroleum ether (b.p. 40-60 °C):diethyl ether as eluent to afford (E)-para-methoxybenzaldehyde oxime (2.51 g, 49%) as the first fraction and (Z)- para-methoxybenzaldehyde oxime3 (1.39 g, 27%) as the second fraction.(Total yield 76%).(E)-para-methoxybenzaldehyde oxime4 : m.p. 63-66 °C; Rf = 0.25 (8:2 petroleum ether (b.p. 40-60 °C):diethyl ether, det: UV); 1H NMR (300MHz, CD3OD, 25 °C); I = 3.85 (3H, s), 6.96 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 8.06 (1H, s). (Z)- para-methoxybenzaldehyde oxime3 : m.p. 135137 °C; Rf = 0.20 (8:2 petroleum ether (b.p. 40-60 °C):diethyl ether, det: UV); 1H NMR (300MHz, CD3OD, 25 °C): I = 3.87 (3H, s), 6.99 (2H, d, J = 8.8 Hz), 7.25 (1H, s), 8.01 (2H, d, J = 8.8 Hz). The compound was used as mixed E/Z isomers. Representative procedure for the rearrangement of aldoximes: To an oven-dried, nitrogen purged Schlenk tube containing oxime (5 mmol), Ru(PPh3)3(CO)H2 (9.2 mg, 0.01 mmol, 0.2 mol%), dppe (4.0 mg, 0.01 mmol, 0.2 mol%) and p-toluenesulfonic acid (7.7 mg, 0.04 mmol, 0.8 mol%) was added degassed anhydrous toluene (5 cm3) and the mixture heated at reflux for 4-8 hours. On completion the reaction was allowed to cool to room temperature, diluted with methanol, and the solvent removed in vacuo.
The
crude
product
was
purified
by
column
chromatography
on
silica
gel
(methanol/dichloromethane as eluent) or recrystallization from suitable solvent(s), furnishing the corresponding amide in excellent yield.
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Benzamide2 (entry 1, Table 4): According to the representative procedure, using (Z)-benzaldehyde oxime (605 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as a white solid (556 mg, 92%). m.p. 128-130 °C; IR (KBr) 3366, 3170, 1657, 1623, 1576, 1449, 1401, 1121, 1024 cm-1; 1H NMR (300MHz, CDCl3, 25 °C): I = 5.95 (2H, br. s, NH2), 7.437.57 (3H, m), 7.81-7.84 (2H, m). 13C NMR (75MHz, CDCl3, 25 °C): I = 127.7, 129.1, 132.5, 170.0. Benzamide2 (entry 2, Table 4): According to the representative procedure, using (E)-benzaldehyde oxime (605 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as a white solid (569 mg, 94%). m.p. 128-130 °C; IR (KBr) 3366, 3170, 1657, 1623, 1576, 1449, 1401, 1121, 1024 cm-1; 1H NMR (300MHz, CDCl3, 25 °C): I = 6.20 (2H, br. s, NH2), 7.427.56 (3H, m), 7.81-7.84 (2H, m).
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C NMR (75MHz, CDCl3, 25 °C): I = 127.7, 129.0, 132.5, 133.8,
170.0. 4-Methoxybenzamide2,3 (entry 3, Table 4): According to the representative procedure, using (Z)-4methoxybenzaldehyde oxime (755 mg, 5 mmol), the title compound was obtained and purified by column chromatography using methanol/dichloromethane as the eluent, affording title compound as a white solid (702 mg, 93%). m.p. 166-168 °C; IR (KBr) 3390, 3171, 1661, 1620, 1574, 1443, 1392, 1252, 1148 cm-1; 1H NMR (300MHz, DMSO-d6, 25 °C): I = 3.79 (3H, s), 6.97 (2H, d, J = 8.8 Hz), 7.17 (1H, br. NH2) 7.84 (3H, m). 13C NMR (75MHz, DMSO-d6, 25 °C): I = 55.6, 113.7, 114.2, 126.9, 129.7, 131.7. 161.9, 167.8. 4-Nitrobenzamide2,4 (entry 4, Table 4): According to the representative procedure, using 4nitrobenzaldehyde oxime (830 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as an off-white solid (779 mg, 94%). m.p. 198-200 °C; IR (KBr) 3378, 3187, 1663, 1620, 1587, 1460, 1370, 1144 cm-1. 1H NMR (300MHz, DMSO-d6, 25 °C): I = 7.71 (1H, br. s, NH), 8.12 (2H, d, J = 8.6 Hz), 8.30 (3H, m). 13C NMR (75MHz, DMSO-d6, 25 °C): I = 123.8, 129.3, 140.3, 149.4, 166.5. 2-Nitrobenzamide5 (entry 5, Table 4): According to the representative procedure, using 2nitrobenzaldehyde oxime (830 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as a pale yellow solid (680 mg, 82%). m.p. 174-176 °C; 1H NMR (300MHz, DMSO-d6, 25 °C): I = 7.60-7.78 (4H, m), 8.12 (1H, dd, J = 7.8 Hz, 1.2 Hz), 8.12 (1H, br. s. NH). 13C NMR (75MHz, DMSO-d6, 25 °C): I = 124.3, 129.2, 131.0, 132.9, 133.7, 147.6, 167.5.
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4-(Trifluoromethoxy)benzamide6 (entry 6, Table 4): According to the representative procedure, using 4-(trifluoromethoxy)benzaldehyde oxime (1.026 g, 1 mmol), the title compound was obtained and purified by recrystallization affording title compound as a white solid (975 mg, 95%). m.p. 151-154 °C; 1
H NMR (300MHz, CDCl3, 25 °C): I = 6.01 (2H, br. s, NH2) 7.22 (2H, d, J = 8.8 Hz ), 7.81 (2H, d, J =
8.8 Hz). 13C NMR (75MHz, CDCl3, 25 °C): I = 121.4, 122.5, 130.6, 134.3, 151.1, 167.5. 2,4-Dichlorobenzamide7 (entry 7, Table 4): According to the representative procedure, using 2,4dichlorobenzaldehyde oxime (950 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as a white solid (835 mg, 88%). m.p. 189-192 °C; IR (KBr) 3379, 3187, 1624, 1587, 1461, 1370, 1144 cm-1; 1H NMR (300MHz, CDCl3, 25 °C): I = 5.93 (1H, br. s, NH), 6.37 (1H, br. s, NH), 7.35 (2H, dd, J = 8.4 Hz, 1.9 Hz), 7.46 (1H, d, J = 1.9Hz), 7.79 (2H, d, J = 8.4 Hz). 13C NMR (75MHz, CDCl3, 25 °C): I = 128.1, 130.7, 132.4, 169.3. 2-Furamide8 (entry 8, Table 4): According to the representative procedure, using 2-furaldehyde oxime (555 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as an off-white solid (443 mg, 80%). m.p. 140-142 °C; 1H NMR (300MHz, CDCl3, 25 °C): I = 6.10 (2H, br. s, NH2), 6.52 (1H, dd, J = 3.6 Hz, 1.8 Hz), 7.17 (1H, dd, J = 3.6 Hz, 0.6 Hz) 7.48 (1H, d, J = 0.6 Hz). 13C NMR (75MHz, CDCl3, 25 °C): I = 112.7, 115.6, 144.8, 147.8, 160.5. 2-Hydroxybenzamide9 (entry 9, Table 4): According to the representative procedure, using 2hydroxybenzaldehyde oxime (685 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as an off-white solid (582 mg, 82%). m.p. 138-140 °C; 1H NMR (300MHz, CDCl3, 25 °C): I = 5.95 (2H, br. s, NH2), 6.87 (1H, t, J = 8.1 Hz), 7.01 (1H, d, J = 8.4 Hz) 7.45 (2H, m), 12.15 (1H, s, OH).
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C NMR (75MHz, DMSO-d6, 25 °C): I = 114.7, 117.8, 118.7,
128.4, 134.5, 161.4, 172.5. Cinnamamide2,10 (entry 10, Table 4): According to the representative procedure, using cinnamaldehyde oxime (870 mg, 5 mmol), the title compound was obtained and purified by recrystallization affording title compound as an off-white solid (782 mg, 90%). m.p. 148-151 °C; IR (KBr) 3374, 3172, 1663, 1632, 1250, 1115 cm-1; 1H NMR (300MHz, DMSO-d6, 25 °C): I = 6.57 (1H, d, J = 15.6 Hz), 7.10 (1H, br. s, NH), 7.35-7.44 (4H, m) 7.53-7.57 (3H, m), 13C NMR (75MHz, DMSOd6, 25 °C): I = 122.7-, 127.9, 129.3, 129.8, 135.2, 139.5, 167.0.
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Butyramide2,11 (entry 11, Table 4): According to the representative procedure, using butyraldehyde oxime
(435 mg, 480 µL, 5 mmol), the title compound was obtained and purified by column
chromatography on silica gel (methanol/dichloromethane as eluent) affording title compound as a white solid (396 mg, 91%). m.p. 114-116 °C; IR (KBr) 3365, 3182, 1663, 1632, 1459 cm-1
1
H NMR
(300MHz, CDCl3, 25 °C): I = 0.90 (3H, t, J = 7.4 Hz), 1.59 (2H, sextet, J = 7.4 Hz), 2.13 (2H, t, J = 7.4 Hz) 5.61 (1H, br. s, NH), 5.99 (1H, br. s, NH). 13C NMR (75MHz, CDCl3, 25 °C): I = 14.1, 19.3, 38.2, 176.3 Octanamide12 (entry 12, Table 4): According to the representative procedure, using octanaldehyde oxime (720 mg, 5 mmol), the title compound was obtained and purified by column chromatography on silica gel (methanol/dichloromethane as eluent) affording title compound as a white solid (626 mg, 87%). m.p. 109-110 °C; 1H NMR (300MHz, CDCl3, 25 °C): I = 0.87 (3H, m), 1.28 (8H, m), 1.58 (4H, m), 2.19 (3H, t), 5.56 (1H, br. s, NH), 5.97 (1H, br. s, NH). 13C NMR (75MHz, CDCl3, 25 °C): I = 14.4, 23.0, 25.9, 29.4, 29.6, 29.8, 32.0, 36.4, 176.4.
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