Tandem Double-Cross-Coupling/Hydrothiolation Reaction of 2-Sulfenyl Benzimidazoles with Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.9b02067

A new tandem palladium-catalyzed reaction involving a Suzuki-Miyaura coupling, a desulfenylative coupling, and a hydrothiolation of a triple bond is reported. Notably, the desulfenylative coupling occurs without copper(I) assistance and the hydrothiolatio

Full text of DOI:10.1021/acs.orglett.9b02067

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Double-Cross-Coupling/Hydrothiolation Reaction of
2‑Sulfenyl Benzimidazoles with Boronic Acids
Alexandra Basilio Lopes, Mickael Choury, Patrick Wagner, and Mihaela Gulea*
́
́
Universite de Strasbourg, CNRS, Laboratoire d’Innovation Therapeutique, LIT UMR 7200, 67412 Illkirch, France
S
* Supporting Information
ABSTRACT: A new tandem palladium-catalyzed reaction involving a
Suzuki−Miyaura coupling, a desulfenylative coupling, and a hydro-
thiolation of a triple bond is reported. Notably, the desulfenylative
coupling occurs without copper(I) assistance and the hydrothiolation is
totally regioselective and stereoselective. The overall process results in the
double incorporation of the boronic acid and the reincorporation of the
sulfenyl moiety into the product structure. Starting from 2-(bromoben-
zylsulfenyl)-1-propargyl benzimidazoles, the transformation led to
variously substituted benzimidazoles bearing a stereodefined alkenyl
sulfide.
ecause of the important role of organosulfur compounds
in synthetic chemistry and in applied fields such as
Scheme 1. Pd-Catalyzed Processes Involving
Desulfenylative Cross-Coupling of 2-Sulfenyl Benzazoles
B
materials science and the pharmaceuticals industry, the
research of efficient methods for the C−S bond formation is
constantly advancing. Among these methods, transition-metal-
catalyzed cross-coupling of S-nucleophiles with aromatic or
alkenyl halides and hydrothiolation of double or triple bonds
were widely studied and developed in recent years.1,2 In
parallel to this, metal-catalyzed reactions involving a C−S bond
cleavage with release of the sulfur function of the S-
electrophilic partner emerged as a complementary and
practical alternative to more classical C−C cross-couplings
using organohalides.3 One well-known method based on C−S
cleavage was developed starting with the 2000 publication by
Liebeskind and Srogl4 of a new reaction consisting of the Pd-
catalyzed coupling of thioesters with boronic acids, in the
presence of a stoichiometric amount of thiophene-2-carbox-
ylate (CuTC) as an activator. This method found a huge
amount of synthetic applications and was extended to other
nucleophilic coupling partners and particularly to hetero-
aromatic sulfides substrates.5 In 2012, the Weller and Willis
group reported the Rh(I)-catalyzed carbothiolation of alkynes
by aryl methyl sulfides, involving an Ar−S bond cleavage.6 This
represents a very interesting atom economical process, as the
methylsulfenyl leaving-group released in the course of the
reaction is integrated in the final product as an alkenyl methyl
sulfide.
and benzothiazoles by Nishihara and co-workers using Pd
catalysis (Scheme 1, eq 2).9 Surprisingly, we did not find
examples involving benzimidazole substrates.
In an approach inspired by these two methodologies and by
an unexpected finding obtained in a previous study (see below
for details), we report here a Pd-catalyzed tandem one-pot
transformation that consists of a classical Suzuki−Miyaura
coupling and a desulfenylative cross-coupling of 2-benzylsul-
fenyl benzimidazole with aryl boronic acids, followed by an
Because of their widespread occurrence in biologically active
compounds and drugs of benzazole moiety,7 it was not
surprisingly that 2-sulfenyl derivatives of these heteroaromatics
have been used as substrates in the above-mentioned metal-
catalyzed cross-coupling reactions. Thus, 2-sulfenyl benzox-
azoles and benzothiazoles have been successfully coupled with
aryl or heteroaryl boronic acids under the Liebeskind−Srogl
reaction conditions (Scheme 1, eq 1).8 Furthermore, the
alkynes carbothiolation was applied to 2-sufenyl benzoxazoles
Received: June 16, 2019
© XXXX American Chemical Society
A
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intermolecular regioselective and stereoselective hydrothiola-
tion of the triple bond of the N-propargyl benzimidazole
(Scheme 1, eq 3). As the result of the overall transformation,
the sulfenyl moiety is reincorporated into the product structure
as an alkenyl benzyl sulfide, and the aryl substituent provided
by the boronic acid partner is introduced twice: once in the 2-
position of the benzimidazole and again on the benzene ring of
the benzylsulfenyl group. It was possible to achieve the two
types of coupling with the boronic acid under the same
reaction conditions, because, in our case, the desulfenylative
coupling occurred efficiently without the use of copper(I)
carboxylate. Thus, substrates bearing an aryl bromide (present
in the form of a bromobenzyl substituent on the S atom) were
used. This choice could be considered as complementary to
the strategies using orthogonal reactivity,10 increasing the
molecular complexity and diversity of the final products.
Initially, substrate 1a was designed to produce thiazocine
3aaA via a Pd-catalyzed 8-exo-dig cyclization/Suzuki coupling
domino reaction (Scheme 2), based on a methodology that
optimize the reaction conditions to obtain 3aa as the main
product. Many experiments have been performed, varying all
parameters (Pd-source, ligand, base, solvent, temperature,
reaction time), and selected results are summarized in Table 1
Table 1. Optimization of the Reaction of 1a with 2a To
a
Access 3aa
b
entry
1
2
Pd catalyst
ligand L
base
yield (%)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
−
−
−
−
K2CO3
K2CO3
K3PO4
LiOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
43
13
44
32
19
15
53
33
66
c
3
4
5
6
7
8
PPh3
TFP
PCy3
cataCXium
PCy3
Scheme 2. Initial Pd-Catalyzed Reaction of Benzimidazole
1a with Boronic Acid 2a
d
9
a
Reaction conditions: 1a (1 equiv), 2a (3 equiv), catalyst loading (15
mol % Pd), ligand (30 mol %), base (3 equiv), dioxane/H2O 8/2 or
b
c
7/3 (0.1 M), 130 °C, 19 h. Isolated yield. Performed at 140 °C, for
8 h. Pd2(dba)3 (5 mol %), ligand (20 mol %).
d
(more details are given in the Supporting Information).
Compared with the initial reaction conditions (Scheme 2), we
increased the amount of boronic acid (since 2 equiv are
required anyway necessary to obtain 3aa), of the base, and the
catalyst loading (from 10 mol % to 15 mol% Pd), and a
significant improvement (43% yield; see Table 1, entry 1) was
obtained by removing TBAI, using K2CO3 as the base,
changing the reaction concentration from 0.05 M to 0.1 M,
and prolonging the reaction time from 3 h (at 130 °C, MW) to
19 h (at 130 °C, in oil bath). Keeping the same catalyst and
base but heating only for 8 h, at 140 °C, in an oil bath, the
yield turned low again (13%; see Table 1, entry 2). Changing
the base to K3PO4 did not modify the result, while the use of
LiOH decreased the yield slightly (Table 1, entries 3 and 4).
The conventional Pd(OAc)2/PPh3 catalytic systems was found
to be less effective (Table 1, entry 5). Then, Pd2(dba)3 was
used in combination with different phosphine ligands, such as
tri(2-furyl)phosphine (TFP), tricyclohexyl phosphine (PCy3),
or di(1-adamantyl)-n-butylphosphine (catCXiumA) (Table 1,
entries 6−8). The best result was obtained with the
Pd2(dba)3/PCy3 combination (Table 1, entry 7) and the
yield was even improved with less catalyst loading (Table 1,
entry 9). The amount of catalyst used in this reaction remains
high, compared, in particular, to domino reactions involving
carbopalladation; however, the presence of a sulfur species
represents a difficult case, because of the catalyst deactivation
caused by the thiophilicity of palladium. Thus, the use of 5
mol % of Pd2(dba)3, enabling a satisfactory yield of 66%, with
respect to three one-pot Pd-catalyzed processes, can reasonably
be accepted. Thus, these last reaction conditions were kept for
the further stages of the study.
was developed previously in our group to access five- and six-
membered sulfur heterocycles.11 In a preliminary experiment,
by reacting 1a with phenyl boronic acid 2a, a very small
amount of the desired product 3aaA was detected (2%),12
together with a majority of product 3aaB resulting from the
competing direct coupling (58%), but also with two other
products, which were identified as the desulfenylative coupling
product 3aaC (19%), and the unexpected alkenyl sulfide 3aa
(11%). Each product was isolated from the crude mixture and
characterized by NMR and mass spectroscopy. We noted that
the hydrothiolation of the triple bond occurred with a
remarkable regioselectivity and stereoselectivity, since alkenyl
sulfide 3aa was present as a single stereoisomer, resulting from
the syn-addition of the thiol2,13 on the carbon bearing the ethyl
substituent. The structure of 3aa and the stereochemistry of its
double bond have been unambiguously assigned by a two-
dimensional nuclear Overhauser spectroscopy (2D-NOESY)
experiment (see spectra in the Supporting Information). In this
context, note that hydrothiolations of internal dissymmetric
alkynes are rather rare. Intrigued by this result and considering
the originality of the tandem transformation, we decided to
The sequence of this Pd-catalyzed tandem reaction would
reasonably consist of three steps: (i) direct Suzuki coupling on
the phenyl bromide moiety of 1a with boronic acid 2a leading
to 3aaB, (ii) desulfenylative coupling of the latter with 2a to
B
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give 3aaC and thiol 4, and (iii) hydrothiolation by 4 of the
triple bond of 3aaC to afford the alkenyl sulfide 3aa as the final
product (Scheme 3, I). To confirm this, we decided to perform
regioselectivity and stereoselectivity, as only one stereoisomer
of the alkenyl sulfide is formed. For comparison, we also
reacted substrate 5 with 2a under classical Liebeskind−Srogl
conditions (1.3 equiv CuTC, 4 mol % Pd2(dba)3, 16 mol %
TFP, in THF, 50 °C, 18 h).8 The result obtained in this case
showed the particularity of our substrate, as the crude mixture
contained the starting product 5, the desulfenylative coupling
product 3aaC, and the hydrothiolation product 6 in a ratio of
67:20:13. Finally, we checked if the presence of the triple bond
is beneficial to the desulfenylative coupling process, which has
no need of Cu(I)-carboxylate in our case. We prepared for this
purpose 2-(benzylthio)-1-methyl-benzimidazole 7 in which the
propargyl chain was replaced by a methyl substituent. Its
reaction with PhB(OH)2, under the same catalytic conditions,
did not afford the coupling product 8; only the starting
material was recovered (Scheme 3, V). The latter result,
together with the low yield obtained in the hydrothiolation of
3aaC with thiol 4, may suggest that the triple bond is ideally
placed to coordinate the palladium−thiolate species, thereby
facilitating the hydrothiolation step in the tandem process. The
regioselectivity could be explained by the fact that the sp-
hybridized carbon bearing the 1-methylene-2-phenyl benzimi-
dazole is more sterically hindered than the ethyl-substituted
one. However, the validation of such hypotheses requires
additional experimental and theoretical studies.
Scheme 3. Proposed Mechanism and Control Experiments
We next investigated the scope and limitations of the
reaction by varying the substituents on the substrate and the
boronic acid partners (Table 2).
Thus, we prepared two other 2-(bromobenzylsulfenyl)-1-
propargyl benzimidazole derivatives 1b and 1c, bearing the
bromide in meta and para position, respectively. Their reaction
with PhB(OH)2 2a, under the optimized reaction conditions,
Table 2. Tandem Reaction of Various Substrates 1 and Aryl
a
Boronic Acids 2
these different steps independently under the same Pd-
catalyzed reaction conditions (Scheme 3, II, III). First,
compound 3aaB was prepared separately from commercial
reagents, by S-benzylation with 2-(bromomethyl)-1,1′-biphen-
yl and subsequent N-propargylation with 1-bromopent-2-yne
of 2-mercaptobenzimidazole. Its reaction with boronic acid 2a
under the established reaction conditions led to the expected
product 3aa in 63% yield, via a tandem desulfenylative cross-
coupling/hydrothiolation (Scheme 3, II). To examine the
triple-bond hydrothiolation, we prepared substrate 3aaC by N-
propargylation of 2-phenyl-benzimidazole, as well as the
appropriated thiol 4 in two steps from 2-(bromomethyl)-
1,1′-biphenyl and potassium thioacetate. Under the same
reaction conditions, the hydrothiolation led to the expected
product 3aa (36% yield), which was separated from the
recovered starting materials, 3aaC and the disulfide formed
from thiol 4 (Scheme 3, III). Although the same Pd-catalyst
and reaction conditions were used, the absence of the boronic
acid and the different nature of the precursor of the active Pd−
S species could explain the lower yield in product 3aa obtained
in this way.
We also examined the importance of the presence of the aryl
bromide and of the triple bond on the reaction (Scheme 3, IV,
V). Suppressing the bromine on the benzene ring of the
substrate, the desulfenylative coupling/hydrothiolation process
worked in a satisfactory manner, leading to the expected
alkenyl sulfide 6 in 48% isolated yield (Scheme 3, IV).
Remarkably, all these hydrothiolations have occurred with total
a
Reaction conditions: 1 (1 equiv), 2 (3 equiv), Pd2(dba)3 (5 mol %),
PCy3 (20 mol %), K2CO3 (3 equiv), dioxane/H2O 4/1 (0.1 M), 130
°C, 19 h; isolated yields are given.
C
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led to the expected products 3ba and 3ca, in higher yields
(70% and 82%, respectively) than that obtained with the ortho
derivative 1a. In the case of substrate 1d, we changed the
substituent on the triple bond, from ethyl to phenyl. The
reaction of 1d with 2a afforded a complex mixture, in which
only a very small amount of the expected alkenyl sulfide 3da
was isolated and characterized by 1H NMR and mass analyses.
We then decided to pursue the study by reacting the substrate
1c with various boronic acids. By using electron-rich or
electron-poor arylboronic acids substituted either in the para
or in meta position, the reaction worked well, leading to the
desired alkenyl sulfides 3 with yields ranging from 46% to 74%.
In the case of product 3cc, the procedure was scaled up on 1
mmol (50% isolated yield). Only in the case of the use of 3-
(nitrophenyl)boronic acid 2f, the crude reaction mixture
contained unreacted substrate 1c, both of coupling products
3cfB and 3cfC, and the desired compound 3cf (2c/3cfB/
3cfC/3cf ratio = 2:1:1:2). After column chromatography, an
inseparable mixture of 3cf and 3cfC in a 3:1 ratio was
obtained. Finally, we also prepared substrate 1e having
bromine in the ortho-position and a methoxy group in the
meta-position and involved it in reactions with three boronic
acids: 2a, 2b, and 2d. The corresponding desired products
were obtained in satisfactory yields, up to 56%.
Scheme 5. One-Pot Suzuki−Miyaura Cross-Coupling and
Desulfenylative Cross-Coupling/Hydrothiolation
products, which were difficult to assign. Separation via column
chromatography was difficult, and, although pure 9 was
isolated with only 35% yield, we succeeded to validate the
proof of concept.
In summary, we have developed a Pd-catalyzed tandem
process involving 2-(bromobenzylsulfenyl)-1-propargyl benzi-
midazoles and boronic acids. It consists of three reactions: first,
a classical Suzuki debrominative cross-coupling; then, a
desulfenylative coupling in the 2-position of the benzimidazole
that does not require copper(I) assistance; and, finally, an
intermolecular regioselective and stereoselective hydrothiola-
tion of the triple bond of the N-propargyl benzimidazole. The
overall process results in the double incorporation of the
boronic acid partner and the reincorporation of the sulfenyl
moiety into the product structure, as an alkenyl benzyl sulfide.
Further studies will be conducted to extend the scope of the
Pd-catalyzed desulfenylative coupling/hydrothiolation tandem
reaction to other related heterocycles. Moreover, the alkenyl
sulfenyl pendent resulting from hydrothiolation can be
converted to other functionalities by known methods.6
Other modifications of the substrate were made to
determine their influence on the efficiency of the reaction
and to identify its limitations. Thus, the heterocyclic part of the
substrate was modified by replacing the benzimidazole by an
imidazole and by an indole (Scheme 4). Starting from the 4,5-
Scheme 4. Scope and Limitations: Replacement of
Benzimidazole by Another Heterocycle
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02067.
Detailed experimental procedures and spectra data for
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gulea@unistra.fr.
ORCID
diphenyl-imidazole derivative 1f and phenyl boronic acid 2a,
the tandem process still worked well, leading to the expected
alkenyl sulfide 3fa; in this case, the use of Pd(PPh3)4 furnished
a better yield than the use of a Pd2(dba)3/PCy3 catalyst (53%
vs 39%). In contrast, the use of indole-based substrate 1g,
which contained the sulfenyl group, under the same
conditions, led only to the direct coupling product 3gaB,
isolated in 43% yield.
Mihaela Gulea: 0000-0002-2945-0078
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Finally, we investigated the challenging possibility to
perform this reaction in one-pot fashion, keeping the same
reaction conditions, by using two different boronic acids: one
for the debrominative coupling and another for the
desulfenylative coupling (see Scheme 5). Therefore, substrate
1c was placed in the reaction conditions with 1 equiv of
boronic acid 2b. After 4 h, the starting material was consumed,
and the main product detected by HPLC was the Suzuki
coupling product (3cbB). At this stage, 1.5 equiv of boronic
acid 2a was added and the reaction continued for 15 h. The
desired product 9 was identified in the crude mixture as the
■
This work has been published under the framework of the IdEx
Unistra and benefits from funding from the state managed by
the French National Research Agency (postdoctoral grant for
A.B.L.). CNRS is acknowledged for financial support. We
thank Dr. D. Garnier and E. Oliva (PACSI, No. GDS 3670) for
NMR and mass analyses. One reviewer is acknowledged for
interesting suggestions.
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D
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