Functionalization of the Imidazole Backbone by Means of a Tailored and Optimized Oxidative Heck Cross-Coupling

Article abstract of DOI:10.1002/adsc.202000909

A general and selective Pd-catalyzed cross-coupling of aromatic boronic acids with vinyl-imidazoles is disclosed. Unlike most cross-coupling reactions, this method operates well in absence of bases avoiding the formation of by-products. The reactivity is highly enhanced by the presence of nitrogen-based ligands, in particular bathocuproine. The method involves MnO₂ as oxidant for the oxidation Pd (0)→Pd (II), a much weaker oxidant than previously reported in the literature. This allows for the use of reactants that possess a multitude of functional groups. A scope and limitation study involving a series of 24 boronic acids, whereof 18 afforded TMs in yields in the range 41–95%. The disclosed method constitutes the first general method for the oxidative Heck cross-coupling on the imidazole scaffold, which moreover operates with a selection of other heterocycles. (Figure presented.).

Full text of DOI:10.1002/adsc.202000909

Title: Functionalization of the imidazole backbone by means of a
tailored and optimized oxidative Heck cross-coupling
Authors: Davide Cirillo, Francesco Angelucci, and Hans-René Bjørsvik
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000909
Link to VoR: https://doi.org/10.1002/adsc.202000909

10.1002/adsc.202000909
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.2020xxxxxx
Functionalization of the Imidazole Backbone by Means of
a Tailored and Optimized Oxidative Heck Cross-Coupling
Davide Cirillo,a Francesco Angelucci,a and Hans-René Bjørsvika*
a
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
*telephone +47 55 58 34 52, e-mail hans.bjorsvik@kj.uib.no, web: https://folk.uib.no/nkjhn/
Received: 31-07-2020
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.2020#####
Abstract. A general and selective Pd-catalyzed cross- A scope and limitation study involving a series of 24 boronic
coupling of aromatic boronic acids with vinyl-imidazoles is acids, whereof 18 afforded TMs in yields in the range 40–
disclosed. Unlike most cross-coupling reactions, this method 95%. The disclosed method constitutes the first general
operates well in absence of bases avoiding the formation of method for the oxidative Heck cross-coupling on the
by-products. The reactivity is highly enhanced by the imidazole scaffold, which moreover operates with a
presence of nitrogen-based ligands, in particular selection of other heterocycles.
bathocuproine. The method involves MnO2 as oxidant for the
Keywords: Synthetic method; Pd catalysis; Oxidative Heck
oxidation Pd (0)  Pd (II), a much weaker oxidant than
cross-coupling; Imidazole; Boronic acid
previously reported in the literature. This allows for the use of
reactants that possess a multitude of functional groups.
mono- and di-halogenation of the imidazole
Introduction
backbone,[10] which then allowed for Suzuki,[11]
Stille,[12] and Sonogashira[13] cross-coupling reactions.
The Heck cross-coupling reaction also allows the
formation of a C–C bond. However, no organometallic
species are required, since it only involves an aromatic
halide and an olefin.[14] In spite of the greener approach
and the great atom economy, the Heck cross-coupling
normally requires high temperatures and long reaction
times to reach full conversion; furthermore, the
selectivity between the regioisomers 1,1 and 1,2 is
often challenging to control.[15]
Imidazole is an ubiquitous structural motif[1] that
can be found in numerous naturally occurring
biomolecules and man-made synthetic compounds.
The imidazole ring is found on its own in the essential
amino acid histidine and its hormone derivative
histamine. Moreover, imidazole fused with a
pyrimidine forms purine that ends up in a variety of
molecules ranging from the nuclear bases adenine and
guanine to the xanthines found in coffee, tea and cocoa.
This preeminence can also be observed in medicinal
chemistry, where the imidazole ring can be found in
compounds that hold a multitude of biological
activities[2] including cytotoxic,[3] antifungal,[4] and
anti-histaminic.[5] Furthermore, imidazole-containing
molecules have been designed to have transversal
applications across different fields ranging from
medical imaging, where 2-nitro-imidazoles are
essential probes for PET imaging of hypoxia,[6] to the
metalorganics, where NHC-ligands are widely
employed for homogenous metal catalysis for
example in olefin metathesis.[7]
There have been several proposed improvements
and innovations to the classical Heck cross-coupling,
such as the decarbonylative approach[16] and the
oxidative Heck cross-coupling.[17,18]
The latter
involves an organoboron reagent in place of the
aromatic halide that is used in the classical Heck cross-
coupling. This strategy replaces the first step of the
catalytic cycle of the Heck cross-coupling, the
oxidative addition, with a trans-metalation and it adds
a new step in the catalytic cycle, which is the oxidation
of the palladium (0) to a palladium (II) species. By
avoiding the oxidative addition, considered the rate-
determining step of the catalytic cycle, the oxidative
Heck cross-coupling normally requires milder
conditions to achieve a full conversion. In addition, by
substantially lowering the reaction temperature, an
improved regioselectivity is achieved.[19]
Preparation of backbone substituted imidazoles has
traditionally been realized through multi-component
reactions.[8] However, during recent years
functionalization of positions 4 and 5 of the imidazole
have been explored, especially through Pd-catalyzed
cross-coupling reactions.[9] In our research group,
such chemistry has been implemented by means of
This strategy has been applied in our research group
both for a medicinal chemistry project and for up-
1
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
scaling,[20] proving the feasibility of the reaction also
when a larger quantity of reagents is requested.
Since the Heck cross-coupling on the imidazole has
also abandoned as it gave only poor yields (a
maximum yield of 37% was attained). Moreover, this
method possessed another burden, namely difficulties
been proven to be particularly challenging;[21,22] herein, to separate starting material from target compound.
we unveil an oxidative Heck cross-coupling method
that allows formation of the 4-styryl-1H-imidazole
scaffold using moderate conditions that afford
excellent selectivity and high yield.
Synthesis of 4-vinylimidazole was reported as a
thermal decarboxylation of urocanic acid,[26]
pathway c of Scheme 1. This strategy provided pure
target compound after distillation, but we were unable
to reproduce the reported yield (we achieved a
maximum yield of 9% only). A suitable compromise
between the reaction outcome and required purity of
target intermediate 4-vinyl-1H-imidazole was
obtained by means of the Wittig reaction using 1H-
imidazole-4-carbaldehyde as substrate, pathway c of
Scheme 1, to obtain a yield of 52%. A similar strategy
relying on carbonyl olefination via aziridination[27]
was also tested; however, it proved to be much more
laborious and failed to give any conversion.
Results and Discussion
Synthesis of the starting material
The first step of our reaction pathway was to install
a suitable unencumbered olefin on the imidazole
backbone. Different strategies were evaluated, see
Scheme 1. Initially we relied on a Stille coupling
reaction previously developed in our research group to
obtain target intermediate, pathway a of Scheme 1.
H
N
H
N
Early screening
c.
The procedure for the oxidative Heck cross-
coupling was initially developed for a medicinal
chemistry project in our group, which needed access
to various molecules comprising a stilbene moiety.[20]
These results spurred us to consider this method for the
late stage functionalization of the imidazole backbone.
Even if some of the initial experiments were
encouraging (affording a yield of  40% conducted on
35 mg scale), attempts to replicate the experiments
revealed irreproducible result only. In some cases, it
was even observed zero conversion of the substrate,
Table 1.
N
N
HOOC
N
0''
1d
PG/AUX
PG/AUX
N
d. or e.
a. or b.
O
N
0a-e
N
I
0’a-e
PG/AUX
PG/AUX
f.
N
N
N
1a-e
N
3a-e
PG/AUX
1a, 3a Tos
1b, 3b DMAS N,N-dimethylsulfamoyl
Tosyl
Experiments conducted at elevated temperature
using microwave oven or with the presence of an
inorganic base[28] failed as well.
1c, 3c Trt
1d, 3d
1e, 3e Thp
Trityl
H
Without PG/AUX group
Tetrahydro-2H-pyran-2-yl
Impurities present in the 4-vinyl-1H-imidazole
substrate (from the previous synthetic step) appeared
to be the cause of the varying success of the oxidative
Heck cross-coupling reaction. This was particularly
evident when the Stille cross-coupling was utilized in
the forerunner step to produce the vinyl-1H-imidazole
that served as substrate for the oxidative Heck cross-
coupling.
The same problem was not equally present when the
substrate 4-vinyl-1H-imidazole substrate was
produced by means of the Wittig reaction, pathway d
of Scheme 1, but a general difficulty in replicating the
initial results remained. This spurred us to a more
thorough screening (Table 1) of the reaction conditions.
The first trials proved the importance of the oxidant for
the success of the reaction. For example, target product
was not achieved when benzoquinone was used as an
oxidant, whereas a yield of 5% only was obtained
when molecular oxygen and Ag2O were used.
Overall, side products comprising the imidazole
scaffold were not observed (GC/LC-MS), but two
different products derived from boronic acid were
observed, namely the corresponding boroxine and the
phenol produced due to the presence of the oxidant.[29]
In contrast to observations in previous work,[18]
homocoupling took place only to a minor extent, 1-2%
(GC) only. From these initial promising screening
Scheme 1. Syntheses of 1-PG/AUX-4-vinyl-1H-imidazole
(1a-e). (a) vinyl-Sn(Bu)3, Pd(PPh3)4, DMF, 2 h, 100 °C. (b)
vinyl-Bpin, Pd(PPh3)4, K2CO3, DMF, 18 h, 100 °C. (c)
220 °C, 18 h. (d) t-BuOK, Me-P(Ph)3Br, THF, 3 h, 20 °C.
(e) i) methyl acetohydrazonate, MgSO4, MeOH, 60 °C; ii)
Me3S(O)I, tBuOK, MeCN, 20 °C, 2 h, then toluene, 90 °C,
16 h. (f) Oxidative Heck cross-coupling method disclosed
herein, which makes use of Ph–B(OH)2 2 as reagent.
The Stille reaction afforded the highest yield (96%)
when the experiment was carried out on a 0.3 mmol
scale. Despite the excellent result, this approach was
soon abandoned not only because the Stille cross-
coupling presents toxicity issues regarding the
organotin reagent and the side Sn-containing by-
products, but also because the removal of
organostannanes proved to be challenging.[23]
Reducing the purification times and ruling out a
possible interference by the tin halides was crucial as
early in our development process we suspected their
presence or absence might have a role in explaining
our initial uneven results in the successive C–C bond
forming step. This led us to investigate a second
synthetic strategy, the Suzuki cross-coupling,[24,25] that
involved the same starting material but with vinyl
boronic acid pinacol ester as reagent. This strategy was
2
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
results, various experimental parameters and reagents
were explored with the ultimate goal of establishing a
selective and high yielding method.
have been applied to the reaction. The catalyst that
afforded the best conversion was Pd(OAc)2, that
afforded yields of 98% and became our catalyst of
choice, which was consistent with previous
findings.[20] Although other Pd(II) species afforded
various levels of conversion, none gave comparable
results in our setup. No conversion was observed
when Pd(0), in the form of Pd(PPh3)4, was employed
as catalyst. This was expected as the Pd would have
been in the wrong oxidation state for the proposed
reaction mechanism (Scheme 7).
Table 1. Early screening experiments tailoring the oxidative
Heck cross-coupling to operate with imidazole as substrate
#
1
2
3
4
5
AUX Oxidant
Tos Cu(OAc)2
CH3 Cu(OAc)2
T[oC] t[h] Lf
Yield-%a
Oxidant screening
50 18
50 18
50 18
50 18
25 18
25 18
50 18
44
0
0
38
0
0
0
0
0
0
L4
L2
L2
L2
L4
L4
L4
L4
L4
L4
L4
L4
L4
L1
The nature of the oxidant is another crucial variable
for the reaction as portrayed in Figure 1d. Cu(OAc)2
that has been proven to operate outstandingly with
other vinyl derivatives,[32] did not work in our setup,
nor did Benzoquinone, another common oxidant.
Oxygen proved to be a valid alternative, but our
screening confirmed MnO2 as the best agent of the
tested series. Its low cost, ease of removal, and the high
yield afforded confirmed it as our chosen standard and
led us to further investigations. In our proposed
catalytic cycle (see Scheme 5) we conjectured that 2
equiv. of MnO2 was necessary for the re-oxidation of
Pd. This appears to be confirmed as only 43%
conversion was observed when 1 equiv. was used,
compared to 93% conversion when 2 were employed
and 98% when a slight excess (3 equiv.) was utilized.
We employed MnO2 that the supplier marked as
activated, however, it is known that the presence of
moisture can affect its activity,[33] so we decided to test
if running the reaction in anhydrous conditions with a
MnO2 that was activated through heating at 150 oC for
12 h would affect the yields.
Tos
Tos
Tos
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
6b Tos
7
Tos
8c Tos
Tos
50
4
9
100 18
10 Tos
11d Tos
12e Tos
13 Tos
14 Tos
Benzoqinone 60 18
O2
O2
O2
O2
80 18
5
0
6
75
100 18
60
60
4
4
a) LC. b) Na2CO3 used as an additive. c) Used microwave
oven for heating. d) Ag2O used as an additive. e) NaHCO3
used as an additive. f) L1, L2, and L4 are described in
Figure 1h.
Solvents
Previous reports disclosed that polar aprotic
solvents are beneficial as reaction medium for the
oxidative Heck cross-coupling reactions.[18,32] In our
own solvent screening, Figure 1a, we reached a similar
conclusion with acetonitrile and 1,4-dioxane both
affording high conversions, followed by DMF.
The only outlier proved to be DMSO that afforded
a yield of 6% only. Yields dramatically decreased
when water was added to the mixture and similarly low
results were obtained when a protic or an apolar
solvent were used as reaction medium.
Since the reaction already proceeded in near full
conversion, we decided to test it on 1 equiv. of MnO2,
as this would make the changes in yield more apparent.
As expected, the yield increased from 43% (in normal
conditions) to 50% (in anhydrous and activated
conditions) corresponding to a quantitative conversion,
highlighting how the presence of water can negatively
influence the completion of the reaction.
Auxiliary / Protective Group
The literature[30] and previous observations in our
research group[12] suggested that the N–H bond of the
imidazole ring might reduce the reactivity of the
substrate in cross-coupling reactions. For this reason,
various protective/auxiliary groups have been
explored with the goal to steer clear of potential side-
reactions and enhance the reactivity of the substrate.
The classes of commonly used protective groups for
the N–H of imidazole comprises: N-Sulfonyl
derivatives, N-alkyl/aryl derivatives, and carbamate
derivatives.[31] From these classes we selected the most
relevant examples: Tosyl (Tos), Trityl (Trt), DMAS,
Thp, and non-protected (H). The protected substrate
was in general synthetized by introducing the
Boronic acid
Despite the excellent yields obtained when an
excess (2 equiv.) of boronic acid was used in the initial
test runs (Table 1), we wanted to investigate if such a
high amount was truly necessary to achieve the full
conversion and what was the minimum amount of
reagent needed to obtain excellent yields during the
reaction. Different experiments were carried out by
using increasingly higher amounts of boronic acid.
The results are shown in Figure 1b. High yields were
achieved already when only 1 equiv. of boronic acid
was employed; however, a slight excess (1.4 equiv.) of
the reagent afforded an excellent yield of 98%.
protective
group
first[12,13,32]
on
the
4-
Catalyst
imidazolecarboxaldehyde followed by a Wittig
reaction whereas 4-vinylimidazole was obtained by
In our catalyst screening, Figure 1c, we decided to
explore the most commonly used Pd catalysts that
3
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
deprotection of the N-tosyl-4-vinylimidazole.[3] The
results of the screening are shown in Figure 1e. As
expected, almost no conversion was observed when
the unprotected 4-vinylimidazole 1d was employed;
however, various outcomes were observed when
different protective groups were employed, suggesting
that the group bound to the imidazole ring plays a role
in enhancing or impeding the coupling reaction. In this
regard, the protective groups act as, and should be
more correctly termed, auxiliary groups. In our
screening, we observed that when a sulphonamide
auxiliary group like Tos or a sulfamide, like DMAS
were used, the target molecules were obtained with
excellent yields.
However, when the ring N is directly connected to
a sp3-hybridized carbon, a substantial decreases in
outcomes were observed: 63% and 2% with Trt and
Thp, respectively.
Reaction temperature
The outcome of the cross-coupling reaction was
investigated at diverse reaction temperatures,
Figure 1f. Reaction temperatures in the range
(70100 oC) were investigated. The cross-coupling
reaction afforded yields in the range 6198%, with the
highest achieved yield at 100 oC.
Figure 1. Screening of experimental variables: (a) type of solvent (select ACN), (b) quantity of boronic acid (utilize 1.4
equiv), (c) type of Pd-catalyst (select Pd(OAc)2), (d) type and quantity of oxidant (utilize MnO2, 3 equiv.). Activated
manganese dioxide: MnO2 was activated by heating at 150 oC for 18 h prior use, (e) type protective/auxiliary group (select
Tos), Tos, DMAS, and Trt were isolated yields and H and Thp were measured by GC. (f) reaction temperature (utilize 100
oC), (g) reaction time (utilize 4 h), (h) type of ligand for catalyst (select Bathocuproine L1). General procedure: 1a (221
µmol), phenyl boronic acid 2 (1.4 equiv.), MnO2 (3 equiv.), Bathocuproine L1 (5%), Pd(OAc)2 (5%), solvent ACN (1 mL).
Reaction time
left overnight (18 h) and worked-up the following
morning, however once the reaction conditions were
optimized in other regards, we observed that a good
conversion to target molecule was already observable
A crucial experimental variable in organic synthesis
is the reaction time. In our initial study of the oxidative
Heck cross-coupling reaction, experiments were often
4
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
after only one hour. The cross-coupling reaction was
thus further examined to reveal the conversion after
various point of time, t  [0 8] h, Figure 1g. This
examination revealed that some experiments reach a
yield of 66% already after only 30 min. and the yield
continued to increase until t  4 h. Decomposition of
target molecule was not observed even at prolonged
reaction time.
facilitate the oxidation Pd(0)  Pd(II).[37] Since the 1,
10-phenanthroline family of ligands has already
proven to be the suitable for this particular kind of
cross-coupling, we limited our screening to the
identification of which member of this family
performed the best under our reaction conditions. The
results of the screening are presented in Figure 1h.
Initially the most promising ligands were
neocuproine L2 and bathophenanthroline L3.
Nevertheless, the presence of both 2,9-dimethyl and
4,7-diphenyl substitutions proved to have a synergistic
effect that increased substantially the yield when
bathocuproine L1 was used as a ligand. The combined
action of bathocuproine L1 and palladium in aerobic
oxidations has previously been described.[40] Another
report previous report[41] also confirms the positive co-
action of L1 and Pd catalysts in an oxidative Heck
approach.
Leaving group of the arene moiety
Although, the reaction afforded excellent yields
using a boronic acid as reagent, these are known to be
unstable at higher temperatures and subject to several
degradation pathways such as protodeboronation or
homocoupling. Even though such side products were
not observed in our investigation, we thought it would
be useful for the general applicability of the method to
investigate whether other leaving groups might be
utilized. Boronic esters are often a more stable, but less
reactive, alternative to boronic acids. In most cases, the
ester is thought to have a “masking” function to the
boronic acid and one of the most common examples is
the pinacol ester.[38] Organotin compounds are a
thinkable alternative, as they still hold a prominent
position in cross-coupling chemistry for their stability
and tunability notwithstanding their toxicity.[23] Our
screening of possible alternatives to boronic acids,
Scheme 2, did not indicate that any improvements
might be obtained. Full conversion was only achieved
when the reactant was a boronic acid 2, whilst no
conversion was observed when the correspondent
boronic ester 4 was employed. A yield of 11% was
obtained when the organotin reagent 5 was employed
in the place of boronic acid.
Other additives
The use of various additives, such as a base or a
silver species, has been previously discussed in the
relevant literature.[39] Contrary to these insights, when
the base K2CO3 was introduced as a part of the reaction
mixture, the reaction was completely inhibited. Ag2O
proved to be detrimental to the performance of the
oxidative Heck coupling reaction, with an overall loss
in yield >20% compared to the reaction run without it.
Scope and Limitation of the method
The developed oxidative Heck method was
explored by utilizing N-tosyl-4-vinyl-1H-imidazole 1a
as substrate and a series of various boronic acids, see
Scheme 3. The method proved to be a general,
selective, and effective strategy to obtain 4-styryl-
imidazoles that tolerate a huge variety of functional
groups. Furthermore, the Z-isomer or the 1,1
substitution were not observed. Even though the
reaction was carried out with a slight excess of the
oxidant MnO2 we observed no oxidation of either the
thioether group (3c), the aldehyde (3l), and the phenol
(3f). The oxidative Heck cross-coupling reaction
proceeded also with both bromo- and iodo-arenes, in
this context it is worth noting that no Suzuki cross-
coupling reaction took place as a competing/parasite
reaction.
Tos
Tos
N
N
2, 4, or 5
MnO2, Pd(OAc)2
ACN, 100 °C, 4 h
Bathocuproine (L1)
N
N
1a
3a
OH
97%
nd
B
2
OH
CH3
O
CH3
CH3
4
5
B
O
CH3
11%
Sn
CH3
3
nd = not detected
The oxidative Heck cross-coupling reaction
afforded high to excellent yields using 3- and 4-
substitued phenylboronic acids as reagents, and
proceeds with good yields also if functional groups
were installed in the 2-position, even with
cumbersome substituents (3m). In general, electron-
rich substituents on the phenyl boronic acid scaffold
afforded higher conversion than the electron deficient
ones. This trend was observed also with the good
yields obtained if electron-rich heterocyclic boronic
acids are employed compared to the lack of conversion
when electron-poor heterocyclic boronic acids were
used. Furthermore, the reaction only worked in the
presence of arylboronic acids whereas no product was
detected when aliphatic or alkenyl boronic acids were
employed. In all unproductive reaction experiments
only the substrate 1a was observed.
Scheme 2. Screening experiments varying the leaving group
of the arene moiety. Reaction conditions: 1a (221 µmol), a
reagent (2, 4 or 5) (1.4 equiv.), MnO2 (3 equiv.),
bathocuproine L1 (5%), Pd(OAc)2 (5%), ACN (1 mL).
Ligand
The oxidative Heck cross-coupling has been carried
out both in ligand-free[17,34,35] and in ligand-based
reactions.[18,36] The addition of a Pd-chelating species
rises from the need of a better regio- and stereo-
selectivity and of avoiding the accumulation of Pd(0)
species that can agglomerate to form clusters of
unreactive Pd that can slow the rate, or even block, the
coupling reaction.
Traditionally, bidentate nitrogen ligands have been
employed in oxidative Heck reactions due to low cost,
greater stablility to air and moisture and because they
5
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
Tos
Tos
R
B(OH)2
2a,f-z
N
N
MnO2, Pd(OAc)2
ACN, 100 °C, 4 h
Bathocuproine (L1)
N
N
R
3a,f-z
1a
Tos
Tos
N
Tos
Tos
Tos
N
Tos
N
N
N
N
N
N
N
N
HO
Br
N
N
N
S
H3C
3g
3j 73%
89%
H3C
3a 92%
3f 91%
3h 81%
3i 90%
Tos
CH3
N
N
Tos
Tos
Tos
Tos
Tos
O
CH3
N
N
N
N
N
H3C
N
N
N
N
O
N
41%[a]
3k
O
H3C
53%[a]
CH3
3l 91%
71%
3p 95%
3n
3o
3m 85%
H3C
O
Tos
Tos
Tos
Tos
Tos
N
N
N
N
Tos
O
N
N
N
N
N
I
F
N
3t 53%[a]
3u 56%[a]
3s 94%
3r 71%
3q 65%[a]
O2N
Tos
Tos
Tos
N
H2N
Tos
N
N
N
N
S
N
N
N
N
N
N
3v54%[a]
3w nd[a,b]
3x nd[a,c]
3y nd (GC)
3z nd (GC)
H3C
H3C
Scheme 3. Scope and limitation of the oxidative Heck cross-coupling reaction at optimized conditions. Reaction conditions:
1a (221 µmol), boronic acid 3a, f-z (1.4 equiv.), MnO2 (3 equiv.), bathocuproine (5%), Pd(OAc)2 (5%), ACN (1 mL). nd
= not detected. [a] The reaction was carried out for 8 h with 2 equiv. of boronic acid. [b] The reaction afforded a yield of
39%, but TM appears to be unstable, since after the purification on HPLC, even more side products were observed. [c] The
reaction was conducted in DMF because the boronic acid was not soluble in ACN or 1,4- dioxane. Traces of TM were
detected using LC-MS.
In order to extend the scope of the developed
method, an experiment using the 2-vinyl-imidazole 6
as substrate was conducted, Scheme 4. When the
vinylic group was installed on another position on the
imidazole ring, the method operated absolutely perfect
producing target product (E)-2-styryl-1-tosyl-1H-
imidazole 7 in a yield of 92%.
Tos
Tos
B(OH)2
N
N
2
MnO2, Pd(OAc)2
ACN, 100 °C, 4 h
Bathocuproine (L1)
N
6
N
7
Scheme 5 Oxidative Heck cross-coupling with vinyl-N-
heterocycles 8a-e. Reaction conditions: the vinyl-compound
(2.2 mmol), phenyl boronic acid 2 (1.4 equiv.), MnO2 (3
equiv.), bathocuproine (5%), Pd(OAc)2 (5%), ACN (10 mL),
and 8a-e (226 µmol), phenyl boronic acid (1.4 equiv.),
MnO2 (3 equiv.), bathocuproine (5%), Pd(OAc)2 (5%),
ACN (1 mL).
Scheme 4. Oxidative Heck cross-coupling on 1-tosyl-2-
vinyl-1H-imidazole 6 using (221 µmol), phenyl boronic
acid 2 (1.4 equiv.), MnO2 (3 equiv.), bathocuproine (5%),
Pd(OAc)2 (5%), ACN (1 mL) to achieve (E)-2-styryl-1-
tosyl-1H-imidazole 7.
The option of double substitution on the vinyl
moiety by using an excess of the boronic acid was
explored. The experiment portrayed in Scheme 6,
afforded a product corresponding to either 3l’ or 3l,’’
suggesting that a double arylation could be feasible
when carried out with an excess of boronic acid and
MnO2. Indeed, when the reaction was performed with
10 equiv. of boronic acid and 6 equiv. of MnO2,
HPLC-MS and NMR analyses revealed three main
products: the mono-substituted imidazole 3l, and the
di-substituted imidazoles 3l’ and 3l.’’ The formation
of the 1:1 mixture of 3l’ and 3l’’ reveals that the regio-
selectivity is lost for the second cross-coupling.
Our method for oxidative Heck cross-coupling was
further explored with other vinyl-N-heterocycles as
substrates, Scheme 5. The reaction was carried out
both on micro-molar and milli-molar scale, which
revealed that the method was scalable.
Overall, the results reveal a high functional group
tolerance for the developed oxidative Heck cross-
coupling method, which includes a mild oxidant
(MnO2), short reaction time, and without acid or base
present.
6
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
Scheme 6. The oxidative Heck cross-coupling reaction in the using excess of both boronic acid 2 and oxidant MnO2.
Mechanism
nitrogen atoms of the imidazole ring and the carbon in
the 2-position can be performed relatively smoothly by
means of existing methods in organic synthesis.
However, functionalization of the backbone of
imidazole is more challenging. Multicomponent
reactions producing the imidazole ring with embedded
functionality have been used, but such a strategy can
also be challenging especially if sterically demanding
groups are to be incorporated on the imidazole
backbone (i.e. position 4 and 5).
Based on the observed experimental results, a
plausible reaction mechanism for the Pd catalytic cycle
of the base-free boron oxidative Heck cross-coupling
reaction was outlined, see Scheme 7.
L-Pd(II)-L
OH
B
Ar
OH
OH
OH
L
B
Tos
N
HBO3 H2O
In this study, the strategy of late stage
functionalization has been used. Imidazole or a simple
and readily available functionalized imidazole ring,
such as imidazole carbaldehyde, can be used as the
starting substrate. Hence, with imidazole carbaldehyde
as the starting substrate, we have designed and
developed a regioselective and high yielding method
for oxidative Heck cross-coupling that provides (E)-4-
styrylimidazole derivatives with broad functional
group tolerability A method that, moreover revealed
potential to be amended to fit other heterocycles. A
substantial difference from previously disclosed
oxidative Heck cross-coupling methods is that it
involves MnO2 as a terminal oxidant, which is cheap,
easy to remove, and offers selectivity towards
oxidation of Pd (0) Pd (II). Several factors emerge
to be crucial for the success of the method, amongst
these the use of boronic acids in the place of boronic
esters, the presence of the auxiliary group Tosyl and
an adequate combination of Pd catalyst and ligand.
Safe for a small number of exceptions, the disclosed
method provided successful coupling products in
yields ranging from a minimum of 41% up to 95%. We
envision that the unveiled method will be useful for the
construction of more complex heterocycle-centered
frameworks, by either further functionalization of the
olefin, of the functional groups located on the
imidazole/heterocycle or on the newly bonded
aromatic ring.
Ar-Pd(II)-L
1
N
LH
Pd(II)
Ar
OOB(OH)2
6
Tos
N
Ar
N
L-(II)Pd
OH
2
H
Ar
B
O
5
OH
(II)Pd
O
Tos
H-Pd(II)-L
N
2MnO
2MnO2
3
Pd(0)
N
Ar
4
TM
LH
Scheme 7. Proposal for a reaction mechanism for the Pd
catalysed base-free boron oxidative Heck cross-coupling
reaction.
The first step is a trans-metalation that produces the
palladium (II) intermediate , which is in contrast
with other coupling reactions where the boronic acid
first is activated through the formation of an “ate”
complex.The coordination of the alkeneis followed
by insertion , β-hydride-  and reductive
eliminations producing target molecule TM and Pd (0)
, respectively. Pd (0) is re-oxidized to Pd (II) by
MnO2. Notably 2 equiv. of the oxidant were needed to
form the peroxopalladium complex , which is
known to react with boronic acid[42] to produce
complex .
Experimental Section
General Experimental Information. All reagents and
solvents were purchased from commercial sources and used
as received. Reagent‐ grade chemicals were purchased from
commercial sources and used without further purification.
All reaction mixtures and samples collected during column
chromatography were monitored by means of TLC analysis
(TLC plates Merck Kieselgel 60 F254). The TLC plates
were observed under UV light at λ 254 nm and λ 365 nm.
All final compounds were purified by either semi-
preparative RP-HPLC or by autoflash chromatography. The
Conclusion
Functionalization of imidazoles is of great
importance for applications in life science and
industrial applications, in particular as NHC ligands
for transition metal catalysis. Functionalization of the
7
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
HPLC eluting mixtures was of acetonitrile and H2O (both
containing 0.1% Formic acid). Fractions of equal purity
4-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide
[140174-48-7] (0b).[13] 1H-imidazole-4-carbaldehyde (5.00
g, 52.0 mmol) and DMAS-Cl (1 equiv., 7.47 g, 5.59 mL,
52.0 mmol) were added to a Schlenk-tube under argon
atmosphere. THF (dry, 30 mL) was then added to dissolve
the mixture and TEA (1 equiv., 7.26 mL, 5.27 g, 52.0 mmol)
was added by a syringe. The reaction mixture was stirred
1
were pooled and dried under nitrogen flow overnight. H
and 13C NMR spectra were recorded using a Bruker
instruments AV 500 and Biospin 850SB. High‐ resolution
mass spectra (HRMS) were performed with a Q‐ TOF
Micro YA263 instrument.
o
under argon for 24 h at 20 C. Afterwards, the solvent was
removed under reduced pressure. The crude product was
extracted from acidic water with DCM (3 200 mL), the
organic phases were combined and dried over Na2SO4 to
afford target compound in a yield of 87% (9.21 g, 45.3
mmol) as a white solid. 1H NMR (500 MHz, CDCl3) δ 9.96
(s, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 1.3 Hz, 1H),
2.93 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 185.55, 142.18,
137.58, 122.49, 39.54, 38.20.
Experimental Procedures.
General Procedures - Oxidative Heck Cross-Coupling
Method A: 1a (55 mg, 221 µmol), bathocuproine (5%, 4 mg,
11 µmol), Pd(OAc)2 (5%, 3 mg, 11 µmol), and the boronic
acid (1.4 equiv., 310 µmol) that was dissolved in acetonitrile
(1 mL) was transferred to a pressure-resistant reaction tube
(10 mL). MnO2 (3 equiv., 58 mg, 665 µmol) was then added
and the reactor tube that was sealed and heated for 4 h at
100 °C. After cooling, the solvent was evaporated under
reduced pressure. The obtained crude was purified by mean
of column chromatography packed with silica and an eluent
composed of hexane and ethyl acetate. The highest intensity
of UV-absorption is around 300 nm for all the products.
N,N-dimethyl-4-vinyl-1H-imidazole-1-sulfonamide
[343880-85-3] (1b). Methyltriphenylphosphonium bromide
(1.2 equiv., 9.49 g, 26.6 mmol) was transferred to a three-
necks round bottom flask (100 mL) under inert and
anhydrous conditions. Then, was suspended in THF (dry,
30 mL), followed by the addition of potassium tert-butoxide
in THF (1 M, 1.1 equiv., 2.73 g, 24.4 mL, 24.4 mmol) by a
syringe (exothermic reaction). The suspension turned into a
pale-yellow color. After 30 min, 0b (4.5 g, 22.1 mmol) was
slowly added (exothermic reaction) to the mixture. The
reaction mixture was stirred for 2 h at 20 oC and controlled
by means of GC-MS. Upon completion of the reaction, the
solvent was evaporated under reduced pressure. The crude
product was extracted from acidic water with DCM (3 200
mL), the organic phases were combined and dried over
Na2SO4. Purification of isolated product by means of
column chromatography packed with silica gel and an
eluent system composed of hexane:ethyl acetate = 75:25
provides target compound in a yield of 62% (3.41 g, 13.7
mmol) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.78
(s, 1H), 7.07 (d, J = 0.8 Hz, 1H), 6.50 (dd, J = 17.4, 11.0 Hz,
1H), 5.90 (dd, J = 17.4, 1.4 Hz, 1H), 5.23 (dd, J = 11.0, 1.5
Hz, 1H), 2.80 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 141.85,
136.82, 127.08, 115.54, 114.27, 38.19.
Method B: In a pressure-resistant reaction tube (10 mL), 1a
(55 mg, 221 µmol), bathocuproine (5%, 4 mg, 11 µmol),
Pd(OAc)2 (5%, 3 mg, 11 µmol), the boronic acid (2.0 equiv.,
442 µmol) was dissolved in acetonitrile (1 mL). To the
mixture, MnO2 (3 equiv., 58 mg, 665 µmol) was added and
the vial was sealed and heated for 8 h at 100 °C. After
cooling, the solvent was evaporated under reduced pressure
and the crude was purified through HPLC (water:ACN +
0.1% HCOOH). The highest intensity of UV-absorption is
around 300 nm for all the products.
1-tosyl-1H-imidazole-4-carbaldehyde [13] [37622-92-7]
(0a). 1H-imidazole-4-carbaldehyde (5.00 g, 52.0 mmol) and
p-toluenesulfonyl chloride (1 equiv., 9.92 g, 52.0 mmol)
were added to a Schlenk-tube under argon atmosphere. THF
(dry, 40 mL) was then added to dissolve the solids and TEA
(1 equiv., 7.26 mL, 5.27 g, 52.0 mmol) was added by a
syringe. The reaction mixture was stirred under argon for 24
h at ambient temperature and checked through GC-MS.
Upon completion of the reaction, the solvent was evaporated
under reduced pressure. The crude product was extracted
from acid water with DCM (3 200 mL), the organic phases
were combined and dried over Na2SO4 to afford the target
compound in a yield of 98% (12.81 g, 51.2 mmol) as a white
solid. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 8.07 (d, J
= 1.3 Hz, 1H), 7.94 (d, J = 1.3 Hz, 1H), 7.89 (dt, J = 8.1, 1.8
Hz, 2H), 7.41 (dt, J = 8.1, 1.8 Hz, 2H), 2.47 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 185.59, 147.44, 142.89, 137.28,
133.82, 130.81, 127.77, 121.86, 21.81.
1-trityl-1H-imidazole-4-carbaldehyde
[33016-47-6]
(0c).[32] To a 250 mL round-bottomed flask 1H-imidazole-
4-carbaldehyde (1.20 g, 12.5 mol), trityl chloride (1.1 equiv.,
3.83 g, 13.7 mol) were dissolved in acetonitrile (40 mL) and
stirred at 20 oC. Afterwards, triethylamine (1.72 equiv., 3.0
mL, 2.17 g, 21.5 mol) was added dropwise and the reaction
was stirred 18h. A mixture of hexane (4 mL) and deionized
water (40 mL) was added and stirred for another 30 min.
The slurry was filtered, and the filter cake was washed with
water (2 10 mL) and dried under reduced pressure to
afford target compound as a white solid in a yield of 84%
(3.55 g, 10.5 mmol). 1H NMR (500 MHz, CDCl3) δ 9.88 (s,
1H), 7.61 (d, J = 1.3 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.41
– 7.33 (m, 9H), 7.15 – 7.08 (m, 6H). 13C NMR (126 MHz,
CDCl3) δ 186.62, 141.55, 140.89, 140.62, 129.67, 128.55,
128.40, 126.76, 76.36.
1-tosyl-4-vinyl-1H-imidazole [185850-13-9] (1a). Under
inert and anhydrous conditions, methyltriphenyl-
phosphonium bromide (1.2 equiv., 8.56 g, 24.0 mmol) was
placed in a three-necks flask and suspended in THF (dry, 30
mL). Then potassium tert-butoxide in THF (1 M, 1.1 equiv.,
2.47 g, 22.0 mL, 22.0 mmol) was added by means of a
syringe. The suspension turns into pale yellow color during
the addition. After 30 min, 0a (5.0 g, 20.0 mmol) was added
slowly (exothermic reaction) to the reaction mixture. The
reaction mixture was stirred for 2 h at 20 oC and controlled
by means of GC-MS. Upon completion of the reaction, the
solvent was evaporated under reduced pressure. The crude
product was extracted from acidic water with DCM (3 200
mL), the organic phases were combined and dried over
Na2SO4. Purification by means of column chromatography
with silica gel and an eluent system composed of
hexane:ethyl acetate = 82:18 provides target compound in a
yield of 52% (2.51 g, 10.35 mmol) as a white solid. 1H NMR
(500 MHz, CDCl3) δ 7.95 (s, 1H), 7.82 (dt, J = 8.4, 1.5 Hz,
2H), 7.35 (dt, J = 8.2, 1.5 Hz, 2H), 7.16 (s, J = 0.7 Hz, 1H),
6.50 (dd, J = 17.4, 11.0 Hz, 1H), 5.92 (dd, J = 17.4, 1.4 Hz,
1H), 5.26 (dd, J = 11.0, 1.4 Hz, 1H), 2.44 (s, 3H).13C NMR
(126 MHz, CDCl3) δ 146.33, 142.77, 136.74, 134.92,
130.45, 127.36, 126.93, 115.85, 113.79, 21.73.
1-trityl-4-vinyl-1H-imidazole [86803-29-4] (1c). Under
inert and anhydrous conditions, methyltriphenyl-
phosphonium bromide (1.2 equiv., 4.43 g, 12.41 mmol) was
transferred to a three-necks round bottom flask and
suspended in THF (dry, 25 mL). Then, potassium tert-
butoxide in THF (1 M, 1.1 equiv., 1.27 g, 11.4 mL, 11.4
mmol) was added by means of a syringe. The mixture turned
into a pale-yellow color. After 30 min, 0c (3.5 g, 10.3 mmol)
was slowly added (exothermic reaction) to the mixture. The
reaction mixture was stirred for 2 h at 20 oC and monitored
by means of GC-MS. Upon completion of the reaction, the
solvent was evaporated under reduced pressure. The crude
product was extracted from acidic water with DCM (3 200
mL), the organic phases were combined and dried over
Na2SO4. Purification of isolated product by means of
column chromatography packed with silica gel and an
eluent system composed of hexane:ethyl acetate = 88:12
provides target compound in a yield of 66% (2.30 g, 6.84
mmol) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.32
(d, J = 1.0 Hz, 1H), 7.28 – 7.22 (m, 9H), 7.10 – 7.04 (m,
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000909
Advanced Synthesis & Catalysis
6H), 6.69 (d, J = 1.2 Hz, 1H), 6.47 (dd, J = 17.4, 11.0 Hz,
1H), 5.75 (dd, J = 17.4, 1.7 Hz, 1H), 5.03 (dd, J = 11.0, 1.8
Hz, 1H).13C NMR (126 MHz, CDCl3) δ 142.35, 139.57,
139.23, 129.79, 128.69, 128.10 (3C+1C), 119.35, 112.15,
75.32.
1-trityl-4-vinyl-1H-imidazole 1c (56 mg, 166 µmol),
phenylboronic acid (1.4 equiv., 28 mg, 233 µmol). Eluent
system composed of hexane: ethyl acetate = 92:08. The title
compound was isolated as a white solid in a yield of 63%
(43 mg, 104 µmol). 1H NMR (500 MHz, CDCl3) δ 7.53 (d,
J = 1.0 Hz, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.38 – 7.27 (m,
12H), 7.25 – 7.13 (m, 7H), 6.93 (d, J = 16.2 Hz, 1H), 6.87
(d, J = 1.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 142.09,
139.28, 138.96, 137.50, 129.78, 128.57, 128.24, 128.20,
127.94, 127.76, 126.29, 119.87, 119.64, 75.68. HRMS
(ESI) m/z: [M+H] calcd for C30H25N2 413.20177; found
413.20199.
4-vinyl-1H-imidazole [3718-04-5] [3] (1d). 1-Tosyl-4-
vinyl-1H-imidazole 1a (1.0 g, 4.0 mmol) was transferred to
a round-bottom flask (50 mL) and dissolved in MeOH (10
mL) whereupon HCl (37%, 2 mL) was added in one portion.
The reaction mixture was refluxed for 2 h. MeOH was
removed under reduced pressure and the crude was
extracted with Et2O (2 100 mL) and HCl solution (1 M,
100 mL). The organic phases were discarded. The aqueous
phase was made alkaline by slow addition of NaOH
(exothermic) and extracted again with Et2O (3 100 mL).
The organic phases were combined, dried over Na2SO4, to
afford target compound in a yield of 85% (323mg, 3.43
(E)-4-(2-([1,1'-biphenyl]-4-yl)vinyl)-1-tosyl-1H-
imidazole [NEW] (3f). The title compound was synthesized
according to the general procedure A using the following
conditions and quantities: [1,1'-biphenyl]-4-ylboronic acid
(61 mg). Eluent system composed of hexane:ethyl acetate =
86:14. The title compound was isolated as a white solid in a
yield of 91% (81 mg, 202 µmol).1H NMR (500 MHz,
CDCl3) δ 8.00 (d, J = 0.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H),
7.61 – 7.55 (m, 4H), 7.52 (d, J = 8.3 Hz, 2H), 7.43 (t, J =
7.7 Hz, 2H), 7.40 – 7.30 (m, 4H), 7.25 (d, J = 1.3 Hz, 1H),
6.91 (d, J = 16.1 Hz, 1H), 2.43 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 146.39, 142.82, 140.60, 136.99, 135.83, 134.92,
130.49, 130.01, 128.82, 127.39 (2C+ 2C), 127.37 (2C+2C),
127.00, 126.92, 118.26, 114.00, 21.75. HRMS (ESI) m/z:
[M+H] calcd for C24H21N2O2S 401.13237; found 401.13256.
1
mmol) as a pale yellow solid. H NMR (500 MHz, CDCl3)
δ 12.92 (s, 1H), 7.54 (s, 1H), 6.96 (s, 1H), 6.54 (dd, J = 17.0,
11.2 Hz, 1H), 5.58 (d, J = 17.4 Hz, 1H), 5.01 (d, J = 10.6
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 135.87, 135.57,
126.63, 120.04, 112.11.
1-(tetrahydro-2H-pyran-2-yl)-4-vinyl-1H-imidazole
[NEW] (1e). 4-Vinyl-1H-imidazole (500 mg, 5.31 mmol)
was transferred to a round-bottomed flask (100 mL) and
o
suspended in DMF (5 mL) at 20 C. pTSA (5 %, 67 mg,
0.265 mmol) and DHP (1.5 equiv., 670 mg, 0.73 mL, 7.97
mmol) were then added. The reaction was capped and
(E)-4-(4-(methylthio)styryl)-1-tosyl-1H-imidazole
[NEW] (3g). The title compound was synthesized according
to the general procedure A using the following conditions
and quantities: (4-(methylthio) phenyl)boronic acid (52 mg).
Eluent system composed of hexane: ethyl acetate = 87:13.
The title compound was isolated as a white solid in a yield
of 89% (67 mg, 180 µmol).1H NMR (500 MHz, CDCl3) δ
7.98 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 7.8 Hz,
4H), 7.29 – 7.18 (m, 4H), 6.82 (d, J = 16.0 Hz, 1H), 2.48 (s,
J = 6.4 Hz, 3H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 146.36, 142.81, 138.25, 136.96, 134.91, 133.67, 130.47,
129.86, 127.36, 126.93, 126.58, 117.57, 113.80, 21.74,
15.71. HRMS (ESI) m/z: [M+H] calcd for C19H19N2O2S2
371.08879; found 371.08833.
o
heated at 100 C for 18h. The post-reaction mixture was
cooled at 20 oC, whereupon the solvent was removed under
reduced pressure. The crude mixture was extracted from
basic water solution (NaOH 1 M, 200 mL) with DCM (2
200 mL). The organic phases were combined, dried over
Na2SO4 and target product was obtained as a yellow oil in a
1
yield of 92% (875 mg, 4.91 mmol). H NMR (500 MHz,
CDCl3) δ 7.60 (s, J = 0.8 Hz, 1H), 7.02 (d, J = 0.8 Hz, 1H),
6.59 (dd, J = 17.4, 11.0 Hz, 1H), 5.83 (dd, J = 17.5, 1.7 Hz,
1H), 5.17 (dd, J = 9.6, 2.4 Hz, 1H), 5.13 (dd, J = 11.0, 1.7
Hz, 1H), 4.08 – 4.02 (m, 1H), 3.70 – 3.62 (m, 1H), 2.05 –
1.88 (m, 3H), 1.73 – 1.58 (m, 3H). 13C NMR (126 MHz,
CDCl3) δ 140.90, 135.77, 128.56, 114.47, 112.31, 84.07,
67.72, 31.43, 24.80, 22.35.
(E)-4-(4-methylstyryl)-1-tosyl-1H-imidazole [NEW] (3h).
The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: p-tolylboronic acid (42 mg). Eluent system
composed of hexane:ethyl acetate = 90:10. The title
compound was isolated as a white solid in a yield of 81%
(E)-4-styryl-1-tosyl-1H-imidazole [NEW] (3a). The title
compound was synthesized according to the general
procedure A using the following conditions and quantities:
phenylboronic acid (38 mg). Eluent system composed of
hexane:ethyl acetate = 90:10. The title compound was
isolated as a white solid in a yield of 92% (66 mg, 203 µmol). (61 mg, 180 µmol). 1H NMR (500 MHz, CDCl3) δ 7.98 (d,
1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 0.5 Hz, 1H), 7.84
(dt, J = 8.5, 1.7 Hz, 2H), 7.47 – 7.43 (m, 2H), 7.39 – 7.29
(m, 5H), 7.26 – 7.21 (m, 2H), 6.87 (d, J = 16.1 Hz, 1H), 2.44
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 146.36, 142.79,
136.95, 136.77, 134.92, 130.51, 130.48, 128.68, 127.88,
127.37, 126.55, 118.21, 113.93, 21.74. HRMS (ESI) m/z:
J = 0.5 Hz, 1H), 7.83 (dt, J = 8.4, 1.7 Hz, 2H), 7.37 – 7.32
(m, 4H), 7.29 (d, J = 16.1 Hz, 1H), 7.21 (d, J = 1.0 Hz, 1H),
7.13 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 16.1 Hz, 1H), 2.43 (s,
3H), 2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 146.32,
142.97, 137.84, 136.91, 134.95, 133.99, 130.46 (2C + 1C),
129.40, 127.35, 126.48, 117.25, 113.61, 21.73, 21.27.
[M+H] calcd for C18H17N2O2S 325.10107; found 325.10131. HRMS (ESI) m/z: [M+H] calcd for C19H19N2O2S
339.11672; found 339.11689.
(E)-N,N-dimethyl-4-styryl-1H-imidazole-1-sulfonamide
[NEW] (3b). The title compound was synthesized
according to the general procedure A using the following
conditions and quantities: N,N-dimethyl-4-vinyl-1H-
imidazole-1-sulfonamide (55 mg, 273 µmol), phenyl-
boronic acid (1.4 equiv., 47 mg, 383 µmol). Eluent system
composed of hexane:ethyl acetate = 87:13. The title
compound was isolated as a white solid in a yield of 92%
(E)-4-(4-bromostyryl)-1-tosyl-1H-imidazole [NEW] (3i).
The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (4-bromophenyl) boronic acid (62 mg). Eluent
system composed of hexane:ethyl acetate = 90:10. The title
compound was isolated as a white solid in a yield of 90%
1
(80 mg, 198 µmol). H NMR (500 MHz, CDCl3) δ 7.99 (s,
1
(70 mg, 252 µmol). H NMR (500 MHz, CDCl3) δ 7.82 (s,
1H), 7.84 (dt, J = 8.6, 1.6 Hz, 2H), 7.44 (dt, J = 8.6, 1.7 Hz,
2H), 7.36 (d, J = 8.2 Hz, 2H), 7.31 (dt, J = 8.5, 1.6 Hz, 2H),
7.27 – 7.22 (m, 2H), 6.85 (d, J = 16.0 Hz, 1H), 2.44 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 146.43, 142.45, 137.03,
135.73, 134.86, 131.81, 130.49, 129.20, 128.00, 127.38,
121.62, 118.90, 114.27, 21.74. HRMS (ESI) m/z: [M+H]
calcd for C18H16BrN2O2S 405.00954; found 405.01439.
1H), 7.46 – 7.39 (m, 2H), 7.35 – 7.24 (m, 3H), 7.22 – 7.13
(m, 2H), 6.87 (d, J = 16.1 Hz, 1H), 2.81 (s, J = 6.0 Hz, 6H).
13C NMR (126 MHz, CDCl3) δ 141.85, 137.03, 136.87,
130.26, 128.71, 127.85, 126.55, 118.37, 114.48, 38.24.
HRMS (ESI) m/z: [M+H] calcd for C13H16N3O2S
278.09632; found 278.09742.
(E)-4-styryl-1-trityl-1H-imidazole [77705-84-1] (3c). The
title compound was synthesized according to the general
procedure A using the following conditions and quantities:
(E)-4-(2-(1-tosyl-1H-imidazol-4-yl)vinyl)phenol [NEW]
(3j). The title compound was synthesized according to the
general procedure A using the following conditions and
9
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
quantities: (4-hydroxyphenyl) boronic acid (43 mg). Eluent
system composed of hexane:ethyl acetate = 75:25. The title
compound was isolated as a white solid in a yield of 73%
(55 mg, 162 µmol). 1H NMR (500 MHz, CD3CN) δ 7.96 (s,
1H), 7.82 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.28
(d, J = 8.4 Hz, 2H), 7.13 (d, J = 16.1 Hz, 1H), 6.99 (s, 1H),
6.74 – 6.66 (m, 3H), 2.34 (s, 3H). 13C NMR (126 MHz,
CD3CN) δ 156.60, 146.59, 142.82, 136.95, 134.41, 130.22,
129.27, 128.56, 127.58, 126.95, 115.73, 115.14, 113.29,
20.39. HRMS (ESI) m/z: [M+H] calcd for C18H17N2O3S
341.09740; found 341.09599.
The title compound was isolated as a white solid in a yield
1
of 53% (41 mg, 117 µmol). H NMR (500 MHz, CDCl3) δ
8.01 (d, J = 0.8 Hz, 1H), 7.86 (dt, J = 8.5, 1.7 Hz, 2H), 7.66
(d, J = 8.1 Hz, 1H), 7.64 (dd, J = 7.8, 1.0 Hz, 1H), 7.59 –
7.52 (m, 2H), 7.38 (d, J = 8.5 Hz, 3H), 7.32 (td, J = 7.7, 1.1
Hz, 1H), 7.10 (d, J = 16.0 Hz, 1H), 2.45 (s, 3H). 13C NMR
(214 MHz, CDCl3) δ 146.54, 141.90, 140.00, 137.08,
133.38, 132.74, 130.55, 130.03, 129.04, 127.71, 127.45,
125.95, 125.91, 123.48, 117.97, 115.19, 21.76. HRMS
(ESI) m/z: [M+Na] calcd for C19H15NaN3O2S 372.07827;
found 372.07855.
(E)-1-tosyl-4-(2,4,6-trimethylstyryl)-1H-imidazole
[NEW] (3k). The title compound was synthesized
according to the general procedure B using the following
conditions and quantities: mesitylboronic acid (73 mg). The
title compound was isolated as a yellow oil in a yield of 41%
(33 mg, 90 µmol).1H NMR (500 MHz, CDCl3) δ 8.00 (s,
1H), 7.85 (d, J = 8.4 Hz, 2H), 7.39 – 7.33 (m, 3H), 7.19 (s,
1H), 6.87 (s, 2H), 6.38 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H),
2.31 (s, 6H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
142.90, 141.76, 136.86, 136.51, 136.21, 131.97, 130.47,
128.78, 128.69, 127.44, 123.24, 117.26, 113.46, 21.75,
21.07, 20.94. HRMS (ESI) m/z: [M+H] calcd for
C21H23N2O2S 367.14802; found 367.14769.
(E)-4-(2-(1-tosyl-1H-imidazol-4-yl)vinyl)benzaldehyde
[NEW] (3p). The title compound was synthesized
according to the general procedure A using the following
conditions and quantities: (4-formyl-phenyl)boronic acid
(46 mg). Eluent system composed of hexane:ethyl acetate =
87:13. The title compound was isolated as a white solid in a
yield of 95% (74 mg, 210 µmol).1H NMR (500 MHz,
CDCl3) δ 9.97 (s, 1H), 8.01 (s, 1H), 7.90 – 7.79 (m, 4H),
7.59 (d, J = 8.2 Hz, 2H), 7.40 – 7.34 (m, 3H), 7.32 (s, 1H),
7.02 (d, J = 16.0 Hz, 1H), 2.44 (s, 3H). 13C NMR (126 MHz,
CD3CN) δ 186.27, 141.24, 137.55, 136.82, 131.86, 130.17,
129.44, 125.23, 124.92, 123.74, 122.10, 121.63, 116.25,
109.87, 16.45. HRMS (ESI) m/z: [M+H] calcd for
C19H17N2O3S 353.09599; found 353.09772.
(E)-4-(4-methoxystyryl)-1-tosyl-1H-imidazole [NEW]
(3l). The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (4-methoxyphenyl) boronic acid (47 mg). Eluent
system composed of hexane:ethyl acetate = 87:13. The title
compound was isolated as a white solid in a yield of 91%
(72 mg, 203 µmol).1H NMR (500 MHz, CDCl3) δ 7.98 (d, J
= 0.6 Hz, 1H), 7.83 (dt, J = 8.4, 1.9 Hz, 2H), 7.37 (ddd, J =
16.0, 7.6, 4.9 Hz, 4H), 7.30 – 7.24 (m, 1H), 7.20 (d, J = 0.9
Hz, 1H), 6.87 (dt, J = 8.8, 1.9 Hz, 2H), 6.73 (d, J = 16.1 Hz,
1H), 3.81 (s, 3H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 159.49, 146.29, 143.08, 134.97, 130.44, 130.08, 129.57,
127.80, 127.34, 116.13, 114.51, 114.13, 113.30, 55.31,
21.72. HRMS (ESI) m/z: [M+H] calcd for C19H19N2O3S
355.11164; found 355.11280.
(E)-4-(2-([1,1'-biphenyl]-2-yl)vinyl)-1-tosyl-1H-
imidazole [NEW] (3q). The title compound was
synthesized according to the general procedure B using the
following conditions and quantities: [1,1'-biphenyl]-2-
ylboronic acid (88 mg). The title compound was isolated as
a white solid in a yield of 65% (58 mg, 145 µmol).1H NMR
(850 MHz, CDCl3) δ 7.92 (d, J = 0.8 Hz, 1H), 7.82 (dt, J =
8.5, 1.8 Hz, 2H), 7.66 (dd, J = 7.5, 1.0 Hz, 1H), 7.42 – 7.39
(m, 2H), 7.37 – 7.31 (m, 7H), 7.29 (d, J = 16.0 Hz, 1H), 7.18
(d, J = 1.2 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H), 2.44 (s, 3H).
13C NMR (214 MHz, CDCl3) δ 146.31, 142.99, 141.36,
140.73, 136.82, 134.91, 134.89, 130.45, 130.43, 129.78,
129.49, 128.18, 127.73, 127.50, 127.39, 127.19, 127.16,
125.87, 119.52, 113.70, 21.74. HRMS (ESI) m/z: [M+H]
calcd for C24H22N2O2S 401.13237; found 401.13287.
(E)-4-(3-methoxystyryl)-1-tosyl-1H-imidazole [NEW]
(3m). The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (3-methoxyphenyl) boronic acid (47 mg). Eluent
system composed of hexane:ethyl acetate = 87:13. The title
compound was isolated as a white solid in a yield of 85%
(67 mg, 189 µmol).1H NMR (500 MHz, CDCl3) δ 7.99 (d, J
= 0.6 Hz, 1H), 7.83 (dt, J = 8.4, 1.7 Hz, 2H), 7.39 – 7.21 (m,
6H), 7.05 (d, J = 7.7 Hz, 1H), 7.00 – 6.97 (m, 1H), 6.86 (d,
J = 16.0 Hz, 1H), 6.83 – 6.79 (m, 1H), 3.82 (s, 3H), 2.44 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 159.85, 146.38, 142.70,
138.22, 136.96, 134.91, 130.48, 130.40, 129.65, 127.37,
119.25, 118.56, 114.01, 113.55, 111.80, 55.22, 21.74.
HRMS (ESI) m/z: [M+H] calcd for C19H19N2O3S
355.11164; found 355.11180.
(E)-4-(4-iodostyryl)-1-tosyl-1H-imidazole [NEW] (3r).
The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (4-Iodophenyl)boronic acid (77 mg). Eluent
system composed of hexane:ethyl acetate = 90:10. The title
compound was isolated as a white solid in a yield of 71%
(71 mg, 158 µmol).1H NMR (500 MHz, CDCl3) δ 7.99 (s,
1H), 7.83 (dt, J = 8.4, 1.7 Hz, 2H), 7.65 (dt, J = 8.4, 1.8 Hz,
2H), 7.36 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 16.3 Hz, 2H), 7.18
(dt, J = 8.8, 1.9, 1.9 Hz, 2H), 6.86 (d, J = 16.0 Hz, 1H), 2.44
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 146.44, 142.42,
137.77, 137.03, 136.30, 134.86, 130.49, 129.31, 128.22,
127.38, 118.99, 114.32, 93.12, 21.75. HRMS (ESI) m/z:
[M+H] calcd for C18H16IN2O2S 450.99772; found
450.99980.
(E)-4-(2-methoxystyryl)-1-tosyl-1H-imidazole [NEW]
(3n). The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (2-methoxyphenyl) boronic acid (47 mg). Eluent
system composed of hexane:ethyl acetate = 87:13.The title
compound was isolated as a white solid in a yield of 71%
(56 mg, 158 µmol). 1H NMR (500 MHz, CDCl3) δ 7.99 (d,
J = 0.6 Hz, 1H), 7.83 (dt, J = 8.4, 1.6 Hz, 2H), 7.60 (d, J =
16.3 Hz, 1H), 7.47 (dd, J = 7.6, 1.6 Hz, 1H), 7.35 (d, J = 8.2
Hz, 2H), 7.25 – 7.20 (m, 2H), 6.97 – 6.91 (m, 2H), 6.88 (d,
J = 8.2 Hz, 1H), 3.86 (s, 3H), 2.44 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 157.22, 146.26, 143.49, 136.88, 135.01,
130.43, 128.87, 127.34, 127.11, 125.81, 125.78, 120.63,
119.08, 113.58, 110.92, 55.38, 21.72. HRMS (ESI) m/z:
(E)-4-(4-fluorostyryl)-1-tosyl-1H-imidazole [NEW] (3s).
The title compound was synthesized according to the
general procedure A using the following conditions and
quantities: (4-fluorophenyl) boronic acid (43 mg). Eluent
system composed of hexane:ethyl acetate = 90:10. The title
compound was isolated as a white solid in a yield of 94%
1
(71 mg, 207 µmol). H NMR (500 MHz, CDCl3) δ 7.99 (s,
1H), 7.86 – 7.81 (m, 2H), 7.44 – 7.38 (m, 2H), 7.36 (d, J =
8.2 Hz, 2H), 7.28 (d, J = 16.2 Hz, 1H), 7.23 (s, 1H), 7.05 –
6.98 (m, 2H), 6.78 (d, J = 16.0 Hz, 1H), 2.43 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 162.46 (d, J = 247.6 Hz), 146.39,
142.61, 136.96, 134.89, 132.97 (d, J = 3.5 Hz), 130.48,
129.28, 128.06 (d, J = 7.8 Hz), 127.36, 117.99 (d, J = 2.0
[M+H] calcd for C19H19N2O3S 355.11164; found 355.11197. Hz), 115.65 (d, J = 21.6 Hz), 113.93, 21.74. HRMS (ESI)
m/z: [M+H] calcd for C18H16FN2O2S 343.09165; found
343.09199.
(E)-2-(2-(1-tosyl-1H-imidazol-4-yl)vinyl)benzonitrile
[NEW] (3o). The title compound was synthesized according
to the general procedure B using the following conditions
and quantities: (2-methoxyphenyl)boronic acid (65 mg).
(E)-4-(3-nitrostyryl)-1-tosyl-1H-imidazole [NEW] (3t).
The title compound was synthesized according to the
10
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
general procedure B using the following conditions and
quantities: (3-nitrophenyl)boronic acid (74 mg). The title
compound was isolated as a white solid in a yield of 53%
g, 9.0 mmol) as a white solid. 1H NMR (500 MHz, CDCl3)
δ 7.67 (dt, J = 8.4, 1.8 Hz, 2H), 7.35 (d, J = 1.6 Hz, 1H),
7.23 (d, J = 8.4 Hz, 2H), 7.05 (dd, J = 17.2, 11.1 Hz, 1H),
6.92 (d, J = 1.6 Hz, 1H), 6.15 (dd, J = 17.2, 1.6 Hz, 1H),
5.42 (dd, J = 11.1, 1.5 Hz, 1H), 2.31 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 146.15, 145.91, 135.08, 130.30, 129.25,
127.23, 122.89, 122.06, 119.60, 21.66.
1
(43 mg, 116 µmol). H NMR (500 MHz, CDCl3) δ 8.32 (t,
J = 1.9 Hz, 1H), 8.08 (ddd, J = 8.2, 2.2, 0.9 Hz, 1H), 8.01 (s,
1H), 7.85 (dt, J = 8.4, 1.8 Hz, 2H), 7.74 – 7.70 (m, 1H), 7.50
(t, J = 8.0 Hz, 1H), 7.41 – 7.30 (m, 4H), 7.00 (d, J = 16.0
Hz, 1H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 148.74,
146.57, 141.83, 138.64, 137.17, 134.76, 132.55, 130.55,
129.63, 127.85, 127.43, 122.25, 121.19, 120.65, 115.16,
21.76. HRMS (ESI) m/z: [M+H] calcd for C18H16N3O4S
370.08615; found 370.08744.
(E)-2-styryl-1-tosyl-1H-imidazole [NEW] (7). The title
compound was synthesized according to the general
procedure A using the following conditions and quantities:
1-tosyl-2-vinyl-1H-imidazole (55 mg, 221 µmol), phenyl-
boronic acid (38 mg). Eluent system composed of
hexane:ethyl acetate= 90:10. The title compound was
isolated as a white solid in a yield of 92% (66 mg, 203 µmol).
1H NMR (500 MHz, CDCl3) δ 7.78 (dt, J = 8.4, 1.7 Hz, 2H),
7.63 – 7.50 (m, 4H), 7.46 (d, J = 1.6 Hz, 1H), 7.42 – 7.37
(m, 2H), 7.36 – 7.29 (m, 3H), 7.06 (d, J = 1.6 Hz, 1H), 2.40
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 146.52, 146.13,
136.38, 135.98, 135.23, 130.36, 129.59, 129.03, 128.86,
127.30, 127.23, 119.55, 113.47, 21.69. HRMS (ESI) m/z:
[M+H] calcd for C18H17N2O2S 325.10107; found 325.10133.
(E)-4-(2-(furan-2-yl)vinyl)-1-tosyl-1H-imidazole [NEW]
(3u). The title compound was synthesized according to the
general procedure B using the following conditions and
quantities: Furan-2-ylboronic acid (50 mg). The title
compound was isolated as a white solid in a yield of 56%
1
(39 mg, 124 µmol). H NMR (500 MHz, CDCl3) δ 7.96 (s,
1H), 7.83 (dt, J = 8.4, 1.8 Hz, 2H), 7.39 – 7.33 (m, 3H), 7.19
(d, J = 1.0 Hz, 1H), 7.10 (d, J = 15.8 Hz, 1H), 6.77 (d, J =
15.8 Hz, 1H), 6.39 (dd, J = 3.3, 1.8 Hz, 1H), 6.32 (d, J = 3.3
Hz, 1H), 2.44 (s, 3H). The compound 19a decomposed and
we were not able to record 13C NMR data and HRMS (ESI)
for this compound.
(E)-4-styrylpyridine [5097-93-8] (9a). The title compound
was synthesized according to the general procedure A with
some amendments for up-scaled use. In particular, the
following conditions and quantities were used: a pressure-
resistant reaction tube (20 mL) was charged with 4-
vinylpyridine (231 mg, 2.20 mmol), bathocuproine (40 mg),
Pd(OAc)2 (25 mg), phenyl-boronic acid (375 mg), MnO2
(535 mg), and ACN (10 mL). Eluent system composed of
hexane:ethyl acetate = 90:10. The title compound was
isolated as a white solid in a yield of 80% (317 mg, 1.75
mmol). 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 4.5, 1.6
Hz, 2H), 7.71 – 7.64 (m, 2H), 7.60 – 7.53 (m, 3H), 7.47 –
7.40 (m, 2H), 7.35 (dt, J = 7.3, 1.0, 1.0 Hz, 1H), 7.27 (d, J
= 16.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 150.01,
144.21, 136.13, 132.96, 128.80, 128.62, 127.04, 125.95,
120.84. HRMS (ESI) m/z: [M+H] calcd for C13H11N
182.09697; found 182.09723.
(E)-4-(2-(thiophen-2-yl)vinyl)-1-tosyl-1H-imidazole
[NEW] (3v). The title compound was synthesized according
to the general procedure B using the following conditions
and quantities: Thiophen-2-ylboronic acid (57 mg). The title
compound was isolated as a white solid in a yield of 54%
1
(40 mg, 121 µmol). H NMR (850 MHz, CDCl3) δ 8.00 (s,
1H), 7.85 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 15.7 Hz, 1H), 7.39
(d, J = 8.3 Hz, 2H), 7.22 (s, 1H), 7.20 (d, J = 5.0 Hz, 1H),
7.06 (d, J = 3.5 Hz, 1H), 7.00 (dd, J = 5.0, 3.6 Hz, 1H), 6.70
(d, J = 15.7 Hz, 1H), 2.47 (s, J = 6.8 Hz, 3H). 13C NMR (214
MHz, CDCl3) δ 146.36, 142.37, 142.21, 136.97, 134.89,
130.46, 127.65, 127.35, 126.69, 124.66, 123.66, 117.73,
113.77, 21.74. HRMS (ESI) m/z: [M+H] calcd for
C16H15N2O2S2 331.05749; found 331.05888.
1-tosyl-1H-imidazole-2-carbaldehyde [155742-57-7].[13]
1H-imidazole-2-carbaldehyde (5.00 g, 52.0 mmol) and p-
toluenesulfonyl chloride (1 eq., 9.92 g, 52.0 mmol) were
added to a Schlenk-tube under argon atmosphere. THF (dry,
40 mL) was added to dissolve the solids. Then, TEA (1
equiv., 7.26 mL, 5.27 g, 52.0 mmol) was added by means of
a syringe. The reaction mixture was stirred under argon for
24 h at ambient temperature and checked through GC-MS.
Upon completion of the reaction, the solvent was evaporated
under reduced pressure. The crude product was extracted
from acid water with DCM (3 200 mL), the organic phases
were reunited and dried over Na2SO4 to afford the desired
compound in a yield of 96% (12.45 g, 49.7 mmol) as a white
solid. The NMR revealed an impure product with traces of
p-toluenesulfonyl chloride present in the product. However,
this impurity does not affect the following reaction and the
isolated product was used in the following Wittig reaction
step. NMR data of the compound was previously
disclosed.[43]
(E)-5-styrylpyrimidine [35782-34-4] (9b). The title
compound was synthesized according to the general
procedure B using the following conditions and quantities:
5-vinylpyrimidine (24 mg, 226 µmol), phenyl-boronic acid
(55 mg). The title compound was isolated as an off-white
1
solid in a yield of 73% (66 mg, 203 µmol). H NMR (500
MHz, CDCl3) δ 9.09 (s, 1H), 8.87 (s, 2H), 7.54 (d, J = 7.4
Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.37 – 7.31 (m, J = 7.3 Hz,
1H), 7.24 (d, J = 16.6 Hz, 1H), 7.00 (d, J = 16.5 Hz, 1H).
13C NMR (126 MHz, CDCl3) δ 157.21, 154.27, 135.99,
132.87, 131.04, 128.92, 128.87, 126.88, 121.12.
(E)-2-styrylfuran [1202-49-9] (9c). The title compound
was synthesized according to the general procedure B using
the following conditions and quantities: 2-vinylfuran (50 mg,
531 µmol), bathocuproine (10 mg), Pd(OAc)2 (6 mg)
phenylboronic acid (130 mg), MnO2 (139 mg), and ACN
(2 mL). The title compound was observed in traces in GC-
MS analysis but was not isolated (<1% yield).
1-tosyl-2-vinyl-1H-imidazole [NEW] (6). Methyl-
triphenylphosphonium bromide (1.2 equiv., 8.56 g, 24.0
mmol) was transferred to a three-necks round bottom flask
(100 mL) under inert and anhydrous conditions. Then, the
solid was suspended in THF (dry, 30 mL). Potassium tert-
butoxide in THF (1 M, 1.1 equiv., 2.47 g, 22.0 mL, 22.0
mmol) was added by means of a syringe (exothermic
reaction). The reaction mixture turns into a pale-yellow
color. After 30 min, 1d (5.0 g, 20.0 mmol) was slowly
(exothermic reaction) added to the mixture and stirred for
(E)-2-styrylthiophene [26708-50-9] (9d). The title
compound was synthesized according to the general
procedure B using the following conditions and quantities:
2-vinyltiophene (50 mg, 454 µmol), bathocuproine (8 mg),
Pd(OAc)2 (5 mg) phenyl-boronic acid (111 mg) MnO2
(118 mg), and ACN (2 mL). The title compound was
isolated as an off-white solid in a yield of yield 77% (65 mg,
1
349 µmol). H NMR (500 MHz, CDCl) δ 7.41 – 7.37 (m,
2H), 7.29 – 7.24 (m, 2H), 7.19 – 7.10 (m, 3H), 6.99 (d, J =
3.6 Hz, 1H), 6.93 (dd, J = 5.1, 3.6 Hz, 1H), 6.86 (d, J = 16.1
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 142.90, 136.98,
128.71, 128.35, 127.61, 126.31, 126.11, 124.35, 121.80
o
2 h at 20 C and monitored by means of GC-MS. Upon
completion of the reaction, the solvent was evaporated
under reduced pressure. The crude product was extracted
from acid water with DCM (3  200 mL), the organic phases
were combined and dried over Na2SO4. Finally, purification
by means of column chromatography packed with silica gel
and an eluent system composed of hexane:ethyl acetate =
82:18 provides the target compound in a yield of 45% (2.24
(E)-1,2-diphenylethene [103-30-0] (9e). The title
compound was synthesized according to the general
procedure A with some amendments for up-scaled use. In
particular, the following conditions and quantities were
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000909
Advanced Synthesis & Catalysis
used: a pressure-resistant reaction tube (20 mL) was charged
with styrene (208 mg, 2.00 mmol), bathocuproine (36 mg),
Pd(OAc)2 (22 mg), phenyl-boronic acid (341mg), MnO2
(521 mg), and ACN (10 mL). Eluent system composed of
hexane:ethyl acetate = 90:10. White solid. Isolated yield
styryl-benzoic acid Framework. (Manuscript in
Preparation).
[21] G. S. Tria, T. Abrams, J. Baird, H. E. Burks, B.
Firestone, L. A. Gaither, L. G. Hamann, G. He, C. A.
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[22] H. E. Burks, T. Abrams, C. A. Kirby, J. Baird, A.
Fekete, L. G. Hamann, S. Kim, F. Lombardo, A. Loo,
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1
62% (224 mg, 1.24 mmol). H NMR (500 MHz, CDCl3) δ
7.54 – 7.50 (m, 4H), 7.36 (dd, J = 8.5, 6.9 Hz, 4H), 7.28 –
7.23 (m, 2H), 7.11 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
137.34, 128.70, 127.63, 126.53.
Acknowledgements
Financial support for this project was obtained for D.C and F.A.
in the form of ESR grants through the PET3D project that was
funded by the European Commission under the H2020 – MSCA-
ITN-2015 programme grant agreement no 675417. The authors
would like to thank Dr. Bjarte Holmelid at the University of Bergen
for his outstanding technical support for HRMS analyses. This
work was partly supported by the Research Council of Norway
through the Norwegian NMR Platform, NNP (226244/F50) and
the excellent technical support of Dr. Jarl Underhaug.
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12
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10.1002/adsc.202000909
Advanced Synthesis & Catalysis
FULL PAPER
Functionalization of the imidazole backbone by
means of a tailored and optimized oxidative Heck
cross-coupling
Adv. Synth. Catal. 2020, 362, 1 – 12
Davide Cirillo, Francesco Angelucci, and
Hans-René Bjørsvik*
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