Solution-phase synthesis of first-generation tetraester dendritic branches involving microwave and/or ultrasonic irradiation

Article abstract of DOI:10.1002/ejoc.200800325

Trifunctionalized aromatic cores were selectively protected to obtain precursors for bidirectional dendritic unit growth through stepwise divergent syntheses. The synthesis of first-generation dendrimer building blocks was performed by nucleophilic substitution of bromomethyl-substituted aromatic cores with diethyl malonate anions in the presence of carbonate in halogen-free solvents. The screening of the reaction parameters revealed the optimum conditions for small- and larger-scale synthesis: these require microwave or ultrasonic irradiation to achieve yields around 70% in reaction times as short as 15 min. As a result of the heterogeneity of the reaction mixtures, efficient stirring was important to suppress by-product formation. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800325

FULL PAPER
DOI: 10.1002/ejoc.200800325
Solution-Phase Synthesis of First-Generation Tetraester Dendritic Branches
Involving Microwave and/or Ultrasonic Irradiation
Frank Wiesbrock,[a] Claudine Patteux,[a] Tomasz K. Olszewski,[a] Amélie Blanrue,[a]
Georgios A. Heropoulos,*[a] Barry R. Steele,[a] Maria Micha-Screttas,[a] and
Theodora Calogeropoulou*[a]
Keywords: Dendrimers / Nucleophilic substitution / Microwave / Ultrasound
Trifunctionalized aromatic cores were selectively protected
to obtain precursors for bidirectional dendritic unit growth
through stepwise divergent syntheses. The synthesis of first-
generation dendrimer building blocks was performed by nu-
cleophilic substitution of bromomethyl-substituted aromatic
cores with diethyl malonate anions in the presence of carbon-
ate in halogen-free solvents. The screening of the reaction
parameters revealed the optimum conditions for small- and
larger-scale synthesis: these require microwave or ultrasonic
irradiation to achieve yields around 70% in reaction times as
short as 15 min. As a result of the heterogeneity of the reac-
tion mixtures, efficient stirring was important to suppress by-
product formation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
have also been used to increase the loading capacity of a
Dendrimers are of particular interest in numerous appli- resin and/or to increase the distance of the reaction sites
cations as diverse as stabilizing agents in suspensions,[1,2] and core of the resin.[10,11] The synthesis of dendrimers can
metal complexation,[1–4] encapsulation of small-to-medium- follow two alternative principle routes: a divergent or a con-
sized organic molecules,[5,6] and delivery of pharmaceuti- vergent approach[12] (Scheme 1). In the case of the more-
cally active compounds.[7–9] Rather recently, dendrimers common divergent route,[13] the synthesis starts from the
Scheme 1. Dendrimer growth from a trifunctional precursor: The upper part of this scheme shows the dendrimer growth from all three
reaction sites. The lower part of this scheme describes the dendrimer growth from only two of the formerly three reaction sites (e.g., after
selective protection of one of the reaction sites).
dendrimer core, which has multiple functional sites. From
this core, the dendrimer grows through stepwise reactions
[a] Institute of Organic and Pharmaceutical Chemistry, National
with molecules with two types of functional groups: one
type reacts with functional sites on the core or on the lower
generation dendrimer, whereas the other type is intended
for the continuation of the dendrimer growth. From the
Hellenic Research Foundation,
48 Vassileos Constandinou Ave., 11635 Athens, Greece
Fax: +30-210-7273-833
E-mail: tcalog@eie.gr
gherop@eie.gr
4344
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4344–4349

Tetraester Dendritic Branches by Microwave Irradiation and/or Ultrasound
stepwise growth it becomes apparent that long reaction cial attention was given to finding the right balance between
times are required to complete each step of the synthesis, reaction speed and yield optimization. Improvement in the
in particular for the higher-generation dendrimers. Hence, yields and product purity by volumetric and quasigradient-
acceleration of the syntheses involved in dendrimer prepa- free heating by microwave irradiation was recently shown
ration is a key prerequisite to make any future application for the synthesis of linear polymers from living polymeriza-
profitable.
tions and dendrimer synthesis.[19–23] A similarly efficient
and uniform heat distribution was expected from an ultra-
sound probe.[24]
The synthesis of tetraesters 3a and 3b from 1a and
1b[15,16] (Scheme 2) in acetonitrile was investigated under
microwave irradiation on a small scale (0.2 mmol) in an ini-
tial temperature screening starting from 100 °C (Table 1). A
maximum yield of tetraester 3a (72%) was obtained at
120 °C within 1 h of reaction time. Shorter reaction times,
concomitant with higher temperatures, favor decomposition
of the reactants (140 °C: 20–30 min, 57%). The yield is also
lower at temperatures less than 120 °C (100 °C: 90–120 min,
63%), which indicates that at higher temperatures side reac-
tions are less accelerated. The yields of tetraester 3b were
generally lower than those of its homologue 3a, with a
maximum yield of 3b of 57% at 120 °C within 20–30 min
of reaction time. Because at 140 °C the yield was 56% and
the reaction time was shorter (6–8 min), this temperature
was chosen for future experiments. Less acceleration at ele-
vated temperatures was observed for the reaction of 1a
Results and Discussion
Current studies in our group focus in particular on the
solution-phase synthesis of dendrimers that can be attached
to resins. Depending on the linkage of the dendrimer on the
resin, these modified resins offer two advantages: temporar-
ily attached dendrimers allow solid-phase dendrimer
growth by, for example, click-chemistry techniques,[14]
whereas permanently attached ones multiply the loading ca-
pacity of the resin and make it an interesting candidate for
solid-phase synthesis in general.[10,11] For the synthesis of
these dendrimers, 1,3,5-trisubstituted benzenes have been
modified in such a way that they carry one benzyl-protected
hydroxy or hydroxymethyl group and two bromomethyl
groups (Scheme 2).[15,16]
For nucleophilic substitution of both bromine atoms,
these precursors were treated with diethyl malonate anions
to yield first-generation dendritic units. According to litera-
ture reports, this reaction can be performed in acetonitrile
with an excess amount of potassium carbonate as base for
the in situ generation of diethyl malonate anions,[17] thus
excluding the formation of gases like hydrogen, which
would be formed with, for example, sodium hydride as
base.[18] Consequently, this reaction can be conveniently
performed in closed vessels at elevated temperatures
(Ͼ82 °C) by employing so-called high-energy techniques,
that is, microwave and ultrasonic irradiation, which could
result in significant acceleration of the reaction time. Spe-
Table 1. Temperature dependence of reaction times and yields for
the conversion of 1a and 1b (0.2 mmol scale) into tetraesters 3a and
3b in acetonitrile (1 mL) by using potassium carbonate (4.5 equiv.)
under microwave irradiation.
T [°C]
1a Ǟ 3a
1b Ǟ 3b
t [min]
Yield [%]
t [min]
Yield [%]
100
120
140
90–120
45–60
20–30
63
72
57
90–120
20–30
6–8
51
57
56
Scheme 2. Scheme for the reactions of 1a,b to yield tetraesters 3a,b by mixed bromo-/diesters 2a,b. The structure of the most prominent
byproduct hexaester 4a, which is observed in particular during scale-up by utilizing ultrasound, contains mono- and disubstituted malon-
ates in a 2:1 ratio. Compounds 2b and 4b were not isolated; comparison of the TLCs of the reactions 1a,b Ǟ 3a,b, however, suggests
analogous byproduct formation.
Eur. J. Org. Chem. 2008, 4344–4349
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4345

G. A. Heropoulos, T. Calogeropoulou et al.
FULL PAPER
(Table 1), and only the reaction of 1b seems to follow the expected 30–60 min to 90–120 min and a decreased yield
“rule of thumb” derived from the Arrhenius equation say- from the expected 72 to 32% (Table 2, Entries 1 and 2).
ing that a temperature increase of 10 K (20 K) should de-
crease the reaction time by a factor of 2 (4).
Further proof of inefficient stirring was exhibited by the
most prominent byproduct 4a, which was recovered in 14%
yield. The structure of this symmetrical molecule was
proven by a 2D gHMBC NMR spectroscopic experiment,
which revealed the medium-range interaction of the protons
(3.154 ppm) and carbon atoms (δ =39.0 ppm) in direct
proximity to the quaternary carbon atom (δ =59.9 ppm;
Figure 1). Byproduct 4a contains two mono- and one di-
substituted diethyl malonate. Deprotonation of the diethyl
From the data obtained (Table 1), only intervals of the
activation energies can be calculated. The reaction of 1b
covers the range of 78–96 kJmol–1, whereas that of 1a spans
a range of 35–57 kJmol–1. This difference in activation en-
ergy is assumed to originate from the presence or absence
of a methylene group between the aromatic ring and the
oxygen atom (Scheme 2), which disables or enables the in-
volvement of the oxygen atom in resonance (de)stabilization
of the overall rate-determining step.
Scale Up under Microwave Irradiation
Scale up is preferentially performed in batch mode, as
the solid potassium carbonate forms a stable suspension in
acetonitrile only when vigorously agitated. The standard
closed-vessel system (CEM Discover) can handle a maxi-
mum volume of 50 mL; in open-vessel (“reflux”) condi-
tions, the maximum volume is limited to 100 mL. Conse-
quently, the set up described in this publication allows a
maximum starting amount of 14 mmol or around 5 g of
1a,b.
For future linkage to a resin, the phenolic core was
favored over the benzylic one, and hence, scale up was fo-
cused on 1a. The first scale-up experiments were performed
on a 1.0-mmol scale at 120 °C. “Standard” closed-vessel
hardware was used: a tube-shaped vial with conical bottom
(inner dimensions: heightϫdiameter = 86 mmϫ12.5 mm)
and a regular-shaped stirring bar (lengthϫdiameter =
10 mmϫ2 m). Stirring of the heterogeneous suspension
Figure 1. Allocation of NMR signals for compound 4a, verified by
a 2D gHMBC NMR experiment. In particular, the 3JH,C couplings
at {1H; 13C} = {3.154; 39.0} was beneficial for the structure deter-
mination. In the left half of this scheme, the corresponding part of
the molecule (energy minimization by HyperChem) is shown for
was inefficient, resulting in an increased reaction time from elucidation.
Table 2. Scale up of the synthesis of tetraester 3a from 1a under various conditions. Unless indicated otherwise, all reactions were
performed at 120 °C with 5.0 mL of solvent per 1.0 mmol of 1a and a molar ratio of 1a:malonate:carbonate, 1:4:5.[a]
n [1a]
[mmol]
System
Remarks
Time
[min]
Yield
[%]
1
2
3
4
5
6
7
8
0.2
1.0
0.8
0.2
1.0
0.2
1.5
0.2
1.5
1.5
1.5
MeCN/K2CO3
MeCN/K2CO3
MeCN/K2CO3
DMF/Cs2CO3
DMF/Cs2CO3
DMF/Cs2CO3
DMF/Cs2CO3
Cs2CO3
MW, closed vessel, small stirring bar
MW, closed vessel, small stirring bar
MW, closed vessel, large stirring bar
MW, closed vessel, small stirring bar
MW, closed vessel, small stirring bar
CH, closed vessel, small stirring bar
CH, reaction at 60 °C, round flask, large stirring bar
MW, solvent free, closed vessel, small stirring bar
MW, open flask, large egg-shaped stirring bar
MW, open flask, large egg-shaped stirring bar, dropwise addition[b]
1. US at room temp.
45–60
90–120
90–120
Ͻ15
20–30
Ͻ15
90–120
10–13
Ͻ30
72
32
55
65
25
54
71
54
67
64
66
9
10
11
DMF/Cs2CO3
DMF/Cs2CO3
DMF/Cs2CO3
Ͻ30
1. 30
2. MW, open flask, large egg-shaped stirring bar
2. Ͻ15
Ͻ13
12
1.5
DMF/Cs2CO3
US at 102 °C, open flask[c]
62
[a] MW: microwave irradiation; CH: conventional heating (oil bath); US: ultrasound. [b] A solution of 1a (1.5 mmol) in DMF (7.5 mL)
was added dropwise to a suspension of diethyl malonate (6.0 mmol) and cesium carbonate (7.5 mmol) in DMF (7.5 mL) over 20 min.
Heating was continued for 10 min. [c] The addition of DMF (15 mL) was required because of the geometry of the flask/overhead probe.
4346
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Eur. J. Org. Chem. 2008, 4344–4349

Tetraester Dendritic Branches by Microwave Irradiation and/or Ultrasound
malonate by undissolved potassium carbonate occurs after the reaction mixture was 102 °C. The reaction was com-
absorption of diethyl malonate onto the solid surface. After plete, and dendritic building block 3a was recovered in 62%
complete reaction of deprotonated diethyl malonate with yield (Table 2, Entry 12).
compound 1a, the product/intermediate should desorb
from the solid surface. As a consequence of inefficient stir-
ring, extended residence times of 2a and 3a on the surface
of solid cesium carbonate can favor second deprotonation.
The importance of efficient stirring was recently shown in a
literature report on the existence or absence of nonthermal
microwave effects.[25]
Conclusions
The syntheses of first-generation dendritic tetraesters
3a,b from bromo bifunctional precursors 1a,b were per-
formed by nucleophilic substitution with diethyl malonate
anions in heterogeneous media, either in MeCN/K2CO3 or
in DMF/Cs2CO3 at elevated temperatures. The comparably
high temperature of 120 °C was optimum for that system in
terms of maximum yield and short reaction times, as re-
vealed by precedent temperature screening. Extended resi-
dence times of intermediates 2a,b and/or products 3a,b on
the solid surface of carbonate favored the formation of by-
products like 4a,b, and therefore, efficient stirring was nec-
essary. Larger-scale syntheses were performed exclusively in
open vessels by using the DMF/Cs2CO3 system. Best yields
of 72 and 58% of 3a,b, respectively, were obtained with the
aid of microwave irradiation with reaction times as low as
15 min. The use of conventional heating or ultrasonic irra-
diation, in contrast, lowered the yield at identical tempera-
tures and proved the superiority of microwave heating over
those two alternatives. This superiority is due to the (quasi)-
gradient-free heating that obviously was maintained despite
the large amounts of solid carbonate present. The solid car-
bonate is the best absorbing material of all reactants in the
reaction mixture, and in this context, it is worth emphasiz-
ing again that thorough stirring was the key strategy for
successful synthesis. It also provided even distribution of
the solid carbonate, and hence, averaged the absorbance of
microwave irradiation and subsequent generation of heat
throughout the reaction mixture. Future experiments will
aim at the solid-phase synthesis of the first-generation den-
dritic tetraesters 3a,b from resin-bound starting material
1a,b. Because of steric hindrance of the resin-bound reac-
tants at the surface of solid carbonate, this strategy will
favor the nucleophilic substitution involving dissolved car-
bonate. Hence, the formation of byproducts of type 4a,b
will not be favored.
Because efficient stirring could not be achieved in a
closed vessel by using MeCN/K2CO3, we changed to DMF/
Cs2CO3 owing to the partial solubility of Cs2CO3 in DMF.
In addition, operation in DMF offers the major advantage
over MeCN that at 120 °C, syntheses are not restricted to
closed-vessel conditions. Comparison of conventional heat-
ing at 120 °C with microwave-assisted heating (Table 2)
indicated higher yields with the latter, which is assumed to
originate from a more uniform heat distribution in the case
of microwave-assisted heating. It is worth mentioning that
solvent-free conditions also failed to give good yields of 3a
(Table 2, Entry 8): obviously the solid carbonate, which acts
as primary absorber, did not provide uniform heat distribu-
tion.
Performance of the reaction on a 1.5-mmol scale in
DMF gave product 3a in 67% yield, which is very close to
the maximum yield of 72% obtained on a 0.2-mmol scale
(Table 2, Entry 9) and is the best yield achieved on a larger
scale. The yield of 3a could not be further increased by
dropwise addition of 1a to a hot suspension of diethyl ma-
lonate and cesium carbonate in DMF (Table 2, Entry 10).
Scale Up Involving Ultrasonic Irradiation
The influence of ultrasound on the scale up of this reac-
tion was also investigated. Application of ultrasonic irradia-
tion (through an ultrasonic bath) to the reaction mixture
in DMF/cesium carbonate at room temperature for 30 min
perhaps decreased the size of the cesium carbonate particles
and hence increased the surface available for reaction. The
suspension itself, however, was not stable and agitation was
required for dispersion of the solid cesium carbonate. The
reaction itself (Table 2, Entry 11) was performed under mi-
crowave irradiation at 120 °C. Product 3a was obtained in
66% yield, showing no improvement relative to the plain
microwave experiment (Table 2, Entry 9). Remarkably, in
Experimental Section
General: Acetonitrile and N,N-dimethylformamide were stored over
molecular sieves (3 Å) under an atmosphere of argon. Cesium car-
both experiments involving ultrasonic irradiation (see be- bonate and potassium carbonate were oven dried. Silica-gel plates
(Merck F254) were used for thin layer chromatography. Chromato-
graphic purification was performed with silica gel (200–400 mesh).
NMR spectra were recorded with a Bruker AC 300 spectrometer
operating at 300 MHz for 1H and 75.43 MHz for 13C. All NMR
spectra were recorded in CDCl3; 1H and 13C NMR spectra are
reported in units of δ relative to internal CHCl3 at 7.26 and
77.0 ppm, respectively. 13C NMR spectra were proton-noise decou-
pled. Infrared spectra of neat samples were recorded with a Bruker
Tensor27 FTIR spectrometer equipped with a single reflection dia-
mond crystal (PIKE Technologies). Mass spectra were recorded
low), byproduct 4a was also formed in large quantities of
more than 10%. On the basis of our previous hypothesis,
the formation of byproduct 4a is assumed to originate from
prolonged absorption times of intermediate 2a and product
3a on the solid surface of the carbonate, which in the ultra-
sonic experiments probably relates to the increased surface
area of cesium carbonate.
The synthesis of tetraester 3a was also performed exclu-
sively by utilizing a self-heating overhead ultrasound probe.
After an exposure time of 10 min, the final temperature of with a Finnigan Mat TSQ7000 mass spectrometer. Analyses indi-
Eur. J. Org. Chem. 2008, 4344–4349
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. A. Heropoulos, T. Calogeropoulou et al.
FULL PAPER
cated by the symbols of the elements were carried out by the micro-
analytical section of the Institute of Organic and Pharmaceutical
Chemistry of the National Hellenic Research Foundation. Micro-
wave-assisted reactions were performed in a CEM Discover micro-
wave apparatus (f = 2.45 GHz, Pmax = 300 W), either in closed-
vessel or in open-vessel operation mode. The internal temperature
of the reaction mixture was measured with an IR pyrometer, the
calibration of which was verified for all experimental set ups (Fig-
ure 2). Reactions under microwave irradiation in closed-vessel
mode were performed in vials specially designed for operation in
the microwave apparatus. In general, the glassware was heated to
140 °C, cooled down in a desiccator and filled with argon prior to
addition of chemicals and solvents. Ultrasonic irradiation was ap-
plied either with a probe (titanium alloy, length 254 mm, diameter
13 mm) controlled by a 650-W, 20-kHz ultrasonic processor (Sonics
and Materials) or through an ultrasonic bath (LSB2 by Falc, f =
40 kHz, Pmax = 150 W). Reference experiments with conventional
heating were performed in preheated oil baths.
5.04 (s, 2 H, OCH2Ar), 6.80 (s, 1 H, CH3R3), 6.84 (s, 1 H, CH3R3),
6.88 (s, 1 H, CH3R3), 7.31–7.44 (m, 5 H, C6H5R) ppm. 13C NMR
(75.43 MHz, CDCl3, 25 °C): δ = 14.0, 34.5, 46.1, 53.6, 61.5, 70.0,
113.3, 115.5, 121.6, 127.5, 128.0, 128.6, 136.6, 139.0, 140.0, 159.1,
168.7 ppm. IR: ν = 1729 [s, δasym(C–O)], 1595 [w, δ(C=C)], 1296
˜
[ms, δ(C–O–C)], 1263 [m, δ(CH2Br)], 1224 [ms, δsym(C–O)], 1030
[ms, δ(=C–H)] cm–1. MS (ESI): m/z (%) = 448.5 (25.1) [M]+, 450.5
(12.1) [M + 2]+.
Tetraethyl 2,2Ј-[5-Benzyloxy-1,3-phenylene]bis(methylene)dimalon-
ate (3a): Rf = 0.33 [petroleum ether (40–60 °C)/ethyl acetate, 4:1].
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.21 (t, J = 7.2 Hz, 12 H,
CH3), 3.14 (d, J = 7.8 Hz, 4 H, ArCH2C), 3.59 [t, J = 7.8 Hz, 2 H,
CH(CO2Et)], 4.08–4.22 (m, 8 H, OCH2C), 5.04 (s, 2 H, OCH2Ar),
6.65 (s, 1 H, CH3R3), 6.69 (s, 2 H, CH3R3), 7.30–7.41 (m, 5 H,
C6H5R) ppm. 13C NMR (75.43 MHz, CDCl3, 25 °C): δ = 14.0,
34.6, 53.7, 61.4, 69.8, 113.7, 121.9, 127.4, 127.9, 128.5, 136.8, 139.6,
159.0, 168.7 ppm. IR: ν = 1729 [s, δasym(C–O)], 1595 [w, δ (C=C)],
˜
1274 [ms, δ(C–O–C)], 1224 (ms, δsym(C–O)], 1031 [ms, δ(=C–H)]
cm–1. MS (ESI): m/z (%) = 551.7 (100) [M + Na]+. C29H36O9
(528.60): calcd. C 65.89, H 6.86; found C 66.10, H 6.95.
Tetraethyl 2,2Ј-[5-Benzyloxymethyl-1,3-phenylene]bis(methylene)di-
malonate (3b): Rf = 0.34 [petroleum ether (40–60 °C)/ethyl acetate,
1
4:1]. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.20 (t, J = 7.2 Hz,
12 H, CH3), 3.17 (d, J = 7.8 Hz, 4 H, ArCH2C), 3.60 [t, J = 7.8 Hz,
2 H, CH(CO2Et)], 4.12–4.18 (m, 8 H, OCH2C), 4.46 (s, 2 H,
OCH2), 4.52 (s, 2 H, OCH2), 6.98 (s, 1 H, CH3R3), 7.06, (s, 2 H,
CH3R3), 7.28–7.36 (m, 5 H, CH5R) ppm. 13C NMR (75.43 MHz,
CDCl3, 25 °C): δ = 14.0, 34.5, 53.8, 61.4, 71.9, 72.2, 126.7, 127.6,
127.8, 128.4, 128.9, 138.1, 138.3, 138.7, 168.7 ppm. IR: ν = 1729
˜
[s, δasym(C–O)], 1606 [w, δ(C=C)], 1266 [ms, δsym(C–O)], 1095 [ms,
δ(C–O–C)], 1031 [ms, δ(=C–H)] cm–1. MS (ESI): m/z (%) = 565.6
(100) [M + Na]+. C30H38O9 (542.63): calcd. C 66.40, H 7.06; found
C 66.69, H 6.98.
Figure 2. Open-vessel operation in the CEM discover microwave
apparatus: Correlation between the temperatures inside the reac-
tion mixture and the temperatures measured by the IR pyrometer.
On the basis of its calibration, the distance between the pyrometer
and the surface of the vial must be kept constant. The space holder
(standard accessory) ensures the proper distance: deviations from
this distance lead to large differences between real and measured
temperatures.
Tetraethyl 2,2Ј-{5,5Ј-[2,2-Bis(ethoxycarbonyl)propane-1,3-diyl]bis[3-
(benzyloxy)-5,1-phenylene]}bis(methylene)dimalonate (4a): Rf = 0.26
[petroleum ether (40–60 °C)/ethyl acetate, 4:1]. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.14–1.23 (m, 18 H), 3.13 (s, 4 H),
3.14 (d, J = 7.8 Hz, 4 H), 3.60 (t, J = 7.8 Hz, 2 H), 4.05–4.22 (m,
12 H), 5.00 (s, 4 H), 6.62 (s, 2 H), 6.67 (s, 2 H), 6.71 (s, 2 H), 7.29–
7.41 (m, 10 H) ppm; for an allocation of signals, see Figure 2. 13C
NMR (75.43 MHz, CDCl3, 25 °C): δ = 13.9, 14.0, 34.7, 39.0, 53.7,
59.9, 61.2, 61.4, 69.8, 114.0, 115.1, 123.3, 127.4, 127.8, 128.5, 136.9,
138.0, 139.2, 158.7, 168.7, 170.7 ppm. gHMBC NMR {1H; 13C}: δ
= {1.20; 61.2, 61.4}, {3.15; 39.0, 53.7, 59.9, 114.0, 115.1, 123.3,
138.0, 139.2, 168.7, 170.7}, {3.60; 34.6, 139.2, 168.7}, {4.14; 13.9,
14.0, 168.7, 170.7}, {5.00; 127.4, 127.8, 136.9, 158.7}, {6.62; 34.7,
39.0, 114.0, 115.1}, {6.67; 39.0, 114.0, 123.3, 158.7}, {6.71; 34.7,
115.1, 123.3, 158.7}, {7.29–7.41; 69.8, 127.4, 127.8, 128.5, 136.9}
ppm. MS (ESI): m/z (%) = 920.2 (6.3) [M + Na]+. C51H60O14
(897.04): calcd. C 68.29, H 6.74; found C 67.97, H 6.80.
General Procedure for the Synthesis of Tetraesters 3a and 3b: Com-
pound 1a or 1b (76.8 or 74.0 mg, 0.2 mmol), diethyl malonate
(128.1 mg, 0.8 mmol), potassium or cesium carbonate (138.2 or
325.8 mg, 1.0 mmol), and the solvent (acetonitrile or DMF,
1.0 mL) were placed in a vial. Subsequently, the reaction mixture
was stirred, and argon was bubbled through the solution for
10 min. The vessel was then heated at the targeted temperature for
the indicated time (Tables 1 and 2). After completion of the reac-
tion, distilled water was added, and the product was extracted from
the mixture with diethyl ether. The organic layer was dried
(Na2SO4), the solvent was evaporated in vacuo, and the crude prod-
uct was purified by flash column chromatography [gradient petro-
leum ether (40–60 °C)/ethyl acetate, 95:5 to 90:10 to 80:20, or petro-
leum ether (40–60 °C)/ethyl acetate, 85:15). All scale-up experi-
ments were performed by maintaining the ratio of the three reac-
tants and solvents as indicated above, with the exception of the
experiments involving the dropwise addition of 1a and the over-
head ultrasonifier, where twice the amount of solvent was used
(15 mL of DMF for 1.5 mmol of 1a).
Acknowledgments
Financial support from the European Commission Marie-Curie
Transfer of Knowledge Programme (MTKD-CT-2004-014399)
“SOPHOLIDES” is gratefully acknowledged.
[1] R. C. Hedden, B. J. Bauer, A. P. Smith, F. Gröhn, E. Amis,
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Received: March 27, 2008
Published Online: July 21, 2008
Eur. J. Org. Chem. 2008, 4344–4349
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4349