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Melting points were determined on a Reichert Microscopic Hot-Stage and are uncorrected. Infra red spectra were recorded on a Perkin Elmer 1725 x FT instrument. 300 MHz 1H and 75 MHz 13C NMR spectra were recorded on a Bruker AC-300P FT spectrometer. HPLC analyses were performed on a Waters 510 Analytical instrument using a model 481 UV absorbance detector linked to a Waters 740 data module. Mass spectral data was obtained on a Kratos MS902 Spectrometer through the Mass Spectroscopy Unit of Sydney University. Micro analytical data was obtained from The Research School of Chemistry at Canberra. Ames tests were carried out at the "Toxicology Unit of WorkSafe Australia" in Sydney. AM1 calculations were performed by the MOPAC (version 6) and MOPAC93 molecular orbital packages on the computer resources of the Department of Chemistry and Department of Computer Science at the University of New England. Stationary points were confirmed by force calculation which provided all force constants as positive numbers. Transition states were similarly confirmed by the presence of a single negative force constant. The keywords PRECISE, POINT, STEP, TS where used were appropriate. A recent development in molecular modelling has been the incorporation of algorithms that enable optimisation of geometric structures and energies in a solvent matrix. For the MOPAC package, the keyword COSMO was used when solvent shell optimisations were required with the dielectric value set at 32, to mimic MeOH as the solvent.
Acetonitrile used was HiPerSolv, 'Far UV' grade (BDH). Ether refers to anhydrous diethyl ether stored over sodium wire. Dichloromethane (DCM) and acetone were distilled and dried over 4Å molecular sieve. Ethyl acetate (EtOAc) and methanol (MeOH) were distilled before use. Hexane (Hex.) refers to hexane of the boiling range 60-70oC. Anhydrous sodium sulfate was used for drying all organic mixtures. Flash chromatography was executed on columns loaded with Kieselgel 60 (Merck). Thin Layer Chromatography was performed on aluminium sheets pre-coated with 0.2 mm of silica gel 60 F254 (Merck). 2,3-But-2-ene, 4-nitrobenzyl bromide, 4-phenoxyphenyl acetate and para-substituted benzoic acids were purchased from Aldrich, as was deuterio-acetonitrile (99.5%-d), deuterium oxide (99.8%-d), and H2O (10% 18O). 1H and 13C NMR designations are: s(singlet); st(singlet of triplets); d(doublet); dd(doublet of doublets); dt(doublet of triplets); t(triplet); q(quartet); qt(quintet); sxt(sextet) and m(multiplet).
Acyloxylation of the N-chloro intermediates were performed in a dedicated fumehood under anhydrous conditions. Careful filtration of the mixture, also in the fumehood, followed by removal of the solvent on a dedicated rotary evaporator and high vacuum pump, provided the alkyl N-acyloxybenzohydroxamates which were handled with extreme care. Generally, simple alkyl N-acyloxybenzohydroxamates were heavy, gummy oils that facilitated easy, safe manipulation of the compounds however occasionally light fine amorphous crystals were obtained which required particular care in handling to ensure that the mutagenic material was not dissipated in the fumehood.
All contaminated glassware was treated with a solution of sodium hydroxide dissolved in 50% aqueous ethanol to destroy the mutagenic compounds. Latex gloves were used at all times when handling contaminated glassware and during chromatographic purification.
Alkyl N-acyloxybenzohydroxamates were stored under refrigeration in designated areas enclosed in plastic containers.
Treatment of the appropriate para-substituted ethyl benzoate with hydroxylamine hydrochloride under basic conditions afforded a precipitate of potassium benzohydroxamate salt from MeOH after refrigeration.256 (The esters were obtained by esterification of the appropriate para-substituted benzoic acid with an excess of ethanol under acidic conditions and were identified by NMR by comparison with authentic spectra). Condensation of the potassium salt with the appropriate alkyl bromide and a 10% excess of sodium carbonate in 50% aqueous MeOH provided the appropriate para-substituted benzohydroxamic ester in good yield.256
The general synthesis of hydroxamic ester from potassium benzohydroxamate and the appropriate benzyl bromide has been described.173,256 Dideuteration of para-substituted benzyl alcohol and para-substituted benzyl bromides was confirmed by comparison with the 1H and 13C spectra of the protio species, as well as the presence of a pentet resonance for the methylene carbon in the 13C spectra where this was present. Deuterated hydroxamates were identified by comparison of their 1H, 13C and mass spectra with the protio species.180 The condensation reaction involving 4-methoxybenzyl bromide and potassium benzohydroxamate did not provide the hydroxamic ester and hence an alternative method is described below.
butyl benzohydroxamate 98a
1-Bromobutane (13.93 g, 100 mmol), potassium benzohydroxamate (11.87 g, 67.0 mmol) and sodium carbonate (7.95 g, 75.0 mmol) was stirred overnight in 50% aq. methanol (300 ml) and refluxed for 2 hours. The crude product was obtained via the general procedure. Purification by flash column chromatography (CHCl3) afforded pure butyl benzohydroxamate (6.68 g, 52%) as an orange oil, b.p. 190 oC @ 0.2 mm Hg (Found: C, 68.53; H, 8.06; N, 7.51. C15NO2 requires C, 68.37; H, 7.82; N, 7.25%); nmax (CHCl3)/cm-1 3225 (NH), 1654 (CO); dH (CDCl3) 0.87 (3H, t), 1.34 (2H, sxt), 1.60 (2H, qt), 3.95 (2H, t), 7.33 (2H, t, m-Ar), 7.44 (1H, t, p-Ar), 7.76 (2H, d, o-Ar), 11.17 (1H, br); dC (CDCl3) 13.44 (q), 16.60 (t), 29.67 (t), 75.84 (t), 127.01 (d), 127.94 (d), 131.25 (d), 131.68 (s), 165.65 (s).
butyl 4-bromobenzohydroxamate 98g
Potassium 4-bromobenzohydroxamate was obtained as colourless prisms in the same manner as potassium benzohydroxamate (82%). 1-bromobutane (17.06 g, 124.5 mmol), potassium 4-bromobenzohydroxamate (19.09 g, 83 mmol) and sodium carbonate (10.8 g, 100 mmol) in 50% aq. MeOH (300 ml) were stirred at room temperature overnight and refluxed for two hours. Workup and recrystallisation (CHCl3/Hex.) provided pure butyl 4-bromobenzohydroxamate (11.5 g, 67%), m.p. 109-110oC (Found: C, 48.71; H, 5.31; N, 5.15, Br 29.46. C14NO2Br requires C, 48.55; H, 5.19; N, 5.15; Br, 29.36%); nmax (CHCl3)/cm-1 3250 (NH), 1696 (CO); dH (CDCl3) 0.89 (3H, t), 1.34 (2H, sxt), 1.60 (2H, qt), 3.95 (2H, t), 7.47 (2H, d J 8.5, m-Ar), 7.63 (2H, d), 10.5 (1H, br, NH); dC (CDCl3) 13.74 (q), 18.91 (t), 29.96 (t), 76.48 (t), 126.48 (s), 128.77 (d), 130.67 (s), 131.62 (d), 165.45 (s). m/z 271 (M+,45%), 262(35), 241(40), 228(40), 215(40), 199(80), 183(100).
butyl 4-chlorobenzohydroxamate 98f
Potassium 4-chlorobenzohydroxamate was obtained in the same manner as potassium benzohydroxamate (60%). 1-bromobutane (10 g, 73.0 mmol), potassium 4-chlorobenzohydroxamate (13.5 g, 73 mmol) and sodium carbonate (10.8 g, 100 mmol) in 50% aq. MeOH (200 ml) were stirred at room temperature overnight and refluxed for two hours. Workup and recrystallisation (CHCl3/Hex.) provided pure butyl 4-chlorobenzohydroxamate (14.1 g, 85%), m.p. 95-96oC (Found: C, 58.09; H, 6.45; N, 6.22; Cl, 15.82. C14NO2Cl requires C, 58.03; H, 6.20; N, 6.15; Cl, 15.57%); nmax (CHCl3)/cm-1 3250 (NH), 1695 (CO); dH (CDCl3) 0.88 (3H, t), 1.33 (2H, sxt), 1.57 (2H, qt), 3.95 (2H, t), 7.30 (2H, d), 7.70 (2H, d, J 8.3, o-Ar), 10.5 (1H, br); dC (CDCl3) 13.66 (q), 18.86 (t), 29.90 (t), 76.37 (t), 128.55 (d), 128.66 (d), 130.21 (s), 137.93 (s, p-Ar), 165.29 (s). m/z 227 (M+,40%), 196(40), 182(45), 139(100), 111(65), 75(50), 28(70).
butyl 4-nitrobenzohydroxamate 98h
Potassium 4-nitrobenzohydroxamate was obtained in the same manner as potassium benzohydroxamate (90%). The title compound was generated via the general condensation and recrystallisation procedure as pale yellow crystals (52%), m.p. 99-101oC (Found: C, 54.99; H, 6.20; N, 11.66. C11H14N2O4 requires C, 55.46; H, 5.92; N, 11.76%); nmax (CHCl3)/cm-1 1695 (CO); dH (CDCl3) 0.90 (3H, t), 1.34 (2H, sxt), 1.66 (2H, qt), 4.03 (2H, t), 7.99 (2H, d), 8.22 (2H, d, J 8.8), 10.5 (1H, br); dC (CDCl3) 13.66 (q), 18.88 (t), 29.93 (t), 76.75 (t), 123.57 (d, m-Ar), 128.47 (d), 137.47 (s), 149.63 (s, p-Ar), 164.14 (s). m/z 238 (M+, 25%), 206(30), 193(70), 167(40), 150(100), 57(55), 41(40), 29(95).
butyl biphenyl-4-carboxohydroxamate 98c
Potassium biphenyl-4-carboxohydroxamate was prepared via the general method (20%). The title compound was generated via the general condensation and recrystallisation procedure as colourless crystals (73%), m.p. 141-142oC (Found: C, 75.80; H, 7.32; N, 4.93. C17H19NO2 requires C, 75.81; H, 7.11; N, 5.20%); nmax (CHCl3)/cm-1 3406 (NH), 1684 (CO); dH (CDCl3) 0.95 (3H, t), 1.44 (2H, sxt), 1.71 (2H, qt), 4.04 (2H, t), 7.4 (3H, m), 7.60 (4H, m), 7.81 (2H, d, J 8.5, o-Ar), 8.8 (1H, br); dC (CDCl3) 13.85 (q), 19.06 (t), 30.08 (t), 76.62 (t), 127.14 (d), 127.26 (d), 127.60 (dd), 128.07 (dt), 128.91 (dd), 130.67 (st), 139.83 (s, i'-Ar), 144.77 (s, p-Ar), 166.38 (s). m/z 269 (M+, 71%), 197(43), 181(100), 153(77), 77(11), 76(15), 29(10).
butyl 4-tert-butylbenzohydroxamate 98e
Potassium 4-tert-butylbenzohydroxamate was obtained as colourless prisms in a yield of 20%. The title compound was generated via the general condensation and workup procedure. Purification by flash column chromatography (15% EtOAc, 85% Hex.) afforded pure butyl 4-tert-butylbenzohydroxamate (1.77 g, 71%) as a clear oil, b.p. 120oC @ 0.1 mm Hg (Found: C, 71.97; H, 9.50; N, 5.39. C15H23NO2 requires C, 72.25; H, 9.30; N, 5.62%); nmax (CHCl3)/cm-1 3259 (NH), 1679 (CO); dH (CDCl3) 0.96 (3H, t), 1.33 (9H, s), 1.45 (2H, m), 1.70 (2H, qt), 4.03 (2H, t), 7.45 (2H, d), 7.75 (2H, d, J 6.8, o-Ar), 9.3 (1H, br); dC (CDCl3) 13.81 (q), 19.01 (t), 30.03 (t), 31.06 (q), 34.89 (s), 76.64 (t), 125.49 (d), 126.92 (d), 129.12 (s), 155.41 (s), 166.42 (s). m/z 249 (M+, 51%), 234(33), 177(30), 161(74), 134(33), 77(19), 57(24), 44(41), 41(100), 29(57).
butyl 4-methylbenzohydroxamate 98d
Potassium 4-methylbenzohydroxamate was obtained as colourless prisms in the same manner as potassium benzohydroxamate (54%). Butyl 4-methylbenzohydroxamate was obtained under the general condensation reaction. Recrystallisation (CHCl3/Hex.) provided pure butyl 4-methylbenzohydroxamate (70%), (Found: C, 69.95; H, 7.99; N, 6.79. C12H17NO2 requires C, 69.54; H, 8.27; N, 6.76%); nmax/cm-1 1695 (CO), 3250 (NH); dH (CDCl3) 0.92 (3H, t), 1.40 (2H, sxt), 1.67 (2H, qt), 2.37 (3H, s), 3.99 (2H, t), 7.18 (2H, d), 7.63 (2H, d, J 8, o-Ar), 9.1 (1H, br); dC (CDCl3) 13.81 (q), 19.01 (t), 21.44 (q), 30.02 (t), 76.45 (t), 127.06 (d), 129.20 (d), 129.20 (s), 142.36 (s, p-Ar), 166.44 (s); m/z 207 (M+, 65%), 175(45), 151(30), 119(100), 91(25).
butyl 4-methoxybenzohydroxamate 98b
Potassium 4-methoxybenzohydroxamate was obtained in the same manner as potassium benzohydroxamate (62%). Butyl 4-methoxybenzohydroxamate was prepared via the general condensation reaction conditions. Recrystallisation (CHCl3/Hex.) provided butyl 4-methoxybenzohydroxamate (40%), m.p. 43-44oC, b.p. 155oC @ 0.25 mmHg (Found: C, 63.58; H, 7.74; N, 6.16. C 17NO3 requires C, 64.55; H, 7.87; N, 6.27%); nmax (CHCl3)/cm-1 1692 (CO), 3250 (NH); dH (CDCl3) 0.89 (3H, t), 1.38 (2H, sxt), 1.63 (2H, qt), 3.80 (3H, s), 3.96 (2H, t), 6.83 (2H, d), 7.75 (2H, d, J 8.9, o-Ar), 10.5 (1H, br); dC (CDCl3) 13.72 (q), 18.92 (t), 29.96 (t), 55.21 (q), 76.39 (t), 113.59 (d, m-Ar), 124.18 (s), 128.97 (d), 162.28 (s, p-Ar), 166.12 (s). m/z 223 (M+,35%), 191(10), 167(10), 151(20), 135(100), 92(40), 77(45), 28(65).
The appropriate 4-substituted benzoic acid (or benzaldehyde) was reduced to the corresponding alcohol by treatment with LiAlH4 in ether (or NaBH4 in ethanol/water). The mixtures were first washed with dilute acid, 10% aq. sodium carbonate, and then extracted with DCM. The appropriate alcohols were obtained by this method in good yields and were of high purity. All alcohols were known compounds and exhibited the appropriate 1H, 13C NMR and IR spectra. Dideuteration of para-substituted benzyl alcohol was confirmed by comparison of the 1H and 13C spectra with those of the protio species, as well as the presence of a quintet resonance for the methylene carbon in the 13C spectra.
4-nitro-a,a-dideuteriobenzyl alcohol
4-Nitrobenzoic acid was converted to 4-nitrobenzoyl chloride in 85% yield. Treatment with sodium borodeuteride in dioxane provided 4-nitro-a,a-dideuteriobenzyl alcohol in 80% yield.
para-Substituted benzyl bromides (chloride) were prepared from the appropriate alcohols by refluxing with HBr/H2SO4 (HCl/H2SO4) in ether.179 The mixture was washed with conc. HCl, H2O, 10% aq Na2CO3, H2O and extracted with DCM. Concentration in vacuo provided the 4-substituted benzyl bromides in good yield (>90%) and of sufficient purity (1H and 13C NMR, IR, m.p.) to be used directly in condensation reactions. While a,a-dideuterio-4-substituted benzyl alcohols displayed a weak but characteristic alpha 13C quintet resonance, after conversion to a,a-dideuterio-para-substituted benzyl bromides and subsequently para-substituted-a,a-dideuteriobenzyl N-acetoxybenzohydroxamates, this resonance proved difficult to detect at 300MHz.
4-bromobenzyl bromide
m.p. 61-62oC (lit.,257 63oC) dH (CDCl3) 4.44 (2H, s), 7.24 (2H, d), 7.46 (2H, d); dC (CDCl3) 32.36 (tt), 122.38 (st), 130.60 (dq), 131.68 (dd), 136.70 (s).
4-chlorobenzyl bromide
m.p. 28-30oC (lit.,257 28-30oC) dH (CDCl3) 4.45 (2H, s), 7.32 (4H, s); dC (CDCl3) 32.34 (t), 128.91 (d), 130.30 (d), 134.20 (s), 136.22 (s).
4-methylbenzyl bromide
m.p. 32-34oC (lit.,257 32-35oC) dH (CDCl3) 2.40 (3H, s), 4.52 (2H, s), 7.19 (2H, d), 7.32 (2H, d); dC (CDCl3) 21.13 (q), 33.67 (t), 128.88 (d), 129.39 (d), 134.77 (s), 138.24 (s).
4-tert-butylbenzyl bromide
dH (CDCl3) 1.3 (3H, s), 4.47 (2H, s), 7.29 (2H, d), 7.34 (2H, d); dC (CDCl3) 31.22 (q), 33.55 (t), 34.57 (s), 125.69 (d), 128.71 (d), 134.71 (s), 151.46 (s).
4-phenylbenzyl bromide
m.p. 101-102.5oC (lit.,257 99-101oC) dH (CDCl3) 4.72 (2H, s), 7.46 (5H, m), 7.64 (4H, m).
4-phenoxybenzyl bromide
dH (CDCl3) 4.49 (2H, s), 6.93 (2H, d), 7.00 (2H, d), 7.12 (1H, t), 7.32 (4H, m); dC (CDCl3) 33.3 (t), 118.6 (d), 119.2 (d), 123.6 (d), 129.8 (d), 130.5 (d), 132.3 (s), 156.5 (s), 157.5 (s).
4-methoxybenzyl chloride
nd=1.5469 (lit.,257 nD=1.5482); nmax/cm-1 1612, 1515 1249; dH (CDCl3) 3.77 (3H, s), 4.56 (2H, s), 6.86 (2H, d), 7.30 (2H, s); dC (CDCl3) 46.27 (t), 55.28 (q), 114.11 (d), 129.88 (s), 130.03 (d), 159.66 (s).
a,a-dideuterio-4-methylbenzyl alcohol
p-Toluic acid (3.0 g, 22.1 mmol) was reduced by refluxing with LiAlD4 (1.01 g, 15 mmol) in dry THF (20 ml) for 24 hours. Workup with D2O provided pure a,a-dideuterio-4-methylbenzyl alcohol (99%). dH (CDCl3) 2.27 (3H, s), 7.03 (2H, d), 7.10 (2H, d); dC (CDCl3) 20.92 (q) 63.82 (qt), 126.94(d), 128.58 (d), 136.88 (s), 137.68 (s);
a,a-dideuterio-4-methylbenzyl bromide
a,a-Dideuterio-4-methylbenzyl alcohol (0.85 g, 14.6 mmol) was refluxed in hydrobromic acid (10 ml) and sulfuric acid (2 ml) for 1 hour. Workup provided pure a,a-dideuterio-4-methylbenzyl bromide (2.82 g, 75%) which was identical to the protio species by 1H and 13C NMR spectroscopy. dH (CDCl3) 2.39 (3H, s), 7.17 (2H, d), 7.31 (2H, d); dC (CDCl3) 21.13 (q), 33.61 (qt), 128.84 (d), 129.42 (d), 134.74 (s), 138.19 (s).
a,a-dideuterio-4-methoxybenzyl alcohol
4-Methoxybenzoic (6 g, 39.4 mmol) acid was reduced by refluxing with LiAlD4 (0.63 g, 15 mmol) in dry ether (50 ml) for 24 hours. Workup with D2O provided pure a,a-dideuterio-4-methoxybenzyl alcohol (76%). dH (CDCl3) 3.77 (3H, s), 6.63 (2H, d), 7.22 (2H, d); dC (CDCl3) 55.24 (q), 63.87 (qt), 113.73 (d), 128.74 (d), 133.04 (s), 158.94 (s).
a,a-dideuterio-4-methoxybenzyl bromide
a,a-Dideuterio-4-methoxybenzyl alcohol (2.0 g, 14.6 mmol) was stirred in hydrobromic acid (6 ml) and sulfuric acid (0.5 ml) for 1 hour. Workup provided pure a,a-dideuterio-4-methoxybenzyl bromide (2.82 g, 95%). dH (CDCl3) 3.77 (3H, s), 6.91 (2H, d), 7.31 (2H, s); dC (CDCl3) 55.28 (q), 114.11 (d), 129.88 (s), 130.03 (d), 159.66 (s).
a,a-dideuterio-4-phenylbenzyl alcohol
Biphenyl-4-carboxylic acid(21.6 g, 108 mmol) was reduced by refluxing with LiAlD4 (10.0 g, 53.7 mmol) in dry ether (70 ml) for 30 hours. Workup with D2O provided pure a,a-dideuterio-4-phenylbenzyl alcohol (53%). dH (CDCl3) 7.41 (1H, t), 7.47 (4H, m), 7.64 (4H, d); dC (CDCl3) 64.4 (qt), 127.05 (d), 127.28 (d), 127.45 (d), 128.75 (d), 139.73 (s), 140.59 (s), 140.78 (s).
a,a-dideuterio-4-phenylbenzyl bromide
a,a-Dideuterio-4-phenylbenzyl alcohol (3.4 g, 12.8 mmol) was refluxed in hydrobromic acid (10 ml) and sulfuric acid (1 ml) for 3 hours. Workup provided pure a,a-dideuterio-4-phenylbenzyl bromide (72%). dH (CDCl3) 7.3 (1H, t), 7.4 (4H, m), 7.5 (4H, m); dC (CDCl3) 32.89 (qt), 127.08 (d), 127.34 (d), 127.49 (d), 128.61 (d), 129.28 (d), 136.55 (s), 140.49 (s), 141.06 (s).
a,a-dideuterio-4-nitrobenzyl alcohol
4-Nitrobenzoic acid (15 g, 90 mmol) was treated with PCl5 (18 g, 86 mmol) to give 4-nitrobenzoyl chloride in 85% yield. Reduction of the acyl chloride by NaBD4 in dioxane gave, upon workup, a,a-dideuterio-4-nitrobenzyl alcohol (2.67 g, 80%). dH (CDCl3) 7.30 (2H, d), 8.04 (2H, d); dC (CDCl3) 63.27 (qt), 123.48 (d), 126.87 (d), 146.98 (s), 148.45 (s);
a,a-dideuterio-4-nitrobenzyl bromide
a,a-Dideuterio-4-nitrobenzyl alcohol (2.67 g, 17.3 mmol) was refluxed in hydrobromic acid (10 ml) and sulfuric acid (1 ml) for 12 hours. Workup provided pure a,a-dideuterio-4-nitrobenzyl bromide (0.4 g, 11%). dH (CDCl3) 7.41 (2H, d), 8.06 (2H, d); dC (CDCl3) 30.71 (qt), 123.85 (d), 129.80 (d), 144.59 (s), 147.47 (s).
The general synthesis of hydroxamic ester from potassium hydroxamate and the appropriate benzyl bromide has been described.
benzyl benzohydroxamate 149a
Potassium benzohydroxamate (10.2 g, 58.5 mmol), benzyl bromide (10.0 g, 58.5 mmol) and sodium carbonate (7.8 g, 73 mmol) were stirred overnight in 50% aq. MeOH (160 ml) and refluxed for 2 hours. Removal of MeOH in vacuo and acidification followed by extraction with DCM provided the crude hydroxamate. Pure benzyl benzohydroxamate (13.6 g, 93%) was obtained as colourless crystals upon recrystallisation (CHCl3/Hex.), m.p. 100-102oC (Found: C, 73.70; H, 5.98; N, 6.16. C14H13NO2 requires C, 73.99; H, 5.77; N, 6.16%); nmax (CHCl3)/cm-1 3250 (NH), 1678 (CO); dH (CDCl3) 4.98 (2H, s), 7.31 (5H, m), 7.37 (2H, t), 7.43 (1H, t, J 7.4, p-Ar), 7.67 (2H, d, J 7.1, o-Ar), 9.55 (1H, br); dC (CDCl3) 78.02 (t), 127.08 (dt, p' -Ar), 128.28 (d), 128.33 (d), 128.40 (d), 129.03 (d), 131.69 (dt), 131.70 (st, i -Ar), 135.13 (s, i' -Ar), 166.26 (s). m/z 227 (M+, 40%), 210(45), 105(45), 91(100), 77(30), 51(15), 28(20).
4-bromobenzyl benzohydroxamate 149g
Refluxing potassium benzohydroxamate (6.68 g, 38.2 mmol), 4-bromobenzyl bromide (9.68 g, 38.7 mmol) and sodium carbonate (4.9 g, 46 mmol) in 50% aq. MeOH (150 ml) gave the title compound (4.69 g, 40%) after workup and recrystallisation (CHCl3/Hex.), m.p. 172-173oC (Found: C, 54.71; H, 3.87; N, 4.38; Br, 26.09. C14H12NO2Br requires C, 54.92; H, 3.95; N, 4.57; Br, 26.10%); nmax (CHCl3)/cm-1 1680; dH (CDCl3) 4.99 (2H, s), 7.32 (2H, d, J 8.4, m'-Ar), 7.41 (2H, t, J 6.8, m-Ar), 7.54 (3H, m), 7.66 (2H, d, J 7, o-Ar), 8.57 (1H, br); 13C dC (CDCl3) 77.46 (t), 122.83 (st, i -Ar), 126.67 (dt), 128.63 (dd), 130.78 (dq), 131.59 (st), 131.68 (dd), 132.09 (dt, p-Ar), 134.13 (s, i' -Ar), 166.50 (s). m/z 307 (M+,20%), 290(60), 169(60), 105(70), 90(50), 77(100), 51(80).
4-chlorobenzyl benzohydroxamate 149h
Refluxing potassium benzohydroxamate (7.66 g, 44 mmol), 4-chlorobenzyl bromide (8.98 g, 44 mmol) and sodium carbonate (5.8 g, 55 mmol) in aq. MeOH (150 ml) gave the title compound (10.92 g, 95%) upon workup and recrystallisation (CHCl3/Hex.), m.p. 158-160oC (Found: C, 64.13; H, 4.69; N, 5.17; Cl,13.52. C14H12NO2Cl requires C, 64.25; H, 4.62; N, 5.35; Cl, 13.55%); nmax (CHCl3)/cm-1 3406 (NH), 1687 (CO); dH (CDCl3) 4.99 (2H, s), 7.36 (4H, s), 7.4 (2H, t, J 7, m-Ar), 7.5 (1H, t, J 7, p-Ar), 7.66 (2H, d, J 7, o-Ar), 8.62 (1H, br); dC (CDCl3) 77.55 (t), 127.01 (dt, m-Ar), 128.75 (dd), 128.83 (dd), 130.63 (dq, p' -Ar), 131.74 (s), 131.21 (dt, p-Ar), 133.75 (s), 134.76 (s), 166.68 (s). m/z 261 (M+, 20%), 244(45), 139(20), 125(100), 105(60), 77(50), 51(25).
4-nitrobenzyl benzohydroxamate 149i
Potassium benzohydroxamate (4.05 g, 23.1 mmol), 4-nitrobenzyl bromide (5.0 g, 23.1 mmol) and sodium carbonate (3.0 g, 28 mmol) provided the crude hydroxamate via the general procedure. Pure 4-nitrobenzyl benzohydroxamate (5.92 g, 94%) was obtained as pale yellow crystals upon recrystallisation (CHCl3/Hex.), m.p. 159-161oC (Found: C, 61.38; H, 4.28; N, 10.04. C14H12N2O4 requires C, 61.76; H, 4.44; N, 10.29%); nmax (CHCl3)/cm-1 3393 (NH), 1691 (CO); dH (CDCl3) 5.14 (2H, s), 7.42 (2H, t, J 7, m-Ar), 7.51 (1H, t, J 7, p-Ar), 7.62 (2H, d, J 7, o-Ar), 7.65 (2H, d, J 8.4, o'-Ar), 8.22 (2H, d, J 6.9, m'-Ar), 8.79 (1H, br); dC (CD3CN) 77.39 (t), 124.46 (dd), 128.04 (dt), 129.58 (d), 130.86 (d), 132.91 (dt), 133.18 (s), 144.62 (s), 148.99 (s), 166.59 (s); m/z 272 (M+, 5%), 136(12), 121(25), 105(100), 91(25), 77(45).
4-nitro-a,a-dideuteriobenzyl benzohydroxamate
Refluxing potassium benzohydroxamate (0.32 g, 1.8 mmol), 4-nitro-a,a-dideuteriobenzyl bromide (0.4 g, 1.84 mmol) and sodium carbonate (0.2 g) in MeOH/H2O (20ml:20ml) for 2 hours provided pure 4-nitro-a,a-dideuteriobenzyl benzohydroxamate (0.342 g, 65%) after workup and recrystallisation (CHCl3/Hex.). m.p. 159-161oC. dH (CDCl3) 7.41 (2H, t), 7.54 (1H,t), 7.65 (2H, d), 7.68 (2H, d), 8.22 (2H, d), 8.78 (1H, br); dC (CDCl3) 77.20 (qt), 123.79 (dd), 127.00 (d), 128.84 (d), 129.53 (d), 131.40 (st), 132.46 (dt), 142.45 (s), 148.08 (s), 167.02 (s); m/z 274(M+, 6%), 138(15), 105(100), 77(38), 51(15).
4-tert-butylbenzyl benzohydroxamate 149f
Potassium benzohydroxamate (5.0 g, 28 mmol), 4-tert-butylbenzyl bromide (3.23 g, 14.2 mmol) and sodium carbonate (2.0 g, 19 mmol) provided pure 4-tert-butylbenzyl benzohydroxamate (2.9 g, 72%) via the general procedure after workup and recrystallisation (DCM/Hex.), m.p. 89-93oC (Found: C, 76.34; H, 7.69; N, 4.77. C18H21NO2 requires C, 76.3; H, 7.47; N, 4.94 %); nmax (CHCl3)/cm-1 3400 (NH), 1685 (CO); dH (CDCl3) 1.32 (9H, s), 5.00 (2H, s), 7.38 (6H, m), 7.47 (1H, t, p-Ar), 7.66 (2H, d, J 7.1, o-Ar), 9.0 (1H, br); dC (CDCl3) 31.27 (q), 34.63 (s), 78.09 (t), 125.57 (dd), 126.92 (s), 127.04 (d), 128.63 (d), 128.70 (s), 129.17 (d), 131.95 (s), 151.90 (s); m/z 283(M+, 20%), 266(25), 147(100), 132(60), 117(45), 105(65), 91(50), 77(55).
4-phenylbenzyl benzohydroxamate 149d
Potassium benzohydroxamate (2.4 g, 13 mmol), 4-phenylbenzyl bromide (2.4 g, 13 mmol) and sodium carbonate (3.0 g, 28 mmol) provided pure 4-phenylbenzyl benzohydroxamate (0.62 g, 16%) after workup and recrystallisation (CHCl3/Hex.), m.p. 177-179oC, (Found: C, 79.07; H, 5.85; N, 4.35. C20H17NO2 requires C, 79.19; H, 5.65; N, 4.62%); nmax (CHCl3)/cm-1 3320 (NH), 1674 (CO); dH (CD3COCD3) 5.03 (2H, s), 7.22 (1H,t), 7.39 (4H, m), 7.42 (1H,t), 7.49 (2H, d), 7.58 (4H, d), 7.63 (2H, d), 9.62 (1H, br); dC (50% CDCl3/CD3CN) 126.05 (d), 126.20 (s), 126.66 (s), 127.68 (dd), 128.03 (d), 128.94 (s), 130.62 (s), 130.92 (dt), 164.91 (s); m/z 303(M+, 4%), 288(55), 286(50), 181(85), 167(100), 152(50), 121(40), 105(60), 77(60).
4-phenyl-a,a-dideuteriobenzyl benzohydroxamate
Potassium benzohydroxamate (1.0 g, 5.7 mmol), 4-phenyl-a,a-dideuteriobenzyl bromide (1.4 g, 5.6 mmol) and sodium carbonate (1.4 g) in refluxing dry THF provided pure 4-phenyl-a,a-dideuteriobenzyl benzohydroxamate (1.01 g, 59%) after workup and recrystallisation (CHCl3/Hex.). m.p. 177-179oC. dH (CDCl3) 7.38-7.53 (8H, m), 7.58 (4H, m), 7.67 (2H, d); dC (CDCl3) 126.12 (d), 126.34 (s), 126.67 (s), 127.68 (dd), 128.11 (d), 128.98 (s), 130.45 (s), 130.98 (dt), 164.91 (s); m/z 305(M+, 5), 288 (40), 183(20), 169(60), 152(32), 105(100), 77(60).
4-methylbenzyl benzohydroxamate 149e
Potassium benzohydroxamate (7.33 g, 42 mmol), 4-methylbenzyl bromide (7.74 g, 41.9 mmol) and sodium carbonate (5.55 g, 51.9 mmol) provided pure 4-methylbenzyl benzohydroxamate (5.92 g, 59%) via the general procedure after workup and recrystallisation (CHCl3/Hex.), m.p. 106-107oC (Found: C, 74.35; H, 6.27; N, 5.57. C15H15NO2 requires C, 74.67; H, 6.27; N, 5.80%); nmax (CHCl3)/cm-1 3200 (NH), 1681 (CO); dH (CDCl3) 2.33 (3H, s), 4.93 (2H, s), 7.11 (2H, d, J 7.8), 7.29 (2H, d, J 7.8), 7.34 (2H, t, J 7.6, m-Ar), 7.45 (1H, t, J 7.6, p-Ar), 7.68 (2H, d, J 7, o-Ar), 9.62 (1H, br); dC (CDCl3) 21.09 (q), 77.96 (t), 127.07 (dt), 128.40 (dd), 129.06 (d), 129.24 (d), 131.74 (dt, p-Ar), 131.85 (s), 132.14 (st), 138.33 (s, p'-Ar), 166.24 (s); m/z 241(M+, 5), 226 (80), 136(13), 121(25), 105(100), 77(70), 51(40).
4-methyl-a,a-dideuteriobenzyl benzohydroxamate
Potassium benzohydroxamate (0.60 g, 3.43 mmol), 4-methyl-a,a-dideuteriobenzyl bromide (0.64 g, 3.42 mmol) and sodium carbonate (1.1 g, 10.3 mmol) provided pure 4-methyl-a,a-dideuteriobenzyl benzohydroxamate (0.62 g, 75%) via the general procedure after workup and recrystallisation (CHCl3/Hex.). dH (CDCl3) 2.33 (3H, s), 7.11 (2H, d, J 7.4), 7.27 (2H, d, J 7.4), 7.34 (2H, t, J 7.3, m-Ar), 7.45 (1H, t, J 7.3, p-Ar), 7.69 (2H, d, J 7.3, o-Ar); dC (CDCl3) 21.11 (q), 127.07 (d), 128.42 (d), 129.08 (d), 129.30 (d), 131.65 (dt), 131.77 (s), 131.99 (s), 138.39 (s), 166 (s); m/z 227(M+-16, 18), 205(35), 121(15), 107(100), 105(38), 91(30), 77(42), 51(41).
4-phenoxybenzyl benzohydroxamate 149b
Potassium benzohydroxamate (5.0 g, 28 mmol), 4-phenoxybenzyl bromide (3.1 g, 12 mmol) and sodium carbonate (7.0 g, 65 mmol) provided pure 4-phenoxybenzyl benzohydroxamate (2.42 g, 65%) after workup and recrystallisation (CHCl3/Hex.), m.p. 186-189oC, (Found: C, 74.94; H, 5.44; N, 4.68. C20H17NO3 requires C, 75.22; H, 5.37; N, 4.39%) nmax (CHCl3)/cm-1 3390 (NH), 1690 (CO); dH (CDCl3) 5.00 (2H, s), 7.00 (4H, m), 7.13 (1H, t, J 6.8, p'''-Ar), 7.43 (6H, m), 7.43 (1H, t, J 7, p-Ar), 7.67 (2H, d, J 7, o-Ar), 8.7 (1H, br); dC (CDCl3) 77.01 (t), 116.59 (dd), 119.21 (d), 123.63 (dt, p'' -Ar), 126.66 (s), 126.98 (d), 128.69 (dd), 128.78 (s), 129.81 (dd), 131.07 (d), 131.74 (d), 132.04 (d), 156.68 (s), 157.95 (s); m/z 302(5), 197(40%), 183(100), 105(25), 77(40), 51(25).
4-methoxybenzyl benzohydroxamate 149c
Benzohydroxamic acid (1.4 g,10 mmol), 4-methoxybenzyl chloride (1.6 g, 10 mmol) and triethylamine (3.0 g, 30 mmol) were refluxed in CHCl3 (30 ml) for 2 hours. After washing with 10% aq. sodium carbonate and dilute HCl, the organic layer was dried and the solvent removed in vacuo affording the crude hydroxamate. Recrystallisation (EtOH/H2O) provided pure 4-methoxybenzyl benzohydroxamate (0.48 g, 19%), m.p. 119-121oC, (Found: C, 70.22; H, 6.04; N, 5.40. C15H15NO3 requires C, 70.02; H, 5.88; N, 5.44%); nmax (CHCl3)/cm-1 3407 (NH), 1684 (CO); dH (CDCl3) 3.75 (3H, s), 4.92 (2H, s), 6.62 (2H, d, J 9, m'-Ar), 7.31 (2H, d, J 9, o'-Ar), 7.34 (2H, t, J 7, m-Ar), 7.43 (1H, t, J 7, p-Ar), 7.68 (2H, d, J 7, o-Ar); dC (CDCl3) 55.15 (q), 77.78 (t), 113.80 (d, m'-Ar), 127.05 (d, o-Ar), 127.33 (s), 128.48 (d, m-Ar), 130.94 (d, o'-Ar), 131.79 (d, p-Ar), 159.83 (s); m/z 257 (M+, 55%), 135(40), 121(100), 105(50), 77(60), 51(50).
4-methoxy-a,a-dideuteriobenzyl benzohydroxamate
Benzohydroxamic acid (2.4 g, 14.7 mmol), 4-methoxy-a,a-dideuteriobenzyl chloride (2.03 g, 14.7 mmol) and triethylamine (3 g) were stirred at room temperature in ether (30 ml) for 20 hours. Workup and recrystallisation (EtOH/H2O) provided pure 4-methoxy-a,a-dideuteriobenzyl benzohydroxamate (0.50 g, 13%). m.p. 115-118oC dH (CDCl3) 3.79 (3H, s), 6.86 (2H, d), 7.33 (2H, d), 7.38 (2H, t), 7.54 (1H, t), 7.66 (2H, d); dC (CDCl3) 55.11 (q), 113.76 (d), 127.04 (d), 127.16 (s), 128.46 (d, m-Ar), 130.92 (d, o'-Ar), 131.19 (d), 131.86 (s, p-Ar), 159.81 (s, p'-Ar), 166.23 (s); m/z 259 (M+, 1%), 242(60), 123(100), 105(40), 77(53), 51(20).
N-Chlorination of alkyl benzohydroxamates was achieved in quantitative yields by stirring with a 3M excess of tert-butyl hypochlorite in DCM or CHCl3 at room temperature for 2-12 hours. The progress of N-chlorination was followed by 1H NMR through monitoring the formation of a slightly downfield resonance (Å d5.1) due of the methylene protons of the N-chloro species and slightly downfield of the corresponding protons in the parent hydroxamic ester. In the dideuterio compounds this probe was not available and N-chlorination of the hydroxamate was assumed to proceed in quantitative yields after 24 hours. 13C shifts in the N-chlorinated species were generally not significant enough to be used to monitor the progress of chlorination. N-chloro compounds were used directly in acetoxylation reactions without the need for further purification.
butyl N-chlorobenzohydroxamate 99a
dH (CDCl3) 0.87 (3H, t), 1.33 (2H, m), 1.56 (2H, m), 4.12 (2H, t), 7.44 (2H, t, m-Ar), 7.54 (1H, t, p-Ar), 7.77 (2H, d, o-Ar).
butyl N-chloro-4-bromobenzohydroxamate 99g
dH (CDCl3) 0.88 (3H, t), 1.31 (2H, sxt), 1.59 (2H, qt), 4.11 (2H, t), 7.57 (2H, d), 7.64 (2H, d).
butyl N-chloro-4-chlorobenzohydroxamate 99f
dH (CDCl3) 0.87 (3H, t), 1.31 (2H, sxt), 1.55 (2H, qt), 4.11 (2H, t), 7.39 (2H, d), 7.71 (2H, d).
butyl N-chloro-4-methylbenzohydroxamate 99d
dH (CDCl3) 0.88 (3H, t), 1.34 (2H, sxt), 1.58 (2H, qt), 2.39 (3H, s), 4.12 (2H, t), 7.21 (2H, d), 7.67 (2H, d).
butyl N-chloro-4-nitrobenzohydroxamate 99h
dH (CDCl3) 0.88 (3H, t), 1.31 (2H, sxt), 1.57 (2H, qt), 4.15 (2H, t), 7.92 (2H, d), 8.30 (2H, d).
butyl N-chloro-4-methoxybenzohydroxamate 99b
dH (CDCl3) 0.89 (3H, t), 1.31 (2H, sxt), 1.58 (2H, qt), 3.84 (3H, s), 4.12 (2H, t), 6.92 (2H, d), 7.78 (2H, d).
butyl N-chloro-4-tert-butylbenzohydroxamate 99e
dH (CDCl3) 0.87 (3H, t), 1.33 (9H, s), 1.34 (2H, sxt), 1.60 (2H, qt), 4.13 (2H, t), 7.44 (2H, d), 7.72 (2H, d).
butyl N-chloro-4-phenylbenzohydroxamate 99c
dH (CDCl3) 0.89 (3H, t), 1.34 (2H, sxt), 1.63 (2H, qt), 4.16 (2H, t), 7.40-7.47 (4H, m), 7.61-7.68 (3H, m), 7.87 (2H, d).
benzyl N-chlorobenzohydroxamate 149a
Benzyl benzohydroxamate (3.41 g, 15 mmol) and tert-butyl hypochlorite (4.87 g, 45 mmol) in DCM was stirred for 5 hours in the dark. Removal of solvent in vacuo provided the title compound which was used immediately without further purification. dH (CDCl3) 5.09 (2H, s), 7.26 (2H, m), 7.30 (3H, m), 7.40 (2H, t), 7.54 (1H, t), 7.68 (2H, d).
4-bromobenzyl N-chlorobenzohydroxamate 149g
dH (CDCl3) 5.03 (2H, s), 7.11 (2H, d), 7.41 (4H, m), 7.52 (1H, t), 7.68 (2H, d).
4-chlorobenzyl N-chlorobenzohydroxamate 149h
The title compound was obtained by the general chlorination procedure in CHCl3. dH (CDCl3) 5.04 (2H, s), 7.17 (2H, d), 7.26 (2H, d), 7.40 (2H, t), 7.54 (1H, t), 7.66 (2H, d).
4-nitrobenzyl N-chlorobenzohydroxamate 149i
dH (CDCl3) 5.21 (2H, s), 7.44 (4H, m), 7.54 (1H, t), 7.70 (2H, d), 8.18 (2H, d).
4-methylbenzyl N-chlorobenzohydroxamate 149e
dH (CDCl3) 2.35 (3H, s), 5.06 (2H, s), 7.15 (4H, s), 7.41 (2H, t), 7.54 (2H, t), 7.72 (2H, d).
4-tert-butylbenzyl N-chlorobenzohydroxamate 149f
The title compound was obtained by the general chlorination procedure in 50% DCM/CHCl3. dH (CDCl3) 1.30 (3H, s), 5.05 (2H, s), 7.16 (2H, d), 7.32 (2H, d), 7.40 (2H, t), 7.53 (1H, t), 7.66 (2H, d).
4-phenylbenzyl N-chlorobenzohydroxamate 149d
The title compound was obtained by chlorination in 50% CH3CN/CH2Cl. dH (CDCl3) 2.35 (3H, s), 5.06 (2H, s), 7.15 (4H, s), 7.41 (2H, t), 7.54 (2H, t), 7.72 (2H, d).
4-phenoxybenzyl N-chlorobenzohydroxamate 149b
dH (CDCl3) 5.05 (2H, s), 6.92 (2H, d), 7.2-7.6, 7.69 (2H, d).
4-methoxybenzyl N-chlorobenzohydroxamate 149c
dH (CDCl3) 3.78 (3H, s), 5.01 (2H, s), 6.82 (2H, s), 7.17 (2H, t), 7.38 (2H, t), 7.53 (1H, d), 7.67 (1H, d).
Method 1
Acetoxylation of the N-chlorohydroxamic ester derivatives was achieved in ether by stirring with a 0.5 molar excess of silver acetate at room temperature in the dark. The progress of the reaction was monitored by HPLC. Reaction times varied from 3-36 hours. Where applicable, fair to excellent yields were obtained by this method. It was not successful with benzyl N-chlorohydroxamates bearing significantly electron-donating and electron-withdrawing para substituents. An alternative, more general method was developed in these cases.
Method 2
Para-substituted benzyl N-chlorobenzohydroxamates were stirred with 1.4 molar equivalents of anhydrous sodium acetate in dry acetone, at room temperature, for 12-72 hours in the dark. The reaction was monitored by 1H NMR. Filtration and concentration provided the N-acetoxy derivatives, frequently with quantitative conversion. Yields were obtained with sufficient purity or isolated by flash chromatography. In all cases, mutagens were characterised spectroscopically.
butyl N-acetoxybenzohydroxamate 100a
The title compound was prepared according method 1 in a yield of 82%. Purification was achieved by flash chromatography (75% DCM:25% Hex.). nmax (CHCl3)/cm-1 1732 (CO), 1795 (CO) dH (CDCl3) 0.89 (3H, t), 1.37 (2H, sxt), 1.62 (2H, qt), 2.09 (3H, s), 4.17 (2H, t), 7.41 (2H, t), 7.47 (1H, d, p-Ar), 7.75 (2H, t). dC (CDCl3) 13.45 (q), 18.42 (q), 18.72 (t), 29.79 (t), 75.06 (t), 128.03 (d), 128.73 (d), 131.57 (s), 132.49 (d), 167.84 (s), 173.91 (s).
butyl N-acetoxy-4-bromobenzohydroxamate 100g
The title compound was prepared according to method 1. Butyl N-chloro-4-bromobenzohydroxamate (2.1 g, 6.86 mmol) in dry ether was stirred in the dark at room temperature with silver acetate (1.11 g, 10.30 mmol) for 24 hours. Filtration and removal of solvent in vacuo provided the crude mutagen. Flash column chromatography (75% DCM: 25% Hex.) provided the title compound in a yield of 48%. nmax (CHCl3)/cm-1 1791 (CH3CO), 1731 (Ar-CO); dH (CDCl3) 0.90 (3H, t), 1.35 (2H, sxt), 1.63 (2H, qt), 2.12 (3H, s, OAc), 4.17 (2H, t), 7.58 (2H, d, J 8.7, m-Ar), 7.64 (2H, d); dC (CDCl3) 13.58 (q), 18.59 (q), 18.63 (t), 29.86 (t), 75.31 (t), 127.54 (s), 130.43 (d), 131.47 (d), 167.94 (s), 173.12 (s).
butyl N-acetoxy-4-chlorobenzohydroxamate 100f
The title compound was prepared according to method 2. Butyl N-chloro-4-chlorobenzohydroxamate (1.15 g, 5.06 mmol) in dry acetone was stirred at room temperature with sodium acetate (0.50 g, 7.08 mmol) for 30 hours in the dark. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (69%) as a viscous oil that solidified upon standing. nmax (CHCl3)/cm-1 1792 (CH3CO), 1728 (Ar-CO); dH (CDCl3) 0.89 (3H, t), 1.35 (2H, sxt), 1.63 (2H, qt), 2.12 (3H, s), 4.17 (2H, t), 7.39 (2H, d), 7.75 (2H, d, J 8.6, o-Ar); dC (CDCl3) 13.47 (q), 18.46 (q), 18.75 (t), 29.78 (t), 75.17 (t), 128.40 (d), 129.80 (s), 130.27 (d, o-Ar), 138.84 (s, p-Ar), 167.82 (s), 172.85 (s).
butyl N-acetoxy-4-methylbenzohydroxamate 100d
Butyl N-chloro-4-methylbenzohydroxamate (1.17 g, 4.28 mmol) in dry acetone (50 ml) was stirred at room temperature with sodium acetate (0.49 g, 6.00 mmol) in the dark for 42 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (76%) as a yellow oil. nmax (CHCl3)/cm-1 1790 (CH3CO), 1730 (Ar-CO); dH (CDCl3) 0.90 (3H, t), 1.35 (2H, sxt), 1.63 (2H, qt), 2.10 (3H, s), 2.39 (3H, s), 4.18 (2H, t), 7.21 (2H, d), 7.67 (2H, d, J 8.2, o-Ar); dC (CDCl3) 13.53 (q), 18.61 (q), 18.81 (t), 21.42 (q), 29.67 (t), 53.32 (t), 75.03 (t), 128.57 (s), 128.78 (d), 129.02 (d), 143.45 (s, p-Ar), 168.01 (s), 173.93 (s).
butyl N-acetoxy-4-nitrobenzohydroxamate 100h
Butyl N-chloro-4-nitrobenzohydroxamate (2.32 g, 7.56 mmol) was stirred with sodium acetate (1.26 g, 7.57 mmol) in dry acetone at room temperature for 40 hours. Filtration and removal of solvent in vacuo provided the crude product. Flash chromatography (75% DCM: 25% Hex.) provided the title compound (89%).nmax (CHCl3)/cm-1 1794 (CH3CO), 1729 (Ar-CO); dH (CDCl3) 0.90 (3H, t), 1.32 (2H, sxt), 1.62 (3H, qt), 2.13 (3H, s), 4.16 (2H, t), 7.91 (2H, d), 8.28 (2H, d); dC (CDCl3) 13.57 (q), 18.47 (q), 18.82 (t), 29.62 (t), 75.72 (t), 123.32 (d, m-Ar), 129.82 (d), 137.58 (s), 149.83 (s, p-Ar), 167.83 (s), 172.15 (s).
butyl N-acetoxy-4-methoxybenzohydroxamate 100b
The title compound was prepared according to method 1 in a yield of 68%. Butyl N-chloro-4-methoxybenzohydroxamate (1.61 g, 6.28 mmol) was stirred with silver acetate (1.57 g, 9.42 mmol) in the dark in dry ether at room temperature for 40 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification was achieved by flash chromatography (75% DCM: 25% Hex.). nmax (CHCl3)/cm-1 1790 (CH3CO), 1728 (Ar-CO); dH (CDCl3) 0.90 (3H, t), 1.36 (2H, sxt), 1.64 (2H, qt), 2.12 (3H, s), 3.84 (3H, s), 4.18 (2H, t), 6.90 (2H, d), 7.78 (2H, d, J 8.9, o-Ar); dC (CDCl3) 13.47 (q), 18.59 (q), 18.76 (t), 29.82 (t), 55.18 (q), 74.78 (t), 113.39 (d, m-Ar), 123.22 (s), 131.28 (d), 163.18 (s, p-Ar), 168.02 (s), 173.18 (s).
butyl N-acetoxy-4-tert-butylbenzohydroxamate 100e
The title compound was prepared according to method 2 in a yield of 58%. Butyl N-chloro-4-tert-benzohydroxamate (0.87 g, 3.05 mmol) was stirred with sodium acetate (0.35 g, 4.21 mmol) in the dark in dry acetone at room temperature for 25 hours. Filtration and removal of solvent in vacuo provided the crude product (58%). Purification was achieved by flash chromatography (15% EtOAc: 85% Hex.). nmax (CHCl3)/cm-1 1787 (CH3CO), 1721 (CO); dH (CDCl3) 0.90 (3H, t), 1.32 (9H, s), 1.33 (2H, sxt), 1.64 (2H, qt), 2.12 (3H, s), 4.19 (2H, t), 7.43 (2H, d), 7.73 (2H, d, J 8.9, o-Ar); dC (CDCl3) 13.57 (q), 18.72 (q), 18.85 (t), 29.93 (t), 30.92 (q), 34.96 (s), 75.11 (t), 116.03 (s), 125.12 (d), 128.54 (s), 128.97 (d), 156.45 (s, p-Ar), 168.08 (s), 173.70 (s).
butyl N-acetoxy-4-phenylbenzohydroxamate 100c
The title compound was prepared according to method 2 in a yield of 82%. Butyl N-chloro-4-phenylbenzohydroxamate (1.16 g, 3.83 mmol) was stirred with sodium acetate (0.44 g, 5.36 mmol) in the dark in dry acetone at room temperature for 35 hours. Filtration and removal of solvent in vacuo provided the crude product (82%). Purification was achieved by flash chromatography (5% EtOAc: 95% Hex.). nmax (CHCl3)/cm-1 1794 (CH3CO), 1721 (CO); dH (CDCl3) 0.91 (3H, t), 1.33 (2H, sxt), 1.64 (2H, qt), 2.14 (3H, s), 4.21 (2H, t), 7.39-7.47 (3H, m), 7.66 (4H, t), 7.86 (2H, d, J 8.9, o-Ar); dC (CDCl3) 13.71 (q), 18.83 (q), 18.97 (t), 30.03 (t), 30.89 (q), 75.36 (t), 126.66 (d), 127.21 (d), 128.25 (d), 128.94 (d), 129.67 (d), 130.24 (s), 139.71 (s), 145.53 (s), 166.24 (s), 173 (s).
benzyl N-acetoxybenzohydroxamate 151a
The title compound was prepared according to method 2. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided (87%) as a viscous oil. nmax (CHCl3)/cm-1 1798 (CH3CO), 1728 (CO); dH (CDCl3) 2.11 (3H, s), 5.19 (2H, s), 7.28-7.48 (7H, m), 7.54 (1H, t), 7.75 (2H, d); dC (CDCl3) 18.62 (q), 77.5 (t), 128.34 (d), 128.52 (d), 128.75 (d), 129.08(d), 129.22 (d), 131.65 (s), 132.84 (d), 134.75 (s), 168.08 (s), 174.12 (s).
4-bromobenzyl N-acetoxybenzohydroxamate 151g
The title compound was prepared according to method 2. 4-bromobenzyl N-chloro-benzohydroxamate (1.87 g, 5.49 mmol) was stirred with sodium acetate (0.63 g, 7.68 mmol) in the dark in dry acetone at room temperature for 22 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided the title compound (94%) as a yellow oil. (Yield via Method 1, 25%). nmax (CHCl3)/cm-1 1791 (CH3CO), 1731 (CO); dH (CDCl3) 2.05 (3H, s), 5.12 (2H, s), 7.23 (2H, d, J 8.3, m'-Ar), 7.40 (2H, t, J 7.1, m-Ar), 7.45 (2H, d, J 8.3, o'-Ar), 7.55 (1H, t, J 7.1, p-Ar), 7.69 (2H, d, J 7.1, o-Ar); dC (CDCl3) 18.56 (q), 76.54 (t), 122.66 (st, p' -Ar), 128.21 (dd, o-Ar), 128.82 (dt, m-Ar), 130.64 (dq, o'-Ar), 131.40 (st, i -Ar), 131.49 (dd, m'-Ar), 132.74 (d, p-Ar), 133.73 (s, i' -Ar), 168.02 (sq, Ac), 174.04 (s).
4-chlorobenzyl N-acetoxybenzohydroxamate 151h
The title compound was prepared according to method 2. 4-chlorobenzyl N-chloro-benzohydroxamate (2.89 g, 9.75 mmol) was stirred with sodium acetate (1.12 g, 13.65 mmol) in the dark in dry acetone at room temperature for 28 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided the title compound as a pale yellow oil (96%) which solidified upon standing. (Yield via Method 1, 45%). nmax (CHCl3)/cm-1 1793 (CH3CO), 1731 (CO); dH (CDCl3) 2.04 (3H, s), 5.14 (2H, s), 7.30 (4H, s), 7.39 (2H, t, J 7.6, m-Ar), 7.53 (1H, t, J 7.6, p-Ar), 7.69 (2H, d, J 7.6, o-Ar); dC (CDCl3) 18.58 (q), 76.54 (t), 128.22 (dd), 128.54 (dd), 128.85 (dt), 130.41 (d), 132.76 (dt), 133.25 (s), 134.48 (s), 168.02 (s), 174.08 (s).
4-nitrobenzyl N-acetoxybenzohydroxamate 151i
The title compound was prepared according to method 2.
4-nitrobenzyl N-chloro-benzohydroxamate (2.30 g, 7.57 mmol)
was stirred with sodium acetate (0.87 g, 10.61 mmol) in the dark in
dry acetone at room temperature for 19 hours. Filtration and removal
of solvent in vacuo provided the crude product. Purification
by flash chromatography (90% Hex.: 10% EtOAc) provided the crude
product (93%) as a yellow oil. (Yield via Method 1, 0%). nmax (CHCl3)/cm-1 1793 (CH3CO), 1740 (CO); dH (CDCl3) 2.04 (3H, s, OAc),
5.29 (2H, s), 7.40 (2H, t, J 8, m-Ar), 7.55 (3H, m),
7.69 (2H, d, J 6.8, m'-Ar), 8.18 (2H, d); dC (CDCl3) 18.66 (q), 75.98 (t), 123.60 (dd), 128.42 (d),
128.87 (d), 129.24 (d), 131.29 (st, i-Ar), 133.04 (dt,
p-Ar), 142.29 (s, i'-Ar), 147.90 (s, p'-Ar),
168.18 (s), 174.20 (s).
4-nitro-a,a-dideuteriobenzyl N-acetoxybenzohydroxamate 151m
Anhydrous sodium acetate (0.12 g, 1.4 mmol) was added in one portion to a stirred solution of 4-nitro-a,a-dideuteriobenzyl N-chlorobenzohydroxamate (0.306 g, 1 mmol) in dry acetone (20 ml). After stirring at room temperature for 24 hours, the mixture was filtered. Removal of solvent in vacuo and flash chromatography (90% Hex.: 10% EtOAc) provided the title compound as a yellow solid in 87% yield. nmax (CHCl3)/cm-1 1793 (CH3CO), 1732 (CO); dH (CDCl3) 2.04 (3H, s), 7.40 (2H, t), 7.54 (1H, t), 7.57 (2H, d), 7.69 (2H, d), 8.16 (2H, d); dC (CDCl3) 18.41 (q), 75.40 (qt), 123.35 (dd), 128.22 (d), 128.65 (d), 129.15 (d), 131.08 (st), 132.85 (dt), 142.04 (s), 147.66 (s), 168.01 (s), 173.98 (s).
4-methylbenzyl N-acetoxybenzohydroxamate 151e
The title compound was prepared according to method 2. 4-methylbenzyl N-chloro-benzohydroxamate (1.82 g, 6.61 mmol) was stirred with sodium acetate (0.76 g, 9.25 mmol) in the dark in dry acetone (35 ml) at room temperature for 19 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided the pure compound (60%) as a yellow oil. (Yield via Method 1, <5%). nmax (CHCl3)/cm-1 1791 (CH3CO), 1729 (CO); dH (CDCl3) 2.05 (3H, s, OAc), 2.33 (3H, s), 5.13 (2H, s), 7.13 (2H, d, J 7.8, m'-Ar), 7.25 (2H, d), 7.40 (2H, t), 7.51 (1H, t), 7.74 (2H, d, J 8, o-Ar); dC (CDCl3) 18.70 (q), 21.20 (q), 77.42 (t), 128.21 (dd), 129.05 (d), 129.12 (d), 129.25 (d), 131.59 (s), 131.65 (s), 132.68 (dt, p-Ar), 138.56 (s, p '-Ar), 168.10 (s), 174.14 (s).
4-methyl-a,a-dideuteriobenzyl N-acetoxybenzohydroxamate 151k
Anhydrous sodium acetate (0.17 g, 2.1 mmol) was added to 4-methyl-a,a-benzyl N -chlorobenzohydroxamate (0.41 g, 1.49 mmol) in dry acetone. Stirring at room temperature for 36 hours followed by filtration and removal of solvent in vacuo provided the crude mixture. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided the pure compound (48%) as a pale yellow oil. dH (CDCl3) 2.04 (3H, s), 2.34 (3H, s), 7.13 (2H, d), 7.3 (2H, d), 7.41 (2H, t), 7.52 (1H, t), 7.76 (2H, d); dC (CDCl3) 18.68 (q), 21.21 (q), 128.23 (d), 129.05 (d), 129.12 (d), 129.25 (d), 131.57 (s), 131.65 (s), 132.68 (d), 138.50 (s), 168.14 (s), 174.09 (s).
4-tert-butylbenzyl N-acetoxybenzohydroxamate 151f
The title compound was prepared according to method 2. Anhydrous sodium acetate (0.30 g, 3.7 mmol) was added to 4-tert-butylbenzyl N-chlorobenzohydroxamate (0.84 g, 2.64 mmol) in dry acetone. Stirring in the dark at room temperature for 48 hours followed by filtration and removal of solvents in vacuo provided the crude mixture. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided 4-tert-butylbenzyl N-acetoxybenzohydroxamate (26%) as a yellow oil. nmax (CHCl3)/cm-1 1790 (CH3CO), 1725 (CO); dH (CDCl3) 1.29 (9H, s), 2.02 (3H, s), 5.14 (2H, t), 7.26-7.40 (6H, m), 7.49 (1H, t, J 7, p-Ar), 7.73 (2H, d, J 7, o-Ar); dC (CDCl3) 18.49 (q), 31.11 (q), 34.44 (s), 77.17 (t), 125.25 (dd, m'-Ar), 128.09 (dd), 128.92 (d), 128.96 (d), 131.46 (s), 131.53 (s), 132.57 (dt, p-Ar), 151.62 (s, p' -Ar), 167.89 (s), 173.94 (s).
4-phenylbenzyl N-acetoxybenzohydroxamate 151d
The title compound was prepared according to method 2 as a yellow oil. Anhydrous sodium acetate (0.12 g, 0.94 mmol) was added to 4-phenylbenzyl N-chlorobenzohydroxamate (0.28 g, 0.82 mmol) in dry acetone. Stirring in the dark at room temperature for 42 hours followed by filtration and removal of solvents in vacuo provided the crude mixture. Purification by flash chromatography (90% Hex.: 10% EtOAc) provided (48%) as a viscous yellow oil. nmax (CHCl3)/cm-1 1791(CH3CO), 1729(CO); dH (CDCl3) 2.03 (3H, s), 5.20 (2H, s), 7.4 (7H, m), 7.51 (5H, m), 7.76 (2H, d); dC (CDCl3) 18.55 (q), 77.11 (t), 126.93 (dd), 127.04 (dd), 127.37 (dt), 128.16 (d), 128.67 (d), 128.91 (d), 129.54 (d), 131.49 (s), 132.66 (dq), 133.53 (s), 140.39 (s), 141.43 (s), 168.10 (s), 174.14 (s).
4-phenyl-a,a-dideuteriobenzyl N-acetoxybenzohydroxamate 151l
The title compound was prepared according to method 2 in acetonitrile (50 ml) and DCM (50 ml). Anhydrous sodium acetate (0.21 g, 2.59 mmol) was added to 4-phenyl-a,a-dideuteriobenzyl N-chlorobenzohydroxamate (0.63 g, 1.85 mmol) in dry acetone. Stirring in the dark at room temperature for 24 hours followed by filtration and removal of solvents in vacuo provided the crude mixture. Purification by flash chromatography (92% Hex.: 8% EtOAc) provided the title compound (60%) as a viscous oil. dH (CDCl3) 2.10 (3H, s), 7.39-7.6 (10H, m), 7.62 (2H, d), 7.81 (2H, d); dC (CDCl3) 18.43 (q), 126.84 (dd), 126.94 (dd), 127.29 (dt), 128.08 (d), 128.60 (d), 128.82 (d), 129.51 (d), 131.43 (s), 132.57 (dt), 133.37 (s), 140.28 (s), 141.34 (s), 167.91 (s), 173.96 (s).
4-phenoxybenzyl N-acetoxybenzohydroxamate 151b
The title compound was prepared according to method 2. 4-phenoxybenzyl N-chloro-benzohydroxamate (1.22 g, 3.45 mmol) was stirred with sodium acetate (0.40 g, 4.81 mmol) in the dark in dry acetone at room temperature for 19 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided (78%) as a very viscous oil. nmax (CHCl3)/cm-1 1795 (CH3CO), 1725 (CO); dH (CDCl3) 2.09 (3H, s), 5.14 (2H, s), 6.9 (4H, m), 7.1 (1H, t, J 7, p''-Ar), 7.2-7.4 (6H, m), 7.53 (1H, t, J 7, p-Ar), 7.71 (2H, d, J 7, o-Ar); dC (CDCl3) 18.75 (q), 54.94 (q), 76.95 (t), 118.61 (d, o'' -Ar), 120.27 (dd, m'-Ar), 128.28 (dd), 129.00 (d), 129.76 (dd), 131.09 (dq), 132.80 (d), 155.46 (st), 157.40 (s), 168.15 (s, Ac), 174.17 (s).
4-methoxybenzyl N-acetoxybenzohydroxamate 151c
The title compound was prepared according to method 2. 4-methoxybenzyl N-chloro-benzohydroxamate (1.90 g, 6.50 mmol) was stirred with sodium acetate (0.67 g, 9.1 mmol) in the dark in dry acetone at room temperature for 18 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (57%). nmax (CHCl3)/cm-1 1795 (CH3CO), 1725 (CO); dH (CDCl3) 2.03 (3H, s), 3.73 (3H, s), 5.09 (2H, s), 6.82 (2H, d, J 7, m'-Ar), 7.26 (2H, d, J 7, o'-Ar), 7.36 (2H, t, J 7, m-Ar), 7.48 (1H, t), 7.69 (2H, d); dC (CDCl3) 18.45 (q), 55.94 (q), 76.95 (t), 113.60 (d, m'-Ar), 126.47 (s, i' -Ar), 128.01 (dd, o-Ar), 128.78 (dt, m-Ar), 130.77 (dq, o'-Ar), 131.44 (st, p-Ar), 132.49 (dt), 159.77 (s, p' -Ar), 168.15 (s), 174.17 (s).
4-methoxy-a,a-dideuteriobenzyl N-acetoxybenzohydroxamate 151j
The title compound was prepared according to method 2. 4-methoxy-a-a-dideuteriobenzyl N-chloro-benzohydroxamate (0.38 g, 1.29 mmol) was stirred with sodium acetate (0.15 g, 1.82 mmol) in the dark in dry acetone at room temperature for 14 hours. Filtration and removal of solvent in vacuo provided the crude product. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (44%) as a pale yellow oil. dH (CDCl3) 2.06 (3H, s), 3.77 (3H, s), 6.83 (2H, d), 7.27 (2H, d), 7.38 (2H, t), 7.51 (1H, t), 7.69 (2H, d); dC (CDCl3) 18.64 (q), 55.13 (q), 77.2 (qt), 113.75 (d), 126.50 (s), 128.15 (dd), 128.94 (dt), 130.91 (dq), 131.58 (st), 132.62 (dt), 159.92 (s), 168.06 (s), 174.07 (s).
Sodium para-substituted benzoate compounds were prepared by treatment of the appropriate acid with aq. Na2CO3. Filtration from the solid and drying provided the sodium salt which was used without further purification.
benzyl N-benzoyloxybenzohydroxamate 172a
Sodium benzoate (0.91 g, 6.3 mmol) was stirred at room temperature with benzyl N-chlorobenzohydroxamate (1.18 g, 4.5 mmol) in acetone for 48 hours. Purification by flash chromatography (88% Hex.: 12% EtOAc) provided the title compound (60%). nmax (CHCl3)/cm-1 1758, 1731 (CO); dH (CDCl3) 5.26 (2H, s), 7.26-7.40 (9H, m), 7.46 (1H,t, J 8, p-Ar), 7.54 (1H, t, p''-Ar), 7.77 (2H, d, J 8, o-Ar), 7.91 (2H, d, J 8, o''-Ar); FACE="Symbol">dC (CDCl3) 77.44 (t), 127.07 (s), 128.18 (d), 128.35 (d), 128.49 (d), 128.54 (d), 128.97 (d), 129.11 (d), 129.85 (dt), 131.51 (s), 132.67 (dt), 133.92 (dt), 134.64 (s), 164.13 (s), 174.28 (s).
benzyl N-(4-chlorobenzoyloxy)benzohydroxamate 172d
The title compound was prepared according to method 2. Purification by flash chromatography (88% Hex.: 12% EtOAc) provided the title compound (83%). nmax (CDCl3)/cm-1 1759, 1734 (CO); dH (CDCl3) 5.26 (2H, s), 7.26 - 7.40 (9H, m), 7.47 (1H,t, J 8), 7.77 (2H, d, J 8), 7.82 (2H, d, J 8); dC (CDCl3) 77.62 (t), 125.51 (st), 128.16 (d), 128.32 (d), 128.54 (d), 128.80 (d), 128.94 (d), 129.08 (d), 131.15 (dd), 131.32 (s), 132.73 (dt), 134.52 (s), 140.32 (s), 163.25 (s), 174.2 (s).
benzyl N-(4-formylbenzoyloxy)benzohydroxamate 172e
The title compound was prepared according to method 2. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (50%). nmax (CDCl3)/cm-1 1761 (ester CO), 1735 (amide CO), 1707 (CHO); dH (CDCl3) 5.27 (2H, s), 7.26 (3H, m), 7.39 (4H, m), 7.49 (1H,t), 7.78 (2H, d, J 8), 7.89 (2H, d, J 8), 8.06 (2H, d, J 8), 10.06 (H, s); dC (CDCl3) 21.61 (q), 77.87 (t), 128.31 (d), 128.45 (d), 128.70 (d), 129.09 (d), 129.19 (d), 129.45 (d), 130.45 (dd), 131.26 (st), 132.10 (st), 132.97 (dt), 134.48 (s), 139.63 (s), 163.21 (s), 174.07 (s), 191.28 (d).
benzyl N-(4-trifluoromethylbenzoyloxy)benzohydroxamate 172f
The title compound was prepared according to method 2. Purification by flash chromatography (85% Hex.: 15% EtOAc) provided the title compound (78%). nmax (CDCl3)/cm-1 1765, 1734 (CO); dH (CDCl3) 5.27 (2H, s), 7.26 (3H, m), 7.39 (4H, m), 7.52 (1H, t), 7.66 (2H, d, J 8), 7.78 (2H, d, J 8), 8.02 (2H, d, J 8); dC (CDCl3) 77.91 (t), 125.52 (dq), 128.35 (d), 128.49 (d), 128.74 (d), 129.12 (d), 129.23 (d), 129.63 (d), 130.33 (dd), 130.59 (s), 131.32 (s), 133.0 (dt), 134.54 (s), 135.03 (s), 163.07 (s), 174.12 (s).
benzyl N-(4-methylbenzoyloxy)benzohydroxamate 172c
The title compound was prepared according to method 2. Purification by flash chromatography (88% Hex.: 12% EtOAc) provided the title compound (47%). nmax (CDCl3)/cm-1 1756, 1733 (CO); dH (CDCl3) 2.38 (3H, s), 5.26 (2H, s), 7.19 (2H, d), 7.2-7.4 (7H, m), 7.47 (1H, t, J 8), 7.77 (2H, d, J 8), 7.81 (2H, d, J 8); dC (CDCl3) 21.61 (q), 77.58 (t), 124.27 (st), 128.15 (d), 128.34 (d), 128.50 (d), 128.99 (d), 129.11 (d), 129.23 (d), 129.94 (d), 131.64 (dt), 132.59 (s), 134.75 (s), 144.94 (s), 164.21 (s), 174.36 (s).
benzyl N-(4-methoxybenzoyloxy)benzohydroxamate 172b
The title compound was prepared according to method 2. Purification by flash chromatography (84% Hex.: 16% EtOAc) provided the title compound (39%). nmax (CDCl3)/cm-1 1750 (ester CO), 1718 (amide CO); dH (CDCl3) 3.73 (3H, s), 5.26 (2H, s), 6.81 (2H, d), 7.25 - 7.47 (8H, m), 7.75 (2H, d, J 8), 7.86 (2H, d, J 8); dC (CDCl3) 55.18 (q), 77.31 (t), 113.73 (d), 118.92 (s), 128.01 (d), 128.20 (d), 128.36 (d), 128.80 (d), 128.98 (d), 131.55 (s), 131.94 (d), 132.43 (d), 134.69 (s), 163.70 (s), 164.04 (s), 174.25 (s).
benzyl N-(4-cyanobenzoyloxy)benzohydroxamate 172g
The title compound was prepared according to method 2. Purification by flash chromatography (86% Hex.: 14% EtOAc) provided the title compound (34%). nmax (CDCl3)/cm-1 2235, 2236 (CN), 1763 (ester CO), 1732 (amide CO); dH (CDCl3) 5.26 (2H, s), 7.25 - 7.44 (7H, m), 7.55 (1H,t, J 8), 7.73 (2H, d, J 8), 7.78 (2H, d, J 8), 8.00 (2H, d, J 8); dC (CDCl3) 78.05 (t), 117.29 (st), 117.62 (s), 128.42 (d), 128.54 (d), 128.92 (d), 129.18 (d), 129.26 (d), 129.56 (d), 130.39 (d), 131.21 (s), 132.30 (d), 133.15 (d), 134.46 (s), 162.70 (s), 174.04 (s).
benzyl N-(4-nitrobenzoyloxy)benzohydroxamate 172h
The title compound was prepared according to method 2. Purification by flash chromatography (88% Hex.: 12% EtOAc) provided the title compound (55%). nmax (CDCl3)/cm-1 1764, 1733 (CO); dH (CDCl3) 5.27 (2H, s), 7.27 - 7.43 (6H, m), 7.54 (1H,t, J 8), 7.79 (2H, d, J 8), 8.05 (2H, d, J 8), 8.21 (2H, d); dC (CDCl3) 78.02 (t), 123.55 (d), 128.32 (d), 128.43 (d), 128.71 (d), 129.08 (d), 129.18 (d), 130.98 (d), 131.07 (dd), 132.67 (s), 133.12 (dt), 134.39 (s), 150.84 (s), 162.37 (s), 173.93 (s).
Oxidation of benzohydroxamic acid in the presence of cyclopentadiene
Benzohydroxamic acid was generated by acidification and crystallisation of potassium benzohydroxamate (20 g) in glacial acetic acid.258 Recrystallisation from EtOAc provided the pure compound, m.p. 126-128C. Cyclopentadiene was prepared by distillation according to a standard literature procedure.179
3-benzoyl-2,3-oxazabicyclo[2.2.1]hept-5-ene 123
N-Bromosuccinimide (1.78 g, 10 mmol) was added over 10 minutes to a stirred solution of Benzohydroxamic acid (1.37 g, 10 mmol), pyridine (0.79 g, 10 mmol) and cyclopentadiene (3.5 ml) in DCM (50 ml). After the solution cleared, the organic layer was washed with water, sat. Na2CO3, water, dried (CaCl2) and then reduced in vacuo. Flash chromatography (CHCl3) and normal-phase preparatory chromatography (CHCl3), provided pure 3-benzoyl-2,3-oxazabicyclo[2.2.1]hept-5-ene (1.55 g, 77%) as a gummy oil. The structure was characterised by 1H, 13C, gated decoupled, 1J and cosy experiments at 323K. dH (DMSO-d6) 1.8 (1H, d), 2.05 (1H, dd), 5.32 (1H, s), 5.42 (1H, s), 6.42 (1H, d) 6.5 (1H, s) 7.39 (2H, t), 7.54 (1H, t), 7.72 (2H, d); dC (DMSO-d6) 47.75 (t), 63.99 (s), 83.91 (s), 127.83 (d, m), 128.09 (d, o), 131.03 (d, p), 132.94 (d), 134.15 (s), 135.01 (s), 171.02 (s). m/z 201 (M+, 4.2%), 122(58), 105(100), 77(90), 51(41).
Bicycloadduct adduct 123 from the acid-catalysed decomposition of butyl N-acetoxybenzohydroxamate 100a in H2O-CH3CN.
Butyl N-acetoxybenzohydroxamate (125 mg, 0.49 mmol) was stirred for 6 hours at 308K in an acidified solution (H2SO4; 170 mL; 0.5 mol/L) of freshly prepared cyclopentadiene (198 mg, 3 mmol) in acetonitrile (4.0 ml) and water (1.0 ml). The solvent was removed under reduced pressure and washed with Na2CO3 (10%) and water and extracted with DCM. 3-benzoyl-2,3-oxazabicyclo[2.2.1]hept-5-ene was separated by normal-phase preparative HPLC (1.4 mg, 1.4%). m/z 203 (M++2, ca. 0.0%), 201(M+, 4.5), 105(100), 77(45), 51(20).
Bicycloadduct adduct 123 from the acid-catalysed decomposition of butyl N-acetoxybenzohydroxamate 100a in H218O-CH3CN.
Butyl N-acetoxybenzohydroxamate (324.2 mg, 1.084 mmol) was stirred for 4 hours at 308K in an acidified solution (H2SO4; 70 mL; 0.4 mol/L) of freshly prepared cyclopentadiene (0.143 g, 2.17 mmol) in acetonitrile (3.5 ml) and water (0.92 ml; 10% 18O labelled). The solvent was removed under reduced pressure and washed with Na2CO3 (10%), water and extracted with DCM. The components were separated by normal-phase preparative HPLC to give 3-benzoyl-2,3-oxazabicyclo[2.2.1]hept-5-ene, incorporating 18O at the 2-position. m/z 203 (M+, 0.4%), 201 (2.7), 105(100), 77(75), 51(25).
Bicycloadduct adduct 123 from the acid-catalysed decomposition of 4-methoxybenzyl N-acetoxybenzohydroxamate 151c
4-Methoxybenzyl N-acetoxybenzohydroxamate 151c (210 mg, 0.817 mmol) was stirred for 6 hours at 308K in an acidified solution (H2SO4; 50 mL; 0.25 mol/L) of freshly prepared cyclopentadiene (0.054 g, 0.628 mmol) in acetonitrile (4 ml) and water (10% 18O labelled, 1 ml). Removal of solvent in vacuo, washing with Na2CO3 (10%), water and extraction with DCM, provided the crude reaction mixture that was separated by normal-phase preparative HPLC to give 3-benzoyl-2,3-oxazabicyclo[2.2.1]hept-5-ene. m/z 203 (M++2, ca. 0.0%), 201(M+, 5.2), 105(100), 77(30), 51(8); A second fraction was 18O enriched 4-methoxybenzyl alcohol. m/z 140 (M++2, 10.3%), 138 (M+, 100%), 137(71.8), 121(58), 109(64), 77(35), 51(10).
18O-labelled 4-methoxybenzyl alcohol via an alternative method.
4-methoxybenzyl bromide (0.5 g, 3.6 mmol) was stirred in approximately 25% aqueous acetonitrile (10% 18O water) for 64 hours. The solution was reduced in vacuo and re-diluted with DCM. Washing with 5% w/v sodium carbonate, water and removal of solvent in vacuo provided pure 4-methoxybenzyl alcohol. The 1H and 13C spectra were identical to authentic 4-methoxybenzyl alcohol. m/z 140 (M++2, 10.3%), 138 (M+, 85%), 137(84.3), 121(100), 109(58), 77(44), 51(15).
4-methoxybenzyl alcohol without 18O.
Reduction of 4-methoxybenzaldehyde with sodium borohydride in ethanol/water provided the title compound as a clear oil. m/z 140 (M++2, 0.7%), 138 (M+, 100%), 137(74.5), 121(93), 109(63), 77(40), 51(15).
The acid-catalysed solvolysis of the alkyl N-acyloxybenzohydroxamates were monitored in the variable temperature probe of the Bruker AC-300P NMR spectrometer (298-338K). 10-40 mg of substrate in CD3CN (400 mL) was diluted with D2O such that after addition of an appropriate volume (2-15 µL) of a solution of sulfuric acid in D2O (typically 0.5-1.5 mol/L), the ratio of CD3CN:D2O was constant at 3.81:1. The acid solution was agitated into the mixture to initiate reaction immediately prior to insertion in the probe.
1H NMR spectra were acquired automatically at pre-programmed intervals and the peak areas for the acetoxy methyl singlet were obtained by integration. Automatically acquired spectra files could not be automatically processed due to software limitations in normalising integration signals between spectra, subsequently all spectra were manually integrated to ensure normalisation of the integrals with reference to the first spectrum.
Arrhenius studies were carried out at appropriate acid concentrations to enable data collection at each temperature. A minimum of five temperatures between 298K and 338K were used for each substrate.
An aliquot of sodium hydroxide solution (200 mL; 0.9M) was added to a 25% aq. acetonitrile solution (50 ml) of alkyl N-acyloxybenzohydroxamate (typically 0.00400 mmol), stirred at 275.4K. The progress of the reaction was monitored by reverse-phase analytical HPLC analysis, with the major product being the alkyl benzoate ester. Where appropriate, naphthalene was used as the internal reference.
Acid-catalysed solvolysis of 100f and 151a
A solution of butyl N-acetoxy-4-chlorobenzohydroxamate 100f (0.01282 mmol) and benzyl N-acetoxybenzohydroxamate 151a (0.01172 mmol) in 25% aq. acetonitrile (50.00 ml) was equilibrated for 1 hour at 298K. Dilute aq. H2SO4 (1.31 ml; 2.55 mol/L) was added and the reaction was stirred for 15 hours. Analytical HPLC analysis of the complex reaction mixture revealed the presence of benzyl benzoate (54%), butyl 4-chlorobenzoate (33%) and the complete lack of the crossover esters, benzyl 4-chlorobenzoate and butyl benzoate.
Base hydrolysis of 100f and 151a
A solution of butyl N-acetoxy-4-chlorobenzohydroxamate (0.013 mmol) and benzyl N-acetoxybenzohydroxamate (0.01174 mmol) in 25% aq. acetonitrile (50.00 ml) was equilibrated for 1 hour at 298K. Dilute aq. NaOH (170 mL; 0.90 M) was added and the reaction was complete within 60 seconds. Analytical HPLC analysis of the reaction mixture revealed the presence of benzyl benzoate (43.3%), butyl 4-chlorobenzoate (46.3%) and the complete lack of the crossover esters, benzyl 4-chlorobenzoate and butyl benzoate.
Lead tetraacetate (LTA)
The compound was synthesised by a standard procedure from red lead and acetic acid.179 Lead oxide red (60 g) was added in 10 g portions, over 1 hour, to a vigorously stirred solution of glacial acetic acid (100 ml) and acetic anhydride (40 ml) at 55-60o C. The solution was cooled and filtered. Recrystallisation of the crude crystals from a solution of glacial acetic acid (95%), acetic anhydride (5%) and charcoal provided pure LTA as colourless crystals which were stored in the dark under acetic acid.
N-4-chlorobenzoyl-N-butoxy-N'-benzoyl-N'-benzyloxyhydrazine 143
The title compound was generated via a standard method.212
LTA (5.3 g, 12.0 mmol) in DCM (20 ml) was added in portions over 1 hour to a DCM solution of butyl 4-chlorobenzohydroxamate (1.7 g, 7.49 mmol) and benzyl benzohydroxamate (1.7 g, 7.49 mmol). Each aliquot added only after the preceding portion of lead acetate had been completely consumed. The solution was stirred at room temperature for a further 1.5 hours. Removal of solvent in vacuo (less then 30 oC) and TLC analysis revealed 3 major components. Separation by flash chromatography (8% EtOAc:92 Hex) provided the three possible dimers, N,N'-butoxy-N,N'-4-chlorobenzoyl hydrazine, N,N'-benzyl-N,N'-benzoyl hydrazine, and N-4-chlorobenzoyl-N-butoxy-N'-benzoyl-N'-benzyloxyhydrazine 143 (as the most polar component). All were unstable compounds but were satisfactorily characterised by 1H, 13C and gated-decoupled NMR spectra.
N-4-chlorobenzoyl-N-butoxy-N'-benzoyl-N'-benzyloxyhydrazine: dH (CDCl3) 0.83 (3H, t), 1.24 (2H, p), 1.51 (2H, p), 4.03 (1H, t), 4.11 (1H, t), 5.05 (1H, d), 5.11 (1H, d), 7.20 (2H, m), 7.25 (3H, m), 7.36 (4H, m) 7.46 (1H, t) 7.6 (4H, dd); dC (CDCl3) 13.62 (q), 18.89 (t), 29.99 (t), 76.01 (t), 78.38 (t), 128.04 (d), 128.31 (d), 128.34 (d), 128.43 (d), 128.66 (d), 129.41 (d), 129.99 (d), 130.63 (s), 131.88 (d), 132.23 (s), 134.30 (s), 138.17 (s), 168.74 (s), 169.68 (s).
N,N'-butoxy-N,N'-4-chlorobenzoyl hydrazine: dH (CDCl3) 0.85 (6H, t), 1.28 (4H, p), 1.51 (4H, p), 4.04 (2H, t) 4.11 (2H, t), 7.34 (4H, d), 7.60 (4H, d). dC (CDCl3) 13.64 (q), 18.93 (t), 30.02 (t), 76.05 (t), 128.40 (d), 129.96 (d), 130.62 (s), 138.25 (s), 168.67 (s).
Thermal decomposition of N-4-chlorobenzoyl-N-butoxy-N'-benzoyl N'-benzyloxyhydrazine 143
N-4-Chlorobenzoyl-N-butoxy-N'-benzoyl-N'-benzyloxyhydrazine (36.7 mg, 0.0811 mmol) was refluxed for 4 hours in dry CHCl3. HPLC analysis of the reaction mixed revealed 2 major components, butyl 4-chlorobenzoate (41%) and benzyl benzoate (57%) and the two crossover esters, benzyl 4-chlorobenzoate (9%) and butyl benzoate (6%) as minor components. The Arrhenius parameters were obtained by solvolysis of N-4-chlorobenzoyl-N-butoxy-N'-benzoyl-N'-benzyloxyhydrazine in CDCl3 over the temperature range 298-332K with the rate being monitored by HPLC or 1H NMR through integration of the resonance of the benzyloxy methylene singlet of the starting material.
butoxyamine
Butyl benzohydroxamate (6 g, 31 mmol) was refluxed in ethanol (50 ml) and concentrated HCl (5 ml) for 3 hours. Benzoic acid was removed by extraction with chloroform (twice) and the aqueous layer was washed with 10% aq. Na2CO3 solution and the crude product was extracted with chloroform. Purification of the low boiling clear liquid was achieved by removal of solvent under rotary evaporator pressures only, followed by flash chromatography (4% EtOAc:96% hexane then DCM). Yield 40%. dH (CDCl3) 0.92 (3H, t), 1.37 (2H, sxt), 1.54 (2H, qt), 3.65 (2H, t). dC (CDCl3) 13.65 (q), 18.95 (t), 30.26 (t), 75.56 (t).
N-butoxy-2,2,3,3-tetramethyl aziridine.
The compound was synthesised by a known procedure.234
LTA (5 g, 13.5 mmol) and excess 2,3-but-2-ene (2.5 g, 30 mmol) where stirred vigorously in DCM at -45o C for 1 hour. Butoxyamine (0.40 g, 4.5 mmol) was added in small portions over 30 minutes and the solution was stirred for a further one hour at -45oC and then one hour at room temperature. The solution was filtered, washed with 10% aq. Na2CO3, filtered and washed with water and dried. DCM was removed in vacuo under water pump pressures only. Flash chromatography (10% Ether:90% Hexane) provided the title compound that was identical by NMR spectroscopy to the literature data (34%). dH (CDCl3) 0.911 (3H, t), 1.15 (6H, s), 1.19 (6H, s), 1.33 (2H, sxt), 1.54 (2H, qt), 3.67 (2H, t).