LETTER
Oxidation of 2-Arylpropanols to 2-Arylpropionic Acids
2647
TEMPO,17 aerobic oxidation with TEMPO,18 or other ox-
idants in the synthesis of profens are under way.
Compound 2c
tR = 6.2 min (R), 8.0 min (S), Daicel AD, hexane–i-PrOH (90:10),
TFA 0.1%, 1 mL/min.
Compound 2d
General Procedure for the Oxidation of 2-Arylpropanols 1a–h
to 2-Arylpropionic Acids 2a–h
tR = 6.8 min (R), 8.0 min (S), Daicel AD, hexane–i-PrOH (90:10),
TFA 0.1%, 1 mL/min.
Method A
Solid KMnO4 (0.88 mmol, 139 mg) was added to a solution of (2S)-
phenyl-propanol 1a in acetone (2 mL) and H2SO4 3 N (2 mL) at 0 °C
under stirring. The solution was kept at 0 °C for 4 more hours and
at r.t. for 30 min. Conversion was followed by TLC. The reaction
was diluted by adding 5 mL of HCl (1 N) and solid Na2SO3 until the
discoloring of the solution. The aqueous phase was extracted twice
with EtOAc (2 × 10 mL), the organic phase was then extracted with
a 2% NaOH solution (2 × 10 mL). The collected aqueous phase was
acidified to pH 1 with HCl (2 N) and extracted twice with CH2Cl2
(2 × 10 mL). The final organic phase was dried over Na2SO4 and
concentrated in vacuum obtaining acid 2a in 36% yield.
Compound 2e
tR = 10.8 min (R), 11.8 min (S), Daicel AD, hexane–i-PrOH (90:10),
TFA 0.1%, 1 mL/min.
Compound 2f
tR = 12.9 min (R), 15.3 min (S), Daicel AD, hexane–i-PrOH (90:10),
TFA 0.1%, 1 mL/min.
Acknowledgment
We are grateful to MIUR, University of Bologna, and Fondazione
del Monte di Bologna e Ravenna for financial support. We would
like to thank Mrs. Marzia Di Lillo and Mr. Stefano Piscitelli for
technical assistance.
Method B
Representative Procedure for Entry 5, Table 1
In a round-bottom flask fitted with a water condenser the following
reagents were added: 2-phenylpropanol 1a (3.65 mmol, 0.5 mL),
Aliquat 138 (2%, 0.07 mmol, 29 mg), KHSO4 (2%, 0.07 mmol, 20
mg), Na2WO4·2 H2O (2%, 0.07 mmol, 24 mg), and H2O2 (2 mL,
30% soln). The solution was kept at 90 °C, and the reaction progress
was followed by GC. The solution was then cooled to r.t. and 10 mL
of a 10% Na2CO3 aq solution were added followed by extraction
with EtOAc (2 × 10 mL). After concentration in this organic phase
unreacted alcohol 1a and byproducts 3a and 4a could be isolated.
The aqueous phase were then acidified with diluted HCl until pH 2
and re-extracted with EtOAc (2 × 10 mL). After evaporation pure
acid 2a (150 mg, 27%) could be obtained.
References and Notes
(1) Ley, S. V.; Madfin, A. In Comprehensive Organic
Synthesis, Vol. 7; Trost, B. M.; Fleming, I.; Ley, S. V., Eds.;
Pergamon: Oxford, 1991, 251.
(2) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic
Chemistry; Springer: Berlin, 1984.
(3) (a) Arends, W. C. E.; Sheldon, R. A. In Modern Oxidation of
Alchols using Environmentally Benign Oxidants, In Modern
Oxidation Methods; Bäckvall, J.-E., Ed.; Wiley-VCH:
Weinheim, 2004, 83. (b) ten Brink, G. J.; Arends, I. W. C.
E.; Sheldon, R. A. Science 2000, 287, 1636.
Method C
(4) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977.
(5) For reviews of TEMPO-catalyzed alcohol oxidations, see:
(a) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H.
Synthesis 1996, 1153. (b) Adam, W.; Saha-Möller, C. R.;
Ganeshpur, P. A. Chem. Rev. 2001, 101, 3499. (c) Sheldon,
R. A.; Arends, I. W. C. E.; ten Brink, G.-J.; Dijksman, A.
Acc. Chem. Res. 2002, 35, 774. (d) Sheldon, R. A.; Arends,
I. W. C. E. Adv. Synth. Catal. 2004, 346, 1051. (e) Vogler,
T.; Studer, A. Synthesis 2008, 1979.
To a stirred solution of alcohol 1a–h (0.4 mmol) in MeCN (2 mL)
the following reagents were added: a solution of NaClO2 (0.8 mmol,
85 mg) in H2O (0.4 mL), TEMPO (0.008 mmol), 0.67 M phosphate
buffer pH 6.7 (1.5 mL), and a solution of commercial household
bleach (5.25% in NaClO, 10.6 mL) in H2O (0.2 mL). The tempera-
ture was maintained at the values reported in Table 2 with a silicon
oil bath. The conversion was monitored by TLC and further por-
tions of TEMPO/NaClO/NaClO2 (0.008:0.4:0.008 mmol ratios)
were eventually added as reported in the Tables. When the reaction
was complete (TLC monitoring) it was quenched at 0 °C by adding
H2O (3 mL), aq sat. solution of NaHCO3 till pH 8 and Na2SO3 (1.4
mmol, 183 mg). After a 30 min stirring, EtOAc (2 mL) was added,
and the solution was stirred for further 15 min. The organic layer
was separated and discharged. HCl (1 N) was then slowly added at
0 °C till pH 2 to the aq solution which was then extracted with
EtOAc (2 × 5 mL). The collected organic phases were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo to af-
ford 2-arylpropionic acids pure by HPLC or NMR analysis.
(6) (a) Giacomini, D.; Galletti, P.; Quintavalla, A.; Gucciardo,
G.; Paradisi, F. Chem. Commun. 2007, 4038.
(b) Giacomini, D.; Cainelli, G.; Galletti, P.; Gucciardo, G.;
Quintavalla, A. WO 2008074717, 2008. (c) Galletti, P.;
Emer, E.; Gucciardo, G.; Quintavalla, A.; Pori, M.;
Giacomini, D. Org. Biomol. Chem. 2010, 8, 4117.
(7) (a) Li, X.; List, B. Chem. Commun. 2007, 1739. (b) Cleij,
M.; Archelas, A.; Furstoss, R. J. Org. Chem. 1999, 64, 5029.
(8) Basak, A.; Nag, A.; Bhattacharya, G.; MandalS, ; Nag, S.
Tetrahedron: Asymmetry 2000, 11, 2403; and references
cited therein.
(9) Compounds 1b–g were obtained by BH3·SMe2 reduction
from commercially available racemic acids. Compound 1h
was easily obtained in a three steps synthesis starting from
ketoprofen (EtOH, BF3·OEt2 cat.; ethylene glycol, TsOH
cat. in toluene; LiAlH4 in THF).
Enantiomeric ratios of acids 2a–h were determined by HPLC anal-
ysis on chiral columns, configuration of the major isomer was estab-
lished by direct comparison with commercial products or by
comparing the optical rotation with reported data.
Compound 2a
tR = 5.5 min (R), 6.0 min (S), Daicel AD, hexane–i-PrOH (92:8),
TFA 0.1%, 1 mL/min.
(10) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44,
1275.
(11) RebeloS, L. H.; Simões, M. M. Q.; Neves, M. G. P. M. S.;
Cavaleiro, J. A. S. J. Mol. Catal. A: Chem. 2003, 201, 9.
(12) Baciocchi, E.; Belvedere, S.; Bietti, M. Tetrahedron Lett.
1998, 39, 4711.
Compound 2b
tR = 7.9 min (R), 8.9 min (S), Daicel OD, hexane–i-PrOH (98:2),
TFA 0.1%, 1 mL/min.
Synlett 2010, No. 17, 2644–2648 © Thieme Stuttgart · New York