products that were not commercially available were prepared by
bleach oxidation and further purification. All bleach oxidation
reactions were exposed to air. The NaOCl solution (1.3–1.8 M)
was stored in a refrigerator and titrated daily. Before use it was
adjusted to pH 9.5 with saturated NaHCO3. GC analysis was
performed on a Shimadzu equipped with an AOC autosampler
using a Varian CP Sil 5 CB column (50 m ¥ 0.53 mm ¥ 1.0
mm) or a Varian CP Wax 52 CB (50 m ¥ 0.53 mm ¥ 2.0 mm).
HPLC analysis was performed on Phenomenex Gemini C18
110 A column (150 ¥ 4.6 mm ¥ 5 mm) using UV detection at
254 nm. The mobile phase consisted of MeOH–H2O 8 : 92 v/v
with 0.1% TFA (4-nitrocinnamaldehyde) or MeOH–H2O 60/40
v/v with 0.1% TFA (N-Boc-L-phenylalaninal) at a flow rate of
1 mL min-1. 1H and 13C NMR spectra were recorded on a Bruker
Avance-400 at 400 MHz and compared with literature spectra
for product identification.
Me4Si) 1.41 (9 H, s, 3 Me), 2.35 (1 H, d, CH2), 2.84 (1 H, d,
CH2), 3.55 (1 H, m, CH2), 3.67 (1 H, m, CH2), 3.86 (1 H, bs,
OH), 4.74 (1 H, bs, CH), 7.18–7.35 (5 H, m, Ph), 9.65 (1 H, bs,
NH).
N-Boc-L-phenylalaninal. Bleach oxidation of the alcohol 4
(1 g, 4 mmol) and work up gave the N-Boc-L-phenylalaninal as a
white solid. It was purified by column chromatography on silica
using heptane–ethyl acetate as eluent to give the aldehyde (0.8 g,
80%) as a yellowish oil; dH (400 MHz; CDCl3; Me4Si) 1.40 (9
H, s, 3 Me), 3.13 (2 H, dd, CH2), 4.44 (1 H, m, CH), 5.05 (1 H,
bs, NH), 7.17–7.35 (5 H, m, Ph) and 9.64 (1 H, s, CHO).
4-Methylcinnamyl alcohol 2b. 4-Methylcinnamyl alcohol 2b
was prepared following a literature procedure.26 The product was
purified by column chromatography on silica using heptane–
dichloromethane–methanol mixtures of increasing polarity as
eluent to give a white solid (14 g, 75%); dH (400 MHz; CDCl3;
Me4Si) 1.62 (1 H, bd, OH), 2.35 (3 H, s, Me), 4.32 (2 H, d, CH2),
6.33 (1 H, dt, CH), 6.60 (1 H, d, CH), 7.14 (2 H, d, Ph),
7.30 (2 H, d, Ph).
General bleach oxidation procedure
To a vigorously stirred and ice water-cooled biphasic mixture of
organic solvent-water containing 5.0 g (0.9 M) alcohol, 1 mol%
N-oxy catalyst, 10 mol% NaBr was added 1.05 equiv. NaOCl
buffered to pH 9.5 with sodium bicarbonate over a period of
60–90 min. After all the bleach had been added, the reaction
mixture was stirred for 2 more hours at 0 ◦C. The layers
were separated and the aqueous layer extracted twice with one
volume of the solvent. The organic layers were collected and
dried over anhydrous sodium sulfate. After filtration, the solvent
was evaporated at reduced pressure and the crude product was
analysed by GC or HPLC (4-nitrophenylcinnamyl alcohol).
Reported conversions refer to the alcohol substrate and were
calculated from the remaining alcohol amount in the crude
product using external standard analysis. Reported aldehyde
yields refer to the crude product and were calculated using
external standard analysis. Reported selectivities refer to the
crude aldehyde product and are calculated as (mmol aldehyde) ¥
(mmol alcohol converted)-1 ¥ 100%.
4-Chlorocinnamyl alcohol 2c. 4-Chlorocinnamyl alcohol 2c
was prepared following a literature procedure.26 The product was
purified by column chromatography on silica using mixtures of
isooctane–dichloromethane as eluent to give the alcohol as a
white solid (19.8 g, 77%); dH (400 MHz; CDCl3; Me4Si) 1.65 (1
H, bs, OH), 4.34 (2 H, dd, CH2), 6.35 (1 H, dt, 15.9, CH), 6.59
(1 H, d, CH) and 7.10–7.35 (4 H, m, Ph).
4-Chlorocinnamaldehyde. Bleach oxidation of the alcohol
2c (1 g) and work up gave 4-chlorocinnamaldehyde as yellow
crystals (1 g, 90%); dH (400 MHz; CDCl3; Me4Si) 6.70 (1 H, dd,
CH), 7.40–7.50 (3 H, m, CH + Ph), 7.52 (2 H, d, Ph) and
9.72 (1 H, d, CHO).
Acknowledgements
We thank George Bandurek (Pfizer) for the statistical analysis.
JFC thanks Pfizer for financial support.
Preparation of aldehyde products and alcohol substrates
3-(Pyridine-3-yl)propanal. Bleach oxidation of the alcohol 3
(1 g, 7 mmol) and work up gave the aldehyde (0.7 g, 71%) as a
brown oil; dH(400 MHz; CDCl3; Me4Si) 2.82 (2 H, t, CH2), 2.96
(2 H, t, CH2), 7.22 (1 H, dd, CHO), 7.53 (1 H, d, Ph) and 8.46
(2 H, m, Ph).
Notes and references
1 R. C. Larok, Comprehensive organic transformations, John Wiley &
Sons, New York, 2nd edn, 1999.
2 R. A. Sheldon, in Green Chemistry in the pharmaceutical industry, ed.
P. J. Dunn, A. S. Wells and M. T. Williams, Wiley-VCH, Weinheim,
1st edn, 2010, pp. 1–20.
N-Boc-L-phenylalaninol 4. To a solution of 2-amino-3-
phenyl-1-propanol (10.0 g, 66 mmol) in 130 ml ethanol was
added Boc anhydride (17.5 g, 80 mmol). The mixture was stirred
at room temperature and after 50 min the reaction was com-
pleted (TLC, SiO2, ethanol, UV). The solvent was evaporated
to dryness under reduced pressure. The residue was dissolved
in 200 ml ethyl acetate, washed with diluted hydrochloric acid
(100 ml, 0.5 M), washed with brine (200 ml) and dried over
anhydrous magnesium sulfate. The product was concentrated to
dryness obtaining a white solid (20.6 g). This compound was
recrystallised from ethyl acetate obtaining white crystals that
contained 10% tert-butanol (1H-NMR). Percolation on silica
using dichloromethane as eluent and evaporation of the solvent
gave a pure white solid (11.1 g, 67%); dH (400 MHz; CDCl3;
3 A. E. J. de Nooy, A. C. Besemer and H. van Bekkum, Synthesis,
1996, 1153–1174.
4 G. Tojo and M. I. Ferna´ndez, in Oxidation of alcohols to aldehydes
and ketones, Springer, New York, 1st edn, 2006, ch. 5, pp. 241–253.
5 P. L. Anelli, C. Biffi, F. Montanari and S. Quici, J. Org. Chem., 1987,
52, 2559–2562.
6 P. L. Anelli, S. Banfi, F. Montanari and S. Quici, J. Org. Chem., 1989,
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7 A. Dijksman, I. W. C. E. Arends and R. A. Sheldon, Chem. Commun.,
2000, 271–272.
8 R. A. Sheldon, I. W. C. E. Arends, G.-J. Ten Brink and A. Dijksman,
Acc. Chem. Res., 2002, 35, 774–781.
9 R. Anthes, O. Bello, S. Benoit, C.-K. Chen, E. Corbett, R. M.
Corbett, A. J. Delmonte, S. Gringas, R. Livingstone, J. Sausker and
M. Soumeillant, Org. Process Res. Dev., 2008, 12, 168–177.
10 S. J. Haycock-Lewandowski, A. Wilder and J. Ahman, Org. Process
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