Antagonistic Effect of Acetates in C–N Bond Formation with In Situ Generated Diazonium Salts: A Combined Theoretical and Experimental Study

Article abstract of DOI:10.1002/ejoc.201600891

The mechanism of the copper-catalyzed arylation of nitrogen heterocycles using anilines via diazonium salts has been studied by combining DFT and experimental data. A Cu^I/Cu^IIIredox mechanism is proposed. Our study has revealed the multiple roles of the acid/base couple AcOH/AcO^–. An in situ formed triazene species maintains a low concentration of diazonium salts in the reaction medium, which ensures limited formation of decomposition products. The results of DFT calculations have explained the lower reactivity of imidazole nucleophiles as compared with pyrazole in the arylation reaction.

Full text of DOI:10.1002/ejoc.201600891

A Journal of
Accepted Article
Title: Antagonist effect of acetates in C-N bond formation with in situ generated dia-
zonium salts: a combined theoretical and experimental study
`
Authors: Marc Taillefer; Laurence Grimaud; Ilaria Ciofini; Julien Berges; Lucas
Perego; Indira Fabre
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600891
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European Journal of Organic Chemistry
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Antagonist effect of acetates in C-N bond formation with in situ
generated diazonium salts: a combined theoretical and
experimental study
Indira Fabre,[a],[b] Lucas A. Perego,[a],[b] Julien Bergès,[c] Ilaria Ciofini,*[b] Laurence Grimaud,*[a] Marc
Taillefer*[c]
Abstract: The mechanism of the copper catalyzed arylation of
nitrogen heterocycles from anilines via diazonium salts has been
studied by combining theoretical outcomes from DFT and
experimental data. A Cu(I)/Cu(III) redox mechanism is proposed.
Our study reveals the multiple roles of the acid-base couple
AcOH/AcO-. The in situ formed triazene species maintains a low
concentration of diazonium salts in the reaction medium, which
ensures limited decomposition products. DFT calculations could
explain the lower reactivity of imidazole nucleophiles as compared to
pyrazole.
diazonium species, including the in situ generation of diazonium
salts from free anilines (with catalytic or stoichiometric amounts
of acid), or the use of aryl triazenes as latent diazonium salts.
[13–15]
Both preformed
and in situ generated[16] diazonium salts
have been used in palladium-catalyzed cross-coupling reactions.
The copper-mediated Sandmeyer reaction, disclosed more than
a century ago,[17] was first described in catalytic conditions by
Beletskaya et al.
using phenanthroline as ligand. Thus
aryl nitriles[19] and aryl
synthesis of aryl halides[18]
,
thiocyanates[20] could be achieved under very mild conditions.
The copper-promoted (0.6 equiv.) trifluoromethylation and
trifluoromethylthiolation of arenediazonium tetrafluoroborates
were also reported recently.[21,22] It may also be noted that the
direct reaction of diazonium salts with amines, proceeding via a
radical mechanism, has also been reported in literature.[23]
Some of us[24] have recently published the first copper-
catalyzed C-N bond formation involving arenediazonium salts.
The method proceeds in ligand-free conditions via an in situ
generation of the latter from anilines and their coupling with
nitrogen heterocycles, using a catalytic amount of acid (see
Table 1). These are mild and safe conditions since hazardous
diazonium salts are not isolated and their concentration is
maintained at a very low level. This procedure generates by-
products of low ecological impact such as tert-butanol, water
and nitrogen gas.
Introduction
Products resulting from transition metal-catalyzed C-N bond
formation find many applications in life and material sciences.
Initiated by the work of Ullmann and Goldberg at the beginning
of the last century, the copper-mediated C-N bond formation
from aryl halides has been known for a long time. [1–4] During the
last fifteen years, extensive work has been performed to render
these reactions safer and more efficient in terms, for example, of
[5–9]
Cu loading as well as to widen their scope.
Nonetheless,
these methodologies still suffer from limitations. For instance,
arylations starting from cheap non-activated aryl chlorides
remain difficult with copper catalysts, whatever the nature of the
nucleophile.[10–12]
Table 1. Cu-catalyzed arylation of pyrazole from aniline via in situ
formation of benzene diazonium
A
possible alternative is to replace aryl halides by
arenediazonium salts. These latter, which can be easily
prepared from available and inexpensive anilines, are usually
able to react in very mild temperature conditions, without
requiring any additives -a base for instance. Moreover, the
reactions release nitrogen (N2), which is inert towards functional
groups. Unfortunately, the leaving group ability of the diazonium
function, giving N2 release, makes these compounds rather
unstable and potentially explosive. Different methods allow to
work under safer conditions, with no need of isolation of
Entry
[Cu] (20 mol%)
Yield (%)
1
2
3
4
Cu
CuI
78
50
22
94
CuOAc
Cu(OAc)2
[a]
I. Fabre, L. A. Perego, Dr L. Grimaud
1 Ecole normale supérieure, PSL Research University, UPMC Univ
Paris 06, CNRS, Département de Chimie, PASTEUR, 24, rue
Lhomond, 75005 Paris, France
2 Sorbonne Universités, UPMC Univ Paris 06, ENS, CNRS,
PASTEUR, 75005 Paris, France
E-mail: Laurence.Grimaud@ens.fr
I. Fabre, L. A. Perego, Dr I. Ciofini
PSL Research University, Institut de Recherche de Chimie Paris,
CNRS Chimie ParisTech, 11 rue P. et M. Curie, 75005Paris, France
E-mail: ilaria.ciofini@chimie-paristech.fr
The purpose of the present study is to elucidate the
mechanism of this reaction with the aim of providing keys to
enhance its yield and broaden its scope. To this end, both
theoretical and experimental approaches were applied to
investigate the different steps of this reaction. These
complementary methods allowed to clearly show the formation
of a triazene species, which plays the role of diazonium reservoir,
the nature of the catalytic species (Cu(I)), as well as the non-
negligible role of the AcOH/AcO- pair.
[b]
[c]
J. Bergès, Dr M. Taillefer
Ecole Nationale Supérieure de Chimie De Montpellier, Institut
Charles Gerhardt Montpellier UMR 5253 CNRS, AM2N, Department
8 rue de l’Ecole Normale, Montpellier 34296 Cedex 5, France
E-mail: marc.taillefer@enscm.fr
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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Results and Discussion
In this reaction, the first step is most likely the
diazotization of the aniline which occurs in the presence of
t-BuONO and acetic acid to form the corresponding
diazonium acetate salt25–27. The diazonium generated in situ
could then be involved in the copper-catalyzed cross-
coupling with one equivalent of pyrazole to form the desired
aryl pyrazole (Scheme 1). However, using a catalytic
amount of acetic acid (20 mol%), the diazonium should be
present at a low concentration (as it will be discussed
below). Therefore, the overall reaction should most
probably rely on two concerted catalytic processes
(Scheme 1). The primary goal of this study will thus be to
elucidate which are the active reagents and the active
copper catalytic species.
Figure 1. 19F NMR monitoring of the formation and decomposition of the
triazene starting from para-fluoroaniline in different conditions: 1 equiv of
aniline, 0.2 equiv of AcOH, 1.1 equiv of tBuONO (black, ■, standard
conditions), 1 equiv of aniline, 1 equiv of AcOH, 1.1 equiv of tBuONO (red, ●),
2.5 equiv of aniline, 1 equiv of AcOH, 1.1 equiv of tBuONO (blue, ▲). α,α,α-
trifluorotoluene was used as internal standard. The relative amount is
calculated against the limiting reactant: aniline for ■ and ●, and tBuNO for ▲.
In all cases, the aniline was fully converted in some hours
into
a single species identified as the triazene by
comparison with the NMR spectra of an authentic sample.
This species decomposes after a few hours yielding
fluorobenzene as the main product, regenerating para-
fluoroaniline, (see Scheme 1 and supporting information). In
our standard conditions (fig 1, ■) the triazene species can
be quantitatively formed because the substoichiometric
amount of acetic acid is consumed by the formation of
diazonium but regenerated by the formation of triazene.
The rates of both formation and decomposition of the
triazene were found faster when low amounts of acetic acid
were used (fig 1, ■). The weak acidity of acetic acid (pKa =
4.75 in water), allows a reasonable stability of the triazene
and its formation does not stop the reaction with copper.
We then checked the ability of triazene to react with the
nucleophile to give the corresponding coupling product.
Gas chromatography (GC) analysis of the reaction between
the triazene (R=F), Cu(OAc)2 and pyrazole (slight excess,
1.3 equiv) in presence of a catalytic amount of acetic acid
(0.5 equiv) showed the slow formation of the desired para-
fluorophenyl pyrazole, along with para-fluoroaniline,
confirming the reactivity of the triazene species. 80 % of
product (GC yield) were formed after 48 h at room
temperature (Scheme 2). This result confirms that the
triazene is an efficient resting state for the diazonium
species.
Scheme 1. Simplified mechanism of the formation of the triazene, its
equilibrium with the reactive diazonium species, and its evolution towards the
expected aryl pyrazole and the reduction product.
The triazene-diazonium equilibrium modulated by
acetic acid
Felpin and coll.[28] showed that when using electron-rich
anilines in palladium-catalyzed arylation of olefins, triazene
species were immediately formed in the reaction medium
due to the coexistence of the diazonium salt in catalytic
amount and an excess of aniline. The sensitivity of the
triazene species toward acidic conditions (methanesulfonic
acid in this case) was suspected to stop the catalytic cycle
in their case. Nevertheless, triazenes are not necessarily
unreactive species and can be used as concealed
diazonium or protected amines[29–31] regenerated by acidic
treatment (usually 5% trifluoroacetic acid, weaker than
MeSO3H).
As we suspected a similar behaviour, the formation of the
diazonium acetate salt was monitored by 19F NMR,
choosing the para-fluoroaniline as model substrate, both
with a catalytic (standard conditions) and a stoichiometric
amount of acetic acid, and with an excess of aniline (see
Figure 1 and Scheme 1, R = F).
Scheme 2. Copper-mediated reaction between the triazene and pyrazole..
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Triazene species can form complexes with copper[30,32]
and are stable towards neutral or basic conditions. To verify
that the diazonium was the active species and not the
triazene, we performed 19F NMR kinetics of the arylation of
pyrazole in different conditions, assuming that the presence
of acid favoured the shift of the equilibrium towards the
formation of diazonium intermediate. The results are
presented in Figure 2.
the product was formed slowly with fluorobenzenei. The
formation of the product is rate-limiting compared to the
triazene formation. When evaluating the reactivity of the
triazene species, its decomposition in the absence of
copper showed formation of aniline and arene. This latter is
formed by reduction of the diazonium, and should involve a
radical intermediate. The reduction of diazonium salts by
alcoholic solvents (here methanol) by dediazoniation via a
homolytic pathway can happen in neutral[33–37], basic[38–41] or
acidic[42–48] media in the presence or not of water and
previous work by DeTar et al.[39,40,47] show that it is favored
by the presence of acetate in methanol, resulting in the
formation of arene and formaldehyde.
Figure 2. Kinetics of the reactivity of the triazene (1 equiv) in MeOH in
presence of pyrazole (1.3 equiv) and Cu(OAc)2 (1 equiv) and different
additives, as monitored by 19F NMR spectroscopy: 1 equiv K2CO3 (black, ×),
no additive (blue, +), 0.5 equiv AcOH (green, ○), 1 equiv AcOH (red, *). α,α,α-
trifluorotoluene was used as internal standard. Dotted decreasing curves show
the consumption of the triazene, solid increasing curves show the formation of
the phenyl pyrazole.
Figure 3. Kinetics of the conversion of para-fluoroaniline (0.5 mmol) in
presence of Cu(OAc)2 (0.066 mmol), pyrazole (0.33 mmol), tBuONO
(0.55 mmol), AcOH (0.1 mmol) in MeOH (0.5 mL) as monitored by 19F
NMR spectroscopy. α,α,α-trifluorotoluene was used as internal standard.
Reaction without AcOH could proceed, but slowly. The
addition of an inorganic base (1 equiv K2CO3) instead of
acetic acid, decreased the rate and almost shut down the
reaction. In the presence of acid (0.5 equiv or 1 equiv of
AcOH to be compared to no additive), the decomposition of
the triazene, and the formation of the expected para-
fluorophenyl pyrazole are faster. These results are
consistent with the hypothesis that the triazene is in
equilibrium with the diazonium which is the active species.
Acetic acid plays an ambivalent role as it is required to
generate the active species from the unreactive triazene but
has a deleterious effect at high concentrations (1 equiv) by
accelerating its decomposition, increasing the quantity of
arene formed, and limiting the final yield (see Figure 2 and
supporting information). Indeed, the amount of arene
obtained allows us to explain the moderate yields of phenyl
pyrazole observed.
As a supplementary evidence, benzyl alcohol was used
as a model alcoholic solvent. The addition of para-
fluorophenyldiazonium
tetrafluoroborate
and
tetrabutylammonium benzoate in stoichiometric amounts
showed immediate gas evolution (N2) and formation of
1
benzaldehyde was confirmed by both H NMR and GC. 19F
NMR showed total conversion of the diazonium after a few
minutes, with fluorobenzene as the main product (see
supporting information). This confirms an in situ reduction of
the diazonium salt to generate small amounts of radicals. In
spite of this destructive action of MeOH, this solvent was
chosen, mainly for solubility issues.
When optimized conditions are applied, high yields are
achieved, meaning that the rate of decomposition of the
triazene is lower than the reaction rate, and that little
amounts of radical species are produced with the
intervention of the solvent. When radical scavengers
(Galvinoxyl and TEMPO) were used in the optimized
conditions, the reaction was not inhibited at all. This
suggests that free radicals are not involved in the cross-
The active copper species
In order to gain further insight into the mechanism, the
kinetics of the global reaction under catalytic conditions was
followed by 19F NMR (see Figure 3). Consumption of para-
fluoroaniline was fast from the beginning and both triazene
and para-fluorophenyl pyrazole formed immediately. After
two hours the amount of triazene started decreasing, and
coupling process, but rather in
a by-path process,
explaining the need for an excess of aniline to overcome its
loss. Nevertheless, a negative result in radical trapping
experiments by using classical radical scavengers does not
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European Journal of Organic Chemistry
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necessarily exclude the involvement of very short-lived
radicals in the coordination sphere of the metal. Therefore,
we performed a radical clock experiment (see Scheme 3).
Scheme 5. Mechanisms of the activation of arenediazonium by Cu(I).
On the basis of all these findings, a suitable catalytic cycle
involving Cu(I) as active catalytic species can be postulated
as depicted in Scheme 6.
Scheme 3. Radical clock experiment.
Optimized conditions applied to 2-allyloxyaniline formed
the cyclized 3-methylbenzofurane as the main product.
Only traces of coupling product could be detected by GC-
MSii. This means that, in addition to the radicals that can be
generated from the decomposition of the triazene, one
cannot exclude the existence of aryl radicals in the
coordination sphere of copper, resulting of the reduction of
the diazonium salt and subsequent oxidation of copper.
This result leads us to propose that Cu(II) constitutes a
convenient pre-catalyst to enter the Cu(I)/Cu(III) catalytic
cycle (see Scheme 4).
Scheme 4. Generation of aryl radical from diazonium salts and their
reactivity
Such a catalytic cycle was proposed even if tBuONO is
able to oxidize Cu(I) to Cu(II) in the reaction medium, as was
evidenced by cyclic voltammetry experiments. Indeed, the
radical by-path is able to regenerate the active form of the
catalyst (see supporting information).
Scheme 6. Proposed catalytic cycle.
Thus we postulated a mechanism consistent with those
generally proposed for the activation of diazonium salts by
transition metals (Scheme 5). The Cu(I) catalyst reacts with
the diazonium salt according to either an oxidative
In this rather complex catalytic cycle, all previously
identified species appear and play a role. The arene
diazonium acetate, in situ formed and in equilibrium with
triazene, can react with the Cu(I) active catalyst in a catalytic
cycle, involving oxidative addition (OA), intramolecular
deprotonation (ID) and reductive elimination (RE) to yield
the targeted coupling product and regenerate Cu(I). Since
this reaction proceeds without the addition of an external
base, it is reasonable to hypothesize that the nucleophile
(pyrazole) is not deprotonated before replacing a ligand on
copper but rather forms on the copper center by
intramolecular deprotonation, the copper acetate ligands
acting as a base. The excess of pyrazole in the reaction
medium (with respect to catalyst and diazonium acetate)
and the affinity of this ligand for copper[56,57] and copper
addition[49–51]
(
a
) or a SET[21,22,52]
(
b
) (from the metal species
or from another reductive agent source), with departure of
the N2 group as a gas. Then reductive elimination ( ) can
proceed, or SRN1( ). Both routes are not completely
c
d
independent since the aryl radical generated by
b can
interact with Cu(II) to generate Cu(III)
.
The choice between
a and b is usually motivated by a
radical clock experiment or by a control experiment in
presence of a radical scavenger.[53–55] In our reaction, Cu(II)
is used in the optimized conditions, meaning that, according
to Scheme 5, radicals must be present in the reaction
medium to initiate the reaction with Cu(II) and the formation
of the coupling product along with Cu(I), which is then
involved in a Cu(I)/Cu(III) catalytic cycle.
acetate[58]
intermediate
1
suggests its complexation to form the
prior to the complexation of the diazonium.
2
In a next step, OA yields to the Cu(III) intermediate
7
with
release of a molecule of nitrogen. Successive ID of a
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European Journal of Organic Chemistry
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pyrazole by an acetate enables the formation of
9
which
VI, ΔE = -18.17 kcal/mol) than when there are two (III
 VII
can then undergo RE to regenerate the initial Cu(I) complex
after ligand exchange (LE). Along with the cross-coupling
product, a molecule of acetic acid is expelled from the
coordination sphere of copper and can thus participate in
the generation of the diazonium salt.
or IV VIII, ΔE≈ -10 kcal/mol). This means that we do not
necessarily have the complexation of two pyrazoles on
copper before the oxidative addition.

Table 2. Heat of formation and structures of the complexes considered.
Hydrogen atoms were removed for clarity. Intramolecuclar hydrogen bonds
are highlighted with black dashed lines
After reductive elimination, Cu(I) is formed which can
directly undergo oxidative addition with the diazonium salt.
This justifies the catalytic activity of CuOAc and CuI as
copper sources (see Table 1). The lower yield for CuOAc
can be explained by the fact that this copper complex is
very moisture and air sensitive and decomposes, giving a
green decomposition product.[60] Interestingly, the catalytic
activity of metallic copper (Table 1, entry 1) comes from the
in situ generation of Cu(I) as well: oxidation of metallic
copper by arene diazonium salts is indeed known to
Cu AcO- + n Pyrazole

Cu(OAc)m(Pyrazole)n(m-1)-+ + m
Complex
I
m
1
n
0
Configuration
Structure
ΔHf (kcal/mol)
-44.07
[35,59]
promote the formation of Cu(I) species from Cu(0)
II
1
1
1
2
-78.75
(ArN2+ + Cu(0)

Ar. + N2 + Cu(I)+).
Considering an active Cu(I) species, we investigated what
could be the stoichiometry of the Cu(I) complex as in the
reaction medium, acetate and pyrazole can both coordinate
copper.
III
1
2
3
-102.10
The preferred formation of a complex was investigated by
cyclic voltammetry (CV) performed in methanol with
IV
1
2
-97.72
+
tetrakisacetonitrile copper(I) hexafluorophosphate CuIS4
-
PF6 as the copper source. The observation of the reduction
wave of Cu(I) in Cu(0) showed the complexation of acetate.
Addition of one to six equivalents of pyrazole showed the
formation of several new copper species in equilibrium. The
same experiment followed by NMR showed very broad
peaks for the pyrazole ligands, suggesting as well the
coexistence of complexes of different stoichiometry. In both
cases, the copper complexes could be neither identified nor
quantified experimentally (see details in Supporting
Information).
V
1
2
2
1
-89.02
-96.92
VI
To discriminate between different Cu(I) complexes,
Density Functional Theory (DFT) was applied. The details
of the computational approach are given in Supporting
Information. Bulk solvent effects (methanol) were
introduced using an implicit solvation model (Polarizable
Continuum Model, PCM).[61] This type of theoretical level
has proven its accuracy in the mechanistic investigations of
copper-catalyzed C-N bond forming reactions.[8,62–65]
The heat of formation for complexes with various numbers
of ligands and various conformations was theoretically
evaluated (see Table 2). We assumed that in a first time a
VII
2
2
2
2
1
2
-107.19
-111.31
VIII
neutral Cu(I) complex was formed (complexes
I to V). When
In order to further confirm the hypothesis of a diazonium
as an active species, DFT calculations were performed to
evaluate the reactivity of the triazene species and a Cu(I)
complex bearing pyrazole and acetate ligands (see
computational details in supporting information). This
triazene can be stabilized by complexation to copper (-
23.10 kcal/mol), but direct oxidative addition into the C-N
bond requires a much higher energy to be achieved in the
reaction conditions (Ea = 54.00 kcal/mol). These results
further confirmed that the triazene constitutes a stable
reservoir for diazonium which is active the coupling partner
in this reaction.
the diazonium acetate approaches, its acetate complexes
the copper ion so that a favourable electrostatic interaction
between the cationic arene diazonium and an anionic Cu(I)
complex bearing two acetates (complexes VI to VIII) can be
envisaged. Results show that adding one pyrazole to
CuOAc is very favorable (
Adding a second pyrazole is less stabilizing (II
, ΔE≈ -10-20 kcal/mol). When the external acetate from
the diazonium complexes to copper, it is more stabilizing
when only one pyrazole molecule is already present (II
I

II, ΔE = -34.68 kcal/mol).

III, IV or
V

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European Journal of Organic Chemistry
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The whole catalytic cycle was then computed starting
from complexes VI, VII and VIII (see Figures 4).
Figure 4. Computed reaction path for the selected copper complexes VI (solid line), VII (dashed line), and VIII (dots). L = pyrazole ligand or free
coordination site. Intermediates with stars are transition states. Transition state structures 5*-VI and 5*-VII, and 5*-VIII are represented. α and β
acetate ligands are highlighted in red and some hydrogen atoms are removed for clarity.
Analyzing the structure of the transition state 5* (Figure
The structural parameters have no significant influence
on the reaction energies except on the complexation
step, which is more favorable when two pyrazoles are
present. They have an important effect on the energy
barriers. Indeed, the copper complex bearing only one
4) we can understand the role of each of the two
acetates coordinated to the copper: one is stabilizing the
approach of the diazonium cation by the oxygen not
coordinated to copper (labelled α), while the other one is
H-bonded to the pyrazole to allow the intramolecular
deprotonation afterwards (labelled β). It would not be
possible for a single acetate complexed to copper to do
both actions.
Overall, the proposed reaction mechanism allows to
explain the observed reactivity in the case of pyrazole
substrate. Nonetheless, to further confirm its validity, it is
important to see if the difference in the reactivity
observed for imidazole substrates could also be justified
by the same mechanism.
Indeed, experimental initial results showed that
applying standard conditions to imidazole leads to a poor
yield (42 %) and different conditions were applied. An
explanation can be found by analyzing the structure of
Cu(III) intermediates VII-7 for pyrazole and for imidazole
(see Figure 5).
pyrazole molecule
(
VI
)
exhibits significantly lower
activation energies for the three key steps of the
reaction, and especially for the most expensive one: the
oxidative addition (11.81 kcal/mol for VI against 21.57
kcal/mol for VII and 25.79 kcal/mol for VIII) which
appears to be the rate determining step. This can be
related to the steric hindrance. Less space is left to the
diazonium cation to approach the copper when
increasing the number of pyrazoles. This forces the
diazonium to adopt a twisted geometry to be able to
undergo the oxidative addition, with a nitrogen atom
further apart from the copper center (Cu-N bond of 2.97
Å for 5*-VII against 1.98 Å for 5*-VI). It is reasonable to
think that if VII or VIII are formed, a pyrazole ligand is
released to form VI before the oxidative addition.
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Whereas in the case of a pyrazole substrate, a
hydrogen bond between a copper ligated acetate and the
acidic proton of the pyrazole can be formed, allowing a
pre-oriented easy intramolecular deprotonation, in the
case of imidazole such an interaction cannot exist (as
depicted in Figure 5). The acidic proton of imidazole
points outside from the copper complex and is too far
from the acetate ligand. An intermolecular deprotonation
pathway was thus postulated with the participation of a
free external acetate.
Figure 5. - Cu(III) intermediates VII-7 bearing pyrazole (left) or
imidazole (right) ligands and distance for intramolecular
deprotonation. The ligands involved in the deprotonation are
highlighted in green and hydrogen atoms on other ligands are
removed for clarity.
We computed this intermolecular deprotonation starting
with VII for the imidazole substrate, but also for the
pyrazole, as
a
validation of our intramolecular
deprotonation mechanism (see Figure 6).
Figure 6. - Intermolecular deprotonation mechanism on pyrazole (dashed line) and imidazole (solid line) starting from VII. The circle refers to any of
the two nitrogen heterocycles. Intermediates with stars are transition states.
The first step of the mechanism is similar, with a
complexation of the diazonium on the anionic Cu(I)
complex, followed by a favorable oxidative addition with
an activation energy EaOA = 23.82 kcal/mol for imidazole
(EaOA = 21.57 kcal/mol for the pyrazole). In the case of
pyrazole, the acidic proton has to break its intramolecular
intermolecular deprotonation is easily achieved (EaID
0.48 kcal/mol for imidazole, Ea = 1.20 kcal/mol for
pyrazole). The departure of acetic acid (VII-16 VII-17
is energetically disfavoured in both cases (ΔE ≈ + 16
kcal/mol). Reductive elimination can finally proceed
easily.
=

)
hydrogen bond with the acetate by twisting (VII-7

VII-
The lower yields obtained for imidazole can thus be
explained by the fact that very few free acetate
molecules are present in the reaction medium due to the
quantitative formation of triazene at the beginning of the
reaction, but also by the energetically disfavored
13), which is kinetically (Eatwist = 10.44 kcal/mol) and
thermodynamically (ΔEtwist = 5.88 kcal/mol) not favorable.
For both substrates, this complex is then stabilized by
the presence of an external acetate
(VII-14) and
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European Journal of Organic Chemistry
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departure of acetic acid from the copper coordination
sphere, necessary for the reductive elimination to
proceed. Furthermore, if we consider an intermolecular
deprotonation for the pyrazole, energy barriers for both
deprotonation and reductive elimination are lower than
for intramolecular deprotonation (1.20 and 1.93 kcal/mol,
respectively, with respect to 3.00 and 3.90 kcal/mol for
intramolecular deprotonation) but the intervention of an
extra acetate introduces two new high barriers: one for
the conformational twisting of the pyrazole and one for
the departure of the acetic acid. These two steps
disfavour the intermolecular deprotonation mechanism.
We have here a clear indication that the intramolecular
mechanism for the deprotonation is favored when
possible (case of pyrazole) and that the intermolecular
one is more challenging although achievable (explaining
lower but non- zero yield obtained with imidazole).
With these conclusions in hand, we can postulate that
better yields should be obtained for imidazole by adding
external acetate. Unfortunately, acetate is also playing a role
in the formation of the starting active species, resulting in a
slower formation of the triazene (due to the overall lower
acidity of the reaction medium). The antagonistic intervention
of acetate and acetic acid in several steps of the reaction as
well as in parallel unreactive pathways explains that their
concentration has to be finely tuned for each family of
substrates envisaged.
Experimental Section
General procedure for the kinetics of the formation and decomposition
of the triazene species in the absence of copper under stoichiometric
conditions:
An oven-dried NMR tube equipped with a DMSO-d6 insert was
charged with dry MeOH (0.5 mL), followed by para-fluoroaniline (0.5
mmol, 47 µL), α,α,α-trifluorotoluene as internal standard (5 µL, 0.041
mmol), t-BuONO (0.55 mmol, 66 µL) and AcOH (0.5 mmol, 29 µL).
The NMR tube was vigorously shaken. 19F NMR was recorded
immediately after and at selected times.
General procedure for the kinetics of arylation of pyrazole with 1,3-
bis(4-fluorophenyl)triaz-1-ene
stoichiometric conditions:
mediated by Cu(OAc)2 under
An oven-dried NMR tube equipped with a DMSO-d6 insert was
charged with Cu(OAc)2 (36.3 mg, 0.2 mmol), 1,3-bis(4-
fluorophenyl)triaz-1-ene (47 mg, 0.2 mmol) and pyrazole (18 mg, 0.26
mmol). The tube was introduced in a Schlenk and three cycles of
vacuum and argon filling were applied. Dry MeOH (0.5 mL) was
added, followed by α,α,α-trifluorotoluene as internal standard (5 µL,
0.041 mmol), and AcOH (11.4 µL, 0.2 mmol). The NMR tube was
vigorously shaken until complete dissolution. 19F NMR was recorded
immediately after and the evolution was then followed with time.
General procedure for the kinetics of arylation of pyrazole with para-
fluoroaniline catalyzed by Cu(OAc)2 under catalytic conditions:
An oven-dried NMR tube equipped with a DMSO-d6 insert was
charged with Cu(OAc)2 (12 mg, 0.066 mmol) and pyrazole (23 mg,
0.33 mmol). The tube was introduced in a Schlenk and three cycles of
vacuum and argon filling were applied. Dry MeOH (0.5 mL) was
added, followed by α,α,α-trifluorotoluene as internal standard (5 µL,
0.041 mmol), para-fluoroaniline (47.4 µL, 0.5 mmol), t-BuONO (66 µL,
0.55 mmol) and AcOH (5.7 µL, 0.1 mmol). The NMR tube was
vigorously shaken until complete dissolution. 19F NMR was performed
immediately after and the evolution was then followed with time.
Conclusions
We used experimental and computational approaches as
complementary tools to investigate the reaction mechanism of
the copper-catalyzed arylation of nitrogen heterocycles from
in situ generated diazonium salts. We showed that a triazene
species is quantitatively formed and acts as a dormant
diazonium reservoir. It maintains a low concentration of active
species in the reaction medium and thus limits the non-
effective parallel formation of arene. For this part of the
reaction, the amount of acid is crucial: it is necessary to
generate the diazonium salt, but accelerates the
decomposition of the triazene to arene if introduced in high
concentration. The role of radical species is also relevant:
they are needed to initiate the reaction, and we cannot
exclude their intervention in the coordination sphere of copper.
As evidenced by computational outcomes used to investigate
the steps of the reaction involving the catalyst, the acetate
plays an important role also in this part of the reaction.
Acetate ligands help the complexation of the diazonium on
copper and allow an easy intramolecular deprotonation of the
pyrazole. This latter step can explain the difference of
reactivity observed between pyrazole and imidazole. Overall,
our investigation allows to show that only a fine tuning of the
antagonistic effect played by the AcOH/AcO- couple in the
complex reaction mechanism enables the optimization of the
reaction conditions.
Synthesis of the reference coupling product 1-phenyl-1H-pyrazole
using the general procedure for the arylation of pyrazole from aniline:
After standard cycles of evacuation and back-filling with argon, a
Schlenk tube equipped with a magnetic stirring bar was charged with
Cu(OAc)2 anhydrous (0.2 mmol, 36.3 mg), pyrazole (1 mmol, 68.1
mg), MeOH (1.5 mL), cooled down to 0°C and, under stirring, t-
BuONO (1.65 mmol, 197 µL) and AcOH (0.3 mmol, 17.2 µL) were
added. A solution of aniline (1.5 mmol, 205 µL) in MeOH (3 mL), was
slowly added using a syringe pump over 2 h. The mixture was then
allowed to warm up to room temperature and stirred for 48 h. The
crude reaction mixture was diluted with EtOAc (20 mL), and washed
with a 10% ammonia solution (5 mL) and brine (5 mL). Volatiles were
removed in vacuo and the residue was purified by flash
chromatography on silica gel (eluent: cyclohexane / ethyl acetate
100:0 to 95:5) to give the title compound as a light yellow oil (110 mg,
76 %). 1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 2.4 Hz, 1H), 7.75-
7.64 (m, 3H), 7.47-7.37 (m, 2H), 7.30-7.22 (m, 1H), 6.46-6.43 (m, 1H)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 141.1, 140.3, 129.5, 126.8,
126.5, 119.3, 107.7 ppm.[24]
Synthesis of the reference coupling product 1-(4-Fluorophenyl)-1H-
pyrazole.
A flask was charged with pyrazole (68.1 mg, 1.0 mmol), CuI (9.5 mg,
0.05 mmol) and K2CO3 (290 mg, 2.1 mmol), closed by a rubber
septum and conditioned under argon. Deoxygenated toluene (1 mL),
4-fluoroiodobenzene
(138.4
µL,
1.2
mmol)
and
N,N’-
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European Journal of Organic Chemistry
10.1002/ejoc.201600891
FULL PAPER
dimethylethylenediamine (21.5 µL, 0.2 mmol) were added sequentially
by syringe. The mixture was stirred at 110 °C for 24 h. The cooled
reaction mixture was diluted with EtOAc (20 mL), and washed with a
10% ammonia solution (5 mL) and brine (5 mL). Volatiles were
removed in vacuo and the residue was purified by flash
chromatography on a short column of silica gel (eluent: petroleum
ether / ethyl acetate 95:5) to give the title compound as an off-white
solid (148 mg, 91%).
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I. Fabre, L. A. Perego, J. Bergès, I.
Ciofini,* L. Grimaud,* M. Taillefer *
Page No. – Page No.
Title
Text for Table of Content
Mechanistic study of Cu-catalyzed arylation of nitrogen heterocycles from anilines via
diazonium salts. The formation of triazene species which acts as a dormant safe
diazonium reservoir and a Cu(I)/Cu(III) redox mechanism are proposed.
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