ChemSusChem
10.1002/cssc.201800684
FULL PAPER
the reaction pathway, identifying the mechanism of formation for
all the reaction by-products and intermediates.
Finally, we can assert that this is a new approach to the
synthesis of hydroxytyrosol, which could be an alternative to the
current industrial process.
Hydrogenation step. The reactions were generally carried out loading in
a stainless steel autoclave and under a nitrogen atmosphere 50 mg of 7,
6
.2 mg of Pd (10% w/w carbon supported), 14 mg of acetic acid, 10 mL
of water. The system was evacuated and flushed with hydrogen for three
times, then the temperature was set at 150 °C and the hydrogen
pressure kept at 6 bars for 7 h reaction. Thereafter, the crude reaction
mixture was cooled down and the autoclave carefully evacuated. Purity
(
A%) of 1 was assessed by HPLC in the following way: 60 µL of the
crude reaction mixture were withdrawn and taken up with water in a 2 mL
volumetric flask. HPLC analysis showed a purity grade of around 70%
Experimental Section
(
A/Atot %). Analytically pure samples of 1 were obtained by flash
General. Products were purified from the reaction mixture by flash
chromatography on silica gel eluting with hexane : ethyl acetate = 50 : 50.
chromatography (230–400 mesh) using as the eluent
a petroleum
1
2
H NMR (400 MHz, D O) δ (ppm): 2.75 (2H, dt, J=6.6, 1.2 Hz), 3.79 (2H,
ether/ethyl acetate mixture (vol. ratios from 8/2 to 7/3). Then, the
products were identified by means of ESI-MS and 1H and 13C NMR and,
whenever possible, by comparison with authentic commercial samples.
ESI-MS spectra (positive or negative) were recorded using a Waters
Micromass ZQ 4000, equipped with a capillary probe (3.54 kV), with a
cone voltage of 20 volts and direct injection (20 μL min−1). Unless
dt, J=6.6, 2.2 Hz), 6.75 (1H, dd, J=8.2, 2.0 Hz), 6.84 (1H, d, J=2.3 Hz),
6
1
13
.88 (1H, d, J=7.8 Hz). C NMR (100 MHz, D
2
O) δ (ppm): 37.79, 63.41,
17.00, 117.49, 122.03, 132.66, 142.97, 143.76, 144.59.
Synthesis of 5,5-dimethyl-1,3-dioxane-2-carbaldehyde (9). In a 100
mL Dean-Stark system, 10 g glyoxal solution (40% w/w in water), 6.8 g
2,2-dimethyl-1,3-propanediol, 0.244 g of p-toluenesulphonic acid were
dissolved in 35 mL of toluene and then the mixture was heated and
refluxed for 7 h (7.5 mL of water were collected, about the theoretical
1
13
otherwise stated, H and C NMR spectra were recorded in deuterated
chloroform at 25 °C on a Varian Inova 300, at 300 MHz and 75 MHz,
1
13
respectively. Chemical shifts (δ) for H and C are given in ppm. The
following abbreviations are used to indicate the multiplicity: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; bs,
broad signal. HPLC method: the instrument was equipped with Kinetex
3
amount calculated). After cooling the crude, 1.5 g of NaHCO were
added and the new mixture was left under magnetic agitation at room
temperature overnight. The day after, the crude was filtered over celite
and the solvent was removed by the use of a rotary evaporator and a
vacuum pump. Finally, the distillation of the filtered solution (using a
Vigreaux column under at about 80 °C at 30 mbar) allow to isolate 0.7 g
of DDC as a pale yellow liquid. H NMR (400 MHz, CDCl
1.17 (3H, s), 3.50 (2H, d, J=11.3 Hz), 3.71 (2H, d, J=11.3 Hz), 4.65 (1H,
3
s), 9.40 (1H, s). C NMR (100 MHz, CDCl ) δ (ppm): 21.51 (CH3), 22.50
(CH3), 30.36 (C), 76.84 (CH2), 76.87 (CH2), 98.44 (CH), 194.33 (CHO).
5
µm EVO C18 100A column, 100x4.6 mm, with UV detector set at λ=270
nm. In a general procedure, 60µL of the reaction mixture were sampled
and diluted with distilled water to obtain a final volume of 2 mL; then the
solution is filtered with a syringe equipped with a 0,45 µm PTFE filter and
injected for the HPLC analysis. The injection volume is 20 µL. After the
injection a 1,5 mL/min of A was eluted for 5 minutes, then the flow was
increased to 2 mL/min and the composition gradually changed to 100%
of B in 30 seconds, then 2 mL/min of 100% of B was maintained for 14
1
3
): 0.75 (3H, s),
13
2
minutes. Solvents: A: H O/Methanol vol. ratio of 98/2 +0.2% wt of formic
acid; B: H O/Methanol vol. ratio of 80/20 +0.2% wt of formic acid
2
Synthesis of 1-(3,4-dihydroxyphenyl)-2-hydroxyethan-1-one (11).
The reactions were carried out loading in a stainless steel autoclave 200
Materials.
dimethoxyacetaldehyde, 2,2-dimethyl-1,3-propanediol, glacial acetic acid,
2 and NaOH were purchased from Sigma-Aldrich and used as such,
Catechol,
glyoxylic
acid,
glyoxal
and
2,2-
2
mg of 7, 10 mL H O, under nitrogen atmosphere. The temperature was
set at 150°C for 1 h reaction. The crude was dried under vacuum and the
1
product was isolated from the mixture by flash chromatography using as
1
without further purifications.
the eluent a CHCl
MHz, D
J=2.3 Hz), 7.45 (1H, dd, J=8.2, 2.0 Hz). C NMR (100 MHz, CD
(
(
3
/CH
3
OH mixture with a 95/5 vol. ratio. H NMR (400
2
O) δ (ppm): 4.93 (2H, s), 6.97 (1H, d, J=8.6 Hz), 7.42 (1H, d,
13
3
OD) δ
ppm): 66.65 (CH2), 116.23 (CH), 116.86 (CH), 123.18 (CH), 128.57
CH), 147.53 (CH), 153.46 (CH), 199.45 (CH).
Catalysts. Pd, Pt, Rh, Ru catalysts were all supported over carbon: Pd
was 10% w/w, while Pt, Rh and Ru were 5% w/w. All catalysts were
purchased from Sigma-Aldrich.
Hydroxyalkylation step. 4-(1-hydroxy-2,2-dimethoxyethyl)benzene-1,2-
diol (7) The reactions were carried out in 5 mL closed cap vials. In a
standard procedure, 130 mg of catechol, 98 mg of DMA solution (60%
w/w in water), 23 mg of NaOH and 1.8 mL of water were added in the
vial; then the vial was closed and the temperature increased to the
desired one (e.g. 80°C). The reaction was carried out under autogenic
Acknowledgements
The Interuniversitary Consortium of Science and Technology of
Materials, INSTM, is gratefully acknowledged for co-financing
the PhD grant of PZ.
pressure. With the aim of isolating enough amount of
7 for the
subsequent studies, few reactions were performed at a bigger scale, in
this way 3 g of crude were collected, the solvent (water) was evaporated
in vacuum and the products were solubilized in methanol. The mandelic
Keywords: hydroxytyrosol, hydroxyalkylation, hydrogenation,
2,2-dimethoxy-acetaldehyde (DMA), catalysis
derivative
7 was isolated from this crude by means of flash
chromatography, using 50 g of silica in a 4.5 cm (inner diameter) column,
[
[
1]
a) C. Kröhnke, O. Schacker and M. Zäh, “Antioxidants”, in Ullmann’s
Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim, 2015; b) J. G. Fernández-Bolaños, Ó. López, J.
Fernández-Bolaños, G. Rodríguez-Gutiérrez, Curr. Org. Chem. 2008,
using an eluent gradient of petroleum ether/ethyl acetate mixture from
1
7
0/30 to 60/40 (vol. ratio) obtaining a brownish oil. H NMR (400 MHz,
2
D O) δ (ppm): 3.27 (3H, s), 3.49 (3H, s), 4.50 (1H, d, J=6.6 Hz), 4.54 (1H,
13
dd, J=8.2, 2.0 Hz), 6.83 (1H, d, J=8.2 Hz), 6.89 (1H, d, J= 2.0 Hz).
NMR (100 MHz, acetone-d6) δ (ppm): 55.92 (CH3), 56.34 (CH3), 73.70
CH), 107.59 (CH), 115.71 (CH), 116.74 (CH), 120.67 (CH), 132.41 (CH),
44.56 (CH), 144.66 (CH).
C
1
2, 442-463; c) M. I. Fernández-Mar, R. Mateos, M.C. García-Parrilla,
B. Puertas, E. Cantos-Villar, Food Chem. 2012, 130, 797–813;
(
1
2]
a) K. L. Tuck, P. J. Hayball, J. Nutr. Biochem. 2002, 13, 636-644; b) I.
Sedej, R. Milczarek, S.C. Wang, R. Sheng, R. de Jesus Avena-Bustillos,
This article is protected by copyright. All rights reserved.