Bulky monodentate biphenylarsine ligands: Synthesis and evaluation of their structure effects in the palladium-catalyzed Heck reaction

Article abstract of DOI:10.1002/ejoc.201403658

Biphenyl-based arsine ligands were prepared in two-step fashion by Pd-catalyzed arsination and microwave-assisted Suzuki-Miyaura coupling, providing sterically demanding arsine ligands in overall isolated yields up to 82 % as air-stable solids. Short reaction times were achieved with the assistance of microwave irradiation in the direct and simple described protocol for the synthesis of biarylarsine ligands. The activities of the biphenyl arsine ligands were explored in Pd-catalyzed Heck coupling. As a general trend, the ligands with "blocked" ortho-positions on the non-arsine-containing ring of the biphenyl backbone performed more efficiently in the coupling reaction. This catalytic system allowed several interesting stilbenes to be obtained in very good yields. Sterically demanding biphenyl-based arsine ligands were prepared in high overall yields by microwave-assisted Suzuki-Miyaura coupling. The ligands were evaluated in the Pd-catalyzed Heck coupling reaction; the most active were those with "blocked" ortho-positions on the non-arsine-containing ring of the biphenyl backbone.

Full text of DOI:10.1002/ejoc.201403658

Job/Unit: O43658
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FULL PAPER
DOI: 10.1002/ejoc.201403658
Bulky Monodentate Biphenylarsine Ligands: Synthesis and Evaluation of Their
Structure Effects in the Palladium-Catalyzed Heck Reaction
Gisela J. Quinteros,[a] Paula M. Uberman,*[a] and Sandra E. Martín*[a]
Keywords: Homogeneous catalysis / Cross coupling / Palladium / Ligand design / As ligands / Microwave chemistry
Biphenyl-based arsine ligands were prepared in two-step activities of the biphenyl arsine ligands were explored in Pd-
fashion by Pd-catalyzed arsination and microwave-assisted
Suzuki–Miyaura coupling, providing sterically demanding
arsine ligands in overall isolated yields up to 82% as air-
catalyzed Heck coupling. As a general trend, the ligands
with “blocked” ortho-positions on the non-arsine-containing
ring of the biphenyl backbone performed more efficiently in
stable solids. Short reaction times were achieved with the as- the coupling reaction. This catalytic system allowed several
sistance of microwave irradiation in the direct and simple de-
scribed protocol for the synthesis of biarylarsine ligands. The
interesting stilbenes to be obtained in very good yields.
positions on the non-arsine-containing ring of the biphenyl
backbone, showed outstanding activity in Pd-catalyzed ar-
sination with perfluoroalkyl iodides (RfI).[9]
Introduction
For the design of more selective and stable catalysts with
high turnovers, the development of appropriate ligands is
one of the first, and most important, factors to consider. In
the field of rational ligand design, the biaryl unit is firmly
established as a key structure in a variety of important
monodentate[1] and bidentate[2] phosphine ligands, many of
which are widely used for transition-metal-catalyzed C–C
and C–heteroatom bond formation. The electron-rich bi-
aryl monophosphines, first introduced by Buchwald,[3] have
been shown to be excellent ligands for numerous Pd-cata-
lyzed processes.[4] Catalyst performances for coupling reac-
tions with Buchwald-type biphenyl-based phosphines have
been further improved by introducing substituents on the
ortho-positions on the non-phosphine-containing arene
units, as well as by increasing the substituents’ steric bulk.[5]
Because the biaryl motif appears to be successful as a
basis for many ligands, it has been used as a main building
block to develop alternative ligand systems.[6] We have also
incorporated this basic design concept and recently de-
scribed the first synthesis of new biphenyl-based arsine li-
gands by an approach including Pd-catalyzed arsination[7,8]
and subsequent Suzuki–Miyaura coupling as the key syn-
thetic tool for biaryl construction.[9] The newly prepared
biphenyl-based ligand, with methoxy groups in the ortho-
It is important to note that, in contrast to the many
phosphine-based ligands that have been synthesized, rela-
tively few arsine ligands have been prepared and applied in
catalysis, probably mainly due to the lack of readily avail-
able As-containing precursor compounds. Arsines have
been shown to be excellent supporting ligands, and there
are several examples in which they have provided more
active or selective catalysts than phosphines in transition-
metal-catalyzed reactions,[9] due to their reactivity and
selectivity in addition to their high stability towards air,
with respect to the structurally related phosphines.[10]
The Pd-catalyzed Heck reaction has become one of the
most powerful tools as a general methodology for sp2–sp2
C–C bond formation,[11,12] finding wide application in the
synthesis of valuable molecules and complex natural prod-
ucts. It is probably one of the most frequently applied Pd-
catalyzed coupling reactions in the fine-chemical and phar-
maceutical industries.[13] A comprehensive overview of the
Heck reaction has recently been published.[14] The tradi-
tional Heck reaction is typically performed with a homo-
geneous catalyst and use of a phosphorus ligand in the pres-
ence of a suitable base.[15] However, numerous other cata-
lysts based on electronically and structurally diverse li-
gands, such as different palladacycles,[16] and non-phos-
phine Pd catalysts, such as N-heterocyclic carbenes (NHCs)
[a] INFIQC CONICET – Universidad Nacional de Córdoba,
Departamento de Química Orgánica, Facultad de Ciencias
Químicas,
[17]
and carbocyclic carbenes,[18] have been employed.
Medina Allende y Haya de la Torre, X5000HUA, Córdoba,
Argentina
A number of studies have shown that sterically de-
manding phosphine ligands can function as active catalysts
in Pd-catalyzed Heck olefination,[15d,15f,15j] with biphenyl-
based phosphines included among them.[19] Furthermore,
bulky phosphoramidite-based palladium catalysts have
E-mail: uberman@fcq.unc.edu.ar
martins@fcq.unc.edu.ar
infiqc.fcq.unc.edu.ar
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403658.
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G. J. Quinteros, P. M. Uberman, S. E. Martín
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shown high activity with aryl iodides.[20] Studies on ligand
effects and kinetics measures revealed that a suitable bal-
ance between the steric and the electronic properties of the
ligands was responsible for the catalyst performance.
On the other hand, arsine ligands have also been used in
the Pd-catalyzed Heck reaction.[21] Intramolecular asym-
metric Heck reactions based on binaphthyl BINAs[22a] and
BINAPAs[22b] ligands have been reported. Only a few exam-
ples in which AsPh3 was determined to be a particularly
useful ligand in the Pd-catalyzed Heck reaction are avail-
Scheme 1. Synthetic strategy for biphenylarsine ligands.
The Pd-catalyzed Suzuki–Miyaura reaction has emerged
able in the literature.[23] Moreover, Heck-related reactions, as an extremely efficient method for the construction of C–
such as Heck-type hydroarylation reactions of bi-, tri-, and C bonds.[13a,26] It is an important tool in total synthesis and
tetracyclic alkenes in the presence of AsPh3 as a highly ef- in medicinal chemistry, as well as in the synthesis of phar-
ficient ligand have also been reported.[24] Recently, tri- maceuticals and fine chemicals.[27,28] Microwave-assisted
phenylarsinyl-functionalized N-heterocyclic carbene ligands heating under controlled conditions has been proven as an
have been synthesized and applied in Heck, hydro-Heck, invaluable technology for organic synthesis[29] and its appli-
and π,σ domino-Heck reactions.[10] With these arsine li- cation has in several cases led to acceleration of reaction
gands less Pd and ligand were needed than in the case of rates and to improvements in yields and selectivity.[30] MW
the phosphine analogue N-heterocyclic carbenes in order to irradiation has been used in Pd-catalyzed coupling reac-
obtain similar yields. Arsines are known to have coordina- tions,[31] in particular in Suzuki–Miyaura reactions,[32] and
tion modes similar to those of phosphines; however, they can today be considered an efficient synthetic methodology.
are recognized to be poorer σ-donors than phosphines, and
Suzuki–Miyaura coupling to build the biaryl structure of
this leads to contrasting steric and electronic effects on co- biarylarsine ligands was carried out with the aid of MW
ordination spheres different from those of phosphines. Prin- irradiation (Scheme 1). In the first instance, Suzuki–Mi-
gle and co-workers investigated the catalytic activity of Pd yaura reactions between arsine 3 and phenylboronic acid
complexes of a series of bulky arsine ligands, exploring their (4a) and between 3 and 2,6-dimethylphenylboronic acid (4b,
stereoelectronic effects.[25] They established that Pd-arsine as a model sterically hindered boronic acid substrate) under
complexes were generally more active in the Heck reaction MW irradiation conditions were examined (see the Sup-
than analogous complexes resulting from phosphine.
porting Information). We started with optimized reaction
As part of our ongoing work on the synthesis and cata- conditions based on our previous results[9] and explored dif-
lytic activity of arsine ligands, here we report an improve- ferent methods and systems for the MW irradiation cou-
ment in the synthetic methodology for production of bi- pling, such as dynamic heating at fixed temperature or fixed
phenyl-based arsine ligands through the use of microwave power in sealed vessels (use of sealed vessels being preferred
(MW) irradiation assistance of Suzuki–Miyaura coupling in order to accomplish significant rate enhancements[30]).
for biaryl construction. Therefore, a fast and efficient meth- The best results were achieved with the MW dynamic
odology to obtain a family of sterically demanding arsine method at a fixed 150 °C. Under the optimized conditions,
ligands in high yields is available. Additionally, as a first the coupling reaction between arsine 3 and boronic acid 4a
approach to exploring the application of these ligands in in the presence of K3PO4 and catalyzed by Pd(OAc)2 in
transition-metal-catalyzed reactions, we studied the scope dioxane/H2O under nitrogen afforded L1 (BAs) in 93%
of the biphenylarsine ligands in Pd-catalyzed Heck ole- yield in only 10 min (Entry 1, Table 1). This is a significant
fination with aryl bromides and iodides by evaluating their improvement on the 24 h required for the conventional pro-
catalytic performance.
cess (time and yields for thermal reaction performed under
the same reaction conditions are provided in square brack-
ets in Table 1).[9] A screening was performed to determine
the optimum Pd source and loading, ligand, and base for
the sterically hindered boronic acid 4b (see the Supporting
Information).[33,34] The optimized conditions were with
Pd(dba)2/PPh3 and K3PO4 as a base with an extra addition
of boronic acid 4b during the reaction and extension of the
Results and Discussion
Synthesis of Biphenyl-Based Arsine Ligands by Microwave-
Assisted Suzuki–Miyaura Coupling
The synthesis of the biarylarsine ligands was carried out reaction time to 80 min (Entry 2, Table 1). Once we had
by a strategy including initial Pd-catalyzed arsination, fol- thoroughly optimized the MW-assisted reaction conditions,
lowed by MW-assisted Suzuki–Miyaura coupling as the key Suzuki–Miyaura couplings with arylboronic acids 4a–i,
synthetic tool for biaryl construction (Scheme 1). (2- bearing different substituents, and bromoarsine 3 were car-
Bromophenyl)diphenylarsine (3) was employed as a syn- ried out (Table 1). These reactions gave biaryl arsine ligands
thetic intermediate for the synthesis of biarylarsine ligands. L3–9 in excellent yields (70–99%). Thus, biphenyl-based ar-
Arsination of the stannane nBu3SnAsPh2 (1) with 1-bromo- sine ligands L1–9 could be readily prepared in two-step
2-iodobenzene (2), catalyzed by (PPh3)2PdCl2 in toluene, af- fashion in overall isolated yields of up to 82% as air-stable
forded the arsine 3 in 83% isolated yield (Scheme 1).[7b,9]
solids. Short reaction times were achieved by using MW-
2
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Bulky Monodentate Biphenylarsine Ligands in the Heck Reaction
Table 1. Suzuki–Miyaura coupling with (2-bromophenyl)di- assisted Suzuki–Miyaura coupling according to the de-
phenylarsine (3) and substituted arylboronic acids 4a–i.[a], [b]
.
scribed protocol for the synthesis of biarylarsine ligands.
Catalytic Activity of Biphenyl Arsine Ligands in Pd-
Catalyzed Heck Reaction
With the set of biphenyl-based arsine ligands to hand,
and in view of the high performances of bulky triarylarsine
ligands in the Heck reaction,[10,25] this coupling reaction
was selected as a model system for evaluation of the cata-
lytic activity of biphenylarsine ligands. To determine the
performance of these ligands, the challenging Heck reaction
between p-bromotoluene (5a) and styrene (6a) was chosen
as the model reaction (Figure 1). In this reaction neither the
aryl halide nor the alkene is activated, so because of the
low reactivities of the coupling partners a more demanding
catalytic activity in terms of the Pd/L complexes is required.
To initiate this study the ligand L6 (diOMeBAs) was se-
lected for evaluation of the reactions conditions, because in
a previous work L6 had shown outstanding activity in a
Pd-catalyzed coupling reaction.[9] A broad range of reaction
conditions – namely, the solvent, base, Pd source, Pd/ligand
ratio, temperature, and reaction time – were systematically
evaluated. Identification of the most suitable solvent for this
reaction showed that the reaction rates were significantly
enhanced by using polar nonprotic solvents, with DMF be-
ing the solvent of choice. It seems that the coordination
abilities of the solvents play an important role in the cata-
lyst activity, probably in connection with catalyst stability.
Moreover, this is consistent with previous reports by
Beller[35] and Herrmann,[36] in which polar nonprotic sol-
vents tended to give the best results for Heck coupling.
[a] Reaction conditions: the coupling reactions were carried out
with bromoarsine 3 (1 equiv.), a boronic acid 4 (1.5 equiv.), a [Pd]
species, a phosphine ligand (Pd/L, 1:4), a base (2 equiv.), and diox-
ane/H2O (4:1, 5 mL) at a fixed 150 °C by the MW dynamic method
in sealed vessels under nitrogen. [b] To simplify comparison be-
tween Suzuki–Miyaura reactions conducted with conventional and
MW-assisted heating, the time and yields for normal thermal reac-
tions carried out under the same conditions are provided in square
brackets; for more detail see ref.[9] [c] GC yields. Isolated yields are
given in parentheses (averages of two or more experiments). In
square brackets the yields for the normal thermal conditions are
given. [d] These coupling reactions were carried out with the appro-
priate boronic acid 4 (1.5 equiv.) and an extra 1.5 equiv. of 4 added
after either 40 min (4b) or 50 min (4d). The reaction times were
increased to 80 min for L2 and 100 min for L4.
Figure 1. Optimization of the reaction conditions with p-bromo-
toluene (5a) and styrene (6a): (a) Pd source, and (b) base.
The most relevant results achieved in the optimization of
Pd sources and bases are shown in Figure 1. The nature of
the Pd precursor proved important, with the best results
being obtained with Pd(OAc)2 (Figure 1, a). Once the palla-
dium source was established, the base effect was studied.
Significant increases in the degree of conversion and selec-
tivity were observed when the inorganic base K2CO3 was
employed (Figure 1, b).
The use of 1 mol-% Pd(OAc)2 and a Pd/L ratio of 1:2
were the best conditions to achieve the Heck product. Ad-
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dition of fewer or more equivalents of ligand (Pd/L ratios relative to other biarylarsine ligands. On the other hand,
of 1:1 and 1:3) decreased the catalyst activity. Thus, with with L7, a more electron-withdrawing arsine, the observed
employment of the ligand L6, K2CO3, Pd(OAc)2, and DMF high activity could be attributable to the formation of a less
at 140 °C, the degree of conversion of 5a into the stilbene 7 electron-rich Pd complex, which could easily promote the
was 43% with a high selectivity in favor of the trans product alkene coordination or insertion.[20]
(trans/gem/cis 38:4:1). It was previously reported that the
In order to compare electron-donating character, as well
reaction between 5a and styrene in the presence of the li- as catalytic activity, the phosphine ligand L10-Phos was
gand 2-diphenylphosphino-2-methylbiphenyl under similar also employed in the Heck coupling of bromotoluene (5a)
reaction conditions took one hour to convert 90% of the and styrene (6a). When L10-Phos was allowed to react un-
reagent, but the stereoselectivity was remarkably poor, with der the optimized conditions a level of conversion lower
a mixture of stilbenes being produced.[19a]
than that seen in the reaction in the presence of L6 was
The activity of the synthesized biphenyl-based arsine li- found (Figure 2). In consequence, although arsines are
gands in Heck coupling was explored. In addition, AsPh3 poorer σ-donors/better π-acceptors than the analogous
and the dimethoxybiphenyl-2-diphenylphosphine ligand phosphines, the catalysts derived from Pd/biphenyl-arsine
(L10/Phos),[37] a phosphorus ligand homologue of L6, were complexes were particularly efficient in the Heck reaction,
screened to compare their activity in the Heck reaction in agreement with the results obtained by Pringle and co-
(Figure 2). As can be seen from Figure 2, the ligand struc- workers.[25] This is not a new finding: previous studies had
ture had a significant effect on the degree of conversion of suggested that the greater π-acceptor ability of sterically
substrate 5a. The ligandless Heck arylation with 6a pro- bulky phosphite ligands increased Heck reaction rates.[15j]
ceeded only with difficulty. It is important to note that all Furthermore, phosphoramidite ligands [P(OR)2NR] with a
reactions led to product 7 with high selectivity for the trans suitable balance between steric and basicity properties pro-
product. Moreover, the efficiency of catalysts derived from vided faster overall Heck reactions with aryl iodides.[20]
biphenyl ligands could be attributed to their steric bulk fav-
In an attempt to determinate the effect of the ligand
oring the formation of the active monophosphine complex structure over the catalytic cycle, the Pd-arsine catalysts
LPd0.[38]
were also evaluated with 4-bromoacetophenone (5e), an ac-
tivated aryl halide, as electrophile (Figure 3). With this sub-
strate, ligands L6, L7, and L4 gave the corresponding cou-
pling product in excellent yields, whereas the ligand L1
showed a lower activity. On comparing this with the results
obtained with the non-activated 4-bromotoluene (5a) (Fig-
ure 2), it might be inferred that the oxidative addition could
be the partially determinate step in this Heck coupling reac-
tion.
Figure 2. Evaluation of arsine and phosphine ligands in the cou-
pling reaction between p-bromotoluene (5a) and styrene (6a).
A notable inhibition of the reaction was observed when
the arsine ligand L1 (BAs) was used; it provided a decelerat-
ing effect on the Heck reaction, possibly due to the forma-
tion of stable palladacycles.[39] The results clearly showed
that the substituents on the non-arsine-containing ring of
the biphenyl backbone of the ligand indeed have a signifi-
cant impact on the efficacy of the reaction [L1 vs. L3
(MeBAs), L4 (triMeBAs), L6 (diOMeBAs), and L7
(CF3BAs)]. Ligands L6 and L7 provided higher yields of
Figure 3. Ligand evaluation in the coupling reaction between p-
bromoacetophenone (5e) and styrene (6a).
It should be considered that an overall catalytic transfor-
the alkene product, being the most active ligands, although mation consists of several elementary steps with different
exhibiting very different electronic characteristics. requirements that will be influenced in different ways by
Substitution of hydrogen atoms with alkoxide groups ligands. As expected, with a less electron-rich arsine ligand
proved to be beneficial to catalyst stability and created more the oxidative addition to aryl bromides could become a
reactive catalyst for coupling processes.[5,40] In view of our slower step. However, a less electron-rich Pd complex de-
results, Pd-O interactions with ligand L6 could contribute rived from arsine ligands could be beneficial for the catalyst
to the stability, and thus to the efficiency, of the catalysts performance during the alkene coordination or insertion.[20]
4
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Bulky Monodentate Biphenylarsine Ligands in the Heck Reaction
With the aim of exploring the scope of the catalytic sys-
All reactions led to the corresponding alkenes with high
tem Pd·L6, several aryl halides and alkenes were examined selectivity for the trans products. Total conversion and high
in the Heck coupling reaction under the optimized condi- yields of the alkene products were obtained with activated
tions (K2CO3, 1 mol-% Pd(OAc)2, 2 mol-% L6, 2 equiv. and deactivated aryl iodides and styrene (6a) or butyl acryl-
K2CO3, DMF, 140 °C). The results are summarized in ate (6b) as coupling partners (Entries 1–3 and 9, Table 2).
Table 2.
Likewise, an ortho-substituted arene provided the desired
product in very good yield (Entry 11, Table 2). Note that
trans-stilbene 14 has been found to exhibit versatile bio-
logical activities.[41]
Table 2. Heck coupling between aryl halides and alkenes catalyzed
by Pd·L6.[a]
When aryl bromides activated with electron-withdrawing
groups or based on a nitrogen heterocycle were employed,
complete conversion and very good yields of the coupling
products in short reaction times were observed (Entries 4–
7, Table 2). The synthesis of substituted heteroaryl deriva-
tives is of great importance; however, only a few examples
of heteroaryl halides in Heck reactions have been re-
ported.[42] Results comparable to ours were obtained with
the same bromoquinoline 5g and employment of higher cat-
alyst loadings or longer reaction times.[41]
In addition, the heterocyclic alkene 4-vinylpyridine (6c)
was employed as coupling partner, and afforded a low yield
of the stilbene 15[43] (Entry 10, Table 2). Likewise, when p-
bromoacetophenone (5e) was allowed to react with the di-
substituted olefin 1,1-diphenylethylene under the optimized
conditions, the desired coupling product 1-[4-(2,2-di-
phenylvinyl)phenyl]ethanone (17) was afforded in only 5%
yield.
Thus, the synthesized biphenyl-based arsine ligands can
form catalytically active complexes with Pd that allow Heck
coupling to be performed with a wide range of electrophiles.
With activated electrophiles, the complex Pd·L6 gave the
coupling products in excellent yields, with high selectivity,
in relative short reaction times, and with low catalyst load-
ings. With more demanding electrophiles, good yield of
alkene products can be obtained.
Conclusions
In summary, the synthesis of biphenylarsines was
achieved by a two-step, high-yielding, Pd-catalyzed process
from commercially available starting materials. MW-as-
sisted Suzuki–Miyaura coupling was employed to build the
biaryl structure of arsine ligands in short reaction times.
Sterically demanding arsine ligands were obtained in over-
all isolated yields of up to 82% as air-stable solids. By this
methodology, the properties of these ligands can be varied
according to the steric and electronic effects associated with
the substituents in the biaryl backbone.
The activity of the synthesized biphenyl-based arsine li-
gands in the Pd-catalyzed Heck reaction was explored. It
was found that ligands with “blocked” ortho-positions on
the non-arsine-containing ring of the biphenyl backbone
were more efficient in catalyzing the coupling reaction. This
effect could be a combination of factors, such as their steric
bulk and the absence of ortho hydrogens, which prevents
the formation of palladacycles. In addition, the Pd-O inter-
actions with ligand L6 could contribute to the stability, and
[a] Reaction conditions: 1 mmol of ArX 5, 1.5 mmol of an alkene
6, 1 mol-% Pd(OAc)2, 2 mol-% L6, 2 mmol K2CO3, 4 mL of DMF,
140 °C, under nitrogen. [b] NMR yields for the trans products. The
yields reported represent the averages of at least two reactions.
[c] Pd(OAc)2, 3 mol-%. [d] GC yields.
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cover MW reactor. After having been allowed to cool to room tem-
perature, the mixture was quenched by addition of water and ex-
tracted three times with CH2Cl2 (30 mL each). The combined or-
ganic layers were dried with anhydrous Na2SO4, filtered, and con-
centrated under reduce pressure. The residue was purified by silica
gel column chromatography to furnish the desired biarylarsine
product.
The products were characterized by 1H NMR, 13C NMR, 31P
NMR, and 19F NMR, 2D NMR, GC–MS, and HRMS. All the
spectroscopic data agreed with those previously reported for com-
pound L1[7b] and for compounds L2–L6 and L9.[9]
thus to the higher catalytic efficiency, of the Pd·L6 complex.
Although arsines are less bulky and poorer σ-donors than
phosphines, the presence of the arsine group has an impor-
tant effect on the catalytic activity; the biphenylphosphine
homologue of ligand L6 showed lower activity in the Heck
reaction.
Finally, Pd·L6 proved to be an effective catalyst for per-
forming coupling between aryl iodides or bromides and sev-
eral alkenes. In addition, with demanding substrates such
as heterocycles or ortho-substituted and non-activated aryl
halides, good results were achieved.
Representative Procedure for Pd-Catalyzed Heck Reaction: The fol-
lowing reaction procedure is representative for all Heck reactions.
A mixture of Pd(OAc)2 (1 mol-%, 0.01 mmol), the appropriate li-
gand (Pd/L, 1:2, 0.02 mmol), the appropriate aryl halide (1 mmol),
the appropriate alkene (1.5 mmol), and K2CO3 (2 mmol) in DMF
(4 mL) was stirred in a Schlenk tube under nitrogen at 140 °C for
the desired time. After having been allowed to cool to room tem-
perature, the mixture was quenched by addition of water and then
extracted three times with ethyl acetate (30 mL each). The com-
bined organic layers were dried with anhydrous Na2SO4, filtered,
and concentrated under reduce pressure. The coupling product was
purified by silica-gel column chromatography. All the spectroscopic
data for the coupling products 7, 8, and 11,[44] 9,[45] 10,[46] 12,[47]
13,[42] 14,[41] 15,[48] and 16[49] agreed with those previously reported.
On the basis of the obtained results, the potential of bi-
phenyl-based arsine ligands in coupling reactions was estab-
lished. Further studies to explore the scope of these ligands
in transition-metal-catalyzed reactions are currently in pro-
gress.
Experimental Section
General Methods: All reactions were performed under nitrogen
with magnetic stirring. All solvents were analytical grade and dis-
tilled before use. Air- and moisture-sensitive liquids and solutions
were transferred by cannula and syringe to introduce them into
Schlenk tubes. Toluene and dioxane were distilled under nitrogen
from sodium benzophenone. DMF was stored under molecular
sieves and then distilled under reduced pressure with bubbling of
nitrogen. (2-Bromophenyl)diphenylarsine (3) was prepared as pre-
viously reported, from the corresponding 2-bromoiodobenzene.[7b]
2-Diphenylphosphino-2Ј,6Ј-dimethoxybiphenyl (L10-Phos) was
prepared by literature methods.[37]
2-Diphenylarsino-2Ј-(trifluoromethyl)biphenyl (L7): Compound L7
was obtained by the General Procedure for Pd-catalyzed Suzuki–
Miyaura reactions under MW irradiation conditions and isolated
from the reaction mixture by silica gel column chromatography (pe-
troleum ether/dichloromethane 80:20) as a white solid (m.p. 127.2–
128.4 °C), in 75% yield. After crystallization from CH3CN, cubic-
type crystals were obtained. 1H NMR (400 MHz, CDCl3): δ = 7.75
(d, J = 7.6 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.37–7.23 (m, 12
H), 7.19–7.16 (m, 3 H), 6.92 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 144.97, 140.91 (d, J = 1.7 Hz, 1 C), 140.14,
139.93, 139.68, 134.08, 134.02, 133.67, 132.66, 130.73, 129.74,
129.12 (q, J = 29.0 Hz, 1 C), 128.74, 128.66, 128.55, 128.33, 128.25,
127.92, 127.86, 126.04 (q, J = 5.2 Hz, 1 C), 124.21 (q, J = 272.6 Hz,
1 C) ppm. 19F NMR (377 MHz, CDCl3): δ = –57.88 ppm. MS: m/z
(%) = 451 (11), 450 (25), 382 (7), 381 (17), 227 (17), 202 (12), 201
(9), 184 (16), 183 (100), 181 (5), 171 (9), 154 (16), 152 (15), 151
(12). HRMS (EI): calcd. for C25H18AsF3 451.0655 [M + H]+; found
451.0649.
GC analyses were performed on a gas chromatograph with a flame
ionization detector and a HP-1 25 mϫ 0.20 mmϫ0.25 μm column.
1H, 13C, 31P, and 19F NMR spectra were recorded in CDCl3 at
400 MHz, 101 MHz, 121 MHz, and 377 MHz, respectively, with a
Bruker Advance II 400 spectrometer. Coupling constants (J) are
given in Hz. GC–MS analyses were performed with a GC/MS
QP 5050 spectrometer equipped with
a
VF-5ms column
(25 mϫ0.20 mmϫ0.33 μm). Ionization was achieved by electronic
impact (70 eV) and positive-mode detection setup. HRMS were re-
corded with Bruker, Micro TOF Q II equipment, operated with an
ESI source in (positive/negative) mode, with use of nitrogen as neb-
ulizing and drying gas and sodium formate (10 mm) for internal
calibration. Melting points were dertermined with Büchi 510 equip-
ment and are uncorrected. Microwave-induced reactions were per-
formed with a single-mode instrument (CEM Focused Microwave
TM Synthesis System, Model Discover) equipped with a noncon-
tact infrared sensor to measure the temperature, a direct pressure
control system to measure the pressure of the reaction vessel con-
tent, and cooling with compressed air.
2-Diphenylarsino-4Ј-NЈ,NЈ-dimethylbiphenyl (L8): Compound L8
was obtained by the General Procedure for Pd-catalyzed Suzuki–
Miyaura coupling under MW irradiation conditions. Product L8
was isolated from the reaction mixture by silica gel column
chromatography (petroleum ether/ethyl acetate 95:5) as a white so-
lid (m.p. 156.1–157.0 °C), in 92% yield. After crystallization from
1
CH3CN, needle-type crystals were obtained. H NMR (400 MHz,
CDCl3): δ = 7.35 (d, J = 3.8 Hz, 2 H), 7.31–7.27 (m, 10 H), 7.21–
7.17 (m, 1 H), 7.13–7.09 (m, 3 H), 6.67–6.63 (m, 2 H), 2.95 (s, 6
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 149.82, 148.53, 140.86,
138.78, 134.56, 134.02, 130.55, 130.46, 130.06, 128.66, 128.62,
128.25, 126.89, 111.75, 40.63 ppm. MS: m/z (%) = 425 (18), 281
(21), 270 (21), 209 (13), 208 (18), 207 (100), 133 (13), 96 (18), 73
(22), 44 (50), 43 (11), 40 (28). HRMS (EI): calcd. for C26H24AsN
426.1203 [M + H]+; found 426.1197.
2-Diphenylphosphino-2Ј,6Ј-dimethoxybiphenyl (L10-Phos):[37] Com-
pound L10-Phos was prepared by the methodology previously de-
scribe in the literature.[32] Product L10-Phos was isolated as a white
solid, after crystallization with ethanol. 1H NMR (400 MHz,
Typical Procedure for Pd-Catalyzed Suzuki–Miyaura Reaction un-
der MW Irradiation Conditions: The following reaction procedure
is representative of all Suzuki–Miyaura cross-coupling reactions.
Pd(OAc)2 (1 mol-%, 0.01 mmol), PPh3 (Pd/L, 1:4, 0.04 mmol), (2-
bromophenyl)diphenylarsine (3, 1 mmol), the appropriate aryl-
boronic acid (4a–i, 1.5 mmol), and K3PO4 (2 mmol) were placed in
a 10 mL MW vessel containing a magnetic stirrer and equipped
with an adapter with a nitrogen inlet, followed by dioxane (4 mL)
and water (1 mL). The vessel was sealed with a pressure lock, and
the mixture was heated by a dynamic method at 150 °C (fix tem-
perature method) for the time reported on Table 2, in a CEM Dis-
6
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Job/Unit: O43658
/KAP1
Date: 11-03-15 18:18:05
Pages: 9
Bulky Monodentate Biphenylarsine Ligands in the Heck Reaction
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(d, J = 13.02 Hz), 138.58 (d, J = 13.02 Hz), 138.15 (d, J = 9.8 Hz),
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(s) ppm. 31P NMR (121 MHz, CDCl3): δ = –12.55 ppm.
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The authors acknowledge financial research support from the Con-
sejo Nacional de Investigaciones Científicas y Técnicas (CON-
ICET), the Fondo para la Investigación Científica y Tecnológica
(FONCYT) and the Secretaría de Ciencia y Técnica, Universidad
Nacional de Córdoba (SECYT-UNC). G. J. Q. gratefully acknowl-
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O43658
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Date: 11-03-15 18:18:05
Pages: 9
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Received: December 22, 2014
Published Online: ᭿
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43658
/KAP1
Date: 11-03-15 18:18:05
Pages: 9
Bulky Monodentate Biphenylarsine Ligands in the Heck Reaction
Arsine Ligand Design
Sterically demanding biphenyl-based arsine
ligands were prepared in high overall yields
by microwave-assisted Suzuki–Miyaura
coupling. The ligands were evaluated in the
Pd-catalyzed Heck coupling reaction; the
most active were those with “blocked“ or-
tho-positions on the non-arsine-containing
ring of the biphenyl backbone.
G. J. Quinteros, P. M. Uberman,*
S. E. Martín* .................................... 1–9
Bulky Monodentate Biphenylarsine Li-
gands: Synthesis and Evaluation of Their
Structure Effects in the Palladium-Cata-
lyzed Heck Reaction
Keywords: Homogeneous catalysis / Cross
coupling / Palladium / Ligand design / As
ligands / Microwave chemistry
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9