J.A. Dines, C.M. Marson / Tetrahedron 72 (2016) 8584e8592
8589
4.2.5. tert-Butyl 8-(hydroxyamino)-8-oxo-2-(phenylcarbamoyl)
octanoate (7)
(CH2CH2CH2COO), 26.5 (CHCH2CH2), 24.4 (CH2CH2COO), 14.1 (CH3);
m/z (EI, %) 321 (Mþ, 8), 277 (43), 232 (54), 179 (36), 135 (97), 93
(100). Anal. Calcd for C17H23NO5 C, 63.53; H, 7.21; N, 4.36. Found C,
63.08; H, 7.18; N, 3.92.
To a solution of 1-tert-butyl 8-ethyl 2-(phenylcarbamoyl)octa-
nedioate (6) (300 mg, 0.79 mmol) in tetrahydrofuran (8 mL) was
added 50% aqueous hydroxylamine (0.53 mL, 7.95 mmol) and 1 M
potassium hydroxide in methanol (2.37 mL, 2.37 mmol) dropwise.
The mixture was stirred at 20 ꢀC for 1 h then acidified with 2 M
hydrochloric acid. The solvent was evaporated to a volume of 5 mL
then water (20 mL) added. The aqueous mixture was extracted with
ethyl acetate (4 ꢁ 15 mL) and the combined yellow extracts dried
over Na2SO4. Evaporation of the solvent gave a yellow oil which was
purified by column chromatography (ethyl acetate) to give the
hydroxamic acid 7 (84 mg, 29%) as a yellow oil; Rf (1% methanol in
4.2.8. Ethyl 7-(hydroxymethyl)-8-oxo-8-(phenylamino)octanoate
(10)
To a stirred solution of 8-ethoxy-8-oxo-2-(phenylcarbamoyl)
octanoic acid (9) (300 mg, 0.94 mmol) in dry tetrahydrofuran
(3.0 mL) at 0 ꢀC was added triethylamine (114 mg, 1.13 mmol) and
ethyl chloroformate (152 mg, 1.40 mmol). The mixture was stirred
at 0 ꢀC for 30 min then filtered. The solid was washed with tetra-
hydrofuran (2 ꢁ 3 mL) and the combined filtrate was cooled to
10 ꢀC. Sodium borohydride (107 mg, 2.82 mmol) was added in one
portion, followed by dropwise addition of methanol (0.6 mL) over a
period of 1 h. After stirring for a further 30 min the reaction was
quenched by dropwise addition of 2 M hydrochloric acid, then
extracted with dichloromethane (2 ꢁ 10 mL). The combined
organic layers were dried (MgSO4), filtered and evaporated. The
residue was purified by column chromatography (3:2 ethyl
acetate:40e60 ꢀC petroleum ether) to give ester 10 (222 mg, 77%)
as a white crystalline solid, mp 132e134 ꢀC; IR nmax 2935, 2669,
ethyl acetate) 0.70; 1H NMR (CDCl3, 300 MHz)
d 9.02 (1H, s, NH),
7.52 (2H, d, J ¼ 7.7 Hz, 2,6-aryl), 7.26 (2H, dd, J ¼ 7.7, 7.5 Hz, 3,5-aryl),
7.06 (1H, t, J ¼ 7.5 Hz, 4-aryl), 3.27 (1H, t, J ¼ 7.0 Hz, CH), 2.13e2.03
(2H, m, CH2CONHOH), 1.95e1.83 (2H, m, CHCH2), 1.64e1.50 (2H, m,
CH2CH3CONHOH), 1.44 (9H, s, C(CH3)3), 1.40e1.25 (4H, m,
CHCH2CH2, CHCH2CH2CH2); 13C NMR (CDCl3, 75 MHz)
d 171.7
(COOC(CH3)3), 171.3 (CONHOH), 167.8 (CONHPh), 137.7 (1-aryl),
128.9 (3,5-aryl), 124.6 (4-aryl), 120.3 (2,6-aryl), 82.7 (C(CH3)3), 54.2
(CH), 32.5 (CH2CONHOH), 30.5 (CHCH2), 28.3 (CHCH2CH2CH2), 28.0
(C(CH3)3), 26.6 (CH2CH2CONHOH), 25.0 (CHCH2CH2); m/z (CI, %)
387 ((M þ Na)þ, 100), 365 (MHþ, 45), 328 (22), 309 (35). HRMS
calcd for C19H29N2O5 (M þ H)þ 365.2071. Found: 365.2079.
1684, 1408 cmꢂ1; 1H NMR (CDCl3, 300 MHz)
d 8.73 (1H, s, NH), 7.53
(2H, d, J ¼ 7.8 Hz, 2,6-aryl), 7.23 (2H, dd, J ¼ 7.8, 7.4 Hz, 3,5-aryl),
7.04 (1H, t, J ¼ 7.4 Hz, 4-aryl), 4.08 (2H, q, J ¼ 7.1 Hz, CH2CH3), 3.95
(1H, br s, OH), 3.73e3.53 (2H, m, CH2OH), 2.45 (1H, m, CH), 2.22
(2H, t, J ¼ 7.4 Hz, CH2COO), 1.56 (3H, CHCHH, CH2CH2COO),
1.40e1.18 (8H, m, CHCHH, CH2CH2CH2COO, CHCH2CH2, CH3); 13C
4.2.6. 8-(Hydroxyamino)-8-oxo-2-(phenylcarbamoyl)octanoic acid
(8)
To a solution of tert-butyl 8-(hydroxyamino)-8-oxo-2-(phenyl-
carbamoyl)octanoate (7) (170 mg, 0.47 mmol) in dichloromethane
(2 mL) was added trifluoroacetic acid (2 mL) and the mixture stir-
red for 30 min. Evaporation of the solvent gave a pale yellow solid
which was washed with cold diethyl ether then with dichloro-
methane to give the hydroxamic acid 8 (116 mg, 80%) as a white
solid, mp 150e152 ꢀC; Rf (5% methanol in ethyl acetate) 0.34; IR
nmax 2931, 2856, 1733, 1597, 1547 cmꢂ1; 1H NMR (CD3OD, 300 MHz)
NMR (CDCl3, 75 MHz) d 174.1 (COOEt), 174.1 (CONH), 138.1 (1-aryl),
128.8 (3,5-aryl), 124.2 (4-aryl), 120.2 (2,6-aryl), 63.5 (CH2OH), 60.4
(CH2CH3), 49.7 (CH), 34.2 (CH2COO), 29.0 (CH2CH2CH2COO), 28.7
(CHCH2), 26.9 (CHCH2CH2), 24.6 (CH2CH2COO), 14.2 (CH3); m/z (CI,
%) 308 (MHþ, 100), 262 (53), 197 (63), 169 (51). Anal. Calcd for
C17H25NO4 C, 66.43; H, 8.20; N, 4.56. Found C, 66.49; H, 8.34; N,
4.65.
d
7.55 (2H, d, J ¼ 7.6 Hz, 2,6-aryl), 7.30 (2H, dd, J ¼ 7.6, 7.3 Hz, 3,5-
4.2.9. N8-hydroxy-2-(hydroxymethyl)-N1-phenyloctanediamide
(11)
aryl), 7.09 (1H, t, J ¼ 7.3 Hz, 4-aryl), 3.44 (1H, t, J ¼ 7.1 Hz, CH), 2.07
(2H, t, J ¼ 6.8 Hz, CH2CONH), 2.02e1.86 (2H, m, CHCH2), 1.76e1.58
(2H, m, CH2CH2CONH), 1.53e1.30 (4H, m, CHCH2CH2,
To a stirred solution of ethyl 7-(hydroxymethyl)-8-oxo-8-(phe-
nylamino)octanoate (10) (600 mg, 1.95 mmol) in tetrahydrofuran
(20 mL) was added 50% aqueous hydroxylamine (0.64 mL,
9.76 mmol) and 1 M potassium hydroxide in methanol (3.9 mL,
3.9 mmol) and the resultant solution stirred for 1.5 h. Methanol was
evaporated from the yellow solution then 0.5 M hydrochloric acid
(10 mL) added. The hydroxamic acid 11 (70 mg, 12%) crystallised
from the aqueous solution as cream solid, mp 150e151 ꢀC; Rf (5%
methanol in ethyl acetate) 0.43; IR nmax 3398, 3291, 3185, 2920,
CHCH2CH2CH2); 13C NMR (CD3OD, 75 MHz)
d 173.4 (COOH), 173.0
(CONHPh), 170.4 (CONHOH), 139.6 (1-aryl), 129.9 (3,5-aryl), 125.5
(4-aryl), 121.4 (2,6-aryl), 54.4 (CH), 33.7 (CH2CONH), 30.2 (CHCH2),
29.9 (CHCH2CH2CH2), 28.1 (CH2CH2CONH), 26.3 (CHCH2CH2); m/z
(CI, %) 331 ((M þ Na)þ, 100), 309 (MHþ, 83). Anal. Calcd for
C
15H20N2O5 C, 58.43; H, 6.54; N, 9.09. Found C, 58.16; H, 6.51; N,
8.75.
1626 cmꢂ1; 1H NMR ((CD3)2SO, 300 MHz)
d 10.30 (1H, s, NH), 9.83
4.2.7. 8-Ethoxy-8-oxo-2-(phenylcarbamoyl)octanoic acid (9)
(1H, s, NHOH), 8.62 (1H, s, NH), 7.62 (2H, d, J ¼ 7.8 Hz, 2,6-aryl), 7.27
(2H, dd, J ¼ 7.8, 7.4 Hz, 3,5-aryl), 7.00 (1H, t, J ¼ 7.4 Hz, 4-aryl), 4.71
(1H, t, J ¼ 5.0 Hz, OH), 3.64e3.55 (1H, m, CHHOH), 3.45 (1H, td,
J ¼ 5.0, 10.2 Hz, CHHOH), 2.57e2.45 (1H, m, CH), 1.90 (2H, t,
J ¼ 7.3 Hz, CH2CONH), 1.54e1.35 (4H, m, CH2CH2CONH, CHCH2),
1.30e1.17 (4H, m, CHCH2CH2CH2, CHCH2CH2); 13C NMR ((CD3)2SO,
Trifluoroacetic acid (9 mL) was added to a solution of 1-tert-
butyl-8-ethyl-2-(phenylcarbamoyl)octanedioate (6) (1.33 g,
3.52 mmol) in dichloromethane (9 mL) and the solution stirred for
6 h. The solvent was evaporated and the residue washed with a 1:1
diethyl ether:40e60 ꢀC petroleum ether to give the acid 9 (0.91 g,
80%) as a white powder, mp 108e110 ꢀC; Rf (1:2 ethyl acetate:-
75 MHz)
d 173.0 (PhNHCO), 169.0 (CONHOH), 139.3 (1-aryl), 128.5
hexane) 0.67; IR nmax 3426, 3340, 2933, 1730, 1600 cmꢂ1
;
1H NMR
(3,5-aryl), 122.9 (4-aryl), 119.1 (2,6-aryl), 62.9 (CH2OH), 49.8 (CH),
32.2 (CH2CONH), 28.7 (CHCH2CH2CH2), 28.6 (CHCH2), 26.6
(CHCH2CH2), 25.0 (CH2CH2CONH); m/z (CI, %) ((M þ Na)þ, 100), 285
(17), 276 (15), 242,13 217.13 Anal. Calcd for C15H22N2O4 C, 61.21; H,
7.53; N, 9.52. Found: C, 60.71; H, 7.49; N, 9.39.
(CDCl3, 300 MHz) 10.17 (1H, br s, OH), 9.05 (1H, s, NH), 7.50 (2H, d,
d
J ¼ 7.8 Hz, 2,6-aryl), 7.30 (2H, dd, J ¼ 7.8, 7.3 Hz, 3,5-aryl), 7.14 (1H, t,
J ¼ 7.3 Hz, 4-aryl), 4.12 (2H, q, J ¼ 7.1 Hz, CH2CH3), 3.47 (1H, t,
J ¼ 6.2 Hz, CH), 2.29 (2H, t, J ¼ 7.3 Hz, CH2COO), 2.06e1.95 (2H, m,
CHCH2), 1.68e1.53 (2H, m, CH2CH2COO), 1.48e1.30 (4H, m,
CH2CH2CH2COO, CHCH2CH2), 1.24 (3H, t, J ¼ 7.1 Hz, CH3); 13C NMR
4.2.10. Ethyl 8-(2-(tert-butoxycarbonylamino)phenylamino)-8-
oxo-7-(phenylcarbamoyl)-octanoate (12)
(CDCl3, 75 MHz) d 175.1 (COOH), 174.6 (COOEt), 169.1 (CONH), 136.7
(1-aryl), 129.1 (3,5-aryl), 125.5 (4-aryl), 120.8 (2,6-aryl), 60.9
(CH2CH3), 52.2 (CH), 34.1 (CH2COO), 31.1 (CHCH2), 28.3
To a stirred solution of 8-ethoxy-8-oxo-2-(phenylcarbamoyl)
octanoic acid (9) (1.0 g, 3.11 mmol) in DMF (30 mL) was added tert-