2566 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
acid 2 in 85-100% yield. The products may be purified by silica
of compound 2j was determined by chiral HPLC after
reduction to the alcohol 1j (Experimental Section). For
Cbz-phenylalanine (2l), the optical purity was measured
by HPLC with a CROWNPAK CR(+) column after
removal of the Cbz-protecting group (H2/Pd in MeOH).
In conclusion, we have demonstrated the utility of the
new procedure for the oxidation of primary alcohols to
the carboxylic acids. This method is efficient and envi-
ronmentally benign using stoichiometric NaClO2, cata-
lytic TEMPO, and NaOCl. Compared with the previously
reported TEMPO/NaOCl/CH2Cl2 protocol,4c the chlorina-
tion problem is greatly reduced, thus offering signifi-
cantly improved yields and purity of the desired products.
No racemization or epimerization is observed for sub-
strates with labile chiral centers. Additionally, no chlo-
rinated solvent is required. However, this procedure is
not applicable to alkenic alcohols and substrates with
exceedingly electron-rich aromatic groups.
gel column chromatography or crystallization.
(S)-2-Met h yl-3-(2′-b r om o-5′-m et h oxyp h en yl)p r op ion ic
a cid (2j): colorless oil; [R]25D ) (+)19.4 (c 1.04, MTBE); 1H NMR
(CDCl3) δ 10.5-8.7 (br, 1H), 7.41 (d, J ) 8.8 Hz, 1H), 6.78 (d, J
) 3.0 Hz, 1H), 6.66 (dd, J ) 8.8, 3.0 Hz, 1H), 3.75 (s, 3H), 3.14
(dd, J ) 13.1, 6.7 Hz, 1H), 3.20-3.06 (m, 1H), 2.77 (dd, J ) 13.1,
7.4 Hz, 1H), 1.23 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ 182.3,
158.7, 139.3, 133.4, 116.9, 115.1, 113.9, 55.4, 39.4, 39.4, 16.7;
IR (thin film) 3500-2500, 1701 cm-1. Anal. Calcd for C11H13O3-
Br: C, 48.37; H, 4.80. Found: C, 48.33; H, 4.56. The enantio-
meric purity of 2j was determined by chiral HPLC after reducing
it to 1j with BH3‚THF. HPLC conditions: column CHIRALCEL
OD-H; hexane/i-PrOH (97/3, 1.00 mL/min); UV detection at 220
nm. Retention times: (R)-isomer, 23.6 min; (S)-isomer, 29.2 min.
Compound 1j: white solid; mp 59-60 °C; [R]25D ) (-)0.68 (c 1.03,
1
MTBE); H NMR (CDCl3) δ 7.40 (d, J ) 8.8 Hz, 1H), 6.75 (d, J
) 3.1 Hz, 1H), 6.63 (dd, J ) 8.8, 3.1 Hz, 1H), 3.76 (s, 3H), 3.59-
3.46 (m, 2H), 2.85 (dd, J ) 13.4, 6.5 Hz, 1H), 2.48 (dd, J ) 13.4,
8.1 Hz, 1H), 2.12-1.95 (m, 1H), 1.76 (s, 1H), 0.95 (d, J ) 6.8
Hz, 3H); 13C NMR (CDCl3) δ 158.6, 141.1, 133.2, 117.0, 113.2,
67.4, 55.4, 39.7, 36.3, 16.4; IR (KBr) 3431 cm-1. Anal. Calcd for
C11H15O2Br: C, 50.98; H, 5.83. Found: C, 51.02; H, 5.74.
Exp er im en ta l Section
(2R,3S,8aS)-2-P h en yl-8a-m eth yl-5-oxo-h exah ydr ooxazolo-
[3,2-a ]p yr id in e-3-ca r boxylic a cid (2k ): recrystallized from
Gen er a l Meth od s. All substrates and reagents were obtained
commercially and used without purification except 1j, which was
prepared in-house. Its synthesis will be disclosed in a future
publication. The products were identified by comparing their
NMR spectra with those of commercially available materials
except for 2j and 2k . The yield was determined by reverse phase
HPLC with Zorbax SB-Phenyl or YMC ODS-AM columns and
MeCN/0.1% H3PO4 as the mobile phase. 1H and 13C NMR spectra
were recorded at 250 and 62.5 MHz, respectively. Chemical shifts
are reported relative to the solvent (chloroform ) 7.26, 76.9 ppm
for 1H and 13C NMR, respectively).
Typ ica l P r oced u r e. A mixture of alcohol 1 (40 mmol),
TEMPO (436 mg, 2.8 mmol), MeCN (200 mL), and sodium
phosphate buffer (150 mL, 0.67 M, pH ) 6.7) is heated to 35 °C.
Then sodium chlorite (NaClO2, 9.14 g 80%, 80.0 mmol in 40 mL
water) and dilute bleach (1.06 mL 5.25% NaOCl diluted into 20
mL, 2.0 mol %) are added simultaneously over 2 h (Caution! Do
not mix bleach and NaClO2 before being added to the reaction
mixture10). The mixture is stirred at 35 °C until the reaction is
complete (<2 A% SM, 2-5 h), then cooled to room temperature.
Water (300 mL) is added, and the pH is adjusted to 8.0 with 2.0
N NaOH (∼48 mL). The reaction is quenched by pouring into
cold (0 °C) Na2SO3 solution (12.2 g in 200 mL water) maintained
at <20 °C. The pH of the aqueous layer should be 8.5-9.0. After
stirring for 0.5 h at room temperature, MTBE (methyl tert-butyl
ether) (200 mL) is added. The organic layer is separated and
discarded. More MTBE (300 mL) is added, and the aqueous layer
is acidified with 2.0 N HCl (∼100 mL) to pH ) 3-4. The organic
layer is separated, washed with water (2 × 100 mL) and brine
(150 mL), and then concentrated to give the crude carboxylic
ethyl acetate, white solid; mp 164-167 °C; [R]25 ) (-)1.75 (c
D
0.51, THF); 1H NMR (CDCl3) δ 9.0-8.0 (br, 1H), 7.47-7.30 (m,
5H), 5.71 (d, J ) 7.7 Hz, 1H), 4.43 (d, J ) 7.7 Hz, 1H), 2.70-
2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.17-1.80 (m, 3H), 1.58 (s, 3H);
13C NMR (CDCl3) δ 172.0, 169.5, 137.5, 128.7, 126.2, 94.7, 77.1,
64.3, 34.5, 29.9, 23.5, 17.3; IR (KBr) 3448 cm-1, 1709. Anal. Calcd
for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.31; H,
6.15; N, 4.98.
Cbz-P h en yla la n in e (2l): 85% yield, no racemization. The
enantiomeric purity of Cbz-phenylalanine (2l) was measured
by HPLC after removal of the Cbz-protecting group (H2/Pd in
MeOH). HPLC conditions: CROWNPAK CR(+) column; pH )
2.0 aqueous HClO4 mobile phase (0.80 mL/min); UV detection
at 220 nm. Retention times: D-phenylalanine, 9.3 min; l-
phenylalanine, 11.6 min.
2-Ch lor o-5-m eth oxyph en ylacetic acid (4): 1H NMR (CDCl3)
δ 7.28 (d, J ) 8.7 Hz, 1H), 6.84 (d, J ) 3.0 Hz, 1H), 6.78 (dd, J
) 8.7, 3.0 Hz, 1H), 3.78 (s, 5H); 13C NMR (CDCl3) δ 177.0, 158.2,
132.4, 130.0, 117.0, 114.4, 55.4, 39.0. Since the signals of the
methylene and the methoxy protons overlap in the 1H NMR run
in CDCl3, the NOE experiment was carried out in CD3CN. Upon
irradiation of the methylene proton, a significant NOE effect was
observed for the isolated aromatic proton.
Ack n ow led gm en t. We thank Robert Reamer for the
NOE experiments on compound 4.
J O982143Y