Transition-Metal-Free Approach for the Direct Arylation of Thiophene: Experimental and Theoretical Investigations towards the (Het)-Aryne Route

Article abstract of DOI:10.1002/ejoc.201801173

This paper presents the results of our investigations on the arylation of thiophene using the transition-metal-free “aryne coupling” methodology. The reaction was studied by both experiment and computation (density functional theory) and comparison with phenyllithium was established. In parallel, the effects of the ligand and the salt on the coupling reaction were examined. The results underline the remarkable effect of such additives on the coupling reaction and the potency of the method to construct hetaryl–aryl backbones which open up promising access to a wide range of heterobiaryl structures using the novel “Het-Aryne” route.

Full text of DOI:10.1002/ejoc.201801173

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A Journal of
Accepted Article
Title: Transition-Metal-Free Approach for the Direct Arylation of
Thiophene: Experimental and Theoretical Investigations towards
the (Het)-Aryne route
Authors: Catherine Demangeat, Tarak Saied, Romain Ramozzi,
Francesca Ingrosso, Manuel Ruiz-Lopez, Armen Panossian,
Frédéric R. Leroux, Yves Fort, and Corinne COMOY
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801173
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Transition-Metal-Free Approach for the Direct Arylation of
Thiophene: Experimental and Theoretical Investigations towards
the (Het)-Aryne route
Catherine Demangeat,[a] Tarak Saied,[a] Romain Ramozzi,[b] Francesca Ingrosso,*[b] Manuel Ruiz-
Lopez,[b] Armen Panossian,[c] Frédéric R. Leroux,[c] Yves Fort,[a] Corinne Comoy*[a]
Abstract: This paper presents the results of our investigations on
the arylation of thiophene using the transition metal-free "Aryne
coupling" methodology. The reaction was studied by both
experiment and computation (density functional theory) and
comparison with phenyllithium was established. In parallel, the
effect of ligand and salt on the coupling reaction was examined.
The results underline the remarkable effect of such additives on
the coupling reaction and the potency of the method to construct
hetaryl-aryl backbones which open up a promising access to a
wide range of heterobiaryl structures using the novel “Het-Aryne”
route.
alternative[4] since it can skip the key preactivation steps of the
coupling partners required in the traditional method. Among
others,[5] Itami and co-workers[6] reported significant advances in
this area. Yet, the regioselectivity of the arylation remains an
important limitation, especially in the oxidative variant of the
coupling. Additionally, heavy-metal contamination of the products
has become subject of a serious demand for their complete
removal in view of biological applications in the pharmaceutical
industry.[7] Consequently, several recent reports have described
the development of transition-metal-free “greener” synthetic
routes to access bi(het)-aryl backbones.[8] The use of such
methods in the direct arylation of heteroarenes has been entirely
reviewed recently.[9]
Not so long ago, some alternative strategies based on aryne
chemistry have emerged.[10] Leroux and co-workers extensively
investigated on an efficient transition metal free aryl-aryl coupling
protocol, the so-called “Aryne coupling” reaction.[11] This
methodology relies on the subsequent generation and trapping of
a
key aryne intermediate with an aryllithium derivative,
proceeding as a chain reaction mechanism through the subtle
interplay of several halogen-lithium exchanges (Scheme 1). The
reaction is initiated by the lithiation of an ortho-
dihalogenobenzene aryne precursor (2) with a small amount of a
thermodynamically stable organolithium intermediate generated
in the former step of the reaction (1), affording the in situ formation
of some aryne traces (3). Then, the key step of this protocol is the
nucleophilic addition of the aryllithium previously prepared, onto
the transient aryne (4) allowing both the biaryl axis formation and
the subsequent aryne regeneration by the in situ bromine or
iodine transfer from the starting material to the resulting 2-
biaryllithium intermediate (5).[12a] This “aryne coupling” has
Introduction
Biaryls and heterobiaryls are ubiquitous in pharmaceuticals,
natural products as well as organic functional materials.[1] The
classical transition-metal-catalyzed cross-coupling reactions
remain the most reliable and powerful tool to connect the two
aromatic partners. The well-established Suzuki-Miyaura cross-
coupling reaction - and its related processes - has been largely
overviewed to this aim.[2,3] Besides this conventional method, the
direct arylation of heteroarenes in which the C-H bond is used as
the reaction center, has recently emerged as a valuable
become
a robust method for the synthesis of various
polyhalogenated biaryls that could be easily further functionalized.
Among other advantages, the use of cheap and easily accessible
coupling partners is worthy to note. Remarkably, this coupling
method was successfully applied to the synthesis of axially chiral
biaryls lately, and the recent development of an
atropodiastereoselective version of this reaction has well
complemented this work.[12]
[a]
[b]
[c]
Universitꢀ de Lorraine, CNRS, L2CM UMR7053
B.P. 70239, 54506 Vandoeuvre-lꢁs-Nancy, France
corinne.comoy@univ-lorraine.fr
Universitꢀ de Lorraine, CNRS, LPCT UMR 7019
B.P. 70239, 54506 Vandoeuvre-lꢁs-Nancy, France
francesca.ingrosso@univ-lorraine.fr
Université de Strasbourg, Université de Haute-Alsace,
CNRS, LIMA, UMR 7042, ECPM, 67000 Strasbourg
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equiv.) was added to the 3-lithiothiophene (entries 1-3). To be
noted that total consumption of starting material 1a was observed
when THF was used as solvent (entries 1-5). Whether precursor
2 was added at lower or at higher temperature did not seem to
sensibly affect the reaction, since the expected product 3a was
obtained in a yield ranging from 54 to 60% after 2h reaction time.
Interestingly, the side product 4, 2,2’-dibromo-biphenyl, resulting
from the homo-coupling of the lithiated aryne precursor, was
observed at -80 °C in 21% yield without sensible decrease of 3a
yield. Additionally, prolonging the reaction time of the aryne
coupling to 6h, or varying the amount of aryne precursor used
(from 1.2 to 1.0 equiv.) have only minor influences on the reaction
(entries 4 and 5). In contrast, moving from THF to a non-
coordinating apolar solvent critically affected the reaction since no
product was observed when performing the reaction in toluene or
hexane, even when the system was warmed up to higher
temperatures.
Scheme 1. Mechanism of the Aryne Coupling as proposed by F.R. Leroux.[12h]
Table 1: Reaction Optimization.
Until now, the use of a heterocyclic coupling partner in this
procedure has never been explored. To the best of our knowledge,
the addition of (hetero)aryllithiums to arynes has only been
sporadically described in the literature.[13-15] However, these
methodologies required the introduction of a third electrophilic
partner since they are not chain procedures.
We report here results on the arylation of thiophene using the
transition metal free "aryne coupling" methodology. To achieve
this goal, a three-fold study has been conducted, including in
parallel: i) extension of the scope of the aryne coupling reaction
to the construction of hetaryl-aryl backbones, ii) observations
regarding the effect of ligand as well as LiBr salt on the reaction,
and iii) mechanistic insight of the coupling reaction using
theoretical calculations.
(Het)ArBr
Solvent
2
n
t
T
(°C)
Yield[a] (%)
1
(h)
eq
3a-b
4
1
THF
1.2
1.2
1.2
1.2
1.0
1.2
1.2
1.2
1.2
1.2
1.2
2
2
2
6
2
2
2
2
2
2
2
-80
54
21
2
THF
-50
-30
-50
-50
-50
-50
-50
-50
-50
-50
60
traces
3
THF
59
-
Results and Discussion
Experimental results:
4
THF
60
traces
5
THF
57
-
6
hexane
toluene
toluene/DME[d]
THF
0[b]
0[c]
45[e]
44[f]
0[g]
36[h]
-
The main purpose of this work was first to adapt the aryne
coupling procedure[11] developed for the synthesis of biaryl
compounds to a new one in adequacy with the heterocyclic
lithiated partner. To this end, we investigated the reaction of 3-
bromothiophene 1a and 1,2-dibromobenzene 2 as a model. In this
preliminary work, the use of 1,2-dibromobenzene as aryne
precursor seems reasonable with regard to its ubiquity in several
previous reports, attesting the appreciable versatility of this
precursor towards diverse aromatic lithiated partners. Thus, in a
first set of experiments, we performed addition of 1,2-
dibromobenzene 2 to the 3-lithiated thiophene 1a under the
variation of classical reaction parameters – such as temperature,
time of condensation, equivalent and solvent, using reaction
7
-
8
-
9
9
-
10
11
toluene
toluene/DME[d]
5
[a] Isolated yields after centrifugal thin-layer chromatography purification. [b] 3-
Bromothiophene 1a was recovered unchanged in 85% yield when hexane
was used as solvent. [c] 3-Bromothiophene 1a was recovered unchanged in
82% yield when toluene was used as solvent. [d] DME (1.0 equiv.) was added
at -80 °C; temperature was allowed to reach -50 °C for 45 min.
conversion rate for the reaction when toluene/DME was used as solvent.
Observed conversion rates were [f]100% in THF, [g]25% in toluene and [h]98%
in toluene/DME
[e]
97%
conditions
derived
from
those
originally
developed.
bromine/lithium exchange allowed preparation of the lithiated
partners using t-butyllithium (t-BuLi, 2.0 equiv.) as the base. The
most significant results are reported in Table 1.
The reactivity of organolithiums is indeed strongly altered in
hydrocarbon solvents and halogen-metal exchange is usually
First in tetrahydrofuran (THF), we examined the influence of
temperature on the coupling step when 1,2-dibromobenzene (1.2
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very slow in such media.[17] Also, chelating ligands as well as
lithium salts are commonly employed to modify the properties of
organolithiums, since they demonstrated high influence on the
nature and reactivity of organometallics aggregates.[16,17,18]
Therefore we envisioned that such additives could allow the
reaction to occur or could improve it when it furnished improvable
yields.
Interestingly, whereas only low conversion rates were observed
when hexane or toluene was used as solvent (15 and 18 %
respectively, entries 6 and 7), the use of dimethoxyethane (DME,
1.0 equiv.) as co-solvent proved to be effective, since it allowed
On the other hand, it has been reported previously[18h,19] that the
use of 2.0 equiv. of t-BuLi in the reaction conditions could
potentially “remove” a full equivalent of ligand by preferential
complexation of the latter with the lithium bromide salt generated
by elimination reaction starting from the t-BuBr formed and the
excess of base (t-BuLi). To address this problem, one solution is
to increase the [ligand:t-BuLi] ratio, either by increasing the
amount of ligand used or by decreasing the stoichiometry of the
base. Attempts to use a [ligand:t-BuLi] ratio of [1:1] in the reaction
performed with DME had a deleterious effect on the yield (29%,
entry 4, Table 2). This result naturally led us to question on the
recovering of 3a in 45 % yield (almost quantitative conversion rate, actual effect of LiBr on the coupling reaction.
entry 8, Table 1). A similar trend was observed for the carbocyclic
analog bromobenzene 1b, although lower yields were generally
obtained.
Subsequently, to acquire further insight on the effect of the
chelating DME on the coupling reaction, we decided to examine
the influence of the ligand stoichiometry on the reaction
developed in toluene (Table 2).
Subsequently, to acquire further insight regarding the influence of
lithium bromide, inevitably generated along with benzyne, as well
as in the first stage of the reaction when using 2.0 equiv. of t-BuLi,
we investigated the effect of this salt when added to the reaction
in toluene during the metalation step, with and without DME
(Table 3). Importantly, in addition to the classical metalation route
employed until now with t-BuLi for 1a (Metalation A), a second
metalation protocol (Metalation B) using n-BuLi (1.0 equiv.) as the
base was developed to avoid the initial formation of LiBr in the
reaction medium, making this metalation pathway the “salt-free
reference method”.
Table 2. Influence of the number of DME equivalents on the coupling
reaction in toluene.
Considering first attempts performed with DME, it is clear that the
salt positively affected the reaction: up to 69% yield was indeed
achieved when an excess of LiBr was added to the reaction using
the usual metalation path A (entry 7, metalation A) overtaking the
previous results obtained without further introduction of salt by
approximately 10 points (58%, entry 3, metalation A). Interestingly,
whether metalation path A or B was used for the metalation of 3-
entry
DME
(m eq)
t-BuLi
(p eq)
Yield[a] (%)
bromothiophene, similar results were obtained when
a
3a
comparable amount of salt was added to the reaction (entries 3-
7). Especially an appreciable increase was reported when more
than 3.0 equiv. of salt were added to the reaction. The LiBr effect
is actually demonstrated by the considerable drop in yield
observed without any salt in the reaction mixture apart from the
one formed concomitantly with benzyne (40%, entry 2 –salt-free
metalation B without LiBr addition). Nevertheless, addition of the
ligand remains essential to the reaction since all experiments
failed to occur when performed without DME, whatever the
amount of LiBr used or the metalation path followed (entry 1). It
appeared overall that the previous hypothesis on the possible
trapping of the ligand by the salt generated in the metalation step
with t-BuLi —that could have explained the considerable
improvement of the yield observed when using an increased
amount of ligand— is not consistent with these observations, and
that the combination of both salt and ligand seemed favorable to
the reaction.
1
2
3
4
5
6
7
0
0.5
1
1
2
4
10
2
2
2
1
2
2
2
0
26
45
29
54
58
56
[a] Isolated yields after centrifugal thin-layer chromatography purification.
The obtained results clearly showed that the use of an increased
amount of ligand had a beneficial effect on the yield. While the
use of
a substoichiometric amount of ligand seemed to
dramatically affect the reaction (entry 2), better yields were not
achieved when increasing the amount of ligand to 10.0 equiv.
(entry 7) and it appeared overall that 4.0 equiv. of ligand proved
to be optimal (entry 6), results remaining pretty close to those
initially obtained in THF (see Table 1, entry 2).
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