Transition-Metal-Free Heterobiaryl Synthesis via Aryne Coupling

Article abstract of DOI:10.1002/ejoc.201900130

We disclose, for the first time, an efficient route for the construction of various heterobiaryl backbones in fair to excellent yields using the Aryne coupling methodology. This study outlined the remarkable effect of external chelating ligands and salt additives on the heterocyclic partner reactivity in the aryne coupling reaction.

Full text of DOI:10.1002/ejoc.201900130

A Journal of
Accepted Article
Title: Transition-Metal-Free Heterobiaryl Synthesis via Aryne Coupling
Authors: Tarak SAIED, Catherine DEMANGEAT, Armen PANOSSIAN,
Frédéric R. LEROUX, Yves FORT, and Corinne COMOY
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900130
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900130
Supported by

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
Transition-Metal-Free Heterobiaryl Synthesis via Aryne Coupling
Tarak Saied,[a] Catherine Demangeat,[a] Armen Panossian,[b] Frédéric R. Leroux,[b] Yves Fort,[a] Corinne
Comoy*[a]
Abstract: We disclose for the first time an efficient route for the
construction of various heterobiaryl backbones in fair to excellent
yields using the Aryne coupling methodology. This study outlined the
remarkable effect of external chelating ligands and salt additives on
the heterocyclic partner reactivity in the aryne coupling reaction.
reaction.[28-43] Very recently, we extended the reaction to the
construction of hetaryl-aryl backbones, developing thus the
“(Het)-Aryne” version of the reaction (scheme 1).[44] However, our
study essentially focused on the thiophene ring as a model
partner. Thanks to experimental and theoretical investigations, we
validated, particularly, a mechanism proposal and we highlighted
significant effects of additives – ligand (dimethoxyethane, DME)
and salt (LiBr)- when performing the reaction in a non-
coordinating solvent.
Introduction
The interest for heterobiaryls and their applications[1-4] is a driving
force for the continuous development of new synthetic methods
towards theses peculiar structures. In comparison to the classical
biaryl compounds, the presence of an heterocycle in the biaryl
structure can provide attractive synthetic and biologic
opportunities although this often complicates the coupling
between the two (hetero)aromatic partners- a favoured synthetic
methods for the construction.[5-8] Indeed, the reduced reactivity of
the substrate, the coordinating property of the heteroatom with the
metal center of the catalyst where applicable, and the reduced
configurational stability of the product usually make the access to
these compounds more complicated, especially the chiral ones.[9-
17]
Scheme 1. Envisioned mechanism for the Aryne coupling of 3-bromothiophene
and dibromobenzene.
Additionally, the unique reactivity of each type of heterocycles
renders difficult the development of a general synthetic route
Thus, based on our previous work, we envision here to extend the
scope of this (Het)-Aryne coupling reaction to the construction of
various hetaryl-aryl backbones, evaluating on the other hand the
effect of a wide range of chelating ligands and salt additives on
this sequence. Polar organometallic chemistry appeared as an
ideal tool toward this aim, considering the high selectivity that can
be achieved in a metalation process of heterocyclic systems.[45-47]
Indeed, directed metalation provides an interesting answer to the
regioselectivity issue often encountered with the transition metal-
catalyzed methodologies usually limiting the scope of the
arylation to the most reactive position of the heterocycle.
compatible with
a range of various heteroaryl containing
compounds, and makes the simple extension of aryl-aryl coupling
methods generally ineffective.[18-20] Therefore, the development of
an efficient method to construct hetaryl-aryl backbones is still a
subject of high significance.
Recently, the drive for sustainable alternatives avoiding the use
of expensive and potentially toxic transition metals has stimulated
efforts for the development of metal-free “greener” synthetic
methods,[21-23] such as the direct arylation of heteroarenes.[7]
These processes often rely on radical-type mechanisms
combining for example the use of aryl halides with
a
diaryliodonium salt[8,24] or a metal-alkoxide with amine bases.[25-27]
However, these alternatives often require the use of the
(hetero)arene coupling component in a very large molar excess
and the regioselectivity of the arylation remains an important issue.
In this context, Leroux et al. reported an efficient transition metal
free aryl-aryl coupling protocol, the so-called “Aryne coupling”
Results and Discussion
We began this work by examining the extension of the scope of
the heteroarene coupling partner in the (Het)-Aryne coupling
previously developed by our group.[44] To this end, we decided to
study three (hetero)-aromatic series (Table 1) in order to evaluate
the electronic influence of the heteroaromatic lithiated partner
generated in the aryne coupling: first, π-deficient systems —
represented by the popular pyridinic moiety—, second, some π
electron-rich systems —with a more specific focus on thiophene
derivatives— and last, two electron-neutral aromatic derivatives
being used as references. Note that, in parallel, several
metalation routes were envisioned for the formation of lithiated
[a]
[b]
Universitꢀ de Lorraine, CNRS, L2CM UMR7053
B.P. 70239, 54506 Vandoeuvre-lꢁs-Nancy, France
corinne.comoy@univ-lorraine.fr
Université de Strasbourg, Université de Haute-Alsace,
CNRS, LIMA, UMR 7042, ECPM, 67000 Strasbourg
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
partners in order to obtain further insight on the influence of the
basic system employed during the aryne coupling. To facilitate the
cross-comparison of results, we initiated this work using a uniform
set of experimental conditions (Table 1) derived from those
originally developed with precursor 1a for the coupling step,[44] as
described hereafter. Thus, our first attempts were carried out by
adding 1,2-dibromobenzene 1a (1.2 equiv.) at -50 °C on the
lithiated heteroaromatic partner [2a-j-Li] (1.0 equiv.) previously
formed and using tetrahydrofuran (THF) as solvent. The resulting
mixture was quenched at this temperature after 2 h of reaction
time.
Table 1. Heteroarene pronucleophile partners in the Het-Aryne coupling reaction
entry
(Het)Ar-Y 2a-j
Metalation conditions
RLi (n eq) t (h)
Products 3a-j
Yields[a] [%]
1
2
nBuLi (1. 2)
1
55
60
tBuLi (2.0)
tBuLi (2.0)
1
1
3
41
4
5
6
nBuLi (1.2)
nBuLi (1.2)
tBuLi (2.0)
1
45
<5
26
1
0.5
LiTMP[b]
(3.0)
7
8
1
1
15
0
LDA (2.0)
9
nBuLi (1.2)
1
31
10
11
-
PhLi[c] (1.0)
-
42
44
tBuLi (2.0)
0.5
[a] Isolated yields after centrifugal thin-layer chromatography purification. [b] Metalation was performed using BF3.Et2O
(1.0 equiv.) as an activator for the heteroarene.[48,49] [c]
A commercial solution of PhLi (1.8 M) in
cyclohexane/ndibutylether: 7/3 was used.
The arylation scope with respect to the heteroaromatic partner is
shown Table 1. Several interesting results already stood out from
this exploratory study. First, the favorable influence of electron-
rich systems on the (Het)-Aryne coupling seemed to clearly
emerge as a general trend. Accordingly, π electron-rich systems
2a-d were found to furnish the best results, affording the expected
heterobiaryls 3a-d in 41-60% yield (entries 1-4, Table 1). Whereas
only up to 26% yield of the aryl-pyridinic products 3e-h were
achieved in the π-deficient series (entries 5-8, Table 1), the
“standard” aryl substrates 2i-j led to the desired biaryl products
3i-j in moderate yields (38-44%, entries 9-10, Table 1).
The reduced size of the enriched heteroaromatic systems could
also have an effect. Indeed, lower yields were obtained when the
reaction was performed with the fused analogs of thiophene (3c
41% and 3d 45% versus 3b 60%, entries 3-4, 5, Table 1).
Especially, when the electron-poor pyridine ring was associated
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
to the furan one, only traces of the expected product 3e were
detected (entry 5, Table 1), i.e. lower amounts than those
obtained with either the naked pyridine (3f, 26%, entry 6, Table 1)
or furan (3a, 55%, entry 1). Subsequently, to improve the
reactivity of the pyridine ring and facilitate its addition onto the
aryne intermediate, we performed the Het-Aryne coupling using
the more enriched 4-dimethylaminopyridine (DMAP) 2g.
Unfortunately, the expected product 3g was isolated only in a low
15% yield, for a conversion rate of 75% (entry 7, Table 1)
indicating that other factors have presumably to be considered. It
is noteworthy that the formation of the aryne intermediate appears
to have occurred since GC-MS analysis of the reaction mixture
revealed the presence of two main products resulting from the
competitive addition of the starting material DMAP 2g after
lithiation or of excess lithium 2,2,6,6-tetramethylpiperidide
(LiTMP), used as the lithiated base, onto benzyne. The latter
hypothesis has been plainly demonstrated when lithium
diisopropylamide (LDA) was employed in the metalation step
starting from 3-chloropyridine 2h (entry 8, Table 1). Under these
conditions, the reaction led exclusively to the addition product of
diisopropylamine (DIA) on benzyne demonstrating the much
higher reactivity of lithium amides in comparison to that of the
generated lithiated pyridine [2f-h-Li]. Although the reaction of
primary and secondary amines with arynes has been well
established,[50,51] addition of tertiary amines to arynes is only
scarcely described in the literature,[52-54] and was far less
expected with regard to the concomitant presence of the lithiated
species.
Based on our previous investigation regarding the remarkable
effect of the chelating DME in a non-coordinating solvent on the
coupling reaction of 3-bromothiophene 2b,[44] we decided then to
evaluate the influence of this additive when added to the reaction
of 3-bromopyridine 2f and bromobenzene 2j using toluene as
solvent (Table 2). We found that the conversion rates are very
close to the reaction yields, which proves that lithiation constitutes
the limiting step for aryne couplings and that all the lithiated
intermediates formed [2b, f, j-Li] react with the precursor 1a. The
absence of conversion in toluene —both in absence and in
presence of the benzyne precursor— confirms well this theory.
The main observed by-products have been identified as products
resulting from the reduction of the dihalogenoaryl precursor and /
or the substrate as well as “homocoupling” products from
precursor 1a.
Table 2. Solvent and additive influence in Het-Aryne coupling reaction.
entry
(Het)Ar-Br 2
Solvent
THF
DME
Products 3
Conversion[a] [%]
Yields[a] [%]
(m equiv.)
0
0
65
<5
48
30
0
60
0
1
2
toluene
toluene
1
0
45
26
0
THF
toluene
0
1
0
0
1
0
0
1
3
4
toluene
17
45
0
15
44
0
THF
toluene
5
6
toluene
THF
39
43
34
42
44
42
29
40
toluene
toluene
7
8
PhLi[b]
[a] Conversion rates and isolated yields after centrifugal thin-layer chromatography purification. [b] A commercial solution of PhLi (1.8
M) in cyclohexane/ndibutylether: 7/3 was used.
In comparison to the results reported for 3-bromothiophene 2b
(entries 1-2, Table 2), the beneficial effect of the ligand was also
observed with 3-bromopyridine 2f and bromobenzene 2j (entries
3-6, Table 2). From these results, it could be reasonable to
speculate that DME strongly promotes the bromine-lithium
exchange required for the formation of the lithiated partners
[2b,f,j-Li] using tBuLi as base (2.0 equiv.) when carried out in
toluene/DME, and probably to a lesser extent, those required for
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
the coupling step too, as already discussed in a preliminary
work.[44] In addition, the complete absence of “homocoupling”
product from 1a when the reaction was carried out in toluene as
solvent, may be consistent with this hypothesis.
still the bidentate skeleton of DME, use of the more rigid diether
LA2 gave the expected product 3b in a lower 25% yield,
suggesting the relevance of the possible fluxional ability of LA1.
Afterwards, the effect of the number of coordinating O-atoms in
the ligand was examined. Interestingly, while polyether LA3
(diglyme) – three coordinating O-atoms – slightly improved the
yield (49%), LA4 (triglyme) – four coordinating O-atoms – was not
favorable, and gave 3b in a lower 30% yield. Then, considering
an identical number of coordinating O-atoms, comparison of LA4
to its related cyclic analog LA5 only revealed minor influence of
the 12-crown-4 ether, although a “macrocyclic effect” could have
been expected.[62,63] In contrast, reducing the cycle size of LA5 -
leading to LA6, the cyclic analog of DME – dropped significantly
the yield (10%). Although the conformational constraint of the
dioxane molecule could have been invoked, it is important to note
that the weak solubility of this compound urged us to consider this
result carefully. On the other hand, substituting the coordinating
O-atom of dioxane by one (LC6, 9%) or two nitrogen atoms (LD2,
8%) has no beneficial effect. Yet, further branching of the
morpholine N-atom with an alkoxy- (LC4) or a methoxydiethylene-
(LC5) side chain proved to be effective and produced comparable
yields (24 and 29% respectively) to that obtained for the related
aminoalkoxide LC1.
Overall, it seems reasonable to suggest that a diethereal ligand
seems more favorable to the reaction than an alkoxide one, and
definitely more advantageous than a tertiary amino ligand. It is
interesting to note that a close parallel may be drawn between the
inhibition of the reaction earlier encountered with DMAP 2g (Table
2), and the relative hindrance displayed herein by amine- and
alkoxide-based ligands. Similarly to our previous hypothesis, our
suspicion suggesting the major product to be the result of the
addition of the ligand onto the transient aryne was once again in
line with results emerging from GC-MS experiments. Such
adducts were quite clearly identified with TMEDA (LD1), DABCO
(LD2) or DMAE (LC1) as ligands, leading either to the
corresponding salt or polyaddition product. These outcomes
clearly demonstrate the high sensitivity of the Het-Aryne coupling
towards the presence of various external nucleophiles.
Based on these results, we decided to explore in detail the ligand
scope of the model reaction formerly developed with thiophene.
Since DME (LA1) proved to furnish encouraging results, we first
investigated the use of its structural analogs LB1, LC1 and LD1
(Table 3), based on a simple ethylene bridge, that is forming a five
membered ring upon chelation with the organolithium,[55-57] in
order to evaluate the effect of the coordinating heteroatom nature.
Comparisons of the results obtained with ligands LA1, LB1, LC1
and LD1 already provide some relevant information. First,
replacement of the two coordinating O-atoms of DME by two
nitrogen ones seemed to dramatically affect the reaction, since
only a disappointing 6% yield was obtained when using the
diamine TMEDA (LD1). This unfavorable influence of TMEDA on
the aryne coupling is consistent with the reported results in the
biphenyl series.[39] In contrast, use of its aminoalkoxide analog,
DMAE[58-61] (LC1) afforded the expected heterobiaryl in a slightly
better – but still modest – 20% yield. Although one could have
expected a favorable influence of the alkoxide moiety, the reaction
failed to occur when using the corresponding dialkoxide ligand
LB1.
Table 3. Screening of various polydentate ligands in the Het-Aryne coupling
reaction.
Additionally, use of the simple THF ether LA7 as ligand provided
the expected heterobiaryl in an interesting 36 % yield. However,
increasing the number of the coordinating O-atoms to three did
not improve the yield (LA8, 28%) which remained quite far from
that obtained with ligand LA3 (49%) featuring an identical
coordinating O-atom number. The probable importance of the
spacing between the coordinating atoms on the effectiveness of
the ligand was confirmed by the result obtained with
dimethoxymethane LA9 (16%).
Last but not least, with asymmetric reactions in view, we screened
a small set of external chiral ligands in connection with ligands
LA1, LB1, LC1 and LD1 earlier examined. Especially, Tomioka’s
diether LA10 and the naturally occurring chiral diamine (-)-
sparteine LD3 were of special interest in view of their successful
use already demonstrated in organolithium chemistry.[55,64-70]
Remarkably, employing the aforementioned chiral diether LA10
provided the expected product in a reasonable 44% yield – almost
matching that of DME – despite the higher crowding displayed by
this ligand. In sharp contrast, the dialkoxide analog LB2 of
Tomioka’s diether did not allow the reaction to occur. Likewise,
use of LC7 afforded the expected heterobiaryl 3b in comparable
results (20%) to those obtained previously in the related achiral
[a] Isolated yields after centrifugal thin-layer chromatography purification.
Overall, since none of these analogs provided yields as good as
that obtained for DME, we next decided to examine a set of
various ethers and polyethers as ligands to evaluate the structural
effect of these compounds on the coupling reaction. Considering
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
series. Finally, a surprising 31% yield was reached when the
benchmark ligand sparteine LD3 was employed, overshooting the
previous results recorded with achiral diamine ligands. This
surprising result could be attributed to the higher steric bulk of (-)-
sparteine as compared to that of diamines LD1 and LD2, possibly
impeding the nucleophilic addition of this ligand onto the aryne.
Considering the best ligands, LA1, 3, 7, 10, we next focused on
further optimizing reaction conditions by varying the stoichiometry
of the ligand. As shown in Table 4, it is clear from these results
that the use of an increased amount of ligand had a beneficial
effect on the yield. Remarkably, when DME and its related analog
diglyme were used, a very similar trend was revealed when rising
the amount of ligand from 0.5 to 10 equiv.
reaction conditions, we investigated the use of several aryne
precursors 1a-d (Table 5) to extend the scope of the model
reaction in toluene, keeping in mind the possible influence of the
nature of the salt generated in the reaction. Note that, the use of
4.0 equiv. of DME will now be considered as the “standard
conditions” when the reaction is carried out in toluene. Although
slightly better results were achieved when using the diglyme
ligand, DME was by far more accessible and cheaper, therefore
we focused on this compound for the following study.
As illustrated in table 5, moving from the dibrominated aryne
precursor 1a to its related analogs 1b-d gave rise to considerable
improvements of the yield. Especially, the iodinated analog 1b
afforded the expected product 5b in a very good 75 % yield and
proved to be the best partner of the series. Interestingly, the
serious increase of the yield observed when replacing a bromine
atom by an iodine one have already been described in the
biphenyl series and could be explained by the much faster
iodine/lithium exchange occurring with this atom as compared to
that with the bromine one.[38-40]
As reported for DME, the use of a substoichiometric amount of
ligand seemed to dramatically affect the reaction. Overall, it
appeared that 4 equiv. of ligand proved to be optimal (entries 5,
10 and 14, Table 4). However, better yields were not achieved
when an increased amount of ligand (10 equiv.) was employed. It
is worthy to note that a close relationship between the yield and
the number of coordinating O-atoms in connection with the
amount of ligand used can be relatively well established when
considering DME (LA1) and diglyme (LA3) ligands. Some results
obtained with THF (LA7, entry 16, Table 4) and Tomioka’s diether
(LA10, entry 13, Table 4) are fairly consistent with this hypothesis.
Table 5. Influence of the aryne precursor on the model reaction using DME
as ligand.
Table 4. Effect of ligand stoichiometry on Het-Aryne coupling.
Aryne precursor
Yields[a] [%]
Aryne precursor
Yields[a] [%]
1
1
3b, 58
5b, 75
3b, 71
5b, 63
entry
tBuLi
Ligand
Yields[a] [%]
[a] Isolated yields after centrifugal thin-layer chromatography purification.
(n equiv.)
structure
(m equiv.)
Nevertheless, the result obtained with 1d was not as high as we
could have imagined especially when considering the impressive
enhancement furnished by the related brominated analog 1c.
Finally, it has to be noted that either LiBr or LiOTf released during
the aryne formation did not affect the reaction, although the effect
of this salt remains delicate to comment because it is accumulated
all along the coupling step.
1
2
3
4
5
6
2
2
1
2
2
2
0.5
1
26
45
29
54
58
56
1
2
4
10
The idea of controlling organolithium reactivity and selectivity by
altering the structure of organometallic aggregates is not new and
has been fully exploited over the past decades. The previous
investigation evaluating the effect of ligands clearly underlined
influences of such compounds on the reactivity of
organolithiums.[44] In this context, “salt effects” have attracted
significant interest in recent years, leading to comprehensive
spectroscopic and theoretical investigations,[71-81] more
specifically in organolithium chemistry where the effects of lithium
halides are commonly encountered.[82-95] Lithium salts are
undoubtedly among the most widely studied salts, being
ubiquitous in a large number of lithiation reactions – either
because they are generated in the reaction, or because they are
involuntarily brought by a contaminated commercial source.
Consequently, many reports investigated lithium halides and
more particularly lithium chloride. In contrast, far less
investigations were conducted on other alkaline or transition
metal salts, often encountered however in cross-coupling
7
2
2
2
2
2
0.5
1
28
49
57
60
58
8
9
2
10
11
4
10
12
13
14
15
16
2
2
2
2
2
0.5
1
20
44
50
36
57
4
1
8
[a] Isolated yields after centrifugal thin-layer chromatography purification.
However, it seemed that there is no obvious correlation when
other amounts or ligands are used which makes detailed
interpretation difficult. Then, in order to further optimize the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
reactions. Especially, the use of these salts in lithiation reactions
has been only scarcely described in literature, nor has been
reported their employment in aryne chemistry. For these reasons,
in addition to the classical lithium halide salts, the next part of this
study investigated the effect of various alkaline and transition
metal salts on the aryne coupling reaction.
effect of other salts to further improve coupling conditions. We
began by investigating the use of different amounts of lithium,
potassium and cesium halides in the salt-free method using nBuLi
as base, at -40 °C for the lithiation of 2b (Table 6) that allow to
avoid the concomitant presence of LiBr. Indeed, contrarily to tBuLi,
the use of one equivalent of nBuLi as a base does not generate
LiX salt in the medium, which allows for studying the influence of
the added salt only. It appeared from our previous study that 2, 5
and 10 equiv. seemed to us the most pertinent values to evaluate
the effect of such salts when added to the reaction.
In a previous study,[44] we proved the positive influence of added
LiBr, which is also the spontaneously generated salt in the
medium upon use of 1,2-dibromobenzene 1a as aryne precursor,
on the reaction yield. These results encouraged us to explore the
Table 6. Salt influence on the model Het-Aryne coupling reaction.
entry
Aryne precursor
n equiv.
Yields[a] of 3b or 5b [%]
1a or 1b
of MX
without MXb
40
Li
K
Br
Cs
Cl
Br
I
Cl
I
Cl
Br
I
1
2
3
4
0
-
-
-
-
-
-
-
-
-
2
5
10
62
67
70
58
65
67
59
67
69
65
74
73
60
68
70
62
75
76
69
73
77
69
76
78
56
69
68
5
6
7
8
0
2
5
10
52
-
-
-
-
-
-
-
-
-
65
78
80
76
80
81
60
74
75
78
89
92
63
85
85
73
85
81
67
85
87
46
52
55
58
61
63
entry
Aryne precursor
n equiv.
Yields[a] of 3b or 5b [%]
1a or 1b
of MX
without MX[b]
40
Br
Cl
CuBr
MgBr2
ZnCl2
AgCl
KCl
9
0
-
-
-
-
-
10
11
12
2
5
10
46
37
29
42
39
35
75
52
49
55
29
27
65
74
73
13
14
15
16
0
2
5
10
52
-
-
-
-
-
51
48
27
50
45
43
66
33
32
71
22
25
78
89
92
[a] Isolated yields after centrifugal thin-layer chromatography purification. [b] Isolated yields after centrifugal thin-layer chromatography purification when toluene
was used as solvent, with DME as additive without salt.
We used either the model precursor 1a or its iodinated analog 1b,
for which better results were obtained. The results show that the
use of an increased amount of salt had globally a beneficial effect
on the yield. Potassium and cesium halides, especially, furnished
the best results. Few improvements were noticed when the salt
was employed in a large excess (10 equiv.) and it appeared
overall that 5.0 equiv. of KCl proved to be the optimal additive.
Furthermore, the ease of handling and the attractive cost of this
additive were an advantage.
As the cation effect could be interesting, we investigated then the
use of copper, magnesium, zinc and silver halides following the
same procedure (entries 9-16, Table 6) to assess the effect of
transition-metal salts and divalent species on the reaction.
Comparison of these results to those obtained previously for KCl
did not show further improvement. The general trend emerging
from this study was clearly contrasting with that reported
discussed above (entries 1-8) since a decrease of the yield was
observed when an increased amount of salt was added to the
reaction. Therefore, we did not further investigate the use of these
salts.
From the above results, the ultimate goal of our study was to
assess the effectiveness of ligand and salt on the coupling of
other (hetero)aromatic partners in order to evaluate if additional
improvement of preliminary results (see Table 1) could be
expected. In this way, we used the optimized conditions obtained
for the aryne precursor 1b: use of DME (4.0 equiv.) and KCl (5.0
equiv.) as additives in toluene. nBuLi was used as the base,
except for the pyridine derivative for which the use of tBuLi was
inevitable. The results are gathered in Table 7. Yields of hetaryl
compounds (3) previously obtained with the dibrominated
precursor 1b were recalled for the sake of comparison.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
It clearly appears that the optimized procedure developed with 3-
bromothiophene 2b could be generalized to other (halogenated)-
heterocyclic systems. The most spectacular achievement was the
results obtained starting from 3-bromopyridine 2f, for which the
yield increased from 26 to 72%. Improvements were also revealed
for benzo[b]thiophene 2d and benzene 2i-j derivatives but not for
furopyridine 2e (entries 3, 6-7 and 4 respectively). Overall, it
appeared that the electronic enrichment of the aromatic
nucleophile seemed to have less influence on the outcome of the
reaction than earlier reported for 1a. Given the high dependency
displayed previously by salts with the nature of the aryne
precursor – and more generally, the high sensitivity of such
additives to any species susceptible to interact with them – it is
highly probable that the effect of KCl salt on the course of the
reaction was also strongly dependent on the nature of the
heterocyclic partner.
Table 7. Extension of the optimized Het-Aryne coupling conditions evaluating the effect of ligand and salt.
entry
1
(Het)Ar-Y 2a-j
Metalation conditions
Products 5a-g
Yields[a] [%]
5a-g (3a-g)
RLi (n equiv.)
T (°C)
t (h)
nBuLi (1.0 equiv.)
-80
1
61 (55)
2
3
nBuLi (1.0 equiv.)
nBuLi (1.2 equiv.)
-40
-80
1
1
89 (60)
61 (45)
4
5
nBuLi (1.2 equiv.)
tBuLi (2.0 equiv.)
-80
-80
1
<5
0.5
72 (26)
6
7
nBuLi (1.2 equiv.)
tBuLi (2.0 equiv.)
-80
-80
1
49 (34)
58 (44)
0.5
[a] Isolated yields after centrifugal thin-layer chromatography purification.
Additionally, it has already been observed in previous reports that
the influence of aryne precursors could also vary with the nature
of the lithiated partner employed in the aryne coupling. In short,
detailed examination considering the unique reactivity of
heterocycles is clearly essential in view of further improvements.
Finally, it is important to note that the concomitant presence of
both KCl and LiBr – resulting from the use of tBuLi as the base in
the metalation step of 3-bromopyridine 2f – is an important
consideration with regard to the tremendous improvement
observed for this compound (Table 7, entry 5) and promises
interesting perspectives in view of further investigations on “salt
effects”.
This work reports the efficient synthesis of various heterobiaryl
compounds based on the transition metal-free aryne coupling
methodology. The effect of both electron-rich and electron-
deficient heteroaromatics on the Het-Aryne coupling reaction
along with the metalation route employed to access the
corresponding heteroaryllithiums were examined. The results
clearly showed the favorable influence of π-electron-rich five-
membered-ring heteroaromatics on the reaction. Additionally,
detailed investigations of both ligand and salt effects on the model
reaction developed with thiophene revealed fundamental effects
of these additives on the reaction when performed in apolar media.
Overall, the use of such compounds in the Het-Aryne coupling
provided impressive enhancement of the yield for a range of
various heterocycles.
Conclusions
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
Experimental Section
MgSO4, and solvents were removed under reduced pressure. The crude
product was purified by centrifugal chromatography to afford compound
5a-g.
General Methods. All reactions were performed under argon atmosphere
in oven- and flame-dried, argon-cooled glassware. All air- and moisture-
sensitive compounds were introduced via syringes through a rubber
septum. 1H and 13C NMR spectra were recorded on a Bruker 200- or 400
MHz spectrometer with CDCl3 as solvent. Chemical shifts are reported in
δ units (parts per million, ppm) and were measured relative to the signals
for residual chloroform (7.26 ppm for 1H NMR and 77.00 ppm for 13C NMR).
Coupling constants J are given in Hz. Coupling patterns are abbreviated
as s (singlet), d (doublet), td (triplet of doublets), m (multiplet). MS
experiments were recorded on a GCMS-QP 2010 spectrometer. Thin-layer
chromatography (TLC) was carried out using 0.25 mm Merck silica-gel (60-
F254) plates and visualized under UV light. Centrifugal thin-layer
chromatography purifications were performed on silica gel (silica gel 60
PF254 containing gypsum).
2-(2-Bromophenyl)furan (3a).[96] Colorless oil, 245 mg, 55% yield. 1H
NMR (400 MHz, CDCl3) δ 6.55 (dd, J = 3.4 Hz, J = 1.8 Hz, 1H), 7.11-7.20
(m, 2H), 7.38 (dd, J = 7.4 Hz, J = 1.2 Hz, 1H), 7.54 (dd, J = 1.8 Hz, J = 0.7
Hz, 1H), 7.66 (d, J = 1.1 Hz, 1H), 7.82 (dd, J = 7.9 Hz, J = 1.7 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 110.6, 111.4, 119.7, 127.4, 128.5, 128.8, 131.3,
134.1, 142.2, 151.3; MS (EI): m/z 222 ([M]+,8), 115 (31), 87 (18), 74 (38),
63 (38), 50 (50), 39 (100).
3-(2-Bromophenyl)thiophene (3b).[44] Colorless oil, 287 mg, 60% yield.
3-(2-Bromophenyl)benzo[b]thiophene (3c).[97] Colorless oil, 237 mg,
41% yield. 1H NMR (400 MHz, CDCl3) δ 7.09-7.16 (m, 1H), 7.22-7.32 (m,
3H), 7.40 (s, 1H), 7.45 (dd, J = 7.7 Hz, J = 1.7 Hz, 1H), 7.61 (dd, J = 8.0
Hz, J = 1.1 Hz, 1H), 7.74 (ddd, J = 12.8 Hz, J = 7.5, 1.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 122.2, 123.1, 124.0, 124.5, 127.5, 129.4, 129.6, 129.3,
132.3, 133.7, 135.4, 139.8, 140.3, 141.2; MS (EI): m/z 290 ([M]+, 100), 289
(16), 288 (97), 208 (28), 165 (89), 104 (25), 83 (10).
Reagents. All reagents were commercially available and used as received
after adequate checks. nBuLi (1.6 M in hexane), tBuLi (1.7 M in pentane)
and PhLi (1.8 M in cyclohexane/ndibutylether: 7/3) were titrated prior to
use against diphenylacetic acid in dry THF. Commercial grade anhydrous
salts were dried on a MB25 Ohaus thermobalance before use. 2-
(Dimethylamino)ethanol (DMAE), diisopropylamine (DIA), N,N,N’,N’-
2-(2-Bromophenyl)benzo[b]thiophene (3d).[98] White solid, 260 mg,
45% yield. 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.26-
7.49 (m, 6H), 7.57-7.64 (m, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.99 – 8.01 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 122.1, 123.2, 123.9, 124.3, 124.5,
124.7, 127.5, 129.6, 132.1, 133.6, 135.5, 139.7, 140.2, 142.4; MS (EI): m/z
288 ([M]+, 53), 208 (37), 165 (65), 139 (18), 104 (21), 87 (26), 74 (54), 50
(72), 39 (100).
tetramethylethylenediamine
(TMEDA),
(S)-(-)-N-methyl-2-
pyrrolidinylmethoxide (LiPM) and diethyleneglycol were freshly distilled
and stored under argon over molecular sieves before use. DME and
hexane were stored over sodium wire before use. THF and toluene were
freshly distilled and stored under argon before use.
General Procedure for the Het-Aryne coupling in THF as solvent.
3-(2-Bromophenyl)pyridine (3f). Colorless solid, 122 mg, 26% yield. 1H
NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 7.9, 1.8
Hz, 1H), 7.28-7.35 (m, 3H), 7.65 (dd, J = 8.0, 1.2 Hz, 1H), 7.69-7.72 (m,
1H), 8.59 (s, 1H), 8.64 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 122.8, 127.7,
129.6, 131.2, 133.3, 133.5, 136.6, 136.8, 139.0, 148.8, 149.9; MS (EI): m/z
233 ([M]+, 68), 154 (45), 127 (57), 101 (24), 87 (37), 74 (99), 63 (68), 39
(100). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C11H9BrN 233.9913;
found 233.9892.
1,2-Dibromobenzene 1a (566.2 mg, 2.4 mmol, 1.2 equiv.) in THF (4 mL)
was added to a solution of heteroaryllithium [2-Li] (2.0 mmol, 1.0 equiv.,
for the preparation of [2-Li] see SI) in THF (6 mL) at -50 °C. After 2 h of
stirring, the reaction mixture was hydrolyzed with water (15 mL) at -50 °C
and was extracted with AcOEt (3 x 10 mL). The combined organic layers
were dried over MgSO4, and solvents were removed under reduced
pressure. The crude product was purified by centrifugal chromatography
to afford compound 3a-j.
2-(2-Bromophenyl)-N,N-dimethylpyridin-4-amine (3g). Yellow oil, 83
mg, 15% yield. 1H NMR (400 MHz, CDCl3) δ 2.98 (s, 6H), 6.45-6.47 (m,
1H), 6.72 (d, J = 2.6 Hz, 1H), 7.17 (td, J = 7.7 Hz, J = 1.8 Hz, 1H), 7.33 (td,
J = 7.5 Hz, J = 1.2 Hz, 1H), 7.45-7.52 (m, 1H), 7.61 (dd, J = 8.0 Hz, J = 1.0
Hz, 1H), 8.28 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 39.2, 105.5,
107.6, 121.9, 127.3, 129.3, 131.3, 133.1, 142.4, 149.3, 154.2, 158.5; MS
(EI): m/z 276 ([M]+, 100), 198 (50), 182 (54), 121 (27), 77 (39), 39 (25);
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C13H14BrN2 277.0335; found
277.0324.
General Procedure for the Het-Aryne coupling in toluene as solvent
and in the presence of DME as ligand.
DME (L1A, 8.0 mmol, 0.82 mL, 4.0 equiv.) was added to a solution of
heteroaryllithium [2-Li] (2.0 mmol, 1.0 equiv., for the preparation of [2-Li]
see SI) in toluene (6 mL), at -78°C. The temperature was allowed to reach
-50 °C during 45 min. and aryne precursor 1a-d (2.4 mmol, 1.2 equiv.) in
toluene (4 mL) was added. After stirring for 2 h at -50 °C, the reaction
mixture was hydrolyzed with water (15 mL) and was extracted with AcOEt
(3 x 10 mL). The combined organic layers were dried over MgSO4, and
solvents were removed under reduced pressure. The crude product was
purified by centrifugal chromatography to afford compound 3b, f, j and 5b.
2-Bromo-2'-methoxybiphenyl (3i).[99] Colorless oil, 146 mg, 31% yield.
1H NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 6.86–6.97 (m, 2H), 7.10 (ddd, J
= 13.6 Hz, J = 7.4 Hz, J = 1.8 Hz, 2H), 7.18-7.35 (m, 3H), 7.57 (dd, J = 8.0
Hz, J = 1.0 Hz, 1H);13C NMR (100 MHz, CDCl3) δ 55.6, 111.0, 120.3, 124.3,
127.0, 128.7, 129.4, 130.3, 130.9, 131.6, 132.5, 139.9, 156.6.
General Procedure for the Het-Aryne coupling in toluene as solvent,
in the presence of DME as ligand and KCl as salt additive.
2-Bromobiphenyl (3j).[44] Colorless oil, 204 mg, 44% yield. 1H NMR (400
MHz, CDCl3) δ 7.08 (tdd, J = 9.3 Hz, J = 8.1 Hz, J = 1.5 Hz, 2H), 7.21 (dd,
J = 7.5 Hz, J = 1.8 Hz, 1H), 7.27-7.36 (m, 2H), 7.38-7.46 (m, 2H), 7.51 (dt,
J = 7.0 Hz, J =3.6 Hz, 1H), 7.58 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.73 (dd,
J = 8.4 Hz, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 123.6, 126.8,
127.2, 128.7, 129.5, 130.7, 131.1, 131.3, 132.3, 132.7, 140.0, 142.1; MS
(EI): m/z 234 ([M]+, 33), 152 (65), 126 (11), 87 (14), 74 (56), 63 (52), 50
(87), 39 (100).
To a solution of heteroaryllithium [2-Li] (2.0 mmol, 1.0 equiv., for the
preparation of [2-Li] see SI) in toluene (6 mL) at the metalation
temperature T °C (for T °C, see SI) was added dried KCl (10.0 mmol, 745.5
mg, 5.0 equiv.). After 5 min. of stirring, DME (L1A, 8.0 mmol, 0.82 mL, 4.0
equiv.) was subsequently added to the reaction mixture at the same
temperature T °C. The temperature was then allowed to reach -50 °C
during 45 min. and 2-bromoiodobenzene 1b (679.0 mg, 2.4 mmol, 1.2
equiv.) in toluene (4 mL) was added. After stirring for 2 h at -50 °C, the
reaction mixture was hydrolyzed with water (15 mL) and was extracted
with AcOEt (3 x 10 mL). The combined organic layers were dried over
2-(2-Iodophenyl)furan (5a). Colorless solid, 329 mg, 61% yield.
Derivative 5a was very unstable, analyses were performed on an analytical
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
sample. 1H NMR (400 MHz, CDCl3) δ 6.53 (dd, J = 3.4 Hz, J = 1.8 Hz, 1H),
6.96-7.01 (m, 1H), 7.05 (dd, J = 3.4 Hz, J = 0.6 Hz, 1H), 7.35-7.47 (m, 2H),
7.64 (dd, J = 7.8 Hz, J = 1.7 Hz, 1H), 7.98 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 94.5, 109.7, 111.1, 128.1, 129.0, 129.4,
135.4, 140.8, 142.3, 153.6; MS (EI): m/z 270 ([M]+,100), 143 (12), 115 (63),
89 (24), 63 (22). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C10H8IO
270.9614; found 270.9610.
Richter, A. Salleo, M. Shkunov, D. Sparrowe, S. Tierney, W. Zhang. Adv.
Mater. 2009, 21, 1091-1109.
[5]
[6]
[7]
L.-C. Campeau, K. Fagnou, Chem. Soc. Rev. 2007, 36, 1058-1068.
D. Zhao, J. You, C. Hu, Chem. Eur. J. 2011, 17, 5466-5492.
R. Rossi, M. Lessi, C. Manzini, G. Marianetti, F. Bellina, Adv. Synth.
Catal. 2015, 357, 3777-3814.
[8]
[9]
M. Koji, D. Toshifumi, K. Yasuyuki, Synlett 2017, 28, 1680-1694.
I. Alkorta, J. Elguero, C. Roussel, N. Vanthuyne, P. Piras, Adv.
Heterocycl. Chem., 2012, 105, 1-188.
3-(2-Iodophenyl)thiophene (5b). Colorless solid, 509 mg, 89% yield. 1H
NMR (400 MHz, CDCl3) δ 6.99-7.12 (m, 1H), 7.12-7.46 (m, 5H), 7.98 (d, J
= 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 99.8, 122.8, 124.9, 127,3,
128.6, 129.1, 131.4, 136.6, 141.5, 145.7; MS (EI): m/z 286 ([M]+,77), 159
(13), 115 (100), 89 (51), 39 (54). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd
for C10H8IS 286.9386, found m/z 286.9357.
[10] E. Kumarasamy, R. Raghunathan, M. P. Sibi, J. Sivaguru, Chem. Rev.
2015, 115, 11239-11300.
[11] D. Bonne, J. Rodriguez, J. Chem. Commun. 2017, 53, 12385-12393.
[12] D. Bonne, J. Rodriguez, Eur. J. Org. Chem. 2018, 2417-2431.
[13] K. Yamaguchi, J. Yamaguchi, A. Studer, K. Itami, Chem. Sci. 2012, 3,
2165-2169.
[14] K. Yamaguchi, H. Kondo, J. Yamaguchi, K. Itami, Chem. Sci. 2013, 4,
3753-3757.
2-(2-Iodophenyl)benzo[b]thiophene (5c).[96] Colorless oil, 410 mg, 61%
yield. 1H NMR (400 MHz, CDCl3) δ 7.08-7.14 (m, 1H), 7.41-7.49 (m, 4H),
7.56 (dd, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.82-7.96 (m, 2H), 8.06 (dd, J = 8.0
Hz, J = 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 99.3, 122.3, 124.1,
124.5, 124.7, 128.2, 129.9, 131.6, 139.6, 139.8, 139.9, 140.2, 140.4,
145.2; HRMS (ESI/Q-TOF) m/z: [M + H]+ 336,9543 calcd for C14H10IS,
found m/z 336,9552.
[15] V. S. Raut, M. Jean, N. Vanthuyne, C. Roussel, T. Constantieux, C.
Bressy, X. Bugaut, D. Bonne, J. Rodriguez, J. Am. Chem. Soc. 2017,
139, 2140-2143.
[16] L. Zhang, J. Zhang, J. Ma, D.-J. Cheng, B. Tan, J. Am. Chem. Soc. 2017,
139, 1714-1717.
[17] J. Rae, J. Frey, S. Jerhaoui, S. Choppin, J. Wencel-Delord, F. Colobert,
ACS, Catal. 2018, 8, 2805–2809.
2-Iodobiphenyl (5d).[100] Colorless oil, 325 mg, 58% yield. 1H NMR (400
MHz, CDCl3) δ 7.12-7.08 (m, 1H), 7.23 (ddd, J = 10.8, 7.6, 1.8 Hz, 2H),
7.29 (dd, J = 7.7, 2.0 Hz, 1H), 7.41 (dtd, J = 8.7, 7.5, 1.2 Hz, 3H), 7.67 (d,
J = 1.0 Hz, 1H), 7.96 (dd, J = 7.9, 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 99.5, 123.5, 127.2, 128.0, 129.3, 129.5, 131.0, 132.6, 138.9, 145.0,
146.1; MS (EI): m/z 281 (16), 280 ([M]+, 75), 152 (100), 126 (25), 86 (25),
76 (74), 51 (19), 39 (38).
[18] X. Chen, L. Zhou, Y. Li, T. Xie, S. Zhou, J. Org. Chem. 2013, 79, 230-
239.
[19] H. Andersson, T. S.-L. Banchelin, S. Das, R. Olsson, F. Almqvist, Chem.
Commun. 2010, 46, 3384-3386.
[20] F.-F. Zhuo, W.-W. Xie, Y.-X. Yang, Y.-X. Zhang, P. Wang, R. Yuan, C.-
S. Da, J. Org. Chem. 2013, 78, 3243-3249.
[21] C. M. Holden, S. M. A. Sohel, M. F. Greaney, Angew. Chem. Int. Ed.
2016, 55, 2450-2453.
3-(2-Iodophenyl)pyridine (5f).[101] Yellow oil, 405 mg, 72% yield. 1H NMR
(400 MHz, CDCl3) δ 7.12 (ddd, J = 7.9 Hz, J = 7.5 Hz, J = 1.7 Hz, 1H),
7.33-7.23 (m, 3H), 7.46-7.39 (m, 2H), 7.71 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H),
7.98 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 99.5,
123.5, 127.2, 128.0, 129.3, 129.5, 130.0, 131.0, 132.6, 138.9, 145.0,
146.1; MS (EI): m/z 281 ([M+] 23), 206 (100), 127 (97), 104 (30), 91 (76),
75 (51), 37 (39).
[22] T. Yanagi, S. Otsuka, Y. Kasuga, K. Fujimoto, K. Murakami, K. Nogi, H.
Yorimisu, A. Osuka, J. Am. Chem. Soc. 2016, 138, 14582-14585.
[23] L. Minuti, F. Piazzolla, A. Temperini, Eur. J. Org. Chem. 2017, 5370-5377.
[24] Y. Kita, K. Morimoto, M. Ito, C. Ogawa, A. Goto, T. Dohi, J. Am. Chem.
Soc. 2009, 131, 1668-1669.
[25] S. Yanagisawa, K. Ueda, T. Taniguchi, K. Itami, Org. Lett. 2008, 10,
4673-4676.
[26] Q. Song, D. Zhang, Q. Zhu, Y. Xu, Org. Lett. 2014, 16, 5272-5274.
[27] O. Vakuliuk, B. Koszarna, D. T. Gryko, Eur. J. Org. Chem. 2011, 2854-
2859.
2-Iodo-2'-methoxybiphenyl (5g).[102] Colorless oil, 303 mg, 49% yield. 1H
NMR (400 MHz, CDCl3) δ 3.84 (s, 3H), 7.02-7.12 (m, 3H), 7.19 (dd, J = 7.4
Hz, J = 1.8 Hz, 1H), 7.34 (dd, J = 7.6 Hz, J = 1.7 Hz, 1H), 7.43–7.48 (m,
2H), 8.00 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
55.7, 100.7, 111.2, 120.5, 120.7, 128.0, 128.8, 129.5, 130.8, 133.5, 138.9,
144.2, 156.4.
[28] F. Leroux, M. Schlosser, Angew. Chem. Int. Ed. 2002, 41, 4272-4274.
[29] F. R. Leroux, L. Bonnafoux, C. Heiss, F. Colobert, D. A. Lanfranchi, Adv.
Synth. Catal. 2007, 349, 2705-2713.
[30] L. Bonnafoux, F. Colobert, F. R. Leroux, Synlett 2010, 19, 2953-2955.
[31] L. Bonnafoux, R. Gramage-Doria, F. Colobert, F. R. Leroux, Chem. Eur.
J. 2011, 17, 11008-11016.
[32] V. Diemer, M. Begaud, F. R. Leroux, F. Colobert, Eur. J. Org. Chem.
2011, 341-354.
Acknowledgments
[33] V. Diemer, J. S. Garcia, F. R. Leroux, F. Colobert, J. Fluorine Chem.
2012, 134, 146-155.
We gratefully acknowledge the French Agence Nationale pour la
Recherche (ANR) (grant number ANR-14-CE06-0003-01,
ChirNoCat), CNRS and Universitꢀ de Lorraine for financial
support. We thank Sandrine Adach and Fabien Lachaud for
technical support and recording mass spectra (UMR L2CM 7053).
[34] L. Bonnafoux, F. R. Leroux, F. Colobert, Beilstein J. Org. Chem. 2011, 7,
1278-1287.
[35] F. R. Leroux, A. Berthelot, L. Bonnafoux, A. Panossian, F. Colobert,
Chem. Eur. J. 2012, 18, 14232-14236.
[36] B. Yalcouye, S. Choppin, A. Panossian, F. R. Leroux, F. Colobert, Eur.
J. Org. Chem. 2014, 6285-6294.
Keywords: • reaction mechanisms • heterocyclic chemistry •
[37] D. Augros, B. Yalcouye, S. Choppin, M. Chessé, A. Panossian, F. R.
Leroux, Eur. J. Org. Chem. 2017, 497-503.
aryne • salt effect • ligand effect
[38] A. Berthelot-Bréhier, A. Panossian, F. Colobert, F. R. Leroux, Org. Chem.
Front. 2015, 2, 634-644.
[1]
[2]
J. J. Mason, J. Bergman, T. Janosik, J. Nat. Prod. 2008, 71, 1447-1450.
G. D. Reddy, S.-J. Park, H. M. Cho, T.-J. Kim, M. E. Lee, J. Med. Chem.
2012, 55, 6438-6444.
[39] B. Yalcouye, A. Berthelot-Bréhier, D. Augros, A. Panossian, S. Choppin,
M. Chessé, F. Colobert, F. R. Leroux, Eur. J. Org. Chem. 2016, 725-732.
[40] D. Augros, B. Yalcouye, A. Berthelot-Bréhier, M. Chessé, S. Choppin, A.
Panossian, F. R. Leroux, Tetrahedron 2016, 72, 5208-5220.
[41] A. Panossian, F. R. Leroux, Chimia. 2016, 70, 43-47.
[3]
[4]
J. Yamaguchi, K. Itami, Bull. Chem. Soc. Jpn. 2017, 90, 367-383.
I. McCulloch, M. Heeney, M. L. Chabinyc, D. DeLongchamp, J. Kline, M.
Cölle, W. Duffy, D. Fischer, D. Gundlach, B. Hamadani, R. Hamilton, L.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
[42] F. R. Leroux, A. Panossian, D. Augros, C. R. Chimie 2017, 682-692.
[43] J. Bortoluzzi, V. Jha, G. Levitre, M. J. Fer, J. Berreur, G. Masson, A.
Panossian, F. R. Leroux, J. Org. Chem. 2018, 83, 7751-7761.
[44] C. Demangeat, T. Saied, R. Ramozzi, F. Ingrosso, M. Ruiz-Lopez, A.
Panossian, F. R. Leroux, Y. Fort, C. Comoy, Eur. J. Org. Chem. 2019,
547-556.
[83] T. L. Rathman, W. F. Bailey, Org. Process. Res. Dev. 2009, 13, 144-151.
[84] W. F. Bailey, X. Jiang, Tetrahedron 2005, 61, 3183-3194.
[85] E. Hevia, R. E. Mulvey, Angew. Chem. Int. Ed. 2011, 5, 6448-6450.
[86] D. R. Armonstrong, W. Clegg, P. Garcia-Alvarez, A. R. Kennedy, M. D.
McCall, L. Russo, E. Hevia, Chem. Eur. J. 2011, 17, 8333-8341.
[87] A. S. Galiano-Roth, Y. J. Kim, J. H. Gilchrist, A. T. Harrison, D. J. Fuller,
D. B. Collum, J. Am. Chem. Soc. 1991, 113, 5053-5055.
[88] M. Ye, S. Logaraij, L. M. Jackman, K. Hillegass, K. A. Hirsh, A. M. Bolliger,
A. L. Grosz, V. Mani, Tetrahedron 1994, 50, 6109-6116.
[89] T. Yasukata, K. Koga, Tetrahedron: Asymmetry 1993, 4, 35-38.
[90] A. Yanagisawa, T. Kikuchi, H. Yamamoto, Synlett, 1998, 174-176.
[91] G. Asensio, P. A. Aleman, L. R. Domingo, M. Medio-Simon, Tetrahedron
Lett. 1998, 39, 3277-3280.
[45] J. Clayden, Organolithiums: Selectivity for synthesis 2002, chap. 1,
Tetrahedron Organic Chemistry Series.
[46] H. J. Reich, Chem. Rev. 2013, 113, 7130-7178.
[47] F. Leroux, J. Mortier, Directed metallation of arenes with organolithiums,
lithium amides, and superbases, in “Arene Chemistry: Reaction
Mechanisms and Methods for Aromatic Compounds” 2016, Mortier, John
Whiley & Sons Inc. p.743-776.
[48] E. Vedejs, X. Chen, J. Am. Chem. Soc. 1996, 118, 1809-1810.
[49] S. Kessar, P. Singh, Chem. Rev. 1997, 97, 721-738.
[50] H. Pellissier, M. Santelli, Tetrahedron 2003, 59, 701-730.
[51] R. Sanz, Org. Prep. Proced. Int. 2008, 40, 215-291.
[52] Y. Fang, Y. Zheng, Z. Wang, Eur. J. Org. Chem. 2012, 1495-1498.
[53] S. S. Bhojgude, T. Kaicharla, A. T. Biju, Org. Lett. 2013, 15, 5452-5455.
[54] P. Huang, B.-Y. He, H.-M. Wang, J.-M. Lu, Synthesis 2015, 47, 221-227.
[55] M. Shindo, K. Koga, K. Tomioka, J. Org. Chem. 1998, 63, 9351-9357.
[56] A. Alexakis, A. Tomassini, S. Leconte, Tetrahedron, 2004, 60, 9479-9484.
[57] J. Praz, L. Guénée, S. Aziz, A. Berkessel, A. Alexakis, Adv. Synth. Catal.
2012, 354, 1780-1790.
[92] B. J. Bunn, N. S. Simpkins, J. Org. Chem. 1993, 58, 533-534.
[93] M. Majewski, R. Lazny, P. Nowak, Tetrahedron Lett. 1995, 36, 5465-
5468.
[94] K. Sugasawa, M. Shindo, H. Noguchi, K. Koga, Tetrahedron Lett. 1996,
37, 7377-7380.
[95] L. Gupta, A. C. Hoepker, K. J. Singh, D. B. Collum, J. Org. Chem. 2009,
74, 2231-2233.
[96] J. Wen, J. Zhang, S.-Y. Chen, J. Li, X.-Q. Yu, Angew. Chem. Int. Ed.
2008, 47, 8897-8900.
[97] M. Kienle, A. Unsinn, P. Knochel, Angew. Chem. Int. Ed. 2010, 49, 4751-
4754.
[58] P. Gros, Y. Fort, G. Quéguiner, P. Caubère, Tetrahedron Lett. 1995, 36,
4791-4794.
[98] T. Truong, M. Mesgar, K. K. A. Le, O. Daugulis, J. Am. Chem. Soc. 2014,
136, 8568-8576.
[59] P. Gros, Y. Fort, P. Caubère, J. Chem. Soc. Perkin Trans. 1 1997, 3071-
3080.
[99] K. V. Kutonova, N. Jung, M. E. Trusova, V. D. Filimonov, P. S. Postnikov,
S. Bräse, Synthesis 2017, 19, 1680-1688.
[60] P. C. Gros, Y. Fort, Eur. J. Org. Chem. 2002, 3375-3383.
[61] P. C. Gros, Y. Fort, Eur. J. Org. Chem. 2009, 4199-4209.
[62] S. Schade, G. Boche, J. Organomet. Chem. 1998, 550, 381-395.
[63] S. Schade, G. Boche, J. Organomet. Chem. 1998, 550, 359-379.
[64] S. E. Denmark, N. Nakajima, O. J.-C. Nicaise, J. Am. Chem. Soc. 1994,
116, 8797-8798.
[100] S. Y. Cho, A. C. Grimsdale, D. J. Jones, S. E. Watkins, A. B. Holmes, J.
Am. Chem. Soc. 2007, 129, 11910-11911.
[101] T. L. Andersen, S. D. Friis, H. Audrain, P. Nordeman, G. Antoni, T.
Skrydstrup, J. Am. Chem. Soc. 2015, 137, 1548-1555.
[102] R. C. Fuson, R. Albright, J. Am. Chem. Soc. 1959, 81, 487-490.
[65] S. E. Denmark, N. Nakajima, C. M. Stiff, O. J.-C. Nicaise, M. Kranz, Adv.
Synth. Catal. 2008, 350, 1023-1045.
[66] D. J. Gallagher, S. Wu, N. A. Nikolic, P. Beak, J. Org. Chem. 1995, 60,
8148–8154.
[67] Y. S. Park, G. A. Weisenburger, P. Beak, J. Am. Chem. Soc. 1997, 119,
10537-10538.
[68] I. Inoue, M. Shindo, K. Koga, K. Tomioka, Tetrahedron, 1994, 50, 4429-
4438.
[69] Y. Yamamoto, H. Nasu, K. Tomioka, Tetrahedron, 2013, 69, 3836-3840.
[70] M. Chrzanowwska, J. Sokolowski, Tetrahedron: Asymmetry 2001, 12,
1435-1440.
[71] S. Desjardins, K. Flinois, H. Oulyadi, D. Davoust, C. Giessner-Prettre, O.
Parisel, J. Maddaluno, Organometallics, 2003, 22, 4090-4097.
[72] B. Lecachey, H. Oulyadi, P. Lameiras, A. Harrison-Marchand, H. Gérard,
J. Maddaluno, J. Org. Chem. 2010, 75, 5976-5983.
[73] T. Fox, H. Hausmann, H. Güunther, Magn. Reson. Chem. 2004, 42, 788-
794.
[74] P. L. Hall, J. H. Gilchrist, A. T. Harrison, D. J. Fuller, D. B. Collum, J. Am.
Chem. Soc. 1991, 113, 9575-9585.
[75] F. E. Romesberg, D. B. Collum, J. Am. Chem. Soc. 1994, 116, 9187-
9197.
[76] F. E. Romesberg, D. B. Collum, J. Am. Chem. Soc. 1994, 116, 9198-
9202.
[77] K. W. Henderson, A. E. Dorigo, Q.-Y. Liu, P. G. Williard, P. v. R. Schleyer,
P. R. Bernstein, J. Am. Chem. Soc. 1996, 118, 1339-1347.
[78] W. Clegg, J. C. Greer, J. M. Hayes, F. S. Mair, P. M. Nolan, P. A. O’Neil,
Inorg. Chim. Acta 1997, 258, 1-9.
[79] L. Pratt, M. Bull. Chem. Soc. Jpn. 2005, 78, 890-898.
[80] A. M. Bruneau, L. Liou, D. B. Collum, J. Am. Chem. Soc. 2014, 136,
2885-2891.
[81] Y. Gimbert, D. Lesage, C. Fressigné, J. Maddaluno, J. Org. Chem. 2017,
82, 8141-8147.
[82] H. J. S. Winkler, H. Winkler, J. Am. Chem. Soc. 1966, 88, 969-974.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900130
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
We disclose for the first time an
efficient route for the construction of
various heterobiaryl backbones in fair
to excellent yields using the Aryne
coupling methodology. This study
outlined the remarkable effect of
external chelating ligands and salt
additives on the heterocyclic partner
reactivity in the aryne coupling
reaction.
Heterobiaryls • Het-aryne coupling *
Tarak Saied, Catherine Demangeat,
Armen Panossian, Frédéric R. Leroux,
Yves Fort, Corinne Comoy.*
Page No. – Page No.
Transition-Metal-Free Heterobiaryl
Synthesis via Aryne Coupling
This article is protected by copyright. All rights reserved.