Preparation of Unsymmetrically Labeled Hydroperoxides
J . Org. Chem., Vol. 63, No. 16, 1998 5553
split into three peaks (at 162.397, 162.417, 162.429), while the
ether carbon at 86.97 ppm was a single peak (conditions of
analysis: 64 000 data points covered a sweep width of 7012.6
Hz) 10: Rf 0.38 (80:20 hexane:ethyl acetate); 1H NMR (300
MHz, CDCl3) δ 8.33 (d, J ) 8.7 Hz, 2H), 8.102 (d, J ) 8.7 Hz,
2H), 1.66 (m, 2H), 1.36 (s, 6H), 1.26 (br m, 10H), 0.85 (t, 3H);
13C NMR (75 MHz, CDCl3) δ 162.41, 150.61, 133.16, 130.36,
130.16, 123.90, 123.64, 86.97, 39.01, 31.80, 30.02, 29.21, 24.38,
24.33, 23.92, 22.68, 14.13; DIP/CIMS (CH4/NH3) m/z 341 (M
+ NH4+), 343 (M + NH4+).
2-Meth yl-2-n on yl h yd r op er oxid e, 6. 2-Methyl-2-nonyl-
p-nitroperbenzoate, 10 (64.4 mg, 199 µmol, 0.07 M), was added
to a 25 mL round-bottom flask with THF (2.5 mL), water (0.38
mL), and LiOH•H2O (25 mg, 594 µmol, 0.21 M). The reaction
was stirred at room temperature for 2 h. THF was removed
under vacuum, and ether (50 mL) was added to the residue.
The solution was washed with saturated sodium bicarbonate
(2 × 20 mL), and the organic layer was dried over magnesium
sulfate. 2-Methyl-2-nonyl hydroperoxide (18 mg, 103 µmol)
was isolated in 52% yield: 1H NMR (300 MHz, CDCl3) δ 7.24
(d, 1H), 1.50 (m, 2H), 1.26 (br s, 10H), 1.19 (s, 3H), 0.86 (t,
3H); 13C NMR (75 MHz, CDCl3) δ 82.96, 38.49, 31.83, 30.11,
29.27, 23.99, 23.79, 22.65, 14.09; GC/CIMS (CH4/NH3) (DIP)
m/z 192 (36, M + NH4+), 194 (100, M + NH4+).
added (881 mg, 5.88 mmol). Chlorotrimethylsilane (0.560 mL,
4.41 mmol) was added dropwise at room temperature with
stirring. The reaction mixture was brought to reflux for 5 h.
Workup involved cooling in an ice bath, the addition of MeOH,
and stirring for 30 min. The mixture was extracted with ether
(3 × 100 mL) and washed with saturated NaCl (2 × 200 mL).
The organic extracts were dried over Na2SO4 and concentrated
under reduced pressure to yield a dark red oil. This material
was purified by chromatography on silica gel (10% EtOAc/
hexane/0.1% Et3N) to give 329 mg (81%) of a pale yellow
solid: mp 70-72 °C; Rf 0.20 (20% EtOAc/hexane); IR (CDCl3)
1
3661, 3154, 2984, 1711, 1698, 1382, 911, 739 cm -1; H NMR
δ 8.42 (bs, 1H), 7.71 (d, 2H), 7.52 (t, 1H), 7.42 (t, 2H), 7.05 (d,
1H, J ) 16.2 Hz), 6.00 (d, 1H, J ) 16.2 Hz), 4.20 (q, 2H), 1.49
(s, 6H), 1.29 (t, 3H); 13C NMR δ 167.86, 166.30, 150.18, 132.08,
132.02, 128.67, 127.13, 125.76, 82.93, 60.71, 24.34, 14.17;
HRMS (calcd for C15H20NO4) 278.1392, found 278.1384.
4-Meth yl-4-[N-(ben zoyl)a m in ooxy]-2-p en ten ol. See the
synthesis of 29 for a representative procedure. This compound
was obtained as a white solid: Rf 0.10 (50% EtOAc/hexane);
mp 101 °C; IR (CDCl3) 3661, 3433, 3154, 2982, 1724, 1467,
1381, 898, 715 cm-1; 1H NMR δ 9.0 (bs, 1H), 7.74 (d, 2H), 7.42
(t, 1H), 7.39 (t, 2H), 5.93 (m, 2H), 4.15 (m, 2H), 1.47 (s, 6H);
13C NMR δ 167.31, 133.87, 132.09, 131.63, 130.51, 128.35,
127.16, 83.23, 62.22, 24.25. Anal. Calcd for C13H17NO3: C,
66.36; H, 7.28; N, 5.95. Found: C, 66.26; H, 7.26; N, 5.89.
1-ter t-Bu tyld ip h en ylsilyloxy-4-m eth yl-4-[N-(ben zoyl)-
a m in ooxy]-2-p en ten e, 18. This compound was obtained as
a colorless oil according to the procedure described for com-
Eth yl r-[N-(ter t-Bu toxycar bon yl)am in ooxy]isobu tyr ate,
13. This compound was prepared in 85% yield as described14
to give 13 as a colorless oil which was analytically pure and
used without further purification: 1H NMR δ 7.56 (bs, 1H),
4.29 (q, 2H), 1.56 (s, 6H), 1.55 (s, 9H), 1.38 (t, 3H); 13C NMR
δ 173.78, 156.78, 83.48, 81.46, 61.22, 28.11, 22.87, 14.08. Anal.
Calcd for C11H21NO5: C, 53.42; H, 8.56; N, 5.66. Found: C,
53.18; H, 8.45; N, 5.83.
1
pound 32: Rf 0.20 (20% EtOAc/hexane); H NMR δ 8.08 (bs,
1H), 7.76 (m, 6H), 7.48 (m, 9H), 5.94 (m, 2H), 4.37 (d, 2H),
1.53 (s, 6H), 1.17 (s, 9H); 13C NMR δ 165.90, 135.52, 135.45,
133.43, 132.87, 131.73, 130.66, 129.69, 128.56, 127.64, 127.03,
2-Met h yl-2-[N-(ter t-b u t oxyca r b on yl)a m in ooxy]p r o-
p a n ol, 14. This compound prepared by literature methods15
precipitated as a white fluffy solid (67%) which was analyti-
cally pure and used without further purification: mp 106-7
°C; IR (CDCl3) 3661, 3638, 3376, 2982, 1726, 1468, 1383, 908
83.25, 63.82, 26.79, 24.50, 19.17; HRMS (calcd for C29H35
SiNO3) 474.2464, found 474.2469.
-
Typ ica l Nitr osa tion w ith NOBF 4. Syn th esis of 20a ,b
a n d 21. Hydroxamate ester 17 (1.0 equiv, 100 mg, 0.358
mmol) was dissolved in CH2Cl2 (3.5 mL, 0.1 M), K2CO3 (10.0
equiv, 494 mg, 3.58 mmol) was added, and the reaction was
cooled to -40 °C. Solid NOBF4 (1.1 equiv, 46 mg, 0.393 mmol)
was added, and the reaction was stirred at -40 °C for 30 min
and then brought to 0 °C for 30 min. The reaction mixture
was kept below 0 °C and quickly filtered through a plug of
K2CO3 into a cooled flask containing 0.7 mL (0.5 M) of Nujol.
The CH2Cl2 was removed under high vacuum at 0 °C, and the
Nujol reaction solution was allowed to warm to room temper-
ature overnight. The evolution of N2 was visible.
The products were recovered by column chromatography on
silica gel. The entire Nujol solution was loaded onto the
column, and elution with hexanes (200 mL) was followed by
10% EtOAc/hexane. A single spot which was both UV active
and stained peroxide positive was concentrated to give 39 mg
(39%) of a mixture of 20a ,b and 21 (9:1 by 1H NMR). This
mixture was separated by HPLC (normal phase, 1.0% 2-pro-
panol/hexane). The diastereomeric epoxides 20a ,b eluted first
and were found to be inseparable: 1H NMR δ 8.13 (m, 2H),
7.62 (m, 1H), 7.48 (m, 2H), 5.11 (d, 1H, J ) 8.7 Hz), 5.02 (d,
1H, J ) 8.7 Hz), 4.33 (q, 2H), 3.28 (d, 1H, J ) 9.0 Hz), 3.25 (d,
1H, J ) 9.0 Hz), 1.60 (s, 3H), 1.54 (s, 3H), 1.43 (s, 6H), 1.29 (t,
3H); 13C NMR δ 167.64, 166.67, 165.16, 164.56, 132.95, 132.78,
129.34, 129.29, 127.84, 72.66, 70.90, 61.30, 61.22, 60.88, 60.25,
58.57, 58.10, 23.94, 23.54, 19.32, 18.11, 13.48, 13.40; GC/MS
(7.03 min MH+) 279, (7.15 min MH+) 279. The perester 21
eluted second: 1H NMR δ 7.94 (d, 2H), 7.62 (m, 1H), 7.47 (m,
2H), 7.12 (d, 1H, J ) 16.2 Hz), 6.09 (d, 1H, J ) 16.2 Hz), 4.23
(q, 2H), 1.57 (s, 6H), 1.32 (t, 3H).
1
cm-1; H NMR δ 6.87 (bs, 1H), 3.39 (s, 2H), 1.47 (s, 6H), 1.19
(s, 9H); 13C NMR δ 159.10, 83.27, 82.58, 65.45, 28.06, 21.29.
Anal. Calcd for C9H19NO4: C, 52.66; H, 9.33; N, 6.82.
Found: C, 52.65; H, 9.38; N, 6.80.
Typ ica l Oxid a tion a n d Wittig Olefin a tion P r oced u r e.
Eth yl 4-Meth yl-4-[N-(ter t-bu toxyca r bon yl)a m in ooxy]-2-
p en ten eoa te, 15. Alcohol 14 (1.14 g, 5.6 mmol), in 5.0 mL of
CH2Cl2, was added at room temperature to a mixture of
pyridinium dichromate (5.26 g, 14.0 mmol), molecular sieves,
and CH2Cl2 (28 mL). The reaction was stirred at room
temperature for 18 h. Filtration through Celite was followed
by washes with EtOAc. The combined organic layers were
concentrated under reduced pressure to yield the crude alde-
hyde, which was unstable to chromatography. It was carried
through to the Wittig olefination without purification.
A
solution of crude aldehyde and (carboethoxymethylene)tri-
phenylphosphorane (1.95 g, 5.6 mmol) in benzene (23 mL) was
brought to reflux for 12 h. Evaporation of the solvent was
followed by chromatography on silica gel (10% EtOAc/hexane/
0.1 Et3N) to give 933 mg of a faint yellow oil (61%): Rf 0.28
(20% EtOAc/hexane); 1H NMR δ 6.99 (d, 2H, J ) 15.9 Hz),
6.78 (bs, 1H), 5.92 (d, 2H, J ) 15.9 Hz), 4.20 (q, 2H), 1.47 (s,
9H), 1.39 (s, 6H), 1.29 (t, 3H); 13C NMR δ 166.15, 152.21,
150.76, 120.48, 81.38, 81.17, 60.24, 27.93, 27.85, 24.03, 13.97.
Anal. Calcd for C13H23NO5: C, 57.12; H, 8.48; N, 5.12.
Found: C, 56.99; H, 8.50; N, 5.19.
E t h yl 4-Met h yl-4-[N-(ter t-b u t oxyca r b on yl)-N-(b en z-
oyl)a m in ooxy]-2-p en ten eoa te, 16. This compond was ob-
tained as a yellow oil: Rf 0.35 (20% EtOAc/hexane); 1H NMR
δ 7.55-7.26 (m, 5H), 7.05 (d, 1H, J ) 16.2 Hz), 5.86 (d, 1H, J
) 16.2 Hz), 4.05 (q, 2H), 1.35 (bs, 6H), 1.14 (s, 9H), 1.12 (t,
3H); 13C NMR δ 171.82, 166.04, 152.38, 149.82, 135.54, 132.23,
130.55, 128.67, 128.30, 128.13, 121.34, 84.55, 84.44, 60.54,
27.43, 14.15. Anal. Calcd for C20H27NO6: C, 63.65; H, 7.21;
N, 3.71. Found: C, 63.47; H, 7.23; N, 3.76.
ter t-Bu t yl r-[N-(Ben zoyl)a m in ooxy]isob u t yr a t e, 25.
Benzohydroxamic acid (3.15 g, 22.9 mmol) and tert-butyl-2-
bromoisobutyrate (5.12 g, 22.9 mmol) were dissolved in DMF
(46 mL) at room temperature. Triethylamine (3.20 mL, 22.9
mmol) was added, and the reaction was brought to 60 °C and
stirrred for 28 h. The cooled reaction mixture was poured into
H2O (500 mL) and extracted with ether (3 × 150 mL). The
organic extracts were dried over Na2SO4 and concentrated
under reduced pressure to yield a mixture of oils and solids.
Eth yl 4-Meth yl-4-[N-(ben zoyl)am in ooxy]-2-pen ten eoate,
17. The Boc-protected hydroxamate 16 (557 mg, 1.47 mmol)
was dissolved in CH3CN (5.0 mL), and sodium iodide was