Solid-Phase Reactive Chromatography (SPRC): A new methodology for wittig and horner-emmons reactions on a column under microwave irradiation

Article abstract of DOI:10.1002/ejoc.200901032

A new methodology named solid-phase reactive chromatography (SPRC), which combines reaction, separation, and purification into a single unit for the preparation of small samples, is described. This method was illustrated in the synthesis of some natural bioactive compounds, namely, methoxylated analogues of resveratrol, alkylresorcinols, and 5-aryl-2,4-pentadienoates, over a column of alumina-KF under microwave irradiation by using the Wittig and HornerEmmons reactions. This approach permitted the preparation of the target olefins with high purity and good to excellent yields in short reaction times.

Full text of DOI:10.1002/ejoc.200901032

FULL PAPER
DOI: 10.1002/ejoc.200901032
Solid-Phase Reactive Chromatography (SPRC): A New Methodology for
Wittig and Horner–Emmons Reactions on a Column under Microwave
Irradiation
Saada C. Dakdouki,[a] Didier Villemin,*[a] and Nathalie Bar[a]
Keywords: Wittig reactions / Solid-phase synthesis / Supported catalysis / Reactive chromatography / Microwave chemistry
A new methodology named solid-phase reactive chromatog-
raphy (SPRC), which combines reaction, separation, and pu-
rification into a single unit for the preparation of small sam-
ples, is described. This method was illustrated in the synthe-
aryl-2,4-pentadienoates, over a column of alumina-KF under
microwave irradiation by using the Wittig and Horner–
Emmons reactions. This approach permitted the preparation
of the target olefins with high purity and good to excellent
sis of some natural bioactive compounds, namely, meth- yields in short reaction times.
oxylated analogues of resveratrol, alkylresorcinols, and 5-
By this technique it is possible to prepare small samples
Introduction
of products by a series of reactions conducted in parallel
with solid-phase extraction (SPE) equipment. This method
provides flexible operating conditions and avoids long li-
quid–liquid extraction procedures. It is advantageous in the
parallel synthesis of small samples of related structures for
screening biologically active molecules or molecules having
defined physical properties.
The importance of chemical reactions using solid sup-
ports in organic synthesis has increased considerably, partly
because the solid support provides an easy and simulta-
neous method to separate reaction products and also be-
cause an excess amount of the solid phase can lead to total
consumption of starting materials. Recently, many cata-
lyzed reactions performed in columns have been de-
scribed;[1–4] such reactions include: (1) esterification reac-
tions catalyzed by acidic ion-exchange resins[5] or by immo-
bilized enzymes;[6] (2) etherification;[7] (3) (de)hydrogena- Results and Discussion
tion;[8–11] (4) ring-closing metathesis,[11] and (5) reactions in-
volving sugars.[12] Typical examples for the adsorbents used
are: zeolites, activated carbon, alumina, immobilized en-
zymes, ion-exchange resins,[13] immobilized palladium,[9,11]
and immobilized gold.[14]
The feasibility of SPRC for the synthesis of some natural
bioactive compounds, including (E)-stilbenes,[15] alkylresor-
cinols,[16] and 5-aryl-2,4-pentadienoates,[17] using the Wittig
and Horner–Emmons reactions was investigated. The reac-
tions were performed with use of the commercially available
polypropylene SPE column (Varian Bond Elut, 6 mL). The
column was packed with a strong base (alumina-KF),
which served as the reactive stationary phase to permit the
formation of the ylide or carbanion in the Wittig and
Horner–Emmons reactions. The reactants were introduced
into the column either without any solvent or with very
small volumes of solvent (0.2 mL). A layer of silica under
the reactive stationary phase allowed the purification of the
formed olefin (Figure 1). The polar side-products of the
Horner reaction (potassium phosphate) and the Wittig re-
action (triphenylphosphane oxide) were retained on the col-
umn. The progress of the reaction was monitored by TLC.
The automation of this method in parallel is envisaged.
Stilbene derivatives are an important class of naturally
occurring compounds exhibiting a wide variety of bio-
logical activities.[15] For instance, resveratrol is known for
We describe herein a new synthetic methodology named
solid-phase reactive chromatography (SPRC) that combines
both the reaction and separation into a single unit. In this
method, the substrates are adsorbed onto a reactive station-
ary phase that is already packed in a column. When the
reaction reaches completion, the products can be eluted by
using the appropriate solvent and passed over a second sta-
tionary phase (silica) located below the first, allowing the
direct and simultaneous purification of the reaction prod-
ucts.
[a] Laboratoire de Chimie Moléculaire et Thioorganique, UMR
CNRS 6507, INC3M, FR 3038, ENSICAEN & Université de
Caen,
14050 Caen, France
Fax: +33-2-31452877
E-mail: didier.villemin@ensicaen.fr
Eur. J. Org. Chem. 2010, 333–337
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
333

S. C. Dakdouki, D. Villemin, N. Bar
FULL PAPER
dehyde was only completely consumed after three days.
When the column was heated at 80 °C for 17 h, stilbene 3a
was produced in 70% yield. Gratifyingly, our attempt to
decrease the reaction time by using microwave irradiation
(T = 100 °C, P = 120 W) was successful. Thus, under these
conditions, the reaction was brought to completion in
5 min, furnishing the olefin in 85% yield.
These reaction conditions were applied to other aromatic
aldehydes as summarized in Table 1. All the olefins were
prepared with high purity and with good to excellent yields
(57–85%). Compounds 3a–f can be transformed into the
corresponding polyhydroxystilbenes by using BBr3 or
ISiMe3.[25]
Although yield of the reaction with aliphatic aldehydes
was not as good as that with aromatic aldehydes, this
method does provide a useful and easy synthetic route to
alkylresorcinols 6a and b (Scheme 1), in particular, the
methoxylated analogue of olivetol 6a.[26] The olefins were
prepared in 41–43% yield and then reduced with Pd/C in
methanol to generate the corresponding saturated com-
pounds (80–86%).
Figure 1. SPE column loaded with a layer of alumina-KF and a
layer of silica.
its anti-inflammatory,[18] antioxidative,[19] vasodilator,[20]
and anticancer chemopreventive properties.[21] In order to
access methoxylated analogues of resveratrol, we prepared
the phosphonate derivatives 2a and 2b. These phosphonates
were synthesized via an Arbuzov reaction by heating the
corresponding benzyl chlorides in triethylphosphite at
130 °C for 4 h.[22]
The experimental conditions used for the synthesis of the
methoxylated (E)-stilbenes were optimized by using anisal-
dehyde and diethyl 3,5-dimethoxybenzylphosphonate
(Table 1, entry 1). Initially, the reactants were introduced
into the column containing alumina-KF without any sol-
vent, and the reaction was allowed to proceed at room tem-
perature. However, under these conditions, the starting al-
Furthermore, because 5-aryl-2,4-pentadienoic acids and
their derivatives exhibit a wide array of biological activi-
ties,[9] we investigated the synthesis of derivatives 8a–c by
using our methodology from the appropriate aldehyde and
phosphonate 7a or 7b. The reaction was incomplete, and we
Table 1. Synthesis of methoxylated analogues of resveratrol over a column of alumina-KF under microwave irradiation.
Entry
1
2
Time [min]
3
Yield [%]
Ref.
[23]
1
2
3
4
5
6
1a
1b
1c
1d
1c
1b
2a
2a
2a
2b
2b
2b
5
9
10
9
9
3a
3b
3c
3d
3e
3f
85
75
75
60
68
57
[24]
–
–
–
[24]
9
Scheme 1. Synthesis of methoxylated analogues of alkylresorcinols.
334
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Reactions on a Column under Microwave Irradiation
Table 2. Synthesis of 5-aryl-2,4-pentadienoates on a column of alumina-KF.
Entry
Aldehyde
7
Time [min]
8
Conversion [%]
Ref.
[29]
[29]
[30]
7
8
9
1c
1c
1a
7b
7a
7a
8
15
18
8a
8b
8c
40
65
66
Table 3. Synthesis of (E)-stilbenes by the Wittig reaction on a column of alumina-KF.
Entry
Aldehyde
9
Time [min]
Product
Yield [%]
E/Z Ratio
10
11
1c
1e
9
9
3
3
3e
10b
75
68
100:0
70:30
obtained 40–66% conversion of the aldehyde (Table 2). The preparation of the target olefins with high purity in short
reduced conversion and yield were attributed to hydrolysis reaction times under microwave irradiation, thus avoiding
of the ester group of the phosphonates employed.
long liquid–liquid extraction procedures and purification
In the context of synthesizing bioactive molecules by protocols. This method might be interesting for cascade re-
using our method, we investigated the synthesis of combres- actions and for the parallel synthesis of sets of small sam-
tatine A-4[16,31] using isovanillin and 3,4,5-trimethoxyben- ples of compounds.
zylphosphonium chloride (9); the latter being prepared by
refluxing 3,4,5-trimethoxybenzyl chloride with tri-
phenylphosphane in toluene for 8 h. The hydroxy group of
isovanillin was protected by using dihydropyran in the pres-
Experimental Section
General Methods: All commercial reagents were purchased from
Acros, Aldrich, or Sigma and were used as received without further
purification. Reaction times were monitored by TLC until no start-
ing material remained. TLC was performed by using Silica gel 60
F254 precoated aluminum sheets. Column chromatography was per-
formed by using Silica gel Si 60 (40–63 µm). Microwave irradiation
was performed with a microwave mono-mode Prolabo Synthewave
402 cavity. 1H, 31P, and 13C NMR spectra were recorded with a
Bruker AC 250 or Bruker AC 400 spectrometer. Chemical shifts (δ)
are expressed in parts per million (ppm) and are referenced to the
internal deuterated solvents with tetramethylsilane as the internal
standard. Data are reported as follows: multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, dd = doublet of doublet, dt =
doublet of triplet, m = multiplet, br. = broad), coupling constants
[expressed in Hertz (Hz)], integral, and assignment. Mass spectra
were recorded with a QTOF Micro (Waters) spectrometer with elec-
ence of catalytic amounts of pyridinium-p-toluenesulfonic
acid in dichloromethane. The reaction of the protected iso-
vanillin (1e) with phosphonium salt 9 was complete in
3 min and afforded the corresponding olefin 10b in 68%
yield as a mixture of E and Z isomers (7:3). On the other
hand, the reaction of piperonal (1c) with phosphonium salt
9 under the same conditions gave only the E isomer 3e in
75% yield (Table 3).
Conclusions
We have used SPRC to prepare some natural bioactive
compounds by the Wittig and Horner–Emmons reactions
on a column of alumina-KF. SPRC integrated both the re-
action and separation into a single unit and permitted the trospray ionization (ESI, positive mode), lockspray orthophospho-
Eur. J. Org. Chem. 2010, 333–337
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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335

S. C. Dakdouki, D. Villemin, N. Bar
FULL PAPER
ric acid, infusion introduction at 10 µL/min, a source temperature
of 80 °C and desolvation temperature of 120 °C.
158.0, 153.3 (2 C), 137.5, 134.1, 127.3, 127.1, 122.9, 119.4, 105.0,
103.4 (2 C), 98.5, 61.0, 56.1 (2 C), 55.5, 55.4 ppm. HRMS: calcd.
for C19H23O5 [M + H]+ 331.1545; found 331.1561.
General Procedure for the Synthesis of (E)-Stilbenes Using the
Horner–Emmons Reaction on-Column: A polypropylene SPE col-
umn (Varian Bond Elut®, 6 mL), equipped with a frit at its lower
end, was charged with silica (1.5 g). Above the layer of silica, a
second layer of alumina-KF (1.8 g) was introduced. An equimolar
mixture of the appropriate aldehyde (1a–d or 4a,b) and a suitable
phosphonate (2a,b or 7a,b) in tetrahydrofuran (0.2 mL) was then
adsorbed over the alumina-KF in the column. The column was
then placed in a quartz reactor and exposed to microwave irradia-
tion (120 W, Tmax = 100 °C) in a resonate cavity for 1.5 min and
then cooled to room temperature (10 min). This process was re-
peated until full consumption of the starting materials was ob-
served. The formed olefin was eluted from the column with dichlo-
romethane (20 mL), and the solvent was evaporated in vacuo to
afford the corresponding olefin.
5-(3,4,5-Trimethoxystyryl)benzo[d][1,3]dioxole (3e): Prepared either
by reaction of piperonal (0.23 g, 0.85 mmol) and diethyl 3,4,5-tri-
methoxybenzylphosphonate (0.27 g, 0.85 mmol) in 68% yield as a
white solid or by the reaction of piperonal (0.08 g, 0.5 mmol), and
3,4,5-trimethoxybenzylphosphonium chloride (0.24 g, 0.5 mmol) in
1
75% yield. H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 1.6 Hz,
1 H, ArH), 6.94 (d, J = 16.0 Hz, 1 H, CH=CH), 6.93 (dd, J = 2.0,
J = 8.4 Hz, 1 H, ArH), 6.86 (d, J = 16.0 Hz, 1 H, CH=CH), 6.79
(d, J = 8.0 Hz, 1 H, ArH), 6.70 (s, 2 H, ArH), 3.91 (s, 6 H, OMe),
3.86 (s, 3 H, OMe) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
153.4 (2 C), 148.2, 147.3, 137.8, 133.2, 131.8, 127.9, 127.0, 121.4,
108.4, 105.5, 103.4 (2 C), 101.2, 61.0, 56.1 (2 C) ppm. HRMS:
calcd. for C18H19O5 [M + H]+ 315.1232; found 315.1225.
1,3-Dimethoxy-5-[(E)-oct-1-enyl]benzene (5b): Prepared by reaction
of heptanal (0.2 g, 1.8 mmol) and diethyl 3,5-dimethoxy-
benzylphosphonate (0.30 g, 1.0 mmol) in 43% yield. 1H NMR
General Procedure for the Synthesis of (E)-Stilbenes Using the Wit-
tig Reaction on-Column: The same procedure described above was
employed, except that the phosphonates were replaced by phospho- (400 MHz, CDCl3): δ = 6.51 (d, J = 2.4 Hz, 2 H, ArH), 6.33 (t, J
nium salt 9 and the column was irradiated for 3 min. Also, a mix-
ture of cyclohexane/ethyl acetate (80:20) was used as eluent instead
of dichloromethane.
= 2.4 Hz, 1 H, ArH), 6.31 (d, J = 16 Hz, 1 H, CH=CH), 6.25–6.18
(td, J = 6.8, 15.6 Hz, 1 H, CH=CH), 3.79 (s, 3 H, OCH3), 2.22–
2.18 (m, 2 H, CH2), 1.40–1.29 (m, 8 H, CH2), 0.91–0.86 (m, 3 H,
CH3) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 160.9 (2 C),
140.1, 131.8, 129.7, 104.0 (2 C), 99.1, 55.3 (2 C), 32.9, 31.7, 29.3,
28.9, 22.6, 14.1 ppm. HRMS: calcd. for C16H25O2 [M + H]+
249.1855; found 249.1867.
4-Methoxy-3-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (1e): To a
well stirred solution of isovanillin (1.52 g, 10 mmol) in anhydrous
dichloromethane (40 mL) was added dihydropyran (6.5 g,
7.7 mmol) and pyridinium-p-toluenesulfonate (0.1 g). The reaction
mixture was stirred overnight at room temperature under a nitrogen
atmosphere, then saturated sodium hydrogen carbonate (50 mL)
was added, and the mixture was extracted with dichloromethane
(3ϫ100 mL). The combined organic layers were dried with magne-
sium sulfate, and the solvent was removed in vacuo to afford the
protected isovanillin as a colorless thick liquid in 75% yield. 1H
1,3-Dimethoxy-5-octylbenzene (6b): A solution of 1,3-dimethoxy-5-
[(E)-oct-1-enyl]benzene (5b; 0.26 g, 1 mmol) in methanol (10 mL)
was placed in a 250 mL glass Parr hydrogenation flask containing
5% Pd/C catalyst, and the mixture was shaken for 18 h under 20 psi
of hydrogen gas. The solution was then filtered through Celite to
remove the catalyst. The solvent was removed under reduced pres-
NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H, HC=O), 7.63 (d, J = sure to afford the corresponding saturated product in 83% yield.
2.0 Hz, 1 H, ArH), 7.52 (dd, J = 2.0, 8.4 Hz, 1 H, ArH), 6.99 (d,
13C NMR (100 MHz, CDCl3): δ = 160.7 (2 C), 145.4, 106.5 (2 C),
J = 8.4 Hz, 1 H, ArH), 5.47 (t, J = 3.6 Hz, 1 H, OCHO), 3.98– 97.6, 55.2 (2 C), 36.3, 31.9, 31.3, 29.5, 29.4, 29.3, 22.7, 14.1 ppm.
3.95 (m, 1 H, CH2O), 3.93 (s, 3 H, OCH3), 3.65–3.60 (m, 1 H,
3,4,5-Trimethoxybenzylphosphonium Chloride (9): Triphenylphos-
phane (4.58 g, 17.4 mmol) was added to a well stirred solution of
3,4,5-trimethoxybenzyl chloride (1.89 g, 8.7 mmol) in toluene
(20 mL). The reaction mixture was then refluxed for 24 h under a
CH2O), 2.04–1.87 (m, 2 H, CH2), 1.72–1.58 (m, 4 H, CH2) ppm.
13C NMR (100 MHz, CDCl3): δ = 190.9, 155.6, 146.6, 130.1, 126.6,
116.7, 111.3, 79.5, 62.4, 56.2, 30.2, 25.1, 18.8 ppm. HRMS: calcd.
for C13H17O4 [M + H]+ 237.1127; found 237.1131.
nitrogen atmosphere. The corresponding phosphonium salt precipi-
5-(3,5-Dimethoxystyryl)benzo[d][1,3]dioxole (3c): Prepared by reac-
tion of piperonal (0.16 g, 1.1 mmol) and diethyl 3,5-dimethoxy-
benzylphosphonate (0.31 g, 1.1 mmol) as a white solid in 75%
tated during the reaction and was collected at the end of the reac-
tion by suction filtration as a white solid in 89% yield. H NMR
(400 MHz, D2O): δ = 7.87–7.83 (m, 3 H, ArH), 7.68–7.59 (m, 12
H, ArH), 6.20 (d, J = 2.4 Hz, 2 H, ArH), 4.64 (d, J = 14.0 Hz, 2
1
1
yield. H NMR (400 MHz, CDCl3): δ = 7.06 (d, J = 1.8 Hz, 1 H,
ArH), 7.00 (d, J = 16.3 Hz, 1 H, CH=CH), 6.93 (dd, J = 1.8, H, CH2P), 3.71 (s, 3 H, OCH3), 3.44 (s, 6 H, OCH3) ppm. 13C
8.3 Hz, 1 H, ArH), 6.86 (d, J = 16.3 Hz, 1 H, CH=CH), 6.79 (d, J NMR (100 MHz, CDCl3): δ = 152.4 (2 C), 135.2, 134.0 (6 C), 129.8
= 8.0 Hz, 1 H, ArH), 6.64 (d, J = 2.3 Hz, 2 H, ArH), 6.38 (t, J =
2.3 Hz, 1 H, ArH), 5.98 (s, 2 H, OCH2O), 3.84 (s, 6 H, OCH3)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 160.9 (2 C), 148.2, 147.4,
139.4, 131.7, 128.9, 126.9, 121.6, 108.4, 105.6, 104.4 (2 C), 101.1,
99.8, 55.4 (2 C) ppm. HRMS: calcd. for C17H17O4 [M + H]+
285.1127; found 285.1130.
(9 C), 123.6, 117.5 (3 C), 108.5 (2 C), 61.0, 55.8 (2 C), 30.2 ppm.
31P NMR (400 MHz, D2O): δ = 22.93 ppm. HRMS: calcd. for
C28H28O3P [M + H]+ 443.1776; found 443.1764.
2-[4-(3,4,5-Trimethoxystyryl)-2-methoxyphenoxy]tetrahydro-2H-
pyran (10b): Prepared by using 3,4,5-trimethoxybenzylphosphon-
ium chloride (9; 0.24 g, 0.5 mmol) and protected isovanillin (1e;
0.12 g, 0.5 mmol) to afford the product as a white solid in 68%
5-(2,4-Dimethoxystyryl)-1,2,3-trimethoxybenzene (3d): Prepared by
reaction of 2,4-dimethoxybenzaldehyde (0.15 g, 0.89 mmol) and di-
ethyl 3,4,5-trimethoxybenzylphosphonate (0.28 g, 0.89 mmol) as a
white solid in 60% yield. 1H NMR (400 MHz, CDCl3): δ = 7.49
(d, J = 8.4 Hz, 1 H, ArH), 7.27 (d, J = 16.4 Hz, 1 H, CH=CH),
6.94 (d, J = 16.4 Hz, 1 H, CH=CH), 6.73 (s, 2 H, ArH), 6.53 (dd,
1
yield as a mixture of E and Z isomers (7:3). E Isomer: H NMR
(500 MHz, CDCl3): δ = 7.33 (d, J = 2 Hz, 1 H, ArH), 7.12 (dd, J
= 2.0, 8.5 Hz, 1 H, ArH), 6.94 (d, J = 16.0 Hz, 1 H, CH=CH),
6.88 (d, J = 16 Hz, 1 H, CH=CH), 6.88 (d, J = 8.5 Hz, 1 H, ArH),
6.71 (s, 2 H, ArH), 5.48 (t, J = 3.0 Hz, 1 H, OCHO), 4.05–4.01 (m,
J = 2.4, J = 8.4 Hz, 1 H, ArH), 6.48 (d, J = 2.4 Hz, 1 H, ArH), 1 H, OCH2), 3.91 (s, 6 H, OCH3), 3.88 (s, 3 H, OCH3), 3.86 (s, 3
3.91 (s, 6 H, OCH3), 3.88 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), H, OCH3), 3.67–3.64 (m, 1 H, OCH2), 2.08–1.90 (m, 2 H, CH2),
3.84 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.5,
1.75–1.62 (m, 4 H, CH2) ppm. 13C NMR (100.6 MHz, CDCl3): δ
336
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Reactions on a Column under Microwave Irradiation
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= (ppm) 153.4 (2 C), 150.1, 146.5, 137.6, 133.4, 130.5, 127.9, 126.8,
121.1, 115.4, 112.4, 103.3 (2 C), 97.5, 62.1, 61.0, 56.2, 56.1 (2 C),
30.4, 25.3, 18.7. HRMS: calcd. for C23H29O6 [M + H]+ 401.1964;
1
found 401.1953. Z Isomer: H NMR (500 MHz, CDCl3): δ = 7.07
(d, J = 2 Hz, 1 H, ArH), 6.91 (br. s, 1 H, ArH), 6.78 (d, J = 8 Hz,
1 H, ArH), 6.51 (s, 2 H, ArH), 6.48 (d, J = 12 Hz, 1 H, CH=CH),
6.42 (d, J = 12 Hz, 1 H, CH=CH), 5.17 (t, J = 3.6 Hz, 1 H,
OCHO), 3.85 (m, 1 H, OCH2), 3.83 (s, 6 H, OCH3), 3.70 (s, 6 H,
OCH3), 3.46–3.40 (m, 1 H, OCH2), 2.03–1.58 (m, 6 H, CH2) ppm.
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We gratefully acknowledge financial support from the “Ministère
de la Recherche et des Nouvelles Technologies”, CNRS (Centre
National de la Recherche Scientique), the “Région Basse-Norman-
die” and the European Union (FEDER funding) for financial sup-
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Received: September 8, 2009
Published Online: December 2, 2009
Eur. J. Org. Chem. 2010, 333–337
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