Mechanism insight and scope of PEPPSI-catalyzed cross-coupling reaction between triarylbismuth and arylbromide

Article abstract of DOI:10.1016/j.molcata.2016.07.016

In this paper we report the first cross-coupling reaction of Ar₃Bi with Ar'X mediated by Pd-NHC complexes by keeping the ability of Ar₃Bi to transfer the three aryl moieties. Investigations were carried out in order to minimize the quantity of the side product Ar-Ar coming from the conversion of Ar₃Bi. The results showed that PEPPSI IPr was a good catalyst precursor. Efforts were focussed on the rule of each additive such as PPh₃ and the base. It was notably found that the presence of PPh₃ (ratio PEPPSI IPr/PPh₃: 1/1) was essential to keep the process efficient. Therefore NHC-Pd-PPh₃ has been assumed as being the catalytic species. Under the optimized reaction conditions the concomitant formation of the undesired biaryl side product was restricted to its inherent formation consecutive to the reduction of the catalyst precursor to Pd(0). In a last study, the scope and the limitation of the new catalytic methodology were examined and a large range of unsymmetrical biaryl compounds Ar-Ar’ bearing various substituents from strongly electron-donating to electron-withdrawing ones have been prepared and fully characterized.

Full text of DOI:10.1016/j.molcata.2016.07.016

Accepted Manuscript
Title: Mechanism insight and scope of PEPPSI-catalyzed
cross-coupling reaction between triarylbismuth and
arylbromide
´ ´
Author: Benedicte Cassirame Sylvie Condon Christophe
Pichon
PII:
S1381-1169(16)30266-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.07.016
MOLCAA 9950
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Journal of Molecular Catalysis A: Chemical
Received date:
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Accepted date:
5-3-2016
21-6-2016
6-7-2016
´ ´
Please cite this article as: Benedicte Cassirame, Sylvie Condon, Christophe Pichon,
Mechanism insight and scope of PEPPSI-catalyzed cross-coupling reaction between
triarylbismuth and arylbromide, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.07.016
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Mechanism insight and scope of PEPPSI-catalyzed cross-coupling reaction
between triarylbismuth and arylbromide
Bénédicte Cassirame, Sylvie Condon, and Christophe Pichon*
Équipe de Synthèse Organique, Institut de Chimie et des Matériaux Paris-Est, Université
Paris-Est Créteil , 2 rue Henri Dunant 94320 Thiais
Corresponding author : +33 249781141 Email address : pichon@icmpe.cnrs.fr

Graphical abstract

Highlights





Cross coupling of Ar3Bi and Ar-Br are catalysed by NHC-Pd-(PPh3).
Ar3Bi plays a dual role: aryl tranfert reagent and reducing agent.
The active species is in-situ obtained by reactions from PEPPSI, Ar3Bi and PPh3.
A Lewis base is compulsory for the activation of aryltransfert.
Phenol, amine, carboxylic acid are compatible with the reaction conditions.
ABSTRACT :
In this paper we report the first cross-coupling reaction of Ar3Bi with Ar’X mediated by Pd-
NHC complexes by keeping the ability of Ar3Bi to transfer the three aryl moieties.
Investigations were carried out in order to minimize the quantity of the side product Ar-Ar
coming from the conversion of Ar3Bi. The results showed that PEPPSI IPr was a good
catalyst precursor. Efforts were focussed on the rule of each additive such as PPh3 and the
base. It was notably found that the presence of PPh3 (ratio PEPPSI IPr/PPh3: 1/1) was
essential to keep the process efficient. Therefore NHC-Pd-PPh3 has been assumed as being
the catalytic species. Under the optimized reaction conditions the concomitant formation of
the undesired biaryl side product was restricted to its inherent formation consecutive to the
reduction of the catalyst precursor to Pd°. In a last study, the scope and the limitation of the
new catalytic methodology were examined and a large range of unsymmetrical biaryl
compounds Ar-Ar’ bearing various substituents from strongly electron-donating to electron-
withdrawing ones have been prepared and fully characterized.
Keywords :
PEPPSI • Triarylbismuth • Biaryl • Cross-coupling • Homogenous catalysis

1.
Introduction
Since the pioneer work of Barton and Coll. published in 1987,[1] triarylbismuths (Ar3Bi) have
reached a great interest as aryl transfer reagents for transition metal-catalyzed reaction.[2]
Most of the common palladium-catalyzed reactions carried out with common nucleophilic
organometallic species such as arylboronic acids are also observed with symmetric
triarylbismuths (Ar3Bi): cross coupling with aryl-, heteroaromatic-, ethylenic-, benzylic-,
allyl-, propargyl-, halides or triflates even with acyl chlorides.[2b] Conjugated addition may
also be performed either under palladium-[3a-b] or rhodium-calalysis.[3c-d] Arylation on
heteroatoms such as oxygen[4], nitrogen[5] can also be performed with ArBi(III) under a
copper catalysis involving an in-situ oxidation of ArBi(III) into ArBi(V). Only one aryl group
is transferred during the process. Arylation of sulphur[6] has been recently described and this
reaction is atom efficient.
Ar3Bi are air- and moisture-stable and easily accessible from Grignard reagents[7] or Gosmini
organozinc reagents.[8] Also triarylbismuth(III) reagents and the corresponding inorganic
product BiX3 are not considered as toxic so far, at least less toxic than other heavy metals and
corresponding by-product such as Ar3SnX.[9] Furthermore most of palladium-catalyzed cross-
coupling reactions allowed the use of subequimolar quantities of Ar3Bi as far as all the three
aryl groups are effectively transferred within the catalytic process. All these features led to
award the title of green reagents to these nucleophilic organometallic compounds.
Many palladium complexes have been proposed as (pre)catalyst for C-C bond formation
using Ar3Bi. Pd(PPh3]4,[10] PdCl2/PPh3,[11] [Pd2Cl2(Cl)2(PR3)2],[12] Pd(OAc)2,[13]
Pd(OAc)2(Cy2NH)2,[14] Pd2(dba)2,[15] have been used within an homogeneous catalytic system
whilst palladium(II) bipyridyl complexe anchored on nanosized mesoporous silica gel MCM-
41,[16] palladium(II) supported on phosphine linked polystyrene resin,[17] or Pd/charcoal,[18]
have been employed in the case of heterogeneous catalysis. It is important to notice that some
of homogeneous catalytic systems are air-sensitive and that the heterogeneous conditions can
seem more convenient and economic from an industrial point of view. However none of them
cannot prevent from the unwanted biaryles Ar-Ar formation coming from the slow
decomposition of Ar3Bi mediated by Pd(II) catalyst. [19] This main drawback has an impact on
yields and on the easiness of the cross-coupling products purification.
Rao has disclosed in a preliminary study a way to inhibit this reaction using a unsymmetrical
arylbismuth reagent.[20] Its structure exhibits a nitrogen lone pair chelating the bismuth atoms

via its 5f empty orbitals. As observed for most of stable nucleophilic arylorganometallic
species, chelation favors the aryl transferred within the transmetalation elementary step of the
proposed catalytic cycle.[21] However this specific structure cannot be considered anymore as
green as symmetrical Ar3Bi reagents, not only because its preparation is not trivial but mainly
because only one of the groups beared by the Bi atom can be transferred. That may explain
why Rao ande co-workers then focused their activities on Ar3Bi to make them attractive
reagents. It was notably found that additives such as Lewis bases (PO4 , CO3 , F-) allow to
minimize the dimerization but without its complete inhibition. Therefore further
investigations must be carried out to propose standard experimental conditions that inhibit as
much as possible the decomposition of Ar3Bi into the dimer Ar-Ar.
3-
2-
2.
Experimental
a. Palladium cross coupling procedure
Under inert atmosphere (N2), in a 25 mL round bottom flask, Ar3Bi (0.208 mmol; 0.35 eq.),
CsF (0.24 g: 1.8 mmol; 3 eq.), PPh3 (0.004 g: 0.018 mmol; 3 mol%), the aryl bromide (0.60
mmol; 1 eq.) was added to DMF (5 mL). The solution was warmed to 90 °C prior addition of
PEPPSI IPr (0.012 g: 0.018 mmol; 3 mol%). The reaction was monitored by GC/MS to follow
the total consumption of the aryl bromide. Cooled to room temperature (RT), the reaction
mixture was diluted by addition of diethyl ether (20 mL) and aqueous HCl 6M (30 mL). After
decantation, the aqueous solution was extracted with diethylether (2 × 20 mL). The collected
organic phases were then washed with HCl 6N (2 × 25 mL), water (25 mL) and brine (25 mL)
prior drying over MgSO4. After concentration under reduced pressure, the resulting crude
product was subjected to purification by column chromatography leading after concentration
under reduced pressure to the title compound.
b. Analytical data
Analytical data of all isolated compounds can be found in the on-line version (supplementary
material). Compounds were fully characterized by 1D and 2D NMR allowing full assignments
of the signals when possible.

3.
Results and discussion
a. General consideration – catalytic system of choice
All the palladium-catalyzed cross-coupling procedures involving Ar3Bi suffer from the
parallel reaction giving access to the undesired dimer Ar-Ar side product. In order to facilitate
the purification and increase the yield, the kinetic rate ratio cross-coupling / dimerization must
be improved: either by favoring the cross-coupling reaction or by disfavoring the side
reaction. Some catalytic cycles have been proposed for the cross-coupling reaction: a less
probable one based on a Pd(II)/Pd(IV) couple[22] compared to the classical one based on a
Pd(0)/Pd(II) catalytic system[20] depicted in Scheme 1 that has been better considered for our
purpose.
A catalytic cycle has also been proposed for the Ar decomposition into Ar-Ar conducted in
protic solvents. (Scheme 2) [19]
Both catalytic cycles showed metathesis steps (step 2 from Scheme 1; steps 1 and 2 from
Scheme 2) and a reductive elimination step (step 3 from Scheme 1; step 3 from Scheme 2).
The main difference is that the desired cross-coupling catalytic cycle contains a Pd(0)
oxidative addition into a C-Br bond (step 1 from Scheme 1). To discriminate the kinetics
between the two reactions, this step must be favored. Recent literature shows that NHCs
[23]
ligands exhibit this step.
In order to keep the easiness of the experimental procedure a
precatalyst must be used, i.e. a Pd(II) complex that must be in-situ reduced to a Pd(0) complex
giving access to the active species. We therefore drew our attention onto Pd(II)/NHC
complexes, easily prepared or available such as 1[24] and 2. [25] We also focused our attention
on PEPPSI catalysts developped by Organ[26] which are known to be robust against oxygen
and likely to be in-situ reduced. (Scheme 3).
Complexes described in Scheme 3 have therefore been tested as precatalysts (firstly with a
loading of 10 mol%) in a typical cross-coupling reaction between p-Tol3Bi and p-
bromoacetophenone. At this stage Lewis base, temperature and solvent have been kept as
those described by Rao: CsF (6 eq), DMF, 90 °C.[27] Catalysts efficiency have been compared
regarding to Rao's classical catalytic system (Pd(OAc)2 + 4 PPh3) on the basis of the GC/MS
analysis of every single crude product mixture: conversion ratio, reaction time for total
consumption of the reagent and cross-coupled product/dimer ratio, in our case 3q / pTol2.
Results are given in Table 1:

Results clearly indicated that bis-NHC complexes 1 and 2 (Table 1: entries 2 and 3) are not
efficient as really low conversions were observed after a few hours at 90 °C as it was also
observed for PEPPSI IPENT (Table 1: entry 6). However less bulky PEPPSI catalysts showed
an interesting reactivity as total conversion was observed. Both PEPPSI IPr and PEPPSI SPr
gave interesting results compared to Pd(OAc)2/2 PPh3 (Table 1: entries 4 and 5 vs entry 1),
but the most common one gave shorter reaction time (Table 1: entries 4 vs 5). PEPPSI IPr has
therefore been kept as precatalyst for the following optimization procedure.
b. triphenylphosphine – quantities and rule
Triphenylphosphine was found essential in each assay yielding good results. (Table 2: entries
1-4 vs 5). Variation on the PEPPSI IPr/PPh3 ratio has been carried out with 10 mol% of
catalyst. Results are given Table 2.
It is worth noting that the loading of PPh3 must be at least equal to those of PEPPSI IPr and
that no improvement was observed with an excess of phosphine. Without triphenylphosphine
no reaction was observed even the dimer formation. Furthermore a ratio PPh3/PEPPSI 4 /1,
2/1 or 1/1 gave similar kinetics. It is commonly stated that 2 equivalents of PPh3 are required
to reduce 1 equivalent of Pd(II) to Pd(0). Therefore the hypothesis that PPh3 could reduced
Pd(II) to Pd(0) is not consistent with the results (Table 2: entry 2 vs entry 3). PPh3 may
therefore act as ligand. However Organ usually involved an (NHC)1Pd(0) species as active
species.[28] At this stage two oxidative addition mechanisms can be involved: an associative
one and a dissociative one.
Organ usually involved a dissociative mechanism when the initial Pd(0) complex NHC-Pd(0)-
Pyr loose the weak ligand 3-chloropyridine.[29] In this hypothesis, the active species would be
a NHC-Pd(0) complex. However this mechanism is not consistent with the crucial rule of
PPh3. The first hypothesis would be that a dissociative mechanism will lead to NHC-Pd(0)
and that in the presence of Ar3Bi this last complex will not be stable enough as it have been
already demonstrated with Pd(PPh3)4.[30] Therefore this NHC-Pd(0) species requires to be
stabilized by an ancillary ligand such as PPh3 via a pool effect (Scheme 4). In the hypothesis
of a NHC-Pd(0) active species an excess of PPh3 regarding to PEPPSI will decrease the
kinetic rate of the coupling reaction as the concentration of the NHC-Pd(0) species will
decrease: this fact was not observed.

The second hypothesis would involve an associative mechanism with an active species
bearing a phosphine ligand: NHC-Pd(0)-PPh3. (see scheme 4) Associative mechanism with
NHC ligand has already been demonstrated by Jutand and coll. using a NHC2Pd(0)
complex.[31] It is worth to notice that they demonstrated that with really bulky NHC ligands,
the mechanism is dissociative with a lower kinetic rate. Based on this hypothesis, the complex
NHC-Pd(II)Cl2-PPh3 4 has been prepared by metathesis of PEPPSI with 1 equivalent of PPh3.
1H and 31P NMR data are consistent with those already described for this complex.[32] Then
this complex has been used in the test cross-coupling reaction described above and led to
similar results (product ratio and kinetic) with those already obtained with PEPPSI/PPh3 in a
1/1 ratio. These results are consistent with an associative mechanism with NHC-Pd(0)-PPh3 as
active species. In our hypothesis, the 3-chloropyridine/triphenylphosphine exchange will take
place prior to the reduction.
c. PEPPSI Reduction
Once the rule of PPh3 assigned as acting as a ligand, the question of how the precatalyst Pd(II)
(PEPPSI) is reduced to Pd(0) active species within the reactive mixture became crucial.
Similarly to what occurs for many Pd-catalyzed cross-coupling reactions using nucleophilic
organometallic reagents,[33] we believe that triarylbismuth reduce the Pd(II) precatalyst into
Pd(0) active species. Such a process would involve two consecutive metatheses on Pd(II)
followed by a reductive elimination step, yielding the Pd(0) species and the dimer Ar-Ar in
the same quantities. (Scheme 5) The –Cl / -pTol exchange on Pd may be similar to those
described by Jain and coll. as really fast and efficient.[22] Effectively, a kinetic study carried
out by GC/MS with internal standard shows that Ar-Ar is produced in little quantities (<3
mol%) within 5 min using a 3 mol% loading of PEPPSI.
Therefore the dual role of Ar3Bi played on the cross-coupling reaction (reagent and reductive
agent) led us to readjust its quantities regarding to the loading of PEPPSI (x mol), the
quantities of arylbromide (1 equivalent) and the number of aryl transferred within each
process. Keeping in mind that the 3 aryl groups will be effectively transferred, it came on that
the quantity of Ar3Bi must be equal to [1/3 + 2/3 x mol%]. The following optimization has
been carried out with this relationship.

d. Loading
At this stage, the loading must be reduced (i) to decrease the financial and toxicological
impact of the procedure, (ii) to reduce the quantity of Ar3Bi used and (iii) to minimize the
inherent concomitant formation of Ar-Ar within the Pd(II)/Pd(0) reduction process. Results
are given in Table 3.
Total consumption of the p-bromoacetophenone was observed until at least 3 mol% of
catalyst was used within 1 h. It is worth noticing that the quantities of dimer decrease with the
loading of catalyst. This observation is in full agreement with the reduction of PEPPSI by
Ar3Bi previously mentioned.
e. Lewis base
In a recent work devoted to the cross-coupling reaction of 2,6-dichloropyridazine with Ar3Bi
under Pd(0)/PPh3 catalysis, influence of the base (CsF, CsCO3, K2CO3) was examined.[34] It
was notably found that the cross-coupling reaction occurred efficiently without any additives
but their beneficial influence was evidenced with Ar3Bi bearing electron withdrawing group (-
CN, -CO2R, -Ac, -CF3) or in the cross-coupling involving triheteroarylbismuths.
At this stage of our study, we decided to focus again on their behaviours. Thus the Lewis base
optimization has been carried out using various inorganic compounds (K2CO3, Cs2CO3,
K3PO3, TBAF, CsF). The results given in Table 4 are pretty similar for most of the Lewis
bases used but slightly better with CsF. Its quantity has been decreased from 6 eq to 3 eq.
With a less important quantity, dimerization mainly took place and reaction occurred only
very slowly without Lewis base.
These new optimized conditions yield 96 % of isolated cross-coupling product 3q after only 1
h at 90 °C. The purification was made easier due to the really low quantity of dimer side-
product (3 % GC yield).
f. Scope and limitation – variation of the aryl moieties on both
reagents
At this stage, variations on both reagents, triarylbismuth and arylbromide, have been
performed in order to extend the scope and to define limitations of our methodology.

Reactions have been monitored by GC/MS analysis mainly in order to determine the time
required for total consumption of the arylbromide. All results are given in Table 5. Runs have
been carried out on a 1 mmol scale of the arylbromide.
First of all, it is important to mention that the GC/MS analysis of every single crude product
showed that only two products can be observed (> 0.5 %): the coupling product and the dimer
coming from the triarylbismuth used. In any case, neither the reduction nor the dimerization
of the aryl bromide was observed not even the protonation of the triarylbismuth even with
acidic compounds engaged.
Usually the desired compound was obtained with a GC yield over 95 % leading to high yields.
Most common substituents (from strongly donating substituent such as -NH2 to strongly
electron-withdrawing (–CF3 or –NO2) can be introduced to the biaryl moiety. Basically two
pathways can be forecasted, depending on the way of introducing the substituents either via
the arylbromides or via Ar3Bi. However the way to prepare unsymmetrical biaryl products
must be driven by the following rule: it is better to introduce electron-donating substituent via
an aryl transfer from Ar3Bi and electron-withdrawing group via the arylbromide. For instance,
in order to access to biaryl compounds bearing an electron-donating group on one aryl moiety
and an electron-withdrawing substituents on the other one, i.e. 3a, 3b, 3d, 3e, 3f, yields turn
to 90 % using electron-donating substituted Ar3Bi to 0 % using electron-withdrawing
substituted Ar3Bi. (entries 2, 4, 7, 10, 12 vs entries 1, 3, 8, 9, 11). Particularly triarylbismuths
bearing strongly electron-withdrawing group such as methyl carboxylate or formyl group
were found particularly poorly reactive whilst in one of our recent work devoted to the cross-
coupling of 3-chloro-6-iodopyridazine with [p-(CO2Me)C6H4]3Bi under Pd(0)/PPh3 catalysis,
led to moderate yields (60 %).[34] Furthermore it is worth noticing that the reaction time is
driven by the electron properties of the substituents beared by the aryl moiety of the Ar3Bi.
Electron-donating (p-OMe, p-Me) or neutral (H, p-F) substitutents on Ar3Bi led to short
reaction time (1 h : entries 2, 4, 7, 10, 12, 15, 16, 19, 20, 27-29, 32, 35-36), and the reaction
time goes longer when the electron-withdrawing properties of the Ar3Bi substituent increase
(m-OMe: 1 h30, entries 6, 31, 34; m-CF3 : 5 - 6 h, entries 11,14). This seems to indicate that
the rate determining step should be the Br/Ar exchange on Pd complex. (step 2 from Scheme
1)
These experimental observations are consistent with the proposed catalytic cycle (Scheme 1
completed by Scheme 5). In one hand, electron-donating substituents on Ar3Bi enhanced the
aryl transfer (for the Pd(0) formation: Scheme 5, and for the cross-coupling reaction: scheme

1 step 2). In the other hand, electron-withdrawing substituents on the aryl halide favoured the
oxidative addition (Scheme 1 step 1).
The acidity of arylbromide reagent is a second restriction to be considered. Indead the use of
really basic ligand such as NHC (pKa NHC.HCl/NHC is given around 22 in DMSO)[35] could
give rise to the decomposition of the active species in the presence of appropriate acids. In the
standard conditions, p-bromophenol and p-bromobenzoic acid do not give access to the
coupling product. But good improvements have been enabled by addition of carbonate prior
to the introduction of PEPPSI to the reagent solution. With p-bromobenzoic acid, this slight
modification was very beneficial since the product was obtained in 72 % yields (entry 23).
However this modification could not be used for each acidic reagent. With p-bromophenol the
upgraded yield remained low (entry 24: 22 %) and even lower with 4-
hydroxymethylbromobenzene (entry 25). With less acidic compound such as p-bromoaniline
(entry 26) and p-bromoacetophenone (entries 27, 28) excellent yields were obtained again. All
these results (entries 23 - 28) are consistent with the pKa order.[36]
The case of the introduction of a methyl group at the ortho position of the biaryl moiety is
tricky: this group cannot be introduce using tris-(o-tolyl)bismuth. In this case (entry 21, Table
5), no reaction was observed whatsoever: neither the formation of the desired product 3l, nor
the dimer formation which indicated that Pd(II) reduction did not occur. Similarly tris-(o-
tolyl)bismuth did not dimerize in protic solvent in the presence of palladium catalyst[19]
indicating that o-Tol substituent does not transfer from Bi to Pd. However, the switching of
the two aryl moieties from the two starting materials (entry 22, Table 5) gave the desired
product 3l, with a moderate yield (entry 22 Table 5).
To finish, it could be noticed that the Pd catalysis is chemoselective and complementary from
the Cu catalysis as no N-arylation was observed on the amino group (entry 26).[5]
4.
Conclusions
In this paper, we have disclosed a new and efficient procedure for the cross-coupling reaction
of Ar3Bi with aryl bromides mediated for the first time by Pd-NHC.
After optimisation of various parameters (loading, ratio of reagent/catalyst and ancillary
ligand) a wide variety of unsymmetrical biaryl compounds bearing electron-withdrawing
substituents as well as electron-donating substituents has been prepared.

Studies based on monitoring kinetic profiles led us to propose a mechanism insight where
triphenylphosphine acts as ancillary ligand and where PEPPSI was reduced by the
triarylbismuth. Therefore this green organometallic play a dual role within our conditions:
reactant and reductive agent.
5.
Acknowledgements
The authors would like to thank MNRT and University Paris-Est Créteil (UPEC) for the grant
allowed to B. Cassirame as well as the NMR and chromatographic services of ICMPE for
technical supports.
6.
References
[1]
[2]
D. H. R. Barton, J.-P. Finet, J. Khamsi, Tetrahedron Lett. 1987, 28, 887-890.
a) For extended reviews on triarylbismuth see: a) J.-P. Finet Chem. Rev 1989, 89, 1487-1501; b) H.
Suzuki, Y. Matano, Organobismuth Chemistry, Elsevier Science, Amsterdam, 2001, ISBN
[044420528] ; b) For uses of symmetrical Ar3Bi in organic syntheses see: a) Bismuth-Mediated
Organic Reactions, T. Ollevier Ed., Topics in Current Chemistry, Springer: Berlin, 2012; b) Condon,
C. Pichon, M. Davi, Org. Prep. Proc Int. 2014, 46(2), 89-131.
[3]
a) T. Nishikata, Y. Yamamoto and N. Miyaura, Chem. Commun. 2004 1822-1823; b) T. Nishikata, I.
D. Gridney and N. Miyaura, Organometallics 2005, 24, 5025-5030; c) S. Venkatraman and C.-J. Li,
Tetrahedron Lett. 2001, 42, 781-784; d) T. Huang, Y. Meng, S. Venkatraman, D. Wang and C.-J. Li,
J. Am. Chem. Soc. 2001, 123, 7451-7452.
[4]
[5]
C. Crifar, P. Petiot, T. Ahmad and A. Gagnon Chem. Eur. J. 2014, 20, 2744-2760.
a) ref [1]; b) H. Suzuki, T. Ikegami and Y. Matano Synthesis 1997, 249-267; c) E. Vassileva, M.
Shopova, C. Fugier and E. Henry Bash Synth. Commun. 1997, 27, 1669-1675; d) D. M. T. Chan
Tetrahedron Lett. 1996, 37, 9013-9016; e) O. Loog, U. Mäeorg and U. Ragnarsson Synthesis 2000,
1591-1597; f) O. Tšubrik, U. Mäeorg, R. Sillard and U. Ragnarsson Tetrahedron 2004, 60, 8363-
8373; g) H. M. Hügel, C. J. Rix and K. Fleck Synlett 2006, 2290-2292; h) P. Starkov, I. Zemskov, R.
Sillard, O. Tšubrik and U. Mäeorg Tetrahedron Lett. 2007, 48, 1155-1157; i) P. Petiot, J. Dansereau
and A. Gagnon RSC Adv. 2014, 4, 22255-22259.
[6]
[7]
S. Yasuike, M. Nishioka, N. Kakusawa and J. Kurita Tetrahedron Lett. 2011, 52, 6403-6406.
a) R. F. De Ketelaere, F. T. Delbeke and G. P. Van der Kelen J. Organomet. Chem. 1971, 30, 365-
368; b) A. Banfi, M. Bartoletti, E. Bellora, M. Bignotti and M. Turconi. Synthesis 1994, 775-776; c)
T. Murafuji, K. Nishio, M. Negasue, A. Tanabe, M. Aono and Y. Sugihara Synthesis 2000,1208-1210.
[8]
[9]
K. Urgin, C. Aubé, C. Pichon, M. Pipelier, V. Blot, C. Thobie-Gautier, E. Léonel, D. Dubreuil and S.
Condon Tetrahedron Lett. 2012, 53, 1894-1896.
a) Bismuth is used in the composition of Pyrela indicated for the treatment of patients with
Helicobacter pylori infection and duodenal disease; b) comparison of toxicity of Ph3Bi and BiCl3 vs
Ph3SnCl: T. Arato, Y. Oyama, K. Tabaru, M. Satoh, H. Hayashi, S. Ishida, Y. Okano Environmental
Toxicology 2002, 17(5), 472-477.
[10]
|11]
[12]
M. L. N. Rao, D. N. Jadhav, P. Dasgupta Org. Lett., 2010, 12, 2048-2051
M. L. N. Rao , D. N.Jadhav, D. Banerjee Tetrahedron, 2008, 64, 5762-5772.
K. R. Chaudhari, A. P. Wadawale and V. K. Jain J. Organomet. Chem. 2012, 698, 15-21.

[13]
a) M.L.N. Rao, D. Banerjee, D.N Jadhav Tetrahedron Lett. 2007, 48, 2707-6647; b) M.L.N. Rao, D.
Banerjee, D.N Jadhav Tetrahedron Lett. 2007, 48, 6644-6647.
[14]
[15]
[16]
M.L.N. Rao, D. Banerjee and R.J. Dhanorkar Tetrahedron Lett. 2010, 51, 6101-6104.
M.L.N. Rao, D. Banerjee and R.J. Dhanorkar Tetrahedron 2010, 66, 3623-3632.
J.-Y. Chen, S.-C. Chen, Y.-J. Tang, C.-Y. Mou and F.-Y. Tsai, J. Mol. Cat. A: Chem. 2009, 307, 88-
92.
[17]
[18]
W.-J. Zhou, K.-H. Wang, J.-X. Wang and D.-F. Huang Eur. J. Org. Chem. 2010, 416-419.
Y. Monguchi, T. Hattori, Y. Miyamoto, T. Yanase, Y. Sawama and H. Sajiki, Adv. Synth. Catal. 2012,
354, 2561-67.
[19]
[20]
T. Ohe, T. Tanaka, M. Kuroda, C. S. Cho, K. Ohe and S. Uemura Bull. Chem. Soc. Jpn. 1999, 72,
1851-1855.
a) M. L. N. Rao, S. Shimada and M. Tanaka Org. Lett 1999, 1, 1271-1273; b) S. Shimada, O.
Yamazaki, T. Tanaka, M.L.N. Rao, Y. Suzuki and M. Tanaka Angew. Chem. Int. Ed 2003, 42, 1845-
1848; c) O. Yamasaki, T. Tanaka, S. Shimada, Y. Suzuki and M. Tanaka Synlett 2004, 1921-1924.
[21]
[22]
[23]
For boronic acids: J.C. Norrild, H. Eggert J. Am. Chem. Soc. 1995, 117, 1479-1484.
K. R. Chaudhari, A. P. Wadawale and V. K. Jain J. Organomet. Chem. 2012, 698, 15-21.
a) N. M. Scott and S. P. Nolan (Ed.) N-Heterocyclic Carbenes in synthesis (chapter 3), VCH,
Weinheim, 2006, ISBN [3-527-31400-8]; b) G. C. Fortman and S. P. Nolan Chem. Soc. Rev. 2011, 40,
5151-5169; c) S. Diez-González, N. Marion and S. P. Nolan Chem. Rev. 2009, 109, 3612-3676.
[24]
[25]
[26]
[27]
[28]
C.-Y Liao, K.-T. Chan, J.-Y. Zeng, C.-H. Hu, C.-Y. Tu and H. Man Lee Organometallics. 2007, 26,
1692-1702
I. Abdellah, B. Cassirame, S. Condon, J.-Y. Nédélec, C. Pichon Current Topics in Electrochemistry
2011, 16, 81-91.
C. J. O'Brien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass, A. Lough, A. C. Hopkinson and
M. G. Organ Chem. Eur. J. 2006, 12, 4743-4748.
M. L. N. Rao, O. Yamasaki, S. Shimada, T. Tanaka, Y. Suzuki, M. Tanaka Org. Lett. 2001, 3, 4103-
4105.
C. Valente, S. Çalimsiz, K. H. Hoi, D. Mallik, M. Sayah and M. G. Organ Angew. Chem. Int. Ed.
2012, 51, 3314-3332.
[29]
[30]
[31]
[32]
[33]
S. Çalimsiz, M. Sayah, D. Mallik and M. G. Organ Angew. Chem. Int. Ed. 2010, 49, 2014-2017.
O. Yamasaki, T. Tanaka, S. Shimada, Y. Suzuki and M. Tanaka Synlett 2004, 1921-1924.
A. Jutand, J. Pytkowicz, S. Roland and P. Mangeney Pure Appl. Chem. 2010, 82, 1393-1402.
A. Flahaut, K. Toutah, P. Mangeney and S. Roland Eur. J. Inorg. Chem. 2009, 35, 5422-5432.
a) K. Sonogashira, Y. Tohda, N. Hagihara Tetrahedron Lett. 2010, 51, 6101-6104. b) A. O. King, N.
Okukado and E. I. Negishi J. Chem. Soc., Chem. Comm., 1977, 683-684.
[34]
K. Urgin, C. Aubé, M. Pipelier, V. Blot, C. Thobie-Gautier, S. Sengmany, J. Lebreton, E. Leonel, D.
Dubreuil and S. Condon Eur. J. Org. Chem, 2013, 117-124.
[35]
[36]
O. W. Kolling and E. A. Mawdsley Inorg. Chem. 1970, 9, 408-409.
K.H. Hall Jr. J. Am. Chem. Soc 1957, 79, 5441-5444.

Scheme 1. Proposed mechanism cycle for the cross-coupling reaction.
Scheme 2. Proposed mechanism cycle for the decomposition of Ar3Bi into Ar-Ar.
Scheme 3. List of NHC palladium precatalysts tested.

Scheme 4. Possible active species in the oxidative addition.
Scheme 5. Postulated pathway for the in-situ preparation of active Pd(0) catalyst from PEPPSI, PPh3 and Ar3Bi.

Table 1. Complexes activity on the cross-coupling reaction
[c]
Entry Pd Complex
Reaction time (h)
Conversion ratio (%) [b]
3q / pTol2
85 / 15
80 / 20
85 / 15
88 / 12
85 / 15
-
[a]
1
2
3
4
5
6
Pd(OAc)2 / 2 PPh3
1.5 h
48 h
8 h
100 %
2 %
1
2
25 %
100 %
100 %
0 %
PEPPSI IPr
PEPPSI SPr
PEPPSI IPENT
0.25 h
8 h
48 h
[a] therefore 40 mol% of PPh3 was used; [b] conversion ratio given as the percentage of reacted Ar-Br
(1 mmol; [c] measured after integration of the assigned signal on GC/MS analysis relatively to internal
standards.
Table 2. Variation of the PPh3 loading
Conversion ratio (%) [a] 3q / pTol2
[b]
Entry
Loading of PPh3 (x mol%)
1
2
3
4
5
40
20
10
5
100 %
100 %
100 %
10 %
0 %
85 / 15
80 / 20
85 / 15
85 / 15
-
0
[a] conversion ratio given as the percentage of reacted Ar-Br (1 mmol); [b] measured after
integration of the assigned signals on GC/MS analysis relatively to internal standards.

Table 3. Optimization of the loading of PEPPSI
[d]
Entry
Loading of PEPPSI IPr (mol%) [a]
Reaction time (h)[b]
Conversion ratio (%) 3q / pTol2
[c]
1
2
3
4
5
6
7
10
5
0.25 h
0.25 h
0.33 h
0.75 h
2.5 h
8 h
100 %
100 %
100%
100 %
95 %
85 %
0 %
85 / 15
91 / 9
93 / 7
96 / 4
98 / 2
> 98 / < 2
-
4
3
2
1
0
8 h
[a] Loading of catalyst is given in mol% relatively to the quantity of arylbromide (1 mmol); [b] reaction time is
given once no change on the reaction profile was observed by GC/MS; [c]: conversion ratio given as the
percentage of reacted Ar-Br; [d] measured after integration of the assigned signals on GC/MS analysis relatively
to internal standards.
Table 4. Lewis base optimisation
[b]
Entry
Lewis Base Quantity (y eq)
Conversion ratio (%) 3q / pTol2
[a]
1
2
3
4
5
6
7
8
9
K2CO3
Cs2CO3
K3PO4
CsF
6
95 %
80 / 20
82 / 17
91 / 9
6
97 %
6
89%
6
100 %
100 %
100 %
100 %
100 %
25 %
96 / 4
CsF
3
97 / 3
CsF
1.5
3
< 5 / > 95
97 / 3
TBAF
TBAF
-
1.5
0
5 / 95
< 5 / > 95
[a]: conversion ratio given as the percentage of reacted Ar-Br (1 mmol); [b] measured by
GC/MS after integration of the assigned signals after GC/MS analysis relatively to internal

standards.
Table 5. Variation on both aryl moieties from Ar3Bi and Ar'-Br
PEPPSI IPr
(3 mol%)
+
Ar Ar'
Ar3Bi
Ar'-Br
1 eq
PPh3 (3 mol%)
CsF (3 eq)
DMF, 90 °C, t
3a-z
0,36 eq
Reagents
Yield
(GC
Reaction
Entry
Coupling Product 3
time (h) [a]
yield)[b]
Ar3Bi
Ar'-Br
0 %
(7 %)
1
2
8 h
1 h
3a
95 %
(97 %)
0 %
3
4
5
8 h
1 h
8 h
(24 %)
3b
91 %
(96 %)
0 %
(15 %)
88 %
(95 %)
6
1.5 h
3c
86 %
(95 %)
7
8
1 h
8 h
3d
0 %
(15 %)
0 %
(7 %)
9
8 h
1 h
Br
3e
3f
90 %
(95 %)
10
CO2Me
69 % [d]
(96 %)
11
12
13
5.5 h
1 h
91 %
(96 %)
0 %
(14 %)
8 h

3g
64 %
(78 %)
14
5 h
97 %
(98 %)
15
16
17
18
19
20
1 h
1 h
1 h
1 h
1 h
1 h
3h
3i
91 %
(95 %)
94 %
(96 %)
92 %
(95 %)
90 %[d]
(98 %)
3k
85 %[d]
(97 %)
0 %
(0 %)
21
22
23
8 h
13 h
1 h
3l
45 %
(55 %)
72 %[c]
(95 %)[c]
3m
3n
3o
3p
3q
3r
22 %[c]
24
25
26
27
28
29
1 h
4 h
1 h
1 h
1 h
1 h
(49 %)[c]
24 %[c]
(26 %)[c]
88 %
(94 %)
96 %
(98 %)
95 %
(97 %)
85 %
(93 %)
3s

77 %
(85 %)
30
1.5 h
3t
86 %
(91 %)
31
32
33
1.25 h
1 h
3u
3v
94 %
(96 %)
91 %
(95 %)
1 h
3w
71 %
(85 %)
34
35
1.25 h
3x
3y
1 h
81 %
19 %
(39 %)
36
1.25 h
3z
[a] reaction time are given once no change in the reaction profile was observed by GC/MS; [b] yields are
given for isolated product. Eventually GC yields are given between bracket; [c] results obtained with addition
of 3 eq of K2CO3; [d] isolated yield lower from GC yield to a close polarity of expected product and Ar-Ar
byproduct.