Improved Multigram Route to a Tricyclic Key Intermediate for Dibenzosuberone-Based p38 Inhibitors via an Optimized Early-Stage Heck Coupling

Article abstract of DOI:10.1021/acs.oprd.1c00081

The p38α MAP kinase has been a heavily investigated target in the last two decades. The structural class of dibenzosuberone-based p38 inhibitors, exemplified by the promising candidate skepinone-L, was already successfully validated in several in vivo mod

Full text of DOI:10.1021/acs.oprd.1c00081

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Article
Improved Multigram Route to a Tricyclic Key Intermediate for
Dibenzosuberone-Based p38 Inhibitors via an Optimized Early-
Stage Heck Coupling
Michael Forster, Heike K. Wentsch-Teltschik, and Stefan A. Laufer*
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ABSTRACT: The p38α MAP kinase has been a heavily investigated target in the last two decades. The structural class of
dibenzosuberone-based p38 inhibitors, exemplified by the promising candidate skepinone-L, was already successfully validated in
several in vivo models of inflammatory as well as oncologic indications. The increasing demand of key intermediates and final
compounds caused by the ongoing development of this inhibitor class urged the conception of an optimized route for the
preparation of the core dibenzosuberone scaffold in multigram quantities. Rerouting of the initial discovery route resulted in an
almost 4-fold increase of overall yield to 46%, the elimination of chromatographic purification, and the substitution of two critical
reaction steps, which hindered a feasible scale-up. The key modification was the introduction and optimization of an early-stage
Heck coupling based on Buchwald precatalysts allowing consistently high yields (ca. 90%) at multigram scales with a favorably low
Pd loading of 0.1 mol %. This newly developed synthetic access to the dibenzosuberone intermediate 2-chloro-7-hydroxy-10,11-
dihydro-5H-dibenzo[a,d][7]annulen-5-one is capable of ensuring the supply of skepinone-L and other candidates during further
development.
KEYWORDS: p38 kinase inhibitors, skepinone-L, Heck coupling, Buchwald precatalysts
application of 1 in the treatment of sorafenib-resistant liver
cancer.7
INTRODUCTION
■
The p38 mitogen-activated protein kinases (MAPK) are key
regulators of stress-activated pathways and the adjunctive
cellular response. Especially, the p38α isoform has been subject
to extensive research as a potential therapeutic target in
inflammatory diseases.1 However, despite a large number of
candidates having entered clinical studies in the past decades,
no small-molecule p38 inhibitor has reached marketing
authorization for this indication so far.2,3 In the recent past,
the application of p38 inhibitors in cancer therapy has
increasingly come into the focus of medicinal chemistry
research opening up new strategies and possibilities in the
treatment of a variety of malignancies.4,5
In one of our own developing programs, we identified the
dibenzosuberone-based inhibitor skepinone-L (1, Figure 1) as
a potent and selective inhibitor of p38α/β. The in vivo
suitability of 1 was already validated within multiple projects
with promising results in inflammatory models,6 and more
recently, we were also able to demonstrate a successful
Fueled by these promising results, our ongoing discovery
programs on this valuable inhibitor class have meanwhile
created a great demand of key intermediates, especially of the
core scaffold structure 2-chloro-7-hydroxy-10,11-dihydro-5H-
dibenzo[a,d][7]annulen-5-one (8, Scheme 1). Since the initial
discovery route showed several apparent drawbacks (Scheme
1), an optimization of the synthesis of dibenzosuberone
intermediate 8 was inevitable.
The initial route started from 3-methoxybenzoic acid (2),
which was condensed with formaldehyde under acidic
conditions to form the corresponding phthalide 3 in moderate
yield. This was subsequently transformed to the aldehyde 4 via
a two-step procedure including the bromination of the
methylene group under Wohl−Ziegler conditions, followed
by basic hydrolysis with aqueous sodium hydroxide. The next
step introduced the second half of the suberone scaffold via a
Wittig reaction. Therefore, the Wittig reagent was prepared in
situ by refluxing equimolar amounts of 3-chlorobenzylchloride
and triphenylphosphine in methanol, prior to the addition of
aldehyde 4 and sodium methanolate. The equimolar formation
Received: March 4, 2021
Figure 1. Structure of p38 inhibitor skepinone-L (1).
© XXXX The Authors. Published by
American Chemical Society
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Scheme 1. Discovery Route to Key Intermediate 8
Figure 2. Rerouting of the initial reported synthesis. Left: previously reported Wittig-based approach by Koeberle et al.6,8 Middle: Heck-based
retrosynthetic transformation reported in this work. Right: Synthetic equivalents 9 and 10 for the Heck reaction.
of triphenylphosphine oxide as a byproduct of the Wittig
reaction complicated the workup of this step. After aqueous
quench, the crude reaction mass had to be extracted several
times with DCM, to remove majority of the phosphine oxide
while carboxylic acid 5 remained in the basic aqueous phase.
The crude product was obtained after acidification and had to
be further purified via recrystallization, resulting in a low yield
of only 40%. In advance of the final ring closure to the
dibenzosuberone scaffold, the double bond of stilbene 5 was
reduced via a standard hydrogenation procedure. An observed
side reaction was the dehydrohalogenation of the chloro
substituent, but this was kept on an acceptable level and a final
recrystallization from aqueous methanol afforded compound 6
in good yield. The main issue in this step was the low solubility
of the free carboxylic acid (30 mL per gram 5) which resulted
in large reaction volumes. The ring closure to the suberone
core was performed as a two-step procedure initiated by the
activation of the carboxylic acid function with thionyl chloride
and subsequent intramolecular Friedel−Crafts acylation with-
out the isolation of the acid chloride intermediate. The workup
of this reaction suffered from a slow phase separation after
aqueous quench and the crude product required chromato-
graphic purification resulting in a moderate yield of 58% for
this step. The final deprotection of the methoxy group was
carried out under acidic conditions using aqueous hydro-
bromic acid along with acetic acid as cosolvent. This
transformation proceeded smoothly and provided the desired
key intermediate 8 in excellent yield.
Besides the fairly low overall yield of ca. 12% over seven
steps, the initial route included two critical steps mainly
hindering a feasible scale-up. The Wittig reaction for the
preparation of the stilbene 5 required equimolar amounts of
triphenylphosphine resulting in an unfavorable atom economy
and delivering only poor yields. Moreover, the intramolecular
Friedel−Crafts acylation for the ring closure to suberone 7 was
accompanied by a tedious workup procedure and unclean
conversion profile which required chromatographic purifica-
tion. Herein, we present our development of a more practical
route to key intermediate 8, which is capable of ensuring the
supply of our ongoing projects and may serve as a valuable
basis for the development of a commercial manufacturing
process of suberone-based p38 inhibitors like skepinone-L (1).
RESULTS AND DISCUSSION
■
Our rerouting considerations were mainly focused on the
exchange of the Wittig reaction for the installation of the C2-
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Scheme 2. Optimized Development Route for the Preparation of Key Intermediate 8
a
Table 1. Initial Optimization of the Heck Coupling Reaction
b
entry
Pd source
Pd loading (mol %)
solvent
base
conversion (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Pd2dba3
1.0
0.5
1.0
0.5
0.2
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
DIPEA
8
6
>99
91
3
>99
>99
>99
96
>99
>99
98
Pd2dba3
t-Bu3P Pd G3
t-Bu3P Pd G3
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
Pd G3 μ-dimer
c
9
MEK
10
11
12
13
14
15
EtOAc
d
1,2-PC
DMA
DMF
DMF
DMF
99
98
98
Et3N
a
Conditions: Reactions were carried out with 1 mmol of 11 and 1.02 equiv of 10 at 0.5 M solvent concentration, using 1.1 equiv of base and 10 mol
% TBAC. t-Bu3P was used in 3-fold excess to Pd0, and the catalyst was preactivated separately with an appropriate amount of base (5-fold excess to
Pd source) before it was added to the other reagents. Reactions were stirred at 80 °C overnight (ca. 16 h) under inert atmosphere, and the
conversions were checked via HPLC (area % ratios of 12 to 11). Palladium sources: Palladium(II)acetate (Pd(OAc)2); Tris-
b
(dibenzylideneacetone)dipalladium (Pd2dba3); [2′-(amino-κN)[1,1′-biphenyl]-2-yl-κC][bis(1,1-dimethylethyl)(2,2-dimethylpropyl)phosphine]-
(methanesulfonato-κO)palladium (t-Bu3P Pd G3); bis[2′-(amino-κN)[1,1′-biphenyl]-2-yl-κC]bis[μ-(methanesulfonato-κO:κO)]dipalladium (Pd
c
d
G3 μ-dimer). MEK: Methylethylketone. 1,2-PC: 1,2-Propylencarbonat.
bridge between the two aromatic rings and resulted in the
evaluation of a Heck coupling for this synthetic transformation
(Figure 2). The retrosynthetic cleavage of the stilbene
derivative 5 on the western end of the double bond yielded
two readily accessible and commercially available starting
materials: 2-bromo-5-methoxybenzoic acid (9) and 1-chloro-3-
coupling, the starting material 9 had to be converted to the
corresponding methyl ester under standard conditions with a
catalytic amount of sulfuric acid in methanol. This step did not
need any optimization and the desired product 11 was isolated
in near-quantitative yield after extractive workup (Scheme 2).
The initial conditions of the subsequent Heck reaction used
tris(dibenzylideneacetone)dipalladium (Pd2dba3) and tri-tert-
butylphosphine (t-Bu3P) as catalytic system, dicyclohexylme-
thylamine (Cy2NMe) as base, dioxane as solvent, and
tetrabutylammoniumchloride (TBAC) as additive. These
a
vinylbenzene (10).
The direct coupling of the free acid 9 and styrene 10 was
initially tested, but no significant conversion to the desired
product was observed under the conditions described later in
this manuscript (vide infra). Therefore, in advance of the Heck
b
parameters were adopted and slightly modified from
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previously described general procedures,9,10 where TBAC is
claimed to increase the catalyst activity and conversions. These
initial conditions worked very well for the coupling of ester 11
and styrene 10, delivering clean and complete conversions with
an already favorably low palladium loading of 1 mol %.
However, since this step is set very early in the synthetic route
and cross-coupling reactions usually require several relatively
costly reagents, it was necessary to optimize these initial
conditions to keep this conversion economically acceptable.
Therefore, we screened a small set of different palladium
sources, various organic bases as well as different solvents to
find an optimal protocol to conduct the reaction on multigram
scale (Table 1).
As the optimization of cross-coupling reactions is a
multiparametrical issue, we first focused on different palladium
sources and loadings (Table 1, entry 1−8). With Pd2dba3, we
observed decreased product formation when reducing the
catalyst below 1 mol %, but achieved high conversions with 0.5
mol % palladium when using Buchwald-type precatalysts of the
third generation11 (Table 1, entry 7). It turned out to be most
convenient to generate the catalytic system in situ from the Pd
G3 μ-dimer (Figure 3) as palladium source and tri-tert-
conditions and delivered only insufficient conversions to the
desired product (Table 1, entries 1 and 2).
Different polar and nonpolar solvents were screened to
evaluate the scope of this parameter, and favorable high
conversions (>95% after 16 h at 80 °C) were achieved with all
of the used examples (Table 1, entries 9−13). Besides the
more process-friendly and greener solvents methylethylketone
(MEK), ethyl acetate (EtOAc), and 1,2-propylene carbonate
(1,2-PC),13 we also tested the water-miscible solvents
dimethylformamide (DMF) and dimethylacetamide (DMA)
to facilitate a possible precipitative workup. An extractive
isolation of 12 was clearly disfavored, since this compound
solidifies only very slowly after evaporation of the organic
phase (mp 56−57 °C), thereby complicating the purification
of this intermediate.
Finally, we also tried to find a substitute for Cy2NMe as a
base and screened the closely related but sterically less
demanding triethylamine (Et3N) and N,N-diisopropylethyl-
amine (DIPEA) for this purpose. Both bases were well
tolerated and delivered almost complete conversions under
these conditions (Table 1, entries 14 and 15).
Based on these initial optimizations, we progressed to
increased batch sizes and further tried to decrease the catalyst
loading as well as the amount of TBAC additive (Table 2).
Gradually, we were able to reduce the necessary amount of
palladium to a very low level of 0.1 mol %, and the
concentration of TBAC from 10 to 1 mol %, which were
considered to be acceptable parameters for the final scale-up.
Over the range of the different gram-sized batches, we achieved
consistently high isolated yields of 85−91% with a very
practical precipitative workup procedure. Since the stilbene 12
has a fairly low melting point (mp 56−57 °C), it shows a
strong tendency to deposit as oily material upon direct dilution
of the reaction mixture with water. This can be avoided by
preceding dilution with MeOH prior to careful addition of
water until precipitation occurs.
Figure 3. Structures of Buchwald Precatalysts.
butylphosphonium tetrafluoroborate (t-Bu3P·HBF4) as a
bench-stable substitute for the pyrophoric and air-sensitive
freebase of this phosphine ligand.12 Surprisingly, the use of
Pd(OAc)2 as palladium source was not compatible with these
While increasing the batch size, we also increased the
substrate concentration from the initial 0.25 up to 0.67 M
corresponding to a reduction of solvent usage greater than
Table 2. Further Heck Optimization on Gram-Scale Batches
a
b
entry
scale (g)
Pd loading (mol %)
TBAC (mol %)
solvent (molarity)
isolated yield (%)
1
2
3
4
5
6
7
8
9
1
2
2
0.5
0.25
0.25
0.1
0.1
0.1
0.1
0.1
0.1
5
DMF (0.5 M)
DMF (0.5 M)
DMF (0.5 M)
DMF (0.67 M)
DMF (0.67 M)
DMF (0.67 M)
EtOAc (0.67 M)
EtOAc (0.67 M)
EtOAc (0.67 M)
91
89
85
87
89
89
88
87
88
2.5
2.5
1
1
1
2
10
50
2
2
10
1
a
Conditions: Reactions were carried out with 1.02 equiv of 10, 1.1 equiv Et3N, and indicated amounts of Pd G3 μ-dimer, t-Bu3P·HBF4, and TBAC.
For entries 1 and 2, the catalytic system was preactivated separately, while for entries 3−9, the ligand and palladium source was added directly to
b
the reaction mixture. The reactions were run for 12 h either at 100 °C for DMF or at reflux temperature for EtOAc. Yield given as isolated yield
after precipitative workup.
D
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60%. This modification did not negatively affect workup or
yield, but significantly reduced the volume of antisolvent
required for precipitation, and therefore also lowered the
amount of waste produced in this step.
Additionally, it turned out that separate preactivation of the
catalytic system, as carried out for the initial optimization
studies (Table 1), was not necessary for the gram-scale
reactions to proceed smoothly and completely. Therefore, the
technical setup of the reaction was further simplified, since it
was sufficient to simply add the ligand and the Pd source as
solids to the thoroughly degassed reaction mixture to initiate
the coupling reaction.
Finally, we were able to apply these optimized Heck
conditions on a 50 g batch to successfully demonstrate the
scalability of this robust protocol, and isolated the desired
product 12 in 89% yield with high purity (HPLC: 96.9 area
%).
Encouraged by these promising results, we also performed
some additional orientating experiments with EtOAc as a green
alternative to DMF and investigated the necessity of TBAC as
additive (Table 2, entries 7−9). Two proof-of-concept batches
on a 2 g scale performed well under the optimized conditions
with and without TBAC as additive without any remarkable
losses in the isolated yield. Another 10 g batch also delivered
12 in 88% isolated yield (Table 2, entry 9) after a similar
precipitative workup with an initial dilution with MeOH
followed by the addition of an equal amount of water. The
complete omission of TBAC and the use of EtOAc as a
process-friendly solvent may further simplify the development
of a manufacturing process in the future.
In advance of the ring closure to dibenzosuberone 7, the
stilbene double bond of 12 first had to be reduced to an ethane
group. In the corresponding step of the previously reported
synthetic route, hydrogenation on a palladium catalyst in a
MeCN/EtOAc mixture delivered very satisfying results despite
some technical drawbacks. The fairly low solubility of the free
acid 5 (11 mg/mL at ambient temperature) turned out to be a
problematic factor requiring large solvent volumes (30 mL/g)
and slow reaction rates due to incomplete dissolution of the
starting material at the beginning of the reaction. Additionally,
formation of the hydrodehalogenation side product 14 (Figure
4) was observed as a competing reaction, especially at longer
reaction times. The optimization efforts for this step therefore
mainly aimed to reduce the amount of used solvent (<20 mL/g
s.m.), reduce the reaction time to less than 12 h, and limit the
formation of side product 14 to an acceptable level (<3 area
%).
Fortunately, methyl ester 12 shows a significantly increased
solubility in organic solvents compared to free acid 5 (Table
S1, Supporting Information), which facilitates the reaction
tremendously. A short screen was performed in different
solvents (data not shown) revealing varying reaction profiles
depending on the solvent used. In pure EtOAc, THF, or
MeCN, the solubility of 12 was favorably high and marginal
dehalogenation was observed, but the reaction rates were very
low, resulting in unacceptably long reaction times. On the
other hand, the conversion in MeOH was very fast, but also
showed an increased formation of des-chloro side product 14
and a low solubility of starting material.
Another finding during these early test reactions was that
cooling of the mixture below ambient temperature (<20 °C)
slowed down the dehydrohalogenation side reaction, but did
not significantly influence the reduction of the double bond,
resulting in a kinetic selectivity under these conditions.
To get an optimized reaction profile and combine the
advantages of different solvents, we carried out the reduction in
a variety of mixtures from the aprotic solvents (MeCN, THF,
and EtOAc) with MeOH (Table 3). The test reactions were
carried out at a 1 gram scale, and the conversions were assayed
via GC-MS after 4 h. Except THF/MeOH (Table 3, entry 2),
all mixtures showed finished or almost complete conversion at
this point and only small variations in the amount of formed
byproduct 14.
Although the solubility in the solvent/MeOH mixtures was
determined to be similarly high as in the pure aprotic solvents
(Table S1, Supporting Information), there was also a tendency
to form oversaturated solutions. At higher substrate concen-
trations (<10 mL/g), this very often resulted in precipitation of
the starting material upon addition of the catalyst and stalled
conversions most probably due to clogging of the heteroge-
neous catalyst. However, within the screened set, the EtOAc/
MeOH mixture showed the best combination of good
solubilizing of starting material and a favorable conversion
profile and was therefore chosen for further scale-up. With a
solvent ratio of 15 mL per gram starting material, the proof-of-
concept batch (ca. 55 g) proceeded under these conditions to
completion within 10 h using a catalyst loading of 2.5 wt %
Pd/C. Product 13 was isolated in quantitative yield containing
1.7 area % of side product 14 according to HPLC.
For final analytical identification and characterization of 14
and the corresponding impurities 15 and 16 (Figure 4), which
were observed in the following steps, we also prepared these
compounds separately via forced hydrodehalogenation.
In the previously reported route, the ring closure reaction to
the dibenzosuberone scaffold was achieved via an intra-
molecular Friedel−Crafts acylation. While being a reliable
and practical method in a smaller scale, this protocol suffered
upon scale-up from several disadvantages like tedious workup
due to bad phase separations and the necessity of chromato-
graphic purification. Our first priority was therefore to establish
a process that does not need column chromatography prior to
the final deprotection of the methyl ether. In earlier reports, we
also used polyphosphoric acid (PPA) in sulfolane to achieve
the same ring closure reaction for structural closely related
molecules,14 but of course, these reagents have several
drawbacks in handling as well. Eaton’s reagent, a saturated
solution of phosphorous pentoxide in methanesulfonic acid, is
a valuable alternative to PPA in such condensations and has
Figure 4. Structures of des-chloro-impurities originating from the
hydrodehalogenation side reaction during the reduction of the
stilbene double bond.
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a
Table 3. Solvent Screening for Double Bond Reduction
b
GC area %
entry
solvent system
12
13
14
1
2
3
4
5
6
MeCN/MeOH (80:20 vol %)
THF/MeOH (80:20 vol %)
THF/MeOH (75:25 vol %)
THF/MeOH (66:34 vol %)
EtOAc/MeOH (75:25 vol %)
EtOAc/MeOH (66:34 vol %)
1.4
44.2
0
0
1.3
0
97.4
55.4
98.9
98.7
98.4
99.2
1.2
0.4
1.1
1.3
0.3
0.8
a
Conditions: Reactions were carried out on a 1 g scale. Catalyst (5 wt % Pd/C) was added after dissolution of starting material, and the reaction
b
was stirred under an atmosphere of hydrogen at <20 °C for 4 h. Conversion was checked via GC-MS and is given as the AUC ratios between s.m.
12, product 13, and des-chloro side product 14.
also been applied previously in large-scale processes.15,16 We
evaluated the application of this reagent in this conversion for
the acid 6, as well as for the ester 13, and observed favorable
conversions to 7 in both cases. The latter came along with the
advantage of the reaction mixture remaining a solution
throughout the complete reaction, whereas the free acid 6
only dissolves slowly in the reagent, resulting in difficult-to-stir
suspensions.
Therefore, we assayed the conversion from 13 to 7 as a
function of the amount of Eaton’s reagent used and different
temperatures, and observed a clear influence of both
parameters on the reaction rate (Figure 5).
As implied by the graphs in Figure 5, the conversion tends to
slow down toward the end of the reaction under all
investigated conditions. At the lower temperature of 60 °C,
only about 80% conversion was achieved even after a
prolonged reaction time of 22 h, whereas the reaction ran
nearly to completion at 70 °C within a shorter time and with
the highest amount of Eaton’s reagent (5 mL of reagent per
gram 13). However, higher temperatures were also accom-
panied by increased formation of byproducts, and therefore,
the final scale-up reaction was carried out at an internal
temperature of 65 °C, resulting in complete conversion (<1%
s.m.) after 26 h.
Despite the relatively clean reaction profile observed via GC-
MS, the reaction mixture darkens quickly upon heating,
resulting in a persistent discoloration after workup. Since the
product 7 has a very low melting point (mp 48−49 °C), any
attempts of purification via crystallization failed, and we
decided to use the crude product in the next step after partial
purification in solution. Therefore, the reaction was first
quenched into water and basified with solid KOH to destroy
any residual anhydrides or other reactive species derived from
Eaton’s reagent. The product was then extracted into toluene,
treated with silica, and activated carbon during azeotropic
drying. After removal of the solvent, crude 7 was isolated in
acceptable purity (HPLC: 90.5 area %) with 15 as the main
impurity (HPLC: 4.6 area %). However, this crude material
did not need further purification to be used directly in the next
step.
Figure 5. Conversion of 13 to 7 under different conditions. Reactions
were carried out at 1 mmol scale with the indicated amount of Eaton’s
reagent per gram of 13 at 60 °C (top graph) or 70 °C (bottom graph)
heating block temperature. The conversions were determined via GC-
MS as the area ratios of 13 and 7.
afford satisfying reaction profiles. The workup procedure was
slightly customized to remove the aforementioned discolor-
ation from the condensation step and decrease the ratio of des-
chlorinated impurities to a tolerable level. The workup started
with quenching the reaction in aqueous methanol, affording 8
as a granular precipitate, which was readily filterable and
already showed a purity of >95% (HPLC). For further
purification, the crude material was refluxed with activated
carbon in an EtOAc/MeOH mixture followed by partial
evaporation of the solvents and isolation of the precipitate by
The final deprotection of the methyl ether was carried out
under relatively harsh conditions using hydrobromic acid in
aqueous acetic acid. These conditions were already applied in
the original route and did not need significant modifications to
F
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filtration. An additional second crop of high purity was
obtained by evaporation of the mother liquor and recrystalliza-
tion of the residue from MeOH.
The combined crops afforded the final key intermediate 8 in
an acceptable yield of 59% and favorable high purity (HPLC:
98.9 area %) with only des-chloro compound 16 as a
detectable impurity.
were measured by the mass spectrometry department, Institute
of Organic Chemistry, Eberhard Karls University of
Tuebingen, on a Bruker maXis 4G ESI-TOF from Daltonik/
Bremen. The instrument was run in ESI+ mode, settings were
as follows: nebulizer gas 1.2 bar, gas flow rate 6.0 L/min,
source temperature 200 °C, capillary voltage +4500 V, end
plate offset −500 V, and m/z range 80−1000 m/z.
Synthesis of Key Intermediate 8 at 50 g Scale. Methyl 2-
Bromo-5-methoxybenzoate (11). In a 500 mL two-neck flask,
2-bromo-5-methoxybenzoic acid 9 (80.1 g, 347 mmol) was
suspended in MeOH (300 mL) and concentrated H2SO4 (6
mL, 2 vol %) was added carefully to the mixture. The reaction
was heated to reflux, and stirring was continued overnight.
TLC indicated complete conversion at this point, and the
mixture was concentrated under reduced pressure. The residue
was taken up in EtOAc (300 mL) and washed successively
with water, aqueous NaHCO3, and brine (200 mL each). After
drying over Na2SO4 and evaporation of solvents, the title
compound 11 (83.3 g, 340 mmol, 98% yield) was obtained as a
CONCLUSIONS
■
In this study, we developed a novel synthetic route to 8, a key
intermediate to the currently highly investigated p38 inhibitor
skepinone-L (1). With this improved route, we were able to
access this valuable building block in a larger multigram scale
with an overall yield of 46%, which corresponds to an almost 4-
fold improvement compared to the initial discovery route.
Moreover, this approach eliminates any chromatographic steps
and has therefore a good potential for further scale-up. The key
modification was the rerouting of the C−C bond formation by
the application of a Heck coupling, which was thoroughly
optimized to deliver good conversions and high yields with
extremely low catalyst loadings. Additionally, we also evaluated
the optional use of green solvent alternatives and were able to
successfully demonstrate the applicability of process-friendly
EtOAc in this reaction. The elimination of the main
problematic steps from the discovery route, Wittig reaction
and Friedel−Crafts acylation, improved atom economy and
simplified workup procedures. Overall, this novel improved
five-step synthetic route is very suitable to provide convenient
access to the necessary multigram amounts of key intermediate
8 that are required for our continually progressing develop-
ment programs on dibenzosuberone-based p38 inhibitors.
1
colorless oil. H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8
Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 6.85 (dd, J = 8.8, 3.2 Hz,
1H), 3.89 (s, 3H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 166.4, 158.6, 135.0, 132.8, 119.0, 116.3, 111.9, 55.6, 52.5.
HRMS (ESI) [M + Na]+ calcd for C9H9BrNaO3 , 266.96273;
+
found 266.96296. GC-MS tret = 3.32 min; m/z (EI): 244 [M]+
HPLC tret = 7.34 min; purity > 99 area %.
Methyl (E)-2-(3-Chlorostyryl)-5-methoxybenzoate (12).
Method A (50 g batch in DMF with 1 mol % TBAC): An
oven-dried 500 mL two-neck flask was charged with 11 (50.0
g, 204 mmol, 1.0 equiv), 3-chlorostyrole 10 (28.8 g, 206 mmol,
1.01 equiv), TBAC (567 mg, 0.6 mmol, 0.01 equiv), Et3N
(31.5 mL, 224 mmol, 1.1 equiv), and DMF (300 mL, HPLC
grade), and the solution was degassed thoroughly via several
vacuum/argon cycles. The catalytic system, consisting of t-
Bu3P·HBF4 (178 mg, 0.6 mmol, 0.3 mol %) and Pd G3 μ-
dimer (75 mg, 0.1 mmol, 0.1 mol %), was added and the
degassing procedure was repeated. The reaction was heated to
100 °C internal temperature, and stirring was continued until
the starting material was consumed. HPLC indicated complete
conversion after 12 h, and the reaction was allowed to cool
back down to ambient temperature. The mixture was then
diluted with 600 mL of MeOH and placed in an ice bath. Cold
water was added dropwise until a slight turbidity was observed
(after about 200 mL). The mixture was seeded with solid
material 12 (ca. 5 mg) from a previous batch and stirring was
continued until a white precipitate was formed. Additional
water was added to produce a thinner suspension (total
amount of water = 1000 mL), and the precipitated solids were
isolated by filtration and washed with 40% aqueous MeOH
and water to yield 12 (55.1 g, 182 mmol, 89% yield) as an off-
white solid after vacuum drying. 1H NMR (400 MHz, CDCl3)
δ 7.94 (d, J = 16.2 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.53−
7.49 (m, 1H), 7.49−7.44 (m, 1H), 7.42−7.37 (m, 1H), 7.34−
7.19 (m, 2H), 7.11−7.04 (m, 1H), 6.84 (d, J = 16.2 Hz, 1H),
3.95 (s, 3H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
167.6, 159.1, 139.8, 134.7, 131.5, 129.9, 129.8, 128.7, 128.4,
128.4, 127.5, 126.6, 124.9, 118.9, 115.2, 55.6, 52.3. HRMS
EXPERIMENTAL SECTION
■
General Information. Reagents, starting materials, and
solvents were of commercial quality and were used without
further purification unless otherwise stated. TLC analysis was
carried out on Merck 60 F254 silica gel plates and visualized
under UV light at 254 and 365 nm. Preparative column
chromatography was carried out on Grace Davison Davisil
LC60A 20−45 μm silica using an Interchim PuriFlash 430
automated flash chromatography system. Melting points were
measured with a Mettler Toledo MP70 and are uncorrected.
LC analysis was performed via RP-HPLC on an Agilent 1100
Series LC with a Phenomenex Luna C8 column (150 mm ×
4.6 mm, 5 μm), and detection was performed with a UV DAD
at 254 and 230 nm wavelengths. Elution was carried out with
the following gradient: aqueous KH2PO4 (0.01 M, pH 2.30)
(solvent A), MeOH (solvent B), 40% B to 85% B in 8 min,
85% B for 5 min, 85% to 40% B in 1 min, 40% B for 2 min,
stop time 16 min, and flow rate 1.5 mL/min. NMR spectra
were recorded on a Bruker Avance 400 NMR spectrometer.
Chemical shifts are reported in ppm relative to TMS, and the
spectra were calibrated against the residual proton peak of the
used deuterated solvent. Mass spectra were obtained via GC-
MS with EI ionization from a Hewlett-Packard HP 6890
coupled with an HP 5973 MSD. Preceding gas chromatog-
raphy was carried out on an HP-5MS column (30 m × 250 μM
× 0.25 μM) with a helium flow rate of 1.2 mL/min using the
following temperature gradient: 160 °C for 1 min, 160 °C to
250 °C in 3.6 min, 250 °C for 1 min, 250 to 280 °C in 2 min,
280 °C for 1 min, 280 to 300 °C in 2 min, 300 °C for 2 min,
and stop time 12.6 min. High-resolution mass spectra (HRMS)
(ESI) [M + Na]+ calcd for C17H15ClNaO3 , 325.06019; found
+
325.06023. GC-MS tret = 7.85 min; m/z (EI): 302 [M]+ HPLC
tret = 10.20 min; purity 96.9 area %.
Method B (10 g batch in EtOAc without TBAC): A 250 mL
two-neck flask was charged with 11 (10.0 g, 40.8 mmol, 1.0
equiv), 10 (5.71 g, 41.2 mmol, 1.01 equiv), Et3N (4.54 g, 44.9
G
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Article
mmol, 1.1 equiv), and EtOAc (60 mL, HPLC grade) and
degassed thoroughly via several vacuum/argon cycles. The
catalytic system, consisting of t-Bu3P·HBF4 (36 mg, 0.12
mmol, 0.3 mol %) and Pd G3 μ-dimer (15 mg, 0.02 mmol, 0.1
mol %), was added and the degassing procedure was repeated.
The reaction was heated to reflux, and stirring was continued
until the starting material was consumed. HPLC indicated
complete conversion after 10 h, and the reaction was allowed
to cool back to ambient temperature and was then diluted with
MeOH (60 mL) and placed in an ice bath. Cold water was
added dropwise until a slight turbidity was observed (after
about 10−15 mL). The mixture was seeded with solid 12 (ca.
5 mg) from a previous batch and stirring was continued until a
white precipitate was formed. Additional water was added to
produce a thinner suspension (total amount of water = 60
mL), and the precipitated solids were isolated by filtration and
washed with chilled 50% aqueous MeOH. The filter cake was
dried at 50 °C in a vacuum oven to obtain the title compound
12 as an off-white solid. Yield: 10.9 g (36.1 mmol, 88%) HPLC
purity 96.9 area %.
separated, and the aqueous phase was extracted once more
with 200 mL of toluene. To the combined organic phases, 27 g
of silica (50 wt % s.m.) and 13 g of charcoal (25 wt % s.m.)
were added, and the toluene solution was dried azeotropically
by refluxing under Dean−Stark conditions for about 2 h. The
solids were filtered off over a bed of Celite and were washed
with an additional 250 mL of toluene. The filtrate was
evaporated to yield the crude 7 (43.9 g, 161 mmol, 90% crude
yield, HPLC purity 90.4 area %) as a red oil, which was directly
carried on to the next step without further purification. To
obtain an analytical sample of 7, a small amount of the crude
material was purified via flash chromatography on SiO2 with
gradient elution (hexane/EtOAc 0−20%). 1H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.9 Hz,
1H), 7.28 (dd, J = 8.5, 2.1 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H),
7.11 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.9 Hz, 1H), 3.83
(s, 3H), 3.11 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 193.5,
158.5, 144.0, 138.9, 138.4, 136.9, 134.5, 132.7, 130.8, 129.1,
127.0, 120.0, 114.3, 55.6, 35.2, 34.0. HRMS (ESI) [M + Na]+
+
calcd for C16H13ClNaO2 , 295.04963; found 295.04980. GC-
MS tret = 6.62 min; m/z (EI): 272 [M]+ HPLC tret = 9.73 min.
2-Chloro-7-hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]-
annulen-5-one (8). The crude 7 from the previous step (43.9
g, 161 mmol) was dissolved in acetic acid (175 mL, 4 mL/g
s.m.), and concentrated hydrobromic acid (88 mL, 2 g/mL
s.m.) was added under stirring at ambient temperature. The
reaction was heated to reflux, and after 6 h, TLC indicated
complete consumption of starting material. The heating source
was removed, and the reaction was allowed to cool to about 70
°C and was then added slowly to a beaker with 520 mL of
aqueous MeOH (50% v/v) at a temperature of 10 °C. The
formed suspension was cooled with an external ice bath and
stirred at 5 °C for about 30 min. The solids were isolated by
vacuum filtration until no further filtrate was collected, and the
filter cake was resuspended in 250 mL of cold MeOH. The
solids were filtered again and washed with cold MeOH to yield
the crude product as a grayish solid (29.9 g, HPLC purity 95.3
area %). For further purification, the material was resuspended
with 3 g of activated carbon (10 wt % crude product) in 240
mL of EtOAc/MeOH (3:1, 8 mL/g) and heated to reflux for 1
h. The charcoal was removed via filtration over Celite, and the
filter bed was rinsed with an additional 80 mL of EtOAc/
MeOH (3:1). The filtrate was concentrated under reduced
pressure, and after about 160 mL, it was distilled off, the
product started to precipitate from the solution. Concentration
was measured until a total amount of ca. 200 mL was distilled
off and a thick suspension was formed. This suspension was
stirred under ice cooling for 30 min before the solids were
filtered and washed with cold MeOH. This afforded a first crop
of 20.4 g after drying at 60 °C in a vacuum oven. The filtrate
was concentrated under reduced pressure, and the residue was
recrystallized from MeOH to obtain a second crop of 4.2 g of
the title compound. The two crops were combined, and the
final key intermediate 8 (24.6 g, 95 mmol, 59% yield) was
Methyl 2-(3-Chlorophenethyl)-5-methoxybenzoate (13).
A 1 L two-neck flask fitted with a glass-sintered gas inlet, and a
thermometer was charged with 12 (54.4 g, 180 mmol), and the
solids were dissolved in EtOAc/MeOH (3:1, 840 mL). Pd/C
(2.72 g, 50% wet) was added subsequently, and the reaction
was thoroughly purged with hydrogen (Caution: This is a
potential safety issue. The operation was carried out in a well-
ventilated fumehood, but to be in line with the common
industrial safety regulations, the reaction mixture should first
be inerted with nitrogen prior to purging with hydrogen).
Stirring was then continued at <20 °C internal temperature
under hydrogen atmosphere until the starting material was
consumed (about 10 h). The reaction mixture was filtered over
a bed of Celite, and the catalyst was washed with EtOAc. The
filtrate was concentrated under reduced pressure to yield a
yellow oil. To remove residual small amounts of catalyst, the
oily residue was redissolved in THF (2 mL/g), passed through
a 0.45 μm filter, and the filtrate was evaporated again to obtain
13 (55.0 g, 180 mmol, quant. yield) as an opaque oil, which
1
was finally dried under high vacuum. H NMR (400 MHz,
CDCl3) δ 7.46 (d, J = 2.8 Hz, 1H), 7.25−7.15 (m, 3H), 7.13−
7.05 (m, 2H), 6.98 (dd, J = 8.4, 2.8 Hz, 1H), 3.91 (s, 3H), 3.82
(s, 3H), 3.21−3.13 (m, 2H), 2.89−2.81 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 167.7, 157.8, 144.2, 135.4, 134.1, 132.3,
130.2, 129.6, 128.8, 126.9, 126.1, 118.5, 115.5, 55.5, 52.1, 38.0,
35.8. HRMS (ESI) [M + Na]+ calcd for C17H17ClNaO3 ,
+
327.07584; found 327.07594. GC-MS tret = 6.62 min; m/z
(EI): 304 [M]+ HPLC tret = 10.39 min; purity 95.3 area %.
2-Chloro-7-methoxy-10,11-dihydro-5H-dibenzo[a,d][7]-
annulen-5-one (7). A 500 mL two-neck flask fitted with a
thermometer and a magnetic stirring bar was charged with 13
(54.6 g, 179 mmol), and Eaton’s reagent (273 mL, 5 mL/g
s.m.) was added at ambient temperature while stirring. The
reaction was heated to an internal temperature of 65 °C, and
stirring was continued until GC-MS indicated less than 1% s.m.
in the mixture (about 26 h). The reaction was then quenched
by adding it slowly (Caution: exothermic) to 1250 mL of
water at room temperature. The exothermic hydrolysis caused
an increase of temperature to about 50−60 °C. The mixture
was then basified by careful addition of solid NaOH while
controlling the temperature by cooling with ice/water.
Subsequently, 400 mL of toluene were added and stirring
was continued vigorously for about 30 min. The phases were
1
obtained as a beige to off-white solid. H NMR (400 MHz,
DMSO) δ 9.64 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.41 (d, J =
2.0 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.33 (d, J = 2.7 Hz,
1H), 7.13 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 8.2, 2.7 Hz, 1H),
3.11−2.99 (m, 4H). 13C NMR (101 MHz, DMSO) δ 192.9,
155.8, 144.2, 138.1, 136.9, 136.7, 132.7, 132.1, 131.0, 128.9,
126.5, 120.2, 115.8, 34.1, 33.0. HRMS (ESI) [M + Na]+ calcd
+
for C15H11ClNaO2 , 281.03398; found 281.03430. GC-MS tret
H
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Article
= 8.08 min; m/z (EI): 258 [M]+ HPLC tret = 8.59 min; purity
98.9 area %.
cake was dried, and the crude product was purified via flash
chromatography on SiO2 with gradient elution (hexane/EtOAc
5−40%) to obtain 16 (170 mg, 0.76 mmol, 75% yield) as a
white crystalline solid. 1H NMR (400 MHz, DMSO) δ 9.62 (s,
1H), 7.82 (dd, J = 7.8, 1.1 Hz, 1H), 7.51−7.42 (m, 1H), 7.37−
7.30 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 8.2 Hz,
1H), 6.93 (dd, J = 8.2, 2.7 Hz, 1H), 3.14−2.94 (m, 4H). 13C
NMR (101 MHz, DMSO) δ 194.3, 155.7, 141.9, 138.5, 138.2,
132.7, 132.3, 130.9, 129.8, 129.3, 126.4, 120.0, 115.7, 34.4,
Synthesis of Des-Chloro Impurities 14, 15, and 16.
Methyl 5-Methoxy-2-phenethylbenzoate (14). Compound
12 (1.20 g, 4.0 mmol, 1.0 equiv) and Et3N (1.11 mL, 8 mmol
2.0 equiv) were dissolved in a glass-lined hydrogenation
reactor in EtOAc/MeOH (ratio 1:1, 30 mL), and Pd/C (60
mg, 50% wet) was added subsequently. The mixture was
purged with hydrogen for several minutes (Caution: This is a
potential safety issue. The operation was carried out in a well-
ventilated fumehood, but to be in line with the common
industrial safety regulations, the reaction mixture should first
be inerted with nitrogen prior to purging with hydrogen)
before the reactor was sealed and pressurized with 6 bar
hydrogen. The reactor was placed in a water bath at 50 °C and
stirring was continued overnight. At this point, GC-MS
indicated complete conversion to the desired product and
the catalyst was filtered off. The filtrate was concentrated under
reduced pressure, and the residue was taken up in 70 mL of
EtOAc. The organic phase was washed successively with water,
aqueous HCl (2 N), and brine (30 mL each) prior to drying
over Na2SO4 and evaporation to obtain 14 (1.05 g, 3.9 mmol,
33.3. HRMS (ESI) [M + Na]+ calcd for C15H12NaO2 ,
+
247.07295; found 247.07313. HPLC tret = 7.38 min; purity
98.8 area %.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00081.
Solubility data for compounds 12 and 5 (Table S1) and
1H and 13C NMR spectra of compounds 7, 8, 11, 12,
and 13 as well as impurities 14, 15, and 16 (PDF)
1
98% yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ
AUTHOR INFORMATION
7.46 (d, J = 2.8 Hz, 1H), 7.35−7.28 (m, 2H), 7.27−7.19 (m,
3H), 7.13 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 8.5, 2.8 Hz, 1H),
3.92 (s, 3H), 3.84 (s, 3H), 3.26−3.15 (m, 2H), 2.94−2.85 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 167.9, 157.7, 142.2,
135.8, 132.4, 130.3, 128.7, 128.4, 125.9, 118.4, 115.4, 55.5,
■
Corresponding Author
Stefan A. Laufer − Department of Pharmaceutical and
Medicinal Chemistry, Institute of Pharmaceutical Sciences,
̈
Eberhard Karls Universität, 72076 Tubingen, Germany;
Cluster of Excellence iFIT (EXC 2180) “Image-Guided and
Functionally Instructed Tumor Therapies”, University of
52.1, 38.4, 36.1. HRMS (ESI) [M + Na]+ calcd for
+
C17H18NaO3 , 293.11482; found 293.11508. GC-MS tret
=
5.68 min; m/z (EI): 270 [M]+ HPLC tret = 9.76 min; purity
97.0 area %.
Tu
Academic Drug Discovery & Development (Tu
72076 Tubingen, Germany; orcid.org/0000-0001-6952-
1486; Email: stefan.laufer@uni-tuebingen.de
̈
bingen, 72076 Tu
̈
bingen, Germany; Tu
̈
bingen Center for
̈
CAD2),
3-Methoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-
one (15). A 20 mL flask was charged with 14 (850 mg, 2.81
mmol) and Eaton’s reagent (4.5 mL). The reaction was heated
up to 65 °C internal temperature, and stirring was continued
overnight at which point, GC-MS indicated complete
consumption of starting material. The reaction was poured
on water and basified with aqueous NaOH with vigorous
stirring. After cooling to ambient temperature, the mixture was
transferred to a separatory funnel and extracted with 30 mL of
EtOAc. The organic phase was washed with water and brine
(20 mL each) prior to drying over Na2SO4 and evaporation.
The residue was purified via flash chromatography on SiO2
with gradient elution (hexane/EtOAc 0−15%) to yield the title
compound 15 (315 mg, 1.32 mmol, 47% yield) as a colorless
̈
Authors
Michael Forster − Department of Pharmaceutical and
Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls Universität, 72076 Tubingen, Germany
̈
Heike K. Wentsch-Teltschik − Department of
Pharmaceutical and Medicinal Chemistry, Institute of
Pharmaceutical Sciences, Eberhard Karls Universität, 72076
Tubingen, Germany
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.1c00081
1
oil. H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 7.7, 1.2 Hz,
Author Contributions
1H), 7.61 (d, J = 2.9 Hz, 1H), 7.44 (td, J = 7.4, 1.5 Hz, 1H),
7.34 (td, J = 7.7, 1.2 Hz, 1H), 7.25−7.19 (m, 1H), 7.13 (d, J =
8.4 Hz, 1H), 7.01 (dd, J = 8.4, 2.9 Hz, 1H), 3.86 (s, 3H),
3.20−3.09 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 195.1,
158.3, 142.0, 139.2, 138.6, 134.7, 132.3, 130.8, 130.6, 129.2,
126.6, 119.7, 114.0, 55.4, 35.1, 34.2. HRMS (ESI) [M + Na]+
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
S.L. and iFIT are funded by the Deutsche Forschungsgemein-
schaft (DFG, German Research Foundation) under Germany’s
Excellence StrategyEXC 2180390900677. TuCAD2 is
funded by the Federal Ministry of Education and Research
+
calcd for C16H14NaO2 , 261.08860; found 261.08871. GC-MS
tret = 6.39 min; m/z (EI): 238 [M]+ HPLC tret = 8.77 min;
purity > 99 area %.
̈
(BMBF) and the Baden-Wurttemberg Ministry of Science as
̈
3-Hydroxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-
one (16). In a 10 mL flask, 15 (240 mg, 1.01 mmol) was
dissolved in acetic acid (2 mL) and concentrated hydrobromic
acid (1 mL) was added at ambient temperature. The reaction
was heated to reflux until TLC indicated complete conversion
(after about 3 h). The reaction mixture was poured on water,
and the white precipitate was isolated by filtration. The filter
part of the Excellence Strategy of the German Federal and
State Governments. M.F. and S.L. thankfully acknowledge
funding by the Landesstiftung Baden-Wuerttemberg (Project
no. BWST_WSF-033).
Notes
The authors declare no competing financial interest.
I
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Article
(9) Littke, A. F.; Fu, G. C. Heck Reactions in the Presence of P(t-
Bu)3: Expanded Scope and Milder Reaction Conditions for the
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(10) Murray, P. M.; Bower, J. F.; Cox, D. K.; Galbraith, E. K.; Parker,
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Salts: Simple, Practical, and Versatile Replacements for Air-Sensitive
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(13) Parker, H. L.; Sherwood, J.; Hunt, A. J.; Clark, J. H. Cyclic
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R. Design, Synthesis, and Biological Evaluation of Phenylamino-
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[a,d]cycloheptan-5-ones: Novel p38 MAP Kinase Inhibitors. J. Med.
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Methanesulfonic Acid. Convenient Alternative to Polyphosphoric
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(16) Ulysse, L. G.; Yang, Q.; McLaws, M. D.; Keefe, D. K.; Guzzo, P.
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ACKNOWLEDGMENTS
■
The authors thank Dr. Bent Pfaffenrot and Dr. Roland Selig for
fruitful scientific discussions during the initialization and
progression of this development study, and Kristine Schmidt
for language proofreading.
ABBREVIATIONS
■
AIBN, azobisisobutyronitrile; DCM, dichloromethane; DIPEA,
diisopropylethylamine; DMA, dimethylacetamide; DMF,
dimethylformamide; DMSO, dimethylsulfoxide; GC-MS, gas
chromatography−mass spectrometry; HPLC, high-perform-
ance liquid chromatography; MAPK, mitogen-activated
protein kinase; MeCN, acetonitrile; NBS, N-bromo succini-
mide; NMR, nuclear magnetic resonance; PPA, polyphosporic
acid; TBAC, tetrabutylammoniumchloride; THF, tetrahydro-
furan; TLC, thin-layer chromatography; TMS, tetramethylsi-
lane
ADDITIONAL NOTES
■
a
3-Chlorostyrene (10) is commercially available, but can also
be prepared over a two-step procedure from 1-bromo-3-
chlorobenzene via a Grignard reaction with acetaldehyde
followed by dehydration of the alcohol.17,18 The styrene itself
is prone to polymerization and should be stabilized with a
radical inhibitor (like p-tert-butylcatechol) and long-term
stored in a brown glass bottle at a lower temperature (5 °C).
(17) Overberger, C. G.; Saunders, J. H. m-Chlorostyrene. Org. Synth.
1948, 28, 31−33.
(18) Overberger, C. G.; Saunders, J. H. m-Chlorophenylmethylcar-
binol. Org. Synth. 1948, 28, 28−30.
b
The general experimental procedure for Heck reaction
reported by Murray et al.10 was performed under the following
conditions: 2 mol % Pd(t-Bu3P)2, 10 mol % TBAC, 1.5 equiv
Cy2NMe in ca. 0.5 M DMA at 80 °C for 24 h. Our initial
conditions replaced the bis-ligated Pd(0) species by t-Bu3P·
HBF4 and Pd2dba3 and used dioxane as a solvent as earlier
described in a report from Littke et al.9
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