Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium

Article abstract of DOI:10.1002/adsc.201500888

An in-depth mechanistic study on the palladium-catalyzed direct arylation of imidazoles at the C-5 position is presented. The interactions of triphenylphosphine (PPh₃)-ligated aryl-Pd species with 1,2-dimethyl-1H-imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine-ligated organo-Pd species are not active and the reaction proceeds through imidazole-ligated organo-Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim-ligated Pd(0) species have been characterized in a Pd(dba)₂/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)₂X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)₃]⁺ is also reported. The ability of these species to effect the C-H arylation of dmim at room temperature in the presence of acetate is also demonstrated.

Full text of DOI:10.1002/adsc.201500888

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DOI: 10.1002/adsc.201500888
Very Important Publication
Mechanistic Studies on the Palladium-Catalyzed Direct C-5
Arylation of Imidazoles: The Fundamental Role of the Azole as
a Ligand for Palladium
Luca Alessandro Perego,a,b,* Laurence Grimaud,b,* and Fabio Bellinaa,*
a
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via Moruzzi 3, 56124 Pisa, Italy
E-mail: fabio.bellina@unipi.it
b
DØpartement de Chimie, Ecole Normale SupØrieure – PSL Research University, Sorbonne UniversitØs – UPMC Univ
Paris 06, CNRS UMR 8640 PASTEUR, 24, rue Lhomond, 75005 Paris, France
E-mail: luca.perego@ens.fr or laurence.grimaud@ens.fr
Received: September 22, 2015; Revised: October 30, 2015; Published online: January 26, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500888.
Abstract: An in-depth mechanistic study on the pal- species have been characterized in a Pd(dba)2/dmim
ladium-catalyzed direct arylation of imidazoles at the model system. A thorough study of the equilibria in-
C-5 position is presented. The interactions of triphe- volving novel [ArPd(dmim)2X] complexes (X=I,
nylphosphine (PPh3)-ligated aryl-Pd species with 1,2- OAc) and the unexpected cationic [ArPd(dmim)3]+
dimethyl-1H-imidazole (dmim) have been studied in is also reported. The ability of these species to effect
À
detail. In contrast with previous suggestions, phos- the C H arylation of dmim at room temperature in
phine-ligated organo-Pd species are not active and the presence of acetate is also demonstrated.
the reaction proceeds through imidazole-ligated
À
À
organo-Pd intermediates. The kinetics of the oxida- Keywords: C C coupling; C H activation; nitrogen
tive addition of aryl halides with dmim-ligated Pd(0) heterocycles; palladium; reaction mechanism
Introduction
the palladium-catalyzed direct arylation of heteroar-
enes with aromatic electrophiles (Scheme 1, b).[3] This
À
Palladium-catalyzed reactions have become the strategy is based on the activation of a C H bond and
method of choice for the preparation of unsymmetri- does not require the use of a stoichiometric amount
cal (hetero)biaryls.[1] A general approach to this sub- of a preformed organometallic reagent. Excellent re-
ject is the use of the now well-established Pd-cata- gioselectivity can often be attained thanks to the pres-
lyzed cross-coupling protocols (Scheme 1, a). Howev- ence of heteroatoms in the aromatic nucleus, which
er, these methods are not atom- and step-economical, are able to differentiate unlike C H bonds by elec-
since they require the preactivation of both coupling tronic effects and metal-coordinating ability.
À
partners. Moreover, they generate a stoichiometric
quantity of potentially toxic metal-containing waste.
Among the wide variety of arylheteroarenes, aryl-
azoles are important structural units, often found in
A more economical and environmentally-friendly natural products and their synthetic analogues,[4] phar-
approach, which may also be suitable for the late- maceuticals,[5] and organic functional materials,[6] so in
stage diversification of functionalized molecules,[2] is the last few years we became interested in the devel-
opment of straightforward and convenient methods
for their synthesis. Inspired by some seminal reports
that appeared before 2000,[7–9] we established an effi-
cient and general protocol for the direct arylation of
imidazoles with high regioselectiviy for the C-5 posi-
tion.[10] These conditions involve the use of 5 mol%
Pd(OAc)2, 10 mol% P(2-furyl)3, CsF or K2CO3 as the
base, in DMF or DMA (N,N-dimethylacetamide) at
1108C for N-methylimidazole and at 1408C for N-
Scheme 1. Comparison between traditional Pd-catalyzed
cross-couplings and direct arylation reactions.
benzyl- and N-arylimidazoles (Scheme 2).[10] PPh3,[9]
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gated aryl-Pd species can effect the direct arylation of
a variety of substrates.[25] Hartwig and co-workers
have also highlighted the key role of a cyclometallated
À
species {Pd(OAc)[(t-Bu)2PCMe2-CH2]}, formed by C
H activation of P(t-Bu)3 in the direct arylation of pyri-
dine N-oxides and benzothiophene.[26] A Heck-type
carbopalladation-dehydropalladation pathway has
been proposed to explain some peculiarities of a b-se-
lective arylation of thiophenes.[27] The C-2 regioselec-
Scheme 2. C-5 regioselective arylation of imidazoles.[10]
[14]
AsPh3,[11] PCy3,[12,13] and P(n-Bu)Ad2
can also be tivity observed in some cases for the functionalization
[15]
used as ligands. Procedures using [Pd(phen)2](PF6)2
of 1,3-azoles has been linked to the enhancement of
or bulky NHC-Pd complexes[14,16] as precatalysts have the C-2 H acidity upon Pd-coordination through the
also been described. Two ligand-free protocols have pyridine-like nitrogen. A proton abstraction mecha-
been reported: the first one employed KOAc and nism called “non-concerted metallation deprotona-
0.01–0.5% Pd(OAc)2 at 1508C,[17] while the second tion” (nCMD) was thus proposed,[28] while a deproto-
used (n-Bu)4NOAc as the base for the C-5 direct ary- nation–ring opening pathway has been demonstrated
lation of several azoles (1-methylpyrazole, oxazole, for the C-2 arylation of benzoxazole.[29] Evidence for
thiazole, 1-methyl-1H-imidazole) under comparatively free-radical processes has also been put forward in
À
mild conditions[18] (70–1108C).[19]
a limited number of cases.[15,30]
Despite the synthetic relevance of Pd-catalyzed
However, none of the studies summarized above is
direct arylation reactions, relatively little attention able to explain the great influence of experimental
has been devoted to understanding their mechanisms. parameters (ratios between substrates, choice of base
Moreover, as well outlined in the reviews compiled and solvent, addition of ligands) on the outcome of
by Echavarren[20a] and Fagnou[20b] in 2010, and by Gor- the coupling reaction. In our opinion, an in-depth
elsky[20c] in 2013, the mechanistic studies performed so study of the mechanisms of direct arylation reactions
À
far have been generally focused only on the C H may give insights useful to develop new and more ef-
bond-breaking step, mainly because it is responsible ficient catalytic systems in terms of activity under
for the experimentally observed regioselection among mild conditions, selectivity and functional group toler-
À
different (hetero)aromatic C H bonds.
Early workers in this field generally believed that
À
ance.
Keeping these premises in mind, we undertook a de-
C H bond activation of these electron-rich heteroaro- tailed mechanistic study of the Pd-catalyzed direct ar-
matics takes place by an SEAr-type mechanism,[9] ylation of imidazoles with a broad focus on the whole
indeed convincing evidence has been found for catalytic cycle. Our results evidenced that PPh3-ligat-
a number of related cases.[21] After the ground-break- ed aryl-Pd species are not able to perform the C H
À
ing discovery of the key role of carboxylates in the functionalization of imidazoles, while novel imida-
functionalization of unsubstituted benzene,[22] a con- zole-coordinated organo-Pd complexes are active
certed metallation-deprotonation (CMD) mechanism even at room temperature.
has been proposed by Fagnou and Gorelsky for the
À
C H functionalization of a number of heterocy-
cles.[20b,c,23] According to this mechanistic hypothesis, Results and Discussion
the carboxylate anion acts as a “proton shuttle” and
assists the simultaneous metallation and deprotona- Kinetic Isotope Effect
tion of the arene while still coordinated to Pd, thus
there is no proper Wheland intermediate.[22,23]
As discussed previously, direct arylation reactions of
Phosphine-ligated arylpalladium carboxylates are imidazoles at the C-5 position are usually carried out
typically proposed to react with arenes to form the with a precatalyst composed of a Pd(II) salt, usually
diaryl-palladium complexes through the CMD path- Pd(OAc)2, and either a phosphine[9–11,31] or no added
way.[20b,c,22,23] Hartwig and Tan have prepared and ligand[6e,17,18] (the so-called ligandless conditions). Cus-
characterized the complex {(2-Me-C6H4)Pd[P(t- tomarily, a 1:2 molar ratio between Pd and a mono-
Bu)3](OPiv)}.[24] Inconsistently with previous propos- dentate ligand is employed.[9–11,31]
als, they showed that these isolated organopalladium
For our mechanistic studies we selected a simple
species do not react readily with benzene to form the model system. 1,2-Dimethyl-1H-imidazole (dmim, 1)
arylation product in more than trace amounts and was chosen in order not to have by-products formed
that phosphine-ligated species are not competent in by N or C-2 arylation. 4-Bromotoluene (2a) was used
the direct arylation of benzene. This conclusion was as the coupling partner along with Pd(OAc)2
also supported by DFT calculations.[24] On the other (5 mol%) as the precatalyst, PPh3 (10 mol%) as the
hand, Ozawa and co-workers showed that a PPh3-li- ligand, and K2CO3 as the base in anhydrous DMA at
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Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles
Scheme 3. Model reaction.
1408C (Scheme 3). The formation of the C-5 arylated
product 3a and of the by-product 4,4’-bitolyl (4a), as
well as the disappearance of starting materials dmim
(1) and 2a was followed by GLC analysis of aliquots
withdrawn periodically from the reaction mixture
using naphthalene as an internal standard.
Figure 1. Determination of KIE for the reactions in
Scheme 4. Experimental points are shown together with ex-
ponential fit: [3a]=A+C1(1ÀeÀkt). Parameter A has been
included because an induction period has been excluded
from the fitted data (vide infra).
Kinetic isotope effect (KIE) experiments were per-
formed. KIE studies have been applied to a great va- first-order kinetics in the imidazole substrate, with the
À
riety of metal-mediated C H activation processes and following formula:
these efforts have been reviewed recently.[32]
For this purpose, 5-deuterio-1,2-dimethyl-1H-imida-
zole (5-D-dmim, 5) was synthesized with 92% deuteri-
um incorporation by low temperature halogen–lithi-
um exchange, followed by quenching with CH3OD
(see the Supporting Information, §2.2 for the experi-
mental procedure). First, the reactions involving
dmim 1 and 5-D-dmim 5 were performed separately
(Scheme 4). If an initial induction period was exclud-
The value obtained is rather consistent with the
one determined by the two separated reactions, and it
is not greatly influenced by varying the aryl bromide
ArBr: kH/kD =2.23 for 4-MeO-C6H4Br and kH/kD =
2.40 for 4-CF3-C6H4Br (see the Supporting Informa-
tion, §1.2).
Electronic Effects
Scheme 4. Reactions for KIE determination.
The influence of the electronic character of the imida-
ed, the amount of 3a formed fitted an exponential zole substrate on the reaction kinetics was also inves-
rise to maximum with respect to time (R2 >0.998, tigated. A variety of 1-aryl-2-methylimidazoles bear-
Figure 1). The two first-order apparent rate constants ing diverse substituents on the aryl ring have been
were determined from the fit parameters (kH = prepared. Relative reaction rates for the arylation
2.1·10À2 minÀ1 and kD =0.77·10À2 minÀ1, Figure 1). The under conditions close to those reported in Scheme 3
ratio of these independently determined rate con- were assessed by competition experiments in order to
stants (i.e., kH/kD) gives 2.7 as KIE value (standard obtain a Hammett plot. Unfortunately no correlation
error: 0.35). This result proves unambiguously that was evident, but electron-poor substrates reacted
the turnover-limiting step of the catalytic cycle in- faster than electron-rich ones (for data and experi-
À
volves the cleavage of the imidazole C-5 H bond mental details, see the Supporting Information, §1.3).
under our conditions, as observed for other direct ary-
lation reactions.[31,33]
Secondly, competition experiments were performed Induction Period and Role of PPh3
introducing both 1 and 5 in the same flask to deter-
mine KIE from the initial and final concentrations of In order to understand why an induction period is ob-
1 and 2 (as assessed by GLC-MS analysis), assuming served at the beginning of the reaction, the model ex-
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periment (Scheme 3) was performed either with PPh3 and tested their reactivity. First, the interaction of
as ligand or without any added ligand and the forma- trans-[ArPd(PPh3)2Br] (6)[37] (6a: Ar=Ph, 6b: Ar=4-
tion of the coupling product 3a was followed with F-C6H4) with dmim in DMF was studied by 31P NMR
time (Figure 2).
spectroscopy. Analogously to what is described in the
literature for primary and secondary aliphatic
amines,[38] dmim displaces one of the PPh3 ligands to
give a mixture of isomeric [ArPd(PPh3)(dmim)Br]
species 7 (Scheme 5). As no change in the 31P NMR
Scheme 5. Displacement of PPh3 by dmim in trans-
[ArPd(PPh3)2Br].
spectrum was observed after the addition of a large
excess of (n-Bu)4NBr, most likely bromide is not dis-
placed and no cationic complex forms. The displace-
ment of a second PPh3 ligand is much more difficult.
The values of the overall equilibrium constant K
Figure 2. Kinetic curve for the formation of 3a under the
conditions reported in Scheme 3.
At the beginning, the reaction in the presence of (Scheme 5) have been estimated by quantitative
PPh3 was significantly slower. A 50% yield was 31P NMR spectroscopy (see the Supporting Informa-
reached in slightly less than 2 h and the homocoupling tion, §1.5) and were found to be lower than 1 (K=
product 4a was formed in a 6% GLC yield.[32] Howev- 0.068 for Ar=Ph, K=0.050 for Ar=4-F-C6H4).[39]
er, under ligandless conditions, the reaction was
Complex 6b was tested under catalytic conditions
faster, reaching 50% yield in about 1 h and the by- and turned out to be a competent precatalyst, provid-
product 4a was formed just in trace amounts (<1% ing a yield comparable to the one obtained with
GLC yield).[34]
Pd(OAc)2, albeit in
a
longer reaction time
The existence of an induction period in the pres- (Scheme 6). Prolonged heating (1408C, 2.5 h) of a mix-
ence of PPh3 suggests that this ligand has an inhibiting ture of 6b (0.02M in DMF) in an NMR tube with
effect on the catalytic reaction. It is well-known that 1.0 equiv. of dmim and 2.0 equiv. of Cs2CO3 caused
a mixture of Pd(OAc)2 and PPh3 rapidly undergoes the precipitation of palladium black without forma-
a redox reaction, even at room temperature, with the tion of the desired coupling product. AgOAc and
formation of Pd(0) species and [AcOPPh3]+ (hydro- CsOAc also failed to promote the reaction
lyzed to Ph3PO by adventitious water).[35] This reac- (Scheme 7).
tion accounts for the depletion of one of the two
A
complex
with
the
composition
added equivalents of PPh3 (with respect to Pd). When [PhPd(PPh3)(dmim)(OAc)] (8), which should be
the model reaction was performed under the condi- structurally very close to a transition state proposed
tions of Scheme 3 but with 4-bromotoluene (2a) re- on the basis of DFT calculations,[23b] was prepared by
placed by 4-fluorobromobenzene (2b), reaction moni- the reaction of the bridged acetate complex
toring by 19F and 31P NMR spectroscopy showed that
one of the two equivalents of PPh3 is oxidized to
Ph3PO just after mixing the reactants at room temper-
ature, while the second equivalent is more slowly oxi-
dized at 1408C. The expected coupling product 3b is
not formed in a sizeable quantity until a substantial
amount of PPh3 has been depleted (for details, see
the Supporting Information §1.4).[36]
In order to confirm that PPh3-ligated palladium
species are not active in the reaction under study, we
characterized the behaviour of some PPh3-ligated
aryl-palladium complexes in the presence of dmim [ArPd(PPh3)2Br] as precatalysts.
Scheme 6. Comparison
of
Pd(OAc)2
and
trans-
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Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles
bases
[(n-Bu)4NOAc,
DBU=1,8-diazabicy-
clo[5.4.0]undec-7-ene, (i-Pr)2NH, see details in the
Supporting Information, §1.6] promoted the forma-
tion of 3c together with high amounts of PhPh, differ-
ently from what happens in the catalytic process.[44]
These results suggest that 8 is an unlikely intermedi-
ate of the catalytic reaction.
The observation of an induction period in the cata-
lytic reaction in the presence of PPh3 and the poor re-
activity of isolated aryl-Pd complexes featuring one or
two PPh3 ligands advocate that the latter are not reac-
tive intermediates of the catalytic cycle. The higher
efficiency of the catalytic reaction under study with li-
Scheme 7. Attempted reaction of trans-[ArPd(PPh3)2Br]
with dmim.
[PhPd(PPh3)(m-OAc)]2 (9)[40] with 2.0 equiv. of dmim gands with lower donating ability than PPh3, such as
[11]
(Scheme 8).[41] Upon treatment of 8 with a large AsPh3 and P(2-furyl)3,[10a,45] is most likely due to the
excess of dmim (100 equiv.), uncoordinated PPh3 ap- ease with which they can be displaced by the imida-
peared in the 31P NMR spectrum. The thermodynamic zole substrate. The direct arylation of azoles at C-5
constant K’ for this equilibrium (Scheme 8) has been can also be performed under mild conditions (708C
estimated from 31P NMR data and the value obtained for oxazole and thiazole, 1108C for N-protected imi-
(5.5·10À5 at 258C) points out that the displacement of dazole) without any added ligand when the soluble
this phosphine ligand is much more difficult than the base (n-Bu)4NOAc is employed, thus underlining the
removal of one PPh3 from [ArPd(PPh3)2Br] (6), with strong inhibitory effect of phosphine ligands.[18]
a value about three orders of magnitude lower.[42]
Such a behaviour can be rationalized in terms of the
so-called thermodynamic trans effect or trans influ- Oxidative Addition with dmim-Ligated Pd(0)
ence.[43]
Given the importance of phosphine-free conditions
for the reaction under study, the feasibility of oxida-
tive addition with dmim as the sole ligand of the
Pd(0) species was investigated. Among the different
methods tested, dmim-ligated Pd(0) was obtained by
displacement of dba (trans,trans-dibenzylideneace-
tone) ligands from Pd(dba)2 in the presence of an
excess of dmim in dichloromethane. The instantane-
ous colour change from purple-violet to orange-
yellow prompted us to study the system by UV-Vis
spectroscopy. It appeared that with 20 equiv. of dmim
the spectrum is virtually indistinguishable from the
one of a solution of dba in an amount compatible
with a complete displacement of the dba ligands (see
the Supporting Information, §1.7, Figure S6).
A similar behaviour was observed by cyclic voltam-
metry (CV) performed in DMF at a steady gold disk
Scheme 8. Synthesis of complex 8 and its PPh3-displacement
equilibrium.
The reactivity of 8 was then investigated in DMF at electrode. A solution of Pd(dba)2 in DMF (2.0 mM)
1208C under various conditions. Heated alone, it gave gives two reduction peaks R1 and R2 (Figure 3). R2
a 30% yield of biphenyl, but only traces of the expect- is assigned to the reduction of uncoordinated dba, as
ed coupling product, 5-Ph-dmim (3c) (Scheme 9). Ad- can be inferred by comparison with an authentic
dition of an excess of dmim 1 or other coordinating sample.[46] On adding increasing amounts of dmim to
this solution, R2 progressively increases and R1 grad-
ually disappears. The maximum reduction current of
R2 is proportional to the concentration of free dba,
so the amount of free dba in solution can be readily
estimated.[46] With 10 equiv. of dmim all dba is appa-
rently displaced from Pd, since R2 doubles after the
addition of an authentic sample of dba. The small re-
duction peak R1 (less than 20% of R2) is assigned to
the reduction of dba bound to palladium, because it is
Scheme 9. Thermal
[PhPd(PPh3)(dmim)(OAc)] (8).
decomposition
of
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ing Pd(dba)2 (2.0 mM) and 10 equiv. of dmim, the
wave O1 disappears and a new large wave O2 ap-
pears, which is assigned to the oxidation of iodide
anion by comparison with a solution of (n-Bu)4NI
(Figure 4, right). These experiments clearly indicate
that dmim-ligated Pd(0) species are active towards
the oxidative addition of PhI, and the process is quite
fast at room temperature. As the oxidative addition
product features free iodide anions it should have
a cationic character, at least in the presence of excess
dmim (Scheme 10).
Scheme 10. Oxidative addition of PhI with dmim-ligated
Pd(0).
Figure 3. Cyclic voltammetry of Pd(dba)2 (2.0 mM in DMF),
in the presence of varying amounts of dmim, as shown in
the inset. Conditions: steady gold disk electrode (ø=
1.0 mm), scan rate 0.1 VsÀ1, 258C, supporting electrolyte (n-
Bu)4NBF4 0.3M.
The ionic nature of the resulting product allowed to
use conductimetry to follow the reaction kinetics.[47]
First, the dependence of the rate for the oxidative ad-
dition of PhI (1.0 equiv.) varying the concentration of
dmim was studied. Final conductivity k1 did not
change for several hours, suggesting that the product
at a maximum when no dmim is present and disap- was chemically stable. Initial rates were estimated as
pears when dba is completely displaced. v=c k/k1, where c is the initial concentration of the
While dba is progressively displaced, a barely no- limiting reagent. The apparent initial rate v steeply in-
ticeable oxidation wave O1 becomes apparent in the creases until the concentration of added dmim is
presence of excess dmim (Figure 4, left), which can be 20 mM (10 equiv.). The rate does not change signifi-
attributed to a dmim-ligated Pd(0) species. On the cantly when more dmim is added (up to 100 equiv.),
1
basis of H NMR data (see the Supporting Informa- this behaviour is consistent with the complete dis-
tion, §1.7, Figure S7) we tentatively propose a stoichi- placement of dba from Pd(0) at high concentration of
ometry of Pd(dmim)3 for the latter complex. On dmim (>10 equiv.) and the reactivity of imidazole-li-
adding one equivalent of PhI to the solution contain- gated Pd(0) towards PhI (Figure 5).
The latter observation suggests that the dissociation
of one of the dmim ligands is either not required for
the oxidative addition to take place or it is fast
enough not to affect the rate of oxidative addition.
This scenario is very different from the oxidative ad-
dition of aryl halides to Pd(PPh3)4. Indeed, the latter
compound gives rise to Pd(PPh3)3 as the main species
in solution and a further ligand dissociation is re-
quired for oxidative addition to take place, since the
reactive intermediate is the 14-electron complex
Pd(PPh3)2. Overall, the reaction has order À1 with re-
spect to PPh3, in accordance to a pre-equilibrium regi-
men.[48]
Further work was carried out replacing PhI with 4-
bromobenzonitrile (10). Oxidative addition using
Figure 4. Left: voltammetric oxidation of Pd(dba)2 (2.0 mM
50 equiv. of 10 with respect to Pd(dba)2 (2.0 mM in
in DMF), in the presence of varying amounts of dmim, as
DMF) in the presence of dmim (20 equiv.) is slower
shown in the inset. Right: voltammetric oxidation of
and more amenable to conductimetric measurements.
Pd(dba)2 (2 mM in DMF), in the presence of 10 equiv. of
Taking into account the kinetic law for the appear-
dmim, before (solid line) and after (dashed line) addition of
ance of the complex resulting from oxidative addition
for a pseudo-first order reaction C(t)=C1 (1ÀeÀkt),
the quantity ln[1ÀC(t)/C1] was plotted as a function
1.0 equiv. of PhI. Conditions: steady gold disk electrode
(1=1.0 mm), scan rate 0.1 VsÀ1, 258C, supporting electro-
lyte (n-Bu)4NBF4 0.3M.
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Table 1. Rate constants for the oxidative additions of ArX
to Pd(dba)2 in DMF in the presence of 20 equiv. of imida-
zole derivative, which is enough to displace quantitatively
dba and make in situ imidazole-ligated Pd(0), dP/dt=k[Pd]
[ArX]. All data are referred to 258C and are deduced from
conductimetric measurements.
Imidazole derivative
ArX
k (mÀ1 sÀ1)
dmim (1)
dmim (1)
Imidazole
PhI
21.8
0.117
30.2
4-CN-C6H4Br (10)
PhI
Figure 5. Initial rates v for the oxidative addition of PhI
(2.0 mM) with Pd(dba)2 (2.0 mM in DMF) in the presence
of varying amounts of dmim, as measured by conductimetry,
temperature: 258C.
suggests that the impossibility to perform the direct
arylation of N-unprotected imidazoles is not due to
inhibition of the oxidative addition step. To the best
of our knowledge, no reaction of this kind has been
of time (t) and k was calculated as the slope of the re- reported in the literature so far.
sulting graph. Under those conditions, the semilogar-
In our hands, a 1:1 mixture of dmim and 2-methyl-
ithmic plot traced as described before is linear for at 1H-imidazole (11) subjected to standard direct aryla-
least four half-lives (R2 >0.999, Figure 6), implying tion conditions did not give any trace of coupling
that the oxidative addition reaction is first order with product (as assessed by GLC-MS of the crude reac-
respect to Pd. Apparent rate constants were also mea- tion mixture), thus showing that not only the N-un-
sured in a similar fashion at different concentrations substituted imidazole is not a substrate for the reac-
of 10. The reaction is first order also with respect to tion, but it is also a catalytic poison (Scheme 11).
this reagent (see the Supporting Information, §1.7,
Figure S8).
Scheme 11. Attempted direct arylation of a mixture of dmim
and 2-methyl-1H-imidazole.
Characterization of dmim-Ligated Arylpalladium
Species
The use of a less polar solvent as toluene for the reac-
tion of Pd(dba)2 with PhI in the presence of dmim al-
Figure 6. Left: oxidative addition of 4-bromobenzonitrile
(10) (50 equiv.) to Pd(dba)2 (2.0 mM in DMF) in the pres-
ence of dmim (20 equiv.), as followed by monitoring the
conductivity k. Right: same data, represented with a semilo-
garithmic plot. Temperature: 258C.
lowed the isolation of
a solid of composition
PhPd(dmim)3I (12a) in excellent yield (Scheme 12).
This solid dissolved to some extent in benzene-d6
and behaved as a 1:1 mixture of dmim (1) and
[PhPd(dmim)2I] (13a), as determined by 1H NMR
We can conclude that the kinetic law for the oxida- spectroscopy and comparison of the chemical shifts
tive addition of ArX to dmim-ligated Pd(0) species, with an authentic sample of dmim. However, in more
generated in situ by displacement of dba from polar solvents (CDCl3, acetone-d6, DMF-d7) complex
Pd(dba)2 with excess dmim, is simply dP/dt=k[Pd] spectra were obtained, indicating the presence of two
[ArX] in which P stands for the concentration of the species in equilibrium: a cationic [PhPd(dmim)3]+
formed product and [Pd] is the total concentration of (14a) and a neutral complex [PhPd(dmim)2I] (13a).
Pd(0) species. Some values of k are summarized in About 30% of the complex is in the ionic form in
Table 1. It is noteworthy that this reaction is compara- CDCl3 at room temperature (the interpreted aliphatic
1
tively fast, even at room temperature.
section of the H NMR spectrum of 12a is shown in
Oxidative addition occurs faster when unsubstituted Figure 7). The cationic complex [PhPd(dmim)3]+
imidazole is used instead of dmim. This observation (14a) alone has been characterized in CDCl3 solution
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Luca Alessandro Perego et al.
Scheme 13. Ionization equilibrium for 13a and 15a.
ductimetry was performed to access the thermody-
namic constants for these two equilibria in pure
CH2Cl2 and in a DMF/CH2Cl2 mixture[49] (80:20 ratio)
(Table 2, see the Supporting Information, §1.9 for ex-
perimental details).
Scheme 12. Synthesis of PhPd(dmim)3I (12a) and its ioniza-
tion in different solvents.
Table 2. Equilibrium constants for the reaction in
Scheme 13, as deduced from conductivity measurements (on
2.0 mM solutions in the specified solvents, 258C).
X
Solvent
K
I
CH2Cl2
CH2Cl2
DMF/CH2Cl2 80:20 vol.
DMF/CH2Cl2 80:20 vol.
0.20
OAc
I
OAc
6.3·10À3
8.6
8.1·10À2
The equilibrium constant KD for the displacement
of iodide by acetate at 258C (Scheme 14, a) can be es-
timated from the data in Table 2 as KD =KI/KOAc
:
KD =32 in CH2Cl2 and KD =110 in DMF/CH2Cl2
(80:20).
From these data it follows that the [PhPd(dmim)2]+
moiety has a greater affinity for AcOÀ than for IÀ.
This suggests that the main palladium species present
in solution during the direct arylation of dmim is
most likely [ArPd(dmim)2(OAc)] (15a), especially
when the very efficient, soluble base (n-Bu)4NOAc is
1
Figure 7. Aliphatic region of the H NMR spectrum of a so-
lution of [PhPd(dmim)3I] (12a) in CDCl3 at 258C. Assign-
ments: + [PhPd(dmim)3]+ (14a), f free uncoordinated dmim
(1), n [PhPd(dmim)2I] (13a).
by H, 13C and 19F NMR spectroscopies with TfOÀ as used,[19] generating high concentrations of free ace-
counterion after anion exchange with AgOTf. De- tate. The comparison with the PPh3-ligated analogues
tailed spectral analyses are reported in the Supporting [PhPd(PPh3)2X] (X=I, OAc) is also interesting. The
1
Information, §1.8.
equilibrium constant for the IÀ/AcOÀ exchange is
In view of the relevance of acetate for the mecha- K’D =0.44 at 208C (Scheme 14, b),[50] thus the softer
nism of the reaction under study, the substitution of
iodide in PhPd(dmim)3I (12a) with AgOAc was at-
tempted. Any effort to isolate a complex in the solid
state invariably failed because of the precipitation of
metallic palladium and extensive decomposition while
removing the solvent (even in high vacuum at 08C).
However, [PhPd(dmim)2(OAc)] (15a) turned out to
be quite stable in dilute benzene solution and could
be characterized in situ by NMR and mass spectrome-
try.
We next studied the equilibria between 13a/15a and
Scheme 14. Anion exchange equilibrium between 13a and
15a, and the same for the PPh3-ligated analogous complexes
the cationic form [PhPd(dmim)3]+ (14a) in the pres-
ence of excess dmim (Scheme 13). Once again, con- (data from ref.[50]).
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Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles
[PhPd(PPh3)2]+ moiety binds preferentially the soft
anion IÀ, while the harder [PhPd(dmim)2]+ has more
affinity for hard AcOÀ.[51] This observation points out
that dmim-ligated organopalladium complexes may
have very different properties from their PPh3-ligated
analogues and generalizations based on the behaviour
of the latter are to be considered with great caution.
Table 4. Reactions of [(4-F-C6H4)Pd(dmim)2(OAc)] (15b)
(generated in situ as a 10 mM solution in CHCl3 from (4-F-
C6H4)Pd(dmim)3I (12b) and AgOAc, room temperature,
16 h) in the presence of additives; yields determined by
19F NMR.
Entry Additive(s)
Residual 15b NMR Yields
3b 4b
1
2
3
(n-Bu)4NOAc 20 equiv. 26%
dmim 10 equiv. 65%
(n-Bu)4NOAc 20 equiv. 6%
+dmim 10 equiv.
71% 3%
32% 3%
92% 2%
Reactivity of dmim-Ligated Arylpalladium Species –
Direct Arylation at Room Temperature
The reactivity of dmim-ligated arylpalladium species
generated from 12a was next investigated in the pres-
ence of different additives (Table 3). It is worth the direct arylation of other aromatic nuclei under
noting that 12a alone does not evolve to the coupling catalytic conditions at room temperature are
product 3c. However, DBU (2.0 equiv.) addition pro- sparse.[52]
moted the formation of 3c although in modest yield.
As the addition of dmim increases the rate of prod-
In the presence of added acetates [AgOAc, (n- uct formation, the actual reactive species should be
Bu)4NOAc] almost quantitative yields of 3c were ob- the cationic complex [ArPd(dmim)3]+ (14). In a first
tained.
approach, the addition of acetate should slow the re-
action down, since it decreases the concentration of
14 by shifting the equilibrium towards the less reac-
tive [ArPd(dmim)2(OAc)] (15) (Scheme 15). Howev-
er, the rate enhancement observed by the addition of
AcOÀ is consistent with a metallation–deprotonation
reaction mechanism with acetate acting as an outer-
sphere base.[53]
On the basis of our experimental findings, we can
reasonably propose the revised mechanism depicted
in Scheme 15, featuring dmim-ligated complexes only.
The structure of imidazole-ligated Pd(0) is not known
at present. As metallic Pd is always formed along
with the coupling product under stoichiometric condi-
tions, we cannot exclude a role of heterogeneous spe-
cies as a Pd(0) reservoir. Oxidative addition occurs
and the Ar-Pd(II) complexes so formed (14, 15)
evolve to a 5-imidazolyl arylpalladium species (16),
which in turn undergoes product-forming reductive
elimination probably after a trans-cis isomerization
Table 3. Reactions of PhPd(dmim)3I (12a) (as a 10 mM solu-
tion in DMF, 1108C, 1 h) in the presence of additives; yields
determined by GLC.[a]
Entry Additive(s)
GLC yields
5-Ph-dmim
PhPh
(3c)
(4c)
1
2
3
4
5
none
0
64%
30%
5%
6%
1%
DBU 2.0 equiv.
AgOAc 1.0 equiv.
(n-Bu)4NOAc 2.0 equiv.
DBU 2.0 equiv., AgOAc
1.0 equiv.
22%
95%
94%
99%
[a]
Yields were determined using a calibration curve with
tetradecane as an internal standard. Product identity has
been confirmed by co-injection of an authentic sample.
Taking into account these preliminary results, we process, as usually assumed.
speculated that acetate was a key element for an effi-
cient reaction to take place, even at lower tempera-
ture. For convenience,
C6H4)Pd(dmim)2(OAc)] (15b) in CHCl3 was prepared
a
solution of [(4-F- Conclusions
by the reaction of isolated (4-F-C6H4)Pd(dmim)3I We have established that phosphine-ligated aryl-Pd
(12b) with AgOAc and treated with (n-Bu)4NOAc complexes are highly unlikely active intermediates in
(20 equiv.) at room temperature. A comparatively fast the direct arylation of imidazoles at C-5. This is in
reaction ensued and palladium black was deposited contrast with what is commonly assumed for the spe-
along with formation of coupling product 3b, as cific case of imidazole derivatives.[23b] Our findings
proven by 19F NMR analyses. The effect of added parallel what was reported by Hartwig for the direct
dmim (10 equiv.) was also evaluated and the best re- arylation of unfunctionalized benzene,[24] but the case
sults were obtained with both the additives (Table 4). of basic heterocycles such as the azoles is fundamen-
These results are remarkable since, to the best of tally different, since the latter compounds can them-
our knowledge, there is no system described in the lit- selves act as ligands.
erature in which direct arylation of azoles at the C-5
We have demonstrated a facile oxidative addition
position can happen at room temperature. Reports on reaction of aryl halides with imidazole-ligated Pd(0),
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Scheme 15. Revised catalytic cycle for the direct arylation of imidazoles.
giving rise to [ArPd(dmim)3]+ in the presence of
excess dmim. We studied the equilibria of the
latter complex with acetate and iodide, generating
[ArPd(dmim)2X] (X=I, OAc). Dmim-ligated Ar-Pd
species are active towards the direct arylation of
dmim at room temperature in the presence of AcOÀ
After vigorous stirring for 2 h at 508C this material was con-
verted to an off-white solid with crystalline appearance.
The reaction mixture was filtered on a sintered glass
funnel and washed thoroughly with Et2O (3”20 mL). The
solid material was dissolved in acetone (20 mL) and the re-
sulting solution was filtered through a short pad of diatoma-
ceous earth. Removal of the solvents at reduced pressure
gave the title compound in the form of a white crystalline
powder; yield: 554 mg (93%).
À
as a base. Preliminary data point out that C H bond
cleavage may occur by a metallation–deprotonation
mechanism involving cationic [ArPd(dmim)3]+ with
AcOÀ acting as an outer-sphere base.[53]
This complex behaves like
a 1:1 mixture of trans-
[PhPd(dmim)2I] (13a) and uncoordinated dmim in benzene.
1H NMR (300 MHz, benzene-d6): d=7.34–7.32 (m, 4H, Pd-
bound dmim C-5-H and 2,6-C6H5Pd), 7.16 (s, 1H, free dmim
C-5-H), 7.06–6.98 (m, 2H, 3,5-C6H5Pd), 6.90–6.86 (m, 1H, 4-
C6H5Pd), 6.27 (d, J=1.2 Hz, 1H, free dmim C-4-H), 5.76 (d,
J=1.5 Hz, 2H, Pd-bound dmim C-4-H), 2.45 (s, 3H, free
dmim, N-CH3), 2.37 (s, 6H, Pd-bound dmim N-CH3), 1.95
(s, 3H, free dmim C-CH3), 1.91 (s, 6H, Pd-bound dmim C-
CH3); ESI-MS (positive ion mode, MeCN): m/z (%)=477.7
(1), 476.6 (10), 475.6 (45), 474.6 (19), 471.4 (62), 470.5 (64),
Further studies are underway in order to confirm
the mechanism we proposed, both experimentally and
computationally. We are confident that our findings
will be helpful for the development of enhanced cata-
À
lytic systems for the C H functionalization of hetero-
arenes, possibly active under very mild conditions and
with ample functional group tolerance
+
469.5 (25) [PhPd(dmim)3 ]; 420.5 (8), 416.4 (20), 414.5 (13)
+
[PhPd(MeCN)(dmim)2 ]; 380.5 (8), 379.4 (42), 377.3 (76),
Experimental Section
376.3 (22), 375.3 (100), 374.3 (86), 373.3 (39), 371.4 (4)
+
[PhPd(dmim)2 ]; 97.2 (69) [dmimH+]; ESI-MS (negative ion
Synthesis of PhPd(dmim)3I (12a)
mode, MeCN): m/z (%)=127.0 (100) [IÀ].
The low solubility of this complex prevented us to get
13C NMR data. Solubility in CDCl3 is higher, but a complex
1H spectrum is obtained because there is an equilibrium be-
tween [PhPd(dmim)3]+ (14a) and [PhPd(dmim)2I] (13a).
Here follow the spectral data for the cationic complex
[PhPd(dmim)3]+ (14a), which has been obtained by exchang-
ing IÀ for TfOÀ by treatment of a solution of the title com-
A 50-mL round-bottom flask with a side arm equipped with
a magnetic stirrer was charged with Pd(dba)2 (575 mg,
1.0 mmol) and conditioned under argon. Degassed toluene
(20 mL) and dmim 1 (355 mL, 4.0 mmol) were added. The
colour of the solution changed from violet to orange-yellow,
and the starting material dissolved completely. When colour
change ceased, iodobenzene (224 mL, 2.0 mmol) was intro-
duced. Within a minute after the addition of PhI a brownish,
sticky mass was formed and adhered to the wall of the flask.
1
pound with excess AgOTf. H NMR (300 MHz, CDCl3): d=
7.01 (br s, 2H, cis-dmim C-4-H), 6.94–6.92 (m, 2H, Ph-Pd),
606
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Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles
6.88 (br s, 1H, trans-dmim C-4-H), 6.88–6.81 [m, 4H, PhPd
(3H) + trans-dmim C-5-H], 6.73 (d, J=1.2 Hz, 2H, cis-
dmim C-5-H), 3.62 (s, 3H, trans-dmim N-CH3), 3.53 (s, 3H,
cis-dmim N-CH3), 2.60 (br s, 6H, cis-dmim C-CH3), 2.46 (br
s, 3H, trans-dmim C-CH3); 13C NMR (75.5 MHz, CDCl3):
d=146.3, 145.9, 145.8, 135.2, 127.6, 126.6, 126.0, 123.5, 121.8,
121.7, 34.2, 33.8, 13.9, 12.6; 19F{1H} NMR (282 MHz,
CDCl3): d=À78.2.
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PhPd(dmim)2(OAc) (15a)
The title compound can be prepared by treatment of a solu-
tion of the corresponding iodide (12a) in benzene with an
excess of AgOAc and removal of the AgI thus formed by
filtration through a short plug of diatomaceous earth. Any
attempt to isolate the title compound in the solid state invar-
iably failed because of extensive decomposition while re-
moving the solvent (even in high vacuum at 08C). Said com-
plex, however, is quite stable as a dilute solution in benzene
and can be characterized as such, together with some free
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1
dmim, which does not interfere. H NMR (300 MHz, ben-
zene-d6): d=7.53 (d, J=1.5 Hz, 2H, dmim C-5-H), 7.48 (dd,
J=8.1, 1.2 Hz, 2H, 2,6-C6H5Pd), 7.03–6.99 (m. 2H, 3,5-
C6H5Pd). 6.92–6.87 (m, 1H, 4-C6H5Pd), 5.79 (d, J=1.5 Hz,
2H, dmim C-4-H), 2.39 (s, 6H, N-CH3), 2.27 (br s, 3H,
AcOÀ), 1.96 (s, 6H, C-CH3); ESI-MS (positive ion mode,
MeCN): m/z (%)=476.5 (10), 475.6 (37), 474.6 (23), 471.5
+
(74), 470.5 (54), 469.5 (22) [PhPd(dmim)3 ]; 420.5 (8), 416.5
+
(20), 414.5 (13) [PhPd(MeCN)(dmim)2 ]; 380.5 (10), 379.3
(56), 377.3 (100), 376.4 (33), 375.3 (97), 374.3 (92), 373.3
+
ˇ
´
(56) [PhPd(dmim)2 ]; 257.3 (31), 255.4 (59) 97.2 (69)
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Acknowledgements
We thank Dr. Anny Jutand and Dr. Christian Amatore for
fruitful discussions as well as Dr. Dennis Kurzbach and Dr.
Marco Lessi for technical help. We thank Scuola Normale
Superiore (Pisa, Italy), ENS and CNRS for financial support.
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[34] In the presence of PPh3 the homocoupling product 4a
is formed mainly at the beginning of the reaction time
(see the Supporting Information, §1.4, Figure S2), when
the appearance of the coupling product 3a is still very
slow and dmim is being consumed at a slow rate. Ac-
tually, the quantity of 4a remains almost constant after
the induction period until the conversion of dmim is
complete. All these observations led us to postulate
that 4a could result from the evolution of the inter-
mediate complex [ArPd(II)(PPh3)(OAc)L] (L stands
for a generic ligand here, L=PPh3, dmim or DMF)
formed after oxidative addition of ArX with the Pd(0)
species generated by the oxidation of the first equiva-
lent of PPh3 (see scheme below). Indeed, it could fur-
ther evolve through reductive elimination of
[AcOPPh3]+, analogously to what was shown previously
for [Pd(OAc)2(PPh3)2] (see ref.[35]). The resulting Pd(0)
species [ArPd(0)Ln]À could add another molecule of
ArX giving the reductive elimination-prone complex
[Ar2Pd(II)LnÀ1X]À. Elimination of ArAr would give
back Pd(0). Overall, ArX acts as an oxidizing agent for
PPh3 and it is reduced to ArAr. See also: C. Amatore,
E. CarrØ, A. Jutand, H. Tanaka, R. Quinghua, S. Torii,
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[19] A comparative table of published reaction conditions is
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles
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W. M. Seganish, M. E. Mowery, S. Riggleman, P. De-
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OAc, since difficulties were encountered with the re-
moval of silver salts from this solvent while preparing
the required solution of [PhPd(dmim)2(OAc)] (15a).
The latter complex was thus prepared in a small
volume of CH2Cl2, silver salts were removed, DMF was
added and the conductimetry experiment performed.
As reported before, it was not possible to isolate the
complex in a pure state because of its ready decompo-
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[50] K’D can be calculated from the ionization constants re-
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(X=I, OAc) in DMF. See: C. Amatore, E. CarrØ, A.
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[39] This K value is of comparable magnitude to those re-
ported in the literature for the displacement of PPh3
from [ArPd(PPh3)2X] by
a secondary amine (see
ref.[38]).
[40] a) V. V. Grushin, H. Alper, Organometallics 1993, 12,
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[41] For as similar synthesis involving benzothiazole instead
of dmim, see ref.[25b]
[42] It should be noted that the displacement of AcOÀ by
dmim is also possible, both in the starting complex and
in the product (see text for a determination of the ther-
modynamic constant for the latter case). The value of
K’ is, thus, to be understood as an apparent constant for
the displacement of PPh3 from all the PPh3-containing
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Manzer, Coord. Chem. Rev. 1973, 10, 335–422. It is,
indeed, a quite general fact that two soft ligands (with
invariably high trans influence, such as PPh3 in the spe-
cific case) destabilize each other with respect to the
substitution with a harder ligand (with less trans influ-
ence, such as dmim). This phenomenon has been called
antisymbiosis by R. G. Pearson in the framework of the
HSAB (hard-soft acid and bases) concept. See also:
b) R. G. Pearson, Inorg. Chem. 1973, 12, 712–713.
[44] A DMF solution of 8 was also heated in the presence
of various additives [(n-Bu)4NOAc, DBU, (i-Pr)2NH,
see Table S8 in the Supporting Information for details).
In some cases, total yields exceeded 100% because of
[53] Similar observations have been made for Ru-catalyzed
arylation of some arenes functionalized with metal-di-
recting groups: a) E. Ferrer Flegeau, C. Bruneau, P. H.
Dixneuf, A. Jutand, J. Am. Chem. Soc. 2011, 133,
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À
the participation of the Ph groups of PPh3 through C P
bond activation. Under catalytic conditions, only trace
amounts of PhPh could be detected. Moreover, a sub-
stantial amount of PPh3 is converted to Ph3PO while 8
evolved.
À
mediated C H activation of arenes in the presence of
bidentate phosphine ligands: c) S. Pascual, P. de Men-
doza, A. A. C. Braga, F. Maseras, A. M. Echavarren,
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